WO2023216533A1 - 一种吲哚生物碱及其制备方法与应用 - Google Patents

一种吲哚生物碱及其制备方法与应用 Download PDF

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WO2023216533A1
WO2023216533A1 PCT/CN2022/130902 CN2022130902W WO2023216533A1 WO 2023216533 A1 WO2023216533 A1 WO 2023216533A1 CN 2022130902 W CN2022130902 W CN 2022130902W WO 2023216533 A1 WO2023216533 A1 WO 2023216533A1
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alkyl
ddd
compound
substituted
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French (fr)
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沈旭
蒋晟
张阔军
王佳颖
唐鹤
黄玉洁
赵桐
钱民怡
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南京中医药大学
中国药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicine and chemical synthesis, and specifically relates to an indole alkaloid and its preparation method, pharmaceutical composition and its use in treating peripheral neuron axon damage, peripheral-related neuropathy, diabetic foot and pulmonary fibrosis. applications in.
  • Diabetes is a serious disease worldwide. It is estimated that by 2045, the number of people with diabetes will reach 629 million. Diabetes has now become the third non-communicable disease that threatens human health and life after cardiovascular diseases and tumors. In my country, diabetes has changed from a rare disease to an epidemic, with the prevalence soaring from an average of 0.67% to 11.6% in the past 30 years. If diabetic patients do not take effective control and treatment methods, they will be easily troubled by multiple diseases complicated by diabetes, including diabetic neuropathy, nephropathy, diabetic foot, etc., which can lead to blindness, renal failure, and even physical disability and death.
  • Diabetic peripheral neuropathy is a chronic diabetic neuropathy caused by long-term hyperglycemia. The incidence rate is as high as 50% to 80%. It is the most common chronic complication of diabetes. Diabetic peripheral neuropathy can affect motor nerves, sensory nerves, and autonomic nerves, causing motor and sensory impairments. Clinically, patients with diabetic peripheral neuropathy have increased vibration and heat perception thresholds that progress to sensory loss along with degeneration of all fibers in the peripheral nerves. At present, the diagnostic methods for diabetic peripheral neuropathy are mainly through sensory testing, electrophysiological testing, nerve fiber morphological examination, imaging examination, etc. However, diabetic peripheral neuropathy has diverse clinical manifestations, different classification methods at home and abroad, various screening and examination methods, and different diagnostic standards.
  • Diabetic foot is a disease caused by long-term hyperglycemia leading to diabetic vasculopathy and/or neuropathy and infection, which in turn leads to tissue necrosis of the feet or lower limbs of diabetic patients. Diabetic foot is one of the most serious complications of diabetes and one of the main causes of disability and death among diabetic patients. It is also a major public health problem that causes a heavy burden on society. With the increase in the incidence of diabetes, the number of patients with diabetic foot is also increasing year by year. Among diabetic patients over 50 years old in my country, the incidence of diabetic foot is as high as 8.1%.
  • diabetic foot is very poor, even higher than the mortality and disability rate of most cancers (except lung cancer, pancreatic cancer, etc.).
  • treatment of diabetic foot is expensive and requires long-term treatment.
  • medical care is mainly used to heal the patient's foot ulcer and avoid the risk of amputation.
  • these treatments cannot completely cure diabetic foot, and it is easy to relapse. Therefore, it is of great practical significance to study the pathogenesis of diabetic foot and develop new and effective therapeutic drugs for diabetic foot.
  • Pulmonary fibrosis is a chronic, progressive, fatal lung disease and the end-stage of many diseases. Its pathogenesis is still unclear. Pulmonary fibrosis seriously affects human respiratory function, manifested by dry cough and progressive dyspnea (feeling that there is not enough air). As the condition and lung damage worsen, the patient's respiratory function continues to deteriorate. The incidence and mortality of idiopathic pulmonary fibrosis are increasing year by year. The average survival time after diagnosis is only 2.8 years. The mortality rate is higher than that of most tumors. It is called a "tumor-like disease". Patients with COVID-19 may also develop pulmonary fibrosis after recovery.
  • Vincamine is a monoterpene indole alkaloid found in Madagascar periwinkle. It can increase cerebral blood flow, oxygen consumption and glucose utilization, and improve dementia and memory impairment.
  • Vinpocetine is a vincamine derivative that selectively increases cerebral blood flow; it can increase and improve the supply of cerebral oxygen, promote metabolism, enhance the deformability of red blood cells, reduce blood viscosity, inhibit platelet aggregation, and improve brain tissue metabolism. .
  • vincamine and vinpocetine face problems such as poor water solubility, unstable metabolism, and short action time. It is known from previous work that vincamine has the potential to treat diabetic complications and pulmonary fibrosis. Therefore, the search for new vincamine/vinpocetine derivatives is of great significance for the treatment of diabetic complications and pulmonary fibrosis.
  • Polyethylene glycol is a type of water-soluble polyether with lower molecular weight obtained by the gradual addition polymerization of ethylene oxide and water or ethylene glycol.
  • Low molecular weight oligomeric polyethylene glycol is a colorless, odorless and hygroscopic viscous liquid. It has both ether chains and hydroxyl groups in the molecule, so it has unique solubility properties and good biocompatibility. It is used in medicine, Fields such as materials and engineering have very important application prospects.
  • the technical problem to be solved by the present invention is to use the non-toxic and easy-to-bind characteristics of PEG to connect it with vinpocetine to overcome the water-insoluble characteristics of vinpocetine.
  • the invention provides an indole alkaloid, its preparation method, pharmaceutical composition and application.
  • the indole alkaloid of the present invention has a stable structure and good water solubility, and has good therapeutic effect on diabetic peripheral neuropathy, diabetic foot and pulmonary fibrosis.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides a compound represented by Formula I, its pharmaceutically acceptable salt, its metabolic precursor, its metabolite, its isomer or its prodrug, and its structure is as follows:
  • X is O or -NR 1 ;
  • R 1 is hydrogen, unsubstituted or R 1-1 substituted C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, "heteroatom selected from N, O, S” or “5-10 membered heteroaryl” with 1-3 heteroatoms, or "heteroatoms selected from one or more types of N, O, S, 1-3 heteroatoms""4-10 membered heterocycloalkyl, C 3-10 cycloalkyl-(C 1-4 alkyl)- or C 6-12 aryl-(C 1-4 alkyl)-;
  • R 1-1 is halogen or hydroxyl
  • Y is -(CH 2 ) m -;
  • n is an integer from 1 to 6;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from hydrogen, unsubstituted or R 3- 1 substituted C 1-6 alkyl, C 6-10 aryl, unsubstituted or R 3-2 substituted C 6-12 aryl-(C 1-4 alkyl)-, heteroaryl, or, hetero Aryl-(C 1-4 alkyl)-, the heteroaryl group is "one or more heteroatoms selected from N, O, S, and the number of heteroatoms is 1-3" 5- 10-membered heteroaryl;
  • R 3-1-1 is hydrogen or C 1-4 alkyl
  • R 3-2 is halogen or hydroxyl
  • R is hydrogen, C 1-6 alkoxy or,
  • R 2 is C 1-6 alkyl or hydrogen
  • n is an integer from 0 to 500;
  • X is O or -NR 1 ;
  • R 1 is hydrogen, unsubstituted or R 1-1 substituted C 1 - 6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, "heteroatom selected from N, O, S” or “5-10 membered heteroaryl” with 1-3 heteroatoms, or "heteroatoms selected from one or more types of N, O, S, 1-3 heteroatoms""4-10 membered heterocycloalkyl, C 3-10 cycloalkyl-(C 1-4 alkyl)- or C 6-12 aryl-(C 1-4 alkyl)-;
  • R 1-1 is halogen or hydroxyl
  • Y is -(CH 2 ) m -;
  • n is an integer from 1 to 6;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from hydrogen, unsubstituted or R 3- 1 substituted C 1-6 alkyl, C 6-10 aryl, unsubstituted or R 3-2 substituted C 6-12 aryl-(C 1-4 alkyl)-, heteroaryl, or, hetero Aryl-(C 1-4 alkyl)-, the heteroaryl group is "one or more heteroatoms selected from N, O, S, and the number of heteroatoms is 1-3" 5- 10-membered heteroaryl;
  • R 3-1-1 is hydrogen or C 1-4 alkyl
  • R 3-2 is halogen or hydroxyl
  • R is hydrogen, hydroxyl, C 1-6 alkoxy or,
  • R 2 is C 1-6 alkyl or hydrogen
  • n is an integer from 0 to 500;
  • R 1 when R 1 is an unsubstituted or R 1-1 substituted C 1-6 alkyl group, the number of R 1-1 is one or more. When there are multiple R 1- 1 , the R 1-1 may be the same or different.
  • the C 1-6 alkyl is C 1-4 alkyl.
  • R 1 when R 1 is a C 6-10 aryl group, the C 6-10 aryl group is phenyl.
  • R 1 when R 1 is C 3-10 cycloalkyl, the C 3-10 cycloalkyl is C 3-6 cycloalkyl.
  • R 1 is C 6-12 aryl-(C 1-4 alkyl)-
  • the C 6-12 aryl-(C 1-4 alkyl)- is benzyl .
  • R 1 is C 3-10 cycloalkyl-(C 1-4 alkyl)-
  • the C 3-10 cycloalkyl-(C 1-4 alkyl)- is C 3-6 cycloalkyl-(C 1-2 alkyl).
  • R 1-1 when R 1-1 is halogen, the halogen is fluorine, chlorine, bromine, or iodine.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from When a C 1-6 alkyl group is substituted or R 3-1 is substituted, the number of R 3-1 is one or more. When there are multiple R 3-1 , the R 3-1 can be Same or different.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from
  • the C 1-6 alkyl group is substituted or R 3-1 substituted
  • the C 1-6 alkyl group is a C 1-4 alkyl group.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from When C 6-12 aryl-(C 1-4 alkyl)- is substituted or substituted by R 3-2 , the number of R 3-2 is one or more. When there are multiple R 3-2 When , the R 3-2 can be the same or different.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from When C 6-12 aryl-(C 1-4 alkyl)- is substituted or R 3-1 is substituted, the C 6-12 aryl-(C 1-4 alkyl)- is C 6-12 Aryl-(C 1-2 alkyl)-.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from “
  • the heteroatom is selected from one or more of N, O, and S.
  • the number of heteroatoms is 1-3 "5-10-membered heteroaryl-(C 1-4 alkyl)-"
  • the 5 ⁇ 10-membered heteroaryl-(C 1-4 alkyl) is 5-9-membered heteroaryl-(CH 2 )-.
  • R 3-1-1 is a C 1-4 alkyl group
  • the C 1-4 alkyl group is methyl, ethyl, n-propyl or isopropyl.
  • m is an integer from 1 to 4.
  • n is an integer from 0 to 400.
  • It is a polyethylene glycol having a linear structure containing -(OCH 2 CH 2 ) n -.
  • R 2 when R 2 is C 1-6 alkyl, the C 1-6 alkyl is C 1-4 alkyl.
  • the C 1-6 alkoxy is C 1-4 alkoxy.
  • R 1 when R 1 is an unsubstituted or R 1-1 substituted C 1-6 alkyl group, the number of R 1-1 is 1, 2 or 3.
  • R 1 when R 1 is an unsubstituted or R 1-1 substituted C 1-6 alkyl group, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl.
  • R 1 when R 1 is a C 3-10 cycloalkyl group, the C 3-10 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 1 is C 3-10 cycloalkyl-(C 1-4 alkyl)-
  • the C 3-10 cycloalkyl-(C 1-4 alkyl)- is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from When a C 1-6 alkyl group is substituted or substituted by R 3-1 , the number of R 3-1 is 1, 2 or 3.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from When substituted or R 3-1 substituted C 1-6 alkyl, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl base or tert-butyl.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from When C 6-12 aryl-(C 1-4 alkyl)- is substituted or substituted by R 3-2 , the number of R 3-2 is 1, 2 or 3.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from When C 6-12 aryl-(C 1-4 alkyl)- is substituted or R 3-2 substituted, the C 6-12 aryl-(C 1-4 alkyl)- is benzyl.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from “
  • the heteroatom is selected from one or more of N, O, and S.
  • the number of heteroatoms is 1-3 "5-10-membered heteroaryl-(C 1-4 alkyl)-"
  • the 5 ⁇ 10-membered heteroaryl-(C 1-4 alkyl) is indolemethyl or imidazolemethyl.
  • m is an integer from 1 to 2.
  • n is an integer from 0 to 100.
  • R 2 when R 2 is a C 1-6 alkyl group, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl or tert-butyl.
  • R is C 1-6 alkoxy
  • the C 1-6 alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy base, sec-butoxy, isobutoxy or tert-butoxy.
  • R 1 is a C 1-6 alkyl group substituted by R 1-1
  • the C 1-6 alkyl group substituted by R 1-1 is trifluoromethyl, or
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from R
  • R 3-1 substituted C 1-6 alkyl group is used, the R 3-1 substituted C 1-6 alkyl group is
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from R
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from R
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from R When 3-2 substituted C 6-12 aryl-(C 1-4 alkyl)-, the unsubstituted or R 3-2 substituted C 6-12 aryl-(C 1-4 alkyl)- -for
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from “
  • the heteroatom is selected from one or more of N, O, and S.
  • the number of heteroatoms is 1-3 "5-10-membered heteroaryl-(C 1-4 alkyl)-"
  • the 5 ⁇ 10-membered heteroaryl-(C 1-4 alkyl) is
  • R 1 is hydrogen, unsubstituted or R 1-1 substituted C 1-6 alkyl or C 3-10 cycloalkyl.
  • R 1-1 is hydroxyl
  • m is an integer from 1 to 2.
  • Z is a single bond
  • R 3 is hydrogen, unsubstituted or R 3-1 substituted C 1-6 alkyl, unsubstituted or R 3-2 substituted C 6-12 aryl-(C 1-4 alkyl )-, heteroaryl-(C 1-4 alkyl)-, the heteroaryl group is "heteroatom selected from one or more of N, O, S, the number of heteroatoms is 1-3 "5-10 membered heteroaryl group.
  • R 3-1-1 is hydrogen
  • R 3-2 is hydroxyl
  • n is an integer from 0 to 400.
  • It is a polyethylene glycol having a linear structure containing -(OCH 2 CH 2 ) n -.
  • X is O or -NR 1 ;
  • R 1 is hydrogen, unsubstituted or R 1-1 substituted C 1-6 alkyl or C 3-10 cycloalkyl;
  • R 1-1 is hydroxyl
  • Y is -(CH 2 ) m -;
  • n is an integer from 1 to 2;
  • Z is a single key
  • R 3 is hydrogen, unsubstituted or R 3-1 substituted C 1-6 alkyl, unsubstituted or R 3-2 substituted C 6-12 aryl-(C 1-4 alkyl)- or heteroaryl -(C 1-4 alkyl)-, the heteroaryl group is "a heteroatom selected from one or more types of N, O, S, and the number of heteroatoms is 1-3" 5-10 yuan heteroaryl;
  • R 3-1-1 is hydrogen
  • R 3-2 is hydroxyl
  • R is hydrogen, C 1-6 alkoxy or,
  • R 2 is C 1-6 alkyl or hydrogen
  • n is an integer from 0 to 400;
  • X is O or -NR 1 ;
  • R 1 is hydrogen, unsubstituted or R 1-1 substituted C 1-6 alkyl or C 3-10 cycloalkyl;
  • R 1-1 is hydroxyl
  • Y is -(CH 2 ) m -;
  • n is an integer from 1 to 2;
  • Z is a single key
  • R 3 is hydrogen, unsubstituted or R 3-1 substituted C 1-6 alkyl, unsubstituted or R 3-2 substituted C 6-12 aryl-(C 1-4 alkyl)- or heteroaryl -(C 1-4 alkyl)-, the heteroaryl group is "a heteroatom selected from one or more types of N, O, S, and the number of heteroatoms is 1-3" 5-10 yuan heteroaryl;
  • R 3-1-1 is hydrogen
  • R 3-2 is hydroxyl
  • R is hydrogen, hydroxyl, C 1-6 alkoxy or,
  • R 2 is C 1-6 alkyl or hydrogen
  • n is an integer from 0 to 400;
  • X is -NR 1 ;
  • R 1 is hydrogen
  • Y is -(CH 2 ) m -;
  • n is an integer from 1 to 2;
  • Z is a single key
  • R 3 is hydrogen, or, unsubstituted or R 3-1 substituted C 1-6 alkyl
  • R 3-1-1 is hydrogen
  • R is hydrogen, C 1-6 alkoxy or
  • R 2 is C 1-6 alkyl or hydrogen
  • n is an integer from 0 to 100;
  • X is -NR 1 ;
  • R 1 is hydrogen
  • Y is -(CH 2 ) m -;
  • n is an integer from 1 to 2;
  • Z is a single key
  • R 3 is hydrogen, or, unsubstituted or R 3-1 substituted C 1-6 alkyl
  • R 3-1-1 is hydrogen
  • R is hydrogen, hydroxyl, C 1-6 alkoxy or
  • R 2 is C 1-6 alkyl or hydrogen
  • n is an integer from 0 to 100;
  • the compound represented by Formula I is any of the following,
  • the present invention also provides a method for preparing a compound represented by formula I.
  • the synthesis includes the following steps: in a solvent, under the action of a base and a condensing agent, the compound represented by formula II and the compound represented by formula III are combined.
  • the condensation reaction shown below is enough;
  • L is -NHR 1 , hydroxyl group R 1 , X, Y, Z and R are as defined above.
  • the present invention also provides a method for preparing a compound represented by formula I.
  • the synthesis includes the following steps: in a solvent, under the action of a base and a condensing agent, the compound represented by formula II and the compound represented by formula III are combined.
  • the condensation reaction shown below is enough;
  • L is -NHR 1 , hydroxyl group R 1 , X, Y, Z and R are as defined above.
  • the solvent is an amide solvent or a halogenated alkane solvent.
  • the base is an organic base or an inorganic base.
  • the condensing agent is carbodiimides, organophosphorus salts or onium salts.
  • the solvent when the solvent is an amide, the amide is N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone.
  • the haloalkane when the solvent is a haloalkane, the haloalkane is methylene chloride.
  • the organic base is triethylamine, DIPEA, or DMAP.
  • the inorganic base is potassium carbonate or cesium carbonate.
  • the condensing agent when the condensing agent is a carbodiimide, the carbodiimide is DCC, DIC or EDCI.
  • the condensing agent when the condensing agent is an organophosphorus salt, the organophosphorus salt is BOP or PyBOP.
  • the condensing agent when the condensing agent is an onium salt, the onium salt is HATU, HBTU or TBTU.
  • the present invention also provides a compound represented by formula I, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt, its metabolic precursor, its metabolite, its isomer or its prodrug in the preparation of medicines.
  • the medicine can be used to prevent and/or treat diabetic complications and pulmonary fibrosis.
  • the present invention also provides a pharmaceutical composition, which includes a compound as shown in formula I, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a metabolic precursor thereof, a metabolite thereof, an isomer thereof or Its prodrugs and pharmaceutical excipients.
  • the dosage of the compound represented by Formula I, its pharmaceutically acceptable salts, its metabolic precursors, its metabolites, its isomers or its prodrugs can be therapeutically effective. quantity.
  • the present invention also provides the use of the above pharmaceutical composition in the preparation of medicines, and the pharmaceutical composition can be used to prevent and/or treat diabetic complications and pulmonary fibrosis.
  • the pharmaceutical excipients can be those widely used in the field of pharmaceutical production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition. They can also provide a method to enable the active ingredients to dissolve at a desired rate after administration, or promote the activity of the composition after administration. Ingredients are absorbed effectively.
  • the pharmaceutical excipients may be inert fillers, or provide certain functions, such as stabilizing the overall pH value of the composition or preventing degradation of the active ingredients of the composition.
  • the pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, and anti-adhesion agents. Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavorings and sweeten
  • compositions of the present invention may 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 freeze-drying processes.
  • compositions of the present invention may be administered in any form, including injectable (intravenous), mucosal, oral (solid and liquid formulations), inhaled, ocular, rectal, topical or parenteral (infusion, injection, implant). Intravenous, subcutaneous, intravenous, intraarterial, intramuscular) administration.
  • the pharmaceutical composition of the present invention may also be in a controlled-release or delayed-release dosage form (eg, liposomes or microspheres).
  • solid oral dosage forms include, but are not limited to, powders, capsules, caplets, softgels, and tablets.
  • liquid formulations 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 formulations.
  • formulations for parenteral administration include, but are not limited to, injectable solutions, dry formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, injectable suspensions, and injectable emulsions.
  • 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 lozenges agent.
  • salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonate or bicarbonate), phosphoric acid (forming phosphate, phosphoric acid- Hydrogen salt, dihydrogen phosphate, sulfuric acid (forming sulfate or hydrogen sulfate), hydriodic acid, phosphorous acid, etc.; and organic acid salts, including acetic acid, propionic acid, isobutyric acid, maleic acid, etc.
  • organic acid salts also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid.
  • Certain specific compounds of the present invention contain basic and acidic functional groups, which can be Conversion to any base or acid addition salt.
  • the free form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound.
  • the free form of the compound and its various salt forms The difference lies in certain physical properties, such as solubility in polar solvents.
  • the "pharmaceutically acceptable salts" of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • isomers refers to compounds that have the same chemical formula but different arrangements of atoms.
  • metabolite refers to the pharmaceutically active product produced by the metabolism of the compound represented by Formula I or its salt in the body. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a period of time sufficient to obtain the metabolites thereof.
  • Metabolites are typically identified by preparing radiolabeled isotopes of the compounds of the invention and administering them parenterally to animals, such as rats, mice, guinea pigs, monkeys, at detectable doses (e.g., greater than about 0.5 mg/kg). , or human, allow sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolation of its transformation products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies capable of binding epitopes present in the metabolites). Metabolite structures are determined in a conventional manner, for example, by MS, LC/MS or NMR analysis.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • the compounds provided by the invention also exist in prodrug forms.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of the present invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of Formula I) is a prodrug within the scope and spirit of the invention.
  • compounds containing carboxyl groups can form physiologically hydrolyzable esters, which serve as prodrugs by hydrolysis in vivo to yield the compound of Formula I itself.
  • the prodrugs are preferably administered orally since hydrolysis occurs in many cases mainly under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or when hydrolysis occurs in the blood.
  • substitution in the present invention can be one or more. When there are multiple “substitutions”, the “substitution” can be the same or different.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight or branched chain alkyl group having the specified number of carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and It is similar to an alkyl group.
  • cycloalkyl refers to a saturated monocyclic or polycyclic alkyl group.
  • the monocyclic cycloalkyl group is preferably a monovalent saturated cyclic alkyl group with 3 to 7 ring carbon atoms, more preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. .
  • Each ring of the polycyclic cycloalkyl group is saturated and can be a bicyclic or tricyclic cycloalkyl group having 4 to 10 carbon atoms.
  • heterocycloalkyl refers to a saturated monocyclic or polycyclic group having heteroatoms.
  • the monocyclic ring preferably contains 1, 2 or 3 3-7 membered saturated monocyclic heterocycloalkyl groups independently selected from N, O and S, examples of which include but are not limited to: pyrrolidinyl, tetrahydrofuran base, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxalidinyl, piperidinyl, morpholinyl, thiomorpholine base, piperazinyl, azepanyl, diazepanyl, oxazepanyl, dioxolanyl, dioxane, etc.
  • the polycyclic ring preferably contains 1, 2 or 3 8- to 10-membered saturated polycyclic heterocycloalkyl groups independently selected from N, O and S on at least one ring, and can be bicyclic or tricyclic, Examples include, but are not limited to, octahydropyrro[1,2-a]pyrazinyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl.
  • aryl refers to an aromatic group with a specified number of carbon atoms, preferably a monocyclic, bicyclic or tricyclic aromatic group. When it is bicyclic or tricyclic, each ring satisfies Huckel's rule.
  • the C 6-10 aryl group in the present invention refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.
  • heteroaryl refers to an aromatic group containing heteroatoms, preferably containing 1, 2 or 3 aromatic 5-6 membered monocyclic rings or 9-10 membered bicyclic rings independently selected from nitrogen, oxygen and sulfur.
  • the 5- to 6-membered monocyclic rings include but are not limited to pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2, 3-Triazolyl, 1,2,4-triazolyl, furazyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole, 1,2,5-oxadiazole , 1,3,4-oxadiazole, thiadiazolyl, dithiazolyl, tetrazolyl, pyridyl, pyranyl, thiopyranyl, diazinyl, pyrazinyl, pyrimidinyl, pyr
  • the 9- to 10-membered bicyclic rings include but are not limited to benzimidazolyl, indolyl, indazolyl, benzofuranyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benziiso Azolyl, quinolyl, isoquinolyl.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the indole alkaloids provided by the present invention have enhanced water solubility.
  • the indole alkaloids provided by the present invention have good therapeutic effects on diabetic complications including diabetic peripheral neuropathy and diabetic foot.
  • the indole alkaloids provided by the present invention have good therapeutic effects on pulmonary fibrosis.
  • Figure 1 is an immunofluorescence image showing that vinpocetine derivative S26 can significantly promote axonal growth of peripheral sensory neurons in mice with type 1 and type 2 diabetic peripheral neuropathy.
  • Figure 2 is a picture of a foot wound showing that vinpocetine derivative S26 can significantly promote the healing of foot ulcers in diabetic foot rats.
