Small molecule degraders of estrogen receptor with cereblon ligands
AssigneeThe Regents of the University of Michigan
InventorsShaomeng Wang, Zhixiang Chen, Rohan Rej, Dimin Wu, Jianfeng Lu, Biao Hu, Mingliang Wang, Ranjan Kumar Acharyya
Life of this patent
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Abstract
The present disclosure relates to compounds of Formula I: and the pharmaceutically acceptable salts and solvates thereof, wherein A, X, J, Y, Z, n, and B 1 are as defined as set forth in the specification. The present disclosure also relates to uses of the compounds, e.g., in treating preventing a condition or disorder responsive to the degradation of estrogen receptor protein (e.g., cancer).
Claims35
A compound of Formula I:
- A-X-J-Y—Z—(CH2)n—B1 I,
- or a pharmaceutically acceptable salt or solvate thereof, wherein:
- A is selected from:
- M1 is selected from 4- to 8-membered heterocyclenyl, phenylenyl, 5-membered heteroarylenyl, and 6-membered heteroarylenyl, wherein the 4- to 8-membered heterocyclenyl, phenylenyl, 5-membered heteroarylenyl, or 6-membered heteroarylenyl is optionally substituted with one or more halo or C1-C3 alkoxy;
- R1a, R1b, R1c, and R1d are independently selected from hydrogen, halo, hydroxy, 5-membered heteroayl, and —B(OH)2, wherein the 5-membered heteroayl is optionally substituted with one or more C1-C4 alkyl;
- or
- R1a and R1b taken together with the carbon atom to which they are attached form an optionally substituted 5- or 6-membered heteroaryl;
- and R1c and R1d are hydrogen;
- R2a is selected from optionally substituted phenyl and optionally substituted C3-C8 cycloalkyl;
- and R2b is hydrogen;
- or
- R2a and R2b taken together with the carbon atom to which they are attached form a C3-C8 cycloalkyl;
- E1 is selected from —C(═O)—, —C≡C—, —O—, —O—(CH2)b—, N(R3e)—, and —(CH2)b—;
- R3e is selected from hydrogen and C1-C4 alkyl;
- b is 0, 1, 2, 3, 4, or 5;
- M2 is selected from 4- to 8-membered heterocyclenyl, phenylenyl, 5-membered heteroarylenyl, and 6-membered heteroarylenyl, wherein the 4- to 8-membered heterocyclenyl, phenylenyl, 5-membered heteroarylenyl, or 6-membered heteroarylenyl is optionally substituted with one or more halo or C1-C3 alkoxy;
- R4a, R4b, R4c, and R4d are independently selected from hydrogen, halo, hydroxy, and —B(OH)2;
- or
- R4a and R4b taken together with the carbon atoms to which they are attached form an optionally substituted 5- or 6-membered heteroaryl;
- and R4c and R4d are hydrogen;
- R5 is C1-C3 alkyl;
- R6 is C1-C4 haloalkyl;
- E2 is selected from —C(═O)—, —C≡C—, —O—, —O—(CH2)c—, —N(R7e)—, and —(CH2)c—;
- R7e is selected from hydrogen and C1-C4 alkyl;
- c is 0, 1, 2, 3, 4, or 5;
- M3 is selected from 4- to 8-membered heterocyclenyl, phenylenyl, 5-membered heteroarylenyl, and 6-membered heteroarylenyl, wherein the 4- to 8-membered heterocyclenyl, phenylenyl, 5-membered heteroarylenyl, or 6-membered heteroarylenyl is optionally substituted with one or more halo or C1-C3 alkoxy;
- R8a, R8b, R8c, and R8d are independently selected from hydrogen, halo, hydroxy, and —B(OH)2;
- R9 is C1-C3 alkyl;
- R10 is C1-C4 haloalkyl optionally substituted with one or more hydroxy, or —(C1-C4 alkyl)-(C3-C8 cycloalkyl) optionally substituted with one or more halo;
- E3 is selected from —C(═O)—, —C≡C—, —O—, —O—(CH2)d—, N(R11e)—, and —(CH2)d—;
- R11e is selected from hydrogen and C1-C4 alkyl;
- d is 0, 1, 2, 3, 4, or 5;
- R12 is selected from C1-C4 alkyl and C1-C4 haloalkyl;
- R13a, R13b, R13c, and R13d are independently selected from hydrogen, halo, hydroxy, and —B(OH)2;
- each R14 is independently selected from hydrogen, halo, and hydroxy;
- e is 0, 1, 2, or 3;
- each R15 is independently selected from hydrogen, halo, and hydroxy;
- f is 0, 1, 2, or 3;
