Pdd compounds

Abstract

The invention relates to pyrridinobenzodiazepines (PDDs) comprising three fused 6-7-6-membered rings linked to aromatic groups, and pharmaceutically acceptable salts thereof, which are useful as medicaments, such as anti-proliferative agents. PDDs may be represented by formula (I): and salts and solvates thereof, wherein the dotted lines indicates the optional presence of a double bond between one or more of C1 and C2, C2 and C3, and C3 and C4; R1 and R2 are substituent groups; R3 is selected from H, C1-12 alkyl and CH2Ph; R4 is selected from phenyl and Cs-9heteroaryl groups optionally substituted, with the proviso that the optionally substituted C 5-9 heteroaryl is not indolyl; R19 is selected from H and (CH2)t-NR2oR21; Y1 is N or CH; Y2 is N or CH; and wherein at least one of Y1 and Y2 is CH; p is 0 or 1; X1 is a connecting group; L is a linker group; X2 is a connecting group or is absent; q is selected from 0, 1, 2, 3, 4, 5 and 6; A is selected from: for each A1 group one of Y3 and Y4 is selected from N-R17, S and O; and the other of Y3 and Y4 is CH; and Y5 is selected from CH, N, S and COH; for each A2 group one of Y6 and Y7 is independently selected from N and CH; and the other of Y6 and Y7 is CH; R13, R14, R17, R20 and R21 are independently selected from H and C1-6 alkyl; and either: (i) R5 and R6 together form a double bond; (ii) R5 is H and R6 is OH; or (iii) R is H and R6 is OC1-6 alkyl; with the proviso that when p is 0 and A is A 1 , then: (a) for at least one A1 group one of Y Sand Y4 is selected from S and O; or (b) for at least one A1 group Y5 is S; or (c) R4 is not pyrrolyl, imidazolyl, optionally substituted pyrrolyl or optionally substituted imidazolyl.

What is claimed: 
     
         1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         and salts and solvates thereof, 
         wherein; 
         the dotted lines indicates the optional presence of a double bond between one or more of C1 and C2, C2 and C3, and C3 and C4; 
         R 1  is selected from R 7 , ═CH 2 , ═CH—(CH 2 ) m —CH 3 , ═O, (CH 2 ) m —OR 7 , (CH 2 ) m —CO 2 R 7 , (CH 2 ) m —NR 7 R 8 , O—(CH 2 ) n —NR 7 R 8 , NH—C(O)—R 7 , O—(CH 2 ) n —NH—C(O)—R 7 , O—(CH 2 ) n —C(O)—NH—R 7 , (CH 2 ) m —SO 2 R 7 , O—SO 2 R 7 , (CH 2 ) m —C(O)R 7  and (CH 2 ) m —C(O)NR 7 R 8 ; 
         R 2 is selected from R 9 , CH 2 , ═CH—(CH 2 ) m —CH 3 , ═O, (CH 2 ) r —OR 9 , (CH 2 ) r —CO 2 R 9 , (CH 2 ) r —NR 9 R 10 , O—(CH 2 ) s —NR 9 , R 10 , NH—C(O)—R 9 , O—(CH 2 ) s —NH—C(O)—R 9 , O—(CH 2 ) s —C(O)—NH—R 9 , (CH 2 ) r —SO 2 R 9 , O—SO 2 R 9 , (CH 2 ) r —COR 9  and (CH 2 ) r —C(O)NR 9 R 10 ; 
         R 3  is selected from H, C 1-12  alkyl and CH 2 Ph; 
         R 4  is selected from phenyl and C 5-9  heteroaryl groups optionally substituted with up to three optional substituent groups selected from OH, C 1-6  alkyl, OC 1-6  alkyl, (CH 2 ) j —CO 2 R 11 , O—(CH 2 ) k —NR 11 R 12 , (CH 2 ) j —NR 11 R 12 , C(═O)—NH—(CH 2 ) k —NR 11 R 12 ; C(═O)—NH—R 24  and C(═O)—NH—(CH 2 ) k —C(═NH)NR 11 R 12 ; with the proviso that the optionally substituted C 5-9  heteroaryl is not indolyl; 
         R 19  is selected from H and (CH 2 ) t —NR 20 R 21 ; 
         Y 1  is N or CH; 
         Y 2  is N or CH; and wherein at least one of Y 1  and Y 2  is CH; 
         p is 0 or 1; 
         j, m, r and t are independently selected from an integer from 0 to 6; 
         k, n and s are independently selected from an integer from 1 to 6; 
         X 1  is selected from O, S, NR 13 , CR 13 R 14 , CR 13 R 14 O, C(═O), C(═O)NR 13 , NR 13 C(═O), O—C(O) and C(O)—O; 
         L is selected from an amino acid, a peptide chain having from 2 to 6 amino acids, an alkylene chain containing from 1 to 12 carbon atoms which may contain one or more carbon-carbon double or triple bonds, a paraformaldehyde chain —(OCH 2 ) 1-12 —, a polyethylene glycol chain —(OCH 2 CH 2 ) 1-6 —, wherein the chain may be interrupted by one or more of O, S, NH, C 5-9  heteroarylene, phenylene, or a combination of the foregoing; 
         X 2  is selected from O, S, NR 15 , CR 15 R 16 , CR 15 R 16 , C(═O), C(═O)NR 15 , NR 15 C(═O), O—C(O) and C(O)—O or is absent; 
         q is selected from 0, 1, 2, 3, 4, 5 and 6; 
         A is selected from: 
       
