Bifunctional cytotoxic agents
View Patent ↗Cytotoxic dimers comprising CBI-based and/or CPI-based sub-units, antibody drug conjugates comprising such dimers, and to methods for using the same to treat cancer and other conditions.
1. A compound of Formula (IIA):
L-P (IIA)
or a pharmaceutically acceptable salt or solvate thereof, wherein:
P is:
F 1 -L 1 -T-L 2 -F 2 (I)
or a pharmaceutically acceptable salt or solvate thereof, wherein:
F 1 and F 2 are each independently selected from ring systems A, and B:
wherein:
each V 1 is independently a bond, O, N(R) or S, for each ring system A in which V 1 appears;
each V 2 is independently O, N(R) or S, for each ring system B in which V 2 appears;
W 1 and W 2 are each independently H, —C 1 -C 5 alkyl or -phenyl, for each ring system A and ring system B in which W 1 and W 2 appear;
each X is independently —OH, —O-acyl, azido, halo, cyanate, thiocyanate, isocyanate, thioisocyanate, or
for each ring system A in which X appears;
each Y is independently selected from a bond, H, —C(O)R A , —C(S)R A , —C(O)OR A , —S(O) 2 OR A , —C(O)N(R A ) 2 , —C(S)N(R A ) 2 , glycosyl, —NO 2 and —P(O)(OR A ) 2 for each ring system in which Y appears, wherein each R A is independently selected from H, —C 1 -C 20 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, aralkyl, —C 1 -C 10 heterocyclyl, —C 3 -C 8 carbocyclyl, —C 1 -C 20 alkylN(R) 2 , —C 1 -C 20 alkylene, —C 1 -C 8 heteroalkylene, —C 6 -C 14 arylene, aralkylene, —C 1 -C 10 heterocyclo, —C 3 -C 8 carbocyclo and —C 1 -C 20 alkylN(R)—, and R F where said R A is optionally substituted with 1 to 3 substituents independently selected from R, and wherein one Y is divalent and is bonded to L,
R F is —N(R 6 )QN(R 5 )C(O)— and is bonded to L at the carbonyl adjacent N(R 5 ), wherein R 5 and R 6 are each independently selected from the group consisting of H, —C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl and —C 3 -C 8 carbocyclyl, or R 5 or R 6 joins with a substituted carbon on Q to form a —C 1 -C 10 heterocyclic or —C 6 -C 14 heteroaryl ring, or R 5 and R 6 join together to form a —C 1 -C 10 heterocyclic or —C 6 -C 14 heteroaryl ring system, and where Q is —C 1 -C 8 alkylene-, —C 1 -C 8 heteroalkylene-, —C 6 -C 14 arylene-, -aralkylene-, —C 1 -C 10 heterocyclo- or —C 3 -C 8 carbocyclo-, wherein Q, R 5 and R 6 are each independently optionally substituted with 1 to 3 substituents independently selected from R;
each Z is independently selected from the group consisting of H, —C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl and —C 3 -C 8 carbocyclyl, and wherein said C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl and —C 3 -C 8 carbocyclyl, are each optionally substituted with 1 to 3 substitutents independently selected from R, for each ring system A and ring system B in which Z appears;
L 1 and L 2 are each independently a direct bond;
T is selected from:
—C(A 1 )X 1 -T 2 -X 1 C(B 1 )—, where T 2 is:
wherein each X 1 is independently a bond, —NR E —, —O— or —S—, wherein A 1 and B 1 are each independently ═O or ═S,
wherein R 1 , R 2 , R 3 , and R 4 are each independently R E , or R 1 and R 2 form a ring system, or R 3 and R 4 form a ring system, or both R 1 and R 2 , and R 3 and R 4 , each independently form ring systems, or R 1 and R 3 form a ring system, or R 2 and R 4 form a ring system, or both R 1 and R 3 , and R 2 and R 4 , each independently form ring systems, where said ring systems are independently selected from —C 3 -C 8 carbocyclycl, or R 1 , R 2 , R 3 and R 4 are each bonds to different carbons on D, wherein g and j are each independently an integer from 0 to 50 and m is an integer from 1 to 50, and wherein D is —C 3 -C 8 carbocyclo optionally substituted with —R E , —C(O)R E , —C(O)OR E , —N(R E ) 2 , —N(R)C(O)R E or —N(R)C(O)OR E , and D is additionally optionally substituted by 1 to 2 R, and
