[go: up one dir, main page]

WO2019001459A1 - 一种肽类化合物、其应用及含其的组合物 - Google Patents

一种肽类化合物、其应用及含其的组合物 Download PDF

Info

Publication number
WO2019001459A1
WO2019001459A1 PCT/CN2018/093088 CN2018093088W WO2019001459A1 WO 2019001459 A1 WO2019001459 A1 WO 2019001459A1 CN 2018093088 W CN2018093088 W CN 2018093088W WO 2019001459 A1 WO2019001459 A1 WO 2019001459A1
Authority
WO
WIPO (PCT)
Prior art keywords
phe
ser
group
nme
leu
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2018/093088
Other languages
English (en)
French (fr)
Inventor
王燕
伊冯娜·安吉尔
武芸
李曼华
胡永韩
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.)
Xdcexplorer (shanghai) Co Ltd
Original Assignee
Xdcexplorer (shanghai) Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xdcexplorer (shanghai) Co Ltd filed Critical Xdcexplorer (shanghai) Co Ltd
Priority to US16/624,063 priority Critical patent/US12129312B2/en
Priority to JP2019572139A priority patent/JP7196113B2/ja
Priority to EP18823088.2A priority patent/EP3647319B1/en
Publication of WO2019001459A1 publication Critical patent/WO2019001459A1/zh
Anticipated expiration legal-status Critical
Priority to US18/593,433 priority patent/US20240209023A1/en
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a peptide compound, its use and compositions containing the same.
  • ChemR23 is the primary receptor for Chemerin.
  • Owman et al. identified a new cDNA sequence from the B lymphoblastic cDNA library.
  • the encoded protein is highly homologous to the G protein-coupled receptor (GPCRs) family and is named ChemR23 (CMKLR1 chemokine-like receptor 1).
  • ChemR23 is mainly expressed in leukocytes, adipocytes, endothelial cells, epithelial cells, osteoclasts, and vascular smooth muscle cells. ChemR23 has long been considered an orphan receptor because no ligand has been found. In 2003, when Wittamer et al.
  • Chemerin is a chemotactic membrane-bound protein secreted by fat cells.
  • the Chemerin gene is also known as tazarotene-induced gene 2 (TIG2) or retinoic acid receptor responder 2 (RARRES2), which is equivalent to the 1997 culture of psoriasis patients by Nag-pal. Found when skin cells.
  • TAG2 tazarotene-induced gene 2
  • RARRES2 retinoic acid receptor responder 2
  • the human chemerin gene is localized to the E2DL3 gene.
  • the Chemerin gene encodes a protein containing 163 amino acid residues. It is an inactive precursor secreted protein, prochemerin, with a relative molecular mass of 18KDa. This precursor protein has low biological activity and requires coagulation, fibrinolysis, and inflammation.
  • the C-terminus is further lysed outside the cell by plasmin, carboxypeptidase or serine protease to become an active protein.
  • Prochemerin is converted to a relative molecular mass of 16 kDa, a reactive chemerin, which is present in serum, plasma and body fluids after hydrolysis of a carboxy-terminal sequence by extracellular proteases.
  • the carboxy terminus of the Chermerin sequence is critical for its biological activity.
  • many prochemerin indented end-derived peptides were synthesized to observe the effect on ChemR23, and the shortest chemerin bioactive peptide was found to be chemerin-9.
  • the sequence of human chemerin-9 is chemerin149-157, YFPGQFAFS; the sequence of mouse-derived chemerin-9 is chemerin148-156, FLPGQFAFS.
  • Human chemerin-9 has similar biological activity as mouse-derived chemerin-9.
  • CMKLR1 has been found to be expressed in many immune cells, including inflammatory mediators (monocytes, macrophages, plasma cell expression/myeloid dendritic cells and natural killer cells), vascular endothelial cells, and neurons, glial cells. Spinal cord and retina, immature dendritic cells, myeloid dendritic cells, macrophages, and natural killer cells. It plays an important role in innate immunity, acquired immunity, inflammatory response, lipogenesis and lipid metabolism, and cell proliferation.
  • Chemerin and its receptor system play an important role in the pathology of viral pneumonia and are therefore likely to become antiviral and anti-inflammatory therapies.
  • Chemerin has a wide range of functions, such as promoting the chemotaxis of dendritic cells, macrophages and NK cells to the site of inflammation, inhibiting the synthesis of proinflammatory mediators TNF ⁇ and IL-6, increasing the production of adiponectin, and promoting the differentiation of adipocytes. Mature, improve insulin sensitivity to insulin and glucose uptake, regulate lipolysis, increase TNF- ⁇ synthesis, increase NF- ⁇ activity, increase VEGF and MMPs synthesis and regulate neovascularization and angiogenesis, etc. . Therefore, Chemerin plays an important role in immune response, inflammatory response, lipogenesis and lipid metabolism (involving obesity, fatty liver, diabetes and metabolic syndrome), and has a good application prospect.
  • Chemerin is also used in asthma, a chronic inflammatory disease of the respiratory tract. Failure to take any anti-inflammatory measures can result in bronchial obstruction or contracture, and may even be life-threatening due to difficulty breathing. Asthma is listed by the World Health Organization as one of the four major chronic diseases in the disease. It is also the second most dead and disabling disease in the world after cancer. In some developed countries in the West, the incidence of asthma is as high as 20%, and some even as high as 40%. The prevalence of asthma in China is growing very fast.
  • peptide drugs Compared with most organic small molecule drugs, peptide drugs have the characteristics of high biological activity, small dosage, low toxic side effects and amino acid metabolism. Compared with macromolecular proteins or antibody drugs, it has a smaller molecular weight, similar protein activity, more significant functions, chemical synthesis, high product purity, controllable quality, and small peptides with almost no immunogenicity. Drug development The prospects are very good. The research and development of peptide drugs has become an emerging international high-tech field with great market potential.
  • the technical problem to be solved is that the existing Chemerin has low activity and poor stability, and the present invention provides a peptide compound, an application thereof and a composition containing the same, which has better stability and better activity. .
  • the present invention provides a peptide compound of the formula I, a pharmaceutically acceptable salt thereof, a tautomer thereof, a solvate thereof, a crystalline form thereof or a prodrug thereof:
  • XX0 is hydrogen, R 0-2 or
  • R 0-1 is CH 3 -, q is 10 to 18 (for example, a range of endpoints of any of the following two values: 10, 11, 12, 13, 14, 15, 16, 17, and 18);
  • m is 6 to 12 (for example, a range in which the following two values are endpoints: 6, 7, 8, 9, 10, 11, and 12);
  • n is 0 to 2 (for example, 0, 1, or 2);
  • All AA0 are independently (eg PEG8), Ahx, Gly or Beta-Ala; all k are independently 4-8 (eg, ranges of endpoints with any of the following two values: 4, 5, 6, 7, and 8), all r Independently 0 or 1;
  • R 0-2-1 R 0-2 is a substituted or unsubstituted C 1 ⁇ C 6 alkyl group (the number of the R 0-2-1 may be one or more ⁇ e.g. 1, 2 , 3, 4 or 5 ⁇ ; when a plurality of R 0-2-1 are present, they are the same or different; all R 0-2-1 may independently be in the C 1 -C 6 alkyl group Tertiary or non-terminal; the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group; the C 1 -C 4 alkyl group may be a methyl group, an ethyl group, a n-propyl group, Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; said "R 0-2-1 substituted C 1 -C 6 alkyl" such as 3,5-dihydroxybenzyl Or 3-phenylpropyl);
  • All R 0-2-1 are independently hydroxy substituted or unsubstituted phenyl (the number of said hydroxyl groups may be one or more ⁇ eg 1, 2, 3, 4 or 5 ⁇ All of the hydroxyl groups may be independently ortho, meta or para to the phenyl group; said "hydroxy substituted phenyl" such as 3,5-dihydroxyphenyl);
  • R 0-3 is R 0-3-1 substituted or unsubstituted C 1 -C 8 alkyl group (the number of R 0-3-1 may be one or more ⁇ for example, 1 or 2 , 3, 4 or 5 ⁇ ; when a plurality of R 0-3-1 are present, they are the same or different; all R 0-3-1 may independently be in the C 1 -C 8 alkyl group Tertiary or non-terminal; the C 1 -C 8 alkyl group may be a C 1 -C 4 alkyl group or a n-pentyl group; the C 1 -C 4 alkyl group may be a methyl group or an ethyl group.
  • R 0-3-2 when there are a plurality of R 0-3-2 , they are the same or different; all R 0-3-2 may be independently at the ortho, meta or para position of the phenyl; the "R 0-3-2 substituted phenyl", for example, 3,5-dihydroxyphenyl, 2,3- Hydroxyphenyl, 2,6-dihydroxyphenyl, 2,3,4-trihydroxyphenyl, 2,3,5-hydroxyphenyl or 4-trifluoromethylphenyl);
  • All R 0-3-1 are independently hydroxy substituted or unsubstituted phenyl (the number of said hydroxyl groups may be one or more ⁇ eg 1, 2, 3, 4 or 5 ⁇ All of the hydroxyl groups may be independently ortho, meta or para to the phenyl group; said "hydroxy substituted phenyl" such as 3,4-dihydroxyphenyl or 3,5-dihydroxyphenyl Or a C 3 -C 6 cycloalkyl group (for example, cyclohexyl);
  • All R 0-3-2 are independently a hydroxyl group or a halogenated C 1 -C 4 alkyl group (the number of said "halogens” may be one or more ⁇ for example, 1, 2, 3 , 4 or 5 ⁇ ; all "halo” may independently be fluorine, chlorine or bromine; when multiple halogens are present, they are the same or different; the C 1 -C 4 alkyl group may be A Base, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; said "halogenated C 1 -C 4 alkyl” such as trifluoromethyl) ;
  • XX1 is an alkyl group having one C 1 -C 4 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and further methyl) a substituted or unsubstituted amino acid (the "substituted amino acid” such as D-NMeTyr): D-Tyr (3F), D-Tyr and D-Phe;
  • XX2 is an amino group substituted or unsubstituted with 1 C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) Any of the following amino acids (the "substituted amino acid” such as NMePhe): 1Nal, 2Nal, Bpa and ⁇ eg Phe, Phe(4-Cl) or Phe(4-Me) ⁇ ; n2 is 0 or 1, and R 2 is a C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl) , n-butyl or isobutyl) or halogen (such as fluorine or chlorine), the carbon atom marked by * is a chiral carbon atom, which is in the R configuration or the S configuration (R 2 may be
  • XX3 is Wherein the *-labeled carbon atom is a chiral carbon atom, which is in the R configuration or the S configuration (eg R 3-1 is a C 4 -C 5 alkyl group (eg n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or 3-methylbutyl) or benzyl; R 3 -2 is a C 1 -C 4 alkyl group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl); For example, NMe-Leu, NMe-Phe, NMe-HoLeu, NEt-Leu, NPr-Leu, NiPr-Leu, Nbu-Leu, NMe-Nle or NMe-Ile);
  • R 3-1 is a C 4 -C 5
  • XX4 is Ala or (E.g Y is -(CR 4-1 R 4-2 )- ⁇ for example -CH 2 -, -CH(OH)- or -CF 2 ⁇ , -(CH 2 ) 2 - or -S-; for example, Aze, Thz , Hyp, Pro, Pro (5Ph), Pro (4Ph), Pro (diF) or HoPro); * labeled carbon atoms are chiral carbon atoms, which are in the R configuration or the S configuration (eg Z is -(CR 4-1 R 4-2 ) n4 - ⁇ for example -CH 2 -, -(CH 2 ) 2 -, -CH(OH)-CH 2 -, -CF 2 -CH 2 -, -CHPh-CH 2 -, -CH 2 -CHPh- or -(CH 2 ) 3 - ⁇ or -S-(CR 4-3 R 4-4 ) n4' - ⁇ eg -S
  • XX5 is D-Ser, D-Hyp, D-Thr, ⁇ Ala, D-NMeSer, 2Nal, 1Nal or D-HoSer;
  • XX6 is Gln, NMe-Gln or NGln;
  • XX7 is NMe-Phe, HoPhe, 1Nal, 2Nal, Bpa, D-Ser or ⁇ eg Phe, Phe(3-Cl), Phe(3-Me), Phe(3-OMe), Phe(4-OMe), Phe(4-Me) or Phe(4-Cl) ⁇ ; n7 is 0 Or 1, R 7 is a C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl), C 1 -C 4 alkoxy (eg methoxy) a group, a ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group or an isobutoxy group, or a halogen (for example, fluorine or chlorine), the carbon atom labeled with * is a chiral carbon atom, which is an R group.
  • XX8 is D-Ala, D-NMeAla, Ala or ⁇ Ala;
  • XX9 is Tic, Phe, NMe-Phe, 1Nal, 2Nal, Bpa, Phe(4-Me), Phe(4-Cl), Phe(4-NO2), HoPhe, Idc, Tic(OH), Oic, Chc, Cha, MeA6c, HoPro, Pro(5Ph), Pro(4Ph), Ala(dip), Bip, azaTic, D-Tic, Ti1c, D-Ti1c, TP5C, TP6C, Tic(6-Me), S-Pip, Ica or D-Oic;
  • XX10 is NhomoSer, or the amino group is a C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl)
  • Substituted or unsubstituted any of the following amino acids such as NMe-Ser or NMe-HoSer: Ser, Thr, Hyp, Asp, D-HoSer and HoSer;
  • P is a hydroxyl group or an amino group.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX0 is hydrogen, R 0-2 or
  • R 0-1 is CH 3 -, q is 10-18;
  • PEG is m is 6 to 12;
  • n 0 to 2;
  • R 0-2 is R 0-2-1 substituted or unsubstituted C 1 -C 6 alkyl
  • R 0-2-1 are independently hydroxy substituted or unsubstituted phenyl
  • R 0-3 is R 0-3-1 substituted or unsubstituted C 1 -C 8 alkyl, or R 0-3-2 substituted or unsubstituted phenyl;
  • All R 0-3-1 are independently hydroxy substituted or unsubstituted phenyl, or C 3 -C 6 cycloalkyl;
  • All R 0-3-2 are independently hydroxy or halogenated C 1 -C 4 alkyl
  • XX1 is any of the following amino acids in which the amino group is substituted or unsubstituted with one C 1 -C 4 alkyl group: D-Tyr (3F), D-Tyr and D-Phe;
  • XX2 is any of the following amino acids in which the amino group is substituted or unsubstituted with one C 1 -C 4 alkyl group: 1Nal, 2Nal, Bpa and N2 is 0 or 1, R 2 is a C 1 -C 4 alkyl group or a halogen, and the * labeled carbon atom is a chiral carbon atom which is in the R configuration or the S configuration;
  • XX3 is Wherein, the *-labeled carbon atom is a chiral carbon atom, which is an R configuration or an S configuration; R 3-1 is a C 4 -C 5 alkyl group or a benzyl group; and R 3-2 is a C 1 -C 4 group; Alkyl
  • XX4 is Ala or *The labeled carbon atom is a chiral carbon atom which is in the R configuration or the S configuration; Z is -(CR 4-1 R 4-2 ) n4 - or -S-(CR 4-3 R 4-4 ) N4'- ; the right end of the -(CR 4-1 R 4-2 ) n4 - and -S-(CR 4-3 R 4-4 ) n4' - is bonded to a chiral carbon atom; n4 is 1 - 3, n4' is 1 or 2; all R 4-1 , R 4-2 , R 4-3 and R 4-4 are independently hydrogen, hydroxy, halogen or phenyl;
  • XX5 is D-Ser, D-Hyp, D-Thr, D-NMeSer, 2Nal, 1Nal or D-HoSer;
  • XX6 is Gln, NMeGln or NGln;
  • XX7 is NMe-Phe, HoPhe, 1Nal, 2Nal, Bpa, D-Ser or N7 is 0 or 1, R 7 is a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group or a halogen, and the * labeled carbon atom is a chiral carbon atom which is in the R configuration or the S configuration;
  • XX8 is D-Ala, D-NMeA, Ala or ⁇ Ala;
  • XX9 is Tic, Phe, NMePhe, 1Nal, 2Nal, Bpa, Phe(4-Me), Phe(4-Cl), Phe(4-NO2), HoPhe, Idc, Tic(OH), Oic, Chc, Cha, MeA6c, HoPro, Pro(5Ph), Pro(4Ph), Ala(dip), Bip, azaTic, D-Tic, Ti1c, D-Ti1c, TP5C, TP6C, Tic(6-Me), Ica or D-Oic;
  • XX10 is NHoSer, or any of the following amino acids in which the amino group is substituted or unsubstituted with one C 1 -C 4 alkyl group: Ser, Thr, Hyp, Asp, D-HoSer and HoSer;
  • P is a hydroxyl group or an amino group.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX0 is hydrogen, R 0-2 or
  • R 0-1 is CH 3 -, q is 10-18;
  • PEG is m is 6 to 12;
  • n 0 to 2;
  • R 0-2 is R 0-2-1 substituted or unsubstituted C 1 -C 6 alkyl
  • R 0-2-1 are independently hydroxy substituted or unsubstituted phenyl
  • R 0-3 is R 0-3-1 substituted or unsubstituted C 1 -C 8 alkyl, or R 0-3-2 substituted or unsubstituted phenyl;
  • All R 0-3-1 are independently hydroxy substituted or unsubstituted phenyl, or C 3 -C 6 cycloalkyl;
  • All R 0-3-2 are independently hydroxy or halogenated C 1 -C 4 alkyl
  • XX1 is any of the following amino acids in which the amino group is substituted or unsubstituted with one C 1 -C 4 alkyl group: D-Tyr (3F), D-Tyr and D-Phe;
  • XX2 is any of the following amino acids in which the amino group is substituted or unsubstituted with one C 1 -C 4 alkyl group: 1Nal, 2Nal, Bpa and N2 is 0 or 1, R 2 is a C 1 -C 4 alkyl group or a halogen, and the * labeled carbon atom is a chiral carbon atom which is in the R configuration or the S configuration;
  • XX3 is Wherein, the *-labeled carbon atom is a chiral carbon atom, which is an R configuration or an S configuration; R 3-1 is a C 4 -C 5 alkyl group or a benzyl group; and R 3-2 is a C 1 -C 4 group; Alkyl
  • XX4 is Ala or *The labeled carbon atom is a chiral carbon atom which is in the R configuration or the S configuration; Z is -(CR 4-1 R 4-2 ) n4 - or -S-(CR 4-3 R 4-4 ) N4'- ; the right end of the -(CR 4-1 R 4-2 ) n4 - and -S-(CR 4-3 R 4-4 ) n4' - is bonded to a chiral carbon atom; n4 is 1 - 3, n4' is 1 or 2; all R 4-1 , R 4-2 , R 4-3 and R 4-4 are independently hydrogen, hydroxy, halogen or phenyl;
  • XX5 is D-Ser, D-Hyp, D-Thr, D-NMeSer, 2Nal, 1Nal or D-HoSer;
  • XX6 is Gln, NMeGln or NGln;
  • XX7 is NMe-Phe, HoPhe, 1Nal, 2Nal, Bpa, D-Ser or N7 is 0 or 1, R 7 is a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group or a halogen, and the * labeled carbon atom is a chiral carbon atom which is in the R configuration or the S configuration;
  • XX8 is D-Ala, D-NMeA, Ala or ⁇ Ala;
  • XX9 is Tic, Phe, NMePhe, 1Nal, 2Nal, Bpa, Phe(4-Me), Phe(4-Cl), Phe(4-NO2), HoPhe, Idc, Tic(OH), Oic, Chc, Cha, MeA6c, Pro(5Ph), Pro(4Ph), Ala(dip), Bip, azaTic, D-Tic, Ti1c, D-Ti1c, TP5C, TP6C, Tic(6-Me), Ica or D-Oic;
  • XX10 is NHoSer, or any of the following amino acids in which the amino group is substituted or unsubstituted with one C 1 -C 4 alkyl group: Ser, Thr, Hyp, Asp, D-HoSer and HoSer;
  • P is a hydroxyl group or an amino group.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX0 is hydrogen, R 0-2 or
  • R 0-1 is CH 3 -, q is 10 to 18 (for example, a range of endpoints of any of the following two values: 10, 11, 12, 13, 14, 15, 16, 17, and 18);
  • m is 6 to 12 (for example, a range in which the following two values are endpoints: 6, 7, 8, 9, 10, 11, and 12);
  • n 2;
  • All AA0 are independently Gly or Beta-Ala;
  • R 0-2-1 R 0-2 is a substituted or unsubstituted C 1 ⁇ C 6 alkyl group (the number of the R 0-2-1 may be one or more ⁇ e.g. 1, 2 , 3, 4 or 5 ⁇ ; when a plurality of R 0-2-1 are present, they are the same or different; all R 0-2-1 may independently be in the C 1 -C 6 alkyl group Tertiary or non-terminal; the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group; the C 1 -C 4 alkyl group may be a methyl group, an ethyl group, a n-propyl group, Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; said "R 0-2-1 substituted C 1 -C 6 alkyl" such as 3-phenylpropyl);
  • All R 0-2-1 are independently phenyl
  • R 0-3 is R 0-3-1 substituted or unsubstituted C 1 -C 8 alkyl group (the number of R 0-3-1 may be one or more ⁇ for example, 1 or 2 , 3, 4 or 5 ⁇ ; when a plurality of R 0-3-1 are present, they are the same or different; all R 0-3-1 may independently be in the C 1 -C 8 alkyl group Tertiary or non-terminal; the C 1 -C 8 alkyl group may be a C 1 -C 4 alkyl group or a n-pentyl group; the C 1 -C 4 alkyl group may be a methyl group or an ethyl group.
  • R 0-3-1 substituted C 1 -C 8 alkyl such as 2-phenyl Ethyl, 3-phenylpropyl, 4-phenylbutyl, 4-phenylbenzyl, diphenylmethyl or cyclohexylmethyl), or R 0-3-2 substituted or unsubstituted phenyl
  • the number of R 0-3-2 may be one or more ⁇ for example, 1, 2, 3, 4 or 5 ⁇ ; when there are a plurality of R 0-3-2 , they The same or different; all R 0-3-2 may be independently at the ortho, meta or para position of the phenyl group; the "R 0-3-2 substituted phenyl group” such as 3,5- Dihydroxyphenyl, 2,3-dihydroxyphenyl, 2,6-dihydroxyphenyl, 2,3,4- Trihydroxyphenyl, 2,3,5-tri
  • All R 0-3-1 are independently phenyl, or a C 3 -C 6 cycloalkyl group (eg cyclohexyl);
  • All R 0-3-2 are independently halogenated C 1 -C 4 alkyl groups (the number of said "halogens” may be one or more ⁇ for example, 1, 2, 3, 4 or 5 ⁇ ; all "halo” may be independently fluoro, chloro or bromo; when there is more halogen, which are identical or different; C 1 ⁇ C 4 alkyl group may be the methyl, ethyl, , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; said "halogenated C 1 -C 4 alkyl” such as trifluoromethyl);
  • XX1 is an alkyl group having one C 1 -C 4 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and further methyl) a substituted or unsubstituted amino acid (the "substituted amino acid” such as D-NMeTyr): D-Tyr (3F) and D-Tyr;
  • XX2 is an amino group substituted or unsubstituted with 1 C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) Any of the following amino acids (the "substituted amino acid” such as NMePhe): 1Nal, 2Nal, Bpa and ⁇ eg Phe, Phe(4-Cl) or Phe(4-Me) ⁇ ; n2 is 0 or 1, and R 2 is a C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl) , n-butyl or isobutyl) or halogen (such as fluorine or chlorine), the carbon atom marked by * is a chiral carbon atom, which is in the R configuration or the S configuration (R 2 may be
  • XX3 is Wherein the *-labeled carbon atom is a chiral carbon atom, which is in the R configuration or the S configuration (eg R 3-1 is a C 4 -C 5 alkyl group (eg n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or 3-methylbutyl) or benzyl; R 3 -2 is a C 1 -C 4 alkyl group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl); For example, NMe-Leu, NMe-Phe, NMe-HoLeu, NEt-Leu, NPr-Leu, NiPr-Leu, Nbu-Leu, NMe-Nle or NMe-Ile);
  • R 3-1 is a C 4 -C 5
  • XX4 is (E.g Y is -(CR 4-1 R 4-2 )- ⁇ for example -CH 2 -, -CH(OH)- or -CF 2 ⁇ , -(CH 2 ) 2 - or -S-; for example, Aze, Thz , Hyp, Pro, Pro (5Ph), Pro (4Ph), Pro (diF) or HoPro); * labeled carbon atoms are chiral carbon atoms, which are in the R configuration or the S configuration (eg Z is -(CR 4-1 R 4-2 ) n4 - ⁇ for example -CH 2 -, -(CH 2 ) 2 -, -CH(OH)-CH 2 -, -CF 2 -CH 2 -, -CHPh-CH 2 -, -CH 2 -CHPh- or -(CH 2 ) 3 - ⁇ or -S-(CR 4-3 R 4-4 ) n4' - ⁇ eg -S-CH 2
  • XX5 is D-Ser, D-Thr, or D-HoSer
  • XX6 is Gln
  • XX7 is 1Nal, 2Nal, or ⁇ eg Phe, Phe(3-Cl), Phe(3-Me), Phe(3-OMe), Phe(4-OMe), Phe(4-Me) or Phe(4-Cl) ⁇ ; n7 is 0 Or 1, R 7 is a C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl), C 1 -C 4 alkoxy (eg methoxy) a group, a ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group or an isobutoxy group, or a halogen (for example, fluorine or chlorine), the carbon atom labeled with * is a chiral carbon atom, which is an R group.
  • Type or S configuration R 7 may be in the ortho, meta or para position of the
  • XX8 is D-Ala
  • XX9 is Tic, Phe(4-Me), Phe(4-Cl), D-Ti1c, or D-Oic;
  • XX10 is NhomoSer, or the amino group is a C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) Substituted or unsubstituted any of the following amino acids (the "substituted amino acid” such as NMe-Ser or NMe-HoSer): Ser and HoSer;
  • P is a hydroxyl group or an amino group.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX0 is hydrogen
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • R 0-1 is CH 3 -, q is 10-16;
  • PEG is m is 6-10;
  • n 2;
  • All AA0 are independently Gly or ⁇ Ala.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • R 0-1 is CH 3 -, q is 10-16;
  • PEG is m is 8;
  • n 2;
  • All AA0 are independently Gly or ⁇ Ala.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • R 0-2 is R 0-2-1 substituted or unsubstituted C 1 -C 6 alkyl
  • All R 0-2-1 are independently phenyl.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • R 0-3 is R 0-3-1 substituted or unsubstituted C 1 -C 8 alkyl, or R 0-3-2 substituted or unsubstituted phenyl;
  • All R 0-3-1 are independently phenyl or a C 3 -C 6 cycloalkyl
  • All R 0-3-2 are independently halogenated C 1 -C 4 alkyl groups.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX1 is any of the following amino acids in which the amino group is substituted or unsubstituted with one C 1 -C 4 alkyl group: D-Tyr (3F) and D-Tyr.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX2 is any of the following amino acids in which the amino group is substituted or unsubstituted with one C 1 -C 4 alkyl group: 1Nal, 2Nal, Bpa, Phe, Phe(4-Cl) and Phe(4-Me).
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX3 is NMe-Leu, NMe-Phe, NMe-HoLeu, NEt-Leu, NPr-Leu, NiPr-Leu, Nbu-Leu, NMe-Nle or NMe-Ile.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX3 is NMe-Leu, NMe-Phe, NMe-HoLeu, NEt-Leu, NPr-Leu, NiPr-Leu or Nbu-Leu.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX4 is *The labeled carbon atom is a chiral carbon atom which is in the R configuration or the S configuration; Z is -(CR 4-1 R 4-2 ) n4 - or -S-(CR 4-3 R 4-4 ) N4'- ; the right end of the -(CR 4-1 R 4-2 ) n4 - and -S-(CR 4-3 R 4-4 ) n4' - is bonded to a chiral carbon atom; n4 is 1 - 3, n4' is 1 or 2; all of R 4-1 , R 4-2 , R 4-3 and R 4-4 are independently hydrogen, hydroxy, halogen or phenyl.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX4 is Thz, Hyp, Pro, Pro (5Ph), Pro (4Ph) or Pro (diF).
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX4 is Thz, Hyp, Pro, Pro (4Ph) or Pro (diF).
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX5 is D-Ser, D-Thr or D-HoSer.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX6 is Gln.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX7 is 1Nal, 2Nal or N7 is 0 or 1
  • R 7 is a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group or a halogen
  • the *-labeled carbon atom is a chiral carbon atom which is in the R configuration or the S configuration.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX7 is 1Nal, 2Nal or Phe.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX8 is D-Ala.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX9 is Tic, Phe, NMePhe, 1Nal, 2Nal, Bpa, Phe(4-Me), Phe(4-Cl), Phe(4-NO2), HoPhe, Idc, Tic(OH), Oic, Chc, Cha, MeA6c, HoPro, Pro(5Ph), Pro(4Ph), Ala(dip), Bip, azaTic, D-Tic, Ti1c, D-Ti1c, TP5C, TP6C, Tic(6-Me), Ica or D-Oic.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX9 is Tic, Phe, NMePhe, 1Nal, 2Nal, Bpa, Phe(4-Me), Phe(4-Cl), Phe(4-NO2), HoPhe, Idc, Tic(OH), Oic, Chc, Cha, MeA6c, Pro(5Ph), Pro(4Ph), Ala(dip), Bip, azaTic, D-Tic, Ti1c, D-Ti1c, TP5C, TP6C, Tic(6-Me), Ica or D-Oic.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX9 is Tic, Phe(4-Me), Phe(4-Cl), D-Ti1c or D-Oic.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX10 is NHoSer, or any of the following amino acids in which the amino group is substituted or unsubstituted with one C 1 -C 4 alkyl group: Ser and HoSer.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • P is a hydroxyl group.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX0 is hydrogen, R 0-2 or
  • R 0-1 is CH 3 -, q is 10 to 18 (for example, a range of endpoints of any of the following two values: 10, 11, 12, 13, 14, 15, 16, 17, and 18);
  • m is 6 to 10 (for example, a range of endpoints with any of the following two values: 6, 7, 8, 9, and 10);
  • n is 0 to 2 (for example, 0, 1, or 2);
  • All AA0 are independently (eg PEG8), Ahx, Gly or Beta-Ala; all k are independently 4-8 (eg, ranges of endpoints with any of the following two values: 4, 5, 6, 7, and 8), all r Independently 0 or 1;
  • R 0-2-1 R 0-2 is a substituted or unsubstituted C 1 ⁇ C 6 alkyl group (the number of the R 0-2-1 may be one or more ⁇ e.g. 1, 2 , 3, 4 or 5 ⁇ ; when a plurality of R 0-2-1 are present, they are the same or different; all R 0-2-1 may independently be in the C 1 -C 6 alkyl group Tertiary or non-terminal; the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group; the C 1 -C 4 alkyl group may be a methyl group, an ethyl group, a n-propyl group, Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; said "R 0-2-1 substituted C 1 -C 6 alkyl" such as 3,5-dihydroxybenzyl Or 3-phenylpropyl);
  • All R 0-2-1 are independently hydroxy substituted or unsubstituted phenyl (the number of said hydroxyl groups may be one or more ⁇ eg 1, 2, 3, 4 or 5 ⁇ All of the hydroxyl groups may be independently ortho, meta or para to the phenyl group; said "hydroxy substituted phenyl" such as 3,5-dihydroxyphenyl);
  • R 0-3 is R 0-3-1 substituted or unsubstituted C 1 -C 8 alkyl group (the number of R 0-3-1 may be one or more ⁇ for example, 1 or 2 , 3, 4 or 5 ⁇ ; when a plurality of R 0-3-1 are present, they are the same or different; all R 0-3-1 may independently be in the C 1 -C 8 alkyl group Tertiary or non-terminal; the C 1 -C 8 alkyl group may be a C 1 -C 4 alkyl group or a n-pentyl group; the C 1 -C 4 alkyl group may be a methyl group or an ethyl group.
  • R 0-3-2 when there are a plurality of R 0-3-2 , they are the same or different; all R 0-3-2 may be independently at the ortho, meta or para position of the phenyl; the "R 0-3-2 substituted phenyl", for example, 3,5-dihydroxyphenyl, 2,3- Hydroxyphenyl, 2,6-dihydroxyphenyl, 2,3,4-trihydroxyphenyl, 2,3,5-hydroxyphenyl or 4-trifluoromethylphenyl);
  • All R 0-3-1 are independently hydroxy substituted or unsubstituted phenyl (the number of said hydroxyl groups may be one or more ⁇ eg 1, 2, 3, 4 or 5 ⁇ All of the hydroxyl groups may be independently ortho, meta or para to the phenyl group; said "hydroxy substituted phenyl" such as 3,4-dihydroxyphenyl or 3,5-dihydroxyphenyl Or a C 3 -C 6 cycloalkyl group (for example, cyclohexyl);
  • All R 0-3-2 are independently a hydroxyl group or a halogenated C 1 -C 4 alkyl group (the number of said "halogens” may be one or more ⁇ for example, 1, 2, 3 , 4 or 5 ⁇ ; all "halo” may independently be fluorine, chlorine or bromine; when multiple halogens are present, they are the same or different; the C 1 -C 4 alkyl group may be A Base, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; said "halogenated C 1 -C 4 alkyl” such as trifluoromethyl) ;
  • XX1 is an alkyl group having one C 1 -C 4 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and further methyl) a substituted or unsubstituted amino acid (the "substituted amino acid” such as D-NMeTyr): D-Tyr and D-Phe;
  • XX2 is an amino group substituted or unsubstituted with 1 C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) Any of the following amino acids (the "substituted amino acid” such as NMePhe): 1Nal, 2Nal, Bpa and ⁇ eg Phe, Phe(4-Cl) or Phe(4-Me) ⁇ ; n2 is 0 or 1, and R 2 is a C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl) , n-butyl or isobutyl) or halogen (such as fluorine or chlorine), the carbon atom marked by * is a chiral carbon atom, which is in the R configuration or the S configuration (R 2 may be
  • XX3 is Wherein the *-labeled carbon atom is a chiral carbon atom, which is in the R configuration or the S configuration (eg R 3-1 is a C 4 -C 5 alkyl group (eg n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or 3-methylbutyl) or benzyl; R 3 -2 is a C 1 -C 4 alkyl group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl); For example, NMe-Leu, NMe-Phe, NMe-HoLeu, NEt-Leu, NPr-Leu, NiPr-Leu, Nbu-Leu, NMe-Nle or NMe-Ile);
  • R 3-1 is a C 4 -C 5
  • XX4 is Ala or (E.g Y is -(CR 4-1 R 4-2 )- ⁇ for example -CH 2 -, -CH(OH)- or -CF 2 ⁇ , -(CH 2 ) 2 - or -S-; for example, Aze, Thz , Hyp, Pro, Pro (5Ph), Pro (4Ph), Pro (diF) or HoPro); * labeled carbon atoms are chiral carbon atoms, which are in the R configuration or the S configuration (eg Z is -(CR 4-1 R 4-2 ) n4 - ⁇ for example -CH 2 -, -(CH 2 ) 2 -, -CH(OH)-CH 2 -, -CF 2 -CH 2 -, -CHPh-CH 2 -, -CH 2 -CHPh- or -(CH 2 ) 3 - ⁇ or -S-(CR 4-3 R 4-4 ) n4' - ⁇ eg -S
  • XX5 is D-Ser, D-Hyp, D-Thr, ⁇ Ala, D-NMeSer, 2Nal, 1Nal or D-HoSer;
  • XX6 is Gln, NMe-Gln or NGln;
  • XX7 is NMe-Phe, HoPhe, 1Nal, 2Nal, Bpa, D-Ser or ⁇ eg Phe, Phe(3-Cl), Phe(3-Me), Phe(3-OMe), Phe(4-OMe), Phe(4-Me) or Phe(4-Cl) ⁇ ; n7 is 0 Or 1, R 7 is a C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl), C 1 -C 4 alkoxy (eg methoxy) a group, a ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group or an isobutoxy group, or a halogen (for example, fluorine or chlorine), the carbon atom labeled with * is a chiral carbon atom, which is an R group.
  • XX8 is D-Ala, D-NMeAla, Ala or ⁇ Ala;
  • XX9 is Tic, Phe, NMe-Phe, 1Nal, 2Nal, Bpa, Phe(4-Me), Phe(4-Cl), Phe(4-NO2), HoPhe, Idc, Tic(OH), Oic, Chc, Cha, MeA6c, HoPro, Pro(5Ph), Pro(4Ph), Ala(dip), Bip, azaTic, D-Tic, Ti1c, D-Ti1c, TP5C, TP6C, Tic(6-Me), S-Pip, Ica or D-Oic;
  • XX10 is NhomoSer, or the amino group is a C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl)
  • Substituted or unsubstituted any of the following amino acids such as NMe-Ser or NMe-HoSer: Ser, Thr, Hyp, Asp, D-HoSer and HoSer;
  • P is a hydroxyl group or an amino group.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX0 is hydrogen
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • R 0-1 is CH 3 -.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • q is 13 to 15 (for example, 13, 14 or 15).
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • m is 6 to 10 (for example, a range in which the following two values are end points: 6, 7, 8, 9, and 10).
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • n 2.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • All AA0 are independently Gly or ⁇ -Ala.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • R 0-3 is a phenyl-substituted C 1 -C 8 alkyl group (the number of R 0-3-1 may be 1 or 2; all phenyl groups may be independently in the C 1 ⁇ C 6 alkyl group or terminal end; said C 1 ⁇ C 8 alkyl group may be an alkyl group or a n-pentyl group C 1 ⁇ C 4; said C 1 ⁇ C 4 alkyl group may be Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; said "phenyl-substituted C 1 -C 8 alkyl" such as 2- Phenylethyl, 3-phenylpropyl or 4-phenylbutyl).
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX1 is an amino group substituted or unsubstituted with 1 C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) D-Tyr (the "substituted D-Tyr” such as D-NMeTyr).
  • 1 C 1 -C 4 alkyl group eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • D-Tyr the "substituted D-Tyr” such as D-NMeTyr
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX2 is an amino group substituted or unsubstituted with 1 C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) Phe (the "substituted Phe” such as NMe-Phe).
  • 1 C 1 -C 4 alkyl group eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • Phe the "substituted Phe” such as NMe-Phe
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX3 is Wherein the *-labeled carbon atom is a chiral carbon atom, which is in the R configuration or the S configuration (eg R 3-1 is isobutyl, 3-methylbutyl or benzyl; R 3-2 is C 1 -C 3 alkyl (eg methyl, ethyl, n-propyl or isopropyl) (described For example, NMe-Leu, NMe-HoLeu or NMe-Phe).
  • R 3-1 is isobutyl, 3-methylbutyl or benzyl
  • R 3-2 is C 1 -C 3 alkyl (eg methyl, ethyl, n-propyl or isopropyl) (described For example, NMe-Leu, NMe-HoLeu or NMe-Phe).
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX4 is (eg Thz, Pro or Pro (diF)); * The labeled carbon atom is a chiral carbon atom, which is in the R configuration or the S configuration (eg Y is -(CR 4-1 R 4-2 )- (for example -CH 2 - or -CF 2 ) or -S-; R 4-1 and R 4-2 are independently hydrogen or halogen (for example, fluorine Or chlorine).
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX5 is D-Ser or D-HoSer.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX6 is Gln.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX7 is Phe, 1Nal or 2Nal.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX8 is D-Ala.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX9 is Tic, D-Ti1c or D-Oic.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX10 is NHoSer, or the amino group is a C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) Substituted or unsubstituted any of the following amino acids (the "substituted amino acid” such as NMe-Ser or NMe-HoSer): Ser and HoSer.
  • the amino acid such as NMe-Ser or NMe-HoSer
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • P is a hydroxyl group or an amino group.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX0 is hydrogen, R 0-2 or
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • n is 0 to 2 (for example, 0, 1, or 2).
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • All AA0 are independently (eg PEG8), Ahx, Gly or ⁇ Ala; all k are independently 4-8 (eg, ranges of endpoints with the following two values: 4, 5, 6, 7, and 8), all r independently Is 0 or 1.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • R 0-2 is a C 1 -C 6 alkyl group (the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group; the C 1 -C 4 alkyl group may be A Base, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • R 0-3 is R 0-3-1 substituted or unsubstituted C 1 -C 8 alkyl group (the number of R 0-3-1 may be one or more ⁇ for example, 1 or 2 , 3, 4 or 5 ⁇ ; when a plurality of R 0-3-1 are present, they are the same or different; all R 0-3-1 may independently be in the C 1 -C 8 alkyl group Tertiary or non-terminal; the C 1 -C 8 alkyl group may be a C 1 -C 4 alkyl group or a n-pentyl group; the C 1 -C 4 alkyl group may be a methyl group or an ethyl group.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • All R 0-3-1 are independently phenyl or a C 3 -C 6 cycloalkyl group (e.g., cyclohexyl).
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX1 is D-NMeTyr, D-Tyr, D-Phe or D-NMePhe.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX3 is NMe-Leu, NEt-Leu, NPr-Leu, NiPr-Leu, NMe-HoLeu, NMe-Nle or NMe-Ile.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX4 is Thz, Pro, Pro (4Ph), Pro (diF), HoPro or Hyp.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX7 is 1Nal, 2Nal, Bpa, Phe, Phe(3-Cl), Phe(4-Cl), Phe(4-Me), Phe(3-Me), Phe(3-OMe), Phe(4-OMe ) or HoPhe.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX9 is Tic, D-Tic, DTi1c, D-Oic, TP5C or TP6C.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX10 is NMe-Ser, NHoSer, NMe-HoSer, D-HoSer, HoSer or Ser.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • R 0-3 is a phenyl-substituted or unsubstituted C 1 -C 8 alkyl group (the number of the phenyl groups may be one or more ⁇ for example, 1, 2, 3, 4 or 5) All phenyl groups may be independently at the terminal or non-terminal end of the C 1 -C 8 alkyl group; the C 1 -C 8 alkyl group may be a C 1 -C 4 alkyl group or a n-pentyl group; The C 1 -C 4 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; a C 1 -C 8 alkyl group, such as a 2-phenylethyl group, or a hydroxy-substituted or unsubstituted phenyl group (the number of the hydroxyl groups may be one or more
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX1 is D-NMeTyr or D-Tyr.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX3 is NMe-Leu, NEt-Leu or NMe-HoLeu.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX4 is Thz, Pro or Pro (diF).
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX7 is 1Nal, 2Nal or Phe.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX9 is Tic, D-Tic or DTi1c.
  • each group in the compound I can be as follows (unannotated definition as described in any of the preceding schemes):
  • XX10 is NMe-Ser, NHoSer or Ser.
  • the compound I can be any of the following compounds:
  • the present invention also provides the use of the above compound I, a pharmaceutically acceptable salt thereof, a tautomer thereof, a crystal form thereof, a solvate thereof or a prodrug thereof for the preparation of a medicament, which is used for the preparation of a medicament Treat and/or prevent diseases associated with ChemR23.
  • the "Chemical disease associated with ChemR23” includes, but is not limited to, for example, an immune disease, an inflammatory disease, a metabolic disease (such as obesity or diabetes), a cardiovascular disease, a bone disease, a tumor (such as cancer), a reproductive system disease, Mental illness, viral infection, asthma or liver disease.
  • the present invention also provides the use of the above Compound I, a pharmaceutically acceptable salt thereof, a tautomer thereof, a crystal form thereof, a solvate thereof or a prodrug thereof for the preparation of a ChemR23 agonist.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound I, a pharmaceutically acceptable salt thereof, a tautomer thereof, a crystal form thereof, a solvate thereof or a prodrug thereof, and a pharmaceutically acceptable excipient .
  • the pharmaceutical excipients may be those excipients widely used in the field of pharmaceutical production.
  • the excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition, and may also provide means for the subject to be dissolved at the desired rate after administration, or to promote the subject's activity after administration of the composition.
  • the ingredients are effectively absorbed.
  • the pharmaceutical excipient can be an inert filler or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
