Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• Prostate cancer is the second leading cause of cancer-related death in men in the US. Androgen deprivation therapy (ADT) and blockade are commonly used to treat prostate cancer. However, relapse occurs with subsequent progression to metastatic castration-resistant prostate cancer (mCRPC) after treatment with androgen biosynthesis inhibitors or androgen receptor (AR) antagonists through multiple acquired resistance mechanisms.
• ADT Androgen deprivation therapy
• mCRPC metastatic castration-resistant prostate cancer
• AR androgen receptor
• AR structural rearrangements or splice variants are more frequently observed in patients after progressing on antiandrogen therapy compared to patients during earlier lines of therapy (e.g., Li et al, Clin Cancer Res 2020). Many of the AR splice variants observed to be expressed in subjects having prostate cancer lack the ligand binding domain of the AR protein.
• AR splice variant AR-V7 is the most abundant AR splice variant lacking the ligand binding domain that is detected in circulating tumor cells from CRPC patients. In preclinical studies, AR-V7 expression increased when cells were cultured in androgen-depleted media, reflecting CPRC, and AR-V7 promoted cell growth (Guo et al, Cancer Res 2009).
• AR-V7 expressing in vivo xenografts improved antitumor activity achieved with enzalutamide
• Other AR splice variants such as AR-V1, AR-V3, AR-V4, AR-V9 and AR-V567es are less prevalent, with clinical data based on fewer cohorts. In a cohort of 78 mCRPC patients, high concordance was observed between AR-V7 and AR-V9 expression (Fettke et al, Eur Urology 2020).
• AR-V7 or AR-V567es Detected AR splice variants in circulating tumor cells in prostate cancer patients were primarily AR-V7 or AR-V567es, and at a lesser prevalence AR-V1, AR-V3 or AR-V4 (Miyamoto et al, Science 2015).
• AR-V7 and AR-V567es were enriched in the treated group (68% and 30%), and AR-V567es typically co-occurred with AR-V7 (8 out of 9) (Liu et al, J Urology 2016).
• PSA prostate-specific antigen
• a compound of Formula (I) Formula (I) or a pharmaceutically acceptable salt thereof wherein: represents a single or a double bond; Z is O or S; X is O, CR 5 , CR 5 OH, or C(R 5 ) 2 , wherein: when X is O, is a single bond; when X is C(R 5 ) 2 , is a single bond; when X is CR 5 OH, is a single bond; or when X is CR 5 , is a double bond; R 1 is aryl, heteroaryl, L-cycloalkyl, -N(R 5 )he
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject having prostate cancer in combination with one or more additional therapeutic agents.
• the one or more additional therapeutic agents is an androgen receptor inhibitor or a CYP17 inhibitor.
• the one or more additional therapeutic agents is an androgen receptor inhibitor.
• the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.
• the androgen receptor inhibitor is enzalutamide.
• the androgen receptor inhibitor is apalutamide.
• the androgen receptor inhibitor is darolutamide.
• the one or more additional therapeutic agents is a CYP17 inhibitor.
• the CYP17 inhibitor is abiraterone.
• the CYP17 inhibitor is abiraterone acetate.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor or a CYP17 inhibitor.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered enzalutamide.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered apalutamide.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered darolutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered a CYP17 inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone acetate. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide..
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered enzalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered apalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered darolutamide.
• the prostate cancer in the subject is selected from treatment-na ⁇ ve prostate cancer, hormone-sensitive prostate cancer, castrate-resistant prostate cancer, metastatic prostate cancer, non-metastatic prostate cancer, and metastatic castrate-resistant prostate cancer.
• the prostate cancer is treatment na ⁇ ve prostate cancer.
• the prostate cancer in the subject is hormone-sensitive prostate cancer.
• the prostate cancer in the subject is castrate-resistant prostate cancer.
• the prostate cancer in the subject is metastatic prostate cancer.
• the prostate cancer in the subject is non-metastatic prostate cancer.
• the prostate cancer in the subject is metastatic castrate-resistant prostate cancer.
• a compound of Formula (I) Formula (I) or a pharmaceutically acceptable salt thereof wherein: represents a single or a double bond; Z is O or S; X is O, CR 5 , CR 5 OH, or C(R 5 ) 2 , wherein: when X is O, is a single bond; when X is C(R 5 ) 2 , is a single bond; when X is CR 5 OH, is a single bond; or when X is CR 5 , is a double bond; R 1 is aryl, heteroaryl, L-cycloalkyl, -N(R 5 )heterocyclyl, or L-heterocyclyl, wherein the aryl, the heteroaryl or the cyclyl portion
• R 2 is -COOR 5 . In other embodiments, R 2 is -C(O)N(R 5 )2. [0012] In other embodiments are provided the methods disclosed herein, wherein in the compounds of Formula (I) , or a pharmaceutically acceptable salt thereof, R 3 is halogen. In some embodiments R 3 is fluorine. [0013] In other embodiments are provided the methods disclosed herein, wherein in the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, X is C(R 5 )2 and is a single bond. In other embodiments, X is CR 5 and is a double bond. In other embodiments, X is O and is a single bond.
• R 1 is aryl optionally substituted with one or more R 4 .
• the aryl is phenyl optionally substituted with one or more R 4 .
• the phenyl is substituted with one, two or three R 4 .
• the one, two or three R 4 are each independently halogen, -PO 3 (C 1 -C 3 alkyl) 2 , hydroxyl, hydroxyalkyl, aralkyl, haloalkyl, -COOR 5 , -Y 1 -C1-C6 alkyl, Y 2 -C1-C6 alkyl, -L-N(R 5 )2, -O-L-N(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, wherein the heterocyclyl portion of the -L- heterocyclyl or -Y 1 -heterocyclyl is optionally substituted with one or more R 7 .
• R 4 is - Y 1 -C 1 -C 6 alkyl and Y 1 is a bond and the C 1 -C 6 alkyl is methyl, ethyl, isopropyl, butyl or pentyl.
• R 4 is -Y 2 -C 1 -C 6 alkyl and Y 2 is a -SO 2 - and the C 1 -C 6 alkyl is methyl.
• R 4 is -Y 2 -haloalkyl and Y 2 is -S- or -SO 2 - and the haloalkyl is trifluoromethyl.
• R 4 is - L-N(R 5 ) 2 and L is a bond and each R 5 is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is hydrogen.
• R 4 is -L-N(R 5 ) 2 and L is methylene or ethylene and each R 5 is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is hydrogen.
• R 4 is -Y 1 -N(R 5 ) 2 , Y 1 is -C(O)- and each R 5 independently is hydrogen, each R 5 is independently methyl or one R 5 is methyl and one R 5 is hydrogen.
• R 4 is -Y 2 -N(R 5 ) 2 , Y 2 is -SO 2 - and each R 5 independently is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is independently hydrogen.
• R 4 is -Y 1 -heterocyclyl and Y 1 is -C(O)- and the heterocyclyl portion of the L-heterocyclyl is piperazinyl or 4-methyl-piperazinyl.
• R 4 is -L-heterocyclyl and L is a bond and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or 3 ⁇ 2 -azabicyclo[3.1.0]hexanyl, each optionally substituted with one or more R 7 selected from oxo, C1-C3 alkyl, alkoxy, hydroxyl, and halogen.
• R 4 is -L-heterocyclyl, wherein L is a methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl piperidinyl, each optionally substituted with one or more R 7 selected from C1-C3 alkyl, alkoxy, hydroxyl and halogen.
• R 4 is -Y 1 -heterocyclyl and Y 1 is -C(O)- and the heterocyclyl portion of the Y 1 -heterocyclyl is morpholinyl optionally substituted with one or more C1-C3 alkyl.
• R 4 is -L-heteroaryl optionally substituted with one or more R 7 .
• the -L-heteroaryl is tetrazolyl.
• R 4 is -PO3(C1-C3 alkyl)2.
• R 4 is -COOR 5 .
• R 4 is hydroxyalkyl.
• R 4 is -O-L-N(R 5 )2.
• R 4 is aralkyl.
• heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, each optionally substituted with one or more R 4 .
• the heteroaryl is substituted with one or more R 4 ; wherein each R 4 is independently cyano, halogen, -Y 1 -C1-C6 alkyl, -Y 2 -C1-C6 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -L-cycloalkyl, -L-N(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 optionally substituted with one or more R 7 .
• the heteroaryl is pyrazolyl optionally substituted with one R 4 independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y 1 -C 1 -C 6 alkyl, -L-N(R 5 ) 2 , L-heterocyclyl or L-heteroaryl, wherein the heteroaryl of the L- heteroaryl or the heterocyclyl portion of the L-heterocyclyl is optionally substituted with one or more R 7 .
• R 4 is -L-heteroaryl and L is methylene wherein the heteroaryl is pyridyl optional substituted with one or more R 7 .
• R 4 is -L-heterocyclyl optionally substituted with one or more R 7 where L is a bond and the heterocyclyl portion of the L-heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl or 4-methylpiperazinyl.
• R 4 is -L-heterocyclyl optionally substituted with one or more R 7 where L is methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl or 4-methylpiperazinyl.
• R 4 is -L-N(R 5 ) 2 where L is methylene and each R 5 is independently hydrogen, each R 5 is independently C 1 -C 3 alkyl or one R 5 is C 1 -C 3 alkyl and one R 5 is hydrogen.
• R 4 is - Y 1 -C 1 -C 6 alkyl where Y 1 is a bond and the C 1 -C 6 alkyl is methyl, ethyl or isopropyl.
• the heteroaryl is pyrazolyl optionally substituted with two R 4 groups each independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, and -Y 1 -C 1 -C 6 alkyl.
• heteroaryl is pyridyl optionally substituted with one R 4 independently selected from cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y 1 -C1-C6 alkyl, -L-N(R 5 )2, -Y 1 -N(R 5 )2, -L-cycloalkyl, or -L- heterocyclyl optionally substituted with one or more R 7 .
• R 1 is -L-cycloalkyl optionally substituted with one or more R 4 .
• R 1 is -L-heterocyclyl optionally substituted with one or more R 4 .
• L is a bond and the heterocyclyl is piperidinyl or tetrahydropyranyl.
• n is 2.
• methods of treating prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from the group consisting of: ,
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject having prostate cancer in combination with one or more additional therapeutic agents.
• the one or more additional therapeutic agents is an androgen receptor inhibitor or a CYP17 inhibitor.
• the one or more additional therapeutic agents is an androgen receptor inhibitor.
• the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.
• the androgen receptor inhibitor is enzalutamide.
• the androgen receptor inhibitor is apalutamide.
• the androgen receptor inhibitor is darolutamide.
• the one or more additional therapeutic agents is a CYP17 inhibitor.
• the CYP17 inhibitor is abiraterone.
• the CYP17 inhibitor is abiraterone acetate.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor or a CYP17 inhibitor.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered enzalutamide.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered apalutamide.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered darolutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered a CYP17 inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone acetate. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide..
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered enzalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered apalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered darolutamide.
• the prostate cancer in the subject is selected from treatment-na ⁇ ve prostate cancer, hormone-sensitive prostate cancer, castrate-resistant prostate cancer, metastatic prostate cancer, non-metastatic prostate cancer, and metastatic castrate-resistant prostate cancer.
• the prostate cancer is treatment na ⁇ ve prostate cancer.
• the prostate cancer in the subject is hormone-sensitive prostate cancer.
• the prostate cancer in the subject is castrate-resistant prostate cancer.
• the prostate cancer in the subject is metastatic prostate cancer.
• the prostate cancer in the subject is non-metastatic prostate cancer.
• the prostate cancer in the subject is metastatic castrate-resistant prostate cancer.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject having prostate cancer in combination with one or more additional therapeutic agents.
• the one or more additional therapeutic agents is an androgen receptor inhibitor or a CYP17 inhibitor.
• the one or more additional therapeutic agents is an androgen receptor inhibitor.
• the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.
• the androgen receptor inhibitor is enzalutamide.
• the androgen receptor inhibitor is apalutamide.
• the androgen receptor inhibitor is darolutamide.
