Selective inhibitors of protein arginine methyltransferase 5 (prmt5)

A compound of Formula I:

• or a pharmaceutically acceptable salt or solvate thereof;
• wherein:
• A is N or C—R3;
• R1 is H, halo, —C1-C6alkyl, —C1-C6alkoxy, —C1-C4haloalkyl, —C3-C6cycloalkyl, —C3-C6halocycloalkyl, —C1-C6alk-O—C1-C6alkyl, —C1-C6alk-S(O)—C1-C6alkyl, —C1-C6alk-S(O)2—C1-C6alkyl, —CR6R6′CN, —NR6R6′, —NHCR6R6′CN, —NHCONR6R6′, —NHC(O)OR7, NHC(O)—C1-C6alkyl, NHC(O)—C1-C6haloalkyl, —NH—C1-C6alk-C(O)—C1-C6alkyl, —NHC(S)NR6R6′, —NH—O—R6, or —NH—NR6R6′;
• R2 is H, halo, —C1-C6alkyl, or NH2;
• R3 is H, halo, —C1-C6alkyl, —C1-C6alkoxy, —C2-C6alkenyl, or —C2-C6alkynyl;
• R4 is H, —C1-C6alkyl, —C1-C6haloalkyl, —C2-C6alkenyl, or —C2-C6alkynyl;
• R5 is H or —C1-C6alkyl;
• R6 and R6′ are each independently H, C1-C6alkyl, or —C1-C6alk-OC1-C6alkyl;
• or R6 and R6′, together with the atom to which they are attached, form a C2-C6heterocycloalkyl ring or a C3-C6cycloalkyl ring;
• R7 is —C1-C6alkyl or —C0-C6alk-C3-C6cycloalkyl;
• X is O, S, NH, or N(C1-C6alkyl), and Y is —(CR9R9′)n—, —CR9═CR9′—, C(═O), —C(═O)—(CR9R9′)n—, —C(═O)—O—(CR9R9′)n—, —CR9R9′—O—, —(CR9R9′)n—O—(CR9R9′)m—, —(CR9R9′)n—NR10, C(═O)NR10, or CH—C1-C4alk-NH2;
• or
• X is —SO2— and Y is —(CR9R9′)n—, —CR9═CR9′—, —CR9R9′—O—, —(CR9R9′)n—O—(CR9R9′)m—, —(CR9R9′)n—NR10, or CH—C1-C4alk-NH2;
• wherein n=1 or 2;
• m=1 or 2;
• each instance of R9 or R9′ is independently H, D, C1-C6alkyl, C1-C6haloalkyl, halo, —C1-C6alkoxy, or hydroxy;
• R10 is H or C1-C6alkyl;
• Z is O, CH2, or CF2;
• and
• Ar is an optionally substituted 6-membered aryl ring, an optionally substituted 6-membered heteroaryl ring, or an optionally substituted 5-membered heteroaryl ring.