Inhibitors of the n-terminal domain of the androgen receptor
AssigneesThe Regents of the University of California, The United States Government as represented by the Department of Veterans Affairs
InventorsMatthew Rettig, Michaei E. Jung, D. Elshan Nakath G. Ralalage, Jiabin An
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Abstract
The present disclosure provides compounds and methods for inhibiting or degrading the N-terminal domain of the androgen receptor, as well as methods for treating cancers such as prostate cancer.
Claims119
A compound having the structure of formula I, II, III, IV, V, VI, VII, VIII, or a pharmaceutically acceptable salt thereof:
- wherein:
- represents a single or double bond;
- A1 is aryl or heteroaryl;
- A2 is aryl or heteroaryl;
- A3 is aryl or heteroaryl;
- A4 is aryl or heteroaryl;
- R1 is selected from H, N(R1aR1b), N-linked heterocyclyl, or N-linked heteroaryl;
- R1a and R1b are independently selected from alkyl, aryl, and aralkyl;
- R2a and R2b are independently selected from H, alkyl, or aryl;
- R3 is selected from H, alkyl, or halo;
- R4a and R4b are independently selected from H, alkyl, or halo;
- R5a is selected from H, alkyl, or halo;
- R12 is hydroxyl, alkyl, alkenyl, alkyloxy, alkylamino, alkylacyl, acylamino, amino, or heterocylyl, and is optionally substituted with one or more R8;
- R7 is H, alkyl or halo;
- each R8 is independently halo, hydroxyl, hydroxyalkyl, alkenyl, acylamino, thioether, oxiranyl, aryl, or aralkyl;
- optionally substituted with one or more R9;
- each R9 is hydroxyl, alkyl or alkenyl;
- and
- X is CH2 or oxygen.
The compound of any one of the preceding claims, provided that:
- A2 is not 4-chlorophenyl phenyl;
- A1 is not unsubstituted phenyl;
- R1 is not N-benzyl methyl amino;
- R2a and R2b are not both H;
- or
- R3 is not H.
The compound of any one of the preceding claims, wherein the compound is not JN018 or a pharmaceutically acceptable salt thereof:
The compound of any one of the preceding claims, wherein A1 and A2 are phenyl.
The compound of any one of the preceding claims, wherein A1 is unsubstituted or substituted by at least one R5, wherein each R5 is independently selected from halo, alkyl, or alkoxy.
The compound of any one of the preceding claims, wherein A1 is unsubstituted.
The compound of any one of the preceding claims, wherein A1 is substituted by at least one R5.
The compound of any one of the preceding claims, wherein A1 is substituted by one or two R5.
The compound of any one of the preceding claims, wherein A2 is unsubstituted or substituted by at least one R6, wherein each R6 is independently selected from halo, alkyl, or alkoxy.
The compound of any one of the preceding claims, wherein A2 is unsubstituted.
The compound of any one of the preceding claims, wherein A2 is substituted by at least one R6.
The compound of any one of the preceding claims, wherein A2 is substituted by one or two R6.
The compound of any one of the preceding claims, wherein A2 is selected from methylphenyl, trifluoromethylphenyl, fluorophenyl, chlorophenyl, or dichlorophenyl.
The compound of any one of the preceding claims, wherein R1 is N(R1aR1b).
The compound of any one of the preceding claims, wherein R1a is alkyl and R1b is aralkyl.
The compound of any one of the preceding claims, wherein R1 is N(R1aR1b), R1a is methyl and R1b is benzyl.
The compound of any one of the preceding claims, wherein R1a and R1b are independently selected from alkyl.
The compound of any one of the preceding claims, wherein R1a and R1b are isobutyl.
The compound of any one of the preceding claims, wherein R1a and R1b are isopropyl.
The compound of any one of the preceding claims, wherein R1a and R1b are methyl.
The compound of any one of the preceding claims, wherein R1 is pyrrolidine, piperidine, or piperazine.
The compound of any one of the preceding claims, wherein R1 is H.
The compound of any one of the preceding claims, wherein R2a and R2b are H.
The compound of any one of the preceding claims, wherein R3 is H.
The compound of any one of the preceding claims, wherein the compound is represented by formula (II) and R4a and R4b are H.
A compound having the structure of formula VII or VIII, or a pharmaceutically acceptable salt thereof:
- wherein:
- represents a single or double bond;
- A3 is aryl or heteroaryl;
- A4 is aryl or heteroaryl;
- R12 is hydroxyl, alkyl, alkenyl, alkyloxy, alkylamino, alkylacyl, acylamino, amino, or heterocyclyl, and is optionally substituted with one or more R8;
- R7 is H, alkyl or halo;
- each R8 is independently halo, hydroxyl, hydroxyalkyl, alkenyl, acylamino, thioether, oxiranyl, aryl, or aralkyl;
- optionally substituted with one or more R9;
- each R9 is hydroxyl, alkyl, alkoxy, or alkenyl;
- and
- X is CH2 or oxygen.
A compound selected from:
Dependencies are inferred from the claim text.