Macromolecule-supported 8-sulfonyl-benzazepine compounds and their uses

A macromolecule-supported compound comprising a macromolecular support covalently attached to one or more 8-sulfonyl-2-aminobenzazepine moieties by a linker, and having Formula I;

• Ms-[L-D]p I
• or a pharmaceutically acceptable salt thereof,
• wherein:
• Ms is the macromolecular support selected from a peptide, a nucleotide, a carbohydrate, a lipid, an antibody construct, a biopolymer, a nanoparticle, and an immune checkpoint inhibitor;
• p is an integer from 1 to 50;
• D is the 8-sulfonyl-2-aminobenzazepine moiety having the formula:
• 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)2—*;
• —(C1-C12 alkyldiyl)-N(R5)2;
• —(C1-C12 alkyldiyl)-OR5;
• —(C3-C12 carbocyclyl);
• —(C3-C12 carbocyclyl)-*;
• —(C3-C12 carbocyclyl)-(C1-C12 alkyldiyl)-NR5—*;
• —(C3-C12 carbocyclyl)-(C1-C12 alkyldiyl)-N(R5)2;
• —(C3-C12 carbocyclyl)-NR3—C(═NR5)NR5—*;
• —(C6-C20 aryl);
• —(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)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)-C(═O)—(C1-C12 alkyldiyl)-N(R5)—*;
• —(C2-C9 heterocyclyl)-NR5—C(═NR5a)NR5—*;
• —(C2-C9 heterocyclyl)-NR5—(C6-C20 aryldiyl)-(C1-C12 alkyldiyl)-N(R5)—*;
• —(C2-C9 heterocyclyl)-(C6-C20 aryldiyl)-*;
• —(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)—*;
• —(C1-C20 heteroaryl)-N(R5)C(═O)—(C1-C12 alkyldiyl)-N(R5)—*;
• —C(═O)—*;
• —C(═O)—(C1-C12 alkyldiyl)-N(R5)—*;
• —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(═NR5a)N(R5)2;
• —NR5C(═NR5a)N(R5)—*;
• —NR5C(═NR5a)R5;
• —N(R5)C(═O)—(C1-C12 alkyldiyl)-N(R5)—*;
• —N(R5)—(C2-C5 heteroaryl);
• —N(R5)—S(═O)2—(C1-C12 alkyl);
• —O—(C1-C12 alkyl);
• —O—(C1-C12 alkyldiyl)-N(R5)2;
• —O—(C1-C12 alkyldiyl)-N(R5)—*;
• —O—(═O)N(R5)2;
• —O—(═O)N(R5)—*;
• —O—(R5)—*;
• —OR5;
• —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), O, N(R5), S, S(O)2, and S(O)2N(R5);
• R5 is independently selected from the group consisting of H, C6-C20 aryl, C3-C12 carbocyclyl, C6-C20 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-C20 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:
• —C(═O)-PEG-;
• —C(═O)-PEG-C(═O)N(R6)—(C1-C12 alkyldiyl)-C(═O)-Gluc-;
• —C(═O)-PEG-O—;
• —C(═O)-PEG-O—C(═O)—;
• —C(═O)-PEG-C(═O)—;
• —C(═O)-PEG-C(═O)-PEP-;
• —C(═O)-PEG-N(R6)—;
• —C(═O)-PEG-N(R6)—C(═O)—;
• —C(═O)-PEG-N(R6)-PEG-C(═O)-PEP-;
• —C(═O)-PEG-N*(R6)2-PEG-C(═O)-PEP-;
• —C(═O)-PEG-C(═O)-PEP-N(R6)—(C1-C12 alkyldiyl)-;
• —C(═O)-PEG-C(═O)-PEP-N(R6)—(C1-C12 alkyldiyl)N(R6)C(═O)—(C2-C5 monoheterocyclyldiyl)-;
• —C(═O)-PEG-SS—(C1-C12 alkyldiyl)-OC(═O)—;
• —C(═O)-PEG-SS—(C1-C12 alkyldiyl)-C(═O)—;
• -succinimidyl-(CH2)m—C(═O)N(R6)-PEG-;
• -succinimidyl-(CH2)m—C(═O)N(R6)-PEG-C(═O)N(R6)—(C1-C12 alkyldiyl)-C(═O)-Gluc-;
• -succinimidyl-(CH2)m—C(═O)N(R6)-PEG-O—;
• -succinimidyl-(CH2)m—C(═O)N(R6)-PEG-O—C(═O)—;
• -succinimidyl-(CH2)m—C(═O)N(R6)-PEG-C(═O)—;
• -succinimidyl-(CH2)—C(═O)N(R6)-PEG-N(R5)—;
• -succinimidyl-(CH2)m—C(═O)N(R6)-PEG-N(PEG-CO2H)-PEG-N(R5)—;
• -succinimidyl-(CH2)m—C(═O)N(R6)-PEG-C(═O)N(PEG-CO2H)-PEG-N(R5)—;
• -succinimidyl-(CH2)—C(═O)N(R6)-PEG-N(R5)—C(═O)—;
• -succinimidyl-(CH2)m—C(═O)N(R6)-PEG-N(PEG-CO2H)-PEG-C(═O)—;
• -succinimidyl-(CH2)m—C(═O)N(R6)-PEG-C(═O)N(PEG-CO2H)-PEG-C(═O)—;
• -succinimidyl-(CH2)m—C(═O)N(R6)-PEG-C(═O)-PEP-;
• and
• -succinimidyl-(CH2)m—C(═O)N(R6)-PEG-SS—(C1-C12 alkyldiyl)-OC(═O)—;
• R6 is independently H or C1-C6 alkyl;
• 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;
• Gluc has the formula:
• PEP has the formula:
• where AA is independently selected from a natural or unnatural amino acid side chain, or one or more of AA, and an adjacent nitrogen atom form a 5-membered ring proline amino acid, and the wavy line indicates a point of attachment;
• Cyc is selected from C6-C20 aryldiyl and C1-C20 heteroaryldiyl, optionally substituted with one or more groups selected from F, Cl, NO2, —OH, —OCH3, and a glucuronic acid having the structure:
• R7 is selected from the group consisting of —CH(R8)O—, —CH2—, —CH2N(R8)—, and —CH(R8)O—C(═O)—, where R8 is selected from H, C1-C6 alkyl, C(═O)—C1-C6 alkyl, and —C(═O)N(R9)2, where R9 is independently selected from the group consisting of H, C1-C12 alkyl, and —(CH2CH2O)n—(CH2)m—OH, where m is an integer from 1 to 5, and n is an integer from 2 to 50, or two R9 groups together form a 5- or 6-membered heterocyclyl ring;
• y is an integer from 2 to 12;
• z is 0 or 1;
• and
• alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl are independently and 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)CONH2, —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)n—(CH2)mCO2H, —O(CH2CH2O)nH, —OCH2F, —OCHF2, —OCF3, —OP(O)(OH)2, —S(O)2N(CH3)2, —SCH3, —S(O)2CH3, and —S(O)3H.