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WO-2026092541-A1 - DRUG-LINKER CONJUGATE CONTAINING PROTEIN DEGRADER, PREPARATION METHOD THEREFOR, AND USE THEREOF

WO2026092541A1WO 2026092541 A1WO2026092541 A1WO 2026092541A1WO-2026092541-A1

Abstract

The present application provides a drug-linker conjugate containing a protein degrader and an antibody-drug conjugate thereof. The present application also provides a preparation method for the drug-linker conjugate and the antibody-drug conjugate, as well as a use of the antibody-drug conjugate in the prevention and/or treatment of diseases associated with abnormal cellular activity, including but not limited to a use in the prevention and/or treatment of tumor diseases.

Inventors

  • CAI, JIAQIANG
  • DENG, Hanwen
  • ZOU, PENG
  • SIMA, Siyuan
  • XUE, Tongtong
  • DENG, CHUN

Assignees

  • 苏州宜联生物医药有限公司

Dates

Publication Date
20260507
Application Date
20251029
Priority Date
20241029

Claims (20)

  1. A drug linker conjugate as shown in Formula I, or a pharmaceutically acceptable salt thereof. in, Lg is the leaving group that reacts with antibodies or their antigen-binding fragments; X is selected from direct bond, -NR m- , or -C(O)-; R m is selected from hydrogen or C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted by one or more substituents selected from hydroxyl, phosphoric acid, sulfonic acid and sugar groups; A is selected from -NR 1 (CH 2 ) m -, -NR 1 (CH 2 ) m Q(CH 2 ) p -, -(O)C(CH 2 ) m -, -(O)C(CH 2 ) m Q(CH 2 ) p -, -S(O) 2 (CH 2 ) m -, -S(O) 2 (CH 2 ) m Q(CH 2 ) p -, -S(O)(CH 2 ) m -or-S(O)(CH 2 ) m Q(CH 2 ) p -; Q is independently selected from -O-, -S-, or -NR 2- ; R1 is independently selected from hydrogen, sulfonyl or C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted by one or more substituents selected from hydroxyl, sulfonic acid, phosphoric acid and sugar groups; R2 is selected from hydrogen or C1-4 alkyl; m and p are each independently selected from any integer between 1 and 5.
  2. The drug linker conjugate as claimed in claim 1, or a pharmaceutically acceptable salt thereof, is characterized in that it satisfies one or more of the following conditions: (1) Lg is selected from halogens, sulfone groups, tertiary amine salts (Me 3 N + , Et 3 N + ), diazonium salts, -OMs, MeSO 2- , MeS-, CF 3 SO 3- , p-toluenesulfonyl groups, Or a substituted phenoxy group, wherein the substituent is selected from halogens and/or nitro groups; Preferably, Lg is selected from fluorine, chlorine, bromine, iodine, -OMs, MeSO2- , MeS-, CF3SO3- or p- toluenesulfonyl ; More preferably, Lg is MeSO₂- ; (2) R m is selected from hydrogen, C1-4 alkyl, hydroxyl-substituted C1-4 alkyl, phosphate-substituted C1-4 alkyl, sulfonic acid-substituted C1-4 alkyl or sugar-substituted C1-4 alkyl; Preferably, Rm is selected from C1-4 alkyl, hydroxylated C1-4 alkyl, n is selected from 1, 2, 3, and 4, and position 1 is connected to the corresponding nitrogen atom; Preferably, Rm is selected from methyl, -CH2CH2OH or Position 1 is connected to the corresponding nitrogen atom; (3) Q is -O-; (4) R1 is independently selected from hydrogen, sulfonyl, C1-4 alkyl, hydroxyl-substituted C1-4 alkyl, phosphate-substituted C1-4 alkyl, sulfonic acid-substituted C1-4 alkyl or sugar-substituted C1-4 alkyl; Preferably, R1 is independently selected from sulfonyl, C1-4 alkyl, hydroxylated C1-4 alkyl, ... n is selected from 1, 2, 3, and 4, and position 1 is connected to the corresponding nitrogen atom; Preferably, R1 is independently selected from methyl , methanesulfonyl, -CH2CH2OH , Position 1 is connected to the corresponding nitrogen atom; (5) R2 is hydrogen or methyl; (6) m is selected from 1, 2 or 3; (7) p is selected from 1, 2 or 3.
  3. The drug linker conjugate or its pharmaceutically acceptable salt as described in claim 1 or 2 is characterized in that it satisfies one or more of the following conditions: (1) X is selected from direct bonds, -N( CH3 )-, Or -C(O)-, with position 1 connected to the corresponding carbon atom and position 2 connected to A; (2)A is selected from -NR 1 (CH 2 ) m -, -NR 1 (CH 2 ) m O(CH 2 ) p -, -NR 1 (CH 2 ) m S(CH 2 ) p -, -NR 1 (CH 2 ) m NR 2 (CH 2 ) p -, -(O)C(CH 2 ) m -, -(O)C(CH 2 ) m O(CH 2 ) p -, -(O)C(CH 2 ) m S(CH 2 ) p -, -(O)C(CH 2 ) m NR 2 (CH 2 ) p -, -S(O) 2 (CH 2 ) m -, -S(O) 2 (CH 2 ) m O(CH 2 ) p -, -S(O) 2 (CH 2 ) m S(CH 2 ) p -, -S(O) 2 (CH 2 ) m NR 2 (CH 2 ) p -, -S(O)(CH 2 ) m -, -S(O)(CH 2 ) m O(CH 2 ) p -, -S(O)(CH 2 ) m S(CH 2 ) p - or -S(O)(CH 2 ) m NR 2 (CH 2 ) p -; Preferably, A is selected from -NR1 ( CH2 ) m- , -NR1 (CH2) mO ( CH2 ) p- , -(O)C( CH2 ) m- , -S(O) 2 ( CH2 ) m- or -S(O)( CH2 ) m- ; Preferably, A is selected from -NR1 ( CH2 ) 3- , -NR1 ( CH2 ) 2O (CH2) 2- , -(O)C( CH2 ) 2- , -(O)C( CH2 ) 3- , -S(O) 2 ( CH2 ) 3- or -S(O)( CH2 ) 3- .
  4. The drug linker conjugate or a pharmaceutically acceptable salt thereof as described in any one of claims 1-3 is characterized in that, Selected from 1 is connected to A.
  5. The drug linker conjugate or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4 is characterized in that, Select from the following structure, with one bit connected to X;
  6. The drug linker conjugate or its pharmaceutically acceptable salt as described in any one of claims 1-5 is characterized in that the drug linker conjugate or its pharmaceutically acceptable salt has the structures shown in Formula I-1, Formula I-2 and Formula I-3: in, A is selected from -S(O) 2 (CH 2 ) m -, -S(O) 2 (CH 2 ) m Q(CH 2 ) p -, -S(O)(CH 2 ) m -, -S(O)(CH 2 ) m Q(CH 2 ) p -, -NR 1 (CH 2 ) m - or -NR 1 (CH 2 ) m Q(CH 2 ) p -; Q, R1 , Lg, m, and p are as defined in any one of claims 1-5; Wherein, A is selected from -NR1 ( CH2 ) m- or -NR1 ( CH2 ) mQ ( CH2 ) p- ; R1 , Q, Lg, m and p are as defined in any one of claims 1-5; Wherein, A is selected from -(O)C( CH2 ) m- and -(O)C( CH2 ) mQ ( CH2 ) p- ; R <sub>m </sub>, Q, Lg, m, and p are as defined in any one of claims 1-5.
  7. The drug linker conjugate as described in any one of claims 1-6, or a pharmaceutically acceptable salt thereof, is characterized in that the drug linker conjugate is selected from:
  8. An antibody-drug conjugate as shown in Formula II, or a pharmaceutically acceptable salt thereof. in, Tb is an antibody or its antigen-binding fragment; q is any integer between 1 and 12; X and A are as defined in any one of claims 1-5.
  9. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof as claimed in claim 8, characterized in that Tb satisfies one or more of the following conditions: (1) The Tb is an antibody or its antigen-binding fragment that has the activity of binding to the surface antigens of solid or blood tumor cells; (2) The Tb is an anti-Her2 antibody or its antigen-binding fragment, or an anti-Trop-2 antibody or its antigen-binding fragment; (3) The Tb is an anti-Her2 antibody or its antigen-binding fragment, such as anbenitamab, coprelotamab, disitamab, gancotamab, margetuximab, pertuzumab, timigutuzumab, zanidatamab, Trastuzumab, Pertuzumab or its antigen-binding fragment; preferably, Tb is Trastuzumab or Pertuzumab; for example, Tb is Trastuzumab; (4) The Tb is an anti-CD123 or CD33 antibody or its antigen-binding fragment; (5) The Tb is an antibody against CD123 or its antigen-binding fragment, such as Pivekimab, Talacotuzumab, h12F1, G4723A, mAb-01 or its antigen-binding fragment. (6) The Tb is an anti-CD33 antibody or its antigen-binding fragment, such as Gemtuzumab, Vadastuximab, Lintuzumab, YLAb-36 or its antigen-binding fragment.
  10. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof as described in claim 8 or 9, characterized in that it is selected from any of the following schemes: (a) The anti-CD123 antibody or its antigen-binding fragment comprises: three HCDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:3 and three LCDRs of the light chain variable region (VL) sequence of SEQ ID NO:4, wherein the CDRs are defined according to the Chothia, AbM, Kabat, IMGT, Contact scheme or any combination thereof; Optionally, the anti-CD123 antibody or its antigen-binding fragment comprises CDR-H1 shown in SEQ ID NO:7, CDR-H2 shown in SEQ ID NO:12, CDR-H3 shown in SEQ ID NO:15, CDR-L1 shown in SEQ ID NO:18, CDR-L2 shown in SEQ ID NO:21, and CDR-L3 shown in SEQ ID NO:24, as defined in the Kabat scheme. Preferably, the anti-CD123 antibody or its antigen-binding fragment comprises: the heavy chain variable region (VH) of SEQ ID NO:3 and the light chain variable region (VL) of SEQ ID NO:4; More preferably, the anti-CD123 antibody or its antigen-binding fragment comprises: the heavy chain of SEQ ID NO:1 and the light chain of SEQ ID NO:2; (b) The anti-CD123 antibody or its antigen-binding fragment comprises: three HCDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:28 and three LCDRs of the light chain variable region (VL) sequence of SEQ ID NO:29, wherein the CDRs are defined according to the Chothia, AbM, Kabat, IMGT, Contact scheme or any combination thereof; Preferably, the anti-CD123 antibody or its antigen-binding fragment comprises: the heavy chain variable region (VH) of SEQ ID NO:28 and the light chain variable region (VL) of SEQ ID NO:29; More preferably, the anti-CD123 antibody or its antigen-binding fragment comprises: the heavy chain shown in SEQ ID NO:26 and the light chain shown in SEQ ID NO:27; or (c) The anti-CD123 antibody or its antigen-binding fragment comprises: three HCDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:32 and three LCDRs of the light chain variable region (VL) sequence of SEQ ID NO:33, wherein the CDRs are defined according to the Chothia, AbM, Kabat, IMGT, Contact scheme or any combination thereof; Preferably, the anti-CD123 antibody or its antigen-binding fragment comprises: the heavy chain variable region (VH) of SEQ ID NO:32 and the light chain variable region (VL) of SEQ ID NO:33; More preferably, the anti-CD123 antibody or its antigen-binding fragment comprises: the heavy chain shown in SEQ ID NO:30 and the light chain shown in SEQ ID NO:31.
  11. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof as described in any one of claims 8-10 is characterized by being selected from any of the following schemes: (a) The anti-CD33 antibody or its antigen-binding fragment comprises: three HCDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:36 and three LCDRs of the light chain variable region (VL) sequence of SEQ ID NO:37, wherein the CDRs are defined according to the Chothia, AbM, Kabat, IMGT, Contact scheme or any combination thereof; Optionally, the anti-CD33 antibody or its antigen-binding fragment comprises CDR-H1 shown in SEQ ID NO:40, CDR-H2 shown in SEQ ID NO:45, CDR-H3 shown in SEQ ID NO:48, CDR-L1 shown in SEQ ID NO:51, CDR-L2 shown in SEQ ID NO:54, and CDR-L3 shown in SEQ ID NO:57, as defined in the Kabat scheme. Preferably, the anti-CD33 antibody or its antigen-binding fragment comprises: the heavy chain variable region (VH) of SEQ ID NO:36 and the light chain variable region (VL) of SEQ ID NO:37; More preferably, the anti-CD33 antibody or its antigen-binding fragment comprises: the heavy chain of SEQ ID NO:34 and the light chain of SEQ ID NO:35; More preferably, the anti-CD33 antibody or its antigen-binding fragment comprises: the heavy chain of SEQ ID NO:66 and the light chain of SEQ ID NO:35; (b) The anti-CD33 antibody or its antigen-binding fragment comprises: three HCDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:60 and three LCDRs of the light chain variable region (VL) sequence of SEQ ID NO:61, wherein the CDRs are defined according to the Chothia, AbM, Kabat, IMGT, Contact scheme or any combination thereof; Preferably, the anti-CD33 antibody or its antigen-binding fragment comprises: the heavy chain variable region (VH) of SEQ ID NO:60 and the light chain variable region (VL) of SEQ ID NO:61; More preferably, the anti-CD33 antibody or its antigen-binding fragment comprises: the heavy chain shown in SEQ ID NO:58 and the light chain shown in SEQ ID NO:59; or (c) The anti-CD33 antibody or its antigen-binding fragment comprises: three HCDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:64 and three LCDRs of the light chain variable region (VL) sequence of SEQ ID NO:65, wherein the CDRs are defined according to the Chothia, ABM, Kabat, IMGT, Contact scheme or any combination thereof; Preferably, the anti-CD33 antibody or its antigen-binding fragment comprises: the heavy chain variable region (VH) of SEQ ID NO:64 and the light chain variable region (VL) of SEQ ID NO:65; More preferably, the anti-CD33 antibody or its antigen-binding fragment comprises: the heavy chain shown in SEQ ID NO:62 and the light chain shown in SEQ ID NO:63.
  12. The antibody-drug conjugate or its pharmaceutically acceptable salt as described in any one of claims 8-11 is characterized in that the antibody-drug conjugate or its pharmaceutically acceptable salt has the structures shown in Formula II-1, Formula II-2 and Formula II-3. in, A is selected from -S(O) 2 (CH 2 ) m -, -S(O) 2 (CH 2 ) m Q(CH 2 ) p -, -S(O)(CH 2 ) m -, -S(O)(CH 2 ) m Q(CH 2 ) P -, -NR 1 (CH 2 ) m - or -NR 1 (CH 2 ) m Q(CH 2 ) p -; Q, R1 , m and p are as defined in any one of claims 1-5, and Tb and q are as defined in any one of claims 8-11; Wherein, A is selected from -NR1 ( CH2 ) m- or -NR1 ( CH2 ) mQ ( CH2 ) p- ; Q, R1 , m and p are as defined in any one of claims 1-5, and Tb and q are as defined in any one of claims 8-11; Wherein, A is selected from -(O)C( CH2 ) m- or -(O)C( CH2 ) mQ ( CH2 ) p- ; Q, Rm , m and p are as defined in any one of claims 1-5, and Tb and q are as defined in any one of claims 8-11.
  13. The antibody-drug conjugate as described in any one of claims 8-12, or a pharmaceutically acceptable salt thereof, is characterized in that the antibody-drug conjugate is selected from:
  14. A bioactive compound as shown in Formula III, or a pharmaceutically acceptable salt thereof. Wherein, X and A are as defined in any one of claims 1-5.
  15. The bioactive compound of claim 14 or a pharmaceutically acceptable salt thereof, characterized in that the bioactive compound is selected from:
  16. A compound as shown in Formula IV or a pharmaceutically acceptable salt thereof. Wherein, A is selected from -NR 1 (CH 2 ) m -, -NR 1 (CH 2 ) m Q(CH 2 ) p -, -(O)C(CH 2 ) m -, -(O)C(CH 2 ) m Q(CH 2 ) p -, -S(O) 2 (CH 2 ) m -, -S(O) 2 (CH 2 ) m Q(CH 2 ) p -, -S(O)(CH 2 ) m -or-S(O)(CH 2 ) m Q(CH 2 ) p -; Q is independently selected from -O-, -S-, or -NR 2- ; R1 is independently selected from hydrogen, sulfonyl or C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted by one or more substituents selected from hydroxyl, sulfonic acid, phosphoric acid and sugar groups; R2 is selected from hydrogen or C1-4 alkyl; m and p are each independently selected from any integer between 1 and 5; B is either hydrogen or a hydroxyl group; And R1 is not a methyl group.
  17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, characterized in that the compound is selected from:
  18. A non-splittable connector as shown in formula V, Wherein, X is defined as in any one of claims 1-5, with position 1 linked to an antibody or its antigen-binding fragment, and position 2 linked to a bioactive molecular fragment.
  19. The non-splittable connector as described in claim 18, wherein the non-splittable connector is selected from: Position 1 is linked to the antibody or its antigen-binding fragment, and position 2 is linked to the bioactive molecule fragment.
  20. A method for preparing an antibody-drug conjugate of Formula II, the method comprising: conjugating an antibody or its antigen-binding fragment Tb with a drug linker conjugate of Formula I; Preferably, the method includes the step of coupling Tb with the drug linker conjugate shown in Formula I in a solvent to form C-S bonds; The molar ratio of Tb to the drug linker conjugate is 1:(1-20), such as 1:(2-16), 1:(2-14), 1:(2-12), or 1:(2-10); The coupling reaction is carried out in water and/or an organic solvent; The organic solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, and nitrile compounds (e.g., acetonitrile); Wherein, the antibody-drug conjugate represented by Formula II is defined as any one of claims 8-13, and the drug linker conjugate represented by Formula I is defined as any one of claims 1-7.

