Pyrrolobenzodiazepines and conjugates thereof
View Patent ↗A compound with the formula I: and salts and solvates thereof.
1. A compound with the formula I:
or a pharmaceutically acceptable salt thereof, wherein:
when there is a double bond present between C2 and C3, R 2 is selected from the group consisting of:
(ia) phenyl, naphthyl, azulenyl, or C 5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C 1-7 alkoxy, C 3-20 heterocyclyloxy, C 5-20 aryloxy, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene;
(ib) C 1-5 saturated aliphatic alkyl;
(ic) C 3-6 saturated cycloalkyl;
wherein each of R 13a , R 13b and R 13c are independently selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 2 group is no more than 5;
wherein one of R 15a and R 15b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
where R 14 is selected from: H; C 1-3 saturated alkyl; C 2-3 alkenyl; C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
when there is a single bond present between C2 and C3,
R 2 is
where R 16a and R 16b are independently selected from H, F, C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 16a and R 16b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
when there is a double bond present between C2′ and C3′, R 12 is selected from the group consisting of:
(ia) phenyl, naphthyl, azulenyl or C 5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C 1-7 alkoxy, C 3-20 heterocycloxy, C 5-20 aryloxy, carboxy, ester, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene;
(ib) C 1-5 saturated aliphatic alkyl;
(ic) C 3-6 saturated cycloalkyl;
wherein each of R 21 , R 22 and R 23 are independently selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 12 group is no more than 5;
wherein one of R 25a and R 25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
where R 24 is selected from: H; C 1-3 saturated alkyl; C 2-3 alkenyl; C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
when there is a single bond present between C2′ and C3′,
R 12 is
where R 26a and R 26b are independently selected from H, F, C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 26a and R 26b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
where R and R′ are independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;
R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, nitro, Me 3 Sn and halo;
R″ is a C 3-12 alkylene group, which chain is interrupted by one or more aromatic rings selected from the group consisting of benzene and pyridine;
Y and Y′ are selected from O, S, or NH;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively;
R 20 is H or Me and R 21a and R 21b are both H or together form ═O;
R L is the group
where the asterisk indicates the point of attachment to the N10 position, G 1 is a functional group to form a connection to a cell binding agent, L 1 is a linker, L 2 is a covalent bond or together with —OC(═O)— forms a self-immolative linker, and L 1 or L 2 is a cleavable linker;
R 11b is selected from OH, OR A , where R A is C 1-4 alkyl, and SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
the heterocyclyl group in C 3-20 heterocycloxy contains 1 to 10 ring heteroatoms selected from N, O and S;
the heteroaryl group in C 5-10 heteroaryl contains 1 to 4 ring heteroatoms selected from N, O and S;
the heterocyclyl group in C 3-7 heterocyclyl contains 1 to 4 ring heteroatoms selected from N, O and S; and
the heterocyclyl group in C 3-20 heterocyclyl contains 1 to 10 ring heteroatoms selected from N, O and S.
2. A compound according to claim 1 , wherein R 7 is a C 1-4 alkyloxy group.
3. A compound according to claim 1 , wherein Y is O, and R″ is C 3-7 alkylene.
4. A compound according to claim 1 , wherein R 6 and R 9 are H.
5. A compound according to claim 1 , wherein there is a double bond between C2′ and C3′, and R 12 is:
(a) a C 5-7 aryl group, which may bear one to three substituent groups selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thiophenyl; or
(b) methyl, ethyl or propyl; or
(c) cyclopropyl;
(d) a group of formula:
wherein the total number of carbon atoms in the R12 group is no more than 4; or
(e) the group;
or
(f) a group of formula:
wherein R 24 is selected from H and methyl.
6. A compound according to claim 1 , wherein there is a single bond between C2′ and C3′, R 12 is
and:
(a) R 26a and R 26b are both H; or
(b) R 26a and R 26b are both methyl; or
(c) one of R 26a and R 26b is H, and the other is selected from C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted.
7. A compound according to claim 1 , wherein there is a double bond between C2 and C3, and R 2 is
(a) a C 5-7 aryl group, which may bears one to three substituent groups selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thiophenyl; or
(b) methyl, ethyl or propyl; or
(c) cyclopropyl; or
(d) a group of formula:
wherein the total number of carbon atoms in the R2 group is no more than 4; or
or
wherein R 14 is selected from H and methyl.
8. A compound according to claim 1 , wherein there is a single bond between C2 and C3, R 2 is
and:
(a) R 16a and R 16b are both H; or
(b) R 16a and R 16b are both methyl; or
(c) one of R 16a and R 16b is H, and the other is selected from C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted.
9. A compound according to claim 1 , wherein R 20 is H or Me and R 21a and R 21b are both H.
10. A compound according to claim 1 , wherein R 20 is H or Me and R 21a and R 21b together form ═O.
11. A compound according to claim 9 , wherein R 20 is H.
12. A compound according to claim 1 , wherein R 11b is OH.
13. A compound according to claim 1 , wherein R 11b is OR A .
14. A compound according to claim 1 , wherein R 11b is SO z M.
15. A compound according to claim 14 , wherein M is Na + and z is 3.
16. A conjugate comprising a compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, linked to a targeting agent.
17. A conjugate of formula IV:
L-(R L ′-D) p (IV)
or a pharmaceutically acceptable salt thereof, wherein L-R L ′ is the group:
where the asterisk indicates the point of attachment to the N10 position, CBA is an antibody or antibody fragment, L 1 is a linker, A is a connecting group connecting L 1 to the antibody or antibody fragment, L 2 is a covalent bond or together with —OC(═O)— forms a self-immolative linker, and L 1 or L 2 is a cleavable linker;
and D is of formula II:
where the wavy line indicates the attachment point of R L ′, when there is a double bond present between C2 and C3, R 2 is selected from the group consisting of:
(ia) phenyl, naphthyl, azulenyl or C 5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro cyano, C 1-7 alkoxy, C 3-20 heterocycloxy, C 5-20 aryloxy, C 1-7 alkyl, C 3-7 heterocyclyl, and bis-oxy-C 1-3 alkylene;
(ib) C 1-5 saturated aliphatic alkyl;
(ic) C 3-6 saturated cycloalkyl;
wherein each of R 13a , R 13b and R 13c are independently selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 2 group is no more than 5;
wherein one of R 15a and R 15b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
where R 14 is selected from: H; C 1-3 saturated alkyl; C 2-3 alkenyl; C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
when there is a single bond present between C2 and C3,
R 2 is
where R 16a and R 16b are independently selected from H, F, C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 16a and R 16b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
when there is a double bond present between C2′ and C3′, R 12 is selected from the group consisting of:
(ia) phenyl, naphthyl, azulenyl or C 5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C 1-7 alkoxy, C 3-20 heterocyclyloxy, C 5-20 aryloxy, carboxy, —C(═O)OC 1-7 alkyl, —C(═O)OC 3-20 heterocyclyl, —C(═O)O 5-20 aryl, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene;
(ib) C 1-5 saturated aliphatic alkyl;
(ic) C 3-6 saturated cycloalkyl;
wherein each of R 21 , R 22 and R 23 are independently selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 12 group is no more than 5;
wherein one of R 25a and R 25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
where R 24 is selected from: H; C 1-3 saturated alkyl; C 2-3 alkenyl; C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
when there is a single bond present between C2′ and C3′,
R 12 is
where R 26a and R 26b are independently selected from H, F, C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 26a and R 26b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
where R and R′ are independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;
wherein the heterocyclyl group in C 3-20 heterocyclyl contains 1 to 10 ring heteroatoms selected from N, O and S;
R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, nitro, Me 3 Sn and halo;
R″ is a C 3-12 alkylene group, which chain is interrupted by one or more aromatic rings selected from the group consisting of benzene and pyridine;
Y and Y′ are selected from O, S, or NH;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively;
R 20 is H or Me and R 21a and R 21b are both H or together form ═O;
R 11b is selected from OH, OR A , where R A is C 1-4 alkyl, and SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
wherein the heterocyclyl group in C 3-20 heterocycloxy contains 1 to 10 ring heteroatoms selected from N, O and S;
wherein the heteroaryl group in C 5-10 heteroaryl contains 1 to 4 ring heteroatoms selected from N, O and S;
wherein the heterocyclyl group in —C(═O)OC 3-20 heterocyclyl contains 1 to 10 ring heteroatoms selected from N, O and S; and
wherein the heterocyclyl group in C 3-7 heterocyclyl contains 1 to 4 ring heteroatoms selected from N, O and S.
