HYDANTOIN CONTAINING DEOXYURIDINE TRIPHOSPHATASE INHIBITORS

• US 20190330210A1
• Filed: 11/21/2017
• Published: 10/31/2019
• Est. Priority Date: 11/23/2016
• Status: Active Grant

• Current Assignee: CV6 Therapeutics Limited
• Original Assignee: CV6 Therapeutics Limited
• Inventors: Spyvee, Mark, Ladner, Robert D.
• Granted Patent: US 11,014,924 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 207/38 2-Pyrrolones
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 217/24 Oxygen atoms
• CPC Class Codes: C07D 233/76 with substituted hydrocarbon radicals attached to the third ring carbon atom
• CPC Class Codes: C07D 233/80 with hetero atoms or acyl radicals directly attached to ring nitrogen atoms
• CPC Class Codes: C07D 239/96 Two oxygen atoms
• CPC Class Codes: C07D 249/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 249/16 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 263/44 Two oxygen atoms
• CPC Class Codes: C07D 265/26 Two oxygen atoms, e.g. isatoic anhydride
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/10 Spiro-condensed systems

Abstract

Provided herein are dUTPase inhibitors, compositions comprising such compounds and methods of using such compounds and compositions.

Claims

1. A compound of Formula (I):

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

3. The compound of any one of claims 1-2, wherein B is selected from the group consisting of:

4. The compound of any one of claims 1-2, wherein B is

5. The compound of claim 4, wherein B is

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

7. The compound of any one of claims 1-2, wherein A is:

8. The compound of claim 1, wherein A is

9. The compound of any one of claims 1-8, wherein L¹ is

—

(CH₂)_q—

, wherein one or more hydrogens are optionally substituted with C₁-C₃ alkyl and/or at least two or more geminal hydrogens are optionally substituted with an optionally substituted 3-5 membered heterocyclyl or an optionally substituted 3-5 membered cycloalkyl, preferably the optionally substituted 3-5 membered cycloalkyl is an optionally substituted cyclopropano, an optionally substituted cyclobutano, an optionally substituted cyclopentano, or an optionally substituted tetrahydrofurano; and

wherein q is 3, 4, 5, 6, 7, or 8;

10. The compound of any one of claims 1-8, wherein L¹ is selected from the group consisting of:

11. The compound of any one of claims 1-8, wherein L¹ is:

12. The compound of any one of claims 1-11, wherein L² is selected from the group consisting of:

—

S(O)₂NH—

, —

C(O)N(CH₃)—

, —

C(O)NH—

, —

S(O)₂N(CH₂C(O)OH)—

, —

NHC(O)NH—

, —

NHC(S)NH—

, —

NH—

,

13. The compound of any one of claims 1-11, wherein L² is —

S(O)₂NR⁵⁰—

wherein the sulfur is attached to L¹.

14. The compound of any one of claims 1-8, wherein -L¹-L²- is selected from the group consisting of:

15. The compound of any one of claims 1-14, wherein L³ is selected from the group consisting of:

16. The compound of any one of claims 1-14, wherein L³ is selected from the group consisting of:

17. The compound of claim 1, wherein -L¹-L²-L³- is selected from the group consisting of:

18. The compound of any one of claims 1-8, wherein -L¹-L²-L³- is selected from the group consisting of:

19. The compound of any one of claims 1-8, wherein -L¹-L²-L³- is selected from the group consisting of:

20. The compound of any one of claims 1-2, wherein -L²-L³-B is selected from the group consisting of:

21. The compound of claim 5, wherein R¹ is H.

22. The compound of claim 5, wherein R³ is H or —

OR²⁰.

23. The compound of claim 5, wherein R² is F or H.

24. The compound of claim 5, wherein B is

25. The compound of claim 1 or claim 2, wherein -L³-B is selected from the group consisting of:

26. The compound of any one of claims 1-2, wherein B is selected from the group consisting of:

27. The compound of any one of claims 1-2, wherein B is

29. A composition comprising a compound of any one of claims 1 to 28, and at least one pharmaceutically acceptable excipient or carrier.

30. A method of one or more of inhibiting dUTPase or enhancing the efficacy of a dUTPase directed therapy comprising contacting the dUTPase with a therapeutically effective amount of the compound of any of claims 1 to 28.

31. A method of reversing resistance to a dUTPase-directed therapy comprising contacting the dUTPase with a therapeutically effective amount of the compound of any of claims 1 to 28.

32. A method of treating a disease whose treatment is impeded by the expression or over expression of dUTPase, comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of any of claims 1 to 28.

33. A method of inhibiting the growth of a cancer cell comprising contacting the cell with a therapeutically effective amount of the compound of any of claims 1 to 28 and a therapeutically effective amount of a dUTPase directed therapeutic, thereby inhibiting the growth of the cancer cell.

34. The method of claim 33, wherein the cancer cell is selected from a colon cancer cell, a colorectal cancer cell, a gastric cancer cell, a head and neck cancer cell, a breast cancer cell, a lung cancer cell or a blood cell.

35. A method of treating a disease in a patient whose treatment is impeded by the expression or overexpression of dUTPase, comprising:

a. screening a cell or tissue sample from the patient;

b. determining the expression level of dUTPase in the sample;

c. administering to a patient whose sample shows over expression of dUTPase, a therapeutically effective amount of the compound of any of claims 1 to 28.

36. The method of claim 35, wherein the disease is cancer.

37. The method of claim 36, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, gastric cancer, esophageal cancer, head and neck cancer, breast cancer, lung cancer, stomach cancer, liver cancer, gall bladder cancer, or pancreatic cancer or leukemia.

38. A kit comprising a compound of any of claims 1 to 28, and instructions for use in a diagnostic or therapeutic method as described herein.

28. A compound selected from Table 1 or 2: