Novel BRD4 binders

Abstract

The present disclosure relates a compound having a structure according to structure (I) including a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a solvate thereof or an isotopically enriched molecule thereof. Said compound is useful as an inhibitor of a bromodomain-containing proteins. The disclosure further relates to a method of preparing said compounds. The disclosure further relates said compound or a pharmaceutically acceptable composition thereof for use in the treatment of cancer.

Description

New PCT applicationApplicant: Tubulis GmbHOur ref.: TUB18480PCTNOVEL BRD4 BINDERS CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims the right of priority of European patent applicationEP24179218 filed with the European Patent Office on 31 May 2024, the entire content ofwhich is incorporated herein for all purposes. TECHNICAL FIELD

[0001] The present invention relates to novel polycyclic binders of BET proteins such asBRD4 that are useful in the treatment of cancer. BACKGROUND

[0002] Bromo- and extra-terminal domain (BET) proteins are important regulators oftranscriptional outputs and this family of proteins has important roles in homoeostasis and cell survival. BET-family members influence cell cycle progression by activating oncogenes such as MYC, JUNB, CCND1 and CCNA1. Consequently, dysregulation of BET proteins has been implicated in many types of cancer. Thus, attempts have been made to synthesize modulating binders of these proteins in order to provide therapeutic agents that target regulated gene expression. Most modulating binders of BET, specially inhibitors, target all the members of BET subfamily, including BRD2, BRD3, BRD4 and BRDT.

[0003] BRD4 (bromodomain-containing protein 4), was originally identified as a transcriptionregulator for RNA polymerase II-mediated gene expression. BRD4 recruits different chromatin and transcriptional regulators to control gene expression and genome wide studies indicate that it is present at a significant proportion of active promoter and enhancer regions, including super-enhancers (Moriniere J., et al, “Cooperative binding of two acetylation marks on a histone tail by a single bromodomain”, Nature (2009) V.461 p.664–8; Shi J. et al, “The mechanisms behind the therapeutic activity of BET bromodomain inhibition”, Mol. Cell. (2014) V.54, p.728–36; Loven J. et al, “Selective inhibition of tumor oncogenes by disruption of superenhancers” Cell (2013) V.153 p.320–34). BRD4 has been implicated in functionsbeyond transcriptional regulation such as maintaining genome stability (Donati et al, “BRD4and cancer: going beyond transcriptional regulation”. Mol. Cancer 2018;17:164). BRD4 has been linked to several classes of diseases, including cancer, immune disorders, and metabolic diseases. Importantly, BRD4 is found to be overexpressed in a variety of cancers(Hu, J et al. “Regulation of programmed cell death by Brd4”. Cell Death Dis. (2022) 13,1059). 1

[0004] It is known in the art that inhibition of BRD4 reduces cancer cell viability in vitro andsuppresses tumor growth in vivo, thus making BRD4 a subject of intense investigation forcancer therapy. Filippakopoulos et al “Selective inhibition of BET bromodomains “, Nature2010 discloses small molecule inhibitors of bromo domain proteins as well as demonstrating said molecules could attenuate the growth of BRD4-dependent carcinoma as a single agent in vivo with mouse xenograft models in mice. WO2013106643A2 relates the application of BRD4 molecules identified in Filippakopoulos et al in combination with von Hippel-Lindau E3ligands to form PROTAC molecules as a possible treatment of cancer. EP2970330B1discloses a BRD4 inhibitor that shows cellular proliferation inhibition and activity in tumorgrowth inhibition in xenograft models. WO2020 / 086858A1, WO2019084030A1, Dragovich etal “Antibody-Mediated Delivery of Chimeric BRD4 Degraders (part 1)”, J. Med. Chem, 2021, 64, pg.2534 to 2575 and Dragovich et al “Antibody-Mediated Delivery of Chimeric BRD4Degraders (part 2)”, J. Med. Chem, 2021, 64, pg. 2576 to 2607 employ BRD4 inhibitors ofEP2970330B1 in further combination with antibody-drug conjugates (ADCs) comprising PROTAC binders based on von Hippel-Lindau E3 ligands combined with the BRD4 inhibitors of EP2970330B1.

[0005] Therapeutic molecules can show large differences in efficacy, PK and toxicology inbetween species and even between individuals of the same species. Moreover, elucidation of the exact causes of said observed differences is not straightforward and often requires significant testing in broad populations of the species and individuals for identifying statistically significant factors that lead to the observations. Furthermore, novel moleculescan lead to unexpected observations within a given biological system that can provide keyinsights that were not possible with similar structures which allows for the improvement oftherapeutic compositions and medicine. Therefore, there is a need for novel therapeuticmolecules that show similar or better activities to known binders. Likewise, there is a need toimprove the efficacy, PK and toxicology of said therapeutic molecules. SUMMARY

[0006] Disclosed herein, BRD4 binders with novel ring systems according to the presentinvention are unexpectedly active. More surprisingly, a strong effect of purified enantiomerson the observed biological activity has also been demonstrated for ring systems according tothe invention. None of the aforementioned prior art disclose or suggest the present structureswhich show unexpectedly binding properties to bromodomain proteins, specifically with regards to BRD4, and further demonstrate inhibitory activity in several cancer cell lines.Thus, the aforementioned needs are addressed by the presently claimed subject-matter.

[0007] A first aspect of the invention relates a compound having a structure according tostructure (I): 2including a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a solvate thereof or an isotopically enriched molecule thereof; wherein Y^^is CHR^, CR^2, O or NR^; R^^is C1-C12 alkyl, C1-C6 alkyl, C1-C3 alkyl,C1-C12 haloalkyl, C1-C6 haloalkyl, C1-C3 haloalkyl, H, D, CH3or CD3; Y^is CH or N; Y^is N, O or S; R^is H, D, C1-C6 alkyl, C1-C6 alkyl halide, C1-C6 alkyl azide, S(O)-C1-C6 alkyl, S(O)2-C1- C6 alkyl, a lone pair of electrons or is not present; Y^is N or CR^; R^is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6haloalkyl, -CN, -C(O)R^a, - C(O)OR^a, -C(O)NR^bR^c, -S(O)R^d, -S(O)2R^a-S(O)2NR^bR^c, or ^1, wherein the C1-C6 alkyl, C2-C6alkenyl, and C2-C6alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of ^1, -CN, -C(O)R^a, -Y^is C(O), S(O)2, CR^1R^or is not present; R^1is H, deuterium, C1-C6alkyl, halogen, or C1-C6haloalkyl; R^is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, - C(O)R^a, -C(O)OR^a, -C(O)NR^bR^c, -S(O)R^d, -S(O)2R^a, -S(O)2NR^bR^c, or ^1, wherein the C1- C6alkyl, C2-C6alkenyl, and C2-C6alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of ^1, - CN, -C(O)R^a, -C(O)OR^a,-C(O)NR^bR^c, -C(O)N(R^b)NR^bR^c, -S(O)R^d, -S(O)2R^a, - S(O)2NR^bR^c, -OR^a, -OC(O)R^d, -NR^bR^c, N(R^b)C(O)R^d, N(R^b)SO2R^d, N(R^b)C(O)OR^d, N(R^b)C(O)NR^bR^c, N(R^b)SO2NR^bR^c, and N(R^b)C(NR^bR^c)=NR^bR^c; R^a, R^b, R^c, R^a, and R^b, at each occurrence, are each independently H, C1-C6alkyl, C2- 3C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, ^1, or -(C1-C6 alkylenyl)-^1; R^c, at each occurrence, is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6 haloalkyl, ^1, -(C1-C6 alkylenyl)-^1, -(C1-C6 alkylenyl)-CN, -(C1-C6 alkylenyl)-OR^^, or -(C1- C6alkylenyl)-C(O)OR^^; R^d, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 haloalkyl, ^1, or -(C1-C6 alkylenyl)-^1; R^d, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 haloalkyl, ^1, -(C1-C6 alkylenyl)-^1, -(C1-C6 alkylenyl)-NR^^R^^, or -(C1-C6 alkylenyl)- N(R^^)C(O)O(R^^); ^1, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each ^1is optionally substituted with 1, 2, 3, 4, or 5 R1^groups; Y^is N, CH, P(O) or O;G^ is H, C ^1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -C(O)R a, -C(O)OR^a, -C(O)NR^bR^c, -S(O)2R^a, -S(O)2NR^bR^c, or ^2; wherein the C1-C6 alkyl, C2- C6alkenyl, and C2-C6alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of ^2, -CN, -C(O)R^a, - C(O)OR^a, -C(O)NR^bR^c, -C(O)N(R^b)NR^bR^c, -S(O)R^d, -S(O)2R^a, -S(O)2NR^bR^c, -OR^a, - OC(O)R^d, -NR^bR^c, N(R^b)C(O)R^d, N(R^b)SO2R^d, N(R^b)C(O)OR^d, N(R^b)C(O)NR^bR^c, N(R^b)SO2NR^bR^c, N(R^b)C(NR^bR^c)=NR^bR^c, a lone pair of electrons or is not present; R^a, R^b, and R^c, at each occurrence, are each independently H, alkyl, C2-C6 alkenyl, C2- C6alkynyl, haloalkyl, ^2, -(C1-C6alkylenyl)-^2, -(C1-C6alkylenyl)-OR^^, -(C1-C6alkylenyl)- S(O)2R^^, -(C1-C6 alkylenyl)-S(O)2NR^^R^^, -(C1-C6 alkylenyl)-C(O)R^^, -(C1-C6 alkylenyl)- C(O)OR^^, -(C1-C6alkylenyl)-C(O)NR^^R^^, -(C1-C6alkylenyl)-NR^^R^^, -(C1-C6alkylenyl)- N(R^^)C(O)R^^, -(C1-C6 alkylenyl)-N(R^^)S(O)2R^^, -(C1-C6 alkylenyl)-N(R^^)C(O)O(R^^), -(C1- C6alkylenyl)-N(R^^)C(O)NR^^R^^, or -(C1-C6alkylenyl)-N(R^^)S(O)2NR^^R^^; R^d, at each occurrence, is independently alkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloalkyl, ^2, - (C1-C6alkylenyl)-^2, -(C1-C6alkylenyl)-OR^^, -(C1-C6alkylenyl)-S(O)2R^^, -(C1-C6alkylenyl)- S(O)2NR^^R^^, -(C1-C6 alkylenyl)-C(O)R^^, -(C1-C6 alkylenyl)-C(O)OR^^, -(C1-C6 alkylenyl)- C(O)NR^^R^^, -(C1-C6 alkylenyl)-NR^^R^^, -(C1-C6 alkylenyl)-N(R^^)C(O)R^^, -(C1-C6 alkylenyl)- N(R^^)S(O)2R^^, -(C1-C6 alkylenyl)-N(R^^)C(O)O(R^^), -(C1-C6 alkylenyl)-N(R^^)C(O)NR^^R^^, or -(C1-C6 alkylenyl)-N(R^^)S(O)2NR^^R^^; ^2, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each ^2is optionally substituted with 1, 2, 3, 4, or 5 R2^groups; AG1is C(RAG1) or N; AG2is C; AG3is C; and AG4is C(RAG4) or N; wherein one, both or none of AG1and AG4are N; RAG1is H, D, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6haloalkyl, -CN, NO2, -4R^3R^is R^4, ^3, -(C1-C6 alkylenyl)-CN, -(C1-C6 alkylenyl)-OR^is R^1, -(C1-C6 alkylenyl)- OC(O)R^is R^2, (C1-C6alkylenyl)-OC(O)NR^is R^3R^is R^4, -(C1-C6alkyleny|)-S(O)2R^is R^1, -(C1-C6 alkylenyl)-S(O)2NR^is R^3R^is R^4, -(C1-C6 alkylenyl)-C(O)R^is R^1, -(C1- C6alkylenyl)-C(O)OR^is R^1, -(C1-C6alkylenyl)-C , -(C1-C6alkylenyl)- NR^is R^3R^is R^4, -(C1-C6 alkylenyl)-N(R^is R^6 alkylenyl)-N(R^is R^3)S(O)2R^is R^2, -(C1-C6 alkylenyl)-N(R^is R^3-C6 alkylenyl)-N(R^is R^3)C(O)NR^is R^3R^is R^4, -(C1-C6 alkylenyl)is R^3R^is R^4, - (C1-C6 alkylenyl)-CN, or -(C1-C6 alkylenyl)-^3; R^is R^1, R^is R^3, and R^is R^4, at each occurrence, are each independently H, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, ^3, -(C1-C6 alkylenyl)-^3, -(C1- C6alkylenyl)-OR^^, -(C1-C6alkylenyl)-S(O)2R^^, -(C1-C6alkylenyl)-S(O)2NR^^R^^, -(C1- C6 alkylenyl)-C(O)R^^, -(C1-C6 alkylenyl)-C(O)OR^^, -(C1-C6 alkylenyl)-C(O)NR^^R^^, -(C1- C6alkylenyl)-NR^^R^^, -(C1-C6alkylenyl)-N(R^^)C(O)R^^, -(C1-C6alkylenyl)-N(R^^)S(O)2R^^, - (C1-C6 alkylenyl)-N(R^^)C(O)O(R^^), -(C1-C6 alkylenyl)-N(R^^)C(O)NR^^R^^, or -(C1- C6alkylenyl)-N(R^^)S(O)2NR^^R^^; R^is R^2, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6haloalkyl, ^3, -(C1-C6alkylenyl)-^3, -(C1-C6alkylenyl)-OR^^, -(C1-C6alkylenyl)-S(O)2R^^, - (C1-C6 alkylenyl)-S(O)2NR^^R^^, -(C1-C6 alkylenyl)-C(O)R^^, -(C1-C6 alkylenyl)-C(O)OR^^, -(C1- C6alkylenyl)-C(O)NR^^R^^, -(C1-C6alkylenyl)-NR^^R^^, -(C1-C6alkylenyl)-N(R^^)C(O)R^^, -(C1- C6 alkylenyl)-N(R^^)S(O)2R^^, -(C1-C6 alkylenyl)-N(R^^)C(O)O(R^^), -(C1-C6 alkylenyl)- N(R^^)C(O)NR^^R^^, or -(C1-C6alkylenyl)-N(R^^)S(O)2NR^^R^^; ^3, at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, orheterocycle; and each ^3 group is optionally substituted with 1, 2, 3, 4, or 5 R4^ groups;RAG4is H, D, C1-C3alkyl, halogen, C1-C3haloalkyl, or -CN; R1^, R2^, and R4^, at each occurrence, is independently selected from the group consisting of oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, NO2, ^2a, -OR^^, -OC(O)R^^, -OC(O)NR^^R^^, -SR^^, -S(O)2R^^, -S(O)2NR^^R^^, -C(O)R^^, -C(O)OR^^, - C(O)NR^^R^^, -NR^^R^^, -N(R^^)C(O)R^^, -N(R^^)S(O)2R^^, -N(R^^)C(O)O(R^^), - N(R^^)C(O)NR^^R^^, -N(R^^)S(O)2NR^^R^^, -(C1-C6 alkylenyl)-CN, -(C1-C6 alkylenyl)-^2a, -(C1- C6 alkylenyl)-OR^^, -(C1-C6 alkylenyl)-OC(O)R^^, -(C1-C6 alkylenyl)-OC(O)NR^^R^^, -(C1- C6 alkylenyl)-S(O)2R^^, -(C1-C6 alkylenyl)-S(O)2NR^^R^^, -(C1-C6 alkylenyl)-C(O)R^^, -(C1- C6alkylenyl)-C(O)OR^^, -(C1-C6alkylenyl)-C(O)NR^^R^^, -(C1-C6alkylenyl)-NR^^R^^, -(C1- C6 alkylenyl)-N(R^^)C(O)R^^, -(C1-C6 alkylenyl)-N(R^^)S(O)2R^^, -(C1-C6 alkylenyl)- N(R^^)C(O)O(R^^), -(C1-C6alkylenyl)-N(R^^)C(O)NR^^R^^, -(C1-C6alkylenyl)- N(R^^)S(O)2NR^^R^^, or -(C1-C6 alkylenyl)-CN; R^1, R^1, R^1, and R^1, at each occurrence, are each independently H, C1-C6alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, ^2a, -(C1-C6 alkylenyl)-OR^1, -(C1-C6 alkylenyl)-NR^3R^4, -(C1-C6 alkylenyl)-C(O)NR^3R^4, or - (C1-C6 alkylenyl)-^2a;R^1, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6haloalkyl, ^2a, or -(C1-C6alkylenyl)-^2a; 5^2a, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each ^2agroup is optionally substituted with 1, 2, 3, 4, or 5 R3^groups; R3^, at each occurrence, is independently oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6haloalkyl, -CN, NO2, -OR^1, -OC(O)R^2, -OC(O)NR^3R^4, -SR^1, -S(O)2R^1, - S(O)2NR^3R^4, -C(O)R^1, -C(O)OR^1, -C(O)NR^3R^4, -NR^3R^4, -N(R^3)C(O)R^2, - N(R^3)S(O)2R^2, -N(R^3)C(O)O(R^2), -N(R^3)C(O)NR^3R^4, -N(R^3)S(O)2NR^3R^4, -(C1- C6 alkylenyl)-OR^1, -(C1-C6 alkylenyl)-OC(O)R^2, -(C1-C6 alkylenyl)-OC(O)NR^3R^4, -(C1- C6 alkylenyl)-S(O)2R^1, -(C1-C6 alkylenyl)-S(O)2NR^3R^4, -(C1-C6 alkylenyl)-C(O)R^1, -(C1- C6alkylenyl)-C(O)OR^1, -(C1-C6alkylenyl)-C(O)NR^3R^4, -(C1-C6alkylenyl)-NR^3R^4, -(C1- C6 alkylenyl)-N(R^3)C(O)R^2, -(C1-C6 alkylenyl)-N(R^3)S(O)2R^2, -(C1-C6 alkylenyl)- N(R^3)C(O)O(R^2), -(C1-C6alkylenyl)-N(R^3)C(O)NR^3R^4, -(C1-C6alkylenyl)- N(R^3)S(O)2NR^3R^4, or -(C1-C6 alkylenyl)-CN; R^1, R^3, and R^4, at each occurrence, are each independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R^2, at each occurrence, is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1- C6 haloalkyl; wherein BG1, BG2, BG3, BG4, BG5, AG2and AG3form a seven membered ring and BG1is C(O), NRBG1a, O, CRBG1bRBG1c, CRBG1b, N, S, Se, S(O), S(O)2, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e, BG2is C(O), NRBG2a, O, CRBG2bRBG2c, CRBG2b, N, S, Se, S(O), S(O)2, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e,BG3 is NRBG3a, CRBG3bRBG3c, CRBG3b, C(O), O, S, N, Se, S(O) or S(O)2,BG4 is NRBG4a, CRBG4bRBG4c, CRBG4b, C(O), O, S, N, Se, S(O) or S(O)2,BG5is C(O), NY^, O, CY^RBG5a, CY^, S, Se, S(O), S(O)2 or P(O)Y^; or wherein BG1, BG2, BG4, BG5, AG2and AG3form a six membered ring and BG1is C(O), NRBG1a, O, N, CRBG1bRBG1c, CRBG1b,S, Se, S(O), S(O)2, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e, BG2is C(O), NRBG2a, O, N, CRBG2bRBG2c, CRBG2b,S, Se, S(O), S(O)2, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e, BG3is a bond between BG2and BG4, or BG3is not present, BG2is directly bonded to BG4,BG4 is NRBG4a, CRBG4bRBG4c, CRBG4b, C(O), O, S, N, Se, S(O) or S(O)2,BG5is C(O), NY^, N, O, CY^RBG5a, CY^, S, Se, S(O), S(O)2or P(O)Y^; orwherein BG1, BG2, BG5, AG2 and AG3 form a five membered ring andBG1is C(O), NRBG1a, O, N, CRBG1bRBG1c, CRBG1b,S, Se, S(O), S(O)2, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e, BG2is C(O), NRBG2a, O, N, CRBG2bRBG2c, CRBG2b,S, Se, S(O), S(O)2, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e, BG3and BG4are a bond between BG2and BG5, or BG3and BG4are not present, 6BG2is directly bonded to BG5, BG5is C(O), NY^, N, O, CY^RBG5a, CY^, S, Se, S(O), S(O)2or P(O)Y^;wherein RBG1a, RBG1b , RBG1c, RBG1d, RBG1e , RBG1e, RBG2a, RBG2b , RBG2c, RBG2d, RBG2e , RBG2e,RBG3a, RBG3b, RBG3c, RBG4a, RBG4b, RBG4c, RBG5a, at each occurrence, are each independently H, D, alcohol, alkenyl, alkyl, alkynyl, amide, amine, amino acid, amino alcohol, amino amide, amino ester, aryl, boryl, ether, ester, halogenyl, heteroaryl, heterocycle, phoshoramidite, phosphinyl, phosphoester, phosphonyl, selenenyl, selenonyl, sulfenyl, sulfonamide, sulfonyl, substituted alcohol, substituted alkene, substituted alkyl, substituted alkyne, substituted amide, substituted amine, substituted aryl, substituted azide, substituted borate, substituted halogen, substituted heteroaromatic, substituted heterocycle, substituted phoshoramidite, substituted phosphinate, substituted phosphoester, substituted phosphonate, substituted selenate, substituted selenyl, substituted sulfonamide, substituted sulfonyl, alkyl alcohol, alkyl amide, alkyl amine, alkyl amino acid, alkyl amino alcohol, alkyl amino amide, alkyl amino ester, alkyl aromatic, alkyl azide, alkyl boronate, alkyl disulfide, alkyl carbonate, alkyl carbamate, alkyl ether, alkyl ester, alkyl halogen, alkyl heterocycle, alkyl heteroaromatic, alkyl phoshoramidite, alkyl phosphinate, alkyl phosphoester, alkyl phosphonyl, alkyl selenate, alkyl sulfenate, alkyl sulfonamide, alkyl thiol, alkyl urea, alkyl thiourea or combinations thereof;wherein Y^^is S(O) RY^^^C(O)RY^, S Y^ Y^ Y^ Y^2 (O)R ^ P(O)(R )2, OR , NHR , OH, O, NH2,CRY^1RY^2C(O)NHRY^^^^ CRY^1RY^2S(O) RY^^^ CRY^1RY^2C(O)RY^, CRY^1RY^2S Y^2 (O)R ^CRY^1RY^2P(O)(RY^)2, CRY^1RY^2ORY^, CRY^1RY^2NHRY^, CRY^1RY^2OH, CRY^1RY^2CHO,CRY^1RY^2NH2, H or D; andwherein RY^at each occurrence, is independently H, O, OH, NH2, C1-C12 alkyl, C1-C12 alcohol, C1-C12 amine, C1-C12 amide, C1-C12 ester, C6-C12 aryl, C4-C12 heterocycle or C5-C12 heteroaryl; wherein RY^1and RY^2at each occurrence, are independently H, D, halogen, C1-C12alkyl, C1- C12alcohol, C1-C12amine, C1-C12amide, C1-C12ester, C6-C12aryl, C4-C12heterocycle or C5- C12 heteroaryl.

[0008] A further aspect of the invention relates a method of preparing a compound forbinding a bromodomain-containing protein according to any one of the product embodiments according to the invention, comprising- providing a compound according to structure (VI-a)7- providing a compound according to (VI-b)- coupling (VI-a) with (VI-b) to obtain either (VI-c) or (VI-d)- cyclizing either (VI-c) or (VI-d) to obtain a structure according to structure (I);or comprising:- providing a compound according to (VI-e)8- providing a compound according to (VI-f)- cross coupling (VI-e) with (VI-f) to obtain (VI-g);- providing a molecule XY^-G^ and reacting with (VI-g) to obtain (VI-h)9- providing X^-Y^ and reacting with (VI-h) to obtain a molecule according to (I);wherein XG1is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, wherein XG2is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, wherein XG4is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, wherein XG5is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, CG1is H, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid, BF3K, SnBu3, SiF3, SiCl3 or SiMe2OH, wherein CG2is NH2, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid, BF3K, SnBu3, SiF3, SiCl3or SiMe2OH, wherein M is H, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid, BF3K, SnBu3, SiF3, SiCl3 or SiMe2OH, wherein XY^is NH2, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid or BF3K, wherein X^-Y^is Cl2C(O), ClC(O)OMe, Cl2S(O)2, Cl2CR^1R^^or (O)CR^1R^.

[0009] A further aspect of the invention relates a pharmaceutically acceptable compositioncomprising a compound according to any one of the product embodiments of the invention.

[0010] A further aspect of the invention relates a compound according to any one of thecompound embodiments of the invention or a pharmaceutically acceptable composition comprising said compound embodiments of the invention, for use in the treatment of cancer.

[0011] A further aspect of the invention relates a method for treating cancer comprisingadministering a compound according to any one of the compound embodiments of the invention or a pharmaceutically acceptable composition comprising said compound embodiments of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 shows chromatograms of enantiomeric separation on an HPLC equippedwith a ChiralPak IB N-3 column (4.6×100 mm, 3 μm) applying isocratic conditions (40:60 EtOH:CO2, 0.2% v / v isopropylamine) at 40 °C with 3 mL / min flow rate at 120 bar for A) X5_racemic, B) chiral column purified X5_first eluting peak and C) chiral column purified 10X5_second eluting peak, the X-axis is given in time (minutes) and Y-axis given as milli absorption units measured at 220 nm wavelength of light.

[0013] Figure 2 shows a racemic chromatogram for X6 separated in a chiral phase HPLCaccording to the conditions given in Figure 1.

[0014] Figure 3 shows chromatograms of A) X120_racemic, B) chiral column purifiedX120_first eluting peak and C) chiral column purified X120_second eluting peak with conditions according to Figure 1 except that isocratic conditions (20:20:20:40 MeOH:EtOH:iPrOH:CO2, 0.2% v / v isopropylamine) at 40 °C with 3 mL / min flow rate at 120 bar were used.

[0015] Figure 4 shows the docking to BRD4 of PAZ1-CO2Me in 4A comparison to PAZ1-NMe2 shown in 4B.11

[0017] Figure 6 shows in vitro anti-cancer efficacy of antibody-PROTAC conjugates. Resultsof X135 in 6A for H441 TROP2+ wherein the Datopotamab -MA-linker- VHL-X135 ADC isplotted as a solid line with solid black squares and Brentuximab -MA-linker-VHL-X135 ADC(isotype control in this setting) is plotted as a broken line with solid black circles, and resultsfor SR-786 CD30+ cells are presented in 6B wherein the Brentuximab-MA-linker- VHL-X135ADC is plotted as a solid line with solid black squares and Datopotamab-MA-linker - VHL-X135 ADC (isotype control in this setting) is plotted as a broken line with solid black circles.

[0018] Figure 7 shows in vitro anti-cancer efficacy data of antibody-PROTAC conjugatesconstructed from X5. Brentuximab- MA-linker-VHL-X5 ADCs were tested on SU-DHL-1, SR-786 and Karpas cell lines and the results are presented in 7A, 7B and 7C respectively.Datopotamab-MA-linker -VHL-X5 ADCs were tested on H441 and BXPC-3 cell lines and theresults are presented in 7D and 7E respectively. Racemic data is plotted with solid circles, ADCs derived from the first eluting enantiomer of X5 are plotted as solid squares and the ADCs derived from the second eluting enantiomer of X5 are plotted as solid triangles.Percent viability of the cells is plotted on the Y-axis and the concentration of the ADCs areplotted on the X-axis in units of ng / mL.

[0019] Figure 8 shows the in vitro anti-cancer efficacy evaluation of racemic vs enantiomericpure versions of X120 in a PROTAC system using a VHL ligand. The X120 based PROTAC compositions were tested on cell lines MDA-MB-453, H441, BXPC-3, HL-60, Karpas-299 andSR786 in viability assays. Percent viability of the cells is plotted on the Y-axis and theconcentration of the PROTAC compositions are plotted on the X-axis in nanomolar. The racemic versions of the PROTACs are plotted in Figure 8A to 8F as solid circles, the first eluting enantiomer versions of the PROTACs are plotted as triangles and the second eluting enantiomer versions of the PROTACs are plotted as solid squares.

[0020] Figure 9 shows in vitro anti-cancer efficacy data of antibody-PROTAC conjugatesconstructed with X54. Specifically, Brentuximab-MA-linker-VHL-X5 ADCs as tested on SR-786 and Karpas-299 cell lines and the results are presented in Figure 9A and 9B respectively. Percent viability of the cells are plotted on the Y-axis and the concentration of the ADCs are plotted on the X-axis in units of ng / mL. 12

[0021] Figure 10 shows a proteomics experiment featuring protein degradation using aPROTAC comprising the enantiomerically pure X120_first eluting BRD4 binder and a VHLtethered ligand. Label-free unbiased proteomics analysis has been conducted with SKBR-3cells (15000 cells per well in a 96 well plate) that have been incubated with 5 nanomolar (Fig.10A), 50 nanomolar (Fig.10B), 200 nanomolar (Fig. 10C) and 500 (Fig. 10D) nanomolarconcentrations of said PROTAC or DMSO as a control (0.1% in all experiments). Thevolcano plots below clearly show selective downregulation of the BET family proteinsmediated by the enantiomerically pure X120_first eluting binder. A high selectivity is shownsince only BRD2, BRD3 and BRD4 are downregulated together with downstream targets ofthe BET family such as MYC. The experiment clearly demonstrates high selectivity of thestructures disclosed herein for the BET family proteins over the other proteome of the cell.

[0022] Figure 11 shows in vivo results in tumor models for direct comparison of Antibody-Drug-Conjugates comprising the enantiopure X120_first eluting BRD4 binder based PROTAC versus Antibody-Drug-Conjugates comprising the known X2 BRD4 binder basedPROTAC. The ADCs in the comparison experiments shared substantially all the samefeatures (antibody, linker, antibody-degrader ratio and VHL ligand) and solely differed in theBET binding moiety. DETAILED DESCRIPTION

[0023] The described features of the invention are substantiated by the followingdescriptions of exemplary embodiments, which are presented in order to support the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. ****************

[0024] Those skilled in the art will recognize, or be able to ascertain, using not more thanroutine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

[0025] It is noted that as used herein, the singular forms “a”, “an”, and “the”, include pluralreferences unless the context clearly indicates otherwise. Thus, for example, reference to “areagent” includes one or more of such different reagents and reference to “the process”includes reference to equivalent steps and methods known to those of ordinary skill in the art that could be modified or substituted for the processes described herein.

[0026] Unless otherwise indicated, the term "at least" preceding a series of elements is to beunderstood to refer to every element in the series. Those skilled in the art will recognize, or 13be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

[0027] The term "and / or" wherever used herein includes the meaning of "and", "or" and "allor any other combination of the elements connected by said term.

[0028] Throughout this specification and the claims which follow, unless the context requiresotherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term “comprising” can be substituted with the term “containing” or “including” or sometimes when used herein with the term “having”. When used herein “consisting of" excludes any element, step, or ingredient not specified.

[0029] The term “including” means “including but not limited to”. “Including” and “includingbut not limited to” are used interchangeably.

[0030] As used herein the terms "about", "approximately" or “essentially” mean within 20%,preferably within 15%, preferably within 10%, and more preferably within 5% of a given value or range. It also includes the concrete number, i.e. “about 20” includes the number of 20.

[0031] As used herein, a linker, or linker group, between two molecules is given its usualmeaning. Use of linkers in ADCs and PROTAC approaches is well known in the art and discussed in detail in the literature, specifically in Lambert, J.M. et al “Chemical Linkers inAntibody–Drug Conjugates” R. Soc. Chem.2022, Drug discovery series no.81, Chapter 1“Introduction to Antibody–Drug Conjugates”. Linkers in PROTAC design are also well knownto the skilled person and reference to a timely review by Troup et al,” Current strategies forthe design of PROTAC linkers: a critical review” Explor. Target Antitumor Ther.2020; 1:273-312 is made. As used herein, the term “equivalent O of the end methylene group of an endsubunit of a polyethylene glycol linker” corresponds to the oxygen of the end hydroxyl group of an unsubstituted polyethylene glycol polymer, i.e. the functional hydroxyl group end of a PEG polymer that can be activated and substituted by an appropriate nucleophile. Asdisclosed herein, the end groups of either or both the PEG and alkane-based polymers thatform linkers between small molecules or PROTAC molecules comprised of small moleculeslinked together that are further conjugated with antibodies to form ADCs can be created withchemistry well known in the art, specifically reference is made to the above references in this paragraph as well as the citations presented therein. Furthermore, alkyl and peg linkers for forming PROTAC molecules are well known from WO2019084030A1 as are linkers suitable for conjugation of said PROTAC with antibodies.

[0032] Unless otherwise indicated, the term "alkyl" by itself or as part of another term ingeneral refers to a substituted or unsubstituted straight chain or branched, saturated hydrocarbon having the indicated number of carbon atoms; e.g., "-(C1-C8)-alkyl" or "-(C1-C10)- 14alkyl” refer to an alkyl group having from 1 to 8 or 1 to 10 carbon atoms, respectively). When the number of carbon atoms is not indicated, the alkyl group may have from 1 to 8 carbon atoms. Representative straight chain -(C1-C8)-alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl and -n-octyl; branched -(C1-C8)-alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, - isopentyl, and -2-methylbutyl. In some aspects, an alkyl group may be unsubstituted. Optionally, an alkyl group may be substituted, such as e.g. with one or more groups.

[0033] Unless otherwise indicated, the term "alkylene" by itself or as part of another term, ingeneral refers to a substituted or unsubstituted branched or straight chain, saturated hydrocarbon radical of the stated number of carbon atoms, preferably 1-10 carbon atoms (- (C1-C10)-alkylene-) or preferably 1 to 8 carbon atoms (-(C1-C8)-alkylene-), and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. When the number of carbon atoms is not indicated, the alkylene group may have from 1 to 8 carbon atoms. Typical alkylene radicals include, but are not limited to: methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,3-n-propylene (- CH2CH2CH2-), and 1,4-n-butylene (-CH2CH2CH2CH2-). In some aspects, an alkylene group may be unsubstituted. Optionally, an alkylene group may be substituted, such as e.g. with one or more groups.

[0034] Unless otherwise indicated, the term "alkenyl" by itself or as part of another term ingeneral refers to a substituted or unsubstituted straight chain or branched, unsaturated hydrocarbon having a double bond and the indicated number of carbon atoms; e.g., "-(C2- C8)-alkenyl" or "-(C2-C10)-alkenyl” refer to an alkenyl group having from 2 to 8 or 2 to 10 carbon atoms, respectively). When the number of carbon atoms is not indicated, the alkenyl group may have from 2 to 8 carbon atoms. Representative -(C2-C8)-alkenyl groups include, but are not limited to, -ethenyl, -1-propenyl, -2-propenyl, -1-butenyl, -2-butenyl, -isobutenyl, - 1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, and -2,3-dimethyl-2- butenyl. In some aspects, an alkenyl group may be unsubstituted. Optionally, an alkenyl group may be substituted, such as e.g. with one or more groups.

[0035] Unless otherwise indicated, the term "alkenylene" by itself of as part of another term,in general refers to a substituted or unsubstituted unsaturated branched or straight chain hydrocarbon radical of the stated number of carbon atoms, preferably 2-10 carbon atoms (- (C2-C10)-alkenylene-) or preferably 2 to 8 carbon atoms (-(C2-C8)-alkenylene-), and having a double bond, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. When the number of carbon atoms is not indicated, the alkenylene group may have from 2 to 8 carbon atoms. Typical alkenylene radicals include, but are not limited to: -ethenylene-, -1- propenylene-, 2-propenylene-, -1-butenylene-, -2-butenylene-, -isobutenylene-, -1- pentenylene-, -2-pentenylene-, -3-methyl-1-butenylene-, -2-methyl-2-butenylene-, and -2,3- dimethyl-2-butenylene-. In some aspects, an alkenylene group may be unsubstituted. Optionally, an alkenylene group may be substituted, such as e.g. with one or more groups. 15

[0036] Unless otherwise indicated, the term "alkynyl" by itself or as part of another term ingeneral refers to a substituted or unsubstituted straight chain or branched, unsaturated hydrocarbon having a triple bond and the indicated number of carbon atoms; e.g., "-(C2-C8)-alkynyl" or "-(C2-C10)-alkynyl” refer to an alkynyl group having from 2 to 8 or 2 to 10 carbonatoms, respectively). When the number of carbon atoms is not indicated, the alkynyl group may have from 2 to 8 carbon atoms. Representative -(C2-C8-)alkynyl groups include, but arenot limited to, -acetylenyl, -1-propynyl, -2-propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl and -3-methyl-1-butynyl. In some aspects, an alkynyl group may be unsubstituted. Optionally, an alkynyl group may be substituted, such as e.g. with one or more groups.

[0037] Unless otherwise indicated, the term "alkynylene" by itself of as part of another term,in general refers to a substituted or unsubstituted, branched or straight chain, unsaturatedhydrocarbon radical of the stated number of carbon atoms, preferably 2-10 carbon atoms (-(C2-C10)-alkynylene-) or preferably 2 to 8 carbon atoms (-(C2-C8)-alkynylene-), and having a triple bond, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. When the number of carbon atoms is not indicated, the alkynylene group may have from 2 to 8 carbon atoms. Typical alkynylene radicals include, but are not limited to: -ethynylene-, -1- propynylene-, -2-propynylene-, -1-butynylene-, -2-butynylene-, -1-pentynylene-, -2-pentynylene- and -3-methyl-1-butynylene-. In some aspects, an alkynylene group may beunsubstituted. Optionally, an alkynylene group may be substituted, such as e.g. with one or more groups.

[0038] Unless otherwise indicated, the term "aryl," by itself or as part of another term, ingeneral means a substituted or unsubstituted monovalent carbocyclic aromatic hydrocarbon radical of 6 to 20 carbon atoms (preferably 6 to 14 carbon atoms, more preferably 6 to 10carbon atoms, in very preferred embodiments 6 carbon atoms) derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ring system. Some aryl groups are represented in the exemplary structures as "Ar". Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, and biphenyl. An exemplary aryl group is a phenyl group. In some aspects, an aryl group may be unsubstituted. Optionally, an aryl group may be substituted, such as e.g. with one or more groups.

[0039] Unless otherwise indicated, the term "arylene", by itself or as part of another term, ingeneral is an aryl group as defined above wherein one of the hydrogen atoms of the aryl group is replaced with a bond (i.e., it is divalent) and can be in the para, meta, or ortho orientations as shown in the following structures, with phenyl as the exemplary group: 16In selected embodiments, the arylene is, e.g., an aryl group as defined above wherein two or more of the hydrogen atoms of the aryl group are replaced with a bond (i.e., the arylene canbe trivalent). In some aspects, an arylene group may be unsubstituted. Optionally, analkynylene group may be substituted, such as e.g. with one or more groups.

[0040] Unless otherwise indicated, the term “heterocycle”, “heterocyclyl”, “heterocyclic ring”or the like, by itself or as part of another term, in general refers to a monovalent substituted or unsubstituted aromatic or non-aromatic monocyclic or bicyclic ring system having the indicated number of carbon atoms (e.g., “(C3-C8)heterocycle” or “(C3-C10)heterocycle” refer to a heterocycle having from 3 to 8 or from 3 to 10 carbon atoms, respectively) and one to four heteroatom ring members independently selected from N, O, P or S, and derived by removal of one hydrogen atom from a ring atom of a parent ring system. One or more N, C or S atoms in the heterocycle can be oxidized. The ring that includes the heteroatom can be aromatic or nonaromatic. Unless otherwise noted, the heterocycle is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Representative examples of a (C3-C8)heterocycle include, but are not limited to, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, pyrrolyl, thiophenyl (thiophene), furanyl, thiazolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, isothiazolyl, and isoxazolyl. In some aspects, a heterocycle group may be unsubstituted. Optionally, a heterocycle group may be substituted, such as e.g. with one or more groups.

[0041] Unless otherwise indicated, the term "heterocyclo", “heterocyclyl”, “heterocyclic ring”or the like, by itself or as part of another term, in general refers to a heterocycle group as defined above and having the indicated number of carbon atoms (e.g., (C3-C8)-heterocycle or (C3-C10)-heterocycle) wherein one of the hydrogen atoms of the heterocycle group is replaced with a bond (i.e., it is divalent). In selected embodiments, the heterocyclo is, e.g., a heterocycle group as defined above wherein two or more of the hydrogen atoms of the heterocycle group are replaced with a bond (i.e., the heterocyclo can be trivalent). In some aspects, a heterocyclo, heterocyclyl or heterocyclic ring may be unsubstituted. Optionally, a heterocyclo, heterocyclyl or heterocyclic ring may be substituted, such as e.g. with one or more groups.

[0042] Unless otherwise indicated, the term "carbocycle", “carbocyclyl”, “carbocyclic ring” orthe like, by itself or as part of another term, in general refers to a monovalent, substituted or unsubstituted aromatic or non-aromatic monocyclic or bicyclic carbocyclic ring system having the indicated number of carbon atoms (e.g., “(C3-C8)carbocycle” or “(C3-C10)carbocycle” refer 17to a carbocycle having from 3 to 8 or from 3 to 10 carbon atoms, respectively) derived by the removal of one hydrogen atom from a ring atom of a parent ring system. As illustrative butnon-limiting examples the carbocycle may be a 3-, 4-, 5-, 6-, 7- or 8-membered carbocycle.The term “carbocycle”, “carbocyclyl”, “carbocyclic ring” or the like may also include cycloalkyl,such as for example (C3-C8)-cycloalkyl, in particular 3-, 4-, 5-, 6-, 7- or 8-memberedcycloalkyl. The term “carbocycle”, “carbocyclyl”, “carbocyclic ring” or the like may also includecycloalkenyl, such as for example (C5-C8)-cycloalkenyl, in particular 5-, 6-, 7- or 8-memberedcycloalkenyl. Representative (C3-C8)-carbocycles include, but are not limited to, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3- cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadienyl, 1,3,5- cycloheptatrienyl, cyclooctyl, and cyclooctadienyl. In some aspects, a carbocycle may be unsubstituted. Optionally, a carbocycle may be substituted, such as e.g. with one or more groups.

[0043] The term “halogen” or “halo”, unless defined otherwise, in general refers to elementsof the 7thmain group; preferably fluorine, chlorine, bromine and iodine; more preferably fluorine, chlorine and bromine; even more preferably, fluorine and chlorine.

[0044] The term “substituted”, “optionally substituted”, “optionally may be substituted” or thelike, unless otherwise indicated, in general means that one or more hydrogen atoms can be each independently replaced with a substituent. Typical substituents include, but are not-C(=NR)NR2. R can be the same or different, are independently selected from (C1-C8)alkyl, (C1-C8)alkylene(C6-C10)aryl or (C6-C10)aryl, optionally two R substituents can together form a 3 to 8-membered ring.

[0045] The term “leaving group”, as used herein, in general denotes a moiety, e.g. an atomor a group of atoms, which is capable to detach from a main or residual part of a substrateduring a reaction or elementary step of a reaction. In particular, a leaving group can bereplaced by another moiety, e.g. an atom or a group of atoms, during a substitution reaction.The substitution reaction may be, for example, a nucleophilic substitution.

[0046] The term “aliphatic or aromatic residue”, or “aliphatic residue” or “aromatic residue”, orthe like, as used herein, in general refers to an aliphatic substituent, such as e.g. but not limited to an alkyl residue, which, however, can be optionally substituted by further aliphatic and / or aromatic substituents. As non-limiting examples an aliphatic residue can be a nucleic acid, an enzyme, a co-enzyme, a nucleotide, an oligonucleotide, a monosaccharide, a polysaccharide, a polymer, a fluorophore, optionally substituted benzene, etc., as long as the direct link of such a molecule to the core structure (in case of R80, e.g., the link to the oxygen atom bound to the phosphorus; or in case of the drug moiety (D), e.g., the link to the group X 18bound to the phosphorus) is aliphatic. An aromatic residue is a substituent, wherein the direct link to the core structure is part of an aromatic system, e.g., an optionally substituted phenyl or triazolyl or pyridyl or nucleotide; as non-limiting example if the direct link of the nucleotide to the core structure is for example via a phenyl-residue. The term “aromatic residue”, as used herein, also includes a heteroaromatic residue.

[0047] The term “peptide” or “polypeptide”, unless otherwise indicated, in general refers toan organic compound comprising two or more amino acids covalently joined by peptide bonds (amide bond). Peptides may be referred to with respect to the number of constituent amino acids, i.e., a dipeptide contains two amino acid residues, a tripeptide contains three, etc. Peptides containing ten or fewer amino acids may be referred to as oligopeptides, while those with more than ten amino acid residues, e.g. with up to about 30 amino acid residues, are polypeptides.

[0048] The term “amino acid”, as used herein, in general refers to an organic compoundhaving a -CH(NH3)-COOH group. In one embodiment, the term “amino acid” refers to a naturally occurring amino acid. As illustrative examples, naturally occurring amino acids include arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, methionine, tryptophan, alanine, isoleucine, leucine, phenylalanine, valine, proline and glycine. However, the term in its broader meaning also encompasses non-naturally occurring amino acids.

[0049] Amino acids and peptides according to the disclosure can also be modified atfunctional groups. Non-limiting examples are saccharides, e.g., N-Acetylgalactosamine(GalNAc), or protecting groups, e.g., Fluorenylmethoxycarbonyl (Fmoc)-modifications or esters.

[0050] The term "antibody", as used herein, is intended to refer to immunoglobulinmolecules, preferably comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains which are typically inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region can comprise e.g. three domains CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain (CL). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is typically composed of three CDRs and up to four FRs arranged from amino-terminus to carboxy-terminus e.g. in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0051] Depending on the amino acid sequence of the constant domain of their heavy chains,intact antibodies can be assigned to different "classes". There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these maybe further divided into 19"subclasses" (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. A preferred class of immunoglobulins for use in the present invention is IgG.

[0052] The heavy-chain constant domains that correspond to the different classes ofantibodies are called [alpha], [delta], [epsilon], [gamma], and [mu], respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. As used herein antibodies are conventionally known antibodies and functional fragments thereof.

[0053] A “human” antibody or antigen-binding fragment thereof is in general defined as onethat is not chimeric (e.g., not “humanized”) and not from (either in whole or in part) a non- human species. A human antibody or antigen-binding fragment thereof can be derived from a human or can be a synthetic human antibody. A “synthetic human antibody” is defined herein as an antibody having a sequence derived, in whole or in part, in silico from synthetic sequences that are based on the analysis of known human antibody sequences. In silico design of a human antibody sequence or fragment thereof can be achieved, for example, by analyzing a database of human antibody or antibody fragment sequences and devising a polypeptide sequence utilizing the data obtained there from. Another example of a human antibody or antigen-binding fragment thereof is one that is encoded by a nucleic acid isolated from a library of antibody sequences of human origin (e.g., such library being based on antibodies taken from a human natural source).

[0054] A “humanized antibody” or humanized antigen-binding fragment thereof is in generaldefined herein as one that is (i) derived from a non-human source (e.g., a transgenic mouse which bears a heterologous immune system), which antibody is based on a human germline sequence; (ii) where amino acids of the framework regions of a non-human antibody are partially exchanged to human amino acid sequences by genetic engineering or (iii) CDR- grafted, wherein the CDRs of the variable domain are from a non-human origin, while one or more frameworks of the variable domain are of human origin and the constant domain (if any) is of human origin.

[0055] A “chimeric antibody” or antigen-binding fragment thereof is in general defined hereinas one, wherein the variable domains are derived from a non-human origin and some or all constant domains are derived from a human origin.

[0056] The term "monoclonal antibody" as used herein in general refers to an antibodyobtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible mutations, e.g., naturally occurring mutations, that may be present in minor amounts. Thus, the term "monoclonal" indicates the character of the antibody as not being a mixture of discrete antibodies. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. In 20addition to their specificity, monoclonal antibody preparations are advantageous in that they are typically uncontaminated by other immunoglobulins. The term "monoclonal” is not to be construed as to require production of the antibody by any particular method. The term monoclonal antibody specifically includes chimeric, humanized and human antibodies.

[0057] "Binding affinity" or “affinity” in general refers to the strength of the total sum of non-covalent interactions between a single binding site of a molecule and its binding partner. Unless indicated otherwise, as used herein, "binding affinity" refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g. an antibody and an antigen). The dissociation constant “KD” is commonly used to describe the affinity between a molecule (such as an antibody) and its binding partner (such as an antigen) i.e. how tightly a ligand binds to a particular protein. Ligand-protein affinities are influenced by non-covalent intermolecular interactions between the two molecules. Affinity can be measured by common methods known in the art, including those described herein. In one embodiment, the "KD" or "KDvalue" according to this invention is measured by using surface plasmon resonance assays using suitable devices including but not limited to Biacore instruments like Biacore T100, Biacore T200, Biacore 2000, Biacore 4000, a Biacore 3000 (GE Healthcare Biacore, Inc.), or a ProteOn XPR36 instrument (Bio-Rad Laboratories, Inc.).

[0058] The term “antibody drug conjugate” or abbreviated ADC is well known to a personskilled in the art, and, as used herein, in general refers to the linkage of an antibody or anantigen binding fragment thereof with a drug, such as a chemotherapeutic agent, a toxin, animmunotherapeutic agent, an imaging probe, and the like.

[0059] The term “small molecule” as used herein in general denotes an organic moleculecomprising at least two carbon atoms, having a molecular weight in the range between 100 and 2000 Dalton, preferably between 100 and 1000 Dalton, and optionally including one or two metal atoms. Optionally, a small molecule may also contain one or more heteroatom(s), such as, for example, N, O, S, P and / or halogen.

[0060] The present disclosure also relates to a “pharmaceutically acceptable salt”. Anypharmaceutically acceptable salt can be used. In particular, the term “pharmaceutically acceptable salt” refers to a salt of a conjugate or compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts have low toxicity and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include, but are not limited to: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- 21naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid,trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) saltsformed when an acidic proton present in the parent compound either is replaced by a metalion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, purely by way of example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. A counterion or anionic counterion can be used in a quaternary amine to maintain electronicneutrality. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–,H2PO4–, HSO4–, sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate,naphthalene–1–sulfonic acid–5–sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0061] As used herein, the term “solvate” may refer to an aggregate that comprises one ormore molecules of a conjugate or compound described herein with one or more molecules of solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the conjugates or compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, while in other cases, the compounds of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.

[0062] A ligand, an inhibitor and a binder can refer to the same compound and may be usedinterchangeably and it would be apparent to a skilled person that each term would be used in a specific context to highlight the function or aspect of the molecule. Specifically, with regards to a ligand / inhibitor and / or binder for von Hippel-Lindau E3 ligase, the terms may be used interchangeably.

[0063] It should be understood that this invention is not limited to the particular methodology,protocols, material, reagents, and substances, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[0064] All publications cited throughout the text of this specification (including all patents,patent application, scientific publications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an 22admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material.

[0065] The content of all documents and patent documents cited herein is incorporated byreference in their entirety.COMPOUNDS ACCORDING TO THE INVENTION

[0066] A first aspect of the inventive compound relates a compound having a structureaccording to structure (I):including a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a solvate thereof or an isotopically enriched molecule thereof; wherein Y^^is CHR^, CR^2, O or NR^; R^^is C1-C12alkyl, C1-C6alkyl, C1-C3alkyl,C1-C12haloalkyl, C1-C6haloalkyl, C1-C3haloalkyl, H, D, CH3 or CD3; Y^is CH or N; Y^is N, O or S; R^is H, D, C1-C6alkyl, C1-C6alkyl halide, C1-C6alkyl azide, S(O)-C1-C6alkyl, S(O)2-C1- C6alkyl, a lone pair of electrons or is not present; Y^is N or CR^; R^is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, -C(O)R^a, - C(O)OR^a, -C(O)NR^bR^c, -S(O)R^d, -S(O)2R^a-S(O)2NR^bR^c, or ^1, wherein the C1-C6alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of ^1, -CN, -C(O)R^a, -23Y^is C(O), S(O)2, CR^1R^or is not present; R^1is H, deuterium, C1-C6alkyl, halogen, or C1-C6haloalkyl; R^is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, - C(O)R^a, -C(O)OR^a, -C(O)NR^bR^c, -S(O)R^d, -S(O)2R^a, -S(O)2NR^bR^c, or ^1, wherein the C1- C6alkyl, C2-C6alkenyl, and C2-C6alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of ^1, -- C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, ^1, or -(C1-C6alkylenyl)-^1; R^c, at each occurrence, is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6haloalkyl, ^1, -(C1-C6alkylenyl)-^1, -(C1-C6alkylenyl)-CN, -(C1-C6alkylenyl)-OR^^, or -(C1- C6 alkylenyl)-C(O)OR^^; R^d, at each occurrence, is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6 haloalkyl, ^1, or -(C1-C6 alkylenyl)-^1; R^d, at each occurrence, is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6 haloalkyl, ^1, -(C1-C6 alkylenyl)-^1, -(C1-C6 alkylenyl)-NR^^R^^, or -(C1-C6 alkylenyl)- N(R^^)C(O)O(R^^); ^1, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each ^1is optionally substituted with 1, 2, 3, 4, or 5 R1^groups;Y^ is N, CH, P(O) or O;G^ is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -C(O)R^a, - C(O)OR^a, -C(O)NR^bR^c, -S(O)2R^a, -S(O)2NR^bR^c, or ^2; wherein the C1-C6 alkyl, C2- C6 alkenyl, and C2-C6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of ^2, -CN, -C(O)R^a, - C(O)OR^a, -C(O)NR^bR^c, -C(O)N(R^b)NR^bR^c, -S(O)R^d, -S(O)2R^a, -S(O)2NR^bR^c, -OR^a, - OC(O)R^d, -NR^bR^c, N(R^b)C(O)R^d, N(R^b)SO2R^d, N(R^b)C(O)OR^d, N(R^b)C(O)NR^bR^c, N(R^b)SO2NR^bR^c, N(R^b)C(NR^bR^c)=NR^bR^c, a lone pair of electrons or is not present; R^a, R^b, and R^c, at each occurrence, are each independently H, alkyl, C2-C6 alkenyl, C2- C6alkynyl, haloalkyl, ^2, -(C1-C6alkylenyl)-^2, -(C1-C6alkylenyl)-OR^^, -(C1-C6alkylenyl)- S(O)2R^^, -(C1-C6 alkylenyl)-S(O)2NR^^R^^, -(C1-C6 alkylenyl)-C(O)R^^, -(C1-C6 alkylenyl)- C(O)OR^^, -(C1-C6alkylenyl)-C(O)NR^^R^^, -(C1-C6alkylenyl)-NR^^R^^, -(C1-C6alkylenyl)- N(R^^)C(O)R^^, -(C1-C6 alkylenyl)-N(R^^)S(O)2R^^, -(C1-C6 alkylenyl)-N(R^^)C(O)O(R^^), -(C1- C6alkylenyl)-N(R^^)C(O)NR^^R^^, or -(C1-C6alkylenyl)-N(R^^)S(O)2NR^^R^^; R^d, at each occurrence, is independently alkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloalkyl, ^2, - (C1-C6alkylenyl)-^2, -(C1-C6alkylenyl)-OR^^, -(C1-C6alkylenyl)-S(O)2R^^, -(C1-C6alkylenyl)- S(O)2NR^^R^^, -(C1-C6 alkylenyl)-C(O)R^^, -(C1-C6 alkylenyl)-C(O)OR^^, -(C1-C6 alkylenyl)- C(O)NR^^R^^, -(C1-C6 alkylenyl)-NR^^R^^, -(C1-C6 alkylenyl)-N(R^^)C(O)R^^, -(C1-C6 alkylenyl)- N(R^^)S(O)2R^^, -(C1-C6 alkylenyl)-N(R^^)C(O)O(R^^), -(C1-C6 alkylenyl)-N(R^^)C(O)NR^^R^^, or 24-(C1-C6 alkylenyl)-N(R^^)S(O)2NR^^R^^; ^2, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each ^2is optionally substituted with 1, 2, 3, 4, or 5 R2^groups; AG1is C(RAG1) or N; AG2is C; AG3is C; and AG4is C(RAG4) or N; wherein one, both or none of AG1and AG4are N; RAG1is H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, NO2, - OR^is R^1, -OC(O)R^is R^2, -OC(O)NR^is R^3R^is R^4, -SR^is R^1, -S(O)2R^is R^1, - S(O)2NR^is R^3R^is R^4, -C(O)R^is R^1, -C(O)OR^is R^1, -C(O)NR^is R^3R^is R^4, -NR^is R^3R^is R^4, -N(R^is R^3)C(O)R^is R^2, -N(R^is R^3)S(O)2R^is R^2, -N(R^is R^3)C(O)O(R^is R^2), -N(R^is R^3)C(O)NR^is R^3R^is R^4, -N(R^is R^3)S(O)2NR^isR^3R^ is R^4, ^3, -(C1-C6 alkylenyl)-CN, -(C1-C6 alkylenyl)-OR^is R^1, -(C1-C6 alkylenyl)- OC(O)R^is R^2, (C1-C6 alkylenyl)-OC(O)NR^is R^3R^is R^4, -(C1-C6 alkyleny|)-S(O)2R^is R^1, -(C1-C6 alkylenyl)-S(O)2NR^is R^3R^is R^4, -(C1-C6 alkylenyl)-C(O)R^is R^1, -(C1- C6 alkylenyl)-C(O)OR^is R^1, -(C1-C6 alkylenyl)-C , -(C1-C6 alkylenyl)- NR^is R^3R^is R^4, -(C1-C6alkylenyl)-N(R^is R^6alkylenyl)-N(R^is R^3)S(O)2R^is R^2, -(C1-C6 alkylenyl)-N(R^is R^3-C6 alkylenyl)-N(R^is R^3)C(O)NR^is R^3R^is R^4, -(C1-C6alkylenyl)is R^3R^is R^4, - (C1-C6 alkylenyl)-CN, or -(C1-C6 alkylenyl)-^3; R^is R^1, R^is R^3, and R^is R^4, at each occurrence, are each independently H, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, ^3, -(C1-C6 alkylenyl)-^3, -(C1- C6alkylenyl)-OR^^, -(C1-C6alkylenyl)-S(O)2R^^, -(C1-C6alkylenyl)-S(O)2NR^^R^^, -(C1- C6 alkylenyl)-C(O)R^^, -(C1-C6 alkylenyl)-C(O)OR^^, -(C1-C6 alkylenyl)-C(O)NR^^R^^, -(C1- C6alkylenyl)-NR^^R^^, -(C1-C6alkylenyl)-N(R^^)C(O)R^^, -(C1-C6alkylenyl)-N(R^^)S(O)2R^^, - (C1-C6 alkylenyl)-N(R^^)C(O)O(R^^), -(C1-C6 alkylenyl)-N(R^^)C(O)NR^^R^^, or -(C1- C6alkylenyl)-N(R^^)S(O)2NR^^R^^; R^is R^2, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6haloalkyl, ^3, -(C1-C6alkylenyl)-^3, -(C1-C6alkylenyl)-OR^^, -(C1-C6alkylenyl)-S(O)2R^^, - (C1-C6 alkylenyl)-S(O)2NR^^R^^, -(C1-C6 alkylenyl)-C(O)R^^, -(C1-C6 alkylenyl)-C(O)OR^^, -(C1- C6alkylenyl)-C(O)NR^^R^^, -(C1-C6alkylenyl)-NR^^R^^, -(C1-C6alkylenyl)-N(R^^)C(O)R^^, -(C1- C6 alkylenyl)-N(R^^)S(O)2R^^, -(C1-C6 alkylenyl)-N(R^^)C(O)O(R^^), -(C1-C6 alkylenyl)- N(R^^)C(O)NR^^R^^, or -(C1-C6alkylenyl)-N(R^^)S(O)2NR^^R^^; ^3, at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle; and each ^3group is optionally substituted with 1, 2, 3, 4, or 5 R4^groups; RAG4is H, D, C1-C3alkyl, halogen, C1-C3haloalkyl, or -CN;R1^, R2^, and R4^, at each occurrence, is independently selected from the group consisting ofoxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, NO2, ^2a, -OR^^, -OC(O)R^^, -OC(O)NR^^R^^, -SR^^, -S(O)2R^^, -S(O)2NR^^R^^, -C(O)R^^, -C(O)OR^^, - C(O)NR^^R^^, -NR^^R^^, -N(R^^)C(O)R^^, -N(R^^)S(O)2R^^, -N(R^^)C(O)O(R^^), - N(R^^)C(O)NR^^R^^, -N(R^^)S(O)2NR^^R^^, -(C1-C6alkylenyl)-CN, -(C1-C6alkylenyl)-^2a, -(C1- C6 alkylenyl)-OR^^, -(C1-C6 alkylenyl)-OC(O)R^^, -(C1-C6 alkylenyl)-OC(O)NR^^R^^, -(C1- 25C6 alkylenyl)-S(O)2R^^, -(C1-C6 alkylenyl)-S(O)2NR^^R^^, -(C1-C6 alkylenyl)-C(O)R^^, -(C1- C6alkylenyl)-C(O)OR^^, -(C1-C6alkylenyl)-C(O)NR^^R^^, -(C1-C6alkylenyl)-NR^^R^^, -(C1- C6 alkylenyl)-N(R^^)C(O)R^^, -(C1-C6 alkylenyl)-N(R^^)S(O)2R^^, -(C1-C6 alkylenyl)- N(R^^)C(O)O(R^^), -(C1-C6alkylenyl)-N(R^^)C(O)NR^^R^^, -(C1-C6alkylenyl)- N(R^^)S(O)2NR^^R^^, or -(C1-C6 alkylenyl)-CN; R^1, R^1, R^1, and R^1, at each occurrence, are each independently H, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, ^2a, -(C1-C6 alkylenyl)-OR^1, -(C1-C6 alkylenyl)- NR^3R^4, -(C^31-C6 alkylenyl)-C(O)NRR^4, or - (C1-C6 alkylenyl)-^2a;R^1, at each occurrence, is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6 haloalkyl, ^2a, or -(C1-C6 alkylenyl)-^2a; ^2a, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each ^2agroup is optionally substituted with 1, 2, 3, 4, or 5 R3^groups; R3^, at each occurrence, is independently oxo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6 haloalkyl, -CN, NO2, -OR^1, -OC(O)R^2, -OC(O)NR^3R^4, -SR^1, -S(O)2R^1, - S(O)2NR^3R^4, -C(O)R^1, -C(O)OR^1, -C(O)NR^3R^4, -NR^3R^4, -N(R^3)C(O)R^2, - N(R^3)S(O)2R^2, -N(R^3)C(O)O(R^2), -N(R^3)C(O)NR^3R^4, -N(R^3)S(O)2NR^3R^4, -(C1- C6alkylenyl)-OR^1, -(C1-C6alkylenyl)-OC(O)R^2, -(C1-C6alkylenyl)-OC(O)NR^3R^4, -(C1- C6 alkylenyl)-S(O)2R^1, -(C1-C6 alkylenyl)-S(O)2NR^3R^4, -(C1-C6 alkylenyl)-C(O)R^1, -(C1- C6alkylenyl)-C(O)OR^1, -(C1-C6alkylenyl)-C(O)NR^3R^4, -(C1-C6alkylenyl)-NR^3R^4, -(C1- C6 alkylenyl)-N(R^3)C(O)R^2, -(C1-C6 alkylenyl)-N(R^3)S(O)2R^2, -(C1-C6 alkylenyl)- N(R^3)C(O)O(R^2), -(C1-C6alkylenyl)-N(R^3)C(O)NR^3R^4, -(C1-C6alkylenyl)- N(R^3)S(O)2NR^3R^4, or -(C1-C6 alkylenyl)-CN;R^1, R^3, and R^4, at each occurrence, are each independently H, C1-C6 alkyl, C2-C6 alkenyl,C2-C6alkynyl, or C1-C6haloalkyl; R^2, at each occurrence, is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1- C6haloalkyl; wherein BG1, BG2, BG3, BG4, BG5, AG2and AG3form a seven membered ring and BG1is C(O), NRBG1a, O, CRBG1bRBG1c, CRBG1b, N, S, Se, S(O), S(O)2, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e, BG2is C(O), NRBG2a, O, CRBG2bRBG2c, CRBG2b, N, S, Se, S(O), S(O)2, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e,BG3 is NRBG3a, CRBG3bRBG3c, CRBG3b, C(O), O, S, N, Se, S(O) or S(O)2,BG4 is NRBG4a, CRBG4bRBG4c, CRBG4b, C(O), O, S, N, Se, S(O) or S(O)2,BG5is C(O), NY^, O, CY^RBG5a, CY^, S, Se, S(O), S(O)2 or P(O)Y^; or wherein BG1, BG2, BG4, BG5, AG2and AG3form a six membered ring and BG1is C(O), NRBG1a, O, N, CRBG1bRBG1c, CRBG1b,S, Se, S(O), S(O)2, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e, BG2is C(O), NRBG2a, O, N, CRBG2bRBG2c, CRBG2b,S, Se, S(O), S(O)2, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e, 26BG3is a bond between BG2and BG4, or BG3is not present, BG2is directly bonded to BG4,BG4 is NRBG4a, CRBG4bRBG4c, CRBG4b, C(O), O, S, N, Se, S(O) or S(O)2,BG5is C(O), NY^, N, O, CY^RBG5a, CY^, S, Se, S(O), S(O)2or P(O)Y^; orwherein BG1, BG2, BG5, AG2 and AG3 form a five membered ring andBG1is C(O), NRBG1a, O, N, CRBG1bRBG1c, CRBG1b,S, Se, S(O), S(O)2, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e, BG2is C(O), NRBG2a, O, N, CRBG2bRBG2c, CRBG2b,S, Se, S(O), S(O)2, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e, BG3and BG4are a bond between BG2and BG5, or BG3and BG4are not present, BG2is directly bonded to BG5, BG5is C(O), NY^, N, O, CY^RBG5a, CY^, S, Se, S(O), S(O)2or P(O)Y^;wherein RBG1a, RBG1b , RBG1c, RBG1d, RBG1e , RBG1e, RBG2a, RBG2b , RBG2c, RBG2d, RBG2e , RBG2e,RBG3a, RBG3b, RBG3c, RBG4a, RBG4b, RBG4c, RBG5a, at each occurrence, are each independently H, D, alcohol, alkenyl, alkyl, alkynyl, amide, amine, amino acid, amino alcohol, amino amide, amino ester, aryl, boryl, ether, ester, halogenyl, heteroaryl, heterocycle, phoshoramidite, phosphinyl, phosphoester, phosphonyl, selenenyl, selenonyl, sulfenyl, sulfonamide, sulfonyl, substituted alcohol, substituted alkene, substituted alkyl, substituted alkyne, substituted amide, substituted amine, substituted aryl, substituted azide, substituted borate, substituted halogen, substituted heteroaromatic, substituted heterocycle, substituted phoshoramidite, substituted phosphinate, substituted phosphoester, substituted phosphonate, substituted selenate, substituted selenyl, substituted sulfonamide, substituted sulfonyl, alkyl alcohol, alkyl amide, alkyl amine, alkyl amino acid, alkyl amino alcohol, alkyl amino amide, alkyl amino ester, alkyl aromatic, alkyl azide, alkyl boronate, alkyl disulfide, alkyl carbonate, alkyl carbamate, alkyl ether, alkyl ester, alkyl halogen, alkyl heterocycle, alkyl heteroaromatic, alkyl phoshoramidite, alkyl phosphinate, alkyl phosphoester, alkyl phosphonyl, alkyl selenate, alkyl sulfenate, alkyl sulfonamide, alkyl thiol, alkyl urea, alkyl thiourea or combinations thereof;wherein Y^^is S(O) RY^^^C(O)RY^, S(O)RY^^ P(O)(RY^) , ORY^, N Y^2 2 HR , OH, O, NH2,CRY^1RY^2C(O)NHRY^^^^ CRY^1RY^2S(O) RY^^^ CRY^1RY^2C( Y^ Y^1 Y^2 Y^2 O)R , CR R S(O)R ^CRY^1RY^2P(O)(RY^)2, CRY^1RY^2ORY^, CRY^1RY^2NHRY^, CRY^1RY^2OH, CRY^1RY^2CHO,CRY^1RY^2NH2, H or D; andwherein RY^at each occurrence, is independently H, O, OH, NH2, C1-C12 alkyl, C1-C12 alcohol, C1-C12 amine, C1-C12 amide, C1-C12 ester, C6-C12 aryl, C4-C12 heterocycle or C5-C12 heteroaryl; wherein RY^1and RY^2at each occurrence, are independently H, D, halogen, C1-C12alkyl, C1- C12alcohol, C1-C12amine, C1-C12amide, C1-C12ester, C6-C12aryl, C4-C12heterocycle or C5- C12 heteroaryl. 27

[0067] Regarding to the form of the compound, general embodiments of the invention relatethat the compound is preferably a combination of two or more of a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a solvate thereof or an isotopically enriched molecule thereof.

[0068] Concerning the biochemical target of the present compound, it is preferred that thecompound is for binding a bromodomain-containing protein. In specific embodiments, thecompound is for binding a bromodomain-containing protein. In more specific embodimentsthe compound is for binding a bromodomain-containing protein. In further specific embodiments, the bromodomain-containing protein is a member of the BET family, preferably the BET family is the bromodomain and extra-terminal domain family. More specifically, the bromodomain-containing protein is BRD2, BRD3, BRD4, BRDT, BRD7 or BRD9. In very specific embodiments, the bromodomain-containing protein is BRD2, BRD3, BRD4 or BRDT. In general, it is preferred that the bromodomain-containing protein is BRD4.

[0069] With respect to the structure of the compound, it is preferred that Y^ is CH.

[0070] In general embodiments according to the invention, it is preferred that Y^ is CH.

[0071] With regards to Y^, it is preferred that Y^ is N. In general, with respect to theembodiments of the substituents bound to Y^, it is preferred that R^is H, D, C1-C3alkyl, C1- C6 alkyl azide, S(O)Me or S(O)2Me. In general, it is preferred that R^is H or D.

[0072] In general embodiments according to the invention, it is preferred that Y^^is NR^. It isfurther preferred that R^^is C1-C3 alkyl, C1-C3 haloalkyl, H, D, CH3 or CD3. In more specific embodiments, R^^is H, D, CH3or CD3. In general, it is preferred that R^^is CH3or CD3.

[0073] Concerning further embodiments regarding the structure of the compound accordingto the invention, it is preferred that structure (I) is according to structure: 28

[0074] In general embodiments, preferably Y^ is CH, CD, C-CN, C-CO2Et, COC(O)NHEt,COC(O)OEt, CCH2CH2F or CCH2CH2-n-morpholine. In specific embodiments, Y^is CH or CD.

[0075] In general, it is preferred that in embodiments of the invention Y^ is CR^1R^. It ispreferred that R^1 is H or D. In further embodiments, R^ is H, D, C1-C6, alkyl, aryl, heteroaryl,heterocycle, cycloalkyl, cycloalkenyl, C1-C6 alkyl, C1-C6 aryl, C1-C6 heteroaryl, C1-C6 heterocycle, C1-C6 cycloalkyl, or C1-C6 cycloalkenyl. In more specific embodiments, it is preferred that R^is H or D.

[0076] It is preferred in general that AG1 is CH or CD. It is preferred in general that AG4 is CHor CD.

