WO2022253033A1 - 一类化学偶联连接子及其用途 - Google Patents

一类化学偶联连接子及其用途 Download PDF

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Publication number
WO2022253033A1
WO2022253033A1 PCT/CN2022/094540 CN2022094540W WO2022253033A1 WO 2022253033 A1 WO2022253033 A1 WO 2022253033A1 CN 2022094540 W CN2022094540 W CN 2022094540W WO 2022253033 A1 WO2022253033 A1 WO 2022253033A1
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Prior art keywords
compound
formula
methyl
antibody
group
Prior art date
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Ceased
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PCT/CN2022/094540
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English (en)
French (fr)
Chinese (zh)
Inventor
田强
汪小蓓
李德亮
张毅涛
叶健
胡瑞斌
宋宏梅
葛均友
王晶翼
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Application filed by Sichuan Kelun Biotech Biopharmaceutical Co Ltd filed Critical Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority to JP2023567997A priority Critical patent/JP2024520283A/ja
Priority to CN202280032554.2A priority patent/CN117255790A/zh
Priority to KR1020237037967A priority patent/KR20240017343A/ko
Priority to US18/559,039 priority patent/US20240252665A1/en
Priority to EP22815080.1A priority patent/EP4349832A1/en
Publication of WO2022253033A1 publication Critical patent/WO2022253033A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
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    • 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
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    • 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
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    • C07D207/444—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 three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
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    • C07D207/44—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 three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—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 three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—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 three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • C07D207/452—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 three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala

Definitions

  • the invention relates to a new type of linker used for chemical conjugation, antibody-conjugated drugs and related compositions prepared from the linker, as well as its preparation method and application in the treatment of tumor-related diseases.
  • ADC Antibody-Drug Conjugates
  • ADC are composed of monoclonal antibody drugs targeting specific antigens and small-molecule cytotoxic drugs coupled through linkers, which have the powerful killing effect of traditional small-molecule chemotherapy and antibody drugs. tumor targeting.
  • 12 ADC drugs have been approved for marketing worldwide, of which 7 are used to treat hematological tumors and 5 are used to treat solid tumors.
  • Antibody-drug conjugates are composed of antibody, linker, payload, and conjugation methods.
  • the coupling mode is the connection mode of the antibody and the drug-linker.
  • Coupling methods are mainly divided into non-point-specific coupling and point-specific coupling.
  • the non-site-specific coupling method was used, which mainly consisted of lysine coupling and cysteine coupling.
  • Chemical methods were used to directly couple the drug to the amino acid residues on the antibody, which did not involve the transformation or modification of the antibody. The number of toxin molecules linked and the coupling site cannot be determined, and the uniformity is not good.
  • the commonly used fixed-point coupling method is to perform specific coupling through genetic engineering sites or special linkers to achieve more uniform coupling and to realize the connection of cytotoxins at specific sites.
  • Antibody-conjugated drugs produced by site-directed coupling can reduce fluctuations in drug efficacy, pharmacokinetics, and CMC quality control caused by differences in the number of coupling sites and couplings.
  • One purpose of this application is to provide a novel linker for chemical conjugation.
  • This type of linker has high reactivity, mild coupling conditions, easy operation, and can realize site-specific coupling. Good stability, clear efficacy in vivo and in vitro.
  • the application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide or isotopically labeled compound thereof , wherein the compound has the structure of formula I:
  • X is selected from leaving groups such as Cl, Br, I, OMs, OTs, OTf or
  • Y is absent or selected from carbonyl
  • Ring A is selected from substituted or unsubstituted C 6-10 aromatic rings, 5-12 membered aromatic heterocycles or 5-12 membered heterocycles;
  • Z 1 is absent or selected from -CH 2 - or C 2-6 alkynylene
  • W 1 does not exist or is selected from one or more of C 1-10 alkylene, -(CH 2 CH 2 O)p-, and -(OCH 2 CH 2 )p-;
  • J 1 is selected from -COOH, -NH 2 , 3-10 membered nitrogen-containing heterocyclic group, sulfonylurea group or hydroxyl group;
  • p is an integer of 1-10.
  • X is selected from one or more of Cl, Br, I, OMs, OTs and OTf.
  • Y is absent.
  • Z is absent or is C2-6 alkynylene.
  • W 1 does not exist or is selected from one or more of C 1-10 alkylene and -(CH 2 CH 2 O)p-.
  • W 1 is C 1-10 alkylene; preferably C 1-6 alkylene, more preferably C 1-3 alkylene.
  • J 1 is -COOH.
  • ring A is selected from substituted or unsubstituted 5-12 membered nitrogen-containing aromatic heterocycles or 5-12 membered nitrogen-containing heterocycles; preferably, ring A is selected from unsubstituted or oxo groups or- COOH-substituted 5-12 membered nitrogen-containing aromatic heterocycle or 5-12 membered nitrogen-containing heterocycle.
  • p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • X is selected from Cl, Br, I, OMs, OTs, OTf and
  • Ring A is selected from 5-12 membered nitrogen-containing aromatic heterocycles or 5-12 membered nitrogen-containing heterocycles that are unsubstituted or substituted by oxo or -COOH;
  • Z 1 is absent or is -CH 2 -;
  • W 1 does not exist or is selected from one or more of C 1-10 alkylene and -(CH 2 CH 2 O)p-;
  • J 1 is -COOH
  • p is an integer of 1-10.
  • formula I is selected from the following structures:
  • the compound of formula I has the following structure:
  • J 1 is -COOH or -NH 2 .
  • the compound of formula I has the following structure:
  • the application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide or isotope-labeled compound thereof , wherein the compound has the structure of formula II:
  • B 1 is each independently selected from a single bond or a 5-12 membered nitrogen-containing aromatic heterocycle at each occurrence;
  • Each occurrence of Y 1 , Y 2 and Y 3 is independently selected from CH and N;
  • W 2 does not exist or is selected from one or more of C 1-10 alkylene, -(CH 2 CH 2 O) p - or -(OCH 2 CH 2 ) p -;
  • J 2 is selected from -COOH, -NH 2 , 3-10 membered nitrogen-containing heterocyclic group, sulfonylurea group or hydroxyl group;
  • p is an integer of 1-10.
  • each occurrence of B 1 is independently selected from a single bond or a 5-6 membered nitrogen-containing aromatic heterocycle; preferably, each occurrence of B 1 is independently selected from a single bond Or a 5-6 membered nitrogen-containing aromatic heterocyclic ring; further preferably, each occurrence of B 1 is independently selected from a single bond or a pyrimidine ring.
  • Y 1 , Y 2 and Y 3 are all N; or Y 1 is CH, Y 2 and Y 3 are all N; or Y 1 is N, Y 2 and Y 3 are all CH; or Y 1 , Y 2 and Y 3 are all CH.
  • Z is absent or is C alkynylene .
  • W 2 is absent or is C 1-10 alkylene.
  • J 2 is selected from -COOH or -NH 2 .
  • each occurrence of B is independently selected from a single bond or a pyrimidine ring
  • Y 1 , Y 2 and Y 3 are all CH;
  • W 2 does not exist or is selected from one or more of C 1-10 alkylene, -(CH 2 CH 2 O) p ;
  • J 2 is -COOH
  • p is an integer of 1-10.
  • the compound of formula II has the following structure:
  • p is an integer of 1-10.
  • p is an integer of 1-8; more preferably, p is an integer of 1-5.
  • the compound of formula II has the following structure:
  • the compound of formula II has the following structure:
  • the present application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide or isotope-labeled compound thereof , wherein the compound has the structure of formula III:
  • V 1 is the group formed when J 1 is connected to L in the compound of formula I in the first aspect of the application; preferably, V 1 is selected from -CO-, -N(R 1 )-, -O-, 3-10 members Nitrogen-containing heterocyclic group or sulfonylurea group, wherein R 1 is H, C 1-6 alkyl or C 2-6 alkoxyalkyl; further preferably, V 1 is selected from -C(O)- and -N (R 1 )-, wherein R 1 is H, C 1-6 alkyl or C 2-6 alkoxyalkyl;
  • L is a linker between V1 and E';
  • E' is selected from H, -NHCH 2 -Lg, -COOH, Wherein, Lg represents a leaving group, such as Cl, Br, I, OMs, OTs, OTf or
  • X, Y, A, Q, Z 1 , W 1 are as defined in any one of the first aspect above.
  • L is selected from one or more of the following groups: C 1-6 alkylene, -N(R 6 )-, carbonyl, -O-, Val, Cit, Phe, Lys, D -Val, Leu, Gly, Phe, Ala, Asn, Val-Cit, Val-Ala, Val-Lys, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), D-Val-Leu-Lys , Gly-Gly-Arg, Ala-Ala-Asn, Gly-Gly-Gly, Gly-Gly-Phe-Gly, Gly-Gly-Gly-Gly-Gly, Wherein R 6 is H, C 1-6 alkyl or C 2-6 alkoxyalkyl, and s is an integer of 1-10.
  • L is selected from one or more of the following groups: Val, Cit, Gly, Phe, Ala, Val-Cit, Val-Ala, Gly-Gly-Phe-Gly,
  • L is selected from
  • L is selected from
  • the present application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide or isotope-labeled compound thereof , wherein the compound has the structure of formula IV:
  • V 2 is the group obtained after J 2 is connected to L in the compound of formula II in the second aspect of the application; preferably, V 2 is selected from -CO-, -N(R 2 )-, -O-, 3-10 members Nitrogen-containing heterocyclic group or sulfonylurea group, wherein R 2 is H, C 1-6 alkyl or C 2-6 alkoxyalkyl; further preferably, V 2 is selected from -C(O)- and -N (R 2 )-, wherein R 2 is H, C 1-6 alkyl or C 2-6 alkoxyalkyl;
  • B 1 , Y 1 , Y 2 , Y 3 , Z 2 and W 2 are as defined in any one of the preceding aspects of the second aspect;
  • L and E' are as defined in any one of the third aspects above.
  • the present application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide or isotope-labeled compound , wherein the compound has the structure of formula V:
  • E is selected from a single bond, -NH-CH 2 -, or the following structures:
  • D is a fragment of a biologically active molecule (such as a cytotoxic drug);
  • X, Y, A, Q, Z 1 , W 1 are as defined in any one of the first aspect above;
  • V and L are as defined in any one of the third aspect.
  • the bioactive molecule is selected from the group consisting of anti-tubulin agents, DNA intercalators, DNA topoisomerase inhibitors and RNA polymerase inhibitors.
  • the biologically active molecule is selected from the group consisting of tubulin inhibitors auristatins and maytansinoids; DNA intercalator pyrrolobenzodiazepines (PBD); DNA topoisomerization Enzyme inhibitors, such as topoisomerase I inhibitors (such as camptothecin, hydroxycamptothecin, 9-aminocamptothecin, SN-38, irinotecan, topotecan, belotecan, rubotecan ) or topoisomerase II inhibitors (such as doxorubicin, doxorubicin, PNU-159682, doxorubicin, daunorubicin, mitoxantrone, podophyllotoxin, or etoposide); RNA polymerization Enzyme inhibitor ⁇ -amanitin, etc.; and pharmaceutically acceptable salts, esters and analogs thereof.
  • PPD DNA intercalator pyrrolobenzodiazepines
  • the biologically active molecule is selected from: topoisomerase I inhibitors (such as camptothecin, hydroxycamptothecin, 9-aminocamptothecin, SN-38, irinotecan, topotecan , belotecan, rubitecan), MMAE and MMAE derivatives.
  • topoisomerase I inhibitors such as camptothecin, hydroxycamptothecin, 9-aminocamptothecin, SN-38, irinotecan, topotecan , belotecan, rubitecan
  • MMAE MMAE derivatives.
  • the bioactive molecule is selected from: MMAE and MMAE derivatives.
  • the D is selected from:
  • the compound of formula V is selected from:
  • the present application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide or isotope-labeled compound thereof , wherein the compound has the structure of formula VI:
  • B 1 , Y 1 , Y 2 , Y 3 , Z 2 and W 2 are as defined in any one of the preceding aspects of the second aspect;
  • V 2 is as defined in any one of the fourth aspect above;
  • the compound of formula VI is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the present application provides a biologically active conjugate, the structure of which is shown in formula VII:
  • Ab is a targeting moiety (such as small molecule ligands, proteins (such as antibodies), polypeptides, non-protein reagents (such as sugars, RNA or DNA)); n is selected from integers or decimals between 1-10;
  • V 1 is selected from -C(O)- or -N(R 1 )-, wherein R 1 is H, C 1-6 alkyl or C 2-6 alkoxyalkyl;
  • L is a linker between V1 and E;
  • E is a structural fragment connecting L and D;
  • D is a fragment of a biologically active molecule (such as a cytotoxic drug);
  • Another aspect of the present invention provides a biologically active conjugate, the structure of which is shown in formula VIII:
  • Ab is a targeting moiety (such as small molecule ligands, proteins (such as antibodies), polypeptides, non-protein reagents (such as sugars, RNA or DNA)); n is selected from integers or decimals between 1-10;
  • V 2 is selected from -C(O)- or -N(R 2 )-, wherein R 2 is H, C 1-6 alkyl or C 2-6 alkoxyalkyl;
  • L is a linker between V2 and E;
  • E is a structural fragment connecting L and D;
  • D is a fragment of a biologically active molecule (such as a cytotoxic drug);
  • the Ab is selected from Epidermal Growth Factor, Trop-2, CD37, HER2, CD70, EGFRvIII, Mesothelin, Folate receptor1, Mucin 1, CD138, CD20, CD19, CD30, SLTRK6, Nectin 4, Tissue factor, Mucin16 , Endothelin receptor, STEAP1, SLC39A6, Guanylylcyclase C, PSMA, CCD79b, CD22, Sodium phosphate cotransporter 2B, GPNMB, Trophoblast glycoprotein, AGS-16, EGFR, CD33, CD66e, CD74, CD56, PD-L1, TACSTD2, DR5, E16, STEAP1, 0772P, MPF, Napi3b, Sema 5b, PSCA hlg, ETBR, MSG783, STEAP2, TrpM4, CRIPTO, CD21, CD79b, FcRH2, NCA, MDP,
  • the Ab is selected from anti-Her2 antibody trastuzumab or anti-Trop2 antibody sacituzumab or anti-ROR1 antibody 19F6_Hu35V1.
  • L is selected from one or more of the following groups: C 1-6 alkylene, -N(R 6 )-, carbonyl, -O-, Val, Cit, Phe, Lys, D -Val, Leu, Gly, Phe, Ala, Asn, Val-Cit, Val-Ala, Val-Lys, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), D-Val-Leu-Lys , Gly-Gly-Arg, Ala-Ala-Asn, Gly-Gly-Gly, Gly-Gly-Phe-Gly, Gly-Gly-Gly-Gly-Gly, Wherein R 6 is H, C 1-6 alkyl or C 2-6 alkoxyalkyl, s is an integer of 1-10;
  • L is selected from the following structures:
  • the E is a single bond, -NH-CH 2 -, or the following structure:
  • the E is -NH-CH 2 -.
  • the bioactive molecule is selected from the group consisting of anti-tubulin agents, DNA intercalators, DNA topoisomerase inhibitors and RNA polymerase inhibitors.
  • the biologically active molecule is selected from the group consisting of tubulin inhibitors auristatins and maytansinoids; DNA intercalator pyrrolobenzodiazepines (PBD); DNA topoisomerization Enzyme inhibitors, such as topoisomerase I inhibitors (such as camptothecin, hydroxycamptothecin, 9-aminocamptothecin, SN-38, irinotecan, topotecan, belotecan, rubotecan ) or topoisomerase II inhibitors (such as doxorubicin, doxorubicin, PNU-159682, doxorubicin, daunorubicin, mitoxantrone, podophyllotoxin, or etoposide); RNA polymerization Enzyme inhibitor ⁇ -amanitin, etc.; and pharmaceutically acceptable salts, esters and analogs thereof.
  • PPD DNA intercalator pyrrolobenzodiazepines
  • the biologically active molecule is selected from: topoisomerase I inhibitors (such as camptothecin, hydroxycamptothecin, 9-aminocamptothecin, SN-38, irinotecan, topotecan , belotecan, rubitecan), MMAE and MMAE derivatives.
  • topoisomerase I inhibitors such as camptothecin, hydroxycamptothecin, 9-aminocamptothecin, SN-38, irinotecan, topotecan , belotecan, rubitecan
  • MMAE MMAE derivatives.
  • the bioactive molecule is selected from: MMAE and MMAE derivatives.
  • the D is selected from:
  • n is 1-8; more preferably n is 3-5.
  • the structure of the biologically active conjugate is as follows, wherein Ab is selected from anti-Her2 antibody trastuzumab or anti-Trop2 antibody sacituzumab or anti-ROR1 antibody 19F6_Hu35V1, n 1 is 1-8; more preferably 3- 5:
  • the structure of the biologically active conjugate is as follows, wherein Ab is selected from anti-Her2 antibody trastuzumab or anti-Trop2 antibody sacituzumab or anti-ROR1 antibody 19F6_Hu35V1, n 1 is 1-8; more preferably 3- 5:
  • alkylene means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or Butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12, eg, 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched aliphatic hydrocarbon group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which are optionally substituted by 1 or more (such as 1 to 3) suitable (e.g.
  • halogen in which case the group is referred to as "haloalkyl”
  • haloalkyl e.g. CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl 5 , CH 2 CF 3 , CH 2 Cl or -CH 2 CH 2 CF 3 etc.
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon group of 1 to 4 carbon atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl or tert-butyl).
  • alkoxy is defined as -O-alkyl, said alkyl being as defined above.
  • C 1-6 alkoxy refers to -OC 1-6 alkyl.
  • alkoxyalkyl is defined as an alkyl group substituted with an alkoxy group, the alkyl group being as defined above.
  • C 2-6 alkoxyalkyl refers to an alkyl group having 2 to 6 carbon atoms substituted with an alkoxy group.
  • alkynylene denotes a divalent hydrocarbon radical comprising at least one carbon-carbon triple bond, preferably having 1, 2, 3, 4, 5 or 6 carbon atoms, for example ethynylene, propynylene group or butynylene.
  • heterocyclyl refers to a saturated or partially unsaturated ring atom in which at least one ring atom is a heteroatom selected from N, O, and S and the remaining ring atoms are C (i.e. A cyclic group having one or more double bonds and/or triple bonds within the ring).
  • a “5-12 membered heterocycle (group)” has 4-11 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (such as 1 , 2, 3 or 4) a saturated or partially unsaturated heterocyclic group of heteroatoms independently selected from N, O and S.
  • a “5-12 membered nitrogen-containing heterocycle (group)” is a heterocycle (group) in which at least one ring-forming atom is N.
  • heterocyclic groups include, but are not limited to: oxiranyl, aziridinyl, azetidinyl (azetidinyl), oxetanyl (oxetanyl), tetrahydrofuranyl, dioxolyl ( dioxolinyl), pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, Piperazinyl or trithianyl.
  • the heterocyclic group can be optionally substituted by one or more (for example, 1, 2, 3 or 4) suitable substituents, and can be optionally combined with one or more aromatic rings, heteroaryl rings
  • aromatic ring or “aryl” refers to a monocyclic or polycyclic aromatic ring system having, for example, 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring-forming Carbon atoms, especially 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms.
  • heteroaryl refers to a monocyclic or polycyclic aromatic ring system having, for example, 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms and which contain at least one heteroatom which may be the same or different (the heteroatom is for example oxygen, nitrogen or sulfur), And, additionally in each case may be benzo-fused.
  • halogen includes F, Cl, Br or I.
  • substituted means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present.
  • the normal valences of the cases and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Selected optional substituents are substituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected Substituent substitution.
  • each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number of atomic substitutions.
  • isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g. , 11C , 13C , and 14C ).
  • isotopes of chlorine such as 36 Cl
  • isotopes of fluorine such as 18 F
  • isotopes of iodine such as 123 I and 125 I
  • isotopes of nitrogen such as 13 N and 15 N); , 17 O and 18 O
  • phosphorus isotopes eg 32 P
  • sulfur isotopes eg 35 S
  • stereoisomer means isomers formed as a result of at least one asymmetric center.
  • compounds with one or more (e.g., one, two, three or four) asymmetric centers which can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers.
  • Certain individual molecules may also exist as geometric isomers (cis/trans).
  • compounds of the present invention may exist as mixtures of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of this application encompasses all such ratios in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) %) isomers or mixtures thereof.
  • Solid lines can be used in this article solid wedge or imaginary wedge Depicting the carbon-carbon bonds of the compounds of the invention.
  • the use of a solid line to delineate a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, solid and imaginary wedges are used to define relative rather than absolute stereochemistry.
  • the compounds of the present invention are intended to be stereoisomers (which include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof).
  • the compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof, such as racemic mixtures and pairs of diastereoisomers.
  • the present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • compositions of the present invention may exist in free form for use in therapy, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which are administered to patients in need thereof Following administration, the compound of the invention or its metabolites or residues can be provided directly or indirectly. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate/carbonate, glucoheptonate, gluconate, nitrate, orotate, palmitate and other similar salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, magnesium salts and other similar salts.
  • esters means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (hydrolyzable under physiological conditions to release the free acid or alcohol form of the present invention) compound).
  • the compounds of the invention may also themselves be esters.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise a polar solvent, such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • a polar solvent such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides; nitrogen-containing heterocycle.
  • tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydrogen peroxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines.
  • MCPBA m-chloroperbenzoic acid
  • hydrogen peroxide alkyl Hydrogen peroxides such as t-butyl hydroperoxide
  • sodium perborate and dioxiranes such as dimethyldioxirane
  • metabolites of the compounds of the present invention ie substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which themselves may have little or no pharmacological activity when administered into or on the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety (such as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))". Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention which contain protecting groups.
  • protecting groups such as those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference.
  • Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • Another aspect of the present invention provides a kind of preparation method of formula I compound, described method comprises the steps:
  • the compounds of formula I-TM1 and formula I-TM2 in the present invention can be synthesized by the following synthetic route.
  • X, Z 1 , W 1 , J 1 are as defined in the general formula above;
  • M is a leaving group that undergoes a substitution reaction, including but not limited to halogen, trifluoromethanesulfonate, p-toluenesulfonate, preferably halogen.
  • a compound of formula I-IM1 is obtained by a substitution reaction between a compound of formula I-SM1 and a compound of MZ 1 -W 1 -J 1 ;
  • the reaction is carried out under basic conditions
  • the reaction is carried out at a suitable temperature, and the temperature is 20°C, 25°C, 50°C, 60°C, 100°C, preferably 20°C;
  • the reaction is carried out in a suitable solvent, including but not limited to acetone, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl Sulfoxide, preferably acetone.
  • a suitable solvent including but not limited to acetone, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl Sulfoxide, preferably acetone.
  • a compound of formula I-IM2 is obtained by a substitution reaction between a compound of formula I-IM1 and sodium azide;
  • the reaction is carried out at a suitable temperature, and the temperature is 20°C, 25°C, 50°C, 60°C, 100°C, preferably 20°C;
  • the reaction is carried out in a suitable solvent, including but not limited to acetone, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl Sulfoxide, preferably acetone.
  • a suitable solvent including but not limited to acetone, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl Sulfoxide, preferably acetone.
  • the compound of formula I-IM3 is obtained through a reduction reaction of the compound of formula I-IM2;
  • this step is carried out in the presence of a suitable reducing agent, which can be selected from palladium catalysts, platinum catalysts, rhodium catalysts, preferably palladium catalysts;
  • this step is carried out at a suitable temperature, the temperature being 20°C, 25°C, 50°C, 60°C, 100°C, preferably 20°C;
  • this step is carried out in a suitable organic solvent, which can be selected from tetrahydrofuran, dichloromethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide , n-heptane, n-hexane, ethyl acetate, preferably ethyl acetate.
  • a suitable organic solvent which can be selected from tetrahydrofuran, dichloromethane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide , n-heptane, n-hexane, ethyl acetate, preferably ethyl acetate.
  • this step is carried out at a suitable temperature, the temperature being 20°C, 25°C, 50°C, 60°C, 100°C, preferably 20°C;
  • this step is carried out in a suitable organic solvent, which can be selected from acetonitrile, ethanol, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, n- Heptane, n-hexane, ethyl acetate, preferably acetonitrile.
  • a suitable organic solvent which can be selected from acetonitrile, ethanol, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, n- Heptane, n-hexane, ethyl acetate, preferably acetonitrile.
  • the compound of formula I-TM2 is obtained by the hydrolysis reaction of the compound of formula I-TM1;
  • the reaction is carried out under alkaline conditions, including but not limited to PB buffer with a pH of 7.0, 7.4 or 8.0;
  • the reaction is carried out at a suitable temperature, the temperature is 20°C, 25°C, 50°C, 60°C, 100°C, preferably 20°C;
  • the reaction is carried out in a suitable solvent, including but not limited to acetonitrile, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, preferably acetonitrile .
  • a suitable solvent including but not limited to acetonitrile, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, preferably acetonitrile .
  • the compound of formula I-TM3 in the present invention can be synthesized by the following synthetic route.
  • L is a leaving group that undergoes a substitution reaction, including but not limited to halogen, trifluoromethanesulfonate, p-toluenesulfonate, preferably halogen, OTf.
  • a compound of formula I-IM4 is obtained by a compound of formula I-IM1 through a coupling reaction
  • the coupling reagents include but are not limited to methylboronic acid, trimethylboroxane, preferably trimethylboroxane;
  • the coupling reaction is carried out in alkaline conditions
  • the base includes but not limited to triethylamine, DIPEA, NMM, sodium tert-butoxide, potassium acetate, sodium acetate, cesium fluoride, fluoride Potassium, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, potassium dihydrogenphosphate, preferably cesium fluoride.
