Small-molecular inhibitors for the beta-catenin/ b-cell lymphoma 9 protein-protein interaction

A compound of Formula I:

• or a pharmaceutically acceptable salt thereof;
• wherein:
• W is CR6 or N;
• X is selected from O or NR1;
• Y is absent or O;
• Z is absent or C(R12)(R13);
• m is 0, 1, or 2;
• n is 1 or 2;
• R1 is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C3-C7cycloalkyl, 4- to 10-membered monocyclic or bicyclic heterocycle, 5- to 10-membered monocyclic or bicyclic aryl, 5- to 10-membered monocyclic or bicyclic heteroaryl, and RL, each of which may be optionally substituted with one or more A groups as allowed by valency;
• R2 is selected from C1-C6alkyl, C3-C7cycloalkyl, (4- to 10-membered monocyclic and bicyclic heterocycle)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl), and RL, each of which may be optionally substituted with one or more B groups as allowed by valency;
• R3, R4, RS, and R6 are independently selected from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, (4- to 10-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl), —ORa, —SRa, —NRaRb, —C(O)Rc, —S(O)Rc, —S(O)2Rc, and RL, each of which may be optionally substituted with one or more A groups as allowed by valency;
• R7, R8, R9, R10, and R11 are independently selected from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, (4- to 10-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl), —ORa, —SRa, —NRaRb, —C(O)Rc, —S(O)Rc, —S(O)2Re, and RL, each of which may be optionally substituted with one or more A groups as allowed by valency;
• R12 and R13 are independently selected from hydrogen, halo, nitro, cyano, azido, C1-C0alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, (4- to 10-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl), —ORa, —SRa, —NRaRb, —C(O)Rc, —S(O)Rc, —S(O)2Rc, and RL, each of which may be optionally substituted with one or more A groups as allowed by valency;
• or R12 and R13 are brought together with the carbon to which they are attached to form a C3-C7 cycloalkyl group or a 4- to 10-membered monocyclic or bicyclic heterocycle group;
• R14 is independently selected at each occurrence from halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, (4- to 10-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl), —ORa, —SRa, —NRaRb, —C(O)Rc, —S(O)Rc, —S(O)2Rc and RL;
• Ra and Rb are independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, (4- to 10-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl), and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl), each of which may be optionally substituted with one or more A groups as allowed by valency;
• Re is independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, (4- to 10-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic aryl)-(C1-C6alkyl), (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl), —ORa, —SRa, and —NRaRb, each of which may be optionally substituted with one or more A groups as allowed by valency;
• A is selected at each occurrence from halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, (4- to 10-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl), C1-C6alkoxy, C1-C6haloalkoxy, thiol, C1-C6thioalkyl, amino, (mono- or dialkyl)amino, —CHO, —COOH, —CONH2, ester, carbamate, urea, sulfonamide, phosphate, phosphonate, and RL;
• B is selected from halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, (4- to 10-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl), (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl), —ORa, —SRa, —NRaRb, —C(O)Rc, —S(O)Rc, —S(O)2Rc, and RL, each of which may be optionally substituted with one or more A groups as allowed by valency;
• and
• RL is a linker conjugated to a PROTAC moiety.