WO2021164793A1 - 用作激酶抑制剂的化合物及其应用 - Google Patents

用作激酶抑制剂的化合物及其应用 Download PDF

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WO2021164793A1
WO2021164793A1 PCT/CN2021/087725 CN2021087725W WO2021164793A1 WO 2021164793 A1 WO2021164793 A1 WO 2021164793A1 CN 2021087725 W CN2021087725 W CN 2021087725W WO 2021164793 A1 WO2021164793 A1 WO 2021164793A1
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alkyl
compound
cycloalkyl
kinase inhibitor
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WO2021164793A8 (zh
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李钧
梁阿朋
牛成山
吴豫生
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郑州同源康医药有限公司
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen 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
    • C07D401/06—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 carbon chain containing only aliphatic 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of nitrogen-containing heterocyclic compounds, and specifically relates to a compound used as a kinase inhibitor and its application.
  • the epidermal growth factor (EGF) receptor belongs to the receptor tyrosine kinase (RTK) family, which includes EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4.
  • RTK receptor tyrosine kinase
  • Epidermal growth factor receptor activates its tyrosine kinase activity through homodimerization or heterodimerization, and then phosphorylates its substrate, thereby activating multiple downstream pathways related to it in the cell, such as those involved in cell survival PI3K-AKT-mTOR pathway and RAS-RAF-MEK-ERK pathway involving cell proliferation, etc.
  • the mutation or amplification of the epidermal growth factor receptor will cause the activation of the epidermal growth factor receptor kinase, leading to the occurrence of many human diseases, such as malignant tumors.
  • many human diseases such as malignant tumors.
  • human diseases such as malignant tumors.
  • more than 10% of American patients have EGFR mutations, while the proportion of EGFR mutations in Asian patients can reach nearly 50%.
  • the incidence of Her2 mutations is about 2-4%.
  • EGFR mutations mainly include deletions, insertions, and point mutations. Among them, the deletion of exon 19 and the L858R point mutation of exon 21 account for nearly 90% of EGFR mutations.
  • the currently marketed EGFR-TKIs include the first-generation Iressa, Tarceva, and Kemena, the second-generation afatinib and dacomitinib, and the third-generation oscitinib.
  • the other 10% of EGFR mutations mainly involve EGFR exons 18 and 20, and insertion mutations in EGFR exon 20 account for about 9% of the entire EGFR mutations.
  • Tumor patients with Her2 mutations the most common Her2 mutation is the insertion mutation in Exon 20 of Her2.
  • Her2 exon 20 insertion mutations no drugs are currently on the market.
  • WO2008150118A2 reports that a series of quinazoline derivatives have the activity of EGFR T790M resistance mutations. At the same time, the patent also reports that this series of compounds have an effect on the skin cancer cell line A431 (this cell line overexpresses WT EGFR) and breast cancer cell lines. SK-Br3 (this cell line overexpresses Her2) has good biological activity, and there is no report on the activity of EGFR and Her2 exon 20 insertion mutations.
  • the compound represented by formula II failed in the clinical development of the deletion of EGFR exon 19 and the L858R point mutation of exon 21.
  • the clinical efficacy of EGFR exon 20 is used for the clinical development of insertion mutations in EGFR exon 20.
  • the treatment window of the drug is too small, and it is likely that the toxic side effects will be relatively large (Signal Transduction and Targeted Therapy, 2019, 4:5), resulting in effective drugs
  • the therapeutic dose cannot be increased, which affects the curative effect. At present, this compound is still under clinical research.
  • the purpose of the present invention is to provide a compound used as a kinase inhibitor to solve the problem of poor inhibitory activity of existing inhibitors against EGFR and Her2 exon 20 insertion mutations.
  • the second object of the present invention is to provide the application of the above-mentioned compounds in the preparation of medicines, which can be used to treat related diseases caused by EGFR mutations and/or Her2 mutations.
  • the technical solution of the compound used as a kinase inhibitor of the present invention is:
  • the compound used as a kinase inhibitor is a compound represented by Formula I, or an isomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
  • X 1 is selected from N or CR 2 ;
  • X 2 is selected from N or CR 3 ;
  • X 3 is selected from N or CR 4 ;
  • L 1 and L 3 are each independently selected from a single bond, or L 2 is selected from a single bond, or
  • A is selected from a C 6-10 aryl group, a C 5-12 heteroaryl group, or a C 6-10 aryl group or a C 5-12 heteroaryl group substituted by 1, 2 or 3 substituents;
  • Substituents are optionally selected from H, halogen, cyano, amino, ester, ureido, carbamate, amide, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 A cycloalkyl group, a C 3-6 cycloalkoxy group, a C 6-10 aryl group, a C 5-12 heteroaryl group, or the substituent is an amino group substituted with 1, 2 or 3 R, an ester group, a ureido group, a urethane group, an amide group, C 1- 6 alkyl group, C 1-6 alkoxy, a C 3-6 cycloalkyl, C 3-6 cycloalkoxy , C 6-10 aryl, C 5-12 heteroaryl;
  • R is selected from halogen, cyano, hydroxyl, amino, ester, ureido, carbamate, amide, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 ring alkyl group, C 3-6 cycloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, a heteroaryl group of C 5- 12;
  • B is a nitrogen-containing heterocyclic group or a nitrogen-containing heterocyclic group substituted by R 1 , the number of nitrogen heteroatoms in the nitrogen-containing heterocyclic group is more than one;
  • the R 1 is selected from Wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from hydrogen, halogen, C 1-12 alkyl, C 3-12 cycloalkyl, C 1-12 alkylamino, or Is a C 1-12 alkyl group, a C 3-12 cycloalkyl group, a C 1-12 alkylamino group substituted by the R; R Y is selected from a C 1-12 alkyl group, and a C 1-12 alkyl group substituted by the R C 1-12 alkyl, C 3-12 cycloalkyl, and R is a substituted C 3-12 cycloalkyl group or a C 1-12 alkyl group, R is a substituted C 1- alkyl, C 3-12 cycloalkyl group 12, the R is a C 3-12 cycloalkyl group substituted with one or more of the carbon atoms is N, O, S or a plurality of hetero atoms Replace
  • R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from H, halogen, cyano, amino, ester, ureido, carbamate, amide, C 1-6 , C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 6-10 aryl, C 5-12 heteroaryl, or Is an amino group, an ester group, a ureido group, a carbamate group, an amide group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 3- 6 cycloalkyl, C 3-6 cycloalkoxy, C 6-10 aryl, C 5-12 heteroaryl;
  • L 2 is selected from When, B is selected from:
  • L 2 is selected from B is selected from When, A is selected from
  • n, m'and n' are each independently selected from 0, 1, 2, 3;
  • C is selected from H, halogen, cyano, amino, ester, ureido, ether, carbamate, amide, C 1-6 alkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl, C 3-6 cycloalkoxy, C 6-10 aryl, C 5-12 heteroaryl, alicyclic ring, or substituted by 1, 2 or 3 of the R
  • the compounds used as kinase inhibitors provided by the present invention have good inhibitory activity on EGFR and Her2 exon 20 insertion mutations, and have great potential to be developed into drugs for treating related diseases.
  • L 2 is selected from single bond, or
  • B is selected from:
  • R 1 is selected from X 2 and X 3 are selected from CH; X 1 is selected from N; L 3 is selected from C is selected from C 1-3 alkyl groups, L 1 is selected from A is selected from Y 1 , Y 2 , and Y 3 are selected from hydrogen; R A1 , R A2 , and R A3 are each independently selected from hydrogen, halogen, and C 1-3 alkyl; R C1 , R C2 are each independently selected from C 1- 3 of the alkyl group.
