Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)

Patent metadata

Field	Value
Publication number	US-11254683-B2
Application number	US-202016985611-A
Country	US
Kind code	B2
Filing date	Aug 5, 2020
Priority date	Mar 14, 2018
Publication date	Feb 22, 2022
Grant date	Feb 22, 2022

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 method of treating a disease in a subject comprising administering to the subject, a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein said compound is a compound of Formula I-A-1:

or a pharmaceutically acceptable salt or solvate thereof;
wherein
A is N or C—R 3 ;
R 1 is halo, NH 2 , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, or —C 1 -C 6 alk—O—C 1 -C 6 alkyl;
R 2 is H, halo, —C 1 -C 6 alkyl, or NH 2 ;
R 3 is H, halo, —C 1 -C 6 alkyl, or —C 1 -C 6 alkoxy;
R 4 is H or —C 1 -C 6 alkyl;
R 5 is H or —C 1 -C 6 alkyl;
X is O, S, SO 2 , NH, or N(C 1 -C 6 alkyl);
each R 9 is independently selected from H, D, F, OH, OCH 3 , CH 3 , or CF 3 ; each R 9′ is independently selected from H, D, F, OH, OCH 3 , CH 3 , or CF 3 ;
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; and
wherein the disease is adenoid cystic carcinoma (ACC), a myeloproliferative disorder, glioblastoma, primary central nervous system lymphoma, acute myeloid leukemia (AML), multiple myeloma (MM), myelodysplastic syndrome (MDS), breast cancer, fallopian tube cancer, ovarian cancer, prostate cancer, pancreatic cancer, or non-Hodgkin lymphoma.

2. The method of claim 1 , wherein said compound is:
(2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloroisochroman-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)-7-chloroisochroman-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-chloroisochroman-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)-6,7-difluoroisochroman-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-difluoroisochroman-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-5-fluoroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof;
(2R,3R,4S,5S)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloroisochroman-1-y 1)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)-6,7-dichloroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof;
(2 S, 3 S,4R, 5R)-2-((R)-6-chloroisochroman-l-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3 ,4-diol, or a pharmaceutically acceptable salt or solvate thereof;
(2S,3 S,4R,5R)-2-((R)-6,7-difluoroisochroman-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;
(2S,3 S,4R,5R)-2-((R)-5,6-difluoroisochroman-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;
(2 S, 3 S,4R, 5R)-2-((R)-6-chloroisochroman- 1-yl)-5-(5-fluoro-4-methyl-7H-pyrrolo[2, 3 -d]pyrimidin-7-yl)tetrahydrofuran-3 ,4-diol, or a pharmaceutically acceptable salt or solvate thereof; or
(2 S,3 S,4R,5R)-2-((R)-6,7-dichloroisochroman- 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 method of claim 2 , wherein said compound is (2S,3S,4R,5R)-2-((R)-6-chloroisochroman-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.

4. The method of claim 1 , wherein the disease is adenoid cystic carcinoma (ACC).

5. The method of claim 3 , wherein the disease is adenoid cystic carcinoma (ACC).

6. The method of claim 1 , wherein the disease is a myeloproliferative disorder.

7. The method of claim 3 , wherein the disease is a myeloproliferative disorder.

8. The method of claim 1 , wherein the disease is glioblastoma.

9. The method of claim 3 , wherein the disease is glioblastoma.

10. The method of claim 1 , wherein the disease is primary central nervous system lymphoma.

11. The method of claim 3 , wherein the disease is primary central nervous system lymphoma.

12. The method of claim 1 , wherein the disease is acute myeloid leukemia (AML).

13. The method of claim 3 , wherein the disease is acute myeloid leukemia (AML).

14. The method of claim 1 , wherein the disease is multiple myeloma (MM).

15. The method of claim 3 , wherein the disease is multiple myeloma (MM).

16. The method of claim 1 , wherein the disease is myelodysplastic syndrome (MDS).

17. The method of claim 3 , wherein the disease is myelodysplastic syndrome (MDS).

18. The method of claim 1 , wherein the disease is breast cancer.

19. The method of claim 3 , wherein the disease is breast cancer.

20. The method of claim 1 , wherein the disease is fallopian tube cancer.

21. The method of claim 3 , wherein the disease is fallopian tube cancer.

22. The method of claim 1 , wherein the disease is ovarian cancer.

23. The method of claim 3 , wherein the disease is ovarian cancer.

24. The method of claim 1 , wherein the disease is prostate cancer.

25. The method of claim 3 , wherein the disease is prostate cancer.

26. The method of claim 1 , wherein the disease is pancreatic cancer.

27. The method of claim 3 , wherein the disease is pancreatic cancer.

28. The method of claim 1 , wherein the disease is non-Hodgkin lymphoma.

29. The method of claim 3 , wherein the disease is non-Hodgkin lymphoma.

30. The method of claim 1 , wherein the compound is administered in combination with one or more other agents.

31. The method of claim 3 , wherein the compound is administered in combination with one or more other agents.

32. The method of claim 30 , wherein the other agent is a JAK kinase inhibitor, a BCL2 inhibitor, or a PARP inhibitor.

33. The method of claim 31 , wherein the other agent is JAK kinase inhibitor, a BCL2 inhibitor, or a PARP inhibitor.

34. The method of claim 32 , wherein the JAK kinase inhibitor is ruxolitinib, and the BCL2 inhibitor is venetoclax.

35. The method of claim 33 , wherein the JAK kinase inhibitor is ruxolitinib, and the BCL2 inhibitor is venetoclax.

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

• A61K31/519

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

• C12N9/1007

  Methyltransferases (general) (2.1.1.) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title