• the one or more additional therapeutic agents is a CYP17 inhibitor.
• the CYP17 inhibitor is abiraterone.
• the CYP17 inhibitor is abiraterone acetate.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor or a CYP17 inhibitor.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered enzalutamide.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered apalutamide.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered darolutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered a CYP17 inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone acetate. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide..
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered enzalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered apalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered darolutamide.
• the prostate cancer in the subject is selected from treatment-na ⁇ ve prostate cancer, hormone- sensitive prostate cancer, castrate-resistant prostate cancer, metastatic prostate cancer, non-metastatic prostate cancer, and metastatic castrate-resistant prostate cancer.
• the prostate cancer is treatment na ⁇ ve prostate cancer.
• the prostate cancer in the subject is hormone- sensitive prostate cancer.
• the prostate cancer in the subject is castrate-resistant prostate cancer.
• the prostate cancer in the subject is metastatic prostate cancer.
• the prostate cancer in the subject is non-metastatic prostate cancer.
• the prostate cancer in the subject is metastatic castrate-resistant prostate cancer.
• a compound of Formula (I) selected from the group consisting of: , , , , , , and , or a pharmaceutically acceptable salt thereof.
• crystalline form of Compound 4 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 8.1o ⁇ 0.2o 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 9.6o ⁇ 0.2o 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.7o ⁇ 0.2o 2-theta, 19.7o ⁇ 0.2o 2-theta, and 22.0o ⁇ 0.2o 2-theta.
• XRPD x-ray powder diffraction
• crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 9.8o ⁇ 0.2o 2-theta, 15.2o ⁇ 0.2o 2-theta, and 17.7o ⁇ 0.2o 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of about 172 oC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 205 oC to about 210 oC.
• XRPD x-ray powder diffraction
• crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 206 oC to about 210 oC, or from about 207 oC to about 210 oC, or from about 208 oC to about 210 oC, or from about 209 oC to about 210 oC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 1% upon heating the sample from about 25 oC to a temperature prior to melting.
• crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 1% upon heating the sample from about 25 oC to about 380 oC.
• XRPD x-ray powder diffraction
• crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 13.7o ⁇ 0.2o 2-theta and 19.2o ⁇ 0.2o 2-theta.
• crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5o ⁇ 0.2o 2-theta, 8.6o ⁇ 0.2o 2-theta, 15.9o ⁇ 0.2o 2-theta, 19.9o ⁇ 0.2o 2-theta, and 24.1o ⁇ 0.2o 2-theta.
• XRPD x-ray powder diffraction
• crystalline form of Compound 4 exhibits further peaks in an x- ray powder diffraction (XRPD) pattern at 10.6o ⁇ 0.2o 2-theta, 11.0o ⁇ 0.2o 2-theta, 15.4o ⁇ 0.2o 2-theta, 21.0o ⁇ 0.2o 2-theta, and 26.3o ⁇ 0.2o 2-theta.
• XRPD x- ray powder diffraction
• crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 oC to about 208 oC, or from about 203 oC to about 206 oC, or from about 203 oC to about 205 oC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 oC to about 380 oC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 oC to about 210 oC.
• crystalline form of Compound 4 exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 13.7o ⁇ 0.2o 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5o ⁇ 0.2o 2-theta, 8.6o ⁇ 0.2o 2-theta, 15.9o ⁇ 0.2o 2-theta, 19.9o ⁇ 0.2o 2-theta, and 24.1o ⁇ 0.2o 2- theta.
• crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6o ⁇ 0.2o 2-theta, 11.0o ⁇ 0.2o 2-theta, 21.0o ⁇ 0.2o 2-theta, and 26.3o ⁇ 0.2o 2-theta.
• XRPD x-ray powder diffraction
• the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 oC to about 210 oC.
• the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 206 oC to about 210 oC.
• crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 oC to about 208 oC, or from about 203 oC to about 206 oC, or from about 203 oC to about 205 oC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 oC to about 380 oC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 oC to about 210 oC.
• crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5o ⁇ 0.2o 2-theta, 8.6o ⁇ 0.2o 2- theta, 15.9o ⁇ 0.2o 2-theta, 19.9o ⁇ 0.2o 2-theta, and 24.1o ⁇ 0.2o 2-theta.
• XRPD x-ray powder diffraction
• crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6o ⁇ 0.2o 2-theta, 11.0o ⁇ 0.2o 2-theta, 21.0o ⁇ 0.2o 2-theta, and 26.3o ⁇ 0.2o 2-theta.
• XRPD x-ray powder diffraction
• the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 oC to about 210 oC.
• the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 206 oC to about 210 oC.
• crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 oC to about 208 oC, or from about 203 oC to about 206 oC, or from about 203 oC to about 205 oC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 oC to about 380 oC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 oC to about 210 oC.
• crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5o ⁇ 0.2o 2-theta, 8.6o ⁇ 0.2o 2- theta, 15.9o ⁇ 0.2o 2-theta, 19.9o ⁇ 0.2o 2-theta, and 24.1o ⁇ 0.2o 2-theta.
• XRPD x-ray powder diffraction
• crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6o ⁇ 0.2o 2-theta, 11.0o ⁇ 0.2o 2-theta, 21.0o ⁇ 0.2o 2-theta, and 26.3o ⁇ 0.2o 2-theta.
• XRPD x-ray powder diffraction
• the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 oC to about 210 oC.
• the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 206 oC to about 210 oC.
• crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 oC to about 208 oC, or from about 203 oC to about 206 oC, or from about 203 oC to about 205 oC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 oC to about 380 oC. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 oC to about 210 oC.
• crystalline form of Compound 4 exhibits less than about 10% degradation when stored at 25 oC and 60% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 oC and 60% relative humidity for at least 7 days.
• crystalline form of Compound 4 exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 9.6o ⁇ 0.2o 2-theta, 5.7o ⁇ 0.2o 2-theta, 19.7o ⁇ 0.2o 2-theta, and 22.0o ⁇ 0.2o 2-theta , and (b) less than about 10% degradation when the crystalline form is stored at 25 oC and 60% relative humidity for at least 7 days.
• XRPD x-ray powder diffraction
• crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 oC and 60% relative humidity for at least 7 days.
• crystalline form of Compound 4 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 7.7o ⁇ 0.2o 2-theta, 13.7o ⁇ 0.2o 2-theta, and 19.2o ⁇ 0.2o 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 25 oC and 60% relative humidity for at least 7 days.
• XRPD x-ray powder diffraction
• crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 40 oC and 75% relative humidity for at least 7 days.
• crystalline form of Compound 4 exhibits (a) a peak in an x-ray powder diffraction (XRPD) pattern at 8.1o ⁇ 0.2o 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 oC and 75% relative humidity for at least 7 days.
• XRPD x-ray powder diffraction
• crystalline form of Compound 4 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 9.6o ⁇ 0.2o 2-theta, 5.7o ⁇ 0.2o 2-theta, 19.7o ⁇ 0.2o 2-theta, and 22.0o ⁇ 0.2o 2-theta , and (b) less than about 10% degradation when the crystalline form is stored at 40 oC and 75% relative humidity for at least 7 days.
• XRPD x-ray powder diffraction
• crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 40 oC and 75% relative humidity for at least 7 days.
• crystalline form of Compound 4 exhibits (a) a peak in an x-ray powder diffraction (XRPD) pattern at 7.7o ⁇ 0.2o 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 oC and 75% relative humidity for at least 7 days.
• XRPD x-ray powder diffraction
• crystalline form of Compound 4 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 7.7o ⁇ 0.2o 2-theta, 13.7o ⁇ 0.2o 2-theta, and 19.2o ⁇ 0.2o 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 oC and 75% relative humidity for at least 7 days.
• XRPD x-ray powder diffraction
• the crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 60 oC for at least one week.
• the compound of Formula (I) is Compound (Compound 5), or a pharmaceutically acceptable salt thereof.
• the methods disclosed herein, wherein the compound of Formula (Compound 6), or a pharmaceutically acceptable salt thereof are provided.
• the methods disclosed herein wherein the compound of Formula (I) is Compound 12: (Compound 12), or a pharmaceutically acceptable salt thereof.
• the prostate cancer in the subject is localized high risk prostate cancer, recurrent prostate cancer, non-metastatic hormone-sensitive prostate cancer (nmHSPC), metastatic hormone-sensitive prostate cancer (mHSPC), non-metastatic castrate- resistant prostate cancer (nmCRPC), or metastatic castrate-resistant prostate cancer (mCRPC).
• the prostate cancer in the subject is localized high risk prostate cancer.
• the prostate cancer in the subject is recurrent prostate cancer.
• the prostate cancer in the subject is non-metastatic hormone-sensitive prostate cancer (nmHSPC). In some embodiments, the prostate cancer in the subject is metastatic hormone-sensitive prostate cancer (mHSPC). In some embodiments, the prostate cancer in the subject is non-metastatic castrate-resistant prostate cancer (nmCRPC). In some embodiments, the prostate cancer in the subject is metastatic castrate-resistant prostate cancer (mCRPC). [0048] Also provided are the methods disclosed herein, wherein the expression of the androgen receptor splice variant lacking the ligand binding domain is determined by measurement of androgen receptor protein in a biologic sample obtained from the subject. In some embodiments, the biologic sample is blood or tissue. In other embodiments, the biologic sample is blood.
• the biologic sample is tissue. In still further embodiments, the tissue is obtained from a biopsy of the prostate cancer in the subject. [0049] Also provided are the methods disclosed herein, wherein the expression of the androgen receptor splice variant lacking the ligand binding domain is determined by measurement of mRNA that encodes androgen receptor protein in a biologic sample obtained from the subject.
• the biologic sample is blood or tissue. In other embodiments, the biologic sample is blood. In other embodiments, the biologic sample is tissue. In still further embodiments, the tissue is obtained from a biopsy of the prostate cancer in the subject. [0050] Also provided are the methods disclosed herein, wherein the methods further comprise administering to the subject one or more additional therapeutic agents.
• the one or more additional therapeutic agents are selected from mitotic inhibitors, antimetabolites, platinum-based agents, N-terminal domain inhibitors of androgen receptor, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, inhibitors of CYP17, inhibitors of androgen receptor protein expression, heat shock protein 90 (HSP90) inhibitors, bromodomain and extra-terminal domain family (BET) inhibitors, and androgen receptor degraders, or combinations thereof.
• PARP poly(adenosine diphosphate-ribose) polymerase
• HSP90 heat shock protein 90
• BET bromodomain and extra-terminal domain family
• androgen receptor degraders or combinations thereof.
• the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide. In one embodiment, the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof. [0052] In some embodiments, the one or more additional therapeutic agents is a CYP17 inhibitor. In some embodiments, the CYP17 inhibitor is abiraterone. In some embodiments, the CYP17 inhibitor is abiraterone acetate.
• the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor or a CYP17 inhibitor.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered enzalutamide.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered apalutamide.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered darolutamide.
• the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered a CYP17 inhibitor.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more androgen receptor inhibitors wherein the subject has not previously been administered abiraterone acetate. In some embodiments, the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered an androgen receptor inhibitor selected from enzalutamide, apalutamide, and darolutamide.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered enzalutamide.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered apalutamide. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in combination with one or more CYP17 inhibitors wherein the subject has not previously been administered darolutamide. In some embodiments, the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof.
• the prostate cancer in the subject is selected from treatment-na ⁇ ve prostate cancer, hormone-sensitive prostate cancer, castrate-resistant prostate cancer, metastatic prostate cancer, non- metastatic prostate cancer, and metastatic castrate-resistant prostate cancer.
• the prostate cancer is treatment na ⁇ ve prostate cancer.
• the prostate cancer in the subject is hormone-sensitive prostate cancer.
• the prostate cancer in the subject is castrate- resistant prostate cancer.
• the prostate cancer in the subject is metastatic prostate cancer.
• the prostate cancer in the subject is non-metastatic prostate cancer.
• the prostate cancer in the subject is metastatic castrate-resistant prostate cancer.
• kits for treating prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor, and wherein the prostate cancer in the subject is treatment-na ⁇ ve.
• the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.
• the androgen receptor inhibitor is enzalutamide.
• the androgen receptor inhibitor is apalutamide.
• the androgen receptor inhibitor is darolutamide.
• the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof.
• kits for treating treatment-na ⁇ ve prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor.
• the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.
• the androgen receptor inhibitor is enzalutamide.
• the androgen receptor inhibitor is apalutamide.
• the androgen receptor inhibitor is darolutamide.
• the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof.
• kits for treating hormone-sensitive prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor.
• the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.
• the androgen receptor inhibitor is enzalutamide.
• the androgen receptor inhibitor is apalutamide.
• the androgen receptor inhibitor is darolutamide.
• the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof.
• methods of treating metastatic prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor.
• the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.
• the androgen receptor inhibitor is enzalutamide.
• the androgen receptor inhibitor is apalutamide.
• the androgen receptor inhibitor is darolutamide.
• the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof.
• methods of treating non-metastatic prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor.
• the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.
• the androgen receptor inhibitor is enzalutamide.
• the androgen receptor inhibitor is apalutamide.
• the androgen receptor inhibitor is darolutamide.
• the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof.
• methods of treating androgen receptor inhibitor-na ⁇ ve prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor.
• the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.
• the androgen receptor inhibitor is enzalutamide.
• the androgen receptor inhibitor is apalutamide.
• the androgen receptor inhibitor is darolutamide.
• the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof.
• methods of treating enzalutamide-na ⁇ ve prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor.
• the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.
• the androgen receptor inhibitor is enzalutamide.
• the androgen receptor inhibitor is apalutamide.
• the androgen receptor inhibitor is darolutamide.
• the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof.
• methods of treating enzalutamide-na ⁇ ve prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound which is pharmaceutically acceptable salt thereof, in combination with enzalutamide.
• methods of treating darolutamide-na ⁇ ve prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound which is pharmaceutically acceptable salt thereof, in combination with darolutamide.
• methods of treating apalutamide-na ⁇ ve prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound which is pharmaceutically acceptable salt thereof, in combination with apalutamide.
• methods of treating enzalutamide-resistant prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor.
• the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.
• the androgen receptor inhibitor is enzalutamide.
• the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof. [0068] In other embodiments are provided methods of treating darolutamide-resistant prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide.
• the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof. [0069] In other embodiments are provided methods of treating apalutamide-resistant prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide.
• the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof. [0070] In other embodiments are provided methods of treating abiraterone-resistant prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an androgen receptor inhibitor. In some embodiments, the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide. In one embodiment, the androgen receptor inhibitor is enzalutamide.
• the androgen receptor inhibitor is apalutamide. In one embodiment, the androgen receptor inhibitor is darolutamide. In some embodiments, the compound of Formula (I) is Compound (Compound 4), or a pharmaceutically acceptable salt thereof. [0071] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents are selected from mitotic inhibitors. In some embodiments, the mitotic inhibitors are selected from paclitaxel, docetaxel, cabazitaxel, tesetaxel, and nab-paclitaxel. [0072] In yet other embodiments, the one or more additional therapeutic agents are selected from antimetabolites.
• the one or more antimetabolites are selected from azacytidine, 5- fluorouracil (5-FU), 6-mercaptopurine (6-MP), capecitabine, cladribine, clofarabine, cytarabine (Ara-C), decitabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexed, pentostatin, pralatrexate, thioguanine, and trifluridine/tipiracil combination.
• the antimetabolite is azacytidine.
• the antimetabolite is 5-fluorouracil (5-FU).
• 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.
• the antimetabolite is nelarabine. In some embodiments, the antimetabolite is pemetrexed. In some embodiments, the antimetabolite is pentostatin. In some embodiments, the antimetabolite is pralatrexate. In some embodiments, the antimetabolite is thioguanine. In some embodiments, the antimetabolite is trifluridine/tipiracil combination. [0073] In some embodiments, the one or more additional therapeutic agents are selected from platinum- based agents.
• the platinum-based agents are selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, pheanthriplatin, picoplatin, and satraplatin.
• the platinum-based agent is cisplatin.
• the platinum-based agent is carboplatin.
• the platinum-based agent is oxaliplatin.
• the platinum-based agent is nedaplatin.
• the platinum-based agent is lobaplatin.
• the platinum-based agent is triplatin tetranitrate.
• the platinum-based agent is pheanthriplatin. In further embodiments, the platinum-based agent is picoplatin. In further embodiments, the platinum-based agent is satraplatin.
• the one or more additional therapeutic agents are selected from N- terminal domain inhibitors of androgen receptor. In some embodiments, the N-terminal domain inhibitor of androgen receptor is selected from EPI-001, EPI-002 (ralaniten), EPI-506, and EPI-7386. In some embodiments, the N-terminal domain inhibitor of androgen receptor is EPI-001. In some embodiments, the N-terminal domain inhibitor of androgen receptor is EPI-002 (ralaniten).
• the N- terminal domain inhibitor of androgen receptor is EPI-506. In some embodiments, the N-terminal domain inhibitor of androgen receptor is EPI-7386. [0075] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents are selected from poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are selected from olaparib, niraparib, rucaparib, talazoparib, veliparib, pamiparib, CEP-9722, and E7016.
• PARP poly(adenosine diphosphate-ribose) polymerase
• 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.
• the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is pamiparib. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is CEP-9722. In some embodiments, the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor is E7016. [0076] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents are selected from inhibitors of CYP17. In one embodiment, the inhibitor of CYP17 is galeterone.
• the methods disclosed herein wherein the one or more additional therapeutic agents are selected from inhibitors of androgen receptor protein expression.
• the inhibitor of androgen receptor protein expression is niclosamide or galeterone.
• the inhibitor of androgen receptor protein expression is niclosamide.
• the inhibitor of androgen receptor protein expression is galeterone.
• the one or more additional therapeutic agents are selected from one or more heat shock protein 90 (HSP90) inhibitors.
• the one or more heat shock protein 90 (HSP90) inhibitors are selected from tanespimycin, luminespib, alvespimycin, ganetespib, BIIB021, onalespib, geldanamycin, NVP-BEP800, SNX-2112 (PF- 04928473), PF-04929113 (SNX-5422), KW-2478, XL888, TAS-116, VER-50589, CH5138303, VER-49009, NMS-E973, zelavespib (PU-H71), and HSP990 (NVP-HSP990).
• the heat shock protein 90 (HSP90) inhibitor is tanespimycin.
• the heat shock protein 90 (HSP90) inhibitor is luminespib. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is alvespimycin. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is ganetespib. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is BIIB021. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is onalespib. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is geldanamycin. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is NVP-BEP800. In some embodiments, the heat shock protein 90 (HSP90) inhibitor is SNX-2112 (PF-04928473).
• 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.
• the heat shock protein 90 (HSP90) inhibitor is zelavespib (PU-H71). In some embodiments, the heat shock protein 90 (HSP90) inhibitor is HSP990 (NVP- HSP990). [0079] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents are selected from one or more bromodomain and extra-terminal domain family (BET) inhibitors.
• BET bromodomain and extra-terminal domain family
• the bromodomain and extra-terminal domain family (BET) inhibitor is selected from JQ1, I-BET 151 (GSK1210151A), I-BET 762 (GSK525762), GSK778 (iBET-BD1), GSK046 (iBET-BD2), OTX-015, TEN-010, CPI-203, CPI-0610, olinone, RVX-208, ABBV-744, LY294002, AZD5153, MT-1, MS645, MS417, SJ432, RVX-208, ABBV-075 (mivebresib), BMS-986158, PLX51107, INCB054329, INCB057643, FT-1101, CC-90010, and ODM-207.
• JQ1 I-BET 151A
• I-BET 762 GSK525762
• GSK778 iBET-BD1
• GSK046 iBET-BD2
• the bromodomain and extra-terminal domain family (BET) inhibitor is JQ1. In one embodiment, the bromodomain and extra- terminal domain family (BET) inhibitor is I-BET 151 (GSK1210151A). In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is I-BET 762 (GSK525762). In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is GSK778 (iBET-BD1). In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is GSK046 (iBET- BD2). In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is OTX-015.
• the bromodomain and extra-terminal domain family (BET) inhibitor is TEN-010. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is CPI-203. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is CPI-0610. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is olinone. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is RVX-208. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is ABBV-744. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is LY294002.
• the bromodomain and extra-terminal domain family (BET) inhibitor is AZD5153. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is MT-1. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is MS645. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is MS417. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is SJ432. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is RVX-208.
• the bromodomain and extra-terminal domain family (BET) inhibitor is ABBV-075 (mivebresib). In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is BMS-986158. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is PLX51107. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is INCB054329. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is INCB057643. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is FT-1101.
• the bromodomain and extra-terminal domain family (BET) inhibitor is CC- 90010. In one embodiment, the bromodomain and extra-terminal domain family (BET) inhibitor is ODM- 207. [0080] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents are selected from androgen receptor degraders. In some embodiments, the androgen receptor degraders are selected from ARV-110, ARV-330, SARD279, SARD033, ARCC-4, UT-34, ARD- 111, ARD-86, ARD-77, ARD-69, ARD-61, LX-1, or LX-2, or a pharmaceutically acceptable salt thereof.
• 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.
• the androgen receptor degrader is ARD-61. In one embodiment, the androgen receptor degrader is LX-1. In one embodiment, the androgen receptor degrader is LX-2. [0081] In other embodiments are provided the methods disclosed herein, wherein the one or more additional therapeutic agents are selected from surgery, radiation, and prostate-specific membrane antigen (PSMA) targeted agents. In one embodiment, the additional therapeutic agent is surgery. In one embodiment, the additional therapeutic agent is radiation. In one embodiment, the additional therapeutic agent is prostate- specific membrane antigen (PSMA) targeted agents. In an embodiment, the prostate-specific membrane antigen (PSMA) targeted agent is 177 Lu-PSMA-617.
• PSMA prostate-specific membrane antigen
• the methods disclosed herein wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is selected from (a) luteinizing hormone-releasing hormone (LHRH) agonists, (b) luteinizing hormone-releasing hormone (LHRH) antagonists, (c) androgen receptor inhibitors, (d) inhibitors of cytochrome P45017A1, and/or (e) antiandrogens.
• LHRH luteinizing hormone-releasing hormone
• LHRH luteinizing hormone-releasing hormone
• LHRH luteinizing hormone-releasing hormone
• LHRH luteinizing hormone-releasing hormone
• c androgen receptor inhibitors
• inhibitors of cytochrome P45017A1 inhibitors of cytochrome P45017A1
• antiandrogens inhibitors of cytochrome P45017A1
• the methods disclosed herein wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is a luteinizing hormone- releasing hormone (LHRH) agonist.
• the luteinizing hormone-releasing hormone (LHRH) agonist is selected from goserelin, histrelin, leuprolide, and triptorelin.
• the luteinizing hormone-releasing hormone (LHRH) agonist is goserelin.
• the luteinizing hormone-releasing hormone (LHRH) agonist is histrelin.
• the luteinizing hormone- releasing hormone (LHRH) agonist is leuprolide. In one embodiment, the luteinizing hormone-releasing hormone (LHRH) agonist is triptorelin. [0084] In other embodiments are provided the methods disclosed herein, wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is a luteinizing hormone- releasing hormone (LHRH) antagonist. In some embodiments, the luteinizing hormone-releasing hormone (LHRH) antagonist is selected from degarelix and relugolix.
• the luteinizing hormone- releasing hormone (LHRH) antagonist is degarelix. In one embodiment, the luteinizing hormone-releasing hormone (LHRH) antagonist is relugolix. [0085] In other embodiments are provided the methods disclosed herein, wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is an androgen receptor inhibitor.
• 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.
• the androgen receptor inhibitor is darolutamide.
• the methods disclosed herein wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is an inhibitor of cytochrome P45017A1.
• the one or more inhibitors of cytochrome P45017A1 is abiraterone acetate.