       
         
           
           
               
               
           
         
         
           for each A1 group one of Y 3  and Y 4  is independently selected from N—R 17 , S and O; and the other of Y 3  and Y 4  is CH; and Y 5  is independently selected from CH, N, S and COH; 
           for each A2 group one of Y 6  and Y 7  is independently selected from N and CH; and the other of Y 6  and Y 7  is CH; 
         
         R 7  and R 9  are independently selected from H, C 1-12  alkyl; C 5-9  heteroaryl, C 6-15  heteroarylatkyl, phenyl and C 7-12  aralkyl groups; wherein the heteroaryl, heteroarylalkyl, phenyl and aralkyl groups are optionally substituted with up to three optional substituent groups selected from C 1-6  alkyl, OH, OC 1-6  alkyl; R 24  is a phenyl optionally substituted with up to three optional substituent groups selected from OH, C 1-6  alkyl, OC 1-6  alkyl, (CH 2 ) j -CO 2 R 11 , O—(CH 2 ) k —NR 11 R 12 , (CH 2 ) j —NR 11 R 12 , C(═O)—NH—(CH 2 ) k —NR 11 R 12  and C(═O)—NH—(CH 2 ) k —C(═NH)NR 11 R 12 ; 
         R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 20  and R 21  are independently selected from H and C 1-6  alkyl; 
         and either:
 (i) R 5  and R 6  together form a double bond; 
 (ii) R 5  is H and R 6  is OH; or 
 (iii) R 5  is H and R 6  is OC 1-6  alkyl; 
 
         with the proviso that when p is 0 and A is A1, then:
 (a) for at least one A1 group one of Y 3  and Y 4  is selected from S and O; or 
 (b) for at least one A1 group Y 5  is S; or 
 (c) R 4  is not pyrrolyl, imidazolyl, optionally substituted pyrrolyl or optionally substituted imidazolyl. 
 
       
     
     
         2 . The compound, salt, or solvate of  claim 1 , wherein q is 1, 2, 3, 4, 5 or 6. 
     
     
         3 . The compound, salt, or solvate of  claim 2 , wherein R 24  is —C 6 H 4 —(CH 2 ) j —R 18 , wherein R 18  is selected from CO 2 R 11  and NR 11 R 12 . 
     
     
         4 . The compound, salt or solvate of  claim 2 , wherein R 1  is selected from R 7 , O—(CH 2 ) n —NH—C(O)—R 7  and O—(CH 2 ) n  —C(O)—NH—R 7 . 
     
     
         5 . The compound, salt or solvate of  claim 2 , wherein R 2  is H. 
     
     
         6 . The compound, salt or solvate of  claim 2 , wherein R 3  is selected from methyl and ethyl. 
     
     
         7 . The compound, salt or solvate of  claim 2 , wherein R 4  is selected from phenyl, pyrrolyl, N-methylpyrrolyl, furanyi, thiophenyi, imidazolyl, N-methylimidazolyl, oxazolyl, thiazolyl, pyridyl, benzofuranyl, benzothiophenyl, benzimidazolyl, N-methylbenzoimidazolyl, benzooxazolyl arid benzothiazolyl, optionally substituted with up to three optional substituent groups selected from OH, C 1-6  alkyl, OC 1-6  alkyl, (CH 2 ) j —CO 2 R 11 , O—(CH 2 ) k —NR 11 R 12 , (CH 2 ) j —NR 11 R 12 , C(═O)——NH—(CH 2 ) k —NR 11 R 12 ; C(═O)—NH—C 6 H 4 —(CH 2 ) j —R 18  and C(═O)—NH—(CH 2 ) k —C(═NH) NR 11 R 12 . 
     
     
         8 . The compound, salt or solvate of  claim 2 , wherein R 4  is selected from: 
       
         
           
           
               
               
           
         
         wherein Z 4  is selected from NH, N—CH 3 , S and O; 
         Z 2  is selected from CH and N; 
         Z 3  is selected from S and O; 
         Z 4  is selected from CH and N; 
         R 22  is selected from (CH 2 ) j CO 2 R 11 , (CH 2 )NR 11 R 12  and C(═O)—NH—C 6 H 4 —(CH 2 ) j —R 18 ; 
         R 18  is selected from CO 2 R 11  and NR 11 R 12 ; 
         j is selected from an integer from 0 to 6; and 
         R 11  and R 12  are independently selected from H and C 1-6  alkyl; and 
         R 23  is selected from H and C 1-6  alkyl. 
       
     
     
         9 . The compound, salt or solvate of  claim 2 , wherein R 5  and R 6  together form a double bond. 
     
     
         10 . The compound, salt or solvate of  claim 2 , wherein compound has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound, salt, or solvate of  claim 2 , wherein the compound has the following structure; 
       
         
           
           
               
               
           
         
         wherein q is selected from 0, 1, 2, 3, 4, 5 and 6; 
         p is 0 or 1; 
         L is an alkylene chain containing from 1 to 12 carbon atoms; 
         Y 1  is N or CH; 
         Y 2  is N or CH; and wherein at least one of Y 1  and Y 2  is CH; 
         Y 5  is selected from CH and N; 
         Z 1  is selected from O, S, NH and N—CH 3 ; 
         Z 2  is selected from CH and N; and 
         Z 3  is selected from S and O; 
         Z 4  is selected from CH and N; 
         R 22  is selected from (CH 2 ) j CO 2 H, (CH 2 ) j CO 2 C 1-6  alkyl, (CH 2 ) j NR 11 R 12  and 
         C(═O)—NH—C 6 H 4 —(CH 2 ) j —R 18 ; 
         R 18  is selected from CO 2 R 11  and NR 11 R 2 ; 
         R 19  is selected from H and (CH 2 ) t —NR 20 R 21 ; 
         j and t are independently selected from an integer from 0 to 6; and 
         R 11 , R 12  and R 23  are independently selected from H and C 1-6  alkyl. and either:
 (i) R 5  and R 6  together form a double bond; 
 (ii) R 5  is H and R 6  is OH; or 
 (iii) R 5  is H and R 6  is OC 1-6  alkyl; 
 
         with the proviso that when the compound is (XVI) and p is 0, that Z 1  is selected from O and S. 
       
     
     
         12 . The compound, salt, or solvate of  claim 2 , selected from the group consisting of; 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . The compound, salt, or solvate of  claim 2 , linked, either directly or indirectly, to a targeting agent to provide a targeted conjugate. 
     
     
         14 . The compound, salt, or solvate of  claim 2 , linked to a linking group. 
     
     
         15 . The compound, salt, or solvate of  claim 1 , wherein p is 1. 
     
     
         16 . The compound, salt, or solvate of  claim 15 , linked, either directly or indirectly, to a targeting agent to provide a targeted conjugate. 
     
     
         17 . The compound, salt, or solvate of  claim 15 , linked to a linking group. 
     
     
         18 . The compound, salt, or solvate of claim i, wherein L is a peptide chain having from 2 to 6 amino acids, an alkylene chain containing from I to 12 carbon atoms which may contain one or more carbon-carbon double or triple bonds, a paraformaldehyde chain, or a polyethylene glycol chain, wherein the chain is interrupted by one or more of O, S, NH, C 5-9  heteroarylene, phenylene, or a combination of the foregoing. 
     
     
         19 . The compound, salt, or solvate of  claim 18 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound, salt, or solvate of  claim 18 , linked, either directly or indirectly, to a targeting agent to provide a targeted conjugate. 
     
