WO2020156319A1 - N-甲酰胺衍生物、其制备方法及其在医药上的用途 - Google Patents

N-甲酰胺衍生物、其制备方法及其在医药上的用途 Download PDF

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WO2020156319A1
WO2020156319A1 PCT/CN2020/073191 CN2020073191W WO2020156319A1 WO 2020156319 A1 WO2020156319 A1 WO 2020156319A1 CN 2020073191 W CN2020073191 W CN 2020073191W WO 2020156319 A1 WO2020156319 A1 WO 2020156319A1
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compound
pharmaceutically acceptable
tautomers
stereoisomers
cancer
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French (fr)
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张盼盼
颜孙力
李英
郭陈莉
钱文建
叶成
胡泰山
陈磊
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浙江海正药业股份有限公司
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    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • C07D403/14—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 three or more hetero rings
    • 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
    • C07D487/08—Bridged systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the field of medical technology, in particular to an N-formamide derivative which can be used as a selective RET kinase inhibitor, its preparation method and its medical use.
  • RET gene The rearrangement gene (RET gene) during transfection is a proto-oncogene that encodes a tyrosine kinase receptor in the human body and regulates cell reproduction and survival.
  • the activation of this gene needs to interact with glial cell-derived neurotrophic factor family receptors and the family of ⁇ receptors to form dimers, through phosphorylation, regulate signal pathways, exercise signal transduction and regulate life The function of the activity.
  • Abnormal expression of RET gene is associated with many cancer diseases. This gene is fused with other genes through chromosomal rearrangement or through site-specific mutation, and can be continuously activated independently of the ligand, leading to abnormal signaling pathways, leading to excessive cell proliferation and cancer.
  • RET gene fusion and mutation are the driving force of some cancers, and they do not overlap with other driver genes and have significant specificity.
  • RET gene fusion is more common in papillary thyroid cancer and non-small cell lung cancer. For example, 30% of sporadic papillary thyroid cancer, 70% of radiation-induced papillary thyroid cancer and about 2% of non-small cell lung cancer are driven by RET fusion genes .
  • Mutations of RET gene are more common in medullary thyroid cancer. For example, more than 50% of medullary thyroid cancer and nearly all congenital medullary carcinoma and multiple endocrine neoplasia are caused by site-directed mutations of RET gene.
  • the present invention provides a compound represented by formula (I) or its stereoisomer, tautomer or its pharmaceutically acceptable salt:
  • X is selected from CH or N;
  • R 1 , R 1' , R 2 , R 2' , R 3 , R 3' , R 4 , R 4' are each independently selected from hydrogen, C 1 -C 6 alkyl or C 1 -C 3 hydroxyalkane base,
  • R 1 and R 1 ', R 2 and R 2', R 3 and R a group of connections 3 ', R 4 and R 4' together form a cyclopropyl, cyclobutyl or oxetanyl ,
  • q 1, 2 or 3;
  • Ring D is selected from aryl or heteroaryl, the aryl or heteroaryl is optionally further substituted by one or more R 5 , each of R 5 is independently selected from halogen, cyano, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group or C 1 -C 3 halogen-containing alkyl group.
  • a preferred embodiment of the present invention provides a compound represented by formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein the B ring is selected from the following structures:
  • One end and two ends are optionally connected to the A ring.
  • a preferred embodiment of the present invention provides a compound represented by formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein the B ring is selected from the following structures:
  • One end and two ends are optionally connected to the A ring.
  • a preferred embodiment of the present invention provides a compound represented by formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein the D ring is selected from phenyl, Or a six-membered heteroaryl group containing 1 to 3 N atoms, the phenyl group, Or a six-membered heteroaryl group containing 1 to 3 N atoms is optionally further substituted by one or more R 5 , and R 5 is independently selected from halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 3 halogen-containing alkyl group, R 5 is preferably halogen, more preferably fluorine.
  • the present invention provides a method for preparing a compound represented by formula (I), the preparation method comprising: in an organic solvent under alkaline conditions, a compound of formula (IB) or a salt thereof, a compound of formula (IA) or a salt thereof And triphosgene to prepare the compound of formula (I),
  • ring D, X, R 1 , R 1' , R 2 , R 2' , R 3 , R 3' , R 4 and R 4' are defined as in formula (I) in any one of the foregoing technical solutions Said.
  • the organic solvent is dichloromethane, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, preferably dichloromethane;
  • the base used in the alkaline conditions is diisopropylethyl Amine or triethylamine, preferably diisopropylethylamine;
  • the reaction temperature of the reaction is -60 to 0°C.
  • the present invention provides a pharmaceutical composition which contains an effective dose of a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier , Excipients or their combination.
  • the present invention provides a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or its pharmaceutical composition (that is, the pharmaceutical composition provided by the above technical scheme of the present invention) in preparation Use of rearrangement kinase inhibitors during transfection.
  • the present invention provides a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof for preparing drugs for treating diseases driven by gene rearrangement during transfection
  • the disease is preferably cancer
  • the cancer is preferably lung cancer, thyroid cancer, colon cancer, breast cancer or pancreatic cancer.
  • the present invention provides a use of a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or its pharmaceutical composition in the treatment of diseases driven by gene rearrangement during transfection ,
  • said disease is preferably cancer
  • said cancer is preferably lung cancer, thyroid cancer, colon cancer, breast cancer or pancreatic cancer.
  • the present invention provides a method for the treatment of diseases driven by gene rearrangement during transfection, which includes the use of a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical combinations thereof
  • the substance is administered to the subject; wherein the disease is preferably cancer, and the cancer is preferably lung cancer, thyroid cancer, colon cancer, breast cancer or pancreatic cancer.
  • Alkyl when regarded as a group or a part of a group means to include a C 1 -C 20 straight chain or branched aliphatic hydrocarbon group. It is preferably a C 1 -C 10 alkyl group, and more preferably a C 1 -C 6 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. Alkyl groups can be substituted or unsubstituted.
  • Cycloalkyl refers to saturated or partially saturated monocyclic, fused, bridged, and spirocyclic carbocyclic rings. It is preferably a C 3 -C 12 cycloalkyl group, and more preferably a C 3 -C 6 cycloalkyl group.
  • monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc., preferably cyclopropyl, cyclo Hexenyl.
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, where the rings can be joined together in a fused manner.
  • aryl includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl.
  • the aryl group is a C 6 -C 10 aryl group, more preferably the aryl group is a phenyl group and a naphthyl group, and most preferably a phenyl group.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic 5- to 6-membered monocyclic ring or 9 to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include but are not limited to furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , Oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzoin Dioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl
  • Hydroxyalkyl refers to an alkyl group containing at least one hydroxy group as a substituent, wherein the definition of the alkyl group is as described above.
  • Halogen refers to fluorine, chlorine, bromine and iodine, preferably chlorine, bromine and fluorine, more preferably fluorine.
  • Halo-containing alkyl group refers to an alkyl group containing at least one halogen atom as a substituent, wherein the definitions of halogen and alkyl are as described above.
  • Cyano refers to -CN.
  • Benzyl refers to -CH 2 -phenyl.
  • Ester group refers to -C(O)O(alkyl) or (cycloalkyl), wherein the definitions of alkyl and cycloalkyl are as described above.
  • DMSO dimethyl sulfoxide
  • Boc means tert-butoxycarbonyl
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms independently of each other substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • substituted or “substituted” mentioned in this specification, unless otherwise specified, mean that the group can be substituted by one or more groups selected from the group consisting of halogen, cyano, alkyl, cycloalkyl, Ester group, hydroxyl group or alkoxy group, etc.;
  • the compounds of the present invention may contain asymmetric centers or chiral centers, so there are different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers and their mixtures, such as racemic mixtures, constitute the present invention Part.
  • Diastereomers can be separated into individual diastereomers by methods such as chromatography, crystallization, distillation or sublimation based on their physical and chemical differences.
  • Enantiomers can be separated to convert a chiral isomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (for example, a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride) , Separate diastereomers, and convert individual diastereomers into corresponding pure enantiomers.
  • a suitable optically active compound for example, a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride
  • the intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included in the scope of the present invention.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D, L or R, S are used to indicate the absolute configuration of the molecular chiral center.
  • the prefixes d, l or (+), (-) are used to name the symbols of the plane-polarized light rotation of the compound.
  • (-) or l means that the compound is levorotatory
  • the prefix (+) or d means that the compound is dextrorotatory.
  • the atoms or atomic groups of these stereoisomers are connected in the same order, but their stereo structures are different.
  • a specific stereoisomer may be an enantiomer, and a mixture of isomers is usually called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers, lacking optical activity.
  • Tautomers or “tautomeric forms” mean that isomers of different energy structures can be converted into each other through a low energy barrier.
  • proton tautomers ie, tautomers of proton transfer
  • interconversions by proton migration such as keto-enol and imine-enamine isomerization
  • Valence (valency) tautomers include the interconversion of recombined bond electrons.
  • the structural formula described in the present invention includes all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): for example, R and S configurations containing asymmetric centers, The (Z) and (E) isomers of the double bond, and the (Z) and (E) conformational isomers. Therefore, a single stereochemical isomer of the compound of the present invention or a mixture of its enantiomers, diastereomers, or geometric isomers all belong to the scope of the present invention.
  • “Pharmaceutically acceptable salts” refer to certain salts of the above compounds that can maintain the original biological activity and are suitable for medical use.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) may be an amine salt formed with a suitable acid.
  • Suitable acids include inorganic and organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, and citric acid.
  • Ethanesulfonic acid fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid , Sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients. Shape agent. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • DIPEA diisopropylethylamine
  • Triphosgene refers to: trichloromethyl carbonate, abbreviated as BTC.
  • T-BuXPhos refers to: 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl.
  • KAc means: potassium acetate
  • DMA means: N,N-dimethylacetamide.
  • PCy 3 means: tricyclohexylphosphine.
  • the examples show the preparation of representative compounds represented by formula (I) and related structure identification data. It must be noted that the following examples are used to illustrate the present invention but not to limit the present invention.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the 1 H NMR spectrum was measured with a Bruker instrument (400MHz), the chemical shift was expressed in ppm, and the tetramethylsilane internal standard (0.00ppm) was used.
  • a FINNIGAN LCQAd (ESI) mass spectrometer manufactured: Thermo, model: Finnigan LCQ advantage MAX was used for mass spectrometry.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm silica gel preparation board.
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.
  • the reactions are carried out in an open atmosphere under an air atmosphere.
  • the solution in the reaction refers to an aqueous solution.
  • reaction temperature is room temperature.
  • the temperature range of room temperature is 20-30°C.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC), and the developing agent system used is: dichloromethane and methanol system, or n-hexane and ethyl acetate system, the volume ratio of the developing agent is based on the compound It can be adjusted for different polarity, and it can also be adjusted by adding a small amount of triethylamine and acidic or alkaline reagents.
  • TLC thin-layer chromatography
  • the intermediate compound (A) of the present invention is prepared by referring to the process of patent WO2016127074A1.
  • Step 2 Synthesis of tert-butyl 4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperazine-1-carboxylate
  • the third step Synthesis of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(1-piperazinyl)pyrimidin-4-amine hydrochloride
  • Step 1 Synthesis of tert-butyl 4-(6-bromo-4-methylpyridin-2-yl)piperazine-1-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)piperidine-1-carboxylate
  • the third step Synthesis of 4-methyl-N-(5-methyl-1H-pyrazol-3-yl)-6-(1-piperazinyl)pyridin-2-amine hydrochloride
  • the third step Synthesis of (S)-1-(6-(4-fluorophenyl)pyridin-3-yl)ethyl-1-amine hydrochloride
  • Test Example 1 Determination of the inhibition of RET kinase activity by the compound of the present invention
  • This test case uses Cisbio's The tyrosine kinase kit (Cat. No. 62TK0PEB) is used to determine the degree of phosphorylation of the biotinylated polypeptide substrate by the time-resolved-fluorescence energy resonance transfer method (TR-FRET).
  • TR-FRET time-resolved-fluorescence energy resonance transfer method
  • Human RET protein (RET kinase) was purchased from Carna bioscience (Japan, Item No. 08-159-5 ⁇ g).
  • the compound to be tested (the compound of the present invention and the compound 164 in WO2018017983A1 as a control) was dissolved in 100% DMSO to a final concentration of 10 mM.
  • step (2) Dissolve 4 ⁇ L of the test compound solution prepared in step (1) with 46 ⁇ L of 100% DMSO, and number the solution obtained in this step as No. 2.
  • the dilution factor is 20 times (that is, take out 1 ⁇ L from the solutions numbered 3-11, and add to the 19 ⁇ L of buffer solution from III to XI).
  • the concentration range of the compound to be tested in the solution system III to XI is 8000nM ⁇ 0.02048nM (9 gradients), and the final concentration of DMSO is 5%.
  • step (4) the 9 gradient concentrations of the test compound solutions numbered from III to XI are sequentially added to the 384-well plate according to the concentration, 4 ⁇ L per well, and two replicate wells are set.
  • the selected control kinase is another receptor tyrosine kinase KDR with similar structure to RET kinase. Purchased from Carna bioscience (Japan, article number 08-191-5 ⁇ g). The step of gradient dilution is the same as that of RET kinase, so that the final concentration range of the test compound in the reaction system is 16000nM ⁇ 0.04nM (use No. 2-10 solution for the gradient dilution of step 4), other reaction conditions are the same as above, and the final concentration of DMSO is 2 %. The same calculation method of the IC 50 values for a test compound value calculation 50 and the RET kinase inhibiting KDR kinase inhibition IC.
  • the compound of the present invention has a significant inhibitory effect on RET kinase activity, and the inhibitory effect is better than compound 164 in WO2018017983A1.
  • the inhibitory activity of the compound of the present invention on RET kinase is better than that on KDR kinase. Therefore, the compounds of the present invention can be used as a kind of effective selective RET kinase inhibitors.

Abstract

本发明提供了一种式(I)所示的可作为选择性RET(转染期间重排)激酶抑制剂的N-甲酰胺衍生物、其制备方法及其在医药上的用途。本发明提供的化合物对RET激酶活性具有显著的抑制作用，且对于RET激酶的抑制活性优于对其他种类激酶的抑制活性，因此可作为一类有效的选择性RET激酶抑制剂，

Description

N-甲酰胺衍生物、其制备方法及其在医药上的用途 技术领域
本发明涉及医药技术领域，尤其是一种可作为选择性RET激酶抑制剂的N-甲酰胺衍生物、其制备方法以及其在医药上的用途。
背景技术
转染期间重排基因(RET基因)是一种原癌基因，在人体内编码酪氨酸激酶受体，对细胞的繁殖和存活进行调控。该基因的活化需要通过与胶质细胞衍生的神经营养因子家族的受体以及该家族的α受体共同作用，来形成二聚体，通过磷酸化作用，调节信号通路，行使信号传导和调节生命活动的功能。RET基因的异常表达与多种癌症疾病相关。该基因通过染色体重排与其他基因发生融合或者是通过定点的变异，可以不依赖配体而处于持续激活状态，导致信号通路异常，从而导致细胞的过度增殖和癌症的产生。
近年来，越来越多证据显示，RET基因融合和突变是某些癌症诱发的驱动力，并且与其他驱动基因并不重合，具有显著的特异性。RET基因融合多见于***状甲状腺癌和非小细胞肺癌，如30％散发的***状甲状腺癌和70％辐射诱导的***状甲状腺癌以及约2％的非小细胞肺癌是由RET的融合基因驱动。RET基因突变多见于甲状腺髓样癌，如超过50％的甲状腺髓样癌以及近乎所有的先天性髓样癌和多发性内分泌腺瘤病是由RET基因的定点突变造成。
目前的治疗手段主要采取具有RET激酶抑制活性的多靶点激酶抑制剂来治疗RET基因融合或突变的癌症病人。但是在此条件下，由于脱靶效应和药物毒性，药物的剂量不足以达到足够抑制异常RET基因表达的水平。此外，在治疗癌症的过程中，癌细胞会通过变异产生耐药性。而一旦耐药性产生，病人的治疗选择将会变得非常的有限。因此，目前非常需要一种选择性的RET激酶抑制剂来治疗RET基因融合或突变的患者。
市场上还未有选择性地针对于RET激酶靶点的药物，目前已经公开了一系列的选择性RET激酶抑制剂专利，其中包括WO2016127074、WO2017079140、WO2017011776、WO2017161269、WO2018017983、WO2018022761、WO2018071454、WO2018136661、WO2018136663等，目前处于临床I期的药物有Blu-667、Loxo-292、GSK-3352589等。但 这些对于抗肿瘤研究是远远不够的，仍有必要研究和开发新的选择性RET激酶抑制剂，来解决未满足的医疗需求。
发明内容
为了克服现有技术的不足之处，本发明提供了一种式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2020073191-appb-000001
其中：
X选自CH或N；
R 1，R 1’，R 2，R 2’，R 3，R 3’，R 4，R 4’各自独立地选自氢、C 1-C 6烷基或C 1-C 3的羟基烷基，
或者R 1和R 1’，R 2和R 2’，R 3和R 3’，R 4和R 4’中的一组或多组各自独立地选自＝O，
或者R 1和R 1’，R 2和R 2’，R 3和R 3’，R 4和R 4’中的一组连接在一起形成环丙基、环丁基或氧杂环丁烷基，
或者R 1和R 2，R 1和R 3，R 1和R 4，R 1’和R 2’，R 1’和R 3’，R 1’和R 4’，R 2和R 3，R 2和R 4，R 2’和R 3’，R 2’和R 4’，R 3和R 4，R 3’和R 4’中的一组连接在一起形成-(CH 2)q-或-(CH 2OCH 2)-；
q为1、2或3；
D环选自芳基或杂芳基，所述芳基或杂芳基任选进一步被一个或多个R 5所取代，所述R 5各自独立地选自卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基或C 1-C 3含卤烷基。
本发明的优选方案提供一种式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐，所述B环选自以下结构：
Figure PCTCN2020073191-appb-000002
Figure PCTCN2020073191-appb-000003
其中1端点、2端点任选与A环相连。
本发明的优选方案提供一种式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐，所述B环选自以下结构：
Figure PCTCN2020073191-appb-000004
其中1端点、2端点任选与A环相连。
本发明的优选方案提供一种式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐，所述D环选自苯基、
Figure PCTCN2020073191-appb-000005
或含有1～3个N原子的六元杂芳基，所述苯基，
Figure PCTCN2020073191-appb-000006
或含有1～3个N原子的六元杂芳基任选进一步被一个或多个R 5所取代，所述R 5独立地选自卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基或C 1-C 3含卤烷基，R 5优选卤素，更优选氟。
本发明的优选方案提供的具体化合物包括但不限于表1所示的化合物：
表1
Figure PCTCN2020073191-appb-000007
Figure PCTCN2020073191-appb-000008
Figure PCTCN2020073191-appb-000009
或其立体异构体、互变异构体或其可药用的盐。
本发明提供一种式(I)所示的化合物的制备方法，所述制备方法包括：在有机溶剂中，碱性条件下，式(I-B)化合物或其盐，式(I-A)化合物或其盐和三光气反应制备得到式(I)化合物，
Figure PCTCN2020073191-appb-000010
其中，D环，X，R 1，R 1’，R 2，R 2’，R 3，R 3’，R 4和R 4’的定义如前述技术方案任一项中的式(I)中所述。
本发明的优选方案中，所述有机溶剂为二氯甲烷、乙腈、四氢呋喃或N,N-二甲基甲酰胺，优选为二氯甲烷；所述碱性条件所用的碱为二异丙基乙基胺或三乙胺，优选为二异丙基乙基胺；所述反应的反应温度为-60～0℃。
本发明提供一种药物组合物，所述的药物组合物含有有效剂量的式(I)化合物或其立体异构体、互变异构体或其可药用的盐，及可药用的载体、赋形剂或它们的组合。
本发明提供一种式(I)化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物(即本发明上述技术方案提供的药物组合物)在制备转染期间重排激酶抑制剂中的用途。
