WO2017219500A1 - 用作egfr抑制剂的嘧啶类化合物及其应用 - Google Patents

用作egfr抑制剂的嘧啶类化合物及其应用 Download PDF

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WO2017219500A1
WO2017219500A1 PCT/CN2016/098057 CN2016098057W WO2017219500A1 WO 2017219500 A1 WO2017219500 A1 WO 2017219500A1 CN 2016098057 W CN2016098057 W CN 2016098057W WO 2017219500 A1 WO2017219500 A1 WO 2017219500A1
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group
compound
egfr
alkyl
formula
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PCT/CN2016/098057
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French (fr)
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吴豫生
牛成山
耿阳
梁阿朋
郭中伟
刘建涛
杨俊亮
霍云峰
韩兴旺
孟庆国
李敬亚
郭瑞云
邹大鹏
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郑州泰基鸿诺医药股份有限公司
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen 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
    • A61K31/495—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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • 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

Definitions

  • the present invention belongs to the field of medical technology, and particularly relates to pyrimidine compounds useful as EGFR inhibitors and their use in the preparation of a medicament for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases, particularly non-small cell lung cancer.
  • the Epidermal Growth Factor Receptor is a transmembrane protein tyrosine kinase of the erbB receptor family.
  • a growth factor ligand eg, epidermal growth factor (EGF)
  • the receptor can homodimerize with an additional EGFR molecule, or with another family member (eg, erbB2 (HER2), erbB3 (HER3) , or erbB4 (HER4)) heterodimerization occurs.
  • HER2 erbB2
  • HER3 erbB3
  • HER4 erbB4
  • Homologous dimerization and/or heterodimerization of the erbB receptor results in phosphorylation of key tyrosine residues in the intracellular domain and results in stimulation of many intracellular signaling pathways involved in cell proliferation and survival.
  • Deregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival, and has been described in
  • erbB family represented as legitimate targets for anticancer drug development, as many drugs targeting EGFR or erbB2 is now widely used in clinical practice, including gefitinib (IRESSA TM), erlotinib ( TARCEVA TM) and lapatinib (TYKERB TM) and the like.
  • IRESSA TM gefitinib
  • TARCEVA erlotinib
  • TYKERB TM lapatinib
  • erbB receptor signaling and its involvement in tumorigenesis are provided in New England Journal of Medicine (2008, 358, 1160-1174) and Biochemical and Biophysical Research Communications (2004, 319, 1-11). Detailed discussion.
  • Lung cancer is the world's highest incidence of cancer. It ranks first among all cancers in China. It is also the cancer with the highest morbidity and mortality in China. About 30% of lung cancer patients in China have EGFR mutations. Among them, L858R and exon 19 deletion mutations account for more than 90%, and such patients are more sensitive to EGFR inhibitors.
  • the existing first-generation EGFR inhibitors such as erlotinib and gefitinib have good curative effect on such patients, which can reduce tumors in more than 60% of patients and significantly prolong the disease. The progression-free survival of human beings. However, the vast majority of patients will acquire resistance within 6-12 months. This resistance pattern is a further mutation of EGFR, which reduces its sensitivity to first-generation EGFR inhibitors.
  • T790M The most common of these mutations is the so-called "gatekeeper" mutation T790M (Science, 2004, Vol. 304, 1497-1500; New England Journal of Medicine 2004, 350, 2129-2139), from the original L- at this site. Threonine (T) is replaced by L-methionine (M), and the mutated EGF tyrosine kinase R no longer binds to gefitinib or erlotinib, thus making the first generation of EGFR inhibitors No longer effective, resulting in such patients currently in a state of no drug availability. Clinically, 50% of patients who developed resistance to first-generation EGFR inhibitors had EGFR T790M mutations. The first generation of EGFR inhibitors, such as gefitinib and erlotinib, in the T790M mutant cell line H1975 were greater than 3 [mu]M and were essentially inactive.
  • the second-generation irreversible pan-EGFR inhibitor (Afatinib BIBW2992) currently on the market is significantly better than the first-generation EGFR inhibitor in patients with EGFR-mutant lung cancer.
  • the second-generation inhibitor also has a strong wild-type EGFR inhibitory activity, and the inhibitory activity against wild-type EGFR is significantly higher than that of the drug-resistant T790M mutation.
  • the toxic side effects such as rash of the patient are severe and the drug-resistant patients have poor efficacy, only small Some first-generation EGFR inhibitor-resistant patients respond to these drugs.
  • WO2012/151561 and WO2013/169401 respectively disclose compounds which are said to have EGFR inhibitory activity and specifically disclose compounds having a 2,4-diaminopyrimidine core structure.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 haloalkyl or cyano;
  • R 2 is selected from a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, a C 1-6 deuterated haloalkoxy group, a C 3-6 cycloalkoxy group, a C 3-6 halogenated group. a cycloalkoxy group, a C 1-6 alkylthio group or a C 1-6 alkylamino group;
  • R 3 is selected from any one of the following structures:
  • R 6 and R 7 are independently selected from C 1-6 alkyl, and the alkyl group is optionally substituted by NR 8 R 9 ,
  • R 6 and R 7 together with the nitrogen atom to which they are attached form a 4-6 membered saturated heterocyclic ring optionally containing an additional hetero atom selected from nitrogen and oxygen, said heterocyclic ring optionally being C 1-6 Alkyl, NR 8 R 9 or C 1-6 acyl,
  • R 8 and R 9 are independently selected from H and C 1-6 alkyl, or R 8 and R 9 together with the nitrogen atom to which they are attached form 4-, optionally containing an additional hetero atom selected from nitrogen and oxygen. 6-membered saturated heterocyclic ring;
  • R 4 is selected from any one of the following structures:
  • R 5 is selected from C 1-12 alkyl, optionally substituted aryl or optionally substituted heteroaryl;
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3 a halogenated cycloalkyl group of -6 or an alkylamino group of 1-6 .
  • the compound of formula I is as shown in formula II:
  • Ar is selected from phenyl or substituted phenyl, heteroaryl or substituted heteroaryl;
  • R 1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl or cyano;
  • R 2 is selected from the group consisting of methoxy, monofluoromethoxy, difluoromethoxy, deuterated monofluoromethoxy, deuterated difluoromethoxy, trifluoromethoxy, C 2-6 alkoxy a halogenated alkoxy group of C 2-6, a cycloalkoxy group of C 3-6 or a halogenated cycloalkoxy group of C 3-6 ;
  • R 3 is selected from any one of the following structures:
  • X 1 , X 2 and X 3 are each independently selected from hydrogen or halogen.
  • the substituted phenyl or heteroaryl group is a monosubstituted, disubstituted or trisubstituted phenyl or heteroaryl group, and the substituents are each independently selected from the group consisting of halogen and cyanide.
  • Base nitro, ester, C 1-4 alkyl or cycloalkyl, C 1-4 alkoxy or cycloalkoxy, C 1-4 haloalkyl, C 1-4 acyl, C 1-6 alkane Amino or cycloalkylamino. In one embodiment, it refers to the ester group of formula -C (O) OC 1-6 alkyl group, preferably -C (O) OMe, -C ( O) OEt like.
  • Ar is a phenyl group which is mono-, di- or tri-substituted by a cyano group or a halogen.
  • R 3 is
  • the compound of formula I is selected from the group consisting of
  • the pharmaceutically acceptable salt is a mineral acid salt or an organic acid salt selected from the group consisting of a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a sulfate salt, a hydrogen sulfate salt, a nitrate salt, and a phosphate salt.
  • An acid phosphate is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, Fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, besylate, salicylate, picrate, valley Alkaloids, salicylates, ascorbates, camphorates, camphorsulfonates.
  • the pyrimidine compound of the present invention is a compound of the formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which inhibits activation or resistance of one or more EGFR Mutations, such as the L858R activating mutant, the Exon19 deletion EGFR activating mutant, and the T790M resistance mutant; this compound increases the inhibitory activity against mutations such as the resistant EGFR T790M, and simultaneously reduces
  • the inhibitory activity against wild-type EGFR can be used to develop third-generation EGFR mutant selective inhibitors with higher activity, better selectivity and lower toxicity.
  • the pyrimidine compound of the present invention has been shown to inhibit the proliferation of the EGFR T790M/L858R double mutant enzyme at a nanomolar concentration, while the inhibition of the wild type EGFR enzyme is relatively weak. Therefore, these compounds can be used not only for the treatment of EGFR-sensitive mutant cancers, but also for the cases of secondary resistance in the current EGFR-TKI treatment; and their mutation selectivity greatly reduces the inhibition of wild-type EGFR. Toxic side effects are an ideal treatment for diseases caused by EGFR mutations.
  • Alkyl refers to a monovalent straight or branched chain saturated hydrocarbon group containing from 1 to 12 carbon atoms consisting solely of carbon and hydrogen atoms.
  • the "alkyl group” is preferably an alkyl group of 1 to 6 carbon atoms, that is, a C 1 -C 6 alkyl group, more preferably a C 1 -C 4 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
  • Alkoxy refers to a radical of the formula -OR wherein R is alkyl as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, t-butoxy, and the like.
  • Halogen (halo) means a fluorine, chlorine, bromine or iodine substituent.
  • Haloalkyl refers to an alkyl group, as defined herein, wherein one or more hydrogens are replaced by the same or different halogens.
  • Examples of the haloalkyl group include -CH 2 Cl, -CH 2 CF 3 , -CH 2 CCl 3 , a perfluoroalkyl group (for example, -CF 3 ), and the like.