  • Figure 3 shows lung CT images showing that vinpocetine derivative S26 can significantly improve the degree of pulmonary fibrosis in mice.
  • deethyl ester product of vinpocetine 200 mg, 0.62 mmol
  • compound 1-1 122 mg, 0.62 mmol
  • dicyclohexylcarbodiimide DCC
  • DMAP 4-dimethylaminopyridine
  • step one For the synthesis of compounds S2 to S52 in the following examples 2 to 52, the synthesis of the vinpocetine deethyl ester product in step one is the same as in example 1.
  • the reaction process and reaction conditions of step two are the same as in example 1.
  • Compound 1 only needs to be -1 can be replaced with corresponding raw materials.
  • Example 2 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-2.
  • the specific structural formula is:
  • Example 3 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-3.
  • the specific structural formula is:
  • Example 4 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-4.
  • the specific structural formula is:
  • Example 5 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-5.
  • the specific structural formula is:
  • Example 6 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-6.
  • the specific structural formula is:
  • Example 7 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-7.
  • the specific structural formula is:
  • Example 8 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-8, and the specific structural formula is:
  • Example 9 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-9.
  • the specific structural formula is:
  • Example 10 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-10.
  • the specific structural formula is:
  • Example 11 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-11.
  • the specific structural formula is:
  • Example 12 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-12.
  • the specific structural formula is:
  • Example 13 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-13.
  • the specific structural formula is:
  • Example 14 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-14, and the specific structural formula is:
  • Example 15 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-15.
  • the specific structural formula is:
  • Example 16 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-16.
  • the specific structural formula is:
  • Example 17 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-17.
  • the specific structural formula is:
  • Example 18 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-18.
  • the specific structural formula is:
  • Example 19 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-19, and the specific structural formula is:
  • Example 20 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-20, and the specific structural formula is:
  • Example 21 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-21, and the specific structural formula is:
  • Example 22 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-22, and the specific structural formula is:
  • Example 23 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-23, and the specific structural formula is:
  • Example 24 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-24, and the specific structural formula is:
  • Example 25 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-25.
  • the specific structural formula is:
  • the vinpocetine deethyl ester product 200 mg, 0.62 mmol
  • compound 1-26 155 mg, 0.62 mmol
  • DCC 156 mg, 0.76 mmol
  • DMAP 8 mg, 0.1 mmol
  • Example 27 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-27.
  • the specific structural formula is:
  • Example 28 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-28.
  • the specific structural formula is:
  • Example 29 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-29, and the specific structural formula is:
  • Example 30 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-30, and the specific structural formula is:
  • Example 31 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-31, and the specific structural formula is:
  • Example 32 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-32, and the specific structural formula is:
  • Example 33 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-33, and the specific structural formula is:
  • Example 34 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-34, and the specific structural formula is:
  • Example 35 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-35.
  • the specific structural formula is:
  • Example 36 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-36.
  • the specific structural formula is:
  • Example 37 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-37.
  • the specific structural formula is:
  • Example 38 compound 1-1 in Example 1 was replaced with the corresponding raw material 1-38.
  • the specific structural formula is:
  • Example 39 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-39, and the specific structural formula is:
  • Example 40 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-40, and the specific structural formula is:
  • Example 41 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-41, and the specific structural formula is:
  • Example 42 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-42, and the specific structural formula is:
  • Example 43 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-43, and the specific structural formula is:
  • Example 44 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-44, and the specific structural formula is:
  • Example 45 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-45, and the specific structural formula is:
  • Example 46 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-46, and the specific structural formula is:
  • Example 47 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-47, and the specific structural formula is:
  • Example 48 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-48, and the specific structural formula is:
  • Example 49 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-49, and the specific structural formula is:
  • Example 50 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-50.
  • the specific structural formula is:
  • Example 51 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-51.
  • the specific structural formula is:
  • Example 52 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-52, and the specific structural formula is:
  • Vinpocetine deethyl ester product 200 mg, 0.62 mmol
  • compound 2-53 196 mg, 0.68 mmol
  • Potassium carbonate (128 mg, 0.93 mmol) and potassium iodide (103 mg) were added to the above solution. 0.62mmol), increase the temperature to 65°C, monitor by TLC until the reaction is complete, stop the reaction, and cool to room temperature. The solvent was evaporated, water (10 mL) was added, and EA was extracted (10 mL ⁇ 3).
  • Example 54 compound 2-53 in Example 53 is replaced with the corresponding raw material 2-54.
  • the specific structural formula is:
  • Example 55 compound 2-53 in Example 53 is replaced with the corresponding raw material 2-55.
  • the specific structural formula is:
  • Example 56 compound 2-53 in Example 56 is replaced with the corresponding raw material 2-56.
  • the specific structural formula is:
  • Example 57 compound 2-53 in Example 57 is replaced with the corresponding raw material 2-57.
  • the specific structural formula is:
  • Example 58 compound 2-53 in Example 58 is replaced with the corresponding raw material 2-58.
  • the specific structural formula is:
  • Example 59 compound 2-53 in Example 59 is replaced with the corresponding raw material 2-59.
  • the specific structural formula is:
  • Example 60 compound 2-53 in Example 60 is replaced with the corresponding raw material 2-60, and the specific structural formula is:
  • Example 61 compound 2-53 in Example 61 is replaced with the corresponding raw material 2-61.
  • the specific structural formula is:
  • Example 62 compound 2-53 in Example 62 is replaced with the corresponding raw material 2-62.
  • the specific structural formula is:
  • Examples 63 to 65 can be obtained according to the synthesis method of Example 1.
  • the generation of the vinpocetine deethyl ester product in step 1 is carried out according to the method in Example 1.
  • the reaction process and reaction of step 2 The conditions are the same as in Example 1, except that the compound 1-1 in Example 1 is replaced with the corresponding raw material.
  • Example 63 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-63, and the specific structural formula is:
  • Example 64 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-64, and the specific structural formula is:
  • Example 65 compound 1-1 in Example 1 is replaced with the corresponding raw material 1-65.
  • the specific structural formula is:
  • Vinpocetine deethyl ester product 200 mg, 0.62 mmol
  • glycine tert-butyl ester hydrochloride 78 mg, 0.62 mmol
  • EDCI 192 mg, 1.00 mmol
  • HOBt 103 mg, 0.76 mmol
  • water DMF 8 ml
  • triethylamine 0.4 mL, 2.94 mmol
  • step 1 is the same as those of Example 66. It is only necessary to replace glycine tert-butyl ester with the corresponding raw material. Yes, step 2 is carried out according to the method in Example 66.
  • Example 67 glycine tert-butyl ester hydrochloride in Example 66 was replaced with the corresponding raw material, and the specific structural formula is:
  • Example 68 glycine tert-butyl ester hydrochloride in Example 66 was replaced with the corresponding raw material, and the specific structural formula is:
  • Example 69 glycine tert-butyl ester hydrochloride in Example 66 is replaced with the corresponding raw material, and the specific structural formula is:
  • Example 70 the glycine tert-butyl ester hydrochloride in Example 66 was replaced with the corresponding raw material.
  • the specific structural formula is:
  • Example 71 glycine tert-butyl ester hydrochloride in Example 66 was replaced with the corresponding raw material, and the specific structural formula is:
  • Example 72 glycine tert-butyl ester hydrochloride in Example 66 is replaced with the corresponding raw material, and the specific structural formula is:
  • Example 73 glycine tert-butyl ester hydrochloride in Example 66 was replaced with the corresponding raw material, and the specific structural formula is:
  • Example 74 glycine tert-butyl ester hydrochloride in Example 66 was replaced with the corresponding raw material, and the specific structural formula is:
  • Example 75 glycine tert-butyl ester hydrochloride in Example 66 was replaced with the corresponding raw material, and the specific structural formula is:
  • Example 76 the glycine tert-butyl ester hydrochloride in Example 66 is replaced with the corresponding raw material.
  • the specific structural formula is:
  • Example 77 the glycine tert-butyl ester hydrochloride in Example 66 was replaced with the corresponding raw material.
  • the specific structural formula is:
  • Example 78 glycine tert-butyl ester hydrochloride in Example 66 was replaced with the corresponding raw material, and the specific structural formula is:
  • Example 79 glycine tert-butyl ester hydrochloride in Example 66 was replaced with the corresponding raw material, and the specific structural formula is:
  • Example 80 glycine tert-butyl ester hydrochloride in Example 66 was replaced with the corresponding raw material, and the specific structural formula is:
  • Example 81 glycine tert-butyl ester hydrochloride in Example 66 was replaced with the corresponding raw material, and the specific structural formula is:
  • Vinpocetine deethyl ester product 200 mg, 0.62 mmol
  • alanine methyl ester hydrochloride 87 mg, 0.62 mmol
  • EDCI 192 mg, 1.00 mmol
  • HOBt 103 mg, 0.76 mmol
  • Example 83 alanine methyl ester hydrochloride in Example 82 is replaced with the corresponding raw material, and the specific structural formula is:
  • Example 84 alanine methyl ester hydrochloride in Example 82 is replaced with the corresponding raw material, and the specific structural formula is:
  • Example 85 alanine methyl ester hydrochloride in Example 85 is replaced with the corresponding raw material.
  • the specific structural formula is:
  • Example 86 alanine methyl ester hydrochloride in Example 82 is replaced with the corresponding raw material, and the specific structural formula is:
  • Example 87 alanine methyl ester hydrochloride in Example 82 is replaced with the corresponding raw material, and the specific structural formula is:
  • the present invention detects the effect of vinpocetine derivatives in promoting the axonal growth of peripheral sensory neurons in DRG (Dorsal root ganglion) peripheral sensory neurons.
  • the experimental results show that the vinpocetine derivatives can significantly promote the axonal growth of peripheral sensory neurons. role.
  • Diabetic peripheral neuropathy first affects sensory neurons, and the main pathological change is axonal atrophy, degeneration, or even disappearance.
  • DRG neurons As peripheral sensory neurons, DRG neurons have axonal growth status that is closely related to the development of diabetic peripheral neuropathy. . Therefore, the compounds in the examples were added to primary DRG neurons and incubated for a certain period of time, and then the growth of DRG neuron axons was detected by immunofluorescence, and the axon length was quantified using Neuro J to evaluate the effects of the compounds on peripheral sensory nerves. Promoting axonal growth.
  • the mouse anti- ⁇ -tubulin III primary antibody used for fluorescent staining was purchased from Sigma.
  • the cell culture reagents were purchased from Gibco.
  • DRG neuronal cells were obtained from C57BL/6J mice. Specific experimental steps: Extract fresh DRG from C57 mice and digest it into a single cell suspension, then inoculate it into a culture plate and culture it overnight. Use vincamine as a positive drug and administer the test compounds S1 to S87 (10 ⁇ M) synthesized in the above examples. Incubate for 24 hours, then remove the original culture medium.
  • the present invention takes the vinpocetine derivative S26 prepared in Example 26 as an example to illustrate its therapeutic effect in vivo.
  • the structure of S26 is shown in the figure below.
  • the present invention detects the effect of S26 on the motor nerve conduction velocity and pain response of diabetic peripheral neuropathy model mice in STZ-induced type 1 diabetes model mice and type 2 diabetes model db/db mice.
  • Experimental results show that S26 can significantly improve the slowed motor nerve conduction velocity and sensory loss in diabetic peripheral neuropathy model mice.
  • Diabetic peripheral neuropathy first affects sensory neurons, and the main pathological changes are axonal atrophy, degeneration or even disappearance. Therefore, it is believed that it can have a therapeutic effect against diabetic peripheral neuropathy by protecting and promoting axon growth of sensory neurons.
  • patients with diabetic peripheral neuropathy may experience symptoms such as slowed nerve conduction velocity, decreased sensation, and fatigue.
  • Behavioral indicators such as motor nerve conduction velocity, mechanical pain threshold, and thermal pain response time are detected in diabetic peripheral neuropathy model mice, which can be used to evaluate the improvement effect of compounds on individual behavioral levels of diabetic peripheral neuropathy; test administration By measuring the axonal growth of peripheral sensory neurons in mice, the protective effect of compounds on peripheral neuron axons can be evaluated.
  • Type 1 diabetic mice Male 8-week-old C57BL/6J mice were purchased from Beijing Vitong Lever Experimental Animal Technology Co., Ltd. After one week of adaptive rearing, STZ (150 mg/kg) was injected intraperitoneally. One week later, blood was collected from the tail vein to detect blood sugar, and mice with random blood sugar greater than 16 mmol/L were selected. Six weeks after STZ injection, the groups were divided into groups according to body weight and blood sugar: control group (non-diabetic rats), model group (DPN rats), and S26 administration group (46.8 mg/kg/day), which were administered continuously for 4 weeks. .
  • control group non-diabetic rats
  • model group DNN rats
  • S26 administration group 46.8 mg/kg/day
  • Type 2 diabetic mice Male 18-week-old BKS db/db mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. After one week of adaptive feeding, the animals were divided into groups according to body weight and blood sugar, namely: control group (db/m rats), model group (db/db rats), and S26 administration group (46.8 mg/kg/day), which were administered continuously by gavage. Medication for 4 weeks.
  • MNCV Motor nerve conduction velocity
  • Electrode placement The stimulating electrode is placed on the nerve trunk, the recording electrode is placed on the muscle belly, and the reference electrode is placed on the tendon; the ground wire is placed between the stimulating electrode and the recording electrode.
  • Calculation of motor nerve conduction velocity Super strong stimulation of the distal and proximal ends of the nerve trunk, two compound muscle action potentials can be recorded on the muscles innervated by the nerve, and their different latencies are measured. The distance divided by the latency difference between the two points is the nerve conduction velocity.
  • the Von frey tactile measurement kit was purchased from Ugo Basile Company.
  • the Von frey fiber can provide a stimulation force of 0.008g-300g.
  • the thickness of the fiber determines the stimulation force provided.
  • Specific experimental method select fibers of appropriate thickness, stimulate the skin vertically, replace the fibers to adjust the stimulation force until the fibers bend.
  • the animal's response to infrared thermal stimulation was measured using an infrared plantar analgesia meter (37370, purchased from Ugo Basile Company) before and every week after administration to characterize the animal's thermal pain sensitivity.
  • an infrared plantar analgesia meter 37370, purchased from Ugo Basile Company
  • the fresh DRG neurons of the mice were digested into single cell suspension and then inoculated into a culture plate and cultured overnight. Immunofluorescence staining was used to label ⁇ -tubulin III (Sigma) protein in DRG neuron cells. Fluorescence microscopy (Leica) was used to image, and then the total length of individual DRG neuron cell axons was traced using the Neuro J plug-in in Image J software.
  • S26 can significantly improve the motor nerve conduction velocity and sensory loss symptoms of type 2 diabetic mice.
  • vinpocetine derivative S26 can significantly improve the axonal growth of DRG neurons in type 1 and type 2 diabetic peripheral neuropathy model mice (fluorescence picture). The quantitative results are shown in Table 8, indicating that vinpocetine derivative S26 has a protective effect on peripheral sensory neuron axons.
  • the present invention detects the effect of vinpocetine derivative S26 on foot ulcer wound healing in diabetic foot model rats in STZ-induced diabetic rats.
  • Experimental results show that after diabetic rats develop foot ulcers, treatment with compound S26 can significantly promote the healing of foot ulcer wounds and reduce the damage area.
  • Diabetic foot ulcer is the most common manifestation of diabetic foot and the main cause of amputation in diabetic patients.
  • DFU Diabetic foot ulcer
  • a certain area of wound was made on the back of the foot of diabetic rats at one time to form a diabetic foot ulcer model, and then compound S26 was given for treatment.
  • the effect of vinpocetine derivative S26 on wound healing of diabetic foot ulcers was evaluated by taking photos of the wounds and quantifying their area size.
  • mice Male 5-week-old SPF grade Sprague Dawley rats were purchased from Beijing Vitong Lever Experimental Animal Technology Co., Ltd. After one week of adaptive feeding, STZ (100 mg/kg) was injected intraperitoneally. 72 hours later, blood was collected from the tail vein to detect blood sugar, and rats with random blood sugar greater than 16.7 mmol/L were selected.
  • the diabetic foot ulcer rat model was established, it was divided into a control group (non-diabetic rats), a model group (DFU rats), and an S26 administration group (46.8 mg/kg/day) based on blood sugar and body weight indicators. The rats were administered continuously for 4 days by gavage. week.
  • the vinpocetine derivative S26 can significantly reduce the area of foot ulcer wounds in diabetic foot rats.
  • the quantitative results of the wound area are shown in Table 9, indicating that the vinpocetine derivative S26 can promote the healing of diabetic foot ulcer wounds. heal.
  • the present invention uses Micro CT to detect the protective effect of vinpocetine derivative S26 on mouse lung tissue in bleomycin-induced pulmonary fibrosis model mice. Experimental results show that treatment with compound S26 can significantly reduce the degree of pulmonary fibrosis in mice.
  • a pulmonary fibrosis model was created by instilling bleomycin solution into the oral trachea of mice, and then treated with Compound S26.
  • the effect of vinpocetine derivative S26 on the degree of bleomycin-induced pulmonary fibrosis in mice was evaluated by taking CT photos and three-dimensional reconstruction of mouse lungs, and quantifying the volume of normal tissue in the mouse lungs.
  • mice Male 8-week-old C57BL/6J mice were purchased from Beijing Vitong Lever. After one week of adaptive breeding, micro-CT was used to examine the lung development of the mice. The mice were divided into blank control group (normal mice), model group and S26 administration group (46.8mg/kg) according to the volume of normal lung tissue. Then an inhalation anesthesia machine was used to induce anesthesia by isoflurane inhalation. The mice in the model group and the administration group were instilled with 5 mg/kg bleomycin solution through the oral trachea to establish a pulmonary fibrosis model. The mice in the control group were instilled with the same volume. of bleomycin solvent. Administration began on the 8th day after modeling and continued intragastric administration for 20 days. Micro-CT imaging was performed before modeling, and on days 8, 18, and 28 after modeling to observe pulmonary fibrosis in mice.
  • vinpocetine derivative S26 can significantly increase the volume of normal lung tissue in pulmonary fibrosis model mice.
  • the quantitative results are shown in Table 10, indicating that vinpocetine derivative S26 can significantly reduce the risk of bleomycin.
  • the degree of pulmonary fibrosis induced in mice has a certain protective effect on lung tissue.

