Aminobenzazepine compounds, immunoconjugates, and uses thereof

An aminobenzazepine-linker compound of Formula II:

• wherein
• Z is selected from H, —O(C1-C8 alkyl), and N(X2R2)(X3R3);
• R1, R2, R3, and R4 are independently 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, where alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl are independently and optionally substituted with one or more groups selected from:
• —(C1-C12 alkyldiyl)-N(R5)—*;
• —(C1-C12 alkyldiyl)-N(R5)2;
• —(C3-C12 carbocyclyl);
• —(C3-C12 carbocyclyl)-*;
• —(C3-C12 carbocyclyl)-(C1-C2 alkyldiyl)-NR5—*;
• —(C3-C12 carbocyclyl)-(C1-C12 alkyldiyl)-N(R5)2;
• —(C3-C12 carbocyclyl)-NR5—C(═NR5)NR5—*;
• —(C6-C20 aryl);
• —(C6-C20 aryl)-*;
• —(C6-C20 aryldiyl)-N(R5)—*;
• —(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
• —(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-N(R5)2;
• —(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-NR5—C(═NR5a)N(R5)—*;
• —(C2-C20 heterocyclyl);
• —(C2-C20 heterocyclyl)-*;
• —(C2-C9 heterocyclyl)-(C1-C12 alkyldiyl)-NR5—*;
• —(C2-C9 heterocyclyl)-(C1-C12 alkyldiyl)-N(R5)2;
• —(C2-C9 heterocyclyl)-NR5—C(═NR5a)NR5—*;
• —(C1-C20 heteroaryl);
• —(C1-C20 heteroaryl)-*;
• —(C1-C20 heteroaryl)-(C1-C12 alkyldiyl)-N(R5)—*;
• —(C1-C20 heteroaryl)-(C1-C12 alkyldiyl)-N(R5)2;
• —(C1-C20 heteroaryl)-NR5—C(═NR5a)N(R5)—*;
• —C(═O)—*;
• —C(═O)—(C2-C20 heterocyclyldiyl)-*;
• —C(═O)N(R5)2;
• —C(═O)N(R5)—*;
• —C(═O)N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)R5;
• —C(═O)N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)N(R5)2;
• —C(═O)NR5—(C1-C12 alkyldiyl)-N(R5)CO2R5;
• —C(═O)NR5—(C1-C12 alkyldiyl)-N(R5)C(═NR5a)N(R5)2;
• —C(═O)NR5—(C1-C12 alkyldiyl)-NR5C(═NR5a)R5;
• —C(═O)NR5—(C1-C8 alkyldiyl)-NR5(C2-C5 heteroaryl);
• —C(═O)NR5—(C1-C20 heteroaryldiyl)-N(R5)—*;
• —C(═O)NR5—(C1-C20 heteroaryldiyl)-*;
• —C(═O)NR5—(C1-C20 heteroaryldiyl)-(C1-C12 alkyldiyl)-N(R5)2;
• —C(═O)NR5—(C1-C20 heteroaryldiyl)-(C2-C20 heterocyclyldiyl)-C(═O)NR5—(C1-C12 alkyldiyl)-NR5—*;
• —N(R5)2;
• —N(R5)—*;
• —N(R5)C(═O)R5;
• —N(R5)C(═O)—*;
• —N(R5)C(═O)N(R5)2;
• —N(R5)C(═O)N(R5)—*;
• —N(R5)CO2R5;
• —NR5C(═N5a)N(R5)2;
• —NR5C(═NR5a)N(R5)—*;
• —NR5C(═NR5a)R5;
• —N(R5)—(C2-C5 heteroaryl);
• —O—(C1-C12 alkyl);
• —O—(C1-C2 alkyldiyl)-N(R5)2;
• —O—(C1-C12 alkyldiyl)-N(R5)—*;
• —S(═O)2—(C2-C20 heterocyclyldiyl)-*;
• —S(═O)2—(C2-C20 heterocyclyldiyl)-(C1-C12 alkyldiyl)-N(R5)2;
• —S(═O)2—(C2-C20 heterocyclyldiyl)-(C1-C12 alkyldiyl)-NR5—*;
• and
• —S(═O)2—(C2-C20 heterocyclyldiyl)-(C1-C12 alkyldiyl)-OH;
• or R2 and R3 together form a 5- or 6-membered heterocyclyl ring;
• X1, X2, X3, and X4 are independently selected from the group consisting of a bond, C(═O), C(═O)N(R5), 0, N(R5), S, S(O)2, and S(O)2N(R5);
