ALONSO MICHAEL N (US)
KUDIRKA ROMAS (US)
SAFINA BRIAN (US)
SARMA GANAPATHY (US)
WO2020252254A1 | 2020-12-17 | |||
WO2020252294A1 | 2020-12-17 | |||
WO2021226440A1 | 2021-11-11 | |||
WO2017046112A1 | 2017-03-23 | |||
WO2017202703A1 | 2017-11-30 | |||
WO2021067242A1 | 2021-04-08 | |||
WO2016096778A1 | 2016-06-23 | |||
WO2020056198A2 | 2020-03-19 |
CLAIMS: 1. 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: or a pharmaceutically acceptable salt thereof, wherein: Ms is the macromolecular support; 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)-*; -(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)-NR5-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-C(=O)N(R5)2; -O-C(=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)m-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)m-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)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)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. 2. The macromolecule-supported compound of claim 1, wherein subscript p is an integer from 1 to 25. 3. The macromolecule-supported compound of claim 2, wherein subscript p is an integer from 1 to 6. 4. The macromolecule-supported compound of claim 1, wherein the macromolecular support is selected from a peptide, a nucleotide, a carbohydrate, a lipid, an antibody construct, a biopolymer, a nanoparticle, and an immune checkpoint inhibitor. 5. The macromolecule-supported compound of any one of claims 1 to 4 wherein X1 is a bond, and R1 is H. 6. The macromolecule-supported compound of any one of claims 1 to 4 wherein X2 is a bond, and R2 is C1-C8 alkyl. 7. The macromolecule-supported compound of any one of claims 1 to 4 wherein X2 and X3 are each a bond, and R2 and R3 are independently selected from C1-C8 alkyl, -O-(C1- C12 alkyl), -(C1-C12 alkyldiyl)-OR5, -(C1-C8 alkyldiyl)-N(R5)CO2R5, -(C1-C12 alkyl)- OC(O)N(R5)2, -O-(C1-C12 alkyl)-N(R5)CO2R5, and -O-(C1-C12 alkyl)-OC(O)N(R5)2. 8. The macromolecule-supported compound of claim 7 wherein R2 is C1-C8 alkyl and R3 is -(C1-C8 alkyldiyl)-N(R5)CO2R4. 9. The macromolecule-supported compound of claim 7 wherein R2 is -CH2CH2CH3 and R3 is selected from -CH2CH2CH2NHCO2(t-Bu), -OCH2CH2NHCO2(cyclobutyl), and ^ CH2CH2CH2NHCO2(cyclobutyl). 10. The macromolecule-supported compound of claim 7 wherein R2 and R3 are each independently selected from -CH2CH2CH3, -OCH2CH3, -OCH2CF3, -CH2CH2CF3, ^ OCH2CH2OH, and -CH2CH2CH2OH. 11. The macromolecule-supported compound of claim 7 wherein R2 and R3 are each -CH2CH2CH3. 12. The macromolecule-supported compound of claim 7 wherein R2 is -CH2CH2CH3 and R3 is -OCH2CH3. 13. The macromolecule-supported compound of any one of claims 1 to 4 wherein X3- R3 is selected from the group consisting of: . 14. The macromolecule-supported compound of any one of claims 1 to 4 wherein X4 is a bond, and R4 is H. 15. The macromolecule-supported compound of any one of claims 1 to 4 where R1 is attached to L. 16. The macromolecule-supported compound of any one of claims 1 to 4 where R2 or R3 is attached to L. 17. The macromolecule-supported compound of claim 16 wherein X3^R3^L is selected from the group consisting of: where the wavy line indicates the point of attachment to N. 18. The macromolecule-supported compound of any one of claims 1 to 4 wherein R4 is C1-C12 alkyl. 19. The macromolecule-supported compound of any one of claims 1 to 4 wherein R4 is -(C1-C12 alkyldiyl)-N(R5)-*; where the asterisk * indicates the attachment site of L. 20. The macromolecule-supported compound of any one of claims 1 to 4 wherein L is -C(=O)-PEG^ or -C(=O)-PEG-C(=O)-. 21. The macromolecule-supported compound of any one of claims 1 to 4 wherein L is attached to a cysteine thiol of the antibody. 22. The macromolecule-supported compound of any one of claims 1 to 4 wherein for the PEG, m is 1 or 2, and n is an integer from 2 to 10. 23. The macromolecule-supported compound of claim 22 wherein n is 10. 24. The macromolecule-supported compound of any one of claims 1 to 4 wherein L comprises PEP and PEP is a dipeptide and has the formula: . 25. The macromolecule-supported compound of claim 24 wherein AA1 and AA2 are independently selected from H, -CH3, -CH(CH3)2, -CH2(C6H5), -CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, -CHCH(CH3)CH3, -CH2SO3H, and -CH2CH2CH2NHC(O)NH2; or AA1 and AA2 form a 5-membered ring proline amino acid. 26. The macromolecule-supported compound of claim 24 wherein AA1 is ^ CH(CH3)2, and AA2 is -CH2CH2CH2NHC(O)NH2. 27. The macromolecule-supported compound of claim 24 wherein AA1 and AA2 are independently selected from GlcNAc aspartic acid, -CH2SO3H, and -CH2OPO3H. 28. The macromolecule-supported compound of claim 24 wherein PEP has the formula: wherein AA1 and AA2 are independently selected from a side chain of a naturally- occurring amino acid. 29. The macromolecule-supported compound of any one of claims 1 to 4 wherein L comprises PEP and PEP is a tripeptide and has the formula: . 30. The macromolecule-supported compound of any one of claims 1 to 4 wherein L comprises PEP and PEP is a tetrapeptide and has the formula: . 31. The macromolecule-supported compound of claim 30 wherein AA1 is selected from the group consisting of Abu, Ala, and Val; AA2 is selected from the group consisting of Nle(O-Bzl), Oic and Pro; AA3 is selected from the group consisting of Ala and Met(O)2; and AA4 is selected from the group consisting of Oic, Arg(NO2), Bpa, and Nle(O-Bzl). 32. The macromolecule-supported compound of any one of claims 1 to 4 wherein L comprises PEP and PEP is selected from the group consisting of Ala-Pro-Val, Asn-Pro-Val, Ala-Ala-Val, Ala-Ala-Pro-Ala, Ala-Ala-Pro-Val, and Ala-Ala-Pro-Nva. 33. The macromolecule-supported compound of any one of claims 1 to 4 wherein L comprises PEP and PEP is selected from the structures: . 34. The macromolecule-supported compound of any one of claims 1 to 4 wherein L is selected from the structures: where the wavy line indicates the attachment to R5. 35. An 8-sulfonyl-2-aminobenzazepine-linker compound selected from Table 2. 36. A macromolecule-supported compound prepared by conjugation of a macromolecule with an 8-sulfonyl-2-aminobenzazepine-linker compound selected from Table 2. 37. A pharmaceutical composition comprising a therapeutically effective amount of a macromolecule-supported compound according to any one of claims 1 to 34, and one or more pharmaceutically acceptable diluent, vehicle, carrier or excipient. 38. A method for treating cancer comprising administering a therapeutically effective amount of a macromolecule-supported compound according to any one of claims 1 to 34 to a patient in need thereof, wherein the cancer is selected from cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, esophageal cancer, bladder cancer, urinary tract cancer, urothelial carcinoma, lung cancer, non-small cell lung cancer, Merkel cell carcinoma, colon cancer, colorectal cancer, gastric cancer, and breast cancer. 39. The method of claim 38, wherein the cancer is susceptible to a pro-inflammatory response induced by TLR7 and/or TLR8 agonism. 40. The method of claim 38, wherein the cancer is selected from triple-negative breast cancer, metastatic Merkel cell carcinoma, and gastroesophageal junction adenocarcinoma. 41. The method of claim 38, wherein the macromolecule-supported compound is administered to the patient intravenously, intratumorally, or subcutaneously. 42. The method of claim 38, wherein the macromolecule-supported compound is administered to the patient at a dose of about 0.01 to 20 mg per kg of body weight. 43. Use of a macromolecule-supported compound according to any one of claims 1 to 34 for treating cancer, wherein the cancer is selected from cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, esophageal cancer, bladder cancer, urinary tract cancer, urothelial carcinoma, lung cancer, non-small cell lung cancer, Merkel cell carcinoma, colon cancer, colorectal cancer, gastric cancer, and breast cancer. 44. A method of preparing a macromolecule-supported compound of Formula I of claim 1 wherein the 8-sulfonyl-2-amino-thienoazepine-linker compound of claim 35 is conjugated with the macromolecule. |
8-SULFONYL-2-AMINOBENZAZEPINE-LINKER COMPOUNDS The MSC of the invention are prepared by conjugation of an anti-CEA antibody with a 8-sulfonyl-2-aminobenzazepine-linker compound, 8SO2Bz-L. The 8-sulfonyl-2- aminobenzazepine-linker compounds comprise a 8-sulfonyl-2-aminobenzazepine (8SO2Bz) moiety covalently attached to a linker unit. The linker units comprise functional groups and subunits which affect stability, permeability, solubility, and other pharmacokinetic, safety, and efficacy properties of the MSC. The linker unit comprises a polyethyleneoxy (PEG) group. The linker unit includes a reactive functional group which reacts, i.e. conjugates, with a reactive functional group of the antibody. For example, a nucleophilic group such as a lysine side chain amino of the antibody reacts with an electrophilic reactive functional group of the 8SO2Bz-L compound to form the MSC. Also, for example, a cysteine thiol of the antibody reacts with a maleimide or bromoacetamide group of the 8SO2Bz-linker compound (8SO2Bz-L) to form the MSC. Reactive electrophilic functional groups (Q in Formula II) suitable for the 8SO2Bz-L linker compounds include, but are not limited to, N-hydroxysuccinimidyl (NHS) esters and N- hydroxysulfosuccinimidyl (sulfo-NHS) esters (amine reactive); carbodiimides (amine and carboxyl reactive); hydroxymethyl phosphines (amine reactive); maleimides (thiol reactive); halogenated acetamides such as N-iodoacetamides (thiol reactive); aryl azides (primary amine reactive); fluorinated aryl azides (reactive via carbon-hydrogen (C-H) insertion); pentafluorophenyl (PFP) esters (amine reactive); tetrafluorophenyl (TFP) esters (amine reactive); imidoesters (amine reactive); isocyanates (hydroxyl reactive); vinyl sulfones (thiol, amine, and hydroxyl reactive); pyridyl disulfides (thiol reactive); and benzophenone derivatives (reactive via C-H bond insertion). Further reagents include, but are not limited, to those described in Hermanson, Bioconjugate Techniques 2 nd Edition, Academic Press, 2008. The invention provides solutions to the limitations and challenges to the design, preparation and use of MSC. Some linkers may be labile in the blood stream, thereby releasing unacceptable amounts of the adjuvant/drug prior to internalization in a target cell (Khot, A. et al (2015) Bioanalysis 7(13):1633–1648). Other linkers may provide stability in the bloodstream, but intracellular release effectiveness may be negatively impacted. Linkers that provide for desired intracellular release typically have poor stability in the bloodstream. Alternatively stated, bloodstream stability and intracellular release are typically inversely related. In addition, in standard conjugation processes, the amount of adjuvant/drug moiety loaded on the antibody, i.e. drug loading, the amount of aggregate that is formed in the conjugation reaction, and the yield of final purified conjugate that can be obtained are interrelated. For example, aggregate formation is generally positively correlated to the number of equivalents of adjuvant/drug moiety and derivatives thereof conjugated to the antibody. Under high drug loading, formed aggregates must be removed for therapeutic applications. As a result, drug loading-mediated aggregate formation decreases MSC yield and can render process scale-up difficult. Exemplary embodiments include a 8-sulfonyl-2-aminobenzazepine-linker compound of Formula II: wherein R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of H, C 1 -C 12 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 12 carbocyclyl, C 6 -C 20 aryl, C 2 -C 9 heterocyclyl, and C 1 -C 20 heteroaryl, where alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl are independently and optionally substituted with one or more groups selected from: -(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -(C 1 -C 12 alkyldiyl)-OR 5 ; -(C 3 -C 12 carbocyclyl); -(C 3 -C 12 carbocyclyl)-*; -(C 3 -C 12 carbocyclyl)-(C 1 -C 12 alkyldiyl)-NR 5 -*; -(C 3 -C 12 carbocyclyl)-(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -(C 3 -C 12 carbocyclyl)-NR 5 -C(=NR 5 )NR 5 -*; -(C 6 -C 20 aryl); -(C 6 -C 20 aryldiyl)-*; -(C 6 -C 20 aryldiyl)-N(R 5 )-*; -(C 6 -C 20 aryldiyl)-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -(C 6 -C 20 aryldiyl)-(C 1 -C 12 alkyldiyl)-(C 2 -C 20 heterocyclyldiyl)-*; -(C 6 -C 20 aryldiyl)-(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -(C 6 -C 20 aryldiyl)-(C 1 -C 12 alkyldiyl)-NR 5 -C(=NR 5a )N(R 5 )-*; -(C 2 -C 20 heterocyclyl); -(C 2 -C 20 heterocyclyl)-*; -(C 2 -C 9 heterocyclyl)-(C 1 -C 12 alkyldiyl)-NR 5 -*; -(C 2 -C 9 heterocyclyl)-(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -(C 2 -C 9 heterocyclyl)-C(=O)-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -(C 2 -C 9 heterocyclyl)-NR 5 -C(=NR 5a )NR 5 -*; -(C 2 -C 9 heterocyclyl)-NR 5 -(C 6 -C 20 aryldiyl)-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -(C 2 -C 9 heterocyclyl)-(C 6 -C 20 aryldiyl)-*; -(C 1 -C 20 heteroaryl); -(C 1 -C 20 heteroaryldiyl)-*; -(C 1 -C 20 heteroaryl)-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -(C 1 -C 20 heteroaryl)-(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -(C 