WO2023202559A1 - 一种苯基丙烯酸类化合物及其制备方法和应用 - Google Patents

一种苯基丙烯酸类化合物及其制备方法和应用 Download PDF

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WO2023202559A1
WO2023202559A1 PCT/CN2023/088888 CN2023088888W WO2023202559A1 WO 2023202559 A1 WO2023202559 A1 WO 2023202559A1 CN 2023088888 W CN2023088888 W CN 2023088888W WO 2023202559 A1 WO2023202559 A1 WO 2023202559A1
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compound
formula
amino
compound represented
hydrogen
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French (fr)
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刘晓宇
陈晓光
李燕
吕世亮
赵岩石
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朗捷睿(苏州)生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This application belongs to the field of medical technology, and specifically relates to a phenyl acrylic acid compound and its preparation method and application.
  • inflammation is a risk factor for tumors.
  • cervical cancer is more likely to be caused by papillomavirus infection; gastric Helicobacter pylori infection tends to increase the risk of gastric cancer; chronic hepatitis may also be the direct cause of liver cancer.
  • Other factors, such as autoimmune enteropathy and colon cancer are closely related, and PM2.5 in the air is also a culprit in inducing lung cancer.
  • Cancer is defined as a non-communicable disease like heart disease, chronic respiratory disease or diabetes. Most of them are chronic diseases that last for a long time and progress slowly. The correlation between inflammation and tumors was first proposed by Galenus 1800 years ago. Many studies have confirmed that persistent inflammation can progress from infection or autoimmune inflammation to tumors.
  • Phenyl acrylic acid compounds are widely found in active natural products. They have a variety of biological activities, such as antibacterial, antioxidant, anti-inflammatory, anti-tumor, etc., and have very broad research prospects. The applicant has long been engaged in the structure of such natural products. Research on the structure-activity relationship between optimization and anti-tumor activity, treatment of autoimmune diseases, and anti-inflammation. Structural modification of natural products can help discover that they have stronger tumor inhibitory activity than the original natural products and can treat autoimmune diseases and inflammatory diseases. Activity, lower toxicity lead, and further become an anti-tumor, anti-inflammatory immune drug.
  • Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. Encoded by the casp3 gene. Elevated levels of caspase-3, p17 fragment, in the blood are a marker of recent myocardial infarction. Current research shows that caspase-3 may play an important role in embryonic and hematopoietic stem cell differentiation and apoptosis. Studies have shown that the expression of caspase-3 is abnormally high in patients with head and neck cancer and breast cancer. Therefore, reducing its expression is also one of the ways to reduce the incidence of cancer to a certain extent.
  • Epidermal growth factor receptor Mutation activation of EGFR is an important factor leading to abnormal biological activities of tumor cells.
  • the T790M mutation in EGFR is a base pair from cytosine (C) to thymine (T).
  • C cytosine
  • T thymine
  • a change in the EGFR tyrosine kinase function that is, the threonine at position 790 in the EGFR tyrosine kinase function is replaced by methionine.
  • This mutation can reactivate EGFR, leading to resistance to tyrosine kinase inhibitors (TKIs).
  • TKIs tyrosine kinase inhibitors
  • Histone-lysine N-methyltransferase EZH2 is an enzyme encoded by the human EZH2 gene. Two transcript variants of this gene have been identified encoding different isoforms; gene sequence changes and epigenetic modification abnormalities are essentially different. Because once the DNA sequence mutates, the gene is difficult to repair or the mutated gene product is difficult to eliminate. However, epigenetic modification abnormalities can potentially be reversed by inhibitors of their associated chromatin-modifying enzymes. Therefore, it is very important to clarify the mechanism of epigenetic modification enzymes in tumor cells, thereby providing a basis for preventing epigenetic modification mutations. Corresponding treatment methods. Currently, there are no marketed drugs for EZH2 inhibitors, and a total of five drugs are in clinical phase I/II studies.
  • Histone deacetylase a type of protease that plays an important role in the structural modification of chromosomes and the regulation of gene expression.
  • HDAC histone deacetylase
  • acetylation of histones is conducive to the dissociation of DNA and histone octamers, and the nucleosome structure relaxes, allowing various transcription factors and co-transcription factors to specifically bind to DNA binding sites and activate genes. of transcription.
  • histone acetylation and histone deacetylation processes are in dynamic balance and are jointly regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC).
  • HAT histone acetyltransferase
  • HDAC histone deacetylase
  • Src kinase a non-receptor protein kinase that is widely found in cancer cells and plays an important role in various processes of cell growth and proliferation, such as gene transcription, cell differentiation, migration, angiogenesis, and prevention of cell death. Apoptosis, etc., the research on Src inhibitors has become a hot spot in anti-tumor drug research. There are currently a series of Src inhibitors in the clinical research stage.
  • Cancer immunotherapy is an increasingly effective cancer treatment strategy.
  • T cells play a key role in immunotherapy.
  • Many immune checkpoints are treasures to be discovered.
  • CTLA-4 and PD-1/PD-L1 monoclonal antibodies After the efficacy is confirmed, competition on this monoclonal antibody track is fierce, so more attention should be paid to other immune checkpoint targets, whose functions determine the efficacy of immunotherapy.
  • TCR signaling The survival and development of T cells are affected by TCR signaling, and the TCR signaling pathway depends on Src family kinases (SFK).
  • Lck is an important member of SFK and is expressed during most of the life cycle of T cells.
  • Lck plays an important role in activating the TCR signaling pathway to activate T cells.
  • CSK is a key regulator of SFK, and its phosphorylation of Lck (Tyr505) inactivates Lck, which inhibits T cell activation through TCR. Therefore, CSK and p-Lck(Tyr505) may be effective targets for future immunomodulatory treatments.
  • CD73 is a 5-primary nucleotidyl hydrolase that hydrolyzes extracellular adenosine monophosphate (AMP) into adenosine.
  • Adenosine is a powerful immunosuppressive molecule that can inhibit the activation of CD8-positive T cells, thereby Help cancer cells escape the "hunting" of T cells.
  • Tumor-infiltrating NK cells upregulate CD73 expression, and the frequency of these CD73+ NK cells correlates with tumor size in breast cancer patients.
  • the findings support that tumors can hijack NK cells for immune evasion and that CD73 expression defines an inducible NK cell population with immunomodulatory properties in the tumor microenvironment.
  • KIR Killer cell immunoglobulin-like receptor, a receptor expressed on the surface of NK cells and some T cells. It can specifically recognize MHC-I class molecules on the cell surface, thereby exerting an immune regulatory function.
  • LAG-3 Lymphocyte Activating Factor 3 protein is a negative immune regulatory molecule receptor distributed in activated T cells, NK cells and dendritic cells that can bind to MHC-II class molecules and has the function of maintaining internal environment stability. And its function of participating in immune regulation is closely related to the occurrence and development of tumors.
  • 4-1BB also known as CD137, is a member of the TNF family expressed on the surface of activated T cells. It is an inducible T cell surface receptor. 4-1BB and its ligands are another addition to the CD28/B7 costimulatory signaling pathway. An important costimulatory molecule.
  • ACAT1 belongs to the specific thiolase superfamily. Its Chinese name is acetoacetyl CoA sulfurylase, also known as acetyl-CoA acetyltransferase (ACAT). Many reports show that ACAT1 is often expressed in an abnormal state in tumor cells and has a negative impact on tumors. plays a vital role in its development. The mechanism by which ACAT1 activity is upregulated in different human cancer cells deserves study. High expression of ACAT1 will reduce its overall survival rate; ACAT1 is overexpressed in MDA-MB-231 human breast cancer cells, and the resulting ketone body reuse drives tumor progression and metastasis. Therefore, phenyl acrylic acid targeting ACAT1 is Research on derivatives may lead to the discovery of new anti-tumor drugs.
  • antioxidant and anti-inflammatory immunity it is related to:
  • phenylacrylic acid structure Since the phenylacrylic acid structure is widely present in the polyphenolic secondary metabolites of plants, it has strong antioxidant and anti-inflammatory properties. It can chelate metal ions and scavenge free radicals [superoxide anion (O 2 - ), hydrogen peroxide (H 2 O 2 ), hydroxyl free radicals radical ( ⁇ OH), hypochlorous acid (HOCl), peroxynitrite anion (ONOO - ) and nitric oxide (NO)]. Phenyl acrylic acid structural compounds have strong antioxidant activity, and their activity in scavenging 1,1-diphenyl-2-trinitrophenylhydrazine (DPPH) free radicals is 2-3 times that of vitamins C and E. The activity of superoxide anion free radicals is 10-30 times that of vitamins C and E.
  • DPPH 1,1-diphenyl-2-trinitrophenylhydrazine
  • tissue inflammatory response was reduced by regulating the mitogen-activated protein kinase/ERK/c-Jun N-terminal kinase signaling pathway. For this reason, it can be called a new therapeutic agent for the treatment of rheumatoid arthritis. Its mechanism is to reduce the DNA binding ability of NF- ⁇ B to the promoter region of B cell activating factor, thereby inhibiting B cell activation mediated through the NF- ⁇ B pathway. Activating factor expression.
  • liver function has a strong protective effect on liver function and can effectively reduce the production of TNF- ⁇ , IL-6 and IL-1 ⁇ inflammatory factors in acute liver injury induced by CCl 4.
  • the mechanism is through nuclear factor E-2 related factor 2 (nuclear factor erythroid 2-related factor 2, Nrf2)-mediated antioxidant and inhibition of Nod-like receptor family pyrin domain 3 inflammasome activation to protect against acute liver injury.
  • nuclear factor E-2 related factor 2 nuclear factor E-2 related factor 2 (nuclear factor erythroid 2-related factor 2, Nrf2)-mediated antioxidant and inhibition of Nod-like receptor family pyrin domain 3 inflammasome activation to protect against acute liver injury.
  • Such compounds can also increase B-cell lymphoma-2 (Bcl2) expression and inhibit cyclooxygenase-2, inducible nitric oxide synthase, Bax (Bcl2 associated X, Bax) and caspases 3. 9-mediated inflammatory response to reduce methotrexate (MTX)-induced
  • This application provides a phenylacrylic acid compound and its preparation method and application.
  • the phenylacrylic acid compound provided by this application can bind well to multiple target proteins and has good bioavailability. It can be used For the preparation of drugs for the prevention or treatment of tumors, autoimmune diseases, inflammatory diseases, neurodegenerative diseases or anti-aging.
  • this application provides a phenyl acrylic acid compound, which has the structure shown in the following formula I:
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, hydroxyl, dimethylamino, cyano, nitro, methylamino, methanesulfonate.
  • C1-C6 for example, it can be C1, C2, C3, C4, C5, C6, etc.) alkoxycarbonyl group
  • C1-C6 for example, it can be C1, C2, C3, C4 , C5, C6, etc.) alkylcarbonyloxy
  • C1-C6 for example, it can be C1, C2, C3, C4, C5, C6, etc.
  • alkylcarbonyloxy for example, it can be C1, C2, C3, C4, C5, C6, etc.
  • C1-C6 for example, it can be C1, C2, C3, C4, C5 , C6, etc.
  • alkoxy group for example, it can be C1, C2, C3, C4, C5, C6, etc.
  • C1-C6 for example, it can be C1, C2, C3, C4, C5, C6, etc.
  • C1-C6 for example, it can be C1, C2, C3, C4, C5, C6, etc.
  • trihalo C1-C6
  • R 5 is selected from hydrogen, amino, C1-C6 (for example, it can be C1, C2, C3, C4, C5, C6, etc.) alkyl, C1-C6 (for example, it can be C1, C2, C3, C4, C5, C6, etc.) ) any one of alkoxymethyl or C1-C6 (for example, it can be C1, C2, C3, C4, C5, C6, etc.) alkylamino;
  • R 6 is selected from hydrogen, hydroxyl, amino, carbonyl, C1-C6 (for example, it can be C1, C2, C3, C4, C5, C6, etc.) alkylamine group, C1-C6 (for example, it can be C1, C2, C3, Any one of C4, C5, C6, etc.) alkoxycarbonyloxy or C1-C6 (for example, it can be C1, C2, C3, C4, C5, C6, etc.) alkoxycarbonyl;
  • X is selected from O or NH
  • Y is selected from any one of O, NH, S, sulfoxide or sulfone.
  • the trihalo in the trihalo C1-C6 alkyl or trihalo C1-C6 alkoxy refers to containing 3 halogens, wherein the trihalo C1-C6 alkyl includes F 3 C1-C6 alkyl, Br 3 C1-C6 alkyl, Cl 3 C1-C6 alkyl, I 3 C1-C6 alkyl, F 2 Br C1-C6 alkyl, F 2 Cl C1-C6 alkyl, F 2 I C1-C6 alkyl, FBr 2 C1-C6 alkyl, FCl 2 C1-C6 alkyl, FI 2 C1-C6 alkyl, ClBr 2 C1-C6 alkyl, ICl 2 C1-C6 alkyl and ClI 2 C1-C6 alkyl; the trihalo C1-C6 alkoxy includes F 3 C1-C6 alkoxy, Br 3 C1-C6 alkoxy, Cl 3 C1-C
  • the trihalo C1-C6 alkyl group includes F 3 C1-C4 alkyl, Br 3 C1-C4 alkyl, Cl 3 C1-C4 alkyl, I 3 C1-C4 alkyl, F 2 Br C1 -C4 alkyl, F 2 Cl C1-C4 alkyl, F 2 I C1-C4 alkyl, FBr 2 C1-C4 alkyl, FCl 2 C1-C4 alkyl, FI 2 C1-C4 alkyl, ClBr 2 C1 -C4 alkyl, ICl 2 C1-C4 alkyl and ClI 2 C1-C4 alkyl;
  • the trihalo C1-C6 alkoxy group includes F 3 C1-C4 alkoxy group, Br 3 C 1-4 alkoxy group base, Cl 3 C1-C4 alkoxy group, I 3 C1-C4 alkoxy group, F 2 Br C1-C4 alkoxy group, F 2 Cl C1-C
  • the trihalo C1-C6 alkyl group includes F 3 C, F 3 CCH 2 , Br 3 C, Br 3 CCH 2 , Cl 3 C, Cl 3 CCH 2 , I 3 C, I 3 CCH 2 , F 2 BrC, F 2 BrCCH 2 , F 2 ClC, F 2 ClCCH 2 , F 2 IC, F 2 ICCH 2 , FBr 2 C, FBr 2 CCH 2 , FCl 2 C, FCl 2 C CH 2 , FI 2 C , FI 2 CCH 2 , ClBr 2 C, ClBr 2 CCH 2 , ICl 2 C, ICl 2 CCH 2 , ClI 2 C and ClI 2 CCH 2 ;
  • the trihalo C1-C6 alkoxy group includes F 3 CO, F 3 CCH 2 O, Br 3 CO, Br 3 CCH 2 O, Cl 3 CO, Cl 3 CCH 2 O, I 3 CO, I 3 CCH 2 O, F 2 BrCO, F 2 BrCCH 2
  • phenylacrylic acid compound is selected from any one of the following formula II to formula V:
  • R 1 and R 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methylamino, methanesulfonyl, dimethylsulfonyl, amino , carboxyl, C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkoxycarbonyl group, C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkylcarbonyloxy group, C1-C4 (for example, it can be It is C1, C2, C3, C4, etc.) alkyl, C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkoxy group, C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkyl Oxymethyleneoxy, trihalo C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkyl,
  • the R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methylamino, methanesulfonyl, dimethylsulfonyl, amino, carboxyl , C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkoxycarbonyl group, C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkylcarbonyloxy group, C1-C4 (for example, it can be C1 , C2, C3, C4, etc.) alkyl, C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkoxy group, trihalo C1-C4 (for example, it can be C1, C2, C3, C4, etc.) Any one of alkyl or trihalo C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkoxy;
  • the R 5 is selected from hydrogen, amino, C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkyl, C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkoxymethyl Or any one of C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkylamine group;
  • the R 6 is selected from hydrogen, hydroxyl, amino, carbonyl, C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkylamine group, C1-C4 (for example, it can be C1, C2, C3, C4, etc.) ) any one of alkoxycarbonyl or C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkoxycarbonyl;
  • the R 7 , R 8 and R 9 are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methylamino, methanesulfonyl, dimethylaminosulfonyl, Amino group, carboxyl group, C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkyl group, C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkoxy group, C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkoxycarbonyl group, C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkylcarbonyloxy group, C1-C3 (for example, it can be C1, C2, C3, etc.) alkanoyl group , C1-C4 (for example, it can be C1, C2, C3, C4, etc.) alkoxym
  • the X is selected from O or NH;
  • the Y is selected from any one of O, NH, S, sulfoxide or sulfone;
  • the p1, p2 and p3 are each independently selected from 1, 2 or 3.
  • the R 1 and R 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, Nitro, methoxycarbonyl, ethoxycarbonyl, methylamino, methanesulfonyl, dimethylsulfonyl, amino, methyl, ethyl, methoxy, ethoxy, C1-C2 (for example, it can be C1, C2, etc.) alkylcarbonyloxy, C1-C2 (for example, it can be C1, C2, etc.) alkoxymethyleneoxy, trihalo C1-C2 (for example, it can be C1, C2, etc.) alkyl or trihalo Any one of C1-C2 (for example, it can be C1, C2, etc.) alkoxy group;
  • the R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methoxycarbonyl, ethoxycarbonyl, methylamino, methanesulfonyl, di Methylaminosulfonyl, amino, methyl, ethyl, methoxy, ethoxy, C1-C2 (for example, it can be C1, C2, etc.) alkylcarbonyloxy, trihalo C1-C2 (for example, it can be C1, C2, etc.) C2, etc.) alkyl or any one of trihalo C1-C2 (for example, it can be C1, C2, etc.) alkoxy;
  • the R 5 is selected from hydrogen, amino, methyl, ethyl, C1-C2 (for example, it can be C1, C2, etc.) alkoxymethyl or C1-C2 (for example, it can be C1, C2, etc.) alkylamine group any of;
  • the R 6 is selected from hydrogen, amino, hydroxyl, carbonyl, C1-C2 (for example, it can be C1, C2, etc.) alkylamine group, C1-C2 (for example, it can be C1, C2, etc.) alkylcarbonyloxy group or C1- Any one of C2 (for example, it can be C1, C2, etc.) alkoxycarbonyl;
  • the R 7 , R 8 and R 9 are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methylamino, methanesulfonyl, dimethylaminosulfonyl, Amino, carboxyl, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propionyl, butyryl, valeryl, isobutyryl, 2-methylbutyl Acyl, C1-C2 (for example, it can be C1, C2, etc.) alkoxymethyleneoxy, trihalo C1-C2 (for example, it can be C1, C2, etc.) alkyl or trihalo C1-C2 (for example, it can be Is C1, C2, etc.) alkoxy group;
  • the X is selected from O or NH;
  • the Y is selected from any one of O, NH, S, sulfoxide or sulfone;
  • the p1, p2 and p3 are each independently selected from 1 or 2.
  • the R 1 and R 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methoxycarbonyl, methylamino, methanesulfonyl, Any one of dimethylsulfonyl, amino, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or methoxymethyleneoxy;
  • the R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methoxycarbonyl, methylamino, methanesulfonyl, dimethylaminosulfonyl , any one of amino, methyl, ethyl, methoxy, ethoxy, trifluoromethyl or trifluoromethoxy;
  • the R 5 is selected from any one of hydrogen, methyl, ethyl, methoxymethyl or amino;
  • R 6 is selected from any one of hydrogen, hydroxyl, amino, carbonyl or C1-C2 (for example, it can be C1, C2, etc.) alkylcarbonyloxy;
  • R 7 , R 8 and R 9 are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methylamino, methanesulfonyl, dimethylsulfonyl, amino, Carboxy, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, formyl, acetyl, propionyl, butyryl, valeryl, isobutyryl or Any of the methoxymethyleneoxy groups;
  • X is selected from O or NH
  • Y is selected from any one or a combination of at least two of O, NH, S, sulfoxide or sulfone;
  • the p1, p2 and p3 are each independently selected from 1.
  • the phenylacrylic acid compound is selected from any one of the following M1-M31:
  • the present application provides a tautomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof of the phenyl acrylic acid compound according to the first aspect.
  • the pharmaceutically acceptable salts include hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, acetate, trifluoroacetate, salicylate Acid, amino acid salt, citrate, maleate, tartrate, fumarate, citrate, lactate, sodium salt, potassium salt, calcium salt, magnesium salt, lithium salt, ammonium salt or can Any one or a combination of at least two of the salts of organic bases that provide physiologically acceptable cations.
  • the salt of the organic base that can provide physiologically acceptable cations includes methylamine salt, dimethylamine salt, trimethylamine salt, piperidine salt, morpholinium salt or tris(2-hydroxyethyl)amine salt. Any one or a combination of at least two of them.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • the compound of formula I may exist in the form of isomers, and the configuration of the carbon of the compound of formula I connecting the R 5 and R 6 groups may be R or S configuration.
  • This application includes all possible stereoisomers as well as mixtures of two or more isomers.
  • cis/trans isomers are present, this application relates to the cis and trans forms as well as mixtures of these forms, if desired the single isomer may be isolated according to conventional methods or prepared by stereoselective synthesis.
  • the present application provides a method for preparing the phenylacrylic acid compound according to the first aspect, the preparation method comprising the following steps:
  • the preparation method includes the following steps: performing a condensation reaction on the compound represented by formula f and the compound represented by formula g, to obtain the compound represented by formula I, and the reaction formula is as follows:
  • the X' is selected from OH or NH 2 ;
  • Y' is selected from tert-butyldimethylsiloxy, tert-butyldiphenylsiloxy, trimethylsiloxy, triethylsiloxy, benzyloxy, p-methoxybenzyloxy, methyl Any one of oxymethyleneoxy, benzyloxycarbonyloxy or tert-butoxycarbonyloxy;
  • Y is selected from any one of OH, NH2 or SH;
  • Z is selected from any one of hydroxyl, chlorine, bromine, iodine, p-toluenesulfonyl or methanesulfonyl.
  • step (1) the condensation reaction is carried out under alkaline conditions.
  • the condensation reaction is carried out in the presence of a condensing agent, and the condensing agent includes EDCI and/or DMAP.
  • the condensing agent includes EDCI and/or DMAP.
  • the temperature of the condensation reaction is 0-30°C (for example, it can be 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, etc.), and the time is 5 -15h (for example, it can be 5h, 7h, 9h, 11h, 13h, 15h, etc.).
  • the molar ratio of the compound represented by formula a to the compound represented by formula b is 1: (0.8-1.5);
  • 0.8-1.5 can be 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, etc.
  • the deprotecting group is performed by hydrolysis reaction or hydrogenation reaction.
  • step (2) the deprotecting group is carried out through a hydrolysis reaction, and the hydrolysis reaction is carried out under acidic conditions or alkaline conditions.
  • step (3) the substitution reaction is carried out under alkaline conditions.
  • the temperature of the substitution reaction is 60-100°C (for example, it can be 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C etc.), the time is 2-6h (for example, it can be 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, etc.).
  • step (3) the molar ratio of the compound represented by formula d to the compound represented by formula e is 1:(1-2);
  • 1-2 can be 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, etc.
  • the compound represented by formula f and the compound represented by formula g undergo a condensation reaction under alkaline conditions.
  • the compound represented by formula f and the compound represented by formula g undergo a condensation reaction in the presence of a condensing agent, and the condensing agent includes EDCI and/or DMAP.
  • the molar ratio of the compound represented by formula f to the compound represented by formula g is 1: (0.8-1.5);
  • 0.8-1.5 can be 0.8, 1, 1.1, 1.2, 1.3, 1.4, 1.5, etc.
  • the present application provides a pharmaceutical composition, which pharmaceutical composition includes an active ingredient and a pharmacodynamically acceptable carrier, and the active ingredient includes the phenyl acrylic compound described in the first aspect or the second
  • the tautomers, enantiomers, diastereomers or pharmaceutically acceptable salts thereof of the phenylacrylic acid compounds described in the aspect are particularly useful as pharmaceuticals, which pharmaceutical composition includes an active ingredient and a pharmacodynamically acceptable carrier, and the active ingredient includes the phenyl acrylic compound described in the first aspect or the second
  • the mass percentage of the active ingredient in the pharmaceutical composition is 0.1-95%, for example, it can be 0.1, 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95 wait.
  • compositions provided in this application can be prepared according to methods known in the art, and can be prepared by combining the active ingredients with one or more pharmaceutically acceptable solid or liquid excipients and/or auxiliaries, and are suitable for human use. or any dosage form for use by animals.
  • the pharmaceutical compositions described in the four aspects can be administered in unit dose form, and the route of administration can be intestinal or parenteral, such as oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eyes, lungs and respiratory tract. , skin, vagina, rectum, etc.
  • the dosage form for administration may be a liquid, solid or semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops agents, nose drops, lotions and liniments, etc.
  • solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosols (powder), sprays, etc.
  • semi-solid dosage forms can be ointments, Gels, pastes, etc.
  • the interaction between the phenyl acrylic acid compound described in the first aspect of the application and the phenyl acrylic acid compound described in the second aspect Isomers, enantiomers, diastereomers or pharmaceutically acceptable salts thereof or the pharmaceutical composition described in the fourth aspect can be made into ordinary preparations, sustained-release preparations, controlled-release preparations, target-release preparations, etc. To formulations and various particulate drug delivery systems.
  • the pharmaceutical composition described in the fourth aspect can be made into tablets, and various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and glidants.
  • the diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.;
  • the wetting agent can be water, ethanol, isopropyl Propanol, etc.;
  • the binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia glue, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl Cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.;
  • the disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyethylene glycol, etc.
  • the agent can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.
  • Tablets can also be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bi-layer and multi-layer tablets.
  • the tautomer, enantiomer, diastereomer or pharmaceutically acceptable salt thereof or the phenylacrylic acid compound described in the second aspect is made into a capsule, which can be mixed with a diluent and a glidant, and the mixture is directly placed in a hard capsule or soft capsule. It can also be made into granules or pellets with diluents, binders, and disintegrants, and then placed in hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants, and glidants used to prepare tablets can also be used to prepare capsules of the compound of the present application.
  • the pharmaceutical composition described in the fourth aspect can be made into an injection.
  • Water, ethanol, isopropyl alcohol, propylene glycol or their mixture can be used as the solvent and an appropriate amount of solubilizers, co-solvents, pH adjusters and osmotic pressure regulators commonly used in this field can be added. agent.
  • the solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.;
  • the pH adjuster can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.;
  • the osmotic pressure regulator can be It is sodium chloride, mannitol, glucose, phosphate, acetate, etc. If preparing freeze-dried powder for injection, mannitol, glucose, etc. can also be added as supporting agents.
  • colorants if necessary, colorants, preservatives, fragrances, flavoring agents or other additives can also be added to the pharmaceutical preparations.
  • the medicine or pharmaceutical composition of the present application can be administered by any known administration method.
  • the present application provides a tautomer, enantiomer, diastereomer or the phenylacrylic acid compound according to the first aspect, the phenylacrylic acid compound described in the second aspect, or the like.
  • a pharmaceutically acceptable salt or the pharmaceutical composition described in the fourth aspect in the preparation of drugs for preventing or treating tumors, autoimmune diseases, inflammatory diseases, neurodegenerative diseases or anti-aging.
  • the tumor is selected from the group consisting of glioma, melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epithelial cancer, head and neck cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer Any one or a combination of at least two of carcinoma, rectal adenocarcinoma, leukemia or lymphoma.
  • the autoimmune disease includes any one or a combination of at least two of rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, psoriasis, dermatitis or lateral sclerosis.
  • the inflammatory disease includes any one or a combination of at least two of polyarteritis, phlebitis, and reflux esophagitis.
  • the neurodegenerative disease includes Alzheimer's disease and/or Parkinson's disease.
  • the dosage of the pharmaceutical composition described in the four aspects can vary widely according to the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and dosage form, etc.
  • the suitable daily dose range of the salt or the pharmaceutical composition of the fourth aspect is 0.001-150 mg/Kg body weight, preferably 0.1-100 mg/Kg body weight, more preferably 1-70 mg/Kg body weight, most preferably 2- 30mg/Kg body weight.
  • the above dosage may be administered as a single dosage unit or divided into several dosage units, depending on the physician's clinical experience and the dosage regimen including the use of other therapeutic modalities.
  • the phenylacrylic acid compound described in the first aspect of the present application, the tautomer, enantiomer, diastereomer or pharmaceutically acceptable salt or pharmaceutically acceptable salt thereof of the phenylacrylic acid compound described in the second aspect can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When other therapeutic drugs have synergistic effects, their doses should be adjusted according to the actual situation.
  • the phenylacrylic acid compounds provided by this application have good binding to multiple target proteins and have good bioavailability, and can be used to prepare preparations for the prevention or treatment of tumors, autoimmune diseases, inflammatory diseases, and neurodegeneration.
  • diseases or anti-aging drugs wherein the tumor diseases are glioma, melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epithelial cancer, head and neck tumors, cervical cancer, ovarian cancer, pancreatic cancer cancer, prostate cancer, colon cancer, rectal adenocarcinoma, leukemia or lymphoma, etc.
  • reaction raw materials in the following examples are all commercially available conventional products.
  • This preparation example provides compound c-1.
  • the preparation method of compound c-1 includes the following steps:
  • This preparation example provides compound c-2.
  • Compound a-1 (536 mg, 2 mmol) and compound b-2 (557 mg, 2.2 mmol) are used as raw materials.
  • the preparation method of compound c-2 is the same as that of compound c-1.
  • Compound c-2 is obtained.
  • the reaction formula of compound c-2 is as follows:
  • This preparation example provides compound c-3.
  • Compound a-1 (536 mg, 2 mmol) and compound b-3 (490 mg, 2.2 mmol) are used as raw materials.
  • the preparation method of compound c-3 is the same as compound c-1.
  • Compound c-3 is obtained.
  • the reaction formula of compound c-3 is as follows:
  • This preparation example provides compound d-1.
