WO2023207710A1 - 一类抗体药物偶联物、其药物组合物及应用 - Google Patents

一类抗体药物偶联物、其药物组合物及应用 Download PDF

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Publication number
WO2023207710A1
WO2023207710A1 PCT/CN2023/089224 CN2023089224W WO2023207710A1 WO 2023207710 A1 WO2023207710 A1 WO 2023207710A1 CN 2023089224 W CN2023089224 W CN 2023089224W WO 2023207710 A1 WO2023207710 A1 WO 2023207710A1
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Prior art keywords
compound
preparation
reaction
μmol
antibody
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PCT/CN2023/089224
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English (en)
French (fr)
Chinese (zh)
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WO2023207710A9 (zh
Inventor
刘金明
任云
何婷
田强
宋宏梅
葛均友
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Application filed by Sichuan Kelun Biotech Biopharmaceutical Co Ltd filed Critical Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority to MX2024010601A priority Critical patent/MX2024010601A/es
Priority to KR1020247029208A priority patent/KR20250002133A/ko
Priority to CA3253667A priority patent/CA3253667A1/en
Priority to CN202380024259.7A priority patent/CN118829451A/zh
Priority to US18/844,739 priority patent/US20250195683A1/en
Priority to JP2024551558A priority patent/JP2025513163A/ja
Priority to EP23795143.9A priority patent/EP4516321A1/en
Priority to AU2023260131A priority patent/AU2023260131A1/en
Publication of WO2023207710A1 publication Critical patent/WO2023207710A1/zh
Publication of WO2023207710A9 publication Critical patent/WO2023207710A9/zh
Anticipated expiration legal-status Critical
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    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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Definitions

  • This application belongs to the field of medicine, and specifically relates to a type of antibody-drug conjugate, its pharmaceutical composition and application.
  • Antibody-drug conjugate couples antibodies and small molecule cytotoxic drugs through specific linkers.
  • the antibody serves as a carrier to transport small molecule drugs into target cells, thereby reducing systemic exposure. Improving safety is a hot topic in the research and development of targeted tumor therapy.
  • ISAC immunostimulating antibody conjugate
  • Combination medication is, on the one hand, the combined use of two existing drugs, such as the combination of cytotoxic drugs and immunostimulants, and on the other hand, the combination of two active ingredients to form a new single drug.
  • bifunctional load immunostimulatory antibody drug conjugates obtained by coupling cytotoxic drugs and immunostimulants to antibodies can simultaneously enter tumor cells and tumor microenvironment immunity. cells, exerting the dual effects of tumor killing of cytotoxic drugs and local immune activation of immune stimulators, thereby improving the efficacy of antibody drug conjugates in treating cancer.
  • the present invention is a bifunctional loaded immunostimulatory antibody drug conjugate obtained by coupling cytotoxic drugs and TLR agonists to antibodies. It can enter tumor cells and tumor microenvironment immune cells at the same time, exerting the tumor killing and killing effects of cytotoxic drugs.
  • the dual effects of local immune activation of TLR agonists have improved cancer treatment effects compared with antibody drug conjugates coupled with cytotoxic drugs alone.
  • the present invention provides an antibody drug conjugate represented by formula (I):
  • Ab is the targeting group
  • M is the linker site connected to the targeting group
  • X is the linker connecting M and Aa;
  • Aa is an amino acid fragment or a peptide fragment formed from two or more amino acids
  • L 1 is a covalent bond or a linker connecting Aa and D 1 ;
  • L 2 is the linker connecting Aa and D 2 ;
  • D 1 is selected from cytotoxic drug fragments
  • D 2 is selected from TLR agonist fragments
  • n is selected from 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • the Ab is a targeting group that can target an antigen of interest to a cell surface receptor or a tumor surface antigen.
  • the Ab is an antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment includes a monoclonal antibody, a polyclonal antibody, a linear antibody, a bispecific antibody, a multispecific antibody, a chimeric antibody, a murine Source antibodies, humanized antibodies, fully human antibodies, and fusion proteins containing the antigen-binding portion of the antibody.
  • the Ab is an antibody or an antigen-binding fragment thereof, wherein the antigen-binding fragment is selected from the group consisting of Fab, Fab', F(ab') 2 , Fv, disulfide-linked Fv, and scFv.
  • the antibody or antigen-binding fragment thereof is selected from the group consisting of anti-Her-2 antibody, anti-EGFR antibody, anti-VEGFR antibody, anti-PD-L1 antibody, anti-PD-1 antibody, anti-CTLA -4 antibodies and anti-Trop-2 antibodies.
  • the antibody or antigen-binding fragment thereof is Trastuzumab.
  • M is a covalent bond or selected from the following structures:
  • each a is independently selected from an integer of 1-5
  • b is selected from an integer of 1-3
  • the 1 position of M is connected to Ab
  • the 2 position is connected to X.
  • M is a covalent bond or selected from the following structures:
  • each a is independently selected from an integer of 1-5
  • b is selected from an integer of 1-3
  • the 1 position of M is connected to Ab
  • the 2 position is connected to X.
  • M is a covalent bond or selected from the following structures:
  • M is a covalent bond or selected from the following structures:
  • M is a covalent bond or selected from the following structures:
  • X is a covalent bond or selected from C 1-6 alkylene, -NH-(CH 2 ) c -C(O)-,
  • each c is independently selected from an integer from 1 to 10; the 3 position of X is connected to M, and the 4 position is connected to Aa.
  • X is a covalent bond
  • each c is independently selected from an integer from 1 to 10 (for example, an integer from 5 to 10, another example from 8 to 10); the 3 position of X is connected to M, and the 4 position is connected to Aa.
  • Aa is selected from amino acid fragments and peptide fragments formed from two or more amino acids, wherein the amino acids are selected from Gly, Phe, Ala, Val, Ser, Thr, His, Trp, Cys, Asp , Glu, Lys, Tyr and Arg, optionally, each amino acid is independently modified by a C 1-6 alkyl or polyethylene glycol hydrophilic structural unit.
  • the polyethylene glycol hydrophilic structural units are selected from Each c is independently selected from an integer of 1-10 (for example, an integer of 5-10, and another example of an integer of 8-10).
  • Aa is selected from fragments of the following amino acids and peptide fragments formed from any combination of two or more of them: Gly, Phe, Ala, Val, Cys, Asp, Glu, Lys, and Arg, and Each amino acid is independently optionally modified with a C 1-6 alkyl or polyethylene glycol hydrophilic structural unit.
  • the polyethylene glycol hydrophilic structural units are selected from Each c is independently selected from an integer of 1-10 (for example, an integer of 5-10, and another example of an integer of 8-10).
  • Aa is selected from fragments of the following amino acids and peptide fragments formed by any combination of two or more of them: Val, Cys, Asp, Glu and Lys, wherein the Glu and Lys carboxyl termini are optional ground cover Modification, wherein each c is independently selected from an integer of 1-10 (for example, an integer of 5-10, another example is an integer of 8-10).
  • Aa is selected from the following structures:
  • each R 7 is independently selected from H, C 1-6 alkyl and polyethylene glycol hydrophilic structural units; each R 8 is independently selected from hydroxyl and polyethylene glycol hydrophilic structural units; the 5 position is connected to X , the 6 position is connected to one of L 1 and L 2 , and the 7 position is connected to the other of L 1 and L 2 .
  • position 5 is connected to X
  • position 6 is connected to L 1
  • position 7 is connected to L 2 .
  • position 5 is connected to X
  • position 6 is connected to L 2
  • position 7 is connected to L 1 .
  • the polyethylene glycol hydrophilic structural units are selected from Each c is independently selected from an integer of 1-10 (for example, an integer of 5-10, and another example of an integer of 8-10).
  • R 7 is H.
  • Aa is selected from the following structures:
  • each R 7 is independently selected from H, C 1-6 alkyl and polyethylene glycol hydrophilic structural units; each R 8 is independently selected from hydroxyl and polyethylene glycol hydrophilic structural units; the 5 position is connected to X , position 6 is connected to one of L 1 and L 2 , position 7 is connected to the other of L 1 and L 2 ; preferably, position 5 is connected to X, position 6 is connected to L 1 , and position 7 is connected to L 2 .
  • the polyethylene glycol hydrophilic structural units are selected from Each c is independently selected from an integer of 1-10 (for example, an integer of 5-10, and another example of an integer of 8-10).
  • L is a covalent bond or is selected from the group consisting of a non-cleavable linker and a cleavable linker, wherein the cleavable linker is cleaved by an enzyme present in a pathological environment selected from the group consisting of proteases, phosphatases, Pyrophosphatase, ⁇ -glucuronidase, ⁇ -galactosidase, and sulfatase.
  • L 1 is a covalent bond or -L a -L b -L c -, where:
  • L a is a covalent bond or selected from C 1-6 alkylene, -NH-(CH 2 ) c -C(O)-, Wherein, each c is independently selected from an integer from 1 to 10;
  • L b is a covalent bond or selected from amino acid fragments and peptide fragments formed from two or more amino acids, wherein the amino acids are selected from Val, Cit, Glu, Lys, Arg, Phe, Leu, Gly, Ala and Asn ;
  • L c is a covalent bond, -NH-CH 2 - or selected from the following structures:
  • L 1 is a covalent bond or -L a -L b -L c -, where:
  • L a is a covalent bond or selected from C 1-6 alkylene, -NH-(CH 2 ) c -C(O)-, Wherein, each c is independently selected from an integer from 1 to 10;
  • L b is a covalent bond or selected from amino acid fragments and peptide fragments formed from two or more amino acids, wherein the amino acids are selected from Val, Cit, Glu, Lys, Arg, Phe, Leu, Gly, Ala and Asn ;
  • L c is a covalent bond, -NH-CH 2 - or selected from the following structures:
  • La is a covalent bond or selected from Wherein, each c is independently selected from an integer of 1-10.
  • L b is a covalent bond or is selected from the following structures:
  • R 9 is selected from H, acetyl, fluorenyloxycarbonyl, trityl and polyethylene glycol hydrophilic structural units.
  • the polyethylene glycol hydrophilic structural unit is Each c is independently selected from an integer of 1-10.