  • L 2 is selected from B is selected from: R 1 is selected from X 2 and X 3 are selected from CH; X 1 is selected from N; L 3 is selected from C is selected from C 1-3 alkyl groups, L 1 is selected from A is selected from Y 1 , Y 2 , and Y 3 are selected from hydrogen; R A1 , R A2 , and R A3 are each independently selected from hydrogen, halogen, and C 1-3 alkyl; R C1 , R C2 are each independently selected from C 1- 3 of the alkyl group.
  • L 2 is selected from or When, the nitrogen heteroatom of the nitrogen-containing heterocycle in B is connected to R 1.
  • L 2 is a single bond, and the nitrogen heteroatom in B is connected to the parent ring.
  • the parent ring is in formula I structure.
  • L 3 is C is a six-membered heterocyclic ring, and the heteroatoms in the six-membered heterocyclic ring are N and/or O.
  • L 2 is selected from B is selected from:
  • L 2 is selected from a single bond; B is selected from: R B is selected from H,
  • L 2 is selected from B is selected from:
  • C is selected from C 1-3 alkyl groups
  • R 1 is selected from R 6 and R 7 are each independently selected from hydrogen and halogen; Y 1 , Y 2 , and Y 3 are selected from hydrogen; R A1 , R A2 , and R A3 are each independently selected from hydrogen, halogen, and C 1-3 alkyl ; R C1 and R C2 are each independently selected from C 1-3 alkyl groups.
  • L 2 is selected from CF 2
  • B is selected from: Among them, m and n are 1 or 2 at the same time
  • L 2 is selected from B is selected from: m, n, m', and n'are 1 at the same time.
  • the compound used as a kinase inhibitor is selected from the following compounds:
  • the C 6-10 aryl group is a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms, for example, a phenyl group or a naphthyl group.
  • the C 5-12 heteroaryl group refers to a monocyclic or bicyclic aromatic group having 5 to 12 ring atoms, of which one or more, preferably, one, two or three ring atoms are Heteroatoms selected from N, O, S, and the remaining ring atoms are carbon.
  • Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazole Group, quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc.
  • Aliphatic heterocycles are heterocyclic groups without aromatic characteristics, such as Wait.
  • Alkylamino refers to a -NHR' group, where R' refers to an alkyl group, for example, methylamino, ethylamino, propylamino and the like.
  • Halogen refers to F, Cl, Br, I elements; Represents the chemical bond connection position.
  • the above compounds have been confirmed by biological activity experiments, have good inhibitory activity on EGFR and Her2 exon 20 insertion mutations, and can be used as the original drugs of related drugs.
  • the "pharmaceutically acceptable salt” of the technical substance refers to a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound.
  • Such salts include:
  • Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids, such as formic acid, acetic acid, and propionic acid , Hexanoic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxyl Benzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2 -Naphthalenesulfonic acid, 4-toluenesul
  • Solvates are compounds containing solvents, such as hydrates, dimethyl sulfoxides and the like.
  • a prodrug refers to a compound that undergoes metabolic or chemical transformation to produce the compound, salt, or solvate of the present invention when treating related diseases.
  • drugs based on the above-mentioned compounds are expected to have better therapeutic effects on related diseases.
  • the EGFR mutation and Her2 mutation are exon 20 insertion mutations.
  • the biological activity experiments confirmed that the above compounds have a good inhibitory effect on the insertion mutation type of exon 20 of the above two kinases.
  • the above compounds can also be used in combination with other drugs for the treatment of cancer.
  • Other drugs used in combination can be ERK inhibitors or MEK inhibitors.
  • the cancer is preferably lung cancer, more preferably lung cancer caused by EGFR and Her2 exon 20 insertion mutations.
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the experiment process is as follows:
  • the synthetic route is as follows:
  • the experiment process is as follows:
  • the structural formula of the compound used as a kinase inhibitor of this example is:
  • the synthetic route is as follows:
  • the structural formula of the compound used as a kinase inhibitor of this example is:
  • the synthetic route is as follows:
  • the structural formula of the compound used as a kinase inhibitor of this example is:
  • the synthetic route is as follows:
  • the experiment process is as follows:
  • the synthetic route is as follows:
  • the experiment process is as follows:
  • the structural formula of the compound used as a kinase inhibitor of this example is:
  • the synthetic route is as follows:
  • the experiment process is as follows:
  • the structural formula of the compound used as a kinase inhibitor of this example is:
  • the synthetic route is as follows:
  • the experiment process is as follows:
  • the structural formula of the compound used as a kinase inhibitor of this example is:
  • the synthetic route is as follows:
  • the experiment process is as follows:
  • Example 7 After reacting overnight, adjust the pH of the mixed solution to about 8 with solid sodium bicarbonate, then add ethyl acetate (50 mL) and water (50 mL) to it, separate the organic phase, and extract the aqueous phase with ethyl acetate (40 mL). The combined organic phases were dried with anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was column chromatography (ethyl acetate as the mobile phase) to obtain the white solid compound Example 7 (53 mg), which was then purified by preparative chromatography to obtain Example 7 -P1 and Example 7-P2 total 15.7 mg, with a yield of 10.2%.
  • Each sample was prepared into a solution with a concentration of 10 mM.
  • test compound was dissolved to a specific concentration in 100% dimethyl sulfoxide. Use Integra Viaflo Assist to assist DMSO for (serial) dilution.
  • the kinase is added to the freshly prepared basic reaction buffer, and any required cofactors are added to the above-mentioned substrate solution.
  • the kinase activity data is expressed as the percentage of kinase activity remaining in the test sample compared to the vehicle (dimethyl sulfoxide) reaction. Using Prism (GRAPHPAD Software) to obtain IC 50 values and the curve fit.
  • Table 2 and Table 3 show the inhibitory activity (IC 50 (nM) value) of the obtained test sample against EGFR exon 20 and Her2exon 20 insertion mutant kinases.
  • IC 50 (nM) value the inhibitory activity of the obtained test sample against EGFR exon 20 and Her2exon 20 insertion mutant kinases.
  • the compound we synthesized has a good inhibitory ability against EGFR exon 20 insertion mutation kinase, most of which have the inhibitory activity of poziotinib quite.
  • the activity of the compound of Example 3 is 2-3 times that of poziotinib.
  • the inhibitory activity of the compound of Example 5 on Her2 insertion mutant kinase is about 4 times that of poziotinib. It is very expected to be further developed into drugs for regulating the activity of EGFR exon 20 insertion mutation kinase or treating EGFR exon 20 insertion mutation kinase related diseases.
  • conventional forms such as capsules or tablets can be used.

