Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)

Patent metadata

Field	Value
Publication number	US-12459950-B2
Application number	US-202217674010-A
Country	US
Kind code	B2
Filing date	Feb 17, 2022
Priority date	Mar 14, 2018
Publication date	Nov 4, 2025
Grant date	Nov 4, 2025

Abstract

The disclosure is directed to compounds of Formula IPharmaceutical compositions comprising compounds of Formula I, as well as methods of their use and preparation, are also described.

First claim

What is claimed:

1 . A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof;
wherein:
A is N or C—R 3 ;
R 1 is H, halo, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 4 haloalkyl, —C 3 -C 6 cycloalkyl, —C 3 -C 6 halocycloalkyl, —C 1 -C 6 alk-O—C 1 -C 6 alkyl, —C 1 -C 6 alk-S(O)—C 1 -C 6 alkyl, —C 1 -C 6 alk-S(O) 2 —C 1 -C 6 alkyl, —CR 6 R 6′ CN, —NR 6 R 6′ , —NHCR 6 R 6′ CN, —NHCONR 6 R 6′ , —NHC(O)OR 7 , NHC(O)—C 1 -C 6 alkyl, NHC(O)—C 1 -C 6 haloalkyl, —NH—C 1 -C 6 alk-C(O)—C 1 -C 6 alkyl, —NHC(S) NR 6 R 6′ , —NH—O—R 6 , or —NH—NR 6 R 6′ ;
R 2 is H, halo, —C 1 -C 6 alkyl, or NH 2 ;
R 3 is H, halo, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 2 -C 6 alkenyl, or —C 2 -C 6 alkynyl;
R 4 is H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 2 -C 6 alkenyl, or —C 2 -C 6 alkynyl;
R 5 is H or —C 1 -C 6 alkyl;
R 6 and R 6′ are each independently H, C 1 -C 6 alkyl, or —C 1 -C 6 alk-OC 1 -C 6 alkyl;
or R 6 and R 6′ , together with the atom to which they are attached, form a C 2 -C 6 heterocycloalkyl ring or a C 3 -C 6 cycloalkyl ring;
R 7 is —C 1 -C 6 alkyl or —C 0 -C 6 alk-C 3 -C 6 cycloalkyl;
X is O, S, NH, or N (C 1 -C 6 alkyl), and Y is —(CR 9 R 9′ ) n —, —CR 9 ═CR 9′ —, C(═O), —C(═O)—(CR 9 R 9′ ) n —, —C(═O)—O—(CR 9 R 9′ ) n —, —CR 9 R 9′ —O—, —(CR 9 R 9′ ) n —O—(CR 9 R 9′ ) m —, —(CR 9 R 9′ ) n —NR 10 , C(═O) NR 10 , or CH—C 1 -C 4 alk-NH 2 ; or
X is —SO 2 — and Y is —(CR 9 R 9′ ) n —, —CR 9 ═CR 9′ —, —CR 9 R 9′ —O—, —(CR 9 R 9′ ) n —O—(CR 9 R 9′ ) m —, -(CR 9 R 9′ ) n —NR 10 , or CH—C 1 -C 4 alk-NH 2 ;
wherein n=1 or 2; m=1 or 2;
each instance of R 9 or R 9′ is independently H, D, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —C 1 -C 6 alkoxy, or hydroxy;
R 10 is H or C 1 -C 6 alkyl;
Z is O, CH 2 , or CF 2 ; 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.

2 . The compound of claim 1 wherein R 1 is halo, —NR 6 R 6′ , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, or —C 1 -C 6 alk-O—C 1 -C 6 alkyl.

3 . The compound of claim 1 , wherein R 2 is H.

4 . The compound of claim 1 , wherein R 4 is H or —C 1 -C 6 alkyl.

5 . The compound of claim 1 , wherein R 5 is H.

6 . The compound of claim 1 , wherein R 5 is —C 1 -C 6 alkyl.

7 . The compound of claim 1 , wherein Ar is an optionally substituted 6-membered aryl ring.

8 . The compound of claim 1 , wherein Ar is an optionally substituted 6-membered heteroaryl ring.

9 . The compound of claim 1 , wherein Ar is an optionally substituted 5-membered heteroaryl ring.

10 . The compound of claim 1 , wherein X is O.

11 . The compound of claim 1 , wherein Y is —(CR 9 R 9′ ) n .

12 . The compound of claim 1 , wherein each R 9 and each R 9′ is independently H, D, —CH 3 , OH, —OCH 3 , F, or CF 3 .

13 . The compound of claim 1 wherein n=1.

14 . The compound of claim 1 wherein n=2.

15 . The compound of claim 1 wherein m=1.

16 . The compound of claim 1 wherein m=2.

17 . The compound of claim 1 , wherein Z is O.

18 . A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

19 . A method of treating a disease or disorder associated with aberrant PRMT5 activity in a subject comprising administering to the subject, a compound of claim 1 .

20 . The method of claim 19 , wherein the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD), CDKN2A deleted cancers; 9P deleted cancers; MTAP deleted cancers; glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.

Assignees

• Prelude Therapeutics Inc

Inventors

• Luengo Juan
• Lin Hong
• Hawkins Michael
• Shetty Rupa
• Pitis Philip
• Saborit Villarroya Gisela

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/7064

  containing condensed or non-condensed pyrimidines · CPC title

• C12N9/1007

  Methyltransferases (general) (2.1.1.) · CPC title