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WO2016188421A1 - Dérivé de 2-phénylimidazole contenant des groupes propynamide, son procédé de préparation, composition pharmaceutique associée, et utilisations associées - Google Patents

Dérivé de 2-phénylimidazole contenant des groupes propynamide, son procédé de préparation, composition pharmaceutique associée, et utilisations associées Download PDF

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Publication number
WO2016188421A1
WO2016188421A1 PCT/CN2016/083236 CN2016083236W WO2016188421A1 WO 2016188421 A1 WO2016188421 A1 WO 2016188421A1 CN 2016083236 W CN2016083236 W CN 2016083236W WO 2016188421 A1 WO2016188421 A1 WO 2016188421A1
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Prior art keywords
group
phenyl
alkyl
imidazol
amide
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Chinese (zh)
Inventor
冯志强
陈晓光
李燕
刘艳杰
金小锋
周婉琪
郑若男
郑义
周川
刘春霞
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Institute of Materia Medica of CAMS and PUMC
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Institute of Materia Medica of CAMS and PUMC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a propiolate-containing 2-phenylimidazole derivative of the formula I, a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a composition containing one or more of such compounds, and a compound of the kind Use in the treatment of neoplastic diseases.
  • Protein kinase is an important class of extensive research. It is a Large families are involved in the control of various signal transduction processes within the cell. Due to their structural and catalytic conservation, they are thought to evolve from a common ancestral gene. Almost all kinases contain a similar 250-300 amino acid catalytic domain. These protein kinases are divided into families according to the phosphorylation substrate, such as protein tyrosine kinase, protein serine/threonine kinase, lipids and the like.
  • protein kinases mediate intracellular signal transduction by affecting the transfer of a phosphoryl group from a nucleoside triphosphate to a protein receptor associated with a signal transduction pathway. These phosphorylation events act as molecular switches that regulate the biological function of the target protein and are ultimately stimulated to respond to a variety of extracellular and other stimuli.
  • the kinase is present in a multi-layered signal transduction pathway upstream of the tumor angiogenic signal transduction pathway and upstream of the tumor cell signal transduction pathway.
  • the serine/threonine protein kinase is located downstream of the signal transduction pathway of tumor and tumor angiogenic cells. Studies have shown that by blocking VEGFR and PDGF receptors upstream, blocking Raf/MEK/ERK downstream can simultaneously reduce tumor angiogenesis and inhibit tumor cell replication, thereby impeding tumor growth.
  • SC stem cells
  • ASC adult stem cells
  • Hedgehog (Hh) signaling pathway is one of the important pathways regulating the development of insect and mammalian embryos in vivo, regulating the differentiation, migration and proliferation of stem cells during development and tissue damage.
  • Hh pathway is closely related to various tumors, such as human skin basal cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, intestinal cancer, stomach cancer, lung cancer, ovarian cancer, leukemia, multiple bone marrow. Tumor, medulloblastoma, etc.
  • Abnormal activation of Hh pathway is related to the formation of CSC, which converts adult normal stem cells into CSC and continues to multiply, playing a key role in tumorigenesis and development.
  • Gli glioma-associated oncogene homoglog
  • Gli glioma-associated oncogene homoglog
  • Gli2 glioma-associated oncogene homoglog
  • Gli3 Gli transcription factors
  • Glil is a highly active transcriptional activator.
  • Gli2 has both transcriptional activation and inhibition functions, mainly in the form of transcriptional activators, and its transcription. The activation function is stronger than Gli3, but weaker than Glil.
  • Gli3 is capable of activating downstream gene transcription under certain tissues and conditions, but is thought to be primarily transcriptional repressor.
  • Glil is a direct transcriptional activator whose activation regulation occurs at the transcriptional level.
  • the expression level of Glil mRNA is a reliable indicator of the activity of Hh signaling pathway.
  • Gli2 and Gli3 are potential transcriptional activators.
  • Target genes regulated by Gli include different types: CyclinD1, CyclinD2, FoxM1, N-Myc, Wnts, PdgfRa, Hes1, IGFBP-6 (insulin-like growth factor binding protein-6), which regulate cell proliferation and differentiation, and are metabolically related.
  • Bmi1 Nanog, angiogenesis-related gene VEGF, epidermal cell-interstitial cell transformation (EMT)-related genes CXCR4, Snail1, Sip1, Elk1 and Msx2, and cell invasion-related gene Osteopontin.
  • Bcl-2 is a major factor regulating apoptosis and is also regulated by Gli.
  • Gli1 regulates the expression of the tumor suppressor gene p53 and O-6-methylguanine DNA methyltransferase (MGMT), and both p53 and MGMT are associated with tumor resistance.
  • Gli is a transcription factor that directly regulates the target gene in the Hh pathway, and is the last common pathway for activation of different levels of this pathway, and plays an important role in the tumorigenesis process. Therefore, inhibition of Gli transcription factor activation may become a new strategy for tumor prevention and treatment.
  • the technical problem solved by the present invention is to provide a propiolate-containing 2-phenylimidazole derivative of the formula I having antitumor activity, a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition and It is used in the preparation of prophylactic or/and antitumor drugs.
  • the present invention provides the following technical solutions:
  • a first aspect of the present invention provides a propiolate-containing 2-phenylimidazole derivative of the formula I and a pharmaceutically acceptable salt thereof,
  • R 1 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, phenyl, mono- or poly-substituted phenyl, wherein the substituent is selected from the group consisting of halogen, hydroxy, cyano, C1-C6 alkyl , C1-C6 alkylamino, di(C1-C6 alkyl)amino, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, said polysubstituted includes two Substituted, trisubstituted, tetrasubstituted or pentasubstituted, the substituents may be the same or different in multiple substitutions;
  • R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl;
  • X is selected from O, S, NH;
  • C is selected from -O-, -NH-,
  • A is selected from the group consisting of H, piperidinyl, N-(C1-C6 alkyl)piperidinyl, piperazinyl, N-(C1-C6 alkyl)piperazinyl, N-(C1-C6 alkanoyl)piperazine , N-cyclopropylpiperazinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, pyrazolone, imidazolone , morpholinyl, pyranyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, Tetrazolyl, oxadiazolyl, bisoxazo
  • n 1 , n 2 are independently selected from 0, 1 , 2 , 3, 4, 5;
  • R 4 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, methylamino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, sulfonate. Amido, mesylamino, methylsulfonyl, sulfamoyl, ethyl, isopropyl, tert-butyl, ethoxy, ethylamino, diethylamino, cyclopropane, cyclobutane.
