WO2023074936A1 - Composé bifonctionnel utilisant un ligand liant le domaine de boîte ubr - Google Patents

Composé bifonctionnel utilisant un ligand liant le domaine de boîte ubr Download PDF

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WO2023074936A1
WO2023074936A1 PCT/KR2021/015256 KR2021015256W WO2023074936A1 WO 2023074936 A1 WO2023074936 A1 WO 2023074936A1 KR 2021015256 W KR2021015256 W KR 2021015256W WO 2023074936 A1 WO2023074936 A1 WO 2023074936A1
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amino
hydroxybenzoyl
compound
mmol
benzenesulfonohydrazide
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Korean (ko)
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권용태
김현태
나정은
지창훈
최하림
이지은
정창안
고아라
박선호
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주식회사 오토텍바이오
서울대학교 산학협력단
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Priority to PCT/KR2021/015256 priority Critical patent/WO2023074936A1/fr
Publication of WO2023074936A1 publication Critical patent/WO2023074936A1/fr

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    • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
    • C07C311/49—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom to nitrogen atoms
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    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D209/34—Oxygen atoms in position 2
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the disclosure herein relates to bifunctional compounds using UBR box domain binding ligands.
  • the UBR box domain is a domain commonly present in the UBR (Ubiquitin protein ligase E3 component n-recognin) protein of the N-end rule pathway.
  • the UBR box domain is known as a substrate binding domain. It is known that the UBR box domain binds to the N-terminal residue of the substrate and is essential for forming multi-ubiquitin chains on the substrate, and the substrate is degraded through this process.
  • a desired target protein (or peptide) can be induced to be degraded more effectively by using a bifunctional compound using a UBR box domain ligand that uses the function of the UBR box domain.
  • the N-terminal pathway rule is a protein degradation system that uses the N-terminus of a specific protein as a degradation signal.
  • the N-terminal pathway rule may include the following protein degradation process.
  • N-recognin recognizes the N-terminal degradation signal of a protein, and the N-recognin can degrade a protein by binding ubiquitin to a protein to be degraded.
  • the N-terminal degradation signal has a positively charged residue (type 1; eg, arginine, lysine, histidine) or a large hydrophobic residue (type 2; phenylalanine, leucine, tryptophan, isoleucine, tyrosine) at the N-terminus.
  • type 1 eg, arginine, lysine, histidine
  • type 2 phenylalanine, leucine, tryptophan, isoleucine, tyrosine
  • N-lecognines may include The present inventors first discovered or cloned N-lecognines, UBR1, UBR2, UBR3, and UBR5, and found that they had a UBR box domain as a substrate recognition domain (Tasaki et al. 2005). At this time, the ubiquitinated substrate produced by the binding of N-lecognin to the N-end rule ligand is delivered to the proteasome and degraded into short peptides.
  • N-terminal residues Nt-Arg, Nt-His, Nt-Lys, Nt-Trp, Nt-Phe, Nt-Tyr, Nt-Leu, Nt-Leu
  • Nt-Leu Nt-Leu
  • the UBR is an abbreviation of Ubiquitin protein ligase E3 component n-recognin, and UBR is N-recognin that recognizes the N-terminal degradation signal of a protein. It is known that at least 7 types of UBRs 1 to 7 exist in mammals.
  • the UBR box domain common to UBR is a zinc finger motif having a size of about 70 residues, and is known as a highly conserved substrate-binding domain.
  • UBR is N-lecognin associated with the N-terminal pathway law, which is a protein degradation pathway
  • the UBR box domain in UBR is a substrate binding domain.
  • UBR1, UBR2, UBR3 and UBR5 act as ubiquitin protein ligase E3 and are known to have a RING domain or a HECT domain.
  • Substrates of the N-terminal law binding to the UBR are degraded by the ubiquitin proteasome pathway.
  • the UBR box domain in the UBR recognizes the N-terminal amino acid of the substrate and ubiquitinates the substrate through the RING domain or the HECT domain, thereby degrading the substrate through the proteasome pathway.
  • misfolded proteins in cells are degraded through the ubiquitin proteasome pathway, as they can aggregate and block the proteasome or impair other cellular functions if left unattended for long periods of time. (Ji and Kwon, 2017).
  • the UBR box domain plays an important role in the intracellular protein degradation pathway by recognizing the N-terminal degradation signal.
  • ligands that bind to the UBR box domain can affect proteolytic pathways in cells. That is, the protein to be degraded (ie, the desired target protein (or peptide)) can be more effectively degraded by using a ligand that binds to the UBR box domain.
  • the protein to be degraded (i.e., the desired target protein (or peptide)) is more specifically synthesized using a bifunctional compound comprising a ligand that binds to the UBR box domain and a ligand that binds to the target protein (or peptide). can be effectively decomposed.
  • a bifunctional compound comprising a ligand that binds to the UBR box domain and a ligand that binds to the target protein (or peptide).
  • These bifunctional compounds position the protein of interest for degradation in proximity to the UBR, particularly the UBR box domain.
  • the protein to be degraded located close to the UBR box domain is ubiquitinated by the UBR box domain and degraded through the proteasome pathway.
  • the present specification relates to a bifunctional compound comprising a ligand that binds to a UBR box domain associated with an intracellular protein degradation pathway and a ligand that binds to a target protein (or peptide).
  • One object of the present invention is to provide a bifunctional compound.
  • Another object of the present invention is to provide a composition for protein degradation comprising a bifunctional compound and a use thereof.
  • Another object of the present invention is to provide a pharmaceutical composition for treating a disease comprising a bifunctional compound and a use thereof.
  • the present application provides a bifunctional compound or a salt thereof.
  • the bifunctional compound includes a UBR box domain binding ligand (UBL) and a target protein (or peptide) binding ligand (TBL).
  • UBL UBR box domain binding ligand
  • TBL target protein binding ligand
  • the bifunctional compound may be a compound having a UBL (UBR box domain binding ligand)-TBL (target protein (or peptide) binding ligand) structure or a salt thereof.
  • the TBL (target protein (or peptide) binding ligand) may be a compound that binds to a target protein (or peptide) to be degraded.
  • the TBL may be a known compound.
  • the UBL (UBR box domain binding ligand) may be a compound having a structure of Formula 1 or a salt thereof.
