Small molecule degraders of androgen receptor
AssigneeThe Regents of the University of Michigan
InventorsShaomeng Wang, Lijie Zhao, Xin Han, Weiguo Xiang
Life of this patent
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Abstract
The present disclosure provides compounds of Formula (I): and the salts or solvates thereof, wherein A1, B1, L, and X2 are as defined in the specification. The present disclosure also relates to uses of the compounds, e.g., as androgen receptor degraders useful for the treatment of diseases (e.g., cancer).
Claims27
A compound of Formula I:
- or a pharmaceutically acceptable salt or solvate thereof, wherein:
- A1 is selected from phenylenyl, 5-membered heteroarylenyl, and 6-membered heteroarylenyl;
- X2 is selected from —C(═O)—, —S(═O)2—, —O—, and —CR4cR4d—;
- or X2 is absent;
- R4c and R4d are independently selected from hydrogen and C1-C4 alkyl;
- L is -J1-J2-J3-J4-J5-;
- wherein J1 is attached to X2;
- J1 is selected from cycloalkylenyl and heterocyclenyl;
- or J1 is absent;
- J2 is selected from —(CH2)b—, —C(═O)—, —CH═CH—, and —C≡C—;
- b is 0, 1, 2, or 3;
- J3 is selected from alkylenyl, heteroalkylenyl, cycloalkylenyl, heterocyclenyl, phenylenyl, and heteroarylenyl;
- or
- J3 is absent;
- J4 is selected from alkylenyl, cycloalkylenyl, and heterocyclenyl;
- or J4 is absent;
- J5 is selected from —(CH2)c—, —O—, —N(R5)—, and —C(═O)—;
- c is 0, 1, 2, or 3;
- R5 is selected from hydrogen and C1-C4 alkyl;
- B1 is selected from:
- Q1 is selected from —CR2a═ and —N═;
- Q2 is selected from —CR2b═ and —N═;
- Q is selected from —CR2c═ and —N═;
- R2a, R2b, R2c, R2d, and R2e are independently selected from hydrogen, halo, amino, C1-C3 alkyl, and C1-C3 alkoxy;
- R3 is selected from hydrogen, deuterium, fluoro, and C1-C4 alkyl;
- m is 1, 2, or 3;
- n is 1, 2, or 3;
- Z and Z1 are —C(═O)—;
- or
- Z is —C(═O)— and Z1 is —CR6aR6b—;
- or
- Z is —CR6aR6b— and Z1 is —C(═O)—;
- Z3 is selected from —CR6cR6d— and —C(═O)—;
- R6a and R6b are independently selected from hydrogen and C1-C3 alkyl;
- or
- R6c and R6d taken together with the carbon to which they are attached from a C3-C6 cycloalkyl;
- R8 is selected from hydrogen and C1-C3 alkyl;
- and
- R10 is selected from hydrogen and C1-C4 alkyl,
- with the proviso the compound of Formula I is not a compound described in Table 1A.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein:
- (i) X2 is —C(═O)—, —S(═O)2—, —O—, or —CR4cR4d—;
- optionally, R4c and R4d are hydrogen;
- or
- (ii) X2 is absent.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein:
- (i) J1 is selected from:
- or
- (ii) J1 is absent;
- and
- optionally, wherein:
- (i) J2 is selected from —(CH2)b— and —C≡C—;
- and b is 0, 1, or 2;
- (ii) J2 is —(CH2)b—;
- and b is 0;
- (iii) J2 is —(CH2)b—;
- and b is 1;
- or
- (iv) J2 is —C≡C—;
- and
- optionally, wherein:
- (i) J3 is selected from cycloalkylenyl and heterocyclenyl;
- or
- (ii) J3 is absent;
- and
- optionally, wherein:
- (i) J4 is selected from alkylenyl, cycloalkylenyl, and heterocyclenyl;
- or
- (ii) J4 is absent.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein:
- (i) J1 is selected from —O— and —N(H)—;
- and B1 is selected from B1-1, B1-2, and B1-3;
- or
- (ii) J1 is selected from —(CH2)c— and —O—;
- c is 0;
- J4 is selected from J4-1, J4-2, J4-3, J4-4, J4-5, and J4-6;
- R7 is selected from hydrogen, halo, cyano, hydroxy, C1-C3 alkyl, and C1-C3 alkoxy;
- and B1 is selected from B1-1, B1-2, B1-3, and B1-4.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein:
