CN116514678A - Novel coronavirus inhibitor, pharmaceutical composition containing same and use thereof - Google Patents

Novel coronavirus inhibitor, pharmaceutical composition containing same and use thereof Download PDF

Info

Publication number
CN116514678A
CN116514678A CN202210072991.9A CN202210072991A CN116514678A CN 116514678 A CN116514678 A CN 116514678A CN 202210072991 A CN202210072991 A CN 202210072991A CN 116514678 A CN116514678 A CN 116514678A
Authority
CN
China
Prior art keywords
straight
branched
chain
phenyl
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202210072991.9A
Other languages
Chinese (zh)
Inventor
尚鲁庆
邓伟龙
邢帅
何瑛琦
胡啸
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nankai University
Original Assignee
Nankai University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nankai University filed Critical Nankai University
Priority to CN202210072991.9A priority Critical patent/CN116514678A/en
Publication of CN116514678A publication Critical patent/CN116514678A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to novel coronavirus inhibitors, pharmaceutical compositions containing them and their use. The inhibitor of the invention has better activity of inhibiting novel coronaviruses and lower cytotoxicity, namely higher safety, and can be used for preventing and/or treating diseases caused by SARS-CoV-2 infection, such as novel coronavirus pneumonia.

Description

Novel coronavirus inhibitor, pharmaceutical composition containing same and use thereof
Technical Field
The present invention relates to compounds for the treatment of novel coronavirus (SARS-CoV-2) infection, pharmaceutical compositions containing the same and uses thereof.
Background
The novel coronavirus pneumonia (COVID-19) is caused by a novel coronavirus (SARS-CoV-2) infection. The novel coronavirus has the advantages of high transmission speed, wide infection range and high prevention and control difficulty. The novel coronavirus transmission modes include droplet transmission and aerosol transmission. The clinical symptoms after infection are commonly shown as fever, dry cough, laryngalgia, dyspnea, nausea, vomiting and the like, and severe patients are accompanied with acute respiratory distress syndrome, septicemia, multiple organ failure and the like. Diagnostically, it was found that mild patients had lymphopenia, leukopenia, increased CRP, severe patients had increased transaminase, lactate dehydrogenase, and the like.
Based on phylogenetic and taxonomical considerations and established conventions, the International Commission on viral classification classifies SARS-CoV-2 as belonging to the genus Coronaviridae of the order nidoviridae. The coronaviruses found to infect humans are HCoV-229E, HCoV-NL63 of the alpha genus and HCoV-HKU1, HCoV-OC43, MERS-CoV, SARA-CoV and SARS-CoV-2 of the beta genus. In addition to SARS-CoV, MERS-CoV and SARS-CoV-2 being highly pathogenic viruses, other human coronaviruses are likely to spread in humans for a long period of time, but typically cause only relatively mild respiratory disease.
SARS-CoV-2 is a single-stranded positive sense RNA virus, having a genome of about 30kbp, with the largest genome in RNA viruses. SARS-CoV-2 is spherical or elliptic and has a diameter of 80-120nm. The surface of the virus under the electron microscope is provided with a rod-shaped protruding part which consists of a trimer spike protein (S) and is divided into a large extracellular domain and a small intracellular domain; the viral envelope is composed of a membrane protein (M) containing three transmembrane structures, wherein some transmembrane envelope proteins (E) are inserted, and the genome RNA is wrapped by a nucleocapsid protein (N) to form a spiral shape and further surrounded by the envelope. The genome is, in order from the 5 'end to the 3' end: 5 'cap structure-leader-UTR-replicase-S-E-M-N-URT-3' polyA. The methylated cap structure and Poly A at both ends allow it to be used as mRNA for direct protein translation of the replicase domain. There are at least 11 open reading frames (Open reading frame, ORFs) on the genome, where the upstream ORF1a and ORF1b contain the replicase domain genes, approximately 20kbp, accounting for 66% of the entire genome, encoding the nonstructural proteins, and downstream is the genome encoding the structural and accessory proteins, approximately 10kbp, interspersed with the structural protein genome. The open reading frame is flanked by untranslated regions 5'UTR and 3' UTR, the 5'UTR being an important structure for genome replication and transcription, the 3' UTR being capable of regulating genome replication and transcription, and the replicase domain gene comprising a leader sequence upstream.
The process of infecting host cells with SARS-CoV-2 is divided into five steps: viral entry, expression of replicase genes, replication transcription and translation of the genome, assembly and release of progeny viruses. The host cells are mainly type II lung epithelial cells. The pathway into the target cell is the specific binding of the S protein to ACE2 receptor on the host cell surface, inducing the protease TMPRSS2 to hydrolyze the S protein, the S protein being activated, the viral envelope fusing with the cytoplasmic membrane, the rapid entry into the host cell by endocytosis of the lipid envelope, vesicle and viral particle fusion, and release of the viral genome into the cytoplasm. After the virus enters the host cell, endolysosomal digestion of viral nucleocapsid proteins is initiated, viral RNA is released, viral genomic RNA can be used as mRNA, translated and frameshifted to produce precursor multimeric proteins pp1a and pp1ab, which are further hydrolyzed by the main protease and papain-like protease to nonstructural proteins required for replication and transcription of the virus. Under the action of virus replicase, the virus genome RNA takes itself as template to synthesize full-length antisense RNA, and the antisense RNA takes itself as template to synthesize new genome RNA. The polymerase can switch templates in the discontinuous transcription process of specific sites of genomic RNA to generate 5 '-nested antisense sgRNA, and the 5' -nested antisense sgRNA is synthesized by taking the template as the template, so that structural proteins and auxiliary proteins are translated, S proteins, E proteins and M proteins are transferred from an endoplasmic reticulum to an endoplasmic reticulum golgi intermediate complex, N proteins form a nucleocapsid to wrap progeny viral RNA, E proteins promote M proteins to form a viral envelope on ERGIC, the viral envelope is assembled into a mature virion, transported to a cytoplasmic membrane through a golgi apparatus and a secretion vesicle, and released outside a host cell by exocytosis.
The immune response occurs mainly in capillaries. On the innate immune level, type i interferon responses are delayed or inhibited during initial infection, viral replication triggers a hyper-inflammatory response and cytokine storm, activated neutrophils and inflammatory mononucleated/macrophages are increased, serum neutrophils and elevated pro-inflammatory cytokines are correlated with the severity of the disease. In terms of adaptive immune responses, helper T cells Th1/Th17 are activated, igA, igM and IgG are usually detectable within two weeks of infection, and lymphopenia may be associated with myelosuppression.
Since the beginning of 2020, there has been a desire to find compounds that are effective in inhibiting novel coronaviruses.
Disclosure of Invention
The invention provides an effective inhibitor aiming at SARS-CoV-2 virus, and also provides a pharmaceutical composition containing the inhibitor and application thereof.
According to a first aspect of the present invention, the present invention relates to a compound of formula I:
wherein:
R 1 represents Z-Y-X-,
x represents a bond; alternatively, O;
y represents a bond; alternatively, C 1-10 Straight-chain or branched alkylene, C 2-10 Straight-chain or branched alkenylene or C 2-10 A linear or branched alkynylene group, the alkylene, alkenylene, or alkynylene group being unsubstituted or substituted with 1 or more halogens;
Z represents H; c (C) 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, S, said cycloalkyl or heterocycloalkyl being unsubstituted or substituted with 1 or more substituents independently selected from halogen, C 1-10 Straight-chain or branched alkyl, C 2-10 Straight-chain or branched alkenyl, C 2-10 Straight or branched alkynyl, C 1-10 Linear or branched alkyl oxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups; alternatively, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, S, said aryl or heteroaryl being unsubstituted or substituted with 1 or more substituents independently selected from halogen, C 1-10 Straight-chain or branched alkyl, C 2-10 Straight-chain or branched alkenyl, C 2-10 Straight or branched alkynyl, C 1-10 Straight or branched chain alkyl oxy, notSubstituted or by C 1-6 Alkyl-substituted phenyl, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups;
provided that when Y is a bond, Z is not H;
R 2 represents phenyl, C 1-10 Straight-chain or branched alkylene phenyl, C 2-10 Straight-chain or branched alkenylene phenyl or C 2-10 Straight or branched alkynylene phenyl, said phenyl being unsubstituted or substituted with 1 or more groups independently selected from halogen, C 1-10 Straight-chain or branched alkyl, C 2-10 Straight-chain or branched alkenyl, C 2-10 Straight or branched alkynyl, C 1-10 Linear or branched alkyl oxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups;
R 3 represents hydrogen; c (C) 1-10 Straight-chain or branched alkyl, C 2-10 Straight-chain or branched alkenyl or C 2-10 A linear or branched alkynyl group, said alkyl, alkenyl or alkynyl group being unsubstituted or substituted with 1 or more halogens; c (C) 3-10 Cycloalkyl, C 1-10 Straight-chain or branched alkylene C 3-10 Cycloalkyl, C 2-10 Straight-chain or branched alkenylene C 3-10 Cycloalkyl, C 2-10 Straight-chain or branched alkynylene C 3-10 Cycloalkyl, phenyl, C 1-10 Straight-chain or branched alkylene phenyl, C 2-10 Straight-chain or branched alkenylene phenyl or C 2-10 A straight or branched alkynylene phenyl group, said cycloalkyl or phenyl group being unsubstituted or substituted with 1 or more groups independently selected from halogen, C 1-10 Straight-chain or branched alkyl, C 2-10 Straight-chain or branched alkenyl, C 2-10 Straight or branched alkynyl, C 1-10 Linear or branched alkyl oxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups;
R 4 represents-CHO.
In a preferred embodiment, in the compounds of formula I:
R 1 represents Z-Y-X-,
x represents a bond; alternatively, O;
y represents a bond; alternatively, C 1-6 Straight-chain or branched alkylene, C 2-6 Straight-chain or branched alkenylene, or C 2-6 A linear or branched alkynylene group, said alkylene, alkenylene, or alkynylene group being unsubstituted or substituted with 1-3 fluorine groups;
z represents H; c (C) 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl containing 1 heteroatom selected from N, O, S, said cycloalkyl or heterocycloalkyl being unsubstituted or substituted with 1-3 groups independently selected from halogen, C 1-6 Straight-chain or branched alkyl, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight or branched alkynyl, C 1-6 Linear or branched alkyl oxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups; alternatively, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, S, said aryl or heteroaryl being unsubstituted or substituted with 1-3 heteroatoms independently selected from halogen, C 1-6 Straight-chain or branched alkyl, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight or branched alkynyl, C 1-6 Linear or branched alkyl oxygen, phenyl, hydroxy, amino, cyano, nitro, trifluoromethyl groups;
provided that when Y is a bond, Z is not H;
R 2 represents phenyl, C 1-6 Straight-chain or branched alkylene phenyl, C 2-6 Straight-chain or branched alkenylene phenyl or C 2-6 Straight or branched alkynylene phenyl groups, said phenyl groups being unsubstituted or substituted with 1 to 3 groups independently selected from halogen, C 1-6 Straight-chain or branched alkyl, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight or branched alkynyl, C 1-6 Linear or branched alkyl oxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups;
R 3 represents hydrogen; methyl, n-propyl, C 4-6 Straight-chain or branched alkyl, C 4-6 Straight-chain or branched alkenyl or C 4-6 A linear or branched alkynyl group, said alkyl, alkenyl or alkynyl group being unsubstituted or substituted with 1 to 3 fluoro groups; c (C) 3-10 Cycloalkyl, C 1-6 Straight-chain or branched alkylene C 3-10 Cycloalkyl, C 2-6 Straight-chain or branched alkenylene C 3-10 Cycloalkyl, C 2-6 Straight-chain or branched alkynylene C 3-10 Cycloalkyl, phenyl, C 1-6 Straight-chain or branched alkylene phenyl, C 2-6 Straight-chain or branched alkenylene phenyl or C 2-6 Straight or branched alkynylene phenyl, said cycloalkyl or phenyl being unsubstituted or substituted with 1 to 3 groups independently selected from halogen, C 1-6 Straight-chain or branched alkyl, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight or branched alkynyl, C 1-6 Linear or branched alkyl oxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups;
R 4 represents-CHO.
In a preferred embodiment, in the compounds of formula I:
R 1 represents Z-Y-X-,
x represents a bond; alternatively, O;
y represents a bond; or, C1-3 straight or branched alkylene, C2-3 straight or branched alkenylene;
Z represents H; a cyclohexenyl or 6 membered heterocycloalkyl containing 1 heteroatom selected from N, O, S, said cycloalkyl or heterocycloalkyl being unsubstituted or substituted with 1-3 groups independently selected from halo, methyl, methoxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy; or, phenyl, naphthyl, pyrrolyl, furanyl, thienyl, indolyl, pyridinyl, isoxazolyl, pyrimidinyl, said substituents being unsubstituted or substituted with 1 to 3 groups independently selected from halogen, methyl, methoxy, phenyl, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy;