本发明提供一种式(I)化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在制备治疗由转染期间重排基因驱动的疾病的药物中的用途，其中所述的疾病优选为癌症，其中所述的癌症优选为肺癌、甲状腺癌、结肠癌、乳腺癌或胰腺癌。
本发明提供一种式(I)化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在治疗由转染期间重排基因驱动的疾病中的用途，其中所述的疾病优选为癌症，其中所述的癌症优选为肺癌、甲状腺癌、结肠癌、乳腺癌或胰腺癌。
本发明提供一种由转染期间重排基因驱动的疾病的治疗方法，包括使用式(I)化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物向受试者进行施用；其中所述的疾病优选为癌症，其中所述的癌症优选为肺癌、甲状腺癌、结肠癌、乳腺癌或胰腺癌。
发明的详细说明
本发明在说明书和权利要求书中所使用的部分术语定义如下：
“烷基”当作一基团或一基团的一部分时是指包括C 1-C 20直链或者带有支链的脂肪烃基团。优选为C 1-C 10烷基，更优选为C 1-C 6烷基。烷基基团的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环。优选为C 3-C 12环烷基，更优选为C 3-C 6环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等，优选环丙基、环己烯基。
“芳基”是指含有一个或者两个环的碳环芳香***，其中所述环可以以稠合的方式连接在一起。术语“芳基”包括比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C 6-C 10芳基，更优选芳基为苯基和萘基，最优选为苯基。芳基可以是取代或未取代的。
“杂芳基”是指芳香族5至6元单环或9至10元双环，其可以包含1至4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基、吡啶基、2-氧代-1，2-二氢吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异噁唑基、噁唑基、噁二唑基、咪唑基、吡咯基、吡唑基、***基、四氮唑基、噻唑基、异噻唑基、1，2，3-噻二唑基、苯并间二氧杂环戊烯基、苯并咪唑基、吲哚基、异吲哚基、1，3-二氧代-异吲哚基、喹啉基、吲唑基、苯并异噻唑基、苯并噁唑基和苯并异噁唑基。杂芳基可以是取代或未取代的。
“羟基”指-OH。
“羟基烷基”指含有至少一个羟基为取代基的烷基，其中烷基的定义如上所述。
“卤素”指氟、氯、溴和碘，优选氯、溴和氟，更优选氟。
“含卤烷基”指含有至少一个卤素原子为取代基的烷基，其中卤素、烷基的定义如上所述。
“氰基”指-CN。
“苄基”指-CH 2-苯基。
“酯基”指-C(O)O(烷基)或(环烷基)，其中烷基、环烷基的定义如上所述。
“DMSO”指二甲基亚砜。
“Boc”指叔丁氧基羰基。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”，如无特别指出，均是指基团可被一个或多个选自以下的基团取代：卤素、氰基、烷基、环烷基、酯基、羟基或烷氧基等；
本发明中立体化学的定义和惯例的使用通常参考以下文献：
S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-HillBook Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构体形式，包括但绝不限于非对映体、对映异构体、阻转异构体及其它们的混合物，如外消旋混合物，组成了本发明的一部分。非对映异构体可以以其物理化学差异为基础，通过层析、结晶、蒸馏或升华等方法被分离为个别非对映异构体。对映异构体可以通过分离，使手性异构混合物转化为非对映异构混合物，其方式是与适当光学活性化合物(例如手性辅助剂，譬如手性醇或Mosher氏酰氯)的反应，分离非对映异构体，且使个别非对映异构体转化为相应的纯对映异构体。本发明的中间体与化合物也可以以不同互变异构形式存在，且所有此种形式被包含在本发明的范围内。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号，(-)或l是指化合物是左旋的，前缀(+)或d是指化合物是右旋的。这些立体异构体的原子或原子团互相连接次序相同，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50:50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。
“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低 能垒互相转化。例如质子互变异构体(即质子移变的互变异构体)包括通过质子迁移的互变，如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括重组成键电子的互变。除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，和几何异构)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体的混合物都属于本发明的范围。
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。式(I)所表示的化合物的可药用的盐可以与合适的酸形成的胺盐，合适的酸包括无机酸和有机酸，例如乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、苹果酸、马来酸、扁桃酸、甲磺酸、硝酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“DIPEA”指：二异丙基乙胺。
“三光气”指：碳酸三氯甲酯，英文简称BTC。
“Pd 2(dba) 3”指：三(二亚苄基丙酮)二钯。
“t-BuXPhos”指：2-二-叔丁膦基-2,4,6-三异丙基联苯。
“KOAc”指：醋酸钾。
“DMA”指：N,N-二甲基乙酰胺。
“PCy 3”指：三环己基膦。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明，以下实施例是用于说明本发明而不是对本发明的限制。化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。 1H NMR图谱用Bruker仪器(400MHz)测定而得，化学位移用ppm 表示，使用四甲基硅烷内标准(0.00ppm)。 1H NMR的表示方法：s＝单峰，d＝双重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供耦合常数时，其单位为Hz。质谱的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo,型号：Finnigan LCQ advantage MAX)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm硅胶制备板。
柱层析一般使用烟台黄海200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organnics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中如无特殊说明，反应均在空气氛下敞口进行。
实施例中如无特殊说明，反应中的溶液是指水溶液。
实施例中如无特殊说明，反应的温度为室温。室温的温度范围是20～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，所使用的展开剂的体系为：二氯甲烷和甲醇体系，或正己烷和乙酸乙酯体系，展开剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。
本发明中间体化合物(A)参照专利WO2016127074A1的工艺制备得到。
实施例1
(S)-N-(1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-4-(4-甲基-6-(5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)哌嗪-1-甲酰胺
Figure PCTCN2020073191-appb-000011
第一步：2-氯-6-甲基-N-(5-甲基-1H-吡唑-3-基)嘧啶-4-胺的合成
Figure PCTCN2020073191-appb-000012
于100mL单口瓶中加入6-甲基-2,4-二氯嘧啶(1a)(9.72g,60mmol)、5-甲基-1H-3-氨基吡唑(a)(7.0g,72mmol)、DMSO(30mL)和DIPEA(11.6g，72mmol)，于60℃反应24小时。TLC监测反应至原料消失，降低温度至室温，反应液中加入200mL乙酸乙酯萃取，有机相分别水洗三次(30mL×3)，饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂得棕黄色粘稠液体。加入80mL二氯甲烷，静置3小时，析出2-氯-6-甲基-N-(5-甲基-1H-吡唑-3-基)嘧啶-4-胺(1c)9.9g，产率74％。
MS m/z(ESI):224.3[M+1].