- R16a, R16b, R16c, and R16d are independently selected from hydrogen, halo, hydroxy, and —B(OH)2;
- R17a, R17b, R17c, R17d, and R17e are independently selected from hydrogen, halo, and hydroxy;
- each R18 is independently selected from hydrogen, halo, and hydroxy;
- g is 0, 1, 2, or 3;
- X is selected from cycloalkylenyl, heterocyclenyl, phenylenyl, and heteroarylenyl, wherein the cycloalkylenyl, heterocyclenyl, phenylenyl, or heteroarylenyl is optionally substituted with one or more C1-C4 alkyl;
- J is selected from —C(═O)—, —(CH2)m—, —(CH2)z1N(R19)—, and —(CH2)z2O—,
- m is 0, 1, 2, or 3;
- z1 is 0, 1, or 2;
- z2 is 0, 1, or 2;
- R19 is selected from hydrogen and C1-C4 alkyl;
- Y is selected from cycloalkylenyl, heterocyclenyl, heteroarylenyl, —C(═O)— and —(CR20aR20b)r—;
- Z is selected from cycloalkylenyl, heterocyclenyl, heteroarylenyl, —C(═O)— and —(CR20cR20d)s—;
- each R20a, R20b, R20c, and R20d is independently selected from hydrogen and C1-C3 alkyl;
- r is 0, 1, 2, 3, 4, or 5;
- s is 0, 1, 2, 3, 4, or 5;
- with the provisos:
- (i) Z is cycloalkylenyl, heterocyclenyl, heteroarylenyl, or —(CR20cR20d)s— when Y is —C(═O)—;
- or
- (ii) Y is cycloalkylenyl, heterocyclenyl, heteroarylenyl, or —(CR20aR20b)r— when Z is —C(═O)—;
- n is 0, 1, 2, or 3;
- B1 is selected from hydrogen, hydroxy,
- R25a and R25b are independently selected from hydrogen, amino, halo, C1-C3 alkyl, and C1-C3 alkoxy;
- R26 is selected from hydrogen, deuterium, fluoro, and C1-C3 alkyl;
- R27 is selected from hydrogen and C1-C3 alkyl;
- Z1 and Z2 are independently selected from —C(═O)— and —CR28aR28b—;
- with the provisos:
- (iv) one of Z1 or Z2 is —C(═O)—;
- or
- (v) both of Z1 and Z2 are —C(═O)—;
- R28a and R28b are independently selected from hydrogen and C1-C3 alkyl;
- or
- R28a and R28b taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
- Z3 and Z4 are independently selected from —C(═O)— and —CR28cR28d—;
- with the provisos:
- (iv) one of Z3 or Z4 is —C(═O)—;
- or
- (v) both of Z3 and Z4 are —C(═O)—;
- R28c and R28d are independently selected from hydrogen and C1-C3 alkyl;
- or
- R28c and R28d taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl;
- X1 is selected from —O—, —S—, and —N(R29)—;
- R29 is selected from hydrogen and C1-C4 alkyl;
- t is 1, 2, or 3;
- u is 1, 2, or 3;
- v is 1, 2, or 3;
- and
- w is 1, 2, or 3.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-1′ or A-1;
- and
- optionally;
- M1 is selected from
- wherein the bond designated with an “*” is attached to E1;
- G1 is selected from —N═ and —CR3a═;
- G2 is selected from —N═ and —CR3b═;
- G3 is selected from —N═ and —CR3c═;
- G4 is selected from —N═ and —CR3d═;
- and R3a, R3b, R3c, R3d are independently selected from hydrogen and halo, with the proviso that E1 is —(CH2)b— when M1 is M1-6;
- and
- optionally;
- M1 is M1-1.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-2;
- and
- optionally;
- M2 is selected from
- wherein the bond designated with an “*” is attached to E2;
- G5 is selected from —N═ and —CR7a═;
- G6 is selected from —N═ and —CR7b═;
- G7 is selected from —N═ and —CR7c═;
- G8 is selected from —N═ and —CR7d═;
- and R7a, R7b, R7c, and R7d are independently selected from hydrogen and halo, with the proviso that E2 is —(CH2)c— when M2 is M2-6;
- and
- optionally;
- M2 is M2-1.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-3;
- and
- optionally;
- M3 is selected from
- wherein the bond designated with an “*” is attached to E3;
- G9 is selected from —N═ and —CR11a═;
- G10 is selected from —N═ and —CR11b═;
- G11 is selected from —N═ and —CR11c═;
- G12 is selected from —N═ and —CR11d═;
- and R11a, R11b, R11c, and R11d are independently selected from hydrogen and halo, with the proviso that E3 is —(CH2)d— when M2 is M3-6;
- and
- optionally;
- M3 is M3-1.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-4 or A-5.
