Treatment of Androgen Receptor Variant Prostate Cancer

Abstract

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

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 386,031, filed December 5, 2022, and U.S. Provisional Application No. 63 / 501,299, filed May 10, 2023, which applications are incorporated herein by reference in their entireties. [Background technology]

[0002] It is estimated that approximately 288,300 new cases of prostate cancer are diagnosed each year in the United States, and approximately 34,700 deaths from prostate cancer occur each year. Despite advances in available treatments for subjects with 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 prevent the development of, or delay the progression of, prostate cancer that is resistant to existing treatments and treatment regimens.

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

[0004] The incidence of genomic AR alterations increases over the course of prostate cancer treatment. The majority (98%) of primary prostate tumors are AR wild-type (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 wild-type prostate tumors decreased from 98% before treatment to 79% after ADT. In metastatic castration-resistant prostate cancer (mCRPC), after tumors developed resistance to ADT, 45% of antiandrogen-naive tumors were AR wild-type; this figure further decreased to 25% after exposure to antiandrogens in the SU2C mCRPC cohort (Source: Stand Up To Cancer; Dan et al., Cell 2015; Abida et al., PNAS 2019). In an ADT-resistant, abiraterone / enzalutamide-naive mCRPC cohort (45% AR wild-type), AR alterations included AR amplification (26%), AR splice variant AR-V7 (11%), and somatic AR mutations (18%). After exposure to abiraterone or enzalutamide (25% AR wild-type), the incidence of AR amplification increased to 36% and the AR splice variant AR-V7 increased to 20%.

[0005] AR structural rearrangements or splice variants are more frequently observed in patients after progression of antiandrogen therapy compared with patients in earlier stages of treatment (e.g., Li et al., Clin Cancer Res 2020). Many of the AR splice variants observed to be expressed in subjects with prostate cancer lack the ligand-binding domain of the AR protein. Expression of androgen receptor protein variants lacking the ligand-binding domain in subjects with prostate cancer is the most widely documented poor prognostic factor and resistance factor to multiple AR-targeted therapies in subjects receiving abiraterone and / or enzalutamide. The AR splice variant AR-V7 is the most abundant AR splice variant lacking the ligand-binding domain detected in circulating tumor cells from patients with CRPC. In preclinical studies, AR-V7 expression increased when cells were cultured in androgen-deprived medium, reflecting CPRC and AR-V7-promoted cell proliferation (Guo et al., Cancer Res 2009). Furthermore, knockdown of AR-V7 in AR-V7-expressing xenografts in vivo improved the antitumor activity achieved by enzalutamide, and AR-V7 expression was 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 common, and clinical data are based on smaller cohorts. In a cohort of 78 mCRPC patients, high concordance between AR-V7 and AR-V9 expression was observed (Fettke et al., Eur Urology 2020). The AR splice variants detected in circulating tumor cells from prostate cancer patients were primarily AR-V7 or AR-V567es, with AR-V1, AR-V3, or AR-V4 detected at lower frequencies (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 increased in the treated groups (68% and 30%), and AR-V567es typically co-occurred with AR-V7 (8 of 9) (Liu et al., J Urology 2016). Clinically, patients with AR-V7-positive prostate tumors had significantly lower prostate-specific antigen (PSA) response rates, progression-free survival, and overall survival compared with AR-V7-negative patients, a finding consistently observed across independent cohorts and trials for both enzalutamide and abiraterone (Li et al., Eur Urology Focus 2018). For example, in a cohort of mCRPC patients who had started standard-of-care treatment with enzalutamide or abiraterone, a 0% PSA response rate and significantly reduced PSA progression-free survival were observed in AR-V7-positive patients compared with AR-V7-negative patients (Antonarakis et al., NEJM 2014).Therefore, there remains a need to discover and develop new methods for treating subjects with prostate cancer, where the prostate cancer has been determined to express an androgen receptor splice variant that lacks the ligand-binding domain, including AR-V7. Summary of the Invention

[0006] Provided herein is a method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking a ligand binding domain, the method comprising administering to a subject a compound of formula (I):

[0007] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony,

[0008] [ka] represents a single or double bond, Z is O or S; X, O, CR 5 , C.R. 5 OH, or C(R 5 )2, where: When X is O,

[0009] [ka] is a single bond, X is C(R 5 )2,

[0010] [ka] is a single bond, X is CR 5 When OH,

[0011] [ka] is a single bond, or X is CR 5 When

[0012] [ka] is a double bond, R 1 is an aryl, heteroaryl, L-cycloalkyl, -N(R 5 )heterocyclyl, or L-heterocyclyl, wherein the L-cycloalkyl, the —N(R 5 ) heterocyclyl, or the aryl, heteroaryl, or cyclyl portion of the above L-heterocyclyl may be one or more R 4 optionally substituted with R 2 , cyano, -COOR 5 , -C(O)N(R 5 )2, or -C(O)N(R 5)2, where each R 5 together with the nitrogen atom to which they are attached, are one or more R 4 forming a 5- to 8-membered heterocycle optionally substituted with Each R 3 are independently C1-C3 alkyl or halogen; Each R 4 are independently oxo, cyano, halogen, -PO3(C1-C3 alkyl)2, hydroxyl, alkoxy, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR 5 , -Y 2 -haloalkyl, -Y 1 -C 1- C6 alkyl, -Y 2 -C1-C6 alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Y 1 -heterocyclyl, -Y 2 -heterocyclyl, -LN(R 5 )2, -OLN(R 5 )2, -C(CF3)N(R 5 )2, -Y 1 -N(R 5 )2, -Y 2 -N(R 5 )2, wherein the aralkyl, the -L-cycloalkyl, the -L-heteroaryl, the -L-heterocyclyl, or the -Y 1 The ring portion of a heterocyclyl may be one or more R 7 optionally substituted with L is a bond or C1-C4 alkylene; Y 1 is a bond, —C(O)—, or —NHC(O)—, Y 2 is a bond, -S-, -SO-, -SO2-, or -NR 5 SO2-, Each R 5 is hydrogen or C1-C3 alkyl, R 6 is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; Each R 7 is an oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -LN(R 5 )2, C1-C6 alkyl, or -Y 1 -heterocyclyl, n is 1 or 2.

[0013] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject with prostate cancer in combination with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are androgen receptor inhibitors or CYP17 inhibitors. In some embodiments, the one or more additional therapeutic agents are androgen receptor inhibitors. 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 are CYP17 inhibitors. In some embodiments, the CYP17 inhibitor is abiraterone. In some embodiments, the CYP17 inhibitor is abiraterone acetate. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered an androgen receptor inhibitor or a CYP17 inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and 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 a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered apalutamide.In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered darolutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered a CYP17 inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered abiraterone. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered abiraterone acetate. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered enzalutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered apalutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered darolutamide. In some embodiments, the prostate cancer in the subject is selected from untreated prostate cancer, hormone-sensitive prostate cancer, castration-resistant prostate cancer, metastatic prostate cancer, non-metastatic prostate cancer, and metastatic castration-resistant prostate cancer. In some embodiments, the prostate cancer is untreated 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 castration-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 castration-resistant prostate cancer.

[0014] Provided herein is a method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking a ligand binding domain, the method comprising administering to a subject a compound of formula (I):

[0015] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony,

[0016] [ka] represents a single or double bond, Z is O or S; X, O, CR 5 , C.R. 5 OH, or C(R 5 )2, where: When X is O,

[0017] [ka] is a single bond, X is C(R 5 )2,

[0018] [ka] is a single bond, X is CR 5 When OH,

[0019] [ka] is a single bond, or X is CR 5 When

[0020] [ka] is a double bond, R 1 is an aryl, heteroaryl, L-cycloalkyl, -N(R 5 )heterocyclyl, or L-heterocyclyl, wherein the L-cycloalkyl, the —N(R 5 ) heterocyclyl, or the aryl, heteroaryl, or cyclyl portion of the above L-heterocyclyl may be one or more R 4 optionally substituted with R 2 , cyano, -COOR 5 , -C(O)N(R 5 )2, or -C(O)N(R 5 )2, where each R 5 together with the nitrogen atom to which they are attached, are one or more R 4 forming a 5- to 8-membered heterocycle optionally substituted with Each R 3 are independently C1-C3 alkyl or halogen; Each R 4 are independently oxo, cyano, halogen, -PO3(C1-C3 alkyl)2, hydroxyl, alkoxy, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR 5 , -Y 2 -haloalkyl, -Y 1 -C 1- C6 alkyl, -Y 2 -C1-C6 alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Y 1 -heterocyclyl, -Y 2 -heterocyclyl, -LN(R 5)2, -OLN(R 5 )2, -C(CF3)N(R 5 )2, -Y 1 -N(R 5 )2, -Y 2 -N(R 5 )2, wherein the aralkyl, the -L-cycloalkyl, the -L-heteroaryl, the -L-heterocyclyl, or the -Y 1 The ring portion of a heterocyclyl may be one or more R 7 optionally substituted with L is a bond or C1-C4 alkylene; Y 1 is a bond, —C(O)—, or —NHC(O)—, Y 2 is a bond, -S-, -SO-, -SO2-, or -NR 5 SO2-, Each R 5 is hydrogen or C1-C3 alkyl, R 6 is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; Each R 7 is an oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -LN(R 5 )2, C1-C6 alkyl, or -Y 1 -heterocyclyl, n is 1 or 2.

[0021] In another embodiment, there is provided a method disclosed herein, wherein in the compound of formula (I), or a pharmaceutically acceptable salt thereof, Z is O. In another embodiment, there is provided a method disclosed herein, wherein in the compound of formula (I), or a pharmaceutically acceptable salt thereof, Z is S.

[0022] In other embodiments, there is provided a method disclosed herein, wherein n is 1 in the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0023] In other embodiments, the methods disclosed herein comprise the step of forming a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 In another embodiment, R 2 -COOR 5 or -C(O)N(R 5 )2. In other embodiments, R 2 -COOR 5 In other embodiments, R 2 is -C(O)N(R 5 )2.

[0024] In other embodiments, the methods disclosed herein comprise the step of forming a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is a halogen. 3 is fluorine.

[0025] In other embodiments, the methods disclosed herein comprise the step of forming a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is C(R 5 )2,

[0026] [ka] In another embodiment, X is a single bond. 5 and

[0027] [ka] is a double bond. In other embodiments, X is O,

[0028] [ka] is a single bond.

[0029] In other embodiments, the methods disclosed herein comprise the step of forming a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 but one or more R 4 In some embodiments, the aryl is aryl optionally substituted with one or more R 4 In other embodiments, the phenyl is optionally substituted with one, two, or three R 4 In some embodiments, one, two, or three R 4 are each independently halogen, -PO3(C1-C3 alkyl)2, hydroxyl, hydroxyalkyl, aralkyl, haloalkyl, -COOR 5 , -Y 1 -C1-C6 alkyl, Y 2 -C1-C6 alkyl, -LN(R 5 )2, -OLN(R 5 )2, -C(CF3)N(R 5 )2, -Y 1 -N(R 5 )2, -Y 2 -N(R 5 )2, Y 2 -haloalkyl, -L-heteroaryl, -L-heterocyclyl, or -Y 1 -heterocyclyl, where L-heterocyclyl or -Y 1 The heterocyclyl portion of the heterocyclyl may be one or more R 7 In other embodiments, R 4 -Y 1 -C1-C6 alkyl, and Y 1 is a bond and C1-C6 alkyl is methyl, ethyl, isopropyl, butyl, or pentyl. 4 -Y 2 -C1-C6 alkyl, and Y 2 is —SO— and C-C alkyl is methyl. In a further embodiment, R 4 -Y 2-haloalkyl, and Y 2 is -S- or -SO2- and haloalkyl is trifluoromethyl. In a further embodiment, R 4 -LN(R 5 )2, L is a bond, and each R 5 is hydrogen or each R 5 is methyl or one R 5 is methyl with one R 5 is hydrogen. In other embodiments, R 4 -LN(R 5 )2, L is methylene or ethylene, and each R 5 is hydrogen or each R 5 is methyl or one R 5 is methyl with one R 5 is hydrogen. In a further embodiment, R 4 Ha-Y 1 -N(R 5 )2 and Y 1 is -C(O)-, and each R 5 are independently hydrogen or each R 5 are independently methyl, or one R 5 is methyl and one R 5 is hydrogen. In other embodiments, R 4 Ha-Y 2 -N(R 5 )2 and Y 2 is -SO2-, and each R 5 are independently hydrogen or each R 5 is methyl or one R 5 is methyl and one R 5 are independently hydrogen. In yet other embodiments, R 4 Ha-Y 1 -heterocyclyl, and Y 1 is —C(O)—, and the heterocyclyl portion of the L-heterocyclyl is piperazinyl or 4-methyl-piperazinyl. 4is -L-heterocyclyl, L is a bond, and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or 3λ 2 -azabicyclo[3.1.0]hexanyl, each of which is one or more R selected from oxo, C-C alkyl, alkoxy, hydroxyl, and halogen. 7 In yet another embodiment, R 4 is -L-heterocyclyl, where L is methylene, and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, each of which is selected from one or more R selected from C1-C3 alkyl, alkoxy, hydroxyl, and halogen. 7 In a further embodiment, R 4 Ha-Y 1 -heterocyclyl, and Y 1 is -C(O)- and Y 1 The heterocyclyl portion of the -heterocyclyl is morpholinyl optionally substituted with one or more C1-C3 alkyl. 4 is one or more R 7 In yet another embodiment, -L-heteroaryl is tetrazolyl. A further embodiment is -L-heteroaryl optionally substituted with R 4 is -PO3(C1-C3 alkyl). In another embodiment, R 4 -COOR 5 In other embodiments, R 4 is hydroxyalkyl. In still other embodiments, R 4 -OLN(R 5 )2. In a further embodiment, R 4 is an aralkyl.

[0030] In other embodiments, the methods disclosed herein comprise the step of forming a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 but one or more R4 In a further embodiment, 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 of which may be substituted with one or more R 4 In a further embodiment, the heteroaryl is optionally substituted with one or more R 4 where each R 4 are independently cyano, halogen, -Y 1 -C1-C6 alkyl, -Y 2 -C1-C6 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -L-cycloalkyl, -LN(R 5 )2, -Y 1 -N(R 5 )2, -L-heteroaryl, -L-heterocyclyl, or -Y 1 -heterocyclyl, the heteroaryl of the above-mentioned -L-heteroaryl or the heterocyclyl portion of the above-mentioned L-heterocyclyl, or Y 1 -heterocyclyl may be one or more R 7 In yet another embodiment, heteroaryl is optionally substituted with hydroxyalkyl, heteroalkyl, haloalkyl, -Y 1 -C1-C6 alkyl, -LN(R 5 )2, L-heterocyclyl, or L-heteroaryl; 4 and the heteroaryl portion of said L-heteroaryl or the heterocyclyl portion of said L-heterocyclyl is optionally substituted with one or more R 7 A further embodiment is optionally substituted with R 4 is -L-heteroaryl, where L is methylene, and the heteroaryl is selected from one or more R 7In yet another embodiment, R is pyridyl optionally substituted with 4 is one or more R 7 In yet another embodiment, R is -L-heterocyclyl optionally substituted with R, where L is a bond and the heterocyclyl portion of said L-heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, or 4-methylpiperazinyl. 4 is one or more R 7 In a further embodiment, R is -L-heterocyclyl optionally substituted by, where L is methylene and the heterocyclyl portion of said L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl, or 4-methylpiperazinyl. 4 -LN(R 5 )2, where L is methylene and each R 5 are independently hydrogen or each R 5 are independently C1-C3 alkyl, or one R 5 is C1-C3 alkyl and one R 5 is hydrogen. In still other embodiments, R 4 Ha-Y 1 -C1-C6 alkyl, and Y 1 is a bond and C1-C6 alkyl is methyl, ethyl, or isopropyl. In further embodiments, heteroaryl is selected from hydroxyalkyl, heteroalkyl, haloalkyl, and -Y 1 two R independently selected from -C1-C6 alkyl; 4 In still other embodiments, heteroaryl is optionally substituted with a cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y 1 -C1-C6 alkyl, -LN(R 5 )2, -Y 1 -N(R 5 )2, -L-cycloalkyl, or one or more R 7one R independently selected from -L-heterocyclyl optionally substituted with 4 and pyridyl optionally substituted with

[0031] In other embodiments, the methods disclosed herein comprise the step of forming a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 but one or more R 4 is -L-cycloalkyl optionally substituted with

[0032] In other embodiments, the methods disclosed herein comprise the step of forming a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 but one or more R 4 In some embodiments, L is a bond and the heterocyclyl is piperidinyl or tetrahydropyranyl.

[0033] In other embodiments, there is provided a method disclosed herein, wherein n is 2 in the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0034] Also provided herein is a method of treating prostate cancer in a subject, comprising:

[0035] [ka]

[0036] [ka]

[0037] [ka]

[0038] [ka]

[0039]

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[0040]

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[0041]

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[0044]

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[0013] Methods are provided comprising administering to a subject a therapeutically effective amount of a compound of Formula (I) selected from the group consisting of: In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered an androgen receptor inhibitor or a CYP17 inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and 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 a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered apalutamide.In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered darolutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered a CYP17 inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered abiraterone. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered abiraterone acetate. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered enzalutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered apalutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered darolutamide. In some embodiments, the prostate cancer in the subject is selected from untreated prostate cancer, hormone-sensitive prostate cancer, castration-resistant prostate cancer, metastatic prostate cancer, non-metastatic prostate cancer, and metastatic castration-resistant prostate cancer. In some embodiments, the prostate cancer is untreated 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 castration-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 castration-resistant prostate cancer.

[0050] Also provided herein is a method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking a ligand binding domain, the method comprising:

[0051] [ka]

[0052] [ka]

[0053] [ka]

[0054] [ka]

[0055] [ka]

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] [ka]

[0061] [ka]

[0062] [ka]

[0063] [ka]

[0064] [ka]

[0065] [ka] The present invention provides a method comprising administering to a subject a therapeutically effective amount of a compound of formula (I) selected from the group consisting of:

[0066] Further provided herein is a method of treating prostate cancer in a subject, comprising:

[0067] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject with prostate cancer in combination with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are androgen receptor inhibitors or CYP17 inhibitors. In some embodiments, the one or more additional therapeutic agents are androgen receptor inhibitors. 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 are CYP17 inhibitors. 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 a subject in combination with one or more androgen receptor inhibitors, and 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 a subject in combination with one or more androgen receptor inhibitors, and 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 a subject in combination with one or more androgen receptor inhibitors, and 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 a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered enzalutamide.In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered apalutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered darolutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered a CYP17 inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered abiraterone acetate. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered abiraterone acetate. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered enzalutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered apalutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously received darolutamide.In some embodiments, the prostate cancer in the subject is selected from untreated prostate cancer, hormone-sensitive prostate cancer, castration-resistant prostate cancer, metastatic prostate cancer, non-metastatic prostate cancer, and metastatic castration-resistant prostate cancer. In some embodiments, the prostate cancer is untreated 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 castration-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 castration-resistant prostate cancer.

[0068] Further provided herein is a method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking a ligand binding domain, the method comprising:

[0069] [ka] or a pharmaceutically acceptable salt thereof.

[0070] In other embodiments, the method disclosed herein comprises the step of: providing a compound of formula (I) containing compound 1:

[0071] [ka] or a pharmaceutically acceptable salt thereof.

[0072] In other embodiments, the method disclosed herein comprises the step of: providing a compound of formula (I) containing compound 2:

[0073] [ka] or a pharmaceutically acceptable salt thereof.

[0074] In other embodiments, the method disclosed herein comprises the step of: providing a compound of formula (I) containing compound 3:

[0075] [ka] or a pharmaceutically acceptable salt thereof.

[0076] In other embodiments, the method disclosed herein comprises the step of: providing a compound of formula (I) containing compound 4:

[0077] [ka] or a pharmaceutically acceptable salt thereof.

[0078] Also provided herein is a method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking a ligand binding domain, the method comprising administering to a subject a compound of formula (I):

[0079] [ka] or a pharmaceutically acceptable salt thereof to the subject, wherein the compound 4 is in a crystalline form. Also provided herein are methods wherein the crystalline form of compound 4 is anhydrous. Also provided herein are methods wherein the crystalline form of compound 4 exhibits a peak at 8.1°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods wherein the crystalline form of compound 4 exhibits an additional peak at 9.6°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods wherein the crystalline form of compound 4 exhibits additional peaks at 5.7°±0.2°2θ, 19.7°±0.2°2θ, and 22.0°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits additional peaks at 9.8°±0.2°2θ, 15.2°±0.2°2θ, and 17.7°±0.2°2θ in an X-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits a peak at about 172°C in a differential scanning calorimetry pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits a peak at about 205°C to about 210°C in a differential scanning calorimetry pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits peaks at about 206°C to about 210°C, or about 207°C to about 210°C, or about 208°C to about 210°C, or about 209°C to about 210°C in a differential scanning calorimetry pattern. Also provided herein is a method, wherein the crystalline form of Compound 4 exhibits less than about 1% mass loss in thermogravimetric analysis when a sample is heated from about 25° C. to a temperature below the melting point. Also provided herein is a method, wherein the crystalline form of Compound 4 exhibits less than about 1% mass loss in thermogravimetric analysis when a sample is heated from about 25° C. to about 380° C.

[0080] Also provided herein are methods wherein the crystalline form of Compound 4 exhibits a peak at 7.7°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods wherein the crystalline form of Compound 4 exhibits additional peaks at 13.7°±0.2°2θ and 19.2°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods wherein the crystalline form of Compound 4 exhibits additional peaks at 5.5°±0.2°2θ, 8.6°±0.2°2θ, 15.9°±0.2°2θ, 19.9°±0.2°2θ, and 24.1°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits additional peaks at 10.6°±0.2°2θ, 11.0±0.2°2θ, 15.4°±0.2°2θ, 21.0°±0.2°2θ, and 26.3°±0.2°2θ in an X-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits a peak at about 203°C to about 210°C in a differential scanning calorimetry pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits a peak at about 203°C to about 208°C, or about 203°C to about 206°C, or about 203°C to about 205°C in a differential scanning calorimetry pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits a mass loss of less than about 2% in thermogravimetric analysis when a sample is heated from about 25°C to about 380°C. Also provided herein is a method, wherein a crystalline form of Compound 4 exhibits a mass loss of less than about 2% upon heating a sample from about 25°C to about 210°C in thermogravimetric analysis.

[0081] Also provided herein are methods in which the crystalline form of Compound 4 exhibits a peak at 7.7°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits an additional peak at 15.4°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits an additional peak at 19.2°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits an additional peak at 13.7°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits additional peaks in an X-ray powder diffraction (XRPD) pattern at 5.5°±0.2°2θ, 8.6°±0.2°2θ, 15.9°±0.2°2θ, 19.9°±0.2°2θ, and 24.1°±0.2°2θ. Also provided herein are methods in which the crystalline form of Compound 4 exhibits additional peaks in an X-ray powder diffraction (XRPD) pattern at 10.6°±0.2°2θ, 11.0±0.2°2θ, 21.0°±0.2°2θ, and 26.3°±0.2°2θ. Also provided herein are methods in which the crystalline form of Compound 4 exhibits peaks in a differential scanning calorimetry pattern between about 203°C and about 210°C. Also provided herein is a method in which the crystalline form of Compound 4 exhibits a peak at about 206°C to about 210°C in a differential scanning calorimetry pattern. Also provided herein is a method in which the crystalline form of Compound 4 exhibits a peak at about 203°C to about 208°C, or about 203°C to about 206°C, or about 203°C to about 205°C in a differential scanning calorimetry pattern. Also provided herein is a method in which the crystalline form of Compound 4 exhibits a mass loss of less than about 2% in thermogravimetric analysis when a sample is heated from about 25°C to about 380°C. Also provided herein is a method in which the crystalline form of Compound 4 exhibits a mass loss of less than about 2% in thermogravimetric analysis when a sample is heated from about 25°C to about 210°C.

[0082] Also provided herein are methods in which the crystalline form of Compound 4 exhibits peaks at 7.7°±0.2°2θ and 15.4°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits a peak at 19.2°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits an additional peak at 13.7°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits additional peaks at 5.5°±0.2°2θ, 8.6°±0.2°2θ, 15.9°±0.2°2θ, 19.9°±0.2°2θ, and 24.1°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits additional peaks at 10.6°±0.2°2θ, 11.0±0.2°2θ, 21.0°±0.2°2θ, and 26.3°±0.2°2θ in an X-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits a peak at about 203°C to about 210°C in a differential scanning calorimetry pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits a peak at about 206°C to about 210°C in a differential scanning calorimetry pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits a peak at about 203°C to about 208°C, or about 203°C to about 206°C, or about 203°C to about 205°C in a differential scanning calorimetry pattern. Also provided herein is a method, wherein the crystalline form of Compound 4 exhibits less than about 2% mass loss in thermogravimetric analysis when a sample is heated from about 25° C. to about 380° C. Also provided herein is a method, wherein the crystalline form of Compound 4 exhibits less than about 2% mass loss in thermogravimetric analysis when a sample is heated from about 25° C. to about 210° C.

[0083] Also provided herein are methods in which the crystalline form of Compound 4 exhibits peaks at 7.7°±0.2°2θ and 19.2°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits a peak at 15.4°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits an additional peak at 13.7°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits additional peaks at 5.5°±0.2°2θ, 8.6°±0.2°2θ, 15.9°±0.2°2θ, 19.9°±0.2°2θ, and 24.1°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits additional peaks at 10.6°±0.2°2θ, 11.0±0.2°2θ, 21.0°±0.2°2θ, and 26.3°±0.2°2θ in an X-ray powder diffraction (XRPD) pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits a peak at about 203°C to about 210°C in a differential scanning calorimetry pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits a peak at about 206°C to about 210°C in a differential scanning calorimetry pattern. Also provided herein are methods in which the crystalline form of Compound 4 exhibits a peak at about 203°C to about 208°C, or about 203°C to about 206°C, or about 203°C to about 205°C in a differential scanning calorimetry pattern. Also provided herein is a method, wherein the crystalline form of Compound 4 exhibits less than about 2% mass loss in thermogravimetric analysis when a sample is heated from about 25° C. to about 380° C. Also provided herein is a method, wherein the crystalline form of Compound 4 exhibits less than about 2% mass loss in thermogravimetric analysis when a sample is heated from about 25° C. to about 210° C.

[0084] Also provided herein are such methods, wherein the crystalline form of Compound 4 exhibits less than about 10% decomposition when stored at 25° C. 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% decomposition when stored at 25° C. and 60% relative humidity for at least 7 days.

[0085] Also provided herein are methods wherein the crystalline form of Compound 4, when stored at 25° C. and 60% relative humidity for at least 7 days, (a) exhibits a peak at 8.1°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern, and (b) exhibits less than about 10% decomposition. Also provided herein are methods wherein the crystalline form of Compound 4, when stored at 25° C. and 60% relative humidity for at least 7 days, (a) exhibits peaks at 9.6°±0.2°2θ, 5.7°±0.2°2θ, 19.7°±0.2°2θ, and 22.0°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern, and (b) exhibits less than about 10% decomposition. 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% decomposition when stored at 25° C. and 60% relative humidity for at least 7 days.

[0086] Also provided herein are methods wherein the crystalline form of Compound 4, when stored at 25° C. and 60% relative humidity for at least 7 days, exhibits (a) a peak at 7.7°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern, and (b) less than about 10% decomposition. Also provided herein are methods wherein the crystalline form of Compound 4, when stored at 25° C. and 60% relative humidity for at least 7 days, exhibits (a) peaks at 7.7°±0.2°2θ, 13.7°±0.2°2θ, and 19.2°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern, and (b) less than about 10% decomposition. 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% decomposition when stored at 25° C. and 60% relative humidity for at least 7 days.

[0087] Also provided herein are such methods, wherein the crystalline form of Compound 4 exhibits less than about 10% decomposition when stored at 40° C. 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% decomposition when stored at 40° C. and 75% relative humidity for at least 7 days.

[0088] Also provided herein are such methods, wherein a crystalline form of Compound 4, when stored at 40° C. and 75% relative humidity for at least 7 days, exhibits (a) a peak at 8.1°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern, and (b) less than about 10% decomposition. Also provided herein are such methods, wherein a crystalline form of Compound 4, when stored at 25° C. and 60% relative humidity for at least 7 days, exhibits (a) peaks at 9.6°±0.2°2θ, 5.7°±0.2°2θ, 19.7°±0.2°2θ, and 22.0°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern, and (b) less than about 10% decomposition. 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% decomposition when stored at 40° C. and 75% relative humidity for at least 7 days.

[0089] Also provided herein are such methods, wherein a crystalline form of Compound 4, when stored at 40° C. and 75% relative humidity for at least 7 days, exhibits (a) a peak at 7.7°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern, and (b) less than about 10% decomposition. Also provided herein are such methods, wherein a crystalline form of Compound 4, when stored at 40° C. and 75% relative humidity for at least 7 days, exhibits (a) peaks at 7.7°±0.2°2θ, 13.7°±0.2°2θ, and 19.2°±0.2°2θ in an x-ray powder diffraction (XRPD) pattern, and (b) less than about 10% decomposition. 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% decomposition when stored at 40° C. and 75% relative humidity for at least 7 days.

[0090] Also provided herein are such methods, wherein the crystalline form of Compound 4 exhibits less than about 10% decomposition when stored at 60° C. for at least 1 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% decomposition when stored at 60° C. for at least 1 week.

[0091] In other embodiments, the method disclosed herein comprises the step of: providing a compound of formula (I) containing compound 5:

[0092] [ka] or a pharmaceutically acceptable salt thereof.

[0093] In other embodiments, the method disclosed herein comprises the step of: providing a compound of formula (I) containing compound 6:

[0094] [ka] or a pharmaceutically acceptable salt thereof.

[0095] In other embodiments, the method disclosed herein comprises the step of: providing a compound of formula (I) containing compound 7:

[0096] [ka] or a pharmaceutically acceptable salt thereof.

[0097] In other embodiments, the method disclosed herein comprises the step of: providing a compound of formula (I) containing compound 8:

[0098] [ka] or a pharmaceutically acceptable salt thereof.

[0099] In other embodiments, the method disclosed herein comprises the step of: providing a compound of formula (I) containing compound 9:

[0100] [ka] or a pharmaceutically acceptable salt thereof.

[0101] In other embodiments, the method disclosed herein comprises the step of: providing a compound of formula (I) in a compound 10:

[0102] [ka] or a pharmaceutically acceptable salt thereof.

[0103] In other embodiments, the method disclosed herein comprises the step of: providing a compound of formula (I) containing compound 11:

[0104] [ka] or a pharmaceutically acceptable salt thereof.

[0105] In other embodiments, the method disclosed herein comprises the step of: providing a compound of formula (I) in a compound 12:

[0106] [ka] or a pharmaceutically acceptable salt thereof.

[0107] In other embodiments, the method disclosed herein is provided, wherein the prostate cancer in the subject is local high-risk prostate cancer, recurrent prostate cancer, non-metastatic hormone-sensitive prostate cancer (nmHSPC), metastatic hormone-sensitive prostate cancer (mHSPC), non-metastatic castration-resistant prostate cancer (nmCRPC), or metastatic castration-resistant prostate cancer (mCRPC). In some embodiments, the prostate cancer in the subject is local 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 castration-resistant prostate cancer (nmCRPC). In some embodiments, the prostate cancer in the subject is metastatic castration-resistant prostate cancer (mCRPC).

[0108] Also provided herein are methods, wherein expression of an androgen receptor splice variant lacking a ligand-binding domain is determined by measuring androgen receptor protein in a biological sample obtained from a subject. In some embodiments, the biological sample is blood or tissue. In other embodiments, the biological sample is blood. In other embodiments, the biological sample is tissue. In yet another embodiment, the tissue is obtained from a prostate cancer biopsy in the subject.

[0109] Also provided herein is a method, wherein the expression of an androgen receptor splice variant lacking a ligand-binding domain is determined by measuring mRNA encoding an androgen receptor protein in a biological sample obtained from a subject. In some embodiments, the biological sample is blood or tissue. In other embodiments, the biological sample is blood. In other embodiments, the biological sample is tissue. In yet another embodiment, the tissue is obtained from a prostate cancer biopsy in the subject.

[0110] Also provided herein is a method disclosed herein, further comprising administering to the subject one or more additional therapeutic agents.In some embodiments, the one or more additional therapeutic agents are selected from antimitotic agents, antimetabolites, platinum-based drugs, androgen receptor N-terminal domain inhibitors, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, CYP17 inhibitors, androgen receptor protein expression inhibitors, heat shock protein 90 (HSP90) inhibitors, bromodomain and extraterminal domain family (BET) inhibitors, and androgen receptor degraders, or combinations thereof.

[0111] In another embodiment, the method disclosed herein is provided, wherein the one or more additional therapeutic agents are androgen receptor inhibitors or CYP17 inhibitors. In some embodiments, the one or more additional therapeutic agents are androgen receptor inhibitors. 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 4:

[0112] [ka] or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the one or more additional therapeutic agents are CYP17 inhibitors. 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) is compound 4:

[0114] [ka] or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered an androgen receptor inhibitor or a CYP17 inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and 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 a subject in combination with one or more androgen receptor inhibitors, and 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 a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered darolutamide. In some embodiments, the compound of formula (I) is compound 4:

[0116] [ka] or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more androgen receptor inhibitors, and 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 a subject in combination with one or more androgen receptor inhibitors, and 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 a subject in combination with one or more androgen receptor inhibitors, and the subject has not previously been administered abiraterone acetate. In some embodiments, the compound of formula (I) is compound 4:

[0118] [ka] or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered enzalutamide. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more CYP17 inhibitors, and 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 a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered darolutamide. In some embodiments, the compound of formula (I) is administered to a subject in combination with one or more CYP17 inhibitors, and the subject has not previously been administered darolutamide.

[0120] [ka] or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the prostate cancer in the subject is selected from untreated prostate cancer, hormone-sensitive prostate cancer, castration-resistant prostate cancer, metastatic prostate cancer, non-metastatic prostate cancer, and metastatic castration-resistant prostate cancer. In some embodiments, the prostate cancer is untreated 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 castration-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 castration-resistant prostate cancer.

[0122] In another embodiment, a method for treating prostate cancer in a subject is provided, 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, wherein the prostate cancer in the subject is untreated. 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 selected from compound 4:

[0123] [ka] or a pharmaceutically acceptable salt thereof.

[0124] In another embodiment, a method for treating untreated prostate cancer in a subject is provided, 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 4:

[0125] [ka] or a pharmaceutically acceptable salt thereof.

[0126] In another embodiment, a method for treating hormone-sensitive prostate cancer in a subject is provided, 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 4:

[0127] [ka] or a pharmaceutically acceptable salt thereof.

[0128] In another embodiment, a method for treating metastatic prostate cancer in a subject is provided, 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 selected from compound 4:

[0129] [ka] or a pharmaceutically acceptable salt thereof.

[0130] In another embodiment, a method for treating non-metastatic prostate cancer in a subject is provided, 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 selected from compound 4:

[0131] [ka] or a pharmaceutically acceptable salt thereof.

[0132] In another embodiment, a method for treating androgen receptor inhibitor-naive prostate cancer in a subject is provided, 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 4:

[0133] [ka] or a pharmaceutically acceptable salt thereof.

[0134] In another embodiment, a method for treating enzalutamide-naive prostate cancer in a subject is provided, 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 4:

[0135] [ka] or a pharmaceutically acceptable salt thereof.

[0136] In other embodiments, there is provided a method of treating enzalutamide-naive prostate cancer in a subject, comprising:

[0137] [ka] or a pharmaceutically acceptable salt thereof in combination with enzalutamide to a subject.

[0138] In other embodiments, there is provided a method of treating darolutamide-naive prostate cancer in a subject, comprising:

[0139] [ka] or a pharmaceutically acceptable salt thereof, in combination with darolutamide to a subject.

[0140] In another embodiment, there is provided a method of treating apalutamide-naive prostate cancer in a subject, comprising:

[0141] [ka] or a pharmaceutically acceptable salt thereof in combination with apalutamide to a subject.

[0142] In another embodiment, a method for treating enzalutamide-resistant prostate cancer in a subject is provided, 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 selected from compound 4:

[0143] [ka] or a pharmaceutically acceptable salt thereof.

[0144] In another embodiment, a method for treating darolutamide-resistant prostate cancer in a subject is provided, 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 4:

[0145] [ka] or a pharmaceutically acceptable salt thereof.

[0146] In another embodiment, a method for treating apalutamide-resistant prostate cancer in a subject is provided, 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 4:

[0147] [ka] or a pharmaceutically acceptable salt thereof.

[0148] In another embodiment, a method for treating abiraterone-resistant prostate cancer in a subject is provided, 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 selected from compound 4:

[0149] [ka] or a pharmaceutically acceptable salt thereof.

[0150] In other embodiments, the methods disclosed herein are provided, wherein the one or more additional therapeutic agents are selected from a mitotic inhibitor, hi some embodiments, the mitotic inhibitor is selected from paclitaxel, docetaxel, cabazitaxel, tesetaxel, and nab-paclitaxel.

[0151] In still other embodiments, the one or more additional therapeutic agents are selected from an antimetabolite. In some embodiments, the one or more antimetabolites are selected from azacitidine, 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 azacitidine. 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.

[0152] In some embodiments, the one or more additional therapeutic agents are selected from platinum-based agents. In some embodiments, the platinum-based agent is 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.

[0153] In yet another embodiment, the one or more additional therapeutic agents are selected from an N-terminal domain inhibitor of the androgen receptor. In some embodiments, the N-terminal domain inhibitor of the androgen receptor is selected from EPI-001, EPI-002 (ralaniten), EPI-506, and EPI-7386. In some embodiments, the N-terminal domain inhibitor of the androgen receptor is EPI-001. In some embodiments, the N-terminal domain inhibitor of the androgen receptor is EPI-002 (ralaniten). In some embodiments, the N-terminal domain inhibitor of the androgen receptor is EPI-506. In some embodiments, the N-terminal domain inhibitor of the androgen receptor is EPI-7386.

[0154] In other embodiments, the methods disclosed herein are provided, wherein the one or more additional therapeutic agents are selected from poly(adenosine diphosphate-ribose) polymerase (PARP). In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is 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.

[0155] In another embodiment, the method disclosed herein is provided, wherein the one or more additional therapeutic agents are selected from a CYP17 inhibitor. In one embodiment, the CYP17 inhibitor is galeterone.

[0156] In other embodiments, the method disclosed herein is provided, wherein the one or more additional therapeutic agents are selected from an inhibitor 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.

[0157] In other embodiments, the methods disclosed herein are provided, 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, onarespib, geldanamycin, NVP-BEP800, SNX-2112 (PF-04928473), PF-04929113 (SNX-5422), KW-2478, XL888, TAS-116, VER-50589, CH5138303, VER-49009, NMS-E973, zeravespib (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 onarespib. 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 zeravespib (PU-H71). In some embodiments, the heat shock protein 90 (HSP90) inhibitor is HSP990 (NVP-HSP990).

[0158] In other embodiments, the methods disclosed herein are provided, wherein the one or more additional therapeutic agents are selected from one or more bromodomain and extraterminal domain family (BET) inhibitors. In some embodiments, the bromodomain and extraterminal domain family (BET) inhibitors include 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 extraterminal domain family (BET) inhibitor is I-BET 151 (GSK1210151A). In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is I-BET 762 (GSK525762). In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is GSK778 (iBET-BD1). In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is GSK046 (iBET-BD2). In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is OTX-015. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is TEN-010. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is CPI-203.In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is CPI-0610. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is orinone. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is RVX-208. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is ABBV-744. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is LY294002. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is AZD5153. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is MT-1. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is MS645. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is MS417. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is SJ432. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is RVX-208. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is ABBV-075 (mibebresib). In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is BMS-986158. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is PLX51107. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is INCB054329. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is INCB057643. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is FT-1101.In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is CC-90010. In one embodiment, the bromodomain and extraterminal domain family (BET) inhibitor is ODM-207.

[0159] In other embodiments, the methods disclosed herein are provided, wherein the one or more additional therapeutic agents are selected from an androgen receptor degrader. In some embodiments, the androgen receptor degrader is 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.

[0160] In another embodiment, a method is provided as disclosed herein, wherein the one or more additional therapeutic agents are selected from surgery, radiation, and a prostate-specific membrane antigen (PSMA)-targeted agent. 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 a prostate-specific membrane antigen (PSMA)-targeted agent. In one embodiment, the prostate-specific membrane antigen (PSMA)-targeted agent is 177 Lu-PSMA-617.

[0161] In another embodiment, there is provided a method disclosed herein, wherein the subject is administered one or more first agents prior to administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject, and the one or more first agents are selected from (a) a luteinizing hormone-releasing hormone (LHRH) agonist, (b) a luteinizing hormone-releasing hormone (LHRH) antagonist, (c) an androgen receptor inhibitor, (d) an inhibitor of cytochrome P45017A1, and / or (e) an antiandrogen.

[0162] In another embodiment, the method disclosed herein is provided, wherein the subject is administered one or more first agents prior to administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject, and the one or more first agents are luteinizing hormone-releasing hormone (LHRH) agonists. 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.

[0163] In another embodiment, the method disclosed herein is provided, wherein the subject is administered one or more first drugs before administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject, and the one or more first drugs are luteinizing hormone-releasing hormone (LHRH) antagonists. In some embodiments, the luteinizing hormone-releasing hormone (LHRH) antagonists are 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.

[0164] In another embodiment, the method disclosed herein is provided, wherein the subject is administered one or more first drugs before administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject, and the one or more first drugs are androgen receptor inhibitors. 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.

[0165] In another embodiment, the method disclosed herein is provided, wherein the subject is administered one or more first agents prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject, and the one or more first agents are cytochrome P450 17A1 inhibitors. In one embodiment, the one or more cytochrome P450 17A1 inhibitors is abiraterone acetate.

[0166] In another embodiment, the method disclosed herein is provided, wherein the subject is administered one or more first agents prior to administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject, and the one or more first agents are antiandrogens. In some embodiments, the antiandrogens are selected from egestrol, bicalutamide, flutamide, and nilutamide. In one embodiment, the antiandrogens are egestrol. In one embodiment, the antiandrogens are bicalutamide. In one embodiment, the antiandrogens are flutamide. In one embodiment, the antiandrogens are nilutamide.

[0167] Also provided is the method disclosed herein, wherein prior to administration of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject, the subject has advanced prostate cancer.

[0168] Also provided herein are methods, wherein the androgen receptor splice variant lacking a 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 a ligand-binding domain is AR-V1. In some embodiments, the androgen receptor splice variant lacking a ligand-binding domain is AR-V3. In some embodiments, the androgen receptor splice variant lacking a ligand-binding domain is AR-V4. In some embodiments, the androgen receptor splice variant lacking a ligand-binding domain is AR-V7. In some embodiments, the androgen receptor splice variant lacking a ligand-binding domain is AR-V9. In some embodiments, the androgen receptor splice variant lacking a ligand-binding domain is AR-V12.

[0169] Incorporation by Reference 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 explanation of the drawings]

[0170] [Figure 1] FIG. 1 shows tumor volumes after days of treatment in castrated male BALB / c nude mice bearing 22Rv1 tumors after administration of vehicle or Compound 4, as described in Example 1. [Figure 2] FIG. 1 shows tumor volumes after days of treatment in male NCG mice bearing C4-2 tumors after administration of vehicle or Compound 4, as described in Example 2. [Figure 3] FIG. 1 shows tumor volumes after days of treatment in castrated male CB17 SCID mice bearing VCaP tumors after administration of vehicle or Compound 4, as described in Example 3. [Figure 4] FIG. 1 shows tumor volumes after days of treatment in untreated male NOG mice bearing CTG-3337 tumors after administration of vehicle or Compound 4, as described in Example 4. [Figure 5] FIG. 1 shows tumor volumes after days of treatment in untreated male NOG mice bearing CTG-3421 tumors after administration of vehicle or Compound 4, as described in Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0171] As used in this specification and the appended claims, unless otherwise specified, the following terms have the meanings indicated below.

[0172] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, and a reference to "the cell" includes one or more cells (or cells) and equivalents thereof known to those of skill in the art, as well as others. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations and specific embodiments within the range are intended to be included. The term "about," when referring to a numerical value or numerical range, means that the referenced numerical value or numerical range is an approximation within experimental variation (or statistical experimental error); therefore, the numerical value or numerical range may, in some instances, vary by 1% to 15% of the stated numerical value 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 certain other embodiments, the embodiments, e.g., compositions of matter, compositions, methods, or processes described herein, "consist of" or "consist essentially of" the recited features.

[0173] "Administering," when used in conjunction with a therapeutic agent, including a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and / or one or more additional therapeutic agents, means administering the therapeutic agent directly, systemically, or locally into or onto a target tissue, or administering a therapeutic agent to a subject, thereby beneficially affecting the tissue to which the therapeutic agent is targeted. Thus, as used herein, the term "administering," when used in conjunction with the compositions described herein, can include, but is not limited to, delivering the composition into or onto a target tissue, or delivering the composition systemically to a subject, for example, by oral administration, thereby allowing the therapeutic agent to reach the target tissue or cell. "Administering" a composition may be by injection, topical administration, oral administration, or other methods, alone or in combination with other known techniques.

[0174] The term "androgen receptor splice variant" as used herein refers to a constitutively active androgen receptor (AR) protein variant that lacks the ligand-binding domain. Such splice variants may result from rearrangements 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 include gene rearrangement breakpoints resulting from deletions, inversions, tandem duplications, and / or translocation events. Such androgen receptor (AR) splice variants are further described 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 can arise from events including, but not limited to, splicing into 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).

[0175] As used herein, terms such as "determine", "determined" and "determining" refer to the fact that the preconditions for the subject exist or the preconditions for the subject are met before administering the compound of formula (I) or its pharmaceutically acceptable salt to the subject.For example, it is specifically contemplated herein that a subject with prostate cancer is eligible for treatment by administering the compound of formula (I) or its pharmaceutically acceptable salt to the subject, and optionally one or more additional therapeutic agents as described herein, if it is confirmed that the androgen receptor splice variant that lacks a ligand-binding domain, such as those described herein (e.g., AR-V7), exists in a biological sample (e.g., blood or tissue) obtained from the subject.

[0176] As used herein, the term "express" and "expresses" means that (a) the androgen receptor splice variant protein lacking the ligand binding domain, or (b) the mRNA encoding the androgen receptor splice variant protein lacking the ligand binding domain, is detected in a biological sample obtained from a subject, such as blood or tissue.The androgen splice variant protein lacking the ligand binding domain, or the mRNA encoding such a protein, can be detected in a biological sample obtained from a subject by the methods described herein and / or any other methods known to those skilled in the art.

[0177] The term "ligand-binding domain" used herein in relation to androgen receptor protein refers to the steroid-binding domain of androgen receptor (AR) protein.The term "androgen receptor splice variant lacking ligand-binding domain" refers to an isoform of androgen receptor protein that is a truncated form and lacks the C-terminal ligand-binding domain but retains the transactivation N-terminal domain.Examples of androgen receptor splice variants lacking ligand-binding domain include, but are not limited to, AR-V1 (also referred to as AR4 by those skilled in the art), AR-V3 (also referred to as AR1 / 2 / 2b by those skilled in the art), AR-V4 (also referred to as AR1 / 2 / 3 / 2b, AR5 by those skilled in the art), AR-V7 (also referred to as AR3 by those skilled in the art), AR-V9 and AR-V12 (also referred to as ARv567es by those skilled in the art).

[0178] The term "animal" as used herein includes, but is not limited to, humans and non-human vertebrates, such as wild, domestic, and livestock animals. As used herein, the terms "subject" and "individual" are intended to include organisms in which a particular disease described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In preferred embodiments, the subject is a primate. In certain embodiments, the primate or subject is human. In certain instances, the human is an adult. In certain instances, the human is a child. In further instances, the human is under 12 years of age. In certain instances, the human is an elderly person. In other instances, the human is 60 years of age or older. Other examples of subjects include laboratory animals, such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The laboratory animal can be an animal model of a disorder, e.g., a transgenic mouse with a hypertension condition.

[0179] The term "antiandrogen" as used herein refers to a drug that counteracts the effects of androgen in a subject.Antiandrogen agents include drugs that act as androgen biosynthesis inhibitors, such as drugs that inhibit 17α-hydroxylase / C17,20-lyase (CYP17).Antiandrogen agents also include drugs that inhibit the subject's ability to utilize androgens by interacting with androgen receptors, for example, by competitively inhibiting androgen binding to androgen receptors, including directly binding to the ligand-binding domain of androgen receptors.Antiandrogen agents can also act as antagonists by inhibiting the nuclear translocation of androgen receptors and their interaction with DNA, thereby inhibiting androgen receptor-mediated transcription.Antiandrogen agents also include AR degraders as described herein.

[0180] By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0181] The term "pharmaceutical composition" means a composition that includes at least one active ingredient, whereby the composition is suitable for investigation of a particular efficacious outcome in a mammal (e.g., but not limited to, 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 on the needs of the artisan.

[0182] The term "resistance" as used herein refers to cancer that no longer responds to administered treatment (e.g., antiandrogen).Determining whether a cancer in a subject, or one or more cells comprising cancer, has become resistant to a particular treatment modality can be performed by methods known to those skilled in the art.For example, in some cases, the responsiveness or non-responsiveness of a cancer in a subject, or one or more cells comprising cancer in a subject, can be evaluated by measuring prostate-specific antigen (PSA) level (e.g., by referring to the Prostate Cancer Working Group 3 (PCWG3) criteria), the increase or decrease in tumor size, using Response Evaluation Criteria in Solid Tumors (RECIST response) (e.g., for a description of RECIST v1.1, see Schwartz, et.al., Eur.J.Cancer, July 2016, vol.62, pp.132-137), the duration of response, or progression-free survival, as the case may be.

[0183] As used herein, the term "therapeutic agent" means an agent utilized to treat, combat, mitigate, prevent, or ameliorate an unwanted disease or disorder in a subject.

[0184] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is desired by a researcher, veterinarian, medical doctor, or other clinician, including one or more of the following: (1) preventing a disease, e.g., preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but who has not yet experienced or exhibited the symptoms or symptomology of the disease, (2) inhibiting a disease, condition, or disorder (i.e., halting further progression of the symptoms and / or symptomology) in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, condition, or disorder, and (3) ameliorating a disease, condition, or disorder (i.e., causing regression of the symptoms and / or symptomology) in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, condition, or disorder.

[0185] As used herein, the terms "treat," "treated," "treatment," or "treating" refer to therapeutic treatment whose purpose is to delay (alleviate) an undesirable physiological disease, disorder, or condition, or to obtain a beneficial or desired clinical outcome. For purposes described herein, a beneficial or desired clinical outcome includes, but is not limited to, alleviation of symptoms, a decrease in the extent of the disease, disorder, or condition, stabilization (i.e., not worsening) of the disease, disorder, or condition, delaying the onset or slowing the progression of the disease, disorder, or condition, palliation of the disease, disorder, or condition, and remission (whether partial or total), or improvement or amelioration of the disease, disorder, or condition, whether detectable or undetectable. Treating includes eliciting a clinically significant response without excessive levels of side effects. Treating also includes prolonging survival compared to expected survival in the absence of treatment.

[0186] 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 appropriate structural circumstances apparent to one of ordinary skill in the art. For example, an "alkyl" moiety generally refers to a monovalent radical (e.g., CH3-CH2-), but in certain circumstances, a divalent linking moiety can be "alkyl," in which case one of ordinary skill in the art would understand alkyl to be the divalent radical equivalent to "alkylene" (e.g., -CH2-CH2-). (Similarly, in situations where a divalent moiety is required and described as "aryl," one of ordinary skill in the art would understand the term "aryl" to refer to the corresponding divalent moiety, i.e., arylene.) All atoms are understood to have the usual number of valencies for bond formation (i.e., carbon is 4, N is 3, O is 2, and S is 2, 4, or 6, depending on the oxidation state of S).

[0187] The term "amino" as used herein refers to --NH.sub.2.

[0188] The term "acetyl" as used herein refers to "-C(O)CH3.

[0189] As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent, where the alkyl and aryl moieties are as defined herein.

[0190] The term "alkyl" as used herein refers to straight and branched chain aliphatic groups having 1 to 12 carbon atoms. Thus, "alkyl" includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C67, C68, C69, C70, C71, C72, C73, C74, C75, C76, C77, C78, ​​C79, C80, C81, C82, C83, C84, C85, C86, C87, C88, C89, C90, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C109, C110, C120, C121, C131, C132, C142, C143, C144 10 , C 11 , and C 12 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0191] The term "alkenyl" as used herein refers to an unsaturated straight- or branched-chain aliphatic group having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Thus, "alkenyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53 10 , C 11 , and C 12 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0192] The term "alkynyl" as used herein refers to an unsaturated straight- or branched-chain aliphatic group having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. Thus, "alkynyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53 10 , C 11 , and C 12 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0193] As used herein, "alkylene," "alkenylene," and "alkynylene" refer to 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, but are not limited to, methylene, ethylene, propylene, and butylene. Exemplary alkenylene groups include, but are not limited to, ethenylene, propenylene, and butenylene. Exemplary alkynylene groups include, but are not limited to, ethynylene, propynylene, and butynylene.

[0194] The term "alkoxy" as used herein refers to -OC1-C6 alkyl.

[0195] The term "cycloalkyl" as used herein refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons. Thus, "cycloalkyl" includes C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C70, C71, C72, C73, C74, C75, C76, C77, C78, ​​C79, C80, C81, C82, C83, C84, C85, C86, C87, C88, C89, C90, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C109, C110, C120, C131, C132, C142, C143, C144, C145, C151, C152, C153 10 , C 11 , and C 12 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0196] As used herein, the term "heteroalkyl" means that one or more carbon atoms in the chain are independently O, S, or NR x is replaced by R x is hydrogen or C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.

[0197] As used herein, the term "aryl" refers to a C-C alkyl group containing one to three aromatic rings. 14 It means an aromatic moiety. Thus, "aryl" refers to C, C 10 , C 13 , and C 14 Exemplary aryl groups include C-C 10 Particular aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl.

[0198] As used herein, the terms "aralkyl" and "arylalkyl" refer to an aryl group covalently bonded to an alkylene group, which in turn is bonded to another group via an alkyl moiety. Exemplary aralkyl groups include, but are not limited to, -(C-C)alkyl (C-C), including benzyl, phenethyl, and naphthylmethyl. 10 ) aryl.

[0199] As used herein, the terms "heterocyclyl" and "heterocyclic" refer to a monocyclic or bicyclic (fused or spiro) ring structure having 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms), e.g., 4 to 8 atoms, wherein one or more ring atoms are independently -C(O)-, N, NR 5 , O, or S, with the remaining ring atoms being quaternary or carbonyl carbons. Examples of heterocyclic groups include, but are not limited to, 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.

[0200] As used herein, the term "L-heterocyclyl" as used herein means a heterocyclyl group covalently attached to another group via an alkylene linker, L, where L is a C1-C4 alkylene.

[0201] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13, or 14 ring atoms, including an aromatic heterocyclic ring (e.g., 6, 10, or 14 π electrons shared in a cyclic arrangement), and having, in addition to carbon atoms, 1 to 3 heteroatoms, each independently N, O, or S. "Heteroaryl" also includes fused polycyclic (e.g., bicyclic) ring systems in which one or more of the fused rings are non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom.

[0202] 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, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, and furanyl. Lazanyl, 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, oxazo Allyl, 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, quinuclinyl thiazinyl, 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, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0203] As used herein, the terms "L-heteroaryl," "heteroaralkyl," and "heteroarylalkyl" refer to a group containing a heteroaryl group covalently bonded to another group via an alkylene linker. Examples of heteroalkyl groups include C1-C6 alkyl groups and heteroaryl groups 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, isoindolylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0204] As used herein, "arylene," "heteroarylene," and "heterocyclylene" refer to a divalent aryl, heteroaryl, or heterocyclyl group, as defined herein above, that is positioned between and serves to connect two other chemical groups.

[0205] As used herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as "optionally substituted" without explicitly reciting substituents, it means that the group optionally has 1 to 4, preferably 1 to 3, and more preferably 1 or 2 non-hydrogen substituents.

[0206] As used herein, the terms "halogen" and "halo" mean chlorine, bromine, fluorine, or iodine.

[0207] The term "haloalkyl" as used herein means an alkyl chain in which one or more hydrogens have been replaced by halogen. Exemplary haloalkyls are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0208] 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 with a hydroxyl.

[0209] 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, in U.S. Patent No. 11,091,495, or may be prepared using other reagents and conventional methods known to those skilled in the art, the contents of which are incorporated herein by reference for that purpose.

[0210] For example, compounds of the present invention and intermediates to compounds of formula (I) may be prepared according to the following general reaction schemes I or II.

[0211] General Reaction Scheme I

[0212] [ka] In General Reaction Scheme I, R 2 -ester substituted imidazo[1,2-c]pyrimidine A can be converted to R by nucleophilic substitution. 3 to an optionally substituted intermediate amine B to give intermediate C. 1 D is coupled to the halogen-substituted intermediate C via a Suzuki reaction in the presence of a suitable base, e.g., sodium carbonate, to form R 2 The ester is converted to an acid by saponification with NaOH to produce the intermediate acid E. This acid is converted to the corresponding amide, which is dehydrated to form the title compound nitrile G.

[0213] General Reaction Scheme II

[0214] [ka] In General Reaction Scheme II, the preferred R 2 A reactant, such as an ester-containing halogenated intermediate C, is converted to an acid intermediate by saponification under a suitable base, and then treated with NH4Cl in the presence of HATU to form an amide, which is subsequently dehydrated to form the nitrile intermediate H. 1 is coupled to intermediate H via a Suzuki reaction using a boronic acid derivative (Y) in the presence of a base. 1 The nitrile group of the containing intermediate G is hydrolyzed in the presence of acid and water to give the title compound amide F.

[0215] In some embodiments, provided is a method for treating prostate cancer in a subject, comprising administering to the subject a pharmaceutically acceptable salt of the compound of formula (I).Desired salt can be prepared by treating free base with any suitable method available in the art, for example, with inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid such as glucuronic acid or galacturonic acid, α-hydroxy acid such as citric acid or tartaric acid, amino acid such as aspartic acid or glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid, etc.In this specification, reference to the compound of formula (I) is also specifically intended to alternatively refer to the pharmaceutically acceptable salt of the compound of formula (I).

[0216] When a compound of formula (I), or a pharmaceutically acceptable salt thereof, is a solid, one of skill in the art will recognize that the compound or salt thereof may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and the specified formula.

[0217] Also provided herein is the use of isotopically labeled compounds of formula (I) or its pharmaceutically acceptable salts, wherein one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from that usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include hydrogen, 2 H and 3 Isotopes such as H, carbon 11 C. 13 C, and 14 Isotopes such as C, chlorine 36 Isotopes such as Cl, fluorine 18 Isotopes such as F, iodine 123 I and 125 isotopes such as I, 13 N and 15 Isotopes such as N, oxygen 15 O. 17 O, and 18 Isotopes such as O, 32 Isotopes such as P, and sulfur 35 Certain isotopically labeled compounds of the present invention, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. 2 Substitution with heavier isotopes, such as H, may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances. 11 C. 18 F, 15 O, and 13Substitution with positron-emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I), or pharmaceutically acceptable salts thereof, can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described herein, using a suitable isotopically labeled reagent in place of a non-labeled reagent that would normally be used.

[0218] In one embodiment, the compositions described herein, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, are used to treat prostate cancer in a subject. Such compositions can be prepared in a pharmaceutically acceptable dosage form for administration to a subject. Pharmaceutically acceptable dosage forms include, for example, liquids, suspensions, powders for reconstitution, tablets, pills, sachets, or hard or soft gelatin capsules (see, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 2011)). st See Ed. Mack Pub. Co., Easton, PA (2005). The compound of formula (I), or a pharmaceutically acceptable salt thereof, may be formulated into a pharmaceutical composition, as described below, in any pharmaceutical form that a person skilled in the art would recognize as appropriate. The pharmaceutical composition of the present invention comprises 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.

[0219] The pharmaceutical carrier used can be either solid or liquid. Exemplary solid carriers include lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, etc. Exemplary liquid carriers include syrup, peanut oil, olive oil, water, etc. Similarly, the composition may contain delayed-release or time-release materials known in the art, such as glyceryl monostearate or glyceryl distearate, alone or in combination with wax, ethylcellulose, hydroxypropylmethylcellulose, methyl methacrylate, etc. Additional additives or excipients may be added to achieve desired formulation properties. For example, bioavailability enhancers such as Labrasol, Gelucire, or formulation components (formulators) such as CMC (carboxymethylcellulose), PG (propylene glycol), or PEG (polyethylene glycol) may be added. For example, when preparing a capsule formulation, Gelucire, a semi-solid vehicle that protects the active ingredient from light, moisture, and oxidation, may be added.

[0220] 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 can vary, but will generally be about 25 mg to about 1 g. If a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial, or a non-aqueous liquid suspension. If a semi-solid carrier is used, the preparation can be in the form of hard or soft gelatin capsules. The compositions of the present invention are prepared in unit dosage forms appropriate for the mode of administration, for example, parenteral or oral administration.

[0221] To obtain a stable water-soluble dosage form, the 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 cosolvent or combination of cosolvents. Examples of suitable cosolvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, and the like, at concentrations ranging from 0 to 60% of the total volume. In an exemplary embodiment, the 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 water or a suitable aqueous vehicle, such as isotonic saline or dextrose solution.

[0222] Appropriate formulation varies depending on the selected route of administration.For injection, the compound of formula (I) or its pharmaceutically acceptable salt can be formulated in aqueous solution, preferably in physiologically compatible buffer solution such as Hanks' solution, Ringer's solution or physiological saline buffer.For transmucosal administration, penetrant suitable for the barrier to be penetrated is used in formulation.Such penetrant is generally known in the art.

[0223] For oral administration, compounds can be formulated by combining the active ingredient with a pharmaceutically acceptable carrier known in the art. Such carriers allow the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the subject to be treated. Pharmaceutical preparations for oral use can be obtained by using a solid excipient mixed with the active ingredient (drug), optionally grinding the resulting mixture, and optionally adding suitable excipients, followed by processing the granular mixture to obtain tablets or dragee cores. Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, and cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0224] The dragee core is provided with a suitable coating.For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.Dyes or pigments can be added to tablets or dragee coatings for identification or to characterize the combination of different active ingredients (medicines).

[0225] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active ingredient can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers can be added. All preparations for oral administration should be in dosages suitable for such administration. For buccal administration, the composition can be in the form of tablets or lozenges formulated in a conventional manner.