  • the preparation method of compound d-1 includes the following steps:
  • This preparation example provides compound d-2, using compound c-2 (500 mg, 1 mmol) as raw material, and the compound d-2 is The preparation method is the same as that of compound d-1, and 352 mg of compound d-2 is obtained as a light yellow solid with a yield of 90.1%.
  • the reaction formula of compound d-2 is as follows:
  • This preparation example provides compound d-3.
  • Compound c-3 (470 mg, 1 mmol) is used as raw material.
  • the preparation method of compound d-3 is the same as compound d-1.
  • Compound d-3 is obtained as a light yellow solid 340 mg with a yield of 94.7 %, the reaction formula of compound d-3 is as follows:
  • This embodiment provides compound M1.
  • the preparation method of compound M1 includes the following steps:
  • a 50mL round-bottomed bottle is filled with (50mg, 0.13mmol) compound d-1, (50mg, 0.2mmol) 3,4-dimethoxyphenylethyl bromide (e-1), (85mg, 0.26mmol) cesium carbonate and 5 mL acetonitrile, refluxed for 4 h, TLC showed completeness, filtered after cooling to obtain 60 mg of crude product, dissolved in 5 mL tetrahydrofuran, added 0.3 mL concentrated hydrochloric acid, stirred for 1 h, concentrated to obtain 47 mg of compound M1, yield 78.3%.
  • This example provides compound M2, in the form of compound d-1 (50 mg, 0.13 mmol) and compound e-2 (80 mg, 0.22 mmol) as the raw material, the preparation method of the compound M2 is the same as that of the compound M1, and 54 mg of the yellow solid of the compound M2 is obtained, with a yield of 84.2%.
  • the reaction formula of the compound M2 is as follows:
  • This embodiment provides compound M3, using compound d-1 (50 mg, 0.14 mmol) and compound e-3 (80 mg, 0.22 mmol) as raw materials.
  • the preparation method of compound M3 is the same as compound M1, and 45 mg of compound M3 is obtained as a yellow solid. The yield is 64.3%.
  • the reaction formula of the compound M3 is as follows:
  • This embodiment provides compound M4, using compound d-3 (130 mg, 0.36 mmol) and compound e-4 (100 mg, 0.54 mmol) as raw materials.
  • the preparation method of compound M4 is the same as compound M1, and 100 mg of compound M4 is obtained as a yellow solid. The yield is 88.5%.
  • the reaction formula of the compound M4 is as follows:
  • This embodiment provides compound M5, using compound d-3 (150 mg, 0.42 mmol) and compound e-5 (134 mg, 0.63 mmol) as raw materials.
  • the preparation method of compound M5 is the same as compound M1, and 150 mg of compound M5 is obtained as a yellow solid. The yield is 88.2%.
  • the reaction formula of the compound M5 is as follows:
  • This embodiment provides compound M6, using compound d-3 (150 mg, 0.42 mmol) and compound e-6 (126 mg, 0.63 mmol) as raw materials.
  • the preparation method of compound M6 is the same as compound M1, and 100 mg of compound M6 is obtained as a yellow solid. The yield is 60.6%.
  • the reaction formula of the compound M6 is as follows:
  • This embodiment provides compound M7, using compound d-3 (150 mg, 0.42 mmol) and compound e-7 (125 mg, 0.63 mmol) as raw materials.
  • the preparation method of compound M7 is the same as compound M1, and 101 mg of compound M7 is obtained as a yellow solid. The yield is 61.9%.
  • the reaction formula of compound M7 is as follows:
  • This embodiment provides compound M8, using compound d-3 (150 mg, 0.42 mmol) and compound e-8 (126 mg, 0.63 mmol) as raw materials.
  • the preparation method of compound M8 is the same as compound M1, and 80 mg of compound M8 is obtained as a yellow solid. The yield is 50%.
  • the reaction formula of the compound M8 is as follows:
  • This example provides compound M9, which uses compound d-3 (150 mg, 0.42 mmol) and compound e-1 (153 mg, 0.63 mmol) as raw materials.
  • the preparation method of compound M9 is the same as compound M1, and 100 mg of compound M9 is obtained as a light yellow solid. , the yield is 54.6%.
  • the reaction formula of the compound M9 is as follows:
  • This example provides compound M10, which uses compound d-3 (150 mg, 0.42 mmol) and compound e-9 (173 mg, 0.63 mmol) as raw materials.
  • the preparation method of compound M10 is the same as compound M1, and 95 mg of compound M10 is obtained as a light yellow solid. , the yield is 48.7%.
  • the reaction formula of the compound M10 is as follows:
  • This embodiment provides compound M11, using compound d-3 (130 mg, 0.36 mmol) and compound e-4 (100 mg, 0.54 mmol) as raw materials.
  • the preparation method of compound M11 is the same as compound M1, without acidification, to obtain compound M11. 110 mg of light yellow solid, yield 66.3%.
  • the reaction formula of compound M11 is as follows:
  • This embodiment provides compound M12, which uses compound d-3 (150 mg, 0.42 mmol) and compound e-5 (134 mg, 0.63 mmol) as raw materials.
  • the preparation method of compound M12 is the same as compound M1, without acidification, to obtain compound M12.
  • Light yellow solid 180 mg, yield 87%.
  • the reaction formula of compound M12 is as follows:
  • This example provides compound M13, which uses compound d-3 (150 mg, 0.42 mmol) and compound e-6 (125 mg, 0.62 mmol) as raw materials.
  • the preparation method of compound M13 is the same as compound M1, without acidification, to obtain compound M13. 120 mg of light yellow solid, yield 59.4%.
  • the reaction formula of compound M13 is as follows:
  • This embodiment provides compound M14, which uses compound d-3 (150 mg, 0.42 mmol) and compound e-7 (125 mg, 0.62 mmol) as raw materials.
  • the preparation method of compound M14 is the same as compound M1, without acidification, to obtain compound M14.
  • the reaction formula of compound M14 is as follows:
  • This example provides compound M15, which uses compound d-3 (60 mg, 0.22 mmol) and compound e-8 (25 mg, 0.18 mmol) as raw materials.
  • the preparation method of compound M15 is the same as compound M1, without acidification, to obtain compound M15. 60 mg of light yellow solid, yield 83.4%.
  • the reaction formula of compound M15 is as follows:
  • This example provides compound M16, which uses compound d-3 (150 mg, 0.42 mmol) and compound e-1 (206 mg, 0.84 mmol) as raw materials.
  • the preparation method of compound M16 is the same as compound M1, without acidification, to obtain compound M16. 150 mg of light yellow solid, yield 68.2%.
  • the reaction formula of compound M16 is as follows:
  • This example provides compound M17, which uses compound d-3 (150 mg, 0.42 mmol) and compound e-9 (173 mg, 0.63 mmol) as raw materials.
  • the preparation method of compound M17 is the same as compound M1, without acidification, to obtain compound M17.
  • the reaction formula of compound M17 is as follows:
  • This example provides compound M18, using compound d-1 (50 mg, 0.13 mmol) and compound e-4 (37 mg, 0.2 mmol) as raw materials.
  • the preparation method of compound M18 is the same as compound M1, and 30 mg of compound M18 is obtained as a light yellow solid. , the yield is 56.6%.
  • the reaction formula of the compound M18 is as follows:
  • This example provides compound M19, which uses compound d-1 (100 mg, 0.26 mmol) and compound e-6 (66 mg, 0.33 mmol) as raw materials.
  • the preparation method of compound M19 is the same as compound M1, and 60 mg of compound M19 is obtained as a light yellow solid. , the yield is 54.4%.
  • the reaction formula of the compound M19 is as follows:
  • This embodiment provides compound M20, using compound d-1 (50 mg, 0.13 mmol) and compound e-5 (70 mg, 0.33 mmol) as raw materials.
  • the preparation method of compound M20 is the same as compound M1, and 40 mg of compound M20 is obtained as a light yellow solid. , the yield is 70.2%.
  • the reaction formula of the compound M20 is as follows:
  • This example provides compound M21, which uses compound d-1 (50 mg, 0.13 mmol) and compound e-7 (45 mg, 0.23 mmol) as raw materials.
  • the preparation method of compound M21 is the same as compound M1, and 40 mg of compound M21 is obtained as a light yellow solid. , the yield is 72.7%.
  • the reaction formula of the compound M21 is as follows:
  • This example provides compound M22, using compound d-1 (80 mg, 0.28 mmol) and compound e-9 (104 mg, 0.38 mmol) as raw materials.
  • the preparation method of compound M22 is the same as compound M1, and 85 mg of compound M22 is obtained as a light yellow solid. , the yield is 61.6%.
  • the reaction formula of the compound M22 is as follows:
  • This example provides compound M23, using compound d-3 (150 mg, 0.42 mmol) and compound e-10 (34 mg, 0.23 mmol) as raw materials.
  • the preparation method of compound M23 is the same as compound M1, and 80 mg of compound M23 is obtained as a light yellow solid. , the yield is 83.3%.
  • the reaction formula of the compound M23 is as follows:
  • This example provides compound M24, which uses compound d-2 (80 mg, 0.27 mmol) and compound e-1 (80 mg, 0.33 mmol) as raw materials.
  • the preparation method of compound M24 is the same as compound M1, and 84 mg of compound M24 is obtained as a light yellow solid. , the yield is 66.7%.
  • the reaction formula of the compound M24 is as follows:
  • This example provides compound M25, using compound d-2 (80 mg, 0.27 mmol) and compound e-4 (64 mg, 0.35 mmol) as raw materials.
  • the preparation method of compound M25 is the same as compound M1, and 80 mg of compound M25 is obtained as a light yellow solid. , the yield is 73.4%.
  • the reaction formula of the compound M25 is as follows:
  • This embodiment provides compound M26, which uses compound f-1 (100 mg, 0.67 mmol) and compound g-1 (233 mg, 0.77 mmol) as raw materials.
  • the preparation method of compound M26 is the same as compound M1, without acidification, to obtain compound M26. 200 mg of light yellow solid, yield 69%.
  • the reaction formula of compound M26 is as follows:
  • This embodiment provides compound M27, which uses compound f-2 (100 mg, 0.56 mmol) and compound g-1 (233 mg, 0.77 mmol) as raw materials.
  • the preparation method of compound M27 is the same as compound M26, without acidification, to obtain compound M27.
  • the reaction formula of compound M27 is as follows:
  • This embodiment provides compound M28, which uses compound f-3 (100 mg, 0.52 mmol) and compound g-1 (233 mg, 0.77 mmol) as raw materials.
  • the preparation method of compound M28 is the same as compound M26, without acidification, to obtain compound M28.
  • Light yellow solid 180 mg, yield 72.6%.
  • the reaction formula of compound M28 is as follows:
  • This embodiment provides compound M29, using compound f-4 (100 mg, 0.60 mmol) and compound g-1 (233 mg, 0.77 mmol) as raw materials.
  • the preparation method of compound M29 is the same as compound M26, without acidification, to obtain compound M29. 150 mg of light yellow solid, yield 55.6%.
  • the reaction formula of compound M29 is as follows:
  • This embodiment provides compound M30, which uses compound f-5 (100 mg, 0.62 mmol) and compound g-1 (233 mg, 0.77 mmol) as raw materials.
  • the preparation method of compound M30 is the same as compound M26, without acidification, to obtain compound M30. 150 mg of light yellow solid, yield 54.2%.
  • the reaction formula of compound M30 is as follows:
  • This example provides compound M31, which uses compound f-6 (100 mg, 0.55 mmol) and compound g-1 (233 mg, 0.77 mmol) as raw materials.
  • the preparation method of compound M31 is the same as compound M26, without acidification, to obtain compound M31. 116 mg of light yellow solid, yield 45%.
  • the reaction formula of compound M31 is as follows:
  • ACAT1 can catalyze the reversible formation of acetoacetyl-CoA from two molecules of acetyl-CoA. Its activity is measured by ACAT1 catalyzing the reaction of the substrate acetoacetyl-CoA with coenzyme A to generate the product acetyl-CoA. Acetoacetyl-CoA has specific absorption in a specific spectrum. Therefore, the impact on ACAT1 enzyme activity is reflected by detecting the increase or decrease in specific spectrum absorption.
  • the ACAT1 recombinant protein was expressed and purified through Escherichia coli, and the concentration of the obtained ACAT1 recombinant protein was 1 mg/mL.
  • the buffers used were 50mM Tris-HCl (pH 8.1), 20mM MgCl 2 and 40mM KCl.
  • 1 ⁇ L of ACAT1 recombinant protein was added, the final concentration of substrate acetyl-CoA was 25 ⁇ M, the CPM probe was added to the final concentration of 100 ⁇ M, and small molecule inhibitors of different concentrations were added.
  • the enzyme was detected using a microplate reader (Biotek Synergy H1) using excitation light of 355nm and emission light of 460nm, and software Prism 7.0 was used to calculate inhibitor IC 50 .
  • PK Pyruvate kinase catalyzes the conversion of phosphoenolpyruvate (PEP) into pyruvate in the presence of adenosine diphosphate (ADP).
  • ADP adenosine diphosphate
  • pyruvate is LDH is converted into lactic acid, if labeled with fluorescent
  • NADH reduced coenzyme I
  • PKLR Two recombinant protein pyruvate kinase isoforms: PKLR (15501-H07E) and PKM2 (11430-H07E) were purchased from Beijing Yiqiao Shenzhou Technology Co., Ltd.
  • the buffer used was 100mM Tris HCl (pH 8.0), 100mM KCl and 10mM MgCl 2 .