  • Haloalkoxy refers to a radical of the formula -OR wherein R is haloalkyl as defined herein.
  • haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.
  • Deuterated haloalkoxy refers to a haloalkoxy group, as defined herein, wherein one or more hydrogens are replaced by deuterium.
  • Cycloalkyl refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring having from 3 to 12, preferably from 3 to 10, more preferably from 3 to 6 ring atoms.
  • the cycloalkyl group can be optionally substituted by one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino or dialkylamino.
  • substituents include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl and the like.
  • Cycloalkoxy refers to a radical of the formula -OR wherein R is cycloalkyl as defined herein.
  • exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • acyl refers to a radical of the formula -C(O)R wherein R is alkyl as defined herein.
  • exemplary acyl groups include acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, t-butyryl and the like.
  • ester group refers to a group of the formula -C(O)OR wherein R is alkyl as defined herein.
  • exemplary ester groups include -C(O)OMe, -C(O)OEt, and the like.
  • Alkylthio refers to a radical of the formula -SR a where R a is H or alkyl as defined herein.
  • Alkylamino refers to a radical of the formula -NR a R b wherein R a is H or alkyl as defined herein and R b is alkyl as defined herein.
  • Cycloalkylamino refers to a radical of the formula -NR a R b wherein R a is H, alkyl as defined herein or cycloalkyl as defined herein, and R b is cycloalkane as defined herein base.
  • aryl refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 20 carbon atoms in the ring portion.
  • the aryl group is preferably a C 6 - 10 aryl group such as a phenyl group, a biphenyl group or a naphthyl group, more preferably a phenyl group.
  • Heteroaryl refers to a monocyclic, bicyclic or tricyclic radical of 5 to 12 ring atoms containing at least one ring heteroatom containing one, two or three selected from N, O or S, remaining
  • the ring atom is an aromatic ring of C, and it should be clear that the point of attachment of the heteroaryl group should be on the aromatic ring.
  • the heteroaryl group is preferably 5-8 ring atoms, more preferably 5-6 ring atoms.
  • heteroaryl groups include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furanyl , pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzo Imidazolyl, benzoxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, fluorenyl, isodecyl, triazolyl, triazinyl , quinoxalinyl, fluorenyl, quinazolinyl, quinazinyl, naphthyridin
  • heterocyclyl refers to a cycloalkyl group as defined herein in which 1, 2 or 3 ring atoms are replaced by a hetero atom selected from N, O or S.
  • the heterocyclic group is preferably a 3-7 membered heterocyclic group, more preferably a 4-6 membered heterocyclic group, and most preferably a 5-6 membered heterocyclic group.
  • Exemplary heterocyclic groups include piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, azetidinyl and the like.
  • the solvate referred to in the present invention means a complex of the compound of the present invention and a solvent. They Alternatively, it may be reacted in a solvent or precipitated or crystallized from a solvent. For example, a complex formed with water is referred to as a hydrate; others include an alcoholate, a ketone compound, and the like.
  • the solvates of the present invention include the compounds of the formula I of the present invention and salts thereof, and solvates of stereoisomers.
  • a stereoisomer as referred to in the present invention means that the compound of formula I in the present invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains a chiral center, the compound contains the enantiomer.
  • the invention includes mixtures of the two isomers and isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When a compound of formula I contains more than one chiral center, diastereomers may be present.
  • Stereoisomers of the invention include resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • a prodrug as referred to in the present invention refers to a parent compound which includes a known amino protecting group and a carboxy protecting group, which are hydrolyzed under physiological conditions or released by an enzymatic reaction.
  • Specific prodrug preparation methods can be referred to the prior art (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. ChemLett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
  • the present invention provides a process for the preparation of the compound of the above formula (I), which comprises dissolving Intermediate A, Intermediate B and p-toluenesulfonic acid in an organic solvent, and reacting in a protective atmosphere at 50 to 100 ° C. After the reaction is completed, dichloromethane and a saturated aqueous solution of sodium carbonate are added, and the layers are separated, and the organic phase is removed to remove the solvent, and then separated and purified;
  • R 1 , R 2 , R 3 , X 1 , X 2 and X 3 are as defined in formula II.
  • the preparation method involves the following reaction formula:
  • the molar ratio of the intermediate A to the intermediate B is from 1 to 5:1.
  • the p-toluenesulfonic acid is added in the form of mono-p-toluenesulfonic acid; the molar ratio of p-toluenesulfonic acid to intermediate B is from 0.5 to 2:1.
  • the organic solvent used was 2-pentanol; the amount of the organic solvent used was 5 ml of an organic solvent per 50 mg of the intermediate B.
  • the protective atmosphere is nitrogen. The separation and purification are carried out by column chromatography.
  • the intermediate A was prepared by the following method:
  • Method 1 Mixing compound a1 with diisopropylethylamine and n-butanol to form a mixture, cooling the mixture to -20 ° C, adding compound a2 to carry out the reaction, then raising the temperature to room temperature, stirring, and removing the solvent of the reaction system. Adding ethyl acetate and water to the residue, layering, taking the organic phase to remove the solvent, separating and purifying, that is, obtaining;
  • Method 2 Mixing compound a1 with diisopropylethylamine, n-butanol, and compound a2 to obtain a mixture, and heating the mixture to 100 ° C overnight, after which the solvent of the reaction system is removed, and ethyl acetate is added to the residue. And water, layering, taking the organic phase to remove the solvent, separating and purifying, that is;
  • Ar and R 1 are as defined in the formula (II).
  • the preparation method of the intermediate A involves the following reaction formula:
  • the molar ratio of the compound a1 to the compound a2 is 1:0.5 to 2.
  • the amount of the diisopropylethylamine is such that 1 to 3 ml of diisopropylethylamine is added per 4 to 9 mmol of the compound a1.
  • the n-butanol is used in an amount of 20 to 30 ml of n-butanol per 4 to 9 mmol of the compound a1.
  • the separation and purification were carried out by column chromatography.
  • the developing solvent used in the column chromatography was a mixture of ethyl acetate and petroleum ether.
  • the intermediate A is selected from the group consisting of:
  • the intermediate B was prepared by the following method:
  • the compound b1 is formed into a phenol sodium salt, and after a substitution reaction with methyl iodide or ethyl difluoroacetate or a mixture of hydrazine and ethyl difluorobromoacetate (precursor of R 2 ), reduction (hydrogenation) and nitration are carried out.
  • the amino group is protected with di-tert-butyl dicarbonate, and then substituted with a precursor of the substituent R 3 , followed by reduction (hydrogenation), and then reacted with acrylic acid, halogen-substituted acrylic acid or acid chloride to obtain an intermediate B.
  • R 2 , R 3 , X 1 , X 2 , X 3 are as defined in formula I or II.
  • the intermediate B can be obtained from any step in accordance with the case where the raw material can be obtained in the prior art.
  • the intermediate B is selected from the group consisting of:
  • the invention provides a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for use as an EGFR inhibitor.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) above and a pharmaceutically acceptable carrier.
  • the compound of the formula I of the present invention can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • dosage forms include those suitable for oral, rectal, topical, intraoral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, and the like).
  • compositions of this invention may be formulated, quantified, and administered in a manner consistent with medical practice.
  • the "effective amount" of a compound administered is determined by the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • the EGFR inhibitor of the present invention can be used for preparing a medicament for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases, such as cancer, diabetes, immune system diseases, neurodegenerative diseases or cardiovascular diseases, and the like, and is particularly suitable for mutation by EGFR.
  • EGFR-related diseases such as cancer, diabetes, immune system diseases, neurodegenerative diseases or cardiovascular diseases, and the like
  • sensitive mutations such as L858R mutation or deletion of exon 19
  • drug-resistant mutations such as EGFR T790M mutation
  • the invention provides a compound of formula I of the invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for use in the modulation of EGFR tyrosine kinase activity or in the treatment of EGFR The application of drugs for related diseases.
  • the modulating EGFR tyrosine kinase activity or treating an EGFR-related disease refers to treating cancer, diabetes, an immune system disease, a neurodegenerative disease, or a cardiovascular disease.
  • the invention provides the use of a compound of formula I according to the invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of non-small cell lung cancer.
  • the EGFR inhibitors of the invention are particularly useful in the preparation of a medicament for the treatment of cancer, such as non-small cell lung cancer.
  • the compound of the formula I of the present invention can be used as a single therapeutic drug in anticancer therapy, or can be used in addition to conventional Surgical or radiation therapy or a combination of chemotherapy or immunotherapy.
  • the above therapy and the EGFR inhibitor of the present invention can be administered in parallel, simultaneously, sequentially, or separately.
  • the medicament for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases of the present invention may further comprise any one or more of the following drugs in addition to the EGFR inhibitor of the present invention: gefitinib, erg Lotitinib, ectatinib, lapatinib, XL647, NVP-AEE-788, ARRY-334543, vandetanib, PF00299804, cetuximab, panituzumab, pertuzumab , zarumimumab, nimotuzumab, MDX-214, CDX-110, IMC-11F8, CNF2024, tancomycin, aspironmycin, IPI-504, NVP-AUY922.
  • eq is the molar equivalent of the reactants.
  • the synthesis of Intermediate A and Intermediate B used is as follows.