  • X 1 is phenyl, cycloalkyl or heterocyclyl optionally substituted or unsubstituted with one or more R 2 ;
  • X 4 is phenyl, cycloalkyl or heterocyclyl optionally substituted with one or more R 3 ;
  • each R 3 is independently alkyl, alkoxy, amino, halo, hydroxyl, alkylamino, dialkylamino, -NO 2 , -CONR'R'', -CO 2 R', -NHCOR', phenyl or heterocyclo is selected from alkyl;
  • each R' and R'' is independently -H or alkyl
  • X 2 is SO 2 , or CR a R b ;
  • R a and R b are each independently H or CH 3 ;
  • X 3 is NH or CH 2 ;
  • B 1 is CH 2 or NH
  • a 1 is CH 2 or NH.
  • the broken line represents a possible attachment point of the linker (L) or the target protein (or peptide) binding ligand (TBL).
  • -X 2 -B 1 -X 3 is selected from the group consisting of -SO 2 -NH-NH, -SO 2 -NH-CH 2 , -SO 2 -CH 2 -NH and -CH 2 -NH-NH;
  • X 1 is phenyl, cycloalkyl or heterocyclyl optionally substituted or unsubstituted with one or more R 2 ;
  • X 4 is phenyl, cycloalkyl or heterocyclyl optionally substituted with one or more R 3 ;
  • each R 3 is selected from alkyl, alkoxy, amino, halo, hydroxyl, alkylamino, dialkylamino, -NO 2 , -CONR'R'', -CO 2 R', -NHCOR', phenyl or heterocycloalkyl selected; wherein each R' and R'' is independently -H or alkyl;
  • A1 is CH 2 or NH
  • I is an integer of 0 or 1.
  • each of X 1 and X 4 is independently substituted or unsubstituted phenyl, cycloalkyl or heterocyclyl; In this case, each of X 1 and X 4 is independently substituted or unsubstituted phenyl, cyclohexyl, cyclopentyl, furanyl, thiazolyl, 1H-pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morphine polynyl, indolinyl, 1H-indolinyl, 1H-indolyl, 1H-indazolyl, isoindolinyl, indolin-2-oneyl, 2,3-dihydro-1H-indenyl and 1H-pyrrolopyri denyl.
  • Each R' and R'' is independently -H or alkyl.
  • Formula 1 provides a compound represented by Formula 1-1 or a salt thereof:
  • the A1 is CH 2 or NH
  • I is an integer of 0 or 1.
  • Formula 1 provides a compound of Formula 1-2 or a salt thereof:
  • Formula 1 provides a compound of Formula 1-3 or a salt thereof:
  • Chemical Formula 1 provides a compound represented by Chemical Formulas 1-4 or a salt thereof.
  • X 4 is phenyl, cycloalkyl or heterocyclyl optionally substituted with one or more R 3 ;
  • each R 3 is independently alkyl, alkoxy, amino, halo, hydroxyl, alkylamino, dialkylamino, -NO 2 , -CONR'R'', -CO 2 R', -NHCOR', is selected from phenyl or heterocycloalkyl;
  • Each R' and R'' is independently -H or alkyl.
  • the broken lines (dotted lines) in Formulas 1-1, 1-2, 1-3, and 1-4 indicate possible attachment points of the linker (L) or the target protein (or peptide) binding ligand (TBL).
  • each of X 1 and X 4 is independently substituted or unsubstituted phenyl, cycloalkyl or heterocyclyl; In this case, each of X 1 and X 4 is independently substituted or unsubstituted phenyl, cyclohexyl, cyclopentyl, furanyl, thiazolyl, 1H-pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morphine polynyl, indolinyl, 1H-indolinyl, 1H-indolyl, 1H-indazolyl, isoindolinyl, indolin-2-oneyl, 2,3-dihydro-1H-indenyl and 1H-pyrrolopyri denyl.
  • the R 2 is amino, or a salt thereof.
  • the X 1 is
  • a phosphorus compound or a salt thereof is provided.
  • Each R' and R'' is independently -H or alkyl.
  • the R 3 is hydroxyl provides a compound or a salt thereof.
  • the X 4 is , or A phosphorus compound or a salt thereof is provided.
  • the UBL may be a compound or a salt thereof selected from the following:
  • the bifunctional compound may be a compound having a UBL (UBR box domain binding ligand) -L (linker) -TBL (target protein (or peptide) binding ligand) structure or a salt thereof.
  • UBL ULR box domain binding ligand
  • L linker
  • TBL target protein (or peptide) binding ligand
  • the TBL (target protein (or peptide) binding ligand) may be a compound that binds to a target protein (or peptide) to be degraded.
  • the TBL may be a known compound.
  • the L may be a compound that connects the UBL (UBR box domain binding ligand) and the TBL (target protein (or peptide) binding ligand) without affecting each function.
  • L may be a known linker compound.
  • the UBL (UBR box domain binding ligand) is the same as described in one embodiment described above.
  • the present application provides a composition for protein degradation comprising a bifunctional compound and a use thereof.
  • the bifunctional compound includes a UBR box domain binding ligand (UBL) and a target protein (or peptide) binding ligand (TBL).
  • UBL UBR box domain binding ligand
  • TBL target protein binding ligand
  • the composition for protein degradation may include a bifunctional compound having a UBL-TBL structure or a UBL-L-TBL structure.
  • the UBL, L and TBL are as described above.
  • the present application provides a pharmaceutical composition containing a bifunctional compound and a method for treating a disease using the same.
  • the bifunctional compound includes a UBR box domain binding ligand (UBL) and a target protein (or peptide) binding ligand (TBL).
  • UBL UBR box domain binding ligand
  • TBL target protein binding ligand
  • the pharmaceutical composition may include a bifunctional compound having a UBL-TBL structure or a UBL-L-TBL structure.
  • the UBL, L and TBL are as described above.
  • the pharmaceutical composition may be used for treatment of disease.
  • the disease is protein (or peptide) degradation, protein mutation, misfolded protein, protein accumulation, aggregated (aggregated) protein (and / or peptide), overexpressed protein, truncated protein, abnormal structure
  • Eggplant may be a disease caused by protein problems, such as protein.
  • a bifunctional compound comprising a ligand binding to a UBR box domain associated with an intracellular protein degradation pathway and a ligand binding to a target protein (or peptide). More specifically, a bifunctional compound can position a protein of interest for degradation in proximity to a UBR, particularly a UBR box domain. At this time, the protein to be degraded located close to the UBR box domain is ubiquitinated by the UBR box domain and can be degraded through the proteasome pathway. Therefore, the protein to be degraded (ie, the desired target protein (or peptide)) can be more effectively degraded by using the bifunctional compound.
