Granted Patent B2

US 12,268,687 · App. 17/776,952 · Granted Apr 8, 2025

Inventors: Iwona Wrona (Sharon, MA); Kerem Ozboya (Cambridge, MA); Matthew Lucas (Lexington, MA); Bhaumik Pandya (Bedford, MA); Bertrand Le Bourdonnec (Northborough, MA)

Assignee: JANSSEN PHARMACEUTICA NV

A61K31/501A61K31/166A61K31/17A61K31/4188A61K31/436A61K31/439A61K31/4439A61K31/454A61K31/4545A61K31/497A61K31/55A61K39/3955

Abstract

Claims (148)

1. A method of treating a primary brain cancer in a subject in need thereof, the method comprising administering an effective amount of the compound of formula (I):

wherein:

m is 0 or 1;

n is 0, 1, or 2;

o is 0, 1, 2, 3, 4, or 5;

C 1 and C 2 optionally combine to form a bond;

each of R 1 , R 2 , R 5 , and R 6 is, independently, H or optionally substituted C 1-6 alkyl;

R 3 is halo, cyano, C 1-6 perfluoroalkyl, optionally substituted C 1-6 alkoxy, or optionally substituted C 1-6 alkyl;

each of X 1 and X 2 is, independently, CH or N, wherein X 1 and X 2 are not both N;

X 3 is CR 4 or N; or X 3 and C 1 or C 2 combine to form an optionally substituted alkene;

X 4 is CH or N;

wherein at least one of X 3 and X 4 is N;

R 4 is H, OR 6 , optionally substituted C 1-6 alkyl, or halo;

L 1 is —C(O)—X 5 — or optionally substituted C 5-10 heteroaryl;

X 5 is NH, O, or optionally substituted C 1-6 alkyl; and

L 2 is O, NR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, or absent; or X 3 and L 2 combine to form an optionally substituted alkene,

or a pharmaceutically acceptable salt thereof;

wherein the compound does not have a structure selected from the group consisting of:

2. The method of claim 1 , wherein the compound has the structure of formula (II):

wherein:

m is 0 or 1;

o is 0, 1, 2, 3, 4, or 5;

C 1 and C 2 optionally combine to form a bond;

each of R 1 , R 2 , and R 5 is, independently, H or optionally substituted C 1-6 alkyl;

R 3 is halo, cyano, C 1-6 perfluoroalkyl, optionally substituted C 1-6 alkoxy, or optionally substituted C 1-6 alkyl;

L 1 is —C(O)—X 5 — or optionally substituted C 5-10 heteroaryl;

X 5 is NH, O, or optionally substituted C 1-6 alkyl; and

L 2 is O, NR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, or absent;

or a pharmaceutically acceptable salt thereof;

wherein the compound does not have the structure selected from the group consisting of:

3. The method of claim 1 , wherein the compound has the structure of formula (III):

wherein:

m is 0 or 1;

n is 0, 1, or 2;

o is 0, 1, 2, 3, 4, or 5;

C 1 and C 2 optionally combine to form a bond;

each of R 1 , R 2 , R 5 , and R 6 is, independently, H or optionally substituted C 1-6 alkyl;

R 3 is halo, cyano, C 1-6 perfluoroalkyl, optionally substituted C 1-6 alkoxy, or optionally substituted C 1-6 alkyl;

X 3 is CR 4 or N; or X 3 and C 1 or C 2 combine to form an optionally substituted alkene;

R 4 is H, OR 6 , optionally substituted C 1-6 alkyl, or halo;

L 1 is —C(O)—X 5 — or optionally substituted C 5-10 heteroaryl;

X 5 is NH, O, or optionally substituted C 1-6 alkyl; and

L 2 is O, NR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, or absent; or X 3 and L 2 combine to form an optionally substituted alkene,

or a pharmaceutically acceptable salt thereof;

wherein the compound does not have the structure selected from the group consisting of:

4. The method of claim 3 , wherein the compound has the structure of formula (III-A):

or

the structure of formula (III-B);

wherein:

o is 0, 1, 2, 3, 4, or 5;

each of R 1 , R 2 , and R 5 is, independently, H or optionally substituted C 1-6 alkyl;

R 3 is halo, cyano, C 1-6 perfluoroalkyl, optionally substituted C 1-6 alkoxy, or optionally substituted C 1-6 alkyl;

L 1 is —C(O)—X 5 — or optionally substituted C 5-10 heteroaryl;

X 5 is NH, O, or optionally substituted C 1-6 alkyl; and

L 2 is O, NR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, or absent;

or a pharmaceutically acceptable salt thereof.