[0077] Regarding further embodiments of the structure of the compound according to theinvention, it is preferred that structure (I) is according to structure: 29

[0078] In general embodiments of the invention, it is preferred that G^ is ^2. In furtherembodiments, it it is preferred that G^ is aryl or heteroaryl. In some embodiments, G^ is anazepine, benzimidazole, benzisothiazole, benzisoxazole, benzoazepine, benzofuran, benzopyrazine, benzopyrazole, benzopyridazine, benzotetrazines, benzothiadazole, benzothiazole, benzothiophene, benzotriazines, benzotriazole, benzoxazole, diazine, furan, imidazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, oxazole, phthalazine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrroline, quinoline, tetrazines,tetrazole, thiadazole, thiazole, thiophene, triazines or triazole. In some embodiments, G^ is asubstituted azepine, substituted benzimidazole, substituted benzisothiazole, substituted benzisoxazole, substituted benzoazepine, substituted benzofuran, substituted benzopyrazine, substituted benzopyrazole, substituted benzopyridazine, substituted benzotetrazines, substituted benzothiadazole, substituted benzothiazole, substituted benzothiophene, substituted benzotriazines, substituted benzotriazole, substituted benzoxazole, substituted diazine, substituted furan, substituted imidazole, substituted indole, substituted indolizine, substituted isoquinoline, substituted isothiazole, substituted isoxazole, substituted oxazole, substituted phthalazine, substituted pyrazine, substituted pyrazole, substituted pyridazine, substituted pyridine, substituted pyrimidine, substituted pyrrole, substituted pyrroline, substituted quinoline, substituted tetrazines, substituted tetrazole, substituted thiadazole, substituted thiazole, substituted thiophene, substituted triazines or substituted triazole.

[0079] Concerning that number of substituents that may be present on G^, is G^ is mono, di,tri or tetra substituted. With respect to the embodiments of said substitution, it is preferred 30that G^is at each occurrence, independently substituted by D, F, Cl, Br, C1-C8 alkyl, C1-C8 alkylamine, C1-C8 alkyl-ol, C1-C8 alkyl-thiol, C1-C8 alkyl azide, C1-C8 alkylnitrile, C1-C8 alkyne, C1-C8alkyl-amide, C1-C8alkyl-sulfoxide or C1-C8alkyl-sulfone. More specifically, it is preferred that G^is at each occurrence, independently substituted by D, F, Cl, Br, C1-C6alkyl, C1-C6alkylamine, C1-C6alkyl-ol, C1-C6alkyl-thiol, C1-C6alkyl azide, C1-C6alkylnitrile, C1-C6alkyne, C -C alkyl-amide, C -C alkyl-sulfoxide or C -C alkyl-sulfone. It is preferre ^1 6 1 6 1 6 d that Gis at each occurrence, independently substituted by D, F, Cl, Br, C1-C3alkyl, C1-C3alkylamine, C1-C3 alkyl-ol, C1-C3 alkyl-thiol, C1-C3 alkyl azide, C1-C3 alkylnitrile, C1-C3 alkyne, C1-C3alkyl-amide, C1-C3alkyl-sulfoxide or C1-C3alkyl-sulfone. In very specific embodiments, it is preferred that G^is at each occurrence, independently substituted by D, F, Cl or Br. It is further preferred that G^is at each occurrence, independently substituted by 1, 2 or 3 fluorine(s). It is further preferred that G^is at each occurrence, independently substituted by 1, 2 or 3 deuterium(s). It is preferred that wherein G^is at each occurrence, independentlysubstituted by 1, 2 or 3 C1-C8 alkyls, preferably C1-C6 alkyls, more preferably C1-C3 alkyls. Itis preferred that G^is at each occurrence, independently substituted by 1, 2 or 3 C1-C8 alkylamines, preferably C1-C6 alkylamines, more preferably C1-C3 alkylamines. It is preferred that G^is at each occurrence, independently substituted by 1, 2 or 3 C1-C8 alkyl-ols, preferably C1-C6alkyl-ols, more preferably C1-C3alkyl-ols. It is preferred that G^is at each occurrence, independently substituted by 1, 2 or 3 C1-C8 alkyl thiols, preferably C1-C6 alkyl thiols, more preferably C1-C3alkyl thiols. It is preferred that G^is at each occurrence, independently substituted by 1, 2 or 3 C1-C8 alkyl azides, preferably C1-C6 alkyl azides, more preferably C1-C3 alkyl azides. It is preferred that G^is at each occurrence, independently substituted by 1, 2 or 3 C1-C8 alkyl azides, preferably C1-C6 alkyl azides, more preferably C1- C3alkyl azides. It is preferred that wherein G^is at each occurrence, independently substituted by 1, 2 or 3 C1-C8 alkyl nitriles, preferably C1-C6 alkyl nitriles, more preferably C1- C3 alkyl nitriles. It is preferred that G^is at each occurrence, independently substituted by 1, 2 or 3 C1-C8 alkynes, preferably C1-C6 alkynes, more preferably C1-C3 alkynes. It is preferred that G^is at each occurrence, independently substituted by 1, 2 or 3 C1-C8 alkyl-amides, preferably C1-C6 alkyl-amides, more preferably C1-C3 alkyl-amides. G^is at each occurrence, independently substituted by 1, 2 or 3 C1-C8alkyl sulfoxides, preferably C1-C6alkyl sulfoxides, more preferably C1-C3alkyl sulfoxides. It is preferred that G^is at each occurrence, independently substituted by 1, 2 or 3 C1-C8alkyl sulfones, preferably C1-C6alkyl sulfones, more preferably C1-C3 alkyl sulfones. 31

[0080] In further embodiments, it is preferred that G^ is chosen from any one of thestructures consisting of:32, wherein X is F, Cl, Br, D or CH3 including combinations of two thereof.

[0081] In more specific embodiments, it is preferred that G^ is chosen from any one of thestructures consisting:, wherein X is F, Cl, Br, D or CH3 including combinations of two thereof. It is preferred that X is F, CH3 or both F and CH3. Preferably, X is F.

[0082] In specific embodiments, it is preferred that G^ is.

[0083] With respect to further embodiments of the structure of the compound according tothe invention, it is preferred that structure (I) is according to structure:34

[0084] In General, it is preferred that R^ is H, D, C1-C3 alkyl, C1-C3 alkyl halide, C1-C6 alkylazide, or S(O)2CH3. It is preferred that R^is H or D.

[0085] Regarding further embodiments of the structure of the compound according to theinvention, it is preferred that structure (I) is according to structure: 35

[0086] According to some embodiments of the invention, BG1, BG2, BG3, BG4, BG5, AG2 and AG3form a seven membered ring.

[0087] According to some embodiments of the invention, BG1, BG2, BG4, BG5, AG2 and AG3 forma six membered ring. It is further preferred that in more specific embodiments, BG2is directly bonded to BG4. It is further preferred that in more specific embodiments, BG3is a bondbetween BG2 and BG4, or BG3 is not present. Optionally, the six membered ring formed by BG1,BG2, BG4, BG5, AG2and AG3is aromatic.

[0088] According to some embodiments of the invention, BG1, BG2, BG5, AG2 and AG3 form afive membered ring. It is further preferred that in more specific embodiments, BG2is directly bonded to BG5. It is further preferred that in more specific embodiments, BG3and BG4are a single bond between BG2and BG5, or BG3and BG4are not present. Optionally, the five membered ring formed by BG1, BG2, BG5, AG2and AG3is aromatic.

[0089] In general embodiments according to the invention, it is preferred that BG1 is C(O),NRBG1a, O, CRBG1bRBG1c, CRBG1b, N, S, Se, S(O), S(O)2, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e. It is preferred that BG1is C(O), NRBG1a, CRBG1bRBG1c, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e. It is preferred that BG1is C(O), NRBG1aor CRBG1bRBG1c.

[0090] Concerning BG2 in general, it is preferred that BG2 is C(O), NRBG2a, O, CRBG2bRBG2c,CRBG2b, N, S, Se, S(O), S(O)2, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e. Preferably, BG236is C(O), NRBG2a, CRBG2bRBG2c, P(O)ORBG2d, P(O)NHRBG2e or P(O)CH2RBG2e. It is preferred thatBG2is C(O), NRBG2aor CRBG2bRBG2c.

[0091] With respect to BG3, in general it is preferred that BG3 is NRBG3a, CRBG3bRBG3c, CRBG3b,C(O), O, S, N, Se, S(O) or S(O)2. It is preferred that BG3 is NRBG3a, CRBG3bRBG3c or C(O).

[0092] Regarding BG4, in general it is preferred that BG4 is NRBG4a, CRBG4bRBG4c, CRBG4b,C(O), O, S, N, Se, S(O) or S(O)2. It is preferred that BG4 is NRBG4a, CRBG4bRBG4c, C(O), O, S,Se, S(O) or S(O)2.

[0093] In general embodiments according to the invention, it is preferred that BG5 is C(O),NY^, CY^RBG5a, CY^, O, S, Se, S(O), S(O)2or P(O)Y^. Preferably, BG5is C(O), NY^, CY^RBG5a, CY^, S(O), S(O)2 or P(O)Y^. It is preferred that BG5is C(O), NY^, CY^RBG5aor CY^.

[0094] In general embodiments according to the invention, it is preferred that Y^^isS(O)^ ^ ^2RY^^C(O)RY , S(O)RY ^ P(O)(RY^)2, ORY^, NHRY^, OH, O, NH2, CRY^1RY^2C(O)NHRY^^^^CRY^1RY^2S(O) RY^^^ CRY^1RY^2C Y^ Y^1 Y^2 Y^ Y^1 Y^2 Y^2 (O)R , CR R S(O)R ^ CR R P(O)(R )2,CRY^1RY^2ORY^, CRY^1RY^2NHRY^, CRY^1RY^2OH, CRY^1RY^2CHO, CRY^1RY^2NH2, H or D. Inmore specific embodiments, it is preferred that Y^^is S(O)2RY^^^ S(O)RY^^CRY^1RY^2C(O)NHRY^^^^ CRY^1RY^2S(O)2RY^^^ CRY^1RY^2C(O)RY^, CRY^1RY^2S(O)RY^^CRY^1RY^2P(O)(RY^)2, CRY^1RY^2NHRY^, H or D. In very specific embodiments, it is preferred that Y^^is S(O)2RY^^^ CRY^1RY^2C(O)NHRY^^^^ CRY^1RY^2S(O)2RY^^^ CRY^1RY^2C(O)RY^ orCRY^1RY^2P(O)(RY^)2.

[0095] Concerning the Y^^substituent RY^, in general it is preferred that RY^ at eachoccurrence, is independently H, O, OH, NH2, C1-C12 alkyl, C1-C12 alcohol, C1-C12 amine, C1-C12amide, C1-C12ester, C6-C12aryl, C4-C12heterocycle or C5-C12heteroaryl. Preferably, RY^at each occurrence, is independently H, O, OH, NH2, C1-C10 alkyl, C1-C10 alcohol, C1-C10 amine, C1-C10amide, C1-C10ester, C6-C10aryl, C4-C10heterocycle or C5-C10heteroaryl. More preferably, RY^at each occurrence, is independently H, O, OH, NH2, C1-C8 alkyl, C1-C8 alcohol, C1-C8amine, C1-C8amide, C1-C8ester, C6-C8aryl, C4-C8heterocycle or C5-C8heteroaryl. More preferably, RY^ at each occurrence, is independently H, O, OH, NH2, C1-C6alkyl, C1-C6alcohol, C1-C6amine, C1-C6amide, C1-C6ester, C6-C6aryl, C4-C6heterocycle orC5-C6 heteroaryl. More preferably, wherein RY^ at each occurrence, is independently H, O,OH, NH2, C1-C5alkyl, C1-C5alcohol, C1-C5amine, C1-C5amide, C1-C5ester, C4-C5heterocycle or C5heteroaryl. More preferably, RY^at each occurrence, is independently H, O,OH, NH2, C1-C4 alkyl, C1-C4 alcohol, C1-C4 amine, C1-C4 amide or C1-C4 ester. Morepreferably, RY^at each occurrence, is independently H, O, OH, NH2, C1-C3alkyl, C1-C3alcohol, C1-C3amine, C1-C3amide or C1-C3ester. In specific embodiments, it is preferredthat RY^ is CH3, OCH3, Et, O, OH or H.

[0096] With respect to the substituents RY^1 and RY^2, it is preferred that at each occurrence,are independently H, D, O, OH, NH2, halogen, C1-C12 alkyl, C1-C12 alcohol, C1-C12 amine, C1- 37C amide, C -C ester, C -C aryl, C -C heterocycle 2Y^1 12 1 12 6 12 4 12 or C5-C1 heteroaryl. Preferably, R and RY^2at each occurrence, are independently H, D, O, OH, NH2, halogen, C1-C10alkyl, C1- C10alcohol, C1-C10amine, C1-C10amide, C1-C10ester, C6-C10aryl, C4-C10heterocycle or C5- C10 heteroaryl. More preferably, RY^1and RY^2at each occurrence, are independently H, D, O, OH, NH2, halogen, C1-C8alkyl, C1-C8alcohol, C1-C8amine, C1-C8amide, C1-C8ester, C6-C8aryl, C4-C8 heterocycle or C5-C8 heteroaryl. More preferably, RY^1and RY^2at each occurrence, are independently H, D, O, OH, NH2, halogen, C1-C6alkyl, C1-C6alcohol, C1-C6amine, C1-C6 amide, C1-C6 ester, C6-C6 aryl, C4-C6 heterocycle or C5-C6 heteroaryl. More preferably, RY^1and RY^2at each occurrence, are independently H, D, O, OH, NH2, F, Cl, Br, C1-C5 alkyl, C1-C5 alcohol, C1-C5 amine, C1-C5 amide, C1-C5 ester, C4-C5 heterocycle or C5 heteroaryl. More preferably, RY^1and RY^2at each occurrence, are independently H, D, O, OH, NH2, F, Cl, Br, C1-C4 alkyl, C1-C4 alcohol, C1-C4 amine, C1-C4 amide or C1-C4 ester. More preferably, RY^1and RY^2at each occurrence, are independently H, D, O, OH, NH2, F, Cl, C1- C3alkyl, C1-C3alcohol, C1-C3amine, C1-C3amide or C1-C3ester. More preferably, RY^1and RY^2at each occurrence, are independently H, D, F, CH3, OCH3, Et, O or OH. In specificembodiments, RY^1 is H or D. In specific embodiments, RY^2 is H or D.

[0097] Regarding further embodiments of the structure of Y^, it is preferred that Y^ is selectedfrom the group of structures consisting of38.

[0098] With regards to the stereogenicity of BG5, in some embodiments it is preferred that BG5is chiral. Preferably, BG5is enantioenriched. It is preferred that BG5is enantioenriched and has an enantiomeric ratio of the predominant enantiomer to the minor enantiomer (calculated as the peak area of the predominant enantiomer / peak area of the minor enantiomer) in the range of from 25 : 1 to 1,000,000 :1, preferably in the range of from 50 : 1 to 100,000 : 1, more preferably in the range of from 100 : 1 to 10,000 : 1, more preferably in the range of from 200 : 1 to 1,000 : 1, more preferably in the range of from 250 : 1 to 500 : 1, determined by HPLC equipped with a chiral stationary phase column and a UV-Vis diode array detector. It is preferred that BG5is enantiopure determined by HPLC equipped with a chiral stationary phase column and a UV-Vis diode array detector, wherein preferably only the predominant enantiomer is detected and the minor enantiomer, when present, is present in a concentration beyond the detection limits UV-Vis diode array detector. It is preferred that BG5has a (+) optical rotation optionally according to ISO 592-1998. It is preferred that BG5 has a(-) optical rotation optionally according to ISO 592-1998. It is preferred that the predominantenantiomer of BG5 has an S configuration. It is preferred that the predominant enantiomer ofBG5has an R configuration.

[0099] In general embodiments according to the invention, it is preferred that RBG1a, RBG1b ,, RBG4a, RBG4b, RBG5a, at each occurrence, are each independently H, D, alcohol, alkenyl, alkyl, alkynyl, amide, amine, amino acid, amino alcohol, amino amide, amino ester, aryl,boryl, ether, ester, halogenyl, heteroaryl, heterocycle, phoshoramidite, phosphinyl,phosphoester, phosphonyl, selenenyl, selenonyl, sulfenyl, sulfonamide, sulfonyl or combinations thereof. Preferably, wherein RBG1a, RBG1b, RBG1c, RBG1d, RBG1e, RBG1e, RBG2a,occurrence, are each independently H, D, substituted alcohol, substituted alkene, substituted 39alkyl, substituted alkyne, substituted amide, substituted amine, substituted aryl, substituted azide, substituted borate, substituted halogen, substituted heteroaromatic, substituted heterocycle, substituted phoshoramidite, substituted phosphinate, substituted phosphoester, substituted phosphonate, substituted selenate, substituted selenyl, substituted sulfonamide, substituted sulfonyl or combinations thereof. More preferably, wherein RBG1a, RBG1b, RBG1c, RBG1d, RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d, RBG2e, RBG2e, RBG3a, RBG3b, RBG3c, RBG4a, RBG4b, RBG4c, RBG5a, at each occurrence, are each independently H, D, alkyl alcohol, alkyl amide, alkyl amine, alkyl amino acid, alkyl amino alcohol, alkyl amino amide, alkyl amino ester, alkyl aromatic, alkyl azide, alkyl boronate, alkyl disulfide, alkyl carbonate, alkyl carbamate, alkyl ether, alkyl ester, alkyl halogen, alkyl heterocycle, alkyl heteroaromatic, alkyl phoshoramidite, alkyl phosphinate, alkyl phosphoester, alkyl phosphonyl, alkyl selenate, alkyl sulfenate, alkylsulfonamide, alkyl thiol, alkyl urea, alkyl thiourea or combinations thereof. More preferably,RBG1a, RBG1b, RBG1c, RBG1d, RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d, RBG2e, RBG2e, RBG3a, RBG3b, RBG3c, RBG4a, RBG4b, RBG4c, RBG5aat each occurrence, are each independently suitable for linking further molecules or are H or D. More preferably, RBG1a, RBG1b, RBG1c, RBG1d, RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d, RBG2eat each occurrence, are each independently suitable for linking further molecules or are H or D. More preferably, RBG1a, RBG1b, RBG1c, RBG1d, RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d, RBG2eat each occurrence, are each independently a linkergroup or are H or D. It is further preferred that RBG1a, RBG1b , RBG1c, RBG1d, RBG1e , RBG1e, RBG2a,RBG2b, RBG2c, RBG2d, RBG2e, RBG2e, RBG3a, RBG3b, RBG3c, RBG4a, RBG4b, RBG4c, RBG5aat each occurrence, are each independently a linker group.

[0100] Regarding further embodiments of the structure of the substituents RBG1a,, RBG2b, RBG2c, RBG2d, RBG2e, RBG2e, RBG3a, RBG3b, ther preferred that RBG1a, RBG1b, RBG1c, RBG1d, RBG1e,, RBG2e, RBG3a, RBG3b, RBG3c, RBG4a, RBG4b, RBG4c, RBG5aat each occurrence, are each independently chosen from the group of structures consisting of:40wherein Y^is a N, C or P atom bound within the BG1, BG2, BG3, BG4, BG5, AG2and AG37 membered ring, the BG1, BG2, BG4, BG5, AG2and AG36 membered ring or the BG1, BG2, BG5, AG2and AG35 membered ring;R^is H, D, C1-C5 alkyl, alkynyl, benzyl, t-boc, phenoxy, PMB, a ligand for a further protein or an amino acid residue of an antibody; Z^is at each occurrence, each independently C6-C12aryl, alkynyl, amino acid, C5-C12cycloalkane or C5-C12heterocycle; 41wherein when present, the end methylene group of an end subunit of a polyethylene glycollinker is bound to, optionally having the equivalent O replaced by, a C, N, O, P or S atomcomprised by Y^, X^and / or Z^; i^is, at each occurrence, each independently in the range of from 1 to 24, preferably in the range of from 2 to 22, more preferably in the range of from 2 to 20, more preferably in the range of from 3 to 18, more preferably in the range of from 4 to 16, more preferably in the range of from 6 to 14; j^is, at each occurrence, each independently in the range of from 1 to 6, preferably in the range of from 1 to 5, more preferably in the range of from 1 to 4, more preferably in the range of from 1 to 3, more preferably in the range of from 1 to 2; k^is, at each occurrence, each independently in the range of from 1 to 12, preferably of from 2 to 10, more preferably of from 2 to 8, more preferably of from 2 to 6, more preferably of from 2 to 5, more preferably of from 2 to 4, more preferably of from 2 to 3; z^is in the range of from 1 to 4, preferably in the range of 1 to 3, more preferably in the range of 1 to 2. Preferably, said structure is independently chosen for each occurrence of RBG1a,thereof. More preferably, said structure is independently chosen for each occurrence of RBG1a, RBG1b, RBG1c, RBG1d, RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2dor RBG2e. It is further preferred that Z^is chosen from the group of structures consisting of:42.

[0101] In embodiments related to the substituents RBG1a, RBG1b , RBG1c, RBG1d, RBG1e ,wherein i^is, at each occurrence, each independently in the range of from 1 to 24, preferably in the range of from 2 to 22, more preferably in the range of from 2 to 20, more preferably in the range of from 3 to 18, more preferably in the range of from 4 to 16, more preferably in the range of from 6 to 14; j^is, at each occurrence, each independently in the range of from 1 to 6, preferably in therange of from 1 to 5, more preferably in the range of from 1 to 4, more preferably in the rangeof from 1 to 3, more preferably in the range of from 1 to 2. More preferably, said structure is independently chosen for each occurrence of RBG1a, RBG1b, RBG1c, RBG1d, RBG1e, RBG1e, RBG2a,combinations thereof. 43

[0102] Concerning specific embodiments of the structure of the compound accordingto the invention, it is preferred that structure (I) is according to structure:

[0103] With respect to more specific embodiments of the structure of the compoundaccording to the invention, it is preferred that structure (I) is selected from the group of structures consisting of:44wherein BG5is N, CH or CD, wherein BG2is C(O), NRBG2aor CRBG2bRBG2c, and wherein BG1is C(O), NRBG1aor CRBG1bRBG1c.

[0104] In very specific embodiments of the structure of the compound according tothe invention, it is preferred that structure (I) is selected from the group of structures consisting of:49505455ITEMS OF THE INVENTION