  • Figure 2 is an experimental result confirming whether the degradation of R-nsp4, which should be degraded by binding to UBR1, is inhibited by compounds (Compounds 2, 3, 7, 12, 14, and 16) using an in vitro transcriptional translation method.
  • FIG. 3 is an experimental result using immunoblotting to confirm whether compounds (Compounds 2 and 3) bind to UBR1 and inhibit degradation of RGS4, a substrate for UBR proteins in embryonic kidney cells, which should be degraded.
  • MST Microscale thermophoresis test results to determine whether compounds (Compounds 1, 2, 5, 8, 9, 11, 12, and 13) and UBR1 bind to each other.
  • 21 is an experimental result confirming the PSA degradation ability of compounds A and compounds C, a prostate cancer-specific antigen, using immunoblotting.
  • UBR Ubiquitin protein ligase E3 component n-recognin
  • the term UBR means an abbreviation for Ubiquitin protein ligase E3 component n-recognin.
  • the UBR is N-lecognin that recognizes the N-terminal residue of a protein, and it is known that at least 7 types of UBRs 1 to 7 exist in mammals.
  • the UBR is N-lecognin, which is involved in the N-terminal law pathway, which is a proteolytic pathway in vivo. Specifically, the UBR recognizes the N-terminal degradation signal (N-degron) of a protein and is involved in the process of degradation of a substrate protein through the ubiquitin proteasome pathway.
  • N-degron N-terminal degradation signal
  • UBR box domain is a domain present in UBR protein and is a zinc finger motif.
  • the UBR proteins include UBR 1 to 7 proteins.
  • the UBR box domain is known as a domain to which a substrate protein binds.
  • the compounds disclosed herein as UBR box domain ligands can bind to the UBR box domain and inhibit binding of the UBR box domain substrate.
  • the compounds disclosed herein as UBR box domain ligands can affect proteolytic pathways in cells.
  • RING domain is known to be present in UBR 1, 2 and 3 proteins.
  • the RING domain may also be used as the term RING ubiquitination domain.
  • the RING domain is a domain present in a protein and is a zinc finger motif.
  • the RING domain is a domain that plays an important role in the process of transferring ubiquitin from E2 to a substrate protein, and the RING domain serves to cause the process of transferring ubiquitin to a substrate protein in one step.
  • the term HECT domain is known to exist within the UBR 5 protein.
  • the HECT domain may also be used as the term HECT ubiquitination domain.
  • the HECT domain is a domain that plays an important role in the process of transferring ubiquitin from E2 to a substrate protein. Ubiquitin in E2 is transferred to the HECT domain and then transferred to the substrate protein. That is, the HECT domain serves to make the process of transferring the ubiquitin to the substrate protein in two steps.
  • zinc finger motif refers to a protein structural motif in which one or more zinc ions are present to stabilize the protein structure.
  • the UBR box domain and RING domain of the present specification are zinc finger motifs.
  • N-degron is a protein degradation signal.
  • protein degradation is regulated depending on the N-terminal residue sequence of the protein, and proteolysis signals present at the N-terminus are collectively referred to as N-degron.
  • the N-degrons include those having a positively charged residue (eg, arginine, lysine, histidine) or a large hydrophobic residue (phenylalanine, leucine, tryptophan, isoleucine, tyrosine) at the N-terminus.
  • the term N-end rule was used based on the relationship that the half-life of a protein is determined by what amino acid residue exists at the N-terminus of the protein.
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • Protec works by inducing selective intracellular protein degradation.
  • Protek consists of two covalently linked protein-binding ligands. One can bind the E3 ubiquitin ligase and the other binds to the target protein signifying degradation. Recruitment of the E3 ligase to the target protein results in ubiquitination and subsequent degradation of the target protein by the proteasome. Since Protek only needs to bind to the target rather than inhibiting the activity of the target protein with high selectivity, many efforts are currently underway to convert previously ineffective inhibitor molecules of the target protein into Protek for next-generation drugs.
  • the protein disclosed herein is characterized by using a bifunctional compound including a ligand that binds to UBR, an E3 ligase, particularly a ligand that binds to the UBR box domain in UBR and a target protein (or peptide) binding ligand. .
  • the UBR box domain binding ligand binds to the UBR box domain.
  • the UBR box domain is known as a domain to which an N-terminal residue sequence or an N-terminal degradation signal binds. This domain is involved in the process of protein degradation by the N-terminal pathway rule.
  • the UBR box domain binding ligand can affect the proteolytic process through the N-terminal law pathway.
  • N-degrons are recognized by N-recognin, and UBR (Ubiquitin protein ligase E3 component n-recognin) was discovered as N-recognin. It is known that the UBR recognizes an N-terminal residue sequence or an N-terminal degradation signal through the UBR box domain. That is, UBR recognizes a protein degradation signal through the UBR box domain, and through this, the protein degradation process proceeds.
  • UBR Ubiquitin protein ligase E3 component n-recognin
  • the protein degradation process by the UBR may include the following.
  • the UBR box domain recognizes a substrate having an N-terminal degradation signal, ubiquitin is bound to the substrate, and the substrate to which ubiquitin is bound can be degraded by the proteasome. That is, a substrate having an N-terminal degradation signal can be degraded by the ubiquitin proteasome system (UPS).
  • UPS ubiquitin proteasome system
  • the protein disclosed herein uses a bifunctional compound including a UBR box domain binding ligand and a target protein (or peptide) binding ligand to position a protein to be degraded in close proximity to the UBR, particularly the UBR box domain let it At this time, the protein to be degraded located close to the UBR box domain is ubiquitinated by the UBR box domain and degraded through the proteasome pathway.
  • the protector may include a UBR box domain binding ligand and a target protein binding ligand.
  • the protector may further include a linker, and the linker may serve to connect the two ligands by being present between the UBR box domain binding ligand and the target protein binding ligand.
  • ligand refers to a substance that specifically binds to a protein.
  • the protein includes an enzyme or a receptor, and when the protein is an enzyme, the ligand may mean a substrate that binds to the enzyme, and when the protein is a receptor, the ligand may mean a hormone that binds to the receptor.