provided that when Y is a bond, Z is not H;
R 2 represent C 1-3 A linear or branched alkylene phenyl group, said phenyl group being unsubstituted or substituted with 1 group selected from halogen, methyl, methoxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy;
R 3 represents hydrogen; methyl, n-propyl, C 4-6 Linear or branched alkyl; c (C) 1-3 Linear or branched alkylene cyclohexanyl or C 1-3 A linear or branched alkylene phenyl group, said cyclohexyl or phenyl group being unsubstituted or substituted with 1 group selected from halogen, methyl, methoxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy;
R 4 represents-CHO.
In a preferred embodiment, in the compounds of formula I:
R 1 represents Z-Y-X-,
x represents a bond; alternatively, O;
y represents a bond; alternatively, CH 2 、CH＝CH；
Z represents a cyclohexenyl or a 6 membered heterocycloalkyl containing 1O atom, said cyclohexenyl or heterocycloalkyl being unsubstituted or substituted with 1 or 2 groups independently selected from halogen, methyl, methoxy, nitro; or, phenyl, naphthyl, pyrrolyl, furanyl, thienyl, indolyl, pyridyl, isoxazolyl, pyrimidinyl, said substituents being unsubstituted or substituted with 1 or 2 groups independently selected from halogen, methyl, vinyl, methoxy, phenyl, nitro;
R 2 represents a methylenephenyl or ethylenephenyl group, said phenyl group being unsubstituted or substituted in ortho, meta or para position with respect to the methylene or ethylene group by 1 group selected from halogen, methoxy, nitro, trifluoromethyl;
R 3 represents methyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl; a methylenecyclohexenyl or methylenephenyl group, said cyclohexenyl or phenyl group being unsubstituted or substituted with 1 group selected from halogen in the ortho, meta or para position to the methylene group;
R 4 represents-CHO.
In a preferred embodiment, the compounds of formula I
R 1 Selected from the group consisting of pentyl, phenyl, ethenylene, methylenephenyl, -O-methylenephenyl, phenylenephenyl, naphthyl, pyrrolyl, furanyl, thienyl, indolyl, methyleneindolyl, pyridyl, isoxazolyl, cyclohexenyl,Tetrahydropyran, said substituents being unsubstituted or substituted with 1 or 2 groups independently selected from fluoro, chloro, bromo, methyl, vinyl, methoxy, nitro;
R 2 selected from the group consisting of methylenephenyl, said phenyl being unsubstituted or substituted with 1 group selected from fluoro, chloro, bromo, methoxy, nitro, trifluoromethyl, ortho, meta or para to the methylene;
R 3 selected from isobutyl; a methylenecyclohexenyl or methylenephenyl group, said cyclohexenyl or phenyl group being unsubstituted or substituted with 1 fluorine at the ortho, meta or para position relative to the methylene group;
R 4 represents-CHO.
In a preferred embodiment, the compound of formula I is selected from:
definition of terms in the present invention:
in the present invention, "halogen" means fluorine, chlorine, bromine, iodine;
in the present invention, "C 1-10 The straight-chain or branched alkyl group "means a straight-chain or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc. This definition applies equally to the corresponding alkyl groups having fewer carbon atoms, e.g. C 1-6 Straight or branched alkyl groups, etc., and corresponding alkyl groups in other more complex substituents, e.g. C 1-10 Linear or branched alkyl oxy groups, and the like;
in the present invention, "C 2-10 Straight chain or linearBranched alkenyl "refers to straight or branched alkenyl groups having 2 to 10 carbon atoms, such as vinyl, allyl, propenyl, and the like. This definition applies equally to the corresponding alkenyl groups having fewer carbon atoms, e.g. C 2-6 Straight or branched alkenyl groups, and the like;
in the present invention, "C 2-10 Straight or branched alkynyl "refers to straight or branched alkynyl groups having 2 to 10 carbon atoms, such as ethynyl, propargyl, propynyl, and the like. This definition applies equally to the corresponding alkynyl groups having fewer carbon atoms, e.g. C 2-6 Straight or branched chain alkynyl groups, and the like;
in the present invention, "C 1-10 By straight or branched alkylene "is meant straight or branched alkylene having 1 to 10 carbon atoms, such as methylene, ethylene, n-propylene, isopropylene, n-butylene. This definition applies equally to the corresponding alkylene groups having fewer carbon atoms, e.g. C 1-6 Straight-chain or branched alkylene groups, etc., and corresponding alkylene groups in other more complex substituents, e.g. C 1-10 Straight-chain or branched-chain alkylene phenyl groups, and the like;
in the present invention, "C 2-10 By straight or branched alkenylene "is meant straight or branched alkenylene having 2 to 10 carbon atoms, such as ethenylene, allylene, propenylene, and the like. This definition applies equally to the corresponding alkenylene radicals having fewer carbon atoms, for example C 2-6 Straight-chain or branched alkenylene groups, etc., and corresponding alkenylene groups in other more complex substituents, e.g. C 2-10 Linear or branched alkenylene phenyl, and the like;
in the present invention, "C 2-10 Straight or branched alkynylene "refers to straight or branched alkynylene groups having 2 to 10 carbon atoms, such as ethynylene, propargyl, propynylene, and the like. This definition applies equally to the corresponding alkynylene radicals having fewer carbon atoms, e.g. C 2-6 Straight-chain or branched alkynylene radicals and the like, as well as corresponding alkynylene radicals suitable for use in other more complex substituents, e.g. C 2-10 Straight-chain or branched alkynylene phenyl groups and the like;
in the present invention, "C 3-10 Cycloalkyl "means cycloalkyl having 3 to 10 carbon atoms, including monocyclic orCondensed rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like;
in the present invention, "3-10 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, S" means a 3-10 membered heterocycloalkyl having 1 or 2 or 3 heteroatoms independently selected from N, O, S, including a single ring or a condensed ring, which is attached through one ring carbon atom or one ring nitrogen atom of the heterocycloalkyl group, such as tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, and the like;
In the present invention, "C 6-10 Aryl "refers to aryl groups having 6 to 10 carbon atoms and includes monocyclic or fused rings, such as phenyl, naphthyl, and the like.
In the present invention, "5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, S" refers to a 5-10 membered heteroaryl having a single or fused ring, having 1 or 2 or 3 heteroatoms independently selected from N, O, S, which is attached through one ring carbon atom or one ring nitrogen atom of the heteroaryl, such as pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, 1,2, 3-triazole, 1, 2-thiadiazole, pyridine, pyrazine, pyrimidine, 1,2, 4-triazine, indole, benzoxazole, benzothiazole, quinoline, and the like;
in the present invention, "alkylene phenyl" means a phenyl group linked via an alkylene group. This definition applies equally to other analogous groups, for example C 1-10 Straight-chain or branched alkylene C 3-10 Cycloalkyl groups, and the like.
According to the present invention, a pharmaceutically acceptable salt means a pharmaceutically acceptable salt of a compound of formula I with an inorganic or organic acid. Inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like, and organic acids such as formic acid, acetic acid, propionic acid, valeric acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid, malonic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, benzoic acid and the like.
The compound of the formula I or the pharmaceutically acceptable salt thereof can inhibit SARS-CoV-2, so that the compound can be used for preventing and/or treating diseases caused by SARS-CoV-2 infection, such as novel coronavirus pneumonia, and can be used alone or simultaneously with other compounds for treating diseases caused by SARS-CoV-2 infection.
According to a second aspect of the present invention, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In a preferred embodiment, the pharmaceutical composition of the present invention further comprises other compounds for treating diseases caused by SARS-CoV-2 infection.
According to a third aspect of the present invention, the present invention relates to a method for the prophylaxis and/or treatment of a disease caused by SARS-CoV-2 infection in a mammal, by administering to the mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention.
In a preferred embodiment, the prophylactic and/or therapeutic methods of the invention also administer to a mammal an additional compound for the treatment of a disease caused by SARS-CoV-2 infection. Other compounds for treating diseases caused by SARS-CoV-2 infection may be administered prior to, concurrently with, or subsequent to the administration of the compounds or compositions of the present invention.
According to a fourth aspect of the present invention, the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of a disease caused by SARS-CoV-2 infection in a mammal.
According to a fifth aspect of the present invention, the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of a disease caused by SARS-CoV-2 infection in a mammal in combination with other compounds for the treatment of a disease caused by SARS-CoV-2 infection.
In the present invention, preferably, the mammal is a human.
In the present invention, preferably, the disease caused by SARS-CoV-2 infection is a novel coronavirus pneumonia.
In the present invention, other compounds for treating diseases caused by SARS-CoV-2 infection are preferred, including but not limited to antiviral agents such as acyclovir, rituximab, monabivalvir and the like, antiinfectives, immunomodulators such as alpha, beta, delta-interferon and the like, primary protease inhibitors, S protease inhibitors, M protein inhibitors, and/or antibiotics and the like.
The pharmaceutical compositions of the present invention may be administered by a variety of routes known in the art including, but not limited to, oral, dermal, intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, pulmonary, epidural, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, ocular, oral, nasal, rectal, bronchial, and the like. Administration may also be through an implanted reservoir or through a drug-loaded stent. The administration may be systemic or local. Preferred routes of administration are oral, intravenous, nasal transmucosal administration, and bronchial sprays.
The pharmaceutical compositions of the present invention may be administered in a variety of pharmaceutical forms known in the art. The pharmaceutical carrier used may be solid or liquid.
The formulation using a solid carrier may be in the form of tablets (including but not limited to various coated tablets, slow-release or controlled-release tablets), powders or pellets placed into hard capsules, lozenges or troches, granules, dispersible powders, and the like. The amount of solid support varies to a large extent but is preferably from about 25mg to about 1.0g. Typical solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. The solid carrier may comprise one or more substances which may act simultaneously as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it may also be an encapsulating material. In powders, the carrier is a finely divided solid which is admixed with the finely divided active ingredient. The active ingredient is mixed in a suitable ratio in a tablet with a carrier having the necessary compression properties, compressed in the desired shape and size. The powders and tablets preferably contain up to 99% active ingredient.
Formulations using liquid carriers may be in the form of syrups, emulsions, soft capsules, sterile injectable solutions or suspensions in ampules or vials or non-aqueous liquid suspensions. Typical liquid carriers include syrup, peanut oil, olive oil, water, and the like. Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, tinctures and sealed compositions. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of the two or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, pigments, viscosity regulators, stabilizing formation of osmotic pressure-regulating agents. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as described above, e.g., cellulose derivatives, preferably carboxymethyl cellulose sodium salt solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., ethylene glycol) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). The carrier for parenteral administration may also be oils such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid compositions for parenteral administration. The liquid carrier for the pressurized composition may be a halocarbon or other pharmaceutically acceptable propellant. Sterile solution or suspension liquid pharmaceutical compositions may be used, for example, for intravenous, intramuscular, intraperitoneal or subcutaneous injection. The suspension may be formulated according to techniques known in the art using a suitable dispersing or wetting agent (such as tween 80) and suspending agent.
To obtain a stable water-soluble dosage form, the compound or pharmaceutically acceptable salt thereof may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3M succinic acid or citric acid solution. Alternatively, the acidic derivative may be dissolved in a suitable alkaline solution. If a soluble form is not available, the compound may be dissolved in a suitable co-solvent or combination thereof. Examples of such suitable cosolvents include, but are not limited to, ethanol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerol, polyoxyethylene fatty acid esters, fatty alcohols or glycerol hydroxy fatty acid esters, and the like, at concentrations ranging from 0-60% total volume.