  • R 1 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, phenyl, mono- or poly-substituted phenyl, wherein the substituent is selected from the group consisting of halogen, hydroxy, cyano, C1-C6 alkyl , C1-C6 alkylamino, di(C1-C6 alkyl)amino, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, said polysubstituted includes two Substituted, trisubstituted, tetrasubstituted or pentasubstituted, the substituents may be the same or different in multiple substitutions;
  • R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl;
  • X is selected from O, S, NH;
  • A is selected from the group consisting of H, piperidinyl, N-(C1-C6 alkyl)piperidinyl, piperazinyl, N-(C1-C6 alkyl)piperazinyl, N-(C1-C6 alkanoyl)piperazine , N-cyclopropylpiperazinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, pyrazolone, imidazolone , morpholinyl, pyranyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, Tetrazolyl, oxadiazolyl, bisoxazo
  • n 1 , n 2 are independently selected from 0, 1 , 2 , 3, 4, 5;
  • R 4 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, methylamino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, sulfonate. Amido, mesylamino, methylsulfonyl, sulfamoyl, ethyl, isopropyl, tert-butyl, ethoxy, ethylamino, diethylamino, cyclopropane, cyclobutane.
  • a more preferred compound is as shown in formula (IA1):
  • R3 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C1-C6 alkoxy, trifluoromethyl, trifluoromethyl Oxyl, methylsulfonyl, carbamoyl, the substitution of R3 on the phenyl ring may be mono- or poly-substituted, and the poly-substitution includes di-, tri-, tetra-, penta-substituted, and the substituents may be the same or different in the case of multiple substitution;
  • R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl;
  • X is selected from O, S;
  • A is selected from the group consisting of H, piperidinyl, N-(C1-C6 alkyl)piperidinyl, piperazinyl, N-(C1-C6 alkyl)piperazinyl, N-(C1-C6 alkanoyl)piperazine , N-cyclopropylpiperazinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolone, imidazolidinone, morpholinyl, pyranyl, pyridyl, pyrrole Base, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, oxadiazolyl, dioxazole , C3-C6 cycloalkyl, C1-C6 al
  • n 1 , n 2 is selected from 0, 1 , 2, 3, 4, 5;
  • R 4 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, methylamino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, sulfonate. Amido, methanesulfonylamino, methanesulfonylethyl, propyl, tert-butyl, ethoxy, ethylamino, diethylamino, cyclopropane, cyclobutane.
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C1-C6 alkoxy, trifluoromethyl, trifluoro Methoxy, methylsulfonyl, carbamoyl, the substitution of R3 on the phenyl ring may be mono- or poly-substituted, and the poly-substitution includes di-, tri-, tetra-, penta-substituted, and the substituents may be the same or different ;
  • R 2 is selected from the group consisting of hydrogen and methyl
  • X is selected from O, S;
  • Ra is selected from H, piperidinyl, N-(C1-C6 alkyl)piperidinyl, piperazinyl, N-(C1-C6 alkyl) piperazinyl, N-(C1-C6 alkanoyl) piperazine , N-cyclopropylpiperazinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolone, imidazolidinone, morpholinyl, pyranyl, pyridyl, pyrrole , pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, oxadiazolyl, C3-C6 Cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino
  • n 1 is selected from 0, 1, 2, 3, 4, 5;
  • R 4 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, methylamino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, sulfonate. Amido, methanesulfonylamino, methylsulfonyl, ethyl, propyl, tert-butyl, ethoxy, ethylamino, diethylamino, cyclopropane, cyclobutane.
  • R 7 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, wherein the substituent is selected from the group consisting of halogen, hydroxy, cyano, di(C1-C6 alkyl)amino, C1-C6 alkoxy, Methanesulfonyl, carbamoyl;
  • R 2 is selected from the group consisting of hydrogen, methyl, C1-C6 alkanoyl
  • X is selected from O, S;
  • A is selected from the group consisting of H, piperidinyl, N-(C1-C6 alkyl)piperidinyl, piperazinyl, N-(C1-C6 alkyl)piperazinyl, N-(C1-C6 alkanoyl)piperazine , N-cyclopropylpiperazinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolone, imidazolidinone, morpholinyl, pyranyl, pyridyl, pyrrole Base, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, oxadiazolyl, dioxazole , C3-C6 cycloalkyl, C1-C6 al
  • n 1 , n 2 is selected from 0, 1 , 2, 3, 4, 5;
  • R 4 is selected from the group consisting of hydrogen, methyl, C1-C6 alkanoyl
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, methylamino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, sulfonate. Amido, methanesulfonylamino, methanesulfonylethyl, propyl, tert-butyl, ethoxy, ethylamino, diethylamino, cyclopropane, cyclobutane.
  • R 7 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, wherein the substituent is selected from the group consisting of halogen, hydroxy, cyano, dimethylamino, methoxy, methylsulfonyl, carbamoyl;
  • R 2 is selected from the group consisting of hydrogen and methyl
  • X is selected from O, S;
  • Ra is selected from H, piperidinyl, N-(C1-C6 alkyl)piperidinyl, piperazinyl, N-(C1-C6 alkyl) piperazinyl, N-(C1-C6 alkanoyl) piperazine , N-cyclopropylpiperazinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolone, imidazolidinone, morpholinyl, pyranyl, pyridyl, pyrrole , pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1- C6 alkylamino, hydroxy, amino, di(C1-C6 alkyl)amino, cyan
  • n 1 is selected from 0, 1, 2, 3, 4, 5;
  • R 4 is selected from the group consisting of hydrogen and methyl
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, methylamino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, A Sulfonyl, ethyl, propyl, tert-butyl, ethoxy, ethylamino, diethylamino, cyclopropane, cyclobutane.