[0226] For intranasal administration or administration by inhalation, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be conveniently delivered in the form of an aerospray formulation from a pressurized pack or nebulizer using a suitable propellant, for example, 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. Gelatin capsules and cartridges for use in inhalers, insufflators, etc. may be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0227] The compound can be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion.The preparation for injection can be presented in a unit dosage form, for example, in ampoules or multi-dose containers, with added preservatives.The composition can be in the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents.

[0228] Pharmaceutical preparations for parenteral administration include aqueous solutions of water-soluble active compounds.In addition, suspensions of active agents can be prepared as suitable 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 can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran.Optionally, suspensions can also contain suitable stabilizers or agents that increase the solubility of compounds, allowing the preparation of highly concentrated solutions.

[0229] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0230] In addition to the formulations described above, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, may also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compound may be formulated with a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative, e.g., as a sparingly soluble salt. A pharmaceutical carrier for hydrophobic compounds is a cosolvent system containing benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be the VPD cosolvent system. VPD is a solution of 3% w / v benzyl alcohol, 8% w / v of the nonpolar surfactant polysorbate 80, and 65% w / v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD cosolvent system (VPD:5W) contains VPD diluted 1:1 with 5% dextrose in water. This cosolvent system dissolves hydrophobic compounds well and itself exhibits low toxicity upon systemic administration. The ratios of the cosolvent system may be suitably altered without compromising its solubility and toxicity characteristics. Furthermore, the identity of the cosolvent components may be altered. For example, other low-toxicity nonpolar surfactants may be used in place of polysorbate 80, the fraction size of polyethylene glycol may be altered, other biocompatible polymers may be substituted for polyethylene glycol, such as polyvinylpyrrolidone, and other sugars or polysaccharides may be substituted for dextrose.

[0231] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents, such as dimethyl sulfoxide (DMSO), may also be used, but usually at the expense of higher toxicity due to the toxic nature of DMSO. Furthermore, compounds may be delivered using sustained-release systems, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agents. Various sustained-release materials have been established and are known to those skilled in the art. Sustained-release capsules may release compounds for weeks to over 100 days, depending on their chemical nature. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization may be used.

[0232] The pharmaceutical compositions may also contain suitable solid- or gel-phase carriers or excipients. These carriers and excipients can significantly improve 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 glycol.

[0233] Additionally, the pharmaceutical composition may be incorporated into a skin patch for delivering the drug directly to the skin.

[0234] Furthermore, a pharmaceutically acceptable formulation of the compound of formula (I), or a pharmaceutically acceptable salt thereof, that can be used to practice the methods disclosed herein may contain the compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 0.5% to about 95% by weight, or about 1% to about 95% by weight, or about 1% to about 75% by weight, or about 5% to about 75% by weight, or about 10% to about 75% by weight, or about 10% to about 50% by weight.

[0235] It will be understood that the actual dosage of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, administered to a subject in need thereof will vary depending on the particular agent used, the particular composition formulated, the mode of administration, and the particular site, host, and disease being treated. One skilled in the art, using conventional dosage-determining tests in light of experimental data for a given compound, may ascertain the optimal dosage for a given set of conditions. For oral administration, exemplary daily doses typically employed range from about 0.001 mg / kg to about 1000 mg / kg of body weight, with treatment courses repeated at appropriate intervals. In some embodiments, a method is provided as disclosed herein, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in an amount between about 0.01 mg / kg / day and about 300 mg / kg / day. In other embodiments, methods are provided herein, wherein a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in an amount between about 0.1 mg / kg per day and about 100 mg / kg per day. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 10 mg and 500 mg per day. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 100 mg and about 400 mg per day. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 150 mg and 350 mg per day. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 150 mg and 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 and 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.

[0236] Furthermore, a pharmaceutically acceptable formulation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, that can be used to practice the methods disclosed herein may contain the compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 2000 mg, or about 10 mg to about 1500 mg, or about 10 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 10 mg to about 500 mg, or about 25 mg to about 500 mg, or about 50 mg to about 500 mg, or about 100 mg to about 500 mg.

[0237] 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. The compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof three times a day.

[0238] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof in a 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 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 in 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 every day of each 28-day cycle.

[0239] In some examples, the methods described herein involve administering compositions and formulations comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents to a subject or subjects in need thereof in multiple cycles repeated on a regular schedule with a rest period between each cycle. For example, in some examples, a treatment cycle consists of one week of treatment followed by three weeks of rest. The length of the treatment cycle varies depending on the treatment given. In some embodiments, the length of the treatment cycle ranges from two to six weeks. In some embodiments, the length of the treatment cycle ranges from three to six weeks. In some embodiments, the length of the treatment cycle ranges from three to four weeks. In some embodiments, the length of the treatment cycle is three weeks (or 21 days). In some embodiments, the length of the treatment cycle is four weeks (or 28 days). In some embodiments, the length of the treatment cycle is 56 days. In some embodiments, the treatment cycle lasts for one, two, three, or four weeks. In some embodiments, the treatment cycle lasts for three weeks. In some embodiments, the treatment cycle lasts for four weeks. Also, the number of treatment doses scheduled within each cycle will vary depending on the drug being given.

[0240] The dosage of the compositions described herein can be determined by any suitable method. When administered to a subject, the maximum tolerated dose (MTD) and maximum response dose (MRD) of the compound of formula (I), or its pharmaceutically acceptable salt, and the additional therapeutic agent can be determined through established animal and human experimental protocols and in the examples described herein. For example, the toxicity and therapeutic effect of the compound of formula (I), or its pharmaceutically acceptable salt, and the additional therapeutic agent can be determined by the LD 50 (a dose lethal to 50% of the population) and ED 50 The LD (the dose therapeutically effective in 50% of a population) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50The data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of such compounds is preferably determined to be an ED that produces minimal toxicity. 50 The circulating concentration range includes: (a) a maximum response of 100 mg / kg / day or more; (b) a maximum tolerated dose of 100 mg / kg / day or more; (c) a maximum response of 100 mg / kg / day or more; (d) a maximum tolerated dose of 100 mg / kg / day or more; (e) a maximum tolerated dose of 100 mg / kg / day or more; (f) a maximum tolerated dose of 100 mg / kg / day

[0241] In some embodiments, the amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical formulation containing the same corresponding to such amount, may vary depending on factors such as the particular salt or form, the disease state and its severity, the identity (e.g., age, weight, sex) of the subject or host requiring treatment, etc. However, the amount can nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the type of liquid formulation, the disease being treated, and the subject or host being treated.

[0242] Also provided herein are such methods, wherein the subject is 18 years of age or older. Also provided herein are such methods, wherein the subject has undergone bilateral orchiectomy. Also provided herein are such methods, wherein the subject is administered a GnRH analog or antagonist prior to administration of a 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.

[0243] Also provided herein is such a method, wherein the subject's prostate cancer progresses after administration of 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 subject's prostate cancer progresses after administration of abiraterone. In some embodiments, the subject's prostate cancer progresses after administration of enzalutamide. In some embodiments, the subject's prostate cancer progresses after administration of apalutamide. In some embodiments, the subject's prostate cancer progresses after administration of darolutamide.

[0244] Also provided herein are such methods, wherein the subject has not undergone more than two chemotherapy regimens prior to administering to the subject a compound of Formula (I).

[0245] Also provided herein are such methods, wherein prior to administering a compound of Formula (I) to the subject, the prostate cancer in the subject shows evidence of progressive disease according to Prostate Cancer Working Group 3 (PCWG3) criteria, including: (a) two or more elevated prostate-specific antigen (PSA) levels at least one week apart, with the most recent result being at least 2.0 ng / mL; (b) a PSA rise of 1.0 ng / mL; (c) two new bone lesions identified on previous systemic therapy; and (d) soft tissue progression according to RECIST 1.1 guidelines.

[0246] Also provided herein are such methods, wherein prior to administering a compound of Formula (I) to the subject, the prostate cancer in the subject exhibits evaluable disease according to RECIST 1.1 guidelines.

[0247] Also provided herein are such methods, wherein the subject exhibits an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 prior to administering a compound of Formula (I) to the subject.

[0248] Also provided herein are such methods, wherein prior to administering a compound of Formula (I) to the subject, the subject exhibits adequate organ function as defined by one or more of the following: (a) ANC of 1500 cells / mm 3 (1.5×103 cells / mm 3 ) or greater, (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 times the ULN, or ≤ 5.0 times the ULN for patients with liver metastases, (e) bilirubin ≤ 1.5 times the ULN, (f) estimated glomerular filtration rate ≥ 60 mL / min, and (g) QTcF ≤ 470 milliseconds.

[0249] Methods for detecting AR splice variants In some embodiments, the present disclosure provides a method for detecting the presence or absence or level of androgen receptor splice variant that lacks ligand binding domain.In some embodiments, the androgen receptor splice variant that lacks ligand binding domain is selected from AR-V1 (also referred to as AR4 by those skilled in the art), AR-V3 (also referred to as AR1 / 2 / 2b by those skilled in the art), AR-V4 (also referred to as AR1 / 2 / 3 / 2b, AR5 by those skilled in the art), AR-V7 (also referred to as AR3 by those skilled in the art), AR-V9, AR-V12 (also referred to as ARv567es by those skilled in the art). 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.

[0250] The presence or absence or levels of such androgen receptor splice variants can be measured in a biological sample obtained from a subject, such as a sample from a solid tumor such as prostate cancer, or from a sample of a relevant biological fluid, such as a blood sample. In some examples, the detection methods disclosed herein are useful for predicting a therapeutic response to a treatment described herein (e.g., administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject), monitoring treatment with a proliferative disease or disorder described herein in a subject, and treating the disease or disorder with this treatment.

[0251] In some embodiments, the presence, absence, and / or level of expression of androgen receptor splice variants is detected in a sample obtained from a subject by analyzing 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 to those skilled in the art. In some embodiments, the sample contains circulating tumor RNA (ctRNA). In some embodiments, the sample contains peripheral blood mononuclear cells (PBMCs). In some embodiments, the sample contains circulating tumor cells (CTCs). In some cases, the genetic material is obtained from a tumor biopsy or liquid biopsy. In some embodiments, the tumor biopsy includes a formalin-fixed, paraffin-embedded biopsy, a fresh frozen biopsy, an unprocessed biopsy, or a frozen biopsy. In some embodiments, the liquid biopsy includes PBMCs, circulating tumor RNA, plasma cell-free RNA, or circulating tumor cells (CTCs). Tumor and liquid biopsies can be subjected to further analytical processing for sample dissociation, cell sorting, and enrichment of cell populations of interest.

[0252] In some embodiments, a method for detecting the presence or level of an androgen receptor splice variant in a biological sample obtained from a subject includes detecting a nucleic acid sequence. In some cases, the nucleic acid sequence includes deoxyribonucleic acid (DNA), such as when detecting complementary DNA (cDNA) of an mRNA transcript. In some cases, the nucleic acid sequence includes a denatured DNA molecule or a fragment thereof. In some cases, the nucleic acid sequence includes DNA selected from the following: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA. In some cases, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denatured double-stranded DNA, synthetic DNA, and combinations thereof. The circular DNA may be cleaved or fragmented. In some cases, the nucleic acid sequence includes ribonucleic acid (RNA). In some cases, the nucleic acid sequence includes fragmented RNA. In some cases, the nucleic acid sequence includes partially degraded RNA. In some cases, the nucleic acid sequence includes microRNA or a portion thereof. In some examples, the nucleic acid sequence comprises an RNA molecule or fragmented RNA molecule (RNA fragment) selected from the following: microRNA (miRNA), pre-miRNA, pri-miRNA (pri-miRNA), mRNA, pre-mRNA, viral RNA, viroid RNA, virusoid RNA, circular RNA (circRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), pre-tRNA, long non-coding RNA (lncRNA), small nuclear RNA (snRNA), circular RNA, cell-free RNA, exosomal RNA, vector-expressed RNA, RNA transcript, synthetic RNA, and combinations thereof.

[0253] In some embodiments, disclosed herein, androgen receptor splice variants are detected by subjecting samples obtained from subjects to nucleic acid-based detection assays.In some examples, nucleic acid-based detection assays include quantitative polymerase chain reaction (qPCR), reverse transcription PCR (RT-qPCR), gel electrophoresis (including, for example, Northern blot 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, sequencing technology includes next-generation sequencing. In some embodiments, the method involves a hybridization assay such as fluorescent 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 specific primers and hybridization of the amplified nucleic acid probe containing a detectable moiety or molecule specific to the target nucleic acid sequence. In some examples, the number of amplification cycles for detecting the target nucleic acid in the qPCR assay is about 5 to about 30 cycles. In some examples, the number of amplification cycles for detecting the target nucleic acid is at least about 5 cycles. In some examples, the number of amplification cycles for detecting the target nucleic acid is up to about 30 cycles. In some examples, 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. In the case of the TaqMan™ method, the probe may be a hydrolyzable probe containing a fluorophore and a quencher that is hydrolyzed by DNA polymerase when hybridized to a target nucleic acid.In some cases, the presence of the target nucleic acid is determined when the number of amplification cycles to reach the threshold is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20. In some examples, hybridization can occur in a standard PCR buffer at a standard hybridization temperature, for example, between about 35°C and about 65°C.

[0254] Further exemplary nucleic acid-based detection assays include the use of nucleic acid probes conjugated or otherwise immobilized on beads, multi-well plates, or other substrates, wherein the nucleic acid probes are configured to hybridize with target nucleic acid sequences.In some examples, the nucleic acid probes are specific to one or more of the polynucleotide sequences encoding the relevant androgen receptor splice variants disclosed herein.In some examples, the nucleic acid probes specific to androgen receptor splice variants comprise nucleic acid probe sequences that are sufficiently complementary to the polynucleotide sequences encoding relevant androgen receptor splice variant proteins.In some examples, the probes comprise transcribed polynucleotide sequences (e.g., RNA, cDNA).In some embodiments, the nucleic acid probes can be, for example, full-length cDNAs or portions thereof, for example, oligonucleotides at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length, which can be sufficient to specifically hybridize with target nucleic acid sequences under standard hybridization conditions. 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 is immobilized on a solid surface, for example, in an Affymetrix gene chip array, and the probe is contacted with the target nucleic acid sequence.

[0255] In some embodiments, the term "probe" in reference to a nucleic acid refers to any nucleic acid molecule that can selectively bind to a specific intended target nucleic acid sequence. In some cases, the probe is specifically designed to be labeled with, for example, a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags known in the art. In some cases, the fluorescent label comprises a fluorophore. In some cases, the fluorophore is an aromatic or heteroaromatic compound. In some cases, the fluorophore is pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzoindole, oxazole, thiazole, benzothiazole, cyanine, carbocyanine, salicylate, anthranilate, xanthene dye, or coumarin. Exemplary xanthene dyes include, for example, 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), and 6-carboxy-X-rhodamine (ROX). Suitable fluorescent probes also include naphthylamine dyes with an amino group at the α or β position. For example, naphthylamino compounds include 1-dimethylaminonaphthyl-5-sulfonate, 1-anilino-8-naphthalenesulfonate, and 2-p-toluidinyl-6-naphthalenesulfonate, 5-(2'-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS).Exemplary coumarins include, for example, 3-phenyl-7-isocyanatocoumarin, acridines such as 9-isothiocyanatoacridine and acridine orange, N-(p-(2-benzoxazolyl)phenyl)maleimide, indodicarbocyanine 3 (C y3), indodicarbocyanine 5 (C y5), indodicarbocyanine 5.5 (C y6), y5.5), cyanines such as 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 BODIPY™ dyes. In some cases, the probe contains FAM as the dye label.

[0256] In some embodiments, detecting one or more androgen receptor splice variants comprises sequencing the genetic material obtained from a sample from a subject.Sequencing can be carried out using any suitable sequencing technology, including but not limited to single molecule real-time (SMRT) sequencing, polony sequencing, ligation sequencing, 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 modern sequencing technologies such as next-generation sequencing, for example, Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next generation sequencing includes high-throughput sequencing methods. Additional sequencing methods available to those of skill in the art may also be used.