Other suitable excipients or carriers that may be used in the above-mentioned compositions are found in standard pharmacological textbooks, for example in "Remington's Pharmaceutical Sciences", 19 th edition.
In order to prevent and treat SARS-CoV-2 induced disease, such as novel coronavirus pneumonia, in monotherapy the compounds of formula I of the invention, or pharmaceutically acceptable salts thereof, are useful in a dosage range of between about 0.01 and about 100mg/kg body weight per day, preferably between 0.5 and 75mg/kg body weight per day. It will be appreciated by those skilled in the art that when a compound of formula I or a pharmaceutically-acceptable salt thereof of the present invention is used in combination with other therapeutic agents, the dosage may be suitably reduced. Typically, the pharmaceutical composition of the invention will be administered about 1 to 5 times per day, or another continuous infusion. Such drugs may be used as chronic or acute treatments. Representative formulations will contain from about 5% to about 95% active ingredient (weight/weight). Preferably, such formulations contain from about 20% to about 80% of the active compound.
It will be appreciated by those skilled in the art that higher or lower doses than those mentioned above may be required. The particular dosage and manner of treatment for a particular patient will depend on a variety of factors including the activity of the particular compound employed, the age, weight, sex, general health of the patient, diet, time of administration, metabolic rate, combination of drugs, and severity and course of the infection, the patient's predisposition to the infection, and the discretion of the treating physician. Generally, treatment is initiated at a small dose that is substantially lower than the optimal dose of the compound. The dosage is then increased by a small increase until the optimal effect is reached in this case. In general, it is desirable to administer the compound in a concentration level that is generally sufficient to produce an effective antiviral result, but that does not cause any deleterious or adverse side effects.
The compounds of the general formula of the present invention can be prepared by the following general synthetic methods. Substituents in these synthetic methods are as defined above.
The process flow comprises the following steps:
in some embodiments of the invention, the preparation method is as follows:
step I-1: preparation of Compound 1
NH in L configuration at room temperature 2 CHR 2 COOH (1.0 eq.) was dissolved in an appropriate amount of methanol and thionyl chloride (1.2 eq.) was slowly added under an ice water bath. Stirring at room temperature for 10min, and transferring to 70 ℃ oil bath for reaction for 3h. After the reaction, the solvent was removed under reduced pressure, and after the product was dissolved in an appropriate amount of dichloromethane, the pH was adjusted to weakly alkaline with TEA in an ice-water bath, boc-NHCHR of L configuration was added in sequence 3 COOH (1.0 eq), EDCI (1.2 eq), HOBt (1.2 eq) and TEA (4.0 eq) were transferred to room temperature for reaction for 12h. After the reaction is completed, water, saturated citric acid solution and saturated NaHCO are sequentially used 3 The organic phase was washed with solution, saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by flash chromatography to give the objective compound 1.
Step I-2: preparation of Compound 2
Compound 1 (1.0 eq.) was dissolved in anhydrous DCM and TFA (15.0 eq.) was slowly added dropwise under ice-water bath and allowed to react for 3h at room temperature. After the reaction was completed, DCM and TFA were removed by distillation under reduced pressure. Dissolving the product with anhydrous DCM, regulating pH with TEA in ice water bath to slightly alkaline, and sequentially adding corresponding R 1 COOH (1.0 eq), EDCI (1.2 eq), HOBt (1.2 eq) and TEA (4.0 eq) were transferred to room temperature for reaction for 12h. Water, saturated citric acid and saturated NaHCO are sequentially used after the reaction is finished 3 The organic phase was washed with saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure by filtration, and the obtained crude product was purified by flash chromatography to give compound 2.
Step I-3: preparation of Compound 3
Sodium borohydride (15.0 eq) was slowly added to a methanol solution of compound 2 (1.0 eq) several times in an ice water bath and stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched by adding a saturated aqueous ammonium chloride solution, and methanol was removed under reduced pressure. The water-soluble impurities were removed by extraction with DCM and water, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated, and the crude product obtained was purified by flash chromatography to give the title compound 3.
Step I-4: preparation of Compound 4
To a solution of compound 3 (1.0 eq) in anhydrous DCM was added DMP (1.2 eq) and stirred for 2 hours. After completion of the reaction, the reaction was quenched by addition of saturated sodium bicarbonate and sodium thiosulfate (2.0 eq.) was added and the organic phase was stirred until clear. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by flash chromatography to give the title compound 4.
As demonstrated in the following examples, the compounds of the present invention or pharmaceutically acceptable salts thereof have better activity in inhibiting novel coronaviruses, and lower cytotoxicity, i.e., higher safety, and can be used for preventing and/or treating diseases caused by SARS-CoV-2 infection, such as novel coronavirus pneumonia.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Further, it is understood that various changes and modifications of the invention will become apparent to those skilled in the art upon reading the description herein, and such equivalents are intended to fall within the scope of the invention as defined by the appended claims.
The temperature is provided in degrees celsius in the examples below. Unless otherwise stated, solution percentages represent weight versus volume, and solution ratios represent volume versus volume. The structure of the compounds in the examples was determined by nuclear magnetic resonance.
Nuclear magnetic resonance spectrum @ 1 H NMR 13 C NMR) was measured with a Bruker 400 spectrometer at a field strength of 400 MHz. Chemical shift is expressed in parts per million (ppm, delta) down-shifted relative to the internal standard tetramethylsilane standard. 1 The multiplicity of peaks in H-NMR is shown below: s = single peak; d = double peak; t = triplet; m=multiple peaks. Coupling constants are expressed in Hz. The solvent peak refers to the internal deuterated reagent. The commercial reagents used are all from their respective sourcesFrom the suppliers, if conditions for treatment are present, are described herein. Dichloromethane (DCM) was obtained by distillation of calcium hydride prior to use.
The following abbreviations are used in the present invention: meOH: methanol; boc: t-butoxycarbonyl; TEA: triethylamine; EA: ethyl acetate; DMP: dess-martin reagent; PE: petroleum ether; EDCI:1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; HOBT: 1-hydroxybenzotriazole hydrate; DBU:1, 8-diazabicyclo undec-7-ene. In addition, "L" represents a naturally occurring amino acid.
Example 1 preparation of Compound 4-1
Step 1 preparation of Compound 1
L-phenylalanine (5.00 g,30.3 mmol) was taken in a 500mL round bottom flask, dissolved in an appropriate amount of MeOH, and thionyl chloride (2.6 mL,35.8 mmol) was slowly added dropwise under ice water bath and the mixture was brought to reflux at 70℃for 3h. After the reaction was completed, the resulting white solid was concentrated under reduced pressure, dissolved in an appropriate amount of anhydrous DCM, and pH was adjusted to weak base with TEA under ice water bath. Boc-L-leucine (7.42 g,29.8 mmol), EDCI (6.84 g,35.7 mmol), HOBt (4.82 g,35.7 mmol) and TEA (17.0 mL,104.0 mmol) were added sequentially at room temperature and reacted for 12h. After completion of the reaction, the mixture was extracted with water (2X 200 mL), a saturated citric acid solution (2X 200 mL), a saturated sodium bicarbonate solution (2X 200 mL), and a saturated brine (2X 200 mL) in this order. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by flash chromatography (PE: ea=6:1) to give compound 1 (6.20 g, yield 53.1%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.34–7.16(m,3H),7.11(d,J＝7.1Hz,2H),6.72(d,J＝6.6 Hz,1H),5.03(d,J＝6.8Hz,1H),4.84(dd,J＝13.0,6.1Hz,1H),4.11(d,J＝7.1Hz,1H),3.70(d, J＝10.4Hz,3H),3.10(qd,J＝13.8,6.0Hz,2H),1.72–1.52(m,2H),1.38(d,J＝38.8Hz,10H), 0.91(t,J＝6.0Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ172.30,171.73,155.54,135.83,129.29,128.51,127.06,79.93, 53.19,53.08,52.24,41.24,37.91,28.29,24.65,22.87,21.96。
Step 2 preparation of Compound 2
Compound 1 (1.00 g,2.55 mmol) was dissolved in an appropriate amount of anhydrous DCM and trifluoroacetic acid (3.00 mL,40.4 mmol) was slowly added and stirred at room temperature for 2h. After the reaction was completed, the volatile solvent was removed under reduced pressure. The resulting oily liquid was dissolved in an appropriate amount of anhydrous DCM and the pH was adjusted to slightly alkaline with TEA under an ice-water bath. P-methoxy cinnamic acid (0.45 g,2.55 mmol), EDCI (0.59 g,3.06 mmol), HOBt (0.41 g,3.06 mmol) and TEA (1.4 mL,10.2 mmol) were added sequentially at room temperature and reacted for 12h. After completion of the reaction, the mixture was extracted with water (2X 50 mL), a saturated citric acid solution (2X 50 mL), a saturated sodium bicarbonate solution (2X 50 mL), and a saturated brine (2X 50 mL) in this order. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by flash chromatography (PE: ea=4:1) to give compound 2 (0.60 g, 52.0% yield) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.63–7.54(m,1H),7.43(t,J＝5.8Hz,2H),7.24–7.14(m, 3H),7.12–7.07(m,2H),7.02(d,J＝7.9Hz,1H),6.84(d,J＝8.8Hz,2H),6.56(d,J＝8.4Hz,1H), 6.31(t,J＝11.9Hz,1H),4.84(dd,J＝14.1,6.3Hz,1H),4.68(td,J＝8.5,5.6Hz,1H),3.81(d,J＝ 4.2Hz,3H),3.70(s,3H),3.12(dd,J＝13.8,5.9Hz,1H),3.04(dd,J＝13.8,6.6Hz,1H),1.74– 1.54(m,3H),0.93(dd,J＝6.0,2.7Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ172.14,171.72,166.22,160.96,141.25,135.78,129.46, 129.30,128.56,127.45,127.01,117.85,114.26,55.33,53.43,52.29,51.62,41.11,37.92,24.78, 22.89,22.25。
Step 3 preparation of Compound 3
Compound 2 (0.60 g,1.33 mmol) was dissolved in an appropriate amount of MeOH and sodium borohydride (0.75 g, 20.0 mmol) was slowly added to the solution in an ice-water bath and reacted at room temperature for 1h. After the reaction is completed, a proper amount of saturated ammonium chloride solution is added for quenching. The solvent was distilled off under reduced pressure, extracted with DCM, the water-soluble impurities were removed, and the DCM layer was collected over anhydrous Na 2 SO 4 After the drying treatment, filtration is carried out. The crude product was purified by flash chromatography on silica gel (PE: ea=2:1) to give compound 3 (0.40 g, 70.8% yield) as a white solid.
1 H NMR(400MHz,MeOD)δ7.51(dd,J＝12.2,3.4Hz,3H),7.26–7.17(m,4H),7.15– 7.07(m,1H),6.93(d,J＝8.7Hz,2H),6.52(d,J＝15.8Hz,1H),4.55–4.44(m,1H),4.17–4.03 (m,1H),3.81(s,3H),3.52(t,J＝7.1Hz,2H),2.90(dt,J＝15.1,7.5Hz,1H),2.80–2.70(m,1H), 1.70–1.59(m,1H),1.58–1.48(m,2H),0.91(dt,J＝23.5,11.8Hz,6H)。
13 C NMR(101MHz,MeOD)δ173.13,167.47,161.29,140.71,138.26,129.16,129.03, 127.97,127.44,125.87,117.58,114.00,62.64,54.48,52.82,52.04,40.63,36.51,24.56,22.05, 20.73。
Step 4 preparation of Compound 4-1
Compound 3 (0.10 g,0.24 mmol) was dissolved in an appropriate amount of anhydrous DCM and dess-Martin oxidant (0.12 g,0.29 mmol) was added at room temperature. After the reaction was monitored by TLC to completion, the reaction was quenched by addition of an appropriate amount of saturated sodium bicarbonate solution and sodium thiosulfate, and stirred at room temperature for 2h. Extraction with DCM, removal of water-soluble impurities, collection of DCM layer, passage over anhydrous Na 2 SO 4 After the drying treatment, filtration is carried out. The crude product was purified by flash chromatography on silica gel (PE: ea=3:1) to give compound 4-1 as a white solid (800 mg, 80.0% yield).
1 H NMR(400MHz,CDCl3)δ9.52(s,1H),7.56–7.43(m,1H),7.36(d,J＝8.7Hz,2H),7.14 (d,J＝7.5Hz,3H),7.07(d,J＝1.2Hz,4H),6.79(d,J＝8.6Hz,2H),6.24–6.17(m,1H),4.65– 4.56(m,1H),4.55–4.46(m,1H),3.75(s,3H),3.11–3.02(m,1H),3.01–2.90(m,1H),1.68– 1.48(m,3H),0.86(dd,J＝5.8,4.8Hz,6H)。
13 C NMR(101MHz,CDCl3)δ197.76,171.62,165.33,160.07,140.56,134.72,128.48, 128.27,127.71,126.25,125.99,116.46,113.29,58.81,54.33,50.55,39.88,33.96,23.80,21.84, 21.19。
EXAMPLE 2 preparation of Compound 4-2
The preparation was identical to compound 4-1 (760 mg, 77.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.59(s,1H),7.82(d,J＝7.0Hz,2H),7.60(dd,J＝13.3,7.5Hz, 4H),7.45(t,J＝7.1Hz,2H),7.40(d,J＝6.3Hz,1H),7.24(d,J＝7.1Hz,1H),7.13(dt,J＝7.1,5.7 Hz,5H),6.92(d,J＝8.1Hz,1H),4.85–4.71(m,1H),4.60(d,J＝6.9Hz,1H),3.19–3.08(m,1H), 3.07–2.94(m,1H),1.81–1.63(m,3H),0.96(s,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.70,172.59,167.21,144.73,139.87,135.72,132.19, 129.24,128.97,128.71,128.12,127.75,127.22,127.05,59.88,52.00,40.99,34.96,24.96,22.88, 22.27。
Example 3: preparation of Compound 4-3