  • the coupling reaction is carried out in the presence of a catalyst, the catalyst including but not limited to tetrakistriphenylphosphine palladium, palladium acetate, Pd 2 (dba) 3 , Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 2 Cl 2 dichloromethane complex, Pd(dppf)Cl 2 , Pd(Amphos)Cl 2 , preferably tetrakistriphenylphosphine palladium.
  • a catalyst including but not limited to tetrakistriphenylphosphine palladium, palladium acetate, Pd 2 (dba) 3 , Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 2 Cl 2 dichloromethane complex, Pd(dppf)Cl 2 , Pd(Amphos)Cl 2 , preferably tetrakistriphenylphosphine palladium.
  • the coupling reaction is carried out at a temperature of 0-200°C, preferably at a temperature of 50-150°C.
  • the reaction is carried out in a suitable solvent, including but not limited to 1,4-dioxane, water, toluene, tetrahydrofuran, N,N-dimethylformamide, N- Methylpyrrolidone, dimethylsulfoxide and any combination thereof, preferably 1,4-dioxane.
  • a suitable solvent including but not limited to 1,4-dioxane, water, toluene, tetrahydrofuran, N,N-dimethylformamide, N- Methylpyrrolidone, dimethylsulfoxide and any combination thereof, preferably 1,4-dioxane.
  • the halogenating reagent includes but not limited to bromine, N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, preferably N-bromosuccinimide;
  • the coupling reaction is performed in the presence of a catalyst, and the catalyst is benzoyl peroxide.
  • the coupling reaction is carried out at a temperature of 0-200°C, preferably at a temperature of 50-150°C.
  • the reaction is carried out in a suitable solvent, including but not limited to halogenated hydrocarbons (such as carbon tetrachloride, methylene chloride, chloroform, 1,2-dichloroethane, etc.) , methanol, ethanol, DMF, acetonitrile, ethers (such as ethylene glycol dimethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (such as toluene, benzene, xylene), water and any combination thereof, preferably tetrachloro carbonized.
  • halogenated hydrocarbons such as carbon tetrachloride, methylene chloride, chloroform, 1,2-dichloroethane, etc.
  • ethers such as ethylene glycol dimethyl ether, tetrahydrofuran, dioxane
  • aromatic hydrocarbons such as toluene, benzene, xylene
  • water and any combination thereof preferably t
  • the compound of formula II-TM1 in the present invention can be synthesized by the following synthetic route.
  • Y 1 , Y 2 , Y 3 , B 1 , J 2 are as defined above in the general formula
  • LG is a leaving group for coupling reaction, including but not limited to halogen, trifluoromethanesulfonate, preferably halogen.
  • a compound of formula II-IM2 is obtained by a compound of formula II-IM1 through a coupling reaction
  • the coupling reaction reagent is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the coupling reaction is carried out in the presence of a catalyst, the catalyst including but not limited to tetrakistriphenylphosphine palladium, palladium acetate, Pd 2 (dba) 3 , Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 2 Cl 2 dichloromethane complex, Pd(dppf)Cl 2 , Pd(Amphos)Cl 2 , preferably tetrakistriphenylphosphine palladium.
  • a catalyst including but not limited to tetrakistriphenylphosphine palladium, palladium acetate, Pd 2 (dba) 3 , Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 2 Cl 2 dichloromethane complex, Pd(dppf)Cl 2 , Pd(Amphos)Cl 2 , preferably tetrakistriphenylphosphine palladium.
  • the coupling reaction is carried out at a temperature of 0-200°C, preferably at a temperature of 50-150°C.
  • the reaction is carried out in a suitable solvent, including but not limited to 1,4-dioxane, water, toluene, tetrahydrofuran, N,N-dimethylformamide, N- Methylpyrrolidone, dimethylsulfoxide and any combination thereof, preferably 1,4-dioxane.
  • a suitable solvent including but not limited to 1,4-dioxane, water, toluene, tetrahydrofuran, N,N-dimethylformamide, N- Methylpyrrolidone, dimethylsulfoxide and any combination thereof, preferably 1,4-dioxane.
  • the compound of formula II-TM1 is obtained by oxidation reaction of the compound of formula II-IM2;
  • the coupling reaction is carried out in the presence of an oxidizing agent, and the catalyst is m-chloroperoxybenzoic acid.
  • the coupling reaction is carried out at a temperature of 0-120°C, preferably at a temperature of 50-80°C.
  • the reaction is carried out in a suitable solvent, including but not limited to halogenated hydrocarbons (such as carbon tetrachloride, methylene chloride, chloroform, 1,2-dichloroethane, etc.) , methanol, ethanol, DMF, acetonitrile, ethers (such as ethylene glycol dimethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (such as toluene, benzene, xylene), water and any combination thereof, preferably methanol.
  • halogenated hydrocarbons such as carbon tetrachloride, methylene chloride, chloroform, 1,2-dichloroethane, etc.
  • methanol such as ethylene glycol dimethyl ether, tetrahydrofuran, dioxane
  • aromatic hydrocarbons such as toluene, benzene, xylene
  • the compounds of the present invention can also be prepared in a variety of ways known to those skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof known to those skilled in the art. Preferred methods include, but are not limited to, those described above.
  • the reactions can be performed in a solvent or mixture of solvents appropriate to the reagents and materials employed and suitable to effect the transformations.
  • Those skilled in the art of organic synthesis will appreciate that the functional groups present on the molecule should be consistent with the proposed transformation. This will sometimes require judgment in modifying the order of synthetic steps or choosing a particular process route over another to obtain the desired compound of the invention.
  • the present invention also provides a pharmaceutical composition, which contains the bioactive conjugate described in the present invention and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical excipients mentioned in this article refer to the excipients and additives used in the production of drugs and the formulation of prescriptions, and refer to the active ingredients that have been reasonably evaluated in terms of safety and are included in pharmaceutical preparations substance.
  • the pharmaceutical composition may be administered in any form as long as it achieves prevention, alleviation, prevention or cure of symptoms of human or animal patients.
  • various appropriate dosage forms can be prepared according to the route of administration.
  • the present application also provides a kit product, which contains the biologically active conjugate of the present invention, or the pharmaceutical composition, and optional drug instructions.
  • Another aspect of the present application provides the use of the biologically active conjugate in the preparation of a medicament for preventing or treating tumor diseases.
  • Another aspect of the present application provides the biologically active conjugate, which is used for preventing or treating tumor diseases.
  • Another aspect of the present application provides a method for preventing or treating tumor diseases, which includes administering an effective amount of the biologically active conjugate of the ZL, or a drug containing the biologically active conjugate to a subject in need thereof. pharmaceutical composition.
