Antibody drug conjugates of kinesin spindel protein (ksp) inhibitors with antib7h3-antibodies

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

• where
• BINDER represents a glycosylated or aglycosylated anti-B7H3 antibody, or represents an antigen-binding fragment thereof,
• L represents a linker,
• n represents a number from 1 to 50, preferably from 1.2 to 20 and particularly preferably from 2 to 8, and
• KSP represents a compound of the formula (I) below:
• where
• R1 represents —H, -L-#1, -MOD or —(CH2)0-3Z,
• where
• Z represents —H, —NHY3, —OY3, —SY3, halogen, —C(═O)—NY1Y2 or —C(═O)—OY3,
• Y1 and Y2 independently of one another represent —H, —NH2, —(CH2CH2O)0-3—(CH2)0-3Z′ (e.g. —(CH2)0-3Z′) or —CH(CH2W)Z′,
• Y3 represents —H or —(CH2)0-3Z′,
• Z′ represents —H, —NH2, —SO3H, —COOH, —NH—C(═O)—CH2—CH2—CH(NH2)COOH or —(C═O—NH—CHY4)1-3COOH;
• W represents H or OH,
• Y4 represents 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 represents H, -MOD, —C(═O)—CHY4—NHY5 or —(CH2)0-3Z,
• where
• Z represents —H, halogen, —OY3, —SY3, —NHY3, —C(═O)—NY1Y2 or —C(═O)—OY3,
• Y1 and Y2 independently of one another represent —H, —NH2 or —(CH2)0-3Z′,
• Y3 represents —H or —(CH2)0-3Z′,
• Z′ represents —H, —SO3H, —NH2 or —COOH;
• Y4 represents 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, and
• Y5 represents —H or —C(═O)—CHY6—NH2,
• Y6 represents straight-chain or branched C1-6-alkyl;
• R4 represents —H, -L-#1, -SGlys-(C═O)0-1—R4′, —C(═O)—CHY4—NHY5 or —(CH2)0-3Z,
• wherein
• SGlys is a group cleavable by lysosomal enzymes, in particular a group consisting of a dipeptide or tripeptide,
• R4′ 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 substituted once or more than once by —NH2, —NH-alkyl, —N(alkyl)2, NH—C(═O)-alkyl, N(alkyl)-C(═O)alkyl, —SO3H, —SO2NH2, —SO2—N(alkyl)2, —COOH, —C(═O)NH2, —C(═O)N(alkyl)2, or —OH, —H or a group —OX—(CH2CH2O)V—R4″,
• where x is 0 or 1
• where v is a number from 1 to 20,
• where R4″ is —H, -alkyl (preferably C1-12-alkyl), —CH2—COOH, —CH2—CH2—COOH, or —CH2—CH2—NH2);
• Z represents —H, halogen, —OY3, —SY3, NHY3, —C(═O)—NY1Y2 or —C(═O)—OY3,
• Y1 and Y2 independently of one another represent —H, —NH2 or —(CH2)0-3Z′,
• Y3 represents —H or —(CH2)0-3Z′,
• Z′ represents —H, —SO3H, —NH2 or —COOH;
• Y4 represents 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 represents —H or —C(═O)—CHY6—NH2, and
• Y6 represents straight-chain or branched C1-6-alkyl;
• or
• R2 and R4 together (with formation of a pyrrolidine ring) represent —CH2—CHR11— or —CHR11—CH2—,
• where
• R11 represents —H, —NH2, —SO3H, —COOH, —SH, halogen (in particular F or Cl), C1-4-alkyl, C1-4-haloalkyl, C1-4-alkoxy, hydroxyl-substituted C1-4-alkyl, —C(═O)—O—(C1-4-alkyl) or —OH;
• A represents —C(═O)—, —S(═O)—, —S(═O)2—, —S(═O)2NH— or —CNNH2—;
• R3 represents -L-#1, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably -L-#1 or a C1-10-alkyl, C6-10-aryl or C6-10-aralkyl, C5-10-heteroalkyl, C1-10-alkyl-O—C6-10-aryl or C5-10-heterocycloalkyl group which may each be substituted by 1-3 —OH groups, 1-3 halogen atoms, 1-3 halogenated alkyl groups (each having 1-3 halogen atoms), 1-3 —O-alkyl groups, 1-3 —SH groups, 1-3 —S-alkyl groups, 1-3 —O—C(═O)-alkyl groups, 1-3 —O—C(═O)—NH-alkyl groups, 1-3 —NH—C(═O)-alkyl groups, 1-3 —NH—C(═O)—NH-alkyl groups, 1-3 —S(═O)n-alkyl groups, 1-3 —S(═O)2—NH-alkyl groups, 1-3 —NH-alkyl groups, 1-3 —N(alkyl)2 groups, 1-3 —NH2 groups or 1-3 —(CH2)0-3Z groups,
• where
• n represents 0, 1 or 2,
• Z represents —H, halogen, —OY3, —SY3, —NHY3, —C(═O)—NY1Y2 or —C(═O)—OY3,
• Y1 and Y2 independently of one another represent —H, —NH2 or —(CH2)0-3Z′,
• Y3 represents —H, —(CH2)0-3—CH(NH—C(═O)—CH3)Z′, —(CH2)0-3—CH(NH2)Z′ or —(CH2)0-3Z′,
• Z′ represents —H, —SO3H, —NH2 or —COOH,
• R5 represents —H, —NH2, —NO2, halogen (in particular F, Cl, Br), —CN, CF3, —OCF3, —CH2F, —CH2F, SH or —(CH2)0-3Z,
• where
• Z represents —H, —OY3, —SY3, halogen, —NHY3, —C(═O)—NY1Y2 or —C(═O)—OY3,
• Y1 and Y2 independently of one another represent —H, —NH2 or —(CH2)0-3Z′,
• Y3 represents —H or —(CH2)0-3Z′,
• Z′ represents —H, —SO3H, —NH2 or —COOH;
• R6 and R7 independently of one another represent —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 represents C1-10-alkyl, fluoro-C1-10-alkyl, C2-10-alkenyl, fluoro-C2-10-alkenyl, 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
• where
• HZ2 represents a 4- to 7-membered heterocycle having up to two heteroatoms selected from the group consisting of N, O and S,
• R9 represents —H, —F, —CH3, —CF3, —CH2F or —CHF2;
• where
• one of the substituents R1, R3 and R4 represents -L-#1,
• L represents the linker and #1 represents the bond to the antibody,
• MOD represents —(NR10)n-(G1)o-G2-G3,
• where
• R10 represents —H or C1-C3-alkyl;
• G1 represents —NHC(═O)—, —C(═O)—NH—
• (where, if G1 represents —NHC(═O)—, R10 does not represent NH2);
• N represents 0 or 1;
• O represents 0 or 1;
• and
• G2 represents 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—, —C(═O)—NRyNRy—,
• where
• Ry represents —H, phenyl, C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkynyl, each of which may be mono- or polysubstituted identically or differently by —NH—C(═O)—NH2, —COOH, —OH, —NH2, —NH—CN—NH2, sulphonamide, sulphone, sulphoxide or sulphonic acid), and/or which may be interrupted one or more times, identically or differently, by —C(═O)—, —CRx═N—O—,
• where
• Rx represents —H, C1-C3-alkyl or phenyl, and
• where
• 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 represents —H or —COOH,
• and
• where the group -MOD preferably has at least one group —COOH;
• and the salts, solvates, salts of the solvates and epimers thereof.