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, Michael 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.
Claims91
A compound having the structure of formula I, II, III, IV, V, VI, VII, or VIII, or a pharmaceutically acceptable salt thereof:
- wherein:
- A1 is aryl or hetaryl;
- A2 is aryl or hetaryl;
- R5 is H, alkyl, or halo;
- R1 is H, alkyl, haloalkyl, aralkyl, or hetaralkyl;
- R2 is H, alkyl, or haloalkyl;
- R3 is H, alkyl, haloalkyl, aryl, or hetaryl;
- R4a and R4b are each independently H or alkyl, or R4a and R4b combine to form oxo;
- is a single bond or a double bond,
- when is a single bond in Formula (II), R1a, R1b, R2a, and R2b are each independently H, alkyl, or alkoxy;
- when is a double bond in Formula (II),
- R1a and R2a are each independently H, alkyl, or alkoxy, and
- R1b and R2b are absent;
- when is a single bond in Formula (VI), R1a and R1b combine to form CH2;
- when is a double bond in Formula (VI), R1a is H or alkyl and R1b is absent;
- R6 is H, alkyl, aralkyl, or hetaralkyl;
- X1 and X2 are each independently NH or O;
- n is 1-4;
- X is O, NH, or S;
- R7 is amino, alkynyl, cyano, cycloalkyl, alkyl, or alkenyl;
- Z is S or C;
- when Z is S, R8a and R8b are each oxo;
- when Z is C,
- R8a and R8b are each independently H or alkyl, or
- R8a and R8b combine to form oxo, or
- R8a and R8b combine to form a cyclopropyl ring including Z.
The compound of any one of the preceding claims, wherein A1 and A2 are cis to each other.
The compound of any one of the preceding claims, wherein A2 is aryl unsubstituted or substituted with one or more R11, wherein each R11 is independently selected from halo, alkyl, haloalkyl, hydroxyl, cyano, alkoxy, alkynyl, or azido.
The compound of any one of the preceding claims, wherein A1 is phenyl.
The compound of any one of the preceding claims, wherein A1 is unsubstituted.
The compound of any one of the preceding claims, wherein R5 is H or alkyl.
The compound of any one of the preceding claims, wherein R5 is H.
The compound of any one of the preceding claims, wherein R1 is H or methyl.
The compound of any one of the preceding claims, wherein R2 is H.
The compound of any one of the preceding claims, wherein R3 is H, haloalkyl, or aryl.
The compound of any one of the preceding claims, wherein R4a and R4b are each H.
The compound of any one of the preceding claims, wherein the compound is of formula III and R6 is aryl.
The compound of any one of the preceding claims, wherein the compound is of formula IV and R3 is H, haloalkyl, or aryl.
The compound of any one of the preceding claims, wherein the compound is:
A solid form, which is Form I of compound JN032
- characterized by X-ray powder diffraction peaks at 2θ angles of about 21.5°, about 22.6°, and about 27.3°.
A solid form, which is Form I of compound JN110
- characterized by X-ray powder diffraction peaks at 2θ angles of about 17.6°, about 22.2°, and about 28.8°.
A solid form, which is Form I of compound JN034
- characterized by X-ray powder diffraction peaks at 2θ angles of about 8.3°, about 17.7°, and about 22.4°.
A solid form, which is Form I of compound JN097
- characterized by X-ray powder diffraction peaks at 2θ angles of about 20.5°, about 23.1°, and about 27.0°.
A solid form, which is Form I of compound JN117
- characterized by X-ray powder diffraction peaks at 2θ angles of about 7.8°, about 16.4°, and about 21.5°.
A solid form, which is Form I of compound JN103
- characterized by X-ray powder diffraction peaks at 2θ angles of about 6.6°, about 18.0°, and about 21.6°.
Dependencies are inferred from the claim text.