Granted Patent B2

US 12,391,705 · App. 17/414,565 · Granted Aug 19, 2025

Inventors: Yaron R. Hadari (Harrison, NY); Michael Schmertzler (St. Petersburg, FL); Theresa M. Williams (Harleysville, PA); Luca Carta (Scarsdale, NY); Rebecca Hutcheson (Stamford, CT); Charles H. Reynolds (Austin, TX)

Assignee: SHY Therapeutics, LLC

C07D495/04A61P35/00C07D401/04C07D401/14C07D403/04C07D403/14C07D519/00

Abstract

Claims (78)

1. A compound of Formula IIIA, IIIA1, IIIA2, IIIB, IIIC, IIID, IIIE or IIIF:

wherein:

—NR 9 R 10 is

R 11 is

 or Br; and

R 12 is phenyl;

wherein:

—NR 9A1 R 10A1 is

R 11A1 is

 or Br; and

R 12A1 is phenyl;

wherein:

—NR 9A2 R 10A2 is

R 11A2 is

 and

R 12A2 is

wherein:

—NR 13 R 14 is

R 15 is

 and

R 16 is

wherein:

—NR 17 R 18 is

R 19 is

R 20 is phenyl; and

R 21 is hydrogen or methyl;

wherein:

—NR 22 R 23 is

R 24 is

R 25 is methyl; and

R 26 is hydrogen or methyl;

wherein:

NR 27 R 28 is

R 29 is hydrogen;

R 30 is hydrogen; and

R 31 is

 or

wherein:

—NR 32 R 33 is

—NR 34 R 35 is

 and

R 36 is phenyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is the compound of Formula (IIIA), (IIIA1) or (IIIA2), or pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is the compound of Formula (IIIB), or pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein the compound is the compound of Formula (IIIC), or pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound is the compound of Formula (IIID), or pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein the compound is the compound of Formula (IIIE), or pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein the compound is the compound of Formula (IIIF), or pharmaceutically acceptable salt thereof.

9. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable carrier.

11. A method of inhibiting the function of one or more members of the Ras superfamily, comprising administering to a subject the compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the one or more members of the Ras superfamily are selected from the group consisting of HRas, KRas, NRas, Rac-1, Rho-A, and a mutant of any of the foregoing.

12. The method of claim 11 , wherein the compound or pharmaceutically acceptable salt thereof binds to the GTP binding domain of the one or more members of the Ras superfamily and inhibits the one or more members of the Ras superfamily with an IC 50 value of less than 10 micromolar.

13. A method of treating cancer, or a KRas, NRas, Rac-1, Rho-A or HRas-associated autoimmune leukoproliferative disorder in a subject comprising administering to the subject the compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer, cervix cancer, urinary tract cancer, breast cancer, breast cancer, or brain cancer, optionally wherein the lung cancer is non-small cell lung cancer, the brain cancer is glioblastoma, and the skin cancer is melanoma.

14. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 9 and a pharmaceutically acceptable carrier.

15. A method of inhibiting the function of one or more members of the Ras superfamily, comprising administering to a subject the compound or pharmaceutically acceptable salt thereof of claim 9 , wherein the one or more members of the Ras superfamily are selected from the group consisting of HRas, KRas, NRas, Rac-1, Rho-A, and a mutant of any of the foregoing.

16. The method of claim 9 , wherein the compound or pharmaceutically acceptable salt thereof binds to the GTP binding domain of the one or more members of the Ras superfamily and inhibits the one or more members of the Ras superfamily with an IC 50 value of less than 10 micromolar.

17. A method of treating cancer, or a KRas, NRas, Rac-1, Rho-A or HRas-associated autoimmune leukoproliferative disorder in a subject comprising administering to the subject the compound or pharmaceutically acceptable salt thereof of claim 9 , wherein the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer, cervix cancer, urinary tract cancer, breast cancer, breast cancer, or brain cancer, optionally wherein the lung cancer is non-small cell lung cancer, the brain cancer is glioblastoma, and the skin cancer is melanoma.

18. A method of treating cancer, or a KRas, NRas, Rac-1, Rho-A, or HRas-associated autoimmune leukoproliferative disorder in a subject comprising administering to the subject the compound or pharmaceutically acceptable salt thereof of claim 2 , wherein the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer, cervix cancer, urinary tract cancer, breast cancer, breast cancer, or brain cancer, optionally wherein the lung cancer is non-small cell lung cancer, the brain cancer is glioblastoma, and the skin cancer is melanoma.

19. The method of claim 18 , wherein the method is for treating pancreatic cancer.

20. The method of claim 17 , wherein the method is for treating pancreatic cancer.

21. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

Assignments (1)

Continuity (2)

References Cited (400)