Pyrrolobenzodiazepines and targeted conjugates

1. A compound with the formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

R 2 is of formula III:

where A is a C 5-7 aryl group, X is selected from the group consisting of:

and NHR N , wherein R N is selected from the group consisting of H and C 1-4 alkyl and either

(i) Q 1 is a single bond, and Q 2 is selected from a single bond and —Z—(CH 2 ) n —, where Z is selected from the group consisting of a single bond, O, S and NH and n is from 1 to 3; or

(ii) Q 1 is —CH═CH—, and Q 2 is a single bond;

R 12 is a C 5-10 aryl group, substituted by a group selected from the group consisting of OH, CO 2 H, and CO 2 R O , where R O is selected from C 1-4 alkyl;

R 6 and R 9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;

R 7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, 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;

either:

(a) R 10 is H, and R 11 is OH, OR A , where R A is C 1-4 alkyl;

(b) R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound, or

(c) R 10 is H and R 11 is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;

R″ is a C 3-12 alkylene group, which chain is optionally interrupted by one or more heteroatoms selected from the group consisting of O, S, and NR N2 where R N2 is H or C 1-4 alkyl, and/or an aromatic ring;

Y and Y′ are selected from the group consisting of O, S, and NH;

R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively and R 10′ and R 11′ are the same as R 10 and R 11 , wherein if R 11 and R 11′ are SO z M, M may represent a divalent pharmaceutically acceptable cation.

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 9 is H and R 6 is selected from H and halo.

5. A compound according to claim 1 , wherein A is phenyl and X is NH 2 .

6. A compound according to claim 1 , wherein Q 1 is a single bond.

7. A compound according to claim 6 , wherein Q 2 is a single bond.

8. A compound according to claim 6 , wherein Q 2 is —Z—(CH 2 ) n —, Z is O or S and n is 1 or 2.

9. A compound according to claim 1 , wherein R 12 is phenyl.

10. A compound according to claim 1 , wherein R 12 is selected from the group consisting of: 4-hydroxy-phenyl, 3-hydroxyphenyl, 4-carboxy-phenyl, 3-carboxy-phenyl, 4-methyloxycarbonyl-phenyl, 3-methyloxycarbonyl-phenyl, 4-ethyloxycarbonyl-phenyl and 4-ethyloxycarbonyl-phenyl.

11. A compound according to claim 1 , wherein R 10 and R 11 form a nitrogen-carbon double bond.

12. A compound according to claim 1 , wherein R 6′ , R 7′ , R 9′ , R 10′ , R 11′ and Y′ are the same as R 6 , R 7 , R 9 , R 10 , R 11 and Y respectively.

13. A compound according to claim 1 , selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

14. A compound of formula II:

wherein:

R 2 is of formula III:

wherein A is a C 5-7 aryl group, X is selected from the group consisting of:

and NHR N , wherein R N is selected from the group consisting of H and C 1-4 alkyl and either

(i) Q 1 is a single bond, and Q 2 is selected from a single bond and —Z—(CH 2 ) n —, where Z is selected from the group consisting of a single bond, O, S and NH and n is from 1 to 3; or

(ii) Q 1 is —CH═CH—, and Q 2 is a single bond;

R 12 is a C 5-10 aryl group, substituted by a group selected from the group consisting of OH, CO 2 H, and CO 2 R O , where R O is selected from C 1-4 alkyl;

R 6 and R 9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;

R 7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, 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″ is a C 3-12 alkylene group, which chain is optionally interrupted by one or more heteroatoms selected from the group consisting of O, S, and NR N2 , where R N2 is H or C 1-4 alkyl, and/or an aromatic ring;

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;

and either:

(a) R 10 is carbamate nitrogen protecting group, and R 11 is O-Prot O , wherein Prot O is an oxygen protecting group; or

(b) R 10 is a hemi-aminal nitrogen protecting group and R 11 is an oxo group;

and R 10′ and R 11′ are the same as R 10 and R 11 .

15. A compound according to claim 14 , wherein R 10 is Troc and R 11 is OTBS.

16. A compound according to claim 14 , wherein R 11 is oxo and R 10 is SEM.

17. A Conjugate having formula IV:

L-(LU-D) p   (IV)

or a pharmaceutically acceptable salt thereof;

wherein L is a Ligand unit selected from an antibody and an antigen-binding fragment of an antibody,

LU is a Linker unit is -A 1 -L 1 -, wherein A 1 is selected from the group consisting of:

where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, and n is 0 to 6;

where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, and n is 0 to 6;

where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1, and m is 0 to 30; and

where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1, and m is 0 to 30; and

L 1 comprises an amino acid sequence which is cleavable by the action of an enzyme,

p is 1 to 20; and

D is a Drug unit which is a PBD dimer with the formula I:

wherein:

R 2 is of formula III:

wherein A is a C 5-7 aryl group, where X is selected from the group consisting of

and R N is selected from the group comprising consisting of H and C 1-4 alkyl, and the asterisk indicates the point of attachment to Q 2 and the wavy line indicates the point of attachment to the Linker Unit and either

(i) Q 1 is a single bond, and Q 2 is selected from a single bond and —Z—(CH 2 ) n —, where Z is selected from the group consisting of a single bond, O, S and NH and n is from 1 to 3; or

(ii) Q 1 is —CH═CH—, and Q 2 is a single bond;

R 12 is a C 5-10 aryl group, substituted by a group selected from the group consisting of OH, CO 2 H, and CO 2 R O , where R O is selected from C 1-4 alkyl;

R 6 and R 9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;

R 7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, 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;

either:

(a) R 10 is H, and R 11 is OH, OR A , wherein R A is C 1-4 alkyl, or

(b) R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound, or

(c) R 10 is H and R 11 is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;

R″ is a C 3-12 alkylene group, which chain is optionally interrupted by one or more heteroatom selected from the group consisting of O, S, and NR N2 , where R N2 is H or C 1-4 alkyl, and/or an aromatic ring;

Y and Y′ are selected from the group consisting of O, S, and NH;

R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively and R 10′ and R 11′ are the same as R 10 and R 11 , wherein if R 11 and R 11′ are SO z M, M may represent a divalent pharmaceutically acceptable cation, wherein LU is connected to D via the X substituent of R 2 .

18. The Conjugate of claim 17 , wherein A 1 is from:

where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, and n is 0 to 6.

19. The Conjugate of claim 17 , wherein L 1 comprises an amino acid sequence which is a dipeptide, which may be selected from the group consisting of valine-alanine, valine-citrulline and phenyalanine-lysine.

20. A drug linker of formula V:

LU-D  (V)

or a pharmaceutically acceptable salt thereof, wherein LU is a Linker unit which is G 1 -L 1 , wherein G 1 is selected from the group consisting of:

where the asterisk indicates the point of attachment to L 1 and n is 0 to 6;

where the asterisk indicates the point of attachment to L 1 and n is 0 to 6;

where the asterisk indicates the point of attachment to L 1 , n is 0 or 1, and m is 0 to 30; and

where the asterisk indicates the point of attachment to L 1 , n is 0 or 1, and m is 0 to 30;

L 1 comprises an amino acid sequence which is cleavable by the action of an enzyme,

and D is a Drug unit which is a PBD dimer with the formula I:

wherein:

R 2 is of formula III:

wherein A is a C 5-7 aryl group, where X is selected from the group consisting of

and R N is selected from the group consisting of H and C 1-4 alkyl, and the asterisk indicates the point of attachment to Q 2 and the wavy line indicates the point of attachment to the Linker Unit and either

(i) Q 1 is a single bond, and Q 2 is selected from a single bond and —Z—(CH 2 ) n —, where Z is selected from the group consisting of a single bond, O, S and NH and n is from 1 to 3; or

(ii) Q 1 is —CH═CH—, and Q 2 is a single bond;

R 12 is a C 5-10 aryl group, substituted by a group selected from the group consisting of OH, CO 2 H, and CO 2 R O , where R O is selected from C 1-4 alkyl;

R 6 and R 9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;

R 7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, 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;

either:

(a) R 10 is H, and R 11 is OH, OR A , wherein R A is C 1-4 alkyl, or

(b) R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound, or

(c) R 10 is H and R 11 is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;

R″ is a C 3-12 alkylene group, which chain is optionally interrupted by one or more heteroatoms selected from the group consisting of O, S, and NR N2 , where R N2 is H or C 1-4 alkyl, and/or an aromatic ring;

Y and Y′ are selected from the group consisting of O, S, or and NH;

R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively and R 10′ and R 11′ are the same as R 10 and R 11 , wherein if R 11 and R 11′ are SO z M, M may represent a divalent pharmaceutically acceptable cation, wherein LU is connected to D via the X substituent of R 2 .

21. A method treating a proliferative disease comprising administering to a subject in need of treatment a therapeutically-effective amount of a Conjugate of claim 17 , wherein the proliferative disease treated is selected from kidney cancer and AML.

22. The Conjugate of claim 19 , wherein Ll comprises an amino acid sequence which is selected from the group consisting of valine-alanine, valine-citrulline and phenyalanine-lysine.