2-amino-4-carboxamide-benzazepine immunoconjugates, and uses thereof

An immunoconjugate comprising an antibody covalently attached to one or more 2-amino-4-carboxamide-benzazepine moieties by a linker, and having Formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• Ab is the antibody;
• p is an integer from 1 to 8;
• X2 and X3 are independently selected from the group consisting of a bond, C(═O), C(═O)N(R5), O, N(R5), S, S(O)2, and S(O)2N(R5);
• Y1 is CR1 or N;
• Y2 is CH or N;
• R1 is selected from the group consisting of H, C3-C12 carbocyclyl, C6-C20 aryl, C2-C9 heterocyclyl, and C1-C20 heteroaryl;
• R2 is selected from the group consisting of H, C1-C12 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C6-C20 aryl, C2-C9 heterocyclyl, and C1-C20 heteroaryl;
• R3 is selected from the group consisting of:
• —(C1-C12 alkyldiyl)-N(R5)—*;
• —(C1-C12 alkyldiyl)-N(R5)—C(═O)*;
• —(C1-C12 alkyldiyl)-N(R5)—C(═O)O—(C3-C12 carbocyclyldiyl)-*;
• —(C1-C12 alkyldiyl)-N(R5)—(C1-C20 heteroaryldiyl)-*;
• —(C1-C12 alkyldiyl)-N(R5)—(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-*;
• —(C1-C12 alkyldiyl)-N(R5)—S(O2)—*;
• —(C1-C12 alkyldiyl)-OC(═O)—(C2-C9 heterocyclyldiyl)-*;
• —(C1-C12 alkyldiyl)-O—*;
• —(C1-C12 alkyldiyl)-(C3-C12 carbocyclyldiyl)-*;
• —(C1-C12 alkyldiyl)-(C6-C20 aryldiyl)-*;
• —(C1-C12 alkyldiyl)-(C6-C20 aryl)-(C1-C12 alkyldiyl)-N(R5)—*;
• —(C1-C12 alkyldiyl)-(C2-C9 heterocyclyldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
• —(C1-C12 alkyldiyl)-(C1-C20 heteroaryldiyl)-N(R5)—*;
• —(C1-C12 alkyldiyl)-(C1-C20 heteroaryldiyl)-*;
• —(C1-C12 alkyldiyl)-(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-*;
• —(C1-C12 alkyldiyl)-(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
• —(C3-C12 carbocyclyldiyl)-*;
• —(C3-C12 carbocyclyldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
• —(C3-C12 carbocyclyldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
• —(C3-C12 carbocyclyldiyl)-NR5—C(═NR5a)—N(R5)—*;
• —(C6-C20 aryldiyl)-*;
• —(C6-C20 aryldiyl)-N(R5)—*;
• —(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
• —(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-(C2-C20 heterocyclyldiyl)-*;
• —(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-N(R5)—C(═NR5a)—N(R5)—*;
• —(C2-C20 heterocyclyldiyl)-*;
• —(C2-C9 heterocyclyldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
• —(C2-C9 heterocyclyldiyl)-N(R5)—C(═NR5a)—N(R5)—*;
• —(C1-C20 heteroaryldiyl)-*;
• —(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
• —(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-O—*;
• and
• —(C1-C20 heteroaryldiyl)-N(R5)—C(═NR5a)—N(R5)—*;
• where the asterisk * indicates the attachment site of the linker L;
• R5 is selected from the group consisting of H, C6-C20 aryl and C1-C12 alkyl, or two R5 groups together form a 5- or 6-membered heterocyclyl ring;
• R5a is selected from the group consisting of C6-C20 aryl and C1-C20 heteroaryl;
