CN114044774A - EGFR inhibitor and preparation method and application thereof - Google Patents

EGFR inhibitor and preparation method and application thereof Download PDF

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CN114044774A
CN114044774A CN202111478791.5A CN202111478791A CN114044774A CN 114044774 A CN114044774 A CN 114044774A CN 202111478791 A CN202111478791 A CN 202111478791A CN 114044774 A CN114044774 A CN 114044774A
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秦炳杰
孔越
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Guangwu Huiwen Biotechnology Beijing Co ltd
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Abstract

The invention discloses an EGFR inhibitor compound represented by the following formula 1, a pharmaceutically acceptable salt thereof, a preparation method thereof, the compound andthe pharmaceutically acceptable salt thereof can be used for preparing medicines for treating lung cancer, colorectal cancer, nasopharyngeal carcinoma, head and neck squamous carcinoma, gastric cancer, esophageal cancer, breast cancer, pancreatic cancer, liver cancer, cervical cancer, ovarian cancer, skin cancer and brain glioma. Also disclosed is a pharmaceutical composition comprising the compound represented by formula 1 or a pharmaceutically acceptable salt thereof.

Description

EGFR inhibitor and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an EGFR inhibitor, and a preparation method and application thereof.
Background
EGFR is a member of the epidermal growth factor receptor (ERBB/HER) family, which also includes the HER2-4(ERBB2-4) (Rutkowska A, Stoczy ń ska-Fidelis E, Janik K,
Figure BDA0003394645140000011
a, Rieske P.EGFR vIII, An Oncogene with Ambiguous Role.J Oncol.2019; 2019:1-20.). Their structure is similar to that of other tyrosine kinase receptors and includes the typical three parts: the extracellular region is responsible for binding to ligands and forming dimers; the hydrophobic transmembrane region binds to the cell membrane; the intracellular domain contains a tyrosine kinase domain which is capable of completing the kinase process and signaling (Wood ER, Truesdale AT, McDonald OB, et al. A Unique Structure for epidemic Growth Factor Receptor Bound to GW572016(Lapatinib): Relationships arm Protein formation, Inhibitor of Off-Rate, and Receptor Activity in Tumor cells. cancer Res.2004; 64: 6652-. The corresponding ligands can bind to the extracellular domains of EGFR, HER3 and HER4 and promote the formation of active dimers, whereas HER2 does not bind directly to ERBB ligands, but its conformation and ligand activation state are similar, favoring dimerization. ERBB family members are involved in different signaling pathways in cells, which in turn have been shown to play a major role in the development and maintenance of solid tumors, so the development of selective ERBB inhibitors has been extensively studied (Aretag CL, Engelman JA. ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer therapeutics. Cancer cell 2014; 25(3): 282-303.).
The EGFR gene is located on human chromosome 7 and is one of the most common driver genes for non-small cell lung cancer (Bhatia P, Sharma V, Alam O, et al. novel quinazoline-based EGFR kinase inhibitors: A review marketing on SAR and molecular locking students (2015-2019), Eur J Med chem.2020; 204: 112640.). Mature EGFR is a transmembrane glycoprotein consisting of 1186 amino acid residues and having a molecular weight of 170kDa (Rude Voldborg B, Damstrup L, span-Thomsen M, Skovgaard Poulsen H. Epidermal Growth Factor Receptor (EGFR) and EGFR mutations, function and position roll in clinical trials. Ann Oncol.1997; 8(12): 1197-1206), widely distributed on epithelial membranes except vascular tissue. 7 ligands such as epidermal growth factor, transforming growth factor, and epithelial regulatory protein can bind to EGFR (Harris RC, Chung E, coffee RJ. EGF Receptor ligands. in: The EGF Receptor family Elsevier; 2003:3-14.), EGFR is activated by binding to The corresponding ligand and causing dimerization of EGFR, tyrosine residues are then autophosphorylated, and RAF/MEK/ERK and PI3K/Akt/PTEN/mTOR downstream signaling pathways in cells can be triggered, thereby affecting cell proliferation, differentiation, migration and apoptosis of certain cells, and studies have shown that over-activation of EGFR signaling pathways is detected in cancers such as non-small cell lung cancer, breast cancer, colon cancer, ovarian cancer, pancreatic cancer (Bhatia P, SAR Med V, Alam O, et al. novel napelline-based EGFR kinase inhibitors: A Receptor binding J. 112640; Marris J. 112640. Cheng J. 3. 12 E, Ciardiello D, Martini G, et al.Implementing anti-Epidermal Growth Factor Receptor (EGFR) therapy in metallic color cancer. pulleys and future perspectives. Ann Oncol.2020; 31(1) 30-40; liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu k. EGFR-TKIs resistance via EGFR-independent signalling pathwalls. mol cancer.2018; 17(1):53.), EGFR has become one of the most interesting targets in tumor therapy research.
Two common strategies currently studied to inhibit epidermal growth factor receptor overexpression include one that acts on the extracellular domain, primarily by competitive binding of monoclonal antibodies to the extracellular domain, thereby blocking ligand-induced activation of EGFR, and the other that small molecule inhibitors bind competitively with ATP to the intracellular kinase domain, inhibiting the autophosphorylation process and downstream signaling of EGFR (Abou-series sm. synthesis and biological evaluation of novel 2, 4' -bis sub-specified phenyl amides as inhibitors of the enzyme inhibitors and of the potential epidermal growth factor receptor inhibitors. eur J Med chem.2010; 45(9):4113-4121.) which are also the most commonly studied EGFR drugs currently.
Disclosure of Invention
Through extensive and intensive research, the applicant designs and synthesizes a series of small molecular compounds with novel structures, and the small molecular compounds have good inhibition effect on various clinically common EGFR kinase mutants.
According to one aspect of the present invention, it is an object of the present invention to provide a compound represented by the following formula 1:
Figure BDA0003394645140000021
wherein, X1、X2、X3、X5、X6And X7Each independently selected from C, N, O and S atom, X4Selected from C, NH, O and S atoms, X8And X9Each independently selected from C and N atoms;
R1selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
n is an integer selected from 0, 1,2, 3 or 4;
R2selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
m is an integer selected from 0, 1,2, 3 or 4;
R3selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, and halogen-substituted alkoxy groups of C1 to C6.
Preferably, X1、X2And X3At least two of which are not C atoms;
preferably, X1And/or X2Is an N or O atom.
Preferably, the compound represented by formula 1 and pharmaceutically acceptable salts thereof are represented by the following formula 2:
Figure BDA0003394645140000031
wherein, X1、X2、X5、X6And X7Each independently selected from C, N, O and S atom, X4Selected from C, NH, O and S atoms, X8And X9Each independently selected from C and N atoms;
R1selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
n is an integer selected from 0, 1,2, 3 or 4;
R2selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
m is an integer selected from 0, 1,2, 3 or 4;
R3selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
preferably, X1And/or X2Is an N or O atom.
Preferably, the compound represented by formula 1 and pharmaceutically acceptable salts thereof are represented by the following formula 3:
Figure BDA0003394645140000032
wherein, X1、X2、X5、X6And X7Each independently selected from C, N, O and S atom, X4Selected from the group consisting of C, NH, O and S atoms;
R1selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
n is an integer selected from 0, 1,2, 3 or 4;
R2selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
m is an integer selected from 0, 1,2, 3 or 4;
R3selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
preferably, X1And/or X2Is an N or O atom.
Preferably, the compound represented by formula 1 and pharmaceutically acceptable salts thereof are represented by the following formula 4:
Figure BDA0003394645140000041
wherein, X5、X6And X7Each independently selected from C, N, O and S atom, X4Selected from C, NH, O and S atoms, X8And X9Each independently selected from C and N atoms;
R1selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
n is an integer selected from 0, 1,2, 3 or 4;
R2selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
m is an integer selected from 0, 1,2, 3 or 4;
R3selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, and halogen-substituted alkoxy groups of C1 to C6.
Preferably, the compound represented by formula 1 and pharmaceutically acceptable salts thereof are represented by the following formula 5:
Figure BDA0003394645140000051
wherein, X5、X6And X7Each independently selected from C, N, O and S atom, X4Selected from the group consisting of C, NH, O and S atoms;
R1selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
n is an integer selected from 0, 1,2, 3 or 4;
R2selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
m is an integer selected from 0, 1,2, 3 or 4;
R3selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, and halogen-substituted alkoxy groups of C1 to C6.
