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WO2025124555A1 - Conjugué ligand-médicament d'analogues de camptothécine et son utilisation - Google Patents

Conjugué ligand-médicament d'analogues de camptothécine et son utilisation Download PDF

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WO2025124555A1
WO2025124555A1 PCT/CN2024/139197 CN2024139197W WO2025124555A1 WO 2025124555 A1 WO2025124555 A1 WO 2025124555A1 CN 2024139197 W CN2024139197 W CN 2024139197W WO 2025124555 A1 WO2025124555 A1 WO 2025124555A1
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alkylene
group
alkyl
membered
cycloalkyl
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Hongyu YANG
Xinghai Wang
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Shanghai Micurx Pharmaceutical Co Ltd
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Shanghai Micurx Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings

Definitions

  • conjugates of camptothecin analogs with a cell-surface receptor-biding molecule for targeted therapy as well as pharmaceutical compositions comprising such a conjugate.
  • intermediates of conjugates of camptothecin analogs and preparation methods thereof are also provided.
  • Cancer is a leading cause of death worldwide.
  • Surgery, chemotherapy, radiotherapy and targeted therapy are the standard-of-care therapies.
  • chemotherapy is widely applied, the use of most chemotherapies is limited by undesired side effects, mostly through action on cells beyond the tumor and its environment, resulting in systemic toxicity and a narrow therapeutic window.
  • the discovery of the unique composition of cancer cell surfaces combined with the understanding of the strong and selective interaction between antibodies and cell-surface antigens opened the way to exploit antibodies as targeted delivery agents for chemotherapies, including highly toxic drugs (Drago, J.Z. et al., Nat. Rev. Clin. Oncol. 2021.; Khongorzul, P. et al., Mol. Cancer Res. 2020, 18, 3–19.; Joubert, N.
  • the resulting molecular entities also known as antibody–drug conjugates (ADCs) consist of three main parts: the antibody responsible for the selective recognition of the cancer cell surface antigen capable of internalizing the ADC, the drug payload responsible for killing the cancer cell once released inside it, and the linker connecting the antibody and payload parts.
  • ADCs antibody–drug conjugates
  • Antibody-drug conjugates combining the selective targeting of tumor cells through antigen-directed recognition and potent cell-killing by cytotoxic payloads, have emerged in recent years as an efficient therapeutic approach for the treatment of various cancers (Nature review Drug Discovery, 2013, 12, 329-332) .
  • the first ADC (Mylotarg) was approved in 2000 (and following withdrawal in 2010, reapproved in 2017)
  • the second ADC (Adcetris) received accelerated approval in 2011 and full approval in 2015.
  • the third (Kadcyla) and fourth (Besponsa) ADCs were approved in 2013 and 2017, respectively.
  • Kadcyla is the first ADC approved for solid tumor treatment. Since 2019, more than ten ADCs have been approved, and there are more than 100 ADCs in clinical development.
  • DNA damaging agents such as calicheamicins, PBD, and duocarmysins
  • microtubule disrupting agents such as maytansins, like DM1 or DM4; auruistatins like MMAE or MMAF; tubulysins
  • topoisomerase inhibitors such as camptothecins like Dxd or SN-38.
  • camptothecins have proved a promising choice with a wider therapeutic index than many other payloads for ADC construction.
  • PFS Progression-Free-Survival
  • OS Overall-Survival
  • camptothecin can induce cell death.
  • Camptothecin and most of its analogs are extremely insoluble in physiological buffer and have demonstrated high adverse drug reaction in the preliminary clinical trial since 1970s.
  • the low solubility of camptothecin can cause their ADC conjugates to aggregate (Burke, P., et al. Bioconjugate Chem. 2009, 20, 6, 1242) which is problematic for scale-up manufacturing production and may cause systematic side-effects resulting from aggregation.
  • the US FDA has only approved three water-soluble camptothecin analogs: topotecan, irinotecan and belotecan in cancer therapy (Palakurthi, S., Expert Opin Drug Deliv. 2015., 12 (12) , 1911) .
  • Most of the camptothecin payloads employed to date for ADC development suffer from low solubility, which further limits the Drug-to-Antibody Ratio and results in low potency.
  • camptothecin analogs linked to a cell-binding molecule Provided are conjugates of camptothecin analogs linked to a cell-binding molecule, camptothecin analog-linker compounds, camptothecin analogs, methods to prepare and to use them.
  • Aspect 1 The present disclosure provides a ligand-drug conjugate having a formula of
  • T is a targeting or binding Ligand
  • L is a Linker Unit
  • n is an integer or fraction of integer selected from 1 to 12;
  • D is a Drug Unit having a formula of D 1
  • p at each occurrence is independently selected from 1 or 2;
  • R 1d is selected from H or halo
  • R 2a and R 2b are independently selected from the group consisting of H, halo, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocycloalkyl; or R 2a and R 2b are combined with the carbon atom to which they are attached to form a C 3 -C 6 cycloalkyl;
  • Z is-R 3a -R 3b ;
  • R 3b is selected from-OH, -SH, and -NHR 3c ;
  • R 3a is selected from the group consisting of -R 3g -C 1 -C 6 alkylene-, -R 3g -C 1 -C 6 alkylene (C 3 -C 10 cycloalkyl) -, -R 3g -C 0 -C 3 alkylene-C 3 -C 10 cycloalkylene-C 0 -C 3 alkylene-, -R 3g -C 1 -C 6 alkylene-R 3g -C 1 -C 6 alkylene-, -R 3g -C 0 -C 3 alkylene-C 5 -C 12 arylene-C 0 -C 3 alkylene-, -R 3g -C 0 -C 3 alkylene-C 5 -C 12 heteroarylene-C 0 -C 3 alkylene-, -R 3g -C 0 -C 3 alkylene-C 3 -C 10 heterocycloalkylene-C 0 -
  • R 3d and R 3e are combined with the nitrogen atom to which they are attached to form an optionally substituted 4 to 9 membered ring containing one or two nitrogen atoms;
  • R 3f is either absent, or selected from the group consisting of -C (O) -N (C 1 -C 3 alkyl) -C 1 -C 8 alkylene-, -N (C 1 -C 3 alkyl) -C (O) -C 1 -C 6 alkylene (C 1 -C 3 alkyl) -, -C 1 -C 6 alkylene-, -C 1 -C 6 alkylene (C 3 -C 10 cycloalkyl) -, -C 3 -C 10 cycloalkylene-, -NH-C (O) -C 1 -C 6 alkylene-, -N (C 1 -C 3 alkyl) -C (O) -C 1 -C 6 alkylene-, -NH-C (O) -C 3 -C 10 cycloalkylene-, -NH-C (O) -C 3 -C 10 heterocycloalkylene-, -
  • R 3c is selected from H or C 1 -C 6 alkyl
  • D is covalently attached to L via any suitable attachment site on D, optionally wherein a hydrogen atom of a hydroxyl, thiol, primary amine, or secondary amine of D is replaced with a bond to L or a tertiary amine of D is quaternized to form a bond to L;
  • X is-C (R 5b ) -or-N-;
  • R 5a is either absent, or R 5a and R 8 taken together with the atom (s) to which they are attached form 3-to 6-membered cycloalkyl, 5-to 6-membered aryl, 5-to 6-membered heteroaryl, or 4-to 8-membered heterocycloalkyl; or R 5a and R 5b taken together with the atom (s) to which they are attached form a 3-to 6-membered cycloalkyl or 4-to 8-membered heterocycloalkyl; wherein 5-to 6-membered aryl, 5-to 6-membered heteroaryl, each “3-to 6-membered cycloalkyl” and each “4-to 8-membered heterocycloalkyl” are independently optionally substituted with one to three R 9 ;
  • R 4 , R 5b , R 6 , R 7 , and R 8 are independently selected from the group consisting of H, halo, hydroxy, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, aryl, and heteroaryl and wherein each of C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, aryl, and heteroaryl is independently optionally substituted with one to four R 9 ; or R 4 and R 5b taken together with the atom (s) to which they are attached form 3-to 6-membered cycloalkyl, or 4-to 8-membered heterocycloalkyl, provided that R 5a and R 5b do not also form a ring; or R 4 and R 7 taken together with the atom (s) to which they are attached form 3-to 6-membered cycloalkyl, or 4-to 8-membered heterocycloalkyl; or R 6 and R 7 taken together with the atom (s) to which they
  • R 9 at each occurrence is independently selected from the group consisting of halo, oxo, hydroxy, cyano, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkoxy, aryl, and heteroaryl; or two R 9 groups when attached to adjacent carbons and taken together with the carbons to which they are attached form a fused C 3 -C 6 cycloalkyl; or two R 9 groups when attached to the same carbon and taken together with the carbon to which they are attached form a spiro C 3 -C 6 cycloalkyl; wherein each C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkoxy, aryl, heteroaryl, fused C 3 -C 6 cycloalkyl, and spiro C 3 -C 6 cycloalkyl is independently optionally substituted with one to three fluoro or hydroxy, and C 1 -
  • n 1 and n 2 are each an integer independently selected from 0, 1, 2, 3, and 4; provided that n 1 +n 2 is 1, 2, 3, or 4.
  • R 3f is selected from the group consisting of -C 3 -C 10 cycloalkylene-, -NH-C (O) -C 1 -C 6 alkylene-, -N (C 1 -C 3 alkyl) -C (O) -C 1 -C 6 alkylene-, -NH-C (O) -C 3 -C 10 cycloalkylene-, -NH-C (O) -O-C 1 -C 6 alkylene-, -NH-C (O) -NH-C 1 -C 6 alkylene-, -C (O) -C 1 -C 8 alkylene-, -C (O) O-C 1 -C 8 alkylene-, and -C (O) -NH-C 1 -C 8 alkylene-.
  • Aspect 1 wherein D is covalently attached to L via an O, S, or N atom of R 3b , wherein a hydrogen atom of -OH, -SH, or-NHR 3c of R 3b is replaced with a bond to L.
  • R 2a and R 2b are independently selected from H, halo, and C 1 -C 3 alkyl.
  • R 3a is selected from-C 1 -C 6 alkylene-, -S-C 1 -C 6 alkylene-, -S (O) 2 -C 1 -C 6 alkylene-, and -NR 3d R 3e -R 3f -; wherein-NR 3d R 3e -R 3f -having a formula selected from
  • R 3a is-C 1 -C 6 alkylene-or-S-C 1 -C 6 alkylene-.
  • R 3a is-NR 3d R 3e -R 3f -; wherein-NR 3d R 3e -R 3f -having a formula selected from
  • R 3f is either absent, or selected from-C 1 -C 6 alkylene-, -NH-C (O) -C 1 -C 6 alkylene-, and -N (C 1 -C 3 alkyl) -C (O) -C 1 -C 6 alkylene-.
  • D having a formula of D 1a , D 1b , D 1c , D 1d , D 1e , D 1f , D 1g , D 1h , D 1m , D 1n , D 1p , or D 1q ,
  • R 1e and R 1f at each occurrence are independently selected from H, halo, and C 1 -C 3 alkyl; R 1a , R 1c , R 1d , R 2a , R 2b and Z at each occurrence are as defined for formula D 1 in Aspect 1 and any embodiments thereof.