The preparation method was the same as for compound 4-1 (440 mg, 45.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.50(s,1H),8.41–8.33(m,1H),7.47–7.41(m,1H),7.40– 7.34(m,1H),7.22–7.17(m,2H),7.14–7.04(m,5H),6.85–6.75(m,1H),5.97–5.85(m,1H), 4.55–4.39(m,2H),3.70(s,2H),3.11–3.03(m,1H),2.96–2.85(m,1H),1.58–1.32(m,3H), 0.81–0.72(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.80,172.20,171.98,136.39,135.85,129.27,128.74, 127.08,123.75,122.78,120.17,118.44,111.56,108.42,59.75,51.46,40.06,34.86,33.26,24.61, 22.74,21.85。
Example 4: preparation of Compounds 4-4
The preparation was carried out in the same manner as in compound 4-1 (600 mg, yield 61.0%).
1 H NMR(400MHz,CDCl 3 )δ9.62(s,1H),8.58(ddd,J＝4.7,1.5,0.9Hz,1H),8.26(d,J＝ 8.4Hz,1H),8.14(d,J＝7.8Hz,1H),7.88(td,J＝7.7,1.7Hz,1H),7.48(ddd,J＝7.6,4.8,1.2Hz, 1H),7.09(d,J＝6.7Hz,5H),6.98(d,J＝6.9Hz,1H),4.67(dt,J＝13.7,4.5Hz,2H),3.16(dd,J＝ 14.1,6.4Hz,1H),3.07(dd,J＝14.1,7.1Hz,1H),1.82(dd,J＝10.4,5.0Hz,1H),1.76–1.63(m, 2H),0.94(dd,J＝10.7,6.3Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.85,172.02,164.61,149.03,148.28,137.41,135.59, 129.22,128.58,126.93,126.58,122.55,59.70,51.54,40.25,34.93,24.81,22.97,21.94。
Example 5: preparation of Compounds 4-5
The preparation was carried out in the same manner as in compound 4-1 (810 mg, yield 81.9%).
1 H NMR(400MHz,CDCl 3 )δ9.78–9.36(m,1H),7.84–7.67(m,2H),7.34–6.99(m,9H), 4.90–4.69(m,1H),4.65–4.35(m,1H),3.44–2.82(m,2H),1.69(m,3H),0.93(s,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.58,172.70,166.39,135.69,129.63,129.55,129.22, 128.71,127.08,115.71,115.49,59.93,52.06,41.00,34.90,24.92,22.84,22.18。
Example 6: preparation of Compounds 4-6
The preparation was identical to compound 4-1 (560 mg, 58.2% yield).
1 H NMR(400MHz,CDCl 3 )δ9.58(s,1H),7.35–7.21(m,3H),7.15(d,J＝7.2Hz,2H),6.95 (d,J＝6.8Hz,1H),6.13(d,J＝8.1Hz,1H),4.59(d,J＝6.8Hz,1H),4.50(d,J＝5.7Hz,1H),3.99 (d,J＝10.6Hz,2H),3.45–3.33(m,2H),3.14(d,J＝6.4Hz,1H),3.09(d,J＝7.2Hz,1H),2.32(s, 1H),1.66(tdd,J＝26.7,17.4,12.5Hz,7H),0.91(t,J＝6.8Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.52,174.53,172.48,135.65,129.24,128.77,127.16,67.14, 59.79,51.31,41.93,41.06,34.91,29.20,28.95,24.86,22.89,22.15。
Example 7: preparation of Compounds 4-7
The preparation was identical to compound 4-1 (660 mg, 67.8% yield).
1 H NMR(400MHz,CDCl3)δ9.60(s,1H),7.66(d,J＝7.5Hz,2H),7.38(d,J＝8.2Hz,2H), 7.17(s,3H),7.12(s,2H),6.98(s,1H),6.88–6.75(m,1H),4.77–4.66(m,1H),4.65–4.57(m, 1H),3.20–3.10(m,1H),3.10–2.99(m,1H),1.77–1.59(m,3H),0.93(s,6H)。
13 C NMR(101MHz,CDCl3)δ198.45,172.40,166.35,138.20,135.53,131.90,129.21, 128.84,128.74,128.60,127.14,59.86,52.03,41.05,34.98,24.92,22.83,22.21。
Example 8: preparation of Compounds 4-8
The preparation method was the same as for compound 4-1 (300 mg, yield 31.5%).
1 H NMR(400MHz,MeOD)δ9.58(s,1H),8.13(s,1H),7.64–7.61(m,1H),7.46(s,1H), 7.31(d,J＝2.9Hz,2H),7.17(dd,J＝5.8,3.0Hz,5H),6.58(d,J＝2.9Hz,1H),4.46(s,1H),4.17–4.04(m,1H),3.27–3.18(m,1H),3.00–2.91(m,1H),1.73(s,3H),0.98–0.94(m,6H)。
13 C NMR(101MHz,MeOD)δ199.19,174.05,173.42,173.26,138.21,136.52,129.04, 128.32,127.95,127.55,126.51,126.05,125.86,120.38,110.85,102.35,60.15,54.88,40.57,34.05, 24.70,22.35,21.30。
Example 9: preparation of Compounds 4-9
The preparation was carried out in the same manner as in compound 4-1 (350 mg, yield 36.0%).
1 H NMR(400MHz,CDCl3)δ9.64(s,1H),9.43–9.33(m,1H),7.70–7.61(m,1H),7.48–7.40(m,1H),7.34–7.29(m,1H),7.09(s,7H),6.97–6.93(m,1H),6.88–6.79(m,1H),4.86–4.66(m,2H),3.21–3.04(m,2H),1.77–1.69(m,3H),0.94(t,J＝6.0Hz,6H)。
13 C NMR(101MHz,CDCl3)δ198.69,161.75,160.66,136.42,135.29,129.20,128.68, 127.10,124.88,122.15,120.83,111.99,103.35,59.79,51.58,41.02,35.10,24.90,22.86,22.21。
Example 10: preparation of Compounds 4-10
The preparation was identical to compound 4-1 (510 mg, 52.3% yield).
1 H NMR(400MHz,CDCl 3 )δ9.44(s,1H),7.91(t,J＝6.2Hz,1H),7.87(s,1H),7.79(d,J＝7.5Hz,1H),7.33(dd,J＝4.0,2.3Hz,1H),7.23–7.15(m,3H),7.11–7.03(m,2H),6.64(d,J＝ 1.1Hz,1H),4.72(dd,J＝13.7,8.4Hz,1H),4.27(q,J＝7.0Hz,1H),3.06(dd,J＝14.1,6.8Hz, 1H),2.97(dd,J＝14.1,7.5Hz,1H),1.74–1.67(m,2H),1.57(td,J＝9.9,4.9Hz,1H),0.86(dd,J ＝6.4,3.5Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.75,174.00,162.89,145.50,143.58,135.85,129.10, 128.67,127.01,121.78,108.58,60.15,51.96,40.81,34.77,24.71,22.83,21.69。
Example 11: preparation of Compounds 4-11
The preparation was identical to compound 4-1 (360 mg, 36.8% yield).
1 H NMR(400MHz,CDCl 3 )δ9.52–9.41(m,1H),9.09–8.94(m,1H),7.27–7.25(m,1H), 7.22–7.19(m,1H),7.08–7.00(m,5H),6.72–6.62(m,1H),6.41–6.34(m,1H),6.33–6.24(m, 1H),4.66–4.55(m,1H),4.52–4.38(m,1H),3.11–2.99(m,1H),2.99–2.88(m,1H),1.65– 1.59(m,2H),1.55–1.50(m,1H),0.84(s,6H)。
13 C NMR(101MHz,CDCl 3 )δ199.13,173.24,165.27,135.71,129.28,128.71,127.02, 121.56,119.08,107.25,59.94,51.35,40.69,34.90,24.81,22.83,22.10。
Example 12: preparation of Compounds 4-12
The preparation was carried out in the same manner as in compound 4-1 (810 mg, yield 82.1%).
1 H NMR(400MHz,CDCl 3 )δ9.59(d,J＝2.4Hz,1H),7.74–7.67(m,2H),7.43(t,J＝8.5Hz, 2H),7.18–7.13(m,3H),7.12–7.04(m,3H),6.80–6.68(m,2H),5.84(dt,J＝17.6,3.5Hz,1H), 5.37(dd,J＝11.1,5.7Hz,1H),4.79–4.68(m,1H),4.66–4.56(m,1H),3.20–3.09(m,1H),3.03 (dd,J＝14.2,7.4Hz,1H),1.79–1.62(m,3H),0.98–0.88(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.68,172.45,167.06,141.09,135.86,135.64,132.54, 129.23,128.71,127.49,127.07,126.34,116.27,59.84,51.87,40.93,34.97,24.92,22.87,22.25。
Example 13: preparation of Compounds 4-13
The preparation was identical to compound 4-1 (750 mg, 76.3% yield).
1 H NMR(400MHz,CDCl 3 )δ9.58(s,1H),7.35–7.20(m,3H),7.15(d,J＝7.1Hz,2H),7.00 (d,J＝6.5Hz,1H),5.94(d,J＝8.0Hz,1H),4.63–4.54(m,1H),4.49(dd,J＝8.3,2.7Hz,1H), 3.15(dd,J＝14.2,6.4Hz,1H),3.07(dd,J＝14.2,7.2Hz,1H),2.06(dd,J＝8.7,5.7Hz,1H),1.77 (d,J＝9.4Hz,4H),1.70–1.55(m,3H),1.51(dd,J＝14.7,6.6Hz,1H),1.44–1.32(m,2H),1.25 (dd,J＝10.8,7.8Hz,2H),0.90(dd,J＝9.4,6.2Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.72,176.30,172.58,135.72,129.25,128.74,127.17,59.76, 51.16,45.20,40.82,34.93,29.67,29.40,25.65,25.58,24.83,22.85,22.12。
Example 14: preparation of Compounds 4-14
The preparation method was the same as for compound 4-1 (400 mg, 40.5% yield).
1 H NMR(400MHz,CDCl 3 )δ9.54(s,1H),7.89–7.83(m,1H),7.38(dd,J＝9.9,6.1Hz,2H), 7.31–7.24(m,1H),7.17(d,J＝6.5Hz,2H),7.12–7.04(m,3H),4.72(d,J＝7.4Hz,1H),4.49(d, J＝6.9Hz,1H),3.10(d,J＝6.3Hz,1H),3.06–2.93(m,1H),1.74–1.61(m,3H),0.91(dd,J＝5.6, 3.7Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.73,172.92,163.05,136.54,135.81,129.24,129.09, 128.68,127.04,126.45,126.29,59.99,51.81,40.86,34.89,24.89,22.86,22.11。
Example 15: preparation of Compounds 4-15
The preparation was identical to compound 4-1 (760 mg, 77.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.62(s,1H),7.64–7.53(m,4H),7.26(s,2H),7.13(s,3H), 6.92–6.82(m,1H),6.75–6.61(m,1H),4.74–4.60(m,2H),3.22–3.12(m,1H),3.11–2.99(m, 1H),1.73(s,3H),0.98–0.88(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.37,172.23,166.43,135.44,131.85,129.22,128.62, 127.16,59.82,51.96,41.05,35.01,24.88,22.83,22.22。
Example 16: preparation of Compounds 4-16
The preparation was identical to compound 4-1 (780 mg, 78.5% yield).
1 H NMR(400MHz,CDCl 3 )δ9.59(s,1H),7.74(d,J＝8.0Hz,2H),7.51(d,J＝7.3Hz,1H), 7.42(t,J＝7.5Hz,2H),7.15(d,J＝5.6Hz,3H),7.11(d,J＝7.0Hz,2H),7.06(d,J＝6.9Hz,1H), 6.72(d,J＝8.1Hz,1H),4.74(s,1H),4.61(d,J＝7.0Hz,1H),3.12(d,J＝6.2Hz,1H),3.05(d,J＝ 7.3Hz,1H),1.79–1.59(m,3H),0.94(t,J＝4.8Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.60,172.47,167.28,135.62,133.61,131.96,129.17, 128.45,127.19,59.76,51.66,40.77,34.87,24.99,22.55,21.99。
Example 17: preparation of Compounds 4-17
The preparation was identical to compound 4-1 (660 mg, 67.1% yield).
1 H NMR(400MHz,CDCl 3 )δ9.52(t,J＝8.1Hz,1H),8.23(dd,J＝6.3,3.4Hz,1H),7.92– 7.79(m,2H),7.50(ddd,J＝11.0,7.4,2.3Hz,3H),7.40–7.30(m,1H),7.24(dd,J＝15.7,8.0Hz, 1H),7.15(ddd,J＝7.6,5.8,4.3Hz,3H),7.09(dd,J＝5.0,2.7Hz,2H),6.67(d,J＝8.3Hz,1H), 4.95–4.76(m,1H),4.53(td,J＝6.8,4.6Hz,1H),3.14–3.02(m,1H),3.01–2.90(m,1H),1.79– 1.58(m,3H),0.99(dd,J＝8.7,6.0Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.64,172.35,169.59,135.75,133.67,133.34,131.08, 130.09,129.22,128.72,128.41,127.33,127.04,126.53,125.34,125.22,124.64,59.85,52.04, 41.19,34.84,25.00,22.89,22.26。
Example 18: preparation of Compounds 4-18
The preparation was carried out in the same manner as in compound 4-1 (480 mg, yield 48.2%).
1 H NMR(400MHz,CDCl 3 )δ9.68–9.56(m,1H),9.27(s,1H),8.98(t,J＝19.2Hz,1H), 8.25(d,J＝8.4Hz,1H),8.11–8.02(m,1H),7.22–7.00(m,6H),6.78(d,J＝6.8Hz,1H),4.73 (dd,J＝13.6,6.8Hz,1H),4.66(td,J＝8.6,5.8Hz,1H),3.14(qd,J＝14.2,6.7Hz,2H),1.79–1.63 (m,3H),0.94(dt,J＝14.8,7.4Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.48,171.40,162.80,159.31,157.88,155.48,135.34, 129.21,128.67,127.08,118.65,59.69,51.74,40.59,34.96,24.83,22.90,21.99。
Example 19: preparation of Compounds 4-19
The preparation was carried out in the same manner as in compound 4-1 (880 mg, yield 90.0%).
1 H NMR(400MHz,CDCl 3 )δ9.58(s,1H),7.52(t,J＝12.0Hz,1H),7.46–7.37(m,3H), 7.25–7.19(m,2H),7.15(ddd,J＝11.3,6.5,4.0Hz,3H),7.01–6.88(m,3H),6.39(d,J＝15.6Hz, 1H),4.79–4.68(m,1H),4.54(dd,J＝13.8,7.0Hz,1H),3.13(dd,J＝14.2,6.3Hz,1H),3.03(dd, J＝14.2,7.4Hz,1H),1.75–1.59(m,3H),0.92(dd,J＝15.5,10.2Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.71,172.95,165.91,164.86,162.37,140.42,135.82, 130.86,130.83,129.72,129.64,129.27,128.73,127.04,119.94,116.07,115.85,59.95,51.79, 41.21,34.92,24.88,22.84,22.27。
Example 20: preparation of Compounds 4-20
The preparation was identical to compound 4-1 (750 mg, 76.3% yield).
1 H NMR(400MHz,CDCl 3 )δ9.61(d,J＝12.6Hz,1H),8.99(s,1H),8.71(d,J＝4.6Hz,1H), 8.13–8.03(m,1H),7.41–7.34(m,1H),7.33–7.28(m,1H),7.15(dt,J＝13.7,7.3Hz,6H),4.80 –4.61(m,2H),3.17(dd,J＝14.1,6.3Hz,1H),3.08(dd,J＝13.9,7.1Hz,1H),1.70(d,J＝5.0Hz, 3H),0.95–0.89(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.45,172.39,165.56,152.37,148.18,135.48,135.41, 129.24,128.74,127.15,123.52,59.87,52.07,40.96,34.96,24.93,22.83,22.13。
Example 21: preparation of Compounds 4-21
The preparation was carried out in the same manner as in compound 4-1 (730 mg, yield 74.5%).
1 H NMR(400MHz,CDCl 3 )δ9.64(s,1H),8.78–8.66(m,2H),7.57(ddd,J＝8.3,5.5,1.7Hz, 2H),7.23–7.17(m,3H),7.15–7.11(m,2H),7.00(d,J＝7.9Hz,1H),6.80(d,J＝6.7Hz,1H), 4.75–4.64(m,2H),3.18(dd,J＝14.2,6.5Hz,1H),3.11(dd,J＝14.2,6.9Hz,1H),1.69(dt,J＝ 18.0,6.7Hz,3H),0.94(dt,J＝10.4,5.2Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.22,172.01,165.35,150.56,140.68,135.27,129.23, 128.81,127.27,120.98,59.86,52.07,41.21,35.02,24.92,22.82,22.19。
Example 22: preparation of Compounds 4-22
The preparation was carried out in the same manner as in compound 4-1 (790 mg, yield 79.1%).
1 H NMR(400MHz,CDCl 3 )δ9.60(s,1H),8.23(d,J＝11.3Hz,1H),7.84(t,J＝9.8Hz,3H), 7.79(dd,J＝8.6,1.5Hz,1H),7.54(ddd,J＝15.0,10.8,3.7Hz,2H),7.21(d,J＝7.1Hz,1H),7.17 –7.04(m,5H),6.98(d,J＝8.2Hz,1H),4.92–4.75(m,1H),4.62(dd,J＝13.8,7.0Hz,1H),3.14 (dd,J＝14.2,6.3Hz,1H),3.02(dd,J＝14.2,7.4Hz,1H),1.82–1.66(m,3H),1.02–0.90(m, 6H)。
13 C NMR(101MHz,CDCl 3 )δ198.70,172.59,167.57,135.66,134.91,132.54,130.74, 129.22,129.01,128.70,128.52,127.90,127.85,127.77,127.03,126.88,123.57,59.86,52.03, 41.03,34.97,24.97,22.90,22.30。
Implementation example 23: preparation of Compounds 4-23
The preparation was identical to compound 4-1 (680 mg, 67.8% yield).
1 H NMR(400MHz,CDCl 3 )δ9.61(d,J＝12.6Hz,1H),8.99(s,1H),8.71(d,J＝4.6Hz,1H), 8.13–8.03(m,1H),7.41–7.34(m,1H),7.33–7.28(m,1H),7.15(dt,J＝13.7,7.3Hz,6H),4.80 –4.61(m,2H),3.17(dd,J＝14.1,6.3Hz,1H),3.08(dd,J＝13.9,7.1Hz,1H),1.70(d,J＝5.0Hz, 3H),0.95–0.89(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.72,172.24,171.28,135.79,134.43,129.28,129.04, 128.74,127.49,127.10,59.75,51.58,43.43,40.56,34.88,24.76,22.76,22.12。
Implementation example 24: preparation of Compounds 4-24
The preparation was identical to compound 4-1 (540 mg, 53.9% yield).
1 H NMR(400MHz,CDCl 3 )δ9.55(s,1H),7.31–7.22(m,5H),7.17(ddd,J＝16.5,9.2,7.2 Hz,5H),6.89(d,J＝6.9Hz,1H),5.93(t,J＝22.9Hz,1H),4.55(q,J＝6.9Hz,1H),4.51–4.38(m, 1H),3.13(dd,J＝14.2,6.4Hz,1H),3.08–2.97(m,1H),2.96–2.85(m,2H),2.50–2.40(m,2H), 1.62–1.49(m,1H),1.48–1.32(m,2H),0.84(dd,J＝15.4,8.5Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.67,172.41,172.27,140.45,135.74,129.29,128.76, 128.59,128.30,127.14,126.37,59.79,51.36,40.81,38.01,34.94,31.48,24.60,22.83,22.09。
Example 25: preparation of Compounds 4-25
The preparation was carried out in the same manner as in compound 4-1 (420 mg, yield 43.6%).
1 H NMR(400MHz,CDCl3)δ9.71(s,1H),9.58(d,J＝1.6Hz,1H),7.32–7.25(m,1H),7.11 (t,J＝5.7Hz,5H),6.93(s,1H),6.68–6.57(m,1H),6.43(d,J＝8.3Hz,1H),6.29–6.18(m,1H), 4.78–4.61(m,2H),3.11(dd,J＝14.1,6.5Hz,1H),3.04(dd,J＝14.0,7.0Hz,1H),1.74–1.59(m, 3H),0.91(dd,J＝11.8,5.7Hz,6H)。
13 C NMR(101MHz,CDCl3)δ198.96,172.58,161.04,135.56,129.21,128.63,127.03, 125.08,122.13,110.13,110.06,59.79,51.24,40.96,35.12,24.85,22.88,22.16。
Example 26: preparation of Compounds 4-26
The preparation was identical to compound 4-1 (450 mg, 46.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.61(s,1H),7.47(s,1H),7.20–7.13(m,3H),7.13–7.08(m, 3H),6.94(t,J＝16.7Hz,1H),6.65(t,J＝16.8Hz,1H),6.53(dd,J＝3.3,1.6Hz,1H),4.73–4.60 (m,2H),3.16(dd,J＝14.1,6.4Hz,1H),3.05(dd,J＝14.1,7.2Hz,1H),1.78–1.56(m,3H),0.98– 0.88(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.68,171.98,158.30,147.21,144.36,135.57,129.25, 128.65,127.01,115.03,112.32,59.78,51.03,40.77,35.00,24.77,22.89,22.09。
Example 27: preparation of Compounds 4-27
The preparation was identical to compound 4-1 (720 mg, 72.3% yield).
1 H NMR(400MHz,CDCl 3 )δ9.59(s,1H),7.51–7.42(m,2H),7.36(td,J＝8.0,5.6Hz,1H), 7.23–7.14(m,4H),7.11(dt,J＝11.6,5.4Hz,3H),7.02(d,J＝8.2Hz,1H),4.72(dd,J＝15.2,7.1 Hz,1H),4.60(q,J＝6.9Hz,1H),3.15(dd,J＝14.2,6.4Hz,1H),3.06(dd,J＝14.2,7.3Hz,1H), 1.75–1.62(m,3H),0.99–0.86(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.54,172.52,166.14,163.93,161.47,135.78,135.71, 135.58,130.26,130.19,129.22,128.74,127.13,122.64,122.61,118.98,118.77,114.74,114.51, 59.90,52.11,40.98,34.94,24.93,22.85,22.18。
Example 28: preparation of Compounds 4-28
The preparation was carried out in the same manner as in compound 4-1 (750 mg, yield 75.6%).