Preferably, in the compounds represented by formula 1 to formula 5 and pharmaceutically acceptable salts thereof,
R1selected from hydrogen atoms, halogens, alkyl groups of C1 to C4, halogen-substituted alkyl groups of C1 to C4, alkoxy groups of C1 to C4, halogen-substituted alkoxy groups of C1 to C4;
n is an integer selected from 0, 1 or 2;
R2selected from hydrogen atoms, halogens, hydroxyl groups, alkyl groups of C1 to C4, halogen-substituted alkyl groups of C1 to C4, alkoxy groups of C1 to C4, halogen-substituted alkoxy groups of C1 to C4;
m is an integer selected from 0, 1 or 2;
R3selected from hydrogen atoms, halogens, alkyl groups of C1 to C4, halogen-substituted alkyl groups of C1 to C4, alkoxy groups of C1 to C4, and halogen-substituted alkoxy groups of C1 to C4.
Preferably, in the compound represented by formula 1 or formula 2,
R1selected from hydrogen atoms, halogens, alkyl groups of C1 to C4, halogen-substituted alkyl groups of C1 to C4, alkoxy groups of C1 to C4, halogen-substituted alkoxy groups of C1 to C4;
n is an integer selected from 0, 1 or 2;
R2selected from hydrogen atoms, halogens, hydroxyl groups, alkyl groups of C1 to C4, halogen-substituted alkyl groups of C1 to C4, alkoxy groups of C1 to C4, halogen-substituted alkoxy groups of C1 to C4;
m is an integer selected from 0, 1 or 2;
R3selected from hydrogen atoms, halogens, alkyl groups of C1 to C4, halogen-substituted alkyl groups of C1 to C4, alkoxy groups of C1 to C4, and halogen-substituted alkoxy groups of C1 to C4.
Further preferably, in the compounds represented by formula 1 to formula 5,
R1、R2and R3Each independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.
Preferably, n is an integer selected from 0 or 1.
Preferably, the halogen is F, Cl or Br.
More preferably, the compound represented by formula 1 according to the present invention is selected from the following compounds:
Figure BDA0003394645140000061
Figure BDA0003394645140000071
according to one aspect of the present invention, it is an object of the present invention to provide a method for preparing compounds represented by formula 1 to formula 5, comprising the steps of:
step 1) is carried out according to the following reaction scheme 1
Figure BDA0003394645140000072
4-chloropyrimidine-5-methyl formate compounds
Figure BDA0003394645140000073
Adding into a reactor, adding solvent for dissolving, and respectively adding triethylamine and reactant(s) ((
Figure BDA0003394645140000074
For example aniline), heated to 100 to 180 ℃, reacted for 10 minutes to 2 hours, spotted to confirm completion of the reaction; slowly pouring the reaction solution into ice water, adjusting the reaction solution to be weakly acidic by using dilute hydrochloric acid under the stirring condition, adjusting the pH value to be 5.0-6.0, continuously stirring for 10-30 minutes, performing suction filtration to obtain a white crude product, and performing medium-pressure chromatographic column separation (dichloromethane and methanol) to obtain a target compound
Figure BDA0003394645140000075
Wherein the substituent X4、X7、X8And X9、R2And R3M is the same as formula 1;
the solvent is selected from dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), tetrahydrofuran, dioxane, acetone, acetonitrile and ethyl acetate.
Step 2) is carried out according to the following reaction scheme 2
Figure BDA0003394645140000081
Reacting formic ester
Figure BDA0003394645140000082
Dissolving in a solvent, adding water, stirring for 1-10 minutes at 0-5 ℃, adding lithium hydroxide monohydrate, continuing stirring for 2-6 hours, and counting plates to monitor the completion of the reaction; adjusting the pH value to be neutral by using dilute hydrochloric acid under the stirring condition; dichloromethane and saturated sodium bicarbonate were addedWashing the organic layer with saturated sodium bicarbonate solution for three times and saturated brine for three times, drying with anhydrous sodium sulfate, and concentrating to obtain the final product
Figure BDA0003394645140000083
Wherein the substituent X4、X7、X8And X9、R2And R3M is the same as formula 1;
the solvent is selected from dioxane, tetrahydrofuran, acetonitrile, acetone, ethanol, methanol, dimethyl sulfoxide, N-dimethylformamide, isopropanol, diethyl ether, benzene and toluene.
Step 3) is carried out according to the following reaction scheme 3
Figure BDA0003394645140000084
Reacting the reactants
Figure BDA0003394645140000085
Dissolving in stirred ethanol, and adding hydrochloride (X) at room temperature1-X2Cl) and triethylamine; refluxing and reacting for 1-6 hours; removing the solvent under reduced pressure, adding water, and stirring for 1-10 min; extracting with dichloromethane for three times, drying with anhydrous sodium sulfate, rotary drying under reduced pressure, and recrystallizing the crude product with isopropanol to obtain the product
Figure BDA0003394645140000091
)；
Wherein the substituent X1、X2、X5And X6、R1And n is as defined in formula 1.
Step 4) is carried out according to the following reaction scheme 4
Figure BDA0003394645140000092
Reacting formic acid reactant
Figure BDA0003394645140000093
Dissolving in solvent, adding 1-hydroxybenzotriazole (HOBt) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC), stirring at room temperature for 1-5 hr, adding the reactant
Figure BDA0003394645140000094
Continuing to react for 1-6 hours, pouring the reaction solution into a saturated sodium bicarbonate aqueous solution after the reaction is finished, adding ethyl acetate, fully oscillating in a separating funnel, standing for layering, washing an organic layer with saturated saline solution for three times, drying with anhydrous sodium sulfate, and performing reduced pressure spin drying to obtain an intermediate product; adding the obtained intermediate product into anhydrous DMF, heating to 100 ℃ for reaction for 20 hours, cooling the reaction liquid to room temperature, adding saturated sodium bicarbonate water solution and ethyl acetate, washing the organic layer twice with water and once with saturated saline solution, drying with anhydrous sodium sulfate, performing reduced pressure spin drying to obtain a crude product, and performing medium-pressure chromatographic column separation (dichloromethane + methanol) to obtain the compound shown in the formula 1;
wherein the substituent X1To X9、R1To R3N and m are as defined for formula 1;
the solvent is selected from DMF, acetonitrile, tetrahydrofuran, DMSO, dioxane, benzene, toluene, dichloromethane, chloroform, ethyl acetate and diethyl ether.
According to one aspect of the present invention, an object of the present invention is to provide use of the compounds represented by formulae 1 to 5 or pharmaceutically acceptable salts thereof in preparing a medicament for treating lung cancer, colorectal cancer, nasopharyngeal cancer, head and neck squamous carcinoma, gastric cancer, esophageal cancer, breast cancer, pancreatic cancer, liver cancer, cervical cancer, ovarian cancer, skin cancer, brain glioma.
According to one aspect of the present invention, it is an object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula 1 according to the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
Detailed Description
Hereinafter, the present invention will be described in detail. Before the description is made, it should be understood that the terms used in the present specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description proposed herein is just a preferable example for the purpose of illustrations only, not intended to limit the scope of the invention, so it should be understood that other equivalents and modifications could be made thereto without departing from the spirit and scope of the invention.
In this document, the terms "comprising," "including," "having," "containing," or any other similar term, are intended to be open-ended franslational phrase (open-ended franslational phrase) and are intended to cover non-exclusive inclusions. For example, a composition or article comprising a plurality of elements is not limited to only those elements recited herein, but may include other elements not expressly listed but generally inherent to such composition or article. In addition, unless expressly stated to the contrary, the term "or" is intended to mean an inclusive "or" rather than an exclusive "or". For example, the condition "a or B" is satisfied in any of the following cases: a is true (or present) and B is false (or not present), a is false (or not present) and B is true (or present), both a and B are true (or present). Furthermore, in this document, the terms "comprising," including, "" having, "" containing, "and" containing "are to be construed as specifically disclosed and to cover both closed and semi-closed conjunctions, such as" consisting of … "and" consisting essentially of ….
All features or conditions defined herein as numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to have covered and specifically disclosed all possible subranges and individual numerical values within the ranges, particularly integer numerical values. For example, a description of a range of "1 to 8" should be considered to have specifically disclosed all subranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, and so on, particularly subranges bounded by all integer values, and should be considered to have specifically disclosed individual values such as 1,2, 3, 4, 5, 6, 7, 8, and so on, within the range. Unless otherwise indicated, the foregoing explanatory methods apply to all matters contained in the entire disclosure, whether broad or not.