1 -C 20 heteroaryl)-NR 5 -C(=NR 5a )N(R 5 )-*; -(C 1 -C 20 heteroaryl)-N(R 5 )C(=O)-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -C(=O)-*; -C(=O)-(C1-C12 alkyldiyl)-N(R 5 )-*; -C(=O)-(C 2 -C 20 heterocyclyldiyl)-*; -C(=O)N(R 5 ) 2 ; -C(=O)N(R 5 )-*; -C(=O)N(R 5 )-(C 1 -C 12 alkyldiyl)-N(R 5 )C(=O)R 5 ; -C(=O)N(R 5 )-(C 1 -C 12 alkyldiyl)-N(R 5 )C(=O)N(R 5 ) 2 ; -C(=O)NR 5 -(C 1 -C 12 alkyldiyl)-N(R 5 )CO 2 R 5 ; -C(=O)NR 5 -(C 1 -C 12 alkyldiyl)-N(R 5 )C(=NR 5a )N(R 5 ) 2 ; -C(=O)NR 5 -(C 1 -C 12 alkyldiyl)-NR 5 C(=NR 5a )R 5 ; -C(=O)NR 5 -(C 1 -C 8 alkyldiyl)-NR 5 (C 2 -C 5 heteroaryl); -C(=O)NR 5 -(C 1 -C 20 heteroaryldiyl)-N(R 5 )-*; -C(=O)NR 5 -(C 1 -C 20 heteroaryldiyl)-*; -C(=O)NR 5 -(C 1 -C 20 heteroaryldiyl)-(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -C(=O)NR 5 -(C 1 -C 20 heteroaryldiyl)-(C 2 -C 20 heterocyclyldiyl)-C(=O)NR 5 -(C 1 -C 12 alkyldiyl)-NR 5 -*; -N(R 5 ) 2 ; -N(R 5 )-*; -N(R 5 )C(=O)R 5 ; -N(R 5 )C(=O)-*; -N(R 5 )C(=O)N(R 5 ) 2 ; -N(R 5 )C(=O)N(R 5 )-*; -N(R 5 )CO 2 R 5 ; -NR 5 C(=NR 5a )N(R 5 ) 2 ; -NR 5 C(=NR 5a )N(R 5 )-*; -NR 5 C(=NR 5a )R 5 ; -N(R 5 )C(=O)-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -N(R 5 )-(C 2 -C 5 heteroaryl); -N(R 5 )-S(=O) 2 -(C 1 -C 12 alkyl); -O-(C 1 -C 12 alkyl); -O-(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -O-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -O-C(=O)N(R 5 ) 2 ; -O-C(=O)N(R 5 )-*; -O-(R 5 )-*; -OR 5 ; -S(=O) 2 -(C 2 -C 20 heterocyclyldiyl)-*; -S(=O) 2 -(C 2 -C 20 heterocyclyldiyl)-(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -S(=O) 2 -(C 2 -C 20 heterocyclyldiyl)-(C 1 -C 12 alkyldiyl)-NR 5 -*; and -S(=O) 2 -(C 2 -C 20 heterocyclyldiyl)-(C 1 -C 12 alkyldiyl)-OH; or R 2 and R 3 together form a 5- or 6-membered heterocyclyl ring; X 1 , X 2 , X 3 , and X 4 are independently selected from the group consisting of a bond, C(=O), C(=O)N(R 5 ), O, N(R 5 ), S, S(O) 2 , and S(O) 2 N(R 5 ); R 5 is independently selected from the group consisting of H, C 6 -C 20 aryl, C 3 -C 12 carbocyclyl, C 6 -C 20 aryldiyl, C 1 -C 12 alkyl, and C 1 -C 12 alkyldiyl, or two R 5 groups together form a 5- or 6-membered heterocyclyl ring; R 5a is selected from the group consisting of C 6 -C 20 aryl and C 1 -C 20 heteroaryl; where the asterisk * indicates the attachment site of L, and where one of R 1 , R 2 , R 3 and R 4 is attached to L; L is the linker selected from the group consisting of: Q-C(=O)-PEG^; Q-C(=O)-PEG-C(=O)N(R 6 )-(C 1 -C 12 alkyldiyl)-C(=O)-Gluc^; Q-C(=O)-PEG-O^; Q-C(=O)-PEG-O-C(=O)-; Q-C(=O)-PEG-C(=O)-; Q-C(=O)-PEG-C(=O)-PEP^; Q-C(=O)-PEG-N(R 6 )-; Q-C(=O)-PEG-N(R 6 )-C(=O)-; Q-C(=O)-PEG-N(R 6 )-PEG-C(=O)-PEP^; Q-C(=O)-PEG-N + (R 6 ) 2 ^PEG-C(=O)-PEP^; Q-C(=O)-PEG-C(=O)-PEP-N(R 6 )-(C 1 -C 12 alkyldiyl)-; Q-C(=O)-PEG-C(=O)-PEP-N(R 6 )-(C 1 -C 12 alkyldiyl)N(R 6 )C(=O)-(C 2 -C 5 monoheterocyclyldiyl)-; Q-C(=O)-PEG-SS-(C 1 -C 12 alkyldiyl)-OC(=O)-; Q-C(=O)-PEG-SS-(C 1 -C 12 alkyldiyl)-C(=O)-; Q-(CH 2 ) m -C(=O)N(R 6 )-PEG^; Q-(CH 2 ) m -C(=O)N(R 6 )-PEG-C(=O)N(R 6 )-(C 1 -C 12 alkyldiyl)-C(=O)-Gluc^; Q-(CH 2 ) m -C(=O)N(R 6 )-PEG-O^; Q-(CH 2 ) m -C(=O)N(R 6 )-PEG-O-C(=O)-; Q-(CH 2 ) m -C(=O)N(R 6 )-PEG-C(=O)-; Q-(CH 2 ) m -C(=O)N(R 6 )-PEG-N(R 5 )-; Q-(CH 2 ) m -C(=O)N(R 6 )-PEG-N(PEG-CO 2 H)-PEG-N(R 5 )-; Q-(CH 2 ) m -C(=O)N(R 6 )-PEG-C(=O)N(PEG-CO 2 H)-PEG-N(R 5 )-; Q-(CH 2 ) m -C(=O)N(R 6 )-PEG-N(R 5 )-C(=O)-; Q-(CH 2 ) m -C(=O)N(R 6 )-PEG-N(PEG-CO 2 H)-PEG-C(=O)-; Q-(CH 2 ) m -C(=O)N(R 6 )-PEG-C(=O)N(PEG-CO 2 H)-PEG-C(=O)-; Q-(CH 2 ) m -C(=O)N(R 6 )-PEG-C(=O)-PEP^; and Q-(CH 2 ) m -C(=O)N(R 6 )-PEG-SS-(C 1 -C 12 alkyldiyl)-OC(=O)-; R 6 is independently H or C 1 -C 6 alkyl; PEG has the formula: -(CH 2 CH 2 O) n -(CH 2 ) 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 C 6 -C 20 aryldiyl and C 1 -C 20 heteroaryldiyl, optionally substituted with one or more groups selected from F, Cl, NO 2 , -OH, -OCH 3 , and a glucuronic acid having the structure: ; R 7 is selected from the group consisting of -CH(R 8 )O^, -CH 2 ^, -CH 2 N(R 8 )-, and ^ CH(R 8 )O-C(=O)-, where R 8 is selected from H, C 1 -C 6 alkyl, C(=O)-C 1 -C 6 alkyl, and ^ C(=O)N(R 9 ) 2 , where R 9 is independently selected from the group consisting of H, C 1 -C 12 alkyl, and -(CH 2 CH 2 O) n -(CH 2 ) m -OH, where m is an integer from 1 to 5, and n is an integer from 2 to 50, or two R 9 groups together form a 5- or 6-membered heterocyclyl ring; y is an integer from 2 to 12; z is 0 or 1; 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 - ; 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, -CH 3 , -CH 2 CH 3 , -CH=CH 2 , -C{CH, -C{CCH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , ^ CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -CH(OH)CH(CH 3 ) 2 , ^ C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 SO 2 CH 3 , -CH 2 OP(O)(OH) 2 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , ^ CH 2 CHF 2 , -CH(CH 3 )CN, -C(CH 3 ) 2 CN, -CH 2 CN, -CH 2 NH 2 , -CH 2 NHSO 2 CH 3 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CO 2 H, -COCH 3 , -CO 2 CH 3 , -CO 2 C(CH 3 ) 3 , -COCH(OH)CH 3 , -CONH 2 , ^ CONHCH 3 , -CON(CH 3 ) 2 , -C(CH 3 ) 2 CONH 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCOCH 3 , ^ N(CH 3 )COCH 3 , -NHS(O) 2 CH 3 , -N(CH 3 )C(CH 3 ) 2 CONH 2 , -N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ^ NHC(=NH)H, -NHC(=NH)CH 3 , -NHC(=NH)NH 2 , -NHC(=O)NH 2 , -NO 2 , =O, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 N(CH 3 ) 2 , -O(CH 2 CH 2 O) n ^ (CH 2 ) m CO 2 H, -O(CH 2 CH 2 O) n H, -OCH 2 F, -OCHF 2 , -OCF 3 , -OP(O)(OH) 2 , -S(O) 2 N(CH 3 ) 2 , ^ SCH 3 , -S(O) 2 CH 3 , and -S(O) 3 H. An exemplary embodiment of the 8-sulfonyl-2-aminobenzazepine-linker compound of Formula II includes wherein Q is selected from:
. An exemplary embodiment of the 8-sulfonyl-2-aminobenzazepine-linker compound of Formula II includes wherein Q is phenoxy substituted with one or more F. An exemplary embodiment of the 8-sulfonyl-2-aminobenzazepine-linker compound of Formula II includes wherein Q is 2,3,5,6-tetrafluorophenoxy. An exemplary embodiment of the 8-sulfonyl-2-aminobenzazepine-linker (8SO2BzL) compound is selected from Table 2. Each compound was synthesized, purified, and characterized by mass spectrometry and shown to have the mass indicated. Additional experimental procedures are found in the Examples. The 8-sulfonyl-2-aminobenzazepine-linker compounds of Table 2 demonstrate the surprising and unexpected property of TLR8 agonist selectivity which may predict useful therapeutic activity to treat cancer and other disorders. The 8-sulfonyl-2-aminobenzazepine-linker intermediate, Formula II compounds of Table 2 may be used in conjugation with a macromolecule support by the methods of Example 201 to form the MSC of Formula I.
Table 2 8-Sulfonyl-Benzazepine-Linker (8SO2BzL) compounds MACROMOLECULE-SUPPORTED COMPOUNDS Immune-stimulating antibody conjugates, i.e. immunoconjugates, direct TLR7/8 agonists into tumors to activate tumor-infiltrating myeloid cells and initiate a broad innate and adaptive anti-tumor immune response (Ackerman, et al., (2021) Nature Cancer 2:18-33. Exemplary embodiments of macromolecule-supported compounds comprise a macromolecular support covalently attached to one or more 8-sulfonyl-2-aminobenzazepine moieties by a linker, and having Formula I: or a pharmaceutically acceptable salt thereof, wherein: Ms is the macromolecular support; p is an integer from 1 to 50; D is the 8-sulfonyl-2-aminobenzazepine moiety having the formula: R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of H, C 1 -C 12 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C6-C20 aryl, C2-C9 heterocyclyl, and C 1 -C 20 heteroaryl, where alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl are independently and optionally substituted with one or more groups selected from: -(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -(C1-C12 alkyldiyl)-N(R 5 )2; -(C 1 -C 12 alkyldiyl)-OR 5 ; -(C 3 -C 12 carbocyclyl); -(C 3 -C 12 carbocyclyl)-*; -(C3-C12 carbocyclyl)-(C1-C12 alkyldiyl)-NR 5 -*; -(C 3 -C 12 carbocyclyl)-(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -(C 3 -C 12 carbocyclyl)-NR 5 -C(=NR 5 )NR 5 -*; -(C 6 -C 20 aryl); -(C 6 -C 20 aryldiyl)-*; -(C 6 -C 20 aryldiyl)-N(R 5 )-*; -(C 6 -C 20 aryldiyl)-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -(C 6 -C 20 aryldiyl)-(C 1 -C 12 alkyldiyl)-(C 2 -C 20 heterocyclyldiyl)-*; -(C 6 -C 20 aryldiyl)-(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -(C 6 -C 20 aryldiyl)-(C 1 -C 12 alkyldiyl)-NR 5 -C(=NR 5a )N(R 5 )-*; -(C 2 -C 20 heterocyclyl); -(C 2 -C 20 heterocyclyl)-*; -(C 2 -C 9 heterocyclyl)-(C 1 -C 12 alkyldiyl)-NR 5 -*; -(C 2 -C 9 heterocyclyl)-(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -(C 2 -C 9 heterocyclyl)-C(=O)-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -(C 2 -C 9 heterocyclyl)-NR 5 -C(=NR 5a )NR 5 -*; -(C 2 -C 9 heterocyclyl)-NR 5 -(C 6 -C 20 aryldiyl)-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -(C 2 -C 9 heterocyclyl)-(C 6 -C 20 aryldiyl)-*; -(C 1 -C 20 heteroaryl); -(C 1 -C 20 heteroaryl)-*; -(C 1 -C 20 heteroaryl)-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -(C 1 -C 20 heteroaryl)-(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -(C 1 -C 20 heteroaryl)-NR 5 -C(=NR 5a )N(R 5 )-*; -(C 1 -C 20 heteroaryl)-N(R 5 )C(=O)-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -C(=O)-*; -C(=O)-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -C(=O)-(C 2 -C 20 heterocyclyldiyl)-*; -C(=O)N(R 5 ) 2 ; -C(=O)N(R 5 )-*; -C(=O)N(R 5 )-(C 1 -C 12 alkyldiyl)-N(R 5 )C(=O)R 5 ; -C(=O)N(R 5 )-(C 1 -C 12 alkyldiyl)-N(R 5 )C(=O)N(R 5 ) 2 ; -C(=O)NR 5 -(C 1 -C 12 alkyldiyl)-N(R 5 )CO 2 R 5 ; -C(=O)NR 5 -(C 1 -C 12 alkyldiyl)-N(R 5 )C(=NR 5a )N(R 5 ) 2 ; -C(=O)NR 5 -(C 1 -C 12 alkyldiyl)-NR 5 C(=NR 5a )R 5 ; -C(=O)NR 5 -(C 1 -C 8 alkyldiyl)-NR 5 (C 2 -C 5 heteroaryl); -C(=O)NR 5 -(C 1 -C 20 heteroaryldiyl)-N(R 5 )-*; -C(=O)NR 5 -(C 1 -C 20 heteroaryldiyl)-*; -C(=O)NR 5 -(C 1 -C 20 heteroaryldiyl)-(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -C(=O)NR 5 -(C 1 -C 20 heteroaryldiyl)-(C 2 -C 20 heterocyclyldiyl)-C(=O)NR 5 -(C 1 -C 12 alkyldiyl)-NR 5 -*; -N(R 5 ) 2 ; -N(R 5 )-*; -N(R 5 )C(=O)R 5 ; -N(R 5 )C(=O)-*; -N(R 5 )C(=O)N(R 5 ) 2 ; -N(R 5 )C(=O)N(R 5 )-*; -N(R 5 )CO 2 R 5 ; -NR 5 C(=NR 5a )N(R 5 ) 2 ; -NR 5 C(=NR 5a )N(R 5 )-*; -NR 5 C(=NR 5a )R 5 ; -N(R 5 )C(=O)-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -N(R 5 )-(C 2 -C 5 heteroaryl); -N(R 5 )-S(=O) 2 -(C 1 -C 12 alkyl); -O-(C 1 -C 12 alkyl); -O-(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -O-(C 1 -C 12 alkyldiyl)-N(R 5 )-*; -O-C(=O)N(R 5 ) 2 ; -O-C(=O)N(R 5 )-*; -O-(R 5 )-*; -OR 5 ; -S(=O) 2 -(C 2 -C 20 heterocyclyldiyl)-*; -S(=O) 2 -(C 2 -C 20 heterocyclyldiyl)-(C 1 -C 12 alkyldiyl)-N(R 5 ) 2 ; -S(=O) 2 -(C 2 -C 20 heterocyclyldiyl)-(C 1 -C 12 alkyldiyl)-NR 5 -*; and -S(=O) 2 -(C 2 -C 20 heterocyclyldiyl)-(C 1 -C 12 alkyldiyl)-OH; or R 2 and R 3 together form a 5- or 6-membered heterocyclyl ring; X 1 , X 2 , X 3 , and X 4 are independently selected from the group consisting of a bond, C(=O), C(=O)N(R 5 ), O, N(R 5 ), S, S(O) 2 , and S(O) 2 N(R 5 ); R 5 is independently selected from the group consisting of H, C 6 -C 20 aryl, C 3 -C 12 carbocyclyl, C 6 -C 20 aryldiyl, C 1 -C 12 alkyl, and C 1 -C 12 alkyldiyl, or two R 5 groups together form a 5- or 6-membered heterocyclyl ring; R 5a is selected from the group consisting of C 6 -C 20 aryl and C 1 -C 20 heteroaryl; where the asterisk * indicates the attachment site of L, and where one of R 1 , R 2 , R 3 and R 4 is attached to L; L is the linker selected from the group consisting of: -C(=O)-PEG^; -C(=O)-PEG-C(=O)N(R 6 )-(C 1 -C 12 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(R 6 )-; -C(=O)-PEG-N(R 6 )-C(=O)-; -C(=O)-PEG-N(R 6 )-PEG-C(=O)-PEP^; -C(=O)-PEG-N + (R 6 ) 2 ^PEG-C(=O)-PEP^; -C(=O)-PEG-C(=O)-PEP-N(R 6 )-(C 1 -C 12 alkyldiyl)-; -C(=O)-PEG-C(=O)-PEP-N(R 6 )-(C 1 -C 12 alkyldiyl)N(R 6 )C(=O)-(C 2 -C 5 monoheterocyclyldiyl)-; -C(=O)-PEG-SS-(C 1 -C 12 alkyldiyl)-OC(=O)-; -C(=O)-PEG-SS-(C 1 -C 12 alkyldiyl)-C(=O)-; -C(=O)-(C 1 -C 12 alkyldiyl)-C(=O)-PEP^; -C(=O)-(C 1 -C 12 alkyldiyl)-C(=O)-PEP-N(R 6 )-(C 1 -C 12 alkyldiyl)-; -C(=O)-(C 1 -C 12 alkyldiyl)-C(=O)-PEP-N(R 6 )-(C 1 -C 12 alkyldiyl)-N(R 5 )-C(=O); -C(=O)-(C 1 -C 12 alkyldiyl)-C(=O)-PEP-N(R 6 )-(C 1 -C 12 alkyldiyl)-N(R 6 )C(=O)- (C 2 -C 5 monoheterocyclyldiyl)-; - succinimidyl-(CH 2 ) m -C(=O)N(R 6 )-PEG^; - succinimidyl-(CH 2 ) m -C(=O)N(R 6 )-PEG-C(=O)N(R 6 )-(C 1 -C 12 alkyldiyl)-C(=O)-Gluc^; - succinimidyl-(CH 2 ) m -C(=O)N(R 6 )-PEG-O^; - succinimidyl-(CH 2 ) m -C(=O)N(R 6 )-PEG-O-C(=O)-; - succinimidyl-(CH 2 ) m -C(=O)N(R 6 )-PEG-C(=O)-; - succinimidyl-(CH 2 ) m -C(=O)N(R 6 )-PEG-N(R 5 )-; - succinimidyl-(CH 2 ) m -C(=O)N(R 6 )-PEG-N(PEG-CO 2 H)-PEG-N(R 5 )-; - succinimidyl-(CH 2 ) m -C(=O)N(R 6 )-PEG-C(=O)N(PEG-CO 2 H)-PEG-N(R 5 )-;- succinimidyl-(CH 2 ) m -C(=O)N(R 6 )-PEG-N(R 5 )-C(=O)-; - succinimidyl-(CH 2 ) m -C(=O)N(R 6 )-PEG-N(PEG-CO 2 H)-PEG-C(=O)-; - succinimidyl-(CH 2 ) m -C(=O)N(R 6 )-PEG-C(=O)N(PEG-CO 2 H)-PEG-C(=O)-;- succinimidyl-(CH 2 ) m -C(=O)N(R 6 )-PEG-C(=O)-PEP^; - succinimidyl-(CH 2 ) m -C(=O)N(R 6 )-PEG-SS-(C 1 -C 12 alkyldiyl)-OC(=O)-;- succinimidyl-(CH 2 ) m -C(=O)-PEP-N(R 6 )-(C 1 -C 12 alkyldiyl)-; - succinimidyl-(CH 2 ) m -C(=O)-PEP-N(R 6 )-(C 1 -C 12 alkyldiyl)N(R 6 )C(=O)-; and- succinimidyl-(CH 2 ) m -C(=O)-PEP-N(R 6 )-(C 1 -C 12 alkyldiyl)N(R 6 )C(=O)-(C 2 -C 5 monoheterocyclyldiyl)-; R 6 is independently H or C 1 -C 6 alkyl; PEG has the formula: -(CH 2 CH 2 O) n -(CH 2 ) 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 C 6 -C 20 aryldiyl and C 1 -C 20 heteroaryldiyl, optionally substituted with one or more groups selected from F, Cl, NO2, -OH, -OCH3, and a glucuronic acid having the structure: ; R 7 is selected from the group consisting of -CH(R 8 )O^, -CH 2 ^, -CH 2 N(R 8 )-, and- CH(R 8 )O-C(=O)-, where R 8 is selected from H, C 1 -C 6 alkyl, C(=O)-C 1 -C 6 alkyl, and- C(=O)N(R 9 ) 2 , where R 9 is independently selected from the group consisting of H, C 1 -C 12 alkyl, and -(CH 2 CH 2 O) n -(CH 2 ) m -OH, where m is an integer from 1 to 5, and n is an integer from 2 to 50, or two R 9 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, -CH 3 , -CH 2 CH 3 , -CH=CH 2 , -C{CH, -C{CCH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 -, CH2CH(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, -CH(OH)CH(CH3-)2, C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 SO 2 CH 3 , -CH 2 OP(O)(OH) 2 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 -, CH 2 CHF 2 , -CH(CH 3 )CN, -C(CH 3 ) 2 CN, -CH 2 CN, -CH 2 NH 2 , -CH 2 NHSO 2 CH 3 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CO 2 H, -COCH 3 , -CO 2 CH 3 , -CO 2 C(CH 3 ) 3 , -COCH(OH)CH 3 , -CONH 2 -, CONHCH 3 , -CON(CH 3 ) 2 , -C(CH 3 ) 2 CONH 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCOCH 3 , - N(CH 3 )COCH 3 , -NHS(O) 2 CH 3 , -N(CH 3 )C(CH 3 ) 2 CONH 2 , -N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , - NHC(=NH)H, -NHC(=NH)CH 3 , -NHC(=NH)NH 2 , -NHC(=O)NH 2 , -NO 2 , =O, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 N(CH 3 ) 2 , -O(CH 2 CH 2 O) n - (CH 2 ) m CO 2 H, -O(CH 2 CH 2 O) n H, -OCH 2 F, -OCHF 2 , -OCF 3 , -OP(O)(OH) 2 , -S(O) 2 N(CH 3 ) 2 -, SCH 3 , -S(O) 2 CH 3 , and -S(O) 3 H. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein X 1 is a bond, and R 1 is H. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein X 2 is a bond, and R 2 is C 1 -C 8 alkyl. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein X 2 and X 3 are each a bond, and R 2 and R 3 are independently selected from C 1 - C 8 alkyl, -O-(C 1 -C 12 alkyl), -(C 1 -C 12 alkyldiyl)-OR 5 , -(C 1 -C 8 alkyldiyl)-N(R 5 )CO 2 R 5 , -(C 1 - C 12 alkyl)-OC(O)N(R 5 ) 2 , -O-(C 1 -C 12 alkyl)-N(R 5 )CO 2 R 5 , and -O-(C 1 -C 12 alkyl)- OC(O)N(R 5 ) 2 . An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein subscript p is an integer from 1 to 25. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein subscript p is an integer from 1 to 6. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein the macromolecular support is selected from a peptide, a nucleotide, a carbohydrate, a lipid, an antibody construct, a biopolymer, a nanoparticle, and an immune checkpoint inhibitor. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein R 2 is C 1 -C 8 alkyl and R 3 is -(C 1 -C 8 alkyldiyl)-N(R 5 )CO 2 R 4 . An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein R 2 is -CH2CH2CH3 and R 3 is selected from -CH2CH2CH2NHCO2(t-Bu-), OCH 2 CH 2 NHCO 2 (cyclobutyl), and -CH 2 CH 2 CH 2 NHCO 2 (cyclobutyl). An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein R 2 and R 3 are each independently selected from -CH 2 CH 2 CH 3 , -OCH 2 CH 3 -, OCH 2 CF 3 , -CH 2 CH 2 CF 3 , -OCH 2 CH 2 OH, and -CH 2 CH 2 CH 2 OH. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein R 2 and R 3 are each -CH 2 CH 2 CH 3 . An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein R 2 is -CH 2 CH 2 CH 3 and R 3 is -OCH 2 CH 3 . An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein X 3 -R 3 is selected from the group consisting of: . An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein X 4 is a bond, and R 4 is H. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein R 1 is attached to L. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein R 2 or R 3 is attached to L. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein X 3 ^R 3 ^L is selected from the group consisting of: where the wavy line indicates the point of attachment to N. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein R 4 is C 1 -C 12 alkyl. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein R 4 is -(C1-C12 alkyldiyl)-N(R 5 )-*; where the asterisk * indicates the attachment site of L. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein L is -C(=O)-PEG^ or -C(=O)-PEG-C(=O)-. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein L is attached to a cysteine thiol of the antibody. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein for the PEG, m is 1 or 2, and n is an integer from 2 to 10; or wherein n is 10. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein L comprises PEP and PEP is a dipeptide and has the formula: . An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein AA 1 and AA 2 are independently selected from H, -CH 3 , -CH(CH 3 ) 2 , -CH 2 (C 6 H 5 ), -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NHC(NH)NH 2 , -CHCH(CH 3 )CH 3 , -CH 2 SO 3 H, and -CH 2 CH 2 CH 2 NHC(O)NH 2 ; or AA 1 and AA 2 form a 5-membered ring proline amino acid. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein AA 1 is -CH(CH 3 ) 2 , and AA 2 is -CH 2 CH 2 CH 2 NHC(O)NH 2 . An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein AA 1 and AA 2 are independently selected from GlcNAc aspartic acid, -CH 2 SO 3 H, and -CH 2 OPO 3 H. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein PEP has the formula: wherein AA1 and AA2 are independently selected from a side chain of a naturally- occurring amino acid. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein L comprises PEP and PEP is a tripeptide and has the formula: . An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein L comprises PEP and PEP is a tetrapeptide and has the formula: . An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein: AA 1 is selected from the group consisting of Abu, Ala, and Val; AA 2 is selected from the group consisting of Nle(O-Bzl), Oic and Pro; AA 3 is selected from the group consisting of Ala and Met(O) 2 ; and AA 4 is selected from the group consisting of Oic, Arg(NO 2 ), Bpa, and Nle(O-Bzl). An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein L comprises PEP and PEP is selected from the group consisting of Ala-Pro- Val, Asn-Pro-Val, Ala-Ala-Val, Ala-Ala-Pro-Ala, Ala-Ala-Pro-Val, and Ala-Ala-Pro-Nva. An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein L comprises PEP and PEP is selected from the structures: . An exemplary embodiment of the macromolecule-supported compound of Formula I includes wherein L is selected from the structures: where the wavy line indicates the attachment to R 5 . The invention includes all reasonable combinations, and permutations of the features, of the Formula I embodiments. In certain embodiments, the Macromolecule-supported compounds of the invention include those with biological activity. The Macromolecule-supported compounds (MSC) of the invention selectively deliver an effective dose of a 8-sulfonyl-2-aminobenzazepine (8SO2Bz) drug to a mammal, whereby greater selectivity (i.e., a lower efficacious dose) may be achieved while increasing the therapeutic index (“therapeutic window”) relative to unconjugated 8SO2Bz. Each MSC of Table 3 was prepared, purified by HPLC, and characterized by mass spectroscopy according to the methods of Example 201. Exemplary MSC 1-4 are conjugates of bezlotoxumab. Bezlotoxumab (ZINPLAVA®, Merck & Co.) is an anti-toxin B monoclonal antibody, 145 kDa MW, shown to be effective in treating Clostridium difficile infection (Lowy I, et al (2010) N. Engl. J. Med.362(3):197–205; Orth P, et al (2014) Journal of Biological Chemistry 289(26):18008–18021; US8257709; US9181632). The antibody sequences of US8257709 and US9181632 are incorporated by reference herein. Exemplary MSC 5-9 are conjugates of BSA monomer, 66 kDa. Bovine serum albumin (BSA) is a globular protein of about 66 kDa MW, used in numerous biochemical applications due to its stability and lack of interference with biological reactions. The BSA structure is a single polypeptide chain consisting of about 583 amino acid residues and no carbohydrates. Table 3 8-Sulfonyl-2-Aminobenzazepine Macromolecule-supported Compounds (MSC) COMPOSITIONS OF MACROMOLECULE-SUPPORTED COMPOUNDS The invention provides a composition, e.g., a pharmaceutically or pharmacologically acceptable composition or formulation, comprising a plurality of macromolecule-supported compounds as described herein and optionally a carrier therefor, e.g., a pharmaceutically or pharmacologically acceptable carrier. The macromolecule-supported compounds can be the same or different in the composition, i.e., the composition can comprise macromolecule- supported compounds that have the same number of adjuvants linked to the same positions on the macromolecule and/or macromolecule-supported compounds that have the same number of 8SO2Bz adjuvants linked to different positions on the antibody construct, that have different numbers of adjuvants linked to the same positions on the antibody construct, or that have different numbers of adjuvants linked to different positions on the antibody construct. In an exemplary embodiment, an MSC composition comprises a mixture of the MSC, wherein the average drug (8SO2Bz) loading per macromolecule support in the mixture of MSC is about 2 to about 5. A composition of MSC of the invention can have an average adjuvant to macromolecule support ratio of about 0.4 to about 10. A skilled artisan will recognize that the number of 8- sulfonyl-2-aminobenzazepine adjuvants conjugated to the macromolecule support may vary in a heterogeneous composition comprising multiple MSC of the invention and thus the adjuvant to macromolecule support ratio can be measured as an average which may be referred to as the drug to macromolecule support ratio. The adjuvant to macromolecule support ratio can be assessed by any suitable means, many of which are known in the art, including conventional means such as mass spectrometry, ELISA assay, and HPLC. The quantitative distribution of MSC in a composition in terms of p may also be determined. In some instances, separation, purification, and characterization of homogeneous MSC where p is a certain value from MSC with other drug loadings may be achieved by means such as reverse phase HPLC or electrophoresis. In some embodiments, the composition further comprises one or more pharmaceutically or pharmacologically acceptable excipients. For example, the MSC of the invention can be formulated for parenteral administration, such as IV administration or administration into a body cavity or lumen of an organ. Alternatively, the MSC can be injected intra-tumorally. Compositions for injection will commonly comprise a solution of the MSC dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and an isotonic solution of one or more salts such as sodium chloride, e.g., Ringer's solution. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These compositions desirably are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well known sterilization techniques. The compositions can contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The composition can contain any suitable concentration of the MSC. The concentration of the MSC in the composition can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. In certain embodiments, the concentration of an MSC in a solution formulation for injection will range from about 0.1% (w/w) to about 10% (w/w). METHOD OF TREATING CANCER WITH MACROMOLECULE-SUPPORTED 8- SULFONYL-BENZAZEPINE COMPOUNDS The invention provides a method for treating cancer. The method includes administering a therapeutically effective amount of an MSC as described herein (e.g., as a composition as described herein) to a subject in need thereof, e.g., a subject that has cancer and is in need of treatment for the cancer. It is contemplated that the MSC of the present invention may be used to treat various hyperproliferative diseases or disorders, e.g. characterized by the overexpression of a tumor antigen. Exemplary hyperproliferative disorders include benign or malignant solid tumors and hematological disorders such as leukemia and lymphoid malignancies. In another aspect, an MSC for use as a medicament is provided. In certain embodiments, the invention provides an MSC for use in a method of treating an individual comprising administering to the individual an effective amount of the MSC. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, e.g., as described herein. In a further aspect, the invention provides for the use of an MSC in the manufacture or preparation of a medicament. In one embodiment, the medicament is for treatment of cancer, the method comprising administering to an individual having cancer an effective amount of the medicament. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, e.g., as described herein. Carcinomas are malignancies that originate in the epithelial tissues. Epithelial cells cover the external surface of the body, line the internal cavities, and form the lining of glandular tissues. Examples of carcinomas include, but are not limited to, adenocarcinoma (cancer that begins in glandular (secretory) cells such as cancers of the breast, pancreas, lung, prostate, stomach, gastroesophageal junction, and colon) adrenocortical carcinoma; hepatocellular carcinoma; renal cell carcinoma; ovarian carcinoma; carcinoma in situ; ductal carcinoma; carcinoma of the breast; basal cell carcinoma; squamous cell carcinoma; transitional cell carcinoma; colon carcinoma; nasopharyngeal carcinoma; multilocular cystic renal cell carcinoma; oat cell carcinoma; large cell lung carcinoma; small cell lung carcinoma; non-small cell lung carcinoma; and the like. Carcinomas may be found in prostrate, pancreas, colon, brain (usually as secondary metastases), lung, breast, and skin. In some embodiments, methods for treating non-small cell lung carcinoma include administering an MSC containing an antibody construct that is capable of binding a tumor-associated antigen. Soft tissue tumors are a highly diverse group of rare tumors that are derived from connective tissue. Examples of soft tissue tumors include, but are not limited to, alveolar soft part sarcoma; angiomatoid fibrous histiocytoma; chondromyoxid fibroma; skeletal chondrosarcoma; extraskeletal myxoid chondrosarcoma; clear cell sarcoma; desmoplastic small round-cell tumor; dermatofibrosarcoma protuberans; endometrial stromal tumor; Ewing’s sarcoma; fibromatosis (Desmoid); infantile fibrosarcoma; gastrointestinal stromal tumor; bone giant cell tumor; tenosynovial giant cell tumor; inflammatory myofibroblastic tumor; uterine leiomyoma; leiomyosarcoma; lipoblastoma; typical lipoma; spindle cell or pleomorphic lipoma; atypical lipoma; chondroid lipoma; well-differentiated liposarcoma; myxoid/round cell liposarcoma; pleomorphic liposarcoma; myxoid malignant fibrous histiocytoma; high-grade malignant fibrous histiocytoma; myxofibrosarcoma; malignant peripheral nerve sheath tumor; mesothelioma; neuroblastoma; osteochondroma; osteosarcoma; primitive neuroectodermal tumor; alveolar rhabdomyosarcoma; embryonal rhabdomyosarcoma; benign or malignant schwannoma; synovial sarcoma; Evan’s tumor; nodular fasciitis; desmoid-type fibromatosis; solitary fibrous tumor; dermatofibrosarcoma protuberans (DFSP); angiosarcoma; epithelioid hemangioendothelioma; tenosynovial giant cell tumor (TGCT); pigmented villonodular synovitis (PVNS); fibrous dysplasia; myxofibrosarcoma; fibrosarcoma; synovial sarcoma; malignant peripheral nerve sheath tumor; neurofibroma; pleomorphic adenoma of soft tissue; and neoplasias derived from fibroblasts, myofibroblasts, histiocytes, vascular cells/endothelial cells, and nerve sheath cells. A sarcoma is a rare type of cancer that arises in cells of mesenchymal origin, e.g., in bone or in the soft tissues of the body, including cartilage, fat, muscle, blood vessels, fibrous tissue, or other connective or supportive tissue. Different types of sarcoma are based on where the cancer forms. For example, osteosarcoma forms in bone, liposarcoma forms in fat, and rhabdomyosarcoma forms in muscle. Examples of sarcomas include, but are not limited to, askin's tumor; sarcoma botryoides; chondrosarcoma; Ewing's sarcoma; malignant hemangioendothelioma; malignant schwannoma; osteosarcoma; and soft tissue sarcomas (e.g., alveolar soft part sarcoma; angiosarcoma; cystosarcoma phyllodesdermatofibrosarcoma protuberans (DFSP); desmoid tumor; desmoplastic small round cell tumor; epithelioid sarcoma; extraskeletal chondrosarcoma; extraskeletal osteosarcoma; fibrosarcoma; gastrointestinal stromal tumor (GIST); hemangiopericytoma; hemangiosarcoma (more commonly referred to as “angiosarcoma”); Kaposi’s sarcoma; leiomyosarcoma; liposarcoma; lymphangiosarcoma; malignant peripheral nerve sheath tumor (MPNST); neurofibrosarcoma; synovial sarcoma; and undifferentiated pleomorphic sarcoma). A teratoma is a type of germ cell tumor that may contain several different types of tissue (e.g., can include tissues derived from any and/or all of the three germ layers: endoderm, mesoderm, and ectoderm), including, for example, hair, muscle, and bone. Teratomas occur most often in the ovaries in women, the testicles in men, and the tailbone in children. Melanoma is a form of cancer that begins in melanocytes (cells that make the pigment melanin). Melanoma may begin in a mole (skin melanoma), but can also begin in other pigmented tissues, such as in the eye or in the intestines. Merkel cell carcinoma is a rare type of skin cancer that usually appears as a flesh-colored or bluish-red nodule on the face, head or neck. Merkel cell carcinoma is also called neuroendocrine carcinoma of the skin. Leukemias are cancers that start in blood-forming tissue, such as the bone marrow, and cause large numbers of abnormal blood cells to be produced and enter the bloodstream. For example, leukemias can originate in bone marrow-derived cells that normally mature in the bloodstream. Leukemias are named for how quickly the disease develops and progresses (e.g., acute versus chronic) and for the type of white blood cell that is affected (e.g., myeloid versus lymphoid). Myeloid leukemias are also called myelogenous or myeloblastic leukemias. Lymphoid leukemias are also called lymphoblastic or lymphocytic leukemia. Lymphoid leukemia cells may collect in the lymph nodes, which can become swollen. Examples of leukemias include, but are not limited to, Acute myeloid leukemia (AML), Acute lymphoblastic leukemia (ALL), Chronic myeloid leukemia (CML), and Chronic lymphocytic leukemia (CLL). Lymphomas are cancers that begin in cells of the immune system. For example, lymphomas can originate in bone marrow-derived cells that normally mature in the lymphatic system. There are two basic categories of lymphomas. One category of lymphoma is Hodgkin lymphoma (HL), which is marked by the presence of a type of cell called the Reed-Sternberg cell. There are currently 6 recognized types of HL. Examples of Hodgkin lymphomas include nodular sclerosis classical Hodgkin lymphoma (CHL), mixed cellularity CHL, lymphocyte- depletion CHL, lymphocyte-rich CHL, and nodular lymphocyte predominant HL. The other category of lymphoma is non-Hodgkin lymphomas (NHL), which includes a large, diverse group of cancers of immune system cells. Non-Hodgkin lymphomas can be further divided into cancers that have an indolent (slow-growing) course and those that have an aggressive (fast-growing) course. There are currently 61 recognized types of NHL. Examples of non-Hodgkin lymphomas include, but are not limited to, AIDS-related Lymphomas, anaplastic large-cell lymphoma, angioimmunoblastic lymphoma, blastic NK-cell lymphoma, Burkitt’s lymphoma, Burkitt-like lymphoma (small non-cleaved cell lymphoma), chronic lymphocytic leukemia/small lymphocytic lymphoma, cutaneous T-Cell lymphoma, diffuse large B-Cell lymphoma, enteropathy-type T-Cell lymphoma, follicular lymphoma, hepatosplenic gamma- delta T-Cell lymphomas, T-Cell leukemias, lymphoblastic lymphoma, mantle cell lymphoma, marginal zone lymphoma, nasal T-Cell lymphoma, pediatric lymphoma, peripheral T-Cell lymphomas, primary central nervous system lymphoma, transformed lymphomas, treatment- related T-Cell lymphomas, and Waldenstrom's macroglobulinemia. Brain cancers include any cancer of the brain tissues. Examples of brain cancers include, but are not limited to, gliomas (e.g., glioblastomas, astrocytomas, oligodendrogliomas, ependymomas, and the like), meningiomas, pituitary adenomas, and vestibular schwannomas, primitive neuroectodermal tumors (medulloblastomas). MSC of the invention can be used either alone or in combination with other agents in a therapy. For instance, an MSC may be co-administered with at least one additional therapeutic agent, such as a chemotherapeutic agent. Such combination therapies encompass combined administration (where two or more therapeutic agents are included in the same or separate formulations), and separate administration, in which case, administration of the MSC can occur prior to, simultaneously, and/or following, administration of the additional therapeutic agent and/or adjuvant. MSC can also be used in combination with radiation therapy. The MSC of the invention (and any additional therapeutic agent) can be administered by any suitable means, including oral, parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Dosing can be by any suitable route, e.g. by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic. Various dosing schedules including but not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein. The MSC is administered to a subject in need thereof in any therapeutically effective amount using any suitable dosing regimen, such as the dosing regimens utilized for labetuzumab, biosimilars thereof, and biobetters thereof. For example, the methods can include administering the MSC to provide a dose of from about 100 ng/kg to about 50 mg/kg to the subject. The MSC dose can range from about 5 mg/kg to about 50 mg/kg, from about 10 μg/kg to about 5 mg/kg, or from about 100 μg/kg to about 1 mg/kg. The MSC dose can be about 100, 200, 300, 400, or 500 μg/kg. The MSC dose can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg/kg. The MSC dose can also be outside of these ranges, depending on the particular conjugate as well as the type and severity of the cancer being treated. Frequency of administration can range from a single dose to multiple doses per week, or more frequently. In some embodiments, the MSC is administered from about once per month to about five times per week. In some embodiments, the MSC is administered once per week. In another aspect, the invention provides a method for preventing cancer. The method comprises administering a therapeutically effective amount of an MSC (e.g., as a composition as described above) to a subject. In certain embodiments, the subject is susceptible to a certain cancer to be prevented. Some embodiments of the invention provide methods for treating cancer as described above, wherein the cancer is breast cancer. Breast cancer can originate from different areas in the breast, and a number of different types of breast cancer have been characterized. For example, the MSC of the invention can be used for treating ductal carcinoma in situ; invasive ductal carcinoma (e.g., tubular carcinoma; medullary carcinoma; mucinous carcinoma; papillary carcinoma; or cribriform carcinoma of the breast); lobular carcinoma in situ; invasive lobular carcinoma; inflammatory breast cancer; and other forms of breast cancer such as triple negative (test negative for estrogen receptors, progesterone receptors, and excess HER2 protein) breast cancer. In some embodiments, methods for treating breast cancer include administering an MSC containing cell binding agent that is capable of binding a tumor-associated antigen (TAA), or tumors over-expressing a TAA In some embodiments, the cancer is susceptible to a pro-inflammatory response induced by TLR7 and/or TLR8. In some embodiments, a therapeutically effective amount of an MSC is administered to a patient in need to treat cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, esophageal cancer, bladder cancer, urinary tract cancer, urothelial carcinoma, lung cancer, non-small cell lung cancer, Merkel cell carcinoma, colon cancer, colorectal cancer, gastric cancer, or breast cancer. The Merkel cell carcinoma cancer may be metastatic Merkel cell carcinoma. The breast cancer may be triple-negative breast cancer. The esophageal cancer may be gastroesophageal junction adenocarcinoma. EXAMPLES Example L-1 Synthesis of 4-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[4-[[2-amino-4- [ethoxy(propyl) carbamoyl]-3H-1-benzazepin-8- yl]sulfonyl]benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoyloxy]-2,3, 5,6-tetrafluoro-benzenesulfonic acid,, 8SO2BzL-1