[0257] In some examples, the number of nucleotides sequenced is 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 examples, the number of nucleotides to be sequenced is from about 1 to about 100,000 nucleotides, from about 1 to about 10,000 nucleotides, from about 1 to about 1,000 nucleotides, from about 1 to about 500 nucleotides, from about 1 to about 300 nucleotides, from about 1 to about 200 nucleotides, from about 1 to about 100 nucleotides, from about 5 to about 100,000 nucleotides, from about 5 to about 10,000 nucleotides, from about 5 to about 1,000 nucleotides, from about 5 to about 500 nucleotides, from about 5 to about 300 nucleotides, from about 5 to about 200 nucleotides, from about 5 to about 100 nucleotides, from about 10 to about 100,000 nucleotides, from about 10 to about 10,000 nucleotides, from about 10 to about 1,000 nucleotides, from about 10 to about 500 nucleotides, from about 10 to about 300 nucleotides, from about 10 to about 200 nucleotides, or from about 10 to about 100 nucleotides. The length of the fragment is in the range of about 20 to about 100,000 nucleotides, about 20 to about 10,000 nucleotides, about 20 to about 1,000 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 100,000 nucleotides, about 30 to about 10,000 nucleotides, about 30 to about 1,000 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 100,000 nucleotides, about 50 to about 10,000 nucleotides, about 50 to about 1,000 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.

[0258] Disclosed herein is a method comprising: (a) providing a biological sample from a subject with prostate cancer; (b) performing an assay to detect the presence or absence of an androgen receptor splice variant lacking a ligand-binding domain in the biological sample from the subject; and (c) using the methods described herein to detect the presence or absence of an androgen receptor splice variant lacking a ligand-binding domain in the biological sample. In some cases, a hybridization assay, such as that described herein, is used to detect mRNA encoding an androgen receptor splice variant lacking a ligand-binding domain in the sample. Exemplary probe sequences hybridizable to the target nucleic acid sequence include at least 10 but not more than 100 consecutive nucleotides containing the relevant sequence. In some cases, RNA sequencing (RNAseq) is used to detect mRNA encoding the relevant androgen receptor splice variant protein.

[0259] The detection of mRNA sometimes involves the amplification of the nucleic acid of interest by polymerase chain reaction (PCR). In some embodiments, the PCR assay involves the use of a primer pair that can amplify at least about 10 consecutive nucleic acid bases in a nucleic acid sequence, thereby amplifying one or more gene products in the biomarker. In fluorescent quantitative PCR, quantification is based on the amount of fluorescent signal (TaqMan and SYBR Green). In some embodiments, the nucleic acid probe is conjugated to a detectable molecule. The detectable molecule can be a fluorophore. The nucleic acid probe can also be conjugated to a quencher.

[0260] In some embodiments, an assay for detecting the presence or absence of mRNA encoding a relevant androgen receptor splice variant lacking a 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 complementary to the 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 primer pair. In some embodiments, the primers comprise a first primer having a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within the relevant nucleic acid sequence that binds to the top strand of the double-stranded hybridization product, and a second primer having a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within the nucleic acid sequence that is reverse complementary to the relevant nucleic acid sequence that binds to the bottom strand of the double-stranded hybridization product.

[0261] In some embodiments, the present disclosure provides a method comprising preparing a complementary DNA (cDNA) library.In some embodiments, the cDNA library is sequenced using a suitable sequencing method disclosed herein.In some embodiments, the cDNA library is labeled, and a plurality of nucleic acid probes are generated and fixed on a fixed surface (such as a microarray).In some embodiments, the plurality of nucleic acid probes can hybridize to at least about 10 consecutive nucleotides of two or more genes in a sample obtained from a subject.In some embodiments, detecting the presence or absence of androgen receptor splice variants comprises detecting high or low level expression of one or more genes compared to a reference level.

[0262] In some embodiments, it is disclosed herein that genetic material is extracted from a biological sample obtained from a subject, such as a blood, serum, or tissue sample. In certain embodiments in which nucleic acids are extracted, the nucleic acids are extracted using any technique that does not interfere with subsequent analysis. In certain embodiments, the technique uses alcohol precipitation using ethanol, methanol, or isopropyl alcohol. In certain embodiments, the technique uses phenol, chloroform, or any combination thereof. In certain embodiments, the technique uses cesium chloride. In certain embodiments, the technique uses sodium acetate, potassium acetate, or ammonium acetate, or any other salt typically used to precipitate DNA. In certain embodiments, the technique utilizes a column- or resin-based nucleic acid purification scheme, such as those commonly available commercially; one non-limiting example would be the GenElute bacterial genomic DNA kit available from Sigma-Aldrich. In certain embodiments, after extraction, the nucleic acids are stored in water, Tris buffer, or Tris-EDTA buffer prior to subsequent analysis. In exemplary embodiments, the nucleic acid material is extracted in water. In some cases, the extraction does not include nucleic acid purification. In certain embodiments, RNA may be extracted from cells using RNA extraction techniques including, for example, acid phenol / guanidine isothiocyanate extraction (RNAzol B, Biogenesis), the RNeasy RNA preparation kit (Qiagen), or the use of PAXgene (PreAnalytix, Switzerland).

[0263] In some aspects, circulating tumor RNA (ctRNA) is used to evaluate the expression level of RNA molecules released into the bloodstream by tumors.In some embodiments, detecting ctRNA is useful, for example, for detecting and diagnosing tumors.Because tumor DNA and RNA acquire multiple genetic mutations, resulting in tumor development, ctRNA is not an exact match for individual DNA and RNA, respectively.The discovery of DNA and RNA with genetic differences is useful for tumor detection.Using ctRNA to diagnose tumor types can reduce the need to obtain tumor tissue samples (tumor biopsy), which can be difficult when tumors are difficult to access, such as tumors in the brain or lung.

[0264] In some embodiments, a decrease in the amount of ctRNA indicates that the solid tumor is shrinking and that treatment with the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is effective. In some embodiments, the absence of ctRNA in the bloodstream indicates that the cancer has not recurred after treatment with the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0265] This document describes a method for evaluating genetic alterations by ctRNA profiling. In some embodiments, genomic profiling is performed after each treatment cycle with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, genetic mutations indicate that cancer has become resistant to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the absence of genetic mutations indicates that cancer has not become resistant to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0266] Disclosed herein is a method for treating prostate cancer in a subject in need thereof, comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, one or more cells comprising prostate cancer in the subject have been determined to express an androgen receptor splice variant lacking a ligand-binding domain. In some embodiments, the expression of the androgen receptor splice variant lacking a ligand-binding domain is measured by immunohistochemistry (IHC) assay. In some embodiments, the expression of the androgen receptor splice variant lacking a ligand-binding domain is measured by immunofluorescence (IF) assay. In some embodiments, the expression of the androgen receptor splice variant lacking a ligand-binding domain is measured by in situ hybridization (ISH) assay. In some embodiments, the expression transcription level of the androgen receptor splice variant lacking a ligand-binding domain is measured using assays such as quantitative polymerase chain reaction (qPCR), microarrays, and RNA sequencing, or commercially available assays from companies such as Fluidigm and Nanostring.

[0267] Disclosed herein is a method for treating prostate cancer in a subject in need thereof, wherein one or more cells comprising prostate cancer are determined to express an androgen receptor splice variant lacking a ligand-binding domain. In some embodiments, the expression of the androgen receptor splice variant lacking a ligand-binding domain is based on the expression level of the androgen receptor splice variant lacking the binding domain that deviates from a reference expression level. In some embodiments, the expression level of the androgen receptor is standardized, for example, by z-score. In some embodiments, the expression level is higher than the reference expression level. In some embodiments, the expression level is lower than the reference expression level. In some embodiments, the reference expression level is derived from an individual or group of individuals without cancer. In some embodiments, the reference expression level is derived from an individual or group of individuals with cancer that does not respond therapeutically 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%.

[0268] In some embodiments, determination of androgen receptor splice variant expression is defined based on the percentage of cells that stain weakly, moderately, or strongly for the relevant androgen receptor variant, with thresholds defining the minimum percentage of cells required to stain positive at various intensity levels (e.g., a% or more of prostate tumor cells weakly stained, b% or more of prostate tumor cells moderately stained, c% or more of prostate tumor cells strongly stained, or combinations thereof). In some embodiments, the one or more cells comprising prostate cancer are those in which about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, or about 95% or more of the prostate tumor cells stain weakly for an androgen receptor splice variant. or greater than about 20%, or greater than about 25%, or greater than about 30%, or greater than about 35%, or greater than about 40%, or greater than about 45%, or greater than about 50%, or greater than about 55%, or greater than about 60%, or greater than about 65%, or greater than about 70%, or greater than about 75%, or greater than about 80%, or greater than about 85%, or greater than about 90%, or greater than about 95% of the cells stain moderately for the androgen receptor splice variant, or any combination thereof, are determined to express an androgen receptor splice variant lacking the ligand binding domain.

[0269] Kits and Products In certain embodiments, kits and products are disclosed 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, etc., and each of the containers contains one of the separate elements that will be used in the methods described herein.Suitable containers include, for example, bottles, vials, syringes, and test tubes.In one embodiment, the container is made of various materials, such as glass or plastic.

[0270] The kit typically includes a label and / or instructions listing the contents, as well as a package insert containing the instructions. A set of instructions is also typically included.

[0271] In one embodiment, a label is on or associated with a container. In one embodiment, a label is on a container when letters, numbers, or other symbols forming the label are attached, molded, or etched into the container itself, and a label is associated with a container when it is present in a receptacle or carrier that holds the container, for example, as a package insert. In one embodiment, a label is used to indicate that the contents are to be used for a particular therapeutic application. Also, the label provides instructions for using the contents, such as in the methods described herein.

[0272] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device containing one or more unit dosage forms containing a compound provided herein. The pack contains, for example, 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 also has a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the drug form for human or veterinary administration. Such notice may be, for example, a drug label approved by the U.S. Food and Drug Administration or an approved package insert. In one embodiment, a composition containing a compound provided herein formulated in a compatible pharmaceutical carrier is prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0273] 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 containing instructions for measuring the expression of an androgen receptor splice variant lacking a ligand binding domain in one or more cells comprising prostate cancer, and using the compound of formula (I), or a pharmaceutically acceptable salt thereof, if one or more of the cells comprising prostate cancer are determined to express an androgen receptor splice variant lacking a ligand binding domain.

[0274] Enumeration of Embodiments 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 a ligand binding domain, the method comprising:

[0275] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony,

[0276] [ka] represents a single or double bond, Z is O or S; X, O, CR 5 , C.R. 5 OH, or C(R 5 )2, where: When X is O,

[0277] [ka] is a single bond, X is C(R 5 )2,

[0278] [ka] is a single bond, X is CR 5 When OH,

[0279] [ka] is a single bond, or X is CR 5 When

[0280] [ka] is a double bond, R 1 is an aryl, heteroaryl, L-cycloalkyl, -N(R 5 )heterocyclyl, or L-heterocyclyl, wherein the L-cycloalkyl, the —N(R 5 ) heterocyclyl, or the aryl, heteroaryl, or cyclyl portion of the above L-heterocyclyl may be one or more R 4 optionally substituted with R 2 , cyano, -COOR 5 , -C(O)N(R 5 )2, or -C(O)N(R 5 )2, where each R 5 together with the nitrogen atom to which they are attached, are one or more R 4 forming a 5- to 8-membered heterocycle optionally substituted with Each R 3 are independently C1-C3 alkyl or halogen; Each R 4 are independently oxo, cyano, halogen, -PO3(C1-C3 alkyl)2, hydroxyl, alkoxy, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR 5 , -Y 2 -haloalkyl, -Y 1 -C 1- C6 alkyl, -Y 2-C1-C6 alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Y 1 -heterocyclyl, -Y 2 -heterocyclyl, -LN(R 5 )2, -OLN(R 5 )2, -C(CF3)N(R 5 )2, -Y 1 -N(R 5 )2, -Y 2 -N(R 5 )2, wherein the aralkyl, the -L-cycloalkyl, the -L-heteroaryl, the -L-heterocyclyl, or the -Y 1 The ring portion of a heterocyclyl may be one or more R 7 optionally substituted with L is a bond or C1-C4 alkylene; Y 1 is a bond, —C(O)—, or —NHC(O)—, Y 2 is a bond, -S-, -SO-, -SO2-, or -NR 5 SO2-, Each R 5 is hydrogen or C1-C3 alkyl, R 6 is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; Each R 7 is an oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -LN(R 5 )2, C1-C6 alkyl, or -Y 1 -heterocyclyl, The method wherein n is 1 or 2.

[0281] Embodiment 2. The method of embodiment 1, wherein Z is O.

[0282] Embodiment 3. The method of embodiment 1, wherein Z is S.

[0283] Embodiment 4. The method of any of embodiments 2 or 3, wherein n is 1.

[0284] Embodiment 5.R 2 5. The method of any one of embodiments 1 to 4, wherein is cyano.

[0285] Embodiment 6.R 2 Ga-COOR 5 5. The method of any one of embodiments 1 to 4, wherein

[0286] Embodiment 7.R 2 -C(O)N(R 5 5. The method of any one of embodiments 1 to 4, wherein

[0287] Embodiment 8.R 3 The method of any one of embodiments 1 to 7, wherein is a halogen.

[0288] Embodiment 9. The method of embodiment 8, wherein the halogen is fluorine.

[0289] Embodiment 10. X is C(R 5 )2,

[0290] [ka] 10. The method of any one of embodiments 1 to 9, wherein is a single bond.

[0291] Embodiment 11.X is CR 5 and

[0292] [ka] 10. The method of any one of embodiments 1 to 9, wherein is a double bond.

[0293] Embodiment 12. X is O;

[0294] [ka] 10. The method of any one of embodiments 1 to 9, wherein is a single bond.

[0295] Embodiment 13.R 1 but one or more R 4 13. The method of any one of embodiments 1-12, wherein R is aryl optionally substituted with R.

[0296] Embodiment 14. The aryl may comprise one or more R 4 14. The method of embodiment 13, wherein R is phenyl optionally substituted with R.

[0297] Embodiment 15. The phenyl has one, two, or three R 4 15. The method of embodiment 14, wherein said amino acid is substituted with

[0298] Embodiment 16. One, two, or three of the above R 4 each independently represents halogen, -PO3(C1-C3 alkyl), hydroxyl, hydroxyalkyl, aralkyl, haloalkyl, -COOR 5 , -Y 1 -C1-C6 alkyl, Y 2 -C1-C6 alkyl, -LN(R 5 )2, -OLN(R 5 )2, -C(CF3)N(R 5 )2, -Y 1 -N(R 5 )2, -Y 2 -N(R 5 )2, Y 2 -haloalkyl, -L-heteroaryl, -L-heterocyclyl, or -Y 1 -heterocyclyl, and L-heterocyclyl or -Y 1 -the heterocyclyl moiety of the heterocyclyl is one or more R 7 16. The method of embodiment 15, optionally substituted with

[0299] Embodiment 17.R 4 Ga-Y 1 -C1-C6 alkyl, and Y 117. The method of embodiment 16, wherein is a bond and C1-C6 alkyl is methyl, ethyl, isopropyl, butyl, or pentyl.

[0300] Embodiment 18.R 4 Ga-Y 2 -C1-C6 alkyl, and Y 2 17. The method of embodiment 16, wherein is —SO 2 — and C 1 -C 6 alkyl is methyl.

[0301] Embodiment 19.R 4 Ga-Y 2 -haloalkyl, and Y 2 17. The method of embodiment 16, wherein is —S— or —SO 2 — and haloalkyl is trifluoromethyl.

[0302] Embodiment 20.R 4 -LN(R 5 )2, L is a bond, and each R 5 is hydrogen or each R 5 is methyl or one R 5 is methyl and one R 5 17. The method of embodiment 16, wherein is hydrogen.

[0303] Embodiment 21.R 4 -LN(R 5 )2, L is methylene or ethylene, and each R 5 is hydrogen or each R 5 is methyl or one R 5 is methyl and one R 5 17. The method of embodiment 16, wherein is hydrogen.