If an amount or other value or parameter is expressed as a range, preferred range, or a list of upper and lower limits, it is to be understood that all ranges subsumed therein for any pair of that range's upper or preferred value and that range's lower or preferred value, whether or not such ranges are separately disclosed, are specifically disclosed herein. Further, when a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.
In this context, numerical values should be understood to have the precision of the number of significant digits of the value, provided that the object of the invention is achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.
In this document, where Markush group (Markush group) or Option language is used to describe features or examples of the invention, those skilled in the art will recognize that a sub-group of all elements or any individual element within a Markush group or list of options may also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it is also meant that claims where X is X1 and claims where X is X1 and/or X2 have been fully described. Furthermore, where Markush group or option terms are used to describe features or examples of the invention, those skilled in the art will recognize that any combination of sub-groups of all elements or individual elements within the Markush group or option list can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," this indicates a claim that X is X1, or X2, or X3, and Y is Y1, or Y2, or Y3, as fully described.
Definition of
The definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are determined according to the periodic table of the elements of the CAS edition, handbook of chemistry and physics, 75 th edition, internal cover, and the specific functional groups are generally defined as described therein. Furthermore, the general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in the following books: thomas Sorrell, Organic Chemistry, University Science symposium, Soxhlet, 1999 (Thomas Sorrell, Organic Chemistry, University Science Books, Sausalitio, 1999); smith and March, Advanced Organic Chemistry by March, 5th Edition, John Wiley & Sons, New York, 2001 (Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001); larock, Integrated Organic functional group Transformations, VCH publishing Co., New York, 1989 (Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989); and carrousers, Some Modern Organic Synthesis Methods, 3rd Edition, Cambridge University Press, Cambridge,1987 (Carruthers, Some Modern Methods of Organic Synthesis,3rd Edition, Cambridge University Press, Cambridge, 1987). The present invention is not intended to be limited in any way by the illustrative list of substituents described herein.
The compounds described herein may contain one or more asymmetric centers and may therefore exist in various isomeric forms, such as enantiomers and/or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be isolated from mixtures by methods known to those skilled in the art, including chiral High Pressure Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al, "Enantiomers, Racemates and resolution" (enertiomers, racemes and solutions) (Wiley Interscience, New York, 1981); wilen et al, Tetrahedron (Tetrahedron) 33: 2725 (1977); eliel, Stereochemistry of Carbon Compounds (Stereochemistry of Carbon Compounds) (McGraw-Hill, NY, 1962); and Wilen, "Resolving Agents and Optical resolution" (Tables of Resolving Agents and Optical resolution), page 268 (E.L. Eliel, eds., university Press of Paris san Francisco, IN 1972). The present disclosure additionally encompasses the following compounds described herein: as a single isomer substantially free of other isomers, or as a mixture of various isomers.
The term "alkyl" refers to a group of straight or branched chain saturated hydrocarbon groups having 1 to 6 carbon atoms ("C1–6Alkyl "). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C)1–5Alkyl "). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C)1-4Alkyl "). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C)1-3Alkyl "). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C)1-2Alkyl "). In some embodiments, the alkyl group has 1 carbon atom ("C)1Alkyl "). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C)2-6Alkyl "). C1–6Examples of alkyl groups include methyl (C)1) Ethyl radical (C)2) Propyl radical (C)3) (e.g., n-propyl, isopropyl), butyl (C)4) (e.g., n-butyl, t-butyl, sec-butyl, isobutyl), pentyl (C)5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl) and hexyl (C)6) (e.g., n-hexyl). Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., halo, such as F). In certain embodiments, alkyl is unsubstituted C1-10Alkyl (e.g. unsubstituted C)1-6Alkyl radicals, e.g. -CH3). In certain embodiments, alkyl is substituted C1-10Alkyl (e.g. substituted C)1-6Alkyl radicals, e.g. CF3)。
The term "pharmaceutically acceptable salt" means a salt which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefitThose salts having a benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, in J.pharmaceutical Sciences,1977,66,1-19 by Berge et al, herein incorporated by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid) or by using other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, persilicates, dodecylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, benzoates, bisulfates, salts of hydrogen, 2-hydroxy-ethanesulfonates, lactobionates, lactates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoatates, pectates, persulfates, 3-phenylpropionates, salts of hydrogen, and mixtures of hydrogen, Phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4 -And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in treating a disorder or to delay or minimize one or more symptoms associated with the disorder. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent that provides a therapeutic benefit in treating the condition, alone or in combination with other therapies. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes, and/or enhances the therapeutic efficacy of another therapeutic agent.
The following examples are given by way of illustration of embodiments of the invention and are not to be construed as limiting the invention, and it will be understood by those skilled in the art that modifications may be made without departing from the spirit and scope of the invention. Unless otherwise specified, reagents and equipment used in the following examples are commercially available products.
In addition, unless otherwise indicated, the reagents and solvents disclosed below were purchased from Beijing Yinaoka technologies, Inc. and1h NMR was measured by using a JNM-ECA-400C superconducting Nuclear Magnetic Resonance (NMR) spectrometer (Japan Electron Co., Ltd.). Mass spectra were measured using an AB Sciex API 3000 LC MS.
Preparation examples: preparation of Compound 21
Figure BDA0003394645140000131
Step 1)
Figure BDA0003394645140000132
Methyl 4-chloropyrimidine-5-carboxylate (172.0mg,1.0mmol) was put into a microwave tube, 3.5ml of DMSO was added and dissolved, and triethylamine (505.0mg, 5.0mmol) and aniline (186.0mg, 2.0mmol) were added, respectively. The reaction was heated to 150 ℃ by microwave for 15 minutes and the reaction was confirmed to be complete by spotting. Slowly pouring the reaction solution into 20ml of ice water, stirring diluted hydrochloric acid to adjust the pH value to be subacidity, continuously stirring for 20 minutes, and performing suction filtration to obtain white coarse powderThe product was subjected to medium pressure chromatography (dichloromethane + methanol) to give 155.7mg of the objective compound in 65.7% yield.1HNMR(400MHz,CDCl3)δ8.84(s,1H),8.35(s,1H),7.80(s,1H),7.65(d,J＝8.8Hz,2H),7.25(t,J＝14.6Hz,2H),6.91(t,J＝8.4Hz,1H),3.65(s,3H)。MS：230.3[M+H]+。
