Granted Patent E1

US 50,776 · App. 18/181,463 · Granted Feb 3, 2026

Inventors: Nathanael S. Gray (Boston, MA); Tinghu Zhang (Brookline, MA); Nicholas Paul Kwiatkowski (Brookline, MA)

Assignee: Dana-Farber Cancer Institute, Inc.

C07D473/16A61K45/06A61P43/00C07D473/34C07D487/04C07K14/4738

Abstract

Claims (141)

1 . A compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —NR a R b , —OR b , —SR b , —C(═O)R b , —C(═O)OR b , or —C(═O)NR a R b , wherein each instance of R a and R b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group selected from the group consisting of an amide, a carbamate, and a sulfonamide when attached to nitrogen, an oxygen protecting group when attached to oxygen, or a sulfur protecting group when attached to sulfur; or R a and R b are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;

each of R 3 and R 4 is independently hydrogen, halogen, or optionally substituted C 1 -C 6 alkyl;

L 1 is a bond, or —NR L1 —(CH 2 ) t —, —O—, or —S—;

R L1 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

t is 0 or an integer between 1 and 5, inclusive;

Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

L 2 is a bond, optionally substituted C 1-4 alkylene, —C(═O)—, —NR L2 —, —C(═O)NR L2 —, —NR L2 C(═O)—, —O—, or —S—, wherein R L2 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

Ring B is absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and

R 2 is of the formula:

wherein:

L 3 is a bond or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NR L3a —, —NR L3a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b —, —C═C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NR L3a —, —NR L3a S(═O)—, —S(═O) 2 —, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, or —NR L3a S(═O) 2 —, wherein R L3a is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R L3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R L3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;

L 4 is a bond or an optionally substituted, branched or unbranched C 1-6 hydrocarbon chain;

each of R E1 , R E2 , and R E3 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR EE , —CH 2 N(R EE ) 2 , —CH 2 SR EE , —OR EE , —N(R EE ) 2 , —Si(R EE ) 3 , or —SR EE , wherein each occurrence of R EE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R EE groups are joined to form an optionally substituted heterocyclic ring;

or R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;

R E4 is a leaving group;

R E5 is halogen;

R E6 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;

each instance of Y is independently O, S, or NR E7 , wherein R E7 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;

a is 1 or 2; and

each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is a bond.

3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally substituted heterocyclyl.

4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is of the formula:

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.

6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally substituted C 1 -C 6 alkyl.

7 . The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

each instance of R 1b is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;

each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and

b1 is 0 or an integer between 1 and 6, inclusive.

8 . The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

each instance of R 1b is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;

each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and

b1 is 0 or an integer between 1 and 6, inclusive.

9 . The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

each instance of R 1b is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;

each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and

b1 is 0 or an integer between 1 and 6, inclusive.

10 . The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted phenyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted cyclohexyl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is —NR L1 —.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —NR L2 (C═O)—.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B is absent.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B is optionally substituted phenyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is of Formula (n-1):

wherein:

each instance of R 1a is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;

each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and

a1 is 0 or an integer between 1 and 6, inclusive.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is of Formula (n-2):

wherein:

each instance of R 1b is independently hydrogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;

each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and

b1 is 0 or an integer between 1 and 6, inclusive.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is of Formula (i-1):

20. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

22. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 1b is —CH 2 CH 2 OH and b1 is 1.

23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —NR a R b .

24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is —NR L1 —CH 2 —.

25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted piperidinyl.

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is of the formula:

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

or a pharmaceutically acceptable salt thereof,

wherein:

each instance of R 1a is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;

each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and

a1 is 0 or an integer between 1 and 6, inclusive.

28. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

each instance of R 1a is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;

each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and

a1 is 0 or an integer between 1 and 6, inclusive.

29. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

each instance of R 1b is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;

each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and

b1 is 0 or an integer between 1 and 6, inclusive.

30. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

each instance of R 1b is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;

each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and

b1 is 0 or an integer between 1 and 6, inclusive.

31. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

each instance of R 1b is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;

each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and

b1 is 0 or an integer between 1 and 6, inclusive.

32. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

each instance of R 1b is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;

each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and

b1 is 0 or an integer between 1 and 6, inclusive.

33. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof,

wherein

each instance of R 1b is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;

each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and

b1 is 0 or an integer between 1 and 6, inclusive.

34. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

each instance of R 1b is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —N(R N1 ) 2 , or —OR O1 ;

each instance of R N1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group;

each instance of R O1 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group; and

b1 is 0 or an integer between 1 and 6, inclusive.

35. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

38. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

Assignments (1)

Continuity (2)

References Cited (400)