  • L 1 is Connector Unit; L 2 is either absent, or a Partitioning Agent; L 3 is an Amino Acid Unit; L 4 is either absent, or a Spacer Unit; and wherein L 1 is connected to T.
  • L 2 is either absent, or selected from the group consisting of - [NR 10 -CH 2 C (O) ] p 2 -, -NR 10 (CH 2 CH 2 O) p 2 CH 2 CH 2 -, -NR 10 - (CH 2 ) p 1 -C (O) -, -O- (CH 2 ) p 1 -C (O) -, -S- (CH 2 ) p 1 -C (O) -, -CH 2 - (CH 2 ) p 1 -C (O) -, -NR 10 - (CH 2 ) p 1 - (CH 2 CH 2 O) p 2 - (CH 2 ) p 3 -C (O) -, -O- (CH 2 ) p 1 - (CH 2 CH 2 O) p 2 - (CH 2 ) p 3 -C (O) -, -O- (CH 2 ) p 1 - (CH 2 CH 2 O)
  • L 3 is an optionally substituted amino acid residue or optionally substituted peptide residue composed of 2 to 7 amino acids; wherein the N terminal of L 3 groups provided above is attached to the right side of L 1 or L 2 and the C terminal of L 3 groups is attached to L 4 or R 3b ;
  • L 4 is either absent, or selected from the group consisting of wherein R 14 and R 15 at each occurrence are independently selected from the group consisting of H, halo, and C 1 -C 3 alkyl; R 11 , R 12 , and R 13 at each occurrence are independently H or C 1 -C 3 alkyl; R 16 is selected from the group consisting of H, -CH 2 CH 2 S (O) 2 CH 3 , -CH 2 CH 2 N (CH 3 ) 2 , and C 1 -C 3 alkyl; wherein the left side of each of the L 4 groups provided above is attached to the C terminal of L 3 and the right side of each of the L 4 groups is attached to R 3b .
  • L 1 is selected from the group consisting of -CH (CH 2 COOH) -C (O) -NH-, -CH (COOH) -CH 2 -C (O) -NH-, -CH 2 C (O) -, wherein Z 1 at each occurrence is selected from the group consisting of C 1 -C 8 alkylene, C 1 -C 8 alkenylene, C 1 -C 8 alkynylene, 5-to 6-membered arylene, and 5-to 6-membered heteroarylene; Y 1 is selected from the group consisting of -O-, -S-, -CH 2 -, 4-to 8-membered heterocycloalkylene, and 5-to 10-membered heteroarylene; q 1 , q 2 , and q 3 are each an integer independently selected from 1, 2, 3, and 4; W and W 1 at each occurrence are independently selected from the group consisting of C 1 -C 8 alkylene, - (C 1 -C 8 alkylene)
  • L 2 is either absent, or selected from the group consisting of - [NR 10 -CH 2 C (O) ] p 2 -, -NR 10 (CH 2 CH 2 O) p 2 CH 2 CH 2 -, -NR 10 - (CH 2 ) p 1 -C (O) -, -O- (CH 2 ) p 1 -C (O) -, -S- (CH 2 ) p 1 -C (O) -, -CH 2 - (CH 2 ) p 1 -C (O) -, -NR 10 - (CH 2 ) p 1 - (CH 2 CH 2 O) p 2 - (CH 2 ) p 3 -C (O) -, -O- (CH 2 ) p 1 - (CH 2 CH 2 O) p 2 - (CH 2 ) p 3 -C (O) -, -O- (CH 2 ) p 1 - (CH 2 CH 2 O)
  • L 3 is an optionally substituted amino acid residue or optionally substituted peptide residue composed of 2 to 7 amino acids; wherein the N terminal of L 3 groups provided above is attached to the right side of L 1 or L 2 and the C terminal of L 3 groups is attached to L 4 or R 3b ;
  • L 4 is either absent, or selected from the group consisting of wherein R 14 and R 15 at each occurrence are independently selected from the group consisting of H, halo, and C 1 -C 3 alkyl; R 11 , R 12 , and R 13 at each occurrence are independently H or C 1 -C 3 alkyl; R 16 is selected from the group consisting of H, -CH 2 CH 2 S (O) 2 CH 3 , -CH 2 CH 2 N (CH 3 ) 2 , and C 1 -C 3 alkyl; wherein the left side of each of the L 4 groups provided above is attached to the C terminal of L 3 and the right side of each of the L 4 groups is attached to R 3b .