Step 2)
Figure BDA0003394645140000133
4-anilinopyrimidine-5-carboxylic acid methyl ester (229.0mg, 1.0mmol) was dissolved in dioxane (15.0ml), water (1.0ml) was added, stirring was carried out at 0 ℃ for 3 minutes, lithium hydroxide monohydrate (126.0mg, 3.0mmol) was added, stirring was continued for 3 hours, and the reaction was monitored by dot plate for completion. And (3) adjusting the pH of the solution to be neutral by using dilute hydrochloric acid. Dichloromethane (15.0ml) and a saturated aqueous solution of sodium hydrogencarbonate (10.0ml) were added, followed by vigorous shaking, separation with a separatory funnel, washing of the organic layer with a saturated aqueous solution of sodium hydrogencarbonate (3X 10ml) and saturated brine (10.0ml), and drying over anhydrous sodium sulfate. Concentration to obtain 150.5mg of 4-anilinopyrimidine-5-carboxylic acid with a yield of 70.5%.1HNMR(400MHz,CDCl3)δ11.78(s,1H),8.82(s,1H),8.37(s,1H),7.65(d,J＝8.8Hz,2H),7.20(t,J＝16.2Hz,2H),6.93(t,J＝8.6Hz,1H)。MS：216.2[M+H]+。
Step 3)
Figure BDA0003394645140000134
Benzonitrile (206mg,2.0mmol) was dissolved in stirred ethanol (10ml), and hydroxylamine hydrochloride (417.0mg, 6.0mmol) and triethylamine (1010.0mg,10.0mmol) were added at room temperature. The reaction was refluxed for 3 hours. The solvent was removed under reduced pressure, water (20ml) was added, and stirring was carried out for 5 minutes. Dichloromethane (3X 10ml) was extracted, dried over anhydrous sodium sulfate and spun dry under reduced pressure. The crude product was recrystallized from isopropanol to yield 232.0mg of a white solid (85.3% yield).1HNMR(400MHz,CDCl3)δ9.80(s,1H),7.69(d,J＝8.4Hz,2H),7.51(m,3H),5.90-5.53(m,2H)。MS：137.1[M+H]+。
Step 4)
Figure BDA0003394645140000141
4-anilinopyrimidine-5-carboxylic acid (100.0mg, 0.47mmol) was dissolved in anhydrous DMF (5.0ml), 1-hydroxybenzotriazole (HOBt, 951.8mg, 7.05mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC, 1092.8mg, 7.05mmol) were added, stirring was carried out at room temperature for 2.5 hours, benzylaminoxime (958.8mg, 7.05mmol) was added, the reaction was continued for 3 hours, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (20ml), ethyl acetate (20ml) was added, shaking was sufficiently carried out in a separatory funnel, the layers were allowed to stand, the organic layer was washed with saturated brine (3X 10ml), dried over anhydrous sodium sulfate, and spin-dried under reduced pressure to obtain an intermediate product. This intermediate product was added to anhydrous DMF (2.0ml), heated to 100 ℃ for reaction for 20 hours, the reaction solution was cooled to room temperature, a saturated aqueous sodium bicarbonate solution (10ml) and ethyl acetate (10ml) were added, the organic layer was washed with water (2X 5ml) and saturated brine (5ml), dried over anhydrous sodium sulfate, and spin-dried under reduced pressure to give 120.5mg of a crude product. Medium pressure chromatography (dichloromethane + methanol) column gave 80.1mg of solid, 54.1% yield.1HNMR(400MHz,CDCl3)δ8.40(s,1H),8.04(d,J＝8.4Hz,2H),7.96(s,1H),7.87(d,J＝8.4Hz,2H),7.51(m,4H),7.35(t,J＝8.8Hz,2H),6.95(t,J＝8.4Hz,1H)。MS：316.3[M+H]+。
Example 1: 4-m-fluoroanilino-5- (3-phenyl-1, 2, 4-oxadiazol-5-yl) pyrimidine (Compound 1)
Figure BDA0003394645140000142
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
4-Chloropyrimidine-5-carboxylic acid methyl ester (172.0mg,1.0mmol), m-fluoroaniline (133.2mg,1.2mmol), benzonitrile (206mg,2.0mmol) to give product 200.5, yield: 60.2 percent
1HNMR(400MHz,CDCl3)δ8.42(s,1H),7.96(s,1H),7.85(d,J＝8.4Hz,2H),7.76(s,1H),7.52(m,4H),7.41(d,J＝8.4Hz,1H),7.30(t,J＝8.8Hz,1H),6.76(d,J＝8.8Hz,1H)。MS：334.4[M+H]+。
Example 2: 4-m-chloroanilino-5- [3- (2-pyridine) -1,2, 4-oxadiazol-5-yl ] pyrimidine (Compound 2)
Figure BDA0003394645140000143
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
methyl 4-chloropyrimidine-5-carboxylate (172.0mg,1.0mmol), m-chloroaniline (133.2mg,1.2mmol), 2-cyanopyridine (208.0mg,2.0mmol) gave the product 204.5mg, yield: 58.3 percent.
1HNMR(400MHz,CDCl3)δ8.62(d,J＝8.4Hz,1H),8.42(s,1H),8.31(d,J＝8.8Hz,2H),7.96(s,1H),7.85(d,J＝8.4Hz,2H),7.52(m,3H),7.41(s,1H),7.25(t,J＝8.8Hz,1H),6.85(d,J＝8.8Hz,1H)。MS：351.8[M+H]+。
Example 34-m-Chloroanilino-5- [3- (p-chlorophenyl) -1,2, 4-oxadiazol-5-yl ] pyrimidine (Compound 3)
Figure BDA0003394645140000151
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
methyl 4-chloropyrimidine-5-carboxylate (172.0mg,1.0mmol), m-chloroaniline (133.2mg,1.2mmol), p-chlorobenzonitrile (275.0mg,2.0mmol) gave 301.8mg of product, yield: 78.5 percent.
1HNMR(400MHz,CDCl3)δ8.45(s,1H),8.20(d,J＝8.6Hz,2H),7.96(s,1H),7.61(d,J＝8.4Hz,2H),7.52(d,J＝8.6Hz,1H),7.48(s,1H),7.42(s,1H),7.25(t,J＝8.8Hz,1H),6.87(d,J＝8.8Hz,1H)。MS：384.1[M+H]+。
Example 44-m-Chloroanilino-5- [3- (o-methylphenyl) -1,2, 4-oxadiazol-5-yl ] pyrimidine (Compound 4)
Figure BDA0003394645140000152
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
4-Chloropyrimidine-5-carboxylic acid methyl ester (172.0mg,1.0mmol), m-chloroaniline (133.2mg,1.2mmol), o-methylbenzonitrile (234.0mg,2.0mmol) to give the product 292.1mg, yield: 80.3 percent.
1HNMR(400MHz,CDCl3)δ8.44(s,1H),7.96(s,1H),7.71(d,J＝8.8Hz,1H),7.52(d,J＝8.6Hz,1H),7.48(s,1H),7.40(s,1H),7.37(t,J＝8.6Hz,1H),7.35(d,J＝8.4Hz,1H),7.30(t,J＝8.6Hz,1H),7.23(t,J＝8.8Hz,1H),6.91(d,J＝8.8Hz,1H),2.56(s,3H)。MS：364.1[M+H]+。
Example 54-m-Chloroanilino-5- [3- (5-pyrimidinyl) -1,2, 4-oxadiazol-5-yl ] pyrimidine (Compound 5)
Figure BDA0003394645140000161
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
methyl 4-chloropyrimidine-5-carboxylate (172.0mg,1.0mmol), m-chloroaniline (133.2mg,1.2mmol), 5-cyanopyrimidine (210.0mg,2.0mmol) to give the product 241.1mg, yield: 68.6 percent.
1HNMR(400MHz,CDCl3)δ9.41(s,1H),9.32(s,2H),8.43(s,1H),7.94(s,1H),7.52(d,J＝8.6Hz,1H),7.48(s,1H),7.42(s,1H),7.23(t,J＝8.8Hz,1H),6.90(d,J＝8.8Hz,1H)。MS：352.5[M+H]+。
Example 64-m-bromophenyl-5- (3-phenyl-1, 2, 4-oxadiazol-5-yl) pyrimidine (Compound 6)
Figure BDA0003394645140000162
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
methyl 4-chloropyrimidine-5-carboxylate (172.0mg,1.0mmol), m-bromoaniline (258.0mg,1.5mmol), benzonitrile (234.0mg,2.0mmol) to give 292.1mg of product, yield: 80.3 percent.
1HNMR(400MHz,CDCl3)δ8.42(s,1H),7.96(s,1H),7.87(d,J＝8.4Hz,2H),7.52(m,4H),7.56(d,J＝8.4Hz,1H),7.29(d,J＝8.8Hz,1H),7.21(s,1H),7.00(t,J＝8.8Hz,1H)。MS：394.2[M+H]+。
Example 74-Metaxylidino-5- (3-phenyl-1, 2, 4-oxadiazol-5-yl) pyrimidine (Compound 7)
Figure BDA0003394645140000163
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
methyl 4-chloropyrimidine-5-carboxylate (172.0mg,1.0mmol), m-dimethylaniline (181.5mg,1.5mmol), benzonitrile (206mg,2.0mmol) to give 273.4mg of product, yield: 79.7 percent.
1HNMR(400MHz,CDCl3)δ8.43(s,1H),7.97(s,1H),7.85(d,J＝8.4Hz,2H),7.76(s,1H),7.50(m,4H),7.38(s,1H),6.98(s,1H),2.15(s,6H)。MS：344.3[M+H]+。
Example 84-m-hydroxyanilino-5- (3-phenyl-1, 2, 4-oxadiazol-5-yl) pyrimidine (Compound 8)
Figure BDA0003394645140000171
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
methyl 4-chloropyrimidine-5-carboxylate (172.0mg,1.0mmol), m-hydroxyaniline (163.5mg,1.5mmol), benzonitrile (206mg,2.0mmol) to give 163.8mg of product, yield: 49.5 percent.
1HNMR(400MHz,CDCl3)δ8.42(s,1H),7.96(s,1H),7.85(d,J＝8.4Hz,2H),7.52(m,4H),7.20(d,J＝8.4Hz,1H),7.05(t,J＝8.8Hz,1H),6.66(s,1H),6.61(d,J＝8.6Hz,1H)。MS：332.1[M+H]+。
Example 94 o-toluidino-5- (3-phenyl-1, 2, 4-oxadiazol-5-yl) pyrimidine (Compound 9)
Figure BDA0003394645140000172
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
methyl 4-chloropyrimidine-5-carboxylate (172.0mg,1.0mmol), m-methylaniline (163.5mg,1.5mmol), benzonitrile (206mg,2.0mmol) to give 182.6mg of the product, yield: 55.5 percent.
1HNMR(400MHz,CDCl3)δ8.46(s,1H),7.93(s,1H),7.87(d,J＝8.4Hz,2H),7.76(s,1H),7.52(m,4H),7.18(m,3H),6.81(t,J＝8.4Hz,1H),2.13(s,3H)。MS：330.1[M+H]+。
Example 104- (3-pyridylamino) -5- (3-phenyl-1, 2, 4-oxadiazol-5-yl) pyrimidine (Compound 10)
Figure BDA0003394645140000173
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
methyl 4-chloropyrimidine-5-carboxylate (172.0mg,1.0mmol), m-aminopyridine (141.0mg,1.5mmol), benzonitrile (206mg,2.0mmol) gave 190.8mg of product, yield: 60.4 percent.
1HNMR(400MHz,CDCl3)δ8.41(s,1H),8.04(s,1H),7.96(s,1H),7.92(s,1H),7.87(d,J＝8.4Hz,2H),7.51(m,3H),7.36(t,J＝8.4Hz,1H),7.11(d,J＝8.4Hz,1H)。MS：317.1[M+H]+。
Example 114-m-chlorophenol-5- (3-phenyl-1, 2, 4-oxadiazol-5-yl) pyrimidine (Compound 11)
Figure BDA0003394645140000181
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
methyl 4-chloropyrimidine-5-carboxylate (172.0mg,1.0mmol), m-chlorophenol (192.8mg,1.5mmol), benzonitrile (206mg,2.0mmol) to give 300.7mg of product, yield: 85.8 percent.
1HNMR(400MHz,CDCl3)δ8.42(s,1H),8.21(s,1H),7.85(d,J＝8.4Hz,2H),7.15(s,1H),7.52(m,3H),7.21(t,J＝8.8Hz,1H),6.94(d,J＝8.4Hz,1H),6.79(d,J＝8.8Hz,1H)。MS：351.5[M+H]+
Example 124-m-methylthiophenol-5- (3-phenyl-1, 2, 4-oxadiazol-5-yl) pyrimidine (Compound 12)
Figure BDA0003394645140000182
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
methyl 4-chloropyrimidine-5-carboxylate (172.0mg,1.0mmol), m-methylthiophenol (186.0mg,1.5mmol), benzonitrile (206mg,2.0mmol) to give 254.7mg of product, yield: 73.6 percent.
1HNMR(400MHz,CDCl3)δ8.95(s,1H),8.36(s,1H),7.85(d,J＝8.4Hz,2H),7.50(m,3H),7.31(d,J＝8.4Hz,1H),7.15(t,J＝8.8Hz,1H),7.10(s,1H),6.76(d,J＝8.8Hz,1H)，2.35(s,1H)。MS：347.1[M+H]+
Example 132-methyl-4-m-chloroanilino-5- (3-phenyl-1, 2, 4-oxadiazol-5-yl) pyrimidine (Compound 13)
Figure BDA0003394645140000183
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
methyl 4-chloro-2-methylpyrimidine-5-carboxylate (186.5mg,1.0mmol), m-chloroaniline (133.2mg,1.2mmol), benzonitrile (206.0mg,2.0mmol) to give 327.8mg of product, yield: 90.1 percent.
1HNMR(400MHz,CDCl3)δ8.50(s,1H),7.87(d,J＝8.4Hz,2H),7.51(m,4H),7.41(d,J＝8.4Hz,1H),7.20(t,J＝8.8Hz,1H),6.89(d,J＝8.6Hz,1H),2.54(s,3H)。MS：364.5[M+H]+
Example 142-m-chloroanilino-3- (3-phenyl-1, 2, 4-oxadiazol-5-yl) pyridine (compound 14)
Figure BDA0003394645140000191
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
methyl 2-chloro-pyridine-3-carboxylate (171.5mg,1.0mmol), m-chloroaniline (133.2mg,1.2mmol), benzonitrile (206.0mg,2.0mmol) to give 187.5mg of product, yield: 53.8 percent
1HNMR(400MHz,CDCl3)δ8.12(d,J＝8.4Hz,1H),7.85(d,J＝8.4Hz,2H),7.78(d,J＝8.4Hz,1H),7.52(m,4H),7.41(d,J＝8.4Hz,1H),7.39(s,1H),7.20(t,J＝8.8Hz,1H),6.96(d,J＝8.8Hz,1H)。MS：349.5[M+H]+
Example 151-m-chloroanilino-2- (3-phenyl-1, 2, 4-oxadiazol-5-yl) benzene (compound 15)
Figure BDA0003394645140000192
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
methyl 2-chlorobenzoate (1170.5mg,1.0mmol), m-chloroaniline (133.2mg,1.2mmol), benzonitrile (206.0mg,2.0mmol) gave 152.2mg of product, yield: 43.8 percent
1HNMR(400MHz,CDCl3)δ7.85(d,J＝8.4Hz,2H),7.73(d,J＝8.4Hz,1H),7.37(d,J＝8.6Hz,1H),7.52(m,4H),7.43(d,J＝8.4Hz,1H),7.39(s,1H),7.20(t,J＝8.8Hz,1H),7.16(t,J＝8.6Hz,1H),6.96(d,J＝8.8Hz,1H)。MS：348.5[M+H]+
Example 164-m-Chloroanilino-5- (3-phenyl-4H-imidazol-5-yl) pyrimidine (Compound 16)
Figure BDA0003394645140000201
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
Figure BDA0003394645140000202
4, 6-chloro-5- (2' -bromoacetonyl) pyrimidine (270.0mg,1.0mmol) was dissolved in DMF (5ml), benzamidine hydrochloride (349.0mg,2.0mmol) was added, the mixture was heated to 60 ℃ for 2.5 hours, and the reaction was monitored by a dot plate for completion. Pouring the reaction solution into ice water (15ml), stirring, adding saturated sodium bicarbonate aqueous solution to adjust the pH value to be neutral, separating out white solid, continuing stirring in ice water bath for 15 minutes, filtering, washing with water, and drying to obtain 248.2mg of a product with the yield of 85.6%. MS: 291.2[ M + H ]]+。
Figure BDA0003394645140000203
145.0mg,0.5mmol of the product obtained in the previous step was dissolved in DMF (2.5ml), and 3.0mg of palladium acetate, cesium carbonate (325.0mg,1.0 mmol) and m-chloroaniline (77.0mg,0.6mmol) were added and the mixture was heated by microwave to 140 ℃ for 20 minutes, followed by spotting and monitoring, and the reaction was terminated. Poured into ice water, and the pH value is adjusted to be weak acidity. Stirring for 5 min to separate out solid, suction filtering, water washing and drying. The crude product was isolated by medium pressure column (dichloromethane: ethyl acetate 10:1) to give 128.8mg of a white solid in 67.8% yield.
1HNMR(400MHz,CDCl3)δ8.50(s,1H),8.21(s,1H),7.76(s,1H),7.51(m,4H),7.40(d,J＝8.4Hz,1H),7.20(t,J＝8.8Hz,1H),6.85(d,J＝8.8Hz,1H),4.22(s,2H)。MS：382.4[M+H]+。
Example 174-m-chloroanilino-5- (3-phenyl-1, 2, 4-triazol-5-yl) pyrimidine (Compound 17)
Figure BDA0003394645140000204
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
Figure BDA0003394645140000211
a, reaction: 4-m-chloroanilino-5-pyrimidine formate (249mg,1.0mmol) was added to thionyl chloride (5ml), heated under reflux for 1 hour, and spin-dried under reduced pressure to give 258mg of the crude acid chloride compound.
B, reaction: 258mg of the crude acid chloride compound was dissolved in methylene chloride (5ml), triethylamine (202mg,2.0mmol) and tert-butyloxycarbonyl hydrazine (264mg,2.0mmol) were added, and the reaction was allowed to react at room temperature for 2 hours, followed by spotting to monitor the completion of the reaction. The reaction mixture was washed with water (3X 5ml) and saturated brine (5ml), and dried over anhydrous sodium sulfate. Spin-drying to obtain crude product 700.0mg, and pure product 566.3mg separated by medium-pressure column, with yield 78.3%. MS: 364.5[ M + H ] +.