  • L c is -NH-CH 2 - or
  • L 1 is a covalent bond or -L a -L b -L c -, where:
  • L a is a covalent bond or selected from Wherein, each c is independently selected from an integer from 1 to 10;
  • L b is a covalent bond or selected from
  • L c is -NH-CH 2 -or
  • L is a covalent bond or is selected from the following structures:
  • position 8 is connected to Aa, and position 9 is connected to D 1 .
  • L is a covalent bond or is selected from the following structures:
  • position 8 is connected to Aa, and position 9 is connected to D 1 .
  • L is :
  • position 8 is connected to Aa, and position 9 is connected to D 1 .
  • L is :
  • position 8 is connected to Aa, and position 9 is connected to D 1 .
  • L is :
  • position 8 is connected to Aa, and position 9 is connected to D 1 .
  • L2 is selected from the group consisting of a non-cleavable linker and a cleavable linker, wherein the cleavable linker is cleaved by an enzyme present in a pathological environment selected from the group consisting of protease, phosphatase, pyrophosphatase, beta -Glucuronidase, beta-galactosidase and sulfatase.
  • L2 is -Ld - Le - Lf- , wherein:
  • L d is a covalent bond or a divalent structure selected from one or more of the following: C 1-6 alkylene, -C(O)-(CH 2 ) d -NH-, Wherein, each d is independently selected from an integer from 1 to 12;
  • L e is a covalent bond or selected from amino acid fragments and peptide fragments formed from two or more amino acids, wherein the amino acids are selected from Val, Cit, Glu, Lys, Arg, Phe, Leu, Gly, Ala and Asn ;
  • L f is a covalent bond, -CH 2 -NH- or selected from the following structures:
  • L2 is -Ld - Le - Lf- , wherein:
  • L d is a covalent bond or a divalent structure selected from one or more of the following: C 1-6 alkylene, -C(O)-(CH 2 ) d -NH-, Wherein, each d is independently selected from an integer from 1 to 12;
  • L e is a covalent bond or selected from amino acid fragments and peptide fragments formed from two or more amino acids, wherein the amino acids are selected from Val, Cit, Glu, Lys, Arg, Phe, Leu, Gly, Ala and Asn ;
  • L f is a covalent bond, -CH 2 -NH- or selected from the following structures:
  • L e is a covalent bond or selected from the following structures:
  • each R 10 is independently selected from H, acetyl, fluorenyloxycarbonyl, trityl and polyethylene glycol hydrophilic structural units; preferably, the polyethylene glycol hydrophilic structural units are Each d is independently selected from an integer from 1 to 10.
  • L is selected from the following structures:
  • position 10 is connected to Aa, and position 11 is connected to D 2 .
  • L is selected from the following structures:
  • position 10 is connected to Aa, and position 11 is connected to D 2 ;
  • L is selected from the following structures:
  • position 10 is connected to Aa, and position 11 is connected to D 2 .
  • L2 is:
  • position 10 is connected to Aa, and position 11 is connected to D2 .
  • L2 is:
  • position 10 is connected to Aa, and position 11 is connected to D2 .
  • D1 is selected from a cytotoxic drug fragment selected from the group consisting of tubulin inhibitors, DNA damaging agents, and topoisomerase inhibitors, including but not limited to Dolastatins, auristatins, maytansines, Tubulysins and cryptomycins
  • the DNA damaging agents include but are not limited to PBDs, ducarmycin (duocarmycin) and calicheamicin (calicheamicin)
  • the topoisomerase inhibitors include but are not limited to camptothecin and its derivatives.
  • the tubulin inhibitor is selected from the group consisting of Aplysia 10, MMAE, MMAF, maytansine, DM1, DM3, and DM4, and the topoisomerase inhibitor is selected from the group consisting of camptothecin, SN- 38. Ixotecan, topotecan, belotecan, 10-hydroxycamptothecin, 9-aminocamptothecin, doxorubicin, epirubicin and PNU-159682.
  • D is selected from the following structures:
  • D2 is a TLR agonist fragment.
  • the TLR agonist is selected from the group consisting of TLR2 agonists, TLR4 agonists, TLR6 agonists, TLR7 agonists, TLR8 agonists, TLR7/8 agonists, and TLR9 agonists.
  • D2 is a TLR agonist fragment selected from the group consisting of a TLR7 agonist, a TLR8 agonist, and a TLR7/8 agonist.
  • D 2 is a TLR agonist fragment
  • the TLR agonist is a compound represented by formula (II):
  • X 1 is selected from N and C;
  • X 2 is selected from N and C;
  • At least one of X 1 and X 2 is selected from N;
  • X 3 is selected from O, S and N;
  • X 4 is selected from O, S, N and CR 4 ;
  • R 1 is selected from C 1-6 alkyl and -C 1-6 alkylene-OC 1-6 alkyl
  • R 2 is selected from hydrogen and the formula -L 3 -L 4 -L 5 -L 6 ;
  • L 3 is selected from covalent bond and C 1-6 alkylene
  • L 4 is selected from covalent bond, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the cycloalkyl, heterocyclyl, aromatic and heteroaryl are optionally substituted by one or more radicals selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy and -C 1-6 alkylene-NH 2 Replaced by regiment;
  • L 5 is selected from covalent bond, -O-, -S-, -C(O)-, -OC(O)-, -C(O)-O-, -OC(O)-O-, -NR 5 -, -C(O)-NR 5 -, -NR 5 -C(O)-, -OC(O)-NR 5 -, -NR 5 -C(O)-O-, -NR 5 -C (O)-NR 5 -, -S(O) r -NR 5 -, -NR 5 -S(O) r -, and -NR 5 -S(O) r -NR 5 -;
  • L 6 is selected from hydrogen, C 1-6 alkyl, -(O-CH 2 CH 2 ) n -OC 1-6 alkyl and -C 1-6 alkylene-(O-CH 2 CH 2 ) n - OC 1-6 alkyl, the alkyl is optionally replaced by one or more hydrogen, halogen, hydroxyl, -NH 2 , -NH-C(O)-OC 1-6 alkyl, C 1-6 Substituted by alkoxy, carboxyl and -C(O)-OC 1-6 alkyl groups;
  • R 3 is selected from hydrogen and the formula -L 7 -L 8 -L 9 -L 10 ;
  • L 7 is selected from covalent bond and C 1-6 alkylene
  • L 8 is selected from covalent bond, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the cycloalkyl, heterocyclyl, aromatic and heteroaryl are optionally substituted by one or more radicals selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy and -C 1-6 alkylene-NH 2 Replaced by regiment;
  • L 9 is selected from covalent bond, -O-, -S-, -C(O)-, -OC(O)-, -C(O)-O-, -OC(O)-O-, -NR 6 -, -C(O)-NR 6 -, -NR 6 -C(O)-, -OC(O)-NR 6 -, -NR 6 -C(O)-O-, -NR 6 -C (O)-NR 6 -, -S(O) p -NR 6 -, -NR 6 -S(O) p -, and -NR 6 -S(O) p -NR 6 -;
  • L 10 is selected from hydrogen, C 1-6 alkyl, -(O-CH 2 CH 2 ) q -OC 1-6 alkyl and -C 1-6 alkylene -(O-CH 2 CH 2 ) q - OC 1-6 alkyl, the alkyl is optionally replaced by one or more hydrogen, halogen, hydroxyl, -NH 2 , -NH-C(O)-OC 1-6 alkyl, C 1-6 Substituted by alkoxy, carboxyl and -C(O)-OC 1-6 alkyl groups;
  • R 4 is selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-10 cycloalkyl;
  • Each R 5 is independently selected from hydrogen and C 1-6 alkyl
  • Each R 6 is independently selected from hydrogen and C 1-6 alkyl
  • Each r is independently 1 or 2;
  • n is independently selected from an integer from 1 to 25;
  • Each p is independently 1 or 2;
  • Each q is independently selected from an integer from 1 to 25;
  • D 2 is connected to L 2 through R 2 or R 3 in formula (II).
  • each n is independently selected from 1-15, preferably, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • each q is independently selected from 1-15, preferably, q is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • X3 is selected from S and N.
  • L is selected from covalent bonds and C 1-3 alkylene.
  • L4 is selected from the group consisting of covalent bond, 3-12 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, any of which Optionally substituted with one or more groups selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy and -C 1-6 alkylene-NH 2 .
  • L 5 is selected from covalent bond, -NR 5 -, -C(O)-NR 5 -, -NR 5 -C(O)-, -OC(O)-NR 5 -, - NR 5 -C(O)-O-, -NR 5 -C(O)-NR 5 -, -S(O) r -NR 5 -, -NR 5 -S(O) r - and -NR 5 - S(O) r -NR 5 -, each R 5 is independently selected from hydrogen and C 1-6 alkyl; preferably, L 5 is selected from covalent bond and -NR 5 -, each R 5 is independently selected from hydrogen and C 1-6 alkyl.
  • L 6 is selected from hydrogen, C 1-6 alkyl, and -C 1-6 alkylene-(O-CH 2 CH 2 ) n -OC 1-6 alkyl, which alkyl is either Optionally one or more selected from hydrogen, halogen, hydroxyl, -NH 2 , -NH-C(O)-OC 1-6 alkyl, C 1-6 alkoxy, carboxyl and -C(O)- OC 1-6 alkyl group substituted, n is 1-10.
  • L is selected from a covalent bond and a 3-12 membered heterocyclyl optionally substituted by one or more members selected from the group consisting of hydrogen, halogen, cyano, and C 1-6 alkyl replaced.
  • L9 is a covalent bond.
  • L 10 is selected from hydrogen, C 1-6 alkyl, and -C 1-6 alkylene-(O-CH 2 CH 2 ) q -OC 1-6 alkyl, q is 1-10 .
  • R 3 is selected from hydrogen and the formula -L 7 -L 8 -L 9 -L 10 ;
  • L 8 is selected from covalent bonds and 3-12 membered heterocyclyl groups, which are optionally replaced by one or more members selected from hydrogen, halogen, cyanide Substituted with C 1-6 alkyl group;
  • L 9 is a covalent bond
  • L 10 is selected from hydrogen, C 1-6 alkyl and -C 1-6 alkylene-(O-CH 2 CH 2 ) q -OC 1-6 alkyl;
  • q is selected from 1-10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.