  • L 2 is either absent, or selected from the group consisting of - [NR 10 -CH 2 C (O) ] p 2 -, -NR 10 (CH 2 CH 2 O) p 2 CH 2 CH 2 -, -NR 10 - (CH 2 ) p 1 -C (O) -, -O- (CH 2 ) p 1 -C (O) -, -S- (CH 2 ) p 1 -C (O) -, -CH 2 - (CH 2 ) p 1 -C (O) -, -NR 10 - (CH 2 ) p 1 - (CH 2 CH 2 O) p 2 - (CH 2 ) p 3 -C (O) -, -O- (CH 2 ) p 1 - (CH 2 CH 2 O) p 2 - (CH 2 ) p 3 -C (O) -, -O- (CH 2 ) p 1 - (CH 2 CH 2 O)
  • L 1 is wherein W 1 is R 17 , R 18 , and R 19 at each occurrence are independently selected from the group consisting of H, - (CH 2 CH 2 O) p 7 - (C 1 -C 6 alkyl) , -SO 3 H, -PO (OH) 2 , and C 1 -C 6 alkyl; R 20 at each occurrence is independently C 1 -C 6 alkylene; p 7 is an integer selected from 1 to 15; W is selected from the group consisting of C 1 -C 8 alkylene, - (C 1 -C 8 alkylene) -cycloalkylene-, arylene, -arylene- (C 1 -C 8 alkylene) -, heteroarylene, and linear heteroalkylene, wherein the linear heteroalkylene comprise 1 to 8 carbon atom (s) , and 1 to 3 heteroatom (s) selected from the group consisting of N, O, S, S (O) , and S (O) 2 , and wherein the alky
  • L 3 is an optionally substituted amino acid residue or optionally substituted peptide residue composed of 2 to 7 amino acids; wherein the N terminal of L 3 groups provided above is attached to the right side of L 1 or L 2 and the C terminal of L 3 groups is attached to L 4 or R 3b ;
  • L 4 is either absent, or selected from the group consisting of wherein R 14 and R 15 at each occurrence are independently selected from the group consisting of H, halo, and C 1 -C 3 alkyl; R 11 , R 12 , and R 13 at each occurrence are independently H or C 1 -C 3 alkyl; R 16 is selected from the group consisting of H, -CH 2 CH 2 S (O) 2 CH 3 , -CH 2 CH 2 N (CH 3 ) 2 , and C 1 -C 3 alkyl; wherein the left side of each of the L 4 groups provided above is attached to the C terminal of L 3 and the right side of each of the L 4 groups is attached to R 3b .
  • L 1 is and wherein Z 1 is selected from the group consisting of C 1 -C 8 alkylene, C 1 -C 8 alkenylene, C 1 -C 8 alkynylene, 5-to 6-membered arylene, and 5-to 6-membered heteroarylene;
  • Y 1 is-O-or-CH 2 -;
  • q 1 and q 2 are each an integer independently selected from 1, 2, 3, and 4.
  • L 3 is an amino acid residue or peptide residue composed of 2 to 7 amino acids; wherein the amino acids are selected from Phenylalanine (F) , Glycine (G) , Valine (V) , Lysine (K) , Citrulline, Serine (S) , Glutamic acid (E) , and Aspartic acid (N) ; wherein the amino acid residue and peptide residue are optionally further substituted by one or more substituent (s) selected from the group consisting of halo, hydroxy, cyano, amino, alkyl, chloroalkyl, hydroxyalkyl, alkoxy, cycloalkyl, - [N (CH 3 ) -CH 2 -C (O) ] g 1 -NH 2 , - [N (CH 3 ) -CH 2 -C (O) ] g 1 -N (CH 3 ) -CH 2 COOH, -C (O) -CH 2
  • R 14 and R 15 are independently selected from the group consisting of H, halo, and C 1 -C 3 alkyl
  • R 16 is selected from the group consisting of H, -CH 2 CH 2 S (O) 2 CH 3 , -CH 2 CH 2 N (CH 3 ) 2 , and C 1 -C 3 alkyl.
  • Z 1 at each occurrence is selected from the group consisting of C 1 -C 8 alkylene, C 2 -C 8 alkenylene, C 2 -C 8 alkynylene, phenylene, and 5-to 6-membered heteroarylene.
  • Z 1 at each occurrence is selected from the group consisting of C 1 -C 8 alkylene, C 2 -C 8 alkenylene, C 2 -C 8 alkynylene.
  • ligand-drug conjugates include, but are not limited to:
  • T is a targeting antibody or ligand binding to antigen; wherein the antibody is selected from chimeric antibody, humanized antibody, and human antibody.
  • T is a monoclonal antibody
  • T is selected from anti-Her2 (ErbB2) antibody, anti-EGFR antibody, anti-B 7 H 3 antibody, anti-c-MET antibody, anti-Her3 (ErbB3) antibody, anti-Her4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MICI antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, anti-Mesothelin antibody, and anti-ROR1 antibody or the fragment binding to the antigen.
  • T is selected from Trastuzumab, Pertuzumab, Nimotuzumab, Enoblituzumab, Emibetuzumab, Inotuzumab, Pinatuzumab, Brentuximab, Gemtuzumab, Bivatuzumab, Lorvotuzumab, cBR96, and Glembatumumab or the fragment binding to the antigen.
  • T is Trastuzumab.
  • Aspect 2 The present disclosure provides a compound having the formula of
  • L is a Linker Unit
  • D is a Drug Unit having a formula of D 1
  • p at each occurrence is independently selected from 1 or 2;
  • R 1d is selected from H or halo
  • R 2a and R 2b are independently selected from the group consisting of H, halo, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocycloalkyl; or R 2a and R 2b are combined with the carbon atom to which they are attached to form a C 3 -C 6 cycloalkyl;
  • Z is-R 3a -R 3b ;
  • R 3b is selected from-OH, -SH, and -NHR 3c ;
  • R 3a is selected from the group consisting of -R 3g -C 1 -C 6 alkylene-, -R 3g -C 1 -C 6 alkylene (C 3 -C 10 cycloalkyl) -, -R 3g -C 0 -C 3 alkylene-C 3 -C 10 cycloalkylene-C 0 -C 3 alkylene-, -R 3g -C 1 -C 6 alkylene-R 3g -C 1 -C 6 alkylene-, -R 3g -C 0 -C 3 alkylene-C 5 -C 12 arylene-C 0 -C 3 alkylene-, -R 3g -C 0 -C 3 alkylene-C 5 -C 12 heteroarylene-C 0 -C 3 alkylene-, -R 3g -C 0 -C 3 alkylene-C 3 -C 10 heterocycloalkylene-C 0 -
  • R 3d and R 3e are combined with the nitrogen atom to which they are attached to form an optionally substituted 4 to 9 membered ring containing one or two nitrogen atoms;
  • R 3f is either absent, or selected from the group consisting of -C (O) -N (C 1 -C 3 alkyl) -C 1 -C 8 alkylene-, -N (C 1 -C 3 alkyl) -C (O) -C 1 -C 6 alkylene (C 1 -C 3 alkyl) -, -C 1 -C 6 alkylene-, -C 1 -C 6 alkylene (C 3 -C 10 cycloalkyl) -, -C 3 -C 10 cycloalkylene-, -NH-C (O) -C 1 -C 6 alkylene-, -N (C 1 -C 3 alkyl) -C (O) -C 1 -C 6 alkylene-, -NH-C (O) -C 3 -C 10 cycloalkylene-, -NH-C (O) -C 3 -C 10 heterocycloalkylene-, -
  • R 3c is selected from H or C 1 -C 6 alkyl
  • D is covalently attached to L via any suitable attachment site on D, optionally wherein a hydrogen atom of a hydroxyl, thiol, primary amine, or secondary amine of D is replaced with a bond to L or a tertiary amine of D is quaternized to form a bond to L;
  • R 9 at each occurrence is independently selected from the group consisting of halo, oxo, hydroxy, cyano, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkoxy, aryl, and heteroaryl; or two R 9 groups when attached to adjacent carbons and taken together with the carbons to which they are attached form a fused C 3 -C 6 cycloalkyl; or two R 9 groups when attached to the same carbon and taken together with the carbon to which they are attached form a spiro C 3 -C 6 cycloalkyl; wherein each C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkoxy, aryl, heteroaryl, fused C 3 -C 6 cycloalkyl, and spiro C 3 -C 6 cycloalkyl is independently optionally substituted with one to three fluoro or hydroxy, and C 1 -
  • n 1 and n 2 are each an integer independently selected from 0, 1, 2, 3, and 4; provided that n 1 +n 2 is 1, 2, 3, or 4.
  • R 3f is selected from the group consisting of -C 3 -C 10 cycloalkylene-, -NH-C (O) -C 1 -C 6 alkylene-, -N (C 1 -C 3 alkyl) -C (O) -C 1 -C 6 alkylene-, -NH-C (O) -C 3 -C 10 cycloalkylene-, -NH-C (O) -O-C 1 -C 6 alkylene-, -NH-C (O) -NH-C 1 -C 6 alkylene-, -C (O) -C 1 -C 8 alkylene-, -C (O) O-C 1 -C 8 alkylene-, and -C (O) -NH-C 1 -C 8 alkylene-.
  • D is covalently attached to L via an O, S, or N atom of R 3b , wherein a hydrogen atom of -OH, -SH, or-NHR 3c of R 3b is replaced with a bond to L.
  • R 2a and R 2b are independently selected from H, halo, and C 1 -C 3 alkyl.
  • R 3a is selected from-C 1 -C 6 alkylene-, -S-C 1 -C 6 alkylene-, -S (O) 2 -C 1 -C 6 alkylene-, and -NR 3d R 3e -R 3f -; wherein-NR 3d R 3e -R 3f -having a formula selected from
  • R 3a is-C 1 -C 6 alkylene-or-S-C 1 -C 6 alkylene-.
  • R 3a is-NR 3d R 3e -R 3f -; wherein-NR 3d R 3e -R 3f -having a formula selected from
  • R 3f is either absent, or selected from-C 1 -C 6 alkylene-, -NH-C (O) -C 1 -C 6 alkylene-, and -N (C 1 -C 3 alkyl) -C (O) -C 1 -C 6 alkylene-.
  • D having a formula of D 1a , D 1b , D 1c , D 1d , D 1e , D 1f , D 1g , D 1h , D 1m , D 1n , D 1p , or D 1q ,
  • R 1e and R 1f at each occurrence are independently selected from H, halo, and C 1 -C 3 alkyl; R 1a , R 1c , R 1d , R 2a , R 2b and Z at each occurrence are as defined for formula D 1 in Aspect 2 and any embodiments thereof.
  • L 3 is an optionally substituted amino acid residue or optionally substituted peptide residue composed of 2 to 7 amino acids; wherein the N terminal of L 3 groups provided above is attached to the right side of L 1a or L 2 and the C terminal of L 3 groups is attached to L 4 or R 3b ;
  • L 4 is either absent, or selected from the group consisting of wherein R 14 and R 15 at each occurrence are independently selected from the group consisting of H, halo, and C 1 -C 3 alkyl; R 11 , R 12 , and R 13 at each occurrence are independently H or C 1 -C 3 alkyl; R 16 is selected from the group consisting of H, -CH 2 CH 2 S (O) 2 CH 3 , -CH 2 CH 2 N (CH 3 ) 2 , and C 1 -C 3 alkyl; wherein the left side of each of the L 4 groups provided above is attached to the C terminal of L 3 and the right side of each of the L 4 groups is attached to R 3b .
  • L 1a is selected from the group consisting of Br-CH 2 C (O) -, wherein Z 1 at each occurrence is selected from the group consisting of C 1 -C 8 alkylene, C 1 -C 8 alkenylene, C 1 -C 8 alkynylene, 5-to 6-membered arylene, and 5-to 6-membered heteroarylene; Y 1 is selected from the group consisting of -O-, -S-, -CH 2 -, 4-to 8-membered heterocycloalkylene, and 5-to 10-membered heteroarylene; q 1 , q 2 , and q 3 are each an integer independently selected from 1, 2, 3, and 4; W and W 1 at each occurrence are independently selected from the group consisting of C 1 -C 8 alkylene, - (C 1 -C 8 alkylene) -cycloalkylene-, arylene, heteroarylene, and linear heteroalkylene, wherein the linear heteroalkylene comprise 1 to 8 carbon atom (s)
  • L 2 is either absent, or selected from the group consisting of - [NR 10 -CH 2 C (O) ] p 2 -, -NR 10 (CH 2 CH 2 O) p 2 CH 2 CH 2 -, -NR 10 - (CH 2 ) p 1 -C (O) -, -O- (CH 2 ) p 1 -C (O) -, -S- (CH 2 ) p 1 -C (O) -, -CH 2 - (CH 2 ) p 1 -C (O) -, -NR 10 - (CH 2 ) p 1 - (CH 2 CH 2 O) p 2 - (CH 2 ) p 3 -C (O) -, -O- (CH 2 ) p 1 - (CH 2 CH 2 O) p 2 - (CH 2 ) p 3 -C (O) -, -O- (CH 2 ) p 1 - (CH 2 CH 2 O)
  • Z 1 at each occurrence is selected from the group consisting of C 1 -C 8 alkylene, C 2 -C 8 alkenylene, C 2 -C 8 alkynylene.
  • Z is-R 3a -R 3b ;
  • R 3b is selected from-OH, -SH, and -NHR 3c ;
  • R 3a is selected from the group consisting of -R 3g -C 1 -C 6 alkylene-, -R 3g -C 1 -C 6 alkylene (C 3 -C 10 cycloalkyl) -, -R 3g -C 0 -C 3 alkylene-C 3 -C 10 cycloalkylene-C 0 -C 3 alkylene-, -R 3g -C 1 -C 6 alkylene-R 3g -C 1 -C 6 alkylene-, -R 3g -C 0 -C 3 alkylene-C 5 -C 12 arylene-C 0 -C 3 alkylene-, -R 3g -C 0 -C 3 alkylene-C 5 -C 12 heteroarylene-C 0 -C 3 alkylene-, -R 3g -C 0 -C 3 alkylene-C 3 -C 10 heterocycloalkylene-C 0 -
  • R 3d and R 3e are combined with the nitrogen atom to which they are attached to form an optionally substituted 4 to 9 membered ring containing one or two nitrogen atoms;
  • R 3f is either absent, or selected from the group consisting of -C (O) -N (C 1 -C 3 alkyl) -C 1 -C 8 alkylene-, -N (C 1 -C 3 alkyl) -C (O) -C 1 -C 6 alkylene (C 1 -C 3 alkyl) -, -C 1 -C 6 alkylene-, -C 1 -C 6 alkylene (C 3 -C 10 cycloalkyl) -, -C 3 -C 10 cycloalkylene-, -NH-C (O) -C 1 -C 6 alkylene-, -N (C 1 -C 3 alkyl) -C (O) -C 1 -C 6 alkylene-, -NH-C (O) -C 3 -C 10 cycloalkylene-, -NH-C (O) -C 3 -C 10 heterocycloalkylene-, -
  • R 3c is selected from H or C 1 -C 6 alkyl
  • X is-C (R 5b ) -or-N-;
  • R 5a is either absent, or R 5a and R 8 taken together with the atom (s) to which they are attached form 3-to 6-membered cycloalkyl, 5-to 6-membered aryl, 5-to 6-membered heteroaryl, or 4-to 8-membered heterocycloalkyl; or R 5a and R 5b taken together with the atom (s) to which they are attached form a 3-to 6-membered cycloalkyl or 4-to 8-membered heterocycloalkyl; wherein 5-to 6-membered aryl, 5-to 6-membered heteroaryl, each “3-to 6-membered cycloalkyl” and each “4-to 8-membered heterocycloalkyl” are independently optionally substituted with one to three R 9 ;
  • R 4 , R 5b , R 6 , R 7 , and R 8 are independently selected from the group consisting of H, halo, hydroxy, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, aryl, and heteroaryl and wherein each of C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, aryl, and heteroaryl is independently optionally substituted with one to four R 9 ; or R 4 and R 5b taken together with the atom (s) to which they are attached form 3-to 6-membered cycloalkyl, or 4-to 8-membered heterocycloalkyl, provided that R 5a and R 5b do not also form a ring; or R 4 and R 7 taken together with the atom (s) to which they are attached form 3-to 6-membered cycloalkyl, or 4-to 8-membered heterocycloalkyl; or R 6 and R 7 taken together with the atom (s) to which they
  • R 9 at each occurrence is independently selected from the group consisting of halo, oxo, hydroxy, cyano, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkoxy, aryl, and heteroaryl; or two R 9 groups when attached to adjacent carbons and taken together with the carbons to which they are attached form a fused C 3 -C 6 cycloalkyl; or two R 9 groups when attached to the same carbon and taken together with the carbon to which they are attached form a spiro C 3 -C 6 cycloalkyl; wherein each C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 8 alkoxy, aryl, heteroaryl, fused C 3 -C 6 cycloalkyl, and spiro C 3 -C 6 cycloalkyl is independently optionally substituted with one to three fluoro or hydroxy, and C 1 -
  • n 1 and n 2 are each an integer independently selected from 0, 1, 2, 3, and 4; provided that n 1 +n 2 is 1, 2, 3, or 4.
  • R 3f is selected from the group consisting of -C 3 -C 10 cycloalkylene-, -NH-C (O) -C 1 -C 6 alkylene-, -N (C 1 -C 3 alkyl) -C (O) -C 1 -C 6 alkylene-, -NH-C (O) -C 3 -C 10 cycloalkylene-, -NH-C (O) -O-C 1 -C 6 alkylene-, -NH-C (O) -NH-C 1 -C 6 alkylene-, -C (O) -C 1 -C 8 alkylene-, -C (O) O-C 1 -C 8 alkylene-, and -C (O) -NH-C 1 -C 8 alkylene-.
  • R 2a and R 2b are independently selected from H, halo, and C 1 -C 3 alkyl.
  • R 3a is selected from-C 1 -C 6 alkylene-, -S-C 1 -C 6 alkylene-, -S (O) 2 -C 1 -C 6 alkylene-, and -NR 3d R 3e -R 3f -; wherein-NR 3d R 3e -R 3f -having a formula selected from
  • R 3a is-C 1 -C 6 alkylene-or-S-C 1 -C 6 alkylene-.
  • halo or “halogen” refers to fluorine (which may be depicted as-F) , chlorine (which may be depicted as-Cl) , bromine (which may be depicted as-Br) , or iodine (which may be depicted as -I) .
  • heteroaryl refers to an aromatic ring structure containing the specified number of ring atoms in which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, and/or sulfur) , with the remaining ring atoms being carbon.
  • a heteroatom i.e., oxygen, nitrogen, and/or sulfur
  • heteroaryls and heterocycloalkyls include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyralyl, pyrrolinyl, pyrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazalidinyl, tiazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazalyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolicdinyl, isothiazolidinyl, thiaoxadiazolyl, oxathiazolyl
  • heteroaryl can also include, when specified as such, ring systems having two rings wherein such rings may be fused and wherein one ring is aromatic and the other ring is not fully part of the conjugated aromatic system (i.e., the heteroaromatic ring can be fused to a cycloalkyl an heterocycloalkyl ring) .
  • a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated group through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, atrivalent nitrogen atom.
  • pyridyl means 2-, 3-or 4-pvridyl
  • thienyl means 2-or 3-thienyl, and so forth.
  • heteroarylene refers to a divalent heteroaryl group, as defined herein.
  • amino protecting group refers to a group which prevents an amino group from reaction when other parts of the molecular are subject to a reaction and can be easily removed.
  • Non-limiting examples include 9-fluorenylmethyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl and the like. These groups can be optionally substituted by one to three substituent (s) selected from the group consisting of halogen, alkoxy and nitro.
  • the amino protecting group is preferably 9-fluorenylmethyloxycarbonyl.
  • deuterated alkyl refers to an alkyl group substituted by one or more deuterium atom (s) , wherein the alkyl is as defined above.
  • cycloalkyl in the context of the term cycloalkyl, cycloalkylene, and heterocycle refers to a partially unsaturated, but not aromatic ring.
  • fused means bicyclic, tricyclic, or polycyclic structures comprised of at least two carbocyclic or heterocyclic structures sharing at least one chemical bond.
  • substituents are described as “independently” having more than one variable, each instance of a substituent is selected independent of the other (s) from the list of variables available. Each substituent therefore may be identical to or different from the other substituent (s) .
  • substituents are described as being “independently selected” from a group, each instance of a substituent is selected independent of the other (s) . Each substituent therefore may be identical to or different from the other substituent (s) .
  • aryl group optionally mono-or di-substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the aryl group is mono-or di-substituted with an alkyl group and situations where the aryl group is not substituted with the alkyl group.
  • “Substituted” refers to one or more hydrogen atoms in a group, preferably up to 5, and more preferably 1 to 3 hydrogen atoms, independently substituted by a corresponding number of substituents. It goes without saying that the substituents only exist in their possible chemical position. The person skilled in the art can determine whether the substitution is possible or impossible by experiments or theory without excessive effort. For example, the combination of amino or hydroxy having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable.
  • a compound of Formula (I) (or other formula number) is defined to include all forms of the compound of Formula (I) , including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof.
  • the compounds disclosed herein, or pharmaceutically acceptable salts thereof may exist in unsolvated and solvated forms.
  • the solvent or water When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers” .
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R-and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) -isomers respectively) .
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture” .
  • the compounds provided herein may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R) -or (S) -stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and Claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry” , 4th edition J. March, John Wiley and Sons, New York, 1992) .
  • a hydrogen (H) or carbon (C) substitution for compounds of the formula I include a substitution with any isotope of the respective atom.
  • a hydrogen (H) substitution includes a 1 H, 2 H (deuterium) , or 3 H (tritium) isotope substitution, as may be desired, for example, for a specific therapeutic or diagnostic therapy, or metabolic study application, or metabolic or chemical stability enhancement.
  • a compound of this disclosure may incorporate a known in the art radioactive isotope or radioisotope, such as 3 H, 15 O, 12 C, or 13 N isotope, to afford a respective radiolabeled compound of formula I.
  • a “pharmaceutically acceptable carrier” means a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable carrier” as used in the specification and Claims includes both one and more than one such carrier.
  • a “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include:
  • 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, and the like; or
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • Treating” , “treatment” , or “therapy” of a disease includes:
  • pharmaceutical composition refers to a mixture of one or more of the compounds described herein or physiologically/pharmaceutically acceptable salts or pro drugs thereof with other chemical components, and other components such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient so as to show biological activity.
  • solvate refers to a pharmaceutically acceptable solvate formed by a ligand-drug conjugate of the present disclosure with one or more solvent molecule (s) .
  • solvent molecules include water, ethanol, acetonitrile, isopropanol, DMSO, and ethyl acetate.
  • carrier used in the composition of the present disclosure refers to a system that can change the way a drug enters the human body and distribution, control the drug release rate, and deliver the drug to the targeted organ.
  • Drug carrier release and targeting systems can reduce drug degradation and loss, reduce side effects and improve bioavailability.
  • excipient is an adjunct in a pharmaceutical formulation other than a main drug, which can also be referred to as an adjuvant, such as adhesives, fillers, disintegrants, lubricants in tablets; matrix parts in the semisolid preparations ointment and cream; preservatives, antioxidants, flavoring agents, fragrances, co-solvents, emulsifiers, solubilizers, osmotic pressure regulators, colorants in liquid preparations and the like.
  • adjuvant such as adhesives, fillers, disintegrants, lubricants in tablets; matrix parts in the semisolid preparations ointment and cream; preservatives, antioxidants, flavoring agents, fragrances, co-solvents, emulsifiers, solubilizers, osmotic pressure regulators, colorants in liquid preparations and the like.
  • X, R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 3b , R 3f , R 4 , R 5a , R 6 , R 7 , R 8 , n 1 , and n 2 are as defined in formula (D 1 ) and any embodiments thereof.
  • A36-3 (35.00 mg, 0.03 mmol, 70.72%yield) was obtained as colorless oil.
  • the potency of compounds of Formula (D 1 ) is higher than that of the comparator compounds Dxd and ref-1 across the four tumor cells. Therefore, the modifications on the camptothecin scaffold of the present invention can improve the anticancer potency.
  • the LCMS method had the following features:
  • the LCMS method had the following features:
  • the PK studies confirmed the compounds of Formula (D 1 ) have higher clearance and lower exposure in plasma. This is surprisingly different from the well-known comparator Dxd, which have 3-4 folds lower clearance. It is deemed the faster clearance of free toxin can reduce systemic toxicities caused by the toxin. This unique property has a great potential to be translated into a safer ADC, whose clinical use is also mainly restricted by the toxicity caused by the toxin.
  • the NCI-N87 cell line (BeNa Culture Collection) was used to create the CDX (Cell Line Derived Xenograft) NCI-N87 xenograft mouse model.
  • CDX Cell Line Derived Xenograft
  • the injection sites were palpated up to three times weekly until tumors are established to an average size of 150 mm 3 as measured via digital calipers.
  • Animals were randomized into groups of 3 mice/group, and the antibody drug conjugates ADC-5 and ADC-ref were administered to the tail vein at a dosage of 10mg/kg, respectively.
  • the blood samples were collected by orbital vein after IV administration at 4h and 24h into heparin-containing tubes, centrifugated at 10000 rpm for 3 mins to get plasma. Samples of lung tissue and tumor tissue were also collected at 4h and 24h. The concentration of payloads were sent to Suzhou Chengyao Biotech Co., Ltd. for analysis.
  • the LCMS method had the following features:
  • the payload concentration of ADC-5 in plasma and lung tissue was significantly lower than that of ADC-ref, the payload concentration of both ADCs in tumor tissue is much higher than that in plasma, and the payload concentration of ADC-5 in tumor is comparable to that of ADC-ref, which ensures the anticancer efficacy.
  • the tumor/plasma and tumor/lung selectivity of ADC-5 is about 3-4 folds higher than ADC-ref, which further support the unique design of the present invention that modification of PK properties of payloads doesn’t impact the delivery of toxin into tumor by ADC, instead, it can reduce the exposure of free payload in plasma and lung.
  • ADCs of the present invention with significantly reduced exposure of payload or toxin provide a novel solution to develop new ADCs with better efficacy and safety.
  • TGI tumor growth inhibition rate
  • the tumor growth inhibition rate of ADC-5 was significantly better than that of the positive control.
  • Such surprising post-treatment effect of the ADCs of the present invention will be particular useful in clinical therapy with a potential to reduce the frequency of administration, suppress the development of drug resistance, increase clinical response rate, or improve overall survival rate.
  • the ADCs of the present invention do not cause reduction of mice body weight, which also supports a good safety profile of ADCs of the present invention.
  • TGI tumor growth inhibition rate
  • the NCI-N87 cell line (BeNa Culture Collection) was used to create the CDX (Cell Line Derived Xenograft) NCI-N87 xenograft mouse model.
  • CDX Cell Line Derived Xenograft
  • the injection sites were palpated up to three times weekly until tumors are established to an average size of 150 mm 3 as measured via digital calipers. Animals were randomized into treatment groups on day 0, 6 mice/group.
  • Rats/group Male SD rat, 180 ⁇ 200g (Shanghai Bikai Keyi Biotechnology Co., Ltd. ) , 4 Rats/group.
  • the payloads were given by i.v. injection at a dosage of 2 mg/kg, respectively, once a day for 4 days.
  • a physiological saline solution containing 5% (w/v) dimethyl sulfoxide and 20% (w/v) (2-hydroxypropyl) - ⁇ -cyclodextrin administration group was set up. Rat weight was measured and recorded every day.

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Abstract

L'invention concerne des conjugués d'analogues de camptothécine avec une molécule de liaison cellulaire de formule : T-(L-D) m. L'invention concerne en outre des méthodes de fabrication des conjugués d'analogues de camptothécine à un agent de liaison cellulaire, ainsi que des méthodes d'application des conjugués dans le traitement ciblé de tumeur.
PCT/CN2024/139197 2023-12-14 2024-12-13 Conjugué ligand-médicament d'analogues de camptothécine et son utilisation Pending WO2025124555A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
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