Treatment of prostate cancer having androgen receptor variants

Abstract

Disclosed herein are methods of treating prostate cancer in a subject in need thereof, wherein the prostate cancer in the subjects expresses one or more androgen receptor splice variants lacking the ligand binding domain, including AR-V7.

Description

TREATMENT OF PROSTATE CANCER HAVING ANDROGEN RECEPTOR VARIANTS CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No.63 / 386,031 filed December 5, 2022 and U.S. Provisional Application Serial No.63 / 501,299 filed May 10, 2023; which are hereby incorporated by reference in their entirety. BACKGROUND OF THE INVENTION

[0002] It is estimated that in the United States there are about 288,300 new cases of prostate cancer diagnosed annually, and about 34,700 deaths from prostate cancer occur annually. Despite advances in available therapies for subjects having prostate cancer, there remains a need to develop new therapies and new regimens for the treatment of prostate cancer, including new treatments and regimens that will result in preventing the development of, or slowing the progress of, prostate cancer that is resistant to existing treatments and treatment regimens.

[0003] Prostate cancer is the second leading cause of cancer-related death in men in the US. Androgen deprivation therapy (ADT) and blockade are commonly used to treat prostate cancer. However, relapse occurs with subsequent progression to metastatic castration-resistant prostate cancer (mCRPC) after treatment with androgen biosynthesis inhibitors or androgen receptor (AR) antagonists through multiple acquired resistance mechanisms. These resistance mechanisms can be AR-dependent mechanisms including AR amplification, somatic AR point mutations, AR structural rearrangements or splice variants, or intra- tumoral androgen production.

[0004] The prevalence of genomic AR alterations increases over the course of prostate cancer treatment. The vast majority (98%) of primary prostate tumors are wildtype for AR (source: The Cancer Genome Atlas, Cell 2015). In a cohort of metastatic hormone sensitive prostate cancer (mHSPC, Stopsack et al, Clin Cancer Res 2020), the prevalence of AR-wildtype prostate tumors decreased from 98% before treatment to 79% after ADT. In the metastatic castrate-resistant prostate cancer (mCRPC) setting after tumors have developed resistance to ADT, 45% of tumors naïve for treatment with an antiandrogen agent were wildtype for AR, and this number further decreased to 25% after exposure to antiandrogen agents in the SU2C mCRPC cohort (source: Stand Up To Cancer; Dan et al, Cell 2015; Abida et al, PNAS 2019). In the ADT-resistant, abiraterone / enzalutamide-naïve mCRPC cohort (45% AR wildtype), AR alterations included AR amplification (26%), AR splice variant AR-V7 (11%) and somatic AR mutations (18%). Once exposed to abiraterone or enzalutamide (25% AR wildtype), the prevalence of AR amplification increased to 36% and AR splice variant AR-V7 to 20%.

[0005] AR structural rearrangements or splice variants are more frequently observed in patients after progressing on antiandrogen therapy compared to patients during earlier lines of therapy (e.g., Li et al, Clin Cancer Res 2020). Many of the AR splice variants observed to be expressed in subjects having prostate cancer lack the ligand binding domain of the AR protein. The expression of an androgen receptor protein variant lacking the ligand binding domain in subjects having prostate cancer is a poor prognostic factor and aresistance factor to multiple AR-targeted therapies, most extensively demonstrated for subjects that have been administered abiraterone and / or enzalutamide. AR splice variant AR-V7 is the most abundant AR splice variant lacking the ligand binding domain that is detected in circulating tumor cells from CRPC patients. In preclinical studies, AR-V7 expression increased when cells were cultured in androgen-depleted media, reflecting CPRC, and AR-V7 promoted cell growth (Guo et al, Cancer Res 2009). Also, knocking down AR- V7 in AR-V7 expressing in vivo xenografts improved antitumor activity achieved with enzalutamide, and AR-V7 expression increased in LNCaP xenografts that developed acquired resistance to enzalutamide (Cao et al, Oncotarget 2014). Other AR splice variants such as AR-V1, AR-V3, AR-V4, AR-V9 and AR-V567es are less prevalent, with clinical data based on fewer cohorts. In a cohort of 78 mCRPC patients, high concordance was observed between AR-V7 and AR-V9 expression (Fettke et al, Eur Urology 2020). Detected AR splice variants in circulating tumor cells in prostate cancer patients were primarily AR-V7 or AR-V567es, and at a lesser prevalence AR-V1, AR-V3 or AR-V4 (Miyamoto et al, Science 2015). In a cohort of 13 treatment-naïve patients and 25 patients treated with abiraterone or enzalutamide, AR-V7 and AR-V567es were enriched in the treated group (68% and 30%), and AR-V567es typically co-occurred with AR-V7 (8 out of 9) (Liu et al, J Urology 2016). Clinically, patients with AR-V7 positive prostate tumors have a significantly lower prostate-specific antigen (PSA) response rate, progression free survival and overall survival compared to AR-V7 negative patients, consistently observed across independent cohorts and studies, for both enzalutamide and abiraterone (Li et al, Eur Urology Focus 2018). As an example, in a cohort of mCRPC patients who were beginning standard-of-care treatment with enzalutamide or abiraterone, a 0% PSA response rate and significantly shortened PSA progression free survival was observed in AR-V7 positive compared to AR-V7 negative patients (Antonarakis et al, NEJM 2014). Thus, there remains a need to discover and develop new methods of treating subjects having prostate cancer wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain, including AR-V7. SUMMARY OF THE INVENTION

[0006] Provided herein are methods of treating prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I)Formula (I) or a pharmaceutically acceptable salt thereof:wherein:represents a single or a double bond; Z is O or S; X is O, CR5, CR5OH, or C(R5)2, wherein: when X is O, is a single bond; when X is C(R5)2, is a single bond; when X is CR5OH, is a single bond; or when X is CR5, is a double bond; R1is aryl, heteroaryl, L-cycloalkyl, -N(R5)heterocyclyl, or L-heterocyclyl, wherein the aryl, the heteroaryl or the cyclyl portion of the L-cycloalkyl, -N(R5)heterocyclyl, or L-heterocyclyl is optionally substituted with one or more R4; R2is cyano, -COOR5, -C(O)N(R5)2, or -C(O)N(R5)2 wherein each R5taken together with the nitrogen atom to which they are attached form a 5 - 8 membered heterocyclic ring optionally substituted with one or more R4; each R3is independently C1-C3 alkyl or halogen; each R4is independently oxo, cyano, halogen, -PO3(C1-C3 alkyl)2, hydroxyl, alkoxy, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR5, -Y2-haloalkyl, -Y1-C1-C6 alkyl, -Y2-C1-C6 alkyl, -L-cycloalkyl, -L- heteroaryl, -L-heterocyclyl, -Y1-heterocyclyl, -Y2-heterocyclyl, -L-N(R5)2, -O-L-N(R5)2, -C(CF3)N(R5)2, -Y1- N(R5)2, -Y2-N(R5)2 wherein the ring portion of the aralkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl or - Y1-heterocyclyl is optionally substituted with one or more R7; L is a bond or C1-C4 alkylene; Y1is a bond, -C(O)-, or -NHC(O)-; Y2is a bond, -S-, -SO-, -SO2-, or -NR5SO2-, each R5is hydrogen or C1-C3 alkyl; R6is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R7is oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L- N(R5)2, C1-C6 alkyl, or -Y1-heterocyclyl; and n is 1 or 2.

[0007] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject having prostate cancer in combination with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is an androgen receptor inhibitor or a CYP17 inhibitor. In some embodiments, the one or more additional therapeutic agents is an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the one or more additional therapeutic agents is a CYP17 inhibitor. In some embodiments, the CYP17 inhibitor is abiraterone. In some embodiments, the CYP17 inhibitor is abiraterone acetate. In some embodiments, the compound of Formula(I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor or a CYP17 inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered enzalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered apalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered darolutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered a CYP17 inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone acetate. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide.. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered enzalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered apalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered darolutamide. In some embodiments, the prostate cancer in the subject is selected fromtreatment-naïve prostate cancer, hormone-sensitive prostate cancer, castrate-resistant prostate cancer, metastatic prostate cancer, non-metastatic prostate cancer, and metastatic castrate-resistant prostate cancer. In some embodiments, the prostate cancer is treatment naïve prostate cancer. In some embodiments, the prostate cancer in the subject is hormone-sensitive prostate cancer. In some embodiments, the prostate cancer in the subject is castrate-resistant prostate cancer. In some embodiments, the prostate cancer in the subject is metastatic prostate cancer. In some embodiments, the prostate cancer in the subject is non-metastatic prostate cancer. In some embodiments, the prostate cancer in the subject is metastatic castrate-resistant prostate cancer.

[0008] Provided herein are methods of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I)Formula (I) or a pharmaceutically acceptable salt thereof: wherein:represents a single or a double bond; Z is O or S; X is O, CR5, CR5OH, or C(R5)2, wherein: when X is O, is a single bond; when X is C(R5)2,is a single bond; when X is CR5OH,is a single bond; or when X is CR5,is a double bond; R1is aryl, heteroaryl, L-cycloalkyl, -N(R5)heterocyclyl, or L-heterocyclyl, wherein the aryl, the heteroaryl or the cyclyl portion of the L-cycloalkyl, -N(R5)heterocyclyl, or L-heterocyclyl is optionally substituted with one or more R4; R2is cyano, -COOR5, -C(O)N(R5)2, or -C(O)N(R5)2wherein each R5taken together with the nitrogen atom to which they are attached form a 5 - 8 membered heterocyclic ring optionally substituted with one or more R4; each R3is independently C1-C3 alkyl or halogen; each R4is independently oxo, cyano, halogen, -PO3(C1-C3 alkyl)2, hydroxyl, alkoxy, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR5, -Y2-haloalkyl, -Y1-C1-C6 alkyl, -Y2-C1-C6 alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Y1-heterocyclyl, -Y2-heterocyclyl, -L-N(R5)2, -O-L-N(R5)2, -C(CF3)N(R5)2, -Y1- N(R5)2, -Y2-N(R5)2wherein the ring portion of the aralkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl or - Y1-heterocyclyl is optionally substituted with one or more R7; L is a bond or C1-C4alkylene; Y1is a bond, -C(O)-, or -NHC(O)-; Y2is a bond, -S-, -SO-, -SO2-, or -NR5SO2-, each R5is hydrogen or C1-C3alkyl; R6is hydrogen, C1-C3alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R7is oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L- N(R5)2, C1-C6 alkyl, or -Y1-heterocyclyl; and n is 1 or 2.

[0009] In other embodiments are provided the methods disclosed herein, wherein in the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, Z is O. In other embodiments are provided the methods disclosed herein, wherein in the compounds of Formula (I) , or a pharmaceutically acceptable salt thereof, Z is S.

[0010] In other embodiments are provided the methods disclosed herein, wherein in the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, n is 1.

[0011] In other embodiments are provided the methods disclosed herein, wherein in the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, R2is cyano. In other embodiments, R2is -COOR5or -C(O)N(R5)2. In other embodiments, R2is -COOR5. In other embodiments, R2is -C(O)N(R5)2.

[0012] In other embodiments are provided the methods disclosed herein, wherein in the compounds of Formula (I) , or a pharmaceutically acceptable salt thereof, R3is halogen. In some embodiments R3is fluorine.

[0013] In other embodiments are provided the methods disclosed herein, wherein in the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, X is C(R5)2 and is a single bond. In other embodiments, X is CR5andis a double bond. In other embodiments, X is O and is a single bond.

[0014] In other embodiments are provided the methods disclosed herein, wherein in the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, R1is aryl optionally substituted with one or more R4. In some embodiments the aryl is phenyl optionally substituted with one or more R4. In other embodiments, the phenyl is substituted with one, two or three R4. In some embodiments the one, two or three R4are each independently halogen, -PO3(C1-C3alkyl)2, hydroxyl, hydroxyalkyl, aralkyl, haloalkyl, -COOR5, -Y1-C1-C6 alkyl, Y2-C1-C6 alkyl, -L-N(R5)2, -O-L-N(R5)2, -C(CF3)N(R5)2, -Y1-N(R5)2, -Y2-N(R5)2, Y2- haloalkyl, -L-heteroaryl, -L-heterocyclyl, or -Y1-heterocyclyl, wherein the heterocyclyl portion of the -L- heterocyclyl or -Y1-heterocyclyl is optionally substituted with one or more R7. In other embodiments, R4is - Y1-C1-C6alkyl and Y1is a bond and the C1-C6alkyl is methyl, ethyl, isopropyl, butyl or pentyl. In still other embodiments, R4is -Y2-C1-C6alkyl and Y2is a -SO2- and the C1-C6alkyl is methyl. In further embodiments,R4is -Y2-haloalkyl and Y2is -S- or -SO2- and the haloalkyl is trifluoromethyl. In further embodiments, R4is - L-N(R5)2and L is a bond and each R5is hydrogen, each R5is methyl or one R5is methyl and one R5is hydrogen. In other embodiments, R4is -L-N(R5)2and L is methylene or ethylene and each R5is hydrogen, each R5is methyl or one R5is methyl and one R5is hydrogen. In further embodiments, R4is -Y1-N(R5)2, Y1is -C(O)- and each R5independently is hydrogen, each R5is independently methyl or one R5is methyl and one R5is hydrogen. In other embodiments, R4is -Y2-N(R5)2, Y2is -SO2- and each R5independently is hydrogen, each R5is methyl or one R5is methyl and one R5is independently hydrogen. In still other embodiments, R4is -Y1-heterocyclyl and Y1is -C(O)- and the heterocyclyl portion of the L-heterocyclyl is piperazinyl or 4-methyl-piperazinyl. In other embodiments, R4is -L-heterocyclyl and L is a bond and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or 3ƛ2-azabicyclo[3.1.0]hexanyl, each optionally substituted with one or more R7selected from oxo, C1-C3 alkyl, alkoxy, hydroxyl, and halogen. In still further embodiments, R4is -L-heterocyclyl, wherein L is a methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl piperidinyl, each optionally substituted with one or more R7selected from C1-C3 alkyl, alkoxy, hydroxyl and halogen. Further embodiments provide R4is -Y1-heterocyclyl and Y1is -C(O)- and the heterocyclyl portion of the Y1-heterocyclyl is morpholinyl optionally substituted with one or more C1-C3 alkyl. In further embodiments, R4is -L-heteroaryl optionally substituted with one or more R7. In still further embodiments, the -L-heteroaryl is tetrazolyl. Further embodiments provide R4is -PO3(C1-C3 alkyl)2. In other embodiments, R4is -COOR5. Other embodiments provide R4is hydroxyalkyl. In yet other embodiments, R4is -O-L-N(R5)2. Further embodiments provide R4is aralkyl.