1 H NMR(400MHz,CDCl 3 )δ9.62(s,1H),8.01(td,J＝7.9,1.6Hz,1H),7.50(tt,J＝14.5,7.2 Hz,1H),7.31–7.22(m,1H),7.20–7.06(m,6H),7.01(t,J＝9.3Hz,2H),4.78–4.61(m,2H), 3.17(dd,J＝14.2,6.3Hz,1H),3.11–2.98(m,1H),1.84–1.56(m,3H),1.01–0.89(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.78,171.99,163.49,161.95,159.49,135.59,133.86, 133.77,132.05,129.21,128.64,127.01,124.88,124.85,120.36,120.25,116.27,116.03,59.73, 51.99,40.53,34.94,24.84,22.91,22.08。
Example 29: preparation of Compounds 4-29
The preparation was carried out in the same manner as in compound 4-1 (820 mg, yield 83.2%).
1 H NMR(400MHz,CDCl 3 )δ9.58(s,1H),7.32–7.18(m,3H),7.15(d,J＝6.9Hz,2H),7.07 (d,J＝6.8Hz,1H),6.11(d,J＝8.2Hz,1H),4.63–4.46(m,2H),3.15(dd,J＝14.2,6.4Hz,1H), 3.10–2.98(m,1H),2.12(t,J＝7.5Hz,2H),1.67–1.49(m,5H),0.96–0.86(m,9H)。
13 C NMR(101MHz,CDCl 3 )δ198.71,173.24,172.62,135.79,129.26,128.72,127.09,59.81, 51.33,40.92,38.33,34.93,24.80,22.81,22.15,19.05,13.69。
Example 30: preparation of Compounds 4-30
The preparation was identical to compound 4-1 (780 mg, 79.6% yield).
1 H NMR(400MHz,CDCl 3 )δ9.57(s,1H),7.32–7.20(m,3H),7.15(dd,J＝7.3,2.9Hz,3H), 6.18(d,J＝8.2Hz,1H),4.62–4.45(m,2H),3.15(dd,J＝14.2,6.4Hz,1H),3.09–2.99(m,1H), 2.19–2.09(m,2H),1.67–1.46(m,5H),1.30(ddd,J＝13.6,9.1,2.3Hz,4H),0.90(dd,J＝13.8, 7.5Hz,9H)。
13 C NMR(101MHz,CDCl 3 )δ198.73,173.42,172.68,135.83,129.26,128.71,127.07,59.81, 51.35,40.94,36.42,34.92,31.39,25.31,24.80,22.80,22.37,22.17,13.94。
Example 31: preparation of Compounds 4-31
The preparation was identical to compound 4-1 (750 mg, 76.2% yield).
1 H NMR(400MHz,CDCl 3 )δ9.61(s,1H),7.69(d,J＝15.8Hz,1H),7.53–7.43(m,1H), 7.33(dtd,J＝11.7,7.6,4.0Hz,1H),7.28–7.23(m,2H),7.20–7.03(m,5H),6.97(d,J＝7.0Hz, 1H),6.55(t,J＝17.9Hz,1H),6.30(t,J＝15.3Hz,1H),4.65(dt,J＝8.4,4.5Hz,2H),3.16(dd,J＝ 14.1,6.4Hz,1H),3.06(dd,J＝14.2,7.3Hz,1H),1.76–1.64(m,3H),0.93(dt,J＝14.5,7.3Hz, 6H)。
13 C NMR(101MHz,CDCl 3 )δ198.64,172.35,165.84,162.92,160.02,135.59,135.04, 131.31,131.22,129.68,129.28,128.77,127.10,124.48,124.44,122.77,122.70,116.32,116.10, 59.81,51.65,40.88,35.02,24.83,22.85,22.19。
Example 32: preparation of Compounds 4-32
The preparation was carried out in the same manner as in compound 4-1 (620 mg, yield 65.4%).
1 H NMR(400MHz,CDCl 3 )δ9.61(s,1H),7.60–7.46(m,1H),7.30(tt,J＝9.1,4.6Hz,1H), 7.27–7.20(m,3H),7.20–7.11(m,4H),7.08–7.00(m,2H),6.47(dd,J＝24.2,6.4Hz,1H),6.42 (dd,J＝15.6,8.4Hz,1H),4.73–4.55(m,2H),3.15(dd,J＝14.2,6.4Hz,1H),3.07(dd,J＝14.2, 7.2Hz,1H),1.75–1.55(m,3H),0.99–0.90(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.56,172.49,165.54,164.25,161.79,140.58,136.92, 135.60,130.46,130.38,129.28,128.77,127.10,123.89,121.35,116.88,116.66,114.23,114.02, 59.85,51.73,41.08,35.01,24.85,22.85,22.21。
Example 33: preparation of Compounds 4-33
The preparation was identical to compound 4-1 (510 mg, 49.5% yield).
1 H NMR(400MHz,CDCl 3 )δ9.61(s,1H),7.24–7.15(m,3H),7.14–7.06(m,3H),6.70(t,J ＝20.0Hz,1H),6.41(d,J＝0.8Hz,1H),4.70(q,J＝6.8Hz,1H),4.62(td,J＝8.7,5.5Hz,1H), 3.21–3.06(m,2H),2.50(d,J＝0.7Hz,3H),1.77–1.56(m,3H),0.99–0.87(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.52,171.44,171.39,159.28,158.07,135.41,129.26, 128.73,127.12,101.43,59.72,51.58,40.58,35.03,24.77,22.87,21.92,12.35。
Example 34: preparation of Compounds 4-34
The preparation method was the same as for compound 4-1 (640 mg, 65.5% yield).
1 H NMR(400MHz,CDCl 3 )δ9.63(d,J＝7.3Hz,1H),8.35–8.14(m,2H),7.96–7.80(m, 2H),7.25–7.18(m,3H),7.16–7.10(m,2H),6.90(t,J＝11.5Hz,1H),6.68(d,J＝7.0Hz,1H), 4.77–4.63(m,2H),3.15(qd,J＝14.2,6.7Hz,2H),1.72–1.68(m,3H),1.00–0.90(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.14,171.96,165.24,149.82,139.12,135.24,129.23, 128.83,128.35,127.29,123.80,59.86,52.25,41.37,35.07,24.95,22.82,22.22。
Example 35: preparation of Compounds 4-35
The preparation was identical to compound 4-1 (560 mg, 57.8% yield).
1 H NMR(400MHz,CDCl 3 )δ9.59(s,1H),7.77–7.64(m,2H),7.18–7.13(m,3H),7.10(dd, J＝7.0,2.6Hz,2H),7.06(d,J＝7.1Hz,1H),6.96–6.85(m,2H),6.54(d,J＝8.2Hz,1H),4.76– 4.65(m,1H),4.61(dd,J＝13.6,7.1Hz,1H),3.85(d,J＝5.8Hz,3H),3.14(dd,J＝14.1,6.2Hz, 1H),3.02(dd,J＝14.1,7.4Hz,1H),1.78–1.59(m,3H),0.92(dt,J＝8.9,4.2Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.71,172.54,166.98,162.57,135.67,129.23,129.00, 128.69,127.03,125.80,113.81,59.81,55.46,51.78,40.84,34.99,24.91,22.88,22.22。
Example 36: preparation of Compounds 4-36
The preparation method was the same as for compound 4-1 (300 mg, yield 80.0%).
1 H NMR(400MHz,DMSO-d6)δ9.54–9.42(m,1H),8.51(d,J＝7.1Hz,1H),8.23(d,J＝ 8.1Hz,1H),7.57(d,J＝7.4Hz,2H),7.50–7.35(m,4H),7.21(tt,J＝13.2,6.7Hz,5H),6.74(d,J ＝15.8Hz,1H),4.48(dd,J＝14.3,8.1Hz,1H),4.35–4.23(m,1H),3.16(dd,J＝14.1,4.2Hz,1H), 2.84(dd,J＝13.8,9.7Hz,1H),1.67–1.55(m,1H),1.45(dt,J＝20.8,7.4Hz,2H),0.99–0.79(m, 6H)。
13 C NMR(101MHz,DMSO-d6)δ200.71,173.16,165.23,139.42,138.10,135.40,129.93, 129.69,129.43,128.65,127.96,126.73,122.51,60.07,51.39,41.59,33.75,24.74,23.41,22.08。
Example 37: preparation of Compounds 4-37
The preparation was identical to compound 4-1 (260 mg, 75.6% yield).
1 H NMR(400MHz,CDCl 3 )δ9.62(d,J＝12.3Hz,1H),7.30–7.23(m,3H),7.15(t,J＝8.0 Hz,2H),6.74(d,J＝6.6Hz,1H),4.85(d,J＝7.6Hz,1H),4.66(d,J＝5.6Hz,1H),4.12(s,1H), 3.20–3.09(m,2H),1.70–1.60(m,2H),1.50(d,J＝7.2Hz,1H),1.43(s,9H),0.93(dd,J＝11.0, 5.1Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.35,172.84,155.59,135.49,129.33,128.77,127.17,59.66, 53.13,41.12,35.12,28.29,24.75,22.90,21.91。
Example 38: preparation of Compounds 4-38
The preparation method was the same as for compound 4-1 (430 mg, 75.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.58(s,1H),7.39–7.29(m,5H),7.28–7.20(m,3H),7.12(d, J＝6.9Hz,2H),6.69(d,J＝5.4Hz,1H),5.24(t,J＝16.4Hz,1H),5.13–5.02(m,2H),4.71–4.57 (m,1H),4.21(d,J＝4.2Hz,1H),3.20–3.03(m,2H),1.71–1.54(m,2H),1.53–1.41(m,1H), 0.90(dd,J＝12.1,8.6Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.55,172.44,156.18,136.11,135.51,129.32,128.77, 128.59,128.30,128.08,127.18,67.19,59.70,53.44,41.20,35.03,24.69,22.88,21.95。
Example 39: preparation of Compounds 4-39
The preparation was carried out in the same manner as in compound 4-1 (450 mg, yield 68.0%).
1 H NMR(400MHz,CDCl 3 )δ9.58(d,J＝5.9Hz,1H),7.32–7.23(m,3H),7.15(d,J＝6.8 Hz,2H),6.86(d,J＝6.8Hz,1H),6.16(t,J＝10.1Hz,1H),4.65–4.56(m,1H),4.54–4.43(m, 1H),3.23–3.03(m,2H),2.15(d,J＝7.5Hz,3H),1.87–1.68(m,6H),1.65–1.51(m,3H),0.91 (dd,J＝7.8,6.3Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.44,174.28,172.44,135.57,129.23,128.80,127.20,59.82, 51.35,42.50,41.12,34.93,32.97,32.76,32.49,25.95,25.86,25.69,25.60,24.87,22.81,22.14。
Example 40: preparation of Compounds 4-40
The preparation was carried out in the same manner as in compound 4-1 (320 mg, yield 55.0%).
1 H NMR(400MHz,CDCl 3 )δ9.58(d,J＝2.8Hz,1H),7.33–7.24(m,3H),7.16(dd,J＝5.2, 3.1Hz,2H),6.81(d,J＝6.6Hz,1H),5.87(t,J＝9.8Hz,1H),4.65–4.57(m,1H),4.46(td,J＝8.8, 5.7Hz,1H),3.20–3.04(m,2H),1.86–1.65(m,16H),1.63–1.48(m,2H),0.91(dt,J＝10.0,5.1 Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.73,178.22,172.51,135.66,129.24,128.81,127.15,59.69, 51.10,40.58,39.09,36.41,35.00,28.02,24.91,22.93,22.08。
Example 41: preparation of Compounds 4-41
The preparation was carried out in the same manner as in compound 4-1 (550 mg, yield 68.2%).
1 H NMR(400MHz,CDCl 3 )δ9.55(s,1H),7.80(t,J＝5.0Hz,1H),7.59(d,J＝15.6Hz,1H), 7.42(d,J＝6.7Hz,2H),7.26(dt,J＝13.4,8.3Hz,4H),6.54(d,J＝15.6Hz,1H),4.93–4.71(m, 1H),4.06(ddd,J＝45.3,19.5,5.2Hz,2H),1.82–1.65(m,3H),0.94(dt,J＝12.5,5.6Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ197.01,173.53,166.29,141.60,134.61,129.81,128.80, 127.89,120.30,51.86,50.02,41.31,24.89,22.91,22.21。
Example 42: preparation of Compounds 4-42
/>
The preparation method was the same as for compound 4-1 (320 mg, yield 65.0%).
1 H NMR(400MHz,CDCl 3 )δ9.61(d,J＝14.5Hz,1H),7.60(d,J＝15.0Hz,1H),7.47(s, 2H),7.40–7.21(m,5H),7.13(d,J＝26.7Hz,3H),6.56–6.37(m,2H),4.67(t,J＝17.2Hz,2H), 3.37(d,J＝13.8Hz,1H),3.08(d,J＝6.0Hz,1H),1.77–1.45(m,3H),0.90(d,J＝32.5Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.09,172.64,165.95,141.90,134.55,134.10,133.89, 131.81,129.95,129.72,128.89,128.59,127.90,127.04,120.01,58.76,51.66,41.11,32.67,24.86, 22.87,22.29。
Example 43: preparation of Compounds 4-43
The preparation was carried out in the same manner as in compound 4-1 (340 mg, yield 55.0%).
1 H NMR(400MHz,CDCl 3 )δ9.64(d,J＝19.1Hz,1H),7.93(t,J＝14.8Hz,1H),7.66–7.59 (m,1H),7.50(t,J＝11.5Hz,3H),7.35(dd,J＝14.9,9.5Hz,5H),6.43–6.35(m,1H),4.87–4.69 (m,1H),4.60(dd,J＝30.5,22.2Hz,1H),3.77–3.52(m,1H),3.17–2.97(m,1H),1.64–1.49(m, 3H),0.92(dd,J＝15.3,9.2Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ197.80,172.53,165.93,142.10,134.45,133.41,130.03, 128.90,128.24,127.92,125.27,119.80,58.97,51.63,40.73,32.15,24.77,22.84,21.88。
Example 44: preparation of Compounds 4-44
The preparation method was the same as for compound 4-1 (800 mg, yield 90.0%).
1 H NMR(400MHz,CDCl 3 )δ9.64(s,1H),7.59(t,J＝17.2Hz,1H),7.52–7.41(m,2H), 7.33(dd,J＝5.8,4.0Hz,4H),6.86(d,J＝8.3Hz,1H),6.50(d,J＝15.6Hz,1H),4.83(dd,J＝13.9, 8.1Hz,1H),4.47(dd,J＝7.8,4.8Hz,1H),2.35–2.18(m,1H),1.84–1.61(m,3H),1.02–0.95 (m,9H),0.92(d,J＝6.9Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ199.62,173.05,165.90,141.51,134.52,129.66,128.81, 128.66,127.89,127.73,120.02,63.35,51.77,41.15,28.78,24.73,22.72,22.19,18.95,17.68。
Example 45: preparation of Compounds 4-45
The preparation was carried out in the same manner as in compound 4-1 (400 mg, yield 49.0%).
1 H NMR(400MHz,CDCl 3 )δ9.56(d,J＝24.7Hz,1H),7.58(t,J＝15.2Hz,1H),7.48(d,J＝6.3Hz,3H),7.39–7.26(m,3H),7.14(t,J＝9.3Hz,2H),7.04(d,J＝7.9Hz,2H),6.66(d,J＝8.0 Hz,1H),6.46(d,J＝15.6Hz,1H),4.69(t,J＝15.9Hz,1H),4.63–4.37(m,1H),3.13(dd,J＝14.1, 5.6Hz,1H),2.93(dd,J＝14.0,7.8Hz,1H),1.63(ddd,J＝34.5,19.3,6.0Hz,3H),1.05–0.86(m, 6H)。
13 C NMR(101MHz,CDCl 3 )δ198.42,172.80,166.07,142.03,134.45,134.36,132.87, 130.65,130.02,128.90,128.79,127.96,119.91,59.67,51.74,40.94,34.18,24.87,22.83,22.31。
Example 46: preparation of Compounds 4-46
The preparation method was the same as for compound 4-1 (850 mg, yield 80.0%).
1 H NMR(400MHz,CDCl 3 )δ9.58(d,J＝14.7Hz,1H),7.62(d,J＝15.6Hz,1H),7.52–7.43 (m,2H),7.34(dd,J＝5.0,1.6Hz,3H),7.09–6.96(m,3H),6.77(dd,J＝16.0,8.6Hz,2H),6.43 (dt,J＝18.9,8.9Hz,2H),4.75–4.65(m,1H),4.63–4.55(m,1H),3.68(d,J＝24.1Hz,3H),3.08 (dt,J＝12.7,6.3Hz,1H),3.04–2.92(m,1H),1.77–1.55(m,3H),0.99–0.89(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.89,172.46,165.94,158.62,141.93,134.55,130.32, 129.96,128.88,127.92,119.93,114.15,59.95,55.10,51.63,40.98,34.15,24.84,22.89,22.23。
Example 47: preparation of Compounds 4-47
The preparation was carried out in the same manner as in compound 4-1 (150 mg, yield 43.0%).
1 H NMR(400MHz,CDCl3)δ9.65(s,1H),7.60(dd,J＝15.6,8.8Hz,1H),7.53–7.45(m, 3H),7.39–7.29(m,3H),7.24–7.10(m,3H),7.09–6.98(m,1H),6.42(ddd,J＝38.7,24.8,8.2 Hz,2H),4.70(td,J＝14.5,8.4Hz,2H),3.40(dd,J＝14.1,5.7Hz,1H),3.08(dt,J＝14.1,9.3Hz, 1H),1.73–1.54(m,3H),0.97–0.88(m,6H)。
13 C NMR(101MHz,CDCl3)δ198.05,172.54,165.95,141.98,135.64,134.53,133.06, 131.78,129.99,128.91,128.80,127.91,127.68,124.65,119.94,58.79,51.63,41.02,35.20,34.93, 24.85,22.88,22.26。
Example 48: preparation of Compounds 4-48
/>
The preparation was carried out in the same manner as in compound 4-1 (230 mg, yield 65.3%).
1 H NMR(400MHz,CDCl 3 )δ9.54(d,J＝9.6Hz,1H),7.62(d,J＝15.6Hz,1H),7.50–7.39 (m,2H),7.35–7.22(m,4H),6.90(d,J＝8.4Hz,1H),6.53(dd,J＝17.5,7.3Hz,1H),4.83–4.72 (m,1H),4.37(tt,J＝34.8,6.6Hz,1H),1.86–1.50(m,10H),1.44(ddd,J＝15.2,9.8,6.4Hz,1H), 1.41–1.25(m,2H),1.17–1.02(m,3H),1.01–0.93(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ199.75,172.88,166.10,141.82,134.59,129.87,128.84, 127.89,120.17,56.86,51.71,41.17,36.00,33.88,33.63,32.50,26.24,26.05,25.95,24.90,22.88, 22.42。
Example 49: preparation of Compounds 4-49
The preparation was identical to compound 4-1 (230 mg, 56.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.60(t,J＝7.3Hz,1H),7.59(dd,J＝15.6,6.7Hz,1H),7.52– 7.43(m,2H),7.39–7.29(m,3H),7.23(t,J＝7.0Hz,1H),7.18–7.10(m,2H),7.06–6.92(m, 2H),6.51(d,J＝8.3Hz,1H),6.45(dd,J＝15.6,6.1Hz,1H),4.76–4.57(m,2H),3.24(dd,J＝ 14.0,6.3Hz,1H),3.08(dd,J＝14.2,7.4Hz,1H),1.75–1.51(m,3H),0.91(ddd,J＝9.5,6.3,3.9 Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.04,172.64,165.92,141.84,134.59,131.91,131.87, 129.91,129.05,128.97,128.88,127.89,124.36,124.33,122.87,120.03,115.56,115.34,59.04, 51.66,41.11,29.71,28.30,24.84,22.86,22.25。
Example 50: preparation of Compounds 4-50
The preparation was identical to compound 4-1 (780 mg, 85.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.47(d,J＝6.4Hz,1H),7.59(t,J＝10.6Hz,2H),7.40(d,J＝ 7.5Hz,2H),7.27(dt,J＝13.2,6.6Hz,3H),7.15(dt,J＝11.7,7.0Hz,3H),7.08(t,J＝6.1Hz,2H), 7.00(d,J＝8.3Hz,1H),6.52(d,J＝15.6Hz,1H),4.84(dd,J＝14.0,7.6Hz,1H),4.37–4.23(m, 1H),2.69–2.53(m,2H),2.15(td,J＝14.0,6.9Hz,1H),1.95–1.82(m,1H),1.82–1.64(m,3H), 0.97(dd,J＝16.0,10.2Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ199.00,173.11,166.21,141.85,140.41,134.55,129.86, 128.82,128.55,128.45,127.91,126.30,120.18,58.52,51.92,41.30,31.50,30.26,24.94,22.86, 22.42。
Example 51: preparation of Compounds 4-51
The preparation method was the same as for compound 4-1 (500 mg, yield 46.0%).
1 H NMR(400MHz,CDCl 3 )δ9.57(s,1H),7.65–7.53(m,2H),7.44(t,J＝8.4Hz,2H),7.35 –7.27(m,3H),7.21–7.15(m,1H),7.12(d,J＝5.6Hz,2H),7.01(d,J＝4.0Hz,1H),6.75(d,J＝ 8.0Hz,1H),6.48(dd,J＝15.6,5.7Hz,1H),4.79–4.65(m,1H),4.45(dd,J＝13.7,7.0Hz,1H), 3.17(td,J＝14.6,5.6Hz,1H),3.03–2.87(m,1H),1.76–1.60(m,2H),1.53(dd,J＝15.1,6.4Hz, 1H),0.98–0.85(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.35,173.06,166.17,141.93,138.26,134.53,129.91, 129.35,128.87,127.92,127.47,127.18,119.96,59.78,51.79,40.93,34.31,24.89,22.83,22.28。
Example 52: preparation of Compounds 4-52
The preparation was carried out in the same manner as in compound 4-1 (600 mg, yield 68.0%).
1 H NMR(400MHz,DMSO-d6)δ9.50(d,J＝21.4Hz,1H),8.58(t,J＝9.4Hz,1H),8.23(d,J ＝8.0Hz,1H),7.58(t,J＝7.0Hz,4H),7.43(dt,J＝11.7,10.5Hz,7H),6.74(t,J＝13.4Hz,1H), 4.40(ddd,J＝21.5,15.5,9.9Hz,2H),3.26(dd,J＝13.9,3.8Hz,1H),2.89(dt,J＝26.6,13.2Hz, 1H),1.55(dd,J＝12.6,6.2Hz,1H),1.50–1.30(m,2H),0.91–0.77(m,6H)。
13 C NMR(101MHz,DMSO-d6)δ200.43,173.21,165.23,139.46,135.35,130.63,129.95, 129.40,127.94,125.36,122.41,59.57,51.47,41.41,33.54,24.69,23.28,22.04。
Example 53: preparation of Compounds 4-53
