Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)

Patent metadata

Field	Value
Publication number	US-11214574-B2
Application number	US-202016888883-A
Country	US
Kind code	B2
Filing date	Jun 1, 2020
Priority date	Mar 14, 2018
Publication date	Jan 4, 2022
Grant date	Jan 4, 2022

Abstract

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.

First claim

What is claimed:

1. A compound of Formula I-G-1

or a pharmaceutically acceptable salt, or solvate thereof, wherein
R 1 is NH 2 , —C 1 -C 6 alkyl, or —C 1 -C 6 alk—O—C 1 -C 6 alkyl;
R 3 is H or halo; and Q 1 , Q 2 , Q 3 , and Q 4 are each independently selected from N, CH, or C—R 8 , wherein R 8 is halo, —C 1 haloalkyl, or C 1 haloalkoxy.

2. The compound of claim 1 , wherein said compound is
(2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5-chloro-1,3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof;
(2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5,6-difluoro-1,3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof;
(2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloro-1,3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof; or
(2 S, 3 S,4R, 5R)-2-((R)-6-chloro-1,3-dihydroisobenzofuran-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof.

3. The compound of claim 2 , that is (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5-chloro-1,3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof.

4. The compound of claim 2 , that is (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5,6-difluoro-1,3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof.

5. The compound of claim 2 , that is (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloro-1,3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof.

6. The compound of claim 2 , that is (2S,3S,4R,5R)-2-((R)-6-chloro-1,3-dihydroisobenzofuran-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof.

7. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

8. The pharmaceutical composition according to claim 7 , wherein the compound is
(2R, 3R,4 S, 5 S)-2-(4-amino-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)-5 -((R)-5-chloro-1, 3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof;
(2R, 3R,4 S, 5 S)-2-(4-amino-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)-5-((R)-5, 6-difluoro-1, 3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof;
(2R, 3R,4 S, 5 S)-2-(4-amino-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)-5-((R)-6-chl oro-1, 3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof; or
(2 S, 3 S,4R, 5R)-2-((R)-6-chloro-1,3-dihydroisobenzofuran-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof.

9. The pharmaceutical composition according to claim 8 , wherein the compound is (2R, 3R,4 S, 5 S)-2-(4-amino-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)-5-((R)-6-chloro-1, 3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof.

10. The pharmaceutical composition according to claim 8 , wherein the compound is (2R, 3R,4 S, 5 S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5, 6-difluoro-1, 3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof.

11. 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 or solvate thereof.

12. A method of treating a disease in a subject comprising administering to the subject, a compound of claim 1 , or a pharmaceutically acceptable salt or solvate 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, sickle cell disease (SCD), CDKN2A deleted cancers; 9P deleted cancers; MTAP deleted cancers; glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.

13. The method according to claim 12 , wherein the compound is
(2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5-chloro-1,3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof;
(2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5,6-difluoro-1,3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof;
(2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloro-1,3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof; or
(2 S,3 S,4R,5R)-2-((R)-6-chloro-1,3-dihydroisobenzofuran-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof.

14. The method according to claim 13 , wherein the compound is (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloro-1,3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof.

15. The pharmaceutical composition according to claim 8 , wherein the compound is (2R,3R,4 S, 5 S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5-chloro-1,3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof.

16. The pharmaceutical composition according to claim 8 , wherein the compound is (2 S,3 S,4R,5R)-2-((R)-6-chloro-1,3-dihydroisobenzofuran-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt, or solvate thereof.

Assignees

• Prelude Therapeutics Inc

Inventors

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

Classifications

• C07H19/14

  Pyrrolo-pyrimidine radicals · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/7064

  containing condensed or non-condensed pyrimidines · CPC title

• 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

• C07H19/24 Primary

  Heterocyclic radicals containing oxygen or sulfur as ring hetero atom · CPC title