  • the pharmaceutical excipient may include one or more of the following excipients: binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
  • excipients binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
  • compositions of the present invention can be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.
  • compositions of the present invention may be formulated for administration in any form, including injection (intravenous), mucosa, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, Administration by injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular).
  • the pharmaceutical compositions of the invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres).
  • solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets.
  • liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
  • topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations.
  • preparations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection.
  • suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and ingots Agent.
  • the present invention also provides a peptide compound of the formula II, a pharmaceutically acceptable salt thereof, a tautomer thereof, a solvate thereof, a crystal form thereof or a prodrug thereof;
  • a peptide compound of the formula II a pharmaceutically acceptable salt thereof, a tautomer thereof, a solvate thereof, a crystal form thereof or a prodrug thereof;
  • the present invention also provides the use of the above compound II, a pharmaceutically acceptable salt thereof, a tautomer thereof, a crystal form thereof, a solvate thereof or a prodrug thereof for the preparation of a medicament, which is used for the preparation of a medicament Treat and/or prevent diseases associated with ChemR23.
  • the "Chemical disease associated with ChemR23” includes, but is not limited to, for example, an immune disease, an inflammatory disease, a metabolic disease (such as obesity or diabetes), a cardiovascular disease, a bone disease, a tumor (such as cancer), a reproductive system disease, Mental illness, viral infection, asthma or liver disease.
  • the present invention also provides the use of the above compound II, a pharmaceutically acceptable salt thereof, a tautomer thereof, a crystal form thereof, a solvate thereof or a prodrug thereof for the preparation of a ChemR23 agonist.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound II, a pharmaceutically acceptable salt thereof, a tautomer thereof, a crystal form thereof, a solvate thereof or a prodrug thereof, and a pharmaceutically acceptable excipient .
  • the pharmaceutical excipients may be those excipients widely used in the field of pharmaceutical production.
  • the excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition, and may also provide means for the subject to be dissolved at the desired rate after administration, or to promote the subject's activity after administration of the composition.
  • the ingredients are effectively absorbed.
  • the pharmaceutical excipient can be an inert filler or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
  • the pharmaceutical excipient may include one or more of the following excipients: binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
  • excipients binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
  • compositions of the present invention can be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.
  • compositions of the present invention may be formulated for administration in any form, including injection (intravenous), mucosa, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, Administration by injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular).
  • the pharmaceutical compositions of the invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres).
  • solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets.
  • liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
  • topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations.
  • preparations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection.
  • suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and ingots Agent.
  • the present invention also provides a peptide compound of the formula III, a pharmaceutically acceptable salt thereof, a tautomer thereof, a solvate thereof, a crystalline form thereof or a prodrug thereof;
  • R 0-2-1 R 0-2 is a substituted or unsubstituted C 1 ⁇ C 6 alkyl group (the number of the R 0-2-1 may be one or more ⁇ e.g. 1, 2 , 3, 4 or 5 ⁇ ; when a plurality of R 0-2-1 are present, they are the same or different; all R 0-2-1 may independently be in the C 1 -C 6 alkyl group Tertiary or non-terminal; the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group; the C 1 -C 4 alkyl group may be a methyl group, an ethyl group, a n-propyl group, Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; said "R 0-2-1 substituted C 1 -C 6 alkyl" such as 3,5-dihydroxybenzyl Or 3-phenylpropyl);
  • All R 0-2-1 are independently hydroxy substituted or unsubstituted phenyl (the number of said hydroxyl groups may be one or more ⁇ eg 1, 2, 3, 4 or 5 ⁇ All of the hydroxyl groups may be independently ortho, meta or para to the phenyl group; said "hydroxy substituted phenyl" such as 3,5-dihydroxyphenyl);
  • R 0-3 is R 0-3-1 substituted or unsubstituted C 1 -C 8 alkyl group (the number of R 0-3-1 may be one or more ⁇ for example, 1 or 2 , 3, 4 or 5 ⁇ ; when a plurality of R 0-3-1 are present, they are the same or different; all R 0-3-1 may independently be in the C 1 -C 8 alkyl group Tertiary or non-terminal; the C 1 -C 8 alkyl group may be a C 1 -C 4 alkyl group or a n-pentyl group; the C 1 -C 4 alkyl group may be a methyl group or an ethyl group.
  • R 0-3-1 substituted C 1 -C 8 alkyl such as 2-phenyl Ethyl, 3-phenylpropyl, 4-phenylbutyl, 4-phenylbenzyl, diphenylmethyl, 3,4-dihydroxybenzyl, 3,5-dihydroxybenzyl, biphenyl- 4-ylmethyl or cyclohexylmethyl), or R 0-3-2 substituted or unsubstituted phenyl (the number of said R 0-3-2 may be one or more ⁇ for example 1 , 2, 3, 4 or 5 ⁇ ; when multiple R 0-3-2 are present, they are the same or different; all R 0-3-2 may be independently in the ortho position of the phenyl group , meta or para; said "R 0-3-2 substituted phenyl” such as 3,5-di Hydroxyphenyl, 2,3-dihydroxy
  • All R 0-3-1 are independently hydroxy substituted or unsubstituted phenyl (the number of said hydroxyl groups may be one or more ⁇ eg 1, 2, 3, 4 or 5 ⁇ All of the hydroxyl groups may be independently ortho, meta or para to the phenyl group; said "hydroxy substituted phenyl" such as 3,4-dihydroxyphenyl or 3,5-dihydroxyphenyl a biphenyl group, or a C 3 -C 6 cycloalkyl group (for example, a cyclohexyl group);
  • All R 0-3-2 are independently a hydroxyl group or a halogenated C 1 -C 4 alkyl group (the number of said "halogens” may be one or more ⁇ for example, 1, 2, 3 , 4 or 5 ⁇ ; all "halo” may independently be fluorine, chlorine or bromine; when multiple halogens are present, they are the same or different; the C 1 -C 4 alkyl group may be A Base, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; said "halogenated C 1 -C 4 alkyl” such as trifluoromethyl) ;
  • R 0-4 is R 0-4-1 substituted or unsubstituted C 1 -C 8 alkyl group (the number of R 0-4-1 may be one or more ⁇ for example, 1 or 2 , 3, 4 or 5 ⁇ ; when a plurality of R 0-4-1 are present, they are the same or different; all R 0-4-1 may independently be in the C 1 -C 8 alkyl group Tertiary or non-terminal; the C 1 -C 8 alkyl group may be a C 1 -C 4 alkyl group or a n-pentyl group; the C 1 -C 4 alkyl group may be a methyl group or an ethyl group.
  • All R 0-4-1 are independently hydroxy substituted or unsubstituted phenyl (the number of said hydroxyl groups may be one or more ⁇ eg 1, 2, 3, 4 or 5 ⁇ All of the hydroxyl groups may be independently ortho, meta or para to the phenyl group; said "hydroxy substituted phenyl" such as 3,4-dihydroxyphenyl or 3,5-dihydroxyphenyl Or a C 3 -C 6 cycloalkyl group (for example, cyclohexyl);
  • R 0-5 is a R 0-5-1 substituted or unsubstituted C 1 -C 8 alkyl group (the number of R 0-5-1 may be one or more ⁇ for example, 1 or 2 , 3, 4 or 5 ⁇ ; when a plurality of R 0-5-1 are present, they are the same or different; all R 0-5-1 may independently be in the C 1 -C 8 alkyl group Tertiary or non-terminal; the C 1 -C 8 alkyl group may be a C 1 -C 4 alkyl group or a n-pentyl group; the C 1 -C 4 alkyl group may be a methyl group or an ethyl group.
  • All R 0-5-1 are independently hydroxy substituted or unsubstituted phenyl (the number of said hydroxyl groups may be one or more ⁇ eg 1, 2, 3, 4 or 5 ⁇ All of the hydroxyl groups may be independently ortho, meta or para to the phenyl group; said "hydroxy substituted phenyl" such as 3,4-dihydroxyphenyl or 3,5-dihydroxyphenyl Or a C 3 -C 6 cycloalkyl group (for example, cyclohexyl);
  • XX1 is an alkyl group having one C 1 -C 4 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and further methyl) a substituted or unsubstituted D-Tyr (the "substituted amino acid" such as D-NMeTyr);
  • XX2 is an amino group substituted or unsubstituted with 1 C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) Any of the following amino acids (the "substituted amino acids” such as NMePhe): ⁇ eg Phe, Phe(4-Cl) or Phe(4-Me) ⁇ ; n2 is 0 or 1, and R 2 is a C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl) , n-butyl or isobutyl) or halogen (such as fluorine or chlorine), the carbon atom marked by * is a chiral carbon atom, which is in the R configuration or the S configuration (R 2 may be in the ortho position of the phenyl group,
  • XX3 is Wherein the *-labeled carbon atom is a chiral carbon atom, which is in the R configuration or the S configuration (eg R 3-1 is a C 4 -C 5 alkyl group (eg n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or 3-methylbutyl) or benzyl; R 3 -2 is hydrogen or a C 1 -C 4 alkyl group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl); For example, Leu, NMe-Leu, NMe-Phe, NMe-HoLeu, NEt-Leu, NPr-Leu, NiPr-Leu, Nbu-Leu, NMe-Nle or NMe-Ile);
  • R 3-1 is a C
  • XX4 is (E.g Y is -(CR 4-1 R 4-2 )- ⁇ for example -CH 2 -, -CH(OH)- or -CF 2 ⁇ , -(CH 2 ) 2 - or -S-; for example, Aze, Thz , Hyp, Pro, Pro (5Ph), Pro (4Ph), Pro (diF) or HoPro); * labeled carbon atoms are chiral carbon atoms, which are in the R configuration or the S configuration (eg Z is -(CR 4-1 R 4-2 ) n4 - ⁇ for example -CH 2 -, -(CH 2 ) 2 -, -CH(OH)-CH 2 -, -CF 2 -CH 2 -, -CHPh-CH 2 -, -CH 2 -CHPh- or -(CH 2 ) 3 - ⁇ or -S-(CR 4-3 R 4-4 ) n4' - ⁇ eg -S-CH 2
  • XX5 is D-Ser
  • XX6 is Gln
  • XX7 is ⁇ eg Phe, Phe(3-Cl), Phe(3-Me), Phe(3-OMe), Phe(4-OMe), Phe(4-Me) or Phe(4-Cl) ⁇ ; n7 is 0 Or 1, R 7 is a C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl), C 1 -C 4 alkoxy (eg methoxy) a group, a ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group or an isobutoxy group, or a halogen (for example, fluorine or chlorine), the carbon atom labeled with * is a chiral carbon atom, which is an R group.
  • Type or S configuration R 7 may be in the ortho, meta or para position of the phenyl group, for example,
  • XX8 is D-Ala
  • XX9 is Tic
  • XX10 is an amino group substituted or unsubstituted with 1 C 1 -C 4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) Ser (the "substituted amino acid” such as NMe-Ser);
  • P is a hydroxyl group or an amino group.
  • the compound III can be any of the following compounds:
  • the present invention also provides the use of the above compound III, a pharmaceutically acceptable salt thereof, a tautomer thereof, a crystal form thereof, a solvate thereof or a prodrug thereof for the preparation of a medicament, which is used for the preparation of a medicament Treat and/or prevent diseases associated with ChemR23.
  • the "Chemical disease associated with ChemR23” includes, but is not limited to, for example, an immune disease, an inflammatory disease, a metabolic disease (such as obesity or diabetes), a cardiovascular disease, a bone disease, a tumor (such as cancer), a reproductive system disease, Mental illness, viral infection, asthma or liver disease.
  • the present invention also provides the use of the above compound III, a pharmaceutically acceptable salt thereof, a tautomer thereof, a crystal form thereof, a solvate thereof or a prodrug thereof for the preparation of a ChemR23 agonist.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound III, a pharmaceutically acceptable salt thereof, a tautomer thereof, a crystal form thereof, a solvate thereof or a prodrug thereof, and a pharmaceutically acceptable excipient .
  • the pharmaceutical excipients may be those excipients widely used in the field of pharmaceutical production.
  • the excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition, and may also provide means for the subject to be dissolved at the desired rate after administration, or to promote the subject's activity after administration of the composition.
  • the ingredients are effectively absorbed.
  • the pharmaceutical excipient can be an inert filler or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
  • the pharmaceutical excipient may include one or more of the following excipients: binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
  • excipients binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
  • compositions of the present invention can be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.
  • compositions of the present invention may be formulated for administration in any form, including injection (intravenous), mucosa, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, Administration by injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular).
  • the pharmaceutical compositions of the invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres).
  • solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets.
  • liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
  • topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations.
  • preparations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection.
  • suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and ingots Agent.
  • the reagents and starting materials used in the present invention are commercially available.
  • XX0 when XX0 is hydrogen, R 0-2 or "XX0-XX1" means a group formed by linking an amino group in XX0 and XX1 (an amino group on a chiral carbon atom or a primary amino group when a plurality of amino groups are present in an amino acid), that is, XX0 is substituted. A hydrogen atom on the amino group in XX1.
  • XX0 The connection with PEG is the same. For example, when XX0 is methyl and XX1 is Phe, "XX0-XX1" means
  • XX1-XX2 means a carboxyl group in XX1 (which may be a carboxyl group on a chiral carbon atom when a plurality of carboxyl groups are present in an amino acid) and an amino group in XX2 (when an amino group has a plurality of amino groups, it may be a hand) Amino groups on a carbon atom, which may also be formed by the attachment of a primary amino group Group.
  • XX10-P refers to a group formed by the substitution of -OH in the carboxyl group (-COOH) of XX10 by P.
  • XX10-P is Means
  • XX10-P means Phe itself. If the right end of the specific sequence ends with amino acid (XX10), it is not clear which group -P is, indicating that the default P is -OH.
  • amino acid includes water-soluble organic compounds having a carboxyl (-COOH) and amino (-NH 2 ) group attached to an a-carbon atom.
  • Amino acids can be represented by the formula R-CH(NH 2 )COOH; the R group is hydrogen or an organic group and determines the nature of any particular amino acid. When R is not hydrogen, the tetrahedral arrangement of four different groups around the a-carbon atom renders the amino acid optically active. The two mirror images are referred to as the L-isomer and the D-isomer.
  • L-amino acids are components of proteins such as eukaryotic proteins.
  • the peptide molecules of the invention comprise L-amino acids.
  • a D-amino acid is present in a peptide molecule of the invention, it is represented by a conventional one-letter amino acid code with the prefix "(D)".
  • the molecule of the present invention may comprise a peptide sequence having an "arbitrary D-amino acid” at a specific position or a peptide sequence having an "arbitrary D-amino acid” at a specific position.
  • the "arbitrary D-amino acid” includes any natural or non-natural (eg, chemically modified) D-amino acid at a particular position in the sequence.
  • Examples of natural D-amino acids are as follows: D-alanine; D-aspartic acid; D-cysteine; D-glutamic acid; D-phenylalanine; D-glycine; D-histidine D-isoleucine; D-lysine; D-leucine; D-methionine; D-asparagine; D-valine; D-glutamine; D-arginine; D- Serine; D-threonine; D-valine; D-tryptophan; D-tyrosine.
  • non-natural D-amino acids are as follows: naphthylalanine; D-pyridylalanine; D-tert-butylserine; D-ornithine; D- ⁇ -aminolysine; D-homoarginine ; D- ⁇ methyl leucine and the substitution of halogens (such as F) and protons in these other unnatural amino acids.
  • the amino acid By forming a peptide bond, the amino acid combines to form a short chain (peptide) or a longer chain (polypeptide).
  • Proteins and/or peptides are known to be composed of approximately 20 common amino acids in different flow ratios, the sequence of which determines the shape, properties and biological effects of the protein and/or peptide.
  • Amino acid residues in such peptides or polypeptide chains are usually represented by their arrangement on the chain, and the first position (ie, position 1) is designated as the N-terminal amino acid of the chain.
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt.
  • exemplary acid salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acid phosphates, isoniazids Acid salt, lactate, salicylate, acid citrate, tartrate, oleate, tannic acid, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, Fumarate, gluconate, glucuronate, sugar, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, besylate, P-toluenesulfonate and pamoate (i.e., 1-1-methylene-bis(2-hydroxy-3-naphthoate)).
  • Suitable base salts include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, barium salts, and diethanolamine salts.
  • Suitable base salts include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, barium salts, and diethanolamine salts.
  • crystalline form refers to one or more crystal structures formed by the different arrangement of molecules in the lattice space upon crystallization.
  • solvate is a crystalline form which, in addition to the active molecule, contains one or more solvent molecules incorporated into the crystal structure.
  • the solvate may include a stoichiometric or non-stoichiometric amount of solvent, and the solvent molecules in the solvent may be present in an ordered or non-ordered arrangement. Solvates containing non-stoichiometric amounts of solvent molecules may be obtained by the solvate losing at least a portion, but not all, of the solvent molecules.
  • a solvate is a hydrate, meaning that the crystalline form of the compound can include water molecules.
  • prodrug refers to a derivative of a compound comprising a biologically reactive functional group such that under biological conditions (in vitro or in vivo), the bioreactive functional group can be cleaved from the compound or otherwise reacted to provide the compound.
  • the prodrug is inactive, or at least less active than the compound itself, such that the compound does not exert its activity until it is cleaved from the biologically reactive functional group.
  • the bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound.
  • a prodrug can comprise a biohydrolyzable group
  • biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, Biohydrolyzable carbamate and biohydrolyzable ureide.
  • the positive progress of the present invention is that the peptide compound of the present invention has better stability and better activity.
  • the peptide sequences of the molecules of the invention can be synthesized by the Fmoc-polyamide solid phase peptide synthesis disclosed in Lu et al (1981) J. Org. Chem. 46, 3433 and references therein.
  • the 9-fluorenylmethoxycarbonyl (Fmoc) group provides temporary N-amino protection. Repeated removal of this highly base labile protecting group was carried out using 20% piperidine in N,N-dimethylformamide.
  • the side chain functional group can be protected as its butyl ether (for the case of serine, threonine and tyrosine), butyl ester (for the case of glutamic acid and aspartic acid), butoxycarboxy derivative ( In the case of lysine and histidine), a trityl derivative (for the case of cysteine) and a 4-methoxy-2,3,6-trimethylbenzenesulfonyl derivative (for The case of arginine).
  • the C-terminal residue is glutamine or asparagine
  • the 4,4'-dimethoxybenzhydryl group is used to protect the side chain amino functionality.
  • the solid phase carrier is based on polydimethylene consisting of three monomers: dimethyl acrylamide (backbone monomer), bisacryloylethylenediamine (crosslinking agent) and acryloyl sarcosinate methyl ester (functionalizing agent). Alkyl-acrylamide polymer.
  • the peptide-resin cleavable linker used is an acid labile 4-hydroxymethyl-phenoxyacetic acid derivative. Except for asparagine and glutamine, all amino acid derivatives were added as their pre-formed symmetrical anhydride derivatives, and reverse N,N-dicyclohexylcarbodiimide/1-hydroxybenzotriazole was used. The coupling method was introduced by adding asparagine and glutamine.
  • Any scavenger present is removed by a simple extraction step in which the crude peptide free of scavenger is provided by freeze-drying the aqueous phase.
  • Reagents for peptide synthesis are generally available from Calbiochem-Novabiochem (UK) Ltd, Nottingham NG7 2QJ, UK. Purification can be achieved by any one or combination of techniques such as size exclusion chromatography, ion exchange chromatography, and (primarily) reverse phase high performance liquid chromatography. Analysis of the peptide can be carried out using thin layer chromatography, reversed phase high performance liquid chromatography, amino acid analysis after acid hydrolysis, and rapid atom bombardment (FAB) mass spectrometry.
  • FAB rapid atom bombardment
  • peptide sequences of the molecules of the invention can also be synthesized using liquid phase methods well known to those skilled in the chemical and biochemical arts.
  • Step 1 The polypeptide is synthesized by standard Fmoc chemistry, and the basic operation is as follows. 600 mg of commercially available 2-CTC resin (1.4 mol/g) was swollen in DCM (10 mL), swelled for 30 min, and Fmoc-Ser(tBu)-OH (120 mg, 0.31 mmol), DIPEA (1 mL, 5.7 mmol) was added. The mixture was treated at room temperature for 3 hours, then methanol (0.5 mL) was added, and the mixture was shaken for 1 hour to terminate the unreacted resin.
  • the resin was washed with DMF, and a 20% piperidine/DMF solution (10 mL) was added and reacted for 20 min, and repeated twice to remove Fmoc.
  • the resin was washed with DMF, and a solution of Fmoc-Tic-OH (359 mg, 0.9 mmol), HATU (342 mg, 0.9 mmol), HOBT (121 mg, 0.9 mmol) in DMF, 10 mL, then DIPEA (350 mg, 2.7 mmol) at room temperature The reaction was carried out for 2 hours to obtain Fmoc-Tic-Ser(tBu)-2-CTC resin.
  • Step 2 (conventional peptide cleavage method): Add the dried resin to 10 mL of TFA/TIS/H 2 O (90/5/5) solution, then shake for 2 hours, remove the resin by filtration, and use 2 mL of TFA/TIS/H. 2 O (90/5/5) solution wash resin. The filtrate was combined, diethyl ether (70 mL) was added to the filtrate, and the mixture was allowed to stand at room temperature for 30 minutes. The obtained mixture was centrifuged at 3,000 rpm for 1 minute, and the crude polypeptide was washed with diethyl ether (50 mL ⁇ 2) and dried.
  • Step 3 The crude product was subjected to a linear gradient elution (10 min) at a flow rate of 50 mL/min, eluent A/B: 80/20-55/45, using: eluent A: 0.05% TFA in water, washed Deliquoring B: 0.05% TFA in acetonitrile on a preparative HPLC using Sunfire C18, 10um, Column (3 x 100 mm). The fractions containing the product were collected and lyophilized to give 500 mg of a white solid.
  • the resin obtained in the first step of Example 1 was swollen with DMF, and then condensed with 3-phenylpropanoic acid (3equivalent), HBTU/HOBt/DIPEA was subjected to condensation conditions, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours.
  • the resin is dried after washing.
  • the polypeptide of interest is cleaved from the resin by the method of step 2 and removed for protection.
  • the crude product YW-71 was purified by HPLC, eluting with a gradient gradient (8.5 min), with a flow rate of 30 mL/min, eluent A/B: 53/47-44/56, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 20.2 mg of a white solid.
  • the crude product of the crude product of Example 1 was dissolved in DMF (4 mL) with phenylethyl isocyanate (132 mg, 0.9 mmol) and diisopropylethylamine (113 mg, 0.9 mmol).
  • a reaction solution containing the product phenethylcarbamothioyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser was obtained.
  • the crude product was subjected to a linear gradient elution (8.5 min) at a flow rate of 30 mL/min, eluent A/B: 53/47-44/56, using: eluent A: 0.05% TFA in water, eluent B : 0.05% TFA in acetonitrile on a preparative HPLC using 2 ⁇ Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 80 mg of a white solid.
  • the crude product of the crude product of Example 1 was purified without purification with phenylthioisocyanate (40 mg, 0.3 mmol) and diisopropylethylamine (113 mg, 0.9 mmol) in DMF (4 mL).
  • a reaction solution containing the product phenethyl isothiocyanate-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser was obtained.
  • the crude product was subjected to a linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 51/49-44/56, using: eluent A: 0.07% ammonium bicarbonate and 0.05% aqueous ammonia Aqueous solution, eluent B: acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 13.7 mg of a white solid.
  • the dried resin was added to 5 mL of TFA/TIS/H 2 O (95/2.5/2.5) solution, followed by shaking for 2.5 hours, and the resin was removed by filtration, using 2 mL of TFA/TIS/H 2 O (90/5/5). The solution washes the resin. The filtrate was combined, diethyl ether (50 mL) was added to the filtrate, and the mixture was allowed to stand at room temperature for 30 minutes, and the resulting mixture was centrifuged at 3000 rpm for 1 minute to remove the supernatant liquid.
  • the resulting precipitate was dissolved in DMF, followed by a linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 69/31-63/37, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 13.7 mg of a white solid.
  • Example 2 The synthesis method of Example 2 was carried out by condensation with 4-phenylpropanoic acid (3equivalent), HBTU/HOBt/DIPEA as a condensation condition, and DMF as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-75 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (8.5 minutes) at a flow rate of 30 mL/min, eluent A/B: 51.5/48.5-43/57, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 20.6 mg of a white solid.
  • Example 2 A synthesis similar to that of Example 2 was carried out by condensation with 5-phenylvaleric acid (3equivalent), HBTU/HOBt/DIPEA as a condensation condition, and DMF as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-76 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (8.5 minutes) at a flow rate of 30 mL/min, eluent A/B: 49/51-41/59, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 20.7 mg of a white solid.
  • Example 2 The synthesis method of Example 2 was carried out by condensation with 4-biphenyl acetic acid (3equivalent), HBTU/HOBt/DIPEA as a condensation condition, and DMF as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-77 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (8.5 min) at a flow rate of 30 mL/min, eluent A/B: 48/52-40/60, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 20.8 mg of a white solid.
  • a synthesis method similar to that of Example 2 was carried out by diphenylacetic acid (3equivalent) condensation, HBTU/HOBt/DIPEA as a condensation condition, and DMF as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-78 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (8.5 minutes) at a flow rate of 30 mL/min, eluent A/B: 49/51-41/59, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 20.9 mg of a white solid.
  • a synthesis method similar to that of Example 2 was carried out by condensation with 3,5-dihydroxybenzoic acid (3equivalent), HATU/HOAt/DIPEA as a condensation condition, and DMF as a solvent, and the mixture was reacted at room temperature for 5 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-79 was purified by HPLC, eluting with a gradient gradient (8.5 min), with a flow rate of 30 mL/min, eluent A/B: 60/40-53/47, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 21.3 mg of a white solid.
  • the crude product YW-90 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 76/24-68/32, using: eluent A: 0.05% An aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 9.8 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-Pro(5Ph)-OH(3equivalent) was used instead of Fmoc-Tic condensation, and HBTU/HOBt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-91 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 73/27-63/37, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 20.1 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-Pro(4Ph)-OH(3equivalent) was used instead of Fmoc-Tic condensation, and HBTU/HOBt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-92 was subjected to HPLC separation and purification, and subjected to linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 70/30-60/40, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 20.1 mg of a white solid.
  • the crude product YW-93 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 74/26-64/36, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Phenomenex Gemini C18, 10um, Column (21.2 x 250 mm). The product-containing fractions were collected and lyophilized to give a white solid (24.9 g) of white solid.
  • the crude product YW-94 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 69/31-63/37, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 20.2 mg of a white solid.
  • the crude product YW-95 was purified by HPLC, eluting with a gradient gradient (8.5 min), with a flow rate of 30 mL/min, eluent A/B: 61/39-55/45, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 20.6 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-HoPro-OH (3equivalent) was used instead of Fmoc-Pro condensation, and HBTU/HOBt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-96 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 72/28-66/34, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give a white solid.
  • the crude product YW-97 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 61/39-54/46, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 38.4 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-NMe-Leu (3equivalent) was used instead of Fmoc-Leu condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-98 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 73/27-63/37, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 24.9 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-NMe-Val (3equivalent) was used instead of Fmoc-Leu condensation, HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-99 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 76/24-70/30, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 19.5 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-NMe-Phe (3equivalent) was used instead of Fmoc-Leu condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-100 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (8.5 minutes) at a flow rate of 30 mL/min, eluent A/B: 65/35-59/41, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 5.8 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-NMe-HoLeu (3equivalent) was used instead of Fmoc-Leu condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-101 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (8.5 min) at a flow rate of 30 mL/min, eluent A/B: 65/35-59/41, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 25.2 mg of a white solid.
  • Step 1 600 mg of commercially available 2-CTC resin (1.4 mol/g) was swollen in DCM (10 mL), swollen for 30 min, and added Fmoc-Ser(tBu)-OH (120 mg, 0.31 mmol), DIPEA (1 mL) 5.7 mmol), treated at room temperature for 3 hours, then methanol (0.5 mL) was added and shaken for 1 hour to terminate the unreacted resin. The resin was washed with DMF, and a 20% piperidine/DMF solution (10 mL) was added and reacted for 20 min, and repeated twice to remove Fmoc.
  • the resin was washed with DMF, and a solution of Fmoc-Tic-OH (600 mg, 1.5 mmol), HATU (570 mg, 1.5 mmol), HOBT (202 mg, 1.5 mmol) in DMF, 10 mL, then DIPEA (580 mg, 4.5 mmol) at room temperature The reaction was carried out for 2 hours to obtain Fmoc-Tic-Ser(tBu)-2-CTC.
  • Other amino acids were introduced in a similar manner to give Pro-[D-Ser(tBu)]-Gln(Trt)-Phe-(D-Ala)-Tic-Ser(tBu)-CTC resin.
  • Step 2 A solution of bromoacetic acid (348 mg, 2.5 mmol) and DIC (630 mg, 5 mmol) in DMF (10 mL) was added to the above mixture, and the mixture was reacted at room temperature for 1 hour, filtered, and the resin was washed with DMF (10 mL ⁇ 6). Then, a solution of 2-methylpropylamine hydrochloride (413 mg, 3.77 mmol), triethylamine (760 mg, 7.52 mmol), DMSO (1 mL) in DMF (10 mL).
  • the resin was washed with DMF (10 mL ⁇ 6) to give NLeu-Pro-[D-Ser(tBu)]-Gln(Trt)-Phe-(D-Ala)-Tic-Ser(tBu)-CTC resin.
  • Step 3 The last 2 amino acid cycles were attached to the above resin using a Fmoc protection and an amino acid coupling reaction.
  • the resin was washed with DCM, methanol, and methyl t-butyl ether, and then dried to give s.
  • Step 4 Add the dried resin to 10 mL of TFA/TIS/H 2 O (95/2.5/2.5) solution, then shake for 2.5 hours, remove the resin by filtration, and use 2 mL of TFA/TIS/H 2 O (90/5). /5) Solution washing resin. The filtrate was combined, diethyl ether (50 mL) was added to the filtrate, and the mixture was allowed to stand at room temperature for 30 minutes, and the resulting mixture was centrifuged at 3000 rpm for 1 minute to remove the supernatant liquid.
  • the resulting precipitate was dissolved in DMF, followed by a linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 71/29-65/35, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 28 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-D-NMeTyr (3equivalent) was used instead of Fmoc-D-Tyr condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-103 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (8.5 minutes) at a flow rate of 20 mL/min, eluent A/B: 73/27-66/34, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 28.5 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-NMe-Phe (3equivalent) was used instead of Fmoc-Phe condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-104 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (8.5 min) at a flow rate of 30 mL/min, eluent A/B: 62/38-55/45, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 28.6 mg of a white solid.
  • Fmoc-NMe-Leu (3equivalent) was used instead of Fmoc-Leu condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours.
  • Fmoc-NMe-Phe (3equivalent) was used instead of Fmoc-Phe condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-105 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (8.5 minutes) at a flow rate of 30 mL/min, eluent A/B: 66.5/33.5-59/41, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 20.3 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-NMe-D-Ser (3equivalent) was used instead of Fmoc-D-Ser condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-106 was subjected to HPLC separation and purification, and subjected to linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 71/29-65/35, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 27.3 mg of a white solid.
  • the crude product YW-107 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 70/30-63/37, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 29.1 mg of white solid.
  • Step 2 A solution of bromoacetic acid (348 mg, 2.5 mmol) and DIC (630 mg, 5 mmol) in DMF (10 mL) was added to the above mixture, and the mixture was reacted at room temperature for 1 hour, filtered, and the resin was washed with DMF (10 mL ⁇ 6). Then, a solution of 3-aminopropionamide hydrochloride (470 mg, 3.77 mmol), triethylamine (760 mg, 7.52 mmol), DMSO (1 mL) in DMF (10 mL). The resin was washed with DMF (10 mL ⁇ 6) to give NGln-Phe-(D-Ala)-Tic-Ser(tBu)-CTC resin.
  • Step 3 The last 5 amino acid cycles were coupled to the above resin using de-Fmoc protection and amino acid coupling reactions.
  • the resin was washed with DCM, methanol, methyl tert-butyl ether, and then dried to give 900 mg of yellow resin.
  • Step 4 Add the dried resin to 10 mL of TFA/TIS/H 2 O (95/2.5/2.5) solution, then shake for 2.5 hours, remove the resin by filtration, and use 2 mL of TFA/TIS/H 2 O (95/2.5 /2.5) Solution wash resin.
  • the filtrate was combined, diethyl ether (50 mL) was added to the filtrate, and the mixture was allowed to stand at room temperature for 30 minutes, and the resulting mixture was centrifuged at 3000 rpm for 1 minute to remove the supernatant liquid.
  • the resulting precipitate was dissolved in DMF, followed by a linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 71/29-65/35, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 16 mg of a white solid.
  • the crude product YW-109 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (8.5 minutes) at a flow rate of 30 mL/min, eluent A/B: 66.5/33.5-59/41, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 28.2 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-NMe-Ser (3equivalent) was used instead of Fmoc-Ser condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-110 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (8.5 minutes) at a flow rate of 30 mL/min, eluent A/B: 66/34-59/41, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 22.8 mg of white solid.
  • Example 2 In a similar manner to the synthesis of Example 2 (YW-71), Fmoc-NMe-Leu (3equivalent) was used instead of Fmoc-Leu condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-111 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 20 mL/min, eluent A/B: 60/40-50/50, use: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 28.8 mg of a white solid.
  • Fmoc-Pro (5-Phenyl) (3equivalent) was used instead of Fmoc-Pro condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-112 was subjected to HPLC separation and purification, and subjected to a linear gradient elution (10 min) at a flow rate of 20 mL/min, eluent A/B: 66/34-59/41, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 5um, Column (19 x 150 mm). The fractions containing the product were collected and lyophilized to give 23.5 mg of a white solid.
  • the crude product YW-113 was subjected to HPLC separation and purification, and subjected to linear gradient elution (8.5 minutes) at a flow rate of 30 mL/min, eluent A/B: 60/40-52/48, using: eluent A: 0.05% Aqueous solution of TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 26.9 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-Thz (3equivalent) was used instead of Fmoc-Pro condensation, HBTU/HOBt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed. The crude product YW-114 was purified by HPLC.
  • the crude product was subjected to a gradient gradient elution (8.5 min) with a flow rate of 30 mL/min, eluent A/B: 64/36-59/41, using: eluent A: An aqueous solution of 0.05% TFA, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 7.1 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-Aze (3equivalent) was used instead of Fmoc-Pro condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-115 was purified by HPLC, eluting with a gradient gradient (8.5 min), flow rate 30mL/min, eluent A/B: 67/33-59/41, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using SHIMADAZU C18, 10um, Column (2 x 21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 25.7 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-1-Nal (3equivalent) was used instead of Fmoc-Phe condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-117 was purified by HPLC, eluting with a gradient gradient (10 min), with a flow rate of 25 mL/min, eluent A/B: 68/32-58/42, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 25.8 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-2Nal (3equivalent) was used instead of Fmoc-Phe condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-118 was purified by HPLC, eluting with a gradient gradient (10 min) at a flow rate of 25 mL/min, eluent A/B: 71/29-63/37, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 25.4 mg of a white solid.
  • Example 2 In a similar manner to the synthesis of Example 1, Fmoc-Bpa (3equivalent) was used instead of Fmoc-Phe condensation, and HATU/HOAt/DIPEA was used as a condensation condition, and DMF was used as a solvent, and the mixture was reacted at room temperature for 3 hours. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-119 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 72/28-62/38, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 24.4 mg of a white solid.
  • Example 1 In a similar manner to the synthesis of Example 1, Fmoc-NMe-Leu (3equivalent) was used instead of Fmoc-Leu condensation, and HATU/HOAt/DIPEA was a condensation condition. Fmoc-Thz (3equivalent) was used instead of Fmoc-Pro condensation, and HBTU/HOBt/DIPEA was a condensation condition. The condensation and de-Fmoc protection conditions of other residues were consistent with Example 1. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-121 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 73/27-63/37, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 27.2 mg of a white solid.
  • Example 40 In a similar manner to the synthesis of Example 40, Fmoc-2Nal (3equivalent) was used instead of Fmoc-Phe condensation, and HATU/HOAt/DIPEA was a condensation condition. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-122 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 70/30-60/40, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 20.4 mg of a white solid.
  • Example 40 In a similar manner to the synthesis of Example 40, Fmoc-NMe-D-Tyr(tBu)(3equivalent) was used instead of Fmoc-D-Tyr(tBu) condensation, and HATU/HOAt/DIPEA was a condensation condition. Fmoc-Ser(tBu)(3equivalent) was used instead of Fmoc-Ser(tBu) condensation, and HATU/HOAt/DIPEA was a condensation condition. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-124 was purified by HPLC, eluting with a linear gradient (10 min), with a flow rate of 25 mL/min, eluent A/B: 73/27-63/37, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 12.8 mg of a white solid.
  • Example 42 In a similar manner to the synthesis of Example 42, Fmoc-2Nal (3equivalent) was used instead of Fmoc-Phe condensation, and HATU/HOAt/DIPEA was a condensation condition. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-125 was purified by HPLC, eluting with a gradient gradient (10 min), with a flow rate of 25 mL/min, eluent A/B: 70/30-51/49, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Phenomenex Gemini C18, 10um, Column (21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 53.7 mg of white solid.
  • the Fmoc protecting group is removed by a conventional method, and the obtained resin is swollen with DMF, and then condensed with 3,5-dihydroxybenzoic acid (3equivalent), and HBTU/HOBt/DIPEA is a condensation condition.
  • the mixture was reacted at room temperature overnight using DMF as a solvent.
  • the resin is dried after washing.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-126 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 74/26-64/36, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 500 mg of a white solid.
  • the crude product YW-127 was purified by HPLC, eluting with a linear gradient (10 min), with a flow rate of 25 mL/min, eluent A/B: 65/35-55/45, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give a white solid.
  • the crude product YW-128 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 64/36-54/46, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give a white solid.
  • the crude product YW-129 was purified by HPLC, eluting with a linear gradient (10 min), with a flow rate of 25 mL/min, eluent A/B: 65/35-58/42, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 5.9 mg of a white solid.
  • the crude product YW-132 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 67/33-57/43, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 9.3 mg of a white solid.
  • Palm-PEG8-Gly-Gly-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH (Compound YW-133 Preparation
  • the Fmoc protecting group was removed by a conventional method, and other amino acids (Fmoc-Gly-OH, 2 times), and Fmoc-(PEG) 8-OH and a fatty chain were similarly ( Palmitic acid) introduces protected Palm-PEG8-Gly-Gly-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser - CTC resin.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-133 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 34/66-27/73, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 33.2 mg of a white solid.
  • Palm-PEG8- ⁇ Ala- ⁇ Ala-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH (Compound YW-134 Preparation
  • the Fmoc protecting group was removed by a conventional method, and other amino acids (Fmoc- ⁇ Ala-OH, 2 times), and Fmoc-(PEG)8-OH and a fatty chain were similarly (in the similar manner) Palmitic acid) introduces protected Palm-PEG8- ⁇ Ala- ⁇ Ala-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser - CTC resin.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-134 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 36/64-26/74, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 404.0 mg of white solid.
  • Example 42 In a similar manner to the synthesis of Example 42, Fmoc-1Nal (3equivalent) was used instead of Fmoc-Phe condensation, and HATU/HOAt/DIPEA was a condensation condition. The resin is dried after washing. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-142 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate of 45 mL/min, eluent A/B: 70/30-64/36, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Phenomenex Gemini C18, 10 um, Column (30 x 250 mm). The fractions containing the product were collected and lyophilized to give 22.1 mg of a white solid.
  • Fmoc-Ser(tBu) was replaced by Fmoc-NMe-Ser(tBu), HATU/HOAt/DIPEA was used for condensation conditions; Fmoc-2Nal was substituted for Fmoc-Phe, and HBTU/HOBt/DIPEA was used for condensation conditions.
  • Fmoc-NMe-Leu replaces Fmoc-Leu
  • HATU/HOAt/DIPEA is a condensation condition
  • Fmoc-D-Tyr(tBu) is replaced by Fmoc-NMe-D-Tyr(tBu)
  • HATU/HOAt/DIPEA is a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-143 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 72/28-64/36, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 28.9 mg of a white solid.
  • Step 1 500 mg of commercially available 2-CTC resin (1.34 mol/g) was swollen in DCM (10 ml), swelled for 30 min, and Fmoc-D-Ala-azaTic-Ser(tBu)-OH (150 mg, 0.24) was added. Methyl acetate (0.1 ml, 0.72 mmol) was treated at room temperature for 40 minutes to give Fmoc-(D-Ala)-azaTic-Ser(tBu)-2-CTC resin. After removing the solution, DCM/MeOH/DIPEA was added.
  • Fmoc-D-Ser(tBu)-OH 383 mg, 0.45 mmol
  • HBTU 170 mg, 0.45 mmol
  • HOBT 60 mg, 0.45 mmol
  • DIPEA 0.1 Ml, 0.45 mmol
  • Step 2 Add the dried resin to 5 mL of TFA/TIS/H 2 O (95/2.5/2.5) solution, then shake for 2 hours, remove the resin by filtration, and use 2 mL of TFA/TIS/H 2 O (95/2.5 /2.5) Solution wash resin. The filtrate was combined, diethyl ether (70 mL) was added to the filtrate, and the obtained precipitate was centrifuged to remove the supernatant.
  • the resulting precipitate was dissolved in DMF, followed by a linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 75/25-65/35, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Phenomenex Gemini 10um, Column (21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 80 mg of a white solid.
  • Example 41 In a similar manner to the synthesis of Example 41, Fmoc-D-Tyr(tBu) was replaced with Fmoc-NMeD-Tyr(tBu), and HATU/HOAt/DIPEA was a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-148 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 70/30-65/35, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 14.6 mg of a white solid.
  • Fmoc-Tic was replaced with Fmoc-D-Tic, and HATU/HOAt/DIPEA was a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-149 was purified by HPLC, eluting with a linear gradient (10 min), with a flow rate of 25 mL/min, eluent A/B: 82/18-72/28, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 43.0 mg of a white solid.
  • Fmoc-Tic was replaced with Fmoc-Ti1c, and HATU/HOAt/DIPEA was a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-150 was purified by HPLC, eluting with a linear gradient (10 min) at a flow rate of 25 mL/min, eluent A/B: 72/28-62/38, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Phenomenex Gmini C18, 10um, Column (21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 31.3 mg of a white solid.
  • Fmoc-Tic was replaced with Fmoc-D-Ti1c, and HATU/HOAt/DIPEA was a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-151 was purified by HPLC, eluting with a gradient gradient (10 min), with a flow rate of 25 mL/min, eluent A/B: 72/28-64/36, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Phenomenex Gmini C18, 10um, Column (21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 44.7 mg of white solid.
  • Fmoc-Tic was replaced with Fmoc-D-Ti1c, HATU/HOAt/DIPEA was a condensation condition; Fmoc-NMeLeu was substituted for Fmoc-Leu, and HATU/HOAt/DIPEA was a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-153 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 73/27-67/33, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 35.0 mg of white solid.
  • Fmoc-D-Ti1c was substituted for Fmoc-Tic, HATU/HOAt/DIPEA was used for condensation conditions; Fmoc-NMe-D-Tyr(tBu) was substituted for Fmoc-D-Tyr(tBu), HATU/ HOAt/DIPEA is a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-154 was purified by HPLC, eluting with a gradient gradient (10 min) at a flow rate of 25 mL/min, eluent A/B: 72/28-66/34, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 57.3 mg of a white solid.
  • Fmoc-NMe-Ser(tBu) replaces Fmoc-Ser(tBu), HATU/HOAt/DIPEA is a condensation condition; Fmoc-D-Ti1c replaces Fmoc-Tic, HATU/HOAt/DIPEA is Condensation conditions.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-155 was purified by HPLC, eluting with a linear gradient (10 min), with a flow rate of 25 mL/min, eluent A/B: 72/28-66/34, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 5.3 mg of a white solid.
  • Fmoc-Tic was replaced with Fmoc-D-Ti1c, HATU/HOAt/DIPEA was a condensation condition; Fmoc-Phe was replaced with Fmoc-2Nal, and HBTU/HOBt/DIPEA was a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-156 was purified by HPLC, eluting with a gradient gradient (10 min) at a flow rate of 25 mL/min, eluent A/B: 63/37-57/43, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 22.9 mg of a white solid.
  • Fmoc-Tic was replaced with Fmoc-D-Ti1c, HATU/HOAt/DIPEA was a condensation condition; Fmoc-Phe was replaced with Fmoc-1Nal, and HBTU/HOBt/DIPEA was a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-157 was purified by HPLC, eluting with a gradient gradient (10 min) at a flow rate of 25 mL/min, eluent A/B: 63/37-57/43, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 41.4 mg of a white solid.
  • Fmoc-Tic was replaced with Fmoc-TP5C, and HATU/HOAt/DIPEA was a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-158 was purified by HPLC, linear gradient elution (10 min), flow rate 25 mL / min, eluent A/B: 70/30-64/36, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 18.6 mg of a white solid.
  • Fmoc-Tic was replaced with Fmoc-TP6C, and HATU/HOAt/DIPEA was a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-159 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 70/30-64/36, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 25.8 mg of a white solid.
  • Fmoc-Ser(tBu) was replaced with Fmoc-Thr(tBu), and HATU/HOAt/DIPEA was a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-160 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 69/31-59/41, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 20.4 mg of a white solid.
  • Step 1 The polypeptide is synthesized by standard Fmoc chemistry, and the basic operation is as follows. 200 mg (0.5 mol/g) of commercially available Rink Amide MBHA resin was swollen in DMF, which was treated with 5 mL of 20% piperidine/DMF for 20 minutes to remove Fmoc, and this was repeated twice.
  • the obtained resin was washed with DMF, and added Fmoc-Ser(tBu)-OH (116 mg, 0.3 mmol), HBTU (114 mg, 0.3 mmol), HOBt (41 mg, 0.3 mmol) in 20 mL DMF solution, then DIPEA (77 mg, 0.6) Methyl), treated at room temperature for 40 minutes, into which Ser(tBu) was introduced to obtain Fmoc-Ser(tBu)-MBHA resin, and other amino acids were introduced in a similar manner to obtain Fmoc-(D-Tyr(tBu))-Phe -(NMe-Leu)-Pro-(D-Ser(tBu))-Gln-Phe-(D-Ala)-Tic-Ser(tBu)-MBHA resin.
  • the resin was treated with 5 mL of 20% piperidine/DMF for 20 minutes to remove Fmoc and this was repeated twice.
  • the obtained resin was washed with DMF, and added 3-Phenylpropanoic acid (45 mg, 0.3 mmol), HBTU (114 mg, 0.3 mmol), HOBt (41 mg, 0.3 mmol) in 10 mL of DMF, then DIPEA (77 mg, 0.6 mmol), room temperature After 4 hours of treatment, 3-Phenylpropanoyl-(D-Tyr(tBu))-Phe-(NMe-Leu)-Pro-(D-Ser(tBu))-Gln-Phe-(D-Ala)-Tic- was obtained.
  • Ser(tBu)-MBHA resin 3-Phenylpropanoyl-(D-Tyr(tBu))-Phe-(NMe-Leu)-Pro-(D-Ser(tBu))-Gln-P
  • Step 2 Add the dried resin to 5 mL of TFA/TIS/H 2 O (95/2.5/2.5) solution, then shake for 2 hours, remove the resin by filtration, and use 2 mL of TFA/TIS/H 2 O (95/2.5 /2.5) Solution wash resin.
  • the filtrate was combined, diethyl ether (70 mL) was added to the filtrate, and the obtained precipitate was centrifuged to remove the supernatant.
  • the resulting precipitate was dissolved in DMF and purified by HPLC.
  • Fmoc-Ser(tBu) was replaced by Fmoc-NMe-Ser(tBu), HATU/HOAt/DIPEA was used for condensation conditions; Fmoc-1Nal was substituted for Fmoc-Phe, and HBTU/HOBt/DIPEA was used for condensation conditions.
  • Fmoc-NMe-Leu replaces Fmoc-Leu
  • HATU/HOAt/DIPEA is a condensation condition
  • Fmoc-D-Tyr(tBu) is replaced by Fmoc-NMeD-Tyr(tBu)
  • HATU/HOAt/DIPEA is a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-162 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 67/33-61/39, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 30.7 mg of white solid.
  • HATU/HOAt/DIPEA is a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-163 was purified by HPLC, eluting with a linear gradient (10 min), with a flow rate of 25 mL/min, eluent A/B: 73/27-63/37, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 56.8 mg of white solid.
  • Fmoc-Phe was replaced with Fmoc-2Nal, HBTU/HOBt/DIPEA was a condensation condition; Fmoc-NMe-Leu was substituted for Fmoc-Leu, and HATU/HOAt/DIPEA was a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-164 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 70/30-60/40, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 73.5 mg of a white solid.
  • Fmoc-1Pal was substituted for Fmoc-Phe, HBTU/HOBt/DIPEA was a condensation condition; Fmoc-NMe-Leu was substituted for Fmoc-Leu, and HATU/HOAt/DIPEA was a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-165 was purified by HPLC, eluting with a gradient gradient (10 min) at a flow rate of 25 mL/min, eluent A/B: 71/29-61/39, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 55.6 mg of white solid.
  • Fmoc-Ser(tBu) was replaced by Fmoc-NMe-Ser(tBu), HATU/HOAt/DIPEA was used for condensation conditions; Fmoc-NMe-Leu was substituted for Fmoc-Leu, and HATU/HOAt/DIPEA was Condensation conditions.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-166 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 75/25-65/35, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 18.8 mg of a white solid.
  • Fmoc-2Pal was substituted for Fmoc-Phe, HBTU/HOBt/DIPEA was used for condensation conditions; Fmoc-NMe-Leu was substituted for Fmoc-Leu, HATU/HOAt/DIPEA was for condensation conditions; and Fmoc-D- was used.
  • NMe-Tyr(tBu) replaces Fmoc-D-Tyr(tBu), and HATU/HOAt/DIPEA is a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-167 was purified by HPLC, eluting with a gradient gradient (10 min), with a flow rate of 25 mL/min, eluent A/B: 69/31-63/37, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 42.7 mg of a white solid.
  • Fmoc-1Nal was substituted for Fmoc-Phe, HBTU/HOBt/DIPEA was used for condensation conditions; Fmoc-NMe-Leu was substituted for Fmoc-Leu, HATU/HOAt/DIPEA was for condensation; and Fmoc-D- was used.
  • NMe-Tyr(tBu) replaces Fmoc-D-Tyr(tBu), and HATU/HOAt/DIPEA is a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-168 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 69/31-63/37, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 47.4 mg of a white solid.
  • Fmoc-Ser(tBu) was replaced by Fmoc-HoSer(tBu), HBTU/HOBt/DIPEA was used for condensation conditions; Fmoc-NMe-Leu was substituted for Fmoc-Leu, and HATU/HOAt/DIPEA was used for condensation conditions.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-171 was separated and purified by HPLC.
  • Step 1 500 mg of commercially available 2-CTC resin (1.34 mol/g) was swollen in DCM (5 mL), swollen for 30 min, and added Fmoc-NHoSer(tBu)-OH (80 mg, 0.2 mmol), DIPEA (0.1 Ml, 0.75 mmol), treated at room temperature for 40 minutes to give Fmoc-NHoSer(tBu)-2-CTC resin. After removing the solution, DCM/MeOH/DIPEA (5 mL, v/v/v: 85:10:5) was added. The reaction was carried out for 30 min, repeated twice, and the excess CCl of 2-CTC was capped and the solution was removed. The resin was washed with DMF, and a 20% piperidine/DMF solution (5 mL) was added and reacted for 20 min, repeated twice, and Fmoc was removed.
  • DCM/MeOH/DIPEA 5 mL, v/v/v: 85:10:
  • Step 2 The resin was washed with DMF, added Fmoc-Tic-OH (240 mg, 0.60 mmol), HATU (228 mg, 0.60 mmol), HOAT (82 mg, 0.60 mmol) in 5 ml of DMF solution, then DIPEA (0.1 ml, 0.75 mmol) The reaction was carried out for 2 hr at room temperature to obtain Fmoc-Tic-NHoSer(tBu)-2-CTC.
  • Step 3 Add the dried resin to 5 mL of TFA/TIS/H 2 O (90/5/5) solution, then shake for 2 hours, remove the resin by filtration, and use 2 mL of TFA/TIS/H 2 O (90/5). /5) Solution washing resin. The filtrate was combined, diethyl ether (70 mL) was added to the filtrate, and the mixture was centrifuged at 3,000 rpm for 1 minute to remove the supernatant.
  • the resulting precipitate was dissolved in DMF, followed by a linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 69/31-59/41, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Phenomenex Gemini 10um, Column (21.2 x 250 mm). The fractions containing the product were collected and lyophilized to give 21 mg of a white solid.
  • Fmoc-Pro was replaced with Fmoc-Pr (diF), HBTU/HOBt/DIPEA was a condensation condition; Fmoc-NMe-Leu was substituted for Fmoc-Leu, and HATU/HOAt/DIPEA was a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-174 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 70/30-64/36, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 26.1 mg of a white solid.
  • Fmoc-D-Ser(tBu) was replaced by Fmoc-D-HoSer(tBu), HATU/HOAt/DIPEA was used for condensation conditions; Fmoc-NMeLeu was substituted for Fmoc-Leu, and HATU/HOAt/DIPEA was Condensation conditions.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-175 was purified by HPLC, eluting with a gradient gradient (10 min) at a flow rate of 25 mL/min, eluent A/B: 73/27-67/33, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 47.8 mg of a white solid.
  • Fmoc-D-Tic was replaced with Fmoc-D-Oic, HATU/HOAt/DIPEA was a condensation condition; Fmoc-NMe-Leu was substituted for Fmoc-Leu, and HATU/HOAt/DIPEA was a condensation condition.
  • the Fmoc protecting group is removed by a conventional method, and the resin is washed and dried.
  • the polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 1, and the protection was removed.
  • the crude product YW-176 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 72/28-66/34, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate C18, 10 um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 28.4 mg of a white solid.
  • the HoSer(tBu)-2-CT resin was obtained in the first step of Example 5, the resin was washed with DMF, and 5 mL of p-nitrobenzenesulfonyl chloride (111 mg, 0.5 mmol) in DMF was added, then DIPEA (0.2 ml, 1.5 mmol) was added. ), react at room temperature for 3 hours. The resin was washed with DMF, DMF (5 mL) was added, and then triphenylphosphine (131 mg, 0.5 mmol), DIAD (201 mg, 0.5 mmol), methanol (0.5 mL).
  • the resin was washed with DMF, thiophenol (0.55 g, 5.0 mmol), DMF (5 mL), DIPEA (0.95 g, 7.5 mmol), and the mixture was reacted at room temperature for 1 hour to remove p-nitrophenylsulfonyl.
  • the resin was washed with DMF. , NH2-NMe-HoSer(tBu)-2-CTC resin was obtained.
  • Step 2 Add the dried resin to 5 mL of TFA/TIS/H 2 O (90/5/5) solution, then shake for 2 hours, remove the resin by filtration, and use 2 mL of TFA/TIS/H 2 O (90/5 /5) Solution washing resin.
  • the filtrate was combined, diethyl ether (70 mL) was added to the filtrate, and the mixture was centrifuged at 3,000 rpm for 1 minute to remove the supernatant.
  • the resulting precipitate was dissolved in DMF, followed by a linear gradient elution (10 min) at a flow rate of 25 mL/min, eluent A/B: 75/25-67/33, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Phenomenex Gemini 10um, Column (21.2 x 250 mm). The product-containing fractions were collected and lyophilized to give 13 mg of a white solid as a s-butylide product.
  • Step 3 The ruthenium-butyrolactone product (13 mg) obtained above was dissolved in tetrahydrofuran (0.5 mL), and a 0.1 N NaOH solution (0.5 mL) was added thereto, and the mixture was reacted for 1 hour at room temperature under ultrasonic wave.
  • reaction solution was added to DMF (1 mL), then a gradient gradient elution (10 min), with a flow rate of 25 mL/min, eluent A/B: 67/33-61/39, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC, using Xtimate 10um, Column (20 x 250 mm). The fractions containing the product were collected and lyophilized to give 6.8 mg of a white solid.
  • the resin was treated with 10 ml of 20% piperidine/DMF for 20 minutes to remove Fmoc. This was repeated twice, the resin was washed with DMF, and Fmoc-Tic-OH (359 mg, 0.9 mmol), HATU (342 mg, 0.9 mmol), HOAt (122 mg, 0.9 mmol) in 10 ml of a DMF solution, then DIPEA (232 mg, 1.8 mmol) was added, and treated at room temperature for 40 minutes, and the resin was washed with DMF to give Fmoc-Tic-[NMe-Ser(tBu)]-CTC resin.
  • the dried resin was added to 10 ml of TFA/TIS/H 2 O (92/4/4) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 1 ml of TFA/TIS/H 2 O (92/4/4). The solution washes the resin. The filtrate was combined, and methyl tert-butyl ether (110 ml) was added to the filtrate. The obtained mixture was centrifuged at 3,000 rpm for 1 minute, and the solid was washed twice with ice diethyl ether and dried. The obtained precipitate was dissolved in DMF, and then subjected to linear concentration gradient elution at a flow rate of 25 ml/min.
  • Eluent A/B 25/75-15/85 used: eluent A: 0.05% TFA in water, eluted Liquid B: 0.05% TFA in acetonitrile, using Xtimate 10u on preparative HPLC. The product containing fractions were collected on a column (20 x 250 mm) and lyophilized to give 47.9 mg of a white solid.
  • amino acids such as D-Ala, Phe, Gln(Trt), D-Ser(tBu), Pro, NEt-Leu, Phe, D-Tyr(tBu) are sequentially introduced to obtain 1.5 g of D-Tyr ( tBu)-Phe-(NEt-Leu)-Pro-[D-Ser(tBu)]-Gln(Trt)-Phe-(D-Ala)-Tic-Ser(tBu)-CTC resin.
  • the resin was washed successively with DMF, methanol, methyl t-butyl ether, and then dried.
  • the dried resin was added to 10 ml of TFA/TIS/H 2 O (92/4/4) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 1 ml of TFA/TIS/H 2 O (92/4/4). The solution washes the resin. The filtrate was combined, and methyl tert-butyl ether (110 ml) was added to the filtrate. The obtained mixture was centrifuged at 3,000 rpm for 1 minute, and the solid was washed twice with ice diethyl ether and dried. The resulting precipitate was dissolved in DMF and then subjected to linear concentration gradient elution (10 min) at a flow rate of 25 ml/min.
  • eluent A/B 72/28-66/34 used: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire, 10u, The product containing fractions were collected on a column (19 x 250 mm) and lyophilized to give 18.8 mg of a white solid.
  • Example 66 Similar to the synthesis method of Example 66, a resin was synthesized on an MBHA resin by a conventional solid phase synthesis method. The Fmoc protecting group is removed by a conventional method, and the resin is washed and dried. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 66 and deprotected.
  • the crude product YW-189 was purified by HPLC, eluting with a gradient gradient (10 min), with a flow rate of 25 mL/min, eluent A/B: 72/28-66/34, using: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 31.5 mg of a white solid.
  • Example 66 Similar to the synthesis method of Example 66, a resin was synthesized on an MBHA resin by a conventional solid phase synthesis method. The Fmoc protecting group is removed by a conventional method, and the resin is washed and dried. The polypeptide of interest was cleaved from the resin by the method of Step 2 of Example 66 and deprotected.
  • the crude product YW-190 was subjected to HPLC separation and purification, linear gradient elution (10 min), flow rate 25 mL/min, eluent A/B: 74/26-68/32, use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire C18, 10um, Column (19 x 250 mm). The fractions containing the product were collected and lyophilized to give 62.8 mg of white solid.
  • amino acids such as D-Ala, Phe, Gln(Trt), D-Ser(tBu), Pro, NMe-Leu, Phe, D-Tyr(tBu), 4-(trifluoromethyl)benzoic acid are introduced in sequence.
  • 1.5 g of the CTC resin of the target polypeptide was obtained. The resin was washed successively with DMF, methanol, methyl t-butyl ether, and then dried.
  • the dried resin was added to 10 ml of TFA/TIS/H 2 O (92/4/4) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 1 ml of TFA/TIS/H 2 O (92/4/4). The solution washes the resin. The filtrate was combined, and methyl tert-butyl ether (110 ml) was added to the filtrate. The obtained mixture was centrifuged at 3,000 rpm for 1 minute, and the solid was washed twice with ice diethyl ether and dried. The resulting precipitate was dissolved in DMF and then subjected to linear concentration gradient elution (10 min) at a flow rate of 25 ml/min.
  • eluent A/B 72/28-66/34 used: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Xtimate 10u, The product containing fractions were collected on a column (20 x 250 mm) and lyophilized to give 27.6 mg of a white solid.
  • amino acids such as D-Ala, Phe, Gln(Trt), D-Ser(tBu), Pro, NMe-Leu, Phe, D-Tyr(tBu) are sequentially introduced to obtain D-Tyr(tBu).
  • -Phe-(NMe-Leu)-Pro-[D-Ser(tBu)]-Gln(Trt)-Phe-(D-Ala)-Tic-Ser(tBu)-CTC resin The obtained resin was swollen in 10 ml of DMF, 3-phenylpropanal (536 mg, 4.0 mmol) and 2 drops of glacial acetic acid were added thereto, and treated at room temperature for 2 hours.
  • the resin was washed with DMF, and sodium borohydride (151 mg. 4 mmol) was added in 3 ml.
  • a mixed solution of methanol and 7 ml of DMF was treated at room temperature for 30 minutes to obtain (3-phenylpropyl)-[D-Tyr(tBu)]-Phe-(NMe-Leu)-Pro-[D-Ser(tBu)]-Gln (Trt)-Phe-(D-Ala)-Tic-Ser(tBu)-CTC resin.
  • the resin was washed successively with DMF, methanol, methyl t-butyl ether, and then dried.
  • the dried resin was added to 15 ml of TFA/TIS/H 2 O (92/4/4) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 1.5 ml of TFA/TIS/H 2 O (92/4/ 4) The solution washes the resin. The filtrate was combined, and methyl tert-butyl ether (150 ml) was added to the filtrate. The obtained mixture was centrifuged at 3,000 rpm for 1 minute, and the solid was washed twice with ice diethyl ether and dried. The resulting precipitate was dissolved in DMF and then subjected to linear concentration gradient elution (10 min) at a flow rate of 25 ml/min.
  • eluent A/B 71/29-61/39 used: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire, 10u, The product containing fractions were collected on a column (19 x 250 mm) and lyophilized to give 49.7 mg of a white solid.
  • amino acids such as D-Ala, Nal-2, Gln(Trt), D-Ser(tBu), Pro(tran-4F), NMe-Leu, Phe, D-Tyr(tBu) are introduced in sequence, Obtain D-Tyr(tBu)-Phe-(NMe-Leu)-Pro-[D-Ser(tBu)]-Gln(Trt)-(Nal-2)-(D-Ala)-Tic-Ser(tBu) - CTC resin. The resin was washed successively with DMF, methanol, methyl t-butyl ether, and then dried.
  • the dried resin was added to 15 ml of TFA/TIS/H 2 O (92/4/4) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 1.5 ml of TFA/TIS/H 2 O (92/4/ 4) The solution washes the resin. The filtrate was combined, and methyl tert-butyl ether (150 ml) was added to the filtrate. The obtained mixture was centrifuged at 3,000 rpm for 1 minute, and the solid was washed twice with ice diethyl ether and dried. The resulting precipitate was dissolved in DMF and then subjected to a linear concentration gradient elution (10 min) at a flow rate of 25 ml/min.
  • eluent A/B 69/31-59/41 used: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire, 10u, The product containing fractions were collected on a column (19 x 250 mm) and lyophilized to give 80.0 mg of a white solid.
  • the resin was treated with 10 ml of 20% piperidine/DMF for 20 minutes to remove Fmoc. This was repeated twice, the resin was washed with DMF, and Fmoc-Tic-OH (359 mg, 0.9 mmol), HATU (342 mg, 0.9 mmol), HOAt (122 mg, 0.9 mmol) in 10 ml of a DMF solution, then DIPEA (232 mg, 1.8 mmol) was added, and treated at room temperature for 40 minutes, and the resin was washed with DMF to give Fmoc-Tic-[NMe-Ser(tBu)]-CTC resin.
  • the dried resin was added to 10 ml of TFA/TIS/H 2 O (92/4/4) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 1 ml of TFA/TIS/H 2 O (92/4/4). The solution washes the resin. The filtrate was combined, and methyl tert-butyl ether (110 ml) was added to the filtrate. The obtained mixture was centrifuged at 3,000 rpm for 1 minute, and the solid was washed twice with ice diethyl ether and dried. The resulting precipitate was dissolved in DMF and then subjected to a linear concentration gradient elution (10 min) at a flow rate of 25 ml/min.
  • eluent A/B 95/5-35/65 use: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire, 10u, The product containing fractions were collected on a column (19 x 250 mm) and lyophilized to give 24.0 mg of a white solid.
  • the resin was treated with 10 ml of 20% piperidine/DMF for 20 minutes to remove Fmoc. This was repeated twice, the resin was washed with DMF, and Fmoc-Tic-OH (359 mg, 0.9 mmol), HATU (342 mg, 0.9 mmol), HOAt (122 mg, 0.9 mmol) in 10 ml of a DMF solution, then DIPEA (232 mg, 1.8 mmol) was added, and treated at room temperature for 40 minutes, and the resin was washed with DMF to give Fmoc-Tic-[NMe-Ser(tBu)]-CTC resin.
  • the dried resin was added to 10 ml of TFA/TIS/H 2 O (92/4/4) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 1 ml of TFA/TIS/H 2 O (92/4/4). The solution washes the resin. The filtrate was combined, and methyl tert-butyl ether (110 ml) was added to the filtrate. The obtained mixture was centrifuged at 3,000 rpm for 1 minute, and the solid was washed twice with ice diethyl ether and dried. The resulting precipitate was dissolved in DMF and then subjected to linear concentration gradient elution (10 min) at a flow rate of 25 ml/min.
  • Eluent A/B 70/30-60/40 used: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile.
  • the product-containing fractions were collected on a preparative HPLC using a Phenomenex C18 column (21.2 x 250 mm) and lyophilized to give a white solid.
  • amino acids such as D-Ala, Nal-2, Gln (Trt), D-Ser (tBu), Pro (tran-4F), NMe-Leu, Phe, D-Tyr (3F) are sequentially introduced. Yield 1.5 g D-Tyr(3F)-Phe-(NMe-Leu)-Pro(tran-4F)-[D-Ser(tBu)]-Gln(Trt)-(Nal-2)-(D-Ala) -Tic-Ser(tBu)-CTC resin. The resin was washed successively with DMF, methanol, methyl t-butyl ether, and then dried.
  • the dried resin was added to 10 ml of TFA/TIS/H 2 O (92/4/4) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 1 ml of TFA/TIS/H 2 O (92/4/4). The solution washes the resin. The filtrate was combined, and methyl tert-butyl ether (110 ml) was added to the filtrate. The obtained mixture was centrifuged at 3,000 rpm for 1 minute, and the solid was washed twice with ice diethyl ether and dried. The resulting precipitate was dissolved in DMF and then subjected to linear concentration gradient elution (10 min) at a flow rate of 25 ml/min.
  • eluent A/B 72/28-66/34 used: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using Sunfire, 10u, The product containing fractions were collected on a column (19 x 250 mm) and lyophilized to give 44.2 mg of a white solid.
  • the dried resin was added to 10 ml of TFA/TIS/H 2 O (92/4/4) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 1 ml of TFA/TIS/H 2 O (92/4/4). The solution washes the resin. The filtrate was combined, and methyl tert-butyl ether (110 ml) was added to the filtrate. The obtained mixture was centrifuged at 3,000 rpm for 1 minute, and the solid was washed twice with ice diethyl ether and dried. The resulting precipitate was dissolved in DMF and then subjected to linear concentration gradient elution (10 min) at a flow rate of 25 ml/min.
  • eluent A/B 33/67-23/77 used: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile.
  • the product-containing fractions were collected on a preparative HPLC using a Phenomenex C18 column (21.2 x 250 mm) and lyophilized to give 63.4 mg of white solid.
  • the resin was treated with 10 ml of 20% piperidine/DMF for 20 minutes to remove Fmoc. This was repeated twice, the resin was washed with DMF, and Fmoc-Tic-OH (359 mg, 0.9 mmol), HATU (342 mg, 0.9 mmol), HOAt (122 mg, 0.9 mmol) in 10 ml of a DMF solution, then DIPEA (232 mg, 1.8 mmol) was added, and treated at room temperature for 40 minutes, and the resin was washed with DMF to give Fmoc-Tic-[NMe-Ser(tBu)]-CTC resin.
  • amino acids such as D-Ala, (Nal-2), Gln(Trt), D-Ser(tBu), DiFluorPro, NMe-Leu, Phe, NMe-D-Tyr(tBu) are sequentially introduced.
  • CTC resin of the target polypeptide 1.5 g. The resin was washed successively with DMF, methanol, methyl t-butyl ether, and then dried.
  • the dried resin was added to 10 ml of TFA/TIS/H 2 O (92/4/4) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 1 ml of TFA/TIS/H 2 O (92/4/4). The solution washes the resin. The filtrate was combined, and methyl tert-butyl ether (110 ml) was added to the filtrate. The obtained mixture was centrifuged at 3,000 rpm for 1 minute, and the solid was washed twice with ice diethyl ether and dried. The resulting precipitate was dissolved in DMF and then subjected to a linear concentration gradient elution (10 min) at a flow rate of 25 ml/min.
  • eluent A/B 68/32-60/40 used: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using XBridge Peptide BEH C18 10u, The product containing fractions were collected on a column (19 mm x 250 mm) and lyophilized to give 43.6 mg of a white solid.
  • the resin was treated with 10 ml of 20% piperidine/DMF for 20 minutes to remove Fmoc. This was repeated twice, the resin was washed with DMF, and Fmoc-Tic-OH (359 mg, 0.9 mmol), HATU (342 mg, 0.9 mmol), HOAt (122 mg, 0.9 mmol) in 10 ml of a DMF solution, then DIPEA (232 mg, 1.8 mmol) was added, and treated at room temperature for 40 minutes, and the resin was washed with DMF to give Fmoc-Tic-[NMe-Ser(tBu)]-CTC resin.
  • amino acids such as D-Ala, (Nal-2), Gln(Trt), D-Ser(tBu), DiFluorPro, NMe-Leu, Phe, D-Tyr (3F) are sequentially introduced to obtain 1.5 g. CTC resin of the target polypeptide.
  • the resin was washed successively with DMF, methanol, methyl t-butyl ether, and then dried.
  • the dried resin was added to 10 ml of TFA/TIS/H 2 O (92/4/4) solution, the mixture was stirred for 2 hours, and the resin was removed by filtration, using 1 ml of TFA/TIS/H 2 O (92/4/4). The solution washes the resin. The filtrate was combined, and methyl tert-butyl ether (110 ml) was added to the filtrate. The obtained mixture was centrifuged at 3,000 rpm for 1 minute, and the solid was washed twice with ice diethyl ether and dried. The resulting precipitate was dissolved in DMF and then subjected to a linear concentration gradient elution (10 min) at a flow rate of 25 ml/min.
  • eluent A/B 68/32-60/40 used: eluent A: 0.05% TFA Aqueous solution, eluent B: 0.05% TFA in acetonitrile, on preparative HPLC using XBridge Peptide BEH C18 10u, The product containing fractions were collected on a column (19 mm x 250 mm) and lyophilized to give 34.1 mg of a white solid.
  • Table 2 The polypeptide prepared in the above examples, and the polypeptide prepared by referring to the above examples are shown in Table 2 below. Table 2 also describes the purity analysis conditions, retention time, characterization data and effect data of each polypeptide (the effect according to Example 1 Method determination)
  • polypeptide sequences described above are the polypeptide sequences disclosed in the patent of P2010-229093A: (D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)- Tic-Ser was used as a positive control.
  • test compound was formulated into a 10 mM working solution in DMSO.
  • V-bottom 384-well plate Take V-bottom 384-well plate, use Echo to dilute the compound (or DMSO) in 500 ⁇ compound plate, 500 ⁇ L, ie 0.5 ⁇ l, into the corresponding position of V-bottom 384-well plate, add 20 ⁇ l of medium to each well, and centrifuge. Shake and mix. Table 4 below shows the concentration of each hole in the second to eleventh column of the intermediate plate (ie, 5 ⁇ compound plate).
  • Min The background value of cells when they are not affected by the compound.
  • Signal The signal value at the corresponding concentration of the compound.
  • the EC 50 of some of the compounds listed in Table 6 is superior to YW-3 and shows strong activity, indicating that the compound of the present invention can effectively bind to Chemerin receptor at the level of in vitro biochemical experiments, and thus the compound of the present invention can be an effective treatment for inflammation. drug.
  • the weighed 5.750 g of Na 2 HPO 4 , 1.141 g of NaH 2 PO 4 ⁇ and 4.095 g of NaCl (Shanghai Titan) were dissolved in 1000 mL of ultrapure water, and the pH was adjusted to 7.4.
  • the configured phosphate buffer is stored in the refrigerator at 4 ° C and is valid for one week.
  • test compound 5 mg was weighed and dissolved in 1 mL of DMSO.
  • the frozen plasma (human: Shanghai Ruizhi Chemical, Rat, Mouse: Shanghai Xipuer-Beikai, Dog, Monkey: Suzhou Xishan Zhongke) was taken out from the -80 °C refrigerator and immediately placed in a water bath at 37 °C. The medium was slightly shaken to melt, and then the thawed plasma was poured into a centrifuge tube, centrifuged at 3000 rpm for 8 min, and the supernatant was taken for the experiment. The pH of the plasma was measured with a pH meter (METTLER TOLEDO), and only plasma having a pH between 7.4 and 8 was used for the experiment. The plasma was placed on an ice bath for later use.
  • test compound solution 5 ⁇ l of 5 mg/mL test compound (see step 2) was added to 195 ⁇ l DMSO; 500 ⁇ M control solution: 20 mM control stock solution (see step 2) was added 195 ⁇ l in DMSO.
  • BSA phosphate buffer solution 0.05 g of BSA is added to 10 mL of phosphate buffer (see step 1);
  • test compound administration solution 40 ⁇ l of 125 ⁇ g/mL test compound solution was added to 960 ⁇ l of 0.5% BSA phosphate buffer solution, shaken and mixed, and the administration solution was placed in a 37 ° C water bath. Heat for 5 minutes.
  • 20 ⁇ M control administration solution 40 ⁇ l of a 500 ⁇ M reference administration solution was added to 960 ⁇ l of 0.5% BSA phosphate buffer solution, shaken and mixed, and the administration solution was preheated in a 37 ° C water bath for 5 minutes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Cardiology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Obesity (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)

Abstract

本发明公开了一种肽类化合物、其应用及含其的组合物。本发明提供了一种如式 I 所示的肽类化合物、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药。该化合物的稳定性较佳且活性较佳。

Description

一种肽类化合物、其应用及含其的组合物
本申请要求申请日为2017年6月27日的中国专利申请CN201710502668.X的优先权。本申请要求申请日为2018年6月25日的中国专利申请CN201810662539.1的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种肽类化合物、其应用及含其的组合物。
背景技术
ChemR23是Chemerin的主要受体。1996年Owman等从B淋巴母细胞cDNA文库中鉴定出一个新的cDNA序列，其编码蛋白质与G蛋白耦联受体(GPCRs)家族高度同源，命名为ChemR23(CMKLRl chemokine-like receptor 1)。ChemR23主要表达于白细胞、脂肪细胞、内皮细胞、上皮细胞、破骨细胞以及血管平滑肌细胞。因未发现其配体，ChemR23曾一直被认为是个孤儿受体。2003年Wittamer等在寻找G蛋白偶联受体chemR23(CMKLR1)的配体时，发现在炎症体液里TIGZ编码的蛋白是其配体，为了便于与chemR23对应，命名为Chemerin。Chemerin在人体的多种组织广泛表达，在脂肪组织、肾上腺、肝脏、肺、胰腺、胎盘、卵巢、皮肤等都有表达，其中主要表达于白色脂肪组织、肝脏和肺。脂肪细胞因子Chemerin是一种由脂肪细胞分泌的具有趋化作用的膜结合蛋白。
Chemerin基因也称他佐罗汀诱导基因2(tazarotene-induced gene2，TIG2)或视黄酸受体反应组件2(retinoicacid receptor responder 2，RARRES2)，由Nag-pal等于1997年培养银屑病患者的皮肤细胞时发现。
人类chemerin基因定位于E2DL3基因。Chemerin基因编码一个含163个氨基酸残基的蛋白质.属无活性前体分泌蛋白，即prochemerin，相对分子质量为18KDa，这种前体蛋白的生物活性很低，需要在凝血、纤溶、炎症级联反应过程中在细胞外进一步经过纤溶酶、羧肽酶或丝氨酸蛋白酶对C末端进行裂解才能成为有活性的蛋白。prochemerin经胞外蛋白酶水解羧基端的一段序列后转变为相对分子质量为16KDa,有活性的chemerin，出现在血清、血浆和体液中。目前认为，内源性活化的chemerin之所以具有如此广泛而多样的生理学效应可能与其胞外存在多种蛋白酶对prochemerin产生不同的酶解方式相关。Chemerin在羧基末端有多个蛋白酶切割位点,研究者也观察到多个酶都能 将chemerin裂解成有活性的蛋白。在某些情况下需要多重裂解以激活chemerin。
Chermerin序列的羧基末端对其保持生物活性至关重要。为研究chemerin的活性肽段，近年来人工合成许多prochemerin缩进末端来源的肽段来观察其对ChemR23的作用，发现最短的chemerin生物活性肽段为chemerin-9。人源chemerin-9的序列为chemerin149-157，YFPGQFAFS；小鼠源chemerin-9的序列为chemerin148-156，FLPGQFAFS。人源chemerin-9和小鼠源chemerin-9有相似的生物活性。
Chemerin最初是以炎症因子被发现的，研究发现chemerin通过其受体CMKLR1促进未成熟的树突细胞和巨噬细胞趋化。目前发现CMKLR1在很多免疫细胞都有表达，包括炎症介质(单核细胞、巨噬细胞、浆细胞表达/髓样树突状细胞和自然杀伤细胞)、血管内皮细胞以及神经元、神经胶质细胞、脊髓和视网膜、未成熟的树突状细胞、髓样树突细胞、巨噬细胞和自然杀伤细胞等。它在先天性免疫，获得性免疫、炎症反应、脂肪生成与脂质代谢、细胞增殖等方面都发挥着重要作用。
Chemerin及其受体系统在病毒性肺炎的病理学中扮演重要角色，因此有可能成为抗病毒和抗炎的疗法。
Chemerin功能广泛，如促进树突细胞、巨噬细胞和NK细胞到炎症位点的趋化作用、抑制促炎介质TNFα和IL-6的合成、增加脂联素的产生、促进脂肪细胞的分化与成熟、提高脂肪细胞对胰岛素的敏感性和葡萄糖的摄取、调节脂解作用、增加TNF-β的合成、提高NF-κβ的活性，增加VEGF和MMPs的合成并调节新生血管生成和血管再生等等。因此，Chemerin在免疫应答、炎症反应、脂肪生成与脂质代谢(涉及肥胖、脂肪肝、糖尿病和代谢综合征)等方面发挥了重要作用，应用前景较好。
Chemerin还可用于哮喘，哮喘是一种呼吸道的慢性炎症疾病。如果没有采取任何抗炎的措施，将会导致支气管阻塞或挛缩，甚至可能因呼吸困难而危及生命。哮喘被世界卫生组织列为疾病中四大顽症之一，它也成为仅次于癌症的世界第二大致死和致残疾病。在西方一些发达国家，哮喘发病率高达20％，有些甚至高达40％。而我国的哮喘患病率增长速度非常快。
体内发现的多种天然趋化素及其酶切产物，都是蛋白质，具有分子量相对较大、制备困难、存在抗原性、稳定性差等缺点，很难大批量生产和开展大动物及人体的实验研究及药物开发。因此，新型的多肽趋化素因子受体1激动剂的研发，预示着治疗一系列炎症和癌症(肿瘤免疫)的新颖方法的开展。
与多数有机小分子药物相比，多肽类药物具有生物活性高、用药剂量小、毒副作用低和代谢终产物为氨基酸等突出特点。与大分子的蛋白质或抗体药相比分子量较小，同 样具有类似蛋白质的活性，功能更显着，可化学合成，产品纯度高，质量可控，较小的肽几乎没有免疫原性，药物开发前景非常好。多肽药物的研究与开发已经成为国际上新兴的生物高科技领域，具有极大的市场潜力。
万有制药株式会社在JP2010-229093A专利中公布了以下多肽序列：(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser。
Figure PCTCN2018093088-appb-000001
发明内容
所要解决的技术问题是现有的Chemerin活性低、稳定性差等缺陷，故而，本发明提供了一种肽类化合物、其应用及含其的组合物，该化合物的稳定性较佳且活性较佳。
本发明提供了一种如式I所示的肽类化合物、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药：
XX0-XX1-XX2-XX3-XX4-XX5-XX6-XX7-XX8-XX9-XX10-P  (I)
其中，XX0为氢、
Figure PCTCN2018093088-appb-000002
R 0-2或
Figure PCTCN2018093088-appb-000003
R 0-1为CH 3-，q为10～18(例如，以下述任两个值为端点的范围：10、11、12、13、14、15、16、17和18)；
PEG为
Figure PCTCN2018093088-appb-000004
m为6～12(例如，以下述任两个值为端点的范围：6、7、8、9、10、11和12)；
n为0～2(例如0、1或2)；
所有的AA0独立地为
Figure PCTCN2018093088-appb-000005
(例如PEG8)、Ahx、Gly或Beta-Ala；所有的k独立地为4～8(例如，以下述任两个值为端点的范围：4、5、6、7和8)，所有的r独立地为0或1；
R 0-2为R 0-2-1取代或未取代的C 1～C 6的烷基(所述的R 0-2-1的个数可为一个或多个{例如1个、2个、3个、4个或5个}；当存在多个R 0-2-1时，它们相同或不同；所有的R 0-2-1可独立地处于所述C 1～C 6烷基的末端或非末端；所述的C 1～C 6的烷基可为C 1～C 4的烷基；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“R 0-2-1取代的C 1～C 6的烷基”例如3,5-二羟基苄基或3-苯基丙基)；
所有的R 0-2-1独立地为羟基取代或未取代的苯基(所述的羟基的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的羟基可独立地处于所述苯基的邻位、间位或对位；所述的“羟基取代的苯基”例如3,5-二羟基苯基)；
R 0-3为R 0-3-1取代或未取代的C 1～C 8的烷基(所述的R 0-3-1的个数可为一个或多个{例如1个、2个、3个、4个或5个}；当存在多个R 0-3-1时，它们相同或不同；所有的R 0-3-1可独立地处于所述C 1～C 8烷基的末端或非末端；所述的C 1～C 8的烷基可为C 1～C 4的烷基或正戊基；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“R 0-3-1取代的C 1～C 8的烷基”例如2-苯基乙基、3-苯基丙基、4-苯基丁基、4-苯基苄基、二苯甲基、3,4-二羟基苄基、3,5-二羟基苄基或环己基甲基)、或、R 0-3-2取代或未取代的苯基(所述的R 0-3-2的个数可为一个或多个{例如1个、2个、3个、4个或5个}；当存在多个R 0-3-2时，它们相同或不同；所有的R 0-3-2可独立地处于所述苯基的邻位、间位或对位；所述的“R 0-3-2取代的苯基”例如3,5-二羟基苯基、2,3-二羟基苯基、2,6-二羟基苯基、2,3,4-三羟基苯基、2,3,5-三羟基苯基或4-三氟甲基苯基)；
所有的R 0-3-1独立地为羟基取代或未取代的苯基(所述的羟基的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的羟基可独立地处于所述苯基的邻位、间位或对位；所述的“羟基取代的苯基”例如3,4-二羟基苯基或3,5-二羟基苯基)、或、C 3～C 6的环烷基(例如环己基)；
所有的R 0-3-2独立地为羟基、或者、卤代的C 1～C 4烷基(所述的“卤”的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的“卤”可独立地为氟、氯或溴；当存在多个卤时，它们相同或不同；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“卤代的C 1～C 4烷基”例如三氟甲基)；
XX1为氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基)取代或未取代的下述任一氨基酸(所述的“取代的氨基酸”例如D-NMeTyr)：D-Tyr(3F)、D-Tyr和D-Phe；
XX2为氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)取代或未取代的下述任一氨基酸(所述的“取代的氨基酸”例如 NMePhe)：1Nal、2Nal、Bpa和、
Figure PCTCN2018093088-appb-000006
{例如Phe、Phe(4-Cl)或Phe(4-Me)}；n2为0或1，R 2为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基或异丁基)或卤素(例如氟或氯)，*标记的碳原子为手性碳原子，其为R构型或S构型(R 2可位于苯基的邻位、间位或对位，例如，当n2为1时，R 2可位于苯基的对位；又例如，其为
Figure PCTCN2018093088-appb-000007
)；
XX3为
Figure PCTCN2018093088-appb-000008
其中，*标记的碳原子为手性碳原子，其为R构型或S构型(例如
Figure PCTCN2018093088-appb-000009
)；R 3-1为C 4～C 5的烷基(例如正丁基、异丁基、仲丁基、叔丁基、正戊基或3-甲基丁基)或苄基；R 3-2为C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)；(所述的
Figure PCTCN2018093088-appb-000010
例如NMe-Leu、NMe-Phe、NMe-HoLeu、NEt-Leu、NPr-Leu、NiPr-Leu、Nbu-Leu、NMe-Nle或NMe-Ile)；
XX4为Ala或
Figure PCTCN2018093088-appb-000011
(例如
Figure PCTCN2018093088-appb-000012
Y为-(CR 4-1R 4-2)-{例如-CH 2-、-CH(OH)-或-CF 2}、-(CH 2) 2-或-S-；又例如Aze、Thz、Hyp、Pro、Pro(5Ph)、Pro(4Ph)、Pro(diF)或HoPro)；*标记的碳原子为手性碳原子，其为R构型或S构型(例如
Figure PCTCN2018093088-appb-000013
)；Z为-(CR 4-1R 4-2) n4-{例如-CH 2-、-(CH 2) 2-、-CH(OH)-CH 2-、-CF 2-CH 2-、-CHPh-CH 2-、-CH 2-CHPh-或-(CH 2) 3-}或-S-(CR 4-3R 4-4) n4’-{例如-S-CH 2-}；所述的-(CR 4-1R 4-2) n4-和-S-(CR 4-3R 4-4) n4’-的右端与手性碳原子连接；n4为1～3(例如1、2或3)，n4’为1或2；所有的R 4-1、R 4-2、R 4-3和R 4-4独立地为氢、羟基、卤素(例如氟或氯)或苯基；
XX5为D-Ser、D-Hyp、D-Thr、βAla、D-NMeSer、2Nal、1Nal或D-HoSer；
XX6为Gln、NMe-Gln或NGln；
XX7为NMe-Phe、HoPhe、1Nal、2Nal、Bpa、D-Ser或
Figure PCTCN2018093088-appb-000014
{例如Phe、Phe(3-Cl)、Phe(3-Me)、Phe(3-OMe)、Phe(4-OMe)、Phe(4-Me)或Phe(4-Cl)}；n7为0或1，R 7为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基或异丁基)、C 1～C 4烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基或异丁氧基)或卤素(例如氟或氯)，*标记的碳原子为手性碳原子，其为R构型或S构型(R 7可位于苯基的邻位、间位或对位，例如，当n7为1时，R 7可位于苯基的对位；又例如，其为
Figure PCTCN2018093088-appb-000015
)；
XX8为D-Ala、D-NMeAla、Ala或βAla；
XX9为Tic、Phe、NMe-Phe、1Nal、2Nal、Bpa、Phe(4-Me)、Phe(4-Cl)、Phe(4-NO2)、HoPhe、Idc、Tic(OH)、Oic、Chc、Cha、MeA6c、HoPro、Pro(5Ph)、Pro(4Ph)、Ala(dip)、Bip、azaTic、D-Tic、Ti1c、D-Ti1c、TP5C、TP6C、Tic(6-Me)、S-Pip、Ica或D-Oic；
XX10为NhomoSer、或、氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)取代或未取代的下述任一氨基酸(所述的“取代的氨基酸”例如NMe-Ser或NMe-HoSer)：Ser、Thr、Hyp、Asp、D-HoSer和HoSer；
P为羟基或氨基。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
其中，XX0为氢、
Figure PCTCN2018093088-appb-000016
R 0-2或
Figure PCTCN2018093088-appb-000017
R 0-1为CH 3-，q为10～18；
PEG为
Figure PCTCN2018093088-appb-000018
m为6～12；
n为0～2；
所有的AA0独立地为
Figure PCTCN2018093088-appb-000019
Ahx、Gly或βAla；所有的k独立地为4～8，所有的r独立地为0或1；
R 0-2为R 0-2-1取代或未取代的C 1～C 6的烷基；
所有的R 0-2-1独立地为羟基取代或未取代的苯基；
R 0-3为R 0-3-1取代或未取代的C 1～C 8的烷基、或、R 0-3-2取代或未取代的苯基；
所有的R 0-3-1独立地为羟基取代或未取代的苯基、或、C 3～C 6的环烷基；
所有的R 0-3-2独立地为羟基、或者、卤代的C 1～C 4烷基；
XX1为氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸：D-Tyr(3F)、D-Tyr和D-Phe；
XX2为氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸：1Nal、2Nal、Bpa和、
Figure PCTCN2018093088-appb-000020
n2为0或1，R 2为C 1～C 4烷基或卤素，*标记的碳原子为手性碳原子，其为R构型或S构型；
XX3为
Figure PCTCN2018093088-appb-000021
其中，*标记的碳原子为手性碳原子，其为R构型或S构型；R 3-1为C 4～C 5的烷基或苄基；R 3-2为C 1～C 4的烷基；
XX4为Ala或
Figure PCTCN2018093088-appb-000022
*标记的碳原子为手性碳原子，其为R构型或S构型；Z为-(CR 4-1R 4-2) n4-或-S-(CR 4-3R 4-4) n4’-；所述的-(CR 4-1R 4-2) n4-和-S-(CR 4-3R 4-4) n4’-的右端与手性碳原子连接；n4为1～3，n4’为1或2；所有的R 4-1、R 4-2、R 4-3和R 4-4独立地为氢、羟基、卤素或苯基；
XX5为D-Ser、D-Hyp、D-Thr、D-NMeSer、2Nal、1Nal或D-HoSer；
XX6为Gln、NMeGln或NGln；
XX7为NMe-Phe、HoPhe、1Nal、2Nal、Bpa、D-Ser或
Figure PCTCN2018093088-appb-000023
n7为0或1，R 7为C 1～C 4烷基、C 1～C 4烷氧基或卤素，*标记的碳原子为手性碳原子，其为R构型或S构型；
XX8为D-Ala、D-NMeA、Ala或βAla；
XX9为Tic、Phe、NMePhe、1Nal、2Nal、Bpa、Phe(4-Me)、Phe(4-Cl)、Phe(4-NO2)、HoPhe、Idc、Tic(OH)、Oic、Chc、Cha、MeA6c、HoPro、Pro(5Ph)、Pro(4Ph)、Ala(dip)、Bip、azaTic、D-Tic、Ti1c、D-Ti1c、TP5C、TP6C、Tic(6-Me)、Ica或D-Oic；
XX10为NHoSer、或、氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸：Ser、Thr、Hyp、Asp、D-HoSer和HoSer；
P为羟基或氨基。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
其中，XX0为氢、
Figure PCTCN2018093088-appb-000024
R 0-2或
Figure PCTCN2018093088-appb-000025
R 0-1为CH 3-，q为10～18；
PEG为
Figure PCTCN2018093088-appb-000026
m为6～12；
n为0～2；
所有的AA0独立地为
Figure PCTCN2018093088-appb-000027
Ahx、Gly或βAla；所有的k独立地为4～8，所有的r独立地为0或1；
R 0-2为R 0-2-1取代或未取代的C 1～C 6的烷基；
所有的R 0-2-1独立地为羟基取代或未取代的苯基；
R 0-3为R 0-3-1取代或未取代的C 1～C 8的烷基、或、R 0-3-2取代或未取代的苯基；
所有的R 0-3-1独立地为羟基取代或未取代的苯基、或、C 3～C 6的环烷基；
所有的R 0-3-2独立地为羟基、或者、卤代的C 1～C 4烷基；
XX1为氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸：D-Tyr(3F)、D-Tyr和D-Phe；
XX2为氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸：1Nal、2Nal、Bpa和、
Figure PCTCN2018093088-appb-000028
n2为0或1，R 2为C 1～C 4烷基或卤素，*标记的碳原子为手性碳原子，其为R构型或S构型；
XX3为
Figure PCTCN2018093088-appb-000029
其中，*标记的碳原子为手性碳原子，其为R构型或S构型；R 3-1为C 4～C 5的烷基或苄基；R 3-2为C 1～C 4的烷基；
XX4为Ala或
Figure PCTCN2018093088-appb-000030
*标记的碳原子为手性碳原子，其为R构型或S构型；Z为-(CR 4-1R 4-2) n4-或-S-(CR 4-3R 4-4) n4’-；所述的-(CR 4-1R 4-2) n4-和-S-(CR 4-3R 4-4) n4’-的右端与手性碳原子连接；n4为1～3，n4’为1或2；所有的R 4-1、R 4-2、R 4-3和R 4-4独立地为氢、羟基、卤素或苯基；
XX5为D-Ser、D-Hyp、D-Thr、D-NMeSer、2Nal、1Nal或D-HoSer；
XX6为Gln、NMeGln或NGln；
XX7为NMe-Phe、HoPhe、1Nal、2Nal、Bpa、D-Ser或
Figure PCTCN2018093088-appb-000031
n7为0或1，R 7为C 1～C 4烷基、C 1～C 4烷氧基或卤素，*标记的碳原子为手性碳原子，其为R构型或S构型；
XX8为D-Ala、D-NMeA、Ala或βAla；
XX9为Tic、Phe、NMePhe、1Nal、2Nal、Bpa、Phe(4-Me)、Phe(4-Cl)、Phe(4-NO2)、HoPhe、Idc、Tic(OH)、Oic、Chc、Cha、MeA6c、Pro(5Ph)、Pro(4Ph)、Ala(dip)、Bip、azaTic、D-Tic、Ti1c、D-Ti1c、TP5C、TP6C、Tic(6-Me)、Ica或D-Oic；
XX10为NHoSer、或、氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸：Ser、Thr、Hyp、Asp、D-HoSer和HoSer；
P为羟基或氨基。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
其中，XX0为氢、
Figure PCTCN2018093088-appb-000032
R 0-2或
Figure PCTCN2018093088-appb-000033
R 0-1为CH 3-，q为10～18(例如，以下述任两个值为端点的范围：10、11、12、13、14、15、16、17和18)；
PEG为
Figure PCTCN2018093088-appb-000034
m为6～12(例如，以下述任两个值为端点的范围：6、7、8、9、10、11和12)；
n为2；
所有的AA0独立地为Gly或Beta-Ala；
R 0-2为R 0-2-1取代或未取代的C 1～C 6的烷基(所述的R 0-2-1的个数可为一个或多个{例如1个、2个、3个、4个或5个}；当存在多个R 0-2-1时，它们相同或不同；所有的R 0-2-1可独立地处于所述C 1～C 6烷基的末端或非末端；所述的C 1～C 6的烷基可为C 1～C 4的烷基；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“R 0-2-1取代的C 1～C 6的烷基”例如3-苯基丙基)；
所有的R 0-2-1独立地为苯基；
R 0-3为R 0-3-1取代或未取代的C 1～C 8的烷基(所述的R 0-3-1的个数可为一个或多个{例如1个、2个、3个、4个或5个}；当存在多个R 0-3-1时，它们相同或不同；所有的R 0-3-1可独立地处于所述C 1～C 8烷基的末端或非末端；所述的C 1～C 8的烷基可为C 1～C 4的烷基或正戊基；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“R 0-3-1取代的C 1～C 8的烷基”例如2-苯基乙基、3-苯基丙基、4-苯基丁基、4-苯基苄基、二苯甲基或环己基甲基)、或、R 0-3-2取代或未取代的苯基(所述的R 0-3-2的个数可为一个或多个{例如1个、2个、3个、4个或5个}；当存在多个R 0-3-2时，它们相同或不同；所有的R 0-3-2可独立地处于所述苯基的邻位、间位或对位；所述的“R 0-3-2取代的苯基”例如3,5-二羟基苯基、2,3-二羟基苯基、2,6-二羟基苯基、2,3,4-三羟基苯基、2,3,5-三羟基苯基或4-三氟甲基苯基)；
所有的R 0-3-1独立地为苯基、或、C 3～C 6的环烷基(例如环己基)；
所有的R 0-3-2独立地为卤代的C 1～C 4烷基(所述的“卤”的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的“卤”可独立地为氟、氯或溴；当存在多个卤时，它们相同或不同；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“卤代的C 1～C 4烷基”例如三氟甲基)；
XX1为氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基)取代或未取代的下述任一氨基酸(所述的“取代的氨基酸”例如D-NMeTyr)：D-Tyr(3F)和D-Tyr；
XX2为氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)取代或未取代的下述任一氨基酸(所述的“取代的氨基酸”例如NMePhe)：1Nal、2Nal、Bpa和、
Figure PCTCN2018093088-appb-000035
{例如Phe、Phe(4-Cl)或Phe(4-Me)}；n2为0或1，R 2为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基或异丁基)或卤素(例如氟或氯)，*标记的碳原子为手性碳原子，其为R构型或S构型(R 2可位于苯基的邻位、间位或对位，例如，当n2为1时，R 2可位于苯基的对位； 又例如，其为
Figure PCTCN2018093088-appb-000036
)；
XX3为
Figure PCTCN2018093088-appb-000037
其中，*标记的碳原子为手性碳原子，其为R构型或S构型(例如
Figure PCTCN2018093088-appb-000038
)；R 3-1为C 4～C 5的烷基(例如正丁基、异丁基、仲丁基、叔丁基、正戊基或3-甲基丁基)或苄基；R 3-2为C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)；(所述的
Figure PCTCN2018093088-appb-000039
例如NMe-Leu、NMe-Phe、NMe-HoLeu、NEt-Leu、NPr-Leu、NiPr-Leu、Nbu-Leu、NMe-Nle或NMe-Ile)；
XX4为
Figure PCTCN2018093088-appb-000040
(例如
Figure PCTCN2018093088-appb-000041
Y为-(CR 4-1R 4-2)-{例如-CH 2-、-CH(OH)-或-CF 2}、-(CH 2) 2-或-S-；又例如Aze、Thz、Hyp、Pro、Pro(5Ph)、Pro(4Ph)、Pro(diF)或HoPro)；*标记的碳原子为手性碳原子，其为R构型或S构型(例如
Figure PCTCN2018093088-appb-000042
)；Z为-(CR 4-1R 4-2) n4-{例如-CH 2-、-(CH 2) 2-、-CH(OH)-CH 2-、-CF 2-CH 2-、-CHPh-CH 2-、-CH 2-CHPh-或-(CH 2) 3-}或-S-(CR 4-3R 4-4) n4’-{例如-S-CH 2-}；所述的-(CR 4-1R 4-2) n4-和-S-(CR 4-3R 4-4) n4’-的右端与手性碳原子连接；n4为1～3(例如1、2或3)，n4’为1或2；所有的R 4-1、R 4-2、R 4-3和R 4-4独立地为氢、羟基、卤素(例如氟或氯)或苯基；
XX5为D-Ser、D-Thr、或D-HoSer；
XX6为Gln；
XX7为1Nal、2Nal、或
Figure PCTCN2018093088-appb-000043
{例如Phe、Phe(3-Cl)、Phe(3-Me)、Phe(3-OMe)、Phe(4-OMe)、Phe(4-Me)或Phe(4-Cl)}；n7为0或1，R 7为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基或异丁基)、C 1～C 4烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基或异丁氧基)或卤素(例如氟或氯)，*标记的碳原子为手性碳原子，其为R构型或S构型(R 7可位于苯基的邻位、间位或对位，例如，当 n7为1时，R 7可位于苯基的对位；又例如，其为
Figure PCTCN2018093088-appb-000044
)；
XX8为D-Ala；
XX9为Tic、Phe(4-Me)、Phe(4-Cl)、D-Ti1c、或D-Oic；
XX10为NhomoSer、或、氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)取代或未取代的下述任一氨基酸(所述的“取代的氨基酸”例如NMe-Ser或NMe-HoSer)：Ser和HoSer；
P为羟基或氨基。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX0为氢。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
R 0-1为CH 3-，q为10～16；
PEG为
Figure PCTCN2018093088-appb-000045
m为6～10；
n为2；
所有的AA0独立地为Gly或βAla。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
R 0-1为CH 3-，q为10～16；
PEG为
Figure PCTCN2018093088-appb-000046
m为8；
n为2；
所有的AA0独立地为Gly或βAla。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
R 0-2为R 0-2-1取代或未取代的C 1～C 6的烷基；
所有的R 0-2-1独立地为苯基。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
R 0-3为R 0-3-1取代或未取代的C 1～C 8的烷基、或、R 0-3-2取代或未取代的苯基；
所有的R 0-3-1独立地为苯基、或、C 3～C 6的环烷基；
所有的R 0-3-2独立地为卤代的C 1～C 4烷基。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX1为氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸：D-Tyr(3F)和D-Tyr。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX2为氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸：1Nal、2Nal、Bpa、Phe、Phe(4-Cl)和Phe(4-Me)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX3为NMe-Leu、NMe-Phe、NMe-HoLeu、NEt-Leu、NPr-Leu、NiPr-Leu、Nbu-Leu、NMe-Nle或NMe-Ile。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX3为NMe-Leu、NMe-Phe、NMe-HoLeu、NEt-Leu、NPr-Leu、NiPr-Leu或Nbu-Leu。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX4为
Figure PCTCN2018093088-appb-000047
*标记的碳原子为手性碳原子，其为R构型或S构型；Z为-(CR 4-1R 4-2) n4-或-S-(CR 4-3R 4-4) n4’-；所述的-(CR 4-1R 4-2) n4-和-S-(CR 4-3R 4-4) n4’-的右端与手性碳原子连接；n4为1～3，n4’为1或2；所有的R 4-1、R 4-2、R 4-3和R 4-4独立地为氢、羟基、卤素或苯基。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX4为Thz、Hyp、Pro、Pro(5Ph)、Pro(4Ph)或Pro(diF)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如 前任一方案所述)：
XX4为Thz、Hyp、Pro、Pro(4Ph)或Pro(diF)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX5为D-Ser、D-Thr或D-HoSer。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX6为Gln。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX7为1Nal、2Nal或
Figure PCTCN2018093088-appb-000048
n7为0或1，R 7为C 1～C 4烷基、C 1～C 4烷氧基或卤素，*标记的碳原子为手性碳原子，其为R构型或S构型。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX7为1Nal、2Nal或Phe。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX8为D-Ala。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX9为Tic、Phe、NMePhe、1Nal、2Nal、Bpa、Phe(4-Me)、Phe(4-Cl)、Phe(4-NO2)、HoPhe、Idc、Tic(OH)、Oic、Chc、Cha、MeA6c、HoPro、Pro(5Ph)、Pro(4Ph)、Ala(dip)、Bip、azaTic、D-Tic、Ti1c、D-Ti1c、TP5C、TP6C、Tic(6-Me)、Ica或D-Oic。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX9为Tic、Phe、NMePhe、1Nal、2Nal、Bpa、Phe(4-Me)、Phe(4-Cl)、Phe(4-NO2)、HoPhe、Idc、Tic(OH)、Oic、Chc、Cha、MeA6c、Pro(5Ph)、Pro(4Ph)、Ala(dip)、Bip、azaTic、D-Tic、Ti1c、D-Ti1c、TP5C、TP6C、Tic(6-Me)、Ica或D-Oic。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX9为Tic、Phe(4-Me)、Phe(4-Cl)、D-Ti1c或D-Oic。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX10为NHoSer、或、氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸：Ser和HoSer。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
P为羟基。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
其中，XX0为氢、
Figure PCTCN2018093088-appb-000049
R 0-2或
Figure PCTCN2018093088-appb-000050
R 0-1为CH 3-，q为10～18(例如，以下述任两个值为端点的范围：10、11、12、13、14、15、16、17和18)；
PEG为
Figure PCTCN2018093088-appb-000051
m为6～10(例如，以下述任两个值为端点的范围：6、7、8、9和10)；
n为0～2(例如0、1或2)；
所有的AA0独立地为
Figure PCTCN2018093088-appb-000052
(例如PEG8)、Ahx、Gly或Beta-Ala；所有的k独立地为4～8(例如，以下述任两个值为端点的范围：4、5、6、7和8)，所有的r独立地为0或1；
R 0-2为R 0-2-1取代或未取代的C 1～C 6的烷基(所述的R 0-2-1的个数可为一个或多个{例如1个、2个、3个、4个或5个}；当存在多个R 0-2-1时，它们相同或不同；所有的R 0-2-1可独立地处于所述C 1～C 6烷基的末端或非末端；所述的C 1～C 6的烷基可为C 1～C 4的烷基；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“R 0-2-1取代的C 1～C 6的烷基”例如3,5-二羟基苄基或3-苯基丙基)；
所有的R 0-2-1独立地为羟基取代或未取代的苯基(所述的羟基的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的羟基可独立地处于所述苯基的邻位、间位或对 位；所述的“羟基取代的苯基”例如3,5-二羟基苯基)；
R 0-3为R 0-3-1取代或未取代的C 1～C 8的烷基(所述的R 0-3-1的个数可为一个或多个{例如1个、2个、3个、4个或5个}；当存在多个R 0-3-1时，它们相同或不同；所有的R 0-3-1可独立地处于所述C 1～C 8烷基的末端或非末端；所述的C 1～C 8的烷基可为C 1～C 4的烷基或正戊基；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“R 0-3-1取代的C 1～C 8的烷基”例如2-苯基乙基、3-苯基丙基、4-苯基丁基、4-苯基苄基、二苯甲基、3,4-二羟基苄基、3,5-二羟基苄基或环己基甲基)、或、R 0-3-2取代或未取代的苯基(所述的R 0-3-2的个数可为一个或多个{例如1个、2个、3个、4个或5个}；当存在多个R 0-3-2时，它们相同或不同；所有的R 0-3-2可独立地处于所述苯基的邻位、间位或对位；所述的“R 0-3-2取代的苯基”例如3,5-二羟基苯基、2,3-二羟基苯基、2,6-二羟基苯基、2,3,4-三羟基苯基、2,3,5-三羟基苯基或4-三氟甲基苯基)；
所有的R 0-3-1独立地为羟基取代或未取代的苯基(所述的羟基的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的羟基可独立地处于所述苯基的邻位、间位或对位；所述的“羟基取代的苯基”例如3,4-二羟基苯基或3,5-二羟基苯基)、或、C 3～C 6的环烷基(例如环己基)；
所有的R 0-3-2独立地为羟基、或者、卤代的C 1～C 4烷基(所述的“卤”的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的“卤”可独立地为氟、氯或溴；当存在多个卤时，它们相同或不同；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“卤代的C 1～C 4烷基”例如三氟甲基)；
XX1为氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基)取代或未取代的下述任一氨基酸(所述的“取代的氨基酸”例如D-NMeTyr)：D-Tyr和D-Phe；
XX2为氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)取代或未取代的下述任一氨基酸(所述的“取代的氨基酸”例如NMePhe)：1Nal、2Nal、Bpa和、
Figure PCTCN2018093088-appb-000053
{例如Phe、Phe(4-Cl)或Phe(4-Me)}；n2为0或1，R 2为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基或异丁基)或卤素(例如氟或氯)，*标记的碳原子为手性碳原子，其为R构型或S构型(R 2可位于苯基的邻位、间位或对位，例如，当n2为1时，R 2可位于苯基的对位； 又例如，其为
Figure PCTCN2018093088-appb-000054
)；
XX3为
Figure PCTCN2018093088-appb-000055
其中，*标记的碳原子为手性碳原子，其为R构型或S构型(例如
Figure PCTCN2018093088-appb-000056
)；R 3-1为C 4～C 5的烷基(例如正丁基、异丁基、仲丁基、叔丁基、正戊基或3-甲基丁基)或苄基；R 3-2为C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)；(所述的
Figure PCTCN2018093088-appb-000057
例如NMe-Leu、NMe-Phe、NMe-HoLeu、NEt-Leu、NPr-Leu、NiPr-Leu、Nbu-Leu、NMe-Nle或NMe-Ile)；
XX4为Ala或
Figure PCTCN2018093088-appb-000058
(例如
Figure PCTCN2018093088-appb-000059
Y为-(CR 4-1R 4-2)-{例如-CH 2-、-CH(OH)-或-CF 2}、-(CH 2) 2-或-S-；又例如Aze、Thz、Hyp、Pro、Pro(5Ph)、Pro(4Ph)、Pro(diF)或HoPro)；*标记的碳原子为手性碳原子，其为R构型或S构型(例如
Figure PCTCN2018093088-appb-000060
)；Z为-(CR 4-1R 4-2) n4-{例如-CH 2-、-(CH 2) 2-、-CH(OH)-CH 2-、-CF 2-CH 2-、-CHPh-CH 2-、-CH 2-CHPh-或-(CH 2) 3-}或-S-(CR 4-3R 4-4) n4’-{例如-S-CH 2-}；所述的-(CR 4-1R 4-2) n4-和-S-(CR 4-3R 4-4) n4’-的右端与手性碳原子连接；n4为1～3(例如1、2或3)，n4’为1或2；所有的R 4-1、R 4-2、R 4-3和R 4-4独立地为氢、羟基、卤素(例如氟或氯)或苯基；
XX5为D-Ser、D-Hyp、D-Thr、βAla、D-NMeSer、2Nal、1Nal或D-HoSer；
XX6为Gln、NMe-Gln或NGln；
XX7为NMe-Phe、HoPhe、1Nal、2Nal、Bpa、D-Ser或
Figure PCTCN2018093088-appb-000061
{例如Phe、Phe(3-Cl)、Phe(3-Me)、Phe(3-OMe)、Phe(4-OMe)、Phe(4-Me)或Phe(4-Cl)}；n7为0或1，R 7为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基或异丁基)、C 1～C 4烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基或异丁氧基)或卤素(例如氟或氯)，*标记的碳原子为手性碳原子，其为R构型或S构型(R 7可位于苯基的邻位、 间位或对位，例如，当n7为1时，R 7可位于苯基的对位；又例如，其为
Figure PCTCN2018093088-appb-000062
)；
XX8为D-Ala、D-NMeAla、Ala或βAla；
XX9为Tic、Phe、NMe-Phe、1Nal、2Nal、Bpa、Phe(4-Me)、Phe(4-Cl)、Phe(4-NO2)、HoPhe、Idc、Tic(OH)、Oic、Chc、Cha、MeA6c、HoPro、Pro(5Ph)、Pro(4Ph)、Ala(dip)、Bip、azaTic、D-Tic、Ti1c、D-Ti1c、TP5C、TP6C、Tic(6-Me)、S-Pip、Ica或D-Oic；
XX10为NhomoSer、或、氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)取代或未取代的下述任一氨基酸(所述的“取代的氨基酸”例如NMe-Ser或NMe-HoSer)：Ser、Thr、Hyp、Asp、D-HoSer和HoSer；
P为羟基或氨基。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX0为氢、
Figure PCTCN2018093088-appb-000063
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
R 0-1为CH 3-。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
q为13～15(例如13、14或15)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
m为6～10(例如，以下述任两个值为端点的范围：6、7、8、9和10)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
n为2。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
所有的AA0独立地为Gly或β-Ala。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
R 0-3为苯基取代的C 1～C 8的烷基(所述的R 0-3-1的个数可为1个或2个；所有的苯基可独立地处于所述C 1～C 6烷基的末端或非末端；所述的C 1～C 8的烷基可为C 1～C 4的烷基或正戊基；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“苯基取代的C 1～C 8的烷基”例如2-苯基乙基、3-苯基丙基或4-苯基丁基)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX1为氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)取代或未取代的D-Tyr(所述的“取代的D-Tyr”例如D-NMeTyr)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX2为氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)取代或未取代的Phe(所述的“取代的Phe”例如NMe-Phe)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX3为 其中，*标记的碳原子为手性碳原子，其为R构型或S构型(例如
Figure PCTCN2018093088-appb-000065
)；R 3-1为异丁基、3-甲基丁基或苄基；R 3-2为C 1～C 3的烷基(例如甲基、乙基、正丙基或异丙基)；(所述的
Figure PCTCN2018093088-appb-000066
例如NMe-Leu、NMe-HoLeu或NMe-Phe)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX4为
Figure PCTCN2018093088-appb-000067
(例如Thz、Pro或Pro(diF))；*标记的碳原子为手性碳原子，其 为R构型或S构型(例如
Figure PCTCN2018093088-appb-000068
)；Y为-(CR 4-1R 4-2)-(例如-CH 2-或-CF 2)或-S-；R 4-1和R 4-2独立地为氢或卤素(例如氟或氯)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX5为D-Ser或D-HoSer。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX6为Gln。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX7为Phe、1Nal或2Nal。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX8为D-Ala。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX9为Tic、D-Ti1c或D-Oic。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX10为NHoSer、或、氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)取代或未取代的下述任一氨基酸(所述的“取代的氨基酸”例如NMe-Ser或NMe-HoSer)：Ser和HoSer。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
P为羟基或氨基。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
其中，XX0为氢、
Figure PCTCN2018093088-appb-000069
R 0-2或
Figure PCTCN2018093088-appb-000070
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
n为0～2(例如0、1或2)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
所有的AA0独立地为
Figure PCTCN2018093088-appb-000071
(例如PEG8)、Ahx、Gly或βAla；所有的k独立地为4～8(例如，以下述任两个值为端点的范围：4、5、6、7和8)，所有的r独立地为0或1。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
R 0-2为C 1～C 6的烷基(所述的C 1～C 6的烷基可为C 1～C 4的烷基；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
R 0-3为R 0-3-1取代或未取代的C 1～C 8的烷基(所述的R 0-3-1的个数可为一个或多个{例如1个、2个、3个、4个或5个}；当存在多个R 0-3-1时，它们相同或不同；所有的R 0-3-1可独立地处于所述C 1～C 8烷基的末端或非末端；所述的C 1～C 8的烷基可为C 1～C 4的烷基或正戊基；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“R 0-3-1取代的C 1～C 8的烷基”例如2-苯基乙基、或环己基甲基)、或、羟基取代或未取代的苯基(所述的羟基的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的羟基可独立地处于所述苯基的邻位、间位或对位；所述的“羟基取代的苯基”例如3,5-二羟基苯基)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
所有的R 0-3-1独立地为苯基、或、C 3～C 6的环烷基(例如环己基)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX1为D-NMeTyr、D-Tyr、D-Phe或D-NMePhe。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX3为NMe-Leu、NEt-Leu、NPr-Leu、NiPr-Leu、NMe-HoLeu、NMe-Nle或NMe-Ile。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX4为Thz、Pro、Pro(4Ph)、Pro(diF)、HoPro或Hyp。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX7为1Nal、2Nal、Bpa、Phe、Phe(3-Cl)、Phe(4-Cl)、Phe(4-Me)、Phe(3-Me)、Phe(3-OMe)、Phe(4-OMe)或HoPhe。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX9为Tic、D-Tic、DTi1c、D-Oic、TP5C或TP6C。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX10为NMe-Ser、NHoSer、NMe-HoSer、D-HoSer、HoSer或Ser。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
R 0-3为苯基取代或未取代的C 1～C 8的烷基(所述的苯基的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的苯基可独立地处于所述C 1～C 8烷基的末端或非末端；所述的C 1～C 8的烷基可为C 1～C 4的烷基或正戊基；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“苯基取代的C 1～C 8的烷基”例如2-苯基乙基)、或、羟基取代或未取代的苯基(所述的羟基的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的羟基可独立地处于所述苯基的邻位、间位或对位；所述的“羟基取代的苯基”例如3,5-二羟基苯基)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX1为D-NMeTyr或D-Tyr。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX3为NMe-Leu、NEt-Leu或NMe-HoLeu。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX4为Thz、Pro或Pro(diF)。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX7为1Nal、2Nal或Phe。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX9为Tic、D-Tic或DTi1c。
在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一方案所述)：
XX10为NMe-Ser、NHoSer或Ser。
在某一技术方案中，所述的化合物I可为下列任一化合物：
Figure PCTCN2018093088-appb-000072
Figure PCTCN2018093088-appb-000073
Figure PCTCN2018093088-appb-000074
Figure PCTCN2018093088-appb-000075
本发明还提供了上述的化合物I、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药在制备药物中的应用，所述的药物用于治疗和/或预防与ChemR23相关的疾病。
所述的“与ChemR23相关的疾病”包括但不限于例如免疫疾病、炎症性疾病、代谢性疾病(例如肥胖或糖尿病)、心血管系统疾病、骨病、肿瘤(例如癌症)、生殖系统疾病、精神疾病、病毒性感染、哮喘或肝脏疾病。
本发明还提供了上述的化合物I、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药在制备ChemR23激动剂中的应用。
本发明还提供了一种药物组合物，其包含上述的化合物I、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药，以及药用辅料。
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以配制用于任何形式给药，包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂：如鼻腔喷雾剂或吸入剂；适于胃肠外给药的液体剂型；栓剂以及锭剂。
本发明还提供了一种如式II所示的肽类化合物、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药；所述的化合物II为下列任一化合物：
Figure PCTCN2018093088-appb-000076
Figure PCTCN2018093088-appb-000077
本发明还提供了上述的化合物II、其药学上可接受的盐、其互变异构体、其晶型、 其溶剂合物或其前药在制备药物中的应用，所述的药物用于治疗和/或预防与ChemR23相关的疾病。
所述的“与ChemR23相关的疾病”包括但不限于例如免疫疾病、炎症性疾病、代谢性疾病(例如肥胖或糖尿病)、心血管系统疾病、骨病、肿瘤(例如癌症)、生殖系统疾病、精神疾病、病毒性感染、哮喘或肝脏疾病。
本发明还提供了上述的化合物II、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药在制备ChemR23激动剂中的应用。
本发明还提供了一种药物组合物，其包含上述的化合物II、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药，以及药用辅料。
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以配制用于任何形式给药，包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂：如鼻腔喷雾剂或吸入剂；适于胃肠外给药的液体剂型；栓剂以及锭剂。
本发明还提供了一种如式III所示的肽类化合物、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药；
XX0-XX1-XX2-XX3-XX4-XX5-XX6-XX7-XX8-XX9-XX10-P  (III)
其中，XX0为R 0-2、
Figure PCTCN2018093088-appb-000078
R 0-2为R 0-2-1取代或未取代的C 1～C 6的烷基(所述的R 0-2-1的个数可为一个或多个{例如1个、2个、3个、4个或5个}；当存在多个R 0-2-1时，它们相同或不同；所有的R 0-2-1可独立地处于所述C 1～C 6烷基的末端或非末端；所述的C 1～C 6的烷基可为C 1～C 4的烷基；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“R 0-2-1取代的C 1～C 6的烷基”例如3,5-二羟基苄基或3-苯基丙基)；
所有的R 0-2-1独立地为羟基取代或未取代的苯基(所述的羟基的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的羟基可独立地处于所述苯基的邻位、间位或对位；所述的“羟基取代的苯基”例如3,5-二羟基苯基)；
R 0-3为R 0-3-1取代或未取代的C 1～C 8的烷基(所述的R 0-3-1的个数可为一个或多个{例如1个、2个、3个、4个或5个}；当存在多个R 0-3-1时，它们相同或不同；所有的R 0-3-1可独立地处于所述C 1～C 8烷基的末端或非末端；所述的C 1～C 8的烷基可为C 1～C 4的烷基或正戊基；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“R 0-3-1取代的C 1～C 8的烷基”例如2-苯基乙基、3-苯基丙基、4-苯基丁基、4-苯基苄基、二苯甲基、3,4-二羟基苄基、3,5-二羟基苄基、联苯-4-基甲基或环己基甲基)、或、R 0-3-2取代或未取代的苯基(所述的R 0-3-2的个数可为一个或多个{例如1个、2个、3个、4个或5个}；当存在多个R 0-3-2时，它们相同或不同；所有的R 0-3-2可独立地处于所述苯基的邻位、间位或对位；所述的“R 0-3-2取代的苯基”例如3,5-二羟基苯基、2,3-二羟基苯基、2,6-二羟基苯基、2,3,4-三羟基苯基、2,3,5-三羟基苯基或4-三氟甲基苯基)；
所有的R 0-3-1独立地为羟基取代或未取代的苯基(所述的羟基的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的羟基可独立地处于所述苯基的邻位、间位或对位；所述的“羟基取代的苯基”例如3,4-二羟基苯基或3,5-二羟基苯基)、联苯基、或、C 3～C 6的环烷基(例如环己基)；
所有的R 0-3-2独立地为羟基、或者、卤代的C 1～C 4烷基(所述的“卤”的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的“卤”可独立地为氟、氯或溴；当存在多个卤时，它们相同或不同；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“卤代的C 1～C 4烷基”例如三氟甲基)；
R 0-4为R 0-4-1取代或未取代的C 1～C 8的烷基(所述的R 0-4-1的个数可为一个或多个{例 如1个、2个、3个、4个或5个}；当存在多个R 0-4-1时，它们相同或不同；所有的R 0-4-1可独立地处于所述C 1～C 8烷基的末端或非末端；所述的C 1～C 8的烷基可为C 1～C 4的烷基或正戊基；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“R 0-4-1取代的C 1～C 8的烷基”例如2-苯基乙基、3-苯基丙基、4-苯基丁基、4-苯基苄基、二苯甲基、3,4-二羟基苄基、3,5-二羟基苄基或环己基甲基)；
所有的R 0-4-1独立地为羟基取代或未取代的苯基(所述的羟基的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的羟基可独立地处于所述苯基的邻位、间位或对位；所述的“羟基取代的苯基”例如3,4-二羟基苯基或3,5-二羟基苯基)、或、C 3～C 6的环烷基(例如环己基)；
R 0-5为R 0-5-1取代或未取代的C 1～C 8的烷基(所述的R 0-5-1的个数可为一个或多个{例如1个、2个、3个、4个或5个}；当存在多个R 0-5-1时，它们相同或不同；所有的R 0-5-1可独立地处于所述C 1～C 8烷基的末端或非末端；所述的C 1～C 8的烷基可为C 1～C 4的烷基或正戊基；所述的C 1～C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；所述的“R 0-5-1取代的C 1～C 8的烷基”例如2-苯基乙基、3-苯基丙基、4-苯基丁基、4-苯基苄基、二苯甲基、3,4-二羟基苄基、3,5-二羟基苄基或环己基甲基)；
所有的R 0-5-1独立地为羟基取代或未取代的苯基(所述的羟基的个数可为一个或多个{例如1个、2个、3个、4个或5个}；所有的羟基可独立地处于所述苯基的邻位、间位或对位；所述的“羟基取代的苯基”例如3,4-二羟基苯基或3,5-二羟基苯基)、或、C 3～C 6的环烷基(例如环己基)；
XX1为氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基)取代或未取代的D-Tyr(所述的“取代的氨基酸”例如D-NMeTyr)；
XX2为氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)取代或未取代的下述任一氨基酸(所述的“取代的氨基酸”例如NMePhe)：
Figure PCTCN2018093088-appb-000079
{例如Phe、Phe(4-Cl)或Phe(4-Me)}；n2为0或1，R 2为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基或异丁基)或卤素(例如氟或氯)，*标记的碳原子为手性碳原子，其为R构型或S构型(R 2可位于苯基的邻位、间位或对位，例如，当n2为1时，R 2可位于苯基的对位；又例如，其为
Figure PCTCN2018093088-appb-000080
)；
XX3为
Figure PCTCN2018093088-appb-000081
其中，*标记的碳原子为手性碳原子，其为R构型或S构型(例如
Figure PCTCN2018093088-appb-000082
)；R 3-1为C 4～C 5的烷基(例如正丁基、异丁基、仲丁基、叔丁基、正戊基或3-甲基丁基)或苄基；R 3-2为氢或C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)；(所述的
Figure PCTCN2018093088-appb-000083
例如Leu、NMe-Leu、NMe-Phe、NMe-HoLeu、NEt-Leu、NPr-Leu、NiPr-Leu、Nbu-Leu、NMe-Nle或NMe-Ile)；
XX4为
Figure PCTCN2018093088-appb-000084
(例如
Figure PCTCN2018093088-appb-000085
Y为-(CR 4-1R 4-2)-{例如-CH 2-、-CH(OH)-或-CF 2}、-(CH 2) 2-或-S-；又例如Aze、Thz、Hyp、Pro、Pro(5Ph)、Pro(4Ph)、Pro(diF)或HoPro)；*标记的碳原子为手性碳原子，其为R构型或S构型(例如
Figure PCTCN2018093088-appb-000086
)；Z为-(CR 4-1R 4-2) n4-{例如-CH 2-、-(CH 2) 2-、-CH(OH)-CH 2-、-CF 2-CH 2-、-CHPh-CH 2-、-CH 2-CHPh-或-(CH 2) 3-}或-S-(CR 4-3R 4-4) n4’-{例如-S-CH 2-}；所述的-(CR 4-1R 4-2) n4-和-S-(CR 4-3R 4-4) n4’-的右端与手性碳原子连接；n4为1～3(例如1、2或3)，n4’为1或2；所有的R 4-1、R 4-2、R 4-3和R 4-4独立地为氢、羟基、卤素(例如氟或氯)或苯基；
XX5为D-Ser；
XX6为Gln；
XX7为
Figure PCTCN2018093088-appb-000087
{例如Phe、Phe(3-Cl)、Phe(3-Me)、Phe(3-OMe)、Phe(4-OMe)、Phe(4-Me)或Phe(4-Cl)}；n7为0或1，R 7为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基或异丁基)、C 1～C 4烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基或异丁氧基)或卤素(例如氟或氯)，*标记的碳原子为手性碳原子，其为R构型或S构型(R 7可位于苯基的邻位、间位或对位，例如，当n7为1时，R 7可 位于苯基的对位；又例如，其为
Figure PCTCN2018093088-appb-000088
)；
XX8为D-Ala；
XX9为Tic；
XX10为氨基被1个C 1～C 4的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)取代或未取代的Ser(所述的“取代的氨基酸”例如NMe-Ser)；
P为羟基或氨基。
在某一技术方案中，所述的化合物III可为下列任一化合物：
Figure PCTCN2018093088-appb-000089
本发明还提供了上述的化合物III、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药在制备药物中的应用，所述的药物用于治疗和/或预防与ChemR23相关的疾病。
所述的“与ChemR23相关的疾病”包括但不限于例如免疫疾病、炎症性疾病、代谢性疾病(例如肥胖或糖尿病)、心血管系统疾病、骨病、肿瘤(例如癌症)、生殖系统疾病、精神疾病、病毒性感染、哮喘或肝脏疾病。
本发明还提供了上述的化合物III、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药在制备ChemR23激动剂中的应用。
本发明还提供了一种药物组合物，其包含上述的化合物III、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药，以及药用辅料。
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以配制用于任何形式给药，包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂：如鼻腔喷雾剂或吸入剂；适于胃肠外给药的液体剂型；栓剂以及锭剂。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳 实例。
本发明所用试剂和原料均市售可得。
如无特别说明，本发明中所用的术语具有以下含义：
结构式中，当XX0为氢、R 0-2或
Figure PCTCN2018093088-appb-000090
时，“XX0-XX1”是指XX0与XX1中的氨基(当氨基酸存在多个氨基时，可以为手性碳原子上的氨基，还可以为伯氨基)连接形成的基团，也即XX0取代了XX1中的氨基上的一个氢原子。“XX0中，
Figure PCTCN2018093088-appb-000091
与PEG的连接”同此。例如，当XX0为甲基、XX1为Phe时，“XX0-XX1”是指
Figure PCTCN2018093088-appb-000092
结构式中，“XX1-XX2”是指XX1中的羧基(当氨基酸存在多个羧基时，可以为手性碳原子上的羧基)与XX2中的氨基(当氨基酸存在多个氨基时，可以为手性碳原子上的氨基，还可以为伯氨基)连接形成的含
Figure PCTCN2018093088-appb-000093
的基团。“AA0-AA0”、“AA0-XX1”、“XX2-XX3”、“XX3-XX4”、“XX4-XX5”、“XX5-XX6”、“XX6-XX7”、“XX7-XX8”、“XX8-XX9”、“XX9-XX10”、“PEG-AA0”同此。例如，当XX6为Phe、XX7为Gly时，“XX6-XX7”是指
Figure PCTCN2018093088-appb-000094
结构式中，“XX10-P”是指XX10的羧基(-COOH)中的-OH被P代替所形成的基团，例如，当XX10为Phe、P为-NH 2时，“XX10-P”是指
Figure PCTCN2018093088-appb-000095
当XX10为Phe、P为-OH时，“XX10-P”是指Phe本身
Figure PCTCN2018093088-appb-000096
若具体序列的右端以氨基酸(XX10)结尾，未明确-P是哪一基团，即表示默认P为-OH。
在本文中使用常规的用于表示氨基酸的单字母或三字母代码来定义本发明所述的肽分子。术语“氨基酸”包括水溶性的、具有与α-碳原子连接的羧基(-COOH)和氨基(-NH 2)基团的有机化合物。氨基酸可以用通式R-CH(NH 2)COOH表示；R基团为氢或有机基团，并且决定了任意具体氨基酸的性质。当R不是氢时，α-碳原子周围的四个不同基团的四面体排列使氨基酸具有光学活性。两种镜像形式被称为L-异构体和D-异构体。通常，仅有L-氨基酸是蛋白质(如真核蛋白质)的组成成分。
除非另作说明，本发明的肽分子包含L-氨基酸。当D-氨基酸存在于本发明的肽分子时，用带有前缀“(D)”的常规单字母氨基酸代码表示。
如所述，本发明的分子可以包含在特定位置具有“任意D-氨基酸”的肽序列或由在特定位置具有“任意D-氨基酸”的肽序列组成。所述“任意D-氨基酸”包括在序列中在特定位置的任意天然或非天然(例如化学修饰的)D-氨基酸。天然D-氨基酸的实例如下：D-丙氨酸；D-天冬氨酸；D-半胱氨酸；D-谷氨酸；D-苯丙氨酸；D-甘氨酸；D-组氨酸；D-异亮氨酸；D-赖氨酸；D-亮氨酸；D-蛋氨酸；D-天冬酰胺；D-脯氨酸；D-谷氨酰胺；D-精氨酸；D-丝氨酸；D-苏氨酸；D-缬氨酸；D-色氨酸；D-酪氨酸。非天然D-氨基酸的实例如下：萘基丙氨酸；D-吡啶基丙氨酸；D-叔丁基丝氨酸；D-鸟氨酸；D-ε氨基赖氨酸；D-高精氨酸；D-α甲基亮氨酸以及用卤素取代(如F)这些和其它非天然氨基酸中的质子。
通过形成肽键，氨基酸结合形成短链(肽)或较长的链(多肽)。已知蛋白质和/或肽由不同流动相比例的大约20种常见氨基酸组成，其序列决定了蛋白质和/或肽的形状、性质和生物学作用。这种肽或多肽链中的氨基酸残基通常用它们在链上的排列位置来表示，第一位(即位点1)指定为链N-末端的氨基酸。
表1氨基酸缩写解释
Figure PCTCN2018093088-appb-000097
Figure PCTCN2018093088-appb-000098
Figure PCTCN2018093088-appb-000099
Figure PCTCN2018093088-appb-000100
Figure PCTCN2018093088-appb-000101
Figure PCTCN2018093088-appb-000102
术语“药学上可接受的盐”指药学上可接受的有机或无机盐。示例性酸盐包括但不限于：硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1-1-亚甲基-双(2-羟基-3-萘甲酸盐))。本发明中所用化合物可与各种氨基酸形成药学上可接受的盐。合适的碱盐包括但不限于铝盐、钙盐、锂盐、镁盐、钾盐、钠盐、锌盐、铋和二乙醇胺盐。药学上可接受的盐的综述见Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“晶型”是指在结晶时，分子在晶格空间的排列不同而形成的一种或多种晶体结构。
术语“溶剂合物”是一种晶体形式，除活性分子以外，它还包含一种或多种融入晶体结构中的溶剂分子。溶剂合物可包括化学计量量或非化学计量量的溶剂，并且溶剂中的溶剂分子可能以有序或非有序排列的形式存在。含有非化学计量量溶剂分子的溶剂合物可能是溶剂合物至少丢失一部分(但并非全部)溶剂分子得到的。在一个特定实施例中，一种溶剂合物是一种水合物，意味着化合物的结晶形式可包括水分子。
术语“前药”是指包含生物反应官能团的化合物的衍生物，使得在生物条件下(体外或体内)，生物反应官能团可从化合物上裂解或以其他方式发生反应以提供所述化合物。通常，前药无活性，或者至少比化合物本身活性低，使得直到将所述化合物从生物反应官能团上裂解后才能发挥其活性。生物反应官能团可在生物条件下水解或氧化以提供所述化合物。例如，前药可包含可生物水解的基团，可生物水解的基团实例包括但不限于可生物水解的磷酸盐、可生物水解的酯、可生物水解的酰胺、可生物水解的碳酸酯、可生物水解的氨基甲酸酯和可生物水解的酰脲。有关前药的综述参见，例如，J.Rautio et al.,Nature Reviews Drug Discovery(2008)7,255-270 and Prodrugs:Challenges和Rewards(V.Stella et al.ed.,Springer,2007).
本发明的积极进步效果在于：本发明的肽类化合物的稳定性较佳且活性较佳。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
可以通过Lu et al(1981)J.Org.Chem.46，3433和其中的参考文献中公开的Fmoc-聚酰胺式固相肽合成法来合成本发明分子的肽序列。用9-芴基甲氧羰基(Fmoc)基团提供临时的N-氨基保护。使用含20％哌啶的N，N-二甲基甲酰胺进行该高度碱不稳定的保护基团的重复去除。可以将侧链官能团保护成其丁基醚(对于丝氨酸、苏氨酸和酪氨酸的情况)、丁基酯(对于谷氨酸和天冬氨酸的情况)、丁基氧羧基衍生物(对于赖氨酸和组氨酸的情况)、三苯甲基衍生物(对于半胱氨酸的情况)和4-甲氧基-2，3，6-三甲基苯磺酰衍生物(对于精氨酸的情况)。当C-末端残基为谷氨酰胺或天冬酰胺时，使用4，4′-二甲氧基二苯甲基基团保护侧链氨基官能团。固相载体基于由二甲基丙烯酰胺(主链单体)、双丙烯酰乙二胺(交联剂)和丙烯酰肌氨酸甲酯(功能化试剂)三种单体组成的聚二甲基-丙烯酰胺聚合物。所使用的肽-树脂可断裂连接剂为酸不稳定的4-羟甲基-苯氧基乙酸衍生物。除了天冬酰胺 和谷氨酰胺之外，全部氨基酸衍生物均作为它们预制的对称酐衍生物加入，而使用反向N，N-二环己基碳二亚胺/1-羟基苯并三唑介导的偶联方法加入天冬酰胺和谷氨酰胺。使用茚三酮、三硝基苯磺酸或吲哚醌(isotin)检测方法来监测所有的偶联和去保护反应。合成完成时，从树脂载体切下肽，同时用含有50％清除剂混合物的95％三氟乙酸处理去除侧链的保护基团。常用的清除剂为乙二硫醇、苯酚、苯甲醚和水，准确的选择取决于所合成的肽的氨基酸组成。通过真空蒸发去除三氟乙酸，接着通过用乙醚研磨而提供粗肽。通过简单的萃取步骤来去除存在的任何清除剂，其中通过冷冻干燥水相提供不含清除剂的粗肽。用于肽合成的试剂通常可购自Calbiochem-Novabiochem(UK)Ltd，Nottingham NG7 2QJ，UK。纯化可以通过例如体积排阻色谱法、离子交换色谱法和(主要地)反相高效液相色谱法等技术中的任意一种或组合来实现。肽的分析可以使用薄层色谱法、反相高效液相色谱法、酸水解后的氨基酸分析以及快速原子轰击(FAB)质谱分析来进行。
还可以使用化学和生物化学领域技术人员所熟知的液相法来合成本发明分子的肽序列。
实施例1
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser(化合物YW-3)的制备
步骤1：多肽通过标准的Fmoc化学合成，基本操作如下。将600mg商购可得的2-CTC树脂(1.4mol/g)溶胀于DCM(10mL)中，溶胀30min，加入Fmoc-Ser(tBu)-OH(120mg,0.31mmol),DIPEA(1mL,5.7mmol)，室温下处理3小时，然后加入甲醇(0.5mL)，振荡1小时，封端没有反应的树脂。树脂用DMF洗涤，加入20％哌啶/DMF溶液(10mL)，反应20min，重复两遍，脱除Fmoc。树脂用DMF洗涤，加入Fmoc-Tic-OH(359mg,0.9mmol),HATU(342mg,0.9mmol),HOBT(121mg,0.9mmol)的DMF溶液10mL，然后加入DIPEA(350mg,2.7mmol),室温下反应2小时，得到Fmoc-Tic-Ser(tBu)-2-CTC树脂。以类似的方式将其他氨基酸引入，得到[D-Tyr(tBu)]-Phe-Leu-Pro-[D-Ser(tBu)]-Gln(Trt)-Phe-(D-Ala)-Tic-Ser(tBu)-CTC树脂。树脂用DCM，甲醇，甲基叔丁基醚洗涤树脂，然后抽干,得到760mg黄色树脂。
步骤2(常规多肽切割方法)：将干燥的树脂加入10mL的TFA/TIS/H 2O(90/5/5)溶液中，接着摇动2小时，过滤除去树脂，用2mL的TFA/TIS/H 2O(90/5/5)溶液洗涤树脂。合并滤液，向滤液中加入乙醚(70mL),室温静置30分钟，得到的混合物在3000转/分钟离心1分钟，多肽粗品用乙醚(50mL×2)洗涤、干燥。
步骤3：粗产物进行线性梯度洗脱(10分钟)，流速为50mL/分钟，洗脱液A/B: 80/20-55/45，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，10um,
Figure PCTCN2018093088-appb-000103
柱(3×100mm)。收集含有产物的级分，冻干，得到500mg白色固体。
质谱[M+2H] 2+/2：609.9
实施例2
3-phenylpropanoyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-71)的制备
将实施例1的步骤1得的树脂用DMF溶胀后，在与3-phenylpropanoic acid(3equivalent)缩合，HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用步骤2方法从树脂上切割下来并脱除保护。粗产物YW-71进行HPLC分离纯化，线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:53/47-44/56，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000104
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到20.2mg白色固体。
实施例3
Phenethylcarbamoyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-72)的制备
将实施例1中多肽粗品的粗品不经纯化，与苯乙基异氰酸酯(132mg,0.9mmol)和二异丙基乙胺(113mg,0.9mmol)一起溶于DMF(4mL)中，混合物振荡2小时，得到含有产物phenethylcarbamothioyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser的反应液。粗产物进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:53/47-44/56，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用2×Sunfire C18，5um,
Figure PCTCN2018093088-appb-000105
柱(19×150mm)。收集含有产物的级分，冻干，得到80mg白色固体。
质谱[M+2H] 2+/2：683.5
实施例4
Phenethylcarbamothioyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-73)的制备
将实施例1中多肽粗品的粗品不经纯化，与苯基硫代异氰酸酯(40mg,0.3mmol)和二异丙基乙胺(113mg,0.9mmol)溶于DMF(4mL)中，混合物振荡2小时，得到含有产物phenethyl isothiocyanate-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser的反应 液。粗产物进行线性梯度洗脱(10分钟)，流速为20mL/分钟，洗脱液A/B:51/49-44/56，使用：洗脱液A:0.07％碳酸氢铵和0.05％氨水的水溶液，洗脱液B:乙腈，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000106
柱(19×150mm)。收集含有产物的级分，冻干，得到13.7mg白色固体。
质谱[M+2H] 2+/2：691.5
实施例5
3-Phenylpropyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-74)的制备
将3-苯基丙醛(50mg,0.37mmol)和醋酸(20mg)的DMF(5mL)溶液加入到将实施例1的步骤1得到的全保护[D-Tyr(tBu)]-Phe-Leu-Pro-[D-Ser(tBu)]-Gln(Trt)-Phe-(D-Ala)-Tic-Ser(tBu)-CTC树脂中，混合物室温反应0.5小时，然后加入硼氢化钠(47mg,1.24mmol)，室温下反应2.5小时。树脂用DCM，甲醇，甲基叔丁基醚洗涤树脂，然后抽干,得到370mg黄色树脂。
将干燥的树脂加入5mL的TFA/TIS/H 2O(95/2.5/2.5)溶液中，接着摇动2.5小时，过滤除去树脂，用2mL的TFA/TIS/H 2O(90/5/5)溶液洗涤树脂。合并滤液，向滤液中加入乙醚(50mL),室温静置30分钟，得到的混合物在3000转/分钟离心1分钟，除去上层液。得到的沉淀用DMF溶解，然后进行线性梯度洗脱(10分钟)，流速为20mL/分钟，洗脱液A/B:69/31-63/37，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000107
柱(19×150mm)。收集含有产物的级分，冻干，得到13.7mg白色固体。
质谱[M+2] 2+/2：669.2
实施例6
4-Phenylbutanoyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-75)的制备
类似实施例2的合成方法，用4-phenylpropanoic acid(3equivalent)缩合，HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-75进行HPLC分离纯化，进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:51.5/48.5-43/57，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000108
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到20.6mg白色固体。
实施例7
5-Phenylvaleroyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-76)的制备
类似实施例2的合成方法，用5-phenylvaleric acid(3equivalent)缩合，HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-76进行HPLC分离纯化，进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:49/51-41/59，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000109
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到20.7mg白色固体。
实施例8
4-Biphenylacetyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-77)的制备
类似实施例2的合成方法，用4-biphenyl acetic acid(3equivalent)缩合，HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-77进行HPLC分离纯化，进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:48/52-40/60，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000110
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到20.8mg白色固体。
实施例9
Diphenylacetyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-78)的制备
类似实施例2的合成方法，用diphenylacetic acid(3equivalent)缩合，HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-78进行HPLC分离纯化，进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:49/51-41/59，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000111
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到20.9mg白色固体。
实施例10
3,5-Dihydroxybenzoyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-79)的制备
类似实施例2的合成方法，用3,5-dihydroxybenzoic acid(3equivalent)缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应5小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-79进行HPLC分离纯化，进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:60/40-53/47，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000112
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到21.3mg白色固体。
实施例11
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-HoPro-Ser-OH(化合物YW-90)的制备
类似实施例1的合成方法，用Fmoc-HoPro-OH(3equivalent)代替Fmoc-Tic缩合，HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-90进行HPLC分离纯化，进行线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:76/24-68/32，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000113
柱(20×250mm)。收集含有产物的级分，冻干，得到9.8mg白色固体。
实施例12
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Pro(5Ph)-Ser-OH(化合物YW-91)的制备
类似实施例1的合成方法，用Fmoc-Pro(5Ph)-OH(3equivalent)代替Fmoc-Tic缩合，HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-91进行HPLC分离纯化，进行线性梯度洗脱(10分钟)，流速为20mL/分钟，洗脱液A/B:73/27-63/37，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000114
柱(19×150mm)。收集含有产物的级分，冻干，得到20.1mg白色固体。
实施例13
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Pro(4Ph)-Ser-OH(化合物YW-92) 的制备
类似实施例1的合成方法，用Fmoc-Pro(4Ph)-OH(3equivalent)代替Fmoc-Tic缩合，HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-92进行HPLC分离纯化，进行线性梯度洗脱(10分钟)，流速为20mL/分钟，洗脱液A/B:70/30-60/40，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000115
柱(19×150mm)。收集含有产物的级分，冻干，得到20.1mg白色固体。
实施例14
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-(S)-isoindoline-1-carboxyl-Ser-OH(化合物YW-93)的制备
类似实施例1的合成方法，用Fmoc-(S)-isoindoline-1-carboxylic acid(3equivalent)代替Fmoc-Tic缩合，HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-93进行HPLC分离纯化，进行线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:74/26-64/36，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Phenomenex Gemini C18，10um,
Figure PCTCN2018093088-appb-000116
柱(21.2×250mm)。收集含有产物的级分，冻干，得到P1白色固体24.9mg,得到P2白色固体23.0mg。
实施例15
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Ala(dip)-Ser-OH(化合物YW-94)的制备
类似实施例1的合成方法，用Fmoc-Ala(dip)-OH(3equivalent)代替Fmoc-Tic缩合，HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-94进行HPLC分离纯化，进行线性梯度洗脱(10分钟)，流速为20mL/分钟，洗脱液A/B:69/31-63/37，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000117
柱(19×150mm)。收集含有产物的级分，冻干，得到20.2mg白色固体。
实施例16
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Bip-Ser-OH(化合物YW-95)的制备
类似实施例1的合成方法，用Fmoc-Bip-OH(3equivalent)代替Fmoc-Tic缩合， HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-95进行HPLC分离纯化，进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:61/39-55/45，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000118
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到20.6mg白色固体。
实施例17
(D-Tyr)-Phe-Leu-HoPro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-96)的制备
类似实施例1的合成方法，用Fmoc-HoPro-OH(3equivalent)代替Fmoc-Pro缩合，HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-96进行HPLC分离纯化，进行线性梯度洗脱(10分钟)，流速为20mL/分钟，洗脱液A/B:72/28-66/34，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000119
柱(19×150mm)。收集含有产物的级分，冻干，得到6.0mg白色固体。
实施例18
(D-Phe)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-97)的制备
类似实施例1的合成方法，用Fmoc-D-Phe(3equivalent)代替Fmoc-D-Tyr缩合，HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-97进行HPLC分离纯化，进行线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:61/39-54/46，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，10um,
Figure PCTCN2018093088-appb-000120
柱(19×250mm)。收集含有产物的级分，冻干，得到38.4mg白色固体。
实施例19
(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-98)的制备
类似实施例1的合成方法，用Fmoc-NMe-Leu(3equivalent)代替Fmoc-Leu缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-98进 行HPLC分离纯化，进行线性梯度洗脱(10分钟)，流速为20mL/分钟，洗脱液A/B:73/27-63/37，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000121
柱(19×150mm)。收集含有产物的级分，冻干，得到24.9mg白色固体。
实施例20
(D-Tyr)-Phe-(NMe-Val)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-99)的制备
类似实施例1的合成方法，用Fmoc-NMe-Val(3equivalent)代替Fmoc-Leu缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-99进行HPLC分离纯化，进行线性梯度洗脱(10分钟)，流速为20mL/分钟，洗脱液A/B:76/24-70/30，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000122
柱(19×150mm)。收集含有产物的级分，冻干，得到19.5mg白色固体。
实施例21
(D-Tyr)-Phe-(NMe-Phe)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-100)的制备
类似实施例1的合成方法，用Fmoc-NMe-Phe(3equivalent)代替Fmoc-Leu缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-100进行HPLC分离纯化，进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:65/35-59/41，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000123
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到5.8mg白色固体。
实施例22
(D-Tyr)-Phe-(NMe-HoLeu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-101)的制备
类似实施例1的合成方法，用Fmoc-NMe-HoLeu(3equivalent)代替Fmoc-Leu缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-101进行HPLC分离纯化，进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B: 65/35-59/41，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000124
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到25.2mg白色固体。
实施例23
(D-Tyr)-Phe-NLeu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-102)的制备
步骤1：将600mg商购可得的2-CTC树脂(1.4mol/g)溶胀于DCM(10mL)中，溶胀30min，加入Fmoc-Ser(tBu)-OH(120mg,0.31mmol),DIPEA(1mL,5.7mmol)，室温下处理3小时，然后加入甲醇(0.5mL)，振荡1小时，封端没有反应的树脂。树脂用DMF洗涤，加入20％哌啶/DMF溶液(10mL)，反应20min，重复两遍，脱除Fmoc。树脂用DMF洗涤，加入Fmoc-Tic-OH(600mg,1.5mmol),HATU(570mg,1.5mmol),HOBT(202mg,1.5mmol)的DMF溶液10mL，然后加入DIPEA(580mg,4.5mmol),室温下反应2小时，得到Fmoc-Tic-Ser(tBu)-2-CTC。以类似的方式将其他氨基酸引入，得到Pro-[D-Ser(tBu)]-Gln(Trt)-Phe-(D-Ala)-Tic-Ser(tBu)-CTC树脂。
步骤2：将溴乙酸(348mg,2.5mmol)和DIC(630mg,5mmol)的DMF(10mL)溶液加入到上述树脂中，混合物室温反应1小时，过滤，树脂用DMF(10mL×6)洗涤。然后向树脂中加入2-甲基丙胺盐酸盐(413mg,3.77mmol)、三乙胺(760mg,7.52mmol)、DMSO(1mL)的DMF(10mL)溶液，混合物室温反应3小时。树脂用DMF(10mL×6)洗涤，得到NLeu-Pro-[D-Ser(tBu)]-Gln(Trt)-Phe-(D-Ala)-Tic-Ser(tBu)-CTC resin。
步骤3：最后的2个氨基酸循环采用脱Fmoc保护和氨基酸偶联反应连接到上述树脂上。树脂用DCM，甲醇，甲基叔丁基醚洗涤树脂，然后抽干，得到866mg黄色树脂。
步骤4：将干燥的树脂加入10mL的TFA/TIS/H 2O(95/2.5/2.5)溶液中，接着摇动2.5小时，过滤除去树脂，用2mL的TFA/TIS/H 2O(90/5/5)溶液洗涤树脂。合并滤液，向滤液中加入乙醚(50mL),室温静置30分钟，得到的混合物在3000转/分钟离心1分钟，除去上层液。得到的沉淀用DMF溶解，然后进行线性梯度洗脱(10分钟)，流速为20mL/分钟，洗脱液A/B:71/29-65/35，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000125
柱(19×150mm)。收集含有产物的级分，冻干，得到28mg白色固体。
质谱[M+2] 2+/2：609.9
实施例24
(D-NMe-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-103) 的制备
类似实施例1的合成方法，用Fmoc-D-NMeTyr(3equivalent)代替Fmoc-D-Tyr缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-103进行HPLC分离纯化，进行线性梯度洗脱(8.5分钟)，流速为20mL/分钟，洗脱液A/B:73/27-66/34，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000126
柱(19×150mm)。收集含有产物的级分，冻干，得到28.5mg白色固体。
实施例25
(D-Tyr)-(NMe-Phe)-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-104)的制备
类似实施例1的合成方法，用Fmoc-NMe-Phe(3equivalent)代替Fmoc-Phe缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-104进行HPLC分离纯化，进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:62/38-55/45，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000127
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到28.6mg白色固体。
实施例26
(D-Tyr)-(NMe-Phe)-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-105)的制备
类似实施例1的合成方法，用Fmoc-NMe-Leu(3equivalent)代替Fmoc-Leu缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。并且用Fmoc-NMe-Phe(3equivalent)代替Fmoc-Phe缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-105进行HPLC分离纯化，进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:66.5/33.5-59/41，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000128
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到20.3mg白色固体。
实施例27
(D-Tyr)-Phe-Leu-Pro-(D-NMeSer)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-106)的制备
类似实施例1的合成方法，用Fmoc-NMe-D-Ser(3equivalent)代替Fmoc-D-Ser缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-106进行HPLC分离纯化，进行线性梯度洗脱(10分钟)，流速为20mL/分钟，洗脱液A/B:71/29-65/35，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000129
柱(19×150mm)。收集含有产物的级分，冻干，得到27.3mg白色固体。
实施例28
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-(NMe-Gln)-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-107)的制备
类似实施例1的合成方法，用Fmoc-NMe-Gln(3equivalent)代替Fmoc-Gln缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-107进行HPLC分离纯化，进行线性梯度洗脱(10分钟)，流速为20mL/分钟，洗脱液A/B:70/30-63/37，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000130
柱(19×150mm)。收集含有产物的级分，冻干，得到29.1mg白色固体。
实施例29
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-NGln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-108)的制备
用实施例5的步骤1，从600mg商购可得的2-CTC树脂(1.4mol/g)开始，用标准的Fmoc化学方法，将各种氨基酸引入，得到Phe-(D-Ala)-Tic-Ser(tBu)-CTC树脂。
步骤2：将溴乙酸(348mg,2.5mmol)和DIC(630mg,5mmol)的DMF(10mL)溶液加入到上述树脂中，混合物室温反应1小时，过滤，树脂用DMF(10mL×6)洗涤。然后向树脂中加入3-氨基丙酰胺盐酸盐(470mg,3.77mmol)、三乙胺(760mg,7.52mmol)、DMSO(1mL)的DMF(10mL)溶液，混合物室温反应3小时。树脂用DMF(10mL×6)洗涤，得到NGln-Phe-(D-Ala)-Tic-Ser(tBu)-CTC resin。
步骤3：最后的5个氨基酸循环采用脱Fmoc保护和氨基酸偶联反应接到上述树脂上。树脂用DCM，甲醇，甲基叔丁基醚洗涤树脂，然后抽干，得到900mg黄色树脂。
步骤4：将干燥的树脂加入10mL的TFA/TIS/H 2O(95/2.5/2.5)溶液中，接着摇动2.5小时，过滤除去树脂，用2mL的TFA/TIS/H 2O(95/2.5/2.5)溶液洗涤树脂。合并滤液，向滤液中加入乙醚(50mL),室温静置30分钟，得到的混合物在3000转/分钟离心1分钟，除去上层液。得到的沉淀用DMF溶解，然后进行线性梯度洗脱(10分钟)，流速为20mL/分钟，洗脱液A/B:71/29-65/35，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000131
柱(19×150mm)。收集含有产物的级分，冻干，得到16mg白色固体。
质谱[M+2] 2+/2：610.0
实施例30
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-NMe-Ala)-Tic-Ser-OH(化合物YW-109)的制备
类似实施例1的合成方法，用Fmoc-D-NMe-Ala(3equivalent)代替Fmoc-D-Ala缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-109进行HPLC分离纯化，进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:66.5/33.5-59/41，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000132
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到28.2mg白色固体。
实施例31
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-(NMe-Ser)-OH(化合物YW-110)的制备
类似实施例1的合成方法，用Fmoc-NMe-Ser(3equivalent)代替Fmoc-Ser缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-110进行HPLC分离纯化,进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:66/34-59/41，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000133
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到22.8mg白色固体。
实施例32
3-Phenylpropanoyl-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-111)的制备
类似实施例2(YW-71)的合成方法，用Fmoc-NMe-Leu(3equivalent)代替Fmoc-Leu缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-111进行HPLC分离纯化,进行线性梯度洗脱(10分钟)，流速为20mL/分钟，洗脱液A/B:60/40-50/50，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000134
柱(19×150mm)。收集含有产物的级分，冻干，得到28.8mg白色固体。
实施例33
(D-Tyr)-Phe-Leu-Pro(5Ph)-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-112)的制备
类似实施例1的合成方法，用Fmoc-Pro(5-Phenyl)(3equivalent)代替Fmoc-Pro缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-112进行HPLC分离纯化，进行线性梯度洗脱(10分钟)，流速为20mL/分钟，洗脱液A/B:66/34-59/41，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，5um,
Figure PCTCN2018093088-appb-000135
柱(19×150mm)。收集含有产物的级分，冻干，得到23.5mg白色固体。
实施例34
(D-Tyr)-Phe-Leu-Pro(4-Ph)-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-113)的制备
类似实施例1的合成方法，用Fmoc-Pro(4-Phenyl)(3equivalent)代替Fmoc-Pro缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-113进行HPLC分离纯化，进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:60/40-52/48，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000136
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到26.9mg白色固体。
实施例35
(D-Tyr)-Phe-Leu-Thz-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-114)的制备
类似实施例1的合成方法，用Fmoc-Thz(3equivalent)代替Fmoc-Pro缩合， HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-114进行HPLC分离纯化，粗产物进行线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:64/36-59/41，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000137
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到7.1mg白色固体。
实施例36
(D-Tyr)-Phe-Leu-Aze-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-115)的制备
类似实施例1的合成方法，用Fmoc-Aze(3equivalent)代替Fmoc-Pro缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-115进行HPLC分离纯化，线性梯度洗脱(8.5分钟)，流速为30mL/分钟，洗脱液A/B:67/33-59/41，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用SHIMADAZU C18，10um,
Figure PCTCN2018093088-appb-000138
柱(2×21.2×250mm)。收集含有产物的级分，冻干，得到25.7mg白色固体。
实施例37
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-1Nal-(D-Ala)-Tic-Ser-OH(化合物YW-117)的制备
类似实施例1的合成方法，用Fmoc-1-Nal(3equivalent)代替Fmoc-Phe缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-117进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:68/32-58/42，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000139
柱(20×250mm)。收集含有产物的级分，冻干，得到25.8mg白色固体。
实施例38
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser-OH(化合物YW-118)的制备
类似实施例1的合成方法，用Fmoc-2Nal(3equivalent)代替Fmoc-Phe缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后 干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-118进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:71/29-63/37，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000140
柱(20×250mm)。收集含有产物的级分，冻干，得到25.4mg白色固体。
实施例39
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Bpa-(D-Ala)-Tic-Ser-OH(化合物YW-119)的制备
类似实施例1的合成方法，用Fmoc-Bpa(3equivalent)代替Fmoc-Phe缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应3小时。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-119进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:72/28-62/38，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000141
柱(20×250mm)。收集含有产物的级分，冻干，得到24.4mg白色固体。
实施例40
(D-Tyr)-Phe-(NMe-Leu)-Thz-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-121)的制备
类似实施例1的合成方法，用Fmoc-NMe-Leu(3equivalent)代替Fmoc-Leu缩合，HATU/HOAt/DIPEA为缩合条件。用Fmoc-Thz(3equivalent)代替Fmoc-Pro缩合，HBTU/HOBt/DIPEA为缩合条件。其他残基的缩合与脱Fmoc保护条件与实施例1一致。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-121进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:73/27-63/37，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000142
柱(20×250mm)。收集含有产物的级分，冻干，得到27.2mg白色固体。
实施例41
(D-Tyr)-Phe-(NMe-Leu)-Thz-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser-OH(化合物YW-122)的制备
类似实施例40的合成方法，用Fmoc-2Nal(3equivalent)代替Fmoc-Phe缩合，HATU/HOAt/DIPEA为缩合条件。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从 树脂上切割下来并脱除保护。粗产物YW-122进行HPLC分离纯化,线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:70/30-60/40，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000143
柱(20×250mm)。收集含有产物的级分，冻干，得到20.4mg白色固体。
实施例42
(NMe-D-Tyr)-Phe-(NMe-Leu)-Thz-(D-Ser)-Gln-Phe-(D-Ala)-Tic-(NMe-Ser)-OH(化合物YW-124)的制备
类似实施例40的合成方法，用Fmoc-NMe-D-Tyr(tBu)(3equivalent)代替Fmoc-D-Tyr(tBu)缩合，HATU/HOAt/DIPEA为缩合条件。用Fmoc-NMe-Ser(tBu)(3equivalent)代替Fmoc-Ser(tBu)缩合，HATU/HOAt/DIPEA为缩合条件。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-124进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:73/27-63/37，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000144
柱(20×250mm)。收集含有产物的级分，冻干，得到12.8mg白色固体。
实施例43
(D-NMe-Tyr)-Phe-(NMe-Leu)-Thz-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-(NMe-Ser)-OH(化合物YW-125)的制备
类似实施例42的合成方法，用Fmoc-2Nal(3equivalent)代替Fmoc-Phe缩合，HATU/HOAt/DIPEA为缩合条件。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-125进行HPLC分离纯化,线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:70/30-51/49，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Phenomenex Gemini C18，10um,
Figure PCTCN2018093088-appb-000145
柱(21.2×250mm)。收集含有产物的级分，冻干，得到53.7mg白色固体。
实施例44
3,5-Dihydroxybenzoyl-(D-NMe-Tyr)-Phe-(NMe-Leu)-Thz-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-NMeSer-OH(化合物YW-126)的制备
类似实施例43的合成方法，序列合成完后，常规方法脱除Fmoc保护基，得到的树脂用DMF溶胀后，与3,5-dihydroxybenzoic acid(3equivalent)缩合，HBTU/HOBt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应过夜。树脂洗涤后干燥。目标多肽用实施例1步骤2方法方法从树脂上切割下来并脱除保护。粗产物YW-126进行HPLC分离纯 化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:74/26-64/36，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000146
柱(20×250mm)。收集含有产物的级分，冻干，得到500mg白色固体。
实施例45
2,3-Dihydroxybenzoyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-127)的制备
将实施例1的步骤1得的树脂用DMF溶胀后，在与2,3-dihydroxybenzoic acid(3equivalent)缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应过夜。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-127进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:65/35-55/45，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000147
柱(20×250mm)。收集含有产物的级分，冻干，得到4.2mg白色固体。
实施例46
2,6-Dihydroxybenzoyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-128)的制备
将实施例1的步骤1得的树脂用DMF溶胀后，在与2,6-dihydroxybenzoic acid(3equivalent)缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应过夜。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-128进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:64/36-54/46，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，10um,
Figure PCTCN2018093088-appb-000148
柱(19×250mm)。收集含有产物的级分，冻干，得到24.2mg白色固体。
实施例47
2,3,4-Trihydroxybenzoyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-129)的制备
将实施例1的步骤1得的树脂用DMF溶胀后，在与2,3,4-dihydroxy-benzoic acid(3equivalent)缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应过夜。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-129进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗 脱液A/B:65/35-58/42，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000149
柱(20×250mm)。收集含有产物的级分，冻干，得到5.9mg白色固体。
实施例48
3,5-Dihydroxyphenylacetyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-132)的制备
将实施例1的步骤1得的树脂用DMF溶胀后，在与3,5-dihydroxyphenyl acetic acid(3equivalent)缩合，HATU/HOAt/DIPEA为缩合条件，以DMF为溶剂，混合物室温反应过夜。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-132进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:67/33-57/43，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000150
柱(20×250mm)。收集含有产物的级分，冻干，得到9.3mg白色固体。
实施例49
Palm-PEG8-Gly-Gly-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-133)的制备
类似实施例19的合成方法得到序列后，常规方法脱除Fmoc保护基，以类似的方式将其他氨基酸(Fmoc-Gly-OH，2次)，和Fmoc-(PEG)8-OH以及脂肪链(Palmitic acid)引入得到保护的Palm-PEG8-Gly-Gly-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-CTC树脂。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-133进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:34/66-27/73，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000151
柱(20×250mm)。收集含有产物的级分，冻干，得到33.2mg白色固体。
实施例50
Palm-PEG8-βAla-βAla-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-134)的制备
类似实施例19的合成方法得到序列后，常规方法脱除Fmoc保护基，以类似的方式将其他氨基酸(Fmoc-βAla-OH，2次)，和Fmoc-(PEG)8-OH以及脂肪链(Palmitic acid)引入得到保护的Palm-PEG8-βAla-βAla-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-CTC树脂。目标多肽用实施例1步骤2 方法从树脂上切割下来并脱除保护。粗产物YW-134进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:36/64-26/74，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000152
柱(20×250mm)。收集含有产物的级分，冻干，得到404.0mg白色固体。
实施例51
(D-NMe-Tyr)-Phe-(NMe-Leu)-Thz-(D-Ser)-Gln-1Nal-(D-Ala)-Tic-(NMe-Ser)-OH(化合物YW-142)的制备
类似实施例42的合成方法，用Fmoc-1Nal(3equivalent)代替Fmoc-Phe缩合，HATU/HOAt/DIPEA为缩合条件。树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-142进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为45mL/分钟，洗脱液A/B:70/30-64/36，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Phenomenex GeminiC18，10um,
Figure PCTCN2018093088-appb-000153
柱(30×250mm)。收集含有产物的级分，冻干，得到22.1mg白色固体。
实施例52
(D-NMe-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-(NMe-Ser)-OH(化合物YW-146)的制备
类似实施例1的合成方法，用Fmoc-NMe-Ser(tBu)替换Fmoc-Ser(tBu)，HATU/HOAt/DIPEA为缩合条件；Fmoc-2Nal替换Fmoc-Phe,HBTU/HOBt/DIPEA为缩合条件；Fmoc-NMe-Leu替换Fmoc-Leu,HATU/HOAt/DIPEA为缩合条件；用Fmoc-NMe-D-Tyr(tBu)替换Fmoc-D-Tyr(tBu)，HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-143进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:72/28-64/36，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，10um,
Figure PCTCN2018093088-appb-000154
柱(19×250mm)。收集含有产物的级分，冻干，得到28.9mg白色固体。
实施例53
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-(D-Ser)-(D-Ala)-azaTic-Ser-OH(化合物YW-147)的制备
步骤1：将500mg商购可得的2-CTC树脂(1.34mol/g)溶胀于DCM(10ml)中，溶胀30min，加入Fmoc-D-Ala-azaTic-Ser(tBu)-OH(150mg,0.24mmol),DIPEA(0.1ml,0.72mmol)，室温下处理40分钟，得到Fmoc-(D-Ala)-azaTic-Ser(tBu)-2-CTC树脂，抽 去溶液后加入DCM/MeOH/DIPEA(20ml，v/v/v：85:10:5)，反应30min，重复两遍，将2-CTC多余的Cl封端，抽去溶液。用DMF将树脂洗干净后，加入20％哌啶/DMF溶液(10mL)，反应15min，重复两遍，脱除Fmoc。将树脂DMF洗干净后，加入Fmoc-D-Ser(tBu)-OH(383mg,0.45mmol),HBTU(170mg,0.45mmol),HOBT(60mg,0.45mmol)的DMF溶液10ml，然后加入DIPEA(0.1ml,0.45mmol),室温下反应1hr，得到Fmoc-(D-Ser(tBu))-(D-Ala)-azaTic-Ser(tBu)-2-CTC。以类似的方式将其他氨基酸引入，得到(D-Tyr(tBu))-Phe-Leu-Pro-(D-Ser(tBu))-Gln(Trt)-(D-Ser(tBu))-(D-Ala)-azaTic-Ser(tBu)-2-CTC树脂。用DCM，甲醇，甲基叔丁基醚洗涤树脂，然后抽干。
步骤2：将干燥的树脂加入5mL的TFA/TIS/H 2O(95/2.5/2.5)溶液中，接着摇动2小时，过滤除去树脂，用2mL的TFA/TIS/H 2O(95/2.5/2.5)溶液洗涤树脂。合并滤液，向滤液中加入乙醚(70mL),离心得到的沉淀，除去上层液。得到的沉淀用DMF溶解，然后进行线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:75/25-65/35，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Phenomenex Gemini 10um,
Figure PCTCN2018093088-appb-000155
柱(21.2×250mm)。收集含有产物的级分，冻干，得到80mg白色固体。
质谱(M+H) +:1159.6(计算值1159.2)
实施例54
(D-NMe-Tyr)-Phe-(NMe-Leu)-Thz-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser-OH(化合物YW-148)的制备
类似实施例41的合成方法，用Fmoc-NMeD-Tyr(tBu)替换Fmoc-D-Tyr(tBu)，HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-148进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:70/30-65/35，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，10um,
Figure PCTCN2018093088-appb-000156
柱(19×250mm)。收集含有产物的级分，冻干，得到14.6mg白色固体。
实施例55
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-D-Tic-Ser-OH(化合物YW-149)的制备
类似实施例1的合成方法，用Fmoc-D-Tic替换Fmoc-Tic，HATU/HOAt/DIPEA为 缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-149进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:82/18-72/28，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000157
柱(20×250mm)。收集含有产物的级分，冻干，得到43.0mg白色固体。
实施例56
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Ti1c-Ser-OH(化合物YW-150)的制备
类似实施例1的合成方法，用Fmoc-Ti1c替换Fmoc-Tic，HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-150进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:72/28-62/38，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Phenomenex Gmini C18，10um,
Figure PCTCN2018093088-appb-000158
柱(21.2×250mm)。收集含有产物的级分，冻干，得到31.3mg白色固体。
实施例57
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-D-Ti1c-Ser-OH(化合物YW-151)的制备
类似实施例1的合成方法，用Fmoc-D-Ti1c替换Fmoc-Tic，HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-151进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:72/28-64/36，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Phenomenex Gmini C18，10um,
Figure PCTCN2018093088-appb-000159
柱(21.2×250mm)。收集含有产物的级分，冻干，得到44.7mg白色固体。
实施例58
(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-D-Ti1c-Ser-OH(化合物YW-153)的制备
类似实施例1的合成方法，用Fmoc-D-Ti1c替换Fmoc-Tic，HATU/HOAt/DIPEA为缩合条件；Fmoc-NMeLeu替换Fmoc-Leu,HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来 并脱除保护。粗产物YW-153进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:73/27-67/33，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000160
柱(20×250mm)。收集含有产物的级分，冻干，得到35.0mg白色固体。
实施例59
(D-NMe-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-D-Ti1c-Ser-OH(化合物YW-154)的制备