第二步：4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯的合成
Figure PCTCN2020073191-appb-000013
在50mL单口瓶中加入2-氯-6-甲基-N-(5-甲基-1H-吡唑-3-基)嘧啶-4-胺(1c)(892mg,4mmol)、1-叔丁氧羰基哌嗪(1d)(1.49g,8mmol)、K 2CO 3(1.66g,12mmol)和25mL DMF，于140℃下反应6个小时，反应液冷却至室温，加入150mL乙酸乙酯萃取，有机相分别水洗三次(15mL×3)，饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂后，柱层析分离(洗脱剂及体积比为：二氯甲烷：甲醇＝20:1)，得4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1f)1.01g，产率67％。
MS m/z(ESI):374.2[M+1].
第三步：6-甲基-N-(5-甲基-1H-吡唑-3-基)-2-(1-哌嗪基)嘧啶-4-胺盐酸盐的合成
Figure PCTCN2020073191-appb-000014
在100mL单口瓶中加入4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1f)(1.24g,3.3mmol)和25mL 1,4-二氧六环，滴加25mL浓度为2.6mol/L的氯化氢/1,4-二氧六环溶液，室温下反应4h，过滤，***洗涤滤饼，真空干燥得6-甲基-N-(5-甲基-1H-吡唑-3-基)-2-(1-哌嗪基)嘧啶-4-胺盐酸盐(1g)1.1g，产率>99％。
MS m/z(ESI):274.2[M+1].
第四步：(S)-N-(1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-4-(4-甲基-6-(5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)哌嗪-1-甲酰胺的合成
Figure PCTCN2020073191-appb-000015
在50mL单口瓶中，加入(S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基-1-胺(A)(279mg,1mmol)和二氯甲烷10mL，冷却至0℃，依次加入三乙胺(1.02g,10mmol)和三光气(446mg,1.5mmol)，保持0℃下反应1h。随后将反应冷却至-50℃，加入6-甲基-N-(5-甲基-1H-吡唑-3-基)-2-(1-哌嗪基)嘧啶-4-胺盐酸盐(1g)(530mg,1.7mmol)，-50℃下反应20分钟，加入2mL甲醇和10mL水淬灭，加入50mL二氯甲烷，萃取，有机相水洗两次(10mL×2)，饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂后，柱层析分离(洗脱剂及体积比为：二氯甲烷：甲醇＝10:1)，得(S)-N-(1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-4-(4-甲基-6-(5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)哌嗪-1-甲酰胺(I-1)291mg，产率57％。
1H NMR(400MHz,DMSO)δ11.89(s,1H),9.35(s,1H),8.66(d,J＝4.5Hz,1H),8.40(d,J＝1.9Hz,1H),7.95(dd,J＝8.5,2.2Hz,1H),7.90(d,J＝4.2Hz,1H),7.86(d,J＝8.5Hz,1H),7.00(d,J＝7.6Hz,1H),6.33-5.98(m,2H),4.92(t,J＝7.2Hz,1H),3.67(s,4H),3.40(s,4H),2.19(s,3H),2.13(s,3H),1.43(d,J＝7.1Hz,3H)ppm.
MS m/z(ESI):506.3[M+1].
参考实施例1，可制备以下化合物(I-2)，化合物(I-3)，化合物(I-4)，化合物(I-5)， 化合物(I-6)和化合物(I-7)。其结构及表征数据如下：
化合物(I-2)：
Figure PCTCN2020073191-appb-000016
1H NMR(400MHz,DMSO)δ12.01(s,1H),9.39(s,1H),8.66(d,J＝4.4Hz,1H),8.40(d,J＝1.7Hz,1H),7.94(dd,J＝8.6,2.0Hz,1H),7.90(d,J＝4.2Hz,1H),7.85(d,J＝8.4Hz,1H),6.97(s,1H),6.18(s,2H),4.94(t,J＝7.2Hz,1H),4.74(s,1H),4.32(d,J＝12.6Hz,1H),4.04(d,J＝11.4Hz,1H),3.93(d,J＝13.2Hz,1H),3.05(d,J＝11.0Hz,2H),2.94-2.79(m,1H),2.20(s,3H),2.18(s,3H),1.44(d,J＝7.1Hz,3H),1.10(d,J＝5.8Hz,3H)ppm.
MS m/z(ESI):520.6[M+1].
化合物(I-3)：
Figure PCTCN2020073191-appb-000017
1H NMR(400MHz,DMSO)δ11.83(s,1H),9.25(s,1H),8.66(d,J＝4.5Hz,1H),8.38(s,1H),7.93(dd,J＝8.5,1.9Hz,1H),7.89(d,J＝4.2Hz,1H),7.85(d,J＝8.5Hz,1H),6.76(d,J＝7.4Hz,1H),6.17(s,1H),6.14(s,1H),4.86(t,J＝7.2Hz,1H),3.78-3.63(m,4H),3.63-3.49(m,2H),2.18(s,3H),2.11(s,3H),1.40(d,J＝7.0Hz,3H),1.34(s,3H),1.26(s,3H)ppm.
MS m/z(ESI):534.3[M+1].
化合物(I-4)：
Figure PCTCN2020073191-appb-000018
1H NMR(400MHz,DMSO)δ11.85(s,1H),9.26(s,1H),8.66(d,J＝4.3Hz,1H),8.40(d,J＝1.6Hz,1H),7.94(dd,J＝8.5,2.0Hz,1H),7.89(d,J＝4.1Hz,1H),7.86(d,J＝8.5Hz,1H),7.09(d,J＝7.5Hz,1H),6.14(s,2H),4.94(t,J＝7.2Hz,1H),4.33-4.18(m,2H),3.38-3.36(m, 2H),2.95(d,J＝9.4Hz,2H),2.19(s,3H),2.10(s,3H),1.73(s,2H),1.57(d,J＝7.4Hz,2H),1.43(d,J＝7.0Hz,3H)ppm.
MS m/z(ESI):532.7[M+1].