18. The conjugate according to claim 17 , wherein L-R L′ is a group:
where the asterisk indicates the point of attachment to the N10 position, CBA is an antibody or antibody fragment, L 1 is a cleavable linker comprises a dipeptide and the group —X 1 —X 2 — in dipeptide, —NH—X 1 —X 2 —CO—, is selected from:
-Phe-Lys-,
-Val-Ala-,
-Val-Lys-,
-Ala-Lys-,
-Val-Cit-,
-Phe-Cit-,
-Leu-Cit-,
-Ile-Cit-,
-Phe-Arg-,
-Trp-Cit-,
A is a connecting group connecting L 1 to the cell binding agent, L 2 is a covalent bond or together with —OC(═O)— forms a self-immolative linker.
19. The conjugate according to claim 18 , wherein C(═O)O and L 2 together form the group:
where the asterisk indicates the point of attachment to the N10 position, the wavy line indicates the point of attachment to the linker L 1 , Y is NH, O, C(═O)NH or C(═O)O, and n is 0 to 3.
20. The conjugate according to claim 18 , wherein A is:
where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the cell binding agent, and n is 0 to 6; or
where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the cell binding agent, n is 0 or 1, and m is 0 to 30.
21. The conjugate according to claim 16 , wherein the cell binding agent of R 10 is an antibody or an active fragment thereof.
22. The conjugate according to claim 21 , wherein the antibody or antibody fragment is an antibody or antibody fragment for a tumour-associated antigen.
23. A compound of formula A:
and salts thereof, wherein
when there is a double bond present between C2 and C3, R 2 is selected from the group consisting of:
(ia) phenyl, naphthyl, azulenyl or C 5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro cyano, C 1-7 alkoxy, C 3-20 heterocyclyloxy, C 5-20 aryloxy, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene;
(ib) C 1-5 saturated aliphatic alkyl;
(ic) C 3-6 saturated cycloalkyl;
wherein each of R 13a , R 13b and R 13c are independently selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 2 group is no more than 5;
wherein one of R 15a and R 15b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
where R 14 is selected from: H; C 1-3 saturated alkyl; C 2-3 alkenyl; C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
when there is a single bond present between C2 and C3,
R 2 is
where R 16a and R 16b are independently selected from H, F, C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 16a and R 16b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
when there is a double bond present between C2′ and C3′, R 12 is selected from the group consisting of:
(ia) phenyl, naphthyl, azulenyl or C 5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C 1-7 alkoxy, C 3-20 heterocyclyloxy, C 5-20 aryloxy, carboxy, —C(═O)OC 1-7 alkyl, —C(═O)OC 3-20 heterocyclyl, —C(═O)OC 5-20 aryl, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene;
(ib) C 1-5 saturated aliphatic alkyl;
(ic) C 3-6 saturated cycloalkyl;
wherein each of R 21 , R 22 and R 23 are independently selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 12 group is no more than 5;
wherein one of R 25a and R 25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
where R 24 is selected from: H; C 1-3 saturated alkyl; C 2-3 alkenyl; C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
when there is a single bond present between C2′ and C3′,
R 12 is
where R 26a and R 26b are independently selected from H, F, C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 26a and R 26b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
where R and R′ are independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;
wherein the heterocyclyl group in C 3-20 heterocyclyloxy contains 1 to 10 ring heteroatoms selected from N, O and S;
R 7 is selected from H, R, OH, OR, SH, SR NH 2 , NHR, NHRR′, nitro, Me 3 Sn and halo;
R″ is a C 3-12 alkylene group, which chain is interrupted by one or more aromatic rings selected from the group consisting of benzene and pyridine;
Y and Y′ are selected from O, S, or NH;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively;
R 20 is H or Me and R 21a and R 21b are both H or together form ═O;
wherein the heterocyclyl group in C 3-20 heterocyclyloxy contains 1 to 10 ring heteroatoms selected from N, O and S;
wherein the heteroaryl group in C 5-10 heteroaryl contains 1 to 4 ring heteroatoms selected from N, O and S;
wherein the heterocyclyl group in —C(═O)OC 3-20 heterocyclyl contains 1 to 10 ring heteroatoms selected from N, O and S; and
wherein the heterocyclyl group in C 3-7 heterocyclyl contains 1 to 4 ring heteroatoms selected from N, O and S.