     
         21 . The compound, salt, or solvate of  claim 18 , linked to a linking group. 
     
     
         22 . The compound, salt, or solvate of  claim 1 , wherein:
 a. the dotted lines indicating the optional presence of a double bond between one or more of C1 and C2, C2 and C3, and C3 and C4 and are absent;   b. R 1  and R 2  are each H ;   c. R 3  is CH 3 ;   d. X 1  is O;   e. L is an alkylene chain containing from i to 12 carbon atoms, which chain is optionally interrupted by one or more of C 5-9  heteroarylene, C 5-9  phenylene or combinations of the foregoing;   f. X 2  is C(═O)NH;   g. q is 0, 1, 2, 3, 4, 5, or 6;   h. A is A1, wherein Y 4  is CH and Y 3  is NCH 3  or A is A2, wherein Y6 and Y 7  are each CH;   i. p is 0 or 1.   
     
     
         23 . The compound, salt, or solvate of  claim 22 , wherein R 4  is selected from the group consisting of: phenyl, pyrrolyl, N-methylpyrrolyl, furanyl, thiophenyl, imidazolyl, N-methylimidazolyl, oxazolyl, thiazolyl, pyridyl, benzofuranyl, benzothiophenyl, benzimidazolyl, N-methylbenzoimidazolyl, benzooxazolyl and benzothiazolyl, each of the foregoing optionally substituted with up to three optional substituent groups selected from OH, C 1-6  alkyl, OC 1-6  alkyl, (CH 2 ) j —CO 2 R 11 , O—(CH 2 ) k —NR 11 R 12 , (CH 2 ) j —NR 11 R 12 , C(═O)—NH—(CH 2 ) k —NR 11 R 2 ; C(═O)—NH—R 24  and C(═O)—NH—(CH 2 ) k —C(═NH)NR 11 R 12 . 
     
     
         24 . The compound, salt, or solvate of  claim 22 , wherein R 4  is selected from the group consisting of: phenyl, N-methylpyrrolyl, thiophenyl, N-methylimidazolyl, oxazolyl, thiazolyl, benzothiophenyl, N-methylbenzoimidazolyl and benzothiazolyl, each of the foregoing optionally substituted with one or two optional substituent groups selected from OH, C 1-6  alkyl, OC 1-6  alkyl, (CH 2 ) j —CO 2 R 11 O—(CH 2 ) k —NR 11 R 12 , (CH 2 ) j —NR 11 R 12 , C(═O)—NH—(CH 2 ) k —NR 11 R 12 ; C(═O)—NH—R 24  and C(═O)—NH—(CH 2 ) k —C(═NH)NR 11 R 12 . 
     
     
         25 . A compound selected from the group consisting of:
 a. methyl (S)-5-(4-(4-((2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido-[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-1H-pyrrole-2-carboxamido)benzo-[b]thiophene-2-carbovlate (13);   b. methyl (S)-5-(4-(4-(1,2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido-[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-1H-imidazole-2-carboxamido)-benzor[b]thiophene-2-carboxylate (17);   c. methyl (S)-4-(4-(4-(4-((2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]-pyrido[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-1H-imidazole-2-carboxamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylate 20);   d. methyl (S)-4-(4-(4-(4-((2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]-pyrido[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-1H-pyrrole-2-carboxamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylate (24);   e. methyl (S)-4-(4-(4-(4-((2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]-pyrido[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-benzamido)phenyl)-1-methyl-1H-pyrrole-2-carboxylate (28);   f. methyl (S)-5-(4-(4-((2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido-[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-benzamido)benzo[b]thiophene-2-carboxylate (30);   g. methyl (S)-4-(4-(4-((2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido-[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-1H-imidazole-2-carboxamido)-benzoate (34);   h. methyl (S)-4-(4-(4-((2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido-[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-1H-pyrrole-2-carboxamido)-benzoate (38);   i. (S)-N-(4-aminophenyl)-4-(4-(4-(4-((2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydro-benzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)butan-amido)-1-methyl-1H-pyrrole-2-carboxamido)phenyl)-1-methyl-1H-pyrrole-2-carboxamide (41);   j. (S)-N-(2-((4-Aminophenyl)carbamoyl)benzo[b]thiophen-5-yl)-4-(4-((2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)-butanamido)-1-methyl-1H-pyrrole-2-carboxamide (47);   k. Methyl 5-(4-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrrole-2-carboxamido)-benzo[b]thiophene-2-carboxylate (62);   l. (S)-N-(4-Aminophenyl)-4-(6-a2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-3-yL)oxy)hexan-amido)-1-methyl-1H-pyrrole-2-carboxamide (66); and   m. (S)-N-(2-Aminoethyl)-4-(4-(4-(4-((2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydro-benzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-1H-pyrrole-2-carboxamido)phenyl)-1-methyl-1H-pyrrole-2-carboxamide (68) and salts and solvates thereof.   
     
