US 12,440,506 B2
Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
Hong Lin, Exton, PA (US); Juan Luengo, Phoenixville, PA (US); Rupa Shetty, Blue Bell, PA (US); Michael Hawkins, Ambler, PA (US); Philip Pitis, North Wales, PA (US); and Gisela Saborit Villarroya, Barcelona (ES)
Assigned to Prelude Therapeutics, Incorporated, Wilmington, DE (US)
Appl. No. 17/601,485
Filed by Prelude Therapeutics, Incorporated, Wilmington, DE (US)
PCT Filed Apr. 3, 2020, PCT No. PCT/US2020/026639
§ 371(c)(1), (2) Date Oct. 5, 2021,
PCT Pub. No. WO2020/206299, PCT Pub. Date Oct. 8, 2020.
Claims priority of provisional application 62/829,923, filed on Apr. 5, 2019.
Prior Publication US 2022/0152073 A1, May 19, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/7064 (2006.01)
CPC A61K 31/7064 (2013.01) 50 Claims
 
1. A method of treating a disease or disorder selected from the group consisting of rejection of transplanted organs or tissue; graft-versus-host diseases multiple sclerosis, myasthenia gravis; pollen allergies; type I diabetes; psoriasis; Crohn's disease; ulcerative colitis, acute respiratory distress syndrome; influenza; COVID-19 (coronavirus disease); or rheumatic fever and post-infectious glomerulonephritis, in a patient in need thereof, comprising administering to said patient an effective amount of 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-C4haloalkyl, —C3-C6cycloalkyl, —C3-C6halocycloalkyl, —C1-C6alkyl-O—C1-C6alkyl, —C1-C6alkyl-S(O)—C1-C6alkyl, —C1-C6alkyl-S(O)2—C1-C6alkyl, —CR6R6′CN, —NR6R6′, —NHCR6R6′CN, —NHCONR6R6′, —NHC(O)OR7, NHC(O)—C1-C6alkyl, NHC(O)—C1-C6haloalkyl, —NH—C1-C6alkyl-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-C6alkyl-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-C4alkyl-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-C4alkyl-NH2;
wherein n=1, 2, or 3; 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.