  • R 1 is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, mono- or poly-substituted phenyl, wherein the substituent is selected from the group consisting of halogen, hydroxy, cyano, methyl, ethyl, propyl, butyl, C1. -C6 alkylamino, di(C1-C6 alkyl)amino, C1-6 alkoxy, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, said polysubstituted includes disubstituted, Trisubstituted, tetrasubstituted or pentasubstituted;
  • R 2 is selected from the group consisting of hydrogen and methyl
  • X is selected from O, S;
  • B is selected from the group consisting of a single bond, -O-, -N-, -CH 2 -, piperidinyldiyl, piperazinyl, azetidinediyl;
  • A is selected from the group consisting of H, piperidinyl, N-(C1-6 alkyl)piperidinyl, piperazinyl, N-(C1-6alkyl)piperazinyl, N-(C1-6 alkanoyl)piperazine , N-cyclopropylpiperazinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolone, imidazolidinone, morpholinyl, triazolyl, tetrazolium a group, a C3-C6 cycloalkyl group, a C1-6 alkoxy group, a hydroxyl group, a di(C1-6 alkyl)amino group, a cyano group, a methanesulfonylamino group, a methanesulfonyl group, an aminoacyl group;
  • n 1 , n 2 are independently selected from 0, 1 , 2 , 3, 4;
  • R 4 is selected from the group consisting of hydrogen and a C1-C6 alkanoyl group
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, methylamino, dimethylamino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, sulfonate. Amido, methanesulfonylamino, methylsulfonyl, sulfamoyl, ethyl, isopropyl.
  • the above-mentioned C1-C6 alkyl group includes a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group; and the C1-C6 alkoxy group includes a methoxy group, an ethoxy group, a propoxy group, and a butyl group.
  • Amino; the C3-C6 cycloalkyl group includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group.
  • the pharmaceutically acceptable salts described above include inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions or energy a salt formed by combining an organic base of a physiologically acceptable cation and an ammonium salt;
  • the inorganic acid being selected from the group consisting of hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; and the organic acid is selected from the group consisting of methanesulfonic acid and p-toluenesulfonic acid , trifluoroacetic acid, citric acid, maleic acid tartaric acid, fumaric acid, citric acid or lactic acid;
  • the alkali metal ion is selected from the group consisting of lithium ions, sodium ions, potassium ions;
  • the alkaline earth metal ions are selected from calcium ions.
  • the organic base capable of providing a physiologically acceptable cation is selected from the group consisting of methylamine, dimethylamine, trimethylamine
  • a second aspect of the present invention provides a method of preparing the compound of the first aspect of the invention, comprising the steps of:
  • Route 1 using fluoro-nitro-nitrobenzonitrile 1 as a raw material, first connecting the R 3 group, then forming an imidazole ring, and finally alkyne acylation;
  • step (a) the fluoro-nitrobenzonitrile 1 is reacted with RH in an alkaline environment to form a R-nitrobenzonitrile 2;
  • step (b) the compound 2 and 1-amino-3,3-diethoxypropane are first subjected to an addition reaction in an alkaline environment, and then the acetal is hydrolyzed in an acidic environment, and further condensed and cyclized to obtain an imidazole ring.
  • step (c) the nitro group-containing compound 3 is reduced with a common nitro reducing agent to obtain an amine group-containing compound 4;
  • step (d) the amine group-containing compound 4 and the acetylene acid are dehydrated by a condensing agent, or the acetylenic acid chloride is reacted with 4 to form an alkyne amide compound 5;
  • step (e) compound 5 is alkylated or acylated in an alkaline environment to give compound 6;
  • step (f) the compound 6 is reacted with a Lawesson reagent to give the amide thio group to obtain the compound 7;
  • step (a) 2-fluoro-5-diethoxymethylnitrobenzene 8 is reacted with RH under alkaline conditions to form 2-R-5-diethoxymethylnitrobenzene 9;
  • step (b) the acetal compound 9 is hydrolyzed under acidic conditions to obtain the aldehyde-based compound 10;
  • step (c) 1,1-dibromo-3,3,3-trifluoroacetone and the compound 10 in the presence of aqueous ammonia in the presence of an addition to eliminate condensation cyclization to give the imidazole ring compound 11;
  • step (d) the nitro group-containing compound 11 is reduced with a common nitro reducing agent to obtain an amine group-containing compound 12;
  • step (e) the amine group-containing compound 12 and the acetylene acid are dehydrated by a condensing agent, or the acetylenic acid chloride is reacted with 12 to form an alkyne amide compound 13;
  • step (f) compound 13 is alkylated or acylated in an alkaline environment to give compound 14;
  • step (g) compound 14 is reacted with Lawesson's reagent to obtain compound 15;
  • Route 3 first forming an imidazole ring, then attaching an R group, and finally an alkyne acylation;
  • step (a) with the fluorom-nitrobenzaldehyde 16 as a raw material, in the presence of lithium tetrafluoroborate and R 5 and R 6 substituted diketone directly heated condensation to form an imidazole ring compound 17;
  • step (b) compound 17 is reacted with RH in an alkaline environment to form a substituted compound 18;
  • step (c) the nitro group-containing compound 18 is reduced with a common nitro reducing agent to obtain an amine group-containing compound 19;
  • step (d) the amine group-containing compound 19 and the acetylene acid are dehydrated by a condensing agent, or the acetylenic acid chloride is reacted with 19 to form an alkyne amide compound 20;
  • step (e) compound 20 is alkylated or acylated in an alkaline environment to give compound 21;
  • step (f) compound 21 is reacted with Lawesson's reagent to obtain compound 22;
  • R1, R2, R4, R5, R6, A, B, C, n1, and n2 are the same as defined in the first aspect of the present invention.
  • the starting materials and intermediates in the above reaction are easily obtained, and the respective steps can be easily synthesized according to the reported literature or by a person skilled in the art by a conventional method in organic synthesis.