The preparation was identical to compound 4-1 (350 mg, 72.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.60–9.49(m,1H),7.77(t,J＝6.6Hz,1H),7.64–7.55(m, 1H),7.47–7.37(m,2H),7.30(ddd,J＝14.4,5.9,1.6Hz,3H),6.89(dddd,J＝23.1,19.1,14.6,5.1 Hz,5H),6.53–6.43(m,1H),4.73(dt,J＝22.6,7.8Hz,1H),4.66–4.56(m,1H),3.18(td,J＝14.1, 5.7Hz,1H),3.02–2.91(m,1H),1.70–1.44(m,3H),0.85(qdd,J＝16.8,10.7,6.1Hz,8H)。
13 C NMR(101MHz,CDCl 3 )δ198.75,173.19,166.19,141.87,134.54,130.18,130.09, 129.90,128.86,128.84,127.92,124.92,120.09,116.44,116.23,114.00,113.79,59.56,51.98, 51.72,41.31,34.24,29.71,24.76,22.77,22.67,22.29。
Example 54: preparation of Compounds 4-54
The preparation was carried out in the same manner as in compound 4-1 (550 mg, yield 69.0%).
1 H NMR(400MHz,CDCl 3 )δ9.61(s,1H),7.61(d,J＝15.6Hz,1H),7.49(d,J＝6.7Hz,2H), 7.36(s,3H),7.16(d,J＝7.0Hz,1H),7.13–7.05(m,2H),6.90(t,J＝8.2Hz,2H),6.42(d,J＝15.6 Hz,1H),6.35(d,J＝8.0Hz,1H),4.72–4.57(m,2H),3.14(dd,J＝14.2,6.0Hz,1H),2.99(dd,J＝ 14.2,7.4Hz,1H),1.75–1.55(m,3H),0.94(t,J＝5.5Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.48,172.51,166.03,142.15,134.45,130.87,130.79, 130.06,128.93,127.93,119.75,115.70,115.49,59.78,51.67,40.78,34.13,24.84,22.85,22.22。
Example 55: preparation of Compounds 4-55
The preparation was identical to compound 4-1 (820 mg, 76.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.41(s,1H),7.56(d,J＝15.4Hz,1H),7.46(s,2H),7.34(s, 3H),7.23(d,J＝20.4Hz,9H),7.02(s,3H),6.72(s,1H),6.42(d,J＝15.6Hz,1H),4.95(s,1H), 4.51(s,1H),3.15–2.86(m,4H)。
13 C NMR(101MHz,CDCl 3 )δ198.56,171.39,165.82,141.98,136.32,135.56,134.50, 130.00,129.37,129.23,128.90,128.76,127.95,127.16,127.09,119.88,59.78,54.47,38.46, 34.95。
Example 56: preparation of Compounds 4-56
The preparation was identical to compound 4-1 (660 mg, 62.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.63(d,J＝10.5Hz,1H),7.62(d,J＝14.8Hz,1H),7.49(s, 2H),7.35(s,3H),7.28–7.13(m,5H),6.92(s,1H),6.47(d,J＝13.9Hz,2H),4.70(d,J＝5.6Hz, 1H),4.53(s,1H),3.12(d,J＝6.5Hz,2H),1.56(s,1H),1.22(d,J＝29.4Hz,2H),0.94(dd,J＝ 16.1,6.6Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ198.31,167.68,159.72,134.65,129.90,129.27,128.82, 127.89,127.16,120.21,59.69,57.67,37.36,35.33,24.69,15.35,11.00。
Example 57: preparation of Compounds 4-57
The preparation was identical to compound 4-1 (740 mg, 77.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.61(s,1H),7.66(d,J＝7.5Hz,1H),7.58(dd,J＝15.1,8.3Hz, 1H),7.47(dd,J＝9.0,6.8Hz,2H),7.30(dd,J＝10.4,5.0Hz,3H),7.24–7.03(m,6H),6.71(d,J＝ 9.5Hz,1H),6.58–6.50(m,1H),4.71(ddd,J＝20.8,16.3,9.1Hz,2H),3.09(dd,J＝14.1,6.6Hz, 1H),3.04–2.93(m,1H),1.07(s,9H)。
13 C NMR(101MHz,CDCl 3 )δ198.76,171.05,165.76,141.65,135.84,134.61,129.85, 129.20,128.86,128.82,128.69,127.91,127.00,120.53,60.39,59.76,35.27,34.91,26.69。
Example 58: preparation of Compounds 4-58
The preparation was identical to compound 4-1 (350 mg, 72.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.62(s,1H),7.59(dd,J＝15.6,5.1Hz,1H),7.48(dd,J＝6.6, 2.6Hz,2H),7.36–7.30(m,4H),7.17(ddd,J＝12.3,10.4,7.1Hz,5H),6.71(d,J＝8.1Hz,1H), 6.51–6.44(m,1H),4.72–4.62(m,2H),3.15(dd,J＝14.1,6.3Hz,1H),3.10–3.00(m,1H),0.97 (t,J＝7.4Hz,3H),0.92–0.84(m,4H)。
13 C NMR(101MHz,CDCl 3 )δ198.68,172.18,165.95,141.75,135.71,134.62,129.90, 129.25,128.88,128.76,127.91,127.07,120.16,59.85,54.28,35.02,31.95,29.72,29.68,29.38, 25.89,22.71,14.14,9.93。
Example 59: preparation of Compounds 4-59
The preparation was identical to compound 4-1 (260 mg, 60.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.60(s,1H),7.62(d,J＝15.5Hz,1H),7.48(s,2H),7.35(s, 3H),7.28–7.16(m,6H),7.05(s,1H),6.50(d,J＝14.5Hz,1H),4.67(s,1H),4.03(t,J＝38.2Hz, 3H),3.06(t,J＝32.6Hz,2H)。
13 C NMR(101MHz,CDCl 3 )δ198.70,169.71,166.69,141.98,135.66,134.55,129.99, 129.24,128.89,128.81,127.96,127.15,119.75,59.94,43.39,34.91。
Example 60: preparation of Compounds 4-60
The preparation method was the same as for compound 4-1 (230 mg, 45.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.52(s,1H),7.57(d,J＝15.7Hz,1H),7.48(s,2H),7.37(s, 3H),7.25–7.15(m,5H),7.10–6.98(m,4H),6.84(d,J＝6.0Hz,1H),6.36(dd,J＝15.5,6.2Hz, 2H),4.86(dd,J＝14.4,7.2Hz,1H),4.62(q,J＝6.6Hz,1H),3.18(d,J＝6.9Hz,2H),3.14–3.06 (m,1H),3.02(dd,J＝13.8,7.2Hz,1H)。
13 C NMR(101MHz,CDCl 3 )δ198.47,170.88,165.94,142.17,135.42,134.47,131.69, 130.04,129.26,128.91,128.80,127.95,127.13,124.48,119.62,115.34,59.77,53.66,35.07, 31.27。
Example 61: preparation of Compounds 4-61
The preparation method was the same as for compound 4-1 (600 mg, 75.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.61(s,1H),7.59(d,J＝15.6Hz,1H),7.50–7.45(m,2H), 7.42(d,J＝7.2Hz,1H),7.36–7.28(m,3H),7.24–7.18(m,2H),7.14(dd,J＝10.4,7.7Hz,3H), 6.80(d,J＝8.0Hz,1H),6.53–6.44(m,1H),4.74(dd,J＝14.4,7.5Hz,1H),4.62(q,J＝7.1Hz, 1H),3.15(dd,J＝14.1,6.3Hz,1H),3.04(dd,J＝14.1,7.4Hz,1H),1.93–1.79(m,1H),1.77– 1.63(m,1H),1.47–1.34(m,2H),0.99–0.87(m,3H)。
13 C NMR(101MHz,CDCl 3 )δ198.73,172.44,165.93,141.72,135.80,134.61,129.89, 129.25,128.88,128.73,127.90,127.03,120.19,59.89,53.01,34.98,34.77,18.87,13.86。
Example 62: preparation of Compounds 4-62
The preparation method was the same as for compound 4-1 (400 mg, 75.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.62(d,J＝8.2Hz,1H),7.60(d,J＝15.6Hz,1H),7.53–7.45 (m,2H),7.39–7.32(m,3H),7.27–7.12(m,6H),6.51(d,J＝7.5Hz,1H),6.43(dd,J＝15.6,8.1 Hz,1H),4.78–4.60(m,2H),3.23–3.13(m,1H),3.06(dd,J＝14.1,7.4Hz,1H),1.40(dd,J＝ 30.9,6.9Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ198.69,172.69,165.81,141.94,135.67,134.56,129.98, 129.26,128.91,128.76,127.91,127.08,119.91,59.88,48.75,34.94,18.24。
Example 63: preparation of Compounds 4-63
The preparation method was the same as for compound 4-1 (420 mg, 65.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.64–9.55(m,1H),7.61(d,J＝15.6Hz,1H),7.49(dd,J＝6.5, 2.9Hz,2H),7.37–7.33(m,3H),7.25(d,J＝5.2Hz,1H),7.22(d,J＝7.5Hz,2H),7.20–7.09(m, 4H),6.42(dt,J＝8.0,6.9Hz,2H),4.69(dd,J＝14.7,8.5Hz,1H),4.61(dd,J＝13.7,7.0Hz,1H), 3.20–3.11(m,1H),3.05(dd,J＝14.1,7.3Hz,1H),1.87–1.49(m,10H),0.91(ddd,J＝20.5,18.6, 10.5Hz,3H)。
13 C NMR(101MHz,CDCl 3 )δ198.72,165.98,141.92,135.71,129.95,129.29,128.90, 128.75,127.92,127.05,119.96,59.84,51.02,39.49,35.02,34.12,33.55,32.83,26.34,26.13, 26.00。
Example 64: preparation of Compounds 4-64
The preparation method was the same as for compound 4-1 (250 mg, 42.0% yield).
1 H NMR(400MHz,DMSO-d6)δ9.55–9.38(m,1H),8.65(dd,J＝12.1,7.4Hz,1H),8.40 (dd,J＝15.2,8.5Hz,1H),7.55(d,J＝6.9Hz,2H),7.45–7.35(m,4H),7.26(s,4H),7.19(dd,J＝ 13.6,6.9Hz,3H),7.15–7.07(m,2H),7.05–6.97(m,2H),6.69(dd,J＝15.8,10.3Hz,1H),4.74 (td,J＝9.3,4.9Hz,1H),4.36(dddd,J＝21.0,9.1,7.5,4.7Hz,1H),3.24–3.11(m,1H),3.08– 2.97(m,1H),2.90–2.67(m,2H)。
13 C NMR(101MHz,DMSO-d6)δ200.64,172.05,165.24,139.63,137.99,135.26,130.36, 130.01,129.78,129.68,129.42,128.72,128.02,126.80,125.79,122.19,60.21,54.09,37.98, 33.81。
Example 65: preparation of Compounds 4-65
The preparation method was the same as for compound 4-1 (220 mg, 40.0% yield).
1 H NMR(400MHz,DMSO-d6)δ9.47(dd,J＝36.7,18.8Hz,1H),8.74–8.54(m,1H),8.40 (dd,J＝18.3,8.0Hz,1H),7.56(dd,J＝18.0,6.9Hz,2H),7.47–7.33(m,4H),7.33–7.15(m,7H), 7.13–7.04(m,2H),6.69(dd,J＝18.7,16.1Hz,1H),4.69(s,1H),4.32(s,1H),3.16(t,J＝14.1Hz, 1H),3.01(t,J＝13.5Hz,1H),2.85(d,J＝20.7Hz,2H)。
13 C NMR(101MHz,DMSO-d6)δ200.67,172.13,165.28,139.64,131.46,131.39,130.03, 129.66,129.42,128.71,128.01,126.80,115.38,115.17,60.18,54.39,33.77。
Example 66: preparation of Compounds 4-66
The preparation method was the same as for compound 4-1 (200 mg, yield 30.0%).
1 H NMR(400MHz,CDCl 3 )δ9.63(t,J＝10.2Hz,1H),7.94(s,1H),7.72(dd,J＝15.4,4.0 Hz,1H),7.47(dt,J＝26.4,14.1Hz,6H),7.24–7.09(m,5H),6.74–6.56(m,1H),4.78(d,J＝4.5 Hz,1H),4.72–4.61(m,1H),3.60–3.49(m,2H),3.28–3.15(m,1H),3.01–2.86(m,1H),2.46 (d,J＝4.3Hz,1H),1.98(s,2H),1.86–1.75(m,1H)。
13 C NMR(101MHz,CDCl 3 )δ199.49,143.59,130.14,129.34,128.98,128.49,128.04, 126.75,117.55,59.68,47.30,34.99,26.57。
Example 67: preparation of Compounds 4-67
Methyl phosphonoacetate diethyl ester (57 ul,0.30 mmol) was dissolved in an appropriate amount of anhydrous tetrahydrofuran and charged with argon. Dropwise adding into tetrahydrofuran solution of sodium bis (trimethylsilyl) amide at-78deg.C, and stirring for 30min. Then, aldehyde (100 mg, 0.25 mmol) was dissolved in tetrahydrofuran and added dropwise to the above reaction solution, followed by stirring for 2 hours. After the reaction was completed, the reaction was quenched by addition of 1M hydrochloric acid solution. The solvent was removed by rotary evaporation under reduced pressure, dissolved in an appropriate amount of dichloromethane, washed successively with water, saturated citric acid, saturated sodium bicarbonate and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary-dried to give a crude product. The crude product was separated by column chromatography on silica gel to give a white solid (80 mg, 78%).
1 H NMR(400MHz,CDCl 3 )δ7.61(d,J＝15.6Hz,1H),7.49(dd,J＝6.6,2.9Hz,2H),7.39– 7.33(m,3H),7.20–7.15(m,2H),7.12(dd,J＝12.8,7.8Hz,3H),7.05(d,J＝8.5Hz,1H),6.94 (dd,J＝15.7,5.2Hz,1H),6.39(dd,J＝15.6,6.2Hz,1H),6.33(d,J＝8.4Hz,1H),5.95–5.85(m, 1H),5.01–4.82(m,1H),4.70–4.55(m,1H),3.71(d,J＝3.3Hz,3H),2.93–2.75(m,2H),1.74– 1.51(m,3H),0.93(dt,J＝13.0,6.5Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ171.64,166.54,166.06,147.06,141.88,136.30,134.56, 129.98,129.33,128.92,128.54,127.90,126.76,121.02,120.05,51.83,51.69,51.15,40.66,40.52, 24.84,22.89,22.32。
Example 68: preparation of Compounds 4-68
Aldehyde (100 mg,0.25 mmol) was dissolved in acetonitrile, diethyl cyanomethylphosphonate (50 uL,0.30 mmol), lithium chloride (13 mg,0.30 mmol) and DBU (58 uL,0.38 mmol) were added in this order and stirred at room temperature for 2h. After the reaction was completed, a saturated ammonium chloride solution was added to quench. The solvent was removed by rotary evaporation under reduced pressure, dissolved in an appropriate amount of dichloromethane, washed successively with water, saturated citric acid, saturated sodium bicarbonate and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary-dried to give a crude product. The crude product was separated by column chromatography on silica gel to give a white solid (60 mg, 59%).
1 H NMR(400MHz,CDCl 3 )δ7.61(dd,J＝9.9,5.7Hz,1H),7.51–7.45(m,2H),7.39–7.33 (m,3H),7.18(dt,J＝23.4,7.4Hz,5H),7.09(d,J＝7.0Hz,1H),6.66(dd,J＝16.4,5.2Hz,1H), 6.41–6.29(m,2H),4.91–4.73(m,1H),4.69–4.50(m,1H),3.64–3.47(m,1H),3.07(dd,J＝ 17.2,9.7Hz,1H),1.76–1.56(m,3H),0.96–0.87(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ171.89,166.51,166.36,153.28,142.27,137.46,134.38, 130.18,129.19,128.99,128.94,128.76,128.68,127.94,127.12,119.68,110.67,100.41,51.88, 41.81,40.03,24.87,22.86,22.18,16.64。
Example 69: preparation of Compounds 4-69
Aldehyde (100 mg,0.25 mmol) was dissolved in 50.0mL anhydrous tetrahydrofuran solution. The system was placed under argon and ethyl magnesium bromide (1.25 mL,1M,1.25 mmol) was added dropwise at-20deg.C using a constant pressure dropping funnel. After the addition, the reaction system was stirred at-20℃for 4h. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was oxidized by Dess-Martin to give compounds 4-69 (70 mg, 68%).
1 H NMR(400MHz,CDCl 3 )δ7.64(dd,J＝15.6,6.8Hz,1H),7.51–7.42(m,2H),7.35–7.31 (m,3H),7.24–7.18(m,2H),7.18–7.14(m,1H),7.13–7.07(m,3H),6.49(d,J＝8.3Hz,1H), 6.44(d,J＝15.6Hz,1H),4.85–4.75(m,1H),4.68(td,J＝8.5,5.6Hz,1H),3.12–3.03(m,1H), 2.99–2.92(m,1H),2.48–2.28(m,2H),1.67(tt,J＝12.8,6.3Hz,2H),1.58(dd,J＝8.7,7.5Hz, 1H),1.00(t,J＝7.2Hz,3H),0.92(t,J＝7.6Hz,6H)。
13 C NMR(101MHz,CDCl 3 )δ209.03,172.04,165.83,141.73,136.02,134.68,129.84, 129.21,128.85,128.65,127.89,126.99,120.16,58.94,51.74,41.30,37.60,34.21,24.85,22.90, 22.24,7.34。
Example 70: preparation of Compounds 4-70
The preparation was identical to that of compounds 4-69 (70 mg, 68%).
1 H NMR(400MHz,CDCl 3 )δ7.63(dd,J＝15.6,7.3Hz,1H),7.48(dd,J＝6.5,2.8Hz,2H), 7.36–7.29(m,3H),7.23–7.11(m,4H),7.08(d,J＝6.9Hz,2H),6.56(d,J＝8.4Hz,1H),6.51–6.32(m,3H),5.84(dd,J＝9.8,1.7Hz,1H),5.20–5.08(m,1H),4.71(td,J＝8.4,5.7Hz,1H),3.15 (dd,J＝13.9,6.3Hz,1H),3.04–2.93(m,1H),1.73–1.55(m,3H),0.96–0.88(m,6H)。
13 C NMR(101MHz,CDCl 3 )δ197.11,172.01,165.75,141.64,135.67,134.74,133.33, 130.45,129.79,129.47,128.84,128.51,127.89,126.96,120.28,57.14,51.79,41.49,37.55,24.85, 22.88,22.27。
Example 71: inhibitor in vitro cytotoxicity (CC) 50 ) Experiment
RD cells were seeded in 96-well plates at 37℃in 5% CO 2 Incubate in incubator for 24 hours. The inhibitor to be tested was diluted into working solutions of 100. Mu.M, 33.33. Mu.M, 11.11. Mu.M, 3.70. Mu.M, 1.23. Mu.M, 0.41. Mu.M, 0.14. Mu.M, 0.046. Mu.M and 0.015. Mu.M, respectively. The cell supernatant in the 96-well plate was aspirated, 100. Mu.L of inhibitor working solution at different concentrations was added to each well, each concentration was repeated 3 times, and a cell control group was set at 37℃with 5% CO 2 Culturing for 24 hours. The cytotoxicity of the inhibitors was detected with WST-1 cell proliferation and cytotoxicity detection kit (Roche), 10. Mu.L of WST-1 was added to each well for staining of living cells, and after 1 hour, fluorescence was read at 490nM in an ELISA reader, and the data was analyzed using GraphPad Prism 7.0. The results are shown in the following table.
Example 72: inhibitor of in vitro cell Activity (EC) 50 ) Experiment
For the inhibition evaluation of the cell activity of SARS-CoV-2, the P3 laboratory of the Chinese institute of Karaoke virus was used to infect cells with SARS-CoV-2 virus (GISAID access No. EPI_ISL_ 402124) according to a certain MOI, then different compounds to be tested were added to the cells, and the compounds which could inhibit the virus amplification were primarily screened out by observing the cytopathic condition. The inhibition effect of the drug on the virus is further clarified by detecting the cytotoxicity of the candidate drug, the influence of the drug on the virus titer and the like, and the EC of the drug to the virus is determined 50 (half effective concentration) the inhibitory effect of the drug on the virus was evaluated. ResultsThe following table.
/>
/>
/>
/>
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (9)

