Androgen receptor modulators
AssigneeTrustees of Dartmouth College
InventorGlenn C. Micalizio
Life of this patent
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Abstract
The present disclosure relates to polycyclic (e.g., tetracyclic) androgen receptor (AR) modulators, synthetic methods for preparing such AR modulators, and methods of using such AR modulators to treat an androgen-dependent condition, such as prostate cancer or BPH. Exemplary compounds have quaternary centers at C9 and C13 in which the quaternary center at C9 projects a substituent on the opposite face of the tetracycle as the substituent at C13.
Claims22
A compound or pharmaceutically acceptable salt thereof, wherein the compound has a structure corresponding to Formula (II-A) or Formula (II-B):
- m is an integer selected from the group consisting of 0, 1, 2, and 3;
- n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8;
- each RA is independently selected from the group consisting of hydrogen, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, halogen, oxo, —ORAX, —SRAY, —S(O)2NRZ1RZ2, —S(O)2RZ1, —S(O)RZ1, —NRZ1RZ2, —N(RZ1)C(O)RZ2, —N(RZ1)S(O)2RZ2, C6-10-aryl, and 5- to 10-membered heteroaryl,
- wherein RAX is hydrogen, C1-6-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, —C(O)—C1-10-alkyl, —C(O)—C6-10-aryl, —C(O)-heteroaryl, —C(O)—O—C1-10-alkyl, —C(O)—O—C6-10-aryl, —C(O)—O-heteroaryl, —C(O)—NRZ1RZ2, —S(O)2NRZ1RZ2, —S(O)2RZ1, C6-10-aryl, or 5- to 10-membered heteroaryl,
- wherein RAY is hydrogen, C1-6-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, —C(O)—C1-10-alkyl, —C(O)—C6-10-aryl, —C(O)-heteroaryl, C6-10-aryl, or 5- to 10-membered heteroaryl,
- wherein each of RZ1 and RZ2 are independently hydrogen, C1-6-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, —(CH2)m—C6-10-aryl, —(CH2)m-5- to 10-membered heteroaryl, hydroxy, or C1-6-alkoxy;
- R3 is oxo or —OR3X, wherein R3X is hydrogen or C1-6-alkyl;
- each of R6A and R6B are independently absent or selected from the group consisting of hydrogen, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, and halogen;
- each of R7A and R7B are independently selected from the group consisting of hydrogen, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, halogen, and hydroxy;
- R9 is A-XA—RX,
- wherein A is a C1-C14-alkylene, C1-C14-haloalkylene, C2-C14-alkenylene, C2-C14-haloalkenylene, C2-C14-alkynylene, or C2-C14-haloalkynylene, each of which is optionally interrupted by one or more of —O—, —NRZ—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NRZ—, —NRZC(O)—, —S(O)y—, —S(O)yNRZ—, —NRZS(O)y—, —C(S)NRZ—, —NRZC(S)—, C6-10-aryl, or 5- to 10-membered heteroaryl;
- XA is absent or selected from the group consisting of —O—, —NRZ—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NRZ—, —NRZC(O)—, —S(O)y—, —S(O)yNRZ—, —NRZS(O)y—, —C(S)NRZ—, —NRZC(S)—, C6-10-aryl, and 5- to 10-membered heteroaryl;
- RX is selected from the group consisting of hydrogen, C1-6-alkyl, C1-6-haloalkyl, C2-6-alkenyl, C2-6-haloalkenyl, C2-6-alkynyl, C2-6-haloalkynyl, C3-7-cycloalkyl, —C(O)—C1-6-alkyl, —C(O)—C6-10-aryl, —C(O)-heteroaryl, —C(O)—NRZ1RZ2, —S(O)2NRZ1RZ2, —NRZ1RZ2, —N(RZ1)C(O)RZ2, —N(RZ1)S(O)2RZ2, C6-10-aryl, and 5- to 10-membered heteroaryl;
- wherein RZ is hydrogen, C1-6-alkyl, C1-6-haloalkyl, C2-6-alkenyl, C2-6-haloalkenyl, C2-6-alkynyl, C2-6-haloalkynyl, C3-7-cycloalkyl, C6-10-aryl, or 5- to 10-membered heteroaryl and y is 0, 1, or 2;
- R13 is selected from the group consisting of C1-C14-alkyl, C1-C14-haloalkyl, C2-C14-alkenyl, C2-C14-haloalkenyl, C2-C14-alkynyl, and C2-C14-haloalkynyl, each of which is optionally interrupted by one or more of —O—, —NRZ—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NRZ—, —NRZC(O)—, —S(O)y—, —S(O)yNRZ—, —NRZS(O)y—, —C(S)NRZ—, —NRZC(S)—, —(CH2)m—C6-10-aryl, and —(CH2)m-5- to 10-membered heteroaryl;
- R14 is absent or selected from the group consisting of hydrogen, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, and halogen;
- each of R15A and R15B are independently absent or selected from the group consisting of hydrogen, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, and halogen;
- R16 is selected from the group consisting of oxo and —ORD, wherein RD is selected from the group consisting of hydrogen, C1-10-alkyl, C1-10-haloalkyl, C2-10-alkenyl, C2-10-haloalkenyl, C2-10-alkynyl, C2-10-haloalkynyl, —(CH2)m—C6-10-aryl, —(CH2)m-5- to 10-membered heteroaryl, —C(O)—C1-10-alkyl, —C(O)—C1-10-haloalkyl, —C(O)—C2-10-alkenyl, —C(O)—C2-10-haloalkenyl, —C(O)—C2-10-alkynyl, —C(O)—C2-10-haloalkynyl, —C(O)—(CH2)m—C6-10-aryl, and —C(O)—(CH2)m-5- to 10-membered heteroaryl;
- each of R17A and R17B are hydrogen;
- and
- each independently represents a single bond or a double bond, provided that the bonds between C4-C5 and C5-C6 are not both double bonds and that the bonds between C8-C14 and C14-C15 are not both double bonds;
- wherein any C6-10-aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, hydroxy, C1-6-alkyl, C1-6-haloalkyl, or C1-6-alkoxy.