C, reaction: the product from B (500mg,1.4mmol) was dissolved in dichloromethane (5ml) and added to trifluoroacetic acid (1.0ml) and stirred at room temperature for 1 hour, and the reaction was monitored by dot-plate for completion. 1N sodium hydroxide aqueous solution was added to adjust the pH to weak alkaline, and dichloromethane (5ml) was further added, and the solution was washed with saturated brine (3X 5ml), dried over anhydrous sodium sulfate, spin-dried, and subjected to medium-pressure column separation (dichloromethane: methanol: 98:2) to obtain 302.5mg of a solid in 82.2% yield. MS: 264.5[ M + H ] +.
Figure BDA0003394645140000212
4-m-chloroanilino-5-formylhydrazinopyrimidine (264.0mg,1.0mmol) and purchased benzamidine (180mg,1.5mmol) were mixed and added to melt, reacted for 10 minutes, cooled to room temperature, and subjected to medium-pressure column separation (dichloromethane: methanol ═ 98:2) to obtain 213.6mg of the objective 4-m-chloroanilino-5- (3-phenyl-1, 2, 4-triazol-5-yl) pyrimidine in a yield of 61.3%.
1HNMR(400MHz,CDCl3)δ8.42(s,1H),8.10(d,J＝8.4Hz,2H),7.96(s,1H),7.76(s,1H),7.52(m,2H),7.47(t,J＝8.6Hz,2H),7.41(d,J＝8.4Hz,1H),7.25(t,J＝8.8Hz,1H),6.89(d,J＝8.4Hz,1H)。MS：349.5[M+H]+。
Example 184-m-Chloroanilino-5- (3-phenyl-1, 2, 4-thiadiazol-5-yl) pyrimidine (Compound 18)
Figure BDA0003394645140000213
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
Figure BDA0003394645140000221
4-m-Chloroanilino-5-carboxylic acid methyl ester pyrimidine (789.0mg,3.0mmol) was dissolved in dry THF (10ml) and cooled to 0-5 ℃. LiBH4(132.0mg,6.0mmol) was added portionwise and reacted at 0-5 ℃ for 5 hours. Adding 5 drops of water, stirring for 10 minutes, carrying out rotary evaporation under reduced pressure, and separating a crude product by using a medium-pressure column (petroleum ether: ethyl acetate: 4:1) to obtain 360.7mg of the target product, namely 4-m-chloroanilino-5-aldehyde pyrimidine, wherein the yield is 51.6%.
Figure BDA0003394645140000222
4-m-chloroanilino-5-formylpyrimidine (100mg,0.43mmol) was dissolved in dimethyl sulfoxide (3ml), benzamidine hydrochloride (151.0mg,0.86mmol), sulfur powder (69.0mg,2.15mmol), tripotassium phosphate trihydrate (343.1mg,1.29mmol) were added, and the mixture was heated to 130 ℃ in the air and reacted for 15 hours. And (5) carrying out plate counting monitoring and finishing the reaction. After cooling to room temperature, DMSO was removed under reduced pressure, and the residue was separated by medium-pressure column (petroleum ether: ethyl acetate: 8:1) to obtain 129.7mg of the objective product in 82.5% yield.
1HNMR(400MHz,CDCl3)δ8.43(s,1H),8.25(d,J＝8.6Hz,2H),7.96(s,1H),7.61(s,1H),7.50(m,4H),7.41(d,J＝8.4Hz,1H),7.22(t,J＝8.6Hz,1H),6.96(d,J＝8.8Hz,1H)。MS：366.4[M+H]+。
Example 194 m-Chloroanilino-5- (5-phenyl-pyrrol-5-yl) pyrimidine (Compound 19)
Figure BDA0003394645140000223
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
Figure BDA0003394645140000224
4, 6-chloro-5- (2' -bromoacetonyl) pyrimidine (270.0mg,1.0mmol) was dissolved in methanol (9ml), an aqueous solution of hydroxylamine hydrochloride (208.5mg,3.0mmol, 1ml of water) was added, and the reaction was allowed to react at 30 ℃ for 10 hours, and the reaction was monitored by a dot plate for completion. The reaction mixture was spin-dried under reduced pressure, 5ml of water was added thereto, the mixture was stirred for 5 minutes, methylene chloride was extracted (3X 5ml), and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Spin-dry under reduced pressure to give 218.7mg of a white solid, 77.3% yield. MS: 283.9[ M + H]+
Figure BDA0003394645140000231
Dissolving the product (150mg,0.5 mmol) in anhydrous ether (5ml), adding tributyl phosphorus (PBu3,121.2mg,0.6mmol), reacting at 30 deg.C for 10 hr, vacuum drying, adding anhydrous tetrahydrofuran (5ml), adding 7-methyl-1, 5, 7-triazabicyclo [4.4.0 ] N]Deca-5-ene (MTBD,306.0mg,2.0mmol), benzoyl chloride (112.4mg,0.8mmol), reacted at 30 ℃ for 5 hours, monitored by a point plate, dried under reduced pressure, and the crude product was isolated under medium pressure (dichloromethane: ethyl acetate ═ 10:1) to give the desired product 991mg, yield 67.9%. MS: 292.1[ M + H]+
Figure BDA0003394645140000232
146.0mg,0.5mmol of the product obtained in the previous step was dissolved in DMF (3.0ml), and 3.0mg of palladium acetate, cesium carbonate (325.0mg,1.0 mmol) and m-chloroaniline (77.0mg,0.6mmol) were added and the mixture was heated to 135 ℃ by microwave for 20 minutes, followed by spotting and monitoring, and the reaction was completed. Poured into ice water, and the pH value is adjusted to be weak acidity. Stirring for 5 min to separate out solid, suction filtering, water washing and drying. The crude product was isolated by medium pressure column (dichloromethane: ethyl acetate 10:1) to give 102.7mg of a white solid in 53.7% yield.
1HNMR(400MHz,CDCl3)δ8.72(s,1H),8.07(d,J＝8.6Hz,2H),7.60(m,3H),7.51(d,J＝8.4Hz,1H),7.40(s,1H),7.19(t,J＝8.8Hz,1H),6.97(d,J＝8.8Hz,1H),6.62(s,1H)。MS：383.4[M+H]+。
Example 204-m-Chloroanilino-5- (3-phenyl-pyrazol-5-yl) pyrimidine (Compound 20)
Figure BDA0003394645140000233
The corresponding compounds were prepared in a similar manner to the preparation examples, except that the corresponding reactants were used as follows:
Figure BDA0003394645140000234
methyl 4-chloropyrimidine-5-carboxylate (172.0mg,1.0mmol) was dissolved in toluene (8ml), phenylmethylketone (180mg,1.5mmol) was added, 60% sodium hydride (80mg,2.0mmol) was added at 0 ℃ and the reaction was continued overnight at 0 ℃ with slow warming to 85 ℃. After the reaction was almost complete, the reaction was cooled to room temperature, 2 drops of water were slowly added, the mixture was dried under reduced pressure, and the residue was separated by medium pressure column (petroleum ether: ethyl acetate: 10:1) to obtain 106.5mg of a white solid with a yield of 41.1%. MS: 261.5[ M + H]+
Figure BDA0003394645140000241
The product (100mg,0.38mmol) obtained in the above step was dissolved in methanol (7ml), semicarbazide hydrochloride (85mg,0.76mmol) was added, and the mixture was refluxed for 25 hours. The residue was subjected to spin-drying under reduced pressure and subjected to medium-pressure column separation (petroleum ether: ethyl acetate: 4:1) to obtain 97.5mg of a product in 38.1% yield. MS: 257.5[ M + H]+
Figure BDA0003394645140000242
The product (100mg,0.39mmol) obtained in the above step was dissolved in t-butanol (5ml), and a saturated ethyl hydrogen chloride solution (1ml) was added to reflux the solution for 5 hours. Cooling precipitated a solid, which was suspended in 5% aqueous sodium hydrogencarbonate (10ml), extracted with ethyl acetate (3X 10ml), the organic layers were combined and washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried under reduced pressure, and the residue was subjected to medium-pressure column separation (dichloromethane), to give 39.0mg of a product, yield 28.8%.
1HNMR(400MHz,CDCl3)δ11.89(s,1H),8.39(s,1H),8.01(d,J＝8.6Hz,2H),7.96(s,1H),7.56(m,3H),7.51(d,J＝8.4Hz,1H),7.40(s,1H),7.19(t,J＝8.8Hz,1H),6.91(d,J＝8.8Hz,1H),6.70(s,1H)。MS：348.5[M+H]+。
Test examples: enzyme Activity assay
Experimental procedure
The compounds to be tested were diluted in DMSO in 4-fold gradient from 2mM onwards, at 10 concentrations. The diluted compound was diluted 40-fold into dilution buffer and mixed well by shaking on a plate shaker. mu.L of 2.5 Xkinase EGFR (Carna, Cat: 08-115) was transferred to 384 reaction plates, 1. mu.L of 5 Xtest compound was added to 384 reaction plates, 1000rpm/min, centrifuged for 1min, and incubated at 25 ℃ for 10 min. Transfer 2. mu.L of 2.5 Xsubstrate mixture to 384 reaction plates, 1000rpm/min, centrifuge for 1min, and incubate for 60 min at 25 ℃. Wherein the final concentration of EGFR system is 0.2nM, the final concentration of ATP is 2 μ M, the final concentration of TK substrate is 1 μ M, and the final concentration of DMSO is 0.5%. A2 xSa-XL 665/TK-antisense-Cryptate mixed solution is prepared by using HTRF detection buffer solution. mu.L of Sa-XL 665/TK-antisense-Cryptate was added to each well, centrifuged at 1000g for 30 seconds, and reacted at room temperature for 1 hour. The fluorescence signals at 615nm (Cryptate and 665nm (XL 665)) were read with a high throughput multi-functional microplate reader (BMG, PHERAStar FSX) and the Ratio (Flu665/Flu615 x 10000) was calculated, the specific compound activity data are shown in Table 1.
Table 1: EGFR enzyme inhibitory Activity of Compounds according to the invention
Compound (I) IC50 nM Compound (I) IC50 nM
1 8.00 11 413.86
2 35.20 12 >1000
3 18.90 13 278.13
4 90.52 14 922.68
5 300.51 15 832.19
6 12.30 16 603.95
7 512.67 17 8.12
8 15.51 18 17.64
9 850.14 19 957.33
10 700.35 20 882.46
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (11)

1. A compound represented by formula 1:
Figure FDA0003394645130000011
wherein, X1、X2、X3、X5、X6And X7Each independently selected from C, N, O and S atom, X4Selected from C, NH, O and S atoms, X8And X9Each independently selected from C and N atoms;
R1selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
n is an integer selected from 0, 1,2, 3 or 4;
R2selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
m is an integer selected from 0, 1,2, 3 or 4;
R3selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
preferably, X1、X2And X3At least two of which are not C atoms;
preferably, X1And/or X2Is an N or O atom.
2. The compound represented by formula 1 and a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by formula 1 and a pharmaceutically acceptable salt thereof are represented by the following formula 2:
Figure FDA0003394645130000012
wherein, X1、X2、X5、X6And X7Each independently selected from C, N, O and S atom, X4Selected from C, NH, O and S atoms, X8And X9Each independently selected from C and N atoms;
R1selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
n is an integer selected from 0, 1,2, 3 or 4;
R2selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
m is an integer selected from 0, 1,2, 3 or 4;
R3selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
preferably, X1And/or X2Is an N or O atom.
3. The compound represented by formula 1 and a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by formula 1 and a pharmaceutically acceptable salt thereof are represented by the following formula 3:
Figure FDA0003394645130000021
wherein, X1、X2、X5、X6And X7Each independently selected from C, N, O and S atom, X4Selected from the group consisting of C, NH, O and S atoms;
R1selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
n is an integer selected from 0, 1,2, 3 or 4;
R2selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
m is an integer selected from 0, 1,2, 3 or 4;
R3selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
preferably, X1And/or X2Is an N or O atom.
4. The compound represented by formula 1 and a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by formula 1 and a pharmaceutically acceptable salt thereof are represented by the following formula 4:
Figure FDA0003394645130000031
wherein, X5、X6And X7Each independently selected from C, N, O and S atom, X4Selected from C, NH, O and S atoms, X8And X9Each independently selected from C and N atoms;
R1selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
n is an integer selected from 0, 1,2, 3 or 4;
R2selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
m is an integer selected from 0, 1,2, 3 or 4;
R3selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, and halogen-substituted alkoxy groups of C1 to C6.
5. The compound represented by formula 1 and a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by formula 1 and a pharmaceutically acceptable salt thereof are represented by the following formula 5:
Figure FDA0003394645130000032
wherein, X5、X6And X7Each independently selected from C, N, O and S atom, X4Selected from the group consisting of C, NH, O and S atoms;
R1selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
n is an integer selected from 0, 1,2, 3 or 4;
R2selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, halogen-substituted alkoxy groups of C1 to C6;
m is an integer selected from 0, 1,2, 3 or 4;
R3selected from hydrogen atoms, halogens, cyano, hydroxyl, alkyl groups of C1 to C6, halogen-substituted alkyl groups of C1 to C6, alkoxy groups of C1 to C6, and halogen-substituted alkoxy groups of C1 to C6.
6. The compounds represented by formulae 1 to 5 according to any one of claims 1 to 5 and pharmaceutically acceptable salts thereof, wherein,
R1selected from hydrogen atom, halogen, alkyl of C1 to C4, halogen substituted alkyl of C1 to C4, alkyl of C1 to C4Oxy, halogen-substituted alkoxy of C1 to C4;
n is an integer selected from 0, 1 or 2;
R2selected from hydrogen atoms, halogens, hydroxyl groups, alkyl groups of C1 to C4, halogen-substituted alkyl groups of C1 to C4, alkoxy groups of C1 to C4, halogen-substituted alkoxy groups of C1 to C4;
m is an integer selected from 0, 1 or 2;
R3selected from hydrogen atoms, halogens, alkyl groups of C1 to C4, halogen-substituted alkyl groups of C1 to C4, alkoxy groups of C1 to C4, halogen-substituted alkoxy groups of C1 to C4;
preferably, the first and second electrodes are formed of a metal,
R1selected from hydrogen atoms, halogens, alkyl groups of C1 to C4, halogen-substituted alkyl groups of C1 to C4, alkoxy groups of C1 to C4, halogen-substituted alkoxy groups of C1 to C4;
n is an integer selected from 0, 1 or 2;
R2selected from hydrogen atoms, halogens, hydroxyl groups, alkyl groups of C1 to C4, halogen-substituted alkyl groups of C1 to C4, alkoxy groups of C1 to C4, halogen-substituted alkoxy groups of C1 to C4;
m is an integer selected from 0, 1 or 2;
R3selected from hydrogen atoms, halogens, alkyl groups of C1 to C4, halogen-substituted alkyl groups of C1 to C4, alkoxy groups of C1 to C4, and halogen-substituted alkoxy groups of C1 to C4.
7. The compounds represented by formulae 1 to 5 according to any one of claims 1 to 5 and pharmaceutically acceptable salts thereof, wherein,
R1、R2and R3Each independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.
Preferably, n is an integer selected from 0 or 1;
preferably, the halogen is F, Cl or Br.
