Compounds as prmt5 degraders and uses thereof

A compound of Formula I

• or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
• T is of Formula I-1
• wherein:
• each is independently a single bond or a double bond, as valency permits;
• X is N(RX1), and RA is oxo;
• or
• X is C(RX2), and RA and RB2, together with the intervening atoms to which they are attached, form C6 aryl or 6-membered heteroaryl, wherein the C6 aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• RX1 is hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• RX2 is hydrogen, halogen, —CN, —NO2, —OH, —NH2, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• RB1, RB2, RB4, and RB5 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, or 5- to 10-membered heteroaryl, wherein the 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 is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• or
• RB1 and RB4, together with the intervening atoms to which they are attached, form 3- to 8-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein the 3- to 8-membered heterocyclyl or 5- to 6-membered heteroaryl is optionally substituted with one or more halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, or C2-6 alkynyl;
• each RC is independently hydrogen, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• nD is 0 or 1;
• Y is O, S, or C(RD), as valency permits;
• and
• each RD is independently
• hydrogen, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2, wherein * denotes attachment to L, and one RD is
• L is of Formula I-2
• wherein:
• * denotes attachment to T, and ** denotes attachment to V;
• each L′ is independently —C(═O)—, —C(═O) N(RL′)—, —N(RL′)C(═O)—, —C(═O)O—, —OC(═O)—, —N(RL′)—, —O—, —O—(C1-6 alkylene)-, —(C1-6 alkylene)-O—, —S—, —S(═O)2—, C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C6-10 arylene, or 5- to 10-membered heteroarylene, wherein the —O—(C1-6 alkylene)-, —(C1-6 alkylene)-O—, C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C6-10 arylene, or 5- to 10-membered heteroarylene is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• each occurrence of RL′ is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, 3- to 8-membered heterocyclyl, —S(═O)2Ra, —S(═O)2ORa, —S(═O)2N(Ra)2, —C(═O)Ra, —C(═O)ORa, or —C(═O)N(Ra)2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, or 3- to 8-membered heterocyclyl is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• and
• each Ra independently is hydrogen, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• l is an integer selected from 0 to 10;
• V is of Formula I-3
• wherein:
• ** denotes attachment to L;
• RV1 is hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• RVN1 is hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• RV2 is hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• each RA′ is independently hydrogen, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• RVN2 is hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• each RV4 is independently hydrogen, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• each RV5 is independently hydrogen, halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more halogen, —CN, —NO2, —OH, or —NH2;
• and
• RV6 is 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, wherein the 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 is optionally substituted with one or more halogen, —CN, —NO2, —OH, —NH2, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl.