Androgen receptor / AKR1C3 dual inhibitor

Abstract

The present invention provides benzamide compounds, compositions containing the benzamides, and uses of the benzamides to inhibit the androgen receptor (AR) and / or aldo-keto reductase family 1 member C3 (AKR1C3). Methods for treating hormone-mediated diseases and conditions, including hormone-related cancers such as castration-resistant prostate cancer, are also described herein. TIFF2023502991000042.tif74128

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 937,136, filed November 18, 2019, which is incorporated by reference in its entirety. [Background technology]

[0002] 2. Background of the Invention Next-generation antiandrogens, such as enzalutamide, apalutamide, and darolutamide, as well as androgen synthesis inhibitors, such as abiraterone, have been approved for the treatment of patients with castration-resistant prostate cancer (CRPC) both before and after chemotherapy. Although these therapies are initially effective, they rapidly lead to the development of resistance to the drugs, resulting in disease progression. There is imminent ongoing research to elucidate potential resistance mechanisms in order to devise ways to target resistance pathways that sustain disease progression during effective AR blockade. Considerable evidence from both clinical and experimental studies has demonstrated that the androgen receptor (AR) and its variant 7 (AR-V7) play a crucial role in promoting CRPC progression during androgen deprivation therapy as well as in inducing resistance to enzalutamide and abiraterone therapy. Recent studies have also suggested that activation of AKR1C3 and enhanced intracellular secretory androgen synthesis contribute to enzalutamide and abiraterone resistance. In enzalutamide / abiraterone-resistant prostate cancer cells, AKR1C3 is overexpressed and intracellular secreted androgens are elevated. Summary of the Invention

[0003] Provided herein are compounds according to formula I: TIFF0007623375000001.tif34128, or a pharma- ceutically acceptable salt thereof, wherein: Z is -CH2-, -C(O)-, -O-, -S-, and -NR a - selected from the group consisting of; Each R 1 -OH, C 1~8 Alkyl, C 1~8 independently selected from the group consisting of alkoxy, and halogen; Each R 2 and R 3 -OH, halogen, -NO2, -CN, C 1~8 Alkyl, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) independently selected from the group consisting of: R 4 -H, α-aminoacyl; -S(O)2N(R a )2, -C(O)N(R a )2, and -C(O)R b selected from the group consisting of; Each R a H and C 1~8 independently selected from the group consisting of alkyl; R b is C 1~8 is alkyl; The subscript m is an integer ranging from 0 to 3; the subscript n is an integer ranging from 0 to 5; and The subscript p is an integer ranging from 1 to 5.

[0004] Also provided herein are pharmaceutical compositions containing one or more compounds described herein and one or more pharma- ceutically acceptable excipients.

[0005] Also provided herein is a method for treating a hormone-mediated disease or condition, such as cancer, e.g., castration-resistant prostate cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition described herein, thereby treating the hormone-mediated disease or condition.

[0006] Also provided herein is a method for inhibiting androgen receptor (AR) and / or aldo-keto reductase family 1 member C3 (AKR1C3).The method includes: contacting AR and / or AKR1C3 with an effective amount of a compound described herein, thereby inhibiting AR and / or AKR1C3. [The present invention 1001] Compounds according to formula I: TIFF0007623375000002.tif34128 or a pharma- ceutically acceptable salt thereof, wherein: Z is -CH 2 -, -C(O)-, -O-, -S-, and -NR a - selected from the group consisting of; Z is -OR 4 Para position or -OR 4 in the ortho position to The subscript m is 0, 1, 2, or 3; Each R 1 But -OH, C 1~8 Alkyl, C 1~8 independently selected from the group consisting of alkoxy, and halogen; The subscript n is 0, 1, 2, 3, 4, or 5; Each R 2 But -OH, halogen, -NO 2 , -CN,C 1~8 Alkyl, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 independently selected from the group consisting of: The subscript p is 2, 3, 4, 5, 0, or 1; Each R 3 But, C 1~8 Haloalkyl, -OH, halogen, -NO 2 , -CN,C 1~8 Alkyl, C 1~8 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 independently selected from the group consisting of: R 4 H, α-aminoacyl; -S(O) 2 N(R a ) 2 , -C(O)N(R a ) 2 , and -C(O)R b selected from the group consisting of; Each R a But H and C 1~8 alkyl; and R b But, C 1~8 is alkyl; where: Z is -OR 4 -CH in para position to 2 -, where subscript m and subscript n are 0, and R 4 is H, then at least one R 3 is C 1~8 Haloalkyl, halogen, -NO 2 、C 2~8 Alkyl, C 1~8 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 selected from the group consisting of; Z is -OR 4 -CH in para position to 2 - and if the compound is a 2,3,4-trihydroxy-benzamide, then at least one R 2 or at least one R 3 -OH, -NO 2 , -CN,C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 selected from the group consisting of; Z is -OR 4 -CH in para position to 2 - and if the compound is a 5-alkyl-6-hydroxy-benzamide, then at least one R 2 or at least one R 3 -OH, -NO 2 , -CN,C 1~8 Alkyl, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 selected from the group consisting of; Z is -OR 4 and the compound is a 2-hydroxy-benzamide, a 2,5-dialkyl-6-hydroxy-benzamide, or a 5-alkyl-6-hydroxy-benzamide. (i) At least one R 2 or at least one R 3 -OH, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 is selected from the group consisting of (ii) The subscript n is 1, and R 2 is 4-chloro or 4-(n-butyl), at least one R 3 -CF 3 OR -NO 2 other than; and Z is -OR 4 and when the compound is a 2,5-dialkyl-6-hydroxy-benzamide or a 5-alkyl-6-hydroxy-benzamide, at least one R 2 or at least one R 3 -OH, C 2~8 Alkyl, C 2~8 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 Selected from the group consisting of: The compound, or a pharma- ceutically acceptable salt thereof. [The present invention 1002] Z is -CH 2 or a pharma- ceutically acceptable salt thereof. [The present invention 1003] The compound of the present invention 1001, wherein Z is -C(O)-, or a pharma- ceutically acceptable salt thereof. [The present invention 1004] The compound of the present invention 1001, wherein Z is -O-, or a pharma- ceutically acceptable salt thereof. [The present invention 1005] 1001. A compound of the present invention, wherein the subscript m is 0, or a pharma- ceutically acceptable salt thereof. [The present invention 1006] Each R 3 But, C 1~8 Haloalkyl, -OH, halogen, -NO 2 , -CN,C 1~8 Alkyl, C 1~8 Alkoxy, C 2~8 Alkenyl, and C 2~8 alkynyl, or a pharma- ceutically acceptable salt thereof. [The present invention 1007] Each R 3 But, C 1~8 Haloalkyl, halogen, and -NO 2 1001. A compound of the present invention, independently selected from the group consisting of: [The present invention 1008] 1001. A compound of the present invention, or a pharma- ceutically acceptable salt thereof, wherein the subscript p is 1 or 2. [The present invention 1009] Structure according to formula IIa: TIFF0007623375000003.tif40128 1008. The compound of the present invention, having the formula: or a pharma- ceutically acceptable salt thereof. [The present invention 1010] R 3b and R 3d C 1~8 The compound of the present invention, wherein the compound is haloalkyl, or a pharma- ceutically acceptable salt thereof. [The present invention 1011] R 3b and R 3d Independently, -CF 3 and -CCl 3 or a pharma- ceutically acceptable salt thereof. [The present invention 1012] Structure according to formula IIb: TIFF0007623375000004.tif35128 1008. The compound of the present invention, having the formula: or a pharma- ceutically acceptable salt thereof. [The present invention 1013] R 3a and R 3c However, halogens and -NO 2 1012. A compound of the present invention, independently selected from the group consisting of: [The present invention 1014] R 3a is -Cl, and R 3c But -NO 2 1013. The compound of the present invention, wherein: [The present invention 1015] Structure according to formula IIc: TIFF0007623375000005.tif34128 1008. The compound of the present invention, having the formula: or a pharma- ceutically acceptable salt thereof. [The present invention 1016] R 3 But, C 1~8 The compound of the present invention, or a pharma- ceutically acceptable salt thereof, wherein: 1015 is haloalkyl. [The present invention 1017] R 3 But -CF 3 and -CCl 3 1015. The compound of the present invention, selected from the group consisting of: [The present invention 1018] 1001 A compound of the present invention, wherein the subscript n is 0, or a pharma- ceutically acceptable salt thereof. [The present invention 1019] 1001. A compound of the present invention, wherein the subscript n is 1, or a pharma- ceutically acceptable salt thereof. [The present invention 1020] R 2 But, C 1~8 Alkyl, C 1~8 Alkoxy, and C 1~8 The compound of the present invention 1019, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of haloalkyl. [The present invention 1021] Structure according to formula IIIa: TIFF0007623375000006.tif41128 1019. The compound of the present invention, or a pharma- ceutically acceptable salt thereof, having the formula: [The present invention 1022] R 3b and R 3d became independent, C 1~8 The compound of the present invention, wherein the compound is haloalkyl, or a pharma- ceutically acceptable salt thereof. [The present invention 1023] R 3b and R 3d But -CF 3 and -CCl 3 1022. A compound of the present invention, independently selected from the group consisting of: or a pharma- ceutically acceptable salt thereof. [The present invention 1024] Structure according to formula IIIb: TIFF0007623375000007.tif36128 1019. The compound of the present invention, or a pharma- ceutically acceptable salt thereof, having the formula: [The present invention 1025] R 3a and R 3c However, halogens and -NO 2 1024. A compound of the present invention, independently selected from the group consisting of: or a pharma- ceutically acceptable salt thereof. [The present invention 1026] R 3a is -Cl, and R 3c But -NO 2 1025. The compound of the present invention, wherein: [The present invention 1027] Structure according to formula IIIc: TIFF0007623375000008.tif34128 1019. The compound of the present invention, or a pharma- ceutically acceptable salt thereof, having the formula: [The present invention 1028] R 3 But, C 1~8 The compound of the present invention 1027, or a pharma- ceutically acceptable salt thereof, which is haloalkyl. [The present invention 1029] R 3 But -CF 3 and -CCl 3 1028. The compound of the present invention, selected from the group consisting of: [The present invention 1030] R 2c But, -OCH 3 1021. The compound of the present invention, wherein: [The present invention 1031] R 4 is H or α-aminoacyl, or a pharma- ceutically acceptable salt thereof. [The present invention 1032] R 4 is selected from the group consisting of l-valinyl and d-valinyl, or a pharma- ceutically acceptable salt thereof. [The present invention 1033] Z is -OR 4 or a pharma- ceutically acceptable salt thereof. [The present invention 1034] The compound of the present invention, wherein Z is in the ortho position relative to -C(O)NH-, or a pharma- ceutically acceptable salt thereof. [The present invention 1035] A compound of the present invention selected from the group consisting of: TIFF0007623375000009.tif212125 and pharma- ceutically acceptable salts thereof. [The present invention 1036] Z is -CH 2 - and; The subscript m and the subscript n are 0; and At least one R 3 But halogen, -NO 2 、C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 Selected from the group consisting of: A compound of the present invention, or a pharma- ceutically acceptable salt thereof. [The present invention 1037] Z is -OR 4 is in the para position to -C(O)-; the compound is a 2-hydroxy-benzamide, a 2,5-dialkyl-6-hydroxy-benzamide, or a 5-alkyl-6-hydroxy-benzamide; and At least one R 2 or at least one R 3 But -OH, C 1~8 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a) 2 Selected from the group consisting of: A compound of the present invention, or a pharma- ceutically acceptable salt thereof. [The present invention 1038] Z is -OR 4 is in the para position to -S-; the compound is a 2,5-dialkyl-6-hydroxy-benzamide or a 5-alkyl-6-hydroxy-benzamide; and At least one R 2 or at least one R 3 But -OH, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 Selected from the group consisting of: A compound of the present invention, or a pharma- ceutically acceptable salt thereof. [The present invention 1039] Any of the compounds of the present invention 1001 to 1038 or a pharma- ceutically acceptable salt thereof, A pharma- ceutically acceptable excipient; 23. A pharmaceutical composition comprising: [The present invention 1040] 1. A method for treating a hormone-mediated disease or condition, comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, thereby treating a hormone-mediated disease or condition. The method comprises: [The present invention 1041] The method of claim 1040, wherein the hormone-mediated disease is cancer. [The present invention 1042] The method of claim 1041, wherein the cancer is castration-resistant prostate cancer. [The present invention 1043] Administering an antiandrogen to the subject. The method of any one of claims 1040 to 1042, further comprising: [The present invention 1044] The method of claim 1043, wherein the antiandrogen is selected from the group consisting of enzalutamide, apalutamide, darolutamide, abiraterone, pharma- ceutically acceptable salts thereof, and combinations thereof. [The present invention 1045] 1. A method for inhibiting the androgen receptor (AR), comprising: contacting the AR with an effective amount of a compound of the present invention or a salt thereof, thereby inhibiting the AR. The method comprises: [The present invention 1046] 1. A method for inhibiting aldo-keto reductase family 1 member C3 (AKR1C3), comprising: contacting AKR1C3 with an effective amount of a compound of the present invention or a salt thereof, thereby inhibiting AKR1C3. The method comprises: [Brief description of the drawings]

[0007] [Figure 1] 1 shows Western blot analysis of AR-FL, AR-V and AKR1C3 protein expression after treatment of CWR22rv1 cells with Compound 1 and Compound 2. [Diagram 2] 1 shows a plot of enzyme activity of LNCaP-AKR1C3 cells treated with either compound 1 or compound 2 for 48 hours, demonstrating that these compounds inhibit AKR1C3 activity. [Diagram 3] 1 shows a plot of enzyme activity in LNCaP-AKR1C3 cells treated with increasing doses of Compound 1 for 48 hours, demonstrating that AKR1C3 is inhibited in a dose-dependent manner. [Figure 4] 1 shows total cell numbers measured after treatment of C4-2B MDVR cells with either Compound 1 or Compound 2, demonstrating that these compounds inhibit cell proliferation. [Diagram 5] 1 shows total cell numbers measured after treatment of C4-2B MDVR cells with increasing doses of Compound 1 for 48 hours, demonstrating a dose-dependent inhibition of cell proliferation. [Figure 6] Total cell numbers measured in enzalutamide (Enza)-resistant MDVR cells, abiraterone (Abi)-resistant AbiR cells, apalutamide (Apal)-resistant ApalR cells, and darolutamide (Daro)-resistant DaroR cells after treatment with the respective antiandrogens Enza (20 μM), Abi (10 μM), Apal (20 μM), Daro (20 μM), or compound 1 (5 μM) for 48 hours are shown. [Figure 7] 1 shows total cell numbers measured after treatment of MCF-7 breast cancer cells with increasing doses of Compound 1 for 48 hours, demonstrating a dose-dependent inhibition of cell proliferation. [Figure 8] Shown is the total cell number measured after treatment of C4-2B AKR1C3 cells with different compounds for 48 hours. [Figure 9A]1 shows the volume of VCaP tumors in mice treated with Compound 1 and vehicle control. [Figure 9B] The body weights of mice treated with Compound 1 and vehicle control in the VCaP model are shown. [Figure 9C] 9A-9C show prostate-specific antigen (PSA) levels in mice treated with Compound 1 and vehicle control in a VCaP model. Collectively, Figures 9A-9C show that Compound 1 inhibits VCaP tumor growth. [Figure 10A] 1 shows LuCaP35CR tumor volumes in mice treated with Compound 1 and vehicle control. [Figure 10B] Body weights of mice treated with Compound 1 and vehicle control in the LuCaP35CR model are shown. [Figure 10C] 1 shows prostate specific antigen (PSA) levels in mice treated with Compound 1 and vehicle control in the LuCaP35CR model. [Figure 10D] 10A-10D show intratumoral testosterone levels in mice treated with Compound 1 and vehicle control in the LuCaP35CR model. Collectively, Figures 10A-10D show that Compound 1 inhibits LuCaP35CR tumor growth. [Figure 11] 1 shows that compound 1 inhibits the conversion of androstenedione to testosterone in LuCaP35CR tumors ex vivo. [Figure 12] Figure 1 shows that Compound 1 and Compound 5 inhibit AR nuclear translocation in LNCaP cells. LNCaP cells cultured in charcoal-stripped FBS conditions were treated with DHT and the indicated compounds. AR expression was visualized by immunofluorescence staining. [Figure 13] Figure 13A: shows RNAseq heatmaps demonstrating that compound 1 and compound 5 inhibit AR activity signature genes in C4-2B MDVR cells. Figure 13B: shows RNAseq heatmaps demonstrating that compound 1 and compound 5 inhibit AR-V7 activity signature genes in C4-2B MDVR cells. [Figure 14]1 shows RNAseq heat maps demonstrating that compounds 1, 2, 5, and 8 inhibit genes associated with cancer cell proliferation and survival in C4-2B MDVR cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Detailed Description of the Invention The present invention is based in part on the realization that inhibition of both AR / ARv7 and AKR1C3 would be an ideal strategy for treating hormone-related cancers, such as advanced prostate cancer, and overcoming resistance to current therapies. Overexpression of AKR1C3 confers resistance to enzalutamide / abiraterone, while downregulation of AKR1C3 sensitizes cells to enzalutamide / abiraterone treatment. Importantly, overexpression of AKR1C3 has been demonstrated in clinical metastatic prostate cancer. As described herein, some new benzamide compounds have surprisingly been found to function as dual inhibitors of AR and AKR1C3. Benzamides inhibit both the expression and activity of AR / ARv7 and AKR1C3 in prostate cancer cells, as well as the proliferation of resistant prostate cancer cells. Furthermore, these compounds inhibit enzalutamide-resistant C4-2B MDVR cell proliferation, abiraterone-resistant cell proliferation, apalutamide-resistant cell proliferation, and darolutamide-resistant cell proliferation.

[0009] I. Definition As used herein, the term "alkyl," by itself or as part of another substituent, refers to a straight or branched chain saturated aliphatic group having the indicated number of carbon atoms. 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 1~7 , C 1~8 , C 1~9 , C 1~10 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 , and C 5~6 For example, C 1~6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and the like. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, and the like. Alkyl groups can be substituted or unsubstituted. Unless otherwise specified, a "substituted alkyl" group can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0010] As used herein, the term "alkoxy" by itself or as part of another substituent refers to a group having the formula -OR, where R is alkyl, as defined above.

[0011] As used herein, the term "alkenyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl includes C, C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C3, C 3~4 , C 3~5 , C 3~6 , C4, C 4~5 , C 4~6 , C5, C 5~6Alkenyl groups can include any number of carbons, such as C, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C30, C41, C52, C6, C70, C81, C92, C102, C113, C124, C135, C146, C157, C168, C179, C181, C192, C193, C194, C195, C196, C197, C198, C201, C202, C213, C225, C230, C241, C252, C301, C310, C320, C430, C440, C450, C460, C470, C480, C490, C510, C520, C610, C620, C730, C740, C750, C760, C810, C92, C93, C94, C95, C105, C116, C127, C137, C142, C143, C157, C168, C179, C215, C181, C197, C225, C198, C199, C232, C241, C252, C310, C320, C430, C440, C450, C460, C470, C480, C510, C520, C610, C720, C730, C740, C75 Unless otherwise specified, "substituted alkenyl" groups are optionally substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, alkoxy, haloalkyl, carboxy, amido, nitro, oxo, and cyano.

[0012] As used herein, the term "alkynyl" by itself or as part of another substituent refers to either a straight or branched chain hydrocarbon having at least two carbon atoms and at least one triple bond. Alkynyl includes C, C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C3, C 3~4 , C 3~5 , C 3~6 , C4, C 4~5 , C 4~6 , C5, C 5~6, and C6. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3 pentadiynyl, 1,4 pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3 hexadiynyl, 1,4 hexadiynyl, 1,5 hexadiynyl, 2,4 hexadiynyl, or 1,3,5 hexatriynyl. Alkynyl groups can be substituted or unsubstituted. Unless otherwise specified, "substituted alkynyl" groups can be substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, alkoxy, haloalkyl, carboxy, amido, nitro, oxo, and cyano.

[0013] As used herein, the terms "halo" and "halogen" refer to fluorine, chlorine, bromine and iodine.

[0014] As used herein, the term "haloalkyl" by itself or as part of another substituent refers to an alkyl group in which some or all of the hydrogen atoms are replaced with halogen atoms. With respect to the alkyl group, a haloalkyl group is one having a C 1~6 For example, haloalkyl includes trifluoromethyl, fluoromethyl, and the like. In some cases, the term "perfluoro" can be used to define a compound or group in which all of the hydrogens have been replaced with fluorine. For example, perfluoromethyl refers to 1,1,1 trifluoromethyl.

[0015] As used herein, the term "hydroxy" refers to the moiety, --OH.

[0016] As used herein, the term "oxo" refers to an oxygen atom that is double bonded to a compound (ie, O=).

[0017] As used herein, the term "amino" refers to the moiety, -NR2, where each R group is H or alkyl. The amino moiety can be ionized to form the corresponding ammonium cation. "Alkylamino" refers to an amino moiety in which at least one of the R groups is alkyl.

[0018] As used herein, the term "α-aminoacyl" refers to the moiety -C(O)CNR'R'', where R' and R'' are independently hydrogen, alkyl, alkynyl, aryl, heteroaryl, cycloaclkyl, or heterocyclyl, each of which is optionally substituted with one or more substituents selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0019] As used herein, the term "aryl" by itself or as part of another substituent refers to an aromatic ring system having any suitable number of carbon ring atoms and any suitable number of rings. Aryl groups include C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C67, C68, C69, C70, C71, C72, C73, C74, C75, C76, C77, C78, ​​C79, C81, C92, C93, C94, C95, C96, C97, C98, C99, C101, C102, C103, C104, C105, C106, C107, C108, C109, C111, C112, C113, C114, C115, C126, C127, C128, C136, C140, C151, C152, C153, C165, C176, C187, C188, C199, C191, C192, C193, C194, C195, C196, C19 10 , C 11 , C 12 , C 13 , C 14 , C 15 or C 16 , and C 6~10 , C 6~12 or C 6~14Aryl groups may be monocyclic, fused to form bicyclic (e.g., benzocyclohexyl) or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl, which has a methylene linking group. Some aryl groups have 6-12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6-10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. Aryl groups may be substituted or unsubstituted. Unless otherwise specified, "substituted aryl" groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0020] As used herein, the term "heteroaryl" by itself or as part of another substituent refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where 1 to 5 of the ring atoms are heteroatoms such as N, O, or S. Additional heteroatoms may also be useful, including, but not limited to, B, Al, Si, and P. The heteroatoms may be oxidized to form moieties such as, but not limited to, S(O) and S(O)2. Heteroaryl groups include C 5~6 , C 3~8 , C 4~8 , C 5~8 , C 6~8 , C 3~9 , C 3~10 , C 3~11 , or C 3~12Any suitable number of heteroatoms can be included in a heteroaryl group, such as 1, 2, 3, 4, or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5. For example, a heteroaryl group can be a C 5~8 Heteroaryl; or C in which 1-3 carbon ring atoms are replaced by heteroatoms 5~8 Heteroaryl; or C in which 1-4 carbon ring atoms are replaced by heteroatoms 5~6 Heteroaryl; or C in which 1-3 carbon ring atoms are replaced by heteroatoms 5~6 It can be heteroaryl. Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1,2,4-isomer and 1,3,5-isomer), thiophene, furan, thiazole, isothiazole, oxazole and isoxazole. Heteroaryl groups can also be fused to aromatic ring systems such as phenyl rings to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene and benzofuran. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted. Unless otherwise specified, a "substituted heteroaryl" group may be optionally substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0021] The heteroaryl group can be linked through any position on the ring. For example, pyrrole includes 1-pyrrole, 2-pyrrole, and 3-pyrrole, pyridine includes 2-pyridine, 3-pyridine, and 4-pyridine, imidazole includes 1-imidazole, 2-imidazole, 4-imidazole, and 5-imidazole, pyrazole includes 1-pyrazole, 3-pyrazole, 4-pyrazole, and 5-pyrazole, triazole includes 1-triazole, 4-triazole, and 5-triazole, tetrazole includes 1-tetrazole and 5-tetrazole, pyrimidine includes 2-pyrimidine, 4-pyrimidine, 5-pyrimidine and 6-pyrimidine, pyridazine includes 3-pyridazine and 4-pyridazine, 1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-triazine, 5-triazine and 6-triazine, 1,3,5-triazine includes 2-triazine, thiophene includes 2-thiophene and 3-thiophene, furan includes 2-furan and 3- includes furan, thiazole includes 2-thiazole, 4-thiazole and 5-thiazole, isothiazole includes 3-isothiazole, 4-isothiazole and 5-isothiazole, oxazole includes 2-oxazole, 4-oxazole and 5-oxazole, isoxazole includes 3-isoxazole, 4-isoxazole and 5-isoxazole, indole includes 1-indole, 2-indole and 3-indole, isoindole includes 1-iso indole includes 2-isoindole, quinoline includes 2-quinoline, 3-quinoline, and 4-quinoline, isoquinoline includes 1-isoquinoline, 3-isoquinoline, and 4-isoquinoline, quinazoline includes 2-quinazoline and 4-quinazoline, cinnoline includes 3-cinnoline and 4-cinnoline, benzothiophene includes 2-benzothiophene and 3-benzothiophene, and benzofuran includes 2-benzofuran and 3-benzofuran.

[0022] Some heteroaryl groups include those having 5 to 10 ring members and 1 to 3 ring atoms containing N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1,2,4-isomer and 1,3,5-isomer), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene and benzofuran. Other heteroaryl groups include those having 5 to 8 ring members and 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1,2,4-isomer and 1,3,5-isomer), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those having 9 to 12 ring members and 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran, and bipyridine. Still other heteroaryl groups include those having 5 to 6 ring members and 1 to 2 ring atoms containing N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0023] Some heteroaryl groups contain 5-10 ring members and only nitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline. Other heteroaryl groups contain 5-10 ring members and only oxygen heteroatoms, such as furan and benzofuran. Some other heteroaryl groups contain 5-10 ring members and only sulfur heteroatoms, such as thiophene and benzothiophene. Still other heteroaryl groups contain 5 to 10 ring members and at least two heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomers, 1,2,4-isomers, and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and cinnoline.

[0024] As used herein, the term "cycloalkyl," by itself or as part of another substituent, refers to a saturated or partially unsaturated monocyclic, fused bicyclic or bridged polycyclic ring assembly containing three to twelve ring atoms or the number of atoms indicated. Cycloalkyl includes any of the C 3~6 , C 4~6 , C 5~6 , C 3~8 , C 4~8 , C 5~8 , C 6~8 , C 3~9 , C 3~10 , C 3~11 , and C 3~12Cycloalkyl groups can contain any number of carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can also be partially unsaturated and have one or more double or triple bonds in the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. Cycloalkyl groups can be saturated monocyclic C 3~8 When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3~6 When it is cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted. Unless otherwise specified, "substituted cycloalkyl" groups can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0025] As used herein, the term "heterocyclyl" by itself or as part of another substituent refers to a saturated ring system having 3 to 12 ring members and 1 to 4 heteroatoms N, O, and S. Additional heteroatoms may also be useful, including, but not limited to, B, Al, Si, and P. The heteroatoms may be oxidized to form moieties such as, but not limited to, S(O) and S(O)2. Heterocyclyl groups include C 3~6 , C 4~6, C 5~6 , C 3~8 , C 4~8 , C 5~8 , C 6~8 , C 3~9 , C 3~10 , C 3~11 , or C 3~12 Any suitable number of carbon ring atoms can be replaced with a heteroatom in a heterocyclyl group, such as 1, 2, 3, or 4, or 1-2, 1-3, 1-4, 2-3, 2-4, or 3-4. Heterocyclyl groups can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocyclyl groups can also be fused to aromatic or non-aromatic ring systems to form members, including but not limited to indoline. Heterocyclyl groups can be unsubstituted or substituted. Unless otherwise specified, "substituted heterocyclyl" groups are optionally substituted with one or more groups selected from halo, hydroxy, amino, oxo (=O), alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0026] The heterocyclyl group can be linked through any position on the ring, for example, aziridine can be 1- or 2-aziridine, azetidine can be 1- or 2-azetidine, pyrrolidine can be 1-, 2-, or 3-pyrrolidine, piperidine can be 1-, 2-, 3-, or 4-piperidine, pyrazolidine can be 1-, 2-, 3-, or 4-pyrazolidine, imidazolidine can be 1-, 2-, 3-, or 4-imidazolidine, and piperazine can be 1-, 2-, 3-, or 4-piperazine. the tetrahydrofuran can be 1- or 2-tetrahydrofuran, the oxazolidine can be 2-, 3-, 4- or 5-oxazolidine, the isoxazolidine can be 2-, 3-, 4- or 5-isoxazolidine, the thiazolidine can be 2-, 3-, 4- or 5-thiazolidine, the isothiazolidine can be 2-, 3-, 4- or 5-isothiazolidine, and the morpholine can be 2-, 3- or 4-morpholine.

[0027] When a heterocyclyl contains 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. A heterocyclyl can also form a ring having 5 to 6 ring members and 1 to 2 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0028] As used herein, the term "amide" refers to the moiety, -NRC(O)R or -C(O)NR2, where each R group is H or alkyl.

[0029] As used herein, the term "acyl" refers to the moiety, --C(O)R, where each R group is alkyl.

[0030] As used herein, the term "nitro" refers to the moiety, --NO.sub.2.

[0031] As used herein, the term "cyano" refers to a carbon atom that is triple bonded to a nitrogen atom (ie, the moiety, --C.ident.N).

[0032] As used herein, the term "carboxy" refers to the moiety, --C(O)OH.

[0033] As used herein, the term "salt" refers to the acid salt or base salt of an active agent such as an androgen receptor inhibitor or an AKR1C3 inhibitor.The acid salt of a basic active agent includes mineral acid salts (e.g., salts formed by using hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acid salts (e.g., salts formed by using acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (e.g., salts formed by reacting amines with methyl iodide, ethyl iodide, etc.).It is understood that pharmaceutically acceptable salts are non-toxic.

[0034] Acidic activators can be contacted with bases to provide base salts, such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.

[0035] The neutral form of the active agent can be regenerated by contacting the salt with a base or acid, and, if necessary, isolating the parent compound in the conventional manner. In some embodiments, the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salt forms may otherwise be identical to the parent form of the compound.

[0036] "Pharmaceutically acceptable" means that the excipient is compatible with other components of the formulation and is not harmful to the recipient. As used herein, the term "pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject. Useful pharmaceutical excipients include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, coatings, sweeteners, flavors, and colorants.

[0037] As used herein, the terms "effective amount" and "therapeutically effective amount" refer to the amount of compound, such as androgen receptor inhibitor, or AKR1C3 inhibitor, or antiandrogen, administered that produces a therapeutic effect.The exact dosage depends on the purpose of treatment and can be ascertained by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11, 1999). th Edition, 2006, Brunton, Ed., McGraw-Hill; and Remington: The Science and Practice of Pharmacy, 21 st (See e.g., The American Journal of Clinical Chemistry, Vol. 13, No. 1, 2005, Hendrickson, Ed., Lippincott, Williams & Wilkins).

[0038] As used herein, the term "cancer" is intended to include any member of the disease class characterized by uncontrolled abnormal cell proliferation.This term includes all known cancers and neoplastic conditions, whether characterized as malignant, benign, recurrent, soft tissue, or solid, and all stages and grades of cancer, including advanced, recurrent, pre-metastatic and post-metastatic cancers.In addition, this term includes androgen-independent, castration-resistant, castration-recurrent, hormone-resistant, drug-resistant, and metastatic castration-resistant cancers. Examples of different types of cancer include prostate cancer (e.g., prostate adenocarcinoma); breast cancer (e.g., triple-negative breast cancer, ductal carcinoma in situ, invasive ductal carcinoma, tubular adenocarcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, cribriform carcinoma, invasive lobular carcinoma, inflammatory breast cancer, lobular carcinoma in situ, Paget's disease, phyllodes tumor); gynecological cancer (e.g., ovarian cancer, cervical cancer, uterine cancer, vaginal cancer, and vulvar cancer); lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, mesothelioma, carcinoid tumor, lung adenocarcinoma); gastrointestinal and digestive tract cancers, such as gastric cancer (e.g., stomach cancer), colorectal cancer, gastrointestinal stromal tumor (GIST), gastrointestinal carcinoid tumor, colon cancer, rectal cancer, anal cancer, bile duct cancer, small intestine cancer, and esophageal cancer); thyroid cancer; gallbladder cancer; liver cancer; pancreatic cancer; appendix cancer; Cancers of the central nervous system (e.g., glioblastoma, neuroblastoma); skin cancer (e.g., melanoma); bone and soft tissue sarcomas (e.g., Ewing's sarcoma); lymphoma; choriocarcinoma; urological cancer (e.g., urothelial bladder cancer); head and neck cancer; and bone marrow and blood cancer (e.g., chronic lymphocytic leukemia, lymphoma). As used herein, a "tumor" includes one or more cancerous cells.

[0039] As used herein, the terms "antiandrogen" and "antiandrogen drug" refer to compounds that alter the androgen pathway by blocking androgen receptors, competing for binding sites on the surface of cells, or affecting or mediating androgen production.Antiandrogens are useful for treating several diseases, including but not limited to prostate cancer.Examples of antiandrogens include, but are not limited to, enzalutamide, abiraterone, bicalutamide, and darolutamide.

[0040] As used herein, the terms "about" and "around" refer to a close range around a numerical value when used to modify that particular value. For example, when "X" is a value, "about X" or "around X" would refer to a value of 0.9X to 1.1X, such as a value of 0.95X to 1.05X, or a value of 0.98X to 1.02X, or a value of 0.99X to 1.01X. Any reference to "about X" or "around X" specifically denotes at least the value X, 0.9X, 0.91X, 0.92X, 0.93X, 0.94X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, 1.05X, 1.06X, 1.07X, 1.08X, 1.09X, and 1.1X, as well as values ​​within this range.

[0041] II. AR / AKR1C3 dual inhibitors Provided herein are compounds according to formula I: TIFF0007623375000010.tif34128, or a pharma- ceutically acceptable salt thereof, wherein: Z is -CH2-, -C(O)-, -O-, -S-, and -NR a - selected from the group consisting of; Each R 1 -OH, C 1~8 Alkyl, C 1~8 independently selected from the group consisting of alkoxy, and halogen; Each R 2 and R 3-OH, halogen, -NO2, -CN, C 1~8 Alkyl, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) independently selected from the group consisting of: R 4 -H, α-aminoacyl; -S(O)2N(R a )2, -C(O)N(R a )2, and -C(O)R b selected from the group consisting of; Each R a H and C 1~8 independently selected from the group consisting of alkyl; R b is C 1~8 is alkyl; The subscript m is an integer ranging from 0 to 3; the subscript n is an integer ranging from 0 to 5; and The subscript p is an integer ranging from 1 to 5.

[0042] In some embodiments, in the compound of formula I, Z is -OR 4 subscript m and subscript n are 0; R 4 is H, then at least one R 3 is halogen, -NO2, C 2~8 Alkyl, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a In some such embodiments, the subscript p may be 1, 2, 3, 4, or 5.

[0043] In some embodiments, in the compound of formula I, Z is -OR 4 and if the compound is a 2,3,4-trihydroxy-benzamide, then at least one R2 or at least one R 3 -OH, -NO2, -CN, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a In some such embodiments, the subscript n can be 1, 2, or 3, and the subscript p can be 1, 2, 3, 4, or 5.

[0044] In some embodiments, in the compound of formula I, Z is -OR 4 and if the compound is a 5-alkyl-6-hydroxy-benzamide, then at least one R 2 or at least one R 3 -OH, -NO2, -CN, C 1~8 Alkyl, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a In some such embodiments, the subscript n can be 1, 2, or 3, and the subscript p can be 1, 2, 3, 4, or 5.

[0045] In some embodiments, in the compound of formula I, Z is -OR 4 and if the compound is a 2-hydroxy-benzamide, a 2,5-dialkyl-6-hydroxy-benzamide, or a 5-alkyl-6-hydroxy-benzamide, (i) at least one R 2 or at least one R 3 -OH, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a (ii) the subscript n is 1 and R 2is 4-chloro or 4-(n-butyl), at least one R 3 is other than -CF3 or -NO2. In some such embodiments, the subscript n can be 1, 2, or 3, and the subscript p can be 1, 2, 3, 4, or 5.

[0046] In some embodiments, in the compound of formula I, Z is -OR 4 and if the compound is a 2,5-dialkyl-6-hydroxy-benzamide or a 5-alkyl-6-hydroxy-benzamide, then at least one R 2 or at least one R 3 -OH, C 2~8 Alkyl, C 2~8 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a In some such embodiments, the subscript n can be 1, 2, or 3, and the subscript p can be 1, 2, 3, 4, or 5.

[0047] As used herein, the term "2,3,4-trihydroxy-benzamide" refers to the compound shown below: TIFF0007623375000011.tif32128 formula, R 4 is H.

[0048] As used herein, the term "5-alkyl-6-hydroxy-benzamide" refers to the compound shown below: TIFF0007623375000012.tif32128In formula, R 4 is H and R 1b is C 1~8 It is an alkyl.

[0049] As used herein, the term "2-hydroxy-benzamide" refers to the compound shown below: TIFF0007623375000013.tif32128In formula, R 4 is H.

[0050] As used herein, the term "2,5-dialkyl-6-hydroxy-benzamide" refers to the compound shown below: TIFF0007623375000014.tif31128In formula, R 4 is H and R 1b and R 1e is C 1~8 It is an alkyl.

[0051] In some embodiments, Z is -OR 4 and the compound is a 2-hydroxy-benzamide or a 5-alkyl-6-hydroxy-benzamide, the subscript n is 1, and R 2 When R is 4-chloro or 4-(n-butyl), at least one R 3 is other than -CF3 or -NO2.

[0052] In some embodiments, Z is -OR 4 and when the compound is a 2-hydroxy-benzamide or a 5-alkyl-6-hydroxy-benzamide, the compound is other than 5-(4-butylbenzoyl)-2-hydroxy-N-[3-(trifluoromethyl)phenyl]-benzamide or 5-(4-chlorobenzoyl)-2-hydroxy-3-methyl-N-[4-nitro-2-(trifluoromethyl)phenyl]-benzamide.

[0053] In some embodiments, Z is -CH2-. In some embodiments, Z is -C(O)-. In some embodiments, Z is -O-.

[0054] In some embodiments, each R 3 -OH, halogen, -NO2, -CN, C 1~8 Alkyl, C1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, and C 2~8 Compounds of formula I are provided, wherein:

[0055] In some embodiments, each R 3 But, C 1~8 Compounds of formula I are provided, wherein each is independently selected from the group consisting of haloalkyl, halogen, and -NO2.

[0056] Compounds according to formula IIa: Also provided herein is TIFF0007623375000015.tif40128 or a pharma- ceutically acceptable salt thereof. In some embodiments, in the compound of formula IIa, R 3b and R 3d is independently C 1~8 Haloalkyl. R 3b and R 3d may be independently, for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, pentachloroethyl, pentafluoroethyl, 1,1,1,3,3,3-hexachloropropyl, 1,1,1,3,3,3-hexafluoropropyl, and the like. 3b and R 3d is independently selected from the group consisting of -CF3 and -CCl3.

[0057] Compounds according to formula IIb: Also provided herein is TIFF0007623375000016.tif35128 or a pharma- ceutically acceptable salt thereof. In some embodiments, in the compound of formula IIb, R 3a and R 3c is independently selected from the group consisting of halogen and -NO2. 3a and R 3cmay be independently fluoro, chloro, bromo, iodo, or -NO. In some embodiments, in the compound of formula IIb, R 3a is -Cl, R 3c is -NO2.

[0058] Compounds according to formula IIc: Also provided herein is TIFF0007623375000017.tif34128, or a pharma- ceutically acceptable salt thereof. 3 is C 1~8 Haloalkyl. R 3 may be, for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, pentachloroethyl, pentafluoroethyl, 1,1,1,3,3,3-hexachloropropyl, 1,1,1,3,3,3-hexafluoropropyl, and the like. 3 is selected from the group consisting of -CF3 and -CCl3.

[0059] In some embodiments, in the compound of formula I, IIa, IIb, or IIc, R 2 is C 1~8 Alkyl, C 1~8 Alkoxy, and C 1~8 In some embodiments, R is selected from the group consisting of haloalkyl. 2 is C 1~8 Alkyl and C 1~8 alkoxy; R 3 is C 1~8 It is haloalkyl.

[0060] Compounds according to formula IIIa: TIFF0007623375000018.tif41128 or a pharma- ceutically acceptable salt thereof is provided herein.

[0061] In some embodiments, R 3b and R3d is independent, C 1~8 Haloalkyl. R 3b and R 3d may be independently, for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, pentachloroethyl, pentafluoroethyl, 1,1,1,3,3,3-hexachloropropyl, 1,1,1,3,3,3-hexafluoropropyl, and the like. 3b and R 3d is independently selected from the group consisting of -CF3 and -CCl3. 2 is C 1~8 Alkyl, C 1~8 Alkoxy, and C 1~8 haloalkyl.

[0062] Compounds according to formula IIIb: TIFF0007623375000019.tif36128 or a pharma- ceutically acceptable salt thereof is provided herein.

[0063] In some embodiments, R 3a and R 3c is independently selected from the group consisting of halogen and -NO2; R 3a and R 3c may independently be fluoro, chloro, bromo, iodo, or -NO. In some embodiments, R 3a is -Cl, R 3c In some such embodiments, R 2 is C 1~8 Alkyl, C 1~8 Alkoxy, and C 1~8 haloalkyl.

[0064] Compounds according to formula IIIc: TIFF0007623375000020.tif34128 or a pharma- ceutically acceptable salt thereof is provided herein.

[0065] In some embodiments, in the compound of formula IIIa, IIIb, or IIIc, R 2c is -OCH3.

[0066] In some embodiments, in the compound of formula I, IIa, IIb, IIc, IIIa, IIIb, or IIIc, Z is -OR 4 It is present in the para position to

[0067] In some embodiments, Z is in the ortho position relative to -C(O)NH- in the compound of Formula I, IIa, IIb, IIc, IIIa, IIIb, or IIIc.

[0068] Also provided herein are compounds according to formula IV, V, or VI: TIFF0007623375000021.tif73146In formula, R 1 , R 2 , R 3 , R 4 , subscript m, subscript n, and subscript p are defined as above. Compounds according to formulas IV, V, and VI can be prepared by the above R 2c , R 3a , R 3b , and R 3c It may further comprise one or more of the groups.

[0069] In some embodiments, in the compound of formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IV, V, and / or VI, R 4 is H or α-aminoacyl. In some embodiments, in the compound of formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IV, V, and / or VI, R 4 is selected from the group consisting of L-valinyl and D-valinyl.

[0070] In some embodiments, compounds of formula I, IIa, IIb, IIc, IIIa, IIIb, IIIc, IV, V, and / or VI are provided where subscript m is 0. In some embodiments, compounds of formula I, IIa, IIb, IIc, IV, V, and / or VI are provided where subscript n is 1 or 2. In some embodiments, compounds of formula I, IV, V, and / or VI are provided where subscript p is 1 or 2.

[0071] In some embodiments, the compound is: TIFF0007623375000022.tif214125 and pharma- ceutically acceptable salts thereof.

[0072] In some embodiments, Z is -CH2-; The subscript m and the subscript n are 0; and At least one R 3 But halogen, -NO2, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 selected from the group consisting of Compounds of formula I are provided: In some such embodiments, subscript p can be 1, 2, 3, 4, or 5.

[0073] In some embodiments, Z is -OR 4 is in the para position to -C(O)-; the compound is a 2-hydroxy-benzamide, a 2,5-dialkyl-6-hydroxy-benzamide, or a 5-alkyl-6-hydroxy-benzamide; and At least one R 2 or at least one R 3 But -OH, C 1~8 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(Ra ) 2 selected from the group consisting of Compounds of formula I are provided: In some such embodiments, subscript n can be 1, 2, or 3, and subscript p can be 1, 2, 3, 4, or 5.

[0074] In some embodiments, Z is -OR 4 is in the para position to -S-; the compound is a 2,5-dialkyl-6-hydroxy-benzamide or a 5-alkyl-6-hydroxy-benzamide; and At least one R 2 or at least one R 3 But -OH, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 selected from the group consisting of Compounds of formula I are provided: In some such embodiments, subscript n can be 1, 2, or 3, and subscript p can be 1, 2, 3, 4, or 5.

[0075] In some embodiments, Z is -CH-, subscript m is 0, subscript n is 0, subscript p is 1, and R 3 is other than 2-hydroxy, 4-cyano, 3-methyl, and 4-methyl. In some embodiments, Z is -CH-, subscript m is 1, and R 1 is 2-methyl, the subscript n is 0, the subscript p is 2, and the first R 3 is 2-chloro and the second R 3 In some embodiments, Z is -CH-, subscript m is 2, and the first R 1 is 2-hydroxy and the second R 1 is 3-hydroxy, the subscript n is 1, and R 2 is 2-isopropyl, the subscript p is 1, and R 3 is other than 2-chloro.

[0076] In some embodiments, Z is -S- and the compound is other than 2,5-dialkyl-6-hydroxy-2-methyl-benzamide or 5-alkyl-6-hydroxy-benzamide. In some embodiments, Z is -C(O)- and the compound is other than 2-hydroxy-benzamide, 2,5-dialkyl-5-hydroxy-benzamide, or 5-alkyl-6-hydroxy-benzamide. In some embodiments, each R 3 -OH, halogen, -NO2, -CN, C 1~8 Alkyl, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, and C 2~8 alkynyl.

[0077] The compounds can be prepared using the methods disclosed herein and routine modifications thereof that will become apparent in light of the disclosure herein and methods known in the art. The synthetic routes include those using commercially available starting materials or those described in March (Advanced Organic Chemistry 6 in Fiesers' Reagents for Organic Synthesis Volumes 1-28 (John Wiley & Sons, 2016). th Ed. John Wiley & Sons, 2007) and Larock (Comprehensive Organic Transformations 3 rdEd. John Wiley & Sons, 2018), which can be prepared according to known methods, may be utilized. Synthesis of exemplary compounds described herein may be accomplished as described in the following examples. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise specified. Optimal reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art through routine optimization procedures. Additionally, as will be apparent to one of ordinary skill in the art, conventional protecting groups may be advantageous in preventing certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, numerous protecting groups are described in detail in Green and Wuts (Protective Groups in Organic Synthesis, 4 th Ed. 2007, Wiley-Interscience, New York) and the references cited therein.

[0078] III. Pharmaceutical Compositions Also provided herein are pharmaceutical compositions comprising one or more AR / AKR1C3 inhibitors (e.g., one or more compounds according to Formula I, IIa, IIb, IIc, IIIa, IIIb, or IIIc above, or a pharma- ceutically acceptable salt thereof) and a pharma- ceutically acceptable excipient.

[0079] Pharmaceutical compositions can be prepared by any of the methods well known in the art of pharmacy and drug delivery (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1 3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); and Remington: The Science and Practice of Pharmacy, 21 st (See, Edition, 2005, Hendrickson, Ed., Lippincott, Williams & Wilkins). In general, the method of preparing the composition includes the step of bringing one or more AR / AKR1C3 inhibitors into association with a carrier containing one or more accessory ingredients. Pharmaceutical compositions can be prepared, for example, by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation. The compositions can be conveniently prepared and / or packaged in unit dosage form. Pharmaceutically acceptable carriers include any of the standard pharmaceutical carriers, buffers and excipients, including phosphate buffered saline solutions, water, and emulsions (such as oil / water or water / oil emulsions), as well as various types of wetting agents and / or adjuvants. The preferred pharmaceutical carrier will depend in part on the intended mode of administration of the active agent.

[0080] The pharmaceutical compositions can include combinations of drugs, e.g., a compound according to Formula I, IIa, IIb, IIc, IIIa, IIIb, or IIIc, combinations thereof, in combination with additional agents, such as antiandrogens (including, but not limited to, enzalutamide, abiraterone, bicalutamide, darolutamide, apalutamide, etc.).

[0081] Pharmaceutical compositions include those suitable for topical, parenteral, pulmonary, nasal, rectal, or oral administration. The most suitable route of administration in any given case will depend in part on the nature and severity of the condition being treated (e.g., prostate, breast, ovarian, or liver cancer, and the particular stage thereof).

[0082] Other pharmaceutical compositions include those suitable for systemic (enteral or parenteral) administration. Systemic administration includes oral, rectal, sublingual, or sublabial administration. Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other delivery modes include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. In certain embodiments, the pharmaceutical composition can be administered intratumorally.

[0083] Compositions for pulmonary administration include, but are not limited to, dry powder compositions consisting of a powder of a compound described herein or a salt thereof, and a suitable carrier and / or lubricant. Compositions for pulmonary administration can be inhaled from any suitable dry powder inhaler device known to those skilled in the art.

[0084] Pharmaceutical compositions can be in a form suitable for oral use.Compositions suitable for oral administration include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, oral patches, oral gels, chewable gums, chewable tablets, effervescent powders, and effervescent tablets.Such compositions can contain one or more agents selected from sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide pharma-ceutical elegant and palatable preparations.

[0085] Tablets generally contain active ingredients mixed with non-toxic pharma- ceutically acceptable excipients, including inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate and sodium phosphate; granulating and disintegrating agents such as corn starch and alginic acid; binders such as polyvinylpyrrolidone (PVP), cellulose, polyethylene glycol (PEG), starch, gelatin and acacia; and lubricants such as magnesium stearate, stearic acid and talc. Tablets may be uncoated or may be enteric or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be utilized. Tablets may also be coated with a semipermeable membrane and any polymeric penetrant according to known techniques to form an osmotic pump composition for controlled release. Compositions for oral administration can be formulated as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate, kaolin, etc.) or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (such as peanut oil, liquid paraffin, or olive oil).

[0086] Pharmaceutical compositions can also be in the form of injectable aqueous or oily solutions or suspensions. Sterile injectable preparations can be formulated using non-toxic parenterally acceptable vehicles, including water, Ringer's solution and isotonic sodium chloride solution, and acceptable solvents such as 1,3-butanediol. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0087] Aqueous suspensions contain the active ingredient mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients include, but are not limited to, suspending agents such as sodium carboxymethylcellulose, methylcellulose, oleaginopropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin, polyoxyethylene stearate, and polyethylene sorbitan monooleate; and preservatives such as ethyl benzoate, n-propyl benzoate, and p-hydroxybenzoate. Oily suspensions can be formulated by suspending the active ingredient in vegetable oils, such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oils such as liquid paraffin. Oily suspensions can contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid. Dispersible powders and granules, which are suitable for preparation of an aqueous suspension by the addition of water, can contain the active ingredient in admixture with a dispersing agent, wetting agent, suspending agent, or combinations thereof. Additional excipients can also be present.

[0088] Pharmaceutical compositions can also be in the form of oil-in-water emulsion.Oily phase can be vegetable oil, for example olive oil or peanut oil, or mineral oil, for example liquid paraffin, or mixtures thereof.Suitable emulsifiers can be natural gums, such as gum acacia or gum tragacanth; natural phospholipids, such as soybean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0089] Transdermal delivery can be achieved by iontophoretic patches and the like. The active ingredient can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the active agent with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0090] The controlled release parenteral formulation of the composition can be prepared as implant, oil injection or as particulate system.For a comprehensive overview of delivery system, see Banga, AJ, THERAPEUTIC PEPTIDES AND PROTEINS: FORMULATION, PROCESSING, AND DELIVERY SYSTEMS, Technomic Publishing Company, Inc., Lancaster, PA, (1995), which is incorporated herein by reference.Particulate system includes microspheres, microparticles, microcapsules, nanocapsules, nanospheres and nanoparticles.

[0091] Polymers can be used for ion-controlled release of active agents. A variety of degradable and non-degradable polymer matrices for use in controlled drug delivery are known in the art (Langer R., Accounts Chem. Res., 26:537-542 (1993)). For example, the block copolymer poloxamer 407 exists as a viscous but mobile liquid at low temperatures, but forms a semi-solid gel at body temperature. It has been shown to be an effective vehicle for the formulation and sustained delivery of recombinant interleukin 2 and urease (Johnston et al., Pharm. Res., 9:425-434 (1992); and Pec et al., J. Parent. Sci. Tech., 44(2):58 65 (1990)). Alternatively, hydroxyapatite has been used as a microcarrier for the controlled release of proteins (Ijntema et al., Int. J. Pharm., 112:215-224 (1994)). In yet another aspect, liposomes are used for controlled release and drug targeting of lipid-encapsulated drugs (Betageri et al., LIPOSOME DRUG DELIVERY SYSTEMS, Technomic Publishing Co., Inc., Lancaster, PA (1993)). A number of additional systems for the controlled delivery of therapeutic proteins are known. See, e.g., U.S. Patent Nos. 5,055,303, 5,188,837, 4,235,871, 4,501,728, 4,837,028, 4,957,735, and 5,019,369, 5,055,303; 5,514,670; 5,413,797; 5,268,164; 5,004,697; 4,902,505; 5,506,206; 5,271,961; 5,254,342, and 5,534,496, each of which is incorporated herein by reference.

[0092] IV. Methods of Treating Androgen-Mediated Diseases Also provided herein is a method for treating an androgen-mediated disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of Formulas I, IIa, IIb, IIc, IIIa, IIIb, or IIIc, or a pharma- ceutically acceptable salt thereof, or a therapeutically effective amount of a pharma- ceutically acceptable composition as described above, thereby treating the hormone-mediated disease or condition.

[0093] In some embodiments, the hormone-mediated disease is cancer. The cancer can be, for example, androgen-independent cancer, metastatic cancer, castration-resistant cancer, castration-recurrent cancer, hormone-resistant cancer, metastatic castration-resistant cancer, or a combination thereof. The compounds according to the present disclosure can be used to treat breast, prostate, endometrial, or renal carcinoma, as well as hepatocellular carcinoma, bladder cancer, renal cancer, gastric cancer, cervical cancer, colon cancer, and lung cancer (e.g., non-small cell lung cancer; NSCLC). These and other cancers are known to express AKR1C3. See, for example, Guise et al. Cancer Res 2010 (70) (4) 1573-1584. In some embodiments, the cancer is prostate cancer, breast cancer, ovarian cancer, or liver cancer.

[0094] In some embodiments, the method includes administering to the subject an antiandrogen selected from the group consisting of enzalutamide, apalutamide, darolutamide, abiraterone, pharma- ceutically acceptable salts thereof, and combinations thereof.

[0095] The compounds and / or pharmaceutical compositions described herein can be administered in any suitable dose in the method. Generally, the compounds and / or compositions are administered in a dose range of about 0.1 milligrams to about 1000 milligrams per kilogram of the subject's body weight (i.e., about 0.1-1000 mg / kg). In some embodiments, the compounds and / or compositions are administered in a dose range of about 1 milligram to about 100 milligrams per kilogram of the subject's body weight (i.e., about 1-100 mg / kg). The dose can be, for example, about 0.1-1000 mg / kg, or about 1-10 mg / kg, or about 10-50 mg / kg, or about 25-50 mg / kg, or about 50-75 mg / kg, or about 1-75-100 mg / kg, or about 1-500 mg / kg, or about 25-250 mg / kg, or about 50-100 mg / kg. The dosage can be about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg / kg. Dosages may vary depending on the requirements of the patient, the severity of the disorder being treated, and the particular formulation being administered. The dosage administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient. The size of the dosage will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of the drug in a particular patient. Determination of the appropriate dosage for a particular situation is within the skill of a typical practitioner. The total dose can be administered in portions over a period of time appropriate to treat cancer or other disease / condition.

[0096] The compounds and / or compositions can be administered for periods of time that vary depending on the nature of the particular disorder, its severity, and the overall condition of the subject to which the compounds and / or compositions are administered. Administration can be twice daily, including, for example, every hour, every 2 hours, every 3 hours, every 4 hours, every 6 hours, every 8 hours, or every 12 hours, or any spaced interval therebetween. Administration can be once daily, or once every 36 or 48 hours, or once a month or several months. After treatment, the subject can be monitored for changes in the subject's condition and for alleviation of the symptoms of the disorder. If the subject does not respond significantly to a particular dosage level, the dosage can be increased, or if alleviation of the symptoms of the disorder is observed, or if the disorder is improved, or if unacceptable side effects are observed at a particular dosage, the dosage can be decreased. The therapeutically effective amount can be administered to the subject in a treatment regimen that includes an interval of at least 1 hour, or 6 hours, or 12 hours, or 24 hours, or 36 hours, or 48 hours between doses. The administrations can be spaced apart by at least 72, 96, 120, 144, 168, 192, 216, or 240 hours (i.e., 3, 4, 5, 6, 7, 8, 9, or 10 days).

[0097] In some embodiments, the method further comprises administering one or more additional anticancer drugs. Examples of anticancer drugs include, but are not limited to, chemotherapeutic agents (e.g., carboplatin, paclitaxel, pemetrexed, etc.), tyrosine kinase inhibitors (e.g., erlotinib, crizotinib, osimertinib, etc.), poly(ADP-ribose) polymerase inhibitors (e.g., olaparib, rucaparib, etc.), and immunotherapeutic agents (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, etc.). In some embodiments, the method comprises radiation therapy, such as external beam radiation; intensity modulated radiation therapy (IMRT); brachytherapy (internal or implant radiation therapy); stereotactic radiation therapy (SBRT) / stereotactic ablative radiation therapy (SABR); stereotactic radiosurgery (SRS); or a combination of such techniques.

[0098] In some of these embodiments, the cancer is an advanced stage cancer. In some of these embodiments, the cancer is drug resistant. In some of these embodiments, the cancer is antiandrogen resistant or androgen independent. In some of these embodiments, the cancer is metastatic. In some of these embodiments, the cancer is metastatic and drug resistant (e.g., antiandrogen resistant). In some of these embodiments, the cancer is castration resistant. In some of these embodiments, the cancer is metastatic and castration resistant. In some of these embodiments, the cancer is enzalutamide resistant. In some of these embodiments, the cancer is enzalutamide and abiraterone resistant. In some of these embodiments, the cancer is enzalutamide, abiraterone, darolutamide, and bicalutamide resistant. In some of these embodiments, the cancer is enzalutamide, abiraterone, bicalutamide, darolutamide, and apalutamide resistant. In other embodiments, the cancer is resistant to (e.g., docetaxel, cabazitaxel, paclitaxel). The cancer (e.g., prostate cancer, breast cancer, ovarian cancer, or liver cancer) can be resistant to any combination of these drugs.

[0099] In some embodiments, the treatment comprises inhibiting cancer cell (e.g., prostate cancer cell, breast cancer cell, ovarian cancer cell, or liver cancer cell) growth, inhibiting cancer cell proliferation, inhibiting cancer cell migration, inhibiting cancer cell invasion, improving cancer symptoms, reducing the size of cancer tumors, reducing the number of cancer tumors, reducing the number of cancer cells, inducing necrosis, pyroptosis, oncosis, apoptosis, autophagy, or other cell death in cancer cells, or enhancing the therapeutic effect of the composition or pharmaceutical composition comprising AR / AKR1C3 inhibitor.In certain cases, the subject does not have cancer.

[0100] In certain methods of treating cancers described herein (e.g., prostate cancer, breast cancer, ovarian cancer, liver cancer, androgen-independent cancer, or drug-resistant cancer), the treatment comprises enhancing the therapeutic effect of an antiandrogen drug (e.g., a nonsteroidal androgen receptor antagonist or a CYP17A1 inhibitor). In certain embodiments, the treatment comprises enhancing the therapeutic effect of enzalutamide. In certain other embodiments, the treatment comprises enhancing the therapeutic effect of abiraterone. In still other embodiments, the treatment comprises enhancing the therapeutic effect of apalutamide. In some other embodiments, the treatment comprises enhancing the therapeutic effect of bicalutamide. The enhancement can be synergistic or additive.

[0101] In certain embodiments of the methods described herein, the treatment comprises reversing, reducing or lowering the resistance of cancer cells (e.g., prostate cancer cells, breast cancer cells, ovarian cancer cells, or liver cancer cells) to antiandrogen drugs.In certain embodiments of the methods described herein, the treatment comprises resensitizing cancer cells (e.g., prostate cancer cells or breast cancer cells) to antiandrogen drugs.In any of the methods described herein, the antiandrogen drug is a compound selected from the group consisting of nonsteroidal androgen receptor antagonists, CYP17A1 inhibitors, and combinations thereof.In certain embodiments, the antiandrogen drug is enzalutamide, apalutamide, bicalutamide, and / or abiraterone acetate.

[0102] In any of the above methods, the treatment may include reversing the resistance of cancer cells (e.g., prostate, breast, ovarian, or liver cancer cells) to antiandrogen drugs (e.g., nonsteroidal androgen receptor antagonists or CYP17A1 inhibitors); reducing or lowering the resistance of cancer cells to antiandrogen drugs; or resensitizing cancer cells to antiandrogen drugs. In some embodiments, the treatment includes reversing the resistance of cancer cells (e.g., prostate, breast, ovarian, or liver cancer cells) to enzalutamide, apalutamide, bicalutamide, darolutamide, abiraterone acetate, or a combination thereof. In some other embodiments, the treatment includes reducing or lowering the resistance of cancer cells to enzalutamide, apalutamide, bicalutamide, darolutamide, abiraterone acetate, or a combination thereof. In some embodiments, the treatment comprises resensitizing the cancer cells to enzalutamide, apalutamide, bicalutamide, abiraterone acetate, darolutamide, or a combination thereof.

[0103] In any of the methods described herein, the cancer is selected from the group consisting of castration-resistant cancer, metastatic castration-resistant cancer, advanced cancer, drug-resistant cancer, antiandrogen-resistant cancer, bicalutamide-resistant cancer, enzalutamide-resistant cancer, abiraterone acetate-resistant cancer, apalutamide-resistant cancer, darolutamide-resistant cancer, AR-V1-, AR-V3-, AR-V7-, AR-V9-, and / or AR-V12-induced drug-resistant cancer, AR-V1-, AR-V3-, AR-V7-, AR-V9-, and / or AR-V12-induced antiandrogen ... AR-V1-, AR-V3-, AR-V7-, AR-V9-, and / or AR-V12-induced enzalutamide-resistant cancer, AR-V1-, AR-V3-, AR-V7-, AR-V9-, and / or AR-V12-induced abiraterone acetate-resistant cancer, AR-V1-, AR-V3-, AR-V7-, AR-V9-, and / or AR-V12-induced apalutamide-resistant cancer, AR-V1-, AR-V3-, AR-V7-, AR-V9-, and / or AR-V12-induced bicalutamide-resistant cancer, and combinations thereof.

[0104] In some embodiments, the test sample is obtained from the subject.The test sample can be obtained before and / or after the AR / AKR1C3 inhibitor is administered to the subject.Non-limiting examples of suitable samples include blood, serum, plasma, cerebrospinal fluid, tissue, saliva, and urine.In some cases, the sample comprises normal tissue.In other cases, the sample comprises cancer tissue.The sample can also be composed of a combination of normal cells and cancer cells.

[0105] In some embodiments, a reference sample is obtained.The reference sample can be obtained, for example, from a subject and can include normal tissue.The reference sample can also be obtained from different subjects and / or a group of subjects.In some cases, the reference sample is obtained from a subject, a different subject, or a group of subjects before and / or after the AR / AKR1C3 inhibitor is administered to the subject, and includes normal tissue.However, in some cases, the reference sample includes cancer tissue and is obtained from a subject and / or from a different subject or a group of subjects.

[0106] In some embodiments, the level of one or more biomarkers is determined in test sample and / or reference sample.Non-limiting examples of suitable biomarkers include prostate specific antigen (PSA), α-methylacyl-CoA racemase (AMACR), endoglin (CD105), engrailed 2 (EN-2), prostate specific membrane antigen (PSMA), caveolin-1, interleukin-6 (IL-6), CD147, members of the S100 protein family (e.g., S100A2, S100A4, S100A8, S100A9, S100A11), annexin A3 (ANXA3), human kallikrein-2 (KLK2), TGF-β1, β-microseminoprotein (MSMB), estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, cyclin D1, and cyclin E.

[0107] Prostate-specific antigen (PSA) is a protein produced primarily by prostate cells. Most PSA is released into semen, but some PSA is also released into the blood. In the blood, PSA exists in unbound and complexed (cPSA) form. Conventional laboratory tests can measure unbound PSA and / or total (unbound and complexed) PSA. Elevated PSA levels can be caused by benign prostatic hyperplasia (BPH) and inflammation of the prostate, but also by prostate cancer. Determining PSA levels can also include determining one or more of PSA velocity (i.e., change in PSA level over time), PSA doubling time (i.e., how quickly PSA level doubles), PSA density (i.e., a comparison of PSA concentration and prostate volume, which can be assessed, for example, by ultrasound), and age-specific PSA range.

[0108] Typically, the level of one or more biomarkers in one or more test samples is compared with the level of one or more biomarkers in one or more reference samples. Depending on the biomarker, an increase or decrease compared to a normal control or reference sample can indicate the presence of cancer or a higher risk of cancer. As a non-limiting example, the level of one or more biomarkers in a test sample taken before and after an AR / AKR1C3 inhibitor is administered to a subject is compared with the level of one or more biomarkers in a reference sample, which is either a normal tissue obtained from the subject or a normal tissue obtained from a different subject or a population of subjects. In some cases, the biomarker is serum, and the level of PSA in a test sample taken from a subject before an AR / AKR1C3 inhibitor is administered to the subject is higher than the level of PSA in the reference sample. In other cases, the level of PSA in a test sample taken from a subject after administration of an AR / AKR1C3 inhibitor is reduced compared to the level of PSA in a test sample taken before administration. Alternatively, as another non-limiting example, the difference in PSA levels between a sample obtained from the subject and the reference sample after administration is less than the difference between the PSA levels in a sample obtained from the subject and the reference sample before administration (i.e., administration results in a decrease in PSA in the test sample such that the difference between the levels measured in the test sample and the levels measured in the reference sample is reduced or eliminated).

[0109] The difference between the reference sample or value and the test sample only needs to be sufficient to be detected.In some embodiments, the increase in the level of biomarker (e.g., PSA) in the test sample, and thus the presence or risk of cancer, is determined when the biomarker level is at least, for example, about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, or 20-fold higher than the negative control.In other embodiments, the decrease in the level of biomarker in the test sample, and thus the presence or risk of cancer, is determined when the biomarker level is at least, for example, about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, or 20-fold lower than the negative control.

[0110] Biomarker levels can be detected using any method known in the art, including the use of antibodies specific to biomarkers.Exemplary methods include, but are not limited to, PCR, Western blot, dot blot, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, FACS analysis, electrochemiluminescence, and multiplex bead assay (e.g., using Luminex or fluorescent microbeads).In some cases, nucleic acid sequencing is utilized.

[0111] In certain embodiments, the presence of one or more biomarkers is indicated by detectable signal (e.g., blot, fluorescence, chemiluminescence, color, radioactivity) in immunoassay or PCR reaction (e.g., quantitative PCR). This detectable signal can be compared with the signal from a control sample or a threshold value. In some embodiments, the presence of a decreased presence is detected when the detectable signal of the biomarker in the test sample is at least, for example, about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, or 20-fold lower than the signal of the antibody in the reference sample or a predetermined threshold value, indicating the presence or increased risk of cancer. In other embodiments, an increased presence is detected when the detectable signal of the biomarker in the test sample is at least, e.g., about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, or 20-fold greater than the signal of the antibody in a reference sample or a predetermined threshold value, indicating an increased presence or risk of cancer.

[0112] Also provided herein is a method for inhibiting the androgen receptor (AR), comprising: contacting the AR with an effective amount of a compound described herein (e.g., a compound according to Formula I, IIa, IIb, IIc, IIIa, IIIb, or IIIc) or a salt thereof, thereby inhibiting the AR.

[0113] Also provided herein is a method for inhibiting aldo-keto reductase family 1 member C3 (AKR1C3), comprising: contacting AKR1C3 with an effective amount of a compound described herein (e.g., a compound according to formula I, IIa, IIb, IIc, IIIa, IIIb, or IIIc) or a salt thereof, thereby inhibiting AKR1C3. Inhibiting AR or AKR1C3 generally comprises contacting AR or AKR1C3 with an amount of a compound sufficient to reduce the activity of AR or AKR1C3 compared to the activity of AR or AKR1C3 in the absence of the compound. For example, contacting AR or AKR1C3 with an inhibitor can result in about 1% to about 99% inhibition (i.e., the activity of inhibited AR or AKR1C3 ranges from 99% to 1% of the activity of AR or AKR1C3 in the absence of the compound). The level of inhibition can range from about 1% to about 10%, or about 10% to about 20%, or about 20% to about 30%, or about 30% to about 40%, or about 40% to about 50%, or about 50% to about 60%, or about 60% to about 70%, or about 70% to about 80%, or about 80% to about 90%, or about 90% to about 99%. The level of inhibition can range from about 5% to about 95%, or about 10% to about 90%, or about 20% to about 80%, or about 30% to about 70%, or about 40% to about 60%. In some embodiments, contacting AR or AKR1C3 with a compound described herein will result in complete (i.e., 100%) inhibition of AR or AKR1C3.

[0114] VI. Kits Also provided herein is a kit for preventing or treating cancer in a subject.The kit is useful for treating any cancer, some non-limiting examples of which include prostate cancer, breast cancer, uterine cancer, ovarian cancer, liver cancer, colorectal cancer, gastric cancer, pancreatic cancer, lung cancer (e.g., mesothelioma, lung adenocarcinoma), esophageal cancer, head and neck cancer, sarcoma, melanoma, thyroid cancer, CNS cancer (e.g., neuroblastoma, glioblastoma), chronic lymphocytic leukemia, and any other cancer described herein.The kit is also suitable for treating androgen-independent, castration-resistant, castration-relapse, hormone-resistant, drug-resistant, and metastatic castration-resistant cancer.

[0115] In some embodiments, the kit comprises an AR / AKR1C3 inhibitor. In some other embodiments, the kit further comprises a pharma- ceutically acceptable carrier. In certain embodiments, the AR / AKR1C3 inhibitor is a compound according to formula I, IIa, IIb, IIc, IIIa, IIIb, and / or IIIc.

[0116] In some embodiments, the antiandrogen drug is a nonsteroidal androgen receptor antagonist, a CYP17A1 inhibitor, or a combination thereof.Suitable nonsteroidal AR antagonists include bicalutamide (Casodex, Cosudex, Calutide, Kalumid), flutamide, nilutamide, apalutamide (ARN-509, JNJ-56021927), darolutamide, enzalutamide (Xtandi), cimetidine and topirutamide.Suitable CYP17A1 inhibitors include abiraterone acetate (Zytiga), ketoconazole, and seviteronel.Any combination of antiandrogens can be used in the kit.

[0117] Materials and reagents for carrying out the various methods described above can be provided in a kit to facilitate carrying out the method. As used herein, the term "kit" includes a combination of items that facilitate a process, assay, analysis, or operation. Kits can be utilized in a wide range of applications, including, for example, diagnosis, prognosis, therapy, and the like.

[0118] The kit may include chemical reagents and other components. In addition, the kit may include, but is not limited to, instructions for the user of the kit, devices and reagents for sample collection and / or purification, devices and reagents for product collection and / or purification, devices and reagents for administering AR / AKR1C3 inhibitors, devices and reagents for determining the level of biomarkers, sample tubes, holders, trays, racks, dishes, plates, solutions, buffers or other chemical reagents, suitable samples used for standardization, normalization, and / or control samples. The kit may also be packaged, for example, in a box with a lid, for convenient storage and safe transport.

[0119] In some embodiments, the kit also includes negative and positive control samples for detection of biomarkers.Non-limiting examples of suitable biomarkers include prostate specific antigen (PSA), α-methylacyl-CoA racemase (AMACR), endoglin (CD105), engrailed 2 (EN-2), prostate specific membrane antigen (PSMA), caveolin-1, interleukin-6 (IL-6), CD147, members of the S100 protein family (e.g., S100A2, S100A4, S100A8, S100A9, S100A11), annexin A3 (ANXA3), human kallikrein-2 (KLK2), TGF-β1, β-microseminoprotein (MSMB), estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, cyclin D1, and cyclin E. In some cases, the one or more biomarkers comprise PSA. In some embodiments, the negative control sample is obtained from an individual or group of individuals without cancer. In other embodiments, the positive control sample is obtained from an individual or group of individuals with cancer. In some embodiments, the kit comprises a sample for making a titration curve of one or more biomarkers in the sample to assist in assessing the quantification level of one or more biomarkers in the test biological sample. EXAMPLES

[0120] VI. Working Examples Example 1. Synthesis of dual AR / AKR1C3 inhibitors TIFF0007623375000023.tif991525-Benzoyl-N-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxybenzamide (3) was prepared as summarized in the scheme above. 2-Hydroxybenzoic acid (a) was esterified to give the methyl ester (b). Acylation of (b) gave the benzophenone (c), which was subsequently hydrolyzed to give the benzoic acid (d). Microwave-assisted amidation of (d) gave compound 3. TIFF0007623375000024.tif20154

[0121] N-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxy-5-(4-methoxybenzoyl)benzamide (8) was prepared as summarized in the following scheme. 2-Hydroxybenzoic acid (a) was esterified to give the methyl ester (b). Acylation of (b) gave the benzophenone (e), which was subsequently hydrolyzed to give the benzoic acid (f). Microwave-assisted amidation of (f) gave compound 8. TIFF0007623375000025.tif20157TIFF0007623375000026.tif108163

[0122] N-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxy-5-(4-methoxybenzyl)benzamide (5) and 5-benzyl-N-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxybenzamide (1) were prepared as summarized in the following scheme: Compounds 8 and 3 were reduced to give compounds 5 and 1, respectively. Compound 1: TIFF0007623375000027.tif19153TIFF0007623375000028.tif115128

[0123] 2-Hydroxy-5-(4-methoxybenzyl)-N-(4-(trifluoromethyl)phenyl)benzamide (6) was prepared similarly. TIFF0007623375000029.tif20156TIFF0007623375000030.tif43128

[0124] The synthesis of N-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxy-6-(4-methoxyphenoxy)benzamide (39) was prepared as summarized in the following scheme. 2-Fluoro-6-hydroxybenzaldehyde (g) was converted to the corresponding ether-protected compound (h). Coupling of compound (h) with 4-methoxyphenol gave oxydibenzene (i), which was subsequently oxidized to give benzoic acid (j). Further reduction of (j) gave hydroxybenzoic acid (k). Final microwave-assisted amidation of (k) gave compound 39. TIFF0007623375000031.tif166141TIFF0007623375000032.tif19157

[0125] Example 2. Inhibition of AR / AR-V and AKR1C3 Expression To determine the ability of compound 1 and compound 2 to inhibit AR / AR-V and AKR1C3 expression, CWR22rv1 cells were treated with the two compounds. Cells were treated with 5 μM compound 1 or 5 μM compound 2 for 48 hours. After treatment, cell lysates were collected and analyzed. Analysis of AR-FL, AR-V, and AKR1C3 protein expression was performed using Western blot analysis. The results of this analysis are shown in the Western blot image in Figure 1.

[0126] Example 3. Inhibition of AKR1C3 activity To examine whether compound 1 and compound 2 are useful in inhibiting AKR1C3 activity, LNCaP-AKR1C3 was treated with either compound 1 or compound 2 for 48 hours. AKR1C3 enzyme activity was determined by aldo-keto reductase (AKR) activity assay kit (Colorimetric), the results of which are shown in Figure 2. Similarly, inhibition of AKR1C3 activity was examined with various doses of compound 1. LNCaP-AKR1C3 cells were treated with increasing doses of compound 1 for 48 hours. Analysis was performed using AKR activity assay kit (Colorimetric), the results of which are shown in Figure 3.

[0127] Example 4. Inhibition of Enzalutamide-resistant Prostate Cancer Cell Growth To examine the ability of the compounds to inhibit cell proliferation, C4-2B MDVR cells were treated with either Compound 1 or Compound 2 for 48 hours. Cell numbers were determined and summarized graphically in Figure 4. Similarly, dose-dependent inhibition of cell proliferation was examined. C4-2B MDVR cells were treated with increasing doses of Compound 1 for 48 hours. Cell numbers at each dose of Compound 1 were determined and summarized graphically in Figure 5.

[0128] Example 5. Inhibition of cancer cell proliferation by AR / AKR1C3 inhibitors and antiandrogens To assess whether compound 1 is an effective inhibitor of antiandrogen-resistant cell proliferation, a series of resistant cells were treated with each of the antiandrogens for 48 hours. Enzalutamide-resistant MDVR cells, abiraterone-resistant AbiR cells, apalutamide-resistant ApaIR cells, and darolutamide-resistant DaroR cells were treated with each of the antiandrogens: enzalutamide (enza) (20 μM), abiraterone (abi) (20 μM), apalutamide (apal) (20 μM), darolutamide (20 μM), or compound 1 (5 μM). Cell numbers were determined for each resistant cell type and are summarized graphically in Figure 6.

[0129] Example 6. Inhibition of prostate cancer cell proliferation in vivo by AR / AKR1C3 inhibitor 1 Next, the effect of Compound 1 in vivo was studied in two separate models. First, intact SCID mice were injected with resistant prostate cancer VCaP cells suspended in Matrigel. Once tumors were palpable, mice were divided into two groups: control or 20 mg / kg Compound 1 administered IP, 5 days per week for 3 weeks. Tumor volume was measured twice a week and mouse weight was monitored. At the end of treatment, tumors and serum were collected for evaluation. As seen in Figure 9A, treatment with Compound 1 significantly reduced tumor volume compared to control, but did not affect mouse weight (Figure 9B). Furthermore, serum PSA was significantly reduced in the group treated with Compound 1 (Figure 9C).

[0130] We also utilized the LuCaP35CR PDX model to investigate the effects of compound 1 in vivo. In this model, SCID mice were castrated and implanted with LuCaP35CR tissue. Once tumors were palpable, mice were divided into two groups: control or 20 mg / kg compound 1 was administered IP, 5 days a week for 3 weeks. Tumor volumes were measured twice a week and mouse weights were monitored. At the end of treatment, tumors and serum were collected for evaluation. Similar to the VCaP model, compound 1 treatment significantly reduced tumor volume (Figure 10A) but did not affect mouse weight (Figure 10B). Serum PSA was also reduced by treatment with compound 1 in this model (Figure 10C). In addition, compound 1 treatment significantly reduced intratumoral testosterone levels (Figure 10D). These data demonstrate that compound 1 is well tolerated and useful for the treatment of castration-resistant prostate cancer.

[0131] Example 7. Inhibition of androstenedione conversion to testosterone by AR / AKR1C3 inhibitor 1 AKR1C3 plays a key role in the synthesis of testosterone by catalyzing the conversion of the adrenal androgens dehydroepiandrosterone (DHEA) and androstenedione (AD) to testosterone. To determine the effect of compound 1 on inhibiting AKR1C3 enzyme activity, an ex vivo tumor-based AKR1C3 enzyme assay was performed. LUCaP35CX tumors expressing high levels of AKR1C3 were cultured in medium supplemented with 0.1% protease digested, heat inactivated, charcoal dextran-treated 10% FBS. After overnight incubation, androstenedione (300 nmol / L) was added with or without compound 1. Supernatants were collected and testosterone was measured. Compound 1 showed dose-dependent inhibition of androstenedione conversion to testosterone (Figure 11).

[0132] Example 8. Inhibition of AR and AR-V7 signaling pathways and genes related to cancer cell proliferation and survival Next, we studied the effect of the new AR / AKR1C3 inhibitors on AR signaling. We found that compound 1 and compound 5 could inhibit DHT-stimulated AR nuclear expression in LNCaP cells (Figure 12). To further confirm the inhibitory role of the compounds on AR signaling, enzalutamide-resistant C4-2B MDVR cells (which have enhanced expression of AR, AR variants, and AKR1C3) were treated with 5 μM compound 1, 5 μM compound 5, or DMSO control. Total RNA was isolated and evaluated using RNAseq. RNAseq analysis revealed that treatment with both compounds significantly reduced the expression of genes related to AR signaling (Figure 13A). Furthermore, these treatments also reduced the expression of AR-V7 signature genes (Figure 13B). Taken together, these data demonstrate that the compounds successfully inhibit the intended targets (i.e., AR / AR-V7 and AKR1C3).

[0133] Furthermore, we studied the effect of the compounds on the expression of genes involved in cancer. Enzalutamide-resistant C4-2B MDVR cells were treated with 5 μM of compounds 1, 2, 5, or 8, or DMSO control. Total RNA was isolated and RNAseq analysis revealed that treatment with the compounds significantly reduced the expression of genes related to cancer cell proliferation and survival (Figure 14).

[0134] VII. Exemplary Embodiments Exemplary aspects provided by the subject matter of this disclosure include, but are not limited to, the following aspects and claims: 1. Compounds according to formula I: TIFF0007623375000033.tif34128, or a pharma- ceutically acceptable salt thereof, wherein: Z is -CH2-, -C(O)-, -O-, -S-, or -NR a - selected from the group consisting of; Each R 1 But -OH, C 1~8 Alkyl, C 1~8independently selected from the group consisting of alkoxy, and halogen; Each R 2 and R 3 -OH, halogen, -NO2, -CN, C 1~8 Alkyl, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) independently selected from the group consisting of: R 4 H, α-aminoacyl; -S(O)2N(R a )2, -C(O)N(R a )2, and -C(O)R b selected from the group consisting of; Each R a But H and C 1~8 independently selected from the group consisting of alkyl; R b But, C 1~8 is alkyl; The subscript m is an integer ranging from 0 to 3; the subscript n is an integer ranging from 0 to 5; and subscript p is an integer ranging from 1 to 5; where: Z is -OR 4 subscript m and subscript n are 0; R 4 is H, then at least one R 3 is halogen, -NO2, C 2~8 Alkyl, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a )2 selected from the group consisting of; Z is -OR 4 and when the compound is a 2,3,4-trihydroxy-benzamide, at least one R 2 or at least one R 3-OH, -NO2, -CN, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a )2 selected from the group consisting of; Z is -OR 4 and when the compound is a 5-alkyl-6-hydroxy-benzamide, at least one R 2 or at least one R 3 -OH, -NO2, -CN, C 1~8 Alkyl, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a )2 selected from the group consisting of; Z is -OR 4 and the compound is a 2-hydroxy-benzamide, a 2,5-dialkyl-6-hydroxy-benzamide, or a 5-alkyl-6-hydroxy-benzamide. (i) At least one R 2 or at least one R 3 -OH, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 selected from the group consisting of (ii) The subscript n is 1, and R 2 is 4-chloro or 4-(n-butyl), at least one R 3 is other than -CF3 or -NO2; and Z is -OR 4 and when the compound is a 2,5-dialkyl-6-hydroxy-benzamide or a 5-alkyl-6-hydroxy-benzamide, at least one R 2 or at least one R 3 -OH, C2~8 Alkyl, C 2~8 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 selected from the group consisting of The compound, or a pharma- ceutically acceptable salt thereof. 2. The compound of embodiment 1, wherein Z is -CH2-, or a pharma- ceutically acceptable salt thereof. 3. The compound of embodiment 1, wherein Z is -C(O)-, or a pharma- ceutically acceptable salt thereof. 4. The compound of embodiment 1, wherein Z is -O-, or a pharma- ceutically acceptable salt thereof. 5. A compound of any of embodiments 1-4, wherein subscript m is 0, or a pharma- ceutically acceptable salt thereof. 6. Each R 3 -OH, halogen, -NO2, -CN, C 1~8 Alkyl, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, and C 2~8 6. The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt thereof, wherein the compound is independently selected from the group consisting of: alkynyl. 7. Each R 3 But, C 1~8 The compound of any of embodiments 1-5, or a pharma- ceutically acceptable salt thereof, wherein the compound is independently selected from the group consisting of haloalkyl, halogen, and -NO2. 8. A compound of any of embodiments 1-7, wherein subscript p is 1 or 2, or a pharma- ceutically acceptable salt thereof. 9. Structure according to formula IIa: The compound of embodiment 8 having the formula: TIFF0007623375000034.tif40128, or a pharma- ceutically acceptable salt thereof. 10. R 3b and R 3d C1~8 10. The compound of embodiment 9, or a pharma- ceutically acceptable salt thereof, wherein: 11. R 3b and R 3d is independently selected from the group consisting of -CF3 and -CCl3, or a pharma- ceutically acceptable salt thereof. 12. Structure according to formula IIb: The compound of embodiment 8 having the formula: TIFF0007623375000035.tif35128, or a pharma- ceutically acceptable salt thereof. 13. R 3a and R 3c is independently selected from the group consisting of halogen and -NO2, or a pharma- ceutically acceptable salt thereof. 14. R 3a is -Cl, and R 3c is -NO2, or a pharma- ceutically acceptable salt thereof. 15. Structure according to formula IIc: The compound of embodiment 8 having the formula: TIFF0007623375000036.tif34128, or a pharma- ceutically acceptable salt thereof. 16. R 3 But, C 1~8 16. The compound of embodiment 15, or a pharma- ceutically acceptable salt thereof, wherein: 17. R 3 is selected from the group consisting of -CF3 and -CCl3, or a pharma- ceutically acceptable salt thereof. 18. The compound of any of the preceding embodiments, wherein the subscript n is 0; or a pharma- ceutically acceptable salt thereof. 19. The compound of any of embodiments 1-17, wherein the subscript n is 1, or a pharma- ceutically acceptable salt thereof. 20. R 2 But, C 1~8Alkyl, C 1~8 Alkoxy, and C 1~8 20. The compound of embodiment 19, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of haloalkyl. twenty one. Structure according to formula IIIa: The compound of embodiment 19 or embodiment 20, having TIFF0007623375000037.tif41128, or a pharma- ceutically acceptable salt thereof. twenty two. R 3b and R 3d became independent, C 1~8 22. The compound of embodiment 21, or a pharma- ceutically acceptable salt thereof, wherein: twenty three. R 3b and R 3d is independently selected from the group consisting of -CF3 and -CCl3, or a pharma- ceutically acceptable salt thereof. twenty four. Structure according to formula IIIb: The compound of embodiment 19 or embodiment 20, having TIFF0007623375000038.tif36128, or a pharma- ceutically acceptable salt thereof. twenty five. R 3a and R 3c is independently selected from the group consisting of halogen and -NO2, or a pharma- ceutically acceptable salt thereof. 26. R 3a is -Cl, and R 3c 26. The compound of embodiment 25, wherein is -NO2, or a pharma- ceutically acceptable salt thereof. 27. Structure according to formula IIIc: The compound of embodiment 19 or embodiment 20, having TIFF0007623375000039.tif34128, or a pharma- ceutically acceptable salt thereof. 28. R 3 But, C 1~8 28. The compound of embodiment 27, or a pharma- ceutically acceptable salt thereof, wherein: 29. R 3 is selected from the group consisting of -CF3 and -CCl3, or a pharma- ceutically acceptable salt thereof. 30. R 2c

[0046] 30. The compound of any of embodiments 21-29, or a pharma- ceutically acceptable salt thereof, wherein: 31. R 4 The compound of any of embodiments 1-30, or a pharma- ceutically acceptable salt thereof, wherein: 32. R 4 is selected from the group consisting of l-valinyl and d-valinyl, or a pharma- ceutically acceptable salt thereof. 33. Z is -OR 4 or a pharma- ceutically acceptable salt thereof. 34. The compound of any of embodiments 1-32, wherein Z is in the ortho position relative to -C(O)NH-; or a pharma- ceutically acceptable salt thereof. 35. The compound of embodiment 1 is selected from the group consisting of: TIFF0007623375000040.tif212125, and pharma- ceutically acceptable salts thereof. 36. Z is -CH2-; The subscript m and the subscript n are 0; and At least one R 3 But halogen, -NO2, C 1~8 Alkoxy, C 1~8 Haloalkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 selected from the group consisting of A compound of embodiment 1, or a pharma- ceutically acceptable salt thereof. 37. Z is -OR 4 is in the para position to -C(O)-; the compound is a 2-hydroxy-benzamide, a 2,5-dialkyl-6-hydroxy-benzamide, or a 5-alkyl-6-hydroxy-benzamide; and At least one R 2 or at least one R 3 But -OH, C 1~8 Alkoxy, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 selected from the group consisting of A compound of embodiment 1, or a pharma- ceutically acceptable salt thereof. 38. Z is -OR 4 is in the para position to -S-; the compound is a 2,5-dialkyl-6-hydroxy-benzamide or a 5-alkyl-6-hydroxy-benzamide; and At least one R 2 or at least one R 3 But -OH, C 2~8 Alkenyl, C 2~8 Alkynyl, and -N(R a ) 2 selected from the group consisting of A compound of embodiment 1, or a pharma- ceutically acceptable salt thereof. 39. A compound according to any one of aspects 1 to 38, or a pharma- ceutically acceptable salt thereof; A pharma- ceutically acceptable excipient; 23. A pharmaceutical composition comprising: 40. 1. A method for treating a hormone-mediated disease or condition, comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of any of embodiments 1-38 or a pharma- ceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition of embodiment 39, thereby treating the hormone-mediated disease or condition. The method comprises: 41. The method of embodiment 40, wherein the hormone-mediated disease is cancer. 42. The method of embodiment 41, wherein the cancer is castration-resistant prostate cancer. 43. Administering an antiandrogen to the subject. 43. The method of any one of embodiments 40-42, further comprising: 44. The method of embodiment 43, wherein the antiandrogen is selected from the group consisting of enzalutamide, apalutamide, darolutamide, abiraterone, pharma- ceutically acceptable salts thereof, and combinations thereof. 45. 1. A method for inhibiting the androgen receptor (AR), comprising: contacting the AR with an effective amount of a compound of any of embodiments 1-38, or a salt thereof, thereby inhibiting the AR. The method comprises: 46. 1. A method for inhibiting aldo-keto reductase family 1 member C3 (AKR1C3), comprising: contacting AKR1C3 with an effective amount of a compound of any of embodiments 1-38, or a salt thereof, thereby inhibiting AKR1C3. The method comprises:

[0135] Although some detail has been given by way of illustration and example for purposes of clarity and understanding, those skilled in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. Further, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Claims

1. Compounds according to formula I: or a pharma- ceutically acceptable salt thereof, wherein: Z is -CH 2 - or -C(O)-; Z is -OR 4 in para position to; The subscript n is 0 or 1; Each R 2 -OH, and C 1～8 independently selected from alkoxy; the subscript p is 0, 1, or 2; Each R 3 But, C 1～8 independently selected from haloalkyl; R 4 But H. The compound, or a pharma- ceutically acceptable salt thereof.

2. Z is -CH 2 2. The compound of claim 1, wherein:

3. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Z is -C(O)-.

4. 4. The compound of any one of claims 1 to 3, wherein the subscript p is 1 or 2, or a pharma- ceutically acceptable salt thereof.

5. Structure according to formula IIa: and R 3b and R 3d are independently selected from C 1-8 haloalkyl, or a pharma- ceutically acceptable salt thereof.

6. R3b and R 3d But -CF 3 and -CCl 3 6. The compound of claim 5, independently selected from the group consisting of:

7. Structure according to formula IIc:

5. The compound of claim 4, having the formula:

8. R 3 But -CF 3 and -CCl 3 8. The compound of claim 7, selected from the group consisting of:

9. 9. The compound of any one of claims 1 to 8, wherein the subscript n is 0; or a pharma- ceutically acceptable salt thereof.

10. 9. The compound of any one of claims 1 to 8, wherein the subscript n is 1, or a pharma- ceutically acceptable salt thereof.

11. R 2 But, C 1～8 11. The compound of claim 10, or a pharma- ceutically acceptable salt thereof, which is alkoxy.

12. Structure according to formula IIIa: having R 3b and R 3d are independently selected from C 1-8 haloalkyl; 11. The compound of claim 10, or a pharma- ceutically acceptable salt thereof, wherein R2c is selected from -OH and C1-8 alkoxy.

13. R 3b and R 3d But -CF 3 and -CCl 3 13. The compound of claim 12, independently selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

14. Structure according to formula IIIc: having 11. The compound of claim 10, or a pharma- ceutically acceptable salt thereof, wherein R2c is selected from -OH and C1-8 alkoxy.

15. R 3 But -CF 3 and -CCl 3 15. The compound of claim 14, selected from the group consisting of:

16. R 2c But, -OCH 3 13. The compound of claim 12, wherein:

17. The compound of claim 1, selected from the group consisting of: and pharma- ceutically acceptable salts thereof.

18. A compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof; A pharma- ceutically acceptable excipient; 23. A pharmaceutical composition comprising:

19. 20. A pharmaceutical composition for treating cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof.

20. 20. The pharmaceutical composition of claim 19, wherein the cancer is castration-resistant prostate cancer.

21. 21. The pharmaceutical composition of claim 19 or 20, wherein the pharmaceutical composition is used in combination with an antiandrogen.

22. 22. The pharmaceutical composition of claim 21, wherein the antiandrogen is selected from the group consisting of enzalutamide, apalutamide, darolutamide, abiraterone, pharma- ceutically acceptable salts thereof, and combinations thereof.

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