US 12,421,220 B2
Bicyclic-substituted glutarimide cereblon binders
Christopher G. Nasveschuk, Stoneham, MA (US); Kiel Lazarski, Boston, MA (US); Yanke Liang, Belmont, MA (US); Alexander W. Hird, Belmont, MA (US); Ning Yin, Lexington, MA (US); Andrew Charles Good, Bideford (GB); Hongwei Huang, Bedford, MA (US); Scott Joseph Eron, Waltham, MA (US); and Gesine Kerstin Veits, Somerville, MA (US)
Assigned to C4 THERAPEUTICS, INC., Watertown, MA (US)
Filed by C4 THERAPEUTICS, INC., Watertown, MA (US)
Filed on Dec. 6, 2024, as Appl. No. 18/972,557.
Application 18/972,557 is a continuation of application No. PCT/US2023/024622, filed on Jun. 6, 2023.
Claims priority of provisional application 63/349,509, filed on Jun. 6, 2022.
Prior Publication US 2025/0122179 A1, Apr. 17, 2025
Int. Cl. C07D 413/04 (2006.01); A61K 31/4709 (2006.01); A61K 31/496 (2006.01); A61K 31/5377 (2006.01); A61K 31/5383 (2006.01); A61K 31/5415 (2006.01); C07D 401/04 (2006.01); C07D 401/14 (2006.01); C07D 413/14 (2006.01); C07D 417/14 (2006.01); C07D 487/10 (2006.01); C07D 498/04 (2006.01)
CPC C07D 413/04 (2013.01) [A61K 31/4709 (2013.01); A61K 31/496 (2013.01); A61K 31/5377 (2013.01); A61K 31/5383 (2013.01); A61K 31/5415 (2013.01); C07D 401/04 (2013.01); C07D 401/14 (2013.01); C07D 413/14 (2013.01); C07D 417/14 (2013.01); C07D 487/10 (2013.01); C07D 498/04 (2013.01)] 26 Claims
 
1. A compound of Formula:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof;
wherein:
m is 0, 1, 2, or 3;
n is 0, 1, or 2;
p is 1;
Q is O;
X1, X2, and X3 are independently selected from the group consisting of CH and CR5;
X4 is CH or CR5;
A is a cycloalkyl, heterocycle, or heteroaryl;
R1 and R6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and halogen;
or R1 and R6 are combined to form a CH2 or CH2CH2 bridge;
each R2 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and —C(O)R9, each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R10;
each R5 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, —NR7R8, —OR7, —SR7, —C(O)R9, —C(S)R9, —S(O)R9, —S(O)2R9, —OC(O)R9, —OC(S)R9, —OS(O)R9, —OS(O)2R9, —SC(O)R9, —OS(O)2R9, —NR7C(O)R9, —NR7C(S)R9, —NR7S(O)R9, —NR7S(O)2R9, —P(O)(R9)2, —SP(O)(R9)2, —NR7P(O)(R9)2, and —OP(O)(R9)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R10;
R7 and R8 at each instance are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and C(O)R14; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R16;
each R9 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, —NR7R8, —OR7, and —SR7; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R10;
each R10 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, —NR11R13, —OR11, —SR11, —C(O)R14, —C(S)R14, —S(O)R14, —S(O)2R14, —OC(O)R14, —OC(S)R14, —OS(O)R14, —OS(O)2R14, —NR11C(O)R14, —NR11C(S)R14, —NR11S(O)R14, —NR11S(O)2R14, —P(O)(R14)2, —NR1P(O)(R14)2, and —OP(O)(R14)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R15a;
R11 and R13 at each instance are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, —C(O)R14, —C(S)R14, —S(S(O)2R14, and —P(O)(R14)2; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R15b;
each R12 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, —NR11R13, —OR11, and —SR11;
each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R15c;
each R14 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, —N(H)(alkyl), and —N(alkyl)2; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R15d;
R15a, R15b, R15c, R15d, and R15e, at each instance are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, —N(H)(alkyl), and —N(alkyl)2;
each R16 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, —NR11R13, —OR11, —SR11, —C(O)R14, —C(S)R14, —S(O)R14, —S(O)2R14, —OC(O)R14, —OC(S)R14, —OS(O)R14, —OS(O)2R14, —NR11C(O)R14, —NR11C(S)R14, —NR11S(O)R14, —NR11S(O)2R14, —P(O)(R14)2, —NR11P(O)(R14)2, and —OP(O)(R14)2; each of which except hydrogen, halogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R15e;
X3b is CH or CR5b;
R5b is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, —C(O)alkyl, —C(S)R9, —S(O)R9, and —S(O)2R9; each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R10;
Tail is selected from

OG Complex Work Unit Chemistry
X31 is selected from the group consisting of bond, heterocycle, aryl, heteroaryl, bicycle, —NR27—, —CR40R41—, —O—, —C(O)—, —C(NR27)—, —C(S)—, —S(O)—, —S(O)2— and —S—; each heterocycle, aryl, heteroaryl, and bicycle is substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R40;
X22 is R5;
R20, R21, R22, R23, and R24 are independently at each occurrence selected from the group consisting of a bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, —SO2—, —S(O)—, —C(S)—, —C(O)NR27—, —NR27C(O)—, —O—, —S—, —NR27—, —C(R40R40)—, —P(O)(OR26)O—, —P(O)(OR26)—, bicycle, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of R40;
R26 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle;
R27 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, heterocycle, aryl, heteroaryl, —C(O)(alkyl, aryl, or heteroaryl), —C(O)O(alkyl, aryl, or heteroaryl), alkenyl, and alkynyl;
R40 is independently at each occurrence selected from the group consisting of hydrogen, R27, alkyl, alkenyl, alkynyl, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, —NH(alkyl), —N(alkyl)2, —NHSO2(alkyl), —N(alkyl)SO2alkyl, —NHSO2(aryl, heteroaryl or heterocycle), —N(alkyl)SO2(aryl, heteroaryl or heterocycle), —NHSO2alkenyl, —N(alkyl)SO2alkenyl, —NHSO2alkynyl, —N(alkyl)SO2alkynyl, haloalkyl, aryl, heteroaryl, and heterocycle; and
R41 is aryl, heteroaryl, or hydrogen.