Granted Patent B2

US 12,377,106 · App. 18/049,547 · Granted Aug 5, 2025

Inventors: Robert J. Brown (San Francisco, CA); Arthur T. Sands (San Francisco, CA)

Assignee: NURIX THERAPEUTICS, INC.

A61K31/5377A61K9/0053A61K31/497A61K31/506A61P35/02

Abstract

Claims (72)

1. A method of treating cancer in a human subject in need thereof, comprising the step of orally administering to the human subject a daily oral dose of about 50 mg to about 500 mg of a compound of formula I

selected from:

or a pharmaceutically acceptable salt thereof,

wherein the cancer is a B cell malignancy.

2. The method of claim 1 , wherein the cancer is selected from the group consisting of chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, Waldenstrom's macroglobulinemia, follicular lymphoma, diffuse large B cell lymphoma, small cell lymphocytic leukemia, primary central nervous system lymphoma, and combinations thereof.

3. The method of claim 1 , wherein the human subject has a C481 mutant Bruton's tyrosine kinase, or a C481S mutant Bruton's tyrosine kinase.

4. The method of claim 1 , wherein the subject has a C481 mutant Bruton's tyrosine kinase and the cancer is chronic lymphocytic leukemia (CLL).

5. The method of claim 1 , wherein the subject has a C481S mutant Bruton's tyrosine kinase and the cancer is chronic lymphocytic leukemia (CLL).

6. The method of claim 1 , wherein the cancer is resistant to ibrutinib, acalabrutinib, pirtobrutinib, or any combination thereof.

7. The method of claim 1 , wherein the human subject has had prior treatment with ibrutinib, acalabrutinib, pirtobrutinib, or any combination thereof.

8. The method of claim 1 , wherein the cancer is chronic lymphocytic leukemia.

9. The method of claim 1 , wherein the cancer is chronic lymphocytic leukemia; and wherein the compound of formula I is:

Compound

Number

Structure

149

10. The method of claim 1 , wherein the cancer is chronic lymphocytic leukemia; and wherein the compound of formula I is:

Compound

Number

Structure

195

11. The method of claim 1 , wherein the compound of formula I is administered to the human subject at a daily dose of about 300 mg; and wherein the compound of formula I is:

Compound

Number

Structure

149

12. The method of claim 1 , wherein the cancer is chronic lymphocytic leukemia; wherein the compound of formula I is administered to the human subject at a daily dose of about 100 mg; and wherein the compound of formula I is:

Compound

Number

Structure

149

13. The method of claim 1 , wherein the compound of formula I is administered to the human subject at a daily dose of about 100 mg; and wherein the compound of formula I is:

Compound

Number

Structure

195

14. The method of claim 1 , wherein the cancer is chronic lymphocytic leukemia; the compound of formula I is administered to the human subject at a daily dose of about 50 mg; and the compound of formula I is:

Compound

Number

Structure

195

15. The method of claim 1 , wherein the cancer is chronic lymphocytic leukemia; the compound of formula I is administered to the human subject at a daily dose of about 100 mg; and the compound of formula I is:

Compound

Number

Structure

195

16. The method of claim 1 , wherein the cancer is diffuse large B cell lymphoma, germinal center B-cell-like (GCB) DLBCL, non-GCB DLBCL, activated B-cell-like (ABC) DLBCL, follicular lymphoma (FL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), or mantle cell lymphoma (MCL).

17. The method of claim 1 , wherein the compound of formula I is administered to the human subject in a form of intermittent dosing; and

wherein the intermittent dosing form comprises an administration period and a break period.

18. The method of claim 17 , wherein the intermittent dosing is repeated throughout the treatment.

19. The method of claim 17 , wherein the administration period is 2 weeks; wherein the break period is 2 weeks; and

further wherein the intermittent dosing is preceded by a loading dose for a period of 4 weeks.

20. The method of claim 17 , wherein the administration period is 3 weeks; wherein the break period is 1 weeks; and

further wherein the intermittent dosing is preceded by a loading dose for a period of 4 weeks.

21. The method of claim 1 , wherein the compound of formula I is administered to the human subject in a form of intermittent dosing;

wherein the intermittent dosing form comprises an administration period and a break period; and

wherein the intermittent dosing is preceded by a loading dose.

22. The method of claim 21 , wherein the intermittent dosing is repeated throughout the treatment.

23. The method of claim 21 , wherein the administration period is 2 weeks; and wherein the break period is 2 weeks.

24. The method of claim 21 , wherein the administration period is 3 weeks; and wherein the break period is 1 week.

25. The method of claim 1 , wherein the human subject has had prior treatment with a Bruton's tyrosine kinase inhibitor.

26. A method of degrading Bruton's tyrosine kinase in a human subject in need thereof, comprising the step of orally administering to the human subject a daily oral dose of about 100 mg to about 500 mg of a compound of formula I

is selected from hydrogen and substituted or unsubstituted heterocycle;

or a pharmaceutically acceptable salt thereof.

27. The method of claim 26 wherein the Bruton's tyrosine kinase is degraded by at least 85%, 90%, or 95% compared to baseline levels.

28. The method of claim 26 , wherein the Bruton's tyrosine kinase is in splenocytes, plasma, peripheral blood mononuclear cells, or circulating B cells.

29. The method of claim 26 , wherein the compound of formula I is administered to the human subject at a daily dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg.

30. The method of claim 26 , wherein the compound of formula I is administered in one, two, three, or four divided doses per day.

31. The method of claim 26 , wherein the compound of formula I is administered daily for one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or thirty or more days.

32. The method of claim 26 , wherein the compound of formula I is administered cyclically.

33. The method of claim 26 , wherein the compound of formula I is administered in a form of a pharmaceutical composition comprising the compound of formula I or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, vehicle, or adjuvant.

34. The method of claim 26 , wherein the human subject has had prior treatment with a Bruton's tyrosine kinase inhibitor.

Assignments (1)

Continuity (3)

References Cited (111)