• the antiandrogen is selected from egestrol, bicalutamide, flutamide, and nilutamide. In one embodiment, the antiandrogen is egestrol. In one embodiment, the antiandrogen is bicalutamide. In one embodiment, the antiandrogen is egestrol flutamide. In one embodiment, the antiandrogen is nilutamide. [0088] Also provided are the methods disclosed herein, wherein the prostate cancer in the subject is progressing prior to administration to the subject of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• 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.
• the androgen receptor splice variant lacking the ligand binding domain is AR-V1.
• the androgen receptor splice variant lacking the ligand binding domain is AR-V3.
• the androgen receptor splice variant lacking the ligand binding domain is AR-V4.
• the androgen receptor splice variant lacking the ligand binding domain is AR-V7.
• the androgen receptor splice variant lacking the ligand binding domain is AR-V9. In some embodiments, the androgen receptor splice variant lacking the ligand binding domain is AR-V12. INCORPORATION BY REFERENCE [0090] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE FIGURES [0091] FIG.1 depicts tumor volume following days of treatment in 22Rv1 tumor-bearing castrated male BALB/c nude mice following administration of vehicle or Compound 4, as described in Example 1.
• FIG.2 depicts tumor volume following days of treatment in C4-2 tumor-bearing male NCG mice following administration of vehicle or Compound 4, as described in Example 2.
• FIG.3 depicts tumor volume following days of treatment in VCaP tumor-bearing castrated male CB17SCID mice following administration of vehicle or Compound 4, as described in Example 3.
• FIG.4 depicts tumor volume following days of treatment in CTG-3337 tumor-bearing intact male NOG mice following administration of vehicle or Compound 4, as described in Example 4.
• FIG.5 depicts tumor volume following days of treatment in CTG-3421 tumor-bearing intact male NOG mice following administration of vehicle or Compound 4, as described in Example 5.
• administering when used in conjunction with a therapeutic, including the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or the one or more additional therapeutic agents, means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a subject whereby the therapeutic positively impacts the tissue to which it is targeted.
• administering when used in conjunction with a composition described herein, can include, but is not limited to, providing a composition into or onto the target tissue; providing a composition systemically to a subject by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells.
• administering a composition may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques.
• androgen receptor splice variant refers to a constitutively active androgen receptor (AR) protein variant lacking the ligand binding domain.
• Such splice variants may result from rearrangement of the gene encoding the androgen receptor (AR) protein in cells, such as prostate cancer cells, or from alternative splicing events at the RNA level.
• Such rearrangements of the gene encoding the androgen receptor (AR) protein at the DNA level may comprise gene rearrangement breakpoints resulting from deletion, inversion, tandem duplication, and/or translocation events.
• AR androgen receptor
• splice variants may arise from events including, but not limited to, splicing to cryptic exons, inclusion of intronic sequences, and exon skipping. Such splice variants are further described in Cao et al., Endocr. Relat. Cancer., volume 23 (12), pages T199-T210 (2016).
• the terms “determine,” “determined,” and “determining,” and the like, as used herein mean that it has been established that a pre-condition in a subject exists, or a condition precedent with respect to a subject has been satisfied, prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• a subject having prostate cancer is eligible for treatment by administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and, optionally, one or more additional therapeutic agents described herein, if it has been established that an androgen receptor splice variant lacking the ligand binding domain, such as those described herein (e.g., AR-V7), is present in a biologic sample (e.g., blood or tissue) obtained from the subject.
• a biologic sample e.g., blood or tissue
• express and “expresses” as used herein mean that (a) an androgen receptor splice variant protein lacking the ligand binding domain, or (b) an mRNA that encodes for an androgen receptor splice variant protein lacking the ligand binding domain is detected in a biologic sample obtained from a subject, such as blood or tissue.
• a biologic sample obtained from a subject such as blood or tissue.
• An androgen splice variant protein lacking the ligand binding domain, or an mRNA encoding for such a protein may be detected in a biologic sample obtained from a subject by methods described herein and/or any other methods known to those having ordinary skill in the art.
• ligand-binding domain as used herein in relation to the androgen receptor protein means the steroid binding domain of the androgen receptor (AR) protein.
• androgen receptor splice variant lacking the ligand-binding domain means an isoform of the androgen receptor protein that is truncated and lacks the C-terminal ligand-binding domain but retains the transactivating N-terminal domain.
• Examples of androgen receptor splice variant lacking the ligand-binding domain include, but are not limited, to AR-V1 (also referred to by those of ordinary skill in the art as AR4), AR-V3 (also referred to by those of ordinary skill in the art as AR1/2/2b), AR-V4 (also referred to by those of ordinary skill in the art as AR1/2/3/2b, AR5), AR-V7 (also referred to by those of ordinary skill in the art as AR3), AR-V9, and AR-V12 (also referred to by those of ordinary skill in the art as ARv567es).
• AR-V1 also referred to by those of ordinary skill in the art as AR4
• AR-V3 also referred to by those of ordinary skill in the art as AR1/2/2b
• AR-V4 also referred to by those of ordinary skill in the art as AR1/2/3/2b, AR5
• AR-V7 also referred to by those of ordinary skill in the art as AR3
• AR-V9 also referred to by
• the terms “subject,” “subject” and “individual” are intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof.
• the subject is a primate.
• the primate or subject is a human.
• the human is an adult. In certain instances, the human is child. In further instances, the human is under the age of 12 years. In certain instances, the human is elderly. In other instances, the human is 60 years of age or older.
• Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows.
• the experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with hypertensive pathology.
• antiandrogen means agents that counteract the effects of androgens in subjects.
• Antiandrogens include agents that act as androgen biosynthesis inhibitors, such as agents that inhibit 17 ⁇ hydroxylase/C17,20-lyase (CYP17).
• Antiandrogens also include agents that inhibit a subject’s ability to utilize androgens by interacting with the androgen receptor, such as by competitively inhibiting androgen binding to androgen receptors, including by binding directly to the ligand-binding domain of the androgen receptor.
• Antiandrogens may also inhibit nuclear translocation of androgen receptors and their interaction with DNA as an antagonist, and impeding androgen receptor-mediated transcription. Antiandrogens also include AR degraders as described herein.
• pharmaceutically acceptable is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• pharmaceutical composition means a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
• resistant refers to the cancer being no longer responsive to the treatment administered (e.g., an antiandrogen).
• a determination of whether a cancer, or one or more cells comprising a cancer, in a subject have become resistant to a specific treatment modality can be made by methods to known to those of ordinary skill in the art.
• responsiveness, or non-responsiveness, as the case may be, of a cancer in a subject, or one or more cells comprising the cancer in a subject can be assessed by measuring prostate-specific antigen (PSA) levels (by, for example, reference to Prostate Cancer Working Group 3 (PCWG3) criteria), increases or decreases in tumor size, use of Response Evaluation Criteria in Solid Tumors (RECIST response) (see, for example, Schwartz, et. al., Eur. J. Cancer, July 2016, vol.62, pp. 132-137, for a description of RECIST v1.1), duration of response, or progression-free survival.
• PSA prostate-specific antigen
• PCWG3 Prostate Cancer Working Group 3
• the term “therapeutic” means an agent utilized to treat, combat, ameliorate, prevent, or improve an unwanted condition or disease of a subject.
• a “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or
• beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease.
• Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
• chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms may also be used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art.
• an “alkyl” moiety generally refers to a monovalent radical (e.g.
• a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH 2 -CH 2 -), which is equivalent to the term “alkylene.”
• alkyl a divalent radical
• aryl a divalent moiety
• All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).
• amino refers to -NH 2 .
• acetyl refers to “-C(O)CH 3 .
• acyl refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl portions are as defined herein.
• alkyl refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms. As such, “alkyl” encompasses C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12 groups.
• alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, and hexyl.
• alkenyl as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms. As such, “alkenyl” encompasses C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12 groups.
• alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
• alkynyl as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms. As such, “alkynyl” encompasses C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12 groups.
• alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
• alkylene alkenylene
• alkynylene alkynylene mean an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
• alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.
• alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene.
• alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.
• alkoxy as used herein refers to -OC1-C6 alkyl.
• cycloalkyl as used herein as employed herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons.
• cycloalkyl includes C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12 cyclic hydrocarbon groups.
• Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
• heteroalkyl refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are independently replaced by O, S, or NR x , wherein R x is hydrogen or C 1 - C 3 alkyl.
• heteroalkyl groups include methoxymethyl, methoxyethyl and methoxypropyl.
• aryl as used herein means a C6-C14 aromatic moiety comprising one to three aromatic rings. As such, “aryl” includes C 6 , C 10 , C 13 , and C 14 cyclic hydrocarbon groups.
• An exemplary aryl group is a C 6 -C 10 aryl group.
• aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
• aralkyl and arylalkyl as used herein mean an aryl group covalently linked to an alkylene group wherein the moiety is linked to another group via the alkyl moiety.
• An exemplary aralkyl group is -(C 1 -C 6 )alkyl(C 6 -C 10 )aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
• heterocyclyl and “heterocyclic” as used herein mean a mono- or bicyclic (fused or spiro) ring structure having from 3 to 12 atoms, (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently -C(O)-, N, NR 5 , O, or S, and the remainder of the ring atoms are quaternary or carbonyl carbons.
• heterocyclic groups include, without limitation, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl.
• L-heterocyclyl as used herein means a heterocyclyl group covalently linked to another group via an alkylene linker L, where L is C1-C4 alkylene.
• heteroaryl as used herein means a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13 or 14 ring atoms comprising an aromatic heterocyclic ring (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array), and having, in addition to carbon atoms, from one to three heteroatoms that are each independently N, O, or S.
• Heteroaryl also includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom.
• fused multicyclic e.g., bicyclic
• heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H
• L-heteroaryl means a group comprising a heteroaryl group covalently linked to another group via an alkylene linker.
• heteroalkyl groups comprise a C 1 -C 6 alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms.
• heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl.
• arylene e.g., arylene, teroarylene, and heterocyclylene as used herein mean an bivalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
• a moiety e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.
• substituents it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents.
• halogen and “halo” as used herein mean chlorine, bromine, fluorine, or iodine.
• haloalkyl as used herein means an alkyl chain in which one or more hydrogens have been replaced by a halogen.
• haloalkyls are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.
• hydroxyalkyl as used herein means an alkyl chain, as defined herein, wherein at least one hydrogen of the alkyl chain has been replaced by hydroxyl.
• the compounds of Formula (I), or pharmaceutically acceptable salts thereof may be prepared using commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, those described in United States Patent No.11,091,495, or may be prepared using other reagents and conventional methods well known to those skilled in the art. The contents of United States Patent No. 11,091,495 are hereby incorporated by reference for that purpose.
• a pharmaceutically acceptable salts of the compounds of Formula (I) comprising administering to the subject a pharmaceutically acceptable salts of the compounds of Formula (I).
• the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a solid, it is understood by those skilled in the art that the compounds or salts thereof may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.
• Also provided herein are uses of isotopically-labeled compounds of Formula (I), or a pharmaceutically acceptable thereof, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
• isotopically-labeled compounds of the invention for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
• radioactive isotopes tritium ( 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.
• Substitution with heavier isotopes such as deuterium, 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
• Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
• PET Positron Emission Topography
• Isotopically- labeled compounds of Formula (I), or a pharmaceutically acceptable salt thereof can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
• the compositions described herein comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof are used for the treatment of prostate cancer in subjects.
• Such compositions may be prepared in pharmaceutically acceptable dosage forms for administration to subjects.
• Pharmaceutically acceptable dosage forms include, for example, liquids, suspensions, powders for reconstitution, tablets, pills, sachets, or capsules of hard or soft gelatin (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
• the compounds of Formula (I), or a pharmaceutically acceptable salt thereof may be formulated into pharmaceutical compositions as described below in any pharmaceutical form recognizable to the skilled artisan as being suitable.
• Pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an inert, pharmaceutically acceptable carrier or diluent.
• the pharmaceutical carriers employed may be either solid or liquid.
• Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like.
• Exemplary liquid carriers are syrup, peanut oil, olive oil, water, and the like.
