SUBSTITUTED BENZO[5,6][1,4]DIAZEPINO[1,2-a]INDOLES FOR THE TREATMENT OF PROLIFERATIVE DISORDERS

A cell-binding agent-cytotoxic agent conjugate represented by the following formula:

• or a pharmaceutically acceptable salt thereof, wherein:
• W1 is —(CH2)n1—;
• W2 is —(CH2)n2—
• n1 is 1, 2 or 3;
• n2 is 0, or 2;
• n3 is 0 or 1;
• R1a and R1a′ are each independently H, halide, —OH, or (C1-C6)alkyl;
• or R1a and R1a′ together form a double bond containing group ═B;
• ═B is selected from a (C2-C6)alkenyl or a carbonyl group, wherein the (C2-C6)alkenyl is optionally substituted with a halogen, —OH, (C1-C3)alkoxy or phenyl;
• Q is Q1-Ar-Q2;
• Q1 is absent, (C1-C6)alkyl, or —CH═CH—;
• Ar is absent or an aryl group;
• Q2 is —H, a (C1-C6)alkyl, a (C1-C6)alkenyl, a polyethylene glycol unit —Rc′—(OCH2CH2)n—Rc, or a substituent selected from a halogen, guanidinium [—NH(C═NH)NH2], —R, —OR, —NR′R″, —NO2, —NCO, —NR′COR″, NR′(C═O)OR″—SR, —SOR′, —SO2R′, —SO3H, —OSO3H, —SO2NR′R″, cyano, an azido, —COR′, —OCOR′ and —OCONR′R″;
• n is an integer from 1 to 10;
• Rc′ is a (C1-C4)alkyl,
• Rc is H, or a (C1-C4)alkyl,
• the double line between N and C represents a single bond or a double bond, provided that when it is a double bond X is absent and Y is —H, or a (C1-C4)alkyl, and when it is a single bond, X is —H, an amine protecting moiety or RL1;
• and
• Y is H of a leaving group selected from —ORY, —OCORY1, —OCOORY1, —OCONRY1RY2, —NRY1RY2, —NRY1CORY2, —NRY1NRY1RY2, an optionally substituted 5- or 6-membered nitrogen-containing heterocycle (e.g., piperidine, tetrahydropyrrole, pyrazole, morpholine, etc. attached through the nitrogen atom), a guanidinium represented by —NRY1(C═NH)NRY1RY2, an amino acid residue, or a peptide represented by —NRCOP′, —SRY, —SORY1, halogen, cyano, azido, —OSO3H, sulfite (—SO3H or —SO2H), metabisulfite (H2S2O5), mono-, di-, tri-, and tetra-thiophosphate (PO3SH3, PO2S2H2, POS3H2, PS2H2), thiophosphate ester (RiO)2PS(ORi), RiS—, RiSO, RiSO2, RiSO3, thiosulfate (HS2O3), dithionite (HS2O4) phosphorodithioate (P(═S)(ORk′)(S)(OH)), hydroxamic acid (Rk′C(═O)NOH), and formaldehyde sulfoxylate (HOCH2SO2—) or a mixture thereof, wherein Ri is a linear or branched alkyl having 1 to 10 carbon atoms and is substituted with at least one substituent selected from —N(Rj)2, —CO2H, —SO3H, and —PO3H;
• Ri can be further optionally substituted with a substituent for an alkyl described herein;
• Rj is a linear or branched alkyl having 1 to 6 carbon atoms;
• Rk′ is a linear, branched or cyclic alkyl, alkenyl or alkynyl having 1 to 10 carbon atoms, aryl, heterocyclyl or heteroaryl;
• P′ is an amino acid residue or a polypeptide containing between 2 to 20 amino acid residues,
• RY, for each occurrence, is independently selected from the group consisting of —H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit —(CH2CH2O)n—Rc, an optionally substituted aryl having 6 to 18 carbon atoms, an optionally substituted 5- to 18-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 3- to 18-membered heterocyclic ring containing 1 to 6 heteroatoms independently selected from O, S, N and P;
• RY1 and RY2 are each independently selected from —H, —OH, —ORY, —NHRY, —NRY2, —CORY, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit;
• RL1 is self-immolative linker bearing a linking moiety that is covalently bonded the cell-binding agent (CBA);
• R1, R2, R3 and R4 are each independently selected from —H, a (C1-C6)alkyl, halogen, —OR, —NR′R″, —NO2, —NR′COR″, —SR, —SOR′, —SO2R′, —SO3H, —OSO3H, —SO2NR′R″, cyano, —COR′, —OCOR′, and —OCONR′R″;
• R, for each occurrence, is —H or a (C1-C6)alkyl;
• R′ and R″ are each independently selected from —H, —OH, —OR, —NHR, —NR2, —COR, or a (C1-C6)alkyl;
• R6 is —H, —R, —OR, —SR, —NR′R″, —NO2, or halogen;
• A is absent or is selected from —O—, —C(═O)—, —CRR′O—, —CRR′—, —S—, —CRR′S—, —NR5 and —CRR′N(R5)—;
• L1 is a spacer,
• Z1 is a bond,
• s3 is the site connected L1 and s4 is the site connected to Ar1;
• R5 is —H or a (C1-C4)alkyl;
• R100 and R101, for each occurrence, are each independently —H, halogen, (C1-C4)alkyl, or (C1-C4)haloalkyl;
• Ar1 is a 6- to 18-membered aromatic ring, a 5- to 18-membered heteroaromatic ring, or —Ar1′—Ar1″—, wherein Ar1′ and Ar1″ are each independently a 6- to 18-membered aromatic ring or a 5- to 18-membered heteroaromatic ring;
• Z2 is
• s5 is the site connected Ar1 and s6 is the site connected to Ar2;
• Ar2 is a 6- to 18-membered aromatic ring, a 5- to 18-membered heteroaromatic ring or —Ar2′—Ar2″—, wherein Ar2′ and Ar2″ are each independently a 6- to 18-membered aromatic ring or a 5 5- to 18-membered heteroaromatic ring;
• s7 is the site connected to Ar2 and s8 is the site connected to Ar3;
• Ar3 is a 6- to 18-membered aromatic ring, a 5- to 18-membered heteroaromatic ring or —Ar3′—Ar3′—, wherein Ar3′ and Ar3″ are each independently a 6- to 18-membered aromatic ring or a 5-to 18-membered heteroaromatic ring;
• LCB is a linker bearing a linking moiety that is covalently linked to the cell-binding agent (CBA);
• w is an integer from 1 to 20;
• Ra is —OH, —Cl, —O(C1-C6)alkyl or —C(═O)ORa is a reactive ester group;
• Rb and Rc are each independently —H, (C1-C4)alkyl or an amine protecting group;
• and provided (i) when the conjugate is represented by formula (V) or (VI), Z1 is not
• (ii) when the conjugate is represented by formula (IV), the conjugate does not comprise a compound represented by
• or a pharmaceutically acceptable salt thereof;
• and
• (iii) when X is RL1, L is H, —C(═O)Ra or —NRbRc.