  • X 1 is C
  • X 2 is N
  • X 3 is S
  • X 4 is selected from CR 4 ;
  • R 1 is selected from C 1-6 alkyl
  • R 2 is selected from the formula -L 3 -L 4 -L 5 -L 6 ;
  • L 3 is selected from covalent bond and C 1-6 alkylene
  • L 4 is selected from covalent bond, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the heterocyclyl, aryl and heteroaryl are optionally replaced by one or more Substituted with a group selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy and -C 1-6 alkylene-NH 2 ;
  • L 5 is selected from covalent bonds and -NR 5 -, and each R 5 is independently selected from hydrogen and C 1-6 alkyl;
  • L 6 is selected from hydrogen, C 1-6 alkyl and -C 1-6 alkylene-(O-CH 2 CH 2 ) n -OC 1-6 alkyl, which is optionally replaced by one or more Each is selected from hydrogen, halogen, hydroxyl, -NH 2 , -NH-C(O)-OC 1-6 alkyl, C 1-6 alkoxy, carboxyl and -C(O)-OC 1-6 alkyl replaced by a group.
  • D2 is selected from the following structures:
  • the antibody drug conjugate is selected from the following structures:
  • Each m is independently selected from 1-10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • the Ab is trastuzumab.
  • the antibody drug conjugate has a DAR value of 2.0-5.0, such as 2.0-2.5, 2.0-3.0, 2.0-3.5, 2.0-4.0, 2.0-4.5, 2.0-5.0, 2.5-3.0, 2.5-3.5, 2.5-4.0, 2.5-4.5, 2.5-5.0, 3.0-3.5, 3.0-4.0, 3.0-4.5, 3.0-5.0, 3.5-4.0, 3.5-4.5, 3.5-5.0, 4.0-4.5, 4.0- 5.0, or 4.0-5.0.
  • 2.0-5.0 such as 2.0-2.5, 2.0-3.0, 2.0-3.5, 2.0-4.0, 2.0-4.5, 2.0-5.0, 2.5-3.0, 2.5-3.5, 2.5-4.0, 2.5-4.5, 2.5-5.0, 3.0-3.5, 3.0-4.0, 3.0-4.5, 3.0-5.0, 3.5-4.0, 3.5-4.5, 3.5-5.0, 4.0-4.5, 4.0- 5.0, or 4.0-5.0.
  • the present invention provides a drug-linker simultaneously coupled with a cytotoxic drug and a TLR agonist, which can be used to prepare the aforementioned antibody-drug conjugate.
  • the present invention provides compounds of formula (III) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, and isotopic labels thereof
  • compounds of formula (III) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, and isotopic labels thereof Compounds, metabolites or prodrugs of:
  • M 1 is the precursor of the linker site connected to a targeting group, wherein the targeting group is as defined in any one of the preceding paragraphs;
  • X is the linker connecting M and Aa;
  • Aa is selected from amino acid fragments and peptide fragments formed from two or more amino acids
  • L 1 is a covalent bond or a linker connecting Aa and D 1 ;
  • L 2 is the linker connecting Aa and D 2 ;
  • D 1 is selected from cytotoxic drug fragments
  • D2 is selected from TLR agonist fragments.
  • M1 is selected from the following structures:
  • each a is independently selected from an integer of 1-5, b is selected from an integer of 1-3, and M a is an activated group of a carboxyl group (for example, a pentafluorophenoxy group).
  • M1 is selected from the following structures:
  • each a is independently selected from an integer of 1-5, b is selected from an integer of 1-3, and M a is the activation group of the carboxyl group.
  • M1 is a covalent bond or selected from the following structures:
  • M1 is a covalent bond or selected from the following structures:
  • X is a covalent bond or selected from C 1-6 alkylene, -NH-(CH 2 ) c -C(O)-,
  • each c is independently selected from an integer from 1 to 10; the 3 position of X is connected to M, and the 4 position is connected to Aa.
  • X is a covalent bond
  • each c is independently selected from an integer from 1 to 10 (for example, an integer from 5 to 10, another example from 8 to 10); the 3 position of X is connected to M, and the 4 position is connected to Aa.
  • Aa is selected from amino acid fragments and peptide fragments formed from two or more amino acids, wherein the amino acids are selected from Gly, Phe, Ala, Val, Ser, Thr, His, Trp, Cys, Asp , Glu, Lys, Tyr and Arg, optionally, each amino acid is independently modified by a C 1-6 alkyl or polyethylene glycol hydrophilic structural unit.
  • the polyethylene glycol hydrophilic structural units are selected from Each c is independently selected from an integer of 1-10 (for example, an integer of 5-10, and another example of an integer of 8-10).
  • Aa is selected from fragments of the following amino acids and peptide fragments formed from any combination of two or more of them: Gly, Phe, Ala, Val, Cys, Asp, Glu, Lys, and Arg, and Each amino acid is independently optionally modified with a C 1-6 alkyl or polyethylene glycol hydrophilic structural unit.
  • the polyethylene glycol hydrophilic structural units are selected from Each c is independently selected from an integer of 1-10 (for example, an integer of 5-10, and another example of an integer of 8-10).
  • Aa is selected from fragments of the following amino acids and is formed by any combination of two or more of them: Peptide fragments formed into: Val, Cys, Asp, Glu and Lys, wherein the Glu and Lys carboxyl termini are optionally replaced by Modification, wherein each c is independently selected from an integer of 1-10 (for example, an integer of 5-10, another example is an integer of 8-10).
  • Aa is selected from the following structures:
  • each R 7 is independently selected from H, C 1-6 alkyl and polyethylene glycol hydrophilic structural units; each R 8 is independently selected from hydroxyl and polyethylene glycol hydrophilic structural units; the 5 position is connected to X , the 6 position is connected to one of L 1 and L 2 , and the 7 position is connected to the other of L 1 and L 2 .
  • position 5 is connected to X
  • position 6 is connected to L 1
  • position 7 is connected to L 2
  • position 5 is connected to X
  • position 6 is connected to L 2
  • position 7 is connected to L 1 .
  • the polyethylene glycol hydrophilic structural units are selected from Each c is independently selected from an integer of 1-10 (for example, an integer of 5-10, and another example of an integer of 8-10).
  • R 7 is H.
  • Aa is selected from the following structures:
  • each R 7 is independently selected from H, C 1-6 alkyl and polyethylene glycol hydrophilic structural units; each R 8 is independently selected from hydroxyl and polyethylene glycol hydrophilic structural units; the 5 position is connected to X , position 6 is connected to one of L 1 and L 2 , position 7 is connected to the other of L 1 and L 2 ; preferably, position 5 is connected to X, position 6 is connected to L 1 , and position 7 is connected to L 2 .
  • the polyethylene glycol hydrophilic structural units are selected from Each c is independently selected from an integer of 1-10 (for example, an integer of 5-10, and another example of an integer of 8-10).
  • L is a covalent bond or is selected from the group consisting of a non-cleavable linker and a cleavable linker, wherein the cleavable linker is cleaved by an enzyme present in a pathological environment selected from the group consisting of proteases, phosphatases, Pyrophosphatase, beta-glucose Aldase, beta-galactosidase, and sulfatase.
  • L 1 is a covalent bond or -L a -L b -L c -, where:
  • L a is a covalent bond or selected from C 1-6 alkylene, -NH-(CH 2 ) c -C(O)-, Wherein, each c is independently selected from an integer from 1 to 10;
  • L b is a covalent bond or selected from amino acid fragments and peptide fragments formed from two or more amino acids, wherein the amino acids are selected from Val, Cit, Glu, Lys, Arg, Phe, Leu, Gly, Ala and Asn ;
  • L c is a covalent bond, -NH-CH 2 - or selected from the following structures:
  • L 1 is a covalent bond or -L a -L b -L c -, where:
  • L a is a covalent bond or selected from C 1-6 alkylene, -NH-(CH 2 ) c -C(O)-, Wherein, each c is independently selected from an integer from 1 to 10;
  • L b is a covalent bond or selected from amino acid fragments and peptide fragments formed from two or more amino acids, wherein the amino acids are selected from Val, Cit, Glu, Lys, Arg, Phe, Leu, Gly, Ala and Asn ;
  • L c is a covalent bond, -NH-CH 2 - or selected from the following structures:
  • La is a covalent bond or selected from Wherein, each c is independently selected from an integer of 1-10. In some embodiments, L b is a covalent bond or is selected from the following structures:
  • R 9 is selected from H, acetyl, fluorenyloxycarbonyl, trityl and polyethylene glycol hydrophilic structural units.
  • the polyethylene glycol hydrophilic structural unit is Each c is independently selected from an integer of 1-10.
  • L c is -NH-CH 2 - or
  • L 1 is a covalent bond or -L a -L b -L c -, where:
  • L a is a covalent bond or selected from Wherein, each c is independently selected from an integer from 1 to 10;
  • L b is a covalent bond or selected from
  • L c is -NH-CH 2 -or
  • L is a covalent bond or is selected from the following structures:
  • position 8 is connected to Aa, and position 9 is connected to D 1 .
  • L is a covalent bond or is selected from the following structures:
  • position 8 is connected to Aa, and position 9 is connected to D 1 .
  • L is selected from the following structures:
  • L is selected from the following structures:
  • position 8 is connected to Aa, and position 9 is connected to D 1 .
  • L is selected from the following structures:
  • position 8 is connected to Aa, and position 9 is connected to D 1 .
  • L2 is selected from the group consisting of a non-cleavable linker and a cleavable linker, wherein the cleavable linker is cleaved by an enzyme present in a pathological environment selected from the group consisting of protease, phosphatase, pyrophosphatase, beta -Glucuronidase, beta-galactosidase and sulfatase.
  • L2 is -Ld - Le - Lf- , wherein:
  • L d is a covalent bond or a divalent structure selected from one or more of the following: C 1-6 alkylene, -C(O)-(CH 2 ) d -NH-, Wherein, each d is independently selected from an integer from 1 to 12;
  • L e is a covalent bond or selected from amino acid fragments and peptide fragments formed from two or more amino acids, wherein the amino acids are selected from Val, Cit, Glu, Lys, Arg, Phe, Leu, Gly, Ala and Asn ;
  • L f is a covalent bond, -CH 2 -NH- or selected from the following structures:
  • L2 is -Ld - Le - Lf- , wherein:
  • L d is a covalent bond or a divalent structure selected from one or more of the following: C 1-6 alkylene, -C(O)-(CH 2 ) d -NH-, Wherein, each d is independently selected from an integer from 1 to 12;
  • L e is a covalent bond or selected from amino acid fragments and peptide fragments formed from two or more amino acids, wherein the amino acids are selected from Val, Cit, Glu, Lys, Arg, Phe, Leu, Gly, Ala and Asn ;
  • L f is a covalent bond, -CH 2 -NH- or selected from the following structures:
  • L e is a covalent bond or selected from the following structures:
  • each R 10 is independently selected from H, acetyl, fluorenyloxycarbonyl, trityl and polyethylene glycol hydrophilic structural units; preferably, the polyethylene glycol hydrophilic structural units are Each d is independently selected from an integer from 1 to 10.