• the compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like. Further additives or excipients may be added to achieve the desired formulation properties.
• a bioavailability enhancer such as Labrasol, Gelucire or the like, or formulator, such as CMC (carboxy- methylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol), may be added.
• CMC carboxy- methylcellulose
• PG propyleneglycol
• PEG polyethyleneglycol
• a semi-solid vehicle that protects active ingredients from light, moisture, and oxidation may be added, e.g., when preparing a capsule formulation.
• a solid carrier the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge.
• the amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g.
• the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.
• a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations.
• the inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g. parenteral or oral administration.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid.
• the compound, or a pharmaceutically acceptable salt thereof may be dissolved in a suitable co-solvent or combinations of co- solvents.
• suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof is dissolved in DMSO and diluted with water.
• the composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer.
• physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer.
• penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
• the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art.
• Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject to be treated.
• Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
• Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP).
• PVP polyvinylpyrrolidone
• disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
• Dragee cores are provided with suitable coatings.
• concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
• Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• the push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
• the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
• suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
• stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
• the compositions may take the form of tablets or lozenges formulated in conventional manner.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
• the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
• the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
• the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
• a suitable vehicle e.g. sterile pyrogen-free water
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof may also be formulated as a depot preparation.
• Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
• the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• a pharmaceutical carrier for hydrophobic compounds is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase.
• the co-solvent system may be a VPD co-solvent system.
• VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the non-polar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
• the VPD co-solvent system (VPD: 5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
• the proportions of a co-solvent system may be suitably varied without destroying its solubility and toxicity characteristics.
• identity of the co- solvent components may be varied: for example, other low-toxicity non-polar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
• other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs.
• DMSO dimethylsulfoxide
• the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
• sustained-release materials have been established and are known by those skilled in the art.
• Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
• additional strategies for protein stabilization may be employed.
• the pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients.
• carriers and excipients may provide marked improvement in the bioavailability of poorly soluble drugs.
• examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
• the pharmaceutical composition may be incorporated into a skin patch for delivery of the drug directly onto the skin.
• the pharmaceutically acceptable formulations of the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that may be used to practice the methods disclosed herein may contain a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of from about 0.5 w/w % to about 95 w/w %, or from about 1 w/w % to about 95 w/w %, or from about 1 w/w % to about 75 w/w %, or from about 5 w/w % to about 75 w/w %, or from about 10 w/w % to about 75 w/w %, or from about 10 w/w % to about 50 w/w %.
• the actual dosages of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to be administered to a subject in need thereof will vary according to the particular agent being used, the particular composition formulated, the mode of administration, and the particular site, host, and disease being treated. Those skilled in the art using conventional dosage-determination tests in view of the experimental data for a given compound may ascertain optimal dosages for a given set of conditions.
• an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals.
• the methods disclosed herein wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount between about 0.01 mg/kg per day to about 300 mg/kg per day. In other embodiments are provided the methods disclosed herein, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount between about 0.1 mg/kg per day to about 100 mg/kg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 10 mg to 500 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 100 mg to about 400 mg per day.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in an amount between about 150 mg to about 350 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 150 mg to about 300 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 160 mg to about 300 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount of about 160 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200 mg per day.
• 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.
• the pharmaceutically acceptable formulations of the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that may be used to practice the methods disclosed herein may contain a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 25 mg to about 500 mg, or from about 50 mg to about 500 mg, or from about 100 mg to about 500 mg.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof once a day.
• 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.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in 28-day cycles.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in multiple 28- day cycles.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof for at least one 28-day cycle.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof on each day of each 28-day cycle.
• the methods described herein comprise administering the compositions and formulations comprising the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, to the subject or subject in need thereof in multiple cycles repeated on a regular schedule with periods of rest in between each cycle. For example, in some instances, treatment given for one week followed by three weeks of rest is one treatment cycle. The length of a treatment cycle depends on the treatment being given. In some embodiments, the length of a treatment cycle ranges from two to six weeks.
• the length of a treatment cycle ranges from three to six weeks. In some embodiments, the length of a treatment cycle ranges from three to four weeks. In some embodiments, the length of a treatment cycle is three weeks (or 21 days). In some embodiments, the length of a treatment cycle is four weeks (28 days). In some embodiments, the length of a treatment cycle is 56 days. In some embodiments, a treatment cycle lasts one, two, three, or four weeks. In some embodiments, a treatment cycle lasts three weeks. In some embodiments, a treatment cycle lasts four weeks. The number of treatment doses scheduled within each cycle also varies depending on the drugs being given. [00163] Dosages of compositions described herein can be determined by any suitable method.
• Maximum tolerated doses (MTD) and maximum response doses (MRD) for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agents when administered to the subject can be determined via established animal and human experimental protocols as well as in the examples described herein.
• toxicity and therapeutic efficacy of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
• the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50.
• the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in a human.
• the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with minimal toxicity.
• the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Additional relative dosages, represented as a percent of maximal response or of maximum tolerated dose, are readily obtained via the protocols.
• the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and/or pharmaceutical formulations comprising them that corresponds to such an amount varies depending upon factors such as the particular salt or form, disease condition and its severity, the identity (e.g., age, weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid formulation type, the condition being treated, and the subject or host being treated.
• Also provided herein are such methods, wherein the subject is 18 years old or older. Also provided herein are such methods, wherein the subject has undergone a bilateral orchiectomy.
• GnRH antagonist is selected from abarelix, cetrorelix, degarelix, elagolix, ganirelix, linzagolix, and relugolix.
• the GnRH antagonist is abarelix.
• the GnRH antagonist is cetrorelix.
• the GnRH antagonist is degarelix.
• the GnRH antagonist is elagolix.
• the GnRH antagonist is ganirelix.
• the GnRH antagonist is linzagolix. In some embodiments, the GnRH antagonist is relugolix. [00166] Also provided herein are such methods, wherein the prostate cancer in the subject has progressed after having been administered at least one androgen receptor antagonist. In some embodiments, the at least one androgen receptor antagonist is selected from abiraterone, enzalutamide, apalutamide, and darolutamide. In some embodiments, the prostate cancer in the subject has progressed after having been administered abiraterone. In some embodiments, the prostate cancer in the subject has progressed after having been administered enzalutamide.
• the prostate cancer in the subject has progressed after having been administered apalutamide. In some embodiments, the prostate cancer in the subject has progressed after having been administered darolutamide. [00167] Also provided herein are such methods, wherein the subject has not received more than 2 chemotherapy regimens prior to the administration to the subject of the compound of Formula (I).
• prostate cancer in the subject exhibits evidence of progressive disease by the Prostate Cancer Working Group 3 (PCWG3) criteria, comprising one or more of (a) 2 or more rising levels of prostate specific antigen (PSA) a minimum of one week apart with the latest result being at least 2.0 ng/mL, (b) 1.0 ng/mL PSA rise, (c) confirmation of 2 new bone lesions on last systemic therapy, and (d) soft tissue progression according to RECIST 1.1 guidelines.
• PCWG3 Prostate Cancer Working Group 3
• the androgen receptor splice variant lacking the ligand binding domain is selected from AR-V1 (also referred to by those of ordinary skill in the art as AR4), AR-V3 (also referred to by those of ordinary skill in the art as AR1/2/2b), AR-V4 (also referred to by those of ordinary skill in the art as AR1/2/3/2b, AR5), AR-V7 (also referred to by those of ordinary skill in the art as AR3), AR-V9, AR-V12 (also referred to by those of ordinary skill in the art as ARv567es).
• AR-V1 also referred to by those of ordinary skill in the art as AR4
• AR-V3 also referred to by those of ordinary skill in the art as AR1/2/2b
• AR-V4 also referred to by those of ordinary skill in the art as AR1/2/3/2b, AR5
• AR-V7 also referred to by those of ordinary skill in the art as AR3
• AR-V9, AR-V12 also referred to by those of ordinary skill
• 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.
• the androgen receptor splice variant is AR-V1.
• the androgen receptor splice variant is AR-V2.
• the androgen receptor splice variant is AR-V3.
• 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.
• 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.
• the androgen receptor splice variant is AR1/2b.
• the presence, absence, or level, of such androgen receptor splice variant may be measured in a biological sample obtained from a subject, such as a sample of a solid tumor, such as a prostate cancer, or from a sample of a relevant biological fluid, such as a blood sample.
• the methods of detection disclosed herein are useful for predicting a therapeutic response to a therapy described herein (e.g., the administration to a subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof), monitor the treatment using the therapy of, and treating with the therapy, a proliferative disease or condition described herein in a subject.
• the presence or an absence, and/or a level of expression of the androgen receptor splice variant is detected in the sample obtained from a subject by analyzing the genetic material in the sample.
• the genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine, and other techniques known by one of skill in the art.
• the sample comprises circulating tumor RNA (ctRNA).
• the sample comprises peripheral blood mononuclear cells (PBMCs).
• PBMCs peripheral blood mononuclear cells
• the sample comprises circulating tumor cells (CTCs).
• the genetic material is obtained from a tumor biopsy or liquid biopsy.
• a tumor biopsy comprises a formalin-fixed paraffin embedded biopsy, a fresh frozen biopsy, a fresh biopsy, or a frozen biopsy.
• a liquid biopsy comprises PBMCs, circulating tumor RNA, plasma cell-free RNA, or circulating tumor cells (CTCs). Tumor and liquid biopsies can undergo additional analytic processing for sample dissociation, cell sorting, and enrichment of cell populations of interest. [00175] In some embodiments, methods of detecting a presence, absence, or level of an androgen receptor splice variant in a biologic sample obtained from the subject involve detecting a nucleic acid sequence.
• the nucleic acid sequence comprises deoxyribonucleic acid (DNA), such as in the case of detecting complementary DNA (cDNA) of an mRNA transcript.
• the nucleic acid sequence comprises a denatured DNA molecule or fragment thereof.
• the nucleic acid sequence comprises DNA selected from: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA.
• the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denaturing double-stranded DNA, synthetic DNA, and combinations thereof.
• the circular DNA may be cleaved or fragmented.
• the nucleic acid sequence comprises ribonucleic acid (RNA). In some instances, the nucleic acid sequence comprises fragmented RNA. In some instances, the nucleic acid sequence comprises partially degraded RNA. In some instances, the nucleic acid sequence comprises a microRNA or portion thereof.
• the nucleic acid sequence comprises an RNA molecule or a fragmented RNA molecule (RNA fragments) selected from: a microRNA (miRNA), a pre-miRNA, a pri-miRNA, a mRNA, a pre-mRNA, a viral RNA, a viroid RNA, a virusoid RNA, circular RNA (circRNA), a ribosomal RNA (rRNA), a transfer RNA (tRNA), a pre-tRNA, a long non-coding RNA (lncRNA), a small nuclear RNA (snRNA), a circulating RNA, a cell-free RNA, an exosomal RNA, a vector-expressed RNA, an RNA transcript, a synthetic RNA, and combinations thereof.
• miRNA microRNA
• pre-miRNA pre-miRNA
• a pri-miRNA a RNA
• mRNA a pre-mRNA
• a pri-miRNA a
• an androgen receptor splice variant is detected by subjecting a sample obtained from the subject to a nucleic acid-based detection assay.
• the nucleic acid-based detection assay comprises quantitative polymerase chain reaction (qPCR), reverse transcription PCT (RT-qPCR), gel electrophoresis (including for e.g., Northern or Southern blot), immunohistochemistry (IHC), immunofluorescence (IF), in situ hybridization (ISH) such as fluorescent in situ hybridization (FISH), cytochemistry, microarray, or sequencing.
• the sequencing technique comprises next generation sequencing.
• the methods involve a hybridization assay such as fluorogenic qPCR (e.g., TaqManTM, SYBR green, SYBR green I, SYBR green II, SYBR gold, ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, Blue View or phycoerythrin), which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acid probes comprising a detectable moiety or molecule that is specific to a target nucleic acid sequence.
• a number of amplification cycles for detecting a target nucleic acid in a qPCR assay is about 5 to about 30 cycles.
• the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles.