  • ADP 0.6mM
  • PEP 0.5mM
  • NADH 180mM
  • FBP 10mM
  • LDH 8units

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Abstract

本申请提供一种苯基丙烯酸类化合物及其制备方法和应用，所述苯基丙烯酸类化合物具有如下式(I)所示结构，本申请提供的苯基丙烯酸类化合物可以与多个靶点蛋白有较好的结合，并且具有较好的生物利用度，可用于制备预防或治疗肿瘤、自身免疫性疾病、炎症性疾病、神经退行性疾病或抗衰老药物。

Description

一种苯基丙烯酸类化合物及其制备方法和应用 技术领域
本申请属于医药技术领域，具体涉及一种苯基丙烯酸类化合物及其制备方法和应用。
背景技术
世界卫生组织国际癌症研究机构(IARC)发布了2020年全球最新癌症负担数据。2020年全球新发癌症病例1929万例，其中中国新发癌症约460万人，中国是世界第一人口大国，新发癌症患者数量复合年增长率高于全球平均水平。预计到2025年新发患者人数将达到520万人，占全球新发患者人数的26.9％。
医学数据表明，炎症是导致肿瘤的危险因素。例如，宫颈癌中由于乳头瘤病毒感染所致的患者较多；胃幽门螺杆菌的感染有增加胃癌风险的趋势；慢性肝炎也可能是诱发肝癌的直接原因。其它因素，如自身免疫性肠病与结肠癌密切相关，空气中的PM2.5也是诱发肺癌的黑手。肿瘤被定义为一种与心脏病、慢性呼吸系统疾病或者糖尿病一样非传染性的疾病。它们大多是长时间的慢性疾病，进展比较缓慢。炎症和肿瘤的相关性是最早在1800年前由Galenus提出的，很多研究已经证实持续的炎症可以使病变从感染或者自身免疫性的炎症进展为肿瘤。
苯基丙烯酸类化合物广泛存在于活性天然产物中，其具有多种生物活性，如抗菌、抗氧化、抗炎、抗肿瘤等，具有非常广阔的研究前景，申请人长期从事此类天然产物的结构优化与抗肿瘤活性、治疗自身免疫性疾病和抗炎症的构效关系研究，针对天然产物的结构改造有助于发现比原天然产物具有更强肿瘤抑制活性、治疗自身免疫性疾病和炎症性疾病活性，更低毒性的先导物，而进一步成为抗肿瘤、抗炎免疫药物。
此申请内容所设计的苯基丙烯酸类衍生物在抗肿瘤潜在的靶点概括如下：
Caspase-3是一种与caspase-8和caspase-9相互作用的caspase蛋白。由casp3基因编码。血液中caspase-3，p17片段的水平升高是最近心肌梗死的一个标志。现在有研究表明caspase-3可能在胚胎和造血干细胞分化、细胞凋亡中起着重要作用。有研究表明头颈癌以及乳腺癌患者中caspase-3的表达量异常的高，因此降低其表达，在一定程度上也是可以减少癌症发病的方法之一。
表皮生长因子受体(EGFR)：EGFR的突变活化是导致肿瘤细胞异常生物学活动的重要因素，其中EGFR中T790M突变是一个碱基对发生从胞嘧啶核苷(C)到胸腺嘧啶(T)的改变，即EGFR酪氨酸激酶功能中790位点的苏氨酸被蛋氨酸取代，这种突变可使得EGFR重新处于被激活状态，从而导致酪氨酸激酶抑制剂(TKI)产生耐药性。而我们将此突变后的蛋白与此类天然产物以及衍生物通过计算机辅助设计的方法对接后发现，此类化合物的打分都很高，提示：苯基丙烯酸类衍生物可以成为此靶点的候选物。
组蛋白-赖氨酸N-甲基转移酶EZH2：EZH2是一个由人类EZH2基因所编码的酶。已鉴定该基因转录出的两种转录物变异体编码不同的亚型；基因序列改变与表观遗传修饰异常有本质的不同。因为DNA序列一旦发生突变，基因就难以修复或变异的基因产物也难以消除。但是表观遗传修饰异常能潜在性地被其相关染色质修饰酶类的抑制剂所逆转。因此，明确肿瘤细胞中的表观遗传修饰酶类的作用机制显得十分重要，进而为阻止表观遗传修饰变异提供 相应治疗手段。目前EZH2抑制剂并未有上市药物，共有五种药物正在临床I/II期研究中。
组蛋白去乙酰化酶(histone deacetylase，HDAC)：一类蛋白酶，对染色体的结构修饰和基因表达调控发挥着重要的作用。一般情况下，组蛋白的乙酰化有利于DNA与组蛋白八聚体的解离，核小体结构松弛，从而使各种转录因子和协同转录因子能与DNA结合位点特异性结合，激活基因的转录。在细胞核内，组蛋白乙酰化与组蛋白去乙酰化过程处于动态平衡，并由组蛋白乙酰化转移酶(histone acetyltransferase，HAT)和组蛋白去乙酰化酶(histone deacetylase，HDAC)共同调控。
Src激酶：一种非受体型蛋白激酶,其广泛存在于癌细胞中,并在细胞生长、增殖的各个过程中都起到重要作用，如基因转录、细胞分化、迁移、血管生成、防止细胞凋亡等，Src抑制剂的研究已成为抗肿瘤药物研究的热点。目前已有一系列Src抑制剂处于临床研究阶段。
癌症免疫治疗是一种越来越有效的癌症治疗策略，T细胞在免疫治疗中起着关键作用，众多免疫检查点是有待发掘的宝藏，自CTLA-4和PD-1/PD-L1单抗疗效得到肯定后，在此的单抗轨道上竞争激烈，因此应更关注于其他免疫检查点靶点上，其功能决定了免疫治疗的疗效。
T细胞的生存和发育受到TCR信号的影响，而TCR信号通路依赖于Src家族激酶(SFK)。Lck是SFK的重要成员，在T细胞的大部分生命周期中都有表达。此外，Lck在激活TCR信号通路以激活T细胞中发挥重要作用。CSK是SFK的关键调节器，其对Lck(Tyr505)的磷酸化使Lck失活，后者通过TCR抑制T细胞活化。因此，CSK和p-Lck(Tyr505)可能是未来免疫调节治疗的有效靶点。
CD73是5-主核苷酸水解酶，可将细胞外腺苷一磷酸(AMP)水解为腺苷，腺苷是一种功能强大的免疫抑制性分子，能够抑制CD8阳性T细胞的活化，进而帮助癌细胞逃逸T细胞的“追杀”。浸润肿瘤的NK细胞上调CD73表达，而这些CD73+NK细胞的发生频率与乳腺癌患者肿瘤的大小相关。研究结果支持肿瘤可以劫持NK细胞以免疫逃避，并且CD73表达定义了可诱导的NK细胞群体，在肿瘤微环境中具有免疫调节特性。
KIR：杀伤细胞免疫球蛋白样受体，表达在NK细胞和部分T细胞表面的受体，能特异性识别细胞表面MHC-I类分子，从而发挥免疫调节功能。
LAG-3：淋巴细胞活化因子3蛋白，是分布于活化T细胞、NK细胞和树突状细胞中的一种可与MHC-II类分子结合的免疫负调节分子受体，具有维持内环境稳定和参与免疫调节的功能，与肿瘤的发生发展密切相关。
4-1BB也称CD137，是表达在活化T细胞表面的TNF家族成员，是一种可诱导的T细胞表面受体，4-1BB及其配体是CD28/B7共刺激信号途径之外的另一重要共刺激分子。
ACAT1属于特异性硫醇酶超家族，中文名称为乙酰乙酰CoA硫化酶，也被称为乙酰CoA乙酰基转移酶(ACAT)，许多报道显示ACAT1在肿瘤细胞中表达通常呈现异常状态，并对肿瘤的发生发展起到至关重要的作用。ACAT1的活性在不同的人类癌症细胞中的上调机制值得研究。ACAT1的高表达会降低其总体生存率；MDA-MB-231人乳腺癌细胞中ACAT1过度表达，所导致的酮体再利用驱动肿瘤的进展和转移，因此对以ACAT1为靶点的苯基丙烯酸类衍生物的研究，可能会发现新型抗肿瘤药物。
在抗氧化和抗炎免疫方面与如下有关：
由于苯基丙烯酸结构广泛存在于植物的多酚类次生代谢产物中，具有很强抗氧化和抗炎特性。其能够螯合金属离子和清除自由基[超氧阴离子(O2 -)、过氧化氢(H2O2)、羟基自由 基(·OH)、次氯酸(HOCl)、过氧亚硝酸盐阴离子(ONOO-)和一氧化氮(NO)]。苯基丙烯酸类结构化合物具有很强的抗氧化活性，其清除1,1-二苯基-2-三硝基苯肼(DPPH)自由基的活性是维生素C和E的2-3倍，清除超氧阴离子自由基的活性是维生素C和E的10-30倍。
在抗炎作用方面，对角叉菜胶致大鼠足跖肿胀炎症模型具有抗炎活性。其机制可通过清除细胞内ROS，抑制p38级联磷酸化和上调核因子κB(nuclear factor kappa-B，NF-κB)信号通路来抑制白介素-8(interleukin-8，IL-8)的产生，从而起到抗炎作用。
然而在硫酸葡聚糖诱导的小鼠溃疡性结肠炎模型中，通过调控丝裂原活化蛋白激酶/ERK/c-Jun氨基末端激酶信号通路来降低组织的炎症反应。为此可称为治疗类风湿关节炎的新型治疗剂，其机制是通过降低了NF-κB与B细胞活化因子启动子区域的DNA结合能力，进而抑制了通过NF-κB途径介导的B细胞活化因子表达。同时具有较强的肝功能保护作用，可有效降低CCl4诱导的急性肝损伤产生TNF-α、IL-6和IL-1β炎症因子，其机制是通过核因子E-2相关因子2(nuclear factor erythroid 2-related factor 2，Nrf2)介导的抗氧化和抑制Nod样受体家族热蛋白结构域3炎症小体的激活来进行急性肝损伤的保护作用。此类化合物也可以通过增加B淋巴细胞瘤-2(B-cell lymphoma-2，Bcl2)表达并抑制环氧化酶-2、诱导型一氧化氮合酶、Bax(Bcl2associated X，Bax)和caspases 3、9介导的炎症反应来降低甲氨蝶呤(methotrexate，MTX)诱导的肝毒。
神经退行性疾病阿尔茨海默病和帕金森病的病理学研究表明，慢性氧化应激和炎症反应会导致神经元受损。基于苯基丙烯酸类较强的抗氧化和抗炎作用，发现它具有很好的神经系统保护作用。一些临床和临床前研究表明，苯基丙烯酸类天然产物对阿尔茨海默病和帕金森病展现出很好的治疗效果。可以改善记忆力减退和海马细胞短暂性全脑缺血后死亡，其机制是通过增加Bcl2、超氧化物歧化酶2和血小板-内皮细胞黏附分子CD31表达，并降低内皮素-1表达来改善空间记忆，防止双侧颈总动脉闭塞后CA1锥体细胞死亡。通过激活SIRT1调节的线粒体功能来预防饱和游离脂肪酸(free fatty acid，FFA)诱导的脂毒性。其机制是通过减少ROS的产生以及增加线粒体质量和线粒体膜电位，减轻了氧化应激和线粒体功能障碍；显著降低促细胞凋亡蛋白Bax表达，从而减少线粒体介导的caspase依赖性细胞凋亡。
尽管苯基丙烯酸类衍生物已被证实具有如上较广的活性作用，但其确切的作用机制以及构效关系需要进一步的研究，需要合成其结构衍生物，并研究其药物作用方式以及可用来治疗的疾病，尤其是炎症相关、肿瘤、自身免疫性疾病、神经退行性疾病和衰老等。
发明内容
本申请提供了一种苯基丙烯酸类化合物及其制备方法和应用，本申请提供的苯基丙烯酸类化合物可以与多个靶点蛋白有较好的结合，并且具有较好的生物利用度，可用于制备预防或治疗肿瘤、自身免疫性疾病、炎症性疾病、神经退行性疾病或抗衰老药物。
第一方面，本申请提供一种苯基丙烯酸类化合物，所述苯基丙烯酸类化合物具有如下式I所示结构：
其中，R1、R2、R3、R4、R7、R8和R9各自独立地选自氢、卤素、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷氧羰基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷羰基氧基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷氧基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷氧基亚甲基氧基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷酰基、三卤代C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷基或三卤代C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷氧基中的任意一种；或者，R1、R2、R7、R8和R9各自独立地选自-O(CH2)nO-，并与其取代的苯基相连成环，n选自1、2或3；
R5选自氢、氨基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷氧基甲基或C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷基胺基中的任意一种；
R6选自氢、羟基、氨基、羰基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷基胺基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷羰基氧基或C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷氧基羰基中的任意一种；
X选自O或NH；以及
Y选自O、NH、S、亚砜或砜中的任意一种。
在本申请中，所述三卤代C1-C6烷基或三卤代C1-C6烷氧基中三卤指的是含3个卤素，其中，所述三卤代C1-C6烷基包括F3C1-C6烷基、Br3C1-C6烷基、Cl3C1-C6烷基、I3C1-C6烷基、F2Br C1-C6烷基、F2Cl C1-C6烷基、F2I C1-C6烷基、FBr2C1-C6烷基、FCl2C1-C6烷基、FI2C1-C6烷基、ClBr2C1-C6烷基、ICl2C1-C6烷基和ClI2C1-C6烷基；所述三卤代C1-C6烷氧基包括F3C1-C6烷氧基、Br3C1-C6烷氧基、Cl3C1-C6烷氧基、I3C1-C6烷氧基、F2Br C1-C6烷氧基、F2Cl C1-C6烷氧基、F2I C1-C6烷氧基、FBr2C1-C6烷氧基、FCl2C1-C6烷氧基、FI2C1-C6烷基、ClBr2C1-C6烷氧基、ICl2C1-C6烷氧基和ClI2C1-C6烷氧基；
优选地，所述三卤代C1-C6烷基包括F3C1-C4烷基、Br3C1-C4烷基、Cl3C1-C4烷基、I3C1-C4烷基、F2Br C1-C4烷基、F2Cl C1-C4烷基、F2I C1-C4烷基、FBr2C1-C4烷基、FCl2C1-C4烷基、FI2C1-C4烷基、ClBr2C1-C4烷基、ICl2C1-C4烷基和ClI2C1-C4烷基；所述三卤代C1-C6烷氧基包括F3C1-C4烷氧基、Br3C1-4烷氧基、Cl3C1-C4烷氧基、I3C1-C4烷氧基、F2Br C1-C4烷氧基、F2Cl C1-C4烷氧基、F2I C1-C4烷氧基、FBr2C1-C4烷氧基、FCl2C1-C4烷氧基、FI2C1-C4烷基、ClBr2C1-C4烷氧基、ICl2C1-4烷氧基、ClI2C1-C4烷氧基；
更优选地，所述三卤代C1-C6烷基包括F3C、F3CCH2、Br3C、Br3CCH2、Cl3C、Cl3CCH2、I3C、I3CCH2、F2BrC、F2BrCCH2、F2ClC、F2ClCCH2、F2IC、F2ICCH2、FBr2C、FBr2CCH2、FCl2C、FCl2C CH2、FI2C、FI2CCH2、ClBr2C、ClBr2CCH2、ICl2C、ICl2CCH2、ClI2C和ClI2CCH2；所述三卤代C1-C6烷氧基包括F3CO、F3CCH2O、Br3CO、Br3CCH2O、Cl3CO、Cl3CCH2O、I3CO、I3CCH2O、F2BrCO、F2BrCCH2O、F2ClCO、F2ClCCH2O、F2ICO、F2ICCH2O、FBr2CO、FBr2CCH2O、FCl2CO、FCl2CCH2O、FI2CO、FI2CCH2O、ClBr2CO、ClBr2CCH2O、ICl2CO、ICl2CCH2O、ClI2CO和ClI2CCH2O。
在本申请中，所述苯基丙烯酸类化合物选自如下式II-式V中的任意一种：
其中，所述R1和R2各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C4(例如可以是C1、C2、C3、C4等)烷氧羰基、C1-C4(例如可以是C1、C2、C3、C4等)烷羰基氧基、C1-C4(例如可以是C1、C2、C3、C4等)烷基、C1-C4(例如可以是C1、C2、C3、C4等)烷氧基、C1-C4(例如可以是C1、C2、C3、C4等)烷氧基亚甲基氧基、三卤代C1-C4(例如可以是C1、C2、C3、C4等)烷基、三卤代C1-C4(例如可以是C1、C2、C3、C4等)烷氧基中的任意一种；
所述R3和R4各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C4(例如可以是C1、C2、C3、C4等)烷氧羰基、C1-C4(例如可以是C1、C2、C3、C4等)烷羰基氧基、C1-C4(例如可以是C1、C2、C3、C4等)烷基、C1-C4(例如可以是C1、C2、C3、C4等)烷氧基、三卤代C1-C4(例如可以是C1、C2、C3、C4等)烷基或三卤代C1-C4(例如可以是C1、C2、C3、C4等)烷氧基中的任意一种；
所述R5选自氢、氨基、C1-C4(例如可以是C1、C2、C3、C4等)烷基、C1-C4(例如可以是C1、C2、C3、C4等)烷氧基甲基或C1-C4(例如可以是C1、C2、C3、C4等)烷基胺基中的任意一种；