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Abstract

本发明涉及一种用作激酶抑制剂的化合物及其应用。该化合物的结构如式Ⅰ所示。本发明提供的用作激酶抑制剂的化合物，对EGFR和Her2外显子20插入突变具有良好的抑制活性，极有潜力开发成治疗相关疾病的药物。

Description

用作激酶抑制剂的化合物及其应用 技术领域
本发明属于含氮杂环化合物领域，具体涉及一种用作激酶抑制剂的化合物及其应用。
背景技术
表皮生长因子(EGF)受体属于受体酪氨酸激酶(RTK)家族，其包括EGFR/ERBB1、HER2/ERBB2/NEU、HER3/ERBB3和HER4/ERBB4。表皮生长因子受体通过同源二聚或异源二聚激活其酪氨酸激酶活性，接着使它的底物磷酸化，从而激活细胞内与它相关的多个下游通路，如涉及细胞存活的PI3K-AKT-mTOR通路和涉及细胞增殖的RAS-RAF-MEK-ERK通路等。表皮生长因子受体的突变或扩增等都会导致表皮生长因子受体激酶的激活，从而导致人类多种疾病的发生，如恶性肿瘤。如在非小细胞肺癌患者中，美国患者中大约有10％以上的患者具有EGFR突变，而亚洲患者中EGFR突变的患者比例能达到近50％。同时，在非小细胞肺癌患者中，具有Her2突变的发病率大约在2-4％。
EGFR突变主要包括缺失、插入和点突变等，其中，外显子19缺失和外显子21的L858R点突变占到EGFR突变的近90％。对于具有这些EGFR突变的肿瘤患者，目前已经上市的EGFR-TKI包括一代的易瑞沙、特罗凯、凯美纳，二代的阿法替尼和达克替尼以及三代的奥西替尼。其他的10％的EGFR突变主要涉及EGFR的外显子18和20，并且，EGFR外显子20的插入突变占到整个EGFR突变的9％左右。具有Her2突变的肿瘤患者，最常见的Her2突变是Her2外显子20的插入突变。对于EGFR和Her2的外显子20插入突变，目前还没有药物上市。
WO2008150118A2中报道了一系列喹唑啉衍生物具有EGFR T790M耐药突变的活性，同时，专利中还报道了此系列化合物对皮肤癌细胞株A431(此细胞株过表达WT EGFR)和乳腺癌细胞株SK-Br3(此细胞株过表达Her2)有较好的生物活性，未见EGFR和Her2外显子20插入突变的活性报道。
此专利中涉及的典型化合物为式Ⅱ所示的化合物(Poziotinib)：
Figure PCTCN2021087725-appb-000001
据报道，式Ⅱ所示的化合物(Poziotinib)在EGFR外显子19缺失和外显子21的 L858R点突变的临床开发中失败，但是，发现其对EGFR外显子20插入的部分患者有一定的临床疗效，转而用于EGFR外显子20插入突变的临床开发。但是由于其对野生型的EGFR也有非常好的抑制剂活性，导致药物的治疗窗口过小，很有可能毒副作用会比较大(Signal Transduction and Targeted Therapy,2019,4:5)，从而导致药物有效治疗剂量不能提高，影响疗效，目前此化合物还在临床研究中。
发明内容
本发明的目的在于提供一种用作激酶抑制剂的化合物，以解决现有抑制剂对EGFR、Her2外显子20插入突变的抑制活性差的问题。
本发明的第二个目的在于提供上述化合物在制备药物方面的应用，该药物可用于治疗由EGFR突变和/或Her2突变导致的相关疾病。
为实现上述目的，本发明的用作激酶抑制剂的化合物的技术方案是：
用作激酶抑制剂的化合物，为式Ⅰ所示的化合物、或其异构体、或其药学上可以接受的盐、溶剂化物或前药；
Figure PCTCN2021087725-appb-000002
式Ⅰ中，X 1选自N或者CR 2；X 2选自N或者CR 3；X 3选自N或者CR 4；
L 1、L 3各自独立的选自单键、
Figure PCTCN2021087725-appb-000003
Figure PCTCN2021087725-appb-000004
或者
Figure PCTCN2021087725-appb-000005
L 2选自单键、
Figure PCTCN2021087725-appb-000006
Figure PCTCN2021087725-appb-000007
或者
Figure PCTCN2021087725-appb-000008
A选自C 6-10的芳基、C 5-12的杂芳基，或为被1、2或3个取代基取代的C 6-10的芳基、C 5-12的杂芳基；取代基任选自H、卤素、氰基、氨基、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6的烷基、C 1-6的烷氧基、C 3-6的环烷基、C 3-6的环烷氧基、C 6-10的芳基、C 5-12的杂芳基，或者所述取代基为被1、2或3个R取代的氨基、酯基、脲基、氨基甲酸酯基、酰胺基、C 1- 6的烷基、C 1-6的烷氧基、C 3-6的环烷基、C 3-6的环烷氧基、C 6-10的芳基、C 5-12的杂芳基；
R选自卤素、氰基、羟基、氨基、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6的烷基、C 1-6的烷氧基、C 3-6的环烷基、C 3-6的环烷氧基、C 2-6的烯基、C 2-6的炔基、C 6-10的芳基、C 5- 12的杂芳基；
B为含氮杂环基团或被R 1取代的含氮杂环基团，所述含氮杂环基团中氮杂原子的数量为一个以上；
所述R 1选自
Figure PCTCN2021087725-appb-000009
Figure PCTCN2021087725-appb-000010
其中Y 1、Y 2、Y 3、Y 4、Y 5各自独立的选自氢、卤素、C 1-12的烷基、C 3-12的环烷基、C 1-12的烷氨基，或为被所述R取代的C 1-12的烷基、C 3-12的环烷基、C 1-12的烷氨基；R Y选自C 1-12的烷基、被所述R取代的C 1-12的烷基、C 3-12的环烷基、被所述R取代C 3-12的环烷基，或为C 1-12的烷基、被所述R取代的C 1-12的烷基、C 3-12的环烷基、被所述R取代的C 3-12的环烷基中的一个或多个碳原子被N、O、S中的一个或多个杂原子替换形成的基团；
R 2、R 3、R 4、R 5、R 6和R 7各自独立的选自H、卤素、氰基、氨基、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6的烷基、C 1-6的烷氧基、C 3-6的环烷基、C 3-6的环烷氧基、C 6-10的芳基、C 5-12的杂芳基，或为被1、2或3个所述R取代的氨基、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6的烷基、C 1-6的烷氧基、C 3-6的环烷基、C 3-6的环烷氧基、C 6-10的芳基、C 5-12的杂芳基；
L 2选自
Figure PCTCN2021087725-appb-000011
时，B选自：
Figure PCTCN2021087725-appb-000012
Figure PCTCN2021087725-appb-000013
L 2选自
Figure PCTCN2021087725-appb-000014
B选自
Figure PCTCN2021087725-appb-000015
时，A选自
Figure PCTCN2021087725-appb-000016
m、n、m’和n’各自独立的选自0、1、2、3；
C选自H、卤素、氰基、氨基、酯基、脲基、醚基、氨基甲酸酯基、酰胺基、C 1-6的烷基、C 1-6的烷氧基、C 3-6的环烷基、C 3-6的环烷氧基、C 6-10的芳基、C 5-12的杂芳基、脂杂环，或为被1、2或3个所述R取代的氨基、酯基、脲基、醚基、氨基甲酸酯基、酰胺基、C 1-6的烷基、C 1-6的烷氧基、C 3-6的环烷基、C 3-6的环烷氧基、C 6-10的芳基、C 5-12的杂芳基、脂杂环。
本发明提供的用作激酶抑制剂的化合物，对EGFR和Her2外显子20插入突变具有良好的抑制活性，极有潜力开发成治疗相关疾病的药物。
为进一步优化对EGFR和Her2突变的抑制效果，优选的，L 2选自单键、
Figure PCTCN2021087725-appb-000017
Figure PCTCN2021087725-appb-000018
或者
Figure PCTCN2021087725-appb-000019
时，B选自：
Figure PCTCN2021087725-appb-000020
更优选的，R 1选自
Figure PCTCN2021087725-appb-000021
X 2、X 3选自CH；X 1选自N；L 3 选自
Figure PCTCN2021087725-appb-000022
C选自C 1-3的烷基、
Figure PCTCN2021087725-appb-000023
L 1选自
Figure PCTCN2021087725-appb-000024
A选自
Figure PCTCN2021087725-appb-000025
Y 1、Y 2、Y 3选自氢；R A1、R A2、R A3各自独立的选自氢、卤素、C 1-3的烷基；R C1、R C2各自独立的选自C 1-3的烷基。
优选的，L 2选自
Figure PCTCN2021087725-appb-000026
B选自：
Figure PCTCN2021087725-appb-000027
Figure PCTCN2021087725-appb-000028
R 1选自
Figure PCTCN2021087725-appb-000029
X 2、X 3选自CH；X 1选自N；L 3选自
Figure PCTCN2021087725-appb-000030
C选自C 1-3的烷基、
Figure PCTCN2021087725-appb-000031
L 1选自
Figure PCTCN2021087725-appb-000032
A选自
Figure PCTCN2021087725-appb-000033
Y 1、Y 2、Y 3选自氢；R A1、R A2、R A3各自独立的选自氢、卤素、C 1-3的烷基；R C1、R C2各自独立的选自C 1-3的烷基。
为进一步优化对EGFR和Her2突变的抑制效果，优选的，L 2选自
Figure PCTCN2021087725-appb-000034
Figure PCTCN2021087725-appb-000035
或者
Figure PCTCN2021087725-appb-000036
时，B中含氮杂环的氮杂原子与R 1相连。
优选的，L 2为单键，B中的氮杂原子与母环相连。母环即式Ⅰ中的
Figure PCTCN2021087725-appb-000037
结构。
优选的，L 3为
Figure PCTCN2021087725-appb-000038
C为六元杂环，六元杂环中的杂原子为N和/或O。
优选的，具有式Ⅱ所示的结构：
Figure PCTCN2021087725-appb-000039
L 2选自
Figure PCTCN2021087725-appb-000040
B选自：
Figure PCTCN2021087725-appb-000041
Figure PCTCN2021087725-appb-000042
L 2选自单键；B选自：
Figure PCTCN2021087725-appb-000043
R B选自H、
Figure PCTCN2021087725-appb-000044
L 2选自
Figure PCTCN2021087725-appb-000045
B选自：
Figure PCTCN2021087725-appb-000046
Figure PCTCN2021087725-appb-000047
C选自C 1-3的烷基、
Figure PCTCN2021087725-appb-000048
R 1选自
Figure PCTCN2021087725-appb-000049
R 6、R 7各自独立的选自氢、卤素；Y 1、Y 2、Y 3选自氢；R A1、R A2、R A3各自独立的选自氢、卤素、C 1-3的烷基；R C1、R C2各自独立的选自C 1-3的烷基。
进一步优选的，L 2选自CF 2，B选自：
Figure PCTCN2021087725-appb-000050
其中，m、n同时为1或2
进一步优选的，L 2选自
Figure PCTCN2021087725-appb-000051
B选自：
Figure PCTCN2021087725-appb-000052
m、n、m’和n’同时为1。
为进一步优化对EGFR和Her2突变的抑制效果，优选的，用作激酶抑制剂的化合物选自下列化合物：
Figure PCTCN2021087725-appb-000053
除非另行说明，在该说明书、权利要求书中使用的以下术语具有以下含义：
C 6-10的芳基是一个具有6至10个环原子的单环或双环芳香烃基，例如，苯基或萘基。
C 5-12的杂芳基指的是一个具有5至12个环原子的单环或二环的芳族基团，其中一个或多个，优选地，一个、两个或三个环原子是选自N、O、S的杂原子，剩余的环原子是碳。代表性实例包括但不限于，吡咯基、噻吩基、噻唑基、咪唑基、呋喃基、吲哚基、异吲哚基、噁唑基、异噁唑基、苯并噻唑基、苯并噁唑基、喹啉基、异喹啉基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基、四唑基等。
脂杂环是没有芳香特征的杂环基团，如
Figure PCTCN2021087725-appb-000054
等。
烷氨基指的是一个-NHR’基团，其中R’指烷基，例如，甲氨基、乙氨基、丙氨基等。
卤素指F、Cl、Br、I元素；
Figure PCTCN2021087725-appb-000055
代表化学键连接位置。
以上化合物通过生物活性实验证实，对EGFR和Her2外显子20插入突变具有良好的抑制活性，可作为相关药物的原药使用。
在以上原药的基础上，原药的“药学上可接受的盐”指的是一种药学上可接受的并且拥有母体化合物的所希望的药理学活性的盐。此类盐包括：
与无机酸形成的酸加成盐，该无机盐例如是盐酸、氢溴酸、硫酸、硝酸、磷酸等；或与有机酸形成的酸加成盐，该有机酸例如是甲酸、乙酸、丙酸、己酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、葡庚糖酸、4,4’-亚甲基双-(3-羟基2-烯-1-羧酸)、3-苯丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟萘甲酸、水杨酸、硬脂酸、粘康酸等；或存在于母体化合物中的酸性质子与一种有机碱(例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲葡糖胺等)配位形成的盐。容易理解，该药学上可接受的盐是无毒的。
溶剂化物为含有溶剂的化合物，如水合物、二甲基亚砜合物等等。
前药为是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂化物。
本发明的上述化合物的应用的技术方案是：
上述用作激酶抑制剂的化合物在制备药物方面的应用，该药物可用于治疗由EGFR 突变和/或Her2突变导致的相关疾病。
基于上述化合物对EGFR和Her2的外显子20插入突变的良好抑制活性，基于上述化合物的药物预期对相关疾病具有较好的治疗效果。
优选的，所述EGFR突变、Her2突变为外显子20插入突变。经生物活性实验证实，上述化合物对以上两种激酶的外显子20的插入突变类型具有较好的抑制效果。
上述化合物也可以和其他药物联用，用于癌症的治疗。其他联用的药物可以是ERK抑制剂或MEK抑制剂。所述癌症，优选为肺癌，更进一步优选为具有EGFR和Her2外显子20插入突变导致的肺癌。
具体实施方式
下面结合具体实施例对本发明的实施方式作进一步说明。以下实施例中涉及的中间体的结构及合成过程说明如下：
中间体1的合成：
中间体1结构式如下：
Figure PCTCN2021087725-appb-000056
合成路线如下：
Figure PCTCN2021087725-appb-000057
具体合成过程如下：
(1)化合物2的合成：在250mL的三口瓶中加入化合物1(33.4g，200mmol)，乙腈(MeCN，400mL)，冰水浴降温至0℃，滴加NBS(N-溴代琥珀酰亚胺，35.6g，0.2mol)的乙腈溶液(200mL)，滴加过程中保持0℃，滴加完毕后升至室温反应12h，TLC显示反应完成。过滤，滤饼用5mL的乙腈洗涤两次，抽干溶剂得黄色固体31g，产率63％。
1HNMR:(DMSO-d6,400Hz)δ:7.77(s,1H),6.42(s,1H),3.80(s,3H).
(2)化合物3的合成：在100mL的单口瓶中加入化合物2(30g,122mmol)，醋酸 甲脒(Formamidine acetate,17.8g，171.8mmol)，乙二醇二甲醚(DME，30mL)，油浴加热外温120℃回流3h。TLC显示反应完成，关闭加热，冷却至室温后放入冰箱中冷却0.5h，过滤，滤饼用40mL乙酸乙酯打浆两次，用40mL水打浆两次，旋蒸蒸干得褐色固体22g，产率71％。
1HNMR:(DMSO-d6,400Hz)δ:8.20(s,1H),8.12(s,1H),7.23(s,1H),4.00(s,3H).
(3)化合物4的合成：在100mL的单口瓶中加入化合物3(4g,15.69mmol)，甲苯(toluene，30mL)，冰水浴降温至0℃，加入DIEA(N,N-二异丙基乙胺，4.75g,36.7mmol)，滴加三氯氧磷(7.31g,47.1mmol)，滴加过程中保持0℃，滴加完毕后油浴加热外温75℃，反应12h。TLC显示反应完成(PE:EA＝5:1,3Rf＝0.5,4Rf＝0.2)。关闭加热，冷却至室温，倒入冰水中搅拌10min，加入二氯甲烷分液，水相用二氯甲烷洗涤两次合并有机相，饱和食盐水洗涤，分液，有机相干燥蒸干，过柱子得2.3g淡黄色固体，产率55％。
1HNMR:(DMSO-d6,400Hz)δ:8.97(s,1H),8.48(s,1H),7.38(s,1H),4.10(s,3H).