Description

A drug linker conjugate containing a protein degrading agent, its preparation method and uses This application claims priority to Chinese patent application 2024115178566, filed on October 29, 2024. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field This application belongs to the field of compounds and relates to a class of drug linker conjugates and their antibody-drug conjugates consisting of an indegradable linker and a protein degrading agent, methods for preparing the drug linker conjugates and their antibody-drug conjugates, pharmaceutical compositions of the antibody-drug conjugates, and the use of the antibody-drug conjugates in the prevention and/or treatment of diseases related to abnormal cell activity, including but not limited to their use in the prevention and/or treatment of tumor diseases. Background Technology Many diseases are related to abnormal intracellular protein function, and the main approach to treating these diseases is with small molecule compounds. However, more than 80% of proteins lack sites that can produce drug-like effects, and these targets are considered unsuitable for traditional small molecule drug development. Targeted protein degradation (TPDs), such as protein degradation-targeting chimeras (PROTACs) and molecular glue degraders (MGDs), mediate the degradation of target proteins through the ubiquitin-proteasome pathway. They can exert their effects without tightly binding to sites affecting protein activity, allowing previously "undruggable" proteins to become novel drug targets. Simultaneously, targeted protein degradation therapy can continuously induce rapid and efficient degradation of pathogenic proteins, reducing the development of drug resistance in target proteins. Several targeted protein degradation agents have entered the clinical development stage. For example, C4 Therapeutics' molecular gel CFT7455, which targets IKZF1/3, was presented at the AACR meeting in April 2022. Although CFT7455 showed clinical benefits of deep target degradation, neutropenia was dose-limited, with 3 out of 5 patients experiencing grade 4 neutropenia and 1 experiencing grade 3 neutropenia. Antibody-drug conjugates (ADCs) combine the tumor-targeting activity of antibodies with the high activity of bioactive compounds, becoming a kind of biological missile with promising therapeutic and safety advantages. Antibodies guide ADCs to bind to target cells, achieving tumor tissue enrichment, reducing exposure to non-target tissues, and mitigating the toxicity that may result from systemic administration of bioactive compounds. ADCs bound to tumor cells are internalized, releasing small molecule drugs intracellularly to treat the disease. Therefore, it is expected that ADCs composed of protein degraders and tumor-targeting antibodies can achieve tumor enrichment, eliminate or reduce the toxic side effects caused by protein degraders acting on non-disease tissues, and improve therapeutic efficacy. Utilizing ADC technology to achieve tumor targeting of protein degraders and reduce their toxic side effects will have high clinical value. ADC linkers are classified as either cleavable or non-cleavable. Cleavable linkers release toxin molecules directly through chemical bond cleavage; non-cleavable linkers do not involve specific bond cleavage but release small molecules related to the toxin molecules through complete or partial hydrolysis of the antibody. Compared to cleavable linkers, using non-cleavable linkers allows for targeted killing effects at tumor or tissue sites. This is because non-cleavable linkers effectively reduce the entry of toxins into the circulatory system due to linker cleavage, thus preventing systemic toxicity. In general, non-cleavable linkers provide a larger therapeutic window than cleavable linkers. Summary of the Invention In a first aspect, this application provides a drug linker conjugate of Formula A or a pharmaceutically acceptable salt thereof; in, Lg is the leaving group that reacts with antibodies or their antigen-binding fragments; Y is selected from direct bonds and -O-; X is selected from direct bonds, -CRmRn- , -NRm- , -C (O)-, -CRmRnC (O)- and 4-6 membered heterocyclic groups; Rm and Rn are each independently selected from hydrogen and C1-4 alkyl groups, wherein the C1-4 alkyl groups are optionally substituted with one or more hydroxyl, phosphate, sulfonic acid and sugar groups; Z1 is selected from -NH-, -CF2- , or -C(O)-; Z2 is selected from -CH2- , -O-, or -NH-; U1 and U2 are each independently selected from -CH2- and -C(O)-, and U1 and U2 are not both -CH2- . A is selected from -NR 1 (CH 2 ) m -, -NR 1 (CH 2 ) m O-, -NR 1 (CH 2 ) m S -, -NR 1 (CH 2 ) m NR 2 -, -NR 1 (CH 2 ) m O(CH2) P -, -NR 1 (CH 2 ) m S(CH 2 ) P -, -NR 1 (CH 2 ) m NR 2 (CH 2 ) P -, -(O)C(CH 2 ) m -, -S(O) 2 (CH 2 ) m -, And -4-6-membered heterocyclic group (CH 2 ) m - and 4-6-membered heterocyclic group, with