wherein each R E is independently selected from the group consisting of H, —C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl, —C 3 -C 8 carbocyclyl, —C(O)OC 1 -C 8 alkyl, —C(O)N(C 1 -C 8 alkyl) 2 , and —C(O)-halo, and wherein each R E is optionally substituted with 1 to 3 substitutents independently selected from R,
and wherein each R is independently selected from the group consisting of H, —C 1 -C 20 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, halo, hydroxyl, alkoxy, —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —NO 2 , —C 6 -C 14 aryl and —C 6 -C 14 heteroaryl, wherein two or more R optionally join to form a ring or rings, and wherein said —C 6 -C 14 aryl and —C 6 -C 14 heteroaryl are optionally substituted with 1 to 5 substituents independently selected from —C 1 -C 10 alkyl, —C 1 -C 10 alkoxy, -halo, —C 1 -C 10 alkylthio, -trifluoromethyl, —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —C 1 -C 10 alkyl-N(C 1 -C 8 alkyl) 2 , —C 1 -C 3 alkylthio, —NO 2 or —C 1 -C 10 heterocyclyl, for each ring system in which R appears;
L is L A -L B -(L C ) 1-3 , wherein L A is selected from the group consisting of -halo, —N(R) 2 , —CON(R) 2 , —S-aryl optionally substituted with —NO 2 or —CON(R) 2 , —S-heteroaryl optionally substituted with —NO 2 , alkyl-SO 2 -heteroaryl, arylSO 2 -heteroaryl-,
L B is L B1 -L B2 -L B3 wherein L B1 is absent or is one or more components selected from the group consisting of —C(O)—, —C(S)—, —C(O)NR—, —C(O)C 1 -C 6 alkyl-, —C(O)NRC 1 -C 6 alkyl-, —C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —, —C(O)C 1 -C 6 alkylNRC(O)—, —C(O)C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —, —C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —C(O)—, —C 1 -C 6 alkyl-S—S—C 1 -C 6 alkylNRC(O)CH 2 —, —C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 NRC(O)CH 2 —, —C(O)C 1 -C 6 alkyl-NRC(O)C 1-6 alkyl-, —N═CR-phenyl-O—C 1 -C 6 alkyl-, —N═CR-phenyl-O—C 1 -C 6 alkyl-C(O)—, —C(O)—C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 NRC(O)—, —C(O)C 1 -C 6 alkyl-phenyl(NR—C(O)C 1 -C 6 alkyl) 1-4 -, —C(O)C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —NRC(O)C 1 -C 6 alkyl-, —C 1 -C 6 alkyl-, —S—, —C(O)—CH(NR—C(O)C 1 -C 6 alkyl)-C 1 -C 6 alkyl- and (—CH 2 —CH 2 —O—) 1-20 ,
wherein L B2 is AA 0-12 , wherein AA is a natural amino acid, a non-natural amino acid or —(CR 15 ) o —S—S—(CR 15 ) p where o and p are each independently an integer from 1 to 20,
L B3 is -PABA-, -PABC- or absent;
L C is absent or independently selected from the group consisting of —C 1 -C 6 alkylene-, —NRC 3 -C 8 -heterocyclylNR—, —NRC 3 -C 8 -carbocyclylNR—, —NRC 1 -C 6 alkylNR—, —NRC 1 -C 6 alkylene-, —S—, —NR—, —NRNR—, —O(CR 2 ) 1-4 S—S(CR 2 ) 1-4 N(R)—, —NRC 1 -C 6 -alkylenephenyleneNR—, —NRC 1 -C 6 alkylenephenyleneSO 2 NR—, —OC 1 -C 6 alkylS-SC 1 -C 6 alkylC(COOR)NR—, —NRC(COOR)C 1 -C 6 alkylS-SC 1 -C 6 alkylO—,
wherein
X A is CR or N,
X B is CH, CR(C(R) 2 ) 1-3 NR, CR(C(R) 2 ) 1-3 O, CR(C(R) 2 ) 1-3 C(O)NR, CR—(C(R) 2 ) 1-3 C(O)NRNR, CR(C(R) 2 ) 1-3 SO 2 NR, CR(C(R) 2 ) 1-3 NRNR, CR(C(R) 2 ) 1-3 NRC(O) or N,
each X C is R,
each X D is —(CH 2 ) 1-5 —, or is absent;
X E is O, S, C(R) 2 , C(R)(C(R) 2 ) 1-3 —NR 2 or NR and
each X F is (C(R) 2 ) 1-3 —NR or C(R) 2 —(C(R) 2 ) 1-3 —O.