[0015] In other embodiments are provided the methods disclosed herein, wherein in the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, R1is heteroaryl optionally substituted with one or more R4. In further embodiments, heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, each optionally substituted with one or more R4. In further embodiments, the heteroaryl is substituted with one or more R4; wherein each R4is independently cyano, halogen, -Y1-C1-C6 alkyl, -Y2-C1-C6 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -L-cycloalkyl, -L-N(R5)2, -Y1-N(R5)2, -L-heteroaryl, -L-heterocyclyl, or -Y1- heterocyclyl, wherein the heteroaryl of the -L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl, or Y1-heterocyclyl is optionally substituted with one or more R7. In still further embodiments, the heteroaryl is pyrazolyl optionally substituted with one R4independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y1-C1-C6alkyl, -L-N(R5)2, L-heterocyclyl or L-heteroaryl, wherein the heteroaryl of the L- heteroaryl or the heterocyclyl portion of the L-heterocyclyl is optionally substituted with one or more R7. Further embodiments provide R4is -L-heteroaryl and L is methylene wherein the heteroaryl is pyridyl optional substituted with one or more R7. In yet further embodiments, R4is -L-heterocyclyl optionally substituted with one or more R7where L is a bond and the heterocyclyl portion of the L-heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl or 4-methylpiperazinyl. Still further embodimentsprovide R4is -L-heterocyclyl optionally substituted with one or more R7where L is methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl or 4-methylpiperazinyl. In further embodiments, R4is -L-N(R5)2where L is methylene and each R5is independently hydrogen, each R5is independently C1-C3alkyl or one R5is C1-C3alkyl and one R5is hydrogen. In yet other embodiments, R4is - Y1-C1-C6alkyl where Y1is a bond and the C1-C6alkyl is methyl, ethyl or isopropyl. In further embodiments, the heteroaryl is pyrazolyl optionally substituted with two R4groups each independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, and -Y1-C1-C6alkyl. Still other embodiments provide the heteroaryl is pyridyl optionally substituted with one R4independently selected from cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y1-C1-C6 alkyl, -L-N(R5)2, -Y1-N(R5)2, -L-cycloalkyl, or -L- heterocyclyl optionally substituted with one or more R7.

[0016] In other embodiments are provided the methods disclosed herein, wherein in the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, R1is -L-cycloalkyl optionally substituted with one or more R4.

[0017] In other embodiments are provided the methods disclosed herein, wherein in the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, R1is -L-heterocyclyl optionally substituted with one or more R4. In some embodiments, L is a bond and the heterocyclyl is piperidinyl or tetrahydropyranyl.

[0018] In other embodiments are provided the methods disclosed herein, wherein in the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, n is 2.

[0019] Also provided herein are methods of treating prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from the group consisting of:,, , , ,, andIn some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject having prostate cancer in combination with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is an androgen receptor inhibitor or a CYP17 inhibitor. In some embodiments, the one or more additional therapeutic agents is an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor isenzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the one or more additional therapeutic agents is a CYP17 inhibitor. In some embodiments, the CYP17 inhibitor is abiraterone. In some embodiments, the CYP17 inhibitor is abiraterone acetate. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor or a CYP17 inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered enzalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered apalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered darolutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered a CYP17 inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone acetate. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide.. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered enzalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or moreCYP17 inhibitors wherein the subject has not previously been administered apalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered darolutamide. In some embodiments, the prostate cancer in the subject is selected from treatment-naïve prostate cancer, hormone-sensitive prostate cancer, castrate-resistant prostate cancer, metastatic prostate cancer, non-metastatic prostate cancer, and metastatic castrate-resistant prostate cancer. In some embodiments, the prostate cancer is treatment naïve prostate cancer. In some embodiments, the prostate cancer in the subject is hormone-sensitive prostate cancer. In some embodiments, the prostate cancer in the subject is castrate-resistant prostate cancer. In some embodiments, the prostate cancer in the subject is metastatic prostate cancer. In some embodiments, the prostate cancer in the subject is non-metastatic prostate cancer. In some embodiments, the prostate cancer in the subject is metastatic castrate-resistant prostate cancer.

[0020] Also provided herein are methods of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from the group consisting of:,,,, and.

[0021] Further provided herein are methods of treating prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from the group consisting of:,, , , , , and or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject having prostate cancer in combination with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is an androgen receptor inhibitor or a CYP17 inhibitor. In some embodiments, the one or more additional therapeutic agents is an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the one or more additional therapeutic agents is a CYP17 inhibitor. In some embodiments, the CYP17 inhibitor is abiraterone. In some embodiments, the CYP17 inhibitor is abiraterone acetate. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor or a CYP17 inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, the compound ofFormula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered enzalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered apalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered darolutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered a CYP17 inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone acetate. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide.. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered enzalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered apalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered darolutamide. In some embodiments, the prostate cancer in the subject is selected from treatment-naïve prostate cancer, hormone- sensitive prostate cancer, castrate-resistant prostate cancer, metastatic prostate cancer, non-metastatic prostate cancer, and metastatic castrate-resistant prostate cancer. In some embodiments, the prostate cancer is treatment naïve prostate cancer. In some embodiments, the prostate cancer in the subject is hormone- sensitive prostate cancer. In some embodiments, the prostate cancer in the subject is castrate-resistant prostate cancer. In some embodiments, the prostate cancer in the subject is metastatic prostate cancer. Insome embodiments, the prostate cancer in the subject is non-metastatic prostate cancer. In some embodiments, the prostate cancer in the subject is metastatic castrate-resistant prostate cancer.

[0022] Further provided herein are methods of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from the group consisting of:,, , , , , and , or a pharmaceutically acceptable salt thereof.

[0023] In other embodiments are provided the methods disclosed herein, wherein the compound of Formula(Compound 1), or a pharmaceutically acceptable salt thereof.

[0024] In other embodiments are provided the methods disclosed herein, wherein the compound of Formula(Compound 2), or a pharmaceutically acceptable salt thereof.

[0025] In other embodiments are provided the methods disclosed herein, wherein the compound of Formula(Compound 3), or a pharmaceutically acceptable salt thereof.

[0026] In other embodiments are provided the methods disclosed herein, wherein the compound of Formula(Compound 4), or a pharmaceutically acceptable salt thereof.

[0027] Also provided herein are methods of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain, comprising administering to the subject a therapeutically effective amount of Compound 4:(Compound 4), or a pharmaceutically acceptable salt thereof, wherein Compound 4 is in crystalline form. Also provided herein are such methods wherein the crystalline form of Compound 4 is an anhydrous form. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 8.1º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 9.6º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.7º ± 0.2º 2-theta, 19.7º ± 0.2º 2-theta, and 22.0º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 9.8º ± 0.2º 2-theta, 15.2º ± 0.2º 2-theta, and 17.7º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of about 172 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 205 ºC to about 210 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 206 ºC to about 210 ºC, or from about 207 ºC to about 210 ºC, or from about 208 ºC to about 210 ºC, or from about 209 ºC to about 210 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 1% upon heating the sample from about 25 ºC to a temperature prior to melting. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 1% upon heating the sample from about 25 ºC to about 380 ºC.

[0028] Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 7.7º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 13.7º ± 0.2º 2-theta and 19.2º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5º ± 0.2º 2-theta, 8.6º ± 0.2º 2-theta, 15.9º ± 0.2º 2-theta, 19.9º ± 0.2º 2-theta, and 24.1º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x- ray powder diffraction (XRPD) pattern at 10.6º ± 0.2º 2-theta, 11.0º ± 0.2º 2-theta, 15.4º ± 0.2º 2-theta, 21.0º ± 0.2º 2-theta, and 26.3º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 ºC to about210 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 ºC to about 208 ºC, or from about 203 ºC to about 206 ºC, or from about 203 ºC to about 205 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 ºC to about 380 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 ºC to about 210 ºC.

[0029] Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 7.7º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further a peak in an x-ray powder diffraction (XRPD) pattern at 15.4º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further a peak in an x-ray powder diffraction (XRPD) pattern at 19.2º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 13.7º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5º ± 0.2º 2-theta, 8.6º ± 0.2º 2-theta, 15.9º ± 0.2º 2-theta, 19.9º ± 0.2º 2-theta, and 24.1º ± 0.2º 2- theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6º ± 0.2º 2-theta, 11.0º ± 0.2º 2-theta, 21.0º ± 0.2º 2-theta, and 26.3º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 ºC to about 210 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 206 ºC to about 210 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 ºC to about 208 ºC, or from about 203 ºC to about 206 ºC, or from about 203 ºC to about 205 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 ºC to about 380 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 ºC to about 210 ºC.

[0030] Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 7.7º ± 0.2º 2-theta and 15.4º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 19.2º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 13.7º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5º ± 0.2º 2-theta, 8.6º ± 0.2º 2- theta, 15.9º ± 0.2º 2-theta, 19.9º ± 0.2º 2-theta, and 24.1º ± 0.2º 2-theta. Also provided herein are suchmethods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6º ± 0.2º 2-theta, 11.0º ± 0.2º 2-theta, 21.0º ± 0.2º 2-theta, and 26.3º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 ºC to about 210 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 206 ºC to about 210 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 ºC to about 208 ºC, or from about 203 ºC to about 206 ºC, or from about 203 ºC to about 205 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 ºC to about 380 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 ºC to about 210 ºC.

[0031] Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 7.7º ± 0.2º 2-theta and 19.2º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 15.4º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 13.7º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5º ± 0.2º 2-theta, 8.6º ± 0.2º 2- theta, 15.9º ± 0.2º 2-theta, 19.9º ± 0.2º 2-theta, and 24.1º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6º ± 0.2º 2-theta, 11.0º ± 0.2º 2-theta, 21.0º ± 0.2º 2-theta, and 26.3º ± 0.2º 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 ºC to about 210 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 206 ºC to about 210 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 ºC to about 208 ºC, or from about 203 ºC to about 206 ºC, or from about 203 ºC to about 205 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 ºC to about 380 ºC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 ºC to about 210 ºC.

[0032] Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 10% degradation when stored at 25 ºC and 60% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 1%,or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 ºC and 60% relative humidity for at least 7 days.

[0033] Also provided herein are such methods wherein the crystalline form of Compound 4 (a) exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 8.1º ± 0.2º 2-theta, and (b) exhibits less than about 10% degradation when the crystalline form is stored at 25 ºC and 60% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Compound 4 (a) exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 9.6º ± 0.2º 2-theta, 5.7º ± 0.2º 2-theta, 19.7º ± 0.2º 2-theta, and 22.0º ± 0.2º 2-theta , and (b) less than about 10% degradation when the crystalline form is stored at 25 ºC and 60% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 ºC and 60% relative humidity for at least 7 days.

[0034] Also provided herein are such methods wherein the crystalline form of Compound 4 (a) exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 7.7º ± 0.2º 2-theta, and (b) exhibits less than about 10% degradation when the crystalline form is stored at 25 ºC and 60% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 7.7º ± 0.2º 2-theta, 13.7º ± 0.2º 2-theta, and 19.2º ± 0.2º 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 25 ºC and 60% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 ºC and 60% relative humidity for at least 7 days.

[0035] Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 10% degradation when the crystalline forms are stored at 40 ºC and 75% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 40 ºC and 75% relative humidity for at least 7 days.

[0036] Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits (a) a peak in an x-ray powder diffraction (XRPD) pattern at 8.1º ± 0.2º 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 ºC and 75% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 9.6º ± 0.2º 2-theta, 5.7º ± 0.2º 2-theta, 19.7º ± 0.2º 2-theta, and 22.0º ± 0.2º 2-theta , and (b) less than about 10% degradation when the crystalline form is stored at 40 ºC and 75%relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 40 ºC and 75% relative humidity for at least 7 days.

[0037] Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits (a) a peak in an x-ray powder diffraction (XRPD) pattern at 7.7º ± 0.2º 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 ºC and 75% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 7.7º ± 0.2º 2-theta, 13.7º ± 0.2º 2-theta, and 19.2º ± 0.2º 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 ºC and 75% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 40 ºC and 75% relative humidity for at least 7 days.

[0038] Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 10% degradation when the crystalline form is stored at 60 ºC for at least one week. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 60 ºC for at least one week.

[0039] In other embodiments are provided the methods disclosed herein, wherein the compound of Formula (I) is Compound(Compound 5), or a pharmaceutically acceptable salt thereof.

[0040] In other embodiments are provided the methods disclosed herein, wherein the compound of Formula(Compound 6), or a pharmaceutically acceptable salt thereof.

[0041] In other embodiments are provided the methods disclosed herein, wherein the compound of Formula(Compound 7), or a pharmaceutically acceptable salt thereof.

[0042] In other embodiments are provided the methods disclosed herein, wherein the compound of Formula(Compound 8), or a pharmaceutically acceptable salt thereof.

[0043] In other embodiments are provided the methods disclosed herein, wherein the compound of Formula (I) is Compound(Compound 9), or a pharmaceutically acceptable salt thereof.

[0044] In other embodiments are provided the methods disclosed herein, wherein the compound of Formula(Compound 10), or a pharmaceutically acceptable salt thereof.

[0045] In other embodiments are provided the methods disclosed herein, wherein the compound of Formula(Compound 11), or a pharmaceutically acceptable salt thereof.

[0046] In other embodiments are provided the methods disclosed herein, wherein the compound of Formula (I) is Compound 12:(Compound 12), or a pharmaceutically acceptable salt thereof.

[0047] In other embodiments are provided the methods disclosed herein, wherein the prostate cancer in the subject is localized high risk prostate cancer, recurrent prostate cancer, non-metastatic hormone-sensitive prostate cancer (nmHSPC), metastatic hormone-sensitive prostate cancer (mHSPC), non-metastatic castrate- resistant prostate cancer (nmCRPC), or metastatic castrate-resistant prostate cancer (mCRPC). In some embodiments, the prostate cancer in the subject is localized high risk prostate cancer. In other embodiments, the prostate cancer in the subject is recurrent prostate cancer. In some embodiments, the prostate cancer in the subject is non-metastatic hormone-sensitive prostate cancer (nmHSPC). In some embodiments, the prostate cancer in the subject is metastatic hormone-sensitive prostate cancer (mHSPC). In some embodiments, the prostate cancer in the subject is non-metastatic castrate-resistant prostate cancer (nmCRPC). In some embodiments, the prostate cancer in the subject is metastatic castrate-resistant prostate cancer (mCRPC).

[0048] Also provided are the methods disclosed herein, wherein the expression of the androgen receptor splice variant lacking the ligand binding domain is determined by measurement of androgen receptor protein in a biologic sample obtained from the subject. In some embodiments, the biologic sample is blood or tissue.In other embodiments, the biologic sample is blood. In other embodiments, the biologic sample is tissue. In still further embodiments, the tissue is obtained from a biopsy of the prostate cancer in the subject.

[0049] Also provided are the methods disclosed herein, wherein the expression of the androgen receptor splice variant lacking the ligand binding domain is determined by measurement of mRNA that encodes androgen receptor protein in a biologic sample obtained from the subject. In some embodiments, the biologic sample is blood or tissue. In other embodiments, the biologic sample is blood. In other embodiments, the biologic sample is tissue. In still further embodiments, the tissue is obtained from a biopsy of the prostate cancer in the subject.

[0050] Also provided are the methods disclosed herein, wherein the methods further comprise administering to the subject one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from mitotic inhibitors, antimetabolites, platinum-based agents, N-terminal domain inhibitors of androgen receptor, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, inhibitors of CYP17, inhibitors of androgen receptor protein expression, heat shock protein 90 (HSP90) inhibitors, bromodomain and extra-terminal domain family (BET) inhibitors, and androgen receptor degraders, or combinations thereof.

[0051] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents is an androgen receptor inhibitor or a CYP17 inhibitor. In some embodiments, the one or more additional therapeutic agents is an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, the one or more additional therapeutic agents is a CYP17 inhibitor. In some embodiments, the CYP17 inhibitor is abiraterone. In some embodiments, the CYP17 inhibitor is abirateroneacetate. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor or a CYP17 inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered enzalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered apalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered darolutamide. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered a CYP17 inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one ormore androgen receptor inhibitors wherein the subject has not previously been administered abiraterone. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone acetate. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered enzalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered apalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered darolutamide. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the prostate cancer in the subject is selected from treatment-naïve prostate cancer, hormone-sensitive prostate cancer, castrate-resistant prostate cancer, metastatic prostate cancer, non- metastatic prostate cancer, and metastatic castrate-resistant prostate cancer. In some embodiments, the prostate cancer is treatment naïve prostate cancer. In some embodiments, the prostate cancer in the subject ishormone-sensitive prostate cancer. In some embodiments, the prostate cancer in the subject is castrate- resistant prostate cancer. In some embodiments, the prostate cancer in the subject is metastatic prostate cancer. In some embodiments, the prostate cancer in the subject is non-metastatic prostate cancer. In some embodiments, the prostate cancer in the subject is metastatic castrate-resistant prostate cancer.

[0057] In other embodiments are provided methods of treating prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor, and wherein the prostate cancer in the subject is treatment-naïve. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0058] In other embodiments are provided methods of treating treatment-naïve prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0059] In other embodiments are provided methods of treating hormone-sensitive prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptorinhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0060] In other embodiments are provided methods of treating metastatic prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0061] In other embodiments are provided methods of treating non-metastatic prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. Insome embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0062] In other embodiments are provided methods of treating androgen receptor inhibitor-naïve prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0063] In other embodiments are provided methods of treating enzalutamide-naïve prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor isdarolutamide. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0064] In other embodiments are provided methods of treating enzalutamide-naïve prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound which ispharmaceutically acceptable salt thereof, in combination with enzalutamide.

[0065] In other embodiments are provided methods of treating darolutamide-naïve prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound which ispharmaceutically acceptable salt thereof, in combination with darolutamide.

[0066] In other embodiments are provided methods of treating apalutamide-naïve prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound which ispharmaceutically acceptable salt thereof, in combination with apalutamide.

[0067] In other embodiments are provided methods of treating enzalutamide-resistant prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0068] In other embodiments are provided methods of treating darolutamide-resistant prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor isdarolutamide. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0069] In other embodiments are provided methods of treating apalutamide-resistant prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0070] In other embodiments are provided methods of treating abiraterone-resistant prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor isdarolutamide. In some embodiments, the compound of Formula (I) is Compound(Compound 4), or a pharmaceutically acceptable salt thereof.

[0071] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents are selected from mitotic inhibitors. In some embodiments, the mitotic inhibitors are selected from paclitaxel, docetaxel, cabazitaxel, tesetaxel, and nab-paclitaxel.

[0072] In yet other embodiments, the one or more additional therapeutic agents are selected from antimetabolites. In some embodiments, the one or more antimetabolites are selected from azacytidine, 5- fluorouracil (5-FU), 6-mercaptopurine (6-MP), capecitabine, cladribine, clofarabine, cytarabine (Ara-C), decitabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexed, pentostatin, pralatrexate, thioguanine, and trifluridine / tipiracil combination. In some embodiments, the antimetabolite is azacytidine. In some embodiments, the antimetabolite is 5-fluorouracil (5-FU). In some embodiments, the antimetabolite is 6-mercaptopurine (6-MP). In some embodiments, the antimetabolite is capecitabine. In some embodiments, the antimetabolite is cladribine. In some embodiments, the antimetabolite is clofarabine. In some embodiments, the antimetabolite is cytarabine (Ara-C). In some embodiments, the antimetabolite is decitabine. In some embodiments, the antimetabolite is floxuridine. In some embodiments, the antimetabolite is fludarabine. In some embodiments, the antimetabolite is gemcitabine. In some embodiments, the antimetabolite is hydroxyurea. In some embodiments, the antimetabolite is methotrexate. In some embodiments, the antimetabolite is nelarabine. In some embodiments, the antimetabolite is pemetrexed. In some embodiments, the antimetabolite is pentostatin. In some embodiments, the antimetabolite is pralatrexate. In some embodiments, the antimetabolite is thioguanine. In some embodiments, the antimetabolite is trifluridine / tipiracil combination.

[0073] In some embodiments, the one or more additional therapeutic agents are selected from platinum- based agents. In some embodiments, the platinum-based agents are selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, pheanthriplatin, picoplatin, and satraplatin. In further embodiments, the platinum-based agent is cisplatin. In further embodiments, the platinum-based agent is carboplatin. In further embodiments, the platinum-based agent is oxaliplatin. In further embodiments, the platinum-based agent is nedaplatin. In further embodiments, the platinum-based agent is lobaplatin. In further embodiments, the platinum-based agent is triplatin tetranitrate. In further embodiments, the platinum-based agent is pheanthriplatin. In further embodiments, the platinum-based agent is picoplatin. In further embodiments, the platinum-based agent is satraplatin.

[0074] In still further embodiments, the one or more additional therapeutic agents are selected from N- terminal domain inhibitors of androgen receptor. In some embodiments, the N-terminal domain inhibitor of androgen receptor is selected from EPI-001, EPI-002 (ralaniten), EPI-506, and EPI-7386. In some embodiments, the N-terminal domain inhibitor of androgen receptor is EPI-001. In some embodiments, the N-terminal domain inhibitor of androgen receptor is EPI-002 (ralaniten). In some embodiments, the N- terminal domain inhibitor of androgen receptor is EPI-506. In some embodiments, the N-terminal domain inhibitor of androgen receptor is EPI-7386.

[0075] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents are selected from poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are selected from olaparib, niraparib, rucaparib, talazoparib, veliparib, pamiparib, CEP-9722, and E7016. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is olaparib. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is niraparib. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is rucaparib. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is talazoparib. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is veliparib. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is pamiparib. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is CEP-9722. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is E7016.

[0076] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents are selected from inhibitors of CYP17. In one embodiment, the inhibitor of CYP17 is galeterone.

[0077] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents are selected from inhibitors of androgen receptor protein expression. In some embodiments, the inhibitor of androgen receptor protein expression is niclosamide or galeterone. In some embodiments, the inhibitor of androgen receptor protein expression is niclosamide. In some embodiments, the inhibitor of androgen receptor protein expression is galeterone.

[0078] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents are selected from one or more heat shock protein 90 (HSP90) inhibitors. In some embodiments, the one or more heat shock protein 90 (HSP90) inhibitors are selected from tanespimycin, luminespib, alvespimycin, ganetespib, BIIB021, onalespib, geldanamycin, NVP-BEP800, SNX-2112 (PF- 04928473), PF-04929113 (SNX-5422), KW-2478, XL888, TAS-116, VER-50589, CH5138303, VER-49009, NMS-E973, zelavespib (PU-H71), and HSP990 (NVP-HSP990). In some embodiments, the heat shock protein 90 (HSP90) inhibitor is tanespimycin. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is luminespib. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is alvespimycin. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is ganetespib. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is BIIB021. In some embodiments, the heat shock protein 90(HSP90) inhibitor is onalespib. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is geldanamycin. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is NVP-BEP800. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is SNX-2112 (PF-04928473). In some embodiments, the heat shock protein 90 (HSP90) inhibitor is PF-04929113 (SNX-5422). In some embodiments, the heat shock protein 90 (HSP90) inhibitor is KW-2478. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is XL888. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is TAS-116. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is VER-50589. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is CH5138303. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is VER-49009. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is NMS-E973. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is zelavespib (PU-H71). In some embodiments, the heat shock protein 90 (HSP90) inhibitor is HSP990 (NVP- HSP990).

[0079] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents are selected from one or more bromodomain and extra-terminal domain family (BET) inhibitors. In some embodiments, the bromodomain and extra-terminal domain family (BET) inhibitor is selected from JQ1, I-BET 151 (GSK1210151A), I-BET 762 (GSK525762), GSK778 (iBET-BD1), GSK046 (iBET-BD2), OTX-015, TEN-010, CPI-203, CPI-0610, olinone, RVX-208, ABBV-744, LY294002, AZD5153, MT-1, MS645, MS417, SJ432, RVX-208, ABBV-075 (mivebresib), BMS-986158, PLX51107, INCB054329, INCB057643, FT-1101, CC-90010, and ODM-207. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is JQ1. In one embodiment, the bromodomain and extra- terminal domain family (BET) inhibitor is I-BET 151 (GSK1210151A). In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is I-BET 762 (GSK525762). In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is GSK778 (iBET-BD1). In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is GSK046 (iBET- BD2). In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is OTX-015. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is TEN-010. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is CPI-203. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is CPI-0610. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is olinone. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is RVX-208. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is ABBV-744. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is LY294002. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is AZD5153. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is MT-1. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is MS645. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is MS417. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is SJ432. In oneembodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is RVX-208. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is ABBV-075 (mivebresib). In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is BMS-986158. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is PLX51107. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is INCB054329. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is INCB057643. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is FT-1101. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is CC- 90010. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is ODM- 207.

[0080] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents are selected from androgen receptor degraders. In some embodiments, the androgen receptor degraders are selected from ARV-110, ARV-330, SARD279, SARD033, ARCC-4, UT-34, ARD- 111, ARD-86, ARD-77, ARD-69, ARD-61, LX-1, or LX-2, or a pharmaceutically acceptable salt thereof. In one embodiment, the androgen receptor degrader is ARV-110. In one embodiment, the androgen receptor degrader is ARV-330. In one embodiment, the androgen receptor degrader is SARD279. In one embodiment, the androgen receptor degrader is SARD033. In one embodiment, the androgen receptor degrader is ARCC- 4. In one embodiment, the androgen receptor degrader is UT-34. In one embodiment, the androgen receptor degrader is ARD-111. In one embodiment, the androgen receptor degrader is ARD-86. In one embodiment, the androgen receptor degrader is ARD-77. In one embodiment, the androgen receptor degrader is ARD-69. In one embodiment, the androgen receptor degrader is ARD-61. In one embodiment, the androgen receptor degrader is LX-1. In one embodiment, the androgen receptor degrader is LX-2.

[0081] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents are selected from surgery, radiation, and prostate-specific membrane antigen (PSMA) targeted agents. In one embodiment, the additional therapeutic agent is surgery. In one embodiment, the additional therapeutic agent is radiation. In one embodiment, the additional therapeutic agent is prostate- specific membrane antigen (PSMA) targeted agents. In an embodiment, the prostate-specific membrane antigen (PSMA) targeted agent is177Lu-PSMA-617.

[0082] In other embodiments are provided the methods disclosed herein, wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is selected from (a) luteinizing hormone-releasing hormone (LHRH) agonists, (b) luteinizing hormone-releasing hormone (LHRH) antagonists, (c) androgen receptor inhibitors, (d) inhibitors of cytochrome P45017A1, and / or (e) antiandrogens.

[0083] In other embodiments are provided the methods disclosed herein, wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is a luteinizing hormone-releasing hormone (LHRH) agonist. In some embodiments, the luteinizing hormone-releasing hormone (LHRH) agonist is selected from goserelin, histrelin, leuprolide, and triptorelin. In one embodiment, the luteinizing hormone-releasing hormone (LHRH) agonist is goserelin. In one embodiment, the luteinizing hormone-releasing hormone (LHRH) agonist is histrelin. In one embodiment, the luteinizing hormone- releasing hormone (LHRH) agonist is leuprolide. In one embodiment, the luteinizing hormone-releasing hormone (LHRH) agonist is triptorelin.

[0084] In other embodiments are provided the methods disclosed herein, wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is a luteinizing hormone- releasing hormone (LHRH) antagonist. In some embodiments, the luteinizing hormone-releasing hormone (LHRH) antagonist is selected from degarelix and relugolix. In one embodiment, the luteinizing hormone- releasing hormone (LHRH) antagonist is degarelix. In one embodiment, the luteinizing hormone-releasing hormone (LHRH) antagonist is relugolix.

[0085] In other embodiments are provided the methods disclosed herein, wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide.

[0086] In other embodiments are provided the methods disclosed herein, wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is an inhibitor of cytochrome P45017A1. In one embodiment, the one or more inhibitors of cytochrome P45017A1 is abiraterone acetate.

[0087] In other embodiments are provided the methods disclosed herein, wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is an antiandrogen. In some embodiments, the antiandrogen is selected from egestrol, bicalutamide, flutamide, and nilutamide. In one embodiment, the antiandrogen is egestrol. In one embodiment, the antiandrogen is bicalutamide. In one embodiment, the antiandrogen is egestrol flutamide. In one embodiment, the antiandrogen is nilutamide.

[0088] Also provided are the methods disclosed herein, wherein the prostate cancer in the subject is progressing prior to administration to the subject of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0089] Also provided are the methods disclosed herein, wherein the androgen receptor splice variant lacking the ligand binding domain is selected from AR-V1, AR-V3, AR-V4, AR-V7, AR-V9, and AR-V12. In some embodiments, the androgen receptor splice variant lacking the ligand binding domain is AR-V1. In someembodiments, the androgen receptor splice variant lacking the ligand binding domain is AR-V3. In some embodiments, the androgen receptor splice variant lacking the ligand binding domain is AR-V4. In some embodiments, the androgen receptor splice variant lacking the ligand binding domain is AR-V7. In some embodiments, the androgen receptor splice variant lacking the ligand binding domain is AR-V9. In some embodiments, the androgen receptor splice variant lacking the ligand binding domain is AR-V12. INCORPORATION BY REFERENCE

[0090] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE FIGURES

[0091] FIG.1 depicts tumor volume following days of treatment in 22Rv1 tumor-bearing castrated male BALB / c nude mice following administration of vehicle or Compound 4, as described in Example 1.

[0092] FIG.2 depicts tumor volume following days of treatment in C4-2 tumor-bearing male NCG mice following administration of vehicle or Compound 4, as described in Example 2.

[0093] FIG.3 depicts tumor volume following days of treatment in VCaP tumor-bearing castrated male CB17SCID mice following administration of vehicle or Compound 4, as described in Example 3.

[0094] FIG.4 depicts tumor volume following days of treatment in CTG-3337 tumor-bearing intact male NOG mice following administration of vehicle or Compound 4, as described in Example 4.

[0095] FIG.5 depicts tumor volume following days of treatment in CTG-3421 tumor-bearing intact male NOG mice following administration of vehicle or Compound 4, as described in Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0096] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0097] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, anembodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

[0098] “Administering” when used in conjunction with a therapeutic, including the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and / or the one or more additional therapeutic agents, means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a subject whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering,” when used in conjunction with a composition described herein, can include, but is not limited to, providing a composition into or onto the target tissue; providing a composition systemically to a subject by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells. “Administering” a composition may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques.

[0099] The term “androgen receptor splice variant” as used herein refers to a constitutively active androgen receptor (AR) protein variant lacking the ligand binding domain. Such splice variants may result from rearrangement of the gene encoding the androgen receptor (AR) protein in cells, such as prostate cancer cells, or from alternative splicing events at the RNA level. Such rearrangements of the gene encoding the androgen receptor (AR) protein at the DNA level may comprise gene rearrangement breakpoints resulting from deletion, inversion, tandem duplication, and / or translocation events. Such androgen receptor (AR) splice variants are described further in Haile et al., Cellular and Molecular Life Sciences, volume 68, pages 3971 to 3981 (2011); and Li et al., Clinical Cancer Research, volume 26, pages 1965 to 1976 (2020). At the RNA level, splice variants may arise from events including, but not limited to, splicing to cryptic exons, inclusion of intronic sequences, and exon skipping. Such splice variants are further described in Cao et al., Endocr. Relat. Cancer., volume 23 (12), pages T199-T210 (2016).

[0100] The terms “determine,” “determined,” and “determining,” and the like, as used herein mean that it has been established that a pre-condition in a subject exists, or a condition precedent with respect to a subject has been satisfied, prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, it is specifically contemplated herein that a subject having prostate cancer is eligible for treatment by administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and, optionally, one or more additional therapeutic agents described herein, if it has been established that an androgen receptor splice variant lacking the ligand binding domain, such as those described herein (e.g., AR-V7), is present in a biologic sample (e.g., blood or tissue) obtained from the subject.

[0101] The terms “express” and “expresses” as used herein mean that (a) an androgen receptor splice variant protein lacking the ligand binding domain, or (b) an mRNA that encodes for an androgen receptor splice variant protein lacking the ligand binding domain is detected in a biologic sample obtained from a subject, such as blood or tissue. An androgen splice variant protein lacking the ligand binding domain, or an mRNA encoding for such a protein, may be detected in a biologic sample obtained from a subject by methods described herein and / or any other methods known to those having ordinary skill in the art.

[0102] The term “ligand-binding domain” as used herein in relation to the androgen receptor protein means the steroid binding domain of the androgen receptor (AR) protein. The term “androgen receptor splice variant lacking the ligand-binding domain” means an isoform of the androgen receptor protein that is truncated and lacks the C-terminal ligand-binding domain but retains the transactivating N-terminal domain. Examples of androgen receptor splice variant lacking the ligand-binding domain include, but are not limited, to AR-V1 (also referred to by those of ordinary skill in the art as AR4), AR-V3 (also referred to by those of ordinary skill in the art as AR1 / 2 / 2b), AR-V4 (also referred to by those of ordinary skill in the art as AR1 / 2 / 3 / 2b, AR5), AR-V7 (also referred to by those of ordinary skill in the art as AR3), AR-V9, and AR-V12 (also referred to by those of ordinary skill in the art as ARv567es).

[0103] The term “animal” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals. As used herein, the terms “subject,” “subject” and “individual” are intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the subject is a primate. In certain embodiments, the primate or subject is a human. In certain instances, the human is an adult. In certain instances, the human is child. In further instances, the human is under the age of 12 years. In certain instances, the human is elderly. In other instances, the human is 60 years of age or older. Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with hypertensive pathology.

[0104] The term “antiandrogen,” as used herein, means agents that counteract the effects of androgens in subjects. Antiandrogens include agents that act as androgen biosynthesis inhibitors, such as agents that inhibit 17 α‑hydroxylase / C17,20-lyase (CYP17). Antiandrogens also include agents that inhibit a subject’s ability to utilize androgens by interacting with the androgen receptor, such as by competitively inhibiting androgen binding to androgen receptors, including by binding directly to the ligand-binding domain of the androgen receptor. Antiandrogens may also inhibit nuclear translocation of androgen receptors and their interaction with DNA as an antagonist, and impeding androgen receptor-mediated transcription. Antiandrogens also include AR degraders as described herein.

[0105] By “pharmaceutically acceptable,” is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0106] The term “pharmaceutical composition” means a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

[0107] The term “resistant” as used herein refers to the cancer being no longer responsive to the treatment administered (e.g., an antiandrogen). A determination of whether a cancer, or one or more cells comprising a cancer, in a subject have become resistant to a specific treatment modality can be made by methods to knownto those of ordinary skill in the art. For example, responsiveness, or non-responsiveness, as the case may be, of a cancer in a subject, or one or more cells comprising the cancer in a subject, can be assessed by measuring prostate-specific antigen (PSA) levels (by, for example, reference to Prostate Cancer Working Group 3 (PCWG3) criteria), increases or decreases in tumor size, use of Response Evaluation Criteria in Solid Tumors (RECIST response) (see, for example, Schwartz, et. al., Eur. J. Cancer, July 2016, vol.62, pp. 132-137, for a description of RECIST v1.1), duration of response, or progression-free survival.

[0108] As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, prevent, or improve an unwanted condition or disease of a subject.

[0109] A “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology).

[0110] The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to therapeutic treatment, wherein the object is to slow (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0111] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms may also be used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an “alkyl” moiety generally refers to a monovalent radical (e.g. CH3-CH2-), in certain circumstances a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term “alkylene.” (Similarly, in circumstances in which a divalent moiety is required and is stated as being “aryl,” those skilledin the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).

[0112] The term “amino” as used herein refers to -NH2.

[0113] The term “acetyl” as used herein refers to “-C(O)CH3.

[0114] The term “acyl” as used herein refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl portions are as defined herein.

[0115] The term “alkyl” as used herein refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms. As such, “alkyl” encompasses C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12 groups. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, and hexyl.

[0116] The term “alkenyl” as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms. As such, “alkenyl” encompasses C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12 groups. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0117] The term “alkynyl” as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms. As such, “alkynyl” encompasses C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12 groups. Examples of alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0118] The terms “alkylene,” “alkenylene,” and “alkynylene” as used herein mean an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Exemplary alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Exemplary alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.

[0119] The term “alkoxy” as used herein refers to -OC1-C6 alkyl.

[0120] The term “cycloalkyl” as used herein as employed herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons. As such, “cycloalkyl” includes C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12 cyclic hydrocarbon groups. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0121] The term “heteroalkyl” as used herein refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are independently replaced by O, S, or NRx, wherein Rxis hydrogen or C1- C3alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl and methoxypropyl.

[0122] The term “aryl” as used herein means a C6-C14 aromatic moiety comprising one to three aromatic rings. As such, “aryl” includes C6, C10, C13, and C14cyclic hydrocarbon groups. An exemplary aryl group is a C6-C10aryl group. Particular aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.

[0123] The terms “aralkyl” and “arylalkyl” as used herein mean an aryl group covalently linked to an alkylene group wherein the moiety is linked to another group via the alkyl moiety. An exemplary aralkyl group is -(C1-C6)alkyl(C6-C10)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.

[0124] The terms “heterocyclyl” and “heterocyclic” as used herein mean a mono- or bicyclic (fused or spiro) ring structure having from 3 to 12 atoms, (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently -C(O)-, N, NR5, O, or S, and the remainder of the ring atoms are quaternary or carbonyl carbons. Examples of heterocyclic groups include, without limitation, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0125] As used herein, term “L-heterocyclyl” as used herein means a heterocyclyl group covalently linked to another group via an alkylene linker L, where L is C1-C4 alkylene.

[0126] The term “heteroaryl” as used herein means a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13 or 14 ring atoms comprising an aromatic heterocyclic ring (e.g., having 6, 10, or 14 π electrons shared in a cyclic array), and having, in addition to carbon atoms, from one to three heteroatoms that are each independently N, O, or S. “Heteroaryl” also includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom.

[0127] Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H- 1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0128] The terms “L-heteroaryl,” “heteroaralkyl” and “heteroarylalkyl” as used herein mean a group comprising a heteroaryl group covalently linked to another group via an alkylene linker. Examples ofheteroalkyl groups comprise a C1-C6alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0129] The terms “arylene,” “heteroarylene,” and “heterocyclylene” as used herein mean an bivalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.

[0130] As employed herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as “optionally substituted” without expressly stating the substituents it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents.

[0131] The terms “halogen” and “halo” as used herein mean chlorine, bromine, fluorine, or iodine.

[0132] The term “haloalkyl” as used herein means an alkyl chain in which one or more hydrogens have been replaced by a halogen. Exemplary haloalkyls are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0133] The term “hydroxyalkyl” as used herein means an alkyl chain, as defined herein, wherein at least one hydrogen of the alkyl chain has been replaced by hydroxyl.

[0134] The compounds of Formula (I), or pharmaceutically acceptable salts thereof, may be prepared using commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, those described in United States Patent No.11,091,495, or may be prepared using other reagents and conventional methods well known to those skilled in the art. The contents of United States Patent No. 11,091,495 are hereby incorporated by reference for that purpose.

[0135] For instance, intermediates for compounds and compounds of formula (I) of the present invention may be prepared according to General Reaction Schemes I or II: General Reaction Scheme I

[0136] In General Reaction Scheme I, R2-ester substituted imidazo[1,2-c]pyrimidine A is coupled to R3optionally substituted intermediate amine B by nucleophilic substitution to yield Intermediate C. A boronic acid derivative (Y)-R1D is coupled via a Suzuki reaction with halogen substituted Intermediate C in the presence of a suitable base, e.g., sodium carbonate, and the R2ester is converted to the acid by saponification with NaOH to generate intermediate acid E. The acid is converted to the corresponding amide, which is dehydrated to form title compound nitrile G. General Reaction Scheme II

[0137] In General Reaction Scheme II, halogenated Intermediate C containing a suitable R2reactant, e.g., an ester, in the presence of a suitable base is converted to acid intermediate by saponification, then treated with NH4Cl in the presence of HATU to form the amide which is subsequently dehydrated to form nitrile Intermediate H. R1is coupled to Intermediate H via a Suzuki reaction using boronic acid derivative (Y) in the presence of base. The nitrile group of R1-containing Intermediate G is hydrolyzed in the presence of acid and water to afford title compound amide F.

[0138] In some embodiments are provided methods of treatment of prostate cancer in a subject, comprising administering to the subject a pharmaceutically acceptable salts of the compounds of Formula (I). The desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. It is specifically contemplated herein that references to the compounds of Formula (I), also refer in the alternative to pharmaceutically acceptable salts of compounds of Formula (I).

[0139] If the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a solid, it is understood by those skilled in the art that the compounds or salts thereof may exist in different crystal orpolymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.

[0140] Also provided herein are uses of isotopically-labeled compounds of Formula (I), or a pharmaceutically acceptable thereof, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S. Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (3H) and carbon-14 (14C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically- labeled compounds of Formula (I), or a pharmaceutically acceptable salt thereof, can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0141] In one aspect, the compositions described herein comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, are used for the treatment of prostate cancer in subjects. Such compositions may be prepared in pharmaceutically acceptable dosage forms for administration to subjects. Pharmaceutically acceptable dosage forms include, for example, liquids, suspensions, powders for reconstitution, tablets, pills, sachets, or capsules of hard or soft gelatin (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)). The compounds of Formula (I), or a pharmaceutically acceptable salt thereof, may be formulated into pharmaceutical compositions as described below in any pharmaceutical form recognizable to the skilled artisan as being suitable. Pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an inert, pharmaceutically acceptable carrier or diluent.

[0142] The pharmaceutical carriers employed may be either solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water, and the like. Similarly, the compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like. Further additives or excipients may be added to achieve the desired formulation properties. For example, abioavailability enhancer, such as Labrasol, Gelucire or the like, or formulator, such as CMC (carboxy- methylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol), may be added. Gelucire, a semi-solid vehicle that protects active ingredients from light, moisture, and oxidation, may be added, e.g., when preparing a capsule formulation.

[0143] If a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension. If a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations. The inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g. parenteral or oral administration.

[0144] To obtain a stable water-soluble dose form, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the compound, or a pharmaceutically acceptable salt thereof, may be dissolved in a suitable co-solvent or combinations of co- solvents. Examples of suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume. In an exemplary embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.

[0145] Proper formulation is dependent upon the route of administration selected. For injection, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0146] For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0147] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.

[0148] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0149] For administration intranasally or by inhalation, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0150] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0151] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0152] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

[0153] In addition to the formulations described above, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may also be formulated as a depot preparation. Such long-acting formulations may beadministered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. A pharmaceutical carrier for hydrophobic compounds is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be a VPD co-solvent system. VPD is a solution of 3% w / v benzyl alcohol, 8% w / v of the non-polar surfactant polysorbate 80, and 65% w / v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD: 5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. The proportions of a co-solvent system may be suitably varied without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co- solvent components may be varied: for example, other low-toxicity non-polar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.

[0154] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide (DMSO) also may be employed, although usually at the cost of greater toxicity due to the toxic nature of DMSO. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

[0155] The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. These carriers and excipients may provide marked improvement in the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0156] Further, the pharmaceutical composition may be incorporated into a skin patch for delivery of the drug directly onto the skin.

[0157] Additionally, the pharmaceutically acceptable formulations of the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that may be used to practice the methods disclosed herein may contain a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of from about 0.5 w / w % to about 95 w / w %, or from about 1 w / w % to about 95 w / w %, or from about 1 w / w % to about 75 w / w %, or from about 5 w / w % to about 75 w / w %, or from about 10 w / w % to about 75 w / w %, or from about 10 w / w % to about 50 w / w %.

[0158] It will be appreciated that the actual dosages of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to be administered to a subject in need thereof, will vary according to the particular agent being used, the particular composition formulated, the mode of administration, and the particular site, host, and disease being treated. Those skilled in the art using conventional dosage-determination tests in view of the experimental data for a given compound may ascertain optimal dosages for a given set of conditions. For oral administration, an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg / kg of body weight, with courses of treatment repeated at appropriate intervals. In some embodiments are provided the methods disclosed herein, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount between about 0.01 mg / kg per day to about 300 mg / kg per day. In other embodiments are provided the methods disclosed herein, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount between about 0.1 mg / kg per day to about 100 mg / kg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 10 mg to 500 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 100 mg to about 400 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 150 mg to about 350 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 150 mg to about 300 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 160 mg to about 300 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount of about 160 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount of about 240 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount of about 280 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount of about 320 mg per day.

[0159] Furthermore, the pharmaceutically acceptable formulations of the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that may be used to practice the methods disclosed herein may contain a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 25 mg to about 500 mg, or from about 50 mg to about 500 mg, or from about 100 mg to about 500 mg.

[0160] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof once a day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof twice a day. thecompound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof three times a day.

[0161] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof in 28-day cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof in multiple 28- day cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof for at least one 28-day cycle. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof on each day of each 28-day cycle.

[0162] In some instances, the methods described herein comprise administering the compositions and formulations comprising the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, to the subject or subject in need thereof in multiple cycles repeated on a regular schedule with periods of rest in between each cycle. For example, in some instances, treatment given for one week followed by three weeks of rest is one treatment cycle. The length of a treatment cycle depends on the treatment being given. In some embodiments, the length of a treatment cycle ranges from two to six weeks. In some embodiments, the length of a treatment cycle ranges from three to six weeks. In some embodiments, the length of a treatment cycle ranges from three to four weeks. In some embodiments, the length of a treatment cycle is three weeks (or 21 days). In some embodiments, the length of a treatment cycle is four weeks (28 days). In some embodiments, the length of a treatment cycle is 56 days. In some embodiments, a treatment cycle lasts one, two, three, or four weeks. In some embodiments, a treatment cycle lasts three weeks. In some embodiments, a treatment cycle lasts four weeks. The number of treatment doses scheduled within each cycle also varies depending on the drugs being given.

[0163] Dosages of compositions described herein can be determined by any suitable method. Maximum tolerated doses (MTD) and maximum response doses (MRD) for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agents when administered to the subject, can be determined via established animal and human experimental protocols as well as in the examples described herein. For example, toxicity and therapeutic efficacy of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in a human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50with minimal toxicity. The dosage may vary within this range depending upon the dosage form employedand the route of administration utilized. Additional relative dosages, represented as a percent of maximal response or of maximum tolerated dose, are readily obtained via the protocols.

[0164] In some embodiments, the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and / or pharmaceutical formulations comprising them that corresponds to such an amount varies depending upon factors such as the particular salt or form, disease condition and its severity, the identity (e.g., age, weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid formulation type, the condition being treated, and the subject or host being treated.