- (i) B1 is B1-1;
- optionally, B1-1 is B1-1-B or B1-1-C:
- optionally, Z and Z1 are —C(═O)—;
- Z is —C(═O)— and Z1 is —CR6aR6b—;
- or Z is —CR6aR6b— and Z1 is —C(═O)—;
- (ii) B1 is B1-2;
- optionally, B1-2 is B1-2-B or B1-2-C:
- (iii) B1 is B1-3;
- optionally, B1-3 is B1-3-B or B1-3-C:
- or
- (iv) B1 is B1-4;
- optionally, B1-4 is B1-4-B or B1-4-C:
- and
- optionally, R10 is C1-C3 alkyl;
- and
- optionally, Q1 is —N═;
- or Q1 is —CR2a, optionally, R2a is selected from hydrogen and halo;
- and
- optionally, Q2 is —N═;
- or Q2 is —CR2b, optionally, R2b is selected from hydrogen and halo;
- and
- optionally, Q is —N═;
- or Q is —CR2c, optionally, R2, is selected from hydrogen and halo.
The compound of any one of the preceding claims, wherein:
- J1 is selected from —(CH2)c— and —C(═O)—;
- c is 0, 1, 2, or 3;
- and
- B1 is selected from B1-5 and B1-6, or a pharmaceutically acceptable salt or solvate thereof.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein
- (i) B1 is B1-5;
- optionally, B1-5 is B1-5-B or B1-5-C:
- optionally, R2d and R2d are independently selected from hydrogen and halo;
- and
- optionally, Z3 is —C(═O)—;
- or Z3 is —CR6aR6b—;
- or
- (ii) B1 is B′-6;
- optionally, B1-6 is B1-6-B or B1-6-C:
- optionally, Z and Z1 are —C(═O)—;
- Z is —C(═O)— and Z1 is —CR6aR6b—;
- or Z is —CR6aR6b— and Z1 is —C(═O)—;
- and
- optionally, R2d and R2d are independently selected from hydrogen and halo.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is selected from:
- and
- optionally, B1 is:
The compound of any one of the preceding claims, being selected from the compounds described in Table 1, or a pharmaceutically acceptable salt or solvate thereof.
A pharmaceutical composition comprising the compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
A method of degrading an AR protein in a subject, comprising administering to the subject the compound of any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof.
Use of the compound of any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for degrading an AR protein in a subject.
The compound of any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof for use in degrading an AR protein in a subject.
A method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject the compound of any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof
Use of the compound of any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for treating or preventing a disease in a subject.
The compound of any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof for use in treating or preventing a disease in a subject.
The method, use, or compound for use in any one of the preceding claims, wherein the subject is a mammal.
The method, use, or compound for use in any one of the preceding claims, wherein the subject is a human.
The method, use, or compound for use in any one of the preceding claims, wherein the disease is associated with degradation of an AR.
The method, use, or compound for use in any one of the preceding claims, wherein the disease is cancer, seborrhea, acne, hyperplasia, sebaceous adenoma, hirsutism, alopecia, or hidradenitis suppurativa;
- optionally, the disease is a cancer;
- optionally, the cancer is selected from the cancers described in Table I;
- optionally, the cancer is breast cancer, ovarian cancer, or prostate cancer;
- and
- optionally, the subject is in need of transgender therapy.
Dependencies are inferred from the claim text.