2. A compound of Formula (IIIA):
AB-(L-P) 1-20 (IIIA)
or a pharmaceutically acceptable salt or solvate thereof, wherein:
AB is an antibody;
P is:
F 1 -L 1 -T-L 2 -F 2 (I)
or a pharmaceutically acceptable salt or solvate thereof, wherein:
F 1 and F 2 are each independently selected from ring systems A, and B:
wherein:
each V 1 is independently a bond, O, N(R) or S, for each ring system A in which V 1 appears;
each V 2 is independently O, N(R) or S, for each ring system B in which V 2 appears;
W 1 and W 2 are each independently H, —C 1 -C 5 alkyl or -phenyl, for each ring system A and ring system B in which W 1 and W 2 appear;
each X is independently —OH, —O-acyl, azido, halo, cyanate, thiocyanate, isocyanate, thioisocyanate, or
for each ring system A in which X appears;
each Y is independently selected from a bond, H, —C(O)R A , —C(S)R A , —C(O)OR A , —S(O) 2 OR A , —C(O)N(R A ) 2 , —C(S)N(R A ) 2 , glycosyl, —NO 2 and —P(O)(OR A ) 2 for each ring system in which Y appears, wherein each R A is independently selected from H, —C 1 -C 20 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, aralkyl, —C 1 -C 10 heterocyclyl, —C 3 -C 8 carbocyclyl, —C 1 -C 20 alkylN(R) 2 , —C 1 -C 20 alkylene, —C 1 -C 8 heteroalkylene, —C 6 -C 14 arylene, aralkylene, —C 1 -C 10 heterocyclo, —C 3 -C 8 carbocyclo and —C 1 -C 20 alkylN(R)—, and R F where said R A is optionally substituted with 1 to 3 substituents independently selected from R, and wherein one Y is divalent and is bonded to L,
R F is —N(R 6 )QN(R 5 )C(O)— and is bonded to L at the carbonyl adjacent N(R 5 ), wherein R 5 and R 6 are each independently selected from the group consisting of H, —C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl and —C 3 -C 8 carbocyclyl, or R 5 or R 6 joins with a substituted carbon on Q to form a —C 1 -C 10 heterocyclic or —C 6 -C 14 heteroaryl ring, or R 5 and R 6 join together to form a —C 1 -C 10 heterocyclic or —C 6 -C 14 heteroaryl ring system, and where Q is —C 1 -C 8 alkylene-, —C 1 -C 8 heteroalkylene-, —C 6 -C 14 arylene-, -aralkylene-, —C 1 -C 10 heterocyclo- or —C 3 -C 8 carbocyclo-, wherein Q, R 5 and R 6 are each independently optionally substituted with 1 to 3 substituents independently selected from R;
each Z is independently selected from the group consisting of H, —C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl and —C 3 -C 8 carbocyclyl, and wherein said C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl and —C 3 -C 8 carbocyclyl, are each optionally substituted with 1 to 3 substitutents independently selected from R, for each ring system A and ring system B in which Z appears;
L 1 and L 2 are each independently a direct bond;
T is selected from:
—C(A 1 )X 1 -T 2 -X 1 C(B 1 )—, where T 2 is:
wherein each X 1 is independently a bond, —NR E —, —O— or —S—, wherein A 1 and B 1 are each independently ═O or ═S,