(4)化合物中间体1的合成：在50mL的单口瓶中加入化合物4(3g,11mmol)，化合物5(3.96g,22mmol)，甲苯(30mL)。油浴加热外温至110℃，反应12h。TLC显示反应完成(PE:EA＝3:1,4Rf＝0.5,6Rf＝0.2)。关闭加热冷却至室温，滴加DIEA溶清为止，加入硅胶拌样蒸干，过柱子，得黄色固体4.25g，产率92.7％。
1HNMR:(DMSO-d6,400Hz)δ:8.75(s,1H),8.52～8.48(m,1H),8.10(s,1H),7.41(s,1H),7.35～7.31(m,2H),4.10(s,3H).
中间体2的合成：
中间体2结构式如下：
Figure PCTCN2021087725-appb-000058
合成路线如下：
Figure PCTCN2021087725-appb-000059
实验过程如下：
(1)取一25mL单口瓶，向其中加入EH-006A(200mg,0.89mmol)及甲醇(6mL)，再于冰浴冷却下向其中分三批加入硼氢化钠(33.8g,0.89mmol)，反应液于室温搅拌反应2小时，TLC检测原料转化完全，于旋蒸上拉干溶剂，向残余物中加入水(10mL)及乙酸乙酯(10mL)，搅拌5分钟后分液收有机层，水相再以乙酸乙酯(10mL)萃取，合并有机相 以无水硫酸镁干燥后减压蒸除溶剂，残余物柱层析得无色油状物EH-006B(222mg)，收率100％。
1HNMR:(CDCl 3,400Hz)δ4.28～4.22(m,1H),3.48～3.44(m,2H),3.31～3.28(m,2H),2.73(s,1H),2.6～2.52(m,2H),2.15～2.08(m,2H),1.57～1.41(m,2H),1.37(s,9H).
(2)取一25mL单口瓶，向其中加入EH-006B(222mg，0.98mmol)，三乙胺(TEA，222.2mg，2.2mmol)及二氯甲烷(5mL)，于氮气保护下置冰浴中搅拌冷却至内温4℃左右，以注射器向其中加入甲磺酰氯(MsCl，212.8mg，1.86mmol)，加毕反应液升至室温搅拌反应1小时，加水(5mL)搅拌洗涤分液，有机相以无水硫酸钠干燥后蒸干溶剂，粗品柱层析(PE:EA＝3-1:1)得浅黄色固体中间体2(259mg)，收率86.9％。
1HNMR:(CDCl 3,400Hz)δ5.12～5.09(m,1H),3.61～3.45(m,2H),3.43～3.26(m,2H),2.99(s,3H),2.66～2.65(m,2H),2.36～2.29(m,2H),1.88～1.82(m,2H),1.45(s,9H).
中间体3的合成：
中间体3结构式如下：
Figure PCTCN2021087725-appb-000060
合成路线如下：
Figure PCTCN2021087725-appb-000061
实验过程如下：
(1)取一250mL三口瓶，向其中加入PZT-1(10g,42.7mmol)，甲苯(85mL)及DIEA(6.46g,49.9mmol)，搅拌均匀后向其中加入三氯氧磷(16.43g,107.2mmol)，反应液于氮气保护下加热至内温75℃，大量白烟生成，混合液于相同温度下搅拌反应3小时，不溶物渐渐溶解，于相同内温下向反应液中加入2-氟-3,4-二氯苯胺(8.45g,46.9mmol)的甲苯(45mL)溶液，加毕反应液于75℃搅拌反应3小时，渐有大量固体不溶物析出，冷却反应液至室温，向其中加入冰水混合物(200g)及乙酸乙酯(200mL)，快速搅拌下以碳酸氢钠固体调节混合液pH值至8左右，有大量固体不溶物，抽滤，滤饼以水洗，再以少量乙酸乙酯(30mL)洗涤，取出滤饼拉干溶剂得白色粉末PZT-3(11.56g)，收率68.5％。
1HNMR:(CDCl 3,400Hz)δ8.72(s,1H),8.48(m,1H),7.55(s,1H),7.33～7.30(m,2H),3.96(s,3H),2.40(s,3H).
(2)化合物中间体3的合成：取一250mL单口瓶，向其中加入PZT-3(11.56g,29.2mmol)及甲醇(173mL)，再于室温下向其中加入浓氨水(53.2g,25％)，反应液于室温搅拌反应过夜，大量白色固体析出，抽滤，滤饼以甲醇(20mL)洗涤，取出滤饼于旋蒸上拉干溶剂得白色粉末中间体3(8.9g)，收率86.4％。
1HNMR:(DMSO-d6,400Hz)δ8.34(s,1H),7.65(s,1H),7.57-7.53(m,2H),,7.33～7.24(m,3H),7.21(s,1H),3.97(s,3H).
一、本发明的用作激酶抑制剂的化合物的具体实施例
实施例1
本实施例的用作激酶抑制剂的化合物，结构式为：
Figure PCTCN2021087725-appb-000062
合成路线如下：
Figure PCTCN2021087725-appb-000063
本实施例的化合物的具体合成过程为：
(1)化合物8的合成：在干燥的100mL三口瓶中依次加入中间体1(208mg,0.5mmol)，Pd 2(dba) 3(三(二亚苄基丙酮)二钯(0),137mg,30mol％)，XPhos(2-二环己基磷-2’,4’,6’,-三异丙基联苯,143mg,60mol％)，NaOtBu(叔丁醇钠,144mg,3.0equiv)，化合物7(212mg,1mmol)，分子筛干燥的二氧六环(10mL)，氩气中100℃反应16h。反应完毕，冷却至室温，加入少量二氯甲烷和水溶液，经硅藻土过滤，混合液分层，水相二氯甲烷萃取，随后，有机相经过饱和食盐水溶液洗涤，干燥和浓缩。最后，通过柱层析分离得到纯产品：黄色固体化合物8(75mg)，收率27％。
1HNMR:(CDCl 3,400Hz)δ:8.61(s,1H),8.46(t,J＝8.6Hz,1H),7.38(s,1H),7.30(dd,J 1＝2.0Hz,J 2＝9.1Hz,1H),7.21(s,1H),6.73(s,1H),3.98(s,3H),3.64-3.72(m,4H),3.36-3.38(m,4H),3.00-3.03(m,2H),1.46(s,9H).
(2)化合物实施例1的合成：在干燥的25mL单口瓶中加入化合物8(70mg,0.13 mmol),加入0.5mL甲醇溶解，室温下HCl/MeOH溶液(盐酸甲醇溶液)沿壁慢加入，氮气下室温搅拌2h，TLC显示化合物8消失，停止反应。溶液直接旋干，得粗产品固体化合物9。按90％的收率进行下一步。所得固体化合物9中加入5mL二氯甲烷，加入三乙胺(64.3mg，5.0equiv)，降至0℃，慢慢滴入DCM稀释好的丙烯酰氯10(11.5mg,1.0equiv)，继续冰浴下反应0.5-1h，TLC显示原料消失。反应完毕，加入水溶液淬灭，加入少量二氯甲烷，经硅藻土过滤，混合液分层，水相二氯甲烷萃取，随后，有机相经过饱和食盐水溶液洗涤，干燥和浓缩。最后，通过制备色谱分离得到纯产品(10mg)，收率15％。
1HNMR:(CD 3OD,400Hz)δ:8.58(s,1H),7.49-7.55(m,2H),7.40(s,1H),,7.20(s,1H),6.63(dd,J 1＝10.3Hz,J 2＝16.8Hz,1H),6.28(dd,J 1＝1.9Hz,J 2＝16.8Hz,1H),5.75(dd,J 1＝1.9Hz,J 2＝10.5Hz,1H),4.08(s,3H),3.95-4.00(m,1H),3.77-3.87(m,3H),3.53-3.67(m,4H),3.09-3.22(m,2H).