Abstract

本发明涉及一种吲哚生物碱及其制备方法与应用。本发明具体公开了一种如式I所示化合物及其制备方法，其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药。本发明通过实验表明，这类吲哚类生物碱不仅能够促进外周感觉神经元轴突生长、改善糖尿病鼠神经传导速度以及感觉缺失症状，还能够促进糖尿病鼠足部溃疡伤口的愈合，从而对糖尿病并发症周围神经病变及糖尿病足都具有良好的治疗作用。本发明通过实验表明，这类吲哚类生物碱还能够明显降低博来霉素诱导的小鼠肺部纤维化程度，对肺部组织起到保护作用。

Description

一种吲哚生物碱及其制备方法与应用 技术领域
本发明属于医药和化学合成领域，具体涉及一种吲哚生物碱和其制备方法、药物组合物及其在治疗与外周神经元轴突损伤、外周相关的神经病变和糖尿病足以及肺纤维化药物中的应用。
背景技术
糖尿病是一种严重的世界性疾病。据估计，到2045年，糖尿病患者的人数将达到6.29亿。糖尿病现已成为继心血管疾病和肿瘤之后，第三位威胁人类健康和生命的非传染性疾病。在我国，糖尿病已从少见病变成流行病，近30年患病率从平均0.67％飙升到11.6％。糖尿病患者若没有采取有效的控制治疗方法，就易被糖尿病并发的多种疾病所困扰，包括糖尿病性神经病变、肾病以及糖尿病足等，出现双目失明、肾衰竭，甚至导致肢体残疾和死亡。
糖尿病周围神经病变(Diabetic peripheral neuropathy，DPN)是因为长期高血糖而引发的糖尿病慢性神经病变，发病率高达50％～80％，是糖尿病最常见的一种慢性并发症。糖尿病周围神经病变可累及运动神经、感觉神经和自主神经，产生运动及感觉障碍。临床上，糖尿病周围神经病变患者的振动和热感知阈值会增加，这些阈值会随着周围神经中所有纤维的变性而发展为感觉丧失。目前，糖尿病周围神经病变的诊断方法主要是通过感觉检测、电生理检测、神经纤维形态学检查、影像学检查等。然而，糖尿病周围神经病变临床表现多样，国内外分类方法各不相同，筛查和检查方法种类繁杂，且诊断标准不一，其防治一直以来都是临床的难点。虽然随着科学技术的快速发展，科学家们对于糖尿病周围神经病变的研究有了突破性的进展，但是仍然缺乏根治糖尿病周围神经病变的特效药。因此，研究和开发新型治疗策略和新型化合物刻不容缓。
糖尿病足(Diabetic foot，DF)是因长期的高血糖导致糖尿病血管病变和(或)神经病变和感染，进而导致糖尿病患者足或下肢组织坏死的一种病变。糖尿病足是糖尿病最严重并发症之一，是糖尿病患者致残、致死的主要原因之一，也是造成社会沉重负担的重大公共卫生问题。随着糖尿病发病率的增加，糖尿病足的患病人数也逐年上升。我国50岁以上的糖尿病患者，糖尿病足的发病率高达8.1％。不幸的是，糖尿病足预后很差，甚至比大多数癌症的病死率和致残率还高(除肺癌、胰腺癌等)。并且糖尿病足治疗费用昂贵，需要长期接受治疗，临床上主要 通过医疗护理使患者的足部溃疡得以愈合，避免截肢的危险。但这些护理并不能完全根治糖尿病足，并且容易复发。所以，研究糖尿病足的发病机制，开发糖尿病足新型有效的治疗药物具有非常重要的现实意义。
肺纤维化(Pulmonary fibrosis，PF)是一种慢性、进行性、致死性的肺部疾病，是多种疾病的终末期，其发病机制至今仍不明确。肺纤维化严重影响人体呼吸功能，表现为干咳、进行性呼吸困难(自觉气不够用)，且随着病情和肺部损伤的加重，患者呼吸功能不断恶化。特发性肺纤维化发病率和死亡率逐年增加，诊断后的平均生存期仅2.8年，死亡率高于大多数肿瘤，被称为一种“类肿瘤疾病”。新冠肺炎的患者在治愈之后还可能会出现肺部纤维化的情况。目前，对肺纤维化患者的治疗多采用吡非尼酮、尼达尼布、氧疗、有创/无创机械通气，肺移植。但这些方法费用成本高，疗效不显著，移植供体不足或免疫排斥反应、患者医从性差限制了其广泛应用。因此，积极探索肺纤维化的发病机制及研发新的干预药物就显得十分重要。
长春胺(Vincamine)是一种单萜类吲哚生物碱，发现于马达加斯加长春花。它能增加脑血流量、耗氧量和葡萄糖利用率，改善痴呆和记忆障碍。长春西汀是一种长春胺衍生物，选择性地增加脑血流量；可增进和改善大脑氧的供给，促进代谢，增强红细胞的变形能力，降低血液黏稠度，抑制血小板聚集，改善脑组织代谢。主要用于治疗脑梗死后遗症，脑出血后遗症，脑动脉硬化等。也用于治疗视网膜血管硬化及血管痉挛、老年人耳聋及眩晕。然而和许多天然产物一样，长春胺和长春西汀面临着水溶性差，代谢不稳定，作用时间短等问题。从前期的工作可知，长春胺具有治疗糖尿病并发症及肺纤维化疾病的潜力。因此，寻找新型长春胺/长春西汀衍生物对于糖尿病并发症及肺纤维化的治疗具有重要意义。
聚乙二醇(Polyethylene glycol，PEG)是由环氧乙烷与水或乙二醇逐步发生加成聚合而得到的一类分子量较低的水溶性聚醚。小分子量的低聚聚乙二醇为无色、无臭有吸湿性的粘稠液体，分子中既有醚链，又有羟基，故具有独特的溶解性能，生物相容性好，在医药、材料和工程等领域具有很重要的应用前景。
发明内容
本发明要解决的技术问题是利用PEG无毒、易于结合的特性，将其与长春西汀连接起来，克服长春西汀不溶于水的特性。本发明提供了一种吲哚生物碱、其制备方法、药物组合物及应用。本发明的吲哚生物碱结构稳定，水溶性好，对糖尿病周围神经病变、糖尿病足以及肺纤维化均具有较好的治疗效果。
本发明通过以下技术方案解决上述技术问题。
本发明提供了一种如式I所示化合物、其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药，其结构如下所示：
Figure PCTCN2022130902-appb-000001
式I中：
X为O或-NR 1；
R 1为氢、未取代或R 1-1取代的C 1-6烷基、C 6-10芳基、C 3-10环烷基、“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基、或、“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”4-10元杂环烷基、C 3-10环烷基-(C 1-4烷基)-或C 6-12芳基-(C 1-4烷基)-；
R 1-1为卤素或羟基；
Y为-(CH 2) m-；
m为1-6的整数；
Z为单键、
Figure PCTCN2022130902-appb-000002
Figure PCTCN2022130902-appb-000003
R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自氢、未取代或R 3-1取代的C 1-6烷基、C 6-10芳基、未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-、杂芳基、或、杂芳基-(C 1-4烷基)-，所述的杂芳基为“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基；
R 3-1为羟基、羧基、氨基、巯基、-(C＝O)NR 3-1-1、或、-NH(C＝NH)NH 2；
R 3-1-1为氢或C 1-4烷基；
R 3-2为卤素或羟基；
R为氢、C 1-6烷氧基或、
Figure PCTCN2022130902-appb-000004
R 2为C 1-6烷基或氢；
n是0～500的整数；
Figure PCTCN2022130902-appb-000005
为具有包含-(OCH 2CH 2) n-的直链、树形、星形或超支化结构的聚乙二醇。
Figure PCTCN2022130902-appb-000006
式I中：
X为O或-NR 1；
R 1为氢、未取代或R 1-1取代的C 1- 6烷基、C 6-10芳基、C 3-10环烷基、“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基、或、“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”4-10元杂环烷基、C 3-10环烷基-(C 1-4烷基)-或C 6-12芳基-(C 1-4烷基)-；
R 1-1为卤素或羟基；
Y为-(CH 2) m-；
m为1-6的整数；
Z为单键、
Figure PCTCN2022130902-appb-000007
Figure PCTCN2022130902-appb-000008
R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自氢、未取代或R 3-1取代的C 1-6烷基、C 6-10芳基、未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-、杂芳基、或、杂芳基-(C 1-4烷基)-，所述的杂芳基为“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基；
R 3-1为羟基、羧基、氨基、巯基、-(C＝O)NR 3-1-1、或、-NH(C＝NH)NH 2；
R 3-1-1为氢或C 1-4烷基；
R 3-2为卤素或羟基；
R为氢、羟基、C 1-6烷氧基或、
Figure PCTCN2022130902-appb-000009
R 2为C 1-6烷基或氢；
n是0～500的整数；
Figure PCTCN2022130902-appb-000010
为具有包含-(OCH 2CH 2) n-的直链、树形、星形或超支化结构的聚乙二醇。
在一些实施方案中，当R 1为未取代或R 1-1取代的C 1-6烷基时，所述的R 1-1的个数为一个或多个，当存在多个R 1-1时，所述的R 1-1可相同或不同。
在一些实施方案中，当R 1为未取代或R 1-1取代的C 1-6烷基时，所述的C 1-6烷基为C 1-4烷基。
在一些实施方案中，当R 1为C 6-10芳基时，所述的C 6-10芳基为苯基。
在一些实施方案中，当R 1为C 3-10环烷基时，所述的C 3-10环烷基为C 3-6环烷基。
在一些实施方案中，当R 1为C 6-12芳基-(C 1-4烷基)-时，所述的C 6-12芳基-(C 1-4烷基)-为苄基。
在一些实施方案中，当R 1为C 3-10环烷基-(C 1-4烷基)-时，所述的C 3-10环烷基-(C 1-4烷基)-为C 3-6环烷基-(C 1-2烷基)。
在一些实施方案中，当R 1-1为卤素时，所述的卤素为氟、氯、溴或碘。
在一些实施方案中，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自未取代或R 3-1取代的C 1-6烷基时，所述的R 3-1的个数为一个或多个，当存在多个R 3-1时，所述的R 3-1可相同或不同。
在一些实施方案中，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自未取代或R 3-1取代的C 1-6烷基时，所述的C 1-6烷基为C 1-4烷基。
在一些实施方案中，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、 R 14和R 15独立地选自未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-时，所述的R 3-2的个数为一个或多个，当存在多个R 3-2时，所述的R 3-2可相同或不同。
在一些实施方案中，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自未取代或R 3-1取代的C 6-12芳基-(C 1-4烷基)-时，所述的C 6-12芳基-(C 1-4烷基)-为C 6-12芳基-(C 1-2烷基)-。
在一些实施方案中，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基-(C 1-4烷基)-时，所述的5～10元杂芳基-(C 1-4烷基)为5-9元杂芳基-(CH 2)-。
在一些实施方案中，当R 3-1-1为C 1-4烷基时，所述的C 1-4烷基为甲基、乙基、正丙基或异丙基。
在一些实施方案中，m为1-4的整数。
在一些实施方案中，n为0～400的整数。
在一些实施方案中，
Figure PCTCN2022130902-appb-000011
为具有包含-(OCH 2CH 2) n-的直链结构的聚乙二醇。
在一些实施方案中，当R 2为C 1-6烷基时，所述的C 1-6烷基为C 1-4烷基。
在一些实施方案中，当R为C 1-6烷氧基时，所述的C 1-6烷氧基为C 1-4烷氧基。
在一些实施方案中，当R 1为未取代或R 1-1取代的C 1-6烷基时，所述的R 1-1的个数为1个、2个或3个。
在一些实施方案中，当R 1为未取代或R 1-1取代的C 1-6烷基时，所述的C 1-6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。
在一些实施方案中，当R 1为C 3-10环烷基时，所述的C 3-10环烷基为环丙基、环丁基、环戊基或环己基。
在一些实施方案中，当R 1为C 3-10环烷基-(C 1-4烷基)-时，所述的C 3-10环烷基-(C 1-4烷基)-为环丙甲基、环丁甲基、环戊甲基或环己甲基。
在一些实施方案中，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自未取代或R 3-1取代的C 1-6烷基时，所述的R 3-1的个数为1个、2个或3个。
在一些实施方案中，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、 R 14和R 15独立地选自未取代或R 3-1取代的C 1-6烷基时，所述的C 1-6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。
在一些实施方案中，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-时，所述的R 3-2的个数为1个、2个或3个。
在一些实施方案中，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-时，所述的C 6-12芳基-(C 1-4烷基)-为苄基。
在一些实施方案中，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基-(C 1-4烷基)-时，所述的5～10元杂芳基-(C 1-4烷基)为吲哚甲基或咪唑甲基。
在一些实施方案中，m为1-2的整数。
在一些实施方案中，n为0～100的整数。
在一些实施方案中，当R 2为C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基。
在一些实施方案中，当R为C 1-6烷氧基时，所述的C 1-6烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基或叔丁氧基。
在一些实施方案中，当R 1为R 1-1取代的C 1-6烷基时，所述的R 1-1取代的C 1-6烷基为三氟甲基、或、
Figure PCTCN2022130902-appb-000012
在一些实施方案中，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自R 3-1取代的C 1-6烷基时，所述的R 3-1取代的C 1-6烷基为
Figure PCTCN2022130902-appb-000013
在一些实施方案中，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自R 3-2取代的C 6-12芳基-(C 1-4烷基)-时，所述的未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-为
Figure PCTCN2022130902-appb-000014
在一些实施方案中，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、 R 14和R 15独立地选自“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基-(C 1-4烷基)-时，所述的5～10元杂芳基-(C 1-4烷基)为
Figure PCTCN2022130902-appb-000015
在一些实施方案中，R 1为氢、未取代或R 1-1取代的C 1-6烷基或C 3-10环烷基。
在一些实施方案中，R 1-1为羟基。
在一些实施方案中，m为1-2的整数。
在一些实施方案中，Z为单键或
Figure PCTCN2022130902-appb-000016
在一些实施方案中，R 3为氢、未取代或R 3-1取代的C 1-6烷基、未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-、杂芳基-(C 1-4烷基)-，所述的杂芳基为“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基。
在一些实施方案中，R 3-1为羟基、羧基、氨基、巯基、-(C＝O)NR 3-1-1、或、-NH(C＝NH)NH 2。
在一些实施方案中，R 3-1-1为氢。
在一些实施方案中，R 3-2为羟基。
在一些实施方案中，n是0～400的整数。
在一些实施方案中，
Figure PCTCN2022130902-appb-000017
为具有包含-(OCH 2CH 2) n-的直链结构的聚乙二醇。
在一些实施方案中，X为O或-NR 1；
R 1为氢、未取代或R 1-1取代的C 1-6烷基或C 3-10环烷基；
R 1-1为羟基；
Y为-(CH 2) m-；
m为1-2的整数；
Z为单键或
Figure PCTCN2022130902-appb-000018
R 3为氢、未取代或R 3-1取代的C 1-6烷基、未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-或杂芳基-(C 1-4烷基)-，所述的杂芳基为“杂原子选自N、O、S中的一种 或多种，杂原子数为1-3个的”5-10元杂芳基；
R 3-1为羟基、羧基、氨基、巯基、-(C＝O)NR 3-1-1、或、-NH(C＝NH)NH 2；
R 3-1-1为氢；
R 3-2为羟基；
R为氢、C 1-6烷氧基或、
Figure PCTCN2022130902-appb-000019
R 2为C 1-6烷基或氢；
n是0～400的整数；
Figure PCTCN2022130902-appb-000020
为具有包含-(OCH 2CH 2) n-的直链结构的聚乙二醇。
在一些实施方案中，X为O或-NR 1；
R 1为氢、未取代或R 1-1取代的C 1-6烷基或C 3-10环烷基；
R 1-1为羟基；
Y为-(CH 2) m-；
m为1-2的整数；
Z为单键或
Figure PCTCN2022130902-appb-000021
R 3为氢、未取代或R 3-1取代的C 1-6烷基、未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-或杂芳基-(C 1-4烷基)-，所述的杂芳基为“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基；
R 3-1为羟基、羧基、氨基、巯基、-(C＝O)NR 3-1-1、或、-NH(C＝NH)NH 2；
R 3-1-1为氢；
R 3-2为羟基；
R为氢、羟基、C 1-6烷氧基或、
Figure PCTCN2022130902-appb-000022
R 2为C 1-6烷基或氢；
n是0～400的整数；
Figure PCTCN2022130902-appb-000023
为具有包含-(OCH 2CH 2) n-的直链结构的聚乙二醇。
在一些实施方案中，X为-NR 1；
R 1为氢；
Y为-(CH 2) m-；
m为1-2的整数；
Z为单键或
Figure PCTCN2022130902-appb-000024
R 3为氢、或、未取代或R 3-1取代的C 1-6烷基；
R 3-1为羟基、羧基、氨基、巯基、-(C＝O)NR 3-1-1、或、-NH(C＝NH)NH 2；
R 3-1-1为氢；
R为氢、C 1-6烷氧基或
Figure PCTCN2022130902-appb-000025
R 2为C 1-6烷基或氢；
n是0～100的整数；
Figure PCTCN2022130902-appb-000026
为具有包含-(OCH 2CH 2) n-的直链结构的聚乙二醇。
在一些实施方案中，X为-NR 1；
R 1为氢；
Y为-(CH 2) m-；
m为1-2的整数；
Z为单键或
Figure PCTCN2022130902-appb-000027
R 3为氢、或、未取代或R 3-1取代的C 1-6烷基；
R 3-1为羟基、羧基、氨基、巯基、-(C＝O)NR 3-1-1、或、-NH(C＝NH)NH 2；
R 3-1-1为氢；
R为氢、羟基、C 1-6烷氧基或
Figure PCTCN2022130902-appb-000028
R 2为C 1-6烷基或氢；
n是0～100的整数；
Figure PCTCN2022130902-appb-000029
为具有包含-(OCH 2CH 2) n-的直链结构的聚乙二醇。
在一些实施方案中，所述的如式I所示化合物为以下任一种，
Figure PCTCN2022130902-appb-000030
Figure PCTCN2022130902-appb-000031
Figure PCTCN2022130902-appb-000032
Figure PCTCN2022130902-appb-000033
Figure PCTCN2022130902-appb-000034
本发明还提供一种如式I所示化合物的制备方法，其合成包括以下步骤：在溶剂中，在碱和缩合剂的作用下，将如式II所示化合物与如式III所示化合物进行如下所示的缩合反应，即可；
Figure PCTCN2022130902-appb-000035
其中，L为-NHR 1、羟基
Figure PCTCN2022130902-appb-000036
R 1、X、Y、Z和R的定义如前所述。
本发明还提供一种如式I所示化合物的制备方法，其合成包括以下步骤：在溶剂中，在碱和缩合剂的作用下，将如式II所示化合物与如式III所示化合物进行如下所示的缩合反应，即可；
Figure PCTCN2022130902-appb-000037
其中，L为-NHR 1、羟基
Figure PCTCN2022130902-appb-000038
R 1、X、Y、Z和R的定义如前所述。
在一些实施方案中，所述的溶剂为酰胺类溶剂或卤代烷烃类溶剂。
在一些实施方案中，所述的碱为有机碱或无机碱。
在一些实施方案中，所述的缩合剂为碳二亚胺类、有机磷盐类或鎓盐类。
在一些实施方案中，当溶剂为酰胺类时，所述的酰胺类为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或N-甲基吡咯烷酮。
在一些实施方案中，当溶剂为卤代烷烃类时，所述的卤代烷烃类为二氯甲烷。
在一些实施方案中，当碱为有机碱时，所述的有机碱为三乙胺、DIPEA、或DMAP。
在一些实施方案中，当碱为无机碱时，所述的无机碱为碳酸钾或碳酸铯。
在一些实施方案中，当缩合剂为碳二亚胺类时，所述的碳二亚胺类为DCC、DIC或EDCI。
在一些实施方案中，当缩合剂为有机磷盐类时，所述的有机磷盐类为BOP或PyBOP.
在一些实施方案中，当缩合剂为鎓盐类时，所述的鎓盐类为HATU、HBTU或TBTU。
本发明还提供了一种如式I所示化合物、其药学上可接受的盐、其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药在制备药物中的应用，所述的药物可用于预防和/或治疗糖尿病并发症以及肺纤维化。
本发明还提供一种药物组合物，其包括如如式I所示化合物、其药学上可接 受的盐、其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药，和药用辅料。
在所述的药物组合物中，所述的如式I所示化合物、其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药的用量可为治疗有效量。
本发明还提供了上述药物组合物在制备药物中的应用，所述的药物组合物可用于预防和/或治疗糖尿病并发症以及肺纤维化。
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。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合 物的游离体形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的游离体形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸(形成碳酸盐或碳酸氢盐)、磷酸(形成磷酸盐、磷酸一氢盐、磷酸二氢盐、硫酸(形成硫酸盐或硫酸氢盐)、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；有机酸盐还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的游离体形式。化合物的游离体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本发明的“药学上可接受的盐”可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
术语“异构体”是指具有相同化学式而有不同的原子排列的化合物。
术语“代谢产物”是指式I所示化合物或其盐通过体内代谢产生的药学活性产物。这种产物可以从例如所给药的化合物的氧化、还原、水解、酰胺化、脱酰胺、酯化、脱酯、葡糖醛酸化、酶促裂解等产生。因此，本发明包括本发明的化合物的代谢产物，包括使本发明的化合物与哺乳动物接触足够得到其代谢产物的一段时间的方法而产生的化合物。
代谢产物的鉴定典型地通过制备本发明化合物的放射性标记的同位素、将其以可检测的剂量(例如，大于约0.5mg/kg)非肠道给予动物，例如大鼠、小鼠、豚鼠、猴、或人，允许充分的时间以发生代谢(典型地约30秒到30小时)和从尿、血液或其它生物样本分离其转化产物。这些产物容易分离，因为它们是被标记的(其它通过利用能够结合存在于代谢物中的抗原表位的抗体分离)。以常规的方式确定代谢物结构，例如，通过MS，LC/MS或NMR分析。通常，代谢物的分析是以与本领域技术人员公知的常规药物代谢研究相同的方法进行的。只要 代谢物产物不是以其它方式在体内不能被发现，否则它们可用于本发明化合物的治疗剂量给药的检定测定法。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。可在体内转化以提供生物活性物质(即式I所示化合物)的任何化合物是在本发明的范围和主旨内的前药。例如，含有羧基的化合物可形成生理上可水解的酯，其通过在体内水解以得到式I所示化合物本身而充当前药。所述前药优选口服给药，这是因为水解在许多情况下主要在消化酶的影响下发生。当酯本身具有活性或水解发生在血液中时，可使用肠胃外给药。
本领域技术人员可以理解，根据本领域中使用的惯例，本申请描述基团的结构式中所使用的
Figure PCTCN2022130902-appb-000039
是指，相应的基团通过该位点与式I所示化合物中的其它片段、基团进行连接。
本发明中的“取代”可为一个或多个，当存在多个“取代”时，所述的“取代”可为相同或不同。
术语“多个”是指2个、3个、4个或5个。
术语“卤素”是指氟、氯、溴或碘。
术语“烷基”是指具有指定的碳原子数的直链或支链烷基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基及其类似烷基。
术语“环烷基”是指饱和的单环或多环的烷基。所述的单环环烷基优选具有3～7个环碳原子、更优选3-6个碳原子的单价饱和的环状烷基，例如环丙基、环丁基、环戊基或环己基。所述的多环环烷基的每个环均是饱和的，可为具有4～10个碳原子的二环或三环环烷基。
术语“杂环烷基”是指具有杂原子的饱和的单环或多环基团。所述的单环优选含有1个、2个或3个独立地选自N、O和S的3～7元饱和的单环杂环烷基，其示例包括但不限于：吡咯烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢吡咯基、氮杂环丁烷基、噻唑烷基、唑烷基、哌啶基、吗啉基、硫 代吗啉基、哌嗪基、氮杂环庚烷基、二氮杂环庚烷基、氧氮杂环庚烷基、二氧戊环基、二氧六环基等。所述的多环优选其中至少一个环上含有1个、2个或3个独立地选自N、O和S的8～10元饱和的多环杂环烷基，可为双环或三环，实例包括但不限于八氢吡咯并[1,2-a]吡嗪基、(1R，5S)-3,8-二氮杂双环[3.2.1]辛基。
术语“芳基”是指具有指定的碳原子数的芳香基团，优选单环、双环或者三环的芳香基团，当为双环或者三环时，每个环均满足休克尔规则。本发明的C 6-10的芳基指含有6～10个碳原子的芳香基团，例如苯基或萘基。
术语“杂芳基”是指含有杂原子的芳香基团，优选含有1个、2个或3个独立选自氮、氧和硫的芳族5～6元单环或9～10元双环。所述的5～6元的单环包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、1,2,3-***基、1,2,4-***基、呋咱基、1,2,3-噁二唑基、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑基、二噻唑基、四唑基、吡啶基、吡喃基、噻喃基、二嗪基、吡嗪基、嘧啶基、哒嗪基、噁嗪基、噻嗪基、二噁英基、二噻英基、1,2,3-三嗪基、1,2,4-三嗪基、1,3,5-三嗪基或四嗪基。所述的9～10元双环包括但不限于苯并咪唑基、吲哚基、吲唑基、苯并呋喃基、苯并噻唑基、苯并异噻唑基、苯并噁唑基、苯并异唑基、喹啉基、异喹啉基。
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。
本发明的积极进步效果在于：
(1)本发明提供的吲哚生物碱水溶性增强。
(2)本发明提供的吲哚生物碱对糖尿病并发症包括糖尿病周围神经病变以及糖尿病足均具有良好的治疗作用。
(3)本发明提供的吲哚生物碱对肺纤维化具有良好的治疗作用。
附图说明
图1为长春西汀衍生物S26能够明显促进1型和2型糖尿病周围神经病变小鼠外周感觉神经元轴突生长的免疫荧光图。
图2为长春西汀衍生物S26能够明显促进糖尿病足大鼠足部溃疡伤口愈合的足部伤口图片。
图3为长春西汀衍生物S26能够明显改善小鼠肺纤维化程度的肺部CT图片。
具体实施方式
下面结合具体实施例对本发明作进一步阐述，但这些实施例不应解释为限制本发明。
实施例1：化合物S1的合成
Figure PCTCN2022130902-appb-000040
步骤一：长春西汀脱乙酯产物的合成
Figure PCTCN2022130902-appb-000041
将长春西汀10g(28.5mmol)溶于乙醇中，向上述反应液中加入的60mL NaOH溶液(1mol/L)中，加热回流，溶液逐渐由浑浊变澄清，TLC点板检测反应进度。待原料完全消失后，将反应液置于0℃下用稀盐酸调节pH值至3，然后减压旋掉乙醇，过滤，收集滤饼，真空干燥，得长春西汀脱乙酯粗品(9.0g，98％)，直接投下一步。
1H NMR(500MHz,DMSO-d6)δ9.80(s,1H),7.56(ddd,J＝19.5,7.9,1.2Hz,2H),7.47(ddd,J＝7.9,7.0,1.2Hz,1H),7.27(ddd,J＝8.1,6.9,1.3Hz,1H),5.79(s,1H),4.57(s,1H),3.06(ddd,J＝11.9,6.5,4.2Hz,1H),2.94(ddd,J＝15.6,6.4,4.2Hz,1H),2.86–2.77(m,2H),2.75(ddd,J＝12.1,6.4,4.2Hz,1H),2.52–2.43(m,1H),1.76–1.51(m,5H),1.42(dq,J＝13.0,7.2Hz,1H),0.88(t,J＝7.2Hz,3H)。
步骤二：化合物S1的合成
Figure PCTCN2022130902-appb-000042
将长春西汀脱乙酯产物(200mg，0.62mmol)，化合物1-1(122mg，0.62mmol)，二环己基碳二亚胺(DCC)(156mg，0.76mmol)，4-二甲氨基吡啶(DMAP)(8mg，0.1mmol)，在室温下溶于二氯甲烷(2mL)中，氮气保护，常温反应12小时。抽滤除去不溶物，滤液加水，二氯甲烷萃取(5mL×3)，合并有机相，饱和食盐水(2mL)洗1次，无水硫酸钠干燥，过滤，浓缩，柱层析分离(柱洗脱液二氯甲烷:甲醇＝30:1)纯化得白色固体S1(214mg，72.0％)。
1H NMR(500MHz,DMSO-d 6)δ8.62(t,J＝5.8Hz,1H),7.54(dd,J＝7.8,1.3Hz,2H),7.46(ddd,J＝7.9,7.0,1.4Hz,1H),7.26(ddd,J＝8.1,6.9,1.2Hz,1H),5.82(s,1H),4.54(s,2H),4.37(dt,J＝12.4,6.2Hz,1H),4.13–4.01(m,2H),3.94(dd,J＝17.6,5.9Hz,1H),3.78–3.42(m,6H),3.39(s,2H),3.09(ddd,J＝12.1,6.4,4.2Hz,1H),2.94(ddd,J＝15.6,6.4,4.2Hz,1H),2.90–2.75(m,2H),2.72(ddd,J＝12.1,6.4,4.2Hz,1H),2.39–2.30(m,1H),1.77–1.68(m,3H),1.72–1.65(m,1H),1.60–1.41(m,2H),0.85(t,J＝7.1Hz,3H)。MS(ESI,m/z):482(M ++1)。
以下实施例2～52中的化合物S2～S52的合成，步骤一长春西汀脱乙酯产物的合成同实施例1，步骤二的反应过程和反应条件均同实施例1，只需将化合物1-1更换为相应原料即可。
实施例2：化合物S2的合成
实施例2中，将实施例1中化合物1-1替换成相对应的原料1-2，具体结构式为
Figure PCTCN2022130902-appb-000043
Figure PCTCN2022130902-appb-000044
1H NMR(500MHz,DMSO-d 6)δ8.62(t,J＝5.8Hz,1H),7.56(ddd,J＝18.4,7.8,1.3Hz,2H),7.46(ddd,J＝8.0,7.0,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.82(s,1H),4.57(s,1H),4.38(dt,J＝12.3,6.2Hz,1H),4.11–3.97(m,2H),3.92(dd,J＝17.5,5.8Hz,1H),3.77–3.43(m,10H),3.39(s,3H),3.05(ddd,J＝11.9,6.5,4.2Hz,1H),2.92(ddd,J＝15.6,6.4,4.3Hz,1H),2.82(ddd,J＝15.4,6.5,4.3Hz,1H),2.80–2.71(m,2H),2.46(ddd,J＝12.8,6.7,4.8Hz,1H),1.74–1.53 (m,4H),1.50–1.42(m,1H),1.46–1.37(m,1H),0.87(t,J＝7.1Hz,3H)。MS(ESI,m/z):526(M ++1)。
实施例3：化合物S3的合成
实施例3中，将实施例1中化合物1-1替换成相对应的原料1-3，具体结构式为
Figure PCTCN2022130902-appb-000045
1H NMR(500MHz,DMSO-d 6)δ8.62(t,J＝5.8Hz,1H),7.60(dd,J＝8.0,1.3Hz,1H),7.53(dd,J＝8.0,1.3Hz,1H),7.47(ddd,J＝8.0,6.9,1.3Hz,1H),7.25(ddd,J＝8.0,6.9,1.2Hz,1H),6.81(s,1H),4.53(s,1H),4.34(dt,J＝12.3,6.2Hz,1H),4.21(dt,J＝12.3,6.2Hz,1H),4.06(dd,J＝17.5,5.8Hz,1H),3.94(dd,J＝17.6,5.7Hz,1H),3.77–3.58(m,12H),3.61–3.53(m,1H),3.54–3.42(m,2H),3.39(s,3H),3.09(ddd,J＝12.1,6.5,4.2Hz,1H),2.98–2.83(m,2H),2.85–2.71(m,2H),2.36(ddd,J＝11.9,6.9,4.7Hz,1H),1.79–1.65(m,3H),1.61–1.46(m,3H),0.86(t,J＝7.2Hz,3H)。MS(ESI,m/z):570(M ++1)。
实施例4：化合物S4的合成
实施例4中，将实施例1中化合物1-1替换成相对应的原料1-4，具体结构式为
Figure PCTCN2022130902-appb-000046
1H NMR(500MHz,DMSO-d 6)δ8.61(t,J＝5.8Hz,1H),7.56(ddd,J＝19.9,7.7,1.2Hz,2H),7.45(ddd,J＝8.0,6.9,1.3Hz,1H),7.27(ddd,J＝8.0,6.9,1.3Hz,1H),6.81(s,1H),4.53(s,1H),4.38(dt,J＝12.2,6.1Hz,1H),4.08(dt,J＝12.4,6.2Hz,1H),4.02(dd,J＝17.6,5.9Hz,1H),3.92(dd,J＝17.6,5.9Hz,1H),3.66(s,9H),3.77–3.42(m,10H),3.39(s,3H),3.05(ddd,J＝12.1,6.4,4.3Hz,1H),2.92(ddd,J＝15.4,6.4,4.3Hz,1H),2.82(ddd,J＝15.6,6.5,4.4Hz,1H),2.80–2.74(m,1H),2.77–2.71(m,1H),2.50–2.40(m,1H),1.75–1.53(m,4H),1.49–1.37(m,2H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):614(M ++1)。
实施例5：化合物S5的合成
实施例5中，将实施例1中化合物1-1替换成相对应的原料1-5，具体结构式为
Figure PCTCN2022130902-appb-000047
1H NMR(500MHz,DMSO-d 6)δ8.56(t,J＝5.8Hz,1H),7.56(ddd,J＝13.4,7.9,1.2Hz,2H),7.44(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.82(s,1H),4.54(s,1H),4.01(dd,J＝17.5,5.8Hz,1H),3.92(dd,J＝17.6,5.7Hz,1H),3.51–3.17(–OCH2CH2),3.39(s,3H),3.07(ddd,J＝11.2,7.2,4.2Hz,1H),2.96–2.87(m,1H),2.86–2.73(m,3H),2.50(ddd,J＝12.0,6.9,4.8Hz,1H),1.74–1.52(m,4H),1.53–1.45(m,1H),1.48–1.39(m,1H),0.88(t,J＝7.1Hz,3H)。
实施例6：化合物S6的合成
实施例6中，将实施例1中化合物1-1替换成相对应的原料1-6，具体结构式为
Figure PCTCN2022130902-appb-000048
Figure PCTCN2022130902-appb-000049
1H NMR(500MHz,DMSO-d 6)δ8.56(t,J＝5.8Hz,1H),7.56(ddd,J＝13.4,7.9,1.2Hz,2H),7.44(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.82(s,1H),4.54(s,1H),4.01(dd,J＝17.5,5.8Hz,1H),3.92(dd,J＝17.6,5.7Hz,1H),3.51–3.17(–OCH2CH2),3.39(s,3H),3.07(ddd,J＝11.2,7.2,4.2Hz,1H),2.96–2.87(m,1H),2.86–2.73(m,3H),2.50(ddd,J＝12.0,6.9,4.8Hz,1H),1.74–1.52(m,4H),1.53–1.45(m,1H),1.48–1.39(m,1H),0.88(t,J＝7.1Hz,3H)。
实施例7：化合物S7的合成
实施例7中，将实施例1中化合物1-1替换成相对应的原料1-7，具体结构式为
Figure PCTCN2022130902-appb-000050
1H NMR(500MHz,DMSO-d 6)δ8.56(t,J＝5.8Hz,1H),7.56(ddd,J＝13.4,7.9,1.2Hz,2H),7.44(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.82(s,1H),4.54(s,1H),4.01(dd,J＝17.5,5.8Hz,1H),3.92(dd,J＝17.6,5.7Hz,1H),3.51–3.17(–OCH2CH2),3.39(s,3H),3.07(ddd,J＝11.2,7.2,4.2Hz,1H),2.96–2.87(m,1H),2.86–2.73(m,3H),2.50(ddd,J＝12.0,6.9,4.8Hz,1H),1.74–1.52(m,4H),1.53–1.45(m,1H),1.48–1.39(m,1H),0.88(t,J＝7.1Hz,3H)。
实施例8：化合物S8的合成
实施例8中，将实施例1中化合物1-1替换成相对应的原料1-8，具体结构式为
Figure PCTCN2022130902-appb-000051
1H NMR(500MHz,DMSO-d 6)δ8.56(t,J＝5.8Hz,1H),7.56(ddd,J＝13.4,7.9,1.2Hz,2H),7.44(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.82(s,1H),4.54(s,1H),4.01(dd,J＝17.5,5.8Hz,1H),3.92(dd,J＝17.6,5.7Hz,1H),3.51–3.17(–OCH2CH2),3.39(s,3H),3.07(ddd,J＝11.2,7.2,4.2Hz,1H),2.96–2.87(m,1H),2.86–2.73(m,3H),2.50(ddd,J＝12.0,6.9,4.8Hz,1H),1.74–1.52(m,4H),1.53–1.45(m,1H),1.48–1.39(m,1H),0.88(t,J＝7.1Hz,3H)。
实施例9：化合物S9的合成
实施例9中，将实施例1中化合物1-1替换成相对应的原料1-9，具体结构式为
Figure PCTCN2022130902-appb-000052
1H NMR(500MHz,DMSO-d 6)δ8.56(t,J＝5.8Hz,1H),7.56(ddd,J＝13.4,7.9,1.2Hz,2H),7.44(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.82(s,1H),4.54(s,1H),4.01(dd,J＝17.5,5.8Hz,1H),3.92(dd,J＝17.6,5.7Hz,1H),3.51–3.17(–OCH2CH2),3.39(s,3H),3.07(ddd,J＝11.2,7.2,4.2Hz,1H),2.96–2.87(m,1H),2.86–2.73(m,3H),2.50(ddd,J＝12.0,6.9,4.8Hz,1H),1.74–1.52(m,4H),1.53–1.45(m,1H),1.48–1.39(m,1H),0.88(t,J＝7.1Hz,3H)。
实施例10：化合物S10的合成
实施例10中，将实施例1中化合物1-1替换成相对应的原料1-10，具体结构式为
Figure PCTCN2022130902-appb-000053
1H NMR(500MHz,DMSO-d 6)δ8.56(t,J＝5.8Hz,1H),7.56(ddd,J＝13.4,7.9,1.2Hz,2H),7.44(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.82(s,1H),4.54(s,1H),4.01(dd,J＝17.5,5.8Hz,1H),3.92(dd,J＝17.6,5.7Hz,1H),3.51–3.17(–OCH2CH2),3.39(s,3H),3.07(ddd,J＝11.2,7.2,4.2Hz,1H),2.96–2.87(m,1H),2.86–2.73(m,3H),2.50(ddd,J＝12.0,6.9,4.8Hz,1H),1.74–1.52(m,4H),1.53–1.45(m,1H),1.48–1.39(m,1H),0.88(t,J＝7.1Hz,3H)。
实施例11：化合物S11的合成
实施例11中，将实施例1中化合物1-1替换成相对应的原料1-11，具体结构式为
Figure PCTCN2022130902-appb-000054
1H NMR(500MHz,DMSO-d 6)δ8.56(t,J＝5.8Hz,1H),7.56(ddd,J＝13.4,7.9,1.2Hz,2H),7.44(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.82(s,1H),4.54(s,1H),4.01(dd,J＝17.5,5.8Hz,1H),3.92(dd,J＝17.6,5.7Hz,1H),3.51–3.17(–OCH2CH2),3.39(s,3H),3.07(ddd,J＝11.2,7.2,4.2Hz,1H),2.96–2.87(m,1H),2.86–2.73(m,3H),2.50(ddd,J＝12.0,6.9,4.8Hz,1H),1.74–1.52(m,4H),1.53–1.45(m,1H),1.48–1.39(m,1H),0.88(t,J＝7.1Hz,3H)。
实施例12：化合物S12的合成
实施例12中，将实施例1中化合物1-1替换成相对应的原料1-12，具体结构式为
Figure PCTCN2022130902-appb-000055
1H NMR(500MHz,DMSO-d 6)δ8.66(d,J＝9.3Hz,1H),7.52(ddd,J＝16.6,7.8,1.3Hz,2H),7.45(ddd,J＝7.9,6.8,1.3Hz,1H),7.26(ddd,J＝8.0,6.8,1.3Hz,1H),6.83(s,1H),4.54(s,1H),4.24(m,1H),3.51–3.17(–OCH2CH2),3.39(s,3H),3.06(ddd,J＝12.1,6.4,4.3Hz,1H),2.92(ddd,J＝15.6,6.4,4.3Hz,1H),2.87–2.79(m,1H),2.82–2.71(m,2H),2.46(ddd,J＝11.9,7.0,4.7Hz,1H),1.79–1.52(m,5H),1.45(dq,J＝13.0,7.2Hz,1H),1.32(d,J＝6.8Hz,3H),0.87(t,J＝7.2Hz,3H)。
实施例13：化合物S13的合成
实施例13中，将实施例1中化合物1-1替换成相对应的原料1-13，具体结构式为
Figure PCTCN2022130902-appb-000056
1H NMR(500MHz,DMSO-d 6)δ8.58(d,J＝9.3Hz,1H),7.59–7.48(m,3H),7.27(ddd,J＝8.1,6.8,1.5Hz,1H),6.82(s,1H),4.53(s,1H),4.45(dt,J＝12.3,6.1Hz,1H),4.31–4.17(m,2H),3.75–3.63(m,8H),3.67–3.58(m,2H),3.62–3.47(m,4H),3.50–3.42(m,1H),3.39(s,3H),3.07(ddd,J＝11.9,6.5,4.3Hz,1H),2.94(ddd,J＝15.4,6.3,4.2Hz,1H),2.87–2.72(m,3H),2.51–2.42(m,1H),1.80–1.52(m,8H),1.42(dq,J＝13.0,7.2Hz,1H),0.96–0.88(m,3H),0.91–0.84(m,6H).MS(ESI,m/z):626(M ++1)。
实施例14：化合物S14的合成
实施例14中，将实施例1中化合物1-1替换成相对应的原料1-14，具体结构式为
Figure PCTCN2022130902-appb-000057
1H NMR(500MHz,DMSO-d 6)δ8.83(d,J＝9.3Hz,1H),7.81(dd,J＝8.0,1.3Hz,1H),7.56(dd,J＝8.0,1.3Hz,1H),7.50(ddd,J＝7.9,7.1,1.3Hz,1H),7.31–7.18(m,6H),6.82(s,1H),4.56(s,1H),4.53–4.33(m,3H),3.67(s,4H),3.75–3.58(m,6H),3.58–3.42(m,4H),3.39(s,3H),3.14–3.04(m,2H),3.06–2.91(m,2H),2.92–2.83(m,1H),2.81(ddd,J＝15.6,6.5,4.2Hz,1H),2.73(ddd,J＝11.9,6.5,4.2Hz,1H),2.40–2.31(m,1H),1.77–1.66(m,3H),1.61–1.51(m,1H),1.54–1.40(m,2H),0.86(t,J＝7.2Hz,3H)。MS(ESI,m/z):660(M ++1)。
实施例15：化合物S15的合成
实施例15中，将实施例1中化合物1-1替换成相对应的原料1-15，具体结构式为
Figure PCTCN2022130902-appb-000058
1H NMR(500MHz,DMSO-d 6)δ8.96(d,J＝9.3Hz,1H),7.64(dd,J＝8.0,1.3Hz,1H),7.58–7.47(m,2H),7.26(ddd,J＝7.9,6.9,1.2Hz,1H),6.82(s,1H),4.55–4.44(m,3H),4.38(dt,J＝12.4,6.2Hz,1H),4.00–3.91(m,1H),3.91–3.80(m,2H), 3.77–3.68(m,1H),3.72–3.62(m,8H),3.65–3.57(m,3H),3.58–3.42(m,3H),3.39(s,2H),3.06(ddd,J＝12.1,6.5,4.3Hz,1H),2.93(ddd,J＝15.4,6.3,4.2Hz,1H),2.87–2.76(m,2H),2.79–2.72(m,1H),2.48(ddd,J＝11.9,6.9,4.8Hz,1H),1.75–1.50(m,5H),1.44(dq,J＝13.0,7.2Hz,1H),0.88(t,J＝7.2Hz,3H)。MS(ESI,m/z):600(M ++1)。
实施例16：化合物S16的合成
实施例16中，将实施例1中化合物1-1替换成相对应的原料1-16，具体结构式为
Figure PCTCN2022130902-appb-000059
1H NMR(500MHz,DMSO-d 6)δ9.15(d,J＝9.3Hz,1H),7.54(dt,J＝7.8,1.4Hz,2H),7.45(ddd,J＝8.0,6.9,1.1Hz,1H),7.27(ddd,J＝8.1,6.9,1.3Hz,1H),7.07(s,1H),6.78(s,1H),4.65(dt,J＝9.3,7.3Hz,1H),4.45(dt,J＝12.4,6.2Hz,1H),4.27(dt,J＝12.2,6.2Hz,1H),4.14(s,1H),3.73–3.60(m,10H),3.61(dd,J＝4.0,2.3Hz,1H),3.59–3.42(m,4H),3.39(s,3H),3.14(ddd,J＝12.1,6.4,4.2Hz,1H),3.01(ddd,J＝12.1,6.5,4.1Hz,1H),2.92(ddd,J＝15.6,6.5,4.2Hz,1H),2.86–2.73(m,3H),2.69(dd,J＝16.9,7.4Hz,1H),2.53(ddd,J＝12.0,6.8,4.7Hz,1H),1.77–1.63(m,3H),1.63–1.44(m,3H),0.85(t,J＝7.2Hz,3H)。MS(ESI,m/z):627(M ++1)。
实施例17：化合物S17的合成
实施例17中，将实施例1中化合物1-1替换成相对应的原料1-17，具体结构式为
Figure PCTCN2022130902-appb-000060
Figure PCTCN2022130902-appb-000061
1H NMR(500MHz,DMSO-d 6)δ8.64(t,J＝5.8Hz,1H),7.61(dd,J＝7.8,1.3Hz,1H),7.58–7.49(m,2H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.87(s,1H),4.54(s,1H),4.02(dd,J＝17.6,5.7Hz,1H),3.94(dd,J＝17.6,5.9Hz,1H),3.51–3.17(–OCH2CH2),3.22(t,J＝6.6Hz,1H),3.08(ddd,J＝11.9,6.5,4.2Hz,1H),2.97(ddd,J＝15.6,6.5,4.2Hz,1H),2.87–2.76(m,2H),2.73(ddd,J＝12.1,6.4,4.2Hz,1H),2.48–2.39(m,1H),1.79–1.40(m,6H),0.85(t,J＝7.2Hz,3H)。
实施例18：化合物S18的合成
实施例18中，将实施例1中化合物1-1替换成相对应的原料1-18，具体结构式为
Figure PCTCN2022130902-appb-000062
1H NMR(500MHz,DMSO-d 6)δ8.60(d,J＝9.2Hz,1H),7.55–7.50(m,1H),7.52–7.41(m,2H),7.26(ddd,J＝8.1,6.8,1.5Hz,1H),6.88(s,1H),4.54(s,1H),4.26(dq,J＝9.2,6.8Hz,1H),3.51–3.17(–OCH 2CH 2),3.06(ddd,J＝12.1,6.5,4.2Hz,1H),2.93(ddd,J＝15.6,6.4,4.2Hz,1H),2.86–2.78(m,1H),2.81–2.71(m,2H),2.61(t,J＝6.6Hz,1H),2.48(ddd,J＝11.8,6.9,4.8Hz,1H),1.76–1.56(m,5H),1.60–1.52(m,1H),1.43(dq,J＝12.8,7.2Hz,1H),1.27(d,J＝6.8Hz,3H),0.88(t,J＝7.2Hz,3H)。
实施例19：化合物S19的合成
实施例19中，将实施例1中化合物1-1替换成相对应的原料1-19，具体结构式为
Figure PCTCN2022130902-appb-000063
1H NMR(500MHz,DMSO-d 6)δ8.64(t,J＝5.8Hz,1H),7.61(dd,J＝7.8,1.3Hz,1H),7.58–7.49(m,2H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.87(s,1H),4.54(s,1H),4.02(dd,J＝17.6,5.7Hz,1H),3.94(dd,J＝17.6,5.9Hz,1H),3.51–3.17(–OCH 2CH 2),3.22(t,J＝6.6Hz,1H),3.08(ddd,J＝11.9,6.5,4.2Hz,1H),2.97(ddd,J＝15.6,6.5,4.2Hz,1H),2.87–2.76(m,2H),2.73(ddd,J＝12.1,6.4,4.2Hz,1H),2.48–2.39(m,1H),1.79–1.40(m,6H),0.85(t,J＝7.2Hz,3H)。
实施例20：化合物S20的合成
实施例20中，将实施例1中化合物1-1替换成相对应的原料1-20，具体结构式为
Figure PCTCN2022130902-appb-000064
1H NMR(500MHz,DMSO-d 6)δ8.60(d,J＝9.2Hz,1H),7.55–7.50(m,1H),7.52–7.41(m,2H),7.26(ddd,J＝8.1,6.8,1.5Hz,1H),6.88(s,1H),4.54(s,1H),4.26(dq,J＝9.2,6.8Hz,1H),3.51–3.17(–OCH 2CH 2),3.06(ddd,J＝12.1,6.5,4.2Hz,1H),2.93(ddd,J＝15.6,6.4,4.2Hz,1H),2.86–2.78(m,1H),2.81–2.71(m,2H),2.61(t,J＝6.6Hz,1H),2.48(ddd,J＝11.8,6.9,4.8Hz,1H),1.76–1.56(m,5H),1.60–1.52(m,1H),1.43(dq,J＝12.8,7.2Hz,1H),1.27(d,J＝6.8Hz,3H),0.88(t,J＝7.2Hz,3H)。
实施例21：化合物S21的合成
实施例21中，将实施例1中化合物1-1替换成相对应的原料1-21，具体结构式为
Figure PCTCN2022130902-appb-000065
1H NMR(500MHz,DMSO-d 6)δ8.64(t,J＝5.8Hz,1H),7.61(dd,J＝7.8,1.3Hz,1H),7.58–7.49(m,2H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.87(s,1H),4.54(s,1H),4.02(dd,J＝17.6,5.7Hz,1H),3.94(dd,J＝17.6,5.9Hz,1H),3.51–3.17(–OCH 2CH 2),3.22(t,J＝6.6Hz,1H),3.08(ddd,J＝11.9,6.5,4.2Hz,1H),2.97(ddd,J＝15.6,6.5,4.2Hz,1H),2.87–2.76(m,2H),2.73(ddd,J＝12.1,6.4,4.2Hz,1H),2.48–2.39(m,1H),1.79–1.40(m,6H),0.85(t,J＝7.2Hz,3H)。
实施例22：化合物S22的合成
实施例22中，将实施例1中化合物1-1替换成相对应的原料1-22，具体结构式为
Figure PCTCN2022130902-appb-000066
1H NMR(500MHz,DMSO-d 6)δ8.60(d,J＝9.2Hz,1H),7.55–7.50(m,1H),7.52–7.41(m,2H),7.26(ddd,J＝8.1,6.8,1.5Hz,1H),6.88(s,1H),4.54(s,1H),4.26(dq,J＝9.2,6.8Hz,1H),3.51–3.17(–OCH2CH2),3.06(ddd,J＝12.1,6.5,4.2Hz,1H),2.93(ddd,J＝15.6,6.4,4.2Hz,1H),2.86–2.78(m,1H),2.81–2.71(m,2H),2.61(t,J＝6.6Hz,1H),2.48(ddd,J＝11.8,6.9,4.8Hz,1H),1.76–1.56(m, 5H),1.60–1.52(m,1H),1.43(dq,J＝12.8,7.2Hz,1H),1.27(d,J＝6.8Hz,3H),0.88(t,J＝7.2Hz,3H)。
实施例23：化合物S23的合成
实施例23中，将实施例1中化合物1-1替换成相对应的原料1-23，具体结构式为
Figure PCTCN2022130902-appb-000067
1H NMR(500MHz,DMSO-d 6)δ8.65(t,J＝5.8Hz,1H),7.56(ddd,J＝16.1,7.8,1.2Hz,2H),7.45(ddd,J＝7.9,7.0,1.2Hz,1H),7.26(ddd,J＝8.1,6.9,1.3Hz,1H),6.82(s,1H),4.54(s,1H),4.34(dt,J＝12.2,6.5Hz,1H),4.11(dt,J＝12.1,6.5Hz,1H),3.99(dd,J＝17.5,5.8Hz,1H),3.89(dd,J＝17.6,5.9Hz,1H),3.85–3.74(m,2H),3.06(ddd,J＝12.1,6.4,4.2Hz,1H),2.92(ddd,J＝15.6,6.4,4.3Hz,1H),2.88–2.71(m,4H),2.51–2.42(m,1H),1.75–1.48(m,5H),1.42(dq,J＝13.0,7.2Hz,1H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):424(M ++1)。
实施例24：化合物S24的合成
实施例24中，将实施例1中化合物1-1替换成相对应的原料1-24，具体结构式为
Figure PCTCN2022130902-appb-000068
1H NMR(500MHz,DMSO-d 6)δ8.61(t,J＝5.8Hz,1H),7.56–7.50(m,1H),7.51–7.42(m,2H),7.26(ddd,J＝8.1,6.4,1.9Hz,1H),6.82(s,1H),4.54(s,1H),4.25(dt,J＝12.3,6.1Hz,1H),4.10(dt,J＝12.3,6.2Hz,1H),3.97(dd,J＝17.5,5.8 Hz,1H),3.90(dd,J＝17.5,5.8Hz,1H),3.84–3.49(m,6H),3.44(dt,J＝12.3,6.3Hz,1H),3.06(ddd,J＝11.9,6.5,4.2Hz,1H),2.93(ddd,J＝15.4,6.4,4.2Hz,1H),2.86–2.71(m,3H),2.48(ddd,J＝11.9,6.9,4.7Hz,1H),1.75–1.51(m,5H),1.43(dq,J＝13.0,7.2Hz,1H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):468(M ++1)。
实施例25：化合物S25的合成
实施例25中，将实施例1中化合物1-1替换成相对应的原料1-25，具体结构式为
Figure PCTCN2022130902-appb-000069
1H NMR(500MHz,DMSO-d 6)δ8.62(t,J＝5.8Hz,1H),7.66–7.60(m,1H),7.53(dd,J＝7.6,1.2Hz,1H),7.47(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝7.9,6.9,1.2Hz,1H),6.82(s,1H),4.54(s,1H),4.31(dt,J＝12.3,6.1Hz,1H),4.14(dt,J＝12.3,6.1Hz,1H),4.01(dd,J＝17.5,5.8Hz,1H),3.91(dd,J＝17.6,5.7Hz,1H),3.84–3.70(m,3H),3.73–3.66(m,3H),3.69–3.61(m,2H),3.65–3.54(m,2H),3.48(dt,J＝12.4,6.3Hz,1H),3.06(ddd,J＝12.1,6.4,4.3Hz,1H),2.90(ddd,J＝15.4,6.2,4.2Hz,1H),2.87–2.70(m,3H),2.44(ddd,J＝12.0,6.9,4.8Hz,1H),1.76–1.42(m,6H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):512(M ++1)。
实施例26：化合物S26的合成
Figure PCTCN2022130902-appb-000070
步骤一：长春西汀脱乙酯产物的合成
Figure PCTCN2022130902-appb-000071
将长春西汀10g(28.5mmol)溶于乙醇中，向上述反应液中加入60mL的NaOH溶液(1mol/L)中，加热回流，溶液逐渐由浑浊变澄清，TLC点板检测反应进度。待原料完全消失后，将反应液置于0℃下用稀盐酸调节pH值至3，然后减压旋掉乙醇，过滤，收集滤饼，真空干燥，得长春西汀脱乙酯粗品(9.0g，98％)，直接投下一步。
1H NMR(500MHz,DMSO-d6)δ9.80(s,1H),7.56(ddd,J＝19.5,7.9,1.2Hz,2H),7.47(ddd,J＝7.9,7.0,1.2Hz,1H),7.27(ddd,J＝8.1,6.9,1.3Hz,1H),5.79(s,1H),4.57(s,1H),3.06(ddd,J＝11.9,6.5,4.2Hz,1H),2.94(ddd,J＝15.6,6.4,4.2Hz,1H),2.86–2.77(m,2H),2.75(ddd,J＝12.1,6.4,4.2Hz,1H),2.52–2.43(m,1H),1.76–1.51(m,5H),1.42(dq,J＝13.0,7.2Hz,1H),0.88(t,J＝7.2Hz,3H)。
步骤二：化合物S1的合成
Figure PCTCN2022130902-appb-000072
将长春西汀脱乙酯产物(200mg，0.62mmol)，化合物1-26(155mg，0.62mmol)，DCC(156mg，0.76mmol)，DMAP(8mg，0.1mmol)，在室温下溶于2mL二氯甲烷中，氮气保护，常温反应12小时。抽滤除去不溶物，滤液加水，二氯甲烷萃取(5mL×3)，合并有机相，饱和食盐水(2mL)洗1次，无水硫酸钠干燥，过滤，浓缩，柱层析分离(二氯甲烷:甲醇＝30:1)纯化得白色固体S26(278mg，81.0％)。 1H NMR(500MHz,DMSO-d 6)δ8.61(t,J＝5.8Hz,1H),7.52(dt,J＝7.8,0.9Hz,1H),7.51–7.42(m,2H),7.26(ddd,J＝8.1,6.1,2.0Hz,1H),6.81(s,1H),4.33(dt,J＝12.2,6.1Hz,1H),4.12(dt,J＝12.4,6.3Hz,1H),4.06–3.87(m, 3H),3.84–3.72(m,2H),3.76–3.66(m,6H),3.70–3.57(m,6H),3.51(dt,J＝11.8,6.6Hz,1H),3.14(ddd,J＝12.1,6.4,4.2Hz,1H),3.01(ddd,J＝12.1,6.4,4.2Hz,1H),2.91(ddd,J＝15.4,6.4,4.1Hz,1H),2.86–2.73(m,2H),2.56(ddd,J＝12.0,7.1,4.8Hz,1H),1.78–1.64(m,3H),1.61–1.49(m,1H),1.51–1.40(m,2H),0.88(t,J＝7.2Hz,3H)。MS(ESI,m/z):556(M ++1)。
实施例27：化合物S27的合成
实施例27中，将实施例1中化合物1-1替换成相对应的原料1-27，具体结构式为
Figure PCTCN2022130902-appb-000073
1H NMR(500MHz,DMSO-d 6)δ8.67(t,J＝5.8Hz,1H),7.62(dd,J＝7.8,1.3Hz,1H),7.53(dd,J＝8.0,1.3Hz,1H),7.43(ddd,J＝8.0,7.0,1.3Hz,1H),7.26(ddd,J＝8.1,6.9,1.3Hz,1H),6.81(s,1H),4.53(s,1H),4.38(dt,J＝12.2,6.1Hz,1H),4.13(dt,J＝12.4,6.2Hz,1H),4.00(dd,J＝17.5,5.8Hz,1H),3.94(dd,J＝17.6,5.9Hz,1H),3.83–3.74(m,1H),3.77–3.70(m,3H),3.74–3.57(m,16H),3.46(dt,J＝12.1,6.5Hz,1H),3.05(ddd,J＝12.1,6.4,4.2Hz,1H),2.85–2.70(m,2H),2.51–2.42(m,1H),1.75–1.41(m,6H),0.85(t,J＝7.2Hz,3H)。MS(ESI,m/z):660(M ++1)。
实施例28：化合物S28的合成
实施例28中，将实施例1中化合物1-1替换成相对应的原料1-28，具体结构式为
Figure PCTCN2022130902-appb-000074
Figure PCTCN2022130902-appb-000075
1H NMR(500MHz,DMSO-d 6)δ8.62(t,J＝5.8Hz,1H),7.62(dd,J＝7.8,1.3Hz,1H),7.54(dd,J＝7.9,1.2Hz,1H),7.42(ddd,J＝7.8,6.9,1.2Hz,1H),7.25(ddd,J＝8.1,7.0,1.3Hz,1H),4.40(dt,J＝12.3,6.1Hz,1H),4.15–3.99(m,3H),3.96(dd,J＝17.6,5.7Hz,1H),3.83–3.54(m,24H),3.12(ddd,J＝12.1,6.4,4.2Hz,1H),3.00(ddd,J＝12.1,6.6,4.2Hz,1H),2.90(ddd,J＝15.4,6.5,4.2Hz,1H),2.84–2.72(m,2H),2.63(ddd,J＝12.0,7.0,4.8Hz,1H),1.80–1.67(m,2H),1.63–1.39(m,4H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):644(M ++1)。
实施例29：化合物S29的合成
实施例29中，将实施例1中化合物1-1替换成相对应的原料1-29，具体结构式为
Figure PCTCN2022130902-appb-000076
1H NMR(500MHz,DMSO-d 6)δ8.66(d,J＝9.2Hz,1H),7.55(ddd,J＝11.9,7.9,1.3Hz,2H),7.47(ddd,J＝8.0,6.9,1.2Hz,1H),7.25(ddd,J＝8.0,6.9,1.2Hz,1H),6.82(s,1H),4.53(s,1H),4.45(dt,J＝12.3,6.1Hz,1H),4.30–4.21(m,2H),3.84–3.44(m,16H),3.06(ddd,J＝12.1,6.5,4.3Hz,1H),2.93(ddd,J＝15.6,6.4,4.3Hz,1H),2.82(ddd,J＝15.6,6.4,4.2Hz,1H),2.82–2.75(m,1H),2.79–2.72(m,1H),2.51–2.42(m,1H),1.74–1.49(m,5H),1.41(dq,J＝12.8,7.2Hz,1H),1.29(d,J＝6.8Hz,2H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):570(M ++1)。
实施例30：化合物S30的合成
实施例30中，将实施例1中化合物1-1替换成相对应的原料1-30，具体结构式为
Figure PCTCN2022130902-appb-000077
1H NMR(500MHz,DMSO-d 6)δ8.70(d,J＝9.1Hz,1H),7.55(ddd,J＝12.1,7.8,1.2Hz,2H),7.45(ddd,J＝8.0,6.9,1.3Hz,1H),7.27(ddd,J＝8.0,6.9,1.3Hz,1H),6.82(s,1H),4.53(s,1H),4.38(dt,J＝12.2,6.1Hz,1H),4.21–4.11(m,2H),3.83–3.43(m,15H),3.07(ddd,J＝12.1,6.4,4.2Hz,1H),2.93(ddd,J＝15.6,6.4,4.3Hz,1H),2.87–2.72(m,3H),2.51–2.42(m,1H),2.15–2.02(m,J＝6.6Hz,1H),1.74–1.52(m,5H),1.41(dq,J＝13.0,7.2Hz,1H),0.95(dd,J＝25.0,6.7Hz,6H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):598(M ++1)。
实施例31：化合物S31的合成
实施例31中，将实施例1中化合物1-1替换成相对应的原料1-31，具体结构式为
Figure PCTCN2022130902-appb-000078
1H NMR(500MHz,DMSO-d 6)δ8.59(d,J＝9.3Hz,1H),7.53(dt,J＝7.8,0.8Hz,1H),7.50–7.41(m,2H),7.27(ddd,J＝8.1,5.8,2.5Hz,1H),6.82(s,1H),4.55–4.37(m,3H),4.29(dt,J＝12.2,6.1Hz,1H),3.83–3.50(m,15H),3.06(ddd,J＝12.1,6.4,4.2Hz,1H),2.93(ddd,J＝15.6,6.4,4.3Hz,1H),2.86–2.71(m,3H),2.46(ddd,J＝11.8,6.8,4.8Hz,1H),1.81(dt,J＝13.6,6.8Hz,1H),1.77–1.51(m,7H),1.41(dq,J＝13.0,7.2Hz,1H),0.95–0.85(m,9H).MS(ESI,m/z):612(M ++1)。
实施例32：化合物S32的合成
实施例32中，将实施例1中化合物1-1替换成相对应的原料1-32，具体结构式为
Figure PCTCN2022130902-appb-000079
1H NMR(500MHz,DMSO-d 6)δ8.51(d,J＝9.1Hz,1H),7.53(dd,J＝8.0,1.3Hz,1H),7.45(ddd,J＝8.1,6.9,1.3Hz,1H),7.39(dd,J＝7.8,1.4Hz,1H),7.27(ddd,J＝8.0,6.9,1.4Hz,1H),6.82(s,1H),4.29(dd,J＝9.0,6.6Hz,1H),4.22(dt,J＝12.3,6.1Hz,1H),4.17–4.08(m,2H),3.83–3.55(m,14H),3.48(ddt,J＝13.1,12.1,6.4Hz,2H),3.12(dt,J＝12.1,5.3Hz,1H),2.96(ddd,J＝12.1,5.9,4.7Hz,1H),2.95–2.84(m,2H),2.86–2.77(m,1H),2.57(ddd,J＝11.7,6.9,4.6Hz,1H),1.83–1.46(m,7H),1.40–1.28(m,1H),0.94–0.82(m,9H).MS(ESI,m/z):612(M ++1)。
实施例33：化合物S33的合成
实施例33中，将实施例1中化合物1-1替换成相对应的原料1-33，具体结构式为
Figure PCTCN2022130902-appb-000080
1H NMR(500MHz,DMSO-d 6)δ8.74(d,J＝9.3Hz,1H),7.60–7.54(m,1H),7.48–7.39(m,2H),7.31–7.18(m,6H),6.82(s,1H),4.59(dt,J＝9.3,7.7Hz,1H),4.55–4.44(m,2H),4.27(dt,J＝12.4,6.2Hz,1H),3.78(ddt,J＝12.8,7.5,6.5Hz, 1H),3.75–3.64(m,6H),3.68–3.61(m,3H),3.64–3.43(m,5H),3.11–2.99(m,2H),3.01–2.90(m,2H),2.88–2.72(m,3H),2.51–2.42(m,1H),1.75–1.48(m,5H),1.41(dq,J＝12.8,7.2Hz,1H),0.86(t,J＝7.2Hz,3H)。MS(ESI,m/z):646(M ++1)。
实施例34：化合物S34的合成
实施例34中，将实施例1中化合物1-1替换成相对应的原料1-34，具体结构式为
Figure PCTCN2022130902-appb-000081
1H NMR(500MHz,DMSO-d 6)δ9.05(d,J＝9.3Hz,1H),7.57–7.51(m,2H),7.44(ddd,J＝8.0,7.0,1.3Hz,1H),7.27(ddd,J＝8.1,7.0,1.3Hz,1H),6.82(s,1H),4.55–4.47(m,2H),4.46(dd,J＝12.3,6.1Hz,1H),4.28(dt,J＝12.4,6.2Hz,1H),3.96–3.87(m,1H),3.89–3.50(m,18H),3.05–2.96(m,1H),2.96–2.83(m,3H),2.86–2.73(m,1H),2.50–2.41(m,1H),1.75–1.54(m,5H),1.42(dq,J＝12.8,7.2Hz,1H),0.88(t,J＝7.1Hz,3H)。MS(ESI,m/z):586(M ++1)。
实施例35：化合物S35的合成
实施例35中，将实施例1中化合物1-1替换成相对应的原料1-35，具体结构式为
Figure PCTCN2022130902-appb-000082
1H NMR(500MHz,DMSO-d 6)δ8.81(d,J＝9.1Hz,1H),7.55(td,J＝8.1,1.3Hz,2H),7.43(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.1,7.0,1.3Hz,1H),6.82(s,1H),4.46(h,J＝6.5Hz,1H),4.31(dd,J＝9.0,7.0Hz,1H),4.16(td,J＝6.3,1.6Hz,2H),4.09(s,1H),3.99(d,J＝6.3Hz,1H),3.83–3.74(m,1H),3.77–3.69(m,1H),3.72–3.64(m,7H),3.68–3.57(m,3H),3.55(dq,J＝12.3,6.2Hz,2H),3.53–3.44(m,1H),3.13(ddd,J＝12.1,6.4,4.2Hz,1H),3.01(ddd,J＝12.1,6.4,4.2Hz,1H),2.90(ddd,J＝15.4,6.5,4.2Hz,1H),2.86–2.74(m,2H),2.60(ddd,J＝12.0,7.0,4.8Hz,1H),1.73–1.43(m,6H),1.13(d,J＝6.6Hz,3H),0.84(t,J＝7.2Hz,3H)。MS(ESI,m/z):600(M ++1)。
实施例36：化合物S36的合成
实施例36中，将实施例1中化合物1-1替换成相对应的原料1-36，具体结构式为
Figure PCTCN2022130902-appb-000083
1H NMR(500MHz,DMSO-d 6)δ8.53(d,J＝9.3Hz,1H),7.59–7.47(m,3H),7.27(ddd,J＝8.1,5.9,2.5Hz,1H),6.92(s,2H),6.84(s,1H),4.38–4.24(m,2H),4.16(dt,J＝9.3,6.0Hz,1H),4.03(s,1H),3.83–3.71(m,1H),3.74–3.66(m,6H),3.69–3.58(m,5H),3.61–3.50(m,3H),3.14(ddd,J＝12.1,6.4,4.2Hz,1H),3.02(ddd,J＝12.3,6.5,4.3Hz,1H),2.95(ddd,J＝15.4,6.6,4.2Hz,1H),2.87–2.74(m,2H),2.66–2.57(m,1H),2.34(dt,J＝15.7,7.8Hz,1H),2.26(dt,J＝15.9,8.0Hz,1H),1.97–1.80(m,2H),1.77–1.64(m,3H),1.64–1.53(m,1H),1.54–1.41(m,2H),0.88(t,J＝7.2Hz,3H)。MS(ESI,m/z):627(M ++1)。
实施例37：化合物S37的合成
实施例37中，将实施例1中化合物1-1替换成相对应的原料1-37，具体结构式为
Figure PCTCN2022130902-appb-000084
1H NMR(500MHz,DMSO-d 6)δ9.44(d,J＝9.3Hz,1H),9.07(s,1H),7.68–7.62(m,1H),7.52(dd,J＝7.8,1.3Hz,1H),7.42(ddd,J＝8.0,7.0,1.3Hz,1H),7.36–7.28(m,1H),7.28–7.20(m,2H),7.16–7.07(m,2H),6.84(d,J＝1.8Hz,1H),6.78(s,1H),4.67(dt,J＝9.3,7.8Hz,1H),4.56(s,1H),4.48(dt,J＝12.4,6.2Hz,1H),4.28(dt,J＝12.2,6.2Hz,1H),3.83–3.73(m,1H),3.76–3.69(m,1H),3.72–3.62(m,7H),3.65–3.57(m,3H),3.59–3.50(m,2H),3.46–3.37(m,1H),3.17–3.07(m,2H),3.04–2.93(m,2H),2.90–2.75(m,3H),2.54–2.45(m,1H),1.76–1.67(m,1H),1.67(ddd,J＝9.1,4.6,2.0Hz,2H),1.67–1.57(m,2H),1.60–1.52(m,1H),1.44(dq,J＝13.0,7.2Hz,1H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):685(M ++1)。
实施例38：化合物S38的合成
实施例38中，将实施例1中化合物1-1替换成相对应的原料1-38，具体结构式为
Figure PCTCN2022130902-appb-000085
1H NMR(500MHz,DMSO-d 6)δ8.70(d,J＝9.1Hz,1H),7.68(dd,J＝8.0,1.3Hz,1H),7.53(dd,J＝7.9,1.3Hz,1H),7.42(ddd,J＝8.0,6.9,1.3Hz,1H),7.31–7.21(m,2H),6.82(s,1H),5.97(t,J＝4.4Hz,1H),5.69(d,J＝6.8Hz,1H),5.45(d,J＝6.8Hz,1H),4.50(dt,J＝12.3,6.2Hz,1H),4.43(dt,J＝9.3,6.0Hz,1H),4.33–4.24(m,2H),3.78(ddt,J＝12.3,7.7,6.6Hz,1H),3.75–3.66(m,6H),3.69–3.57(m,5H),3.60–3.48(m,3H),3.45(dtd,J＝14.3,5.7,4.3Hz,1H),3.33(dtd,J＝14.3,5.8,4.3Hz,1H),3.09(ddd,J＝11.9,6.4,4.3Hz,1H),2.99–2.90(m,2H),2.87(ddd,J＝12.1,6.6,4.4Hz,1H),2.80(ddd,J＝15.2,6.4,4.3Hz,1H),2.47(ddd,J＝11.9,7.1,4.7Hz,1H),2.16–1.99(m,2H),1.81–1.63(m,2H),1.63–1.43(m,4H),0.88(t,J＝7.2Hz,3H)。MS(ESI,m/z):641(M ++1)。
实施例39：化合物S39的合成
实施例39中，将实施例1中化合物1-1替换成相对应的原料1-39，具体结构式为
Figure PCTCN2022130902-appb-000086
1H NMR(500MHz,DMSO-d 6)δ8.74(d,J＝9.3Hz,1H),7.56–7.49(m,2H),7.46(ddd,J＝7.9,6.8,1.3Hz,1H),7.27(ddd,J＝8.1,6.9,1.4Hz,1H),6.82(s,1H),4.52–4.40(m,2H),4.25(dt,J＝12.4,6.2Hz,1H),4.02(s,1H),3.85–3.69(m,3H),3.72–3.66(m,2H),3.67(ddd,J＝7.0,3.1,1.3Hz,6H),3.67–3.57(m,3H),3.61–3.48(m,2H),3.48–3.39(m,1H),3.18–3.08(m,2H),3.01(ddd,J＝12.3,6.6,4.2Hz,1H),2.96–2.88(m,1H),2.91–2.84(m,1H),2.80–2.70(m,3H),2.58(ddd,J＝11.8,6.8,4.7Hz,1H),1.77–1.59(m,4H),1.59–1.39(m,2H),0.88(t,J＝7.2Hz,3H)。MS(ESI,m/z):585(M ++1)。
实施例40：化合物S40的合成
实施例40中，将实施例1中化合物1-1替换成相对应的原料1-40，具体结构式为
Figure PCTCN2022130902-appb-000087
1H NMR(500MHz,DMSO-d 6)δ8.70(d,J＝9.3Hz,1H),7.60–7.48(m,3H),7.27(ddd,J＝8.1,6.9,1.4Hz,1H),6.82(s,1H),4.55–4.44(m,2H),4.32–4.22(m,2H),3.83–3.44(m,15H),3.06(ddd,J＝12.1,6.4,4.2Hz,1H),2.93(ddd,J＝15.6,6.4,4.2Hz,1H),2.86–2.64(m,4H),2.57–2.40(m,2H),1.80–1.70(m,1H),1.74–1.63(m,2H),1.66–1.55(m,3H),1.53(t,J＝6.1Hz,2H),1.48–1.22(m,5H),1.10(dp,J＝13.2,6.6Hz,1H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):627(M ++1)。
实施例41：化合物S41的合成
实施例41中，将实施例1中化合物1-1替换成相对应的原料1-41，具体结构式为
Figure PCTCN2022130902-appb-000088
1H NMR(500MHz,DMSO-d 6)δ9.11(d,J＝9.1Hz,1H),7.63(dd,J＝7.8,1.4Hz,1H),7.60–7.49(m,2H),7.27(ddd,J＝8.1,7.0,1.3Hz,1H),7.05(s,2H),6.78(s,1H),4.60(dt,J＝9.3,7.3Hz,1H),4.53(s,1H),4.28(ddt,J＝24.5,12.3,6.2Hz,2H),3.83–3.45(m,14H),3.10(ddd,J＝11.9,6.5,4.2Hz,1H),3.02(ddd,J＝15.4,6.5,4.2Hz,1H),2.89–2.66(m,5H),2.46(ddd,J＝11.8,6.8,4.6Hz,1H),1.75–1.67(m,1H),1.71–1.62(m,2H),1.66–1.41(m,4H),0.85(t,J＝7.2Hz,3H)。MS(ESI,m/z):613(M ++1)。
实施例42：化合物S42的合成
实施例42中，将实施例1中化合物1-1替换成相对应的原料1-42，具体结构式为
Figure PCTCN2022130902-appb-000089
1H NMR(500MHz,DMSO-d 6)δ9.33(d,J＝9.3Hz,1H),7.53(dd,J＝8.0,1.3Hz,1H),7.45(ddd,J＝8.1,6.9,1.3Hz,1H),7.40(dd,J＝7.8,1.5Hz,1H),7.27(ddd,J＝8.1,6.9,1.5Hz,1H),6.78(s,1H),4.80–4.72(m,2H),4.32(dt,J＝12.4,6.1Hz,1H),4.30–4.21(m,2H),3.86(dt,J＝12.3,6.6Hz,1H),3.83–3.72(m,1H),3.76–3.62(m,9H),3.66–3.58(m,1H),3.52(h,J＝6.1Hz,2H),3.40(dt,J＝12.3,6.5Hz,1H),3.14–3.06(m,1H),3.01–2.86(m,3H),2.87–2.75(m,2H),2.74(dd,J＝16.3,7.3Hz,1H),2.62–2.53(m,1H),1.77–1.46(m,7H),0.85(t,J＝7.2Hz,3H)。MS(ESI,m/z):614(M ++1)。
实施例43：化合物S43的合成
实施例43中，将实施例1中化合物1-1替换成相对应的原料1-43，具体结构式为
Figure PCTCN2022130902-appb-000090
1H NMR(500MHz,DMSO-d 6)δ8.53(d,J＝9.3Hz,1H),7.52(dt,J＝7.9,0.9Hz,1H),7.49–7.42(m,2H),7.27(ddd,J＝8.1,4.9,3.3Hz,1H),6.84(s,1H),4.53(s,1H),4.48–4.38(m,2H),4.36–4.22(m,2H),3.83–3.75(m,1H),3.79–3.73(m, 1H),3.77–3.66(m,3H),3.70–3.59(m,6H),3.63–3.55(m,1H),3.54–3.44(m,2H),3.06(ddd,J＝11.9,6.5,4.2Hz,1H),2.95–2.83(m,2H),2.80(ddd,J＝15.6,6.4,4.2Hz,1H),2.70(ddd,J＝12.1,6.4,4.2Hz,1H),2.39–2.17(m,4H),2.11(dtd,J＝12.8,8.1,5.9Hz,1H),1.77–1.63(m,3H),1.57(dtt,J＝13.2,7.0,4.8Hz,1H),1.49(ddd,J＝12.1,7.4,4.9Hz,1H),1.41(dq,J＝12.8,7.2Hz,1H),0.85(t,J＝7.2Hz,3H)。MS(ESI,m/z):628(M ++1)。
实施例44：化合物S44的合成
实施例44中，将实施例1中化合物1-1替换成相对应的原料1-44，具体结构式为
Figure PCTCN2022130902-appb-000091
1H NMR(500MHz,DMSO-d 6)δ8.63(d,J＝9.3Hz,1H),7.70(s,1H),7.58(ddd,J＝14.4,7.9,1.3Hz,2H),7.50(ddd,J＝8.0,6.9,1.3Hz,1H),7.25(ddd,J＝8.0,6.9,1.3Hz,1H),6.98(dt,J＝8.7,1.0Hz,2H),6.82(s,1H),6.70–6.64(m,2H),4.75(dt,J＝9.3,7.7Hz,1H),4.56(s,1H),4.30(td,J＝6.1,1.6Hz,2H),3.83–3.73(m,1H),3.76–3.70(m,1H),3.73–3.63(m,8H),3.67–3.47(m,5H),3.14–3.05(m,2H),3.03(ddt,J＝13.9,7.7,1.1Hz,1H),2.93(ddd,J＝15.6,6.4,4.3Hz,1H),2.89–2.78(m,2H),2.72(ddd,J＝11.9,6.4,4.3Hz,1H),2.41–2.33(m,1H),1.74–1.48(m,6H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):662(M ++1)。
实施例45：化合物S45的合成
实施例45中，将实施例1中化合物1-1替换成相对应的原料1-45，具体结构式为
Figure PCTCN2022130902-appb-000092