  • the compounds of formula I may exist in solvated or unsolvated forms, and crystallization from different solvents may result in different solvates.
  • the pharmaceutically acceptable salts of the formula I include different acid addition salts, such as the acid addition salts of the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, Trifluoroacetic acid, citric acid, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid.
  • the pharmaceutically acceptable salts of formula I also include various alkali metal salts (lithium, sodium, potassium salts), alkaline earth metal salts (calcium, magnesium salts) and ammonium salts, and organics which provide physiologically acceptable cations.
  • Salts of bases such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine and tris(2-hydroxyethyl)amine. All of these salts within the scope of the invention can be prepared by conventional methods. During the preparation of the compounds of the formula I and their solvates and salts thereof, polycrystalline or eutectic may occur under different crystallization conditions.
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect of the present invention as an active ingredient, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier Or an excipient.
  • a third aspect of the present invention provides a compound according to the first aspect of the present invention as an activity.
  • a pharmaceutical composition of the ingredients can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the content of the compound of the present invention in its pharmaceutical composition is usually from 0.1 to 95% by weight.
  • the compound of the present invention or the pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.
  • the dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions, tinctures, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.
  • the compounds of the present invention can be formulated into common preparations, as sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • diluents may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • wetting agent may be water, ethanol, or different Propyl alcohol, etc.
  • the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl group
  • disintegrant can be dry starch, microcrystalline cellulose, low-
  • Tablets may also be further formed into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • the active ingredient of the compound of the present invention and a diluent can be used.
  • the flow agent is mixed and the mixture is placed directly in a hard or soft capsule.
  • the active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule.
  • the various diluents, binders, wetting agents, disintegrants, glidants of the formulations used to prepare the tablets of the present invention are also useful in the preparation of capsules of the compounds of the invention.
  • water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizing agent, a solubilizing agent, a pH adjusting agent, and an osmotic pressure adjusting agent which are commonly used in the art may be added.
  • the solubilizing agent or co-solvent may be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.; the pH adjusting agent may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulating agent may It is sodium chloride, mannitol, glucose, phosphate, acetate, and the like.
  • mannitol, glucose or the like may also be added as a proppant.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like.
  • a suitable daily dose of the compound of the invention will range from 0.001 to 150 mg/kg body weight, preferably from 0.01 to 100 mg/kg body weight.
  • the above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
  • the compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.
  • a fourth aspect of the present invention provides the use of the compound of the first aspect of the present invention for the preparation of a medicament for preventing or/and treating a tumor, wherein the tumor is selected from the group consisting of liver cancer, kidney cancer, lung cancer, pancreatic cancer, gastric cancer, Colorectal cancer, bladder cancer, breast cancer, ovarian cancer, skin cancer, thyroid cancer, blood cancer, squamous cell carcinoma, glioma, and head and neck cancer.
  • the compounds of the invention are a class of Gli1 transcriptional activity inhibitors.
  • Gli glioma-associated oncogene homoglog
  • Gli is a nuclear transcription factor in the Hh signaling pathway, and its functional state changes will directly lead to changes in the transcriptional level of the target gene downstream of the Hh signaling pathway. Activation of the Hh signaling pathway ultimately leads to full-length modification of the terminal transcription factor Gli, which initiates transcription of the target gene into the nucleus.
  • Gli transcription factors Glil, Gli2, GIi3
  • Glil is a highly active transcriptional activator.
  • Gli2 has both transcriptional activation and inhibition functions, mainly in the form of transcriptional activators, and its transcription.
  • Gli3 is capable of activating downstream gene transcription under certain tissues and conditions, but is thought to be primarily transcriptional repressor.
  • Glil is a direct transcriptional activator whose activation regulation occurs at the transcriptional level.
  • the expression level of Glil mRNA is a reliable indicator of the activity of Hh signaling pathway.
  • Gli2 and Gli3 are potential transcriptional activators.
  • Target genes regulated by Gli include different types: CyclinD1, CyclinD2, FoxM1, N-Myc, Wnts, PdgfRa, Hes1, IGFBP-6 (insulin-like growth factor binding protein-6), which regulate cell proliferation and differentiation, and are metabolically related.
  • Bmi1, Nanog angiogenesis-related gene VEGF, epidermal cell-interstitial cell transformation (EMT)-related genes CXCR4, Snail1, Sip1, Elk1 and Msx2, and cell invasion-related gene Osteopontin.
  • Bcl-2 is a major factor regulating apoptosis and is also regulated by Gli.
  • Gli1 regulates the expression of the tumor suppressor gene p53 and O-6-methylguanine DNA methyltransferase (MGMT), and both p53 and MGMT are associated with tumor resistance. These suggest that activation of this pathway may be related not only to tumorigenesis and reproduction, but also to tumor recurrence, metastasis and drug resistance. Gli1 is a transcription factor that directly regulates the target gene in the Hh pathway, and is the last common pathway for activation of different levels of this pathway, and plays an important role in the tumorigenesis process. Therefore, inhibition of Gli1 transcription factor activation can not only effectively inhibit tumorigenesis, but also inhibit tumor metastasis and drug resistance, which may become a new strategy for tumor prevention and treatment.
  • MGMT O-6-methylguanine DNA methyltransferase
  • the compound of the invention has high bioavailability and can be used for the treatment of various human malignant tumors, including the tumor diseases such as glioma, brain tumor, lymphoma, liver cancer, gastric cancer, kidney cancer, lung cancer, pancreatic cancer. , colorectal cancer, bladder cancer and breast cancer, ovarian cancer, squamous cell carcinoma, leukemia, head and neck cancer.
  • tumor diseases such as glioma, brain tumor, lymphoma, liver cancer, gastric cancer, kidney cancer, lung cancer, pancreatic cancer.
  • colorectal cancer, bladder cancer and breast cancer ovarian cancer
  • squamous cell carcinoma leukemia, head and neck cancer.
  • Figure 4 MRI detection of coronal plane of each animal in the FL18 22.5 mg/kg group.
  • Figure 5 MRI detection of coronal planes of each animal in the FL18 45.0 mg/kg group.