  • Ar is selected from a phenyl group or a substituted phenyl group, or a heteroaryl group or a substituted heteroaryl group
  • the substituted phenyl group or heteroaryl group is monosubstituted, Disubstituted or trisubstituted phenyl or heteroaryl, each independently selected from halo, cyano, nitro, ester, C 1-4 alkyl or cycloalkyl, C 1-4 alkoxy or a cycloalkoxy group, a C 1-4 haloalkyl group, a C 1-4 acyl group, a C 1-6 alkylamino group or a cycloalkylamino group;
  • R 1 is selected from hydrogen, halogen, trifluoromethyl or cyano; and
  • R 2 is selected from the group consisting of Oxy, monofluoromethoxy,
  • X 1 , X 2 and X 3 are each independently selected from hydrogen or halogen.
  • the preparation method of the intermediate A is the method A1, the method A2 or the method A3, as follows.
  • Ar is selected from phenyl or substituted phenyl, or heteroaryl or substituted heteroaryl
  • the substituted phenyl or heteroaryl is a mono-, di- or tri-substituted phenyl or heteroaryl
  • the substituents are each independently selected from halogen, cyano, nitro, ester, C 1-4 alkyl or cycloalkyl, C 1-4 alkoxy or cycloalkoxy, C 1-4 haloalkyl, C 1-4 acyl, C 1-6 alkylamino or cycloalkylamino.
  • the preparation method of the intermediate B is the method B1 or the method B2, specifically as follows.
  • Method B1 includes the following steps:
  • reaction formula involved in method B1 is as follows:
  • Method B2 includes the following steps:
  • reaction formula involved in method B2 is as follows:
  • Method B3 includes the following steps:
  • reaction formula involved in method B3 is as follows:
  • R 3 , X 1 , X 2 , X 3 are as defined in formula I or II.
  • the pyrimidine compound of this embodiment has a structural formula of the formula I-1:
  • the pyrimidine compound of the present Example was prepared by dissolving 50 mg (0.15 mmol) of Intermediate B, 150 mg (0.5 mmol) of Intermediate A and 35 mg (0.18 mmol) of p-toluenesulfonic acid monohydrate in 5 ml of 2 - pentanol, then warmed to 50 ° C, stirred under nitrogen atmosphere overnight, TLC showed that the starting material disappeared, spin dry volume, then added 20 ml of dichloromethane and 20 ml of saturated aqueous sodium carbonate, layered, then washed with 20 ml of dichloromethane The aqueous phase was combined twice, and the organic phase was combined, dried and dried.
  • the intermediate A1-1 was produced by the above method A1; the intermediate B1-1 was produced by the above method B1.
  • the pyrimidine compound of the present example is the mesylate salt of the pyrimidine compound (I-6) shown in Example 6, and its structural formula is as shown in Formula I-30:
  • the pyrimidine compound (methanesulfonate) of the present embodiment is prepared by adding 0.37 g of the compound I-6 to a 50 ml single-mouth bottle, adding 10 ml of acetone and 1 ml of water, and slowly adding it after stirring. 64 mg of methanesulfonic acid, after the addition, reacted at 50 ° C for 3 h, the reaction solution was evaporated to dryness, then 6 ml of acetonitrile was added to warm to 70 ° C and stirred for 30 min, and the solid was gradually cooled to precipitate a solid, which was washed with acetonitrile. After drying, 140 mg of a white solid was obtained as Compound I-30. The purity was 98.5% by HPLC.
  • the preparation method involves the following reaction formula:
  • the method was used to determine the inhibitory effect of the test substance on the activity of double mutant EGFR kinase (EGFR T790M/L858R kinase) and wild type EGFR kinase (EGFR WT). Both wild-type EGFR and mutant EGFR (T790M/L858R) kinases used in this assay were purchased from Carna Bioscience.
  • the compound to be tested was formulated into a 10 mM (mmol/L) DMSO solution, and the control compound AZD9291 was formulated into a 1 mM (mmol/L) DMSO solution.
  • test compound solution dilutes the test compound solution to 12 concentrations (or other desired test concentration) on a 384-well plate of TECAN EVO200 by 3-fold dilution.
  • the compound of the formula I of the present invention has a very good inhibitory activity against EGFR, and in particular, the inhibitory activity against EGFR mutations (especially the EGFR T790M/L858R mutation) is significantly higher than that of the prior art compound AZD9291, Examples are 1, 3, 9, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, and the like. Under the premise of achieving the same therapeutic effect, the amount of administration can be greatly reduced, thereby greatly reducing other side effects caused by the drug.
  • the compound of the formula I of the present invention has low inhibitory activity against wild-type EGFR, and is significantly superior to the same-generation prior art compound AZD9291, as in Examples 1, 2, 3, 4, 6, 8, and the like.
  • the selective inhibitory activity against the enzyme can be 10 to 60 times, which is significantly better than that of the prior art compound AZD9291, and is more selective than the second generation EGFR inhibitor.
  • problems such as severe toxic side effects such as rash of the patient due to strong inhibition of wild-type EGFR can be well reduced.
  • the compounds of the present invention also exhibit advantageous physical properties (such as water solubility, etc.) and favorable metabolic characteristics (such as better pharmacokinetic characteristics such as bioavailability). ).
  • Test methods and procedures are carried out using methods well known to those skilled in the art, and the reagents used in the methods are commercially available.
  • the cells were formulated into a 25,000 cells/mL solution, and then 40 ⁇ L was taken to the designated 384-well test plate.
  • test plate was incubated at room temperature for 30 minutes to stabilize the luminescence signal.
  • the exemplified compounds of the present invention showed strong inhibitory activity against EGFR mutant cells (H1975, PC-9), and most of the compounds of the present invention were EGFR mutants compared to the control compound AZD9291.
  • the inhibitory activity of cell growth was 4 to 7 times higher than that of the control compound AZD9291.
  • control compound AZD9291 (trade name: meridinib) was as follows:

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Abstract

提供了一种式I所示的嘧啶类化合物、其药学上可接受的盐、立体异构体、溶剂化物或前药。该嘧啶类化合物可以抑制一种或多种EGFR的激活或抗性突变，可用于EGFR敏感型突变癌症的治疗，还适用于目前EGFR-TKI治疗中产生继发性耐药的病例，是一种理想的由EGFR突变导致的疾病的治疗药物。

Description

用作EGFR抑制剂的嘧啶类化合物及其应用 技术领域
本发明属于医药技术领域，具体涉及用作EGFR抑制剂的嘧啶类化合物及其在制备用于调节EGFR酪氨酸激酶活性或治疗EGFR相关疾病，尤其是非小细胞肺癌的药物方面的应用。
背景技术
表皮生长因子受体EGFR(Epidermal Growth Factor Receptor)是erbB受体家族的跨膜蛋白酪氨酸激酶的一种。当其与生长因子配体(例如表皮生长因子(EGF))结合时，受体可以与附加的EGFR分子发生同源二聚，或者与另一家族成员(例如erbB2(HER2)、erbB3(HER3)、或者erbB4(HER4))发生异源二聚。erbB受体的同源二聚和/或异源二聚导致胞内域中关键酪氨酸残基的磷酸化，并且导致对参与细胞增殖和生存的许多细胞内信号传导通路的刺激。erbB家族信号传导的失调促进增殖、侵入、转移、血管生成、和肿瘤细胞生存，并且已在许多的人类癌症中(包括肺癌、头颈部癌和乳腺癌等)得到描述。
因此，以erbB家族为代表作为抗癌药物开发的合理靶点，如靶向EGFR或erbB2的许多药物现在已经在临床上广泛的应用，包括吉非替尼(IRESSATM)、厄洛替尼(TARCEVATM)和拉帕替尼(TYKERBTM)等。New England Journal of Medicine(2008，第358期，1160-1174)和Biochemical and Biophysical Research Communications(2004，第319期，1-11)中提供了对erbB受体信号传导及其在肿瘤发生中的参与的详细论述。
肺癌是全球发病率最高的癌症，在中国肺癌发病率位居所有癌症中第一位，也是中国发病率和死亡率最高的癌症，在中国的肺癌病人中，大约30％的病人具有EGFR突变，其中L858R和外显子19缺失突变占大约90％以上，这类病人对EGFR抑制剂更为敏感。现有已上市第一代EGFR抑制剂如厄洛替尼、吉非替尼等对这类病人有较好的疗效，能够使其中60％以上的病人肿瘤缩小，明显延长病 人的无进展生存期。但绝大多数病人在6-12个月会获得耐药，这种耐药模式是EGFR的进一步突变，这就降低了其对第一代EGFR抑制剂的敏感性。这些突变中最常见的是所谓的“gatekeeper”突变T790M(Science,2004,Vol.304,1497-1500；New England Journal of Medicine 2004,350,2129-2139)，由原来在该位点的L-苏氨酸(T)为L-甲硫氨酸(M)替代，变异后的EGF酪氨酸激酶R不再与吉非替尼、厄洛替尼结合，从而使第一代EGFR抑制剂将不再起效，导致这类病人目前处于无药可用的状态。临床发现对第一代EGFR抑制剂产生耐药的病人中有50％检测都有EGFR T790M突变。在T790M突变细胞系H1975中第一代EGFR抑制剂，如吉非替尼和厄洛替尼，均大于3μM，基本没有活性。
目前开发上市的第二代不可逆pan-EGFR抑制剂(Afatinib BIBW2992)对EGFR突变肺癌病人疗效显著好于第一代EGFR抑制剂。但第二代抑制剂同时也具有很强的野生型EGFR抑制活性，对野生型EGFR的抑制活性显著高于耐药T790M突变，病人皮疹等毒副作用严重且耐药病人疗效较差，仅有小部分第一代EGFR抑制剂耐药病人对这类药物产生应答。
为了提高对耐药EGFR T790M等突变的抑制活性，并且同时降低对野生型EGFR的抑制活性，开发活性更高、选择性更好、毒性更低的第三代EGFR突变体选择性抑制剂具有重要的意义。
WO2012/151561和WO2013/169401分别公开了据称具有EGFR抑制活性的化合物并具体公开了具有2,4-二氨基嘧啶母核结构的化合物。在WO2012/151561和WO2013/169401中所公开的化合物中，均必须带有至少一个磷酰基(-P(O)(RA)(RB))基团。
发明内容
一方面，本发明提供了式I所示的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药：
Figure PCTCN2016098057-appb-000001
其中，R1选自氢、卤素、C1-6的卤代烷基或氰基；
R2选自C1-6的烷氧基、C1-6的卤代烷氧基、C1-6的氘代卤代烷氧基、C3-6的 环烷氧基、C3-6的卤代环烷氧基、C1-6的烷硫基或C1-6的烷氨基；
R3选自如下任意一种结构：
-NR6R7；或-OR6；
其中R6和R7独立地选自C1-6烷基，所述烷基任选被NR8R9取代，
或者R6和R7与它们所连接的氮原子一起形成任选地含有选自氮和氧的另外的杂原子的4-6元饱和杂环，所述杂环任选被C1-6的烷基、NR8R9或C1-6酰基取代，
R8和R9独立地选自H和C1-6烷基，或者R8和R9与它们所连接的氮原子一起形成任选地含有选自氮和氧的另外的杂原子的4-6元饱和杂环；
；
R4选自如下任意一种结构：
Figure PCTCN2016098057-appb-000002
R5选自C1-12的烷基、任选取代的芳基或任选取代的杂芳基；
X1、X2、X3、X4、X5各自独立的选自氢、卤素、C1-6的烷基、C1-6的卤代烷基、C3-6的环烷基、C3-6的卤代环烷基或C1-6的烷氨基。
优选的，式Ⅰ化合物如式Ⅱ所示：
Figure PCTCN2016098057-appb-000003
其中，Ar选自苯基或取代的苯基、杂芳基或取代的杂芳基；
R1选自氢、卤素、三氟甲基或氰基；
R2选自甲氧基、单氟甲氧基、二氟甲氧基、氘代单氟甲氧基、氘代二氟甲氧基、三氟甲氧基、C2-6的烷氧基、C2-6的卤代烷氧基、C3-6的环烷氧基或C3-6的卤代环烷氧基；
R3选自如下任意一种结构：
Figure PCTCN2016098057-appb-000004
X1、X2、X3各自独立的选自氢或卤素。
当Ar为取代的苯基或杂芳基时，所述取代的苯基或杂芳基为一取代、二取代或三取代的苯基或杂芳基，取代基各自独立的选自卤素、氰基、硝基、酯基、C1-4烷基或环烷基、C1-4烷氧基或环烷氧基、C1-4卤代烷基、C1-4酰基、C1-6烷氨基或环烷氨基。在一个实施方案中，酯基是指式-C(O)OC1-6烷基的基团，优选-C(O)OMe、-C(O)OEt等。
在一个优选的实施方案中，Ar为被氰基或卤素一取代、二取代或三取代的苯基。
在一个优选的实施方案中，R3是
Figure PCTCN2016098057-appb-000005
优选的，所述式I化合物选自：
Figure PCTCN2016098057-appb-000006
Figure PCTCN2016098057-appb-000007