[0165] Also provided herein are such methods, wherein the subject is 18 years old or older. Also provided herein are such methods, wherein the subject has undergone a bilateral orchiectomy. Also provided herein are such methods, wherein the subject has been administered a GnRH analogue or antagonist prior to the administration of the compound of Formula (I). Also provided herein are such methods, wherein the GnRH antagonist is selected from abarelix, cetrorelix, degarelix, elagolix, ganirelix, linzagolix, and relugolix. In some embodiments, the GnRH antagonist is abarelix. In some embodiments, the GnRH antagonist is cetrorelix. In some embodiments, the GnRH antagonist is degarelix. In some embodiments, the GnRH antagonist is elagolix. In some embodiments, the GnRH antagonist is ganirelix. In some embodiments, the GnRH antagonist is linzagolix. In some embodiments, the GnRH antagonist is relugolix.

[0166] Also provided herein are such methods, wherein the prostate cancer in the subject has progressed after having been administered at least one androgen receptor antagonist. In some embodiments, the at least one androgen receptor antagonist is selected from abiraterone, enzalutamide, apalutamide, and darolutamide. In some embodiments, the prostate cancer in the subject has progressed after having been administered abiraterone. In some embodiments, the prostate cancer in the subject has progressed after having been administered enzalutamide. In some embodiments, the prostate cancer in the subject has progressed after having been administered apalutamide. In some embodiments, the prostate cancer in the subject has progressed after having been administered darolutamide.

[0167] Also provided herein are such methods, wherein the subject has not received more than 2 chemotherapy regimens prior to the administration to the subject of the compound of Formula (I).

[0168] Also provided herein are such methods, wherein prior to the administration to the subject of the compound of Formula (I), the prostate cancer in the subject exhibits evidence of progressive disease by the Prostate Cancer Working Group 3 (PCWG3) criteria, comprising one or more of (a) 2 or more rising levels of prostate specific antigen (PSA) a minimum of one week apart with the latest result being at least 2.0 ng / mL, (b) 1.0 ng / mL PSA rise, (c) confirmation of 2 new bone lesions on last systemic therapy, and (d) soft tissue progression according to RECIST 1.1 guidelines.

[0169] Also provided herein are such methods, wherein prior to the administration to the subject of the compound of Formula (I), the prostate cancer in the subject exhibits evaluable disease according to RECIST 1.1 guidelines.

[0170] Also provided herein are such methods, wherein prior to the administration to the subject of the compound of Formula (I), the subject exhibits an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0171] Also provided herein are such methods, wherein prior to the administration to the subject of the compound of Formula (I), the subject exhibits adequate organ function defined by one or more of: (a) ANC ≥1500 cells / mm3(1.5 × 103 cells / mm3); (b) platelets ≥100,000 / μL (100 × 109 / L); (c) hemoglobin ≥9.0 g / dL (90 g / L); (d) AST (SGOT) or ALT (SGPT) ≤2.5 × ULN, ≤5.0 × ULN for patients with liver metastases; (e) bilirubin ≤1.5 × ULN; (f) estimated glomerular filtration rate ≥60 mL / min; and (g) QTcF ≤470 msec. Methods of detecting AR splice variants

[0172] Disclosed herein, in some embodiments, are methods of detecting the presence, absence, or level, of an androgen receptor splice variant lacking the ligand binding domain. In some embodiments, the androgen receptor splice variant lacking the ligand binding domain is selected from AR-V1 (also referred to by those of ordinary skill in the art as AR4), AR-V3 (also referred to by those of ordinary skill in the art as AR1 / 2 / 2b), AR-V4 (also referred to by those of ordinary skill in the art as AR1 / 2 / 3 / 2b, AR5), AR-V7 (also referred to by those of ordinary skill in the art as AR3), AR-V9, AR-V12 (also referred to by those of ordinary skill in the art as ARv567es). In further embodiments, the androgen receptor splice variant lacking the ligand binding domain is selected from AR-V1, AR-V2, AR-V3, AR-V4, AR-V5, AR-V6, AR-V7, AR-V8, AR-V9, AR- V10, AR-V11, AR-V12, AR-V13, AR-V14, AR-V15, AR-V18, AR8, ARv5es, ARv56es, ARv7es, ARv567es, and AR1 / 2b. In some embodiments, the androgen receptor splice variant is AR-V1. In some embodiments, the androgen receptor splice variant is AR-V2. In some embodiments, the androgen receptor splice variant is AR-V3. In some embodiments, the androgen receptor splice variant is AR-V4. In some embodiments, the androgen receptor splice variant is AR-V5. In some embodiments, the androgen receptor splice variant is AR-V6. In some embodiments, the androgen receptor splice variant is AR-V7. In some embodiments, the androgen receptor splice variant is AR-V8. In some embodiments, the androgen receptor splice variant is AR-V9. In some embodiments, the androgen receptor splice variant is AR-V10. In some embodiments, the androgen receptor splice variant is AR-V11. In some embodiments, the androgen receptor splice variant is AR-V12. In some embodiments, the androgen receptor splice variant is AR-V13. In some embodiments, the androgen receptor splice variant is AR-V14. In some embodiments, the androgen receptor splice variant is AR-V15. In some embodiments, the androgen receptor splice variant is AR-V18. In some embodiments, the androgen receptor splice variant is AR8. In some embodiments, the androgen receptor splice variant is ARv5es. In some embodiments, the androgen receptor splice variant is ARv56es. In some embodiments, the androgen receptor splice variant is ARv7es. In some embodiments, the androgen receptor splice variant is ARv567es. In some embodiments, the androgen receptor splice variant is AR1 / 2b.

[0173] The presence, absence, or level, of such androgen receptor splice variant may be measured in a biological sample obtained from a subject, such as a sample of a solid tumor, such as a prostate cancer, or from a sample of a relevant biological fluid, such as a blood sample. In some instances, the methods of detection disclosed herein are useful for predicting a therapeutic response to a therapy described herein (e.g.,the administration to a subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof), monitor the treatment using the therapy of, and treating with the therapy, a proliferative disease or condition described herein in a subject.

[0174] In some embodiments, the presence or an absence, and / or a level of expression of the androgen receptor splice variant is detected in the sample obtained from a subject by analyzing the genetic material in the sample. In some embodiments, the genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine, and other techniques known by one of skill in the art. In some embodiments the sample comprises circulating tumor RNA (ctRNA). In some embodiments the sample comprises peripheral blood mononuclear cells (PBMCs). In some embodiments the sample comprises circulating tumor cells (CTCs). In some cases, the genetic material is obtained from a tumor biopsy or liquid biopsy. In some embodiments, a tumor biopsy comprises a formalin-fixed paraffin embedded biopsy, a fresh frozen biopsy, a fresh biopsy, or a frozen biopsy. In some embodiments, a liquid biopsy comprises PBMCs, circulating tumor RNA, plasma cell-free RNA, or circulating tumor cells (CTCs). Tumor and liquid biopsies can undergo additional analytic processing for sample dissociation, cell sorting, and enrichment of cell populations of interest.

[0175] In some embodiments, methods of detecting a presence, absence, or level of an androgen receptor splice variant in a biologic sample obtained from the subject involve detecting a nucleic acid sequence. In some cases, the nucleic acid sequence comprises deoxyribonucleic acid (DNA), such as in the case of detecting complementary DNA (cDNA) of an mRNA transcript. In some instances, the nucleic acid sequence comprises a denatured DNA molecule or fragment thereof. In some instances, the nucleic acid sequence comprises DNA selected from: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA. In some instances, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denaturing double-stranded DNA, synthetic DNA, and combinations thereof. The circular DNA may be cleaved or fragmented. In some instances, the nucleic acid sequence comprises ribonucleic acid (RNA). In some instances, the nucleic acid sequence comprises fragmented RNA. In some instances, the nucleic acid sequence comprises partially degraded RNA. In some instances, the nucleic acid sequence comprises a microRNA or portion thereof. In some instances, the nucleic acid sequence comprises an RNA molecule or a fragmented RNA molecule (RNA fragments) selected from: a microRNA (miRNA), a pre-miRNA, a pri-miRNA, a mRNA, a pre-mRNA, a viral RNA, a viroid RNA, a virusoid RNA, circular RNA (circRNA), a ribosomal RNA (rRNA), a transfer RNA (tRNA), a pre-tRNA, a long non-coding RNA (lncRNA), a small nuclear RNA (snRNA), a circulating RNA, a cell-free RNA, an exosomal RNA, a vector-expressed RNA, an RNA transcript, a synthetic RNA, and combinations thereof.

[0176] Disclosed herein, in some embodiments, an androgen receptor splice variant is detected by subjecting a sample obtained from the subject to a nucleic acid-based detection assay. In some instances, the nucleic acid-based detection assay comprises quantitative polymerase chain reaction (qPCR), reverse transcription PCT (RT-qPCR), gel electrophoresis (including for e.g., Northern or Southern blot), immunohistochemistry (IHC), immunofluorescence (IF), in situ hybridization (ISH) such as fluorescent in situ hybridization (FISH), cytochemistry, microarray, or sequencing. In some embodiments, the sequencing technique comprises nextgeneration sequencing. In some embodiments, the methods involve a hybridization assay such as fluorogenic qPCR (e.g., TaqMan™, SYBR green, SYBR green I, SYBR green II, SYBR gold, ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, Blue View or phycoerythrin), which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acid probes comprising a detectable moiety or molecule that is specific to a target nucleic acid sequence. In some instances, a number of amplification cycles for detecting a target nucleic acid in a qPCR assay is about 5 to about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles. For TaqMan™ methods, the probe may be a hydrolysable probe comprising a fluorophore and quencher that is hydrolyzed by DNA polymerase when hybridized to a target nucleic acid. In some cases, the presence of a target nucleic acid is determined when the number of amplification cycles to reach a threshold value is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles. In some instances, hybridization may occur at standard hybridization temperatures, e.g., between about 35 ºC and about 65 ºC in a standard PCR buffer.

[0177] An additional exemplary nucleic acid-based detection assay comprises the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi-well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence. In some instances, the nucleic acid probe is specific to one or more of a polynucleotide sequence that encodes a relevant androgen receptor splice variant as disclosed herein. In some instances, the nucleic acid probe specific to an androgen receptor splice variant comprises a nucleic acid probe sequence sufficiently complementary to the polynucleotide sequence that encodes the relevant androgen receptor splice variant protein. In some instances, the probe comprises a transcribed polynucleotide sequence (e.g., RNA, cDNA). In some embodiments, the nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length and sufficient to specifically hybridize under standard hybridization conditions to the target nucleic acid sequence. In some embodiments, the target nucleic acid sequence is immobilized on a solid surface and contacted with a probe, for example by running the isolated target nucleic acid sequence on an agarose gel and transferring the target nucleic acid sequence from the gel to a membrane, such as nitrocellulose. In some embodiments, the probe(s) are immobilized on a solid surface, for example, in an Affymetrix gene chip array, and the probe(s) are contacted with the target nucleic acid sequence.

[0178] In some embodiments, the term “probe” with regards to nucleic acids, refers to any nucleic acid molecule that is capable of selectively binding to a specifically intended target nucleic acid sequence. In some instances, probes are specifically designed to be labeled, for example, with a radioactive label, afluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags that are known in the art. In some instances, the fluorescent label comprises a fluorophore. In some instances, the fluorophore is an aromatic or heteroaromatic compound. In some instances, the fluorophore is a pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzindole, oxazole, thiazole, benzothiazole, canine, carbocyanine, salicylate, anthranilate, xanthenes dye, coumarin. Exemplary xanthene dyes include, e.g., fluorescein and rhodamine dyes. Fluorescein and rhodamine dyes include, but are not limited to 6-carboxyfluorescein (FAM), 2′7′-dimethoxy-4′5′-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N; N′-tetramethyl-6-carboxyrhodamine (TAMRA), 6-carboxy-X-rhodamine (ROX). Suitable fluorescent probes also include the naphthylamine dyes that have an amino group in the alpha or beta position. For example, naphthylamino compounds include 1- dimethylaminonaphthyl-5-sulfonate, 1-anilino-8-naphthalene sulfonate, and 2-p-toluidinyl-6-naphthalene sulfonate, 5-(2′-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS). Exemplary coumarins include, e.g., 3-phenyl-7-isocyanatocoumarin; acridines, such as 9-isothiocyanatoacridine and acridine orange; N-(p-(2- benzoxazolyl)phenyl) maleimide; cyanines, such as, e.g., indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3-(-carboxy-pentyl)-3′-ethyl-5,5′-dimethyloxacarbocyanine (CyA); 1H, 5H, 11H, 15H-Xantheno[2,3, 4-ij: 5,6, 7-i′j′]diquinolizin-18-ium, 9-[2 (or 4)-[[[6-[2,5-dioxo-1- pyrrolidinyl)oxy]-6-oxohexyl]amino]sulfonyl]-4 (or 2)-sulfophenyl]-2,3, 6,7, 12,13, 16,17-octahydro-inner salt (TR or Texas Red); or BODIPYTM dyes. In some cases, the probe comprises FAM as the dye label.

[0179] In some embodiments, detecting the one or more androgen receptor splice variants comprises sequencing genetic material obtained from a sample from the subject. Sequencing can be performed with any appropriate sequencing technology, including but not limited to single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis. Sequencing methods also include next-generation sequencing, e.g., modern sequencing technologies such as Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed.

[0180] In some instances, a number of nucleotides that are sequenced are at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 300, 400, 500, 2000, 4000, 6000, 8000, 10000, 20000, 50000, 100000, or more than 100000 nucleotides. In some instances, the number of nucleotides sequenced is in a range of about 1 to about 100000 nucleotides, about 1 to about 10000 nucleotides, about 1 to about 1000 nucleotides, about 1 to about 500 nucleotides, about 1 to about 300 nucleotides, about 1 to about 200 nucleotides, about 1 to about 100 nucleotides, about 5 to about 100000 nucleotides, about 5 to about 10000 nucleotides, about 5 to about 1000 nucleotides, about 5 to about 500 nucleotides, about 5 to about 300 nucleotides, about 5 to about 200 nucleotides, about 5 to about 100 nucleotides, about 10 to about 100000 nucleotides, about 10 to about 10000 nucleotides, about 10 to about 1000 nucleotides, about 10 to about 500 nucleotides, about 10 to about 300nucleotides, about 10 to about 200 nucleotides, about 10 to about 100 nucleotides, about 20 to about 100000 nucleotides, about 20 to about 10000 nucleotides, about 20 to about 1000 nucleotides, about 20 to about 500 nucleotides, about 20 to about 300 nucleotides, about 20 to about 200 nucleotides, about 20 to about 100 nucleotides, about 30 to about 100000 nucleotides, about 30 to about 10000 nucleotides, about 30 to about 1000 nucleotides, about 30 to about 500 nucleotides, about 30 to about 300 nucleotides, about 30 to about 200 nucleotides, about 30 to about 100 nucleotides, about 50 to about 100000 nucleotides, about 50 to about 10000 nucleotides, about 50 to about 1000 nucleotides, about 50 to about 500 nucleotides, about 50 to about 300 nucleotides, about 50 to about 200 nucleotides, or about 50 to about 100 nucleotides.

[0181] Disclosed herein are methods comprising: (a) providing a biologic sample obtained from a subject with prostate cancer; (b) assaying to detect in the biologic sample obtained from the subject a presence or absence of an androgen receptor splice variant lacking the ligand binding domain; and (c) detecting the presence or absence of the androgen receptor splice variant lacking the ligand binding domain in the biologic sample using the methods described herein. In some cases, a hybridization assay, such as those described herein, is used to detect the mRNA encoding the androgen receptor splice variant lacking the ligand binding domain in the sample. Exemplary probe sequences that are hybridizable to a target nucleic acid sequence comprise at least 10, but no more than 100 contiguous nucleotides comprising the relevant sequence. In some cases, RNA sequencing (RNAseq) is used to detect the mRNA encoding the relevant androgen receptor splice variant protein.

