Small molecule apoptosis promoters
The invention provides small molecule mimics of the Smac peptide that are dimer- or dimer-like compounds having two amide-containing domains connected by a linker. These compounds are useful to promote apoptosis. The invention includes pharmaceutical compositions comprising such compounds and methods to use them to treat conditions including cancer and autoimmune disorders.
1. A compound having the formula (1):
or a pharmaceutically acceptable salt or hydrate form thereof; and including any stereoisomeric forms thereof;
wherein each J and J′ is independently H, CN, C1-C4 alkyl or C1-C4 alkyloxycarbonyl; each Y and Y′ independently represents optionally substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these; or is ═O, OR, SR, S(O)R, SO 2 R, SO 2 NR 2 , NR 2 , OC(O)R, NRC(O)R, NRCOOR, NRC(O)NR 2 , NRSO 2 R, CN, C(O)NR 2 , C(O)R, COOR, NO 2 or halo, wherein each R is independently H, C 1 -C 8 alkyl, C5-C12 aryl or C5-C20 arylalkyl, or a heteroform of one of these; or is any other substituent suitable for an alkyl group;
and wherein two Y or Y′ groups on the same ring can cyclize to form a 3-6 membered ring that can be saturated, unsaturated or aromatic, and which ring may include a heteroatom selected from O, S and N as a ring member and may be substituted;
each W and W′ independently represents C═O, C═S, or an optionally substituted C 2 -C 6 alkylene or C 2 -C 6 heteroalkylene; or W can be a bond where X comprises an optionally substituted C5-C6 aryl or heteroaryl ring; and/or W′ can be a bond where X′ comprises an optionally substituted C5-C6 or heteroaryl ring;
each X and X′ independently represents an optionally substituted C5-C20 ring system comprising at least one aromatic ring and up to four heteroatoms selected from N, O and S, as a ring member, and can represent either a single 5-15 membered cyclic group or two 5-10 membered cyclic groups that are both attached to the same atom of W or W′, provided that each X and X′ comprises at least one aryl or heteroaryl ring;
each Q and Q′ independently represents —CH 2 —, —CH(OR)—, —CH(R)—, —(CH 2 ) r D-, —CH(R)D-, or —CR═CR— or —C≡C—, wherein r is 1-4, each D is independently O, NR, or S, and wherein each R is independently H, or optionally substituted C 1 -C 8 alkyl or optionally substituted C 1 -C 8 heteroalkyl; or one or both of Q and Q′ can be a bond where L comprises a ring;
each n and n′ is independently 0-3;
each m and m′ is independently 0-4;
each R 1 and R 1′ is independently H or optionally substituted C1-C4 alkyl;
each Z and Z′ is independently an optionally substituted C1-C6 aminoalkyl; and
L represents a linker that is a C2-C20 hydrocarbyl group, optionally containing from 1-6 heteroatoms selected from N, O and S, which linker is 2 to 10 atoms in length when counted along the shortest path between Q and Q′, and which may be optionally substituted;
with the proviso that L does not comprise a disulfide bond.
2. The compound of claim 1 , having the formula (2):
or a pharmaceutically acceptable salt form thereof; and including any stereoisomeric forms thereof;
wherein each Y is optionally substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these; or is ═O, OR, NR 2 , OC(O)R, NRC(O)R, wherein each R is independently H, C 1 -C 8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these;
W represents C═O, C═S, or an optionally substituted C 2 -C 6 alkylene or optionally substituted C 2 -C 6 heteroalkylene; or W can be a bond where X comprises an optionally substituted 5-membered or 6-membered aryl or heteroaryl ring;
X represents an optionally substituted C5-C20 ring system comprising at least one aromatic ring and up to four heteroatoms selected from N, O and S, and can represent either a single 5-15 membered cyclic group or two 5-10 membered cyclic groups that are both attached to the same atom of W, provided that X comprises at least one aryl or heteroaryl ring;
each Q represents —CH 2 —, —CH(OR)—, —CH(R)—, —CH 2 O—, —CH(R)O— or —(CH 2 ) 4 NH—, wherein R is H, C 1 -C 4 alkyl or C 1 -C 4 heteroalkyl; or one or both of Q and Q′ can be a bond where L comprises a ring;
m is 0-4;
Z represents an optionally substituted C1-C6 aminoalkyl group; and
L represents a C 2 -C 8 alkylene C5-C12 arylene, or C5-C20 arylalkylene linker, or a heteroform of one of these, each of which may be optionally substituted and may be saturated or unsaturated;
with the proviso that L does not comprise a disulfide bond.