A compound or pharmaceutically acceptable salt thereof, wherein the compound has a structure corresponding to Formula (IV-A1) or Formula (IV-B1):
- m is an integer selected from the group consisting of 0, 1, 2, and 3;
- R3 is oxo or —OR3X, wherein R3X is hydrogen or C1-6-alkyl;
- R9 is A-XA—RX,
- wherein A is a C1-C14-alkylene, C1-C14-haloalkylene, C2-C14-alkenylene, C2-C14-haloalkenylene, C2-C14-alkynylene, or C2-C14-haloalkynylene, each of which is optionally interrupted by one or more of —O—, —NRZ—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NRZ—, —NRZC(O)—, —S(O)y—, —S(O)yNRZ—, —NRZS(O)y—, —C(S)NRZ—, —NRZC(S)—, C6-10-aryl, or 5- to 10-membered heteroaryl;
- XA is absent or selected from the group consisting of —O—, —NRZ—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NRZ—, —NRZC(O)—, —S(O)y—, —S(O)yNRZ—, —NRZS(O)y—, —C(S)NRZ—, —NRZC(S)—, C6-10-aryl, and 5- to 10-membered heteroaryl;
- RX is selected from the group consisting of hydrogen, C1-6-alkyl, C1-6-haloalkyl, C2-6-alkenyl, C2-6-haloalkenyl, C2-6-alkynyl, C2-6-haloalkynyl, C3-7-cycloalkyl, —C(O)—C1-6-alkyl, —C(O)—C6-10-aryl, —C(O)-heteroaryl, —C(O)—NRZ1RZ2, —S(O)2NRZ1RZ2, —NRZ1RZ2, —N(RZ1)C(O)RZ2, —N(RZ1)S(O)2RZ2, C6-10-aryl, and 5- to 10-membered heteroaryl;
- wherein RZ is hydrogen, C1-6-alkyl, C1-6-haloalkyl, C2-6-alkenyl, C2-6-haloalkenyl, C2-6-alkynyl, C2-6-haloalkynyl, C3-7-cycloalkyl, C6-10-aryl, or 5- to 10-membered heteroaryl and y is 0, 1, or 2;
- wherein each of RZ1 and RZ2 are independently hydrogen, C1-6-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, —(CH2)m—C6-10-aryl, —(CH2)m-5- to 10-membered heteroaryl, hydroxy, or C1-6-alkoxy;
- R13 is selected from the group consisting of C1-C14-alkyl, C1-C14-haloalkyl, C2-C14-alkenyl, C2-C14-haloalkenyl, C2-C14-alkynyl, and C2-C14-haloalkynyl, each of which is optionally interrupted by one or more of —O—, —NRZ—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NRZ—, —NRZC(O)—, —S(O)y—, —S(O)yNRZ—, —NRZS(O)y—, —C(S)NRZ—, —NRZC(S)—, —(CH2)m—C6-10-aryl, and —(CH2)m-5- to 10-membered heteroaryl;
- R16 is selected from the group consisting of oxo and —ORD, wherein RD is selected from the group consisting of hydrogen, C1-10-alkyl, C1-10-haloalkyl, C2-10-alkenyl, C2-10-haloalkenyl, C2-10-alkynyl, C2-10-haloalkynyl, —(CH2)m—C6-10-aryl, —(CH2)m-5- to 10-membered heteroaryl, —C(O)—C1-10-alkyl, —C(O)—C1-10-haloalkyl, —C(O)—C2-10-alkenyl, —C(O)—C2-10-haloalkenyl, —C(O)—C2-10-alkynyl, —C(O)—C2-10-haloalkynyl, —C(O)—(CH2)m—C6-10-aryl, and —C(O)—(CH2)m-5- to 10-membered heteroaryl;
- and
- each independently represents a single bond or a double bond;
- wherein any C6-10-aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, hydroxy, C1-6-alkyl, C1-6-haloalkyl, or C1-6-alkoxy.
A compound or pharmaceutically acceptable salt thereof, wherein the compound has a structure corresponding to:
Dependencies are inferred from the claim text.