[0182] Detection of the mRNA, in some cases, involves amplification of the subject’s nucleic acid by the polymerase chain reaction (PCR). In some embodiments, the PCR assay involves use of a pair of primers capable of amplifying at least about 10 contiguous nucleobases within a nucleic acid sequence, thereby amplifying the one or more gene products in the biomarker. In fluorogenic quantitative PCR, quantitation is based on amount of fluorescence signals (TaqMan and SYBR green). In some embodiments, the nucleic acid probe is conjugated to a detectable molecule. The detectable molecule may be a fluorophore. The nucleic acid probe may also be conjugated to a quencher.

[0183] In some embodiments, the assay for detecting the presence or absence of mRNA encoding a relevant androgen receptor splice variant lacking the ligand binding domain comprises reverse-transcribing the relevant mRNA molecule to produce a corresponding complementary DNA (cDNA) molecule. In some embodiments, the assay further comprises contacting the cDNA molecule with a nucleic acid probe comprising a nucleic acid sequence that is complementary to a nucleic acid sequence of the cDNA molecule. In some embodiments, the assay comprises detecting a double-stranded hybridization product between the nucleic acid probe and the cDNA molecule. In some embodiments, the hybridization product is further amplified using a pair of primers. In some embodiments, the primers comprises a first primer with a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within a relevant nucleic acid sequence that binds to a top strand of the double-stranded hybridization product; and a second primer with a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within anucleic acid sequence that is reverse complement to the relevant nucleic acid sequence that binds to a bottom strand of the double-stranded hybridization product.

[0184] Disclosed herein, in some embodiments, are methods comprising preparing a complementary DNA (cDNA) library. In some embodiments, the cDNA library is sequenced using suitable sequence methodologies disclosed herein. In some embodiments, the cDNA library is labeled, a plurality of nucleic acid probes is generated, and fixed to an immobile surface (such as a microarray). In some embodiments, the plurality of nucleic acid probes is capable of hybridizing to at least about 10 contiguous nucleotides of the two or more genes in a sample obtained from the subject. In some embodiments, detecting the presence of or absence of an androgen receptor splice variant includes detecting a high or a low level of expression of one or more genes as compared to a reference level.

[0185] Disclosed herein, in some embodiments, genetic material is extracted from a biologic sample obtained from a subject, e.g., a sample of blood, serum, or tissue. In certain embodiments where nucleic acids are extracted, the nucleic acids are extracted using any technique that does not interfere with subsequent analysis. In certain embodiments, this technique uses alcohol precipitation using ethanol, methanol, or isopropyl alcohol. In certain embodiments, this technique uses phenol, chloroform, or any combination thereof. In certain embodiments, this technique uses cesium chloride. In certain embodiments, this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA. In certain embodiments, this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In certain embodiments, after extraction the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis. In an exemplary embodiment, the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification. In certain embodiments, RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol / guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasy RNA preparation kits (Qiagen) or PAXgene (PreAnalytix, Switzerland).

[0186] In some aspects, circulating tumor RNA (ctRNA) is used to assess the expression levels of RNA molecules, shed by the tumor into the blood stream. In some embodiments, detection of ctRNA is useful, for example, for detecting and diagnosing a tumor. Because tumor DNA and RNA has acquired multiple genetic mutations, leading to tumor development, ctRNA are not an exact match to the individual’s DNA and RNA, respectively. Finding DNA and RNA with genetic differences aids in tumor detection. Diagnosing the type of tumor using ctRNA can reduce the need for getting a sample of the tumor tissue (tumor biopsy), which can be challenging when a tumor is difficult to access, such as a tumor in the brain or lung.

[0187] In some embodiments, a decrease in the quantity of ctRNA suggests the solid tumor is shrinking and treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is effective. In some embodiments, a lack of ctRNA in the bloodstream indicates that the cancer has not returned after treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0188] Described herein are methods of assessing genetic alterations by ctRNA profiling. In some embodiments, the genomic profiling is performed after each treatment cycle with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the gene mutations indicate that the cancer is becoming resistant to the treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the lack of gene mutations indicate that the cancer is not becoming resistant to the treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0189] Disclosed herein are methods of treating prostate cancer in a subject in need thereof; the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof). In some embodiments, one or more cells comprising the prostate cancer in the subject has been determined to express an androgen receptor splice variant lacking the ligand binding domain. In some embodiments, the expression of an androgen receptor splice variant lacking the ligand binding domain is measured by immunohistochemistry (IHC) assays. In some embodiments, the expression of an androgen receptor splice variant lacking the ligand binding domain is measured by immunofluorescence (IF) assays. In some embodiments, the expression of an androgen receptor splice variant lacking the ligand binding domain is measured by in situ hybridization (ISH) assays. In some embodiments, the expression of an androgen receptor splice variant lacking the ligand binding domain transcript levels are measured using assays such as quantitative polymerase chain reaction (qPCR), microarray, and RNA sequencing, or assays commercially available from companies such as Fluidigm and Nanostring.

[0190] Disclosed herein is a method of treating prostate cancer in a subject in need thereof wherein one or more of the cells comprising the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain. In some embodiments, expression of an androgen receptor splice variant lacking the ligand binding domain is based on the expression level of the androgen receptor splice variant lacking the binding domain deviating from a reference expression level. In some embodiments, the expression level of the androgen receptor is standardized, such as through a z-score. In some embodiments, the expression level is high, relative to the reference expression level. In some embodiments, the expression level is low, relative to the reference expression level. In some embodiments, the reference expression level is derived from an individual, or a group of individuals, that do not have cancer. In some embodiments, the reference expression level is derived from an individual, or a group of individuals, that have cancer that does not therapeutically respond to the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the expression level deviates from the reference expression level by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0191] In some embodiments, the determination of expression of an androgen receptor splice variant is defined based on the percentage of cells that stain weakly, moderately, or strongly for the relevant androgen receptor variant, with the threshold defining the minimal percentage of cells that are required to stain positive at the various intensity levels (≥a% of prostate tumor cells stain weakly, ≥b% of prostate tumor cells stain moderately, ≥c% of prostate tumor cells stain strongly, or a combination thereof). In some embodiments, theone or more of the cells comprising the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain when ≥ about 10%, ≥ about 15%, ≥ about 20%, ≥ about 25%, ≥ about 30%, ≥ about 35%, ≥ about 40%, ≥ about 45%, ≥ about 50%, ≥ about 55%, ≥ about 60%, ≥ about 65%, ≥ about 70%, ≥ about 75%, ≥ about 80%, ≥ about 85%, ≥ about 90%, or ≥ about 95% of the prostate tumor cells stain weakly for the androgen receptor splice variant; when ≥ about 10%, ≥ about 15%, ≥ about 20%, ≥ about 25%, ≥ about 30%, ≥ about 35%, ≥ about 40%, ≥ about 45%, ≥ about 50%, ≥ about 55%, ≥ about 60%, ≥ about 65%, ≥ about 70%, ≥ about 75%, ≥ about 80%, ≥ about 85%, ≥ about 90%, or ≥ about 95% of the prostate tumor cells stain moderately for the androgen receptor splice variant; when ≥ about 10%, ≥ about 15%, ≥ about 20%, ≥ about 25%, ≥ about 30%, ≥ about 35%, ≥ about 40%, ≥ about 45%, ≥ about 50%, ≥ about 55%, ≥ about 60%, ≥ about 65%, ≥ about 70%, ≥ about 75%, ≥ about 80%, ≥ about 85%, ≥ about 90%, or ≥ about 95% of the prostate tumor cells stain strongly for the androgen receptor splice variant; or any combinations thereof. Kits and articles of manufacture

[0192] Disclosed herein, in certain embodiments, are kits and articles of manufacture for use with one or more methods and compositions described herein. Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.

[0193] A kit typically includes labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

[0194] In one embodiment, a label is on or associated with the container. In one embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In one embodiment, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.

[0195] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for drugs, or the approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatiblepharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0196] Disclosed herein is a kit comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer in a subject in need thereof and a package insert comprising instructions for measuring the expression of an androgen receptor splice variant lacking the ligand binding domain in one or more of the cells comprising the prostate cancer and using the compound of Formula (I), or a pharmaceutically acceptable salt thereof, if one or more of the cells comprising the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain. Numbered Embodiments

[0197] Embodiment 1. A method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I)Formula (I) or a pharmaceutically acceptable salt thereof: wherein: represents a single or a double bond; Z is O or S; X is O, CR5, CR5OH, or C(R5)2, wherein: when X is O,is a single bond; when X is C(R5)2, is a single bond; when X is CR5OH,is a single bond; or when X is CR5is a double bond; R1is aryl, heteroaryl, L-cycloalkyl, -N(R5)heterocyclyl, or L-heterocyclyl, wherein the aryl, the heteroaryl or the cyclyl portion of the L-cycloalkyl, -N(R5)heterocyclyl, or L-heterocyclyl is optionally substituted with one or more R4; R2is cyano, -COOR5, -C(O)N(R5)2, or -C(O)N(R5)2 wherein each R5taken together with the nitrogen atom to which they are attached form a 5 - 8 membered heterocyclic ring optionally substituted with one or more R4; each R3is independently C1-C3 alkyl or halogen;each R4is independently oxo, cyano, halogen, -PO3(C1-C3alkyl)2, hydroxyl, alkoxy, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR5, -Y2-haloalkyl, -Y1-C1-C6alkyl, -Y2-C1-C6alkyl, -L-cycloalkyl, -L- heteroaryl, -L-heterocyclyl, -Y1-heterocyclyl, -Y2-heterocyclyl, -L-N(R5)2, -O-L-N(R5)2, -C(CF3)N(R5)2, -Y1- N(R5)2, -Y2-N(R5)2wherein the ring portion of the aralkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl or - Y1-heterocyclyl is optionally substituted with one or more R7; L is a bond or C1-C4alkylene; Y1is a bond, -C(O)-, or -NHC(O)-; Y2is a bond, -S-, -SO-, -SO2-, or -NR5SO2-, each R5is hydrogen or C1-C3 alkyl; R6is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R7is oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L- N(R5)2, C1-C6 alkyl, or -Y1-heterocyclyl; and n is 1 or 2.

[0198] Embodiment 2. The method of embodiment 1, wherein Z is O.

[0199] Embodiment 3. The method of embodiment 1, wherein Z is S.

[0200] Embodiment 4. The method of any of embodiments 2 or 3, wherein n is 1.

[0201] Embodiment 5. The method of any of embodiments 1-4, wherein R2is cyano.

[0202] Embodiment 6. The method of any of embodiments 1-4, wherein R2is -COOR5.

[0203] Embodiment 7. The method of any of embodiments 1-4, wherein R2is -C(O)N(R5)2.

[0204] Embodiment 8. The method of any of embodiments 1-7, wherein R3is halogen.

[0205] Embodiment 9. The method of embodiment 8, wherein the halogen is fluorine.

[0206] Embodiment 10. The method of any of embodiments 1-9, wherein X is C(R5)2 and is a single bond.

[0207] Embodiment 11. The method of any of embodiments 1-9, wherein X is CR5and is a double bond.

[0208] Embodiment 12. The method of any of embodiments 1-9, wherein X is O and is a single bond.

[0209] Embodiment 13. The method of any of embodiments 1-12 wherein R1is aryl optionally substituted with one or more R4.

[0210] Embodiment 14. The method of embodiment 13, wherein the aryl is phenyl optionally substituted with one or more R4.

[0211] Embodiment 15. The method of embodiment 14, wherein the phenyl is substituted with one, two or three R4.

[0212] Embodiment 16. The method of embodiment 15, wherein the one, two or three R4are each independently halogen, -PO3(C1-C3alkyl)2, hydroxyl, hydroxyalkyl, aralkyl, haloalkyl, -COOR5, -Y1-C1-C6alkyl, Y2-C1-C6alkyl, -L-N(R5)2, -O-L-N(R5)2, -C(CF3)N(R5)2, -Y1-N(R5)2, -Y2-N(R5)2, Y2-haloalkyl, -L-heteroaryl, -L-heterocyclyl, or -Y1-heterocyclyl, wherein the heterocyclyl portion of the -L-heterocyclyl or - Y1-heterocyclyl is optionally substituted with one or more R7.

[0213] Embodiment 17. The method of embodiment 16, wherein R4is -Y1-C1-C6alkyl and Y1is a bond and the C1-C6alkyl is methyl, ethyl, isopropyl, butyl, or pentyl.

[0214] Embodiment 18. The method of embodiment 16, wherein R4is -Y2-C1-C6alkyl and Y2is a -SO2- and the C1-C6alkyl is methyl.

[0215] Embodiment 19. The method of embodiment 16, wherein R4is -Y2-haloalkyl and Y2is -S- or -SO2- and the haloalkyl is trifluoromethyl.

[0216] Embodiment 20. The method of embodiment 16, wherein R4is -L-N(R5)2 and L is a bond and each R5is hydrogen, each R5is methyl or one R5is methyl and one R5is hydrogen.

[0217] Embodiment 21. The method of embodiment 16, wherein R4is -L-N(R5)2 and L is methylene or ethylene and each R5is hydrogen, each R5is methyl or one R5is methyl and one R5is hydrogen.

[0218] Embodiment 22. The method of embodiment 16, wherein R4is -Y1-N(R5)2, Y1is -C(O)- and each R5independently is hydrogen, each R5is independently methyl or one R5is methyl and one R5is hydrogen.

[0219] Embodiment 23. The method of embodiment 16, wherein R4is -Y2-N(R5)2, Y2is -SO2- and each R5independently is hydrogen, each R5is methyl or one R5is methyl and one R5is independently hydrogen.

[0220] Embodiment 24. The method of embodiment 16, , wherein R4is -Y1-heterocyclyl and Y1is -C(O)- and the heterocyclyl portion of the L-heterocyclyl is piperazinyl or 4-methyl-piperazinyl.

[0221] Embodiment 25. The method of embodiment 16, wherein R4is -L-heterocyclyl and L is a bond and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or 3ƛ2-azabicyclo[3.1.0]hexanyl, each optionally substituted with one or more R7selected from oxo, C1-C3 alkyl, alkoxy, hydroxyl and halogen.

[0222] Embodiment 26. The method of embodiment 16, wherein R4is -L-heterocyclyl, wherein L is a methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl piperidinyl, each optionally substituted with one or more R7selected from C1-C3 alkyl, alkoxy, hydroxyl and halogen.

[0223] Embodiment 27. The method of embodiment 16, wherein R4is -Y1-heterocyclyl and Y1is -C(O)- and the heterocyclyl portion of the Y1-heterocyclyl is morpholinyl optionally substituted with one or more C1-C3 alkyl.

[0224] Embodiment 28. The method of embodiment 16, wherein R4is -L-heteroaryl optionally substituted with one or more R7.

[0225] Embodiment 29. The method of embodiment 28, wherein the -L-heteroaryl is tetrazolyl.

[0226] Embodiment 30. The method of embodiment 16, wherein R4is -PO3(C1-C3alkyl)2.

[0227] Embodiment 31. The method of embodiment 16, wherein R4is -COOR5.

[0228] Embodiment 32. The method of embodiment 16, wherein R4is hydroxyalkyl.

[0229] Embodiment 33. The method of embodiment 16, wherein R4is -O-L-N(R5)2.

[0230] Embodiment 34. The method of embodiment 16, wherein R4is aralkyl.