Preparation of 8-bromo-N-ethoxy-N-propyl-2-(tritylamino)-3H-1-benzazepine-4 - carboxamide, 8SO2BzL-1b To a mixture of 8-bromo-2-(tritylamino)-3H-1-benzazepine-4-carboxylic acid, 8SO2BzL-1a (1 g, 1.91 mmol, 1 eq) and N-ethoxypropan-1-amine (320 mg, 2.29 mmol, 1.2 eq, HCl) in DCM (15 mL) and DMA (5 mL) was added EDCI (1.10 g, 5.73 mmol, 3.0 eq) in one portion at 25°C, and then stirred at 25°C for 0.5 h. The mixture was concentrated to remove DCM. Then the residue was diluted with aq.NaHCO 3 until the pH to between 8 and 9. The mixture was extracted with EtOAc (30 mL x 3). The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=1/0,3/1) to afford 8SO2BzL-1b (0.7 g, 1.15 mmol, 60.21% yield) as white solid. 1 H NMR (CDCl 3 , 400 MHz) δ 7.38-7.15 (m, 15H), 7.06-6.94 (m, 2H), 6.72 (s, 1H), 6.16 (s, 1H), 4.03-3.83 (m, 2H), 3.73 (t, J=7.2 Hz, 2H), 2.78 (s, 2H), 1.89-1.64 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H), 0.99 (t, J=7.2 Hz, 3H). LC/MS [M+H] 608.2 (calculated); LC/MS [M+H] 608.2 (observed). Preparation of methyl 4-[[4-[ethoxy(propyl)carbamoyl]-2-(tritylamino)-3H-1- benzazepin-8-yl]sulfanyl]benzoate, 8SO2BzL-1c To a mixture of 8SO2BzL-1b (0.35 g, 575 umol, 1.0 eq) and methyl 4-sulfanylbenzoate (116 mg, 690 umol, 1.2 eq) in DMF (4 mL) was added dicyclohexyl[2’,4’,6’-tris)propan-2- yl)[1,1’-biphenyl]phosphane, XPhos, CAS Reg. No.564483-18-7, Huang, X., et al (2003) J. Am. Chem. Soc.125(22):6653–6655; Bruno, N.C. et al, (2013) Chemical Science, 4(3):916–920, (82.3 mg, 173 umol, 0.3 eq), Cs2CO3 (375 mg, 1.15 mmol, 2.0 eq) and [2-(2- aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropyl phenyl)phenyl]phosphane, Pd-Xphos-G2, CAS Reg. No.1310584-14-5 (226 mg, 288 umol, 0.5 eq) in one portion at 25 °C under N 2, and then stirred at 120 °C for 12 h. The mixture was diluted water (20 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=1/0, 3/1) to afford 8SO2BzL-1c (0.25 g, 359.26 umol, 62.47% yield). LC/MS [M+H] 696.3 (calculated); LC/MS [M+H] 696.2 (observed). Preparation of methyl 4-[[4-[ethoxy(propyl)carbamoyl]-2-(tritylamino)-3H-1- benzazepin-8-yl]sulfonyl]benzoate, 8SO2BzL-1d To a mixture of 8SO2BzL-1c (0.25 g, 359 umol, 1.0 eq) in DCM (2 mL), THF (2 mL) and H 2 O (2 mL) was added potassium peroxymonosulfate, KHSO 5 , Oxone (663 mg, 1.08 mmol, 3.0 eq) in one portion at 25°C, and then stirred at 25 °C for 12 h. The mixture was diluted with water and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=1/0, 1/1) to afford 8SO2BzL-1d (0.2 g, 274.78 umol, 76.48% yield) as yellow oil. LC/MS [M+H] 728.27 (calculated); LC/MS [M+H] 728.2 (observed). Preparation of methyl 4-[[2-amino-4-[ethoxy(propyl)carbamoyl]-3H-1-benzazepin-8- yl]sulfonyl]benzoate, 8SO2BzL-1e To a mixture of 8SO2BzL-1d (0.1 g, 137 umol, 1.0 eq) in DCM (4 mL) was added TFA (313 mg, 2.75 mmol, 203 uL, 20.0 eq) in one portion at 25°C, and then stirred at 50 °C for 12 h. The mixture was concentrated in vacuum to give a residue, the residue was purified by prep- HPLC(column: Phenomenex Luna 80*30mm*3um;mobile phase: [water(0.1%TFA)- acetonitrile, ACN];B%: 15%-35%,8min) to give 8SO2BzL-1e (0.046 g, 94.74 umol, 68.96% yield) as white solid. 1 H NMR (CDCl 3 , 400 MHz) δ8.21 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 8.4 Hz, 2H), 8.04 (s, 1H), 7.95-7.87 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 6.97 (d, J = 1.2 Hz, 1H), 3.95 (s, 3H), 3.93-3.82 (m, 2H), 3.70 (t, J = 7.2 Hz, 2H), 3.23 (s, 2H), 1.82-1.66 (m, 2H), 1.21 (t, J = 7.2 Hz, 3H), 0.96 (t, J = 7.2 Hz, 3H). LC/MS [M+H] 485.16 (calculated); LC/MS [M+H] 486.1 (observed). Preparation of 4-[[2-amino-4-[ethoxy(propyl)carbamoyl]-3H-1-benzazepin-8- yl]sulfonyl]benzoic acid, 8SO2BzL-1f To a mixture of 8SO2BzL-e (0.24 g, 494 umol, 1.0 eq) in MeOH (2 mL), H2O (2 mL) and THF (2 mL) was added LiOH.H2O (62.2 mg, 1.48 mmol, 3.0 eq) in one portion at 25°C, and then stirred at 25°C for 2 h. The mixture was quenched with HCl (1 M) to adjust pH to between 6 and 7 and the aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 8SO2BzL-1f (0.23 g, crude) as yellow oil . 1 H NMR (DMSO, 400 MHz) δ 8.16-8.06 (m, 4H), 7.61-7.54 (m, 2H), 7.49 (dd, J = 1.6, 8.0 Hz, 1H), 7.11 (s, 1H), 3.82 (q, J = 7.2 Hz, 2H), 3.59 (t, J = 7.2 Hz, 2H), 2.89 (s, 2H), 1.70-1.55 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H). LC/MS [M+H] 472.1 (calculated); LC/MS [M+H] 472.1 (observed). Preparation of tert-butyl 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[4-[[2-amino-4-[ethoxy(prop yl) carbamoyl]-3H-1-benzazepin-8-yl]sulfonyl]benzoyl]amino]ethox y]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoate, 8SO2BzL-1g To a mixture of 8SO2BzL-1f (0.2 g, 424 umol, 1.0 eq) in DMF (4 mL) was added tert- butyl 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2- aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy ]ethoxy]ethoxy] propanoate (248 mg, 424 umol, 1.0 eq), DIEA (164 mg, 1.27 mmol, 222 uL, 3.0 eq), and Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium, HATU, CAS Reg. No. 148893- 10-1 (177 mg, 467 umol, 1.1 eq) in one portion at 25°C, and then stirred at 25°C for 0.5 h. The mixture was diluted with water and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 8SO2BzL-1g (0.5 g, crude) as yellow oil. LC/MS [M+H] 1039.5 (calculated); LC/MS [M+H] 1039.5(observed). Preparation of 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[4-[[2-amino-4-[ethoxy(prop yl) carbamoyl]-3H-1-benzazepin-8-yl]sulfonyl]benzoyl]amino]ethox y]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid, 8SO2BzL-1h To a mixture of 8SO2BzL-1g (0.5 g, 481 umol, 1.0 eq) in CH 3 CN (1 mL) and H 2 O (3 mL) was added TFA (439 mg, 3.85 mmol, 285 uL, 8.0 eq) in one portion at 25°C, and then stirred at 80 °C for 1 hours. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC(column: Phenomenex Luna 80*30mm*3um; mobile phase: [water(0.1%TFA)-ACN];B%: 10%-35%,8min) to give 8SO2BzL-1h (0.15 g, 152.57 umol, 31.71% yield) as yellow oil. 1 H NMR (MeOD, 400 MHz) δ 8.14-8.08 (m, 2H), 8.06-7.95 (m, 4H), 7.78 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 3.94 (q, J = 6.8 Hz, 2H), 3.75-3.70 (m, 4H), 3.65- 3.50 (m, 40H), 3.40 (s, 2H), 2.53 (t, J = 6.4 Hz, 2H), 1.82-1.69 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H). LC/MS [M+H] 982.45 (calculated); LC/MS [M+H] 983.4 (observed). Preparation of 8SO2BzL-1 To a mixture of 8SO2BzL-1h (0.15 g, 152.57 umol, 1.0 eq) in DCM (3 mL) and DMA (0.5 mL) was added sodium;2,3,5,6-tetrafluoro-4-hydroxy-benzenesulfonate (164 mg, 610 umol, 4.0 eq) and EDCI (146 mg, 763 umol, 5.0 eq) in one portion at 25°C, and then stirred at 25°C for 0.5 h. The mixture was concentrated to give a residue. The residue was purified by prep- HPLC(column: Phenomenex Luna 80*30mm*3um;mobile phase: [water(0.1%TFA)-ACN];B%: 15%-40%,8min) to give 8SO2BzL-1 (58.9 mg, 48.63 umol, 31.87% yield) as light yellow solid. 1 H NMR (MeOD, 400 MHz) δ 8.11-8.06 (m, 2H), 8.05-7.99 (m, 3H), 7.95 (dd, J = 2.0, 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H), 3.93 (q, J = 7.2 Hz, 2H), 3.86 (t, J = 6.0 Hz, 2H), 3.71 (t, J = 7.2 Hz, 2H), 3.67-3.53 (m, 34H), 3.53-3.48 (m, 6H), 3.42 (s, 2H), 2.97 (t, J = 6.0 Hz, 2H), 1.83-1.65 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H). LC/MS [M+H] 1211.4 (calculated); LC/MS [M+H] 1211.3 (observed). Example L-2 Synthesis of 2-amino-4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2- (2,5-dioxopyrrol-1- yl)acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]et hoxy]ethoxy]ethoxy]ethoxy]eth oxycarbonylamino]ethoxy-propyl-carbamoyl]-3H-1-benzazepine-8 -sulfonic acid, 8SO2BzL-2 Preparation of 2-amino-4-[2-(tert-butoxycarbonylamino)ethoxy-propyl -carbamoyl]-3H- 1-benzazepine-8-sulfonic acid, 8SO2BzL-2b To a mixture of tert-butyl N-[2-[(2-amino-8-benzylsulfanyl-3H-1-benzazepine -4- carbonyl)-propyl-amino]oxyethyl]carbamate, 8SO2BzL-2a (0.15 g, 286 umol, 1.0 eq) in H 2 O (0.15 mL) and AcOH (0.5 mL) was added N-chlorosuccinimide, NCS (153 mg, 1.14 mmol, 4.0 eq) in one portion at 25 °C, and then stirred at 25 °C for 1 h. The mixture was diluted with aq. NaHCO3 to adjust pH between 7 and 8. Then the mixture was extracted with EtOAc (10 mL x 3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC(column: Phenomenex Luna 80*30mm*3um;mobile phase: [water(TFA)-ACN];B%: 5%-35%,8min) to give 8SO2BzL-2b (11.5 mg, 23.83 umol, 8.34% yield) as yellow solid. NMR (DMSO, 400 MHz) δ 11.87 (s, 1H), 9.78 (s, 1H), 8.81 (s, 1H), 7.66 (s, 1H), 7.55 (s, 2H), 7.34-7.27 (m, 1H), 3.92-3.78 (m, 2H), 3.63 (t, J = 7.2 Hz, 2H), 3.31 (s, 2H), 3.16-3.01 (m, 2H), 1.70-1.60 (m, 2H), 1.36 (s, 9H), 0.89(t, J = 7.2 Hz, 3H). LC/MS [M+H] 483.2(calculated); LC/MS [M+H] 483.1 (observed). Preparation of 2-amino-4-[2-aminoethoxy(propyl)carbamoyl]-3H-1- benzazepine-8- sulfonic acid, 8SO2BzL-2c To a solution of 8SO2BzL-2b (150 mg, 310.85 umol, 1 eq) in EtOAc (10.0 mL) was added HCl/EtOAc (4 M, 20.0 mL, 257 eq), and then stirred at 25 °C for 1 h. The mixture was concentrated to give 8SO2BzL-2c (200 mg, crude) as white solid. LC/MS [M+H] 383.1(calculated); LC/MS [M+H] 383.2 (observed). Preparation of 8SO2BzL-2 To a solution of 8SO2BzL-2c (70.0 mg, 167.11 umol, 1 eq, HCl) in DMF (1.00 mL) was added DIEA (90.0 mg, 668 umol, 120 uL, 4 eq) and 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-(2,5- dioxopyrrol-1- yl)acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]et hoxy]ethoxy]ethoxy]ethoxy]eth yl (4-nitrophenyl) carbonate (70.0 mg, 83.5 umol, 0.5 eq), and then stirred at 0 °C for 1 h. The mixture was filtered and purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3um;mobile phase: [water(TFA)-ACN];B%: 1%-30%,8min) to give 8SO2BzL-2 (15 mg, 12.92 umol, 7.73% yield, TFA) as light yellow oil. 1 H NMR (MeOD, 400 MHz) δ7.89-7.77 (m, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 6.89 (s, 2H), 4.17 (s, 2H), 3.97 (br t, J = 4.8 Hz, 2H), 3.86-3.79 (m, 2H), 3.75 (t, J = 7.2 Hz, 2H), 3.66-3.58 (m, 38H), 3.56-3.49 (m, 4H), 3.42- 3.35 (m, 4H), 1.81-1.73 (m, 2H), 1.00 (t, J = 7.6 Hz, 3H). LC/MS [M+H] 1047.4(calculated); LC/MS [M+H] 1047.7 (observed). Example L-3 Synthesis of 2-amino-8-(N-(1-(2,5-dioxo-2,5-dihydro-1H-pyrrol- 1-yl)-2-oxo-6,9,12,15,18,21,24,27,30,33-decaoxa-3-azapentatr iacontan-35-yl)-N- methylsulfamoyl)-N-ethoxy-N-propyl-3H-benzo[b]azepine-4-carb oxamide, 8SO2BzL-3
Preparation of 2-amino-N-ethoxy-8-((4-methoxybenzyl)thio)-N-propyl-3H- benzo[b]azepine-4-carboxamide, 8SO2BzL-3b To a mixture of 2-amino-8-bromo-N-ethoxy-N-propyl-3H-benzo[b]azepine-4- carboxamide, 8SO2BzL-3a (0.96 g, 1.99 mmol) and 4-methoxy-α-toluenethiol (0.37 g, 2.39 mmol) in dioxane (10 mL), was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, Xantphos, CAS Reg. No.161265-03-8 (0.06 g, 0.10 mmol), Pd 2 (dba) 3 (0.05 g, 0.05 mmol), and then triethylamine (0.56 mL, 3.99 mmol). The mixture was heated to reflux for 1 h then cooled. The solvent was removed by evaporation and the crude product was purified by silica gel chromatography using a gradient of 1-10% MeOH/DCM over 12 column volumes to give 8SO2BzL-3b (0.72 g, 82%). Preparation of 2-amino-4-(ethoxy(propyl)carbamoyl)-3H-benzo[b]azepine-8-sul fonyl chloride, 8SO2BzL-3c To a solution of 8SO2BzL-3b (0.72 g, 1.64 mmol) in acetonitrile/water (9:1), 10 mL at 10 deg C was added in portions N-chlorosuccinimide (0.66 g, 4.91 mmol). After addition was complete, stirred for an additional 20 min to give 8SO2BzL-3c crude product solution, used as is in the next step. Preparation of tert-butyl (2-((2-amino-4-(ethoxy(propyl)carbamoyl)-3H-benzo[b]azepin- 8-yl)sulfonyl)-5,8,11,14,17,20,23,26,29,32-decaoxa-2-azatetr atriacontan-34-yl)carbamate, 8SO2BzL-3d An aliquot of 8SO2BzL-3c (1.00 mL, 0.16 mmol) was added dropwise to a stirring mixture of tert-butyl (5,8,11,14,17,20,23,26,29,32-decaoxa-2-azatetratriacontan-34 - yl)carbamate (0.12 g, 0.19 mmol) and triethylamine (0.09 mL, 0.64 mmol) in acetonitrile (3 mL). After 15 min the reaction was concentrated and purified by reverse phase chromatography using a gradient of 10-90% ACN/water (+0.1% TFA) over 10 min to obtain 8SO2BzL-3d (0.08 g, 51%). Preparation of 2-amino-8-(N-(32-amino-3,6,9,12,15,18,21,24,27,30- decaoxadotriacontyl)-N-methylsulfamoyl)-N-ethoxy-N-propyl-3H -benzo[b]azepine-4- carboxamide hydrogen chloride, 8SO2BzL-3e To a solution of 8SO2BzL-3d (0.08 g, 0.08 mmol) in ACN (3 mL) was added aq. HCl (6M, 3 mL) and the mixture was stirred at room temp. for 45 min. The solvent was removed and the isolated syrup was azeotroped with ACN (3 mL) to provide the HCl salt of 8SO2BzL-3e (0.06 g, 85%) as a hazy, white film. Preparation of 8SO2BzL-3 To a solution of 8SO2BzL-3e HCl (0.06 g, 0.07 mmol) in DMF (3 mL) was added triethylamine (0.04 mL, 0.28 mmol).2,5-Dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)acetate (0.02 g, 0.08 mmol) was added in parts. After completion of addition, acetic acid (9 uL) was added and the solvent was removed by vacuum. After purification by reverse phase HPLC, 8SO2BzL-3 (0.03 g, 48%) was obtained as a clear oil after evaporation of solvent. LC/MS [M+H] 1001.48 (calculated); LC/MS [M+H] 1074.88 (observed). Example L-4 Synthesis of 2-amino-8-(N-(1-(2,5-dioxo-2,5-dihydro-1H-pyrrol- 1-yl)-2-oxo-6,9,12,15,18,21,24,27,30,33-decaoxa-3-azapentatr iacontan-35-yl)sulfamoyl)-N- ethoxy-N-propyl-3H-benzo[b]azepine-4-carboxamide, 8SO2BzL-4
Preparation of tert-butyl (32-((2-amino-4-(ethoxy(propyl)carbamoyl)-3H- benzo[b]azepine)-8-sulfonamido)-3,6,9,12,15,18,21,24,27,30-d ecaoxadotriacontyl)carbamate, 8SO2BzL-4b To a solution of tert-butyl (32-amino-3,6,9,12,15,18,21,24,27,30- decaoxadotriacontyl)carbamate, Boc-amino-PEG10-amine (0.10 g, 0.16 mmol) and DIPEA (0.14 mL, 0.80 mmol) in DMF (4 mL) was added a solution of 2-amino-4- (ethoxy(propyl)carbamoyl)-3H-benzo[b]azepine-8-sulfonyl chloride, 8SO2BzL-4a (0.16 M, 1.00 mL, 0.16 mmol) in DMF. After 20 min the reaction was concentrated and then purified on reverse phase HPLC using a gradient of 10-90% ACN/water over 10 min to give 8SO2BzL-4b (0.07 g, 47%) after removal of solvent. Preparation of 2-amino-8-(N-(32-amino-3,6,9,12,15,18,21,24,27,30- decaoxadotriacontyl)sulfamoyl)-N-ethoxy-N-propyl-3H-benzo[b] azepine-4-carboxamide, SO2BzL-4c To a solution of 8SO2BzL-4b (0.07 g, 0.07 mmol) in acetonitrile (3 mL) was added aq. HCl (6M, 3 mL) and the mixture was stirred at RT for 45 min. The solvent was removed and the isolated syrup was azeotroped with ACN (3 mL) to provide 8SO2BzL-4c HCl salt (0.06 g, 82%) as a hazy, white film. Preparation of 8SO2BzL-4 To a solution of 8SO2BzL-4c HCl (0.06 g, 0.06 mmol) in DMF (3 mL) was added triethylamine (0.03 mL, 0.25 mmol). 2,5-Dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)acetate (0.02 g, 0.07 mmol) was added in parts. After completion of addition, acetic acid (9 uL) was added and the solvent was removed by vacuum. After purification by reverse phase HPLC, 8SO2BzL-4 (0.04 g, 69%) was obtained after solvent removal. LC/MS [M+H] 987.45 (calculated); LC/MS [M+H] 987.86 (observed). Example L-5 Synthesis of 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2-oxo- 6,9,12,15,18,21,24,27,30,33-decaoxa-3-azapentatriacontan-35- yl (2-((2-amino-N-propyl-8- sulfamoyl-3H-benzo[b]azepine-4-carboxamido)oxy)ethyl)carbama te, 8SO2BzL-5