1. A compound of formula I:
wherein:
R 1 represents Z-Y-X-,
x represents a bond; alternatively, O;
y represents a bond; alternatively, C 1-10 Straight-chain or branched alkylene, C 2-10 Straight-chain or branched alkenylene or C 2-10 A linear or branched alkynylene group, the alkylene, alkenylene, or alkynylene group being unsubstituted or substituted with 1 or more halogens;
z represents H; c (C) 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, S, said cycloalkyl or heterocycloalkyl being unsubstituted or substituted with 1 or more substituents independently selected from halogen, C 1-10 Straight-chain or branched alkyl, C 2-10 Straight-chain or branched alkenyl, C 2-10 Straight or branched alkynyl, C 1-10 Linear or branched alkyl oxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups; alternatively, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, S, said aryl or heteroaryl being unsubstituted or substituted with 1 or more substituents independently selected from halogen, C 1-10 Straight-chain or branched alkyl, C 2-10 Straight-chain or branched alkenyl, C 2-10 Straight or branched alkynyl, C 1-10 Straight-chain or branched alkyl oxy, unsubstituted or substituted by C 1-6 Alkyl-substituted phenyl, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups;
provided that when Y is a bond, Z is not H;
R 2 represents phenyl, C 1-10 Straight-chain or branched alkylene phenyl, C 2-10 Straight-chain or branched alkenylene phenyl or C 2-10 Straight or branched alkynylene phenyl, said phenyl being unsubstituted or substituted with 1 or more groups independently selected from halogen, C 1-10 Straight-chain or branched alkyl, C 2-10 Straight-chain or branched alkenyl, C 2-10 Straight or branched alkynyl, C 1-10 Linear or branched alkyl oxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups;
R 3 represents hydrogen; c (C) 1-10 Straight-chain or branched alkyl, C 2-10 Straight-chain or branched alkenyl or C 2-10 A linear or branched alkynyl group, said alkyl, alkenyl or alkynyl group being unsubstituted or substituted with 1 or more halogens; c (C) 3-10 Cycloalkyl, C 1-10 Straight-chain or branched alkylene C 3-10 Cycloalkyl, C 2-10 Straight-chain or branched alkenylene C 3-10 Cycloalkyl, C 2-10 Straight-chain or branched alkynylene C 3-10 Cycloalkyl, phenyl, C 1-10 Straight-chain or branched alkylene phenyl, C 2-10 Straight-chain or branched alkenylene phenyl or C 2-10 A straight or branched alkynylene phenyl group, said cycloalkyl or phenyl group being unsubstituted or substituted with 1 or more groups independently selected from halogen, C 1-10 Straight-chain or branched alkyl, C 2-10 Straight-chain or branched alkenyl, C 2-10 Straight or branched alkynyl, C 1-10 Linear or branched alkyl oxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups;
R 4 represents-CHO.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R 1 represents Z-Y-X-,
x represents a bond; alternatively, O;
y represents a bond; alternatively, C 1-6 Straight-chain or branched alkylene, C 2-6 Straight-chain or branched alkenylene, or C 2-6 A linear or branched alkynylene group, said alkylene, alkenylene, or alkynylene group being unsubstituted or substituted with 1-3 fluorine groups;
z represents H; c (C) 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl containing 1 heteroatom selected from N, O, S, said cycloalkyl or heterocycloalkyl being unsubstituted or substituted with 1-3 groups independently selected from halogen, C 1-6 Straight-chain or branched alkyl, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight or branched alkynyl, C 1-6 Linear or branched alkyl oxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups; alternatively, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, S, said aryl or heteroaryl being unsubstituted or substituted with 1-3 heteroatoms independently selected from halogen, C 1-6 Straight-chain or branched alkyl, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight or branched alkynyl, C 1-6 Linear or branched alkyl oxygen, phenyl, hydroxy, amino, cyano, nitro, trifluoromethyl groups;
provided that when Y is a bond, Z is not H;
R 2 represents phenyl, C 1-6 Straight-chain or branched alkylene phenyl, C 2-6 Straight-chain or branched alkenylene phenyl or C 2-6 Straight or branched alkynylene phenyl groups, said phenyl groups being unsubstituted or substituted with 1 to 3 groups independently selected from halogen, C 1-6 Straight-chain or branched alkyl, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight or branched alkynyl, C 1-6 Linear or branched alkyl oxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups;
R 3 represents hydrogen; methyl, n-propyl, C 4-6 Straight-chain or branched alkyl, C 4-6 Straight-chain or branched alkenyl or C 4-6 A linear or branched alkynyl group, said alkyl, alkenyl or alkynyl group being unsubstituted or substituted with 1 to 3 fluoro groups; c (C) 3-10 Cycloalkyl, C 1-6 Straight-chain or branched alkylene C 3-10 Cycloalkyl, C 2-6 Straight-chain or branched alkenylene C 3-10 Cycloalkyl, C 2-6 Straight-chain or branched alkynylene C 3-10 Cycloalkyl, phenyl, C 1-6 Straight-chain or branched alkylene phenyl, C 2-6 Straight-chain or branched alkenylene phenyl or C 2-6 Straight or branched alkynylene phenyl, said cycloalkyl or phenyl being unsubstituted or substituted with 1 to 3 groups independently selected from halogen, C 1-6 Straight-chain or branched alkyl, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight or branched alkynyl, C 1-6 Linear or branched alkyl oxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups;
R 4 represents-CHO.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R 1 represents Z-Y-X-,
x represents a bond; alternatively, O;
y represents a bond; or, C1-3 straight or branched alkylene, C2-3 straight or branched alkenylene;
z represents H; a cyclohexenyl or 6 membered heterocycloalkyl containing 1 heteroatom selected from N, O, S, said cycloalkyl or heterocycloalkyl being unsubstituted or substituted with 1-3 groups independently selected from halo, methyl, methoxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy; or, phenyl, naphthyl, pyrrolyl, furanyl, thienyl, indolyl, pyridinyl, isoxazolyl, pyrimidinyl, said substituents being unsubstituted or substituted with 1 to 3 groups independently selected from halogen, methyl, methoxy, phenyl, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy;
provided that when Y is a bond, Z is not H;
R 2 represent C 1-3 A linear or branched alkylene phenyl group, said phenyl group being unsubstituted or substituted with 1 group selected from halogen, methyl, methoxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy;
R 3 Represents hydrogen; methyl, n-propyl, C 4-6 Linear or branched alkyl; c (C) 1-3 Linear or branched alkylene cyclohexanyl or C 1-3 A linear or branched alkylene phenyl group, said cyclohexyl or phenyl group being unsubstituted or substituted with 1 group selected from halogen, methyl, methoxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy;
R 4 represents-CHO.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R 1 represents Z-Y-X-,
x represents a bond; alternatively, O;
y represents a bond; alternatively, CH 2 、CH＝CH；
Z represents a cyclohexenyl or a 6 membered heterocycloalkyl containing 1O atom, said cyclohexenyl or heterocycloalkyl being unsubstituted or substituted with 1 or 2 groups independently selected from halogen, methyl, methoxy, nitro; or, phenyl, naphthyl, pyrrolyl, furanyl, thienyl, indolyl, pyridyl, isoxazolyl, pyrimidinyl, said substituents being unsubstituted or substituted with 1 or 2 groups independently selected from halogen, methyl, vinyl, methoxy, phenyl, nitro;
R 2 represents a methylenephenyl or ethylenephenyl group, said phenyl group being unsubstituted or substituted in ortho, meta or para position with respect to the methylene or ethylene group by 1 group selected from halogen, methoxy, nitro, trifluoromethyl;
R 3 Represents methyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl; a methylenecyclohexenyl or methylenephenyl group, said cyclohexenyl or phenyl group being unsubstituted or substituted with 1 group selected from halogen in the ortho, meta or para position to the methylene group;
R 4 represents-CHO.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R 1 selected from the group consisting of pentyl, phenyl, ethenylphenyl, methylenephenyl, -O-methylenephenyl, phenyleophenyl, naphthyl, pyrrolyl, furanyl, thienyl, indolyl, methyleneindolyl, pyridyl, isoxazolyl, cyclohexenyl, tetrahydropyran, said substituents being unsubstituted or substituted with 1 or 2 groups independently selected from fluoro, chloro, bromo, methyl, vinyl, methoxy, nitro;
R 2 selected from the group consisting of methylenephenyl, said phenyl being unsubstituted or substituted with 1 group selected from fluoro, chloro, bromo, methoxy, nitro, trifluoromethyl, ortho, meta or para to the methylene;
R 3 selected from isobutyl; a methylenecyclohexenyl or methylenephenyl group, said cyclohexenyl or phenyl group being unsubstituted or substituted with 1 fluorine at the ortho, meta or para position relative to the methylene group;
R 4 represents-CHO.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from:
。
7. a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I as defined in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Preferably, the pharmaceutical composition further comprises other compounds for treating diseases caused by SARS-CoV-2 infection.
Preferably, the other compound for treating a disease caused by SARS-CoV-2 infection is selected from antiviral agents such as acyclovir, adefovir, monabivalir and the like, antiinfectives, immunomodulators such as alpha, beta, delta-interferon and the like, primary protease inhibitors, S protease inhibitors, M protein inhibitors, and/or antibiotics and the like.
8. Use of a compound of formula I as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylaxis and/or treatment of a disease caused by SARS-CoV-2 infection in a mammal.
Preferably, the mammal is a human.
Preferably, the disease caused by SARS-CoV-2 infection is a novel coronavirus pneumonia.
9. Use of a compound of formula I as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylaxis and/or treatment of a disease caused by SARS-CoV-2 infection in a mammal in combination with other compounds for the treatment of a disease caused by SARS-CoV-2 infection.
Preferably, the mammal is a human.
Preferably, the disease caused by SARS-CoV-2 infection is a novel coronavirus pneumonia.
Preferably, the other compound for treating a disease caused by SARS-CoV-2 infection is selected from antiviral agents such as acyclovir, adefovir, monabivalir and the like, antiinfectives, immunomodulators such as alpha, beta, delta-interferon and the like, primary protease inhibitors, S protease inhibitors, M protein inhibitors, and/or antibiotics and the like.
CN202210072991.9A 2022-01-21 2022-01-21 Novel coronavirus inhibitor, pharmaceutical composition containing same and use thereof Pending CN116514678A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210072991.9A CN116514678A (en) 2022-01-21 2022-01-21 Novel coronavirus inhibitor, pharmaceutical composition containing same and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210072991.9A CN116514678A (en) 2022-01-21 2022-01-21 Novel coronavirus inhibitor, pharmaceutical composition containing same and use thereof