类似实施例1的合成方法，用Fmoc-D-Ti1c替换Fmoc-Tic，HATU/HOAt/DIPEA为缩合条件；Fmoc-NMe-D-Tyr(tBu)替换Fmoc-D-Tyr(tBu),HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-154进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:72/28-66/34，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000161
柱(20×250mm)。收集含有产物的级分，冻干，得到57.3mg白色固体。
实施例60
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-D-Ti1c-(NMe-Ser)-OH(化合物YW-155)的制备
类似实施例1的合成方法，Fmoc-NMe-Ser(tBu)替换Fmoc-Ser(tBu),HATU/HOAt/DIPEA为缩合条件；用Fmoc-D-Ti1c替换Fmoc-Tic，HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-155进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:72/28-66/34，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000162
柱(20×250mm)。收集含有产物的级分，冻干，得到5.3mg白色固体。
实施例61
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-2Nal-(D-Ala)-D-Ti1c-Ser-OH(化合物YW-156)的制备
类似实施例1的合成方法，用Fmoc-D-Ti1c替换Fmoc-Tic，HATU/HOAt/DIPEA为缩合条件；用Fmoc-2Nal替换Fmoc-Phe，HBTU/HOBt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-156进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/ 分钟，洗脱液A/B:63/37-57/43，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000163
柱(20×250mm)。收集含有产物的级分，冻干，得到22.9mg白色固体。
实施例62
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-1Nal-(D-Ala)-D-Ti1c-Ser-OH(化合物YW-157)的制备
类似实施例1的合成方法，用Fmoc-D-Ti1c替换Fmoc-Tic，HATU/HOAt/DIPEA为缩合条件；用Fmoc-1Nal替换Fmoc-Phe，HBTU/HOBt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-157进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:63/37-57/43，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000164
柱(20×250mm)。收集含有产物的级分，冻干，得到41.4mg白色固体。
实施例63
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-TP5C-Ser-OH(化合物YW-158)的制备
类似实施例1的合成方法，用Fmoc-TP5C替换Fmoc-Tic，HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-158进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:70/30-64/36，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000165
柱(20×250mm)。收集含有产物的级分，冻干，得到18.6mg白色固体。
实施例64
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-TP6C-Ser-OH(化合物YW-159)的制备
类似实施例1的合成方法，用Fmoc-TP6C替换Fmoc-Tic，HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-159进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:70/30-64/36，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000166
柱(20×250mm)。收集含有产物的级分，冻干，得到25.8mg白色固体。
实施例65
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Thr-OH(化合物YW-160)的制备
类似实施例1的合成方法，用Fmoc-Thr(tBu)替换Fmoc-Ser(tBu)，HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-160进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:69/31-59/41，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000167
柱(20×250mm)。收集含有产物的级分，冻干，得到20.4mg白色固体。
实施例66
3-Phenylpropanoyl-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-NH 2(化合物YW-161)的制备
步骤1：多肽通过标准的Fmoc化学合成，基本操作如下。将200mg(0.5mol/g)商购可得的Rink Amide MBHA树脂溶胀于DMF中，该树脂用5mL 20％哌啶/DMF处理20分钟以除去Fmoc，重复两遍此操作。得到的树脂用DMF洗涤，加入Fmoc-Ser(tBu)-OH(116mg,0.3mmol),HBTU(114mg,0.3mmol),HOBt(41mg,0.3mmol)的20mL DMF溶液，然后加入DIPEA(77mg,0.6mmol)，室温下处理40分钟，向其中引入Ser(tBu)，得到Fmoc-Ser(tBu)-MBHA树脂，以类似的方式将其他氨基酸引入，得到Fmoc-(D-Tyr(tBu))-Phe-(NMe-Leu)-Pro-(D-Ser(tBu))-Gln-Phe-(D-Ala)-Tic-Ser(tBu)-MBHA树脂。该树脂用5mL 20％哌啶/DMF处理20分钟以除去Fmoc，重复两遍此操作。得到的树脂用DMF洗涤，加入3-Phenylpropanoic acid(45mg,0.3mmol),HBTU(114mg,0.3mmol),HOBt(41mg,0.3mmol)的10mL DMF溶液，然后加入DIPEA(77mg,0.6mmol)，室温下处理4小时，得到3-Phenylpropanoyl-(D-Tyr(tBu))-Phe-(NMe-Leu)-Pro-(D-Ser(tBu))-Gln-Phe-(D-Ala)-Tic-Ser(tBu)-MBHA树脂。
步骤2：将干燥的树脂加入5mL的TFA/TIS/H 2O(95/2.5/2.5)溶液中，接着摇动2小时，过滤除去树脂，用2mL的TFA/TIS/H 2O(95/2.5/2.5)溶液洗涤树脂。合并滤液，向滤液中加入乙醚(70mL),离心得到的沉淀，除去上层液。得到的沉淀用DMF溶解，用HPLC纯化。线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:59/41-49/51，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000168
柱(20×250mm)。收集含有产物的级分，冻干，得到 32.7mg白色固体。
实施例67
(D-NMe-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-1Nal-(D-Ala)-Tic-NMeSer-OH(化合物YW-162)的制备
类似实施例1的合成方法，用Fmoc-NMe-Ser(tBu)替换Fmoc-Ser(tBu)，HATU/HOAt/DIPEA为缩合条件；Fmoc-1Nal替换Fmoc-Phe,HBTU/HOBt/DIPEA为缩合条件；Fmoc-NMe-Leu替换Fmoc-Leu,HATU/HOAt/DIPEA为缩合条件；用Fmoc-NMeD-Tyr(tBu)替换Fmoc-D-Tyr(tBu)，HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-162进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:67/33-61/39，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000169
柱(20×250mm)。收集含有产物的级分，冻干，得到30.7mg白色固体。
实施例68
(D-NMe-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-163)的制备
类似实施例1的合成方法，用Fmoc-NMe-Leu替换Fmoc-Leu,HATU/HOAt/DIPEA为缩合条件；用Fmoc-NMeD-Tyr(tBu)替换Fmoc-D-Tyr(tBu)，HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-163进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:73/27-63/37，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000170
柱(20×250mm)。收集含有产物的级分，冻干，得到56.8mg白色固体。
实施例69
(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser-OH(化合物YW-164)的制备
类似实施例1的合成方法，用Fmoc-2Nal替换Fmoc-Phe,HBTU/HOBt/DIPEA为缩合条件；Fmoc-NMe-Leu替换Fmoc-Leu,HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-164进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:70/30-60/40，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA 的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000171
柱(20×250mm)。收集含有产物的级分，冻干，得到73.5mg白色固体。
实施例70
(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-1Nal-(D-Ala)-Tic-Ser-OH(化合物YW-165)的制备
类似实施例1的合成方法，用Fmoc-1Nal替换Fmoc-Phe,HBTU/HOBt/DIPEA为缩合条件；Fmoc-NMe-Leu替换Fmoc-Leu,HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-165进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:71/29-61/39，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000172
柱(20×250mm)。收集含有产物的级分，冻干，得到55.6mg白色固体。
实施例71
(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-(NMe-Ser)-OH(化合物YW-166)的制备
类似实施例1的合成方法，用Fmoc-NMe-Ser(tBu)替换Fmoc-Ser(tBu)，HATU/HOAt/DIPEA为缩合条件；Fmoc-NMe-Leu替换Fmoc-Leu,HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-166进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:75/25-65/35，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，10um,
Figure PCTCN2018093088-appb-000173
柱(19×250mm)。收集含有产物的级分，冻干，得到18.8mg白色固体。
实施例72
(D-NMe-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser-OH(化合物YW-167)的制备
类似实施例1的合成方法，用Fmoc-2Nal替换Fmoc-Phe,HBTU/HOBt/DIPEA为缩合条件；Fmoc-NMe-Leu替换Fmoc-Leu,HATU/HOAt/DIPEA为缩合条件；用Fmoc-D-NMe-Tyr(tBu)替换Fmoc-D-Tyr(tBu)，HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-167进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:69/31-63/37，使用：洗脱液A:0.05％TFA的水溶液，洗脱液 B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000174
柱(20×250mm)。收集含有产物的级分，冻干，得到42.7mg白色固体。
实施例73
(D-NMe-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-1Nal-(D-Ala)-Tic-Ser-OH(化合物YW-168)的制备
类似实施例1的合成方法，用Fmoc-1Nal替换Fmoc-Phe,HBTU/HOBt/DIPEA为缩合条件；Fmoc-NMe-Leu替换Fmoc-Leu,HATU/HOAt/DIPEA为缩合条件；用Fmoc-D-NMe-Tyr(tBu)替换Fmoc-D-Tyr(tBu)，HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-168进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:69/31-63/37，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000175
柱(20×250mm)。收集含有产物的级分，冻干，得到47.4mg白色固体。
实施例74
(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-HoSer-OH(化合物YW-171)的制备
类似实施例1的合成方法，用Fmoc-HoSer(tBu)替换Fmoc-Ser(tBu),HBTU/HOBt/DIPEA为缩合条件；Fmoc-NMe-Leu替换Fmoc-Leu,HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-171进行HPLC分离纯化，
实施例75
(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-NHoSer-OH(化合物YW-172)的制备
步骤1：将500mg商购可得的2-CTC树脂(1.34mol/g)溶胀于DCM(5mL)中，溶胀30min，加入Fmoc-NHoSer(tBu)-OH(80mg,0.2mmol),DIPEA(0.1ml,0.75mmol)，室温下处理40分钟，得到Fmoc-NHoSer(tBu)-2-CTC树脂，抽去溶液后加入DCM/MeOH/DIPEA(5mL，v/v/v：85:10:5)，反应30min，重复两遍，将2-CTC多余的Cl封端，抽去溶液。树脂用DMF洗涤，加入20％哌啶/DMF溶液(5mL)，反应20min，重复两遍，脱除Fmoc。
步骤2：树脂用DMF洗涤，加入Fmoc-Tic-OH(240mg,0.60mmol),HATU(228mg,0.60mmol),HOAT(82mg,0.60mmol)的DMF溶液5ml，然后加入DIPEA(0.1ml,0.75 mmol),室温下反应2hr，得到Fmoc-Tic-NHoSer(tBu)-2-CTC。以类似的方式将其他氨基酸引入，得到(D-Tyr(tBu))-Phe-(NMe-Leu)-Pro-(D-Ser(tBu))-Gln-Phe-(D-Ala)-Tic-NHoSer(tBu)-2-CTC树脂。树脂用DCM，甲醇，甲基叔丁基醚洗涤树脂，然后抽干。
步骤3：将干燥的树脂加入5mL的TFA/TIS/H 2O(90/5/5)溶液中，接着摇动2小时，过滤除去树脂，用2mL的TFA/TIS/H 2O(90/5/5)溶液洗涤树脂。合并滤液，向滤液中加入乙醚(70mL),得到的混合物在3000转/分钟离心1分钟，除去上层液。得到的沉淀用DMF溶解，然后进行线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:69/31-59/41，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Phenomenex Gemini 10um,
Figure PCTCN2018093088-appb-000176
柱(21.2×250mm)。收集含有产物的级分，冻干，得到21mg白色固体。
质谱(M+H) +:1246.6(计算值1246.6)
实施例77
(D-Tyr)-Phe-(NMe-Leu)-Pro(diF)-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-174)的制备
类似实施例1的合成方法，用Fmoc-Pr(diF)替换Fmoc-Pro,HBTU/HOBt/DIPEA为缩合条件；Fmoc-NMe-Leu替换Fmoc-Leu,HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-174进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:70/30-64/36，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000177
柱(20×250mm)。收集含有产物的级分，冻干，得到26.1mg白色固体。
实施例78
(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-HoSer)-Gln-Phe-(D-Ala)-Tic-Ser-OH(化合物YW-175)的制备
类似实施例1的合成方法，用Fmoc-D-HoSer(tBu)替换Fmoc-D-Ser(tBu),HATU/HOAt/DIPEA为缩合条件；Fmoc-NMeLeu替换Fmoc-Leu,HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-175进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:73/27-67/33，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18， 10um,
Figure PCTCN2018093088-appb-000178
柱(19×250mm)。收集含有产物的级分，冻干，得到47.8mg白色固体。
实施例79
(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-(D-Oic)-Ser-OH(化合物YW-176)的制备
类似实施例1的合成方法，用Fmoc-D-Oic替换Fmoc-D-Tic,HATU/HOAt/DIPEA为缩合条件；Fmoc-NMe-Leu替换Fmoc-Leu,HATU/HOAt/DIPEA为缩合条件。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例1步骤2方法从树脂上切割下来并脱除保护。粗产物YW-176进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:72/28-66/34，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Xtimate C18，10um,
Figure PCTCN2018093088-appb-000179
柱(20×250mm)。收集含有产物的级分，冻干，得到28.4mg白色固体。
实施例80
(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-(NMe-HoSer)-OH(化合物YW-177)的制备
用实施例5的步骤1得到HoSer(tBu)-2-CT树脂，树脂用DMF洗涤，加入对硝基苯磺酰氯(111mg,0.5mmol)的DMF溶液5mL，然后加入DIPEA(0.2ml,1.5mmol)，室温下反应3小时。树脂用DMF洗涤，加入DMF(5mL)，然后加入三苯基磷(131mg，0.5mmol)，DIAD(201mg，0.5mmol)，甲醇(0.5mL)，氮气保护下室温反应3小时。树脂用DMF洗涤，加入苯硫酚(0.55g，5.0mmol)，DMF(5mL)，DIPEA(0.95g，7.5mmol)，室温下反应1小时，脱除对硝基苯磺酰基，树脂用DMF洗涤，得到NH2-NMe-HoSer(tBu)-2-CTC树脂。加入Fmoc-Tic-OH(240mg,0.60mmol)，HATU(228mg,0.60mmol)，HOAT(82mg,0.60mmol)的DMF溶液5ml，然后加入DIPEA(0.1ml,0.75mmol)，室温下反应2hr，树脂用DMF洗涤，得到Fmoc-Tic-NMe-HoSer(tBu)-2-CTC。以类似的方式将其他氨基酸引入，得到(D-Tyr(tBu))-Phe-(NMe-Leu)-Pro-(D-Ser(tBu))-Gln-Phe-(D-Ala)-Tic-(NMe-HoSer(tBu))-2-CTC树脂。树脂用DMF,DCM，甲醇，甲基叔丁基醚洗涤，然后抽干。
步骤2：将干燥的树脂加入5mL的TFA/TIS/H 2O(90/5/5)溶液中，接着摇动2小时，过滤除去树脂，用2mL的TFA/TIS/H 2O(90/5/5)溶液洗涤树脂。合并滤液，向滤液中加入乙醚(70mL),得到的混合物在3000转/分钟离心1分钟，除去上层液。得到的沉淀用DMF溶解，然后进行线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B: 75/25-67/33，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Phenomenex Gemini 10um,
Figure PCTCN2018093088-appb-000180
柱(21.2×250mm)。收集含有产物的级分，冻干，得到13mg白色固体，为Υ-丁内酯产物。
步骤3：将上述得到的Υ-丁内酯产物(13mg)溶于四氢呋喃(0.5mL)中，加入0.1NNaOH溶液(0.5mL)，室温下超声波中反应1小时。反应液加入DMF(1mL)，然后进行线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:67/33-61/39，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Xtimate10um,
Figure PCTCN2018093088-appb-000181
柱(20×250mm)。收集含有产物的级分，冻干，得到6.8mg白色固体。
质谱(M+H) +:1260.6(计算值1260.6)
实施例80:
Palm-PEG8-(beta-Ala)-(beta-Ala)-(D-NMeTyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-(NMe-Ser)(化合物YW-179)的制备
将1.0g商购可得的CTC树脂溶胀于DMF中，加入Fmoc-[NMe-Ser(tBu)]-OH(119mg,0.3mmol)的10ml DMF溶液，然后加入DIPEA(155mg,1.2mmol)，室温下处理16小时，树脂用DMF洗涤，用甲醇(320mg，10mmol)和DIPEA(310mg，2.4mmol)的10ml DMF溶液封端，树脂用DMF洗涤，得到Fmoc-[NMe-Ser(tBu)]-CTC树脂。该树脂用10ml 20％哌啶/DMF处理20分钟以除去Fmoc，重复两遍此操作，树脂用DMF洗涤，加入Fmoc-Tic-OH(359mg,0.9mmol),HATU(342mg,0.9mmol),HOAt(122mg,0.9mmol)的10ml DMF溶液，然后加入DIPEA(232mg,1.8mmol),室温下处理40分钟,树脂用DMF洗涤，得到Fmoc-Tic-[NMe-Ser(tBu)]-CTC树脂。以类似的方式，依次将D-Ala,2Nal,Gln(Trt),D-Ser(tBu),Pro，NMe-Leu,Phe,D-NMeTyr(tBu),βAla,βAla,PEG8,Palm等氨基酸引入，得到1.6g目标多肽的CTC树脂。树脂依次用DMF、甲醇、甲基叔丁基醚洗涤，然后抽干。
将干燥的树脂加入10ml的TFA/TIS/H 2O(92/4/4)溶液中，该混合物搅拌2小时，过滤除去树脂，用1ml的TFA/TIS/H 2O(92/4/4)溶液洗涤树脂。合并滤液，向滤液中加入甲基叔丁基醚(110ml),得到的混合物在3000转/分钟离心1分钟，固体用冰乙醚洗涤两次，并抽干。得到的沉淀用DMF溶解，然后进行线性浓度梯度洗脱,流速为25ml/分钟，洗脱液A/B:25/75-15/85使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Xtimate 10u,
Figure PCTCN2018093088-appb-000182
柱(20×250mm)收集含有产物的级分，冻干，得到47.9mg白色固体
质谱(M/2+H) +:1058.1
实施例81:
(D-Tyr)-Phe-(NEt-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser(化合物YW-183)的制备
将1.0g商购可得的CTC树脂溶胀于DMF中，加入Fmoc-Ser(tBu)-OH(115mg,0.3mmol)的10ml DMF溶液，然后加入DIPEA(155mg,1.2mmol)，室温下处理16小时，树脂用DMF洗涤，用甲醇(320mg，10mmol)和DIPEA(310mg，2.4mmol)的10mlDMF溶液封端，树脂用DMF洗涤，得到Fmoc-Ser(tBu)-CTC树脂。该树脂用10ml 20％哌啶/DMF处理20分钟以除去Fmoc，重复两遍此操作，树脂用DMF洗涤，加入Fmoc-Tic-OH(359mg,0.9mmol),HATU(342mg,0.9mmol),HOAt(122mg,0.9mmol)的10ml DMF溶液，然后加入DIPEA(232mg,1.8mmol),室温下处理40分钟,树脂用DMF洗涤，得到Fmoc-Tic-Ser(tBu)-CTC树脂。以类似的方式，依次将D-Ala,Phe,Gln(Trt),D-Ser(tBu),Pro，NEt-Leu,Phe,D-Tyr(tBu)等氨基酸引入，得到1.5g D-Tyr(tBu)-Phe-(NEt-Leu)-Pro-[D-Ser(tBu)]-Gln(Trt)-Phe-(D-Ala)-Tic-Ser(tBu)-CTC树脂。树脂依次用DMF、甲醇、甲基叔丁基醚洗涤，然后抽干。
将干燥的树脂加入10ml的TFA/TIS/H 2O(92/4/4)溶液中，该混合物搅拌2小时，过滤除去树脂，用1ml的TFA/TIS/H 2O(92/4/4)溶液洗涤树脂。合并滤液，向滤液中加入甲基叔丁基醚(110ml),得到的混合物在3000转/分钟离心1分钟，固体用冰乙醚洗涤两次，并抽干。得到的沉淀用DMF溶解，然后进行线性浓度梯度洗脱(10分钟),流速为25ml/分钟，洗脱液A/B:72/28-66/34使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Sunfire,10u,
Figure PCTCN2018093088-appb-000183
柱(19×250mm)收集含有产物的级分，冻干，得到18.8mg白色固体
质谱(M+H) +:1246.6
实施例82
(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-NH 2(化合物YW-189)的制备
类似实施例66的合成方法，用常规固相合成方法，在MBHA树脂上合成树脂。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例66步骤2方法从树脂上切割下来并脱除保护。粗产物YW-189进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:72/28-66/34，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，10um,
Figure PCTCN2018093088-appb-000184
柱(19×250mm)。收集含有产物的级分，冻干，得到31.5mg白色固体。
实施例83
(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-NH 2(化合物YW-190)的制备
类似实施例66的合成方法，用常规固相合成方法，在MBHA树脂上合成树脂。常规方法脱除Fmoc保护基，树脂洗涤后干燥。目标多肽用实施例66步骤2方法从树脂上切割下来并脱除保护。粗产物YW-190进行HPLC分离纯化，线性梯度洗脱(10分钟)，流速为25mL/分钟，洗脱液A/B:74/26-68/32，使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈溶液，在制备型的HPLC上，使用Sunfire C18，10um,
Figure PCTCN2018093088-appb-000185
柱(19×250mm)。收集含有产物的级分，冻干，得到62.8mg白色固体。
实施例84:
4-(Trifluoromethyl)benzoyl-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser(化合物YW-195)的制备
将1.0g商购可得的CTC树脂溶胀于DMF中，加入Fmoc-Ser(tBu)-OH(115mg,0.3mmol)的10ml DMF溶液，然后加入DIPEA(155mg,1.2mmol)，室温下处理16小时，树脂用DMF洗涤，用甲醇(320mg，10mmol)和DIPEA(310mg，2.4mmol)的10mlDMF溶液封端，树脂用DMF洗涤，得到Fmoc-Ser(tBu)-CTC树脂。该树脂用10ml 20％哌啶/DMF处理20分钟以除去Fmoc，重复两遍此操作，树脂用DMF洗涤，加入Fmoc-Tic-OH(359mg,0.9mmol),HATU(342mg,0.9mmol),HOAt(122mg,0.9mmol)的10ml DMF溶液，然后加入DIPEA(232mg,1.8mmol),室温下处理40分钟,树脂用DMF洗涤，得到Fmoc-Tic-Ser(tBu)-CTC树脂。以类似的方式，依次将D-Ala,Phe,Gln(Trt),D-Ser(tBu),Pro，NMe-Leu,Phe,D-Tyr(tBu),4-(trifluoromethyl)benzoic acid等氨基酸引入，得到1.5g目标多肽的CTC树脂。树脂依次用DMF、甲醇、甲基叔丁基醚洗涤，然后抽干。
将干燥的树脂加入10ml的TFA/TIS/H 2O(92/4/4)溶液中，该混合物搅拌2小时，过滤除去树脂，用1ml的TFA/TIS/H 2O(92/4/4)溶液洗涤树脂。合并滤液，向滤液中加入甲基叔丁基醚(110ml),得到的混合物在3000转/分钟离心1分钟，固体用冰乙醚洗涤两次，并抽干。得到的沉淀用DMF溶解，然后进行线性浓度梯度洗脱(10分钟),流速为25ml/分钟，洗脱液A/B:72/28-66/34使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Xtimate 10u,
Figure PCTCN2018093088-appb-000186
柱(20×250mm)收集含有产物的级分，冻干，得到27.6mg白色固体
质谱(M+H) +:1404.6
实施例85:
(3-phenyl propyl)-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser(化合物YW-207)的制备
将1.2g商购可得的CTC树脂溶胀于DMF中，加入Fmoc-Ser(tBu)-OH(153mg,0.4mmol)的10ml DMF溶液，然后加入DIPEA(207mg,1.6mmol)，室温下处理16小时，树脂用DMF洗涤，用甲醇(384mg，12mmol)和DIPEA(413mg，3.2mmol)的10ml DMF溶液封端，树脂用DMF洗涤，得到Fmoc-Ser(tBu)-CTC树脂。该树脂用10ml 20％哌啶/DMF处理20分钟以除去Fmoc，重复两遍此操作，树脂用DMF洗涤，加入Fmoc-Tic-OH(479mg,1.2mmol),HATU(456mg,1.2mmol),HOAt(163mg,1.2mmol)的10ml DMF溶液，然后加入DIPEA(310mg,2.4mmol),室温下处理40分钟,树脂用DMF洗涤，得到Fmoc-Tic-Ser(tBu)-CTC树脂。以类似的方式，依次将D-Ala,Phe,Gln(Trt),D-Ser(tBu),Pro，NMe-Leu,Phe,D-Tyr(tBu)等氨基酸引入，得到D-Tyr(tBu)-Phe-(NMe-Leu)-Pro-[D-Ser(tBu)]-Gln(Trt)-Phe-(D-Ala)-Tic-Ser(tBu)-CTC树脂。得到的树脂溶胀于10ml DMF中，加入3-苯基丙醛(536mg,4.0mmol)和2滴冰醋酸，室温下处理2小时，树脂用DMF洗涤，加入硼氢化钠(151mg.4mmol)的3ml甲醇和7ml DMF的混合溶液，室温下处理30分钟，得到(3-phenylpropyl)-[D-Tyr(tBu)]-Phe-(NMe-Leu)-Pro-[D-Ser(tBu)]-Gln(Trt)-Phe-(D-Ala)-Tic-Ser(tBu)-CTC树脂。树脂依次用DMF、甲醇、甲基叔丁基醚洗涤，然后抽干。
将干燥的树脂加入15ml的TFA/TIS/H 2O(92/4/4)溶液中，该混合物搅拌2小时，过滤除去树脂，用1.5ml的TFA/TIS/H 2O(92/4/4)溶液洗涤树脂。合并滤液，向滤液中加入甲基叔丁基醚(150ml),得到的混合物在3000转/分钟离心1分钟，固体用冰乙醚洗涤两次，并抽干。得到的沉淀用DMF溶解，然后进行线性浓度梯度洗脱(10分钟),流速为25ml/分钟，洗脱液A/B:71/29-61/39使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Sunfire,10u,
Figure PCTCN2018093088-appb-000187
柱(19×250mm)收集含有产物的级分，冻干，得到49.7mg白色固体
质谱(M/2+H) +:676.2
实施例86：
(D-Tyr)-Phe-(NMe-Leu)-[Pro(tran-4F)]-(D-Ser)-Gln-(Nal-2)-(D-Ala)-Tic-Ser(化合物YW-210)的制备
将1.2g商购可得的CTC树脂溶胀于DMF中，加入Fmoc-Ser(tBu)-OH(153mg,0.4mmol)的10ml DMF溶液，然后加入DIPEA(207mg,1.6mmol)，室温下处理16小时， 树脂用DMF洗涤，用甲醇(384mg，12mmol)和DIPEA(413mg，3.2mmol)的10ml DMF溶液封端，树脂用DMF洗涤，得到Fmoc-Ser(tBu)-CTC树脂。该树脂用10ml 20％哌啶/DMF处理20分钟以除去Fmoc，重复两遍此操作，树脂用DMF洗涤，加入Fmoc-Tic-OH(479mg,1.2mmol),HATU(456mg,1.2mmol),HOAt(163mg,1.2mmol)的10ml DMF溶液，然后加入DIPEA(310mg,2.4mmol),室温下处理40分钟,树脂用DMF洗涤，得到Fmoc-Tic-Ser(tBu)-CTC树脂。以类似的方式，依次将D-Ala,Nal-2,Gln(Trt),D-Ser(tBu),Pro(tran-4F)，NMe-Leu,Phe,D-Tyr(tBu)等氨基酸引入，得到D-Tyr(tBu)-Phe-(NMe-Leu)-Pro-[D-Ser(tBu)]-Gln(Trt)-(Nal-2)-(D-Ala)-Tic-Ser(tBu)-CTC树脂。树脂依次用DMF、甲醇、甲基叔丁基醚洗涤，然后抽干。
将干燥的树脂加入15ml的TFA/TIS/H 2O(92/4/4)溶液中，该混合物搅拌2小时，过滤除去树脂，用1.5ml的TFA/TIS/H 2O(92/4/4)溶液洗涤树脂。合并滤液，向滤液中加入甲基叔丁基醚(150ml),得到的混合物在3000转/分钟离心1分钟，固体用冰乙醚洗涤两次，并抽干。得到的沉淀用DMF溶解，然后进行线性浓度梯度洗脱(10分钟),流速为25ml/分钟，洗脱液A/B:69/31-59/41使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Sunfire,10u,
Figure PCTCN2018093088-appb-000188
柱(19×250mm)收集含有产物的级分，冻干，得到80.0mg白色固体
质谱(M+H) +:1301.7
实施例87:
(NMe-D-Tyr)-Phe-(NMe-Leu)-Pro(tran-4F)-(D-Ser)-Gln-(Nal-2)-(D-Ala)-Tic-(NMe-Ser)(化合物YW-220)的制备
将1.0g商购可得的CTC树脂溶胀于DMF中，加入Fmoc-[NMe-Ser(tBu)]-OH(119mg,0.3mmol)的10ml DMF溶液，然后加入DIPEA(155mg,1.2mmol)，室温下处理16小时，树脂用DMF洗涤，用甲醇(320mg，10mmol)和DIPEA(310mg，2.4mmol)的10ml DMF溶液封端，树脂用DMF洗涤，得到Fmoc-[NMe-Ser(tBu)]-CTC树脂。该树脂用10ml 20％哌啶/DMF处理20分钟以除去Fmoc，重复两遍此操作，树脂用DMF洗涤，加入Fmoc-Tic-OH(359mg,0.9mmol),HATU(342mg,0.9mmol),HOAt(122mg,0.9mmol)的10ml DMF溶液，然后加入DIPEA(232mg,1.8mmol),室温下处理40分钟,树脂用DMF洗涤，得到Fmoc-Tic-[NMe-Ser(tBu)]-CTC树脂。以类似的方式，依次将D-Ala,(Nal-2),Gln(Trt),D-Ser(tBu),Pro(tran-4F)，NMe-Leu,Phe,NMe-D-Tyr(tBu)等氨基酸引入，得到1.5g目标多肽的-CTC树脂。树脂依次用DMF、甲醇、甲基叔丁基醚洗涤，然后抽干。
将干燥的树脂加入10ml的TFA/TIS/H 2O(92/4/4)溶液中，该混合物搅拌2小时，过滤除去树脂，用1ml的TFA/TIS/H 2O(92/4/4)溶液洗涤树脂。合并滤液，向滤液中加入甲基叔丁基醚(110ml),得到的混合物在3000转/分钟离心1分钟，固体用冰乙醚洗涤两次，并抽干。得到的沉淀用DMF溶解，然后进行线性浓度梯度洗脱(10分钟),流速为25ml/分钟，洗脱液A/B:95/5-35/65使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Sunfire,10u,
Figure PCTCN2018093088-appb-000189
柱(19×250mm)收集含有产物的级分，冻干，得到24.0mg白色固体
质谱(M+H) +:1328.6
实施例88:
(D-Tyr(3F))-Phe-(NMe-Leu)-Pro(tran-4F)-(D-Ser)-Gln-(Nal-2)-(D-Ala)-Tic-(NMe-Ser)(化合物YW-221)的制备
将1.0g商购可得的CTC树脂溶胀于DMF中，加入Fmoc-[NMe-Ser(tBu)]-OH(119mg,0.3mmol)的10ml DMF溶液，然后加入DIPEA(155mg,1.2mmol)，室温下处理16小时，树脂用DMF洗涤，用甲醇(320mg，10mmol)和DIPEA(310mg，2.4mmol)的10ml DMF溶液封端，树脂用DMF洗涤，得到Fmoc-[NMe-Ser(tBu)]-CTC树脂。该树脂用10ml 20％哌啶/DMF处理20分钟以除去Fmoc，重复两遍此操作，树脂用DMF洗涤，加入Fmoc-Tic-OH(359mg,0.9mmol),HATU(342mg,0.9mmol),HOAt(122mg,0.9mmol)的10ml DMF溶液，然后加入DIPEA(232mg,1.8mmol),室温下处理40分钟,树脂用DMF洗涤，得到Fmoc-Tic-[NMe-Ser(tBu)]-CTC树脂。以类似的方式，依次将D-Ala,(Nal-2),Gln(Trt),D-Ser(tBu),Pro(tran-4F),NMe-Leu,Phe,D-Tyr(3F)等氨基酸引入，得到1.5g目标多肽的CTC树脂。树脂依次用DMF、甲醇、甲基叔丁基醚洗涤，然后抽干。
将干燥的树脂加入10ml的TFA/TIS/H 2O(92/4/4)溶液中，该混合物搅拌2小时，过滤除去树脂，用1ml的TFA/TIS/H 2O(92/4/4)溶液洗涤树脂。合并滤液，向滤液中加入甲基叔丁基醚(110ml),得到的混合物在3000转/分钟离心1分钟，固体用冰乙醚洗涤两次，并抽干。得到的沉淀用DMF溶解，然后进行线性浓度梯度洗脱(10分钟),流速为25ml/分钟，洗脱液A/B:70/30-60/40使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Phenomenex C18柱(21.2×250mm)收集含有产物的级分，冻干，得到19.8mg白色固体
质谱(M/2+H) +:667.0
实施例89:
[D-Tyr(3F)]-Phe-(NMe-Leu)-Pro(tran-4F)-(D-Ser)-Gln-(Nal-2)-(D-Ala)-Tic-Ser(化合物YW-222)的制备
将1.0g商购可得的CTC树脂溶胀于DMF中，加入Fmoc-Ser(tBu)-OH(115mg,0.3mmol)的10ml DMF溶液，然后加入DIPEA(155mg,1.2mmol)，室温下处理16小时，树脂用DMF洗涤，用甲醇(320mg，10mmol)和DIPEA(310mg，2.4mmol)的10ml DMF溶液封端，树脂用DMF洗涤，得到Fmoc-Ser(tBu)-CTC树脂。该树脂用10ml 20％哌啶/DMF处理20分钟以除去Fmoc，重复两遍此操作，树脂用DMF洗涤，加入Fmoc-Tic-OH(359mg,0.9mmol),HATU(342mg,0.9mmol),HOAt(122mg,0.9mmol)的10ml DMF溶液，然后加入DIPEA(232mg,1.8mmol),室温下处理40分钟,树脂用DMF洗涤，得到Fmoc-Tic-Ser(tBu)-CTC树脂。以类似的方式，依次将D-Ala,Nal-2,Gln(Trt),D-Ser(tBu),Pro(tran-4F)，NMe-Leu,Phe,D-Tyr(3F)等氨基酸引入，得到1.5g D-Tyr(3F)-Phe-(NMe-Leu)-Pro(tran-4F)-[D-Ser(tBu)]-Gln(Trt)-(Nal-2)-(D-Ala)-Tic-Ser(tBu)-CTC树脂。树脂依次用DMF、甲醇、甲基叔丁基醚洗涤，然后抽干。
将干燥的树脂加入10ml的TFA/TIS/H 2O(92/4/4)溶液中，该混合物搅拌2小时，过滤除去树脂，用1ml的TFA/TIS/H 2O(92/4/4)溶液洗涤树脂。合并滤液，向滤液中加入甲基叔丁基醚(110ml),得到的混合物在3000转/分钟离心1分钟，固体用冰乙醚洗涤两次，并抽干。得到的沉淀用DMF溶解，然后进行线性浓度梯度洗脱(10分钟),流速为25ml/分钟，洗脱液A/B:72/28-66/34使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Sunfire,10u,
Figure PCTCN2018093088-appb-000190
柱(19×250mm)收集含有产物的级分，冻干，得到44.2mg白色固体
质谱(M/2+H) +:660.3
实施例90:
Palm-PEG8-Gly-Gly-(D-Tyr)-Phe-(NMe-Leu)-Pro(tran-4F)-(D-Ser)-Gln-(Nal-2)-(D-Ala)-Tic-Ser(化合物YW-223)的制备
将1.0g商购可得的CTC树脂溶胀于DMF中，加入Fmoc-Ser(tBu)-OH(115mg,0.3mmol)的10ml DMF溶液，然后加入DIPEA(155mg,1.2mmol)，室温下处理16小时，树脂用DMF洗涤，用甲醇(320mg，10mmol)和DIPEA(310mg，2.4mmol)的10ml DMF溶液封端，树脂用DMF洗涤，得到Fmoc-Ser(tBu)-CTC树脂。该树脂用10ml 20％哌啶/DMF处理20分钟以除去Fmoc，重复两遍此操作，树脂用DMF洗涤，加入Fmoc-Tic-OH(359mg,0.9mmol),HATU(342mg,0.9mmol),HOAt(122mg,0.9mmol)的10ml DMF溶液，然后加入DIPEA(232mg,1.8mmol),室温下处理40分钟,树脂用DMF 洗涤，得到Fmoc-Tic-Ser(tBu)-CTC树脂。以类似的方式，依次将D-Ala,Nal-2,Gln(Trt),D-Ser(tBu),Pro(tran-4F)，NMe-Leu,Phe,D-Tyr,Gly,Gly,PEG8,Palm等氨基酸引入，得到1.6g目标多肽的CTC树脂。树脂依次用DMF、甲醇、甲基叔丁基醚洗涤，然后抽干。
将干燥的树脂加入10ml的TFA/TIS/H 2O(92/4/4)溶液中，该混合物搅拌2小时，过滤除去树脂，用1ml的TFA/TIS/H 2O(92/4/4)溶液洗涤树脂。合并滤液，向滤液中加入甲基叔丁基醚(110ml),得到的混合物在3000转/分钟离心1分钟，固体用冰乙醚洗涤两次，并抽干。得到的沉淀用DMF溶解，然后进行线性浓度梯度洗脱(10分钟),流速为25ml/分钟，洗脱液A/B:33/67-23/77使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用Phenomenex C18柱(21.2×250mm)收集含有产物的级分，冻干，得到63.4mg白色固体
质谱(M/3+H) +:693.0
实施例91：
(NMe-D-Tyr)-Phe-(NMe-Leu)-DiFluorPro-(D-Ser)-Gln-(Nal-2)-(D-Ala)-Tic-(NMe-Ser)(化合物YW-225)的制备
将1.0g商购可得的CTC树脂溶胀于DMF中，加入Fmoc-[NMe-Ser(tBu)]-OH(119mg,0.3mmol)的10ml DMF溶液，然后加入DIPEA(155mg,1.2mmol)，室温下处理16小时，树脂用DMF洗涤，用甲醇(320mg，10mmol)和DIPEA(310mg，2.4mmol)的10ml DMF溶液封端，树脂用DMF洗涤，得到Fmoc-[NMe-Ser(tBu)]-CTC树脂。该树脂用10ml 20％哌啶/DMF处理20分钟以除去Fmoc，重复两遍此操作，树脂用DMF洗涤，加入Fmoc-Tic-OH(359mg,0.9mmol),HATU(342mg,0.9mmol),HOAt(122mg,0.9mmol)的10ml DMF溶液，然后加入DIPEA(232mg,1.8mmol),室温下处理40分钟,树脂用DMF洗涤，得到Fmoc-Tic-[NMe-Ser(tBu)]-CTC树脂。以类似的方式，依次将D-Ala,(Nal-2),Gln(Trt),D-Ser(tBu),DiFluorPro，NMe-Leu,Phe,NMe-D-Tyr(tBu)等氨基酸引入，得到1.5g目标多肽的CTC树脂。树脂依次用DMF、甲醇、甲基叔丁基醚洗涤，然后抽干。
将干燥的树脂加入10ml的TFA/TIS/H 2O(92/4/4)溶液中，该混合物搅拌2小时，过滤除去树脂，用1ml的TFA/TIS/H 2O(92/4/4)溶液洗涤树脂。合并滤液，向滤液中加入甲基叔丁基醚(110ml),得到的混合物在3000转/分钟离心1分钟，固体用冰乙醚洗涤两次，并抽干。得到的沉淀用DMF溶解，然后进行线性浓度梯度洗脱(10分钟),流速为25ml/分钟，洗脱液A/B:68/32-60/40使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用XBridge Peptide BEH C18 10u,
Figure PCTCN2018093088-appb-000191
柱(19 mm×250mm)收集含有产物的级分，冻干，得到43.6mg白色固体
质谱(M/2+H) +:674.0
实施例92:
(D-Tyr(3F))-Phe-(NMe-Leu)-(DiFluorPro)-(D-Ser)-Gln-(Nal-2)-(D-Ala)-Tic-(NMe-Ser)(化合物YW-226)的制备
将1.0g商购可得的CTC树脂溶胀于DMF中，加入Fmoc-[NMe-Ser(tBu)]-OH(119mg,0.3mmol)的10ml DMF溶液，然后加入DIPEA(155mg,1.2mmol)，室温下处理16小时，树脂用DMF洗涤，用甲醇(320mg，10mmol)和DIPEA(310mg，2.4mmol)的10ml DMF溶液封端，树脂用DMF洗涤，得到Fmoc-[NMe-Ser(tBu)]-CTC树脂。该树脂用10ml 20％哌啶/DMF处理20分钟以除去Fmoc，重复两遍此操作，树脂用DMF洗涤，加入Fmoc-Tic-OH(359mg,0.9mmol),HATU(342mg,0.9mmol),HOAt(122mg,0.9mmol)的10ml DMF溶液，然后加入DIPEA(232mg,1.8mmol),室温下处理40分钟,树脂用DMF洗涤，得到Fmoc-Tic-[NMe-Ser(tBu)]-CTC树脂。以类似的方式，依次将D-Ala,(Nal-2),Gln(Trt),D-Ser(tBu),DiFluorPro，NMe-Leu,Phe,D-Tyr(3F)等氨基酸引入，得到1.5g目标多肽的CTC树脂。树脂依次用DMF、甲醇、甲基叔丁基醚洗涤，然后抽干。
将干燥的树脂加入10ml的TFA/TIS/H 2O(92/4/4)溶液中，该混合物搅拌2小时，过滤除去树脂，用1ml的TFA/TIS/H 2O(92/4/4)溶液洗涤树脂。合并滤液，向滤液中加入甲基叔丁基醚(110ml),得到的混合物在3000转/分钟离心1分钟，固体用冰乙醚洗涤两次，并抽干。得到的沉淀用DMF溶解，然后进行线性浓度梯度洗脱(10分钟),流速为25ml/分钟，洗脱液A/B:68/32-60/40使用：洗脱液A:0.05％TFA的水溶液，洗脱液B:0.05％TFA的乙腈，在制备型的HPLC上，使用XBridge Peptide BEH C18 10u,
Figure PCTCN2018093088-appb-000192
柱(19mm×250mm)收集含有产物的级分，冻干，得到34.1mg白色固体
质谱(M/2+H) +:676.0
上述实施例制得的多肽，以及参照上述实施例制得的多肽见下表2，表2还记载了各多肽的纯度分析条件、保留时间、表征数据以及效果数据(其按照效果实施例1的方法测定)
表2实施例列表
Figure PCTCN2018093088-appb-000193
Figure PCTCN2018093088-appb-000194
Figure PCTCN2018093088-appb-000195
Figure PCTCN2018093088-appb-000196
Figure PCTCN2018093088-appb-000197
Figure PCTCN2018093088-appb-000198
Figure PCTCN2018093088-appb-000199
Figure PCTCN2018093088-appb-000200
Figure PCTCN2018093088-appb-000201
Figure PCTCN2018093088-appb-000202
Figure PCTCN2018093088-appb-000203
表2中的纯度分析条件具体如下：
条件A:洗脱液A/B＝95/5-35/65
流动相:A:水(0.01％TFA),B:ACN(0.01％TFA)
流动相比例:5％B within 0-3min,线性梯度洗脱5-65％B within 20min
流速:1.2ml/min
色谱柱:Eclipse XDB-C18,4.6*150mm,5um
箱温:40℃
条件B:洗脱液A/B＝95/5-35/65
流动相:A:水(0.01％TFA),B:ACN(0.01％TFA)
流动相比例:5％B within 0-3min,线性梯度洗脱5-65％B within 20min
流速:1.0ml/min
色谱柱:AGLIENT ZORBAX Eclipse XDB,C18,4.6*150mm,5um
温度:40℃
条件C:洗脱液A/B＝95/5-35/65
流动相:A:水(0.01％TFA),B:ACN(0.01％TFA)
流动相比例:5％B within 0-3min,线性梯度洗脱5-65％B with 20min
流速:1.0ml/min
色谱柱:SunFire C18,4.6*150mm,3.5um
温度:40℃
条件D:洗脱液A/B＝95/5-35/65
流动相:A:水(0.05％TFA),B:ACN(0.05％TFA)
流动相比例:5％B within 0-3min,线性梯度洗脱5-65％B within 20min
流速:1.2ml/min
色谱柱:Eclipse XDB-C18,4.6*150mm,5um
条件E:洗脱液A/B＝85/15-25/75
流动相:A:水(0.01％TFA),B:ACN(0.01％TFA)
流动相比例:15％B within 0-3min,线性梯度洗脱15-75％B with 20min
流速:1.0ml/min
色谱柱:SunFire C18,4.6*150mm,3.5um
温度:40℃
条件F:洗脱液A/B＝95/5-35/65
流动相:A:水(0.05％TFA),B:ACN(0.05％TFA)
流动相比例:5％B within 0-3min,线性梯度洗脱5-65％B within 20min
流速:1.2ml/min
色谱柱:SunFire C18,4.6*150mm,3.5um
条件G:洗脱液A/B＝80/20-20/80
流动相:A:水(0.01％TFA),B:ACN(0.01％TFA)
流动相比例:20％B within 0-3min,线性梯度洗脱20-80％B with 20min
流速:1.0ml/min
色谱柱:SunFire C18,4.6*150mm,3.5um
温度:40℃
条件H:洗脱液A/B＝50/50-0/100
流动相:A:水(0.05％TFA),B:ACN(0.05％TFA)
流动相比例:50％B within 0-3min,线性梯度洗脱50-100％B within 20min
流速:1.0mL/min
色谱柱:XBridge Peptide BEH C18,4.6*150mm,3.5um
柱温:40℃
条件I:洗脱液A/B＝80/20-5/95
流动相:A:水(0.01％TFA),B:ACN(0.01％TFA)
流动相比例:20％B within 0-2min,线性梯度洗脱20-95％B within 25min
流速:1.0mL/min
色谱柱:SunFire C18,4.6*150mm,3.5um
柱温:40℃
条件J:洗脱液A/B＝95/5-35-65
流动相:水(0.05％TFA),B:ACN(0.05％TFA)
流动相比例:5％B within 0-3min,线性梯度洗脱5-65％B within 20min
流速:1.0mL/min
色谱柱:XBridge Peptide BEH C18,4.6*150mm,3.5um
柱温:40℃
条件K:洗脱液A/B＝50/50-0/100
流动相:A:A:水(0.01％TFA),B:ACN(0.01％TFA)
流动相比例:50％B within 0-3min,线性梯度洗脱50-100％B within 20min
流速:1.0ml/min
色谱柱:SunFire C18,4.6*150mm,3.5um
柱温:40℃
条件L:洗脱液A/B＝80/20-5/95
流动相:A:水(0.05％TFA),B:ACN(0.05％TFA)
流动相比例:20％B within 0-2min,线性梯度洗脱20-95％B within 25min
流速:1.0ml/min
色谱柱:XBridge Peptide BEH,4.6*150mm,3.5um
柱温:40℃
条件M:洗脱液A/B＝80/20-20/80
流动相:A:水(0.05％TFA),B:ACN(0.05％TFA)
流动相比例:20％B within 0-1min,线性梯度洗脱20-80％B within 20min
流速:1.0mL/min
色谱柱:XBridge Peptide BEH C18,4.6*150mm,3.5um
柱温:40℃
条件N:洗脱液A/B＝70/30-0/100
流动相:A:水(0.05％TFA),B:ACN(0.05％TFA)
流动相比例:30％B within 0-3min,线性梯度洗脱30-100％B within 20min
流速:1.0mL/min
柱温:40℃
色谱柱:XBridge Peptide BEH C18,4.6*150mm,3.5um
效果实施例1：药理学实验数据：
上述的多肽序列均以万有制药株式会社在P2010-229093A专利中公布的多肽序列：(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser作为阳性对照。
Figure PCTCN2018093088-appb-000204
测试化合物对Tango TM CMKLR1-bla U2OS细胞(Invitrogen Cat.nos.K1551)的激活作用
上述实验中各化合物对Tango TM CMKLR1-bla U2OS细胞的激活作用进行测定，具体操作如下：
第1天：细胞种板
1.显微镜下(CKX41,OLYMPUS，物镜×4倍，目镜×10倍)观察，确定细胞状态良好；
2.去除培养基，用DPBS把细胞洗两遍,加入3ml的0.05％胰酶，置于37℃、5％CO 2培养箱(Thermo Fisher,Waltham,Massachusetts,USA)3-5min，待细胞变圆后，加入3-5ml培养基(培养基配方：DMEM90％，Dialyzed FBS10％，NEAA0.1mM，HEPES(pH7.3)25mM，Penicillin100U/ml，Streptomycin100μg/ml)终止消化；
2.将消化下来的细胞转移到15mL离心管(430790，Corning)中，1000rpm离心5min(5810R，eppendorf，hamburg，Germany)，弃上清；
3.加入7ml培养基(DMEM+10％FBS)，吹打成单细胞悬液，细胞计数仪计数，用培养基将细胞悬液调整到所需细胞密度250000个/ml；
4.接种至384孔细胞板中(Corning 3712)，每孔40μL使细胞数为10000个/孔，空白对照加入32μl培养基；
5.37℃、5％CO 2培养过夜。
第2天：加药和检测
1.200×化合物板配制
1.1将待测化合物用DMSO配成10mM的工作液。
1.2在Echo-384孔板中A至P行的第2列加入45μL 10mM待测化合物。用Precision进行化合物的3倍稀释(3-11列加入30μL DMSO，从第2列中吸取15μl药物溶液至第3列，吹打混合均匀；再从第3列中吸取15μl溶液至第4列，吹打混合均匀，依次继续将 药物进行3倍比稀释，共10个浓度。)Echo-384孔板的第1和第12列补充30μl DMSO，下表3为200×化合物板第2至11列每孔药物的浓度。
表3 200×化合物板第2至11列每孔药物的浓度
列数 2 3 4 5 6 7 8 9 10 11
浓度(μm) 10000 3333 1111 370 123 41 13 4.6 1.5 0.5
2.中间板配制
取V型底384孔板，用Echo转200×化合物板中的稀释好的化合物(或DMSO)500nL即0.5μl到对应位置的V型底384孔板中，每孔加入20μl培养基，离心，震荡混匀。下表4为中间板(即5×化合物板)第2至11列每孔药物的浓度
表4 5×化合物板第2至11列每孔药物的浓度
列数 2 3 4 5 6 7 8 9 10 11
浓度(μm) 250 83.3 27.8 9.3 3.1 1.0 0.34 0.11 0.04 0.01
3.加药
3.1从培养箱中取出细胞板，显微镜下观察。取中间板中稀释好的化合物或DMSO加入细胞板中，每孔10μl到对应位置的细胞板中,每孔已经预制40μl培养基。
3.2将细胞置于37℃、5％CO 2中继续培养4h。
表5 1×化合物板第2至11列每孔药物的浓度
列数 2 3 4 5 6 7 8 9 10 11
浓度(μm) 50 16.7 5.6 1.9 0.62 0.21 0.07 0.02 0.008 0.003
4.激活效用检测
4.1用1mM CCF4-AM，solution B，Solution C，Solution D配置适量的6×的检测液。LiveBLAzer TM-FRET B/G Loading kit(K1095，Thermo Fisher,Waltham,Massachusetts,USA)试剂盒中含有CCF-4AM以及solutionB、solutionC，solutionD同样购自invitrogen(K1157，Thermo Fisher,Waltham,Massachusetts,USA)。
4.2将细胞在显微镜下观察，细胞板平衡至室温。
4.3吸取6μl的CCF-4AM溶解的solution A，60μl的solution B,904μl solution C,30μl的solution D于EP管中，吹打震荡，混合均匀得6×检测液。将配制好的6×检测液加入384孔板中，用排枪吸取每孔10μL。
4.4将细胞板1000rpm离心后，置于摇床上450rpm震荡1min，然后常温静置1.5h。
4.5 Enspire微孔板检测仪检测各孔荧光信号，(λex＝409nm，λem＝460/530nm)读取信号值。
5.使用XLfit(5.4.0.8，ID Business Solutions Limited)进行数据处理。
数值处理：激活率＝(Signal-Min)/(Max-Min)*100％
Max：加入高浓度阳性药后human Chemokine like receptor 1被激活的本底值。
Min：细胞不受化合物影响时的本底值。
Signal：化合物相应浓度下的信号值。
以化合物浓度和相应的激活率做四参数曲线拟合，得到相应化合物的EC 50。数据用XLfit软件中方程进行拟合。
表6化合物药理实验生物活性结果
多肽编号 EC50(μM) 多肽编号 EC50(μM) 多肽编号 EC50(μM)
YW-71 0.031 YW-117 0.0039 YW-159 0.018
YW-72 0.045 YW-118 0.0069 YW-161 0.003
YW-73 0.028 YW-119 0.0099 YW-162 0.0026
YW-74 0.0062 YW-121 0.0007 YW-163 0.0022
YW-75 0.05 YW-122 0.0006 YW-164 0.0011
YW-76 0.043 YW-124 0.0013 YW-165 0.0015
YW-77 0.053 YW-125 0.0006 YW-166 0.005
YW-78 0.026 YW-127 0.01 YW-167 0.0008
YW-79 0.0047 YW-128 0.02 YW-168 0.0012
YW-96 0.039 YW-129 0.0091 YW-171 0.029
YW-97 0.05 YW-132 0.0055 YW-172 0.0058
YW-98 0.003 YW-133 0.0007 YW-174 0.0012
YW-100 0.042 YW-134 0.0007 YW-175 0.091
YW-101 0.0029 YW-142 0.0009 YW-176 0.0038
YW-103 0.0094 YW-146 0.0014 YW-177 0.025
YW-104 0.08 YW-147 no fit YW-182 0.041
YW-105 0.0106 YW-148 0.0005 YW-183 0.0092
YW-110 0.013 YW-149 0.021 YW-184 0.016
YW-111 0.002 YW-150 0.062 YW-185 0.0059
YW-112 0.17 YW-151 0.027 YW-186 0.011
YW-113 0.0086 YW-153 0.0085 YW-189 0.0068
YW-114 0.005 YW-154 0.034 YW-190 0.0027
YW-115 0.19 YW-158 0.065 YW-3 0.019
表6所列的部分化合物EC 50优于YW-3，显示出较强的活性，表明本发明的化合物在体外生化实验水平可以有效结合Chemerin受体，因此本发明的化合物可以成为炎症的有效治疗药物。
效果实施例2：部分化合物的血浆稳定性实验数据：
1. 50mM磷酸盐缓冲液(50mM磷酸钠盐和70mM NaCl)的配制：
将称取的5.750g Na 2HPO 4,1.141g NaH 2PO 4·和4.095g NaCl(Shanghai Titan)溶于1000mL超纯水，并调节pH至7.4。配置好的磷酸缓冲液放在冰箱4℃储存，有效期为一周。
2.化合物储备液的配制：
1)5mg/mL受试化合物：称取5mg的化合物溶于1mL的DMSO。
2)20mM对照品：2.728mg的奴弗卡因溶于0.5mL的DMSO。3.878mg的苯氟雷司溶于0.5mL的DMSO(Amresco)。
3.准备实验用血浆：
将冻存的血浆(人：上海睿智化学，大鼠、小鼠：上海西普尔－必凯，犬、猴：苏州西山中科)从-80℃冰箱中取出，立即置于37℃的水浴锅中，轻微振荡使其融化，然后将解冻后的血浆倒入离心管中，3000rpm离心8min，取上清用于实验。用pH计(METTLER TOLEDO)检测血浆的pH值，只有pH值在7.4～8之间的血浆才被用于实 验。将血浆放在冰浴上备用。
4.给药溶液的配制：
1)125μg/mL受试化合物溶液：将5μl的5mg/mL的受试化合物(见步骤2)加入到195μl DMSO中；500μM对照品溶液：将20mM的对照品储备液(见步骤2)加入到195μl DMSO中。
2)0.5％BSA磷酸盐缓冲溶液：将0.05g的BSA加入到10mL磷酸盐缓冲液中(见步骤1)；
3)5μg/mL受试化合物给药溶液：将40μl的125μg/mL受试化合物溶液加入到960μl 0.5％BSA磷酸盐缓冲溶液中，振荡混匀，并将给药溶液放于37℃水浴中预热5分钟。
20μM对照品给药溶液：将40μl的500μM对照品给药溶液加入到960μl 0.5％BSA磷酸盐缓冲溶液中，振荡混匀，并将给药溶液放于37℃水浴中预热5分钟。
5.将10μl的5μg/mL受试化合物和20μM对照品给药溶液分别加入到96孔板上设置为不同时间点(0分钟、1小时、2小时和4小时)的孔中，复样数为3。
6.将500μl含5％FA的ACN(IS)加入到设置为0分钟点的孔中，然后加入90μl血浆，混匀后贴上封口膜放于4℃(复样数为3)。
7.将90μl血浆分别加到设置时间点为1小时、2小时和4小时的孔中，复样数为3，并开始计时。(反应终浓度受试化合物为500ng/mL；对照品为2μM)
8.然后在计时器显示1小时、2小时和4小时时，分别加入500μl含5％FA的ACN(IS)溶液到相应时间点的孔中终止反应，混匀后贴上封口膜放于4℃。
9.将96孔板上不同时间点的所有样品(0分钟、1小时、2小时和4小时)放在振荡器(IKA,MTS 2/4)上600rpm/min震荡10分钟，然后在离心机(Thermo Multifuge×3R)上采用5594×g将样品离心15分钟。
10.从离心后的样品中取出150μL上清液送至LC-MS/MS进行分析(常规的多肽LC-MS/MS分析方法)。
表7化合物的血浆稳定性实验数据
Figure PCTCN2018093088-appb-000205
Figure PCTCN2018093088-appb-000206
注1：表7中的Very long是指血浆稳定性测试(4小时)没有发现明显的多肽血浆浓度的降解。

Claims (34)

  1. 一种如式I所示的肽类化合物、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于：
    XX0-XX1-XX2-XX3-XX4-XX5-XX6-XX7-XX8-XX9-XX10-P (I)
    其中，XX0为氢、
    Figure PCTCN2018093088-appb-100001
    R 0-2或
    Figure PCTCN2018093088-appb-100002
    R 0-1为CH 3-，q为10～18；
    PEG为
    Figure PCTCN2018093088-appb-100003
    m为6～12；
    n为0～2；
    所有的AA0独立地为
    Figure PCTCN2018093088-appb-100004
    Ahx、Gly或Beta-Ala；所有的k独立地为4～8，所有的r独立地为0或1；
    R 0-2为未取代或R 0-2-1取代的C 1～C 6的烷基；
    所有的R 0-2-1独立地为未取代或羟基取代的苯基；
    R 0-3为未取代或R 0-3-1取代的C 1～C 8的烷基、或、未取代或R 0-3-2取代的苯基；
    所有的R 0-3-1独立地为未取代或羟基取代的苯基、或、C 3～C 6的环烷基；
    所有的R 0-3-2独立地为羟基、或者、卤代的C 1～C 4烷基；
    XX1为氨基未取代或氨基被1个C 1～C 4的烷基取代的下述任一氨基酸：D-Tyr(3F)、D-Tyr和D-Phe；
    XX2为氨基未取代或氨基被1个C 1～C 4的烷基取代的下述任一氨基酸：1Nal、2Nal、Bpa、和、
    Figure PCTCN2018093088-appb-100005
    n2为0或1，R 2为C 1～C 4烷基或卤素，*标记的碳原子为手性碳原子，其为R构型或S构型；
    XX3为
    Figure PCTCN2018093088-appb-100006
    R 3-1为C 4～C 5的烷基或苄基；R 3-2为C 1～C 4的烷基，*标记的碳原子为手性碳原子，其为R构型或S构型；
    XX4为Ala或
    Figure PCTCN2018093088-appb-100007
    Z为-(CR 4-1R 4-2) n4-或-S-(CR 4-3R 4-4) n4’-；所述的-(CR 4-1R 4-2) n4-和-S-(CR 4-3R 4-4) n4’-的右端与手性碳原子连接；n4为1～3，n4’为1或2；所有的R 4-1、R 4-2、R 4-3和R 4-4独立地为氢、羟基、卤素或苯基；*标记的碳原子为手性碳原子，其为R构型或S构型；
    XX5为D-Ser、D-Hyp、D-Thr、βAla、D-NMeSer、2Nal、1Nal或D-HoSer；
    XX6为Gln、NMe-Gln或NGln；
    XX7为NMe-Phe、HoPhe、1Nal、2Nal、Bpa、D-Ser或
    Figure PCTCN2018093088-appb-100008
    n7为0或1，R 7为C 1～C 4烷基、C 1～C 4烷氧基或卤素，*标记的碳原子为手性碳原子，其为R构型或S构型；
    XX8为D-Ala、D-NMeAla、Ala或βAla；
    XX9为Tic、Phe、NMe-Phe、1Nal、2Nal、Bpa、Phe(4-Me)、Phe(4-Cl)、Phe(4-NO2)、HoPhe、Idc、Tic(OH)、Oic、Chc、Cha、MeA6c、HoPro、Pro(5Ph)、Pro(4Ph)、Ala(dip)、Bip、azaTic、D-Tic、Ti1c、D-Ti1c、TP5C、TP6C、Tic(6-Me)、S-Pip、Ica或D-Oic；
    XX10为NhomoSer、或者、氨基未取代或氨基被1个C 1～C 4的烷基取代的下述任一氨基酸：Ser、Thr、Hyp、Asp、D-HoSer和HoSer；
    P为羟基或氨基。
  2. 如权利要求1所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，所述的q为以下述任两个值为端点的范围：10、11、12、13、14、15、16、17和18；
    和/或，所述的m为以下述任两个值为端点的范围：6、7、8、9、10、11和12；
    和/或，所述的n为0、1或2；
    和/或，所述的k独立地为以下述任两个值为端点的范围：4、5、6、7和8；
    和/或，所述的R 0-2-1的个数为一个或多个，当存在多个R 0-2-1时，它们相同或不同；
    和/或，所述的R 0-2-1独立地处于所述C 1～C 6烷基的末端或非末端；
    和/或，当所述的R 0-2为未取代或R 0-2-1取代的C 1～C 6的烷基时，所述的C 1～C 6的烷基为C 1～C 4的烷基；
    和/或，所述的R 0-2-1中，所述的羟基的个数为一个或多个；
    和/或，所述的R 0-2-1中，所述的羟基独立地处于所述苯基的邻位、间位或对位；
    和/或，所述的R 0-3-1的个数为一个或多个，当存在多个R 0-3-1时，它们相同或不同；
    和/或，所述的R 0-3-1独立地处于所述C 1～C 8烷基的末端或非末端；
    和/或，当所述的R 0-3为未取代或R 0-3-1取代的C 1～C 8的烷基时，所述的C 1～C 8的烷基为C 1～C 4的烷基或正戊基；
    和/或，所述的R 0-3-2的个数为一个或多个，当存在多个R 0-3-2时，它们相同或不同；
    和/或，所述的R 0-3-2独立地处于所述苯基的邻位、间位或对位
    和/或，所述的R 0-3-1中，所述的羟基的个数为一个或多个；
    和/或，所述的R 0-3-1中，所有的羟基独立地处于所述苯基的邻位、间位或对位；
    和/或，所述的R 0-3-1中，所述的C 3～C 6的环烷基为环己基；
    和/或，所述的R 0-3-2中，所述的“卤”的个数为一个或多个，当存在多个卤时，它们相同或不同；
    和/或，所述的R 0-3-2中，所述的“卤”独立地为氟、氯或溴；
    和/或，所述的R 0-3-2中，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，所述的XX1中，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，所述的XX2中，所述的
    Figure PCTCN2018093088-appb-100009
    为
    Figure PCTCN2018093088-appb-100010
    和/或，当所述的XX2为“氨基未取代或氨基被1个C 1～C 4的烷基取代的下述任一氨基酸”时，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，所述的R 2中，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基或异丁基；
    和/或，所述的R 2中，所述的卤素为氟或氯；
    和/或，所述的XX3中，所述的
    Figure PCTCN2018093088-appb-100011
    为
    Figure PCTCN2018093088-appb-100012
    和/或，所述的R 3-1中，所述的C 4～C 5的烷基为正丁基、异丁基、仲丁基、叔丁基、正戊基或3-甲基丁基；
    和/或，所述的R 3-2中，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，所述的XX4中，所述的
    Figure PCTCN2018093088-appb-100013
    为
    Figure PCTCN2018093088-appb-100014
    和/或，所述的n4为1、2或3；
    和/或，所述的R 4-1中，所述的卤素为氟或氯；
    和/或，所述的R 4-2中，所述的卤素为氟或氯；
    和/或，所述的R 4-3中，所述的卤素为氟或氯；
    和/或，所述的R 4-4中，所述的卤素为氟或氯；
    和/或，所述的XX7中，所述的
    Figure PCTCN2018093088-appb-100015
    为
    Figure PCTCN2018093088-appb-100016
    和/或，所述的R 7中，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基或异丁基；
    和/或，所述的R 7中，所述的C 1～C 4烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基或异丁氧基；
    和/或，所述的R 7中，所述的卤素为氟或氯；
    和/或，所述的XX10中，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
  3. 如权利要求2所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，所述的q为10～14；
    和/或，所述的m为6～10；
    和/或，所述的n为2；
    和/或，所述的AA0中，所述的
    Figure PCTCN2018093088-appb-100017
    为PEG8；
    和/或，所述的R 0-2-1中，所述的“羟基取代的苯基”为3,5-二羟基苯基；
    和/或，当所述的R 0-3为未取代或R 0-3-1取代的C 1～C 8的烷基、所述的C 1～C 8的烷基为C 1～C 4的烷基时，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，所述的R 0-3-1中，所述的“羟基取代的苯基”为3,4-二羟基苯基或3,5-二羟基苯基；
    和/或，所述的R 0-3-1中，所述的C 3～C 6的环烷基为环己基；
    和/或，所述的R 0-3-2中，所述的“卤代的C 1～C 4烷基”为三氟甲基；
    和/或，所述的XX1中，所述的C 1～C 4的烷基为甲基；
    和/或，所述的XX2中，所述的
    Figure PCTCN2018093088-appb-100018
    为Phe、Phe(4-Cl)或Phe(4-Me)；
    和/或，所述的XX3为NMe-Leu、NMe-Phe、NMe-HoLeu、NEt-Leu、NPr-Leu、NiPr-Leu、Nbu-Leu、NMe-Nle或NMe-Ile；
    和/或，所述的XX4中，所述的-(CR 4-1R 4-2) n4-为-CH 2-、-(CH 2) 2-、-CH(OH)-CH 2-、-CF 2-CH 2-、-CHPh-CH 2-、-CH 2-CHPh-或-(CH 2) 3-；
    和/或，所述的XX4中，所述的S-(CR 4-3R 4-4) n4’-为-S-CH 2-；
    和/或，所述的XX7中，所述的
    Figure PCTCN2018093088-appb-100019
    为Phe、Phe(3-Cl)、Phe(3-Me)、Phe(3-OMe)、Phe(4-OMe)、Phe(4-Me)或Phe(4-Cl)；
    和/或，当所述的XX10为“氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸”时，所述的“氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸”为NMe-Ser或NMe-HoSer。
  4. 如权利要求3所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，所述的m为8；
    和/或，所述的R 0-2中，所述的“R 0-2-1取代的C 1～C 6的烷基”为3,5-二羟基苄基或3-苯基丙基；
    和/或，所述的R 0-3中，所述的“R 0-3-1取代的C 1～C 8的烷基”为2-苯基乙基、3-苯基丙基、4-苯基丁基、4-苯基苄基、二苯甲基、3,4-二羟基苄基、3,5-二羟基苄基或环己基甲基；
    和/或，所述的R 0-3中，所述的“R 0-3-2取代的苯基”为3,5-二羟基苯基、2,3-二羟基苯基、2,6-二羟基苯基、2,3,4-三羟基苯基、2,3,5-三羟基苯基或4-三氟甲基苯基；
    和/或，当所述的XX1为“氨基被1个C 1～C 4的烷基取代的下述任一氨基酸”时，所述的“氨基被1个C 1～C 4的烷基取代的下述任一氨基酸”为D-NMeTyr；
    和/或，当所述的XX2为“氨基被1个C 1～C 4的烷基取代的下述任一氨基酸”时，所述的“氨基被1个C 1～C 4的烷基取代的下述任一氨基酸”为NMePhe；
    和/或，所述的XX4中，所述的
    Figure PCTCN2018093088-appb-100020
    为Aze、Thz、Hyp、Pro、Pro(5Ph)、Pro(4Ph)、 Pro(diF)或HoPro。
  5. 如权利要求1所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，XX0为氢；
    和/或，当所述的XX0为
    Figure PCTCN2018093088-appb-100021
    时，所有的AA0独立地为Gly或βAla；
    和/或，R 0-2为未取代或R 0-2-1取代的C 1～C 6的烷基，所有的R 0-2-1独立地为苯基；
    和/或，R 0-3为未取代或R 0-3-1取代的C 1～C 8的烷基、或、未取代或R 0-3-2取代的苯基；所有的R 0-3-1独立地为苯基、或、C 3～C 6的环烷基；所有的R 0-3-2独立地为卤代的C 1～C 4烷基；
    和/或，XX1为氨基未取代或氨基被1个C 1～C 4的烷基取代的下述任一氨基酸：D-Tyr(3F)和D-Tyr；
    和/或，XX2为氨基未取代或氨基被1个C 1～C 4的烷基取代的下述任一氨基酸：1Nal、2Nal、Bpa、Phe、Phe(4-Cl)和Phe(4-Me)；
    和/或，XX3为NMe-Leu、NMe-Phe、NMe-HoLeu、NEt-Leu、NPr-Leu、NiPr-Leu、Nbu-Leu、NMe-Nle或NMe-Ile；
    和/或，XX4为
    Figure PCTCN2018093088-appb-100022
    和/或，XX5为D-Ser、D-Thr或D-HoSer；
    和/或，XX6为Gln；
    和/或，XX7为1Nal、2Nal或
    Figure PCTCN2018093088-appb-100023
    和/或，XX8为D-Ala；
    和/或，XX9为Tic、Phe、NMePhe、1Nal、2Nal、Bpa、Phe(4-Me)、Phe(4-Cl)、Phe(4-NO2)、HoPhe、Idc、Tic(OH)、Oic、Chc、Cha、MeA6c、HoPro、Pro(5Ph)、Pro(4Ph)、Ala(dip)、Bip、azaTic、D-Tic、Ti1c、D-Ti1c、TP5C、TP6C、Tic(6-Me)、Ica或D-Oic；
    和/或，XX10为NHoSer、或、氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸：Ser和HoSer；
    和/或，P为羟基。
  6. 如权利要求5所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，XX3为NMe-Leu、NMe-Phe、NMe-HoLeu、NEt-Leu、NPr-Leu、NiPr-Leu或Nbu-Leu；
    和/或，XX4为Thz、Hyp、Pro、Pro(5Ph)、Pro(4Ph)或Pro(diF)；
    和/或，XX7为1Nal、2Nal或Phe；
    和/或，XX9为Tic、Phe(4-Me)、Phe(4-Cl)、D-Ti1c或D-Oic。
  7. 如权利要求1所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，XX5为D-Ser、D-Hyp、D-Thr、D-NMeSer、2Nal、1Nal或D-HoSer；
    XX9为Tic、Phe、NMePhe、1Nal、2Nal、Bpa、Phe(4-Me)、Phe(4-Cl)、Phe(4-NO2)、HoPhe、Idc、Tic(OH)、Oic、Chc、Cha、MeA6c、HoPro、Pro(5Ph)、Pro(4Ph)、Ala(dip)、Bip、azaTic、D-Tic、Ti1c、D-Ti1c、TP5C、TP6C、Tic(6-Me)、Ica或D-Oic。
  8. 如权利要求1所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，n为2；
    所有的AA0独立地为Gly或Beta-Ala；
    所有的R 0-2-1独立地为苯基；
    所有的R 0-3-1独立地为苯基、或、C 3～C 6的环烷基；
    所有的R 0-3-2独立地为卤代的C 1～C 4烷基；
    XX1为氨基未取代或氨基被1个C 1～C 4的烷基取代的下述任一氨基酸：D-Tyr(3F)和D-Tyr；
    XX4为
    Figure PCTCN2018093088-appb-100024
    XX5为D-Ser、D-Thr、或D-HoSer；
    XX6为Gln；
    XX7为1Nal、2Nal、或
    Figure PCTCN2018093088-appb-100025
    XX8为D-Ala；
    XX9为Tic、Phe(4-Me)、Phe(4-Cl)、D-Ti1c、或D-Oic；
    XX10为NhomoSer、或者、氨基未取代或氨基被1个C 1～C 4的烷基取代的下述任一氨基酸：Ser和HoSer。
  9. 如权利要求1所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于：
    XX0为氢、
    Figure PCTCN2018093088-appb-100026
    R 0-2或
    Figure PCTCN2018093088-appb-100027
    R 0-1为CH 3-，q为10～18；
    PEG为
    Figure PCTCN2018093088-appb-100028
    m为6～10；
    n为0～2；
    所有的AA0独立地为
    Figure PCTCN2018093088-appb-100029
    Ahx、Gly或βAla；所有的k独立地为4～8，所有的r独立地为0或1；
    R 0-2为R 0-2-1取代或未取代的C 1～C 6的烷基；
    所有的R 0-2-1独立地为羟基取代或未取代的苯基；
    R 0-3为R 0-3-1取代或未取代的C 1～C 8的烷基、或、R 0-3-2取代或未取代的苯基；
    所有的R 0-3-1独立地为羟基取代或未取代的苯基、或、C 3～C 6的环烷基；
    所有的R 0-3-2独立地为羟基、或者、卤代的C 1～C 4烷基；
    XX1为氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸：D-Tyr和D-Phe；
    XX2为氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸：1Nal、2Nal、Bpa和、
    Figure PCTCN2018093088-appb-100030
    n2为0或1，R 2为C 1～C 4烷基或卤素，*标记的碳原子为手性碳原子，其为R构型或S构型；
    XX3为
    Figure PCTCN2018093088-appb-100031
    其中，*标记的碳原子为手性碳原子，其为R构型或S构型；R 3-1为C 4～C 5的烷基或苄基；R 3-2为C 1～C 4的烷基；
    XX4为Ala或
    Figure PCTCN2018093088-appb-100032
    *标记的碳原子为手性碳原子，其为R构型或S构型；Z为-(CR 4-1R 4-2) n4-或-S-(CR 4-3R 4-4) n4’-；所述的-(CR 4-1R 4-2) n4-和-S-(CR 4-3R 4-4) n4’-的右端与手性碳原子连接；n4为1～3，n4’为1或2；所有的R 4-1、R 4-2、R 4-3和R 4-4独立地为氢、羟基、 卤素或苯基；
    XX5为D-Ser、D-Hyp、D-Thr、βAla、D-NMeSer、2Nal、1Nal或D-HoSer；
    XX6为Gln、NMeGln或NGln；
    XX7为NMe-Phe、HoPhe、1Nal、2Nal、Bpa、D-Ser或
    Figure PCTCN2018093088-appb-100033
    n7为0或1，R 7为C 1～C 4烷基、C 1～C 4烷氧基或卤素，*标记的碳原子为手性碳原子，其为R构型或S构型；
    XX8为D-Ala、D-NMeA、Ala或βAla；
    XX9为Tic、Phe、NMePhe、1Nal、2Nal、Bpa、Phe(4-Me)、Phe(4-Cl)、Phe(4-NO2)、HoPhe、Idc、Tic(OH)、Oic、Chc、Cha、MeA6c、HoPro、Pro(5Ph)、Pro(4Ph)、Ala(dip)、Bip、azaTic、D-Tic、Ti1c、D-Ti1c、TP5C、TP6C、Tic(6-Me)、S-Pip、Ica或D-Oic；
    XX10为NHoSer、或、氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸：Ser、Thr、Hyp、Asp、D-HoSer和HoSer；
    P为羟基或氨基。
  10. 如权利要求9所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，所述的q为以下述任两个值为端点的范围：10、11、12、13、14、15、16、17和18；
    和/或，所述的m为以下述任两个值为端点的范围：6、7、8、9和10；
    和/或，所述的n为0、1或2；
    和/或，所述的k独立地为以下述任两个值为端点的范围：4、5、6、7和8；
    和/或，所述的R 0-2-1的个数为一个或多个，当存在多个R 0-2-1时，它们相同或不同；
    和/或，所述的R 0-2-1独立地处于所述C 1～C 6烷基的末端或非末端；
    和/或，所述的R 0-2中的C 1～C 6的烷基为C 1～C 4的烷基；
    和/或，所述的R 0-2-1中，所述的羟基的个数为一个或多个；
    和/或，所述的R 0-2-1中，所述的羟基独立地处于所述苯基的邻位、间位或对位；
    和/或，所述的R 0-3-1的个数为一个或多个，当存在多个R 0-3-1时，它们相同或不同；
    和/或，所述的R 0-3-1独立地处于所述C 1～C 8烷基的末端或非末端；
    和/或，所述的R 0-3中的C 1～C 8的烷基为C 1～C 4的烷基或正戊基；
    和/或，所述的R 0-3-2的个数为一个或多个，当存在多个R 0-3-2时，它们相同或不同；
    和/或，所述的R 0-3-2独立地处于所述苯基的邻位、间位或对位
    和/或，所述的R 0-3-1中，所述的羟基的个数为一个或多个；
    和/或，所述的R 0-3-1中，所有的羟基独立地处于所述苯基的邻位、间位或对位；
    和/或，所述的R 0-3-1中，所述的C 3～C 6的环烷基为环己基；
    和/或，所述的R 0-3-2中，所述的“卤”的个数为一个或多个，当存在多个卤时，它们相同或不同；
    和/或，所述的R 0-3-2中，所述的“卤”独立地为氟、氯或溴；
    和/或，所述的R 0-3-2中，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，所述的XX1中，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，所述的XX2中，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，所述的R 2中，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基或异丁基；
    和/或，所述的R 2中，所述的卤素为氟或氯；
    和/或，所述的R 2中，所述的
    Figure PCTCN2018093088-appb-100034
    为
    Figure PCTCN2018093088-appb-100035
    和/或，所述的XX3中，所述的
    Figure PCTCN2018093088-appb-100036
    为
    Figure PCTCN2018093088-appb-100037
    和/或，所述的R 3-1中，所述的C 4～C 5的烷基为正丁基、异丁基、仲丁基、叔丁基、正戊基或3-甲基丁基；
    和/或，所述的R 3-2中，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，所述的XX4中，所述的
    Figure PCTCN2018093088-appb-100038
    为
    Figure PCTCN2018093088-appb-100039
    和/或，所述的n4为1、2或3；
    和/或，所述的R 4-1中，所述的卤素为氟或氯；
    和/或，所述的R 4-2中，所述的卤素为氟或氯；
    和/或，所述的R 4-3中，所述的卤素为氟或氯；
    和/或，所述的R 4-4中，所述的卤素为氟或氯；
    和/或，所述的R 7中，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基或异丁基；
    和/或，所述的R 7中，所述的C 1～C 4烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基或异丁氧基；
    和/或，所述的R 7中，所述的卤素为氟或氯；
    和/或，所述的XX7中，所述的
    Figure PCTCN2018093088-appb-100040
    为
    Figure PCTCN2018093088-appb-100041
    和/或，所述的XX10中，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
  11. 如权利要求10所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，所述的AA0中，所述的
    Figure PCTCN2018093088-appb-100042
    为PEG8；
    和/或，当所述的R 0-2中的C 1～C 6的烷基为C 1～C 4的烷基时，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，所述的R 0-2-1中，所述的“羟基取代的苯基”为3,5-二羟基苯基；
    和/或，当所述的R 0-3中的C 1～C 8的烷基为C 1～C 4的烷基时，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，所述的R 0-3-1中，所述的“羟基取代的苯基”为3,4-二羟基苯基或3,5-二羟基苯基；
    和/或，所述的R 0-3-2中，所述的“卤代的C 1～C 4烷基”为三氟甲基；
    和/或，所述的XX1中，所述的“取代的氨基酸”为D-NMeTyr；
    和/或，所述的XX2中，所述的
    Figure PCTCN2018093088-appb-100043
    为Phe、Phe(4-Cl)或Phe(4-Me)；
    和/或，所述的XX3中，所述的
    Figure PCTCN2018093088-appb-100044
    为NMe-Leu、NMe-Phe、NMe-HoLeu、NEt-Leu、NPr-Leu、NiPr-Leu、Nbu-Leu、NMe-Nle或NMe-Ile；
    和/或，所述的XX4中，所述的
    Figure PCTCN2018093088-appb-100045
    为
    Figure PCTCN2018093088-appb-100046
    Y为-(CR 4-1R 4-2)-、-(CH 2) 2-或-S-；
    和/或，所述的XX7中，所述的
    Figure PCTCN2018093088-appb-100047
    为Phe、Phe(3-Cl)、Phe(3-Me)、Phe(3-OMe)、Phe(4-OMe)、Phe(4-Me)或Phe(4-Cl)；
    和/或，所述的XX10中，所述的“取代的氨基酸”为NMe-Ser或NMe-HoSer。
  12. 如权利要求11所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，所述的AA0中，所述的
    Figure PCTCN2018093088-appb-100048
    为PEG8；
    和/或，所述的“R 0-2-1取代的C 1～C 6的烷基”为3,5-二羟基苄基或3-苯基丙基；
    和/或，所述的“R 0-3-1取代的C 1～C 8的烷基”为2-苯基乙基、3-苯基丙基、4-苯基丁基、4-苯基苄基、二苯甲基、3,4-二羟基苄基、3,5-二羟基苄基或环己基甲基；
    和/或，所述的“R 0-3-2取代的苯基”为3,5-二羟基苯基、2,3-二羟基苯基、2,6-二羟基苯基、2,3,4-三羟基苯基、2,3,5-三羟基苯基或4-三氟甲基苯基；
    和/或，所述的XX2中，所述的“取代的氨基酸”为NMe-Phe；
    和/或，所述的XX4中，所述的
    Figure PCTCN2018093088-appb-100049
    为Aze、Thz、Hyp、Pro、Pro(5Ph)、Pro(4Ph)、Pro(diF)或HoPro。
  13. 如权利要求12所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，XX0为氢、
    Figure PCTCN2018093088-appb-100050
    和/或，R 0-1为CH 3-；
    和/或，q为13～15；
    和/或，m为6～10；
    和/或，n为2；
    和/或，所有的AA0独立地为Gly或βAla；
    和/或，R 0-3为苯基取代的C 1～C 8的烷基；
    和/或，XX1为氨基被1个C 1～C 4的烷基取代或未取代的D-Tyr；
    和/或，XX2为氨基被1个C 1～C 4的烷基取代或未取代的Phe：
    和/或，XX3为
    Figure PCTCN2018093088-appb-100051
    其中，*标记的碳原子为手性碳原子，其为R构型或S构型；R 3-1为异丁基、3-甲基丁基或苄基；R 3-2为C 1～C 3的烷基；
    和/或，XX4为
    Figure PCTCN2018093088-appb-100052
    *标记的碳原子为手性碳原子，其为R构型或S构型；Y为-(CR 4-1R 4-2)-或-S-；R 4-1和R 4-2独立地为氢或卤素；
    和/或，XX5为D-Ser或D-HoSer；
    和/或，XX6为Gln；
    和/或，XX7为Phe、1Nal或2Nal；
    和/或，XX8为D-Ala；
    和/或，XX9为Tic、D-Ti1c或D-Oic；
    和/或，XX10为NHoSer、或、氨基被1个C 1～C 4的烷基取代或未取代的下述任一氨基酸：Ser和HoSer；
    和/或，P为羟基或氨基。
  14. 如权利要求9所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，XX0为氢、
    Figure PCTCN2018093088-appb-100053
    R 0-2或
    Figure PCTCN2018093088-appb-100054
    和/或，R 0-1为CH 3-；
    和/或，q为13～15；
    和/或，m为6～10；
    和/或，n为0～2；
    和/或，所有的AA0独立地为
    Figure PCTCN2018093088-appb-100055
    Ahx、Gly或βAla；所有的k独立地为4～8，所有的r独立地为0或1；
    和/或，R 0-2为C 1～C 6的烷基；
    和/或，R 0-3为R 0-3-1取代或未取代的C 1～C 8的烷基、或、羟基取代或未取代的苯基；
    和/或，所有的R 0-3-1独立地为苯基、或、C 3～C 6的环烷基；
    和/或，XX1为D-NMeTyr、D-Tyr、D-Phe或D-NMePhe；
    和/或，XX3为NMe-Leu、NEt-Leu、NPr-Leu、NiPr-Leu、NMe-HoLeu、NMe-Nle或NMe-Ile；
    和/或，XX4为Thz、Pro、Pro(4Ph)、Pro(diF)、HoPro或Hyp；
    和/或，XX7为1Nal、2Nal、Bpa、Phe、Phe(3-Cl)、Phe(4-Cl)、Phe(4-Me)、Phe(3-Me)、Phe(3-OMe)、Phe(4-OMe)或HoPhe；
    和/或，XX9为Tic、D-Tic、DTi1c、D-Oic、TP5C或TP6C；
    和/或，XX10为NMe-Ser、NHoSer、NMe-HoSer、D-HoSer、HoSer或Ser。
  15. 如权利要求9所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，XX0为氢、
    Figure PCTCN2018093088-appb-100056
    和/或，R 0-1为CH 3-；
    和/或，q为13～15；
    和/或，m为6～10；
    和/或，n为0～2；
    和/或，所有的AA0独立地Gly或βAla；
    和/或，R 0-3为苯基取代或未取代的C 1～C 8的烷基、或、羟基取代或未取代的苯基；
    和/或，XX1为D-NMeTyr或D-Tyr；
    和/或，XX3为NMe-Leu、NEtLeu或NMe-HoLeu；
    和/或，XX4为Thz、Pro或Pro(diF)；
    和/或，XX7为1Nal、2Nal或Phe；
    和/或，XX9为Tic、D-Tic或DTi1c；
    和/或，XX10为NMe-Ser、NHoSer或Ser。
  16. 如权利要求1所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，所述的化合物I为下列任一化合物：
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Phe)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-HoLeu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-(NMe-Phe)-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    3-Phenylpropanoyl-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Thz-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Thz-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser
    (NMe-D-Tyr)-Phe-(NMe-Leu)-Thz-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (NMe-D-Tyr)-Phe-(NMe-Leu)-Thz-(D-Ser)-Gln-Phe-(D-Ala)-Tic-(NMe-Ser)
    (NMe-D-Tyr)-Phe-(NMe-Leu)-Thz-(D-Ser)-Gln-2NaI-(D-Ala)-Tic-(NMe-Ser)
    Palm-PEG8-Gly-Gly-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    Palm-PEG8-βAla-βAla-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (NMe-D-Tyr)-Phe-(NMe-Leu)-Thz-(D-Ser)-Gln-1Nal-(D-Ala)-Tic-(NMe-Ser)
    (NMe-D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-(NMe-Ser)
    (D-NMe-Tyr)-Phe-(NMe-Leu)-Thz-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-(D-Ti1c)-Ser
    3-Phenylpropanoyl-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-NH2
    (D-NMe-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-1Nal-(D-Ala)-Tic-(NMe-Ser)
    (D-NMe-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-1Nal-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-(NMe-Ser)
    (D-NMe-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser
    (D-NMe-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-1Nal-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-(HoSer)
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-(NHoSer)
    (D-Tyr)-Phe-(NMe-Leu)-Pro(diF)-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-HoSer)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-(D-Oic)-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-(NMe-HoSer)
    Palm-PEG8-Gly-Gly-(D-NMe-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-(NMe-Ser)
    Palm-PEG8-βAla-βAla-(D-NMe-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-(NMe-Ser)
    Tetradecanoyl-PEG8-βAla-βAla-(D-NMe-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-(NMe-Ser)
    Dodecanoyl-PEG8-βAla-βAla-(NMe-D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-(NMe-Ser)
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-(D-Tic)-(NMe-Ser)
    (D-Tyr)-Phe-(NEt-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NPr-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    3-Phenylpropanoyl-(D-Tyr)-Phe-(NEt-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    3-Phenylpropanoyl-(D-Tyr)-Phe-(NPr-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-(D-Tic)-Ser-NH2
    DiMe-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    Hexanoyl-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (2-Cyclohexylacetyl)-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    4-(Trifluoromethyl)benzoyl-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Hyp-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-1Nal-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-2Nal-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Bpa-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe(4-Me)-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe(4-Cl)-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Thr)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Phe(4-Me)-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Phe(4-Cl)-Ser
    3-phenylpropyl-(D-Tyr)-Phe-(NMe-Leu)-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro(4Ph)-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-NMeLeu-Pro(4Ph)-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-NMe-Tyr)-Phe-NMeLeu-Pro(4Ph)-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser
    Palm-PEG8-βAla-βAla-(D-NMe-Tyr)-Phe-(NMe-Leu)-Pro(4Ph)-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro(4Ph)-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser
    (D-NMeTyr)-Phe-NMeLeu-Pro(4Ph)-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-(NMe-Ser)
    [D-Tyr(3F)]-Phe-(NMe-Leu)-Pro(4Ph)-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-(NMe-Ser)
    [D-Tyr(3F)]-Phe-(NMe-Leu)-Pro(4Ph)-(D-Ser)-Gln-2Nal-(D-Ala)-TicSer
    Palm-PEG-Gly-Gly-(D-Tyr)-Phe-NMeLeu-Pro(4Ph)-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-(NMe-Leu)-Pro(diF)-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-NMeSer
    (D-NMeTyr)-Phe-NMeLeu-Pro(diF)-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-(NMe-Ser)
    [D-Tyr(3F)]-Phe-NMeLeu-Pro(diF)-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-(NMe-Ser)。
  17. 如权利要求1～16中任一项所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药在制备药物中的应用，所述的药物用于治疗和/或预防与ChemR23相关的疾病。
  18. 如权利要求17所述的应用，其特征在于，所述的“与ChemR23相关的疾病”为免疫疾病、炎症性疾病、代谢性疾病、心血管系统疾病、骨病、肿瘤、生殖系统疾病、精神疾病、病毒性感染、哮喘或肝脏疾病。
  19. 如权利要求1～16中任一项所述的肽类化合物I、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药在制备ChemR23激动剂中的应用。
  20. 一种药物组合物，其包含如权利要求1～16中任一项所述的化合物I、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药，以及药用辅料。
  21. 一种如式II所示的肽类化合物、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药；所述的化合物II为下列任一化合物：
    (D-Tyr)-Phe-Leu-(S-Pip)-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Phe)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-NMe-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-(NMe-Phe)-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-(NMe-Ser)
    (D-Tyr)-Phe-Leu-Pro(5-phenyl)-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-Leu-Pro(4-phenyl)-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-Leu-Thz-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-Leu-Aze-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-1Nal-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-2Nal-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Bpa-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-(D-Tic)-Ser
    (D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Ti1c-Ser
    (D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-(D-Ti1c)-Ser
    (D-NMe-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-(D-Ti1c)-Ser
    (D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-TP5C-Ser
    (D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-TP6C-Ser
    (D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser-NH2
    (D-Tyr)-Phe-Nva-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (D-Tyr)-Phe-Nle-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser。
  22. 如权利要求21所述的肽类化合物II、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药在制备药物中的应用，所述的药物用于治疗和/或预防与ChemR23相关的疾病。
  23. 如权利要求22所述的应用，其特征在于，所述的“与ChemR23相关的疾病”为免疫疾病、炎症性疾病、代谢性疾病、心血管系统疾病、骨病、肿瘤、生殖系统疾病、精神疾病、病毒性感染、哮喘或肝脏疾病。
  24. 如权利要求21所述的肽类化合物II、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药在制备ChemR23激动剂中的应用。
  25. 一种药物组合物，其包含如权利要求21所述的化合物II、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药，以及药用辅料。
  26. 一种如式III所示的肽类化合物、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于：
    XX0-XX1-XX2-XX3-XX4-XX5-XX6-XX7-XX8-XX9-XX10-P (III)
    其中，XX0为R 0-2、
    Figure PCTCN2018093088-appb-100057
    R 0-2为未取代或R 0-2-1取代的C 1～C 6的烷基；
    所有的R 0-2-1独立地为未取代或羟基取代的苯基；
    R 0-3为未取代或R 0-3-1取代的C 1～C 8的烷基、或、未取代或R 0-3-2取代的苯基；
    所有的R 0-3-1独立地为未取代或羟基取代的苯基、联苯基、或、C 3～C 6的环烷基；
    所有的R 0-3-2独立地为羟基、或者、卤代的C 1～C 4烷基；
    R 0-4为未取代或R 0-4-1取代的C 1～C 6的烷基；
    所有的R 0-4-1独立地为未取代或羟基取代的苯基、或、C 3～C 6的环烷基；
    R 0-5为未取代或R 0-5-1取代的C 1～C 6的烷基；
    所有的R 0-5-1独立地为未取代或羟基取代的苯基、或、C 3～C 6的环烷基；
    XX1为氨基未取代或氨基被1个C 1～C 4的烷基取代的D-Tyr；
    XX2为氨基未取代或氨基被1个C 1～C 4的烷基取代的
    Figure PCTCN2018093088-appb-100058
    n2为0或1，R 2为C 1～C 4烷基或卤素，*标记的碳原子为手性碳原子，其为R构型或S构型；
    XX3为
    Figure PCTCN2018093088-appb-100059
    R 3-1为C 4～C 5的烷基或苄基；R 3-2为氢或C 1～C 4的烷基，*标记的碳原子为手性碳原子，其为R构型或S构型；
    XX4为
    Figure PCTCN2018093088-appb-100060
    Z为-(CR 4-1R 4-2) n4-或-S-(CR 4-3R 4-4) n4’-；所述的-(CR 4-1R 4-2) n4-和-S-(CR 4-3R 4-4) n4’-的右端与手性碳原子连接；n4为1～3，n4’为1或2；所有的R 4-1、R 4-2、R 4-3和R 4-4独立地为氢、羟基、卤素或苯基；*标记的碳原子为手性碳原子，其为R构型或S构型；
    XX5为D-Ser；
    XX6为Gln；
    XX7为
    Figure PCTCN2018093088-appb-100061
    n7为0或1，R 7为C 1～C 4烷基、C 1～C 4烷氧基或卤素，*标记的碳原子为手性碳原子，其为R构型或S构型；
    XX8为D-Ala；
    XX9为Tic；
    XX10为氨基未取代或氨基被1个C 1～C 4的烷基取代的Ser；
    P为羟基或氨基。
  27. 如权利要求26所述的肽类化合物III、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，所述的R 0-2-1的个数为一个或多个，当存在多个R 0-2-1时，它们相同或不同；
    和/或，所述的R 0-2-1独立地处于所述C 1～C 6烷基的末端或非末端；
    和/或，所述的R 0-2-1中，所述的羟基的个数为一个或多个；
    和/或，所述的R 0-2-1中，所述的羟基独立地处于所述苯基的邻位、间位或对位；
    和/或，当所述的R 0-2为未取代或R 0-2-1取代的C 1～C 6的烷基时，所述的C 1～C 6的烷基为C 1～C 4的烷基；
    和/或，所述的R 0-3-1的个数为一个或多个，当存在多个R 0-3-1时，它们相同或不同；
    和/或，所述的R 0-3-1独立地处于所述C 1～C 8烷基的末端或非末端；
    和/或，所述的R 0-3-1中，所述的羟基的个数为一个或多个；
    和/或，所述的R 0-3-1中，所有的羟基独立地处于所述苯基的邻位、间位或对位；
    和/或，所述的R 0-3-1中，所述的C 3～C 6的环烷基为环己基；
    和/或，所述的R 0-3-2的个数为一个或多个，当存在多个R 0-3-2时，它们相同或不同；
    和/或，所述的R 0-3-2独立地处于所述苯基的邻位、间位或对位；
    和/或，所述的R 0-3-2中，所述的“卤”的个数为一个或多个，当存在多个卤时，它们相同或不同；
    和/或，所述的R 0-3-2中，所述的“卤”独立地为氟、氯或溴；
    和/或，所述的R 0-3-2中，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，当所述的R 0-3为未取代或R 0-3-1取代的C 1～C 8的烷基时，所述的C 1～C 8的烷基为C 1～C 4的烷基或正戊基；
    和/或，所述的R 0-4-1的个数为一个或多个，当存在多个R 0-4-1时，它们相同或不同；
    和/或，所述的R 0-4-1独立地处于所述C 1～C 8烷基的末端或非末端；
    和/或，所述的R 0-4-1中，所述的羟基的个数为一个或多个；
    和/或，所述的R 0-4-1中，所有的羟基独立地处于所述苯基的邻位、间位或对位；
    和/或，所述的R 0-4-1中，所述的C 3～C 6的环烷基为环己基；
    和/或，当所述的R 0-4为未取代或R 0-4-1取代的C 1～C 8的烷基时，所述的C 1～C 8的烷基为C 1～C 4的烷基或正戊基；
    和/或，所述的R 0-5-1的个数为一个或多个，当存在多个R 0-5-1时，它们相同或不同；
    和/或，所述的R 0-5-1独立地处于所述C 1～C 8烷基的末端或非末端；
    和/或，所述的R 0-5-1中，所述的羟基的个数为一个或多个；
    和/或，所述的R 0-5-1中，所有的羟基独立地处于所述苯基的邻位、间位或对位；
    和/或，所述的R 0-5-1中，所述的C 3～C 6的环烷基为环己基；
    和/或，当所述的R 0-5为未取代或R 0-5-1取代的C 1～C 8的烷基时，所述的C 1～C 8的烷基为C 1～C 4的烷基或正戊基；
    和/或，所述的XX1中，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正 丁基、异丁基、仲丁基或叔丁基；
    和/或，所述的XX2中，所述的
    Figure PCTCN2018093088-appb-100062
    为
    Figure PCTCN2018093088-appb-100063
    和/或，当所述的XX2为“氨基未取代或氨基被1个C 1～C 4的烷基取代的下述任一氨基酸”时，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，所述的R 2中，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基或异丁基；
    和/或，所述的R 2中，所述的卤素为氟或氯；
    和/或，所述的XX3中，所述的
    Figure PCTCN2018093088-appb-100064
    为
    Figure PCTCN2018093088-appb-100065
    和/或，所述的R 3-1中，所述的C 4～C 5的烷基为正丁基、异丁基、仲丁基、叔丁基、正戊基或3-甲基丁基；
    和/或，所述的R 3-2中，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，所述的XX4中，所述的
    Figure PCTCN2018093088-appb-100066
    为
    Figure PCTCN2018093088-appb-100067
    和/或，所述的n4为1、2或3；
    和/或，所述的R 4-1中，所述的卤素为氟或氯；
    和/或，所述的R 4-2中，所述的卤素为氟或氯；
    和/或，所述的R 4-3中，所述的卤素为氟或氯；
    和/或，所述的R 4-4中，所述的卤素为氟或氯；
    和/或，所述的XX7中，所述的
    Figure PCTCN2018093088-appb-100068
    为
    Figure PCTCN2018093088-appb-100069
    和/或，所述的R 7中，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基或异丁基；
    和/或，所述的R 7中，所述的C 1～C 4烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基或异丁氧基；
    和/或，所述的R 7中，所述的卤素为氟或氯；
    和/或，所述的XX10中，所述的C 1～C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
  28. 如权利要求27所述的肽类化合物III、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，当所述的R 0-2为R 0-2-1取代的C 1～C 6的烷基时，所述的“R 0-2-1取代的C 1～C 6的烷基”为3,5-二羟基苄基或3-苯基丙基；
    和/或，当所述的R 0-3为R 0-3-1取代的C 1～C 8的烷基时，所述的“R 0-3-1取代的C 1～C 8的烷基”为2-苯基乙基、3-苯基丙基、4-苯基丁基、4-苯基苄基、二苯甲基、3,4-二羟基苄基、3,5-二羟基苄基、联苯-4-基甲基或环己基甲基；
    和/或，当所述的R 0-3为R 0-3-2取代的苯基时，所述的“R 0-3-2取代的苯基”为3,5-二羟基苯基、2,3-二羟基苯基、2,6-二羟基苯基、2,3,4-三羟基苯基、2,3,5-三羟基苯基或4-三氟甲基苯基；
    和/或，当所述的R 0-4为R 0-4-1取代的C 1～C 8的烷基时，所述的“R 0-4-1取代的C 1～C 8的烷基”为2-苯基乙基、3-苯基丙基、4-苯基丁基、4-苯基苄基、二苯甲基、3,4-二羟基苄基、3,5-二羟基苄基或环己基甲基；
    和/或，当所述的R 0-5为R 0-5-1取代的C 1～C 8的烷基时，所述的“R 0-5-1取代的C 1～C 8的烷基”为2-苯基乙基、3-苯基丙基、4-苯基丁基、4-苯基苄基、二苯甲基、3,4-二羟基苄基、3,5-二羟基苄基或环己基甲基；
    和/或，所述的XX1中，所述的C 1～C 4的烷基为甲基；
    和/或，所述的XX2为Phe、Phe(4-Cl)或Phe(4-Me)；
    和/或，所述的XX3为Leu、NMe-Leu、NMe-Phe、NMe-HoLeu、NEt-Leu、NPr-Leu、NiPr-Leu、Nbu-Leu、NMe-Nle或NMe-Ile；
    和/或，所述的XX4中，所述的-(CR 4-1R 4-2) n4-为-CH 2-、-(CH 2) 2-、-CH(OH)-CH 2-、-CF 2-CH 2-、-CHPh-CH 2-、-CH 2-CHPh-或-(CH 2) 3-；
    和/或，所述的XX4中，所述的-S-(CR 4-3R 4-4) n4’-为-S-CH 2-；
    和/或，所述的XX7为Phe、Phe(3-Cl)、Phe(3-Me)、Phe(3-OMe)、Phe(4-OMe)、Phe(4-Me)或Phe(4-Cl)；
    和/或，所述的XX10中，所述的C 1～C 4的烷基为甲基。
  29. 如权利要求28所述的肽类化合物III、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药，其特征在于，所述的XX4为Aze、Thz、Hyp、Pro、Pro(5Ph)、Pro(4Ph)、Pro(diF)或HoPro。
  30. 如权利要求26所述的肽类化合物III、其药学上可接受的盐、其互变异构体、 其溶剂合物、其晶型或其前药，其特征在于，所述的化合物III为下列任一化合物：
    (3-Phenylpropanoyl)-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (Phenethylcarbamoyl)-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (Phenethylcarbamothioyl)-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    3-Phenylpropyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (4-Phenylbutanoyl)-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (5-Phenylpentanoyl)-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (4-Biphenylacetyl)-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (Diphenylacetyl)-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    (3,5-Dihydroxybenzoyl)-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    2,3-Dihydroxybenzoyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    2,6-Dihydroxybenzoyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    2,3,4-Trihydroxybenzoyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    3,5-Dihydroxyphenylacetyl-(D-Tyr)-Phe-Leu-Pro-(D-Ser)-Gln-Phe-(D-Ala)-Tic-Ser
    3,4-Dihydroxyphenylacetyl-(D-Tyr)-Phe-Leu-Pro-(D-ser)-Gln-Phe-(D-Ala)-Tic-Ser。
  31. 如权利要求26～30中任一项所述的肽类化合物III、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药在制备药物中的应用，所述的药物用于治疗和/或预防与ChemR23相关的疾病。
  32. 如权利要求31所述的应用，其特征在于，所述的“与ChemR23相关的疾病”为免疫疾病、炎症性疾病、代谢性疾病、心血管系统疾病、骨病、肿瘤、生殖系统疾病、精神疾病、病毒性感染、哮喘或肝脏疾病。
  33. 如权利要求26～30中任一项所述的肽类化合物III、其药学上可接受的盐、其互变异构体、其溶剂合物、其晶型或其前药在制备ChemR23激动剂中的应用。
  34. 一种药物组合物，其包含如权利要求26～30中任一项所述的化合物III、其药学上可接受的盐、其互变异构体、其晶型、其溶剂合物或其前药，以及药用辅料。
PCT/CN2018/093088 2017-06-27 2018-06-27 一种肽类化合物、其应用及含其的组合物 Ceased WO2019001459A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US16/624,063 US12129312B2 (en) 2017-06-27 2018-06-27 Peptide compound, application thereof and composition containing same
JP2019572139A JP7196113B2 (ja) 2017-06-27 2018-06-27 ペプチド系化合物、その応用及びそれを含む組成物
EP18823088.2A EP3647319B1 (en) 2017-06-27 2018-06-27 Peptide compound, application thereof and composition containing same
US18/593,433 US20240209023A1 (en) 2017-06-27 2024-03-01 Peptide compound, application thereof and composition containing same

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201710502668 2017-06-27
CN201710502668.X 2017-06-27
CN201810662539 2018-06-25
CN201810662539.1 2018-06-25

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US16/624,063 A-371-Of-International US12129312B2 (en) 2017-06-27 2018-06-27 Peptide compound, application thereof and composition containing same
US18/593,433 Continuation US20240209023A1 (en) 2017-06-27 2024-03-01 Peptide compound, application thereof and composition containing same

Publications (1)

Publication Number Publication Date
WO2019001459A1 true WO2019001459A1 (zh) 2019-01-03

Family

ID=64740401

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/093088 Ceased WO2019001459A1 (zh) 2017-06-27 2018-06-27 一种肽类化合物、其应用及含其的组合物

Country Status (6)

Country Link
US (2) US12129312B2 (zh)
EP (1) EP3647319B1 (zh)
JP (1) JP7196113B2 (zh)
CN (1) CN109134610B (zh)
TW (1) TWI796339B (zh)
WO (1) WO2019001459A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021021915A1 (en) * 2019-08-01 2021-02-04 Okyo Pharma Limited Compositions comprising chemerin analogs and methods of use

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW202535901A (zh) * 2023-12-27 2025-09-16 日商中外製藥股份有限公司 使用獨立型縮合劑的胜肽化合物的製造方法
CN118240026A (zh) * 2024-04-02 2024-06-25 中国药科大学 一种抗菌肽Thanatin衍生肽及其医药用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010229093A (ja) 2009-03-27 2010-10-14 Banyu Pharmaceut Co Ltd 新規ＣｈｅｍｅｒｉｎＲアゴニスト
WO2013117581A1 (en) * 2012-02-10 2013-08-15 Charite - Universitätsmedizin Berlin Metabolically stable variants of chemerin 9

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07324097A (ja) * 1994-05-30 1995-12-12 Daicel Chem Ind Ltd インターロイキン６拮抗剤、及びペプチド類または医薬として許容されるその塩類
US7419658B2 (en) 2001-07-09 2008-09-02 Euroscreen S.A. Isolated ligand of ChemerinR
CA2567635A1 (en) * 2004-05-21 2005-12-01 Eli Lilly And Company Selective vpac2 receptor peptide agonists
AU2006201635A1 (en) * 2005-10-20 2007-05-10 Ludwig Institute For Cancer Research Novel inhibitors and methods for their preparation
CN104434888A (zh) * 2013-09-17 2015-03-25 深圳先进技术研究院 Cmklr1小分子拮抗剂在防治非酒精性脂肪肝及肝炎中的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010229093A (ja) 2009-03-27 2010-10-14 Banyu Pharmaceut Co Ltd 新規ＣｈｅｍｅｒｉｎＲアゴニスト
WO2013117581A1 (en) * 2012-02-10 2013-08-15 Charite - Universitätsmedizin Berlin Metabolically stable variants of chemerin 9

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
"rodrugs: Challenges and Rewards", 2007, SPRINGER
J. RAUTIO ET AL., NATURE REVIEWS DRUG DISCOVERY, vol. 7, 2008, pages 255 - 270
LU ET AL., J.ORG. CHEM., vol. 46, 1981, pages 3433
ROH, S.G. ET AL.: "Physiological Roles of Adipokines, Hepatokines, and Myokines in Ruminants", ASIAN-AUST. J. ANIM. SCI., vol. 29, no. 1, 31 January 2016 (2016-01-31), XP055562593 *
See also references of EP3647319A4
SHIMAMURA, K. ET AL.: "Identification of a Stable Chemerin Analog with Potent Activity Toward ChemR23", PEPTIDES, vol. 30, 20 June 2009 (2009-06-20), XP055061081 *
SUZUKI, Y. ET AL.: "The Regulation of Chemerin and CMKLR1 Genes Expression by TNF-#, Adiponectin, and Chemerin Analog in Bovine Differentiated Adipocytes", ASIAN-AUST. J. ANIM. SCI., vol. 25, no. 9, 30 September 2012 (2012-09-30), XP055562595 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021021915A1 (en) * 2019-08-01 2021-02-04 Okyo Pharma Limited Compositions comprising chemerin analogs and methods of use
JP2022543598A (ja) * 2019-08-01 2022-10-13 オーケーワイオー ファーマ リミティド ケメリン類似体を含む組成物とその使用方法
EP4218927A3 (en) * 2019-08-01 2023-08-09 Okyo Pharma Limited Compositions comprising chemerin analogs and methods of use
JP7651553B2 (ja) 2019-08-01 2025-03-26 オーケーワイオー ファーマ リミティド ケメリン類似体を含む組成物とその使用方法

Also Published As

Publication number Publication date
EP3647319A1 (en) 2020-05-06
CN109134610B (zh) 2022-07-08
US12129312B2 (en) 2024-10-29
EP3647319A4 (en) 2020-12-23
US20210403506A1 (en) 2021-12-30
TW201904986A (zh) 2019-02-01
CN109134610A (zh) 2019-01-04
EP3647319C0 (en) 2025-04-09
JP2020525484A (ja) 2020-08-27
US20240209023A1 (en) 2024-06-27
JP7196113B2 (ja) 2022-12-26
EP3647319B1 (en) 2025-04-09
TWI796339B (zh) 2023-03-21

Similar Documents

Publication Publication Date Title
TWI882061B (zh) 介白素-23受體之肽抑制劑及其治療發炎性疾病之用途
JP7670605B2 (ja) インターロイキン－２３受容体のペプチド阻害剤および炎症性疾患を治療するためのその使用
TWI404726B (zh) 腫瘤轉移抑制素衍生物及其用途
CN115279782A (zh) 白介素-23受体的肽抑制剂及其用于治疗炎性疾病的用途
CN115925790A (zh) 用于合成α4β7肽拮抗剂的方法
US20240209023A1 (en) Peptide compound, application thereof and composition containing same
TWI386417B (zh) 轉移抑素衍生物及其用途
WO2017114238A1 (zh) 一种合成Etelcalcetide的方法
CN103314010A (zh) h[Gly2]GLP-2的固相合成
WO2009131191A1 (ja) メタスチン誘導体およびその用途
SG171937A1 (en) Process for preparing therapeutic peptide
US20220033440A1 (en) An improved process for the preparation of plecanatide
EP1179537B1 (en) Solid phase peptide synthesis method
WO2021249505A1 (zh) 一种德谷胰岛素衍生物及其制备方法和应用
JP2023552500A (ja) 長時間作用型グルカゴン誘導体
CN105968186A (zh) 具有长效化作用的胰高血糖素(Glu)类似物及其应用
WO2021249564A1 (zh) 一种索玛鲁肽衍生物及其制备方法和应用
JP2025020218A (ja) Ｍｍｐ２阻害作用を有するポリペプチド
TW202334178A (zh) 一種Kiss1肽類化合物、其應用及含其的組合物
TW202042836A (zh) 血球凝集素結合肽
WO1990004605A1 (en) Calcitonin gene related peptide analogues
JP2022173143A (ja) Ｍｍｐ２阻害作用を有するポリペプチドを有効成分として含有する医薬
CN118460518A (zh) 一种多肽及其用途
CN115232200A (zh) 长效化Exendin-4类似物及其应用
HK40083331A (zh) 介白素-23受体的肽抑制剂及其治疗炎性疾病的用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18823088

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019572139

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2018823088

Country of ref document: EP

Effective date: 20200127

WWG Wipo information: grant in national office

Ref document number: 2018823088

Country of ref document: EP