  • Measuring instrument Nuclear magnetic resonance spectroscopy was performed with a Vaariaan Mercury Model 300 or 400 NMR. Mass spectrometry was performed using a ZAD-2F and VG300 mass spectrometer.
  • Butynoic acid (83 mg, 0.99 mmol) was dissolved in 5 ml of benzene, and oxalyl chloride (0.17 ml, 254 mg, 2.0 mmol) was added and reacted at 50 ° C for 3 hours.
  • the benzene and oxalyl chloride were distilled off under reduced pressure, and then dissolved in anhydrous THF, and added to the compound 5-(2-1H-imidazole)-2-(3-morpholinylpropanyl)phenylamine (100 mg, 0.33) at 0 °C.
  • the aqueous phase was added with sodium carbonate to adjust the pH to 8-10 to precipitate a solid.
  • the solid was purified by column chromatography (dichloromethane/methanol 100:1) to give 2-(4-(2-morpholinylethanol)-3-nitrate.
  • Base-1H-imidazole yellow solid 159 mg.
  • Butynoic acid (67 mg, 0.8 mmol) was dissolved in 5 ml of benzene, and oxalyl chloride (0.14 ml, 203 mg, 1.6 mmol) was added and reacted at 50 ° C for 3 hours.
  • the benzene and oxalyl chloride were distilled off under reduced pressure, and then dissolved in anhydrous THF, and added to the compound 5-(2-1H-imidazole)-2-(2-morpholinethanol) aniline (80 mg, 0.28 mmol) at 0 °C.
  • Butynoic acid (83 mg, 0.99 mmol) was dissolved in 5 ml of benzene, and oxalyl chloride (0.17 ml, 254 mg, 2.0 mmol) was added and reacted at 50 ° C for 3 hours.
  • the benzene and oxalyl chloride were distilled off under reduced pressure, dissolved in anhydrous THF, and added dropwise to the compound 5-(2-1H-imidazole)-2-((2-ethoxy)-2-ethoxyl at 0 °C.
  • the butyric acid (65 mg, 0.8 mmol) was dissolved in 5 ml of benzene, and oxalyl chloride (0.14 ml, 203 mg, 1.6 mmol) was added and reacted at 50 ° C for 3 hours.
  • the benzene and oxalyl chloride were distilled off under reduced pressure, dissolved in anhydrous THF, and added dropwise to the compound 5-(2-1H-imidazole)-2-((2-methoxy)-2-ethoxyl at 0 °C.
  • Example 6 Using 2-dimethylaminoethanol instead of ethylene glycol methyl ether, the procedure of Example 6 was followed to give N-(5-(imidazol-2-yl)-2-(2-dimethylaminoethoxy)phenyl. ) butyne-2-amide.
  • the aqueous phase was added with sodium carbonate to adjust the pH to 8-10 to precipitate a solid.
  • the solid was purified by column chromatography (dichloromethane/methanol 120:1) to give 2-(cyclopropylmethoxy)-3-nitro)-1H. - Imidazole yellow solid 272 mg.
  • Butynoic acid (165 mg, 1.96 mmol) was dissolved in 5 ml of benzene, and oxalyl chloride (0.50 ml, 747 mg, 5.89 mmol) was added and reacted at 50 ° C for 3 hours.
  • the benzene and oxalyl chloride were distilled off under reduced pressure, and then dissolved in anhydrous THF, and added to the compound 5-(2-1H-imidazole)-2-(cyclopropylmethoxy)phenylamine (150 mg, 0.65 mmol) at 0 °C.
  • Example 9 By replacing the cyclopropanol with pyridine-3-methanol, the procedure of Example 9 was followed to give N-(5-(imidazol-2-yl)-2-(pyridine-3-methoxy)phenyl)butyne- 2-amide.
  • the phenylpropynoic acid (145 mg, 0.99 mmol) was dissolved in 5 ml of benzene, and oxalyl chloride (0.17 ml, 254 mg, 2.0 mmol) was added and reacted at 50 ° C for 3 hours.
  • the benzene and oxalyl chloride were distilled off under reduced pressure, dissolved in anhydrous THF, and added dropwise to the compound 5-(2-1H-imidazole)-2-((2-ethoxy)-2-ethoxyl at 0 °C.
  • the compound 2-(3-nitro-4-cyclopropoxyphenyl)imidazole (500 mg, 1.93 mmol) was dissolved in THF Sodium hydroxide (154 mg, 3.84 mmol) of methyl iodide (545 mg, 141.94 mmol) was added. The reaction was carried out at room temperature for 24 hours. To the reaction mixture, 50 ml of ethyl acetate/water (1:1) was added for extraction. The organic phase was washed once with saturated brine, dried and evaporated to ethyldiamine.
  • Butynoic acid (164 mg, 2.0 mmol) was dissolved in 10 ml of benzene, and oxalyl chloride (0.2 ml, 4.0 mmol) was added and reacted at 50 ° C for 3 hours.
  • the benzene and oxalyl chloride were distilled off under reduced pressure, and then dissolved in anhydrous THF, and added dropwise to the compound N-methyl-2-(3-amino-4-cyclopropylmethoxyphenyl)imidazole (243 mg, 1.0 mmol) at 0 °C.
  • the p-fluorobenzaldehyde (5 g, 40.3 mmol) was placed in a round bottom flask, 150 ml of concentrated sulfuric acid was added, and sodium nitrate (3.8 g, 44.3 mmol) was added in portions at 0°C, and the mixture was stirred at room temperature for 2 hours, and the reaction solution was poured carefully. In ice water, a solid was precipitated and suction filtered to give 6.4 g of fluorom-nitrobenzaldehyde as a white solid.
  • Butynoic acid (59 mg, 0.7 mmol) was dissolved in benzene, oxalyl chloride (0.12 ml, 1.4 mmol) was added, and stirred at 50 ° C for 2 hours. The benzene was spun off and dissolved in THF.
  • the p-fluorobenzaldehyde (2.6 g, 21 mmol) was dissolved in 50 ml of concentrated sulfuric acid, and sodium nitrate was added in portions under ice bath. (2.0 g, 23 mmol), stirred at room temperature and stirred for 8 hours.