[0105] The invention relates the following items:1. A compound having a structure according to structure (I):56including a pharmaceutically acceptable salt thereof, an enantiomer thereof, adiastereomer thereof, a solvate thereof or an isotopically enriched molecule thereof;wherein Y^^is CHR^, CR^2, O or NR^; R^^is C1-C12alkyl, C1-C6alkyl, C1-C3alkyl,C1-C12haloalkyl, C1-C6haloalkyl, C1-C3haloalkyl, H, D, CH3 or CD3; Y^is CH or N;Y^ is N, O or S;R^ is H, D, C1-C6 alkyl, C1-C6 alkyl halide, C1-C6 alkyl azide, S(O)-C1-C6 alkyl, S(O)2-C1-C6 alkyl, a lone pair of electrons or is not present;Y^is N or CR^; R^is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, - C(O)R^a, -C(O)OR^a, -C(O)NR^bR^c, -S(O)R^d, -S(O)2R^a-S(O)2NR^bR^c, or ^1, wherein the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of ^1, -CN, -C(O)R^a, -C(O)OR^a, -C(O)NR^bR^c, -C(O)N(R^b)NR^bR^c, -S(O)R^d, -S(O)2R^a, -S(O)2NR^bR^c, -OR^a, -OC(O)R^d, -NR^bR^c, N(R^b)C(O)R^d, N(R^b)SO2R^d, N(R^b)C(O)OR^d, N(R^b)C(O)NR^bR^c, N(R^b)SO2NR^bR^c, and N(R^b)C(NR^bR^c)=NR^bR^c; Y^is C(O), S(O)2, CR^1R^or is not present; R^1is H, deuterium, C1-C6 alkyl, halogen, or C1-C6 haloalkyl; R^is H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6haloalkyl, -C(O)R^a, -C(O)OR^a, -C(O)NR^bR^c, -S(O)R^d, -S(O)2R^a, -S(O)2NR^bR^c, or ^1, wherein the C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of ^1, -CN, -C(O)R^a, -C(O)OR^a,-C(O)NR^bR^c, -C(O)N(R^b)NR^bR^c, - S(O)R^d, -S(O)2R^a, -S(O)2NR^bR^c, -OR^a, -OC(O)R^d, -NR^bR^c, N(R^b)C(O)R^d, N(R^b)SO2R^d, N(R^b)C(O)OR^d, N(R^b)C(O)NR^bR^c, N(R^b)SO2NR^bR^c, and N(R^b)C(NR^bR^c)=NR^bR^c; R^a, R^b, R^c, R^a, and R^b, at each occurrence, are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, ^1, or -(C1-C6 alkylenyl)-^1; R^c, at each occurrence, is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, ^1, -(C1-C6 alkylenyl)-^1, -(C1-C6 alkylenyl)-CN, -(C1-C6 alkylenyl)- OR^^, or -(C1-C6 alkylenyl)-C(O)OR^^; R^d, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6haloalkyl, ^1, or -(C1-C6alkylenyl)-^1; R^d, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6haloalkyl, ^1, -(C1-C6alkylenyl)-^1, -(C1-C6alkylenyl)-NR^^R^^, or -(C1-C6alkylenyl)- N(R^^)C(O)O(R^^); ^1, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each ^1is optionally substituted with 1, 2, 3, 4, or 5 R1^groups;Y^ is N, CH, P(O) or O;G^ is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C ^6 haloalkyl, -C(O)R a, -C(O)OR^a, -C(O)NR^bR^c, -S(O)2R^a, -S(O)2NR^bR^c, or ^2; wherein the C1-C6 alkyl, C2- C6 alkenyl, and C2-C6 alkynyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of ^2, -CN, - 57C(O)R^a, -C(O)OR^a, -C(O)NR^bR^c, -C(O)N(R^b)NR^bR^c, -S(O)R^d, -S(O)2R^a, - S(O)2NR^bR^c, -OR^a, -OC(O)R^d, -NR^bR^c, N(R^b)C(O)R^d, N(R^b)SO2R^d, N(R^b)C(O)OR^d, N(R^b)C(O)NR^bR^c, N(R^b)SO2NR^bR^c, N(R^b)C(NR^bR^c)=NR^bR^c, a lone pair of electrons or is not present; R^a, R^b, and R^c, at each occurrence, are each independently H, alkyl, C2-C6alkenyl, C2-C6 alkynyl, haloalkyl, ^2, -(C1-C6 alkylenyl)-^2, -(C1-C6 alkylenyl)-OR^^, -(C1- C6alkylenyl)-S(O)2R^^, -(C1-C6alkylenyl)-S(O)2NR^^R^^, -(C1-C6alkylenyl)-C(O)R^^, - (C1-C6 alkylenyl)-C(O)OR^^, -(C1-C6 alkylenyl)-C(O)NR^^R^^, -(C1-C6 alkylenyl)- NR^^R^^, -(C1-C6alkylenyl)-N(R^^)C(O)R^^, -(C1-C6alkylenyl)-N(R^^)S(O)2R^^, -(C1- C6 alkylenyl)-N(R^^)C(O)O(R^^), -(C1-C6 alkylenyl)-N(R^^)C(O)NR^^R^^, or -(C1- C6alkylenyl)-N(R^^)S(O)2NR^^R^^; R^d, at each occurrence, is independently alkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloalkyl, ^2, -(C1-C6alkylenyl)-^2, -(C1-C6alkylenyl)-OR^^, -(C1-C6alkylenyl)- S(O)2R^^, -(C1-C6 alkylenyl)-S(O)2NR^^R^^, -(C1-C6 alkylenyl)-C(O)R^^, -(C1- C6alkylenyl)-C(O)OR^^, -(C1-C6alkylenyl)-C(O)NR^^R^^, -(C1-C6alkylenyl)-NR^^R^^, - (C1-C6 alkylenyl)-N(R^^)C(O)R^^, -(C1-C6 alkylenyl)-N(R^^)S(O)2R^^, -(C1-C6 alkylenyl)- N(R^^)C(O)O(R^^), -(C1-C6alkylenyl)-N(R^^)C(O)NR^^R^^, or -(C1-C6alkylenyl)- N(R^^)S(O)2NR^^R^^; ^2, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each ^2is optionally substituted with 1, 2, 3, 4, or 5 R2^groups; AG1is C(RAG1) or N; AG2is C; AG3is C; and AG4is C(RAG4) or N; wherein one, both or none of AG1and AG4are N; RAG1is H, D, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, C1-C6haloalkyl, -CN, NO2, -OR^is R^1, -OC(O)R^is R^2, -OC(O)NR^is R^3R^is R^4, -SR^is R^1, - S(O)2R^is R^1, -S(O)2NR^is R^3R^is R^4, -C(O)R^is R^1, -C(O)OR^is R^1, - C(O)NR^is R^3R^is R^4, -NR^is R^3R^is R^4, -N(R^is R^3)C(O)R^is R^2, -N(R^is R^3)S(O)2R^is R^2, -N(R^is R^3)C(O)O(R^is R^2), -N(R^is R^3)C(O)NR^is R^3R^is R^4, -N(R^ is R^3)S(O)2NR^ is R^3R^ is R^4, ^3, -(C1-C6 alkylenyl)-CN, -(C1-C6alkylenyl)-OR^is R^1, -(C1-C6alkylenyl)-OC(O)R^is R^2, (C1-C6alkylenyl)- is R^4, -(C1-C6 alkyleny|)-S(O)2R^is R^1, -(C1-C6 alkylenyl)- s R^4, -(C1-C6alkylenyl)-C(O)R^is R^1, -(C1-C6alkylenyl)- 1-C6 alkylenyl)-C(O)NR^is R^3R^is R^4, -(C1-C6 alkylenyl)-NR^-C6alkylenyl)-N(R^is R^3)C(O)R^is R^2, -(C1-C6alkylenyl)-N(R^2, -(C1-C6 alkylenyl)-N(R^is R^3)C(O)O(R^is R^2), -(C1- C6alkylenyl)-N(R^is R^3)C(O)NR^is R^3R^is R^4, -(C1-C6alkylenyl)-N(R^is R^3)S(O)2NR^is R^3R^is R^4, -(C1-C6 alkylenyl)-CN, or -(C1-C6 alkylenyl)-^3; R^is R^1, R^is R^3, and R^is R^4, at each occurrence, are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, ^3, -(C1-C6 alkylenyl)-^3, - (C1-C6alkylenyl)-OR^^, -(C1-C6alkylenyl)-S(O)2R^^, -(C1-C6alkylenyl)-S(O)2NR^^R^^, - (C1-C6 alkylenyl)-C(O)R^^, -(C1-C6 alkylenyl)-C(O)OR^^, -(C1-C6 alkylenyl)- C(O)NR^^R^^, -(C1-C6alkylenyl)-NR^^R^^, -(C1-C6alkylenyl)-N(R^^)C(O)R^^, -(C1- C6 alkylenyl)-N(R^^)S(O)2R^^, -(C1-C6 alkylenyl)-N(R^^)C(O)O(R^^), -(C1-C6 alkylenyl)- N(R^^)C(O)NR^^R^^, or -(C1-C6alkylenyl)-N(R^^)S(O)2NR^^R^^; R^is R^2, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2- C6alkynyl, C1-C6haloalkyl, ^3, -(C1-C6alkylenyl)-^3, -(C1-C6alkylenyl)-OR^^, -(C1- C6 alkylenyl)-S(O)2R^^, -(C1-C6 alkylenyl)-S(O)2NR^^R^^, -(C1-C6 alkylenyl)-C(O)R^^, - 58(C1-C6alkylenyl)-C(O)OR^^, -(C1-C6alkylenyl)-C(O)NR^^R^^, -(C1-C6alkylenyl)- NR^^R^^, -(C1-C6 alkylenyl)-N(R^^)C(O)R^^, -(C1-C6 alkylenyl)-N(R^^)S(O)2R^^, -(C1- C6alkylenyl)-N(R^^)C(O)O(R^^), -(C1-C6alkylenyl)-N(R^^)C(O)NR^^R^^, or -(C1- C6 alkylenyl)-N(R^^)S(O)2NR^^R^^; ^3, at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle; and each ^3group is optionally substituted with 1, 2, 3, 4, or 5 R4^groups; RAG4is H, D, C1-C3 alkyl, halogen, C1-C3 haloalkyl, or -CN;R1^, R2^, and R4^, at each occurrence, is independently selected from the groupconsisting of oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, - CN, NO2, ^2a, -OR^^, -OC(O)R^^, -OC(O)NR^^R^^, -SR^^, -S(O)2R^^, -S(O)2NR^^R^^, - C(O)R^^, -C(O)OR^^, -C(O)NR^^R^^, -NR^^R^^, -N(R^^)C(O)R^^, -N(R^^)S(O)2R^^, - N(R^^)C(O)O(R^^), -N(R^^)C(O)NR^^R^^, -N(R^^)S(O)2NR^^R^^, -(C1-C6alkylenyl)-CN, - (C1-C6 alkylenyl)-^2a, -(C1-C6 alkylenyl)-OR^^, -(C1-C6 alkylenyl)-OC(O)R^^, -(C1- C6alkylenyl)-OC(O)NR^^R^^, -(C1-C6alkylenyl)-S(O)2R^^, -(C1-C6alkylenyl)- S(O)2NR^^R^^, -(C1-C6 alkylenyl)-C(O)R^^, -(C1-C6 alkylenyl)-C(O)OR^^, -(C1- C6alkylenyl)-C(O)NR^^R^^, -(C1-C6alkylenyl)-NR^^R^^, -(C1-C6alkylenyl)- N(R^^)C(O)R^^, -(C1-C6 alkylenyl)-N(R^^)S(O)2R^^, -(C1-C6 alkylenyl)-N(R^^)C(O)O(R^^), -(C1-C6alkylenyl)-N(R^^)C(O)NR^^R^^, -(C1-C6alkylenyl)-N(R^^)S(O)2NR^^R^^, or -(C1- C6 alkylenyl)-CN; R^1, R^1, R^1, and R^1, at each occurrence, are each independently H, C1-C6alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, ^2a, -(C1-C6 alkylenyl)-OR^1, -(C1-C6 alkylenyl)-NR^3R^4, -(C1-C6 alkylenyl)-C(O)NR^3R^4, or - (C1-C6 alkylenyl)-^2a;R^1, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6haloalkyl, ^2a, or -(C1-C6alkylenyl)-^2a;^2a, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, orcycloalkenyl; and each ^2agroup is optionally substituted with 1, 2, 3, 4, or 5 R3^groups; R3^, at each occurrence, is independently oxo, C1-C6alkyl, C2-C6alkenyl, C2- C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, NO2, -OR^1, -OC(O)R^2, -OC(O)NR^3R^4, - SR^1, -S(O)2R^1, -S(O)2NR^3R^4, -C(O)R^1, -C(O)OR^1, -C(O)NR^3R^4, -NR^3R^4, -N(R^3)C(O)R^2, -N(R^3)S(O)2R^2, -N(R^3)C(O)O(R^2), -N(R^3)C(O)NR^3R^4, -N(R^3)S(O)2NR^3R^4, -(C1-C6alkylenyl)-OR^1, -(C1-C6alkylenyl)-OC(O)R^2, -(C1- C6 alkylenyl)-OC(O)NR^3R^4, -(C1-C6 alkylenyl)-S(O)2R^1, -(C1-C6 alkylenyl)- S(O)2NR^3R^4, -(C1-C6alkylenyl)-C(O)R^1, -(C1-C6alkylenyl)-C(O)OR^1, -(C1- C6 alkylenyl)-C(O)NR^3R^4, -(C1-C6 alkylenyl)-NR^3R^4, -(C1-C6 alkylenyl)- N(R^3)C(O)R^2, -(C1-C6alkylenyl)-N(R^3)S(O)2R^2, -(C1-C6alkylenyl)- N(R^3)C(O)O(R^2), -(C1-C6 alkylenyl)-N(R^3)C(O)NR^3R^4, -(C1-C6 alkylenyl)- N(R^3)S(O)2NR^3R^4, or -(C1-C6alkylenyl)-CN; R^1, R^3, and R^4, at each occurrence, are each independently H, C1-C6 alkyl, C2- C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R^2, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6haloalkyl;wherein BG1, BG2, BG3, BG4, BG5, AG2 and AG3 form a seven membered ring andBG1is C(O), NRBG1a, O, CRBG1bRBG1c, CRBG1b, N, S, Se, S(O), S(O)2, P(O)ORBG1d, 59P(O)NHRBG1eor P(O)CH2RBG1e, BG2is C(O), NRBG2a, O, CRBG2bRBG2c, CRBG2b, N, S, Se, S(O), S(O)2, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e,BG3 is NRBG3a, CRBG3bRBG3c, CRBG3b, C(O), O, S, N, Se, S(O) or S(O)2,BG4 is NRBG4a, CRBG4bRBG4c, CRBG4b, C(O), O, S, N, Se, S(O) or S(O)2,BG5is C(O), NY^, O, CY^RBG5a, CY^, S, Se, S(O), S(O)2 or P(O)Y^; orwherein BG1, BG2, BG4, BG5, AG2 and AG3 form a six membered ring andBG1is C(O), NRBG1a, O, N, CRBG1bRBG1c, CRBG1b,S, Se, S(O), S(O)2, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e, BG2is C(O), NRBG2a, O, N, CRBG2bRBG2c, CRBG2b,S, Se, S(O), S(O)2, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e, BG3is a bond between BG2and BG4, or BG3is not present, BG2is directly bonded to BG4,BG4 is NRBG4a, CRBG4bRBG4c, CRBG4b, C(O), O, S, N, Se, S(O) or S(O)2,BG5is C(O), NY^, N, O, CY^RBG5a, CY^, S, Se, S(O), S(O)2or P(O)Y^; orwherein BG1, BG2, BG5, AG2 and AG3 form a five membered ring andBG1is C(O), NRBG1a, O, N, CRBG1bRBG1c, CRBG1b,S, Se, S(O), S(O)2, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e, BG2is C(O), NRBG2a, O, N, CRBG2bRBG2c, CRBG2b,S, Se, S(O), S(O)2, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e, BG3and BG4are a bond between BG2and BG5, or BG3and BG4are not present, BG2is directly bonded to BG5, BG5is C(O), NY^, N, O, CY^RBG5a, CY^, S, Se, S(O), S(O)2or P(O)Y^; wherein RBG1a, RBG1b, RBG1c, RBG1d, RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d, RBG2e, RBG2e, RBG3a, RBG3b, RBG3c, RBG4a, RBG4b, RBG4c, RBG5a, at each occurrence, are each independently H, D, alcohol, alkenyl, alkyl, alkynyl, amide, amine, amino acid, amino alcohol, amino amide, amino ester, aryl, boryl, ether, ester, halogenyl, heteroaryl, heterocycle, phoshoramidite, phosphinyl, phosphoester, phosphonyl, selenenyl, selenonyl, sulfenyl, sulfonamide, sulfonyl, substituted alcohol, substituted alkene, substituted alkyl, substituted alkyne, substituted amide, substituted amine, substituted aryl, substituted azide, substituted borate, substituted halogen, substituted heteroaromatic, substituted heterocycle, substituted phoshoramidite, substituted phosphinate, substituted phosphoester, substituted phosphonate, substituted selenate, substituted selenyl, substituted sulfonamide, substituted sulfonyl, alkyl alcohol, alkyl amide, alkyl amine, alkyl amino acid, alkyl amino alcohol, alkyl aminoamide, alkyl amino ester, alkyl aromatic, alkyl azide, alkyl boronate, alkyl disulfide,alkyl carbonate, alkyl carbamate, alkyl ether, alkyl ester, alkyl halogen, alkyl heterocycle, alkyl heteroaromatic, alkyl phoshoramidite, alkyl phosphinate, alkyl phosphoester, alkyl phosphonyl, alkyl selenate, alkyl sulfenate, alkyl sulfonamide,alkyl thiol, alkyl urea, alkyl thiourea or combinations thereof;wherein Y^^is S(O) RY^^^C(O)RY^, S( Y^ Y^ Y^ Y^2 O)R ^ P(O)(R )2, OR , NHR , OH, O, NH2,CRY^1RY^2C(O)NHRY^^^^ CRY^1RY^2S(O) ^ ^ ^ ^ ^2RY ^^ CRY 1RY 2C(O)RY , CRY 1RY^2S(O)RY^^CRY^1RY^2P(O)(RY^)2, CRY^1RY^2ORY^, CRY^1RY^2NHRY^, CRY^1RY^2OH, CRY^1RY^2CHO,CRY^1RY^2NH2, H or D; and60wherein RY^at each occurrence, is independently H, O, OH, NH2, C1-C12alkyl, C1-C12alcohol, C1-C12 amine, C1-C12 amide, C1-C12 ester, C6-C12 aryl, C4-C12 heterocycle or C5-C12heteroaryl; wherein RY^1and RY^2at each occurrence, are independently H, D, halogen, C1-C12 alkyl, C1-C12alcohol, C1-C12amine, C1-C12amide, C1-C12ester, C6-C12aryl, C4-C12heterocycle or C5-C12 heteroaryl.2. The compound of item 1, wherein the compound is a combination of two or more of apharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a solvate thereof, an isotopically enriched molecule thereof.3. The compound of item 1 or 2, wherein the compound is for binding a bromodomain-containing protein.4. The compound of item 3, wherein the bromodomain-containing protein is a memberof the BET family, preferably the BET family is the bromodomain and extra-terminal domain family.5. The compound of any one of items 2 to 4, wherein the bromodomain-containingprotein is BRD2, BRD3, BRD4, BRDT, BRD7 or BRD9.6. The compound of any one of the preceding items, wherein the bromodomain-containing protein is BRD2, BRD3, BRD4 or BRDT.7. The compound of any one of the preceding items, wherein the bromodomain-containing protein is BRD4.8. The compound of any one of the preceding items, wherein Y^ is CH.9. The compound of any one of the preceding items, wherein Y^ is N.10. The compound of any one of the preceding items, wherein R^ is H, D, C1-C3 alkyl,C -C alkyl azide, S ^1 6 (O)Me or S(O)2Me, preferably is H or D, more preferably R is H.11. The compound of any one of the preceding items, wherein Y^^is NR^.12. The compound of any one of the preceding items, wherein R^^is C1-C3 alkyl, C1-C3haloalkyl, H, D, CH3 or CD3.13. The compound of any one of the preceding items, wherein R^^is H, D, CH3 or CD3.14. The compound of any one of the preceding items, wherein R^^is CH3 or CD3.15. The compound of any one of the preceding items, wherein structure (I) is according tostructure: 6116. The compound of any one of the preceding items, wherein Y^ is CH, CD, C-CN, C-CO2Et, COC(O)NHEt, COC(O)OEt, CCH2CH2F or CCH2CH2-n-morpholine.17. The compound of any one of the preceding items, wherein Y^ is CH or CD, preferablyY^is CH.18. The compound of any one of the preceding items, wherein Y^ is CR^1R^,^preferablyY^ is CH , CD or CHD, more pref ^2 2 erably Y is CH2.19. The compound of any one of the preceding items, wherein R^1 is H or D, preferably H.20. The compound of any one of the preceding items, wherein R^ is H, D, C1-C6, alkyl,aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, C1-C6alkyl, C1-C6aryl, C1-C6heteroaryl, C1-C6 heterocycle, C1-C6 cycloalkyl, or C1-C6 cycloalkenyl.21. The compound of any one of the preceding items, wherein R^ is H or D, preferably H.22. The compound of any one of the preceding items, wherein AG1 is N, CH or CD,preferably AG1is CH or CD, more preferably AG1is CH.23. The compound of any one of the preceding items, wherein AG4 is N, CH or CD,preferably AG4is CH or CD, more preferably AG4is CH.24. The compound of any one of the preceding items, wherein Y^ is N or CH, preferablyY^ is N.6225. The compound of any one of the preceding items, wherein structure (I) is according tostructure:26. The compound of any one of the preceding items, wherein G^ is ^2.27. The compound of any one of the preceding items, wherein G^ is aryl or heteroaryl.28. The compound of any one of the preceding items, wherein G^ is an azepine,benzimidazole, benzisothiazole, benzisoxazole, benzoazepine, benzofuran, benzopyrazine, benzopyrazole, benzopyridazine, benzotetrazines, benzothiadazole, benzothiazole, benzothiophene, benzotriazines, benzotriazole, benzoxazole, diazine, furan, imidazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, oxazole, phthalazine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrroline, quinoline, tetrazines, tetrazole, thiadazole, thiazole, thiophene, triazines or triazole.29. The compound of any one of the preceding items, wherein G^ is a substitutedazepine, substituted benzimidazole, substituted benzisothiazole, substituted benzisoxazole, substituted benzoazepine, substituted benzofuran, substituted benzopyrazine, substituted benzopyrazole, substituted benzopyridazine, substitutedbenzotetrazines, substituted benzothiadazole, substituted benzothiazole, substituted benzothiophene, substituted benzotriazines, substituted benzotriazole, substituted benzoxazole, substituted diazine, substituted furan, substituted imidazole, substituted indole, substituted indolizine, substituted isoquinoline, substituted isothiazole, substituted isoxazole, substituted oxazole, substituted phthalazine, substituted 63pyrazine, substituted pyrazole, substituted pyridazine, substituted pyridine, substituted pyrimidine, substituted pyrrole, substituted pyrroline, substituted quinoline, substituted tetrazines, substituted tetrazole, substituted thiadazole, substituted thiazole, substituted thiophene, substituted triazines or substituted triazole.30. The compound of any one of items 26 to 29, wherein G^ is mono, di, tri or tetrasubstituted.31. The compound of any one of items 26 to 30, wherein G^ is at each occurrence,independently substituted by D, F, Cl, Br, C1-C8alkyl, C1-C8alkylamine, C1-C8alkyl-ol, C1-C8 alkyl-thiol, C1-C8 alkyl azide, C1-C8 alkylnitrile, C1-C8 alkyne, C1-C8 alkyl-amide, C1-C8 alkyl-sulfoxide or C1-C8 alkyl-sulfone.32. The compound of any one of items 26 to 31, wherein G^ is at each occurrence,independently substituted by D, F, Cl, Br, C1-C6alkyl, C1-C6alkylamine, C1-C6alkyl-ol, C1-C6 alkyl-thiol, C1-C6 alkyl azide, C1-C6 alkylnitrile, C1-C6 alkyne, C1-C6 alkyl-amide, C1-C6 alkyl-sulfoxide or C1-C6 alkyl-sulfone.33. The compound of any one of items 26 to 32, wherein G^ is at each occurrence,independently substituted by D, F, Cl, Br, C1-C3alkyl, C1-C3alkylamine, C1-C3alkyl-ol, C1-C3 alkyl-thiol, C1-C3 alkyl azide, C1-C3 alkylnitrile, C1-C3 alkyne, C1-C3 alkyl-amide, C1-C3 alkyl-sulfoxide or C1-C3 alkyl-sulfone.34. The compound of any one of items 26 to 33, wherein G^ is at each occurrence,independently substituted by D, F, Cl or Br.35. The compound of any one of items 26 to 34, wherein G^ is at each occurrence,independently substituted by 1, 2 or 3 fluorine(s).36. The compound of any one of items 26 to 35, wherein G^ is at each occurrence,independently substituted by 1, 2 or 3 deuterium(s).37. The compound of any one of items 26 to 36, wherein G^ is at each occurrence,independently substituted by 1, 2 or 3 C1-C8 alkyls, preferably C1-C6 alkyls, more preferably C1-C3alkyls.38. The compound of any one of items 26 to 37, wherein G^ is at each occurrence,independently substituted by 1, 2 or 3 C1-C8alkylamines, preferably C1-C6alkylamines, more preferably C1-C3 alkylamines.39. The compound of any one of items 26 to 38, wherein G^ is at each occurrence,independently substituted by 1, 2 or 3 C1-C8 alkyl-ols, preferably C1-C6 alkyl-ols, more preferably C1-C3alkyl-ols. 6440. The compound of any one of items 26 to 39, wherein G^ is at each occurrence,independently substituted by 1, 2 or 3 C1-C8 alkyl thiols, preferably C1-C6 alkyl thiols, more preferably C1-C3alkyl thiols.41. The compound of any one of items 26 to 40, wherein G^ is at each occurrence,independently substituted by 1, 2 or 3 C1-C8alkyl azides, preferably C1-C6alkyl azides, more preferably C1-C3 alkyl azides.42. The compound of any one of items 26 to 41, wherein G^ is at each occurrence,independently substituted by 1, 2 or 3 C1-C8 alkyl nitriles, preferably C1-C6 alkyl nitriles, more preferably C1-C3 alkyl nitriles.43. The compound of any one of items 26 to 42, wherein G^ is at each occurrence,independently substituted by 1, 2 or 3 C1-C8 alkynes, preferably C1-C6 alkynes, more preferably C1-C3alkynes.44. The compound of any one of items 26 to 43, wherein G^ is at each occurrence,independently substituted by 1, 2 or 3 C1-C8alkyl-amides, preferably C1-C6alkyl- amides, more preferably C1-C3 alkyl-amides.45. The compound of any one of items 26 to 44, wherein G^ is at each occurrence,independently substituted by 1, 2 or 3 C1-C8 alkyl sulfoxides, preferably C1-C6 alkyl sulfoxides, more preferably C1-C3alkyl sulfoxides.46. The compound of any one of items 26 to 45, wherein G^ is at each occurrence,independently substituted by 1, 2 or 3 C1-C8alkyl sulfones, preferably C1-C6alkyl sulfones, more preferably C1-C3 alkyl sulfones.47. The compound of any one of the preceding items, wherein G^ is chosen from any oneof the structures consisting of:65, wherein X is F, Cl, Br, D or CH3including combinations of two thereof.48. The compound of any one of the preceding items, wherein G^ is chosen from any oneof the structures consisting: 67, wherein X is F, Cl, Br, D or CH3including combinations of two thereof.49. The compound of item 47 or 48, wherein X is F, CH3 or both F and CH3.50. The compound of any one of items 47 to 49, wherein X is F.51. The compound of any one of the preceding items, wherein G^ is.52. The compound of any one of the preceding items, wherein structure (I) is according tostructure: 6853. The compound of any one of the preceding items, wherein R^ is H, D, C1-C3 alkyl, C1-C3 alkyl halide, C1-C6 alkyl azide, or S(O)2CH3.54. The compound of any one of the preceding items, wherein R^ is H or D, preferably H.55. The compound of any one of the preceding items, wherein structure (I) is according tostructure: 6956. The compound of any one of the preceding items, wherein BG1, BG2, BG3, BG4, BG5, AG2and AG3form a seven membered ring.57. The compound of any one of the preceding items, wherein BG1, BG2, BG4, BG5, AG2 andAG3form a six membered ring.58. The compound of item 57, wherein BG2 is directly bonded to BG4.59. The compound of item 57 or 58, wherein BG3 is a bond between BG2 and BG4, or BG3 isnot present.60. The compound of any one of items 57 to 59, wherein the six membered ring formedby BG1, BG2, BG4, BG5, AG2 and AG3 is aromatic.61. The compound of any one of the preceding items, wherein BG1, BG2, BG5, AG2 and AG3form a five membered ring.62. The compound of item 61, wherein BG2 is directly bonded to BG5.63. The compound of item 61 or 621, wherein BG3 and BG4 are a single bond between BG2and BG5, or BG3and BG4are not present.64. The compound of any one of items 61 to 63, wherein the five membered ring formedby BG1, BG2, BG5, AG2 and AG3 is aromatic.7065. The compound of any one of the preceding items, wherein BG1 is C(O), NRBG1a, O,CRBG1bRBG1c, CRBG1b, N, S, Se, S(O), S(O)2, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e.66. The compound of any one of the preceding items, wherein BG1 is C(O), NRBG1a,CRBG1bRBG1c, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e.67. The compound of any one of the preceding items, wherein BG1 is C(O), NRBG1a orCRBG1bRBG1c.68. The compound of any one of the preceding items, wherein BG2 is C(O), NRBG2a, O,CRBG2bRBG2c, CRBG2b, N, S, Se, S(O), S(O)2, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e.69. The compound of any one of the preceding items, wherein BG2 is C(O), NRBG2a,CRBG2bRBG2c, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e.70. The compound of any one of the preceding items, wherein BG2 is C(O), NRBG2a orCRBG2bRBG2c.71. The compound of any one of the preceding items, wherein BG3 is NRBG3a,CRBG3bRBG3c, CRBG3b, C(O), O, S, N, Se, S(O) or S(O)2.72. The compound of any one of the preceding items, wherein BG3 is NRBG3a, CRBG3bRBG3cor C(O).73. The compound of any one of the preceding items, wherein BG4 is NRBG4a,CRBG4bRBG4c, CRBG4b, C(O), O, S, N, Se, S(O) or S(O)2.74. The compound of any one of the preceding items, wherein BG4 is NRBG4a,CRBG4bRBG4c, C(O), O, S, Se, S(O) or S(O)2.75. The compound of any one of the preceding items, wherein BG5 is C(O), NY^,CY^RBG5a, CY^, O, S, Se, S(O), S(O)2or P(O)Y^.76. The compound of any one of the preceding items, wherein BG5 is C(O), NY^,CY^RBG5a, CY^, S(O), S(O)2or P(O)Y^.77. The compound of any one of the preceding items, wherein BG5 is C(O), NY^, CY^RBG5aor CY^.78. The compound of any one of the preceding items, wherein Y^^is S(O)2RY^^^C(O)RY^,S(O)RY^^ P(O)(RY^) , ORY^, NHRY^, OH, O, NH , CRY^1RY^2C(O)NHRY^2 2 ^^^CRY^1RY^2S(O) RY^^^ CRY^1RY^2C Y^ Y^1 Y^2 Y^ Y^1 Y^2 Y^2 (O)R , CR R S(O)R ^ CR R P(O)(R )2,CRY^1RY^2ORY^, CRY^1RY^2NHRY^, CRY^1RY^2OH, CRY^1RY^2CHO, CRY^1RY^2NH2, H or D.7179. The compound of any one of the preceding items, wherein Y^^is S(O) RY^ Y^2 ^^ S(O)R ^CRY^1RY^2C(O)NHRY^^^^ CRY^1RY^2S(O) RY^^^ Y^1 Y^2 Y^ Y^1 Y^2 Y^2 CR R C(O)R , CR R S(O)R ^CRY^1RY^2P(O)(RY^)2, CRY^1RY^2NHRY^, H or D.80. The compound of any one of the preceding items, wherein Y^^is S(O)2RY^^^ CRY^1RY^2C(O)NHRY^^^^ CRY^1RY^2S(O) RY^^^ CRY^1RY^2C(O)RY^ or CRY^1RY^2P Y^2 (O)(R )2.81. The compound of any one of the preceding items, wherein RY^ at each occurrence, isindependently H, O, OH, NH2, C1-C12alkyl, C1-C12alcohol, C1-C12amine, C1-C12amide, C1-C12 ester, C6-C12 aryl, C4-C12 heterocycle or C5-C12 heteroaryl.82. The compound of any one of the preceding items, wherein RY^ at each occurrence, isindependently H, O, OH, NH2, C1-C10 alkyl, C1-C10 alcohol, C1-C10 amine, C1-C10amide, C1-C10ester, C6-C10aryl, C4-C10heterocycle or C5-C10heteroaryl.83. The compound of any one of the preceding items, wherein RY^ at each occurrence, isindependently H, O, OH, NH2, C1-C8alkyl, C1-C8alcohol, C1-C8amine, C1-C8amide, C1-C8 ester, C6-C8 aryl, C4-C8 heterocycle or C5-C8 heteroaryl.84. The compound of any one of the preceding items, wherein RY^ at each occurrence, isindependently H, O, OH, NH2, C1-C6 alkyl, C1-C6 alcohol, C1-C6 amine, C1-C6 amide, C1-C6 ester, C6-C6 aryl, C4-C6 heterocycle or C5-C6 heteroaryl.85. The compound of any one of the preceding items, wherein RY^ at each occurrence, isindependently H, O, OH, NH2, C1-C5 alkyl, C1-C5 alcohol, C1-C5 amine, C1-C5 amide, C1-C5ester, C4-C5heterocycle or C5heteroaryl.86. The compound of any one of the preceding items, wherein RY^ at each occurrence, isindependently H, O, OH, NH2, C1-C4alkyl, C1-C4alcohol, C1-C4amine, C1-C4amide or C1-C4 ester.87. The compound of any one of the preceding items, wherein RY^ at each occurrence, isindependently H, O, OH, NH2, C1-C3 alkyl, C1-C3 alcohol, C1-C3 amine, C1-C3 amide or C1-C3ester.88. The compound of any one of the preceding items, wherein RY^ is CH3, OCH3, Et, O,OH, H.89. The compound of any one of the preceding items, wherein RY^1 and RY^2 at eachoccurrence, are independently H, D, O, OH, NH2, halogen, C1-C12alkyl, C1-C12alcohol, C1-C12 amine, C1-C12 amide, C1-C12 ester, C6-C12 aryl, C4-C12 heterocycle or C5-C12heteroaryl.90. The compound of any one of the preceding items, wherein RY^1 and RY^2 at eachoccurrence, are independently H, D, O, OH, NH2, halogen, C1-C10alkyl, C1-C1072alcohol, C1-C10amine, C1-C10amide, C1-C10ester, C6-C10aryl, C4-C10heterocycle or C5-C10 heteroaryl.91. The compound of any one of the preceding items, wherein RY^1 and RY^2 at eachoccurrence, are independently H, D, O, OH, NH2, halogen, C1-C8 alkyl, C1-C8 alcohol, C1-C8 amine, C1-C8 amide, C1-C8 ester, C6-C8 aryl, C4-C8 heterocycle or C5-C8 heteroaryl.92. The compound of any one of the preceding items, wherein RY^1 and RY^2 at eachoccurrence, are independently H, D, O, OH, NH2, halogen, C1-C6alkyl, C1-C6alcohol, C1-C6 amine, C1-C6 amide, C1-C6 ester, C6-C6 aryl, C4-C6 heterocycle or C5-C6 heteroaryl.93. The compound of any one of the preceding items, wherein RY^1 and RY^2 at eachoccurrence, are independently H, D, O, OH, NH2, F, Cl, Br, C1-C5alkyl, C1-C5alcohol, C1-C5 amine, C1-C5 amide, C1-C5 ester, C4-C5 heterocycle or C5 heteroaryl.94. The compound of any one of the preceding items, wherein RY^1 and RY^2 at eachoccurrence, are independently H, D, O, OH, NH2, F, Cl, Br, C1-C4 alkyl, C1-C4 alcohol, C1-C4amine, C1-C4amide or C1-C4ester.95. The compound of any one of the preceding items, wherein RY^1 and RY^2 at eachoccurrence, are independently H, D, O, OH, NH2, F, Cl, C1-C3alkyl, C1-C3alcohol, C1- C3 amine, C1-C3 amide or C1-C3 ester.96. The compound of any one of the preceding items, wherein RY^1 and RY^2 at eachoccurrence, are independently H, D, F, CH3, OCH3, Et, O or OH.97. The compound of any one of the preceding items, wherein RY^1 is H or D.98. The compound of any one of the preceding items, wherein RY^2 is H or D.99. The compound of any one of the preceding items, wherein Y^ is selected from thegroup of structures consisting of:73100. The compound of any one of the preceding items, wherein Y^ is selected from thegroup of structures consisting of.101. The compound of any one of the preceding items, wherein Y^ is selected from thegroup of structures consisting of:75preferably, Y^has the structure of:.102. The compound of any one of the preceding items, wherein BG5 is chiral.103. The compound of any one of the preceding items, wherein BG5 is enantioenriched.104. The compound of any one of the preceding items, wherein BG5 is enantioenriched andhas an enantiomeric ratio of the predominant enantiomer to the minor enantiomer (calculated as the peak area of the predominant enantiomer / peak area of the minor enantiomer) in the range of from 25 : 1 to 1,000,000 :1, preferably in the range of from 50 : 1 to 100,000 : 1, more preferably in the range of from 100 : 1 to 10,000 : 1, more preferably in the range of from 200 : 1 to 1,000 : 1, more preferably in the range of from 250 : 1 to 500 : 1, determined by HPLC equipped with a chiral stationary phase column and a UV-Vis diode array detector.105. The compound of any one of the preceding items, wherein BG5 is enantiopuredetermined by HPLC equipped with a chiral stationary phase column and a UV-Vis diode array detector, wherein preferably only the predominant enantiomer is detected and the minor enantiomer, when present, is present in a concentration beyond the detection limits UV-Vis diode array detector.106. The compound of any one of the items 102 to 105, wherein BG5 has a (+) opticalrotation optionally according to ISO 592-1998.107. The compound of any one of the items 102 to 105, wherein BG5 has a (-) opticalrotation optionally according to ISO 592-1998.108. The compound of any one of the items 102 to 107, wherein the predominantenantiomer of BG5has an S configuration.109. The compound of any one of the items 102 to 108, wherein the predominantenantiomer of BG5has an R configuration.110. The compound of any one of the preceding items, wherein RBG1a, RBG1b , RBG1c, RBG1d,, RBG4b, RBG4c, RBG5a, at each occurrence, are each independently H, D, alcohol, alkenyl, alkyl, alkynyl, amide, amine, amino acid, amino alcohol, amino amide, amino ester, aryl, boryl, ether, ester, halogenyl, heteroaryl, heterocycle, phoshoramidite, phosphinyl, phosphoester, phosphonyl, selenenyl, selenonyl, sulfenyl, sulfonamide, sulfonyl or combinations thereof.111. The compound of any one of the preceding items, wherein RBG1a, RBG1b , RBG1c, RBG1d,, 76RBG4b , RBG4c, RBG5a, at each occurrence, are each independently H, D, substitutedalcohol, substituted alkene, substituted alkyl, substituted alkyne, substituted amide, substituted amine, substituted aryl, substituted azide, substituted borate, substituted halogen, substituted heteroaromatic, substituted heterocycle, substituted phoshoramidite, substituted phosphinate, substituted phosphoester, substituted phosphonate, substituted selenate, substituted selenyl, substituted sulfonamide, substituted sulfonyl or combinations thereof.112. The compound of any one of the preceding items, wherein RBG1a, RBG1b , RBG1c, RBG1d,RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d, RBG2e, RBG2e, RBG3a, RBG3b, RBG3c, RBG4a, RBG4b , RBG4c, RBG5a, at each occurrence, are each independently H, D, alkyl alcohol,alkyl amide, alkyl amine, alkyl amino acid, alkyl amino alcohol, alkyl amino amide, alkyl amino ester, alkyl aromatic, alkyl azide, alkyl boronate, alkyl disulfide, alkylcarbonate, alkyl carbamate, alkyl ether, alkyl ester, alkyl halogen, alkyl heterocycle, alkyl heteroaromatic, alkyl phoshoramidite, alkyl phosphinate, alkyl phosphoester, alkyl phosphonyl, alkyl selenate, alkyl sulfenate, alkyl sulfonamide, alkyl thiol, alkyl urea, alkyl thiourea or combinations thereof.113. The compound of any one of the preceding items, wherein RBG1a, RBG1b , RBG1c, RBG1d,RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d, RBG2e, RBG2e, RBG3a, RBG3b, RBG3c, RBG4a, RBG4b, RBG4c, RBG5aat each occurrence, are each independently suitable for linking further molecules or are H or D.114. The compound of any one of the preceding items, wherein RBG1a, RBG1b, RBG1c, RBG1d,RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d, RBG2eat each occurrence, are each independently suitable for linking further molecules or are H or D.115. The compound of any one of the preceding items, wherein RBG1a, RBG1b , RBG1c, RBG1d,RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d, RBG2e, RBG2e, RBG3a, RBG3b, RBG3c, RBG4a, RBG4b, RBG4c, RBG5aat each occurrence, are each independently a linker group.116. The compound of any one of the preceding items, wherein RBG1a, RBG1b, RBG1c, RBG1d,RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d,occurrence, are each independently a linker group or are H or D.117. The compound of any one of the preceding items, wherein RBG1a, RBG1b , RBG1c, RBG1d,RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d, RBG2e, RBG2e, RBG3a, RBG3b, RBG3c, RBG4a, RBG4b,occurrence, are each independently chosen from the group of structures consisting of:77wherein Y^is a N, C or P atom bound withinthe BG1, BG2, BG3, BG4, BG5, AG2 and AG37 membered ring,the BG1, BG2, BG4, BG5, AG2 and AG3 6 membered ring or78the BG1, BG2, BG5, AG2 and AG3 5 membered ring;R^is H, D, C1-C5 alkyl, alkynyl, benzyl, t-boc, phenoxy, PMB, a ligand for a further protein or an amino acid residue of an antibody;Z^is at each occurrence, each independently C6-C12aryl, alkynyl, amino acid, C5-C12cycloalkane or C5-C12heterocycle; wherein when present, the end methylene group of an end subunit of a polyethylene glycol linker is bound to, optionally having the equivalent O replaced by, a C, N, O, P or S atom comprised by Y^, X^and / or Z^; i^is, at each occurrence, each independently in the range of from 1 to 24, preferably in the range of from 2 to 22, more preferably in the range of from 2 to 20, more preferably in the range of from 3 to 18, more preferably in the range of from 4 to 16, more preferably in the range of from 6 to 14; j^is, at each occurrence, each independently in the range of from 1 to 6, preferably in the range of from 1 to 5, more preferably in the range of from 1 to 4, more preferably in the range of from 1 to 3, more preferably in the range of from 1 to 2; k^is, at each occurrence, each independently in the range of from 1 to 12, preferably of from 2 to 10, more preferably of from 2 to 8, more preferably of from 2 to 6, more preferably of from 2 to 5, more preferably of from 2 to 4, more preferably of from 2 to 3; z^is in the range of from 1 to 4, preferably in the range of 1 to 3, more preferably in the range of 1 to 2.118. The compound of item 117, wherein the structure is independently chosen for eachoccurrence of RBG1a, RBG1b, RBG1c, RBG1d, RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d, RBG2eincluding combinations thereof.119. The compound of item 117 or 118, wherein the structure is independently chosen foreach occurrence of RBG1a, RBG1b, RBG1c, RBG1d, RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2dor RBG2e.120. The compound of any one of items 117 to 119, wherein Z^ is chosen from the groupof structures consisting of:79.. The compound of any one of the preceding items, wherein RBG1a, RBG1b , RBG1c, RBG1d,RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d, RBG2e, RBG2e, RBG3a, RBG3b, RBG3c, RBG4a, RBG4b, RBG4c, RBG5aat each occurrence, are each independently chosen from the group of structures consisting of:wherein i^is, at each occurrence, each independently in the range of from 1 to 24, preferably in the range of from 2 to 22, more preferably in the range of from 2 to 20, more preferably in the range of from 3 to 18, more preferably in the range of from 4 to 8016, more preferably in the range of from 6 to 14; j^is, at each occurrence, each independently in the range of from 1 to 6, preferably in the range of from 1 to 5, more preferably in the range of from 1 to 4, more preferably in the range of from 1 to 3, more preferably in the range of from 1 to 2.122. The compound of item 121, wherein the structure is independently chosen for eachoccurrence of RBG1a, RBG1b, RBG1c, RBG1d, RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d, RBG2eincluding combinations thereof.123. The compound of any one of the preceding items, wherein structure (I) is according tostructure:124. The compound of any one of the preceding items, wherein structure (I) is selectedfrom the group of structures consisting of: 81wherein BG5 is N, CH or CD,wherein BG2is C(O), NRBG2aor CRBG2bRBG2c, and wherein BG1is C(O), NRBG1aor CRBG1bRBG1c.125. The compound of any one of the preceding items, wherein structure (I) is selectedfrom the group of structures consisting of: 86X21 X51X129 X130X154 X165PAZ2-NBu (1) PAZ3-SO2Et9596PAZ3-iPr PAZ3-SO2-oxetane97PAZ3-SO2-azetidine PAZ3-SO2-azetidineMe.126. The compound of any one of the preceding items, wherein structure (I) is selectedfrom the group of structures consisting of:X5_1 X5_298X54 X65X119 X120X134 X135PAZ2-NMe (1) PAZ2-NMe (2)PAZ2-NBu (2) 104PAZ3-CH2-SO2Me PAZ3-CH2-COOH105PAZ3-SO2-azetidine PAZ3-SO2-azetidineMe.127. A method of preparing a compound for binding a bromodomain-containing proteinaccording to any one of items 1 to 126, comprising -providing a compound according to structure (VI-a)106- providing a compound according to (VI-b)- coupling (VI-a) with (VI-b) to obtain either (VI-c) or (VI-d)- cyclizing either (VI-c) or (VI-d) to obtain a structure according to structure (I);or comprising:- providing a compound according to (VI-e)107- providing a compound according to (VI-f)- providing a molecule XY^-G^ and reacting with (VI-g) to obtain (VI-h)108-providing X^-Y^ and reacting with (VI-h) to obtain a molecule according to (I);wherein XG1is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, wherein XG2is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, wherein XG4is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, wherein XG5 is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH,CG1 is H, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid, BF3K, SnBu3, SiF3,SiCl3 or SiMe2OH,wherein CG2is NH2, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid, BF3K, SnBu3, SiF3, SiCl3 or SiMe2OH,wherein M is H, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid, BF3K, SnBu3, SiF3, SiCl3 or SiMe2OH,wherein XY^is NH2, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid or BF3K, wherein X^-Y^ is Cl2C(O), ClC(O)OMe, Cl2S(O)2, Cl2CR^1R^^or (O)CR^1R^.128. The method of item 127, wherein (VI-a) is according to (VII-a)109129. The method of item 127 or 128, wherein (VI-b) is according to (VII-b)130. The method of any one of items 127 to 129, wherein (VI-e) is according to (VII-e)131. The method of any one of items 127 to 130, wherein (VI-f) is according to (VII-f)132. The method of any one of items 127 to 131, wherein CG2 is NH2.133. The method of any one of items 127 to 132, wherein XY^-G^ is Br-G^.134. The method of any one of items 127 to 133, wherein X^-Y^ is formaldehyde, preferablyadded as paraformaldehyde, gaseous formaldehyde or formalin.135. The method of any one of items 127 to 1347, wherein R^ is converted to a H group,preferably immediately prior to reaction of X^-Y^^with (VI-h).136. A pharmaceutically acceptable composition comprising a compound according to anyone of items 1 to 126. 110137. The pharmaceutically acceptable composition of item 136, wherein said compositionis a solution suitable for intravenous administration.138. The pharmaceutically acceptable composition of item 136 or 37, wherein saidcomposition is suitable for oral administration.139. The pharmaceutically acceptable composition of any one of items 136 to 138, whereinsaid composition comprises a dosage of from 0.01 mg to 2000 mg of the compound according to any one of items 1 to 126 per 1 kg of the patient, preferably of from 0.1 mg to 1000 mg of the compound according to any one of items 1 to 126 per 1 kg of the patient.140. A compound according to any one of items 1 to 126 or the pharmaceuticallyacceptable composition of any one of items 136 to 139, for use in the treatment of cancer.141. A method for treating cancer comprising administering a compound according to anyone of items 1 to 126 or a pharmaceutically acceptable composition according to any one of items 136 to 139. FURTHER ASPECTS OF THE INVENTION

[0106] Further aspects of the invention relate a method of preparing a compound forbinding a bromodomain-containing protein according to any one of the compound embodiments according to the invention, comprising- providing a compound according to structure (VI-a)- providing a compound according to (VI-b)111- coupling (VI-a) with (VI-b) to obtain either (VI-c) or (VI-d)- cyclizing either (VI-c) or (VI-d) to obtain a structure according to structure (I);or comprising:- providing a compound according to (VI-e)- providing a compound according to (VI-f)112- cross coupling (VI-e) with (VI-f) to obtain (VI-g);- providing a molecule XY^-G^ and reacting with (VI-g) to obtain (VI-h)- providing X^-Y^ and reacting with (VI-h) to obtain a molecule according to (I);wherein XG1is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, wherein XG2is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, wherein XG4is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, wherein XG5is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, CG1is H, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid, BF3K, SnBu3, SiF3, SiCl3or SiMe2OH, 113wherein CG2is NH2, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid, BF3K, SnBu3, SiF3, SiCl3 or SiMe2OH, wherein M is H, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid, BF3K, SnBu3, SiF3, SiCl3 or SiMe2OH, wherein XY^is NH2, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid or BF3K, wherein X^-Y^is Cl2C(O), ClC(O)OMe, Cl2S(O)2, Cl2CR^1R^^or (O)CR^1R^.

