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WO2024227437A1 - 白介素-23受体的肽抑制剂制备及其用途 - Google Patents

白介素-23受体的肽抑制剂制备及其用途 Download PDF

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Publication number
WO2024227437A1
WO2024227437A1 PCT/CN2024/090789 CN2024090789W WO2024227437A1 WO 2024227437 A1 WO2024227437 A1 WO 2024227437A1 CN 2024090789 W CN2024090789 W CN 2024090789W WO 2024227437 A1 WO2024227437 A1 WO 2024227437A1
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Prior art keywords
peptide
compound
residues
trp
analog
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English (en)
French (fr)
Inventor
李瑶
陈雷
刘磊
黄海涛
唐平明
张晨
严庞科
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tibet Haisco Pharmaceutical Co Ltd
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Tibet Haisco Pharmaceutical Co Ltd
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Publication of WO2024227437A1 publication Critical patent/WO2024227437A1/zh
Priority to MX2025013162A priority Critical patent/MX2025013162A/es
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids

Definitions

  • the present invention relates to novel peptide inhibitors of the interleukin-23 receptor and their use in treating or preventing a variety of diseases and conditions, including inflammatory bowel disease, Crohn's disease and psoriasis.
  • the interleukin-23 (IL-23) cytokine has been implicated as playing a critical role in the pathogenesis of autoimmune diseases such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • IL-23R is expressed on a variety of adaptive and innate immune cells, including Th17 cells, ⁇ T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphocytes, which are abundant in the intestine.
  • IL-23R gene expression and protein levels were found to be elevated in patients with IBD.
  • TNF tumor necrosis factor
  • the produced IL-23 is enriched in the intestine, where it plays a key role in regulating the balance between tolerance and immunity through T cell-dependent and T cell-independent enteritis pathways, through its effects on helper T cell 1 (Th1) and Th17-related cytokines and inhibition of regulatory T cell responses in the intestine, which favor inflammation.
  • polymorphism of the IL-23 receptor (IL-23R) has been associated with susceptibility to inflammatory bowel disease (IBD), further establishing the key role of the IL-23 pathway in intestinal homeostasis.
  • Psoriasis is a chronic skin disease that affects 2% to 3% of the general population and has been shown to be mediated by the body's T cell inflammatory response mechanism.
  • IL-23 is one of several interleukins that is considered a key player in the pathogenesis of psoriasis, and is said to maintain chronic autoimmune inflammation through induction of interleukin-17, regulation of memory T cells, and activation of macrophages.
  • the expression of IL-23 and IL-23R has been shown to be increased in tissues of psoriasis patients, and antibodies that neutralize IL-23 show IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.
  • IL-23 is a heterodimer composed of a unique p19 subunit and the p40 subunit of IL-12, which is a helper T cell 1 (TH1) development cytokine involved in the production of interferon- ⁇ (IFN- ⁇ ).
  • T cell 1 helper T cell 1
  • IFN- ⁇ interferon- ⁇
  • both IL-23 and IL-12 contain the p40 subunit, they have different phenotypic properties.
  • IL-12-deficient animals are susceptible to inflammatory autoimmune diseases, while IL-23-deficient animals are resistant, presumably because the number of CD4+T cells producing IL-6, IL-17 and TNF in the CNS of IL-23-deficient animals is reduced.
  • IL-23 binds to IL-23R, a heterodimeric receptor composed of IL-12R ⁇ 1 and IL-23R subunits.
  • IL-23 binding to IL-23R activates Jak-stat signaling molecules, Jak2, Tyk2, as well as Stat1, Stat3, Stat4, and Stat5, although activation of Stat4 is substantially weaker and forms a different DNA-bound Stat complex in response to IL-23 than IL-12.
  • IL-23R constitutively binds to Jak2 and to Stat3 in a ligand-dependent manner.
  • IL-23 preferentially acts on memory CD4(+) T cells.
  • Therapeutic moieties that inhibit the IL-23 pathway have been identified for the treatment of IL-23-related diseases.
  • a large number of antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab (a humanized antibody that binds IL-23) that has been approved for the treatment of psoriasis.
  • Peptide inhibitors that bind to IL-23R and inhibit the binding of IL-23 to IL-23R have recently been identified.
  • the present invention discloses a novel peptide inhibitor of interleukin-23 receptor, its stereoisomers or pharmaceutically acceptable salts or solvates, or pharmaceutical compositions containing them, and use of the peptide inhibitor in treating or preventing diseases or conditions including inflammatory bowel disease, Crohn's disease and psoriasis.
  • the peptide compound of the present invention has protein stability, is stable to plasma proteases, epithelial proteases, gastric and intestinal proteases, lung surface proteases, intracellular proteases, etc.; has specific targeting to IL-23; has a long plasma half-life, and has good pharmacokinetic and pharmacodynamic properties.
  • the present invention relates to a cyclic peptide compound, a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate or dimer thereof, wherein the peptide compound has an amino acid sequence of formula (I), formula (II), formula (II-1), formula (III), formula (III-1), formula (IV), formula (IV-1), or formula (V):
  • the peptide compound is a dimer compound, wherein the dimer compound is formed by linking the peptide compound and the amino acid residues in the peptide compound via a polyethylene glycol chain; the polyethylene glycol chain is
  • n is any integer selected from 0-99;
  • the peptide compound is optionally conjugated with a modifying group at Xa 1 or at Xa 5 ;
  • the peptide compound is optionally conjugated with a modifying group at Xa 1 , Xa 5 or Xa 7 ;
  • the modifying group is p is any integer selected from 0-50, q is any integer selected from 0-50
  • the modifying group is p is selected from any integer between 0 and 50, q is selected from any integer between 0 and 50;
  • the modifying group is
  • p is selected from any integer between 0 and 5
  • q is selected from any integer between 0 and 5;
  • the modifying group is
  • p is 1 and q is 2;
  • Xa1 and Xa6 are each independently selected from Pen, Pcn, Asn, Ala, Ala(3-amino), Ala(2-ethyne), Ala(3-azido), Ala(2-ethene), Val(2-ethene), Asp, 2,4-diaminobutyric acid, Ser, Cys, Hcys, Glu, and the residues of Xa1 and Xa6 react to form a peptide ring or form a cyclic peptide via L1 ;
  • Xa1 and Xa6 are each independently selected from Pen, Asn, Ala, Ala (3-amino), Ala (2-ethyne), Ala (3-azido), Ala (2-ethene), Val (2-ethene), Asp, 2,4-diaminobutyric acid, Ser, Cys, Hcys, Glu, and the residues of Xa1 and Xa6 react to form a peptide ring;
  • Xa1 and Xa6 are each independently selected from Pen, Asn, Ala, Ala(3-amino), Ala(2-ethyne), Ala(3-azido), Ala(2-ethene), Val(2-ethene), and the residues of Xa1 and Xa6 react to form a peptide ring;
  • residues of Xa 1 and Xa 6 preferably undergo condensation reaction, RCM ring-closing reaction, etc. to form a peptide ring;
  • Xa 1 , Xa 6 are selected from Pen;
  • Xa 1 and Xa 6 are each independently selected from Asn or Ala(3-amino);
  • Xa 1 is selected from Asn
  • Xa 6 is selected from Ala(3-amino);
  • Xa 1 and Xa 6 are each independently selected from Ala (2-ethyne) or Ala (3-azido);
  • Xa1 is selected from Ala(3-azido)
  • Xa6 is selected from Ala(2-ethyne);
  • Xa 1 , Xa 6 are selected from Val(2-ethene);
  • Xa 1 , Xa 6 are selected from Ala (2-ethene);
  • Xa 1 and Xa 6 are each independently selected from Asp or Ala (3-amino);
  • Xa 1 , Xa 6 are selected from 2,4-diaminobutyric acid
  • Xa 1 and Xa 6 are each independently selected from 2,4-diaminobutyric acid or Asp;
  • Xa 1 and Xa 6 are each independently selected from Ser or Ala (3-amino);
  • Xa 1 and Xa 6 are each independently selected from 2,4-diaminobutyric acid or Ser;
  • Xa 1 , Xa 6 are selected from Ala(3-amino);
  • Xa 1 and Xa 6 are each independently selected from Cys or Asp;
  • Xa 1 and Xa 6 are each independently selected from Glu or Ala(3-amino);
  • Xa 1 and Xa 6 are each independently selected from Hcys or Asp;
  • the residues of Xa1 and Xa6 are reacted to form the following structure:
  • the residues of Xa1 and Xa6 are reacted to form the following structure:
  • the residues of Xa1 and Xa6 are reacted to form the following structure:
  • the * end is the Xa 1 end, Xa 1 and Xa 2 are connected through the * position, and the NH 2 end is connected to the protecting group;
  • the * end is the Xa 1 end, Xa 1 and Xa 2 are connected through the * position, and the NH 2 end is conjugated with a modifying group;
  • the modifying group conjugated to the NH2 terminus is selected from
  • the modifying group conjugated to the NH2 terminus is selected from
  • Xa2 is selected from Asn, His or analogs of Asn and His;
  • Xa2 is selected from Asn;
  • Xa2 is selected from Asn, His, or an analog of His selected from
  • Xa2 is selected from Asn, His, or an analog of His selected from
  • Xa2 is selected from Asn or an analog of His selected from
  • Xa3 is selected from Thr or an analog of Thr
  • Xa3 is selected from Thr;
  • Xa4 is selected from Trp or an analog of Trp
  • Xa4 is selected from an analog of Trp selected from
  • Xa5 is selected from Lys, Gln, Arg, Cit, or an analog of Lys, Gln, Cit, Arg; alternatively, the Xa5 residue is conjugated to a modifying group;
  • Xa5 is selected from Lys, Gln, Arg, Cit, or an analog of Lys, Gln, Cit, Arg;
  • Xa5 is selected from Lys, Gln, Arg, Cit, or an analog of Arg selected from
  • Xa5 is selected from Lys, Gln, Arg, or analogs of Lys, Gln and Arg;
  • Xa5 is selected from Lys, Gln, Arg, or an analog of Lys or Arg;
  • Xa5 is selected from Lys or an analog of Lys
  • Xa5 is selected from Lys
  • Xa 5 is selected from Lys, Gln, Arg, or an analog of Lys or Arg; the analog of Arg or Lys is selected from In some embodiments, Xa5 is selected from Lys, Gln, Arg or an analog of Arg selected from
  • the modifying group to which the Xa5 residue is conjugated is selected from
  • the modifying group to which the Xa5 residue is conjugated is selected from
  • Xa7 is selected from Phe or an analog of Phe; alternatively, the Xa7 residue is conjugated to a modifying group;
  • Xa7 is selected from Phe or an analog of Phe
  • Xa7 is selected from Phe or an analog of Phe selected from
  • Xa7 is selected from Phe or an analog of Phe selected from
  • Xa7 is selected from Phe or an analog of Phe selected from
  • the modifying group to which the Xa7 residue is conjugated is selected from
  • Xa8 is selected from Phe, Trp, 2-Nal, or analogs of Phe, Trp and 2-Nal;
  • Xa8 is selected from Phe, Trp, 2-Nal, or analogs of Phe, Trp and 2-Nal; the analogs of Phe, Trp and 2-Nal are selected from
  • Xa8 is selected from Phe, Trp, 2-Nal, or analogs of Phe, Trp and 2-Nal; the analogs of Phe, Trp and 2-Nal are selected from
  • Xa8 is selected from Phe, Trp, 2-Nal or analogs of Phe, Trp and 2-Nal; the analogs of Phe, Trp and 2-Nal are selected from
  • Xa9 is selected from Thp or an analog of Thp;
  • Xa9 is selected from Thp or an analog of Thp selected from
  • Xa9 is selected from Thp or an analog of Thp selected from
  • Xa10 is selected from Glu, Cys or analogs of Glu and Cys;
  • Xa 10 is selected from Glu or an analog of Glu
  • Xa 10 is selected from Glu
  • Xa 10 is selected from Glu or Cys
  • Xa11 is selected from Asn, Lys, or analogs of Asn and Lys;
  • Xa 11 is selected from Asn or Lys
  • Xa 11 is selected from Asn
  • Xa 11 is selected from Lys
  • Xa12 is selected from 3-Pal, Phe, Asp, or analogs of 3-Pal, Phe and Asp;
  • Xa 12 is selected from 3-Pal or Phe;
  • Xa13 is selected from Sarc or an analog of Sarc
  • Xa 13 is selected from Sarc
  • the residues of any amino acids among Xa 1 , Xa 2 , Xa 3 , Xa 4 , Xa 5 , Xa 7 , Xa 8 , Xa 9 , Xa 10 , Xa 11 , Xa 12 , and Xa 13 are condensed directly or linked via L 1 to form one or more peptide rings;
  • the residues of any amino acid among Xa 1 , Xa 2 , Xa 3 , Xa 4 , Xa 5 , Xa 7 , Xa 8 , Xa 9 , Xa 10 , Xa 11 , Xa 12 , and Xa 13 are linked via L 1 to form a peptide ring;
  • the residues of any amino acid among Xa 2 , Xa 3 , Xa 4 , Xa 5 , Xa 7 , Xa 8 , Xa 9 , Xa 10 , Xa 11 , Xa 12 , and Xa 13 are linked via L 1 to form a peptide ring;
  • any two amino acid residues among Xa 2 , Xa 3 , Xa 4 , Xa 5 , Xa 7 , Xa 8 , Xa 9 , Xa 10 , Xa 11 , Xa 12 , and Xa 13 are linked via L 1 to form a peptide ring;
  • any three amino acid residues of Xa 2 , Xa 3 , Xa 4 , Xa 5 , Xa 7 , Xa 8 , Xa 9 , Xa 10 , Xa 11 , Xa 12 , and Xa 13 are linked via L 1 to form a peptide ring;
  • polypeptides are separated by covalent bonds formed between the reactive groups Xa 1 , Xa 6 , and Xa 10 and the molecular scaffold to form a polypeptide ring containing at least two rings;
  • 2-Nal and Xa12 residues are linked via L1 to form a peptide ring; and/or
  • residues Xa9 and Xa12 are linked via L1 to form a peptide ring; and/or
  • Lys(Ac) and Xa7 residues are linked via L1 to form a peptide ring;
  • residues Xa7 and Xa11 are linked via L1 to form a peptide ring; and/or
  • residues Xa1 and Xa10 are linked via L1 to form a peptide ring; and/or
  • residues Xa1 and Xa11 are linked via L1 to form a peptide ring; and/or
  • Xa9 and Sarc residues are linked via L1 to form a peptide ring;
  • Xa 11 and Sarc residues are linked via L 1 to form a peptide ring;
  • Xa 1 and Glu residues are linked via L 1 to form a peptide ring, and Xa 11 and Sarc residues are linked via L 1 to form a peptide ring;
  • Trp (R 1 ) and the residue of Xa 5 are linked via L 1 to form a peptide ring;
  • Trp (CH 3 ) and Lys (Ac) are linked via L 1 to form a peptide ring;
  • 2-Nal and the residues of Xa 12 are linked via L 1 to form a peptide ring;
  • residues Xa 9 and Xa 12 are linked via L 1 to form a peptide ring;
  • Lys(Ac) and the residues of Xa7 are linked via L1 to form a peptide ring;
  • residues Xa7 and Xa11 are linked via L1 to form a peptide ring;
  • the residues of Xa 1 and Glu are linked via L 1 to form a peptide ring;
  • the residues of Xa 1 and Xa 10 are linked via L 1 to form a peptide ring;
  • the residues of Xa 1 and Xa 11 are linked via L 1 to form a peptide ring;
  • the residues of 2-Nal and Sarc are linked to form a peptide ring via L1 ;
  • Xa 9 and the residue of Sarc are linked via L 1 to form a peptide ring;
  • Xa 11 and the residue of Sarc are linked via L 1 to form a peptide ring;
  • the residues of Xa 1 , Sarc and Glu are linked via L 1 to form a peptide ring;
  • the residues of Xa 1 and Xa 6 react to form a peptide ring; and Trp (R 1 ) and the residue of Xa 5 are directly condensed or linked via L 1 to form a peptide ring;
  • the residues of Trp (CH 3 ) and Lys (Ac) are directly condensed or linked via L 1 to form a peptide ring;
  • L 1 is selected from W 1 -R L -W 2 ;
  • RL is selected from a bond, C1-6 alkylene, C2-4 alkenylene, C2-4 alkynylene, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl , 6-10 membered aryl, -( OCH2CH2 ) a- , wherein the alkylene, alkenylene, alkynylene, cycloalkyl, heterocycloalkyl, heteroaryl, aryl are optionally further substituted with 1-4 RL1s ;
  • RL is selected from a bond, C1-6 alkylene, C2-4 alkenylene, C2-4 alkynylene, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 6-10 membered aryl, wherein the alkylene, alkenylene, alkynylene, cycloalkyl, heterocycloalkyl, heteroaryl, aryl are optionally further substituted with 1-4 RL1 ;
  • W 1 and W 2 are each independently selected from a bond, C 1-6 alkylene, -O-, -S-, -NR W1 -, -CONR W1 -, -NR W1 CO-, -C( ⁇ O)O- or -OC( ⁇ O)-, one or more -CH 2 - in the alkylene is optionally replaced by 1-4 groups selected from -O-, -S-, -NR W1 - or -CO-, and the alkylene is optionally further substituted by 1-4 substituents selected from halogen, ⁇ O, C 1-4 alkyl, halogenated C 1-4 alkyl, CN, OH and NH 2 ;
  • R W1 is selected from H, C 1-4 alkyl, halogen
  • r is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • r is selected from 0, 1, 2, 3, 4 or 5;
  • r is selected from 0, 1, 2 or 3;
  • a is any integer selected from 0 to 10;
  • a is selected from 1, 2, 3, 4, 5 or 6;
  • a is selected from 3, 4, 5 or 6;
  • the protecting group is selected from Ac, glutaryl, succinyl, NH 2 or OH;
  • the protecting groups Ac, glutaryl, and succinyl of the present invention are connected to the N-terminus of the amino acid; the protecting groups NH 2 and OH are connected to the C-terminus of the amino acid;
  • there is no protecting group at the N-terminus and the C-terminus provided that: (1) when Xa 1 at the N-terminus is linked to other amino acid residues via L 1 , there is no protecting group at the N-terminus;
  • the C-terminal protecting group does not exist; alternatively, the polypeptide is separated by covalent bonds formed by reactive groups Xa 1 , Xa 6 , and Xa 10 with the molecular scaffold to form a polypeptide ring containing at least two rings;
  • the molecular scaffold is selected from:
  • the molecular scaffold is selected from:
  • the peptide compound is not selected from the following structure: (Ac)Pen-Asn-Thr-Trp(CH 3 )-Lys(Ac)-Pen-Phe[4-(2-aminoethoxy)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH 2 ), wherein a disulfide bond is formed between Pen and Pen.
  • the present invention provides a cyclic peptide compound, a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate or dimer thereof, wherein the peptide compound has an amino acid sequence of formula (I):
  • Xa2 is selected from Asn, His, or an analog of Asn or His;
  • Xa3 is selected from Thr or an analog of Thr
  • Xa4 is selected from Trp or an analog of Trp
  • Xa5 is selected from Lys, Gln, Arg, Cit, or an analog of Lys, Gln, Cit, Arg;
  • Xa7 is selected from Phe or an analog of Phe
  • Xa8 is selected from Phe, Trp, 2-Nal, or an analog of Phe, Trp, or 2-Nal;
  • Xa9 is selected from Thp or an analog of Thp;
  • Xa10 is selected from Glu, Cys, or analogs of Glu or Cys;
  • Xa11 is selected from Asn, Lys, or an analog of Asn or Lys;
  • Xa12 is selected from 3-Pal, Phe, Asp, or an analog of 3-Pal, Phe, Asp;
  • Xa13 is selected from Sarc or an analog of Sarc
  • the residues of any amino acids among Xa 1 , Xa 2 , Xa 3 , Xa 4 , Xa 5 , Xa 7 , Xa 8 , Xa 9 , Xa 10 , Xa 11 , Xa 12 , and Xa 13 are condensed directly or linked via L 1 to form one or more peptide rings;
  • L 1 is selected from W 1 -R L -W 2 ;
  • RL is selected from a bond, C1-6 alkylene, C2-4 alkenylene, C2-4 alkynylene, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl , 6-10-membered aryl, -( OCH2CH2 ) a- , wherein the alkylene, alkenylene, alkynylene, cycloalkyl, heterocycloalkyl, heteroaryl, and aryl are optionally further substituted with 1-4 RL1s ; in some embodiments, RL is selected from a bond, C1-6 alkylene, C2-4 alkenylene, C2-4 alkynylene, 3-6 -membered cycloalkyl, 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl, and 6-10-membered aryl, wherein the alkylene, alkenylene, alkynylene, cycloalkyl
  • a is any integer selected from 0 to 10;
  • W 1 and W 2 are each independently selected from a bond, C 1-6 alkylene, -O-, -S-, -NR W1 -, -CONR W1 -, -NR W1 CO-, -C( ⁇ O)O- or -OC( ⁇ O)-, one or more -CH 2 - in the alkylene is optionally replaced by 1-4 groups selected from -O-, -S-, -NR W1 - or -CO-, and the alkylene is optionally further substituted by 1-4 substituents selected from halogen, ⁇ O, C 1-4 alkyl, halogenated C 1-4 alkyl, CN, OH and NH 2 ;
  • R W1 is selected from H, C 1-4 alkyl, halogen
  • the protecting group is selected from Ac, glutaryl, succinyl, NH 2 or OH;
  • polypeptides are separated by covalent bonds formed between the reactive groups Xa 1 , Xa 6 , and Xa 10 and the molecular scaffold to form a polypeptide ring containing at least two rings;
  • the peptide compound is optionally conjugated with a modifying group at Xa 1 or at Xa 5 ; or alternatively, the peptide compound is optionally conjugated with a modifying group at Xa 1 , Xa 5 or Xa 7 ;
  • the peptide compound is not selected from the following structure: (Ac)Pen-Asn-Thr-Trp(CH 3 )-Lys(Ac)-Pen-Phe[4-(2-aminoethoxy)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH 2 ), wherein a disulfide bond is formed between Pen and Pen.
  • peptide compound has an amino acid sequence of formula (I):
  • Xa1 and Xa6 are each independently selected from Pen, Asn, Ala, Ala(3-amino), Ala(2-ethyne), Ala(3-azido), Ala(2-ethene), Val(2-ethene), Asp, 2,4-diaminobutyric acid, Ser, Cys, Hcys, Glu, and the residues of Xa1 and Xa6 react to form a peptide ring;
  • Xa2 is selected from Asn, His, or analogs of Asn and His;
  • Xa3 is selected from Thr or an analog of Thr
  • Xa4 is selected from Trp or an analog of Trp
  • Xa 5 is selected from Lys, Gln, Arg, Cit, or an analog of Lys, Gln, Cit, Arg; in some embodiments, Xa 5 is selected from Lys, Gln, Arg, or an analog of Lys, Gln, Arg;
  • Xa7 is selected from Phe or an analog of Phe
  • Xa8 is selected from Phe, Trp, 2-Nal, or an analog of Phe, Trp, or 2-Nal;
  • Xa9 is selected from Thp or an analog of Thp;
  • Xa10 is selected from Glu, Cys, or analogs of Glu or Cys;
  • Xa11 is selected from Asn, Lys, or an analog of Asn or Lys;
  • Xa12 is selected from 3-Pal, Phe, Asp, or an analog of 3-Pal, Phe, Asp;
  • Xa13 is selected from Sarc or an analog of Sarc
  • the residues of any amino acids among Xa1 , Xa2 , Xa3 , Xa4 , Xa5 , Xa7 , Xa8 , Xa9 , Xa10 , Xa11 , Xa12 , and Xa13 are directly condensed or linked via L1 to form one or more peptide rings; in some embodiments, the residues of any amino acids among Xa1 , Xa2 , Xa3 , Xa4 , Xa5 , Xa7 , Xa8 , Xa9 , Xa10 , Xa11 , Xa12 , and Xa13 are linked via L1 to form one or more peptide rings;
  • L 1 is selected from W 1 -R L -W 2 ;
  • RL is selected from a bond, C1-6 alkylene, C2-4 alkenylene, C2-4 alkynylene, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 6-10 membered aryl, wherein the alkylene, alkenylene, alkynylene, cycloalkyl, heterocycloalkyl, heteroaryl, aryl are optionally further substituted with 1-4 RL1s ;
  • W 1 and W 2 are each independently selected from a bond, C 1-6 alkylene, -O-, -S-, -NR W1 -, -CONR W1 -, -NR W1 CO-, -C( ⁇ O)O- or -OC( ⁇ O)-, one or more -CH 2 - in the alkylene is optionally replaced by 1-4 groups selected from -O-, -S-, -NR W1 - or -CO-, and the alkylene is optionally further substituted by 1-4 substituents selected from halogen, ⁇ O, C 1-4 alkyl, halogenated C 1-4 alkyl, CN, OH and NH 2 ;
  • R W1 is selected from H, C 1-4 alkyl, halogen
  • the protecting group is selected from Ac, glutaryl, succinyl, NH 2 or OH;
  • polypeptides are separated by covalent bonds formed between the reactive groups Xa 1 , Xa 6 , and Xa 10 and the molecular scaffold to form at least two polypeptide rings;
  • the peptide compound is not selected from the following structure: (Ac)Pen-Asn-Thr-Trp(CH 3 )-Lys(Ac)-Pen-Phe[4-(2-aminoethoxy)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH 2 ), wherein a disulfide bond is formed between Pen and Pen.
  • peptide compound has an amino acid sequence of formula (I):
  • Xa1 and Xa6 are each independently selected from Pen, Asn, Ala, Ala(3-amino), Ala(2-ethyne), Ala(3-azido), Ala(2-ethene), Val(2-ethene), Asp, 2,4-diaminobutyric acid, Ser, Cys, Hcys, Glu, and the residues of Xa1 and Xa6 react to form a peptide ring;
  • Xa2 is selected from Asn, His or analogs of Asn and His;
  • Xa3 is selected from Thr or an analog of Thr
  • Xa4 is selected from Trp or an analog of Trp
  • Xa5 is selected from Lys, Gln, Arg or an analog of Lys, Gln and Arg;
  • Xa7 is selected from Phe or an analog of Phe
  • Xa8 is selected from Phe, Trp, 2-Nal or analogs of Phe, Trp and 2-Nal;
  • Xa9 is selected from Thp or an analog of Thp;
  • Xa10 is selected from Glu, Cys or analogs of Glu and Cys;
  • Xa11 is selected from Asn, Lys or analogs of Asn and Lys;
  • Xa12 is selected from 3-Pal, Phe, Asp or an analog of 3-Pal, Phe and Asp;
  • Xa13 is selected from Sarc or an analog of Sarc
  • the residues of any amino acid among Xa 1 , Xa 2 , Xa 3 , Xa 4 , Xa 5 , Xa 7 , Xa 8 , Xa 9 , Xa 10 , Xa 11 , Xa 12 , and Xa 13 are linked via L 1 to form one or more peptide rings;
  • L 1 is selected from W 1 -R L -W 2 ;
  • RL is selected from a bond, C1-6 alkylene, C2-4 alkenylene, C2-4 alkynylene, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 6-10 membered aryl, wherein the alkylene, alkenylene, alkynylene, cycloalkyl, heterocycloalkyl, heteroaryl, aryl are optionally further substituted with 1-4 RL1s ;
  • W 1 and W 2 are each independently selected from a bond, C 1-6 alkylene, -O-, -S-, -NR W1 -, -CONR W1 -, -NR W1 CO-, -C( ⁇ O)O- or -OC( ⁇ O)-, one or more -CH 2 - in the alkylene is optionally replaced by 1-4 groups selected from -O-, -S-, -NR W1 - or -CO-, and the alkylene is optionally further substituted by 1-4 substituents selected from halogen, ⁇ O, C 1-4 alkyl, halogenated C 1-4 alkyl, CN, OH and NH 2 ;
  • R W1 is selected from H, C 1-4 alkyl, halogen
  • the protecting group is selected from Ac, glutaryl, succinyl, NH 2 or OH;
  • the peptide compound is not selected from the following structure: (Ac)Pen-Asn-Thr-Trp(CH 3 )-Lys(Ac)-Pen-Phe[4-(2-aminoethoxy)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH 2 ), wherein a disulfide bond is formed between Pen and Pen.
  • peptide compound has an amino acid sequence of formula (I):
  • Xa1 and Xa6 are each independently selected from Pen, Asn, Ala, Ala(3-amino), Ala(2-ethyne), Ala(3-azido), Ala(2-ethene), Val(2-ethene), and the residues of Xa1 and Xa6 react to form a peptide ring;
  • Xa2 is selected from Asn, His or analogs of Asn and His;
  • Xa3 is selected from Thr or an analog of Thr
  • Xa4 is selected from Trp or an analog of Trp
  • Xa5 is selected from Lys or an analog of Lys
  • Xa7 is selected from Phe or an analog of Phe
  • Xa8 is selected from Phe, Trp, 2-Nal or analogs of Phe, Trp and 2-Nal;
  • Xa9 is selected from Thp or an analog of Thp;
  • Xa10 is selected from Glu or an analog of Glu
  • Xa11 is selected from Asn, Lys or analogs of Asn and Lys;
  • Xa12 is selected from 3-Pal, Phe, Asp or an analog of 3-Pal, Phe and Asp;
  • Xa13 is selected from Sarc or an analog of Sarc
  • any amino acid residue among Xa 2 , Xa 3 , Xa 4 , Xa 5 , Xa 7 , Xa 8 , Xa 9 , Xa 10 , Xa 11 , Xa 12 , and Xa 13 are linked via L 1 to form a peptide ring;
  • L 1 is selected from W 1 -R L -W 2 ;
  • RL is selected from a bond, C1-6 alkylene, C2-4 alkenylene, C2-4 alkynylene, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 6-10 membered aryl, wherein the alkylene, alkenylene, alkynylene, cycloalkyl, heterocycloalkyl, heteroaryl, aryl are optionally further substituted with 1-4 RL1s ;
  • W 1 and W 2 are each independently selected from a bond, C 1-6 alkylene, -O-, -S-, -NR W1 -, -CONR W1 -, -NR W1 CO-, -C( ⁇ O)O- or -OC( ⁇ O)-, one or more -CH 2 - in the alkylene is optionally replaced by 1-4 groups selected from -O-, -S-, -NR W1 - or -CO-, and the alkylene is optionally further substituted by 1-4 substituents selected from halogen, ⁇ O, C 1-4 alkyl, halogenated C 1-4 alkyl, CN, OH and NH 2 ;
  • R W1 is selected from H, C 1-4 alkyl, halogen
  • the protecting group is selected from Ac, glutaryl, succinyl, NH 2 or OH;
  • the peptide compound is not selected from the following structure: (Ac)Pen-Asn-Thr-Trp(CH 3 )-Lys(Ac)-Pen-Phe[4-(2-aminoethoxy)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH 2 ), wherein a disulfide bond is formed between Pen and Pen.
  • the peptide compound As a more specific second technical solution of the present invention, the peptide compound, its stereoisomer or its pharmaceutically acceptable salt or solvate or dimer, wherein the peptide compound has an amino acid sequence of formula (II) or formula (II-1):
  • residues of Xa 1 and Xa 6 react to form a peptide ring; or the residues of Xa 1 and Xa 6 are linked via L 1 to form a peptide ring;
  • the peptide compound has an amino acid sequence of formula (II-1):
  • the peptide compound, its stereoisomer or its pharmaceutically acceptable salt or solvate or dimer wherein the peptide compound has an amino acid sequence of formula (III) or formula (III-1):
  • residues of Xa 1 and Xa 6 react to form a peptide ring; or the residues of Xa 1 and Xa 6 are linked via L 1 to form a peptide ring;
  • Trp (R 1 ) and the residue of Xa 5 are directly condensed or linked via L 1 to form a peptide ring;
  • Trp (CH 3 ) and Lys (Ac) residues are directly condensed or linked via L 1 to form a peptide ring;
  • Xa 1 , Xa 6 , Xa 10 and the molecular framework form a bicyclic peptide
  • the peptide compound has an amino acid sequence of formula (III) or formula (III-1):
  • Trp (R 1 ) and the residue of Xa 5 are linked via L 1 to form a peptide ring;
  • Trp (CH 3 ) and Lys (Ac) are linked via L 1 to form a peptide ring;
  • Xa 1 , Xa 6 , Xa 10 and the molecular framework form a bicyclic peptide
  • the peptide compound has an amino acid sequence of formula (III-1):
  • Trp (R 1 ) and the residue of Xa 5 are linked via L 1 to form a peptide ring;
  • Trp (CH 3 ) and Lys (Ac) are linked via L 1 to form a peptide ring;
  • the peptide compound has an amino acid sequence of formula (III-1):
  • Trp (CH 3 ) and Lys (Ac) are linked through L 1 to form a peptide ring;
  • the peptide compound As a more specific fourth technical solution of the present invention, the peptide compound, its stereoisomer or its pharmaceutically acceptable salt or solvate or dimer, wherein the peptide compound has an amino acid sequence of formula (IV), formula (IV-1) or formula (V):
  • residues of Xa 1 and Xa 6 react to form a peptide ring; or the residues of Xa 1 and Xa 6 are linked via L 1 to form a peptide ring;
  • residues Xa9 and Xa12 are linked via L1 to form a peptide ring; and/or
  • Lys(Ac) and Xa7 residues are linked via L1 to form a peptide ring;
  • residues Xa7 and Xa11 are linked via L1 to form a peptide ring; and/or
  • residues Xa1 and Xa11 are linked via L1 to form a peptide ring; and/or
  • residues Xa1 and Xa10 are linked via L1 to form a peptide ring; and/or
  • Xa9 and Sarc residues are linked via L1 to form a peptide ring;
  • Xa 11 and Sarc residues are linked via L 1 to form a peptide ring;
  • Xa 1 , Xa 6 , Xa 10 and the molecular framework form a bicyclic peptide
  • the conditions are: (1) when Xa 1 at the N-terminus is linked to other amino acid residues via L 1 , the N-terminus protecting group does not exist;
  • the peptide compound has an amino acid sequence of formula (IV) or formula (IV-1):
  • residues Xa9 and Xa12 are linked via L1 to form a peptide ring; and/or
  • Lys(Ac) and Xa7 residues are linked via L1 to form a peptide ring;
  • residues Xa7 and Xa11 are linked via L1 to form a peptide ring; and/or
  • residues Xa1 and Xa11 are linked via L1 to form a peptide ring; and/or
  • residues Xa1 and Xa10 are linked via L1 to form a peptide ring; and/or
  • Xa9 and Sarc residues are linked via L1 to form a peptide ring;
  • Xa 11 and Sarc residues are linked via L 1 to form a peptide ring;
  • the conditions are: (1) when Xa 1 at the N-terminus is linked to other amino acid residues via L 1 , the N-terminus protecting group does not exist;
  • the peptide compound has an amino acid sequence of formula (IV-1):
  • residues Xa9 and Xa12 are linked via L1 to form a peptide ring; and/or
  • Lys(Ac) and Xa7 residues are linked via L1 to form a peptide ring;
  • residues Xa7 and Xa11 are linked via L1 to form a peptide ring; and/or
  • residues Xa1 and Xa11 are linked via L1 to form a peptide ring; and/or
  • Xa9 and Sarc residues are linked via L1 to form a peptide ring;
  • Xa 11 and Sarc residues are linked via L 1 to form a peptide ring;
  • the conditions are: (1) when Xa 1 at the N-terminus is linked to other amino acid residues via L 1 , the N-terminus protecting group does not exist;
  • Xa 1 , Xa 6 , Xa 10 and the molecular framework form a bicyclic peptide
  • Xa 1 , Xa 6 , Xa 10 and the molecular framework form a bicyclic peptide
  • the peptide compound, its stereoisomer or its pharmaceutically acceptable salt or solvate or dimer wherein the peptide compound and the amino acid residues in the peptide compound are connected through a polyethylene glycol chain to form a dimer compound; the polyethylene glycol chain is
  • n is any integer selected from 0-99;
  • the peptide compound, its stereoisomer or its pharmaceutically acceptable salt or solvate or dimer wherein the modifying group is p is selected from any integer between 0 and 50, q is selected from any integer between 0 and 50; in some embodiments, the modifying group is p is selected from any integer between 0 and 50, q is selected from any integer between 0 and 50;
  • modifying group is p is selected from any integer between 0 and 5
  • q is selected from any integer between 0 and 5;
  • the * end is Xa 1 end, Xa 1 and Xa 2 are connected through the * position, and the NH 2 end is connected to a protecting group; or the * end is Xa 1 end, Xa 1 and Xa 2 are connected through the * position, and the NH 2 end is connected to a protecting group or the NH 2 end is conjugated with a modifying group;
  • Xa2 is selected from Asn, His, or an analog of His, wherein the analog of His is selected from Or the His analogue is selected from Or the His analogue is selected from
  • Xa 3 is selected from Thr;
  • Xa 4 is selected from the group consisting of Trp analogs selected from
  • Xa5 is selected from Lys, Gln, Arg, Cit, or an analog of Arg or Lys, wherein the analog of Arg or Lys is selected from
  • the Xa 5 residue is conjugated to a modifying group
  • Xa7 is selected from Phe or an analog of Phe selected from
  • the Xa7 residue is conjugated to a modifying group
  • Xa8 is selected from Phe, Trp, 2-Nal, or analogs of Phe, Trp and 2-Nal; the analogs of Phe, Trp and 2-Nal are selected from Or choose from
  • Xa9 is selected from Thp or an analog of Thp selected from
  • Xa 10 is selected from Glu or Cys
  • Xa 11 is selected from Asn or Lys
  • Xa12 is selected from 3-Pal or Phe;
  • the molecular framework is selected from: Or choose from
  • the * end is the Xa 1 end, Xa 1 and Xa 2 are connected through the * position, and the NH 2 end is connected to the protecting group;
  • Xa2 is selected from Asn, His or an analog of His, wherein the analog of His is selected from
  • Xa 4 is selected from the group consisting of Trp analogs selected from
  • Xa5 is selected from Lys, Gln, Arg or an analog of Arg, wherein the analog of Arg is selected from
  • Xa7 is selected from Phe or an analog of Phe selected from
  • Xa8 is selected from Phe, Trp, 2-Nal or analogs of Phe, Trp and 2-Nal; the analogs of Phe, Trp and 2-Nal are selected from
  • Xa9 is selected from Thp or an analog of Thp selected from
  • Xa 10 is selected from Glu or Cys
  • Xa 11 is selected from Asn or Lys
  • Xa12 is selected from 3-Pal or Phe;
  • the molecular framework is selected from:
  • residues of Xa1 and Xa6 react to form the following structure: Alternatively, the residues of Xa1 and Xa6 react to form the following structure: Alternatively, the residues of Xa1 and Xa6 react to form the following structure:
  • the * end is the Xa 1 end, Xa 1 and Xa 2 are connected through the * position, and the NH 2 end is connected to the protecting group;
  • Xa2 is selected from Asn, His or an analog of His, wherein the analog of His is selected from
  • Xa 4 is selected from the group consisting of Trp analogs selected from
  • Xa5 is selected from Lys, Gln, Arg or an analog of Arg selected from
  • Xa7 is selected from Phe or an analog of Phe selected from In some embodiments, Xa7 is selected from Phe or an analog of Phe selected from
  • Xa8 is selected from Phe, Trp, 2-Nal or analogs of Phe, Trp and 2-Nal; the analogs of Phe, Trp and 2-Nal are selected from Or the Trp analogue is selected from
  • Xa9 is selected from Thp or an analog of Thp selected from
  • Xa 10 is selected from Glu or Cys
  • Xa 11 is selected from Asn or Lys
  • Xa12 is selected from 3-Pal or Phe;
  • the molecular scaffold is selected from:
  • the peptide compound, its stereoisomer or its pharmaceutically acceptable salt or solvate or dimer wherein
  • r is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • a is selected from 3, 4, 5 or 6;
  • the peptide compound, its stereoisomer or its pharmaceutically acceptable salt or solvate or dimer wherein the peptide compound is selected from one of the structures in the following Table 1:
  • the present invention also relates to a pharmaceutical composition, comprising the peptide compound or a pharmaceutically acceptable salt thereof as described in any one of the first to eleventh technical solutions above, and a pharmaceutically acceptable carrier and/or excipient.
  • the present invention also relates to a use of the peptide compound or its pharmaceutically acceptable salt described in any one of the first to eleventh technical solutions, or the pharmaceutical composition, in the preparation of a drug for preventing and treating a disease or condition in which IL-23 is overexpressed in a diseased tissue of a subject.
  • the diseases or conditions that overexpress IL-23 include inflammatory bowel disease, Crohn's disease and psoriasis.
  • the present invention also relates to a pharmaceutical composition or pharmaceutical preparation, which comprises 1-1500 mg of the peptide compound or a pharmaceutically acceptable salt thereof described in any one of the first to eleventh technical solutions mentioned above, and a pharmaceutically acceptable carrier and/or excipient.
  • the present invention also relates to a method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of the peptide compound or a pharmaceutically acceptable salt thereof as described in any one of the first to eleventh technical solutions above, the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably inflammatory bowel disease, Crohn's disease and psoriasis.
  • the present invention also provides a composition or pharmaceutical preparation, which contains the peptide compound or a pharmaceutically acceptable salt thereof as described in any one of the above schemes, and a pharmaceutically acceptable carrier and/or excipient.
  • the pharmaceutical composition can be in the form of a unit preparation (a unit preparation is also referred to as a "preparation specification").
  • composition or pharmaceutical preparation of the present invention contains 1-1500 mg of the peptide compound or a pharmaceutically acceptable salt thereof described in any one of the aforementioned schemes, and a pharmaceutically acceptable carrier and/or excipient.
  • the present invention also provides the use of the peptide compound or a pharmaceutically acceptable salt thereof described in any one of the above schemes in the preparation of a drug for preventing and treating a disease or condition in which IL-23 is overexpressed in a diseased tissue of a subject.
  • the disease or condition in which IL-23 is overexpressed includes inflammatory bowel disease, Crohn's disease and psoriasis.
  • the present invention also provides a method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of a peptide compound or a pharmaceutically acceptable salt thereof as shown in any one of the aforementioned schemes, the disease preferably being inflammatory bowel disease, Crohn's disease and psoriasis, and the therapeutically effective amount preferably being 1-1500 mg.
  • the mammal in the present invention does not include a human.
  • an "effective amount” or “therapeutically effective amount” described in the present application refers to the administration of a sufficient amount of the compound disclosed in the present application, which will alleviate one or more symptoms of the disease or condition being treated to some extent. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms or causes of the disease, or any other desired changes in the biological system.
  • an "effective amount” for therapeutic use is the amount of a composition comprising a peptide compound disclosed in the present application or a pharmaceutically acceptable salt thereof required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-100
  • the pharmaceutical composition or formulation of the present invention contains the above-mentioned therapeutically effective amount of the peptide compound of the present invention or a pharmaceutically acceptable salt thereof;
  • the present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the peptide compound of the present invention or a pharmaceutically acceptable salt thereof and a carrier and/or excipient.
  • the pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").
  • the pharmaceutical composition includes but is not limited to 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 0mg, 240mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 850
  • a method for treating a disease in a mammal or a human comprising administering to a subject a therapeutically effective amount of a peptide compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or excipient, the therapeutically effective amount being preferably 1-1500 mg, and the disease being preferably inflammatory bowel disease, Crohn's disease and psoriasis.
  • a method for treating a disease in a mammal or a human comprising administering a pharmaceutical peptide compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or excipient to a subject at a daily dose of 1-1500 mg/day
  • the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 20-1500 mg/day, 25-1500 mg/day, 50-1500 mg/day, 75-1500 mg/day, 100-1500 mg/day, 200-1500 mg/day, 10-1000 mg/day, 20-1000 mg/day, 25-1000 mg/day, 50-1000 mg/day, 75-1000 mg/day, 100-1000 mg/day In some embodiments, the daily dose includes but is not limited to 1 mg/day, 5 mg/day, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 800 mg/day, 100 mg/day, 200 mg/day, 400 mg/day, 600
  • the present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains the peptide compound of the present invention or a pharmaceutically acceptable salt thereof, and the amount of the compound of the present invention or its stereoisomer or pharmaceutically acceptable salt is the same as that in the above-mentioned pharmaceutical composition.
  • the amount of the compound according to the invention or its stereoisomer or pharmaceutically acceptable salt in the present invention is in each case calculated as the free base.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • peptide refers broadly to a sequence of two or more amino acids linked together by peptide bonds. It should be understood that the term neither implies a specific length of amino acid polymer, nor is it intended to imply or distinguish whether the polypeptide is produced using recombinant technology, chemical synthesis or enzyme synthesis or whether it is naturally present.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (deuterium, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes 19 F, chlorine isotopes include 35 Cl and 37 Cl, bromine isotopes include 79 Br and 81 Br. Radiolabeled compounds of the compounds disclosed in the present invention can be prepared using standard methods known in the art.
  • Dimer of the present invention refers to a peptide comprising two or more monomer subunits in a broad sense. Some dimers contain two DRPs. Dimers of the present invention include homodimers and heterodimers. The monomer subunits of the dimer can be connected at its C-terminus or N-terminus, or it can be connected via internal amino acid residues. Each monomer subunit of the dimer can be connected by the same site, or each can be connected by different sites (e.g., C-terminus, N-terminus or internal sites).
  • cyclization or "peptide ring formation” as used herein refers to a reaction in which one part of a polypeptide molecule is connected to another part of the polypeptide molecule to form a closed ring, or one part of a polypeptide molecule is connected to several other parts of the polypeptide molecule to form multiple closed rings, such as by forming a disulfide bridge or other similar bonds, or by linker connection.
  • Derivatives or “analogs” as described herein refer to products derived from the replacement of hydrogen atoms or atomic groups in a compound by other atoms or atomic groups. It should be understood that amino acid analogs of peptide compounds as defined herein are within the scope of the present invention.
  • suitable modified amino acid derivatives include one or more modifications selected from the following: N-terminal and/or C-terminal modification; replacement of one or more amino acid residues with one or more non-natural amino acid residues (e.g., replacement of one or more polar amino acid residues with one or more isosteric or isoelectronic amino acids; replacement of one or more non-polar amino acid residues with other non-natural isosteric or isoelectronic amino acids); addition of spacer groups; replacement of one or more oxidation-sensitive amino acid residues with one or more oxidation-tolerant amino acid residues; replacement of one or more amino acid residues with alanine, and replacement of one or more L-amino acid residues with one or more D-amino acid residues; N-alkylation of one or more amide bonds in the bicyclic peptide ligand; replacement of one or more peptide bonds with a surrogate bond; modification of peptide backbone length; replacement or substitution of a hydrogen on the ⁇
  • “Pharmaceutically acceptable salt” refers to a salt of the compound of the present invention which retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.
  • a “pharmaceutical composition” refers to a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals thereof, with other ingredients, wherein the other ingredients include physiologically/pharmaceutically acceptable carriers and/or excipients.
  • Carrier refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the targeted organ.
  • Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.
  • Excipient refers to a substance that is not a therapeutic agent in itself but is used as a diluent, adjuvant, binder and/or vehicle that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration.
  • pharmaceutical excipients can serve a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners.
  • Examples of pharmaceutical excipients include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and cross-linked carboxymethylcellulose (e.g., cross-linked sodium carboxymethylcellulose); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl
  • the structures of the compounds were determined by mass spectrometry (MS).
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • Step 2 Dissolve compound 1b (7.4 g, 45.9 mmol) in dichloromethane (100 mL), add triethylamine (7 g, 68.9 mmol) and di-tert-butyl dicarbonate (12 g, 55.2 mmol), stir the reaction overnight, then add dichloromethane (100 mL) to dilute, wash three times with water (100 mL), and then concentrate the organic phase to obtain compound 1c (10 g, 83.2%).
  • Step 3 Dissolve ( ⁇ ) benzyloxycarbonyl-a-phosphonoglycine trimethyl ester (14 g, 42.3 mmol) in dichloromethane (100 mL), add DBU (6.43 g, 42.3 mmol) after nitrogen replacement and stir for 30 min, then dissolve compound 1c (10 g, 38.4 mmol) in dichloromethane (100 mL) and add dropwise to the reaction, continue stirring overnight, dilute the reaction mixture with dichloromethane (100 mL) and wash with 5% citric acid aqueous solution (100 mL) and saturated brine (100 mL), then dry with anhydrous sodium sulfate, filter and spin dry.
  • EA: PE 3: 1) to obtain compound 1d (12 g, 67.1%).
  • Step 4 Compound 1d (5 g, 10.74 mmol) was dissolved in a mixed solution of methanol (50 mL) and dichloromethane (20 mL), (+)-1,2-bis(2S,5S)-2,5-diethylcyclobutanephosphine benzene(cyclooctadiene)trifluoromethanesulfonate rhodium (0.5 g, 0.69 mmol) was added, and an autoclave was filled with hydrogen to a pressure of about 4.0 bar. The mixture was stirred at room temperature for 3 h, the solid was filtered out, and the reaction solution was concentrated to obtain compound 1e (5 g, 99.8%).
  • Step 5 Dissolve compound 1e (5 g, 10.69 mmol) in a mixed solution of methanol (50 mL) and dichloromethane (20 mL), add palladium carbon (10%, 1 g), stir overnight under a hydrogen atmosphere, then filter out the solid, and spin dry the reaction solution to obtain compound 1f (3.2 g, 89.7%).
  • Step 6 Compound 1f (3.2 g, 9.60 mmol) was added to dichloromethane (30 mL), and trifluoroacetic acid (10 mL) was added dropwise. The reaction was stirred at room temperature for 2 h. LCMS monitored that the raw material was completely consumed, and the crude compound 1g was directly dried and used in the next step without purification.
  • Step 7 Dissolve compound 1g (2.2 g, 9.43 mmol) in tetrahydrofuran (20 mL), add lithium hydroxide monohydrate (1.58 g, 37.7 mmol) and water (20 mL), and stir the reaction at room temperature overnight. Use ethyl acetate to extract (10 mL x 3) to remove impurities, and then adjust the pH of the aqueous phase to neutral with dilute hydrochloric acid (1N). The product precipitated, filtered and dried to obtain compound 1h (2 g, 96.7%).
  • Step 1 Compound 2a (10.0 g, 75.65 mmol) was dissolved in dichloromethane (100 mL), SnCl 4 (23.7 g, 90.78 mmol) was added dropwise to the above reaction solution, and the temperature was lowered to 0°C. After 5 min, 1,1-dichlorodimethyl ether (9.6 g, 83.22 mmol) was added dropwise, and the mixture was stirred at 0°C for 3 h.
  • Step 2 ( ⁇ ) benzyloxycarbonyl-a-phosphonoglycine trimethyl ester (9.9 g, 29.93 mmol) was dissolved in dichloromethane (100 mL), and DBU (4.9 g, 32.42 mmol) was added after nitrogen replacement and stirred for 30 min, and then compound 2b (4.0 g, 24.94 mmol) was dissolved in dichloromethane (100 mL) and added dropwise to the reaction, stirred overnight, and the reaction mixture was diluted with dichloromethane (100 mL) and washed with 5% citric acid aqueous solution (100 mL) and saturated brine (100 mL), then dried over anhydrous sodium sulfate, filtered and spin-dried.
  • Step 3 Dissolve compound 2c (6.0 g, 16.42 mmol) in a mixed solution of methanol (50 mL) and dichloromethane (20 mL), add (+)-1,2-bis(2S,5S)-2,5-diethylcyclobutanephosphine benzene(cyclooctadiene)trifluoromethanesulfonate rhodium (0.6 g, 0.84 mmol), fill the autoclave with hydrogen to a pressure of about 4.0 bar, stir at room temperature for 3 h, filter out the solid, and concentrate the reaction solution to obtain compound 2d (5.9 g, 98%).
  • Step 4 Dissolve compound 2d (5.9 g, 9.08 mmol) in a mixed solution of methanol (50 mL) and dichloromethane (20 mL), add palladium carbon (10%, 1 g), stir overnight under hydrogen atmosphere, then filter out the solid, and spin dry the reaction solution to obtain compound 2e (3.5 g, 93.4%).
  • Step 5 Dissolve compound 2e (3.5 g, 15.00 mmol) in tetrahydrofuran (35 mL), add lithium hydroxide monohydrate (1.4 g, 59.71 mmol) and water (25 mL), and stir the reaction at room temperature overnight. Use ethyl acetate to extract (20 mL x 3) to remove impurities, and then adjust the pH of the aqueous phase to neutral with dilute hydrochloric acid (1N). The product precipitates, is filtered and dried to obtain compound 2f (2.8 g, 85.1%).
  • Step 1 Compound 3a (10.0 g, 73.43 mmol) was dissolved in dichloromethane (100 mL), TiCl 4 (25.5 g, 134.38 mmol) was added dropwise to the above reaction solution, and the temperature was lowered to 0°C. After 5 min, 1,1-dichlorodimethyl ether (9.4 g, 81.51 mmol) was added dropwise, and the mixture was stirred at 0°C for 3 h.
  • Step 2 Compound 3b (3.0 g, 18.27 mmol), tert-butyl (2-bromoethyl)carbamate (4.9 g, 21.91 mmol), potassium carbonate (5.1 g, 36.54 mmol), sodium iodide (0.8 g, 5.47 mmol) were dissolved in N,N-dimethylformamide (20 mL) and stirred at 25°C for 16 h.
  • Step 3 ( ⁇ ) benzyloxycarbonyl-a-phosphonoglycine trimethyl ester (6.2 g, 18.74 mmol) was dissolved in dichloromethane (100 mL), and DBU (3.1 g, 20.31 mmol) was added after nitrogen replacement and stirred for 30 min, and then compound 3c (4.8 g, 15.62 mmol) was dissolved in dichloromethane (100 mL) and added dropwise to the reaction, stirred overnight, and the reaction mixture was diluted with dichloromethane (100 mL) and washed with 5% citric acid aqueous solution (100 mL) and saturated brine (100 mL), then dried over anhydrous sodium sulfate, filtered and spin-dried.
  • Step 4 Compound 3d (6.0 g, 11.71 mmol) was dissolved in a mixed solution of methanol (50 mL) and dichloromethane (20 mL), (+)-1,2-bis(2S,5S)-2,5-diethylcyclobutanephosphine benzene(cyclooctadiene)trifluoromethanesulfonate rhodium (0.6 g, 0.83 mmol) was added, and an autoclave was filled with hydrogen to a pressure of about 4.0 bar. The mixture was stirred at room temperature for 3 h, the solid was filtered out, and the reaction solution was concentrated to obtain compound 3e (5.9 g, 98%).
  • Step 5 Dissolve compound 3e (5.9 g, 11.46 mmol) in a mixed solution of methanol (50 mL) and dichloromethane (20 mL), add palladium carbon (10%, 1 g), stir overnight under hydrogen environment, then filter out the solid, and spin dry the reaction solution to obtain compound 3f (3.7 g, 84.5%).
  • Step 6 Dissolve compound 3f (3.7 g, 9.72 mmol) in tetrahydrofuran (25 mL), add lithium hydroxide monohydrate (1.2 g, 48.6 mmol) and water (25 mL), and stir the reaction at room temperature overnight. Use ethyl acetate to extract (15 mL x 3) to remove impurities, and then adjust the pH of the aqueous phase to neutral with dilute hydrochloric acid (1N). The product precipitates, is filtered and dried to obtain compound 3g (3.2 g, 89.8%).
  • Step 2 ( ⁇ ) benzyloxycarbonyl-a-phosphonoglycine trimethyl ester (6.1 g, 18.47 mmol) was dissolved in dichloromethane (100 mL), and DBU (3.1 g, 20.02 mmol) was added after nitrogen replacement and stirred for 30 min, and then compound 4b (4.1 g, 15.40 mmol) was dissolved in dichloromethane (100 mL) and added dropwise to the reaction, stirred overnight, and the reaction mixture was diluted with dichloromethane (100 mL) and washed with 5% citric acid aqueous solution (100 mL) and saturated brine (100 mL), then dried over anhydrous sodium sulfate, filtered and spin-dried.
  • Step 3 Dissolve compound 4c (4.4 g, 9.33 mmol) in a mixed solution of methanol (40 mL) and dichloromethane (20 mL), add (+)-1,2-bis(2S,5S)-2,5-diethylcyclobutanephosphine benzene(cyclooctadiene)trifluoromethanesulfonate rhodium (0.6 g, 0.83 mmol), fill the autoclave with hydrogen to a pressure of about 4.0 bar, stir at room temperature for 3 h, filter out the solid, and concentrate the reaction solution to obtain compound 4d (4.3 g, 97%).
  • Step 4 Compound 4d (4.3 g, 9.08 mmol) was dissolved in a mixed solution of methanol (50 mL) and dichloromethane (20 mL), palladium carbon (10%, 1 g) was added, and the mixture was stirred overnight under a hydrogen atmosphere. The solid was then filtered off and the reaction solution was dried to obtain compound 4e (2.9 g, 94.1%).
  • Step 5 Dissolve compound 4e (3.0 g, 8.84 mmol) in tetrahydrofuran (25 mL), add lithium hydroxide monohydrate (0.9 g, 37.6 mmol) and water (25 mL), and stir the reaction at room temperature overnight. Use ethyl acetate to extract (20 mL x 3) to remove impurities, and then adjust the pH of the aqueous phase to neutral with dilute hydrochloric acid (1N). The product precipitates, is filtered and dried to obtain compound 4f (2.4 g, 83.4%).
  • Step 3 Compound 5c (4.6 g, 0.028 mol) was added to acetonitrile (46 mL) and water (46 mL), and then 9-fluorenylmethyl-N-succinimidyl carbonate (Fmoc-Osu) (10.5 g, 0.03 mol) and sodium bicarbonate (24.4 g, 0.28 mol) were added, and the reaction was allowed to react at room temperature overnight.
  • Step 4 Compound 5d (5.0 g, 0.013 mol) was added to dichloromethane (50 mL), and then 85% m-chloroperbenzoic acid (m-CPBA) (7.9 g, 0.039 mol) was added in batches to react at room temperature overnight. The reaction was monitored by LC-MS to be complete, and the reaction was quenched with sodium thiosulfate solution (100 mL), stirred for 30 min, extracted with ethyl acetate (200 mL), and the ethyl acetate phase was concentrated to dryness.
  • m-CPBA m-chloroperbenzoic acid
  • A trifluoroacetic acid
  • B
  • Step 2 DMF (6.5 g, 89.18 mmol) was added dropwise into phosphorus oxychloride (70 mL) at 0°C.
  • compound 6b 7.0 g, 44.59 mmol
  • phosphorus oxychloride 30 mL
  • dichloromethane 100 mL ⁇ 3
  • Step 4 ( ⁇ ) benzyloxycarbonyl-a-phosphonoglycine trimethyl ester (7.0 g, 21.05 mmol) was dissolved in dichloromethane (100 mL), and DBU (6.43 g, 42.3 mmol) was added after nitrogen replacement and stirred for 30 min, and then compound 6d (6.0 g, 21.05 mmol) was dissolved in dichloromethane (100 mL) and added dropwise to the reaction, and continued to stir overnight.
  • Step 5 Dissolve compound 6e (5.7 g, 11.6 mmol) in methanol (50 mL), add (+)-1,2-bis(2S,5S)-2,5-diethylcyclobutanephosphine benzene(cyclooctadiene)trifluoromethanesulfonate rhodium (420 mg, 0.58 mmol), use an autoclave to fill with hydrogen to a pressure of about 2.5 MPa, stir at room temperature overnight, filter out the solid, and concentrate the reaction solution to obtain compound 6f (5.7 g, 99.9%).
  • Step 6 Dissolve compound 6f (3.0 g, 6.1 mmol) in dichloromethane (50 mL), add triethylamine (3.1 g, 30.5 mmol) under ice bath, and then add
  • Step 7 Dissolve compound 6g (1.5g, 5.8mmol) in tetrahydrofuran (20mL), add lithium hydroxide monohydrate (1.58g, 37.7mmol) and water (20mL), stir the reaction at room temperature for 2h, then adjust the pH of the aqueous phase to neutral with dilute hydrochloric acid (1N), and proceed directly to the next step.
  • Step 1 Add the known compound 7a (20 g, 0.09 mol) to methanol (46 mL) and tetrahydrofuran (460 mL), then add sodium hydroxide (3.6 g, 0.09 mol), and react at room temperature for 18 h. LCMS showed that the raw material was completely reacted.
  • Step 3 Pyridine (27.84 g, 0.352 mol) was added to dichloromethane (800 mL), cooled to -20°C, and trifluoromethanesulfonic anhydride (94.8 g, 0.336 mol) was added dropwise. After the addition was completed, 2-bromoethanol (40 g, 0.32 mol) was added to the system, stirred at -20°C for 30 minutes, and concentrated at 30°C to remove dichloromethane. The residue was dissolved with MTBE and filtered. The mother liquor was concentrated to dryness at 25°C.
  • Step 4 Compound 7d (21.6 g, 0.072 mol) was added to tetrahydrofuran (430 mL), and lithium aluminum hydride (5.47 g, 0.144 mol) was added in batches. The mixture was reacted at room temperature for 2 h. The reaction was completed after TLC monitoring. 5.5 mL of water was slowly added dropwise, and then 5.5 mL of 15% sodium hydroxide solution was slowly added dropwise. Finally, 16.5 mL of water was added dropwise, and then anhydrous sodium sulfate was added and stirred for 30 min. The mixture was filtered and the mother liquor was concentrated to dryness to obtain 7e (15.9 g, yield: 81%).
  • Step 5 Compound 7e (12.5 g, 0.046 mol) was added to aqueous ammonia (250 mL) and reacted at room temperature for 18 h. TLC monitoring showed that the raw material was not completely reacted. The crude product 7f was directly concentrated to dryness and used for the next step.