  • a compound as a UBR box domain ligand provided herein refers to a compound that binds to a UBR box domain, and is used interchangeably with UBR box domain binding ligand (UBL) in the present specification.
  • the UBL refers to a compound that binds to a UBR box domain in a UBR protein.
  • the UBL refers to a compound that binds to a UBR box domain present in one or more proteins of UBR1 to 7.
  • UBL can compete with substrates of the UBR box domain. That is, the UBL can inhibit the substrate of the UBR box domain from binding.
  • the UBL may inhibit substrate degradation by inhibiting binding of the substrate.
  • a target protein (or peptide) binding ligand refers to a compound that binds to a target protein (or peptide) to be degraded.
  • the TBL may be a known compound.
  • the term “compound” relates to any particular chemical compound described herein, and includes tautomers, regioisomers, geometric isomers and, where applicable, stereoisomers, which include: Optical isomers (enantiomers) and other stereoisomers (diastereomers) thereof, as well as pharmaceutically acceptable salts and derivatives thereof (including prodrug forms) where applicable in the context are included.
  • the term compound generally refers to a single compound or is also stereoisomers, regioisomers and/or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched compounds of the described compounds. It may contain other compounds such as mixtures.
  • the term also, in context, refers to a prodrug form of a compound that has been modified to facilitate administration and delivery of the compound to the site of action. It will be appreciated by those skilled in the art that the molecules described herein are generally described stable compounds.
  • aminoalkyl refers to an alkyl moiety substituted with an amino group.
  • the aminoalkyl group includes -CH(NH 2 )CH 3 and -CH 2 (NH 2 ).
  • cycloalkyl refers to a carbocyclic group containing one or more saturated ring structures and includes bicyclics. Cycloalkyl includes, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Heterocycloalkyl refers to a ring structure containing at least one heteroatom selected from P, N, O and S in addition to the ring-carbon atom in the above cycloalkyl.
  • heterocyclyl refers to an unsaturated, saturated or partially unsaturated monocyclyl, bicyclic, or tricyclic group of 2 to 14 ring carbon atoms, in addition to the ring-carbon atoms P, N, O and and one or more heteroatoms selected from S.
  • the heterocyclyl includes heterocycloalkyl.
  • the heterocyclic group is attached to another moiety through a carbon or heteroatom and is optionally substituted on the carbon or heteroatom.
  • heterocyclyls include azetidinyl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzo Thiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl ( indolinyl, isoindolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl ), isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,
  • the bifunctional compound includes a UBR box domain binding ligand (UBL) and a target protein (or peptide) binding ligand (TBL).
  • UBL UBR box domain binding ligand
  • TBL target protein binding ligand
  • UBR box domain binding ligand UBL
  • TBL Target protein binding ligand
  • UBL UBL box domain binding ligand
  • L linker
  • TBL Target protein binding ligand
  • UBR box domain binding ligand (UBL)
  • the UBR box domain-binding ligand disclosed herein was designed in consideration of the structure of the UBR box domain and the binding form between the UBR box domain and the N-terminal pathway substrate.
  • Various amino acids present in the UBR box domain interact and bind with amino acids of the N-terminal pathway substrate through ionic interaction, hydrogen bond, and hydrophobic interaction.
  • a low-molecular-weight compound capable of forming a suitable binding mode with the UBR box domain is synthesized and provided.
  • compounds represented by Chemical Formulas 1 to 55 are provided.
  • UBL UBR box domain binding ligand
  • the UBR box domain binding ligand (UBL) disclosed herein has a core structure that allows it to bind well to the UBR box domain.
  • the binding mode between the UBR box domain and the amino acid of the N-terminal pathway substrate was analyzed to derive the core structure of the compound.
  • UBL provided herein may have a structure of [Formula 1] below derived based on a core structure that binds well to the UBR box domain. [Formula 1] is as follows:
  • the dashed line (dotted line) in Chemical Formula 1 indicates the attachment point of the linker (L) or the target protein (or peptide) binding ligand (TBL).
  • X 2 may be a structure that induces a folding structure in the compound disclosed herein.
  • the folding structure may help X 1 of the compound disclosed herein smoothly maintain charge-charge interaction or hydrogen bonding or hydrophobic action with the UBR box domain and increase bonding strength.
  • the X 2 may be one of various structures that may cause a bending structure.
  • X 2 may be SO 2 or CR a R b .
  • R a and R b may be each independently selected from H or CH 3 .
  • X 2 may be CH 2 , CH(CH 3 ) or C(CH 3 ) 2 .
  • the X 2 may be SO 2 .
  • a 1 may be, in one embodiment, CH 2 or NH.
  • B 1 may be, in one embodiment, CH 2 or NH.
  • X 3 may be, in one embodiment, CH 2 or NH.
  • X 3 may not be CH 2 .
  • Chemical Formula 1 may have a structure selected from the following:
  • -X 2 -B 1 -X 3 is selected from the group consisting of -SO 2 -NH-NH, -SO 2 -NH-CH 2 , -SO 2 -CH 2 -NH and -CH 2 -NH-NH;
  • A1 is CH 2 or NH
  • I is an integer of 0 or 1.
  • Chemical Formula 1 may have a structure selected from the following:
  • dashed lines (dotted lines) in Chemical Formulas 1-1 to 1-4 represent possible attachment points of the linker (L) or the target protein (or peptide) binding ligand (TBL).
  • X 1 in Formula 1 is Corresponding to the side chain of the first residue (N1) of the N-degron, X 1 is expected to bind to the negatively charged-surrounded region.
  • X 1 in Chemical Formula 1 may have a ring structure including a moiety that has an electric charge or forms a hydrogen bond.
  • the X 1 may have a ring structure having a planar structure including a moiety that has an electric charge or forms a hydrogen bond.
  • X 1 in Chemical Formula 1 may include a structure capable of binding to a linker.
  • X 1 may be phenyl, cycloalkyl or heterocyclyl optionally substituted with one or more R 2 .
  • X 1 is phenyl , cyclohexyl, cyclopentyl, furanyl, thiazolyl, 1H-pyrazolyl, pyrrolidinyl, piperidinyl, p Ferrazinyl, morpholinyl, indolinyl, 1H-indolinyl, 1H-indolyl, 1H-indazolyl, isoindolinyl, indolin-2-oneyl, 2,3-dihydro-1H-indenyl and 1H -pyrrolopyridinyl.
  • R 2 may be amino.