wherein R 1 , R 2 , R 3 , and R 4 are each independently R E , or R 1 and R 2 form a ring system, or R 3 and R 4 form a ring system, or both R 1 and R 2 , and R 3 and R 4 , each independently form ring systems, or R 1 and R 3 form a ring system, or R 2 and R 4 form a ring system, or both R 1 and R 3 , and R 2 and R 4 , each independently form ring systems, where said ring systems are independently selected from —C 3 -C 8 carbocyclycl, or R 1 , R 2 , R 3 and R 4 are each bonds to different carbons on D, wherein g and j are each independently an integer from 0 to 50 and m is an integer from 1 to 50, and wherein D is —C 3 -C 8 carbocyclo optionally substituted with —R E , —C(O)R E , —C(O)OR E , —N(R E ) 2 , —N(R)C(O)R E or —N(R)C(O)OR E , and D is additionally optionally substituted by 1 to 2 R, and
wherein each R E is independently selected from the group consisting of H, —C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl, —C 3 -C 8 carbocyclyl, —C(O)OC 1 -C 8 alkyl, —C(O)N(C 1 -C 8 alkyl) 2 , and —C(O)-halo, and wherein each R E is optionally substituted with 1 to 3 substitutents independently selected from R,
and wherein each R is independently selected from the group consisting of H, —C 1 -C 20 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, halo, hydroxyl, alkoxy, —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —NO 2 , —C 6 -C 14 aryl and —C 6 -C 14 heteroaryl, wherein two or more R optionally join to form a ring or rings, and wherein said —C 6 -C 14 aryl and —C 6 -C 14 heteroaryl are optionally substituted with 1 to 5 substituents independently selected from —C 1 -C 10 alkyl, —C 1 -C 10 alkoxy, -halo, —C 1 -C 10 alkylthio, -trifluoromethyl, —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —C 1 -C 10 alkyl-N(C 1 -C 8 alkyl) 2 , —C 1 -C 3 alkylthio, —NO 2 or —C 1 -C 10 heterocyclyl, for each ring system in which R appears,
L is L A -L B -(L) 1-3 ;
L A is selected from: a bond to AB, —NR-(bond to AB), alkyl-SO 2 -heteroaryl, arylSO 2 -heteroaryl-, (bond to AB) (d (bond to AB)
L B is L B1 -L B2 -L B3
wherein L B1 is absent or is one or more components selected from the group consisting of —C(O)—, —C(S)—, —C(O)NR—, —C(O)C 1 -C 6 alkyl-, —C(O)NRC 1 -C 6 alkyl-, —C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —, —C(O)C 1 -C 6 alkylNRC(O)—, —C(O)C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —, —C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —C(O)—, —C 1 -C 6 alkyl-S—S—C 1 -C 6 alkylNRC(O)CH 2 —, —C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 NRC(O)CH 2 —, —C(O)C 1 -C 6 alkyl-NRC(O)C 1-6 alkyl-, —N═CR-phenyl-O—C 1 -C 6 alkyl-, —N═CR-phenyl-O—C 1 -C 6 alkyl-C(O)—, —C(O)—C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 NRC(O)—, —C(O)C 1 -C 6 alkyl-phenyl(NR—C(O)C 1 -C 6 alkyl) 1-4 -, —C(O)C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —NRC(O)C 1 -C 6 alkyl-, —C 1 -C 6 alkyl-, —S—, —C(O)—CH(NR—C(O)C 1 -C 6 alkyl)-C 1 -C 6 alkyl- and (—CH 2 —CH 2 —O—) 1-20 ;
L B2 is AA 0-12 , wherein AA is a natural amino acid, a non-natural amino acid or —(CR 15 ) o —S—S—(CR 15 ) p where o and p are each independently an integer from 1 to 20,
L B3 is -PABA-, -PABC- or is absent,
L C is absent or is independently selected from the group consisting of —C 1 -C 6 alkylene-, —NRC 3 -C 8 -heterocyclylNR—, —NRC 3 -C 8 -carbocyclylNR—, —NRC 1 -C 6 alkylNR—, —NRC 1 -C 6 alkylene-, —S—, —NR—, —NRNR—, —O(CR 2 ) 1-4 S—S(CR 2 ) 1-4 N(R)—, —NRC 1 -C 6 -alkylenephenyleneNR—, —NRC 1 -C 6 alkylenephenyleneSO 2 NR—, —OC 1 -C 6 alkylS-SC 1 -C 6 alkylC(COOR)NR—, —NRC(COOR)C 1 -C 6 alkylS-SC 1 -C 6 alkylO—,
wherein
X A is CR or N,
X B is CH, CR(C(R) 2 ) 1-3 NR, CR(C(R) 2 ) 1-3 O, CR(C(R) 2 ) 1-3 C(O)NR, CR—(C(R) 2 ) 1-3 C(O)NRNR, CR(C(R) 2 ) 1-3 SO 2 NR, CR(C(R) 2 ) 1-3 NRNR, CR(C(R) 2 ) 1-3 NRC(O) or N,
each X C is R;
each X D is —(CH 2 ) 1-5 —, or is absent;
X E is O, S, C(R) 2 , C(R)(C(R) 2 ) 1-3 —NR 2 or NR, and
each X F is (C(R) 2 ) 1-3 —NR or C(R) 2 —(C(R) 2 ) 1-3 —O.
3. A compound of the Formula:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
F 1 and F 2 are each independently selected from ring systems A, and B:
wherein:
each V 1 is independently a bond, O, N(R) or S, for each ring system A in which V 1 appears;
each V 2 is independently O, N(R) or S, for each ring system B in which V 2 appears;
W 1 and W 2 are each independently H, —C 1 -C 5 alkyl or -phenyl, for each ring system A and ring system B in which W 1 and W 2 appear;
each X is independently —OH, —O-acyl, azido, halo, cyanate, thiocyanate, isocyanate, thioisocyanate, or
for each ring system A in which X appears;
each Y is independently selected from the group consisting of H, —C 1 -C 6 alkyl-R A , —C(O)R A , —C(S)R A , —C(O)OR A , —S(O) 2 OR A , —C(O)N(R A ) 2 , —C(S)N(R A ) 2 , and —PO(OR A ) 2 , for each ring system A in which Y appears, wherein each R A is independently selected from the group consisting of H, —C 1 -C 20 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, aralkyl, —C 1 -C 10 heterocyclyl, —C 3 -C 8 carbocyclyl and —C 1 -C 20 alkylN(R) 2 , wherein said —C 1 -C 20 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, aralkyl, —C 1 -C 10 heterocyclyl, —C 3 -C 8 carbocyclyl and —C 1 -C 20 alkylN(R) 2 are optionally substituted with 1 to 3 substitutents independently selected from R;
each Z is independently selected from the group consisting of H, —C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl- and —C 3 -C 8 carbocyclyl, and wherein said C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl and —C 3 -C 8 carbocyclyl, are each optionally substituted with 1 to 3 substitutents independently selected from R, for each ring system A and ring system B in which Z appears;
L 1 and L 2 are each independently a direct bond;
T is selected from:
—C(A 1 )X 1 -T 2 -X 1 C(B 1 )—, where T 2 is:
wherein each X 1 is independently a bond, —NR E —, —O— or —S—, wherein A 1 and B 1 are each independently ═O or ═S, wherein R 1 , R 2 , R 3 , and R 4 are each independently R E , or R 1 and R 2 form a ring system, or R 3 and R 4 form a ring system, or both R 1 and R 2 , and R 3 and R 4 each independently form ring systems, or R 1 and R 3 form a ring system, or R 2 and R 4 form a ring system, or both R 1 and R 3 , and R 2 and R 4 each independently form ring systems, where the ring systems are independently selected from —C 1 -C 10 heterocyclyl or —C 3 -C 8 carbocyclycl, or R 1 , R 2 , R 3 and R 4 are each bonds to different carbons on D, wherein g and j are each independently an integer from 0 to 50 and m is an integer from 1 to 50, and wherein D is —C 3 -C 8 carbocyclo substituted with N(R E )C(O)— where the carbonyl is bonded to L, or —C(O)— where the carbonyl is bonded to L, and additionally optionally substituted by 1 to 2 R;
where each R E is independently selected from the group consisting of H, —C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, -aryl, -aralkyl, —C 1 -C 10 heterocyclyl, —C 3 -C 8 carbocyclyl, —C(O)OC 1 -C 8 alkyl, —C(O)N(C 1 -C 8 alkyl) 2 , and —C(O)-halo, and wherein each R E is optionally substituted with 1 to 3 substitutents independently selected from R;
L is L A -L B -(L C ) 1-3 ;
L A is selected from -halo, —N(R) 2 , —CON(R) 2 , —S-aryl optionally substituted with —NO 2 or —CONR 2 , —S-heteroaryl optionally substituted with —NO 2 , alkyl-SO 2 -heteroaryl, arylSO 2 -heteroaryl-,
L B is L B1 -L B2 -L B3
wherein L B1 is absent or is one or more components selected from the group consisting of —C(O)—, —C(S)—, —C(O)NR—, —C(O)C 1 -C 6 alkyl-, —C(O)NRC 1 -C 6 alkyl-, —C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —, —C(O)C 1 -C 6 alkylNRC(O)—, —C(O)C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —, —C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —C(O)—, —C 1 -C 6 alkyl-S—S—C 1 -C 6 alkyl NRC(O)CH 2 —, —C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 NRC(O)CH 2 —, —C(O)C 1 -C 6 alkyl-NRC(O)C 1-6 alkyl-, —N═CR-phenyl-O—C 1 -C 6 alkyl-, —N═CR-phenyl-O—C 1 -C 6 alkyl-C(O)—, —C(O)—C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 NRC(O)—, —C(O)C 1 -C 6 alkyl-phenyl(NR—C(O)C 1 -C 6 alkyl) 1-4 -, —C(O)C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —NRC(O)C 1 -C 6 alkyl-, —C 1 -C 6 alkyl-, —S—, —C(O)—CH(NR—C(O)C 1 -C 6 alkyl)-C 1 -C 6 alkyl- and (—CH 2 —CH 2 —O—) 1-20 ;
L B2 is AA 0-12 , wherein AA is a natural amino acid, a non-natural amino acid or —(CR 15 ) o —S—S—(CR 15 ) p where o and p are each independently an integer from 1 to 20,
L B3 is -PABA-, -PABC- or is absent;
L C is absent or is independently selected from the group consisting of —C 1 -C 6 alkylene-, —NRC 3 -C 8 -heterocyclylNR—, —NRC 3 -C 8 -carbocyclylNR—, —NRC 1 -C 6 alkylNR—, —NRC 1 -C 6 alkylene-, —S—, —NR—, —NRNR—, —O(CR 2 ) 1-4 S—S(CR 2 ) 1-4 N(R)—, —NRC 1 -C 6 -alkylenephenyleneNR—, —NRC 1 -C 6 alkylenephenyleneSO 2 NR—, —OC 1 -C 6 alkylS-SC 1 -C 6 alkylC(COOR)NR—, —NRC(COOR)C 1 -C 6 alkylS-SC 1 -C 6 alkylO—,
wherein
X A is CR or N,
X B is CH, CR(C(R) 2 ) 1-3 NR, CR(C(R) 2 ) 1-3 O, CR(C(R) 2 ) 1-3 C(O)NR, CR—(C(R) 2 ) 1-3 C(O)NRNR, CR(C(R) 2 ) 1-3 SO 2 NR, CR(C(R) 2 ) 1-3 NRNR, CR(C(R) 2 ) 1-3 NRC(O) or N;
each X C is R;
each X D is —(CH 2 ) 1-5 —, or is absent;
X E is O, S, C(R) 2 , C(R)(C(R) 2 ) 1-3 —NR 2 or NR, and
each X F is (C(R) 2 ) 1-3 —NR or C(R) 2 —(C(R) 2 ) 1-3 —O.
