Selective inhibitors of protein arginine methlytransferase 5 (PRMT5)
The disclosure is directed to compounds of Formula I Pharmaceutical compositions comprising compounds of Formula I, as well as methods of their use and preparation, are also described.
1. A compound of Formula I:
or a pharmaceutically acceptable salt or solvate thereof;
wherein
R 1 is —C 0 -C 6 alk-C 1 -C 6 alkyl, —C 0 -C 6 alk-C 1 -C 6 haloalkyl, —C 1 -C 6 alk-O—C 1 -C 6 alkyl, —C 1 -C 6 alk-S—C 1 -C 6 alkyl, —C 1 -C 6 alk-S—C 1 -C 6 alk-CO 2 H, —C 1 -Chalk-aryl, —C 1 -C 6 alk-O-aryl, —C 1 -C 6 alk-NH-aryl, —C 1 -C 6 alk-S-aryl, —C 0 -C 6 alk-heteroaryl, —C 1 -C 6 alk-O-heteroaryl, —C 1 -C 6 alk-S-heteroaryl, —C 1 -C 6 alk-NH-heteroaryl, or —C(O)NH-aryl;
R 2 is —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 2 -C 6 alkenyl, or —C 2 -C 6 alkynyl;
R 3 is H, halo, NH 2 , or —C 1 -C 6 alkyl;
R 4 is H, halo, —C 1 -C 6 alkyl, —C 1 -C 6 alk-O—C 1 -C 6 alkyl, —NR 6 R 6′ , —NHCONR 6 R 6′ , —NHC(S)NR 6 R 6′ , —NH—O—R 6 , or —NH—NR 6 R 6′ ;
R 5 is H, halo, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, or —C 1 -C 6 alk-OH; and
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 3 -C 6 heterocycloalkyl ring.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —C 1 -C 6 alk-O-heteroaryl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —C 1 -C 6 alk-S-heteroaryl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —C 1 -C 6 alk-NH-heteroaryl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —C 1 -C 6 alk-heteroaryl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —C 1 -C 6 alk-O-aryl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —C 1 -C 6 alk-aryl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —C(O)NH-aryl.
9. The compound of claim 1 wherein R 2 is —C 1 -C 6 alkyl.
10. The compound of claim 1 wherein R 2 is —C 1 -C 6 haloalkyl.
11. The compound of claim 1 wherein R 2 is —C 2 -C 6 alkenyl.
12. The compound of claim 1 wherein R 2 is —C 2 -C 6 alkynyl.
13. The compound of claim 1 wherein R 3 is H.
14. The compound of claim 1 wherein R 4 is H.
15. The compound of claim 1 wherein R 4 is —C 1 -C 6 alkyl.
16. The compound of claim 1 wherein R 4 is chloro, fluoro, bromo, or iodo.
17. The compound of claim 1 wherein R 4 is —NR 6 R 6′ , wherein R 6 and R 6′ are both H.
18. The compound of claim 1 wherein R 4 is —NHCONR 6 R 6′ , wherein R 6 and R 6′ are both —C 1 -C 6 alkyl.
19. The compound of claim 1 wherein R 4 is —NH—O—R 6 , wherein R 6 is —C 1 -C 6 alkyl.
20. The compound of claim 1 wherein R 4 is —NH—NR 6 R 6′ , wherein R 6 and R 6′ are both —C 1 -C 6 alkyl or wherein R 6 is —C 1 -C 6 alkyl and R 6′ is preferably H.
21. The compound of claim 1 wherein R 5 is H.
22. The compound of claim 1 wherein R 5 is halo.
23. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
24. A method of inhibiting a protein arginine methyltransferase 5 (PRMT5) enzyme, comprising: contacting the PRMT5 enzyme with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
25. A method of treating a disease in a subject comprising administering to the subject, a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disease is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia 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 (CIVIL), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, hemoglobinopathies, b-thalassemia, or sickle cell disease (SCD).
26. The method of claim 25 , wherein the compound, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more other agents.