  • L is selected from the following structures:
  • position 10 is connected to Aa, and position 11 is connected to D 2 .
  • L is selected from the following structures:
  • position 10 is connected to Aa, and position 11 is connected to D 2 ;
  • L is selected from the following structures:
  • position 10 is connected to Aa, and position 11 is connected to D 2 .
  • L is selected from the following structures:
  • position 10 is connected to Aa, and position 11 is connected to D2 .
  • L is selected from the following structures:
  • position 10 is connected to Aa, and position 11 is connected to D2 .
  • D1 is selected from a cytotoxic drug fragment selected from the group consisting of tubulin inhibitors, DNA damaging agents, and topoisomerase inhibitors, including but not limited to Dolastatins, auristatins, maytansines, Tubulysins and cryptomycins
  • the DNA damaging agents include but are not limited to PBDs, ducarmycin (duocarmycin) and calicheamicin (calicheamicin)
  • the topoisomerase inhibitors include but are not limited to camptothecin and its derivatives.
  • the tubulin inhibitor is selected from the group consisting of Aplysia 10, MMAE, MMAF, maytansine, DM1, DM3, and DM4, and the topoisomerase inhibitor is selected from the group consisting of camptothecin, SN- 38. Ixotecan, topotecan, belotecan, 10-hydroxycamptothecin, 9-aminocamptothecin, doxorubicin, epirubicin and PNU-159682.
  • D is selected from the following structures:
  • D2 is a TLR agonist fragment.
  • the TLR agonist is selected from the group consisting of TLR2 agonists, TLR4 agonists, TLR6 agonists, TLR7 agonists, TLR8 agonists, TLR7/8 agonists, and TLR9 agonists.
  • D2 is a TLR agonist fragment selected from the group consisting of a TLR7 agonist, a TLR8 agonist, and a TLR7/8 agonist.
  • D 2 is a TLR agonist fragment
  • the TLR agonist is a compound represented by formula (II):
  • X 1 is selected from N and C;
  • X 2 is selected from N and C;
  • At least one of X 1 and X 2 is selected from N;
  • X 3 is selected from O, S and N;
  • X 4 is selected from O, S, N and CR 4 ;
  • R 1 is selected from C 1-6 alkyl and -C 1-6 alkylene-OC 1-6 alkyl
  • R 2 is selected from hydrogen and the formula -L 3 -L 4 -L 5 -L 6 ;
  • L 3 is selected from covalent bond and C 1-6 alkylene
  • L 4 is selected from covalent bond, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the cycloalkyl, heterocyclyl, aromatic and heteroaryl are optionally substituted by one or more radicals selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy and -C 1-6 alkylene-NH 2 Replaced by regiment;
  • L 5 is selected from covalent bond, -O-, -S-, -C(O)-, -OC(O)-, -C(O)-O-, -OC(O)-O-, -NR 5 -, -C(O)-NR 5 -, -NR 5 -C(O)-, -OC(O)-NR 5 -, -NR 5 -C(O)-O-, -NR 5 -C (O)-NR 5 -, -S(O) r -NR 5 -, -NR 5 -S(O) r -, and -NR 5 -S(O) r -NR 5 -;
  • L 6 is selected from hydrogen, C 1-6 alkyl, -(O-CH 2 CH 2 ) n -OC 1-6 alkyl and -C 1-6 alkylene-(O-CH 2 CH 2 ) n - OC 1-6 alkyl, the alkyl is optionally replaced by one or more hydrogen, halogen, hydroxyl, -NH 2 , -NH-C(O)-OC 1-6 alkyl, C 1-6 Substituted by alkoxy, carboxyl and -C(O)-OC 1-6 alkyl groups;
  • R 3 is selected from hydrogen and the formula -L 7 -L 8 -L 9 -L 10 ;
  • L 7 is selected from covalent bond and C 1-6 alkylene
  • L 8 is selected from covalent bond, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the cycloalkyl, heterocyclyl, aromatic and heteroaryl are optionally substituted by one or more radicals selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy and -C 1-6 alkylene-NH 2 Replaced by regiment;
  • L 9 is selected from covalent bond, -O-, -S-, -C(O)-, -OC(O)-, -C(O)-O-, -OC(O)-O-, -NR 6 -, -C(O)-NR 6 -, -NR 6 -C(O)-, -OC(O)-NR 6 -, -NR 6 -C(O)-O-, -NR 6 -C (O)-NR 6 -, -S(O) p -NR 6 -, -NR 6 -S(O) p -, and -NR 6 -S(O) p -NR 6 -;
  • L 10 is selected from hydrogen, C 1-6 alkyl, -(O-CH 2 CH 2 ) q -OC 1-6 alkyl and -C 1-6 alkylene -(O-CH 2 CH 2 ) q - OC 1-6 alkyl, the alkyl is optionally replaced by one or more hydrogen, halogen, hydroxyl, -NH 2 , -NH-C(O)-OC 1-6 alkyl, C 1-6 Substituted by alkoxy, carboxyl and -C(O)-OC 1-6 alkyl groups;
  • R 4 is selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-10 cycloalkyl;
  • Each R 5 is independently selected from hydrogen and C 1-6 alkyl
  • Each R 6 is independently selected from hydrogen and C 1-6 alkyl
  • Each r is independently 1 or 2;
  • n is independently selected from an integer from 1 to 25;
  • Each p is independently 1 or 2;
  • Each q is independently selected from an integer from 1 to 25;
  • D 2 is connected to L 2 through R 2 or R 3 in formula (II).
  • each n is independently selected from 1-15, preferably, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • each q is independently selected from 1-15, preferably, q is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • X3 is selected from S and N.
  • L is selected from covalent bonds and C 1-3 alkylene.
  • L4 is selected from the group consisting of covalent bond, 3-12 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, any of which Optionally substituted with one or more groups selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy and -C 1-6 alkylene-NH 2 .
  • L 5 is selected from covalent bond, -NR 5 -, -C(O)-NR 5 -, -NR 5 -C(O)-, -OC(O)-NR 5 -, - NR 5 -C(O)-O-, -NR 5 -C(O)-NR 5 -, -S(O) r -NR 5 -, -NR 5 -S(O) r - and -NR 5 - S(O) r -NR 5 -, each R 5 is independently selected from hydrogen and C 1-6 alkyl; preferably, L 5 is selected from covalent bond and -NR 5 -, each R 5 is independently selected from hydrogen and C 1-6 alkyl.
  • L 6 is selected from hydrogen, C 1-6 alkyl, and -C 1-6 alkylene-(O-CH 2 CH 2 ) n -OC 1-6 alkyl, which alkyl is either Optionally one or more selected from hydrogen, halogen, hydroxyl, -NH 2 , -NH-C(O)-OC 1-6 alkyl, C 1-6 alkoxy, carboxyl and -C(O)- OC 1-6 alkyl group substituted, n is 1-10.
  • L is selected from a covalent bond and a 3-12 membered heterocyclyl optionally substituted by one or more members selected from the group consisting of hydrogen, halogen, cyano, and C 1-6 alkyl replaced.
  • L9 is a covalent bond.
  • L 10 is selected from hydrogen, C 1-6 alkyl, and -C 1-6 alkylene-(O-CH 2 CH 2 ) q -OC 1-6 alkyl, q is 1-10 .
  • R 3 is selected from hydrogen and the formula -L 7 -L 8 -L 9 -L 10 ;
  • L 8 is selected from covalent bonds and 3-12 membered heterocyclyl groups, which are optionally replaced by one or more members selected from hydrogen, halogen, cyanide Substituted with C 1-6 alkyl group;
  • L 9 is a covalent bond
  • L 10 is selected from hydrogen, C 1-6 alkyl and -C 1-6 alkylene-(O-CH 2 CH 2 ) q -OC 1-6 alkyl;
  • q is selected from 1-10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.
  • X 1 is C
  • X 2 is N
  • X 3 is S
  • X 4 is selected from CR 4 ;
  • R 1 is selected from C 1-6 alkyl
  • R 2 is selected from the formula -L 3 -L 4 -L 5 -L 6 ;
  • L 3 is selected from covalent bond and C 1-6 alkylene
  • L 4 is selected from covalent bond, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the heterocyclyl, aryl and heteroaryl are optionally replaced by one or more Substituted with a group selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy and -C 1-6 alkylene-NH 2 ;
  • L 5 is selected from covalent bonds and -NR 5 -, and each R 5 is independently selected from hydrogen and C 1-6 alkyl;
  • L 6 is selected from hydrogen, C 1-6 alkyl and -C 1-6 alkylene-(O-CH 2 CH 2 ) n -OC 1-6 alkyl, which is optionally replaced by one or more Each is selected from hydrogen, halogen, hydroxyl, -NH 2 , -NH-C(O)-OC 1-6 alkyl, C 1-6 alkoxy, carboxyl and -C(O)-OC 1-6 alkyl replaced by a group.
  • D2 is selected from the following structures:
  • the present invention provides a pharmaceutical composition, which contains any of the above-mentioned antibody drug conjugates, compounds (such as drug linkers, TLR agonists or cytotoxic drugs) or their pharmaceutically acceptable Salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and one or more pharmaceutical excipients .
  • the present invention provides any of the aforementioned antibody drug conjugates, compounds (such as drug linkers, TLR agonists or cytotoxic drugs) or pharmaceutically acceptable salts, esters, stereoisomers thereof
  • compounds such as drug linkers, TLR agonists or cytotoxic drugs
  • pharmaceutically acceptable salts, esters, stereoisomers thereof The use of isomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs in the preparation of antibody drug conjugates, especially in the preparation of any of the preceding items The antibody drug conjugate.
  • the present invention provides any of the aforementioned antibody drug conjugates, compounds (such as drug linkers, TLR agonists or cytotoxic drugs) or pharmaceutically acceptable salts, esters, stereoisomers thereof isomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions for use in the preparation of treatments and/or prevention of cancer (e.g., HER2-positive cancer , such as HER2-positive gastric cancer, breast cancer or non-small cell lung cancer).
