초록

A compound of formula I: or a pharmaceutically acceptable salt or solvate thereof.

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1. A compound of formula III: or a pharmaceutically acceptable salt thereof,wherein:R22 is selected from: (a) formula IVa:  where A is a phenyl group, and either (i) Q1 is a single bond, and Q2 is selected from a single bond and —Z—(CH2)n—, where Z is selected from a single bond, O, S and NH and n i

1. A compound of formula III: or a pharmaceutically acceptable salt thereof,wherein:R22 is selected from: (a) formula IVa:  where A is a phenyl group, and either (i) Q1 is a single bond, and Q2 is selected from a single bond and —Z—(CH2)n—, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or(ii) Q1 is —CH═CH—, and Q2 is a single bond;(b) formula IVb:  where RC1, RC2 and RC3 are independently selected from H and unsubstituted C1-2 alkyl;(c) formula IVc:  where Q is selected from OH, SH and NRN, and RN is selected from H, methyl and ethylX is selected from the group consisting of: OH, SH, CO2H, COH, N═C═O, NHNH2, CONHNH2,  and NHRN, wherein RN is selected from the group consisting of H and C1-4 alkyl;L4 is selected from a single bond and a group of: wherein n is 0 to 3;  wherein n is as defined above;  wherein n is as defined above; and  wherein n is as defined above, E is O, S or NR, D is N, CH, or CR, and F is N, CH, or CR;L3 is:  where X is such that L3 is an amino-acid residue, a dipeptide residue or a tripeptide residue;Prot is selected from Fmoc (fluorenylmethyloxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl) and Boc (t-butoxycarbonyl);R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR′, nitro, Me3Sn and halo;R6′, R7′, R9′ are selected from the same groups as R6, R7 and R9 respectively;when there is a double bond present between C2′ and C3′, R12 is selected from the group consisting of: (ia) phenyl, naphthyl or azulenyl group or C5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C1-7 alkoxy, C3-20 heterocyclyloxy, C5-20 aryloxy, carboxy, —C(═O)OC1-7alkyl, —C(═O)OC3-20heterocyclyl, —C(═O)OC5-20aryl, C1-7 alkyl, C3-7 heterocyclyl; and bis-oxy-C1-3 alkylene;(ib) C1-5 saturated aliphatic alkyl;(ic) C3-6 saturated cycloalkyl;  wherein each of R21, R22 and R23 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R12 group is no more than 5;  wherein one of R25a and R25b 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 R24 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 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′,R12 is H or where R26a and R26b are independently selected form H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R26a and R26b is H, the other is selected from nitrile and a C1-4 alkyl ester; R″ is a C3-12 alkylene group, which chain is interrupted by one or more aromatic rings selected from benzene or pyridine;Y and Y′ are selected from O, S, or NH;either: (A) R20 is H or Me and R21a and R21b are both H or together form ═O and either: (i) R10 is H, R11a is H and R11b is OH or ORA, where RA is C1-4 alkyl; or(ii) R10 and R11b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R11a is H; or(iii) R10 is H, R11a is H and R11b is SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; or(B) R10 is H or Me and R11a and R11b are both H or together form ═O and either: (i) R20 is H, R21a is H and R21b is OH or ORA, where RA is C1-4 alkyl; or(ii) R20 and R21b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R11a is H; or(iii) R20 is H, R21a is H and R21b is SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;wherein the C3-20 heterocyclyloxy group and —C(═O)OC3-20heterocyclyl group independently contain 1 to 10 ring heteroatoms selected from N, O and S;the C3-7 heterocyclyl group contains 1 to 4 ring heteroatoms selected from N, O and S. 2. A Conjugate having formula V: L-(LU-D)p  (V)wherein L is an antibody or antibody fragment,LU is a Linker unit,p is 1 to 20; andD is a Drug unit which is a PBD dimer according to formula I: or a pharmaceutically acceptable salt thereof,wherein:R2 is of formula IIa, formula IIb or formula IIc:  where A is a phenyl group, and either (i) Q1 is a single bond, and Q2 is selected from a single bond and —Z—(CH2)n—, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or(ii) Q1 is —CH═CH—, and Q2 is a single bond; where;RC1, RC2 and RC3 are independently selected from H and unsubstituted C1-2 alkyl; where Q is selected from OH, SH and NRN, and RN is selected from H, methyl and ethyl X is selected from the group consisting of: OH, SH, CO2H, COH, N═C═O, NHNH2, CONHNH2,  and NHRN, wherein RN is selected from the group consisting of H and C1-4 alkyl;and either:when there is a double bond present between C2′ and C3′, R12 is selected from the group consisting of: (ia) phenyl, naphthyl or azulenyl group or C5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C1-7 alkoxy, C3-20 heterocyclyloxy, C5-20 aryloxy, carboxy, —C(═O)OC1-7alkyl, —C(═)OC3-20heterocycyl, —C(═O)OC5-20aryl, C1-7 alkyl, C3-7 heterocyclyl; and bis-oxy-C1-3 alkylene;(ib) C1-5 saturated aliphatic alkyl;(ic) C3-6 saturated cycloalkyl;  wherein each of R21, R22 and R23 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl, and cyclopropyl, where the total number of carbon atoms in the R12 group is no more than 5;  wherein one of R25a and R25b 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 R24 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 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′,R12 is H or where R26a and R26b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R26a and R26b is H, the other is selected from nitrile and a C1-4 alkyl ester; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;where R and R′ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl with 1 to 10 ring heteroatoms selected from N, O, and S, and C5-20 aryl groups;R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR′, nitro, Me3Sn and halo;R″ is a C3-12 alkylene group, which chain is interrupted by one or more aromatic rings selected from benzene or pyridine;Y and Y′ are selected from O, S, or NH;R6′, R7′, R9′ are selected from the same groups as R6, R7 and R9 respectively;either: (A) R20 is H or Me and R21a and R21b are both H or together form ═O and either: (i) R10 is H, R11a is H and R11b is OH or ORA, where RA is C1-4 alkyl; or(ii) R10 and R11b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R11a is H; or(iii) R10 is H, R11a is H and R11b is SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; or(B) R10 is H or Me and R11a and R11b are both H or together form ═O and either: (i) R20 is H, R21a is H and R21b is OH or ORA, where RA is C1-4 alkyl; or(ii) R20 and R21b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R11a is H; or(iii) R20 is H, R21a is H and R21b is SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;wherein LU is connected to D via the X substituent of R2 wherein the Linker unit (LU) has the formula (Va): -A1-L3-L4-,  (Va)wherein:-A1- is a Stretcher unit,p is from 1-20;L4 is selected from a single bond and a group of: wherein n is 0 to 3;  wherein n is as defined above;  wherein n is as defined above; and  wherein n is as defined above, E is O, S or NR, D is N, CH, or CR, and F is N, CH, or CR;L3 is:  where X is such that L3 is an amino-acid residue, a dipeptide residue or a tripeptide residue; wherein -A1- is selected from where the asterisk indicates the point of attachment to L3, 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 L3, 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 L3, the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1, and m is 0 to 30; or where the asterisk indicates the point of attachment to L3, the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1, and m is 0 to 30; wherein the C3-20 heterocyclyloxy group and —C(═O)OC3-20heterocyclyl group independently contain 1 to 10 ring heteroatoms selected from N, O and S;the C3-7 heterocyclyl group contains 1 to 4 ring heteroatoms selected from N, O and S. 3. The Conjugate of claim 2, wherein the Linker unit (LU) has formula (Va), L3 is a dipeptide, L4 is a single bond, and wherein A1 is selected from: where the asterisk indicates the point of attachment to L3, 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 L3, 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 L3, the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1, and m is 0 to 30; or where the asterisk indicates the point of attachment to L3, the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1, and m is 0 to 30. 4. A drug linker of formula VI: LU-D  (VI)or a pharmaceutically acceptable salt thereof, wherein LU is a Linker unit and where D is a Drug unit which is a PBD dimer according to formula I: wherein:R2 is of formula IIa, formula IIb or formula IIc:  where A is a phenyl group, and either (i) Q1 is a single bond, and Q2 is selected from a single bond and —Z—(CH2)n—, where Z is selected from a single bond O, S and NH and n is from 1 to 3; or(ii) Q1 is —CH═CH—, and Q2 is a single bond; where;RC1, RC2 and RC3 are independently selected from H and unsubstituted C1-2 alkyl;where X is selected from *—O—q, *—S—q, *—CO2—q, *—CO—q, *—NH(C═O)—q, *—NHNH—q, *—CONHNH—q,  wherein RN is selected from the group consisting of H and C1-4 alkyl, and the asterix indicates the point of attachment to the remainder of the Drug unit and the wavy line or q indicates the point of attachment to the Linker Unit;and either:when there is a double bond present between C2′ and C3′, R12 is selected from the group consisting of: (ia) phenyl, naphthyl or azulenyl group or C5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C1-7 alkoxy, C3-20 heterocyclyloxy, C5-20 aryloxy, carboxy, —C(═O)OC1-7alkyl, —C(═O)OC3-20heterocyclyl, —C(═O)OC5-20aryl, C1-7 alkyl, C3-7 heterocyclyl; and bis-oxy-C1-3 alkylene;(ib) C1-5 saturated aliphatic alkyl;(ic) C3-6 saturated cycloalkyl;  wherein each of R21, R22 and R23 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R12 group is no more than 5;  wherein one of R25a and R25b 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 R24 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which is 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′,R12 is H or  where R26a and R26b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R26a and R26b is H, the other is selected from nitrile and a C1-4 alkyl ester; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo; wherein R and R′ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl with 1 to 10 ring heteroatoms selected from N, O and S and C5-20 aryl groups;R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR′, nitro Me3Sn and halo;R″ is a C3-12 alkylene group, which chain is interrupted by one or more aromatic rings selected from benzene or pyridine;Y and Y′ are selected from O, S, or NH;R6′, R7′, R9′ are selected from the same groups as R6, R7, and R9 respectively;either: (A) R20 is H or Me and R21a and R21b are both H or together form ═O and either: (i) R10 is H, R11a is H and R11b is OH or ORA, where RA is C1-4 alkyl; or(ii) R10 and R11b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R11a is H; or(iii) R10 is H, R11a is H and R11b is SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; or(B) R10 is H or Me and R11a and R11b are both H or together form ═O and either: (i) R20 is H, R21a is H and R21b is OH or ORA, where RA is C1-4 alkyl; or(ii) R20 and R21b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R11a is H; or(iii) R20 is H, R21a is H and R21b is SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;wherein the C3-20 heterocyclyloxy group and —C(═O)OC3-20heterocyclyl group independently contain 1 to 10 ring heteroatoms selected from N, O and S;the C3-7 heterocyclyl group contains 1 to 4 ring heteroatoms selected from N, O and S;wherein the Linker unit (LU) has the formula (Va): G1-L3-L4-,  (Va)wherein:-G1- is a Stretcher unit,p is from 1-20;L4 is selected from a single bond and a group of: wherein n is 0 to 3;  wherein n is as defined above;  wherein n is as defined above; and  wherein n is as defined above E is O, S or NR, D is N, CH, or CR, and F is N, CH, or CR;L3 is:  where X is such that L3 is an amino-acid residue, a dipeptide residue or a tripeptide residue;wherein -G1- is selected from where the asterisk indicates the point of attachment to L3 and n is 0 to 6; where the asterisk indicates the point of attachment to L3 and n is 0 to 6; where the asterisk indicates the point of attachment to L3, n is 0 or 1, and m is 0 to 30; or where the asterisk indicates the point of attachment to L3, n is 0 or 1 and m is 0 to 30. 5. A conjugate according to claim 2, wherein R7 is a C1-4 alkyloxy group. 6. A conjugate according to claim 2, wherein Y is O and R″ is C3-7 alkylene which chain is interrupted by one or more aromatic rings selected from benzene or pyridine. 7. A conjugate according to claim 2, wherein R6 and R9 are H. 8. A conjugate according to claim 2, wherein there is a double bond between C2′ and C3′, and R12 is: (a) a C5-7 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; or(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 R24 is selected from H and methyl. 9. A conjugate according to claim 2, wherein there is a single bond between C2′ and C3′, R12 is and: (a) R26a and R26b are both H; or(b) R26a and R26b are both methyl; or(c) one of R26a and R26b is H, and the other is selected from C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted. 10. A conjugate according to claim 2, wherein R2 is of formula IIa, and A is phenyl, Q1 is a single bond, and Q2 is a single bond. 11. A compound according to claim 2, wherein R2 is of formula IIb, and RC1, RC2 and RC3 are all H. 12. A conjugate according to claim 10, wherein X is NH2. 13. A conjugate according to claim 2, wherein R2 is of formula IIc, and Q is NRN, wherein RN is H or methyl. 14. A conjugate according to claim 2, wherein R6′, R7′, R9′ and Y′ are the same as R6, R7, R9, and Y respectively. 15. A conjugate according to claim 2, wherein R20 is H or Me and R21a and R21b are both H. 16. A conjugate according to claim 2, wherein R20 is H or Me and R21a and R21b together form ═O. 17. A conjugate according to claim 15, wherein R10 and R11b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R11a is H. 18. A conjugate according to claim 2, wherein R10 is H or Me and R11a and R11b are both H. 19. A conjugate according to claim 2, wherein R10 is H or Me and R11a and R11b together form ═O. 20. A conjugate according to claim 18, wherein R20 and R21b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R11a is H.