5. The method of claim 3 , wherein the compound has the structure of formula (III-C):

or

the compound has the structure of formula (III-D):

wherein:

o is 0, 1, 2, 3, 4, or 5;

C 1 and C 2 optionally combine to form a bond;

each of R 1 , R 2 , R 5 , and R 6 is, independently, H or optionally substituted C 1-6 alkyl;

R 3 is halo, cyano, C 1-6 perfluoroalkyl, optionally substituted C 1-6 alkoxy, or optionally substituted C 1-6 alkyl;

X 3 is CR 4 or N; or X 3 and C 1 or C 2 combine to form an optionally substituted alkene;

R 4 is H, OR 6 , optionally substituted C 1-6 alkyl, or halo;

L 1 is —C(O)—X 5 — or optionally substituted C 5-10 heteroaryl;

X 5 is NH, O, or optionally substituted C 1-6 alkyl; and

L 2 is O, NR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, or absent; or X 3 and L 2 combine to form an optionally substituted alkene,

or a pharmaceutically acceptable salt thereof;

wherein the compound does not have the structure selected from the group consisting of:

6. The method of claim 5 , wherein the compound has the structure of formula (III-D-1):

or

the structure of formula (III-D-2):

wherein:

o is 0, 1, 2, 3, 4, or 5;

C 1 and C 2 optionally combine to form a bond;

each of R 1 , R 2 , R 5 , and R 6 is, independently, H or optionally substituted C 1-6 alkyl;

R 3 is halo, cyano, C 1-6 perfluoroalkyl, optionally substituted C 1-6 alkoxy, or optionally substituted C 1-6 alkyl;

R 4 is H, OR 6 , optionally substituted C 1-6 alkyl, or halo;

L 1 is —C(O)—X 5 — or optionally substituted C 5-10 heteroaryl;

X 5 is NH, O, or optionally substituted C 1-6 alkyl; and

L 2 is O, NR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, or absent;

or a pharmaceutically acceptable salt thereof;

wherein the compound does not have the structure selected from the group consisting of:

7. The method of claim 1 , wherein the compound has the structure of formula (IV):

wherein:

m is 0 or 1;

n is 0, 1, or 2;

o is 0, 1, 2, 3, 4, or 5;

C 1 and C 2 optionally combine to form a bond;

each of R 1 , R 2 , R 5 , and R 6 is, independently, H or optionally substituted C 1-6 alkyl;

R 3 is halo, cyano, C 1-6 perfluoroalkyl, optionally substituted C 1-6 alkoxy, or optionally substituted C 1-6 alkyl;

X 3 is CR 4 or N; or X 3 and C 1 or C 2 combine to form an optionally substituted alkene;

R 4 is H, OR 6 , optionally substituted C 1-6 alkyl, or halo;

L 1 is —C(O)—X 5 — or optionally substituted C 5-10 heteroaryl;

X 5 is NH, O, or optionally substituted C 1-6 alkyl; and

L 2 is O, NR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, or absent; or X 3 and L 2 combine to form an optionally substituted alkene,

or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 , wherein the compound has the structure of formula (IV-A):

wherein:

o is 0, 1, 2, 3, 4, or 5;

each of R 1 , R 2 , and R 5 is, independently, H or optionally substituted C 1-6 alkyl;

R 3 is halo, cyano, C 1-6 perfluoroalkyl, optionally substituted C 1-6 alkoxy, or optionally substituted C 1-6 alkyl;

L 1 is —C(O)—X 5 — or optionally substituted C 5-10 heteroaryl;

X 5 is NH, O, or optionally substituted C 1-6 alkyl; and

L 2 is O, NR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, or absent;

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , wherein the compound has the structure of formula (V):

wherein:

m is 0 or 1;

n is 0, 1, or 2;

o is 0, 1, 2, 3, 4, or 5;

C 1 and C 2 optionally combine to form a bond;

each of R 1 , R 2 , R 5 , and R 6 is, independently, H or optionally substituted C 1-6 alkyl;

R 3 is halo, cyano, C 1-6 perfluoroalkyl, optionally substituted C 1-6 alkoxy, or optionally substituted C 1-6 alkyl;

each of X 1 and X 2 is, independently, CH or N, wherein X 1 and X 2 are not both N;

L 1 is —C(O)—X 5 — or optionally substituted C 5-10 heteroaryl;

X 5 is NH, O, or optionally substituted C 1-6 alkyl; and

L 2 is O, NR 5 , optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heteroalkyl, or absent;

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein R 1 is H, methyl or ethyl, or R 2 is H or methyl.

11. The method of claim 1 , wherein L 1 is

or L 2 is O or optionally substituted C 1-6 alkyl.

12. The method of claim 1 , wherein o is 1 or 2.

13. The method of claim 1 , wherein R 3 is halo.

14. The method of claim 1 , wherein the compound is administered as a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. The method of claim 1 , wherein the primary brain cancer is a glioma.

16. The method of claim 15 , wherein the glioma is an astrocytoma.

17. The method of claim 16 , wherein the astrocytoma is a glioblastoma.

18. The method of claim 1 , wherein the cancer is determined or predicted to be resistant to one or more chemotherapeutic agents.

19. The method of claim 1 , wherein the cancer has failed to respond to one or more chemotherapeutic agents.

20. The method of claim 19 , wherein the one or more chemotherapeutic agents is selected from the group consisting of: temozolomide, carmustine, bevacizumab, lomustine, everolimus, vincristine, and procarbazine.

21. The method of claim 20 , wherein the one or more chemotherapeutic agents is temozolomide.

22. The method of claim 1 , wherein the subject is further administered one or more additional therapeutic interventions.

23. The method of claim 22 , wherein the one or more additional therapeutic interventions comprises surgery, radiation, and/or one or more additional chemotherapeutic agents.

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

or a pharmaceutically acceptable salt thereof.

25. The method of claim 24 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

26. The method of claim 24 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

27. The method of claim 24 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

28. The method of claim 24 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

29. The method of claim 24 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Assignments (2)

Continuity (1)

References Cited (400)