Pyrrolobenzodiazepine dimer prodrug and ligand-linker conjugate compound of the same
The present invention relates to a pyrrolobenzodiazepine dimer prodrug and a ligand-linker conjugate compound thereof, a composition containing these, and therapeutic use thereof particularly as an anticancer drug. The stability of the compounds themselves and the stability thereof in plasma are excellent and the compounds are advantageous in terms of manifestation of toxicity, and thus the compounds are industrially useful in that it is possible to target proliferative diseases such as cancer, to perform a specific treatment, to maximize the drug efficacy, and to minimize the occurrence of side effects.
1. A compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof:
wherein
R 1 and R 1 ′ are each independently selected from H, OH, ═O, ═CH 2 , CN, R m , OR m , =CH—R m′ ═C(R m′ ) 2 , O—SO 2 —R m , CO 2 R m , COR m , halo, and dihalo;
R m′ is selected from R m , CO 2 R m , COR m , CHO, CO 2 H, and halo;
R m is selected from substituted or unsubstituted C 1-12 alkyl, substituted or unsubstituted C 2-12 alkenyl, substituted or unsubstituted C 2-12 alkynyl, substituted or unsubstituted C 5-20 aryl, substituted or unsubstituted C 3-6 heteroaryl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocyclyl, substituted or unsubstituted 3- to 7-membered heterocycloalkyl, and substituted or unsubstituted 5- to 7-membered heteroaryl, wherein when the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocycloalkyl, or 5- to 7-membered heteroaryl is substituted, wherein the respective hydrogen atoms in the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocycloalkyl, or 5- to 7-membered heteroaryl are each independently substituted with any one or more selected from methoxy, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 5-20 aryl, C 5-20 heteroaryl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocycloalkyl, and 5- to 7-membered heteroaryl;
R 2 , R 3 , R 5 , R 2 ′, R 3 ′, and R 5 ′ are each independently selected from H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m R m′ , NO 2 , Me 3 Sn, and halo;
R 4 and R 4 ′ are each independently selected from H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m R m′ , NO 2 , Me 3 Sn, halo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocycloalkyl, substituted or unsubstituted C 5-12 aryl, substituted or unsubstituted 5- to 7-membered heteroaryl, —CN, —NCO, —OR n , —OC(O)R n , —OC(O)NR n R n′ , —OS(O)R n , —OS(O) 2 R n , —SR n , —S(O)R n , —S(O) 2 R n , —S(O)NR n R n′ , —S(O) 2 NR n R n′ , —OS(O)NR n R n′ , —OS(O) 2 NR n R n′ , —NR n R n′ , —NR n C(O)R o , —NR n C(O)OR o , —NR n C(O)NR o R o′ , —NR n S(O)R o , —NR n S(O) 2 R o , —NR n S(O)NR o R o′ , —NR n S(O) 2 NR o R o′ , —C(O)R n , —C(O)OR n , and —C(O)NR n R n′ , wherein the hydrogen atoms in the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 5-12 aryl, and 5- to 7-membered heteroaryl may be each independently substituted with the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 5-12 aryl, 5- to 7-membered heteroaryl, —OR p , —OC(O)R p , —OC(O)NR p R p′ , —OS(O)R p , —OS(O) 2 R p , —SR p , —S(O)R p , —S(O) 2 R p , —S(O)NR p R p′ , —S(O) 2 NR p R p′ , —OS(O)NR p R p′ , —OS(O) 2 NR p R p′ , —NR p R p′ , —NR p C(O)R q , —NR p C(O)OR q , —NR p C(O)NR q H, —NR p S(O)R q , —NR p S(O) 2 R q , —NR p S(O)NR q H, —NR p S(O) 2 NR q H, —C(O)R p , —C(O)OR p , or —C(O)NR p R p when the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 5-12 aryl, and 5- to 7-membered heteroaryl are substituted;
R n , R n′ , R o , R o′ R p , R p′ , and R q are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, and 5- to 7-membered heteroaryl;
X′ is selected from —C(O)O—, —S(O)O—, —C(O)—, —C(O)NR—, —S(O) 2 NR—, —P(O)R′NR—, —S(O)NR—, and —PO 2 NR—;
Xa′ is a bond or substituted or unsubstituted C 1-6 alkylene, wherein C 1-6 alkylene is substituted with C 1-8 alkyl, or C 3-8 cycloalkyl when being substituted;
R and R′ each independently denote H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted C 1-8 alkylthio, substituted or unsubstituted C 3-20 heteroaryl, substituted or unsubstituted C 5-20 aryl, or mono- or di-C 1-8 alkylamino, wherein the C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, and C 5-20 aryl are substituted with a substituent selected from OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NHNH 2 , halo, C 1-6 alkyl, C 1-6 alkoxy, and C 6-12 aryl when being substituted;
Y and Y′ are each independently selected from O, S, and N(H);