1H NMR(500MHz,DMSO-d 6)δ8.70(d,J＝9.3Hz,1H),8.35(dd,J＝2.0,1.1Hz,1H),7.67(dd,J＝7.6,1.4Hz,1H),7.59(dd,J＝7.7,1.2Hz,1H),7.50(ddd,J＝8.0,6.9,1.3Hz,1H),7.32(t,J＝2.0Hz,1H),7.25(ddd,J＝8.1,7.0,1.3Hz,1H),6.83(s,1H),4.73(dt,J＝9.3,7.8Hz,1H),4.55–4.44(m,2H),4.28(dt,J＝12.4,6.2Hz,1H),3.83–3.43(m,15H),3.22–3.13(m,1H),3.07(ddd,J＝11.9,6.5,4.2Hz,1H),3.03–2.92(m,2H),2.85(ddd,J＝15.6,6.4,4.2Hz,1H),2.83–2.73(m,2H),2.52–2.43(m,1H),1.75–1.51(m,6H),1.43(dq,J＝12.8,7.2Hz,1H),0.87(t,J＝7.1Hz,3H)。MS(ESI,m/z):636(M ++1)。
实施例46：化合物S46的合成
实施例46中，将实施例1中化合物1-1替换成相对应的原料1-46，具体结构式为
Figure PCTCN2022130902-appb-000093
1H NMR(500MHz,DMSO-d 6)δ8.93(d,J＝9.3Hz,1H),7.54(ddd,J＝7.6,4.2,1.2Hz,2H),7.46(ddd,J＝7.9,7.0,1.2Hz,1H),7.26(ddd,J＝8.1,6.9,1.3Hz,1H),6.82(s,1H),4.60–4.51(m,2H),4.45(dt,J＝12.2,6.1Hz,1H),4.26(dt,J＝12.2,6.1Hz,1H),3.78(ddt,J＝12.8,7.5,6.5Hz,1H),3.75–3.44(m,14H),3.12–3.01(m,2H),2.98–2.87(m,2H),2.87–2.74(m,3H),2.54–2.45(m,1H),1.86–1.80(m,1H),1.74–1.53(m,5H),1.44(dq,J＝13.0,7.2Hz,1H),0.86(t,J＝7.2 Hz).MS(ESI,m/z):602(M ++1)。
实施例47：化合物S47的合成
实施例47中，将实施例1中化合物1-1替换成相对应的原料1-47，具体结构式为
Figure PCTCN2022130902-appb-000094
1H NMR(500MHz,DMSO-d 6)δ8.86(t,J＝5.8Hz,1H),7.88(d,J＝9.3Hz,1H),7.56(ddd,J＝20.3,7.8,1.3Hz,2H),7.46(ddd,J＝8.0,7.0,1.3Hz,1H),7.27(ddd,J＝8.0,7.0,1.3Hz,1H),6.82(s,1H),4.53(s,1H),4.47–4.38(m,1H),4.35(t,J＝6.2Hz,2H),3.96(dd,J＝17.5,5.8Hz,1H),3.90–3.44(m,13H),3.05(ddd,J＝11.9,6.5,4.2Hz,1H),2.92(ddd,J＝15.6,6.4,4.2Hz,1H),2.86–2.70(m,3H),2.49–2.40(m,1H),1.77–1.51(m,5H),1.42(dq,J＝13.0,7.2Hz,1H),1.32(d,J＝6.8Hz,3H),0.89(t,J＝7.1Hz,3H)。MS(ESI,m/z):660583(M ++1)。
实施例48：化合物S48的合成
实施例48中，将实施例1中化合物1-1替换成相对应的原料1-48，具体结构式为
Figure PCTCN2022130902-appb-000095
1H NMR(500MHz,DMSO-d 6)δ8.81(t,J＝5.8Hz,1H),8.14(d,J＝9.3Hz,1H),7.52(ddd,J＝10.7,8.1,1.4Hz,2H),7.42(ddd,J＝7.8,7.0,1.3Hz,1H),7.25(ddd,J＝8.0,6.9,1.3Hz,1H),6.82(s,1H),4.53(dt,J＝12.4,6.2Hz,1H),4.33–4.22(m,2H),4.10–3.98(m,3H),3.96–3.85(m,3H),3.85–3.46(m,15H),3.13 (ddd,J＝12.1,6.4,4.2Hz,1H),3.01(ddd,J＝12.1,6.6,4.2Hz,1H),2.92(ddd,J＝15.4,6.4,4.1Hz,1H),2.85–2.73(m,2H),2.55(ddd,J＝11.7,6.9,4.7Hz,1H),1.77–1.63(m,3H),1.54(dtt,J＝12.8,7.4,4.8Hz,1H),1.48–1.37(m,2H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):643(M ++1)。
实施例49：化合物S49的合成
实施例49中，将实施例1中化合物1-1替换成相对应的原料1-49，具体结构式为
Figure PCTCN2022130902-appb-000096
1H NMR(500MHz,DMSO-d 6)δ8.84(t,J＝5.8Hz,1H),8.12(d,J＝9.3Hz,1H),7.52(ddd,J＝24.2,7.9,1.3Hz,2H),7.42(ddd,J＝8.0,6.9,1.3Hz,1H),7.25(ddd,J＝8.0,6.9,1.4Hz,1H),7.07(s,2H),6.82(s,1H),4.67(dt,J＝9.2,7.3Hz,1H),4.36–4.23(m,2H),4.06–3.98(m,2H),3.86–3.71(m,2H),3.74–3.62(m,9H),3.66–3.58(m,1H),3.55(ddt,J＝13.0,9.0,6.4Hz,2H),3.46(dq,J＝12.2,6.1Hz,2H),3.14(ddd,J＝12.1,6.4,4.2Hz,1H),3.02(ddd,J＝12.1,6.6,4.2Hz,1H),2.94–2.72(m,4H),2.62–2.53(m,2H),1.77–1.55(m,4H),1.50–1.39(m,2H),0.88(t,J＝7.2Hz,3H)。MS(ESI,m/z):670(M ++1)。
实施例50：化合物S50的合成
实施例50中，将实施例1中化合物1-1替换成相对应的原料1-50，具体结构式为
Figure PCTCN2022130902-appb-000097
Figure PCTCN2022130902-appb-000098
1H NMR(500MHz,DMSO-d 6)δ8.70(t,J＝5.8Hz,1H),8.20(d,J＝9.3Hz,1H),7.53(ddd,J＝10.7,7.7,1.2Hz,2H),7.42(ddd,J＝8.0,6.9,1.2Hz,1H),7.25(ddd,J＝8.0,6.9,1.3Hz,1H),6.82(s,1H),4.72(dt,J＝9.3,7.5Hz,1H),4.56(s,1H),4.48(dt,J＝12.4,6.2Hz,1H),4.30(dt,J＝12.4,6.2Hz,1H),4.00(dd,J＝17.5,5.8Hz,1H),3.87(dd,J＝17.5,5.8Hz,1H),3.83–3.56(m,14H),3.51(dt,J＝12.3,6.1Hz,1H),3.43(dt,J＝12.0,6.6Hz,1H),3.03(ddd,J＝11.9,6.4,4.3Hz,1H),2.92(ddd,J＝15.0,6.6,4.3Hz,1H),2.88–2.78(m,3H),2.81–2.75(m,1H),2.70(dd,J＝16.4,7.4Hz,1H),2.49–2.39(m,1H),1.78–1.63(m,3H),1.60–1.43(m,3H),0.85(t,J＝7.2Hz,3H)。MS(ESI,m/z):671(M ++1)。
实施例51：化合物S51的合成
实施例51中，将实施例1中化合物1-1替换成相对应的原料1-51，具体结构式为
Figure PCTCN2022130902-appb-000099
1H NMR(500MHz,DMSO-d 6)δ8.87(t,J＝5.8Hz,1H),8.03(d,J＝9.3Hz,1H),7.50(dd,J＝7.9,1.3Hz,1H),7.43(ddd,J＝8.1,6.9,1.3Hz,1H),7.36(dd,J＝8.0,1.3Hz,1H),7.25(ddd,J＝8.1,6.8,1.3Hz,1H),6.82(s,1H),4.48(dt,J＝12.3,6.1Hz,1H),4.34–4.22(m,2H),4.05(s,1H),3.98(dd,J＝17.4,5.9Hz,1H),3.87(dd,J＝17.5,5.8Hz,1H),3.83–3.56(m,12H),3.54(dt,J＝12.8,6.4Hz,2H),3.52–3.45(m,1H),3.14(ddd,J＝12.1,6.4,4.2Hz,1H),3.02(ddd,J＝12.1,6.4,4.2Hz,1H),2.91(ddd,J＝15.4,6.4,4.1Hz,1H),2.83(ddd,J＝11.9,7.0,4.7Hz,1H),2.72 (ddd,J＝15.4,6.4,4.2Hz,1H),2.57(ddd,J＝11.8,6.9,4.7Hz,1H),1.79–1.40(m,9H),0.96–0.83(m,9H).MS(ESI,m/z):669(M ++1)。
实施例52：化合物S52的合成
实施例52中，将实施例1中化合物1-1替换成相对应的原料1-52，具体结构式为
Figure PCTCN2022130902-appb-000100
1H NMR(500MHz,DMSO-d 6)δ8.86(t,J＝5.8Hz,1H),7.71(d,J＝9.1Hz,1H),7.56(ddd,J＝19.0,7.9,1.4Hz,2H),7.42(ddd,J＝8.0,7.0,1.3Hz,1H),7.25(ddd,J＝8.0,7.0,1.3Hz,1H),6.82(s,1H),4.53(s,1H),4.47–4.38(m,2H),4.25–4.14(m,2H),4.00–3.91(m,2H),3.86(dd,J＝17.5,5.8Hz,1H),3.83–3.43(m,15H),3.05(ddd,J＝12.1,6.4,4.3Hz,1H),2.92(ddd,J＝15.4,6.3,4.2Hz,1H),2.81(ddd,J＝15.6,6.4,4.2Hz,1H),2.79–2.70(m,2H),2.49–2.40(m,1H),1.76–1.52(m,5H),1.42(dq,J＝13.0,7.2Hz,1H),1.10(d,J＝6.6Hz,3H),0.89(t,J＝7.2Hz,3H)。MS(ESI,m/z):657(M ++1)。
实施例53：化合物S53的合成
Figure PCTCN2022130902-appb-000101
长春西汀脱乙酯产物(200mg，0.62mmol)、化合物2-53(196mg，0.68mmol)溶于DMF(5mL)中，向上述溶液中加入碳酸钾(128mg，0.93mmol)和碘化钾(103mg，0.62mmol)，升高温度至65℃，TLC监测至反应完全，停止反应，冷却至室温。蒸掉溶剂，加入水(10mL)，EA萃取(10mL×3)，合并有机相，饱和食盐水洗涤(10mL)，无水硫酸镁干燥，过滤，浓缩，柱层析(洗 脱二氯甲烷:甲醇＝30:1)制得化合物S53(163mg，60％)。
1H NMR(500MHz,DMSO-d6)δ7.58–7.52(m,1H),7.44–7.36(m,2H),7.32–7.23(m,1H),6.89(s,1H),4.66(dt,J＝11.5,7.1Hz,1H),4.59(s,1H),4.47(dt,J＝11.4,7.1Hz,1H),4.29–4.15(m,2H),3.89–3.74(m,2H),3.24(t,J＝7.3Hz,1H),3.06(ddd,J＝11.9,6.5,4.2Hz,1H),2.93(ddd,J＝15.4,6.3,4.2Hz,1H),2.86–2.54(m,6H),2.51–2.43(m,1H),1.76–1.52(m,5H),1.42(dq,J＝12.8,7.2Hz,1H),0.88(t,J＝7.2Hz,3H)。MS(ESI,m/z):439(M ++1)。
以下实施例54～62中的化合物S54～S62均可按实施例53的合成方法获得，反应过程和反应条件均同实施例53，只需将实施例53中的原料2-53替换成相对应的原料即可。
实施例54：化合物S54的合成
实施例54中，将实施例53中化合物2-53替换成相对应的原料2-54，具体结构式为
Figure PCTCN2022130902-appb-000102
1H NMR(500MHz,DMSO-d 6)δ7.54(ddd,J＝13.4,7.9,1.4Hz,2H),7.43–7.36(m,1H),7.31–7.23(m,1H),6.89(s,1H),4.66(dt,J＝11.5,7.1Hz,1H),4.59(s,1H),4.48(dt,J＝11.5,7.1Hz,1H),3.51–3.17(–OCH2CH2),3.24(t,J＝7.3Hz,1H),3.06(ddd,J＝12.1,6.4,4.2Hz,1H),2.94(ddd,J＝15.4,6.4,4.2Hz,1H),2.86–2.71(m,3H),2.69–2.52(m,2H),2.47(ddd,J＝11.7,6.8,4.7Hz,1H),1.75–1.51(m,6H),1.42(dq,J＝13.0,7.2Hz,1H),0.88(t,J＝7.2Hz,3H)。
实施例55：化合物S55的合成
实施例55中，将实施例53中化合物2-53替换成相对应的原料2-55，具体结构式为
Figure PCTCN2022130902-appb-000103
Figure PCTCN2022130902-appb-000104
1H NMR(500MHz,DMSO-d 6)δ7.54(ddd,J＝13.4,7.9,1.4Hz,2H),7.43–7.36(m,1H),7.31–7.23(m,1H),6.89(s,1H),4.66(dt,J＝11.5,7.1Hz,1H),4.59(s,1H),4.48(dt,J＝11.5,7.1Hz,1H),3.51–3.17(–OCH2CH2),3.24(t,J＝7.3Hz,1H),3.06(ddd,J＝12.1,6.4,4.2Hz,1H),2.94(ddd,J＝15.4,6.4,4.2Hz,1H),2.86–2.71(m,3H),2.69–2.52(m,2H),2.47(ddd,J＝11.7,6.8,4.7Hz,1H),1.75–1.51(m,6H),1.42(dq,J＝13.0,7.2Hz,1H),0.88(t,J＝7.2Hz,3H)。
实施例56：化合物S56的合成
实施例56中，将实施例56中化合物2-53替换成相对应的原料2-56，具体结构式为
Figure PCTCN2022130902-appb-000105
1H NMR(500MHz,DMSO-d 6)δ7.55(ddd,J＝7.6,5.0,1.3Hz,2H),7.48(ddd,J＝8.0,7.0,1.3Hz,1H),7.27(ddd,J＝8.1,6.9,1.3Hz,1H),6.89(s,1H),4.69–4.50(m,3H),4.36(dt,J＝12.3,6.1Hz,1H),4.05(dt,J＝12.4,6.2Hz,1H),3.84–3.74(m,1H),3.78–3.71(m,2H),3.73–3.64(m,1H),3.67–3.52(m,2H),3.47(dt,J＝12.3,6.3Hz,1H),3.06(ddd,J＝12.1,6.4,4.2Hz,1H),2.93(ddd,J＝15.6,6.4,4.2Hz,1H),2.83(ddd,J＝15.6,6.4,4.3Hz,1H),2.81–2.72(m,2H),2.69–2.54(m,2H),2.51–2.43(m,1H),1.75–1.52(m,5H),1.39(dq,J＝13.0,7.2Hz,1H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):483(M ++1)。
实施例57：化合物S57的合成
实施例57中，将实施例57中化合物2-53替换成相对应的原料2-57，具体结构式为
Figure PCTCN2022130902-appb-000106
1H NMR(500MHz,DMSO-d 6)δ7.55(dd,J＝7.9,1.3Hz,1H),7.52–7.43(m,2H),7.27(ddd,J＝8.1,6.7,1.7Hz,1H),6.90(s,1H),4.70–4.61(m,2H),4.46–4.31(m,2H),4.13(dt,J＝12.2,6.1Hz,1H),3.84–3.56(m,11H),3.44(dt,J＝12.1,6.5Hz,1H),3.06–2.97(m,1H),2.98–2.89(m,1H),2.87–2.72(m,4H),2.56(dt,J＝16.1,7.1Hz,1H),2.46(ddd,J＝11.9,6.8,4.7Hz,1H),1.75–1.51(m,6H),1.46(dq,J＝12.8,7.1Hz,1H),0.88(t,J＝7.2Hz,3H)。MS(ESI,m/z):527(M ++1)。
实施例58：化合物S58的合成
实施例58中，将实施例58中化合物2-53替换成相对应的原料2-58，具体结构式为
Figure PCTCN2022130902-appb-000107
1H NMR(500MHz,DMSO-d 6)δ7.58–7.45(m,3H),7.27(ddd,J＝8.0,6.9,1.4Hz,1H),6.89(s,1H),4.61(dt,J＝11.4,7.1Hz,1H),4.47(dt,J＝11.4,7.1Hz,1H),4.32(dt,J＝12.2,6.1Hz,1H),4.12–4.03(m,2H),3.84–3.57(m,14H),3.58–3.49(m,1H),3.14(ddd,J＝12.1,6.4,4.2Hz,1H),3.02(ddd,J＝12.1,6.6,4.2Hz,1H),2.94(ddd,J＝15.4,6.5,4.2Hz,1H),2.85–2.75(m,2H),2.72–2.51(m,3H),1.75–1.63(m,2H),1.63–1.53(m,1H),1.53(tt,J＝5.2,1.5Hz,1H),1.53–1.43(m,2H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):571(M ++1)。
实施例59：化合物S59的合成
实施例59中，将实施例59中化合物2-53替换成相对应的原料2-59，具体结构式为
Figure PCTCN2022130902-appb-000108
1H NMR(500MHz,DMSO-d 6)δ7.55(ddd,J＝9.1,7.8,1.4Hz,2H),7.48(ddd,J＝8.0,7.0,1.3Hz,1H),7.27(ddd,J＝8.1,7.0,1.3Hz,1H),6.89(s,1H),4.65(dt,J＝11.3,7.1Hz,1H),4.59–4.50(m,2H),4.35(dt,J＝12.4,6.2Hz,1H),4.06(dt,J＝12.4,6.2Hz,1H),3.83–3.74(m,1H),3.77–3.69(m,1H),3.73–3.60(m,15H),3.64–3.57(m,1H),3.56(dt,J＝12.3,6.5Hz,1H),3.48(dt,J＝12.5,6.3Hz,1H),3.06(ddd,J＝11.9,6.4,4.2Hz,1H),2.93(ddd,J＝15.4,6.3,4.2Hz,1H),2.83(ddd,J＝15.4,6.4,4.3Hz,1H),2.81–2.72(m,2H),2.69–2.54(m,2H),2.46(ddd,J＝11.8,6.8,4.7Hz,1H),1.75–1.51(m,6H),1.39(dq,J＝13.0,7.3Hz,1H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):615(M ++1)。
实施例60：化合物60的合成
实施例60中，将实施例60中化合物2-53替换成相对应的原料2-60，具体结构式为
Figure PCTCN2022130902-appb-000109
1H NMR(500MHz,DMSO-d 6)δ7.55(td,J＝7.8,1.2Hz,2H),7.40(ddd,J＝7.9,7.0,1.3Hz,1H),7.26(ddd,J＝8.1,7.1,1.3Hz,1H),6.89(s,1H),4.65(dt,J＝11.5,7.1Hz,1H),4.59–4.50(m,2H),4.35(dt,J＝12.3,6.1Hz,1H),4.06(dt,J＝12.4,6.2Hz,1H),3.83–3.73(m,1H),3.76–3.69(m,1H),3.73–3.63(m,17H),3.67–3.61(m,1H),3.65–3.58(m,1H),3.62–3.52(m,1H),3.55–3.43(m,1H),3.06(ddd,J＝11.9,6.4,4.2Hz,1H),2.93(ddd,J＝15.4,6.3,4.2Hz,1H),2.87–2.77(m,1H),2.81–2.72(m,2H),2.69–2.54(m,2H),2.46(ddd,J＝11.8,6.9,4.8 Hz,1H),1.75–1.50(m,5H),1.39(dq,J＝13.0,7.2Hz,1H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):659(M ++1)。
实施例61：化合物S61的合成
实施例61中，将实施例61中化合物2-53替换成相对应的原料2-61，具体结构式为
Figure PCTCN2022130902-appb-000110
1H NMR(500MHz,DMSO-d 6)δ7.54(dd,J＝7.9,1.4Hz,1H),7.48(ddd,J＝8.0,6.9,1.3Hz,1H),7.43(dd,J＝7.8,1.4Hz,1H),7.27(ddd,J＝8.0,6.8,1.3Hz,1H),6.95(s,1H),4.56(s,1H),4.31(dt,J＝12.3,6.1Hz,1H),4.23(td,J＝6.1,2.9Hz,2H),4.17(dt,J＝12.2,6.1Hz,1H),3.83–3.58(m,15H),3.53(dt,J＝12.1,6.4Hz,1H),3.07(ddd,J＝12.1,6.5,4.2Hz,1H),2.94(ddd,J＝15.4,6.4,4.2Hz,1H),2.86–2.70(m,3H),2.54–2.37(m,3H),2.22–2.10(m,1H),1.99(dtt,J＝14.0,7.1,6.0Hz,1H),1.76–1.62(m,3H),1.64–1.49(m,2H),0.85(t,J＝7.2Hz,3H)。MS(ESI,m/z):585(M ++1)。
实施例62：化合物S62的合成
实施例62中，将实施例62中化合物2-53替换成相对应的原料2-62，具体结构式为
Figure PCTCN2022130902-appb-000111
1H NMR(500MHz,DMSO-d 6)δ7.53(dd,J＝7.8,1.3Hz,1H),7.45(dd,J＝7.9,1.2Hz,1H),7.39(ddd,J＝7.9,6.8,1.3Hz,1H),7.26(ddd,J＝8.1,6.8,1.3Hz,1H), 4.32–4.16(m,3H),4.13(dt,J＝12.3,6.2Hz,1H),3.83–3.57(m,23H),3.45(dt,J＝12.3,6.5Hz,1H),3.13(ddd,J＝12.1,6.4,4.2Hz,1H),2.90(ddd,J＝15.4,6.4,4.2Hz,1H),2.83–2.73(m,2H),2.69(ddd,J＝12.1,6.4,4.2Hz,1H),2.52–2.37(m,3H),2.26–2.14(m,1H),2.13–2.01(m,1H),1.75–1.50(m,6H),1.40(dq,J＝12.8,7.2Hz,1H),0.91(t,J＝7.2Hz,3H)。MS(ESI,m/z):673(M ++1)。
以下实施例63～65中的化合物S63～S65均可按实施例1的合成方法获得，步骤一长春西汀脱乙酯产物的生成按照实施例1中的方法进行，步骤二的反应过程和反应条件均同实施例1，只需将实施例1中的化合物1-1替换成相应的原料即可。
实施例63：化合物S63的合成
实施例63中，将实施例1中化合物1-1替换成相对应的原料1-63，具体结构式为
Figure PCTCN2022130902-appb-000112
1H NMR(500MHz,DMSO-d 6)δ7.57–7.48(m,2H),7.47(dd,J＝8.0,1.5Hz,1H),7.25(ddd,J＝8.0,6.8,1.5Hz,1H),6.84(s,1H),4.53(s,1H),4.34(dt,J＝12.3,6.2Hz,1H),4.23(dt,J＝12.4,6.2Hz,1H),4.09(d,J＝13.4Hz,1H),3.89(d,J＝13.4Hz,1H),3.84–3.58(m,15H),3.61–3.53(m,1H),3.49(dt,J＝12.4,6.3Hz,1H),3.06(ddd,J＝11.9,6.5,4.2Hz,1H),2.93(ddd,J＝15.4,6.3,4.2Hz,1H),2.88(s,2H),2.86–2.73(m,3H),2.47(ddd,J＝11.9,6.8,4.8Hz,1H),1.74–1.49(m,5H),1.43(dq,J＝13.0,7.2Hz,1H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):570(M ++1)。
实施例64：化合物S64的合成
实施例64中，将实施例1中化合物1-1替换成相对应的原料1-64，具体结构式为
Figure PCTCN2022130902-appb-000113
Figure PCTCN2022130902-appb-000114
1H NMR(500MHz,DMSO-d 6)δ7.60(dd,J＝8.0,1.3Hz,1H),7.52(dd,J＝7.9,1.3Hz,1H),7.43(ddd,J＝8.0,6.9,1.3Hz,1H),7.27(ddd,J＝8.1,6.9,1.3Hz,1H),6.88(s,1H),4.53(s,1H),4.25(dt,J＝12.4,6.2Hz,1H),4.18–4.04(m,2H),3.88(d,J＝13.3Hz,1H),3.83–3.57(m,15H),3.51–3.42(m,1H),3.22(p,J＝5.7Hz,1H),3.06(ddd,J＝11.9,6.4,4.2Hz,1H),2.92(ddd,J＝15.6,6.4,4.3Hz,1H),2.86–2.71(m,3H),2.46(ddd,J＝11.9,6.8,4.8Hz,1H),1.75–1.49(m,5H),1.43(dq,J＝12.8,7.2Hz,1H),1.39–1.30(m,2H),1.08–0.99(m,2H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):596(M ++1)。
实施例65：化合物S65的合成
实施例65中，将实施例1中化合物1-1替换成相对应的原料1-65，具体结构式为
Figure PCTCN2022130902-appb-000115
1H NMR(500MHz,DMSO-d 6)δ7.94(t,J＝4.2Hz,1H),7.62(dd,J＝7.8,1.3Hz,1H),7.53(dd,J＝7.9,1.2Hz,1H),7.45(ddd,J＝7.9,7.0,1.2Hz,1H),7.27(ddd,J＝8.1,7.0,1.3Hz,1H),6.83(s,1H),5.53(t,J＝4.3Hz,1H),4.52(s,1H),4.35(dt,J＝12.3,6.2Hz,1H),4.13(dt,J＝12.4,6.2Hz,1H),3.83–3.57(m,13H),3.55–3.47(m,1H),3.48(ddt,J＝5.8,5.2,3.4Hz,2H),3.48–3.39(m,1H),3.42–3.27(m,2H),3.05(ddd,J＝11.9,6.5,4.3Hz,1H),2.93(ddd,J＝15.6,6.4,4.3Hz,1H),2.86–2.72(m,3H),2.50–2.42(m,1H),1.76–1.50(m,5H),1.40(dq,J＝13.0,7.2Hz,1H),0.85(t,J＝7.2Hz,3H)。MS(ESI,m/z):585(M ++1)。
实施例66：化合物S66的合成
Figure PCTCN2022130902-appb-000116
步骤一：化合物3-66的合成
将长春西汀脱乙酯产物(200mg，0.62mmol)，甘氨酸叔丁酯盐酸盐(78mg，0.62mmol)，EDCI(192mg，1.00mmol)，HOBt(103mg，0.76mmol)在室温下溶于无水DMF(8ml)中，搅拌，加入三乙胺(0.4mL，2.94mmol)，氮气保护，常温反应10小时。旋转蒸发除去DMF，二氯甲烷溶解，二氯甲烷萃取(3×20mL)，饱和食盐水洗涤(1×20mL)，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化，得到中间体化合物3-66(230mg，90％)。 1H NMR(500MHz,Chloroform-d)δ8.62(t,J＝5.8Hz,1H),7.53(dt,J＝7.7,1.4Hz,2H),7.44(ddd,J＝8.1,6.9,1.3Hz,1H),5.83(s,1H),4.54(s,1H),3.99(dd,J＝17.5,5.8Hz,1H),3.91(dd,J＝17.6,5.9Hz,1H),3.06(ddd,J＝12.1,6.5,4.3Hz,1H),2.92(ddd,J＝15.6,6.4,4.3Hz,1H),2.86–2.72(m,4H),1.75–1.63(m,3H),1.67–1.51(m,3H),1.49–1.38(m,1H),1.42(s,9H),0.88(t,J＝7.2Hz,3H).
步骤二：化合物S66的合成
将化合物3-66(160mg，0.35mmol)溶于二氯甲烷(5ml)中，0℃下加入2.5mL三氟乙酸，转移至室温，TLC监测直至反应完全。停止反应，减压蒸掉溶剂和三氟乙酸，***(20mL)打浆，过滤，收集滤饼，真空干燥，得长春西汀甘氨酸产物S66(119mg，90％)。
1H NMR(500MHz,DMSO-d 6)δ11.01(s,1H),8.94(t,J＝5.8Hz,1H),7.55(ddd,J＝16.8,7.9,1.3Hz,2H),7.47(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.2Hz,1H),5.67(s,1H),4.57(s,1H),4.15(dd,J＝17.4,5.7Hz,1H),3.95(dd,J＝17.4,5.9Hz,1H),3.06(ddd,J＝11.9,6.5,4.2Hz,1H),2.93(ddd,J＝15.4,6.3,4.2Hz,1H),2.86–2.71(m,3H),2.52–2.43(m,1H),1.76–1.54(m,5H),1.41(dq,J＝13.0,7.2Hz,1H),0.88(t,J＝7.2Hz,3H)。MS(ESI,m/z):380(M ++1)。
以下实施例67～87中的化合物S67～S87均可按实施例66的合成方法获得，步骤一的反应过程和反应条件均同实施例66，只需将甘氨酸叔丁酯替换成相应 的原料即可，步骤二按照实施例66中的方法进行。
实施例67：化合物S67的合成
实施例67中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000117
1H NMR(500MHz,DMSO-d 6)δ8.97(d,J＝9.3Hz,1H),7.52(ddd,J＝20.6,7.7,1.2Hz,2H),7.43(ddd,J＝8.0,7.0,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.83(s,1H),4.56–4.44(m,2H),3.06(ddd,J＝11.9,6.5,4.3Hz,1H),2.92(ddd,J＝15.4,6.4,4.2Hz,1H),2.86–2.71(m,3H),2.47(ddd,J＝11.9,6.8,4.7Hz,1H),1.90(dt,J＝13.6,6.8Hz,1H),1.76–1.53(m,8H),1.41(dq,J＝13.0,7.2Hz,1H),0.95–0.85(m,9H).MS(ESI,m/z):436(M ++1)。
实施例68：化合物S68的合成
实施例68中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000118
1H NMR(500MHz,DMSO-d 6)δ9.41(d,J＝9.3Hz,1H),7.65(dd,J＝7.9,1.3Hz,1H),7.54(dd,J＝7.9,1.3Hz,1H),7.45(ddd,J＝8.0,7.0,1.3Hz,1H),7.25(ddd, J＝8.0,6.9,1.1Hz,1H),6.80(s,1H),4.62(t,J＝7.1Hz,1H),4.54(s,1H),4.33(dt,J＝9.3,6.4Hz,1H),3.93–3.79(m,2H),3.06(ddd,J＝12.1,6.4,4.3Hz,1H),2.92(ddd,J＝15.6,6.4,4.3Hz,1H),2.87–2.72(m,3H),2.50–2.42(m,1H),1.75–1.53(m,6H),1.46(dq,J＝13.0,7.2Hz,1H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):410(M ++1)。
实施例69：化合物S69的合成
实施例69中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000119
1H NMR(500MHz,DMSO-d 6)δ9.44(d,J＝9.2Hz,1H),7.64(dd,J＝8.0,1.2Hz,1H),7.57–7.48(m,2H),7.26(ddd,J＝8.0,7.0,1.3Hz,1H),6.82(s,1H),4.54(s,1H),4.41(dd,J＝9.2,6.8Hz,2H),4.06(h,J＝6.6Hz,1H),3.07(ddd,J＝12.1,6.1,4.5Hz,1H),2.95–2.71(m,4H),2.39(ddd,J＝13.1,6.8,4.7Hz,1H),1.75–1.48(m,7H),1.10(d,J＝6.6Hz,3H),0.86(t,J＝7.2Hz,3H)。MS(ESI,m/z):424(M ++1)。
实施例70：化合物S70的合成
实施例70中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000120
Figure PCTCN2022130902-appb-000121
1H NMR(500MHz,DMSO-d 6)δ9.73(d,J＝9.2Hz,1H),7.54(dd,J＝7.8,1.3Hz,1H),7.48(dd,J＝7.7,1.3Hz,1H),7.43(ddd,J＝7.9,6.8,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.5Hz,1H),6.79(s,1H),4.71(dt,J＝9.3,7.3Hz,1H),4.54(s,1H),3.06(ddd,J＝11.9,6.4,4.2Hz,1H),3.02–2.88(m,2H),2.86–2.68(m,4H),2.51–2.43(m,1H),1.76–1.54(m,5H),1.42(dq,J＝13.0,7.2Hz,1H),0.88(t,J＝7.2Hz,3H)。MS(ESI,m/z):438(M ++1)。
实施例71：化合物S71的合成
实施例71中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000122
1H NMR(500MHz,DMSO-d 6)δ9.57(d,J＝9.3Hz,1H),7.62(dd,J＝8.0,1.3Hz,1H),7.54(dd,J＝8.0,1.3Hz,1H),7.44(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),7.06(s,2H),6.79(s,1H),4.59(dt,J＝9.3,7.5Hz,1H),4.00(s,1H),3.14(ddd,J＝12.1,6.4,4.2Hz,1H),3.02(ddd,J＝12.1,6.6,4.2Hz,1H),2.98–2.73(m,3H),2.70(dd,J＝17.0,7.3Hz,1H),2.62–2.53(m,1H),1.77–1.64(m,3H),1.60–1.40(m,3H),0.88(t,J＝7.2Hz,3H)。MS(ESI,m/z):437(M ++1)。
实施例72：化合物S72的合成
实施例72中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具 体结构式为
Figure PCTCN2022130902-appb-000123
1H NMR(500MHz,DMSO-d 6)δ9.03(d,J＝9.3Hz,1H),7.64(dd,J＝8.1,1.4Hz,1H),7.57–7.49(m,2H),7.25(ddd,J＝8.0,7.0,1.3Hz,1H),6.80(s,1H),4.54(s,1H),4.24(dt,J＝9.3,5.3Hz,1H),3.38(dt,J＝7.1,5.7Hz,1H),3.31(dt,J＝7.1,6.0Hz,1H),3.23–3.13(m,1H),3.13–3.03(m,2H),2.94–2.80(m,3H),2.75(ddd,J＝12.1,6.0,4.7Hz,1H),2.42–2.33(m,1H),1.74–1.48(m,7H),0.86(t,J＝7.2Hz,3H)。MS(ESI,m/z):409(M ++1)。
实施例73：化合物S73的合成
实施例73中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000124
1H NMR(500MHz,DMSO-d 6)δ9.30(d,J＝9.3Hz,1H),7.55(ddd,J＝22.5,7.9,1.3Hz,2H),7.45(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.1,6.9,1.2Hz,1H),6.80(s,1H),4.66–4.55(m,2H),3.06(ddd,J＝12.1,6.4,4.2Hz,1H),2.93(ddd,J＝15.6,6.4,4.3Hz,1H),2.86–2.71(m,3H),2.47(ddd,J＝11.9,6.8,4.7Hz, 1H),1.76–1.53(m,6H),1.43(dq,J＝13.0,7.2Hz,1H),1.37(d,J＝6.8Hz,3H),0.88(t,J＝7.2Hz,3H)。MS(ESI,m/z):394(M ++1)。
实施例74：化合物S74的合成
实施例74中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000125
1H NMR(500MHz,DMSO-d 6)δ9.34(d,J＝9.2Hz,1H),7.57(ddd,J＝25.9,7.8,1.2Hz,2H),7.45(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.82(s,1H),4.54(s,1H),4.22(dd,J＝9.0,6.6Hz,1H),3.06(ddd,J＝11.9,6.4,4.2Hz,1H),2.92(ddd,J＝15.4,6.3,4.2Hz,1H),2.82(ddd,J＝15.4,6.5,4.3Hz,1H),2.81–2.71(m,2H),2.51–2.42(m,1H),2.08–1.95(m,J＝6.7Hz,1H),1.75–1.53(m,4H),1.54–1.46(m,1H),1.42(dq,J＝13.0,7.2Hz,1H),0.97(dd,J＝24.9,6.6Hz,6H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):422(M ++1)。
实施例75：化合物S75的合成
实施例75中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000126
1H NMR(500MHz,DMSO-d 6)δ9.16(d,J＝9.3Hz,1H),7.77(dd,J＝8.1,1.4Hz,1H),7.58(dd,J＝8.0,1.3Hz,1H),7.52(ddd,J＝7.9,7.0,1.1Hz,1H),7.29–7.19(m,6H),6.83(s,1H),4.65(dt,J＝9.3,7.7Hz,1H),4.54(s,1H),3.14–3.01(m,2H),3.03–2.92(m,2H),2.86(ddd,J＝15.6,6.4,4.2Hz,1H),2.84–2.74(m,2H),2.54–2.45(m,1H),1.75–1.64(m,2H),1.68–1.61(m,1H),1.59(dddd,J＝12.8,6.9,4.9,1.8Hz,1H),1.57–1.48(m,1H),1.44(dq,J＝12.8,7.2Hz,1H),0.87(t,J＝7.2Hz,3H)。MS(ESI,m/z):470(M+ +1)。
实施例76：化合物S76的合成
实施例76中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000127
1H NMR(500MHz,DMSO-d 6)δ8.79(t,J＝5.8Hz,1H),8.19(d,J＝9.3Hz,1H),7.53(ddd,J＝15.9,7.8,1.2Hz,2H),7.46(ddd,J＝8.0,6.9,1.2Hz,1H),7.26(ddd,J＝8.0,6.9,1.4Hz,1H),6.80(s,1H),4.68(dt,J＝9.3,5.6Hz,1H),4.54(s,1H),4.04(dd,J＝17.4,5.7Hz,1H),3.90(dd,J＝17.5,5.8Hz,1H),3.14–3.03(m,2H),3.01–2.87(m,2H),2.88–2.75(m,2H),2.73(ddd,J＝12.1,6.4,4.2Hz,1H),2.41–2.32(m,1H),2.08(t,J＝6.6Hz,1H),1.75–1.63(m,3H),1.61–1.39(m,3H),0.84(t,J＝7.2Hz,3H)。MS(ESI,m/z):483(M ++1)。
实施例77：化合物S77的合成
实施例77中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000128
1H NMR(500MHz,DMSO-d 6)δ8.79(t,J＝5.8Hz,1H),8.19(d,J＝9.3Hz,1H),7.53(ddd,J＝15.9,7.8,1.2Hz,2H),7.46(ddd,J＝8.0,6.9,1.2Hz,1H),7.26(ddd,J＝8.0,6.9,1.4Hz,1H),6.80(s,1H),4.68(dt,J＝9.3,5.6Hz,1H),4.54(s,1H),4.04(dd,J＝17.4,5.7Hz,1H),3.90(dd,J＝17.5,5.8Hz,1H),3.14–3.03(m,2H),3.01–2.87(m,2H),2.88–2.75(m,2H),2.73(ddd,J＝12.1,6.4,4.2Hz,1H),2.41–2.32(m,1H),2.08(t,J＝6.6Hz,1H),1.75–1.63(m,3H),1.61–1.39(m,3H),0.84(t,J＝7.2Hz,3H)。MS(ESI,m/z):494(M ++1)。
实施例78：化合物S78的合成
实施例78中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000129
1H NMR(500MHz,DMSO-d 6)δ8.84(t,J＝5.8Hz,1H),8.16(d,J＝9.3Hz,1H),7.71(dd,J＝8.0,1.3Hz,1H),7.65(s,1H),7.58(dd,J＝7.9,1.3Hz,1H),7.51(ddd,J＝8.0,6.9,1.3Hz,1H),7.25(ddd,J＝8.0,7.0,1.3Hz,1H),6.99(dt,J＝8.7, 1.0Hz,2H),6.82(s,1H),6.70–6.64(m,2H),4.63(dt,J＝9.3,7.7Hz,1H),4.53(s,1H),3.97(dd,J＝17.4,5.7Hz,1H),3.90(dd,J＝17.5,5.8Hz,1H),3.16–3.04(m,2H),3.03–2.89(m,2H),2.86(ddd,J＝15.6,6.4,4.3Hz,1H),2.83–2.73(m,2H),2.48(ddd,J＝12.0,6.9,4.8Hz,1H),1.76–1.50(m,5H),1.44(dq,J＝13.0,7.2Hz,1H),0.88(t,J＝7.1Hz,3H)。MS(ESI,m/z):542(M ++1)。
实施例79：化合物S79的合成
实施例79中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000130
1H NMR(500MHz,DMSO-d 6)δ8.85(t,J＝5.8Hz,1H),8.14(d,J＝9.3Hz,1H),7.54(ddd,J＝7.5,4.8,1.2Hz,2H),7.46(ddd,J＝8.0,7.0,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.1Hz,1H),6.82(s,1H),4.54(s,1H),4.36(dt,J＝9.3,6.8Hz,1H),3.97(dd,J＝17.4,5.7Hz,1H),3.87(dd,J＝17.5,5.8Hz,1H),3.06(ddd,J＝12.1,6.5,4.3Hz,1H),2.93(ddd,J＝15.4,6.4,4.3Hz,1H),2.81(ddd,J＝15.4,6.5,4.2Hz,1H),2.80–2.71(m,2H),2.51–2.42(m,1H),1.84(dt,J＝13.7,6.9Hz,1H),1.75–1.66(m,1H),1.70–1.62(m,2H),1.65–1.59(m,1H),1.62–1.49(m,2H),1.53–1.44(m,2H),0.92(d,J＝6.9Hz,3H),0.90–0.82(m,6H).MS(ESI,m/z):493(M ++1)。
实施例80：化合物S80的合成
实施例80中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000131
1H NMR(500MHz,DMSO-d 6)δ8.79(t,J＝5.8Hz,1H),8.05(d,J＝9.0Hz,1H),7.56(ddd,J＝14.7,7.9,1.3Hz,2H),7.45(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.2Hz,1H),6.82(s,1H),4.63(dd,J＝9.0,6.6Hz,1H),4.54(s,1H),3.97(dd,J＝17.5,5.8Hz,1H),3.88(dd,J＝17.5,5.8Hz,1H),3.05(ddd,J＝12.1,6.5,4.3Hz,1H),2.92(ddd,J＝15.6,6.4,4.3Hz,1H),2.81(ddd,J＝15.6,6.4,4.2Hz,1H),2.75(ddd,J＝12.0,6.5,4.3Hz,2H),2.46(ddd,J＝12.0,7.0,4.9Hz,1H),2.15–2.02(m,J＝6.6Hz,1H),1.78–1.52(m,5H),1.42(dq,J＝13.0,7.2Hz,1H),0.98(d,J＝6.7Hz,3H),0.96–0.86(m,6H).MS(ESI,m/z):479(M ++1)。
实施例81：化合物S81的合成
实施例81中，将实施例66中甘氨酸叔丁酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000132
1H NMR(500MHz,DMSO-d 6)δ8.78(t,J＝5.8Hz,1H),8.33(d,J＝9.3Hz,1H),7.53(ddd,J＝12.2,7.9,1.3Hz,2H),7.45(ddd,J＝8.0,6.9,1.2Hz,1H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.80(s,1H),4.59–4.52(m,2H),4.49(dt,J＝9.3,6.4Hz,1H),4.04(dd,J＝17.5,5.8Hz,1H),3.94–3.76(m,3H),3.07(ddd,J＝12.1,6.5, 4.2Hz,1H),2.92(ddd,J＝15.4,6.4,4.2Hz,1H),2.88–2.69(m,3H),2.41–2.31(m,1H),1.78–1.70(m,1H),1.73–1.63(m,3H),1.60–1.49(m,1H),1.45(dq,J＝13.0,7.2Hz,1H),0.84(t,J＝7.1Hz,3H)。MS(ESI,m/z):467(M ++1)。
实施例82：化合物S82的合成
Figure PCTCN2022130902-appb-000133
将长春西汀脱乙酯产物(200mg，0.62mmol)，丙氨酸甲酯盐酸盐(87mg，0.62mmol)，EDCI(192mg，1.00mmol)，HOBt(103mg，0.76mmol)在室温下溶于无水DMF(8ml)中，搅拌，加入三乙胺(0.4mL，2.94mmol)，氮气保护，常温反应10小时。旋转蒸发除去DMF，二氯甲烷溶解，二氯甲烷萃取(3×20mL)，饱和食盐水洗涤(1×20mL)，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化，得到化合物S82(218mg，86％)。
1H NMR(500MHz,DMSO-d 6)δ8.64(d,J＝9.1Hz,1H),7.55(ddd,J＝20.2,7.7,1.2Hz,2H),7.46(ddd,J＝7.9,7.0,1.2Hz,2H),7.26(ddd,J＝8.0,6.9,1.2Hz,1H),6.82(s,1H),4.54(s,1H),4.45(dq,J＝9.3,6.8Hz,1H),3.70(s,2H),3.07(ddd,J＝11.9,6.5,4.2Hz,1H),2.93(ddd,J＝15.4,6.4,4.2Hz,1H),2.88–2.77(m,2H),2.75(ddd,J＝12.1,6.4,4.3Hz,1H),2.44(ddd,J＝11.9,6.9,4.7Hz,1H),1.78–1.51(m,5H),1.43(dq,J＝12.8,7.1Hz,1H),1.34(d,J＝6.8Hz,3H),0.87(t,J＝7.1Hz,3H)。MS(ESI,m/z):408(M ++1)。
以下实施例83～87中的化合物S83～S87的合成均按实施例82的合成方法获得，反应过程和反应条件均同实施例82，只需将丙氨酸甲酯盐酸盐替换成相应的原料即可。
实施例83：化合物S83的合成
实施例83中，将实施例82中丙氨酸甲酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000134
Figure PCTCN2022130902-appb-000135
1H NMR(500MHz,DMSO-d 6)δ8.55(t,J＝5.8Hz,1H),7.60(dd,J＝7.8,1.4Hz,1H),7.53(dd,J＝7.9,1.3Hz,1H),7.46(ddd,J＝8.0,6.9,1.3Hz,2H),7.26(ddd,J＝8.1,6.9,1.2Hz,1H),6.81(s,1H),4.08(dd,J＝17.5,5.8Hz,1H),3.98–3.89(m,2H),3.68(s,2H),3.13(ddd,J＝12.3,6.4,4.1Hz,1H),3.01(ddd,J＝12.1,6.4,4.1Hz,1H),2.93(ddd,J＝15.4,6.4,4.1Hz,1H),2.85(ddd,J＝11.7,6.9,4.6Hz,1H),2.77(ddd,J＝15.4,6.4,4.2Hz,1H),2.57(ddd,J＝11.8,6.9,4.7Hz,1H),1.77–1.64(m,3H),1.60–1.51(m,1H),1.55–1.47(m,1H),1.50–1.40(m,1H),0.89(t,J＝7.1Hz,3H)。MS(ESI,m/z):394(M ++1)。
实施例84：化合物S84的合成
实施例84中，将实施例82中丙氨酸甲酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000136
1H NMR(500MHz,DMSO-d 6)δ8.67(d,J＝9.0Hz,1H),7.55(ddd,J＝21.7,7.7,1.3Hz,2H),7.43(ddd,J＝7.9,7.0,1.2Hz,2H),7.26(ddd,J＝8.0,6.9,1.3Hz,1H),6.80(s,1H),4.54(s,1H),4.24(dd,J＝9.2,6.6Hz,1H),3.61(s,2H),3.05(ddd,J＝12.1,6.4,4.2Hz,1H),2.91(ddd,J＝15.6,6.4,4.3Hz,1H),2.85–2.70(m,3H),2.51–2.42(m,1H),2.20–2.06(m,J＝6.7Hz,1H),1.76–1.53(m,5H),1.41(dq,J ＝13.0,7.2Hz,1H),1.00(dd,J＝25.0,6.7Hz,6H),0.88(t,J＝7.2Hz,3H)。MS(ESI,m/z):436(M ++1)。
实施例85：化合物S85的合成
实施例85中，将实施例85中丙氨酸甲酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000137
1H NMR(500MHz,DMSO-d 6)δ8.94(d,J＝9.3Hz,1H),7.52(ddd,J＝7.9,6.7,1.3Hz,2H),7.44(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.0,7.0,1.3Hz,2H),6.80(s,1H),4.63–4.52(m,2H),4.38(t,J＝7.1Hz,1H),3.98–3.85(m,2H),3.68(s,2H),3.06(ddd,J＝12.1,6.5,4.3Hz,1H),2.93(ddd,J＝15.6,6.4,4.2Hz,1H),2.85–2.77(m,1H),2.81–2.70(m,2H),2.51–2.42(m,1H),1.76–1.54(m,5H),1.42(dq,J＝13.0,7.2Hz,1H),0.88(t,J＝7.2Hz,3H)。MS(ESI,m/z):424(M ++1)。
实施例86：化合物S86的合成
实施例86中，将实施例82中丙氨酸甲酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000138
Figure PCTCN2022130902-appb-000139
1H NMR(500MHz,DMSO-d 6)δ8.83(t,J＝5.8Hz,1H),8.00(d,J＝9.3Hz,1H),7.60–7.49(m,3H),7.25(ddd,J＝8.1,6.8,1.3Hz,1H),6.82(s,1H),4.54(s,1H),4.45(dt,J＝9.3,6.8Hz,1H),4.08(dd,J＝17.5,5.8Hz,1H),3.90(dd,J＝17.5,5.8Hz,1H),3.68(s,2H),3.07(ddd,J＝12.1,6.4,4.2Hz,1H),2.94(ddd,J＝15.4,6.3,4.2Hz,1H),2.88–2.72(m,3H),2.48(ddd,J＝11.8,6.9,4.8Hz,1H),1.75–1.49(m,9H),1.43(dq,J＝13.0,7.2Hz,1H),0.96–0.83(m,9H).MS(ESI,m/z):507(M ++1)。
实施例87：化合物S87的合成
实施例87中，将实施例82中丙氨酸甲酯盐酸盐替换成相对应的原料，具体结构式为
Figure PCTCN2022130902-appb-000140
1H NMR(500MHz,DMSO-d 6)δ8.85(t,J＝5.8Hz,1H),7.87(d,J＝9.0Hz,1H),7.56(ddd,J＝13.1,7.9,1.2Hz,2H),7.45(ddd,J＝8.0,6.9,1.3Hz,1H),7.26(ddd,J＝8.0,6.9,1.2Hz,1H),6.69(s,1H),4.38(s,1H),4.30(dd,J＝9.1,6.5Hz,1H),3.97(dd,J＝17.5,5.8Hz,1H),3.87(dd,J＝17.4,5.9Hz,1H),3.60(s,2H),3.05(ddd,J＝11.9,6.4,4.2Hz,1H),2.92(ddd,J＝15.6,6.4,4.3Hz,1H),2.86–2.74(m,2H),2.77–2.71(m,1H),2.46(ddd,J＝11.9,7.0,4.7Hz,1H),2.20–2.07(m,J＝6.7 Hz,1H),1.73–1.53(m,3H),1.45(ddd,J＝12.2,6.9,5.1Hz,1H),1.11(s,2H),0.99(dd,J＝24.9,6.6Hz,6H).MS(ESI,m/z):479(M ++1)。
效果实施例1：长春西汀衍生物促进外周感觉神经元轴突的生长
本发明在外周感觉神经元DRG(Dorsal root ganglion)中检测长春西汀衍生物促进外周感觉神经元轴突生长的作用，实验结果表明，长春西汀衍生物具有明显促进外周感觉神经元轴突生长的作用。
1.实验原理
糖尿病周围神经病变首先累及感觉神经元，且主要的病理变化是轴突萎缩变性，甚至消失，而DRG神经元作为外周感觉神经元，它的轴突生长状态和糖尿病周围神经病变的发展过程密切相关。因此，将实施例中的化合物加入原代DRG神经元中共同孵育一定时间，然后通过免疫荧光法检测DRG神经元轴突的生长，并用Neuro J定量轴突长度，以此评价化合物对外周感觉神经元轴突生长的促进作用。
2.实验材料与方法
用于荧光染色的鼠抗β-tubulin III一抗购于Sigma公司，细胞培养试剂均购于Gibco公司，DRG神经元细胞取自C57BL/6J小鼠。具体实验步骤：提取C57小鼠的新鲜DRG消化成单细胞悬液后接种至培养板中贴壁培养过夜，以长春胺为阳性药，给予以上实施例合成的待测化合物S1～S87(10μM)孵育24h，然后移去原有培养基，PBS洗涤后每孔加入4％多聚甲醛固定15min，0.3％TritonX-100透化5min，4％BSA室温封闭1h，一抗(1:1000)4℃过夜，山羊抗鼠荧光二抗(1:300)室温避光孵育1h，封片后荧光显微镜(Leica)成像。图片用Image J软件中的Neuro J插件追踪单个DRG神经元的轴突总长度，计算相对于空白对照组轴突总长度的倍数。
3.实验结果
结果如表1所示，相对于阳性药，实施例各化合物能够较好地促进原代DRG神经元轴突的生长。特别是S3、S26、S27、S62、S66等化合物效果更突出。
表1相对轴突总长度
化合物编号 相对轴突总长度 化合物编号 相对轴突总长度
S1 9.7 S45 10.5
S2 9.5 S46 10.7
S3 13.2 S47 11.2
S4 11.5 S48 11.4
S5 12.5 S49 12.0
S6 11.4 S50 11.3
S7 10.5 S51 9.8
S8 11.2 S52 9.5
S9 10.7 S53 9.9
S10 10.5 S54 9.7
S11 9.8 S55 10.5
S12 12.3 S56 11.3
S13 11.6 S57 10.8
S14 10.5 S58 11.4
S15 11.3 S59 10.6
S16 11.2 S60 12.0
S17 12.6 S61 11.3
S18 11.3 S62 12.8
S19 10.9 S63 10.9
