SELECTIVE ANDROGEN RECEPTOR DEGRADER (SARD) O-LINKED LIGANDS

AND METHODS OF USE THEREOF

GOVERNMENT INTEREST STATEMENT

[0001] This invention was made with government support under R01 CA229164, awarded by the National Cancer Institute. The government has certain rights in the invention.

FIELD OF THE DISCLOSURE

[0002] This disclosure is directed to selective androgen receptor degrader (SARD) compounds, and pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, triple negative breast cancer, other cancers expressing the androgen receptor, androgenic alopecia or other hyperandrogemc dermal diseases, spinal (and) bulbar muscular atrophy (SBMA), amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

BACKGROUND OF THE DISCLOSURE

[0003] Prostate cancer (PCa) is one of the most frequently diagnosed noncutaneous cancers among men in the US and is the second most common cause of cancer deaths with more than 200,000 new cases and over 30,000 deaths each year in the United States. PCa therapeutics market is growing at an annual rate of 15-20% globally.

[0004] Androgen-deprivation therapy (ADT) is the standard of treatment for advanced PCa. Patients with advanced prostate cancer undergo ADT, either by luteinizing hormone releasing hormone (LHRH) agonists, LHRH antagonists or by bilateral orchiectomy. Despite initial response to ADT, disease progression is inevitable and the cancer emerges as castration-resistant prostate cancer (CRPC). Up to 30% of patients with prostate cancer that undergo primary treatment by radiation or surgery will develop metastatic disease within 10 years of the primary treatment. Approximately’ 50,000 patients a year will develop metastatic disease, which is termed metastatic CRPC (mCRPC). [0005] Patients with CRPC have a median survival of 12-18 months. Though castration-resistant, CRPC is still dependent on the androgen receptor (AR) signaling axis for continued growth. The primary reason for CRPC re-emergence is re-activation of AR by alternate mechanisms such as: 1) intracrine androgen synthesis, 2) AR splice variants (AR.-SV), e.g., that lack ligand binding domain (LBD), 3) AR-LBD mutations with potential to resist AR antagonists (z.e., mutants that are not sensitive to inhibition by AR antagonists, and in some cases AR antagonists act as agonists of the AR bearing these LBD mutations), and 4) amplications of the AR gene within the tumor.

[0006] A critical barrier to progress in treating CRPC is that AR signaling inhibitors such as enzalutamide, bicalutamide, and abiraterone, acting through the LBD, fail to inhibit growth driven by the N-terminal domain (NTD)-dependent constitutively active AR-SV. Recent high- impact clinical trials with enzalutamide and abiraterone in CRPC? patients demonstrated that 0% of AR-V7 (the predominant AR-SV) expressing patients responded to either of the treatments, indicating the requirement for next generation AR antagonists that target AR-SVs. In addition, a significant number of CRPC patients are becoming refractory to abiraterone or enzalutamide, emphasizing the need for next generation AR antagonists.

[0007] Current evidences demonstrate that CRPC? growth is dependent on constitutively active AR including AR-SV’ s that lack the LBD such as AR-V7 and therefore cannot be inhibited by conventional antagonists. AR inhibition and degradation through binding to a domain that is distinct from the AR LBD provides alternate strategies to manage CRPC.

[0008] Molecules that degrade the AR prevent any inadvertent AR activation through growth factors or signaling pathways, or promiscuous ligand-dependent activation. In addition, molecules that inhibit the constitutive activation of AR-SVs are extremely important to provide extended benefit to CRPC patients.

[0009] Currently only a few chemotypes are known to degrade AR which include the SARDs ARN-509, AZD-3514, and ASC-J9. However, these molecules degrade AR indirectly at much higher concentrations than their binding coefficient and they fail to degrade the AR-SVs that have become in recent years the primary reason for resurgence of treatment-resistant CRPC.

SUMMARY OF THE DISCLOSURE [0010] One embodiment encompasses a selective androgen receptor degrader (SARD) compound represented by the structure of formula I: wherein

T is I L OH. OR, ()( OR OCH ₂ C(=CH ₂ )C(=O)OCH3, ( Hr \HCO( Hr or M R 'OR;

Ri is H, CI-I ₃ , CI-bF, CHF2, CF3, CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF3, F, I, Br, Cl, CN, or C(R) ₃ ;

Z is NO2, CN, COOH. COR, M K'OR. or CONHR;

X is CH or N;

Ris H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,

F, Cl, Br, I, or OH; and

A is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q ¹ , Q ² , Q ³ , or Q ⁴ , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO?., hydroxyl, alkoxy, OR, arylalkyl, NCS, maieimide, NHCOOR, N(R)z, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0011] In another embodiment, this disclosure is directed to a SARD compound represented by the structure of formula IA:

wherein

T is H, OH, OR, OCOR, OCH2C(=CH2)C(=O)OCH3, CH3, NHCOCHy or NHCOR;

R : is H, ('l l :. CH2F, CHF2, ('!• :. CH ₂ CH ₃ , or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF ₃ , F, I, Br, Cl, CN, or C(R) ₃ ;

Z is NO2, CN, COOH, COR, NHCOR or COM IR;

X is CH or N;

RisH, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF ₃ , CH -Cl. CH2CH2CI, aryl,

F, Cl, Br, I, or OH, and

A is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q ¹ , Q ² , Q ³ , or Q ⁴ , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF ₃ , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO?., hydroxyl, alkoxy, OR, arylalkyl, NCS, malemnde, NHCOOR, N(R) ₂ , NHCOR, COM IR. COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0012] In another embodiment, this disclosure is directed to a SARD compound represented by the structure of formula IB: wherein

T is H, OH, OR, OCOR, OCHjCi—CHzICi—OIOCH?, CH3, NHCOCH3, or NHCOR;

Ri is II, CI -fe, CII2F, CI- IF?, CF3, CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring,

Y is H, CF3, F, I, Br, Cl, CN, or C(R ) 3;

Z is NO2, CN, COOH, COR, NUCOR, or CONHR;

X is CH orN;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,

F, Cl, Br, I, or OH; and

A is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q ¹ , Q ² , Q ³ , or Q ⁴ , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, aiylalkyl, NCS, maleimide, NHCOOR, N(R)?„ NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0013] The disclosure encompasses a SARD compound represented by the structure of formula II: wherein

T is H, OH, OR, OCOR, OCH ₂ C(=CH2)C(=O)OCH ₃ , CH ₃ , NHCOCH3, or NHCOR;

Ri is H, CI <3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; or T and Ri formr a 3-8 carbocyclic or heterocyclic ring;

Y is II, CF3, F, I, Br, Cl, CN, or C(R h ;

Z is NO _? „ CN, COOH, COR, NHCOR, or CONHR;

X is CH or N;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CFFCHiCl, aryl,

F, Cl, Br, I, or OH; and

A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q ¹ , Q ² , Qy or Q ⁴ , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aiyd, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N( R) 2, NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0014] In another embodiment, this disclosure is directed to a SARD compound represented by the structure of formula IIA:

wherein

T is H, OH, OR, OCOR, OCH2C(=CH2)C(=O)OCH3, CH3, NHCOCH3, or NHCOR;

Ri is H, CH3, CHZF, CHF2, CF ₃ , CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF ₃ , F, I, Br, Cl, CN, or C(R) ₃ ;

Z is NO2, CN, COOH, COR, NHCOR, or CONHR;

X is CH or N;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF ₃ , CH2CI, CH2CH2CI, aryl,

F, Cl, Br, I, or OH; and

A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q ¹ , Q ² , Q ³ , or Q ⁴ , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF ₃ , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleirnide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0015] In another embodiment, this disclosure is directed to a SARD compound represented by the structure of formula IIB:

wherein

T is H, OH, OR, OCOR, OCH2C(=CH2)C(=O)OCH3, CH3, NHCOCH3, or NHCOR;

Ri is II, CH3, CH2F , CHF2, CF3, CH2CH3, or CF2CF3; or T and R1 form a 3-8 carbocyclic or heterocyclic ring,

Y is H, CF ₃ , F, I, Br, Cl, CN, or C(R) 3;

Z is NO2, CN, COOH, COR, NHCOR, or CONHR;

X is CH orN;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,

F, Cl, Br, I, or OH; and

A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q ¹ , Q ² , Q ³ , or Q ⁴ , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, C1, Br, I, CN, NO2., hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, N ICOOR . N(R)2., NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0016] The disclosure encompasses a SARD compound represented by the structure of formula III: wherein

T is H, OH, OR, OCOR, OCH-O ( C H 2( = 0)0( 1 C. CH3, NHCOCH3, or NI K OR.

Ri is H, CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; or T and Ri formr a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF3, F, I, Br, Cl, CN, or C(R) ₃ ;

Z is NO2, CN, COOH, COR, NHCOR, or CONHR;

X is CH or N;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF ₃ , CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and

A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q ¹ , Q ² , O'. or Q ⁴ , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) ₂ , NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0017] In another embodiment, this disclosure is directed to a SARD compound represented by the structure of formula III A: wherein

T is H, OH, OR. OCOR, OCH ₂ C(-CH ₂ )C(-O)OCH ₃ , CH3, NHCOCH3, or NHCOR;

Ri is H, Cl b. CU T. CHF2, CF ₃ , CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring; Y is 11, CF ₃ , F. I, Br, Cl, CN, or C( R ) 3;

Z is NO2, CN, COOH, COR, NHCOR, or CONHR;

X is CH or N;

Ris H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,

F, Cl, Br, I, or OH; and

A is a pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q ¹ , Q ² , Q i or Q ⁴ , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0018] In another embodiment, this disclosure is directed to a SARD compound represented by the structure of formula IIIB: wherein

T is H, OH, OR, OCOR, OCHjCi—CHzlCt—OlOCH?, CH3, NHCOCH3, or NHCOR;

Ri is H, CHy CH2F, CHF2, CFy CH2CH3, or CF2CF3; or T and Ri form a 3-8 carbocyclic or heterocyclic ring,

Y is H, CF3, F, I, Br, Cl, CN, or C(R) ₃ ;

Z is NO2, CN, COOH, COR, NHCOR, or CONHR;

X is CH orN; Ris H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl,

F, Cl, Br, I, or OH; and

A is a pyrrole, pyrroline, pyrrolidine, pyrazoie, pyrazoline, pyrazolidine, triazole, imidazole, imidazoline, imidazolidine, or morpholine ring, said ring optionally substituted with at least one of Q ¹ , Q ² , Q ^J , or Q ⁴ , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)2, NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof,

[0019] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula IV: wherein

Z is NO2, CN, COOH, COR, NHCOR, or CONHR;

X is CH or N;

Y is H, CF3, F, I, Br, Cl, CN, or C(R)i;

Ri is H, CI-I3, CH2F, CHF2, CFs, CH.-CH 3, or CF2CF3;

T is H, OH, OR. OCOR, OCI l-C( CH -)('( OjOCI h. Cl b. NFICOCH3, or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;

R is FI, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CFs, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and

Q ² , Q’, or Q ⁴ are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF3, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Ci, Br, I, CN, NOz, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) ₂ , NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0020] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula IVA: wherein

Z is NO2, CN, COOi L COR, NHCOR, or CONHR;

X is CH or N;

Y is H, CF3, F, I, Br, Cl, CN, or C(R) ₃ ;

Ri is H, CH3, CH2F, CHF2, CF ₃ , CH2CH3, or CF2CF3;

T is H, OH, OR. ()( OR. OCH.'Ci CH'lCi O)OCH CH 3, NHCOCH3, or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF3, CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and

Q ² , Q ³ , or Q ⁴ are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CFs, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) ₂ , NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hy drate or any combination thereof. [0021] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula IVB:

IVB wherein

Z is NO2, CN, COOH, COR, NHCOR, or CONHR;

X is CH or N;

Y is H, ('!• :. F, I, Br, Cl, CN, or C(R) ₃ ;

Ri is H, CH ₃ , CH2F, CHF2, CF ₃ , CH ₂ CH ₃ , or CF2CF3;

T is H, OH, OR. O( OR. OCH ₂ C(=CH ₂ )C(=O)OCH ₃ , CH.. NHCOCH 3 , or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF ₃ , CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and

Q ² , Q ³ , or Q ⁴ are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF ₃ , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) ₂ , NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0022] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula V:

V wherein

Z is NO2, CN, COOH, COR, NHCOR, or CONHR;

X is CH or N;

Y is H, ('!• :. F, I, Br, Cl, CN, or C(R) ₃ ;

Ri is H, CH ₃ , CH2F, CHF2, CF ₃ , CH ₂ CH ₃ , or CF2CF3;

T is H, OH, OR. O( OR . OCH ₂ C(=CH ₂ )C(=O)OCH ₃ , CH.. NHCOCH 3 , or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF ₃ , CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and

Q ² , Q ³ , or Q ⁴ are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF ₃ , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) ₂ , NHCOR, CONHR, COOR or COR: or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0023] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VA: wherein

Z is NO2, CN, COOH, COR, NHCOR, or CONHR;

X is CH or N;

Y is H, CF ₃ , F, I, Br, Cl, CN, or C(R) ₃ ;

R : is H, Ci h. Ci Nd CHF.'. CF ₃ , CH Ci I ₃ , or CF.'CN.

T is i i. OH, OR, OCOR, OCi i <( Ci i ’.)('( =O)OCH ₃ , CH ₃ , NHCOCHs, or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;

Ris H, alkyl, alkenyl, haloalkyl, alcohol, CH2CH2OH, CF ₃ , CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and

O', Q ³ , or Q ⁴ are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF ₃ , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R)?., NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0024] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VB: wherein

Z is NOz, CN, COOH, COR, NHCOR, or CONHR;

X is CH or N;

Y is I L CL\ IL I, Br, Cl, CN, or C(R) ₃ ;

Ri is H, CH ₃ , CH2F, CHF2, CF _3> CH ₂ CH ₃ , or CF2CF3;

T is H, OH, OR. (X OR . OCH ₂ C(=CH ₂ )C(=O)OCH ₃ , OI L.. NT ICOCH 3 , or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH ₂ CH ₂ OH, CF ₃ , CH2CI, CH2CH2CI, aryl, F, Cl, Br, I, or OH; and

Q ² , Q ³ , or Q ⁴ are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF ₃ , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO2, hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) ₂ , NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0025] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VI: wherein

Z is NO?., CN, COOH, COR, NHCOR, or CONHR;

X is CH or N;

¥ is H, C F ₃ , F, I, Br, Cl, CN, or C(R) ₃ ;

Ri is H, CH ₃ , CH?F, CHF?, CF ₃ , CH?CH ₃ , or CF?CF ₃ ;

T is H, OH, OR, OCOR, OCH ₂ C(=CH ₂ )C(=O)OCH ₃ , CH ₃ , NHCOCH3, or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH ₂ CH ₂ OH, CF ₃ , CH2CI, CH ₂ CH?C1, aryl, F, Cl, Br, I, or OH; and

Q ² , Q ³ , or Q ⁴ are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF ₃ , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO ₂ , hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) ₂ , NHCOR, CONHR, COOR or COR; or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0026] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VIA:

wherein

Z is NO?., CN, COOH, COR, NHCOR, or CONHR;

X is CH or N;

¥ is H, CH. F, I, Br, Cl, CN, or C(R) ₃ ;

Ri is H, CH ₃ , CH?F, CHF?, CF ₃ , CH?CH ₃ , or CF?CF ₃ ;

T is H, OH, OR, OCOR, OCH ₂ C(=CH ₂ )C(=O)OCH ₃ , CH ₃ , NHCOCH3, or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;

Ris H, alkyl, alkenyl, haloalkyl, alcohol, CH ₂ CH ₂ OH, CF ₃ , CH2CI, CH ₂ CH?C1, aryl, F, Cl, Br, I, or OH; and

Q ² , Q ³ , or Q ⁴ are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF ₃ , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO ₂ , hydroxyl, alkoxy, OR, arylalkyl, NCS, maleimide, NHCOOR, N(R) ₂ , NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0027] In another embodiment, the disclosure encompasses a selective androgen receptor degrader compound represented by the structure of formula VIB:

wherein

Z is NO?., CN, COOH, COR, NHCOR, or CONHR;

X is CH or N;

¥ is H, CF ₃ , F, I, Br, Cl, CN, or C(R) ₃ ;

Ri is H, CH ₃ , CH?F, CHF?, CF ₃ , CH?CH ₃ , or CF?CF ₃ ;

T is H, OH, OR, OCOR, OCH ₂ C(=CH ₂ )C(=O)OCH ₃ , CH ₃ , NHCOCH?, or NHCOR; or T and Ri form a 3-8 carbocyclic or heterocyclic ring;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH ₂ CH ₂ OH, CF ₃ , CH2CI, CH ₂ CH?C1, aryl, F, Cl, Br, I, or OH; and

Q ² , Q\ or Q' ^: are each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF ₃ , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO ₂ , hydroxyl, alkoxy, OR, arylalkyl, NCS, maleinride, NHCOOR, N(R) ₂ , NHCOR, CONHR, COOR or COR; or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0028] Yet another embodiment encompasses the SARD compound represented by the structure of any one of the following compounds:

CPD. 13

[0029] One embodiment encompasses the SARD compound having at least one of the following properties: binds to the AR through an alternate binding and degradation domain (BDD), e.g, in the NTD, binds to the AR through the AR ligand binding domain (LBD); exhibits AR- splice variant (AR-SV) degradation activity; exhibits AR-full length (AR-FL) degradation activity including pathogenic mutations thereof, exhibits AR-SV inhibitory activity (z.e., is an AR-SV antagonist); exhibits AR-FL inhibitory activity (i.e., is an AR-FL antagonist) including pathogenic mutations thereof, possesses dual AR-SV degradation and AR-SV inhibitory functions, and/or dual AR-FL degradation and AR-FL inhibitory functions.