  • the X 1 may be selected from the following structure:
  • the X 1 may be selected from the following structure:
  • X 4 corresponds to the side chain of the second residue (N2) of the N-degron and may have a ring or chain structure to fill the bonding space when combined with the UBR box. .
  • the ring or chain structure may have a charge or a moiety forming a hydrogen bond may be introduced to increase bonding strength.
  • X 4 may include a structure capable of serving to bind to a linker when the compound of the present specification is used in combination with another substance later.
  • X 4 may be phenyl, cycloalkyl or heterocyclyl optionally substituted with one or more R3.
  • X 4 is phenyl, cyclohexyl , cyclopentyl, furanyl, thiazolyl, 1H-pyrazolyl, pyrrolidinyl, piperidinyl, p Ferrazinyl, morpholinyl, indolinyl, 1H-indolinyl, 1H-indolyl, 1H-indazolyl, isoindolinyl, indolin-2-oneyl, 2,3-dihydro-1H-indenyl and 1H -pyrrolopyridinyl.
  • each R 3 is independently alkyl, alkoxy, amino, halo, hydroxyl, alkylamino, dialkylamino, -NO 2 , -CONR'R'', -CO 2 R', -NHCOR', phenyl or Heterocycloalkyl.
  • R 3 may be hydroxyl.
  • each of R' and R'' may independently be -H or alkyl.
  • the X 4 may be selected from:
  • the X 4 may be selected from:
  • the compounds disclosed herein may exist in the form of stereoisomers or salts thereof, and isomers or salts of such compounds are included in the scope of the present specification.
  • UBR box domain binding ligand (UBL)
  • the compound disclosed herein may have a structure of [Formula 1-1]:
  • A1 is CH 2 or NH
  • I is an integer of 0 or 1.
  • X 1 and X 4 are ii) of ⁇ UBR box domain binding ligand> described above X 1 and iii) X 4 are equally applicable.
  • a specific exemplary compound for [Formula 1-1] may be selected from the following.
  • the broken line (dotted line) indicating the attachment point of the linker (L) or the target protein (or peptide) binding ligand (TBL) is omitted.
  • the UBL disclosed herein may have a structure of [Formula 1-2]:
  • X 1 and X 4 are ii) of ⁇ UBR box domain binding ligand> described above The same applies to X 1 and iii) X 4 .
  • Specific exemplary compounds for [Formula 1-2] may be selected from the following.
  • the broken line (dotted line) indicating the attachment point of the linker (L) or the target protein (or peptide) binding ligand (TBL) is omitted.
  • UBL disclosed herein may have a structure of [Formula 1-3]:
  • X 1 and X 4 are ii) of ⁇ UBR box domain binding ligand> described above X 1 and iii) X 4 are equally applicable.
  • Specific exemplary compounds for [Formula 1-3] may be selected from the following.
  • the broken line (dotted line) indicating the attachment point of the linker (L) or the target protein (or peptide) binding ligand (TBL) is omitted.
  • compound number compound 12 4-Amino- N- (2-(4-hydroxyphenyl)-2-oxoethyl)benzenesulfonamide 50 4-Amino-N-(2-(4-hydroxyphenyl)-2-oxoethyl)-3-morpholinobenzenesulfonamide 51 3,5-diamino-N-(2-(4-hydroxyphenyl)-2-oxoethyl)benzenesulfonamide
  • UBL disclosed herein may have a structure of [Formula 1-4]:
  • X 1 and X 4 are ii) of ⁇ UBR box domain binding ligand> described above X 1 and iii) X 4 are equally applicable.
  • Specific exemplary compounds for [Formula 1-4] may be selected from the following.
  • the broken line (dotted line) indicating the attachment point of the linker (L) or the target protein (or peptide) binding ligand (TBL) is omitted.
  • the UBL may be considered in the form of one of its possible isomers or a form of a mixture thereof.
  • all stereoisomers including enantiomers and diastereomers, or mixtures thereof (eg, racemic mixtures) are contemplated.
  • the UBL disclosed herein may be considered in the form of a salt thereof.
  • the salt includes a pharmaceutically acceptable salt.
  • Salts disclosed herein include acid addition salts or basic addition salts.
  • Exemplary acids forming the salt include hydrochloric acid, sulfuric acid, phosphoric acid, glycolic acid, lactic acid, pyruvic acid, citric acid, succinic acid, glutaric acid, and the like
  • exemplary bases forming the salt include lithium, sodium, potassium, calcium, magnesium , methylamine, trimethylamine, and the like. However, it is not limited thereto and can be easily selected by those skilled in the art.
  • TBL Target protein (or peptide) binding ligand
  • the target protein (or peptide) binding ligand disclosed herein is designed in various ways according to the target protein (or peptide) to be degraded.
  • the target protein (or peptide) binding ligand (TBL) may be a known compound known to bind to a target protein (or peptide).
  • the TBL may be an inhibitor compound of a known target protein (or peptide).
  • the TBLs are Hsp90 inhibitors, kinase inhibitors, androgen receptor inhibitors, HDM2 & MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear It may be a hormone receptor compound, an immunosuppressive compound or a compound targeting the aryl hydrocarbon receptor (AHR), but is not limited thereto.
  • the TBLs also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of known compounds, as well as other small molecules capable of targeting a protein of interest.
  • the target protein which is any protein that binds to the TBL of the bifunctional compound and is ubiquitinated by UBR and degraded by proteasome, is, for example, a structural protein, a receptor, an enzyme, a cell surface protein, or a cell surface protein.
  • Proteins that act on various functions such as catalytic activity, aromatase activity, locomotor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteins involved in proteolysis, biosynthesis, kinases activity, oxidoreductase activity, transferase activity, hydrolase activity, ligase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate) , receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimuli, behavior proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (protein transporters) activity, nuclear transport, including ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcriptional regulator activity, cell It may include proteins with exo-organizing and biogenic activities, translation
  • the target proteins can be derived from eukaryotes and prokaryotes, including humans, other animals, including domestic animals, microorganisms and plants for the determination of targets for antibiotics and other antimicrobials, and even viruses, among others, as targets for drug therapy. May contain protein.