[0107] It is further preferred that (VI-a) is according to (VII-a)

[0108] It is further preferred that (VI-b) is according to (VII-b)

[0109] It is further preferred that (VI-e) is according to (VII-e)114

[0110] It is further preferred that (VI-f) is according to (VII-f)

[0111] It is preferred that CG2 is NH2.

[0112] It is preferred that XY^-G^ is Br-G^.

[0113] It is preferred that X^-Y^ is formaldehyde, preferably added asparaformaldehyde, gaseous formaldehyde or formalin.

[0114] It is preferred that R^ is converted to a H group, preferably immediately prior toreaction of X^-Y^^with (VI-h).

[0115] A further aspect of the invention relates a pharmaceutically acceptablecomposition comprising a compound according to any one of the compound embodiments according to the invention. It is preferred that said composition is a solution suitable for intravenous administration. It is preferred that said composition is suitable for oral administration. It is further preferred that said composition comprises a dosage of from 0.01mg to 2000 mg per 1 kg of the patient of the compound, preferably of from 0.1 mg to 1000mg per 1 kg of the patient of the compound, according to any one of the compound embodiments according to the invention.

[0116] A further aspect of the invention relates a compound according to any one ofthe compound embodiments according to the invention or a pharmaceutically acceptable composition comprising a compound according to any one of the compound embodiments according to the invention for use in the treatment of cancer.

[0117] A further aspect of the invention relates a method for treating cancercomprising administering a compound according to any one of the compound embodimentsaccording to the invention or a pharmaceutically acceptable composition comprising a compound according to any one of the compound embodiments according to the invention. 115EXAMPLES

[0118] An even better understanding of the present invention and of its advantageswill be evident from the following examples, offered for illustrative purposes only. The examples are not intended to limit the scope of the present invention in any way.

[0119] Chemicals, solvents and antibodiesChemicals and solvents were purchased from Merck (Merck group, Germany), TCI (Tokyo chemical industry CO., LTD., Japan), Iris Biotech (Iris Biotech GmbH, Germany), BLD Pharmatech Ltd. (China), MCE (MedChemExpress, USA) and Carl Roth (Carl Roth GmbH + Co. KG, Germany) and used without further purification. Dry solvents were purchased from Merck (Merck group, Germany).PAZ1, also termed herein as X2, was prepared according to WO2020 / 086858A1,WO2019084030A1or Dragovich et al.

[0120] Preparative HPLCPreperative HPLC was performed on a BÜCHI Pure C-850 Flash-Prep system (BÜCHI Labortechnik AG, Switzerland) using a VP 250 / 10 Macherey-Nagel Nucleodur C18 HTec Spum column (Macherey-Nagel GmbH & Co. Kg, Germany) for smaller scales. Examples for gradients that were used: Method C: A = H2O + 0.1% TFA (trifluoroacetic acid), B = MeCN (acetonitrile) + 0.1% TFA, flow rate 6 ml / min, 30% B 0-5 min, 30-70% B 5-35 min, 99% B 35- 45 min. Method D: A = H2O, B = MeCN (acetonitrile), flow rate 6 ml / min, 30% B 0-5 min, 30- 70% B 5-35 min, 99% B 35-45 min. For larger scales, a VP 250 / 21 Macherey-Nagel Nucleodur C18 HTec Spum column (Macherey-Nagel GmbH & Co. Kg, Germany) was used with the following gradients were used: Method E: A = H2O + 0.1% TFA (trifluoroacetic acid),B = MeCN (acetonitrile) + 0.1% TFA, flow rate 14 ml / min, 30% B 0-5 min, 30-70% B 5-35min, 99% B 35-45 min. Large scales have been purified with a VP 250 / 32 Macherey-Nagel Nucleodur C18 HTec Spum column (Macherey-Nagel GmbH & Co. Kg, Germany) with the following gradients: Method F: A = H2O + 0.1% TFA (trifluoroacetic acid), B = MeCN 116(acetonitrile) + 0.1% TFA, flow rate 32 ml / min, 30% B 0-5 min, 30-90% B 5-35 min, 99% B 35-45 min.

[0121] High resolution LC / MSSmall molecules were analyzed using a Waters H-class instrument equipped with a quaternary solvent manager, a Waters sample manager-FTN, a Waters PDA detector and a Waters column manager. Mass analysis was conducted with a Waters XEVO G2-XS QTof analyzer. Proteins were ionized in positive ion mode applying a cone voltage of 40 kV. An Acquity UPLC-BEH C18 column (300 Å, 1.7 µm,2.1 mm x 50 mm) was used for separation. Samples were eluted at a column temperature of 45°C with a flow rate of 0.4 mL / min. The following gradient was used: A: 0.1% formic acid in H2O; B: 0.1% formic acid in MeCN.2% B 0-1 min, 2-98% B 1-5 min, 98%B 5-5.5 min, 98-2% B 5.5-6 min, 2% B 6-7min.

[0122] Low resolution LC / MSSmall molecules were analyzed on a Vanquish Flex UHPLC System with a DAD detector, Split Sampler FT (4°C), Column Compartment H (45°C) and binary pump F (Thermo Fisher Scientific, USA) using a Waters Acquity UPLC-CSH C18 column (130 Å, 1.7 µm, 2.1 mm x 100 mm) with a flow rate of 0.4 mL / min. UV chromatograms were recorded at 220 or 254 nm.The following gradient was used: A: 0.1% formic acid in H2O; B: 0.1% formic acid in MeCN.2% B 0-1 min, 2-98% B 1-5 min, 98%B 5-6 min, 98-2% B 6-6.5 min.

[0123] General procedure A: Chloroethylation of primary Amines and in situpeptide coupling

[0124] Chloroethylation of primary amines via reductive aminationChloroacetaldehyde (14.0 equiv., from 55 w% in H2O) and p-TsOH·H2O (0.2 equiv.) wereadded to a solution / suspension of the primary amine / ammonium hydrochloride (10.0 equiv.)in DCM (0.01 M) one portion. The mixture was stirred at r.t. for 15 min, a milky solution wasobserved and NaCNBH3 (12.0 equiv.) was added as a solid in one portion. The mixture wasstirred at r.t. for 2 h, was then concentrated under reduced pressure to yield the secondaryamine in a crude mixture.

[0125] Peptide coupling with PAZ1-COOH117To a solution of PAZ1-COOH (X2) (1.0 equiv.) in anhydrous DMF (20 mM) was added DIPEA(20.0 equiv.) and the resulting mixture was added to a solution of the crude mixturecontaining the (2-chloroethyl)amine obtained in step 1, chloroethylamine derivative (400 mM / DMF), followed by TOTU (1.2 equiv. from 100 mM / DMF). The resulting mixture was stirred at r.t. for 1 h, before being poured into MeCN:H2O (1:1, 2×) and directly subjected to purification by preparative HPLC (H2O / MeCN, 0.1% TFA) to yield the modified PAZ1-derivative as a colourless solid after lyophilization.

[0126] General procedure B: CyclisationTo a PAZ1 (2-chloroethyl)amide (0.001 M in anhydrous THF) was added a solution of KOtBuportionwise (4×2.5 equiv. from 50 mM in anhydrous THF). After the addition of >1.5 equiv. ofKOtBu the colourless solution turned yellow. Strong green fluorescence was observed (exc.360 nm). The mixture was stirred at r.t. for 30 min and reaction progress was monitored byLC-MS. In case of incomplete conversion, the mixture was heated to 50 °C and further stirredfor 1 h. The mixture was concentrated under reduced pressure and taken into MeCN:H2O(1:1) and directly subjected to purification by preparative HPLC (H2O / MeCN, 0.1% TFA) toyield the modified PAZ2-derivative as a colourless solid after lyophilization.

[0127] General procedure C: Deprotection tert-butyl ester precursorsTo a cold solution of PAZ2-linker-CO2tBu (1.0 equiv., 20 mM in anhydrous DCM) was added80% TFA in anhydrous DCM (400 vol%). The resulting mixture was stirred at 0 °C for 2 h,before being concentrated under Argon stream. The residue containing PAZ2-linker-CO2H was directly used without further purification. PREPARATION OF PAZ2 EXAMPLES 118

[0128] PAZ1-(bis(2-chloroethyl)amide) (X3)To a solution of PAZ1-COOH (X2) (24.0 mg, 47.9 μmol) in anhydrous DMF (25 mM, 1.9 mL)was added DIPEA (62 mg, 82 μL, 10.0 equiv.), bis(chloroethyl)amine hydrochloride X1(68.5 mg, 383.6 μmol, from 200 mM / DMF, 8.0 equiv.), followed by TOTU (18.1 mg,55.1 μmol, 1.15 equiv. from 100 mM / DMF). The resulting mixture was stirred at r.t. for 0.5 h,before being poured into MeCN:H2O (1:1, 5.0 mL) and directly subjected to purification bypreparative HPLC (H2O / MeCN, 0.1% TFA) to yield PAZ1-bis(N,N-chloroethyl)amide (X3) as ayellow solid after lyophilization (29.8 mg, 47.7 μmol, 99%).HPLC-LRMS ESI+-MS for C27H26Cl2F2N5O4S+(M+H)+: calc. m / z: 624.1, found m / z 624.1.1H-NMR (400 MHz, DMSO-d6) δ (ppm) 11.93 (d, J = 2.7 Hz, 1H), 8.09 (d, J = 2.6 Hz, 1H),7.96 (s, 1H), 7.71 (s, 1H), 7.27 (d, J = 2.7 Hz, 1H), 7.18 (s, 1H), 4.54 (s, 2H), 3.79 (s, 4H),3.63 (s, 3H), 3.43 – 3.37 (m, 2H), 3.02 (s, 3H).

[0129] PAZ2-C2-Cl (X4)PAZ1-bis(N,N-chloroethyl)amide X3 (10.0 mg, 16.0 μmol) was dissolved in anhydrous THF(1 mM) and a solution of KOtBu (18.0 mg, 160.3 μmol, 10.0 equiv. from 50 mM / THF) wasadded dropwise under vigorous stirring. The resulting mixture was stirred at r.t. for 1 h, beforebeing concentrated under reduced pressure. The residue was taken into MeCN:H2O (1:1,5.0 mL) and directly subjected to purification by preparative HPLC to yield PAZ2-N-chloroethylamide (X4) as a yellow solid after lyophilization (7.6 mg, 12.9 μmol, 81%).HPLC-LRMS ESI+-MS for C27H25ClF2N5O4S+(M+H)+: calc. m / z: 588.1, found m / z 588.1. 119

[0130] Cl-C2-PAZ2-Me (X20)PAZ1-bis(N,N-chloroethyl)amide X3 (1.3 mg, 2.1 μmol) was dissolved in anhydrous THF(1 mM, 2 mL) and a solution of KOtBu (2.4 mg, 21 μmol, 10.0 equiv. from a 50 mM / THF)was added dropwise under vigorous stirring. The resulting mixture was stirred at r.t. for 1 h.After full conversion of X3 to X4 was monitored by LC-MS, a solution of iodomethane(1.5 mg, 10.4 μmol, 5 equiv., from 50 mM / THF) was added in one portion. The resultingmixture was stirred at r.t. for 15 h, was then concentrated under reduced pressure, taken intoMeCN:H2O (1:1, 2.0 mL) and directly subjected to purification by preparative HPLC to yieldX20 as a colourless solid (0.5 mg, 0.9 μmol, 43%).HRMS (ESI+): for C28H34ClF2N8O4S+ (M+H)+: calc. m / z: 602.14349; found m / z: 602.14378.1H-NMR (400 MHz, DMSO-d6) δ (ppm) = 8.12 (d, J = 2.5 Hz, 1H), 7.98 (s, 1H), 7.79 (s, 1H),7.71 – 7.63 (m, 1H), 7.34 – 7.24 (m, 2H), 4.93 (d, J = 10.6 Hz, 1H), 4.01 (s, 3H), 3.78 – 3.67(m, 3H), 3.61 (s, 1H), 3.59 (s, 3H), 2.95 – 2.82 (m, 2H), 2.79 (s, 3H), 2.77 – 2.73 (m, 2H).PAZ1-bis(N,N-chloroethyl)amide X3 (1.3 mg, 2.1 μmol) was dissolved in anhydrous THF(1 mM, 2 mL) and a solution of KOtBu (2.4 mg, 21 μmol, 10.0 equiv. from a 50 mM / THF)was added dropwise under vigorous stirring. The resulting mixture was stirred at r.t. for 1 h.After full conversion of X3 to X4 was monitored by LC-MS, a solution of methane sulfonylchloride (1.2 mg, 10.4 μmol, 5 equiv., from 50 mM / THF) was added in one portion. Theresulting mixture was stirred at r.t. for 15 h, was then concentrated under reduced pressure,taken into MeCN:H2O (1:1, 2.0 mL) and directly subjected to purification by preparativeHPLC to yield X21 as a colourless solid (0.4 mg, 0.7 μmol, 33%).HRMS (ESI+): for C28H27ClF2N8O6S2+ (M+H)+: calc. m / z: 666.10539; found m / z: 666.10457.1H-NMR (400 MHz, DMSO-d6) δ (ppm) = 8.18 (d, J = 2.5 Hz, 1H), 8.14 (s, 1H), 8.02 (s, 1H),7.79 (s, 1H), 7.73 (t, J = 10.2 Hz, 1H), 7.29 (s, 2H), 4.93 (d, J = 11.0 Hz, 1H), 3.95 (s, 3H),3.75 (s, 4H), 3.68 (s, 3H), 2.99 – 2.83 (m, 2H), 2.79 (s, 3H), 2.40 – 2.35 (m, 1H).120

[0132] PAZ2-C2-N3 (X5)(racemate)PAZ2-N-chloroethylamide (X4) (7.6 mg, 12.9 μmol) was dissolved in anhydrous DMSO(5.0 mM) and a solution of sodium azide (16.8 mg, 258.5 μmol, 20 equiv. from 50 mM / DMSO) was added in one portion. The resulting solution (2.5 mM in DMSO) was stirred at r.t.for 15 h and was then directly subjected to purification by preparative HPLC to yield PAZ2-N-azidoethylamide (X5) as a yellow solid after lyophilization (7.3 mg, 12.3 μmol, 95%).eluting enantiomersThe chiral purity of the X5_racemic mixture (dissolved at 2 mg / mL in EtOH:THF, 1:1) wasanalyzed using a ChiralPak IB N-3 (4.6×100 mm, 3 μm) applying isocractic conditions (40:60EtOH:CO2, 0.2% v / v isopropylamine) at 40 °C with 3 mL / min flow rate at 120 bar. The chiralpurity was determined with two species at RT 2.07 min, 49.96%, RT 2.92 min, 50.04%. Apreparative sample of X5 (3.4 mg, 5.7 μmol) was subjected to chiral purification using thesame conditions yielding the individual enantiomers X5_first eluting (1.2 mg, 2.0 μmol,70%) and X5_second eluting (1.2 mg, 2.0 μmol, 70%).X5_racemic: HRMS (ESI+): for C27H25F2N8O4S+ (M+H)+: calc. m / z: 595.16821; found m / z:595.16797. 1H-NMR (800 MHz, DMSO-d6) δ (ppm) = 11.93 (d, J = 2.6 Hz, 1H), 8.12 (d, J =2.6 Hz, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.64 (s, 1H), 7.30 (s, 1H), 7.28 (d, J = 2.7 Hz, 1H),4.94 (d, J = 11.0 Hz, 1H), 3.65 (d, J = 7.6 Hz, 2H), 3.63 (s, 2H), 3.51 (t, J = 6.1 Hz, 3H), 3.26(t, J = 13.8 Hz, 2H), 2.90 – 2.83 (m, 1H), 2.79 (s, 3H), 2.54 (s, 4H), 2.36 (dd, J = 14.7, 11.9Hz, 1H). 13C-NMR (201 MHz, DMSO-d6) δ (ppm) = 167.5, 157.9, 157.7, 153.8, 153.7, 152.4,147.9, 146.6, 146.6, 145.5, 143.6, 134.9, 134.3, 131.8, 129.7, 129.6, 129.3, 128.4, 127.9,127.3, 122.9, 122.4, 116.6, 113.9, 113.8, 113.7, 111.1, 66.1, 48.7, 46.0, 45.8, 45.6, 38.5,36.1, 27.0.Figure 1 shows A) X5_racemic, B) chiral column purified X5_first eluting peak and C) chiralcolumn purified X5_second eluting peak.121Table 1. Retention times for Figure 1 A, 1B and 1CPAZ1-bis(N,N-chloroethyl)amide X3 (10.5 mg, 16.8 μmol) was dissolved in anhydrous THF(1 mM) and a solution of KOtBu (18.9 mg, 168.2 μmol, 10.0 equiv. from a 50 mM / THF) wasadded dropwise under vigorous stirring. The resulting mixture was stirred at r.t. for 1 h. Afterfull conversion of X3 to X4 was monitored by LC-MS, aq. NaOH (1.2 mL, 1.2 mmol, 50 equiv.from 1 M) was added in one portion. The mixture was then heated to 50 °C and further stirredfor 15 h. The resulting mixture was concentrated under reduced pressure, then taken intoMeCN:H2O (1:1, 5.0 mL) and directly subjected to purification by preparative HPLC to yieldPAZ2-N-hydroxyethylamide (X6_racemic) as a colourless solid after lyophilization (3.8 mg,6.5 μmol, 39%).eluting enantiomersThe chiral purity of racemic X6 (dissolved at 1 mg / mL in EtOH:THF, 1:1) was analyzed usinga ChiralPak IB N-3 (4.6×100 mm, 3 μm) applying isocractic conditions (40:60 EtOH:CO2,1220.2% v / v isopropylamine) at 40 °C with 3 mL / min flow rate at 125 bar. The chiral purity wasdetermined with two species at RT 2.07 min, 49.6%, RT 2.92 min, 49.5%. X6_racemic: HPLC-LRMS ESI+-MS for C27H26F2N5O5S+(M+H)+: calc. m / z: 570.2, found m / z570.2. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) = 11.93 (d, J = 2.7 Hz, 1H), 8.11 (d, J = 2.5Hz, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 7.65 (ddd, J = 11.2, 8.2, 2.6 Hz, 1H), 7.31 (s, 1H), 7.27 (d,J = 2.7 Hz, 1H), 4.92 (d, J = 10.7 Hz, 1H), 3.63 (s, 3H), 3.55 (d, J = 5.9 Hz, 2H), 3.47 (s, 2H),2.87 (d, J = 25.6 Hz, 1H), 2.79 (s, 2H), 2.41 – 2.32 (m, 1H).Figure 2 shows a racemic chromotgram for X6 separated in a chiral phase HPLC with X-axisgiven in time and Y-axis given as mili-absorption units measured at 220 nm wavelength of light. Table 2. Retention times for Figure 2X6 (1.0 mg, 1.8 μmol) was dissolved in anhydrous DMSO (2 mM, 0.35 mL) and Cs2CO3(2.9 mg, 8.8 μmol, 5.0 equiv.) was added in one portion.1-chloro-3-iodopropane (0.4 mg,2.1 μmol, 42 μL from 50 mM / DMSO) was added and the resulting mixture was stirred at r.t.for 2 h. A solution of sodium azide (5.7 mg, 87.7 μmol, 50 equiv., 1.75 mL from 50 mM / DMSO) was added, then the mixture was heated to 50 °C and was further stirred for 15 h.The resulting mixture was taken into MeCN:H2O (1:1, 5.0 mL) was directly subjected topurification by preparative HPLC to yield X7 as a colourless solid (0.6 mg, 0.9 μmol, 49%).HRMS (ESI+): for C30H31F2N8O5S+ (M+H)+: calc. m / z: 653.21007; found m / z: 653.20850.1H-NMR (600 MHz, DMSO-d6) δ (ppm) = 8.12 (d, J = 2.6 Hz, 1H), 7.96 (s, 1H), 7.80 (s, 1H),7.67 (ddd, J = 11.2, 8.2, 2.5 Hz, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 4.92 (d, J = 11.0 Hz, 1H),3.60 (s, 3H), 3.56 (t, J = 6.0 Hz, 2H), 3.29 (t, J = 6.7 Hz, 2H), 3.24 (d, J = 13.0 Hz, 2H), 2.84(s, 1H), 2.78 (s, 3H), 2.34 (t, J = 13.3 Hz, 1H), 1.99 (t, J = 6.8 Hz, 2H).123

[0135] HO-C2-PAZ2-C5-N3 (X8)X6 (1.0 mg, 1.8 μmol) was dissolved in anhydrous DMSO (2 mM, 0.35 mL) and Cs2CO3(2.9 mg, 8.8 μmol, 5.0 equiv.) was added in one portion.1-azido-5-(p-toluenesulfonate)pentane (1.0 mg, 3.5 μmol, 2.0 equiv.) was added and the resultingmixture was stirred at r.t. for 0.5 h, was then heated to 50 °C and further stirred for 15 h. Theresulting mixture was taken into MeCN:H2O (1:1, 5.0 mL) was directly subjected topurification by preparative HPLC to yield X8 as a colourless solid (0.6 mg, 0.9 μmol, 50%).HRMS (ESI+): for C32H35F2N8O5S+ (M+H)+: calc. m / z: 681.24137; found m / z: 681.24611.1H-NMR (600 MHz, DMSO-d6) δ (ppm) = 8.12 (d, J = 2.5 Hz, 1H), 7.96 (s, 1H), 7.78 (s, 1H),7.67 (ddd, J = 11.2, 8.1, 2.5 Hz, 1H), 7.37 (s, 1H), 7.30 (s, 1H), 5.92 (s, 1H), 4.92 (d, J = 10.9Hz, 1H), 4.41 (d, J = 60.7 Hz, 2H), 3.59 (s, 3H), 3.56 (t, J = 6.1 Hz, 2H), 3.28 (t, J = 6.8 Hz,2H), 3.24 (d, J = 13.2 Hz, 1H), 2.78 (s, 3H), 2.37 – 2.31 (m, 1H), 1.74 (p, J = 7.2 Hz, 2H),1.52 (p, J = 7.0 Hz, 2H), 1.28 – 1.21 (m, 2H).

[0136] PAZ1-(2-chloroethyl)-C6-N3 (X11)X11 was prepared according to General Procedure A (1. chloroethylation; 2. peptidecoupling).6-azido-1-amino-pentane hydrochloride X9 (100 μmol, 0.2 mL from 0.5 M / MTBE, 10 equiv.)was diluted in DCM (10 mL, 0.01 M) and chloroacetaldehyde (28 μL from aq.55% v / v,25 equiv.) was added in one portion at r.t. The mixture was stirred for 15 min. beforeNaCNBH3 (7.5 mg, 120 μmol, 12 equiv.) was added as a solid in one portion. The mixturewas stirred at r.t. for 2 h, was then concentrated under reduced pressure to obtain X10 as acrude material. 124To a solution of PAZ1-COOH (X2) (4.0 mg, 8.0 μmol, 1.0 equiv.) in anhydrous DMF (20 mM,0.4 mL) was added DIPEA (13.6 μL, 80 μmol, 10.0 equiv.) and a solution of the material X10obtained in step 1 (dissolved at 200 mM / DMF), followed by TOTU (3.0 mg, 9.2 μmol, 1.15equiv. from 100 mM / DMF). The resulting mixture was stirred at r.t. for 1 h, then taken intoMeCN:H2O (1:1, 5.0 mL) and directly subjected to purification by preparative HPLC to yieldX11 (1.9 mg, 2.8 μmol, 35%) as a colourless solid after lyophilization.HRMS (ESI+): for C31H34ClF2N8O4S+ (M+H)+: calc. m / z: 687.20748; found m / z: 687.20755.

[0137] PAZ2-C6-N3 (X12)X12 was prepared according to General Procedure B (cyclisation).X11 (0.8 mg, 1.2 μmol) was dissolved in anhydrous THF (1 mM) and a solution of KOtBu(1.0 mg, 8.8 μmol, 7.5 equiv. from 50 mM / THF) was added dropwise under vigorous stirring.The resulting mixture was heated to 50 °C and further stirred for 2 h, before beingconcentrated under reduced pressure. The residue was taken into MeCN:H2O (1:1, 2.0 mL)and directly subjected to purification by preparative HPLC to yield PAZ2-C6-N3 (X12) as acolourless solid after lyophilization (0.1 mg, 0.2 μmol, 17%).HRMS (ESI+): for C31H33F2N8O4S+ (M+H)+: calc. m / z: 651.23081; found m / z: 651.22588.

[0138] PAZ1-(2-chloroethyl)-PEG2-N3 (X15)X15 was prepared according to General Procedure A (1. chloroethylation; 2. peptidecoupling). 125X13 (34.6 mg, 100 μmol, 10 equiv.) was dissolved in DCM (10 mL, 0.01 M) andchloroacetaldehyde (28 μL from aq. 55 v / v, 25 equiv.) was added in one portion at r.t. Themixture was stirred for 15 min. before NaCNBH3 (7.5 mg, 120 μmol, 12 equiv.) was added asa solid in one portion. The mixture was stirred at r.t. for 2 h, was then concentrated underreduced pressure to obtain X14 as a crude material.To a solution of PAZ1-COOH (X2) (4.0 mg, 8.0 μmol, 1.0 equiv.) in anhydrous DMF (20 mM,0.4 mL) was added DIPEA (13.6 μL, 80 μmol, 10.0 equiv.) and a solution of the material X14obtained in step 1 (dissolved at 200 mM / DMF), followed by TOTU (3.0 mg, 9.2 μmol, 1.15equiv. from 100 mM / DMF). The resulting mixture was stirred at r.t. for 1 h, then taken intoMeCN:H2O (1:1, 5.0 mL) and directly subjected to purification by preparative HPLC to yieldX15 (3.1 mg, 4.3 μmol, 54%) as a colourless solid after lyophilization.HPLC-LRMS ESI+-MS for C31H34ClF2N8O6S+ (M+H)+: calc. m / z: 719.2, found m / z 719.2.

[0139] PAZ2-PEG2-N3 (X16)X16 was prepared according to General Procedure B (cyclisation).X15 (2.6 mg, 3.6 μmol) was dissolved in anhydrous THF (1 mM) and a solution of KOtBu(4.0 mg, 36.1 μmol, 10 equiv. from 50 mM / THF) was added dropwise under vigorousstirring. The resulting mixture was heated to 50 °C and further stirred for 2 h, before beingconcentrated under reduced pressure. The residue was taken into MeCN:H2O (1:1, 3.0 mL)126and directly subjected to purification by preparative HPLC to yield PAZ2-PEG2-N3(X16) as acolourless solid after lyophilization (0.6 mg, 0.9 μmol, 25%).HRMS (ESI+): for C31H33F2N8O6S+ (M+H)+: calc. m / z: 683.22063; found m / z: 683.22048.1H-NMR (600 MHz, DMSO-d6) δ (ppm) = 12.03 – 11.85 (m, 1H), 8.11 (d, J = 2.6 Hz, 1H),7.99 (s, 1H), 7.80 (s, 1H), 7.65 (d, J = 10.0 Hz, 1H), 7.30 (s, 1H), 7.28 (d, J = 2.7 Hz, 1H),6.53 (s, 2H), 4.92 (d, J = 10.9 Hz, 1H), 4.28 (s, 1H), 3.63 (s, 3H), 3.62 – 3.52 (m, 10H), 2.78(s, 3H), 2.33 (t, J = 13.5 Hz, 1H).

[0140] PAZ1-(2-chloroethyl)-C7-CO2tBu (X113)X113 was prepared according to General Procedure A (1. chloroethylation; 2. peptidecoupling).tert-butyl 8-aminooctanoate X111 (36.5 mg, 170 μmol, 10 equiv.) was dissolved in DCM(17 mL, 0.01 M), then 4-toluene sulfonic acid monohydrate (3.2 mg, 17 μmol, 1 equiv.) and2-chloroacetaldehyde (29 μL from aq.55% v / v, 12 equiv.) was added in one portion at r.t. Themixture was stirred for 15 min before NaCNBH3 (10.7 mg, 170 μmol, 10 equiv.) was added asa solid in one portion. The mixture was stirred at r.t. for 2 h, was then concentrated underreduced pressure to obtain X112 as a crude material.To a solution of PAZ1-COOH (X2) (8.5 mg, 17 μmol, 1.0 equiv.) in anhydrous DMF (20 mM,0.8 mL) was added DIPEA (58 μL, 340 μmol, 20 equiv.) and a solution of the material X112obtained in step 1 (dissolved at 200 mM / DMF), followed by TOTU (6.7 mg, 20 μmol, 1.2equiv. from 100 mM / DMF). The resulting mixture was stirred at r.t. for 1 h, then taken intoMeCN:H2O (1:1, 5.0 mL) and directly subjected to purification by preparative HPLC to yieldX113 (11.7 mg, 15.4 μmol, 91%) as a colourless solid after lyophilization.HRMS (ESI+): for C37H45ClF2N5O6S+ (M+H)+: calc. m / z: 760.27417; found m / z: 760.27595.127

[0141] PAZ2-C7-CO2tBu (X114)X114 was prepared according to General Procedure B (cyclisation).X113 (11.0 mg, 14.4 μmol) was dissolved in anhydrous THF (12.0 mL, 1 mM) and a solutionof KOtBu (10.4 mg, 92.6 μmol, 6.4 equiv. from 50 mM / THF) was added dropwise undervigorous stirring. The resulting mixture was heated to 50 °C and further stirred for 2 h, beforebeing concentrated under reduced pressure. The residue was taken into MeCN:H2O (1:1,5.0 mL) and directly subjected to purification by preparative HPLC to yield X114 as acolourless solid after lyophilization (3.8 mg, 5.3 μmol, 36%).HRMS (ESI+): for C37H44F2N5O6S+ (M+H)+: calc. m / z: 724.29749; found m / z: 724.29720.

[0142] PAZ2-C7-CO2H (X115)X115 was prepared according to General Procedure C (tBu ester deprotection).To a cold solution of X114 (3.8 mg, 5.3 μmol) in anhydrous DCM (0.1 mL) was added 80%TFA in anhydrous DCM (0.4 mL) and the resulting mixture was stirred at 0 °C for 2 h, beforebeing concentrated under reduced pressure. X115 was obtained as colourless solid (3.2 mg,4.8 μmol, 91%) and used without further purification.HRMS (ESI+): for C33H36F2N5O6S+ (M+H)+: calc. m / z: 668.23489; found m / z: 668.23292.

[0143] PAZ1-(2-chloroethyl)-C8-CO2tBu (X118)X118 was prepared according to General Procedure A (1. chloroethylation; 2. peptidecoupling). 128tert-butyl 9-aminononaoate X116 (146.4 mg, 639 μmol, 8 equiv.) was dissolved in DCM(60 mL, 0.01 M), then 4-toluene sulfonic acid monohydrate (30 mg, 160 μmol, 2 equiv.) and2-chloroacetaldehyde (137 μL from aq.55% v / v, 12 equiv.) was added in one portion at r.t.The mixture was stirred for 15 min before NaCNBH3 (45.2 mg, 719 μmol, 9 equiv.) wasadded as a solid in one portion. The mixture was stirred at r.t. for 2 h, was then concentratedunder reduced pressure to obtain X117 as a crude material.To a solution of PAZ1-COOH (X2) (40.0 mg, 80 μmol, 1.0 equiv.) in anhydrous DMF (20 mM,4.0 mL) was added DIPEA (272 μL, 1.6 mmol, 20 equiv.) and a solution of the material X117obtained in step 1 (dissolved at 200 mM / DMF), followed by TOTU (95.9 mg, 96 μmol, 1.2equiv. from 100 mM / DMF). The resulting mixture was stirred at r.t. for 1 h, then taken intoMeCN:H2O (1:1, 5.0 mL) and directly subjected to purification by preparative HPLC to yieldX118 (39.9 mg, 52 μmol, 65%) as a colourless solid after lyophilization.HRMS (ESI+): for C38H47ClF2N5O6S+ (M+H)+: calc. m / z: 774.28082; found m / z: 774.29123.

[0144] PAZ2-C8-CO2tBu (X119)X119 was prepared according to General Procedure B (cyclisation).129X118 (6.0 mg, 7.75 μmol) was dissolved in anhydrous THF (6.0 mL, 1 mM) and a solution ofKOtBu (8.7 mg, 77.4 μmol, 10 equiv. from 50 mM / THF) was added dropwise under vigorousstirring. The resulting mixture was heated to 50 °C and further stirred for 2 h, before beingconcentrated under reduced pressure. The residue was taken into MeCN:H2O (1:1, 5.0 mL)and directly subjected to purification by preparative HPLC to yield X119 as a colourless solidafter lyophilization (2.7 mg, 3.6 μmol, 47%).HRMS (ESI+): for C38H46F2N5O6S+ (M+H)+: calc. m / z: 738.31314; found m / z: 738.31140.

[0145] PAZ2-C8-CO2H (X120)X120 was prepared according to General Procedure C (tBu ester deprotection).To a cold solution of X119 (10.0 mg, 13.6 μmol) in anhydrous DCM (0.5 mL) was added 80%TFA in anhydrous DCM (1.6 mL) and the resulting mixture was stirred at 0 °C for 2 h, beforebeing concentrated under reduced pressure. X120 was obtained as colourless solid (6.5 mg,9.55 μmol, 70%) after purification by preparative HPLC.The chiral purity of racemic X120 (dissolved at 4.8 mg / mL in MeCN) was analyzed using aChiralPak IB N-3 (4.6×100 mm, 3 μm) applying isocractic conditions (20:20:20:40MeOH:EtOH:iPrOH:CO2, 0.2% v / v isopropylamine) at 40 °C with 3 mL / min flow rate at120 bar. The chiral purity was determined with two species at RT 2.81 min, 48.4%, RT 4.25min, 48.2%. A sample of X120 (5.8 mg, 8.5 μmol) was subjected to preparative chiral SFCchromatography using a ChiralPak IB N (4.6×100 mm, 3 μm) (20:20:20:40MeOH:EtOH:iPrOH:CO2, 0.2% v / v isopropylamine) at 40 °C with 3 mL / min flow rate at130120 bar yielding X120_first eluting (1.9 mg, 2.8 μmol, 66% recovery) and X120_secondeluting (2.5 mg, 3.8 μmol, 89% recovery) as colourless solids.X120 (racemic): HPLC-LRMS ESI+-MS for C34H38F2N5O6S+ (M+H)+: calc. m / z: 682.3, foundm / z 682.2.X1201stand 2ndeluting enantiomers X120_first eluting HPLC-LRMS+-MS for C34H38F2N5O6S+(M+H)+: calc. m / z: 682.3, found m / z 682.2. X120_second eluting HPLC-LRMS ESI+-MS for C34H38F2N5O6S+(M+H)+: calc. m / z: 682.3, found m / z 682.2.Figure 3 shows A) X120_racemic, B) chiral column purified X120_first eluting peak and C)chiral column purified X120_second eluting peak. Table 3. Retention times for Figure 3A, 3B and 3C131

[0146] PAZ1-(2-chloroethyl)-C9-CO2tBu (X123)X123 was prepared according to General Procedure A (1. chloroethylation; 2. peptidecoupling).tert-butyl 10-aminodecanoate hydrochloride X121 (47.4 mg, 170 μmol, 10 equiv.) wasdissolved in DCM (17 mL, 0.01 M), then 4-toluene sulfonic acid monohydrate (6.4 mg,34 μmol, 2.0 equiv.) and 2-chloroacetaldehyde (58 μL from aq.55% v / v, 24 equiv.) wasadded in one portion at r.t. The mixture was stirred for 15 min before NaCNBH3 (21.3 mg,340 μmol, 20 equiv.) was added as a solid in one portion. The mixture was stirred at r.t. for 2h, was then concentrated under reduced pressure to obtain X122 as a crude material.To a solution of PAZ1-COOH (X2) (8.50 mg, 17 μmol, 1.0 equiv.) in anhydrous DMF (20 mM,0.9 mL) was added DIPEA (58 μL, 340 μmol, 20 equiv.) and a solution of the material X122obtained in step 1 (dissolved at 200 mM / DMF), followed by TOTU (6.7 mg, 20 μmol, 1.2equiv. from 100 mM / DMF). The resulting mixture was stirred at r.t. for 1 h, then taken intoMeCN:H2O (1:1, 5.0 mL) and directly subjected to purification by preparative HPLC to yieldX123 (7.3 mg, 9.25 μmol, 54%) as a colourless solid after lyophilization.HPLC-LRMS ESI+-MS for C39H49ClF2N5O6S+(M+H)+: calc. m / z: 788.3, found m / z 788.3.