8. The compound represented by formula 1 to formula 5 and a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the compound represented by formula 1 to formula 5 and a pharmaceutically acceptable salt thereof are selected from the group consisting of:
Figure FDA0003394645130000051
9. a method for preparing a compound represented by formula 1 to formula 5 and a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, comprising the steps of:
step 1) is carried out according to the following reaction scheme 1
Figure FDA0003394645130000061
4-chloropyrimidine-5-methyl formate compounds
Figure FDA0003394645130000062
Adding into a reactor, adding solvent for dissolving, and respectively adding triethylamine and reactant(s) ((
Figure FDA0003394645130000063
For example aniline), heated to 100 to 180 ℃, reacted for 10 minutes to 2 hours, spotted to confirm completion of the reaction; slowly pouring the reaction solution into ice water, adjusting the reaction solution to be weakly acidic by using dilute hydrochloric acid under the stirring condition, adjusting the pH value to be 5.0-6.0, continuously stirring for 10-30 minutes, performing suction filtration to obtain a white crude product, and performing medium-pressure chromatographic column separation (dichloromethane and methanol) to obtain a target compound
Figure FDA0003394645130000064
Wherein the substituent X4、X7、X8And X9、R2And R3M is the same as formula 1 of claim 1;
the solvent is selected from dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), tetrahydrofuran, dioxane, acetone, acetonitrile and ethyl acetate;
step 2) is carried out according to the following reaction scheme 2
Figure FDA0003394645130000065
Figure FDA0003394645130000071
Reacting formic ester
Figure FDA0003394645130000072
Dissolving in a solvent, adding water, stirring for 1-10 minutes at 0-5 ℃, adding lithium hydroxide monohydrate, continuing stirring for 2-6 hours, and counting plates to monitor the completion of the reaction; adjusting the pH value to be neutral by using dilute hydrochloric acid under the stirring condition; adding dichloromethane and saturated aqueous solution of sodium bicarbonate, shaking, washing, separating with separating funnel, washing organic layer with saturated aqueous solution of sodium bicarbonate for three times and saturated saline solution for three times, drying with anhydrous sodium sulfate, and concentrating to obtain product
Figure FDA0003394645130000073
Wherein the substituent X4、X7、X8And X9、R2And R3M is the same as formula 1 of claim 1;
the solvent is selected from dioxane, tetrahydrofuran, acetonitrile, acetone, ethanol, methanol, dimethyl sulfoxide, N-dimethylformamide, isopropanol, diethyl ether, benzene and toluene;
step 3) is carried out according to the following reaction scheme 3
Figure FDA0003394645130000074
Reacting the reactants
Figure FDA0003394645130000075
Adding the mixture into stirred ethanol for dissolving, and adding hydrochloride (X1-X2. Cl) and triethylamine at room temperature; refluxing and reacting for 1-6 hours; removing the solvent under reduced pressure, adding water, and stirring for 1-10 min; extracting with dichloromethane for three times, drying with anhydrous sodium sulfate, rotary drying under reduced pressure, and recrystallizing the crude product with isopropanol to obtain the product
Figure FDA0003394645130000076
)；
Wherein the substituent X1、X2、X5And X6R1, n are as defined in formula 1 of claim 1;
step 4) is carried out according to the following reaction scheme 4
Figure FDA0003394645130000081
Reacting formic acid reactant
Figure FDA0003394645130000082
Dissolving in solvent, adding 1-hydroxybenzotriazole (HOBt) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC), stirring at room temperature for 1-5 hr, adding the reactant
Figure FDA0003394645130000083
Continuing to react for 1-6 hours, pouring the reaction solution into a saturated sodium bicarbonate aqueous solution after the reaction is finished, adding ethyl acetate, fully oscillating in a separating funnel, standing for layering, washing an organic layer with saturated saline solution for three times, drying with anhydrous sodium sulfate, and performing reduced pressure spin drying to obtain an intermediate product; adding the intermediate product into anhydrous DMF, heating to 100 deg.C, reacting for 20 hr, cooling the reaction solution to room temperature, adding saturated sodium bicarbonate water solution and ethyl acetate, washing the organic layer twice with water and once with saturated saline, drying with anhydrous sodium sulfate, and reducing pressureSpin-drying to obtain crude product, and separating with medium pressure chromatographic column (dichloromethane + methanol) to obtain compound of formula 1;
wherein the substituent X1To X9R1 and R3, n and m are as defined in formula 1 of claim 1;
the solvent is selected from DMF, acetonitrile, tetrahydrofuran, DMSO, dioxane, benzene, toluene, dichloromethane, chloroform, ethyl acetate and diethyl ether.
10. Use of the compound represented by formula 1 to formula 5 or a pharmaceutically acceptable salt thereof according to claims 1 to 8 for the preparation of a medicament for treating lung cancer, colorectal cancer, nasopharyngeal cancer, head and neck squamous cancer, gastric cancer, esophageal cancer, breast cancer, pancreatic cancer, liver cancer, cervical cancer, ovarian cancer, skin cancer, brain glioma.
11. A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formulae 1 to 5 or a pharmaceutically acceptable salt thereof according to claims 1 to 8 and a pharmaceutically acceptable excipient.
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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004052280A2 (en) * 2002-12-10 2004-06-24 Imclone Systems Incorporated Anti-angiogenic compounds and their use in cancer treatment
US20040267017A1 (en) * 2001-09-26 2004-12-30 Bierer Donald E 3-pyridyl or 4-isoquinolinyl thiazoles as c17, 20 lyase inhibitors
US20050113423A1 (en) * 2003-03-12 2005-05-26 Vangoor Frederick F. Modulators of ATP-binding cassette transporters
WO2007061923A2 (en) * 2005-11-18 2007-05-31 Takeda San Diego, Inc. Glucokinase activators
JP2008308495A (en) * 2007-05-17 2008-12-25 Kissei Pharmaceut Co Ltd New catechol derivative, medicinal composition containing the same and its use
US20090048301A1 (en) * 2003-07-09 2009-02-19 Imclone Systems Incorporated Heterocyclic compounds and their use as anticancer agents
US20100227845A1 (en) * 2007-10-18 2010-09-09 Zhicai Wu Substituted 1,2,4-oxadiazoles and analogs thereof as cb2 receptor modulators, useful in the treatment of pain, respiratory and non-respiratory diseases
KR20150078018A (en) * 2013-12-30 2015-07-08 한미약품 주식회사 Novel isoxazole compound having therapeutic effect on cancers
US20180297963A1 (en) * 2015-08-31 2018-10-18 The Regents Of The University Of California Broad spectrum antiviral compounds and uses thereof
WO2018230528A1 (en) * 2017-06-13 2018-12-20 株式会社富士薬品 Novel nitrocatechol derivative
CN110041302A (en) * 2019-03-01 2019-07-23 南方医科大学 2- amino -4- substituted pyridine derivative and its synthetic method and application

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040267017A1 (en) * 2001-09-26 2004-12-30 Bierer Donald E 3-pyridyl or 4-isoquinolinyl thiazoles as c17, 20 lyase inhibitors
WO2004052280A2 (en) * 2002-12-10 2004-06-24 Imclone Systems Incorporated Anti-angiogenic compounds and their use in cancer treatment
US20050113423A1 (en) * 2003-03-12 2005-05-26 Vangoor Frederick F. Modulators of ATP-binding cassette transporters
US20090048301A1 (en) * 2003-07-09 2009-02-19 Imclone Systems Incorporated Heterocyclic compounds and their use as anticancer agents
WO2007061923A2 (en) * 2005-11-18 2007-05-31 Takeda San Diego, Inc. Glucokinase activators
JP2008308495A (en) * 2007-05-17 2008-12-25 Kissei Pharmaceut Co Ltd New catechol derivative, medicinal composition containing the same and its use
US20100227845A1 (en) * 2007-10-18 2010-09-09 Zhicai Wu Substituted 1,2,4-oxadiazoles and analogs thereof as cb2 receptor modulators, useful in the treatment of pain, respiratory and non-respiratory diseases
KR20150078018A (en) * 2013-12-30 2015-07-08 한미약품 주식회사 Novel isoxazole compound having therapeutic effect on cancers
US20180297963A1 (en) * 2015-08-31 2018-10-18 The Regents Of The University Of California Broad spectrum antiviral compounds and uses thereof
WO2018230528A1 (en) * 2017-06-13 2018-12-20 株式会社富士薬品 Novel nitrocatechol derivative
CN110041302A (en) * 2019-03-01 2019-07-23 南方医科大学 2- amino -4- substituted pyridine derivative and its synthetic method and application

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
COLUMBUS, OHIO, US REGISTRY[ONLINE]: ""STN检索报告"", 《STN REGISTRY》, pages 1 - 45 *
DONGHUI HUO ET AL.: ""Discovery of Novel Epidermal Growth Factor Receptor (EGFR) Inhibitors Using Computational Approaches"", 《JOURNAL OF CHEMICAL INFORMATION AND MODELING》, vol. 62, pages 5149 - 5164 *
PILAR CORNAGO ET AL.: ""A molecular balance to measure the strength of NeH/p hydrogen bonds based on the tautomeric equilibria of C-benzylphenyl substituted NH-pyrazoles"", 《TETRAHEDRON》, vol. 64, pages 3667 - 3673, XP022520402, DOI: 10.1016/j.tet.2008.02.026 *
XIAOHU OUYANG ET AL.: ""Synthesis and structure–activity relationships of 1, 2, 4-triazoles as a novel class of potent tubulin polymerization inhibitors"", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 15, pages 5154 - 5159 *

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