  • TBL can have the structure of Formula 2 below:
  • W 1 is or is
  • each R 3 is independently H or -CN
  • each R 4 is independently H, halogen or -CF 3 ;
  • Y 1 and Y 2 are each independently O or S;
  • R 1 and R 2 are each independently H or a methyl group
  • W 2 is a bond, C1-6 aryl, biphenyl, biphenylyl or heteroaryl, each optionally substituted with 1, 2 or 3 R W2 ;
  • the dashed line represents an attachment point with the UBR box domain binding ligand (UBL) or linker (L).
  • the W 1 is selected from the group consisting of:
  • the W 2 is selected from the group consisting of:
  • the TBL may be an androgen receptor binding compound.
  • TBL can be an androgen receptor binding compound.
  • the androgen receptor binding compound may be selected from the group consisting of:
  • TBL can have the structure of Formula 3 below:
  • each X 1 and X 2 is independently selected from N or CH;
  • R 1 is independently selected from OH, O(CO)R a , O-lower alkyl, wherein R a is an alkyl or aryl group in an ester;
  • R 2 is selected from H, OH, halogen, CN, CF 3 , SO 2 -alkyl, O-lower alkyl;
  • R 3 is selected from H, halogen
  • the dashed line represents an attachment point with the UBR box domain binding ligand (UBL) or linker (L).
  • the TBL may be an estrogen receptor binding compound.
  • TBLs can be designed in various ways according to various types of target proteins (or peptides). Also, since known compounds or inhibitor compounds known to bind target proteins (or peptides) can be used for TBL, TBL is not limited to any of the embodiments described above.
  • the linker disclosed herein is a compound that chemically connects or binds a UBR box domain binding ligand (UBL) and a target protein (or peptide) binding ligand (TBL).
  • the linker may be a compound that does not affect the functions of the UBR box domain binding ligand (UBL) and the target protein (or peptide) binding ligand (TBL).
  • the functions of the UBR box domain binding ligand (UBL) and the target protein (or peptide) binding ligand (TBL) may be binding to the UBR box domain and binding to the target protein (or peptide), respectively.
  • the linker a known linker well known in the art may be used.
  • the linker may be arbitrarily selected from linkers described in Korean Patent Application No. 10-2020-7032733, US Patent Application No. 17/006193, and US Patent Application No. 17/082839.
  • the linker can be designed in various ways considering the structures of UBL and TBL.
  • the linker can be selected from the group consisting of:
  • n and m of the linker are each independently 0, 1, 2, 3, 4, 5 or 6.
  • the broken line represents an attachment point to the UBR box domain binding ligand (UBL) or target protein (or peptide) binding ligand.
  • the linker can be selected from the group consisting of:
  • n and p are each independently 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • o 0, 1, or 2;
  • R is H, methyl or ethyl
  • R 1 and R 2 are each independently O or NH.
  • a bifunctional compound disclosed herein may be considered in the form of a salt thereof.
  • the salt includes a pharmaceutically acceptable salt.
  • Salts disclosed herein include acid addition salts or basic addition salts.
  • Exemplary acids forming the salt include hydrochloric acid, sulfuric acid, phosphoric acid, glycolic acid, lactic acid, pyruvic acid, citric acid, succinic acid, glutaric acid, and the like
  • exemplary bases forming the salt include lithium, sodium, potassium, calcium, magnesium , methylamine, trimethylamine, and the like. However, it is not limited thereto and can be easily selected by those skilled in the art.
  • the bifunctional compound may have a UBL-TBL or UBL-L-TBL structure.
  • the UBL may have a structure of Chemical Formula 1. At this time, the description of the structure of Formula 1 above ⁇ 1. UBR box domain binding ligand> as described in the section.
  • the TBL may have a structure of Chemical Formula 2. At this time, the description of the structure of Formula 2 above ⁇ 2. It is the same as described in the section Target Protein (or Peptide) Binding Ligand>.
  • the linker may be selected from the group consisting of:
  • n and p are each independently 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • o 0, 1, or 2;
  • R is H, methyl or ethyl
  • R 1 and R 2 are each independently O or NH.
  • the bifunctional compound can be selected from the group consisting of:
  • the bifunctional compound may have a UBL-TBL or UBL-L-TBL structure.
  • the UBL may have a structure of Chemical Formula 1. At this time, the description of the structure of Formula 1 above ⁇ 1. UBR box domain binding ligand> as described in the section.
  • the TBL may have a structure of Chemical Formula 3. At this time, the description of the structure of Formula 3 above ⁇ 2. It is the same as described in the section Target Protein (or Peptide) Binding Ligand>.
  • the linker may be selected from the group consisting of:
  • n and p are each independently 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • o 0, 1, or 2;
  • R is H, methyl or ethyl
  • R 1 and R 2 are each independently O or NH.
  • the bifunctional compound can be selected from the group consisting of:
  • One aspect disclosed herein relates to the use of a bifunctional compound.
  • the bifunctional compounds disclosed herein can be used to prepare compositions for target protein (or peptide) degradation.
  • the bifunctional compound disclosed herein can be used as PROTAC.
  • the bifunctional compound includes a UBR box domain binding ligand (UBL) and a target protein (or peptide) binding ligand (TBL).
  • UBL UBR box domain binding ligand
  • TBL target protein binding ligand
  • the bifunctional compound may use the property that UBL binds to the UBR box domain to position the target protein (or peptide) bound to the TBL of the bifunctional compound to be close to the UBR, particularly the UBR box domain.
  • the target protein (or peptide) located close to the UBR box domain is ubiquitinated by the UBR box domain and can be degraded through the proteasome pathway.
  • the protein to be degraded ie, the desired target protein (or peptide)
  • the composition containing the bifunctional compound can be used for inducing or promoting the degradation of a target protein (or peptide) by the ubiquitin-proteasome pathway by binding to the UBR box domain.
  • the bifunctional compound disclosed herein induces or promotes degradation of a target protein (or peptide) through binding to UBR (FIGS. 20 to 23).
  • the bifunctional compound disclosed herein has a property of inducing or promoting target protein (or peptide) degradation. Therefore, by using such a bifunctional compound, it is possible to induce or promote degradation of problematic proteins in the body, and diseases caused by protein problems can be treated using this mechanism.
  • Diseases caused by the protein problem include abnormal protein (or peptide) degradation, protein mutation, misfolded protein, protein accumulation, aggregated protein (and/or peptide), overexpressed protein, truncated protein, abnormal It may be a disease or disorder caused by a protein problem, such as a protein having a structure.