[0147] PAZ2-C9-CO2tBu (X124)X124 was prepared according to General Procedure B (cyclisation).132X123 (1.5 mg, 1.90 μmol) was dissolved in anhydrous THF (2.0 mL, 1 mM) and a solution ofKOtBu (2.2 mg, 20.0 μmol, 10 equiv. from 50 mM / THF) was added dropwise under vigorous stirring. The resulting mixture was heated to 60 °C and further stirred for 2 h, before being concentrated under reduced pressure. The residue was taken into MeCN:H2O (1:1, 5.0 mL)and directly subjected to purification by preparative HPLC to yield X124 as a colourless solidafter lyophilization (0.7 mg, 0.93 μmol, 49%).HPLC-LRMS ESI+-MS for C39H48F2N5O6S+ (M+H)+: calc. m / z: 752.3, found 752.4:

[0148] PAZ2-C9-CO2H (X125)X125 was prepared according to General Procedure C (tBu ester deprotection).To a cold solution of X124 (0.7 mg, 0.93 μmol) in anhydrous DCM (0.1 mL) was added 80%TFA in anhydrous DCM (0.3 mL) and the resulting mixture was stirred at 0 °C for 2 h, beforebeing concentrated under reduced pressure. X125 was obtained as colourless solid (0.6 mg,0.86 μmol, 92%) and used without further purification.HRMS (ESI+): for C35H40F2N5O6S+ (M+H)+: calc. m / z: 696.26619; found m / z: 696.26429.

[0149] PAZ1-(2-chloroethyl)-C10-CO2tBu (X128)X128 was prepared according to General Procedure A (1. chloroethylation; 2. peptidecoupling). 133tert-butyl 11-aminoundecanoate hydrochloride X126 (25.9 mg, 101 μmol, 9 equiv.) wasdissolved in DCM (10 mL, 0.01 M), then 4-toluene sulfonic acid monohydrate (3.2 mg,17 μmol, 1.5 equiv.) and 2-chloroacetaldehyde (18 μL from aq.55% v / v, 11 equiv.) was addedin one portion at r.t. The mixture was stirred for 15 min before NaCNBH3 (6.2 mg, 101 μmol,9 equiv.) was added as a solid in one portion. The mixture was stirred at r.t. for 2 h, was thenconcentrated under reduced pressure to obtain X127 as a crude material.To a solution of PAZ1-COOH (X2) (5.6 mg, 11 μmol, 1.0 equiv.) in anhydrous DMF (20 mM,0.6 mL) was added DIPEA (29 μL, 167 μmol, 15 equiv.) and a solution of the material X127obtained in step 1 (dissolved at 200 mM / DMF), followed by TOTU (4.2 mg, 13 μmol, 1.2equiv. from 100 mM / DMF). The resulting mixture was stirred at r.t. for 1 h, then taken intoMeCN:H2O (1:1, 5.0 mL) and directly subjected to purification by preparative HPLC to yieldX128 (6.1 mg, 9.8 μmol, 87%) as a colourless solid after lyophilization.HRMS (ESI+): for C40H51ClF2N5O6S+ (M+H)+: calc. m / z: 802.32112; found m / z: 802.31998.

[0150] PAZ2-C10-CO2tBu (X129)X129 was prepared according to General Procedure B (cyclisation).134X128 (5.7 mg, 14.4 μmol) was dissolved in anhydrous THF (7.0 mL, 1 mM) and a solution ofKOtBu (8.0 mg, 71 μmol, 10 equiv. from 50 mM / THF) was added dropwise under vigorousstirring. The resulting mixture was heated to 50 °C and further stirred for 2 h, before beingconcentrated under reduced pressure. The residue was taken into MeCN:H2O (1:1, 5.0 mL)and directly subjected to purification by preparative HPLC to yield X129 as a colourless solidafter lyophilization (2.5 mg, 3.3 μmol, 46%).HRMS (ESI+): for C40H50F2N5O6S+ (M+H)+: calc. m / z: 766.34444; found m / z: 766.34672.

[0151] PAZ2-C10-CO2H (X130)X130 was prepared according to General Procedure C (tBu ester deprotection).To a cold solution of X129 (2.5 mg, 3.3 μmol) in anhydrous DCM (0.15 mL) was added 80%TFA in anhydrous DCM (0.45 mL) and the resulting mixture was stirred at 0 °C for 2 h, beforebeing concentrated under reduced pressure. X130 was obtained as colourless solid (1.8 mg,4.8 μmol, 76%) and used without further purification.HRMS (ESI+): for C36H42F2N5O6S+ (M+H)+: calc. m / z: 710.28184; found m / z: 710.28418.

[0152] PAZ1-(2-chloroethyl)-C11-CO2tBu (X133)X133 was prepared according to General Procedure A (1. chloroethylation; 2. peptidecoupling). 135tert-butyl 12-aminododecanoate hydrochloride X131 (35.2 mg, 130 μmol, 10 equiv.) wasdissolved in DCM (12 mL, 0.01 M), then 4-toluene sulfonic acid monohydrate (4.9 mg,26 μmol, 2 equiv.) and 2-chloroacetaldehyde (26 μL from aq.55% v / v, 14 equiv.) was addedin one portion at r.t. The mixture was stirred for 15 min before NaCNBH3 (9.8 mg, 156 μmol,12 equiv.) was added as a solid in one portion. The mixture was stirred at r.t. for 2 h, wasthen concentrated under reduced pressure to obtain X132 as a crude material.To a solution of PAZ1-COOH (X2) (6.5 mg, 13 μmol, 1.0 equiv.) in anhydrous DMF (20 mM,0.7 mL) was added DIPEA (66 μL, 390 μmol, 30 equiv.) and a solution of the material X127obtained in step 1 (dissolved at 200 mM / DMF), followed by TOTU (5.1 mg, 15.5 μmol, 1.2equiv. from 100 mM / DMF). The resulting mixture was stirred at r.t. for 1 h, then taken intoMeCN:H2O (1:1, 5.0 mL) and directly subjected to purification by preparative HPLC to yieldX133 (6.5 mg, 8.4 μmol, 65%) as a colourless solid after lyophilization.HPLC-LRMS ESI+-MS for C41H53ClF2N5O6S+(M+H)+: calc. m / z: 816.3, found m / z 816.4.

[0153] PAZ2-C11-CO2tBu (X134)X134 was prepared according to General Procedure B (cyclisation).136X133 (6.5 mg, 8.0 μmol) was dissolved in anhydrous THF (8.0 mL, 1 mM) and a solution ofKOtBu (6.2 mg, 56 μmol, 7 equiv. from 50 mM / THF) was added dropwise under vigorousstirring. The resulting mixture was heated to 50 °C and further stirred for 2 h, before beingconcentrated under reduced pressure. The residue was taken into MeCN:H2O (1:1, 5.0 mL)and directly subjected to purification by preparative HPLC to yield X134 as a colourless solidafter lyophilization (3.6 mg, 4.9 μmol, 46%).HPLC-LRMS ESI+-MS for C41H52F2N5O6S+ (M+H)+: calc. m / z: 780.4, found m / z 780.4

[0154] PAZ2-C11-CO2H (X135)X135 was prepared according to General Procedure C (tBu ester deprotection).To a cold solution of X134 (3.6 mg, 4.6 μmol) in anhydrous DCM (0.1 mL) was added 80%TFA in anhydrous DCM (0.4 mL) and the resulting mixture was stirred at 0 °C for 2 h, beforebeing concentrated under reduced pressure. X135 was obtained as colourless solid (3.0 mg,4.2 μmol, 91%) and used without further purification.HRMS (ESI+): for C37H44F2N5O6S+ (M+H)+: calc. m / z: 724.29749; found m / z: 724.30331.

[0155] PAZ1-(2-chloroethyl)-C13-CO2tBu (X143)X143 was prepared according to General Procedure A (1. chloroethylation; 2. peptidecoupling). 137tert-butyl 14-aminotdecanoate X141 (47.8 mg, 160 μmol, 8 equiv.) was dissolved in DCM (16mL, 0.01 M), then 4 toluene sulfonic acid monohydrate (7.5 mg, 4.0 μmol, 2 equiv.) and 2-chloroacetaldehyde (46 μL from aq.55% v / v, 16 equiv.) was added in one portion at r.t. The mixture was stirred for 15 min before NaCNBH3 (18.5 mg, 295 μmol, 15 equiv.) was added as a solid in one portion. The mixture was stirred at r.t. for 2 h, was then concentrated underreduced pressure to obtain X142 as a crude material.X143To a solution of PAZ1 COOH (X2) (10.0 mg, 20 μmol, 1.0 equiv.) in anhydrous DMF (20 mM,2.0 mL) was added DIPEA (98 μL, 475 μmol, 28 equiv.) and a solution of the material X142 obtained in step 1 (dissolved at 200 mM / DMF), followed by TOTU (7.8 mg, 24.0 μmol, 1.2 equiv. from 100 mM / DMF). The resulting mixture was stirred at r.t. for 1 h, then taken into MeCN:H2O (1:1, 5.0 mL) and directly subjected to purification by preparative HPLC to yieldX143 (4.6 mg, 5.4 μmol, 27%) as a colourless solid after lyophilization.HRMS (ESI+): for C43H57ClF2N5O6S+ (M+H)+: calc. m / z: 844.36807; found m / z: 844.39356.

[0156] PAZ2-C13-CO2tBu (X144)X144 was prepared according to General Procedure B (cyclisation).138X143 (4.6 mg, 5.4 μmol) was dissolved in anhydrous THF (5.4 mL, 1 mM) and a solution ofKOtBu (6.0 mg, 54 μmol, 10 equiv. from 50 mM / THF) was added dropwise under vigorousstirring. The resulting mixture was stirred at r.t. for 2 h, before being concentrated underreduced pressure. The residue was taken into MeCN:H2O (1:1, 5.0 mL) and directly subjected to purification by preparative HPLC to yield X144 as a colourless solid after lyophilization (0.3 mg, 0.4 μmol, 7%).HRMS (ESI+): for C43H56F2N5O6S+ (M+H)+: calc. m / z: 808.39139; found m / z: 808.39466.

[0157] PAZ2-C13-CO2H (X145)X145 was prepared according to General Procedure C (tBu ester deprotection).To a cold solution of X144 (0.3 mg, 0.4 μmol) in anhydrous DCM (0.1 mL) was added 80%TFA in anhydrous DCM (0.3 mL) and the resulting mixture was stirred at 0 °C for 2 h, beforebeing concentrated under reduced pressure. X145 was obtained as colourless solid (0.2 mg,0.3 μmol, 75%) and used without further purification.HRMS (ESI+): for C39H48F2N5O6S+ (M+H)+: calc. m / z: 752.32879; found m / z: 752.32913.

[0158] PAZ1-(2-chloroethyl)-C14-CO2tBu (X148)X148 was prepared according to General Procedure A (1. chloroethylation; 2. peptidecoupling). 139tert-butyl 15-aminopentadecanoate X146 (40.7 mg, 130 μmol, 10 equiv.) was dissolved inDCM (12 mL, 0.01 M), then 4-toluene sulfonic acid monohydrate (4.9 mg, 26 μmol, 2 equiv.)and 2-chloroacetaldehyde (24 μL from aq.55% v / v, 13 equiv.) was added in one portion at r.t.The mixture was stirred for 15 min before NaCNBH3 (9.8 mg, 156 μmol, 12 equiv.) wasadded as a solid in one portion. The mixture was stirred at r.t. for 2 h, was then concentratedunder reduced pressure to obtain X147 as a crude material.To a solution of PAZ1-COOH (X2) (6.5 mg, 13 μmol, 1.0 equiv.) in anhydrous DMF (20 mM,0.7 mL) was added DIPEA (44 μL, 260 μmol, 20 equiv.) and a solution of the material X147obtained in step 1 (dissolved at 200 mM / DMF), followed by TOTU (5.1 mg, 15.5 μmol, 1.2equiv. from 100 mM / DMF). The resulting mixture was stirred at r.t. for 1 h, then taken intoMeCN:H2O (1:1, 5.0 mL) and directly subjected to purification by preparative HPLC to yieldX148 (5.9 mg, 6.9 μmol, 53%) as a colourless solid after lyophilization.HRMS (ESI+): for C44H59ClF2N5O6S+ (M+H)+: calc. m / z: 822.40704; found m / z: 822.40846.

[0159] PAZ2-C14-CO2tBu (X149)X149 was prepared according to General Procedure B (cyclisation).140X148 (5.9 mg, 6.9 μmol) was dissolved in anhydrous THF (6.8 mL, 1 mM) and a solution ofKOtBu (4.6 mg, 41 μmol, 6 equiv. from 50 mM / THF) was added dropwise under vigorousstirring. The resulting mixture was stirred at r.t. for 2 h, before being concentrated underreduced pressure. The residue was taken into MeCN:H2O (1:1, 5.0 mL) and directlysubjected to purification by preparative HPLC to yield X149 as a colourless solid afterlyophilization (2.4 mg, 3.3 μmol, 48%).HPLC-LRMS ESI+-MS for C44H58F2N5O6S+(M+H)+: calc. m / z: 822.4, found m / z 822.4.

[0160] PAZ2-C14-CO2H (X150)X150 was prepared according to General Procedure C (tBu ester deprotection).To a cold solution of X149 (2.4 mg, 2.9 μmol) in anhydrous DCM (0.1 mL) was added 80%TFA in anhydrous DCM (0.4 mL) and the resulting mixture was stirred at 0 °C for 2 h, beforebeing concentrated under reduced pressure. X150 was obtained as colourless solid (2.1 mg,2.7 μmol, 93%) and used without further purification.HRMS (ESI+): for C40H50F2N5O6S+ (M+H)+: calc. m / z: 766.34444; found m / z: 766.34672.141

[0161] PAZ1-(2-chloroethyl)-C15-CO2tBu (X153)X153 was prepared according to General Procedure A (1. chloroethylation; 2. peptidecoupling).tert-butyl 16-aminohexadecanoate X151 (56.7 mg, 173 μmol, 13.3 equiv.) was dissolved inDCM (17 mL, 0.01 M), then 4-toluene sulfonic acid monohydrate (4.9 mg, 26 μmol, 2 equiv.)and 2-chloroacetaldehyde (26 μL from aq.55% v / v, 14 equiv.) was added in one portion at r.t.The mixture was stirred for 15 min before NaCNBH3 (9.0 mg, 143 μmol, 11 equiv.) wasadded as a solid in one portion. The mixture was stirred at r.t. for 2 h, was then concentratedunder reduced pressure to obtain X152 as a crude material.To a solution of PAZ1-COOH (X2) (6.5 mg, 13 μmol, 1.0 equiv.) in anhydrous DMF (20 mM,0.7 mL) was added DIPEA (44 μL, 260 μmol, 20 equiv.) and a solution of the material X152obtained in step 1 (dissolved at 200 mM / DMF), followed by TOTU (5.1 mg, 15.5 μmol, 1.2equiv. from 100 mM / DMF). The resulting mixture was stirred at r.t. for 1 h, then taken intoMeCN:H2O (1:1, 5.0 mL) and directly subjected to purification by preparative HPLC to yieldX153 (3.6 mg, 4.2 μmol, 32%) as a colourless solid after lyophilization.HPLC-LRMS 7.82 min (9 min, H2O / MeCN / 0.1% FA); ESI+-MS for C45H61ClF2N5O6S+ (M+H)+:calc. m / z: 872.4, found m / z 872.4. 142

[0162] PAZ2-C15-CO2tBu (X154)X154 was prepared according to General Procedure B (cyclisation).X153 (3.6 mg, 4.1 μmol) was dissolved in anhydrous THF (4.1 mL, 1 mM) and a solution ofKOtBu (4.6 mg, 41 μmol, 10 equiv. from 50 mM / THF) was added dropwise under vigorousstirring. The resulting mixture was stirred at r.t. for 2 h, before being concentrated underreduced pressure. The residue was taken into MeCN:H2O (1:1, 5.0 mL) and directlysubjected to purification by preparative HPLC to yield X154 as a colourless solid afterlyophilization (1.8 mg, 2.1 μmol, 51%).HPLC-LRMS ESI+-MS for C45H59F2N5O6S+(M+H)+: calc. m / z: 836.4, found m / z 836.5.

[0163] PAZ2-C15-CO2H (X155)X155 was prepared according to General Procedure C (tBu ester deprotection).To a cold solution of X154 (1.8 mg, 2.1 μmol) in anhydrous DCM (0.1 mL) was added 80%TFA in anhydrous DCM (0.4 mL) and the resulting mixture was stirred at 0 °C for 2 h, beforebeing concentrated under reduced pressure. X135 was obtained as colourless solid (1.5 mg,1.9 μmol, 90%) and used without further purification.HPLC-LRMS ESI+-MS for C41H52F2N5O6S+(M+H)+: calc. m / z: 780.4, found m / z 780.4. 143PREPARATION OF PAZ3 EXAMPLES

[0164] tert-butyl4-(5-chloropentanoyl)-6-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (X43)To a solution of 6-nitro-1,2,3,4-tetrahydroquinoxaline (4.5 g, 25 mmol, 1.0 equiv.) inanhydrous DCM (0.5 L, 0.05 M) was added DIPEA (4.3 mL, 1.0 equiv.) and the mixture wascooled to 0°C. To this mixture was added a solution of 5-chloro-pentanoylchloride (3.9 g, 1.0eq.) in DCM (50 mL, 0.5 M). The mixture was allowed to warm to r.t. and further stirred for2 h. To this mixture was added a solution of DMAP (0.61 g, 5 mmol, 0.2 equiv.) and DIPEA(8.5 mL, 2.0 equiv.), followed by Boc2O (17.0 g, 78 mmol, 3.1 equiv.). The resulting clearorange solution was further stirred at r.t. for 15 h, was then heated to 35 °C and was furtherstirred for 24 h. The resulting solution was washed with aq. NaHCO3 solution (4 × 0.4 L),dried over Na2SO4and concentrated under reduced pressure. Purification was achievedusing flash column chromatography (silica, 50 g, cyclohexane:EtOAc, 19:1^1:1) to yieldintermediate 5-chloro-1-(7-nitro-3,4-dihydroquinoxalin-1(2H)-yl)pentan-1-one X42 (4.22 g,14.2 mmol) and the desired X43 (4.56 g, 11.5 mmol, 46%) as orange oils. The intermediateX42 was dissolved in anhydrous DCM (0.2 L, 0.07 M), and triethylamine (10 mL, 75 mmol,3.0 equiv.), DMAP (0.6 g, 5 mmol, 0.2 equiv.) and Boc2O (3.9 g, 0.7 equiv.) was added. Theresulting orange solution was stirred at r.t. for 48 h, before being washed with aq. NaHCO3solution (3 × 0.3 L), dried over Na2SO4 and concentrated under reduced pressure.Purification by flash column chromatography yielded additional X43 (4.13 g, 10.4 mmol,42%) that was combined with the material obtained in the first step to overall yield X43(8.69 g, 21.8 mmol, 87%) as an orange oil.X42HPLC-LRMS ESI+-MS for C H ClN O + (M+H)+: calc. m / z: 298. 113 17 3 3 1, found m / z 298.0. H-NMR(400 MHz, CDCl3) δ (ppm) = 8.87 – 8.29 (m, 2H), 7.90 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 9.0Hz, 1H), 5.22 (s, 1H), 3.93 – 3.81 (m, 2H), 3.62 – 3.43 (m, 4H), 2.70 – 2.53 (m, 2H), 1.90 –1.77 (m, 4H). 13C-NMR (101 MHz, CDCl3) δ (ppm) = 171.5, 143.9, 136.9, 123.2, 122.7,121.2, 113.1, 44.8, 42.4, 38.0, 33.3, 32.0, 22.9. X43 HPLC-LRMS ESI+-MS for C14H17ClN3O5+(M-C4H8+H)+: calc. m / z: 342.1, found m / z 342.0. 1441H-NMR (600 MHz, CDCl3) δ (ppm) = 8.20 (s, 1H), 8.09 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H),3.92 (t, J = 5.7 Hz, 2H), 3.87 (t, J = 5.7 Hz, 2H), 3.53 (t, J = 6.0 Hz, 2H), 2.57 (t, J = 7.1 Hz,2H), 1.93 – 1.76 (m, 4H), 1.55 (s, 9H).13C-NMR (101 MHz, CDCl3) δ (ppm) = 170.9, 152.6, 142.3, 138.9, 131.0, 123.4, 121.3,120.0, 83.4, 47.4, 44.7, 33.3, 32.0, 28.3, 22.8.

[0165] tert-butyl-6-amino-4-(5-chloropentanoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (X44)X43 (560 mg, 1.41 mmol) was dissolved in MeOH (70 mL, 0.02 M) and Pd / C (56 mg, 10 w%)was added. The mixture was put under H2 atmosphere using repeated evacuation followed by flushing with H2 gas and finally equilibrated with an H2 balloon. The mixture was stirred atr.t. for 15 h, was then filtered over Celite and concentrated under reduced pressure. X44 wasobtained as a colourless solid (453 mg, 1.23 mmol, 87%) and was directly used withoutfurther purification. Purification of analytical samples was achieved using either FCC(cyclohexane / EtOAc) or preparative HPLC (MeCN / H2O / 0.1% TFA).HPLC-LRMS ESI+-MS for C18H27ClN3O3+(M+Na)+: calc. m / z: 390.2, found m / z 390.2.1H-NMR (400 MHz, CDCl3) δ (ppm) = 7.66 (s, 1H), 6.54 (d, J = 7.6 Hz, 1H), 6.42 (s, 1H), 3.85(t, J = 6.0 Hz, 2H), 3.74 (t, J = 6.2 Hz, 2H), 3.64 (d, J = 8.9 Hz, 2H), 3.51 (t, J = 5.9 Hz, 2H),2.55 (t, J = 7.2 Hz, 2H), 1.86 – 1.73 (m, 4H), 1.50 (s, 9H).13C-NMR (101 MHz, CDCl3) δ(ppm) = 171.5, 153.6, 142.6, 125.3, 113.4, 110.6, 81.3, 46.7, 44.7, 43.2, 33.1, 32.0, 28.5,28.5, 23.0.

[0166] tert-butyl-6-amino-4-(5-chloropentanoyl)-7-iodo-3,4-dihydroquinoxaline-1(2H)-carboxylate (X45)To a solution of X44 (28.0 mg, 76 μmol) in Et2O (0.01 M) was added iodine (38.6 mg, 152 μmol, 2.0 equiv.) as a solid, followed by DMSO (19 μL, 267 μmol, 3.5 equiv.) in one portion. The solution turned dark red and was stirred at r.t. for 30 min, before being concentrated. Purification by FCC yielded X45 (19.6 mg, 40 μmol, 52%) as a colourless solid.TLC Rf = 0.67 (cyclohexane:EtOAc; 70:30).145HPLC-LRMS ESI+-MS for C18H25IClNaN3O3+(M+Na)+: calc. m / z: 516.0, found m / z 516.1.1H-NMR (400 MHz, CDCl3) δ (ppm) = 8.17 (s, 1H), 6.61 (s, 1H), 4.03 (s, 2H), 3.85 (t, J = 6.2Hz, 2H), 3.81 – 3.69 (m, 2H), 3.53 (t, J = 5.8 Hz, 2H), 2.53 (t, J = 6.1 Hz, 2H), 2.17 (s, 2H),1.94 – 1.75 (m, 4H), 1.52 (s, 9H).

[0167] Synthesis of tert-butyl 6-amino-4-(5-chloropentanoyl)-7-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (X47)X46 was prepared according to Wang, X. et al “Structure-guided discovery of novel potentand efficacious proteolysis targeting chimera (PROTAC) degrader of BRD4”, Biorg. Chem. V. 115, (2021) p 105238.A solution of X45 (0.0040 g, 0.081 mmol), Pd(dppf)Cl2 (0.0061 g, 0.008 mmol), X46 (0.049 g,0.113 mmol), NaHCO3(0.017 g, 0.203 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL) was heated to 90 °C for 1 h. The reaction was monitored by using UPLC-mass analysis. The mixture was cooled to 25 °C and was concentrated to get the crude material which was purified by silica gel chromatography using a gradient elution (MeOH: cyclohexane; 0:100 to10:90) to give X47 (0.02 g, 37%) as a yellowish compound.LCMS: calculated for C33H38ClN5O6S: 667.2231, found 668.2 (M+H).1H-NMR (400 MHz, CDCl3) δ (ppm) = 7.96 (d, J = 8.0 Hz, 2H), 7.90 – 7.84 (m, 1H), 7.73 (s,1H), 7.31 (d, J = 8.1 Hz, 2H), 7.17 (s, 1H), 6.77 (s, 1H), 6.40 (d, J = 3.5 Hz, 1H), 3.91 (s, 2H), 3.82 (d, J = 6.2 Hz, 2H), 3.54 (d, J = 6.1 Hz, 2H), 3.50 (s, 3H), 2.59 (s, 2H), 2.41 (s, 3H), 1.94– 1.76 (m, 4H), 1.49 (s, 9H).146

[0168] tert-butyl 4-(5-chloropentanoyl)-6-((3,5-difluoropyridin-2-yl)amino)-7-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (X49)To a solution of X47 (0.017 g, 0.025 mmol) in 1,4-dioxane (1.0 mL) was added Cs2CO3(0.0164 g, 0.05 mmol), BrettPhos (0.007 g, 0.013 mmol), BrettPhos 3G (0.005 g, 0.005mmol) and X48 (0.015 g, 0.076 mmol). The resulted reaction mixture was then stirred at 90°C for 12 h. The reaction was monitored by using UPLC-mass analysis. The mixture was cooled to 25 °C and was concentrated to get the crude material which was purified by silica gel chromatography using a gradient elution (EtOAc: cyclohexane; 0:100 to 60:40) to giveX49 (0.006 g, 30%) as yellowish compound.LCMS: calculated for C38H39ClF2N6O6S: 780.2308, found 781.3 (M+H)

[0169] Synthesis of tert-butyl 4-(5-chloropentanoyl)-6-((3,5-difluoropyridin-2-yl)amino)-7-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (X50)To a solution of X49 (0.006 g, 0.008 mmol) in THF (1 mL) was added TBAF (0.023 mL, 0.023mmol, 1 M in THF). The resulted reaction mixture was stirred at 60 °C for 2 h and monitored by using UPLC-mass analysis. The mixture was cooled to 25 °C, diluted with water and was subsequently extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, and was concentrated to get crude material which was purified by silica gel chromatography using a gradient elution (MeOH: CH2Cl2; 0:100 to20:80) to give X50 (0.00278 g, 58%) as a yellowish compound.LCMS: calculated for C31H33ClF2N6O4: 626.2220, found 627.2 (M+H) 147

[0170] Synthesis of tert-butyl 6-(5-chloropentanoyl)-4-(3,5-difluoropyridin-2-yl)-12-methyl-13-oxo-1,3,4,6,7,8,12,13-octahydro-9H-1,4,6,9,12-pentaazabenzo[cd]naphtho[2,3-f]azulene-9-carboxylate (X51)To a solution of X50 (0.003 g, 0.005 mmol) in acetic acid (0.5 mL) was addedparaformaldehyde (0.004 g, 0.014 mmol). The reaction mixture was stirred heated at 75 °C for 1 h and the progress of the reaction was monitored by using UPLC-mass analysis. The mixture was cooled to 25 °C and was concentrated to get crude material which was purified by silica gel chromatography using a gradient elution (MeOH: CH2Cl2; 0:100 to 20:80) to givethe product to give X51 (0.0015 g, 49%) as a yellowish compound.LCMS: calculated for C32H33ClF2N6O4: 638.2220, found 639.2 (M+H)

[0171] Synthesis of tert-butyl 6-(5-azidopentanoyl)-4-(3,5-difluoropyridin-2-yl)-12-methyl-13-oxo-1,3,4,6,7,8,12,13-octahydro-9H-1,4,6,9,12-pentaazabenzo[cd]naphtho[2,3-f]azulene-9-carboxylate (X52)To a solution of X51 (0.0015 g, 0.002 mmol) in DMSO (1 mL) was added NaN3 (0.005 g,0.007 mmol). The reaction mixture was stirred at 60 °C for 12 h. The reaction was monitored by using UPLC-mass analysis. The reaction mixture was diluted with water and was subsequently extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, and was concentrated under vacuum to get X52 which was used for the next step without need of further purification. LCMS: calculated for C32H33F2N9O2: 645.2624, found 646.3 (M+H) 148

[0172] Synthesis of 6-(5-azidopentanoyl)-4-(3,5-difluoropyridin-2-yl)-12-methyl-1,3,4,6,7,8,9,12-octahydro-13H-1,4,6,9,12-pentaazabenzo[cd]naphtho[2,3-f]azulen-13-one (X53)To the cold solution of X52 (0.0057 g, 0.009 mmol) in CH2Cl2 (0.100 mL) was added 80%TFAin CH2Cl2 (0.4 mL). The resulted solution was stirred at 0 °C at 2h. The reaction was monitored by using UPLC-mass analysis. Solvent was evaporated by the continuous flow ofargon (repeated 3 times) and the resulting solid X53 was used for the next step without theneed of purification. LCMS: calculated for C27H25F2N9O2: 545.2099, found 546.3 (M+H)

[0173] Synthesis of 6-(5-azidopentanoyl)-4-(3,5-difluoropyridin-2-yl)-12-methyl-9-(methylsulfonyl)-1,3,4,6,7,8,9,12-octahydro-13H-1,4,6,9,12-pentaazabenzo[cd]naphtho[2,3- f]azulen-13-one (X54)To a cold solution of the X53 (0.002 g, 0.004 mmol) in CH2Cl2 (1 mL) was added Et3N(0.0015 mL, 0.011 mmol) followed by methanesulfonyl chloride (0.0003 mL, 0.004 mmol). The resulted reaction mixture was stirred at 22 °C for 4 h. The reaction was monitored by using UPLC-mass analysis. The reaction mixture was diluted with water and was subsequently extracted with CH2Cl2(10 mL x 2). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, and was concentrated to get crude material which was diluted with 0.1% TFA in water (1 ml) and purified via preparative HPLC eluting with a gradient method at 14 ml / min on a VP 250 / 21 Macherey-Nagel Nucleodur C18 HTec Spum column (Macherey-Nagel GmbH & Co. Kg, Germany) to obtain X54 as yellowish compound.1H-NMR (800 MHz, DMSO-d6) δ (ppm) = 11.88 (d, J = 2.7 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H),7.86 (s, 1H), 7.60 (ddd, J = 12.3, 8.1, 2.5 Hz, 1H), 7.53 (s, 1H), 7.25 (d, J = 2.7 Hz, 1H), 5.92149(s, 1H), 4.21 (s, 1H), 4.04 (s, 1H), 3.90 (s, 1H), 3.80 (s, 1H), 3.61 (s, 3H), 3.15 (s, 3H), 1.54(s, 2H), 1.48 (s, 2H), 1.31 – 1.20 (m, 2H).LCMS: calculated for C28H27F2N9O4S: 623.1875, found 624.2 (M+H)

[0174] Synthesis of X71Step 1: To the cold solution of X52 (139 mg, 0.215 mmol) in THF (5 mL) was added NaH (16mg, 0.323 mmol, 50% suspension), followed by toluenesulfonyl chloride (258 mg, 0.323 mmol) and the resulting reaction mixture was stirred at r.t. for 1 h, was then diluted with water and, subsequently, extracted with EtOAc (2 × 10 mL). The combined organic layers werewashed with brine (3 × 10 mL), dried over Na2SO4, concentrated and purified by silica gelchromatography using a gradient elution (EtOAc:cyclohexane; 0:100 to 90:10) to give X70(156 mg, 0.195 mmol, 91%).Analytical data for X70: HPLC-LRMS (ESI+): for C39H40F2N9O6S+ (M+H)+: calc. m / z 800.3,found m / z 800.4. HRMS (ESI+): for C39H40F2N9O6S+ (M+H)+: calc. m / z 800.27848, found m / z800.27633. Step 2: The material obtained in step 1 (X70) (0.156 g, 0.195 mmol) was dissolved in DCM(0.5 mL), 20% TFA in DCM (3.5 mL) was added at 0 °C and the resulting solution was stirredat 0 °C for 2 h. Solvent was evaporated by the continuous flow of argon (redissolved 2 timesin DCM and evaporated) to yield X71 as a trifluoroacetate salt (159 mg, 0.195 mmol, 100%)which was directly used for further steps.Analytical data for X71: HPLC-LRMS (ESI+): for C34H32F2N9O4S+ (M+H)+: calc. m / z 700.2,found m / z 700.4. HRMS (ESI+): for C34H32F2N9O4S+ (M+H)+: calc. m / z 700.22605, found m / z700.21710.

[0175] PAZ3-SO2Et (X72)Step 1 (N-sulfonylation): To a cold solution of the X71 (5.0 mg, 7.1 μmol, 1.0 eq.) inanhydrous DCM (2.0 mL) was added Et3N (70 μL, 50 μmol, 7.0 eq.) followed by 150ethanesulfonyl chloride (2.0 μL, 21 μmol, 3.0 eq.). The resulted reaction mixture was stirred at r.t. for 4 h, was then diluted with water and subsequently extracted with DC The combined organic layers were washed with brine (3 × 10 mL), dried overwas concentrated to yield crude material which was diluted with MeCN:H2O (2TFA) and purified via preparative HPLC eluting the sulfonylated intermediate1.9 μmol, 27%) which was used further in the next step.Step 2 (N-detosylation): The material obtained in step 1 was dissolved in THF (1.0 mL) andTBAF (6 μL, 6 vmol, from 1 M in THF, 3.0 eq.). The resulted reaction mixture was stirred atr.t. for 16 h. The mixture was diluted with MeCN:H2O (2 mL, 1:1, 0.1% TFA) and purified viapreparative HPLC to obtain X72 (0.5 mg, 0.8 μmol, 42%, 11% over 2 steps).HPLC-LRMS (ESI+): for C29H30F2N9O4S+ (M+H)+: calc. m / z 638.2; found m / z 638.3. HRMS(ESI+): for C29H30F2N9O4S+ (M+H)+: calc. m / z 638.21040; found m / z 638.20581.