3. The compound of claim 1 , having the formula (3):
or a pharmaceutically acceptable salt or hydrate form thereof;
wherein each R 2 is independently H, or an optionally substituted C 1 -C 8 alkyl or optionally substituted C 1 -C 8 heteroalkyl group, and the two R 2 groups on one nitrogen can cyclize to form an optionally substituted azacyclic group having 3-8 ring members, which azacyclic group may be saturated, unsaturated or aromatic, and may contain 1-2 additional heteroatoms selected from N, O and S as ring members;
each R 3 is H, or an optionally substituted C 1 -C 8 alkyl or optionally substituted C 1 -C 8 heteroalkyl group, and R 3 can cyclize with R 2 on an adjacent nitrogen atom to form an optionally substituted azacyclic group having 3-8 ring members, which azacyclic group may be saturated, unsaturated or aromatic, and may contain 1-2 additional heteroatoms selected from N, O and S as ring members;
each R 4 is H, OH, or an optionally substituted C 1 -C 8 alkyl or optionally substituted C 1 -C 8 heteroalkyl group;
each Y is optionally substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these; or is ═O, OR, NR 2 , OC(O)R, NRC(O)R, wherein each R is independently H, C 1 -C 8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these;
each W represents a group of the form —C(O)NR(CHR) p —, where p is 0-2, and each R is independently H, C 1 -C 4 alkyl or C 1 -C 4 heteroalkyl; or W can be a bond where X comprises an optionally substituted 5-membered or 6-membered aryl or heteroaryl ring;
each X represents an optionally substituted C5-C20 ring system comprising at least one aromatic ring and up to four heteroatoms selected from N, O and S, and can represent either a single 5-15 membered cyclic group or two 5-10 membered cyclic groups that are both attached to the same atom of W, provided that X comprises at least one aryl or heteroaryl ring;
m is 0-4; and
L represents a C 2 -C 8 alkylene C5-C12 arylene, or C5-C20 arylalkylene linker, or a heteroform of one of these, each of which may be optionally substituted and may be saturated or unsaturated;
with the proviso that L does not comprise a disulfide bond.
4. The compound of claim 1 , having the formula (5):
or a pharmaceutically acceptable salt form thereof; and including any stereoisomeric forms thereof;
wherein each J and J′ is independently H, CN, C1-C4 alkyl or C1-C4 alkyloxycarbonyl;
each V and V′ is independently O or S;
each Y represents optionally substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these; or is ═O, OR, SR, S(O)R, SO 2 R, SO 2 NR 2 , NR 2 , OC(O)R, NRC(O)R, NRCOOR, NRC(O)NR 2 , NRSO 2 R, CN, C(O)NR 2 , C(O)R, COOR, NO 2 or halo, wherein each R is independently H, C 1 -C 8 alkyl, C5-C12 aryl or C5-C20 arylalkyl, or a heteroform of one of these; or is any other substituent suitable for an alkyl group;
and wherein two Y or Y′ groups on the same ring can cyclize to form a 3-6 membered ring that can be saturated, unsaturated or aromatic, and which ring may include a heteroatom selected from 0, S and N as a ring member and may be substituted;
each W and W′ independently represents C═O, C═S, or an optionally substituted C 2 -C 6 alkylene or C 2 -C 6 heteroalkylene; or W and/or W′ can be a bond where X and/or X′ comprises an optionally substituted 5-membered or 6-membered aryl or heteroaryl ring;
each X and X′ independently represents an optionally substituted C5-C20 ring system comprising at least one aromatic ring and up to four heteroatoms selected from N, O and S, and can represent either a single 5-15 membered cyclic group or two 5-10 membered cyclic groups that are both attached to the same atom of W or W′, provided that each X and X′ comprises at least one aryl or heteroaryl ring;
each Q and Q′ independently represents —CH 2 —, —CH(OR)—, —CH(R)—, —(CH 2 ) r A-, —CH(R)A-, or —CR═CR— or —C≡C—, wherein r is 1-4, each A is independently O, NR, or S, and wherein each R is independently H, C 1 -C 8 alkyl or C 1 -C 8 heteroalkyl; or one or both of Q and Q′ can be a bond where L comprises a ring;
each m and m′ is independently 0-4;
each R 1 and R 1′ is independently H or optionally substituted C 1 -C 4 alkyl;
each Z and Z′ is independently an optionally substituted C 1 -C 6 aminoalkyl; and
L represents a linker that is a C2-C20 hydrocarbyl group, optionally containing from 1-6 heteroatoms selected from N, O and S, which linker is 2 to 10 atoms in length when counted along the shortest path between Q and Q′, and which may be optionally substituted;
with the proviso that L does not comprise a disulfide bond.