  • diseases caused by these protein problems include asthma, autoimmune diseases such as multiple sclerosis, various cancers, chorionic diseases, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity (PKD1) or 4 (PKD2) Freder-Willi syndrome, sickle cell disease, Tay-Sarks disease, Turner syndrome, Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, atherosclerosis, attention deficit hyperactivity Disorders, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, diabetes mellitus type 1, diabetes mellitus type 2, epilepsy, Guillain Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease,
  • bifunctional compounds disclosed herein can be used in the manufacture of pharmaceutical compositions for treating a subject in need thereof.
  • the treatment includes an effect of improving symptoms of a specific medical condition or delaying the progression of a disease.
  • the subject includes humans and non-human animals.
  • the pharmaceutical composition may include a pharmaceutically acceptable carrier, excipients and/or additives together with the dual functional compound.
  • pharmaceutically acceptable carriers, excipients and/or additives include, but are not limited to, water, saline, glycols, glycerol, animal and vegetable fats, oils, starches, etc. Pharmaceutically acceptable carriers, excipients known in the art and/or additives.
  • kits for treatment comprising administering a bifunctional compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject in need thereof. At this time, administration of the bifunctional compound or a pharmaceutically acceptable salt thereof is
  • a mixture of A1 (methyl 4-hydroxybenzoate, 2.00 g, 13 mmol, 1.0 eq) and hydrazine monohydrate (20 mL) was stirred at 100° C. for 16 h.
  • A4 (3-fluoro- N '-(4-hydroxybenzoyl)-4-nitrobenzenesulfonohydrazide, 500 mg, 1.41 mmol, 1.0 eq) and morpholine (184 mg, 2.11 mmol, 1.5 eq) was added K 2 CO 3 (486 mg, 3.52 mmol, 2.5 eq) at 25 °C. The mixture was then stirred at 25° C. for 16 hours. The solution was poured into water (30 mL). The mixture was extracted with EA (30 mL x 3).
  • a mixture of A2 (4-hydroxybenzohydrazide, 500 mg, 3.29 mmol, 1.0 eq) and 4-acetylbenzene-1-sulfonyl chloride (717 mg, 3.29 mmol, 1.0 eq) in pyridine (5 mL) was Stirred at 25° C. for 3 hours. The mixture was cooled and carefully poured into water. The mixture was extracted with EA (50 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to give A18 (4-acetyl-N'-(4-hydroxybenzoyl)benzenesulfonohydrazide, 0.5 g, crude) as a brown solid. lost.
  • A24 (2-amino-1-(4-(benzyloxy)phenyl)ethan-1-one hydrochloride in DCM (20 mL), 2.00 g, 7.20 mmol, 1.0 eq), a mixture of 4-nitrobenzene-1-sulfonyl chloride (1.60 g, 7.20 mmol, 1.0 eq) and TEA (2.19 g, 21.6 mmol, 3.0 eq) at 20 °C for 1 hour stirred while The mixture was poured into water and extracted with DCM. The organic layer was washed with water and brine, dried over Na 2 SO 4 and concentrated to give a crude product which was stirred in PE for 30 minutes.
  • a mixture of A26 (4-cyano- N '-(4-hydroxybenzoyl)benzenesulfonohydrazide, 200 mg, 0.63 mmol, 1.0 eq) in HCl/EtOH (5 mL, 6 mol/L) was 25 It was stirred for 3 hours at °C. The solution was concentrated and MeOH was added. The mixture was concentrated again. The residue was added to MeOH (10 mL) followed by NH 4 OAc (485 mg, 6.30 mmol, 10 eq). The mixture was stirred at 25 °C for 16 hours.
  • A30 (4-(benzyloxy) -N -(((4-nitrophenyl)thio)methyl)benzamide, 500 mg, 1.27 mmol, 1.0 eq) and m-CPBA (656 g, A mixture of 3.80 mmol, 3.0 eq) was stirred at 20 °C for 16 h. The mixture was aq. It was poured with Na 2 O 3 S 2 and extracted. The organic layer was aq. washed with NaHCO 3 and brine, dried over Na 2 SO 4 and concentrated to give A31 (4-(benzyloxy) -N -(((4-nitrophenyl)sulfonyl)methyl)benzamide, 300 mg, crude) It was obtained as a white solid.
  • A34 (6-nitro-[1,1'-biphenyl]-3-sulfonyl chloride, 200 mg, 0.67 mmol, 1.0 eq) and 4-hydroxybenzohydrazide (122 mg, A mixture of 0.81 mmol, 1.2 eq) was stirred at 30 °C for 0.5 h. The mixture was carefully poured into the water. The mixture was extracted with EA (50 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to A35 ( N ′-(4-hydroxybenzoyl)-6-nitro-[1,1′-biphenyl]-3-sulfonohydra Zide, 200 mg, crude) was obtained as a brown solid.
  • A4 (3-fluoro- N '-(4-hydroxybenzoyl)-4-nitrobenzenesulfonohydrazide, 400 mg, 1.13 mmol, 1.0 eq) and K 2 CO 3 (389 mg, 2.81 mmol, 2.5 eq) was added pyrrolidine (96 mg, 1.35 mmol, 1.2 eq) at 10 °C. The mixture was then stirred at 25° C. for 16 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL x 3).
  • A4 (3-fluoro- N '-(4-hydroxybenzoyl)-4-nitrobenzenesulfonohydrazide, 400 mg, 1.13 mmol, 1.0 eq) and K 2 CO 3 (389 mg, 2.81 mmol, 2.5 eq) was added piperidine (115 mg, 1.35 mmol, 1.2 eq) at 10°C. The mixture was then stirred at 25° C. for 16 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL x 3).
  • A52 (3-fluoro- N '-( 1H -indole-4-carbonyl)-4-nitrobenzenesulfonohydrazide, 200 mg, 0.52 mmol, 1.0 eq) and K 2 in DMF (5 mL)
  • morpholine 54 mg, 0.62 mmol, 1.2 eq
  • the solution was then stirred at 25° C. for 16 hours.
  • the solution was poured into water (30 mL) and extracted with EA (30 mL x 3).
  • A4 (3-fluoro- N '-(4-hydroxybenzoyl)-4-nitrobenzenesulfonohydrazide, 500 mg, 1.41 mmol, 1.0 eq) and K 2 CO 3 (290 mg) in DMF (5 mL).
  • mg, 2.10 mmol, 1.5 eq was added tert-butyl piperazine-1-carboxylate (315 mg, 1.69 mmol, 1.2 eq) at 10°C.
  • the mixture was then stirred at 10° C. for 16 hours.
  • the solution was poured into water (30 mL) and extracted with EA (30 mL x 3).
  • A56 tert -butyl 4-(5-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)-2-nitrophenyl)piperazine-1-carboxylate, 250 in EtOH (3 mL) mg, 0.48 mmol, 1.0 eq) sat. aq. NH 4 Cl (3 mL) and Fe (135 mg, 2.41 mmol, 5.0 eq) were added. The mixture was then stirred at 85° C. for 1 hour. The solution was filtered and the filtrate was poured into water (30 mL) and extracted with EA (30 mL x 3).
  • a mixture of A71 (methyl 1H-indole-6-carboxylate, 500 mg, 2.86 mmol, 1.0 eq) and hydrazine monohydrate (10 mL) was stirred at 100 ° C for 3 h. The mixture was then cooled to 0 °C and filtered. The filtercake was washed with ice water and dried in vacuo to give A72 (1H-indole-6-carbohydrazide, 300 mg, yield 60.0%) as a white solid.
  • A73 400 mg, 1.11 mmol, 1.0 eq
  • DCM 15 mL
  • TFA 5 mL
  • NaBH 3 CN 209 mg, 3.33 mmol, 3.0 eq
  • the solution was then stirred at 15° C. for 1 hour.
  • the solution was filtered, and the filtercake was washed with PE and dried to give A74 (N'-(indoline-6-carbonyl)-4-nitrobenzenesulfonohydrazide, 200 mg crude) as a yellow solid.
  • Boc 2 was added to a mixture of A75 (methyl 1H-indole-3-carboxylate, 1.00 g, 5.71 mmol, 1.0 eq) and triethylamine (TEA, 1.16 g, 11.4 mmol, 2.0 eq) in DCM (10 mL). O (1.37 g, 6.28 mmol, 1.1 eq) was added dropwise at 20 °C. The mixture was then stirred at 20° C. for 12 hours. The solution was poured into water (60 mL) and extracted with DCM (60 mL x 3).
  • Morpholine (193 mg, 2.22 mmol, 1.2 eq) was added to a mixture of A83 (700 mg, 1.85 mmol, 1.0 eq) and K 2 CO 3 (640 mg, 4.64 mmol, 2.5 eq) in DMF (7 mL). was added at °C. The mixture was then stirred at 25° C. for 16 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL x 3).
  • Morpholine (350 mg, 4.02 mmol, 1.2 eq) was added to a mixture of A89 (1.50 g, 3.35 mmol, 1.0 eq) and K 2 CO 3 (1.16 g, 8.37 mmol, 2.5 eq) in DMF (15 mL). was added at °C. The mixture was then stirred at 25° C. for 16 hours. The solution was poured into water (50 mL) and extracted with EA (30 mL x 3).
  • Zinc powder (5 g, 78 mmol) was added slowly over 3 hours to a stirred suspension of A92 (8 g, 39 mmol) in glacial acetic acid (50 mL). During the zinc addition, the temperature of the reaction mixture was maintained below 40 ° C. The reaction mixture was stirred at room temperature for 24 hours. The precipitated zinc salt was then filtered off and washed with glacial acetic acid. Acetic acid was removed under reduced pressure. The solid residue was triturated with deionized water and recrystallized to give A93 (N-(2,2-dichlorovinyl)acetamide, 3 g) as a white solid.
  • Lawesson's reagent (7.6 g, 18.8 mmol) was added to a stirred solution of A94 (5 mmol) in toluene (30 mL). The reaction mixture was refluxed for 8 hours and the solvent was removed under reduced pressure. The residue was triturated with 10% aqueous NaOH and adjusted to pH 9. The crude product was filtered, dried and recrystallized from 2-propanol. The liquid product was extracted with dichloromethane to give A95 (4-(benzylthio)-2-methylthiazole, crude, 2.5 g) as a yellow oil.
  • Compound 44 was synthesized as a white solid (26.7% yield) in the same manner as in Experimental Example 1-45 using tert-butyl ((1s,4s)-4-hydroxycyclohexyl)carbamate instead of A97 as a starting material.
  • a mixture of A104 (5.00 g, 18.9 mmol, 1.0 eq) and potassium thioacetate (4.30 g, 37.7 mmol, 2.0 eq) in DMF (50 mL) was stirred at 70 °C for 16 h.
  • the mixture was treated with H 2 O (200 mL) and extracted with EA (200 mL x 2).
  • the combined organic layers were washed with H 2 O (100 mL x 3), brine (100 mL), dried and concentrated.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente divulgation concerne un composé bifonctionnel utilisant un ligand liant le domaine de boîte UBR. Le domaine de boîte UBR est un domaine couramment présent dans la protéine UBR (composant n-recognine de la protéine d'ubiquitine ligase E3) de la voie obéissant à la règle des N-terminaux. A cet égard, le domaine de boîte UBR est connu sous la forme d'un domaine auquel un substrat se lie. Le domaine de boîte UBR se lie au résidu à extrémité N-terminale d'un substrat, joue un rôle essentiel dans la formation de chaînes multi-ubiquitine dans le substrat, et il est connu que le substrat est dégradé par ce procédé. L'utilisation du ligand de domaine de boîte UBR qui tire avantage de la fonction de domaine de boîte UBR permet d'utiliser le composé bifonctionnel pour induire une protéine cible (ou un peptide) pour être dégradée de manière plus efficace.
PCT/KR2021/015256 2021-10-27 2021-10-27 Composé bifonctionnel utilisant un ligand liant le domaine de boîte ubr WO2023074936A1 (fr)

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US20180222857A1 (en) * 2015-06-09 2018-08-09 Monash University Aryl sulfonohydrazides
KR20200071098A (ko) * 2017-10-13 2020-06-18 길리애드 사이언시즈, 인코포레이티드 Hiv 프로테아제 억제제로서의 1-벤질-2-이미노-4-페닐-5-옥소이미다졸리딘 유도체

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US20180222857A1 (en) * 2015-06-09 2018-08-09 Monash University Aryl sulfonohydrazides
KR20200071098A (ko) * 2017-10-13 2020-06-18 길리애드 사이언시즈, 인코포레이티드 Hiv 프로테아제 억제제로서의 1-벤질-2-이미노-4-페닐-5-옥소이미다졸리딘 유도체

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