Benzazepine compounds, conjugates, and uses thereof
Benzazepine compounds, conjugates, and pharmaceutical compositions for use in the treatment of disease, such as cancer, are disclosed herein. The disclosed benzazepine compounds are useful, among other things, in the treating of cancer and modulating TLR8. Additionally, benzazepine compounds incorporated into a conjugate with an antibody construct are described herein.
1. A compound represented by the structure of Formula (IIA):
or a pharmaceutically acceptable salt thereof, wherein:
represents an optional double bond;
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 a bond and —C(O)—;
R 1 and R 2 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl;
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 , —S(O) 2 R 10 , C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl;
R 5 is selected from unsaturated C 4 -s 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, wherein each C 3-12 carbocycle, and 3- to 12-membered heterocycle in R 5 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; and
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, 3- to 12-membered heterocycle, and haloalkyl.
2. The compound or salt of claim 1 , wherein the compound or salt of Formula (IIA) is selected from:
and a salt of any one thereof.
3. The compound or salt of claim 1 , wherein the compound or salt is further covalently bound to a linker, L 3 .
4. The compound of salt of claim 3 , wherein L 3 is covalently bound to a substitutable nitrogen of the compound or salt.
5. The compound or salt of claim 3 , wherein L 3 is a noncleavable linker.
6. The compound or salt of claim 5 , wherein L 3 is represented by the formula:
wherein RX comprises a reactive moiety, the wavy line indicates the attachment site to the compound or salt of formula IIA and n=0-9.
7. The compound or salt of claim 6 , wherein RX comprises a leaving group or a maleimide.
8. The compound or salt of claim 5 , wherein L 3 is represented by the formula:
wherein R X comprises a reactive moiety and the wavy line indicates the attachment site to the compound or salt of formula IIA.
9. The compound or salt of claim 8 , wherein R X comprises a leaving group or a maleimide.
10. The compound or salt of claim 3 , wherein L 3 is a cleavable linker.
11. The compound or salt of claim 10 , wherein L 3 is cleavable by a lysosomal enzyme.
12. The compound or salt of claim 11 , wherein L 3 is represented by the formula:
wherein:
L 4 represents the C-terminus of the peptide, 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 , the wavy line indicates the attachment site to the compound or salt of formula IIA, 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 .
13. The compound or salt of claim 12 , wherein RX comprises a leaving group or a maleimide.
14. The compound or salt of claim 3 , wherein the compound or salt is covalently attached to an antibody construct through L 3 to form a conjugate having the following formula:
wherein Antibody is the antibody construct, L 3 is the linker and D is the compound or salt.
15. The compound or salt of claim 14 , wherein each L 3 is attached to the antibody construct at a lysine or cysteine residue.
16. A pharmaceutical composition comprising the conjugate of claim 14 and at least one pharmaceutically acceptable excipient.
17. The pharmaceutical composition of claim 16 , wherein the composition is formulated for intravenous administration.
18. A method of treating breast cancer, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 16 , wherein the antibody construct specifically binds to human HER2, TROP2 or Liv-1.
19. The method of claim 18 , wherein the antibody construct comprises pertuzumab, trastuzumab, sacituzumab, ladiratuzumab or an antigen binding fragment thereof.
20. The method of claim 19 , wherein the average drug-antibody ratio of the composition is from about 2 to about 8.
21. The compound or salt of claim 2 selected from:
and a salt of any one thereof.