实施例2
本实施例的用作激酶抑制剂的化合物，结构式为：
Figure PCTCN2021087725-appb-000064
合成路线如下：
Figure PCTCN2021087725-appb-000065
具体合成过程如下：
在干燥的50mL单口瓶中依次加入中间体1(107.7mg,0.25mmol)，Pd 2(dba) 3(68.6mg,30mol％)，XPhos(71.5mg,60mol％)，NaOtBu(72mg,3.0equiv)，化合物7(53.3mg,0.75mmol)，分子筛干燥的二氧六环(5mL)，氩气中100℃反应16h。反应完毕，冷却至室温，加入少量二氯甲烷和水溶液，经硅藻土过滤，混合液分层，水相二氯甲烷萃取，随后，有机相经过饱和食盐水溶液洗涤，干燥和浓缩。最后，通过制备色谱分离得到纯产品(10mg)，收率10％。
1HNMR:(CDCl 3,400Hz)δ:8.53(s,1H),7.49-7.55(m,2H),7.29(d,J＝4.1Hz,1H),7.14(s,1H),4.06(s,3H),3.59-3.62(m,4H),2.00-2.04(m,4H).
实施例3
本实施例的用作激酶抑制剂的化合物，结构式为：
Figure PCTCN2021087725-appb-000066
合成路线如下：
Figure PCTCN2021087725-appb-000067
实验过程如下：
(1)化合物H2的合成：在100mL三口瓶中，加入化合物中间体1(0.828g,2mmol)和无水THF(四氢呋喃，30mL)，然后加入NaH(0.32g,6mmol)，然后降温至-78℃，氮气保护下加入正丁基锂(0.96mL,2.4mmol)，然后在此温度下搅拌反应1h，之后把化合物A-1(0.584g,2.4mmol)溶于无水THF(5mL)中，在-78℃条件下，缓慢加入，滴加完毕，自然升至室温搅拌过夜。将氯化铵水溶液(30mL)加入到反应液中，乙酸乙酯(30mL)萃取三次，合并有机相，干燥，柱层析纯化(PE：EA＝1:1)得产品0.3g，收率27％。
1HNMR:(CDCl 3,400Hz)δ8.74(s,1H),8.48(s,1H),7.38(t,J＝7.6Hz，1H),7.36～7.30(m，2H)，4.20～4.15(m,5H)，4.05(s,3H),1.44(s，9H).
(2)化合物H3的合成：在20mL单口瓶中加入化合物H2(0.3g，0.57mmol)，DAST(二乙胺基三氟化硫，10mL)，DCM(二氯甲烷，5mL)氮气保护下升温至40℃，搅拌反应3h，然后将反应液小心加入碳酸氢钠水溶液中，然后乙酸乙酯萃取三次，合并有机相，柱层析(PE:EA＝1:1)得到产品90mg，收率28％。
(3)化合物H4的合成：将化合物H3(70mg，0.13mmol)溶于4N HCl/MeOH中，室温搅拌3h，然后旋干直接下一步。
(4)化合物实施例3的合成：在20mL单口瓶中加入化合物H4(65mg,0.13 mmol)，TEA(三乙胺，80mg,0.78mmol)和DCM(10mL)，氮气保护下，降至0℃，加入丙烯酰氯(12mg,0.13mmol)的DCM溶液(2mL)，在此温度条件下反应0.5h，加入碳酸氢钠水溶液(20mL)，DCM萃取三次，合并有机相，干燥，旋干制备分离得到产品10mg，收率15％。
1HNMR:(CD 3OD,400Hz)δ8.82(s,1H),8.75(s,1H),8.57～8.51(m,2H),7.36(s,1H)，6.39～6.24(m,2H),5.77～5.74(m,1H),4.43～4.40(m,2H),4.12～4.09(m,5H),3.97～3.90(m,1H).
实施例4
本实施例的作激酶抑制剂的化合物，结构式为：
Figure PCTCN2021087725-appb-000068
合成路线如下：
Figure PCTCN2021087725-appb-000069
实验过程如下：
(1)化合物H11的合成：将化合物H2(52mg,0.1mmol)溶于4N HCl/MeOH中，室温搅拌3h，然后旋干直接下一步。
(2)化合物实施例4的合成：在20mL单口瓶中加入化合物H11(52mg,0.1mmol)，TEA(60mg,0.6mmol)和DCM(10mL)，氮气保护下，降至0℃，加入丙烯酰氯(9mg，0.1mmol)的DCM溶液(2mL)，在此温度条件下反应0.5h，加入碳酸氢钠水溶液(20mL)，DCM萃取三次，合并有机相，干燥，旋干，制备色谱分离得到产品15mg，收率21％。
1HNMR:(CD 3OD,400Hz)δ9.02(s,1H),8.75(s,1H),8.57～8.51(m,2H),7.38(s,1H)，6.39～6.27(m,2H),5.77～5.74(m,1H),4.54～4.50(m,2H),4.35～4.30(m,3H),4.18(s,3H).
实施例5
本实施例的用作激酶抑制剂的化合物，结构式为：
Figure PCTCN2021087725-appb-000070
合成路线如下：
Figure PCTCN2021087725-appb-000071
实验过程如下：
(1)化合物H5的合成：在100mL三口瓶中，加入化合物中间体1(1.242g，3mmol)和无水THF(30mL)，然后加入NaH(0.48g,9mmol)，然后降温至-78℃，氮气保护下加入正丁基锂(1.44mL,3.6mmol)，然后在此温度下搅拌反应1h，之后把化合物A-2(0.978g，3.6mmol)溶于无水THF(5mL)中，在-78℃条件下，缓慢加入，滴加完毕，自然升至室温搅拌过夜。将氯化铵水溶液(30mL)加入到反应液中，乙酸乙酯(30mL)萃取三次，合并有机相，干燥，柱层析纯化(PE：EA＝1:1)得产品0.51g，收率23％。
1HNMR:(CDCl 3,400Hz)δ8.75(s,1H),8.44(t,J＝8.4Hz，1H),8.11(s,1H),7.58(s,1H),7.35～7.32(m,2H),4.13～4.06(m,5H),3.47～3.40(m,1H),2.90～2.83(m,2H),1.88～1.83(m,2H),1.65～1.60(m,2H),1.46(s,9H).
(2)化合物H6的合成：在20mL单口瓶中加入化合物H5(0.5g,0.91mmol)，BAST(5mL)，DCM(5mL)氮气保护下升温至45℃，搅拌反应4.5h，然后将反应液小心加入碳酸氢钠水溶液中，然后乙酸乙酯萃取三次，合并有机相，柱层析(PE:EA＝1:1)得到产品50mg，收率10％。
(3)化合物H7的合成：将化合物H6(50mg，0.1mmol)溶于4N HCl/MeOH中，室温搅拌3h，然后旋干直接下一步。
(4)实施例5的化合物合成：在20mL单口瓶中加入化合物H7(45mg，0.1mmol)，TEA(60mg，0.6mmol)和DCM(10mL)，氮气保护下，降至0℃，加入丙烯酰氯(9mg，0.1mmol)的DCM溶液(2mL)，在此温度条件下反应0.5h，加入碳酸氢钠 水溶液(20mL)，DCM萃取三次，合并有机相，干燥，旋干，制备色谱分离得到产品8mg，收率12％。
1HNMR:(CD 3OD,400Hz)δ8.75(s,1H),8.70(s,1H),8.53～8.50(m,2H),7.36(s,1H)，6.79～6.73(m,1H),6.21～6.16(m,1H),5.75～5.72(m,1H),4.23～4.18(m,1H),4.12～4.09(m,1H),3.34(s,3H),3.17～2.89(m,3H),1.83～1.68(m,2H),1.55～1.46(m,2H).