• R5 is selected from the group consisting of H, C6-C2 aryl, C6-C2 aryldiyl, C1-C12 alkyl, and C1-C12 alkyldiyl, or two R5 groups together form a 5- or 6-membered heterocyclyl ring;
• R5a is selected from the group consisting of C6-C2 aryl and C1-C20 heteroaryl;
• where the asterisk * indicates the attachment site of L, and where one of R1, R2, R3 and R4 is attached to L;
• L is the linker selected from the group consisting of:
• Q-C(═O)-(PEG)-;
• Q-C(═O)-(PEG)-C(═O)—;
• Q-C(═O)-(PEG)-O—;
• Q-C(═O)-(PEG)-C(═O)-(PEP)-;
• Q-C(═O)-(PEG)-C(═O)N(R5)-(C1-C12 alkyldiyl)-;
• Q-C(═O)-(PEG)-C(═)N(R5)-(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
• Q-C(═O)-(PEG)-C(═O)N(R5)-(C1-C12 alkyldiyl)-(MCgluc)-;
• Q-C(═O)-(PEG)-C(═O)-(MCgluc)-;
• Q-C(═O)-(PEG)-C(═O)-(PEP)-N(R5)-(C1-C12 alkyldiyl)-;
• Q-C(═O)-(PEG)-C(═O)-(PEP)-N(R5)-(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
• Q-C(═O)-(PEG)-N(R5)—;
• Q-C(═O)-(PEG)-N(R5)-(PEG)-C(═O)-(PEP)-;
• Q-C(═O)-(PEG)-N+(R5)2-(PEG)-C(═O)-(PEP)-;
• Q-C(═O)-(PEG)-C(═O)—N(R5)CH(AA1)C(═O)-(PEG)-C(═O)-(PEP)-;
• Q-C(═O)-(PEG)-C(═O)—N(R5)CH(AA1)C(═O)—N(R5)-(C1-C12 alkyldiyl)-;
• Q-C(═O)-(PEG)-SS-(C1-C12 alkyldiyl)-OC(═O)-;
• Q-C(═O)-(PEG)-SS-(C1-C12 alkyldiyl)-C(═O)—;
• Q-C(═O)—(C1-C12 alkyldiyl)-C(═O)-(PEP)-;
• Q-C(═O)—(C1-C12 alkyldiyl)-C(═O)-(PEP)-N(R5)—(C1-C12 alkyldiyl)-;
• Q-C(═O)—(C1-C12 alkyldiyl)-C(═O)-(PEP)-N(R5)-(C1-C12 alkyldiyl)-N(R5)—C(═O);
• Q-C(═O)—(C1-C12 alkyldiyl)-C(═O)-(PEP)-N(R5)-(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
• Q-C(═O)—CH2CH2OCH2CH2—(C1-C20 heteroaryldiyl)-CH2O-(PEG)-C(═O)-(MCgluc)-;
• Q-C(═O)—CH2CH2OCH2CH2—(C1-C20 heteroaryldiyl)-CH2O-(PEG)-C(═O)-(MCgluc)-N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
• and
• Q-(CH2)m—C(═O)-(PEP)-N(R5)—(C1-C12 alkyldiyl)-N(R5)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
• where PEG has the formula:
• —(CH2CH2O)n—(CH2)m—;
• 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 AA 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;
• R6 is selected from the group consisting of C6-C2 aryldiyl and C1-C20 heteroaryldiyl, substituted with —CH2O—C(═O)- and optionally with:
• and
• MCgluc is selected from the groups:
• where q is 1 to 8, and AA is an amino acid side chain;
• and
• Q is selected from the group consisting of N-hydroxysuccinimidyl, N-hydroxysulfosuccinimidyl, maleimide, and phenoxy substituted with one or more groups independently selected from F, Cl, NO2, and SO3;
• 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)2OH, —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, —NHC(═NH)H, —NHC(═NH)CH3, —NHC(═NH)NH2, —NHC(═O)NH2, —NO2, ═O, —OH, —OCH3, —OCH2CH3, —OCH2CH2OCH3, —OCH2CH2OH, —OCH2CH2N(CH3)2, —O(CH2CH2O)—(CH2)mCO2H, —O(CH2CH2O)nH, —OP(O)(OH)2, —S(O)2N(CH3)2, —SCH3, —S(O)2CH3, and —S(O)3H.