R 6 is a substituted or unsubstituted saturated or unsaturated C 3-12 hydrocarbon chain, wherein the chain may be interrupted by one or more heteroatoms, NMe, or a substituted or unsubstituted aromatic ring, the chain or aromatic ring may be substituted with —NH, —NR m , —NHC(O)R m , —NHC(O)CH 2 —[OCH 2 CH 2 ] n —R, or —[CH 2 CH 2 O] n —R at any one or more positions of hydrogen atoms on the chain or aromatic ring or unsubstituted, wherein R m and R are each as defined for R m and R above, and n is an integer from 1 to 12;
R 7 and R 7 ′ are each independently H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 7-membered heteroaryl, —OR r , —OC(O)R r , —OC(O)NR r R r′ , —OS(O)R r , —OS(O) 2 R r , —SR r , —S(O)R r , —S(O) 2 R r , —S(O)NR r R r′ , —S(O) 2 NR r R r′ , —OS(O)NR r R r′ , —OS(O) 2 NR r R r′ , —NR r R r′ , —NR r C(O)R s , —NRC(O)OR s , —NRC(O)NR s R s , —NR s (O)R s , —NR r S(O) 2 R s , —NR s (O)NR s R s′ , —NR r S(O) 2 NR s R s , —C(O)R r , —C(O)OR s , or —C(O)NR r R r′ , wherein the hydrogen atoms in the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, and 5- to 7-membered heteroaryl are each independently substituted with C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, 5- to 7-membered heteroaryl, —OR t , —OC(O)R t , —OC(O)NR t R t′ , —OS(O)R t , —OS(O) 2 R t , —SR t , —S(O)R t , —S(O) 2 R t , —S(O)NR t R t′ , —S(O) 2 NR t R t′ , —OS(O)NR t R t′ , —OS(O) 2 NR t R t′ , —NR t R t′ , —NR t C(O)R u , —NR t C(O)OR u , —NR t C(O)NR u R u′ , —NR t S(O)R u , —NR t S(O) 2 R u , —NR t S(O)NR u R u′ , —NR t S(O) 2 NR u R u′ , —C(O)R t , —C(O)OR t , or —C(O)NR t R t′ when the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10 aryl, and 5- to 7-membered heteroaryl are substituted;
R r , R r′ , R s , R s′ , R t , R t′ , R u , and R u′ are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-13 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 5-10 aryl, and 5- to 7-membered heteroaryl;
G′ denotes a glucuronide group or a galactoside group;
each Z′ is independently selected from H, C 1-8 alkyl, halo, NO 2 , CN,
R 9 , R 10 , and R 16 are each independently selected from H, C 1-8 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, and methyloxyethyl;
n is an integer from 1 to 3;
W denotes —C(O)—, —C(O)NR″—, —C(O)O—, —S(O) 2 NR″—, —P(O)R′″NR″—, —S(O)NR″—, or —PO 2 NR″; and
R″ and R′″ each independently denote H, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, C 3-20 heteroaryl, or C 6-20 aryl.
2. The compound of claim 1 , wherein the compound has a structure represented by Formula Ia, Ib, or a pharmaceutically acceptable salt thereof:
3. The compound of claim 2 , wherein R 1 ′ is C 3-6 cycloalkyl.
4. The compound of claim 2 , wherein R 1 ′ is substituted or unsubstituted phenyl.
5. The compound of claim 2 , wherein R 1 ′ is 5- to 7-membered heteroaryl.
6. The compound of claim 2 , wherein R 1 ′ is C 1-12 alkyl.
7. The compound of claim 2 , wherein R 1 ′ is C 1-12 alkenyl.
8. The compound of claim 2 , wherein R 1 is substituted or unsubstituted phenyl.
9. The compound of claim 2 , wherein R 1 is OH.
10. The compound of claim 2 , wherein R 1 is C 1-12 alkenyl.
11. The compound of claim 2 , wherein R 1 is C 1-12 alkyl.
12. The compound of claim 2 , wherein R 2 and R 2 ′ are each H.
13. The compound of claim 2 , wherein R 3 and R 3 ′ are each H.
14. The compound of claim 2 , wherein R 4 and R 4 ′ are each H.
15. The compound of claim 2 , wherein R 5 and R 5 ′ are each H.
16. The compound of claim 2 , wherein R 6 is an unsubstituted saturated C 3-12 hydrocarbon chain.
17. The compound of claim 2 , wherein R 7 and R 7 ′ are each H.
18. The compound of claim 2 , wherein X′ is —C(O)O—.
19. The compound of claim 2 , wherein Xa′ is unsubstituted C 1-6 alkylene.
20. The compound of claim 2 , wherein G′ is a glucuronide group.
21. The compound of claim 2 , wherein G′ is a galactoside group.
22. The compound of claim 2 , wherein Z′ is
23. The compound of claim 22 , wherein R 9 is H.
24. The compound of claim 22 , wherein R 16 is methyloxyethyl.
25. The compound of claim 22 , wherein n is 1.
26. The compound of claim 2 , wherein:
R 1 ′ is C 3-6 cycloalkyl, substituted or unsubstituted phenyl, 5- to 7-membered heteroaryl, C 1-12 alkyl, or C 1-12 alkenyl;
R 1 is substituted or unsubstituted phenyl, OH, C 1-12 alkenyl, or C 1-12 alkyl;
R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 7 , R 7 ′, and R 9 are each H;
R 6 is an unsubstituted saturated C 3-12 hydrocarbon chain;
X′ is —C(O)O—;
Xa′ is unsubstituted C 1-6 alkylene;
Z′ is
R 16 is methyloxyethyl; and
n is 1.
27. The compound of claim 1 , wherein the compound is:
or
a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
29. A method of treating cancer in a subject in need thereof comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to the subject.