Antibody drug conjugates of kinesin spindel protein (KSP) inhibitors with anti-CD123-antibodies

A conjugate of an antibody with one or more drug molecules of the formula below:

• wherein
• BINDER is an anti-CD 123 antibody which is a chimeric or humanized variant of the antibody 7G3 or 12F1 or is an antigen-binding fragment thereof;
• L is a linker;
• n is a number from 1 to 50;
• and
• KSP is a compound of the formula (I) below:
• Formula (I):
• wherein
• R1 is —H, -L-#1, -MOD or —(CH2)0-3Z,
• wherein
• Z is —H, —NHY3, —OY3, —SY3, halogen, —C(═O)—NY1Y2 or —C(═O)—OY3,
• Y1 and Y2 are independently of one another —H, —NH2, —(CH2CH2O)0-3—(CH2)0-3Z′ or —CH(CH2W)Z′,
• Y3 is —H or —(CH2)0-3Z′,
• Z′ is —H, —NH2, —SO3H, —COOH, —NH—C(═O)—CH2—CH2—CH(NH2)COOH or —(CO—NH—CHY4)1-3COOH,
• W is H or OH, and
• Y4 is straight-chain or branched C1-6 alkyl which is optionally substituted by —NH—C(═O)—NH2, or represents aryl or benzyl which are optionally substituted by —NH2;
• R2 is —H, -MOD, —C(═O)—CHY4—NHY5 or —(CH2)0-3Z,
• wherein
• Z is —H, halogen, —OY3, —SY3, —NHY3, —C(═O)—NY1Y2 or —C(═O)—OY3,
• Y1 and Y2 are independently of one another —H, —NH2 or —(CH2)0-3Z′,
• Y3 is —H or —(CH2)0-3Z′,
• Z′ is —H, —SO3H, —NH2 or —COOH;
• Y4 is straight-chain or branched C1-6-alkyl which is optionally substituted by —NH—C(═O)—NH2, or represents aryl or benzyl which are optionally substituted by —NH2,
• Y5 is —H or —C(═O)—CHY6—NH2, and
• Y6 is straight-chain or branched C1-6-alkyl;
• R4 is —H, -L-#1, -SGlys-(C═O)0-1—R4′, —C(═O)—CHY4—NHY5 or —(CH2)0-3Z, wherein
• SGlys is a group which can be cleaved by lysosomal enzymes,
• wherein R4′ is a C1-10-alkyl, C5-10-aryl or C6-10-aralkyl, C5-10-heteroalkyl, C1-10-alkyl-O—C6-10-aryl, C5-10-heterocycloalkyl, heteroaryl, heteroarylalkyl, heteroarylalkoxy, C1-10-alkoxy, C6-10-aryloxy or C6-10-aralkoxy,
• C5-10-heteroaralkoxy, C1-10-alkyl-O—C6-10-aryloxy, C5-10-heterocycloalkoxy group which may be mono- or polysubstituted by —NH2, —NH-alkyl,
• —N(alkyl)2, —NH—C(═O)-alkyl, —N(alkyl)-C(═O)-alkyl, —SO3H, —S(═O)2—NH2, —S(═O)2—N(alkyl)2, —COOH, —C(═O)—NH2, —C(═O)—N(Alkyl)2 or —OH, —H or a group —Ox—(CH2CH2O)v—R4″,
• wherein x is 0 or 1,
• wherein v is a number from 1 to 20,
• wherein R4″ is —H, -alkyl,
• —CH2—COOH, —CH2—CH2—COOH, or —CH2—CH2—NH2;
• wherein Z is —H, halogen, —OY3, —SY3, —NHY3, —C(═O)—NY1Y2 or —C(═O)—OY3,
• wherein Y1 and Y2 are independently of one another —H, —NH2 or —(CH2)0-3Z′,
• wherein Y3 is —H or —(CH2)0-3Z′,
• wherein Z′ is —H, —SO3H, —NH2 or —COOH;
• wherein Y4 is straight-chain or branched C1-6-alkyl which is optionally substituted by —NH—C(═O)—NH2, or represents aryl or benzyl which are optionally substituted by —NH2,
• wherein Y5 is —H or —C(═O)—CHY6—NH2, and
• wherein Y6 is straight-chain or branched C1-6-alkyl;
• or
• R2 and R4 taken together (with formation of a pyrrolidine ring) are —CH2—CHR11— or —CHR11—CH2—,
• wherein
• R11 is —H, —NH2, —SO3H, —COOH, —SH, halogen, C1-4-alkyl, C1-4-haloalkyl, C1-4-alkoxy, hydroxyl-substituted
• C1-4-alkyl, C(═O)—O—(C1-4-alkyl) or —OH;
• A is —C(═O)—, —S(═O)—, —S(═O)2—, —S(═O)2—NH— or —C(═N—NH2)—;
• R3 is -L-#1, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl group,
• R5 is —H, —NH2, —NO2, halogen, —CN, CF3, —OCF3, —CH2F, —CH2F, SH or —(CH2)0-3Z, wherein
• Z is —H, —OY3, —SY3, halogen, —NHY3, —C(═O)—NY1Y2 or —C(═O)—OY3
• Y1 and Y2 are independently of one another —H, —NH2 or —(CH2)0-3Z′,
• Y3 is —H or —(CH2)0-3Z′, and
• Z′ is —H, —SO3H, —NH2 or —COOH;
• R6 and R7 are independently of one another —H, cyano, C1-10-alkyl, fluoro-C1-10-alkyl, C2-10-alkenyl, fluoro-C2-10-alkenyl, C2-10-alkynyl, fluoro-C2-10-alkynyl, hydroxy, —NO2, —NH2, —COOH or halogen;
• R8 is C1-10-alkyl, fluoro-C1-10-alkyl, C2-10-alkenyl, fluoro-C2-10-alkyl, C2-10-alkynyl, fluoro-C2-10-alkynyl, C4-10-cycloalkyl, fluoro-C4-10-cycloalkyl or —(CH2)0-2—(HZ2), which may be mono- or disubstituted, identically or differently, by —OH, —COOH or —NH2, and
• wherein
• HZ2 is a 4- to 7-membered heterocycle having up to two heteroatoms selected from the group consisting of N, O and S;
• R9 is —H, —F, —CH3, —CF3, —CH2F or —CHF2;
• wherein
• one of the substituents R1, R3 or R4 is -L-#1,
• L is the linker and #1 is the bond to the antibody,
• MOD is —(NR10)n-(G1)o-G2-G3,
• wherein
• R10 is —H or C1-C3-alkyl;
• G1 is —NH—C(═O)— or —C(═O)—NH— (wherein, if G1 is —NH—C(═O)—, R10 is not —NH2);
• n is 0 or 1;
• o is 0 or 1;
• and
• G2 is a straight-chain or branched hydrocarbon chain which has 1 to 10 carbon atoms and which may be interrupted once or more than once by one or more of the groups —O—, —S—, —S(═O)—, S(═O)2, —NRy—, —NRyC(═O)—, C(═O)—NRy—, —NRyNRy—, —S(═O)2—NRyNRy—, or —C(═O)—NRyNRy—
• wherein
• Ry is —H, phenyl, C1-C10-alkyl, C2-C10-alkenyl or C2-C0o-alkynyl, each of which may be mono- or disubstituted, identically or differently, by —NH—C(═O)—NH2, —COOH, —OH, —NH2, —NH—CNNH2, sulphonamide, sulphone, sulphoxide or sulphonic acid,
• and/or which may be interrupted once or more than once, identically or differently, by —C(═O)—, —CRx═N—O—, wherein
• Rx is —H, C1-C3-alkyl or phenyl, and
• wherein
• the hydrocarbon chain including a C1-C10-alkyl group optionally substituted on the hydrocarbon group as side chain may be substituted by —NH—C(═O)NH2, —COOH, —OH, —NH2, —NH—CN—NH2, sulphonamide, sulphone, sulphoxide or sulphonic acid, G3 is —H or —COOH, and
• wherein the group -MOD has at least one group —COOH;
• or a salt, a solvate, a salt of a solvate, or an epimer thereof.