Preparation of tert-butyl (2-((2-amino-8-((4-methoxybenzyl)thio)-N-propyl-3H- benzo[b]azepine-4-carboxamido)oxy)ethyl)carbamate, 8SO2BzL-b To a mixture of tert-butyl (2-((2-amino-8-bromo-N-propyl-3H-benzo[b]azepine-4- carboxamido)oxy)ethyl)carbamate, 8SO2BzL-5a (0.96 g, 1.99 mmol) and 4-methoxy-α- toluenethiol (0.37 g, 2.39 mmol) in dioxane (10 mL), added Xantphos (0.06 g, 0.10 mmol), Pd 2 (dba) 3 (0.05 g, 0.05 mmol), then triethylamine (0.56 mL, 3.99 mmol). The mixture was heated to reflux for 1 h then cooled. The solvent was removed by evaporation and the crude product was purified by silica gel chromatography using a gradient of 1-10% MeOH/DCM over 12 column volume to give 8SO2BzL-5b (0.78 g, 71%) as a yellow solid. Preparation of tert-butyl (2-((2-amino-8-(chlorosulfonyl)-N-propyl-3H-benzo[b]azepine- 4-carboxamido)oxy)ethyl)carbamate, 8SO2BzL-5c To a solution of 8SO2BzL-5b (0.78 g, 1.41 mmol) in acetonitrile/water (9:1, 10 mL), at 0 deg C was added in three equal portions N-chlorosuccinimide (0.56 g, 4.22 mmol). After the addition was complete, the product 8SO2BzL-5c was used as is without further purification. Preparation of tert-butyl (2-((2-amino-N-propyl-8-sulfamoyl-3H-benzo[b]azepine-4- carboxamido)oxy)ethyl)carbamate, 8SO2BzL-5d To a solution of 8SO2BzL-5c (2.00 mL, 0.28 mmol) in acetonitrile/water (9:1) at 0 deg was added ammonium hydroxide solution (0.20 mL, 1.66 mmol). After 10 minutes the solvent was removed, and the crude product was purified by reverse phase HPLC using a gradient of 10- 90% acetonitrile/water to give 8SO2BzL-5d (0.06 g, 41%) as a yellow film after evaporation of solvent. Preparation of 8SO2BzL-5e A solution of 8SO2BzL-5e (0.06 g, 0.11 mmol) in acetonitrile (2 mL) and 6 N HCl (2.00 mL, 12.00 mmol) was stirred at room temperature for 45 minutes. The solvent was removed by vacuum to give 8SO2BzL-5e as the HCl salt (0.05 g, 101%). Preparation of 8SO2BzL-5 To a solution of 8SO2BzL-5e (0.04 g, 0.10 mmol) in DMF (4 mL) at room temperature was added triethylamine (0.06 mL, 0.40 mmol). To this mixture was added a solution of 1-(2,5- dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2-oxo-6,9,12,15,18,21,24,2 7,30,33-decaoxa-3- azapentatriacontan-35-yl (4-nitrophenyl) carbonate, PNPC-PEG10-Mal (0.08 g, 0.10 mmol) in DMF (2 mL). After 20 min acetic acid (6 uL) was added and reaction was concentrated under vacuum and prified by reverse phase HPLC using a gradient of 10-90% ACN/water (+0.1% TFA) over 10 min to give 8SO2BzL-5 (0.04 g, 37%) after concentration of pure fractions. LC/MS [M+H] 1046.45 (calculated); LC/MS [M+H] 1046.88 (observed). Example L-6 Synthesis of 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2-oxo- 6,9,12,15,18,21,24,27,30,33-decaoxa-3-azapentatriacontan-35- yl (2-((2-amino-8-(N,N- dimethylsulfamoyl)-N-propyl-3H-benzo[b]azepine-4-carboxamido )oxy)ethyl)carbamate, 8SO2BzL-6
Preparation of tert-butyl N-[2-[(2-amino-8-benzylsulfanyl-3H-1-benzazepine -4- carbonyl)-propyl-amino]oxyethyl]carbamate, 8SO2BzL-6b To a mixture of tert-butyl N-[2-[(2-amino-8-bromo-3H-1-benzazepine-4-carbonyl) - propyl-amino]oxyethyl]carbamate, 8SO2BzL-6a (0.5 g, 1.04 mmol, 1.0 eq) and benzylthiol, benzylmercaptan, phenylmethanethiol, BnSH, CAS Reg. No.100-53-8 (155 mg, 1.25 mmol, 146.05 uL, 1.2 eq) in dioxane (15 mL) was added 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene, Xantphos, CAS Reg. No.161265-03-8 (120 mg, 208 umol, 0.2 eq) tris)dibenzylideneacetone)dipalladium, Pd 2 (dba) 3 , CAS Reg. No.51364-51-3 (190 mg, 208 umol, 0.2 eq) and diisopropylethylamine, DIEA (268 mg, 2.08 mmol, 362 uL, 2.0 eq) in one portion at 25 °C under N 2 , and then stirred at 110°C for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The mixture was further purification by prep-HPLC (column: Phenomenex Luna 80*30mm*3um;mobile phase: [water(TFA)-ACN];B%: 25%- 55%,8min) to give 8SO2BzL-6b (0.5 g, 952.97 umol, 91.75% yield) as yellow solid. 1 H NMR (MeOD, 400 MHz) δ 7.49 (d, J = 8.4 Hz, 1H), 7.43-7.38 (m, 3H), 7.36-7.22 (m, 5H), 4.30 (s, 2H), 3.91 (t, J = 5.2 Hz, 2H), 3.73 (t, J = 7.2 Hz, 2H), 3.32 (s, 2H), 3.24 (t, J = 5.2 Hz, 2H), 1.81- 1.70 (m, 2H), 1.34 (s, 9H), 0.98 (t, J = 7.2 Hz, 3H). LC/MS [M+H] 525.2 (calculated); LC/MS [M+H] 525.2 (observed). Preparation of tert-butyl N-[2-[[2-amino-8-(dimethylsulfamoyl)-3H-1-benzazepine -4- carbonyl]-propyl-amino]oxyethyl]carbamate, 8SO2BzL-6c To a solution of 8SO2BzL-6b (50.0 mg, 95.30 umol, 1 eq) in CH 3 CN (1.00 mL) and H 2 O (0.10 mL) was added AcOH (60.0 mg, 953 umol, 50.0 uL, 10 eq), N-chlorosuccinimide, NCS (50.0 mg, 381 umol, 4 eq) at 25°C , and then stirred at this temperature for 10 min, then N- methylmethanamine;hydrochloride, dimethylamine HCl (80.0 mg, 953 umol, 10 eq) and DIEA (250 mg, 1.91 mmol, 330 uL, 20 eq) was added. The mixture was stirred at 0 °C for another 1h. The mixture was filtered and purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3um;mobile phase: [water(TFA)-ACN];B%: 10%-40%,8min) to give 8SO2BzL-6c (12 mg, 23.55 umol, 24.71% yield) as white solid. 1 H NMR (MeOD, 400 MHz) δ7.92-7.72 (m, 3H), 7.50 (s, 1H), 3.94 (t, J = 5.2 Hz, 2H), 3.75 (t, J = 7.2 Hz, 2H), 3.44 (s, 2H), 3.26 (br t, J = 5.2 Hz, 2H), 2.77 (s, 6H), 1.77 (sxt, J = 7.2 Hz, 2H), 1.37 (s, 9H), 0.99 (t, J = 7.2 Hz, 3H). LC/MS [M+H] 510.2 (calculated); LC/MS [M+H] 510.3 (observed). Preparation of 2-amino-N-(2-aminoethoxy)-8-(N,N-dimethylsulfamoyl)-N-propyl -3H- benzo[b]azepine-4-carboxamide hydrogen chloride, 8SO2BzL-6d A solution of 8SO2BzL-6c (0.04 g, 0.08 mmol) in acetonitrile (2 mL) and 6 N HCl (1.41 mL, 8.46 mmol) was stirred at room temperature for 45 minutes. The solvent was removed by vacuum to give 8SO2BzL-6d (0.04 g, 100%). Preparation of 8SO2BzL-6 To a solution of 8SO2BzL-6d (0.04 g, 0.10 mmol) in DMF (4 mL) at room temperature added triethylamine (0.04 mL, 0.28 mmol). To this mixture was added a solution 1-(2,5-dioxo- 2,5-dihydro-1H-pyrrol-1-yl)-2-oxo-6,9,12,15,18,21,24,27,30,3 3-decaoxa-3-azapentatriacontan- 35-yl (4-nitrophenyl)carbonate (0.06 g, 0.07 mmol) in DMF (2 mL). After 20 min acetic acid (6 uL) was added and reaction was concentrated under vacuum and purified by reverse phase HPLC using a gradient of 10-90% ACB/water (+0.1% TFA) over 10 min to give 8SO2BzL-6 (0.04 g, 51%) after concentration of pure fractions. LC/MS [M+H] 1074.48 (calculated); LC/MS [M+H] 1074.90 (observed). Example L-9 Synthesis of 2-amino-8-(N-(1-(2,5-dioxo-2,5-dihydro-1H-pyrrol- 1-yl)-2-oxo-6,9,12,15,18,21,24,27,30,33-decaoxa-3-azapentatr iacontan-35-yl)sulfamoyl)-N,N- dipropyl-3H-benzo[b]azepine-4-carboxamide, 8SO2BzL-9
Preparation of 2-amino-8-((4-methoxybenzyl)thio)-N,N-dipropyl-3H-benzo[b]az epine-4- carboxamide, 8SO2BzL-9b To a mixture of 2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamid e, 8SO2BzL-9a (0.96 g, 1.99 mmol) and 4-methoxy-α-toluenethiol (0.37 g, 2.39 mmol) in dioxane (10 mL), added Xantphos (0.06 g, 0.10 mmol), Pd 2 (dba) 3 (0.05 g, 0.05 mmol), then triethylamine (0.56 mL, 3.99 mmol). The mixture was heated to reflux for 1 h then cooled. The solvent was removed by evaporation and the crude product was purified by silica gel chromatography using a gradient of 1-10% MeOH/DCM over 12 column volumes to give 8SO2BzL-9b (0.69 g, 79%). Preparation of 2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepine-8-sulfonyl chloride, 8SO2BzL-9c To a solution of 8SO2BzL-9b (0.68 g, 1.55 mmol) in acetonitrile/water (9:1), 10 mL at 10 deg C was added N-chlorosuccinimide, NCS in thirds (0.62 g, 4.66 mmol). After addition was complete, stirred for an additional 20 min. to give 8SO2BzL-9c. Preparation of tert-butyl (32-((2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepine)-8- sulfonamido)-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl) carbamate, 8SO2BzL-9d An aliquot of 8SO2BzL-9c (1.00 mL, 0.15 mmol) obtained previously was added drop- wise to a stirring mixture of tert-butyl (32-amino-3,6,9,12,15,18,21,24,27,30- decaoxadotriacontyl)carbamate (0.11 g, 0.18 mmol) and triethylamine (0.08 mL, 0.60 mmol) in acetonitrile (3 mL). After 15 min the reaction was concentrated and purified by reverse phase chromatography using a gradient of 10-90% ACN/water (+0.1% TFA) over 10 min to 8SO2BzL-9d (0.07 g, 51%). Preparation of 2-amino-8-(N-(32-amino-3,6,9,12,15,18,21,24,27,30- decaoxadotriacontyl)sulfamoyl)-N,N-dipropyl-3H-benzo[b]azepi ne-4-carboxamide, 8SO2BzL- 9e To a solution of 8SO2BzL-9d (0.07 g, 0.08 mmol) in acetonitrile (3 mL) was added aq. HCl (6M, 3 mL) and the mixture was stirred at RT for 45 min. The solvent was removed and the isolated syrup was azeotroped with acetonitrile (3 mL) to provide 8SO2BzL-9e as the HCl salt (0.06 g, 86%) as a hazy, white film. Preparation of 8SO2BzL-9 To a solution of 8SO2BzL-9e HCl (0.06 g, 0.06 mmol) in DMF (3 mL) was added triethylamine (0.03 mL, 0.25 mmol).2,5-Dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)acetate (0.02 g, 0.07 mmol) was added in parts. After completion of addition, acetic acid (9 uL) was added and the solvent was removed by vacuum. After purification by reverse phase HPLC to give 8SO2BzL-9 (0.03 g, 43%) after evaporation. LC/MS [M+H] 985.47 (calculated); LC/MS [M+H] =985.88 (observed). Example L-10 Synthesis of 2-amino-8-(N-(1-(2,5-dioxo-2,5-dihydro-1H-pyrrol- 1-yl)-2-oxo-6,9,12,15,18,21,24,27,30,33-decaoxa-3-azapentatr iacontan-35-yl)-N- methylsulfamoyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxami de, 8SO2BzL-10
Preparation of tert-butyl (2-((2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8- yl)sulfonyl)-5,8,11,14,17,20,23,26,29,32-decaoxa-2-azatetrat riacontan-34-yl)carbamate, 8SO2BzL-10b An solution of 2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepine-8-sulfonyl chloride, 8SO2BzL-10a (1.00 mL, 0.15 mmol) in acetonitrile was added dropwise to a stirring mixture of tert-butyl (5,8,11,14,17,20,23,26,29,32-decaoxa-2-azatetratriacontan-34 -yl)carbamate (0.11 g, 0.18 mmol) and triethylamine (0.08 mL, 0.60 mmol) in acetonitrile (3 mL). After 15 min the reaction was concentrated and purified by reverse phase chromatography using a gradient of 10- 90% ACN/water (+0.1% TFA) over 10 min to obtain 8SO2BzL-10b (0.05 g, 37%). Preparation of 2-amino-8-(N-(32-amino-3,6,9,12,15,18,21,24,27,30- decaoxadotriacontyl)-N-methylsulfamoyl)-N,N-dipropyl-3H-benz o[b]azepine-4-carboxamide, 8SO2BzL-10c To a solution of 8SO2BzL-10b (0.05 g, 0.05 mmol) in acetonitrile (3 mL) was added aq. HCl (6M, 3 mL) and the mixture was stirred at room temperature, RT for 45 min. The solvent was removed and the isolated syrup was azeotroped with ACN (3 mL) to provide 8SO2BzL-10c as the HCl salt (0.04 g, 91%) as a hazy, white film. Preparation of 8SO2BzL-10 To a solution of 8SO2BzL-10c HCl (0.04 g, 0.05 mmol) in DMF (3 mL) was added triethylamine (0.03 mL, 0.20 mmol).2,5-Dioxopyrrolidin-1-yl 2-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)acetate (0.02 g, 0.06 mmol) was added in parts. After completion of addition, acetic acid (9 uL) was added and the solvent was removed by vacuum. After purification by reverse phase HPLC, 8SO2BzL-10 (0.02 g, 42%) was obtained after evaporation. LC/MS [M+H] 999.49 (calculated); LC/MS [M+H] 999.92 (observed). Example L-12 Synthesis of 2-amino-6-[5-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2- (2,5-dioxopyrrol-1- yl)acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]et hoxy]ethoxy]ethoxy]ethoxy]pro panoylamino]pentyl]-4-[ethoxy(propyl)carbamoyl]-3H-1-benzaze pine-8-sulfonic acid, 8SO2BzL-12