  • Step 10 Compound 7j (1.25 g, 3.3 mmol) was added to methanol (13 mL) and water (4 mL), and then lithium hydroxide (554 mg, 13.2 mmol) was added, and the mixture was reacted at room temperature for 4 h. LCMS monitored that the reaction of the raw material was complete. The reaction solution was directly used for the next step.
  • Step 11 Adjust the pH of the reaction solution in the previous step to 5-6 with 1N HCl, and then adjust the pH to 8-9 with sodium bicarbonate aqueous solution, then add 9-fluorenylmethyl-N-succinimidyl carbonate (1.3g, 3.96mmol) and sodium bicarbonate (2.77g, 33mmol), stir at room temperature for 2h, LCMS shows that the raw material reaction is complete.
  • Step 2 Dissolve compound 9b (7.0 g, 47.95 mmol) in dichloromethane (50 ml), add triethylamine (14.53 g, 143.85 mmol), add dropwise into methanesulfonyl chloride (6.59 g, 57.54 mmol) at zero degrees, react at room temperature for 1 hour, quench with water under ice bath, extract with dichloromethane, combine the organic phases and spin dry, and concentrate to obtain the crude product of compound 9c.
  • Step 3 The crude compound 9c from the previous step was dissolved in tetrahydrofuran/water (60 mL/30 ml), potassium peroxymonosulfonate (24.91 g, 71.93 mmol) was added at zero degrees, and the reaction was allowed to react overnight at room temperature. The mixture was extracted with ethyl acetate, the organic phases were combined and dried by rotation, and recrystallized from methyl tert-butyl ether to obtain compound 9d (4.8 g, two-step yield 52%).
  • Step 4 Compound 9d (7.0 g, 36.08 mmol) was dissolved in 1,2-dichloroethane (200 mL). After nitrogen replacement, thionyl chloride (3.26 ml, 45 mmol) was added and refluxed for 1 hour. After cooling to room temperature, NCS (7.2 g, 54.12 mmol) and 10 drops of 4M hydrogen chloride-1,4-dioxane were added, refluxed overnight, cooled to room temperature, methanol (25 ml) was added, and the reaction was continued for 1 hour. After the reaction was completed, the mixture was directly concentrated and dried, chloroform was added at zero degrees, the liquid was collected by filtration, and concentrated to obtain a crude compound 9e.
  • Step 7 Compound 9g (1 g, 5.38 mmol) was placed in a 50 ml round-bottom flask, 3 M hydrochloric acid solution (10 mL) was added, and the mixture was stirred at 100 °C for 5 h. After the reaction was completed, the mixture was extracted with methyl tert-butyl ether, and the aqueous phase was directly concentrated to obtain compound 9h hydrochloride.
  • Step 8 Compound 9h (1 g, 6.8 mmol) was placed in a 50 ml round-bottom flask, trifluoroacetic acid (5 ml) and triphenylmethanol (2.12 g, 8.16 mmol) were added, stirred at room temperature for 10 min, and the target compound 9i was obtained by spin drying and directly carried out to the next step.
  • sodium bicarbonate 5.g, 68mmol
  • 9-fluorenylmethyl-N-succinimidyl carbonate 3.44g, 10.2mmol
  • the racemate was chiral separated: instrument: SFC Prep 150AP; chromatographic column: Daicel AD-H (19mm ⁇ 250mm); the sample was dissolved in methanol and filtered with a 0.45 ⁇ m filter to prepare a sample solution.
  • Preparative chromatography conditions mobile phase A, B composition: mobile phase A: CO2; mobile phase B: methanol; isocratic elution, mobile phase B content 25%; flow rate 40ml/min.
  • Intermediate 9 (P1) (890 mg) was obtained in 3.8 min and intermediate 10 (P2) (910 mg) was obtained in 4.2 min.
  • Step 3 Dissolve compound 11d (9.00 g, 55.8 mmol) in dichloromethane (400 ml) at 0°C, add imidazole (4.94 g, 72.6 mmol), iodine (18.4 g, 72.6 mmol) and triphenylphosphine (19.0 g, 72.6 mmol), and warm to room temperature to react overnight.
  • Step 4 Add zinc powder (2.43 g, 37.2 mmol) and iodine (94.5 mg, 0.372 mmol) to a round-bottom flask, heat with a heating gun under nitrogen protection for 5 minutes, cool to room temperature and nitrogen protection three times, then add a solution of compound 11e (3.17 g, 11.7 mmol) in DMF (50 mL) by injection after cooling to 0°C, and warm to room temperature for reaction for about 2 hours. Cuprous cyanide (950 mg, 10.6 mmol) and lithium chloride (900 mg, 21.2 mmol) were added to a round-bottom flask, heated to 150°C under nitrogen protection for 2 hours, and then injected with DMF (10 mL) after cooling to room temperature.
  • DMF 10 mL
  • Step 5 Compound 11f (3.47 g, 6.49 mmol) was dissolved in ethyl acetate (200 ml), Pd/C (2.0 g) was added, and a hydrogen balloon was inserted to react at room temperature overnight. After TLC monitoring, the solid was directly filtered out and washed with ethyl acetate, and the organic phases were combined and concentrated to obtain a crude product of compound 11g (3.21 g).
  • Step 8 Compound 11i (2.41 g, 4.27 mmol) was dissolved in a mixed solvent of dichloromethane (50 ml) and trifluoroacetic acid (50 ml) and reacted at room temperature. After the reaction was completed by TLC monitoring, it was directly concentrated under reduced pressure, and the crude product was redissolved in dichloromethane (100 ml), and the pH was adjusted to about 7 with saturated sodium bicarbonate aqueous solution.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Step 1 The synthesis of 1B was carried out using standard Fmoc chemistry:
  • Step 2 Add 60 ml of lysis solution (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1.2-ethanedithiol + 2% water) to a 100 ml reaction bottle, stir well and add peptide resin 1B (6.5 g), stir at room temperature for 2 hours. Filter the resin to obtain the filtrate, add the filtrate to 500 ml of methyl tert-butyl ether (methyl tert-butyl ether is cooled to 0°C in advance), white floccules precipitate, centrifuge (3 min at 3000 rpm). The white precipitate is washed three times with methyl tert-butyl ether and vacuum dried to obtain off-white solid crude peptide 1C (2.4 g), which is directly used in the next step reaction.
  • lysis solution 91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1.2-ethanedithiol + 2% water
  • Step 3 In a 2L reaction bottle, add water (750ml), acetonitrile (250ml), 1C (2g, 1.06mmol) in sequence, stir evenly, slowly add iodine/acetonitrile solution (0.1mol/L) until the reaction solution turns light yellow, add ascorbic acid to quench, and prepare HPLC purification.
  • Separation method 1. Instrument: waters2767 preparative liquid phase; chromatographic column: SunFire@PrepC18 (19mm ⁇ 250mm). 2. The sample is filtered with a 0.45 ⁇ m filter to prepare a sample solution. 3.
  • Preparative chromatographic conditions a. Mobile phase A, B composition: A: 0.1% trifluoroacetic acid/H 2 O, B: CH 3 CN; b. Gradient elution: mobile phase content 5%-45%; c. Flow rate: 12ml/min; d. Elution time: 30min, retention time: 16min. Lyophilization gave compound 1 (400mg, purity 99%).
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Step 1 The synthesis of 2B was carried out using standard Fmoc chemistry:
  • Step 2 Add 60 ml of lysis solution (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1.2-ethanedithiol + 2% water) to a 100 ml reaction bottle, stir well and add peptide resin 2B (6.3 g), stir at room temperature for 2 hours. Filter the resin to obtain the filtrate, add the filtrate to 500 ml of methyl tert-butyl ether (methyl tert-butyl ether is cooled to 0°C in advance), white floccules precipitate, centrifuge (3 min at 3000 rpm). The white precipitate is washed three times with methyl tert-butyl ether and vacuum dried to obtain off-white solid crude peptide 2C (2.5 g), which is directly used in the next step reaction.
  • lysis solution 91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1.2-ethanedithiol + 2% water
  • Step 3 In a 2L reaction bottle, add water (750ml), acetonitrile (250ml), and 2C (2g, 1.06mmol) in sequence. After stirring evenly, slowly add iodine/acetonitrile solution (0.1mol/L) until the reaction solution turns light yellow, add ascorbic acid to quench, and prepare HPLC purification. Separation method: 1. Instrument: waters2767 preparative liquid phase; chromatographic column: SunFire@PrepC18 (19mm ⁇ 250mm). 2. The sample is filtered with a 0.45 ⁇ m filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: A: 0.1% trifluoroacetic acid/H 2 O, B: CH 3 CN; b. Gradient elution: mobile phase content 5%-45%; c. Flow rate: 12ml/min; d. Elution time: 30min, retention time: 16min. Lyophilization gave compound 2 (410mg, purity 99%)
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Step 1 7B was synthesized using standard Fmoc chemistry:
  • Step 2 Add 50 ml of lysis solution (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1.2-ethanedithiol + 2% water) to a 100 ml reaction bottle, stir well and add peptide resin 7B (6 g), stir at room temperature for 2 hours. Filter the resin to obtain the filtrate, add the filtrate to 300 ml of methyl tert-butyl ether (methyl tert-butyl ether is cooled to 0°C in advance), white floccules precipitate, centrifuge (3 min at 3000 rpm). The white precipitate is washed three times with methyl tert-butyl ether and vacuum dried to obtain off-white solid crude peptide 7C (2.2 g), which is directly used in the next step reaction.
  • lysis solution 91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1.2-ethanedithiol + 2% water
  • Step 3 In a 2L reaction bottle, add water (750ml), acetonitrile (250ml), 7C (2g, 1.02mmol) in sequence, stir evenly, slowly add iodine/acetonitrile solution (0.1mol/L) until the reaction solution turns light yellow, add ascorbic acid to quench, and prepare HPLC purification.
  • Separation method 1. Instrument: waters2767 preparative liquid phase; chromatographic column: SunFire@PrepC18 (19mm ⁇ 250mm). 2. The sample is filtered with a 0.45 ⁇ m filter to prepare a sample solution. 3.
  • Preparative chromatographic conditions a. Mobile phase A, B composition: A: 0.1% trifluoroacetic acid/H 2 O, B: CH 3 CN; b. Gradient elution: mobile phase content 5%-45%; c. Flow rate: 12ml/min; d. Elution time: 30min, retention time: 16min. Compound 7 (50mg, purity 98%) was obtained.
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • Step 1 Using the above materials as raw materials, compound 10B was obtained by the method of compound 1.
  • Step 2 Add 30 ml of dichloromethane to a solid phase synthesis reactor, add phenylsilane (1 g) and tetrakis(triphenylphosphine)palladium (462 mg) in sequence, react for 8 hours under nitrogen, wash the resin with dichloromethane 5 times, wash it with N,N-dimethylformamide 5 times, wash it with 0.5% sodium diethyldithiocarbamate N,N-dimethylformamide solution for 15 min+15 min, and then wash it with N,N-dimethylformamide three times to obtain peptide resin 10C.
  • Step 3 Add 2% hydrazine hydrate solution in N,N-dimethylformamide into the reactor and react for 30 min+30 min. Wash with N,N-dimethylformamide solution 5 times to obtain peptide resin 10D.
  • Step 4 Add N-methylpyrrolidone (20 ml), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (417.2 mg, 1.1 mmol), and DIEA (0.19 ml, 1.1 mmol) into a solid phase synthesis reactor and react at room temperature for 16 h. Monitor with ninhydrin and it turns colorless. Drain the solvent and wash the resin with N,N-dimethylformamide 3 times, methanol 2 times, dichloromethane 1 time, methanol 2 times, and vacuum dry to obtain peptide resin 10E (5.2 g).
  • Step 5 Add 60 ml of lysis solution (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1.2-ethanedithiol + 2% water) to a 100 ml reaction bottle, stir evenly, then add peptide resin 10E (5.2 g), and stir at room temperature for 2 hours. Filter the resin to obtain a filtrate, add the filtrate to 500 ml of methyl tert-butyl ether (methyl tert-butyl ether is cooled to 0°C in advance), white floccules precipitate, and centrifuge (3 min at 3000 rpm).
  • lysis solution 91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1.2-ethanedithiol + 2% water
  • Embodiment 11 is a diagrammatic representation of Embodiment 11:
  • Step 1 Using the above materials as raw materials, compound 11B was obtained by the method of compound 1
  • Step 2 Add 30 ml of dichloromethane to a solid phase synthesis reactor, add phenylsilane (1 g) and tetrakis(triphenylphosphine)palladium (462 mg) in sequence, react for 8 hours under nitrogen, wash the resin with dichloromethane 5 times, wash with N,N-dimethylformamide 5 times, wash with 0.5% sodium diethyldithiocarbamate N,N-dimethylformamide solution for 15 min+15 min, and then wash three times with N,N-dimethylformamide to obtain peptide resin 11C.
  • Step 3 Add 20% piperidine in N,N-dimethylformamide solution into the reactor and react for 30 min. Wash with N,N-dimethylformamide solution 5 times to obtain peptide resin 11D.
  • Step 4 Add N-methylpyrrolidone (20 ml), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (417.2 mg, 1.1 mmol), and DIEA (0.19 ml, 1.1 mmol) into a solid phase synthesis reactor and react at room temperature for 16 h. Monitor with ninhydrin and the resin turns colorless. Drain the solvent and wash the resin with N,N-dimethylformamide 3 times, methanol 2 times, dichloromethane 1 time, methanol 2 times, and vacuum dry to obtain peptide resin 11E.
  • Step 5 Add 50 ml of lysis solution (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1.2-ethanedithiol + 2% water) to a 100 ml reaction bottle, stir well, add peptide resin 11E (5 g), and stir at room temperature for 2 hours. Filter the resin to obtain a filtrate, add the filtrate to 500 ml of methyl tert-butyl ether (methyl tert-butyl ether is cooled to 0°C in advance), white floccules precipitate, and centrifuge (3 min at 3000 rpm). The white precipitate is washed three times with methyl tert-butyl ether and vacuum dried to obtain an off-white solid crude peptide 11F (1.5 g).
  • lysis solution 91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1.2-ethanedithiol + 2% water
  • Step 6 In a 2L reaction bottle, add water (1050ml), acetonitrile (450ml), 11F (1.5g, 0.76mmol) in sequence, stir evenly, slowly add iodine/acetonitrile solution (0.1mol/L) until the reaction solution turns light yellow, add ascorbic acid to quench, and prepare HPLC purification.
  • Separation method 1. Instrument: Waters2767 preparative liquid phase; chromatographic column SunFire@PrepC18 (19mm ⁇ 250mm). 2. The sample is filtered with a 0.45 ⁇ m filter to prepare a sample solution. 3.
  • Preparative chromatographic conditions a. Mobile phase A, B composition: A: 0.1% trifluoroacetic acid/H 2 O, B: CH 3 CN; b. Gradient elution: mobile phase content 5%-45%; c. Flow rate: 12ml/min; d. Elution time: 30min, retention time: 16min. Lyophilization gave white solid compound 11 (28mg, purity 99%).
  • Embodiment 12 is a diagrammatic representation of Embodiment 12
  • Embodiment 13 is a diagrammatic representation of Embodiment 13:
  • Embodiment 14 is a diagrammatic representation of Embodiment 14:
  • Embodiment 15 is a diagrammatic representation of Embodiment 15:
  • Embodiment 16 is a diagrammatic representation of Embodiment 16:
  • Embodiment 17 is a diagrammatic representation of Embodiment 17:
  • Embodiment 18 is a diagrammatic representation of Embodiment 18:
  • Embodiment 19 is a diagrammatic representation of Embodiment 19:
  • Step 3 In a 3L reaction bottle, add water (1050ml), acetonitrile (450ml), 19C (1.5g, 0.8mmol) in sequence, stir evenly, add 1,3,5-tri(bromomethyl)benzene (0.26g, 0.8mmol), adjust pH to 8 with ammonium bicarbonate, react for 16h and prepare HPLC purification. Separation method: 1. Instrument: Waters2767 preparative liquid phase; chromatographic column SunFire@PrepC18 (19mm ⁇ 250mm). 2. Samples were filtered through a 0.45 ⁇ m filter. Filter to prepare sample solution. 3. Preparation of chromatographic conditions: a.
  • Mobile phase A, B composition A: 0.1% trifluoroacetic acid/H 2 O, B: CH 3 CN; b. Gradient elution: mobile phase content 5%-45%; c. Flow rate: 12 ml/min; d. Elution time: 30 min, retention time: 17 min. Freeze-drying to obtain white solid compound 19 (50 mg, purity 97%).
  • Embodiment 20 is a diagrammatic representation of Embodiment 20.
  • Embodiment 21 is a diagrammatic representation of Embodiment 21.
  • step 14 the solid phase synthesis method of compound 1 was adopted to step 14, and then Dde was removed with 2% hydrazine hydrate/DMF. Then, the method of compound 1 was used to continue the synthesis to obtain compound 21 (30 mg, purity 97%).
  • Embodiment 22 is a diagrammatic representation of Embodiment 22.
  • Embodiment 23 is a diagrammatic representation of Embodiment 23.
  • step 14 the solid phase synthesis method of compound 1 was adopted to step 14, and then Dde was removed with 2% hydrazine hydrate/DMF. Then, the method of compound 1 was used to continue the synthesis to obtain compound 23 (25 mg, purity 95%).
  • Embodiment 24 is a diagrammatic representation of Embodiment 24.
  • Embodiment 25 is a diagrammatic representation of Embodiment 25.
  • Step 1 Using the above-mentioned materials as raw materials, compound 25B was obtained by the method of compound 1.
  • Step 2 Add 30 ml of dichloromethane to a solid phase synthesis reactor, add phenylsilane (1 g) and tetrakis(triphenylphosphine)palladium (462 mg) in sequence, and react for 8 hours under nitrogen. Wash the resin with dichloromethane 5 times, N,N-dimethylformamide 5 times, wash with 0.5% sodium diethyldithiocarbamate N,N-dimethylformamide solution for 15 min+15 min, and then wash three times with N,N-dimethylformamide to obtain peptide resin 25C.
  • Step 3 Add 20% piperidine in N,N-dimethylformamide solution into the reactor and react for 30 min. Wash with N,N-dimethylformamide solution 5 times, wash with methanol 3 times, and dry under vacuum to obtain peptide resin 25D (5 g).
  • Step 4 Add 50 ml of cleavage solution (2% trifluoroacetic acid + 98% dichloromethane) to a 100 ml reaction bottle, stir evenly, add peptide resin 25D (5 g), stir at room temperature for 0.5 hour, filter the resin to obtain a filtrate, cleave the peptide resin again according to the above cleavage method, collect the filtrates obtained twice, extract and wash twice with water, extract and wash once with saturated brine, dry with anhydrous sodium sulfate, and vacuum dry to obtain compound 25E (2.3 g).
  • cleavage solution 20% trifluoroacetic acid + 98% dichloromethane
  • Step 5 Dichloromethane (1.2 L), compound 25E (2.3 g, 0.68 mmol), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (417.2 mg, 1.1 mmol), and DIEA (0.19 ml, 1.1 mmol) were added to a 2 L flask, and the reaction was carried out at room temperature for 16 h. MS showed that the reaction was basically completed. The mixture was extracted and washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate, and dried under vacuum to obtain compound 25F (2.1 g).
  • Step 6 Add 60 ml of lysis solution (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1.2-ethanedithiol + 2% water) to a 100 ml reaction bottle, stir well and add compound 25F (2.1 g), and stir at room temperature for 2 hours. Filter the resin to obtain the filtrate, add the filtrate to 600 ml of methyl tert-butyl ether (methyl tert-butyl ether is cooled to 0°C in advance), white floccules precipitate, and centrifuge (3 min at 3000 rpm). The white precipitate is washed three times with methyl tert-butyl ether and vacuum dried to obtain off-white solid crude peptide 25G (1.2 g).
  • lysis solution 91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1.2-ethanedithiol + 2% water
  • Step 7 In a 2L reaction bottle, add water (1050ml), acetonitrile (450ml), 25G (1.2g, 0.6mmol) in sequence, stir evenly, slowly add iodine/acetonitrile solution (0.1mol/L) until the reaction solution turns light yellow, add ascorbic acid to quench, and prepare HPLC purification.
  • Separation method 1. Instrument: Waters2767 preparative liquid phase; chromatographic column SunFire@PrepC18 (19mm ⁇ 250mm). 2. Filter the sample with a 0.45 ⁇ m filter head to prepare a sample solution. 3.
  • Preparative chromatographic conditions a. Mobile phase A, B composition: A: 0.1% trifluoroacetic acid/H 2 O, B: CH 3 CN; b. Gradient elution: mobile phase content 5%-45%; c. Flow rate: 12 ml/min; d. Elution time: 30 min, retention time: 16 min. Lyophilization gave a white solid 25 (80 mg, purity 95%).
  • Embodiment 26 is a diagrammatic representation of Embodiment 26.
  • Embodiment 27 is a diagrammatic representation of Embodiment 27.
  • compound 27 (65 mg, purity 99%) was obtained by the method of compound 25.
  • Embodiment 28 is a diagrammatic representation of Embodiment 28:
  • Embodiment 29 is a diagrammatic representation of Embodiment 29.
  • compound 29 (140 mg, purity 99%) was obtained by the method of compound 25.
  • Embodiment 30 is a diagrammatic representation of Embodiment 30.
  • Embodiment 31 is a diagrammatic representation of Embodiment 31.
  • Embodiment 32 is a diagrammatic representation of Embodiment 32.
  • compound 32 (200 mg, 99%) was obtained by the method of compound 19.
  • Embodiment 33 is a diagrammatic representation of Embodiment 33.
  • Embodiment 34 is a diagrammatic representation of Embodiment 34.
  • Embodiment 35 is a diagrammatic representation of Embodiment 35.
  • Embodiment 36 is a diagrammatic representation of Embodiment 36.
  • Embodiment 37 is a diagrammatic representation of Embodiment 37.
  • Embodiment 38 is a diagrammatic representation of Embodiment 38.
  • Embodiment 39 is a diagrammatic representation of Embodiment 39.
  • Embodiment 40 is a diagrammatic representation of Embodiment 40.
  • Embodiment 41 is a diagrammatic representation of Embodiment 41.
  • Embodiment 42 is a diagrammatic representation of Embodiment 42.
  • Embodiment 43 is a diagrammatic representation of Embodiment 43.
  • Step 1 Using the above materials as raw materials, compound 44B was obtained by the method of compound 1.
  • Step 2 Add 30 ml of dichloromethane to a solid phase synthesis reactor, add phenylsilane (1 g) and tetrakis(triphenylphosphine)palladium (462 mg) in sequence, react for 8 hours under nitrogen, wash the resin with dichloromethane 5 times, wash with N,N-dimethylformamide 5 times, wash with 0.5% sodium diethyldithiocarbamate N,N-dimethylformamide solution for 15 min+15 min, and then wash three times with N,N-dimethylformamide to obtain peptide resin 44C.
  • Step 3 Add 20% piperidine in N,N-dimethylformamide solution into the reactor and react for 30 min. Wash with N,N-dimethylformamide solution 5 times to obtain peptide resin 44D.
  • Step 4 Add N-methylpyrrolidone (20 ml), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (417.2 mg, 1.1 mmol), and DIEA (0.19 ml, 1.1 mmol) into a solid phase synthesis reactor and react at room temperature for 24 hours. Monitor with ninhydrin to obtain a colorless resin. Drain the solvent and wash the resin with N,N-dimethylformamide 3 times, methanol 2 times, dichloromethane 1 time, and methanol 2 times. Drain under vacuum to obtain peptide resin 44E/F (5 g).
  • Step 5 Add 40 ml of lysate (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1.2-ethanedithiol + 2% water) to a 100 ml reaction bottle, stir well and then add peptide resin 44E/F (5 g), stir at room temperature for 2 hours. Filter the resin to obtain a filtrate, add the filtrate to 300 ml of methyl tert-butyl ether (methyl tert-butyl ether is cooled to 0°C in advance), white floccules precipitate, and centrifuge (3 min at 3000 rpm).
  • Embodiment 45 is a diagrammatic representation of Embodiment 45.
  • Step 3 In a 3L reaction bottle, add water (750ml), acetonitrile (750ml), 45C (1.5g, 0.8mmol) in sequence, stir evenly, add bismuth bromide (0.36g, 0.8mmol), adjust pH to 8 with ammonium bicarbonate, react for 16h, and then purify by preparative HPLC. Separation method: 1. Instrument: Waters2767 preparative liquid; chromatographic column SunFire@PrepC18 (19mm ⁇ 250mm). 2. The sample was filtered with a 0.45 ⁇ m filter to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: A: 0.1% trifluoroacetic acid/H 2 O, B: CH 3 CN; b. Gradient elution: mobile phase content 5%-45%; c. Flow rate: 12ml/min; d. Elution time: 30min, retention time: 17min. Freeze-dried to obtain white solid compound 45 (57mg, purity 90%).
  • Embodiment 46 is a diagrammatic representation of Embodiment 46.
  • Embodiment 47 is a diagrammatic representation of Embodiment 47.
  • Embodiment 48 is a diagrammatic representation of Embodiment 48.
  • Embodiment 49 is a diagrammatic representation of Embodiment 49.
  • Embodiment 50 is a diagrammatic representation of Embodiment 50.
  • compound 50 (100 mg) was obtained by the method of compound 25.
  • Embodiment 51 is a diagrammatic representation of Embodiment 51.
  • compound 51 (75 mg) was obtained by the method of compound 25.
  • Embodiment 52 is a diagrammatic representation of Embodiment 52.
  • Embodiment 53 is a diagrammatic representation of Embodiment 53.
  • Embodiment 54 is a diagrammatic representation of Embodiment 54:
  • Embodiment 55 is a diagrammatic representation of Embodiment 55:
  • the TR-FRET method was used to test the inhibition of IL-23 ⁇ /IL-12 ⁇ & IL-23R binding by the compounds.
  • Protein IL-23 ⁇ /IL-12 ⁇ (ACRO, Cat#ILB-H52W5) and IL-23R (ACRO, Cat#ILR-H82F3) solutions were prepared in reaction buffer PPI (PerkinElmer, Cat#61DB10RDF).
  • the final concentrations of IL-23 ⁇ /IL-12 ⁇ and IL-23R in the reaction mixture were both 0.3 nM.
  • the starting concentration of the positive reference Guselkumab was 30 nM, 3-fold dilution, 10 doses.
  • 0.1 ⁇ L of the diluted positive reference in the reaction buffer was delivered to a 384-well plate (Grenier, Cat#784075) by acoustic liquid delivery technology (Echo655), centrifuged at 1000 rpm for 1 minute; 2.5 ⁇ L of IL-23 ⁇ /IL-12 ⁇ solution was transferred to the 384 reaction plate and centrifuged at 1000 rpm for 1 minute, incubated at 25°C for 60 minutes; 2.5 ⁇ L of IL-23R solution was transferred to a 384 reaction plate and centrifuged at 1000 rpm for 1 minute; 5 ⁇ L Streptavidin-Tb cryptate and Anti 6HIS-d2 detection mixture was transferred to a 384 reaction plate and centrifuged at 1000 rpm for 1 minute, incubated at 25°C for 60 minutes; finally, HTRF signal (Ratio 665/620 nm) was read using a BMG high-throughput drug screening multifunctional microplate reader. IC 50 values and nonlinear regression curve fitting were
  • the compounds of the present invention have significant inhibitory ability on the binding of IL-23 ⁇ /IL-12 ⁇ and IL-23R.
  • HEK-blue IL23 reporter gene cell line (Invivogen, hkb-il23) was cultured in DMEM + 10% FBS + 100ug/mL Normocin medium. When the cell density reached When the cell count reaches 80%-90%, 5000 cells/well are plated in a 384-well plate and cultured overnight at 37°C and 5% CO2 . The compound stock solution is then diluted in DMSO and 40 nL of the dilution is transferred to a 384-well culture plate by Echo. Incubate at 37°C and 5% CO2 for 0.5 hours.
  • nL/well rhIL23 (R&D, 1290-IL) is added to a 384-well cell culture plate at a final concentration of 1 ng/mL and incubated at 37°C and 5% CO2 for 24 hours.
  • 18 ⁇ L Quanti-Blue TM solution is added to a new 384-well plate, and 2 ⁇ L/well cell culture supernatant is transferred to the 384-well plate prepared in step 6, and incubated at 37°C and 5% CO2 for 1 hour.
  • the IC50 calculation formula is as follows:
  • the compounds of the present invention have significant inhibitory ability on the binding between IL23p19 and IL23R.
  • Cryopreserved human PBMCs were thawed and seeded on plates pre-coated with CD3 antibodies, with 1 ⁇ 10 ⁇ 6 cells seeded in each well.
  • CD28 antibodies were then added to the plate, and the cells were incubated at 37°C, 5% CO 2 for 5 days.
  • the cells were seeded on 96-well plates at a density of 100K cells per well.
  • the diluted compounds were transferred to a 96-well cell culture plate and incubated at 37°C, 5% CO 2 for 1 hour.
  • rhIL23 (R&D, 1290-IL) was added to the cell culture plate and incubated at 37°C, 5% CO 2 for 30 minutes.
  • Cells in the wells Lysis was performed on ice for 30 minutes with lysis buffer containing 1 ⁇ PHOSstop solution and centrifuged at 1000 rpm for 1 minute. The supernatant was then transferred to a 96-well ELISA plate and pSTAT3 ELISA was performed according to the instructions of the kit (CST, 7300CA). The absorbance at 450 nM was read on a PHERAstar FSX (BMG LRBTECH). The inhibition rate of the compound was evaluated using the following formula and the IC 50 was fitted using Graphpad.
  • the IC50 calculation formula is as follows:
  • the compounds of the present invention have a significant inhibitory effect on STAT3 phosphorylation.
  • mice Male Balb/c mice, 20-25 g, 18 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice On the day of the experiment, Balb/c mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.
  • the compounds of the present invention have good pharmacokinetic characteristics in mice, for example, compounds 7, 16, and 24 have excellent pharmacokinetic characteristics in mice.
  • Plasma samples with a concentration level of 1000 ng/mL were prepared and divided into EP tubes at time points of 0h and 6h; the 0h sample was directly added with acetonitrile solution containing internal standard, and the 6h sample was placed at 37°C for the corresponding time and then added with acetonitrile solution containing internal standard.
  • the concentration of the test substance in the sample was detected by LC-MS/MS method, and the residual rate was calculated by the ratio of the peak area of the test substance to the internal standard in the time point sample and the sample at time zero.
  • Sampling and testing First test the blank solution (artificial gastric juice or artificial intestinal juice), then take the prepared sample (freshly prepared for immediate use) and put it into the injection tray for immediate injection, and then inject a shot of sample at 4.5h, 9.5h, and 18h respectively.

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Abstract

提供了一种白介素-23受体的新型肽抑制剂，其立体异构体或药学上可接受的盐或溶剂化物，或含它们的药物组合物，及所述肽抑制剂在治疗或预防包括炎症性肠病、克罗恩病和银屑病等疾病或病症中的用途。

Description

白介素-23受体的肽抑制剂制备及其用途 技术领域
本发明涉及白介素-23受体的新型肽抑制剂及其治疗或预防多种疾病和病症的用途，所述疾病和病症包括炎症性肠病、克罗恩病和银屑病。
背景技术
白介素-23(IL-23)细胞因子已被认为在诸如多发性硬化、哮喘、类风湿性关节炎、银屑病和炎症性肠病(IBD)等自身免疫性疾病的发病机理中发挥决定性作用。急性和慢性IBD小鼠的模型研究显示IL-23R和下游效应细胞因子在疾病发病机制中起主要作用。IL-23R在多种适应性免疫细胞和固有免疫细胞上表达，所述细胞包括Th17细胞、γδT细胞、自然杀伤(NK)细胞、树突细胞、巨噬细胞和固有淋巴细胞，这些细胞在肠中大量存在。在肠粘膜表面，发现IL-23R基因表达和蛋白水平在IBD患者中升高。研究认为IL-23通过促进产生IL-6、IL-17和肿瘤坏死因子(TNF)的病原性CD4+T细胞群体的发展来介导该作用。
产生的IL-23在肠中富集，其通过对辅助性T细胞1(Th1)和Th17相关细胞因子的作用以及抑制肠中的调节性T细胞应答(其利于炎症)，通过T细胞依赖性和T细胞非依赖性的肠炎通路在调节耐受性和免疫性之间的平衡中发挥关键作用。另外，IL-23受体(IL-23R)的多形现象已与炎性肠病(IBD)的易感性相关，进一步确立了IL-23路径在肠稳态中的关键作用。
银屑病为一种影响2％至3％总人群的慢性皮肤病，已表明其由身体T细胞发炎反应机制介导。IL-23是数种白细胞介素之一，被认为是银屑病发病机理的关键角色，据称其经由诱导白介素-17、调节记忆T细胞，以及活化巨噬细胞来维持慢性自身免疫性炎症。已表明IL-23和IL-23R的表达在银屑病患者组织中增加，并且中和IL-23的抗体显示银屑病动物模型中银屑病发展的IL-23依赖性抑制。
IL-23是由独特的p19亚基和IL-12的p40亚基组成的异二聚体，其是参与产生干扰素-γ(IFN-γ)的辅助性T细胞1(TH1)发展细胞因子。尽管IL-23和IL-12均含有p40亚基，但是它们具有不同的表型特性。例如，IL-12缺陷型动物易患炎症性自身免疫性疾病，而IL-23缺陷型动物具有抗性，据推测是因为IL-23缺陷型动物的CNS中产IL-6、IL-17和TNF的CD4+T细胞数减少。IL-23与IL-23R结合，所述IL-23R是由IL-12Rβ1和IL-23R亚基组成的异二聚体受体。IL-23与IL-23R的结合激活Jak-stat信号转导分子，Jak2、Tyk2以及Stat1、Stat3、Stat4和Stat5，尽管Stat4的激活实质上较弱，并且在对IL-23应答时相比于IL-12形成不同的DNA结合Stat复合物。IL-23R与Jak2组成性地结合，并且以配体依赖的方式与Stat3结合。相比于主要作用于初始CD4(+)T细胞的IL-12，IL-23优先作用于记忆性CD4(+)T细胞。
已鉴别出抑制IL-23路径的治疗部分，用于治疗IL-23相关疾病。已鉴定了与IL-23或IL-23R结合的大量抗体，包括已被批准用于治疗银屑病的乌司奴单抗(ustekinumab)(结合IL-23的人源化抗体)。最近已经鉴定了与IL-23R结合并抑制IL-23与IL-23R结合的多肽抑制剂。用乌司奴单抗和布雷奴单抗(briakinumab)(其靶向常见的p40亚基)以及tildrakizumab、guselkumab、MEDI2070和BI-655066(其靶向IL-23的独特p19亚基)进行的克罗恩病或银屑病的临床试验突出了IL-23信号转导的阻断在治疗人炎症性疾病中的潜能。虽然这些发现是有前景的，但是关于鉴定优先靶向肠中IL-23通路的稳定且选择性药剂仍具有挑战性，所述药剂可以用于治疗肠炎(包括克罗恩病、溃疡性结肠炎和相关病症)。
因此本领域仍然需要靶向IL-23通路的新疗法，其可以用来治疗和预防IL-23相关的疾病，包括与自身免疫相关的疾病。此外，特异性靶向来自肠腔侧IL-23R的化合物和方法可以为IBD患者提供治疗益处。本发明通过提供结合IL-23R以抑制与IL-23结合和信号转导并适于口服使用的新型肽抑制剂来解决这些需求。
发明内容
本发明公开了一种白介素-23受体的新型肽抑制剂，其立体异构体或药学上可接受的盐或溶剂化物，或含它们的药物组合物，及所述肽抑制剂在治疗或预防包括炎症性肠病、克罗恩病和银屑病等疾病或病症中的用途。
本发明的肽化合物具有蛋白稳定性，对血浆蛋白酶、上皮蛋白酶、胃和肠蛋白酶、肺表面蛋白酶、细胞内蛋白酶等稳定；对IL-23具有特异靶向性；具有较长的血浆半衰期，具有好的药代动力学和药效动力学特性。
本发明涉及一种环肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述肽化合物具有式(I)、式(II)、式(II-1)、式(III)、式(III-1)、式(IV)、式(IV-1)、式(V)的氨基酸序列：
Xa1－Xa2-Xa3－Xa4-Xa5-Xa6-Xa7-Xa8-Xa9-Xa10-Xa11－Xa12-Xa13    (I)
(Ac)Xa1－Xa2-Thr-Xa4-Xa5-Xa6-Xa7-Xa8-Xa9-Xa10-Asn-(3-Pal)-Sarc(NH2)   (II)
(Ac)Xa1－Xa2-Thr-Xa4-Lys(Ac)-Xa6-Xa7-Xa8-Xa9-Glu-Asn-(3-Pal)-Sarc(NH2)   (II-1)(SEQ ID NO.1)
(Ac)Xa1-Xa2-Thr-Trp(R1)-Xa5-Xa6-Xa7-Xa8-Xa9-Xa10-Asn-(3-Pal)-sarc(NH2)   (III)
(Ac)Xa1-Xa2-Thr-Trp(CH3)-Lys(Ac)-Xa6-Xa7-Xa8-Xa9-Glu-Asn-(3-Pal)-Sarc(NH2)   (III-1)(SEQ ID NO.2)
(N-端)Xa1-Asn-Thr-Trp(R1)-Xa5-Xa6-Xa7-(2-Nal)-Xa9-Xa10-Xa11-Xa12-Sarc(C-端)   (IV)
(N-端)Xa1-Asn-Thr-Trp(CH3)-Lys(Ac)-Xa6-Xa7-(2-Nal)-Xa9-Glu-Xa11-Xa12-Sarc(C-端)   (IV-1)(SEQ ID NO.3)
(N-端)Xa1-His-Thr-Trp(R1)-Xa5-Xa6-Xa7-(2-Nal)-Xa9-Xa10-Xa11-Xa12-Sarc(C-端)   (V)
作为选择，所述肽化合物为二聚体化合物，所述二聚体化合物是由肽化合物与肽化合物中氨基酸残基经过聚乙二醇链相连形成的；所述聚乙二醇链为
n选自0-99的任意整数；
作为选择，所述肽化合物任选地在Xa1处或在Xa5处缀合修饰性基团；
或者作为选择，所述肽化合物任选地在Xa1处、Xa5处或Xa7处缀合修饰性基团；
在一些实施方案中，所述修饰性基团为 p选自0-50的任意整数，q选自0-50的任意整数
在一些实施方案中，所述修饰性基团为 p选自0-50的任意整数，q选自0-50的任意整数；
在一些实施方案中，所述修饰性基团为
其中，p选自0-5的任意整数，q选自0-5的任意整数；
在一些实施方案中，所述修饰性基团为
在一些实施方案中，所述p为1，q为2；
其中Xa1与Xa6各自独立地选自Pen、Pcn、Asn、Ala、Ala(3-amino)、Ala(2-ethyne)、Ala(3-azido)、Ala(2-ethene)、Val(2-ethene)、Asp、2,4-二氨基丁酸、Ser、Cys、Hcys、Glu，且Xa1与Xa6的残基之间经过反应形成肽环或者经L1形成环肽；
在一些实施方案中，Xa1与Xa6各自独立地选自Pen、Asn、Ala、Ala(3-amino)、Ala(2-ethyne)、Ala(3-azido)、Ala(2-ethene)、Val(2-ethene)、Asp、2,4-二氨基丁酸、Ser、Cys、Hcys、Glu，且Xa1与Xa6的残基之间经过反应形成肽环；
在一些实施方案中，Xa1与Xa6各自独立地选自Pen、Asn、Ala、Ala(3-amino)、Ala(2-ethyne)、Ala(3-azido)、Ala(2-ethene)、Val(2-ethene)，且Xa1与Xa6的残基之间经过反应形成肽环；
其中，Xa1与Xa6的残基之间优选经过缩合反应、RCM关环反应等形成肽环；
在一些实施方案中，Xa1、Xa6选自Pen；
在一些实施方案中，Xa1、Xa6各自独立地选自Asn或Ala(3-amino)；
在一些实施方案中，Xa1选自Asn、Xa6选自Ala(3-amino)；
在一些实施方案中，Xa1、Xa6各自独立地选自Ala(2-ethyne)或Ala(3-azido)；
在一些实施方案中，Xa1选自Ala(3-azido)、Xa6选自Ala(2-ethyne)；
在一些实施方案中，Xa1、Xa6选自Val(2-ethene)；
在一些实施方案中，Xa1、Xa6选自Ala(2-ethene)；
在一些实施方案中，Xa1、Xa6各自独立地选自Asp或Ala(3-amino)；
在一些实施方案中，Xa1、Xa6选自2,4-二氨基丁酸；
在一些实施方案中，Xa1、Xa6各自独立地选自2,4-二氨基丁酸或Asp；
在一些实施方案中，Xa1、Xa6各自独立地选自Ser或Ala(3-amino)；
在一些实施方案中，Xa1、Xa6各自独立地选自2,4-二氨基丁酸或Ser；
在一些实施方案中，Xa1、Xa6选自Ala(3-amino)；
在一些实施方案中，Xa1、Xa6各自独立地选自Cys或Asp；
在一些实施方案中，Xa1、Xa6各自独立地选自Glu或Ala(3-amino)；
在一些实施方案中，Xa1、Xa6各自独立地选自Hcys或Asp；
在一些实施方案中，Xa1与Xa6的残基经过反应形成如下结构：
在一些实施方案中，Xa1与Xa6的残基经过反应形成如下结构：
在一些实施方案中，Xa1与Xa6的残基经过反应形成如下结构：
其中*端为Xa1端，Xa1与Xa2通过*位置连接，NH2末端与保护基团相连；
或者*端为Xa1端，Xa1与Xa2通过*位置连接，NH2末端缀合修饰性基团；
在一些实施方案中，NH2末端缀合的修饰性基团选自
在一些实施方案中，NH2末端缀合的修饰性基团选自
Xa2选自Asn，His或Asn和His的类似物；
在一些实施方案中，Xa2选自Asn；
在一些实施方案中，Xa2选自Asn、His，或His的类似物，所述His的类似物选自
在一些实施方案中，Xa2选自Asn、His，或His的类似物，所述His的类似物选自
在一些实施方案中，Xa2选自Asn或His的类似物，所述His的类似物选自
Xa3选自Thr或Thr的类似物；
在一些实施方案中，Xa3选自Thr；
Xa4选自Trp或Trp的类似物；
在一些实施方案中，Xa4选自Trp的类似物，所述Trp的类似物选自
Xa5选自Lys、Gln、Arg、Cit，或Lys、Gln、Cit、Arg的类似物；作为选择，Xa5残基缀合修饰性基团；
Xa5选自Lys、Gln、Arg、Cit，或Lys、Gln、Cit、Arg的类似物；
在一些实施方案中，Xa5选自Lys，Gln，Arg，Cit，或Arg的类似物，所述Arg的类似物选自
在一些实施方案中，Xa5选自Lys，Gln，Arg，或Lys，Gln和Arg的类似物；
在一些实施方案中，Xa5选自Lys，Gln，Arg，或Lys、Arg的类似物；
在一些实施方案中，Xa5选自Lys或Lys的类似物；
在一些实施方案中，Xa5选自Lys；
在一些实施方案中，Xa5选自Lys，Gln，Arg，或Lys、Arg的类似物；所述Arg、Lys的类似物选自在一些实施方案中，Xa5选自Lys，Gln，Arg或Arg的类似物，所述Arg的类似物选自
在一些实施方案中，Xa5残基缀合的修饰性基团选自
在一些实施方案中，Xa5残基缀合的修饰性基团选自
Xa7选自Phe或Phe的类似物；作为选择，Xa7残基缀合修饰性基团；
Xa7选自Phe或Phe的类似物；
在一些实施方案中，Xa7选自Phe或Phe的类似物，所述Phe的类似物选自
在一些实施方案中，Xa7选自Phe或Phe的类似物，所述Phe的类似物选自
在一些实施方案中，Xa7选自Phe或Phe的类似物，所述Phe的类似物选自
在一些实施方案中，Xa7残基缀合的修饰性基团选自

Xa8选自Phe，Trp，2-Nal，或Phe，Trp和2-Nal的类似物；
在一些实施方案中，Xa8选自Phe，Trp，2-Nal，或Phe，Trp和2-Nal的类似物；所述Phe，Trp和2-Nal的类似物选自
在一些实施方案中，Xa8选自Phe，Trp，2-Nal，或Phe，Trp和2-Nal的类似物；所述Phe，Trp和2-Nal的类似物选自
在一些实施方案中，Xa8选自Phe，Trp，2-Nal或Phe，Trp和2-Nal的类似物；所述Phe，Trp和2-Nal的类似物选自
Xa9选自Thp或Thp的类似物；
在一些实施方案中，Xa9选自Thp或Thp的类似物，所述Thp的类似物选自
在一些实施方案中，Xa9选自Thp或Thp的类似物，所述Thp的类似物选自
Xa10选自Glu，Cys或Glu和Cys的类似物；
在一些实施方案中，Xa10选自Glu或Glu的类似物；
在一些实施方案中，Xa10选自Glu；
在一些实施方案中，Xa10选自Glu或Cys；
Xa11选自Asn、Lys，或Asn和Lys的类似物；
在一些实施方案中，Xa11选自Asn或Lys；
在一些实施方案中，Xa11选自Asn；
在一些实施方案中，Xa11选自Lys；
Xa12选自3-Pal、Phe、Asp，或3-Pal、Phe和Asp的类似物；
在一些实施方案中，Xa12选自3-Pal或Phe；
Xa13选自Sarc或Sarc的类似物；
在一些实施方案中，Xa13选自Sarc；
作为选择，Xa1、Xa2、Xa3、Xa4、Xa5、Xa7、Xa8、Xa9、Xa10、Xa11、Xa12、Xa13中的任意氨基酸的残基直接缩合或者经过L1链接从而形成一个或多个肽环；
在一些实施方案中，Xa1、Xa2、Xa3、Xa4、Xa5、Xa7、Xa8、Xa9、Xa10、Xa11、Xa12、Xa13中的任意氨基酸的残基经过L1链接从而形成肽环；
在一些实施方案中，Xa2、Xa3、Xa4、Xa5、Xa7、Xa8、Xa9、Xa10、Xa11、Xa12、Xa13中的任意氨基酸的残基经过L1链接从而形成肽环；
在一些实施方案中，Xa2、Xa3、Xa4、Xa5、Xa7、Xa8、Xa9、Xa10、Xa11、Xa12、Xa13中的任意两个氨基酸的残基经过L1链接从而形成肽环；
在一些实施方案中，Xa2、Xa3、Xa4、Xa5、Xa7、Xa8、Xa9、Xa10、Xa11、Xa12、Xa13中的任意三个氨基酸的残基经过L1链接从而形成肽环；
作为选择，多肽被反应基团Xa1、Xa6、Xa10与分子支架形成的共价键隔开而形成至少含有2个环的多肽环；
在一些实施方案中，2-Nal与Xa12的残基之间经过L1链接形成肽环；和/或者
Xa9与Xa12的残基之间经过L1链接形成肽环；和/或者
Lys(Ac)与Xa7的残基之间经过L1链接形成肽环；和/或者
Xa7与Xa11的残基之间经过L1链接形成肽环；和/或者
2-Nal与Glu的残基之间经过L1链接形成肽环；和/或者
Xa1与Glu的残基之间经过L1链接形成肽环；和/或者
Xa1与Xa10的残基之间经过L1链接形成肽环；和/或者
Xa1与Xa11的残基之间经过L1链接形成肽环；和/或者
2-Nal与Sarc的残基之间经过L1链接成肽环；和/或者
Xa9与Sarc的残基之间经过L1链接形成肽环；和/或者
Xa11与Sarc的残基之间经过L1链接形成肽环；和/或者
Xa1、Sarc与Glu的残基之间经过L1链接形成肽环；
在一些实施方案中，Xa1与Glu的残基之间经过L1链接形成肽环，Xa11与Sarc的残基之间经过L1链接形成肽环；
在一些实施方案中，Trp(R1)与Xa5的残基之间经过L1链接形成肽环；
R1选自H、C1-4烷基、C3-6环烷基、4-8元杂环烷基，所述烷基、环烷基、杂环烷基任选进一步被1-4个选自卤素、＝O、C1-4烷基、卤代C1-4烷基、CN、OH和NH2的取代基取代；
在一些实施方案中，R1选自C1-2烷基、环丙基、环丁基、环戊基、环己基，所述烷基、环丙基、环丁基、环戊基、环己基任选进一步被1-4个选自F、Cl、Br、＝O、甲基、乙基、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2F、-CHF2、-CF3、CN、OH和NH2的取代基取代；
在一些实施方案中，Trp(CH3)与Lys(Ac)的残基之间经过L1链接形成肽环；
在一些实施方案中，2-Nal与Xa12的残基之间经过L1链接形成肽环；
在一些实施方案中，Xa9与Xa12的残基之间经过L1链接形成肽环；
在一些实施方案中，Lys(Ac)与Xa7的残基之间经过L1链接形成肽环；
在一些实施方案中，Xa7与Xa11的残基之间经过L1链接形成肽环；
在一些实施方案中，Xa1与Glu的残基之间经过L1链接形成肽环；
在一些实施方案中，Xa1与Xa10的残基之间经过L1链接形成肽环；
在一些实施方案中，Xa1与Xa11的残基之间经过L1链接形成肽环；
在一些实施方案中，2-Nal与Sarc的残基之间经过L1链接成肽环；
在一些实施方案中，Xa9与Sarc的残基之间经过L1链接形成肽环；
在一些实施方案中，Xa11与Sarc的残基之间经过L1链接形成肽环；
在一些实施方案中，Xa1、Sarc与Glu的残基之间经过L1链接形成肽环；
在一些实施方案中，Xa1与Xa6的残基之间经过反应形成肽环；且Trp(R1)与Xa5的残基之间直接缩合或者经过L1链接形成肽环；
在一些实施方案中，Trp(CH3)与Lys(Ac)的残基之间直接缩合或者经过L1链接形成肽环；
L1选自W1-RL-W2；
RL选自键、C1-6亚烷基、C2-4亚烯基、C2-4亚炔基、3-6元环烷基、4-6元杂环烷基、5-6元杂芳基、6-10元芳基、-(OCH2CH2)a-，所述的亚烷基、亚烯基、亚炔基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1-4个RL1取代；
在一些实施方案中，RL选自键、C1-6亚烷基、C2-4亚烯基、C2-4亚炔基、3-6元环烷基、4-6元杂环烷基、5-6元杂芳基、6-10元芳基，所述的亚烷基、亚烯基、亚炔基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1-4个RL1取代；
RL1各自独立地选自卤素、＝O、C1-4烷基、C2-4烯基、C1-4烷氧基、3-6元环烷基、COOH、NH2、-NH-C(＝O)-C1-4烷基，所述的烷基、烷氧基、环烷基任选进一步被1-4个选自卤素、CN、OH和NH2的取代基取代；
在一些实施方案中，RL1各自独立地选自卤素、＝O、C1-4烷基、C2-4烯基、C1-4烷氧基、3-6元环烷基、COOH、NH2，所述的烷基、烷氧基、环烷基任选进一步被1-4个选自卤素、CN、OH和NH2的取代基取代；
W1、W2各自独立地选自键、C1-6亚烷基、-O-、-S-、-NRW1-、-CONRW1-、-NRW1CO-、-C(＝O)O-或-OC(＝O)-，所述亚烷基中的一个或多个-CH2-任选被1-4个选自-O-、-S-、-NRW1-或-CO-的基团替代，所述亚烷基任选进一步被1-4个选自卤素、＝O、C1-4烷基、卤代C1-4烷基、CN、OH和NH2的取代基取代；
RW1选自H、C1-4烷基、卤素；
在一些实施方案中，L1选自键、乙烯基、丙烯基、丁烯基、-O-(CH2)r-O-(CH2)r-NH-C(＝O)-、-O-(CH2)r-O-(CH2)r-、-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-C(＝O)-、-NH-C(＝O)-、-C(＝O)-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-C(＝O)-(CH2)r-、-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-、C1-6亚烷基、-C(＝O)-、-C(＝O)-(CH2)r-NH-、-(CH2)r-O-(CH2)r-NH-、-O-(CH2)r-O-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-、-(CH2)r-NH-C(＝O)-(CH2)r-、-C(＝O)-(CH2)-(OCH2CH2)a-NH-；
在一些实施方案中，L1选自键、乙烯基、丙烯基、丁烯基、-O-(CH2)r-O-(CH2)r-NH-C(＝O)-、-O-(CH2)r-O-(CH2)r-、-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-C(＝O)-、-NH-C(＝O)-、-C(＝O)-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-C(＝O)-(CH2)r-、-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-、C1-2亚烷基、-C(＝O)-、-C(＝O)-(CH2)r-NH-、 -(CH2)r-O-(CH2)r-NH-、-O-(CH2)r-O-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-；
在一些实施方案中，L1选自键、乙烯基、丙烯基、丁烯基、-O-(CH2)r-O-(CH2)r-NH-C(＝O)-、-O-(CH2)r-O-(CH2)r-、-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-C(＝O)-、-NH-C(＝O)-、-C(＝O)-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-C(＝O)-(CH2)r-、-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-、C1-2亚烷基、-C(＝O)-、-C(＝O)-(CH2)r-NH-、-(CH2)r-O-(CH2)r-NH-、-O-(CH2)r-O-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-(CH2)r-NH-；
在一些实施方案中，L1选自键、乙烯基、丙烯基、丁烯基、-O-(CH2)r-O-(CH2)r-NH-C(＝O)-、-O-(CH2)r-O-(CH2)r-、-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-C(＝O)-、-NH-C(＝O)-、-C(＝O)-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-C(＝O)-(CH2)r-、-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-、C1-2亚烷基、-C(＝O)-、-C(＝O)-(CH2)r-NH-、
在一些实施方案中，L1选自键、乙烯基、丙烯基、丁烯基、-O-(CH2)r-O-(CH2)r-NH-C(＝O)-、-O-(CH2)r-O-(CH2)r-、-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-C(＝O)-、-NH-C(＝O)-、-C(＝O)-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-C(＝O)-(CH2)r-、-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-、C1-2亚烷基、-C(＝O)-(CH2)r-NH-、
在一些实施方案中，L1选自键、乙烯基、丙烯基、丁烯基、-O-(CH2)r-O-(CH2)r-NH-C(＝O)-、-O-(CH2)r-O-(CH2)r-、-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-、-C(＝O)-(CH2)r-O-(CH2)r-O- (CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-C(＝O)-、-NH-C(＝O)-、-C(＝O)-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-C(＝O)-(CH2)r-、-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-、C1-2亚烷基、-C(＝O)-(CH2)r-NH-、
r选自0、1、2、3、4、5、6、7、8、9或10；
在一些实施方案中，r选自0、1、2、3、4或5；
在一些实施方案中，r选自0、1、2或3；
a选自0-10的任意整数；
在一些实施方案中，a选自1、2、3、4、5或6；
在一些实施方案中，a选自3、4、5或6；
并且所述肽化合物任选地与保护基团连接；
所述保护基团选自Ac、戊二酰基、琥珀酰基、NH2或OH；
无特殊说明的情况下，本发明所述保护基团Ac、戊二酰基、琥珀酰基与氨基酸N端相连；所述保护基团NH2、OH与氨基酸C端相连；
在一些实施方案中，N-端和C-端存在或不存在保护基团；
在一些实施方案中，N-端和C-端存在保护基团，所述保护基团选自Ac或NH2；
在一些实施方案中，N-端和C-端不存在保护基团，条件是：(1)、当N-端的Xa1与其他氨基酸的残基经过L1链接时，N-端的保护基团不存在；
(2)、当C-端的Sarc与其他氨基酸的残基经过L1链接时，C-端的保护基团不存在；作为选择，多肽被反应基团Xa1、Xa6、Xa10与分子支架形成的共价键隔开而形成至少含有2个环的多肽环；
在一些实施方案中，所述的分子架选自：
在一些实施方案中，所述的分子架选自：
条件是：所述肽化合物不选自如下结构：(Ac)Pen-Asn-Thr-Trp(CH3)-Lys(Ac)-Pen-Phe[4-(2-氨基乙氧基)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH2)，其中Pen与Pen之间形成二硫键。
作为本发明的更具体的第一技术方案，本发明提供了一种环肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述肽化合物具有式(I)的氨基酸序列：
Xa1-Xa2-Xa3-Xa4-Xa5-Xa6-Xa7-Xa8-Xa9-Xa10-Xa11-Xa12-Xa13    (I)
其中Xa1与Xa6各自独立地选自Pen、Pcn、Asn、Ala、Ala(3-amino)、Ala(2-ethyne)、Ala(3-azido)、Ala(2-ethene)、Val(2-ethene)、Asp、2，4-二氨基丁酸、Ser、Cys、Hcys、Glu，且Xa1与Xa6的残基之间经过反应形成肽环或者经L1形成环肽；在一些实施方案中，Xa1与Xa6各自独立地选自Pen、Asn、Ala、Ala(3-amino)、Ala(2-ethyne)、Ala(3-azido)、Ala(2-ethene)、Val(2-ethene)、Asp、2，4-二氨基丁酸、Ser、Cys、Hcys、Glu，且Xa1与Xa6的残基之间经过反应形成肽环；
Xa2选自Asn、His，或Asn、His的类似物；
Xa3选自Thr或Thr的类似物；
Xa4选自Trp或Trp的类似物；
Xa5选自Lys、Gln、Arg、Cit，或Lys、Gln、Cit、Arg的类似物；
Xa7选自Phe或Phe的类似物；
Xa8选自Phe、Trp、2-Nal，或Phe、Trp、2-Nal的类似物；
Xa9选自Thp或Thp的类似物；
Xa10选自Glu、Cys，或Glu、Cys的类似物；
Xa11选自Asn、Lys，或Asn、Lys的类似物；
Xa12选自3-Pal、Phe、Asp，或3-Pal、Phe、Asp的类似物；
Xa13选自Sarc或Sarc的类似物；
作为选择，Xa1、Xa2、Xa3、Xa4、Xa5、Xa7、Xa8、Xa9、Xa10、Xa11、Xa12、Xa13中的任意氨基酸的残基直接缩合或者经过L1链接从而形成一个或多个肽环；
L1选自W1-RL-W2；
RL选自键、C1-6亚烷基、C2-4亚烯基、C2-4亚炔基、3-6元环烷基、4-6元杂环烷基、5-6元杂芳基、6-10元芳基、-(OCH2CH2)a-，所述的亚烷基、亚烯基、亚炔基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1-4个RL1取代；在一些实施方案中，RL选自键、C1-6亚烷基、C2-4亚烯基、C2-4亚炔基、3-6元环烷基、4-6元杂环烷基、5-6元杂芳基、6-10元芳基，所述的亚烷基、亚烯基、亚炔基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1-4个RL1取代；
a选自0-10的任意整数；
RL1各自独立地选自卤素、＝O、C1-4烷基、C2-4烯基、C1-4烷氧基、3-6元环烷基、COOH、NH2、-NH-C(＝O)-C1-4烷基，所述的烷基、烷氧基、环烷基任选进一步被1-4个选自卤素、CN、OH和NH2的取代基取代；
W1、W2各自独立地选自键、C1-6亚烷基、-O-、-S-、-NRW1-、-CONRW1-、-NRW1CO-、-C(＝O)O-或-OC(＝O)-，所述亚烷基中的一个或多个-CH2-任选被1-4个选自-O-、-S-、-NRW1-或-CO-的基团替代，所述亚烷基任选进一步被1-4个选自卤素、＝O、C1-4烷基、卤代C1-4烷基、CN、OH和NH2的取代基取代；
RW1选自H、C1-4烷基、卤素；
并且所述肽化合物任选地与保护基团连接；
所述保护基团选自Ac、戊二酰基、琥珀酰基、NH2或OH；
作为选择，多肽被反应基团Xa1、Xa6、Xa10与分子支架形成的共价键隔开而形成至少含有2个环的多肽环；
作为选择，所述肽化合物任选地在Xa1处或在Xa5处缀合修饰性基团；或者作为选择，所述肽化合物任选地在Xa1处、Xa5处或Xa7处缀合修饰性基团；
条件是：所述肽化合物不选自如下结构：(Ac)Pen-Asn-Thr-Trp(CH3)-Lys(Ac)-Pen-Phe[4-(2-氨基乙氧基)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH2)，其中Pen与Pen之间形成二硫键。
进一步的，其中所述肽化合物具有式(I)的氨基酸序列：
Xa1-Xa2-Xa3-Xa4-Xa5-Xa6-Xa7-Xa8-Xa9-Xa10-Xa11-Xa12-Xa13   (I)
其中Xa1与Xa6各自独立地选自Pen、Asn、Ala、Ala(3-amino)、Ala(2-ethyne)、Ala(3-azido)、Ala(2-ethene)、Val(2-ethene)、Asp、2，4-二氨基丁酸、Ser、Cys、Hcys、Glu，且Xa1与Xa6的残基之间经过反应形成肽环；
Xa2选自Asn、His，或Asn和His的类似物；
Xa3选自Thr或Thr的类似物；
Xa4选自Trp或Trp的类似物；
Xa5选自Lys、Gln、Arg、Cit，或Lys、Gln、Cit、Arg的类似物；在一些实施方案中，Xa5选自Lys、Gln、Arg，或Lys、Gln、Arg的类似物；
Xa7选自Phe或Phe的类似物；
Xa8选自Phe、Trp、2-Nal，或Phe，Trp、2-Nal的类似物；
Xa9选自Thp或Thp的类似物；
Xa10选自Glu、Cys，或Glu、Cys的类似物；
Xa11选自Asn、Lys，或Asn、Lys的类似物；
Xa12选自3-Pal、Phe、Asp，或3-Pal、Phe、Asp的类似物；
Xa13选自Sarc或Sarc的类似物；
作为选择，Xa1、Xa2、Xa3、Xa4、Xa5、Xa7、Xa8、Xa9、Xa10、Xa11、Xa12、Xa13中的任意氨基酸的残基直接缩合或者经过L1链接从而形成一个或多个肽环；在一些实施方案中，Xa1、Xa2、Xa3、Xa4、Xa5、Xa7、Xa8、Xa9、Xa10、Xa11、Xa12、Xa13中的任意氨基酸的残基经过L1链接从而形成一个或多个肽环；
L1选自W1-RL-W2；
RL选自键、C1-6亚烷基、C2-4亚烯基、C2-4亚炔基、3-6元环烷基、4-6元杂环烷基、5-6元杂芳基、6-10元芳基，所述的亚烷基、亚烯基、亚炔基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1-4个RL1取代；
RL1各自独立地选自卤素、＝O、C1-4烷基、C2-4烯基、C1-4烷氧基、3-6元环烷基、COOH、NH2、-NH-C(＝O)-C1-4烷基，所述的烷基、烷氧基、环烷基任选进一步被1-4个选自卤素、CN、OH和NH2的取代基取代；
W1、W2各自独立地选自键、C1-6亚烷基、-O-、-S-、-NRW1-、-CONRW1-、-NRW1CO-、-C(＝O)O-或-OC(＝O)-，所述亚烷基中的一个或多个-CH2-任选被1-4个选自-O-、-S-、-NRW1-或-CO-的基团替代，所述亚烷基任选进一步被1-4个选自卤素、＝O、C1-4烷基、卤代C1-4烷基、CN、OH和NH2的取代基取代；
RW1选自H、C1-4烷基、卤素；
并且所述肽化合物任选地与保护基团连接；
所述保护基团选自Ac、戊二酰基、琥珀酰基、NH2或OH；
作为选择，多肽被反应基团Xa1、Xa6、Xa10与分子支架形成的共价键隔开而形成至少含有2个多肽环；
条件是：所述肽化合物不选自如下结构：(Ac)Pen-Asn-Thr-Trp(CH3)-Lys(Ac)-Pen-Phe[4-(2-氨基乙氧基)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH2)，其中Pen与Pen之间形成二硫键。
进一步的，其中所述肽化合物具有式(I)的氨基酸序列：
Xa1-Xa2-Xa3-Xa4-Xa5-Xa6-Xa7-Xa8-Xa9-Xa10-Xa11-Xa12-Xa13    (I)
其中Xa1与Xa6各自独立地选自Pen、Asn、Ala、Ala(3-amino)、Ala(2-ethyne)、Ala(3-azido)、Ala(2-ethene)、Val(2-ethene)、Asp、2，4-二氨基丁酸、Ser、Cys、Hcys、Glu，且Xa1与Xa6的残基之间经过反应形成肽环；
Xa2选自Asn，His或Asn和His的类似物；
Xa3选自Thr或Thr的类似物；
Xa4选自Trp或Trp的类似物；
Xa5选自Lys，Gln，Arg或Lys，Gln和Arg的类似物；
Xa7选自Phe或Phe的类似物；
Xa8选自Phe，Trp，2-Nal或Phe，Trp和2-Nal的类似物；
Xa9选自Thp或Thp的类似物；
Xa10选自Glu，Cys或Glu和Cys的类似物；
Xa11选自Asn、Lys或Asn和Lys的类似物；
Xa12选自3-Pal、Phe、Asp或3-Pal、Phe和Asp的类似物；
Xa13选自Sarc或Sarc的类似物；
作为选择，Xa1、Xa2、Xa3、Xa4、Xa5、Xa7、Xa8、Xa9、Xa10、Xa11、Xa12、Xa13中的任意氨基酸的残基经过L1链接从而形成一个或多个肽环；
L1选自W1-RL-W2；
RL选自键、C1-6亚烷基、C2-4亚烯基、C2-4亚炔基、3-6元环烷基、4-6元杂环烷基、5-6元杂芳基、6-10元芳基，所述的亚烷基、亚烯基、亚炔基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1-4个RL1取代；
RL1各自独立地选自卤素、＝O、C1-4烷基、C2-4烯基、C1-4烷氧基、3-6元环烷基、COOH、NH2、-NH-C(＝O)-C1-4烷基，所述的烷基、烷氧基、环烷基任选进一步被1-4个选自卤素、CN、OH和NH2的取代基取代；
W1、W2各自独立地选自键、C1-6亚烷基、-O-、-S-、-NRW1-、-CONRW1-、-NRW1CO-、-C(＝O)O-或-OC(＝O)-，所述亚烷基中的一个或多个-CH2-任选被1-4个选自-O-、-S-、-NRW1-或-CO-的基团替代，所述亚烷基任选进一步被1-4个选自卤素、＝O、C1-4烷基、卤代C1-4烷基、CN、OH和NH2的取代基取代；
RW1选自H、C1-4烷基、卤素；
并且所述肽化合物任选地与保护基团连接；
所述保护基团选自Ac、戊二酰基、琥珀酰基、NH2或OH；
条件是：所述肽化合物不选自如下结构：(Ac)Pen-Asn-Thr-Trp(CH3)-Lys(Ac)-Pen-Phe[4-(2-氨基乙氧基)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH2)，其中Pen与Pen之间形成二硫键。
进一步的，其中所述肽化合物具有式(I)的氨基酸序列：
Xa1-Xa2-Xa3-Xa4-Xa5-Xa6-Xa7-Xa8-Xa9-Xa10-Xa11-Xa12-Xa13    (I)
其中Xa1与Xa6各自独立地选自Pen、Asn、Ala、Ala(3-amino)、Ala(2-ethyne)、Ala(3-azido)、Ala(2-ethene)、Val(2-ethene)，且Xa1与Xa6的残基之间经过反应形成肽环；
Xa2选自Asn，His或Asn和His的类似物；
Xa3选自Thr或Thr的类似物；
Xa4选自Trp或Trp的类似物；
Xa5选自Lys或Lys的类似物；
Xa7选自Phe或Phe的类似物；
Xa8选自Phe，Trp，2-Nal或Phe，Trp和2-Nal的类似物；
Xa9选自Thp或Thp的类似物；
Xa10选自Glu或Glu的类似物；
Xa11选自Asn、Lys或Asn和Lys的类似物；
Xa12选自3-Pal、Phe、Asp或3-Pal、Phe和Asp的类似物；
Xa13选自Sarc或Sarc的类似物；
作为选择，Xa2、Xa3、Xa4、Xa5、Xa7、Xa8、Xa9、Xa10、Xa11、Xa12、Xa13中的任意氨基酸的残基经过L1链接从而形成肽环；
L1选自W1-RL-W2；
RL选自键、C1-6亚烷基、C2-4亚烯基、C2-4亚炔基、3-6元环烷基、4-6元杂环烷基、5-6元杂芳基、6-10元芳基，所述的亚烷基、亚烯基、亚炔基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1-4个RL1取代；
RL1各自独立地选自卤素、＝O、C1-4烷基、C2-4烯基、C1-4烷氧基、3-6元环烷基、COOH、NH2，所述的烷基、烷氧基、环烷基任选进一步被1-4个选自卤素、CN、OH和NH2的取代基取代；
W1、W2各自独立地选自键、C1-6亚烷基、-O-、-S-、-NRW1-、-CONRW1-、-NRW1CO-、-C(＝O)O-或-OC(＝O)-，所述亚烷基中的一个或多个-CH2-任选被1-4个选自-O-、-S-、-NRW1-或-CO-的基团替代，所述亚烷基任选进一步被1-4个选自卤素、＝O、C1-4烷基、卤代C1-4烷基、CN、OH和NH2的取代基取代；
RW1选自H、C1-4烷基、卤素；
并且所述肽化合物任选地与保护基团连接；
所述保护基团选自Ac、戊二酰基、琥珀酰基、NH2或OH；
条件是：所述肽化合物不选自如下结构：(Ac)Pen-Asn-Thr-Trp(CH3)-Lys(Ac)-Pen-Phe[4-(2-氨基乙氧基)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH2)，其中Pen与Pen之间形成二硫键。
作为本发明的更具体的第二技术方案，所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述肽化合物具有式(II)、式(II-1)的氨基酸序列：
(Ac)Xa1-Xa2-Thr-Xa4-Xa5-Xa6-Xa7-Xa8-Xa9-Xa10-Asn-(3-Pal)-Sarc(NH2)   (II)
(Ac)Xa1-Xa2-Thr-Xa4-Lys(Ac)-Xa6-Xa7-Xa8-Xa9-Glu-Asn-(3-Pal)-Sarc(NH2)   (II-1)
其中，Xa1与Xa6的残基之间经过反应形成肽环；或者Xa1与Xa6的残基之间经过L1链接形成肽环；
其他基团定义与前文任意技术方案一致。
进一步的，其中所述肽化合物具有式(II-1)的氨基酸序列：
(Ac)Xa1-Xa2-Thr-Xa4-Lys(Ac)-Xa6-Xa7-Xa8-Xa9-Glu-Asn-(3-Pal)-Sarc(NH2)   (II-1)
其中，Xa1与Xa6的残基之间经过反应形成肽环；
其他基团定义与前文任意技术方案一致。
作为本发明的更具体的第三技术方案，其中所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述肽化合物具有式(III)、式(III-1)的氨基酸序列：
(Ac)Xa1-Xa2-Thr-Trp(R1)-Xa5-Xa6-Xa7-Xa8-Xa9-Xa10-Asn-(3-Pal)-Sarc(NH2)    (III)
(Ac)Xa1-Xa2-Thr-Trp(CH3)-Lys(Ac)-Xa6-Xa7-Xa8-Xa9-Glu-Asn-(3-Pal)-Sarc(NH2)   (III-1)
其中，Xa1与Xa6的残基之间经过反应形成肽环；或者Xa1与Xa6的残基之间经过L1链接形成肽环；
且Trp(R1)与Xa5的残基之间直接缩合或者经过L1链接形成肽环；
或Trp(CH3)与Lys(Ac)的残基之间直接缩合或者经过L1链接形成肽环；
或Xa1、Xa6、Xa10与分子架形成双环肽；
R1选自H、C1-4烷基、C3-6环烷基、4-8元杂环烷基，所述烷基、环烷基、杂环烷基任选进一步被1-4个选自卤素、＝O、C1-4烷基、卤代C1-4烷基、CN、OH和NH2的取代基取代；
进一步的，其中所述肽化合物具有式(III)、式(III-1)的氨基酸序列：
(Ac)Xa1-Xa2-Thr-Trp(R1)-Xa5-Xa6-Xa7-Xa8-Xa9-Xa10-Asn-(3-Pal)-Sarc(NH2)    (III)
(Ac)Xa1-Xa2-Thr-Trp(CH3)-Lys(Ac)-Xa6-Xa7-Xa8-Xa9-Glu-Asn-(3-Pal)-Sarc(NH2)    (III-1)
其中，Xa1与Xa6的残基之间经过反应形成肽环；
且Trp(R1)与Xa5的残基之间经过L1链接形成肽环；
或Trp(CH3)与Lys(Ac)的残基之间经过L1链接形成肽环；
或Xa1、Xa6、Xa10与分子架形成双环肽；
R1选自H、C1-4烷基、C3-6环烷基、4-8元杂环烷基，所述烷基、环烷基、杂环烷基任选进一步被1-4个选自卤素、＝O、C1-4烷基、卤代C1-4烷基、CN、OH和NH2的取代基取代；
其他基团定义与前文任意技术方案一致。
进一步的，其中所述肽化合物具有式(III-1)的氨基酸序列：
(Ac)Xa1-Xa2-Thr-Trp(R1)-Xa5-Xa6-Xa7-Xa8-Xa9-Xa10-Asa-(3-Pal)-Sarc(NH2)   (III)
(Ac)Xa1-Xa2-Thr-Trp(CH3)-Lys(Ac)-Xa6-Xa7-Xa8-Xa9-Glu-Asn-(3-Pal)-Sarc(NH2)   (III-1)
其中，Xa1与Xa6的残基之间经过反应形成肽环；
且Trp(R1)与Xa5的残基之间经过L1链接形成肽环；
或Trp(CH3)与Lys(Ac)的残基之间经过L1链接形成肽环；
R1选自H、C1-4烷基、C3-6环烷基、4-8元杂环烷基，所述烷基、环烷基、杂环烷基任选进一步被1-4个选自卤素、＝O、C1-4烷基、卤代C1-4烷基、CN、OH和NH2的取代基取代；
其他基团定义与前文任意技术方案一致。
进一步的，其中所述肽化合物具有式(III-1)的氨基酸序列：
(Ac)Xa1-Xa2-Thr-Trp(CH3)-Lys(Ac)-Xa6-Xa7-Xa8-Xa9－Glu－Asn-(3-Pal)-Sarc(NH2)   (III-1)
其中，Xa1与Xa6的残基之间经过反应形成肽环；
且Trp(CH3)与Lys(Ac)的残基之间经过L1链接形成肽环；
其他基团定义与前文任意技术方案一致。
作为本发明的更具体的第四技术方案，其中所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述肽化合物具有式(IV)、式(IV-1)或式(V)的氨基酸序列：
(N-端)Xa1-Asn-Thr-Trp(R1)-Xa5-Xa6-Xa7-(2-Nal)-Xa9-Xa10-Xa11-Xa12-Sarc(C-端)    (IV)
(N-端)Xa1-Asn-Thr-Trp(CH3)-Lys(Ac)-Xa6-Xa7-(2-Nal)-Xa9-Glu-Xa11-Xa12-Sarc(C-端)   (IV-1)
或者(N-端)Xa1-His-Thr-Trp(R1)-Xa5-Xa6-Xa7-(2-Nal)-Xa9-Xa10-Xa11-Xa12-Sarc(C-端)   (V)
其中，Xa1与Xa6的残基之间经过反应形成肽环；或者Xa1与Xa6的残基之间经过L1链接形成肽环；
N-端和C-端存在或不存在保护基团；
或者N-端缀合修饰性基团；
2-Nal与Xa12的残基之间经过L1链接形成肽环；和/或者
Xa9与Xa12的残基之间经过L1链接形成肽环；和/或者
Lys(Ac)与Xa7的残基之间经过L1链接形成肽环；和/或者
Xa7与Xa11的残基之间经过L1链接形成肽环；和/或者
2-Nal与Glu的残基之间经过L1链接形成肽环；和/或者
Xa1与Glu的残基之间经过L1链接形成肽环；和/或者
Xa1与Xa11的残基之间经过L1链接形成肽环；和/或者
Xa1与Xa10的残基之间经过L1链接形成肽环；和/或者
2-Nal与Sarc的残基之间经过L1链接成肽环；和/或者
Xa9与Sarc的残基之间经过L1链接形成肽环；和/或者
Xa11与Sarc的残基之间经过L1链接形成肽环；和/或者
Xa1、Sarc与Glu的残基之间经过L1链接形成肽环；和/或者
或Xa1、Xa6、Xa10与分子架形成双环肽；
R1选自C1-2烷基、环丙基、环丁基、环戊基、环己基，所述烷基、环丙基、环丁基、环戊基、环己基任选进一步被1-4个选自F、Cl、Br、＝O、甲基、乙基、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2F、-CHF2、-CF3、CN、OH和NH2的取代基取代；
条件是：(1)、当N-端的Xa1与其他氨基酸的残基经过L1链接时，N-端的保护基团不存在；
(2)、当C-端的Sarc与其他氨基酸的残基经过L1链接时，C-端的保护基团不存在；
其他基团定义与前文任意技术方案一致。
进一步的，其中所述肽化合物具有式(IV)、式(IV-1)的氨基酸序列：
(N-端)Xa1-Asn-Thr-Trp(R1)-Xa5-Xa6-Xa7-(2-Nal)-Xa9-Xa10-Xa11-Xa12-Sarc(C-端)   (IV)
(N-端)Xa1-Asn-Thr-Trp(CH3)-Lys(Ac)-Xa6-Xa7-(2-Nal)-Xa9-Glu-Xa11-Xa12-Sarc(C-端)   (IV-1)其中，Xa1与Xa6的残基之间经过反应形成肽环；
N-端和C-端存在或不存在保护基团；2-Nal与Xa12的残基之间经过L1链接形成肽环；和/或者
Xa9与Xa12的残基之间经过L1链接形成肽环；和/或者
Lys(Ac)与Xa7的残基之间经过L1链接形成肽环；和/或者
Xa7与Xa11的残基之间经过L1链接形成肽环；和/或者
2-Nal与Glu的残基之间经过L1链接形成肽环；和/或者
Xa1与Glu的残基之间经过L1链接形成肽环；和/或者
Xa1与Xa11的残基之间经过L1链接形成肽环；和/或者
Xa1与Xa10的残基之间经过L1链接形成肽环；和/或者
2-Nal与Sarc的残基之间经过L1链接成肽环；和/或者
Xa9与Sarc的残基之间经过L1链接形成肽环；和/或者
Xa11与Sarc的残基之间经过L1链接形成肽环；和/或者
Xa1、Sarc与Glu的残基之间经过L1链接形成肽环；
R1选自C1-2烷基、环丙基、环丁基、环戊基、环己基，所述烷基、环丙基、环丁基、环戊基、环己基任选进一步被1-4个选自F、Cl、Br、＝O、甲基、乙基、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2F、-CHF2、-CF3、CN、OH和NH2的取代基取代；
条件是：(1)、当N-端的Xa1与其他氨基酸的残基经过L1链接时，N-端的保护基团不存在；
(2)、当C-端的Sarc与其他氨基酸的残基经过L1链接时，C-端的保护基团不存在；
其他基团定义与前文任意技术方案一致。
进一步的，其中所述肽化合物具有式(IV-1)的氨基酸序列：
(N-端)Xa1-Asn-Thr-Trp(CH3)-Lys(Ac)-Xa6-Xa7-(2-Nal)-Xa9-Glu-Xa11-Xa12-Sarc(C-端)   (IV-1)
其中，Xa1与Xa6的残基之间经过反应形成肽环；
N-端和C-端存在或不存在保护基团；
2-Nal与Xa12的残基之间经过L1链接形成肽环；和/或者
Xa9与Xa12的残基之间经过L1链接形成肽环；和/或者
Lys(Ac)与Xa7的残基之间经过L1链接形成肽环；和/或者
Xa7与Xa11的残基之间经过L1链接形成肽环；和/或者
2-Nal与Glu的残基之间经过L1链接形成肽环；和/或者
Xa1与Glu的残基之间经过L1链接形成肽环；和/或者
Xa1与Xa11的残基之间经过L1链接形成肽环；和/或者
2-Nal与Sarc的残基之间经过L1链接成肽环；和/或者
Xa9与Sarc的残基之间经过L1链接形成肽环；和/或者
Xa11与Sarc的残基之间经过L1链接形成肽环；和/或者
Xa1、Sarc与Glu的残基之间经过L1链接形成肽环；
条件是：(1)、当N-端的Xa1与其他氨基酸的残基经过L1链接时，N-端的保护基团不存在；
(2)、当C-端的Sarc与其他氨基酸的残基经过L1链接时，C-端的保护基团不存在；
其他基团定义与前文任意技术方案一致。作为本发明的更具体的第五技术方案，所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中
Xa1与Xa6的残基之间经过反应形成肽环或者经L1形成环肽，且Xa4与Xa5、Xa1与Xa10、Xa8与Xa10、Xa8与Xa12、Xa8与Xa13、Xa9与Xa13、Xa5与Xa7、Xa11与Xa13、Xa1与Xa11、Xa7与Xa11中的一组或两组的残基之间直接缩合或者经过L1链接形成肽环；
或Xa1、Xa6、Xa10与分子架形成双环肽；
其他基团定义与前文任意技术方案一致。
进一步的，所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中Xa1与Xa6的残基之间经过反应形成肽环，且Xa4与Xa5、Xa1与Xa10、Xa8与Xa10、Xa8与Xa12、Xa8与Xa13、Xa9与Xa13、Xa5与Xa7、Xa11与Xa13、Xa1与Xa11、Xa7与Xa11中的一组或两组的残基之间直接缩合或者经过L1链接形成肽环；
或Xa1、Xa6、Xa10与分子架形成双环肽；
其他基团定义与前文任意技术方案一致。
作为本发明的更具体的第六技术方案，所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述肽化合物与肽化合物中氨基酸残基经过聚乙二醇链相连，形成二聚体化合物；所述聚乙二醇链为
n选自0-99的任意整数；
其他基团定义与前文任意技术方案一致。作为本发明的更具体的第七技术方案，所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述修饰性基团为 p选自0-50的任意整数，q选自0-50的任意整数；在一些实施方案中，所述修饰性基团为 p选自0-50的任意整数，q选自0-50的任意整数；
其他基团定义与前文任意技术方案一致。
进一步的，其中所述修饰性基团为p选自0-5的任意整数，q选自0-5的任意整数；
其他基团定义与前文任意技术方案一致。
进一步的，其中所述修饰性基团为
其他基团定义与前文任意技术方案一致。
作为本发明的更具体的第八技术方案，其中所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中
Xa1与Xa6的残基经过反应形成如下结构：
其中*端为Xa1端，Xa1与Xa2通过*位置连接，NH2末端与保护基团相连；或者*端为Xa1端，Xa1与Xa2通过*位置连接，NH2末端与保护基团相连或NH2末端缀合修饰性基团；
Xa2选自Asn、His，或His的类似物，所述His的类似物选自或者所述His的类似物选自或者所述His的类似物选自
Xa3选自Thr；
Xa4选自Trp的类似物，所述Trp的类似物选自
Xa5选自Lys，Gln，Arg，Cit，或Arg、Lys的类似物，所述Arg、Lys的类似物选自
或者作为选择，Xa5残基缀合修饰性基团；
Xa7选自Phe或Phe的类似物，所述Phe的类似物选自
或者作为选择，Xa7残基缀合修饰性基团；
Xa8选自Phe，Trp，2-Nal，或Phe，Trp和2-Nal的类似物；所述Phe，Trp和2-Nal的类似物选自或者选自
Xa9选自Thp或Thp的类似物，所述Thp的类似物选自
Xa10选自Glu或Cys；
Xa11选自Asn或Lys；
Xa12选自3-Pal或Phe；
所述的分子架选自： 或者选自
其他基团定义与前文任意技术方案一致。
进一步的，所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中Xa1与Xa6的残基经过反应形成如下结构：
其中*端为Xa1端，Xa1与Xa2通过*位置连接，NH2末端与保护基团相连；
Xa2选自Asn、His或His的类似物，所述His的类似物选自
Xa4选自Trp的类似物，所述Trp的类似物选自
Xa5选自Lys，Gln，Arg或Arg的类似物，所述Arg的类似物选自
Xa7选自Phe或Phe的类似物，所述Phe的类似物选自
Xa8选自Phe，Trp，2-Nal或Phe，Trp和2-Nal的类似物；所述Phe，Trp和2-Nal的类似物选自
Xa9选自Thp或Thp的类似物，所述Thp的类似物选自
Xa10选自Glu或Cys；
Xa11选自Asn或Lys；
Xa12选自3-Pal或Phe；
所述的分子架选自：
其他基团定义与前文任意技术方案一致。
进一步的，所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中
Xa1与Xa6的残基经过反应形成如下结构： 或者Xa1与Xa6的残基经过反应形成如下结构： 或者Xa1与Xa6的残基经过反应形成如下结构：
其中*端为Xa1端，Xa1与Xa2通过*位置连接，NH2末端与保护基团相连；
Xa2选自Asn、His或His的类似物，所述His的类似物选自
Xa4选自Trp的类似物，所述Trp的类似物选自
Xa5选自Lys，Gln，Arg或Arg的类似物，所述Arg的类似物选自
Xa7选自Phe或Phe的类似物，所述Phe的类似物选自 在一些实施方案中，Xa7选自Phe或Phe的类似物，所述Phe的类似物选自
Xa8选自Phe，Trp，2-Nal或Phe，Trp和2-Nal的类似物；所述Phe，Trp和2-Nal的类似物选自或者所述Trp的类似物选自
Xa9选自Thp或Thp的类似物，所述Thp的类似物选自
Xa10选自Glu或Cys；
Xa11选自Asn或Lys；
Xa12选自3-Pal或Phe；
其他基团定义与前文任意技术方案一致。
作为本发明的更具体的第九技术方案，其中所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述的分子架选自： 在一些实施方案中，所述的分子架选自：
其他基团定义与前文任意技术方案一致。
作为本发明的更具体的第十技术方案，所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中
L1选自键、乙烯基、丙烯基、丁烯基、-O-(CH2)r-O-(CH2)r-NH-C(＝O)-、-O-(CH2)r-O-(CH2)r-、-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-C(＝O)-、-NH-C(＝O)-、-C(＝O)-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-C(＝O)-(CH2)r-、-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-、C1-6亚烷基、-C(＝O)-、-C(＝O)-(CH2)r-NH-、 -(CH2)r-O-(CH2)r-NH-、-O-(CH2)r-O-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-、-(CH2)r-NH-C(＝O)-(CH2)r-、-C(＝O)-(CH2)-(OCH2CH2)a-NH-；
进一步的，L1选自键、乙烯基、丙烯基、丁烯基、-O-(CH2)r-O-(CH2)r-NH-C(＝O)-、-O-(CH2)r-O-(CH2)r-、-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-C(＝O)-、-NH-C(＝O)-、-C(＝O)-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-C(＝O)-(CH2)r-、-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-、C1-2亚烷基、-C(＝O)-、-C(＝O)-(CH2)r-NH-、-(CH2)r-O-(CH2)r-NH-、-O-(CH2)r-O-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-；
进一步的，L1选自键、乙烯基、丙烯基、丁烯基、-O-(CH2)r-O-(CH2)r-NH-C(＝O)-、-O-(CH2)r-O-(CH2)r-、-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-C(＝O)-、-NH-C(＝O)-、-C(＝O)-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-C(＝O)-(CH2)r-、-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-、C1-2亚烷基、-C(＝O)-、-C(＝O)-(CH2)r-NH-、或选自-(CH2)r-O-(CH2)r-NH-、-O-(CH2)r-O-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-(CH2)r-NH-；
进一步，所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中L1选自键、乙烯基、丙烯基、丁烯基、-O-(CH2)r-O-(CH2)r-NH-C(＝O)-、-O-(CH2)r-O-(CH2)r-、-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-C(＝O)-、-NH-C(＝O)-、-C(＝O)-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-C(＝O)-(CH2)r-、-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-、C1-2亚烷基、-C(＝O)-(CH2)r-NH-、或者L1选自
r选自0、1、2、3、4、5、6、7、8、9或10；
a选自3、4、5或6；
其他基团定义与前文任意技术方案一致。
作为本发明的更具体的第十一技术方案，所述的肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述肽化合物选自以下表一中结构之一：
表一：















本发明还涉及一种药物组合物，其包含前述第一至第十一中任一技术方案所述的肽化合物或其药学上可接受的盐，以及药学上可接受的载体和/或赋形剂。
本发明还涉及一种用途，前述第一至第十一中任一技术方案所述的肽化合物或其药学上可接受的盐，或者所述药物组合物，在制备预防和治疗受试者患病组织中过度表达IL-23的疾病或病症药物中的应用。
进一步的，所述过度表达IL-23的疾病或病症包括炎症性肠病、克罗恩病和银屑病。
本发明还涉及一种药物组合物或药物制剂，所述的药物组合物或药物制剂包含选1-1500mg的前述第一至第十一中任一技术方案所述的肽化合物或其药学上可接受的盐，以及药学上可接受的载体和/或赋形剂。
本发明还涉及一种用于治疗哺乳动物或人的疾病的方法，所述方法包括给予受试者治疗有效量的前述第一至第十一中任一技术方案所述的肽化合物或其药学上可接受的盐，治疗有效量优选1-1500mg，所述的疾病优选炎症性肠病、克罗恩病和银屑病。
本发明还提供一种组合物或药物制剂，其中含有前述任意一项方案所述的肽化合物或其药学上可接受的盐，以及药学上可接受的载体和/或辅料。该药物组合物可以为单位制剂形式(单位制剂也被称为“制剂规格”)。
进一步地，本发明的组合物或药物制剂，其中含有1-1500mg的前述任意一项方案所述的肽化合物或其药学上可接受的盐，以及药学上可接受的载体和/或辅料。
本发明还提供了前述任意一项方案所述的肽化合物或其药学上可接受的盐在制备预防和治疗受试者患病组织中过度表达IL-23的疾病或病症药物中的应用。进一步地，所述过度表达IL-23的疾病或病症包括炎症性肠病、克罗恩病和银屑病。
本发明还提供了一种用于治疗哺乳动物或人的疾病的方法，所述方法包括给予受试者治疗有效量的前述任意一项方案所示的肽化合物或其药学上可接受的盐，所述疾病优选为炎症性肠病、克罗恩病和银屑病，优选所述治疗有效量为1-1500mg。一些实施方案中，本发明中所述哺乳动物不包括人。
本申请中所述“有效量”或“治疗有效量”是指给予足够量的本申请公开的化合物，其将在某种程度上缓解所治疗的疾病或病症的一种或多种症状。在一些实施方案中，结果是减少和/或缓和疾病的体征、症状或原因，或生物系统的任何其它希望改变。例如，针对治疗用途的“有效量”是提供临床上显著的疾病症状降低所需的包含本申请公开的肽化合物或其药学上可接受的盐的组合物的量。治疗有效量的实例包括但不限于1-1500mg、1-1400mg、1-1300mg、1-1200mg、1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、1-500mg、1-400mg、1-300mg、1-250mg、1-200mg、1-150mg、1-125mg、1-100mg、1-80mg、1-60mg、1-50mg、1-40mg、1-25mg、1-20mg、5-1500mg、5-1000mg、5-900mg、5-800mg、5-700mg、5-600mg、5-500mg、5-400mg、5-300mg、5-250mg、5-200mg、5-150mg、5-125mg、5-100mg、5-90mg、5-70mg、5-80mg、5-60mg、5-50mg、5-40mg、5-30mg、5-25mg、5-20mg、10-1500mg、10-1000mg、10-900mg、10-800mg、10-700mg、10-600mg、10-500mg、10-450mg、10-400mg、10-300mg、10-250mg、10-200mg、10-150mg、10-125mg、10-100mg、10-90mg、10-80mg、10-70mg、10-60mg、10-50mg、10-40mg、10-30mg、10-20mg；20-1500mg、20-1000mg、20-900mg、20-800mg、20-700mg、20-600mg、20-500mg、20-400mg、20-350mg、20-300mg、20-250mg、20-200mg、20-150mg、20-125mg、20-100mg、20-90mg、20-80mg、20-70mg、20-60mg、20-50mg、20-40mg、20-30mg；50-1500mg、50-1000mg、50-900mg、50-800mg、50-700mg、50-600mg、50-500mg、50-400mg、50-300mg、50-250mg、50-200mg、50-150mg、50-125mg、50-100mg；100-1500mg、100-1000mg、100-900mg、100-800mg、100-700mg、100-600mg、100-500mg、100-400mg、100-300mg、100-250mg、100-200mg；
在一些实施方案中，本发明的药物组合物或制剂含有上述治疗有效量的本发明肽化合物或其药学上可接受的盐；
本发明涉及一种药物组合物或药物制剂，所述的药物组合物或药物制剂包含治疗有效量的本发明所述的肽化合物或其药学上可接受的盐以及载体和/或赋形剂。该药物组合物可以为单位制剂形式(单位制剂中主药的量也被称为“制剂规格”)。在一些实施方案中，该药物组合物包括但不限于1mg、1.25mg、2.5mg、5mg、10mg、12.5mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg、525mg、550mg、575mg、600mg、625mg、650mg、675mg、700mg、725mg、750mg、775mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg的本发明肽化合物或其药学上可接受的盐。
一种用于治疗哺乳动物或人的疾病的方法，所述方法包括给予受试者治疗有效量的本发明肽化合物或其药学上可接受的盐，以及药学上可接受的载体和/或赋形剂，治疗有效量优选1-1500mg，所述的疾病优选炎症性肠病、克罗恩病和银屑病。
一种用于治疗哺乳动物或人的疾病的方法所述方法包括，将药物本发明肽化合物或其药学上可接受的盐，以及药学上可接受的载体和/或赋形剂，以1-1500mg/天的日剂量给予受试者，所述日剂量可以为单剂量或分剂量，在一些实施方案中，日剂量包括但不限于10-1500mg/天、20-1500mg/天、25-1500mg/天、50-1500mg/天、75-1500mg/天、100-1500mg/天、200-1500mg/天、10-1000mg/天、20-1000mg/天、25-1000mg/天、50-1000mg/天、75-1000mg/天、100-1000mg/天、200-1000mg/天、25-800mg/天、50-800mg/天、100-800mg/天、200-800mg/天、25-400mg/天、50-400mg/天、100-400mg/天、200-400mg/天，在一些实施方案中，日剂量包括但不限于1mg/天、5mg/天、10mg/天、20mg/天、25mg/天、50mg/天、75mg/天、100mg/天、125mg/天、150mg/天、200mg/天、300mg/天、400mg/天、600mg/天、800mg/天、1000mg/天、1200mg/天、1400mg/天、1500mg/天。
本发明涉及一种试剂盒，该试剂盒可以包括单剂量或多剂量形式的组合物，该试剂盒包含本发明肽化合物或其药学上可接受的盐，本发明化合物或者其立体异构体或药学上可接受的盐量与上述药物组合物中其量相同。
本发明中本发明化合物或者其立体异构体或药学上可接受的盐的量在每种情况下以游离碱的形式换算。
“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。
术语
在本发明未特殊说明的情况下，本发明的术语具有以下含义：
本发明所述“肽”广义上是指两个或更多个氨基酸通过肽键连接在一起的序列。应理解该术语既不暗示特定长度的氨基酸聚合物，也不旨在暗示或区分多肽是否是使用重组技术、化学合成或酶合成产生的或是否为天然存在的。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(氘，又称为重氢)、氚(T，又称为超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。可以使用本领域已知的标准方法制备本发明公开的化合物的放射性标记的化合物。
本发明所述“二聚体”广义上是指包含两个或更多个单体亚基的肽。某些二聚体包含两个DRP。本发明的二聚体包括同源二聚体和异源二聚体。二聚体的单体亚基可以在其C-端或N-端处连接，或者其可以经由内部氨基酸残基连接。二聚体的各单体亚基可以通过同一位点连接，或者各自可以通过不同位点(例如，C-端、N-端或内部位点)连接。
本文使用的术语“环化”或“形成肽环”是指这样的反应：其中多肽分子的一部分与所述多肽分子的另一部分连接形成一个闭合环，或者多肽分子的一部分与所述多肽分子的其他几部分连接形成多个闭合环，如通过形成二硫桥或其它类似键，或者通过linker连接。
发明所述“Ac”是指“乙酰基”；
本文所述的“衍生物”或“类似物”是指一种化合物中的氢原子或原子团被其他原子或原子团取代而衍生的产物。应当理解，如本文定义的肽化合物的氨基酸类似物在本发明的范围内。这种合适的修饰的氨基酸衍生物的示例包含一个或多个选自以下的修饰：N-末端和/或C-末端修饰；用一个或多个非天然氨基酸残基替换一个或多个氨基酸残基(例如用一个或多个等排或等电子氨基酸替换一个或多个极性氨基酸残基；用其它非天然的等排或等电子氨基酸替换一个或多个非极性氨基酸残基)；加入间隔物基团；用一个或多个氧化耐受性氨基酸残基替换一个或多个氧化敏感性氨基酸残基；用丙氨酸替换一个或多个氨基酸残基，用一个或多个D-氨基酸残基替换一个或多个L-氨基酸残基；双环肽配体中一个或多个酰胺键的N-烷基化；用替代键(surrogate bond)替换一个或多个肽键；肽骨架长度修饰；用另一个化学基团替代或取代一个或多个氨基酸残基的α-碳上的氢，用合适的胺、硫醇、羧酸和酚反应性试剂修饰氨基酸如甘氨酸、丙氨酸、苯丙氨酸、半胱氨酸、赖氨酸、谷氨酸/天冬氨酸和酪氨酸等，以功能化所述氨基酸，和引入或替换氨基酸，以引入适合于官能化的正交反应性，例如携带叠氮化物或炔烃基团的氨基酸分别允许用携带炔烃或叠氮化物的部分进行官能化。
除非特别说明，所有氨基酸均以L-构型使用。
部分常见氨基酸名称及其三字母缩写和单字母缩写见下表：
2-Nal:
3-Pal:
Thp:
Pen：
Pcn:
Ala(3-amino)：
Ala(2-ethyne)：
Ala(3-azido)：
Ala(2-ethene)：
Val(2-ethene)：
2,4-二氨基丁酸：
“药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”表示一种或多种本文所述化合物或其立体异构体、溶剂化物、药学上可接受的盐或共晶，与其他组成成分的混合物，其中其他组分包含生理学/药学上可接受的载体和/赋形剂。
“载体”指的是：不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性，并能改变药物进入人体的方式和在体内的分布、控制药物的释放速度并将药物输送到靶向器官的体系，非限制性的实例包括微囊与微球、纳米粒、脂质体等。
“赋形剂”指的是：其本身并非治疗剂，用作稀释剂、辅料、粘合剂和/或媒介物，用于添加至药物组合物中以改善其处置或储存性质或允许或促进化合物或药物组合物形成用于给药的单位剂型。如本领域技术人员所已知的，药用赋形剂可提供各种功能且可描述为润湿剂、缓冲剂、助悬剂、润滑剂、乳化剂、崩解剂、吸收剂、防腐剂、表面活性剂、着色剂、矫味剂及甜味剂。药用赋形剂的实例包括但不限于：(1)糖，例如乳糖、葡萄糖及蔗糖；(2)淀粉，例如玉米淀粉及马铃薯淀粉；(3)纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素、乙酸纤维素、羟丙基甲基纤维素、羟丙基纤维素、微晶纤维素及交联羧甲基纤维素(例如交联羧甲基纤维素钠)；(4)黄蓍胶粉；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，例如可可脂 及栓剂蜡；(9)油，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油；(10)二醇，例如丙二醇；(11)多元醇，例如甘油、山梨醇、甘露醇及聚乙二醇；(12)酯，例如油酸乙酯及月桂酸乙酯；(13)琼脂；(14)缓冲剂，例如氢氧化镁及氢氧化铝；(15)海藻酸；(16)无热原水；(17)等渗盐水；(18)林格溶液(Ringer’s solution)；(19)乙醇；(20)pH缓冲溶液；(21)聚酯、聚碳酸酯和/或聚酐；及(22)其他用于药物制剂中的无毒相容物质。
具体实施方式
以下将通过实施例对本发明的内容进行详细描述。实施例中未注明具体条件的，按照常规条件的实验方法进行。所举实施例是为了更好地对本发明的内容进行说明，但并不能理解为本发明的内容仅限于所举实例。本领域常规技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本发明的保护范围。
检测方法
化合物的结构是通过质谱(MS)来确定的。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；
简写说明：
DCM：二氯甲烷
DMF:N,N-二甲基甲酰胺
DIEA：N,N-二异丙基乙胺
MeOH：甲醇
TFA：三氟乙酸
DMSO:二甲基亚砜
DIC：N,N'-二异丙基碳二亚胺
HOBT：1-羟基苯并三唑
HOAT:N-羟基-7-氮杂苯并三氮唑
中间体1:
第一步:将亚硝酸钠(42.14g,610.7mmol)加入到DMF(300mL)和水(400mL)中，氮气置换后在0℃下滴加盐酸(2mol/L,103mL)，然后将化合物1a(10g,76.3mmol)溶于DMF(300mL)，在2h内滴加到反应溶液中，将反应移动至室温搅拌过夜，点板检测到原料消耗完毕，加入水(2L)，使用乙酸乙酯萃取(500mL x 3)，合并有机相并旋干，使用硅胶色谱柱分离纯化(EA:PE＝5:1)得到化合物1b(7.4g,60.6％)。
LC-MS(ESI):m/z＝161.0[M+H]+.
第二步:将化合物1b(7.4g,45.9mmol)溶于二氯甲烷(100mL)中，加入三乙胺(7g,68.9mmol)和二碳酸二叔丁酯(12g,55.2mmol)，反应搅拌过夜，然后加入二氯甲烷(100mL)稀释，用水洗涤三次(100mL)，然后将有机相浓缩得到化合物1c(10g,83.2％)。
LC-MS(ESI):m/z＝261.0[M+H]+.
第三步:将(±)苄基氧基羰基-a-膦酰甘氨酸三甲酯(14g,42.3mmol)溶于二氯甲烷(100mL)中，氮气置换后加入DBU(6.43g,42.3mmol)并搅拌30min，然后将化合物1c(10g,38.4mmol)溶于二氯甲烷(100mL)滴加到反应中，继续搅拌过夜，将反应混合物用二氯甲烷稀释(100mL)并用5％柠檬酸水溶液(100mL)和饱和食盐水(100mL)洗涤，然后用无水硫酸钠干燥，过滤并旋干。使用硅胶色谱柱分离纯化(EA:PE＝3:1)得到化合物1d(12g,67.1％)。
LC-MS(ESI):m/z＝466.2[M+H]+.
第四步:将化合物1d(5g,10.74mmol)溶于甲醇(50mL)二氯甲烷(20mL)的混合溶液中，加入(+)-1,2-双(2S,5S)-2,5-二乙基环丁磷烷苯(环辛二烯)三氟甲磺酸铑(0.5g,0.69mmol)，使用高压釜填充氢气至压力约4.0bar，室温下搅拌3h，滤除固体，将反应溶液浓缩得到化合物1e(5g,99.8％)。
LC-MS(ESI):m/z＝468.2[M+H]+.
第五步:将化合物1e(5g,10.69mmol)溶于甲醇(50mL)二氯甲烷(20mL)的混合溶液中，加入钯碳(10％,1g)，于氢气环境下搅拌过夜，然后滤除固体，将反应溶液旋干得到化合物1f(3.2g,89.7％)。
LC-MS(ESI):m/z＝334.2[M+H]+.
第六步:将化合物1f(3.2g,9.60mmol)添加到二氯甲烷(30mL)中，滴加三氟乙酸(10mL)，反应在室温下搅拌2h，LCMS监测到原料消耗完毕，直接旋干得到化合物1g粗品，无需纯化直接用于下一步反应。
LC-MS(ESI):m/z＝234.1[M+H]+.
第七步:将化合物1g(2.2g,9.43mmol)溶于四氢呋喃(20mL)，加入氢氧化锂一水合物(1.58g,37.7mmol)和水(20mL)，反应在室温下搅拌过夜，使用乙酸乙酯萃取(10mL x 3)出杂质，然后用稀盐酸(1N)调节水相pH至中性，产物析出，过滤后干燥得到化合物1h(2g,96.7％)。
LC-MS(ESI):m/z＝220.1[M+H]+.
第八步:将化合物1h(2g,9.12mmol)溶于乙腈(20mL)和水(20mL)的混合溶液中，加入碳酸氢钠(3.83g,45.6mmol)和9-芴甲基-N-琥珀酰亚胺基碳酸酯(4.6g,13.7mmol)，反应在室温下搅拌过夜，反应完毕后滴加稀盐酸调节pH至中性，40℃下真空浓缩旋去大部分乙腈，过滤收集固体得到产物粗品，使用硅胶色谱柱分离纯化(DCM:MeOH＝10:1)得到中间体1(2.5g,62.1％)。
LC-MS(ESI):m/z＝442.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.81(s,1H),7.87(d,2H),7.68–7.57(m,3H),7.54–7.43(m,1H),7.42–7.35(m,2H),7.32–7.22(m,2H),7.06(d,1H),6.99–6.90(m,1H),4.44–4.34(m,1H),4.21–3.93(m,3H),3.43–3.25(m,2H),2.47(s,3H).
中间体2：
第一步：将化合物2a(10.0g,75.65mmol)溶解于二氯甲烷(100mL)，SnCl4(23.7g,90.78mmol)滴加至上述反应液，降温至0℃。5min后，滴加1,1-二氯二甲醚(9.6g,83.22mmol)，0℃下搅拌3h。反应结束后，向反应体系内加入200mL水，所得溶液用二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，柱层析(EA:PE＝1:50)得到化合物2b(4.1g,33.8％)。
LC-MS(ESI):m/z＝161.1[M+H]+。
第二步：将(±)苄基氧基羰基-a-膦酰甘氨酸三甲酯(9.9g,29.93mmol)溶于二氯甲烷(100mL)中，氮气置换后加入DBU(4.9g,32.42mmol)并搅拌30min，然后将化合物2b(4.0g,24.94mmol)溶于二氯甲烷(100mL)滴加到反应中，搅拌过夜，将反应混合物用二氯甲烷稀释(100mL)并用5％柠檬酸水溶液(100mL)和饱和食盐水(100mL)洗涤，然后用无水硫酸钠干燥，过滤并旋干。使用硅胶色谱柱分离纯化(EA:PE＝5:1)得到化合物2c(6.1g,66.9％)。
LC-MS(ESI):m/z＝366.2[M+H]+。
第三步：将化合物2c(6.0g,16.42mmol)溶于甲醇(50mL)二氯甲烷(20mL)的混合溶液中，加入(+)-1,2-双(2S,5S)-2,5-二乙基环丁磷烷苯(环辛二烯)三氟甲磺酸铑(0.6g,0.84mmol)，使用高压釜填充氢气至压力约4.0bar，室温下搅拌3h，滤除固体，将反应溶液浓缩得到化合物2d(5.9g,98％)。
LC-MS(ESI):m/z＝368.2[M+H]+。
第四步：将化合物2d(5.9g,9.08mmol)溶于甲醇(50mL)二氯甲烷(20mL)的混合溶液中，加入钯碳(10％,1g)，于氢气环境下搅拌过夜，然后滤除固体，将反应溶液旋干得到化合物2e(3.5g,93.4％)。
LC-MS(ESI):m/z＝234.1[M+H]+。
第五步：将化合物2e(3.5g,15.00mmol)溶于四氢呋喃(35mL)，加入氢氧化锂一水合物(1.4g,59.71mmol)和水(25mL)，反应在室温下搅拌过夜，使用乙酸乙酯萃取(20mL x 3)出杂质，然后用稀盐酸(1N)调节水相pH至中性，产物析出，过滤后干燥得到化合物2f(2.8g,85.1％)。
LC-MS(ESI):m/z＝220.1[M+H]+。
第六步：将化合物2f(2.7g,12.31mmol)溶于乙腈(25mL)和水(25mL)的混合溶液中，加入碳酸氢钠(10.3g,123.10mmol)和9-芴甲基-N-琥珀酰亚胺基碳酸酯(5.0g,14.77mmol)，反应在室温下搅拌过夜，反应完毕后滴加稀盐酸调节pH至中性，40℃下真空浓缩旋去大部分乙腈，过滤收集固体得到产物粗品，使用硅胶色谱柱分离纯化(DCM:MeOH＝12:1)得到中间体2(1.3g,23.9％)。
LC-MS(ESI):m/z＝442.2[M+H]+。
1H NMR(400MHz,MeOD)δ7.77(d,2H),7.60–7.48(m,2H),7.37(t,2H),7.26(q,2H),6.94–6.78(m,3H),4.46–4.21(m,2H),4.14(dt,2H),3.13(dd,1H),2.86(dd,1H),2.67(s,4H),1.71(s,4H).
中间体3：
第一步：将化合物3a(10.0g,73.43mmol)溶解于二氯甲烷(100mL)，TiCl4(25.5g,134.38mmol)滴加至上述反应液，降温至0℃。5min后，滴加1,1-二氯二甲醚(9.4g,81.51mmol)，0℃下搅拌3h。反应结束后，向反应体系内加入200mL水，所得溶液用二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，柱层析(EA:PE＝1:4)得到化合物3b(5.58g,46.3％)。
LC-MS(ESI):m/z＝163.2[M+H]+。
第二步：将化合物3b(3.0g,18.27mmol)、(2-溴乙基)氨基甲酸叔丁酯(4.9g,21.91mmol)、碳酸钾(5.1g,36.54mmol)、碘化钠(0.8g,5.47mmol)溶于N,N-二甲基甲酰胺(20mL)，25℃下搅拌16h。反应结束后，加水100mL，乙酸乙酯(50mL×3)萃取反应液三次，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，柱层析(EA:PE＝4:1)得到化合物3c(4.9g,87％)。
LC-MS(ESI):m/z＝306.1[M+H]+。
第三步：将(±)苄基氧基羰基-a-膦酰甘氨酸三甲酯(6.2g,18.74mmol)溶于二氯甲烷(100mL)中，氮气置换后加入DBU(3.1g,20.31mmol)并搅拌30min，然后将化合物3c(4.8g,15.62mmol)溶于二氯甲烷(100mL)滴加到反应中，搅拌过夜，将反应混合物用二氯甲烷稀释(100mL)并用5％柠檬酸水溶液(100mL)和饱和食盐水(100mL)洗涤，然后用无水硫酸钠干燥，过滤并旋干。使用硅胶色谱柱分离纯化(EA:PE＝3:1)得到化合物3d(6.1g,76.2％)。
LC-MS(ESI):m/z＝511.1[M+H]+。
第四步：将化合物3d(6.0g,11.71mmol)溶于甲醇(50mL)二氯甲烷(20mL)的混合溶液中，加入(+)-1,2-双(2S,5S)-2,5-二乙基环丁磷烷苯(环辛二烯)三氟甲磺酸铑(0.6g,0.83mmol)，使用高压釜填充氢气至压力约4.0bar，室温下搅拌3h，滤除固体，将反应溶液浓缩得到化合物3e(5.9g,98％)。
LC-MS(ESI):m/z＝513.2[M+H]+。
第五步：将化合物3e(5.9g,11.46mmol)溶于甲醇(50mL)二氯甲烷(20mL)的混合溶液中，加入钯碳(10％,1g)，于氢气环境下搅拌过夜，然后滤除固体，将反应溶液旋干得到化合物3f(3.7g,84.5％)。
LC-MS(ESI):m/z＝379.4[M+H]+。
第六步：将化合物3f(3.7g,9.72mmol)溶于四氢呋喃(25mL)，加入氢氧化锂一水合物(1.2g,48.6mmol)和水(25mL)，反应在室温下搅拌过夜，使用乙酸乙酯萃取(15mL x 3)出杂质，然后用稀盐酸(1N)调节水相pH至中性，产物析出，过滤后干燥得到化合物3g(3.2g,89.8％)。
LC-MS(ESI):m/z＝365.2[M+H]+。
第七步：将化合物3g(2.7g,7.41mmol)溶于乙腈(25mL)和水(25mL)的混合溶液中，加入碳酸氢钠(6.2g,74.16mmol)和9-芴甲基-N-琥珀酰亚胺基碳酸酯(3.3g,9.63mmol)，反应在室温下搅拌过夜，反应完毕后滴加稀盐酸调节pH至中性，40℃下真空浓缩旋去大部分乙腈，过滤收集固体得到产物粗品，使用硅胶色谱柱分离纯化(DCM:MeOH＝10:1)得到中间体3(2.7g,62.1％)。
LC-MS(ESI):m/z＝587.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),7.88(d,2H),7.67(s,2H),7.41(d,2H),7.36–7.24(m,2H),7.03–6.88(m,2H),6.65(d,1H),4.26–4.09(m,4H),3.91(s,2H),3.28(s,2H),2.99(d,1H),2.90–2.68(m,5H),2.51(s,1H),1.98(s,2H),1.39(s,9H).
中间体4：
第一步：将化合物4a(2.0g,14.09mmol)、N-(叔丁氧羰基)乙醇胺(4.5g,28.18mmol)溶于N,N-二甲基乙酰胺(20mL)，加入碳酸钾(3.9g,28.18mmol)，80℃与微波中搅拌2h。反应结束后，向反应体系内加入20mL水，所得溶液用乙酸乙酯(40×3)萃取三次，无水硫酸钠干燥，减压浓缩，柱层析(PE:PE＝4:1)得到化合物4b(0.9g,24.0％)。
LC-MS(ESI):m/z＝267.2[M+H]+。
第二步：将(±)苄基氧基羰基-a-膦酰甘氨酸三甲酯(6.1g,18.47mmol)溶于二氯甲烷(100mL)中，氮气置换后加入DBU(3.1g,20.02mmol)并搅拌30min，然后将化合物4b(4.1g,15.40mmol)溶于二氯甲烷(100mL)滴加到反应中，搅拌过夜，将反应混合物用二氯甲烷稀释(100mL)并用5％柠檬酸水溶液(100mL)和饱和食盐水(100mL)洗涤，然后用无水硫酸钠干燥，过滤并旋干。使用硅胶色谱柱分离纯化(EA:PE＝3:1)得到化合物4c(4.5g,62.0％)。
LC-MS(ESI):m/z＝472.2[M+H]+。
第三步：将化合物4c(4.4g,9.33mmol)溶于甲醇(40mL)二氯甲烷(20mL)的混合溶液中，加入(+)-1,2-双(2S,5S)-2,5-二乙基环丁磷烷苯(环辛二烯)三氟甲磺酸铑(0.6g,0.83mmol)，使用高压釜填充氢气至压力约4.0bar，室温下搅拌3h，滤除固体，将反应溶液浓缩得到化合物4d(4.3g,97％)。
LC-MS(ESI):m/z＝474.2[M+H]+。
第四步：将化合物4d(4.3g,9.08mmol)溶于甲醇(50mL)二氯甲烷(20mL)的混合溶液中，加入钯碳(10％,1g)，于氢气环境下搅拌过夜，然后滤除固体，将反应溶液旋干得到化合物4e(2.9g,94.1％)。
LC-MS(ESI):m/z＝340.3[M+H]+。
第五步：将化合物4e(3.0g,8.84mmol)溶于四氢呋喃(25mL)，加入氢氧化锂一水合物(0.9g,37.6mmol)和水(25mL)，反应在室温下搅拌过夜，使用乙酸乙酯萃取(20mL x 3)出杂质，然后用稀盐酸(1N)调节水相pH至中性，产物析出，过滤后干燥得到化合物4f(2.4g,83.4％)。
LC-MS(ESI):m/z＝326.2[M+H]+。
第六步：将化合物4f(2.4g,7.38mmol)溶于乙腈(20mL)和水(20mL)的混合溶液中，加入碳酸氢钠(6.2g,73.8mmol)和9-芴甲基-N-琥珀酰亚胺基碳酸酯(3.2g,9.59mmol)，反应在室温下搅拌过夜，反应完毕后滴加稀盐酸调节pH至中性，40℃下真空浓缩旋去大部分乙腈，过滤收集固体得到产物粗品，使用硅胶色谱柱分离纯化(DCM:MeOH＝10:1)得到中间体4(1.9g,47.0％)。
LC-MS(ESI):m/z＝548.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ12.80(s,1H),8.02(d,1H),7.88(d,2H),7.73(d,1H),7.66–7.58(m,3H),7.41(t,2H),7.30(dd,2H),6.93(s,1H),6.70(d,1H),4.24–4.09(m,6H),3.26(q,2H),3.02(dd,1H),2.87–2.75(m,1H),1.37(s,9H).
中间体5：
第一步：将已知化合物5a(5g，0.043mol)加入到三氟乙醇中(50mL)，再加入叔丁基异氰(7.15g，0.086mol)和乙酸铵(13.3g，0.172mol)，室温反应3d。TLC示反应完全，反应液浓缩至干，C18反相柱纯化，流动相A,B组成：流动相A：乙腈；流动相B：水(含0.1％TFA)，(A/B＝35/65)分离提纯得到化合物5b(9.5g，收率：85％)。
LCMS m/z＝259.2[M+1]+。
第二步：将化合物5b(7.5g，0.029mol)加入到6N HCl中(75mL)，100℃反应过夜，LCMS示原料反应完全。浓缩至干，C18反相柱纯化，流动相A,B组成：流动相A：乙腈；流动相B：水(含0.1％TFA)，(A/B＝5/95)分离提纯得到化合物5c(4.6g，收率：98％)。
LCMS m/z＝162.1[M+1]+。
第三步：将化合物5c(4.6g，0.028mol)加入到乙腈(46mL)和水(46mL)中，再加入9-芴甲基-N-琥珀酰亚胺基碳酸酯(Fmoc-Osu)(10.5g，0.03mol)和碳酸氢钠(24.4g，0.28mol)，室温反应过夜。LC-MS监测反应完全，用1N HCl调PH至5-6，浓缩除去乙腈，加乙酸乙酯(200mL)萃取，乙酸乙酯相浓缩至干，柱层析纯化(DCM:MeOH＝10:1)得到化合物5d(6.3g，收率：58％)。
LCMS m/z＝384.2[M+1]+。
第四步：将化合物5d(5.0g，0.013mol)加入到二氯甲烷(50mL)中，再分批加入间氯过氧苯甲酸85％(m-CPBA)(7.9g，0.039mol)室温反应过夜。LC-MS监测反应完全，用硫代硫酸钠溶液淬灭反应(100mL)，搅拌30min，加乙酸乙酯(200mL)萃取，乙酸乙酯相浓缩至干。液相制备柱分离提纯(液相制备条件：C18反相制备柱，流动相为含0.1％三氟乙酸的去离子水(A)，含0.1％三氟乙酸的乙腈(B)，梯度洗脱，B含量＝5％～70％，洗脱时间15min，流速12mL/min，柱温：30℃，保留时间：8.54min)得到中间体5(3.5g,收率：64％)。
1H NMR(400MHz,CDCl3)δ7.78-7.76(d,2H),7.60-7.58(d,2H),7.43-7.40(t,2H),7.34-7.31(t,2H),4.52-4.51(d,2H),4.22-4.19(t,1H),3.03(s,4H),2.60-2.50(m,4H).
LCMS m/z＝433.1[M+H2O]+。
中间体6:
第一步:将化合物6a(10.0g,51.28mmol)，环丙基硼酸(8.8g,102.56mmol)，碳酸铯(50.46g,153.84mmol)，加入到二氧六环(200mL)和水(40mL)中，加入1,1'-双(二苯基膦)二茂铁]二氯化钯(3.8g,5.13mmol)，氮气置换后在80℃下反应过夜，浓缩后使用硅胶色谱柱分离纯化(EA:PE＝5:2)得到化合物6b(7.0g,86.9％)。
LC-MS(ESI):m/z＝158.1[M+H]+。
第二步:将DMF(6.5g,89.18mmol),在0℃的条件下滴入三氯氧磷(70mL)中，十分钟后在0℃的条件下将化合物6b(7.0g,44.59mmol)溶于三氯氧磷(30mL)中，室温下反应1h，冰浴下用饱和碳酸氢钠中和到Ph＝7～8，用二氯甲烷萃取(100mL×3)，合并有机相并旋干，浓缩后使用硅胶色谱柱分离纯化(EA:PE＝5:2)得到化合物6c(4.5g,54.5％)。
LC-MS(ESI):m/z＝186.2[M+H]+。
第三步:将化合物6c(4.5g,24.32mmol)溶于乙腈(50mL)中，加入二碳酸二叔丁酯(10.6g,48.64mmol)，再加入4-二甲氨基吡啶(3.6g,29.18mmol)，室温下反应2h，用二氯甲烷萃取(100mL×3)，合并有机相并旋干，浓缩后使用硅胶色谱柱分离纯化(EA:PE＝5:1)得到化合物6d(6.0,86.9％)。
LC-MS(ESI):m/z＝230.2[M-56+H]+。
第四步:将(±)苄基氧基羰基-a-膦酰甘氨酸三甲酯(7.0g,21.05mmol)溶于二氯甲烷(100mL)中，氮气置换后加入DBU(6.43g,42.3mmol)并搅拌30min，然后将化合物6d(6.0g,21.05mmol)溶于二氯甲烷(100mL)滴加到反应中，继续搅拌过夜，将反应混合物用二氯甲烷稀释(100mL)并用5％柠檬酸水溶液(100mL)和饱和食盐水(100mL)洗涤，然后用无水硫酸钠干燥，过滤并旋干。使用硅胶色谱柱分离纯化(EA:PE＝3:1)得到化合物6e(5.7g,55.3％)。
LC-MS(ESI):m/z＝491.3[M+H]+。
第五步:将化合物6e(5.7g,11.6mmol)溶于甲醇(50mL)中，加入(+)-1,2-双(2S,5S)-2,5-二乙基环丁磷烷苯(环辛二烯)三氟甲磺酸铑(420mg,0.58mmol)，使用高压釜填充氢气至压力约2.5Mpa，室温下搅拌过夜，滤除固体，将反应溶液浓缩得到化合物6f(5.7g,99.9％)。
LC-MS(ESI):m/z＝493.2[M+H]+。
第六步:将化合物6f(3.0g,6.1mmol)溶于二氯甲烷(50mL)中，冰浴下加入三乙胺(3.1g,30.5mmol)，再加入
碘代三甲硅烷(6.1g,30.5mmol)室温下搅拌16h，室温浓缩后加入甲醇(5mL)淬灭反应，使用C18反向柱分离纯化(含0.5％TFA水:乙腈＝3:10)得到化合物6g(1.5g,95.5％)。
LC-MS(ESI):m/z＝259.1[M+H]+。
第七步:将化合物6g(1.5g,5.8mmol)溶于四氢呋喃(20mL)，加入氢氧化锂一水合物(1.58g,37.7mmol)和水(20mL)，反应在室温下搅拌2h，然后用稀盐酸(1N)调节水相pH至中性，直接下一步。
LC-MS(ESI):m/z＝245.1[M+H]+。
第八步:向上一步得到的反应液加入碳酸氢钠(4.9g,58.0mmol)和9-芴甲基-N-琥珀酰亚胺基碳酸酯(2.9g,8.7mmol)，反应在室温下搅拌过夜，反应完毕后滴加稀盐酸调节pH至5～6，40℃下真空浓缩旋去大部分乙腈，用二氯甲烷萃取(100mL×3)，合并有机相并旋干，使用硅胶色谱柱分离纯化(DCM:MeOH＝10:1)得到中间体6(1.2g,两步收率44.4％)。
LC-MS(ESI):m/z＝467.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),7.89–7.85(m,2H),7.63(d,2H),7.42–7.34(m,3H),7.32–7.24(m,2H),7.16–6.98(m,2H),6.88–6.80(m,1H),6.60(d,1H),4.22–4.14(m,3H),4.11–4.05(m,1H),3.26–3.19(m,1H),3.07–2.98(m,1H),2.25–2.15(m,1H),1.00–0.92(m,2H),0.72–0.62(m,2H).
中间体7和中间体8：
第一步：将已知化合物7a(20g，0.09mol)加入到甲醇(46mL)和四氢呋喃(460mL)中，再加入氢氧化钠(3.6g，0.09mol)，室温反应18h。LCMS示原料反应完全，反应液浓缩至干，加水稀释(300mL)，用1N HCl 调PH至5-6，加乙酸乙酯(300mL)萃取，乙酸乙酯相浓缩至干，柱层析纯化(DCM:MeOH＝10:1)得到化合物7b(17.8g，收率：95％)。
LCMS m/z＝207.1[M+1]+。
第二步：将化合物7b(17.8g，0.086mol)加入到四氢呋喃中(1L)，降温至0℃，滴加硼烷二甲硫醚溶液(10mol/L，10mL)，滴毕反应2h，LCMS示原料反应完全。滴加甲醇(30mL)淬灭多余硼烷，浓缩至干，加乙酸乙酯(500mL)和水(500mL)萃取，乙酸乙酯相浓缩至干，柱层析纯化(DCM:MeOH＝10:1)得到化合物7c(15g，收率：91％)。
LCMS m/z＝215.2[M+23]+。
第三步：将吡啶(27.84g，0.352mol)加入到二氯甲烷(800mL)中，降温至-20℃，滴加三氟甲磺酸酐(94.8g，0.336mol)，滴毕，向体系中加入2-溴乙醇(40g，0.32mol)，-20℃搅拌30分钟，低温30℃浓缩除去二氯甲烷，残余物用MTBE溶解，过滤，母液低温25℃浓缩至干，取部分(59.2g，0.231mol)加入到7c(14.8g，0.077mol)的甲苯溶液中(440mL)，再加入DIEA(29.6g，0.231mol)，加毕，90℃搅拌过夜，TLC示原料反应完全。浓缩至干，加乙酸乙酯(500mL)和水(500mL)萃取，乙酸乙酯相浓缩至干，柱层析纯化(PE:EA＝2:1)得到化合物7d(21.6g，收率：94％)。
第四步：将化合物7d(21.6g，0.072mol)加入到四氢呋喃(430mL)中，再分批加入氢化锂铝(5.47g，0.144mol)，室温反应2h，TLC监测反应完全。缓慢滴加5.5mL水，再缓慢滴加5.5mL15％氢氧化钠溶液，最后再滴加16.5mL水，再加入无水硫酸钠搅拌30min，过滤，母液浓缩至干得到7e(15.9g，收率：81％)。
LCMS m/z＝271.2[M+1]+。
第五步：将化合物7e(12.5g，0.046mol)加入氨水(250mL)中，室温反应18h，TLC监测原料未反应完全。直接浓缩至干得到粗品7f，用于下一步反应。
LCMS m/z＝208.2[M+1]+。
第六步：将化合物7f粗品加入到乙腈(120mL)和水(120mL)中，再加入二碳酸二叔丁酯(10.0g，0.046mol)和碳酸钠(9.75g，0.092mol)，室温搅拌18h，浓缩出去乙腈，加乙酸乙酯(200mL)萃取，浓缩至干，柱层析纯化(PE:EA＝1:1)得到化合物7g(5.4g，收率：38％)。
LCMS m/z＝252.2[M+1-56]+。
第七步：将化合物7g(5.4g，0.017mol)加入到二氯甲烷(54mL)中，降温至0℃，加入四溴化碳(9.7g，0.28mol)和三苯基膦(7.7g，0.28mol)，室温反应18h，LCMS监测反应完全。浓缩至干，柱层析纯化(PE:EA＝2:1)得到7h(2.4g，收率：35％)。
LCMS m/z＝314.2[M+1-56]+。
第八步：将化合物7h(2.4g，0.006mol)加入到DMF(24mL)中，再加入二苯亚甲基甘氨酸甲酯(3.15g，0.012mol)和叔丁醇钾(1.74g，0.015mol)，室温反应18h，LCMS监测原料未反应完全。加乙酸乙酯(100mL)和水(100mL)萃取，乙酸乙酯相用水反洗两次，浓缩至干，柱层析纯化(PE:EA＝1:1)得到7i(1.8g，收率：51％)。
LCMS m/z＝543.2[M+1]+。
第九步：将化合物7i(1.8g，3.3mmol)加入到四氢呋喃(32mL)中，再加入1N HCl(16mL)，室温反应1h，LCMS监测原料反应完全。碳酸钠水溶液调PH至8-9，加乙酸乙酯(100mL)和水(50mL)萃取，乙酸乙酯相浓缩至干，柱层析纯化(DCM:MeOH＝10:1)得到7j(1.25g，收率：100％)。
LCMS m/z＝323.2[M+1-56]+。
第十步：将化合物7j(1.25g，3.3mmol)加入到甲醇(13mL)和水(4mL)中，再加入氢氧化锂(554mg，13.2mmol)，室温反应4h，LCMS监测原料反应完全。反应液直接用于下一步反应。
LCMS m/z＝309.2[M+1-56]+。
第十一步：将上一步反应液用1N HCl调PH至5-6，再用碳酸氢钠水溶液调PH至8-9，再加入9-芴甲基-N-琥珀酰亚胺基碳酸酯(1.3g，3.96mmol)和碳酸氢钠(2.77g，33mmol)，室温搅拌2h，LCMS示原料反应完全。用1N HCl调PH至7，加乙酸乙酯(100mL)和水(100mL)萃取，乙酸乙酯相浓缩至干，柱层析纯化(DCM:MeOH＝10:1)得到消旋体1.8g，消旋体经手性拆分:仪器:SFC Prep 150AP；色谱柱:大赛璐AD-H(19mm×250mm)；样品用甲醇溶解，用0.45μm滤头过滤，制成样品液。制备色谱条件：流动相A,B组成：流动相A：CO2；流动相B：甲醇；等度洗脱，流动相B含量25％；流量40ml/min。4.1min得到中间体7(P1)(730mg，收率：38％)和4.6min得到中间体8(P2)(750mg，收率：39％)。
中间体7 1H NMR(400MHz,CDCl3)δ7.77-7.75(d,2H),7.60-7.57(t,2H),7.41-7.37(t,2H),7.32-7.29(t,2H),4.49-4.41(m,3H),4.23-4.20(t,1H),3.73 -3.68(m,6H),3.59-3.55(m,2H),3.51-3.49(m,2H),3.31-3.27(m,2H),2.22-2.04(m,2H),1.45(s,9H).
LCMS m/z＝487.2[M+1-100]+。
中间体8 1H NMR(400MHz,CDCl3)δ7.75-7.73(d,2H),7.59-7.56(t,2H),7.39-7.36(t,2H),7.30-7.27(t,2H),4.47-4.39(m,3H),4.22-4.19(t,1H),3.70-3.64(m,6H),3.57-3.53(m,2H),3.51-3.49(m,2H),3.31-3.27(m,2H),2.20-2.03(m,2H),1.44(s,9H).
LCMS m/z＝487.2[M+1-100]+。
中间体9和中间体10:
第一步:将化合物9a(10.4g,70.5mmol)溶于四氢呋喃(200mL)中，氮气置换后在零度下加入钛酸四异丙酯(4ml,13.6mmol)和滴加乙基溴化镁(58.67ml，176mmol)，升至室温反应过夜，反应结束后在零度下加水淬灭，乙酸乙酯萃取，合并有机相并旋干，浓缩后使用硅胶色谱柱分离纯化(EA:PE＝1:5)得到化合物9b(7.0g,71％)。
1H NMR(400MHz,CDCl3)δ＝4.68(t,1H),3.47(s,1H),3.39(s,6H),1.88(d,2H),0.77(t,2H),0.45(t,2H).
第二步:将化合物9b(7.0g,47.95mmol)溶于二氯甲烷(50ml)中，添加三乙胺(14.53g，143.85mmol)，在零度下滴入甲磺酰氯(6.59g，57.54mmol)中，在室温下反应1h，冰浴下加水淬灭，用二氯甲烷萃取，合并有机相并旋干，浓缩后得到化合物9c粗品。
1H NMR(400MHz,CDCl3)δ＝4.69(t,1H),3.37(s,6H),3.01(s,3H),2.15(d,2H),1.30-1.26(m,2H),0.81(d,2H).
第三步:将上步化合物9c粗品溶于四氢呋喃/水(60mL/30ml)中，在零度下加入过氧单磺酸钾(24.91g,71.93mmol)，室温下反应过夜，用乙酸乙酯萃取，合并有机相并旋干，甲基叔丁基醚重结晶得到化合物9d(4.8g,两步收率52％)。
LC-MS(ESI):m/z＝195.1[M+H]+。
第四步:将化合物9d(7.0g,36.08mmol)溶于1,2-二氯乙烷(200mL)中，氮气置换后加入二氯亚砜(3.26ml,45mmol)回流1小时，冷却至室温添加NCS(7.2g，54.12mmol)和10滴4M氯化氢-1,4-二氧六环，回流过夜，冷却至室温，添加甲醇(25ml)，继续反应1h，反应结束直接浓缩旋干，在零度下加入氯仿，过滤收集液体，浓缩得到化合物9e粗品。
LC-MS(ESI):m/z＝243.1[M+H]+
第五步:将化合物9e粗品溶于二氯甲烷(20mL)中，在零度下加入三乙胺(5.47g，54.12mmol)，在该温度下继续搅拌3h，加水淬灭，二氯甲烷萃取，合并有机相并浓缩，用硅胶色谱柱分离纯化(EA:PE＝1:5)得到化合物9f(3.5g,两步收率66％)。
LC-MS(ESI):m/z＝147.1[M+H]+
第六步:将化合物9f(3.0g,20.55mmol)溶于乙腈(50mL)中，添加碳酸氢钠(17.26g,205.5mmol)，再加入硫代乙酰胺(1.54g,20.55mmol)，在80℃下搅拌5h，过滤浓缩，用硅胶色谱柱分离纯化(EA:PE＝1:1)得到化合物9g(3g,79％)。
LC-MS(ESI):m/z＝186.2[M+H]+。
第七步:将化合物9g(1g,5.38mmol)置于50ml圆底烧瓶，添加3M盐酸溶液(10mL)，在100℃下搅拌5h，反应结束，甲基叔丁基醚萃取，水相直接浓缩得化合物9h盐酸盐。
LC-MS(ESI):m/z＝148.2[M+H]+。
第八步::将化合物9h(1g,6.8mmol)置于50ml圆底烧瓶，加入三氟乙酸(5ml)和三苯基甲醇(2.12g,8.16mmol)，在室温下搅拌10min，旋干得目标化合物9i直接进行下一步。
LC-MS(ESI):m/z＝388.5[M-H]+。
第八步::将上步化合物9i粗品溶于乙腈和水(50ml/10ml)，加入碳酸氢钠(5.7g，68mmol)和9-芴甲基-N-琥珀酰亚胺基碳酸酯(3.44g,10.2mmol)，在室温下搅拌3h，过滤加饱和食盐水(30ml)，乙酸乙酯萃取，合并有机相并浓缩，用硅胶色谱柱分离纯化(DCM:MeOH＝10:1)得到消旋体2.2g，两步收率：43％。消旋体经手性拆分:仪器:SFC Prep 150AP；色谱柱:大赛璐AD-H(19mm×250mm)；样品用甲醇溶解，用0.45μm滤头过滤，制成样品液。制备色谱条件：流动相A,B组成：流动相A：CO2；流动相B：甲醇；等度洗脱，流动相B含量25％；流量40ml/min。3.8min得到中间体9(P1)(890mg)和4.2min得到中间体10(P2)(910mg)。
中间体9：
1H NMR(400MHz,CDCl3)δ＝7.78(d,2H),7.61–7.49(m,8H),7.42–7.39(m,2H),7.34–7.30(m,2H),7.28–7.22(m,6H),7.22–7.14(m,3H),5.00(d,1H),4.34(d,2H),4.19(t,1H),3.88(d,1H),1.06–0.92(m,1H),0.85–0.75(m,1H),0.75–0.63(m,1H),0.28–0.19(m,1H).
中间体10：
1H NMR(400MHz,CDCl3)δ＝7.77(d,2H),7.59–7.54(m,8H),7.42–7.39(m,2H),7.33–7.30(m,2H),7.26–7.22(m,6H),7.21–7.13(m,3H),5.00(d,1H),4.34(d,2H),4.19(t,1H),3.89(d,1H),1.02–0.97(m,1H),0.86–0.74(m,1H),0.73–0.62(m,1H),0.26–0.20(m,1H).
中间体11:
第一步:将化合物11a(20.0g,59.6mmol)溶于乙酸乙酯(150mL)中，室温下加入环己烷(75ml)和叔丁基三氯乙酰亚胺酯(32.5g,149mmol)，升至30℃反应48小时，反应结束后直接减压浓缩，粗品经硅胶色谱柱分离纯化(EA:PE＝10:90)得到化合物11b(23.2g,99.4％)。
1H NMR(400MHz,Chloroform-d)δ7.76(d,2H),7.61(d,2H),7.39(t,2H),7.31(t,2H),5.67(d,1H),4.40(ddd,3H),4.24(t,1H),2.76(t,2H),2.04(d,1H),1.50(s,9H).
第二步:将化合物11b(10.0g,25.5mmol)溶于干燥N,N-二甲基甲酰胺(200ml)中，加入硝酸银(434mg，2.55mmol)和N-溴代丁二酰亚胺(5.46g，30.7mmol)，加完后于室温下反应过夜。反应结束后加水(500mL)淬灭，以乙酸乙酯(200mL×5)萃取，合并有机相并以无水硫酸钠干燥，浓缩后得粗品，经硅胶柱层析纯化(EA:PE＝10:90)得到11c(10.5g,87.4％)。
LC-MS(ESI):m/z＝470.1[M+H]+。
第三步:于0℃下将化合物11d(9.00g,55.8mmol)溶于二氯甲烷(400ml)中，加入咪唑(4.94g，72.6mmol)、碘(18.4g，72.6mmol)和三苯基膦(19.0g，72.6mmol)，加完后升至室温反应过夜。反应结束后加饱和硫代硫酸钠水溶液(100mL)和水(500mL)淬灭，以乙酸乙酯(200mL×5)萃取，合并有机相并以无水硫酸钠干燥，浓缩后得粗品，经硅胶柱层析纯化(EA:PE＝50:50)得到11e(8.90g,63.6％)。
LC-MS(ESI):m/z＝272.0[M+H]+。
第四步:将锌粉(2.43g,37.2mmol)和碘(94.5mg,0.372mmol)加至圆底烧瓶中，氮气保护下用加热枪加热5分钟，冷却至室温后氮气保护三次，降至0℃后注射加入化合物11e(3.17g,11.7mmol)的DMF(50mL)溶液，升至室温反应约2小时。另将氰化亚铜(950mg,10.6mmol)和氯化锂(900mg,21.2mmol)加至圆底烧瓶中，氮气保护下升温至150℃反应2小时，降至室温后注射加入DMF(10mL)，继续搅拌10分钟，降至-15℃后，将锌粉活化的化合物11e的DMF溶液注射加入其中，5分钟后将化合物11c(5.00g,10.6mmol)的DMF(40mL)溶液注射加入其中，随后升至室温并搅拌反应过夜。反应结束后加水(500mL)淬灭，以乙酸乙酯(200mL×5)萃取，合并有机相并以无水硫酸钠干燥，浓缩后得粗品，经硅胶柱层析纯化(EA:PE＝70:30)得到11f(3.47g,61.1％)。
LC-MS(ESI):m/z＝535.3[M+H]+。
第五步:将化合物11f(3.47g,6.49mmol)溶于乙酸乙酯(200ml)中，加入Pd/C(2.0g)，插入氢气球后于室温下反应过夜。TLC监测原料消失后直接过滤除去固体并用乙酸乙酯洗净，合并有机相后直接浓缩得到化合物11g的粗品(3.21g)。
LC-MS(ESI):m/z＝539.3[M+H]+。
第六步:将化合物11g(3.21g)粗品溶于1,2-二氯乙烷(200mL)中，加入三甲基氢氧化锡(4.31g，23.8mmol)，升至70℃反应过夜。反应结束后降至室温并直接减压浓缩，粗品经硅胶色谱柱分离纯化(DCM:MeOH＝80:20)得到化合物11h(2.90g,两步收率85.2％)。
LC-MS(ESI):m/z＝525.3[M+H]+。
第七步:将化合物11h(2.90g,5.53mmol)溶于干燥N,N-二甲基甲酰胺(150ml)中，加入碳酸钠(2.34g，22.1mmol)和3-溴丙烯(2.01g，16.6mmol)，加完后于室温下反应3天。反应结束后加水(500mL)淬灭，以乙酸乙酯(200mL×5)萃取，合并有机相并以无水硫酸钠干燥，浓缩后得粗品，经硅胶柱层析纯化(EA:PE＝70:30)得到11i(2.41g,77.2％)。
LC-MS(ESI):m/z＝565.3[M+H]+。
第八步:将化合物11i(2.41g,4.27mmol)溶于二氯甲烷(50ml)和三氟乙酸(50ml)的混合溶剂中，于室温下反应。TLC监测反应结束后，直接减压浓缩，所得粗品重新溶于二氯甲烷(100ml)中，以饱和碳酸氢钠水溶液调节pH为7左右，加入水后以二氯甲烷(100mL×5)萃取，合并有机相并以无水硫酸钠干燥，浓缩后得粗品，再经二氯甲烷打浆后得到中间体11(1.69g,77.9％)。
1H NMR(400MHz,Methanol-d4)δ7.79(d,2H),7.67(t,2H),7.39(t,2H),7.31(td,2H),6.01–5.88(m,1H),5.33(dq,1H),5.22(dq,1H),4.62(dq,2H),4.42–4.33(m,3H),4.23(t,1H),4.13(dd,1H),3.26–3.19(m,1H),1.98(s,3H),1.89–1.77(m,2H),1.75–1.62(m,2H),1.46–1.37(m,4H).
LC-MS(ESI):m/z＝509.2[M+H]+。
实施例1：
第一步：1B的合成采用标准的Fmoc化学方法：
1.向反应器中加入Rink Amide MBHA Resin树脂(1mmol，1.4g，sub:0.7mmol/g)和二氯甲烷溶剂，溶胀30min，加入20％哌啶/DMF，混合30分钟。
2.抽干并以DMF淋洗五次。
3.加入Fmoc-Sar-OH保护的氨基酸溶液，混合30秒后加入偶联试剂，氮气鼓泡1.5小时，茚三酮监测反应。
4.抽干并以DMF淋洗三次。
5.加入20％哌啶/DMF，混合30分钟。
6.抽干并以DMF淋洗五次。
7.加入Fmoc保护的氨基酸溶液，混合30秒后加入偶联试剂，氮气鼓泡1.5小时，茚三酮监测反应。
8.抽干并以DMF淋洗三次
9.下一个氨基酸偶联重复步骤5-8。
10.最后一步MeOH淋洗两次，DCM淋洗一次，MeOH淋洗两次，真空抽干，得到肽树脂1B(6.5g)，直接用于下一步反应。
第二步：100ml反应瓶中加入裂解液60ml(91％三氟乙酸+4％三异丙基硅烷+3％1.2-乙二硫醇+2％水)，搅拌均匀后加入肽树脂1B(6.5g)，室温搅拌2小时。过滤树脂得滤液，滤液加入到500ml甲基叔丁基醚中(甲基叔丁基醚提前降温至0℃)，白色絮状物析出，离心(3min at 3000rpm)。白色沉淀用甲基叔丁基醚洗涤三次，真空干燥得到类白色固体粗肽1C(2.4g)，直接用于下一步反应。
LCMS m/z＝627.6[M/3+H]+,940.9[M/2+H]+
第三步：在2L反应瓶中，依次加入水(750ml)、乙腈(250ml)、1C(2g，1.06mmol)，搅拌均匀后，缓慢滴加碘/乙腈溶液(0.1mol/L)至反应液呈淡黄色，加入抗坏血酸淬灭，制备HPLC纯化。分离方法：1.仪器：waters2767制备液相；色谱柱：SunFire@PrepC18(19mm×250mm)。2.样品用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a流动相A，B组成：A:0.1％三氟乙酸/H2O，B:CH3CN；b.梯度洗脱：流动相含量5％-45％；c.流速：12ml/min；d.洗脱时间：30min，保留时间：16min。冻干得到化合物1(400mg，纯度99％)。
LCMS m/z＝626.9[M/3+H]+,939.9[M/2+H]+
实施例2：
第一步：2B的合成采用标准的Fmoc化学方法：
1.向反应器中加入Rink Amide MBHA Resin树脂(1mmol，1.4g，sub:0.7mmol/g)和二氯甲烷溶剂，溶胀30min，加入20％哌啶/DMF，混合30分钟。
2.抽干并以DMF淋洗五次。
3.加入Fmoc-Sar-OH保护的氨基酸溶液，混合30秒后加入偶联试剂，氮气鼓泡1.5小时，茚三酮监测反应。
4.抽干并以DMF淋洗三次。
5.加入20％哌啶/DMF，混合30分钟。
6.抽干并以DMF淋洗五次。
7.加入Fmoc保护的氨基酸溶液，混合30秒后加入偶联试剂，氮气鼓泡1.5小时，茚三酮监测反应。
8.抽干并以DMF淋洗三次
9.下一个氨基酸偶联重复步骤5-8。
10.最后一步MeOH淋洗两次，DCM淋洗一次，MeOH淋洗两次，真空抽干，得到肽树脂2B(6.3g)，直接用于下一步反应。

第二步：100ml反应瓶中加入裂解液60ml(91％三氟乙酸+4％三异丙基硅烷+3％1.2-乙二硫醇+2％水)，搅拌均匀后加入肽树脂2B(6.3g)，室温搅拌2小时。过滤树脂得滤液，滤液加入到500ml甲基叔丁基醚中(甲基叔丁基醚提前降温至0℃)，白色絮状物析出，离心(3min at 3000rpm)。白色沉淀用甲基叔丁基醚洗涤三次，真空干燥得到类白色固体粗肽2C(2.5g)，直接用于下一步反应。
LCMS m/z＝637.3[M/3+H]+,955.4[M/2+H]+
第三步：在2L反应瓶中，依次加入水(750ml)、乙腈(250ml)、2C(2g，1.06mmol)，搅拌均匀后，缓慢滴加碘/乙腈溶液(0.1mol/L)至反应液呈淡黄色，加入抗坏血酸淬灭，制备HPLC纯化。分离方法：1.仪器：waters2767制备液相；色谱柱：SunFire@PrepC18(19mm×250mm)。2.样品用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a流动相A，B组成：A:0.1％三氟乙酸/H2O，B:CH3CN；b.梯度洗脱：流动相含量5％-45％；c.流速：12ml/min；d.洗脱时间：30min，保留时间：16min。冻干得到化合物2(410mg，纯度99％)
LCMS m/z＝636.6[M/3+H]+,954.4[M/2+H]+
实施例3：

以上述物料表为原料，采用化合物1的合成方法得到化合物3(50mg，纯度95％)
LCMS m/z＝961.0[M/2+H]+
实施例4：

以上述物料表为原料，采用化合物1的方法得到化合物4(50mg，纯度99％)。
LCMS m/z＝961.5[M/2+H]+。
实施例5：

以上述物料表为原料，采用化合物1的方法得到化合物5(50mg，纯度95％)。
LCMS m/z＝950.3[M/2+H]+。
实施例6：

以上述物料表为原料，采用化合物1的方法得到化合物6(50mg，纯度94％)。
LCMS m/z＝963.4[M/2+H]+。
实施例7：
第一步：7B的合成采用标准的Fmoc化学方法：
1.向反应器中加入Rink Amide MBHA Resin树脂(1mmol，1.4g，sub:0.7mmol/g)和二氯甲烷溶剂，溶胀30min，加入20％哌啶/DMF，混合30分钟。
2.抽干并以DMF淋洗五次。
3.加入Fmoc-Sar-OH保护的氨基酸溶液，混合30秒后加入偶联试剂，氮气鼓泡1.5小时，茚三酮监测反应。
4.抽干并以DMF淋洗三次。
5.加入20％哌啶/DMF，混合30分钟。
6.抽干并以DMF淋洗五次。
7.加入Fmoc保护的氨基酸溶液，混合30秒后加入偶联试剂，氮气鼓泡1.5小时，茚三酮监测反应。
8.抽干并以DMF淋洗三次
9.下一个氨基酸偶联重复步骤5-8。
10.最后一步MeOH淋洗两次，DCM淋洗一次，MeOH淋洗两次，真空抽干，得到肽树脂7B(6g)，直接用于下一步反应。

第二步：100ml反应瓶中加入裂解液50ml(91％三氟乙酸+4％三异丙基硅烷+3％1.2-乙二硫醇+2％水)，搅拌均匀后加入肽树脂7B(6g)，室温搅拌2小时。过滤树脂得滤液，滤液加入到300ml甲基叔丁基醚中(甲基叔丁基醚提前降温至0℃)，白色絮状物析出，离心(3min at 3000rpm)。白色沉淀用甲基叔丁基醚洗涤三次，真空干燥得到类白色固体粗肽7C(2.2g)，直接用于下一步反应。
LCMS m/z＝655.2[M/3+H]+,982.1[M/2+H]+
第三步：在2L反应瓶中，依次加入水(750ml)、乙腈(250ml)、7C(2g，1.02mmol)，搅拌均匀后，缓慢滴加碘/乙腈溶液(0.1mol/L)至反应液呈淡黄色，加入抗坏血酸淬灭，制备HPLC纯化。分离方法：1.仪器：waters2767制备液相；色谱柱：SunFire@PrepC18(19mm×250mm)。2.样品用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a流动相A，B组成：A:0.1％三氟乙酸/H2O，B:CH3CN；b.梯度洗脱：流动相含量5％-45％；c.流速：12ml/min；d.洗脱时间：30min，保留时间：16min。得到化合物7(50mg，纯度98％)。
LCMS m/z＝981.0[M/2+H]+。
实施例8：

以上述物料表为原料，采用化合物1的方法得到化合物8(50mg，纯度99％)。
LCMS m/z＝950.3[M/2+H]+。
实施例9：

以上述物料表为原料，采用化合物1的方法得到化合物9(25mg，纯度97％)。
LCMS m/z＝973.6[M/2+H]+。
实施例10


第一步：以上述物料表为原料，采用化合物1的方法得到化合物10B。
第二步：固相合成反应器中加入二氯甲烷30ml，依次加入苯硅烷(1g)，四(三苯基膦)钯(462mg),鼓氮气反应8小时，用二氯甲烷洗涤树脂5次，N,N-二甲基甲酰胺洗涤5次，0.5％二乙基二硫代氨基甲酸钠的N,N-二甲基甲酰胺溶液洗涤15min+15min，再用N,N-二甲基甲酰胺洗涤三次，得到肽树脂10C。
第三步：2％水合肼的N,N-二甲基甲酰胺溶液加入到反应器中反应30min+30min,N,N-二甲基甲酰胺溶液洗涤5次，得到肽树脂10D。
第四步：固相合成反应器中加入N-甲基吡咯烷酮(20ml),苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(417.2mg,1.1mmol)，DIEA(0.19ml,1.1mmol),室温反应16h，茚三酮监测无色，抽干溶剂并以N,N-二甲基甲酰胺洗涤树脂3次，甲醇洗涤树脂2次，二氯甲烷洗涤树脂1次，甲醇洗涤树脂2次，真空抽干得到肽树脂10E(5.2g)。
第五步：100ml反应瓶中加入裂解液60ml(91％三氟乙酸+4％三异丙基硅烷+3％1.2-乙二硫醇+2％水)，搅拌均匀后加入肽树脂10E(5.2g)，室温搅拌2小时。过滤树脂得滤液，滤液加入到500ml甲基叔丁基醚中(甲基叔丁基醚提前降温至0℃)，白色絮状物析出，离心(3min at 3000rpm)。白色沉淀用甲基叔丁基醚洗涤三次，真空干燥得到类白色固体粗肽化合物10(1.8g)，制备HPLC纯化。分离方法：1.仪器：waters2767制备液相；色谱柱：SunFire@PrepC18(19mm×250mm)。2.样品用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a流动相A，B组成：A:0.1％三氟乙酸/H2O，B:CH3CN；b.梯度洗脱：流动相含量5％-45％；c.流速：12ml/min；d.洗脱时间：30min，保留时间：17min。冻干得到白色固体化合物10(25mg，纯度91.9％)。
LCMS m/z＝1821.3[M+H]+。
实施例11：


第一步：以上述物料表为原料，采用化合物1的方法得到化合物11B
第二步：固相合成反应器中加入二氯甲烷30ml，依次加入苯硅烷(1g)，四(三苯基膦)钯(462mg),鼓氮气反应8小时，用二氯甲烷洗涤树脂5次，N,N-二甲基甲酰胺洗涤5次，0.5％二乙基二硫代氨基甲酸钠的N,N-二甲基甲酰胺溶液洗涤15min+15min，再用N,N-二甲基甲酰胺洗涤三次，得到肽树脂11C。
第三步：20％哌啶的N,N-二甲基甲酰胺溶液加入到反应器中反应30min,N,N-二甲基甲酰胺溶液洗涤5次，得到肽树脂11D。
第四步：固相合成反应器中加入N-甲基吡咯烷酮(20ml),苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(417.2mg,1.1mmol)，DIEA(0.19ml,1.1mmol),室温反应16h，茚三酮监测无色，抽干溶剂并以N,N-二甲基甲酰胺洗涤树脂3次，甲醇洗涤树脂2次，二氯甲烷洗涤树脂1次，甲醇洗涤树脂2次，真空抽干得到肽树脂11E。
第五步：100ml反应瓶中加入裂解液50ml(91％三氟乙酸+4％三异丙基硅烷+3％1.2-乙二硫醇+2％水)，搅拌均匀后加入肽树脂11E(5g)，室温搅拌2小时。过滤树脂得滤液，滤液加入到500ml甲基叔丁基醚中(甲基叔丁基醚提前降温至0℃)，白色絮状物析出，离心(3min at 3000rpm)。白色沉淀用甲基叔丁基醚洗涤三次，真空干燥得到类白色固体粗肽11F(1.5g)。
第六步：在2L反应瓶中，依次加入水(1050ml)、乙腈(450ml)、11F(1.5g，0.76mmol)，搅拌均匀后，缓慢滴加碘/乙腈溶液(0.1mol/L)至反应液呈淡黄色，加入抗坏血酸淬灭，制备HPLC纯化。分离方法：1.仪器：waters2767制备液相；色谱柱SunFire@PrepC18(19mm×250mm)。2.样品用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a流动相A，B组成：A:0.1％三氟乙酸/H2O，B:CH3CN；b.梯度洗脱：流动相含量5％-45％；c.流速：12ml/min；d.洗脱时间：30min，保留时间：16min。冻干得到白色固体化合物11(28mg，纯度99％)。
LCMS m/z＝987.5[M/2+H]+658.8[M/3+H]+。
实施例12：

以上述物料表为原料，采用化合物1的方法得到化合物12(300mg，纯度98％)。
LCMS m/z＝967.5[M/2+H]+645.5[M/3+H]+。
实施例13：

以上述物料表为原料，采用化合物1的方法得到化合物13(350mg，纯度98％)。
LCMS m/z＝953.1[M/2+H]+635.9[M/3+H]+。
实施例14：

以上述物料表为原料，采用化合物1的合成方法得到化合物14(8mg，纯度95％)。
LCMS m/z＝963.4[M/2+H]+642.7[M/3+H]+。
实施例15：

以上述物料表为原料，采用化合物1的方法得到化合物15(130mg，纯度98％)。
LCMS m/z＝984.2[M/2+H]+，656.3[M/3+H]+。
实施例16：

以上述物料表为原料，采用化合物1的方法得到化合物16(400mg，纯度94％)。
LCMS m/z＝997.4[M/2+H]+，665.2[M/3+H]+。
实施例17：

以上述物料表为原料，采用化合物1的方法得到化合物17(40mg，纯度93％)。
LCMS m/z＝984.0[M/2+H]+，656.5[M/3+H]+。
实施例18：

以上述物料表为原料，采用化合物1的方法得到化合物18(40mg，纯度94％)。
LCMS m/z＝984.0[M/2+H]+，656.5[M/3+H]+。
实施例19：

以上述物料表为原料，采用化合物1的方法得到化合物19C(1.5g)。
第三步：在3L反应瓶中，依次加入水(1050ml)、乙腈(450ml)、19C(1.5g，0.8mmol)，搅拌均匀后，加入1,3,5-三(溴甲基)苯(0.26g，0.8mmol)，碳酸氢铵调pH＝8，反应16h后制备HPLC纯化。分离方法：1.仪器：waters2767制备液相；色谱柱SunFire@PrepC18(19mm×250mm)。2.样品用0.45μm滤头过 滤，制成样品液。3.制备色谱条件：a流动相A，B组成：A:0.1％三氟乙酸/H2O，B:CH3CN；b.梯度洗脱：流动相含量5％-45％；c.流速：12ml/min；d.洗脱时间：30min，保留时间：17min。冻干得到白色固体化合物19(50mg，纯度97％)。
LCMS m/z＝1001.5[M/2+H]+，667.8[M/3+H]+。
实施例20：


以上述物料表为原料，采用化合物1的方法得到化合物20(40mg，纯度96％)。
LCMS m/z＝890.1[M/3+H]+。
实施例21：

以上述物料表为原料，采用化合物1的方法固相合成至第14步后，用2％水合肼/DMF脱Dde，然后采用化合物1方法继续合成得到化合物21(30mg，纯度97％)。
LCMS m/z＝904.0[M/3+H]+。
实施例22：

以上述物料表为原料，采用化合物10的方法得到化合物22(15mg，纯度87％)。
LCMS m/z＝908.7[M/2+H]+。
实施例23：

以上述物料表为原料，采用化合物1的方法固相合成至第14步后，用2％水合肼/DMF脱Dde，然后采用化合物1方法继续合成得到化合物23(25mg，纯度95％)。
LCMS m/z＝909.2[M/2+H]+。
实施例24：

以上述物料表为原料，采用化合物1的方法得到化合物24(180mg，纯度96％)。
LCMS m/z＝996.2[M/2+H]+，664.6[M/3+H]+。
实施例25：

第一步：以上述物料表为原料，采用化合物1的方法得到化合物25B。
第二步：固相合成反应器中加入二氯甲烷30ml，依次加入苯硅烷(1g)，四(三苯基膦)钯(462mg),鼓氮气反应8小时，用二氯甲烷洗涤树脂5次，N,N-二甲基甲酰胺洗涤5次，0.5％二乙基二硫代氨基甲酸钠的N,N-二甲基甲酰胺溶液洗涤15min+15min，再用N,N-二甲基甲酰胺洗涤三次，得到肽树脂25C。
第三步：20％哌啶的N,N-二甲基甲酰胺溶液加入到反应器中反应30min，N,N-二甲基甲酰胺溶液洗涤5次，甲醇洗涤三次，真空抽干，得到肽树脂25D(5g)。
第四步：100ml反应瓶中加入裂解液50ml(2％三氟乙酸+98％二氯甲烷)，搅拌均匀后加入肽树脂25D(5g)，室温搅拌0.5小时，过滤树脂得滤液，将肽树脂按照以上裂解方法再裂解一次，收集两次得到的滤液，用水萃洗两次，饱和食盐水萃洗一次，无水硫酸钠干燥，真空抽干得到化合物25E(2.3g)。
第五步：2L烧瓶中加入二氯甲烷(1.2L),化合物25E(2.3g，0.68mmol)，苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(417.2mg,1.1mmol)，DIEA(0.19ml,1.1mmol),室温反应16h，MS显示基本反应完全，用水萃洗两次，饱和食盐水萃洗一次，无水硫酸钠干燥，真空抽干得到化合物25F(2.1g)。
第六步：100ml反应瓶中加入裂解液60ml(91％三氟乙酸+4％三异丙基硅烷+3％1.2-乙二硫醇+2％水)，搅拌均匀后加入化合物25F(2.1g)，室温搅拌2小时。过滤树脂得滤液，滤液加入到600ml甲基叔丁基醚中(甲基叔丁基醚提前降温至0℃)，白色絮状物析出，离心(3min at 3000rpm)。白色沉淀用甲基叔丁基醚洗涤三次，真空干燥得到类白色固体粗肽25G(1.2g)。
第七步：在2L反应瓶中，依次加入水(1050ml)、乙腈(450ml)、25G(1.2g，0.6mmol)，搅拌均匀后，缓慢滴加碘/乙腈溶液(0.1mol/L)至反应液呈淡黄色，加入抗坏血酸淬灭，制备HPLC纯化。分离方法：1.仪器：waters2767制备液相；色谱柱SunFire@PrepC18(19mm×250mm)。2.样品用0.45μm滤头过滤，制成样品液。 3.制备色谱条件：a流动相A，B组成：A:0.1％三氟乙酸/H2O，B:CH3CN；b.梯度洗脱：流动相含量5％-45％；c.流速：12ml/min；d.洗脱时间：30min，保留时间：16min。冻干得到白色固体25(80mg，纯度95％)。
LCMS m/z＝1010.9[M/2+H]+674.3[M/3+H]+。
实施例26：

以上述物料表为原料，采用化合物25的方法得到化合物26(50mg，纯度98％)。
LCMS m/z＝1003.7[M/2+H]+，669.7[M/3+H]+。
实施例27：

以上述物料表为原料，采用化合物25的方法得到化合物27(65mg，纯度99％)。
LCMS m/z＝1003.8[M/2+H]+。
实施例28：

以上述物料表为原料，采用化合物25的方法得到化合物28(48mg，纯度95％)。
LCMS m/z＝988.8[M/2+H]+。
实施例29：

以上述物料表为原料，采用化合物25的方法得到化合物29(140mg，纯度99％)。
LCMS m/z＝1047.9[M/2+H]+。
实施例30：

以上述物料表为原料，采用化合物19的方法得到化合物30(180mg，纯度92％)。
LCMS m/z＝1008.5[M/2+H]+，672.8[M/3+H]+。
实施例31：

以上述物料表为原料，采用化合物19的方法得到化合物31(279mg，纯度94％)。
LCMS m/z＝1008.4[M/2+H]+，672.9[M/3+H]+。
实施例32：

以上述物料表为原料，采用化合物19的方法得到化合物32(200mg，99％)。
LCMS m/z＝1126.6[M/2+H]+，751.6[M/3+H]+。
实施例33：

以上述物料表为原料，采用化合物19的方法得到化合物33(190mg，97％)。
LCMS m/z＝1002.9[M/2+H]+，669.3[M/3+H]+。
实施例34：

以上述物料表为原料，采用化合物25的方法得到化合物34(130mg，纯度94％)。
LCMS m/z＝1000.0[M/2+H]+，667.2[M/3+H]+。
实施例35：

以上述物料表为原料，采用化合物1的方法得到化合物35(150mg，纯度94％)。
LCMS m/z＝1122.3[M/2+H]+，748.5[M/3+H]+。
实施例36：


以上述物料表为原料，采用化合物1的方法得到化合物36(300mg，纯度96％)。
LCMS m/z＝805.0[M/3+H]+。
实施例37：


以上述物料表为原料，采用化合物1的合成方法得到化合物37(100mg，纯度95％)
LCMS m/z＝948.5[M/2+H]+
实施例38：

以上述物料表为原料，采用化合物25的方法得到化合物38(45mg，纯度95％)。
LCMS m/z＝981.7[M/2+H]+。
实施例39：

以上述物料表为原料，采用化合物1的方法得到化合物39(110mg，纯度97％)。
LCMS m/z＝807.5[M/3+H]+。
实施例40：

以上述物料表为原料，采用化合物1的方法得到化合物40(150mg，纯度94％)。
LCMS m/z＝996.4[M/2+H]+，664.7[M/3+H]+。
实施例41：

以上述物料表为原料，采用化合物1的方法得到化合物41(150mg，纯度97％)。
LCMS m/z＝996.7[M/2+H]+，664.8[M/3+H]+。
实施例42：

以上述物料表为原料，采用化合物1的方法得到化合物42(35mg，纯度98％)。
LCMS m/z＝996.2[M/2+H]+，664.5[M/3+H]+。
实施例43：

以上述物料表为原料，采用化合物10的方法得到化合物43(95mg，纯度97％)。
LCMS m/z＝965.9[M/2+H]+，644.4[M/3+H]+。
实施例44

第一步：以上述物料表为原料，采用化合物1的方法得到化合物44B。
第二步：固相合成反应器中加入二氯甲烷30ml，依次加入苯硅烷(1g)，四(三苯基膦)钯(462mg),鼓氮气反应8小时，用二氯甲烷洗涤树脂5次，N,N-二甲基甲酰胺洗涤5次，0.5％二乙基二硫代氨基甲酸钠的N,N-二甲基甲酰胺溶液洗涤15min+15min，再用N,N-二甲基甲酰胺洗涤三次，得到肽树脂44C。
第三步：20％哌啶的N,N-二甲基甲酰胺溶液加入到反应器中反应30min,N,N-二甲基甲酰胺溶液洗涤5次，得到肽树脂44D。
第四步：固相合成反应器中加入N-甲基吡咯烷酮(20ml),苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(417.2mg,1.1mmol)，DIEA(0.19ml,1.1mmol),室温反应24h，茚三酮监测无色，抽干溶剂并以N,N-二甲基甲酰胺洗涤树脂3次，甲醇洗涤树脂2次，二氯甲烷洗涤树脂1次，甲醇洗涤树脂2次，真空抽干得到肽树脂44E/F(5g)。
第五步：100ml反应瓶中加入裂解液40ml(91％三氟乙酸+4％三异丙基硅烷+3％1.2-乙二硫醇+2％水)，搅拌均匀后加入肽树脂44E/F(5g)，室温搅拌2小时。过滤树脂得滤液，滤液加入到300ml甲基叔丁基醚中(甲基叔丁基醚提前降温至0℃)，白色絮状物析出，离心(3min at 3000rpm)。白色沉淀用甲基叔丁基醚洗涤三次，真空干燥得到类白色固体粗肽化合物44E/F(1.5g)，制备HPLC纯化。分离方法：1.仪器：waters2767制备液相；色谱柱：SunFire@PrepC18(19mm×250mm)。2.样品用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a流动相A，B组成：A:5mmol/L乙酸铵/H2O，B:CH3CN；b.梯度洗脱：流动相含量5％-45％；c.流速：12ml/min；d.洗脱时间：30min。冻干得到白色固体化合物44-1(77mg，纯度94％，保留时间13.198min),44-2(44mg，纯度98％，保留时间14.509)。
44-1，LCMS m/z＝903.8[M/2+H]+，603.0[M/3+H]+。
44-2，LCMS m/z＝904.1[M/2+H]+。
实施例45：

以上述物料表为原料，采用化合物1的方法得到化合物45C(1.5g)。
第三步：在3L反应瓶中，依次加入水(750ml)、乙腈(750ml)、45C(1.5g，0.8mmol)，搅拌均匀后，加入溴化铋(0.36g，0.8mmol)，碳酸氢铵调pH＝8，反应16h后制备HPLC纯化。分离方法：1.仪器： waters2767制备液相；色谱柱SunFire@PrepC18(19mm×250mm)。2.样品用0.45μm滤头过滤，制成样品液。3.制备色谱条件：a流动相A，B组成：A:0.1％三氟乙酸/H2O，B:CH3CN；b.梯度洗脱：流动相含量5％-45％；c.流速：12ml/min；d.洗脱时间：30min，保留时间：17min。冻干得到白色固体化合物45(57mg，纯度90％)。
LCMS m/z＝1047.1[M/2+H]+，698.5[M/3+H]+。
实施例46：


以上述物料表为原料，采用化合物1的方法得到化合物46(105mg，纯度92％)。
LCMS m/z＝851.7[M/3+H]+。
实施例47：

以上述物料表为原料，采用化合物21的方法合成得到化合物47(320mg，纯度95％)。
LCMS m/z＝818.9[M/3+H]+，614.5[M/4+H]+。
实施例48：


以上述物料表为原料，采用化合物1的方法得到化合物48(200mg，纯度97％)。
LCMS m/z＝1049.7[M/2+H]+，833.7[M/3+H]+。
实施例49：


以上述物料表为原料，采用化合物21的方法合成得到化合物49(220mg，纯度95％)。
LCMS m/z＝1271.0[M/2+H]+，847.7[M/3+H]+。
实施例50：

以上述物料表为原料，采用化合物25的方法得到化合物50(100mg)。
LCMS m/z＝1046.0[M/2+H]+。
实施例51：

以上述物料表为原料，采用化合物25的方法得到化合物51(75mg)。
LCMS m/z＝1046.0[M/2+H]+。
实施例52：


以上述物料表为原料，采用化合物44的方法得到化合物52(400mg)。
LCMS m/z＝935.5[M/2+H]+，623.9[M/3+H]+。
实施例53：

以上述物料表为原料，采用化合物25的方法得到化合物53(72mg)。
LCMS m/z＝1049.6[M/2+H]+,700.2[M/3+H]+。
实施例54：

以上述物料表为原料，采用化合物1的方法得到化合物54(400mg)。
LCMS m/z＝995.0[M/2+H]+。
实施例55：

以上述物料表为原料，采用化合物1的方法得到化合物55(410mg)。
LCMS m/z＝982.0[M/2+H]+。
生物测试方法
1.IL-23α/IL-12β&IL-23R结合测试实验
用TR-FRET方法测试化合物对IL-23α/IL-12β&IL-23R结合的抑制。在反应缓冲液PPI((PerkinElmer，Cat#61DB10RDF)中制备蛋白IL-23α/IL-12β(ACRO，Cat#ILB-H52W5)和IL-23R(ACRO，Cat#ILR-H82F3)溶液。反应混合物中IL-23α/IL-12β和IL-23R的最终浓度均为0.3nM。阳性参照品Guselkumab起始浓度为30nM,3倍稀释，10dose。通过声学液体输送技术(Echo655)将反应缓冲液中稀释好的阳性参照品0.1μL输送到384孔板(Grenier，Cat#784075)中，1000rpm离心1分钟；转移2.5μL IL-23α/IL-12β溶液到384反应板中并1000rpm离心1分钟，于25℃孵育60分钟；转移2.5μL IL-23R溶液到384反应板中，1000rpm离心1分钟；转移5μL Streptavidin-Tb cryptate和Anti 6HIS-d2检测混合液到384反应板中并1000rpm离心1分钟，于25℃孵育60分钟；最后用BMG高通量药筛多功能酶标仪读HTRF信号(Ratio 665/620nm)。使用GraphPad Prism软件获得IC50值和非线性回归曲线拟合。
表1
结论：本发明化合物例如实施例化合物，对IL-23α/IL-12β和IL-23R结合具有显著抑制能力。
2.IL-23R报告基因实验
该试验目的是评估化合物在报告基因系统中抑制IL23p19和IL23R结合的能力。HEK-blue IL23报告基因细胞系(Invivogen，hkb-il23)在DMEM+10％FBS+100ug/mL Normocin培养基中培养。当细胞的密度达 到80％-90％时，按照5000个细胞/孔铺到384孔板中，在37℃和5％CO2条件下培养过夜。然后将化合物库存溶液稀释在DMSO中，通过Echo将稀释物的40nL转移到384孔培养板中。在37℃和5％CO2下孵育0.5小时。将40nL/孔rhIL23(R&D，1290-IL)加入到384孔细胞培养板中，最终浓度为1ng/mL，在37℃和5％CO2下孵育24小时。加入18μL Quanti-BlueTM溶液加入到新的384孔板中，将2μL/孔细胞培养上清转移到第6步准备的384孔板中，在37℃和5％CO2下孵育1小时。在BMG上读取620-655nM的吸光值。使用以下公式评估化合物的结合能力并使用Graphpad拟合IC50。
抑制率计算公式：
DMSO对照组平均值
无IL23刺激组平均值
IC50计算公式如下：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:化合物浓度
Y：化合物抑制率
表2测试化合物对IL-23R的抑制
结论：本发明化合物例如实施例化合物，对IL23p19和IL23R结合具有显著抑制能力。
3.PBMC中IL-23刺激pSTAT3检测试验
冷冻保存的人PBMC解冻并种到预先覆盖CD3抗体的板子上，每个孔种1×10^6个细胞。然后加入CD28抗体到板上，细胞在37℃，5％ CO2下孵育5天。第五天，FBS饥饿刺激4小时后将细胞种植到96孔板上，每孔密度为100K个细胞。将稀释好的化合物转移到96孔细胞培养板上，37℃，5％ CO2下孵育1小时。加入rhIL23(R&D，1290-IL)到细胞培养板中，在37℃，5％ CO2下孵育30分钟。孔中的细胞 用含1×PHOSstop溶液的裂解缓冲液在冰上裂解30分钟，1000rpm下离心1分钟。然后将上清液转移到96孔ELISA板上，根据试剂盒(CST，7300CA)说明进行pSTAT3 ELISA检测。在PHERAstar FSX(BMG LRBTECH)上读取450nM处吸光值。使用以下公式评估化合物的抑制率并使用Graphpad拟合IC50。
抑制率计算公式：
DMSO对照组平均值
无IL23刺激组平均值
IC50计算公式如下：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:化合物浓度
Y：化合物抑制率。
表3 pSTAT3抑制
结论：本发明化合物例如实施例化合物，对STAT3磷酸化具有明显抑制作用。
4、小鼠药代动力学测试
4.1试验动物：雄性Balb/c小鼠，20～25g，18只/化合物。购于成都达硕实验动物有限公司。
4.2试验设计：试验当天，将Balb/c小鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。
表4.给药信息

注：静脉给药溶媒:PBS；灌胃给药溶媒：PBS
于给药前及给药后异氟烷麻醉经眼眶取血0.06mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。
表5.测试化合物在小鼠血浆中的药代动力学参数

-：不适用。
结论：本发明化合物例如实施例化合物在小鼠体内具有良好的药代动力学特征，比如化合物7、16、24在小鼠体内药代动力学特征优异。
5、血浆稳定性测试
本实验采用人、猴、犬、大鼠和小鼠五种属血浆来评价化合物7的血浆稳定性。
制备浓度水平为1000ng/mL的血浆样本，分装至时间点为0h和6h的EP管中；其中0h样本直接加入含内标的乙腈溶液，6h样本在37℃条件下放置至相应时间后加入含内标的乙腈溶液。采用LC-MS/MS方法检测样品中受试物浓度，剩余率由时间点样品与零时刻样品中待测物与内标峰面积之比计算得出。
实验结果：在测试条件下，浓度水平为1000ng/mL时，测试化合物剩余率的见下表6。
表6 37℃放置6h剩余率％

6、胃肠液稳定性测试
1.溶液配制
1.1稀盐酸配置：量取盐酸23.4ml,加水稀释至1000ml,即得。
1.2人工胃液配制：取稀盐酸1.64ml,加水约80ml与胃蛋白酶1g,摇匀后，加水稀释成100ml,即得。
1.3配制0.1mol/L NaOH：称取NaOH 0.4g，加水100ml溶解后即得。
1.4人工肠液配制：取磷酸二氢钾0.68g,加水50ml使溶解，用0.1mol/L氢氧化钠溶液调节pH值至6.8；另取胰酶1g,加水适量使溶解，将两液混合后，加水稀释至1000ml,即得。
2.样品配制
取样品约12.5mg至25ml容量瓶中加人工胃液(或者人工肠液)溶解并稀释至刻度线即可。
3.分析方法
仪器型号Agilent 1260Infinity；流动相A:10mmol/L K2HPO4流动相B:乙腈；柱子:phenomenex Gemini@3um C18150*4.6mm；波长：224nm；柱温：30℃；样品盘温度：37℃；进样时间：35min；进样体积：10ul；进样方式：梯度进样；梯度方法。梯度流动相如表7。
表7梯度流动相
样品浓度：0.5mg/ml
4.取样检测及结果
取样检测：首先检测空白溶液(人工胃液或者人工肠液)，然后取配制好的样品(临用新配)放入进样盘立即进样，再分别在4.5h,9.5h,18h时各进一针样品。
检测结果见表8。
表8胃肠液稳定性
结论：化合物7具有良好的人工胃肠液稳定性。

Claims (15)

  1. 一种环肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述肽化合物具有式(I)的氨基酸序列：
    Xa1 -Xa2-Xa3-Xa4-Xa5-Xa6-Xa7-Xa8-Xa9-Xa10-Xa11-Xa12-Xa13   (I)
    其中Xa1与Xa6各自独立地选自Pen、Pcn、Asn、Ala、Ala(3-amino)、Ala(2-ethyne)、Ala(3-azido)、Ala(2-ethene)、Val(2-ethene)、Asp、2,4-二氨基丁酸、Ser、Cys、Hcys、Glu，且Xa1与Xa6的残基之间经过反应形成肽环或者经L1形成环肽；
    Xa2选自Asn、His，或Asn、His的类似物；
    Xa3选自Thr或Thr的类似物；
    Xa4选自Trp或Trp的类似物；
    Xa5选自Lys、Gln、Arg、Cit，或Lys、Gln、Cit、Arg的类似物；
    Xa7选自Phe或Phe的类似物；
    Xa8选自Phe、Trp、2-Nal，或Phe、Trp、2-Nal的类似物；
    Xa9选自Thp或Thp的类似物；
    Xa10选自Glu、Cys，或Glu、Cys的类似物；
    Xa11选自Asn、Lys，或Asn、Lys的类似物；
    Xa12选自3-Pal、Phe、Asp，或3-Pal、Phe、Asp的类似物；
    Xa13选自Sarc或Sarc的类似物；
    作为选择，Xa1、Xa2、Xa3、Xa4、Xa5、Xa7、Xa8、Xa9、Xa10、Xa11、Xa12、Xa13中的任意氨基酸的残基直接缩合或者经过L1链接从而形成一个或多个肽环；
    L1选自W1-RL-W2；
    RL选自键、C1-6亚烷基、C2-4亚烯基、C2-4亚炔基、3-6元环烷基、4-6元杂环烷基、5-6元杂芳基、6-10元芳基、-(OCH2CH2)a-，所述的亚烷基、亚烯基、亚炔基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1-4个RL1取代；
    a选自0-10的任意整数；RL1各自独立地选自卤素、＝O、C1-4烷基、C2-4烯基、C1-4烷氧基、3-6元环烷基、COOH、NH2、-NH-C(＝O)-C1-4烷基，所述的烷基、烷氧基、环烷基任选进一步被1-4个选自卤素、CN、OH和NH2的取代基取代；
    W1、W2各自独立地选自键、C1-6亚烷基、-O-、-S-、-NRW1-、-CONRW1-、-NRW1CO-、-C(＝O)O-或-OC(＝O)-，所述亚烷基中的一个或多个-CH2-任选被1-4个选自-O-、-S-、-NRW1-或-CO-的基团替代，所述亚烷基任选进一步被1-4个选自卤素、＝O、C1-4烷基、卤代C1-4烷基、CN、OH和NH2的取代基取代；
    RW1选自H、C1-4烷基、卤素；
    并且所述肽化合物任选地与保护基团连接；
    所述保护基团选自Ac、戊二酰基、琥珀酰基、NH2或OH；
    作为选择，多肽被反应基团Xa1、Xa6、Xa10与分子支架形成的共价键隔开而形成至少含有2个环的多肽环；
    作为选择，所述肽化合物任选地在Xa1处、Xa5处或Xa7处缀合修饰性基团；
    条件是：所述肽化合物不选自如下结构：(Ac)Pen-Asn-Thr-Trp(CH3)-Lys(Ac)-Pen-Phe[4-(2-氨基乙氧基)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH2)，其中Pen与Pen之间形成二硫键。
  2. 根据权利要求1所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述肽化合物具有式(II)、式(II-1)的氨基酸序列：
    (Ac)Xa1-Xa2-Thr-Xa4-Xa5-Xa6-Xa7-Xa8-Xa9-Xa10-Asn-(3-Pal)-Sarc(NH2)  (II)
    (Ac)Xa1-Xa2-Thr-Xa4-Lys(Ac)-Xa6-Xa7-Xa8-Xa9-Glu-Asn-(3-Pal)-Sarc(NH2)  (II-1)(SEQ 
    ID NO.1)
    其中，Xa1与Xa6的残基之间经过反应形成肽环或者经过L1链接形成肽环。
  3. 根据权利要求1所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述肽化合物具有式(III)、式(III-1)的氨基酸序列：
    (Ac)Xa1-Xa2-Thr-Trp(R1)Xa5-Xa6-Xa7-Xa8-Xa9-Xa10-Asn-(3-Pal)-Sarc(NH2)  (III)
    (Ac)Xa1-Xa2-Thr-Trp(CH3)-Lys(Ac)-Xa6-Xa7-Xa8-Xa9-Glu-Asn-(3-Pal)-Sarc(NH2)  (III-1)
    (SEQ ID NO.2)
    其中，Xa1与Xa6的残基之间经过反应形成肽环或者经L1形成环肽；
    且Trp(R1)与Xa5的残基之间直接缩合或者经过L1链接形成肽环；
    或Trp(CH3)与Lys(Ac)的残基之间直接缩合或者经过L1链接形成肽环；
    或Xa1、Xa6、Xa10与分子架形成双环肽；
    R1选自H、C1-4烷基、C3-6环烷基、4-8元杂环烷基，所述烷基、环烷基、杂环烷基任选进一步被1-4个选自卤素、＝O、C1-4烷基、卤代C1-4烷基、CN、OH和NH2的取代基取代。
  4. 根据权利要求1所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述肽化合物具有式(IV)、式(IV-1)、式(V)的氨基酸序列：
    (N-端)Xa1-Asn-Thr-Trp(R1)-Xa5-Xa6-Xa7-(2-Nal)-Xa9-Xa10-Xa11-Xa12-Sarc(C-端)  (IV)
    (N-端)Xa1-Asn-Thr-Trp(CH3)-Lys(Ac)-Xa6-Xa7-(2-Nal)-Xa9-Glu-Xa11-Xa12-Sarc(C-端)  
    (IV-1)(SEQ ID NO.3)
    (N-端)Xa1-His-Thr-Trp(R1)-Xa5-Xa6-Xa7-(2-Nal)-Xa9-Xa10-Xa11-Xa12-Sarc(C-端)  (V)
    其中，Xa1与Xa6的残基之间经过反应形成肽环或经过L1链接形成肽环；
    N-端和C-端存在或不存在保护基团；
    或者N-端缀合修饰性基团；
    2-Nal与Xa12的残基之间经过L1链接形成肽环；和/或者
    Xa9与Xa12的残基之间经过L1链接形成肽环；和/或者
    Lys(Ac)与Xa7的残基之间经过L1链接形成肽环；和/或者
    Xa7与Xa11的残基之间经过L1链接形成肽环；和/或者
    2-Nal与Glu的残基之间经过L1链接形成肽环；和/或者
    Xa1与Glu的残基之间经过L1链接形成肽环；和/或者
    Xa1与Xa11的残基之间经过L1链接形成肽环；和/或者
    Xa1与Xa10的残基之间经过L1链接形成肽环；和/或者
    2-Nal与Sarc的残基之间经过L1链接成肽环；和/或者
    Xa9与Sarc的残基之间经过L1链接形成肽环；和/或者
    Xa11与Sarc的残基之间经过L1链接形成肽环；和/或者
    Xa1、Sarc与Glu的残基之间经过L1链接形成肽环；和/或者
    或Xa1、Xa6、Xa10与分子架形成双环肽；
    R1选自C1-2烷基、环丙基、环丁基、环戊基、环己基，所述烷基、环丙基、环丁基、环戊基、环己基任选进一步被1-4个选自F、Cl、Br、＝O、甲基、乙基、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2F、-CHF2、-CF3、CN、OH和NH2的取代基取代；
    条件是：(1)、当N-端的Xa1与其他氨基酸的残基经过L1链接时，N-端的保护基团不存在；
    (2)、当C-端的Sarc与其他氨基酸的残基经过L1链接时，C-端的保护基团不存在。
  5. 根据权利要求1所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中：
    Xa1与Xa6的残基之间经过反应形成肽环或者经L1形成环肽，且Xa4与Xa5、Xa1与Xa10、Xa8与Xa10、Xa8与Xa12、Xa8与Xa13、Xa9与Xa13、Xa5与Xa7、Xa11与Xa13、Xa1与Xa11、Xa7与Xa11中的一组或两组的残基之间直接缩合或者经过L1链接形成肽环；
    或Xa1、Xa6、Xa10与分子架形成双环肽。
  6. 根据权利要求1所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述肽化合物为二聚体化合物，所述二聚体化合物是由肽化合物与肽化合物中氨基酸残基经过聚乙二醇链相连形成的；所述聚乙二醇链为
    n选自0-99的任意整数。
  7. 根据权利要求1所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述修饰性基团为 p选自0-50的任意整数，q选自0-50的任意整数。
  8. 根据权利要求1-7任意一项所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中
    Xa1与Xa6的残基经过反应形成如下结构：
    其中*端为Xa1端，Xa1与Xa2通过*位置连接，NH2末端与保护基团相连或NH2末端缀合修饰性基团；
    Xa2选自Asn、His，或His的类似物，所述His的类似物选自
    Xa3选自Thr；
    Xa4选自Trp的类似物，所述Trp的类似物选自
    Xa5选自Lys，Gln，Arg，Cit，或Arg、Lys的类似物，所述Arg、Lys的类似物选自
    作为选择，Xa5残基缀合修饰性基团；
    Xa7选自Phe或Phe的类似物，所述Phe的类似物选自
    作为选择，Xa7残基缀合修饰性基团；
    Xa8选自Phe，Trp，2-Nal，或Phe，Trp和2-Nal的类似物；所述Phe，Trp和2-Nal的类似物选自
    Xa9选自Thp或Thp的类似物，所述Thp的类似物选自
    Xa10选自Glu或Cys；
    Xa11选自Asn或Lys；
    Xa12选自3-Pal或Phe；
    所述的分子架选自：
  9. 根据权利要求1所述肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中 L1选自键、乙烯基、丙烯基、丁烯基、-O-(CH2)r-O-(CH2)r-NH-C(＝O)-、-O-(CH2)r-O-(CH2)r-、-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-、-C(＝O)-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-C(＝O)-、-NH-C(＝O)-、-C(＝O)-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-C(＝O)-(CH2)r-、-(CH2)r-O-(CH2)r-、-O-(CH2)r-NH-、C1-6亚烷基、-C(＝O)-、-C(＝O)-(CH2)r-NH-、 -(CH2)r-O-(CH2)r-NH-、-O-(CH2)r-O-(CH2)r-O-(CH2)r-O-(CH2)r-NH-、-(CH2)r-NH-、-C(＝O)-(CH2)r-O-(CH2)r-NH-、-(CH2)r-NH-C(＝O)-(CH2)r-、-C(＝O)-(CH2)-(OCH2CH2)a-NH-；
    r选自0、1、2、3、4、5、6、7、8、9或10；
    a选自3、4、5或6。
  10. 根据权利要求1所述的肽化合物，其立体异构体或者其药学上可接受的盐或溶剂化物或二聚体，其中所述肽化合物选自表一结构之一。
  11. 一种药物组合物，其包含权利要求1至10中任一项所述的肽化合物或其药学上可接受的盐，以及药学上可接受的载体和/或赋形剂。
  12. 权利要求1至10中任一项所述的肽化合物或其药学上可接受的盐，或者权利要求11所述药物组合物，在制备预防和治疗受试者患病组织中过度表达IL-23的疾病或病症药物中的应用。
  13. 根据权利要求12所述的应用，所述过度表达IL-23的疾病或病症包括炎症性肠病、克罗恩病和银屑病。
  14. 一种药物组合物或药物制剂，所述的药物组合物或药物制剂包含1-1500mg的权利要求1至10中任一项所述的肽化合物或其药学上可接受的盐，以及药学上可接受的载体和/或赋形剂。
  15. 一种用于治疗哺乳动物或人的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1至10中任一项所述的肽化合物或其药学上可接受的盐，治疗有效量优选1-1500mg，所述的疾病优选炎症性肠病、克罗恩病和银屑病。
PCT/CN2024/090789 2023-05-04 2024-04-30 白介素-23受体的肽抑制剂制备及其用途 Pending WO2024227437A1 (zh)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107206254A (zh) * 2014-07-17 2017-09-26 领导医疗有限公司 白细胞介素‑23受体的口服肽抑制剂以及其治疗炎症性肠病的用途
CN108348580A (zh) * 2015-07-15 2018-07-31 领导医疗有限公司 白细胞介素-23受体的肽抑制剂以及其治疗炎症性疾病的用途
US20200040037A1 (en) * 2018-07-12 2020-02-06 Protagonist Therapeutics, Inc. Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases
CN114341161A (zh) * 2019-07-10 2022-04-12 领导医疗有限公司 白细胞介素-23受体的肽抑制剂及其用于治疗炎症性疾病的用途
CN115279782A (zh) * 2020-01-15 2022-11-01 詹森生物科技公司 白介素-23受体的肽抑制剂及其用于治疗炎性疾病的用途
CN115298196A (zh) * 2020-01-15 2022-11-04 詹森生物科技公司 介白素-23受体的肽抑制剂及其治疗炎性疾病的用途
US20230129095A1 (en) * 2020-01-15 2023-04-27 Protagonist Therapeutics, Inc. Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107206254A (zh) * 2014-07-17 2017-09-26 领导医疗有限公司 白细胞介素‑23受体的口服肽抑制剂以及其治疗炎症性肠病的用途
CN113563423A (zh) * 2014-07-17 2021-10-29 领导医疗有限公司 白细胞介素-23受体的口服肽抑制剂以及其治疗炎症性肠病的用途
CN108348580A (zh) * 2015-07-15 2018-07-31 领导医疗有限公司 白细胞介素-23受体的肽抑制剂以及其治疗炎症性疾病的用途
US20200040037A1 (en) * 2018-07-12 2020-02-06 Protagonist Therapeutics, Inc. Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases
CN114341161A (zh) * 2019-07-10 2022-04-12 领导医疗有限公司 白细胞介素-23受体的肽抑制剂及其用于治疗炎症性疾病的用途
CN115279782A (zh) * 2020-01-15 2022-11-01 詹森生物科技公司 白介素-23受体的肽抑制剂及其用于治疗炎性疾病的用途
CN115298196A (zh) * 2020-01-15 2022-11-04 詹森生物科技公司 介白素-23受体的肽抑制剂及其治疗炎性疾病的用途
US20230129095A1 (en) * 2020-01-15 2023-04-27 Protagonist Therapeutics, Inc. Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases

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