所述药学上可接受的盐为无机酸盐或有机酸盐，所述无机酸盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐；所述有机酸盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、苦味酸盐、谷氨酸盐、水杨酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐。
本发明的嘧啶类化合物，为式I所示的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药，该化合物可以抑制一种或多种EGFR的激活或抗性突变，例如L858R激活突变体、Exon19缺失EGFR激活突变体、T790M抗性突变体；该化合物提高了对耐药EGFR T790M等突变的抑制活性，并且同时降低 了对野生型EGFR的抑制活性，可用于开发活性更高、选择性更好、毒性更低的第三代EGFR突变体选择性抑制剂。
本发明的嘧啶类化合物，体外实验表明其在纳摩尔浓度下即可抑制EGFR T790M/L858R双突变酶的增殖，而对野生型EGFR酶的抑制则相对较弱。因此，此类化合物不但可用于EGFR敏感型突变癌症的治疗，还适用于目前EGFR-TKI治疗中产生继发性耐药的病例；同时其突变选择性大大减少了因抑制野生型EGFR而产生的毒副作用，是一种理想的由EGFR突变导致的疾病的治疗药物。
除非特别说明，否则在本申请(包括说明书和权利要求书)所用的以下术语具有下面所给出的定义。
“烷基”指的是仅由碳和氢原子组成的含有1至12个碳原子的单价直链或支链饱和烃基团。“烷基”优选为1至6个碳原子的烷基基团，即C1-C6烷基，更优选为C1-C4烷基。烷基基团的实例包括但不限于甲基、乙基、丙基、异丙基、异丁基、仲丁基、叔丁基、戊基、正己基、辛基、十二烷基等。
“烷氧基”指的是式-OR基团，其中R是本文所定义的烷基基团。烷氧基基团的实例包括但不限于甲氧基、乙氧基、异丙氧基、叔丁氧基等。
“卤素(卤代)”是指氟、氯、溴或碘取代基。
“卤代烷基”指的是其中一个或多个氢被相同或不同的卤素代替的本文所定义的烷基。卤代烷基的实例包括-CH2Cl、-CH2CF3、-CH2CCl3、全氟烷基(例如，-CF3)等。
“卤代烷氧基”指的是式-OR基团，其中R是本文所定义的卤代烷基基团。卤代烷氧基基团的实例包括但不限于三氟甲氧基、二氟甲氧基、2,2,2-三氟乙氧基等。
“氘代卤代烷氧基”是指其中一个或多个氢被氘替换的本文所定义的卤代烷氧基基团。
“环烷基”指的是由单-或二环组成的单价饱和碳环基团，其具有3-12个、优选3-10个、更优选3-6个环原子。环烷基可以任选地被一个或多个取代基所取代，其中各取代基独立地为羟基、烷基、烷氧基、卤素、卤代烷基、氨基、单烷基氨基或二烷基氨基。环烷基基团的实例包括但不限于环丙基、环丁基、环戊基、 环己基、环庚基等。
“环烷氧基”指的是式-OR基团，其中R为如本文所定义的环烷基。示例性的环烷基氧基包括环丙基氧基、环丁基氧基、环戊基氧基、环己基氧基等。
“酰基”指的是式-C(O)R基团，其中R为如本文所定义的烷基。示例性的酰基包括乙酰基、正丙酰基、异丙酰基、正丁酰基、异丁酰基、叔丁酰基等。
酯基是指式-C(O)OR的基团，其中R为如本文所定义的烷基。示例性的酯基包括-C(O)OMe、-C(O)OEt等。
“烷硫基”指的是式-SRa基团，其中Ra为H或如本文所定义的烷基。
“烷氨基”指的是式-NRaRb基团，其中Ra为H或如本文所定义的烷基，Rb为如本文所定义的烷基。
“环烷氨基”指的是式-NRaRb基团，其中Ra为H、如本文所定义的烷基或如本文所定义的环烷基，Rb为如本文所定义的环烷基。
术语"芳基"指在环部分具有6-20个碳原子的单环或二环芳香烃基团。芳基优选是C6-10芳基，例如苯基、联苯基或萘基，更优选是苯基。
“杂芳基”指的是5至12个环原子的单环、二环或三环基团，其含有至少一个包含一、二或三个选自N、O或S的环杂原子、剩余的环原子是C的芳环，应当清楚地是，杂芳基的连接点应当位于芳环上。杂芳基优选具体5-8个环原子，更优选具有5-6个环原子。杂芳基基团的实例包括但不限于：咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、噁二唑基、噻二唑基、吡嗪基、噻吩基、呋喃基、吡喃基、吡啶基、吡咯基、吡唑基、嘧啶基、喹啉基、异喹啉基、苯并呋喃基、苯并呋喃基、苯并噻吩基、苯并噻喃基、苯并咪唑基、苯并噁唑基、苯并噁二唑基、苯并噻唑基、苯并噻二唑基、苯并吡喃基、吲哚基、异吲哚基、三唑基、三嗪基、喹喔啉基、嘌呤基、喹唑啉基、喹嗪基、萘啶基、蝶啶基、咔唑基、氮杂
Figure PCTCN2016098057-appb-000008
基、二氮杂
Figure PCTCN2016098057-appb-000009
基、吖啶基等。
术语“杂环基”指其中1、2或3个环原子被选自N、O或S的杂原子替换的文中所定义的环烷基。杂环基优选为3-7元杂环基，更优选为4-6元杂环基，最优选为5-6元杂环基。示例性的杂环基团包括哌啶基、哌嗪基、吗啉基、硫吗啉基、吡咯烷基、氮杂环丁基等。
本发明中所提及的溶剂化物是指本发明的化合物与溶剂形成的配合物。它们 或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。例如，与水形成的配合物称为水合物；其他还包括醇合物、酮合物等。本发明所述的溶剂化物包括本发明式I所示的化合物及其盐、立体异构体的溶剂化物。
本发明所提及的立体异构体是指本发明中式I所示的化合物可以含有一个或多个手性中心，并以不同的光学活性形式存在。当化合物含有一个手性中心时，化合物包含对映异构体。本发明包括这两种异构体和异构体的混合物，如外消旋混合物。对映异构体可以通过本技术领域已知的方法拆分，例如结晶以及手性色谱等方法。当式I所示的化合物含有多于一个手性中心时，可以存在非对应异构体。本发明的立体异构体包括拆分过的光学纯的特定异构体以及非对应异构体的混合物。非对映异构体可以由本技术领域已知方法拆分，比如结晶以及制备色谱。
本发明所提及的前药是指包括已知的氨基保护基和羧基保护基，在生理条件下被水解或经由酶反应释放得到的母体化合物。具体的前药制备方法可参照现有技术(Saulnier，M.G.；Frennesson，D.B.；Deshpande，M.S.；Hansel，S.B and Vysa，D.M.Bioorg.Med.ChemLett.1994,4，1985-1990；和Greenwald，R.B.；Choe，Y.H.；Conover，C.D.；Shum，K.；Wu，D.；Royzen，M.J.Med.Chem.2000，43，475.)。
另一方面，本发明提供了上述式(I)化合物的制备方法，包括将中间体A、中间体B和对甲苯磺酸溶解在有机溶剂中，在保护气氛、50～100℃条件下反应，反应结束后加入二氯甲烷和饱和碳酸钠水溶液，分层，取有机相去除溶剂后，分离纯化，即得；
所述中间体A、中间体B的结构式分别如下所示：
Figure PCTCN2016098057-appb-000010
其中，Ar、R1、R2、R3、X1、X2、X3如式II中所定义。
该制备方法涉及的反应式如下：
Figure PCTCN2016098057-appb-000011
所述中间体A与中间体B的摩尔比为1～5:1。所述对甲苯磺酸是以一水对甲苯磺酸的形式加入的；对甲苯磺酸与中间体B的摩尔比为0.5～2:1。所用的有机溶剂为2-戊醇；所述有机溶剂的用量为：每50mg中间体B对应使用有机溶剂5ml。所述保护气氛为氮气。所述分离纯化是采用柱层析进行分离。
所述中间体A是由以下方法制备的：
方法1：将化合物a1与二异丙基乙胺、正丁醇混合得混合物，将混合物冷却至-20℃，加入化合物a2进行反应，后升温至室温，搅拌过夜后，去除反应体系的溶剂，在残留物中加入乙酸乙酯和水，分层，取有机相去除溶剂，分离纯化，即得；
或者，方法2：将化合物a1与二异丙基乙胺、正丁醇、化合物a2混合得混合物，将混合物加热至100℃反应过夜，后去除反应体系的溶剂，在残留物中加入乙酸乙酯和水，分层，取有机相去除溶剂，分离纯化，即得；
所述化合物a1、化合物a2的结构式如下所示：
Figure PCTCN2016098057-appb-000012
其中，Ar、R1同式(II)中所定义。
中间体A的制备方法涉及的反应式如下：
Figure PCTCN2016098057-appb-000013
其中，化合物a1与化合物a2的摩尔比为1:0.5～2。所述二异丙基乙胺的用量为：每4～9mmol的化合物a1对应加入1～3ml的二异丙基乙胺。所述正丁醇的用量为：每4～9mmol的化合物a1对应加入20～30ml的正丁醇。在制备中间体A时，所述分离纯化是采用柱层析进行分离。所述柱层析使用的展开剂为乙酸乙酯与石油醚的混合物。
优选的，所述中间体A选自如下化合物：
Figure PCTCN2016098057-appb-000014
Figure PCTCN2016098057-appb-000015
所述中间体B是由以下方法制备的：
将化合物b1制成酚钠盐，与碘甲烷或二氟溴乙酸乙酯或氘水与二氟溴乙酸乙酯的混合物(R2的前体)发生取代反应后，经还原(氢化)、硝化，用二碳酸二叔丁酯保护氨基，再与取代基R3的前体发生取代反应，后还原(氢化)，再与丙烯酸、卤素取代的丙烯酸或酰氯反应得到中间体B。
涉及的反应式如下：
Figure PCTCN2016098057-appb-000016
其中，R2、R3、X1、X2、X3如式I或II中所定义。
上述中间体B的制备方法中，可根据现有技术中可获得原料的情况，从任意一步开始直到获得中间体B。
优选的，中间体B选自如下的化合物：
Figure PCTCN2016098057-appb-000017
Figure PCTCN2016098057-appb-000018
另一方面，本发明提供了用作EGFR抑制剂上述的式(I)化合物、其药学上可接受的盐、立体异构体、溶剂化物或前药。
另一方面，本发明提供了包含上述式(I)化合物和药学上可接受的载体的药物组合物。
可将本发明的式I化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药，与一种或多种药用载体制成适合的剂型施用。这些剂型包括适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)的那些。
本发明的药物组合物可以以符合医学实践规范的方式配制，定量和给药。给予化合物的“有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。
本发明的EGFR抑制剂可用于制备调控EGFR酪氨酸激酶活性或治疗EGFR相关疾病方面的药物，如癌症、糖尿病、免疫系统疾病、神经退行性疾病或心血管疾病等，尤其适用于由EGFR突变，包括敏感型突变(如L858R突变或外显因子19缺失)和耐药性突变(如EGFR T790M突变)，引起的非小细胞肺癌的治疗药物。