     
         26 . A compound selected from the group consisting of:
 a. (S)-4-(4-((2-Methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-N-(4-(1-methyl-5-(phenylcarbamoyl)-1H-pyrrol-3-yl)phenyl)-1H-pyrrole-2-carboxamide (15);   b. (S)-4-(4-((2-Methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-N-(4-(1-methyl-5-(p-tolylcarbamoyl)-1H-pyrrol-3-yl)phenyl)-1H-pyrrole-2-carboxamide (19);   c. Methyl (S)-4-(4-(4-(4-(4-(2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-1H-pyrrole-2-carboxamido)phenye-1-methyl-1H-pyrrole-2-carboxamido)benzoate (24);   d. (S)-4-(4-(4-(4-((2-Methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-1H-pyrrole-2-carboxamido)phenyl)-1-methyl-N-phenyl-1H-imidazole-2-carboxamide (30);   e. (S)-4-(4-((2-Methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-N-(4-(1-methyl-5-(phenylcarbamoyl)-1H-pyrrol-3-yl)phenyl)-1H-imidazole-2-carboxamide (35);   f. Methyl (S)-4-(2-(3-(((2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)methyl)phenyl)acetamido)-1-methyl-1H-pyrrole-2-carboxylate (53);   g. Ethyl (S)-4-(2-(3-(((2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)methyl)phenyl)acetamido)-1-methyl-1H-imidazole-2-carboxylate (55);   h. (S)-2-(4-(2-(3-(((2-Methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)methyl)phenyl)acetamido)-1-methyl-1H-imidazole-2-carboxarnido)-N-phenylbenzo[d]thiazole-5-carboxamide (60);   i. (S)-2-(4-(4-((2-Methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-1H-imidazole-2-carboxamido)-N-phenylbenzo[d]thiazole-5-carboxamide (66);   j. (S)-4-(2-(3-(((2-Methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)methyl)phenyl)acetamido)-1-methyl-N-(4-(1-methyl-5-(phenylcarbamoyl)1H-pyrrol-3-yl)phenyl)-1H-pyrrole-2-carboxamide (71);   k. 4-((2S,5S)-37-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5-isopropyl-2-methyl-4,7,35-trioxo-10,13,16,19,22,25,28,31-octaoxa-3,6,34-triazaheptatriacontanamido)benzyl (6S,6aS)-6-hydroxy-2-methoxy-3-(4-((1-methyl-5-((4-(1-methyl-5-(phenylcarbamoyl)-1H-pyrrol-3-yl)phenyl)carbamoyl)-1H-pyrrol-3-yl)amino)-4-oxobutoxy)-12-oxo-6,6a,7,8,9,10-bexahydrobenzo pyrido[1,2-a][1,4]diazepine-5(12H)-carboxylate (81);   l. N-(4-((S)-2-((S)-2-(6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)phenyl)-4-(4-(4-(4-(((S)-2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-1H-pyrrole-2-carboxamido)phenyl)-1-methyl-1H-pyrrole-2-carboxamide (82); and   m. N-(4-((2S,5S)-37-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5-isopropyl-2-methyl-4,7,35-trioxo-10,13,16,19,22,25,28,31-octaoxa-3,6,34-triazaheptatriacontanamido)phenyl)-4-(4-(4-(4-(((S)-2-methoxy-12-oxo-6a,7,8,9,10,12-hexahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-3-yl)oxy)butanamido)-1-methyl-1H-pyrrole-2-carboxamido)phenyl)-1-methyl-1H-pyrrole-2-carboxamide (86).   
     
     
         27 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient, carrier or diluent 
     
     
         28 . A method of treatment of a patient suffering from a proliferative disease, comprising administering to said patient a therapeutically effective amount of a compound of  claim 1  or a pharmaceutical composition of  claim 27 .