  • the tumor disease is a solid tumor or hematological malignancy; for example, selected from colon cancer, gastric cancer, breast cancer, lung cancer (for example, non-small cell lung cancer, specifically lung adenocarcinoma), lymphoma .
  • an effective amount refers to an amount of a conjugate which, when administered, alleviates to some extent one or more symptoms of the condition being treated.
  • treating means reversing, alleviating the applied disorder or condition, or the progression of one or more symptoms of such a disorder or condition.
  • an “individual” or “subject” as used herein includes a human or non-human animal.
  • exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • the mouse antibody 19F6 was obtained by immunizing Balb/c, C57Bl/6, NZB and A/J mice through hybridoma screening, and the humanized antibody sequence 19F6_Hu35v1 (heavy chain variable region, SEQ ID NO: 1; light chain variable region, SEQ ID NO: 2), the heavy chain constant region of the above humanized antibody is human IgG1 heavy chain constant region (SEQ ID NO: 18), the light chain constant region is human kappa Light chain constant region (SEQ ID NO: 19).
  • the nuclear magnetic resonance ( 1 H NMR) measuring instrument used a Bruker 400MHz nuclear magnetic resonance instrument; deuterated chloroform (CDCl 3 ); the internal standard substance was tetramethylsilane (TMS).
  • NMR nuclear magnetic resonance
  • the measuring instrument of mass spectrometry uses Agilent (ESI) mass spectrometer, model is Agilent 6120B.
  • Step 1 Synthesis of tert-butyl 2-(3,4-diazido-2,5-dioxy-2,5-dihydro-1H-pyrrol-1-yl)acetate (1-2)
  • Dissolve compound 1-1 (0.40g, 1.08mmol, synthetic method refer to patent WO2019057964) and sodium azide (141.00mg, 2.17mmol) in acetone (10mL), react at 25°C for 8h, and use high performance liquid chromatography mass spectrometry The reaction was monitored by chromatography. Water was added to the reaction liquid and extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 0.28 g of the crude product of the title compound, which was directly used in the next reaction without purification.
  • Step 2 Synthesis of tert-butyl 2-(3,4-diamino-2,5-dioxy-2,5-dihydro-1H-pyrrol-1-yl)acetate (1-3)
  • Dissolve compound 1-2 (0.15g, 0.51mmol) and 10% palladium carbon (15.00mg) in ethanol (20mL), replace with hydrogen three times, react at 25°C for 3h under hydrogen atmosphere, and monitor with HPLC-MS reaction.
  • the reaction solution was filtered with celite, and the filtrate was concentrated under reduced pressure to obtain 101.00 mg of the crude product of the title compound, which was directly used in the next reaction without purification.
  • Step 1 Synthesis of tert-butyl 2-(3,4-dimethyl-2,5-dioxy-2,5-dihydro-1H-pyrrol-1-yl)acetate (2-1)
  • Step 2 Synthesis of tert-butyl 2-(3,4-bis(bromomethyl)-2,5-dioxy-2,5-dihydro-1H-pyrrol-1-yl)acetate (2-2 )
  • compound 2-1 72.00mg, 0.30mmol
  • NBS 118.00mg, 0.66mmol
  • dibenzoyl peroxide 7.00mg, 0.03mmol
  • Example 3 4-((S)-2-((S)-2-(2-(3,4-bis(bromomethyl)-2,5-dioxo-2,5-dihydro-1H -pyrrol-1-yl)acetamido)-3-methylbutylamino)-5-ureidopentamido)benzyl ((S)-1-((3R,4S,5S)-1-( (S)-2-((1R,2R)-3-((1S),2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl -3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxohept-4-yl)(methyl)amino)-3-methyl-1 -oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate (drug-linker 3)
  • Step 1 4-((S)-2-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutylamino)-5- Ureadopentamido)benzyl ((S)-1-((S)-1-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-( (1S,2R)-1-Hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3 -Methoxy-5-methyl-1-oxohept-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl Synthesis of -1-oxobutan-2-yl)(methyl)carbamate (3-2)
  • Step 2 4-((S)-2-((S)-2-amino-3-methylbutylamino)-5-ureidopentanamido)benzyl ((S)-1-((S) )-1-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-((1S,2R)-1-hydroxy-1-phenylpropane-2- Base) amino)-1-methoxy-2-methyl-3-oxypropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxohept-4-yl) (Methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl(methyl)carbamate Synthesis (3-3)
  • Step 3 4-((S)-2-((S)-2-(2-(3,4-bis(bromomethyl)-2,5-dioxo-2,5-dihydro-1H -pyrrol-1-yl)acetamido)-3-methylbutylamino)-5-ureidopentamido)benzyl ((S)-1-((3R,4S,5S)-1-( (S)-2-((1R,2R)-3-((1S),2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl -3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxohept-4-yl)(methyl)amino)-3-methyl-1 Synthesis of -oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate (3)
  • Step 1 (9H-fluoren-9-yl)methyl((3R,4S,7S,10S,21S)-21-benzyl-4-((S)-sec-butyl)-3-(2-( (S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl -3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-7,10-diisopropyl-5,11-dimethyl-6,9,12,17,20,23 , Synthesis of 26-heptaoxo-2,14-dioxa-5,8,11,16,19,22,25-heptylpimelicamide-27-yl) carbamate (4-2)
  • Step 2 (S)-2-((2S,13S)-19-amino-13-benzyl-2-isopropyl-3-methyl-4,9,12,15,18-pentaoxo- 6-oxa-3,8,11,14,17-heptanezone)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3- (((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)- Synthesis of 3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (4-3)
  • Step 3 (S)-2-((2S,13S)-13-benzyl-22-(3,4-bis(bromomethyl)-2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)-2-isopropyl-3-methyl-4,9,12,15,18,21-hexaoxo-6-oxa-3,8,11,14,17 ,20-Hexaazadocosaneamido)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R) -1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropane)pyrrolidin-1-yl)-3-methoxy-5 Synthesis of -methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (4)