因此，另一方面，本发明提供了本发明的式I化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药在制备用于调控EGFR酪氨酸激酶活性或治疗EGFR相关疾病的药物方面的应用。
在一个实施方案中，所述调控EGFR酪氨酸激酶活性或治疗EGFR相关疾病是指治疗癌症、糖尿病、免疫系统疾病、神经退行性疾病或心血管疾病。
在另一个实施方案中，本发明提供了本发明的式I化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药在制备治疗非小细胞肺癌的药物方面的应用。本发明的EGFR抑制剂尤其适用于制备治疗癌症，如非小细胞肺癌的药物。
本发明的式I化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药，在抗癌治疗中可以作为单独治疗的药物应用，或者除此之外还可以与常规的手术或放射疗法或化学疗法或免疫疗法联合应用。上述疗法与本发明的EGFR抑制剂可以并列地、同时地、序贯地、或分别地给药。
本发明的用于调控EGFR酪氨酸激酶活性或治疗EGFR相关疾病的药物，除本发明的EGFR抑制剂之外，还可以包含以下药物中的任意一种或多种：吉非替尼、厄洛替尼、埃克替尼、拉帕替尼、XL647、NVP-AEE-788、ARRY-334543、凡德他尼、PF00299804、西妥昔单抗、帕尼突单抗、帕妥珠单抗、扎鲁木单抗、尼妥珠单抗、MDX-214、CDX-110、IMC-11F8、CNF2024、坦螺旋霉素、阿螺旋霉素、IPI-504、NVP-AUY922。
具体实施方式
下面结合具体实施方式对本发明作进一步的说明。
具体实施方式中，eq均为反应物的摩尔当量。
具体实施方式中，所用的中间体A和中间体B的合成如下。在中间体A和中间体B的合成反应式中，Ar选自苯基或取代的苯基，或者杂芳基或取代的杂芳基，所述取代的苯基或杂芳基为一取代、二取代或三取代的苯基或杂芳基，取代基各自独立的选自卤素、氰基、硝基、酯基、C1-4烷基或环烷基、C1-4烷氧基或环烷氧基、C1-4卤代烷基、C1-4酰基、C1-6烷氨基或环烷氨基；R1选自氢、卤素、三氟甲基或氰基；R2选自甲氧基、单氟甲氧基、二氟甲氧基、氘代单氟甲氧基、氘代二氟甲氧基、三氟甲氧基、C2-6的烷氧基、C2-6的卤代烷氧基、C3-6的环烷氧基或C3-6的卤代环烷氧基；R3选自如下任意一种结构：
Figure PCTCN2016098057-appb-000019
X1、X2、X3各自独立的选自氢或卤素。
中间体A的制备方法为方法A1、方法A2或方法A3，具体如下。
方法A1：将7.8mmol的化合物a1-1加入到100ml的单口瓶中，加入3ml的二异丙基乙胺和30ml的正丁醇得混合物；采用冷浴将混合物冷却至-20℃，慢慢的滴加化合物a2(13.8mmol)，加完后低温反应1h，去冷浴升温至室温，搅拌过夜，将溶剂减压蒸干，将残留物加入100ml的乙酸乙酯(EA)，再加入50ml的水洗涤2次，将有机相蒸干，残余物进行柱层析分离(洗脱剂为乙酸乙酯:石油醚＝1:30(体积比))，即得中间体A1。
上述方法A1涉及的反应式如下：
Figure PCTCN2016098057-appb-000020
其中，Ar选自苯基或取代的苯基，或者杂芳基或取代的杂芳基，所述取代的苯基或杂芳基为一取代、二取代或三取代的苯基或杂芳基，取代基各自独立的选自卤素、氰基、硝基、酯基、C1-4烷基或环烷基、C1-4烷氧基或环烷氧基、C1-4卤代烷基、C1-4酰基、C1-6烷氨基或环烷氨基。
方法A2：将4.35mmol的化合物a1-2加入到50ml的单口瓶中，加入1ml的二异丙基乙胺和20ml的正丁醇，再加入2.2mmol的化合物a2得混合物，将混合物加热至100℃反应过夜，将溶剂减压蒸干，残留物加入50ml的乙酸乙酯(EA)，加入50ml的水洗涤2次，将有机相蒸干，残余物进行柱层析分离，即得中间体A2。
上述方法A2涉及的反应式如下：
Figure PCTCN2016098057-appb-000021
其中，Ar如式II中所定义；
方法A3：将9mmol的化合物a1-3加入到50ml的单口瓶中，加入1ml的二异丙基乙胺和25ml的正丁醇，再加入9mmol的化合物a2得混合物，将混合物加热至100℃反应过夜，将溶剂减压蒸干，残留物加入50ml的乙酸乙酯(EA)，加入50ml的水洗涤2次，将有机相蒸干，残余物进行柱层析分离(洗脱剂为乙酸乙酯:石油醚＝1:20(体积比))，即得中间体A3。
上述方法A3涉及的反应式如下：
Figure PCTCN2016098057-appb-000022
其中，Ar如式II中所定义。
中间体B的制备方法为方法B1或方法B2，具体如下。
方法B1包括下列步骤：
1)化合物b1-2的合成：将50g化合物b1-1溶解在250ml四氢呋喃中，将12.6g氢氧化钠溶解在250ml水中，将两溶液混合搅拌过夜，旋蒸除去四氢呋喃，将水相用二氯甲烷洗涤两次，旋蒸除去大部分水，将剩余部分自然挥干，真空干燥箱彻底干燥，得到55g橘黄色固体，为化合物b1-2。该化合物的分析数据如下：1H-NMR(400MHz，&DMSO)：δ：7.73(t,J＝8.22,1H)；6.02(dd,J＝2.97，13.79,1H)；5.77(dt,J＝2.87，7.45,1H)。
2)化合物b1-3的合成：将7g化合物b1-2与17.5g碳酸钾加入反应瓶中，然后氩气保护下，向反应瓶中加入700ml的DMF(二甲基甲酰胺)、70g氘水与17.5g溴代二氟乙酸乙酯，逐渐升温至50℃，搅拌过夜，TLC显示原料大部分消失，冷却后，将反应液用水稀释，用二氯甲烷萃取三次，合并有机相，用水洗涤5次，将有机层干燥旋干，残留物经柱层析分离得到6.2g淡黄色油状物，为化合物b1-3。该化合物的分析数据如下：1H-NMR(400MHz，CDCl3)：δ：8.01(q,J＝5.58，3.51,1H)；7.07-7.15(m,2H)。
3)化合物b1-4的合成：将1g化合物b1-3溶解在25ml乙醇中，加入钯碳，氢气氛围下，室温常压搅拌过夜；TLC检测原料消失，过滤掉钯碳，乙醇洗涤，旋干溶剂得到0.78g化合物b1-4，为黄色油状物。该化合物的分析数据如下：1H-NMR(400MHz，CDCl3)：：δ：6.70-6.84(m,3H)；3.71(br,2H)；MS m/z(ESI):179[M+H]+。
4)化合物b1-5的合成：将0.78g化合物b1-4分批加入冰水浴冷却的5ml浓硫酸中，温度低于10℃，使其全部溶解，然后加入0.45g硝酸钾，室温搅拌过夜，反应结束，将反应液倒入冰水中，然后用氨水碱化，用乙酸乙酯萃取有机层，合并有机层，用饱和食盐水洗涤一次，干燥旋干有机层，残留物进行柱层析分离， 得到0.8g黄色固体，即为化合物b1-5。该化合物的分析数据如下：1H-NMR(400MHz，CDCl3)：δ：7.46(d,J＝6.48,1H)；6.99(d,J＝10.94,1H)；4.03(br,1H)；MS m/z(ESI):224[M+H]+。
5)化合物b1-6的合成：将3.1g化合物b1-5与171mg的DMAP(4-二甲氨基吡啶)溶解在40ml乙腈中，冰浴下加入3.6g的(Boc)2O(二碳酸二叔丁酯)，然后逐渐升至室温搅拌过夜，TLC检测原料消失，然后直接旋干反应液，残留物进行柱层析分离，得到3g黄色固体，即为化合物b1-6。该化合物的分析数据如下：1H-NMR(400MHz，CDCl3)：δ：8.99(d,J＝8.10,1H)；7.07(d,J＝12.15,1H)；6.85(br,1H)；MS m/z(ESI):324[M+H]+。
6)化合物b1-7的合成：将1.5g化合物b1-6、950mg的N,N,N'-三甲基乙二胺与1.8g二异丙基二胺溶解在20ml的DMAC(N,N-二甲基乙酰胺)中，然后升温至60℃搅拌过夜，TLC检测原料消失，将反应液倒入水与乙酸乙酯(EA)中，水层再用乙酸乙酯(EA)洗涤一次，然后合并EA层用水洗涤5次去除DMA，然后干燥旋干有机层；残留物进行柱层析分离，得到2.2g黄色固体，即为化合物b1-7。
7)化合物b1-8的合成：将2.2g化合物b1-7溶解在40ml的乙酸乙酯(EA)中，然后加入0.2g钯碳，氢气氛围下，室温搅拌过夜，TLC检测原料消失，过滤掉钯碳，旋干母液得到2g黄色油状物，即为化合物b1-8。该化合物的分析数据如下：1H-NMR(400MHz，CDCl3)：δ：7.47(s,1H)；6.78(s,1H)；6.69(br,1H)；4.25(br,2H)；2.85(t,J＝6.89,1H)；2.62(s,3H)；2.36(t,J＝6.48,1H)；2.25(s,6H)；MS m/z(ESI):376[M+H]+。
8)中间体B-1的合成：将2g化合物b1-8溶解在40ml二氯甲烷中，然后加入0.83g二异丙基乙胺，然后氮气保护下，冰盐浴降温至0℃左右，然后滴加0.55g丙烯酰氯，滴加完毕后逐渐升温至室温，搅拌两个小时，TLC检测原料消失，接着旋干反应液，再向剩余物中加入5ml浓盐酸，搅拌两个小时，TLC显示原料消失，然后用饱和碳酸钠水溶液调PH至8左右，使体系碱化，用(乙酸乙酯)EA萃取反应液三次，合并有机层，干燥，旋干，残留物进行柱层析分析，得到750mg黄色油状物，即为中间体B1。该化合物的分析数据如下：1H-NMR(400MHz，CDCl3)：δ：8.07(s,1H)；6.92(s,1H)；6.39(dd,J＝1.63，17.09,1H)； 6.22(dd,J＝10.48，17.47,1H)；5.68(dd,J＝1.42，9.91,1H)；3.81(br,2H)；2.77(t,J＝5.44,1H)；2.63(s,3H)；2.23(s,8H)；MS m/z(ESI):330[M+H]+。
方法B1涉及的反应式如下：
Figure PCTCN2016098057-appb-000023
方法B2包括下列步骤：
1)化合物b2-2的合成：取50g化合物b2-1，加入500ml甲醇全溶解，加入10g的Pd/C(钯碳)，35℃下氢化反应两天；点板监控，原料反应完毕，直接滤除Pd/C，旋干甲醇相得到化合物b2-2粗品39g。
2)化合物b2-3的合成：取化合物b2-2粗品39g，加入到500ml的浓硫酸中(冰盐浴)，在T<10℃条件下搅拌全溶，保持在该温度下加入1ep的硝酸钾，室温下搅拌过夜；次日将反应液倒入冰水中，用氨水调节PH>7，乙酸乙酯萃取，干燥，进行柱层析分离，得到44g产品，即为化合物b2-3。该化合物的分析数据如下：1H NMR(CDCl3)δ7.39(d,J＝7.2Hz,1H),6.63(d,J＝12.4Hz,1H),3.94(s,3H),3.90(宽峰,2H)。