Preparation of 2-amino-8-bromo-N-ethoxy-6-iodo-N-propyl -3H-1-benzazepine-4- carboxamide, 8SO2BzL-12b To a solution of 2-amino-8-bromo-6-iodo-3H-1-benzazepine-4-carboxylic acid, 8SO2BzL-12a (2.0 g, 4.91 mmol, 1.0 eq) in DCM (20 mL) and DMA (10 mL) was added methanesulfonic acid, CH 3 SO 3 H (472 mg, 4.91 mmol, 350 uL, 1.0 eq), N-ethoxypropan-1- amine (823 mg, 5.90 mmol, 1.2 eq, HCl) and EDCI (3.77 g, 19.7 mmol, 4 eq). The mixture was stirred at 25°C for 2 hrs. The pH of the reaction mixture was adjusted to~9 with sat.Na 2 CO 3 . The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The crude product was triturated with EtOAc at 25 o C for 10 min to afford 8SO2BzL- 12b (1.24 g, 2.52 mmol, 51.3% yield) as yellow solid. LC/MS [M+H] 491.97 (calculated); LC/MS [M+H] 491.9 (observed). Preparation of tert-butyl N-[5-[2-amino-8-bromo-4-[ethoxy(propyl)carbamoyl]-3H- 1- benzazepin-6-yl]pent-4-ynyl]carbamate, 8SO2BzL-12c A mixture of 8SO2BzL-12b (800 mg, 1.63 mmol, 1.0 eq), tert-butyl N-pent-4- ynylcarbamate (328 mg, 1.79 mmol, 1.1 eq), Pd(PPh 3 ) 2 Cl 2 (114 mg, 163 umol, 0.1 eq), cuprous iodide, CuI (61.9 mg, 325 umol, 0.2 eq) in DMF (16 mL) and Et 3 N (6 mL) was degassed and purged with N 2 for 3 times, then stirred at 80 °C for 2 hrs under N 2 atmosphere. The mixture was poured into ice-water (w/w = 1/1) (20 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=1/0, 2/1) to afford 8SO2BzL-12c (690 mg, 1.26 mmol, 77.5% yield) as yellow oil. 1 H NMR (MeOD, 400MHz)δ 7.53 (s, 1H), 7.27 (s, 2H), 3.93 (q, J = 7.2 Hz, 2H), 3.74 (t, J = 7.2 Hz, 2H), 3.19 (t, J = 7.2 Hz, 2H), 2.90-2.83 (m, 2H), 2.51 (t, J = 7.2 Hz, 2H), 1.82-1.70 (m, 4H), 1.43 (s, 9H), 1.17 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H). LC/MS [M+H] 547.2 (calculated); LC/MS [M+H] 547.2 (observed). Preparation of tert-butyl N-[5-[2-amino-8-benzylsulfanyl-4-[ethoxy(propyl) carbamoyl]- 3H-1-benzazepin-6-yl]pent-4-ynyl]carbamate, 8SO2BzL-12d A mixture of 8SO2BzL-12c (350 mg, 639 umol, 1.0 eq), phenylmethanethiol, BnSH (0.25 g, 2.01 mmol, 236 uL, 3.15 eq), DIEA (165 mg, 1.28 mmol, 223 uL, 2.0 eq), Xantphos (74.0 mg, 128 umol, 0.2 eq) and Pd 2 (dba) 3 (117 mg, 128 umol, 0.2 eq) in dioxane (10 mL) was degassed and purged with N2 for 3 times, then stirred at 110 °C for 1 hr under N2 atmosphere. The residue was poured into ice-water (w/w = 1/1) (10 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10mL x 1), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=1/0, 0/1) to afford 8SO2BzL-12d (300 mg, 508 umol, 79.4% yield) as yellow solid. 1 H NMR (MeOD, 400MHz)δ 7.56 (s, 1H), 7.37- 7.34 (m, 2H), 7.30-7.19 (m, 3H), 7.09 (d, J = 1.6 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 4.20 (s, 2H), 3.93 (q, J = 7.2 Hz, 2H), 3.73 (t, J = 7.2 Hz, 2H), 3.30 (s, 2H), 3.19 (t, J = 6.8 Hz, 2H), 2.49 (t, J = 7.2 Hz, 2H), 1.81-1.72 (m, 4H), 1.43 (s, 9H), 1.16 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H). LC/MS [M+H] 591.3 (calculated); LC/MS [M+H] 591.3 (observed). Preparation of tert-butyl N-[5-[2-amino-8-chlorosulfonyl-4-[ethoxy(propyl) carbamoyl]- 3H-1-benzazepin-6-yl]pent-4-ynyl]carbamate, 8SO2BzL-12e To a solution of 8SO2BzL-12d (300 mg, 508 umol, 1.0 eq) in MeCN (6 mL) and H 2 O (0.6 mL) was added AcOH (305 mg, 5.08 mmol, 290 uL, 10 eq) and NCS (271 mg, 2.03 mmol, 4.0 eq), and then stirred at 25°C for 1 hr. The reaction mixture was poured into ice-water (w/w = 1/1) (10 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the crude product 8SO2BzL-12e (250 mg, 441 umol, 86.8% yield) as yellow oil which was used in the next step without further purification. LC/MS [M+H] 567.2(calculated); LC/MS [M+H] 567.3 (observed). Preparation of 2-amino-6-(5-aminopent-1-ynyl)-4-[ethoxy(propyl)carbamoyl] -3H-1- benzazepine-8-sulfonic acid, 8SO2BzL-12f A solution of 8SO2BzL-12e (250 mg, 441 umol, 1.0 eq) in MeCN (2.5 mL) and H2O (13 mL) was stirred at 100 °C for 1 hr. The mixture was concentrated in vacuum. The crude product 8SO2BzL-12f (200 mg, 412 umol, 93.5% yield, HCl) as yellow solid was used in the next step without further purification. LC/MS [M+H] 449.18(calculated); LC/MS [M+H] 449.1 (observed). Preparation of 2-amino-6-[5-(tert-butoxycarbonylamino)pent-1-ynyl]- 4- [ethoxy(propyl)carbamoyl]-3H-1-benzazepine-8-sulfonic acid, 8SO2BzL-12g To a solution of 8SO2BzL-12f (200 mg, 446 umol, 1.0 eq) in THF (5 mL) and H 2 O (5 mL) was added NaHCO 3 (112 mg, 1.34 mmol, 52 uL, 3.0 eq) and Boc 2 O (146 mg, 669 umol, 154 uL, 1.5 eq), and then stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure at 30°C. The residue was purified by prep-HPLC(column: Phenomenex Luna 80*30mm*3um;mobile phase: [water(TFA)-ACN];B%: 10%-40%,8min) to afford 8SO2BzL- 12g (100 mg, 182 umol, 40.9% yield) as yellow solid. 1 H NMR (MeOD, 400MHz)δ 7.84 (d, J = 1.2 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.63 (s, 1H), 3.98 (d, J = 7.2 Hz, 2H), 3.76 (t, J = 6.8 Hz, 2H), 3.38 (s, 2H), 3.18 (t, J = 6.8 Hz, 2H), 2.54 (t, J = 7.2 Hz, 2H), 1.81-1.76 (m, 4H), 1.43 (s, 9H), 1.20 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H). LC/MS [M+H] 549.2 (calculated); LC/MS [M+H] 549.3 (observed). Preparation of 2-amino-6-[5-(tert-butoxycarbonylamino)pentyl]-4- [ethoxy(propyl)carbamoyl]-3H-1-benzazepine-8-sulfonic acid, 8SO2BzL-12h A mixture of 8SO2BzL-12g (100 mg, 182 umol, 1.0 eq), Pd(OH) 2 /C (64.0 mg, 91.1 umol, 20% purity, 0.5 eq) in MeOH (10 mL) was degassed and purged with H 2 (367 ug, 182 umol, 1 eq) for 3 times, and then stirred at 25°C for 1 hr under H 2 (30 psi) atmosphere. The mixture was filtered. The residue was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3um;mobile phase: [water(TFA)-ACN];B%: 5%-55%,8min) to afford 8SO2BzL-12h (72 mg, 130 umol, 71.5% yield) as white solid. 1 H NMR (MeOD, 400MHz)δ 7.70 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 1.2 Hz, 1H), 7.46 (s, 1H), 3.98 (q, J = 7.2 Hz, 2H), 3.76 (t, J = 6.8 Hz, 2H), 3.36 (s, 2H), 3.02 (t, J = 6.8 Hz, 2H), 2.84 (t, J = 8.0 Hz, 2H), 1.83-1.74 (m, 2H), 1.71-1.59 (m, 2H), 1.52-1.34 (m, 13H), 1.20 (t, J = 7.2 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H). LC/MS [M+H] 553.26 (calculated); LC/MS [M+H] 553.2 (observed). Preparation of 2-amino-6-(5-aminopentyl)-4-[ethoxy(propyl)carbamoyl] -3H-1- benzazepine-8-sulfonic acid, 8SO2BzL-12i To a solution of 8SO2BzL-12h (60 mg, 108 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 1 mL, 37 eq), and then stirred at 20 °C for 1 hr. The mixture was concentrated in vacuum to afford 8SO2BzL-12i (50 mg, 102 umol, 94.2% yield, HCl) as white solid. LC/MS [M+H] 453.2 (calculated); LC/MS [M+H] 453.2 (observed). Preparation of 8SO2BzL-12 To a solution of 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-(2,5-dioxopyrrol-1-yl)ac etyl] amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethox y]ethoxy]ethoxy]propanoic acid (68.2 mg, 102 umol, 1.0 eq) in DMF (1 mL) was added DIEA (66.1 mg, 511 umol, 89 uL, 5.0 eq), 8SO2BzL-12i (50 mg, 102 umol, 1 eq, HCl) and HATU (38.9 mg, 102 umol, 1.0 eq). And it was stirred at 25°C for 0.5 hr. The mixture was filtered and purified by prep- HPLC(column: Phenomenex Luna 80*30mm*3um;mobile phase: [water(TFA)-ACN];B%: 5%- 35%,8min) to afford 8SO2BzL-12 (14 mg, 12.7 umol, 12.43% yield) as yellow oil. 1 H NMR (MeOD, 400MHz)δ 7.72 (s, 1H), 7.68 (s, 1H), 7.48 (s, 1H), 6.91 (s, 2H), 4.19 (s, 2H), 4.01 (q, J = 7.2 Hz, 2H), 3.80-3.55 (m, 42H), 3.43-3.35 (m, 4H), 3.19 (t, J = 6.8 Hz, 2H), 2.88 (t, J = 8.0 Hz, 2H), 2.42 (t, J = 6.4 Hz, 2H), 1.80 (q, J = 7.2 Hz, 2H), 1.74-1.64 (m, 2H), 1.60-1.51 (m, 2H), 1.45-1.43 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H), 1.02 (t, J = 7.2 Hz, 3H). LC/MS [M+H] 1101.5 (calculated); LC/MS [M+H] 1101.9 (observed). Example L-13 Synthesis of 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2-oxo- 6,9,12,15,18,21,24,27,30,33-decaoxa-3-azapentatriacontan-35- yl (2-((2-amino-8-(N- methylsulfamoyl)-N-propyl-3H-benzo[b]azepine-4-carboxamido)o xy)ethyl)carbamate, 8SO2BzL-13 Preparation of tert-butyl (2-((2-amino-8-(N-methylsulfamoyl)-N-propyl-3H- benzo[b]azepine-4-carboxamido)oxy)ethyl)carbamate, 8SO2BzL-13b To a solution of tert-butyl (2-((2-amino-8-(chlorosulfonyl)-N-propyl-3H- benzo[b]azepine-4-carboxamido)oxy)ethyl)carbamate, 8SO2BzL-13a (0.14 M, 2.00 mL, 0.28 mmol) in acetonitrile/water (9:1) at 0 deg was added a methylamine solution (2 M in THF, 0.70 mL, 1.40 mmol). After 10 minutes the solvent was removed and the crude product was purified by reverse phase HPLC using a gradient of 10-90% acetonitrile/water to give 8SO2BzL-13b (0.09 g, 68%) as a yellow film after evaporation of solvent. Preparation of 2-amino-N-(2-aminoethoxy)-8-(N-methylsulfamoyl)-N-propyl-3H- benzo[b]azepine-4-carboxamide, 8SO2BzL-13c A solution of 8SO2BzL-13b (0.09 g, 0.19 mmol) in acetonitrile (2 mL) and 6 N HCl (2.00 mL, 12.00 mmol) was stirred at room temperature for 45 minutes. The solvent was removed by vacuum to give 8SO2BzL-13c as the HCl salt (0.08 g, 99%). Preparation of 8SO2BzL-13 To a solution of 8SO2BzL-13c HCl (0.03 g, 0.06 mmol) in DMF (4 mL) at room temperature added triethylamine (0.04 mL, 0.26 mmol). To this mixture was added a solution of 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2-oxo-6,9,12,15,18, 21,24,27,30,33-decaoxa-3- azapentatriacontan-35-yl (4-nitrophenyl) carbonate, PNPC-PEG10-mal (0.05 g, 0.06 mmol) in DMF (2 mL). After 20 min., acetic acid (6 uL) was added and reaction was concentrated under vacuum and purified by reverse phase HPLC using a gradient of 10-90% ACN/water (+0.1% TFA) over 10 min. to give 8SO2BzL-13 (0.04 g, 52%) after concentration of pure fractions. LC/MS [M+H] 1060.47 (calculated); LC/MS [M+H] 1060.89 (observed). Example L-15 Synthesis of 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-(2,5-dioxopyrrol- 1 yl)acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]et hoxy]ethoxy]ethoxy]ethoxy]eth yl N-[2-[[2-amino-8-(thiazol-2-ylsulfamoyl)-3H-1-benzazepine-4- carbonyl]-propyl- amino]oxyethyl]carbamate, 8SO2BzL-15
Preparation of ethyl 8-bromo-2-(tritylamino)-3H-1-benzazepine-4-carboxylate, 8SO2BzL-15b A mixture of ethyl 2-amino-8-bromo-3H-1-benzazepine-4-carboxylate, 8SO2BzL-15a (5 g, 16.1 mmol, 1 eq), TrtCl (6.76 g, 24.2 mmol, 1.5 eq), TEA (4.91 g, 48.5 mmol, 6.75 mL, 3 eq) and DMAP (395 mg, 3.23 mmol, 0.2 eq) in DCM (50 mL) was degassed and purged with N 2 for 3 times, and then stirred at 40°C for 16 h under N 2 atmosphere. The reaction mixture was quenched by addition H 2 O (50 mL) and extracted with EtOAc (100 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , Petroleum ether:Ethyl acetate=100:1 to 0:1) to give 8SO2BzL-15b (7.8 g, 14.1 mmol, 87.4% yield) as a yellow oil. LC/MS [M+H] 551.1 (calculated); LC/MS [M+H] 551.1 (observed). Preparation of ethyl 8-benzylsulfanyl-2-(tritylamino)-3H-1-benzazepine-4-carboxyl ate, 8SO2BzL-15c A mixture of 8SO2BzL-15b (3 g, 5.44 mmol, 1 eq), DIEA (1.41 g, 10.8 mmol, 1.90 mL, 2 eq ^(1E,4E)-1,5-diphenylpenta-1,4- dien-3-one;palladium, Pd 2 (dba) 3 , CAS Reg. No.51364- 51-3 (996 mg, 1.09 mmol, 0.2 eq) and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)- diphenyl-phosphane, Xphos (629 mg, 1.09 mmol, 0.2 eq) in dioxane (30 mL) was degassed and purged with N 2 for 3 times, then phenylmethanethiol, BnSH (1.35 g, 10.8 mmol, 1.27 mL, 2 eq) was added ^ the mixture was stirred at 110°C for 1 h under N 2 atmosphere. The reaction mixture was quenched by addition H 2 O (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL) dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , Petroleum ether:Ethyl acetate=100:1 to 0:18) to give 8SO2BzL-15c (2.3 g, 3.87 mmol, 71.1% yield) as a yellow oil. Preparation of ethyl 8-chlorosulfonyl-2-(tritylamino)-3H-1-benzazepine-4-carboxyl ate, 8SO2BzL-15d A mixture of 8SO2BzL-15c (3 g, 5.04 mmol, 1 eq) , NCS (2.69 g, 20.2 mmol, 4 eq), AcOH (3.03 g, 50.4 mmol, 2.88 mL, 10 eq) in MeCN (30 mL) and H2O (3 mL) was stirred at 25°C for 1 h. The reaction mixture was quenched by addition H2O (50 mL), and extracted with EtOAc (50 mL). The combined organic layers were wash with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether:Ethyl acetate=99:1 to 0:1) to give 8SO2BzL-15d (2 g, 3.50 mmol, 69.4% yield) as a yellow solid. LC/MS [M+H] 571.1 (calculated); LC/MS [M+H] 571.2 (observed). Preparation of ethyl 8-(thiazol-2-ylsulfamoyl)-2-(tritylamino)-3H -1-benzazepine-4- carboxylate, 8SO2BzL-15e A mixture of 8SO2BzL-15d (1.5 g, 2.63 mmol, 1 eq) and 1-methylimidazole (258 mg, 3.15 mmol, 251 uL, 1.2 eq) in MeCN (30 mL) was degassed and purged with N 2 for 3 times and then stirred at 25°C for 2 h under N 2 atmosphere. Then 4,5-dihydrothiazol-2-amine (1.07 g, 10.5 mmol, 4 eq) was added and the result mixture was stirred at 25°C for another 16 h under N 2 atmosphere. The reaction mixture was quenched by addition H 2 O (50 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether:Ethyl acetate=100:1 to 0:1) to give 8SO2BzL-15e (0.5 g, 787 umol, 29.9% yield) as a yellow solid. 1 H NMR (MeOD, 400 MHz) δ7.71 (s, 1H), 7.23 (m, 20H), 6.75 (d, J = 4.8 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.98 (s, 2H), 1.38 (t, J = 7.2 Hz, 3H). LC/MS [M+H] 635.17 (calculated); LC/MS [M+H] 635.1 (observed). Preparation of 8-(N-(thiazol-2-yl)sulfamoyl)-2-(tritylamino)-3H -benzo[b]azepine-4- carboxylic acid, 8SO2BzL-15f A mixture of 8SO2BzL-15e (0.5 g, 787.69 umol, 1 eq), LiOH.H2O (264 mg, 6.30 mmol, 8 eq) in H2O (4 mL) and THF (4 mL) was stirred at 25 °C for 3 hr. The reaction solution was quenched by added 2M HCl to adjust pH = ~6, then filtered to give 8SO2BzL-15f (0.45 g, 699.66 umol, 88.82% yield, HCl) as a white solid. LC/MS [M+H] 607.1 (calculated); LC/MS [M+H] 607.2 (observed). Preparation of tert-butyl N-[2-[propyl-[8-(thiazol-2-ylsulfamoyl)-2-(tritylamino)-3H- 1- benzazepine-4-carbonyl]amino]oxyethyl]carbamate, 8SO2BzL-15g A mixture of 8SO2BzL-15f (0.42 g, 692 umol, 1 eq), tert-butyl N-[2- (propylaminooxy)ethyl]carbamate (181 mg, 830 umol, 1.2 eq), methanesulfonic acid (133 mg, 1.38 mmol, 98.5 uL, 2 eq), EDCI (663 mg, 3.46 mmol, 5 eq) in DMA (5 mL) and DCM (5 mL) was degassed and purged with N 2 for 3 times, and then stirred at 25°C for 2 hr under N 2 atmosphere. The reaction mixture was quenched by addition Na 2 HCO 3 (3 mL) until pH about 7, and extracted with EtOAc (5 mL*3). The combined organic layers were washed with brine (5 mL), dried over Na 2 SO 4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , Petroleum ether:Ethyl acetate=99:1 to 20:80) to give 8SO2BzL-15g (0.5 g, 619 umol, 89.5% yield) as a yellow solid. LC/MS [M+H] 807.3 (calculated); LC/MS [M+H] 807.3 (observed). Preparation of 2-amino-N-(2-aminoethoxy)-N-propyl-8-(thiazol-2-ylsulfamoyl) -3H-1- benzazepine-4-carboxamide, 8SO2BzL-15h A mixture of 8SO2BzL-15g (0.5 g, 619 umol, 1 eq), TFA (5.65 g, 49.5 mmol, 3.67 mL, 80 eq) in DCM (10 mL) was stirred at 25 °C for 16 h. The reaction mixture was quenched by addition H 2 O (5 mL), and extracted with MTBE (10 mL) (5 mL x 2) to remove the excess TFA. The combined water layers was concentrated under reduced pressure to give 8SO2BzL-15h (0.25 g, 432 umol, 69.7% yield, TFA) as a white solid. LC/MS [M+H] 465.1 (calculated); LC/MS [M+H] 465.1 (observed). Preparation of 8SO2BzL-15 A mixture of 8SO2BzL-15h (0.2 g, 288 umol, 1 eq, 2TFA), 2-[2-[2-[2-[2-[2-[2-[2-[2-[2- [2-[[2-(2,5-dioxopyrrol-1- yl)acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]et hoxy]ethoxy]ethoxy]ethoxy]eth yl (4-nitrophenyl)carbonate (232 mg, 288 umol, 1 eq), DIEA (111 mg, 866 umol, 150 uL, 3 eq) in DMF (0.5 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 0°C for 1 h under N2 atmosphere. The reaction solution was quenched with TFA until pH = ~6. The residue was purified by prep-HPLC (column: Phenomenex Luna 80 x 30mm x 3um; mobile phase: [water (TFA)-ACN]; B%:15%-40%, 8min) to give 8SO2BzL-15 (15.0 mg, 13.2 umol, 4.6% yield) as a white solid. 