[0030] Another embodiment encompasses pharmaceutical compositions comprising a SARD compound according to this disclosure, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition may be formulated for topical use. The topical pharmaceutical composition may be a solution, lotion, salve, cream, ointment, liposome, spray, gel, foam, roller stick, cleansing soaps or bars, emulsion, mousse, aerosol, or shampoo.

[0031] The disclosure encompasses a method of treating prostate cancer (PCa) or increasing survival in a male subject in need of treatment comprising administering to the subject a therapeutically effective amount of a compound defined by formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPI). 44, CPD. 45, or CPD. 13. The prostate cancer includes, but is not limited to, advanced prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combination thereof. Another embodiment encompasses the method further comprising administering androgen deprivation therapy. Alternatively, the method may treat a prostate or other cancer that is resistant to treatment with known androgen receptor antagonist(s) or ADT. In another embodiment, the method may treat enzalutamide resistant prostate cancer. In another embodiment, the method may treat abiraterone resistant prostate cancer. Yet another embodiment encompasses a method of treating prostate or other AR antagonist resistant cancer with a SARD compound of the disclosure wherein the androgen receptor antagonists) is at least one of enzalutamide, bical utamide, abiraterone, ARN-509, ODM-201 , EPI- 001 , AZD-3514, galeterone, ASC-J9, flutamide, hydroxyfl utamide, nilutamide, cyproterone acetate, ketoconazole, or spironolactone.

[0032] Yet another embodiment encompasses a method of treating prostate or other cancers using a SARD compound of the disclosure wherein the other cancers are selected from breast cancer such as TNBC, testicular cancer, cancers associated with partial androgen insensitivity syndromes (PAIS) such as gonadal tumors and seminoma, uterine cancer, ovarian cancer, cancer of the fallopian tubes or peritoneum, salivary gland cancer, bladder cancer, urogenital cancer, brain cancer, skin cancer, lymphoma, mantle cell lymphoma, liver cancer, hepatocellular carcinoma, renal cancer, renal cell carcinoma, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, colon cancer, perianal adenoma, or central nervous system cancer. In another embodiment, the breast cancer is triple negative breast cancer (TNBC).

[0033] The disclosure encompasses a method of reducing the levels of AR-sphce variants in a subject comprising administering to the subject a therapeutically effective amount of a compound of this disclosure, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. The method may comprise further reducing the levels of AR-full length in the subject. [0034] Another embodiment encompasses a method of treating Spinal (and) Bulbar Muscular Atrophy (SBMA) (also referred to herein as “Kennedy’s disease”) in a subject comprising administering to the subject a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPI). 44, CPD. 45, or CPD. 13 or a compound of another formula of the disclosure.

[0035] Yet another embodiment encompasses a method of: (a) treating acne in a subject; (b) decreasing sebum production in a subject; (c) treating hirsutism in a subject, e.g., female facial hair; (d) treating alopecia in a subject, e.g., androgenic alopecia; (e) treating a hormonal condition in female; (f) treating sexual perversion, hypersexuality', or paraphilias in a subject; (g) treating androgen psychosis in a subject; (h) treating virilization in a subject; (i) treating complete or partial androgen insensitivity ⁷ syndrome in a subject; (j) increasing or modulating ovulation in an animal; (k) treating of cancer in a subject; or any combination thereof, by administering a compound of this disclosure or a pharmaceutical composition thereof.

[0036] One embodiment encompasses methods of reducing the levels of polyglutamine (polyQ) AR polymorphs in a subject comprising administering a compound according to this disclosure. The method may inhibit, degrade, or both the function of the polyglutamine (polyQ) AR polymorphs (polyQ- AR). The polyQ- AR may be a short polyQ polymorph or a long polyQ polymorph. When the polyQ- AR is a short polyQ polymorph, the method further treats dermal disease. When the polyQ- AR is a long polyQ polymorph, the method further treats Kennedy’s disease.

[0037] Another embodiment encompasses methods of treating amyotrophic lateral sclerosis (ALS) in a subject by administering a therapeutically effective amount of the compound of the disclosure, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof; or a pharmaceutical composition thereof.

[0038] Another embodiment encompasses methods of treating abdominal aortic aneurysm (AAA) in a subject by administering a therapeutically effective amount of the compound of the disclosure, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof; or a pharmaceutical composition thereof.

[0039] Yet another embodiment encompasses methods of treating uterine fibroids in a subject by administering a therapeutically effective amount of the compound of this disclosure, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof; or a pharmaceutical composition thereof.

DETAILED DESCRIPTION

[0040] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present disclosure.

[0041] Androgens act in cells by binding to the AR, a member of the steroid receptor superfamily of transcription factors. As the growth and maintenance of prostate cancer (PCa) is largely controlled by circulating androgens, treatment of PCa heavily relies on therapies that target AR Treatment with AR antagonists such as enzalutamide, bicalutamide or hydroxyfl utamide to disrupt receptor activation has been successfully used in the past to reduce PCa growth. All currently available AR antagonists competitively bind AR and recruit corepressors such as NCoR and SMRT to repress transcription of target genes. However, altered intracellular signaling, AR mutations, and increased expression of coactivators lead to functional impairment of antagonists or even transformation of antagonists into agonists. Studies have demonstrated that mutation of W741 and T877 within AR converts bicalutamide and hydroxyflutamide, respectively , to agonists. Similarly, increased intracellular cytokines recruit coactivators instead of corepressors to AR- responsive promoters subsequently converting bicalutamide to an agonist. Similarly, mutations that have been linked to enzalutamide resistance include F876, H874, T877, and di-mutants T877/S888, T877ZD890, F876/T877 (z.e., MR49 cells), and H874/T877 (Genome Biol. (2006) 17:10 (doi: 10.1186/sl3059-015-0864-l)). Abiraterone resistance mutations include L702H mutations which results in activation of the AR by glucocorticoids such as prednisone, causing resistance to abiraterone because abiraterone is usually prescribed in combination with prednisone. If resistance develops to enzalutamide then often the patient is refractory to abiraterone also and vice versa; or the duration of response is very’ short. This situation highlights the need for a definitive androgen ablation therapy’ to prevent AR reactivation in advanced prostate cancers. [0042] Despite initial response to androgen deprivation therapy (ADT), PCa disease progression is inevitable and the cancer emerges as castration-resistant prostate cancer (CRPC). The primary reason for castration resistant prostate cancer (CRPC) re-emergence is re-activation of androgen receptor (AR) by alternate mechanisms such as:

(a) intracrine androgen synthesis;

(b) expression of AR splice variants (AR-SV), e.g, that lack ligand binding domain (LBD);

(c) AR-L.BD mutations with potential to resist antagonists;

(d) hyper-sensitization of AR to low androgen levels, e.g., due to AR gene amplification or AR mutation;

(e) amplication of the AR gene within the tumor; and

(f) over expression of coactivators.

[0043] This disclosure describes novel AR antagonists with unique pharmacology that strongly (high potency and efficacy) and selectively bind AR (better than known antagonists in some cases; bind to LBD and/or NTD), antagonize AR, and degrade AR full length (AR-FL) and AR-SV. Selective androgen receptor degrader (SARD) compounds possess dual degradation and AR-SV inhibitory functions and hence are distinct from any available CRPC therapeutics. These novel selective androgen receptor degrader (SARD) compounds inhibit the growth of PCa cells and tumors that are dependent on AR-FL and AR-SV for proliferation.

[0044] SARDs have the potential to evolve as new therapeutics to treat CRPCs that are unbeatable with any other antagonists. This unique property of degrading AR-SV has extremely important health consequences for prostate cancer. Till date only one synthetic molecule (EPI-001) and some marine natural products such as the sinkotamides and glycerol ether Naphetenone B, are reported to bind to AR-NTD and inhibit AR function and PCa cell growth, albeit at lower affinity and inability to degrade the receptor. The SARDs reported herein also bind to AR-NTD and inhibit NTD-driven (e.g., ligand independent) AR activity.

[0045] The positive correlation between AR and PCa and the lack of a fail-safe AR antagonist, emphasizes the need for molecules that inhibit AR function through novel or alternate mechanisms and/or binding sites, and that can elicit antagonistic activities within an altered cellular environment. [0046] Although traditional antiandrogens such as enzalutamide, bicalutamide and flutamide and androgen deprivation therapies (ADT) were approved for use in prostate cancer, there is significant evidence that antiandrogens could also be used in a variety of other hormone dependent and hormone independent cancers. For example, antiandrogens have been tested in breast cancer (enzalutamide; Breast Cancer Res. (2014) 16(1): R7), non-small cell lung cancer (shRNAi AR), renal cell carcinoma (ASC-J9), partial androgen insensitivity syndrome (PAIS) associated malignancies such as gonadal tumors and seminoma, advanced pancreatic cancer (World J. Gastroenterology 20(29):9229), cancer of the ovary', fallopian tubes, or peritoneum, cancer of the salivary gland (Head and Neck (2016) 38: 724-731; ADT was tested in AR-expressing recurrent metastatic salivary gland cancers and was confirmed to have benefit on progression free survival and overall survival endpoints), bladder cancer (Oncotarget 6 (30): 29860-29876); Int J. Endocrinol (2015), Article ID 384860), pancreatic cancer, lymphoma (including mantle cell), and hepatocellular carcinoma. Use of a more potent antiandrogen such as a SARD in these cancers may more efficaciously treat the progression of these and other cancers. Other cancers may also benefi t from SARD treatment such as breast cancer (e.g., triple negative breast cancer (TNBC)), testicular cancer, cancers associated with partial androgen insensitivity syndromes (PAIS) such as gonadal tumors and seminoma, uterine cancer, ovarian cancer, cancer of the fallopian tubes or peritoneum, salivary gland cancer, bladder cancer, urogenital cancer, brain cancer, skin cancer, lymphoma, mantle cell lymphoma, liver cancer, hepatocellular carcinoma, renal cancer, renal cell carcinoma, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC), gastric cancer, colon cancer, perianal adenoma, or central nervous system cancer. Triple negative breast cancer (TNBC) is a type of breast cancer lacking the expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor kinase. As such, TNBC lacks the hormone and kinase therapeutic targets used to treat other types of primary breast cancers. Correspondingly, chemotherapy is often the initial pharmacotherapy for TNBC. Interestingly, AR is often still expressed in TNBC and may offer a hormone targeted therapeutic alternative to chemotherapy. In ER-positive breast cancer, AR is a positive prognostic indicator as it is believed that activation of AR limits and/or opposes the effects of the ER in breast tissue and tumors. However, in the absence of ER, it is possible that AR actually' supports the growth of breast cancer tumors. Though the role of AR is not fully understood in TNBC, we have evidence that certain TNBC’s may be supported by androgen independent activation of AR-SVs lacking the LBD or androgen-dependent activation of AR full length. As such, enzalutamide and other LBD-directed traditional AR antagonists would not be able to antagonize AR-SVs in these TNBC’s. However, SARDs which are capable of destroying AR-SVs through a binding site in the NTD of AR would be able to antagonize AR in these TNBC’s and provide an anti-tumor effect.

[0047] Traditional antiandrogens such as bicalutamide and flutamide were approved for use in prostate cancer. Subsequent studies have demonstrated the utility of antiandrogens (e.g., flutamide, spironolactone, cyproterone acetate, finasteride and chlormadmone acetate) in androgen-dependent dermatological conditions such as androgenic alopecia (male pattern baldness), acne vulgaris, and hirsutism (e.g, in female facial hair). Prepubertal castration prevents sebum production and androgenic alopecia but this can be reversed by use of testosterone, suggesting its androgen-dependence.

[0048] The AR gene has a polymorphism of glutamine repeats (polyQ) within exon 1 which when shortened may augment AR transactivation (/.<?., hyperandrogenism). It has been found that shortened polyQ polymorphisms are more common in people with alopecia, hirsutism, and acne. Classic antiandrogens are undesirable for these purposes because they are ineffective through dermal dosing and their long-term systemic use raises the risks of untoward sexual effects such as gynecomastia and impotence. Further, similar to CPRC discussed above, inhibition of ligand- dependent AR activity alone may not be sufficient as AR can be activated by various cellular factors other than the endogeneous androgens testosterone (T) and dihydrotestosterone (DHT), such as growth factors, kinases, co-activator overexpression and/or promiscuous activation by other hormones (e.g., estrogens or glucocorticoids). Consequently, blocking the binding of T and DHT to AR with a classical antiandrogen may not be sufficient to have the desired efficacy.

[0049] An emerging concept is the topical application of a SARD to destroy the AR locally to the affected areas of the skin or other tissue without exerting any systemic antiandrogemsm. For this use, a SARD that does not penetrate the skin or is rapidly metabolized would be preferrable.

[0050] Supporting this approach is the observation that cutaneous wound healing has been demonstrated to be suppressed by androgens. Castration of mice accelerates cutaneous wound healing while attenuating the inflammation in the wounds. The negative correlation between androgen levels and cutaneous healing and inflammation, in part, explains another mechanism by which high levels of endogenous androgens exacerbate hyperandrogenic dermatological conditions. Further, it provides a rationale for the treatment of wounds such as diabetic ulcers or even trauma, or skin disorders with an inflammatory component such as acne or psoriasis, with a topical SARD.

[0051] Androgenic alopecia occurs in -50% of Caucasian males by midlife and up to 90% by 80 years old. Minoxidil (a topical vasodilator) and finasteride (a systemic 5alpha reductase type II inhibitor) are FDA approved for alopecia but require 4-12 months of treatment to produce a therapeutic effect and only arrest hair loss in most with mild to moderate hair regrowth in 30- 60%, Since currently available treatments have slow and limited efficacy that varies widely between individuals, and produce unwanted sexual side effects, it is important to find a novel approach to treat androgenic alopecia and other hyperandrogenic dermatologic diseases.

[0052] Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of upper and lower motor neurons and skeletal muscle atrophy. Epidemiologic and experimental evidence suggest the involvement of androgens in ALS pathogenesis (The anabolic/androgenic steroid nandrolone exacerbates gene expression modifications induced by mutant SOD1 in muscles of mice models of amyotrophic lateral sclerosis. Galbiati M, Onesto E, Zito A, Crippa V, Rusmmi P, Mariotti R, Bentivoglio M, Bendotti C, Poletti A. Pharmacol. Res. 2012, 65(2), 221-230), but the mechanism through which androgens modify the ALS phenotype is unknown. A transgenic animal model of ALS demonstrated improved survival upon surgical castration (i.e., androgen ablation). Treatment of these castrated animals with the androgen agonist nandrolone decanoate worsened disease manifestations. Castration reduces the AR level, which may be the reason for extended survival. The survival benefit is reversed by androgen agonist (Androgens affect muscle, motor neuron, and survival in a mouse model of SOD 1 -related amyotrophic lateral sclerosis. Aggarwal T, Polanco MJ, Scaramuzzino C, Rocchi A, Milioto C, Emionite L, Ognio E, Sambataro F, Galbiati M, Poleti A, Pennuto M. Neurobiol. Aging. 2014 35(8), 1929-1938). Notably, stimulation with nandrolone decanoate promoted the recruitment of endogenous androgen receptor into biochemical complexes that were insoluble in sodium dodecyl sulfate, a finding consistent with protein aggregation. Overall, these results shed light on the role of androgens as modifiers of ALS pathogenesis via dysregulation of androgen receptor homeostasis. Antiandrogens should block the effects of nandrolone undecanoate or endogeneous androgens and reverse the toxicides due to AR aggegregation. Further, an antiandrogen that can block both action of LBD-dependent AR agonists and lower AR protein levels, such as the SARDs of this disclosure, would be therapeutic in ALS. Riluzole is an available drug for ALS treatment, however, it only provides short-term effects. There is an urgent need for drugs that extend the survival of ALS patients.