所述R6选自氢、羟基、氨基、羰基、C1-C4(例如可以是C1、C2、C3、C4等)烷基胺基、C1-C4(例如可以是C1、C2、C3、C4等)烷羰基氧基或C1-C4(例如可以是C1、C2、C3、C4等)烷氧基羰基中的任意一种；
所述R7、R8和R9各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C4(例如可以是C1、C2、C3、C4等)烷基、C1-C4(例如可以是C1、C2、C3、C4等)烷氧基、C1-C4(例如可以是C1、C2、C3、C4等)烷氧羰基、C1-C4(例如可以是C1、C2、C3、C4等)烷羰基氧基、C1-C3(例如可以是C1、C2、C3等)烷酰基、C1-C4(例如可以是C1、C2、C3、C4等)烷氧基亚甲基氧基、三卤代C1-C4(例如可以是C1、C2、C3、C4等)烷基或三卤代C1-C4(例如可以是C1、C2、C3、C4等)烷氧基中的任意一种；
所述X选自O或NH；
所述Y选自O、NH、S、亚砜或砜中的任意一种；以及
所述p1、p2和p3各自独立地选自1、2或3。
在本申请中，所述R1和R2各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、 硝基、甲氧羰基、乙氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、C1-C2(例如可以是C1、C2等)烷羰基氧基、C1-C2(例如可以是C1、C2等)烷氧基亚甲基氧基、三卤代C1-C2(例如可以是C1、C2等)烷基或三卤代C1-C2(例如可以是C1、C2等)烷氧基中的任意一种；
所述R3和R4各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、乙氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、C1-C2(例如可以是C1、C2等)烷羰基氧基、三卤代C1-C2(例如可以是C1、C2等)烷基或三卤代C1-C2(例如可以是C1、C2等)烷氧基中的任意一种；
所述R5选自氢、氨基、甲基、乙基、C1-C2(例如可以是C1、C2等)烷氧基甲基或C1-C2(例如可以是C1、C2等)烷基胺基中的任意一种；
所述R6选自氢、氨基、羟基、羰基、C1-C2(例如可以是C1、C2等)烷基胺基、C1-C2(例如可以是C1、C2等)烷羰基氧基或C1-C2(例如可以是C1、C2等)烷氧基羰基中的任意一种；
所述R7、R8和R9各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、甲基、乙基、甲氧基、乙氧基、甲氧羰基、乙氧羰基、甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基、2-甲基丁酰基、C1-C2(例如可以是C1、C2等)烷氧基亚甲基氧基、三卤代C1-C2(例如可以是C1、C2等)烷基或三卤代C1-C2(例如可以是C1、C2等)烷氧基；
所述X选自O或NH；
所述Y选自O、NH、S、亚砜或砜中的任意一种；以及
所述p1、p2和p3各自独立地选自1或2。
在本申请中，所述R1和R2各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、三氟甲基、三氟甲氧基或甲氧基亚甲基氧基中的任意一种；
所述R3和R4各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、三氟甲基或三氟甲氧基中的任意一种；
所述R5选自氢、甲基、乙基、甲氧基甲基或氨基中的任意一种；
R6选自氢、羟基、氨基、羰基或C1-C2(例如可以是C1、C2等)烷羰基氧基中的任意一种；
R7、R8和R9各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、甲基、乙基、甲氧基、乙氧基、三氟甲基、三氟甲氧基、甲氧羰基、甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基或甲氧基亚甲基氧基中的任意一种；
X选自O或NH；
Y选自O、NH、S、亚砜或砜中的任意一种或至少两种的组合；
所述p1、p2和p3各自独立地选自1。
在本申请中，所述苯基丙烯酸类化合物选自如下M1-M31中的任意一种：

第二方面，本申请提供一种根据第一方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐。
优选地，所述药学上可接受的盐包括盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、甲磺酸盐、对甲苯磺酸盐、乙酸盐、三氟乙酸盐、水杨酸盐、氨基酸盐、枸杞酸盐、马来酸盐、酒石酸盐、富马酸盐、柠檬酸盐、乳酸盐、钠盐、钾盐、钙盐、镁盐、锂盐、铵盐或能提供生理上可接受的阳离子的有机碱的盐中的任意一种或至少两种的组合。
优选地，所述能提供生理上可接受的阳离子的有机碱的盐包括甲胺盐、二甲胺盐、三甲胺盐、哌啶盐、吗啉盐或三(2-羟乙基)胺盐中的任意一种或至少两种的组合。
在本申请中，术语“卤素”是指氟、氯、溴或碘。
根据本申请，式I化合物可以异构体的形式存在，式I化合物连接R5、R6基团的碳的构型可为R或S构型。
本申请包括所有可能的立体异构体以及两种或多种异构体的混合物。
如果存在顺/反异构体，本申请涉及顺式形式和反式形式以及这些形式的混合物，如果需要单一异物体可根据常规方法分离或通过立体选择合成制备。
本申请中的所有盐都可以采用常规方法制备。另外，式I所示化合物溶剂化物和其盐的制备过程中，不同结晶条件可能出现多晶或共晶。
第三方面，本申请提供一种根据第一方面所述的苯基丙烯酸类化合物的制备方法，所述制备方法包括以下步骤：
(1)将式a所示化合物与式b所示化合物进行缩合反应，得到式c所示化合物，反应式如下所示：
(2)将式c所示化合物进行脱保护基，得到式d所示化合物，反应式如下所示：
(3)将式d所示化合物和式e所示化合物进行取代反应，得到式I所示化合物，反应式如下所示：
或者，所述制备方法包括以下步骤：将式f所示化合物与式g所示化合物进行缩合反应，得到式I所示化合物，反应式如下所示：
其中，所述X’选自OH或NH2；
Y’选自叔丁基二甲基硅氧基、叔丁基二苯基硅氧基、三甲基硅氧基、三乙基硅氧、苄氧基、对甲氧基卞氧基、甲氧基亚甲基氧基、苄氧羰酰基氧基或叔丁氧羰基氧基中的任意一种；
Y”选自OH、NH2或SH中的任意一种；以及
Z选自羟基、氯、溴、碘、对甲苯磺酰基或甲磺酰基中的任意一种。
在本申请中，步骤(1)中，所述缩合反应在碱性条件下进行。
优选地，步骤(1)中，所述缩合反应在缩合剂的存在下进行，所述缩合剂包括EDCI和/或DMAP。
优选地，步骤(1)中，所述缩合反应的温度为0-30℃(例如可以是0℃、5℃、10℃、15℃、20℃、25℃、30℃等)，时间为5-15h(例如可以是5h、7h、9h、11h、13h、15h等)。
优选地，步骤(1)中，所述式a所示化合物与式b所示化合物的摩尔比为1:(0.8-1.5)；
其中，“0.8-1.5”可以是0.8、0.9、1、1.1、1.2、1.3、1.4、1.5等。
优选地，步骤(2)中，所述脱保护基通过水解反应或氢化反应进行。
优选地，步骤(2)中，所述脱保护基通过水解反应进行，所述水解反应在酸性条件或碱性条件下进行。
优选地，步骤(3)中，所述取代反应在碱性条件下进行。
优选地，步骤(3)中，所述取代反应的温度为60-100℃(例如可以是60℃、65℃、70℃、75℃、80℃、85℃、90℃、95℃、100℃等)，时间为2-6h(例如可以是2、2.5、3、3.5、4、4.5、5、5.5、6等)。
优选地，步骤(3)中，所述式d所示化合物与式e所示化合物的摩尔比为1:(1-2)；
其中，“1-2”可以是1、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2等。
优选地，所述式f所示化合物与式g所示化合物在碱性条件下进行缩合反应。
优选地，所述式f所示化合物与式g所示化合物在缩合剂的存在下进行缩合反应，所述缩合剂包括EDCI和/或DMAP。
优选地，所述式f所示化合物与式g所示化合物的摩尔比为1:(0.8-1.5)；
其中，“0.8-1.5”可以是0.8、1、1.1、1.2、1.3、1.4、1.5等。
第四方面，本申请提供一种药物组合物，所述药物组合物包括活性成分和药效学上可接受的载体，所述活性成分包括第一方面所述的苯基丙烯酸类化合物或第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐。
优选地，所述药物组合物中所述活性成分的质量百分含量为0.1-95％，例如可以是0.1、1、10、20、30、40、50、60、70、80、90、95等。
本申请提供的药物组合物可根据本领域公知的方法制备，可通过将活性成分与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。
本申请第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物可以采用单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本申请第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互 变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本申请第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物制成胶囊剂，可以将其与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将其先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本申请化合物的胶囊剂。
为将本申请第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本申请的药物或药物组合物可用任何公知的给药方法给药。
第五方面，本申请提供一种根据第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物在制备预防或治疗肿瘤、自身免疫性疾病、炎症性疾病、神经退行性疾病或抗衰老药物中的应用。
优选地，所述肿瘤选自神经胶质瘤、黑色素瘤、胃癌、肺癌、乳腺癌、肾癌、肝癌、口腔上皮癌、头颈部肿瘤、宫颈癌、卵巢癌、胰腺癌、前列腺癌、结肠癌、直肠腺癌、白血病或淋巴瘤中的任意一种或至少两种的组合。
优选地，所述自身免疫性疾病包括类风湿关节炎、系统性红斑狼疮、溃疡性结肠炎、银屑病、皮炎或脊髓侧索硬化症中的任意一种或至少两种的组合。
优选地，所述炎症性疾病包括多发性动脉炎、静脉炎、反流性食管炎中的任意一种或至少两种的组合。
优选地，所述神经退行性疾病包括老年性痴呆和/或帕金森病。
本申请第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本申请第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物的每天的合适剂量范围为0.001-150mg/Kg体重，优选为0.1-100mg/Kg体重，更优选为1-70mg/Kg体重，最优选为2-30mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本申请第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物可单独服用，或与其他治疗药物或对症药物合并使用。当其它治疗药物存在协同作用时，应根据实际情况调整其剂量。
相对于现有技术，本申请具有以下有益效果：
本申请提供的苯基丙烯酸类化合物与多个靶点蛋白都有较好的结合，并且具有较好的生物利用度，可用于制备预防或治疗肿瘤、自身免疫性疾病、炎症性疾病、神经退行性疾病或抗衰老药物，其中所述的肿瘤疾病是神经胶质瘤、黑色素瘤、胃癌、肺癌、乳腺癌、肾癌、肝癌、口腔上皮癌、头颈部肿瘤、宫颈癌、卵巢癌、胰腺癌、前列腺癌、结肠癌、直肠腺癌、白血病或淋巴瘤等。
具体实施方式
下面通过具体实施方式来进一步说明本申请的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本申请，不应视为对本申请的具体限制。
以下实施例中反应原料均为商购可获得的常规产品。
制备例1
本制备例提供化合物c-1，所述化合物c-1的制备方法包括以下步骤：
将(536mg，2mmol)(E)-3-(3,4-bis(methoxymethoxy)phenyl)acrylic acid(a-1)、(559mg，2.2mmol)4-tert-butyldimethylsilyloxy-3-methoxyphenol(b-1)、(575mg，3mmol)EDCI、10mg DMAP溶于20mL二氯甲烷中，0℃滴入三乙胺(0.56mL，4mmol)25℃反应10h；反应结束后加入乙酸乙酯和水，分液，取有机相，无水硫酸钠干燥，过滤，浓缩，柱层析(PE:EA＝5:1)分离得0.63g化合物c-1，黄色固化油，收率62.4％。
1H NMR(500MHz,CDCl3)δ7.79(s,1H),7.42(s,1H),7.19(s,2H),6.83(d,J＝8.5Hz,1H),6.69(s,1H),6.63(dd,J＝8.6,2.7Hz,1H),6.49(d,J＝15.9Hz,1H),5.27(d,J＝5.3Hz,4H),3.79(s,3H),3.54(s,3H),3.52(s,3H),1.00(s,9H),0.16(s,6H).
13C NMR(101MHz,CDCl3)δ165.8,151.2,149.5,147.5,146.0,145.1,142.7,128.7,123.8,120.6,116.2,115.9,115.8,113.6,106.2,95.6,94.8,56.4,56.3,55.6,25.7,18.5,-4.6.
制备例2
本制备例提供化合物c-2，以化合物a-1(536mg，2mmol)和化合物b-2(557mg，2.2mmol)为原料，所述化合物c-2的制备方法同化合物c-1，得化合物c-2白色固体600mg，收率62％，所述化合物c-2的反应式如下所示：
1H NMR(400MHz,CDCl3)δ7.75(d,J＝15.2Hz,1H),7.65-7.67(m,2H),7.47(m,1H),7.42(d,J＝15.2Hz,1H),7.26-7.28(m,1H),7.19(d,J＝8.0Hz,1H),7.05(d,J＝8Hz,1H),5.22(s,2H),5.22(s,2H),3.90(s,3H),3.60(s,3H),3.53(s,3H),1.03(s,9H),0.33(s,6H).
制备例3
本制备例提供化合物c-3，以化合物a-1(536mg，2mmol)和化合物b-3(490mg，2.2mmol)为原料，所述化合物c-3的制备方法同化合物c-1，得化合物c-3白色固体650mg，收率68.4％，所述化合物c-3的反应式如下所示：
1H NMR(400MHz,CDCl3)δ7.80(d,J＝15.6Hz,1H),7.63-7.68(m,2H),7.49(m,1H),7.41(d,J＝15.6Hz,1H),7.26-7.28(m,1H),7.19(d,J＝8.8Hz,1H),7.05(d,J＝8.8Hz,1H),5.24(s,2H),5.24(s,2H),3.60(s,3H),3.53(s,3H),1.02(s,9H),0.34(s,6H).
制备例4
本制备例提供化合物d-1，所述化合物d-1的制备方法包括以下步骤：
将(500mg，1mmol)化合物c-1溶于THF中，0℃下加入四丁基氟化铵(1.5mL，1.5mmol)，30min后加入饱和氯化铵中止反应，乙酸乙酯加入，分液，有机相用无水硫酸钠干燥，过滤，浓缩，柱层析(PE:EA＝5:1)得0.35g化合物d-1，黄色固体，收率89.7％。
1H NMR(400MHz,CDCl3)δ7.77(d,J＝15.9Hz,1H),7.42(s,1H),7.18(s,2H),6.90(d,J＝8.5Hz,1H),6.70(d,J＝2.6Hz,1H),6.65(dd,J＝8.5,2.6Hz,1H),6.49(d,J＝15.9Hz,1H),5.68(s,1H),5.27(d,J＝4.2Hz,4H),3.85(s,3H),3.53(s,3H),3.52(s,3H).