  • the reaction solution was poured into ice cubes, stirring was continued, and a white solid precipitated. After suction filtration, the filter cake was washed three times to obtain 3.4 g of p-fluoro-nitrobenzaldehyde white solid.
  • the p-fluoro-nitrobenzaldehyde (5.0 g, 30.1 mmol) was dissolved in 200 ml of methanol, p-toluenesulfonic acid (516 mg, 3.01 mmol), trimethyl orthoformate (9.9 ml, 9.57 g, 90.3 mmol), room temperature After stirring for 3 hours, the reaction mixture was concentrated, diluted with ethyl acetate (300 ml), washed with saturated sodium hydrogen carbonate solution, and washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After vortexing off the solvent, 6.3 g of fluorom-nitrobenzaldehyde dimethanol acetal yellow oil was obtained.
  • 4-cyclopropoxy-3-nitrobenzaldehyde dimethanol acetal (1.4 g, 5.0 mmol) was dissolved in 50 ml of acetone, 50 ml of 6N hydrochloric acid was added, and the mixture was stirred at room temperature for 2 hours, and then sodium carbonate was adjusted to neutral.
  • the mixture was diluted with 200 ml of ethyl acetate, the layers were separated, and the organic phase was washed with water, and then washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate to give a 4-cyclopropylmethoxy-3-nitrobenzaldehyde compound (1.1 g).
  • 1,1-Dibromo-3,3,3-trifluoroacetone (1.1 ml, 2.2 g, 8.0 mmol), sodium acetate (617 mg, 8.0 mmol) was dissolved in 10 ml of water, refluxed for 30 minutes, cooled, and 30 ml of methanol was added.
  • the dissolved compound 4-cyclopropylmethoxy-3-nitrobenzaldehyde (885 mg, 4.0 mmol), 10 ml of aqueous ammonia was stirred at room temperature for 48 hr, and the reaction mixture was diluted with 100 ml of ethyl acetate. The organic phase was washed with water and washed with saturated brine.
  • Butynoic acid (113 mg, 1.4 mmol) was dissolved in 5 ml of benzene, and oxalyl chloride (0.34 ml, 514 mg, 4.1 mmol) was added and reacted at 50 ° C for 3 hours.
  • the benzene and oxalyl chloride were distilled off under reduced pressure, dissolved in anhydrous THF, and added dropwise to the compound 2-(4-cyclopropylmethoxy-3-aminophenyl)-5-trifluoromethylimidazole at 0 °C.
  • the p-fluorobenzaldehyde (2.6 g, 21 mmol) was dissolved in 50 ml of concentrated sulfuric acid, and sodium nitrate (2.0 g, 23 mmol) was added portionwise, and the mixture was stirred at room temperature for 8 hours.
  • the reaction solution was poured into ice cubes, stirring was continued, and a white solid precipitated. After suction filtration, the filter cake was washed three times to obtain 3.4 g of p-fluoro-nitrobenzaldehyde white solid.
  • the compound p-fluoro-nitrobenzaldehyde (5.0 g, 30.1 mmol) was dissolved in 200 ml of methanol, p-toluenesulfonic acid (516 mg, 3.01 mmol), trimethyl orthoformate (9.9 ml, 9.57 g, 90.3 mmol), After stirring at room temperature for 3 hours, the reaction mixture was concentrated, diluted with ethyl acetate (300 ml), washed with saturated sodium hydrogen carbonate solution, and washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After vortexing off the solvent, 6.3 g of fluorom-nitrobenzaldehyde dimethanol acetal yellow oil was obtained.
  • P-fluoro-nitrobenzaldehyde dimethanol acetal (3.0 g, 13.9 mmol), ethylene glycol ether (4.0 ml, 3.8 g, 41.7 mmol), sodium hydroxide (1.7 g, 41.7 mmol) in a round bottom flask Medium, 100 ml of 1,4-dioxane, 40 ml of water was added, and the mixture was stirred at 50 ° C for 5 hours.
  • 4-Ethoxyethoxy-3-nitrobenzaldehyde dimethanol acetal (1.5 g, 5.0 mmol) was dissolved in 50 ml of acetone, and 50 ml of 6N hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 2 hours, and the sodium carbonate was adjusted to pH to neutrality. Diluted with 200 ml of ethyl acetate, layered, washed once with organic phase, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate. There was obtained 1.2 g of 4-ethoxyethoxy-3-nitrobenzaldehyde.
  • 1,1-Dibromo-3,3,3-trifluoroacetone (0.83 ml, 1.7 g, 6.0 mmol)
  • sodium acetate (463 mg, 6.0 mmol) was dissolved in 10 ml of water, refluxed for 30 minutes, then cooled, and 30 ml of methanol was added.
  • Dissolved 4-ethoxyethoxy-3-nitrobenzaldehyde (718 mg, 3.0 mmol), 10 ml of aqueous ammonia, stirred at room temperature for 48 hours.
  • the reaction mixture was diluted with 100 ml of ethyl acetate.
  • the organic phase was washed once with saturated brine.
  • Butynoic acid (126 mg, 1.5 mmol) was dissolved in 5 ml of benzene, and oxalyl chloride (0.38 ml, 571 mg, 4.5 mmol) was added and reacted at 50 ° C for 3 hours.
  • the benzene and oxalyl chloride were distilled off under reduced pressure, and then dissolved in anhydrous THF, and the compound 2-(4-ethoxyethoxy-3-aminophenyl)-5-trifluoromethylimidazole was added dropwise at 0 °C.
  • Example 15 Substituting 2-dimethylaminoethanol for cyclopropanol, the procedure of Example 15 was followed to give N-(5-(5-trifluoromethylimidazol-2-yl)-2-(2-dimethylaminoethyl) Oxy)phenyl)butyn-2-amide.
  • Example 15 By replacing the cyclopropanol with pyridin-3-yl-methanol, the procedure of Example 15 was followed to give N-(5-(5-trifluoromethylimidazol-2-yl)-2-(pyridin-3-yl-- Oxy)phenyl)butyn-2-amide.
  • the p-fluorobenzaldehyde (2.6 g, 21 mmol) was dissolved in 50 ml of concentrated sulfuric acid, and sodium nitrate (2.0 g, 23 mmol) was added portionwise, and the mixture was stirred at room temperature for 8 hours.
  • the reaction solution was poured into ice cubes, stirring was continued, and a white solid precipitated. After suction filtration, the filter cake was washed three times to obtain 3.4 g of p-fluoro-nitrobenzaldehyde white solid.
  • the p-fluoro-nitrobenzaldehyde (5.0 g, 30.1 mmol) was dissolved in 200 ml of methanol, p-toluenesulfonic acid (516 mg, 3.01 mmol), trimethyl orthoformate (9.9 ml, 9.57 g, 90.3 mmol), room temperature After stirring for 3 hours, the reaction mixture was concentrated, diluted with ethyl acetate (300 ml), washed with saturated sodium hydrogen carbonate solution, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. After vortexing off the solvent, 6.3 g of fluorom-nitrobenzaldehyde dimethanol acetal yellow oil was obtained.
  • P-methoxyethoxy m-nitrobenzaldehyde dimethanol acetal (1.4g, 5.0mmol) was dissolved in 50ml of acetone, added with 50ml of 6N hydrochloric acid, stirred at room temperature for 2 hours, sodium carbonate was adjusted to neutral, and ethyl acetate was added. The ester was diluted with 200 ml, layered, washed with organic phase, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate.
  • 1,1-Dibromo-3,3,3-trifluoroacetone (1.1 ml, 2.2 g, 8.0 mmol), sodium acetate (617 mg, 8.0 mmol) was dissolved in 10 ml of water, refluxed for 30 minutes, cooled, and 30 ml of methanol was added.
  • the dissolved p-methoxyethoxy m-nitrobenzaldehyde (900 mg, 4.0 mmol), 10 ml of aqueous ammonia was stirred at room temperature for 48 hours, and the reaction mixture was diluted with 100 ml of ethyl acetate.
  • Butynoic acid (113 mg, 1.4 mmol) was dissolved in 5 ml of benzene, and oxalyl chloride (0.34 ml, 514 mg, 4.1 mmol) was added and reacted at 50 ° C for 3 hours.
  • the benzene and oxalyl chloride were distilled off under reduced pressure, and then dissolved in anhydrous THF, and added dropwise to the solution of 2-(4-methoxyethoxy-3-aminophenyl)-5-trifluoromethylimidazole (135 mg) at 0 °C.
  • 2-(4-Ethoxyethoxy-3-nitrophenyl)-5-trifluoromethylimidazole (665 mg, 1.93 mmol) was dissolved in THF and sodium hydroxide (154 mg, 3.. (545 mg, 141.94 mmol). The reaction was carried out at room temperature for 24 hours. To the reaction mixture, 50 ml of ethyl acetate/water (1:1) was added for extraction. The organic phase was washed once with saturated brine, dried and evaporated to ethyldiamine. .
  • N-Methyl-2-(4-ethoxyethoxy-3-nitrophenyl)-5-trifluoromethylimidazole (359 mg, 1.0 mmol) was dissolved in 10 mL of methanol, 1 mL water, NH 4 Cl (651mg, 10.0mmol), zinc powder (534mg, 10.0mmol), heated under reflux for 2 hours, cooled and filtered to remove zinc powder. The filtrate was concentrated and extracted with ethyl acetate/water (1:1) 20 ml. The organic phase was water and saturated.
  • Butynoic acid (164 mg, 2.0 mmol) was dissolved in 10 ml of benzene, and oxalyl chloride (0.2 ml, 4.0 mmol) was added and reacted at 50 ° C for 3 hours.
  • the benzene and oxalyl chloride were distilled off under reduced pressure, dissolved in anhydrous THF, and added dropwise to N-methyl-2-(4-ethoxyethoxy-3-aminophenyl)-5-trifluoromethyl at 0 °C.
  • Imidazole (329 mg, 1.0 mmol) in THF and pyridine (0.2 ml, 2.0 mmol), after the dropwise addition, the mixture was transferred to room temperature and reacted for 4 hours.
  • Example 16 By replacing the butynoic acid with phenylpropynoic acid, the procedure of Example 16 was followed to give N-(5-(5-trifluoromethylimidazol-2-yl)-2-(ethoxyethoxy)phenyl. ) phenylpropyne-2-amide.
  • Example 11 Using p-cyanophenylpropynoic acid instead of phenylpropynoic acid, the procedure of Example 11 was followed to give N-(5-(imidazol-2-yl)-2-(ethoxyethoxy)phenyl)p-cyanide. Phenylpropyne amide.
  • Example 11 Using p-chlorophenylpropynoic acid instead of phenylpropynoic acid, the procedure of Example 11 was followed to give N-(5-(imidazol-2-yl)-2-(ethoxyethoxy)phenyl)-p-chlorobenzene. Propiylamide.
  • Example 11 Using m-chlorophenylpropynoic acid in place of phenylpropynoic acid, the procedure of Example 11 was followed to give N-(5-(imidazol-2-yl)-2-(ethoxyethoxy)phenyl)m-chlorobenzene. Propiylamide.
  • Example 11 Using p-methylphenylpropynoic acid instead of phenylpropynoic acid, the procedure of Example 11 was followed to give N-(5-(imidazol-2-yl)-2-(ethoxyethoxy)phenyl)-p- Phenylpropyne amide.
  • Example 11 By replacing the phenylpropynoic acid with p-trifluoromethylphenylpropynoic acid, the procedure of Example 11 was followed to give N-(5-(imidazol-2-yl)-2-(ethoxyethoxy)phenyl) p-Trifluoromethylphenylpropynylamide.
  • Example 11 Using p-methoxyphenylpropynoic acid instead of phenylpropynoic acid, the procedure of Example 11 was followed to give N-(5-(imidazol-2-yl)-2-(ethoxyethoxy)phenyl). Methoxyphenylpropynylamide.