• L is selected from the group consisting of:
• —C(═O)-PEG-C(═O)—;
• —C(═O)-PEG-C(═O)—PEP-;
• —C(═O)-PEG-N(R5)—;
• —C(═O)-PEG-N(R5)—C(═O)—;
• —C(═O)-PEG-NR5-PEG-C(═O)—PEP-;
• —C(═O)-PEG-N+(R5)2-PEG-C(═O)—PEP-;
• —C(═O)-PEG-NR5CH(AA1)C(═O)-PEG-C(═O)—PEP-;
• —C(═O)-PEG-O—;
• —C(═O)-PEG-SS—(C1-C12 alkyldiyl)-OC(═O)—;
• —C(═O)-PEG-SS—(C1-C12 alkyldiyl)-C(═O)—;
• —C(═O)-PEG-;
• —C(═O)-PEG-C(═O)N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
• —C(═O)-PEG-C(═O)N(R5)—(C1-C12 alkyldiyl)-;
• —C(═O)—(C1-C12 alkyldiyl)-C(═O)—PEP-;
• —C(═O)—(C1-C12 alkyldiyl)-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-;
• —C(═O)—(C1-C12 alkyldiyl)-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-N(R5)—C(═O);
• —C(═O)—(C1-C12 alkyldiyl)-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
• —C(═O)—CH2CH2OCH2CH2—(C1-C20 heteroaryldiyl)-CH2O-PEG-C(═O)-(MCgluc)-;
• —C(═O)—CH2CH2OCH2CH2—(C1-C20 heteroaryldiyl)-CH2O-PEG-C(═O)-(MCgluc)-N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
• —C(═O)-PEG-C(═O)N(R5)—(C1-C12 alkyldiyl)-;
• —C(═O)-PEG-C(═O)N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
• —C(═O)-PEG-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-;
• —C(═O)-PEG-C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
• -succinimidyl-(CH2)m—C(═O)N(R5)-PEG-C(═O)—;
• -succinimidyl-(CH2)m—C(═O)N(R5)-PEG-N(R5)—;
• -succinimidyl-(CH2)m—C(═O)N(R5)-PEG-N(R5)—C(═O)—;
• -succinimidyl-(CH2)m—C(═O)N(R5)-PEG-C(═O)—PEP-;
• -succinimidyl-(CH2)m—C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)-;
• -succinimidyl-(CH2)m—C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—;
• and
• -succinimidyl-(CH2)m—C(═O)—PEP-N(R5)—(C1-C12 alkyldiyl)N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
• PEG has the formula:
• —(CH2CH2O)n—(CH2)m— where m is an integer from 1 to 5, and n is an integer from 2 to 50;
• PEP has the formula:
• where AA1 and AA2 are independently selected from an amino acid side chain, or AA1 or AA2 and an adjacent nitrogen atom form a 5-membered ring proline amino acid, and the wavy line indicates a point of attachment;
• and
• where alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, aryl, aryldiyl carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CN, —CH3, —CH2CH3, —CH═CH2, —C≡CH, —C≡CCH3, —CH2CH2CH3, —CH(CH3)2, —CH2CH(CH3)2, —CH2OH, —CH2OCH3, —CH2CH2OH, —C(CH3)20H, —CH(OH)CH(CH3)2, —C(CH3)2CH2OH, —CH2CH2SO2CH3, —CH2OP(O)(OH)2, —CH2F, —CHF2, —CF3, —CH2CF3, —CH2CHF2, —CH(CH3)CN, —C(CH3)2CN, —CH2CN, —CH2NH2, —CH2NHSO2CH3, —CH2NHCH3, —CH2N(CH3)2, —CO2H, —COCH3, —CO2CH3, —CO2C(CH3)3, —COCH(OH)CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —NH2, —NHCH3, —N(CH3)2, —NHCOCH3, —N(CH3)COCH3, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, —NO2, ═O, —OH, —OCH3, —OCH2CH3, —OCH2CH2OCH3, —OCH2CH2OH, —OCH2CH2N(CH3)2, —O(CH2CH2O)n—(CH2)mCO2H, —O(CH2CH2O)nH, —OP(O)(OH)2, —S(O)2N(CH3)2, —SCH3, —S(O)2CH3, and —S(O)3H.