[0231] Embodiment 35. The method of any of embodiments 1-12, wherein R1is heteroaryl optionally substituted with one or more R4.

[0232] Embodiment 36. The method of embodiment 35, wherein the heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 5,6-dihydro-4H-pyrrolo[1,2- b]pyrazolyl, each optionally substituted with one or more R4.

[0233] Embodiment 37. The method of embodiment 36, wherein the heteroaryl is substituted with one or more R4; wherein each R4is independently cyano, halogen, -Y1-C1-C6alkyl, -Y2-C1-C6alkyl, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -L-cycloalkyl, -L-N(R5)2, -Y1-N(R5)2, -L-heteroaryl, -L-heterocyclyl, or -Y1-heterocyclyl, wherein the heteroaryl of the -L-heteroaryl or the heterocyclyl portion of the L- heterocyclyl, or Y1-heterocyclyl is optionally substituted with one or more R7.

[0234] Embodiment 38. The method of embodiment 37, wherein the heteroaryl is pyrazolyl optionally substituted with one R4independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y1-C1-C6 alkyl, - L-N(R5)2, L-heterocyclyl or L-heteroaryl, wherein the heteroaryl of the L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl is optionally substituted with one or more R7.

[0235] Embodiment 39. The method of embodiment 38, wherein R4is -L-heteroaryl and L is methylene wherein the heteroaryl is pyridyl optional substituted with one or more R7.

[0236] Embodiment 40. The method of embodiment 38, wherein R4is -L-heterocyclyl optionally substituted with one or more R7where L is a bond and the heterocyclyl portion of the L-heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, or 4-methylpiperazinyl.

[0237] Embodiment 41. The method of embodiment 38, wherein R4is -L-heterocyclyl optionally substituted with one or more R7where L is methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl, or 4- methylpiperazinyl.

[0238] Embodiment 42. The method of embodiment 38, wherein R4is -L-N(R5)2 where L is methylene and each R5is independently hydrogen, each R5is independently C1-C3 alkyl or one R5is C1-C3 alkyl and one R5is hydrogen.

[0239] Embodiment 43. The method of embodiment 38, wherein R4is -Y1-C1-C6 alkyl where Y1is a bond and the C1-C6 alkyl is methyl, ethyl, or isopropyl.

[0240] Embodiment 44. The method of embodiment 38, wherein the heteroaryl is pyrazolyl optionally substituted with two R4groups each independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, and - Y1-C1-C6alkyl.

[0241] Embodiment 45. The method of embodiment 36, wherein the heteroaryl is pyridyl optionally substituted with one R4independently selected from cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y1-C1-C6alkyl, -L-N(R5)2,-Y1-N(R5)2, -L-cycloalkyl, or -L-heterocyclyl optionally substituted with one or more R7.

[0242] Embodiment 46. The method of any of embodiments 1-12 wherein R1is -L-cycloalkyl optionally substituted with one or more R4.

[0243] Embodiment 47. The method of any of embodiments 1-12 wherein R1is -L-heterocyclyl optionally substituted with one or more R4.

[0244] Embodiment 48. The method of embodiment 47, wherein L is a bond and the heterocyclyl is piperidinyl or tetrahydropyranyl.

[0245] Embodiment 49. The method of any of embodiments 1-3, wherein n is 2.

[0246] Embodiment 50. A method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:,,,, and

[0247] Embodiment 51. A method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:,and , or a pharmaceutically acceptable salt thereof.

[0248] Embodiment 52. The method of embodiment 51, wherein the compound isor a pharmaceutically acceptable salt thereof.

[0249] Embodiment 53. The method of embodiment 51, wherein the compound is:pharmaceutically acceptable salt thereof.

[0250] Embodiment 54. The method of embodiment 51, wherein the compound is:a pharmaceutically acceptable salt thereof.

[0251] Embodiment 55. The method of embodiment 51, wherein the compound is:pharmaceutically acceptable salt thereof.

[0252] Embodiment 56. The method of embodiment 51, wherein the compound is:pharmaceutically acceptable salt thereof.

[0253] Embodiment 57. The method of embodiment 51, wherein the compound is:pharmaceutically acceptable salt thereof.

[0254] Embodiment 58. The method of embodiment 51, wherein the compound is:pharmaceutically acceptable salt thereof.

[0255] Embodiment 59. The method of embodiment 51, wherein the compound is:pharmaceutically acceptable salt thereof.

[0256] Embodiment 60. The method of embodiment 51, wherein the compound is:a pharmaceutically acceptable salt thereof.

[0257] Embodiment 61. The method of embodiment 51, wherein the compound i, pharmaceutically acceptable salt thereof.

[0258] Embodiment 62. The method of embodiment 51, wherein the compound is:pharmaceutically acceptable salt thereof.

[0259] Embodiment 63. The method of embodiment 51, wherein the compound is:, or a pharmaceutically acceptable salt thereof.

[0260] Embodiment 64. The method of any one of embodiments 1 to 63, wherein the prostate cancer in the subject is localized high risk prostate cancer, recurrent prostate cancer, non-metastatic hormone-sensitive prostate cancer (nmHSPC), metastatic hormone-sensitive prostate cancer (mHSPC), non-metastatic castrate- resistant prostate cancer (nmCRPC), or metastatic castrate-resistant prostate cancer (mCRPC).

[0261] Embodiment 65. The method of any one of embodiments 1 to 64, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount between about 0.01 mg / kg per day to about 300 mg / kg per day.

[0262] Embodiment 66. The method of any one of embodiments 1 to 64, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount between about 0.1 mg / kg per day to about 100 mg / kg per day.

[0263] Embodiment 67. The method of any one of embodiments 1 to 66, wherein the expression of the androgen receptor splice variant lacking the ligand binding domain is determined by measurement of androgen receptor protein in a biologic sample obtained from the subject.

[0264] Embodiment 68. The method of embodiment 67, wherein the biologic sample is blood or tissue.

[0265] Embodiment 69. The method of embodiment 68, wherein the biologic sample is blood.

[0266] Embodiment 70. The method of embodiment 68, wherein the biologic sample is tissue.

[0267] Embodiment 71. The method of embodiment 70, wherein the tissue is obtained from a biopsy of the prostate cancer in the subject.

[0268] Embodiment 72. The method of any one of embodiments 1 to 66, wherein the expression of the androgen receptor splice variant lacking the ligand binding domain is determined by measurement of mRNA that encodes androgen receptor protein in a biologic sample obtained from the subject.

[0269] Embodiment 73. The method of embodiment 72, wherein the biologic sample is blood or tissue.

[0270] Embodiment 74. The method of embodiment 73, wherein the biologic sample is blood.

[0271] Embodiment 75. The method of embodiment 73, wherein the biologic sample is tissue.

[0272] Embodiment 76. The method of embodiment 75,wherein the tissue is obtained from a biopsy of the prostate cancer in the subject.

[0273] Embodiment 77. The method of any one of embodiments 1 to 76, further comprising administering to the subject one or more additional therapeutic agents.

[0274] Embodiment 78. The method of embodiment 77, wherein the one or more additional therapeutic agents are selected from mitotic inhibitors, antimetabolites, platinum-based agents, N-terminal domain inhibitors of androgen receptor, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, inhibitors of CYP17, inhibitors of androgen receptor protein expression, heat shock protein 90 (HSP90) inhibitors, bromodomain and extra-terminal domain family (BET) inhibitors, and androgen receptor degraders, or combinations thereof.

[0275] Embodiment 79. The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from mitotic inhibitors.

[0276] Embodiment 80. The method of embodiment 79, wherein the mitotic inhibitors are selected from paclitaxel, docetaxel, cabazitaxel, tesetaxel, and nab-paclitaxel.

[0277] Embodiment 81. The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from antimetabolites.

[0278] Embodiment 82. The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from platinum-based agents.

[0279] Embodiment 83. The method of embodiment 82, wherein the platinum-based agents are selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, pheanthriplatin, picoplatin, and satraplatin.

[0280] Embodiment 84. The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from N-terminal domain inhibitors of androgen receptor.

[0281] Embodiment 85. The method of embodiment 84, wherein the N-terminal domain inhibitor of androgen receptor is selected from EPI-001, EPI-002 (ralaniten), EPI-506, and EPI-7386.

[0282] Embodiment 86. The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors.

[0283] Embodiment 87. The method of embodiment 86, wherein the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are selected from olaparib, niraparib, rucaparib, talazoparib, veliparib, pamiparib, CEP-9722, and E7016.

[0284] Embodiment 88. The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from inhibitors of CYP17.

[0285] Embodiment 89. The method of embodiment 88, wherein the inhibitor of CYP17 is galeterone.

[0286] Embodiment 90. The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from inhibitors of androgen receptor protein expression.

[0287] Embodiment 91. The method of embodiment 90, wherein the inhibitor of androgen receptor protein expression is niclosamide or galeterone.

[0288] Embodiment 92. The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from one or more heat shock protein 90 (HSP90) inhibitors.

[0289] Embodiment 93. The method of embodiment 92, wherein the one or more heat shock protein 90 (HSP90) inhibitors are selected from tanespimycin, luminespib, alvespimycin, ganetespib, BIIB021, onalespib, geldanamycin, NVP-BEP800, SNX-2112 (PF-04928473), PF-04929113 (SNX-5422), KW-2478, XL888, TAS-116, VER-50589, CH5138303, VER-49009, NMS-E973, zelavespib (PU-H71), and HSP990 (NVP-HSP990).

[0290] Embodiment 94. The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from bromodomain and extra-terminal domain family (BET) inhibitors.

[0291] Embodiment 95. The method of embodiment 94, wherein the bromodomain and extra-terminal domain family (BET) inhibitor is selected from JQ1, I-BET 151 (GSK1210151A), I-BET 762 (GSK525762), GSK778 (iBET-BD1), GSK046 (iBET-BD2), OTX-015, TEN-010, CPI-203, CPI-0610, olinone, RVX-208, ABBV-744, LY294002, AZD5153, MT-1, MS645, MS417, SJ432, RVX-208, ABBV-075 (mivebresib), BMS-986158, PLX51107, INCB054329, INCB057643, FT-1101, CC-90010, and ODM-207.

[0292] Embodiment 96. The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from androgen receptor degraders.

[0293] Embodiment 97. The method of embodiment 96, wherein the androgen receptor degraders are selected from ARV-110, ARV-330, SARD279, SARD033, ARCC-4, UT-34, ARD-111, ARD-86, ARD-77, ARD-69, ARD-61, LX-1, or LX-2, or a pharmaceutically acceptable salt thereof.

[0294] Embodiment 98. The method of embodiment 77, wherein the one or more additional therapeutic agents are selected from surgery, radiation, and prostate-specific membrane antigen (PSMA) targeted agents.

[0295] Embodiment 99. The method of any one of embodiments 1 to 98, wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is selected from (a) luteinizing hormone-releasing hormone (LHRH) agonists, (b) luteinizing hormone-releasing hormone (LHRH) antagonists, (c) androgen receptor inhibitors, (d) inhibitors of cytochrome P45017A1, and / or (e) antiandrogens.

[0296] Embodiment 100. The method of embodiment 99, wherein the one or more first agents is a luteinizing hormone-releasing hormone (LHRH) agonist.

[0297] Embodiment 101. The method of embodiment 100, wherein the luteinizing hormone-releasing hormone (LHRH) agonist is selected from goserelin, histrelin, leuprolide, and triptorelin.

[0298] Embodiment 102. The method of embodiment 99, wherein the one or more first agents is a luteinizing hormone-releasing hormone (LHRH) antagonist.

[0299] Embodiment 103. The method of embodiment 102, wherein the luteinizing hormone-releasing hormone (LHRH) antagonist is selected from degarelix and relugolix.

[0300] Embodiment 104. The method of embodiment 99, wherein the one or more first agents is an androgen receptor inhibitor.

[0301] Embodiment 105. The method of embodiment 104, wherein the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.

[0302] Embodiment 106. The method of embodiment 99, wherein the one or more first agents is an inhibitor of cytochrome P45017A1.

[0303] Embodiment 107. The method of embodiment 106, wherein the one or more inhibitors of cytochrome P45017A1 is abiraterone acetate.

[0304] Embodiment 108. The method of embodiment 99, wherein the one or more first agents is an antiandrogen.

[0305] Embodiment 109. The method of embodiment 108, wherein the antiandrogen is selected from egestrol, bicalutamide, flutamide, and nilutamide.

[0306] Embodiment 110. The method of any one of embodiments 1 to 109, wherein the prostate cancer in the subject is progressing prior to administration to the subject of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0307] Embodiment 111. The method of any one of embodiments 1 to 110, wherein the androgen receptor splice variant lacking the ligand binding domain is selected from AR-V1, AR-V3, AR-V4, AR-V7, AR-V9, and AR-V12. EXAMPLES Example 1: Administration of Compound 4 to 22Rv1 tumor-bearing castrated male BALB / c nude mice

[0308] The 22Rv1 tumor-bearing castrated male BALB / c nude mice were divided into two groups when the tumors in the mice reached on average 135 mm3in volume: (a) the first group (n = 10) was orally administered vehicle once per day for 28 days, and (b) the second group (n = 10) was orally administered Compound 4 once per day at a dose of 100 mg / kg for 28 days. The tumor volume in each mouse in each group was then measured on days 1, 4, 7, 10, 14, 17, 21, 25, and 28 following the administration of vehicle or Compound 4. FIG.1 shows the average tumor volume for the mice (± SEM) in each group. Tumor growthwas inhibited significantly in the group of tumor-bearing mice to which Compound 4 was administered (t- test, p <0.05 versus the control (vehicle) group), with a tumor growth inhibition (TGI) of 69.2%. Example 2: Administration of Compound 4 to C4-2 tumor-bearing castrated male NCG mice

[0309] The C4-2 tumor-bearing male NCG mice were castrated when the tumors reached on average 212 mm3in size and were then divided into two groups: (a) the first group (n = 10) was orally administered vehicle once per day for 21 days, and (b) the second group (n = 10) was orally administered Compound 4 once per day at a dose of 100 mg / kg for 21 days. The tumor volume in each mouse in each group was then measured on days 1, 4, 7, 10, 14, 17, 20, and 21 following the administration of vehicle or Compound 4. FIG. 2 shows the average tumor volume for the mice (± SEM) in each group. Tumor growth was inhibited significantly in the group of tumor-bearing mice to which Compound 4 was administered (t-test, p =0.0003, versus the control (vehicle) group), with a tumor growth inhibition (TGI) of 69.4%. Example 3: Administration of Compound 4 to VCaP tumor-bearing castrated male CB17SCID mice

[0310] The VCaP tumor-bearing castrated male CB17SCID mice were divided into two groups after the tumors reached on average 195 mm3in volume: (a) the first group (n = 10) was orally administered vehicle once per day for 21 days, and (b) the second group (n = 10) was orally administered Compound 4 once per day at a dose of 100 mg / kg for 21 days. The tumor volume in each mouse in each group was then measured on days 1, 3, 6, 10, 13, 17, 20, and 21 following the administration of vehicle or Compound 4. FIG.3 shows the average tumor volume for the mice (± SEM) in each group. Tumor growth was inhibited in the group of tumor-bearing mice to which Compound 4 was administered (t-test, p =0.054, versus the control (vehicle) group), with a tumor growth inhibition (TGI) of 47.0%. Example 4: Administration of Compound 4 to CTG-3337 tumor-bearing intact male NOG mice

[0311] The intact CTG-3337 tumor-bearing male NOG mice were divided into two groups after the tumors had reached 216 mm3on average in volume: (a) the first group (n = 5) was orally administered vehicle once per day for 27 days; and (b) the second group (n = 5) was orally administered Compound 4 once per day for 27 days at a dose of 100 mg / kg. The tumor volume in each mouse in each group was then measured on days 1, 4, 7, 11, 14, 18, 20, 25, and 27 following the administration of vehicle or Compound 4. FIG.4 shows the average tumor volume for the mice (± SEM) in each group. The group of tumor-bearing mice to which Compound 4 was administered demonstrated significant tumor growth inhibition of 68% (t-test, p <0.001, versus the control (vehicle) group). Example 5: Administration of Compound 4 to CTG-3421 tumor-bearing intact male NOG mice

[0312] The intact CTG-3421 tumor-bearing male NOG mice were divided into two groups after the tumors had reached 190 mm3on average in volume: (a) the first group (n = 5) was orally administered vehicle once per day for 28 days; and (b) the second group (n = 5) was orally administered Compound 4 once per day for 14 days at a dose of 100 mg / kg, and then were orally administered Compound 4 once per day at a dose of 200 mg / kg for 14 days. The tumor volume in each mouse in each group was then measured on days 1, 5, 7, 12, 15, 19, 22, 26, and 28 following the administration of vehicle or Compound 4. FIG.5 shows the average tumor volume for the mice (± SEM) in each group. The group of tumor-bearing mice to which Compound 4was administered demonstrated significant tumor growth inhibition of 54% (t-test, p <0.05, versus the control (vehicle) group). Example 6: Treatment of AR-positive prostate cancer models with Compound 4

[0313] Four (4) cell line derived xenograft (CDX) and ten (10) patient-derived xenograft (PDX) models of AR-positive prostate cancer were selected for in vivo efficacy studies with Compound 4. The AR positivity of these models was confirmed based on expression of a transcriptional 21-gene AR signature (from Beltran et al, Nature Medicine 2016, and further restricted to genes that are induced by R1881 and repressed by AR inhibitors in LNCaP cells (Hieronymus et al, Cancer Cell 2006)), calculated as the averaged z-scored expression of the 21 genes, as well as the expression of luminal markers AR, KLK3, FOLH1, TMPRSS2, AMACR, NKX3-1, and FOXA1. The presence of AR splice variant AR-V7 in these tumors was determined using four exemplar AR-V7 testing modalities. The first two modalities relied on RNA-sequencing data from vehicle treated CDX and untreated PDX models with quantification against known transcripts, including AR full length (transcript AR-201) and AR-V7 (transcript AR-204). First, AR-V7 status was determined based on absolute expression levels of AR-V7. AR-V7-negative was defined as having absolute AR-V7 expression < 2, AR-V7-low (+) as ranging from 2 to <5, AR-V7-intermediate (++) as ranging from 5 to 100, and AR- V7-high (+++) as >100. Secondly, AR-V7 status was assessed based on the ratio of AR-V7 expression to the total abundance of all AR transcripts. Models with relative AR-V7 expression <10% were considered AR- V7-negative, AR-V7-low (+) models expressed 10-30% AR-V7, AR-V7-intermediate (++) models expressed >30-50% AR-V7, and AR-V7-high (+++) models expressed >50% AR-V7. Thirdly, western blotting (WB) was used to quantitate AR-V7 protein levels relative to beta-tubulin, in four vehicle-treated tumors per model, using the RevMAb clone RM7 (tables 1 and 2 show the average AR-V7 / b-tubulin level per model). For the CDX models, DU145 was included as negative control (average AR-V7 to beta-tubulin level of 0.0097). For the PDX models, AR-negative model CTG-3581 was included as negative control (average AR- V7 to beta-tubulin level of 0.0098). Based on WB results, AR-V7-negative was defined as AR-V7 / b-tubulin protein levels <0.01, AR-V7-low (+) as ranging from 0.01 to <0.1, AR-V7-intermediate (++) as ranging from 0.1 to 0.2, and AR-V7-high (+++) as >0.2. Lastly, immunohistochemistry (IHC) was used as an orthogonal method to quantitate AR-V7 protein levels using the same antibody. AR-V7-negative was defined as absent AR-V7 staining in the majority of tumor cells, AR-V7-low (+) as weak AR-V7 staining in a subset of tumor cells, AR-V7-intermediate (++) as weak to moderate AR-V7 staining in the majority of tumor cells, and AR- V7-high (+++) as moderate to strong AR-V7 staining in the majority of tumor cells.

[0314] In this example, models were considered positive for the splice variant AR-V7 when supported by at least 2 AR-V7 testing modalities (listed as global AR-V7 status in tables 1 and 2). CDX model 22Rv1 expresses high levels, and CDX model VCaP intermediate levels, of AR-V7, consistently observed at the absolute mRNA and protein level. CDX models C4-2 and LNCaP are negative for AR-V7. AR-V7 status in these models derived from RNA-sequencing, Western Blotting and IHC, are consistent with AR-V7 protein quantification by Western Blot in Sharp et al, JCI 2019, based on RevMAb clone RM7 and Abcam EPR15656.22Rv1 and VCaP expressed AR-V7 protein based on both antibodies, while LNCaP was negativefor AR-V7 (Sharp et al, JCI 2019). Three out of 10 PDX models (CTG-3337, CTG-3421, and CTG-3610) consistently expressed AR-V7 at the mRNA level and the protein level by both WB and IHC, with models CTG-3337 and CTG-3610 expressing intermediate-to-high AR-V7 levels and model CTG-3421 expressing low-to-intermediate AR-V7 levels. For three other PDX models, weak AR-V7 staining was observed by IHC in a subset of tumor cells. Among those models, the weak sub-clonal AR-V7 staining was corroborated by intermediate absolute AR-V7 mRNA expression for model CTG-2427, yet the weak positivity was not corroborated at the mRNA level for models CTG-2428 and CTG-2429.

[0315] The four AR-positive prostate cancer CDX models were treated once per day with Compound 4 at a concentration of 100 mg / kg. Three out of four models responded to treatment with Compound 4 using a TGI cutoff of 40% (FIG.1, FIG.2, FIG.3). Two of the three responsive models express intermediate-to-high levels of AR-V7, while non-responsive model LNCaP is AR-V7-negative. Ten AR-positive prostate cancer PDX models were treated once per day with Compound 4 at a concentration of 100-200 mg / kg. Two PDX models responded to Compound 4 (FIG.4, FIG.5), using a more stringent TGI cutoff of 50% given the smaller cohort size (5 mice / group for PDX vs.10 mice / group for CDX efficacy studies) and dose escalation to 200 mg / kg once daily in some PDX models. The two (2) responsive PDX models were determined to express AR-V7, versus two of the eight non-responsive PDX models. The data for the four cell line xenograft (CDX) models is shown in Table 1, while the data for the ten patient-derived xenograft (PDX) models is shown in Table 2. In Tables 1 and 2: AR= androgen receptor; QD = once daily; TGI = tumor growth inhibition; ND = not done. Taken together, four of five (80%) responsive CDX and PDX models express AR-V7, and seven of nine (78%) non-responsive CDX and PDX models are AR-V7-negative. Among the six AR-V7 expressing AR-positive prostate cancer models, four (67%) responded to treatment with Compound 4. Table 1Table 2Example 7: Preparation of crystalline Form 1 of Compound 4

[0316] 150 µL of methanol was added to 50 mg of the free base of Compound 4 and the resulting slurry was stirred at room temperature for one day. The resulting solids were vacuum filtered and dried under ambient condition overnight to afford Form 1 of Compound 4. Example 8A: Preparation of crystalline Form 2 of Compound 4

[0317] 400 mg of the free base of Compound 4 was dissolved in 1.5 mL of 2-methyltetrahydrofuran at 50 ºC, to which was added 1.5 mL n-heptane at about 47 °C, and the resulting mixture was cooled 10 °C. The resulting solids were vacuum filtered and allowed to air dry overnight under ambient conditions to afford Form 2 of Compound 4. Example 8B: Preparation of crystalline Form 2 of Compound 4

[0318] A quantity of the free base of Compound 4 was dissolved in 2-methyltetrahydrofuran (10 volumes) and then distilled to 3 volumes. The temperature of the solution was adjusted to about 25 ºC and the resulting slurry was stirred for greater than 30 minutes. To the slurry was added n-heptane (7 volumes) over 2 hours and the resulting mixture was stirred for greater than 4 hours. The resulting solid was filtered, the filter cake was washed with 30% 2-methyltetrahydrofuran / heptane (2 volumes) and dried in a vacuum oven to provide Form 2 of Compound 4. Example 9: X-ray powder diffraction (XRPD) analysis of Form 1 and Form 2 of Compound 4

[0319] XRPD analyses of crystalline polymorphic forms of Compound 4 were performed using Panalytical X’pert3X-ray powder diffractometer. Samples were spread on the middle of a zero-background Si holder. The 2-theta position was calibrated against a Panalytical Si reference standard disc. The parameters used for the analyses are set forth in Table 3. Table 3

[0320] Polymorphic Form 1 of Compound 4 was analyzed by XRPD as set forth above and exhibited the peaks set forth in Table 4. The error associated with each º2-theta position was determined to be ± 0.2º theta. Table 4

[0321] Polymorphic Form 2 of Compound 4 was analyzed by XRPD as set forth above and exhibited the peaks set forth in Table 5. The error associated with each º2-theta position was determined to be ± 0.2 º- theta. Table 5Example 10: Thermal gravimetric analyses and differential scanning calorimetry analyses of Form 1 and Form 2 of Compound 4

[0322] Thermal gravimetric analysis (TGA) data were collected using TA Discovery TGA 550 TGA from TA Instruments, and differential scanning calorimetry (DSC) analyses were performed using a TA Q2000 DSC from TA Instruments using the parameters set forth in Table 6. Table 6

[0323] A thermal gravimetric analysis (TGA) of a sample of Form 1 of Compound 4, when conducted under the conditions set forth in Table 4, exhibited a weight loss of about 1% upon heating the sample from room temperature to about the onset of melting (about 207 ºC). A differential scanning calorimetry (DSC) analysis of Form 1 of Compound 4, when conducted under the conditions set forth in Table 4, exhibited peaks at between about 170 ºC and 172 ºC, and between about 207 ºC and 208 ºC.

[0324] A thermal gravimetric analysis (TGA) of a sample of Form 2 of Compound 4, when conducted under the conditions set forth in Table 4, exhibited a weight loss of about 2% upon heating the sample from room temperature to about the onset of melting (about 204 ºC). A differential scanning calorimetry (DSC) analysis of Form 2 of Compound 4, when conducted under the conditions set forth in Table 4, exhibited a peak between about 203 ºC and 204 ºC. Example 11: Preparation of crystalline Form 2 of Compound 4

[0325] A reactor was evacuated and charged with nitrogen to atmospheric pressure. The reactor was then charged with a solution of Compound 4 (approximately 2.41 kg as determined by solution assay using HPLC) in 2-methyltetrahydrofuran (2-MeTHF, 36 kg, 15 volumes) and the batch was concentrated to a batch volume of about 5 L (about 2 volumes) via distillation under reduced pressure. The resulting solution was adjusted to about 25 °C and then n-heptane (0.4 kg, 0.2 volumes) was added in portions over a period of about 3 hours. The resulting solution was then seeded with Compound 4 Form 2 (9 g, 0.4 wt%), the resulting mixture was stirred for about 1.3 hours, and then additional n-heptane (24 kg, 10 volumes) was added over about 6 hours. The resulting slurry was stirred for about 4.25 hours at 25 °C and then filtered. The reactor was then rinsed with n-heptane (5.8 kg, 2.5 V), and this mixture was rinsed forward to the filter cake, which was deliquored and the solids were dried under reduced pressure at 40 °C and 50 °C for 19 hours to provide 2.48 kg of Form 2 of Compound 4.

Claims

CLAIMS WHAT IS CLAIMED:

1. A method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I)Formula (I) or a pharmaceutically acceptable salt thereof: wherein:represents a single or a double bond; Z is O or S; X is O, CR5, CR5OH, or C(R5)2, wherein: when X is O,is a single bond; when X is C(R5)2,is a single bond; when X is CR5OH,is a single bond; or when X is CR5,is a double bond; R1is aryl, heteroaryl, L-cycloalkyl, -N(R5)heterocyclyl, or L-heterocyclyl, wherein the aryl, the heteroaryl or the cyclyl portion of the L-cycloalkyl, -N(R5)heterocyclyl, or L-heterocyclyl is optionally substituted with one or more R4; R2is cyano, -COOR5, -C(O)N(R5)2, or -C(O)N(R5)2wherein each R5taken together with the nitrogen atom to which they are attached form a 5 - 8 membered heterocyclic ring optionally substituted with one or more R4; each R3is independently C1-C3alkyl or halogen; each R4is independently oxo, cyano, halogen, -PO3(C1-C3 alkyl)2, hydroxyl, alkoxy, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR5, -Y2-haloalkyl, -Y1-C1-C6alkyl, -Y2-C1-C6alkyl, -L- cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Y1-heterocyclyl, -Y2-heterocyclyl, -L-N(R5)2, -O-L- N(R5)2, -C(CF3)N(R5)2, -Y1-N(R5)2, -Y2-N(R5)2 wherein the ring portion of the aralkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl or -Y1-heterocyclyl is optionally substituted with one or more R7; L is a bond or C1-C4 alkylene; Y1is a bond, -C(O)-, or -NHC(O)-;Y2is a bond, -S-, -SO-, -SO2-, or -NR5SO2-, each R5is hydrogen or C1-C3alkyl; R6is hydrogen, C1-C3alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R7is oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, - L-N(R5)2, C1-C6alkyl, or -Y1-heterocyclyl; and n is 1 or 2.

2. The method of claim 1, wherein Z is O.

3. The method of claim 1 or 2, wherein n is 1.

4. The method of any of claims 1-3, wherein R2is cyano.

5. The method of any of claims 1-4, wherein R3is halogen.

6. The method of claim 5, wherein the halogen is fluorine.

7. The method of any of claims 1-6 wherein X is C(R5)2 and is a single bond.

8. The method of any of claims 1-7, wherein the aryl is phenyl optionally substituted with one or more R4.

9. The method of claim 8, wherein the phenyl is substituted with one, two or three R4.

10. The method of claim 9, wherein the one, two or three R4are each independently halogen, -PO3(C1-C3 alkyl)2, hydroxyl, hydroxyalkyl, aralkyl, haloalkyl, -COOR5, -Y1-C1-C6 alkyl, Y2-C1-C6 alkyl, -L- N(R5)2, -O-L-N(R5)2, -C(CF3)N(R5)2, -Y1-N(R5)2, -Y2-N(R5)2, Y2-haloalkyl, -L-heteroaryl, -L- heterocyclyl, or -Y1-heterocyclyl, wherein the heterocyclyl portion of the -L-heterocyclyl or -Y1- heterocyclyl is optionally substituted with one or more R7.

11. A method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:,, and.

12. A method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:,, and, or a pharmaceutically acceptable salt thereof.

13. The method of any one of claims 1-12, wherein the prostate cancer in the subject is localized high risk prostate cancer, recurrent prostate cancer, non-metastatic hormone-sensitive prostate cancer (nmHSPC), metastatic hormone-sensitive prostate cancer (mHSPC), non-metastatic castrate-resistant prostate cancer (nmCRPC), or metastatic castrate-resistant prostate cancer (mCRPC).

14. The method of any one of claims 1-13, wherein the androgen receptor splice variant lacking the ligand binding domain is selected from AR-V1, AR-V3, AR-V4, AR-V7, AR-V9, and AR-V12.

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