4. A compound of Formula (IIIB):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
AB is an antibody;
F 1 and F 2 are each independently selected from ring systems A, and B:
wherein:
each V 1 is independently a bond, O, N(R) or S, for each ring system A in which V 1 appears;
each V 2 is independently O, N(R) or S, for each ring system B in which V 2 appears;
W 1 and W 2 are each independently H, —C 1 -C 5 alkyl or -phenyl, for each ring system A and ring system B in which W 1 and W 2 appear;
each X is independently —OH, —O-acyl, azido, halo, cyanate, thiocyanate, isocyanate, thioisocyanate, or
for each ring system A in which X appears;
each Y is independently selected from the group consisting of H, —C 1 -C 6 alkyl-R A , —C(O)R A , —C(S)R A , —C(O)OR A , —S(O) 2 OR A , —C(O)N(R A ) 2 , —C(S)N(R A ) 2 , and —PO(OR A ) 2 , for each ring system A in which Y appears, wherein each R A is independently selected from the group consisting of H, —C 1 -C 20 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, aralkyl, —C 1 -C 10 heterocyclyl, —C 3 -C 8 carbocyclyl and —C 1 -C 20 alkylN(R) 2 , wherein said —C 1 -C 20 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, aralkyl, —C 1 -C 10 heterocyclyl, —C 3 -C 8 carbocyclyl and —C 1 -C 20 alkylN(R) 2 are optionally substituted with 1 to 3 substitutents independently selected from R;
each Z is independently selected from the group consisting of H, —C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl and —C 3 -C 8 carbocyclyl, and wherein said C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl and —C 3 -C 8 carbocyclyl, are each optionally substituted with 1 to 3 substitutents independently selected from R, for each ring system A and ring system B in which Z appears;
L 1 and L 2 are each independently a direct bond;
T is selected from:
—C(A 1 )X 1 -T 2 -X 1 C(B 1 )—, where T 2 is:
wherein each X 1 is independently a bond, —NR E —, —O— or —S—, wherein A 1 and B 1 are each independently ═O or ═S, wherein R, R 2 , R 3 , and R 4 are each independently R E , or R 1 and R 2 form a ring system, or R 3 and R 4 form a ring system, or both R 1 and R 2 , and R 3 and R 4 each independently form ring systems, or R 1 and R 3 form a ring system, or R 2 and R 4 form a ring system, or both R 1 and R 3 , and R 2 and R 4 each independently form ring systems, where the ring systems are independently selected from —C 1 -C 10 heterocyclyl or —C 3 -C 8 carbocyclycl, or R 1 , R 2 , R 3 and R 4 are each bonds to different carbons on D, wherein g and j are each independently an integer from 0 to 50 and m is an integer from 1 to 50, and wherein D is —C 3 -C 8 carbocyclo substituted with N(R E )C(O)— where the carbonyl is bonded to L, or —C(O)— where the carbonyl is bonded to L, and additionally optionally substituted by 1 to 2 R;
where each R E is independently selected from the group consisting of H, —C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, -aryl, -aralkyl, —C 1 -C 10 heterocyclyl, —C 3 -C 8 carbocyclyl, —C(O)OC 1 -C 8 alkyl, —C(O)N(C 1 -C 8 alkyl) 2 , and —C(O)-halo, and wherein each R E is optionally substituted with 1 to 3 substitutents independently selected from R;