实施例6
本实施例的用作激酶抑制剂的化合物，结构式为：
Figure PCTCN2021087725-appb-000072
合成路线如下：
Figure PCTCN2021087725-appb-000073
实验过程如下：
(1)化合物H12的合成：将化合物H5(55mg，0.1mmol)溶于4N HCl/MeOH中，室温搅拌3h，然后旋干直接下一步。
(2)化合物实施例6的合成：在20mL单口瓶中加入化合物H12(52mg，0.1mmol)，TEA(60mg，0.6mmol)和DCM(10mL)，氮气保护下，降至0℃，加入丙烯酰氯(9mg，0.1mmol)的DCM溶液(2mL)，在此温度条件下反应0.5h，加入碳酸氢钠水溶液(20mL)，DCM萃取三次，合并有机相，干燥，旋干，制备色谱分离得到产品10mg，收率20％。
1HNMR:(CD 3OD,400Hz)δ8.77(s,1H),8.68(s,1H),7.55～7.50(m,2H),7.37(s,1H),6.81～6.74(m,1H),6.21～6.17(m,1H),6.75～6.72(m,1H),4.48～4.45(m,2H),4.16～4.11(m,5H),3.63～3.57(m,1H),3.57～3.50(m,1H),3.05～2.94(m,1H),2.01～195(m,2H),1.67～1.60(m,2H).
实施例7
本实施例的用作激酶抑制剂的化合物，结构式为：
Figure PCTCN2021087725-appb-000074
合成路线如下：
Figure PCTCN2021087725-appb-000075
实验过程如下：
(1)化合物EH-006D的合成：取一25mL单口瓶，向其中加入中间体3(273.9mg，0.77mmol)及中间体2(236mg，0.77mmol)，再加入无水碳酸钾(320.7mg,2.32mmol)及DMF(11mL)，混合液置于85℃油浴中加热搅拌反应过夜，减压蒸干溶剂，向残余物中加入水(70mL)及乙酸乙酯(50mL)，搅拌分液收有机相，水相再以乙酸乙酯(50mL)萃取一次，合并有机相，以无水硫酸钠干燥后减压蒸去溶剂，粗品柱层析(PE:EA＝1:1)得白色固体EH-006D(169mg)，收率38.9％。
(2)化合物EH-006E的合成：取一50mL单口瓶，向其中加入EH-006D(169mg,0.30mmol)及甲醇(6mL)，未能完全溶解，于室温下向其中再加入浓盐酸(6mL，37％)，固体完全溶解，得一黄色溶液，室温搅拌2小时后蒸干溶剂，得黄色粉末EH-006E(160mg)，收率99.3％。
(3)化合物实施例7的合成：取一50mL三口瓶，向其中加入EH-006E(160mg，0.30mmol)，碳酸氢钠(150.7mg，1.79mmol)，THF(4mL)及纯水(4mL)，于氮气保护下冰浴冷却反应液至4℃左右，与此条件下以注射器向反应液中加入丙烯酰氯(40.6mg，0.45mmol)的THF(3mL)溶液，加毕撤去冰浴，室温搅拌反应过夜，以固体碳酸氢钠调节混合液pH值至8左右，再向其中加入乙酸乙酯(50mL)及水(50mL)，分液收有机相，水相再以乙酸乙酯(40mL)萃取，合并有机相以无水硫酸钠干燥后减压蒸干溶剂，残余物柱层析(乙酸乙酯为流动相)得白色固体化合物实施例7(53mg)，再以制备色谱纯化得实施例7-P1和实施例7-P2共15.7mg，收率10.2％。
1HNMR:(CDCl 3,400Hz)δ11.23(s,1H),8.40(s,1H),1.88(s,1H),7.35～7.30(m,2H),7.25～7.21(m,1H),6.43～6.37(m,1H),6.31～6.27(m,1H),5.68～5.66(d,J＝8Hz,1H),5.12(s,1H),3.98(s,3H),3.79～3.70(m,2H),3.43～3.41(m,2H),3.05～2.94(m,2H),2.29～2.21(m,2H),2.04～1.98(m,2H).
实施例8-22
实施例8-22的用作激酶抑制剂的化合物，结构式分别列于下表1中。
表1 实施例8-22的用作激酶抑制剂的化合物
Figure PCTCN2021087725-appb-000076
Figure PCTCN2021087725-appb-000077
Figure PCTCN2021087725-appb-000078
二、应用实施例，通过以下生物活性测试，对本发明涉及的化合物对EGFR外显子20(EGFR exon 20)插入突变的抑制活性进行说明。
使用激酶活性实验方法(Kinase activity Assay)在ATP Km浓度下筛选实施例制备的化合物对EGFR exon 20插入突变激酶的活性，并使用星形孢菌素(Staurosporine)做对照品，化合物的生物活性筛选将在10个浓度下重复测定。
1、受试样品
各样品分别配成浓度为10mM的溶液。
2、实验方法
1)为实验用激酶准备基本缓冲溶液和淬灭缓冲溶液
20mMHepes(pH 7.5)、10mM MgCl 2、1mM EGTA、0.02％Brij35、0.02mg/ml BSA、0.1mM Na 3VO 4、2mM DTT、1％DMSO。
2)为实验用激酶准备化合物
测试化合物在100％二甲基亚砜中溶解至特定浓度。用Integra Viaflo Assist辅助DMSO进行(连续)稀释。
3)反应步骤
将激酶加入新制备的基本反应缓冲液，向上述底物溶液中加入任何所需的辅因子。
将EGFR exon 20插入突变激酶加入到底物溶液中，轻轻混合；用Acoustic technology(Echo550；nanoliter range)将100％二甲基亚砜中的化合物送入激酶反应混合物中，在室温下培养20分钟。
向反应混合物中加入33P-ATP(Specific activity 10Ci/l)，开始反应，在室温下孵育2小时，用filter-binding方法检测放射性。
激酶活性数据表示为与媒剂(二甲基亚砜)反应相比，试验样品中剩余激酶活性的 百分比。使用Prism(GRAPHPAD软件)获得IC 50值和曲线拟合。
得到的受试样品对EGFR exon 20和Her2exon20插入突变激酶的抑制活性(IC 50(nM)值)测试结果如表2和表3所示。表2中，A<4.0nM，4.0nM≤B<40nM，C≥40nM；ND：未检测。
表2本发明化合物对EGFR exon20和Her2exon20插入突变激酶的抑制剂活性
Figure PCTCN2021087725-appb-000079
本发明的部分化合物的具体IC50值详见下表3。
表3不同化合物对EGFR exon 20和Her2exon20插入突变激酶的抑制活性
Figure PCTCN2021087725-appb-000080
Figure PCTCN2021087725-appb-000081
(ND：未检测)
从上表可知，通过体外生物活性筛选，以星形孢菌素(Staurosporine)为对照品，我们所合成的化合物对EGFR exon 20插入突变激酶均有很好的抑制能力，大部分与poziotinib抑制活性相当。其中，实施例3的化合物的活性是poziotinib活性的2-3倍。实施例5的化合物对Her2插入突变激酶的抑制活性是poziotinib活性的4倍左右。非常有望进一步开发成为用于调节EGFR exon 20插入突变激酶活性或治疗EGFR exon 20插入突变激酶相关疾病方面的药物。具体在制备药物时，可以采用胶囊剂或片剂等常规形式。

Claims (10)

  1. 用作激酶抑制剂的化合物，其特征在于，为式Ⅰ所示的化合物、或其异构体、或其药学上可以接受的盐、溶剂化物或前药；
    Figure PCTCN2021087725-appb-100001
    式Ⅰ中，X 1选自N或者CR 2；X 2选自N或者CR 3；X 3选自N或者CR 4；
    L 1、L 3各自独立的选自单键、
    Figure PCTCN2021087725-appb-100002
    Figure PCTCN2021087725-appb-100003
    或者
    Figure PCTCN2021087725-appb-100004
    L 2选自单键、
    Figure PCTCN2021087725-appb-100005
    Figure PCTCN2021087725-appb-100006
    或者
    Figure PCTCN2021087725-appb-100007