5. The compound of claim 1 , having the formula (6):
or a pharmaceutically acceptable salt or hydrate form thereof; and including any stereoisomeric forms thereof;
wherein V is O or S;
Y is optionally substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these; or is ═O, OR, NR 2 , OC(O)R, NRC(O)R, wherein each R is independently H or C 1 -C 8 alkyl, C5-C12 aryl or C5-C20 arylalkyl, or a heteroform of one of these;
W represents C═O, C═S, or an optionally substituted C 2 -C 6 alkylene or optionally substituted C 2 -C 6 heteroalkylene; or W can be a bond where X comprises an optionally substituted 5-membered or 6-membered aryl or heteroaryl ring;
X represents an optionally substituted C5-C20 ring system comprising at least one aromatic ring and up to four heteroatoms selected from N, O and S, and can represent either a single 5-15 membered cyclic group or two 5-10 membered cyclic groups that are both attached to the same atom of W, provided that X comprises at least one aryl or heteroaryl ring;
each Q represents —CH 2 —, —CH(OR)—, —CH(R)—, —CH 2 O—, —CH(R)O— or —(CH 2 ) 4 NH—, wherein R is H, C 1 -C 4 alkyl or C 1 -C 4 heteroalkyl; or Q can be a bond where L comprises a ring; m is 0-4;
Z represents an optionally substituted C1-C6 aminoalkyl group; and
L represents a C 2 -C 8 alkylene C5-C12 arylene, or C5-C20 arylalkylene linker, or a heteroform of one of these, each of which may be optionally substituted and may be saturated or unsaturated;
with the proviso that L does not comprise a disulfide bond.
6. The compound of claim 1 , having the formula (8):
or a pharmaceutically acceptable salt form thereof; and including any stereoisomeric forms thereof;
wherein V′ is O or S;
each Y and Y′ independently represents optionally substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these; or ═O, OR, NR 2 , OC(O)R, NRC(O)R, wherein each R is independently H or C 1 -C 8 alkyl, C5-C12 aryl or C5-C20 arylalkyl, or a heteroform of one of these;
each W and W′ independently represents C═O, C═S, or an optionally substituted C 2 -C 6 alkylene or C 2 -C 6 heteroalkylene; or W and/or W′ can be a bond where X and/or X′ comprises an optionally substituted 5-membered or 6-membered aryl or heteroaryl ring;
each X and X′ independently represents an optionally substituted C5-C20 ring system comprising at least one aromatic ring and up to four heteroatoms selected from N, O and S, and can represent either a single 5-15 membered cyclic group or two 5-10 membered cyclic groups that are both attached to the same atom of W or W′, provided that each X and X′ comprises at least one aryl or heteroaryl ring;
each Q and Q′ independently represents —CH 2 —, —CH(OR)—, —CH(R)—, —CH 2 O—, —CH(R)O— or —(CH 2 ) 4 NH—, wherein R is H, C 1 -C 4 alkyl or C 1 -C 4 heteroalkyl; or one or both of Q and Q′ can be a bond where L comprises a ring;
n is 0-3;
each m and m′ is independently 0-4;
each R 1 and R 1′ is independently H or optionally substituted C1-C4 alkyl;
each Z and Z′ is independently an optionally substituted C1-C6 aminoalkyl; and
L represents a C 2 -C 8 alkylene C5-C12 arylene, or C5-C20 arylalkylene linker, or a heteroform of one of these, each of which may be optionally substituted and may be saturated or unsaturated;
with the proviso that L does not comprise a disulfide bond.