[0176] General procedure D: Reductive amination of PAZ derivativesStep 1 (reductive amination): To a solution of X71 (1.0 eq.) in DCE (0.01 M) was added therespective aldehyde (5.0 eq.) and Na(OAc)3BH (5.0 eq.). The resulting reaction mixture was stirred at 50 °C for 4 h, was then diluted with DCM and washed with sat. aq. NaHCO3. The combined organic layers were dried over Na2SO4, concentrated to yield crude materialcontaining X73’-X78’ which was used for the consequent step without further purification.Step 2 (N-detosylation): The material obtained in step 1 was dissolved in THF (0.01 M) andTBAF (3.0 eq. from 1 M in THF) was added. The resulting reaction mixture was stirred at 50°C for 5 h, was then diluted with MeCN:H2O (2 mL, 1:1, 0.1% TFA) and purified viapreparative HPLC to obtain X73-X78 (17 to 44% yield over 2 steps).

[0177] PAZ3-Me (X73)151X73 (1.6 mg, 2.9 μmol, 41% over 2 steps) was prepared according to the general procedureD from X71 (5.0 mg, 7.1 μmol, 1.0 eq.), para-formaldehyde (1.1 mg, 36 μmol, 5.0 eq.),Na(OAc)3BH (7.6 mg, 36 μmol, 5.0 eq.), and, subsequently, TBAF (21 μL, 21 μmol, 3.0 eq.).HPLC-LRMS (ESI+): C28H28F2N9O2+ (M+H)+: calc. m / z 560.2; found m / z 560.4. HRMS (ESI+):for C28H28F2N9O2+ (M+H)+: calc. m / z 560.23285; found m / z 560.22675.

[0178] PAZ3-Et (X74)X74 (1.5 mg, 2.6 μmol, 37% over 2 steps) was prepared according to the general procedureD from X71 (5.0 mg, 7.1 μmol, 1.0 eq.), acetaldehyde (2 μL, 36 μmol, 5.0 eq.), Na(OAc)3BH(7.6 mg, 36 μmol, 5.0 eq.), and, subsequently, TBAF (21 μL, 21 μmol, 3.0 eq.).HPLC-LRMS (ESI+): C29H30F2N9O2+ (M+H)+: calc. m / z 574.2; found m / z 574.3. HRMS (ESI+):for C29H30F2N9O2+ (M+H)+: calc. m / z 574.24850; found m / z 574.24502.

[0179] PAZ3-C2-SO2Me (X75)2(methylsulfonyl)acetaldehyde was prepared in situ via Dess-Martin oxidation from 2-(methlsulfonyl)ethanol (10 mg, 0.08 mmol, 1.0 eq.) and Dess-Martin periodinane (51 mg,0.12 mmol, 1.5 eq.) in DCM (0.1 M). X75 (0.6 mg, 1.1 μmol, 26% over 2 steps) was preparedaccording to the general procedure D from X71 (3.0 mg, 4.3 μmol, 1.0 eq.),2(methylsulfonyl)acetaldehyde (2.6 mg, 21 μmol, 5.0 eq.), Na(OAc)3BH (9.1, 43 μmol,10.0 eq.), and, subsequently, TBAF (6 μL, 6 μmol, 3.0 eq.).HPLC-LRMS (ESI+): C30H31F2N9O4S+ (M+H)+: calc. m / z 652.2; found m / z 652.3. HRMS(ESI+): for C30H31F2N9O4S+ (M+H)+: calc. m / z 652.22605; found m / z 652.22841.152

[0180] PAZ3-C1-sulfolane (X76)Sulfolane-3-carbaldehyde was prepared in situ via Dess-Martin oxidation from 2-(3-sulfolanyl)ethanol 12 mg, 0.08 mmol, 1.0 eq.) and Dess-Martin periodinane (51 mg,0.12 mmol, 1.5 eq.) in DCM (0.1 M). X76 (0.5 mg, 0.7 μmol, 17% over 2 steps) was preparedaccording to the general procedure D from X71 (3.0 mg, 4.3 μmol, 1.0 eq.), sulfolane-3-carbaldehyde (2.6 mg, 21 μmol, 5.0 eq.), Na(OAc)3BH (9.1, 43 μmol, 10.0 eq.), and,subsequently, TBAF (6 μL, 6 μmol, 3.0 eq.).HPLC-LRMS (ESI+): C32H34F2N9O4S+ (M+H)+: calc. m / z 678.2; found m / z 678.4. HRMS(ESI+): for C32H34F2N9O4S+ (M+H)+: calc. m / z 678.24170; found m / z 678.23375.

[0181] PAZ3-C1-thiazole (X77)X77 (1.4 mg, 2.1 μmol, 30% over 2 steps) was prepared according to the general procedureD from X71 (5.0 mg, 7.1 μmol, 1.0 eq.), 2-methyl-1,3-thiazole-4-carboxaldehyde (4.5 mg, 36μmol, 5.0 eq.), Na(OAc)3BH (7.6 mg, 36 μmol, 5.0 eq.), and, subsequently, TBAF (19 μL,19 μmol, 3.0 eq.).HPLC-LRMS (ESI+): C32H31F2N10O2S+ (M+H)+: calc. m / z 657.2; found m / z 657.4. HRMS(ESI+): for C32H31F2N10O2S+ (M+H)+: calc. m / z 657.23147; found m / z 657.22935.

[0182] PAZ3-C1-tetrahydrofuran (X78)153X78 (1.6 mg, 2.5 μmol, 44% over 2 steps) was prepared according to the general procedureD from X71 (4.0 mg, 5.7 μmol, 1.0 eq.), tetrahydrofuran-3-carbaldehyde (2.9 mg, 29 μmol,5.0 eq.), Na(OAc)3BH (6.1 mg, 29 μmol, 5.0 eq.), and, subsequently, TBAF (11 μL, 11 μmol,3.0 eq.).HPLC-LRMS (ESI+): C32H34F2N9O3+ (M+H)+: calc. m / z 630.3; found m / z 630.4. HRMS (ESI+):for C32H34F2N9O3+ (M+H)+: calc. m / z 630.27472; found m / z 630.27108.

[0183] PAZ3-C1oxetane (X79) / PAZ3-propanediol (X80)X79 (0.9 mg, 1.5 μmol, 26% over 2 steps) was prepared according to the general procedureD from X71 (4.0 mg, 5.7 μmol, 1.0 eq.), oxetane-2-carbaldehyde (2.5 mg, 29 μmol, 5.0 eq.),Na(OAc)3BH (6.1 mg, 29 μmol, 5.0 eq.), and, subsequently, TBAF (12 μL, 12 μmol, 3.0 eq.).During the N-detosylation reaction, X80 (1.2 mg, 1.9 μmol, 33%) was isolated andcharacterized as an additional PAZ3 derivative.Analytical data for X79:foundm / z 616.3. HRMS (ESI+): for C31H32F2N9O3+ (M+H)+: calc. m / z 616.25907; found m / z616.25114.Analytical data for X80: HPLC-LRMS (ESI+): C31H34F2N9O4+ (M+H)+: calc. m / z 634.3; foundm / z 634.3. HRMS (ESI+): for C31H34F2N9O4+ (M+H)+: calc. m / z 634.26963; found m / z634.27226.

[0184] General procedure E: (thio)urea formation of PAZ derivativesStep 1 (urea / thiourea formation): To a solution of X71 (1.0 eq.) in dioxane (0.003 M) wasadded DIPEA (10.0 eq.) and the respective isocyanate / thioisocyanate (3.0 eq.). The resulting reaction mixture was stirred at 50 °C for 16 h, the solvent was then evaporated to yield crudematerial containing X81’-X84’ which was used for the consequent step without furtherpurification. 154Step 2 (N-detosylation): The material obtained in step 1 was dissolved in THF (0.01 M) andTBAF (3.0 eq. from 1 M in THF) was added. The resulting reaction mixture was stirred at 50°C for 5 h, was then diluted with MeCN:H2O (2 mL, 1:1, 0.1% TFA) and purified viapreparative HPLC to obtain X81-X84 (12 to 65% yield over 2 steps).

[0185] PAZ3-ethylurea (X81)X81 (0.5 mg, 0.8 μmol, 29% over 2 steps) was prepared according to the general procedureE from X71 (2.0 mg, 2.8 μmol, 1.0 eq.), ethyl isocyanate (1.5 μL, 9 μmol, 3.0 eq.), DIPEA (5μL, 29 μmol, 10 eq), and, subsequently, TBAF (8 μL, 8 μmol, 3.0 eq.).HPLC-LRMS (ESI+): C30H31F2N10O3+ (M+H)+: calc. m / z 617.3; found m / z 617.4. HRMS(ESI+): for C30H31F2N10O3+ (M+H)+: calc. m / z 617.25432; found m / z 617.24895.

[0186] PAZ3-CONH-C1-sulfolane (X82)X82 (0.7 mg, 1.0 μmol, 23% over 2 steps) was prepared according to the general procedureE from X71 (3.0 mg, 4.3 μmol, 1.0 eq.), 3-(isocyanatomethyl)-1λ6-sulfolane-1,1-dione(2.3 μL, 1.3 μmol, 3.0 eq.), DIPEA (7.5 μL, 43 μmol, 10 eq), and, subsequently, TBAF (5 μL,5 μmol, 3.0 eq.).HPLC-LRMS (ESI+): C33H35F2N10O5S+ (M+H)+: calc. m / z 721.2; found m / z 721.3. HRMS(ESI+): for C33H35F2N10O5S+ (M+H)+: calc. m / z 721.24752; found m / z 721.24588.

[0187] PAZ3-methylthiourea (X83)155X83 (0.9 mg, 1.5 μmol, 35% over 2 steps) was prepared according to the general procedureE from X71 (3.0 mg, 4.3 μmol, 1.0 eq.), methyl isothiocyanate (1 μL, 1.3 μmol, 3.0 eq.),DIPEA (7.5 μL, 43 μmol, 10 eq), and, subsequently, TBAF (8 μL, 8 μmol, 3.0 eq.).HPLC-LRMS (ESI+): C29H29F2N10O2S+ (M+H)+: calc. m / z 619.2; found m / z 619.3. HRMS(ESI+): for C29H29F2N10O2S+ (M+H)+: calc. m / z 619.21582; found m / z 619.20744.

[0188] PAZ3-ethylthiourea (X84)X84 (0.8 mg, 1.3 μmol, 30% over 2 steps) was prepared according to the general procedureE from X71 (3.0 mg, 4.3 μmol, 1.0 eq.), ethyl isothiocyanate (1 μL, 1.3 μmol, 3.0 eq.), DIPEA(7.5 μL, 43 μmol, 10 eq), and, subsequently, TBAF (8 μL, 8 μmol, 3.0 eq.).HPLC-LRMS (ESI+): C30H31F2N10O2S+ (M+H)+: calc. m / z 633.2; found m / z 633.4. HRMS(ESI+): for C30H31F2N10O2S+ (M+H)+: calc. m / z 633.23147; found m / z 633.23333.

[0189] PAZ3-C(O)CH2-SO2Me (X85)Step 1: A suspension of methanesulfonyl acetic acid (41.0 mg, 0.3 mmol, 50 eq.) and oxalylchloride (200 μL, 0.3 mmol, 50 eq.) in anhydrous DCM (1.0 mL) was added one drop of DMFat r.t. and the resulting mixture was stirred at r.t. for 0.5 h, was then concentrated undercontinuous argon flow.Step 2: The material obtained in step 1 was taken into DCM (0.5 mL) and added dropwise asolution of X71 (3.0 mg, 4.3 μmol, 1.0 eq.) and DIPEA (0.1 mL, 0.6 mmol, 100 eq.) in DCM(1 mL). The resulting mixture was stirred at r.t. for 1 h, was then concentrated undercontinuous argon flow to yield crude material containing X85’ which was used for theconsequent step without further purification.Step 3: The material obtained in step 1 was dissolved in THF (0.01 M) and TBAF (3.0 eq.from 1 M in THF) was added. The resulting reaction mixture was stirred at 50 °C for 5 h, was 156then diluted with MeCN:H2O (2 mL, 1:1, 0.1% TFA) and purified via preparative HPLC toobtain X85 (1.0 mg, 1.5 μmol, 35% over 3 steps).HPLC-LRMS (ESI+): C30H31F2N9O5S+ (M+H)+: calc. m / z 666.2; found m / z 666.2. HRMS(ESI+): for C30H31F2N9O5S+(M+H)+: calc. m / z 666.20532; found m / z 666.21660. Synthesis of PAZ4 Derivatives

[0190] Synthesis of ethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitrobenzoate (X59)To a solution of X55 (2 g, 11.16 mmol) in 1 M solution of NaOH (11.16 mL) was refluxed 100°C for 2 h. The reaction was monitored by using UPLC-mass analysis. The resulted reaction mixture was cooled to 0 °C and acidified by using 6 N HCl. It was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 3), dried overNa2SO4, and was concentrated to get X56 (2 g, 82%) which was used for the next stepwithout need of purification. The solution of X56 (0.5 g, 2.534 mmol) in DMF (1 mL) wasadded Imidazole (0.539 g, 1.89 mmol) and TBDMS-Cl (0.10 g, 7.91 mmol). The resulted reaction mixture was stirred at 22 °C for 1 h. The reaction was monitored by using UPLC- mass analysis. The resulting reaction mixture was then diluted with water and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with water (20 mL x 3) andbrine (20 mL x 3), dried over Na2SO4, and concentrated to X57 (0.417 g, 53%) which wasused for the next step without need of purification.The solution of X57 (0.417 g, 1.334 mmol) in DMF (1 mL) was added Cs2CO3 (0.523 g, 1.61mmol) and X58 (0.250 mL, 3.35 mmol). The resulted reaction mixture was stirred at 22 °C for16h. The reaction was monitored by using UPLC-mass analysis. The resulting reaction mixture was then diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water (20 mL x 3) and brine (20 mL x 3), dried over Na2SO4, and concentrated to get the crude material which was purified by silica gel chromatography using a gradient elution (EtOAc: cyclohexane; 0:100 to 30:70) to give X59 (0.160 g, 35%) as a yellowish compound.TLC (Silica gel, 5% MeOH in CH2Cl2), Rf (X57) = 0.1, Rf (X59) = 0.9, UV active.157

[0191] Synthesis of ethyl 5-amino-2-(((tert-butyldimethylsilyl)oxy)methyl)benzoate(X60)To the solution of X59 (0.160 g, 0.471 mmol) in MeOH was added Pd / C (0.016 g). Theresulted solution was stirred at 22 °C for 2 h under H2 atmosphere. The reaction was monitored by using UPLC-mass analysis. After completion of the reaction, it filtered throughcelite pad and concentrated to get the X60 (0.127 g) which was used for the next stepwithout need of purification.TLC (Silica gel, 40% EtOAc in Cyclohexane), Rf (X59) = 0.6, Rf (X60) = 0.4, UV active.

[0192] Synthesis of ethyl 5-amino-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-iodobenzoate (X61)To a solution of X60 (0.126 g, 0.407 mmol) in DMF (1 mL) was added NIS (0.129 g, 0.575mmol). The resulted reaction mixture was stirred at 22 °C for 1 h. The reaction was monitored by using UPLC-mass analysis. The reaction mixture was quenched with saturated solution of Na2S2O3(5 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with water (20 mL x 3) and brine (20 mL x 3), dried over Na2SO4, and concentrated to get crude material which was purified by silica gel chromatography using agradient elution (EtOAc: cyclohexane; 0:100 to 20:80) to give X61 (0.071 g, 40%) as ayellowish compound.1H-NMR (600 MHz, DMSO-d6) δ (ppm) = 8.02 (d, J = 1.2 Hz, 1H), 7.30 (s, 1H), 4.94 (d, J =1.0 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.10 (s, 2H), 2.16 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H), 0.95(s, 9H). LCMS: calculated for C16H26INO3Si: 435.0727, found 436.1 (M+H) 158

[0193] Synthesis of ethyl 5-amino-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoate (X62)A solution of X61 (0.015 g, 0.034 mmol), Pd(PPh3)4 (0.0041 g, 0.004 mmol), X46 (0.0207 g,0.048 mmol), K2CO3 (0.0143 g, 0.103 mmol) in 1,4-dioxane (1 mL) and water (0.125 mL) was heated to 60 °C for 16 h. The reaction was monitored by using UPLC-mass analysis. The reaction was cooled to 25 °C and concentrated to get the crude material which was purified by silica gel chromatography using a gradient elution (EtOAc: cyclohexane; 0:100 to 50:50)to give X62 (0.010 g, 48%) as a white solid.LCMS: calculated for C31H39N3O6SSi: 609.2329, found 610.3 (M+H)

[0194] Synthesis of ethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-((3,5-difluoropyridin-2-yl)amino)-4-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4- yl)benzoate (X63)To a solution of X62 (0.010 g, 0.016 mmol) in 1,4-dioxane (1.0 mL) was added Cs2CO3(0.0106 g, 0.032 mmol), BrettPhos (0.0044 g, 0.008 mmol), BrettPhos 3G (0.003 g, 0.003mmol) and X48 (0.0095 g, 0.049 mmol). The resulted reaction mixture was then heated at 90°C for 12 h. The reaction was monitored by using UPLC-mass analysis. The mixture was cooled to 25 °C and was concentrated to get the crude material which was purified by silica gel chromatography using a gradient elution (EtOAc: cyclohexane; 0:100 to 60:40) to giveX63 (0.004 g, 42%) as a yellowish compound.LCMS: calculated for C36H40F2N4O6SSi: 722.2406, found 723.3 (M+H) 159

[0195] Synthesis of 4-(6-((3,5-difluoropyridin-2-yl)amino)-1-oxo-1,3-dihydroisobenzofuran-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (X64)To a solution of X63 (0.037 g, 0.051 mmol) in THF (1 mL) was added TBAF (0.154 mL, 0.154mmol, 1 M in THF). The resulted reaction mixture was stirred at 60 °C for 2 h and monitored by using UPLC-mass analysis. The reaction mixture was diluted with water and was subsequently extracted with EtOAc (10 mL x 2). The combined organic layers were washedwith brine (10 mL x 3), dried over Na2SO4, and was concentrated to get X64 (0.027 g, 86%)which was used as it is for the next step without need of purification.LCMS: calculated for C21H14F2N4O3i: 408.1, found 409.1 (M+H)

[0196] Synthesis of 4-(3,5-difluoropyridin-2-yl)-11-methyl-1,4,8,11-tetrahydro-6H-7-oxa-1,4,11-triazabenzo[cd]indeno[5,6-f]azulene-6,12(3H)-dione (65)To a solution of X64 (0.0027 g, 0.066 mmol) in acetic acid (0.5 mL) was addedparaformaldehyde (0.006 g, 0.198 mmol). The reaction mixture was stirred heated at 75 °C for 1 h and the progress of the reaction was monitored by using UPLC-mass analysis. Themixture was cooled to 25 °C and was concentrated to get crude material which was purifiedby silica gel chromatography using a gradient elution (EtOAc: cyclohexane; 0:100 to 60:40)to give X65 (0.017 g) as a yellowish compound.1H-NMR (600 MHz, DMSO-d6) δ (ppm) = 9.97 (s, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.75 (s, 1H),7.67 (s, 1H), 7.42 (s, 1H), 7.16 (d, J = 2.5 Hz, 1H), 6.96 (ddd, J = 11.5, 7.5, 2.5 Hz, 1H), 6.04(d, J = 15.9 Hz, 1H), 5.38 (s, 2H), 4.27 (d, J = 15.8 Hz, 1H), 3.76 (s, 3H).LCMS: calculated for C22H14F2N4O6: 420.1034, found 421.2 (M+H) 160

[0197] Synthesis of X68Step 1: A solution of X65 (12 mg, 29 μmol, 1.0 eq.) in 1 M solution of NaOH (1.1 mg, 29μmol, 1.0 eq.) was stirred at 70 °C for 2 h. A suspension was observed and 0.2 mL of MeOHwere added to form a homogenous mixture. The resulting mixture was further stirred at 70 °Cfor 16 h, was then cooled, acidified using 6 N HCl and extracted with DCM (3 × 50 mL). Thecombined organic layers were washed with water (3 × 20 mL) and brine (3 × 20 mL), driedover Na2SO4 and concentrated to yield crude material containing X66 which was used for thenext step without need of purification. LRMS for C22H17F2N4O4+ (M+H)+: calc. m / z 439.1,found m / z 439.1.Step 2: The material obtained in step 1 containing X66 was dissolved in DMSO (0.5 mL) andmixed with DIPEA (45 μL, 0.3 mmol, 10.0 eq.) and X67 (23.3 mg, 0.233 mmol, 10.0 eq.).Then PyBOP (13.3 mg, 26 μmol, 0.9 eq.) in DMSO (0.1 mL) was added. The resultingmixture was stirred at r.t. for 1 h, was then diluted with MeCN:H2O (2 mL, 1:1, 0.1% TFA) andpurified via preparative HPLC to obtain X68 (4.0 mg, 7.7 μmol, 27% yield).HPLC-LRMS (ESI+): C25H23F2N8O3+ (M+H)+: calc. m / z 521.2; found m / z 521.3. HRMS (ESI+):for C25H23F2N8O3+ (M+H)+: calc. m / z 521.18557; found m / z 521.19938.

[0198] Synthesis of PAZ4-C3-N3 (X69)X68 (4.0 mg, 7.7 μmol, 1.0 eq.) was dissolved in DCM (2 mL) and NEt3 (5 μL, 40 μmol, 5.2eq.) and methanesulfonyl chloride (1 μL, 1 μmol, 1.5 eq.) were added at 0 °C and theresulting mixture was stirred at r.t. for 2 h. The solvent was evaporated by the continuousflow of argon and diluted with was then diluted with MeCN:H2O (2 mL, 1:1, 0.1% TFA) andpurified via preparative HPLC to obtain X69 (2.0 mg, 4.0 μmol, 52% yield).HPLC-LRMS (ESI+): C25H21F2N8O2+ (M+H)+: calc. m / z 503.2; found m / z 503.3. HRMS (ESI+):for C25H21F2N8O2+ (M+H)+: calc. m / z 503.17500; found m / z 503.1734EXPERIMENTAL PROCEDURE FOR IN SILICO BRD4 BINDING CALCULATIONS 161

[0199] Reference compounds PAZ1-CO2Me and PAZ1-NMe2PAZ1-CO2Me and PAZ1-NMe2 were used as reference compounds for comparison to the prior art documents EP2970330B1, WO2020 / 086858A1, WO2019084030A1, Dragovich et al “Antibody-Mediated Delivery of Chimeric BRD4 Degraders (part 1)”, J. Med. Chem, 2021, 64, pg.2534 to 2575 and Dragovich et al “Antibody-Mediated Delivery of Chimeric BRD4 Degraders (part 2)”, J. Med. Chem, 2021, 64, pg.2576 to 2607.

[0200] PAZ2 Examples

[00201] PAZ3 Examples162

[0202] General in silico experimentsThe in silico screening of PAZ examples as BRD4 binding ligands was performed usingSeeSAR 13.0.5 (Midas) from BioSolveIT, GmbH (Sankt Augustin, Germany). The Proteinand Binding Site Mode was used to define the Protein Binding Site within the BRD4 protein,the Molecule Editor Mode for creating new ligand structures, the Docking Mode to createvarious docking poses from each of the existing and new ligand structures and, finally, theAnalyzer Mode to calculate and visualize the Estimated Affinities, H-Bond Network, TorsionQuality and Intra- / Intermolecular Clashes of each ligand structure in the defined binding site.In SeeSAR, the Estimated Affinities (also generally referred to as binding affinities) arecalculated and then visualized as affinity ranges from mM < μM < nM < pM reflecting accumulated beneficial or contradicting intra- / intermolecular binding interactions of the ligandin the binding site (Gadgoli et al., J. Chem. Inf. Model.2022). Moreover, the individual factorsTorsion Quality and Intra- / Intermolecular Clashes are visualized using a traffic light systemusing red (non-beneficial), orange (medium) and green (beneficial) colors.

[0203] Docking procedureFor structure evaluations, the Estimated Affinities of PAZ ligand structures were comparedon the mM < μM < nM < pM range (1012logarithmic scale) relative to the calculatedEstimated Affinity of the reference PAZ1-CO2Me that was co-crystallized in the knownprotein binding pocket of BRD4 (PDB: 7KHL. Dragovic et al., J. Med. Chem.2021). Thereby,the original orientation of the ligand PAZ1-CO2Me in the binding pocket was used to createinitial docking poses using the Docking Mode applying the following restrictions: MaximumNumber of Poses (6), Standard Clash Tolerance and allowing only Chair Ring164Conformations. The Analyzer Mode was then used to calculate the reference EstimatedAffinity following structure optimisation of these poses in the previously defined binding site.The PAZ ligand structures were then derived from PAZ1-CO2Me starting from its originalorientation using the Molecular Editor Mode by changing or adding individual atoms and / orcreating new ring connections and named accordingly (e.g., the BRD4-binding azepane-containing core PAZ2 substituted with a methyl group as PAZ2-NMe (1) where (1) or (2)indicates individual stereoisomers; or the BRD4-binding piperazine-containing core PAZ3 substituted with a N-ethylsulfonamide named as PAZ3-SO2Et). The new ligand structureswere transferred to the Docking Mode to create docking poses with variable restrictions (e.g.,Maximum Number of Poses (4 or 6 or 20), Standard Clash Tolerance and allowing Chair(and Twisted Boat) Ring Conformations). Again, the Analyzer Mode was then used tocalculate the reference Estimated Affinity following structure optimisation of these poses inthe previously defined binding site and results were interpreted with respect to previously calculated properties for PAZ1-CO2Me.

[0204] Validation of the methodology (PAZ1-CO2Me vs. PAZ1-NMe2)Docking poses of reference PAZ1-CO2Me derived from the originally co-crystallizedorientation with the reference example PAZ1-NMe2created by using the Molecule EditorMode. The results show good Estimated Affinity for the individual poses of PAZ1-CO2Me inagreement with the experimentally measured binding affinity of PAZ1-CO2Me to the BRD4protein. The structurally closely related derivative PAZ1-NMe2 (reference compound) alsoshowed excellent calculated Estimated Affinity indicating equal or possibly higher bindingaffinity of this adapted structure to BRD4.Figure 4A shows the docking of PAZ1-CO2Me in comparison to PAZ1-NMe2 shown in Figure4B. Table 4. Representative comparative results of docking reference examples PAZ1-CO2Me and PAZ1-NMe2entry Pose Identifier Pose Structure Est. affinity (nM) Torsion Intra-X Inter-X_ _165

[0205] In silico screening of PAZ2-type ligand structuresComparison of ligand structures containing the BRD4-binding azepane-containing core PAZ2created from PAZ1-CO2Me as originally co-crystallized using the Molecule Editor Mode. Theresults show good Estimated Affinity of PAZ2-derived structures to the BRD4 binding. Mostposes of PAZ2-NH (1), PAZ2-NMe (1) and PAZ2-NBu (1) representing stereoisomer (1)show good Estimated Affinities whereas only a few poses of PAZ2-NH (2) representingstereoisomer (2) were found to have Estimated Affinity to BRD4. Moreover, this effect seems to be more pronounced with increasingly long substitution H < Me < Bu. In summary, these results suggest good binding affinities of PAZ2-derived ligand structures to BRD4 are experimentally to expect with a stereospecific effect preferring stereoisomer (1).Figure 5A shows dockingFigure 5B shows dockingFigure 5C shows dockingFigure 5D shows docking166Table 4. Results of docking PAZ2 examples entry Pose Identifier Pose Structure Est. affinity (nM) Torsion Intra-X Inter-X1 PAZ1-CO2Me_8_003 3 PAZ1-COOMe 1.6 – 130 orange red green2 PAZ1-CO2Me_8_001 1 PAZ1-COOMe 5.6 – 800 green green green167

[0206] In silico screening of PAZ3-type ligand structuresStructures containing the BRD4-binding piperazine-containing core PAZ3 were created fromPAZ1-CO2Me as originally co-crystallized using the Molecule Editor Mode. The results showexcellent Estimated Affinity of PAZ3-derived structures to the BRD4 binding with increasedaffinities compared to PAZ1-CO2Me. In particular, these experiments show the Structure- Activity-Relationship (SAR) around the piperazine-nitrogen atom corresponding to BG5ring member of claim 1 by introducing structures derived from N-alkylation, N-acylation or N- sulfonylation at this position. The docking experiments unexpectedly revealed ligand structures with methylene-elongated substitution at the BG5position that are particularly beneficial for binding with the highest Estimated Affinities. Potential elongated substitutions may include but are not limited to esters (PAZ3-CH2-COOMe), carboxylic acids (PAZ3-CH2- COOH), sulfones, (PAZ3-CH2-SO2Me) or phosphonates / phosphinates (PAZ3-CH2-PO(OH)Me / AZ3-CH2-POMe2). In summary, these results suggest excellent binding affinitiesfor PAZ3-derived ligand structures to BRD4 these affinities are influenced by varioussubstitutions at the BG5 ring member according to structure (I) of claim 1.Table 5. Results of docking PAZ3 examples Pose Identifier Structure Est. aff. (nM) Torsion Intra-XInter- X2PAZ3-N-CH2PO(OH)Me_1_001 PAZ3-CH2-PO(OH)Me 0.3 – 13 orange orange green3 PAZ3-N-CH2CO2Me_1_002 PAZ3-CH2-COOMe 0.3 – 20 orange orange green4 PAZ3-N-CH2SO2Me_1_002 PAZ3-CH2-SO2Me 0.4 – 20 red orange green5 PAZ3-N-CH2POMe2_1_004 PAZ3-CH2-POMe2 0.4 - 25 orange green green6 PAZ3-N-CH2PO(OH)Me_1_003 PAZ3-CH2-PO(OH)Me 0.5 - 32 orange orange green7 PAZ3-N-CH2CO2Me_1_004 PAZ3-CH2-COOMe 0.5 - 35 orange green green8 PAZ3-N-CH2SO2Me_1_001 PAZ3-CH2-SO2Me 0.6 - 40 red green green9 PAZ3-NSO2Et_1_001 PAZ3-SO2Et 0.6 - 50 red orange green10 PAZ3-N-CH2SO2Me_1_004 PAZ3-CH2-SO2Me 0.8 - 63 red green green11 PAZ3-N-CH2COOH_1_004 PAZ3-CH2-COOH 0.9 - 80 orange green green12 PAZ3-N-CH2SO2Me_1_003 PAZ3-CH2-SO2Me 0.9 - 80 red green green13 PAZ3-N-CH2CO2Me_1_001 PAZ3-CH2-COOMe 1 - 160 orange green green14 PAZ3-NSO2Me_1_001 PAZ3-SO2Me 1 – 160 red orange green15 PAZ3-N-CH2COOH_1_003 PAZ3-CH2-COOH 1.3 – 200 orange orange green16 PAZ3-NSO2Et_1_004 PAZ3-SO2Et 5 – 600 red green green17 PAZ3-NSO2-cPr_1_004 PAZ3-SO2CyPr 10 – 1,000 orange red green18 PAZ3-NiPr_1_001 PAZ3-iPr 13 – 1,000 orange orange green19 PAZ3-NiEt_1_004 PAZ3-iEt 16 – 1,300 orange orange green20 PAZ3-NiPr_1_004 PAZ3-iPr 20 – 1,600 orange orange green21 PAZ3-NSO2-3’oxetane_1_001 PAZ3-SO2-oxetane 25 – 1,600 red red green22 PAZ3-NSO2-3’azetidine_1_002 PAZ3-SO2-azetidine 25 – 1,800 red red green168PAZ3-NSO2-3’azetidine- 23PAZ3-SO2-azetidineMe 28 – 1,800 red red greenMe_1_001 24 PAZ3-NSO2-cPr_1_001 PAZ3-SO2CyPr 32 – 2,000 orange red green25 PAZ3-NSO2-3’oxetane_1_004 PAZ3-SO2-oxetane 40 – 2,500 orange red green26 PAZ3-NSO2-Pr_1_002 PAZ3-SO2Pr 40 – 2,500 orange orange green27 PAZ3-NSO2-2’imidazole_1_001 PAZ3-SO2-imidazole 63 – 4,000 red orange green28 PAZ3-NSO2-Ph_1_002 PAZ3-SO2Ph 79 – 5,000 red red green29 PAZ3-NCO2Me _1_002 PAZ3-COOMe / orange red red30 PAZ3-NSO2-2’imidazole_1_002 PAZ3-SO2-imidazole / orange orange red

[0207] Pharmacophore constraint guided in silico screening of PAZ-type ligandstructures For the following experiments, SeeSAR 14 has been used instead of SeeSAR13 and the Docking was performed using “pharmacophore docking” applying restrictions of positioning of the following atoms in the pentacyclic backbone of PAZ2 as follows:

[0208] Pharmacophore constraint docking: As an alternative to unconstraint docking(described in previous section) new structure poses (for sterically or chemically demanding substitutions) were guided by pharmacophore anchor points in the ligand backbone that weredescribed as crucial anchor points for the ligand-protein interaction of reference ligands suchas Compound 6 as reported by Dragovich et al (J. Med. Chem. 2021, 64, pg 2578 Figure 2).As all new ligand structures created by the Molecular Editor Mode share these characteristicchemical anchors in the ligand backbone, these ligands are then docked with comparablegeometry. Without the intention of being bound by theory, this approach is believed to providemore precise docking results. The following scheme is describing the anchor points in detailthat were used in this calculation:169This experiment compares additional ligand structures containing the BRD4-binding piperazine-containing core PAZ3 created from Compound 6 as originally co-crystallized using the Molecule Editor Mode. Calculations applied pharmacophore-constraint docking with the constraints explained in the previous scheme with the following specifications: 4 geometrical poses, medium clash tolerance, chair-conformation only. The results show excellent Estimated Affinity of additional PAZ3-derived structures to the BRD4 binding with evenincreased affinities compared to Compound 6. In particular, this experiment proves SARresults calculated in the previous section applying unconstraint docking reflecting strong binding of PAZ3SO2Me, PAZ3-CH2-SO2Me or PAZ3-CH2-POMe2. A number of additionally highly interesting and unexpected functional groups are found to strongly enhance binding to BRD4, such as PAZ3-CH2-tetrahydrothiophen, PAZ3-methylthiazole or PAZ3-3,4- pyrrolidinone. In summary, these results suggest excellent binding affinities for further, more complicated PAZ3-derived ligand structures to BRD4 are experimentally to expect and these affinities may be influenced by various substitutions at the piperazine nitrogen atom.

