Benzazepine compounds, conjugates, and uses thereof

1. A compound represented by the structure of Formula (IIB):

or a pharmaceutically acceptable salt thereof, wherein:

L 10 is selected from —C(O)—, and —C(O)N(R 10 )—*, wherein * represents where L 10 is bound to R 5 —;

L 2 is selected from —C(O)— and —C(O)N(R 10 )—;

R 1 and R 2 are independently selected from hydrogen; and C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10 , —SR 10 , —C(O)N(R 10 ) 2 , —N(R 10 ) 2 , —S(O)R 10 , —S(O) 2 R 10 , —C(O)R 10 , —C(O)OR 10 , —OC(O)R 10 , —NO 2 , ═O, ═S, ═N(R 10 ), and —CN;

R 4 is selected from:

—OR 10 , —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —C(O)R 10 , —C(O)OR 10 , —S(O)R 10 , and —S(O) 2 R 10 ; and

C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10 , —SR 10 , —C(O)N(R 10 ) 2 , —N(R 10 )C(O)R 10 , —N(R 10 )C(O)N(R 10 ) 2 , —N(R 10 ) 2 , —C(O)R 10 , —C(O)OR 10 , —OC(O)R 10 , —NO 2 , ═O, ═S, ═N(R 10 ), —CN, C 3-12 carbocycle, and 3- to 12-membered heterocycle; and

C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10 , —SR 10 , —C(O)N(R 10 ) 2 , —N(R 10 )C(O)R 10 , —N(R 10 )C(O)N(R 10 ) 2 , —N(R 10 ) 2 , —C(O)R 10 , —C(O)OR 10 , —OC(O)R 10 , —NO 2 , ═O, ═S, ═N(R 10 ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 5 is selected from unsaturated C 4-8 carbocycle; bicyclic carbocycle; and fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle, wherein R 5 is optionally substituted and wherein substituents are independently selected at each occurrence from:

halogen, —OR 10 , —SR 10 , —C(O)N(R 10 ) 2 , —N(R 10 )C(O)R 10 , —N(R 10 )C(O)N(R 10 ) 2 , —N(R 10 ) 2 , —C(O)R 10 , —C(O)OR 10 , —OC(O)R 10 , —NO 2 , ═O, ═S, ═N(R 10 ), and —CN; and

C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10 , —SR 10 , —C(O)N(R 10 ) 2 , —N(R 10 )C(O)R 10 , —N(R 10 )C(O)N(R 10 ) 2 , —N(R 10 ) 2 , —C(O)R 10 , —C(O)OR 10 , —OC(O)R 10 , —NO 2 , ═O, ═S, ═N(R 10 ), —CN, C 3-12 carbocycle, and 3- to 12-membered heterocycle; and

C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10 , —SR 10 , —C(O)N(R 10 ) 2 , —N(R 10 )C(O)R 10 , —N(R 10 )C(O)N(R 10 ) 2 , —N(R 10 ) 2 , —C(O)R 10 , —C(O)OR 10 , —OC(O)R 10 , —NO 2 , ═O, ═S, ═N(R 10 ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 10 is independently selected at each occurrence from:

hydrogen, —NH 2 , and —C(O)OCH 2 C 6 H 5 ; and

C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , ═O, ═S, —C(O)OCH 2 C 6 H 5 , —NHC(O)OCH 2 C 6 H 5 , C 1-10 alkyl, —C 1-10 haloalkyl, —O—C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle;

R 20 , R 21 , R 22 , and R 23 are independently selected from hydrogen, halogen, OR 10 , —SR 10 , —N(R 10 ) 2 , —S(O)R 10 , —S(O) 2 R 10 , —C(O)R 10 , —C(O)OR 10 , —OC(O)R 10 , —NO 2 , ═O, ═S, ═N(R 10 ), —CN, C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl; and

R 24 and R 25 are independently selected from hydrogen, halogen, —OR 10 , —SR 10 , —N(R 10 ) 2 , —S(O)R 10 , —S(O) 2 R 10 , —C(O)R 10 , —C(O)OR 10 , —OC(O)R 10 , —NO 2 , ═O, ═S, ═N(R 10 ), —CN, C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl; or R 24 and R 25 taken together form an optionally substituted saturated C 3-7 carbocycle.

2. The compound or salt of claim 1 , wherein R 20 , R 21 , R 22 , and R 23 are independently selected from hydrogen, halogen, —OH, —OR 10 , —NO 2 , —CN, and C 1-10 alkyl.

3. The compound or salt of claim 2 , wherein R 20 , R 21 , R 22 , and R 23 are each hydrogen.

4. The compound or salt of claim 1 , wherein R 24 and R 25 are each hydrogen.

5. The compound or salt of claim 1 , wherein R 1 and R 2 are each hydrogen.

6. The compound or salt of claim 1 , wherein L 10 is selected from —C(O)N(R 10 )—*.

7. The compound or salt of claim 6 , wherein R 10 of —C(O)N(R 10 )—* is selected from hydrogen and C 1-6 alkyl.

8. The compound or salt of claim 7 , wherein L 10 is —C(O)NH—*.

9. The compound or salt of claim 1 , wherein R 5 is an optionally substituted 8- to 12-membered bicyclic carbocycle.

10. The compound or salt of claim 1 , wherein R 5 is an 8- to 12-membered bicyclic carbocycle optionally substituted with one or more substituents independently selected from —OR 10 , —N(R 10 ) 2 , and ═O.