  • the cells in the logarithmic growth phase were trypsinized to prepare a cell solution having a concentration of 0.8 to 2 ⁇ 10 4 cells/ml, and seeded in a 96-well plate at 1000 cells/well, and 100 ⁇ l was added to each well.
  • add fresh medium containing different concentrations of drugs and corresponding solvent controls add 100 ⁇ l per well (final concentration of DMSO ⁇ 0.5%), set 5 to 7 dose groups per drug, and set at least three parallel holes in each group.
  • SH-SY5Y human neuroblastoma cell line
  • T98G human glioblastoma cell line
  • Daoy Human medulloblastoma cell line
  • HCT116 human colon cancer cell line
  • A549 Human lung adenocarcinoma cell line
  • the Luciferase reporter system is a reporter system that uses luciferin as a substrate to detect the activity of firefly luciferase. Luciferase catalyzes the oxidation of luciferin to oxyluciferin, which emits bioluminescence during the oxidation of luciferin. The bioluminescence released during the oxidation of luciferin can then be determined by a fluorometer, also known as a luminometer or liquid scintillation meter. The bioluminescent system of fluorescein and luciferase can detect gene expression extremely sensitively and efficiently. It is a detection method for detecting the interaction of transcription factors with DNA of the promoter region of the target gene.
  • Dual Luciferase Reporter Assay Combining Firefly and Marine Cochlear Luciferase Advanced Co-Reporter Gene Assay Techniques When using firefly luciferase to quantify gene expression, a second reporter gene is typically used to reduce experimental variation.
  • a specific fragment of the promoter of the target gene Gli target was inserted into the reporter plasmid in front of the firefly luciferase expression sequence, pGM-GLI-Lu (constructed by Jiman Biotechnology Co., Ltd.), and pGMR-TK was used as the internal reference plasmid (purchased in Jiman Limited).
  • Tumor cell cells were transiently co-transfected with pGM-GLI-Lu plasmid and pGMR-TK plasmid using liposome. Tumor cells were seeded at a concentration of 3 x 10 5 /ml in 96-well plates at 100 ⁇ l per well. The medium in which the cells were cultured was DMEM containing 10% serum and no double antibody. Transient co-transfection with Lipofectamine 2000 (Invitrogen) was performed when cells were grown to greater than about 90% confluency.
  • Solution 1 0.5 ⁇ l lipofectamine 2000 + 24.5 ⁇ l serum-free medium per well (total volume 25 ⁇ l) (incubation for 5 min).
  • Solution 2 25 ⁇ l serum-free medium + 0.2 ⁇ g pGM-GLI-Lu plasmid and 0.01 ⁇ g pGMR-TK plasmid per well (total volume 25 ⁇ l).
  • F firefly luciferase
  • R Renilla luciferase
  • GDC0449 is the positive control in the experiment (GDC0449 is the first oral, highly selective Hedgehog signaling pathway small molecule inhibitor developed by Swiss Roche Pharmaceuticals in the US pharmaceutical factory).
  • GDC0449 is the first oral, highly selective Hedgehog signaling pathway small molecule inhibitor developed by Swiss Roche Pharmaceuticals in the US pharmaceutical factory.
  • the transcriptional activity of Gli1 in SHSY-5Y cells was inhibited, and the IC 50 was 223.7 nmol/L.
  • Example 16 inhibited the transcriptional activity of Gli1 in SHSY-5Y cells in a dose-dependent manner with an IC 50 of 75.1. Nmol/L.
  • Example 11 inhibits the growth of ectopic brain tumor U87MG
  • Example 11 inhibits the growth of orthotopic brain tumor U87MG
  • mice 5-6 weeks old Balb/c female nude mice were used in the experiment, and the nude mice were housed. After anesthesia was intraperitoneally injected with 50 mg/kg sodium pentobarbital, the animal was placed in a prone position on a mouse brain stereotaxic apparatus. After disinfecting the scalp of nude mice with alcohol and iodine, the scalpel was cut into the scalp of the nude mouse, and the incision was cleaned by 3% H 2 O 2 to expose the skull. 2mm behind the anterior iliac crest, 1.5mm on the right side, and drilled in the dental drill. The No.
  • 26 microsyringe was injected with 5 ⁇ l of tumor solution (about 2 ⁇ 10 6 cells, the needle depth was 3 mm, the needle was withdrawn 0.5 mm, and the injection time was about 5 minutes). After stopping the needle for 10 minutes, the needle was slowly pulled and the incision was sterilized. Intraperitoneal injection of 50,000 units of penicillin to fight infection. Randomized group administration was started 5 days after the operation, and MRI was performed on the 14th day after the operation to calculate the tumor volume and the inhibition rate.
  • the section spacing is (0.5 mm), and the volume is calculated by adding the area of the section where each tumor is located (3.14 ⁇ long diameter of tumor / 2 ⁇ short diameter of tumor / 2) ⁇ 0.5. **p ⁇ 0.01; ***p ⁇ 0.001 compared to the vehicle control group.
  • a continuous tomogram of the tumor was observed for MRI scans of different animals, with a spacing of 0.5 mm per layer.
  • the figure can measure the cross-sectional area of the intracranial tumor of each animal.
  • the calculation method of the volume is: the area of the section where each tumor is located (3.14 ⁇ long diameter of tumor / 2 ⁇ short diameter of tumor / 2) ⁇ 0.5 .
  • Tumor volume was calculated and statistical analysis was performed. The experimental results are shown in Figure 2-5.

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Abstract

La présente invention concerne un dérivé de 2-phénylimidazole qui contient des groupes propynamide et qui est représenté par la formule I, un sel pharmaceutique de celui-ci, son procédé de préparation, une composition contenant le ou les composés, et des utilisations desdits composés dans la préparation de médicaments destinés à prévenir ou à traiter des maladies tumorales.
PCT/CN2016/083236 2015-05-25 2016-05-25 Dérivé de 2-phénylimidazole contenant des groupes propynamide, son procédé de préparation, composition pharmaceutique associée, et utilisations associées Ceased WO2016188421A1 (fr)

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