S20 10.8 S64 11.3
S21 9.9 S65 11.0
S22 10.2 S66 12.8
S23 10.3 S67 11.3
S24 11.7 S68 11.0
S25 12.3 S69 12.3
S26 13.7 S70 10.8
S27 12.9 S71 10.5
S28 12.2 S72 11.3
S29 12.5 S73 12.1
S30 12.6 S74 10.9
S31 11.8 S75 10.7
S32 12.3 S76 11.1
S33 10.9 S77 10.8
S34 10.5 S78 10.2
S35 12.1 S79 10.6
S36 11.7 S80 11.3
S37 10.8 S81 11.9
S38 10.3 S82 12.5
S39 11.2 S83 12.7
S40 11.4 S84 11.0
S41 11.0 S85 11.8
S42 10.3 S86 11.0
S43 11.2 S87 11.7
S44 9.9 长春胺 9.5
。
效果实施例2：长春西汀衍生物S26改善糖尿病周围神经病变的运动神经传导速度以及感觉缺失
本发明以实施例26制备得到的长春西汀衍生物S26为例，阐述其在体内的治疗效果，S26结构如下图所示。本发明在STZ诱导的1型糖尿病模型小鼠以及2型糖尿病模型db/db小鼠身上检测S26对糖尿病周围神经病变模型小鼠的运动神经传导速度及痛觉响应的影响。实验结果表明，S26可以明显改善糖尿病周围神经病变模型小鼠运动神经传导速度减慢以及感觉缺失现象。
Figure PCTCN2022130902-appb-000141
1.实验原理
糖尿病周围神经病变首先累及感觉神经元，主要病理变化是轴突萎缩变性甚至消失等。故认为可通过保护和促进感觉神经元轴突生长以起到抗糖尿病周围神经病变的治疗效果。此外，糖尿病周围神经病变患者会出现神经传导速度减慢，感觉减退、乏力等症状。在糖尿病周围神经病变模型小鼠身上检测其运动神经传导速度、机械痛阈值以及热痛觉反应时间等行为学指标，可用来评估化合物对糖 尿病周围神经病变个体行为学水平上的改善作用；检测给药后小鼠外周感觉神经元轴突生长的情况，可以评价化合物对外周神经元轴突的保护作用。
2.实验材料与方法
1)动物分组给药情况
1型糖尿病小鼠：雄性8周龄C57BL/6J小鼠购自北京维通利华实验动物技术有限公司。适应性饲养一周后腹腔注射STZ(150mg/kg)，一周后尾静脉采血检测血糖，挑选随机血糖大于16mmol/L的小鼠。STZ注射6周后根据体重和血糖进行分组，分别为：对照组(非糖尿病鼠)、模型组(DPN鼠)、S26给药组(46.8mg/kg/day)，连续灌胃给药4周。
2型糖尿病小鼠：雄性18周龄BKS db/db小鼠购自江苏集萃药康生物科技有限公司。适应性饲养一周后根据体重和血糖进行分组，分别为：对照组(db/m鼠)、模型组(db/db鼠)、S26给药组(46.8mg/kg/day)，连续灌胃给药4周。
2)运动神经传导速度检测实验
在给药前，给药2周和给药4周时，检测每组小鼠左右两侧的运动神经传导速度(Motor nerve conduction velocity，MNCV)，两侧速度求均值作为每只鼠的神经传导速度。具体实验方法：①电极放置：刺激电极置于神经干，记录电极置于肌腹，参考电极置于肌腱；地线置于刺激电极和记录电极之间。②运动神经传导速度的计算：超强刺激神经干远端和近端，在该神经支配的肌肉上可记录到2次复合肌肉动作电位，测定其不同的潜伏期，用远端和近端之间的距离除以两点间潜伏期差，即为神经的传导速度。计算公式为：神经传导速度(m/s)＝两点间距离(cm)×10/两点间潜伏期差(ms)。
3)机械痛阈值检测实验
本实验是基于啮齿类动物的爪受到机械刺激时会缩回反射的原理。Von frey触觉测量套件购于Ugo Basile公司，Von frey纤维丝可提供0.008g-300g的刺激力，纤维丝的粗细决定提供刺激力的大小。具体实验方法：选定粗细得当的纤维丝，垂直地刺激皮肤，更换纤维丝调整刺激力大小，直到纤维丝弯曲。一只鼠测定6次以确定阈值，根据50％threshold＝(10^(X f+kδ))/10000计算小鼠50％的机械痛阈值，分别于给药前及给药后每周检测。
4)热痛觉潜伏期检测实验
在给药前及给药后每周利用红外足底测痛仪(37370，购于Ugo Basile公司)检测动物对红外热刺激的反应来表征动物的热痛觉灵敏度。将小鼠提前放入机器配套单笼中适应20min后对小鼠足底进行热刺激，随着时间的延长温度会逐渐升高，当小鼠抬脚或移动离开热源时机器自动停止并记录下热刺激时间，即为热痛觉潜伏期。通过比较热刺激时间的长短来评价热痛觉灵敏度。
5)背根节神经元细胞轴突生长实验
给药结束后，取小鼠的新鲜DRG神经元消化成单细胞悬液后接种至培养板中贴壁培养过夜。利用免疫荧光染色法标记DRG神经元细胞的β-tubulinⅢ(Sigma)蛋白。荧光显微镜(Leica)成像，然后用Image J软件中的Neuro J插件追踪单个DRG神经元细胞轴突的总长度。
3.实验结果
如表2-4所示，化合物S26能够明显改善1型糖尿病周围神经病变小鼠的运动神经传导速度以及感觉缺失症状。两组数据间采用T test进行显著性分析。 *p<0.05， **p<0.01， ***p<0.001代表模型组vs.对照组或db/db vs.db/m； #p<0.05， ##p<0.01， ###p<0.001代表给药组vs.模型组或S26vs.db/db。
表2运动神经传导速度(Mean±SD.，n＝3，m/s)
Figure PCTCN2022130902-appb-000142
表3 50％机械痛阈值(Mean±SD.，n＝6，g)
Figure PCTCN2022130902-appb-000143
表4热痛觉潜伏期(Mean±SD.，n＝6，s)
Figure PCTCN2022130902-appb-000144
如表5-7所示，S26能够明显改善2型糖尿病小鼠的运动神经传导速度以及感觉缺失症状。
表5运动神经传导速度(Mean±SD.，n＝3，m/s)
Figure PCTCN2022130902-appb-000145
表6 50％机械痛阈值(Mean±SD.，n＝6，g)
Figure PCTCN2022130902-appb-000146
表7热痛觉潜伏期(Mean±SD.，n＝6，s)
Figure PCTCN2022130902-appb-000147
Figure PCTCN2022130902-appb-000148
如图1所示，长春西汀衍生物S26能够明显改善1型和2型糖尿病周围神经病变模型小鼠DRG神经元的轴突生长情况(荧光图)。定量结果如表8所示，说明长春西汀衍生物S26对外周感觉神经元轴突具有保护作用。
表8轴突总长度(Mean±SD.，n＝6，pixel)
1型 对照组 模型组 S26给药组
轴突总长度 5732.65±690.58 2656.97±165.97 *** 6374.12±371.56 ###
2型 db/m db/db S26
轴突总长度 5845.64±1020.82 2963.02±906.22 *** 6070.18±579.43 ###
。
效果实施例3：长春西汀衍生物S26促进糖尿病足模型大鼠的足部溃疡伤口愈合
本发明在STZ诱导的糖尿病大鼠身上检测长春西汀衍生物S26对糖尿病足模型大鼠足部溃疡伤口愈合的影响。实验结果表明，在糖尿病大鼠足部溃疡后，给予化合物S26治疗可以明显促进足部溃疡伤口的愈合，减小损伤面积。
1.实验原理
糖尿病足溃疡(Diabetic foot ulcer，DFU)是糖尿病足最常见的表现形式，也是造成糖尿病患者截肢的主要原因。本实验在糖尿病大鼠足背部一次性造成一定面积的伤口，形成糖尿病足溃疡模型，然后给予化合物S26治疗。通过对伤口进行拍照并定量其面积大小来评估长春西汀衍生物S26对糖尿病足足部溃疡伤口愈合的影响。
2.实验材料与方法
1)糖尿病大鼠模型的建立
雄性5周龄SPF级Sprague Dawley大鼠购自北京维通利华实验动物技术有限公司。适应性饲养一周后腹腔注射STZ(100mg/kg)，72h后尾静脉采血检测血糖，挑选随机血糖大于16.7mmol/L的大鼠。
2)糖尿病足溃疡大鼠模型的建立
STZ注射4周后采用吸入式麻醉机，异氟烷吸入诱导麻醉，通过一次性5mm皮肤活检打孔器和Westcott剪刀在糖尿病大鼠的后脚背部造成一个完整的圆形皮肤伤口。糖尿病足溃疡大鼠模型建立后，根据血糖和体重指标分为对照组(非糖尿病鼠)、模型组(DFU鼠)和S26给药组(46.8mg/kg/day)，连续灌胃给药4周。
3)糖尿病足大鼠溃疡面积观察
分别在给药后的第0天、第3天、第7天、第14天、第21天和第28天观察每一只鼠的足部溃疡伤口，使用相机拍摄图像后，通过比例尺的换算，Image J软件定量伤口面积。
3.实验结果
如图2所示，长春西汀衍生物S26能够明显降低糖尿病足大鼠足部溃疡伤口的面积，伤口面积定量结果如表9所示，说明长春西汀衍生物S26能够促进糖尿病足溃疡伤口的愈合。
表9足部溃疡伤口面积(Mean±SD.，n＝6，mm 2)
Figure PCTCN2022130902-appb-000149
效果实施例4：长春西汀衍生物S26减轻博来霉素诱导的小鼠肺部纤维化程度
本发明利用Micro CT在博来霉素诱导的肺纤维化模型小鼠身上检测长春西汀衍生物S26对小鼠肺组织的保护作用。实验结果表明，给予化合物S26治疗可以明显减轻小鼠肺部纤维化程度。
1.实验原理
本实验通过对小鼠进行口腔气管滴注博来霉素溶液来造成肺纤维化模型，然后给予化合物S26治疗。通过对小鼠肺部进行CT拍照和三维重构，定量小鼠肺部正常组织的体积大小来评估长春西汀衍生物S26对博来霉素诱导的小鼠肺部纤维化程度的影响。
2.实验材料与方法
雄性8周龄C57BL/6J小鼠购自北京维通利华，适应性饲养一周后用micro-CT检查小鼠肺部发育情况。根据肺部正常组织体积大小将小鼠分为空白对照组(正常鼠)、模型组和S26给药组(46.8mg/kg)。然后采用吸入式麻醉机，异氟烷吸入诱导麻醉，将模型组及给药组小鼠经口腔气管滴注5mg/kg的博莱霉素溶液，建立肺纤维化模型，对照组滴注等体积的博来霉素溶剂。造模后第8天开始给药，连续灌胃给药20天。在造模前，造模后第8天、第18天以及第28天进行micro-CT成像，观察小鼠肺部纤维化情况。
3.实验结果
如图3所示，长春西汀衍生物S26能够明显增加肺纤维化模型小鼠肺部正常组织的体积，定量结果如表10所示，说明长春西汀衍生物S26能够显著减轻博来霉素诱导的小鼠肺部纤维化程度，对肺部组织具有一定的保护作用。
表10肺部正常组织体积(Mean±SD.，n＝4，mm 3)
Figure PCTCN2022130902-appb-000150
以上实施例仅为本发明的示例性实施例，不用于限制本发明，本发明的保护范围由权利要求书限定。本领域技术人员可以在本发明的实质和保护范围内，对本发明做出各种修改或等同替换，这种修改或等同替换也应视为落在本发明的保护范围内。

Claims (15)

  1. 一种如式I所示化合物、其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药，特征在于，所述的化合物的结构式如下所示：
    Figure PCTCN2022130902-appb-100001
    式I中：
    X为O或-NR 1；
    R 1为氢、未取代或R 1-1取代的C 1- 6烷基、C 6-10芳基、C 3-10环烷基、“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基、或“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”4-10元杂环烷基、C 3-10环烷基-(C 1-4烷基)-或C 6-12芳基-(C 1-4烷基)-；
    R 1-1为卤素或羟基；
    Y为-(CH 2) m-；
    m为1-6的整数；
    Z为单键、
    Figure PCTCN2022130902-appb-100002
    Figure PCTCN2022130902-appb-100003
    R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自氢，未取代或R 3-1取代的C 1- 6烷基、C 6-10芳基，未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-、杂芳 基、或、杂芳基-(C 1-4烷基)-；所述的杂芳基为“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基；
    R 3-1为羟基、羧基、氨基、巯基、-(C＝O)NR 3-1-1、或、-NH(C＝NH)NH 2；
    R 3-1-1为氢或C 1-4烷基；
    R 3-2为卤素或羟基；
    R为氢、羟基、C 1-6烷氧基或、
    Figure PCTCN2022130902-appb-100004
    R 2为C 1-6烷基或氢；
    n是0～500的整数；
    Figure PCTCN2022130902-appb-100005
    为具有包含-(OCH 2CH 2) n-的直链、树形、星形或超支化结构的聚乙二醇。
  2. 一种如权利要求1所述的如式I所示化合物、其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药，其特征在于，当R 1为未取代或R 1-1取代的C 1-6烷基时，所述的R 1-1的个数为一个或多个，当存在多个R 1-1时，所述的R 1-1可相同或不同；
    和/或，当R 1为未取代或R 1-1取代的C 1-6烷基时，所述的C 1-6烷基为C 1-4烷基；
    和/或，当R 1为C 6-10芳基时，所述的C 6-10芳基为苯基；
    和/或，当R 1为C 3-10环烷基时，所述的C 3-10环烷基为C 3-6环烷基；
    和/或，当R 1为C 6-12芳基-(C 1-4烷基)-时，所述的C 6-12芳基-(C 1-4烷基)-为苄基；
    和/或，当R 1为C 3-10环烷基-(C 1-4烷基)-时，所述的C 3-10环烷基-(C 1-4烷基)-为C 3-6环烷基-(C 1-2烷基)；
    和/或，当R 1-1为卤素时，所述的卤素为氟、氯、溴或碘；
    和/或，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自未取代或R 3-1取代的C 1-6烷基时，所述的R 3-1的个数为一个或多个，当存在多个R 3-1时，所述的R 3-1可相同或不同；
    和/或，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自未取代或R 3-1取代的C 1-6烷基时，所述的C 1-6烷基为C 1-4烷基；
    和/或，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-时，所述的R 3-2的个数为一个或多个，当存在多个R 3-2时，所述的R 3-2可相同或不同；
    和/或，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自未取代或R 3-1取代的C 6-12芳基-(C 1-4烷基)-时，所述的C 6-12芳基-(C 1-4烷基)-为C 6-12芳基-(C 1-2烷基)-；
    和/或，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基-(C 1-4烷基)-时，所述的5～10元杂芳基-(C 1-4烷基)为5-9元杂芳基-(CH 2)-；
    和/或，当R 3-1-1为C 1-4烷基时，所述的C 1-4烷基为甲基、乙基、正丙基或异丙基；
    和/或，m为1-4的整数；
    和/或，n为0～400的整数；
    和/或，
    Figure PCTCN2022130902-appb-100006
    为具有包含-(OCH 2CH 2) n-的直链结构的聚乙二醇；
    和/或，当R 2为C 1-6烷基时，所述的C 1-6烷基为C 1-4烷基；
    和/或，当R为C 1-6烷氧基时，所述的C 1-6烷氧基为C 1-4烷氧基。
  3. 一种如权利要求1所述的如式I所示化合物、其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药，其特征在于，当R 1为未取代或R 1-1取代的C 1-6烷基时，所述的R 1-1的个数为1个、2个或3个；
    和/或，当R 1为未取代或R 1-1取代的C 1-6烷基时，所述的C 1-6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R 1为C 3-10环烷基时，所述的C 3-10环烷基为环丙基、环丁基、环戊基或环己基；
    和/或，当R 1为C 3-10环烷基-(C 1-4烷基)-时，所述的C 3-10环烷基-(C 1-4烷基)-为环丙甲基、环丁甲基、环戊甲基或环己甲基；
    和/或，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自未取代或R 3-1取代的C 1-6烷基时，所述的R 3-1的个数为1个、2个或3个；
    和/或，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自未取代或R 3-1取代的C 1-6烷基时，所述的C 1-6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R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-时，所述的R 3-2的个数为1个、2个或3个；
    和/或，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-时，所述的C 6-12芳基-(C 1-4烷基)-为苄基；
    和/或，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自 “杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基-(C 1-4烷基)-时，所述的5～10元杂芳基-(C 1-4烷基)为吲哚甲基或咪唑甲基；
    和/或，m为1-2的整数；
    和/或，n为0～100的整数；
    和/或，当R 2为C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基；
    和/或，当R为C 1-6烷氧基时，所述的C 1-6烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基或叔丁氧基。
  4. 一种如权利要求1所述的如式I所示化合物、其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药，其特征在于，当R 1为R 1-1取代的C 1-6烷基时，所述的R 1-1取代的C 1-6烷基为三氟甲基、或、
    Figure PCTCN2022130902-appb-100007
    和/或，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自R 3-1取代的C 1-6烷基时，所述的R 3-1取代的C 1-6烷基为
    Figure PCTCN2022130902-appb-100008
    Figure PCTCN2022130902-appb-100009
    和/或，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自R 3-2取代的C 6-12芳基-(C 1-4烷基)-时，所述的R 3-2取代的C 6-12芳基-(C 1-4烷基)-为
    Figure PCTCN2022130902-appb-100010
    和/或，当R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基-(C 1-4烷基)- 时，所述的5～10元杂芳基-(C 1-4烷基)为
    Figure PCTCN2022130902-appb-100011
  5. 一种如权利要求1所述的如式I所示化合物、其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药，其特征在于，R 1为氢、未取代或R 1-1取代的C 1-6烷基或C 3-10环烷基；
    和/或，R 1-1为羟基；
    和/或，m为1-2的整数；
    和/或，Z为单键或
    Figure PCTCN2022130902-appb-100012
    和/或，R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自氢、未取代或R 3-1取代的C 1-6烷基、未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-、杂芳基-(C 1-4烷基)-，所述的杂芳基为“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基；
    和/或，R 3-1为羟基、羧基、氨基、巯基、-(C＝O)NR 3-1-1、或、-NH(C＝NH)NH 2；
    和/或，R 3-1-1为氢；
    和/或，R 3-2为羟基；
    和/或，n是0～400的整数；
    和/或，
    Figure PCTCN2022130902-appb-100013
    为具有包含-(OCH 2CH 2) n-的直链结构的聚乙二醇。
  6. 一种如权利要求1所述的如式I所示化合物、其药学上可接受的盐、其代谢前体、 其代谢产物、其异构体或其前药，其特征在于，
    X为O或-NR 1；
    R 1为氢、未取代或R 1-1取代的C 1-6烷基或C 3-10环烷基；
    R 1-1为羟基；
    Y为-(CH 2) m-；
    m为1-2的整数；
    Z为单键或
    Figure PCTCN2022130902-appb-100014
    R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15独立地选自氢、未取代或R 3-1取代的C 1-6烷基、未取代或R 3-2取代的C 6-12芳基-(C 1-4烷基)-或杂芳基-(C 1-4烷基)-，所述的杂芳基为“杂原子选自N、O、S中的一种或多种，杂原子数为1-3个的”5-10元杂芳基；
    R 3-1为羟基、羧基、氨基、巯基、-(C＝O)NR 3-1-1、或、-NH(C＝NH)NH 2；
    R 3-1-1为氢；
    R 3-2为羟基；
    R为氢、羟基、C 1-6烷氧基或、
    Figure PCTCN2022130902-appb-100015
    R 2为C 1-6烷基或氢；
    n是0～400的整数；
    Figure PCTCN2022130902-appb-100016
    为具有包含-(OCH 2CH 2) n-的直链结构的聚乙二醇。
  7. 一种如权利要求1所述的如式I所示化合物、其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药，其特征在于，
    X为-NR 1；
    R 1为氢；
    Y为-(CH 2) m-；
    m为1-2的整数；
    Z为单键或
    Figure PCTCN2022130902-appb-100017
    R 3为氢、或、未取代或R 3-1取代的C 1-6烷基；
    R 3-1为羟基、羧基、氨基、巯基、-(C＝O)NR 3-1-1、或、-NH(C＝NH)NH 2；
    R 3-1-1为氢；
    R为氢、羟基、C 1-6烷氧基或、
    Figure PCTCN2022130902-appb-100018
    R 2为C 1-6烷基或氢；
    n是0～100的整数；
    Figure PCTCN2022130902-appb-100019
    为具有包含-(OCH 2CH 2) n-的直链结构的聚乙二醇。
  8. 一种如权利要求1所述的如式I所示化合物、其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药，其特征在于，所述的如式I所示化合物为以下任一化合物：
    Figure PCTCN2022130902-appb-100020
    Figure PCTCN2022130902-appb-100021
    Figure PCTCN2022130902-appb-100022
    Figure PCTCN2022130902-appb-100023
    Figure PCTCN2022130902-appb-100024
  9. 一种如权利要求1所述的如式I所示化合物的制备方法，其特征在于，合成包括以下步骤：在溶剂中，在碱和缩合剂的作用下，将如式II所示化合物与如式III所示化合物进行如下所示的缩合反应，即可；
    Figure PCTCN2022130902-appb-100025
    其中，L为-NHR 1、羟基
    Figure PCTCN2022130902-appb-100026
    R 1、X、Y、Z和R的定义如权利要求1-8中任一项所述。
  10. 如权利要求9所述的如式I所示化合物的制备方法，其特征在于，所述的溶剂为酰胺类溶剂或卤代烷烃类溶剂；
    和/或，所述的碱为有机碱或无机碱；
    和/或，所述的缩合剂为碳二亚胺类、有机磷盐类或鎓盐类。
  11. 一种药物组合物，其特征在于，它包括如权利要求1-8中任一项所述的如式I所示化合物、其药学上可接受的盐、其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药，和药用辅料。
  12. 一种如权利要求1-8中任一项所述的如式I所示化合物、其药学上可接受的盐、其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药在制备预防或治疗糖尿病并发症药物中的用途；所述的糖尿病为1型糖尿病和2型糖尿病；所述的糖尿病并发症主要是指糖尿病周围神经病变和糖尿病足。
  13. 一种如权利要求11所述的药物组合物在制备预防或治疗糖尿病并发症药物中的用途；所述的糖尿病为1型糖尿病和2型糖尿病；所述的糖尿病并发症主要是指糖尿病周围神经病变和糖尿病足。
  14. 一种如权利要求1-8中任一项所述的如式I所示化合物、其药学上可接受的盐、其药学上可接受的盐、其代谢前体、其代谢产物、其异构体或其前药在制备预防或治疗肺纤维化疾病药物中的用途。
  15. 一种如权利要求11所述的药物组合物在制备预防或治疗肺纤维化疾病药物中的用途。
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5141398A (zh) * 1974-06-21 1976-04-07 Synthelabo
DE2531108A1 (de) * 1975-07-11 1977-02-03 Synthelabo Vincaminderivate, verfahren zu ihrer herstellung und sie enthaltende arzneimittel
WO2013076646A1 (en) * 2011-11-22 2013-05-30 Richter Gedeon Nyrt. A new diaza-benzofluoranthene derivative as drug
WO2016124129A1 (zh) * 2015-02-04 2016-08-11 南京明德新药研发股份有限公司 二氮杂-苯并荧蒽类化合物
CN114920743A (zh) * 2022-05-09 2022-08-19 南京中医药大学 一种吲哚生物碱及其制备方法与应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02167279A (ja) * 1988-09-30 1990-06-27 Taisho Pharmaceut Co Ltd アポビンカミン酸誘導体
HU214600B (hu) * 1995-12-22 1998-04-28 Richter Gedeon Vegyészeti Gyár Rt. Transz-apovinkaminsav-észter-származékok, az azokat tartalmazó gyógyszerkészítmények és eljárás ezek előállítására

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5141398A (zh) * 1974-06-21 1976-04-07 Synthelabo
DE2531108A1 (de) * 1975-07-11 1977-02-03 Synthelabo Vincaminderivate, verfahren zu ihrer herstellung und sie enthaltende arzneimittel
WO2013076646A1 (en) * 2011-11-22 2013-05-30 Richter Gedeon Nyrt. A new diaza-benzofluoranthene derivative as drug
WO2016124129A1 (zh) * 2015-02-04 2016-08-11 南京明德新药研发股份有限公司 二氮杂-苯并荧蒽类化合物
CN107614498A (zh) * 2015-02-04 2018-01-19 哈药集团制药总厂 二氮杂‑苯并荧蒽类化合物
CN114920743A (zh) * 2022-05-09 2022-08-19 南京中医药大学 一种吲哚生物碱及其制备方法与应用

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