11. The compound or salt of claim 10 , wherein R 5 is an optionally substituted indane, or optionally substituted tetrahydronaphthalene.

12. The compound or salt of claim 1 , wherein R 5 is selected from an optionally substituted fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle.

13. The compound or salt of claim 12 , wherein R 5 is an optionally substituted fused 5-5, fused 5-6, or fused 6-6 bicyclic heterocycle with one or more substituents independently selected from —C(O)OR 10 , —N(R 10 ) 2 , —OR 10 , and optionally substituted C 1-10 alkyl.

14. The compound or salt of claim 1 , wherein R 5 is an optionally substituted fused 6-6 bicyclic heterocycle.

15. The compound or salt of claim 14 , wherein the fused 6-6 bicyclic heterocycle is an optionally substituted pyridine-piperidine.

16. The compound or salt of claim 15 , wherein L 10 is bound to a carbon atom of the pyridine of the fused pyridine-piperidine.

17. The compound or salt of claim 1 , wherein R 5 is selected from tetrahydroquinoline, tetrahydroisoquinoline, tetrahydronaphthyridine, cyclopentapyridine, and dihydrobenzoxaborole, any one of which is optionally substituted.

18. The compound or salt of claim 17 , wherein substituents on R 5 are independently selected at each occurrence from:

halogen, —OR 10 , —SR 10 , —C(O)N(R 10 ) 2 , —N(R 10 )C(O)R 10 , —N(R 10 ) 2 , —C(O)R 10 , —C(O)OR 10 , —OC(O)R 10 , —NO 2 , ═O, and —CN; and

C 1-10 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 10 , —SR 10 , —N(R 10 ) 2 , —C(O)R 10 , —C(O)OR 10 , —NO 2 , ═O, and —CN.

19. The compound or salt of claim 1 , wherein R 5 is not substituted.

20. The compound or salt of claim 1 , wherein L 2 is —C(O)—.

21. The compound or salt of claim 1 , wherein R 4 is —N(R 10 ) 2 .

22. The compound or salt of claim 21 , wherein R 10 of —N(R 10 ) 2 is independently selected at each occurrence from optionally substituted C 1-6 alkyl.

23. The compound or salt of claim 22 , wherein -L 2 -R 4 is

24. The compound or salt of claim 1 , wherein the compound is selected from:

and

a salt of any one thereof.

25. The compound or salt of claim 1 , wherein

L 10 is —C(O)N(H)—*,

L 2 is —C(O)—,

R 1 and R 2 are hydrogen;

R 4 is —N(R 10 ) 2 , wherein R 10 of —N(R 10 ) 2 is independently selected at each occurrence from optionally substituted C 1-6 alkyl; and

R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are independently selected from hydrogen.

26. The compound or salt of claim 25 , wherein R 5 is an optionally substituted 8- to 12-membered bicyclic carbocycle.

27. The compound or salt of claim 25 , wherein R 5 is selected from an optionally substituted fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle.

28. The compound or salt of claim 1 , wherein the compound is further covalently bound to a linker, L 3 .

29. The compound or salt of claim 28 , wherein L 3 is attached, valence permitting, to a substitutable nitrogen atom of the compound represented by the structure of Formula (IIB).

30. The compound or salt of claim 28 , wherein L 3 is a noncleavable linker.

31. The compound or salt of claim 28 , wherein L 3 is a cleavable linker.

32. The compound or salt of claim 31 , wherein L 3 is cleavable by a lysosomal enzyme.

33. The compound or salt of claim 28 , wherein L 3 is represented by the formula:

wherein:

L 4 represents the C-terminus of the peptide and L 5 is selected from a bond, alkylene and heteroalkylene, wherein L 5 is optionally substituted with one or more groups independently selected from R 32 , and RX is a reactive moiety; and

R 32 is independently selected at each occurrence from halogen, —OH, —CN, —O-alkyl, —SH, ═O, ═S, —NH 2 , —NO 2 ; and C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —O— alkyl, —SH, ═O, ═S, —NH 2 , and —NO 2 .

34. The compound or salt of claim 33 , wherein RX comprises a maleimide.

35. The compound or salt of claim 33 , wherein the peptide of L 3 comprises Val-Cit or Val-Ala.

36. The compound or salt of claim 28 , wherein L 3 is represented by the formula:

wherein RX comprises a reactive moiety, and n=0-9.

37. The compound or salt of claim 28 , wherein L 3 is further covalently bound to an antibody construct.

38. The compound or salt of claim 37 , wherein L 3 is attached to the antibody construct at a lysine or cysteine residue.

39. A pharmaceutical composition comprising the compound or salt of claim 1 and at least one pharmaceutically acceptable excipient.

40. A method of treating cancer, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 39 .

41. A method of preparing an antibody conjugate of the formula

wherein Antibody is an antibody construct and D is a compound or salt of claim 1 , wherein L 3 -D is contacted with an antibody construct.