Publications (1)

Publication Number Publication Date
CN116514678A true CN116514678A (en) 2023-08-01

Family

ID=87403414

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210072991.9A Pending CN116514678A (en) 2022-01-21 2022-01-21 Novel coronavirus inhibitor, pharmaceutical composition containing same and use thereof

Country Status (1)

Country Link
CN (1) CN116514678A (en)

Similar Documents

Publication Publication Date Title
US10150740B2 (en) 6,7-dihydropyrido[2,1-A]phthalazin-2-ones for the treatment and prophylaxis of hepatitis B virus infection
EP3325477B1 (en) Novel tricyclic 4-pyridone-3-carboxylic acid derivatives for the treatment and prophylaxis of hepatitis b virus infection
US10968217B2 (en) Tetrahydropyridopyrimidines for the treatment and prophylaxis of hepatitis B virus infection
US9809575B2 (en) Pharmaceutical compounds
JP2018526336A (en) Novel tetracyclic 4-oxo-pyridine-3-carboxylic acid derivatives for the treatment and prevention of hepatitis B virus infection
US10023554B2 (en) Halogen-substituted heterocyclic compound salt
CN107949563B (en) Pyrazolo [1,5-a ] triazin-4-amine derivatives useful in therapy
US20230227437A1 (en) Immunomodulator
CN116514678A (en) Novel coronavirus inhibitor, pharmaceutical composition containing same and use thereof
JP5938537B1 (en) Prodrug
AU2021260048B2 (en) Antiviral 1,3-di-oxo-indene compounds
CN117069685B (en) Cinnamoyl alkyl polyketone compound, preparation method and application thereof
US11840526B2 (en) Compounds and method for preparing the same
US20240083884A1 (en) Compounds and method for preparing the same
CN113801187A (en) Preparation and application of Michael acceptor type main protease inhibitor targeting novel coronavirus
JP5408660B2 (en) Paraterphenyl compound, pharmacologically acceptable salt thereof, production method and use thereof
CN116438176A (en) 2-phenylbenzotriazol-5-amine derivatives for the treatment and prevention of Hepatitis B Virus (HBV) infection
CN113402414A (en) Benzoic acid derivative and preparation method and pharmaceutical application thereof
CN113004250A (en) Process for preparing substituted triazole derivatives
AU2521501A (en) 2-arylquinoline derivatives, preparation and therapeutic use thereof
JP2000355584A (en) Production of 2-phenyl-3-aminopyridine, phenyl- substituted derivative of the compound and salt of the compound

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination