WO2022100696A1 - Multi-specific bioconjugate linker and synthetic method therefor - Google Patents

Multi-specific bioconjugate linker and synthetic method therefor Download PDF

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WO2022100696A1
WO2022100696A1 PCT/CN2021/130337 CN2021130337W WO2022100696A1 WO 2022100696 A1 WO2022100696 A1 WO 2022100696A1 CN 2021130337 W CN2021130337 W CN 2021130337W WO 2022100696 A1 WO2022100696 A1 WO 2022100696A1
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group
independently selected
compound
alkane
reactant
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PCT/CN2021/130337
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French (fr)
Chinese (zh)
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陈鹏
林锋
林坚
张衡
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北京大学
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Priority to CN202180065148.1A priority Critical patent/CN116390912A/en
Publication of WO2022100696A1 publication Critical patent/WO2022100696A1/en

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    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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Definitions

  • the present application relates to the field of biomedicine, in particular to a multispecific biological coupling linker and a synthesis method thereof.
  • Multispecific drug molecules are a hot spot in tumor therapy today. Compared with the traditional drug design that relies on the corresponding mode of one target and one drug, multispecific drugs can target multiple targets at the same time, so they can strike cancer cells more accurately and efficiently, and reduce the toxic and side effects caused by off-target effects.
  • bispecific antibodies and multispecific antibodies have shown good effects in tumor treatment, there are still many challenges in the development of multispecific antibody drugs.
  • One of the most important problems at present is the preparation of multispecific antibodies.
  • Most of the traditional multispecific antibody preparation platforms use the method of antibody fusion expression for production. This method has the problem of antibody mismatch, which makes the downstream purification process extremely difficult, so it is difficult to expand production.
  • the application provides a compound, which can be a multispecific bioconjugate linker (T-Linker) or a multispecific conjugate (T-Body).
  • the present application may have one or more of the following effects: (1)
  • the compound of the present application may be a multispecific compound, and the multispecific conjugate may exhibit good antitumor activity, and the IC 50 value may be lower than 10 (2)
  • the reaction can realize fixed-point, quantitative and modular connection, and finally a multi-specific conjugate with a clear structure, uniformity and controllable quality can be obtained.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof , which has the structure shown in formula Ia or formula Ib:
  • Wa is a trivalent group, and Wb is a tetravalent group
  • Said A, B and C are each independently selected from the following group:
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl, represents the attachment site;
  • R 12 , R 13 and R 14 are not alkynyl
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl, represents the attachment site;
  • R 12 , R 13 and R 14 are not alkynyl
  • R 12 , R 13 and R 14 are not amino groups.
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl, represents the attachment site;
  • R 12 , R 13 and R 14 are not amino groups.
  • R is selected from the group consisting of hydrogen, protium , deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido, urea, alkane, cycloalkane radicals, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl, represents the attachment site;
  • R is selected from the group consisting of hydrogen, protium , deuterium, tritium, halogen and alkane, represents the attachment site.
  • the compound, wherein: A is B is C is
  • the W is a trivalent group or a tetravalent group, the W is optionally substituted with one or more Rs,
  • the J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
  • R, R 1 , R 1a and R 1b are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl, represents the attachment site;
  • m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 are each independently selected from a number of 0 or more.
  • the compound wherein J 1 , J 2 , and J 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing;
  • n1, m2, and m3 are each independently selected from the group: 0, 1, 2, and 3.
  • the compound wherein X1, X2, and X3 are each independently selected from the group consisting of -NH- and -O-.
  • K 1 , K 2 , and K 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing;
  • n1, n2, and n3 are each independently selected from the group: 0, 1, 2, and 3.
  • the compound wherein (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -alkyi-polyethylene glycol-chain Alkyl-, alkane and polyethylene glycol, or n1, n2 or n3 are each independently zero.
  • the compound, wherein (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -(CH 2 )-(CH 2 -O -CH 2 ) 3 -(CH 2 )-, -(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -, -(CH 2 ) 2 -, and -(CH 2 ) 8 -, or n1, n2 or n3 are each independently 0.
  • R 1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane
  • n1, n2, and n3 are each independently selected from the group: 0, 1, 2, and 3.
  • the compound wherein L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, and aryl, or any combination of the foregoing; wherein q1 , q2 , and q3 is each independently selected from the group consisting of 0, 1, 2, and 3.
  • the compound wherein (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of - alkane-aryl-, alkane radical and polyethylene glycol, or q1, q2 and q3 are each independently zero.
  • the compound wherein (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of: -CH 2 -aryl-, -(CH 2 ) 2- , and -CH2- , or q1, q2 and q3 are each independently 0.
  • W is selected from the following group:
  • Trivalent alkane trivalent cycloalkyl, trivalent heterocycloalkyl, trivalent alkenyl, trivalent alkynyl, trivalent aryl, and trivalent heteroaryl.
  • W is selected from the following group:
  • the X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 and X 18 are each independently selected from the group consisting of C, N, O, S, P, CH, CH 2 , NH, P(O) and P(S);
  • W is selected from the following group:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the Wc is a trivalent group, and Wd is a tetravalent group
  • Said A 2 , B 2 and C 2 are each independently selected from the following group:
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
  • the two linking sites of the A2 are arbitrarily linked to Wc and P1, the two linking sites of the B2 are arbitrarily linked to Wc and P2, the two linking sites of the C2 are arbitrarily linked Connect with Wc and P3 ;
  • P 1 , P 2 and P 3 are each independently selected from the group consisting of lipids, proteins, nucleic acids, small molecules and polysaccharides, or any combination thereof.
  • a 2 is B2 is C2 is or covalent bond;
  • a 2 is B2 is C2 is or covalent bond
  • a 2 is Or a covalent bond
  • B 2 is a covalent bond
  • C 2 is a covalent bond
  • a 2 is B2 is C2 is or covalent bond; or
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
  • the two linking sites of the A2 are arbitrarily linked to Wc and P1
  • the two linking sites of the B2 are arbitrarily linked to Wc and P2
  • the two linking sites of the C2 are arbitrarily linked Connect with Wc and P3 .
  • a 2 is B2 is C2 is or covalent bond;
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
  • the attachment site Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
  • a 2 is B2 is C2 is or covalent bond;
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
  • the attachment site Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
  • a 2 is B2 is C2 is or covalent bond;
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
  • the attachment site Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
  • a 2 is B2 is C2 is or a covalent bond
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane, Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
  • a 2 is B2 is, C2 is or a covalent bond
  • R 12 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane, Represents the attachment sites, the two attachment sites of the A2 are arbitrarily attached to Wc and P1, the two attachment sites of the B2 are arbitrarily attached to Wc and P2, the two attachment sites of the C2 The attachment site is arbitrarily attached to Wc and P3 .
  • the W is a trivalent group or a tetravalent group, the W is optionally substituted with one or more Rs,
  • the J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
  • R, R 1 , R 1a and R 1b are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl, represents the attachment site;
  • m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 are each independently selected from a number of 0 or more.
  • the compound wherein J 1 , J 2 , and J 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing;
  • n1, m2, and m3 are each independently selected from the group: 0, 1, 2, and 3.
  • the compound wherein X1, X2, and X3 are each independently selected from the group consisting of -NH- and -O-.
  • the compound wherein K 1 , K 2 , and K 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein n1, n2 , and n3 are each independently selected from the group consisting of 0, 1, 2, and 3.
  • the compound wherein (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -alkyi-polyethylene glycol-chain Alkyl-, alkane and polyethylene glycol, or n1, n2 or n3 are each independently zero.
  • the compound, wherein (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -(CH 2 )-(CH 2 -O -CH 2 ) 3 -(CH 2 )-, -(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -, -(CH 2 ) 2 -, and -(CH 2 ) 8 -, or n1, n2 or n3 are each independently 0.
  • R 1 is selected from the following group: hydrogen, protium, deuterium, tritium, and alkane; wherein n1, n2, and n3 are each independently selected from the following group: 0, 1, 2 and 3.
  • the compound wherein L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, and aryl, or any combination of the foregoing; wherein q1 , q2 , and q3 is each independently selected from the group consisting of 0, 1, 2, and 3.
  • the compound wherein (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of - alkane-aryl-, alkane radical and polyethylene glycol, or q1, q2 and q3 are each independently zero.
  • the compound wherein (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of: -CH 2 -aryl-, -(CH 2 ) 2- , and -CH2- , or q1, q2 and q3 are each independently 0.
  • W is selected from the following group:
  • Trivalent alkane trivalent cycloalkyl, trivalent heterocycloalkyl, trivalent alkenyl, trivalent alkynyl, trivalent aryl, and trivalent heteroaryl.
  • W is selected from the following group:
  • the X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 and X 18 are each independently selected from the group consisting of C, N, O, S, P, CH, CH 2 , NH, P(O) and P(S);
  • the --- represents a double bond or a single bond.
  • W is selected from the following group:
  • the compound wherein P1, P2 and P3 are each independently selected from the group consisting of nucleic acid molecules, dye molecules, cytokines, antigens, and antibodies or antigen-binding fragments thereof, or any of the foregoing combination.
  • the compound wherein the antibody is selected from the group consisting of monoclonal antibodies, single chain antibodies, chimeric antibodies, humanized antibodies, fully human antibodies, and nanobodies.
  • the compound, wherein the antibody targets a target selected from the group consisting of 4-1BB, EGFR, CD3, Her2, CD47 and CD20.
  • the compound wherein the amino acid sequence of the antibody is selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 10, SEQ ID NO: : 11, and SEQ ID NO: 12.
  • the compound is selected from the group consisting of:
  • P1, P2 and P3 are each independently selected from antibodies targeting a target selected from the group consisting of 4-1BB, EGFR, CD3, Her2, CD47 and CD20.
  • amino acid sequences of P 1 , P 2 and P 3 can be respectively:
  • SEQ ID NO: 1 SEQ ID NO: 2, and SEQ ID NO: 3, or
  • SEQ ID NO: 1 SEQ ID NO: 10
  • SEQ ID NO: 3 SEQ ID NO: 3
  • SEQ ID NO: 1 SEQ ID NO: 11, and SEQ ID NO: 3, or
  • SEQ ID NO: 1 SEQ ID NO: 12, and SEQ ID NO: 3, or
  • SEQ ID NO: 12 SEQ ID NO: 2, and SEQ ID NO: 3, or
  • SEQ ID NO: 1 SEQ ID NO: 2, and SEQ ID NO: 10, or
  • SEQ ID NO: 1 SEQ ID NO: 2, and SEQ ID NO: 11, or
  • SEQ ID NO: 1 SEQ ID NO: 2, and SEQ ID NO: 12, or
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, which can have the structure shown in formula Ia or formula Ib:
  • R is selected from the group consisting of hydrogen, protium , deuterium, tritium, halogen and alkane, represents the attachment site;
  • J 1 , J 2 , and J 3 are each independently selected from the following group: alkane, and polyethylene glycol, or any combination of the foregoing; m1, m2, and m3 are each independently selected from the following group: 0, 1, 2 and 3;
  • X 1 , X 2 , and X 3 are each independently selected from the group consisting of: -NH- and -O-;
  • (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -alkyi-polyethylene glycol-alkyi-, alkane, and polyethylene glycol, or n1, n2 or n3 are each independently 0;
  • R 1 is selected from The following group: hydrogen, protium, deuterium, tritium, and alkane;
  • n1, n2, and n3 are each independently selected from the following group: 0, 1, 2, and 3;
  • (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of - alkane-aryl-, alkane and polyethylene glycol, or q1 , q2 and q3 each independently is 0;
  • W is selected from the following group:
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, which can have the structure shown in formula Ia or formula Ib:
  • A is B is C is A group wherein R is selected from the group consisting of hydrogen, protium , deuterium, tritium, halogen and alkane, represents the attachment site;
  • J 1 , J 2 , and J 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing, and m 1 , m 2 , and m 3 are each independently selected from the group 0, 1, 2 and 3;
  • X 1 , X 2 , and X 3 are each independently selected from the group consisting of: -NH- and -O-;
  • (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -(CH 2 )-(CH 2 -O-CH 2 ) 3 -(CH 2 )-,- (CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -, -(CH 2 ) 2 -, and -(CH 2 ) 8 -, or n1, n2 or n3 each independently is 0;
  • (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of -CH 2 -aryl-, -(CH 2 ) 2 -, and -CH 2 -, or q1 , q2 and q3 are independently 0;
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, which can have the structure shown in formula IIa or formula IIb:
  • A2 is B2 is C2 is or a covalent bond; wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane, Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is optionally attached to Wc and P3 ;
  • J 1 , J 2 , and J 3 are each independently selected from the following group: alkane, and polyethylene glycol, or any combination of the foregoing; m1, m2, and m3 are each independently selected from the following group: 0, 1, 2 and 3;
  • X 1 , X 2 , and X 3 are each independently selected from the group consisting of: -NH- and -O-;
  • (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -alkyi-polyethylene glycol-alkyi-, alkane, and polyethylene glycol, or n1, n2 or n3 are each independently 0;
  • R 1 is selected from The following group: hydrogen, protium, deuterium, tritium, and alkane;
  • n1, n2, and n3 are each independently selected from the following group: 0, 1, 2, and 3;
  • (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of - alkane-aryl-, alkane and polyethylene glycol, or q1 , q2 and q3 each independently is 0;
  • W is selected from the following group:
  • P1, P2, and P3 are each independently selected from the group consisting of nucleic acid molecules, dye molecules, cytokines, antigens, and antibodies or antigen-binding fragments thereof, or any combination of the foregoing.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, which can have the structure shown in formula IIa or formula IIb:
  • A2 is B2 is, C2 is or a covalent bond; wherein R 12 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane, Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is optionally attached to Wc and P3 ;
  • J 1 , J 2 , and J 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing, and m 1 , m 2 , and m 3 are each independently selected from the group 0, 1, 2 and 3;
  • X 1 , X 2 , and X 3 are each independently selected from the group consisting of: -NH- and -O-;
  • (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -(CH 2 )-(CH 2 -O-CH 2 ) 3 -(CH 2 )-,- (CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -, -(CH 2 ) 2 -, and -(CH 2 ) 8 -, or n1, n2 or n3 each independently is 0;
  • (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of -CH 2 -aryl-, -(CH 2 ) 2 -, and -CH 2 -, or q1 , q2 and q3 are independently 0;
  • P 1 , P 2 and P 3 are each independently selected from the group consisting of: an antibody targeting 4-1BB, an antibody targeting EGFR, an antibody targeting CD3, an antibody targeting Her2, an antibody targeting CD47, an antibody targeting Antibodies to CD20, branched peptides containing CMV, neo2 protein, IFN ⁇ protein, fluorescein isothiocyanate (FITC), and CPG nucleic acids.
  • the present application provides a method for preparing the compound described in the present application, comprising:
  • the reactant 1 is HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -A,
  • the reactant 2 is HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -B,
  • the reactant 3 is HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -C,
  • the W is a trivalent group, the W is optionally substituted with one or more R,
  • the J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
  • R, R 1 , R 1a and R 1b are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl;
  • m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 are each independently selected from a number greater than 0;
  • A, B and C are each independently selected from the following group:
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl;
  • R 12 , R 13 and R 14 are not alkynyl
  • the order of addition of reactant 1, reactant 2 and reactant 3 is determined according to the introduction order of A, B and C, and the introduction order of A, B and C is from first to first followed by:
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl.
  • the present application provides a method for preparing the compound described in the present application, comprising:
  • the reactant 4 is A 1 -P 1 ,
  • the reactant 5 is B 1 -P 2 ,
  • the reactant 6 is C 1 -P 3 ,
  • a 1 of reactant 4 reacts with A of the compound described in formula Ia
  • B 1 of reactant 5 reacts with B of the compound described in formula Ia
  • C 1 of reactant 6 reacts with the compound described in formula Ia C reaction
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl.
  • kits comprising a compound described herein or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof, or A pharmaceutically acceptable salt thereof, and/or the pharmaceutical composition described herein.
  • the tumor is selected from the group consisting of tumors associated with expression of 4-1BB, EGFR, CD3, Her2, CD47 and CD20.
  • the tumor is selected from the group consisting of solid tumors and hematological cancers.
  • the tumor is selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer cancer, melanoma, liver, bladder, stomach and esophagus.
  • a method of treating and/or preventing tumors comprising administering to a subject in need thereof a compound described in this application or a tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition described herein and/or the kit described herein.
  • the tumor may be associated with the following group expression: 4-1BB, EGFR, CD3, Her2, CD47 and CD20.
  • the tumors are selected from the group consisting of solid tumors and hematological cancers.
  • the tumors may be selected from the group consisting of: lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer , pancreatic, breast, melanoma, liver, bladder, stomach and esophageal cancers.
  • Figure 1 shows the hydrogen NMR spectrum of a multispecific biologically coupled linker 1 (Scaffold1) described in the present application.
  • FIG. 2 shows the mass spectrum of a multi-specific bioconjugation linker 1 (Scaffold1) described in this application
  • FIG. 3 shows the hydrogen NMR spectrum of a multispecific biologically coupled linker 2 (Scaffold2) described in the present application
  • Figure 4 shows the mass spectrogram of a multispecific bioconjugation linker 2 (Scaffold2) described in the present application
  • Figure 5 shows the N3-NHS-NHS nuclear magnetic spectrum of the intermediate N3-NHS-NHS of the synthetic multispecific bioconjugate linker 1 (Scaffold1) or linker 2 (Scaffold2) described in the present application.
  • Figure 6 shows the SDS-PAGE chart of a multispecific conjugate EGFR-CD3-FITC described in the present application.
  • Figure 7 shows the mass spectrum of a multispecific conjugate EGFR-CD3-FITC described in the present application.
  • Figure 8 shows the SDS-PAGE chart of a multispecific conjugate EGFR-CD3-CPG described in the present application.
  • Figure 9 shows the mass spectrum of a multispecific conjugate EGFR-CD3-CPG described in the present application.
  • Figure 10 shows the SDS-PAGE chart of a multispecific conjugate EGFR-CD3-CMV described in the present application.
  • Figure 11 shows the mass spectrum of a multispecific conjugate EGFR-CD3-CMV described in the present application.
  • Figure 12 shows the SDS-PAGE image of a multispecific conjugate EGFR-CD3-neo2 described in the present application.
  • Figure 13 shows the mass spectrum of a multispecific conjugate EGFR-CD3-neo2 described in the present application.
  • Figure 14 shows the SDS-PAGE chart of a multispecific conjugate EGFR-CD3-IFN ⁇ described in the present application.
  • Figure 15 shows the mass spectrum of a multispecific conjugate EGFR-CD3-IFN ⁇ described in the present application.
  • Figure 16 shows an SDS-PAGE image of a multispecific conjugate, EGFR-CD3-4-1BB, described in the present application.
  • Figure 17 shows the mass spectrum of a multispecific conjugate EGFR-CD3-4-1BB described in the present application.
  • Figure 18 shows the tumor cell growth inhibition results of a multispecific conjugate EGFR-CD3-4-1BB described in the present application.
  • Figure 19 shows the reaction scheme of a multispecific conjugate EGFR-CD3-CMV described in this application.
  • Figure 20 shows the reaction scheme of a multispecific conjugate EGFR-CD3-4-1BB described in this application.
  • Figure 21 shows the reaction routes of EGFR-TZ-4-1BB and EGFR-CD3-Gly in the control group described in the present application.
  • Figure 22 shows the hydrogen NMR spectrum of the multispecific bioconjugated linker 3 (Scaffold3).
  • Figure 23 shows the mass spectrogram of the multispecific bioconjugate tether 3 (Scaffold3).
  • Figure 24 shows the hydrogen NMR spectrum of the multispecific bioconjugated linker 4 (Scaffold4).
  • Figure 25 shows the mass spectrogram of multispecific bioconjugated tether 4 (Scaffold4).
  • Figure 26 shows the N3-NHS-NHS* mass spectrum of intermediates for the synthesis of multispecific bioconjugates tether 3 (Scaffold3) or tether 4 (Scaffold4).
  • Figure 27 shows SDS-PAGE characterization of EGFR-CD3-LCFA.
  • Figure 28 shows mass spectrometry characterization of EGFR-CD3-LCFA.
  • Figure 29 shows the SDS-PAGE characterization of EGFR-CD3-ASO.
  • Figure 30 shows the mass spectrometry characterization of EGFR-CD3-ASO.
  • Figure 31 shows the reaction scheme for the preparation of EGFR-CD3-M1.
  • Figure 32 shows the SDS-PAGE characterization of EGFR-CD3-M1.
  • Figure 33 shows the mass spectrometry characterization of EGFR-CD3-M1.
  • Figure 34 shows the reaction scheme for the preparation of EGFR-CD3-PDL1.
  • Figure 35 shows the SDS-PAGE characterization of EGFR-CD3-PDL1.
  • Figure 36 shows mass spectrometry characterization of EGFR-CD3-PDL1.
  • Figure 37 shows the reaction scheme for the preparation of HER2-CD3-PDL1.
  • Figure 38 shows mass spectrometry characterization of HER2-CD3-PDL1.
  • Figures 39A-39B show the results of binding of EGFR-CD3-PDL1 to EGFR, CD3, and PDL1 target proteins.
  • polypeptide In this application, the terms “protein” or “polypeptide” are used interchangeably and generally refer to a chain of at least two (2) or more amino acids linked together by peptide or amide bonds, independent of post-translational modifications (eg, glycosylation, acylation, phosphorylation, etc.). Antibodies are specifically intended to be included within the scope of this definition.
  • the polypeptides of the present invention may comprise more than one subunit, wherein each subunit is encoded by a separate DNA sequence.
  • a protein may also comprise more than one polypeptide unit, including dimers, trimers, tetramers, or various higher order structures.
  • the terms “equivalent” or “percent equivalent” are used interchangeably and generally refer to the number of moles of "X" relative to the number of moles of "Y". For example, 5 molar equivalents of X relative to Y means that if 1 mole of Y is used, 5 moles of X can be used.
  • X group selection "corresponds" to Y group generally means that when X group chooses a certain group, correspondingly, Y group chooses another specific group.
  • the choice of A1 of reactant 4 corresponding to A of the compound described in formula Ia can be when A is , correspondingly, A1 can choose Corresponding.
  • order of introduction generally refers to the order in which a plurality of different specified groups are introduced into a starting compound.
  • the order in which the starting compounds are introduced may refer to the of reactant 1, then added with of reactant 2, finally added with of reactant 3, introduced first reintroduction last import For example, introduce before the replace with Additional acid was added for Boc removal.
  • group X can be attached to groups Y and Z in "either orientation" and generally means that when a group X is used to link a group Y and a group Z, the group X Two or more attachment sites of can optionally be attached to the group Y or the group Z.
  • the group The attachment to the group W and the group P can be in either orientation and can be a group The C atom connecting the group W, the N atom connecting the group P, can also be the group The N atom connects the group W, and the C atom connects the group P.
  • enantiomer generally refers to two stereoisomers of a compound, which may be non-superimposable mirror images of each other.
  • polysaccharide generally refers to molecules composed of chains of monosaccharide units linked by glycosidic bonds.
  • polysaccharide may include molecules composed of two or more monosaccharide units, eg, including molecules in which the longest monosaccharide chain is 3 to 9 monosaccharide units.
  • polysaccharide can include linear and branched molecules, isolated and polypeptide-bound molecules, sialylated and non-sialylated molecules.
  • diastereomer generally refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers can have different physical properties, eg, melting points, boiling points, spectral properties, and reactivities.
  • tautomer or “tautomeric form” are used interchangeably and generally refer to structural isomers of different energies that can be interconverted through a low energy barrier.
  • protontautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some of the bonding electrons.
  • racemate or “racemic mixture” refers to a composition consisting of two enantiomeric species in equimolar amounts.
  • lipid generally refers to linear, branched, saturated or unsaturated aliphatic carboxylic acids, phospholipids or sterols.
  • aliphatic carboxylic acids are lauric acid, palmitic acid, stearic acid, oleic acid, and ( CH3 ( CH2 ) n ) 2CHCOOH , where n is a number of at least 1.
  • the phospholipid may be a phosphatidylethanolamine, such as dioleoylphosphatidylethanolamine.
  • nucleic acid generally refer to polymers of nucleotides (eg, ribonucleotides or deoxyribonucleotides), and include naturally occurring (adenine, guanine, cytosine, uracil and thymine), non-naturally occurring and modified nucleic acids.
  • the term is not limited by the length of the polymer (eg, the number of monomers).
  • Nucleic acids can be single-stranded or double-stranded, and generally contain 5'-3' phosphodiester linkages, although in some cases nucleotide analogs may have other linkages. Monomers are often called nucleotides.
  • unnatural nucleotide or “modified nucleotide” refers to a nucleotide that contains a modified nitrogenous base, sugar or phosphate group, or that incorporates a non-natural moiety into its structure .
  • non-natural nucleotides include dideoxynucleotides, biotinylated, aminated, deaminated, alkylated, benzylated, and fluorescently labeled nucleotides.
  • the term "compound” generally refers to a substance having two or more different elements.
  • the compound of the present application may be an organic compound.
  • the compound of the present application may be a compound with a molecular weight of 500 or less, a compound with a molecular weight of 1,000 or less, or a compound with a molecular weight of 1,000 or more, or a compound of 10,000 or more and 100,000 or more. compound.
  • a compound can also refer to a compound connected by chemical bonds, for example, it can be a compound in which one or more molecules with a molecular weight of less than 1000 are connected with a biological macromolecule by chemical bonds, and the biological macromolecule can be a polysaccharide, protein , nucleic acids, peptides, etc.
  • the compounds of the present application can include compounds in which proteins are linked to one or more molecules with a molecular weight of less than 1000, can include compounds in which proteins are linked to one or more molecules with a molecular weight of less than 10,000, and can include proteins and one or more molecular weights.
  • mixture generally refers to a blend of two or more separate compounds.
  • antibody or “antibody or antigen-binding fragment thereof” generally refers to immunological binding reagents extending to all antibodies from all species, including dimeric, trimeric and multimeric antibodies, Bispecific antibodies, chimeric antibodies, fully human antibodies, humanized antibodies, recombinant and engineered antibodies, nanobodies and fragments thereof.
  • antibody or fragment thereof may refer to any antibody-like molecule having an antigen-binding region, and the term includes fragments of antigen-binding active substances such as Fab', Fab, F(ab') 2 , single domain antibodies (DABs), Fv, scFv (single chain Fv), linear antibodies, diabodies, nanobodies, etc.
  • antigen-binding fragment can refer to one or more fragments of an antibody that retain the ability to specifically bind an antigen.
  • fragments of full-length antibodies can be used for the antigen-binding function of antibodies.
  • Techniques for making and using various antibody-based constructs and fragments are well known in the art. In one embodiment, it may refer to one or more of an anti-EGFR antibody, an anti-CD3 antibody, and an anti-41-BB antibody.
  • the term "Nanobody” generally refers to those antibodies as defined in WO 2008/020079 or WO 2009/138519, and thus in particular aspects generally refers to VHHs, humanized VHHs or camelized VHs (eg camelids) Human VHs) or generally sequence-optimized VHHs (eg, optimized for chemical stability and/or solubility, maximal overlap with known human framework regions and maximal expression).
  • L is selected from the group consisting of alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing, in one implementation
  • L 1 can be an alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or polyethylene glycol group
  • L 1 can be a combination of alkane and aryl or a combination of alkane and polyethylene glycol, and in one embodiment can refer to -alkyi-aryl- or -alkyi-polyethylene glycol Alcohol-alkyi-.
  • trivalent group or “trivalent group” generally refers to a group having 3 bonding positions in the group.
  • trivalent groups include, but are not limited to, trivalent alkane groups, trivalent cycloalkyl groups, trivalent heterocycloalkyl groups, trivalent alkenyl groups, trivalent alkynyl groups, trivalent aryl groups, and trivalent heteroaryl groups.
  • trivalent groups include, but is not limited to, trivalent alkane groups, trivalent cycloalkyl groups, trivalent heterocycloalkyl groups, trivalent alkenyl groups, trivalent alkynyl groups, trivalent aryl groups, and trivalent heteroaryl groups.
  • in one embodiment may include, but is not limited to
  • tetravalent group generally refers to a group having 4 bonding positions in the group.
  • polyethylene glycol generally refers to an ethylene oxide derived polymer group in branched or linear form represented by the general formula -( OCH2CH2 ) n- , where n is an integer of 3, 4, 5, 6, 7, 8, 9 or greater.
  • Polyethylene glycol chains include polymers of ethylene glycol having an average total molecular weight selected from the range of about 500 to about 40,000 Daltons. The average molecular weight of PEG chains is indicated numerically, eg, PEG-5,000 refers to polyethylene glycol chains having an average total molecular weight of about 5,000.
  • Polyethylene glycols can be substituted or unsubstituted.
  • halogen is generally meant to include fluorine, chlorine, bromine and iodine.
  • urea generally refers to -(HN-CO-) 2N- .
  • alkyi generally refers to a residue derived from an alkane group by removal of a hydrogen atom. Alkyl groups can be substituted or unsubstituted, substituted or unsubstituted.
  • alkyi generally refers to a saturated straight or branched aliphatic hydrocarbon group having a residue derived from the removal of a hydrogen atom from the same carbon atom or two different carbon atoms of the parent alkane, which may contain 1 Straight or branched chain groups of up to 20 carbon atoms, eg, alkane groups containing 1 to 12 carbon atoms, eg, 1 to 6 carbon atoms.
  • alkane groups include, but are not limited to, methyl, ethyl, propyl, propyl, butyl, and the like.
  • Alkyl groups may be substituted or unsubstituted, substituted or unsubstituted, for example when substituted, substituents may be substituted at any available point of attachment, which may be independently optionally selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy substituted by one or more substituents in the group, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo, such as hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH
  • cycloalkyl generally refers to residues having a hydrogen atom removed from the same carbon atom or multiple different carbon atoms of a carbocyclic ring.
  • cycloalkane generally refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, the carbocyclic ring containing 3 to 20 carbon atoms, may contain 3 to 12 carbon atoms, may contain 3 to 10 carbon atoms, may Contains 3 to 8 carbon atoms.
  • Non-limiting examples of monocyclic carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, cyclooctane etc.; polycyclic carbocycles may include spiro, fused and bridged carbocycles. Cycloalkyl groups can be substituted or unsubstituted.
  • heterocycloalkyl generally refers to stable non-aromatic 3- to 7-membered monocyclic structures, fused 7- to 10-membered bicyclic heterocyclic structures or bridged 6- to 10-membered monocyclic structures.
  • Member bicyclic heterocyclic structures which may be either saturated or partially saturated, and which, in addition to carbon atoms, contain one or more heteroatoms, wherein the heteroatoms may be selected from the following groups : oxygen, sulfur and nitrogen. For example, it contains 1-4 heteroatoms as defined above.
  • nitrogen may include nitrogen that has undergone a substitution reaction.
  • Heterocycloalkyl can be substituted or unsubstituted.
  • alkenyl generally refers to a straight or branched chain hydrocarbon group containing one or more double bonds.
  • alkenyl groups include allyl, homoallyl, vinyl, crotyl, butenyl, pentenyl, and hexenyl.
  • C2-6 alkenyl groups having more than one double bond include butadienyl, pentadienyl, hexadienyl, and hexatrienyl and branched forms thereof.
  • the position of the unsaturated bond (double bond) can be anywhere in the carbon chain.
  • Alkenyl groups can be substituted or unsubstituted.
  • alkynyl generally refers to unsaturated straight or branched chain alkynyl groups such as ethynyl, 1-propynyl, propargyl, butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.
  • aryl generally refers to a residue having a hydrogen atom removed from the same carbon atom or multiple different carbon atoms of an aromatic ring.
  • aromatic ring may refer to a 6- to 14-membered all-carbon monocyclic or fused polycyclic ring (ie, rings that share adjacent pairs of carbon atoms) having a conjugated pi-electron system, and may be 6 to 10 membered, such as benzene and Naphthalene.
  • the aromatic ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring.
  • Aryl may be substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio.
  • heteroaryl generally refers to residues having a hydrogen atom removed from the same carbon atom or multiple different carbon atoms of a heteroaromatic ring.
  • heteroaromatic ring refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms may be selected from the group consisting of oxygen, sulfur and nitrogen.
  • Heteroaryl can be 5 to 10 membered, 5 membered or 6 membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazole Base et al.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents can be one or more of the following groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy group, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio and heterocycloalkylthio.
  • alkoxy generally refers to an alkyl group to which is attached an oxygen group.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, t-butoxy, and the like.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the specification may include both instances where the heterocyclic group is substituted with an alkyl group and where the heterocyclic group is not substituted with an alkyl group. situation.
  • substituted generally means that one or more hydrogen atoms in a group, eg up to 5, eg 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents.
  • Substituents are only in their possible chemical positions, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • structures described herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms.
  • the hydrogen atom is replaced by deuterium or tritium, or the carbon atom is replaced by carbon 13 or 1 carbon 14, the compounds whose structure is consistent with the present application are all within the scope of the present application.
  • the term "small molecule” generally refers to any chemical moiety or other moiety having a molecular weight below about 5000 Daltons (Da). In some embodiments, the molecular weight of the small molecule is less than about 2500 Daltons, about 1000 Daltons, or about 500 Daltons. In some embodiments, the small molecule may not be a polymer. In some embodiments, the small molecule may not be a protein. In some embodiments, the small molecule may not be a nucleic acid. In some embodiments, the small molecule may not be a polysaccharide. In some embodiments, small molecules can be biologically active and/or function to affect biological processes. In some embodiments, the small molecule may be a natural product or first prepared by chemical synthesis. For example, in one embodiment the small molecule can be a therapeutic drug, chemical toxin, or detection substance, such as the dye molecule FITC.
  • the term "antigen" generally refers to the peptides, polypeptides and proteins encoded by the genetic constructs of the present invention against which an immune response is induced.
  • the target protein can be an immunogenic protein against which immunity needs to be induced, it can have at least one epitope in common with a protein from a pathogen or an undesired cell type, such as a cancer cell or involved in autoimmune cells.
  • An immune response directed against the target protein can protect the individual against a particular infection or disease associated with the target protein, or can treat the individual for such infection or disease.
  • cytokine generally includes, for example, interleukins, interferons, chemokines, hematopoietic growth factors, tumor necrosis factors and transforming growth factors. Generally, they can be low molecular weight proteins that can regulate the maturation, activation, proliferation and differentiation of cells of the immune system.
  • the term "dye molecule” generally refers to a substance that dyes a target substance.
  • the "dye molecule” may comprise a fluorescent label, but may also include a near-infrared fluorescent label. Fluorescent labeling is achieved using chemically reactive derivatives of fluorophores. Common reactive groups can include amine-reactive isothiocyanate derivatives such as FITC and TRITC (derivatives of fluorescein and rhodamine), amine-reactive succinimidyl esters such as NHS-fluorescein, and sulfhydryl A base-reactive maleimide-activated fluor such as fluorescein-5-maleimide.
  • any of these reactive dyes can react with another molecule to create a stable covalent bond between the fluorophore and the labeled molecule.
  • suitable fluorescent labels encompassed by this application are Alexa Fluor, DylightFluor and ATTO dyes.
  • fluorescent proteins such as GFP, YFP or CFP are encompassed by this application.
  • activatable dye molecules that are activated by pH changes or voltage, temperature are contemplated by this application.
  • pharmaceutically acceptable salts generally refer to salts of the compounds of the present application that are safe for use in mammals Properties and/or effectiveness, and may have due biological activity, the compounds of the present application may form salts with acids
  • pharmaceutically acceptable salts include: hydrochloride, hydrobromide, hydroiodic acid Salt, Sulfate, Bisulfate, Citrate, Acetate, Succinate, Ascorbate, Oxalate, Nitrate, Pearate, Hydrogen Phosphate, Dihydrogen Phosphate, Salicylate, Lemon Hydrogenate, tartrate, maleate, fumarate, formate, benzoate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate.
  • the term "pharmaceutically acceptable carrier” generally refers to any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier may be suitable for parenteral (eg, intravenous, intramuscular, subcutaneous, intrathecal) administration (eg, by injection or infusion).
  • parenteral eg, intravenous, intramuscular, subcutaneous, intrathecal
  • the active compound can be coated in materials to protect the compound from the action of acids and other natural conditions that may inactivate the compound.
  • Boc or "t-Butyloxy carbonyl” generally refers to an amino protecting group commonly used in organic synthesis.
  • Cu+ or “copper” generally refers to a monovalent copper catalyst.
  • Cu+ can be CuCN, CuSCN, CuI or CuBr.
  • SrtA ligase generally refers to a ligase that mediates a coupling reaction.
  • SrtA ligase-mediated conjugation reaction Choen,Long,et al.”Improved variants of SrtA for site-specific conjugation on antibodies and proteins with high efficiency.”Scientific reports 6.1(2016):1-12.
  • the principle Yes: SrtA ligase can specifically recognize the LPETG sequence shown in SEQ ID NO: 7, and connect the substrate molecule whose N-terminus is naked glycine to the target protein.
  • the term “specific” generally refers to the selective recognition of a specific epitope of an antigen by an antibody.
  • native antibodies are monospecific.
  • the term “multispecific” refers to the selectivity of having two or more antigen binding sites, at least two of which bind different antigens or different epitopes of the same antigen.
  • it can be multispecific for at least two different antigens (ie EGFR as the first antigen and 4-1BB as the second antigen).
  • the multispecific antibodies according to the invention may be bispecific.
  • the multispecific antibody according to the invention may be trispecific.
  • the term "coupling” generally refers to the joining of two compounds by a covalent bond or by a strong non-covalent interaction, eg, by a covalent bond.
  • the present application provides linkages through which an N3 possessed by one compound and an alkynyl group possessed by another compound can react to form a covalent bond, and a conjugate of the two compounds can be formed.
  • linker generally refers to a central compound to which different other compounds can be attached.
  • the central compound can be linked to one or more other compounds by covalent bonds or by strong non-covalent interactions to form another larger compound.
  • the linkers of the present application can be linked to one or more compounds having lipids, proteins, nucleic acids, small molecules or polysaccharides, or any combination thereof, to form a conjugate.
  • the term "about” generally refers to a range of 0.5%-10% above or below the specified value, such as 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5% or 10%.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable compound thereof , which has the structure shown in formula Ia or formula Ib:
  • the Wa can be a trivalent group, and Wb can be a tetravalent group;
  • Said A, B and C may each be independently selected from the following group:
  • R 12 , R 13 and R 14 may each independently be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl, represents the attachment site;
  • the A, B and C may each be independently selected from the group consisting of:
  • R, R 12 can each be independently selected from the following group: hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido, urea, Alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl, each X may be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen;
  • R is C 5 H 11 and X is H, or R is CH 2 OH and X is H, or R is CH 2 CH 3 and X is F, in A, B and C, cannot and simultaneously exist;
  • R is CH 3 and X is F, or R is CH 2 CH 3 and X is F, in A, B and C, cannot and simultaneously exist,
  • the selection of A, B and C groups may be of the following group:
  • R 12 , R 13 and R 14 may each independently be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl, represents the attachment site;
  • R 12 , R 13 and R 14 are not alkynyl
  • R 12 , R 13 and R 14 are not amino groups.
  • selection of A, B and C groups may be of the following group:
  • R 12 , R 13 and R 14 may each independently be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl, represents the attachment site;
  • R 12 , R 13 and R 14 are not amino groups.
  • selection of A, B and C groups may be of the following group:
  • R 12 can be selected from the following group: hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido, urea, alkane, cyclic Alkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl, represents the attachment site;
  • R 12 can be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane, represents the attachment site.
  • a can be B can be C can be wherein R 12 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane, represents the attachment site.
  • Wa can be a trivalent group
  • Wb can be a tetravalent group
  • the W may be a trivalent group or a tetravalent group, and the W may be optionally substituted with one or more Rs,
  • the J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 may each be independently selected from the group consisting of: alkane, cycloalkyl, heterocycloalkyl , alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
  • R, R 1 , R 1a and R 1b may each be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfo Amido, Urea, Alkyl, Cycloalkyl, Heterocycloalkyl, Alkenyl, Alkynyl, Aryl, and Heteroaryl, represents the attachment site;
  • m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 may each be independently selected from a number of 0 or more.
  • J 1 , J 2 , and J 3 may each be independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein m1 , m2 , and m3 can each be independently selected from the group: 0, 1, 2, and 3.
  • X 1 , X 2 , and X 3 can each be independently selected from the group consisting of -NH- and -O-.
  • K 1 , K 2 , and K 3 may each be independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein n1 , n2 , and n3 can each be independently selected from the group: 0, 1, 2, and 3.
  • (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 may each be independently selected from the group consisting of: -alkyi-polyethylene glycol-alkyi-, alkane, and Polyethylene glycol, or n1, n2 or n3 can each independently be zero.
  • (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 can each be independently selected from the group: -(CH 2 )-(CH 2 -O-CH 2 ) 3 -(CH 2 )-, -( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2- , -( CH2 ) 2- , and -( CH2 ) 8- , or n1, n2 Or n3 may each independently be zero.
  • R1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; wherein, n1, n2, and n3 can each be independently selected from the group consisting of 0, 1, 2, and 3.
  • R 1 are selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; or p1 , p2 or p3 may each independently be zero.
  • L 1 , L 2 , and L 3 may each be independently selected from the group consisting of alkane, and aryl, or any combination of the foregoing; wherein q1 , q2 , and q3 may Each is independently selected from the group: 0, 1, 2, and 3.
  • (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 may each be independently selected from the group consisting of: -alkyi-aryl-, alkane, and polyethylene glycol, or q1, q2 and q3 can each independently be zero.
  • (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 may each be independently selected from the group consisting of -CH 2 -aryl-, -(CH 2 ) 2 -, and -CH 2 -, or q1, q2 and q3 are each independently 0.
  • W can be selected from the following group:
  • Trivalent alkane trivalent cycloalkyl, trivalent heterocycloalkyl, trivalent alkenyl, trivalent alkynyl, trivalent aryl, and trivalent heteroaryl.
  • W can be selected from the following group:
  • the X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 and X 18 may each be independently selected from the group consisting of C, N, O, S, P, CH, CH 2 , NH, P(O) and P(S);
  • the --- represents a double bond or a single bond.
  • W is selected from the following group:
  • the compound may be any organic compound.
  • the compound may be any organic compound.
  • J 1 , J 2 , and J 3 may each independently be selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein m1 , m2 , and m3 may each independently be selected from the following groups: 0, 1, 2 and 3;
  • X 1 , X 2 , and X 3 can each be independently selected from the group of: -NH- and -O-;
  • (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 can each be independently selected from the group of: -(CH 2 )-(CH 2 -O-CH 2 ) 3 -(CH 2 ) -, -( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2- , -( CH2 ) 2- , and -( CH2 ) 8- , or n1, n2, or n3 can be independently 0;
  • (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 may each be independently selected from the group consisting of: -CH 2 -aryl-, -(CH 2 ) 2 -, -CH 2 -, alkane base and polyethylene glycol, or q1, q2 and q3 may each independently be 0;
  • W can be selected from the following group:
  • W can be selected from the following group:
  • the La, Lb and Lc may each be independently selected from the group consisting of linear hydrocarbon chains, linear heterohydrocarbon chains containing 1 or more heteroatoms, containing 1 or more heteroatoms A branched branched hydrocarbon chain, and a linear heterohydrocarbon chain containing one or more heteroatoms containing one or more branches.
  • the La, Lb, and Lc may each be independently selected from the group consisting of linear alkyl chains, and linear heteroalkyl chains containing 1 or more heteroatoms.
  • the La, Lb and Lc may each be selected from -C nx H 2nx -, where nx is a number greater than zero.
  • nx is a number of 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more.
  • nx is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • the La, Lb and Lc may each be independently selected from polymers.
  • the La, Lb, and Lc may each be independently selected from the group consisting of glycans, polyamino acids, polynucleotides, and polylactic acids.
  • the La, Lb and Lc may each independently be a glycan.
  • Glycans can be monomers or polymers of sugar residues, and can be linear or branched.
  • Glycans may include natural sugar residues (eg, glucose, N-acetylglucosamine, N-acetylneuraminic acid, galactose, mannose, fucose, hexose, arabinose, ribose, xylose, etc.) and/or modified sugars (eg, 2'-fluororibose, 2'-deoxyribose, mannose phosphate, 6'-sulfoN-acetylglucosamine, etc.).
  • the La, Lb and Lc may each independently be homopolymers and heteropolymers of sugar residues.
  • the La, Lb and Lc may each independently be a polynucleotide.
  • Polynucleotides can include single- and double-stranded nucleotide polymers.
  • the nucleotides that make up a polynucleotide can be ribonucleotides or deoxyribonucleotides, or a modified form of either class of nucleotides.
  • the La, Lb and Lc may each independently be a base-modified polynucleotide,
  • the La, Lb, and Lc may each independently be polyglycine, for example, may be polyglycine in which more than one glycine is polymerized. In certain embodiments, there may be 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more glycine-polymerized polyglycines . In certain embodiments, there may be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 glycine-polymerized polyglycines.
  • each of the groups may be independently selected from the following groups, which may mean that each group is selected from one or more of the following groups, or may mean that some of the groups are selected from the following groups: one or more of the group, and another portion of the group is selected from one or more of the following groups in any of the definitions for said group in this application.
  • the compound may be selected from the group consisting of:
  • the compound may be selected from the group consisting of:
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof
  • a pharmaceutically acceptable salt having the structure shown in Formula IIa or Formula IIb, wherein:
  • the Wc is a trivalent group, and Wd is a tetravalent group
  • Said A 2 , B 2 and C 2 are each independently selected from the following group:
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
  • the two linking sites of the A2 are arbitrarily linked to Wc and P1, the two linking sites of the B2 are arbitrarily linked to Wc and P2, the two linking sites of the C2 are arbitrarily linked Connect with Wc and P3 ;
  • P 1 , P 2 and P 3 are each independently selected from the group consisting of lipids, proteins, nucleic acids, small molecules and polysaccharides, or any combination thereof.
  • a 2 , B 2 and C 2 may each be independently selected from the group consisting of:
  • a 2 is B2 is C2 is or covalent bond;
  • a 2 is B2 is C2 is or covalent bond
  • a 2 is Or a covalent bond
  • B 2 is a covalent bond
  • C 2 is a covalent bond
  • a 2 is B2 is C2 is or covalent bond; or
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
  • the two linking sites of the A2 are arbitrarily linked to Wc and P1
  • the two linking sites of the B2 are arbitrarily linked to Wc and P2
  • the two linking sites of the C2 are arbitrarily linked Connect with Wc and P3 .
  • a 2 , B 2 and C 2 may each be independently selected from the following group:
  • a 2 is B2 is C2 is or covalent bond;
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
  • the attachment site Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
  • a 2 , B 2 and C 2 may each be independently selected from the following group:
  • a 2 is B2 is C2 is or covalent bond;
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
  • the attachment site Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
  • R 12 , R 13 and R 14 may each be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
  • the two linking sites of A2 can be arbitrarily linked with Wc and P1
  • the two linking sites of B2 can be linked with Wc and P2 arbitrarily
  • the two linking sites of C2 The two attachment sites can optionally be attached to Wc and P3 .
  • a 2 , B 2 and C 2 can each be: A 2 is B2 is C2 is or a covalent bond; wherein R 12 , R 13 and R 14 may each be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane, Represents the linking site, the two linking sites of A2 can be arbitrarily linked with Wc and P1, the two linking sites of B2 can be linked with Wc and P2 arbitrarily, and the two linking sites of C2 The two attachment sites can optionally be attached to Wc and P3 .
  • A2 can be B2 can be, C2 can be or a covalent bond; wherein R 12 can be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane, Represents the linking site, the two linking sites of A2 can be arbitrarily linked with Wc and P1, the two linking sites of B2 can be linked with Wc and P2 arbitrarily, and the two linking sites of C2
  • the two attachment sites can optionally be attached to Wc and P3 .
  • the W can be a trivalent group optionally substituted with one or more R,
  • the J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 may each be independently selected from the group consisting of: alkane, cycloalkyl, heterocycloalkyl , alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
  • R, R 1 , R 1a and R 1b may each be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfo Amido, Urea, Alkyl, Cycloalkyl, Heterocycloalkyl, Alkenyl, Alkynyl, Aryl, and Heteroaryl, represents the attachment site;
  • m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 may each be independently selected from a number of 0 or more.
  • J 1 , J 2 , and J 3 may each be independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein m1 , m2 , and m3 can each be independently selected from the group: 0, 1, 2, and 3.
  • X 1 , X 2 , and X 3 can each be independently selected from the group consisting of -NH- and -O-.
  • K 1 , K 2 , and K 3 may each be independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein n1 , n2 , and n3 can each be independently selected from the group: 0, 1, 2, and 3.
  • (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 may each be independently selected from the group consisting of: -alkyi-polyethylene glycol-alkyi-, alkane, and Polyethylene glycol, or n1, n2 or n3 can each independently be zero.
  • (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 can each be independently selected from the group: -(CH 2 )-(CH 2 -O-CH 2 ) 3 -(CH 2 )-, -( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2- , -( CH2 ) 2- , and -( CH2 ) 8- , or n1, n2 Or n3 may each independently be zero.
  • R1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; wherein, n1, n2, and n3 can each be independently selected from the group consisting of 0, 1, 2, and 3 .
  • R 1 are selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; or p1 , p2 or p3 may each independently be zero.
  • L 1 , L 2 , and L 3 can each be independently selected from the group consisting of alkane, and aryl, or any combination of the foregoing; wherein q1 , q2 , and q3 can each be Independently selected from the group: 0, 1, 2, and 3.
  • (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 may each be independently selected from the group consisting of: -alkyi-aryl-, alkane, and polyethylene glycol, or q1, q2 and q3 can each independently be zero.
  • (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 may each be independently selected from the group consisting of: -CH 2 -aryl-, -(CH 2 ) 2 -, and -CH 2 -, or q1, q2 and q3 can each independently be 0.
  • W may be selected from the group of:
  • Trivalent alkane trivalent cycloalkyl, trivalent heterocycloalkyl, trivalent alkenyl, trivalent alkynyl, trivalent aryl, and trivalent heteroaryl.
  • W can be selected from the following group:
  • the X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 and X 18 may each be independently selected from the group consisting of C, N, O, S, P, CH, CH 2 , NH, P(O) and P(S);
  • the --- represents a double bond or a single bond.
  • W can be selected from the following group:
  • P1, P2 , and P3 are each independently selected from the group consisting of lipids, proteins, nucleic acids, small molecules, and polysaccharides, or any combination thereof.
  • lipids in the present application can be fatty acids.
  • lipids in the present application can be long chain fatty acids LCFA.
  • P1, P2 and P3 may each be independently selected from the group consisting of nucleic acid molecules, dye molecules, cytokines, antigens, fusion proteins, and antibodies or antigen-binding fragments thereof.
  • the nucleic acid molecule therein may comprise CPG.
  • a nucleic acid molecule of the present application may comprise an antisense oligonucleotide ASO.
  • the nucleic acid molecules of the present application may comprise ASOs targeting STAT3.
  • the nucleic acid molecule of the present application may comprise Me C*T*A *T*T*T*G*G*A*T*G*T* MeC * A *G*MeC , as shown in SEQ ID NO: 13
  • the sequence shown represents a locked nucleic acid LNA, for example its nucleoside may contain a bicyclic sugar linking a bridge between the 4'- and 2'-positions, MeC represents methyl C, * represents the nucleoside of phosphorothioate Phosphorothioate connection between.
  • the proteins of the present application may comprise the following group: branched peptides containing CMV antigens, neo2 proteins (fusion proteins of cytokines IL2/IL5), IFN ⁇ proteins, and M1 proteins (short peptides that penetrate the blood-brain barrier).
  • the antibody may be selected from the group consisting of monoclonal antibodies, single chain antibodies, chimeric antibodies, humanized antibodies, fully human antibodies and nanobodies.
  • the antibody targets a target that can be selected from the group consisting of 4-1BB, EGFR, CD3, Her2, CD47 and CD20.
  • the antibody targets a target that can be selected from the group consisting of 4-1BB, EGFR, CD3, Her2, and PD-L1.
  • amino acid sequence of the antibody can be selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12.
  • amino acid sequence of the antibody may be selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12 , and SEQ ID NO:15.
  • the compound may be any organic compound.
  • the compound may be any organic compound.
  • J 1 , J 2 , and J 3 may each independently be selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein m1 , m2 , and m3 may each independently be selected from the following groups: 0, 1, 2 and 3;
  • X 1 , X 2 , and X 3 can each be independently selected from the group of: -NH- and -O-;
  • (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 can each be independently selected from the group of: -(CH 2 )-(CH 2 -O-CH 2 ) 3 -(CH 2 ) -, -( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2- , -( CH2 ) 2- , and -( CH2 ) 8- , or n1, n2, or n3 can be independently 0;
  • (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 may each be independently selected from the group consisting of: -CH 2 -aryl-, -(CH 2 ) 2 -, -CH 2 -, alkane base and polyethylene glycol, or q1, q2 and q3 may each independently be 0;
  • W can be selected from the following group:
  • A2 can be B2 can be, C2 can be or a covalent bond; wherein R 12 can be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane, represents the attachment site,
  • P 1 , P 2 and P 3 are each independently selected from the group consisting of lipids, proteins, nucleic acids, small molecules and polysaccharides, or any combination thereof;
  • the two linking sites of the A2 can be arbitrarily linked to Wc and P1
  • the two linking sites of the B2 can be arbitrarily linked to Wc and P2
  • the two linking sites of the C2 Can be arbitrarily connected to Wc and P3 .
  • the a linking site of is connected to P 1 , the b linking site is connected to (L 1 ) q1 in Wc, The b junction site of the is connected to P 2 , the a junction site is connected to (L 2 ) q2 in Wc, and the C 2
  • the ⁇ -linking site of is connected to P 3 , and the ⁇ -linking site is connected to (L 3 ) q3 in Wc.
  • W can be selected from the following group:
  • the one compound may be selected from the group consisting of:
  • P 1 , P 2 and P 3 may each be independently selected from the group consisting of lipids, proteins, nucleic acids, small molecules and polysaccharides, or any combination thereof.
  • P 1 , P 2 and P 3 may each be independently selected from lipids. Wherein, P 1 , P 2 and P 3 may each be independently selected from the group consisting of aliphatic carboxylic acids, phospholipids and sterols. In one embodiment, P 1 , P 2 and P 3 may each be independently selected from linear, branched, saturated or unsaturated aliphatic carboxylic acids.
  • P 1 , P 2 and P 3 may each be independently selected from proteins. In one embodiment, P 1 , P 2 and P 3 may each be independently selected from polypeptides.
  • the protein or polypeptide may contain post-expression modifications, eg, glycosylation, acetylation, phosphorylation, and the like.
  • the protein or polypeptide may comprise one or more amino acid analog polypeptides, polypeptides with substituted bonds, and modified polypeptides known in the art, including both naturally occurring and non-naturally occurring modifications.
  • P 1 , P 2 and P 3 can each be independently selected from nucleic acids.
  • the nucleic acid may refer to a polymer of nucleotides (eg, ribonucleotides or deoxyribonucleotides), and includes naturally occurring (adenine, guanine, cytosine, uracil, and thymine), non-natural Existing and modified nucleic acids.
  • the nucleic acid may not be limited by the length of the polymer (eg, the number of monomers).
  • the nucleic acid can be single-stranded or double-stranded, and generally contains a 5'-3' phosphodiester linkage, although nucleotide analogs can also have other linkages.
  • the monomers of such nucleic acids are often referred to as nucleotides.
  • the non-natural nucleotide or the modified nucleotide refers to a nucleotide containing a modified nitrogenous base, sugar or phosphate group, or a nucleotide incorporating a non-natural moiety in its structure.
  • the non-natural nucleotides can include dideoxynucleotides, biotinylated, aminated, deaminated, alkylated, benzylated, and fluorescently labeled nucleotides.
  • P 1 , P 2 and P 3 can each be independently selected from small molecules.
  • the small molecule can be a mitotic inhibitor, an antitumor antibiotic immunomodulator, a vector for gene therapy, an alkylating agent, an antiangiogenic agent, an antimetabolite, a boron-containing agent, a chemoprotective agent, a hormone, an antihormonal agent , corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclide agents, topoisomerase inhibitors, kinase inhibitors and radiosensitizers.
  • P1, P2 and P3 may each be independently selected from polysaccharides.
  • the polysaccharide may include molecules composed of two or more monosaccharide units, eg, may include molecules in which the longest monosaccharide chain is 3 to 9 monosaccharide units.
  • the polysaccharide can include both linear and branched chain molecules. Any combination of the polysaccharide and lipid, protein, nucleic acid, or small molecule can include isolated as well as polypeptide-bound molecules, sialylated and non-sialylated molecules.
  • P 1 , P 2 and P 3 may each be independently selected from antibodies targeting a target selected from the group consisting of 4-1BB, EGFR, CD3, Her2, CD47 and CD20.
  • amino acid sequences of P 1 , P 2 and P 3 can be respectively:
  • SEQ ID NO: 1 SEQ ID NO: 2, and SEQ ID NO: 3, or
  • SEQ ID NO: 1 SEQ ID NO: 10
  • SEQ ID NO: 3 SEQ ID NO: 3
  • SEQ ID NO: 1 SEQ ID NO: 11, and SEQ ID NO: 3, or
  • SEQ ID NO: 1 SEQ ID NO: 12, and SEQ ID NO: 3, or
  • SEQ ID NO: 12 SEQ ID NO: 2, and SEQ ID NO: 3, or
  • SEQ ID NO: 1 SEQ ID NO: 2, and SEQ ID NO: 10, or
  • SEQ ID NO: 1 SEQ ID NO: 2, and SEQ ID NO: 11, or
  • SEQ ID NO: 1 SEQ ID NO: 2, and SEQ ID NO: 12, or
  • P 1 , P 2 and P 3 in the present application can each independently be a protein having a sequence recognizable by a ligase to which a substrate molecule can be attached.
  • P 1 , P 2 and P 3 in the present application can each independently be a protein with a LPETG sequence, and the LPETG sequence as shown in SEQ ID NO: 7 can be ligated by a ligase, such as SrtA ligase, specific identify.
  • P 1 , P 2 and P 3 in the present application can each be independently selected from VHH Nanobodies targeting EGFR, VHH Nanobodies targeting CD3, VHH Nanobodies targeting 4-1BB, target VHH Nanobodies to Her2, VHH Nanobodies Targeting CD47, VHH Nanobodies Targeting CD20, Branched Peptides Containing CMV Antigens, Fusion Proteins of Cytokine IL2/IL5, Cytokine IFN ⁇ , Dye Molecules FITC and CPG Nucleic Acid Molecules .
  • the present application provides a method for preparing a compound, which includes reacting the compound represented by formula (Ia-I) with reactant 1, reactant 2 and reactant 3;
  • the reactant 1 can be HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -A,
  • the reactant 2 can be HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -B,
  • the reactant 3 can be HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -C,
  • the W may be a trivalent group, and the W may be optionally substituted with one or more R,
  • the J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 may each be independently selected from the group consisting of: alkane, cycloalkyl, heterocycloalkyl , alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
  • R, R 1 , R 1a and R 1b may each be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfo amide, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl;
  • m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 can each be independently selected from a number greater than 0;
  • A, B and C can each independently be selected from the following group:
  • R 12 , R 13 and R 14 may each independently be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl;
  • R 12 , R 13 and R 14 are not alkynyl
  • Boc removal can be performed by adding an acid (0%-300% hydrochloric acid or trifluoroacetic acid).
  • the order of addition of reactant 1, reactant 2 and reactant 3 can be determined according to the introduction order of A, B and C, and the introduction order of A, B and C can be sequentially for:
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl.
  • the compound represented by formula (Ia-I) reacts with reactant 1, reactant 2 and reactant 3 according to the equivalent ratio of 20/1 to 1/20 equivalent range, adding 1%-100 % molar equivalent of triethylamine or ethylenediamine or dimethylaminopyridine or pyridine or N,N-diisopropylethylamine as a catalyst, the reaction conditions are 4-100 ° C, the reaction solvent can be water, water-based Other solutions, DMF, DMSO, methanol, acetonitrile, tetrahydrofuran, dichloromethane or its corresponding mixed solvent, etc., the reaction concentration can be in the range of 1 nanomolar to 10 mol, and the reaction time can be 0-24h.
  • step 1 the starting material NHS reagent can be reacted with N3-Amine in a ratio of 1/1.2.
  • the reaction conditions can be DMF (N,N-dimethylformamide) as a solvent, a catalytic amount of TEA (Triethylamine) as a catalyst, react at 25 ° C for 2 hours, after the reaction, the solvent can be removed by rotary evaporation, and then HPLC (high performance liquid chromatography) can be used to purify, the first intermediate N3-NHS-NHS can be obtained .
  • DMF N,N-dimethylformamide
  • TEA Triethylamine
  • Step 2 N3-NHS-NHS and TZ-Amine can be reacted in a ratio of 1/1.2.
  • the reaction conditions can be DMF (N,N-dimethylformamide) as a solvent, a catalytic amount of TEA (three Ethylamine) as a catalyst, react at 25 ° C for 2 hours, after the reaction, the solvent can be removed by rotary evaporation, and then HPLC (high performance liquid chromatography) can be used to purify, and the second intermediate, that is, multispecific biological coupling can be obtained.
  • the connecting arm 2 (Scaffold2).
  • Step 3 The second intermediate, the linking arm 2 (Scaffold2) of the multispecific biological coupling, can be reacted with Boc-Gly-Amine in a ratio of 1/1.2, and the reaction conditions can be DMF (N,N - dimethylformamide) as a solvent, a catalytic amount of TEA (triethylamine) as a catalyst, react at 25 ° C for 2 hours, after the reaction is completed, the solvent can be removed by rotary evaporation, and then HPLC (high performance liquid chromatography) can be used to carry out purification.
  • DMF N,N - dimethylformamide
  • TEA triethylamine
  • the product obtained after purification can be dissolved in DCM (dichloromethane), and then TFA (trifluoroacetic acid) with a volume ratio of 20% can be added, and the Boc (tert-butoxycarbonyl) group can be removed by reacting at room temperature for 5 minutes. Then, HPLC (High Performance Liquid Chromatography) can be used to purify to obtain the final product, that is, the linker arm 1 (Scaffold1) of the multispecific bioconjugation.
  • DCM dichloromethane
  • TFA trifluoroacetic acid
  • Boc tert-butoxycarbonyl
  • HPLC High Performance Liquid Chromatography
  • the present application also provides a method for preparing a compound, which can make any one of the compounds described in formula Ia in the present application react with reactant 4, reactant 5 and reactant 6;
  • the reactant 4 is A 1 -P 1 ,
  • the reactant 5 is B 1 -P 2 ,
  • the reactant 6 is C 1 -P 3 ,
  • a 1 of reactant 4 reacts with A of the compound described in formula Ia
  • B 1 of reactant 5 reacts with B of the compound described in formula Ia
  • C 1 of reactant 6 reacts with the compound described in formula Ia C reaction
  • R 12 , R 13 and R 14 may each independently be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamide alkyl, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl.
  • At least one of A, B or C when at least one of A, B or C is , at least one of the corresponding A 1 , B 1 or C 1 is
  • R, R 12 can each be independently selected from the following group: hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido, urea, Alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl, each X can be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen.
  • a group in A, B or C and the corresponding group in A 1 , B 1 or C 1 can be A for B is C is , A1 is B1 is C1 is wherein R 12 may be hydrogen.
  • Cu + can be added as a catalyst in the reaction.
  • adding a catalytic amount of Cu+ produces Cu+ as a catalyst in other forms.
  • E.g, 1-100% equivalent of SrtA ligase can be added as a catalyst in the reaction.
  • the reaction of the compound of formula Ia with reactant 4, reactant 5 and reactant 6 can be carried out according to the molar ratio of 20/1 to 1/20, and the reaction solvent can be water, water-based Other solutions, DMF, DMSO, methanol, acetonitrile, tetrahydrofuran, dichloromethane or its corresponding mixed solvent, etc., the reaction concentration can be in the range of 1 nanomolar to 100 mol, and the reaction time can be 0-24 hours.
  • the reaction solvent can be water, water-based Other solutions, DMF, DMSO, methanol, acetonitrile, tetrahydrofuran, dichloromethane or its corresponding mixed solvent, etc.
  • the reaction concentration can be in the range of 1 nanomolar to 100 mol
  • the reaction time can be 0-24 hours.
  • the application provides a pharmaceutical composition, which may contain a compound of any one of the application, or a tautomer, meso, racemate, enantiomer, diastereomer, or tautomer, meso, racemate, enantiomer, or diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.
  • the present application provides a kit, which can comprise the compound described in any one of the present application or its tautomer, meso, racemate, enantiomer, An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and/or the pharmaceutical composition of any of the present application.
  • the application provides a compound described herein or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, use of the pharmaceutical composition of the present application and/or the kit of the present application in the preparation of a medicament for treating and/or preventing tumors.
  • the tumor may be selected from tumors associated with expression of the following group: 4-1BB, EGFR, CD3, Her2, CD47, and CD20.
  • the expression correlation may refer to a high expression and/or positive correlation with the target therein.
  • the expression correlation may refer to correlation with the high expression of the target therein.
  • the expression correlation may refer to a positive correlation with a target therein.
  • the tumor can be selected from the group consisting of solid tumors and hematological cancers.
  • the tumor may be selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric and esophageal cancer.
  • the present application provides methods for treating and/or preventing tumors, comprising administering to a subject in need thereof a compound described herein or a tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, pharmaceutical compositions of the present application and/or kits of the present application.
  • the tumor may be selected from tumors associated with expression of the following group: 4-1BB, EGFR, CD3, Her2, CD47, and CD20.
  • the expression correlation may refer to a high expression and/or positive correlation with the target therein.
  • the expression correlation may refer to correlation with the high expression of the target therein.
  • the expression correlation may refer to a positive correlation with a target therein.
  • the tumor can be selected from the group consisting of solid tumors and hematological cancers.
  • the tumor may be selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric and esophageal cancer.
  • the application provides a compound described in the application or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of the present application and/or the kit of the present application, which are used for the treatment and/or prevention of tumors.
  • the tumor may be selected from tumors associated with expression of the following group: 4-1BB, EGFR, CD3, Her2, CD47, and CD20.
  • the expression correlation may refer to a high expression and/or positive correlation with the target therein.
  • the expression correlation may refer to correlation with the high expression of the target therein.
  • the expression correlation may refer to a positive correlation with a target therein.
  • the tumor can be selected from the group consisting of solid tumors and hematological cancers.
  • the tumor may be selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric and esophageal cancer.
  • N3-Amine, TZ-Amine, Boc-Gly-Amine, FITC-Amine, DBCO-Gly, BCN-Gly were purchased from Xi'an Dianhua Biotechnology Co., Ltd. or Click Chemistry Tools. Other compounds and solvents were purchased from Sigma-Aldrich (Shanghai) Trading Co., Ltd. or Beijing Bailingwei Technology Co., Ltd. unless otherwise specified.
  • CPG-Amine nucleic acid was purchased from Suzhou Jinweizhi Biotechnology Co., Ltd., and its nucleotide sequence, as shown in SEQ ID NO: 4, is specifically: 5 ⁇ -TCC ATG ACG TTC CTG ACG TT-3 ⁇ , its 5 ⁇ contains C12 amino modification.
  • the branched peptide containing CMV antigen was purchased from Nanjing Yuanpeptide Biotechnology Co., Ltd., and its structure is shown in formula CMV:
  • amino acids of the three branches are shown in SEQ ID NO: 5, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.
  • VHH Nanobodies were expressed in E. coli.
  • amino acid sequence of the VHH Nanobody targeting EGFR is specifically:
  • amino acid sequence of the VHH Nanobody targeting CD3, as shown in SEQ ID NO: 3, is specifically:
  • amino acid sequence of the VHH Nanobody targeting 4-1BB is shown in SEQ ID NO: 1, specifically:
  • SrtA ligase (eg, the amino acid sequence can be set forth in SEQ ID NO: 16) is expressed from E. coli.
  • the principle of SrtA ligase-mediated coupling reaction (Chen, Long, et al. Scientific reports 6.1 (2016): 1-12.) is: SrtA ligase can specifically recognize LPETG as shown in SEQ ID NO: 7 sequence, the N-terminal of the substrate molecule with naked glycine is transferred to the target protein.
  • neo2 protein of the application is a fusion protein of cytokine IL2/IL5, as shown in SEQ ID NO: 8, specifically:
  • IFN ⁇ protein of the application as shown in SEQ ID NO: 9, is specifically:
  • EGFR-DBCO adopts SrtA ligase-mediated coupling reaction.
  • the LPETG sequence exists on the EGFR-targeting VHH nanobody, and SrtA ligase can link the substrate molecule DBCO-Gly with a naked glycine at the N-terminus to the EGFR nanobody.
  • 1 mmol of DBCO-Gly and 5 ⁇ mol of SrtA ligase were added to 100 micromolar VHH nanobody PBS solution, and EGFR-DBCO could be obtained after 2 hours of reaction at room temperature.
  • the yield after purification by size exclusion was about 80%.
  • CD3-BCN was prepared by SrtA ligase-mediated coupling reaction.
  • the LPETG sequence exists on the CD3-targeting VHH nanobody, and SrtA ligase can link the substrate molecule BCN-Gly with a naked glycine at the N-terminus to the CD3 nanobody.
  • SrtA ligase can link the substrate molecule BCN-Gly with a naked glycine at the N-terminus to the CD3 nanobody.
  • To 100 micromoles of CD3-targeting VHH nanobody PBS solution 1 mmol of BCN-Gly and 5 micromoles of SrtA ligase were added, and CD3-BCN could be obtained after 2 hours of reaction at room temperature. The yield after purification by size exclusion was about 90%.
  • T-Linker The method for preparing a multi-specific biological coupling linker (T-Linker) provided in this application synthesizes linker 1 (Scaffold1) and linker 2 (Scaffold2), and the specific reaction formula is as follows:
  • Step 1 React the starting material NHS reagent with N3-Amine in a ratio of 1/1.2, the reaction conditions are DMF (N,N-dimethylformamide) as a solvent, a catalytic amount of TEA (triethylamine) ) as a catalyst, react at 25°C for 2 hours, and after the reaction is completed, the solvent is removed by rotary evaporation, and then purified by HPLC (high performance liquid chromatography) to obtain the first intermediate N3-NHS-NHS with a yield of 74%.
  • DMF N,N-dimethylformamide
  • TEA triethylamine
  • Step 2 React N3-NHS-NHS and TZ-Amine in a ratio of 1/1.2, the reaction conditions are DMF (N,N-dimethylformamide) as a solvent, a catalytic amount of TEA (triethylamine) ) as a catalyst, react at 25 ° C for 2 hours, remove the solvent by rotary evaporation after the reaction, and then purify with HPLC (high performance liquid chromatography) to obtain the second intermediate that is the connecting arm 2 ( Scaffold2) in 65% yield.
  • DMF N,N-dimethylformamide
  • TEA triethylamine
  • Step 3 The second intermediate, the linking arm 2 (Scaffold2) of the multispecific biological coupling, is reacted with Boc-Gly-Amine in a ratio of 1/1.2, and the reaction conditions are DMF (N,N-di methylformamide) as a solvent and a catalytic amount of TEA (triethylamine) as a catalyst to react at 25°C for 2 hours. After the reaction, the solvent was removed by rotary evaporation, and then purified by HPLC (high performance liquid chromatography).
  • DMF N,N-di methylformamide
  • TEA triethylamine
  • the 1 H-NMR characterization results of tether 1 are: 1 H NMR (CD3OD, 400MHz) ⁇ (ppm): 10.28 (s, 1H), 8.45-8.43 (d, 2H), 8.38-8.36 (m, 4H) ),7.89-7.87(d,1H),7.62-7.60(d,1H),7.51-7.49(d,2H),7.43-7.40(d,1H),7.35-7.33(d,1H),5.45(s ,1H),3.84(s,4H),3.64(s,2H),3.60-3.38(m,18H),3.26-3.22(m,6H),1.89-1.84(m,6H),1.72-1.66(m , 6H).
  • ESI-MS characterization results are: C53H82N14O15, 1154.3 (m/z); [M+H] + : 1155.5, [M+Na] + : 1177.5 (m/z).
  • the 1 H-NMR characterization results of tether 2 are: 1 H NMR (CD3OD, 400MHz) ⁇ (ppm): 10.43(s, 1H), 8.69(d, 1H), 8.66(m, 2H), 8.47- 8.45(d,2H),8.35-8.31(m,2H),7.59-7.57(d,2H),7.53-7.47(m,2H),3.88(s,2H),3.67(s,2H),3.61- 3.43 (m, 12H), 3.31-3.26 (m, 4H), 1.91-1.84 (m, 4H), 1.74-1.67 (m, 4H).
  • ESI-MS characterization results are: C45H60N12O14, 992.4 (m/z); [M+H] + : 993.4, [M+Na] + : 1015.3 (m/z).
  • the 1 H-NMR method was used to characterize the intermediate N3-NHS-NHS in the process of synthesizing linker 1 (Scaffold1) and linker 2 (Scaffold2), and the results shown in Figure 5 were obtained.
  • the analysis is as follows: 1 H NMR (CD2Cl2, 400MHz) ) ⁇ (ppm): 8.97-8.96(t, 1H), 8.875-8.871(d, 2H), 7.79-7.77(t, 1H), 6.92(s, 1H), 3.93(s, 2H), 3.69-3.60 (m,8H),3.56-3.54(m,2H),3.46-3.4(m,4H),3.37-3.32(m,2H),2.17(s,8H),1.96-1.90(dd,2H),1.69 -1.75(dd,2H).
  • Step 1 The starting material NHS reagent is reacted with N3-Amine* in a ratio of 1/1.2.
  • the reaction conditions are DMF (N,N-dimethylformamide) as a solvent, a catalytic amount of TEA (triethylformamide) amine) as a catalyst, reacted at 25°C for 2 hours, after the reaction was completed, the solvent was removed by rotary evaporation, and then purified by HPLC (high performance liquid chromatography) to obtain the first intermediate N3-NHS-NHS* with a yield of 74 %.
  • DMF N,N-dimethylformamide
  • TEA triethylformamide
  • Step 2 React N3-NHS-NHS* and TZ-Amine* in a ratio of 1/1.2, the reaction conditions are DMF (N,N-dimethylformamide) as a solvent, a catalytic amount of TEA (three Ethylamine) as a catalyst, reacted at 25 ° C for 2 hours, after the reaction, the solvent was removed by rotary evaporation, and then purified by HPLC (high performance liquid chromatography) to obtain the second intermediate, that is, the connecting arm of the multispecific biological coupling 4 (Scaffold4) in 75% yield.
  • DMF N,N-dimethylformamide
  • TEA three Ethylamine
  • Step 3 The second intermediate, the linking arm 4 (Scaffold4) of the multispecific biological coupling, is reacted with Boc-Gly-Amine* in a ratio of 1/1.2, and the reaction conditions are DMF (N,N- Dimethylformamide) was used as solvent, catalytic amount of TEA (triethylamine) was used as catalyst, and the reaction was carried out at 25°C for 2 hours. After the reaction, the solvent was removed by rotary evaporation, and then purified by HPLC (high performance liquid chromatography).
  • DMF N,N- Dimethylformamide
  • TEA triethylamine
  • the 1 H-NMR characterization results of tether 3 are: 1 H NMR (CD3OD, 400MHz) ⁇ (ppm): 10.20(s, 1H), 8.17-8.15(d, 2H), 8.08-8.06(m, 3H) ), 7.34-7.32(d, 2H), 3.83(s, 2H), 3.66(s, 2H), 3.44-3.37(m, 12H), 2.05(s, 2H).
  • ESI-MS characterization results are: C29H34N14O6, 674.3 (m/z); [M+H] + : 675.2, [M+Na]+: 697.3 (m/z).
  • T-Linker The multispecific bioconjugation linker (T-Linker) contained in this application can be prepared and characterized by methods and procedures similar to those above.
  • Multispecific conjugates such as multispecific conjugates EGFR-CD3-FITC
  • T-Body multispecific conjugates provided by the multispecific biological conjugation linker (T-Linker) provided in this application.
  • T-Linker multispecific biological conjugation linker
  • the preparation method is as follows: firstly, the connecting arm 2 (Scaffold2) of the above-mentioned multispecific biological coupling is reacted with FITC-Amine.
  • FITC-Amine final concentration 10 mmol
  • DMF N,N-dimethylformamide
  • 1 mmol linker 2 Scaffold2
  • N3-TZ-FITC and CD3-BCN were reacted at a molar ratio of 1/1.
  • reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and after reacting at room temperature for 1 hour, N3-CD3-FITC was purified by size exclusion chromatography. Finally, N3-CD3-FITC reacts with EGFR-DBCO at a molar ratio of 1/1.
  • the reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and EGFR-CD3-FITC was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
  • EGFR-CD3-FITC was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 6, and its purity was >90%.
  • the multi-specific conjugate (T-Body) is synthesized by the method for preparing the multi-specific bioconjugate (T-Linker) provided in this application, such as multi-specific conjugation EGFR-CD3-LCFA (LCFA is a long-chain fatty acid)
  • the preparation method of EGFR-CD3-LCFA can be the same as the preparation of EGFR-CD3-FITC in the example, the difference can be that FITC is replaced by LCFA, and the specific reaction formula is as follows :
  • EGFR-CD3-LCFA was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 27, and its purity was >90%.
  • the results of characterization of EGFR-CD3-LCFA by LC-MS are shown in FIG. 28 .
  • Multispecific conjugates such as multispecific conjugates EGFR-CD3-CPG
  • T-Body multispecific conjugates provided by the multispecific biological conjugation linker (T-Linker) provided in this application
  • T-Linker multispecific biological conjugation linker
  • the preparation method is as follows: firstly, the connecting arm 2 (Scaffold2) of the above-mentioned multispecific biological coupling is reacted with CPG-Amine. 1 mmol of Scaffold 2 was added to a PBS (phosphate buffered saline) solution containing 100 ⁇ mol of CPG-Amine, reacted at room temperature for 2 hours, and purified by HPLC to obtain N3-TZ-CPG. Then, N3-TZ-CPG and CD3-BCN were reacted at a molar ratio of 1/1.
  • PBS phosphate buffered saline
  • reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and N3-CD3-CPG was obtained by size exclusion chromatography after reaction at room temperature for 1 hour. Finally, N3-CD3-CPG reacts with EGFR-DBCO at a molar ratio of 1/1.
  • the reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and EGFR-CD3-CPG was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
  • EGFR-CD3-CPG was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 8, and its purity was >90%.
  • the multi-specific conjugate (T-Body) was synthesized by the method for preparing the multi-specific bioconjugate (T-Linker) provided in this application, such as multi-specific conjugation EGFR-CD3-ASO.
  • the antisense oligonucleotide ASO of STAT3 can be used, which can be sequenced as Me C*T*A *T*T*T*G*G*A*T*G*T* Me C* A*G* MeC , SEQ ID NO: 13 (underlined represents a locked nucleic acid LNA, for example, its nucleoside may comprise a bicyclic sugar linking the 4'- and 2'-position bridges, MeC represents methyl C, * represents phosphorothioate Internucleoside linkage of ester Phosphorothioate).
  • the preparation method of EGFR-CD3-ASO can be the same as the preparation of EGFR-CD3-FITC in the embodiment, the difference can be that FITC is replaced by ASO, and the specific reaction formula is as follows:
  • EGFR-CD3-ASO was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 29, and its purity was >90%.
  • the results of characterization of EGFR-CD3-ASO by LC-MS are shown in FIG. 30 .
  • the multispecific conjugate (T-Body) is synthesized by the method for preparing the multispecific bioconjugate (T-Linker) provided in this application, such as the multispecific conjugate EGFR-CD3-CMV , EGFR-CD3-neo2, EGFR-CD3-IFN ⁇ and EGFR-CD3-M1.
  • the preparation method of EGFR-CD3-CMV is as follows: firstly, the connecting arm 1 (Scaffold1) of the above-mentioned multispecific biological coupling is reacted with the branched peptide containing the CMV antigen. 1 mmol of tether 1 (Scaffold1) was added to PBS (phosphate buffered saline) solution containing 100 ⁇ mol of branched peptide, then 5 ⁇ mol of SrtA ligase was added, and after 2 hours of reaction at room temperature, size exclusion purification was used to obtain N3 -TZ-CMV. Then, N3-TZ-CMV and CD3-BCN were reacted at a molar ratio of 1/1.
  • PBS phosphate buffered saline
  • reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and N3-CD3-CMV was obtained by size exclusion chromatography after reaction at room temperature for 1 hour. Finally, N3-CD3-CMV reacts with EGFR-DBCO at a molar ratio of 1/1.
  • the reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as the solvent, and the EGFR-CD3-CMV was purified by size exclusion chromatography after reacting at room temperature for 2 hours.
  • the specific reaction formula is shown in Figure 19.
  • EGFR-CD3-CMV was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 10, and its purity was >90%.
  • the preparation method of EGFR-CD3-neo2 is as follows: firstly, the connecting arm 1 (Scaffold1) of the above-mentioned multispecific biological coupling is reacted with the neo2 sequence shown in SEQ ID NO: 8 of the application. 1 mmol of tether 1 (Scaffold1) was added to PBS (phosphate buffered saline) solution containing 100 ⁇ mol of branched peptide, then 5 ⁇ mol of SrtA ligase was added, and after 2 hours of reaction at room temperature, size exclusion purification was used to obtain N3 -TZ-neo2.
  • PBS phosphate buffered saline
  • N3-TZ-neo2 was reacted with CD3-BCN at a molar ratio of 1/1.
  • the reaction concentration was 100 micromolar
  • PBS phosphate buffered saline
  • N3-CD3-neo2 was obtained by size exclusion chromatography after reaction at room temperature for 1 hour.
  • N3-CD3-neo2 reacts with EGFR-DBCO at a molar ratio of 1/1.
  • the reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and EGFR-CD3-neo2 was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
  • EGFR-CD3-neo2 was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 12, and its purity was >90%.
  • the preparation method of EGFR-CD3-IFN ⁇ is as follows: firstly, the connecting arm 1 (Scaffold1) of the above-mentioned multispecific biological coupling is reacted with the IFN ⁇ sequence shown in SEQ ID NO: 9 of the present application. 1 mmol of tether 1 (Scaffold1) was added to PBS (phosphate buffered saline) solution containing 100 ⁇ mol of branched peptide, then 5 ⁇ mol of SrtA ligase was added, and after 2 hours of reaction at room temperature, size exclusion purification was used to obtain N3 -TZ-IFN ⁇ . Then, N3-TZ-IFN ⁇ and CD3-BCN were reacted at a molar ratio of 1/1.
  • PBS phosphate buffered saline
  • reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and N3-CD3-IFN ⁇ was obtained by size exclusion chromatography after reacting at room temperature for 1 hour. Finally, N3-CD3-IFN ⁇ reacts with EGFR-DBCO at a molar ratio of 1/1.
  • the reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as the solvent, and the EGFR-CD3-IFN ⁇ was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
  • EGFR-CD3-IFN ⁇ was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 14, and its purity was >90%.
  • the linking arm 1 (Scaffold1) of the above-mentioned multispecific biological coupling is reacted with M1 (M1 is a short peptide that penetrates the blood-brain barrier) shown in SEQ ID NO: 14 of the present application to obtain EGFR- CD3-M1, the specific reaction formula is shown in Figure 31.
  • EGFR-CD3-M1 was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 32, and its purity was >90%.
  • EGFR-CD3-PDL1 was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 35, and its purity was >90%.
  • Multispecific conjugates such as trispecific VHH nanobody EGFR-CD3-4, were synthesized by the method for preparing multispecific conjugates (T-Body) by the multispecific biological coupling linker (T-Linker) provided in this application -1BB, the specific reaction formula is shown in Figure 20.
  • the preparation method is as follows: firstly, the above-mentioned multispecific biologically coupled connecting arm 1 (Scaffold1) is reacted with a VHH nanobody targeting 4-1BB. 1 mmol of linker 1 (Scaffold1) was added to PBS (phosphate buffered saline solution) solution containing 100 ⁇ mol of VHH Nanobody, and then 5 ⁇ mol of SrtA ligase was added, reacted at room temperature for 2 hours and purified by size exclusion. N3-TZ-4-1BB. Then, N3-TZ-4-1BB and CD3-BCN were reacted at a molar ratio of 1/1.
  • PBS phosphate buffered saline solution
  • reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and N3-CD3-4-1BB was obtained by size exclusion chromatography after reaction at room temperature for 1 hour. Finally, N3-CD3-4-1BB reacts with EGFR-DBCO at a molar ratio of 1/1.
  • the reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and EGFR-CD3-4-1BB was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
  • EGFR-CD3-4-1BB was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 16, and its purity was >90%.
  • a multispecific conjugate such as a trispecific VHH nanobody HER2-CD3-PDL1
  • the specific reaction formula is shown in FIG. 37 .
  • the preparation method is as follows: firstly, the above-mentioned multispecific biologically coupled connecting arm 1 (Scaffold1) is reacted with a VHH nanobody targeting PDL1. 1 mmol of linker 1 (Scaffold1) was added to PBS (phosphate buffered saline solution) solution containing 100 ⁇ mol of VHH Nanobody, and then 5 ⁇ mol of SrtA ligase was added, reacted at room temperature for 2 hours and purified by size exclusion. N3-TZ-PDL1. Then, N3-TZ-PDL1 and CD3-BCN were reacted at a molar ratio of 1/1.
  • the reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and N3-CD3-PDL1 was obtained by size exclusion chromatography after reaction at room temperature for 1 hour.
  • the preparation method of HER2-DBCO is the same as that of EGFR-DBCO, except that the VHH nanobody targeting EGFR is replaced with a HER2 binding protein.
  • N3-CD3-PDL1 reacts with HER2-DBCO at a molar ratio of 1/1.
  • the reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and HER2-CD3-PDL1 was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
  • PBMCs were obtained from Shanghai Auxers Biotechnology Co., Ltd., and the tumor cells used were A431 cells derived from ATCC.
  • the specific experimental details are as follows:
  • A431 cells were seeded in 96-well plates at a cell seeding density of 10,000 cells per well in a volume of 100 ⁇ l.
  • the medium used was DMEM medium containing 20% FBS (fetal bovine serum) and 10% double antibody (penicillin-streptomycin mixture).
  • the culture condition was a 37°C incubator with 5% carbon dioxide.
  • the old medium in the 96-well plate was aspirated and 100 ⁇ l of new medium was added. Then, 100 microliters of 1640 medium containing 150,000 PBMCs (containing 20% FBS (fetal bovine serum), 10% double antibody (penicillin-streptomycin mixture)) was added to each well. Then, the experimental group was added with different concentrations of EGFR-CD3-4-1BB, the control group was added with the corresponding concentration of EGFR-TZ-4-1BB or EGFR-CD3-Gly, and the blank group was added with the corresponding volume of PBS (phosphate buffered saline solution).
  • the preparation methods of the control group EGFR-TZ-4-1BB and EGFR-CD3-Gly refer to the above examples and are shown in FIG. 21 .
  • the tether (Scaffold1) reacts with CD3-BCN at a molar ratio of 1/1.
  • the reaction concentration was 100 micromolar
  • PBS phosphate buffered saline
  • N3-CD3-Gly was obtained by size exclusion chromatography after reaction at room temperature for 1 hour.
  • N3-CD3-Gly was reacted with EGFR-DBCO at a molar ratio of 1/1.
  • the reaction concentration was 100 micromolar
  • PBS phosphate buffered saline
  • EGFR-CD3-Gly was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
  • the LDH lactate dehydrogenase cytotoxicity assay was used to test the killing effect of the above experimental groups on tumor cells.
  • the kit used was KTA1030LDH Cytotoxicity Assay Kit LDH Cytotoxicity Assay Kit (Abbkine), and the specific operation steps were carried out according to the instructions provided by the kit. The results are shown in FIG. 18 .
  • Octet RED96 assays the binding of EGFR-CD3-PDL1 multispecific antibody to EGFR, CD3, PDL1 receptors.
  • FIG 39A-39B The binding characteristics of EGFR-PDL1-CD3 multispecific antibody to EGFR, CD3, and PDL1 receptor proteins are shown in Figure 39A-39B, in which Figure 39(A) shows the binding of EGFR-CD3-PDL1 to EGFR, CD3, and PDL1 proteins Curve, the binding height in the curve from low to high corresponds to EGFR-CD3-PDL1 concentrations of 50nM, 100nM, 200nM, 400nM, 800nM; Figure 39(B) shows the binding capacity of EGFR-CD3-PDL1 to different targets.
  • the results show that the multispecific conjugate (T-Body) of the present application can simultaneously maintain the respective activities of multiple functional domains, such as receptor binding activity.
  • the present application uses the above examples to illustrate the multispecific bioconjugation link provided in the present application and its synthesis, the multispecific conjugates prepared by using the bioconjugate link, and their preparation methods and uses.
  • the present application is not limited to the above-mentioned process steps, that is, it does not mean that the present application must rely on the above-mentioned process steps to be implemented.
  • Those skilled in the art should understand that any improvement to the application, the equivalent replacement of the selected raw materials in the application, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the application.

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Abstract

Disclosed in the present application are a multi-specific bioconjugate linker and a synthetic method therefor, and specifically, a compound or a tautomer, a mesomer, a racemate, an enantiomer, or a diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. Also disclosed in the present application are a preparation method for the compound and use in tumor treatment.

Description

多特异生物偶联连接臂及其合成方法Multispecific biological conjugation linker and its synthesis method 技术领域technical field
本申请涉及生物医药领域，具体涉及一种多特异生物偶联连接臂及其合成方法。The present application relates to the field of biomedicine, in particular to a multispecific biological coupling linker and a synthesis method thereof.
背景技术Background technique
多特异药物分子是当今肿瘤治疗的热点。相比于传统药物设计依赖于一个靶标一个药物的对应模式，多特异药物能同时靶向多个靶标，因此能够更加精准、高效地对癌细胞进行打击，减少脱靶效应引起的毒副作用。Multispecific drug molecules are a hot spot in tumor therapy today. Compared with the traditional drug design that relies on the corresponding mode of one target and one drug, multispecific drugs can target multiple targets at the same time, so they can strike cancer cells more accurately and efficiently, and reduce the toxic and side effects caused by off-target effects.
虽然双特异抗体和多特异抗体在肿瘤治疗中表现出良好的效果，然而研发多特异抗体药物的发展仍然存在着诸多挑战，目前最主要的问题之一是多特异抗体的制备。传统多特异抗体制备平台大多采用抗体融合表达的方式进行生产，这种方式存在着抗体错配的问题，导致下游纯化工艺异常艰难，因此难以扩大生产。目前存在一些多功能化合物，但这类化合物不具有特异性和生物正交性，易造成相互干扰，无法真正实现多种化合物的精准偶联。Although bispecific antibodies and multispecific antibodies have shown good effects in tumor treatment, there are still many challenges in the development of multispecific antibody drugs. One of the most important problems at present is the preparation of multispecific antibodies. Most of the traditional multispecific antibody preparation platforms use the method of antibody fusion expression for production. This method has the problem of antibody mismatch, which makes the downstream purification process extremely difficult, so it is difficult to expand production. At present, there are some multifunctional compounds, but these compounds are not specific and bioorthogonal, which are easy to cause mutual interference, and cannot truly realize the precise coupling of multiple compounds.
发明内容SUMMARY OF THE INVENTION
本申请提供了一种化合物，所述化合物可以是多特异生物偶联连接臂(T-Linker)或多特异偶联物(T-Body)。本申请可以具有以下一种或多种的效果：(1)本申请的化合物可以是多特异的化合物，所述多特异偶联物可以表现出良好的抗肿瘤活性，IC 50值可以低于10纳摩尔；(2)本申请的化合物的制备方法中，反应可以实现定点、定量、模块化连接，最终可以得到结构明确、均一、质量可控的多特异偶联物。 The application provides a compound, which can be a multispecific bioconjugate linker (T-Linker) or a multispecific conjugate (T-Body). The present application may have one or more of the following effects: (1) The compound of the present application may be a multispecific compound, and the multispecific conjugate may exhibit good antitumor activity, and the IC 50 value may be lower than 10 (2) In the preparation method of the compound of the present application, the reaction can realize fixed-point, quantitative and modular connection, and finally a multi-specific conjugate with a clear structure, uniformity and controllable quality can be obtained.
本申请提供了一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，其具有如式Ia或式Ib所示的结构：The application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof , which has the structure shown in formula Ia or formula Ib:
Figure PCTCN2021130337-appb-000001
Figure PCTCN2021130337-appb-000001
所述Wa为三价基团，Wb为四价基团；The Wa is a trivalent group, and Wb is a tetravalent group;
所述A，B和C各自独立地选自以下组：Said A, B and C are each independently selected from the following group:
Figure PCTCN2021130337-appb-000002
Figure PCTCN2021130337-appb-000002
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
Figure PCTCN2021130337-appb-000003
代表连接位点； wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000003
represents the attachment site;
其中，A，B和C中，
Figure PCTCN2021130337-appb-000004
不能和
Figure PCTCN2021130337-appb-000005
同时存在； Among them, A, B and C,
Figure PCTCN2021130337-appb-000004
cannot and
Figure PCTCN2021130337-appb-000005
simultaneously exist;
其中，A，B和C中，
Figure PCTCN2021130337-appb-000006
不能和
Figure PCTCN2021130337-appb-000007
Figure PCTCN2021130337-appb-000008
同时存在； Among them, A, B and C,
Figure PCTCN2021130337-appb-000006
cannot and
Figure PCTCN2021130337-appb-000007
Figure PCTCN2021130337-appb-000008
simultaneously exist;
其中，A，B和C中，
Figure PCTCN2021130337-appb-000009
不能和
Figure PCTCN2021130337-appb-000010
同时存在； Among them, A, B and C,
Figure PCTCN2021130337-appb-000009
cannot and
Figure PCTCN2021130337-appb-000010
simultaneously exist;
当A，B和C中，
Figure PCTCN2021130337-appb-000011
同时存在时，所述R 12，R 13和R 14不为炔基； When A, B and C,
Figure PCTCN2021130337-appb-000011
When present at the same time, the R 12 , R 13 and R 14 are not alkynyl;
当A，B和C中，
Figure PCTCN2021130337-appb-000012
同时存在时，所述R 12，R 13和R 14不为氨基， When A, B and C,
Figure PCTCN2021130337-appb-000012
When present at the same time, the R 12 , R 13 and R 14 are not amino groups,
A，B和C不同时为
Figure PCTCN2021130337-appb-000013
A, B and C are not simultaneously
Figure PCTCN2021130337-appb-000013
在一种实施方式中的化合物，其中：In one embodiment the compound, wherein:
(1)A为
Figure PCTCN2021130337-appb-000014
B为
Figure PCTCN2021130337-appb-000015
C为
Figure PCTCN2021130337-appb-000016
Figure PCTCN2021130337-appb-000017
(1) A is
Figure PCTCN2021130337-appb-000014
B is
Figure PCTCN2021130337-appb-000015
C is
Figure PCTCN2021130337-appb-000016
Figure PCTCN2021130337-appb-000017
(2)A为
Figure PCTCN2021130337-appb-000018
C为
Figure PCTCN2021130337-appb-000019
或 (2) A is
Figure PCTCN2021130337-appb-000018
C is
Figure PCTCN2021130337-appb-000019
or
(3)A为
Figure PCTCN2021130337-appb-000020
B为
Figure PCTCN2021130337-appb-000021
C为
Figure PCTCN2021130337-appb-000022
Figure PCTCN2021130337-appb-000023
或 (3) A is
Figure PCTCN2021130337-appb-000020
B is
Figure PCTCN2021130337-appb-000021
C is
Figure PCTCN2021130337-appb-000022
Figure PCTCN2021130337-appb-000023
or
(4)A为
Figure PCTCN2021130337-appb-000024
B为
Figure PCTCN2021130337-appb-000025
C为
Figure PCTCN2021130337-appb-000026
Figure PCTCN2021130337-appb-000027
或 (4) A is
Figure PCTCN2021130337-appb-000024
B is
Figure PCTCN2021130337-appb-000025
C is
Figure PCTCN2021130337-appb-000026
Figure PCTCN2021130337-appb-000027
or
(5)A为
Figure PCTCN2021130337-appb-000028
B为
Figure PCTCN2021130337-appb-000029
C为
Figure PCTCN2021130337-appb-000030
或 (5) A is
Figure PCTCN2021130337-appb-000028
B is
Figure PCTCN2021130337-appb-000029
C is
Figure PCTCN2021130337-appb-000030
or
(6)A为
Figure PCTCN2021130337-appb-000031
B为
Figure PCTCN2021130337-appb-000032
C为
Figure PCTCN2021130337-appb-000033
或 (6) A is
Figure PCTCN2021130337-appb-000031
B is
Figure PCTCN2021130337-appb-000032
C is
Figure PCTCN2021130337-appb-000033
or
(7)A为
Figure PCTCN2021130337-appb-000034
Figure PCTCN2021130337-appb-000035
B为
Figure PCTCN2021130337-appb-000036
C为
Figure PCTCN2021130337-appb-000037
或 (7) A is
Figure PCTCN2021130337-appb-000034
Figure PCTCN2021130337-appb-000035
B is
Figure PCTCN2021130337-appb-000036
C is
Figure PCTCN2021130337-appb-000037
or
(8)A为
Figure PCTCN2021130337-appb-000038
Figure PCTCN2021130337-appb-000039
B为
Figure PCTCN2021130337-appb-000040
C为
Figure PCTCN2021130337-appb-000041
Figure PCTCN2021130337-appb-000042
或 (8) A is
Figure PCTCN2021130337-appb-000038
Figure PCTCN2021130337-appb-000039
B is
Figure PCTCN2021130337-appb-000040
C is
Figure PCTCN2021130337-appb-000041
Figure PCTCN2021130337-appb-000042
or
(9)A为
Figure PCTCN2021130337-appb-000043
Figure PCTCN2021130337-appb-000044
B为
Figure PCTCN2021130337-appb-000045
C为
Figure PCTCN2021130337-appb-000046
Figure PCTCN2021130337-appb-000047
或 (9) A is
Figure PCTCN2021130337-appb-000043
Figure PCTCN2021130337-appb-000044
B is
Figure PCTCN2021130337-appb-000045
C is
Figure PCTCN2021130337-appb-000046
Figure PCTCN2021130337-appb-000047
or
(10)A为
Figure PCTCN2021130337-appb-000048
B为
Figure PCTCN2021130337-appb-000049
C为
Figure PCTCN2021130337-appb-000050
或 (10) A is
Figure PCTCN2021130337-appb-000048
B is
Figure PCTCN2021130337-appb-000049
C is
Figure PCTCN2021130337-appb-000050
or
(11)A为
Figure PCTCN2021130337-appb-000051
Figure PCTCN2021130337-appb-000052
B为
Figure PCTCN2021130337-appb-000053
C为
Figure PCTCN2021130337-appb-000054
或 (11) A is
Figure PCTCN2021130337-appb-000051
Figure PCTCN2021130337-appb-000052
B is
Figure PCTCN2021130337-appb-000053
C is
Figure PCTCN2021130337-appb-000054
or
(12)A为
Figure PCTCN2021130337-appb-000055
B为
Figure PCTCN2021130337-appb-000056
C为
Figure PCTCN2021130337-appb-000057
Figure PCTCN2021130337-appb-000058
或 (12) A is
Figure PCTCN2021130337-appb-000055
B is
Figure PCTCN2021130337-appb-000056
C is
Figure PCTCN2021130337-appb-000057
Figure PCTCN2021130337-appb-000058
or
(13)A为
Figure PCTCN2021130337-appb-000059
B为
Figure PCTCN2021130337-appb-000060
C为
Figure PCTCN2021130337-appb-000061
Figure PCTCN2021130337-appb-000062
或 (13) A is
Figure PCTCN2021130337-appb-000059
B is
Figure PCTCN2021130337-appb-000060
C is
Figure PCTCN2021130337-appb-000061
Figure PCTCN2021130337-appb-000062
or
(14)A为
Figure PCTCN2021130337-appb-000063
B为
Figure PCTCN2021130337-appb-000064
C为
Figure PCTCN2021130337-appb-000065
Figure PCTCN2021130337-appb-000066
(14) A is
Figure PCTCN2021130337-appb-000063
B is
Figure PCTCN2021130337-appb-000064
C is
Figure PCTCN2021130337-appb-000065
Figure PCTCN2021130337-appb-000066
(15)A为
Figure PCTCN2021130337-appb-000067
B为
Figure PCTCN2021130337-appb-000068
C为
Figure PCTCN2021130337-appb-000069
(15) A is
Figure PCTCN2021130337-appb-000067
B is
Figure PCTCN2021130337-appb-000068
C is
Figure PCTCN2021130337-appb-000069
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
Figure PCTCN2021130337-appb-000070
代表连接位点； wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000070
represents the attachment site;
当A，B和C中，
Figure PCTCN2021130337-appb-000071
同时存在时，所述R 12，R 13和R 14不为炔基； When A, B and C,
Figure PCTCN2021130337-appb-000071
When present at the same time, the R 12 , R 13 and R 14 are not alkynyl;
当A，B和C中，
Figure PCTCN2021130337-appb-000072
同时存在时，所述R 12，R 13和R 14不为氨基。 When A, B and C,
Figure PCTCN2021130337-appb-000072
When present at the same time, the R 12 , R 13 and R 14 are not amino groups.
在一种实施方式中所述的化合物，其中：In one embodiment, the compound, wherein:
(1)A为
Figure PCTCN2021130337-appb-000073
B为
Figure PCTCN2021130337-appb-000074
C为
Figure PCTCN2021130337-appb-000075
或 (1) A is
Figure PCTCN2021130337-appb-000073
B is
Figure PCTCN2021130337-appb-000074
C is
Figure PCTCN2021130337-appb-000075
or
(2)A为
Figure PCTCN2021130337-appb-000076
B为
Figure PCTCN2021130337-appb-000077
C为
Figure PCTCN2021130337-appb-000078
Figure PCTCN2021130337-appb-000079
或 (2) A is
Figure PCTCN2021130337-appb-000076
B is
Figure PCTCN2021130337-appb-000077
C is
Figure PCTCN2021130337-appb-000078
Figure PCTCN2021130337-appb-000079
or
(3)A为
Figure PCTCN2021130337-appb-000080
B为
Figure PCTCN2021130337-appb-000081
C为
Figure PCTCN2021130337-appb-000082
(3) A is
Figure PCTCN2021130337-appb-000080
B is
Figure PCTCN2021130337-appb-000081
C is
Figure PCTCN2021130337-appb-000082
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
Figure PCTCN2021130337-appb-000083
代表连接位点； wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000083
represents the attachment site;
当A，B和C中，
Figure PCTCN2021130337-appb-000084
同时存在时，所述R 12，R 13和R 14不为氨基。 When A, B and C,
Figure PCTCN2021130337-appb-000084
When present at the same time, the R 12 , R 13 and R 14 are not amino groups.
在一种实施方式中所述的化合物，其中：In one embodiment, the compound, wherein:
(1)A为
Figure PCTCN2021130337-appb-000085
B为
Figure PCTCN2021130337-appb-000086
C为
Figure PCTCN2021130337-appb-000087
或 (1) A is
Figure PCTCN2021130337-appb-000085
B is
Figure PCTCN2021130337-appb-000086
C is
Figure PCTCN2021130337-appb-000087
or
(2)A为
Figure PCTCN2021130337-appb-000088
B为
Figure PCTCN2021130337-appb-000089
C为
Figure PCTCN2021130337-appb-000090
或 (2) A is
Figure PCTCN2021130337-appb-000088
B is
Figure PCTCN2021130337-appb-000089
C is
Figure PCTCN2021130337-appb-000090
or
(3)A为
Figure PCTCN2021130337-appb-000091
B为
Figure PCTCN2021130337-appb-000092
C为
Figure PCTCN2021130337-appb-000093
(3) A is
Figure PCTCN2021130337-appb-000091
B is
Figure PCTCN2021130337-appb-000092
C is
Figure PCTCN2021130337-appb-000093
其中R 12选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺 基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
Figure PCTCN2021130337-appb-000094
代表连接位点； wherein R is selected from the group consisting of hydrogen, protium , deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido, urea, alkane, cycloalkane radicals, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000094
represents the attachment site;
当A，B和C中，
Figure PCTCN2021130337-appb-000095
同时存在时，所述R 12不为氨基。 When A, B and C,
Figure PCTCN2021130337-appb-000095
When both are present, the R 12 is not amino.
在一种实施方式中所述的化合物，其中：In one embodiment, the compound, wherein:
(1)A为
Figure PCTCN2021130337-appb-000096
B为
Figure PCTCN2021130337-appb-000097
C为
Figure PCTCN2021130337-appb-000098
或 (1) A is
Figure PCTCN2021130337-appb-000096
B is
Figure PCTCN2021130337-appb-000097
C is
Figure PCTCN2021130337-appb-000098
or
(2)A为
Figure PCTCN2021130337-appb-000099
B为
Figure PCTCN2021130337-appb-000100
C为
Figure PCTCN2021130337-appb-000101
或 (2) A is
Figure PCTCN2021130337-appb-000099
B is
Figure PCTCN2021130337-appb-000100
C is
Figure PCTCN2021130337-appb-000101
or
(3)A为
Figure PCTCN2021130337-appb-000102
B为
Figure PCTCN2021130337-appb-000103
C为
Figure PCTCN2021130337-appb-000104
(3) A is
Figure PCTCN2021130337-appb-000102
B is
Figure PCTCN2021130337-appb-000103
C is
Figure PCTCN2021130337-appb-000104
其中R 12选自以下组：氢，氕，氘，氚，卤素和链烷基，
Figure PCTCN2021130337-appb-000105
代表连接位点。 wherein R is selected from the group consisting of hydrogen, protium , deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000105
represents the attachment site.
在一种实施方式中所述的化合物，其中：A为
Figure PCTCN2021130337-appb-000106
B为
Figure PCTCN2021130337-appb-000107
C为
Figure PCTCN2021130337-appb-000108
Figure PCTCN2021130337-appb-000109
In one embodiment, the compound, wherein: A is
Figure PCTCN2021130337-appb-000106
B is
Figure PCTCN2021130337-appb-000107
C is
Figure PCTCN2021130337-appb-000108
Figure PCTCN2021130337-appb-000109
其中R 12选自以下组的基团：包括氢，氕，氘，氚，卤素和链烷基，
Figure PCTCN2021130337-appb-000110
代表连接位点。 A group wherein R is selected from the group consisting of hydrogen, protium , deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000110
represents the attachment site.
在一种实施方式中所述的化合物，其中：In one embodiment, the compound, wherein:
Figure PCTCN2021130337-appb-000111
Figure PCTCN2021130337-appb-000111
所述W为三价基团或四价基团，所述W任选地被一个或多个R取代，The W is a trivalent group or a tetravalent group, the W is optionally substituted with one or more Rs,
所述La为-(J 1) m1-C(＝O)-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-； The La is -(J 1 ) m1 -C(=O)-X 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -;
所述Lb为-(J 2) m2-C(＝O)-X 2-(K 2) n2-(Y 2) p2-(L 2) q2-； The Lb is -(J 2 ) m2 -C(=O)-X 2 -(K 2 ) n2 -(Y 2 ) p2 -(L 2 ) q2 -;
所述Lc为-(J 3) m3-C(＝O)-X 3-(K 3) n3-(Y 3) p3-(L 3) q3-； The Lc is -(J 3 ) m3 -C(=O)-X 3 -(K 3 ) n3 -(Y 3 ) p3 -(L 3 ) q3 -;
所述J 1，J 2，J 3，K 1，K 2，K 3，L 1，L 2，和L 3各自独立地选自以下组：链烷基，环烷基，杂环烷基，烯基，炔基，芳基，杂芳基，和聚乙二醇，或前述任意组合； The J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
所述X 1，X 2，X 3，Y 1，Y 2，和Y 3各自独立地选自以下组：-NR 1-，-O-，-S-，-C(＝O)-，-C(＝S)-，-C(R 1a)(R 1b)-，-NR 1-C(＝O)-，-C(＝O)-NR 1-，-NR 1-C(＝S)-，-C(＝S)-NR 1-，-O-C(＝O)-，-C(＝O)-O-，-O-C(＝S)-，-C(＝S)-O-，-O-C(＝O)-O-，-O-C(＝O)-NR 1-，-NR 1-C(＝O)-O-，和-NR 1a-C(＝O)-NR 1b-； Said X 1 , X 2 , X 3 , Y 1 , Y 2 , and Y 3 are each independently selected from the group of: -NR 1 -, -O-, -S-, -C(=O)-, - C(=S)-, -C(R 1a )(R 1b )-, -NR 1 -C(=O)-, -C(=O)-NR 1 -, -NR 1 -C(=S) -, -C(=S)-NR 1 -, -OC(=O)-, -C(=O)-O-, -OC(=S)-, -C(=S)-O-, - OC(=O)-O-, -OC(=O)-NR 1 -, -NR 1 -C(=O)-O-, and -NR 1a -C(=O)-NR 1b -;
R，R 1，R 1a和R 1b各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
Figure PCTCN2021130337-appb-000112
代表连接位点； R, R 1 , R 1a and R 1b are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000112
represents the attachment site;
其中，m1，m2，m3，n1，n2，n3，p1，p2，p3，q1，q2，和q3各自独立地选自0以上的数。Wherein, m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 are each independently selected from a number of 0 or more.
在一种实施方式中所述的化合物，其中，J 1，J 2，和J 3各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合； In one embodiment, the compound, wherein J 1 , J 2 , and J 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing;
其中，m1，m2，和m3各自独立地选自以下组：0、1、2和3。wherein m1, m2, and m3 are each independently selected from the group: 0, 1, 2, and 3.
在一种实施方式中所述的化合物，其中，X 1，X 2，和X 3各自独立地选自以下组：-NH-和-O-。 In one embodiment, the compound , wherein X1, X2, and X3 are each independently selected from the group consisting of -NH- and -O-.
在一种实施方式中所述的化合物，其中，K 1，K 2，和K 3各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合； In one embodiment, the compound, wherein K 1 , K 2 , and K 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing;
其中，n1，n2，和n3各自独立地选自以下组：0、1、2和3。wherein n1, n2, and n3 are each independently selected from the group: 0, 1, 2, and 3.
在一种实施方式中所述的化合物，其中，(K 1) n1，(K 2) n2，和(K 3) n3各自独立地选自以下组：-链烷基-聚乙二醇-链烷基-，链烷基和聚乙二醇，或n1，n2或n3各自独立地为0。 In one embodiment, the compound, wherein (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -alkyi-polyethylene glycol-chain Alkyl-, alkane and polyethylene glycol, or n1, n2 or n3 are each independently zero.
在一种实施方式中所述的化合物，其中，(K 1) n1，(K 2) n2，和(K 3) n3各自独立地选自以下组：-(CH 2)-(CH 2-O-CH 2) 3-(CH 2)-，-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-，-(CH 2) 2-，和-(CH 2) 8-，或n1，n2或n3各自独立地为0。 In one embodiment, the compound, wherein (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -(CH 2 )-(CH 2 -O -CH 2 ) 3 -(CH 2 )-, -(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -, -(CH 2 ) 2 -, and -(CH 2 ) 8 -, or n1, n2 or n3 are each independently 0.
在一种实施方式中所述的化合物，其中，Y 1，Y 2，和Y 3各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-； In one embodiment, the compound, wherein Y 1 , Y 2 , and Y 3 are each independently selected from the group consisting of: -C(=O)-, -NR 1 -C(=O)-,- NR 1 -, and -O-;
R 1选自以下组：氢，氕，氘，氚，和链烷基； R 1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane;
其中，n1，n2，和n3各自独立地选自以下组：0、1、2和3。wherein n1, n2, and n3 are each independently selected from the group: 0, 1, 2, and 3.
在一种实施方式中所述的化合物，其中，(Y 1) p1，(Y 2) p2，和(Y 3) p3各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-，R 1选自以下组：氢，氕，氘，氚，和链烷基；或p1，p2或p3各自独立地为0。 In one embodiment, the compound, wherein (Y 1 ) p1 , (Y 2 ) p2 , and (Y 3 ) p3 are each independently selected from the group consisting of: -C(=O)-, -NR 1 -C( = O)-, -NR1-, and -O-, R1 are selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; or p1, p2 or p3 are each independently 0.
在一种实施方式中所述的化合物，其中，L 1，L 2，和L 3各自独立地选自以下组：链烷基，和芳基，或前述任意组合；其中，q1，q2，和q3各自独立地选自以下组：0、1、2和3。 In one embodiment, the compound, wherein L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, and aryl, or any combination of the foregoing; wherein q1 , q2 , and q3 is each independently selected from the group consisting of 0, 1, 2, and 3.
在一种实施方式中所述的化合物，其中，(L 1) q1，(L 2) q2，和(L 3) q3各自独立地选自以下组：-链烷基-芳基-，链烷基和聚乙二醇，或q1，q2和q3各自独立地为0。 In one embodiment, the compound, wherein (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of - alkane-aryl-, alkane radical and polyethylene glycol, or q1, q2 and q3 are each independently zero.
在一种实施方式中所述的化合物，其中，(L 1) q1，(L 2) q2，和(L 3) q3各自独立地选自以下组：-CH 2-芳基-，-(CH 2) 2-，和-CH 2-，或q1，q2和q3各自独立地为0。 In one embodiment, the compound, wherein (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of: -CH 2 -aryl-, -(CH 2 ) 2- , and -CH2- , or q1, q2 and q3 are each independently 0.
例如，La、Lb和Lc可以各自独立地选自以下组：-C(＝O)-NH-(CH 2) 8-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 8-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 8-NH-，-C(＝O)-NH-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-NH-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-和-C(＝O)-O-。 For example, La, Lb, and Lc may each be independently selected from the group: -C(=O)-NH-( CH2 ) 8 -NH-C(=O) -CH2 -phenyl-, -C(= O)-NH-(CH 2 ) 8 -NH-C(=O)-CH 2 -, -C(=O)-NH-(CH 2 ) 8 -NH-, -C(=O)-NH- (CH 2 ) 2 -NH-C(=O)-CH 2 -phenyl-, -C(=O)-NH-(CH 2 ) 2 -NH-C(=O)-CH 2 -, -C (=O)-NH-(CH 2 ) 2 -NH-, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- C(=O) -CH2 -phenyl-,-C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH-C(= O)-CH 2 -, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- and -C(=O)-O -.
例如，La、Lb和Lc可以各自独立地选自以下组：-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-和-C(＝O)-O-。 For example, La, Lb and Lc can each be independently selected from the group: -C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH- C(=O) -CH2 -phenyl-,-C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH-C(= O)-CH 2 -, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- and -C(=O)-O -.
在一种实施方式中所述的化合物，其中：In one embodiment, the compound, wherein:
W选自以下组：W is selected from the following group:
Figure PCTCN2021130337-appb-000113
三价的链烷基，三价的环烷基，三价的杂环烷基，三价的烯基，三价的炔基，三价的芳基，和三价的杂芳基。
Figure PCTCN2021130337-appb-000113
Trivalent alkane, trivalent cycloalkyl, trivalent heterocycloalkyl, trivalent alkenyl, trivalent alkynyl, trivalent aryl, and trivalent heteroaryl.
在一种实施方式中所述的化合物，其中：In one embodiment, the compound, wherein:
W选自以下组：W is selected from the following group:
Figure PCTCN2021130337-appb-000114
Figure PCTCN2021130337-appb-000114
所述X 1，X 2，X 3，X 4，X 5，X 6，X 7，X 8，X 9，X 10，X 11，X 12，X 13，X 14，X 15，X 16，X 17和X 18各自独立地选自以下组：C，N，O，S，P，CH，CH 2，NH，P(O)和P(S)； The X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 and X 18 are each independently selected from the group consisting of C, N, O, S, P, CH, CH 2 , NH, P(O) and P(S);
W选自以下组：W is selected from the following group:
Figure PCTCN2021130337-appb-000115
Figure PCTCN2021130337-appb-000115
Figure PCTCN2021130337-appb-000116
Figure PCTCN2021130337-appb-000116
在一种实施方式中所述的化合物，其选自以下组：In one embodiment, the compound is selected from the group consisting of:
Figure PCTCN2021130337-appb-000117
Figure PCTCN2021130337-appb-000117
Figure PCTCN2021130337-appb-000118
Figure PCTCN2021130337-appb-000118
Figure PCTCN2021130337-appb-000119
Figure PCTCN2021130337-appb-000119
Figure PCTCN2021130337-appb-000120
Figure PCTCN2021130337-appb-000120
在一种实施方式中所述的化合物，其选自以下组：In one embodiment, the compound is selected from the group consisting of:
Figure PCTCN2021130337-appb-000121
Figure PCTCN2021130337-appb-000121
一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，其具有如式IIa或式IIb所示的结构，其中：A compound or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, having as The structure shown in formula IIa or formula IIb, wherein:
Figure PCTCN2021130337-appb-000122
Figure PCTCN2021130337-appb-000122
所述Wc为三价基团，Wd为四价基团；The Wc is a trivalent group, and Wd is a tetravalent group;
所述A 2，B 2和C 2各自独立地选自以下组： Said A 2 , B 2 and C 2 are each independently selected from the following group:
Figure PCTCN2021130337-appb-000123
Figure PCTCN2021130337-appb-000124
和共价键；
Figure PCTCN2021130337-appb-000123
Figure PCTCN2021130337-appb-000124
and covalent bonds;
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基， wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000125
代表连接位点，
Figure PCTCN2021130337-appb-000125
represents the attachment site,
所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接； The two linking sites of the A2 are arbitrarily linked to Wc and P1, the two linking sites of the B2 are arbitrarily linked to Wc and P2, the two linking sites of the C2 are arbitrarily linked Connect with Wc and P3 ;
其中P 1，P 2和P 3各自独立地选自以下组：脂质、蛋白质、核酸、小分子和多糖，或其任意组合。 wherein P 1 , P 2 and P 3 are each independently selected from the group consisting of lipids, proteins, nucleic acids, small molecules and polysaccharides, or any combination thereof.
在一种实施方式中所述的化合物，其中：In one embodiment, the compound, wherein:
(1)A 2为
Figure PCTCN2021130337-appb-000126
B 2为
Figure PCTCN2021130337-appb-000127
C 2为
Figure PCTCN2021130337-appb-000128
Figure PCTCN2021130337-appb-000129
Figure PCTCN2021130337-appb-000130
或共价键；或 (1) A 2 is
Figure PCTCN2021130337-appb-000126
B2 is
Figure PCTCN2021130337-appb-000127
C2 is
Figure PCTCN2021130337-appb-000128
Figure PCTCN2021130337-appb-000129
Figure PCTCN2021130337-appb-000130
or covalent bond; or
(2)A 2为
Figure PCTCN2021130337-appb-000131
Figure PCTCN2021130337-appb-000132
B 2为
Figure PCTCN2021130337-appb-000133
Figure PCTCN2021130337-appb-000134
C 2为
Figure PCTCN2021130337-appb-000135
Figure PCTCN2021130337-appb-000136
或共价键；或 (2) A 2 is
Figure PCTCN2021130337-appb-000131
Figure PCTCN2021130337-appb-000132
B2 is
Figure PCTCN2021130337-appb-000133
Figure PCTCN2021130337-appb-000134
C2 is
Figure PCTCN2021130337-appb-000135
Figure PCTCN2021130337-appb-000136
or covalent bond; or
(3)A 2为
Figure PCTCN2021130337-appb-000137
B 2为
Figure PCTCN2021130337-appb-000138
C 2为
Figure PCTCN2021130337-appb-000139
Figure PCTCN2021130337-appb-000140
或共价键；或 (3) A 2 is
Figure PCTCN2021130337-appb-000137
B2 is
Figure PCTCN2021130337-appb-000138
C2 is
Figure PCTCN2021130337-appb-000139
Figure PCTCN2021130337-appb-000140
or covalent bond; or
(4)A 2为
Figure PCTCN2021130337-appb-000141
B 2为
Figure PCTCN2021130337-appb-000142
C 2为
Figure PCTCN2021130337-appb-000143
Figure PCTCN2021130337-appb-000144
或共价键；或 (4) A 2 is
Figure PCTCN2021130337-appb-000141
B2 is
Figure PCTCN2021130337-appb-000142
C2 is
Figure PCTCN2021130337-appb-000143
Figure PCTCN2021130337-appb-000144
or covalent bond; or
(5)A 2为
Figure PCTCN2021130337-appb-000145
Figure PCTCN2021130337-appb-000146
B 2为
Figure PCTCN2021130337-appb-000147
C 2为
Figure PCTCN2021130337-appb-000148
Figure PCTCN2021130337-appb-000149
Figure PCTCN2021130337-appb-000150
或共价键；或 (5) A 2 is
Figure PCTCN2021130337-appb-000145
Figure PCTCN2021130337-appb-000146
B2 is
Figure PCTCN2021130337-appb-000147
C2 is
Figure PCTCN2021130337-appb-000148
Figure PCTCN2021130337-appb-000149
Figure PCTCN2021130337-appb-000150
or covalent bond; or
(6)A 2为
Figure PCTCN2021130337-appb-000151
Figure PCTCN2021130337-appb-000152
B 2为
Figure PCTCN2021130337-appb-000153
Figure PCTCN2021130337-appb-000154
C 2为
Figure PCTCN2021130337-appb-000155
Figure PCTCN2021130337-appb-000156
或共价键；或 (6) A 2 is
Figure PCTCN2021130337-appb-000151
Figure PCTCN2021130337-appb-000152
B2 is
Figure PCTCN2021130337-appb-000153
Figure PCTCN2021130337-appb-000154
C2 is
Figure PCTCN2021130337-appb-000155
Figure PCTCN2021130337-appb-000156
or covalent bond; or
(7)A 2为
Figure PCTCN2021130337-appb-000157
Figure PCTCN2021130337-appb-000158
B 2为
Figure PCTCN2021130337-appb-000159
C 2为
Figure PCTCN2021130337-appb-000160
或共价键；或 (7) A 2 is
Figure PCTCN2021130337-appb-000157
Figure PCTCN2021130337-appb-000158
B2 is
Figure PCTCN2021130337-appb-000159
C2 is
Figure PCTCN2021130337-appb-000160
or covalent bond; or
(8)A 2为
Figure PCTCN2021130337-appb-000161
Figure PCTCN2021130337-appb-000162
Figure PCTCN2021130337-appb-000163
B 2为
Figure PCTCN2021130337-appb-000164
C 2为
Figure PCTCN2021130337-appb-000165
或共价键；或 (8) A 2 is
Figure PCTCN2021130337-appb-000161
Figure PCTCN2021130337-appb-000162
Figure PCTCN2021130337-appb-000163
B2 is
Figure PCTCN2021130337-appb-000164
C2 is
Figure PCTCN2021130337-appb-000165
or covalent bond; or
(9)A 2为
Figure PCTCN2021130337-appb-000166
Figure PCTCN2021130337-appb-000167
Figure PCTCN2021130337-appb-000168
B 2为
Figure PCTCN2021130337-appb-000169
C 2为
Figure PCTCN2021130337-appb-000170
或共价键；或 (9) A 2 is
Figure PCTCN2021130337-appb-000166
Figure PCTCN2021130337-appb-000167
Figure PCTCN2021130337-appb-000168
B2 is
Figure PCTCN2021130337-appb-000169
C2 is
Figure PCTCN2021130337-appb-000170
or covalent bond; or
(10)A 2为
Figure PCTCN2021130337-appb-000171
Figure PCTCN2021130337-appb-000172
Figure PCTCN2021130337-appb-000173
或共价键，B 2为共价键，C 2为共价键；或 (10) A 2 is
Figure PCTCN2021130337-appb-000171
Figure PCTCN2021130337-appb-000172
Figure PCTCN2021130337-appb-000173
Or a covalent bond, B 2 is a covalent bond, and C 2 is a covalent bond; or
(11)A 2为
Figure PCTCN2021130337-appb-000174
B 2为
Figure PCTCN2021130337-appb-000175
Figure PCTCN2021130337-appb-000176
C 2为
Figure PCTCN2021130337-appb-000177
Figure PCTCN2021130337-appb-000178
Figure PCTCN2021130337-appb-000179
或共价键；或 (11) A 2 is
Figure PCTCN2021130337-appb-000174
B2 is
Figure PCTCN2021130337-appb-000175
Figure PCTCN2021130337-appb-000176
C2 is
Figure PCTCN2021130337-appb-000177
Figure PCTCN2021130337-appb-000178
Figure PCTCN2021130337-appb-000179
or covalent bond; or
(12)A 2为
Figure PCTCN2021130337-appb-000180
B 2为
Figure PCTCN2021130337-appb-000181
C 2为
Figure PCTCN2021130337-appb-000182
Figure PCTCN2021130337-appb-000183
或共价键；或 (12) A 2 is
Figure PCTCN2021130337-appb-000180
B2 is
Figure PCTCN2021130337-appb-000181
C2 is
Figure PCTCN2021130337-appb-000182
Figure PCTCN2021130337-appb-000183
or covalent bond; or
(13)A 2为
Figure PCTCN2021130337-appb-000184
B 2为
Figure PCTCN2021130337-appb-000185
C 2为
Figure PCTCN2021130337-appb-000186
或共价键； (13) A 2 is
Figure PCTCN2021130337-appb-000184
B2 is
Figure PCTCN2021130337-appb-000185
C2 is
Figure PCTCN2021130337-appb-000186
or covalent bond;
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基， wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000187
代表连接位点，
Figure PCTCN2021130337-appb-000187
represents the attachment site,
所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。 The two linking sites of the A2 are arbitrarily linked to Wc and P1, the two linking sites of the B2 are arbitrarily linked to Wc and P2, the two linking sites of the C2 are arbitrarily linked Connect with Wc and P3 .
在一种实施方式中所述的化合物，其中：In one embodiment, the compound, wherein:
(1)A 2为
Figure PCTCN2021130337-appb-000188
B 2为
Figure PCTCN2021130337-appb-000189
Figure PCTCN2021130337-appb-000190
C 2为
Figure PCTCN2021130337-appb-000191
或共价键；或 (1) A 2 is
Figure PCTCN2021130337-appb-000188
B2 is
Figure PCTCN2021130337-appb-000189
Figure PCTCN2021130337-appb-000190
C2 is
Figure PCTCN2021130337-appb-000191
or covalent bond; or
(2)A 2为
Figure PCTCN2021130337-appb-000192
B 2为
Figure PCTCN2021130337-appb-000193
Figure PCTCN2021130337-appb-000194
C 2为
Figure PCTCN2021130337-appb-000195
Figure PCTCN2021130337-appb-000196
或共价键；或 (2) A 2 is
Figure PCTCN2021130337-appb-000192
B2 is
Figure PCTCN2021130337-appb-000193
Figure PCTCN2021130337-appb-000194
C2 is
Figure PCTCN2021130337-appb-000195
Figure PCTCN2021130337-appb-000196
or covalent bond; or
(3)A 2为
Figure PCTCN2021130337-appb-000197
Figure PCTCN2021130337-appb-000198
B 2为
Figure PCTCN2021130337-appb-000199
C 2为
Figure PCTCN2021130337-appb-000200
Figure PCTCN2021130337-appb-000201
或共价键； (3) A 2 is
Figure PCTCN2021130337-appb-000197
Figure PCTCN2021130337-appb-000198
B2 is
Figure PCTCN2021130337-appb-000199
C2 is
Figure PCTCN2021130337-appb-000200
Figure PCTCN2021130337-appb-000201
or covalent bond;
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基， wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000202
代表连接位点，所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。
Figure PCTCN2021130337-appb-000202
Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
在一种实施方式中所述的化合物，其中：In one embodiment, the compound, wherein:
(1)A 2为
Figure PCTCN2021130337-appb-000203
B 2为
Figure PCTCN2021130337-appb-000204
Figure PCTCN2021130337-appb-000205
C 2为
Figure PCTCN2021130337-appb-000206
或共价键；或 (1) A 2 is
Figure PCTCN2021130337-appb-000203
B2 is
Figure PCTCN2021130337-appb-000204
Figure PCTCN2021130337-appb-000205
C2 is
Figure PCTCN2021130337-appb-000206
or covalent bond; or
(2)A 2为
Figure PCTCN2021130337-appb-000207
B 2为
Figure PCTCN2021130337-appb-000208
C 2为
Figure PCTCN2021130337-appb-000209
或共价键；或 (2) A 2 is
Figure PCTCN2021130337-appb-000207
B2 is
Figure PCTCN2021130337-appb-000208
C2 is
Figure PCTCN2021130337-appb-000209
or covalent bond; or
(3)A 2为
Figure PCTCN2021130337-appb-000210
B 2为
Figure PCTCN2021130337-appb-000211
Figure PCTCN2021130337-appb-000212
C 2为
Figure PCTCN2021130337-appb-000213
或共价键； (3) A 2 is
Figure PCTCN2021130337-appb-000210
B2 is
Figure PCTCN2021130337-appb-000211
Figure PCTCN2021130337-appb-000212
C2 is
Figure PCTCN2021130337-appb-000213
or covalent bond;
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基， wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000214
代表连接位点，所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。
Figure PCTCN2021130337-appb-000214
Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
在一种实施方式中所述的化合物，其中：In one embodiment, the compound, wherein:
(1)A 2为
Figure PCTCN2021130337-appb-000215
B 2为
Figure PCTCN2021130337-appb-000216
Figure PCTCN2021130337-appb-000217
C 2为
Figure PCTCN2021130337-appb-000218
或共价键；或 (1) A 2 is
Figure PCTCN2021130337-appb-000215
B2 is
Figure PCTCN2021130337-appb-000216
Figure PCTCN2021130337-appb-000217
C2 is
Figure PCTCN2021130337-appb-000218
or covalent bond; or
(2)A 2为
Figure PCTCN2021130337-appb-000219
B 2为
Figure PCTCN2021130337-appb-000220
C 2为
Figure PCTCN2021130337-appb-000221
或共价键；或 (2) A 2 is
Figure PCTCN2021130337-appb-000219
B2 is
Figure PCTCN2021130337-appb-000220
C2 is
Figure PCTCN2021130337-appb-000221
or covalent bond; or
(3)A 2为
Figure PCTCN2021130337-appb-000222
B 2为
Figure PCTCN2021130337-appb-000223
Figure PCTCN2021130337-appb-000224
C 2为
Figure PCTCN2021130337-appb-000225
或共价键； (3) A 2 is
Figure PCTCN2021130337-appb-000222
B2 is
Figure PCTCN2021130337-appb-000223
Figure PCTCN2021130337-appb-000224
C2 is
Figure PCTCN2021130337-appb-000225
or covalent bond;
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素和链烷基， wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000226
代表连接位点，所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。
Figure PCTCN2021130337-appb-000226
Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
在一种实施方式中所述的化合物，其中：A 2为
Figure PCTCN2021130337-appb-000227
Figure PCTCN2021130337-appb-000228
B 2为
Figure PCTCN2021130337-appb-000229
Figure PCTCN2021130337-appb-000230
C 2为
Figure PCTCN2021130337-appb-000231
或共价键；其中R 12，R 13和 R 14各自独立地选自以下组：氢，氕，氘，氚，卤素和链烷基，
Figure PCTCN2021130337-appb-000232
代表连接位点，所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。 The compound described in one embodiment, wherein: A 2 is
Figure PCTCN2021130337-appb-000227
Figure PCTCN2021130337-appb-000228
B2 is
Figure PCTCN2021130337-appb-000229
Figure PCTCN2021130337-appb-000230
C2 is
Figure PCTCN2021130337-appb-000231
or a covalent bond; wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000232
Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
在一种实施方式中所述的化合物，其中：A 2为
Figure PCTCN2021130337-appb-000233
B 2为，
Figure PCTCN2021130337-appb-000234
C 2为
Figure PCTCN2021130337-appb-000235
或共价键；其中R 12选自以下组：氢，氕，氘，氚，卤素和链烷基，
Figure PCTCN2021130337-appb-000236
代表连接位点，所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。 The compound described in one embodiment, wherein: A 2 is
Figure PCTCN2021130337-appb-000233
B2 is,
Figure PCTCN2021130337-appb-000234
C2 is
Figure PCTCN2021130337-appb-000235
or a covalent bond; wherein R 12 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000236
Represents the attachment sites, the two attachment sites of the A2 are arbitrarily attached to Wc and P1, the two attachment sites of the B2 are arbitrarily attached to Wc and P2, the two attachment sites of the C2 The attachment site is arbitrarily attached to Wc and P3 .
在一种实施方式中所述的化合物，其中：In one embodiment, the compound, wherein:
Figure PCTCN2021130337-appb-000237
为
Figure PCTCN2021130337-appb-000238
Figure PCTCN2021130337-appb-000237
for
Figure PCTCN2021130337-appb-000238
Figure PCTCN2021130337-appb-000239
为
Figure PCTCN2021130337-appb-000240
Figure PCTCN2021130337-appb-000239
for
Figure PCTCN2021130337-appb-000240
所述W为三价基团或四价基团，所述W任选地被一个或多个R取代，The W is a trivalent group or a tetravalent group, the W is optionally substituted with one or more Rs,
所述La为-(J 1) m1-C(＝O)-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-； The La is -(J 1 ) m1 -C(=O)-X 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -;
所述Lb为-(J 2) m2-C(＝O)-X 2-(K 2) n2-(Y 2) p2-(L 2) q2-； The Lb is -(J 2 ) m2 -C(=O)-X 2 -(K 2 ) n2 -(Y 2 ) p2 -(L 2 ) q2 -;
所述Lc为-(J 3) m3-C(＝O)-X 3-(K 3) n3-(Y 3) p3-(L 3) q3-； The Lc is -(J 3 ) m3 -C(=O)-X 3 -(K 3 ) n3 -(Y 3 ) p3 -(L 3 ) q3 -;
所述J 1，J 2，J 3，K 1，K 2，K 3，L 1，L 2，和L 3各自独立地选自以下组：链烷基，环烷基，杂环烷基，烯基，炔基，芳基，杂芳基，和聚乙二醇，或前述任意组合； The J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
所述X 1，X 2，X 3，Y 1，Y 2，和Y 3各自独立地选自以下组：-NR 1-，-O-，-S-，-C(＝O)-，-C(＝S)-，-C(R 1a)(R 1b)-，-NR 1-C(＝O)-，-C(＝O)-NR 1-，-NR 1-C(＝S)-，-C(＝S)-NR 1-，-O-C(＝O)-，-C(＝O)-O-，-O-C(＝S)-，-C(＝S)-O-，-O-C(＝O)-O-，-O-C(＝O)-NR 1-，-NR 1-C(＝O)-O-，和-NR 1a-C(＝O)-NR 1b-； Said X 1 , X 2 , X 3 , Y 1 , Y 2 , and Y 3 are each independently selected from the group of: -NR 1 -, -O-, -S-, -C(=O)-, - C(=S)-, -C(R 1a )(R 1b )-, -NR 1 -C(=O)-, -C(=O)-NR 1 -, -NR 1 -C(=S) -, -C(=S)-NR 1 -, -OC(=O)-, -C(=O)-O-, -OC(=S)-, -C(=S)-O-, - OC(=O)-O-, -OC(=O)-NR 1 -, -NR 1 -C(=O)-O-, and -NR 1a -C(=O)-NR 1b -;
R，R 1，R 1a和R 1b各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
Figure PCTCN2021130337-appb-000241
代表连接位点； R, R 1 , R 1a and R 1b are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000241
represents the attachment site;
其中，m1，m2，m3，n1，n2，n3，p1，p2，p3，q1，q2，和q3各自独立地选自0以上的数。Wherein, m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 are each independently selected from a number of 0 or more.
在一种实施方式中所述的化合物，其中，J 1，J 2，和J 3各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合； In one embodiment, the compound, wherein J 1 , J 2 , and J 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing;
其中，m1，m2，和m3各自独立地选自以下组：0、1、2和3。wherein m1, m2, and m3 are each independently selected from the group: 0, 1, 2, and 3.
在一种实施方式中所述的化合物，其中，X 1，X 2，和X 3各自独立地选自以下组：-NH-和-O-。 In one embodiment, the compound , wherein X1, X2, and X3 are each independently selected from the group consisting of -NH- and -O-.
在一种实施方式中所述的化合物，其中，K 1，K 2，和K 3各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合；其中，n1，n2，和n3各自独立地选自以下组：0、1、2和3。 In one embodiment, the compound, wherein K 1 , K 2 , and K 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein n1, n2 , and n3 are each independently selected from the group consisting of 0, 1, 2, and 3.
在一种实施方式中所述的化合物，其中，(K 1) n1，(K 2) n2，和(K 3) n3各自独立地选自以下组：-链烷基-聚乙二醇-链烷基-，链烷基和聚乙二醇，或n1，n2或n3各自独立地为0。 In one embodiment, the compound, wherein (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -alkyi-polyethylene glycol-chain Alkyl-, alkane and polyethylene glycol, or n1, n2 or n3 are each independently zero.
在一种实施方式中所述的化合物，其中，(K 1) n1，(K 2) n2，和(K 3) n3各自独立地选自以下组：-(CH 2)-(CH 2-O-CH 2) 3-(CH 2)-，-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-，-(CH 2) 2-，和-(CH 2) 8-，或n1，n2或n3各自独立地为0。 In one embodiment, the compound, wherein (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -(CH 2 )-(CH 2 -O -CH 2 ) 3 -(CH 2 )-, -(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -, -(CH 2 ) 2 -, and -(CH 2 ) 8 -, or n1, n2 or n3 are each independently 0.
在一种实施方式中所述的化合物，其中，Y 1，Y 2，和Y 3各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-；R 1选自以下组：氢，氕，氘，氚，和链烷基；其中，n1，n2，和n3各自独立地选自以下组：0、1、2和3。 In one embodiment, the compound, wherein Y 1 , Y 2 , and Y 3 are each independently selected from the group consisting of: -C(=O)-, -NR 1 -C(=O)-,- NR 1 -, and -O-; R 1 is selected from the following group: hydrogen, protium, deuterium, tritium, and alkane; wherein n1, n2, and n3 are each independently selected from the following group: 0, 1, 2 and 3.
在一种实施方式中所述的化合物，其中，(Y 1) p1，(Y 2) p2，和(Y 3) p3各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-，R 1选自以下组：氢，氕，氘，氚，和链烷基；或p1，p2或p3各自独立地为0。 In one embodiment, the compound, wherein (Y 1 ) p1 , (Y 2 ) p2 , and (Y 3 ) p3 are each independently selected from the group consisting of: -C(=O)-, -NR 1 -C( = O)-, -NR1-, and -O-, R1 are selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; or p1, p2 or p3 are each independently 0.
在一种实施方式中所述的化合物，其中，L 1，L 2，和L 3各自独立地选自以下组：链烷基，和芳基，或前述任意组合；其中，q1，q2，和q3各自独立地选自以下组：0、1、2和3。 In one embodiment, the compound, wherein L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, and aryl, or any combination of the foregoing; wherein q1 , q2 , and q3 is each independently selected from the group consisting of 0, 1, 2, and 3.
在一种实施方式中所述的化合物，其中，(L 1) q1，(L 2) q2，和(L 3) q3各自独立地选自以下组：-链烷基-芳基-，链烷基和聚乙二醇，或q1，q2和q3各自独立地为0。 In one embodiment, the compound, wherein (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of - alkane-aryl-, alkane radical and polyethylene glycol, or q1, q2 and q3 are each independently zero.
在一种实施方式中所述的化合物，其中，(L 1) q1，(L 2) q2，和(L 3) q3各自独立地选自以下组：-CH 2-芳基-，-(CH 2) 2-，和-CH 2-，或q1，q2和q3各自独立地为0。 In one embodiment, the compound, wherein (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of: -CH 2 -aryl-, -(CH 2 ) 2- , and -CH2- , or q1, q2 and q3 are each independently 0.
在一种实施方式中所述的化合物，其中：In one embodiment, the compound, wherein:
W选自以下组：W is selected from the following group:
Figure PCTCN2021130337-appb-000242
三价的链烷基，三价的环烷基，三价的杂环烷基，三价的烯基，三价的炔基，三价的芳基，和三价的杂芳基。
Figure PCTCN2021130337-appb-000242
Trivalent alkane, trivalent cycloalkyl, trivalent heterocycloalkyl, trivalent alkenyl, trivalent alkynyl, trivalent aryl, and trivalent heteroaryl.
在一种实施方式中所述的化合物，其中：In one embodiment, the compound, wherein:
W选自以下组：W is selected from the following group:
Figure PCTCN2021130337-appb-000243
Figure PCTCN2021130337-appb-000243
所述X 1，X 2，X 3，X 4，X 5，X 6，X 7，X 8，X 9，X 10，X 11，X 12，X 13，X 14，X 15，X 16，X 17和X 18各自独立地选自以下组：C，N，O，S，P，CH，CH 2，NH，P(O)和P(S)； The X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 and X 18 are each independently selected from the group consisting of C, N, O, S, P, CH, CH 2 , NH, P(O) and P(S);
所述---表示双键或单键。The --- represents a double bond or a single bond.
在一种实施方式中所述的化合物，其中：In one embodiment, the compound, wherein:
W选自以下组：W is selected from the following group:
Figure PCTCN2021130337-appb-000244
Figure PCTCN2021130337-appb-000244
Figure PCTCN2021130337-appb-000245
Figure PCTCN2021130337-appb-000245
Figure PCTCN2021130337-appb-000246
Figure PCTCN2021130337-appb-000246
在一种实施方式中所述的化合物，其中P 1，P 2和P 3各自独立地选自以下组：核酸分子、染料分子、细胞因子、抗原、和抗体或其抗原结合片段，或前述任意组合。 In one embodiment the compound , wherein P1, P2 and P3 are each independently selected from the group consisting of nucleic acid molecules, dye molecules, cytokines, antigens, and antibodies or antigen-binding fragments thereof, or any of the foregoing combination.
在一种实施方式中所述的化合物，其中所述抗体选自下组：单克隆抗体、单链抗体、嵌合抗体、人源化抗体、全人源抗体和纳米抗体。In one embodiment the compound, wherein the antibody is selected from the group consisting of monoclonal antibodies, single chain antibodies, chimeric antibodies, humanized antibodies, fully human antibodies, and nanobodies.
在一种实施方式中所述的化合物，其中所述抗体靶向选自下组的靶点：4-1BB、EGFR、CD3、Her2、CD47和CD20。In one embodiment the compound, wherein the antibody targets a target selected from the group consisting of 4-1BB, EGFR, CD3, Her2, CD47 and CD20.
在一种实施方式中所述的化合物，其中所述抗体的氨基酸序列选自以下组：SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:10、SEQ ID NO:11、和SEQ ID NO:12。In one embodiment the compound, wherein the amino acid sequence of the antibody is selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 10, SEQ ID NO: : 11, and SEQ ID NO: 12.
在一种实施方式中所述的化合物，其选自以下组：In one embodiment, the compound is selected from the group consisting of:
Figure PCTCN2021130337-appb-000247
Figure PCTCN2021130337-appb-000247
Figure PCTCN2021130337-appb-000248
Figure PCTCN2021130337-appb-000248
其中，P 1，P 2和P 3各自独立地选自靶向选自下组的靶点的抗体：4-1BB、EGFR、CD3、Her2、CD47和CD20。 wherein P1, P2 and P3 are each independently selected from antibodies targeting a target selected from the group consisting of 4-1BB, EGFR, CD3, Her2, CD47 and CD20.
在一种实施方式中所述的化合物，其为：The compound described in one embodiment is:
Figure PCTCN2021130337-appb-000249
Figure PCTCN2021130337-appb-000249
其中，P 1，P 2和P 3的氨基酸序列可以分别为： Wherein, the amino acid sequences of P 1 , P 2 and P 3 can be respectively:
SEQ ID NO:1、SEQ ID NO:2、和SEQ ID NO:3，或SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, or
SEQ ID NO:1、SEQ ID NO:10、和SEQ ID NO:3，或SEQ ID NO: 1, SEQ ID NO: 10, and SEQ ID NO: 3, or
SEQ ID NO:1、SEQ ID NO:11、和SEQ ID NO:3，或SEQ ID NO: 1, SEQ ID NO: 11, and SEQ ID NO: 3, or
SEQ ID NO:1、SEQ ID NO:12、和SEQ ID NO:3，或SEQ ID NO: 1, SEQ ID NO: 12, and SEQ ID NO: 3, or
SEQ ID NO:10、SEQ ID NO:2、和SEQ ID NO:3，或SEQ ID NO: 10, SEQ ID NO: 2, and SEQ ID NO: 3, or
SEQ ID NO:11、SEQ ID NO:2、和SEQ ID NO:3，或SEQ ID NO:11, SEQ ID NO:2, and SEQ ID NO:3, or
SEQ ID NO:12、SEQ ID NO:2、和SEQ ID NO:3，或SEQ ID NO: 12, SEQ ID NO: 2, and SEQ ID NO: 3, or
SEQ ID NO:1、SEQ ID NO:2、和SEQ ID NO:10，或SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 10, or
SEQ ID NO:1、SEQ ID NO:2、和SEQ ID NO:11，或SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 11, or
SEQ ID NO:1、SEQ ID NO:2、和SEQ ID NO:12，或SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 12, or
SEQ ID NO:10、SEQ ID NO:11、和SEQ ID NO:12。SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12.
在一种实施方式中，本申请提供一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，其可以具有如式Ia或式Ib所示的结构：In one embodiment, the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, which can have the structure shown in formula Ia or formula Ib:
Figure PCTCN2021130337-appb-000250
Figure PCTCN2021130337-appb-000250
其中：in:
Figure PCTCN2021130337-appb-000251
为
Figure PCTCN2021130337-appb-000252
Figure PCTCN2021130337-appb-000251
for
Figure PCTCN2021130337-appb-000252
Figure PCTCN2021130337-appb-000253
为
Figure PCTCN2021130337-appb-000254
Figure PCTCN2021130337-appb-000253
for
Figure PCTCN2021130337-appb-000254
其中：in:
(1)A为
Figure PCTCN2021130337-appb-000255
B为
Figure PCTCN2021130337-appb-000256
C为
Figure PCTCN2021130337-appb-000257
或 (1) A is
Figure PCTCN2021130337-appb-000255
B is
Figure PCTCN2021130337-appb-000256
C is
Figure PCTCN2021130337-appb-000257
or
(2)A为
Figure PCTCN2021130337-appb-000258
B为
Figure PCTCN2021130337-appb-000259
C为
Figure PCTCN2021130337-appb-000260
或 (2) A is
Figure PCTCN2021130337-appb-000258
B is
Figure PCTCN2021130337-appb-000259
C is
Figure PCTCN2021130337-appb-000260
or
(3)A为
Figure PCTCN2021130337-appb-000261
B为
Figure PCTCN2021130337-appb-000262
C为
Figure PCTCN2021130337-appb-000263
(3) A is
Figure PCTCN2021130337-appb-000261
B is
Figure PCTCN2021130337-appb-000262
C is
Figure PCTCN2021130337-appb-000263
其中R 12选自以下组：氢，氕，氘，氚，卤素和链烷基，
Figure PCTCN2021130337-appb-000264
代表连接位点； wherein R is selected from the group consisting of hydrogen, protium , deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000264
represents the attachment site;
所述La为-(J 1) m1-C(＝O)-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-； The La is -(J 1 ) m1 -C(=O)-X 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -;
所述Lb为-(J 2) m2-C(＝O)-X 2-(K 2) n2-(Y 2) p2-(L 2) q2-； The Lb is -(J 2 ) m2 -C(=O)-X 2 -(K 2 ) n2 -(Y 2 ) p2 -(L 2 ) q2 -;
所述Lc为-(J 3) m3-C(＝O)-X 3-(K 3) n3-(Y 3) p3-(L 3) q3-； The Lc is -(J 3 ) m3 -C(=O)-X 3 -(K 3 ) n3 -(Y 3 ) p3 -(L 3 ) q3 -;
其中，J 1，J 2，和J 3各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合；m1，m2，和m3各自独立地选自以下组：0、1、2和3； Wherein, J 1 , J 2 , and J 3 are each independently selected from the following group: alkane, and polyethylene glycol, or any combination of the foregoing; m1, m2, and m3 are each independently selected from the following group: 0, 1, 2 and 3;
X 1，X 2，和X 3各自独立地选自以下组：-NH-和-O-； X 1 , X 2 , and X 3 are each independently selected from the group consisting of: -NH- and -O-;
(K 1) n1，(K 2) n2，和(K 3) n3各自独立地选自以下组：-链烷基-聚乙二醇-链烷基-，链烷基和聚乙二醇，或n1，n2或n3各自独立地为0； (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -alkyi-polyethylene glycol-alkyi-, alkane, and polyethylene glycol, or n1, n2 or n3 are each independently 0;
Y 1，Y 2，和Y 3各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-；R 1选自以下组：氢，氕，氘，氚，和链烷基；n1，n2，和n3各自独立地选自以下组：0、1、2和3； Y 1 , Y 2 , and Y 3 are each independently selected from the group consisting of -C(=O)-, -NR 1 -C(=O)-, -NR 1 -, and -O-; R 1 is selected from The following group: hydrogen, protium, deuterium, tritium, and alkane; n1, n2, and n3 are each independently selected from the following group: 0, 1, 2, and 3;
(L 1) q1，(L 2) q2，和(L 3) q3各自独立地选自以下组：-链烷基-芳基-，链烷基和聚乙二醇，或q1，q2和q3各自独立地为0； (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of - alkane-aryl-, alkane and polyethylene glycol, or q1 , q2 and q3 each independently is 0;
W选自以下组：W is selected from the following group:
Figure PCTCN2021130337-appb-000265
Figure PCTCN2021130337-appb-000265
Figure PCTCN2021130337-appb-000266
Figure PCTCN2021130337-appb-000266
Figure PCTCN2021130337-appb-000267
例如，La、Lb和Lc可以各自独立地选自以下组：-C(＝O)-NH-(CH 2) 8-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 8-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 8-NH-，-C(＝O)-NH-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，- C(＝O)-NH-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-NH-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-和-C(＝O)-O-。
Figure PCTCN2021130337-appb-000267
For example, La, Lb, and Lc may each be independently selected from the group: -C(=O)-NH-( CH2 ) 8 -NH-C(=O) -CH2 -phenyl-, -C(= O)-NH-(CH 2 ) 8 -NH-C(=O)-CH 2 -, -C(=O)-NH-(CH 2 ) 8 -NH-, -C(=O)-NH- (CH 2 ) 2 -NH-C(=O)-CH 2 -phenyl-,-C(=O)-NH-(CH 2 ) 2 -NH-C(=O)-CH 2 -,-C (=O)-NH-(CH 2 ) 2 -NH-, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- C(=O) -CH2 -phenyl-,-C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH-C(= O)-CH 2 -, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- and -C(=O)-O -.
例如，La、Lb和Lc可以各自独立地选自以下组：-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-和-C(＝O)-O-。 For example, La, Lb and Lc can each be independently selected from the group: -C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH- C(=O) -CH2 -phenyl-,-C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH-C(= O)-CH 2 -, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- and -C(=O)-O -.
在一种实施方式中，本申请提供一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，其可以具有如式Ia或式Ib所示的结构：In one embodiment, the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, which can have the structure shown in formula Ia or formula Ib:
Figure PCTCN2021130337-appb-000268
Figure PCTCN2021130337-appb-000268
其中：in:
Figure PCTCN2021130337-appb-000269
为
Figure PCTCN2021130337-appb-000270
Figure PCTCN2021130337-appb-000271
为
Figure PCTCN2021130337-appb-000272
Figure PCTCN2021130337-appb-000269
for
Figure PCTCN2021130337-appb-000270
Figure PCTCN2021130337-appb-000271
for
Figure PCTCN2021130337-appb-000272
其中：A为
Figure PCTCN2021130337-appb-000273
B为
Figure PCTCN2021130337-appb-000274
C为
Figure PCTCN2021130337-appb-000275
其中R 12选自以下组的基团：包括氢，氕，氘，氚，卤素和链烷基，
Figure PCTCN2021130337-appb-000276
代表连接位点； Among them: A is
Figure PCTCN2021130337-appb-000273
B is
Figure PCTCN2021130337-appb-000274
C is
Figure PCTCN2021130337-appb-000275
A group wherein R is selected from the group consisting of hydrogen, protium , deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000276
represents the attachment site;
所述La为-(J 1) m1-C(＝O)-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-； The La is -(J 1 ) m1 -C(=O)-X 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -;
所述Lb为-(J 2) m2-C(＝O)-X 2-(K 2) n2-(Y 2) p2-(L 2) q2-； The Lb is -(J 2 ) m2 -C(=O)-X 2 -(K 2 ) n2 -(Y 2 ) p2 -(L 2 ) q2 -;
所述Lc为-(J 3) m3-C(＝O)-X 3-(K 3) n3-(Y 3) p3-(L 3) q3-； The Lc is -(J 3 ) m3 -C(=O)-X 3 -(K 3 ) n3 -(Y 3 ) p3 -(L 3 ) q3 -;
J 1，J 2，和J 3各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合，m1，m2，和m3各自独立地选自以下组：0、1、2和3； J 1 , J 2 , and J 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing, and m 1 , m 2 , and m 3 are each independently selected from the group 0, 1, 2 and 3;
X 1，X 2，和X 3各自独立地选自以下组：-NH-和-O-； X 1 , X 2 , and X 3 are each independently selected from the group consisting of: -NH- and -O-;
(K 1) n1，(K 2) n2，和(K 3) n3各自独立地选自以下组：-(CH 2)-(CH 2-O-CH 2) 3-(CH 2)-，-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-，-(CH 2) 2-，和-(CH 2) 8-，或n1，n2或n3各自独立地为0； (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -(CH 2 )-(CH 2 -O-CH 2 ) 3 -(CH 2 )-,- (CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -, -(CH 2 ) 2 -, and -(CH 2 ) 8 -, or n1, n2 or n3 each independently is 0;
(Y 1) p1，(Y 2) p2，和(Y 3) p3各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-，R 1选自以下组：氢，氕，氘，氚，和链烷基；或p1，p2或p3各自独立地为0； (Y 1 ) p1 , (Y 2 ) p2 , and (Y 3 ) p3 are each independently selected from the group consisting of: -C(=O)-, -NR 1 -C(=O)-, -NR 1 -, and -O-, R1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; or p1, p2 or p3 are each independently 0;
(L 1) q1，(L 2) q2，和(L 3) q3各自独立地选自以下组：-CH 2-芳基-，-(CH 2) 2-，和-CH 2-，或q1，q2和q3各自独立地为0； (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of -CH 2 -aryl-, -(CH 2 ) 2 -, and -CH 2 -, or q1 , q2 and q3 are independently 0;
W为W is
Figure PCTCN2021130337-appb-000277
Figure PCTCN2021130337-appb-000277
例如，La、Lb和Lc可以各自独立地选自以下组：-C(＝O)-NH-(CH 2) 8-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 8-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 8-NH-，-C(＝O)-NH-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-NH-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-和-C(＝O)-O-。 For example, La, Lb, and Lc may each be independently selected from the group: -C(=O)-NH-( CH2 ) 8 -NH-C(=O) -CH2 -phenyl-, -C(= O)-NH-(CH 2 ) 8 -NH-C(=O)-CH 2 -, -C(=O)-NH-(CH 2 ) 8 -NH-, -C(=O)-NH- (CH 2 ) 2 -NH-C(=O)-CH 2 -phenyl-, -C(=O)-NH-(CH 2 ) 2 -NH-C(=O)-CH 2 -, -C (=O)-NH-(CH 2 ) 2 -NH-, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- C(=O) -CH2 -phenyl-,-C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH-C(= O)-CH 2 -, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- and -C(=O)-O -.
例如，La、Lb和Lc可以各自独立地选自以下组：-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-和-C(＝O)-O-。 For example, La, Lb and Lc can each be independently selected from the group: -C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH- C(=O) -CH2 -phenyl-,-C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH-C(= O)-CH 2 -, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- and -C(=O)-O -.
在一种实施方式中，本申请提供一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，其可以具有如式IIa或式IIb所示的结构：In one embodiment, the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, which can have the structure shown in formula IIa or formula IIb:
Figure PCTCN2021130337-appb-000278
Figure PCTCN2021130337-appb-000278
其中，in,
Figure PCTCN2021130337-appb-000279
为
Figure PCTCN2021130337-appb-000280
Figure PCTCN2021130337-appb-000281
为
Figure PCTCN2021130337-appb-000282
Figure PCTCN2021130337-appb-000279
for
Figure PCTCN2021130337-appb-000280
Figure PCTCN2021130337-appb-000281
for
Figure PCTCN2021130337-appb-000282
其中，in,
A 2为
Figure PCTCN2021130337-appb-000283
B 2为
Figure PCTCN2021130337-appb-000284
Figure PCTCN2021130337-appb-000285
C 2为
Figure PCTCN2021130337-appb-000286
或共价键；其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素和链烷基，
Figure PCTCN2021130337-appb-000287
代表连接位点，所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接； A2 is
Figure PCTCN2021130337-appb-000283
B2 is
Figure PCTCN2021130337-appb-000284
Figure PCTCN2021130337-appb-000285
C2 is
Figure PCTCN2021130337-appb-000286
or a covalent bond; wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000287
Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is optionally attached to Wc and P3 ;
所述La为-(J 1) m1-C(＝O)-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-； The La is -(J 1 ) m1 -C(=O)-X 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -;
所述Lb为-(J 2) m2-C(＝O)-X 2-(K 2) n2-(Y 2) p2-(L 2) q2-； The Lb is -(J 2 ) m2 -C(=O)-X 2 -(K 2 ) n2 -(Y 2 ) p2 -(L 2 ) q2 -;
所述Lc为-(J 3) m3-C(＝O)-X 3-(K 3) n3-(Y 3) p3-(L 3) q3-； The Lc is -(J 3 ) m3 -C(=O)-X 3 -(K 3 ) n3 -(Y 3 ) p3 -(L 3 ) q3 -;
其中，J 1，J 2，和J 3各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合；m1，m2，和m3各自独立地选自以下组：0、1、2和3； Wherein, J 1 , J 2 , and J 3 are each independently selected from the following group: alkane, and polyethylene glycol, or any combination of the foregoing; m1, m2, and m3 are each independently selected from the following group: 0, 1, 2 and 3;
X 1，X 2，和X 3各自独立地选自以下组：-NH-和-O-； X 1 , X 2 , and X 3 are each independently selected from the group consisting of: -NH- and -O-;
(K 1) n1，(K 2) n2，和(K 3) n3各自独立地选自以下组：-链烷基-聚乙二醇-链烷基-，链烷基和聚乙二醇，或n1，n2或n3各自独立地为0； (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -alkyi-polyethylene glycol-alkyi-, alkane, and polyethylene glycol, or n1, n2 or n3 are each independently 0;
Y 1，Y 2，和Y 3各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-；R 1选自以下组：氢，氕，氘，氚，和链烷基；n1，n2，和n3各自独立地选自以下组：0、1、2和3； Y 1 , Y 2 , and Y 3 are each independently selected from the group consisting of -C(=O)-, -NR 1 -C(=O)-, -NR 1 -, and -O-; R 1 is selected from The following group: hydrogen, protium, deuterium, tritium, and alkane; n1, n2, and n3 are each independently selected from the following group: 0, 1, 2, and 3;
(L 1) q1，(L 2) q2，和(L 3) q3各自独立地选自以下组：-链烷基-芳基-，链烷基和聚乙二醇，或q1，q2和q3各自独立地为0； (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of - alkane-aryl-, alkane and polyethylene glycol, or q1 , q2 and q3 each independently is 0;
W选自以下组：W is selected from the following group:
Figure PCTCN2021130337-appb-000288
Figure PCTCN2021130337-appb-000288
Figure PCTCN2021130337-appb-000289
Figure PCTCN2021130337-appb-000289
Figure PCTCN2021130337-appb-000290
P 1，P 2和P 3各自独立地选自以下组：核酸分子、染料分子、细胞因子、抗原、和抗体或其抗原结合片段，或前述任意组合。
Figure PCTCN2021130337-appb-000290
P1, P2, and P3 are each independently selected from the group consisting of nucleic acid molecules, dye molecules, cytokines, antigens, and antibodies or antigen-binding fragments thereof, or any combination of the foregoing.
例如，La、Lb和Lc可以各自独立地选自以下组：-C(＝O)-NH-(CH 2) 8-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 8-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 8-NH-，-C(＝O)-NH-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-NH-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-和-C(＝O)-O-。 For example, La, Lb, and Lc may each be independently selected from the group: -C(=O)-NH-( CH2 ) 8 -NH-C(=O) -CH2 -phenyl-, -C(= O)-NH-(CH 2 ) 8 -NH-C(=O)-CH 2 -, -C(=O)-NH-(CH 2 ) 8 -NH-, -C(=O)-NH- (CH 2 ) 2 -NH-C(=O)-CH 2 -phenyl-, -C(=O)-NH-(CH 2 ) 2 -NH-C(=O)-CH 2 -, -C (=O)-NH-(CH 2 ) 2 -NH-, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- C(=O) -CH2 -phenyl-,-C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH-C(= O)-CH 2 -, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- and -C(=O)-O -.
例如，La、Lb和Lc可以各自独立地选自以下组：-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-和-C(＝O)-O-。 For example, La, Lb and Lc can each be independently selected from the group: -C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH- C(=O) -CH2 -phenyl-,-C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH-C(= O)-CH 2 -, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- and -C(=O)-O -.
在一种实施方式中，本申请提供一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，其可以具有如式IIa或式IIb所示的结构：In one embodiment, the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, which can have the structure shown in formula IIa or formula IIb:
Figure PCTCN2021130337-appb-000291
Figure PCTCN2021130337-appb-000291
其中，in,
Figure PCTCN2021130337-appb-000292
为
Figure PCTCN2021130337-appb-000293
Figure PCTCN2021130337-appb-000292
for
Figure PCTCN2021130337-appb-000293
Figure PCTCN2021130337-appb-000294
为
Figure PCTCN2021130337-appb-000295
Figure PCTCN2021130337-appb-000294
for
Figure PCTCN2021130337-appb-000295
其中，in,
A 2为
Figure PCTCN2021130337-appb-000296
B 2为，
Figure PCTCN2021130337-appb-000297
C 2为
Figure PCTCN2021130337-appb-000298
或共价键；其中R 12选自以下组：氢，氕，氘，氚，卤素和链烷基，
Figure PCTCN2021130337-appb-000299
代表连接位点，所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接； A2 is
Figure PCTCN2021130337-appb-000296
B2 is,
Figure PCTCN2021130337-appb-000297
C2 is
Figure PCTCN2021130337-appb-000298
or a covalent bond; wherein R 12 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000299
Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is optionally attached to Wc and P3 ;
所述La为-(J 1) m1-C(＝O)-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-； The La is -(J 1 ) m1 -C(=O)-X 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -;
所述Lb为-(J 2) m2-C(＝O)-X 2-(K 2) n2-(Y 2) p2-(L 2) q2-； The Lb is -(J 2 ) m2 -C(=O)-X 2 -(K 2 ) n2 -(Y 2 ) p2 -(L 2 ) q2 -;
所述Lc为-(J 3) m3-C(＝O)-X 3-(K 3) n3-(Y 3) p3-(L 3) q3-； The Lc is -(J 3 ) m3 -C(=O)-X 3 -(K 3 ) n3 -(Y 3 ) p3 -(L 3 ) q3 -;
J 1，J 2，和J 3各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合，m1，m2，和m3各自独立地选自以下组：0、1、2和3； J 1 , J 2 , and J 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing, and m 1 , m 2 , and m 3 are each independently selected from the group 0, 1, 2 and 3;
X 1，X 2，和X 3各自独立地选自以下组：-NH-和-O-； X 1 , X 2 , and X 3 are each independently selected from the group consisting of: -NH- and -O-;
(K 1) n1，(K 2) n2，和(K 3) n3各自独立地选自以下组：-(CH 2)-(CH 2-O-CH 2) 3-(CH 2)-，-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-，-(CH 2) 2-，和-(CH 2) 8-，或n1，n2或n3各自独立地为0； (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -(CH 2 )-(CH 2 -O-CH 2 ) 3 -(CH 2 )-,- (CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -, -(CH 2 ) 2 -, and -(CH 2 ) 8 -, or n1, n2 or n3 each independently is 0;
(Y 1) p1，(Y 2) p2，和(Y 3) p3各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-，R 1选自以下组：氢，氕，氘，氚，和链烷基；或p1，p2或p3各自独立地为0； (Y 1 ) p1 , (Y 2 ) p2 , and (Y 3 ) p3 are each independently selected from the group consisting of: -C(=O)-, -NR 1 -C(=O)-, -NR 1 -, and -O-, R1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; or p1, p2 or p3 are each independently 0;
(L 1) q1，(L 2) q2，和(L 3) q3各自独立地选自以下组：-CH 2-芳基-，-(CH 2) 2-，和-CH 2-，或q1，q2和q3各自独立地为0； (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of -CH 2 -aryl-, -(CH 2 ) 2 -, and -CH 2 -, or q1 , q2 and q3 are independently 0;
W为W is
Figure PCTCN2021130337-appb-000300
Figure PCTCN2021130337-appb-000300
P 1，P 2和P 3各自独立地选自以下组：靶向4-1BB的抗体、靶向EGFR的抗体、靶向CD3的抗体、靶向Her2的抗体、靶向CD47的抗体、靶向CD20的抗体、含有CMV的分支肽、neo2蛋白、IFNα蛋白、异硫氰酸荧光素(FITC)、和CPG核酸。 P 1 , P 2 and P 3 are each independently selected from the group consisting of: an antibody targeting 4-1BB, an antibody targeting EGFR, an antibody targeting CD3, an antibody targeting Her2, an antibody targeting CD47, an antibody targeting Antibodies to CD20, branched peptides containing CMV, neo2 protein, IFNα protein, fluorescein isothiocyanate (FITC), and CPG nucleic acids.
例如，La、Lb和Lc可以各自独立地选自以下组：-C(＝O)-NH-(CH 2) 8-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 8-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 8-NH-，-C(＝O)-NH-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-NH-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-和-C(＝O)-O-。 For example, La, Lb, and Lc may each be independently selected from the group: -C(=O)-NH-( CH2 ) 8 -NH-C(=O) -CH2 -phenyl-, -C(= O)-NH-(CH 2 ) 8 -NH-C(=O)-CH 2 -, -C(=O)-NH-(CH 2 ) 8 -NH-, -C(=O)-NH- (CH 2 ) 2 -NH-C(=O)-CH 2 -phenyl-, -C(=O)-NH-(CH 2 ) 2 -NH-C(=O)-CH 2 -, -C (=O)-NH-(CH 2 ) 2 -NH-, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- C(=O) -CH2 -phenyl-,-C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH-C(= O)-CH 2 -, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- and -C(=O)-O -.
例如，La、Lb和Lc可以各自独立地选自以下组：-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-苯基-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-C(＝O)-CH 2-，-C(＝O)-NH-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-NH-和-C(＝O)-O-。 For example, La, Lb and Lc can each be independently selected from the group: -C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH- C(=O) -CH2 -phenyl-,-C(=O)-NH-( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2 -NH-C(= O)-CH 2 -, -C(=O)-NH-(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -NH- and -C(=O)-O -.
在一方面本申请提供一种本申请所述的化合物的制备方法，其包括：In one aspect, the present application provides a method for preparing the compound described in the present application, comprising:
使式(Ia-I)所示的化合物与反应物1、反应物2和反应物3反应；The compound represented by formula (Ia-I) is reacted with reactant 1, reactant 2 and reactant 3;
或使式(Ia-I)所示的化合物与反应物1和反应物2反应；Or make the compound shown in formula (Ia-I) react with reactant 1 and reactant 2;
或使式(Ia-I)所示的化合物与反应物1反应；Or make the compound represented by formula (Ia-I) react with reactant 1;
Figure PCTCN2021130337-appb-000301
Figure PCTCN2021130337-appb-000301
所述反应物1为H-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-A， The reactant 1 is HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -A,
所述反应物2为H-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-B， The reactant 2 is HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -B,
所述反应物3为H-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-C， The reactant 3 is HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -C,
所述W为三价基团，所述W任选地被一个或多个R取代，The W is a trivalent group, the W is optionally substituted with one or more R,
所述J 1，J 2，J 3，K 1，K 2，K 3，L 1，L 2，和L 3各自独立地选自以下组：链烷基，环烷基，杂环烷基，烯基，炔基，芳基，杂芳基，和聚乙二醇，或前述任意组合； The J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
所述X 1，X 2，X 3，Y 1，Y 2，和Y 3各自独立地选自以下组：-NR 1-，-O-，-S-，-C(＝O)-，-C(＝S)-，-C(R 1a)(R 1b)-，-NR 1-C(＝O)-，-C(＝O)-NR 1-，-NR 1-C(＝S)-，-C(＝S)-NR 1-，-O-C(＝O)-，-C(＝O)-O-，-O-C(＝S)-，-C(＝S)-O-，-O-C(＝O)-O-，-O-C(＝O)-NR 1-，-NR 1-C(＝O)-O-，和-NR 1a-C(＝O)-NR 1b-； Said X 1 , X 2 , X 3 , Y 1 , Y 2 , and Y 3 are each independently selected from the group of: -NR 1 -, -O-, -S-, -C(=O)-, - C(=S)-, -C(R 1a )(R 1b )-, -NR 1 -C(=O)-, -C(=O)-NR 1 -, -NR 1 -C(=S) -, -C(=S)-NR 1 -, -OC(=O)-, -C(=O)-O-, -OC(=S)-, -C(=S)-O-, - OC(=O)-O-, -OC(=O)-NR 1 -, -NR 1 -C(=O)-O-, and -NR 1a -C(=O)-NR 1b -;
R，R 1，R 1a和R 1b各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基； R, R 1 , R 1a and R 1b are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl;
其中，m1，m2，m3，n1，n2，n3，p1，p2，p3，q1，q2，和q3各自独立地选自0以上的数；wherein, m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 are each independently selected from a number greater than 0;
A，B和C各自独立地选自以下组：A, B and C are each independently selected from the following group:
Figure PCTCN2021130337-appb-000302
Figure PCTCN2021130337-appb-000303
Figure PCTCN2021130337-appb-000302
Figure PCTCN2021130337-appb-000303
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基； wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl;
其中，A，B和C中，
Figure PCTCN2021130337-appb-000304
不能和
Figure PCTCN2021130337-appb-000305
同时存在； Among them, A, B and C,
Figure PCTCN2021130337-appb-000304
cannot and
Figure PCTCN2021130337-appb-000305
simultaneously exist;
其中，A，B和C中，
Figure PCTCN2021130337-appb-000306
不能和
Figure PCTCN2021130337-appb-000307
Figure PCTCN2021130337-appb-000308
同时存在； Among them, A, B and C,
Figure PCTCN2021130337-appb-000306
cannot and
Figure PCTCN2021130337-appb-000307
Figure PCTCN2021130337-appb-000308
simultaneously exist;
其中，A，B和C中，
Figure PCTCN2021130337-appb-000309
不能和
Figure PCTCN2021130337-appb-000310
同时存在； Among them, A, B and C,
Figure PCTCN2021130337-appb-000309
cannot and
Figure PCTCN2021130337-appb-000310
simultaneously exist;
当A，B和C中，
Figure PCTCN2021130337-appb-000311
同时存在时，所述R 12，R 13和R 14不为炔基； When A, B and C,
Figure PCTCN2021130337-appb-000311
When present at the same time, the R 12 , R 13 and R 14 are not alkynyl;
当A，B和C中，
Figure PCTCN2021130337-appb-000312
同时存在时，所述R 12，R 13和R 14不为氨基， When A, B and C,
Figure PCTCN2021130337-appb-000312
When present at the same time, the R 12 , R 13 and R 14 are not amino groups,
A，B和C不同时为
Figure PCTCN2021130337-appb-000313
A, B and C are not simultaneously
Figure PCTCN2021130337-appb-000313
其中，当A、B或C为
Figure PCTCN2021130337-appb-000314
时，在所述式(Ia-I)所示的化合物与反应物1、反应物2或反应物3反应前，将
Figure PCTCN2021130337-appb-000315
替换为
Figure PCTCN2021130337-appb-000316
在所述式(Ia-I)所示的化合物与反应物1、反应物2或反应物3反应后，加入酸进行Boc脱除。 where, when A, B or C is
Figure PCTCN2021130337-appb-000314
, before the compound represented by the formula (Ia-I) reacts with reactant 1, reactant 2 or reactant 3, the
Figure PCTCN2021130337-appb-000315
replace with
Figure PCTCN2021130337-appb-000316
After the compound represented by the formula (Ia-I) reacts with reactant 1, reactant 2 or reactant 3, an acid is added to remove Boc.
在一种实施方式中所述的制备方法，根据A、B和C的引入顺序决定反应物1、反应物2和反应物3的加入顺序，所述A、B和C的引入顺序从先到后依次为：
Figure PCTCN2021130337-appb-000317
Figure PCTCN2021130337-appb-000318
In the preparation method described in one embodiment, the order of addition of reactant 1, reactant 2 and reactant 3 is determined according to the introduction order of A, B and C, and the introduction order of A, B and C is from first to first followed by:
Figure PCTCN2021130337-appb-000317
Figure PCTCN2021130337-appb-000318
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基。 wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl.
一方面本申请提供一种本申请所述化合物的制备方法，其包括：On the one hand, the present application provides a method for preparing the compound described in the present application, comprising:
使本申请所述任一项中式Ia所述的化合物与反应物4、反应物5和反应物6反应；Making the compound described in any one of the formula Ia described in this application react with reactant 4, reactant 5 and reactant 6;
所述反应物4为A 1-P 1， The reactant 4 is A 1 -P 1 ,
所述反应物5为B 1-P 2， The reactant 5 is B 1 -P 2 ,
所述反应物6为C 1-P 3， The reactant 6 is C 1 -P 3 ,
其中，反应物4的A 1与式Ia所述的化合物的A反应，反应物5的B 1与式Ia所述的化合物的B反应，反应物6的C 1与式Ia所述的化合物的C反应； Wherein, A 1 of reactant 4 reacts with A of the compound described in formula Ia, B 1 of reactant 5 reacts with B of the compound described in formula Ia, and C 1 of reactant 6 reacts with the compound described in formula Ia C reaction;
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000319
时，A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000320
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000319
, at least one of A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000320
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000321
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000322
Figure PCTCN2021130337-appb-000323
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000321
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000322
Figure PCTCN2021130337-appb-000323
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000324
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000325
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000324
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000325
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000326
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000327
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000326
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000327
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000328
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000329
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000328
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000329
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000330
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000331
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000330
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000331
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000332
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000333
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000332
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000333
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000334
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000335
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000334
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000335
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000336
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000337
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000336
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000337
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000338
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000339
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000338
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000339
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000340
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000341
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000340
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000341
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000342
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000343
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000342
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000343
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基。 wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl.
在一种实施方式中所述的制备方法，The preparation method described in one embodiment,
其中，
Figure PCTCN2021130337-appb-000344
的反应中加入Cu +作为催化剂。 in,
Figure PCTCN2021130337-appb-000344
Cu + was added as a catalyst in the reaction.
在一种实施方式中所述的制备方法，The preparation method described in one embodiment,
其中，
Figure PCTCN2021130337-appb-000345
的反应中加入1-100％当量的SrtA连接酶作为催化剂。 in,
Figure PCTCN2021130337-appb-000345
1-100% equivalent of SrtA ligase was added as a catalyst to the reaction.
一种药物组合物，其含有本申请所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，和药学上可接受的载体。A pharmaceutical composition containing the compound described in the present application or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
一种试剂盒，其包含本申请所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，和/或本申请所述的药物组合物。A kit comprising a compound described herein or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof, or A pharmaceutically acceptable salt thereof, and/or the pharmaceutical composition described herein.
含有本申请所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，本申请所述的药物组合物和/或本申请所述的试剂盒在制备用于治疗和/或预防肿瘤的药物中的用途。Contains a compound described herein or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof , the use of the pharmaceutical composition described in this application and/or the kit described in this application in the preparation of a medicament for treating and/or preventing tumors.
在一种实施方式中所述的用途，所述肿瘤选自与以下组表达相关的肿瘤：4-1BB、EGFR、CD3、Her2、CD47和CD20。In one embodiment of the use, the tumor is selected from the group consisting of tumors associated with expression of 4-1BB, EGFR, CD3, Her2, CD47 and CD20.
在一种实施方式中所述的用途，所述肿瘤选自以下组：实体瘤和血液癌。In one embodiment of the use, the tumor is selected from the group consisting of solid tumors and hematological cancers.
在一种实施方式中所述的用途，所述肿瘤选自以下组：肺癌、肾癌、尿道癌、结肠直肠癌、前列腺癌、多形性成胶质细胞瘤、卵巢癌、胰腺癌、乳腺癌、黑色素瘤、肝癌、膀胱癌、胃癌和食道癌。In one embodiment of the use, the tumor is selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer cancer, melanoma, liver, bladder, stomach and esophagus.
一种治疗和/或预防肿瘤的方法，包括向有需要的受试者施用本申请所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，本申请所述的药物组合物和/或本申请所述的试剂盒。A method of treating and/or preventing tumors, comprising administering to a subject in need thereof a compound described in this application or a tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition described herein and/or the kit described herein.
根据本申请所述的治疗和/或预防肿瘤的方法，所述肿瘤可以与以下组表达相关的肿瘤：4-1BB、EGFR、CD3、Her2、CD47和CD20。According to the method of treating and/or preventing a tumor described herein, the tumor may be associated with the following group expression: 4-1BB, EGFR, CD3, Her2, CD47 and CD20.
根据本申请所述的治疗和/或预防肿瘤的方法，所述肿瘤选自以下组：实体瘤和血液癌。According to the methods of treating and/or preventing tumors described herein, the tumors are selected from the group consisting of solid tumors and hematological cancers.
根据本申请所述的治疗和/或预防肿瘤的方法，所述肿瘤可以选自以下组：肺癌、肾癌、尿道癌、结肠直肠癌、前列腺癌、多形性成胶质细胞瘤、卵巢癌、胰腺癌、乳腺癌、黑色素瘤、肝癌、膀胱癌、胃癌和食道癌。According to the methods of treating and/or preventing tumors described herein, the tumors may be selected from the group consisting of: lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer , pancreatic, breast, melanoma, liver, bladder, stomach and esophageal cancers.
一种本申请所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，本申请所述的药物组合物和/或本申请所述的试 剂盒，其用于治疗和/或预防肿瘤。A compound described in this application or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof Salt, the pharmaceutical composition described in this application and/or the kit described in this application, which are used for treating and/or preventing tumors.
一种本申请所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，本申请所述的药物组合物和/或本申请所述的试剂盒，其用于治疗和/或预防肿瘤，所述肿瘤选自以下组：实体瘤和血液癌。A compound described in this application or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof Salt, the pharmaceutical composition described in the present application and/or the kit described in the present application, which are used for the treatment and/or prevention of tumors selected from the group consisting of solid tumors and hematological cancers.
一种本申请所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，本申请所述的药物组合物和/或本申请所述的试剂盒，其用于治疗和/或预防肿瘤，所述肿瘤可以选自与以下组表达相关的肿瘤：4-1BB、EGFR、CD3、Her2、CD47和CD20。A compound described in this application or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof Salt, the pharmaceutical composition described in the present application and/or the kit described in the present application, which are used for the treatment and/or prevention of tumors, and the tumors can be selected from tumors related to the expression of the following groups: 4-1BB, EGFR , CD3, Her2, CD47 and CD20.
一种本申请所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，和/或包含其的药物组合物，其用于治疗和/或预防肿瘤，所述肿瘤可以选自以下组：肺癌、肾癌、尿道癌、结肠直肠癌、前列腺癌、多形性成胶质细胞瘤、卵巢癌、胰腺癌、乳腺癌、黑色素瘤、肝癌、膀胱癌、胃癌和食道癌。A compound described in this application or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof Salts, and/or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of tumors that can be selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, pleomorphic Glioblastoma, ovarian, pancreatic, breast, melanoma, liver, bladder, stomach, and esophageal cancers.
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的，本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地，本申请的附图和说明书中的描述仅仅是示例性的，而非为限制性的。Other aspects and advantages of the present application can be readily appreciated by those skilled in the art from the following detailed description. Only exemplary embodiments of the present application are shown and described in the following detailed description. As those skilled in the art will recognize, the content of this application enables those skilled in the art to make changes to the specific embodiments disclosed without departing from the spirit and scope of the invention to which this application relates. Accordingly, the drawings and descriptions in the specification of the present application are only exemplary and not restrictive.
附图说明Description of drawings
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明如下：The invention to which this application relates is set forth with particularity characteristic of the appended claims. The features and advantages of the inventions involved in this application can be better understood by reference to the exemplary embodiments described in detail hereinafter and the accompanying drawings. A brief description of the drawings is as follows:
图1显示的是本申请所述一种多特异生物偶联的连接臂1(Scaffold1)的核磁氢谱图。Figure 1 shows the hydrogen NMR spectrum of a multispecific biologically coupled linker 1 (Scaffold1) described in the present application.
图2显示的是本申请所述一种多特异生物偶联的连接臂1(Scaffold1)的质谱图Figure 2 shows the mass spectrum of a multi-specific bioconjugation linker 1 (Scaffold1) described in this application
图3显示的是本申请所述一种多特异生物偶联的连接臂2(Scaffold2)的核磁氢谱图Figure 3 shows the hydrogen NMR spectrum of a multispecific biologically coupled linker 2 (Scaffold2) described in the present application
图4显示的是本申请所述一种多特异生物偶联的连接臂2(Scaffold2)的质谱图Figure 4 shows the mass spectrogram of a multispecific bioconjugation linker 2 (Scaffold2) described in the present application
图5显示的是本申请所述合成多特异生物偶联连接臂1(Scaffold1)或连接臂2(Scaffold2)的中间体N3-NHS-NHS核磁氢谱图。Figure 5 shows the N3-NHS-NHS nuclear magnetic spectrum of the intermediate N3-NHS-NHS of the synthetic multispecific bioconjugate linker 1 (Scaffold1) or linker 2 (Scaffold2) described in the present application.
图6显示的是本申请所述一种多特异偶联物EGFR-CD3-FITC的SDS-PAGE图。Figure 6 shows the SDS-PAGE chart of a multispecific conjugate EGFR-CD3-FITC described in the present application.
图7显示的是本申请所述一种多特异偶联物EGFR-CD3-FITC的质谱图。Figure 7 shows the mass spectrum of a multispecific conjugate EGFR-CD3-FITC described in the present application.
图8显示的是本申请所述一种多特异偶联物EGFR-CD3-CPG的SDS-PAGE图。Figure 8 shows the SDS-PAGE chart of a multispecific conjugate EGFR-CD3-CPG described in the present application.
图9显示的是本申请所述一种多特异偶联物EGFR-CD3-CPG的质谱图。Figure 9 shows the mass spectrum of a multispecific conjugate EGFR-CD3-CPG described in the present application.
图10显示的是本申请所述一种多特异偶联物EGFR-CD3-CMV的SDS-PAGE图。Figure 10 shows the SDS-PAGE chart of a multispecific conjugate EGFR-CD3-CMV described in the present application.
图11显示的是本申请所述一种多特异偶联物EGFR-CD3-CMV的质谱图。Figure 11 shows the mass spectrum of a multispecific conjugate EGFR-CD3-CMV described in the present application.
图12显示的是本申请所述一种多特异偶联物EGFR-CD3-neo2的SDS-PAGE图。Figure 12 shows the SDS-PAGE image of a multispecific conjugate EGFR-CD3-neo2 described in the present application.
图13显示的是本申请所述一种多特异偶联物EGFR-CD3-neo2的质谱图。Figure 13 shows the mass spectrum of a multispecific conjugate EGFR-CD3-neo2 described in the present application.
图14显示的是本申请所述一种多特异偶联物EGFR-CD3-IFNα的SDS-PAGE图。Figure 14 shows the SDS-PAGE chart of a multispecific conjugate EGFR-CD3-IFNα described in the present application.
图15显示的是本申请所述一种多特异偶联物EGFR-CD3-IFNα的质谱图。Figure 15 shows the mass spectrum of a multispecific conjugate EGFR-CD3-IFNα described in the present application.
图16显示的是本申请所述一种多特异偶联物EGFR-CD3-4-1BB的SDS-PAGE图。Figure 16 shows an SDS-PAGE image of a multispecific conjugate, EGFR-CD3-4-1BB, described in the present application.
图17显示的是本申请所述一种多特异偶联物EGFR-CD3-4-1BB的质谱图。Figure 17 shows the mass spectrum of a multispecific conjugate EGFR-CD3-4-1BB described in the present application.
图18显示的是本申请所述一种多特异偶联物EGFR-CD3-4-1BB的肿瘤细胞生长抑制结果。Figure 18 shows the tumor cell growth inhibition results of a multispecific conjugate EGFR-CD3-4-1BB described in the present application.
图19显示的是本申请所述一种多特异偶联物EGFR-CD3-CMV的反应路线。Figure 19 shows the reaction scheme of a multispecific conjugate EGFR-CD3-CMV described in this application.
图20显示的是本申请所述一种多特异偶联物EGFR-CD3-4-1BB的反应路线。Figure 20 shows the reaction scheme of a multispecific conjugate EGFR-CD3-4-1BB described in this application.
图21显示的是本申请所述对照组EGFR-TZ-4-1BB和EGFR-CD3-Gly反应路线。Figure 21 shows the reaction routes of EGFR-TZ-4-1BB and EGFR-CD3-Gly in the control group described in the present application.
图22显示的是多特异生物偶联的连接臂3(Scaffold3)的核磁氢谱图。Figure 22 shows the hydrogen NMR spectrum of the multispecific bioconjugated linker 3 (Scaffold3).
图23显示的是多特异生物偶联的连接臂3(Scaffold3)的质谱图。Figure 23 shows the mass spectrogram of the multispecific bioconjugate tether 3 (Scaffold3).
图24显示的是多特异生物偶联的连接臂4(Scaffold4)的核磁氢谱图。Figure 24 shows the hydrogen NMR spectrum of the multispecific bioconjugated linker 4 (Scaffold4).
图25显示的是多特异生物偶联的连接臂4(Scaffold4)的质谱图。Figure 25 shows the mass spectrogram of multispecific bioconjugated tether 4 (Scaffold4).
图26显示的是合成多特异生物偶联连接臂3(Scaffold3)或连接臂4(Scaffold4)的中间体N3-NHS-NHS*质谱图。Figure 26 shows the N3-NHS-NHS* mass spectrum of intermediates for the synthesis of multispecific bioconjugates tether 3 (Scaffold3) or tether 4 (Scaffold4).
图27显示的是EGFR-CD3-LCFA的SDS-PAGE表征图。Figure 27 shows SDS-PAGE characterization of EGFR-CD3-LCFA.
图28显示的是EGFR-CD3-LCFA的质谱表征图。Figure 28 shows mass spectrometry characterization of EGFR-CD3-LCFA.
图29显示的是EGFR-CD3-ASO的SDS-PAGE表征图。Figure 29 shows the SDS-PAGE characterization of EGFR-CD3-ASO.
图30显示的是EGFR-CD3-ASO的质谱表征图。Figure 30 shows the mass spectrometry characterization of EGFR-CD3-ASO.
图31显示的是EGFR-CD3-M1的制备反应路线。Figure 31 shows the reaction scheme for the preparation of EGFR-CD3-M1.
图32显示的是EGFR-CD3-M1的SDS-PAGE表征图。Figure 32 shows the SDS-PAGE characterization of EGFR-CD3-M1.
图33显示的是EGFR-CD3-M1的质谱表征图。Figure 33 shows the mass spectrometry characterization of EGFR-CD3-M1.
图34显示的是EGFR-CD3-PDL1的制备反应路线。Figure 34 shows the reaction scheme for the preparation of EGFR-CD3-PDL1.
图35显示的是EGFR-CD3-PDL1的SDS-PAGE表征图。Figure 35 shows the SDS-PAGE characterization of EGFR-CD3-PDL1.
图36显示的是EGFR-CD3-PDL1的质谱表征图。Figure 36 shows mass spectrometry characterization of EGFR-CD3-PDL1.
图37显示的是HER2-CD3-PDL1的制备反应路线。Figure 37 shows the reaction scheme for the preparation of HER2-CD3-PDL1.
图38显示的是HER2-CD3-PDL1的质谱表征图。Figure 38 shows mass spectrometry characterization of HER2-CD3-PDL1.
图39A-39B显示的是EGFR-CD3-PDL1与EGFR、CD3、PDL1靶标蛋白的结合结果图。Figures 39A-39B show the results of binding of EGFR-CD3-PDL1 to EGFR, CD3, and PDL1 target proteins.
具体实施方式Detailed ways
以下由特定的具体实施例说明本申请发明的实施方式，熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。The embodiments of the invention of the present application are described below with specific specific examples, and those skilled in the art can easily understand other advantages and effects of the invention of the present application from the contents disclosed in this specification.
术语定义Definition of Terms
在本申请中，术语“蛋白质”或“多肽”可互换使用，通常是指通过肽键或酰胺键连接在一起的至少两个(2)或多个氨基酸的链，并且独立于翻译后修饰(例如，糖基化、酰基化、磷酸化等等)。抗体特别意在包括在该定义的范围内。本发明的多肽可以包含一个以上的亚基，其中每个亚基由单独的DNA序列编码。蛋白质也可以包含一个以上的多肽单位，包括二聚体、三聚体、四聚体或多种更高等级的结构。In this application, the terms "protein" or "polypeptide" are used interchangeably and generally refer to a chain of at least two (2) or more amino acids linked together by peptide or amide bonds, independent of post-translational modifications (eg, glycosylation, acylation, phosphorylation, etc.). Antibodies are specifically intended to be included within the scope of this definition. The polypeptides of the present invention may comprise more than one subunit, wherein each subunit is encoded by a separate DNA sequence. A protein may also comprise more than one polypeptide unit, including dimers, trimers, tetramers, or various higher order structures.
在本申请中，术语“当量”或“当量百分比”可以互换使用，通常是指“X”的摩尔数相对于“Y”的摩尔数。例如，相对于Y，5摩尔当量的X表示如果使用1摩尔Y，则可以使用5摩尔X。In this application, the terms "equivalent" or "percent equivalent" are used interchangeably and generally refer to the number of moles of "X" relative to the number of moles of "Y". For example, 5 molar equivalents of X relative to Y means that if 1 mole of Y is used, 5 moles of X can be used.
在本申请中，术语X基团的选取与Y基团“对应”通常是指当X基团选取某一基团时，相应地，Y基团选取另一特定基团。例如，反应物4的A1的选取与式Ia所述的化合物的A对应可以是当A为
Figure PCTCN2021130337-appb-000346
时，相应地，A1可以选取
Figure PCTCN2021130337-appb-000347
与之对应。 In this application, the term X group selection "corresponds" to Y group generally means that when X group chooses a certain group, correspondingly, Y group chooses another specific group. For example, the choice of A1 of reactant 4 corresponding to A of the compound described in formula Ia can be when A is
Figure PCTCN2021130337-appb-000346
, correspondingly, A1 can choose
Figure PCTCN2021130337-appb-000347
Corresponding.
在本申请中，术语“引入顺序”通常是指将多个不同的特定基团引入起始化合物的顺序。例如，将
Figure PCTCN2021130337-appb-000348
引入起始化合物的顺序，在一种实施方式中可以是指通过先在起始化合物中加入具有
Figure PCTCN2021130337-appb-000349
的反应物1，再加入具有
Figure PCTCN2021130337-appb-000350
的反应物2，最后加入具有
Figure PCTCN2021130337-appb-000351
的反应物3，以先引入
Figure PCTCN2021130337-appb-000352
再引入
Figure PCTCN2021130337-appb-000353
最后引 入
Figure PCTCN2021130337-appb-000354
例如，引入
Figure PCTCN2021130337-appb-000355
之前可以先将
Figure PCTCN2021130337-appb-000356
替换为
Figure PCTCN2021130337-appb-000357
再加入酸进行Boc脱除。 In this application, the term "order of introduction" generally refers to the order in which a plurality of different specified groups are introduced into a starting compound. For example, will
Figure PCTCN2021130337-appb-000348
The order in which the starting compounds are introduced, in one embodiment, may refer to the
Figure PCTCN2021130337-appb-000349
of reactant 1, then added with
Figure PCTCN2021130337-appb-000350
of reactant 2, finally added with
Figure PCTCN2021130337-appb-000351
of reactant 3, introduced first
Figure PCTCN2021130337-appb-000352
reintroduction
Figure PCTCN2021130337-appb-000353
last import
Figure PCTCN2021130337-appb-000354
For example, introduce
Figure PCTCN2021130337-appb-000355
before the
Figure PCTCN2021130337-appb-000356
replace with
Figure PCTCN2021130337-appb-000357
Additional acid was added for Boc removal.
在本申请中，术语基团X与基团Y和基团Z的连接可以处于“任一定向”通常是指在基团X用于连接基团Y和基团Z时，所述基团X的两个或更多个连接位点可以任意地与基团Y或基团Z连接。例如，基团
Figure PCTCN2021130337-appb-000358
与基团W和基团P的连接可以处于任一定向，可以是基团
Figure PCTCN2021130337-appb-000359
的C原子连接基团W，N原子连接基团P，也可以是基团
Figure PCTCN2021130337-appb-000360
N原子连接基团W，C原子连接基团P。 In this application, the term group X can be attached to groups Y and Z in "either orientation" and generally means that when a group X is used to link a group Y and a group Z, the group X Two or more attachment sites of can optionally be attached to the group Y or the group Z. For example, the group
Figure PCTCN2021130337-appb-000358
The attachment to the group W and the group P can be in either orientation and can be a group
Figure PCTCN2021130337-appb-000359
The C atom connecting the group W, the N atom connecting the group P, can also be the group
Figure PCTCN2021130337-appb-000360
The N atom connects the group W, and the C atom connects the group P.
在本申请中，术语“对映异构体”通常是指化合物的两种立体异构体，它们可以是彼此不可重叠的镜像。In this application, the term "enantiomer" generally refers to two stereoisomers of a compound, which may be non-superimposable mirror images of each other.
在本申请中，术语“多糖”通常是指由以糖苷键连接的单糖单元链构成的分子。例如，术语“多糖”可以包括由两个或更多个单糖单元组成的分子，例如包括其中最长的单糖链为3至9个单糖单元的分子。术语“多糖”可以包括直链和支链的分子，分离的以及与多肽结合的分子，唾液酸化的和非唾液酸化的分子。In this application, the term "polysaccharide" generally refers to molecules composed of chains of monosaccharide units linked by glycosidic bonds. For example, the term "polysaccharide" may include molecules composed of two or more monosaccharide units, eg, including molecules in which the longest monosaccharide chain is 3 to 9 monosaccharide units. The term "polysaccharide" can include linear and branched molecules, isolated and polypeptide-bound molecules, sialylated and non-sialylated molecules.
在本申请中，术语“非对映异构体”通常是指具有两个或更多个手性中心并且其分子不是彼此的镜像的立体异构体。非对映异构体可以具有不同的物理性质，例如、熔点、沸点、波谱性质和反应性。In this application, the term "diastereomer" generally refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers can have different physical properties, eg, melting points, boiling points, spectral properties, and reactivities.
在本申请中，术语“互变异构体”或“互变异构形式”可互换使用，通常是指可通过低能垒(low energybarrier)互相转化的不同能量的结构异构体。例如，质子互变异构体(protontautomer)(也称为质子移变互变异构体(prototropic tautomer))包括通过质子迁移进行的互相转化，诸如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组进行的互相转化。In this application, the terms "tautomer" or "tautomeric form" are used interchangeably and generally refer to structural isomers of different energies that can be interconverted through a low energy barrier. For example, protontautomers (also known as prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons.
在本申请中，术语“内消旋体”通常是指分子内含有不对称性的原子，但具有对称因素而使分子内总旋光度为零。术语"外消旋体"或"外消旋混合物"是指由等摩尔量的两种对映异构体物质构成的组合物。In this application, the term "mesome" generally refers to atoms that contain asymmetry in the molecule, but have a symmetry factor such that the total optical rotation in the molecule is zero. The term "racemate" or "racemic mixture" refers to a composition consisting of two enantiomeric species in equimolar amounts.
在本申请中，术语“脂质”通常是指直链、支链、饱和或不饱和脂族羧酸、磷脂或固醇。脂族羧酸的实例为月桂酸、棕榈酸、硬脂酸、油酸以及(CH 3(CH 2) n) 2CHCOOH，其中n为至少为1的数。磷脂的可以是磷脂酰乙醇胺，如二油酰磷脂酰乙醇胺。 In this application, the term "lipid" generally refers to linear, branched, saturated or unsaturated aliphatic carboxylic acids, phospholipids or sterols. Examples of aliphatic carboxylic acids are lauric acid, palmitic acid, stearic acid, oleic acid, and ( CH3 ( CH2 ) n ) 2CHCOOH , where n is a number of at least 1. The phospholipid may be a phosphatidylethanolamine, such as dioleoylphosphatidylethanolamine.
在本申请中，术语“核酸”、“多核苷酸”和“寡核苷酸”通常是指核苷酸(例如核糖核苷酸或脱氧核糖核苷酸)的聚合物，并且包括天然存在的(腺嘌呤、鸟嘌呤、胞嘧啶、尿嘧啶和胸腺嘧啶)、非天然存在的和经修饰的核酸。该术语不受聚合物的长度(例如单体数目)限制。核酸可以是单链或双链的，并且一般含有5'-3'磷酸二酯键，尽管在一些情况下，核苷酸类似物可以具有其他连接。单体通常称为核苷酸。术语“非天然核苷酸”或“经修饰的核苷酸”指含有经修饰的含氮碱基、糖或磷酸基的核苷酸，或者在其结构中掺入非天然部分的核苷酸。非天然核苷酸的例子包括双脱氧核苷酸、生物素化、胺化、脱氨基、烷基化、苄基化和荧光标记的核苷酸。In this application, the terms "nucleic acid," "polynucleotide," and "oligonucleotide" generally refer to polymers of nucleotides (eg, ribonucleotides or deoxyribonucleotides), and include naturally occurring (adenine, guanine, cytosine, uracil and thymine), non-naturally occurring and modified nucleic acids. The term is not limited by the length of the polymer (eg, the number of monomers). Nucleic acids can be single-stranded or double-stranded, and generally contain 5'-3' phosphodiester linkages, although in some cases nucleotide analogs may have other linkages. Monomers are often called nucleotides. The term "unnatural nucleotide" or "modified nucleotide" refers to a nucleotide that contains a modified nitrogenous base, sugar or phosphate group, or that incorporates a non-natural moiety into its structure . Examples of non-natural nucleotides include dideoxynucleotides, biotinylated, aminated, deaminated, alkylated, benzylated, and fluorescently labeled nucleotides.
在本申请中，术语“化合物”通常指具有两种或两种以上不同元素的物质。例如，本申请的化合物可以是有机化合物，例如本申请的化合物可以是分子量500以下的化合物，可以是分子量1000以下的化合物，也可以是分子量1000以上的化合物，也可以是10000以上、100000以上的化合物。在本申请中，化合物还可以是指通过化学键相连的化合物，例如可以是一个或多个分子量1000以下的分子通过化学键与生物大分子相连的化合物，所述生物大分子可以是高聚糖、蛋白、核酸、多肽等。例如本申请的化合物可以包括蛋白质与一个或多个分子量1000以下的分子相连的化合物，可以是包括蛋白质与一个或多个分子量10000以下的分子相连的化合物，可以是包括蛋白质与一个或多个分子量100000以下的分子相连的化合物。In this application, the term "compound" generally refers to a substance having two or more different elements. For example, the compound of the present application may be an organic compound. For example, the compound of the present application may be a compound with a molecular weight of 500 or less, a compound with a molecular weight of 1,000 or less, or a compound with a molecular weight of 1,000 or more, or a compound of 10,000 or more and 100,000 or more. compound. In this application, a compound can also refer to a compound connected by chemical bonds, for example, it can be a compound in which one or more molecules with a molecular weight of less than 1000 are connected with a biological macromolecule by chemical bonds, and the biological macromolecule can be a polysaccharide, protein , nucleic acids, peptides, etc. For example, the compounds of the present application can include compounds in which proteins are linked to one or more molecules with a molecular weight of less than 1000, can include compounds in which proteins are linked to one or more molecules with a molecular weight of less than 10,000, and can include proteins and one or more molecular weights. A compound with less than 100,000 molecules linked together.
在本申请中，术语“混合物”通常是指两种或多种单独化合物的共混物。In this application, the term "mixture" generally refers to a blend of two or more separate compounds.
在本申请中，术语“抗体”或“抗体或其抗原结合片段”通常是指免疫学上的结合试剂延伸至来自所有物种的所有抗体，包括二聚体、三聚体和多聚体抗体，双特异性抗体，嵌合抗体，全人源抗体，人源化抗体，重组和改造的抗体，纳米抗体以及它们的片段。术语“抗体或其片段”可以指具有抗原结合区的任意抗体样分子，该术语包括抗原结合活性物质片段如Fab′、Fab、F(ab′) 2、单结构域抗体(DABs)、Fv、scFv(单链Fv)、线性抗体、双抗体、纳米抗体等等。术语“抗原结合片段”可以指抗体的保持特异性结合抗原的能力的一个或多个片段。例如，可利用全长抗体的片段来进行抗体的抗原结合功能。制备和使用各种基于抗体的构建物和片段的技术在本领域中是公知的。在一种实施方式中可以是指抗EGFR抗体抗CD3抗体、抗41-BB抗体中一个或多个。 In this application, the term "antibody" or "antibody or antigen-binding fragment thereof" generally refers to immunological binding reagents extending to all antibodies from all species, including dimeric, trimeric and multimeric antibodies, Bispecific antibodies, chimeric antibodies, fully human antibodies, humanized antibodies, recombinant and engineered antibodies, nanobodies and fragments thereof. The term "antibody or fragment thereof" may refer to any antibody-like molecule having an antigen-binding region, and the term includes fragments of antigen-binding active substances such as Fab', Fab, F(ab') 2 , single domain antibodies (DABs), Fv, scFv (single chain Fv), linear antibodies, diabodies, nanobodies, etc. The term "antigen-binding fragment" can refer to one or more fragments of an antibody that retain the ability to specifically bind an antigen. For example, fragments of full-length antibodies can be used for the antigen-binding function of antibodies. Techniques for making and using various antibody-based constructs and fragments are well known in the art. In one embodiment, it may refer to one or more of an anti-EGFR antibody, an anti-CD3 antibody, and an anti-41-BB antibody.
在本申请中，术语“纳米抗体”通常是指如WO 2008/020079或WO 2009/138519中所定义的那些抗体，并且因此在特定方面通常表示VHH、人源化VHH或骆驼化VH(例如骆驼化人VH)或通常序列优化的VHH(例如针对化学稳定性和/或溶解度进行优化，与已知的人框架区最大重叠和最大表达)。In the present application, the term "Nanobody" generally refers to those antibodies as defined in WO 2008/020079 or WO 2009/138519, and thus in particular aspects generally refers to VHHs, humanized VHHs or camelized VHs (eg camelids) Human VHs) or generally sequence-optimized VHHs (eg, optimized for chemical stability and/or solubility, maximal overlap with known human framework regions and maximal expression).
在本申请中，术语其中“任意组合”通常是指所述基团可以是选自所述组中的任意数量的基团的以任意顺序组合后的基团。例如，L 1选自以下组：链烷基，环烷基，杂环烷基，烯基，炔基，芳基，杂芳基，和聚乙二醇，或前述任意组合，在一种实施方式中可以是指L 1可以是链烷基，环烷基，杂环烷基，烯基，炔基，芳基，杂芳基，或聚乙二醇，在一种实施方式中可以是指L 1可以是链烷基和芳基的组合或链烷基与聚乙二醇的组合，在一种实施方式中可以是指-链烷基-芳基-或-链烷基-聚乙二醇-链烷基-。 In this application, the term "in any combination" generally means that the group may be any number of groups selected from the group, combined in any order. For example, L is selected from the group consisting of alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing, in one implementation In one embodiment, it can mean that L 1 can be an alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or polyethylene glycol group, and in one embodiment, it can mean L 1 can be a combination of alkane and aryl or a combination of alkane and polyethylene glycol, and in one embodiment can refer to -alkyi-aryl- or -alkyi-polyethylene glycol Alcohol-alkyi-.
在本申请中，术语“三价的”基团或“三价基团”通常是指在所述基团中具有3个键合位置的基团。例如，三价基团包括但不限于三价的链烷基，三价的环烷基，三价的杂环烷基，三价的烯基，三价的炔基，三价的芳基，和三价的杂芳基。例如，在一种实施方式中可以包括但不限于
Figure PCTCN2021130337-appb-000361
In this application, the term "trivalent" group or "trivalent group" generally refers to a group having 3 bonding positions in the group. For example, trivalent groups include, but are not limited to, trivalent alkane groups, trivalent cycloalkyl groups, trivalent heterocycloalkyl groups, trivalent alkenyl groups, trivalent alkynyl groups, trivalent aryl groups, and trivalent heteroaryl groups. For example, in one embodiment may include, but is not limited to
Figure PCTCN2021130337-appb-000361
在本申请中，术语“四价基团”通常是指在所述基团中具有4个键合位置的基团。In this application, the term "tetravalent group" generally refers to a group having 4 bonding positions in the group.
在本申请中，术语“聚乙二醇”或“PEG”通常是指以通式-(OCH 2CH 2) n-表示的处于支链或直链形式的氧化乙烯衍生的聚合物基团，其中n是3、4、5、6、7、8、9或更大的整数。聚乙二醇链包括乙二醇的聚合物，具有选自大约500到大约40,000道尔顿范围的平均总分子量。PEG链的平均分子量以数字指示，例如，PEG-5,000指的是具有平均大约5,000的总分子量的聚乙二醇链。聚乙二醇可以是取代的或非取代的。 In this application, the term "polyethylene glycol" or "PEG" generally refers to an ethylene oxide derived polymer group in branched or linear form represented by the general formula -( OCH2CH2 ) n- , where n is an integer of 3, 4, 5, 6, 7, 8, 9 or greater. Polyethylene glycol chains include polymers of ethylene glycol having an average total molecular weight selected from the range of about 500 to about 40,000 Daltons. The average molecular weight of PEG chains is indicated numerically, eg, PEG-5,000 refers to polyethylene glycol chains having an average total molecular weight of about 5,000. Polyethylene glycols can be substituted or unsubstituted.
在本申请中，术语“卤素”通常是指包括氟、氯、溴和碘。In this application, the term "halogen" is generally meant to include fluorine, chlorine, bromine and iodine.
在本申请中，术语“脲”通常是指-(HN-CO-) 2N-。 In this application, the term "urea" generally refers to -(HN-CO-) 2N- .
在本申请中，术语“链烷基”通常是指链烷基除去氢原子所衍生的残基。链烷基可以是取代的或非取代的，替代或者非替代的。术语“链烷基”通常指饱和的直链或支链脂肪族烃基，其具有从母体烷的相同碳原子或两个不同的碳原子上除去氢原子所衍生的残基，其可以为包含1至20个碳原子的直链或支链基团，例如含有1至12个碳原子，例如含有1至6个碳原子的链烷基。链烷基的非限制性实例包括但不限于甲基、乙基、丙基、丙基、丁基等。链烷基可以是取代的或非取代的，替代或者非替代的，例如当被取代时，取代基可以在任何 可使用的连接点上被取代，所述取代基可以独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基所取代，例如可以是氢、氕、氘、氚、卤素、-NO 2、-CN、-OH、-SH、-NH 2、-C(O)H、-CO 2H、-C(O)C(O)H、-C(O)CH 2C(O)H、-S(O)H、-S(O) 2H、-C(O)NH 2、-SO 2NH 2、-OC(O)H、-N(H)SO 2H或C 1-6脂肪族基团。 In this application, the term "alkyi" generally refers to a residue derived from an alkane group by removal of a hydrogen atom. Alkyl groups can be substituted or unsubstituted, substituted or unsubstituted. The term "alkyi" generally refers to a saturated straight or branched aliphatic hydrocarbon group having a residue derived from the removal of a hydrogen atom from the same carbon atom or two different carbon atoms of the parent alkane, which may contain 1 Straight or branched chain groups of up to 20 carbon atoms, eg, alkane groups containing 1 to 12 carbon atoms, eg, 1 to 6 carbon atoms. Non-limiting examples of alkane groups include, but are not limited to, methyl, ethyl, propyl, propyl, butyl, and the like. Alkyl groups may be substituted or unsubstituted, substituted or unsubstituted, for example when substituted, substituents may be substituted at any available point of attachment, which may be independently optionally selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy substituted by one or more substituents in the group, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo, such as hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO2H , -C(O)C(O)H, -C(O) CH2C (O)H, - S(O)H, -S(O)2H, -C (O) NH2 , -SO2NH2 , -OC ( O)H, -N(H) SO2H or C1-6 aliphatic group.
在本申请中，术语“环烷基”通常是指具有从碳环的相同碳原子或多个不同的碳原子上除去氢原子所衍生的残基。术语“环烷”通常指饱和或部分不饱和单环或多环环状烃，碳环包含3至20个碳原子，可以包含3至12个碳原子，可以包含3至10个碳原子，可以包含3至8个碳原子。单环碳环的非限制性实例包括环丙烷、环丁烷、环戊烷、环戊烯、环己烷、环己烯、环己二烯、环庚烷、环庚三烯、环辛烷等；多环碳环可以包括螺环、稠环和桥环的碳环。环烷基可以是取代的或非取代的。In this application, the term "cycloalkyl" generally refers to residues having a hydrogen atom removed from the same carbon atom or multiple different carbon atoms of a carbocyclic ring. The term "cycloalkane" generally refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, the carbocyclic ring containing 3 to 20 carbon atoms, may contain 3 to 12 carbon atoms, may contain 3 to 10 carbon atoms, may Contains 3 to 8 carbon atoms. Non-limiting examples of monocyclic carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, cyclooctane etc.; polycyclic carbocycles may include spiro, fused and bridged carbocycles. Cycloalkyl groups can be substituted or unsubstituted.
在本申请中，术语“杂环烷基”通常是指稳定的不具有芳香性的3元-7元单环结构，融合的7元-10元双环杂环结构或桥联的6元-10元双环杂环结构，这些环状结构即可以是饱和的，也可以是部分饱和的，除碳原子外，这些环状结构中还含有一个或多个杂原子，其中杂原子可以选自以下组：氧、硫和氮。例如是含有1-4个上述定义的杂原子。当用来表示杂环环状结构上的原子时，术语“氮”可以包括发生过取代反应的氮。杂环烷基可以是取代的或非取代的。In this application, the term "heterocycloalkyl" generally refers to stable non-aromatic 3- to 7-membered monocyclic structures, fused 7- to 10-membered bicyclic heterocyclic structures or bridged 6- to 10-membered monocyclic structures. Member bicyclic heterocyclic structures, which may be either saturated or partially saturated, and which, in addition to carbon atoms, contain one or more heteroatoms, wherein the heteroatoms may be selected from the following groups : oxygen, sulfur and nitrogen. For example, it contains 1-4 heteroatoms as defined above. When used to refer to an atom on a heterocyclic ring structure, the term "nitrogen" may include nitrogen that has undergone a substitution reaction. Heterocycloalkyl can be substituted or unsubstituted.
在本申请中，术语“烯基”通常是指含有一个或多个双键的直链或支链烃基。烯基的示例性实例包括烯丙基、高烯丙基、乙烯基、巴豆基、丁烯基、戊烯基和己烯基。具有一个以上双键的C 2-6链烯基的示例性实例包括丁二烯基、戊二烯基、己二烯基和己三烯基以及它们的支化形式。不饱和键(双键)的位置可以是在碳链的任何一个位置。烯基可以是取代的或非取代的。 In this application, the term "alkenyl" generally refers to a straight or branched chain hydrocarbon group containing one or more double bonds. Illustrative examples of alkenyl groups include allyl, homoallyl, vinyl, crotyl, butenyl, pentenyl, and hexenyl. Illustrative examples of C2-6 alkenyl groups having more than one double bond include butadienyl, pentadienyl, hexadienyl, and hexatrienyl and branched forms thereof. The position of the unsaturated bond (double bond) can be anywhere in the carbon chain. Alkenyl groups can be substituted or unsubstituted.
在本申请中，术语“炔基”通常是指不饱和直链或支链炔基，例如乙炔基、1-丙炔基、炔丙基、丁炔基等。炔基可以是取代的或非取代的。In this application, the term "alkynyl" generally refers to unsaturated straight or branched chain alkynyl groups such as ethynyl, 1-propynyl, propargyl, butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.
在本申请中，术语“芳基”通常是指具有从芳环的相同碳原子或多个不同的碳原子上除去氢原子所衍生的残基。术语“芳环”可以指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)，可以为6至10元，例如苯和萘。所述芳环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。芳基可以是取代的或非取代的，当被取代时，取代基可以为一个或多个以下基团，其独立地选自以下 组：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基和杂环烷硫基。In this application, the term "aryl" generally refers to a residue having a hydrogen atom removed from the same carbon atom or multiple different carbon atoms of an aromatic ring. The term "aromatic ring" may refer to a 6- to 14-membered all-carbon monocyclic or fused polycyclic ring (ie, rings that share adjacent pairs of carbon atoms) having a conjugated pi-electron system, and may be 6 to 10 membered, such as benzene and Naphthalene. The aromatic ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring. Aryl may be substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio.
在本申请中，术语“杂芳基”通常是指具有从杂芳环的相同碳原子或多个不同的碳原子上除去氢原子所衍生的残基。术语“杂芳环”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子可以选自以下组：氧、硫和氮。杂芳基可以为5至10元，可以为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或非取代的，当被取代时，取代基可以为一个或多个以下基团，其独立地选自以下组：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基和杂环烷硫基。In this application, the term "heteroaryl" generally refers to residues having a hydrogen atom removed from the same carbon atom or multiple different carbon atoms of a heteroaromatic ring. The term "heteroaromatic ring" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms may be selected from the group consisting of oxygen, sulfur and nitrogen. Heteroaryl can be 5 to 10 membered, 5 membered or 6 membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazole Base et al. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents can be one or more of the following groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy group, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio and heterocycloalkylthio.
在本申请中，术语“烷氧基”通常是指烷基在其上连接有一个氧基团。代表性的烷氧基基团包括甲氧基、乙氧基、丙氧基、叔丁氧基等。In this application, the term "alkoxy" generally refers to an alkyl group to which is attached an oxygen group. Representative alkoxy groups include methoxy, ethoxy, propoxy, t-butoxy, and the like.
在本申请中，术语“任选”或“任选地”通常是指随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明可以包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。In this application, the terms "optional" or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may, but need not, be present, and the specification may include both instances where the heterocyclic group is substituted with an alkyl group and where the heterocyclic group is not substituted with an alkyl group. situation.
在本申请中，术语“取代的”通常是指基团中的一个或多个氢原子，例如为最多5个，例如为1～3个氢原子彼此独立地被相应数目的取代基取代。取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。In the present application, the term "substituted" generally means that one or more hydrogen atoms in a group, eg up to 5, eg 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. Substituents are only in their possible chemical positions, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
除非另有指明，否则本申请所述的结构还可以包括仅在是否存在一个或多个同位素富集原子方面存在差别的化合物。举例而言，除了氢原子被氘或氚所取代，或碳原子被碳13或1碳14所取代之外，其余部分均与本申请结构一致的化合物均在本申请的范围之内。Unless otherwise indicated, structures described herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, except that the hydrogen atom is replaced by deuterium or tritium, or the carbon atom is replaced by carbon 13 or 1 carbon 14, the compounds whose structure is consistent with the present application are all within the scope of the present application.
在本申请中，术语“小分子”通常是指分子量低于约5000道尔顿(Da)的任何化学部分或其它部分。在一些实施方式中，小分子的分子量低于约2500道尔顿、约1000道尔顿或约500道尔顿。在一些实施方式中，小分子可以不是聚合物。在一些实施方式中，小分子可以不是蛋白质。在一些实施方式中，小分子可以不是核酸。在一些实施方式中，小分子可以不是多糖。在一些实施方式中，小分子可以具有生物学活性和/或发挥影响生物过程的作用。 在一些实施方式中，小分子可以是天然产物或首先经化学合成制备。例如，在一种实施方式中小分子可以治疗性药物、化学毒素或检测物质，例如染料分子FITC。In this application, the term "small molecule" generally refers to any chemical moiety or other moiety having a molecular weight below about 5000 Daltons (Da). In some embodiments, the molecular weight of the small molecule is less than about 2500 Daltons, about 1000 Daltons, or about 500 Daltons. In some embodiments, the small molecule may not be a polymer. In some embodiments, the small molecule may not be a protein. In some embodiments, the small molecule may not be a nucleic acid. In some embodiments, the small molecule may not be a polysaccharide. In some embodiments, small molecules can be biologically active and/or function to affect biological processes. In some embodiments, the small molecule may be a natural product or first prepared by chemical synthesis. For example, in one embodiment the small molecule can be a therapeutic drug, chemical toxin, or detection substance, such as the dye molecule FITC.
在本申请中，术语“抗原”通常是指由本发明的基因构建体编码的肽、多肽和蛋白，它们作为针对其诱导免疫应答的目标。靶蛋白可以是需要针对其诱导免疫的免疫原性蛋白，其可以与来自病原体或不希望的细胞类型的蛋白具有至少一个相同的表位，所述不希望的细胞类型例如可以为癌症细胞或参与自身免疫病的细胞。针对靶蛋白的免疫应答，可以将保护个体抵抗与靶蛋白相关的特定感染或疾病，或者可以治疗个体的上述感染或疾病。In this application, the term "antigen" generally refers to the peptides, polypeptides and proteins encoded by the genetic constructs of the present invention against which an immune response is induced. The target protein can be an immunogenic protein against which immunity needs to be induced, it can have at least one epitope in common with a protein from a pathogen or an undesired cell type, such as a cancer cell or involved in autoimmune cells. An immune response directed against the target protein can protect the individual against a particular infection or disease associated with the target protein, or can treat the individual for such infection or disease.
在本申请中，术语“细胞因子”通常包括，例如，白细胞介素、干扰素、趋化因子、造血生长因子，肿瘤坏死因子和转化生长因子。一般来说，它们可以是低分子量蛋白质，其可以调节免疫系统的细胞的成熟、活化、增殖和分化。In this application, the term "cytokine" generally includes, for example, interleukins, interferons, chemokines, hematopoietic growth factors, tumor necrosis factors and transforming growth factors. Generally, they can be low molecular weight proteins that can regulate the maturation, activation, proliferation and differentiation of cells of the immune system.
在本申请中，术语“染料分子”通常是指对目标物质进行染色的物质。例如，所述“染料分子”可以包含荧光标记物，而且还可以包括近红外荧光标记物。使用荧光团的化学反应性衍生物来实现荧光标记。常见的反应性基团可以包括胺反应性异硫氰酸盐衍生物诸如FITC和TRITC(荧光素和罗丹明的衍生物)、胺反应性琥珀酰亚氨基酯诸如NHS-荧光素、和硫氢基反应性马来酰亚胺活化的荧光素(fluor)诸如荧光素-5-马来酰亚胺。任何这些反应性染料可以与另一种分子的反应产生荧光团和经标记的分子间形成的稳定共价键。本申请涵盖的其它合适的荧光标记物是Alexa Fluor、DylightFluor和ATTO染料。例如，本申请涵盖的荧光蛋白诸如GFP、YFP或CFP。例如，本申请涵盖的通过pH变化或电压、温度活化的可活化染料分子。In this application, the term "dye molecule" generally refers to a substance that dyes a target substance. For example, the "dye molecule" may comprise a fluorescent label, but may also include a near-infrared fluorescent label. Fluorescent labeling is achieved using chemically reactive derivatives of fluorophores. Common reactive groups can include amine-reactive isothiocyanate derivatives such as FITC and TRITC (derivatives of fluorescein and rhodamine), amine-reactive succinimidyl esters such as NHS-fluorescein, and sulfhydryl A base-reactive maleimide-activated fluor such as fluorescein-5-maleimide. Any of these reactive dyes can react with another molecule to create a stable covalent bond between the fluorophore and the labeled molecule. Other suitable fluorescent labels encompassed by this application are Alexa Fluor, DylightFluor and ATTO dyes. For example, fluorescent proteins such as GFP, YFP or CFP are encompassed by this application. For example, activatable dye molecules that are activated by pH changes or voltage, temperature are contemplated by this application.
在本申请中，术语“可药用的盐”、“药学上可接受的盐”或“可药用盐”通常是指本申请化合物的盐，这类盐用于哺乳动物体内时可以具有安全性和/或有效性，且可以具有应有的生物活性，本申请化合物可以与酸形成盐，药学上可接受的盐的非限制性实例包括：盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、柠檬酸盐、乙酸盐、琥珀酸盐、抗坏血酸盐、草酸盐、硝酸盐、梨酸盐、磷酸氢盐、磷酸二氢盐、水杨酸盐、柠檬酸氢盐、酒石酸盐、马来酸盐、富马酸盐、甲酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐。In this application, the terms "pharmaceutically acceptable salts", "pharmaceutically acceptable salts" or "pharmaceutically acceptable salts" generally refer to salts of the compounds of the present application that are safe for use in mammals Properties and/or effectiveness, and may have due biological activity, the compounds of the present application may form salts with acids, non-limiting examples of pharmaceutically acceptable salts include: hydrochloride, hydrobromide, hydroiodic acid Salt, Sulfate, Bisulfate, Citrate, Acetate, Succinate, Ascorbate, Oxalate, Nitrate, Pearate, Hydrogen Phosphate, Dihydrogen Phosphate, Salicylate, Lemon Hydrogenate, tartrate, maleate, fumarate, formate, benzoate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate.
在本申请中，术语“药学上可接受的载体”通常是指生理学上相容的任何和所有溶剂、分散基质、涂层、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。例如，载体可以适用于肠胃外(例如，静脉内、肌内、皮下、鞘内)施用(例如，通过注射或输注)。根据给药途 径，活性化合物可以包被在材料中以保护化合物免受可能使化合物失活的酸和其他自然条件的作用。In this application, the term "pharmaceutically acceptable carrier" generally refers to any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. For example, the carrier may be suitable for parenteral (eg, intravenous, intramuscular, subcutaneous, intrathecal) administration (eg, by injection or infusion). Depending on the route of administration, the active compound can be coated in materials to protect the compound from the action of acids and other natural conditions that may inactivate the compound.
在本申请中，术语“Boc”或是“叔丁氧羰基(t-Butyloxy carbonyl)”，通常是指一种有机合成中常用的氨基保护基团。In this application, the term "Boc" or "t-Butyloxy carbonyl" generally refers to an amino protecting group commonly used in organic synthesis.
在本申请中，术语“Cu+”或“一价铜”通常是指一价铜催化剂。例如，Cu+可以是CuCN，CuSCN,CuI或CuBr。In this application, the term "Cu+" or "copper" generally refers to a monovalent copper catalyst. For example, Cu+ can be CuCN, CuSCN, CuI or CuBr.
在本申请中，术语“SrtA连接酶”通常是指一种介导的偶联反应的连接酶。SrtA连接酶介导的偶联反应(Chen,Long,et al."Improved variants of SrtA for site-specific conjugation on antibodies and proteins with high efficiency."Scientific reports 6.1(2016):1-12.)其原理是：SrtA连接酶能特异性识别如SEQ ID NO：7所示的LPETG序列，将N端为裸露甘氨酸的底物分子连接到目标蛋白上。In this application, the term "SrtA ligase" generally refers to a ligase that mediates a coupling reaction. SrtA ligase-mediated conjugation reaction (Chen,Long,et al."Improved variants of SrtA for site-specific conjugation on antibodies and proteins with high efficiency."Scientific reports 6.1(2016):1-12. The principle Yes: SrtA ligase can specifically recognize the LPETG sequence shown in SEQ ID NO: 7, and connect the substrate molecule whose N-terminus is naked glycine to the target protein.
在本申请中，术语“特异”通常是指抗体对抗原的特定表位的选择性识别。例如天然抗体是单特异性的。如在本申请中，术语“多特异”指具有两个或多个抗原结合位点的选择性，其中至少两个结合不同的抗原或者相同抗原的不同表位。例如对至少两个不同的抗原(即作为第一抗原的EGFR和作为第二抗原的4-1BB)可以是多特异性的。在本发明的一个实施方案中，根据本发明的多特异性抗体可以是双特异性的。在本发明的另一实施方案中，根据本发明的多特异性抗体可以是三特异性的。In this application, the term "specific" generally refers to the selective recognition of a specific epitope of an antigen by an antibody. For example, native antibodies are monospecific. As in this application, the term "multispecific" refers to the selectivity of having two or more antigen binding sites, at least two of which bind different antigens or different epitopes of the same antigen. For example, it can be multispecific for at least two different antigens (ie EGFR as the first antigen and 4-1BB as the second antigen). In one embodiment of the invention, the multispecific antibodies according to the invention may be bispecific. In another embodiment of the invention, the multispecific antibody according to the invention may be trispecific.
在本申请中，术语“偶联”通常是指通过共价键或通过强的非共价相互作用连接两个化合物，例如通过共价键的连接。例如本申请提供了通过一种化合物具有的N3与另一种化合物具有的炔基可以反应形成共价键的连接，并可以形成两种化合物的偶联物。In this application, the term "coupling" generally refers to the joining of two compounds by a covalent bond or by a strong non-covalent interaction, eg, by a covalent bond. For example, the present application provides linkages through which an N3 possessed by one compound and an alkynyl group possessed by another compound can react to form a covalent bond, and a conjugate of the two compounds can be formed.
在本申请中，术语“连接臂”通常是指一种可以连接不同其它化合物的中心化合物。所述中心化合物可以通过共价键或通过强的非共价相互作用连接一个或多个其它化合物以形成另一种更大的化合物。例如本申请的连接臂可以与一个或多个具有脂质、蛋白质、核酸、小分子或多糖，或其任意组合的化合物连接以形成偶联物。In this application, the term "linker" generally refers to a central compound to which different other compounds can be attached. The central compound can be linked to one or more other compounds by covalent bonds or by strong non-covalent interactions to form another larger compound. For example, the linkers of the present application can be linked to one or more compounds having lipids, proteins, nucleic acids, small molecules or polysaccharides, or any combination thereof, to form a conjugate.
在本申请中，术语“包含”通常是指包括明确指定的特征，但不排除其他要素。术语“以上”、“以下”通常是指包含本数的情况。In this application, the term "comprising" generally means including the expressly specified features, but not excluding other elements. The terms "above" and "below" generally refer to the inclusion of this number.
在本申请中，术语“约”通常是指在指定数值以上或以下0.5％-10％的范围内变动，例如在指定数值以上或以下0.5％、1％、1.5％、2％、2.5％、3％、3.5％、4％、4.5％、5％、5.5％、6％、6.5％、7％、7.5％、8％、8.5％、9％、9.5％或10％的范围内变动。In this application, the term "about" generally refers to a range of 0.5%-10% above or below the specified value, such as 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5% or 10%.
发明详述Detailed description of the invention
一方面，本申请提供一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，其具有如式Ia或式Ib所示的结构：In one aspect, the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable compound thereof , which has the structure shown in formula Ia or formula Ib:
Figure PCTCN2021130337-appb-000362
Figure PCTCN2021130337-appb-000362
所述Wa可以为三价基团，Wb可以为四价基团；The Wa can be a trivalent group, and Wb can be a tetravalent group;
所述A，B和C可以各自独立地选自以下组：Said A, B and C may each be independently selected from the following group:
Figure PCTCN2021130337-appb-000363
Figure PCTCN2021130337-appb-000363
其中R 12，R 13和R 14可以各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
Figure PCTCN2021130337-appb-000364
代表连接位点； wherein R 12 , R 13 and R 14 may each independently be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000364
represents the attachment site;
其中，A，B和C中，
Figure PCTCN2021130337-appb-000365
不能和
Figure PCTCN2021130337-appb-000366
同时存在； Among them, A, B and C,
Figure PCTCN2021130337-appb-000365
cannot and
Figure PCTCN2021130337-appb-000366
simultaneously exist;
其中，A，B和C中，
Figure PCTCN2021130337-appb-000367
不能和
Figure PCTCN2021130337-appb-000368
Figure PCTCN2021130337-appb-000369
同时存在； Among them, A, B and C,
Figure PCTCN2021130337-appb-000367
cannot and
Figure PCTCN2021130337-appb-000368
Figure PCTCN2021130337-appb-000369
simultaneously exist;
其中，A，B和C中，
Figure PCTCN2021130337-appb-000370
不能和
Figure PCTCN2021130337-appb-000371
同时存在；当A，B和C中，
Figure PCTCN2021130337-appb-000372
同时存在时，所述R 12，R 13和R 14不为炔基； Among them, A, B and C,
Figure PCTCN2021130337-appb-000370
cannot and
Figure PCTCN2021130337-appb-000371
exist at the same time; when A, B and C,
Figure PCTCN2021130337-appb-000372
When present at the same time, the R 12 , R 13 and R 14 are not alkynyl;
当A，B和C中，
Figure PCTCN2021130337-appb-000373
同时存在时，所述R 12，R 13和R 14不为氨基， When A, B and C,
Figure PCTCN2021130337-appb-000373
When present at the same time, the R 12 , R 13 and R 14 are not amino groups,
A，B和C不同时为
Figure PCTCN2021130337-appb-000374
A, B and C are not simultaneously
Figure PCTCN2021130337-appb-000374
在另一种实施方式中，所述A，B和C可以各自独立地选自以下组：
Figure PCTCN2021130337-appb-000375
Figure PCTCN2021130337-appb-000376
In another embodiment, the A, B and C may each be independently selected from the group consisting of:
Figure PCTCN2021130337-appb-000375
Figure PCTCN2021130337-appb-000376
其中R，R 12可以各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，每个X可以各自独立地选自以下组：氢，氕，氘，氚，卤素； wherein R, R 12 can each be independently selected from the following group: hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido, urea, Alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl, each X may be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen;
其中，当R为C 5H 11，X为H，或R为CH 2OH，X为H，或R为CH 2CH 3，X为F 时，A，B和C中，
Figure PCTCN2021130337-appb-000377
不能和
Figure PCTCN2021130337-appb-000378
同时存在； wherein, when R is C 5 H 11 and X is H, or R is CH 2 OH and X is H, or R is CH 2 CH 3 and X is F, in A, B and C,
Figure PCTCN2021130337-appb-000377
cannot and
Figure PCTCN2021130337-appb-000378
simultaneously exist;
其中，当R为CH 3，X为F，或R为CH 2CH 3，X为F时，A，B和C中，
Figure PCTCN2021130337-appb-000379
不能和
Figure PCTCN2021130337-appb-000380
同时存在， Wherein, when R is CH 3 and X is F, or R is CH 2 CH 3 and X is F, in A, B and C,
Figure PCTCN2021130337-appb-000379
cannot and
Figure PCTCN2021130337-appb-000380
simultaneously exist,
其中，A，B和C中，
Figure PCTCN2021130337-appb-000381
不能和
Figure PCTCN2021130337-appb-000382
同时存在， Among them, A, B and C,
Figure PCTCN2021130337-appb-000381
cannot and
Figure PCTCN2021130337-appb-000382
simultaneously exist,
其中，A，B和C中，
Figure PCTCN2021130337-appb-000383
不能和
Figure PCTCN2021130337-appb-000384
同时存在。 Among them, A, B and C,
Figure PCTCN2021130337-appb-000383
cannot and
Figure PCTCN2021130337-appb-000384
simultaneously exist.
在一种实施方式中，A、B和C基团的选择可以是以下组：In one embodiment, the selection of A, B and C groups may be of the following group:
(1)A为
Figure PCTCN2021130337-appb-000385
B为
Figure PCTCN2021130337-appb-000386
C为
Figure PCTCN2021130337-appb-000387
Figure PCTCN2021130337-appb-000388
Figure PCTCN2021130337-appb-000389
或 (1) A is
Figure PCTCN2021130337-appb-000385
B is
Figure PCTCN2021130337-appb-000386
C is
Figure PCTCN2021130337-appb-000387
Figure PCTCN2021130337-appb-000388
Figure PCTCN2021130337-appb-000389
or
(2)A为
Figure PCTCN2021130337-appb-000390
B为
Figure PCTCN2021130337-appb-000391
C为
Figure PCTCN2021130337-appb-000392
或 (2) A is
Figure PCTCN2021130337-appb-000390
B is
Figure PCTCN2021130337-appb-000391
C is
Figure PCTCN2021130337-appb-000392
or
(3)A为
Figure PCTCN2021130337-appb-000393
B为
Figure PCTCN2021130337-appb-000394
C为
Figure PCTCN2021130337-appb-000395
Figure PCTCN2021130337-appb-000396
Figure PCTCN2021130337-appb-000397
或 (3) A is
Figure PCTCN2021130337-appb-000393
B is
Figure PCTCN2021130337-appb-000394
C is
Figure PCTCN2021130337-appb-000395
Figure PCTCN2021130337-appb-000396
Figure PCTCN2021130337-appb-000397
or
(4)A为
Figure PCTCN2021130337-appb-000398
B为
Figure PCTCN2021130337-appb-000399
C为
Figure PCTCN2021130337-appb-000400
Figure PCTCN2021130337-appb-000401
或 (4) A is
Figure PCTCN2021130337-appb-000398
B is
Figure PCTCN2021130337-appb-000399
C is
Figure PCTCN2021130337-appb-000400
Figure PCTCN2021130337-appb-000401
or
(5)A为
Figure PCTCN2021130337-appb-000402
B为
Figure PCTCN2021130337-appb-000403
C为
Figure PCTCN2021130337-appb-000404
Figure PCTCN2021130337-appb-000405
或 (5) A is
Figure PCTCN2021130337-appb-000402
B is
Figure PCTCN2021130337-appb-000403
C is
Figure PCTCN2021130337-appb-000404
Figure PCTCN2021130337-appb-000405
or
(6)A为
Figure PCTCN2021130337-appb-000406
B为
Figure PCTCN2021130337-appb-000407
C为
Figure PCTCN2021130337-appb-000408
Figure PCTCN2021130337-appb-000409
或 (6) A is
Figure PCTCN2021130337-appb-000406
B is
Figure PCTCN2021130337-appb-000407
C is
Figure PCTCN2021130337-appb-000408
Figure PCTCN2021130337-appb-000409
or
(7)A为
Figure PCTCN2021130337-appb-000410
Figure PCTCN2021130337-appb-000411
B为
Figure PCTCN2021130337-appb-000412
C为
Figure PCTCN2021130337-appb-000413
Figure PCTCN2021130337-appb-000414
或 (7) A is
Figure PCTCN2021130337-appb-000410
Figure PCTCN2021130337-appb-000411
B is
Figure PCTCN2021130337-appb-000412
C is
Figure PCTCN2021130337-appb-000413
Figure PCTCN2021130337-appb-000414
or
(8)A为
Figure PCTCN2021130337-appb-000415
Figure PCTCN2021130337-appb-000416
B为
Figure PCTCN2021130337-appb-000417
C为
Figure PCTCN2021130337-appb-000418
或 (8) A is
Figure PCTCN2021130337-appb-000415
Figure PCTCN2021130337-appb-000416
B is
Figure PCTCN2021130337-appb-000417
C is
Figure PCTCN2021130337-appb-000418
or
(9)A为
Figure PCTCN2021130337-appb-000419
Figure PCTCN2021130337-appb-000420
B为
Figure PCTCN2021130337-appb-000421
C为
Figure PCTCN2021130337-appb-000422
或 (9) A is
Figure PCTCN2021130337-appb-000419
Figure PCTCN2021130337-appb-000420
B is
Figure PCTCN2021130337-appb-000421
C is
Figure PCTCN2021130337-appb-000422
or
(10)A为
Figure PCTCN2021130337-appb-000423
Figure PCTCN2021130337-appb-000424
B为
Figure PCTCN2021130337-appb-000425
C为
Figure PCTCN2021130337-appb-000426
或 (10) A is
Figure PCTCN2021130337-appb-000423
Figure PCTCN2021130337-appb-000424
B is
Figure PCTCN2021130337-appb-000425
C is
Figure PCTCN2021130337-appb-000426
or
(11)A为
Figure PCTCN2021130337-appb-000427
Figure PCTCN2021130337-appb-000428
B为
Figure PCTCN2021130337-appb-000429
或 (11) A is
Figure PCTCN2021130337-appb-000427
Figure PCTCN2021130337-appb-000428
B is
Figure PCTCN2021130337-appb-000429
or
(12)A为
Figure PCTCN2021130337-appb-000430
B为
Figure PCTCN2021130337-appb-000431
C为
Figure PCTCN2021130337-appb-000432
Figure PCTCN2021130337-appb-000433
或 (12) A is
Figure PCTCN2021130337-appb-000430
B is
Figure PCTCN2021130337-appb-000431
C is
Figure PCTCN2021130337-appb-000432
Figure PCTCN2021130337-appb-000433
or
(13)A为
Figure PCTCN2021130337-appb-000434
B为
Figure PCTCN2021130337-appb-000435
C为
Figure PCTCN2021130337-appb-000436
Figure PCTCN2021130337-appb-000437
或 (13) A is
Figure PCTCN2021130337-appb-000434
B is
Figure PCTCN2021130337-appb-000435
C is
Figure PCTCN2021130337-appb-000436
Figure PCTCN2021130337-appb-000437
or
(14)A为
Figure PCTCN2021130337-appb-000438
B为
Figure PCTCN2021130337-appb-000439
C为
Figure PCTCN2021130337-appb-000440
Figure PCTCN2021130337-appb-000441
(14) A is
Figure PCTCN2021130337-appb-000438
B is
Figure PCTCN2021130337-appb-000439
C is
Figure PCTCN2021130337-appb-000440
Figure PCTCN2021130337-appb-000441
其中R 12，R 13和R 14可以各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
Figure PCTCN2021130337-appb-000442
代表连接位点； wherein R 12 , R 13 and R 14 may each independently be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000442
represents the attachment site;
当A，B和C中，
Figure PCTCN2021130337-appb-000443
同时存在时，所述R 12，R 13和R 14不为炔基； When A, B and C,
Figure PCTCN2021130337-appb-000443
When present at the same time, the R 12 , R 13 and R 14 are not alkynyl;
当A，B和C中，
Figure PCTCN2021130337-appb-000444
同时存在时，所述R 12，R 13和R 14不为氨基。 When A, B and C,
Figure PCTCN2021130337-appb-000444
When present at the same time, the R 12 , R 13 and R 14 are not amino groups.
在另一种实施方式中，A、B和C基团的选择可以是以下组：In another embodiment, the selection of A, B and C groups may be of the following group:
(1)A为
Figure PCTCN2021130337-appb-000445
B为
Figure PCTCN2021130337-appb-000446
C为
Figure PCTCN2021130337-appb-000447
Figure PCTCN2021130337-appb-000448
或 (1) A is
Figure PCTCN2021130337-appb-000445
B is
Figure PCTCN2021130337-appb-000446
C is
Figure PCTCN2021130337-appb-000447
Figure PCTCN2021130337-appb-000448
or
(2)A为
Figure PCTCN2021130337-appb-000449
B为
Figure PCTCN2021130337-appb-000450
C为
Figure PCTCN2021130337-appb-000451
或 (2) A is
Figure PCTCN2021130337-appb-000449
B is
Figure PCTCN2021130337-appb-000450
C is
Figure PCTCN2021130337-appb-000451
or
(3)A为
Figure PCTCN2021130337-appb-000452
B为
Figure PCTCN2021130337-appb-000453
C为
Figure PCTCN2021130337-appb-000454
(3) A is
Figure PCTCN2021130337-appb-000452
B is
Figure PCTCN2021130337-appb-000453
C is
Figure PCTCN2021130337-appb-000454
其中R 12，R 13和R 14可以各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
Figure PCTCN2021130337-appb-000455
代表连接位点； wherein R 12 , R 13 and R 14 may each independently be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000455
represents the attachment site;
当A，B和C中，
Figure PCTCN2021130337-appb-000456
同时存在时，所述R 12，R 13和R 14不为氨基。 When A, B and C,
Figure PCTCN2021130337-appb-000456
When present at the same time, the R 12 , R 13 and R 14 are not amino groups.
在另一种实施方式中，A、B和C基团的选择可以是以下组：In another embodiment, the selection of A, B and C groups may be of the following group:
(1)A为
Figure PCTCN2021130337-appb-000457
B为
Figure PCTCN2021130337-appb-000458
C为
Figure PCTCN2021130337-appb-000459
或 (1) A is
Figure PCTCN2021130337-appb-000457
B is
Figure PCTCN2021130337-appb-000458
C is
Figure PCTCN2021130337-appb-000459
or
(2)A为
Figure PCTCN2021130337-appb-000460
B为
Figure PCTCN2021130337-appb-000461
C为
Figure PCTCN2021130337-appb-000462
或 (2) A is
Figure PCTCN2021130337-appb-000460
B is
Figure PCTCN2021130337-appb-000461
C is
Figure PCTCN2021130337-appb-000462
or
(3)A为
Figure PCTCN2021130337-appb-000463
B为
Figure PCTCN2021130337-appb-000464
C为
Figure PCTCN2021130337-appb-000465
(3) A is
Figure PCTCN2021130337-appb-000463
B is
Figure PCTCN2021130337-appb-000464
C is
Figure PCTCN2021130337-appb-000465
其中R 12可以选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂 芳基，
Figure PCTCN2021130337-appb-000466
代表连接位点； wherein R 12 can be selected from the following group: hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido, urea, alkane, cyclic Alkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000466
represents the attachment site;
当A，B和C中，
Figure PCTCN2021130337-appb-000467
同时存在时，所述R 12不为氨基。 When A, B and C,
Figure PCTCN2021130337-appb-000467
When both are present, the R 12 is not amino.
例如，其中R 12可以选自以下组：氢，氕，氘，氚，卤素和链烷基，
Figure PCTCN2021130337-appb-000468
代表连接位点。 For example, where R 12 can be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000468
represents the attachment site.
例如，其中：A可以为
Figure PCTCN2021130337-appb-000469
B可以为
Figure PCTCN2021130337-appb-000470
C可以为
Figure PCTCN2021130337-appb-000471
Figure PCTCN2021130337-appb-000472
其中R 12可以选自以下组的基团：包括氢，氕，氘，氚，卤素和链烷基，
Figure PCTCN2021130337-appb-000473
代表连接位点。 For example, where: A can be
Figure PCTCN2021130337-appb-000469
B can be
Figure PCTCN2021130337-appb-000470
C can be
Figure PCTCN2021130337-appb-000471
Figure PCTCN2021130337-appb-000472
wherein R 12 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000473
represents the attachment site.
在本申请中，所述Wa可以为三价基团，Wb可以为四价基团；例如：In this application, the Wa can be a trivalent group, and Wb can be a tetravalent group; for example:
Figure PCTCN2021130337-appb-000474
可以为
Figure PCTCN2021130337-appb-000475
Figure PCTCN2021130337-appb-000474
can be
Figure PCTCN2021130337-appb-000475
Figure PCTCN2021130337-appb-000476
可以为
Figure PCTCN2021130337-appb-000477
Figure PCTCN2021130337-appb-000476
can be
Figure PCTCN2021130337-appb-000477
所述W可以为三价基团或四价基团，所述W可以任选地被一个或多个R取代，The W may be a trivalent group or a tetravalent group, and the W may be optionally substituted with one or more Rs,
所述La可以为-(J 1) m1-C(＝O)-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-； The La may be -(J 1 ) m1 -C(=O)-X 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -;
所述Lb可以为-(J 2) m2-C(＝O)-X 2-(K 2) n2-(Y 2) p2-(L 2) q2-； The Lb may be -(J 2 ) m2 -C(=O)-X 2 -(K 2 ) n2 -(Y 2 ) p2 -(L 2 ) q2 -;
所述Lc可以为-(J 3) m3-C(＝O)-X 3-(K 3) n3-(Y 3) p3-(L 3) q3-； The Lc may be -(J 3 ) m3 -C(=O)-X 3 -(K 3 ) n3 -(Y 3 ) p3 -(L 3 ) q3 -;
所述J 1，J 2，J 3，K 1，K 2，K 3，L 1，L 2，和L 3可以各自独立地选自以下组：链烷基，环烷基，杂环烷基，烯基，炔基，芳基，杂芳基，和聚乙二醇，或前述任意组合； The J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 may each be independently selected from the group consisting of: alkane, cycloalkyl, heterocycloalkyl , alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
所述X 1，X 2，X 3，Y 1，Y 2，和Y 3可以各自独立地选自以下组：-NR 1-，-O-，-S-，-C(＝O)-，-C(＝S)-，-C(R 1a)(R 1b)-，-NR 1-C(＝O)-，-C(＝O)-NR 1-，-NR 1-C(＝S)-，-C(＝S)-NR 1-，- O-C(＝O)-，-C(＝O)-O-，-O-C(＝S)-，-C(＝S)-O-，-O-C(＝O)-O-，-O-C(＝O)-NR 1-，-NR 1-C(＝O)-O-，和-NR 1a-C(＝O)-NR 1b-； Said X 1 , X 2 , X 3 , Y 1 , Y 2 , and Y 3 may each be independently selected from the group of: -NR 1 -, -O-, -S-, -C(=O)-, -C(=S)-, -C(R 1a )(R 1b )-, -NR 1 -C(=O)-, -C(=O)-NR 1 -, -NR 1 -C(=S )-, -C(=S)-NR 1 -, -OC(=O)-, -C(=O)-O-, -OC(=S)-, -C(=S)-O-, -OC(=O)-O-, -OC(=O)-NR 1 -, -NR 1 -C(=O)-O-, and -NR 1a -C(=O)-NR 1b -;
R，R 1，R 1a和R 1b可以各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
Figure PCTCN2021130337-appb-000478
代表连接位点； R, R 1 , R 1a and R 1b may each be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfo Amido, Urea, Alkyl, Cycloalkyl, Heterocycloalkyl, Alkenyl, Alkynyl, Aryl, and Heteroaryl,
Figure PCTCN2021130337-appb-000478
represents the attachment site;
其中，m1，m2，m3，n1，n2，n3，p1，p2，p3，q1，q2，和q3可以各自独立地选自0以上的数。Wherein, m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 may each be independently selected from a number of 0 or more.
在另一种实施方式中，其中，J 1，J 2，和J 3可以各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合；其中，m1，m2，和m3可以各自独立地选自以下组：0、1、2和3。 In another embodiment, wherein J 1 , J 2 , and J 3 may each be independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein m1 , m2 , and m3 can each be independently selected from the group: 0, 1, 2, and 3.
在另一种实施方式中，其中，X 1，X 2，和X 3可以各自独立地选自以下组：-NH-和-O-。 In another embodiment, wherein X 1 , X 2 , and X 3 can each be independently selected from the group consisting of -NH- and -O-.
在另一种实施方式中，其中，K 1，K 2，和K 3可以各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合；其中，n1，n2，和n3可以各自独立地选自以下组：0、1、2和3。 In another embodiment, wherein K 1 , K 2 , and K 3 may each be independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein n1 , n2 , and n3 can each be independently selected from the group: 0, 1, 2, and 3.
例如，其中，(K 1) n1，(K 2) n2，和(K 3) n3可以各自独立地选自以下组：-链烷基-聚乙二醇-链烷基-，链烷基和聚乙二醇，或n1，n2或n3可以各自独立地为0。 For example, where (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 may each be independently selected from the group consisting of: -alkyi-polyethylene glycol-alkyi-, alkane, and Polyethylene glycol, or n1, n2 or n3 can each independently be zero.
例如，其中，(K 1) n1，(K 2) n2，和(K 3) n3可以各自独立地选自以下组：-(CH 2)-(CH 2-O-CH 2) 3-(CH 2)-，-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-，-(CH 2) 2-，和-(CH 2) 8-，或n1，n2或n3可以各自独立地为0。 For example, where (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 can each be independently selected from the group: -(CH 2 )-(CH 2 -O-CH 2 ) 3 -(CH 2 )-, -( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2- , -( CH2 ) 2- , and -( CH2 ) 8- , or n1, n2 Or n3 may each independently be zero.
在另一种实施方式中，其中，Y 1，Y 2，和Y 3可以各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-；R 1选自以下组：氢，氕，氘，氚，和链烷基；其中，n1，n2，和n3可以各自独立地选自以下组：0、1、2和3。 In another embodiment, wherein, Y 1 , Y 2 , and Y 3 may each be independently selected from the group of: -C(=O)-, -NR 1 -C(=O)-, -NR 1 - , and -O-; R1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; wherein, n1, n2, and n3 can each be independently selected from the group consisting of 0, 1, 2, and 3.
例如，其中，(Y 1) p1，(Y 2) p2，和(Y 3) p3可以各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-，R 1选自以下组：氢，氕，氘，氚，和链烷基；或p1，p2或p3可以各自独立地为0。 For example, where (Y 1 ) p1 , (Y 2 ) p2 , and (Y 3 ) p3 may each be independently selected from the group of: -C(=O)-, -NR 1 -C(=O)-, -NR 1 -, and -O-, R 1 are selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; or p1 , p2 or p3 may each independently be zero.
在另一种实施方式中，其中，L 1，L 2，和L 3可以各自独立地选自以下组：链烷基，和芳基，或前述任意组合；其中，q1，q2，和q3可以各自独立地选自以下组：0、1、2和3。 In another embodiment, wherein L 1 , L 2 , and L 3 may each be independently selected from the group consisting of alkane, and aryl, or any combination of the foregoing; wherein q1 , q2 , and q3 may Each is independently selected from the group: 0, 1, 2, and 3.
例如，其中，(L 1) q1，(L 2) q2，和(L 3) q3可以各自独立地选自以下组：-链烷基-芳基-，链烷基和聚乙二醇，或q1，q2和q3可以各自独立地为0。 For example, where (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 may each be independently selected from the group consisting of: -alkyi-aryl-, alkane, and polyethylene glycol, or q1, q2 and q3 can each independently be zero.
例如，其中，(L 1) q1，(L 2) q2，和(L 3) q3可以各自独立地选自以下组：-CH 2-芳基-，-(CH 2) 2-， 和-CH 2-，或q1，q2和q3各自独立地为0。 For example, wherein, (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 may each be independently selected from the group consisting of -CH 2 -aryl-, -(CH 2 ) 2 -, and -CH 2 -, or q1, q2 and q3 are each independently 0.
在另一种实施方式中，其中：In another embodiment, wherein:
W可以选自以下组：W can be selected from the following group:
Figure PCTCN2021130337-appb-000479
三价的链烷基，三价的环烷基，三价的杂环烷基，三价的烯基，三价的炔基，三价的芳基，和三价的杂芳基。
Figure PCTCN2021130337-appb-000479
Trivalent alkane, trivalent cycloalkyl, trivalent heterocycloalkyl, trivalent alkenyl, trivalent alkynyl, trivalent aryl, and trivalent heteroaryl.
例如，其中：For example, where:
W可以选自以下组：W can be selected from the following group:
Figure PCTCN2021130337-appb-000480
Figure PCTCN2021130337-appb-000480
所述X 1，X 2，X 3，X 4，X 5，X 6，X 7，X 8，X 9，X 10，X 11，X 12，X 13，X 14，X 15，X 16，X 17和X 18可以各自独立地选自以下组：C，N，O，S，P，CH，CH 2，NH，P(O)和P(S)； The X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 and X 18 may each be independently selected from the group consisting of C, N, O, S, P, CH, CH 2 , NH, P(O) and P(S);
所述---表示双键或单键。The --- represents a double bond or a single bond.
例如，其中：For example, where:
W选自以下组：W is selected from the following group:
Figure PCTCN2021130337-appb-000481
Figure PCTCN2021130337-appb-000481
Figure PCTCN2021130337-appb-000482
Figure PCTCN2021130337-appb-000482
在另一种实施方式中，所述化合物可以为In another embodiment, the compound may be
Figure PCTCN2021130337-appb-000483
Figure PCTCN2021130337-appb-000483
所述La为-(J 1) m1-C(＝O)-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-； The La is -(J 1 ) m1 -C(=O)-X 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -;
所述Lb为-(J 2) m2-C(＝O)-X 2-(K 2) n2-(Y 2) p2-(L 2) q2-； The Lb is -(J 2 ) m2 -C(=O)-X 2 -(K 2 ) n2 -(Y 2 ) p2 -(L 2 ) q2 -;
所述Lc为-(J 3) m3-C(＝O)-X 3-(K 3) n3-(Y 3) p3-(L 3) q3-； The Lc is -(J 3 ) m3 -C(=O)-X 3 -(K 3 ) n3 -(Y 3 ) p3 -(L 3 ) q3 -;
其中，J 1，J 2，和J 3可以各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合；其中，m1，m2，和m3可以各自独立地选自以下组：0、1、2和3； wherein J 1 , J 2 , and J 3 may each independently be selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein m1 , m2 , and m3 may each independently be selected from the following groups: 0, 1, 2 and 3;
其中，X 1，X 2，和X 3可以各自独立地选自以下组：-NH-和-O-； wherein X 1 , X 2 , and X 3 can each be independently selected from the group of: -NH- and -O-;
其中，(K 1) n1，(K 2) n2，和(K 3) n3可以各自独立地选自以下组：-(CH 2)-(CH 2-O-CH 2) 3-(CH 2)-，-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-，-(CH 2) 2-，和-(CH 2) 8-，或n1，n2或n3可以各自独立地为0； wherein (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 can each be independently selected from the group of: -(CH 2 )-(CH 2 -O-CH 2 ) 3 -(CH 2 ) -, -( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2- , -( CH2 ) 2- , and -( CH2 ) 8- , or n1, n2, or n3 can be independently 0;
(Y 1) p1，(Y 2) p2，和(Y 3) p3可以各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-，R 1选自以下组：氢，氕，氘，氚，和链烷基；或p1，p2或p3可以各自独立地为0； (Y 1 ) p1 , (Y 2 ) p2 , and (Y 3 ) p3 may each be independently selected from the group consisting of: -C(=O)-, -NR 1 -C(=O)-, -NR 1 - , and -O-, R1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; or p1, p2 or p3 may each independently be 0;
(L 1) q1，(L 2) q2，和(L 3) q3可以各自独立地选自以下组：-CH 2-芳基-，-(CH 2) 2-，-CH 2-，链烷基和聚乙二醇，或q1，q2和q3可以各自独立地为0； (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 may each be independently selected from the group consisting of: -CH 2 -aryl-, -(CH 2 ) 2 -, -CH 2 -, alkane base and polyethylene glycol, or q1, q2 and q3 may each independently be 0;
W可以选自以下组：W can be selected from the following group:
Figure PCTCN2021130337-appb-000484
Figure PCTCN2021130337-appb-000484
A可以为
Figure PCTCN2021130337-appb-000485
B可以为
Figure PCTCN2021130337-appb-000486
C可以为
Figure PCTCN2021130337-appb-000487
其中R 12可以选自以下组的基团：包括氢，氕，氘，氚，卤素和链烷基，
Figure PCTCN2021130337-appb-000488
代表连接位点。 A can be
Figure PCTCN2021130337-appb-000485
B can be
Figure PCTCN2021130337-appb-000486
C can be
Figure PCTCN2021130337-appb-000487
wherein R 12 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000488
represents the attachment site.
例如W可以选自以下组：For example W can be selected from the following group:
Figure PCTCN2021130337-appb-000489
Figure PCTCN2021130337-appb-000489
在另一种实施方式中，所述La、Lb和Lc可以各自独立地选自以下组：线性烃链、含有1个或1个以上杂原子的线性杂烃链、含有1个或1个以上分支的分支烃链、和含有1个或1个以上分支的含有1个或1个以上杂原子的线性杂烃链。In another embodiment, the La, Lb and Lc may each be independently selected from the group consisting of linear hydrocarbon chains, linear heterohydrocarbon chains containing 1 or more heteroatoms, containing 1 or more heteroatoms A branched branched hydrocarbon chain, and a linear heterohydrocarbon chain containing one or more heteroatoms containing one or more branches.
在另一种实施方式中，所述La、Lb和Lc可以各自独立地选自以下组：线性烷基链、和含有1个或1个以上杂原子的线性杂烷基链。In another embodiment, the La, Lb, and Lc may each be independently selected from the group consisting of linear alkyl chains, and linear heteroalkyl chains containing 1 or more heteroatoms.
在另一种实施方式中，所述La、Lb和Lc可以各自选自-C nxH 2nx-，其中nx为大于0的数。例如，nx为1以上、2以上、3以上、4以上、5以上、6以上、7以上、8以上、或9以上的数。例如，nx为1、2、3、4、5、6、7、8、9、或10. In another embodiment, the La, Lb and Lc may each be selected from -C nx H 2nx -, where nx is a number greater than zero. For example, nx is a number of 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more. For example, nx is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
在另一种实施方式中，所述La、Lb和Lc可以各自独立地选自聚合物。In another embodiment, the La, Lb and Lc may each be independently selected from polymers.
在另一种实施方式中，所述La、Lb和Lc可以各自独立地选自以下组：聚糖、聚氨基酸、聚核苷酸、和聚乳酸。In another embodiment, the La, Lb, and Lc may each be independently selected from the group consisting of glycans, polyamino acids, polynucleotides, and polylactic acids.
在另一种实施方式中，所述La、Lb和Lc可以各自独立地为聚糖。聚糖可以是糖残基的单体或聚合物，并且可以是直链或支链的。聚糖可包括天然糖残基(例如，葡萄糖，N-乙酰基葡糖胺，N-乙酰神经氨酸，半乳糖，甘露糖，岩藻糖，己糖，阿拉伯糖，核糖，木糖等)和/或修饰的糖(例如，2'-氟代核糖，2'-脱氧核糖，磷酸甘露糖，6'-磺基N-乙酰基葡糖胺等)。在另一种实施方式中，所述La、Lb和Lc可以各自独立地为糖残基的均聚物和杂聚物。In another embodiment, the La, Lb and Lc may each independently be a glycan. Glycans can be monomers or polymers of sugar residues, and can be linear or branched. Glycans may include natural sugar residues (eg, glucose, N-acetylglucosamine, N-acetylneuraminic acid, galactose, mannose, fucose, hexose, arabinose, ribose, xylose, etc.) and/or modified sugars (eg, 2'-fluororibose, 2'-deoxyribose, mannose phosphate, 6'-sulfoN-acetylglucosamine, etc.). In another embodiment, the La, Lb and Lc may each independently be homopolymers and heteropolymers of sugar residues.
在另一种实施方式中，所述La、Lb和Lc可以各自独立地为聚核苷酸。聚核苷酸可以包括单链和双链核苷酸聚合物。组成聚核苷酸的核苷酸可以是核糖核苷酸或脱氧核糖核苷酸，或任一类核苷酸的经修饰形式。在另一种实施方式中，所述La、Lb和Lc可以各自独立地为碱基修饰的聚核苷酸，In another embodiment, the La, Lb and Lc may each independently be a polynucleotide. Polynucleotides can include single- and double-stranded nucleotide polymers. The nucleotides that make up a polynucleotide can be ribonucleotides or deoxyribonucleotides, or a modified form of either class of nucleotides. In another embodiment, the La, Lb and Lc may each independently be a base-modified polynucleotide,
在另一种实施方式中，所述La、Lb和Lc可以各自独立地为聚甘氨酸，例如可以是1个以上甘氨酸聚合的聚甘氨酸。在某些实施方式中，可以是1个以上、2个以上、3个以上、4个以上、5个以上、6个以上、7个以上、8个以上、或9个以上甘氨酸聚合的聚甘氨酸。在某些实施方式中，可以是1个、2个、3个、4个、5个、6个、7个、8个、9个、或10个甘氨酸聚合的聚甘氨酸。In another embodiment, the La, Lb, and Lc may each independently be polyglycine, for example, may be polyglycine in which more than one glycine is polymerized. In certain embodiments, there may be 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more glycine-polymerized polyglycines . In certain embodiments, there may be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 glycine-polymerized polyglycines.
在另一种实施方式中，所述各个基团可以各自独立地选自以下组，可以是指各个基团都 选自以下组的一个或多个，也可以是指其中部分基团选自以下组的一个或多个，另外一部分基团选自本申请中对于所述基团任一定义中的以下组的一个或多个。In another embodiment, each of the groups may be independently selected from the following groups, which may mean that each group is selected from one or more of the following groups, or may mean that some of the groups are selected from the following groups: one or more of the group, and another portion of the group is selected from one or more of the following groups in any of the definitions for said group in this application.
在另一种实施方式中，所述化合物可以选自以下组：In another embodiment, the compound may be selected from the group consisting of:
Figure PCTCN2021130337-appb-000490
Figure PCTCN2021130337-appb-000490
Figure PCTCN2021130337-appb-000491
Figure PCTCN2021130337-appb-000491
Figure PCTCN2021130337-appb-000492
Figure PCTCN2021130337-appb-000492
Figure PCTCN2021130337-appb-000493
Figure PCTCN2021130337-appb-000493
在另一种实施方式中，所述化合物可以选自以下组：In another embodiment, the compound may be selected from the group consisting of:
Figure PCTCN2021130337-appb-000494
Figure PCTCN2021130337-appb-000494
在另一方面，本申请提供一种合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，其具有如式IIa或式IIb所示的结构，其中：In another aspect, the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof A pharmaceutically acceptable salt having the structure shown in Formula IIa or Formula IIb, wherein:
Figure PCTCN2021130337-appb-000495
Figure PCTCN2021130337-appb-000495
所述Wc为三价基团，Wd为四价基团；The Wc is a trivalent group, and Wd is a tetravalent group;
所述A 2，B 2和C 2各自独立地选自以下组： Said A 2 , B 2 and C 2 are each independently selected from the following group:
Figure PCTCN2021130337-appb-000496
Figure PCTCN2021130337-appb-000497
和共价键；
Figure PCTCN2021130337-appb-000496
Figure PCTCN2021130337-appb-000497
and covalent bonds;
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基， wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000498
代表连接位点，
Figure PCTCN2021130337-appb-000498
represents the attachment site,
所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接； The two linking sites of the A2 are arbitrarily linked to Wc and P1, the two linking sites of the B2 are arbitrarily linked to Wc and P2, the two linking sites of the C2 are arbitrarily linked Connect with Wc and P3 ;
其中P 1，P 2和P 3各自独立地选自以下组：脂质、蛋白质、核酸、小分子和多糖，或其任意组合。 wherein P 1 , P 2 and P 3 are each independently selected from the group consisting of lipids, proteins, nucleic acids, small molecules and polysaccharides, or any combination thereof.
在一种实施方式中，其中A 2，B 2和C 2可以各自独立地选自以下组： In one embodiment, wherein A 2 , B 2 and C 2 may each be independently selected from the group consisting of:
(1)A 2为
Figure PCTCN2021130337-appb-000499
B 2为
Figure PCTCN2021130337-appb-000500
C 2为
Figure PCTCN2021130337-appb-000501
Figure PCTCN2021130337-appb-000502
Figure PCTCN2021130337-appb-000503
或共价键；或 (1) A 2 is
Figure PCTCN2021130337-appb-000499
B2 is
Figure PCTCN2021130337-appb-000500
C2 is
Figure PCTCN2021130337-appb-000501
Figure PCTCN2021130337-appb-000502
Figure PCTCN2021130337-appb-000503
or covalent bond; or
(2)A 2为
Figure PCTCN2021130337-appb-000504
Figure PCTCN2021130337-appb-000505
B 2为
Figure PCTCN2021130337-appb-000506
Figure PCTCN2021130337-appb-000507
C 2为
Figure PCTCN2021130337-appb-000508
Figure PCTCN2021130337-appb-000509
或共价键；或 (2) A 2 is
Figure PCTCN2021130337-appb-000504
Figure PCTCN2021130337-appb-000505
B2 is
Figure PCTCN2021130337-appb-000506
Figure PCTCN2021130337-appb-000507
C2 is
Figure PCTCN2021130337-appb-000508
Figure PCTCN2021130337-appb-000509
or covalent bond; or
(3)A 2为
Figure PCTCN2021130337-appb-000510
B 2为
Figure PCTCN2021130337-appb-000511
C 2为
Figure PCTCN2021130337-appb-000512
Figure PCTCN2021130337-appb-000513
或共价键；或 (3) A 2 is
Figure PCTCN2021130337-appb-000510
B2 is
Figure PCTCN2021130337-appb-000511
C2 is
Figure PCTCN2021130337-appb-000512
Figure PCTCN2021130337-appb-000513
or covalent bond; or
(4)A 2为
Figure PCTCN2021130337-appb-000514
B 2为
Figure PCTCN2021130337-appb-000515
C 2为
Figure PCTCN2021130337-appb-000516
Figure PCTCN2021130337-appb-000517
或共价键；或 (4) A 2 is
Figure PCTCN2021130337-appb-000514
B2 is
Figure PCTCN2021130337-appb-000515
C2 is
Figure PCTCN2021130337-appb-000516
Figure PCTCN2021130337-appb-000517
or covalent bond; or
(5)A 2为
Figure PCTCN2021130337-appb-000518
Figure PCTCN2021130337-appb-000519
B 2为
Figure PCTCN2021130337-appb-000520
C 2为
Figure PCTCN2021130337-appb-000521
Figure PCTCN2021130337-appb-000522
Figure PCTCN2021130337-appb-000523
或共价键；或 (5) A 2 is
Figure PCTCN2021130337-appb-000518
Figure PCTCN2021130337-appb-000519
B2 is
Figure PCTCN2021130337-appb-000520
C2 is
Figure PCTCN2021130337-appb-000521
Figure PCTCN2021130337-appb-000522
Figure PCTCN2021130337-appb-000523
or covalent bond; or
(6)A 2为
Figure PCTCN2021130337-appb-000524
Figure PCTCN2021130337-appb-000525
B 2为
Figure PCTCN2021130337-appb-000526
Figure PCTCN2021130337-appb-000527
C 2为
Figure PCTCN2021130337-appb-000528
Figure PCTCN2021130337-appb-000529
或共价键；或 (6) A 2 is
Figure PCTCN2021130337-appb-000524
Figure PCTCN2021130337-appb-000525
B2 is
Figure PCTCN2021130337-appb-000526
Figure PCTCN2021130337-appb-000527
C2 is
Figure PCTCN2021130337-appb-000528
Figure PCTCN2021130337-appb-000529
or covalent bond; or
(7)A 2为
Figure PCTCN2021130337-appb-000530
Figure PCTCN2021130337-appb-000531
B 2为
Figure PCTCN2021130337-appb-000532
C 2为
Figure PCTCN2021130337-appb-000533
或共价键；或 (7) A 2 is
Figure PCTCN2021130337-appb-000530
Figure PCTCN2021130337-appb-000531
B2 is
Figure PCTCN2021130337-appb-000532
C2 is
Figure PCTCN2021130337-appb-000533
or covalent bond; or
(8)A 2为
Figure PCTCN2021130337-appb-000534
Figure PCTCN2021130337-appb-000535
Figure PCTCN2021130337-appb-000536
B 2为
Figure PCTCN2021130337-appb-000537
C 2为
Figure PCTCN2021130337-appb-000538
或共价键；或 (8) A 2 is
Figure PCTCN2021130337-appb-000534
Figure PCTCN2021130337-appb-000535
Figure PCTCN2021130337-appb-000536
B2 is
Figure PCTCN2021130337-appb-000537
C2 is
Figure PCTCN2021130337-appb-000538
or covalent bond; or
(9)A 2为
Figure PCTCN2021130337-appb-000539
Figure PCTCN2021130337-appb-000540
Figure PCTCN2021130337-appb-000541
B 2为
Figure PCTCN2021130337-appb-000542
C 2为
Figure PCTCN2021130337-appb-000543
或共价键；或 (9) A 2 is
Figure PCTCN2021130337-appb-000539
Figure PCTCN2021130337-appb-000540
Figure PCTCN2021130337-appb-000541
B2 is
Figure PCTCN2021130337-appb-000542
C2 is
Figure PCTCN2021130337-appb-000543
or covalent bond; or
(10)A 2为
Figure PCTCN2021130337-appb-000544
Figure PCTCN2021130337-appb-000545
Figure PCTCN2021130337-appb-000546
或共价键，B 2为共价键，C 2为共价键；或 (10) A 2 is
Figure PCTCN2021130337-appb-000544
Figure PCTCN2021130337-appb-000545
Figure PCTCN2021130337-appb-000546
Or a covalent bond, B 2 is a covalent bond, and C 2 is a covalent bond; or
(11)A 2为
Figure PCTCN2021130337-appb-000547
B 2为
Figure PCTCN2021130337-appb-000548
Figure PCTCN2021130337-appb-000549
C 2为
Figure PCTCN2021130337-appb-000550
Figure PCTCN2021130337-appb-000551
Figure PCTCN2021130337-appb-000552
或共价键；或 (11) A 2 is
Figure PCTCN2021130337-appb-000547
B2 is
Figure PCTCN2021130337-appb-000548
Figure PCTCN2021130337-appb-000549
C2 is
Figure PCTCN2021130337-appb-000550
Figure PCTCN2021130337-appb-000551
Figure PCTCN2021130337-appb-000552
or covalent bond; or
(12)A 2为
Figure PCTCN2021130337-appb-000553
B 2为
Figure PCTCN2021130337-appb-000554
C 2为
Figure PCTCN2021130337-appb-000555
Figure PCTCN2021130337-appb-000556
或共价键；或 (12) A 2 is
Figure PCTCN2021130337-appb-000553
B2 is
Figure PCTCN2021130337-appb-000554
C2 is
Figure PCTCN2021130337-appb-000555
Figure PCTCN2021130337-appb-000556
or covalent bond; or
(13)A 2为
Figure PCTCN2021130337-appb-000557
B 2为
Figure PCTCN2021130337-appb-000558
C 2为
Figure PCTCN2021130337-appb-000559
或共价键； (13) A 2 is
Figure PCTCN2021130337-appb-000557
B2 is
Figure PCTCN2021130337-appb-000558
C2 is
Figure PCTCN2021130337-appb-000559
or covalent bond;
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基， wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000560
代表连接位点，
Figure PCTCN2021130337-appb-000560
represents the attachment site,
所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。 The two linking sites of the A2 are arbitrarily linked to Wc and P1, the two linking sites of the B2 are arbitrarily linked to Wc and P2, the two linking sites of the C2 are arbitrarily linked Connect with Wc and P3 .
例如，其中A 2，B 2和C 2可以各自独立地选自以下组： For example, wherein A 2 , B 2 and C 2 may each be independently selected from the following group:
(1)A 2为
Figure PCTCN2021130337-appb-000561
B 2为
Figure PCTCN2021130337-appb-000562
Figure PCTCN2021130337-appb-000563
C 2为
Figure PCTCN2021130337-appb-000564
或共价键；或 (1) A 2 is
Figure PCTCN2021130337-appb-000561
B2 is
Figure PCTCN2021130337-appb-000562
Figure PCTCN2021130337-appb-000563
C2 is
Figure PCTCN2021130337-appb-000564
or covalent bond; or
(2)A 2为
Figure PCTCN2021130337-appb-000565
B 2为
Figure PCTCN2021130337-appb-000566
Figure PCTCN2021130337-appb-000567
C 2为
Figure PCTCN2021130337-appb-000568
Figure PCTCN2021130337-appb-000569
或共价键；或 (2) A 2 is
Figure PCTCN2021130337-appb-000565
B2 is
Figure PCTCN2021130337-appb-000566
Figure PCTCN2021130337-appb-000567
C2 is
Figure PCTCN2021130337-appb-000568
Figure PCTCN2021130337-appb-000569
or covalent bond; or
(3)A 2为
Figure PCTCN2021130337-appb-000570
Figure PCTCN2021130337-appb-000571
B 2为
Figure PCTCN2021130337-appb-000572
C 2为
Figure PCTCN2021130337-appb-000573
Figure PCTCN2021130337-appb-000574
或共价键； (3) A 2 is
Figure PCTCN2021130337-appb-000570
Figure PCTCN2021130337-appb-000571
B2 is
Figure PCTCN2021130337-appb-000572
C2 is
Figure PCTCN2021130337-appb-000573
Figure PCTCN2021130337-appb-000574
or covalent bond;
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基， wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000575
代表连接位点，所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。
Figure PCTCN2021130337-appb-000575
Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
例如，其中A 2，B 2和C 2可以各自独立地选自以下组： For example, wherein A 2 , B 2 and C 2 may each be independently selected from the following group:
(1)A 2为
Figure PCTCN2021130337-appb-000576
B 2为
Figure PCTCN2021130337-appb-000577
Figure PCTCN2021130337-appb-000578
C 2为
Figure PCTCN2021130337-appb-000579
或共价键；或 (1) A 2 is
Figure PCTCN2021130337-appb-000576
B2 is
Figure PCTCN2021130337-appb-000577
Figure PCTCN2021130337-appb-000578
C2 is
Figure PCTCN2021130337-appb-000579
or covalent bond; or
(2)A 2为
Figure PCTCN2021130337-appb-000580
B 2为
Figure PCTCN2021130337-appb-000581
C 2为
Figure PCTCN2021130337-appb-000582
或共价键；或 (2) A 2 is
Figure PCTCN2021130337-appb-000580
B2 is
Figure PCTCN2021130337-appb-000581
C2 is
Figure PCTCN2021130337-appb-000582
or covalent bond; or
(3)A 2为
Figure PCTCN2021130337-appb-000583
B 2为
Figure PCTCN2021130337-appb-000584
Figure PCTCN2021130337-appb-000585
C 2为
Figure PCTCN2021130337-appb-000586
或共价键； (3) A 2 is
Figure PCTCN2021130337-appb-000583
B2 is
Figure PCTCN2021130337-appb-000584
Figure PCTCN2021130337-appb-000585
C2 is
Figure PCTCN2021130337-appb-000586
or covalent bond;
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基， wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
Figure PCTCN2021130337-appb-000587
代表连接位点，所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。
Figure PCTCN2021130337-appb-000587
Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
例如，R 12，R 13和R 14可以各自独立地选自以下组：氢，氕，氘，氚，卤素和链烷基， For example, R 12 , R 13 and R 14 may each be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000588
代表连接位点，所述A 2的两个连接位点可以任意地与Wc和P 1连接，所述B 2的两个连接位点可以任意地与Wc和P 2连接，所述C 2的两个连接位点可以任意地与Wc和P 3连接。
Figure PCTCN2021130337-appb-000588
Represents the linking site, the two linking sites of A2 can be arbitrarily linked with Wc and P1, the two linking sites of B2 can be linked with Wc and P2 arbitrarily, and the two linking sites of C2 The two attachment sites can optionally be attached to Wc and P3 .
例如，其中A 2，B 2和C 2可以各自为：A 2为
Figure PCTCN2021130337-appb-000589
B 2为
Figure PCTCN2021130337-appb-000590
Figure PCTCN2021130337-appb-000591
C 2为
Figure PCTCN2021130337-appb-000592
或共价键；其中R 12，R 13和R 14可以各自独立地选自以下组：氢，氕，氘，氚，卤素和链烷基，
Figure PCTCN2021130337-appb-000593
代表连接位点，所述A 2的两个连接位点可以任意地与Wc和P 1连接，所述B 2的两个连接位点可以任意地与Wc和P 2连接，所述C 2的两个连接位点可以任意地与Wc和P 3连接。 For example, where A 2 , B 2 and C 2 can each be: A 2 is
Figure PCTCN2021130337-appb-000589
B2 is
Figure PCTCN2021130337-appb-000590
Figure PCTCN2021130337-appb-000591
C2 is
Figure PCTCN2021130337-appb-000592
or a covalent bond; wherein R 12 , R 13 and R 14 may each be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000593
Represents the linking site, the two linking sites of A2 can be arbitrarily linked with Wc and P1, the two linking sites of B2 can be linked with Wc and P2 arbitrarily, and the two linking sites of C2 The two attachment sites can optionally be attached to Wc and P3 .
例如，A 2可以为
Figure PCTCN2021130337-appb-000594
B 2可以为，
Figure PCTCN2021130337-appb-000595
C 2可以为
Figure PCTCN2021130337-appb-000596
或共价键；其中R 12可以选自以下组：氢，氕，氘，氚，卤素和链烷基，
Figure PCTCN2021130337-appb-000597
代表连接位点，所述A 2的两个连接位点可以任意地与Wc和P 1连接，所述B 2的两个连接位点可以任意地与Wc和P 2连接，所述C 2的两个连接位点可以任意地与Wc和P 3连接。 For example, A2 can be
Figure PCTCN2021130337-appb-000594
B2 can be,
Figure PCTCN2021130337-appb-000595
C2 can be
Figure PCTCN2021130337-appb-000596
or a covalent bond; wherein R 12 can be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000597
Represents the linking site, the two linking sites of A2 can be arbitrarily linked with Wc and P1, the two linking sites of B2 can be linked with Wc and P2 arbitrarily, and the two linking sites of C2 The two attachment sites can optionally be attached to Wc and P3 .
在另一种实施方式中，
Figure PCTCN2021130337-appb-000598
可以为
Figure PCTCN2021130337-appb-000599
Figure PCTCN2021130337-appb-000600
可以为
Figure PCTCN2021130337-appb-000601
In another embodiment,
Figure PCTCN2021130337-appb-000598
can be
Figure PCTCN2021130337-appb-000599
Figure PCTCN2021130337-appb-000600
can be
Figure PCTCN2021130337-appb-000601
所述W可以为三价基团，所述W任选地被一个或多个R取代，The W can be a trivalent group optionally substituted with one or more R,
所述La可以为-(J 1) m1-C(＝O)-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-； The La may be -(J 1 ) m1 -C(=O)-X 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -;
所述Lb可以为-(J 2) m2-C(＝O)-X 2-(K 2) n2-(Y 2) p2-(L 2) q2-； The Lb may be -(J 2 ) m2 -C(=O)-X 2 -(K 2 ) n2 -(Y 2 ) p2 -(L 2 ) q2 -;
所述Lc可以为-(J 3) m3-C(＝O)-X 3-(K 3) n3-(Y 3) p3-(L 3) q3-； The Lc may be -(J 3 ) m3 -C(=O)-X 3 -(K 3 ) n3 -(Y 3 ) p3 -(L 3 ) q3 -;
所述J 1，J 2，J 3，K 1，K 2，K 3，L 1，L 2，和L 3可以各自独立地选自以下组：链烷基，环烷基，杂环烷基，烯基，炔基，芳基，杂芳基，和聚乙二醇，或前述任意组合； The J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 may each be independently selected from the group consisting of: alkane, cycloalkyl, heterocycloalkyl , alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
所述X 1，X 2，X 3，Y 1，Y 2，和Y 3可以各自独立地选自以下组：-NR 1-，-O-，-S-，-C(＝O)-，-C(＝S)-，-C(R 1a)(R 1b)-，-NR 1-C(＝O)-，-C(＝O)-NR 1-，-NR 1-C(＝S)-，-C(＝S)-NR 1-，-O-C(＝O)-，-C(＝O)-O-，-O-C(＝S)-，-C(＝S)-O-，-O-C(＝O)-O-，-O-C(＝O)-NR 1-，-NR 1-C(＝O)-O-，和-NR 1a-C(＝O)-NR 1b-； Said X 1 , X 2 , X 3 , Y 1 , Y 2 , and Y 3 may each be independently selected from the group of: -NR 1 -, -O-, -S-, -C(=O)-, -C(=S)-, -C(R 1a )(R 1b )-, -NR 1 -C(=O)-, -C(=O)-NR 1 -, -NR 1 -C(=S )-, -C(=S)-NR 1 -, -OC(=O)-, -C(=O)-O-, -OC(=S)-, -C(=S)-O-, -OC(=O)-O-, -OC(=O)-NR 1 -, -NR 1 -C(=O)-O-, and -NR 1a -C(=O)-NR 1b -;
R，R 1，R 1a和R 1b可以各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
Figure PCTCN2021130337-appb-000602
代表连接位点； R, R 1 , R 1a and R 1b may each be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfo Amido, Urea, Alkyl, Cycloalkyl, Heterocycloalkyl, Alkenyl, Alkynyl, Aryl, and Heteroaryl,
Figure PCTCN2021130337-appb-000602
represents the attachment site;
其中，m1，m2，m3，n1，n2，n3，p1，p2，p3，q1，q2，和q3可以各自独立地选自0以上的数。Wherein, m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 may each be independently selected from a number of 0 or more.
在另一种实施方式中，其中，J 1，J 2，和J 3可以各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合；其中，m1，m2，和m3可以各自独立地选自以下组：0、1、2和3。 In another embodiment, wherein J 1 , J 2 , and J 3 may each be independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein m1 , m2 , and m3 can each be independently selected from the group: 0, 1, 2, and 3.
在另一种实施方式中，其中，X 1，X 2，和X 3可以各自独立地选自以下组：-NH-和-O-。 In another embodiment, wherein X 1 , X 2 , and X 3 can each be independently selected from the group consisting of -NH- and -O-.
在另一种实施方式中，其中，K 1，K 2，和K 3可以各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合；其中，n1，n2，和n3可以各自独立地选自以下组：0、1、2和3。 In another embodiment, wherein K 1 , K 2 , and K 3 may each be independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein n1 , n2 , and n3 can each be independently selected from the group: 0, 1, 2, and 3.
例如，其中，(K 1) n1，(K 2) n2，和(K 3) n3可以各自独立地选自以下组：-链烷基-聚乙二醇-链烷基-，链烷基和聚乙二醇，或n1，n2或n3可以各自独立地为0。 For example, where (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 may each be independently selected from the group consisting of: -alkyi-polyethylene glycol-alkyi-, alkane, and Polyethylene glycol, or n1, n2 or n3 can each independently be zero.
例如，其中，(K 1) n1，(K 2) n2，和(K 3) n3可以各自独立地选自以下组：-(CH 2)-(CH 2-O-CH 2) 3-(CH 2)-，-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-，-(CH 2) 2-，和-(CH 2) 8-，或n1，n2或n3可以各自独立地为0。 For example, where (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 can each be independently selected from the group: -(CH 2 )-(CH 2 -O-CH 2 ) 3 -(CH 2 )-, -( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2- , -( CH2 ) 2- , and -( CH2 ) 8- , or n1, n2 Or n3 may each independently be zero.
在一种实施方式中，其中，Y 1，Y 2，和Y 3可以各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-；R 1选自以下组：氢，氕，氘，氚，和链烷基；其中，n1，n2，和n3可以各自独立地选自以下组：0、1、2和3。 In one embodiment, wherein, Y 1 , Y 2 , and Y 3 may each be independently selected from the group of: -C(=O)-, -NR 1 -C(=O)-, -NR 1 - , and -O-; R1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; wherein, n1, n2, and n3 can each be independently selected from the group consisting of 0, 1, 2, and 3 .
例如，其中，(Y 1) p1，(Y 2) p2，和(Y 3) p3可以各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-，R 1选自以下组：氢，氕，氘，氚，和链烷基；或p1，p2或p3可以各自独立地为0。 For example, where (Y 1 ) p1 , (Y 2 ) p2 , and (Y 3 ) p3 may each be independently selected from the group of: -C(=O)-, -NR 1 -C(=O)-, -NR 1 -, and -O-, R 1 are selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; or p1 , p2 or p3 may each independently be zero.
在一种实施方式中，其中，L 1，L 2，和L 3可以各自独立地选自以下组：链烷基，和芳基，或前述任意组合；其中，q1，q2，和q3可以各自独立地选自以下组：0、1、2和3。 In one embodiment, wherein L 1 , L 2 , and L 3 can each be independently selected from the group consisting of alkane, and aryl, or any combination of the foregoing; wherein q1 , q2 , and q3 can each be Independently selected from the group: 0, 1, 2, and 3.
例如，其中，(L 1) q1，(L 2) q2，和(L 3) q3可以各自独立地选自以下组：-链烷基-芳基-，链烷基和聚乙二醇，或q1，q2和q3可以各自独立地为0。 For example, where (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 may each be independently selected from the group consisting of: -alkyi-aryl-, alkane, and polyethylene glycol, or q1, q2 and q3 can each independently be zero.
例如，其中，(L 1) q1，(L 2) q2，和(L 3) q3可以各自独立地选自以下组：-CH 2-芳基-，-(CH 2) 2-，和-CH 2-，或q1，q2和q3可以各自独立地为0。 For example, where (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 may each be independently selected from the group consisting of: -CH 2 -aryl-, -(CH 2 ) 2 -, and -CH 2 -, or q1, q2 and q3 can each independently be 0.
在一种实施方式中，W可以选自以下组：In one embodiment, W may be selected from the group of:
Figure PCTCN2021130337-appb-000603
三价的链烷基，三价的环烷基，三价的杂环烷基，三价的烯基，三价的炔基，三价的芳基，和三价的杂芳基。
Figure PCTCN2021130337-appb-000603
Trivalent alkane, trivalent cycloalkyl, trivalent heterocycloalkyl, trivalent alkenyl, trivalent alkynyl, trivalent aryl, and trivalent heteroaryl.
例如，W可以选自以下组：For example, W can be selected from the following group:
Figure PCTCN2021130337-appb-000604
Figure PCTCN2021130337-appb-000604
所述X 1，X 2，X 3，X 4，X 5，X 6，X 7，X 8，X 9，X 10，X 11，X 12，X 13，X 14，X 15，X 16，X 17和X 18可以各自独立地选自以下组：C，N，O，S，P，CH，CH 2，NH，P(O)和P(S)； The X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 and X 18 may each be independently selected from the group consisting of C, N, O, S, P, CH, CH 2 , NH, P(O) and P(S);
所述---表示双键或单键。The --- represents a double bond or a single bond.
例如，W可以选自以下组：For example, W can be selected from the following group:
Figure PCTCN2021130337-appb-000605
Figure PCTCN2021130337-appb-000605
Figure PCTCN2021130337-appb-000606
Figure PCTCN2021130337-appb-000606
在另一种实施方式中，其中P 1，P 2和P 3各自独立地选自以下组：脂质、蛋白质、核酸、小分子和多糖，或其任意组合。 In another embodiment, wherein P1, P2 , and P3 are each independently selected from the group consisting of lipids, proteins, nucleic acids, small molecules, and polysaccharides, or any combination thereof.
例如，本申请中的脂质可以为脂肪酸。例如，本申请中的脂质可以为长链脂肪酸LCFA。For example, lipids in the present application can be fatty acids. For example, lipids in the present application can be long chain fatty acids LCFA.
在另一种实施方式中，其中P 1，P 2和P 3可以各自独立地选自以下组：核酸分子、染料分子、细胞因子、抗原、融合蛋白、和抗体或其抗原结合片段。 In another embodiment, wherein P1, P2 and P3 may each be independently selected from the group consisting of nucleic acid molecules, dye molecules, cytokines, antigens, fusion proteins, and antibodies or antigen-binding fragments thereof.
例如，其中的核酸分子可以包含CPG。例如，本申请的核酸分子可以包含反义寡核苷酸ASO。例如，本申请的核酸分子可以包含靶向STAT3的ASO。例如，本申请的核酸分子可以包含 Me C*T*A*T*T*T*G*G*A*T*G*T* MeC* A*G* MeC ，SEQ ID NO：13所示的序列(划线代表锁核酸LNA，例如其核苷可以包含连接4'-位和2'-位的桥的二环糖，MeC代表甲基C，*代表硫代磷酸酯Phosphorothioate的核苷间连接。 For example, the nucleic acid molecule therein may comprise CPG. For example, a nucleic acid molecule of the present application may comprise an antisense oligonucleotide ASO. For example, the nucleic acid molecules of the present application may comprise ASOs targeting STAT3. For example, the nucleic acid molecule of the present application may comprise Me C*T*A *T*T*T*G*G*A*T*G*T* MeC * A *G*MeC , as shown in SEQ ID NO: 13 The sequence shown (underlined represents a locked nucleic acid LNA, for example its nucleoside may contain a bicyclic sugar linking a bridge between the 4'- and 2'-positions, MeC represents methyl C, * represents the nucleoside of phosphorothioate Phosphorothioate connection between.
例如，本申请的蛋白质可以包含以下组：含有CMV抗原的分支肽、neo2蛋白(细胞因 子IL2/IL5的融合蛋白)、IFNα蛋白、和M1蛋白(穿血脑屏障的短肽)。For example, the proteins of the present application may comprise the following group: branched peptides containing CMV antigens, neo2 proteins (fusion proteins of cytokines IL2/IL5), IFNα proteins, and M1 proteins (short peptides that penetrate the blood-brain barrier).
例如，所述抗体可以选自下组：单克隆抗体、单链抗体、嵌合抗体、人源化抗体、全人源抗体和纳米抗体。For example, the antibody may be selected from the group consisting of monoclonal antibodies, single chain antibodies, chimeric antibodies, humanized antibodies, fully human antibodies and nanobodies.
例如，其中所述抗体靶向可以选自下组的靶点：4-1BB、EGFR、CD3、Her2、CD47和CD20。例如，其中所述抗体靶向可以选自下组的靶点：4-1BB、EGFR、CD3、Her2、和PD-L1。For example, wherein the antibody targets a target that can be selected from the group consisting of 4-1BB, EGFR, CD3, Her2, CD47 and CD20. For example, wherein the antibody targets a target that can be selected from the group consisting of 4-1BB, EGFR, CD3, Her2, and PD-L1.
例如，其中所述抗体的氨基酸序列可以选自以下组：SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:10、SEQ ID NO:11、和SEQ ID NO:12。例如，其中所述抗体的氨基酸序列可以选自以下组：SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、和SEQ ID NO:15。For example, wherein the amino acid sequence of the antibody can be selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12. For example, wherein the amino acid sequence of the antibody may be selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12 , and SEQ ID NO:15.
在另一种实施方式中，所述化合物可以为In another embodiment, the compound may be
Figure PCTCN2021130337-appb-000607
Figure PCTCN2021130337-appb-000607
所述La为-(J 1) m1-C(＝O)-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-； The La is -(J 1 ) m1 -C(=O)-X 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -;
所述Lb为-(J 2) m2-C(＝O)-X 2-(K 2) n2-(Y 2) p2-(L 2) q2-； The Lb is -(J 2 ) m2 -C(=O)-X 2 -(K 2 ) n2 -(Y 2 ) p2 -(L 2 ) q2 -;
所述Lc为-(J 3) m3-C(＝O)-X 3-(K 3) n3-(Y 3) p3-(L 3) q3-； The Lc is -(J 3 ) m3 -C(=O)-X 3 -(K 3 ) n3 -(Y 3 ) p3 -(L 3 ) q3 -;
其中，J 1，J 2，和J 3可以各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合；其中，m1，m2，和m3可以各自独立地选自以下组：0、1、2和3； wherein J 1 , J 2 , and J 3 may each independently be selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein m1 , m2 , and m3 may each independently be selected from the following groups: 0, 1, 2 and 3;
其中，X 1，X 2，和X 3可以各自独立地选自以下组：-NH-和-O-； wherein X 1 , X 2 , and X 3 can each be independently selected from the group of: -NH- and -O-;
其中，(K 1) n1，(K 2) n2，和(K 3) n3可以各自独立地选自以下组：-(CH 2)-(CH 2-O-CH 2) 3-(CH 2)-，-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-，-(CH 2) 2-，和-(CH 2) 8-，或n1，n2或n3可以各自独立地为0； wherein (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 can each be independently selected from the group of: -(CH 2 )-(CH 2 -O-CH 2 ) 3 -(CH 2 ) -, -( CH2 ) 2- ( CH2 -O- CH2 ) 3- ( CH2 ) 2- , -( CH2 ) 2- , and -( CH2 ) 8- , or n1, n2, or n3 can be independently 0;
(Y 1) p1，(Y 2) p2，和(Y 3) p3可以各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-，R 1选自以下组：氢，氕，氘，氚，和链烷基；或p1，p2或p3可以各自独立地为0； (Y 1 ) p1 , (Y 2 ) p2 , and (Y 3 ) p3 may each be independently selected from the group consisting of: -C(=O)-, -NR 1 -C(=O)-, -NR 1 - , and -O-, R1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; or p1, p2 or p3 may each independently be 0;
(L 1) q1，(L 2) q2，和(L 3) q3可以各自独立地选自以下组：-CH 2-芳基-，-(CH 2) 2-，-CH 2-，链烷 基和聚乙二醇，或q1，q2和q3可以各自独立地为0； (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 may each be independently selected from the group consisting of: -CH 2 -aryl-, -(CH 2 ) 2 -, -CH 2 -, alkane base and polyethylene glycol, or q1, q2 and q3 may each independently be 0;
W可以选自以下组：W can be selected from the following group:
Figure PCTCN2021130337-appb-000608
Figure PCTCN2021130337-appb-000608
A 2可以为
Figure PCTCN2021130337-appb-000609
B 2可以为，
Figure PCTCN2021130337-appb-000610
C 2可以为
Figure PCTCN2021130337-appb-000611
或共价键；其中R 12可以选自以下组：氢，氕，氘，氚，卤素和链烷基，
Figure PCTCN2021130337-appb-000612
代表连接位点， A2 can be
Figure PCTCN2021130337-appb-000609
B2 can be,
Figure PCTCN2021130337-appb-000610
C2 can be
Figure PCTCN2021130337-appb-000611
or a covalent bond; wherein R 12 can be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
Figure PCTCN2021130337-appb-000612
represents the attachment site,
其中P 1，P 2和P 3各自独立地选自以下组：脂质、蛋白质、核酸、小分子和多糖，或其任意组合； wherein P 1 , P 2 and P 3 are each independently selected from the group consisting of lipids, proteins, nucleic acids, small molecules and polysaccharides, or any combination thereof;
所述A 2的两个连接位点可以任意地与Wc和P 1连接，所述B 2的两个连接位点可以任意地与Wc和P 2连接，所述C 2的两个连接位点可以任意地与Wc和P 3连接。 The two linking sites of the A2 can be arbitrarily linked to Wc and P1, the two linking sites of the B2 can be arbitrarily linked to Wc and P2, the two linking sites of the C2 Can be arbitrarily connected to Wc and P3 .
例如，
Figure PCTCN2021130337-appb-000613
的a连接位点与P 1连接，b连接位点与Wc中的(L 1) q1连接，
Figure PCTCN2021130337-appb-000614
的b连接位点与P 2连接，a连接位点与Wc中的(L 2) q2连接，C 2
Figure PCTCN2021130337-appb-000615
的a连接位点与P 3连接，a连接位点与Wc中的(L 3) q3连接。 E.g,
Figure PCTCN2021130337-appb-000613
The a linking site of is connected to P 1 , the b linking site is connected to (L 1 ) q1 in Wc,
Figure PCTCN2021130337-appb-000614
The b junction site of the is connected to P 2 , the a junction site is connected to (L 2 ) q2 in Wc, and the C 2
Figure PCTCN2021130337-appb-000615
The α-linking site of is connected to P 3 , and the α-linking site is connected to (L 3 ) q3 in Wc.
例如W可以选自以下组：For example W can be selected from the following group:
Figure PCTCN2021130337-appb-000616
Figure PCTCN2021130337-appb-000616
在另一种实施方式中，其中所述一种化合物可以选自以下组：In another embodiment, wherein the one compound may be selected from the group consisting of:
Figure PCTCN2021130337-appb-000617
Figure PCTCN2021130337-appb-000617
其中，P 1，P 2和P 3可以各自独立地选自以下组：脂质、蛋白质、核酸、小分子和多糖， 或其任意组合。 Wherein, P 1 , P 2 and P 3 may each be independently selected from the group consisting of lipids, proteins, nucleic acids, small molecules and polysaccharides, or any combination thereof.
在一种实施方式中，P 1，P 2和P 3可以各自独立地选自脂质。其中，P 1，P 2和P 3可以各自独立地选自以下组：脂族羧酸、磷脂和固醇。在一种实施方式中，P 1，P 2和P 3可以各自独立地选自直链、支链、饱和或不饱和脂族羧酸。 In one embodiment, P 1 , P 2 and P 3 may each be independently selected from lipids. Wherein, P 1 , P 2 and P 3 may each be independently selected from the group consisting of aliphatic carboxylic acids, phospholipids and sterols. In one embodiment, P 1 , P 2 and P 3 may each be independently selected from linear, branched, saturated or unsaturated aliphatic carboxylic acids.
在一种实施方式中，P 1，P 2和P 3可以各自独立地选自蛋白质。在一种实施方式中，P 1，P 2和P 3可以各自独立地选自多肽。所述蛋白质或多肽可以包含表达后修饰，例如，糖基化、乙酰化作用、磷酸化作用等等。所述蛋白质或多肽可以包含一个或多个氨基酸类似物的多肽、有取代键的多肽、以及本领域已知的修饰的多肽，所述修饰既包括自然发生的也包括非自然发生的修饰。 In one embodiment, P 1 , P 2 and P 3 may each be independently selected from proteins. In one embodiment, P 1 , P 2 and P 3 may each be independently selected from polypeptides. The protein or polypeptide may contain post-expression modifications, eg, glycosylation, acetylation, phosphorylation, and the like. The protein or polypeptide may comprise one or more amino acid analog polypeptides, polypeptides with substituted bonds, and modified polypeptides known in the art, including both naturally occurring and non-naturally occurring modifications.
在一种实施方式中，P 1，P 2和P 3可以各自独立地选自核酸。所述核酸可以是指核苷酸(例如核糖核苷酸或脱氧核糖核苷酸)的聚合物，并且包括天然存在的(腺嘌呤、鸟嘌呤、胞嘧啶、尿嘧啶和胸腺嘧啶)、非天然存在的和经修饰的核酸。所述核酸可以不受聚合物的长度(例如单体数目)限制。所述核酸可以是单链或双链的，并且一般含有5'-3'磷酸二酯键，核苷酸类似物还可以具有其他连接。所述核酸的单体通常称为核苷酸。所述非天然核苷酸或所述经修饰的核苷酸指含有经修饰的含氮碱基、糖或磷酸基的核苷酸，或者在其结构中掺入非天然部分的核苷酸。所述非天然核苷酸可以包括双脱氧核苷酸、生物素化、胺化、脱氨基、烷基化、苄基化和荧光标记的核苷酸。 In one embodiment, P 1 , P 2 and P 3 can each be independently selected from nucleic acids. The nucleic acid may refer to a polymer of nucleotides (eg, ribonucleotides or deoxyribonucleotides), and includes naturally occurring (adenine, guanine, cytosine, uracil, and thymine), non-natural Existing and modified nucleic acids. The nucleic acid may not be limited by the length of the polymer (eg, the number of monomers). The nucleic acid can be single-stranded or double-stranded, and generally contains a 5'-3' phosphodiester linkage, although nucleotide analogs can also have other linkages. The monomers of such nucleic acids are often referred to as nucleotides. The non-natural nucleotide or the modified nucleotide refers to a nucleotide containing a modified nitrogenous base, sugar or phosphate group, or a nucleotide incorporating a non-natural moiety in its structure. The non-natural nucleotides can include dideoxynucleotides, biotinylated, aminated, deaminated, alkylated, benzylated, and fluorescently labeled nucleotides.
在一种实施方式中，P 1，P 2和P 3可以各自独立地选自小分子。所述小分子可以是有丝分裂抑制剂、抗肿瘤抗生素免疫调节剂、用于基因治疗的载体、烷化剂、抗血管生成剂、抗代谢物、含硼剂、化学保护剂、激素、抗激素剂、皮质类固醇、光活性治疗剂、寡核苷酸、放射性核素剂、拓扑异构酶抑制剂、激酶抑制剂和放射增敏剂。 In one embodiment, P 1 , P 2 and P 3 can each be independently selected from small molecules. The small molecule can be a mitotic inhibitor, an antitumor antibiotic immunomodulator, a vector for gene therapy, an alkylating agent, an antiangiogenic agent, an antimetabolite, a boron-containing agent, a chemoprotective agent, a hormone, an antihormonal agent , corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclide agents, topoisomerase inhibitors, kinase inhibitors and radiosensitizers.
在一种实施方式中，P 1，P 2和P 3可以各自独立地选自多糖。所述多糖可以包括由两个或更多个单糖单元组成的分子，例如可以包括其中最长的单糖链为3至9个单糖单元的分子。所述多糖可以包括直链和支链的分子。所述多糖与脂质、蛋白质、核酸、或小分子的任意组合可以包括分离的以及与多肽结合的分子，唾液酸化的和非唾液酸化的分子。 In one embodiment, P1, P2 and P3 may each be independently selected from polysaccharides. The polysaccharide may include molecules composed of two or more monosaccharide units, eg, may include molecules in which the longest monosaccharide chain is 3 to 9 monosaccharide units. The polysaccharide can include both linear and branched chain molecules. Any combination of the polysaccharide and lipid, protein, nucleic acid, or small molecule can include isolated as well as polypeptide-bound molecules, sialylated and non-sialylated molecules.
其中，P 1，P 2和P 3可以各自独立地选自靶向选自下组的靶点的抗体：4-1BB、EGFR、CD3、Her2、CD47和CD20。 Wherein, P 1 , P 2 and P 3 may each be independently selected from antibodies targeting a target selected from the group consisting of 4-1BB, EGFR, CD3, Her2, CD47 and CD20.
例如，P 1，P 2和P 3的氨基酸序列可以分别为： For example, the amino acid sequences of P 1 , P 2 and P 3 can be respectively:
SEQ ID NO:1、SEQ ID NO:2、和SEQ ID NO:3，或SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, or
SEQ ID NO:1、SEQ ID NO:10、和SEQ ID NO:3，或SEQ ID NO: 1, SEQ ID NO: 10, and SEQ ID NO: 3, or
SEQ ID NO:1、SEQ ID NO:11、和SEQ ID NO:3，或SEQ ID NO: 1, SEQ ID NO: 11, and SEQ ID NO: 3, or
SEQ ID NO:1、SEQ ID NO:12、和SEQ ID NO:3，或SEQ ID NO: 1, SEQ ID NO: 12, and SEQ ID NO: 3, or
SEQ ID NO:10、SEQ ID NO:2、和SEQ ID NO:3，或SEQ ID NO: 10, SEQ ID NO: 2, and SEQ ID NO: 3, or
SEQ ID NO:11、SEQ ID NO:2、和SEQ ID NO:3，或SEQ ID NO:11, SEQ ID NO:2, and SEQ ID NO:3, or
SEQ ID NO:12、SEQ ID NO:2、和SEQ ID NO:3，或SEQ ID NO: 12, SEQ ID NO: 2, and SEQ ID NO: 3, or
SEQ ID NO:1、SEQ ID NO:2、和SEQ ID NO:10，或SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 10, or
SEQ ID NO:1、SEQ ID NO:2、和SEQ ID NO:11，或SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 11, or
SEQ ID NO:1、SEQ ID NO:2、和SEQ ID NO:12，或SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 12, or
SEQ ID NO:10、SEQ ID NO:11、和SEQ ID NO:12。SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12.
在另一方面，本申请中的P 1，P 2和P 3可以各自独立地为具有连接酶可识别序列的蛋白，所述连接酶可以将底物分子连接到所述蛋白上。在另一方面，本申请中的P 1，P 2和P 3可以各自独立地为具有LPETG序列的蛋白，LPETG序列如SEQ ID NO：7所示可以被连接酶，例如SrtA连接酶，特异性识别。 In another aspect, P 1 , P 2 and P 3 in the present application can each independently be a protein having a sequence recognizable by a ligase to which a substrate molecule can be attached. On the other hand, P 1 , P 2 and P 3 in the present application can each independently be a protein with a LPETG sequence, and the LPETG sequence as shown in SEQ ID NO: 7 can be ligated by a ligase, such as SrtA ligase, specific identify.
在另一方面，本申请中的P 1，P 2和P 3可以各自独立地选自靶向EGFR的VHH纳米抗体、靶向CD3的VHH纳米抗体、靶向4-1BB的VHH纳米抗体、靶向Her2的VHH纳米抗体、靶向CD47的VHH纳米抗体、靶向CD20的VHH纳米抗体、含CMV抗原的分支肽、细胞因子IL2/IL5的融合蛋白、细胞因子IFNα、染料分子FITC和CPG核酸分子。 In another aspect, P 1 , P 2 and P 3 in the present application can each be independently selected from VHH Nanobodies targeting EGFR, VHH Nanobodies targeting CD3, VHH Nanobodies targeting 4-1BB, target VHH Nanobodies to Her2, VHH Nanobodies Targeting CD47, VHH Nanobodies Targeting CD20, Branched Peptides Containing CMV Antigens, Fusion Proteins of Cytokine IL2/IL5, Cytokine IFNα, Dye Molecules FITC and CPG Nucleic Acid Molecules .
化合物的制备方法Preparation method of compound
在一方面，本申请提供了一种化合物的制备方法，包括可以使式(Ia-I)所示的化合物与反应物1、反应物2和反应物3反应；In one aspect, the present application provides a method for preparing a compound, which includes reacting the compound represented by formula (Ia-I) with reactant 1, reactant 2 and reactant 3;
或可以使式(Ia-I)所示的化合物与反应物1和反应物2反应；Or can make the compound shown in formula (Ia-I) react with reactant 1 and reactant 2;
或可以使式(Ia-I)所示的化合物与反应物1反应；Or can make the compound shown in formula (Ia-I) react with reactant 1;
Figure PCTCN2021130337-appb-000618
Figure PCTCN2021130337-appb-000618
所述反应物1可以为H-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-A， The reactant 1 can be HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -A,
所述反应物2可以为H-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-B， The reactant 2 can be HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -B,
所述反应物3可以为H-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-C， The reactant 3 can be HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -C,
所述W可以为三价基团，所述W可以任选地被一个或多个R取代，The W may be a trivalent group, and the W may be optionally substituted with one or more R,
所述J 1，J 2，J 3，K 1，K 2，K 3，L 1，L 2，和L 3可以各自独立地选自以下组：链烷基，环烷基，杂环烷基，烯基，炔基，芳基，杂芳基，和聚乙二醇，或前述任意组合； The J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 may each be independently selected from the group consisting of: alkane, cycloalkyl, heterocycloalkyl , alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
所述X 1，X 2，X 3，Y 1，Y 2，和Y 3可以各自独立地选自以下组：-NR 1-，-O-，-S-，-C(＝O)-，-C(＝S)-，-C(R 1a)(R 1b)-，-NR 1-C(＝O)-，-C(＝O)-NR 1-，-NR 1-C(＝S)-，-C(＝S)-NR 1-，-O-C(＝O)-，-C(＝O)-O-，-O-C(＝S)-，-C(＝S)-O-，-O-C(＝O)-O-，-O-C(＝O)-NR 1-，-NR 1-C(＝O)-O-，和-NR 1a-C(＝O)-NR 1b-； Said X 1 , X 2 , X 3 , Y 1 , Y 2 , and Y 3 may each be independently selected from the group of: -NR 1 -, -O-, -S-, -C(=O)-, -C(=S)-, -C(R 1a )(R 1b )-, -NR 1 -C(=O)-, -C(=O)-NR 1 -, -NR 1 -C(=S )-, -C(=S)-NR 1 -, -OC(=O)-, -C(=O)-O-, -OC(=S)-, -C(=S)-O-, -OC(=O)-O-, -OC(=O)-NR 1 -, -NR 1 -C(=O)-O-, and -NR 1a -C(=O)-NR 1b -;
R，R 1，R 1a和R 1b可以各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基； R, R 1 , R 1a and R 1b may each be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfo amide, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl;
其中，m1，m2，m3，n1，n2，n3，p1，p2，p3，q1，q2，和q3可以各自独立地选自0以上的数；wherein, m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 can each be independently selected from a number greater than 0;
A，B和C可以各自独立地选自以下组：A, B and C can each independently be selected from the following group:
Figure PCTCN2021130337-appb-000619
Figure PCTCN2021130337-appb-000620
Figure PCTCN2021130337-appb-000619
Figure PCTCN2021130337-appb-000620
其中R 12，R 13和R 14可以各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基； wherein R 12 , R 13 and R 14 may each independently be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl;
其中，A，B和C中，
Figure PCTCN2021130337-appb-000621
不能和
Figure PCTCN2021130337-appb-000622
同时存在； Among them, A, B and C,
Figure PCTCN2021130337-appb-000621
cannot and
Figure PCTCN2021130337-appb-000622
simultaneously exist;
其中，A，B和C中，
Figure PCTCN2021130337-appb-000623
不能和
Figure PCTCN2021130337-appb-000624
Figure PCTCN2021130337-appb-000625
同时存在； Among them, A, B and C,
Figure PCTCN2021130337-appb-000623
cannot and
Figure PCTCN2021130337-appb-000624
Figure PCTCN2021130337-appb-000625
simultaneously exist;
其中，A，B和C中，
Figure PCTCN2021130337-appb-000626
不能和
Figure PCTCN2021130337-appb-000627
同时存在； Among them, A, B and C,
Figure PCTCN2021130337-appb-000626
cannot and
Figure PCTCN2021130337-appb-000627
simultaneously exist;
当A，B和C中，
Figure PCTCN2021130337-appb-000628
同时存在时，所述R 12，R 13和R 14不为炔基； When A, B and C,
Figure PCTCN2021130337-appb-000628
When present at the same time, the R 12 , R 13 and R 14 are not alkynyl;
当A，B和C中，
Figure PCTCN2021130337-appb-000629
同时存在时，所述R 12，R 13和R 14不为氨基， When A, B and C,
Figure PCTCN2021130337-appb-000629
When present at the same time, the R 12 , R 13 and R 14 are not amino groups,
A，B和C不同时为
Figure PCTCN2021130337-appb-000630
A, B and C are not simultaneously
Figure PCTCN2021130337-appb-000630
其中，当A、B或C为
Figure PCTCN2021130337-appb-000631
时，在所述式(Ia-I)所示的化合物与反应物1、反应物2或反应物3反应前，可以将
Figure PCTCN2021130337-appb-000632
替换为
Figure PCTCN2021130337-appb-000633
在所述式(Ia-I)所示的化合物与反应物1、反应物2或反应物3反应后，可以加入酸进行Boc脱除。 where, when A, B or C is
Figure PCTCN2021130337-appb-000631
, before the compound represented by the formula (Ia-I) reacts with reactant 1, reactant 2 or reactant 3, the
Figure PCTCN2021130337-appb-000632
replace with
Figure PCTCN2021130337-appb-000633
After the compound represented by the formula (Ia-I) reacts with reactant 1, reactant 2 or reactant 3, an acid can be added to remove Boc.
例如，可以加入酸(0％-300％盐酸或三氟乙酸)进行Boc脱除。For example, Boc removal can be performed by adding an acid (0%-300% hydrochloric acid or trifluoroacetic acid).
在另一种实施方式中，可以根据A、B和C的引入顺序决定反应物1、反应物2和反应物3的加入顺序，所述A、B和C的引入顺序从先到后可以依次为：
Figure PCTCN2021130337-appb-000634
Figure PCTCN2021130337-appb-000635
In another embodiment, the order of addition of reactant 1, reactant 2 and reactant 3 can be determined according to the introduction order of A, B and C, and the introduction order of A, B and C can be sequentially for:
Figure PCTCN2021130337-appb-000634
Figure PCTCN2021130337-appb-000635
其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基。 wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl.
例如，当需要引入
Figure PCTCN2021130337-appb-000636
时，可以根据上述从先到后的引入顺序先引入
Figure PCTCN2021130337-appb-000637
再引入
Figure PCTCN2021130337-appb-000638
最后引入
Figure PCTCN2021130337-appb-000639
来决定先加入N3-Amine、再加入TZ-Amine，最后加入Boc-Gly-Amine。 For example, when it is necessary to introduce
Figure PCTCN2021130337-appb-000636
, it can be introduced first according to the above-mentioned first-to-last order of introduction
Figure PCTCN2021130337-appb-000637
reintroduction
Figure PCTCN2021130337-appb-000638
last import
Figure PCTCN2021130337-appb-000639
to decide to add N3-Amine first, then TZ-Amine, and finally Boc-Gly-Amine.
例如，在上述步骤中式(Ia-I)所示的化合物与反应物1、反应物2和反应物3均是按照当量比为20/1到1/20当量区间进行反应，加入1％-100％摩尔当量的三乙胺或乙二胺或二甲氨基吡啶或吡啶或N,N-二异丙基乙胺作为催化剂，反应条件为4-100℃，反应溶剂可以是水、 以水为基础的其他溶液、DMF、DMSO、甲醇、乙腈、四氢呋喃、二氯甲烷或其对应混合溶剂等，反应浓度可以为1纳摩尔到10摩尔区间，反应时间可以为0-24h。For example, in the above steps, the compound represented by formula (Ia-I) reacts with reactant 1, reactant 2 and reactant 3 according to the equivalent ratio of 20/1 to 1/20 equivalent range, adding 1%-100 % molar equivalent of triethylamine or ethylenediamine or dimethylaminopyridine or pyridine or N,N-diisopropylethylamine as a catalyst, the reaction conditions are 4-100 ° C, the reaction solvent can be water, water-based Other solutions, DMF, DMSO, methanol, acetonitrile, tetrahydrofuran, dichloromethane or its corresponding mixed solvent, etc., the reaction concentration can be in the range of 1 nanomolar to 10 mol, and the reaction time can be 0-24h.
例如，步骤一：可以将起始原料NHS试剂与N3-Amine按照比例为1/1.2的方式进行反应，反应条件可以为DMF(N,N-二甲基甲酰胺)作为溶剂，催化量的TEA(三乙胺)作为催化剂，25℃反应2小时，反应结束后可以通过旋蒸除去溶剂，然后可以用HPLC(高效液相色谱法)进行纯化，可以得到第一个中间体N3-NHS-NHS。For example, step 1: the starting material NHS reagent can be reacted with N3-Amine in a ratio of 1/1.2. The reaction conditions can be DMF (N,N-dimethylformamide) as a solvent, a catalytic amount of TEA (Triethylamine) as a catalyst, react at 25 ° C for 2 hours, after the reaction, the solvent can be removed by rotary evaporation, and then HPLC (high performance liquid chromatography) can be used to purify, the first intermediate N3-NHS-NHS can be obtained .
步骤二：可以将N3-NHS-NHS与TZ-Amine按照比例为1/1.2的方式进行反应，反应条件可以为DMF(N,N-二甲基甲酰胺)作为溶剂，催化量的TEA(三乙胺)作为催化剂，25℃反应2小时，反应结束后可以通过旋蒸除去溶剂，然后可以用HPLC(高效液相色谱法)进行纯化，可以得到第二个中间体也就是多特异生物偶联的连接臂2(Scaffold2)。Step 2: N3-NHS-NHS and TZ-Amine can be reacted in a ratio of 1/1.2. The reaction conditions can be DMF (N,N-dimethylformamide) as a solvent, a catalytic amount of TEA (three Ethylamine) as a catalyst, react at 25 ° C for 2 hours, after the reaction, the solvent can be removed by rotary evaporation, and then HPLC (high performance liquid chromatography) can be used to purify, and the second intermediate, that is, multispecific biological coupling can be obtained. The connecting arm 2 (Scaffold2).
步骤三：将第二个中间体也就是多特异生物偶联的连接臂2(Scaffold2)可以与Boc-Gly-Amine按照比例为1/1.2的方式进行反应，反应条件可以为DMF(N,N-二甲基甲酰胺)作为溶剂，催化量的TEA(三乙胺)作为催化剂，25℃反应2小时，反应结束后可以通过旋蒸除去溶剂，然后可以用HPLC(高效液相色谱法)进行纯化。纯化后得到的产物可以溶于DCM(二氯甲烷)中，随后可以加入体积比为20％的TFA(三氟乙酸)，室温反应5分钟可以将Boc(叔丁氧羰基)基团脱除。然后，可以采用HPLC(高效液相色谱法)纯化得到最终产物也就是多特异生物偶联的连接臂1(Scaffold1)。Step 3: The second intermediate, the linking arm 2 (Scaffold2) of the multispecific biological coupling, can be reacted with Boc-Gly-Amine in a ratio of 1/1.2, and the reaction conditions can be DMF (N,N - dimethylformamide) as a solvent, a catalytic amount of TEA (triethylamine) as a catalyst, react at 25 ° C for 2 hours, after the reaction is completed, the solvent can be removed by rotary evaporation, and then HPLC (high performance liquid chromatography) can be used to carry out purification. The product obtained after purification can be dissolved in DCM (dichloromethane), and then TFA (trifluoroacetic acid) with a volume ratio of 20% can be added, and the Boc (tert-butoxycarbonyl) group can be removed by reacting at room temperature for 5 minutes. Then, HPLC (High Performance Liquid Chromatography) can be used to purify to obtain the final product, that is, the linker arm 1 (Scaffold1) of the multispecific bioconjugation.
在另一方面，本申请还提供一种化合物的制备方法，可以使本申请中任一项式Ia所述的化合物与反应物4、反应物5和反应物6反应；On the other hand, the present application also provides a method for preparing a compound, which can make any one of the compounds described in formula Ia in the present application react with reactant 4, reactant 5 and reactant 6;
所述反应物4为A 1-P 1， The reactant 4 is A 1 -P 1 ,
所述反应物5为B 1-P 2， The reactant 5 is B 1 -P 2 ,
所述反应物6为C 1-P 3， The reactant 6 is C 1 -P 3 ,
其中，反应物4的A 1与式Ia所述的化合物的A反应，反应物5的B 1与式Ia所述的化合物的B反应，反应物6的C 1与式Ia所述的化合物的C反应； Wherein, A 1 of reactant 4 reacts with A of the compound described in formula Ia, B 1 of reactant 5 reacts with B of the compound described in formula Ia, and C 1 of reactant 6 reacts with the compound described in formula Ia C reaction;
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000640
时，A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000641
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000640
, at least one of A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000641
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000642
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000643
Figure PCTCN2021130337-appb-000644
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000642
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000643
Figure PCTCN2021130337-appb-000644
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000645
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000646
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000645
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000646
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000647
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000648
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000647
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000648
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000649
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000650
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000649
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000650
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000651
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000652
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000651
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000652
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000653
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000654
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000653
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000654
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000655
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000656
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000655
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000656
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000657
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000658
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000657
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000658
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000659
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000660
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000659
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000660
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000661
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000662
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000661
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000662
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000663
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000664
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000663
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000664
其中R 12，R 13和R 14可以各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基。 wherein R 12 , R 13 and R 14 may each independently be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamide alkyl, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl.
在一些实施方式中，当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000665
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000666
In some embodiments, when at least one of A, B or C is
Figure PCTCN2021130337-appb-000665
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000666
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000667
时，对应的A 1，B 1或 C 1至少有一个为
Figure PCTCN2021130337-appb-000668
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000667
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000668
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000669
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000670
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000669
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000670
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000671
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000672
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000671
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000672
当A、B或C至少有一个为
Figure PCTCN2021130337-appb-000673
时，对应的A 1，B 1或C 1至少有一个为
Figure PCTCN2021130337-appb-000674
when at least one of A, B or C is
Figure PCTCN2021130337-appb-000673
, at least one of the corresponding A 1 , B 1 or C 1 is
Figure PCTCN2021130337-appb-000674
其中R，R 12可以各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，每个X可以各自独立地选自以下组：氢，氕，氘，氚，卤素。 wherein R, R 12 can each be independently selected from the following group: hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido, urea, Alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl, each X can be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen.
例如，A、B或C中的基团与对应的A 1，B 1或C 1中的基团可以是A为
Figure PCTCN2021130337-appb-000675
B为
Figure PCTCN2021130337-appb-000676
C为
Figure PCTCN2021130337-appb-000677
时，A 1为
Figure PCTCN2021130337-appb-000678
B 1为
Figure PCTCN2021130337-appb-000679
C 1为
Figure PCTCN2021130337-appb-000680
其中R 12可以是氢。 For example, a group in A, B or C and the corresponding group in A 1 , B 1 or C 1 can be A for
Figure PCTCN2021130337-appb-000675
B is
Figure PCTCN2021130337-appb-000676
C is
Figure PCTCN2021130337-appb-000677
, A1 is
Figure PCTCN2021130337-appb-000678
B1 is
Figure PCTCN2021130337-appb-000679
C1 is
Figure PCTCN2021130337-appb-000680
wherein R 12 may be hydrogen.
例如，
Figure PCTCN2021130337-appb-000681
的反应中可以加入Cu +作为催化剂。例如，加入催化量Cu+以其他形式产生Cu+作为催化剂。 E.g,
Figure PCTCN2021130337-appb-000681
Cu + can be added as a catalyst in the reaction. For example, adding a catalytic amount of Cu+ produces Cu+ as a catalyst in other forms.
例如，
Figure PCTCN2021130337-appb-000682
的反应中可以加入1-100％当量的SrtA连接酶作为催化剂。 E.g,
Figure PCTCN2021130337-appb-000682
1-100% equivalent of SrtA ligase can be added as a catalyst in the reaction.
例如，式Ia所述的化合物与反应物4、反应物5和反应物6反应可以是按照摩尔比为20/1到1/20的比例区间进行反应，反应溶剂可以是水、以水为基础的其他溶液、DMF、DMSO、甲醇、乙腈、四氢呋喃、二氯甲烷或其对应混合溶剂等，反应浓度可以为1纳摩尔到100摩尔区间，反应时间可以为0-24小时。For example, the reaction of the compound of formula Ia with reactant 4, reactant 5 and reactant 6 can be carried out according to the molar ratio of 20/1 to 1/20, and the reaction solvent can be water, water-based Other solutions, DMF, DMSO, methanol, acetonitrile, tetrahydrofuran, dichloromethane or its corresponding mixed solvent, etc., the reaction concentration can be in the range of 1 nanomolar to 100 mol, and the reaction time can be 0-24 hours.
治疗方法和用途Treatment methods and uses
一方面，本申请提供一种药物组合物，其可以含有本申请中任一项的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，和药学上可接受的载体。In one aspect, the application provides a pharmaceutical composition, which may contain a compound of any one of the application, or a tautomer, meso, racemate, enantiomer, diastereomer, or tautomer, meso, racemate, enantiomer, or diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.
一方面，本申请提供一种试剂盒，其可以包含本申请中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，和/或本申请中任一项所述的药物组合物。In one aspect, the present application provides a kit, which can comprise the compound described in any one of the present application or its tautomer, meso, racemate, enantiomer, An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and/or the pharmaceutical composition of any of the present application.
另一方面，本申请提供了本申请所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，本申请的药物组合物和/或本申请的试剂盒在制备用于治疗和/或预防肿瘤的药物中的用途。例如，所述肿瘤可以选自与以下组表达相关的肿瘤：4-1BB、EGFR、CD3、Her2、CD47和CD20。例如，所述表达相关可以是指，与其中的靶点高表达和/或靶点阳性相关。例如，所述表达相关可以是指，与其中的靶点高表达相关。例如，所述表达相关可以是指，与其中的靶点阳性相关。例如，所述肿瘤可以选自以下组：实体瘤和血液癌。例如，所述肿瘤可以选自以下组：肺癌、肾癌、尿道癌、结肠直肠癌、前列腺癌、多形性成胶质细胞瘤、卵巢癌、胰腺癌、乳腺癌、黑色素瘤、肝 癌、膀胱癌、胃癌和食道癌。In another aspect, the application provides a compound described herein or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, use of the pharmaceutical composition of the present application and/or the kit of the present application in the preparation of a medicament for treating and/or preventing tumors. For example, the tumor may be selected from tumors associated with expression of the following group: 4-1BB, EGFR, CD3, Her2, CD47, and CD20. For example, the expression correlation may refer to a high expression and/or positive correlation with the target therein. For example, the expression correlation may refer to correlation with the high expression of the target therein. For example, the expression correlation may refer to a positive correlation with a target therein. For example, the tumor can be selected from the group consisting of solid tumors and hematological cancers. For example, the tumor may be selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric and esophageal cancer.
另一方面，本申请提供了治疗和/或预防肿瘤的方法，包括向有需要的受试者施用本申请所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，本申请的药物组合物和/或本申请的试剂盒。例如，所述肿瘤可以选自与以下组表达相关的肿瘤：4-1BB、EGFR、CD3、Her2、CD47和CD20。例如，所述表达相关可以是指，与其中的靶点高表达和/或靶点阳性相关。例如，所述表达相关可以是指，与其中的靶点高表达相关。例如，所述表达相关可以是指，与其中的靶点阳性相关。例如，所述肿瘤可以选自以下组：实体瘤和血液癌。例如，所述肿瘤可以选自以下组：肺癌、肾癌、尿道癌、结肠直肠癌、前列腺癌、多形性成胶质细胞瘤、卵巢癌、胰腺癌、乳腺癌、黑色素瘤、肝癌、膀胱癌、胃癌和食道癌。In another aspect, the present application provides methods for treating and/or preventing tumors, comprising administering to a subject in need thereof a compound described herein or a tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, pharmaceutical compositions of the present application and/or kits of the present application. For example, the tumor may be selected from tumors associated with expression of the following group: 4-1BB, EGFR, CD3, Her2, CD47, and CD20. For example, the expression correlation may refer to a high expression and/or positive correlation with the target therein. For example, the expression correlation may refer to correlation with the high expression of the target therein. For example, the expression correlation may refer to a positive correlation with a target therein. For example, the tumor can be selected from the group consisting of solid tumors and hematological cancers. For example, the tumor may be selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric and esophageal cancer.
另一方面，本申请提供了一种本申请所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，本申请的药物组合物和/或本申请的试剂盒，其用于治疗和/或预防肿瘤。例如，所述肿瘤可以选自与以下组表达相关的肿瘤：4-1BB、EGFR、CD3、Her2、CD47和CD20。例如，所述表达相关可以是指，与其中的靶点高表达和/或靶点阳性相关。例如，所述表达相关可以是指，与其中的靶点高表达相关。例如，所述表达相关可以是指，与其中的靶点阳性相关。例如，所述肿瘤可以选自以下组：实体瘤和血液癌。例如，所述肿瘤可以选自以下组：肺癌、肾癌、尿道癌、结肠直肠癌、前列腺癌、多形性成胶质细胞瘤、卵巢癌、胰腺癌、乳腺癌、黑色素瘤、肝癌、膀胱癌、胃癌和食道癌。In another aspect, the application provides a compound described in the application or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of the present application and/or the kit of the present application, which are used for the treatment and/or prevention of tumors. For example, the tumor may be selected from tumors associated with expression of the following group: 4-1BB, EGFR, CD3, Her2, CD47, and CD20. For example, the expression correlation may refer to a high expression and/or positive correlation with the target therein. For example, the expression correlation may refer to correlation with the high expression of the target therein. For example, the expression correlation may refer to a positive correlation with a target therein. For example, the tumor can be selected from the group consisting of solid tumors and hematological cancers. For example, the tumor may be selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric and esophageal cancer.
不欲被任何理论所限，下文中的实施例仅仅是为了阐释本申请的融合蛋白，制备方法和用途等，而不用于限制本申请发明的范围。Without intending to be limited by any theory, the following examples are only used to illustrate the fusion protein, preparation method and use of the present application, and are not intended to limit the scope of the invention of the present application.
实施例Example
本申请所用的材料和设备包括：Materials and equipment used in this application include:
N3-Amine、TZ-Amine、Boc-Gly-Amine、FITC-Amine、DBCO-Gly、BCN-Gly均购买于西安点化生物科技有限公司或点击化学(Click Chemistry Tools)。其他化合物、溶剂如未作特殊说明均购买于西格玛奥德里奇(上海)贸易有限公司或北京百灵威科技有限公司。N3-Amine, TZ-Amine, Boc-Gly-Amine, FITC-Amine, DBCO-Gly, BCN-Gly were purchased from Xi'an Dianhua Biotechnology Co., Ltd. or Click Chemistry Tools. Other compounds and solvents were purchased from Sigma-Aldrich (Shanghai) Trading Co., Ltd. or Beijing Bailingwei Technology Co., Ltd. unless otherwise specified.
CPG-Amine核酸购买于苏州金唯智生物科技有限公司，其核苷酸序列，如SEQ ID NO：4所示，具体为：5`-TCC ATG ACG TTC CTG ACG TT-3`，其5`含有C12氨基修饰。CPG-Amine nucleic acid was purchased from Suzhou Jinweizhi Biotechnology Co., Ltd., and its nucleotide sequence, as shown in SEQ ID NO: 4, is specifically: 5`-TCC ATG ACG TTC CTG ACG TT-3`, its 5` contains C12 amino modification.
含有CMV抗原的分支肽购买于南京源肽生物科技有限公司，其结构如式CMV所示：The branched peptide containing CMV antigen was purchased from Nanjing Yuanpeptide Biotechnology Co., Ltd., and its structure is shown in formula CMV:
Figure PCTCN2021130337-appb-000683
Figure PCTCN2021130337-appb-000683
3个分支的氨基酸分别如SEQ ID NO：5、SEQ ID NO：5和SEQ ID NO：6所示。The amino acids of the three branches are shown in SEQ ID NO: 5, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.
VHH纳米抗体均是大肠杆菌表达。VHH Nanobodies were expressed in E. coli.
其中靶向EGFR的VHH纳米抗体氨基酸序列，如SEQ ID NO：2所示，具体为：The amino acid sequence of the VHH Nanobody targeting EGFR, as shown in SEQ ID NO: 2, is specifically:
Figure PCTCN2021130337-appb-000684
Figure PCTCN2021130337-appb-000684
其中靶向CD3的VHH纳米抗体氨基酸序列，如SEQ ID NO：3所示，具体为：The amino acid sequence of the VHH Nanobody targeting CD3, as shown in SEQ ID NO: 3, is specifically:
Figure PCTCN2021130337-appb-000685
Figure PCTCN2021130337-appb-000685
其中靶向4-1BB的VHH纳米抗体氨基酸序列，如SEQ ID NO：1所示，具体为：The amino acid sequence of the VHH Nanobody targeting 4-1BB is shown in SEQ ID NO: 1, specifically:
Figure PCTCN2021130337-appb-000686
Figure PCTCN2021130337-appb-000686
SrtA连接酶(例如氨基酸序列可以如SEQ ID NO：16所示)由大肠杆菌表达。SrtA连接酶介导的偶联反应(Chen,Long,et al.Scientific reports 6.1(2016):1-12.)其原理是：SrtA连接酶能特异性识别如SEQ ID NO：7所示的LPETG序列，将N端为裸露甘氨酸的底物分子转到目标蛋白上。SrtA ligase (eg, the amino acid sequence can be set forth in SEQ ID NO: 16) is expressed from E. coli. The principle of SrtA ligase-mediated coupling reaction (Chen, Long, et al. Scientific reports 6.1 (2016): 1-12.) is: SrtA ligase can specifically recognize LPETG as shown in SEQ ID NO: 7 sequence, the N-terminal of the substrate molecule with naked glycine is transferred to the target protein.
其中本申请的neo2蛋白为细胞因子IL2/IL5的融合蛋白，如SEQ ID NO：8所示，具体为：Wherein the neo2 protein of the application is a fusion protein of cytokine IL2/IL5, as shown in SEQ ID NO: 8, specifically:
Figure PCTCN2021130337-appb-000687
Figure PCTCN2021130337-appb-000687
其中本申请的IFNα蛋白，如SEQ ID NO：9所示，具体为：Wherein the IFNα protein of the application, as shown in SEQ ID NO: 9, is specifically:
CDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVR KYFQRITLYLKEKKYSPCAWEVVRAEIMRSFSLSTNLQESLRSKELPETGHHHHHH。所使用的仪器包括：Waters制备型高效液相色谱仪(HPLC)、Waters液相色谱质谱联用(LC-MS)，使用的色谱柱为C18柱；尺寸排阻Gel-filtration system，使用Superdex 75HR 16/600色谱柱；Bio-red凝胶成像系统；Bruker 400M核磁。CDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMRSFSLSTNLQESLRSKELPETGHHHHHH. The instruments used include: Waters Preparative High Performance Liquid Chromatograph (HPLC), Waters Liquid Chromatography Mass Spectrometry (LC-MS), the chromatographic column used is a C18 column; size exclusion Gel-filtration system, using Superdex 75HR 16/600 column; Bio-red gel imaging system; Bruker 400M NMR.
模块的制备方法：How to make the module:
(1)EGFR-DBCO的制备(1) Preparation of EGFR-DBCO
EGFR-DBCO的制备采用SrtA连接酶介导的偶联反应。靶向EGFR的VHH纳米抗体上存在LPETG序列，SrtA连接酶能将N端为裸露甘氨酸的底物分子DBCO-Gly连接到EGFR纳米抗体上。具体地，100微摩尔VHH纳米抗体PBS溶液中，加入1毫摩尔的DBCO-Gly和5微摩尔SrtA连接酶，室温反应2小时后，能够得到EGFR-DBCO。通过尺寸排阻纯化后产率约为80％。The preparation of EGFR-DBCO adopts SrtA ligase-mediated coupling reaction. The LPETG sequence exists on the EGFR-targeting VHH nanobody, and SrtA ligase can link the substrate molecule DBCO-Gly with a naked glycine at the N-terminus to the EGFR nanobody. Specifically, 1 mmol of DBCO-Gly and 5 μmol of SrtA ligase were added to 100 micromolar VHH nanobody PBS solution, and EGFR-DBCO could be obtained after 2 hours of reaction at room temperature. The yield after purification by size exclusion was about 80%.
(2)CD3-BCN的制备(2) Preparation of CD3-BCN
CD3-BCN的制备采用SrtA连接酶介导的偶联反应。靶向CD3的VHH纳米抗体上存在LPETG序列，SrtA连接酶能将N端为裸露甘氨酸的底物分子BCN-Gly连接到CD3纳米抗体上。100微摩尔靶向CD3的VHH纳米抗体PBS溶液中，加入1毫摩尔的BCN-Gly和5微摩尔SrtA连接酶，室温反应2小时后，能够得到CD3-BCN。通过尺寸排阻纯化后产率约为90％。CD3-BCN was prepared by SrtA ligase-mediated coupling reaction. The LPETG sequence exists on the CD3-targeting VHH nanobody, and SrtA ligase can link the substrate molecule BCN-Gly with a naked glycine at the N-terminus to the CD3 nanobody. To 100 micromoles of CD3-targeting VHH nanobody PBS solution, 1 mmol of BCN-Gly and 5 micromoles of SrtA ligase were added, and CD3-BCN could be obtained after 2 hours of reaction at room temperature. The yield after purification by size exclusion was about 90%.
实施例1多特异生物偶联连接臂的制备Example 1 Preparation of multispecific bioconjugation linker
本申请提供的制备多特异生物偶联连接臂(T-Linker)的方法合成了连接臂1(Scaffold1)、连接臂2(Scaffold2)，具体反应式如下所示：The method for preparing a multi-specific biological coupling linker (T-Linker) provided in this application synthesizes linker 1 (Scaffold1) and linker 2 (Scaffold2), and the specific reaction formula is as follows:
Figure PCTCN2021130337-appb-000688
Figure PCTCN2021130337-appb-000688
步骤一：将起始原料NHS试剂与N3-Amine按照比例为1/1.2的方式进行反应，反应条件为DMF(N,N-二甲基甲酰胺)作为溶剂，催化量的TEA(三乙胺)作为催化剂，25℃反应2小时，反应结束后通过旋蒸除去溶剂，然后用HPLC(高效液相色谱法)进行纯化，得到第一个中间体N3-NHS-NHS，产率为74％。Step 1: React the starting material NHS reagent with N3-Amine in a ratio of 1/1.2, the reaction conditions are DMF (N,N-dimethylformamide) as a solvent, a catalytic amount of TEA (triethylamine) ) as a catalyst, react at 25°C for 2 hours, and after the reaction is completed, the solvent is removed by rotary evaporation, and then purified by HPLC (high performance liquid chromatography) to obtain the first intermediate N3-NHS-NHS with a yield of 74%.
步骤二：将N3-NHS-NHS与TZ-Amine按照比例为1/1.2的方式进行反应，反应条件为DMF(N,N-二甲基甲酰胺)作为溶剂，催化量的TEA(三乙胺)作为催化剂，25℃反应2小时，反应结束后通过旋蒸除去溶剂，然后用HPLC(高效液相色谱法)进行纯化，得到第二个中间体也就是多特异生物偶联的连接臂2(Scaffold2)，产率为65％。Step 2: React N3-NHS-NHS and TZ-Amine in a ratio of 1/1.2, the reaction conditions are DMF (N,N-dimethylformamide) as a solvent, a catalytic amount of TEA (triethylamine) ) as a catalyst, react at 25 ° C for 2 hours, remove the solvent by rotary evaporation after the reaction, and then purify with HPLC (high performance liquid chromatography) to obtain the second intermediate that is the connecting arm 2 ( Scaffold2) in 65% yield.
步骤三：将第二个中间体也就是多特异生物偶联的连接臂2(Scaffold2)与Boc-Gly-Amine按照比例为1/1.2的方式进行反应，反应条件为DMF(N,N-二甲基甲酰胺)作为溶剂，催化量的TEA(三乙胺)作为催化剂，25℃反应2小时，反应结束后通过旋蒸除去溶剂，然后用HPLC(高效液相色谱法)进行纯化。纯化后得到的产物溶于DCM(二氯甲烷)中，随后加入体积比为20％的TFA(三氟乙酸)，室温反应5分钟将Boc(叔丁氧羰基)基团脱除。然后，采用HPLC(高效液相色谱法)纯化得到最终产物也就是多特异生物偶联的连接臂1(Scaffold1)，收率为48％。Step 3: The second intermediate, the linking arm 2 (Scaffold2) of the multispecific biological coupling, is reacted with Boc-Gly-Amine in a ratio of 1/1.2, and the reaction conditions are DMF (N,N-di methylformamide) as a solvent and a catalytic amount of TEA (triethylamine) as a catalyst to react at 25°C for 2 hours. After the reaction, the solvent was removed by rotary evaporation, and then purified by HPLC (high performance liquid chromatography). The product obtained after purification was dissolved in DCM (dichloromethane), then TFA (trifluoroacetic acid) with a volume ratio of 20% was added, and the Boc (tert-butoxycarbonyl) group was removed by reacting at room temperature for 5 minutes. Then, HPLC (High Performance Liquid Chromatography) was used to purify to obtain the final product, that is, the multispecific biologically coupled linker 1 (Scaffold1), with a yield of 48%.
用 1H-NMR法及液相色谱-质谱(ESI-MS)法分别对所制得的连接臂1(Scaffold1)、连接臂2(Scaffold2)进行表征得到图1-4所示的结果，分析如下： The prepared linker 1 (Scaffold1) and linker 2 (Scaffold2) were characterized by 1 H-NMR method and liquid chromatography-mass spectrometry (ESI-MS) method, respectively, and the results shown in Figure 1-4 were obtained. as follows:
连接臂1(Scaffold1) 1H-NMR表征结果为： 1H NMR(CD3OD,400MHz)δ(ppm):10.28 (s,1H),8.45-8.43(d,2H),8.38-8.36(m,4H),7.89-7.87(d,1H),7.62-7.60(d,1H),7.51-7.49(d,2H),7.43-7.40(d,1H),7.35-7.33(d,1H),5.45(s,1H),3.84(s,4H),3.64(s,2H),3.60-3.38(m,18H),3.26-3.22(m,6H),1.89-1.84(m,6H),1.72-1.66(m,6H)。ESI-MS表征结果为：C53H82N14O15,1154.3(m/z)；[M+H] +：1155.5,[M+Na] +：1177.5(m/z)。 The 1 H-NMR characterization results of tether 1 (Scaffold1) are: 1 H NMR (CD3OD, 400MHz)δ(ppm): 10.28 (s, 1H), 8.45-8.43 (d, 2H), 8.38-8.36 (m, 4H) ),7.89-7.87(d,1H),7.62-7.60(d,1H),7.51-7.49(d,2H),7.43-7.40(d,1H),7.35-7.33(d,1H),5.45(s ,1H),3.84(s,4H),3.64(s,2H),3.60-3.38(m,18H),3.26-3.22(m,6H),1.89-1.84(m,6H),1.72-1.66(m , 6H). ESI-MS characterization results are: C53H82N14O15, 1154.3 (m/z); [M+H] + : 1155.5, [M+Na] + : 1177.5 (m/z).
连接臂2(Scaffold2) 1H-NMR表征结果为： 1H NMR(CD3OD,400MHz)δ(ppm):10.43(s,1H),8.69(d,1H),8.66(m,2H),8.47-8.45(d,2H),8.35-8.31(m,2H),7.59-7.57(d,2H),7.53-7.47(m,2H),3.88(s,2H),3.67(s,2H),3.61-3.43(m,12H),3.31-3.26(m,4H),1.91-1.84(m,4H),1.74-1.67(m,4H)。ESI-MS表征结果为：C45H60N12O14,992.4(m/z)；[M+H] +：993.4,[M+Na] +：1015.3(m/z)。 The 1 H-NMR characterization results of tether 2 (Scaffold2) are: 1 H NMR (CD3OD, 400MHz)δ(ppm): 10.43(s, 1H), 8.69(d, 1H), 8.66(m, 2H), 8.47- 8.45(d,2H),8.35-8.31(m,2H),7.59-7.57(d,2H),7.53-7.47(m,2H),3.88(s,2H),3.67(s,2H),3.61- 3.43 (m, 12H), 3.31-3.26 (m, 4H), 1.91-1.84 (m, 4H), 1.74-1.67 (m, 4H). ESI-MS characterization results are: C45H60N12O14, 992.4 (m/z); [M+H] + : 993.4, [M+Na] + : 1015.3 (m/z).
用 1H-NMR法对合成连接臂1(Scaffold1)、连接臂2(Scaffold2)过程中中间体N3-NHS-NHS进行表征得到图5所示的结果，分析如下： 1H NMR(CD2Cl2,400MHz)δ(ppm):8.97-8.96(t,1H),8.875-8.871(d,2H),7.79-7.77(t,1H),6.92(s,1H),3.93(s,2H),3.69-3.60(m,8H),3.56-3.54(m,2H),3.46-3.4(m,4H),3.37-3.32(m,2H),2.17(s,8H),1.96-1.90(dd,2H),1.69-1.75(dd,2H)。 The 1 H-NMR method was used to characterize the intermediate N3-NHS-NHS in the process of synthesizing linker 1 (Scaffold1) and linker 2 (Scaffold2), and the results shown in Figure 5 were obtained. The analysis is as follows: 1 H NMR (CD2Cl2, 400MHz) )δ(ppm): 8.97-8.96(t, 1H), 8.875-8.871(d, 2H), 7.79-7.77(t, 1H), 6.92(s, 1H), 3.93(s, 2H), 3.69-3.60 (m,8H),3.56-3.54(m,2H),3.46-3.4(m,4H),3.37-3.32(m,2H),2.17(s,8H),1.96-1.90(dd,2H),1.69 -1.75(dd,2H).
本申请提供了采用上述类似的方法和步骤，制备连接臂3(Scaffold3)、连接臂4(Scaffold4)，具体反应式可以如下所示：The present application provides methods and steps similar to those described above to prepare connecting arm 3 (Scaffold3) and connecting arm 4 (Scaffold4). The specific reaction formula can be as follows:
Figure PCTCN2021130337-appb-000689
Figure PCTCN2021130337-appb-000689
步骤一：将起始原料NHS试剂与N3-Amine*按照比例为1/1.2的方式进行反应，反应条件为DMF(N,N-二甲基甲酰胺)作为溶剂，催化量的TEA(三乙胺)作为催化剂，25℃反应2小时，反应结束后通过旋蒸除去溶剂，然后用HPLC(高效液相色谱法)进行纯化，得到第一个中间体N3-NHS-NHS*，产率为74％。Step 1: The starting material NHS reagent is reacted with N3-Amine* in a ratio of 1/1.2. The reaction conditions are DMF (N,N-dimethylformamide) as a solvent, a catalytic amount of TEA (triethylformamide) amine) as a catalyst, reacted at 25°C for 2 hours, after the reaction was completed, the solvent was removed by rotary evaporation, and then purified by HPLC (high performance liquid chromatography) to obtain the first intermediate N3-NHS-NHS* with a yield of 74 %.
步骤二：将N3-NHS-NHS*与TZ-Amine*按照比例为1/1.2的方式进行反应，反应条件为DMF(N,N-二甲基甲酰胺)作为溶剂，催化量的TEA(三乙胺)作为催化剂，25℃反应2小时，反应结束后通过旋蒸除去溶剂，然后用HPLC(高效液相色谱法)进行纯化，得到第二个中间体也就是多特异生物偶联的连接臂4(Scaffold4)，产率为75％。Step 2: React N3-NHS-NHS* and TZ-Amine* in a ratio of 1/1.2, the reaction conditions are DMF (N,N-dimethylformamide) as a solvent, a catalytic amount of TEA (three Ethylamine) as a catalyst, reacted at 25 ° C for 2 hours, after the reaction, the solvent was removed by rotary evaporation, and then purified by HPLC (high performance liquid chromatography) to obtain the second intermediate, that is, the connecting arm of the multispecific biological coupling 4 (Scaffold4) in 75% yield.
步骤三：将第二个中间体也就是多特异生物偶联的连接臂4(Scaffold4)与Boc-Gly-Amine*按照比例为1/1.2的方式进行反应，反应条件为DMF(N,N-二甲基甲酰胺)作为溶剂，催化量的TEA(三乙胺)作为催化剂，25℃反应2小时，反应结束后通过旋蒸除去溶剂，然后用HPLC(高效液相色谱法)进行纯化。纯化后得到的产物溶于DCM(二氯甲烷)中，随后加入体积比为20％的TFA(三氟乙酸)，室温反应5分钟将Boc(叔丁氧羰基)基团脱除。然后，采用HPLC(高效液相色谱法)纯化得到最终产物也就是多特异生物偶联的连接臂3(Scaffold3)，收率为46％。Step 3: The second intermediate, the linking arm 4 (Scaffold4) of the multispecific biological coupling, is reacted with Boc-Gly-Amine* in a ratio of 1/1.2, and the reaction conditions are DMF (N,N- Dimethylformamide) was used as solvent, catalytic amount of TEA (triethylamine) was used as catalyst, and the reaction was carried out at 25°C for 2 hours. After the reaction, the solvent was removed by rotary evaporation, and then purified by HPLC (high performance liquid chromatography). The product obtained after purification was dissolved in DCM (dichloromethane), then TFA (trifluoroacetic acid) with a volume ratio of 20% was added, and the Boc (tert-butoxycarbonyl) group was removed by reacting at room temperature for 5 minutes. Then, HPLC (High Performance Liquid Chromatography) was used to purify to obtain the final product, namely the multispecific biologically coupled linker 3 (Scaffold3), with a yield of 46%.
用 1H-NMR法及液相色谱-质谱(ESI-MS)法分别对所制得的连接臂3(Scaffold3)、连接臂4(Scaffold4)进行表征得到图22-25所示的结果，分析如下： The prepared tether 3 (Scaffold3) and tether 4 (Scaffold4) were characterized by 1 H-NMR method and liquid chromatography-mass spectrometry (ESI-MS) method, respectively, and the results shown in Figures 22-25 were obtained. as follows:
连接臂3(Scaffold3) 1H-NMR表征结果为： 1H NMR(CD3OD,400MHz)δ(ppm):10.20(s,1H),8.17-8.15(d,2H),8.08-8.06(m,3H),7.34-7.32(d,2H),3.83(s,2H),3.66(s,2H),3.44-3.37(m,12H),2.05(s,2H)。ESI-MS表征结果为：C29H34N14O6,674.3(m/z)；[M+H] +：675.2,[M+Na]+：697.3(m/z)。 The 1 H-NMR characterization results of tether 3 (Scaffold3) are: 1 H NMR (CD3OD, 400MHz)δ(ppm): 10.20(s, 1H), 8.17-8.15(d, 2H), 8.08-8.06(m, 3H) ), 7.34-7.32(d, 2H), 3.83(s, 2H), 3.66(s, 2H), 3.44-3.37(m, 12H), 2.05(s, 2H). ESI-MS characterization results are: C29H34N14O6, 674.3 (m/z); [M+H] + : 675.2, [M+Na]+: 697.3 (m/z).
连接臂4(Scaffold4)1H-NMR表征结果为：1H NMR(CD3OD,400MHz)δ(ppm):10.29(s,1H),8.69(s,1H),8.55-8.44(m,4H),7.53-7.51(m,2H),7.49-7.47(d,2H),7.41-7.39(m,2H),3.91(s,2H),3.57-3.46(m,8H),2.94(s,4H),2.67(s,2H)。ESI-MS表征结果为：C29H28N12O8,672.2(m/z)；[M+H]+：673.1,[M+Na]+：695.1(m/z)。The results of 1H-NMR characterization of tether 4 (Scaffold4) are: 1H NMR (CD3OD, 400MHz)δ(ppm): 10.29(s,1H), 8.69(s,1H), 8.55-8.44(m,4H), 7.53- 7.51(m, 2H), 7.49-7.47(d, 2H), 7.41-7.39(m, 2H), 3.91(s, 2H), 3.57-3.46(m, 8H), 2.94(s, 4H), 2.67( s, 2H). ESI-MS characterization results are: C29H28N12O8, 672.2 (m/z); [M+H]+: 673.1, [M+Na]+: 695.1 (m/z).
用ESI-MS对合成连接臂3(Scaffold3)、连接臂4(Scaffold4)过程中中间体N3-NHS-NHS*进行表征得到图26所示的结果,分析如下：C21H19N7O10,529.1(m/z)；[M+H]+：530.2,[M+Na]+：552.1(m/z)。The intermediate N3-NHS-NHS* in the synthesis of tether 3 (Scaffold3) and tether 4 (Scaffold4) was characterized by ESI-MS, and the results shown in Figure 26 were obtained. The analysis is as follows: C21H19N7O10, 529.1 (m/z) ; [M+H]+: 530.2, [M+Na]+: 552.1 (m/z).
本申请包含的多特异生物偶联连接臂(T-Linker)可以通过以上类似的方法和步骤进行制备和表征。The multispecific bioconjugation linker (T-Linker) contained in this application can be prepared and characterized by methods and procedures similar to those above.
实施例2多特异偶联物的制备Example 2 Preparation of Multispecific Conjugates
EGFR-CD3-FITCEGFR-CD3-FITC
通过本申请提供的多特异生物偶联连接臂(T-Linker)制备多特异偶联物(T-Body)的方法合成了多特异偶联物，例如多特异性偶联物EGFR-CD3-FITC，具体反应式如下所示：Multispecific conjugates, such as multispecific conjugates EGFR-CD3-FITC, are synthesized by the method for preparing multispecific conjugates (T-Body) provided by the multispecific biological conjugation linker (T-Linker) provided in this application. , the specific reaction formula is as follows:
Figure PCTCN2021130337-appb-000690
Figure PCTCN2021130337-appb-000690
其制备方法是，首先将上述多特异生物偶联的连接臂2(Scaffold2)和FITC-Amine反应。1毫摩尔连接臂2(Scaffold2)的DMF(N,N-二甲基甲酰胺)溶液中加入FITC-Amine(终浓度10毫摩尔)，室温反应2小时后采用HPLC纯化得到N3-TZ-FITC。然后，N3-TZ-FITC与CD3-BCN按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应1小时后，采用尺寸排阻色谱纯化得到N3-CD3-FITC。最后，N3-CD3-FITC与EGFR-DBCO按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应2小时后采用尺寸排阻色谱纯化得到EGFR-CD3-FITC。The preparation method is as follows: firstly, the connecting arm 2 (Scaffold2) of the above-mentioned multispecific biological coupling is reacted with FITC-Amine. FITC-Amine (final concentration 10 mmol) was added to the DMF (N,N-dimethylformamide) solution of 1 mmol linker 2 (Scaffold2), reacted at room temperature for 2 hours and purified by HPLC to obtain N3-TZ-FITC . Then, N3-TZ-FITC and CD3-BCN were reacted at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and after reacting at room temperature for 1 hour, N3-CD3-FITC was purified by size exclusion chromatography. Finally, N3-CD3-FITC reacts with EGFR-DBCO at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and EGFR-CD3-FITC was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
EGFR-CD3-FITC通过SDS-PAGE考马斯亮蓝染色后表征如图6所示，其纯度>90％。EGFR-CD3-FITC was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 6, and its purity was >90%.
EGFR-CD3-FITC通过LC-MS表征结果如图7所示。The results of characterization of EGFR-CD3-FITC by LC-MS are shown in Figure 7.
EGFR-CD3-LCFAEGFR-CD3-LCFA
采用上述类似的方法，通过本申请提供的多特异生物偶联连接臂(T-Linker)制备多特异偶联物(T-Body)的方法合成了多特异偶联物，例如多特异性偶联物EGFR-CD3-LCFA(LCFA为长链脂肪酸)，EGFR-CD3-LCFA制备方法与实施例EGFR-CD3-FITC的制备可以相同，区别可以在于将FITC换成了LCFA，具体反应式如下所示：Using the method similar to the above, the multi-specific conjugate (T-Body) is synthesized by the method for preparing the multi-specific bioconjugate (T-Linker) provided in this application, such as multi-specific conjugation EGFR-CD3-LCFA (LCFA is a long-chain fatty acid), the preparation method of EGFR-CD3-LCFA can be the same as the preparation of EGFR-CD3-FITC in the example, the difference can be that FITC is replaced by LCFA, and the specific reaction formula is as follows :
Figure PCTCN2021130337-appb-000691
Figure PCTCN2021130337-appb-000691
EGFR-CD3-LCFA通过SDS-PAGE考马斯亮蓝染色后表征如图27所示，其纯度>90％。EGFR-CD3-LCFA通过LC-MS表征结果如图28所示。EGFR-CD3-LCFA was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 27, and its purity was >90%. The results of characterization of EGFR-CD3-LCFA by LC-MS are shown in FIG. 28 .
实施例3多特异偶联物的制备Example 3 Preparation of Multispecific Conjugates
EGFR-CD3-CPGEGFR-CD3-CPG
通过本申请提供的多特异生物偶联连接臂(T-Linker)制备多特异偶联物(T-Body)的方法合成了多特异偶联物，例如多特异性偶联物EGFR-CD3-CPG，具体反应式如下所示：Multispecific conjugates, such as multispecific conjugates EGFR-CD3-CPG, are synthesized by the method for preparing multispecific conjugates (T-Body) provided by the multispecific biological conjugation linker (T-Linker) provided in this application , the specific reaction formula is as follows:
Figure PCTCN2021130337-appb-000692
Figure PCTCN2021130337-appb-000692
其制备方法是，首先将上述多特异生物偶联的连接臂2(Scaffold2)和CPG-Amine反应。1毫摩尔连接臂2(Scaffold2)加入到含100微摩尔CPG-Amine的PBS(磷酸缓冲盐溶液)溶液中，室温下反应2小时后采用HPLC纯化得到N3-TZ-CPG。然后，N3-TZ-CPG与CD3-BCN按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应1小时后采用尺寸排阻色谱纯化得到N3-CD3-CPG。最后，N3-CD3-CPG与EGFR-DBCO按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应2小时后采用尺寸排阻色谱纯化得到EGFR-CD3-CPG。The preparation method is as follows: firstly, the connecting arm 2 (Scaffold2) of the above-mentioned multispecific biological coupling is reacted with CPG-Amine. 1 mmol of Scaffold 2 was added to a PBS (phosphate buffered saline) solution containing 100 μmol of CPG-Amine, reacted at room temperature for 2 hours, and purified by HPLC to obtain N3-TZ-CPG. Then, N3-TZ-CPG and CD3-BCN were reacted at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and N3-CD3-CPG was obtained by size exclusion chromatography after reaction at room temperature for 1 hour. Finally, N3-CD3-CPG reacts with EGFR-DBCO at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and EGFR-CD3-CPG was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
EGFR-CD3-CPG通过SDS-PAGE考马斯亮蓝染色后表征如图8所示，其纯度>90％。EGFR-CD3-CPG was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 8, and its purity was >90%.
EGFR-CD3-CPG通过LC-MS表征结果如图9所示。The results of characterization of EGFR-CD3-CPG by LC-MS are shown in Figure 9.
EGFR-CD3-ASOEGFR-CD3-ASO
采用上述类似的方法，通过本申请提供的多特异生物偶联连接臂(T-Linker)制备多特异偶联物(T-Body)的方法合成了多特异偶联物，例如多特异性偶联物EGFR-CD3-ASO。例如，可以使用STAT3的反义寡核苷酸ASO，其序列可以为 Me C*T*A*T*T*T*G*G*A*T*G*T* MeC* A*G* MeC ，SEQ ID NO：13(划线代表锁核酸LNA，例如其核苷可以包含连接4'-位和2'-位的桥的二环糖，MeC代表甲基C，*代表硫代磷酸酯Phosphorothioate的核苷间连接)。EGFR-CD3-ASO制备方法与实施例EGFR-CD3-FITC的制备可以相同，区别可以在于将FITC换成了ASO，具体反应式如下所示： Using a method similar to the above, the multi-specific conjugate (T-Body) was synthesized by the method for preparing the multi-specific bioconjugate (T-Linker) provided in this application, such as multi-specific conjugation EGFR-CD3-ASO. For example, the antisense oligonucleotide ASO of STAT3 can be used, which can be sequenced as Me C*T*A *T*T*T*G*G*A*T*G*T* Me C* A*G* MeC , SEQ ID NO: 13 (underlined represents a locked nucleic acid LNA, for example, its nucleoside may comprise a bicyclic sugar linking the 4'- and 2'-position bridges, MeC represents methyl C, * represents phosphorothioate Internucleoside linkage of ester Phosphorothioate). The preparation method of EGFR-CD3-ASO can be the same as the preparation of EGFR-CD3-FITC in the embodiment, the difference can be that FITC is replaced by ASO, and the specific reaction formula is as follows:
Figure PCTCN2021130337-appb-000693
Figure PCTCN2021130337-appb-000693
EGFR-CD3-ASO通过SDS-PAGE考马斯亮蓝染色后表征如图29所示，其纯度>90％。EGFR-CD3-ASO通过LC-MS表征结果如图30所示。EGFR-CD3-ASO was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 29, and its purity was >90%. The results of characterization of EGFR-CD3-ASO by LC-MS are shown in FIG. 30 .
实施例4多特异偶联物的制备Example 4 Preparation of Multispecific Conjugates
通过本申请提供的多特异生物偶联连接臂(T-Linker)制备多特异偶联物(T-Body)的方 法合成了多特异偶联物，例如多特异性偶联物EGFR-CD3-CMV、EGFR-CD3-neo2、EGFR-CD3-IFNα和EGFR-CD3-M1。The multispecific conjugate (T-Body) is synthesized by the method for preparing the multispecific bioconjugate (T-Linker) provided in this application, such as the multispecific conjugate EGFR-CD3-CMV , EGFR-CD3-neo2, EGFR-CD3-IFNα and EGFR-CD3-M1.
EGFR-CD3-CMVEGFR-CD3-CMV
EGFR-CD3-CMV制备方法是，首先将上述多特异生物偶联的连接臂1(Scaffold1)和含有CMV抗原的分支肽反应。1毫摩尔连接臂1(Scaffold1)加入到含100微摩尔分支肽PBS(磷酸缓冲盐溶液)溶液中，然后加入上述5微摩尔SrtA连接酶，室温下反应2小时后采用尺寸排阻纯化得到N3-TZ-CMV。然后，N3-TZ-CMV与CD3-BCN按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应1小时后采用尺寸排阻色谱纯化得到N3-CD3-CMV。最后，N3-CD3-CMV与EGFR-DBCO按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应2小时后采用尺寸排阻色谱纯化得到EGFR-CD3-CMV，具体反应式如图19所示。The preparation method of EGFR-CD3-CMV is as follows: firstly, the connecting arm 1 (Scaffold1) of the above-mentioned multispecific biological coupling is reacted with the branched peptide containing the CMV antigen. 1 mmol of tether 1 (Scaffold1) was added to PBS (phosphate buffered saline) solution containing 100 μmol of branched peptide, then 5 μmol of SrtA ligase was added, and after 2 hours of reaction at room temperature, size exclusion purification was used to obtain N3 -TZ-CMV. Then, N3-TZ-CMV and CD3-BCN were reacted at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and N3-CD3-CMV was obtained by size exclusion chromatography after reaction at room temperature for 1 hour. Finally, N3-CD3-CMV reacts with EGFR-DBCO at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as the solvent, and the EGFR-CD3-CMV was purified by size exclusion chromatography after reacting at room temperature for 2 hours. The specific reaction formula is shown in Figure 19.
EGFR-CD3-CMV通过SDS-PAGE考马斯亮蓝染色后表征如图10所示，其纯度>90％。EGFR-CD3-CMV was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 10, and its purity was >90%.
EGFR-CD3-CMV通过LC-MS表征结果如图11所示。The results of characterization of EGFR-CD3-CMV by LC-MS are shown in Figure 11 .
EGFR-CD3-neo2EGFR-CD3-neo2
EGFR-CD3-neo2制备方法是，首先将上述多特异生物偶联的连接臂1(Scaffold1)和序列为本申请SEQ ID NO：8所示的neo2反应。1毫摩尔连接臂1(Scaffold1)加入到含100微摩尔分支肽PBS(磷酸缓冲盐溶液)溶液中，然后加入上述5微摩尔SrtA连接酶，室温下反应2小时后采用尺寸排阻纯化得到N3-TZ-neo2。然后，N3-TZ-neo2与CD3-BCN按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应1小时后采用尺寸排阻色谱纯化得到N3-CD3-neo2。最后，N3-CD3-neo2与EGFR-DBCO按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应2小时后采用尺寸排阻色谱纯化得到EGFR-CD3-neo2。The preparation method of EGFR-CD3-neo2 is as follows: firstly, the connecting arm 1 (Scaffold1) of the above-mentioned multispecific biological coupling is reacted with the neo2 sequence shown in SEQ ID NO: 8 of the application. 1 mmol of tether 1 (Scaffold1) was added to PBS (phosphate buffered saline) solution containing 100 μmol of branched peptide, then 5 μmol of SrtA ligase was added, and after 2 hours of reaction at room temperature, size exclusion purification was used to obtain N3 -TZ-neo2. Then, N3-TZ-neo2 was reacted with CD3-BCN at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and N3-CD3-neo2 was obtained by size exclusion chromatography after reaction at room temperature for 1 hour. Finally, N3-CD3-neo2 reacts with EGFR-DBCO at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and EGFR-CD3-neo2 was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
EGFR-CD3-neo2通过SDS-PAGE考马斯亮蓝染色后表征如图12所示，其纯度>90％。EGFR-CD3-neo2 was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 12, and its purity was >90%.
EGFR-CD3-neo2通过LC-MS表征结果如图13所示。The results of characterization of EGFR-CD3-neo2 by LC-MS are shown in FIG. 13 .
EGFR-CD3-IFNαEGFR-CD3-IFNα
EGFR-CD3-IFNα制备方法是，首先将上述多特异生物偶联的连接臂1(Scaffold1)和序列为本申请SEQ ID NO：9所示IFNα反应。1毫摩尔连接臂1(Scaffold1)加入到含100微摩尔分支肽PBS(磷酸缓冲盐溶液)溶液中，然后加入上述5微摩尔SrtA连接酶，室温下反应2小时后采用尺寸排阻纯化得到N3-TZ-IFNα。然后，N3-TZ-IFNα与CD3-BCN按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下 反应1小时后采用尺寸排阻色谱纯化得到N3-CD3-IFNα。最后，N3-CD3-IFNα与EGFR-DBCO按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应2小时后采用尺寸排阻色谱纯化得到EGFR-CD3-IFNα。The preparation method of EGFR-CD3-IFNα is as follows: firstly, the connecting arm 1 (Scaffold1) of the above-mentioned multispecific biological coupling is reacted with the IFNα sequence shown in SEQ ID NO: 9 of the present application. 1 mmol of tether 1 (Scaffold1) was added to PBS (phosphate buffered saline) solution containing 100 μmol of branched peptide, then 5 μmol of SrtA ligase was added, and after 2 hours of reaction at room temperature, size exclusion purification was used to obtain N3 -TZ-IFNα. Then, N3-TZ-IFNα and CD3-BCN were reacted at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and N3-CD3-IFNα was obtained by size exclusion chromatography after reacting at room temperature for 1 hour. Finally, N3-CD3-IFNα reacts with EGFR-DBCO at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as the solvent, and the EGFR-CD3-IFNα was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
EGFR-CD3-IFNα通过SDS-PAGE考马斯亮蓝染色后表征如图14所示，其纯度>90％。EGFR-CD3-IFNα was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 14, and its purity was >90%.
EGFR-CD3-IFNα通过LC-MS表征结果如图15所示。The results of characterization of EGFR-CD3-IFNα by LC-MS are shown in FIG. 15 .
EGFR-CD3-M1EGFR-CD3-M1
采用上述类似的制备方法，将上述多特异生物偶联的连接臂1(Scaffold1)和序列为本申请SEQ ID NO：14所示M1(M1为穿血脑屏障的短肽)反应，得到EGFR-CD3-M1，具体反应式如图31所示。Using the above-mentioned preparation method similar to the above, the linking arm 1 (Scaffold1) of the above-mentioned multispecific biological coupling is reacted with M1 (M1 is a short peptide that penetrates the blood-brain barrier) shown in SEQ ID NO: 14 of the present application to obtain EGFR- CD3-M1, the specific reaction formula is shown in Figure 31.
EGFR-CD3-M1通过SDS-PAGE考马斯亮蓝染色后表征如图32所示，其纯度>90％。EGFR-CD3-M1 was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 32, and its purity was >90%.
EGFR-CD3-M1通过LC-MS表征结果如图33所示。The results of characterization of EGFR-CD3-M1 by LC-MS are shown in FIG. 33 .
EGFR-CD3-PDL1EGFR-CD3-PDL1
采用上述类似的制备方法，将上述多特异生物偶联的连接臂1(Scaffold1)和序列为本申请SEQ ID NO：15所示PDL1(PDL1为抗PDL1的VHH抗体)反应，得到EGFR-CD3-PDL1，具体反应式如图34所示。Using the above-mentioned preparation method similar to the above, the above-mentioned multispecific biologically coupled linker 1 (Scaffold1) is reacted with PDL1 shown in SEQ ID NO: 15 of the present application (PDL1 is an anti-PDL1 VHH antibody) to obtain EGFR-CD3- PDL1, the specific reaction formula is shown in Figure 34.
EGFR-CD3-PDL1通过SDS-PAGE考马斯亮蓝染色后表征如图35所示，其纯度>90％。EGFR-CD3-PDL1 was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 35, and its purity was >90%.
EGFR-CD3-PDL1通过LC-MS表征结果如图36所示。The results of characterization of EGFR-CD3-PDL1 by LC-MS are shown in FIG. 36 .
实施例5多特异偶联物的制备Example 5 Preparation of Multispecific Conjugates
EGFR-CD3-4-1BBEGFR-CD3-4-1BB
通过本申请提供的多特异生物偶联连接臂(T-Linker)制备多特异偶联物(T-Body)的方法合成了多特异偶联物，例如三特异性VHH纳米抗体EGFR-CD3-4-1BB，具体反应式如图20所示。Multispecific conjugates, such as trispecific VHH nanobody EGFR-CD3-4, were synthesized by the method for preparing multispecific conjugates (T-Body) by the multispecific biological coupling linker (T-Linker) provided in this application -1BB, the specific reaction formula is shown in Figure 20.
其制备方法是，首先将上述多特异生物偶联的连接臂1(Scaffold1)和靶向4-1BB的VHH纳米抗体反应。1毫摩尔连接臂1(Scaffold1)加入到含100微摩尔VHH纳米抗体PBS(磷酸缓冲盐溶液)溶液中，然后加入上述5微摩尔SrtA连接酶，室温下反应2小时后采用尺寸排阻纯化得到N3-TZ-4-1BB。然后，N3-TZ-4-1BB与CD3-BCN按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应1小时后采用尺寸排阻色谱纯化得到N3-CD3-4-1BB。最后，N3-CD3-4-1BB与EGFR-DBCO按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应2小时后采用尺寸排阻色谱纯化得到EGFR-CD3-4-1BB。The preparation method is as follows: firstly, the above-mentioned multispecific biologically coupled connecting arm 1 (Scaffold1) is reacted with a VHH nanobody targeting 4-1BB. 1 mmol of linker 1 (Scaffold1) was added to PBS (phosphate buffered saline solution) solution containing 100 μmol of VHH Nanobody, and then 5 μmol of SrtA ligase was added, reacted at room temperature for 2 hours and purified by size exclusion. N3-TZ-4-1BB. Then, N3-TZ-4-1BB and CD3-BCN were reacted at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and N3-CD3-4-1BB was obtained by size exclusion chromatography after reaction at room temperature for 1 hour. Finally, N3-CD3-4-1BB reacts with EGFR-DBCO at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and EGFR-CD3-4-1BB was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
EGFR-CD3-4-1BB通过SDS-PAGE考马斯亮蓝染色后表征如图16所示，其纯度>90％。EGFR-CD3-4-1BB was characterized by SDS-PAGE staining with Coomassie brilliant blue as shown in Figure 16, and its purity was >90%.
EGFR-CD3-4-1BB通过LC-MS表征结果如图17所示。The results of characterization of EGFR-CD3-4-1BB by LC-MS are shown in FIG. 17 .
HER2-CD3-PDL1HER2-CD3-PDL1
通过本申请提供的多特异生物偶联连接臂制备多特异偶联物的方法合成了多特异偶联物，例如三特异性VHH纳米抗体HER2-CD3-PDL1，具体反应式如图37所示。A multispecific conjugate, such as a trispecific VHH nanobody HER2-CD3-PDL1, was synthesized by the method for preparing a multispecific bioconjugate provided by the present application. The specific reaction formula is shown in FIG. 37 .
其制备方法是，首先将上述多特异生物偶联的连接臂1(Scaffold1)和靶向PDL1的VHH纳米抗体反应。1毫摩尔连接臂1(Scaffold1)加入到含100微摩尔VHH纳米抗体PBS(磷酸缓冲盐溶液)溶液中，然后加入上述5微摩尔SrtA连接酶，室温下反应2小时后采用尺寸排阻纯化得到N3-TZ-PDL1。然后，N3-TZ-PDL1与CD3-BCN按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应1小时后采用尺寸排阻色谱纯化得到N3-CD3-PDL1。同时，制备HER2-DBCO，其制备方法和EGFR-DBCO相同，区别在于将靶向EGFR的VHH纳米抗体替换为HER2结合蛋白。最后，N3-CD3-PDL1与HER2-DBCO按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应2小时后采用尺寸排阻色谱纯化得到HER2-CD3-PDL1。The preparation method is as follows: firstly, the above-mentioned multispecific biologically coupled connecting arm 1 (Scaffold1) is reacted with a VHH nanobody targeting PDL1. 1 mmol of linker 1 (Scaffold1) was added to PBS (phosphate buffered saline solution) solution containing 100 μmol of VHH Nanobody, and then 5 μmol of SrtA ligase was added, reacted at room temperature for 2 hours and purified by size exclusion. N3-TZ-PDL1. Then, N3-TZ-PDL1 and CD3-BCN were reacted at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and N3-CD3-PDL1 was obtained by size exclusion chromatography after reaction at room temperature for 1 hour. At the same time, the preparation method of HER2-DBCO is the same as that of EGFR-DBCO, except that the VHH nanobody targeting EGFR is replaced with a HER2 binding protein. Finally, N3-CD3-PDL1 reacts with HER2-DBCO at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and HER2-CD3-PDL1 was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
HER2-CD3-PDL1通过LC-MS表征结果如图38所示。The results of characterization of HER2-CD3-PDL1 by LC-MS are shown in FIG. 38 .
实施例6多特异偶联物EGFR-CD3-4-1BB抑制肿瘤细胞生长Example 6 Multispecific conjugate EGFR-CD3-4-1BB inhibits tumor cell growth
上述制备的EGFR-CD3-4-1BB在抗肿瘤中的应用，具体为EGFR-CD3-4-1BB介导的PBMCs对肿瘤细胞的杀伤。PBMCs来源于上海澳赛尔斯生物技术有限公司，采用的肿瘤细胞为来源于ATCC的A431细胞。具体实验细节如下：The application of the EGFR-CD3-4-1BB prepared above in anti-tumor is specifically the killing of tumor cells by PBMCs mediated by EGFR-CD3-4-1BB. PBMCs were obtained from Shanghai Auxers Biotechnology Co., Ltd., and the tumor cells used were A431 cells derived from ATCC. The specific experimental details are as follows:
第1天，在96孔板中接种A431细胞，细胞接种密度为10000个细胞每个孔，体积为100微升。所使用的培养基为含有20％FBS(胎牛血清)、10％双抗(青霉素-链霉素混合液)的DMEM培养基。培养条件为含5％二氧化碳的37℃培养箱。On day 1, A431 cells were seeded in 96-well plates at a cell seeding density of 10,000 cells per well in a volume of 100 μl. The medium used was DMEM medium containing 20% FBS (fetal bovine serum) and 10% double antibody (penicillin-streptomycin mixture). The culture condition was a 37°C incubator with 5% carbon dioxide.
第2天，将96孔板中旧培养基吸走，加入100微升新的培养基。然后每孔加入100微升含有150000个PBMCs的1640培养基(含20％FBS(胎牛血清)、10％双抗(青霉素-链霉素混合液))。然后，实验组加入不同浓度的EGFR-CD3-4-1BB，对照组加入对应浓度的EGFR-TZ-4-1BB或EGFR-CD3-Gly，空白组加入对应体积的PBS(磷酸缓冲盐溶液)。其中对照组EGFR-TZ-4-1BB和EGFR-CD3-Gly制备方式参考上述实施例并且如图21所示。On day 2, the old medium in the 96-well plate was aspirated and 100 μl of new medium was added. Then, 100 microliters of 1640 medium containing 150,000 PBMCs (containing 20% FBS (fetal bovine serum), 10% double antibody (penicillin-streptomycin mixture)) was added to each well. Then, the experimental group was added with different concentrations of EGFR-CD3-4-1BB, the control group was added with the corresponding concentration of EGFR-TZ-4-1BB or EGFR-CD3-Gly, and the blank group was added with the corresponding volume of PBS (phosphate buffered saline solution). The preparation methods of the control group EGFR-TZ-4-1BB and EGFR-CD3-Gly refer to the above examples and are shown in FIG. 21 .
具体地，1毫摩尔连接臂(Scaffold1)加入到含100微摩尔靶向4-1BB的VHH纳米抗体PBS(磷酸缓冲盐溶液)溶液中，然后加入上述5微摩尔SrtA连接酶，室温下反应2小时后采用尺寸排阻纯化得到N3-TZ-4-1BB。然后，N3-TZ-4-1BB与EGFR-DBCO按照摩尔比1/1 进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应2小时后采用尺寸排阻色谱纯化得到EGFR-TZ-4-1BB。Specifically, 1 mmol of the linker arm (Scaffold1) was added to the PBS (phosphate buffered saline) solution containing 100 μmol of VHH Nanobody targeting 4-1BB, and then 5 μmol of SrtA ligase was added, and the reaction was carried out at room temperature for 2 After 1 hour, size exclusion purification gave N3-TZ-4-1BB. Then, N3-TZ-4-1BB was reacted with EGFR-DBCO at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and EGFR-TZ-4-1BB was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
具体地，连接臂(Scaffold1)与CD3-BCN按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应1小时后采用尺寸排阻色谱纯化得到N3-CD3-Gly。然后，N3-CD3-Gly与EGFR-DBCO按照摩尔比1/1进行反应。反应浓度为100微摩尔，PBS(磷酸缓冲盐溶液)作为溶剂，在室温条件下反应2小时后采用尺寸排阻色谱纯化得到EGFR-CD3-Gly。Specifically, the tether (Scaffold1) reacts with CD3-BCN at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and N3-CD3-Gly was obtained by size exclusion chromatography after reaction at room temperature for 1 hour. Then, N3-CD3-Gly was reacted with EGFR-DBCO at a molar ratio of 1/1. The reaction concentration was 100 micromolar, PBS (phosphate buffered saline) was used as a solvent, and EGFR-CD3-Gly was obtained by size exclusion chromatography after reaction at room temperature for 2 hours.
第3天，采用LDH乳酸脱氢酶细胞毒性检测实验来测试上述实验组对肿瘤细胞的杀伤作用。所采用的试剂盒为KTA1030LDH Cytotoxicity Assay Kit LDH Cytotoxicity Assay Kit(Abbkine)，具体操作步骤按照试剂盒提供的说明书进行。其结果如图18所示。On the third day, the LDH lactate dehydrogenase cytotoxicity assay was used to test the killing effect of the above experimental groups on tumor cells. The kit used was KTA1030LDH Cytotoxicity Assay Kit LDH Cytotoxicity Assay Kit (Abbkine), and the specific operation steps were carried out according to the instructions provided by the kit. The results are shown in FIG. 18 .
实施例7多特异偶联物与多靶标的结合力Example 7 Binding ability of multispecific conjugates to multitargets
采用
Figure PCTCN2021130337-appb-000694
Octet RED96对EGFR-CD3-PDL1多特异性抗体和EGFR、CD3、PDL1受体的结合进行测定。首先准备带有Biotin标签的EGFR、CD3、PDL1受体蛋白(购买于义翘神州)。将上述蛋白溶于PBS溶液，配成100ug/ml的浓度。准备好50nM、100nM、200nM、400nM、800nM的EGFR-PDL1-CD3多特异性抗体PBS溶液。随后通过链霉亲和素偶联的Biosensor传感器进行结合力测定，使用
Figure PCTCN2021130337-appb-000695
Octet RED96通用的结合力测定方法。测定主要包括固化、结合、解离三个主要过程，测定结束后通过仪器自带多浓度动力学分析软件拟合得到EGFR-PDL1-CD3多特异性抗体与不同受体结合的Kon、Kdis以及最终的KD值。 use
Figure PCTCN2021130337-appb-000694
Octet RED96 assays the binding of EGFR-CD3-PDL1 multispecific antibody to EGFR, CD3, PDL1 receptors. First, prepare EGFR, CD3, and PDL1 receptor proteins with Biotin tags (purchased from Yiqiao Shenzhou). The above proteins were dissolved in PBS solution to prepare a concentration of 100ug/ml. Prepare 50nM, 100nM, 200nM, 400nM, 800nM EGFR-PDL1-CD3 multispecific antibody PBS solutions. Binding was subsequently measured by a streptavidin-coupled Biosensor sensor using
Figure PCTCN2021130337-appb-000695
Octet RED96 Generic binding assay method. The determination mainly includes three main processes of solidification, binding and dissociation. After the determination, the Kon, Kdis and final EGFR-PDL1-CD3 multispecific antibodies bound to different receptors are obtained by fitting the multi-concentration kinetic analysis software of the instrument. the KD value.
EGFR-PDL1-CD3多特异性抗体与EGFR、CD3、PDL1受体蛋白的结合表征如图39A-39B所示，其中图39(A)表示EGFR-CD3-PDL1与EGFR、CD3、PDL1蛋白的结合曲线，曲线中结合高度从低到高对应EGFR-CD3-PDL1浓度为50nM、100nM、200nM、400nM、800nM；其中图39(B)表示EGFR-CD3-PDL1与不同靶标结合的结合力。结果显示，本申请的多特异偶联物(T-Body)可以同时保持多个功能域各自的活性，例如受体结合活性。The binding characteristics of EGFR-PDL1-CD3 multispecific antibody to EGFR, CD3, and PDL1 receptor proteins are shown in Figure 39A-39B, in which Figure 39(A) shows the binding of EGFR-CD3-PDL1 to EGFR, CD3, and PDL1 proteins Curve, the binding height in the curve from low to high corresponds to EGFR-CD3-PDL1 concentrations of 50nM, 100nM, 200nM, 400nM, 800nM; Figure 39(B) shows the binding capacity of EGFR-CD3-PDL1 to different targets. The results show that the multispecific conjugate (T-Body) of the present application can simultaneously maintain the respective activities of multiple functional domains, such as receptor binding activity.
本申请通过上述实施例来说明本申请提供的多特异生物偶联连接臂及其合成、利用该生物偶联连接臂制备的多特异偶联物以及它们的制备方法和用途。但本申请并不局限于上述工艺步骤，即不意味着本申请必须依赖上述工艺步骤才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请所选用原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本申请的保护范围和公开范围之内。The present application uses the above examples to illustrate the multispecific bioconjugation link provided in the present application and its synthesis, the multispecific conjugates prepared by using the bioconjugate link, and their preparation methods and uses. However, the present application is not limited to the above-mentioned process steps, that is, it does not mean that the present application must rely on the above-mentioned process steps to be implemented. Those skilled in the art should understand that any improvement to the application, the equivalent replacement of the selected raw materials in the application, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the application.

Claims (60)

  1. 一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，其具有如式Ia或式Ib所示的结构：A compound or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, having as Structure shown in formula Ia or formula Ib:
    Figure PCTCN2021130337-appb-100001
    Figure PCTCN2021130337-appb-100001
    所述Wa为三价基团，Wb为四价基团；The Wa is a trivalent group, and Wb is a tetravalent group;
    所述A，B和C各自独立地选自以下组：Said A, B and C are each independently selected from the following group:
    Figure PCTCN2021130337-appb-100002
    Figure PCTCN2021130337-appb-100002
    其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
    Figure PCTCN2021130337-appb-100003
    代表连接位点；     wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
    Figure PCTCN2021130337-appb-100003
    represents the attachment site;
    其中，A，B和C中，
    Figure PCTCN2021130337-appb-100004
    不能和
    Figure PCTCN2021130337-appb-100005
    同时存在；     Among them, A, B and C,
    Figure PCTCN2021130337-appb-100004
    cannot and
    Figure PCTCN2021130337-appb-100005
    simultaneously exist;
    其中，A，B和C中，
    Figure PCTCN2021130337-appb-100006
    不能和
    Figure PCTCN2021130337-appb-100007
    Figure PCTCN2021130337-appb-100008
    同时存在；     Among them, A, B and C,
    Figure PCTCN2021130337-appb-100006
    cannot and
    Figure PCTCN2021130337-appb-100007
    Figure PCTCN2021130337-appb-100008
    simultaneously exist;
    其中，A，B和C中，
    Figure PCTCN2021130337-appb-100009
    不能和
    Figure PCTCN2021130337-appb-100010
    同时存在；     Among them, A, B and C,
    Figure PCTCN2021130337-appb-100009
    cannot and
    Figure PCTCN2021130337-appb-100010
    simultaneously exist;
    其中，A，B和C中，
    Figure PCTCN2021130337-appb-100011
    不能和
    Figure PCTCN2021130337-appb-100012
    Figure PCTCN2021130337-appb-100013
    同时存在；     Among them, A, B and C,
    Figure PCTCN2021130337-appb-100011
    cannot and
    Figure PCTCN2021130337-appb-100012
    Figure PCTCN2021130337-appb-100013
    simultaneously exist;
    当A，B和C中，
    Figure PCTCN2021130337-appb-100014
    同时存在时，所述R 12，R 13和R 14不为炔基；     When A, B and C,
    Figure PCTCN2021130337-appb-100014
    When present at the same time, the R 12 , R 13 and R 14 are not alkynyl;
    当A，B和C中，
    Figure PCTCN2021130337-appb-100015
    同时存在时，所述R 12，R 13和R 14不为氨基，     When A, B and C,
    Figure PCTCN2021130337-appb-100015
    When present at the same time, the R 12 , R 13 and R 14 are not amino groups,
    A，B和C不同时为
    Figure PCTCN2021130337-appb-100016
    A, B and C are not simultaneously
    Figure PCTCN2021130337-appb-100016
  2. 根据权利要求1所述的化合物，其中：The compound of claim 1, wherein:
    (1)A为
    Figure PCTCN2021130337-appb-100017
    B为
    Figure PCTCN2021130337-appb-100018
    C为
    Figure PCTCN2021130337-appb-100019
    Figure PCTCN2021130337-appb-100020
    Figure PCTCN2021130337-appb-100021
    或     (1) A is
    Figure PCTCN2021130337-appb-100017
    B is
    Figure PCTCN2021130337-appb-100018
    C is
    Figure PCTCN2021130337-appb-100019
    Figure PCTCN2021130337-appb-100020
    Figure PCTCN2021130337-appb-100021
    or
    (2)A为
    Figure PCTCN2021130337-appb-100022
    B为
    Figure PCTCN2021130337-appb-100023
    C为
    Figure PCTCN2021130337-appb-100024
    或     (2) A is
    Figure PCTCN2021130337-appb-100022
    B is
    Figure PCTCN2021130337-appb-100023
    C is
    Figure PCTCN2021130337-appb-100024
    or
    (3)A为
    Figure PCTCN2021130337-appb-100025
    B为
    Figure PCTCN2021130337-appb-100026
    C为
    Figure PCTCN2021130337-appb-100027
    Figure PCTCN2021130337-appb-100028
    Figure PCTCN2021130337-appb-100029
    或     (3) A is
    Figure PCTCN2021130337-appb-100025
    B is
    Figure PCTCN2021130337-appb-100026
    C is
    Figure PCTCN2021130337-appb-100027
    Figure PCTCN2021130337-appb-100028
    Figure PCTCN2021130337-appb-100029
    or
    (4)A为
    Figure PCTCN2021130337-appb-100030
    B为
    Figure PCTCN2021130337-appb-100031
    C为
    Figure PCTCN2021130337-appb-100032
    Figure PCTCN2021130337-appb-100033
    或     (4) A is
    Figure PCTCN2021130337-appb-100030
    B is
    Figure PCTCN2021130337-appb-100031
    C is
    Figure PCTCN2021130337-appb-100032
    Figure PCTCN2021130337-appb-100033
    or
    (5)A为
    Figure PCTCN2021130337-appb-100034
    B为
    Figure PCTCN2021130337-appb-100035
    C为
    Figure PCTCN2021130337-appb-100036
    或     (5) A is
    Figure PCTCN2021130337-appb-100034
    B is
    Figure PCTCN2021130337-appb-100035
    C is
    Figure PCTCN2021130337-appb-100036
    or
    (6)A为
    Figure PCTCN2021130337-appb-100037
    B为
    Figure PCTCN2021130337-appb-100038
    C为
    Figure PCTCN2021130337-appb-100039
    Figure PCTCN2021130337-appb-100040
    或     (6) A is
    Figure PCTCN2021130337-appb-100037
    B is
    Figure PCTCN2021130337-appb-100038
    C is
    Figure PCTCN2021130337-appb-100039
    Figure PCTCN2021130337-appb-100040
    or
    (7)A为
    Figure PCTCN2021130337-appb-100041
    Figure PCTCN2021130337-appb-100042
    B为
    Figure PCTCN2021130337-appb-100043
    C为
    Figure PCTCN2021130337-appb-100044
    Figure PCTCN2021130337-appb-100045
    或     (7) A is
    Figure PCTCN2021130337-appb-100041
    Figure PCTCN2021130337-appb-100042
    B is
    Figure PCTCN2021130337-appb-100043
    C is
    Figure PCTCN2021130337-appb-100044
    Figure PCTCN2021130337-appb-100045
    or
    (8)A为
    Figure PCTCN2021130337-appb-100046
    Figure PCTCN2021130337-appb-100047
    B为
    Figure PCTCN2021130337-appb-100048
    C为
    Figure PCTCN2021130337-appb-100049
    或     (8) A is
    Figure PCTCN2021130337-appb-100046
    Figure PCTCN2021130337-appb-100047
    B is
    Figure PCTCN2021130337-appb-100048
    C is
    Figure PCTCN2021130337-appb-100049
    or
    (9)A为
    Figure PCTCN2021130337-appb-100050
    Figure PCTCN2021130337-appb-100051
    B为
    Figure PCTCN2021130337-appb-100052
    C为
    Figure PCTCN2021130337-appb-100053
    或     (9) A is
    Figure PCTCN2021130337-appb-100050
    Figure PCTCN2021130337-appb-100051
    B is
    Figure PCTCN2021130337-appb-100052
    C is
    Figure PCTCN2021130337-appb-100053
    or
    (10)A为
    Figure PCTCN2021130337-appb-100054
    B为
    Figure PCTCN2021130337-appb-100055
    C为
    Figure PCTCN2021130337-appb-100056
    或     (10) A is
    Figure PCTCN2021130337-appb-100054
    B is
    Figure PCTCN2021130337-appb-100055
    C is
    Figure PCTCN2021130337-appb-100056
    or
    (11)A为
    Figure PCTCN2021130337-appb-100057
    Figure PCTCN2021130337-appb-100058
    B为
    Figure PCTCN2021130337-appb-100059
    C为
    Figure PCTCN2021130337-appb-100060
    或     (11) A is
    Figure PCTCN2021130337-appb-100057
    Figure PCTCN2021130337-appb-100058
    B is
    Figure PCTCN2021130337-appb-100059
    C is
    Figure PCTCN2021130337-appb-100060
    or
    (12)A为
    Figure PCTCN2021130337-appb-100061
    B为
    Figure PCTCN2021130337-appb-100062
    C为
    Figure PCTCN2021130337-appb-100063
    Figure PCTCN2021130337-appb-100064
    或     (12) A is
    Figure PCTCN2021130337-appb-100061
    B is
    Figure PCTCN2021130337-appb-100062
    C is
    Figure PCTCN2021130337-appb-100063
    Figure PCTCN2021130337-appb-100064
    or
    (13)A为
    Figure PCTCN2021130337-appb-100065
    B为
    Figure PCTCN2021130337-appb-100066
    C为
    Figure PCTCN2021130337-appb-100067
    Figure PCTCN2021130337-appb-100068
    或     (13) A is
    Figure PCTCN2021130337-appb-100065
    B is
    Figure PCTCN2021130337-appb-100066
    C is
    Figure PCTCN2021130337-appb-100067
    Figure PCTCN2021130337-appb-100068
    or
    (14)A为
    Figure PCTCN2021130337-appb-100069
    B为
    Figure PCTCN2021130337-appb-100070
    C为
    Figure PCTCN2021130337-appb-100071
    Figure PCTCN2021130337-appb-100072
    (14) A is
    Figure PCTCN2021130337-appb-100069
    B is
    Figure PCTCN2021130337-appb-100070
    C is
    Figure PCTCN2021130337-appb-100071
    Figure PCTCN2021130337-appb-100072
    (15)A为
    Figure PCTCN2021130337-appb-100073
    B为
    Figure PCTCN2021130337-appb-100074
    C为
    Figure PCTCN2021130337-appb-100075
    (15) A is
    Figure PCTCN2021130337-appb-100073
    B is
    Figure PCTCN2021130337-appb-100074
    C is
    Figure PCTCN2021130337-appb-100075
    其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
    Figure PCTCN2021130337-appb-100076
    代表连接位点；     wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
    Figure PCTCN2021130337-appb-100076
    represents the attachment site;
    当A，B和C中，
    Figure PCTCN2021130337-appb-100077
    同时存在时，所述R 12，R 13和R 14不为炔基；     When A, B and C,
    Figure PCTCN2021130337-appb-100077
    When present at the same time, the R 12 , R 13 and R 14 are not alkynyl;
    当A，B和C中，
    Figure PCTCN2021130337-appb-100078
    同时存在时，所述R 12，R 13和R 14不为氨基。     When A, B and C,
    Figure PCTCN2021130337-appb-100078
    When present at the same time, the R 12 , R 13 and R 14 are not amino groups.
  3. 根据权利要求1-2中任一项所述的化合物，其中：The compound of any one of claims 1-2, wherein:
    (1)A为
    Figure PCTCN2021130337-appb-100079
    B为
    Figure PCTCN2021130337-appb-100080
    C为
    Figure PCTCN2021130337-appb-100081
    Figure PCTCN2021130337-appb-100082
    或     (1) A is
    Figure PCTCN2021130337-appb-100079
    B is
    Figure PCTCN2021130337-appb-100080
    C is
    Figure PCTCN2021130337-appb-100081
    Figure PCTCN2021130337-appb-100082
    or
    (2)A为
    Figure PCTCN2021130337-appb-100083
    B为
    Figure PCTCN2021130337-appb-100084
    C为
    Figure PCTCN2021130337-appb-100085
    或     (2) A is
    Figure PCTCN2021130337-appb-100083
    B is
    Figure PCTCN2021130337-appb-100084
    C is
    Figure PCTCN2021130337-appb-100085
    or
    (3)A为
    Figure PCTCN2021130337-appb-100086
    B为
    Figure PCTCN2021130337-appb-100087
    C为
    Figure PCTCN2021130337-appb-100088
    (3) A is
    Figure PCTCN2021130337-appb-100086
    B is
    Figure PCTCN2021130337-appb-100087
    C is
    Figure PCTCN2021130337-appb-100088
    其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
    Figure PCTCN2021130337-appb-100089
    代表连接位点；     wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
    Figure PCTCN2021130337-appb-100089
    represents the attachment site;
    当A，B和C中，
    Figure PCTCN2021130337-appb-100090
    同时存在时，所述R 12，R 13和R 14不为氨基。     When A, B and C,
    Figure PCTCN2021130337-appb-100090
    When present at the same time, the R 12 , R 13 and R 14 are not amino groups.
  4. 根据权利要求1-3中任一项所述的化合物，其中：The compound of any one of claims 1-3, wherein:
    (1)A为
    Figure PCTCN2021130337-appb-100091
    B为
    Figure PCTCN2021130337-appb-100092
    C为
    Figure PCTCN2021130337-appb-100093
    或     (1) A is
    Figure PCTCN2021130337-appb-100091
    B is
    Figure PCTCN2021130337-appb-100092
    C is
    Figure PCTCN2021130337-appb-100093
    or
    (2)A为
    Figure PCTCN2021130337-appb-100094
    B为
    Figure PCTCN2021130337-appb-100095
    C为
    Figure PCTCN2021130337-appb-100096
    或     (2) A is
    Figure PCTCN2021130337-appb-100094
    B is
    Figure PCTCN2021130337-appb-100095
    C is
    Figure PCTCN2021130337-appb-100096
    or
    (3)A为
    Figure PCTCN2021130337-appb-100097
    B为
    Figure PCTCN2021130337-appb-100098
    C为
    Figure PCTCN2021130337-appb-100099
    (3) A is
    Figure PCTCN2021130337-appb-100097
    B is
    Figure PCTCN2021130337-appb-100098
    C is
    Figure PCTCN2021130337-appb-100099
    其中R 12选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
    Figure PCTCN2021130337-appb-100100
    代表连接位点；     wherein R is selected from the group consisting of hydrogen, protium , deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido, urea, alkane, cycloalkane radicals, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
    Figure PCTCN2021130337-appb-100100
    represents the attachment site;
    当A，B和C中，
    Figure PCTCN2021130337-appb-100101
    同时存在时，所述R 12不为氨基。     When A, B and C,
    Figure PCTCN2021130337-appb-100101
    When both are present, the R 12 is not amino.
  5. 根据权利要求1-4中任一项所述的化合物，其中：The compound of any one of claims 1-4, wherein:
    (1)A为
    Figure PCTCN2021130337-appb-100102
    B为
    Figure PCTCN2021130337-appb-100103
    C为
    Figure PCTCN2021130337-appb-100104
    或     (1) A is
    Figure PCTCN2021130337-appb-100102
    B is
    Figure PCTCN2021130337-appb-100103
    C is
    Figure PCTCN2021130337-appb-100104
    or
    (2)A为
    Figure PCTCN2021130337-appb-100105
    B为
    Figure PCTCN2021130337-appb-100106
    C为
    Figure PCTCN2021130337-appb-100107
    或     (2) A is
    Figure PCTCN2021130337-appb-100105
    B is
    Figure PCTCN2021130337-appb-100106
    C is
    Figure PCTCN2021130337-appb-100107
    or
    (3)A为
    Figure PCTCN2021130337-appb-100108
    B为
    Figure PCTCN2021130337-appb-100109
    C为
    Figure PCTCN2021130337-appb-100110
    (3) A is
    Figure PCTCN2021130337-appb-100108
    B is
    Figure PCTCN2021130337-appb-100109
    C is
    Figure PCTCN2021130337-appb-100110
    其中R 12选自以下组：氢，氕，氘，氚，卤素和链烷基，
    Figure PCTCN2021130337-appb-100111
    代表连接位点。     wherein R is selected from the group consisting of hydrogen, protium , deuterium, tritium, halogen and alkane,
    Figure PCTCN2021130337-appb-100111
    represents the attachment site.
  6. 根据权利要求1-5中任一项所述的化合物，其中：A为
    Figure PCTCN2021130337-appb-100112
    B为
    Figure PCTCN2021130337-appb-100113
    C为
    Figure PCTCN2021130337-appb-100114
    The compound according to any one of claims 1-5, wherein: A is
    Figure PCTCN2021130337-appb-100112
    B is
    Figure PCTCN2021130337-appb-100113
    C is
    Figure PCTCN2021130337-appb-100114
    其中R 12选自以下组的基团：包括氢，氕，氘，氚，卤素和链烷基，
    Figure PCTCN2021130337-appb-100115
    代表连接位点。     A group wherein R is selected from the group consisting of hydrogen, protium , deuterium, tritium, halogen and alkane,
    Figure PCTCN2021130337-appb-100115
    represents the attachment site.
  7. 根据权利要求1-6中任一项所述的化合物，其中：The compound of any one of claims 1-6, wherein:
    Figure PCTCN2021130337-appb-100116
    为
    Figure PCTCN2021130337-appb-100117
    Figure PCTCN2021130337-appb-100118
    为
    Figure PCTCN2021130337-appb-100119
    Figure PCTCN2021130337-appb-100116
    for
    Figure PCTCN2021130337-appb-100117
    Figure PCTCN2021130337-appb-100118
    for
    Figure PCTCN2021130337-appb-100119
    所述W为三价基团或四价基团，所述W任选地被一个或多个R取代，The W is a trivalent group or a tetravalent group, the W is optionally substituted with one or more Rs,
    所述La为-(J 1) m1-C(＝O)-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-； The La is -(J 1 ) m1 -C(=O)-X 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -;
    所述Lb为-(J 2) m2-C(＝O)-X 2-(K 2) n2-(Y 2) p2-(L 2) q2-； The Lb is -(J 2 ) m2 -C(=O)-X 2 -(K 2 ) n2 -(Y 2 ) p2 -(L 2 ) q2 -;
    所述Lc为-(J 3) m3-C(＝O)-X 3-(K 3) n3-(Y 3) p3-(L 3) q3-； The Lc is -(J 3 ) m3 -C(=O)-X 3 -(K 3 ) n3 -(Y 3 ) p3 -(L 3 ) q3 -;
    所述J 1，J 2，J 3，K 1，K 2，K 3，L 1，L 2，和L 3各自独立地选自以下组：链烷基，环烷基，杂环烷基，烯基，炔基，芳基，杂芳基，和聚乙二醇，或前述任意组合； The J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
    所述X 1，X 2，X 3，Y 1，Y 2，和Y 3各自独立地选自以下组：-NR 1-，-O-，-S-，-C(＝O)-，-C(＝S)-，-C(R 1a)(R 1b)-，-NR 1-C(＝O)-，-C(＝O)-NR 1-，-NR 1-C(＝S)-，-C(＝S)-NR 1-，-O-C(＝O)-，-C(＝O)-O-，-O-C(＝S)-，-C(＝S)-O-，-O-C(＝O)-O-，-O-C(＝O)-NR 1-，-NR 1-C(＝O)-O-，和-NR 1a-C(＝O)-NR 1b-； Said X 1 , X 2 , X 3 , Y 1 , Y 2 , and Y 3 are each independently selected from the group consisting of: -NR 1 -, -O-, -S-, -C(=O)-, - C(=S)-, -C(R 1a )(R 1b )-, -NR 1 -C(=O)-, -C(=O)-NR 1 -, -NR 1 -C(=S) -, -C(=S)-NR 1 -, -OC(=O)-, -C(=O)-O-, -OC(=S)-, -C(=S)-O-, - OC(=O)-O-, -OC(=O)-NR 1 -, -NR 1 -C(=O)-O-, and -NR 1a -C(=O)-NR 1b -;
    R，R 1，R 1a和R 1b各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
    Figure PCTCN2021130337-appb-100120
    代表连接位点；     R, R 1 , R 1a and R 1b are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
    Figure PCTCN2021130337-appb-100120
    represents the attachment site;
    其中，m1，m2，m3，n1，n2，n3，p1，p2，p3，q1，q2，和q3各自独立地选自0以 上的数。wherein m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 are each independently selected from a number of 0 or more.
  8. 根据权利要求7所述的化合物，其中，J 1，J 2，和J 3各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合； The compound of claim 7 , wherein J1, J2, and J3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing;
    其中，m1，m2，和m3各自独立地选自以下组：0、1、2和3。wherein m1, m2, and m3 are each independently selected from the group: 0, 1, 2, and 3.
  9. 根据权利要求7-8中任一项所述的化合物，其中，X 1，X 2，和X 3各自独立地选自以下组：-NH-和-O-。 The compound of any one of claims 7-8, wherein X1, X2, and X3 are each independently selected from the group consisting of -NH- and -O-.
  10. 根据权利要求7-9中任一项所述的化合物，其中，K 1，K 2，和K 3各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合； The compound of any one of claims 7-9, wherein K 1 , K 2 , and K 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing;
    其中，n1，n2，和n3各自独立地选自以下组：0、1、2和3。wherein n1, n2, and n3 are each independently selected from the group: 0, 1, 2, and 3.
  11. 根据权利要求7-10中任一项所述的化合物，其中，(K 1) n1，(K 2) n2，和(K 3) n3各自独立地选自以下组：-链烷基-聚乙二醇-链烷基-，链烷基和聚乙二醇，或n1，n2或n3各自独立地为0。 The compound of any one of claims 7-10, wherein (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: - alkane-polyethylene Diol-alkyi-, alkane and polyethylene glycol, or n1, n2 or n3 are each independently zero.
  12. 根据权利要求7-11中任一项所述的化合物，其中，(K 1) n1，(K 2) n2，和(K 3) n3各自独立地选自以下组：-(CH 2)-(CH 2-O-CH 2) 3-(CH 2)-，-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-，-(CH 2) 2-，和-(CH 2) 8-，或n1，n2或n3各自独立地为0。 The compound of any one of claims 7-11, wherein (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -(CH 2 )-( CH 2 -O-CH 2 ) 3 -(CH 2 )-, -(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -, -(CH 2 ) 2 -, and -(CH 2 ) 8 -, or n1, n2 or n3 are each independently 0.
  13. 根据权利要求7-12中任一项所述的化合物，其中，Y 1，Y 2，和Y 3各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-； The compound of any one of claims 7-12, wherein Y 1 , Y 2 , and Y 3 are each independently selected from the group consisting of: -C(=O)-, -NR 1 -C(=O )-, -NR 1 -, and -O-;
    R 1选自以下组：氢，氕，氘，氚，和链烷基； R 1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane;
    其中，n1，n2，和n3各自独立地选自以下组：0、1、2和3。wherein n1, n2, and n3 are each independently selected from the group: 0, 1, 2, and 3.
  14. 根据权利要求7-13中任一项所述的化合物，其中，(Y 1) p1，(Y 2) p2，和(Y 3) p3各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-，R 1选自以下组：氢，氕，氘，氚，和链烷基；或p1，p2或p3各自独立地为0。 The compound of any one of claims 7-13, wherein (Y 1 ) p1 , (Y 2 ) p2 , and (Y 3 ) p3 are each independently selected from the group consisting of: -C(=O)- , -NR 1 -C(=O)-, -NR 1 -, and -O-, R 1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; or p1, p2 or p3 are each independently ground is 0.
  15. 根据权利要求7-14中任一项所述的化合物，其中，L 1，L 2，和L 3各自独立地选自以下组：链烷基，和芳基，或前述任意组合；其中，q1，q2，和q3各自独立地选自以下组：0、1、2和3。 The compound of any one of claims 7-14, wherein L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, and aryl, or any combination of the foregoing; wherein q1 , q2, and q3 are each independently selected from the group consisting of 0, 1, 2, and 3.
  16. 根据权利要求7-15中任一项所述的化合物，其中，(L 1) q1，(L 2) q2，和(L 3) q3各自独立地选自以下组：-链烷基-芳基-，链烷基和聚乙二醇，或q1，q2和q3各自独立地为0。 The compound of any one of claims 7-15, wherein (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of: - alkane-aryl -, alkane and polyethylene glycol, or q1, q2 and q3 are each independently zero.
  17. 根据权利要求7-16中任一项所述的化合物，其中，(L 1) q1，(L 2) q2，和(L 3) q3各自独立地选自以下组：-CH 2-芳基-，-(CH 2) 2-，和-CH 2-，或q1，q2和q3各自独立地为0。 The compound of any one of claims 7-16, wherein (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of: -CH 2 -aryl- , -(CH 2 ) 2 -, and -CH 2 -, or q1, q2 and q3 are each independently 0.
  18. 根据权利要求7-17中任一项所述的化合物，其中：The compound of any one of claims 7-17, wherein:
    W选自以下组：W is selected from the following group:
    Figure PCTCN2021130337-appb-100121
    三价的链烷基，三价的环烷基，三价的杂环烷基，三价的烯基，三价的炔基，三价的芳基，和三价的杂芳基。
    Figure PCTCN2021130337-appb-100121
    Trivalent alkane, trivalent cycloalkyl, trivalent heterocycloalkyl, trivalent alkenyl, trivalent alkynyl, trivalent aryl, and trivalent heteroaryl.
  19. 根据权利要求7-18中任一项所述的化合物，其中：The compound of any one of claims 7-18, wherein:
    W选自以下组：W is selected from the following group:
    Figure PCTCN2021130337-appb-100122
    Figure PCTCN2021130337-appb-100122
    所述X 1，X 2，X 3，X 4，X 5，X 6，X 7，X 8，X 9，X 10，X 11，X 12，X 13，X 14，X 15，X 16，X 17和X 18各自独立地选自以下组：C，N，O，S，P，CH，CH 2，NH，P(O)和P(S)； The X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 and X 18 are each independently selected from the group consisting of C, N, O, S, P, CH, CH 2 , NH, P(O) and P(S);
    所述---表示双键或单键。The --- represents a double bond or a single bond.
  20. 根据权利要求7-19中任一项所述的化合物，其中：The compound of any one of claims 7-19, wherein:
    W选自以下组：W is selected from the following group:
    Figure PCTCN2021130337-appb-100123
    Figure PCTCN2021130337-appb-100123
    Figure PCTCN2021130337-appb-100124
    Figure PCTCN2021130337-appb-100124
  21. 根据权利要求1-20中任一项所述的化合物，其选自以下组：The compound of any one of claims 1-20, which is selected from the group consisting of:
    Figure PCTCN2021130337-appb-100125
    Figure PCTCN2021130337-appb-100125
    Figure PCTCN2021130337-appb-100126
    Figure PCTCN2021130337-appb-100126
    Figure PCTCN2021130337-appb-100127
    Figure PCTCN2021130337-appb-100127
  22. 根据权利要求1-21中任一项所述的化合物，其选自以下组：The compound of any one of claims 1-21, which is selected from the group consisting of:
    Figure PCTCN2021130337-appb-100128
    Figure PCTCN2021130337-appb-100128
    Figure PCTCN2021130337-appb-100129
    Figure PCTCN2021130337-appb-100129
  23. 一种化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，其具有如式IIa或式IIb所示的结构，其中：A compound or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, having as The structure shown in formula IIa or formula IIb, wherein:
    Figure PCTCN2021130337-appb-100130
    Figure PCTCN2021130337-appb-100130
    所述Wc为三价基团，Wd为四价基团；The Wc is a trivalent group, and Wd is a tetravalent group;
    所述A 2，B 2和C 2各自独立地选自以下组： Said A 2 , B 2 and C 2 are each independently selected from the following group:
    Figure PCTCN2021130337-appb-100131
    Figure PCTCN2021130337-appb-100132
    和共价键；
    Figure PCTCN2021130337-appb-100131
    Figure PCTCN2021130337-appb-100132
    and covalent bonds;
    其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基， wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
    Figure PCTCN2021130337-appb-100133
    代表连接位点，
    Figure PCTCN2021130337-appb-100133
    represents the attachment site,
    所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接； The two linking sites of the A2 are arbitrarily linked to Wc and P1, the two linking sites of the B2 are arbitrarily linked to Wc and P2, the two linking sites of the C2 are arbitrarily linked Connect with Wc and P3 ;
    其中P 1，P 2和P 3各自独立地选自以下组：脂质、蛋白质、核酸、小分子和多糖，或其任意组合。 wherein P 1 , P 2 and P 3 are each independently selected from the group consisting of lipids, proteins, nucleic acids, small molecules and polysaccharides, or any combination thereof.
  24. 根据权利要求23所述的化合物，其中：The compound of claim 23, wherein:
    (1)A 2为
    Figure PCTCN2021130337-appb-100134
    B 2为
    Figure PCTCN2021130337-appb-100135
    C 2为
    Figure PCTCN2021130337-appb-100136
    Figure PCTCN2021130337-appb-100137
    或共价键；或     (1) A 2 is
    Figure PCTCN2021130337-appb-100134
    B2 is
    Figure PCTCN2021130337-appb-100135
    C2 is
    Figure PCTCN2021130337-appb-100136
    Figure PCTCN2021130337-appb-100137
    or covalent bond; or
    (2)A 2为
    Figure PCTCN2021130337-appb-100138
    Figure PCTCN2021130337-appb-100139
    B 2为
    Figure PCTCN2021130337-appb-100140
    Figure PCTCN2021130337-appb-100141
    C 2为
    Figure PCTCN2021130337-appb-100142
    Figure PCTCN2021130337-appb-100143
    或共价键；或     (2) A 2 is
    Figure PCTCN2021130337-appb-100138
    Figure PCTCN2021130337-appb-100139
    B2 is
    Figure PCTCN2021130337-appb-100140
    Figure PCTCN2021130337-appb-100141
    C2 is
    Figure PCTCN2021130337-appb-100142
    Figure PCTCN2021130337-appb-100143
    or covalent bond; or
    (3)A 2为
    Figure PCTCN2021130337-appb-100144
    B 2为
    Figure PCTCN2021130337-appb-100145
    C 2为
    Figure PCTCN2021130337-appb-100146
    Figure PCTCN2021130337-appb-100147
    或共价键；或     (3) A 2 is
    Figure PCTCN2021130337-appb-100144
    B2 is
    Figure PCTCN2021130337-appb-100145
    C2 is
    Figure PCTCN2021130337-appb-100146
    Figure PCTCN2021130337-appb-100147
    or covalent bond; or
    (4)A 2为
    Figure PCTCN2021130337-appb-100148
    B 2为
    Figure PCTCN2021130337-appb-100149
    C 2为
    Figure PCTCN2021130337-appb-100150
    Figure PCTCN2021130337-appb-100151
    Figure PCTCN2021130337-appb-100152
    或共价键；或     (4) A 2 is
    Figure PCTCN2021130337-appb-100148
    B2 is
    Figure PCTCN2021130337-appb-100149
    C2 is
    Figure PCTCN2021130337-appb-100150
    Figure PCTCN2021130337-appb-100151
    Figure PCTCN2021130337-appb-100152
    or covalent bond; or
    (5)A 2为
    Figure PCTCN2021130337-appb-100153
    Figure PCTCN2021130337-appb-100154
    B 2为
    Figure PCTCN2021130337-appb-100155
    C 2为
    Figure PCTCN2021130337-appb-100156
    Figure PCTCN2021130337-appb-100157
    Figure PCTCN2021130337-appb-100158
    或共价键；或     (5) A 2 is
    Figure PCTCN2021130337-appb-100153
    Figure PCTCN2021130337-appb-100154
    B2 is
    Figure PCTCN2021130337-appb-100155
    C2 is
    Figure PCTCN2021130337-appb-100156
    Figure PCTCN2021130337-appb-100157
    Figure PCTCN2021130337-appb-100158
    or covalent bond; or
    (6)A 2为
    Figure PCTCN2021130337-appb-100159
    Figure PCTCN2021130337-appb-100160
    B 2为
    Figure PCTCN2021130337-appb-100161
    Figure PCTCN2021130337-appb-100162
    C 2为
    Figure PCTCN2021130337-appb-100163
    Figure PCTCN2021130337-appb-100164
    或共价键；或     (6) A 2 is
    Figure PCTCN2021130337-appb-100159
    Figure PCTCN2021130337-appb-100160
    B2 is
    Figure PCTCN2021130337-appb-100161
    Figure PCTCN2021130337-appb-100162
    C2 is
    Figure PCTCN2021130337-appb-100163
    Figure PCTCN2021130337-appb-100164
    or covalent bond; or
    (7)A 2为
    Figure PCTCN2021130337-appb-100165
    Figure PCTCN2021130337-appb-100166
    B 2为
    Figure PCTCN2021130337-appb-100167
    C 2为
    Figure PCTCN2021130337-appb-100168
    Figure PCTCN2021130337-appb-100169
    或共价键；或     (7) A 2 is
    Figure PCTCN2021130337-appb-100165
    Figure PCTCN2021130337-appb-100166
    B2 is
    Figure PCTCN2021130337-appb-100167
    C2 is
    Figure PCTCN2021130337-appb-100168
    Figure PCTCN2021130337-appb-100169
    or covalent bond; or
    (8)A 2为
    Figure PCTCN2021130337-appb-100170
    Figure PCTCN2021130337-appb-100171
    Figure PCTCN2021130337-appb-100172
    B 2为
    Figure PCTCN2021130337-appb-100173
    C 2为
    Figure PCTCN2021130337-appb-100174
    或共价键；或     (8) A 2 is
    Figure PCTCN2021130337-appb-100170
    Figure PCTCN2021130337-appb-100171
    Figure PCTCN2021130337-appb-100172
    B2 is
    Figure PCTCN2021130337-appb-100173
    C2 is
    Figure PCTCN2021130337-appb-100174
    or covalent bond; or
    (9)A 2为
    Figure PCTCN2021130337-appb-100175
    Figure PCTCN2021130337-appb-100176
    Figure PCTCN2021130337-appb-100177
    B 2为
    Figure PCTCN2021130337-appb-100178
    C 2为
    Figure PCTCN2021130337-appb-100179
    或共价键；或     (9) A 2 is
    Figure PCTCN2021130337-appb-100175
    Figure PCTCN2021130337-appb-100176
    Figure PCTCN2021130337-appb-100177
    B2 is
    Figure PCTCN2021130337-appb-100178
    C2 is
    Figure PCTCN2021130337-appb-100179
    or covalent bond; or
    (10)A 2为
    Figure PCTCN2021130337-appb-100180
    Figure PCTCN2021130337-appb-100181
    Figure PCTCN2021130337-appb-100182
    或共价键，B 2为共价键，C 2为共价键；或     (10) A 2 is
    Figure PCTCN2021130337-appb-100180
    Figure PCTCN2021130337-appb-100181
    Figure PCTCN2021130337-appb-100182
    Or a covalent bond, B 2 is a covalent bond, and C 2 is a covalent bond; or
    (11)A 2为
    Figure PCTCN2021130337-appb-100183
    B 2为
    Figure PCTCN2021130337-appb-100184
    Figure PCTCN2021130337-appb-100185
    C 2为
    Figure PCTCN2021130337-appb-100186
    Figure PCTCN2021130337-appb-100187
    Figure PCTCN2021130337-appb-100188
    或共价键；或     (11) A 2 is
    Figure PCTCN2021130337-appb-100183
    B2 is
    Figure PCTCN2021130337-appb-100184
    Figure PCTCN2021130337-appb-100185
    C2 is
    Figure PCTCN2021130337-appb-100186
    Figure PCTCN2021130337-appb-100187
    Figure PCTCN2021130337-appb-100188
    or covalent bond; or
    (12)A 2为
    Figure PCTCN2021130337-appb-100189
    B 2为
    Figure PCTCN2021130337-appb-100190
    C 2为
    Figure PCTCN2021130337-appb-100191
    Figure PCTCN2021130337-appb-100192
    或共价键；或     (12) A 2 is
    Figure PCTCN2021130337-appb-100189
    B2 is
    Figure PCTCN2021130337-appb-100190
    C2 is
    Figure PCTCN2021130337-appb-100191
    Figure PCTCN2021130337-appb-100192
    or covalent bond; or
    (13)A 2为
    Figure PCTCN2021130337-appb-100193
    B 2为
    Figure PCTCN2021130337-appb-100194
    C 2为
    Figure PCTCN2021130337-appb-100195
    Figure PCTCN2021130337-appb-100196
    或共价键；     (13) A 2 is
    Figure PCTCN2021130337-appb-100193
    B2 is
    Figure PCTCN2021130337-appb-100194
    C2 is
    Figure PCTCN2021130337-appb-100195
    Figure PCTCN2021130337-appb-100196
    or covalent bond;
    其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基， wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
    Figure PCTCN2021130337-appb-100197
    代表连接位点，
    Figure PCTCN2021130337-appb-100197
    represents the attachment site,
    所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。 The two linking sites of the A2 are arbitrarily linked to Wc and P1, the two linking sites of the B2 are arbitrarily linked to Wc and P2, the two linking sites of the C2 are arbitrarily linked Connect with Wc and P3 .
  25. 根据权利要求23-24中任一项所述的化合物，其中：The compound of any one of claims 23-24, wherein:
    (1)A 2为
    Figure PCTCN2021130337-appb-100198
    B 2为
    Figure PCTCN2021130337-appb-100199
    Figure PCTCN2021130337-appb-100200
    C 2为
    Figure PCTCN2021130337-appb-100201
    或共价键；或     (1) A 2 is
    Figure PCTCN2021130337-appb-100198
    B2 is
    Figure PCTCN2021130337-appb-100199
    Figure PCTCN2021130337-appb-100200
    C2 is
    Figure PCTCN2021130337-appb-100201
    or covalent bond; or
    (2)A 2为
    Figure PCTCN2021130337-appb-100202
    B 2为
    Figure PCTCN2021130337-appb-100203
    C 2为
    Figure PCTCN2021130337-appb-100204
    Figure PCTCN2021130337-appb-100205
    或共价键；或     (2) A 2 is
    Figure PCTCN2021130337-appb-100202
    B2 is
    Figure PCTCN2021130337-appb-100203
    C2 is
    Figure PCTCN2021130337-appb-100204
    Figure PCTCN2021130337-appb-100205
    or covalent bond; or
    (3)A 2为
    Figure PCTCN2021130337-appb-100206
    Figure PCTCN2021130337-appb-100207
    B 2为
    Figure PCTCN2021130337-appb-100208
    C 2为
    Figure PCTCN2021130337-appb-100209
    Figure PCTCN2021130337-appb-100210
    或共价键；     (3) A 2 is
    Figure PCTCN2021130337-appb-100206
    Figure PCTCN2021130337-appb-100207
    B2 is
    Figure PCTCN2021130337-appb-100208
    C2 is
    Figure PCTCN2021130337-appb-100209
    Figure PCTCN2021130337-appb-100210
    or covalent bond;
    其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基， wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
    Figure PCTCN2021130337-appb-100211
    代表连接位点，所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。
    Figure PCTCN2021130337-appb-100211
    Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
  26. 根据权利要求23-25中任一项所述的化合物，其中：The compound of any one of claims 23-25, wherein:
    (1)A 2为
    Figure PCTCN2021130337-appb-100212
    B 2为
    Figure PCTCN2021130337-appb-100213
    Figure PCTCN2021130337-appb-100214
    C 2为
    Figure PCTCN2021130337-appb-100215
    或共价键；或     (1) A 2 is
    Figure PCTCN2021130337-appb-100212
    B2 is
    Figure PCTCN2021130337-appb-100213
    Figure PCTCN2021130337-appb-100214
    C2 is
    Figure PCTCN2021130337-appb-100215
    or covalent bond; or
    (2)A 2为
    Figure PCTCN2021130337-appb-100216
    B 2为
    Figure PCTCN2021130337-appb-100217
    C 2为
    Figure PCTCN2021130337-appb-100218
    或共价键；或     (2) A 2 is
    Figure PCTCN2021130337-appb-100216
    B2 is
    Figure PCTCN2021130337-appb-100217
    C2 is
    Figure PCTCN2021130337-appb-100218
    or covalent bond; or
    (3)A 2为
    Figure PCTCN2021130337-appb-100219
    B 2为
    Figure PCTCN2021130337-appb-100220
    Figure PCTCN2021130337-appb-100221
    C 2为
    Figure PCTCN2021130337-appb-100222
    或共价键；     (3) A 2 is
    Figure PCTCN2021130337-appb-100219
    B2 is
    Figure PCTCN2021130337-appb-100220
    Figure PCTCN2021130337-appb-100221
    C2 is
    Figure PCTCN2021130337-appb-100222
    or covalent bond;
    其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基， wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
    Figure PCTCN2021130337-appb-100223
    代表连接位点，所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。
    Figure PCTCN2021130337-appb-100223
    Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
  27. 根据权利要求23-26中任一项所述的化合物，其中：The compound of any one of claims 23-26, wherein:
    (1)A 2为
    Figure PCTCN2021130337-appb-100224
    B 2为
    Figure PCTCN2021130337-appb-100225
    Figure PCTCN2021130337-appb-100226
    C 2为
    Figure PCTCN2021130337-appb-100227
    或共价键；或     (1) A 2 is
    Figure PCTCN2021130337-appb-100224
    B2 is
    Figure PCTCN2021130337-appb-100225
    Figure PCTCN2021130337-appb-100226
    C2 is
    Figure PCTCN2021130337-appb-100227
    or covalent bond; or
    (2)A 2为
    Figure PCTCN2021130337-appb-100228
    B 2为
    Figure PCTCN2021130337-appb-100229
    C 2为
    Figure PCTCN2021130337-appb-100230
    或共价键；或     (2) A 2 is
    Figure PCTCN2021130337-appb-100228
    B2 is
    Figure PCTCN2021130337-appb-100229
    C2 is
    Figure PCTCN2021130337-appb-100230
    or covalent bond; or
    (3)A 2为
    Figure PCTCN2021130337-appb-100231
    B 2为
    Figure PCTCN2021130337-appb-100232
    Figure PCTCN2021130337-appb-100233
    C 2为
    Figure PCTCN2021130337-appb-100234
    或共价键；     (3) A 2 is
    Figure PCTCN2021130337-appb-100231
    B2 is
    Figure PCTCN2021130337-appb-100232
    Figure PCTCN2021130337-appb-100233
    C2 is
    Figure PCTCN2021130337-appb-100234
    or covalent bond;
    其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素和链烷基， wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
    Figure PCTCN2021130337-appb-100235
    代表连接位点，所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。
    Figure PCTCN2021130337-appb-100235
    Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
  28. 根据权利要求23-27中任一项所述的化合物，其中：A 2为
    Figure PCTCN2021130337-appb-100236
    Figure PCTCN2021130337-appb-100237
    B 2为
    Figure PCTCN2021130337-appb-100238
    Figure PCTCN2021130337-appb-100239
    C 2为
    Figure PCTCN2021130337-appb-100240
    或共价键；其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素和链烷基，
    Figure PCTCN2021130337-appb-100241
    代表连接位点，所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。     The compound of any one of claims 23-27, wherein: A is
    Figure PCTCN2021130337-appb-100236
    Figure PCTCN2021130337-appb-100237
    B2 is
    Figure PCTCN2021130337-appb-100238
    Figure PCTCN2021130337-appb-100239
    C2 is
    Figure PCTCN2021130337-appb-100240
    or a covalent bond; wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
    Figure PCTCN2021130337-appb-100241
    Represents the attachment sites, the two attachment sites of the A2 are arbitrarily attached to Wc and P1, the two attachment sites of the B2 are arbitrarily attached to Wc and P2, the two attachment sites of the C2 The attachment site is arbitrarily attached to Wc and P3 .
  29. 根据权利要求23-28中任一项所述的化合物，其中：A 2为
    Figure PCTCN2021130337-appb-100242
    B 2为，
    Figure PCTCN2021130337-appb-100243
    C 2为
    Figure PCTCN2021130337-appb-100244
    或共价键；其中R 12选自以下组：氢，氕，氘，氚，卤素和链烷基，
    Figure PCTCN2021130337-appb-100245
    代表连接位点，所述A 2的两个连接位点任意地与Wc和P 1连接，所述B 2的两个连接位点任意地与Wc和P 2连接，所述C 2的两个连接位点任意地与Wc和P 3连接。     The compound of any one of claims 23-28, wherein: A is
    Figure PCTCN2021130337-appb-100242
    B2 is,
    Figure PCTCN2021130337-appb-100243
    C2 is
    Figure PCTCN2021130337-appb-100244
    or a covalent bond; wherein R 12 is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and alkane,
    Figure PCTCN2021130337-appb-100245
    Represents the attachment site, the two attachment sites of the A 2 are arbitrarily attached to Wc and P 1 , the two attachment sites of the B 2 are arbitrarily attached to Wc and P 2 , the two attachment sites of the C 2 The attachment site is arbitrarily attached to Wc and P3 .
  30. 根据权利要求23-29中任一项所述的化合物，其中：The compound of any one of claims 23-29, wherein:
    Figure PCTCN2021130337-appb-100246
    为
    Figure PCTCN2021130337-appb-100247
    Figure PCTCN2021130337-appb-100248
    为
    Figure PCTCN2021130337-appb-100249
    Figure PCTCN2021130337-appb-100246
    for
    Figure PCTCN2021130337-appb-100247
    Figure PCTCN2021130337-appb-100248
    for
    Figure PCTCN2021130337-appb-100249
    所述W为三价基团或四价基团，所述W任选地被一个或多个R取代，The W is a trivalent group or a tetravalent group, the W is optionally substituted with one or more Rs,
    所述La为-(J 1) m1-C(＝O)-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-； The La is -(J 1 ) m1 -C(=O)-X 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -;
    所述Lb为-(J 2) m2-C(＝O)-X 2-(K 2) n2-(Y 2) p2-(L 2) q2-； The Lb is -(J 2 ) m2 -C(=O)-X 2 -(K 2 ) n2 -(Y 2 ) p2 -(L 2 ) q2 -;
    所述Lc为-(J 3) m3-C(＝O)-X 3-(K 3) n3-(Y 3) p3-(L 3) q3-； The Lc is -(J 3 ) m3 -C(=O)-X 3 -(K 3 ) n3 -(Y 3 ) p3 -(L 3 ) q3 -;
    所述J 1，J 2，J 3，K 1，K 2，K 3，L 1，L 2，和L 3各自独立地选自以下组：链烷基，环烷基，杂环烷基，烯基，炔基，芳基，杂芳基，和聚乙二醇，或前述任意组合； The J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
    所述X 1，X 2，X 3，Y 1，Y 2，和Y 3各自独立地选自以下组：-NR 1-，-O-，-S-，-C(＝O)-，-C(＝S)-，-C(R 1a)(R 1b)-，-NR 1-C(＝O)-，-C(＝O)-NR 1-，-NR 1-C(＝S)-，-C(＝S)-NR 1-，-O-C(＝O)-，-C(＝O)-O-，-O-C(＝S)-，-C(＝S)-O-，-O-C(＝O)-O-，-O-C(＝O)-NR 1-，-NR 1-C(＝O)-O-，和-NR 1a-C(＝O)-NR 1b-； Said X 1 , X 2 , X 3 , Y 1 , Y 2 , and Y 3 are each independently selected from the group consisting of: -NR 1 -, -O-, -S-, -C(=O)-, - C(=S)-, -C(R 1a )(R 1b )-, -NR 1 -C(=O)-, -C(=O)-NR 1 -, -NR 1 -C(=S) -, -C(=S)-NR 1 -, -OC(=O)-, -C(=O)-O-, -OC(=S)-, -C(=S)-O-, - OC(=O)-O-, -OC(=O)-NR 1 -, -NR 1 -C(=O)-O-, and -NR 1a -C(=O)-NR 1b -;
    R，R 1，R 1a和R 1b各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基，
    Figure PCTCN2021130337-appb-100250
    代表连接位点；     R, R 1 , R 1a and R 1b are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl,
    Figure PCTCN2021130337-appb-100250
    represents the attachment site;
    其中，m1，m2，m3，n1，n2，n3，p1，p2，p3，q1，q2，和q3各自独立地选自0以上的数。Wherein, m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 are each independently selected from a number of 0 or more.
  31. 根据权利要求30所述的化合物，其中，J 1，J 2，和J 3各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合； The compound of claim 30, wherein J 1 , J 2 , and J 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing;
    其中，m1，m2，和m3各自独立地选自以下组：0、1、2和3。wherein m1, m2, and m3 are each independently selected from the group: 0, 1, 2, and 3.
  32. 根据权利要求30-31中任一项所述的化合物，其中，X 1，X 2，和X 3各自独立地选自以下组：-NH-和-O-。 The compound of any one of claims 30-31, wherein X1, X2, and X3 are each independently selected from the group consisting of -NH- and -O-.
  33. 根据权利要求30-32中任一项所述的化合物，其中，K 1，K 2，和K 3各自独立地选自以下组：链烷基，和聚乙二醇，或前述任意组合；其中，n1，n2，和n3各自独立地选自以下组：0、1、2和3。 The compound of any one of claims 30-32, wherein K 1 , K 2 , and K 3 are each independently selected from the group consisting of alkane, and polyethylene glycol, or any combination of the foregoing; wherein , n1, n2, and n3 are each independently selected from the group: 0, 1, 2, and 3.
  34. 根据权利要求30-33中任一项所述的化合物，其中，(K 1) n1，(K 2) n2，和(K 3) n3各自独立地选自以下组：-链烷基-聚乙二醇-链烷基-，链烷基和聚乙二醇，或n1，n2或n3各自独立地为0。 The compound of any one of claims 30-33, wherein (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: - alkane-polyethylene Diol-alkyi-, alkane and polyethylene glycol, or n1, n2 or n3 are each independently zero.
  35. 根据权利要求30-34中任一项所述的化合物，其中，(K 1) n1，(K 2) n2，和(K 3) n3各自独立地选自以下组：-(CH 2)-(CH 2-O-CH 2) 3-(CH 2)-，-(CH 2) 2-(CH 2-O-CH 2) 3-(CH 2) 2-，-(CH 2) 2-，和-(CH 2) 8-，或n1，n2或n3各自独立地为0。 The compound of any one of claims 30-34, wherein (K 1 ) n1 , (K 2 ) n2 , and (K 3 ) n3 are each independently selected from the group consisting of: -(CH 2 )-( CH 2 -O-CH 2 ) 3 -(CH 2 )-, -(CH 2 ) 2 -(CH 2 -O-CH 2 ) 3 -(CH 2 ) 2 -, -(CH 2 ) 2 -, and -(CH 2 ) 8 -, or n1, n2 or n3 are each independently 0.
  36. 根据权利要求30-35中任一项所述的化合物，其中，Y 1，Y 2，和Y 3各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-；R 1，R 1a和R 1b各自独立地选自以下组：氢，氕，氘，氚，和链烷基；其中，n1，n2，和n3各自独立地选自以下组：0、1、2和3。 The compound of any one of claims 30-35, wherein Y 1 , Y 2 , and Y 3 are each independently selected from the group consisting of: -C(=O)-, -NR 1 -C(=O ) - , -NR1-, and -O- ; R1, R1a , and R1b are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; wherein, n1, n2, and n3 Each is independently selected from the group: 0, 1, 2, and 3.
  37. 根据权利要求30-36中任一项所述的化合物，其中，(Y 1) p1，(Y 2) p2，和(Y 3) p3各自独立地选自以下组：-C(＝O)-，-NR 1-C(＝O)-，-NR 1-，和-O-，R 1选自以下组：氢，氕，氘，氚，和链烷基；或p1，p2或p3各自独立地为0。 The compound of any one of claims 30-36, wherein (Y 1 ) p1 , (Y 2 ) p2 , and (Y 3 ) p3 are each independently selected from the group consisting of: -C(=O)- , -NR 1 -C(=O)-, -NR 1 -, and -O-, R 1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and alkane; or p1, p2 or p3 are each independently ground is 0.
  38. 根据权利要求30-37中任一项所述的化合物，其中，L 1，L 2，和L 3各自独立地选自以下组：链烷基，和芳基，或前述任意组合；其中，q1，q2，和q3各自独立地选自以下组：0、1、2和3。 The compound of any one of claims 30-37, wherein L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, and aryl, or any combination of the foregoing; wherein q1 , q2, and q3 are each independently selected from the group consisting of 0, 1, 2, and 3.
  39. 根据权利要求30-38中任一项所述的化合物，其中，(L 1) q1，(L 2) q2，和(L 3) q3各自独立地选自以下组：-链烷基-芳基-，链烷基和聚乙二醇，或q1，q2和q3各自独立地为0。 The compound of any one of claims 30-38, wherein (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of: - alkane-aryl -, alkane and polyethylene glycol, or q1, q2 and q3 are each independently zero.
  40. 根据权利要求30-39中任一项所述的化合物，其中，(L 1) q1，(L 2) q2，和(L 3) q3各自独立地选自以下组：-CH 2-芳基-，-(CH 2) 2-，和-CH 2-，或q1，q2和q3各自独立地为0。 The compound of any one of claims 30-39, wherein (L 1 ) q1 , (L 2 ) q2 , and (L 3 ) q3 are each independently selected from the group consisting of: -CH 2 -aryl- , -(CH 2 ) 2 -, and -CH 2 -, or q1, q2 and q3 are each independently 0.
  41. 根据权利要求30-40中任一项所述的化合物，其中：The compound of any one of claims 30-40, wherein:
    W选自以下组：W is selected from the following group:
    Figure PCTCN2021130337-appb-100251
    三价的链烷基，三价的环烷基，三价的杂环烷基，三价的烯基，三价的炔基，三价的芳基，和三价的杂芳基。
    Figure PCTCN2021130337-appb-100251
    Trivalent alkane, trivalent cycloalkyl, trivalent heterocycloalkyl, trivalent alkenyl, trivalent alkynyl, trivalent aryl, and trivalent heteroaryl.
  42. 根据权利要求30-41中任一项所述的化合物，其中：The compound of any one of claims 30-41, wherein:
    W选自以下组：W is selected from the following group:
    Figure PCTCN2021130337-appb-100252
    Figure PCTCN2021130337-appb-100252
    所述X 1，X 2，X 3，X 4，X 5，X 6，X 7，X 8，X 9，X 10，X 11，X 12，X 13，X 14，X 15，X 16，X 17和X 18各自独立地选自以下组：C，N，O，S，P，CH，CH 2，NH，P(O)和P(S)； The X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 and X 18 are each independently selected from the group consisting of C, N, O, S, P, CH, CH 2 , NH, P(O) and P(S);
    所述---表示双键或单键。The --- represents a double bond or a single bond.
  43. 根据权利要求30-42中任一项所述的化合物，其中：The compound of any one of claims 30-42, wherein:
    W选自以下组：W is selected from the following group:
    Figure PCTCN2021130337-appb-100253
    Figure PCTCN2021130337-appb-100253
    Figure PCTCN2021130337-appb-100254
    Figure PCTCN2021130337-appb-100254
    Figure PCTCN2021130337-appb-100255
    Figure PCTCN2021130337-appb-100255
  44. 根据权利要求23-43中任一项所述的化合物，其中P 1，P 2和P 3各自独立地选自以下组：核酸分子、染料分子、细胞因子、抗原、和抗体或其抗原结合片段，或前述任意组合。 The compound of any one of claims 23-43 , wherein P1, P2, and P3 are each independently selected from the group consisting of nucleic acid molecules, dye molecules, cytokines, antigens, and antibodies or antigen-binding fragments thereof , or any combination of the foregoing.
  45. 根据权利要求44所述的化合物，其中所述抗体选自下组：单克隆抗体、单链抗体、嵌合抗体、人源化抗体、全人源抗体和纳米抗体。The compound of claim 44, wherein the antibody is selected from the group consisting of monoclonal antibodies, single chain antibodies, chimeric antibodies, humanized antibodies, fully human antibodies, and nanobodies.
  46. 根据权利要求44-45中任一项所述的化合物，其中所述抗体靶向选自下组的靶点：4-1BB、EGFR、CD3、Her2、CD47和CD20。The compound of any one of claims 44-45, wherein the antibody targets a target selected from the group consisting of 4-1BB, EGFR, CD3, Her2, CD47, and CD20.
  47. 根据权利要求44-46中任一项所述的化合物，其中所述抗体的氨基酸序列选自以下组：SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:10、SEQ ID NO:11、和SEQ ID NO:12。The compound of any one of claims 44-46, wherein the amino acid sequence of the antibody is selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 10 , SEQ ID NO: 11, and SEQ ID NO: 12.
  48. 根据权利要求23-47中任一项所述的化合物，其选自以下组：The compound of any one of claims 23-47, which is selected from the group consisting of:
    Figure PCTCN2021130337-appb-100256
    Figure PCTCN2021130337-appb-100256
    Figure PCTCN2021130337-appb-100257
    Figure PCTCN2021130337-appb-100257
    其中，P 1，P 2和P 3各自独立地选自靶向选自下组的靶点的抗体：4-1BB、EGFR、CD3、Her2、CD47和CD20。 wherein P1, P2 and P3 are each independently selected from antibodies targeting a target selected from the group consisting of 4-1BB, EGFR, CD3, Her2, CD47 and CD20.
  49. 根据权利要求23-48中任一项所述的化合物，其为：The compound of any one of claims 23-48, which is:
    Figure PCTCN2021130337-appb-100258
    Figure PCTCN2021130337-appb-100258
    其中，P 1，P 2和P 3的氨基酸序列分别为SEQ ID NO:1、SEQ ID NO:2、和SEQ ID NO:3，或SEQ ID NO:1、SEQ ID NO:10、和SEQ ID NO:3，或SEQ ID NO:1、SEQ ID NO:11、和SEQ ID NO:3，或SEQ ID NO:1、SEQ ID NO:12、和SEQ ID NO:3。 Wherein, the amino acid sequences of P 1 , P 2 and P 3 are respectively SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, or SEQ ID NO:1, SEQ ID NO:10, and SEQ ID NO:3, or SEQ ID NO:1, SEQ ID NO:11, and SEQ ID NO:3, or SEQ ID NO:1, SEQ ID NO:12, and SEQ ID NO:3.
  50. 一种权利要求1-22中任一项所述的化合物的制备方法，其包括：A preparation method of the compound described in any one of claim 1-22, it comprises:
    使式(Ia-I)所示的化合物与反应物1、反应物2和反应物3反应；The compound represented by formula (Ia-I) is reacted with reactant 1, reactant 2 and reactant 3;
    或使式(Ia-I)所示的化合物与反应物1和反应物2反应；Or make the compound shown in formula (Ia-I) react with reactant 1 and reactant 2;
    或使式(Ia-I)所示的化合物与反应物1反应；Or make the compound represented by formula (Ia-I) react with reactant 1;
    Figure PCTCN2021130337-appb-100259
    Figure PCTCN2021130337-appb-100259
    所述反应物1为H-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-A， The reactant 1 is HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -A,
    所述反应物2为H-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-B， The reactant 2 is HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -B,
    所述反应物3为H-X 1-(K 1) n1-(Y 1) p1-(L 1) q1-C， The reactant 3 is HX 1 -(K 1 ) n1 -(Y 1 ) p1 -(L 1 ) q1 -C,
    所述W为三价基团，所述W任选地被一个或多个R取代，The W is a trivalent group, the W is optionally substituted with one or more R,
    所述J 1，J 2，J 3，K 1，K 2，K 3，L 1，L 2，和L 3各自独立地选自以下组：链烷基，环烷基，杂环烷基，烯基，炔基，芳基，杂芳基，和聚乙二醇，或前述任意组合； The J 1 , J 2 , J 3 , K 1 , K 2 , K 3 , L 1 , L 2 , and L 3 are each independently selected from the group consisting of alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and polyethylene glycol, or any combination of the foregoing;
    所述X 1，X 2，X 3，Y 1，Y 2，和Y 3各自独立地选自以下组：-NR 1-，-O-，-S-，-C(＝O)-，-C(＝S)-，-C(R 1a)(R 1b)-，-NR 1-C(＝O)-，-C(＝O)-NR 1-，-NR 1-C(＝S)-，-C(＝S)-NR 1-，-O-C(＝O)-，-C(＝O)-O-，-O-C(＝S)-，-C(＝S)-O-，-O-C(＝O)-O-，-O-C(＝O)-NR 1-，-NR 1-C(＝O)-O-，和-NR 1a-C(＝O)-NR 1b-； Said X 1 , X 2 , X 3 , Y 1 , Y 2 , and Y 3 are each independently selected from the group consisting of: -NR 1 -, -O-, -S-, -C(=O)-, - C(=S)-, -C(R 1a )(R 1b )-, -NR 1 -C(=O)-, -C(=O)-NR 1 -, -NR 1 -C(=S) -, -C(=S)-NR 1 -, -OC(=O)-, -C(=O)-O-, -OC(=S)-, -C(=S)-O-, - OC(=O)-O-, -OC(=O)-NR 1 -, -NR 1 -C(=O)-O-, and -NR 1a -C(=O)-NR 1b -;
    R，R 1，R 1a和R 1b各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基； R, R 1 , R 1a and R 1b are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxy, alkoxy, amino, amido, ester, sulfonamide radical, urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl;
    其中，m1，m2，m3，n1，n2，n3，p1，p2，p3，q1，q2，和q3各自独立地选自0以上的数；wherein, m1, m2, m3, n1, n2, n3, p1, p2, p3, q1, q2, and q3 are each independently selected from a number greater than 0;
    A，B和C各自独立地选自以下组：A, B and C are each independently selected from the following group:
    Figure PCTCN2021130337-appb-100260
    Figure PCTCN2021130337-appb-100261
    Figure PCTCN2021130337-appb-100260
    Figure PCTCN2021130337-appb-100261
    其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基； wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl;
    其中，A，B和C中，
    Figure PCTCN2021130337-appb-100262
    不能和
    Figure PCTCN2021130337-appb-100263
    同时存在；     Among them, A, B and C,
    Figure PCTCN2021130337-appb-100262
    cannot and
    Figure PCTCN2021130337-appb-100263
    simultaneously exist;
    其中，A，B和C中，
    Figure PCTCN2021130337-appb-100264
    不能和
    Figure PCTCN2021130337-appb-100265
    Figure PCTCN2021130337-appb-100266
    同时存在；     Among them, A, B and C,
    Figure PCTCN2021130337-appb-100264
    cannot and
    Figure PCTCN2021130337-appb-100265
    Figure PCTCN2021130337-appb-100266
    simultaneously exist;
    其中，A，B和C中，
    Figure PCTCN2021130337-appb-100267
    不能和
    Figure PCTCN2021130337-appb-100268
    同时存在；     Among them, A, B and C,
    Figure PCTCN2021130337-appb-100267
    cannot and
    Figure PCTCN2021130337-appb-100268
    simultaneously exist;
    当A，B和C中，
    Figure PCTCN2021130337-appb-100269
    同时存在时，所述R 12，R 13和R 14不为炔基；     When A, B and C,
    Figure PCTCN2021130337-appb-100269
    When present at the same time, the R 12 , R 13 and R 14 are not alkynyl;
    当A，B和C中，
    Figure PCTCN2021130337-appb-100270
    同时存在时，所述R 12，R 13和R 14不为氨基，     When A, B and C,
    Figure PCTCN2021130337-appb-100270
    When present at the same time, the R 12 , R 13 and R 14 are not amino groups,
    A，B和C不同时为
    Figure PCTCN2021130337-appb-100271
    A, B and C are not simultaneously
    Figure PCTCN2021130337-appb-100271
    其中，当A、B，或C为
    Figure PCTCN2021130337-appb-100272
    时，在所述式(Ia-I)所示的化合物与反应物1、反应物2或反应物3反应前，将
    Figure PCTCN2021130337-appb-100273
    替换为
    Figure PCTCN2021130337-appb-100274
    在所述式(Ia-I)所示的化合物与反应物1、反应物2或反应物3反应后，加入酸进行Boc脱除。     where, when A, B, or C is
    Figure PCTCN2021130337-appb-100272
    , before the compound represented by the formula (Ia-I) reacts with reactant 1, reactant 2 or reactant 3, the
    Figure PCTCN2021130337-appb-100273
    replace with
    Figure PCTCN2021130337-appb-100274
    After the compound represented by the formula (Ia-I) reacts with reactant 1, reactant 2 or reactant 3, an acid is added to remove Boc.
  51. 根据权利要求50所述的制备方法，根据A、B和C的引入顺序决定反应物1、反应物2和反应物3的加入顺序，所述A、B和C的引入顺序从先到后依次为：
    Figure PCTCN2021130337-appb-100275
    Figure PCTCN2021130337-appb-100276
    According to the preparation method of claim 50, the order of addition of reactant 1, reactant 2 and reactant 3 is determined according to the introduction order of A, B and C, and the introduction order of A, B and C is from first to last. for:
    Figure PCTCN2021130337-appb-100275
    Figure PCTCN2021130337-appb-100276
    其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基。 wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl.
  52. 一种权利要求23-49中任一项所述的化合物的制备方法，其包括：A preparation method of the compound described in any one of claim 23-49, it comprises:
    使权利要求1-22中任一项中式Ia所述的化合物与反应物4、反应物5和反应物6反应；Making the compound described in formula Ia in any one of claim 1-22 react with reactant 4, reactant 5 and reactant 6;
    所述反应物4为A 1-P 1， The reactant 4 is A 1 -P 1 ,
    所述反应物5为B 1-P 2， The reactant 5 is B 1 -P 2 ,
    所述反应物6为C 1-P 3， The reactant 6 is C 1 -P 3 ,
    其中，反应物4的A 1与式Ia所述的化合物的A反应，反应物5的B 1与式Ia所述的化合物的B反应，反应物6的C 1与式Ia所述的化合物的C反应； Wherein, A 1 of reactant 4 reacts with A of the compound described in formula Ia, B 1 of reactant 5 reacts with B of the compound described in formula Ia, and C 1 of reactant 6 reacts with the compound described in formula Ia C reaction;
    当A、B或C至少有一个为
    Figure PCTCN2021130337-appb-100277
    时，A 1，B 1或C 1至少有一个为
    Figure PCTCN2021130337-appb-100278
    when at least one of A, B or C is
    Figure PCTCN2021130337-appb-100277
    , at least one of A 1 , B 1 or C 1 is
    Figure PCTCN2021130337-appb-100278
    当A、B或C至少有一个为
    Figure PCTCN2021130337-appb-100279
    时，对应的A 1，B 1或C 1至少有一个为
    Figure PCTCN2021130337-appb-100280
    Figure PCTCN2021130337-appb-100281
    when at least one of A, B or C is
    Figure PCTCN2021130337-appb-100279
    , at least one of the corresponding A 1 , B 1 or C 1 is
    Figure PCTCN2021130337-appb-100280
    Figure PCTCN2021130337-appb-100281
    当A、B或C至少有一个为
    Figure PCTCN2021130337-appb-100282
    时，对应的A 1，B 1或C 1至少有一个为
    Figure PCTCN2021130337-appb-100283
    when at least one of A, B or C is
    Figure PCTCN2021130337-appb-100282
    , at least one of the corresponding A 1 , B 1 or C 1 is
    Figure PCTCN2021130337-appb-100283
    当A、B或C至少有一个为
    Figure PCTCN2021130337-appb-100284
    时，对应的A 1，B 1或C 1至少有一个为
    Figure PCTCN2021130337-appb-100285
    when at least one of A, B or C is
    Figure PCTCN2021130337-appb-100284
    , at least one of the corresponding A 1 , B 1 or C 1 is
    Figure PCTCN2021130337-appb-100285
    当A、B或C至少有一个为
    Figure PCTCN2021130337-appb-100286
    时，对应的A 1，B 1或C 1至少有一个为
    Figure PCTCN2021130337-appb-100287
    when at least one of A, B or C is
    Figure PCTCN2021130337-appb-100286
    , at least one of the corresponding A 1 , B 1 or C 1 is
    Figure PCTCN2021130337-appb-100287
    当A、B或C至少有一个为
    Figure PCTCN2021130337-appb-100288
    时，对应的A 1，B 1或C 1至少有一个为
    Figure PCTCN2021130337-appb-100289
    when at least one of A, B or C is
    Figure PCTCN2021130337-appb-100288
    , at least one of the corresponding A 1 , B 1 or C 1 is
    Figure PCTCN2021130337-appb-100289
    当A、B或C至少有一个为
    Figure PCTCN2021130337-appb-100290
    时，对应的A 1，B 1或C 1至少有一个为
    Figure PCTCN2021130337-appb-100291
    when at least one of A, B or C is
    Figure PCTCN2021130337-appb-100290
    , at least one of the corresponding A 1 , B 1 or C 1 is
    Figure PCTCN2021130337-appb-100291
    当A、B或C至少有一个为
    Figure PCTCN2021130337-appb-100292
    时，对应的A 1，B 1或C 1至少有一个为
    Figure PCTCN2021130337-appb-100293
    when at least one of A, B or C is
    Figure PCTCN2021130337-appb-100292
    , at least one of the corresponding A 1 , B 1 or C 1 is
    Figure PCTCN2021130337-appb-100293
    当A、B或C至少有一个为
    Figure PCTCN2021130337-appb-100294
    时，对应的A 1，B 1或C 1至少有一个为
    Figure PCTCN2021130337-appb-100295
    when at least one of A, B or C is
    Figure PCTCN2021130337-appb-100294
    , at least one of the corresponding A 1 , B 1 or C 1 is
    Figure PCTCN2021130337-appb-100295
    当A、B或C至少有一个为
    Figure PCTCN2021130337-appb-100296
    时，对应的A 1，B 1或C 1至少有一个为
    Figure PCTCN2021130337-appb-100297
    when at least one of A, B or C is
    Figure PCTCN2021130337-appb-100296
    , at least one of the corresponding A 1 , B 1 or C 1 is
    Figure PCTCN2021130337-appb-100297
    当A、B或C至少有一个为
    Figure PCTCN2021130337-appb-100298
    时，对应的A 1，B 1或C 1至少有一个为
    Figure PCTCN2021130337-appb-100299
    when at least one of A, B or C is
    Figure PCTCN2021130337-appb-100298
    , at least one of the corresponding A 1 , B 1 or C 1 is
    Figure PCTCN2021130337-appb-100299
    当A、B或C至少有一个为
    Figure PCTCN2021130337-appb-100300
    时，对应的A 1，B 1或C 1至少有一个为
    Figure PCTCN2021130337-appb-100301
    when at least one of A, B or C is
    Figure PCTCN2021130337-appb-100300
    , at least one of the corresponding A 1 , B 1 or C 1 is
    Figure PCTCN2021130337-appb-100301
    其中R 12，R 13和R 14各自独立地选自以下组：氢，氕，氘，氚，卤素，硝基，氰基，羟基，烷氧基，氨基，酰胺基，酯基，磺酰胺基，脲，链烷基，环烷基，杂环烷基，烯基，炔基，芳基，和杂芳基。 wherein R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, nitro, cyano, hydroxyl, alkoxy, amino, amido, ester, sulfonamido , urea, alkane, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl.
  53. 根据权利要求52所述的制备方法，The preparation method according to claim 52,
    其中，
    Figure PCTCN2021130337-appb-100302
    的反应中加入Cu +作为催化剂。     in,
    Figure PCTCN2021130337-appb-100302
    Cu + was added as a catalyst in the reaction.
  54. 根据权利要求52-53中任一项所述的制备方法，The preparation method according to any one of claims 52-53,
    其中，
    Figure PCTCN2021130337-appb-100303
    的反应中加入1-100％当量的SrtA连接酶作为催化剂。     in,
    Figure PCTCN2021130337-appb-100303
    1-100% equivalent of SrtA ligase was added as a catalyst to the reaction.
  55. 一种药物组合物，其含有权利要求1-49中任一项的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，和药学上可接受的载体。A pharmaceutical composition comprising a compound of any one of claims 1-49 or a tautomer, meso, racemate, enantiomer, diastereomer, or tautomer, meso, racemate, enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  56. 一种试剂盒，其包含权利要求1-49中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，和/或权利要求55所述的药物组合物。A kind of test kit, it comprises the compound described in any one of claim 1-49 or its tautomer, meso, racemate, enantiomer, diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof, and/or the pharmaceutical composition of claim 55.
  57. 含有权利要求1-49中任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物形式，或其可药用的盐，权利要求55所述的药物组合物和/或权利要求56所述的试剂盒在制备用于治疗和/或预防肿瘤的药物中的用途。Contains the compound of any one of claims 1-49, or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, use of the pharmaceutical composition of claim 55 and/or the kit of claim 56 in the preparation of a medicament for treating and/or preventing tumors.
  58. 根据权利要求57所述的用途，所述肿瘤选自与以下组表达相关的肿瘤：4-1BB、EGFR、CD3、Her2、CD47和CD20。The use of claim 57, wherein the tumor is selected from the group consisting of tumors associated with the expression of 4-1BB, EGFR, CD3, Her2, CD47 and CD20.
  59. 根据权利要求57-58中任一项所述的用途，所述肿瘤选自以下组：实体瘤和血液癌。The use of any one of claims 57-58, wherein the tumor is selected from the group consisting of solid tumors and hematological cancers.
  60. 根据权利要求57-59中任一项所述的用途，所述肿瘤选自以下组：肺癌、肾癌、尿道癌、结肠直肠癌、前列腺癌、多形性成胶质细胞瘤、卵巢癌、胰腺癌、乳腺癌、黑色素瘤、肝癌、膀胱癌、胃癌和食道癌。The use of any one of claims 57-59, wherein the tumor is selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, Pancreatic, breast, melanoma, liver, bladder, stomach and esophageal cancers.
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