  • Step 1 (9H-fluoren-9-yl)methyl((3R,4S,7S,10S,21S)-21-benzyl-4-((S)-sec-butyl)-3-(2-( (S)-2–(((1R,2R)-3-(((1S,2R)-1-hydroxyl-1-phenylpropan-2-yl)amino)-1-methoxy-2-methanol Base-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-7,10-diisopropyl-5,11-dimethyl-6,9,12,17,20 ,23,26,29-Octaoxo-2,14,32,35,38,41-Hexaoxa-5,8,11,16,19,22,25,28-Octaazapentacosane Synthesis of -43-yl) carbamate (5-2)
  • Step 2 1-amino-N-(((3R,4S,7S,10S,21S)-21-benzyl-4-((S)-sec-butyl)-3-(2-((S)- 2-((1R,2R)-3-(((((S,2R)-1-hydroxy-1-phenylpropanyl-2-yl)amino)-1-methoxy-2-methyl-3 -Oxypropyl)pyrrolidin-1-yl)-2-oxyethyl)-7,10-diisopropyl-5,11-dimethyl-6,9,12,17,20,23,26 -Heptaoxo-2,14-dioxa-5,8,11,16,19,22,25-heptaazaheptacosan-27-yl)-3,6,9,12-tetraoxo Synthesis of Heteropentadecane-15-amide (5-3)
  • Step 3 N-(((3R,4S,7S,10S,21S)-21-benzyl-4-((S)-sec-butyl)-3-(2-((S)-2-(( 1R,2R)-3-((((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrole Alk-1-yl)-2-oxyethyl)-7,10-diisopropyl-5,11-dimethyl-6,9,12,17,20,23,26-heptaoxo-2 ,14-Dioxa-5,8,11,16,19,22,25-heptaazaheptacos-27-yl)-1-(2-(3,4-bis(bromomethyl) Synthesis of -2,5-dioxa-2-,5-dihydro-1H-pyrrol-1-yl)acetamido)-3
  • Example 8 4-((2S,5S)-41-(3,4-bis(bromomethyl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)- 5-isopropyl-2-methyl-4,7,11,40-tetraoxo-9,15,18,21,24,27,30,33,36-nonaoxa-3,6,12 ,39-tetraazapentadecanoyl)phenyl
  • Step 1 (S)-2-(32-Azido-5-oxo-3,9,12,15,18,21,24,27,30-nonaoxa-6-azatritetradecamide Synthesis of )-N-((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl)-3-methylbutylamine (8-3)
  • Step 2 4-((2S,5S)-38-azido-5-isopropyl-2-methyl-4,7,11-trioxo-9,15,18,21,24,27, Synthesis of 30,33,36-nonaoxa-3,6,12-triazatricoctadecanoylamido)benzyl(4-nitrophenyl)carbonate (8-4)
  • Step 3 4-((2S,5S)-38-azido-5-isopropyl-2-methyl-4,7,11-trioxo-9,15,18,21,24,27 ,30,33,36-Naoxa-3,6,12-Triazatricoctadecanoylamido)benzyl ((S)-1-(((S)-1-(((3R,4S ,5S)-1-((S)-2-((1R,2R)-3)-((1S,2R)-1-hydroxyl-1-phenylpropan-2-yl)amino)-1- Methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl) Amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl) carbonate )
  • Step 4 4-((2S,5S)-38-amino-5-isopropyl-2-methyl-4,7,11-trioxo-9,15,18,21,24,27,30 ,33,36-Naoxa-3,6,12-Triazatricoctadecanoylamido)benzyl ((S)-1-(((S)-1-(((3R,4S,5S )-1-((S)-2-((1R,2R)-3)-((1S,2R)-1-hydroxyl-1-phenylpropan-2-yl)amino)-1-methoxy Base-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino) Synthesis of -3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)
  • Step 5 4-((2S,5S)-41-(3,4-bis(bromomethyl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)- 5-isopropyl-2-methyl-4,7,11,40-tetraoxo-9,15,18,21,24,27,30,33,36-nonaoxa-3,6,12 ,39-tetraazapentadecanoyl)phenyl((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R ,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropane)pyrrolidine-1 -yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1
  • Step 2 2-(2-(2-(2-(3,4-diazido-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy ) Synthetic (9-3) of ethoxy) tert-butyl acetate
  • Step 4 2-(2-(2-(2-(2-(2,3-bis(bromomethyl)-5,7-dioxo-5,7-dihydro-6H-pyrrole[3,4-b ] pyrazin-6-yl) ethoxy) ethoxy) acetic acid synthesis (I-3)
  • Example 10 4-((2S,5S)-17-(2,3-bis(bromomethyl)-5,7-dioxo-5,7-dihydro-6H-pyrrole[3,4-b ]pyrazin-6-yl)-5-isopropyl-4,7-dioxo-2-(3-ureidopropyl)-9,12,15-trioxa-3,6-diaze Heptadecanamido)benzyl ((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)- 3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl )-3-methoxy-5-methyl-1-oxoheptane-4-yl)(methyl)amino)-3-methyl-1-o
  • Embodiment Eleven 3,5-bis(2-(methylsulfonyl)pyrimidin-4-yl)benzoic acid (II-19)
  • Example 12 4-((31S,34S)-1-(3,5-bis(2-(methylsulfonyl)pyrimidin-4-yl)phenyl)-31-isopropyl-1,29,32 -Trioxo-34-(3-ureidopropyl))-5,8,11,14,17,20,23,26-octaoxa-2,30,33-triazapentatetradecane -35-amido)benzyl ((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3 -(((1S,2R)-1-Hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl) -3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-
  • Step 1 4-((34S,37S)-34-isopropyl-2,2-dimethyl-4,32,35-trioxo-37-(3-ureidopropyl)-3,8 ,11,14,17,20,23,26,29-Naoxa-5,33,36-Triazaoctadecane-38-amido)benzyl ((S)-1-(((S )-1-((((3R,4S,5S)-1-((S)-)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-benzene Propan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxo Heptane-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-ox
  • Step 2 4-((29S,32S)-1-amino-29-isopropyl-27,30-dioxo-32-(3-ureidopropyl)-3,6,9,12,15 ,18,21,24-Octoxa-28,31-diazatritetradecane-33-amido)benzyl ((S)-1-(((S)-1-(((3R, 4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1- Methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxobutan-4-yl)(methyl)amino )-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)
  • Step 3 4-((31S,34S)-1-(3,5-bis(2-(methylsulfonyl)pyrimidin-4-yl)phenyl)-31-isopropyl-1,29,32- Trioxo-34-(3-ureidopropyl))-5,8,11,14,17,20,23,26-octaoxa-2,30,33-triazapentatetradecane- 35-amido)benzyl ((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3- (((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)- 3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan
  • Example 13 N-((S)-10-benzyl-1-((1S,9S)-9-ethyl-5-fluoro-9-hydroxyl-4-methyl-10,13-dioxy -1,2,3,9,10,12,13,15-Octahydrobenzo[de]pyrano[3',4':6,7]indoleazino[1,2-b]quino Lin-1-yl)amino)-1,6,9,12,15-pentaoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-yl)-1- (2-(2,3-bis(bromomethyl)-5,7-dioxo-5H-pyrrolo[3,4-b]pyrazin-6(7H)-yl)acetamide)-3, 6,9,12-tetraoxapentadecanamide (drug-linker 13)
  • Step 1 (9H-fluoro-9-yl)methyl((S)-10-benzyl-1-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl -10,13-Dioxo-1,2,3,9,10,12,13,15-Octahydrobenzo[de]pyrano[3',4':6,7]indoleazino [1,2-b]quinolin-1-yl)amino)-1,6,9,12,15-pentaoxo-3-oxa-5,8,11,14-tetraazahexadecane Synthesis of -16-yl)) carbamate (13-3)
  • Step 2 (S)-2-(2-aminoacetamido)acetamido)-N-(2-((2-(((1S,9S)-9-ethyl-5-fluoro-9- Hydroxy-4-methyl-10,13-dioxocode-1,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano[3',4':6, 7] Synthesis of indolazino[1,2-b]quinolin-1-yl)amino)-2-oxoethoxy)methyl)-2-oxo-3-phenylpropanamide (13- 4)
  • Step 3 (9H-fluoren-9-yl)methyl((S)-10-benzyl-1-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl -10,13-Dioxy-1,2,3,9,10,12,15-octahydrobenzo[de]pyrano[3',4':6,7]indoleazino[1 ,2-b]quinolin-1-yl)amino)-1,6,9,9,15,18-hexaoxo-3,21,24,27,30-pentaoxa-5,8,11 , Synthesis of 14,17-pentaazatricarboxylate (13-6)
  • Step 4 1-amino-N-((S)-10-benzyl-1-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13- Dioxo-1,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano[3',4':6,7]indoleazino[1,2- b] quinolin-1-yl)amino-1,6,9,12,15-pentaoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-yl)- Synthesis of 3,6,9,12-tetraoxa-15-decaneamide(13-7)
  • Step 5 N-((S)-10-benzyl-1-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxy- 1,2,3,9,10,12,13,15-Octahydrobenzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline -1-yl)amino)-1,6,9,12,15-pentoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-yl)-1-( 2-(2,3-bis(bromomethyl)-5,7-dioxo-5H-pyrrolo[3,4-b]pyrazin-6(7H)-yl)acetamide)-3,6 , Synthesis of 9,12-tetraoxapentadecanamide (13)
  • Step 1 1-(3,5-bis(2-(methylsulfonyl)pyrimidin-4-yl)phenyl)-1-oxo-5,8,11-trioxa-2-azatridecane Synthesis of tert-butyl alkane-13-oleate (15-2)
  • Step 1 (9H-fluoro-9-yl)methyl((S)-10-benzyl-1-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl -10,13-Dioxo-1,2,3,9,10,12,13,15-Octahydrobenzo[de]pyrano[3',4':6,7]indoleazino [1,2-b]quinolin-1-yl)amino)-1,6,9,12,15,18-hexaoxo-3,21,24,27,30,33,36,39,42 Synthesis of -nonoxa-5,8,11,14,17-pentaazatetradec-44-yl)carbamate (16-2)
  • the mesylate salt of compound 13-4 (132.00 mg, 148.84 ⁇ mol) was dissolved in DMF (5 mL), and HATU (90.55 mg, 238.14 ⁇ mol), compound 16-1 (148.19 mg, 223.26 ⁇ mol) and DIPEA (96.18 mg , 744.19 ⁇ mol, 132.48 ⁇ L), reacted at 25°C for 2 hours.
  • the reaction solvent was dried under reduced pressure, and the concentrate was directly prepared by high performance liquid phase, and freeze-dried to obtain the title compound 16-2 (110.00 mg).
  • Step 2 1-amino-N-((S)-10-benzyl-1-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13- Dioxo-1,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano[3',4':6,7]indoleazino[1,2- b] quinolin-1-yl)amino-1,6,9,12,15-pentaoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-yl)-3 , Synthesis of 6,9,12,15,18,21,2-octaoxapane-27-amide (16-3)
  • Step 3 N-((S)-10-benzyl-1-((1R,9R)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo- 1,2,3,9,10,12,13,15-Octahydrobenzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline -1-yl)amino)-1,6,9,12,15,18,46-heptaoxo-3,21,24,27,30,33,36,39,42,48,51,54- Dodecyloxa-5,8,11,14,17,45-hexaazahexapentan-56-yl)-3,5-bis(2-(methylsulfonyl)pyrimidin-4-yl)benzene Synthesis of Formamide(16)
  • anti-ROR1 antibody 19F6_Hu35V1, 3-20mg/mL, referred to as 19F6 in Table 1) dilute with 0.1M edetate disodium solution (pH 7.60), and then adjust with 1M Na 2 HPO 4 solution When the pH reached 7.60, 10 mM TCEP (tris(2-carboxyethyl)phosphine) solution (pH 7.60) was added to mix well, and left at room temperature for 2 h.
  • TCEP tris(2-carboxyethyl)phosphine
  • the molecular weight of ADC samples was determined by SEC-MS, and the drug/antibody ratio (DAR) was calculated.
  • Sample chamber temperature 8°C; column temperature: no column temperature control; UV: 280nm;
  • Mobile phase 20mM ammonium acetate, flow rate: 0.1ml/min, 20min, sample injection volume: 50ug;
  • Mass spectrometer model AB Sciex Triple TOF 5600+;
  • the SEC-MS molecular weight analysis of the coupled 19F6-ADC III-5-A is shown in Table 2, and the DAR is 3.87.
  • the SEC-MS molecular weight analysis of the coupled 19F6-ADC III-6-A is shown in Table 3, and the DAR is 4.42.
  • the SEC-MS molecular weight analysis of the coupled 19F6-ADC IV-1-A is shown in Table 4, and the DAR is 3.74.
  • the SEC-MS molecular weight analysis of the coupled 19F6-ADC IV-1-B is shown in Table 5, and the DAR is 3.75.
  • the SEC-MS molecular weight analysis of the coupled 19F6-ADC IV-1-C is shown in Table 6, and the DAR is 3.82.
  • the SEC-MS molecular weight analysis of the coupled 19F6-ADC IV-1-D is shown in Table 7, and the DAR is 3.87.
  • the SEC-MS molecular weight analysis of the coupled 19F6-ADC IV-7-A is shown in Table 8, and the DAR is 3.98.
  • Co-incubation of the compound of the present invention and tumor cells after the cells are attached to the wall, the culture medium in the cells is removed, and the diluted bioactive molecule (the compound of the present invention) is added to the wells of the above plate, and incubated for 96 hours.
  • ADC formed by the new conjugation method can kill tumor cells, and the application of the new conjugation method to ADC molecules is effective.

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