  • cancer e.g., HER2-positive cancer , such as HER2-positive gastric cancer, breast cancer or non-small cell lung cancer.
  • the present invention provides any of the aforementioned antibody drug conjugates, compounds (such as drug linkers, TLR agonists or cytotoxic drugs) or pharmaceutically acceptable salts, esters, stereoisomers thereof isomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions for the treatment and/or prevention of cancer (e.g., HER2 positive cancer, such as HER2-positive gastric cancer, breast cancer, or non-small cell lung cancer).
  • cancer e.g., HER2 positive cancer, such as HER2-positive gastric cancer, breast cancer, or non-small cell lung cancer.
  • the present invention provides a method of treating and/or preventing cancer (e.g., HER2-positive cancer, such as HER2-positive gastric cancer, breast cancer, or non-small cell lung cancer), comprising administering to a subject in need thereof treatment and/or prevention of cancer. /or a prophylactically effective amount of any of the aforementioned antibody-drug conjugates, compounds (such as drug linkers, TLR agonists or cytotoxic drugs) or their pharmaceutically acceptable salts, esters, stereoisomers, Tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions.
  • cancer e.g., HER2-positive cancer, such as HER2-positive gastric cancer, breast cancer, or non-small cell lung cancer
  • the present invention provides methods for preparing compounds represented by formula (III) of the present invention.
  • LG 1 and LG 2 represent leaving groups, including but not limited to halogen, hydroxyl, succinimide ester, active ester, etc.
  • PG 1 and PG 2 represent protecting groups, including but not limited to benzyloxycarbonyl ( Cbz), tert-butoxycarbonyl (Boc), fluorenyloxycarbonyl (Fmoc), benzyl, acetyl, tert-butyl, etc.
  • L 1a is the precursor structure to form L 1 , preferably containing an unsaturated double bond, and occurs through The addition reaction on the unsaturated double bond connects Aa;
  • D 1 , D 2 , L 1 , L 2 , X, Aa and M 1 are as defined above;
  • Step 1 Compound III-1 and compound III-2 undergo a condensation reaction to obtain compound III-3;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethyl Formamide.
  • the reaction is preferably carried out in the presence of a condensing agent.
  • the condensation agent may be selected from 1-hydroxybenzotriazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 2-(7-azobenzotriazole) -N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazole-1 -oxytris(dimethylamino)phosphonium hexafluorophosphate, preferably a combination of 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride .
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, and 4-dimethylaminopyridine, with N,N-diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the condensation reaction is preferably carried out for a suitable time, such as 1 to 12 hours.
  • Step 2 Compound III-3 undergoes deprotection reaction to obtain compound III-4;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from 1,4-dioxane, dichloromethane, tetrahydrofuran and any combination thereof, with dichloromethane being preferred.
  • the reaction is preferably carried out in the presence of a suitable acid, which may be selected from hydrochloric acid, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 12 hours.
  • Step 3 Compound III-4 and compound III-5 undergo a condensation reaction to obtain compound III-6;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethyl Formamide.
  • the reaction is preferably carried out in the presence of a condensing agent.
  • the condensation agent may be selected from 1-hydroxybenzotriazole, 2-ethoxy-1-ethyl Oxycarbonyl-1,2-dihydroquinoline, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3 -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, preferably 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, and 4-dimethylaminopyridine, with N,N-diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the condensation reaction is preferably carried out for a suitable time, such as 1 to 12 hours.
  • Step 4 Compound III-6 undergoes deprotection reaction to obtain compound III-7;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from 1,4-dioxane, dichloromethane, tetrahydrofuran and any combination thereof, with dichloromethane being preferred.
  • the reaction is preferably carried out in the presence of a suitable acid, which may be selected from acetic acid, hydrobromic acid, hydrochloric acid, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the reaction can be carried out with the addition of triethylsilane as an ion trapping agent.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 12 hours.
  • Step 5 Addition reaction occurs between compound III-7 and compound III-8 to obtain compound III-9;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from 1,4-dioxane, dichloromethane, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethyl Formamide.
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, and 4-dimethylaminopyridine, with N,N-diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 12 hours.
  • Step 6 Compound III-9 and compound III-10 undergo a cyclization reaction to obtain compound III;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, water and any combination thereof, preferably dimethyl sulfoxide Mixed solvent with water.
  • the reaction is preferably carried out in the presence of a metal catalyst.
  • the metal catalyst may be selected from copper sulfate, cuprous iodide, cuprous bromide, copper acetate, preferably copper sulfate.
  • the reaction is preferably carried out in the presence of ascorbic acid or sodium ascorbate.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the condensation reaction is preferably carried out for a suitable time, such as 1 to 12 hours.
  • the present invention provides another method for preparing the compound of formula (III), which includes the following steps:
  • LG 1 , LG 2 and LG 3 represent leaving groups, including but not limited to halogen, hydroxyl, succinimide ester, active ester, etc.
  • PG 1 and PG 2 represent protecting groups, including but not limited to benzyl Oxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenyloxycarbonyl (Fmoc), benzyl, acetyl, tert-butyl, etc.;
  • D 1 , D 2 , L 1 , L 2 , Aa and M 1 are as defined above;
  • Step 1 Compound III-11 and compound III-12 undergo a condensation reaction to obtain compound III-13;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethyl Formamide.
  • the reaction is preferably carried out in the presence of a condensing agent.
  • the condensation agent may be selected from 1-hydroxybenzotriazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 2-(7-azobenzotriazole) -N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazole-1 -oxytris(dimethylamino)phosphonium hexafluorophosphate, preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, and 4-dimethylaminopyridine, with N,N-diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the condensation reaction is preferably carried out for a suitable time, such as 1 to 12 hours.
  • Step 2 Compound III-13 undergoes deprotection reaction to obtain compound III-14;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from 1,4-dioxane, dichloromethane, tetrahydrofuran and any combination thereof, with dichloromethane being preferred.
  • the reaction is preferably carried out in the presence of a suitable acid, which may be selected from hydrochloric acid, trifluoroacetic acid, zinc bromide, preferably zinc bromide.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 12 hours.
  • Step 3 Compound III-14 and compound III-5 undergo a condensation reaction to obtain compound III-15;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethyl Formamide.
  • the reaction is preferably carried out in the presence of a condensing agent.
  • the condensation agent may be selected from 1-hydroxybenzotriazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 2-(7-azobenzotriazole) -N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, preferably 2-(7-azobenzotris Azole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, and 4-dimethylaminopyridine, with N,N-diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the condensation reaction is preferably carried out for a suitable time, such as 1 to 12 hours.
  • Step 4 Compound III-15 undergoes deprotection reaction to obtain compound III-16;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from N,N-dimethylformamide, dichloromethane, tetrahydrofuran and any combination thereof, preferably N,N-dimethylformamide.
  • the reaction is preferably carried out in the presence of a suitable base, which may be selected from diethylamine and piperidine, preferably piperidine.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 6 hours.
  • Step 5 Compound III-16 and compound III-17 undergo a substitution reaction to obtain compound III;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from dichloromethane, tetrahydrofuran, 1,2-dichloroethane, diethyl ether, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethylformamide.
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, and 4-dimethylaminopyridine, with N,N-diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 12 hours.
  • the present invention provides another method for preparing the compound of formula (III), which includes the following steps:
  • LG 1 , LG 2 and LG 3 represent leaving groups, including but not limited to halogen, hydroxyl, succinimide ester, active ester, etc.
  • PG 1 and PG 2 represent protecting groups, including but not limited to benzyl Oxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenyloxycarbonyl (Fmoc), benzyl, acetyl, tert-butyl, etc.;
  • D 1 , D 2 , L 1 , L 2 , Aa and M 1 are as defined above;
  • Step 1 Compound III-18 and compound III-19 undergo a condensation reaction to obtain compound III-20;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethyl Formamide.
  • the reaction is preferably carried out in the presence of a condensing agent.
  • the condensation agent may be selected from 1-hydroxybenzotriazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 2-(7-azobenzotriazole) -N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazole-1 -oxytris(dimethylamino)phosphonium hexafluorophosphate, preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, and 4-dimethylaminopyridine, with N,N-diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the condensation reaction is preferably carried out for a suitable time, such as 1 to 12 hours.
  • Step 2 Compound III-20 undergoes deprotection reaction to obtain compound III-21;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from 1,4-dioxane, dichloromethane, tetrahydrofuran and any combination thereof, with dichloromethane being preferred.
  • the reaction is preferably carried out in the presence of a suitable acid, which may be selected from hydrochloric acid, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 12 hours.
  • Step 3 Compound III-21 and compound III-22 undergo a condensation reaction to obtain compound III-23;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethyl Formamide.
  • the reaction is preferably carried out in the presence of a condensing agent.
  • the condensation agent may be selected from 1-hydroxybenzotriazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 2-(7-azobenzotriazole) -N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazole-1 -oxytris(dimethylamino)phosphonium hexafluorophosphate, preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, and 4-dimethylaminopyridine, with N,N-diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the condensation reaction is preferably carried out for a suitable time, such as 1 to 12 hours.
  • Step 4 Compound III-23 undergoes deprotection reaction to obtain compound III-24;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from N,N-dimethylformamide, dichloromethane, tetrahydrofuran and any combination thereof, preferably N,N-dimethylformamide.
  • the reaction is preferably carried out in the presence of a suitable base, which may be selected from diethylamine and piperidine, preferably piperidine.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 6 hours.
  • Step 5 Compound III-24 and compound III-25 undergo a substitution reaction to obtain compound III;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from dichloromethane, tetrahydrofuran, 1,2-dichloroethane, diethyl ether, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethylformamide. Said anti This should preferably be carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, and 4-dimethylaminopyridine, with N,N-diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 12 hours.
  • Aa is a polypeptide fragment formed by two or more amino acids
  • Aa is -Aa 1 -Aa 2 -, where Aa 1 and Aa 2 are the amino acid fragments constituting Aa;
  • the invention provides a method for preparing formula (III) Another method of compound, which includes the following steps:
  • LG 1 , LG 2 and LG 3 represent leaving groups, including but not limited to halogen, hydroxyl, succinimide ester, active ester, etc.