13C NMR(101MHz,CDCl3)δ166.1,149.6,147.5,146.7,146.1,143.8,143.4,128.7,123.8,116.2,115.8,115.8,114.4,113.8,105.3,95.6,95.1,77.4,77.1,76.8,56.4,56.3,56.0.
制备例5
本制备例提供化合物d-2，以化合物c-2(500mg，1mmol)为原料，所述化合物d-2的 制备方法同化合物d-1，得化合物d-2淡黄色固体352mg，收率90.1％，所述化合物d-2的反应式如下所示：
1H NMR(400MHz,CDCl3)δ9.90(s,1H),9.17(s,1H),7.48(d,J＝8.9Hz,2H),7.45(d,J＝15.7Hz,1H),7.38(d,J＝2.0Hz,1H),7.25–7.09(m,1H),6.73(d,J＝8.9Hz,1H),6.65(d,J＝15.6Hz,1H),5.29(s,2H),5.29(s,2H),4.12(s,3H),3.56(s,3H),3.53(s,3H).
制备例6
本制备例提供化合物d-3，以化合物c-3(470mg，1mmol)为原料，所述化合物d-3的制备方法同化合物d-1，得化合物d-3淡黄色固体340mg，收率94.7％，所述化合物d-3的反应式如下所示：
1H NMR(400MHz,d-DMSO)δ9.91(s,1H),9.16(s,1H),7.47(d,J＝8.9Hz,2H),7.43(d,J＝15.7Hz,1H),7.36(d,J＝2.0Hz,1H),7.21–7.09(m,1H),6.70(d,J＝8.9Hz,1H),6.64(d,J＝15.6Hz,1H),5.24(s,2H),5.22(s,2H),3.42(s,3H),3.40(s,3H).
13C NMR(101MHz,d-DMSO)δ163.0,153.3,148.2,147.0,139.0,131.1,129.1,122.9,120.9,120.7,116.8,115.1,115.1,94.8,94.6,55.8,40.2,39.9,39.7,39.5,39.3,39.1,38.9.
实施例1
本实施例提供化合物M1，所述化合物M1的制备方法包括以下步骤：
50mL圆底瓶中装有(50mg，0.13mmol)化合物d-1，(50mg，0.2mmol)3,4-二甲氧基苯乙基溴(e-1)，(85mg，0.26mmol)碳酸铯和5mL乙腈，回流反应4h，TLC显示完全，冷却后过滤得粗品60mg，溶于5mL四氢呋喃中，加入0.3mL浓盐酸，搅拌1h后，浓缩得47mg化合物M1，收率78.3％。
1H NMR(400MHz,CDCl3)δ7.71(d,J＝15.9Hz,1H),7.09(d,J＝2.0Hz,1H),7.03(dd,J＝8.2,2.0Hz,1H),6.89(d,J＝2.1Hz,1H),6.85(d,J＝7.9Hz,2H),6.80(d,J＝1.1Hz,2H),6.73–6.67(m,2H),6.36(d,J＝15.9Hz,1H),5.97–5.86(m,2H),4.16(t,J＝7.3Hz,2H),3.88–3.84(m,9H),3.09(t,J＝7.3Hz,2H)；
13C NMR(151MHz,CDCl3)δ166.3,149.3,148.6,147.6,147.0,146.7,146.6,144.9,143.9,131.4,127.3,123.6,121.0,116.5,114.6,114.3,113.2,112.5,111.9,111.3,107.4,70.0,58.0,55.9,55.3,35.2.
实施例2
本实施例提供化合物M2，以化合物d-1(50mg，0.13mmol)和化合物e-2(80mg，0.22 mmol)为原料，所述化合物M2的制备方法同化合物M1，得化合物M2黄色固体54mg，收率84.2％，所述化合物M2的反应式如下所示：
1H NMR(400MHz,CDCl3)δ7.73(d,J＝15.9Hz,1H),7.11(d,J＝2.0Hz,1H),7.06(dd,J＝8.2,2.1Hz,1H),7.01(d,J＝1.8Hz,1H),6.93(d,J＝8.9Hz,1H),6.90–6.85(m,3H),6.83(dd,J＝8.6,2.7Hz,2H),6.39(d,J＝15.8Hz,1H),4.89(d,J＝3.2Hz,1H),4.43(qd,J＝6.3,3.1Hz,1H),3.91–3.83(m,9H),1.20(d,J＝6.4Hz,3H).
13C NMR(151MHz,CDCl3)δ166.2,149.4,148.8,148.3,146.9,146.0,144.9,143.9,132.2,127.2,122.8,118.7,115.6,114.5,113.1,112.6,110.8,109.6,82.0,74.6,58.3,53.9,28.7,12.4.
实施例3
本实施例提供化合物M3，以化合物d-1(50mg，0.14mmol)和化合物e-3(80mg，0.22mmol)为原料，所述化合物M3的制备方法同化合物M1，得化合物M3黄色固体45mg，收率64.3％，所述化合物M3的反应式如下所示：
1H NMR(400MHz,CDCl3)δ7.73(d,J＝15.9Hz,1H),7.11(d,J＝2.0Hz,1H),7.04(dd,J＝8.2,2.1Hz,1H),6.95–6.89(m,3H),6.89–6.78(m,4H),6.38(d,J＝16.0Hz,1H),4.68(d,J＝8.4Hz,1H),4.26–4.18(m,1H),3.90(s,3H),3.87(s,3H),3.85(s,3H),1.18(d,J＝6.3Hz,3H).
实施例4
本实施例提供化合物M4，以化合物d-3(130mg，0.36mmol)和化合物e-4(100mg，0.54mmol)为原料，所述化合物M4的制备方法同化合物M1，得化合物M4黄色固体100mg，收率88.5％，所述化合物M4的反应式如下所示：
1H NMR(400MHz,Acetone-d6)δ7.63(d,J＝9.1Hz,2H),7.48(d,J＝15.5Hz,1H),7.37–7.25(m,4H),7.19(t,J＝6.3Hz,1H),7.07(d,J＝2.1Hz,1H),6.95(dd,J＝8.2,2.1Hz,1H),6.89–6.76(m,3H),6.54(d,J＝15.5Hz,1H),4.16(t,J＝6.9Hz,2H),3.04(t,J＝6.9Hz,3H).
13C NMR(101MHz,Acetone-d6)δ164.3,156.7,149.0,146.0,140.6,138.9,133.8,130.1,129.0,128.3,127.0,122.5,121.3,119.7,116.2,115.3,113.3,68.5,36.3.
实施例5
本实施例提供化合物M5，以化合物d-3(150mg，0.42mmol)和化合物e-5(134mg，0.63mmol)为原料，所述化合物M5的制备方法同化合物M1，得化合物M5黄色固体150mg，收率88.2％，所述化合物M5的反应式如下所示：
1H NMR(400MHz,Acetone-d6)δ8.05(d,J＝3.6Hz,1H),7.61(s,2H),7.47(d,J＝15.5Hz,1H),7.22(d,J＝8.5Hz,2H),7.06(s,1H),6.94(d,J＝8.1Hz,1H),6.87–6.77(m,5H),6.53(d,J＝15.5Hz,1H),4.10(t,J＝6.9Hz,2H),2.96(t,J＝6.9Hz,2H).
13C NMR(101MHz,Acetone-d6)δ163.9,158.4,155.0,147.0,145.4,140.6,130.5,129.9,127.5,120.9,120.6,120.5,119.0,115.5,115.4,114.5,114.0,113.9,113.7,68.9,55.0,36.2.
实施例6
本实施例提供化合物M6，以化合物d-3(150mg，0.42mmol)和化合物e-6(126mg，0.63mmol)为原料，所述化合物M6的制备方法同化合物M1，得化合物M6黄色固体100mg，收率60.6％，所述化合物M6的反应式如下所示：
1H NMR(400MHz,Acetone-d6)δ9.07(s,1H),8.30(s,1H),8.06(s,1H),7.63(d,J＝9.0Hz,2H),7.46(s,1H),7.35(dd,J＝8.5,5.7Hz,2H),7.10–7.00(m,3H),6.94(dd,J＝8.2,2.1Hz,1H),6.86–6.77(m,2H),6.54(d,J＝15.6Hz,1H),4.15(t,J＝6.8Hz,2H),3.04(d,J＝6.8Hz,2H).
13C NMR(101MHz,Acetone)δ165.0,162.8,160.9,155.4,147.9,145.4,139.6,134.9,134.8,133.1,130.8,130.7,127.5,120.9,120.6,120.5,119.0,115.5,115.0,114.7,114.5,114.0,66.1,34.6.
实施例7
本实施例提供化合物M7，以化合物d-3(150mg，0.42mmol)和化合物e-7(125mg，0.63mmol)为原料，所述化合物M7的制备方法同化合物M1，得化合物M7黄色固体101mg，收率61.9％，所述化合物M7的反应式如下所示：
1H NMR(400MHz,Acetone-d6)δ9.06(s,1H),8.30(s,1H),8.06(d,J＝3.5Hz,1H),7.63(d,J＝8.5Hz,2H),7.48(d,J＝15.5Hz,1H),7.19(d,J＝8.0Hz,2H),7.12–7.03(m,3H),6.94(dd,J＝8.1,2.1Hz,1H),6.84(dd,J＝14.3,8.6Hz,3H),6.54(d,J＝15.5Hz,1H),4.12(t,J＝6.9Hz,2H),2.99(t,J＝7.0Hz,2H).
13C NMR(101MHz,Acetone)δ164.1,153.4,147.1,145.9,140.6,136.4,133.7,128.9,127.5,120.9,120.6,119.0,115.5,114.5,111.9,70.5,68.8,38.0,21.4.
实施例8
本实施例提供化合物M8，以化合物d-3(150mg，0.42mmol)和化合物e-8(126mg，0.63mmol)为原料，所述化合物M8的制备方法同化合物M1，得化合物M8黄色固体80mg，收率50％，所述化合物M8的反应式如下所示：
1H NMR(400MHz,Acetone-d6)δ9.07(s,1H),8.33(s,1H),8.09(s,1H),7.63(d,J＝9.0Hz,2H),7.48(d,J＝15.5Hz,1H),7.13(d,J＝8.4Hz,2H),7.07(d,J＝2.1Hz,1H),6.94(dd,J＝8.2,2.1Hz,1H),6.84(dd,J＝14.4,8.6Hz,3H),6.75(d,J＝8.5Hz,2H),6.49(s,1H),4.09(t,J＝7.0Hz,2H),2.94(t,J＝7.0Hz,2H).
13C NMR(101MHz,Acetone)δ161.4,156.0,153.7,148.1,143.8,140.6,130.5,128.5,125.5,121.6,120.6,118.3,115.5,115.1,114.5,114.0,69.1,35.3.
实施例9
本实施例提供化合物M9，以化合物d-3(150mg，0.42mmol)和化合物e-1(153mg，0.63mmol)为原料，所述化合物M9的制备方法同化合物M1，得化合物M9淡黄色固体100mg，收率54.6％，所述化合物M9的反应式如下所示：
1H NMR(400MHz,Acetone-d6)δ9.05(s,1H),8.30(s,1H),8.05(s,1H),7.63(d,J＝8.6Hz,2H),7.48(d,J＝15.5Hz,1H),7.06(d,J＝2.1Hz,1H),6.95(d,J＝9.0Hz,2H),6.89–6.78(m,4H),6.54(d,J＝15.5Hz,1H),4.13(t,J＝7.0Hz,2H),2.97(t,J＝7.0Hz,2H).
13C NMR(101MHz,Acetone)δ164.0,155.0,150.6,148.6,147.1,144.7,141.3,135.2,131.1,128.1,121.0,120.6,119.0,116.1,114.5,114.0,113.2,112.1,68.9,55.3,55.2,37.4.
实施例10
本实施例提供化合物M10，以化合物d-3(150mg，0.42mmol)和化合物e-9(173mg，0.63mmol)为原料，所述化合物M10的制备方法同化合物M1，得化合物M10淡黄色固体95mg，收率48.7％，所述化合物M10的反应式如下所示：
1H NMR(400MHz,Acetone-d6)δ9.15(s,1H),8.32(s,1H),8.08(s,1H),7.61(s,2H),7.46(d,J＝15.6Hz,1H),7.04(s,1H),6.92(d,J＝6.3Hz,1H),6.83(d,J＝17.2Hz,3H),6.61(s,2H),6.53(d,J＝15.2Hz,1H),4.13(s,2H),3.76(s,7H),3.65(s,3H),2.95(s,2H).
13C NMR(101MHz,Acetone)δ163.7,155.0,152.4,147.2,145.4,141.3,136.9,134.2,133.1,127.9,121.3,120.7,118.4,115.5,114.6,113.7,107.0,68.4,59.0,56.3,37.3.
实施例11
本实施例提供化合物M11，以化合物d-3(130mg，0.36mmol)和化合物e-4(100mg，0.54mmol)为原料，所述化合物M11的制备方法同化合物M1，不经酸化，得化合物M11淡黄色固体110mg，收率66.3％，所述化合物M11的反应式如下所示：
1H NMR(400MHz,Chloroform-d)δ7.63(d,J＝15.5Hz,1H),7.49(d,J＝8.3Hz,2H),7.38–7.20(m,8H),7.12(d,J＝5.8Hz,2H),6.86(d,J＝9.0Hz,2H),6.38(d,J＝15.4Hz,1H),5.25(s,4H),4.15(t,J＝7.1Hz,2H),3.52(s,2H),3.50(s,3H),3.08(t,J＝7.1Hz,2H).
13C NMR(101MHz,CDCl3)δ162.9,157.4,148.8,146.2,142.1,137.7,132.3,129.7,129.0,128.5,126.5,123.5,121.6,119.9,116.2,115.0,95.9,94.4,70.9,56.4,34.8.
实施例12
本实施例提供化合物M12，以化合物d-3(150mg，0.42mmol)和化合物e-5(134mg，0.63mmol)为原料，所述化合物M12的制备方法同化合物M1，不经酸化，得化合物M12淡黄色固体180mg，收率87％，所述化合物M12的反应式如下所示：
1H NMR(400MHz,Chloroform-d)δ7.64(d,J＝15.4Hz,1H),7.49(d,J＝10.3Hz,2H),7.37(s,1H),7.19(d,J＝8.6Hz,3H),7.13(d,J＝3.9Hz,2H),6.85(dd,J＝8.7,6.2Hz,4H),6.38(d,J＝15.5Hz,1H),5.25(s,5H),4.10(d,J＝7.1Hz,2H),3.02(d,J＝7.0Hz,2H).
13C NMR(101MHz,CDCl3)δ163.9,158.3,155.7,149.6,148.1,140.5,131.3,130.7,130.0,127.7,122.9,121.6,120.3,117.2,114.6,114.0,100.1,94.7,68.1,57.2,55.3,34.9.
实施例13
本实施例提供化合物M13，以化合物d-3(150mg,0.42mmol)和化合物e-6(125mg，0.62mmol)为原料，所述化合物M13的制备方法同化合物M1，不经酸化，得化合物M13淡黄色固体120mg，收率59.4％，所述化合物M13的反应式如下所示：
1H NMR(400MHz,CDCl3)δ7.67(s,1H),7.51(d,J＝8.2Hz,2H),7.38(s,1H),7.28–7.18(m,4H),7.14(d,J＝4.0Hz,2H),7.00(t,J＝8.7Hz,2H),6.87(d,J＝9.0Hz,2H),6.40(d,J＝15.4Hz,1H),5.27(s,4H),4.14(t,J＝6.9Hz,2H),3.53(d,J＝9.6Hz,6H).