3)化合物b2-4的合成：取20g的化合物b2-3，加入到500ml的二氯甲烷中，冰盐浴冷却到-5℃，滴加1.1eq的二碳酸二叔丁酯的二氯甲烷溶液，滴毕，加入0.2eq的DMAP(4-二甲氨基吡啶)，自然升温到室温，搅拌过夜；次日，点板， 反应完毕，进行柱层析分离，得到24g黄色固体，即为化合物b2-4。该化合物的分析数据如下：1H NMR(CDCl3)δ8.89(s,1H),6.97(s,1H),6.71(d,J＝12.4Hz,1H),3.97(s,3H),1.53(s,9H)；MS:C12H15FN2O5(M-H)-的计算值:286.1,实测值:285.0。
4)化合物b2-5的合成：取13.5g的化合物b2-4，加入到200ml的DMAC(N,N-二甲基乙酰胺)中，搅拌下全溶；再加入2eq的N,N,N’-三甲基乙二胺和3eq的DIEA(N,N-二异丙基乙胺)，升温到110℃搅拌过夜；次日，反应完毕，得到22g油状物粗品化合物b2-5。该化合物的分析数据如下：1H NMR(CDCl3)δ8.54(s,1H),6.85(s,1H),6.60(s,1H),3.90(s,3H),3.22(t,J＝6.8Hz,2H),2.81(s,3H),2.55(t,J＝7.2Hz,2H),2.26(s,6H),1.49(s,9H)；MS:C17H28N4O5(M+H)+的计算值:368.21,实测值:369.3。
5)化合物b2-6的合成：取22g粗品化合物b2-5，加入到400ml的乙酸乙酯中，搅拌下全溶，再加入4.07g的Pd/C(钯碳)，20℃下氢化反应过夜；次日，原料反应完毕，直接滤除Pd/C，浓缩，得到化合物b2-6粗品17g，为黑色油状物。该化合物的分析数据如下：1H NMR(CDCl3)δ7.517(s,1H),6.941(s,1H),6.61(s,1H),4.10(m,2H),3.76(s,3H),2.92(m,2H),2.62(s,3H),2.40(m,2H),2.27(s,6H),1.49(s,9H)；MS:C17H30N4O3(M+H)+的计算值:338.23,实测值:339.4。
6)化合物b2-7的合成：取17.3g化合物b2-6粗品，加入500ml的二氯甲烷和1.2eq的DIEA(N,N-二异丙基乙胺)，冰盐浴冷却到-5℃，氩气保护下滴加1.1eq的丙烯酰氯，滴毕，自然升温到室温，3小时后，反应完毕，直接低温下旋蒸浓缩除去溶剂，得到23g粗品化合物b2-7。
7)中间体B-2的合成：取23g粗品化合物b2-7，加入到50ml的THF中，冰盐浴冷却到-5℃，加入浓盐酸100ml，温度T<10℃，搅拌2小时后，点板反应完毕，进行柱层析分离，得到5.2g产品，即为中间体B2。该化合物的分析数据如下：1H NMR(CDCl3)δ10.10(s,1H),7.97(s,1H),6.68(s,1H),6.41-6.21(m,2H),5.65(m,1H),3.81(s,3H),3.76(s,2H),2.82(m,2H),2.65(s,3H),2.20(s,6H)；MS:C15H24N4O2(M+H)+的计算值:292.19,实测值:293.3。
方法B2涉及的反应式如下：
Figure PCTCN2016098057-appb-000024
方法B3包括下列步骤：
1)化合物b3-2的合成：取50g原料化合物b3-1，加入到500ml的DMF中，再加入1.5eq的二氟溴乙酸乙酯和2eq的碳酸钾，先室温搅拌10min，加入3eq的水，氩气保护下油浴升温到50℃，4小时后原料反应完毕，降温到0℃，加水淬灭，用二氯甲烷和石油醚等比例混合的有机相萃取，有机相干燥，浓缩，进行柱层析分离，得到化合物b3-2产品77g。该化合物的分析数据如下：1H NMR(CDCl3)δ8.03(dd,J＝9.2,5.6Hz,1H),7.149-7.081(m,2H),6.645(t,J＝72.4Hz,1H)。
2)化合物b3-3的合成：取77g化合物b3-2，加入700ml无水乙醇全溶解，加入Pd/C(钯碳)13g，20℃下氢化反应过夜；点板监控，原料反应完毕，直接滤除Pd/C，旋干得到化合物b3-3粗品55g。该化合物的分析数据如下：1H NMR(CDCl3)δ6.84-6.70(m,3H),6.468(t,J＝73.6Hz,1H),3.16(宽峰,2H)；MS:C7H6F3NO(M+H)+的计算值:178.04,实测值:178.00。
3)化合物b3-4的合成：取化合物b3-3粗品55g，加入到600ml的浓硫酸中(冰盐浴)，，T<10℃搅拌全溶，保持在该温度下加入1ep硝酸钾，室温下搅拌过夜；次日，倒入冰水中，用氨水调节PH>7，乙酸乙酯萃取，干燥，进行柱层析分离，得到63g黄褐色产品，即为化合物b3-4。该化合物的分析数据如下：1H NMR(CDCl3)δ7.46(d,J＝7.2Hz,1H),7.01(d,J＝11.2Hz,1H),6.597(t,J＝72.4Hz,1H),4.047(宽峰,2H)。
4)化合物b3-5的合成：取11.1g化合物b3-4，加入到200ml的二氯甲烷中， 冰盐浴冷却到-5℃，滴加1.1eq的二碳酸二叔丁酯的二氯甲烷溶液，滴毕，加入0.2eq的DMAP(4-二甲氨基吡啶)，自然升温到室温，搅拌过夜，次日，点板，反应完毕，进行柱层析分离，得到9.7g黄色产品，即为化合物b3-5。该化合物的分析数据如下：1H NMR(CDCl3)δ9.00(d,J＝8Hz,1H),7.07(d,J＝10.8Hz,1H),6.864(s,1H),6.661(t,J＝71.2Hz,1H),1.541(s,9H)；MS:C12H13F3N2O5(M-H)-的计算值:323.08,实测值:321.1。
5)化合物b3-6的合成：取0.82g的化合物b3-5，用10ml的DMAC(N,N-二甲基乙酰胺)溶解，加入2eq的R3H和3eq的DIEA(N,N-二异丙基乙胺)，氩气保护下，80℃反应过夜；次日检测，原料消失；80℃下，旋蒸除去DMA，加入50ml饱和碳酸钠水溶液和50ml二氯甲烷，二氯甲烷再萃取2次，合并有机相，干燥，浓缩，得到化合物b3-6粗品。当R3为
Figure PCTCN2016098057-appb-000025
时，得到1.3g的化合物b3-6，其分析数据如下：MS:C16H21F2N3O6(M+H)+的计算值:389.14,实测值:390.2。
6)化合物b3-7的合成：取1.2g化合物b3-6，用100mL乙酸乙酯溶解，加入0.4eq的Pd/C(钯碳)，20℃氢化反应过夜；次日检测，原料消失，滤除Pd/C，浓缩，进行柱层析分离，得到化合物b3-7产品。当R3为
Figure PCTCN2016098057-appb-000026
时，得到0.7g的化合物b3-7，其分析数据如下：1H NMR(CDCl3)δ9.32(br,1H),9.23(s,1H),6.96(s,1H),6.73(s,1H),6.47(t,J＝74.8Hz,1H),5.85(m,1H),5.24(m,1H),3.86(m,4H),2.83(m,4H),1.53(s,9H)；MS:C16H23F2N3O4(M+H)+的计算值:359.17,实测值:360.2。
7)化合物b3-8的合成：取原料丙烯酸(或者取代的丙烯酸)0.1g，用20ml的DCM(二氯甲烷)溶解，加入0.7eq的草酰氯和一滴DMF，氩气保护下，-5℃反应4小时生成酰氯，得酰氯溶液待用；同时，在另一个反应瓶中，取出0.2g(0.5eq)的化合物b3-7，用20ml干燥的二氯甲烷溶解，加入0.15g的DIEA，-5℃下，把制好的酰氯溶液打入反应液中，反应过夜；次日直接旋干，得化合物b3-8。 当使用
Figure PCTCN2016098057-appb-000027
作为原料且R3为
Figure PCTCN2016098057-appb-000028
时，化合物b3-8的分析数据如下：MS:C19H24F3N3O5(M+H)+的计算值:431.17,实测值:432.2。
8)中间体B-3的合成：取0.1g的化合物b3-8，加入3ml的浓盐酸，加入时有气泡放出，搅拌3分钟即可；反应液滴加到10ml的饱和碳酸钠溶液中，滴毕，溶液PH>10；用二氯甲烷30ml萃取2次，干燥，浓缩得到产品，即为中间体B3。当步骤7)中使用
Figure PCTCN2016098057-appb-000029
作为原料且R3为
Figure PCTCN2016098057-appb-000030
时，获得0.08g中间体B3，其分析数据如下：MS:C14H16F3N6O6(M+H)+的计算值:331.11,实测值:332.1。
方法B3涉及的反应式如下：
Figure PCTCN2016098057-appb-000031
其中R3、X1、X2、X3如式I或II中所定义。
实施例1
本实施例的嘧啶类化合物，其结构式如式I-1所示：
Figure PCTCN2016098057-appb-000032
本实施例的嘧啶类化合物的制备方法如下：将50mg(0.15mmol)的中间体B、150mg(0.5mmol)的中间体A与35mg(0.18mmol)的一水对甲苯磺酸溶解在5ml的2-戊醇中，然后升温至50℃，氮气保护下搅拌过夜，TLC显示原料基本消失，旋干容积，然后加入20ml二氯甲烷和20ml饱和碳酸钠水溶液，分层，再用20ml二氯甲烷洗涤水相两次，合并有机相，干燥旋干，TLC分离得到20mg产品，即为化合物I-1。该化合物的分析数据如下：1H-NMR(400MHz，CDCl3)：δ：10.18(br,1H)；9.19(br,1H)；8.38(s,1H)；7.52(dt,J＝2.39，11.32,1H),7.16-7.24(m,2H)；7.03-7.06(m,2H)；6.86(br,1H)；6.71(t,J＝7.11,1H)；6.30-6.38(m,2H)；5.67(dd,J＝2.62，9.58,1H)；2.84(t,J＝5.27,2H)；2.70(s,3H)；2.37(t,J＝4.91,2H)；2.30(s,6H)；MS m/z(ESI):585[M+H]+。
上述制备方法涉及的反应式如下：
Figure PCTCN2016098057-appb-000033
其中，中间体A1-1是采用上述的方法A1制成的；中间体B1-1是采用上述的方法B1制成的。
实施例2-29的嘧啶类化合物及其制备方法所用的中间体A、中间体B如表1所示，其余同实施例1。
表1实施例2-29的嘧啶类化合物及其制备方法所用的中间体A、中间体B
Figure PCTCN2016098057-appb-000034
Figure PCTCN2016098057-appb-000035
Figure PCTCN2016098057-appb-000036
Figure PCTCN2016098057-appb-000037
Figure PCTCN2016098057-appb-000038
Figure PCTCN2016098057-appb-000039
Figure PCTCN2016098057-appb-000040
Figure PCTCN2016098057-appb-000041
实施例30
本实施例的嘧啶类化合物，为实施例6所示的嘧啶类化合物(I-6)的甲磺酸盐，其结构式如式I-30所示：
Figure PCTCN2016098057-appb-000042
本实施例的嘧啶类化合物(甲磺酸盐)的制备方法为：将0.37g的化合物I-6加入50ml的单口瓶中，加入10ml的丙酮和1ml的水，加完后搅拌下慢慢加入64mg的甲磺酸，加完后在50℃条件下反应3h，将反应液蒸干后加入6ml的乙腈升温至70℃搅拌30min，慢慢冷却使固体析出，将固体滤出，用乙腈洗涤，干燥后得到白色的固体140mg，即为化合物I-30。采用HPLC检测其纯度为98.5％。所得化合物I-30的分析数据为：HNMR(400M,d6-DMSO):9.35(s 1H),9.14(s,1H),8.76(s,1H),8.70(s,1H),8.36(s,1H),7.95(s,2H),7.85(d,J＝8.10Hz,1H),7.41(m,2H),6.97(s,1H),6.60(m,1H),6.24(d,J＝16.7Hz,1H)，5.78(d,J＝11.4Hz,1H),3.82(s,3H),3.26(s,4H),2.79(s,6H),2.59(s,3H),2.31(s,3H)。
该制备方法涉及的反应式如下：
Figure PCTCN2016098057-appb-000043
实验例
1、本实验例对实施例1-29的嘧啶类化合物对野生型EGFR和突变型EGFR激酶的活性抑制作用进行检测。
利用本方法测定待测物对双突变型EGFR激酶(EGFR T790M/L858R激酶)、野生型EGFR激酶(EGFR WT)活性的抑制作用。本检测方法中所用的野生型EGFR和突变型EGFR(T790M/L858R)激酶均购自Carna Bioscience(卡纳生物科学)。
实验设计：
待测化合物的准备：
1、将待测试的化合物配制成10mM(mmol/L)的DMSO溶液，对照样化合物AZD9291配制成1mM(mmol/L)的DMSO溶液。
2、通过3-倍稀释，将待测化合物溶液连续稀释到12个浓度(或别的所需的测试浓度)在TECAN EVO200的384孔板上。
3、使用Echo550转移20nL测试溶液到384孔板上(Coring 3570)。使用DMSO作为空白对照。
进行酶测试：
1、准备含有酶、基质、辅因子的1.3X酶溶液，如下表2所示。
2、在室温下，每个孔板的孔中加入15μL的1.3X酶溶液培养30分钟。
3、加入5μL的4X ATP溶液开始测试反应。最终每个孔中的溶液体积应为20μL，含有的成分如下表2所示。
4、孔板在室温下培养90分钟，然后加入40μL的终止缓冲液(含有0.5M EDTA)终止测试反应。
5、使用EZ检测分析每个孔的实验数据。
表2酶测试中酶溶液参数表
Figure PCTCN2016098057-appb-000044
数据分析：
1、使用read转化率(CR)，根据如下公式计算抑制比率：
Figure PCTCN2016098057-appb-000045
2、按照如下公式，使用XLFit(equation 201)计算IC50和Ki值，
Figure PCTCN2016098057-appb-000046
检测结果如下表3所示。
表3野生型EGFR和突变型EGFR激酶的活性抑制检测结果
Figure PCTCN2016098057-appb-000047
Figure PCTCN2016098057-appb-000048
结合上述实验结果，本发明的嘧啶类化合物与现有技术相比具有如下优点：
(1)本发明的式I所示的化合物对EGFR有非常好的抑制活性，尤其对EGFR突变(特别是EGFR T790M/L858R突变)的抑制活性非常明显的高于现有技术化合物AZD9291的活性，如实施例1、3、9、11、12、14、15、16、17、18、19、20、21、22等等。在达到相同的治疗效果的前提下，可以大大减少给药量，从而大大减少药物所引起的其他副作用。
(2)本发明的式Ⅰ所示的化合物对野生型EGFR具有低的抑制活性，明显优于同代现有技术化合物AZD9291，如实施例1、2、3、4、6、8等等，对酶的选择性抑制活性可以达到10～60倍，明显的优于现有技术化合物AZD9291的3倍，且比第二代EGFR抑制剂的选择性更高。在药物应用方面，可以很好的减少由于对野生型EGFR强抑制而导致病人皮疹等严重的毒副作用等问题。
(3)与其他已知的EGFR突变抑制剂相比，本发明化合物还显示出有利的物理性质(如水溶性等)，有利的代谢特征(如较好的药代动力学特征，如生物利用度)。
2、化合物对细胞生长抑制活性测试：
测试方法和步骤采用本领域技术人员熟知的方法进行，方法中所用试剂均可市购得到。
测试方法：
2.1实验步骤：
(1)使用Echo(非接触式纳升级声波移液系统)取40nL待测化合物溶液到测试板。
(2)将细胞配制成25000细胞/mL的溶液，然后取40μL到指定的384孔测试板上。
(3)培养板在37℃，5％的二氧化碳，95％的湿度下培养72小时。
(4)每孔中加入40μL的
Figure PCTCN2016098057-appb-000049
试剂。
(5)将测试板在室温下，孵育30分钟，以稳定发光信号。
(6)密封测试板，以1000转/分钟的离心速度来去除气泡。
(7)将测试板在摇床上摇动1分钟。
(8)读取测试板数据。
2.2数据处理
(1)使用下面的公式计算残留率：
Figure PCTCN2016098057-appb-000050
S：测试样品读数
V：空白样读数
M：AZD9291测试样(1μM用于测试PC-9和H1975，30μM用于A431测试)
读数
使用XLFIT(V5.3.1.3)软件计算IC50
检测结果如表4所示：
表4化合物对细胞抑制活性
Figure PCTCN2016098057-appb-000051
Figure PCTCN2016098057-appb-000052
从表4可以看出，本发明的示例化合物对EGFR突变型细胞(H1975、PC-9)表现出较强的抑制活性，与对照样化合物AZD9291相比，本发明的大部分化合物对EGFR突变型细胞生长的抑制活性比对照化合物AZD9291提高了4～7倍。
对照化合物AZD9291(商品名：迈瑞替尼)结构如下：
Figure PCTCN2016098057-appb-000053

Claims (12)

  1. 式I所示的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药：
    Figure PCTCN2016098057-appb-100001
    其中，R1选自氢、卤素、C1-6的卤代烷基或氰基；
    R2选自C1-6的烷氧基、C1-6的卤代烷氧基、C1-6的氘代卤代烷氧基、C3-6的环烷氧基、C3-6的卤代环烷氧基、C1-6的烷硫基或C1-6的烷氨基；
    R3选自如下任意一种结构：
    -NR6R7；或-OR6；其中R6和R7独立地选自C1-6烷基，所述烷基任选被NR8R9取代，
    或者R6和R7与它们所连接的氮原子一起形成任选地含有选自氮和氧的另外的杂原子的4-6元饱和杂环，所述杂环任选被C1-6的烷基、NR8R9或C1-6酰基取代，
    R8和R9独立地选自H和C1-6烷基，或者R8和R9与它们所连接的氮原子一起形成任选地含有选自氮和氧的另外的杂原子的4-6元饱和杂环
    ；
    R4选自如下任意一种结构：
    Figure PCTCN2016098057-appb-100002
    R5选自C1-12的烷基、任选取代的芳基或任选取代的杂芳基；
    X1、X2、X3、X4、X5各自独立地选自氢、卤素、C1-6的烷基、C1-6的卤代烷基、C3-6的环烷基、C3-6的卤代环烷基或C1-6的烷氨基。
  2. 根据权利要求1所示的具有式II结构的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药：
    Figure PCTCN2016098057-appb-100003
    其中，Ar选自苯基或取代的苯基、杂芳基或取代的杂芳基；
    R1选自氢、卤素、三氟甲基或氰基；
    R2选自甲氧基、单氟甲氧基、二氟甲氧基、氘代单氟甲氧基、氘代二氟甲氧基、三氟甲氧基、C2-6的烷氧基、C2-6的卤代烷氧基、C3-6的环烷氧基或C3-6的卤代环烷氧基；
    R3选自如下任意一种结构：
    Figure PCTCN2016098057-appb-100004
    X1、X2、X3各自独立的选自氢或卤素。
  3. 根据权利要求1-2所述的化合物，其中，当Ar为取代的苯基或杂芳基时，所述取代的苯基或杂芳基为一取代、二取代或三取代的苯基或杂芳基，取代基各自独立的选自卤素、氰基、硝基、酯基、C1-4烷基、C3-6环烷基、C1-4烷氧基、C3-6环烷氧基、C1-4卤代烷基、C1-4酰基、C1-6烷氨基或C3-6环烷氨基。
  4. 根据权利要求1-2所述的化合物，其中，Ar为被氰基或卤素一取代、二取代或三取代的苯基。
  5. 权利要求1-4中任一项所述的化合物，其中R3是
    Figure PCTCN2016098057-appb-100005
  6. 根据权利要求1所述的化合物，选自：
    Figure PCTCN2016098057-appb-100006
    Figure PCTCN2016098057-appb-100007
  7. 根据权利要求1-6中任一项所述的化合物，其中：所述药学上可接受的盐为无机酸盐或有机酸盐，所述无机酸盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐；所述有机酸盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、苦味酸盐、谷氨酸盐、水杨酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐。
  8. 一种药物组合物，包含权利要求1-7中任一项所述的化合物以及药学上可接受的载体。
  9. 用作EGFR抑制剂的权利要求1-7中任一项所述的化合物。
  10. 权利要求1-7中任一项所述的化合物在制备用于调控EGFR酪氨酸激酶活性或治疗EGFR相关疾病的药物中的应用。
  11. 根据权利要求10所述的应用，其中，所述疾病选自癌症、糖尿病、免疫系统疾病、神经退行性疾病和心血管疾病。
  12. 权利要求1-7中任一项所述的化合物在制备用于治疗非小细胞肺癌的药物中的应用。
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