  • PG 1 , PG 2 and PG 3 represent protecting groups, including but not limited to Not limited to benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenyloxycarbonyl (Fmoc), benzyl, acetyl, tert-butyl, etc.
  • Aa 1 and Aa 2 are amino acid fragments constituting Aa;
  • D 1 , D 2 , L 1 , L 2 , X, Aa and M 1 are as defined above;
  • Step 1 Compound III-26 and compound III-27 undergo a condensation reaction to obtain compound III-28;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethyl Formamide.
  • the reaction is preferably carried out in the presence of a condensing agent.
  • the condensation agent may be selected from 1-hydroxybenzotriazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 2-(7-azobenzotriazole) -N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazole-1 -oxytris(dimethylamino)phosphonium hexafluorophosphate, preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, preferably N,N-diisopropylethylamine amine.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the condensation reaction is preferably carried out for a suitable time, such as 1 to 12 hours.
  • Step 2 Compound III-28 undergoes deprotection reaction to obtain compound III-29;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from 1,4-dioxane, dichloromethane, tetrahydrofuran and any combination thereof, with 1,4-dioxane being preferred.
  • the reaction is preferably carried out in the presence of a suitable acid, which may be selected from acetic acid, hydrobromic acid, hydrochloric acid, trifluoroacetic acid, preferably hydrochloric acid.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 12 hours.
  • Step 3 Compound III-29 and compound III-30 undergo a condensation reaction to obtain compound III-31;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethyl Formamide.
  • the reaction is preferably carried out in the presence of a condensing agent.
  • the condensation agent may be selected from 1-hydroxybenzotriazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 2-(7-azobenzotriazole) -N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazole-1 -oxytris(dimethylamino)phosphonium hexafluorophosphate, preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, and 4-dimethylaminopyridine, with N,N-diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the condensation reaction is preferably carried out for a suitable time, such as 1 to 12 hours.
  • Step 4 Compound III-31 undergoes deprotection reaction to obtain compound III-32;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from 1,4-dioxane, dichloromethane, tetrahydrofuran and any combination thereof, with dichloromethane being preferred.
  • the reaction is preferably carried out in the presence of a suitable acid, which may be selected from hydrochloric acid, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 12 hours.
  • Step 5 Compound III-32 and compound III-33 undergo a condensation reaction to obtain compound III-34;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethyl Formamide.
  • the reaction is preferably carried out in the presence of a condensing agent.
  • the condensation agent may be selected from 1-hydroxybenzotriazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 2-(7-azobenzotriazole) -N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazole-1 -oxytris(dimethylamino)phosphonium hexafluorophosphate, preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, preferably N,N-diisopropylethylamine amine.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the condensation reaction is preferably carried out for a suitable time, such as 1 to 12 hours.
  • Step 6 Compound III-34 undergoes deprotection reaction to obtain compound III-35;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from N,N-dimethylformamide, dichloromethane, tetrahydrofuran and any combination thereof, preferably N,N-dimethylformamide.
  • the reaction is preferably carried out in the presence of a suitable base, which may be selected from diethylamine and piperidine, preferably piperidine.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 6 hours.
  • Step 7 Compound III-35 and compound III-36 undergo a substitution reaction to obtain compound III;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from dichloromethane, tetrahydrofuran, 1,2-dichloroethane, diethyl ether, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethylformamide.
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, and 4-dimethylaminopyridine, with N,N-diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 12 hours.
  • Aa is a polypeptide fragment formed by two or more amino acids
  • Aa is -Aa 1 -Aa 2 -; the present invention provides another method for preparing the compound of formula (III), which includes the following steps:
  • LG 1 , LG 2 and LG 3 represent leaving groups, including but not limited to halogen, hydroxyl, succinimide ester, active ester, etc.
  • PG 1 and PG 2 represent protecting groups, including but not limited to benzyl Oxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenyloxycarbonyl (Fmoc), benzyl, acetyl, tert-butyl, etc.
  • Aa 1 and Aa 2 are respectively amino acid fragments or composed of two or more amino acids The polypeptide fragment formed;
  • D 1 , D 2 , L 1 , L 2 , X, Aa and M 1 are as defined above;
  • Step 1 Compound III-37 and compound III-38 undergo a condensation reaction to obtain compound III-39;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethyl Formamide.
  • the reaction is preferably carried out in the presence of a condensing agent.
  • the condensation agent may be selected from 1-hydroxybenzotriazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 2-(7-azobenzotriazole) -N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazole-1 -oxytris(dimethylamino)phosphonium hexafluorophosphate, preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, and 4-dimethylaminopyridine, with N,N-diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the condensation reaction is preferably carried out for a suitable time, such as 1 to 12 hours.
  • Step 2 Compound III-39 undergoes deprotection reaction to obtain compound III-40;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from N,N-dimethylformamide, dichloromethane, tetrahydrofuran and any combination thereof, preferably N,N-dimethylformamide.
  • the reaction is preferably carried out in the presence of a suitable base, which may be selected from diethylamine and piperidine, preferably piperidine.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 6 hours.
  • Step 3 Compound III-40 and compound III-41 undergo a condensation reaction to obtain compound III-42;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethyl Formamide.
  • the reaction is preferably carried out in the presence of a condensing agent.
  • the condensation agent may be selected from 1-hydroxybenzotriazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 2-(7-azobenzotriazole) -N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazole-1 -oxytris(dimethylamino)phosphonium hexafluorophosphate, preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, and 4-dimethylaminopyridine, with N,N-diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the condensation reaction is preferably carried out for a suitable time, such as 1 to 12 hours.
  • Step 4 Compound III-42 undergoes deprotection reaction to obtain compound III-43;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from 1,4-dioxane, dichloromethane, tetrahydrofuran and any combination thereof, with dichloromethane being preferred.
  • the reaction is preferably carried out in the presence of a suitable acid, which may be selected from hydrochloric acid, trifluoroacetic acid, zinc bromide, preferably zinc bromide.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 12 hours.
  • Step 5 Compound III-43 undergoes a substitution reaction with compound III-44 to obtain compound III;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from dichloromethane, tetrahydrofuran, 1,2-dichloroethane, diethyl ether, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethylformamide.
  • the reaction is preferably carried out in the presence of a base.
  • the base can be selected from N,N-diisopropylethylamine, triethylamine, pyridine, and 4-dimethylaminopyridine, with N,N-diisopropylethylamine being preferred.
  • the reaction is preferably carried out at a suitable temperature, preferably -10-60°C.
  • the reaction is preferably carried out for a suitable time, for example 1 to 12 hours.
  • antibody refers to an immunoglobulin molecule usually composed of two pairs of polypeptide chains, each pair having a light chain (LC) and a heavy chain (HC).
  • Antibody light chains can be classified into kappa (kappa) and lambda (lambda) light chains.
  • Heavy chains can be classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
  • the variable and constant regions are connected by a "J" region of approximately 12 or more amino acids, and the heavy chain also contains a "D" region of approximately 3 or more amino acids.
  • Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH).
  • the heavy chain constant region consists of 3 domains (CH1, CH2 and CH3).
  • Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL).
  • the light chain constant region consists of one domain, CL.
  • the constant domain is not directly involved in the binding of antibodies to antigens, but exhibits a variety of effector functions, such as mediating the interaction of immunoglobulins with host tissues or factors, including various cells of the immune system (e.g., effector cells) and classical complement. Binding of the first component of the system (C1q).
  • VH and VL regions can also be subdivided into regions of high variability called complementarity determining regions (CDRs), interspersed with more conservative regions called framework regions (FRs).
  • CDRs complementarity determining regions
  • FRs framework regions
  • Each VH and VL consists of 3 CDRs and 4 FRs arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions (VH and VL) of each heavy chain/light chain pair respectively form the antigen-binding site.
  • the assignment of amino acids to regions or domains can follow various numbering systems known in the art.
  • CDR complementarity determining region
  • the variable regions of the heavy chain and light chain each contain three CDRs, named CDR1, CDR2 and CDR3.
  • CDR1, CDR2 and CDR3 The precise boundaries of these CDRs can be defined according to various numbering systems known in the art, for example according to the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia numbering system (Chothia & Lesk (1987) J. Mol. Biol. 196:901-917; Chothia et al.
  • the CDRs contained in the antibody or antigen-binding fragment thereof can be determined according to various numbering systems known in the art, for example, by the Kabat, Chothia, IMGT or AbM numbering system.
  • the antibody or antigen-binding fragment thereof contains CDRs defined by the Chothia numbering system.
  • framework region or "FR” residues refers to those amino acid residues in an antibody variable region other than the CDR residues as defined above.
  • antigen-binding fragment of an antibody refers to a polypeptide that is a fragment of an antibody, such as a fragment of a full-length antibody, that retains the ability to specifically bind to the same antigen that the full-length antibody binds and/or competes with the full-length antibody.
  • Specific binding of antigen which is also called the "antigen-binding moiety”. See generally, Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nd ed., Raven Press, NY (1989)), which is incorporated herein by reference in its entirety for all purposes. It can be obtained by recombinant DNA technology Or antigen-binding fragments of the antibody are produced by enzymatic or chemical cleavage of the intact antibody.
  • Non-limiting examples of antigen-binding fragments include Fab fragments, Fab' fragments, F(ab)' 2 fragments, F(ab)' 3 fragments, Fd , Fv, scFv, di-scFv, (scFv) 2 , disulfide-stabilized Fv proteins ("dsFv"), single domain antibodies (sdAb, Nanobodies) and such polypeptides, which contain an antigen sufficient to confer specificity to the polypeptide At least a portion of an antibody with binding capacity.
  • Engineered antibody variants are reviewed in Holliger et al., 2005; Nat Biotechnol, 23:1126-1136.
  • Fd means an antibody fragment consisting of VH and CH1 domains
  • dAb fragment means an antibody fragment consisting of a VH domain (Ward et al., Nature 341:544 546 (1989))
  • Fab fragment means an antibody fragment consisting of VL, VH, CL and CH1 domains
  • F(ab') 2 fragment means an antibody fragment comprising two Fab fragments connected by a disulfide bridge on the hinge region
  • Fab'fragment means the fragment obtained by reducing the disulfide bond connecting the two heavy chain fragments in the F(ab') 2 fragment, consisting of an intact light chain and the Fd fragment of the heavy chain (consisting of the VH and CH1 structures domain composition) composition.
  • Fv means an antibody fragment consisting of the VL and VH domains of a single arm of an antibody. Fv fragments are generally considered to be the smallest antibody fragments that can form a complete antigen-binding site. It is generally believed that six CDRs confer the antigen-binding specificity of an antibody. However, even a variable region (such as an Fd fragment, which contains only three antigen-specific CDRs) can recognize and bind the antigen, although its affinity may be lower than that of the intact binding site.
  • Fc means a complex composed of the second and third constant regions of the first heavy chain of an antibody and the second and third constant regions of the second heavy chain. Antibody fragments formed by disulfide bonding of regions. The Fc fragment of an antibody has many different functions but does not participate in antigen binding.
  • scFv refers to a single polypeptide chain comprising VL and VH domains linked by a linker (see, e.g., Bird et al., Science 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); and Pluckthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, Roseburg and Moore, eds., Springer-Verlag, New York, pp. 269-315 (1994)).
  • Such scFv molecules may have the general structure: NH2 -VL-linker-VH-COOH or NH2 -VH-linker-VL-COOH.
  • Suitable prior art linkers consist of repeated GGGGS amino acid sequences or variants thereof.
  • a linker having the amino acid sequence (GGGGS) 4 can be used, but variants thereof can also be used (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90:6444-6448).
  • Other linkers useful in the present invention are provided by Alfthan et al. (1995), Protein Eng. 8:725-731, Choi et al. (2001), Eur. J. Immunol.
  • a disulfide bond may also exist between VH and VL of scFv.
  • the VH and VL domains can be positioned relative to each other in any suitable arrangement. For example, scFv containing NH2 -VH-VH-COOH, NH2- VL-VL-COOH.
  • Each of the above antibody fragments retains the ability to specifically bind to the same antigen that the full-length antibody binds, and/or competes with the full-length antibody for specific binding to the antigen.
  • antibody includes not only intact antibodies but also antigen-binding fragments of the antibodies, unless the context clearly indicates otherwise.
  • Antigen-binding fragments of an antibody can be obtained from a given antibody (e.g., the antibodies provided by the invention) using conventional techniques known to those skilled in the art (e.g., recombinant DNA technology or enzymatic or chemical fragmentation methods) ), and the antigen-binding fragments of the antibody are screened for specificity in the same manner as for intact antibodies.
  • mouse-derived antibody refers to antibodies obtained by fusing B cells of immunized mice with myeloma cells, selecting murine hybrid fusion cells that can both proliferate indefinitely and secrete antibodies, and then screen , Antibody preparation and antibody purification; or it refers to the antibodies secreted by plasma cells after B cells differentiate and proliferate after the antigen invades the mouse body.
  • humanized antibody refers to a non-human antibody that has been genetically engineered and whose amino acid sequence has been modified to increase sequence homology with that of a human antibody.
  • CDR region of a humanized antibody comes from a non-human antibody (donor antibody), and all or part of the non-CDR region (for example, variable region FR and/or constant region) comes from a human source.
  • Immunoglobulins receptor antibodies. Humanized antibodies usually retain the expected properties of the donor antibody, including but not limited to, antigen specificity, affinity, reactivity, ability to increase immune cell activity, ability to enhance immune response, etc.
  • the antibody may be a mouse, rat, rabbit, or non-human primate with desired properties (e.g., antigen specificity, affinity, reactivity, ability to increase immune cell activity, and/or the ability to enhance an immune response) (e.g., cynomolgus monkey) antibodies.
  • desired properties e.g., antigen specificity, affinity, reactivity, ability to increase immune cell activity, and/or the ability to enhance an immune response
  • desired properties e.g., antigen specificity, affinity, reactivity, ability to increase immune cell activity, and/or the ability to enhance an immune response
  • desired properties e.g., antigen specificity, affinity, reactivity, ability to increase immune cell activity, and/or the ability to enhance an immune response
  • cynomolgus monkey e.g., cynomolgus monkey
  • amino acids are generally represented by one-letter and three-letter abbreviations well known in the art.
  • alanine can be represented by A or Ala.
  • alkyl refers to a straight-chain or branched saturated hydrocarbon group obtained by removing one hydrogen atom, such as “C 1-20 alkyl”, “C 1-10 alkyl”, “C 1-6 alkyl” , “C 1-4 alkyl”, “C 1-3 alkyl”, etc. Specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.
  • alkylene refers to a group obtained by removing 2 hydrogen atoms from a straight-chain or branched saturated hydrocarbon group, such as “C 1-20 alkylene”, “C 1-10 alkylene”, “C 3-10 “Alkylene”, “C 5-8 alkylene”, “C 1-6 alkylene”, “C 1-4 alkylene”, “C 1-3 alkylene”, etc. Specific examples include but Not limited to: methylene, ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene or 1,6-hexylene, etc.
  • cycloalkyl refers to a saturated cyclic saturated hydrocarbon group, including, but not limited to, monocycloalkyl and bicycloalkyl (such as spirocycloalkyl, pentacycloalkyl and bridged cycloalkyl).
  • C 3-10 cycloalkyl refers to a cycloalkyl group having 3 to 10 ring-forming carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • heterocyclyl refers to a saturated or partially saturated cyclic structure containing at least one ring member selected from N, O and S. Specific examples include but are not limited to 3-12-membered heterocyclyl, 3-8-membered heterocyclyl, 5-6-membered heterocyclyl, etc., such as tetrahydrofuryl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, etc.
  • heteroaryl refers to an aromatic cyclic structure containing at least one ring member selected from N, O and S. Specific examples include but are not limited to 5-10 membered heteroaryl, 5-6 membered heteroaryl, etc., such as furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, iso Oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2 ,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3- Triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetra
  • aryl refers to a group obtained by removing a hydrogen atom from the carbon atom of the aromatic nucleus of an aromatic hydrocarbon molecule.
  • C 6-10 aromatic Group specific examples include but are not limited to phenyl, naphthyl, anthracenyl, etc.
  • fragment refers to the remaining part of a compound molecule after losing one or more atoms or groups of atoms.
  • cytotoxic drug fragment refers to the remaining portion of the cytotoxic drug obtained after losing a hydrogen atom or hydroxyl group of the cytotoxic drug described herein and connecting it to the linker in the antibody drug conjugate.
  • the cytotoxic drug fragment is represented by D1 .
  • TLR agonist fragment refers to the remaining portion of the TLR agonist described herein that is obtained by losing one or more atoms or groups of atoms and connecting the TLR agonist to a linker in an antibody drug conjugate.
  • the TLR agonist fragment is represented by D2 .
  • each substituent or value is selected independently of the other.
  • each substituent or value may be the same or different from another (other) substituent or value.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of the present invention except that one or more atoms are substituted with the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature. or atomic substitution of mass number.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (eg, 2 H, 3 H, deuterium D, tritium T); isotopes of carbon (eg, 11 C, 13 C, and 14 C); chlorine Isotopes of fluorine (e.g. 18 F); isotopes of iodine (e.g.
  • isotopes of nitrogen e.g. 13 N and 15 N
  • isotopes of oxygen e.g. 15 O, 17 O and 18 O
  • isotopes of phosphorus such as 32 P
  • isotopes of sulfur such as 35 S.
  • Certain isotopically labeled compounds of the invention eg, those incorporating radioactive isotopes
  • the radioactive isotopes tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and detect.
  • positron emitting isotopes eg 11 C, 18 F, 15 O and 13 N
  • PTT positron emission tomography
  • Isotopically labeled compounds of the invention may be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using appropriate isotopically labeled reagents in place of the previously employed non-labeled reagents.
  • Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, for example, D2O , acetone- d6 or DMSO- d6 .
  • stereoisomer means an isomer formed due to at least one asymmetric center. In compounds with one or more (eg 1, 2, 3 or 4) asymmetric centers, it can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and Individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. wait.
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • compositions of the present invention may exist in free form for therapeutic use, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, solvates, metabolites or prodrugs that, upon administration to a patient in need thereof, can directly or indirectly Compounds of the invention or metabolites or residues thereof are provided. Therefore, when reference is made herein to "a compound of the invention", it is also intended to encompass the various derivative forms of the compound described above.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts.
  • suitable salts see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise a polar solvent as a structural element of the crystal lattice of said compound.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • nitrogen-containing heterocycles are capable of forming N-oxides; those skilled in the art will recognize that nitrogen-containing heterocycles are capable of forming N-oxides. Nitrogen-containing heterocycle. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocyclic and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyldioxirane are used to oxidize heterocyclic and tertiary amines.
  • MCPBA m-chloroperoxybenzoic acid
  • alkyl Hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate and dioxirane such as dimethyldioxirane
  • metabolites of the compounds of the invention ie substances formed in the body upon administration of the compounds of the invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound.
  • the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce metabolites thereof.
  • the invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity when administered into the body or its Examples can be passed Such as hydrolytic cleavage and conversion into compounds of the invention having the desired activity.
  • prodrugs will be functional group derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems,” Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by EB Roche, American Pharmaceutical Association).
  • prodrugs of the present invention may be prepared, for example, by using certain moieties known to those skilled in the art as "pro-moiety” (eg as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)) Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • Antibody-drug conjugates are also characterized by the average loading of the drug moiety (e.g., cytotoxic drugs and TLR agonists) to the antibody-binding moiety, often referred to as the drug-to-antibody ratio (DAR) of the conjugated sample.
  • the drug moiety e.g., cytotoxic drugs and TLR agonists
  • the average DAR of the ADC can be calculated.
  • the DAR of a given antibody drug conjugate sample represents the average number of drug (payload) molecules attached to a tetrameric antibody containing two light chains and two heavy chains.
  • the drug to antibody ratio has an exact value for a particular antibody drug conjugate molecule (e.g., m in formula (I)), it is understood that when used to describe samples containing many molecules, this value will often is an average value, which is due to some degree of non-uniformity typically associated with the coupling step.
  • the average loading of an antibody drug conjugate sample is referred to herein as the drug to antibody ratio or "DAR".