13C NMR(101MHz,CDCl3)δ163.8,162.9,159.6,154.0,148.8,146.7,141.5,134.7,131.4,130.4,130.3,128.3,123.5,121.5,119.4,116.2,115.3,115.1,114.9,68.4,53.6,36.0.
实施例14
本实施例提供化合物M14，以化合物d-3(150mg,0.42mmol)和化合物e-7(125mg，0.62mmol)为原料，所述化合物M14的制备方法同化合物M1，不经酸化，得化合物M14淡黄色固体150mg，收率75％，所述化合物M14的反应式如下所示：
1H NMR(400MHz,d-DMSO)δ10.55(s,1H),8.68(d,J＝1.6Hz,1H),7.80-7.82(m,2H),7.58(dd,J＝3.0Hz,8.8Hz,1H),7.21-7.23(m,2H),7.09-7.12(m,3H),6.96-7.01(m,1H),6.77-6.80(m,1H),4.23(t,J＝7.2Hz,2H),3.82(s,3H),3.02(t,J＝7.2Hz,2H),2.26(s,3H)；
13C NMR(101MHz,CDCl3)δ165.4,154.8,148.8,147.1,142.0,136.1,133.6,129.8,128.4,123.5,121.5,119.5,116.2,112.0,95.5,94.8,68.3,56.4,35.4,20.5.
实施例15
本实施例提供化合物M15，以化合物d-3(60mg，0.22mmol)和化合物e-8(25mg，0.18mmol)为原料，所述化合物M15的制备方法同化合物M1，不经酸化，得化合物M15淡黄色固体60mg，收率83.4％，所述化合物M15的反应式如下所示：
1H NMR(400MHz,Chloroform-d)δ7.65(d,J＝15.4Hz,1H),7.54–7.33(m,3H),7.15(dd,J＝13.9,6.6Hz,5H),6.92–6.73(m,5H),6.40(d,J＝13.7Hz,1H),5.26(s,5H),4.11(t,J＝6.3Hz,3H),3.54(s,3H),3.52(s,3H),3.01(t,J＝7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ164.0,156.7,155.8,154.8,149.4,147.4,141.1,131.2,130.1,130.0,129.2,123.6,122.1,119.4,117.0,115.4,115.0,114.7,95.5,94.8,77.3,69.3,68.4,56.3,34.9.
实施例16
本实施例提供化合物M16，以化合物d-3(150mg，0.42mmol)和化合物e-1(206mg，0.84mmol)为原料，所述化合物M16的制备方法同化合物M1，不经酸化，得化合物M16淡黄色固体150mg，收率68.2％，所述化合物M16的反应式如下所示：
1H NMR(400MHz,Chloroform-d)δ7.65(d,J＝15.3Hz,1H),7.51(d,J＝8.2Hz,2H),7.35(d,J＝20.2Hz,2H),7.13(q,J＝8.1Hz,2H),6.88(d,J＝9.0Hz,2H),6.82(s,3H),6.40(d,J＝15.4Hz,1H),4.14(t,J＝7.0Hz,2H),3.88(s,3H),3.87(s,3H),3.54(s,3H),3.51(s,3H),3.03(t,J＝7.0Hz,2H).
13C NMR(101MHz,CDCl3)δ163.5,156.1,149.6,147.7,147.4,138.2,130.8,128.4,123.5,122.5,120.9,119.0,117.3,113.9,112.4,110.8,96.0,93.9,68.1,57.7,55.9,36.1,29.7.
实施例17
本实施例提供化合物M17，以化合物d-3(150mg，0.42mmol)和化合物e-9(173mg，0.63mmol)为原料，所述化合物M17的制备方法同化合物M1，不经酸化，得化合物M17淡黄色固体106mg，收率45.7％，所述化合物M17的反应式如下所示：
1H NMR(400MHz,Chloroform-d)δ7.66(d,J＝15.4Hz,1H),7.51(d,J＝7.9Hz,2H),7.39(s,1H),7.23–7.11(m,3H),6.89(d,J＝8.8Hz,2H),6.50(s,2H),6.40(d,J＝15.4Hz,1H),5.27(s,4H),4.17(t,J＝7.0Hz,2H),3.86(s,6H),3.84(s,3H),3.54(s,3H),3.52(s,3H),3.03(t,J＝7.0Hz,2H).
13C NMR(101MHz,CDCl3)δ152.0,148.9,147.5,141.6,135.4,132.8,127.2,123.1,120.6,119.4,117.3,115.0,113.5,106.0,95.9,95.2,77.3,69.1,68.6,62.2,59.4,56.4,54.8.
实施例18
本实施例提供化合物M18，以化合物d-1(50mg，0.13mmol)和化合物e-4(37mg，0.2mmol)为原料，所述化合物M18的制备方法同化合物M1，得化合物M18淡黄色固体30mg，收率56.6％，所述化合物M18的反应式如下所示：
1H NMR(400MHz,Acetone-d6)δ7.60(d,J＝9.1Hz,2H),7.45(d,J＝15.5Hz,1H),7.34–7.25(m,4H),7.16(t,J＝6.3Hz,1H),7.04(d,J＝2.1Hz,1H),6.95(dd,J＝8.2,2.1Hz,1H),6.89–6.76(m,3H),6.54(d,J＝15.5Hz,1H),4.13(t,J＝6.9Hz,2H),3.84(s,3H),3.01(t,J＝6.9Hz,3H).
实施例19
本实施例提供化合物M19，以化合物d-1(100mg，0.26mmol)和化合物e-6(66mg，0.33mmol)为原料，所述化合物M19的制备方法同化合物M1，得化合物M19淡黄色固体60mg，收率54.4％，所述化合物M19的反应式如下所示：
1H NMR(400MHz,Acetone-d6)δ9.05(s,1H),8.32(s,1H),8.04(s,1H),7.63(d,J＝9.0Hz,2H),7.46(s,1H),7.35(dd,J＝8.5,5.7Hz,2H),7.10–7.00(m,3H),6.94(dd,J＝8.2,2.1Hz,1H),6.86–6.77(m,2H),6.54(d,J＝15.6Hz,1H),4.15(t,J＝7.2Hz,2H),3.84(s,3H),3.02(d,J＝6.8Hz,2H).
实施例20
本实施例提供化合物M20，以化合物d-1(50mg，0.13mmol)和化合物e-5(70mg，0.33mmol)为原料，所述化合物M20的制备方法同化合物M1，得化合物M20淡黄色固体40mg，收率70.2％，所述化合物M20的反应式如下所示：
1H NMR(400MHz,Acetone-d6)δ8.07(d,J＝3.6Hz,1H),7.63(s,2H),7.47(d,J＝15.6Hz,1H),7.22(d,J＝8.6Hz,2H),7.06(s,1H),6.94(d,J＝8.1Hz,1H),6.87–6.77(m,5H),6.53(d,J＝15.5Hz,1H),4.12(t,J＝6.9Hz,2H),3.84(s,3H),2.96(t,J＝6.9Hz,2H).
实施例21
本实施例提供化合物M21，以化合物d-1(50mg，0.13mmol)和化合物e-7(45mg，0.23mmol)为原料，所述化合物M21的制备方法同化合物M1，得化合物M21淡黄色固体40mg，收率72.7％，所述化合物M21的反应式如下所示：
1H NMR(400MHz,d-DMSO)δ10.54(s,1H),8.66(d,J＝2.0Hz,1H),7.81(dd,J＝2.0Hz,8.8Hz,1H),7.72(s,1H),7.65(d,J＝7.6Hz,1H),7.24-7.27(m,2H),7.15-7.19(m,1H),7.07(d,J＝8.8Hz,1H),6.94-6.98(m,1H),6.85-6.89(m,2H),6.81(d,J＝7.6Hz,1H),4.21(t,J＝7.2Hz,2H),3.82(s,3H),3.72(s,3H),3.00(t,J＝6.8Hz,2H).
实施例22
本实施例提供化合物M22，以化合物d-1(80mg，0.28mmol)和化合物e-9(104mg，0.38mmol)为原料，所述化合物M22的制备方法同化合物M1，得化合物M22淡黄色固体85mg，收率61.6％，所述化合物M22的反应式如下所示：
1H NMR(400MHz,CDCl3)δ7.64(d,J＝15.4Hz,1H),7.50(d,J＝7.9Hz,2H),7.35(s,1H),7.25–7.11(m,3H),6.89(d,J＝8.8Hz,2H),6.50(s,2H),6.40(d,J＝15.4Hz,1H),5.27(s,4H),4.17(t,J＝7.0Hz,2H),3.86(s,6H),3.84(s,3H),3.54(s,3H),3.52(s,3H),3.01(t,J＝7.0Hz,2H).
实施例23
本实施例提供化合物M23，以化合物d-3(150mg，0.42mmol)和化合物e-10(34mg，0.23mmol)为原料，所述化合物M23的制备方法同化合物M1，得化合物M23淡黄色固体80mg，收率83.3％，所述化合物M23的反应式如下所示：
1H NMR(400MHz,CDCl3)δ10.42(s,1H),8.65-8.66(m,1H),7.81-7.83(m,1H),7.69(s,1H),7.47-7.49(m,1H),7.24-7.27(m,2H),7.06-7.08(m,1H),6.96-6.99(m,1H),6.86-6.88(m,2H),6.69-6.71(m,1H),5.80(s,2H),4.21-4.22(m,2H),3.01(t,J＝6.8Hz,2H).
实施例24
本实施例提供化合物M24，以化合物d-2(80mg，0.27mmol)和化合物e-1(80mg，0.33mmol)为原料，所述化合物M24的制备方法同化合物M1，得化合物M24淡黄色固体84mg，收率66.7％，所述化合物M24的反应式如下所示：
1H NMR(400MHz,Acetone-d6)δ8.95(s,1H),8.25(s,1H),8.00(s,1H),7.60(d,J＝8.6Hz,2H),7.48(d,J＝15.6Hz,1H),7.06(d,J＝2.4Hz,1H),6.95(d,J＝9.2Hz,2H),6.89–6.78(m,4H),6.54(d,J＝15.5Hz,1H),4.13(t,J＝7.0Hz,2H),3.84(s,3H),2.97(t,J＝7.0Hz,2H).
实施例25
本实施例提供化合物M25，以化合物d-2(80mg，0.27mmol)和化合物e-4(64mg，0.35mmol)为原料，所述化合物M25的制备方法同化合物M1，得化合物M25淡黄色固体80mg，收率73.4％，所述化合物M25的反应式如下所示：
1H NMR(400MHz,Acetone-d6)δ7.60(d,J＝9.1Hz,2H),7.50(d,J＝15.5Hz,1H),7.39–7.25(m,4H),7.14(t,J＝6.3Hz,1H),7.03(d,J＝2.1Hz,1H),6.95(dd,J＝8.2,2.1Hz,1H),6.89–6.76(m,3H),6.54(d,J＝15.5Hz,1H),4.16(t,J＝6.9Hz,2H),3.84(s,3H),3.02(t,J＝6.9Hz,3H).
实施例26
本实施例提供化合物M26，以化合物f-1(100mg，0.67mmol)和化合物g-1(233mg，0.77mmol)为原料，所述化合物M26的制备方法同化合物M1，不经酸化，得化合物M26淡黄色固体200mg，收率69％，所述化合物M26的反应式如下所示：
1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.53(d,J＝8.6Hz,2H),7.42(d,J＝15.6Hz,1H),7.23-7.26(m,2H),7.06(d,J＝2.4Hz,1H),6.95(d,J＝9.2Hz,2H),6.89–6.78(m,4H),6.54(d,J＝15.5Hz,1H),4.12(t,J＝7.0Hz,2H),3.93(s,3H),3.92(s,3H),3.86(s,3H),2.99(t,J＝7.0Hz,2H).
实施例27
本实施例提供化合物M27，以化合物f-2(100mg，0.56mmol)和化合物g-1(233mg，0.77mmol)为原料，所述化合物M27的制备方法同化合物M26，不经酸化，得化合物M27淡黄色固体106mg，收率40.8％，所述化合物M27的反应式如下所示：
1H NMR(400MHz,CDCl3)δ7.23(s,1H),7.53(d,J＝8.6Hz,2H),7.38(d,J＝15.6Hz,1H),7.23-7.26(m,1H),7.06(s,1H),6.95(d,J＝9.2Hz,2H),6.89–6.78(m,4H),6.54(d,J＝15.5Hz,1H),4.12(t,J＝7.0Hz,2H),3.91(s,3H),3.88(s,3H),3.83(s,3H),2.99(t,J＝7.0Hz,2H).
实施例28
本实施例提供化合物M28，以化合物f-3(100mg，0.52mmol)和化合物g-1(233mg，0.77mmol)为原料，所述化合物M28的制备方法同化合物M26，不经酸化，得化合物M28淡黄色固体180mg，收率72.6％，所述化合物M28的反应式如下所示：
1H NMR(400MHz,CDCl3)δ8.60(m,1H),7.80(m,1H),7.66(s,1H),7.47-7.49(m,1H),7.24-7.27(m,2H),7.06-7.08(m,1H),6.96-6.99(m,1H),6.86-6.88(m,2H),6.69-6.71(m,1H),5.77(s,2H),3.91(s,3H),3.88(s,3H),3.83(s,3H),4.21-4.22(m,2H),2.99(t,J＝6.8Hz,2H).
实施例29
本实施例提供化合物M29，以化合物f-4(100mg，0.60mmol)和化合物g-1(233mg，0.77mmol)为原料，所述化合物M29的制备方法同化合物M26，不经酸化，得化合物M29淡黄色固体150mg，收率55.6％，所述化合物M29的反应式如下所示：
1H NMR(400MHz,CDCl3)δ7.77(m,1H),7.66(s,1H),7.47-7.49(m,2H),7.24-7.27(m,2H),7.06-7.08(m,2H),6.96-6.99(m,1H),6.86-6.88(m,2H),6.69-6.71(m,1H),3.89(s,3H),3.86(s,3H),3.80(s,3H),4.21-4.22(m,2H),2.99(t,J＝6.8Hz,2H).
实施例30
本实施例提供化合物M30，以化合物f-5(100mg，0.62mmol)和化合物g-1(233mg，0.77mmol)为原料，所述化合物M30的制备方法同化合物M26，不经酸化，得化合物M30淡黄色固体150mg，收率54.2％，所述化合物M30的反应式如下所示：
1H NMR(400MHz,CDCl3)δ7.88(m,1H),7.49(s,1H),7.47(m,2H),7.20(m,2H),7.06-7.08(m,2H),6.99(m,1H),6.86-6.88(m,2H),6.69-6.71(m,1H),3.89(s,3H),3.86(s,3H),3.80(s,3H),3.72(s,3H),4.23(m,2H),2.969(t,J＝6.8Hz,2H).
