Compounds and compositions as smarca2/4 degraders and uses thereof

A compound of Formula II

• or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
• T is of Formula II-1
• wherein:
• A1 is CRA1 or N;
• A2 is CRA2 or N;
• A3 is CRA3 or N;
• A4 is CRA4 or N;
• RA1, RA2, RA3, and RA4 are independently hydrogen, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, —SRb, —S(═O)Ra, —S(═O)2Ra, —S(═O)2ORb, —S(═O)2NRcRd, —NRcS(═O)2Ra, —NRcS(═O)Ra, —NRcS(═O)2ORb, —NRc S(═O)2NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —OS(═O)2Ra, —OS(═O)2ORb, —OS(═O)2NRcRd, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —C(═O)Ra, —C(═O)ORb, or —C(═O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• each RC is independently hydrogen, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, —SRb, —S(═O)Ra, —S(═O)2Ra, —S(═O)2ORb, —S(═O)2NRcRd, —NRc S(═O)2Ra, —NRc S(═O)Ra, —NRc S(═O)2ORa, —NRcS(═O)2NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —OS(═O)2Ra, —OS(═O)2ORb, —OS(═O)2NRcRd, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —C(═O)Ra, —C(═O)ORb, or —C(═O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• two RC together form an oxo;
• or
• two RC, together with the carbon atom to which they are attached, form Ring D
• Ring D is C3-12 carbocycle or 3- to 12-membered heterocycle;
• each RD is independently oxo, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, —SRb, —S(═O)Ra, —S(═O)2Ra, —S(═O)2ORb, —S(═O)2NRcRd, —NRc S(═O)2Ra, —NRc S(═O)Ra, —NRc S(═O)2ORb, —NRcS(═O)2NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —OS(═O)2Ra, —OS(═O)2ORb, —OS(═O)2NRcRd, —OC(═O)Ra, —OC(═O)OR, —OC(═O)NRcRd, —C(═O)Ra, —C(═O)ORb, or —C(═O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• d is an integer selected from 0 to 10, as valency permits;
• E1 is CRE1 or N;
• E2 is CRE2 or N;
• E3 is CRE3 or N;
• E4 is CRE4 or N;
• RE1, RE2, RE3, and RE4 are independently
• hydrogen, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, —SRb, —S(═O)Ra, —S(═O)2Ra, —S(═O)2ORb, —S(═O)2NRcRd, —NRc S(═O)2Ra, —NRc S(═O)Ra, —NRc S(═O)2OR′, —NRcS(═O)2NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —OS(═O)2Ra, —OS(═O)2ORb, —OS(═O)2NRcRd, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —C(═O)Ra, —C(═O)ORb, or —C(═O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• wherein one of RE1, RE2, RE3, and RE4 is
• or
• one of RE2, RE3, or RE4 is
• denotes attachment to L;
• Ring F is C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• each RF is independently oxo, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, —SRb, —S(═O)Ra, —S(═O)2Ra, —S(═O)2ORb, —S(═O)2NRcRd, —NRc S(═O)2Ra, —NRc S(═O)Ra, —NRcS(═O)2ORb, —NRcS(═O)2NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —OS(═O)2Ra, —OS(═O)2ORb, —OS(═O)2NRcRd, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —C(═O)Ra, —C(═O)ORb, or —C(═O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• and
• f is an integer selected from 0 to 10, as valency permits,
• L is of Formula II-2
• wherein:
• * denotes attachment to T and ** denotes attachment to V;
• each L′ is independently C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C6-10 arylene, 5- to 10-membered heteroarylene, —C(═O)—, —C(═O)N(RL′)—, —C(═O)O—, —N(RL′)—, —O—, —S—, or —S(═O)2—, wherein the alkylene, heteroalkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more Ru;
• each occurrence of RL′ is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, —S(═O)2R®, —S(═O)2ORb, —S(═O)2NRcRd, —C(═O) R*, —C(═O)ORb, or —C(═O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• and
• l is an integer selected from 0 to 5,
• V is of Formula II-3-i, II-3-ii, II-3-iii, II-3-iv, II-3-v, II-3-vi, II-3-vii, or II-3-viii
• wherein:
• ** denotes attachment to L;
• Ring A′ is 5- to 7-membered heterocycle;
• each RA′ is independently oxo, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• a′ is an integer selected from 0 to 10, as valency permits;
• Ring B′ is C3-6 carbocycle or 3- to 6-membered heterocycle;
• each RB′ is independently oxo, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• b′ is an integer selected from 0 to 10, as valency permits;
• Ring C′ is C6 aryl or 5- to 6-membered heteroaryl;
• each RC′ is independently halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• c′ is an integer selected from 0 to 5, as valency permits;
• Ring D′ is C6 aryl or 5- to 6-membered heteroaryl;
• each RD′ is independently halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• or
• RD′ and RV4, together with the intervening atoms, form C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• d′ is an integer selected from 0 to 5, as valency permits;
• Ring E′ is C3-8 carbocycle or 3- to 8-membered heterocycle;
• each RE′ is independently oxo, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• e′ is an integer selected from 0 to 5, as valency permits;
• Ring F′ is C6 aryl or 5- to 6-membered heteroaryl;
• each RF′ is independently halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• f′ is an integer selected from 0 to 5, as valency permits;
• RV1 is —N(RV1i)C(═O)RV1ii or 5- to 6-membered heteroaryl optionally substituted with one or more Ru;
• RV1i is hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru;
• RV1i is C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more RV1iia,
• each RV1ia is independently oxo, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, —(C1-6 alkylene)-(3- to 12-membered heterocyclyl), C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• RV2 is hydrogen, C1-6 alkyl, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, carbocyclyl, heterocyclyl is optionally substituted with one or more Ru;
• RV3 is hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, —S(═O)2Ra, —S(═O)2ORb, —S(═O)2NRcRd, —C(═O)Ra, —C(═O)ORb, or —C(═O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru;
• each RV4 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more RV4a, or
• two RV4, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru;
• each RV4a is independently oxo, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-12 heteroalkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, —C(═O)ORb, or —C(═O)NRcRd, wherein the alkyl, heteroalkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• and
• RV5 is hydrogen, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, or —C(═O)Ra, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;
• wherein:
• each Ru is independently oxo, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, —SRb, —S(═O)Ra, —S(═O)2Ra, —S(═O)2ORb, —S(═O)2NRcRd, —NRc S(═O)2Ra, —NRc S(═O)Ra, —NRc S(═O)2ORa, —NRc S(═O)2NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORa, —OS(═O)2Ra, —OS(═O)2OR, —OS(═O)2NRcRd, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —C(═O)Ra, —C(═O)ORb, or —C(═O)NRcRd;
• wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl;
• or
• two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz;
• each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• and
• each Rc and Rd is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
• or
• Rc and Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl,
• wherein each occurrence of Ra, Rb, Rc, and Rd is independently and optionally substituted with one or more Rz;
• and
• each Rz is independently oxo, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.