1 H NMR (MeOD-d 4 , 400 MHz) δ7.97 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.39 (s, 1H), 7.18 (d, J = 4.8 Hz, 1H), 6.90 (s, 2H), 6.81 (d, J = 4.8 Hz, 1H), 4.17 (s, 2H), 3.74 (m, 2H), 3.67 (m, 2H), 3.59 (m, 42H), 3.38 (m, 6H), 1.80- 1.72 (m, 2H) 1.00 (t, J = 7.2 Hz, 3H). LC/MS [M+H] 1129.4 (calculated); LC/MS [M+H] 1129.5 (observed). Example 201 Preparation of Macromolecule-supported compounds (MSC) To prepare a lysine-conjugated MSC, a macromolecule is buffer exchanged into a conjugation buffer containing 100 mM boric acid, 50 mM sodium chloride, 1 mM ethylenediaminetetraacetic acid at pH 8.3, using G-25 SEPHADEX TM desalting columns (Sigma-Aldrich, St. Louis, MO) or Zeba™ Spin Desalting Columns (Thermo Fisher Scientific). The eluates are then each adjusted to a concentration of about 1-10 mg/ml using the buffer and then sterile filtered. The macromolecule is pre-warmed to 20-30 °C and rapidly mixed with 2-20 (e.g., 7-10) molar equivalents of a tetrafluorophenyl (TFP) or sulfonic tetrafluorophenyl (sulfoTFP) ester, 8-sulfonyl-2-aminobenzazepine-linker (8SO2Bz-L) compound of Formula II dissolved in dimethylsulfoxide (DMSO) or dimethylacetamide (DMA) to a concentration of 5 to 20 mM. The reaction is allowed to proceed for about 16 hours at 30 °C and the MSC is separated from reactants by running over two successive G-25 desalting columns or Zeba™ Spin Desalting Columns equilibrated in phosphate buffered saline (PBS) at pH 7.2 to provide the MSC. Adjuvant-MSC ratio is determined by liquid chromatography mass spectrometry analysis using a C4 reverse phase column on an ACQUITY TM UPLC H-class (Waters Corporation, Milford, MA) connected to a XEVO TM G2-XS TOF mass spectrometer (Waters Corporation). To prepare a cysteine-conjugated MSC, a macromolecule is buffer exchanged into a conjugation buffer containing PBS, pH 7.2 with 2 mM EDTA using Zeba™ Spin Desalting Columns (Thermo Fisher Scientific). The interchain disulfides are reduced using 2–4 molar excess of Tris (2-carboxyethyl) phosphine (TCEP) or dithiothreitol (DTT) at 37 °C for about 30 min to 2 hours. Excess TCEP or DTT was removed using a Zeba™ Spin Desalting column pre- equilibrated with the conjugation buffer. The concentration of the buffer-exchanged macromolecule was adjusted to approximately 5 to 20 mg/ml using the conjugation buffer and sterile-filtered. The maleimide-8SO2Bz-L compound is either dissolved in dimethylsulfoxide (DMSO) or dimethylacetamide (DMA) to a concentration of 5 to 20 mM. For conjugation, the macromolecule is mixed with 10 to 20 molar equivalents of maleimide-8SO2Bz-L. In some instances, additional DMA or DMSO up to 20% (v/v), was added to improve the solubility of the maleimide-8SO2Bz-L in the conjugation buffer. The reaction is allowed to proceed for approximately 30 min to 4 hours at 20 °C. The resulting conjugated MSC is purified away from the unreacted maleimide-8SO2Bz-L using two successive Zeba™ Spin Desalting Columns. The columns are pre-equilibrated with phosphate-buffered saline (PBS), pH 7.2. Adjuvant to antibody ratio (DAR) is estimated by liquid chromatography mass spectrometry analysis using a C4 reverse phase column on an ACQUITY TM UPLC H-class (Waters Corporation, Milford, MA) connected to a XEVO TM G2-XS TOF mass spectrometer (Waters Corporation). For conjugation, the macromolecule may be dissolved in an aqueous buffer system known in the art that will not adversely impact the stability or antigen-binding specificity of the macromolecule. Phosphate buffered saline may be used. The 8SO2Bz-L compound is dissolved in a solvent system comprising at least one polar aprotic solvent as described elsewhere herein. In some such aspects, 8SO2Bz-L is dissolved to a concentration of about 5 mM, about 10 mM, about 20 mM, about 30 mM, about 40 mM or about 50 mM, and ranges thereof such as from about 5 mM to about 50mM or from about 10 mM to about 30 mM in pH 8 Tris buffer (e.g., 50 mM Tris). In some aspects, the 8-sulfonyl-2-aminobenzazepine-linker intermediate is dissolved in DMSO (dimethylsulfoxide), DMA (dimethylacetamide), acetonitrile, or another suitable dipolar aprotic solvent. Alternatively in the conjugation reaction, an equivalent excess of 8SO2Bz-L solution may be diluted and combined with macromolecule solution. The 8SO2Bz-L solution may suitably be diluted with at least one polar aprotic solvent and at least one polar protic solvent, examples of which include water, methanol, ethanol, n-propanol, and acetic acid. The molar equivalents of 8SO2Bz-L to macromolecule may be about 1.5:1, about 3:1, about 5:1, about 10:1, about 15:1, or about 20:1, and ranges thereof, such as from about 1.5:1 to about 20:1 from about 1.5:1 to about 15:1, from about 1.5:1 to about 10:1,from about 3:1 to about 15:1, from about 3:1 to about 10:1, from about 5:1 to about 15:1 or from about 5:1 to about 10:1. The reaction may suitably be monitored for completion by methods known in the art, such as LC- MS. The conjugation reaction is typically complete in a range from about 1 hour to about 16 hours. After the reaction is complete, a reagent may be added to the reaction mixture to quench the reaction. If antibody thiol groups are reacting with a thiol-reactive group such as maleimide of the 8-sulfonyl-2-aminobenzazepine-linker intermediate, unreacted antibody thiol groups may be reacted with a capping reagent. An example of a suitable capping reagent is ethylmaleimide. Following conjugation, the MSC may be purified and separated from unconjugated reactants and/or conjugate aggregates by purification methods known in the art such as, for example and not limited to, size exclusion chromatography, hydrophobic interaction chromatography, ion exchange chromatography, chromatofocusing, ultrafiltration, centrifugal ultrafiltration, tangential flow filtration, and combinations thereof. For instance, purification may be preceded by diluting the MSC, such in 20 mM sodium succinate, pH 5. The diluted solution is applied to a cation exchange column followed by washing with, e.g., at least 10 column volumes of 20 mM sodium succinate, pH 5. The conjugate may be suitably eluted with a buffer such as PBS. LCMS method: Adjuvant to antibody ratio (DAR) is estimated by liquid chromatography mass spectrometry analysis on an ACQUITY TM UPLC H-class (Waters Corporation, Milford, MA) connected to a XEVO TM G2-XS TOF mass spectrometer (Waters Corporation) using a C4 reverse phase column (ACQUITY TM UPLC Protein BEH C4, 300 Å, 1.7 μm, 2.1 mm x 50 mm). A gradient was used at a flow rate of 0.4 mL/min with water + 0.1% formic acid (Eluent A) and acetonitrile + 0.1% formic acid (Eluent B) starting at 1% B for 1 minute, changing to 90% B over 6 minutes, holding at 90% B for 0.5 min, changing to 1% B over 0.5 min, and holding at 1% B for 0.5 min. A mass spectrum was extracted from the TIC and deconvoluted using MaxENT1 algorithm to identify masses for DAR estimation. Example 202 HEK Reporter Assay HEK293 reporter cells expressing human TLR7 or human TLR8 were purchased from Invivogen and vendor protocols were followed for cellular propagation and experimentation. Briefly, cells were grown to 80-85% confluence at 5% CO 2 in DMEM supplemented with 10% FBS, Zeocin, and Blasticidin. Cells were then seeded in 96-well flat plates at 4x10 4 cells/well with substrate containing HEK detection medium and immunostimulatory molecules (MSC). Activity was measured using a plate reader at 620-655 nm wavelength. Example 203 Assessment of Macromolecule-supported compound (MSC) Activity In Vitro This example shows that Macromolecule-supported compounds (MSC) of the invention are effective at eliciting immune activation, and therefore are useful for the treatment of cancer. a) Isolation of Human Antigen Presenting Cells: Human myeloid antigen presenting cells (APCs) were negatively selected from human peripheral blood obtained from healthy blood donors (Stanford Blood Center, Palo Alto, California) by density gradient centrifugation using a ROSETTESEP TM Human Monocyte Enrichment Cocktail (Stem Cell Technologies, Vancouver, Canada) containing monoclonal antibodies against CD14, CD16, CD40, CD86, CD123, and HLA-DR. Immature APCs were subsequently purified to >90% purity via negative selection using an EASYSEP TM Human Monocyte Enrichment Kit (Stem Cell Technologies) without CD16 depletion containing monoclonal antibodies against CD14, CD16, CD40, CD86, CD123, and HLA-DR. b) Myeloid APC Activation Assay: 2 x 10 5 APCs are incubated in 96-well plates (Corning, Corning, NY) containing Iscove’s modified Dulbecco’s medium, IMDM (Lonza) supplemented with 10% FBS, 100 U/mL penicillin, 100 μg/mL (micrograms per milliliter) streptomycin, 2 mM L-glutamine, sodium pyruvate, non-essential amino acids, and where indicated, various concentrations of MSC of the invention (as prepared according to the Example above). Cell-free supernatants are analyzed after 18 hours via ELISA to measure TNFD secretion as a readout of a proinflammatory response. c) PBMC Activation Assay: Human peripheral blood mononuclear cells were isolated from human peripheral blood obtained from healthy blood donors (Stanford Blood Center, Palo Alto, California) by density gradient centrifugation. PBMCs were incubated in 96- well plates (Corning, Corning, NY) in a co-culture with CEA-expressing tumor cells (e.g. MKN- 45, HPAF-II) at a 10:1 effector to target cell ratio. Cells were stimulated with various concentrations of MSC of the invention (as prepared according to the Example above). Cell-free supernatants were analyzed by cytokine bead array using a LegendPlex™ kit according to manufacturer’s guidelines (BioLegend®, San Diego, CA). d) Isolation of Human Conventional Dendritic Cells: Human conventional dendritic cells (cDCs) were negatively selected from human peripheral blood obtained from healthy blood donors (Stanford Blood Center, Palo Alto, California) by density gradient centrifugation. Briefly, cells are first enriched by using a ROSETTESEP TM Human CD3 Depletion Cocktail (Stem Cell Technologies, Vancouver, Canada) to remove T cells from the cell preparation. cDCs are then further enriched via negative selection using an EASYSEP TM Human Myeloid DC Enrichment Kit (Stem Cell Technologies). e) cDC Activation Assay: 8 x 10 4 APCs were co-cultured with tumor cells expressing the ISAC target antigen at a 10:1 effector (cDC) to target (tumor cell) ratio. Cells were incubated in 96-well plates (Corning, Corning, NY) containing RPMI-1640 medium supplemented with 10% FBS, and where indicated, various concentrations of the indicated MSC of the invention (as prepared according to the example above). Following overnight incubation of about 18 hours, cell-free supernatants were collected and analyzed for cytokine secretion (including TNFD) using a BioLegend LEGENDPLEX cytokine bead array. Activation of myeloid cell types can be measured using various screen assays in addition to the assay described in which different myeloid populations are utilized. These may include the following: monocytes isolated from healthy donor blood, M-CSF differentiated Macrophages, GM-CSF differentiated Macrophages, GM-CSF+IL-4 monocyte-derived Dendritic Cells, conventional Dendritic Cells (cDCs) isolated from healthy donor blood, and myeloid cells polarized to an immunosuppressive state (also referred to as myeloid derived suppressor cells or MDSCs). Examples of MDSC polarized cells include monocytes differentiated toward immunosuppressive state such as M2a MΦ (IL4/IL13), M2c MΦ (IL10/TGFb), GM-CSF/IL6 MDSCs and tumor-educated monocytes (TEM). TEM differentiation can be performed using tumor-conditioned media (e.g.786.O, MDA-MB-231, HCC1954). Primary tumor-associated myeloid cells may also include primary cells present in dissociated tumor cell suspensions (Discovery Life Sciences). Assessment of activation of the described populations of myeloid cells may be performed as a mono-culture or as a co-culture with cells expressing the antigen of interest which the MSC may bind to. Following incubation for 18-48 hours, activation may be assessed by upregulation of cell surface co-stimulatory molecules using flow cytometry or by measurement of secreted proinflammatory cytokines. For cytokine measurement, cell-free supernatant is harvested and analyzed by cytokine bead array (e.g. LegendPlex from Biolegend) using flow cytometry. All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.