化合物(I-5)：
Figure PCTCN2020073191-appb-000019
1H NMR(400MHz,DMSO)δ11.83(s,1H),9.28(s,1H),8.67(d,J＝4.0Hz,1H),8.40(s,1H),7.95(d,J＝7.4Hz,1H),7.90(d,J＝4.1Hz,1H),7.86(d,J＝8.3Hz,1H),6.80(d,J＝7.1Hz,1H),6.16(s,2H),4.99(t,J＝7.2Hz,1H),4.53(d,J＝13.3Hz,2H),4.35-4.15(m,2H),2.95(d,J＝10.8Hz,2H),2.19(s,3H),2.11(s,3H),1.44(d,J＝6.8Hz,3H),1.11(s,6H)ppm.
MS m/z(ESI):534.3[M+1].
化合物(I-6)：
Figure PCTCN2020073191-appb-000020
1H NMR(400MHz,CDCl 3)δ8.37(d,J＝1.9Hz,1H),8.35(d,J＝4.4Hz,1H),7.87(d,J＝8.5Hz,1H),7.76(dd,J＝8.5,2.1Hz,1H),7.56(d,J＝4.2Hz,1H),6.04(s,2H),5.69(d,J＝6.5Hz,1H),5.11-5.06(m,1H),3.83-3.63(m,6H),2.26(s,3H),2.22(s,3H),1.56(d,J＝7.0Hz,3H),1.12-0.94(m,4H)ppm.
MS m/z(ESI):532.7[M+1].
化合物(I-7)：
Figure PCTCN2020073191-appb-000021
1H NMR(400MHz,DMSO)δ11.85(s,1H),9.26(s,1H),8.66(d,J＝4.3Hz,1H),8.40(d,J＝1.6Hz,1H),7.94(dd,J＝8.5,2.0Hz,1H),7.89(d,J＝4.1Hz,1H),7.86(d,J＝8.5Hz,1H), 7.09(d,J＝7.5Hz,1H),6.14(brs,2H),5.00-4.80(m,1H),4.33-4.15(m,2H),3.44-3.35(m,2H),2.95(d,J＝9.4Hz,2H),2.19(s,3H),2.10(s,3H),1.73(s,2H),1.57(d,J＝7.4Hz,2H),1.43(d,J＝7.0Hz,3H)ppm.
MS m/z(ESI):532.3[M+1].
实施例2
(S)-N-(1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)吡啶-2-基)哌嗪-1-甲酰胺
Figure PCTCN2020073191-appb-000022
第一步：4-(6-溴-4-甲基吡啶-2-基)哌嗪-1-甲酸叔丁酯的合成
Figure PCTCN2020073191-appb-000023
在100mL单口瓶中加入2-溴-6-氟-4-甲基吡啶(2a)(950mg,5mmol)、1-叔丁氧羰基哌嗪(1d)(1.4g,7.5mmol)、K 2CO 3(2.09g,15mmol)以及35mL DMF，于140℃下反应6h。反应液冷却至室温，加入200mL乙酸乙酯，水洗三次(20mL×3)，饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂后，柱层析分离(洗脱剂及体积比为：二氯甲烷：甲醇＝30:1)，得4-(6-溴-4-甲基吡啶-2-基)哌嗪-1-甲酸叔丁酯(2b)1.45g，产率81％。
MS m/z(ESI):[M+1]357.1.
第二步：4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)吡啶-2-基)哌啶-1-甲酸叔丁酯的合成
Figure PCTCN2020073191-appb-000024
在100mL单口瓶中加入4-(6-溴-4-甲基吡啶-2-基)哌嗪-1-甲酸叔丁酯(2b)(1.07g,3 mmol)、5-甲基-1H-3-氨基吡唑(a)(582mg,7.5mmol)、Pd 2(dba) 3(550mg,0.6mmol)、t-BuXPhos(510mg,1.2mmol)、KOAc(882mg,9mmol)和15mL DMA，抽换氮气三次，于140℃下反应2h。待反应液冷却至室温，加入200mL乙酸乙酯，水洗三次(20mL×3)，饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压除去溶剂后，柱层析分离(洗脱剂及体积比为：二氯甲烷：甲醇＝20:1)，得4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)吡啶-2-基)哌啶-1-甲酸叔丁酯(2c)421mg，产率38％。
MS m/z(ESI):[M+1]373.2.
第三步：4-甲基-N-(5-甲基-1H-吡唑-3-基)-6-(1-哌嗪基)吡啶-2-胺盐酸盐的合成
Figure PCTCN2020073191-appb-000025
在50mL单口瓶中加入4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)吡啶-2-基)哌啶-1-甲酸叔丁酯(2c)(421mg,1.1mmol)和8mL二氧六环，加入浓度为2.6mol/L氯化氢/1,4-二氧六环溶液(20mL)，室温下反应4h，浓缩，真空干燥得4-甲基-N-(5-甲基-1H-吡唑-3-基)-6-(1-哌嗪基)吡啶-2-胺盐酸盐(2d)440mg，产率>99％。
MS m/z(ESI):[M+1]273.2.
第四步：(S)-N-(1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)吡啶-2-基)哌嗪-1-甲酰胺的合成
Figure PCTCN2020073191-appb-000026
在50mL单口瓶中，加入(S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基-1-胺(A)(140mg,0.5mmol)和5mL二氯甲烷，冷却至0℃，依次加入三乙胺(510mg,5mmol)和三光气(223 mg,0.75mmol)，保持0℃反应1h。随后将反应冷却至-50℃，加入化合物(2d)(232mg,0.75mmol)，-50℃下反应1个小时，加入2mL甲醇和10mL水淬灭，加入50mL二氯甲烷，有机相水洗两次(10mL×2)，饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压除去溶剂后，柱层析分离(洗脱剂及体积比为：二氯甲烷：甲醇＝30:1)，收集混合物再次用硅胶制备板分离(展开剂及体积比为：二氯甲烷：甲醇＝12:1)，得(S)-N-(1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)吡啶-2-基)哌嗪-1-甲酰胺(I-8)11mg，产率5％。
1H NMR(400MHz,DMSO)δ11.60(s,1H),8.63(d,J＝4.3Hz,1H),8.58(s,1H),8.37(s,1H),7.91(d,J＝6.9Hz,1H),7.86(d,J＝4.2Hz,1H),7.83(d,J＝8.4Hz,1H),6.96(d,J＝7.5Hz,1H),6.30(s,1H),5.97(s,1H),5.93(s,1H),4.89(t,J＝7.2Hz,1H),3.38(s,8H),2.14(s,3H),2.08(s,3H),1.40(d,J＝6.9Hz,3H)ppm.