实施例31
本实施例提供化合物M31，以化合物f-6(100mg，0.55mmol)和化合物g-1(233mg，0.77mmol)为原料，所述化合物M31的制备方法同化合物M26，不经酸化，得化合物M31淡黄色固体116mg，收率45％，所述化合物M31的反应式如下所示：
HR-MS(ESI)calcd for C26H28O6N2(M+H)+:464.1730,found 464.1710.
药理实验
实验例1
苯基丙烯酸类衍生物对ACAT1靶点的IC50测定
(一)实验方法
ACAT1小分子抑制剂的筛选方法
ACAT1可以催化两分子的乙酰基辅酶A可逆形成乙酰乙酰基辅酶A。其活性测定是通过ACAT1催化底物乙酰乙酰辅酶A与辅酶A反应，生成产物乙酰辅酶A。基于乙酰乙酰辅酶A在特定光谱有特定吸收，因此，通过检测特定光谱吸收的增多或减少来反映对ACAT1酶活性的影响。
ACAT1重组蛋白通过大肠杆菌进行表达纯化，获得的ACAT1重组蛋白浓度为1mg/mL。进行ACAT1小分子抑制剂筛选时，采用的缓冲液为50mM Tris-HCl(pH 8.1)、20mM MgCl2和40mM KCl。在200μL的酶催化体系中，分别加入ACAT1重组蛋白1μL，底物乙酰辅酶A终浓度为25μM，加入CPM探针至终浓度为100μM，以及不同浓度的小分子抑制剂。通过酶标仪(Biotek Synergy H1)，采用激发光355nm和发射光460nm，进行检测，采用软件Prism 7.0进行抑制剂IC50的计算。
(二)实验结果
体外对ACAT1活性影响的筛选结果见表1。实验结果表明，化合物1、5、7、9、10、12和17对ACAT1具有较强的抑制活性。
表1
由上述表1数据可知，化合物M1、M5、M7、M9、M10、M12和M17对ACAT1具有较强的抑制活性，IC50值均在100μmol/L以下。
实验例2
苯基丙烯酸类衍生物对丙酮酸激酶活性影响
(一)实验方法
丙酮酸激酶小分子调节剂筛选方法
原理：在二磷酸腺苷(ADP)存在的条件下丙酮酸激酶(PK)催化磷酸烯醇式丙酮酸(PEP)转化成丙酮酸，在还原型辅酶I(NADH)存在情况下，丙酮酸被LDH转化为乳酸，若标记荧 光于NADH上，此时有荧光的NADH变为荧光的NAD。
两个重组蛋白丙酮酸激酶亚型：PKLR(15501-H07E)、PKM2(11430-H07E)均购自北京义翘神州科技股份有限公司。进行PK活性筛选时，缓冲液采用100mM Tris HCl(pH 8.0)、100mM KCl和10mM MgCl2。在200μL的酶催化体系中，分别加入各种底物和酶至终浓度为ADP(0.6mM)、PEP(0.5mM)、NADH(180mM)、FBP(10mM)和LDH(8units)，另外添加不同浓度的小分子抑制剂。通过酶标仪(Biotek Synergy H1)，检测340nm吸收光的变化，进行检测，采用软件Prism 7.0进行抑制或激活活性的计算。
(二)实验结果
化合物在体外对丙酮酸激酶活性的影响见表2。
表2
由表2数据可知，化合物M1和M3对PKM2具有一定的抑制活性，而化合物M2对PKLR和PKM2均具有一定的激活作用。
申请人声明，本申请通过上述实施例来说明本申请的一种苯基丙烯酸类化合物及其制备方法和应用，但本申请并不局限于上述实施例，即不意味着本申请必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本申请的保护范围和公开范围之内。

Claims (10)

  1. 一种苯基丙烯酸类化合物，其具有如下式I所示结构：
    其中，R1、R2、R3、R4、R7、R8和R9各自独立地选自氢、卤素、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C6烷氧羰基、C1-C6烷羰基氧基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基亚甲基氧基、C1-C6烷酰基、三卤代C1-C6烷基或三卤代C1-C6烷氧基中的任意一种；或者，R1、R2、R7、R8、R9各自独立地选自-O(CH2)nO-，并与其取代的苯基相连成环，n选自1、2或3；
    R5选自氢、氨基、C1-C6烷基、C1-C6烷氧基甲基或C1-C6烷基胺基中的任意一种；
    R6选自氢、羟基、氨基、羰基、C1-C6烷基胺基、C1-C6烷羰基氧基或C1-C6烷氧基羰基中的任意一种；
    X选自O或NH；以及
    Y选自O、NH、S、亚砜或砜中的任意一种。
  2. 根据权利要求1所述的苯基丙烯酸类化合物，其中，所述苯基丙烯酸类化合物选自如下式II-式V中的任意一种：
    其中，所述R1、R2各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C4烷氧羰基、C1-C4烷羰基氧基、C1-C4烷基、C1-C4烷氧基、C1-C4烷氧基亚甲基氧基、三卤代C1-C4烷基、三卤代C1-C4烷氧基中的任意一种；
    所述R3和R4各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C4烷氧羰基、C1-C4烷羰基氧基、C1-C4烷基、C1-C4烷氧基、三卤代C1-C4烷基或三卤代C1-C4烷氧基中的任意一种；
    所述R5选自氢、氨基、C1-C4烷基、C1-C4烷氧基甲基或C1-C4烷基胺基中的任意一种；
    所述R6选自氢、羟基、氨基、羰基、C1-C4烷基胺基、C1-C4烷羰基氧基或C1-C4烷氧基羰基中的任意一种；
    所述R7、R8和R9各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C4烷基、C1-C4烷氧基、C1-C4烷氧羰基、C1-C4烷羰基氧基、C1-C3烷酰基、C1-C4烷氧基亚甲基氧基、三卤代C1-C4烷基或三卤代C1-C4烷氧基中的任意一种；
    所述X选自O或NH；
    所述Y选自O、NH、S、亚砜或砜中的任意一种；以及
    所述p1、p2和p3各自独立地选自1、2或3。
  3. 根据权利要求2所述的苯基丙烯酸类化合物，其中，所述R1、R2各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、乙氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、C1-C2烷羰基氧基、C1-C2烷氧基亚甲基氧基、三卤代C1-C2烷基或三卤代C1-C2烷氧基中的任意一种；
    所述R3、R4各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、乙氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、C1-C2烷羰基氧基、三卤代C1-C2烷基或三卤代C1-C2烷氧基中的任意一种；
    所述R5选自氢、氨基、甲基、乙基、C1-C2烷氧基甲基或C1-C2烷基胺基中的任意一种；
    所述R6选自氢、氨基、羟基、羰基、C1-C2烷基胺基、C1-C2烷羰基氧基或C1-C2烷氧基羰基中的任意一种；
    所述R7、R8和R9各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、甲基、乙基、甲氧基、乙氧基、甲氧羰基、乙氧羰基、甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基、2-甲基丁酰基、C1-C2烷氧基亚甲基氧基、三卤代C1-C2烷基或三卤代C1-C2烷氧基；
    所述X选自O或NH；
    所述Y选自O、NH、S、亚砜或砜中的任意一种；以及
    所述p1、p2和p3各自独立地选自1或2。
  4. 根据权利要求2或3所述的苯基丙烯酸类化合物，其中，所述R1、R2各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、三氟甲基、三氟甲氧基或甲氧基亚甲基氧基中的任意一种；
    所述R3、R4各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、三氟甲基或三氟甲氧基中的任意一种；
    所述R5选自氢、甲基、乙基、甲氧基甲基或氨基中的任意一种；
    R6选自氢、羟基、氨基、羰基、或C1-C2烷羰基氧基中的任意一种；
    R7、R8和R9各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、甲基、乙基、甲氧基、乙氧基、三氟甲基、三氟甲氧基、甲氧羰基、甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基或甲氧基亚甲基氧基中的任意一种；
    X选自O或NH；
    Y选自O、NH、S、亚砜或砜中的任意一种或至少两种的组合；以及
    所述p1、p2和p3各自独立地选自1。
  5. 根据权利要求1-4中任一项所述的苯基丙烯酸类化合物，其中，所述苯基丙烯酸类化合物选自如下M1-M31中的任意一种：

  6. 一种根据权利要求1-5中任一项所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐；
    优选地，所述药学上可接受的盐包括盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、甲磺酸盐、对甲苯磺酸盐、乙酸盐、三氟乙酸盐、水杨酸盐、氨基酸盐、枸杞酸盐、马来酸盐、酒石酸盐、富马酸盐、柠檬酸盐、乳酸盐、钠盐、钾盐、钙盐、镁盐、锂盐、铵盐或能提供生理上可接受的阳离子的有机碱的盐中的任意一种或至少两种的组合；
    优选地，所述能提供生理上可接受的阳离子的有机碱的盐包括甲胺盐、二甲胺盐、三甲胺盐、哌啶盐、吗啉盐或三(2-羟乙基)胺盐中的任意一种或至少两种的组合。
  7. 一种根据权利要求1-5中任一项所述的苯基丙烯酸类化合物的制备方法，其包括以下步骤：
    (1)将式a所示化合物与式b所示化合物进行缩合反应，得到式c所示化合物，反应式如下所示：
    (2)将式c所示化合物进行脱保护基，得到式d所示化合物，反应式如下所示：
    (3)将式d所示化合物和式e所示化合物进行取代反应，得到式I所示化合物，反应式如下所示：
    或者，所述制备方法包括以下步骤：将式f所示化合物与式g所示化合物进行缩合反应，得到式I所示化合物，反应式如下所示：
    其中，所述X’选自OH或NH2；
    Y’选自叔丁基二甲基硅氧基、叔丁基二苯基硅氧基、三甲基硅氧基、三乙基硅氧、苄氧基、对甲氧基卞氧基、甲氧基亚甲基氧基、苄氧羰酰基氧基或叔丁氧羰基氧基中的任意一种；
    Y”选自OH、NH2或SH中的任意一种；
    Z选自羟基、氯、溴、碘、对甲苯磺酰基或甲磺酰基中的任意一种。
  8. 根据权利要求7所述的制备方法，其中，步骤(1)中，所述缩合反应在碱性条件下进行；
    优选地，步骤(1)中，所述缩合反应在缩合剂的存在下进行，所述缩合剂包括EDCI和/或DMAP；
    优选地，步骤(1)中，所述缩合反应的温度为0-30℃，时间为5-15h；
    优选地，步骤(1)中，所述式a所示化合物与式b所示化合物的摩尔比为1:(0.8-1.5)；
    优选地，步骤(2)中，所述脱保护基通过水解反应或氢化反应进行；
    优选地，步骤(2)中，所述脱保护基通过水解反应进行，所述水解反应在酸性条件或碱性条件下进行；
    优选地，步骤(3)中，所述取代反应在碱性条件下进行；
    优选地，步骤(3)中，所述取代反应的温度为60-100℃，时间为2-6h；
    优选地，步骤(3)中，所述式d所示化合物与式e所示化合物的摩尔比为1:(1-2)；
    优选地，所述式f所示化合物与式g所示化合物在碱性条件下进行缩合反应；
    优选地，所述式f所示化合物与式g所示化合物在缩合剂的存在下进行缩合反应，所述缩合剂包括EDCI和/或DMAP；
    优选地，所述式f所示化合物与式g所示化合物的摩尔比为1:(0.8-1.5)。
  9. 一种药物组合物，其包括活性成分和药效学上可接受的载体，所述活性成分包括权利要求1-5中任一项所述的苯基丙烯酸类化合物或权利要求6所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐；
    优选地，所述药物组合物中所述活性成分的质量百分含量为0.1-95％。
  10. 一种根据权利要求1-5中任一项所述的苯基丙烯酸类化合物、权利要求6所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或权利要求9所述的药物组合物在制备预防或治疗肿瘤、自身免疫性疾病、炎症性疾病、神经退行性疾病或抗衰老药物中的应用；
    优选地，所述肿瘤选自神经胶质瘤、黑色素瘤、胃癌、肺癌、乳腺癌、肾癌、肝癌、口腔上皮癌、头颈部肿瘤、宫颈癌、卵巢癌、胰腺癌、前列腺癌、结肠癌、直肠腺癌、白血病或淋巴瘤中的任意一种或至少两种的组合；
    优选地，所述自身免疫性疾病包括类风湿关节炎、系统性红斑狼疮、溃疡性结肠炎、银屑病、皮炎或脊髓侧索硬化症中的任意一种或至少两种的组合；
    优选地，所述炎症性疾病包括多发性动脉炎、静脉炎、反流性食管炎中的任意一种或至少两种的组合；
    优选地，所述神经退行性疾病包括老年性痴呆和/或帕金森病。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10224119A1 (de) * 2002-05-29 2003-12-11 Bioagency Ag 2-Phenylendiaminderivate als Insektizide
CN101679228A (zh) * 2007-06-05 2010-03-24 盖尔德马研究及发展公司 为ppar型受体的活化剂的新型3-苯基丙烯酸衍生物、其制备方法和其在化妆品或者药物组合物中的用途
CN104109120A (zh) * 2013-04-22 2014-10-22 中国医学科学院药物研究所 N′-芳丙烯酰基邻吡啶酰肼衍生物及其制法和药物组合物与用途
CN111763164A (zh) * 2019-04-02 2020-10-13 中国医学科学院药物研究所 一类邻位羰基氨基取代苯衍生物的制备方法和用途
CN111777501A (zh) * 2019-04-03 2020-10-16 中国医学科学院药物研究所 咖啡酸苯乙酯类衍生物，其制法和其药物组合物与用途
CN114644560A (zh) * 2022-04-20 2022-06-21 朗捷睿(苏州)生物科技有限公司 一种苯基丙烯酸类化合物及其制备方法和应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10008522A1 (de) * 2000-02-24 2001-09-06 Hassan Jomaa Verwendung von 2-PHenylendiaminderivaten zur Behandlung von Infektionen
DE10014141A1 (de) * 2000-03-22 2001-10-11 Jomaa Hassan 2-Phenylendiaminderivate als Herbizide
US20170081347A1 (en) * 2014-04-14 2017-03-23 The Trustees Of Boston College Functionalized azaborine compounds and azaborine-containing biarylcarboxamides, and compositions and methods thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10224119A1 (de) * 2002-05-29 2003-12-11 Bioagency Ag 2-Phenylendiaminderivate als Insektizide
CN101679228A (zh) * 2007-06-05 2010-03-24 盖尔德马研究及发展公司 为ppar型受体的活化剂的新型3-苯基丙烯酸衍生物、其制备方法和其在化妆品或者药物组合物中的用途
CN104109120A (zh) * 2013-04-22 2014-10-22 中国医学科学院药物研究所 N′-芳丙烯酰基邻吡啶酰肼衍生物及其制法和药物组合物与用途
CN111763164A (zh) * 2019-04-02 2020-10-13 中国医学科学院药物研究所 一类邻位羰基氨基取代苯衍生物的制备方法和用途
CN111777501A (zh) * 2019-04-03 2020-10-16 中国医学科学院药物研究所 咖啡酸苯乙酯类衍生物，其制法和其药物组合物与用途
CN114644560A (zh) * 2022-04-20 2022-06-21 朗捷睿(苏州)生物科技有限公司 一种苯基丙烯酸类化合物及其制备方法和应用

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