7. The compound of claim 1 , having the formula (9):
or a pharmaceutically acceptable salt form thereof; and including any stereoisomeric forms thereof;
wherein each J and J′ is independently H, CN, C1-C4 alkyl or C1-C4 alkoxycarbonyl;
each R 6 and R 6′ is independently H, C1-C4 alkyl or C1-C4 heteroalkyl;
each W and W′ independently represents C═O, C═S, or an optionally substituted C 2 -C 6 alkylene or C 2 -C 6 heteroalkylene; or W and/or W′ can be a bond where X and/or X′ comprises an optionally substituted 5-membered or 6-membered aryl or heteroaryl ring;
each X and X′ independently represents an optionally substituted C5-C20 ring system comprising at least one aromatic ring and up to four heteroatoms selected from N, O and S, and can represent either a single 5-15 membered cyclic group or two 5-10 membered cyclic groups that are both attached to the same atom of W or W′, provided that each X and X′ comprises at least one aryl or heteroaryl ring;
each Q and Q′ independently represents —CH 2 —, —CH(OR)—, —CH(R)—, —(CH 2 ) r A-, —CH(R)A-, or —CR═CR— or —C≡C—, wherein r is 1-4, each A is independently O, NR, or S, and wherein each R is independently H, C 1 -C 8 alkyl or C 1 -C 8 heteroalkyl; or one or both of Q and Q′ can be a bond where L comprises a ring;
each R 1 and R 1′ is independently H or optionally substituted C1-C4 alkyl;
each Z and Z′ is independently an optionally substituted C1-C6 aminoalkyl; and
L represents a linker that is a C2-C20 hydrocarbyl group, optionally containing from 1-6 heteroatoms selected from N, O and S, which linker is 2 to 10 atoms in length when counted along the shortest path between Q and Q′, and which may be optionally substituted;
with the proviso that L does not comprise a disulfide bond.
8. The compound of claim 1 , having the formula (11):
or a pharmaceutically acceptable salt or hydrate form thereof; and including any stereoisomeric forms thereof;
wherein R 6′ is H, C1-C4 alkyl or C1-C4 heteroalkyl;
each Y independently represents optionally substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these; or is ═O, OR, NR 2 , OC(O)R, NRC(O)R, wherein each R is independently H or C 1 -C 8 alkyl, C5-C12 aryl or C5-C20 arylalkyl, or a heteroform of one of these;
each W and W′ independently represents C═O, C═S, or an optionally substituted C 2 -C 6 alkylene or C 2 -C 6 heteroalkylene; or W and/or W′ can be a bond where X and/or X′ comprises an optionally substituted 5-membered or 6-membered aryl or heteroaryl ring;
each X and X′ independently represents an optionally substituted C5-C20 ring system comprising at least one aromatic ring and up to four heteroatoms selected from N, O and S, and can represent either a single 5-15 membered cyclic group or two 5-10 membered cyclic groups that are both attached to the same atom of W or W′, provided that each X and X′ comprises at least one aryl or heteroaryl ring;
each Q and Q′ independently represents —CH 2 —, —CH(OR)—, —CH(R)—, —CH 2 O—, —CH(R)O— or —(CH 2 ) 4 NH—, wherein R is H, C 1 -C 4 alkyl or C 1 -C 4 heteroalkyl; or one or both of Q and Q′ can be a bond where L comprises a ring;
n is 0-3;
m is 0-4;
each R 1 and R 1′ is independently H or optionally substituted C1-C4 alkyl;
each Z and Z′ is independently an optionally substituted C1-C6 aminoalkyl; and
L represents a C 2 -C 8 alkylene C5-C12 arylene, or C5-C20 arylalkylene linker, or a heteroform of one of these, each of which may be optionally substituted and may be saturated or unsaturated;
with the proviso that L does not comprise a disulfide bond.