MS m/z(ESI):[M+1]505.3.
实施例3
(S)-N-(1-(6-(4-氟-苯基)吡啶-3-基)乙基)-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)胺基)嘧啶-2-基)哌嗪-1-甲酰胺
Figure PCTCN2020073191-appb-000027
第一步：1-(6-(4-氟苯)吡啶-3-基)乙基-1-酮的合成
Figure PCTCN2020073191-appb-000028
在250mL单口瓶中加入1-(6-溴-吡啶-3-基)乙基-1-酮(3a)(4.0g,20mmol)、4-氟苯硼酸(3b)(4.2g,30mmol)、Pd 2(dba) 3(920mg,1mmol)、PCy 3(560mg,2mmol)、碳酸钠(8.5g,80mmol)和1,4-二氧六环/水(70mL/7mL)混合溶剂，抽换氮气三次，于100℃下反应过夜。反应结束后降温至室温，硅藻土过滤，用200mL乙酸乙酯洗涤，水洗三次(40mL×3)， 饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂后，柱层析分离(洗脱剂及体积比为：二氯甲烷：甲醇＝20:1)，得1-(6-(4-氟苯基)吡啶-3-基)-乙酮(3c)4.5g，产率>99％。
MS m/z(ESI):[M+1]216.1
第二步：(S)-N-((S)-1-(6-(4-氟苯基)吡啶-3-基)乙基)-2-甲基丙基-2-磺酰亚胺的合成
Figure PCTCN2020073191-appb-000029
于250mL三口瓶中加入1-(6-(4-氟苯)吡啶-3-基)乙基-1-酮(3c)(4.5g,21mmol)、(R)-(+)-叔丁基亚磺酰胺(2.56g,21mmol)和50mL四氢呋喃，抽换氮气三次，加入四钛酸乙酯(9.62g,42mmol),于75℃下反应17小时,TLC监测反应至原料消失，降低温度至-78℃，缓慢滴加三仲丁基硼氢化锂(11.97g,63mmol),维持-78℃反应2小时后，恢复室温，滴加15mL甲醇淬灭，加入100mL冰水，析出固体，硅藻土过滤，乙酸乙酯洗涤，减压蒸馏除去溶剂，加入300mL乙酸乙酯，水洗三次(40mL×3)，饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，柱层析(洗脱剂及体积比为：石油醚：乙酸乙酯＝7:3)分离得(S)-N-((S)-1-(6-(4-氟苯基)吡啶-3-基)乙基)-2-甲基丙基-2-磺酰亚胺(3d)2g,产率31％。
MS m/z(ESI):321.1[M+1].
第三步：(S)-1-(6-(4-氟苯基)吡啶-3-基)乙基-1-胺盐酸盐的合成
Figure PCTCN2020073191-appb-000030
在100mL单口瓶中加入(S)-N-((S)-1-(6-(4-氟苯基)吡啶-3-基)乙基)-2-甲基丙基-2-磺酰亚胺(3d)(2g,6.2mmol)和20mL 1,4-二氧六环，滴加25mL浓度为2.6mol/L的氯化氢/1,4-二氧六环溶液，室温下反应2h，过滤，乙酸乙酯洗涤滤饼，真空干燥得(S)-1-(6-(4-氟苯基)吡啶-3-基)乙基-1-胺盐酸盐(3e)1.5g，产率84％。
MS m/z(ESI):217.1[M+1].
Figure PCTCN2020073191-appb-000031
第四步：(S)-N-(1-(6-(4-氟-苯基)吡啶-3-基)乙基)-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)胺基)嘧啶-2-基)哌嗪-1-甲酰胺的合成
在50mL单口瓶中，加入(S)-1-(6-(4-氟苯基)吡啶-3-基)乙基-1-胺盐酸盐(3e)(126mg,0.5mmol)，三光气(225mg,0.75mmol)和5mL二氯甲烷，冷却至-20℃，加入三乙胺(758mg,7.5mmol)，保持-20℃下反应1h。加入6-甲基-N-(5-甲基-1H-吡唑-3-基)-2-(1-哌嗪基)嘧啶-4-胺盐酸盐(1g)(186mg,0.6mmol)，保持-20℃下反应30分钟，加入1mL甲醇和5mL水淬灭，加入50mL二氯甲烷，有机相水洗两次(10mL×2)，饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂后，柱层析分离(洗脱剂及体积比为：二氯甲烷：甲醇＝10:1)，得到的粗品再一次通过硅胶制备板分离(展开剂及体积比为：二氯甲烷：甲醇＝10:1)，得(S)-N-(1-(6-(4-氟-苯基)吡啶-3-基)乙基)-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)胺基)嘧啶-2-基)哌嗪-1-甲酰胺(I-9)30mg，产率12％。
1H NMR(400MHz,DMSO-d 6)δ11.85(s,1H),9.28(s,1H),8.61(s,1H),8.14-8.07(m,2H),7.90(d,J＝8.2Hz,1H),7.81(d,J＝8.3Hz,1H),7.30(t,J＝8.8Hz,2H),6.98(d,J＝7.5Hz,1H),6.19(s,1H),6.13(s,1H),4.99-4.82(m,1H),3.67(s,4H),3.40(s,4H),2.20(s,3H),2.12(s,3H),1.44(d,J＝7.1Hz,3H)ppm.
MS m/z(ESI):516.3[M+1].