wherein each R is independently selected from the group consisting of H, —C 1 -C 20 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, halo, hydroxyl, alkoxy, —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —NO 2 , —C 6 -C 14 aryl and —C 6 -C 14 heteroaryl, wherein two or more R optionally join to form a ring or rings, and wherein said —C 6 -C 14 aryl and —C 6 -C 14 heteroaryl are optionally substituted with 1 to 5 substituents independently selected from —C 1 -C 10 alkyl, —C 1 -C 10 alkoxy, -halo, —C 1 -C 10 alkylthio, -trifluoromethyl, —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —C 1 -C 10 alkyl-N(C 1 -C 8 alkyl) 2 , —C 1 -C 3 alkylthio, —NO 2 or —C 1 -C 10 heterocyclyl, for each ring system in which R appears;
L is L A -L B -(L C ) 1-3 ;
L A is selected from: a bond to AB, —NR-(bond to AB), alkyl-SO 2 -heteroaryl, arylSO 2 -heteroaryl-,
L B1 -L B2 -L B3
wherein L B1 is absent or is one or more components selected from the group consisting of —C(O)—, —C(S)—, —C(O)NR—, —C(O)C 1 -C 6 alkyl-, —C(O)NRC 1 -C 6 alkyl-, —C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —, —C(O)C 1 -C 6 alkylNRC(O)—, —C(O)C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —, —C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —C(O)—, —C 1 -C 6 alkyl-S—S—C 1 -C 6 alkylNRC(O)CH 2 —, —C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 NRC(O)CH 2 —, —C(O)C 1 -C 6 alkyl-NRC(O)C 1-6 alkyl-, —N═CR-phenyl-O—C 1 -C 6 alkyl-, —N═CR-phenyl-O—C 1 -C 6 alkyl-C(O)—, —C(O)—C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 NRC(O)—, —C(O)C 1 -C 6 alkyl-phenyl(NR—C(O)C 1 -C 6 alkyl) 1-4 -, —C(O)C 1 -C 6 alkyl(OCH 2 CH 2 ) 1-6 —NRC(O)C 1 -C 6 alkyl-, —C 1 -C 6 alkyl-, —S—, —C(O)—CH(NR—C(O)C 1 -C 6 alkyl)-C 1 -C 6 alkyl- and (—CH 2 —CH 2 —O—) 1-20 ;
L B2 is AA 0-12 , wherein AA is a natural amino acid, a non-natural amino acid or —(CR 15 ) o —S—S—(CR 15 ) p where o and p are each independently an integer from 1 to 20,
L B3 is -PABA-, -PABC- or is absent;
L C is absent or is independently selected from the group consisting of —C 1 -C 6 alkylene-, —NRC 3 -C 8 -heterocyclylNR—, —NRC 3 -C 8 -carbocyclylNR—, —NRC 1 -C 6 alkylNR—, —NRC 1 -C 6 alkylene-, —S—, —NR—, —NRNR—, —O(CR 2 ) 1-4 S—S(CR 2 ) 1-4 N(R)—, —NRC 1 -C 6 -alkylenephenyleneNR—, —NRC 1 -C 6 alkylenephenyleneSO 2 NR—, —OC 1 -C 6 alkylS-SC 1 -C 6 alkylC(COOR)NR—, —NRC(COOR)C 1 -C 6 alkylS-SC 1 -C 6 alkylO—,
wherein
X A is CR or N,
X B is CH, CR(C(R) 2 ) 1-3 NR, CR(C(R) 2 ) 1-30 , CR(C(R) 2 ) 1-3 C(O)NR, CR—(C(R) 2 ) 1-3 C(O)NRNR, CR(C(R) 2 ) 1-3 SO 2 NR, CR(C(R) 2 ) 1-3 NRNR, CR(C(R) 2 ) 1-3 NRC(O) or N;
each X C is R;
each X D is —(CH 2 ) 1-5 —, or is absent;
X E is O, S, C(R) 2 , C(R)(C(R) 2 ) 1-3 —NR 2 or NR, and
each X F is (C(R) 2 ) 1-3 —NR or C(R) 2 —(C(R) 2 ) 1-3 —O.
5. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
6. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
where X is an IL13 antibody or Y is VEGF antibody.
7. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
where X is an IL13 antibody or Y is VEGF antibody.
8. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
where X is an IL13 antibody or Y is VEGF antibody.