    A选自C 6-10的芳基、C 5-12的杂芳基，或为被1、2或3个取代基取代的C 6-10的芳基、C 5-12的杂芳基；取代基任选自H、卤素、氰基、氨基、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6的烷基、C 1-6的烷氧基、C 3-6的环烷基、C 3-6的环烷氧基、C 6-10的芳基、C 5-12的杂芳基，或者所述取代基为被1、2或3个R取代的氨基、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6的烷基、C 1-6的烷氧基、C 3-6的环烷基、C 3-6的环烷氧基、C 6-10的芳基、C 5-12的杂芳基；
    R选自卤素、氰基、羟基、氨基、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6的烷基、C 1-6的烷氧基、C 3-6的环烷基、C 3-6的环烷氧基、C 2-6的烯基、C 2-6的炔基、C 6-10的芳基、C 5-12的杂芳基；
    B为含氮杂环基团或被R 1取代的含氮杂环基团，所述含氮杂环基团中氮杂原子的数量为一个以上；
    所述R 1选自
    Figure PCTCN2021087725-appb-100008
    Figure PCTCN2021087725-appb-100009
    其中Y 1、Y 2、Y 3、Y 4、Y 5各自独立的选自氢、 卤素、C 1-12的烷基、C 3-12的环烷基、C 1-12的烷氨基，或为被所述R取代的C 1-12的烷基、C 3-12的环烷基、C 1-12的烷氨基；R Y选自C 1-12的烷基、被所述R取代的C 1-12的烷基、C 3- 12的环烷基、被所述R取代C 3-12的环烷基，或为C 1-12的烷基、被所述R取代的C 1-12的烷基、C 3-12的环烷基、被所述R取代的C 3-12的环烷基中的一个或多个碳原子被N、O、S中的一个或多个杂原子替换形成的基团；
    R 2、R 3、R 4、R 5、R 6和R 7各自独立的选自H、卤素、氰基、氨基、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6的烷基、C 1-6的烷氧基、C 3-6的环烷基、C 3-6的环烷氧基、C 6-10的芳基、C 5-12的杂芳基，或为被1、2或3个所述R取代的氨基、酯基、脲基、氨基甲酸酯基、酰胺基、C 1-6的烷基、C 1-6的烷氧基、C 3-6的环烷基、C 3-6的环烷氧基、C 6-10的芳基、C 5-12的杂芳基；
    L 2选自
    Figure PCTCN2021087725-appb-100010
    时，B选自：
    Figure PCTCN2021087725-appb-100011
    L 2选自
    Figure PCTCN2021087725-appb-100012
    B选自
    Figure PCTCN2021087725-appb-100013
    时，A选自
    Figure PCTCN2021087725-appb-100014
    m、n、m’和n’各自独立的选自0、1、2、3；
    C选自H、卤素、氰基、氨基、酯基、脲基、醚基、氨基甲酸酯基、酰胺基、C 1-6的烷基、C 1-6的烷氧基、C 3-6的环烷基、C 3-6的环烷氧基、C 6-10的芳基、C 5-12的杂芳基、脂杂环，或为被1、2或3个所述R取代的氨基、酯基、脲基、醚基、氨基甲酸酯基、酰胺基、C 1-6的烷基、C 1-6的烷氧基、C 3-6的环烷基、C 3-6的环烷氧基、C 6-10的芳基、C 5-12的杂芳基、脂杂环。
  2. 如权利要求1所述的用作激酶抑制剂的化合物，其特征在于，L 2选自单键、
    Figure PCTCN2021087725-appb-100015
    Figure PCTCN2021087725-appb-100016
    或者
    Figure PCTCN2021087725-appb-100017
    时，B选自：
    Figure PCTCN2021087725-appb-100018
    Figure PCTCN2021087725-appb-100019
  3. 如权利要求2所述的用作激酶抑制剂的化合物，其特征在于，R 1选自
    Figure PCTCN2021087725-appb-100020
    Figure PCTCN2021087725-appb-100021
    X 2、X 3选自CH；X 1选自N；L 3选自
    Figure PCTCN2021087725-appb-100022
    C选自C 1-3的烷基、
    Figure PCTCN2021087725-appb-100023
    L 1选自
    Figure PCTCN2021087725-appb-100024
    A选自
    Figure PCTCN2021087725-appb-100025
    Y 1、Y 2、Y 3选自氢；R A1、R A2、R A3各自独立的选自氢、卤素、C 1-3的烷基；R C1、R C2各自独立的选自C 1-3的烷基。
  4. 如权利要求1所述的用作激酶抑制剂的化合物，其特征在于，L 2选自
    Figure PCTCN2021087725-appb-100026
    B选自：
    Figure PCTCN2021087725-appb-100027
    R 1选自
    Figure PCTCN2021087725-appb-100028
    X 2、X 3选自CH；X 1选自N；L 3选自
    Figure PCTCN2021087725-appb-100029
    C 选自C 1-3的烷基、
    Figure PCTCN2021087725-appb-100030
    L 1选自
    Figure PCTCN2021087725-appb-100031
    A选自
    Figure PCTCN2021087725-appb-100032
    Y 1、Y 2、Y 3选自氢；R A1、R A2、R A3各自独立的选自氢、卤素、C 1-3的烷基；R C1、R C2各自独立的选自C 1-3的烷基。
  5. 如权利要求1所述的用作激酶抑制剂的化合物，其特征在于，具有式Ⅱ所示的结构：
    Figure PCTCN2021087725-appb-100033
    L 2选自
    Figure PCTCN2021087725-appb-100034
    B选自：
    Figure PCTCN2021087725-appb-100035
    L 2选自单键；B选自：
    Figure PCTCN2021087725-appb-100036
    R B选自H、
    Figure PCTCN2021087725-appb-100037
    L 2选自
    Figure PCTCN2021087725-appb-100038
    B选自：
    Figure PCTCN2021087725-appb-100039
    C选自C 1-3的烷基、
    Figure PCTCN2021087725-appb-100040
    R 1选自
    Figure PCTCN2021087725-appb-100041
    R 6、R 7各自独立的选自氢、卤素；Y 1、Y 2、Y 3选自氢；
    R A1、R A2、R A3各自独立的选自氢、卤素、C 1-3的烷基；R C1、R C2各自独立的选自C 1- 3的烷基。
  6. 如权利要求5所述的用作激酶抑制剂的化合物，其特征在于，L 2选自CF 2，B选自：
    Figure PCTCN2021087725-appb-100042
    其中，m、n同时为1或2。
  7. 如权利要求5所述的用作激酶抑制剂的化合物，其特征在于，L 2选自
    Figure PCTCN2021087725-appb-100043
    B选自：
    Figure PCTCN2021087725-appb-100044
    m、n、m’和n’同时为1。
  8. 如权利要求1～7中任一项所述的用作激酶抑制剂的化合物，其特征在于，选自下列化合物：
    Figure PCTCN2021087725-appb-100045
    Figure PCTCN2021087725-appb-100046
  9. 一种如权利要求1-8中任一项所述的用作激酶抑制剂的化合物在制备药物方面的应用，该药物可用于治疗由EGFR突变和/或Her2突变导致的相关疾病。
  10. 如权利要求9所述的应用，其特征在于，所述EGFR突变、Her2突变为外显子20插入突变。
PCT/CN2021/087725 2020-02-19 2021-04-16 用作激酶抑制剂的化合物及其应用 WO2021164793A1 (zh)

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