[0053] Androgen receptor action promotes uterine proliferation. Hyperandrogenicity of the short polyQ AR has been associated with increased leiomyoma or uterine fibroids. (Hsieh YY, Chang CC, Tsai FJ, Lin CC, Yeh LS, Peng CT. J. Assist. Reprod. Genet. 2004, 21 (12), 453-457). A separate study of Brazilian women found that shorter and longer [CAG](n) repeat alleles of AR were exclusive to the leiomyoma group in their study (Rosa FE, Canevari Rde A, Ambrosio EP, Ramos Cirilo PD, Pontes A, Rainho CA, Rogato SR. Clin. Chem. Lab. Med. 200S, 46(6), 814- 823). Similarly, in Asian Indian women long polyQ AR was associated with endometriosis and leiomyoma and can be regarded as high-risk markers. SARDs could be used in women with uterine fibroids, especially those expressing shorter and longer [CAG](n) repeat alleles, to treat existing uterine fibroids, prevent worsening of fibroids and/or ameliorate carcinogenicity associated with fibroids.

[0054] An abdominal aortic aneurysm (AAA) is an enlarged area m the lower part of the aorta, the major blood vessel that supplies blood to the body. The aorta, about the thickness of a garden hose, runs from your heart through the center of your chest and abdomen. Because the aorta is the body’s mam supplier of blood, a ruptured abdominal aortic aneurysm can cause life- threatening bleeding. Depending on the size and the rate at which your abdominal aortic aneurysm is growing, treatment may vary from watchful waiting to emergency surgery. Once an abdominal aortic aneurysm is found, doctors will closely monitor it so that surgery can be planned if it's necessary. Emergency surgery for a ruptured abdominal aortic aneury sm can be risky. AR blockade (pharmacologic or genetic) reduces AAA. Davis et al. (Davis JP, Salmon Al, Pope NH, Lu G, Su G, Meher A, Ailawadi G, Upchurch GR Jr. J Vase Sure (2016) 63(6): 1602-1612) showed that flutamide (50 mg/kg) or ketoconazole (150 mg/kg) attenuated porcine pancreatic elastase (0.35 U/mL) induced AAA by 84.2% and 91.5% compared to vehicle (121%). Further AR -/- mice showed attenuated AAA growth (64.4%) compared to wildtype (both treated with elastase). Correspondingly, administration of a SARD to a patient suffering from an AAA may help reverse, treat or delay progression of AAA to the point where surgery is needed.

[0055] X-linked spinal-bulbar muscular atrophy (SBMA-also known as Kennedy’s disease) is a muscular atrophy that arises from a defect in the androgen receptor gene on the X chromosome. Proximal limb and bulbar muscle weakness results in physical limitations including dependence on a wheelchair in some cases. The mutation results in a protracted polyglutamine tract added to the N-terminal domain of the androgen receptor (polyQ AR). Binding and activation of this lengthened polyQ AR by endogeneous androgens (testosterone and DHT) results in unfolding and nuclear translocation of the mutant androgen receptor. The androgen-induced toxicity and androgen-dependent nuclear accumulation of polyQ AR protein seems to be central to the pathogenesis. Therefore, the inhibition of the androgen-activated polyQ AR might be a therapeutic option (A. Baniahmad. Inhibition of the androgen receptor by antiandrogens in spmobulbar muscle atrophy. J. Mol. Neurosci. 2016 58(3), 343-347). These steps are required for pathogenesis and result in partial loss of transactivation function (i.e., an androgen insensitivity) and a poorly understood neuromuscular degeneration. Support of use antiandrogen comes in a report in which the antiandrogen flutamide protects male mice from androgen-dependent toxicity in three models of spinal bulbar muscular atrophy (Renier KJ, Troxell-Smith SM, Johansen J A, Katsuno M, Adachi H, Sobue G, Chua JP, Sun Kim II, Lieberman AP, Breedlove SM, Jordan CL. Endocrinology 2014, 155(7), 2624-2634). Currently there are no disease-modifying treatments but rather only symptom directed treatments. Efforts to target the polyQ AR of Kennedy’s disease as the proximal mediator of toxicity by harnessing cellular machinery to promote its degradation, i.e., through the use of a SARD, hold 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 degradation of polyQ AR polymorphism is also expected, indicating that they are promising leads for treatment of SBMA.

[0056] Here we describe pyrrole, pyrazole, triazole, imidazole, and morpholine based selective androgen receptor degrader (SARD) compounds that may bind to the LBD and/or an alternate binding and degradation domain (BDD) located in the NTD, antagonize AR, and degrade AR thereby blocking ligand-dependent and ligand-independent AR activities. This novel mechanism produces improved efficacy when dosed systemically for prostate cancer) or topically (<?.g, dermatological diseases).

[0057] The disclosure encompasses novel selective androgen receptor degrader (SARD) compounds encompassed by Formula I, which inhibit the growth of prostate cancer (PCa) cells and tumors that are dependent on AR full length (AR-FL) including pathogenic and resistance mutations and wildtype, and/or AR splice variants (AR-SV) for proliferation.

[0058] As used herein, unless otherwise defined, a “selective androgen receptor degrader” (SARD) compound is an androgen receptor antagonist capable of inhibiting the growth of PCa cells and tumors that are dependent on AR-full length (AR-FL) and/or AR splice variants (AR-SV) for proliferation. The SARD compound may not bind to ligand binding domain (LBD). Alternatively, a “selective androgen receptor degrader” (SARD) compound is an androgen receptor antagonist capable of causing degradation of a variety of pathogenic mutant variant AR’s and wildtype AR and hence are capable of exerting anti-androgenism is a wide variety of pathogenic altered cellular environments found in the disease states embodied in this disclosure. In one embodiment, the SARD is orally active. In another embodiment, the SARD is applied topically to the site of action.

[0059] The SARD compound may bind to the N-terminal domain (NTD) of the AR; to an alternate binding and degradation domain (BDD) of the AR, to both the AR ligand binding domain (LBD) and to an alternate binding and degradation domain (BDD); or to both the N- terminal domain (NTD) and to the ligand binding domain (LBD) of the AR. In one embodiment, the BDD may be located in the NTD. In one embodiment, the BDD is located in the AF-1 region of the NTD. Alternatively, the SARD compound may be capable of: inhibiting growth driven by the N-tenninal domain (NTD)-dependent constitutively active AR-SV; or inhibiting the AR through binding to a domain that is distinct from the AR LBD. Also, the SARD compound may be a strong (i.e., highly potent and highly efficacious) selective androgen receptor antagonist, which antagonizes the AR stronger than other known AR antagonists (e.g., enzalutamide, bicalutamide and abiraterone).

[0060] The SARD compound may be a selective androgen receptor antagonist, which targets AR-SVs, which cannot be inhibited by conventional antagonists. The SARD compound may exhibit one of several activities including, but not limited to: AR-SV degradation activity'; AR- FL degradation activity; AR-SV inhibitory’ activity (i.e., is an AR-SV antagonist); AR-FL inhibitory activity' (i.e., is an AR-FL antagonist); inhibition of the constitutive activation of AR- SVs; or inhibition of the constitutive activation of AR-FLs. Alternatively, the SARD compound may possess dual AR-SV degradation and AR-SV inhibitory functions, and/or dual AR-FL degradation and AR-FL inhibitory functions; or alternatively possess all four of these activities.

[0061] The SARD compound may also degrade AR-FL and AR-SV. The SARD compound may degrade the AR through binding to a domain that is distinct from the AR LBD. The SARD compound may possess dual degradation and AR-SV inhibitory functions that are distinct from any available CRPC therapeutics. The SARD compound may inhibit the re-activation of the AR by alternate mechanisms such as: intracrine androgen synthesis, expression of AR-SV that lack ligand binding domain (LBD) and AR-LBD mutations with potential to resist antagonists, or inhibit re-activated androgen receptors present in pathogenic altered cellular environments.

[0062] Examples of AR-splice variants include, but are not limited to, AR-V7 and ARv567es (a.k.a. AR-V12; S. Sun, etal. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest. (2010) 120(8), 2715- 2730). Nonlimiting examples of AR mutations conferring antiandrogen resistance are: W741L, T877A, and F876L (J. D. Joseph et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. (2013) 3(9), 1020-1029) mutations. Many other LBD resistance conferring mutations are known in the art and will continue to be discovered. AR-V7 is a splice variant of AR that lacks the LBD (A. H. Bryce & E. S. Antonarakis. Androgen receptor splice variant 7 in castration-resistant prostate cancer: Clinical considerations. Int J Urol. (2016 Jun 3). doi: 10.1111/iju.13134. [Epub ahead of print]). It is constitutively active and has been demonstrated to be responsible for aggressive PCa and resistance to endocrine therapy .

[0063] The disclosure encompasses novel selective androgen receptor degrader (SARD) compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any’ of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 which bind to the AR through an alternate binding and degradation domain (BDD). The SARDs may’ further bind the AR ligand binding domain (LBD). [0064] The SARD compounds may be used in treating CRPC that cannot be treated with any other antagonist. The SARD compounds may treat CRPC by degrading AR-SVs. The SARD compounds may maintain their antagonistic activity in AR mutants that normally convert AR antagonists to agonists. For instance, the SARD compounds maintain their antagonistic activity to AR mutants W741L, T877A, and F876L (J. D. Joseph el al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN- 509. Cancer Discov. (2013) 3(9): 1020-1029). Alternatively, the SARD compounds elicit antagonistic activity within an altered cellular environment in which LBD-targeted agents are not effective or in which NTD-dependent AR activity is constitutively active.

[0065] In one embodiment, A of formula I, IA, IB, II, IIA, TIB, III, TITA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB is a five or six-membered saturated or unsaturated ring having at least one nitrogen atom. In another embodiment, A is a substituted or unsubstituted pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, morpholine, or other heterocyclic ring. In another embodiment, A is a five or six-membered heterocyclic ring.

[0066] In a particular embodiment of formulas I, I A, IB, II, ILA, IIB, III, III A, IIIB, IV,

IVA, IVB, V, VA, VB, VI, ATA, or VIB, Q ¹ is hydrogen. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, V A, VB, VI, ATA, or VIB, Q ¹ is CN. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ^! is F. In a particular embodiment of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ¹ is NCS. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ¹ is maleimide. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA,

IVB, V, VA, VB, VI, VIA, or VIB, Q ^l is NHCOOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB, Q ¹ is N(R)?„ In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ^{ is CONHR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ^j is NHCOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ^f is Cl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ^{ is Br. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ^{ is I. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ^l is NO?.. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, I VB,

V, VA, VB, VI, VIA, or VIB, Q ¹ is phenyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI. VIA, or VIB, Q' ¹ is 4-fluorophenyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB,

VI, VIA, or MB, Q ¹ is CF?. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ¹ is substituted or unsubstituted alkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV ⁷ , IVA, IVB, V ⁷ , VA, VB, V ⁷ !, VIA, or VIB, Q ^! is substituted or unsubstituted cycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB, Q ¹ is substituted or unsubstituted heterocycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB, Q ¹ is haloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ¹ is substituted or unsubstituted aryl. In a particular embodiment of formulas I, LA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ¹ is hydroxyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ¹ is alkoxy. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ^! is OR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ^! is arylalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ^] is amine. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ¹ is amide. In a particular embodiment of formulas I --- VI, IA, IB, IIA, and IIB, Q ^f is COOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ¹ is COR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ^f is keto.

[0067] In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, I V, I VA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is CN. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is hydrogen. In a particular embodiment of fomiuias I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is keto. In a particular embodiment of fomiuias I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is NCS. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is maleimide. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is NHCOOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB. V, VA, VB. V. VIA, or VIB, Q ² is N(R) ₂ . In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is CONHR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² , is NHCOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is F. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is Cl. In a particular embodiment of formulas I, LA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is Br. In a particular embodiment of formulas I, LA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB,Q ² is I. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IILA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is NO2. In a particular embodiment of formulas I, IA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is phenyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is 4-fluorophenyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is CFs. In a particular embodiment of formulas I, IA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is substituted or unsubstituted alkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is substituted or unsubstituted cycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is substituted or unsubstituted heterocycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is haloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is substituted or unsubstituted aryl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IV A, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is hydroxyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB,

III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is alkoxy. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is OR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB,

V, VA, VB, VI, VIA, or VIB, Q ² is arylalkyl. In a particular embodiment of formulas I, IA, IB, II,

IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, V A, VB, VI, VIA, or VIB, Q ² is amine. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is amide. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB,

IV, IVA, IVB, V, V A, VB, VI, VIA, or VIB, Q ² is COOR. In a particular embodiment of formulas

I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is COR.

[0068] In a particular embodiment of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV,

IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q' is CN. In a particular embodiment of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is F. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is NCS. In a particular embodiment of formulas I, I A, IB, II, ILA, IIB, III, IIIA, IIIB,

IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is maleimide. In a particular embodiment of formulas I, LA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is NHCOOR. In a particular embodiment of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA,

IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is N(R)?.. In a particular embodiment of formulas I, LA, IB,

II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is CONFER.. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB,

VI, VIA, or VIB, Q\ is NHCOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is hydrogen. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is keto. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IV A, IVB,

V, VA, VB, VI, VIA, or VIB, Q ³ is Cl. In a particular embodiment of formulas I, IA, IB, II, IIA,

IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is Br. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is I. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is NCh. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is phenyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q' is 4-fluorophenyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q' is CF3. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is substituted or unsubstituted alkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB,Q ³ is substituted or unsubstituted cycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB,Q ³ is substituted or unsubstituted heterocycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, O' is haloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB. Q- is substituted or unsubstituted aryl. In a particular embodiment of formulas I, IA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VLA,

VB, VI, VIA, or VIB, Q ³ is hydroxyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB,

III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is alkoxy. In a particular embodiment of formulas I, LA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is OR. In a particular embodiment of formulas I, LA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is arylalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is amine. In a particular embodiment of formulas I, I A, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q" is amide. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB,

IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is COOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is COR.

[0069] In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, I VA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is CN. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is F. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is NCS. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is maleimide. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIE, Q ⁴ is NHCOOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is N(R)2. In a particular embodiment of formulas I, IA, IB,

II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is CONHR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ , is NHCOR. In a particular embodiment of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is hydrogen. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is keto. In a particular embodiment of formulas I, IA, IB, II, II A, IIB, III, IIIA, IIIB, IV, IVA, IVB,

V, VA, VB, V ⁷ !, VIA, or VIB, Q ⁴ is Cl. In a particular embodiment of formulas I, LA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IV A, IVB, V ⁷ , VA, VB, VI, VIA, or VIB, Q ⁴ is Br. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VI A, or VIB, Q ⁴ is I. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, TUB, IV, IVA, IVB, V,

VA, VB, VI, VIA, or VIB, Q ⁴ is NO2. In a particular embodiment of formulas I, IA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is phenyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is 4-fluorophenyl. In a particular embodiment of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IV ⁷ A, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is CF3. In a particular embodiment of formulas I, IA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is substituted or unsubstituted alkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB,

III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is substituted or unsubstituted cycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is substituted or unsubstituted heterocycloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB,

VI, VIA, or VIB, Q ⁴ is haloalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV ⁷ , IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is substituted or unsubstituted aryl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, I VA, IVB, V, V A,

VB, VI, VIA, or VIB, Q ⁴ is hydroxyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V ⁷ , VA, VB, VI, VIA, or VIB, Q ⁴ is alkoxy. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is OR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IV A, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is arylalkyl. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is amine. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, I VB, V, VA, VB, VI, VIA, or VIB, Q ⁷ is amide. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, V A, VB, VI, VIA, or VIB, Q ⁴ is COOR. In a particular embodiment of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is COR.

[0070] In a particular embodiment of formula IV ⁷ , IVA, IVB, V ⁷ , VA, VB, VI, VIA, or VIB, Q ¹ is H, CN, CFs, phenyl, 4-fluorophenyl, F, Br, or NHCOOC(CHs)3.

[0071] In a particular embodiment of formula IV ⁷ , IVA, IVB, V ⁷ , VA, VB, VI, VIA, or In a particular embodiment of formulalV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, Q ² is H, CN, CFi, phenyl, 4-fluorophenyl, F, Br, or NHCOOCfCFhh.

[0072] In a particular embodiment of formula IV, IV ⁷ A, IVB, V, VA, VB, VI, VIA, or VIB, Q ³ is H, CN, CFs, phenyl, 4-fluorophenyl, F, Br, or NHCOOC(CH ₃ )3.

[0073] In a particular embodiment of formula IV, IV ⁷ A, IVB, V, VA, VB, VI, VIA, or VIB, Q ⁴ is H, CN, CFs, phenyl, 4-fluorophenyl, F, Br, or NHCOOC(CH ₃ )3.

[0074] In a particular embodiment of formula IV, IV ⁷ A, IVB, V, VA, VB, VI, VIA, or VIB, X is CH.

[0075] As used herein, the term “heterocycle” or “heterocyclic ring” group refers to a ring structure comprising in addition to carbon atoms, at least one atom of sulfur, oxygen, nitrogen or any combination thereof, as part of the ring. The heterocycle may be a 3-12 membered ring; 4- 8 membered ring; a 5-7 membered ring; or a 6 membered ring. Preferably, the heterocycle is a 5 to 6 membered ring. Typical examples of heterocycles include, but are not limited to, piperidine, pyridine, furan, thiophene, pyrrole, pyrrolidine, pyrazole, pyrazine, piperazine or pyrimidine. Examples of Cs-Cs heterocyclic rings include pyran, dihydropyran, tetrahydropyran, dihydropyrrole, tetrahydropyrrole, pyrazine, dihydropyrazine, tetrahydropyrazine, pyrimidine, dihydropyrimidine, tetrahydropyrimidone, pyrazole, dihydropyrazole, tetrahydropyrazole, triazole, tetrazole, piperidine, piperazine, pyridine, dihydropyridine, tetrahydropyridine, morpholine, thiomorpholine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, thiazole, imidazole, isoxazole, and the like. The heterocycle ring may be fused to another saturated or unsaturated cycloalkyl or a saturated or unsaturated heterocyclic ring. When the heterocycle ring is substituted, the substituents include at least one of halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylaniido, dialkylamido, cyano, nitro, CO2H, amino, alkylaniino, dialkylamino, carboxyl, thiol, or thioalkyl.

[0076] The term “cycloalkyl” refers to a non-aromatic, monocyclic or polycyclic ring comprising carbon and hydrogen atoms. A cycloalkyl group can have one or more carbon-carbon double bonds in the ring so long as the ring is not rendered aromatic by their presence. Examples of cycloalkyl groups include, but are not limited to, (C3-C7) cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes and (C3-C7) cycloalkenyl groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl, and unsaturated cyclic and bicyclic terpenes. Examples of Cb-Cs carbocyclic include cyclopentane, cyclopentene, cyclohexane, and cyclohexene rings. A cycloalkyl group can be unsubstituted or substituted by at least one substituent. Preferably, the cycloalkyl group is a monocyclic ring or bicyclic ring.

[0077] The term “alkyl” refers to a saturated aliphatic hydrocarbon, including straight- chained and branched-chained. Typically, the alkyl group has 1-12 carbons, 1 -7 carbons, 1-6 carbons, or 1-4 carbon atoms. A branched alkyl is an alkyl substituted by alkyl side chains of 1 to 5 carbons. The branched alkyl may have an alkyl substituted by a C1-C5 haloalkyl. Additionally, the alkyl group may be substituted by at least one of halogen, haloalkyl, hydroxyl, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, ammo, alkylaniino, dialkydamino, carboxyl, thio or thioalkyl.

[0078] An “arylalkyl” group refers to an alkyl bound to an aryl, wherein alkyl and aryl are as defined herein. An example of an ary lalkyl group is a benzyl group.

[0079] An “alkenyl” group refers to an unsaturated hydrocarbon, including straight chain and branched chain having one or more double bonds. The alkenyl group may have 2-12 carbons, preferably the alkenyl group has 2-6 carbons or 2-4 carbons. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, cyclohexenyl, etc. The alkenyl group may be substituted by at least one halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio, or thioalkyl. [0080] As used herein ther term “aryl” group refers to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted. When present, substituents include, but are not limited to, at least one halogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy, thio or thioalkyl. Nonlimiting examples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridmyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like. The aryl group may be a 4-12 membered ring, preferably the aryl group is a 4-8 membered ring. Also the aryl group may be a 6 or 5 membered ring.

[0081] As used herein, the term “haloalkyl” group refers to an alkyl group that is substituted by one or more halogen atoms, e.g., by F, Cl, Br or I.

[0082] A “hydroxyl” group refers to an OH group. It is understood by a person skilled in the art that when T, Q ¹ , Q ^z , Q ³ , or Q ⁴ , in the compounds of the present disclosure is OR, then R is not OH.

[0083] The term “halogen” or “halo” refers to a halogen, F, Cl, Br or I.

[0084] In one embodiment, the compounds and/or its use and/or, its derivative, optical isomer, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal or combinations thereof are provided.

[0085] In one embodiment, the methods make use of “pharmaceutically acceptable salts” of the compounds, which may be produced, by reaction of a compound of this disclosure with an acid or base.

[0086] The compounds may be converted into pharmaceutically acceptable salts. A pharmaceutically acceptable salt may be produced by reaction of a compound with an acid or base.

[0087] Suitable pharmaceutically acceptable salts of amines may be prepared from an inorganic acid or from an organic acid. Examples of inorganic salts of amines include, but are not limited to, bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphates, sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen substituted alkylsulfonates, halogen substituted arylsulfonates), sulfonates, or thiocyanates. [0088] Examples of organic salts of amines may be selected from aliphatic, cycloaliphatic, aromatic, arahphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilates, algenates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, carboxylates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides, decanoates, enanthuates, ethanesulfonates, edetates, edisylates, estolates, esylates, fumarates, formates, fluorides, galacturonates, gluconates, glutamates, glycolates, glucorates, glucoheptanoates, glycerophosphates, gluceptates, glycollylarsanilates, glutarates, glutamates, heptanoates, hexanoates, hydroxymaleates, hydroxycarboxlic acids, hexylresorcinates, hydroxy benzoates, hydroxynaphthoates, hydrofluorates, lactates, lactobionates, laurates, malates, maleates, methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates, methane sulfonates, methylbromides, methylnitrates, methylsulfonates, monopotassium maleates, mucates, monocarboxylates, nitrates, naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, napsylates, 7V-methylglucamines, oxalates, octanoates, oleates, pamoates, phenylacetates, picrates, phenylbenzoates, pivalates, propionates, phthalates, pectinates, phenylpropionates, palmitates, pantothenates, polygalacturates, pyruvates, quinates, salicylates, succinates, stearates, sulfanilates, subacetates, tartarates, theophyllineacetates, p- toluenesulfonates (tosylates), trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates, triethiodide, tricarboxylates, undecanoates and valerates. Examples of inorganic salts of carboxylic acids or phenols may be selected from ammonium, alkali metals, and alkaline earth metals. Alkali metals include, but are not limited to, lithium, sodium, potassium, or cesium. Alkaline earth metals include, but are not limited to, calcium, magnesium, aluminium; zinc, barium, cholines, or quaternary ammoniums. Examples of organic salts of carboxylic acids or phenols may be selected from arginine, organic amines to include aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, r-butylamines, benethamines (A ^; ~benzylphenethylaniine), dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines, hydrabamines, imidazoles, lysines, methylamines, meglammes, JV-methyl-D-glucamines, N,N ’-dibenzylethylenediamines, nicotinamides, organic amines, ornithines, pyridines, picolines, piperazines, procaine, tris(hydroxymethyl)methylamines, triethylamines, triethanolamines, trimethylamines, tromethamines and ureas.

[0089] Salts may be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of a existing salt for another ion or suitable ion-exchange resin.

[0090] The methods of the disclosure may use an uncharged compound or a pharmaceutically acceptable salt of the compound. In particular, the methods use pharmaceutically acceptable salts of compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V,

VA, VB, VI, VIA, or VIB. The pharmaceutically acceptable salt may be an amine salt or a salt of a phenol of the compounds of formulas I, I A, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, ALA,

VB, VI, VIA, or VTB.

[0091] In one embodiment, the methods make use of a free base, free acid, non charged or non-complexed compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V,

VA, VB, VI, VIA, or VIB, and/or its isomer, pharmaceutical product, hydrate, polymorph, or combinations thereof.

[0092] In one embodiment, the methods make use of an optical isomer of a compound of formulas I, IA, IB, II, IIA, IIB, 111, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB. In one embodiment, the methods make use of an isomer of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB. In one embodiment, the methods make use of a pharmaceutical product of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, V A, VB, VI, VIA, or VIB. In one embodiment, the methods make use of a hydrate of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA,

VB, VI, VIA, or VIB. In one embodiment, the methods make use of a polymorph of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VTB. In one embodiment, the methods make use of a metabolite of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VTB. In another embodiment, the methods make use of a composition comprising a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB, as described herein, or, in another embodiment, a combination of isomer, metabolite, pharmaceutical product, hydrate, polymorph of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB.

[0093] As used herein, the term “isomer” includes, but is not limited to, optical isomers, structural isomers, or conformational isomers,

[0094] The term “isomer” is meant to encompass optical isomers of the SARD compound. It will be appreciated by those skilled in the art that the SARDs of the present disclosure contain at least one chiral center. Accordingly, the compounds may exist as optically-active (such as an (/?) isomer or (S) isomer) or racemic forms. Optically active compounds may exist as enantiomer! cal ly enriched mixtures. Some compounds may also exhibit polymorphism. It is to be understood that the present disclosure encompasses any racemic, optically active, polymorphic, or stereroisomeric form, or mixtures thereof Thus, the disclosure may encompass SARD compounds as pure (A’)-isomers or as pure (A)-isomers. It is known in the art how to prepare optically active forms. For example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary' phase.

[0095] Compounds may be hydrates of the compounds. As used herein, the term “hydrate” includes, but is not limited to, hemihydrate, monohydrate, dihydrate, or trihydrate. The disclosure also includes use of A'-oxides of the ammo substituents of the compounds described herein.

[0096] This disclosure provides, in other embodiments, use of metabolites of the compounds as herein described. In one embodiment, “metabolite” means any substance produced from another substance by metabolism or a metabolic process.

[0097] In one embodiment, the compounds of this disclosure are prepared according to Example 1.

Biological Activity of Selective Androgen Receptor Degraders

[0098] A method of treating prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a compound or its pharmaceutically acceptable salt, represented by a compound of formula I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB.

[0099] A method of treating prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a compound or its pharmaceutically acceptable salt, or isomer, represented by a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB.

[0100] The prostate cancer may be advanced prostate cancer, refractory prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (rnCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combination thereof.

[0101] The prostate cancer may depend on AR-FL and/or AR-SV for proliferation. The prostate or other cancer may be resistant to treatment with an androgen receptor antagonist. The prostate or other cancer may be resistant to treatment with enzalutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, spironolactone, or any combination thereof. The method may also reduce the levels of AR, AR-FL, AR-FL with antiandrogen resistance-conferring AR-LBD mutations, AR-SV, gene-amplified AR, or any combination thereof.

[0102] In one embodiment, this disclosure provides a method of treating enzalutamide resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a compound of this disclosure, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0103] In one embodiment, this disclosure provides a method of treating abiraterone resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a compound of formula I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

[0104] In one embodiment, this disclosure provides a method of treating triple negative breast cancer comprising administering to the subject a therapeutically effective amount of a compound of this disclosure, or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. [0105] The method may further comprise a second therapy such as androgen deprivation therapy (ADT) or LHRH agonist or antagonist. LHRH agonists include, but are not limited to, leuprolide acetate.

[0106] The disclosure encompasses a method of treating or inhibiting the progression of prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a SARD compound or pharmaceutically acceptable salt, wherein the compound is at least one of compounds of formula I, I A. IB, II, ll A. IIB, III, Hl A. IIIB, IV, IVA, IVB. V, VA, VB. AT, ATA, or ATB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.

[0107] The disclosure encompasses a method of treating or inhibiting the progression of refractory prostate cancer (PCa) or increasing the survival of a male subject suffering from refractory prostate cancer comprising administering to the subject a therapeutically effective amount of a SARD compound or pharmaceutically acceptable salt, wherein the compound is represented by a compound of formulas I, IA, IB, II, IIA, IIB, Ill, IIIA, IIIB, IV, IA ^r A, IVB, A ^r , AA, VB, AT, VIA, or ATB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.

[0108] The disclosure encompasses a method of treating or increasing the survival of a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering to the subject a therapeutically effective amount of a SARD wherein the compound is represented by a compound of formulas I, IA, IB, II, ILA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, ATA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.

[0109] The method may further comprise administering androgen deprivation therapy to the subject.

[0110] The disclosure encompasses a method of treating or inhibiting the progression of enzalutamide resistant prostate cancer (PCa) or increasing the survival of a male subject suffering from enzalutamide resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a SARI) compound or pharmaceutically acceptable salt, wherein the compound is represented by a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13. [0111] The method may further comprise administering androgen deprivation therapy to the subject.

[0112] The disclosure encompasses a method of treating or inhibiting the progression of tripie negative breast cancer (TNBC) or increasing the survival of a female subject suffering from triple negative breast cancer comprising administering to the subject a therapeutically effective amount of a SARD compound or pharmaceutically acceptable salt, wherein the compound is represented by a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, XT, ATA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.

[0113] As used herein, the term “increase the survival” refers to a lengthening of time when describing the survival of a male subject. Thus in this context, the compounds may be used to increase the survival of men with advanced prostate cancer, refractory prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC) or high-risk nmCRPC.

[0114] Alternatively, as used herein, the terms “increase”, increasing” and “increased” may be used interchangeably and refer to an entity becoming progressively greater (as in size, amount, number, or intensity), wherein for example the entity is sex hormone-binding globulin (SHBG) or prostate-specific antigen (PSA).

[0115] The compounds and compositions of the disclosure may be used for increasing metastasis-free survival (MFS) in a subject suffering from non-metastatic prostate cancer. The non- metastatic prostate cancer may be non-metastatic advanced prostate cancer, non-metastatic CRPC (nmCRPC), or high-risk nmCRPC.

[0116] The SARD compounds described herein may be used to provide a dual action. For example, the SARD compounds may treat prostate cancer and prevent metastasis. The prostate cancer may be refractory prostate cancer: advanced prostate cancer; castration resistant prostate cancer (CRPC); metastatic CRPC (mCRPC); non-metastatic CRPC (nmCRPC); or high-risk nmCRPC.

[0117] The SARD compounds described herein may be used to provide a dual action. For example, the SARD compounds may treat TNBC and prevent metastasis.

[0118] Men with advanced prostate cancer who are at high risk for progression to castration resistant prostate cancer (CRPC) are men on ADT with serum total testosterone concentrations greater than 20 ng/dL or men with advanced prostate cancer who at the time of starting ADT had either (1) confirmed Gleason pattern 4 or 5 prostate cancer, (2) metastatic prostate cancer, (3) a PSA doubling time <3 months, (4) a PSA >20 ng/mL, or (5) a PSA relapse in < 3 years after definitive local therapy (radical prostatectomy or radiation therapy).

[0119] Normal levels of prostate specific antigen (PSA) are dependent on several factors, such as age and the size of a male subject's prostate, among others. PSA levels in the range between 2,5-10 ng/mL are considered “borderline high” while levels above 10 ng/mL are considered “high,” A rate change or “PSA velocity” greater than 0.75/year is considered high. PSA levels may increase despite ongoing ADT or a history of ADT, surgical castration or despite treatment with antiandrogens and/or LHRH agonist.

[0120] Men with high risk non-metastatic castration resistant prostate cancer (high-risk nmCRPC) may include those with rapid PSA doubling times, having an expected progression-free survival of approximately 18 months or less (Miller K, Moul JW, Gleave M, et al. 2013. “Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer,” Prostate Cane Prost Dis. Feb; 16: 187-192). This relatively rapid progression of their disease underscores the importance of novel therapies for these individuals.

[0121] The methods of the disclosure may treat subjects with PSA levels greater than 8 ng/mL where the subject suffers from high-risk nmCRPC. The patient population includes subjects suffering from nmCRPC where PSA doubles in less than 8 months or less than 10 months. The method may also treat patient populations where the total serum testosterone levels are greater than 20 ng/mL in a subject suffering from high-risk nmCRPC. In one case, the serum free testosterone levels are greater than those observed in an orchiechtomized male in a subject suffering from high- risk nmCRPC.

[0122] The pharmaceutical compositions of the disclosure may further comprise at least one LHRH agonist or antagonist, antiandrogen, anti-programmed death receptor 1 (anti-PD-1) drugs or anti-PD-Ll drugs. LHRH agonist includes, but is not limited to, leuprolide acetate (Lupron®) (US 5,480,656; US 5,575,987; 5,631,020; 5,643,607; 5,716,640; 5,814,342; 6,036,976 hereby incorporated by reference) or goserelin acetate (Zoladex®) (US 7,118,552; 7,220,247; 7,500,964 hereby incorporated by reference). LHRH antagonists include, but are not limited to, degarelix or abarelix. Antiandrogens include, but are not limited to, bicalutaniide, flutamide, finasteride, dutasteride, enzalutamide, nilutamide, chlormadinone, abiraterone, or any combination thereof. Anti-PD-1 drugs include, but are not limited to, AMP-224, nivolumab, pembrolizumab, pidihzumab, and AMP-554. Anti-PD-Ll drugs include, but are not limited to, BMS-936559, atezolizumab, durvalumab, avelumab, and MPDL3280A. Anti-CTLA-4 drugs include, but are not limited to, ipilimumab and tremelimumab.

[0123] Treatment of prostate cancer, advanced prostate cancer, CRPC, mCRPC and/or nmCRPC may result in clinically meaningful improvement in prostate cancer related symptoms, function and/or survival. Clinically meaningful improvement can be determined by an increase in radiographic progression free survival (rPFS) if cancer is metastatic, or an increase metastasis-free survival (MFS) if cancer is non-metastatic, among others,

[0124] The disclosure encompasses methods of lowering serum prostate specific antigen (PSA) levels in a male subject suffering from prostate cancer, advanced prostate cancer, metastatic prostate cancer or castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount, of a SARD compound, wherein the compound is represented by the structure of formulas I, I A, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, AT, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.

[0125] The disclosure encompasses a method of secondary hormonal therapy that reduces serum PSA in a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13, that reduces serum PSA in a male subject suffering from castration resistant prostate cancer.

[0126] The disclosure encompasses a method of reducing levels of AR, AR-full length (AR-FL), AR-FL with antiandrogen resistance-conferring AR-LBD mutations, AR-splice variant (AR-SV), and/or amplications of the AR gene within the tumor in the subject in need thereof comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, I V, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13, to reduce the level of AR, AR-full length (AR-FL), AR-FL with antiandrogen resistance-conferring AR-LBD mutations, AR-spiice variant (AR- SV), and/or amplications of the AR gene within the tumor.

[0127] The method may increase radiographic progression free survival (rPFS) or metastasis-free survival (MFS).

[0128] Subjects may have non-metastatic cancer; failed androgen deprivation therapy (ADT), undergone orchidectomy, or have high or increasing prostate specific antigen (PSA) levels; subjects may be a patient with prostate cancer, advanced prostate cancer, refractory prostate cancer, CRPC patient, metastatic castration resistant prostate cancer (mCRPC) patient, or non-metastatic castration resistant prostate cancer (nmCRPC) patient. In these subjects, the refractory may be enzalutamide resistant prostate cancer. In these subjects, the nmCRPC may be high-risk nmCRPC. Further the subject may be on androgen deprivation therapy (ADT) with or without castrate levels of total T.

[0129] As used herein, the phrase “a subject suffering from castration resistant prostate cancer” refers to a subject with at least one of the following characteristics: has been previously treated with androgen deprivation therapy (ADT); has responded to the ADT and currently has a serum PSA > 2 ng/mL or >2 ng/rnL and representing a 25% increase above the nadir achieved on the ADT; a subject which despite being maintained on androgen deprivation therapy is diagnosed to have serum PSA progression, a castrate level of serum total testosterone (<50 ng/dL) or a castrate level of serum total testosterone (<20 ng/dL). The subject may have rising serum PSA on two successive assessments at least 2 weeks apart; been effectively treated with ADT; or has a history of serum PSA response after initiation of ADT.

[0130] As used herein, the term “serum PSA progression” refers to a 25% or greater increase in serum PSA and an absolute increase of 2 ng/ml or more from the nadir; or to serum PSA >2 ng/mL, or >2 ng/mL and a 25% increase above the nadir after the initiation of androgen deprivation therapy (ADT). The term “nadir” refers to the lowest PSA level while a patient is undergoing ADT.

[0131] The term “serum PSA response” refers to at least one of the following: at least 90% reduction in serum PSA value prior to the initiation of ADT; to <10 ng/mL undetectable level of serum PSA (<0.2 ng/mL) at any time; at least 50% decline from baseline in serum PSA; at least 90% decline from baseline in serum PSA; at least 30% decline from baseline in serum PSA; or at least 10% decline from baseline in serum PSA.

[0132] The methods comprise administering a combination of forms of ADT and a compound of this disclosure. Forms of ADT include a LHRH agonist. LHRH agonist includes, but is not limited to, leuprolide acetate (Lupron®)(US 5,480,656; US 5,575,987; 5,631 ,020; 5,643,607; 5,716,640; 5,814,342; 6,036,976 hereby incorporated by reference) or goserelin acetate (Zoladex®) (US 7,1 18,552; 7,220,247; 7,500,964 hereby incorporated by reference). Forms of ADT include, but are not limited to LHRH antagonists, reversible antiandrogens, or bilateral orchidectomy. LHRH antagonists include, but are not limited to, degarelix and abarelix. Antiandrogens include, but are not limited to, bicalutamide, flutamide, finasteride, dutasteride, enzalutamide, ARN-509, ODM-201, nilutamide, chlormadinone, abiraterone, or any combination thereof.

[0133] The methods of the disclosure encompass administering at least one compound of the disclosure and a lyase inhibitor (e.g., abiraterone).

[0134] The term “advanced prostate cancer” refers to metastatic cancer having originated in the prostate, and having widely metastasized to beyond the prostate such as the surrounding tissues to include the seminal vesicles the pelvic lymph nodes or bone, or to other parts of the body. Prostate cancer pathologies are graded with a Gleason grading from 1 to 5 in order of increasing malignancy. Patients with significant risk of progressive disease and/or death from prostate cancer should be included in the definition and any patient with cancer outside the prostate capsule with disease stages as low as IIB clearly has “advanced” disease. “Advanced prostate cancer” can refer to locally advanced prostate cancer. Similarly, “advanced breast cancer” refers to metastatic cancer having originated in the breast, and having widely metastasized to beyond the breast to surrounding tissues or other parts of the body such as the liver, brain, lungs, or bone.

[0135] The term “refractory” may refer to cancers that do not respond to treatment. E.g. , prostate or breast cancer may be resistant at the beginning of treatment or it may become resistant during treatment. “Refractory cancer” may also be referred to herein as “resistant cancer”.

[0136] The term “castration resistant prostate cancer” (CRPC) refers to advanced prostate cancer that is worsening or progressing while the patient remains on ADT or other therapies to reduce testosterone, or prostate cancer which is considered hormone refractory’, hormone naive, androgen independent or chemical or surgical castration resistant. CRPC may be the result of AR activation by intracrine androgen synthesis: expression of AR splice variants ( AR- SV) that lack ligand binding domain (LBD); or expression of AR-LBD mutations with potential to resist antagonists. Castration resistant prostate cancer (CRPC) is an advanced prostate cancer which developed despite ongoing ADT and/or surgical castration. Castration resistant prostate cancer is defined as prostate cancer that continues to progress or worsen or adversely affect the health of the patient despite prior surgical castration, continued treatment with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (e.g., degarelix or abarelix), antiandrogens (e.g., bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitimb (Iressa®), cabozantimb (Cometriq™, also known as XI/184)) or other prostate cancer therapies (e.g, vaccines (sipuleucel- T (Provenge®), GV AX, etc.), herbal (PC-SPES) and lyase inhibitor (abiraterone)) as evidenced by increasing or higher serum levels of prostate specific antigen (PSA), metastasis, bone metastasis, pain, lymph node involvement, increasing size or serum markers for tumor growth, worsening diagnostic markers of prognosis, or patient condition.

[0137] Castration resistant prostate cancer may be defined as hormone naive prostate cancer. In men with castration resistant prostate cancer, the tumor cells may have the ability to grow' in the absence of androgens (hormones that promote the development and maintenance of male sex characteristics).

[0138] Many early prostate cancers require androgens for growth, but advanced prostate cancers are androgen-independent, or hormone naive.

[0139] The term “androgen deprivation therapy” (ADT) may include orchiectomy; administering luteinizing hormone-releasing hormone (LHRH) analogs; administering luteinizing hormone-releasing hormone (LHRH) antagonists; administering 5a.-reductase inhibitors; administering antiandrogens, administering inhibitors of testosterone biosynthesis, administering estrogens; or administering l7a-hydroxylase/C17,20 lyase (CYP17A1) inhibitors. LHRH drugs lower the amount of testosterone made by the testicles. Examples of LHRH analogs available in the United States include leuprolide (Lupron®, Viadur®, Eligard®), goserehn (Zoladex®), triptorelm (Trelstar®), and histrelin (Vantas®). Antiandrogens block the body's ability to use any androgens. Examples of antiandrogens drugs include enzalutamide (Xtandi®), flutamide (Eulexin®), bicalutamide (Casodex®), and nilutamide (Nilandron®). Luteinizing hormone- releasing hormone (LHRH) antagonists include abarelix (Plenaxis®) or degarelix (Firmagon®) (approved for use by the FD A in 2008 to treat advanced prostate cancer). 5a-Reductase inhibitors block the body’s ability to convert testosterone to the more active androgen, 5a- dihydrotestosterone (DHT) and include drugs such as finasteride (Proscar®) and dutasteride (Avodart®). Inhibitors of testosterone biosynthesis include drugs such as ketoconazole (Nizoral®). Estrogens include diethylstilbestrol or 17P-estradiol. 17a-Hydroxylase/C17,20 lyase (CYP17A1) inhibitors include abiraterone (Zytiga®).

[0140] The disclosure encompasses a method of treating antiandrogen-resi stant prostate cancer. The antiandrogen may include, but is not limited to, bicalutamide, hydroxyflutamide, flutamide, enzalutamide or abiraterone.

Treatment of Triple Negative Breast Cancer (TNBC)

[0141] Triple negative breast cancer (TNBC) is a type of breast cancer lacking the expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor kinase. As such, TNBC lacks the hormone and kinase therapeutic targets used to treat other types of primary breast cancers. Correspondingly, chemotherapy is often the initial pharmacotherapy for TNBC. Interestingly, AR is often still expressed in TNBC and may offer a hormone targeted therapeutic alternative to chemotherapy. In ER-positive breast cancer, AR is a positive prognostic indicator as it is believed that activation of AR limits and/or opposes the effects of the ER in breast tissue and tumors. However, in the absence of ER, it is possible that AR actually supports the growth of breast cancer tumors. Though the role of AR is not fully understood in TNBC, we have evidence that certain TNBC’s may be supported by androgen independent activation of AR-SVs lacking the LBD or androgen-dependent activation of AR full length. As such, enzalutamide and other LBD-directed traditional AR antagonists would not be able to antagonize AR-SVs in these TNBC’s. However, SARDs of this disclosure which are capable of destroying AR-SVs through a binding site in the NTD of AR would be able to antagonize AR in these TNBC’s and provide an anti-tumor effect.

Treatment of Kennedy’s Disease [0142] Muscle atrophy (MA) is characterized by wasting away or diminution of muscle and a decrease in muscle mass. For example, post-polio MA is muscle wasting that occurs as part of the post-polio syndrome (PPS). The atrophy includes weakness, muscle fatigue, and pain. Another type of MA is X-linked spinal-bulbar muscular atrophy (SBMA - also known as Kennedy’s Disease), This disease arises from a defect in the androgen receptor gene on the X chromosome, affects only males, and its onset is in late adolescence to adulthood. Proximal limb and bulbar muscle weakness results in physical limitations including dependence on a wheelchair in some cases. The mutation results in an extended polyglutamine tract at the N-terminal domain of the androgen receptor (polyQ AR).

[0143] Binding and activation of the polyQ AR by endogeneous androgens (testosterone and DHT) results in unfolding and nuclear translocation of the mutant androgen receptor. The androgen-induced toxicity and androgen-dependent nuclear accumulation of polyQ AR protein seems to be central to the pathogenesis. Therefore, the inhibition of the androgen- activated polyQ AR might be a therapeutic option (A. Baniahmad. Inhibition of the androgen receptor by antiandrogens in spinobulbar muscle atrophy. J. Mol. Neurosci. 2016 58(3), 343- 347). These steps are required for pathogenesis and result in partial loss of transactivation function (/.<?., an androgen insensitivity) and a poorly understood neuromuscular degeneration. Peripheral polyQ AR anti-sense therapy rescues disease in mouse models of SBMA (Cell Reports 7 , 774-784, May 8, 2014). Further support of use antiandrogen comes in a report in which the antiandrogen flutamide protects male mice from androgen-dependent toxicity' in three models of spinal bulbar muscular atrophy (Renier KJ, Troxell-Smith SM, Johansen JA, Katsuno M, Adachi H, Sobue G, Chua JP, Sun Kim H, Lieberman AP, Breedlove SM, Jordan CL. Endocrinology 2014, 155(7), 2624-2634). These steps are required for pathogenesis and result in partial loss of transactivation function (i.e., an androgen insensitivity) and a poorly understood neuromuscular degeneration. Currently there are no disease-modifying treatments but rather only symptom directed treatments. Efforts to target the polyQ AR as the proximal mediator of toxicity by harnessing cellular machinery to promote its degradation hold promise for therapeutic intervention.

[0144] Selective androgen receptor degraders such as those reported herein bind to, inhibit transactivation, and degrade all androgen receptors tested to date (full length, splice variant, antiandrogen resistance mutants, etc.), indicating that they are promising leads for treatment diseases whose pathogenesis is androgen-dependent such as SBMA.

[0145] The disclosure encompasses methods of treating Kennedy’s disease comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI. MA, or MB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.

[0146] As used herein, the term “androgen receptor associated conditions” or “androgen sensitive diseases or disorders” or “androgen-dependent diseases or disorders” are conditions, diseases, or disorders that are modulated by or whose pathogenesis is dependent upon the activity of the androgen receptor. The androgen receptor is expressed in most tissues of the body however it is overexpressed in, inter alia, the prostate and skin. ADT has been the mainstay of prostate cancer treatment for many years, and SARDs may also be useful in treating various prostate cancers, benign prostatic hypertrophy, prostamegaly, and other maladies of the prostate.

[0147] The disclosure encompasses methods of treating benign prostatic hypertrophy comprising administering a therapeutically effective amount of at least, one compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, MA, or MB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.

[0148] The disclosure encompasses methods of treating prostamegaly comprising administering a therapeutically effective amount of at least one compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB.

[0149] The disclosure encompasses methods of treating hyperproliferative prostatic disorders and diseases comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.

[0150] The effect of the AR on the skin is apparent in the gender dimorphism and puberty related dermatological problems common to teens and early adults. The hyperandrogenism of puberty stimulates terminal hair growth, sebum production, and predisposes male teens to acne, acne vulgaris, seborrhea, excess sebum, hidradenitis suppurativa, hirsutism, hypertrichosis, hyperpilosity, androgenic alopecia, male pattern baldness, and other dermatological maladies. 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 disclosure potently inhibit ligand-dependent and ligand-independent AR activation, and (in some cases) have short biological half-lives in the serum, suggesting that topically formulated SARDs of this disclosure could be applied to the areas affected by acne, seborrheic dermatitis, and/or hirsutism without risk of systemic side effects.

[0151] The disclosure encompasses methods of treating acne, acne vulgaris, seborrhea, seborrheic dermatitis, hidradenitis supporativa, hirsutism, hypertrichosis, hyperpilosity, or alopecia comprising administering a therapeutically effective amount of a compound of formulas I, TA, IB, II, II A, IIB, III, IIIA, IIIB, IV, IV.A, IVB, \ ^r , V A, VB, VI, VIA, or VI B, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.

[0152] The compounds and/or compositions described herein may be used for treating hair loss, alopecia, androgenic alopecia, alopecia areata, alopecia secondary to chemotherapy, alopecia secondary to radiation therapy, alopecia induced by scarring or alopecia induced by stress. Generally “hair loss” or “alopecia” refers to baldness as in the very common type of male-pattern baldness. Baldness typically begins with patch hair loss on the scalp and sometimes progresses to complete baldness and even loss of body hair. Hair loss affects both males and females.

[0153] The disclosure encompasses methods of treating androgenic alopecia comprising administering a therapeutically effective amount of a compound of formula I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.

[0154] SARDs of this disclosure may also be useful in the treatment of hormonal conditions in females which can have hyperandrogenic pathogenesis such as precocious puberty, early puberty, dysmenorrhea, amenorrhea, multilocular uterus syndrome, endometriosis, hysteromyoma, abnormal uterine bleeding, early menarche, fibrocystic breast disease, fibroids of the uterus, ovarian cysts, polycystic ovary syndrome, pre-eclampsia, eclampsia of pregnancy, preterm labor, premenstrual syndrome, and/or vaginal dryness.

[0155] The disclosure encompasses methods of treating precocious puberty or early puberty, dysmenorrhea or amenorrhea, multilocular uterus syndrome, endometriosis, hysteromyoma, abnormal uterine bleeding, hyper-androgenic diseases (such as polycystic ovary syndrome (PCOS)), fibrocystic breast disease, fibroids of the uterus, ovarian cysts, polycystic ovary’ syndrome, pre-eclampsia, eclampsia of pregnancy, preterm labor, premenstrual syndrome, or vaginal dryness comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.

[0156] SARDs of this disclosure may also find utility in treatment of sexual perversion, hypersexuality, paraphilias, androgen psychosis, virilization, androgen insensitivity syndromes (AIS) (such as complete AIS (CAIS) and partial AIS (PAIS)), and improving ovulation in an animal.

[0157] The disclosure encompasses methods of treating sexual perversion, hypersexuality, paraphilias, androgen psychosis, virilization androgen, insensitivity syndromes, increasing or modulating or improving ovulation comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, TUB, IV, IVA, IVB, V, VA, VB, VI, VI A, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13.

[0158] SARDs of this disclosure may also be useful for treating hormone-dependent cancers such as prostate cancer, breast cancer, testicular cancer, ovarian cancer, hepatocellular carcinoma, urogenital cancer, etc. In another embodiment, the breast cancer is triple negative breast cancer. Further, local or systemic SARD administration may be useful for treatment of precursors of hormone-dependent cancers such as prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferation (ASAP).

[0159] The disclosure encompasses methods of treating breast cancer, testicular cancer, uterine cancer, ovarian cancer, urogenital cancer, precursors of prostate cancer, or AR related or AR expressing solid tumors, comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13. A precursor of prostate cancers may be prostatic intraepithelial neoplasia (PIN) or atypical small acinar proliferation (ASAP). The tumor may be hepatocellular carcinoma (HCC) or bladder cancer. Serum testosterone may be positively linked to the development of HCC. Based on epidemiologic, experimental observations, and notably the fact that men have a substantially higher risk of bladder cancer than women, androgens and/or the AR may also play a role in bladder cancer initiation. [0160] Although traditional antiandrogens such as enzalutamide, bicalutamide and flutamide and androgen deprivation therapies (ADT) such as leuprolide were approved for use in prostate cancer, there is significant evidence that antiandrogens could also be used in a variety of other hormone-dependent and hormone-independent cancers. For example, antiandrogens have been successfully tested in breast cancer (enzalutamide; Breast Cancer Res (2014) 16(1): R7), non- small cell lung cancer (shRNAi AR), renal cell carcinoma (ASC-J9), partial androgen insensitivity associated malignancies such as gonadal tumors and seminoma, advanced pancreatic cancer (World J Gastroenterology 20(29): 9229), cancer of the ovary, fallopian tubes, or peritoneum, cancer of the salivary gland (Head and Neck (2016) 38: 724-731; ADT was tested in AR-expressing recurrent metastatic salivary gland cancers and was confirmed to have benefit on progression free survival and overall survival endpoints), bladder cancer (Oncotarget 6 (30): 29860-29876); Int J Endocrinol (2015), Article ID 384860 ), pancreatic cancer, lymphoma (including mantle cell), and hepatocellular carcinoma. Use of a more potent antiandrogen such as a SARD in these cancers may treat the progression of these and other cancers. Other cancers may also benefit from SARD treatment such as testicular cancer, uterine cancer, ovarian cancer, urogenital cancer, breast cancer, brain cancer, skin cancer, lymphoma, liver cancer, renal cancer, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, perianal adenoma, or central nervous system cancer.

[0161] SARDs of this disclosure may also be useful for treating other cancers containing AR such as breast, brain, skin, ovarian, bladder, lymphoma, liver, kidney, pancreas, endometrium, lung (e.g, NSCLC), colon, perianal adenoma, osteosarcoma, CNS, melanoma, hypercalcemia of malignancy and metastatic bone disease, etc.

[0162] Thus, the disclosure encompasses methods of treating hypercalcemia of malignancy, metastatic bone disease, brain cancer, skin cancer, bladder cancer, lymphoma, liver cancer, renal cancer, osteosarcoma, pancreatic cancer, endometrial cancer, lung cancer, central nervous system cancer, gastric cancer, colon cancer, melanoma, amyotrophic lateral sclerosis (ALS), and/or uterine fibroids comprising administering a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13. The lung cancer may be non-small cell lung cancer (NSCLC). [0163] SARDs of this disclosure may also be useful for the treating of non-hormone- dependent cancers. Non-hormone-dependent cancers include liver, salivary’ duct, etc.

[0164] In another embodiment, the SARDs of this disclosure are used for treating gastric cancer. In another embodiment, the SARDs of this disclosure are used for treating salivary duct carcinoma. In another embodiment, the SARDs of this disclosure are used for treating bladder cancer. In another embodiment, the SARDs of this disclosure are used for treating esophageal cancer. In another embodiment, the SARDs of this disclosure are used for treating pancreatic cancer. In another embodiment, the SARDs of this disclosure are used for treating colon cancer. In another embodiment, the SARDs of this disclosure are used for treating non-small cell lung cancer. In another embodiment, the S ARDs of this disclosure are used for treating renal cell carcinoma.

[0165] AR plays a role in cancer initiation in hepatocellular carcinoma (HCC). Therefore, targeting AR may be an appropriate treatment for patients with early stage HCC. In late- stage HCC disease, there is evidence that metastasis is suppressed by androgens. In another embodiment, the SARDs of this disclosure are used for treating hepatocellular carcinoma (HCC).

[0166] Locati et al. in Head & Neck, 2016, 724-731 demonstrated the use of androgen deprivation therapy (ADT) in AR-expressing recurrent/metastatic salivary gland cancers and confirmed improved progression free survival and overall survival endpoints with ADT. In another embodiment, the SARDs of this disclosure are used for treating salivary gland cancer.

[0167] Kawahara et al. in Oncotarget, 2015, Vol 6 (30), 29860-29876 demonstrated that ELK 1 inhibition, together with AR inactivation, has the potential of being a therapeutic approach for bladder cancer. McBeth et al. Int J Endocrinology, 2015, Vol 2015, Article ID 384860 suggested that the combination of antiandrogen therapy pl us glucocorticoids as treatment of bladder cancer as this cancer is believed to have an inflammatory etiology. In another embodiment, the SARDs of this disclosure are used for treating bladder cancer, optionally in combination with glucocorticoids.

Abdominal Aortic Aneurysm (AAA)

[0168] An abdominal aortic aneurysm (AAA) is an enlarged area in the lower part of the aorta, the major blood vessel that supplies blood to the body. The aorta, about the thickness of a garden hose, runs from your heart through the center of your chest and abdomen. Because the aorta is the body's main supplier of blood, a ruptured abdominal aortic aneurysm can cause life- threatening bleeding. Depending on the size and the rate at which your abdominal aortic aneurysm is growing, treatment may vary from watchful waiting to emergency surgery. Once an abdominal aortic aneurysm is found, doctors will closely monitor it so that surgery’ can be planned if it's necessary. Emergency surgery’ for a ruptured abdominal aortic aneurysm can be risky. AR blockade (pharmacologic or genetic) reduces AAA. Davis et al. (Davis JP, Salmon M, Pope NH, Lu G, Su G, Meher A, Ailawadi G, Upchurch GR Jr. J Vase Surg (2016) 63(6): 1602-1612) showed that flutamide (50 mg/kg) or ketoconazole (150 mg/kg) attenuated AAA induced by porcine pancreatic elastase (0.35 U/mL) by 84.2% and 91.5% compared to vehicle (121 %). Further AR -/- mice showed attenuated AAA growth (64.4%) compared to wildtype (both treated with elastase). Correspondingly, administration of a SARD to a patient suffering from an AAA may help reverse, treat or delay progression of AAA to the point where surgery/ is needed.

Treatment, of Wounds

[0169] Wounds and/or ulcers are normally found protruding 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. The term “wound” denotes a bodily injury with disruption of the normal integrity of tissue structures, sore, lesion, necrosis, and/or ulcer. The term “sore” refers to any lesion of the skin or mucous membranes and the term “ulcer” refers to a local defect, or excavation, of the surface of an organ or tissue, which is produced by the sloughing of necrotic tissue. “Lesion” generally includes any tissue defect. “Necrosis” refers to dead tissue resulting from infection, injury, inflammation, or infarctions. All of these are encompassed by the term “wound,” which denotes any wound at any particular stage 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).

[0170] Examples of wounds which can be treated in accordance with the present disclosure are aseptic wounds, contused wounds, incised wounds, lacerated wounds, non- penetrating wounds (?.<?. wounds in which there is no disruption of the skin but there is injury to underlying structures), open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, subcutaneous wounds, etc. Examples of sores include, but are not limited to, bed sores, canker sores, chrome sores, cold sores, pressure sores, etc. Examples of ulcers include, but are not limited to, peptic ulcer, duodenal ulcer, gastric ulcer, gouty ulcer, diabetic ulcer, hypertensive ischemic ulcer, stasis ulcer, ulcus cruris (venous ulcer), sublingual ulcer, submucous ulcer, symptomatic ulcer, trophic ulcer, tropical ulcer, veneral ulcer, e.g., caused by gonorrhoea (including urethritis, endocervicitis and proctitis). Conditions related to wounds or sores which may be successfully treated according to the disclosure include, but are not limited to, burns, anthrax, tetanus, gas gangrene, scalatina, erysipelas, sycosis barbae, folliculitis, impetigo contagiosa, impetigo bullosa, etc. It is understood, that there may be an overlap between the use of the terms “wound” and “ulcer,” or “wound” and “sore” and, furthermore, the terms are often used at random.

[0171] The kinds of wounds to be treated according to the disclosure include also: i) general wounds such as, e.g., surgical, traumatic, infectious, ischemic, thermal, chemical and bullous wounds, li) wounds specific for the oral cavity such as, e.g., post-extraction wounds, endodontic wounds especially in connection with treatment of cysts and abscesses, ulcers and lesions of bacterial, viral or autoimmunological origin, mechanical, chemical, thermal, infectious and lichenoid wounds; herpes ulcers, stomatitis aphthosa, acute necrotising ulcerative gingivitis and burning mouth syndrome are specific examples; and iii) wounds on the skin such as, e.g., neoplasm, burns (e.g. chemical, thermal), lesions (bacterial, viral, autoimmunological), bites and surgical incisions. Another way of classifying wounds is by tissue loss, where: i) small tissue loss (due to surgical incisions, minor abrasions, and minor bites) or ii) significant tissue loss. The later group includes ischemic ulcers, pressure sores, fistulae, lacerations, severe bites, thermal burns and donor site wounds (in soft and hard tissues) and infarctions. Other wounds include ischemic ulcers, pressure sores, fistulae, severe bites, thermal burns, or donor site wounds.

[0172] Ischemic ulcers and pressure sores are wounds, which normally only heal very slowly and especially in such cases an improved and more rapid healing is of great importance to the patient. Furthermore, the costs involved in the treatment of patients suffering from such wounds are markedly reduced when the healing is improved and takes place more rapidly.

[0173] Donor site wounds are wounds which e.g., occur in connection with removal of hard tissue from one part of the body to another part of the body e.g., in connection with transplantation. The wounds resulting from such operations are very painful and an improved healing is therefore most valuable. [0174] In one case, the wound to be treated is selected from the group consisting of aseptic wounds, infarctions, contused wounds, incised wounds, lacerated wounds, non-penetrating wounds, open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, and subcutaneous wounds.

[0175] The disclosure encompasses methods of treating a subject suffering from a wound comprising administering to the subject a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, IIB, III, TITA, IIIB, IV, IVA, IVB, V, VA, VB, AT, ATA, or ATB, or any of compounds CPD, 9, CPD. 44, CPD. 45, or CPD. 13, pharmaceutically acceptable salt thereof, or a pharmaceutical compostion thereof.

[0176] The disclosure encompasses methods of treating a subject suffering from a burn comprising administering to the subject a therapeutically effective amount of a compound of formulas I, IA, IB, II, IIA, TIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, AT, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13, pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0177] The term “skin” is used in a very broad sense embracing the epidermal layer of the skin and in those cases where the skin surface is more or less injured also the dermal layer of the skin. Apart from the stratum corneum, the epidermal layer of the skin is the outer (epithelial) layer and the deeper connective tissue layer of the skin is called the dermis.

[0178] Since the skin is the most exposed part of the body, it is particularly susceptible to various kinds of injuries such as, e.g., ruptures, cuts, abrasions, burns and frostbites or inj uries arising from various diseases. Furthermore, much skin is often destroyed in accidents. However, due to the important barrier and physiologic function of the skin, the integrity of the skin is important to the well-being of the individual, and any breach or rupture represents a threat that must be met by the body in order to protect its continued existence.

[0179] Apart from injuries on the skin, injuries may also be present in all kinds of tissues (i.e., soft and hard tissues). Injuries on soft tissues including mucosal membranes and/or skin are especially relevant in connection with the present disclosure.

[0180] Healing of a wound on the skin or on a mucosal membrane undergoes a series of stages that results either in repair or regeneration of the skin or mucosal membrane. In recent years, regeneration and repair have been distinguished as the two types of healing that may occur. Regeneration may be defined as a biological process whereby the architecture and function of lost tissue are completely renewed. Repair, on the other hand, is a biological process whereby continuity of disrupted tissue is restored by new tissues which do not replicate the structure and function of the lost ones.

[0X81] The majority of wounds heal through repair, meaning that the new tissue formed is structurally and chemically unlike the original tissue (scar tissue). In the early stage of the tissue repair, one process which is almost always involved is the formation of a transient connective tissue in the area of tissue injury. This process starts by formation of a new extracellular collagen matrix by fibroblasts. This new extracellular collagen matrix is then the support for a connective tissue during the final healing process. The final healing is, in most tissues, a scar formation containing connective tissue. In tissues which have regenerative properties, such as, e.g., skin and bone, the final healing includes regeneration of the original tissue. This regenerated tissue has frequently also some scar characteristics, e.g., a thickening of a healed bone fracture.

[0182] Under normal circumstances, the body provides mechanisms for healing inj ured skm or mucosa in order to restore the integrity of the skin barrier or the mucosa. The repair process for even minor ruptures or wounds may take a period of time extending from hours and days to weeks. However, in ulceration, the healing can be very slow and the wound may persist for an extended period of time, i.e., months or even years.

[0183] Burns are associated with reduced testosterone levels, and hypogonadism is associated with delayed wound healing. The disclosure encompasses methods for treating a subject suffering from a wound or a burn by administering at least one SARD compound according to this disclosure. The SARD may promote resolving of the burn or wound, participates in the healing process of a burn or a wound, or, treats a secondary complication of a burn or wound.

[0184] The treatment of burns or wounds may further use at least one growth factor such as epidermal growth factor (EGF), transforming growth factor-a (TGF-a), platelet derived growth factor (PDGF), fibroblast growth factors (FGFs) including acidic fibroblast growth factor (a-FGF) and basic fibroblast growth factor (P-FGF), transforming growth factor-P (TGF-3) and insulin like growth factors (IGF-1 and IGF-2), or any combination thereof, which promote wound healing. [0185] Wound healing may be measured by many procedures known in the art, including, but not limited to, wound tensile strength, hydroxyproline or collagen content, procollagen expression, or re-epithelialization. As an example, a SARD as described herein may be administered orally or topically at a dosage of about 0.1-10 mg per day. Therapeutic effectiveness is measured as effectiveness in enhancing wound healing as compared to the absence of the SARD compound. Enhanced wound healing may be measured by known techniques such as decrease in healing time, increase in collagen density', increase in hydroxyproline, reduction in complications, increase in tensile strength, and increased cellulanty of scar tissue.

[0186] The term “reducing the pathogenesis” is to be understood to encompass reducing tissue damage, or organ damage associated with a particular disease, disorder or condition. The term may include reducing the incidence or severity of an associated disease, disorder or condition, with that in question or reducing the number of associated diseases, disorders or conditions with the indicated, or symptoms associated thereto.

Pharmaceutical Compositions

[0187] The compounds may be used in pharmaceutical compositions. As used herein, “pharmaceutical composition” means either the compound or pharmaceutically acceptable salt of the active ingredient with a pharmaceutically acceptable carrier or diluent. A “therapeutically effective amount” as used herein refers to that amount which provides a therapeutic effect for a given indication and administration regimen.

[0188] As used herein, the term “administering” refers to bringing a subject in contact with a compound of the present disclosure. As used herein, administration can be accomplished in vitro, i.e., in a test tube, or in vivo, i.e., in cells or tissues of living organisms, for example humans. The subjects may be a male or female subject or both.

[0189] Numerous standard references are available that describe procedures for preparing various compositions or formulations suitable for administration of the compounds. Examples of methods of making formulations and preparations can be found in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).

[0190] The mode of administration and dosage form are closely related to the therapeutic amounts of the compounds or compositions which are desirable and efficacious for the given treatment application.

[0191] The pharmaceutical compositions of the disclosure can be administered to a subject by any method known to a person skilled in the art. These methods include, but are not limited to, orally, parenterally, intravascularly, paracancerally, transmucosally, transdermally, intramuscularly, intranasally, intravenously, intradermally, subcutaneously, sublingually, intraperitoneally, mtraventricularly, intracranially, intra vaginal ly, by inhalation, rectally, or intratum orally. These methods include any means in which the composition can be delivered to tissue (e.g., needle or catheter). Alternatively, a topical administration may be desired for application to dermal, ocular, or mucosal surfaces. Another method of administration is via aspiration or aerosol formulation. The pharmaceutical compositions may be administered topically to body surfaces, and are thus formulated in a form suitable for topical administration. Suitable topical formulations include gels, ointments, creams, lotions, drops and the like. For topical administrations, the compositions are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.

[0192] Suitable dosage forms include, but are not limited to, oral, rectal, sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterile administration, and other dosage forms for sy stemic delivery of active ingredients. Depending on the indication, formulations suitable for oral or topical administration are preferred.

Topical Administration

[0193] The compounds of formulasl, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 may be administered topically. As used herein, “topical administration” refers to application of the compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 (and optional carrier) directly to the skin and/or hair. The topical composition can be in the form of solutions, lotions, salves, creams, ointments, liposomes, sprays, gels, foams, roller sticks, and any other formulation routinely used in dermatology.

[0194] Topical administration is used for incidations found on the skin, such as hirsutism, alopecia, acne, and excess sebum. The dose will vary, but as a general guideline, the compound will be present in a dermatologically acceptable carrier in an amount of from about 0.01 to 50 w/w %, and more typically from about 0.1 to 10 w/w %. Typically, the dermatological preparation will be applied to the affected area from 1 to 4 times daily. “Dermatologically acceptable” refers to a carrier which may be applied to the skin or hair, and which will allow the drug to diffuse to the site of action. More specifically “site of action”, it refers to a site where inhibition of androgen receptor or degradation of the androgen receptor is desired.

[0195] The compounds of formulas I, IA, IB, II, IIA, TIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13, maybe used topically to relieve alopecia, especially androgenic alopecia. Androgens have a profound effect on both hair growth and hair loss. In most body sites, such as the beard and pubic skin, androgens stimulate hair growth by prolonging the growth phase of the hair cycle (anagen) and increasing follicle size. Hair growth on the scalp does not require androgens but, paradoxically, androgens are necessary' for the balding on the scalp in genetically predisposed individuals (androgenic alopecia) where there is a progressive decline in the duration of anagen and in hair follicle size. Androgenic alopecia is also common in women where it usually presents as a diffuse hair loss rather than showing the paterning seen in men.

[0196] While the compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 will most typically be used to alleviate androgenic alopecia, the compounds may be used to alleviate any type of alopecia. Examples of non-androgenic alopecia include, but are not limited to, alopecia areata, alopecia due to radiotherapy or chemotherapy , scarring alopecia, or stress related alopecia.

[0197] The compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 can be applied topically to the scalp and hair to prevent, or treat balding. Further, the compound of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD 45, or CPD. 13 can be applied topically in order to induce or promote the growth or regrowth of hair on the scalp.

[0198] The disclosure also encompasses topically administering a compound of formula I, I A. IB, II, II A, I IB, III, I II A, I IIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 to treat or prevent the growth of hair in areas 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 (e.g., a female face). Such inappropriate hair growth occurs most commonly in women and is frequently seen at menopause. The topical administration of the compounds of formulas I, IA, IB, II, IIA, IIB, III, TITA, IIIB, IV, IV A, IVB, V, V A, VB, VI, VTA, or VIB, or any of compounds CPD, 9, CPD. 44, CPD. 45, or CPD. 13 will alleviate this condition leading to a reduction, or elimination of this inappropriate, or undesired, hair growth.

[0199] The compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 may also be used topically to decrease sebum production. Sebum is composed of triglycerides, wax esters, fatty acids, sterol esters and squalene. Sebum is produced in the acinar cells of the sebaceous glands and accumulates as these cells age. At maturation, the acinar cells lyse, releasing sebum into the luminal duct so that it may be deposited on the surface of the skin.

[0200] In some individuals, an excessive quantity of sebum is secreted onto the skin. This can have a number of adverse consequences. It can exacerbate acne, since sebum is the primary food source for Propionbacterium acnes, the causative agent of acne. It can cause the skin to have a greasy appearance, typically considered cosmetically unappealing.

[0201] Formation of sebum is regulated by growth factors and a variety of hormones including androgens. The cellular and molecular mechanism by which androgens exert their influence on the sebaceous gland has not been fully elucidated. However, clinical experience documents the impact androgens have on sebum production. Sebum production is significantly increased during puberty, when androgen levels are their highest. The compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VTA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 inhibit the secretion of sebum and thus reduce the amount of sebum on the surface of the skin. The compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, 111 B, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 can be used to treat a variety of dermal diseases such as acne or seborrheic dermatitis.

[0202] In addition to treating diseases associated with excess sebum production, the compounds of formulas I, IA, IB, II, IIA, TIB, III, IIIA, TUB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 can also be used to achieve a cosmetic effect. Some consumers believe that they are afflicted with overactive sebaceous glands. They feel that their skin is oily and thus unattractive. These indiviuals may use the compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, XT, VTA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 to decrease the amount of sebum on their skin. Decreasing the secretion of sebum will alleviate oily skin in mdvi duals afflicted with such conditions.

[0203] To treat these topical indications, the disclosure encompasses cosmetic or pharmaceutical compositions (such as dermatological compositions), comprising at least one of the compounds of formulas I, IA, IB, II, IIA, TIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13. Such dermatological compositions will contain from 0.001% to 10% w/w% of the cornpound(s) in admixture with a dermatologically acceptable carrier, and more typically, from 0.1 to 5 w/w % of the compounds. Such compositions will typically be applied from 1 to 4 times daily. The reader’s attention is directed to Remington’s Pharmaceutical Science, Edition 17, Mark Publishing Co., Easton, PA for a discussion of how to prepare such formulations.

[0204] The compositions of the disclosure may also include solid preparations such as cleansing soaps or bars. These compositions are prepared according to methods known in the art.

[0205] Formulations such as aqueous, alcoholic, or aqueous-alcoholic solutions, or creams, gels, emulsions or mousses, or aerosol compositions with a propellant may be used to treat indications that arise where hair is present. Thus, the composition can also be a hair care composition. Such hair care compositions include, but are not limited to, shampoo, a hair-setting lotion, a treating lotion, a styling cream or gel, a dye composition, or a lotion or gel for preventing hair loss. The amounts of the various constituents in the dermatological compositions are those conventionally used in the fields considered. [0206] Medicinal and cosmetics containing the compounds of formulas I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB, V, VA, VB, VI, VIA, or VIB, or any of compounds CPD. 9, CPD. 44, CPD. 45, or CPD. 13 will typically be packaged for retail distribution (i.e., an article of manufacture). Such articles will be labeled and packaged in a manner to instruct the patient how to use the product. Such instructions will include the condition to be treated, duration of treatment, dosing schedule, etc,

[0207] Antiandrogens, such as finasteride or flutamide, have been shown to decrease androgen levels or block androgen action in the skin to some extent but suffer from undesirable systemic effects. An alternative approach is to topically apply a selective androgen receptor degrader (SARD) compound to the affected areas. Such SARD compound would exhibit potent but local inhibition of AR activity, local degradation of AR activity, would not penetrate to the systemic circulation of the subject, or would be rapidly metabolized upon entry into the blood, limiting systemic exposure.

[0208] To prepare such pharmaceutical dosage forms, the active ingredient may be mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration.

[0209] ,As used herein “pharmaceutically acceptable carriers or diluents” are well known to those skilled in the art. The carrier or diluent may be a solid carrier or diluent for solid formuations, a liquid carrier or diluent for liquid formulations, or mixtures thereof.

[0210] Solid carriers/diluents include, but are not limited to, a gum, a starch (e.g, corn starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcry stalline cellulose), an acrylate (e.g, polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.

Oral and Parenteral Administration

[0211] In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like. For solid oral preparations such as, powders, capsules, and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Due to their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, tablets may be sugar coated or enteric coated by standard techniques.

[0212] For parenteral formulations, the carrier will usually comprise sterile water, though other ingredients may be included, such as ingredients that aid solubility or for preservation. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed.

[0213] In some applications, it may be advantageous to utilize the active agent in a “vectorized” form, such as by encapsulation of the active agent in a liposome or other encapsulant medium, or by fixation of the active agent, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.

[0214] Methods of treatment using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient. Optionally, a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught.

[0215] A tablet may be made by compression or molding, or wet granulation, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with, for example, a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent. Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.

[0216] A syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s). Such accessory ingredients) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.

[0217] Formulations suitable for parenteral administration may comprise a sterile aqueous preparation of the active compound, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form.

[0218] Parenteral administration may comprise any suitable form of systemic delivery. Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, mtra -abdominal (e.g, intraperitoneal), etc., and may be effected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired admini strati on modal ity .

[0219] Nasal and other mucosal spray formulations (e.g., inhalable forms) can comprise purified aqueous solutions of the active compounds with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes. Alternatively, they can be in the form of finely divided solid powders suspended in a gas carrier. Such formulations may be delivered by any suitable means or method, e.g., by nebulizer, atomizer, metered dose inhaler, or the like.

[0220] Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.

[0221] Transdennal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.

[0222] In addition to the aforementioned ingredients, formulations of this disclosure may further include one or more ingredient selected from diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.

[0223] The formulations may be of immediate release, sustained release, delayed-onset release or any other release profile known to one skilled in the art.

[0224] For administration to mammals, and particularly humans, it is expected that the physician wall determine the actual dosage and duration of treatment. For administration to mammals, and particularly humans, it is expected that the physician will determine the actual dosage and duration of treatment, which wiil be most suitable for an individual and can vary with the age, weight, genetics and/or response of the particular individual.

[0225] The methods of the disclosure comprise administration of a compound at a therapeutically effective amount. The theraperutically effective amount may include various dosages.

[0226] In one embodiment, a compound of this disclosure is administered at a dosage of 1-3000 mg per day. In additional embodiments, a compound of this disclosure is administered at a dose of 1 -10 mg per day, 3-26 mg per day, 3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 10-26 mg per day, 15-60 mg per day, 50-100 mg per day, 50-200 mg per day, 100-250 mg per day, 125-300 mg per day, 20-50 mg per day, 5-50 mg per day, 200-500 mg per day, 125-500 mg per day, 500-1000 mg per day, 200-1000 mg per day, 1000-2000 mg per day, 1000-3000 mg per day, 125-3000 mg per day, 2000-3000 mg per day, 300-1500 mg per day or 100-1000 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 25 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 40 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 50 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 67.5 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 75 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 80 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 100 mg per day.

In one embodiment, a compound of this disclosure is administered at a dosage of 125 mg per day.

In one embodiment, a compound of this disclosure is administered at a dosage of 250 mg per day.

In one embodiment, a compound of this disclosure is administered at a dosage of 300 mg per day.

In one embodiment, a compound of this disclosure is administered at a dosage of 500 mg per day.

In one embodiment, a compound of this disclosure is administered at a dosage of 600 mg per day.

In one embodiment, a compound of this disclosure is administered at a dosage of 1000 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 1500 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 2000 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 2500 mg per day. In one embodiment, a compound of this disclosure is administered at a dosage of 3000 mg per day. [0227] The methods may comprise administering a compound at various dosages. For example, the compound may be administered at a dosage of 3 mg, 10 mg, 30 mg, 40 mg, 50 mg, 80 mg, 100 mg, 120 mg, 125 mg, 200 mg, 250 mg, 300 mg, 450 mg, 500 mg, 600 mg, 900 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg or 3000 mg.

[0228] Alternatively, the compound may be administered at a dosage of 0.1 mg/kg/day. The compound may administered at a dosage between 0.2 to 30 mg/kg/day, or 0.2 mg/kg/day, 0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, 50 mg/kg/day or 100 mg/kg/day.

[0229] The pharmaceutical composition may be a solid dosage form, a solution, or a transdermal patch. Solid dosage forms include, but are not limited to, tablets and capsules.

[0230] The following examples are presented in order to more fully illustrate the preferred embodiments of the disclosure. They should in no way, however, be construed as limiting the broad scope of the disclosure.

EXAMPLES

EXAMPLE 1

Synthesis of SARDs

Synthetic Scheme for l-(3-(4-Cvano-3-(trifluoromethyr)phenoxy)-2-hvdroxy-2-methyl propyl)-lH- pyrazole-4-carbonitrile - CPD. 9

4-((2-methylallyl)oxy)-2-(trifhioromethyl)benzordtrile (C12H10F3JNQ) - CPD. 10

[0231] To a solution of 4-hydroxy-2-(trifluoromethyl)benzonitrile (0.55g, 0.0029393mol) and K2CO3 (1.22g, 0.0088179mol) in lOmL of dry 2-butanone was added 3- bromo-2-methylprop-l-ene (0.60g, 0.00409mol). The resulting mixture was stirred for overnight under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and reduced volume under vacuum. The product was purified by a silica gel column using DCM as eluent to afford 0.685g (96.6%) of the titled compound as colorless oil. [0232] 1HNMR (400MHz, DMSO-d6) 5 8.10(d, J=8.4Hz, 1H, ArH), 7.52(d, J=2.4Hz, 1H, ArH), 7.44(dd, J=8.4Hz, J=2.4Hz, 1H, ArH), 5.07(s, 1H, CH=C), 5.00(s, 1H, CH=C), 4.69(s, 2H, CH2), 1.706(s, 3H, CH3).

[0233] Mass (ESI, Positive): [M+H]+.

[0234] Mass (ESI, Positive): [M+H]+.

[0235] HRMS [C12H11F3N2O+]: calcd 242.0793 found 242.0793 [M+H]+. Purity: 98.29% (HPLC).

[0236] HRMS [C 12H9F3N2O-]: calcd 240.0636 found 240.0624 [M H ]- Purity: 98.29% (HPLC).

4-((2-methyIoxiran-2-yl)methoxy)-2-(trif]uoromethy])benzo nitrile (C 12H10F3NQ2) - CPD. 43

[0237] To a solution of 4-((2-methylallyl)oxy)-2-(trifluoromethyl)benzonitrile (0.65g, 0.0026974mol) in lOmL of dry DCM was added 3-chlorobenzoperoxoic acid (mCPBA, 0.93g, 0.0053895moi). The resulting mixture was stirred for overnight under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and reduced volume under vacuum. The product was purified by a silica gel column using DCM as eluent to afford 0.68g (98.5%) of the titled compound as white solid.

: HNMR (400MHZ, DMSO-de) 5 8.11 (d, J=8.8Hz, 1H, ArH), 7.54(d, J=2.4Hz, 1H, ArH), 7.46(dd, J=8.8Hz, J=2.4Hz, 1H, ArH), 4.43(d, J 9. H E. 1 H, CH Cg 4.10(d, J 9.1 Hz. 1H, CH=C), 2.83(d, J=4.8Hz, 1H, CH), 2.50(d, J=4.8Hz, 1H, CH), 1 ,38(s, 3H, CH ₃ ).

[0239] Mass (ESI, Positive): [ M H ]

[0240] HRMS [CI ₂ HIIF3NO ₂ ⁺ ]: calcd 258.0742 found 258.0742 [M+H] ⁺ . Purity: 90.73% (HPLC).

[0241] HRMS [C 12H9F3NO2 "]: calcd 256.0585 found 256.0585 [M+H]“. Purity: 90.73% (HPLC). l-(3-(4-cyano-3-(trifluoromethyl)phenoxy)-2-hydroxy-2-methyl propyl)-lH-pyrazo1e-4- carbonitrile (C16H13F3N4O2) - CPD. 9

[0242] To a solution of 1 H-pyrazole-4-carbonitrile (0.136g, 0.0014578mol) in anhydrous THF (lOmL), which was cooled in an ice water bath under an argon atmosphere, was added sodium hydride (60% dispersion in oil, 0.078g, 0.0019438mol). After addition, the resulting mixture was stirred for three hours. 4-((2-methyloxiran-2-yl)methoxy)-2- (trifluoromethyl) benzonitrile (0.25g, 0.0009719mol) was added to above solution, and the resulting reaction mixture was stirred overnight at room temperature under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The product was purified by a silica gel column using hexanes and ethyl acetate (1:1) as eluent to afford 0.224g (65.9%) of the titled compound as off-white oil.

[0243] ^! HNMR (400MHZ, DMSO-de) 6 8.48(s, 1H, Pyrazole-H), 8. 12(d, J=8.2Hz, 1H, ArH), 8.05(s, 1H, Pyrazole-H), 7.51(d, J=2.4Hz, 1H, ArH), 7.44(dd, J=8.4Hz, J=2.4Hz, ArH), 5.40(s, 1H, OH), 4.35(s, 2H, CH ₂ ), 3.99-3.94(m, 2H, ('l l.’).. 1.16(s, 3H, ( f l -)

[0244] Mass (ESI, Positive): I X I 11 ] .

[0245] HRMS [C16H15F3N5O ⁺ ]: calcd 351.1069 found [M+H] ⁺ . Purity: 98.30% (HPLC).

[0246] HRMS [CieHnFsNsO’]: calcd 349.0912 found 349.0912 [M+H]“. Purity: 98.30% (HPLC).

Synthetic Scheme for 4-(3-(4-cyanophenoxy)-2-hydroxy-2-methylpropoxy)-2- (trifluoromethyl)benzonitrile (C19H15F3N2O3) - CPD. 44

4-(3-(4-cvanophenoxy)-2-hvdroxy-2-methylpropoxy)-2-(trifl uoromethyl)benzonitrile

(C19H15F3N2O3) - CPD. 44

[0247] A solution of 4-((2-methyloxiran-2-yl)methoxy)-2-

(trifluoromethyl)benzonitrile (0.20g, 0.0007776mol), 4-cyanophenol (0.111g, 0.000933 Imoi), and potassium carbonate (0.215g, 0.0015552mol) in 10ml of 2-butanone was heated at reflux for 12 hours under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The product was purified by a silica gel column using DCM and ethyl acetate (19: 1) as eluent to afford 0.23g (79.3%) of the titled compound as yellowish solid.

[0248] T INMR (400MHz, DMSO-ds) 3 8.09(d, J=8.4Hz, 1H, ArH), 7.76-7.73(m, 2H,

Ari l). 7.51(d, J=2.4Hz, I I I. ArH), 7.46(dd, J=8.4Hz, J=2.4Hz, 1H, ArH), 7.14-7.1 l(m, 2H, ArH), 5.32(s, 1H, OH), 4.19-4.12(m, 2H, CH:j. 4.09(d, .1 9.611:.-. 1H, CH), 4.02(d, ,1 9.6Hz. 1H, CH), 1.32(s, 3H, CM ).

[0249] Mass (ESI, Positive): [ M H ] ,

[0250] HRMS [CwHuFsNzOid]: calcd 377.1113, found 377.1105 [M+H] ⁺ Purity: 97.19% (HPLC). Synthetic scheme for Methyl 2-(((l-(4-cyano-lH-pyrazol-l-yl)-3-(4-cvano-3-

(trifluoromethyl)phenoxy)-2-methylpropan-2-yl)oxy)methyl) acrylate (C21H19F3N4O4) - CPD.

45

Methyl 2-(((l-(4-cvano-lH-pyrazol-1-vl)-3-(4-cyano-3-(trifluorometh yl)phenoxv)-2- methylpropan-2-yl)oxY)methyl)acrylate (C21H19F3N4O4) - CPD. 45

[0251] To a solution of 4-(3-(4~cyanophenoxy)-2-hydroxy-2-methylpropoxy)-2- (tnfluoromethyl)benzomtrile (0.20g, 0.000571 mol) in anhydrous THF (5mL), which was cooled in an ice water bath under an argon atmosphere, was added sodium hydride (60% dispersion in oil, 0.046g, 0.0011418moi). After addition, the resulting mixture was stirred for three hours. Methyl 2- (bromomethyl)acrylate (0.307g, 0.0017128niol) was added to above solution, and the resulting reaction mixture was stirred overnight at room temperature under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The product was purified by a silica gel column using DCM and ethyl acetate (19: 1 to 9: 1) as eluent to afford 30mg (11.7%) of the titled compound as off-white oil.

[0252] ’HNMR (400MHz, DMSO-de) 8 8.47(s, 1H, Pyrazole-H), 8. 13(d, J=8.4Hz, 1H, ArH), 8.06(s, 1H, Pyrazole-H), 7.55(d, J=2.4Hz, 1H, ArH), 7.45(dd, J=8.4Hz, J=2.4Hz, 1H), 6.13(d, J=1.2Hz, 1H, CH=C), 5.80(d, J=2.0Hz, 1H, CH=C), 4.49(s, 2H, CH ₂ ), 4.26-4.23(m, 1H, CH), 4.15-4. 12(m„ 1H, CH), 3.74-3.71 (m, 2H, CH ₂ ), 3.68(s, 3H,OCH ₃ ), 1.26(s, 3H, CH ₃ ).

[0253] Mass (ESI, Positive): i A I • 11 ] .

[0254] HRMS [CEiIhoFsN-iO-C]: calcd 449.1437, found 449.1440 [M+Hf. Purity; 91.39% (HPLC).

Synthetic scheme for l-(3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2- methy1propyl)- lH-pyrazole-4-carbonitrile (C16H14F3N5O) - CPD. 13

4-((2-methylallyl)amino)-2-(trif3uoromethyl)benzonitrile (C12H11F3N2) - CPD. 46

[0255] To a solution of 4-amino-2-(trifluoromethyl)benzonitrile (0.50g, 0.0026862mol) and K2CO3 (1.12g, 0.0080586mol) in lOmL of dry acetonitrile was added 3- bromo-2-methylprop-l-ene (0.54g, 0.0040293mol). The resulting mixture was heated at reflux for overnight under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and reduced volume under vacuum. The product was purified by a silica gel column using hexanes and ethyl acetate (3:1) as eluent to afford 0.44g (68.2%) of the titled compound as oil.

[0256] ⁱ I iN.MR (400MHz. DMSO-de) 8 7.71 (d, ,1 8.2Hz. 1H, ArH), 7.53(t, J=6.4Hz, 1H, NH), 7.01(d, J=1.6Hz, 1H, ArH), 6.80(d, J 8.2Hz, H I. ArH), 4.84(d. .1 =1.2Hz, 2H, CH ₂ =C), 3.75(d, J 6.0Hz. 2H, C1 H. 1.70(s, 3H, CH A

[0257] Mass (ESI, Positive): [ M H ]

[0258] HRMS [ C 1 ₂ H i 0F3N ₂ " ] : calcd 239.0796 found 239.0795 [ M-H ]". Purity

4-(((2-methyloxiran-2-yl)methyl)amino)-2-(trifluoromethyl )benzonitrile (C12H11F3N2O)

- CPD. 47

[0259] To a solution of 4-((2-methylallyl)ammo)-2-(trifluoromethyl)benzonitrile (0.44g, 0.0018316moi) in lOmL of dry DCM was added 3-chlorobenzoperoxoic acid (mCPBA, 0.63g, 0.0036632mol). The resulting mixture was stirred for overnight under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and reduced volume under vacuum. The product was purified by a silica gel column using DCM and ethyl acetate (98:2) as eluent to afford 0.29g (61.7%) of the titled compound as colorless oil.

[0260] ^! HNMR (400MHz. DMSO-de) 8 7.72(d, .1 8.2Hz. 1H, ArH), 7.53(t, J=6.4Hz, 1H, NH), 7.1 l(d, J 2.0Hz. 1H, ArH), 6.93(dd, J =8.2Hz, J=2.0Hz, ArH), 3.51-3.46(m, 1H, CH), 3.27-3.22(m, 1H, CH), 2.66(d, J 6.0Hz. 1H, CH), 2.61 (d, J=6.0Hz, 1H, CH), 1.28(s, 3H, CH ₃ ).

[0261] Mass (ESI, Positive): i M H |

[0262] HRMS [C12H13F3N2O ⁺ ]: calcd 257.0902 found [M+H] ⁺ . Purity: % (HPLC).

[0263] HRMS [C12H11F3N2O "]: calcd 255.0745 found 255.0748 [M-H]’. Purity: 97.67

% (HPEC),

1 -(3-((4-c\ ^, ano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methy lpropYl)-1H- pyrazole-4 -carbonitrile (C16H14F3N5O) - CPD. 13

[0264] To a solution of lH-pyrazole-4-carbonitrile (0.093g, 0.0009757mol) in anhydrous THF (lOmL), which was cooled in an ice water bath under an argon atmosphere, was added sodium hydride (60% dispersion in oil, 0.117g, 0.003 mol). After addition, the resulting mixture was stirred for three hours. 4-(((2-methyloxiran-2-yl)methyl)amino)-2- (trifluoromethyl)benzonitrile (0.25g, 0.0009757mol) was added to above solution, and the resulting reaction mixture was stirred overnight at room temperature under argon. The reaction was quenched by water, extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The product was purified by a silica gel column using DCM and methanol (19:1 to 9:1) as eluent to afford 0.22g (6-4.7%) of the titled compound as off-white oil.

[0265] T-INMR (400MHz, DMSO-de) 5 8.45(s, 1H, Pyrazole-H), 8.07(s, 1H, Pyrazole- 1 1). 7.71 (d, J 8.21 iz. HI, ArH), 7.53(8. J 641 Iz. H i. XI I) 7.20-7.18(m, 2H, M l ArH), 6.95(dd, J 8.41 lz. .1 2.0Hz. ArH), 5.16(s, 1H, OH), 4.27-4.23(m, 2H, CTb), 3.20-3.16(m, 2H, CH ₂ ), 1.05(s, 3H, CIL).

[0266] Mass (ESI, Positive): [M+H] ⁺ .

[0267] HRMS i CM I rl+X T) j: calcd 350.1129 found [M+Hf. Purity: % (HPLC).

[0268] HRMS [CMHisFiNsO’]: calcd 348.1072 found 348.1089[M+H]'. Purity: 87.63% (HPLC).

EXAMPLE 2

Octanol-Water Partition Coefficient (Log P)

[0269] Log P is the log of the octanol-water partition coefficient, commonly used early in drug discovery efforts as a rough estimate of whether a particular molecule is likely to cross biological membranes. Log P was calculated using ChemDraw Ultra version is 12.0.2.1016 (Perkin-Elmer, Waltham, Massachusetts 02-451). Calculated Log P values are reported in Table 1 in the column labeled ‘Log P (-0.-4 to +5.6)’, Lipinski’s rule of five is a set of criteria intended to predict oral bioavailability. One of these criteria for oral bioavailability is that the Log P is between the values shown in the column heading (“0.4 (relatively hydrophilic) to +5.6 (relatively lipophilic) range), or more generally stated <5. The compounds tested exhibit acceptable water solubility.

EXAMPLE 3

Transactivation Assay

[0270] Methods: HEK-293 cells were transfected with the indicated receptors and GRE-LUC and CMV-renilla luc. Cells were treated 24 hours after transfection and luciferase assay performed 48 hours after transfection. The SARD compounds did not inhibit transactivation of receptors other than AR until 10 pM. The experimental method is described below,

[0271] Human AR was cloned into a CMV vector backbone and was used for the transactivation study. HEK-293 cells were plated at 120,000 cells per well of a 24 well plate in DME + 5% csFBS. The cells were transfected using Lipofectamine (Invitrogen, Carlsbad, CA) with 0.25 pg GRE-LUC, 0.01 pg CMV-LUC (renilla luciferase) and 25 ng of the AR The cells were treated 24 h after transfection and the luciferase assay performed 48 h after transfection. Transactivation results were based on measured luciferase light emissions and reported as relative light unit intensity' (RLU). The assay was run in antagonist mode (ICso) using known agonist R1881 at its ECso concentration of 0. 1 Nm and increasing concentrations of SARDs of this disclosure. Antagonist data are represented as ICso (Nm) obtained from four parameter logistics curve and are reported in Table 1 in the column labeled ‘ICso’.

[0272] Results'. In vivo pharmacodynamics demonstrate potent and highly efficacious antagonism of androgen dependent tissues.

EXAMPLE 4

Human Androgen Receptor (Har) Ligand Binding Domain (LBD) Affinity Assay

[0273] Methods: Har-LBD (633-919) was cloned into pGex4t.1. Large scale GST- tagged AR-LBD was prepared and purified using a GST column. Recombinant AR-LBD was combined with [ ³ H]mibolerone (PerkmElmer, Waltham, MA) in buffer A (10 Mm Tris, Ph 7.4, 1.5 Mm disodium EDTA, 0.25 sucrose, 10 Mm sodium molybdate, 1 Mm PMSF) to determine the equilibrium dissociation constant (Ka) of [’H]mibolerone. Protein was incubated with increasing concentrations of [ ³ H]mibolerone with and without a high concentration of unlabeled mibolerone at 4°C for 18 h in order to determine total and non-specific binding. Non-specific binding was then subtracted from total binding to determine specific binding and non-linear regression for the ligand binding curve with one site saturation was used to determine the Kd of mibolerone.

[0274] Increasing concentrations of SARDs or DHT (range: 10' ^!2 to 10’ ⁴ M) were incubated with [ ^J H]mibolerone and AR-LBD using the conditions described above. Following incubation, the ligand bound AR-LBD complex was isolated using BiogelHT hydroxyapatite, washed and counted in a scintillation counter after adding scintillation cocktail.

[0275] Results: The results of this assay are reported as Ki values (Nm) inTable 1.

EXAMPLE 5

In Vitro Assays to Determine SARD Activity

[0276] LNCaP or ADI androgen receptor degradation (fill! length AR): The compounds were tested for their effect on full length AR protein expression.

[0277] Methods: LNCaP or ADI cells expressing full length AR were plated at 750,000-1 ,000,000 cells/well of a 6 well plate in growth medium (RPMI + 10% FBS). Twenty four hours after plating, the medium was changed to RPMI + 1% csFBS without phenol red and maintained in this medium for 2 days. The medium again was changed to RPMI + 1% csFBS without phenol red and cells were treated with SARDs (1 Nm to 10 Mm) in combination with 0.1 Nm R1881. After 24 h of treatment, cells were washed with cold PBS and harvested. Protein was extracted using salt-containing lysis buffer with three freeze-thaw cycles. The protein concentration was estimated and five microgram of total protein was loaded on a SDS-PAGE, fractionated, and transferred to a PVDF membrane. The membrane was probed with AR N-20 antibody (SantaCruz Biotechnology, Inc., Dallas, Texas 75220) and actin antibody (Sigma-Aldrich, St. Louis, MO).

[0278] Results: Degradation in LNCaP or ADI cells are reported in Table 1 in the column labeled ‘Full Length % Inhibition at 1, 10 uM’.

[0279] 22RV1 or I)567es androgen receptor degradation (splice variant (S.V.)

AR): The effect of SARD treatment on the AR levels was measured in androgen-refractory 22RV- 1 or D567es prostate cancer cells.

[0280] Methods: 22RV1 or D567es cells expressing AR splice variants were plated at 750,000-1,000,000 cells/well of a 6 well plate in growth medium (RPMI + 10% FBS). Twenty four hours after plating, medium was changed and treated. After 24-30 h of treatment, cells were washed with cold PBS and harvested. Protein was extracted using salt-containing lysis buffer with three freeze-thaw cycles. Protein concentration was estimated and five microgram of total protein was loaded on a SDS-PAGE, fractionated, and transferred to a PVDF membrane. The membrane was probed with AR N-20 antibody (Santa Cruz Biotechnology, Inc., Dallas, Texas 75220) and actin antibody (Sigma -Aid rich, St. Louis, MO).

[0281] Results’. Degradation in 22RV1 or D567es cells are reported in Table 1 in the column labeled “S.V. % inhibition at 10 μM.”

EXAMPLE 6

Metabolism Studies with Mouse Liver Microsomes (DMPK (MLM)) -

Metabolic stability in Phase I & Phase II pathways

[0282] In this assay, the test compound was incubated with liver microsomes and disappearance of drug was determined using discovery grade LC-MS/MS. To simulate Phase II metabolic pathway (glucuronidation), UDPGA and alamethicin were included in the assay. From %PCR (% Parent Compound Remaining), rate of compound disappearance is determined (slope of concentration vs. time plot) and in vitro CLint (pl/min/mg protein) was calculated.

[0283] Results’. The results of this assay utilizing mouse liver microsomes (MLM) are reported in Table 1 in the column labeled “DMPK (MLM) T1/2 (min) & CLint (uL/min/mg)”. The first value is the calculated half-life (T1/2) of the test article in MLM expressed in minutes and the 2 ^nd value is the intrinsic CL (CLint) of the test article in MLM expressed as Ml/mm/mg protein.

LC-MS/MS analysis

[0284] The analysis of the compounds tinder investigation was performed using LC- MS/MS system consisting of Agilent 1100 HPLC with an MDS/Sciex 4000 Q-Trap™ mass spectrometer. The separation was achieved using a Cis analytical column (Alltima™, 2.1 X 100 mm, 3 pm) protected by a Cis guard cartridge system (SecuntyGuard™ ULTRA Cartridges UHPL.C for 4.6 mm ID columns, Phenomenex). Mobile phase was consisting of channel A (95% acetonitrile + 5% water + 0,1 % formic acid) and channel C (95% water + 5% acetonitrile + 0.1% formic acid) and was delivered at a flow rate of 0.4 Ml/min. The volume ratio of acetonitrile and water was optimized for each of the analytes. Multiple reaction monitoring scans were made with curtain gas, collision gas, nebulizer gas, and auxiliary gas optimized for each compound, and source temperature at 55O°C. Molecular ions were formed using an ion spray voltage of -4200 V (negative mode). Declustering potential, entrance potential, collision energy, product ion mass, and cell exit potential were optimized for each compound.

[0285] While the disclosure has been illustrated and described in detail in the foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. The disclosure is not limited to the disclosed embodiments. Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed disclosure, from a study of the drawings, the disclosure and the appended claims.

[0286] All references cited herein are incorporated herein by reference in their entirety. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

[0287] Unless otherwise defined, all terms (including technical and scientific terms) are to be given their ordinary and customary meaning to a person of ordinary skill in the art, and are not to be limited to a special or customized meaning unless expressly so defined herein. It should be noted that the use of particular terminology when describing certain features or aspects of the disclosure should not be taken to imply that the terminology is being re-defined herein to be restricted to include any specific characteristics of the features or aspects of the disclosure with which that terminology is associated. Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as ‘known’, ‘normal’, ‘standard’, and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead should be read to encompass known, normal, or standard technologies that may be available or known now or at any time in the future; and use of terms like ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the disclosure, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the disclosure. Likewise, a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise. Similarly, a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or’ unless expressly stated otherwise.

[0288] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments. Roman numerals and Arabic numerals can be used interchangeably.

[0289] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0290] It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory’ phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and/or “an” should typically be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, typically means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc,” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc. ). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0291] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term ‘about.’ Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0292] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it is apparent to those skilled in the art that certain changes and modifications may be practiced. Therefore, the description and examples should not be construed as limiting the scope of the disclosure to the specific embodiments and examples described herein, but rather to also cover all modification and alternatives coming with the true scope and spirit of the disclosure.