[0209] Table 6. Results for PAZ3 ligands under constrained guided in silicodocking170171172173P61 PAZ3-2,3-pyrrolidinone 22 2.2 220P69 PAZ3-3-thiophene 230 23 2300P70 PAZ3-3,5-thiazole 9.4 0.94 94P71 PAZ3-2,4-thiazole 350 35 3500PPPPPP174175IN VITRO CELLULAR EVAULATION OF BINDERS

[0210] General informationThe BRD4 binders were tested in the form of direct binders of BRD4 by means of a grating-coupled interferometry (GCI) and as PROTAC systems that were conjugated with an appropriate antibody to form an antibody-drug conjugate (ADC). GCI methods of measuring binding kinetics are known to give highly detailed information with conditions that are optimal for high throughput screening while maintaining superb sensitivity (for a review see Saftics et al, “Data evaluation for surface-sensitive label-free methods to obtain real-time kinetic and structural information of thin films: A practical review with related software packages”, Advances in Colloid and Interface Science, Volume 294, 2021,102431,ISSN 0001-8686, https: / / doi.org / 10.1016 / j.cis.2021.102431). Direct binding measurements were determined by the Repeated Analyte Pulses of Increasing Duration (waveRAPID) method described by Kartal et al in “waveRAPID—A Robust Assay for High-Throughput Kinetic Screens with the Creoptix WAVEsystem” SLAS Discovery, Volume 26, Issue 8, 2021, Pages 995-1003, ISSN 2472-5552, https: / / doi.org / 10.1177 / 24725552211013827). The test PROTAC systems were always based on the same VHL binder for comparative purposes in order to evaluate the contribution of the BRD4 binding interactions. In the following examples, the term VHL refersto a chemical structure binding to the VHL E3 ligase protein. Several potent VHL binders with176appropriate linker positions are known from WO2020 / 086858A1, WO2019084030A1, Dragovich et al “Antibody-Mediated Delivery of Chimeric BRD4 Degraders (part 1)”, J. Med. Chem, 2021, 64, pg.2534 to 2575 and Dragovich et al “Antibody-Mediated Delivery of Chimeric BRD4 Degraders (part 2)”, J. Med. Chem, 2021, 64, pg.2576 to 2607. Linkers wereformed at the identical positions using linkers with a Michael acceptor (MA-linker) forantibody conjugation analogous to WO2020 / 086858A1, WO2019084030A1 or Dragovich etal. Said MA-linkers may be present with the VHL binder which may also be bound by meansof a second linker to the BRD4 binders according to the present disclosure. VHL bindersbearing appropriate functional groups such as basic amines, acids, alkynes or alcohols(VHL-NH2representing a VHL binder with a primary amine, VHL-OH representing a VHL binder with an alcohol, VHL-linker-CH2CCH representing a VHL binder with a pendent linkerwith a propagyl group) may be coupled to linker groups bound to said BRD4 binderaccording to the present disclosure. Likewise, MA-linker-VHL indicates a VHL binder with a linker having a Michael acceptor analogous to WO2020 / 086858A1, WO2019084030A1, Dragovich et al “Antibody-Mediated Delivery of Chimeric BRD4 Degraders (part 1)”, J. Med. Chem, 2021, 64, pg.2534 to 2575 and Dragovich et al “Antibody-Mediated Delivery of Chimeric BRD4 Degraders (part 2)”, J. Med. Chem, 2021, 64, pg.2576 to 2607.

[0211] BRD4 Binding measurements by grating-coupled interferometryGrating-coupled interferometry is well known binding analysis method in the art and the waveRAPID method specifically has been discussed at length by Önder Kartal, FabioAndres, May Poh Lai, Rony Nehme, Kaspar Cottier, “waveRAPID—A Robust Assay for High-Throughput Kinetic Screens with the Creoptix WAVEsystem”, SLAS Discovery, Volume 26,Issue 8, 2021, Pages 995-1003, ISSN 2472-5552,(https: / / doi.org / 10.1177 / 24725552211013827), incorporated herein by reference.

[0212] Experimental Procedure for GCI measurementPreparation of biotinylated BRD4BD1+BD2with biotin:BRD4 ratio of 1:1Commercial human BRD4 (250 μL, 4.1 nmol, 1.0 eq. at 0.8 mg / mL) (HY-P7846 fromMedChemExpress: N-10*His;N-Flag-BRD4BD1+BD2expressed in E.coli; Gene ID: 23476; MW= 49030 Da) was subjected to buffer exchange from the storage buffer to DPBS. A freshsolution (2 mM in MQ-H2O) of NHS-PEG4-biotin (10 μL, 20.4 nmol, 5.0 eq.) (EZ-LINKTM fromThermo-Scientific) was added in one portion and the resulting mixture was incubated at 0 °Cfor 1 h and was then subjected to a second buffer exchange to obtain the biotinylated BRD4in fresh DPBS at 0.8 mg / mL. The average ratio of ca.1:1 between biotin:BRD4 wasdetermined by protein mass spectrometry.

[0213] Assay development and referencingHigh-throughput grating-coupled interferometry (GCI) was performed on a Creoptix WAVEdelta from Malvern Panalytical using a regenerable Streptavidin sensor chip coated with immobilized BRD4 protein on the surface via affinity-capture. Results were analysed using CreoptixTMWAVEcontrol, version 4.7.2. 177Initially, an RG_SA (modified Streptavidin) solution in running buffer (PBS pH 7.4, 0.005% Tween-20) was injected for 400 sec at 2.5 μL / min to functionalise the chip surface with astreptavidin surface density of ca.2500 pg / mm2. Subsequently, the biotinylated BRD4solution (diluted to 20 μg / mL in PBS pH 7.4, 0.005% Tween-20) was injected for 300 sec at2.5 μL / min and the protein was captured by the pre-immobilized streptavidin. Finally, thecapture stability was assessed by rinsing the surface with PBS pH 7.4 for 1200 sec at 30 μL / min and stable protein surface density of ca.1000 pg / mm2(MW = 49 kDa) was observed.

[0214] WaveRAPID ligand affinity assessmentCapture and protein surfaces were freshly prepared for each waveRAPID cycle. After each analysis cycle, streptavidin-protein-analyte complexes were removed from the chip surfaceby injection of 30% MeCN in 250 mM aq. NaOH (2 × 30 sec injection at 20 μL / min). Theanalyte solutions (at 100 nM or 1000 nM) were injected in pulses of increasing duration withassociation times of 25-200 sec and dissociation times of 300-600 sec depending on the binding affinity of the analytes. Full coverage of each individual bromodomain (BD) with a ligand (MW = 400-700 Da) contributed ca.5 pg / mm2in experimental surface density, so that full coverage of both BDs is assumed with values between 8-15 pg / mm2.The experiment was calibrated against 0.5% DMSO injected at the beginning and end of each cycle. Data are double-referenced and fitted using a 1:1 kinetic binding model was applied assuming identical binding affinity of the analyte to BRD4BD1and BRD4BD2.

[0215] Table 7: Binding affinity to BRD4BD1+BD2 measured by GCI178

[0216] General procedure F: Coupling of PAZ acids with VHL-NH2A mixture of solutions of PAZ-COOH (1.0 eq.), TOTU (1.1 eq.) and DIPEA (10 eq.) in DMSO was added to the clear solution of VHL-NH2 (1.2 eq.) in DMSO at a final concentration of 5 mM PAZ-COOH. The resulted reaction mixture was stirred at room temperature and the progress of the reaction was monitored by using UPLC-mass analysis. After the completion of the reaction, it was diluted with DMSO to 1 mM and used in cellular experiments without further purification. 179

[0217] General procedure G: Triazole formation of PAZ azides with VHL-alkynesA Mastermix was prepared: 120 uL of sodium ascorbate (50 mM), 10 uL of CuSO4 (25 mM), 20 uL of THPTA (12.5 mM), all in water. The VHL-alkyne (10 mM in THF) was mixed withPAZ-N3 (10 mM) in DMSO, each 5 uL, 1:1. To this mixture was added 13 uL of the Mastermixto achieve a final mixture at 2 mM, 25 uL total volume. After the completion of the reaction, itwas diluted with DMSO to 1 mM and used in cellular experiments without further purification.

[0218] General procedure H: Coupling of PAZ acids with VHL comprising anantibody linker comprising a Michael acceptorA mixture of solution PAZ-COOH (1.1 eq.), PyBOP (1.1 eq.) and DIPEA (10 eq.) was addedto the clear solution of MA- linker-VHL (1 eq.) in DMSO (50 mM). The reaction mixture wasstirred at room temperature and the progress of the reaction was monitored by using UPLC- mass analysis. After the completion of the reaction, it was diluted with 0.1% TFA in water (1 ml) and purified via preparative HPLC eluting with a gradient method at 14 ml / min on a VP 250 / 12 Macherey-Nagel Nucleodur C18 HTec Spum column (Macherey-Nagel GmbH & Co. Kg, Germany) to obtain, injected on the medium sized HPLC column and purified by usingthe gradient method to yield MA-linker -VHL-PAZ comprising a Michael acceptor forconjugation with antibodies that comprise available cysteines.

[0219] General procedure I: Conjugation of linked PAZ-VHL to monoclonalantibodies The antibody has available reactive cysteine for conjugation to a Michael acceptor present on the MA-linker bound to the VHL-PAZ construct. Analogous cysteine / Michael acceptor systems are well known in the art, such as in WO2020 / 086858A1, WO2019084030A1 or Dragovich et al. The reaction mixtures were purified by preparative size-exclusion chromatography with a 25 ml Superdex™ 200 Increase 10 / 300GL (Cytiva, Sweden) and a flow of 0.8 ml / min eluting with sterile PBS (Merck, Germany). The antibody containing fractions were pooled and 180concentrated by spin-filtration (Amicon® Ultra- 2mL MWCO: 30 kDa, Merck, Germany). TheADC concentrations were determined in a 96-well plate with a Pierce™ Rapid Gold BCA Protein Assay Kit (Thermo Fisher Scientific, USA) with pre-diluted protein assay standards of bovine gamma globulin (Thermo Fisher Scientific, USA).

[0220] General Procedure J: Investigation of the in vitro anti-tumor activity ondifferent cell lines To investigate direct cytotoxicity of PROTACs or PROTACs conjugated to tumor-targeting antibodies, respective cells were seeded in a 96-well plate (flat bottom, 5000 cells / well, suspended in 100µl medium) and incubated for 7 days with increasing concentrations of theADCs in medium (0-3 µg / ml) or PROTACs (0-1000 nM) to generate a dose-response curve.Before viability analysis, the supernatant over the adherent cells was removed and replaced by fresh medium. Killing was analyzed afterwards, using resazurin (Merck group, Germany) as the cell viability dye at a final concentration of 55 µM. Fluorescence emission at 590 nM was measured on a Microplate reader Infinite M1000 Pro (Tecan). Cell viability was measured by dividing the fluorescence of ADC-treated cells with the fluorescence from control cells, treated in the same way with medium only.

[0221] In vitro evaluation of PAZ2 as PROTACs conjugated to tumor-targetingantibodiesX135 was reacted with a MA-linker -VHL construct according to general procedure H. Thepurified MA-linker -VHL-X135 construct was then conjugated separately to bothDatopotamab and Brentuximab according to general procedure I. The resultant ADCs bothDatopotamab and Brentuximab were tested on H441 TROP2+ cells and SR-786 CD30+ celllines. The results are presented in Figure 6A for H441 TROP2+ wherein the Datopotamab -MA-linker -X135 ADC is plotted as a solid line with solid black squares and Brentuximab - MA-linker -VHL-X135 ADC is plotted as a broken line with solid black circles.Results for SR-786 CD30+ cells are presented in Figure 6B wherein the Brentuximab MA-linker -VHL-X135 ADC is plotted as a solid line with solid black squares and Datopotamab -MA-linker -VHL-X135 ADC is plotted as a broken line with solid black circles.

[0222] In vitro evaluation of racemic vs enantiomeric pure versions of X5Racemic and enantiomerically pure sources of X5 were reacted with a MA-linker -VHLconstruct according to general procedure G. Identical PEG linkers comprising an alkynegroup for click reaction with the azide of each version of X5 were used. The MA-linker -VHL-X5 constructs were then conjugated separately to both Datopotamab and Brentuximabaccording to general procedure I. Brentuximab- MA-linker -VHL-X5 ADCs were tested onSU-DHL-1, SR-786 and Karpas cell lines and the results are presented in Figure 7A, 7B and7C respectively. Datopotamab - MA-linker -VHL-X5 ADCs were tested on H441 and BXPC-3cell lines and the results are presented in Figure 7D and 7E respectively. Racemic data is 181plotted with solid circles, ADCs derived from the first eluting enantiomer of X5 are plotted as solid squares and the ADCs derived from the second eluting enantiomer of X5 are plotted as solid triangles. Percent viability of the cells are plotted on the Y-axis and the concentration of the ADCs are plotted on the X-axis in units of ng / mL. As may be taken from the overall results for both antibodies and all 5 cell lines, there is a strong enantiomeric effect wherein the first eluting enantiomer of X5 is significantly more active than the racemic mixture of enantiomers which in turn is more active than the pure second eluting enantiomer of X5.These results are in good agreement with the in-silico calculations based on substantially thesame BRD4 structures.

[0223] In vitro evaluation of racemic vs enantiomeric pure versions of X120 inthe form of a VHL based PROTACRacemic and enantiomerically pure sources of X120 were reacted with a VHL amineaccording to general procedure F. The resultant PROTACs were tested on cell lines MDA- MB-453, H441, BXPC-3, HL-60, Karpas-299 and SR786 in viability assays. Percent viabilityof the cells are plotted on the Y-axis and the concentration of the PROTACs are plotted onthe X-axis in nanomolar. The racemic versions of the PROTACs are plotted in Figure 8A to8F as solid circles, the first eluting enantiomer versions of the PROTACs are plotted astriangles and the second eluting enantiomer versions of the PROTACs are plotted as solidsquares. As shown in all cell lines, the results for X120 show an enantiomeric effect inagreement with those of the ADC of X5 and with the in-silico experiments. Moreover, thePROTACs derived from X120 surprisingly demonstrate a strong effect on the viability of all six cancer cell lines when the appropriate enantiomer is employed.

[0224] In vitro cellular evaluation of X54 as PROTACs conjugated to tumor-targeting antibodiesX54 was reacted with a MA-linker-VHL construct according to general procedure H. An alkyllinker comprising an alkyne group for click reaction with the azide of X54 was used. Thepurified MA-linker-VHL-X5 construct was then conjugated to Brentuximab according togeneral procedure I. Brentuximab- MA-linker -VHL-X5 ADCs as tested on SR-786 andKarpas-299 cell lines and the results are presented in Figure 9A and 9B respectively. Percentviability of the cells are plotted on the Y-axis and the concentration of the ADCs are plotted on the X-axis in units of ng / mL. As may be taken from the overall results for both antibodieson both cell lines, X54 ADC-PROTACs are substantially active. These results are in goodagreement with the in-silico calculations based on substantially the same BRD4 structure.

[0225] In vitro cellular evaluation of PAZ2 as PROTACs conjugated to tumor-targeting antibodiesThe azides in the table 8 below were transferred into Protacs using the general procedure G.The VHL based PROTACs (VHL-PAZ) have been converted into MA-linker-VHL-PAZ constructs as previously reported by Dragovich et al and conjugated to Brentuximab and Datopotamab and the IC50 in antiproliferative activity evaluated as described in the general procedure H. 182

[0226] Table 8: Antiproliferative cellular activity of PAZ3 / 4 BET binders in theDAC format via CD30 / Trop2 Click-based DAC assembly using pre-assembled Bren / Dato-P5-Alco5-VHL-C4-alkyne tools antibodies. DACs from Brentuximab targeting Karpas-299, SR-786 (CD30) or Datopotamabtargeting BxPC-3, H441 (Trop2) with DAR8 and Treatment for 7 days at 37 °C.

[0227] Proteomics experimentsEnantiomerically pure X120_first eluting was reacted with a VHL amine according to general procedure F. The resultant PROTACs were tested for protein degradation using a proteomicsexperiment. Label-free unbiased proteomics analysis has been conducted with SKBR-3 cells(15000 cells per well in a 96 well plate) that have been incubated with 5, 50, 200 and 500nM X120_first eluting based PROTAC or DMSO only (0.1% in all experiments). The proteome of the cells was analyzed after 3 h of incubation via LC-MS / MS as previously reported by Sathe, Gajanan et al, “Proteomic approaches advancing targeted protein degradation” 183Trends in Pharmacological Sciences, Volume 44, Issue 11, pg.786 – 801. The volcano plotsbelow clearly show selective downregulation of the BET family proteins mediated by theenantiomerically pure X120_first eluting binder. Highest selectivity is shown since onlyBRD2,3 and 4 are downregulated together with downstream targets of the BET family such as MYC. The experiment clearly demonstrates highest selectivity of the structures disclosed herein for the BET family proteins over the other proteome of the cell.

[0228] In vivo tumor suppression resultsA series of in vivo models were conducted to directly compare the BRD4 binding properties of the X120 first eluting enantiomer versus the known BRD4 binder X2 in antibody-drugconjugate (ADC) formats. antibody, linker, antibody-degrader ratio and VHL ligands of theADCs are identical in order to evaluate the contribution of the BRD4 binders to the effect of the in vivo model. The BRD4 binder X120_first eluting was reacted with a MA-linker -VHLconstruct according to general procedure F. PAZ1 (termed X2 here and compound 9according to Dragovich et al) has been used to construct the VHL-based degrader GNE-987and turned into MA-linker-GNE-987 (see compound 9 BRD4 binder according to Dragovichet al reference 6). The purified MA-linker -VHL-X120_first eluting and MA-linker-GNE-987constructs was then conjugated separately to Trastuzumab, a Her2-binding antibody, Enfortumab, a NECTIN4 binding antibody, an HER3 binding antibody and a non-binding antibody (isotype control) according to general procedure I. The resultant ADCs were testedin vivo in Her2+ (Figure 11A), Nectin4+ (Figure 11B) and Her3+ (Figure 11C) positive tumormodels. The Trastuzumab based constructs have been evaluated in the Her2+ model NCI-N87. Theresults are shown in Figure 11. In all tested dose-levels it can be seen that the ADCs thathave been constructed with the VHL-X120_first eluting described herein are clearly superior over the constructs based on the previously known X2. References All publications cited throughout the text of this specification (including all patents, patent application, scientific publications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Tothe extent the material incorporated by reference contradicts or is inconsistent with thisspecification, the specification will supersede any such material.(1) Sathe, Gajanan et al, “Proteomic approaches advancing targeted proteindegradation” Trends in Pharmacological Sciences, Volume 44, Issue 11, pg.786 – 801;(2) Gadgoli et al., J. Chem. Inf. Model.2022;(3) Saftics et al, “Data evaluation for surface-sensitive label-free methods to obtain real-time kinetic and structural information of thin films: A practical review with related 184software packages”, Advances in Colloid and Interface Science, Volume 294, 2021,102431,ISSN 0001-8686, https: / / doi.org / 10.1016 / j.cis.2021.102431;(4) Kartal et al in “waveRAPID—A Robust Assay for High-Throughput Kinetic Screenswith the Creoptix WAVEsystem” SLAS Discovery, Volume 26, Issue 8, 2021, Pages 995-1003, ISSN 2472-5552, https: / / doi.org / 10.1177 / 24725552211013827;(5) Dragovich et al “Antibody-Mediated Delivery of Chimeric BRD4 Degraders (part 1)”, J.Med. Chem, 2021, 64, pg.2534 to 2575;(6) Dragovich et al “Antibody-Mediated Delivery of Chimeric BRD4 Degraders (part 2)”, J.Med. Chem, 2021, 64, pg.2576 to 2607;(7) Wang, X. et al “Structure-guided discovery of novel potent and efficacious proteolysistargeting chimera (PROTAC) degrader of BRD4”, Biorg. Chem. V.115, (2021) p 105238;(8) Troup et al,” Current strategies for the design of PROTAC linkers: a critical review”Explor. Target Antitumor Ther.2020; 1:273-312;(9) Lambert, J.M. et al “Chemical Linkers in Antibody–Drug Conjugates” R. Soc. Chem.2022, Drug discovery series no. 81, Chapter 1 “Introduction to Antibody–DrugConjugates”;(10) Filippakopoulos et al “Selective inhibition of BET bromodomains “, Nature 2010;(11) Hu, J et al. “Regulation of programmed cell death by Brd4”. Cell Death Dis. (2022) 13,1059;(12) Donati et al, “BRD4 and cancer: going beyond transcriptional regulation”. Mol. Cancer2018;17:164;(13) Loven J. et al, “Selective inhibition of tumor oncogenes by disruption ofsuperenhancers” Cell (2013) V.153 p.320–34;(14) Shi J. et al, “The mechanisms behind the therapeutic activity of BET bromodomaininhibition”, Mol. Cell. (2014) V.54, p.728–36;(15) Moriniere J., et al, “Cooperative binding of two acetylation marks on a histone tail by asingle bromodomain”, Nature (2009) V.461 p.664–8; WO2013106643A;(16) WO2020 / 086858A1;(17) WO2019084030A1;(18) EP2970330B1185

Claims

CLAIMS1. A compound having a structure according to structure (I):including a pharmaceutically acceptable salt thereof, an enantiomer thereof, a diastereomer thereof, a solvate thereof or an isotopically enriched molecule thereof;wherein Y^^is NR^; R^^is C1-C12alkyl, C1-C12haloalkyl, H, D, CH3or CD3; Y^is CH; Y^is N; R^ is H, D, C1-C6 alkyl, C1-C6 alkyl halide, C1-C6 alkyl azide, S(O)-C1-C6 alkyl, S(O)2-C1-C6 alkyl, a lone pair of electrons or is not present;Y^is CH or CD; Y^ is CR^1R^^^^R^1 is H or D; R^ is H or D;Y^ is N, CH, P(O) or O;G^ is aryl or heteroaryl;AG1 is CH, CD or N;AG2is C; AG3is C; AG4 is CH, CD or N;wherein one, both or none of AG1and AG4are N; wherein BG1, BG2, BG3, BG4, BG5, AG2 and AG3 form a seven membered ring and186BG1is C(O), NRBG1a, O, CRBG1bRBG1c, CRBG1b, N, S, Se, S(O), S(O)2, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e, BG2is C(O), NRBG2a, O, CRBG2bRBG2c, CRBG2b, N, S, Se, S(O), S(O)2, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e,BG3 is NRBG3a, CRBG3bRBG3c, CRBG3b, C(O), O, S, N, Se, S(O) or S(O)2,BG4 is NRBG4a, CRBG4bRBG4c, CRBG4b, C(O), O, S, N, Se, S(O) or S(O)2,BG5 is C(O), NY^, O, CY^RBG5a, CY^, S, Se, S(O), S(O) ^2 or P(O)Y ; orwherein BG1, BG2, BG4, BG5, AG2 and AG3 form a six membered ring andBG1is C(O), NRBG1a, O, N, CRBG1bRBG1c, CRBG1b,S, Se, S(O), S(O)2, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e, BG2is C(O), NRBG2a, O, N, CRBG2bRBG2c, CRBG2b,S, Se, S(O), S(O)2, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e, BG3is a bond between BG2and BG4, or BG3is not present, BG2is directly bonded to BG4,BG4 is NRBG4a, CRBG4bRBG4c, CRBG4b, C(O), O, S, N, Se, S(O) or S(O)2,BG5is C(O), NY^, N, O, CY^RBG5a, CY^, S, Se, S(O), S(O)2 or P(O)Y^; orwherein BG1, BG2, BG5, AG2 and AG3 form a five membered ring andBG1is C(O), NRBG1a, O, N, CRBG1bRBG1c, CRBG1b,S, Se, S(O), S(O)2, P(O)ORBG1d, P(O)NHRBG1eor P(O)CH2RBG1e, BG2is C(O), NRBG2a, O, N, CRBG2bRBG2c, CRBG2b,S, Se, S(O), S(O)2, P(O)ORBG2d, P(O)NHRBG2eor P(O)CH2RBG2e, BG3and BG4are a bond between BG2and BG5, or BG3and BG4are not present, BG2is directly bonded to BG5, BG5is C(O), NY^, N, O, CY^RBG5a, CY^, S, Se, S(O), S(O)2 or P(O)Y^; wherein RBG1a, RBG1b, RBG1c, RBG1d, RBG1e, RBG1e, RBG2a, RBG2b, RBG2c, RBG2d, RBG2e, RBG2e, RBG3a, RBG3b, RBG3c, RBG4a, RBG4b, RBG4c, RBG5a, at each occurrence, are each independently H, D, alcohol, alkenyl, alkyl, alkynyl, amide, amine, amino acid, amino alcohol, amino amide, amino ester, aryl, boryl, ether, ester, halogenyl, heteroaryl, heterocycle, phoshoramidite, phosphinyl, phosphoester, phosphonyl, selenenyl, selenonyl, sulfenyl, sulfonamide, sulfonyl, substituted alcohol, substituted alkene, substituted alkyl, substituted alkyne, substituted amide, substituted amine, substituted aryl, substituted azide, substituted borate, substituted halogen, substituted heteroaromatic, substituted heterocycle, substituted phoshoramidite, substituted phosphinate, substituted phosphoester, substituted phosphonate, substituted selenate, substituted selenyl, substituted sulfonamide, substituted sulfonyl, alkyl alcohol, alkyl amide, alkyl amine, alkyl amino acid, alkyl amino alcohol, alkyl aminoamide, alkyl amino ester, alkyl aromatic, alkyl azide, alkyl boronate, alkyl disulfide,alkyl carbonate, alkyl carbamate, alkyl ether, alkyl ester, alkyl halogen, alkyl heterocycle, alkyl heteroaromatic, alkyl phoshoramidite, alkyl phosphinate, alkylphosphoester, alkyl phosphonyl, alkyl selenate, alkyl sulfenate, alkyl sulfonamide,alkyl thiol, alkyl urea, alkyl thiourea or combinations thereof;wherein Y^^is S(O) RY^^^C(O)RY^, S(O)RY^^ P(O)(RY^) , ORY^, NH Y^2 2 R , OH, O, NH2,CRY^1RY^2C(O)NHRY^^^^ CRY^1RY^2S(O) RY^^^ CRY^1RY^2C(O)RY^, CRY^1RY^2S( Y^2 O)R ^CRY^1RY^2P(O)(RY^)2, CRY^1RY^2ORY^, CRY^1RY^2NHRY^, CRY^1RY^2OH, CRY^1RY^2CHO, 187CRY^1RY^2NH2, H or D; andwherein RY^at each occurrence, is independently H, O, OH, NH2, C1-C12 alkyl, C1-C12 alcohol, C1-C12amine, C1-C12amide, C1-C12ester, C6-C12aryl, C4-C12heterocycle or C5-C12 heteroaryl; wherein RY^1and RY^2at each occurrence, are independently H, D, halogen, C1-C12alkyl, C1-C12 alcohol, C1-C12 amine, C1-C12 amide, C1-C12 ester, C6-C12 aryl, C4-C12 heterocycle or C5-C12 heteroaryl.

2. The compound of claim 1, wherein the compound is for binding a bromodomain-containing protein, preferably the bromodomain-containing protein is a member of the BET family, preferably the BET family is the bromodomain and extra-terminal domain family, more preferably the bromodomain-containing protein is BRD2, BRD3, BRD4, BRDT, BRD7 or BRD9, more preferably wherein the bromodomain-containing protein is BRD2, BRD3, BRD4 or BRDT, more preferably the bromodomain-containing protein is BRD4.

3. The compound of any one of the preceding claims, wherein:R^ is H, D, C1-C3 alkyl, C1-C6 alkyl azide, S(O)Me or S(O)2Me, preferably is H or D;R^^is C1-C3 alkyl, C1-C3 haloalkyl, H, D, CH3 or CD3, preferably is H, D, CH3 or CD3, more preferably is CH3or CD3; AG1is CH or CD; and / or AG4is CH or CD.

4. The compound of any one of the preceding claims, wherein structure (I) is accordingto structure: 1885. The compound of any one of the preceding claims, wherein structure (I) is according1896. The compound of any one of the preceding claims, wherein G^ is chosen from anyone of the structures consisting of:190, wherein X is F, Cl, Br, D or CH3 including combinations of two thereof, preferably X is F, CH3 or both F and CH3, more preferably X is F,optionally wherein G^ is chosen from any one of the structures consisting:.

7. The compound of any one of the preceding claims, wherein G^ is.

8. The compound of any one of the preceding claims, wherein structure (I) is accordingto structure: 1921939. The compound of any one of the preceding claims, wherein BG1, BG2, BG3, BG4, BG5,AG2and AG3form a seven membered ring.

10. The compound of any one of the preceding claims, wherein BG1, BG2, BG4, BG5, AG2and AG3form a six membered ring.

11. The compound of any one of the preceding claims, wherein BG1, BG2, BG5, AG2 and AG3form a five membered ring.

12. The compound of any one of the preceding claims, wherein:194BG3 is NRBG3a, CRBG3bRBG3c, CRBG3b, C(O), O, S, N, Se, S(O) or S(O)2, preferably BG3is NRBG3a, CRBG3bRBG3cor C(O); BG4 is NRBG4a, CRBG4bRBG4c, CRBG4b, C(O), O, S, N, Se, S(O) or S(O)2, preferably BG4is NRBG4a, CRBG4bRBG4c, C(O), O, S, Se, S(O) or S(O)2;BG5is C(O), NY^, CY^RBG5a, CY^, O, S, Se, S(O), S(O)2 or P(O)Y^, preferably BG5is C(O), NY^, CY^RBG5a, CY^, S(O), S(O)2or P(O)Y^, more preferably BG5is C(O), NY^, CY^RBG5aor CY^.

13. The compound of any one of the preceding claims, wherein Y^^is S(O)2RY^^^C(O)RY^,S(O)RY^^ P(O)(RY^)2, ORY^, NHRY^, OH, O, NH2, CRY^1RY^2C(O)NHRY^^^^ CRY^1RY^2S(O)2RY^^^ CRY^1RY^2C(O)RY^, CRY^1RY^2S(O)RY^^ CRY^1RY^2P(O)(RY^)2,CRY^1RY^2ORY^, CRY^1RY^2NHRY^, CRY^1RY^2OH, CRY^1RY^2CHO, CRY^1RY^2NH2, H or D,preferably Y^^is S(O)2RY^^^ S(O)RY^^ CRY^1RY^2C(O)NHRY^^^^ CRY^1RY^2S(O)2RY^^^ CRY^1RY^2C(O)RY^, CRY^1RY^2S(O)RY^^ CRY^1RY^2P(O)(RY^) ^ ^ ^2, CRY 1RY 2NHRY , H or D,more preferably Y^^is S(O)2RY^^^ CRY^1RY^2C(O)NHRY^^^^ CRY^1RY^2S(O)2RY^^^ CRY^1RY^2C(O)RY^or CRY^1RY^2P(O)(RY^)2; and / or wherein RY^at each occurrence, is independently H, O, OH, NH2, C1-C12alkyl, C1-C12alcohol, C1-C12 amine, C1-C12 amide, C1-C12 ester, C6-C12 aryl, C4-C12 heterocycle or C5-C12 heteroaryl, preferably RY^at each occurrence, is independently H, O, OH, NH2, C1-C10 alkyl, C1-C10 alcohol, C1-C10 amine, C1-C10 amide, C1-C10 ester, C6-C10 aryl, C4- C10heterocycle or C5-C10heteroaryl, more preferably RY^at each occurrence, is independently H, O, OH, NH2, C1-C8 alkyl, C1-C8 alcohol, C1-C8 amine, C1-C8 amide, C1-C8 ester, C6-C8 aryl, C4-C8 heterocycle or C5-C8 heteroaryl, more preferably RY^at each occurrence, is independently H, O, OH, NH2, C1-C6 alkyl, C1-C6 alcohol, C1-C6 amine, C1-C6amide, C1-C6ester, C6-C6aryl, C4-C6heterocycle or C5-C6heteroaryl, more preferably RY^at each occurrence, is independently H, O, OH, NH2, C1-C5alkyl, C1-C5alcohol, C1-C5amine, C1-C5amide, C1-C5ester, C4-C5heterocycle or C5195heteroaryl, more preferably RY^at each occurrence, is independently H, O, OH, NH2, C1-C4 alkyl, C1-C4 alcohol, C1-C4 amine, C1-C4 amide or C1-C4 ester, more preferably RY^at each occurrence, is independently H, O, OH, NH2, C1-C3 alkyl, C1-C3 alcohol, C1-C3 amine, C1-C3 amide or C1-C3 ester, more preferably RY^is CH3, OCH3, Et, O, OH, H; and / or wherein RY^1and RY^2at each occurrence, are independently H, D, O, OH, NH2, halogen, C1-C12 alkyl, C1-C12 alcohol, C1-C12 amine, C1-C12 amide, C1-C12 ester, C6- C12 aryl, C4-C12 heterocycle or C5-C12 heteroaryl, preferably RY^1and RY^2at each occurrence, are independently H, D, O, OH, NH2, halogen, C1-C10alkyl, C1-C10alcohol, C1-C10 amine, C1-C10 amide, C1-C10 ester, C6-C10 aryl, C4-C10 heterocycle or C5-C10 heteroaryl, more preferably RY^1and RY^2at each occurrence, are independently H, D, O, OH, NH2, halogen, C1-C8 alkyl, C1-C8 alcohol, C1-C8 amine, C1-C8amide, C1-C8ester, C6-C8aryl, C4-C8heterocycle or C5-C8heteroaryl, more preferably RY^1and RY^2at each occurrence, are independently H, D, O, OH, NH2, halogen, C1-C6alkyl, C1-C6alcohol, C1-C6amine, C1-C6amide, C1-C6ester, C6-C6aryl, C4-C6 heterocycle or C5-C6 heteroaryl, more preferably RY^1and RY^2at each occurrence, are independently H, D, O, OH, NH2, F, Cl, Br, C1-C5alkyl, C1-C5alcohol, C1-C5 amine, C1-C5 amide, C1-C5 ester, C4-C5 heterocycle or C5 heteroaryl, more preferably RY^1and RY^2at each occurrence, are independently H, D, O, OH, NH2, F, Cl, Br, C1-C4 alkyl, C1-C4 alcohol, C1-C4 amine, C1-C4 amide or C1-C4 ester, more preferably RY^1and RY^2at each occurrence, are independently H, D, O, OH, NH2, F, Cl, C1-C3 alkyl, C1-C3 alcohol, C1-C3 amine, C1-C3 amide or C1-C3 ester, more preferably RY^1and RY^2at each occurrence, are independently H, D, F, CH3, OCH3, Et, O or OH, more preferably RY^1is H or D and / or RY^2is H or D.. The compound of any one of the preceding claims, wherein Y^ is selected from thegroup of structures consisting of:196.

15. The compound of any one of the preceding claims, wherein Y^ has the structure of:.

16. The compound of any one of the preceding claims, wherein structure (I) is selectedfrom the group of structures consisting of:198X52 X53X69’ X69X72 X73X76 X77X80 X81X82 X83X134 X135PAZ2-NMe (1) PAZ2-NMe (2)206PAZ2-NBu (2) 207PAZ3-CH2-SO2Me PAZ3-CH2-COOH208PAZ3-SO2-azetidine PAZ3-SO2-azetidineMe.

17. A method of preparing a compound for binding a bromodomain-containing proteinaccording to any one of claims 1 to 16, comprising -providing a compound according to structure (VI-a)209- providing a compound according to (VI-b)- coupling (VI-a) with (VI-b) to obtain either (VI-c) or (VI-d)- cyclizing either (VI-c) or (VI-d) to obtain a structure according to structure (I);or comprising:- providing a compound according to (VI-e)210- providing a compound according to (VI-f)- providing a molecule XY^-G^ and reacting with (VI-g) to obtain (VI-h)211-providing X^-Y^ and reacting with (VI-h) to obtain a molecule according to (I);wherein XG1is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, wherein XG2is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, wherein XG4is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, wherein XG5is H, Cl, Br, I, OTosyl, OTf, carbonyl or OH, CG1 is H, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid, BF3K, SnBu3, SiF3,SiCl3 or SiMe2OH,wherein CG2is NH2, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid, BF3K, SnBu3, SiF3, SiCl3 or SiMe2OH,wherein M is H, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid, BF3K, SnBu3, SiF3, SiCl3 or SiMe2OH,wherein XY^is NH2, Cl, Br, I, OTosyl, OTf, OH, boronic ester, boronic acid or BF3K, wherein X^-Y^ is Cl2C(O), ClC(O)OMe, Cl2S(O)2, Cl2CR^1R^^or (O)CR^1R^.

18. A pharmaceutically acceptable composition comprising a compound according to anyone of claims 1 to 16.

19. A compound according to any one of claims 1 to 16 or the pharmaceuticallyacceptable composition of claim 18, for use in the treatment of cancer.

20. A method for treating cancer comprising administering a compound according to anyone of claims 1 to 16 or a pharmaceutically acceptable composition according to claim 18. 212

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