The compound of any one of the preceding claims, being of Formula II or III:
- or a pharmaceutically acceptable salt or solvate thereof, wherein R1e is selected from hydrogen and halo;
- and
- optionally, R1b is hydroxy and R1e is hydrogen or fluoro;
- and
- optionally, R1e is hydrogen;
- and
- optionally, E1 is —O—;
- or E1 is —(CH2)b— and b is 0.
The compound of any one of the preceding claims, being of Formula IV or V:
- or a pharmaceutically acceptable salt or solvate thereof;
- and
- optionally, R4b is hydroxy;
- and
- optionally, R5 is methyl;
- and
- optionally, R6 is selected from —CH2CF2CH3, —CH2CF2H, and —CH2CF3;
- and
- optionally, E2 is —(CH2)c— and c is 0.
The compound of any one of the preceding claims, being of Formula VI:
- or a pharmaceutically acceptable salt or solvate thereof;
- and
- optionally, R9 is methyl;
- and
- optionally, R10 is selected from —CH2CF2CH3, —CH2CF2H, and —CH2CF3;
- and
- optionally, E3 is —(CH2)d— and d is 0.
The compound of any one of the preceding claims, being of Formula VII:
- or a pharmaceutically acceptable salt or solvate thereof;
- and
- optionally, R12 is selected from —CH2CH3 and —CH2CH2C1;
- and
- optionally, R13c is hydroxy.
The compound of any one of the preceding claims, being of Formula VII:
- or a pharmaceutically acceptable salt or solvate thereof;
- and
- optionally, R6b is hydroxy;
- and
- optionally, R17c is fluoro.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein X is heterocyclenyl;
- and
- optionally, wherein:
- (i) X is optionally substituted 4- to 8-membered heterocyclenyl;
- and
- optionally, X is selected from
- or
- (ii) X is a 7- to 14-membered spiroheterocyclenyl;
- and
- optionally, X is
- and n1, n2, n3, and n4 are independently 0, 1, 2, 3, or 4, with the proviso that the sum of n1, n2, n3, and n4 is 4, 5, 6, 7, 8, 9, or 10;
- and
- optionally, X is selected from
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein J is —(CH2)m— and m is 0 or 1;
- and
- optionally, m is 0.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is selected from heterocyclenyl, —C(═O)— and —(CH2)r—;
- and
- optionally, wherein:
- (i) Y is optionally substituted 4- to 8-membered heterocyclenyl;
- and
- optionally, Y is
- (ii) Y is —(CH2)r—;
- or
- (iii) Y is —C(═O)—.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is selected from heterocyclenyl and —(CH2)s—;
- and
- optionally, wherein:
- (i) Z is optionally substituted 4- to 8-membered heterocyclenyl;
- and
- optionally, Z is
- (ii) Z is —(CH2)s—;
- or
- (iii) Z is —C(═O)—.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 or 1.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is B1-1-A, B1-1-B, or B1-1-C;
- and
- optionally, t is 1 or 2;
- and
- optionally, u is 1;
- or u is 2.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is B1-2-A, B1-2-B, or B1-2-C;
- and
- optionally, t is 1 or 2;
- and
- optionally, u is 1;
- or u is 2.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is B1-3-A, B1-3-B, or B1-3-C;
- and
- optionally, t is 1 or 2;
- and
- optionally, u is 1;
- or u is 2;
- and
- optionally, v is 1;
- and
- optionally, w is 1;
- or w is 2.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is B1-4-A, B1-4-B, or B1-4-C.
- optionally, t is 1 or 2;
- and
- optionally, u is 1;
- or u is 2;
- and
- optionally, R27 is hydrogen.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is B1-5-A, B1-5-B, B1-5-C, B1-6-A, B1-6-B, B1-6-C, B1-7-A, B1-7-B, or B1-7-C;
- and
- optionally, X1 is —O—.
The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R25a is hydrogen;
- and
- optionally, R25b is hydrogen;
- and
- optionally, R26 is hydrogen;
- and
- optionally, Z1 is —C(═O)—;
- or Z1 is —CH2—;
- and
- optionally, Z2 is —C(═O)—.
The compound of any one of the preceding claims, being selected from the compounds described in Table 1, and pharmaceutically acceptable salts and solvates thereof.
The compound of any one of the preceding claims, or a salt or solvate thereof, wherein B1 is selected from hydrogen or hydroxy;
- optionally, wherein the compound is selected from the compounds described in Table 2, and pharmaceutically acceptable salts and solvates 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 ER 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 ER 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 ER 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 ER protein.
The method, use, or compound for use in any one of the preceding claims, wherein the disease is a cancer;
- optionally, the cancer is selected from the cancers described in Table I;
- and
- optionally, the cancer is breast cancer.
Dependencies are inferred from the claim text.