生物学评价
测试例1、本发明化合物对RET激酶活性抑制的测定
本测试例使用Cisbio公司的
Figure PCTCN2020073191-appb-000032
酪氨酸激酶试剂盒(货号62TK0PEB)，通过测定生物素化的多肽底物磷酸化程度，以时间分辨-荧光能量共振转移方法(TR-FRET)进行测定。人源RET蛋白(RET激酶)购买于Carna bioscience(日本，货号08-159-5μg)。
实验步骤如下：
⑴将待测化合物(本发明化合物和作为对照的WO2018017983A1中的化合物164)溶解于100％的DMSO中，使其终浓度为10mM。
⑵用46μL的100％DMSO溶解4μL步骤(1)配制的待测化合物溶液，将本步骤得到的溶液编为2号。
⑶将2号溶液进行后续梯度稀释，稀释倍数为5倍(即20μL的100％DMSO加5μL溶液)，共稀释9个梯度，编号为3到11号。
注：2号不用于第(4)步的稀释。
(除特别说明，以下步骤均需要在冰上进行)
⑷用试剂盒(Cisbio，货号62TK0PEB)中提供的缓冲液对编号为3到11号的溶液继续进行稀释，稀释倍数为20倍(即从编号3-11的溶液中各取出1μL，加入到含有19μL缓冲液的III到XI号的溶液中)。此时，III到XI号溶液体系中待测化合物的浓度范围为8000nM～0.02048nM(9个梯度)，DMSO终浓度为5％。
⑸将步骤(4)中编号为III到XI号的9个梯度浓度的待测化合物溶液按浓度依次加入到384孔板中，每孔4μL，设置两个复孔。
⑹每孔加2μL的人源RET蛋白，冰上孵育10分钟。
⑺每孔加入2μL的ATP(Sigma#A7699)和2μL的生物素化多肽底物(Cisbio，货号62TK0PEB)启动磷酸化反应。在37℃下孵育半小时。
⑻每孔中加入5μL偶联有铕系元素化合物的抗磷酸化酪氨酸抗体(试剂盒内提供，货号62TK0PEB)和5μL偶联有修饰化的别藻蓝蛋白XL665的链霉亲和素(Cisbio，货号62TK0PEB)。
⑼室温下继续孵育1小时。孵育结束后，用酶标仪(BMG Labtech，型号：FLUOStar Omega)的TF-FRET模式读取各孔在发射波长为665nm和615nm下的荧光强度，自动算出比值。
⑽通过与空白对照组(不加抑制剂)荧光强度比值进行对比，计算化合物在各浓度下 的抑制率，进而通过GraphPad Prism5以对数浓度-抑制率进行曲线拟合，计算化合物的IC 50值，结果见下表2。
选用的对照激酶为与RET激酶结构类似的另一种受体酪氨酸激酶KDR。购买自Carna bioscience(日本，货号08-191-5μg)。梯度稀释步骤同RET激酶，使待测化合物在反应体系中的终浓度范围为16000nM～0.04nM(用2-10号溶液进行步骤4的梯度稀释)，其他反应条件同上，DMSO的终浓度为2％。待测化合物对KDR激酶抑制的IC 50值计算方法与RET激酶抑制的IC 50值计算方法相同。
表2.本发明化合物对RET激酶和KDR激酶抑制的IC 50值
化合物编号 RET(IC 50) KDR(IC 50) KDR/RET比
I-1 0.7nM 295nM 433
I-8 2.5nM 157nM 63
I-9 5.3nM 264nM 50
164 73nM 2300nM 32
从上表可以看出，本发明的化合物对RET激酶活性具有显著的抑制作用，且抑制作用的效果优于WO2018017983A1中的化合物164。本发明化合物对于RET激酶的抑制活性优于对KDR激酶的抑制活性。因此本发明化合物可作为一类有效的选择性RET激酶抑制剂。
备注：化合物164的结构式如下所示，其制备方法参见WO2018017983A1。
Figure PCTCN2020073191-appb-000033
除非特别限定，本发明所用术语均为本领域技术人员通常理解的含义。
本发明所描述的实施方式仅出于示例性目的，并非用以限制本发明的保护范围，本领域技术人员可在本发明的范围内作出各种其他替换、改变和改进，因而，本发明不限于上述实施方式，而仅由权利要求限定。

Claims (10)

  1. 一种式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐，
    Figure PCTCN2020073191-appb-100001
    其中：
    X选自CH或N；
    R 1，R 1’，R 2，R 2’，R 3，R 3’，R 4，R 4’各自独立地选自氢、C 1-C 6烷基或C 1-C 3的羟基烷基，
    或者R 1和R 1’，R 2和R 2’，R 3和R 3’，R 4和R 4’中的一组或多组各自独立地选自＝O，
    或者R 1和R 1’，R 2和R 2’，R 3和R 3’，R 4和R 4’中的一组连接在一起形成环丙基、环丁基或氧杂环丁烷基，
    或者R 1和R 2，R 1和R 3，R 1和R 4，R 1’和R 2’，R 1’和R 3’，R 1’和R 4’，R 2和R 3，R 2和R 4，R 2’和R 3’，R 2’和R 4’，R 3和R 4，R 3’和R 4’中的一组连接在一起形成-(CH 2)q-或-(CH 2OCH 2)-；
    q为1、2或3；
    D环选自芳基或杂芳基，所述芳基或杂芳基任选进一步被一个或多个R 5所取代，所述R 5各自独立地选自卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基或C 1-C 3含卤烷基。
  2. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其特征在于，所述B环选自以下结构：
    Figure PCTCN2020073191-appb-100002
    Figure PCTCN2020073191-appb-100003
    其中1端点、2端点任选与A环相连。
  3. 根据权利要求2所述的化合物或其立体异构体、互变异构体或其可药用的盐，其特征在于，所述B环选自以下结构：
    Figure PCTCN2020073191-appb-100004
    其中1端点、2端点任选与A环相连。
  4. 根据权利要求1-3任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其特征在于，所述D环选自苯基、
    Figure PCTCN2020073191-appb-100005
    或含有1～3个N原子的六元杂芳基；所述苯基、
    Figure PCTCN2020073191-appb-100006
    或含有1～3个N原子的六元杂芳基任选进一步被一个或多个R 5所取代，所述R 5各自独立地选自卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基或C 1-C 3含卤烷基，R 5优选卤素，更优选氟。
  5. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其 特征在于，其中所述的化合物具体结构包括：
    Figure PCTCN2020073191-appb-100007
  6. 权利要求1所示的式(I)化合物的制备方法，其特征在于，所述制备方法包括：在有机溶剂中，碱性条件下，式(I-B)化合物或其盐，式(I-A)化合物或其盐和三光气反应制备得到式(I)化合物，
    Figure PCTCN2020073191-appb-100008
    其中，D环，X，R 1，R 1’，R 2，R 2’，R 3，R 3’，R 4和R 4’的定义如权利要求1中所述。
  7. 根据权利要求6所述的制备方法，其特征在于，所述有机溶剂为二氯甲烷、乙腈、四氢呋喃或N,N-二甲基甲酰胺，优选为二氯甲烷；所述碱性条件所用的碱为二异丙基乙基胺或三乙胺，优选为二异丙基乙基胺；所述反应的反应温度为-60～0℃。
  8. 一种药物组合物，所述的药物组合物含有有效剂量的权利要求1～5中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，及可药用的载体、赋形剂或它们的组合。
  9. 权利要求1～5中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或权利要求8所述的药物组合物在制备转染期间重排激酶抑制剂中的用途。
  10. 权利要求1～5中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或权利要求8所述的药物组合物在制备治疗由转染期间重排基因驱动的疾病的药物中的用途，其中所述的疾病优选为癌症，其中所述的癌症优选为肺癌、甲状腺癌、结肠癌、乳腺癌或胰腺癌。
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