  • the DAR value (drug/antibody ratio of the conjugated sample) of the antibody drug conjugate is 1-10, for example: 1-2, 1-3, 1-4, 1-5, 1 ⁇ 6, 1 ⁇ 7, 1 ⁇ 8, 1 ⁇ 9, 1 ⁇ 10, 2 ⁇ 3, 2 ⁇ 4, 2 ⁇ 5, 2 ⁇ 6, 2 ⁇ 7, 2 ⁇ 8, 2 ⁇ 9, 2 ⁇ 10 ,3 ⁇ 4,3 ⁇ 5,3 ⁇ 6,3 ⁇ 7,3 ⁇ 8,3 ⁇ 9,3 ⁇ 10,4 ⁇ 5,4 ⁇ 6,4 ⁇ 7,4 ⁇ 8,4 ⁇ 9,4 ⁇ 10, 5 ⁇ 6, 5 ⁇ 7, 5 ⁇ 8, 5 ⁇ 9, 5 ⁇ 10, 6 ⁇ 7, 6 ⁇ 8, 6 ⁇ 9, 6 ⁇ 10, 7 ⁇ 8, 7 ⁇ 9, 7 ⁇ 10 , 8 to 9, 8 to 10, or 9 to 10, preferably 3 to 8, for example, 3.0 to 3.5, 3.0 to 4.0, 3.0 to 4.5, 3.0 to 5.0, 3.0 to 5.5, 3.0 to 6.0, 3.5 to 4.0, 3.5 ⁇ 4.5, 3.5 ⁇ 5.0,
  • treatment generally refers to the partial or complete stabilization or cure of a disease and/or the side effects resulting from the disease.
  • treatment encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of the disease, i.e., prevents their progression; or (b) alleviates the symptoms of the disease, i.e., causes regression of the disease or symptoms.
  • prevention refers to inhibiting and delaying the onset of a disease, including not only prevention before the development of the disease, but also prevention of the recurrence of the disease after treatment.
  • vertebrate refers to a mammal.
  • Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats.
  • the mammal is a human.
  • an effective amount refers to an amount effective in the necessary dosage and time to achieve the desired therapeutic effect.
  • the “therapeutically effective amount” may vary depending on factors such as the disease state, age, sex and weight of the individual and the ability of the active ingredient to elicit the desired response in the individual.
  • a therapeutically effective amount also encompasses an amount of an active ingredient in which the therapeutically beneficial effects outweigh any toxic or harmful consequences.
  • a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce the size of the tumor; inhibit (ie, slow down to a certain extent, preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (ie, slow down to a certain extent, preferably stop) Tumor metastasis; inhibiting tumor growth to a certain extent; and/or alleviating one or more symptoms related to cancer to a certain extent.
  • the structure of the compound is determined by nuclear magnetic resonance ( 1 H NMR) or mass spectrometry (MS).
  • the measurement instrument of 1 H NMR is JEOL Eclipse 400 nuclear magnetic instrument.
  • the measurement solvent is deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or hexadeuterated dimethyl sulfoxide (DMSO-d 6 ), and the internal standard is For tetramethylsilane (TMS), chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • the measuring instrument for MS is Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
  • Instrument model Agilent 1260, chromatographic column: Waters SunFire Prep C18OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); chromatographic column temperature: 25°C; flow rate: 20.0mL/min; detection wavelength: 214nm; elution gradient: (0min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: acetonitrile; mobile phase B: 0.05% formic acid aqueous solution.
  • the thin layer chromatography silica gel plate uses an aluminum plate (20 ⁇ 20cm) produced by Merck, and the specification used for thin layer chromatography separation and purification is GF 254 (1mm) produced in Yantai.
  • the reaction is monitored by thin layer chromatography (TLC) or LC-MS; the developing solvent systems used include: methylene chloride and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system.
  • TLC thin layer chromatography
  • LC-MS LC-MS
  • the volume of solvent The ratio can be adjusted according to the polarity of the compound or by adding triethylamine, etc.
  • Instrument model Biotage rapid medium pressure preparative chromatography, chromatographic column: Agela C18 reverse column (Spherical; 20-35 ⁇ m; 100A); chromatographic column temperature: 25°C; flow rate: 28.0mL/min; detection wavelength: 220nm; mobile phase A : Acetonitrile; Mobile phase B: 0.05% formic acid aqueous solution;
  • Microwave reaction uses Biotage Initiator+ (400W, RT ⁇ 300°C) microwave reactor.
  • Column chromatography generally uses 200 to 300 mesh silica gel as the carrier.
  • the eluent system includes: methylene chloride and methanol system, as well as petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.
  • reaction temperature is room temperature (20°C to 35°C).
  • the reagents used in this invention were purchased from Acros Organics, Aldrich Chemical Company, Tebo Chemical and other companies.
  • the first step Preparation of: (4-((6-nitrothieno[3,2-b]pyridin-7-yl)amino)butyl)carbamic acid tert-butyl ester
  • Second step Preparation of tert-butyl 4-((6-aminothieno[3,2-b]pyridin-7-yl)amino)butyl)carbamate
  • Step 3 Preparation of: (4-((6-pentanolamidothieno[3,2-b]pyridin-7-yl)amino)butyl)carbamic acid tert-butyl ester
  • Step 4 Preparation of (4-(2-butyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)butyl)carbamic acid tert-butyl ester
  • Step 7 1-(4-((tert-butoxycarbonyl)amino)butyl)-2-butyl-7-methyl-1H-imidazo[4,5-d]thieno[3,2- b] Preparation of pyridine-5-oxide
  • Step 8 (4-(4-amino-2-butyl-7-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)butyl ) Preparation of tert-butyl carbamate
  • Step 10 N-(4-(4-amino-2-butyl-7-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl) Preparation of butyl)-4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexane-1-carboxamide
  • Step 11 2-((1-((4-((4-((4-(4-(4-(4-amino-2-butyl-7-methyl-1H-imidazo[4,5-d]thieno[3, Preparation of 2-b]pyridin-1-yl)butyl)carbamoyl)cyclohexyl)methyl)-2,5-dioxopyrrolidin-3-yl)thio)acetic acid (Int1)
  • Step 6 7-bromo-2-butyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-1-carboxylic acid tert-butyl ester and 7-bromo-2-butan Preparation of tert-butyl-3H-imidazo[4,5-d]thieno[3,2-b]pyridine-3-carboxylate mixture
  • Step 7 7-bromo-1-(tert-butoxycarbonyl)-2-butyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine 5-oxide and 7- Preparation of bromo-3-(tert-butoxycarbonyl)-2-butyl-3H-imidazo[4,5-d]thieno[3,2-b]pyridine 5-oxide mixture
  • Step 8 7-bromo-2-butyl-4-(tert-butylamino)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-1-carboxylic acid tert-butyl Mixture of ester and 7-bromo-2-butyl-4-(tert-butylamino)-3H-imidazo[4,5-d]thieno[3,2-b]pyridine-3-carboxylic acid tert-butyl ester Preparation
  • Step 9 4-(2-butyl-4-(tert-butylamino)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-7-yl)-3, Preparation of tert-butyl 6-dihydropyridine-1(2H)-carboxylate
  • Step 10 4-(2-butyl-4-(tert-butylamino)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-7-yl)piperidine- Preparation of 1-carboxylic acid tert-butyl ester
  • Triethylamine (0.69g, 6.82mmol) was added to a solution of compound Int3-1 (2g, 3.41mmol) in dichloromethane (30mL), and methylsulfonyl chloride (0.58g, 5.12mmol) was added to the reaction solution while cooling in an ice-water bath. ) and stir at room temperature overnight. After the reaction is complete, dilute the reaction with methylene chloride. It was then washed with sodium carbonate solution and brine in sequence, and the organic phase was concentrated to obtain the title compound of this step (2.2 g, yield: 95.6%).
  • Dess-Martin oxidant (1.23 g, 29.3 mmol) was added to a solution of compound Int9-1 (1 g, 19.5 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature overnight.
  • Step 1 Preparation of benzyl 4-(((6-nitrothieno[3,2-b]pyridin-7-yl)amino)methyl)piperidine-1-carboxylate
  • Step 2 Preparation of 4-(((6-aminothieno[3,2-b]pyridin-7-yl)amino)methyl)piperidine-1-carboxylic acid benzyl ester
  • Step 3 Preparation of 4-(((6-pentanoamidothieno[3,2-b]pyridin-7-yl)amino)methyl)piperidine-1-carboxylic acid benzyl ester
  • Step 5 4-((7-bromo-2-butyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)methyl)piperidine-1 -Preparation of benzyl carboxylate
  • Step 6 4-((2-butyl-7-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)methyl)piperidine- Preparation of 1-carboxylic acid benzyl ester
  • Step 7 1-((1-((benzyloxy)carbonyl)piperidin)-4-yl)methyl)-2-butyl-7-methyl-1H-imidazo[4,5-d Preparation of ]thieno[3,2-b]pyridine-5-oxide
  • Step 8 4-((4-amino-2-butyl-7-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)methyl ) Preparation of piperidine-1-carboxylic acid benzyl ester
  • Step 2 Preparation of N 7 -((tetrahydro-2H-pyran-4-yl)methyl)thieno[3,2-b]pyridine-6,7-diamine
  • Step 7 7-bromo-N-(tert-butyl)-2-butyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5- Preparation of d]thieno[3,2-b]pyridin-4-amine
  • Step 8 4-(2-butyl-4-(tert-butylamino)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5- Preparation of d]thieno[3,2-b]pyridin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
  • Step 9 4-(2-butyl-4-(tert-butylamino)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5- Preparation of d]thieno[3,2-b]pyridin-7-yl)piperidine-1-carboxylic acid tert-butyl ester
  • Example 1-1 Using the synthetic route of Example 1-1, the reaction raw material 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(prop-2-yne-1 -yl)hexanamide was replaced with 6-(2-(methanesulfonyl)pyrimidin-5-yl)-N-(prop-2-yn-1-yl)hexa-5-ynamide to obtain the title compound of this step (3mg, yield: 5.6%).
  • Example 1-1 The synthetic route of Example 1-1 is adopted, and the reaction raw material compound Int5 is replaced by the compound Int6, 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-( Prop-2-yn-1-yl)hexanamide replaced with 6-(2-(methanesulfonyl)pyrimidin-5-yl)-N-(prop-2-yn-1-yl)hexa-5-ynamide , the title compound of this step (5 mg, yield: 8%) was obtained.
  • Example 1-1 The synthetic route of Example 1-1 was adopted, and the reaction raw material compound Int5 was replaced by compound Int6 to obtain the title compound of this step (10 mg, yield: 6%).

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