9. The compound of claim 1 , having the formula (12):
or a pharmaceutically acceptable salt form thereof; and including any stereoisomeric forms thereof;
wherein R 6′ is H, C1-C4 alkyl or C1-C4 heteroalkyl;
V is O or S;
each Y independently represents optionally substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these; or is ═O, OR, NR 2 , OC(O)R, NRC(O)R, wherein each R is independently H or C 1 -C 8 alkyl, C5-C12 aryl or C5-C20 arylalkyl, or a heteroform of one of these;
each W and W′ independently represents C═O, C═S, or an optionally substituted C 2 -C 6 alkylene or optionally substituted C 2 -C 6 heteroalkylene; or W and/or W′ can be a bond where X and/or X′ comprises an optionally substituted 5-membered or 6-membered aryl or heteroaryl ring;
each X and X′ independently represents an optionally substituted C5-C20 ring system comprising at least one aromatic ring and up to four heteroatoms selected from N, O and S, and can represent either a single 5-15 membered cyclic group or two 5-10 membered cyclic groups that are both attached to the same atom of W or W′, provided that each X and X′ comprises at least one aryl or heteroaryl ring;
each Q and Q′ independently represents —CH 2 —, —CH(OR)—, —CH(R)—, —CH 2 O—, —CH(R)O— or —(CH 2 ) 4 NH—, wherein R is H, C 1 -C 4 alkyl or C 1 -C 4 heteroalkyl; or one or both of Q and Q′ can be a bond where L comprises a ring;
m is 0-4;
each R 1 and R 1′ is independently H or optionally substituted C1-C4 alkyl;
each Z and Z′ is independently an optionally substituted C1-C6 aminoalkyl; and
L represents a C 2 -C 8 alkylene C5-C12 arylene, or C5-C20 arylalkylene linker, or a heteroform of one of these, each of which may be optionally substituted and may be saturated or unsaturated;
with the proviso that L does not comprise a disulfide bond.
10. The compound of claim 1 , having the formula (13):
or a pharmaceutically acceptable salt form thereof; and including any stereoisomeric forms thereof;
wherein each J and J′ is independently H, CN, C1-C4 alkyl or C1-C4 alkoxycarbonyl;
each ═B and ═B′ independently represents ═O, ═S, F 2 or H 2 ;
each W and W′ independently represents C═O, C═S, or an optionally substituted C 2 -C 6 alkylene or C 2 -C 6 heteroalkylene; or W and/or W′ can be a bond where X and/or X′ comprises a 5-membered or 6-membered aryl or heteroaryl ring;
each X and X′ independently represents an optionally substituted C5-C20 ring system comprising at least one aromatic ring and up to four heteroatoms selected from N, O and S, and can represent either a single 5-15 membered cyclic group or two 5-10 membered cyclic groups that are both attached to the same atom of W or W′, provided that each X and X′ comprises at least one aryl or heteroaryl ring;
each Q and Q′ independently represents —CH 2 —, —CH(OR)—, —CH(R)—, —(CH 2 ) r A-, —CH(R)A-, or —CR═CR— or —C≡C—, wherein r is 1-4, each A is independently O, NR, or S, and wherein each R is independently H, C 1 -C 8 alkyl or C 1 -C 8 heteroalkyl; or one or both of Q and Q′ can be a bond where L comprises a ring;
each n and n′ is independently 0-3;
each q and q′ is independently 1-4;
each R 1 and R 1′ is independently H or optionally substituted C1-C4 alkyl;
each Z and Z′ is independently an optionally substituted C1-C6 aminoalkyl; and
L represents a linker that is a C2-C20 hydrocarbyl group, optionally containing from 1-6 heteroatoms selected from N, O and S, which linker is 2 to 10 atoms in length when counted along the shortest path between Q and Q′, and which may be optionally substituted;
with the proviso that L does not comprise a disulfide bond.
11. The compound of claim 1 , having the formula (15):
or a pharmaceutically acceptable salt form thereof; and including any stereoisomeric forms thereof;
wherein ═B′ represents ═O, ═S, F 2 or H 2 ;
each Y independently represents optionally substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these; or is ═O, OR, NR 2 , OC(O)R, NRC(O)R, wherein each R is independently H or C 1 -C 8 alkyl, C5-C12 aryl or C5-C20 arylalkyl, or a heteroform of one of these;
each W and W′ independently represents C═O, C═S, or an optionally substituted C 2 -C 6 alkylene or C 2 -C 6 heteroalkylene; or W and/or W′ can be a bond where X and/or X′ comprises a 5-membered or 6-membered aryl or heteroaryl ring;
each X and X′ independently represents an optionally substituted C5-C20 ring system comprising at least one aromatic ring and up to four heteroatoms selected from N, O and S, and can represent either a single 5-15 membered cyclic group or two 5-10 membered cyclic groups that are both attached to the same atom of W or W′, provided that each X and X′ comprises at least one aryl or heteroaryl ring;
each Q and Q′ independently represents —CH 2 —, —CH(OR)—, —CH(R)—, —CH 2 O—, —CH(R)O— or —(CH 2 ) 4 NH—, wherein R is H, C 1 -C 4 alkyl or C 1 -C 4 heteroalkyl; or one or both of Q and Q′ can be a bond where L comprises a ring;
each n and n′ is independently 0-3;
m is 0-4;
q′ is 1-4;
each R 1 and R 1′ is independently H or optionally substituted C1-C4 alkyl;
each Z and Z′ is independently an optionally substituted C1-C6 aminoalkyl; and
L represents a C 2 -C 8 alkylene C5-C12 arylene, or C5-C20 arylalkylene linker, or a heteroform of one of these, each of which may be optionally substituted and may be saturated or unsaturated;
with the proviso that L does not comprise a disulfide bond.
12. The compound of claim 1 , having the formula (16):
or a pharmaceutically acceptable salt form thereof; and including any stereoisomeric forms thereof;
wherein ═B′ represents ═O, ═S, F 2 or H 2 ;
V is O or S;
each Y independently represents optionally substituted C1-C8 alkyl, C5-C12 aryl, C5-C20 arylalkyl, or a heteroform of one of these; or is ═O, OR, NR 2 , OC(O)R, NRC(O)R, wherein each R is independently H or C 1 -C 8 alkyl, C5-C12 aryl or C5-C20 arylalkyl, or a heteroform of one of these;
each W and W′ independently represents C═O, C═S, or an optionally substituted C 2 -C 6 alkylene or C 2 -C 6 heteroalkylene; or W and/or W′ can be a bond where X and/or X′ comprises a 5-membered or 6-membered aryl or heteroaryl ring;
each X and X′ independently represents an optionally substituted C5-C20 ring system comprising at least one aromatic ring and up to four heteroatoms selected from N, O and S, and can represent either a single 5-15 membered cyclic group or two 5-10 membered cyclic groups that are both attached to the same atom of W or W′, provided that each X and X′ comprises at least one aryl or heteroaryl ring;
each Q and Q′ independently represents —CH 2 —, —CH(OR)—, —CH(R)—, —CH 2 O—, —CH(R)O— or —(CH 2 ) 4 NH—, wherein R is H, C 1 -C 4 alkyl or C 1 -C 4 heteroalkyl; or one or both of Q and Q′ can be a bond where L comprises a ring;
n′ is 0-3;
m is 0-4;
q′ is 1-4;
each R 1 and R 1′ is independently H or optionally substituted C1-C4 alkyl;
each Z and Z′ is independently an optionally substituted C1-C6 aminoalkyl; and
L represents a C 2 -C 8 alkylene C5-C12 arylene, or C5-C20 arylalkylene linker, or a heteroform of one of these, each of which may be optionally substituted and may be saturated or unsaturated;
with the proviso that L does not comprise a disulfide bond.
13. The compound of claim 1 , having the formula (17):
or a pharmaceutically acceptable salt form thereof; and including any stereoisomeric forms thereof;
wherein ═B′ represents ═O, ═S, F 2 or H 2 ;
R 6 is H, C1-C4 alkyl or C1-C4 heteroalkyl;
each W and W′ independently represents C═0, C═S, or an optionally substituted C 2 -C 6 alkylene or C 2 -C 6 heteroalkylene; or W and/or W′ can be a bond where X and/or X′ comprises a 5-membered or 6-membered aryl or heteroaryl ring;
each X and X′ independently represents an optionally substituted C5-C20 ring system comprising at least one aromatic ring and up to four heteroatoms selected from N, O and S, and can represent either a single 5-15 membered cyclic group or two 5-10 membered cyclic groups that are both attached to the same atom of W or W′, provided that each X and X′ comprises at least one aryl or heteroaryl ring;
each Q and Q′ independently represents —CH 2 —, —CH(OR)—, —CH(R)—, —CH 2 O—, —CH(R)O— or —(CH 2 ) 4 NH—, wherein R is H, C 1 -C 4 alkyl or C 1 -C 4 heteroalkyl; or one or both of Q and Q′ can be a bond where L comprises a ring;
n′ is 0-3;
q′ is 1-4;
each R 1 and R 1 is independently H or optionally substituted C 1 -C 4 alkyl;
each Z and Z′ is independently an optionally substituted C1-C6 aminoalkyl; and
L represents a C 2 -C 8 alkylene C5-C12 arylene, or C5-C20 arylalkylene linker, or a heteroform of one of these, each of which may be optionally substituted and may be saturated or unsaturated;
with the proviso that L does not comprise a disulfide bond.
14. The compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt form thereof.
15. A compound having a formula selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
16. A compound having a formula selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
17. A compound having a formula selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.