[0304] Embodiment 22.R 4 Ga-Y 1 -N(R 5 )2 and Y 1 is -C(O)-, and each R 5 are independently hydrogen or each R 5 are independently methyl, or one R 5 is methyl and one R 517. The method of embodiment 16, wherein is hydrogen.

[0305] Embodiment 23.R 4 Ga-Y 2 -N(R 5 )2 and Y 2 is -SO2-, and each R 5 are independently hydrogen or each R 5 is methyl or one R 5 is methyl and one R 5 17. The method of embodiment 16, wherein

[0306] Embodiment 24.R 4 Ga-Y 1 -heterocyclyl, and Y 1 17. The method of embodiment 16, wherein is —C(O)— and the heterocyclyl moiety of the L-heterocyclyl is piperazinyl or 4-methyl-piperazinyl.

[0307] Embodiment 25.R 4 is -L-heterocyclyl, L is a bond, and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or 3λ 2 -azabicyclo[3.1.0]hexanyl, each of which is oxo, C 1 17. The method of embodiment 16, optionally substituted with one or more R7 selected from -C3 alkyl, alkoxy, hydroxyl, and halogen.

[0308] Embodiment 26.R 4 is -L-heterocyclyl, L is methylene, and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, or piperidinyl, each of which is C 1 17. The method of embodiment 16, optionally substituted with one or more R7 selected from -C3 alkyl, alkoxy, hydroxyl, and halogen.

[0309] Embodiment 27.R4 Ga-Y 1 -heterocyclyl, and Y 1 is -C(O)- and Y 1 The method of embodiment 16, wherein the heterocyclyl moiety of the heterocyclyl is morpholinyl optionally substituted with one or more C1-C3 alkyl.

[0310] Embodiment 28.R 4 but one or more R 7 17. The method of embodiment 16, wherein the -L-heteroaryl is optionally substituted with

[0311] Embodiment 29 The method of embodiment 28, wherein said -L-heteroaryl is tetrazolyl.

[0312] Embodiment 30.R 4 17. The method of embodiment 16, wherein is —PO3(C1-C3 alkyl)2.

[0313] Embodiment 31.R 4 But, -COOR 5 17. The method of embodiment 16, wherein

[0314] Embodiment 32.R 4 17. The method of embodiment 16, wherein is hydroxyalkyl.

[0315] Embodiment 33.R 4 -OLN(R 5 17. The method of embodiment 16, wherein:

[0316] Embodiment 34.R 4 17. The method of embodiment 16, wherein is aralkyl.

[0317] Embodiment 35.R 1 but one or more R 4 13. The method of any one of embodiments 1-12, wherein R is heteroaryl optionally substituted with R.

[0318] Embodiment 36. 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 of which is selected from the group consisting of one or more R 4 36. The method of embodiment 35, optionally substituted with

[0319] Embodiment 37. The heteroaryl is selected from the group consisting of one or more R 4 where each R 4 are independently cyano, halogen, -Y 1 -C1-C6 alkyl, -Y 2 -C1-C6 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -L-cycloalkyl, -LN(R 5 )2, -Y 1 -N(R 5 )2, -L-heteroaryl, -L-heterocyclyl, or -Y 1 -heterocyclyl, wherein the heteroaryl of the -L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl, or Y 1 -heterocyclyl is one or more R 7 37. The method of embodiment 36, optionally substituted with

[0320] Embodiment 38. The heteroaryl is selected from the group consisting of hydroxyalkyl, heteroalkyl, haloalkyl, -Y 1 -C1-C6 alkyl, -LN(R 5 )2, L-heterocyclyl, or L-heteroaryl, wherein the heteroaryl portion of said L-heteroaryl or the heterocyclyl portion of said L-heterocyclyl is selected from one or more R 7 38. The method of embodiment 37, optionally substituted with

[0321] Embodiment 39.R4 is -L-heteroaryl, L is methylene, and said heteroaryl is selected from the group consisting of one or more R 7 39. The method of embodiment 38, wherein R is pyridyl optionally substituted with

[0322] Embodiment 40.R 4 but one or more R 7 39. The method of embodiment 38, wherein -L-heterocyclyl optionally substituted with, L is a bond, and the heterocyclyl portion of said L-heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, or 4-methylpiperazinyl.

[0323] Embodiment 41.R 4 but one or more R 7 39. The method of embodiment 38, wherein L is -L-heterocyclyl optionally substituted by, wherein L is methylene, and the heterocyclyl portion of said L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl, or 4-methylpiperazinyl.

[0324] Embodiment 42.R 4 -LN(R 5 )2, L is methylene, and each R 5 are independently hydrogen or each R 5 are independently C1-C3 alkyl, or one R 5 is C1-C3 alkyl and one R 5 39. The method of embodiment 38, wherein is hydrogen.

[0325] Embodiment 43.R 4 But -Y 1 -C1-C6 alkyl, and Y 1 is a bond and C1-C6 alkyl is methyl, ethyl, or isopropyl.

[0326] Embodiment 44. The heteroaryl is selected from the group consisting of hydroxyalkyl, heteroalkyl, haloalkyl, and -Y 1 The method of embodiment 38, wherein the pyrazolyl is optionally substituted with two R4 groups each independently selected from -C1-C6 alkyl.

[0327] Embodiment 45. The heteroaryl is cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y 1 -C1-C6 alkyl, -LN(R 5 )2, -Y1-N(R 5 ) one R independently selected from -L-cycloalkyl, -L-heterocyclyl optionally substituted with one or more R 4 37. The method of embodiment 36, wherein R is pyridyl optionally substituted with

[0328] Embodiment 46.R 1 but one or more R 4 13. The method of any one of embodiments 1-12, wherein R is -L-cycloalkyl optionally substituted with

[0329] Embodiment 47.R 1 but one or more R 4 13. The method of any one of embodiments 1-12, wherein R is -L-heterocyclyl optionally substituted with

[0330] Embodiment 48. The method of embodiment 47, wherein L is a bond and said heterocyclyl is piperidinyl or tetrahydropyranyl.

[0331] Embodiment 49. The method of any one of embodiments 1 to 3, wherein n is 2.

[0332] 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 a ligand binding domain, the method comprising:

[0333]

change

[0334]

change

[0335]

change

[0336]

change

[0337]

change

[0338]

change

[0339]

change

[0340]

change

[0341]

change

[0342]

change

[0343]

change

[0344] [ka]

[0345] [ka]

[0346] [ka]

[0347] [ka] or a pharmaceutically acceptable salt thereof.

[0348] 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 a ligand binding domain, the method comprising:

[0349] [ka] or a pharmaceutically acceptable salt thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound selected from the group consisting of:

[0350] Embodiment 52. The compound is:

[0351] [ka] or a pharmaceutically acceptable salt thereof.

[0352] Embodiment 53. The compound is:

[0353] [ka] or a pharmaceutically acceptable salt thereof.

[0354] Embodiment 54. The compound is

[0355] [ka] or a pharmaceutically acceptable salt thereof.

[0356] Embodiment 55. The compound is:

[0357] [ka] or a pharmaceutically acceptable salt thereof.

[0358] Embodiment 56. The compound is:

[0359] [ka] or a pharmaceutically acceptable salt thereof.

[0360] Embodiment 57. The compound is

[0361] [ka] or a pharmaceutically acceptable salt thereof.

[0362] Embodiment 58. The compound is

[0363] [ka] or a pharmaceutically acceptable salt thereof.

[0364] Embodiment 59. The compound is:

[0365] [ka] or a pharmaceutically acceptable salt thereof.

[0366] Embodiment 60. The compound is:

[0367] [ka] or a pharmaceutically acceptable salt thereof.

[0368] Embodiment 61. The compound is

[0369] [ka] or a pharmaceutically acceptable salt thereof.

[0370] Embodiment 62. The compound is

[0371] [ka] or a pharmaceutically acceptable salt thereof.

[0372] Embodiment 63. The compound is

[0373] [ka] or a pharmaceutically acceptable salt thereof.

[0374] 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 castration-resistant prostate cancer (nmCRPC), or metastatic castration-resistant prostate cancer (mCRPC).

[0375] 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 of between about 0.01 mg / kg per day and about 300 mg / kg per day.

[0376] 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 of between about 0.1 mg / kg per day and about 100 mg / kg / day per day.

[0377] 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 measuring androgen receptor protein in a biological sample obtained from the subject.

[0378] Embodiment 68. The method of embodiment 67, wherein the biological sample is blood or tissue.

[0379] Embodiment 69. The method of embodiment 68, wherein the biological sample is blood.

[0380] Embodiment 70. The method of embodiment 68, wherein the biological sample is tissue.

[0381] Embodiment 71 The method of embodiment 70, wherein the tissue is obtained from a biopsy of the prostate cancer in the subject.

[0382] 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 measuring mRNA encoding the androgen receptor protein in a biological sample obtained from the subject.

[0383] Embodiment 73 The method of embodiment 72, wherein the biological sample is blood or tissue.

[0384] Embodiment 74 The method of embodiment 73, wherein the biological sample is blood.

[0385] Embodiment 75 The method of embodiment 73, wherein the biological sample is tissue.

[0386] Embodiment 76 The method of embodiment 75, wherein the tissue is obtained from a biopsy of the prostate cancer in the subject.

[0387] Embodiment 77. The method of any one of embodiments 1 to 76, further comprising administering one or more additional therapeutic agents to said subject.

[0388] Embodiment 78. The method of embodiment 77, wherein the one or more additional therapeutic agents are selected from antimitotic agents, antimetabolites, platinum-based agents, androgen receptor N-terminal domain inhibitors, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, CYP17 inhibitors, inhibitors of androgen receptor protein expression, heat shock protein 90 (HSP90) inhibitors, bromodomain and extraterminal domain family (BET) inhibitors, and androgen receptor degraders, or combinations thereof.

[0389] Embodiment 79. The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from antimitotic agents.

[0390] Embodiment 80. The method of embodiment 79, wherein the mitotic inhibitor is selected from paclitaxel, docetaxel, cabazitaxel, tesetaxel, and nab-paclitaxel.

[0391] Embodiment 81 The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from antimetabolites.

[0392] Embodiment 82. The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from platinum-based agents.

[0393] Embodiment 83. The method of embodiment 82, wherein the platinum-based agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, phenthriplatin, picoplatin, and satraplatin.

[0394] Embodiment 84 The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from an N-terminal domain inhibitor of the androgen receptor.

[0395] Embodiment 85. The method of embodiment 84, wherein the androgen receptor N-terminal domain inhibitor is selected from EPI-001, EPI-002 (laraniten), EPI-506, and EPI-7386.

[0396] 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.

[0397] Embodiment 87. The method of embodiment 86, wherein the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is selected from olaparib, niraparib, rucaparib, talazoparib, veliparib, pamiparib, CEP-9722, and E7016.

[0398] Embodiment 88 The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from a CYP17 inhibitor.

[0399] Embodiment 89. The method of embodiment 88, wherein the CYP17 inhibitor is galeterone.

[0400] Embodiment 90 The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from inhibitors of androgen receptor protein expression.

[0401] Embodiment 91 The method of embodiment 90, wherein said inhibitor of androgen receptor protein expression is niclosamide or galeterone.

[0402] 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.

[0403] 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, onarespib, geldanamycin, NVP-BEP800, SNX-2112 (PF-04928473), PF-04929113 (SNX-5422), KW-2478, XL888, TAS-116, VER-50589, CH5138303, VER-49009, NMS-E973, zeravespib (PU-H71), and HSP990 (NVP-HSP990).

[0404] Embodiment 94 The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from bromodomain and extraterminal domain family (BET) inhibitors.

[0405] Embodiment 95. The bromodomain and extraterminal domain family (BET) inhibitor is selected from the group consisting of 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.

[0406] Embodiment 96 The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from androgen receptor degraders.

[0407] Embodiment 97. The method of embodiment 96, wherein the androgen receptor degrading agent is 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.

[0408] Embodiment 98. The method of embodiment 77, wherein the one or more additional therapeutic agents are selected from surgery, radiation, and a prostate-specific membrane antigen (PSMA)-targeted agent.

[0409] Embodiment 99. The method of any one of embodiments 1-98, wherein the subject is administered one or more first agents prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject, and the one or more first agents are selected from (a) a luteinizing hormone-releasing hormone (LHRH) agonist, (b) a luteinizing hormone-releasing hormone (LHRH) antagonist, (c) an androgen receptor inhibitor, (d) a cytochrome P450 17A1 inhibitor, and / or (e) an antiandrogen.

[0410] Embodiment 100. The method of embodiment 99, wherein the one or more first agents is a luteinizing hormone-releasing hormone (LHRH) agonist.

[0411] Embodiment 101. The method of embodiment 100, wherein the luteinizing hormone-releasing hormone (LHRH) agonist is selected from goserelin, histrelin, leuprolide, and triptorelin.

[0412] Embodiment 102. The method of embodiment 99, wherein the one or more first agents is a luteinizing hormone-releasing hormone (LHRH) antagonist.

[0413] Embodiment 103. The method of embodiment 102, wherein the luteinizing hormone-releasing hormone (LHRH) antagonist is selected from degarelix and relugolix.

[0414] Embodiment 104 The method of embodiment 99, wherein the one or more first agents are androgen receptor inhibitors.

[0415] Embodiment 105. The method of embodiment 104, wherein the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.

[0416] Embodiment 106 The method of embodiment 99, wherein the one or more first agents are cytochrome P450 17A1 inhibitors.

[0417] Embodiment 107. The method of embodiment 106, wherein the one or more cytochrome P450 17A1 inhibitors is abiraterone acetate.

[0418] Embodiment 108 The method of embodiment 99, wherein the one or more first agents are antiandrogen agents.

[0419] Embodiment 109. The method of embodiment 108, wherein the antiandrogen is selected from egestrol, bicalutamide, flutamide, and nilutamide.

[0420] Embodiment 110. The method of any one of embodiments 1 to 109, wherein the prostate cancer in the subject has progressed prior to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the subject.

[0421] 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. [Example]

[0422] Example 1: Administration of Compound 4 to castrated male BALB / c nude mice bearing 22Rv1 tumors Castrated male BALB / c nude mice bearing 22Rv1 tumors were cultured until the tumor volume in the mice reached an average of 135 mm 3When the tumor volume reached 100 mg / kg, the mice were divided into two groups: (a) Group 1 (n = 10) was orally administered vehicle once daily for 28 days; (b) Group 2 (n = 10) was orally administered compound 4 at a dose of 100 mg / kg once daily 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 after vehicle or compound 4 administration. Figure 1 shows the mean tumor volume (±SEM) of the mice in each group. Tumor growth was significantly inhibited in the tumor-bearing mice treated with compound 4 (t-test, p < 0.05 vs. the control (vehicle) group), with a tumor growth inhibition rate (TGI) of 69.2%.

[0423] Example 2: Administration of Compound 4 to castrated male NCG mice bearing C4-2 tumors Male NCG mice bearing C4-2 tumors were cultured until tumor size reached an average of 212 mm 3 Mice were castrated when they reached 18 days of age and then divided into two groups: (a) Group 1 (n = 10) was orally administered vehicle once daily for 21 days; (b) Group 2 (n = 10) was orally administered compound 4 at a dose of 100 mg / kg once daily 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 after administration of vehicle or compound 4. Figure 2 shows the mean tumor volume (±SEM) of mice in each group. Tumor growth was significantly inhibited in the group of tumor-bearing mice administered compound 4 (t-test, p = 0.0003 vs. the control (vehicle) group), with a tumor growth inhibition rate (TGI) of 69.4%.

[0424] Example 3: Administration of Compound 4 to castrated male CB17 SCID mice bearing VCaP tumors Castrated male CB17 SCID mice bearing VCaP tumors were cultured until tumor volumes reached an average of 195 mm 3After reaching a maturity of 100 mg / kg, the mice were divided into two groups: (a) Group 1 (n=10) was orally administered vehicle once daily for 21 days; (b) Group 2 (n=10) was orally administered compound 4 at a dose of 100 mg / kg once daily 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 after vehicle or compound 4 administration. Figure 3 shows the mean tumor volume (±SEM) of mice in each group. Tumor growth was inhibited in the tumor-bearing mice treated with compound 4 (t-test, p=0.054 vs. the control (vehicle) group), with a tumor growth inhibition rate (TGI) of 47.0%.

[0425] Example 4: Administration of Compound 4 to Naive Male NOG Mice Bearing CTG-3337 Tumors Untreated, male NOG mice bearing CTG-3337 tumors were cultured until tumor volumes reached an average of 216 mm 3 After reaching a median age of 10 days, the mice were divided into two groups: (a) Group 1 (n=5) was orally administered vehicle once daily for 27 days; (b) Group 2 (n=5) was orally administered compound 4 at a dose of 100 mg / kg once daily for 27 days. The tumor volume in each mouse in each group was then measured on days 1, 4, 7, 11, 14, 18, 20, 25, and 27 after administration of vehicle or compound 4. Figure 4 shows the mean tumor volume (±SEM) of mice in each group. The group of tumor-bearing mice administered compound 4 showed a significant tumor growth inhibition rate of 68% (t-test, p<0.001 vs. the control (vehicle) group).

[0426] Example 5: Administration of Compound 4 to Naive Male NOG Mice Bearing CTG-3421 Tumors Untreated, male NOG mice bearing CTG-3421 tumors were cultured until tumor volumes reached an average of 190 mm 3After reaching a median age of 10 days, the mice were divided into two groups: (a) Group 1 (n = 5) was orally administered vehicle once daily for 28 days; (b) Group 2 (n = 5) was orally administered compound 4 at a dose of 100 mg / kg once daily for 14 days, followed by orally administered compound 4 at a dose of 200 mg / kg once daily 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 after vehicle or compound 4 administration. Figure 5 shows the mean tumor volume (±SEM) of the mice in each group. The group of tumor-bearing mice administered compound 4 showed a significant tumor growth inhibition rate of 54% (t-test, p<0.05 vs. the control (vehicle) group).

[0427] Example 6: Treatment of an AR-positive prostate cancer model with Compound 4 Four cell line-derived xenografts (CDXs) and ten AR-positive prostate cancer patient-derived xenografts (PDXs) were selected for in vivo efficacy testing with Compound 4. AR positivity in these models was confirmed based on expression of a 21-gene transcriptional AR signature (from Beltran et al., Nature Medicine 2016, further restricted to genes induced by R1881 and repressed by AR inhibitors in LNCaP cells (Hieronymus et al., Cancer Cell 2006)), calculated as the mean z-score expression of 21 genes, as well as expression of the luminal markers AR, KLK3, FOLH1, TMPRSS2, AMACR, NKX3-1, and FOXA1. The presence of the AR splice variant AR-V7 in these tumors was determined using four exemplary AR-V7 testing modalities. The first two modalities relied on RNA sequencing data from vehicle-treated CDX and untreated PDX models by quantification against known transcripts, including full-length AR (transcript AR-201) and AR-V7 (transcript AR-204). First, AR-V7 status was determined based on absolute AR-V7 expression levels. AR-V7 negativity was defined as absolute AR-V7 expression below 2, AR-V7 low expression (+) as a range of 2 to 5, AR-V7 moderate expression (++) as a range of 5 to 100, and AR-V7 high expression (+++) as >100. Second, AR-V7 status was assessed based on the ratio of AR-V7 expression to the total abundance of all AR transcripts. Models with a relative AR-V7 expression of less than 10% were considered AR-V7 negative; AR-V7 low-expressing (+) models expressed 10% to 30% AR-V7; AR-V7 moderate-expressing (++) models expressed greater than 30% to 50% AR-V7; and AR-V7 high-expressing (+++) models expressed greater than 50% AR-V7. Third, Western blotting (WB) was used to quantify AR-V7 protein levels relative to β-tubulin in four vehicle-treated tumors per model using RevMAb clone RM7 (Tables 1 and 2 show the mean AR-V7 / β-tubulin levels per model).For CDX models, DU145 was included as a negative control (mean AR-V7 relative to β-tubulin levels was 0.0097). For PDX models, CTG-3581, an AR-negative model, was included as a negative control (mean AR-V7 relative to β-tubulin levels was 0.0098). Based on WB results, AR-V7 negativity was defined as an AR-V7 / β-tubulin protein level below 0.01, AR-V7 low expression (+) was defined as a range of 0.01 to <0.1, AR-V7 moderate expression (++) was defined as a range of 0.1 to 0.2, and AR-V7 high expression (+++) was defined as >0.2. Finally, immunohistochemistry (IHC) was used as an orthogonal method to quantify AR-V7 protein levels using the same antibody. AR-V7 negativity was defined as the absence of AR-V7 staining in the majority of tumor cells, AR-V7 low expression (+) as weak AR-V7 staining in a subset of tumor cells, AR-V7 moderate expression (++) as weak to moderate AR-V7 staining in the majority of tumor cells, and AR-V7 high expression (+++) as moderate to strong AR-V7 staining in the majority of tumor cells.

[0428] In this example, models were considered positive for splice variant AR-V7 if supported by at least two AR-V7 testing modalities (listed as global AR-V7 status in Tables 1 and 2). The CDX model 22Rv1 expressed high levels of AR-V7, while the CDX model VCaP expressed intermediate levels, which was consistently observed at the absolute mRNA and protein levels. The CDX models C4-2 and LNCaP were negative for AR-V7. The AR-V7 status in these models derived from RNA sequencing, Western blotting, and IHC is consistent with the AR-V7 protein quantified by Western blot in Sharp et al., JCI 2019, based on RevMAb clone RM7 and Abcam EPR15656. While 22Rv1 and VCaP expressed AR-V7 protein based on both antibodies, LNCaP was negative for AR-V7 (Sharp et al., JCI 2019). Three of the 10 PDX models (CTG-3337, CTG-3421, and CTG-3610) consistently expressed AR-V7 at the mRNA and protein levels by both WB and IHC, with models CTG-3337 and CTG-3610 expressing moderate to high AR-V7 levels and model CTG-3421 expressing low to moderate AR-V7 levels. For the three other PDX models, weak AR-V7 staining was observed by IHC in a subset of tumor cells. Among these models, weak subclonal AR-V7 staining was supported by moderate absolute AR-V7 mRNA expression in model CTG-2427, but weak positivity was not supported at the mRNA level in models CTG-2428 and CTG-2429.

[0429] Four AR-positive prostate cancer CDX models were treated with Compound 4 at a concentration of 100 mg / kg once daily. Three of the four models responded to treatment with Compound 4 using a 40% TGI cutoff (Figures 1, 2, and 3). Two of the three responsive models express moderate to high levels of AR-V7, while the non-responsive model, LNCaP, is AR-V7 negative. Ten AR-positive prostate cancer PDX models were treated with Compound 4 at concentrations of 100–200 mg / kg once daily. Two PDX models responded to Compound 4 using a more stringent TGI cutoff of 50% (Figures 4 and 5), which accounted for the smaller cohort size (5 mice / group for PDX vs. 10 mice / group for the CDX efficacy study) and dose escalation to 200 mg / kg once daily in some PDX models. Two responsive PDX models were determined to express AR-V7, whereas two of the eight non-responsive PDX models were determined to express AR-V7. Data for four cell line xenograft (CDX) models are shown in Table 1, and data for ten patient-derived xenograft (PDX) models are shown in Table 2. In Tables 1 and 2, AR = androgen receptor, QD = once daily, TGI = tumor growth inhibition, and ND = not performed. In summary, four of the five responsive CDX and PDX models (80%) expressed AR-V7, while seven of the nine non-responsive CDX and PDX models (78%) were AR-V7 negative. Of the six AR-V7-expressing, AR-positive prostate cancer models, four (67%) responded to treatment with Compound 4.

[0430] [Table 1]

[0431] [Table 2]

[0432] Example 7: Preparation of Crystalline Form 1 of Compound 4 150 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 1 day. The resulting solid was vacuum filtered and dried overnight under ambient conditions to give Form 1 of Compound 4.

[0433] Example 8A: Preparation of Crystalline Form 2 of Compound 4 400 mg of the free base of Compound 4 was dissolved in 1.5 mL of 2-methyltetrahydrofuran at 50° C., to which 1.5 mL of n-heptane was added at about 47° C., and the resulting mixture was cooled to 10° C. The resulting solid was vacuum filtered and air-dried overnight under ambient conditions to obtain Form 2 of Compound 4.

[0434] Example 8B: Preparation of Crystalline Form 2 of Compound 4 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 approximately 25°C, and the resulting slurry was stirred for >30 minutes. n-Heptane (7 volumes) was added to the slurry over 2 hours, and the resulting mixture was stirred for >4 hours. The resulting solid was filtered, and the filter cake was washed with 30% 2-methyltetrahydrofuran / heptane (2 volumes) and dried in a vacuum oven to obtain Form 2 of Compound 4.

[0435] Example 9: X-ray Powder Diffraction (XRPD) Analysis of Forms 1 and 2 of Compound 4 XRPD analysis of the crystalline polymorphism of compound 4 was performed using Panalytical X'pert 3 The analysis was performed using an X-ray powder diffractometer. The sample was spread in the center of a zero-background Si holder. The 2θ position was calibrated against a Panalytical Si reference standard disk. The parameters used for the analysis are listed in Table 3.

[0436] [Table 3]

[0437] Polymorphic Form 1 of Compound 4 was analyzed by XRPD as described above and showed the peaks listed in Table 4. The error associated with each °2θ position was determined to be ±0.2 °θ.

[0438] [Table 4]

[0439] Polymorphic Form 2 of Compound 4 was analyzed by XRPD as described above and showed the peaks listed in Table 5. The error associated with each °2θ position was determined to be ±0.2 °θ.

[0440] [Table 5]

[0441] Example 10: Thermogravimetric and Differential Scanning Calorimetry Analysis of Compound 4 Form 1 and Form 2 Thermogravimetric analysis (TGA) data was collected using a TA Instruments TA Discovery TGA 550 TGA, and differential scanning calorimetry (DSC) analysis was performed using a TA Instruments TA Q2000 DSC using the parameters listed in Table 6.

[0442] [Table 6]

[0443] Thermogravimetric analysis (TGA) of a sample of Form 1 of Compound 4, when performed under the conditions set forth in Table 4, showed a weight loss of approximately 1% when the sample was heated from room temperature to near the onset of melting (approximately 207°C). Differential scanning calorimetry (DSC) analysis of Form 1 of Compound 4, when performed under the conditions set forth in Table 4, showed peaks between approximately 170°C and 172°C and between approximately 207°C and 208°C.

[0444] Thermogravimetric analysis (TGA) of a sample of Form 2 of Compound 4, when performed under the conditions set forth in Table 4, showed a weight loss of approximately 2% when the sample was heated from room temperature to near the onset of melting (approximately 204°C). Differential scanning calorimetry (DSC) analysis of Form 2 of Compound 4, when performed under the conditions set forth in Table 4, showed a peak between approximately 203°C and 204°C.

[0445] Example 11: Preparation of Crystalline Form 2 of Compound 4 The reactor was evacuated and filled 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 (approximately 2 volumes) by distillation under reduced pressure. The resulting solution was adjusted to about 25°C, and n-heptane (0.4 kg, 0.2 volumes) was then added in portions over about 3 hours. The resulting solution was then seeded with compound 4 Form 2 (9 g, 0.4 wt%), and 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 at 25°C for about 4.25 hours and then filtered. The reactor was then rinsed with n-heptane (5.8 kg, 2.5 V), and this mixture was rinsed onto the filter cake, which was deliquored, and the solid was dried under reduced pressure at 40° C. and 50° C. for 19 hours to give 2.48 kg of Form 2 of Compound 4.

Claims

1. 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 a ligand binding domain, the method comprising administering to a subject a compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, 【Chemistry 2】 represents a single or double bond, Z is O or S; X is O, CR ５ , C.R. ５ OH, or C(R ５ ) ２ where: When X is O, 【Transformation 3】 is a single bond, X is C(R ５ ) ２ When 【Chemistry 4】 is a single bond, X is CR ５ When OH, 【Transformation 5】 is a single bond, or X is CR ５ When 【Transformation 6】 is a double bond, R １ is an aryl, heteroaryl, L-cycloalkyl, —N(R ５ )heterocyclyl, or L-heterocyclyl, wherein the L-cycloalkyl, the —N(R ５ ) heterocyclyl, or the aryl, heteroaryl, or cyclyl portion of said L-heterocyclyl may be one or more R ４ optionally substituted with R ２ is cyano, -COOR ５ , -C(O)N(R ５ ) ２ , or —C(O)N(R ５ ) ２ where each R ５ together with the nitrogen atom to which they are attached, may be one or more R ４ forming a 5- to 8-membered heterocycle optionally substituted with Each R ３ are independently １ -C ３ is alkyl or halogen, Each R ４ are independently oxo, cyano, halogen, -PO ３ (C １ -C ３ alkyl) ２ , hydroxyl, alkoxy, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR ５ , -Y ２ -haloalkyl, -Y １ -C １－ C ６ Alkyl, -Y ２ -C １ -C ６ Alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Y １ -heterocyclyl, -Y ２ -heterocyclyl, -L-N(R ５ ) ２ , -OL-N(R ５ ) ２ , -C(CF ３ ) N (R ５ ) ２ , -Y １ -N(R ５ ) ２ , -Y ２ -N(R ５ ) ２ wherein said aralkyl, said -L-cycloalkyl, said -L-heteroaryl, said -L-heterocyclyl, or said -Y １ The ring portion of a heterocyclyl may be one or more R ７ optionally substituted with L is a bond or C １ -C ４ is alkylene, Y １ is a bond, —C(O)—, or —NHC(O)—, Y ２ is a bond, -S-, -SO-, -SO ２ - or -NR ５ SO ２ - and Each R ５ is hydrogen or C １ -C ３ is alkyl, R ６ is hydrogen, C １ -C ３ alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; Each R ７ is oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-N(R ５ ) ２ , C １ -C ６ Alkyl, or -Y １ -heterocyclyl, The method wherein n is 1 or 2.

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

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

4. R ２ The method of any one of claims 1 to 3, wherein is cyano.

5. R ３ The method of any one of claims 1 to 4, wherein is a halogen.

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

7. X is C(R ５ ) ２ and 【Transformation 7】 The method according to any one of claims 1 to 6, wherein is a single bond.

8. The aryl may be one or more R ４ 8. The method of any one of claims 1 to 7, wherein R is phenyl optionally substituted with R.

9. The phenyl may have one, two, or three R ４ The method of claim 8 , wherein the compound is substituted with

10. The one, two, or three R ４ are each independently a halogen, -PO ３ (C １ -C ３ alkyl) ２ , hydroxyl, hydroxyalkyl, aralkyl, haloalkyl, -COOR ５ , -Y １ -C １ -C ６ Alkyl, Y ２ -C １ -C ６ Alkyl, -L-N(R ５ ) ２ , -OL-N(R ５ ) ２ , -C(CF ３ ) N (R ５ ) ２ , -Y １ -N(R ５ ) ２ , -Y ２ -N(R ５ ) ２ , Y ２ -haloalkyl, -L-heteroaryl, -L-heterocyclyl, or -Y １ -heterocyclyl, wherein said -L-heterocyclyl or said -Y １ The heterocyclyl moiety of the heterocyclyl may be one or more R ７ 10. The method of claim 9, wherein

11. 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 a ligand binding domain, the method comprising: 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 or a pharmaceutically acceptable salt thereof.

12. 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 a ligand binding domain, the method comprising: 【Chemistry 20】 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

13. 13. The method of any one of claims 1 to 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 castration-resistant prostate cancer (nmCRPC), or metastatic castration-resistant prostate cancer (mCRPC).

14. 14. The method of any one of claims 1 to 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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