• the probe may be a hydrolysable probe comprising a fluorophore and quencher that is hydrolyzed by DNA polymerase when hybridized to a target nucleic acid.
• the presence of a target nucleic acid is determined when the number of amplification cycles to reach a threshold value is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles.
• hybridization may occur at standard hybridization temperatures, e.g., between about 35 oC and about 65 oC in a standard PCR buffer.
• An additional exemplary nucleic acid-based detection assay comprises the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi-well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence.
• the nucleic acid probe is specific to one or more of a polynucleotide sequence that encodes a relevant androgen receptor splice variant as disclosed herein.
• the nucleic acid probe specific to an androgen receptor splice variant comprises a nucleic acid probe sequence sufficiently complementary to the polynucleotide sequence that encodes the relevant androgen receptor splice variant protein.
• the probe comprises a transcribed polynucleotide sequence (e.g., RNA, cDNA).
• the nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length and sufficient to specifically hybridize under standard hybridization conditions to the target nucleic acid sequence.
• 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.
• the probe(s) are immobilized on a solid surface, for example, in an Affymetrix gene chip array, and the probe(s) are contacted with the target nucleic acid sequence.
• the term “probe” with regards to nucleic acids refers to any nucleic acid molecule that is capable of selectively binding to a specifically intended target nucleic acid sequence.
• probes are specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags that are known in the art.
• the fluorescent label comprises a fluorophore.
• the fluorophore is an aromatic or heteroaromatic compound.
• the fluorophore is a pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzindole, oxazole, thiazole, benzothiazole, canine, carbocyanine, salicylate, anthranilate, xanthenes dye, coumarin.
• xanthene dyes include, e.g., fluorescein and rhodamine dyes.
• Fluorescein and rhodamine dyes include, but are not limited to 6-carboxyfluorescein (FAM), 2′7′-dimethoxy-4′5′-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N; N′-tetramethyl-6-carboxyrhodamine (TAMRA), 6-carboxy-X-rhodamine (ROX).
• Suitable fluorescent probes also include the naphthylamine dyes that have an amino group in the alpha or beta position.
• naphthylamino compounds include 1- dimethylaminonaphthyl-5-sulfonate, 1-anilino-8-naphthalene sulfonate, and 2-p-toluidinyl-6-naphthalene sulfonate, 5-(2′-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS).
• EDANS 5-(2′-aminoethyl)aminonaphthalene-1-sulfonic acid
• Exemplary coumarins include, e.g., 3-phenyl-7-isocyanatocoumarin; acridines, such as 9-isothiocyanatoacridine and acridine orange; N-(p-(2- benzoxazolyl)phenyl) maleimide; cyanines, such as, e.g., indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3-(-carboxy-pentyl)-3′-ethyl-5,5′-dimethyloxacarbocyanine (CyA); 1H, 5H, 11H, 15H-Xantheno[2,3, 4-ij: 5,6, 7-i′j′]diquinolizin-18-ium, 9-[2 (or 4)-[[[6-[2,5-dioxo-1- pyrrolidinyl)oxy]
• detecting the one or more androgen receptor splice variants comprises sequencing genetic material obtained from a sample from the subject. Sequencing can be performed with any appropriate sequencing technology, including but not limited to single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis.
• SMRT single-molecule real-time
• Sequencing methods also include next-generation sequencing, e.g., modern sequencing technologies such as Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed. [00180] In some instances, a number of nucleotides that are sequenced are at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 300, 400, 500, 2000, 4000, 6000, 8000, 10000, 20000, 50000, 100000, or more than 100000 nucleotides.
• next-generation sequencing e.g., modern sequencing technologies such as Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed.
• the number of nucleotides sequenced is in a range of about 1 to about 100000 nucleotides, about 1 to about 10000 nucleotides, about 1 to about 1000 nucleotides, about 1 to about 500 nucleotides, about 1 to about 300 nucleotides, about 1 to about 200 nucleotides, about 1 to about 100 nucleotides, about 5 to about 100000 nucleotides, about 5 to about 10000 nucleotides, about 5 to about 1000 nucleotides, about 5 to about 500 nucleotides, about 5 to about 300 nucleotides, about 5 to about 200 nucleotides, about 5 to about 100 nucleotides, about 10 to about 100000 nucleotides, about 10 to about 10000 nucleotides, about 10 to about 1000 nucleotides, about 10 to about 500 nucleotides, about 10 to about 300 nucleotides, about 10 to about 200 nucleotides, about 10 to about 100 nucleotides, about
• a method comprising: (a) providing a biologic sample obtained from a subject with prostate cancer; (b) assaying to detect in the biologic sample obtained from the subject a presence or absence of an androgen receptor splice variant lacking the ligand binding domain; and (c) detecting the presence or absence of the androgen receptor splice variant lacking the ligand binding domain in the biologic sample using the methods described herein.
• a hybridization assay such as those described herein, is used to detect the mRNA encoding the androgen receptor splice variant lacking the ligand binding domain in the sample.
• Exemplary probe sequences that are hybridizable to a target nucleic acid sequence comprise at least 10, but no more than 100 contiguous nucleotides comprising the relevant sequence.
• RNA sequencing RNAseq
• Detection of the mRNA involves amplification of the subject’s nucleic acid by the polymerase chain reaction (PCR).
• the PCR assay involves use of a pair of primers capable of amplifying at least about 10 contiguous nucleobases within a nucleic acid sequence, thereby amplifying the one or more gene products in the biomarker.
• the nucleic acid probe is conjugated to a detectable molecule.
• the detectable molecule may be a fluorophore.
• the nucleic acid probe may also be conjugated to a quencher.
• the assay for detecting the presence or absence of mRNA encoding a relevant androgen receptor splice variant lacking the ligand binding domain comprises reverse-transcribing the relevant mRNA molecule to produce a corresponding complementary DNA (cDNA) molecule.
• the assay further comprises contacting the cDNA molecule with a nucleic acid probe comprising a nucleic acid sequence that is complementary to a nucleic acid sequence of the cDNA molecule. In some embodiments, the assay comprises detecting a double-stranded hybridization product between the nucleic acid probe and the cDNA molecule. In some embodiments, the hybridization product is further amplified using a pair of primers.
• the primers comprises a first primer with a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within a relevant nucleic acid sequence that binds to a top strand of the double-stranded hybridization product; and a second primer with a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within a nucleic acid sequence that is reverse complement to the relevant nucleic acid sequence that binds to a bottom strand of the double-stranded hybridization product.
• methods comprising preparing a complementary DNA (cDNA) library.
• the cDNA library is sequenced using suitable sequence methodologies disclosed herein.
• the cDNA library is labeled, a plurality of nucleic acid probes is generated, and fixed to an immobile surface (such as a microarray).
• the plurality of nucleic acid probes is capable of hybridizing to at least about 10 contiguous nucleotides of the two or more genes in a sample obtained from the subject.
• detecting the presence of or absence of an androgen receptor splice variant includes detecting a high or a low level of expression of one or more genes as compared to a reference level.
• genetic material is extracted from a biologic sample obtained from a subject, e.g., a sample of blood, serum, or tissue.
• nucleic acids are extracted using any technique that does not interfere with subsequent analysis.
• this technique uses alcohol precipitation using ethanol, methanol, or isopropyl alcohol.
• this technique uses phenol, chloroform, or any combination thereof.
• this technique uses cesium chloride.
• this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA.
• this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich.
• RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol/guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasy RNA preparation kits (Qiagen) or PAXgene (PreAnalytix, Switzerland).
• RNAzol B acid phenol/guanidine isothiocyanate extraction
• Qiagen RNeasy RNA preparation kits
• PAXgene PreAnalytix, Switzerland.
• circulating tumor RNA circulating tumor RNA (ctRNA) is used to assess the expression levels of RNA molecules, shed by the tumor into the blood stream.
• detection of ctRNA is useful, for example, for detecting and diagnosing a tumor. Because tumor DNA and RNA has acquired multiple genetic mutations, leading to tumor development, ctRNA are not an exact match to the individual’s DNA and RNA, respectively. Finding DNA and RNA with genetic differences aids in tumor detection. Diagnosing the type of tumor using ctRNA can reduce the need for getting a sample of the tumor tissue (tumor biopsy), which can be challenging when a tumor is difficult to access, such as a tumor in the brain or lung. [00187] In some embodiments, a decrease in the quantity of ctRNA suggests the solid tumor is shrinking and treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is effective.
• a lack of ctRNA in the bloodstream indicates that the cancer has not returned after treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• the genomic profiling is performed after each treatment cycle with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• the gene mutations indicate that the cancer is becoming resistant to the treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• the lack of gene mutations indicate that the cancer is not becoming resistant to the treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• one or more cells comprising the prostate cancer in the subject has been determined to express an androgen receptor splice variant lacking the ligand binding domain.
• the expression of an androgen receptor splice variant lacking the ligand binding domain is measured by immunohistochemistry (IHC) assays.
• the expression of an androgen receptor splice variant lacking the ligand binding domain is measured by immunofluorescence (IF) assays.
• the expression of an androgen receptor splice variant lacking the ligand binding domain is measured by in situ hybridization (ISH) assays.
• the expression of an androgen receptor splice variant lacking the ligand binding domain transcript levels are measured using assays such as quantitative polymerase chain reaction (qPCR), microarray, and RNA sequencing, or assays commercially available from companies such as Fluidigm and Nanostring.
• qPCR quantitative polymerase chain reaction
• microarray microarray
• RNA sequencing or assays commercially available from companies such as Fluidigm and Nanostring.
• expression of an androgen receptor splice variant lacking the ligand binding domain is based on the expression level of the androgen receptor splice variant lacking the binding domain deviating from a reference expression level.
• the expression level of the androgen receptor is standardized, such as through a z-score.
• the expression level is high, relative to the reference expression level.
• the expression level is low, relative to the reference expression level.
• the reference expression level is derived from an individual, or a group of individuals, that do not have cancer.
• the reference expression level is derived from an individual, or a group of individuals, that have cancer that does not therapeutically respond to the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the expression level deviates from the reference expression level by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.
• the determination of expression of an androgen receptor splice variant is defined based on the percentage of cells that stain weakly, moderately, or strongly for the relevant androgen receptor variant, with the threshold defining the minimal percentage of cells that are required to stain positive at the various intensity levels ( ⁇ a% of prostate tumor cells stain weakly, ⁇ b% of prostate tumor cells stain moderately, ⁇ c% of prostate tumor cells stain strongly, or a combination thereof).
• the one or more of the cells comprising the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain when ⁇ about 10%, ⁇ about 15%, ⁇ about 20%, ⁇ about 25%, ⁇ about 30%, ⁇ about 35%, ⁇ about 40%, ⁇ about 45%, ⁇ about 50%, ⁇ about 55%, ⁇ about 60%, ⁇ about 65%, ⁇ about 70%, ⁇ about 75%, ⁇ about 80%, ⁇ about 85%, ⁇ about 90%, or ⁇ about 95% of the prostate tumor cells stain weakly for the androgen receptor splice variant; when ⁇ about 10%, ⁇ about 15%, ⁇ about 20%, ⁇ about 25%, ⁇ about 30%, ⁇ about 35%, ⁇ about 40%, ⁇ about 45%, ⁇ about 50%, ⁇ about 55%, ⁇ about 60%, ⁇ about 65%, ⁇ about 70%, ⁇ about 75%, ⁇ about 80%, ⁇ about 85%, ⁇ about 90%, or ⁇ about
• kits and articles of manufacture for use with one or more methods and compositions described herein.
• Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
• Suitable containers include, for example, bottles, vials, syringes, and test tubes.
• the containers are formed from a variety of materials such as glass or plastic.
• a kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.
• a label is on or associated with the container.
• a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
• a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.
• the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein.
• the pack for example, contains metal or plastic foil, such as a blister pack.
• the pack or dispenser device is accompanied by instructions for administration.
• the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
• a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
• Such notice for example, is the labeling approved by the U.S. Food and Drug Administration for drugs, or the approved product insert.
• compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
• kits comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer in a subject in need thereof and a package insert comprising instructions for measuring the expression of an androgen receptor splice variant lacking the ligand binding domain in one or more of the cells comprising the prostate cancer and using the compound of Formula (I), or a pharmaceutically acceptable salt thereof, if one or more of the cells comprising the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain.
• a package insert comprising instructions for measuring the expression of an androgen receptor splice variant lacking the ligand binding domain in one or more of the cells comprising the prostate cancer and using the compound of Formula (I), or a pharmaceutically acceptable salt thereof, if one or more of the cells comprising the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain.
• a method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) Formula (I) or a pharmaceutically acceptable salt thereof: wherein: represents a single or a double bond; Z is O or S; X is O, CR 5 , CR 5 OH, or C(R 5 ) 2 , wherein: when X is O, is a single bond; when X is C(R 5 ) 2 , is a single bond; when X is CR 5 OH, is a single bond; or when X is CR 5 is a double bond; R 1 is aryl, heteroaryl, L-cycloalkyl, -N(R 5 )heterocyclyl, or L-heterocyclyl, wherein the aryl, the heteroaryl or the cyclyl portion of the L-cycloalkyl,
• Embodiment 2 The method of embodiment 1, wherein Z is O.
• Embodiment 3. The method of embodiment 1, wherein Z is S.
• Embodiment 4. The method of any of embodiments 2 or 3, wherein n is 1.
• Embodiment 5. The method of any of embodiments 1-4, wherein R 2 is cyano.
• Embodiment 6. The method of any of embodiments 1-4, wherein R 2 is -COOR 5 .
• Embodiment 7. The method of any of embodiments 1-4, wherein R 2 is -C(O)N(R 5 )2.
• Embodiment 8. The method of any of embodiments 1-7, wherein R 3 is halogen.
• Embodiment 9. The method of embodiment 8, wherein the halogen is fluorine.
• Embodiment 10. The method of any of embodiments 1-9, wherein X is C(R 5 )2 and is a single bond.
• Embodiment 11. The method of any of embodiments 1-9, wherein X is CR 5 and is a double bond.
• Embodiment 12. The method of any of embodiments 1-9, wherein X is O and is a single bond.
• Embodiment 13 The method of any of embodiments 1-12 wherein R 1 is aryl optionally substituted with one or more R 4 .
• Embodiment 15 The method of embodiment 14, wherein the phenyl is substituted with one, two or three R 4 .
• Embodiment 16 The method of embodiment 13, wherein the aryl is phenyl optionally substituted with one or more R 4 .
• Embodiment 17 The method of embodiment 16, wherein R 4 is -Y 1 -C 1 -C 6 alkyl and Y 1 is a bond and the C 1 -C 6 alkyl is methyl, ethyl, isopropyl, butyl, or pentyl.
• Embodiment 18 The method of embodiment 16, wherein R 4 is -Y 2 -C 1 -C 6 alkyl and Y 2 is a -SO 2 - and the C 1 -C 6 alkyl is methyl.
• Embodiment 19 Embodiment 19.
• Embodiment 20 The method of embodiment 16, wherein R 4 is -L-N(R 5 )2 and L is a bond and each R 5 is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is hydrogen.
• Embodiment 21 The method of embodiment 16, wherein R 4 is -L-N(R 5 )2 and L is methylene or ethylene and each R 5 is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is hydrogen.
• Embodiment 22 The method of embodiment 16, wherein R 4 is -Y 1 -N(R 5 )2, Y 1 is -C(O)- and each R 5 independently is hydrogen, each R 5 is independently methyl or one R 5 is methyl and one R 5 is hydrogen.
• Embodiment 23 The method of embodiment 16, wherein R 4 is -Y 2 -N(R 5 )2, Y 2 is -SO2- and each R 5 independently is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is independently hydrogen.
• Embodiment 24 Embodiment 24.
• R 4 is -L-heterocyclyl, wherein L is a methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl piperidinyl, each optionally substituted with one or more R 7 selected from C1-C3 alkyl, alkoxy, hydroxyl and halogen.
• R 4 is -L-heterocyclyl, wherein L is a methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl piperidinyl, each optionally substituted with one or more R 7 selected from C1-C3 alkyl, alkoxy, hydroxyl and halogen.
• Embodiment 16 wherein R 4 is -Y 1 -heterocyclyl and Y 1 is -C(O)- and the heterocyclyl portion of the Y 1 -heterocyclyl is morpholinyl optionally substituted with one or more C1-C3 alkyl.
• Embodiment 28 The method of embodiment 16, wherein R 4 is -L-heteroaryl optionally substituted with one or more R 7 .
• Embodiment 29 The method of embodiment 28, wherein the -L-heteroaryl is tetrazolyl.
• Embodiment 30 Embodiment 30.
• Embodiment 31 The method of embodiment 16, wherein R 4 is -PO 3 (C 1 -C 3 alkyl) 2 .
• Embodiment 31 The method of embodiment 16, wherein R 4 is -COOR 5 .
• Embodiment 32 The method of embodiment 16, wherein R 4 is hydroxyalkyl.
• Embodiment 33 The method of embodiment 16, wherein R 4 is -O-L-N(R 5 ) 2 .
• Embodiment 34 The method of embodiment 16, wherein R 4 is aralkyl.
• Embodiment 35 The method of any of embodiments 1-12, wherein R 1 is heteroaryl optionally substituted with one or more R 4 .
• Embodiment 36 The method of embodiment 35, wherein the heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 5,6-dihydro-4H-pyrrolo[1,2- b]pyrazolyl, each optionally substituted with one or more R 4 .
• Embodiment 37 Embodiment 37.
• each R 4 is independently cyano, halogen, -Y 1 -C 1 -C 6 alkyl, -Y 2 -C 1 -C 6 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -L-cycloalkyl, -L-N(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 optionally substituted with one or more R 7 .
• Embodiment 38 The method of embodiment 37, wherein the heteroaryl is pyrazolyl optionally substituted with one R 4 independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y 1 -C1-C6 alkyl, - L-N(R 5 )2, L-heterocyclyl or L-heteroaryl, wherein the heteroaryl of the L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl is optionally substituted with one or more R 7 .
• R 4 independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y 1 -C1-C6 alkyl, - L-N(R 5 )2, L-heterocyclyl or L-heteroaryl, wherein the heteroaryl of the L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl is optionally substituted with one or more R 7 .
• Embodiment 40 The method of embodiment 38, wherein R 4 is -L-heterocyclyl optionally substituted with one or more R 7 where L is a bond and the heterocyclyl portion of the L-heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, or 4-methylpiperazinyl.
• Embodiment 41 Embodiment 41.
• R 4 is -L-heterocyclyl optionally substituted with one or more R 7 where L is methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl, or 4- methylpiperazinyl.
• Embodiment 42 Embodiment 42.
• Embodiment 48 The method of embodiment 47, wherein L is a bond and the heterocyclyl is piperidinyl or tetrahydropyranyl.
• Embodiment 49 The method of any of embodiments 1-3, wherein n is 2.
• Embodiment 50 The method of any of embodiments 1-3, wherein n is 2.
• a method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: ,
• Embodiment 51 A method of treating prostate cancer in a subject, wherein the prostate cancer has been determined to express an androgen receptor splice variant lacking the ligand binding domain, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: ,
• Embodiment 52 The method of embodiment 51, wherein the compound is or a pharmaceutically acceptable salt thereof.
• Embodiment 53 The method of embodiment 51, wherein the compound is: pharmaceutically acceptable salt thereof.
• Embodiment 54 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
• Embodiment 55 The method of embodiment 51, wherein the compound is: pharmaceutically acceptable salt thereof.
• Embodiment 56 The method of embodiment 51, wherein the compound is: pharmaceutically acceptable salt thereof.
• Embodiment 57 The method of embodiment 51, wherein the compound is: pharmaceutically acceptable salt thereof.
• Embodiment 58 The method of embodiment 51, wherein the compound is: pharmaceutically acceptable salt thereof.
• Embodiment 59 The method of embodiment 51, wherein the compound is: pharmaceutically acceptable salt thereof.
• Embodiment 60 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
• Embodiment 61 The method of embodiment 51, wherein the compound i , pharmaceutically acceptable salt thereof.
• Embodiment 62 The method of embodiment 51, wherein the compound is: pharmaceutically acceptable salt thereof.
• Embodiment 63 The method of embodiment 51, wherein the compound is: , or a pharmaceutically acceptable salt thereof.
• Embodiment 64 The method of any one of embodiments 1 to 63, wherein the prostate cancer in the subject is localized high risk prostate cancer, recurrent prostate cancer, non-metastatic hormone-sensitive prostate cancer (nmHSPC), metastatic hormone-sensitive prostate cancer (mHSPC), non-metastatic castrate- resistant prostate cancer (nmCRPC), or metastatic castrate-resistant prostate cancer (mCRPC).
• Embodiment 65 The method of any one of embodiments 1 to 64, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount between about 0.01 mg/kg per day to about 300 mg/kg per day.
• Embodiment 66 Embodiment 66.
• Embodiment 67 The method of any one of embodiments 1 to 66, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount between about 0.1 mg/kg per day to about 100 mg/kg per day.
• Embodiment 67 The method of any one of embodiments 1 to 66, wherein the expression of the androgen receptor splice variant lacking the ligand binding domain is determined by measurement of androgen receptor protein in a biologic sample obtained from the subject.
• Embodiment 68 The method of embodiment 67, wherein the biologic sample is blood or tissue.
• Embodiment 69 The method of embodiment 68, wherein the biologic sample is blood.
• Embodiment 70 Embodiment 70.
• Embodiment 71 The method of embodiment 70, wherein the tissue is obtained from a biopsy of the prostate cancer in the subject.
• Embodiment 72 The method of any one of embodiments 1 to 66, wherein the expression of the androgen receptor splice variant lacking the ligand binding domain is determined by measurement of mRNA that encodes androgen receptor protein in a biologic sample obtained from the subject.
• Embodiment 73 The method of embodiment 72, wherein the biologic sample is blood or tissue.
• Embodiment 74 The method of embodiment 73, wherein the biologic sample is blood.
• Embodiment 75 The method of embodiment 73, wherein the biologic sample is blood.
• Embodiment 73 wherein the biologic sample is tissue.
• Embodiment 76 The method of embodiment 75,wherein the tissue is obtained from a biopsy of the prostate cancer in the subject.
• Embodiment 77 The method of any one of embodiments 1 to 76, further comprising administering to the subject one or more additional therapeutic agents.
• Embodiment 78 Embodiment 78.
• Embodiment 77 wherein the one or more additional therapeutic agents are selected from mitotic inhibitors, antimetabolites, platinum-based agents, N-terminal domain inhibitors of androgen receptor, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, inhibitors of CYP17, inhibitors of androgen receptor protein expression, heat shock protein 90 (HSP90) inhibitors, bromodomain and extra-terminal domain family (BET) inhibitors, and androgen receptor degraders, or combinations thereof.
• PRP poly(adenosine diphosphate-ribose) polymerase
• HSP90 heat shock protein 90
• BET bromodomain and extra-terminal domain family
• Embodiment 80 Embodiment 80.
• Embodiment 81 The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from antimetabolites.
• Embodiment 82. The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from platinum-based agents.
• Embodiment 84 The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from N-terminal domain inhibitors of androgen receptor.
• Embodiment 85 The method of embodiment 84, wherein the N-terminal domain inhibitor of androgen receptor is selected from EPI-001, EPI-002 (ralaniten), EPI-506, and EPI-7386.
• 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.
• Embodiment 87 The method of embodiment 86, wherein the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are selected from olaparib, niraparib, rucaparib, talazoparib, veliparib, pamiparib, CEP-9722, and E7016.
• Embodiment 88 Embodiment 88.
• Embodiment 78 wherein the one or more additional therapeutic agents are selected from inhibitors of CYP17.
• Embodiment 89 The method of embodiment 88, wherein the inhibitor of CYP17 is galeterone.
• Embodiment 90 The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from inhibitors of androgen receptor protein expression.
• Embodiment 91 The method of embodiment 90, wherein the inhibitor of androgen receptor protein expression is niclosamide or galeterone.
• 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.
• HSP90 heat shock protein 90
• Embodiment 93 The method of embodiment 92, wherein the one or more heat shock protein 90 (HSP90) inhibitors are selected from tanespimycin, luminespib, alvespimycin, ganetespib, BIIB021, onalespib, geldanamycin, NVP-BEP800, SNX-2112 (PF-04928473), PF-04929113 (SNX-5422), KW-2478, XL888, TAS-116, VER-50589, CH5138303, VER-49009, NMS-E973, zelavespib (PU-H71), and HSP990 (NVP-HSP990).
• HSP90 heat shock protein 90
• Embodiment 95 The method of embodiment 94, wherein the bromodomain and extra-terminal domain family (BET) inhibitor is selected from JQ1, I-BET 151 (GSK1210151A), I-BET 762 (GSK525762), GSK778 (iBET-BD1), GSK046 (iBET-BD2), OTX-015, TEN-010, CPI-203, CPI-0610, olinone, RVX-208, ABBV-744, LY294002, AZD5153, MT-1, MS645, MS417, SJ432, RVX-208, ABBV-075 (mivebresib), BMS-986158, PLX51107, INCB054329, INCB057643, FT-1101, CC-90010, and ODM-207.
• BET bromodomain and extra-terminal domain family
• Embodiment 96 The method of embodiment 78, wherein the one or more additional therapeutic agents are selected from androgen receptor degraders.
• Embodiment 97 The method of embodiment 96, wherein the androgen receptor degraders are selected from ARV-110, ARV-330, SARD279, SARD033, ARCC-4, UT-34, ARD-111, ARD-86, ARD-77, ARD-69, ARD-61, LX-1, or LX-2, or a pharmaceutically acceptable salt thereof.
• Embodiment 98 The method of embodiment 77, wherein the one or more additional therapeutic agents are selected from surgery, radiation, and prostate-specific membrane antigen (PSMA) targeted agents.
• PSMA prostate-specific membrane antigen
• Embodiment 99 The method of any one of embodiments 1 to 98, wherein the subject has been administered one or more first agents prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or more first agents is selected from (a) luteinizing hormone-releasing hormone (LHRH) agonists, (b) luteinizing hormone-releasing hormone (LHRH) antagonists, (c) androgen receptor inhibitors, (d) inhibitors of cytochrome P45017A1, and/or (e) antiandrogens.
• Embodiment 100 The method of embodiment 99, wherein the one or more first agents is a luteinizing hormone-releasing hormone (LHRH) agonist.
• Embodiment 101 The method of embodiment 100, wherein the luteinizing hormone-releasing hormone (LHRH) agonist is selected from goserelin, histrelin, leuprolide, and triptorelin.
• Embodiment 102 The method of embodiment 99, wherein the one or more first agents is a luteinizing hormone-releasing hormone (LHRH) antagonist.
• Embodiment 103 The method of embodiment 102, wherein the luteinizing hormone-releasing hormone (LHRH) antagonist is selected from degarelix and relugolix.
• Embodiment 104 The method of embodiment 99, wherein the one or more first agents is an androgen receptor inhibitor.
• Embodiment 105 The method of embodiment 104, wherein the androgen receptor inhibitor is selected from enzalutamide, apalutamide, and darolutamide.
• Embodiment 106 The method of embodiment 99, wherein the one or more first agents is an inhibitor of cytochrome P45017A1.
• Embodiment 107 The method of embodiment 106, wherein the one or more inhibitors of cytochrome P45017A1 is abiraterone acetate.
• Embodiment 108 The method of embodiment 99, wherein the one or more first agents is an antiandrogen.
• Embodiment 109 Embodiment 109.
• Embodiment 110 The method of any one of embodiments 1 to 109, wherein the prostate cancer in the subject is progressing prior to administration to the subject of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• 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 1 Administration of Compound 4 to 22Rv1 tumor-bearing castrated male BALB/c nude mice
• the tumor volume in each mouse in each group was then measured on days 1, 4, 7, 10, 14, 17, 21, 25, and 28 following the administration of vehicle or Compound 4.
• FIG.1 shows the average tumor volume for the mice ( ⁇ SEM) in each group.
• Example 3 Administration of Compound 4 to VCaP tumor-bearing castrated male CB17SCID mice
• the tumor volume in each mouse in each group was then measured on days 1, 3, 6, 10, 13, 17, 20, and 21 following the administration of vehicle or Compound 4.
• FIG.3 shows the average tumor volume for the mice ( ⁇ SEM) in each group.
• FIG.4 shows the average tumor volume for the mice ( ⁇ SEM) in each group.
• the group of tumor-bearing mice to which Compound 4 was administered demonstrated significant tumor growth inhibition of 68% (t-test, p ⁇ 0.001, versus the control (vehicle) group).
• Example 5 Administration of Compound 4 to CTG-3421 tumor-bearing intact male NOG mice
• the tumor volume in each mouse in each group was then measured on days 1, 5, 7, 12, 15, 19, 22, 26, and 28 following the administration of vehicle or Compound 4.
• FIG.5 shows the average tumor volume for the mice ( ⁇ SEM) in each group.
• the group of tumor-bearing mice to which Compound 4 was administered demonstrated significant tumor growth inhibition of 54% (t-test, p ⁇ 0.05, versus the control (vehicle) group).
• Example 6 Treatment of AR-positive prostate cancer models with Compound 4 [00313] Four (4) cell line derived xenograft (CDX) and ten (10) patient-derived xenograft (PDX) models of AR-positive prostate cancer were selected for in vivo efficacy studies with Compound 4.
• CDX cell line derived xenograft
• PDX patient-derived xenograft
• the AR positivity of these models was confirmed based on expression of a transcriptional 21-gene AR signature (from Beltran et al, Nature Medicine 2016, and further restricted to genes that are induced by R1881 and repressed by AR inhibitors in LNCaP cells (Hieronymus et al, Cancer Cell 2006)), calculated as the averaged z-scored expression of the 21 genes, as well as the expression of luminal markers AR, KLK3, FOLH1, TMPRSS2, AMACR, NKX3-1, and FOXA1.
• the presence of AR splice variant AR-V7 in these tumors was determined using four exemplar AR-V7 testing modalities.
• AR-V7 status was determined based on absolute expression levels of AR-V7.
• AR-V7-negative was defined as having absolute AR-V7 expression ⁇ 2, AR-V7-low (+) as ranging from 2 to ⁇ 5, AR-V7-intermediate (++) as ranging from 5 to 100, and AR- V7-high (+++) as >100.
• AR-V7 status was assessed based on the ratio of AR-V7 expression to the total abundance of all AR transcripts.
• Models with relative AR-V7 expression ⁇ 10% were considered AR- V7-negative, AR-V7-low (+) models expressed 10-30% AR-V7, AR-V7-intermediate (++) models expressed >30-50% AR-V7, and AR-V7-high (+++) models expressed >50% AR-V7.
• WB western blotting
• Tables 1 and 2 show the average AR-V7/b-tubulin level per model.
• DU145 was included as negative control (average AR-V7 to beta-tubulin level of 0.0097).
• AR-negative model CTG-3581 was included as negative control (average AR- V7 to beta-tubulin level of 0.0098). Based on WB results, AR-V7-negative was defined as AR-V7/b-tubulin protein levels ⁇ 0.01, AR-V7-low (+) as ranging from 0.01 to ⁇ 0.1, AR-V7-intermediate (++) as ranging from 0.1 to 0.2, and AR-V7-high (+++) as >0.2. Lastly, immunohistochemistry (IHC) was used as an orthogonal method to quantitate AR-V7 protein levels using the same antibody.
• IHC immunohistochemistry
• AR-V7-negative was defined as absent AR-V7 staining in the majority of tumor cells, AR-V7-low (+) as weak AR-V7 staining in a subset of tumor cells, AR-V7-intermediate (++) as weak to moderate AR-V7 staining in the majority of tumor cells, and AR- V7-high (+++) as moderate to strong AR-V7 staining in the majority of tumor cells.
• models were considered positive for the splice variant AR-V7 when supported by at least 2 AR-V7 testing modalities (listed as global AR-V7 status in tables 1 and 2).
• CDX model 22Rv1 expresses high levels, and CDX model VCaP intermediate levels, of AR-V7, consistently observed at the absolute mRNA and protein level.
• CDX models C4-2 and LNCaP are negative for AR-V7.
• AR-V7 status in these models derived from RNA-sequencing, Western Blotting and IHC, are consistent with AR-V7 protein quantification by Western Blot in Sharp et al, JCI 2019, based on RevMAb clone RM7 and Abcam EPR15656.22Rv1 and VCaP expressed AR-V7 protein based on both antibodies, while LNCaP was negative for AR-V7 (Sharp et al, JCI 2019).
• Three out of 10 PDX models (CTG-3337, CTG-3421, and CTG-3610) consistently expressed AR-V7 at the mRNA level and the protein level by both WB and IHC, with models CTG-3337 and CTG-3610 expressing intermediate-to-high AR-V7 levels and model CTG-3421 expressing low-to-intermediate AR-V7 levels.
• CTG-3337 and CTG-3610 expressing intermediate-to-high AR-V7 levels
• model CTG-3421 expressing low-to-intermediate AR-V7 levels.
• weak AR-V7 staining was observed by IHC in a subset of tumor cells.
• the weak sub-clonal AR-V7 staining was corroborated by intermediate absolute AR-V7 mRNA expression for model CTG-2427, yet the weak positivity was not corroborated at the mRNA level for models CTG-2428 and CTG-2429.
• the four AR-positive prostate cancer CDX models were treated once per day with Compound 4 at a concentration of 100 mg/kg.
• Three out of four models responded to treatment with Compound 4 using a TGI cutoff of 40% (FIG.1, FIG.2, FIG.3).
• Two of the three responsive models express intermediate-to-high levels of AR-V7, while non-responsive model LNCaP is AR-V7-negative.
• Example 7 Preparation of crystalline Form 1 of Compound 4 [00316] 150 ⁇ L of methanol was added to 50 mg of the free base of Compound 4 and the resulting slurry was stirred at room temperature for one day. The resulting solids were vacuum filtered and dried under ambient condition overnight to afford Form 1 of Compound 4.
• Example 8A Preparation of crystalline Form 2 of Compound 4 [00317] 400 mg of the free base of Compound 4 was dissolved in 1.5 mL of 2-methyltetrahydrofuran at 50 oC, to which was added 1.5 mL n-heptane at about 47 °C, and the resulting mixture was cooled 10 °C.
• Example 8B Preparation of crystalline Form 2 of Compound 4 [00318] A quantity of the free base of Compound 4 was dissolved in 2-methyltetrahydrofuran (10 volumes) and then distilled to 3 volumes. The temperature of the solution was adjusted to about 25 oC and the resulting slurry was stirred for greater than 30 minutes. To the slurry was added n-heptane (7 volumes) over 2 hours and the resulting mixture was stirred for greater than 4 hours.
• Example 9 X-ray powder diffraction (XRPD) analysis of Form 1 and Form 2 of Compound 4 [00319] XRPD analyses of crystalline polymorphic forms of Compound 4 were performed using Panalytical X’pert 3 X-ray powder diffractometer. Samples were spread on the middle of a zero-background Si holder. The 2-theta position was calibrated against a Panalytical Si reference standard disc. The parameters used for the analyses are set forth in Table 3.
• TGA Thermal gravimetric analysis
• DSC differential scanning calorimetry
• Example 11 Preparation of crystalline Form 2 of Compound 4 [00325]
• a reactor was evacuated and charged with nitrogen to atmospheric pressure. The reactor was then charged with a solution of Compound 4 (approximately 2.41 kg as determined by solution assay using HPLC) in 2-methyltetrahydrofuran (2-MeTHF, 36 kg, 15 volumes) and the batch was concentrated to a batch volume of about 5 L (about 2 volumes) via distillation under reduced pressure. The resulting solution was adjusted to about 25 °C and then n-heptane (0.4 kg, 0.2 volumes) was added in portions over a period of about 3 hours.

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• 2023
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