US 12,459,950 B2
Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
Juan Luengo, Phoenixville, PA (US); Hong Lin, Exton, PA (US); Michael Hawkins, Ambler, PA (US); Rupa Shetty, Blue Bell, PA (US); Philip Pitis, North Wales, PA (US); and Gisela Saborit Villarroya, Barcelona (ES)
Assigned to Prelude Therapeutics, Incorporated, Wilmington, DE (US)
Filed by Prelude Therapeutics, Incorporated, Wilmington, DE (US)
Filed on Feb. 17, 2022, as Appl. No. 17/674,010.
Application 17/674,010 is a continuation of application No. 16/985,611, filed on Aug. 5, 2020, granted, now 11,254,683.
Application 16/985,611 is a continuation of application No. 16/888,883, filed on Jun. 1, 2020, granted, now 11,214,574, issued on Jan. 4, 2022.
Application 16/888,883 is a continuation of application No. 16/376,100, filed on Apr. 5, 2019, granted, now 10,711,007, issued on Jul. 14, 2020.
Application 16/376,100 is a continuation of application No. PCT/US2019/022288, filed on Mar. 14, 2019.
Claims priority of provisional application 62/742,048, filed on Oct. 5, 2018.
Claims priority of provisional application 62/666,726, filed on May 4, 2018.
Claims priority of provisional application 62/642,727, filed on Mar. 14, 2018.
Prior Publication US 2022/0177481 A1, Jun. 9, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 487/04 (2006.01); A61P 35/00 (2006.01); C07D 519/00 (2006.01)
CPC C07D 487/04 (2013.01) [A61P 35/00 (2018.01); C07D 519/00 (2013.01)] 20 Claims
 
1. A compound of Formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or solvate thereof;
wherein:
A is N or C—R3;
R1 is H, halo, —C1-C6alkyl, —C1-C6alkoxy, —C1-C4 haloalkyl, —C3-C6 cycloalkyl, —C3-C6 halocycloalkyl, —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-C6 haloalkyl, —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-C6 haloalkyl, —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-C6 heterocycloalkyl ring or a C3-C6 cycloalkyl ring;
R7 is —C1-C6alkyl or —C0-C6alk-C3-C6 cycloalkyl;
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-C6 haloalkyl, 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.