WO2018210246A1 - 一种三嗪化合物及其药学上可接受的盐 - Google Patents

一种三嗪化合物及其药学上可接受的盐 Download PDF

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WO2018210246A1
WO2018210246A1 PCT/CN2018/086929 CN2018086929W WO2018210246A1 WO 2018210246 A1 WO2018210246 A1 WO 2018210246A1 CN 2018086929 W CN2018086929 W CN 2018086929W WO 2018210246 A1 WO2018210246 A1 WO 2018210246A1
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compound
pharmaceutically acceptable
mmol
amino
acceptable salt
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PCT/CN2018/086929
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English (en)
French (fr)
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朱程刚
徐良亮
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朱程刚
徐良亮
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Priority to CN201880031520.5A priority Critical patent/CN110891950B/zh
Priority to EP18801601.8A priority patent/EP3705478B1/en
Publication of WO2018210246A1 publication Critical patent/WO2018210246A1/zh

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    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a triazine compound for treating cancer and a pharmaceutically acceptable salt thereof, and more particularly to a compound for treating small cell lung cancer and a pharmaceutically acceptable salt thereof.
  • EGFR is known to be a member of the transmembrane protein tyrosine kinase of the erbB receptor family. Homologous dimerization and/or heterodimerization of the erbB receptor results in phosphorylation of certain tyrosine residues in the intracellular domain and activates a variety of intracellular signaling pathways involved in cell proliferation and survival. Deregulation of erbB family signaling can lead to cell proliferation, invasion, metastasis, and angiogenesis, and has been reported in cancers such as lung cancer, head and neck cancer, and breast cancer.
  • EGFR activating mutations eg, L858R and delE746_A750
  • These most prevalent EGFR activating mutations (L858R and delE746_A750) have increased affinity for small molecule tyrosine kinase inhibitors (eg, gefitinib and erlotinib) relative to wild-type (WT) EGFR, The affinity of adenosine triphosphate (ATP) is decreased.
  • small tyrosine kinase inhibitors eg, gefitinib and erlotinib
  • the novel compound should be relative to an activating mutant form of EGFR (eg, a L858R EGFR mutant, or a delE746_A750 mutant or an Exon19 deletion EGFR mutant) and/or a resistant mutant form of EGFR (eg, a T790M EGFR mutant). That said, it has favorable activity and/or selectivity for wild-type EGFR.
  • an activating mutant form of EGFR eg, a L858R EGFR mutant, or a delE746_A750 mutant or an Exon19 deletion EGFR mutant
  • a resistant mutant form of EGFR eg, a T790M EGFR mutant
  • anilino-triazine compounds which have a high inhibitory effect on the mutant form of EGFR and have a relatively high affinity for wild type EGFR. Low inhibition.
  • these compounds have good pharmacological effects, acceptable toxicological effects, and favorable pharmacokinetic properties.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 is -NR 5 R 6 , wherein R 5 and R 6 are each independently selected from C 1 -C 6 alkyl, wherein the alkyl group is unsubstituted or substituted with -NR 7 R 8 ;
  • R 2 is selected from C 2 -C 6 alkenyl groups which are unsubstituted or substituted by -NR 7 R 8 ;
  • R 7 and R 8 are each independently selected from H or C 1 -C 6 alkyl at each occurrence;
  • R 3 is selected from a substituted or unsubstituted fused bicyclic group, and the fused bicyclic ring is a five-membered ring and a six-membered ring fused;
  • R 4 is selected from C 1 -C 6 alkyl.
  • a 1 , A 4 , and A 9 are each independently selected from N or C; and A 2 , A 3 , A 5 , A 6 , A 7 , and A 8 are each independently selected from N, NR a , CR a , CR a R b , wherein R a and R b are each independently selected from H, C 1 -C 6 alkyl and halogen, or R a , R b and together with the same carbon atom to which they are attached form a C 3 -C 6 ring
  • a 2 is selected from N, CH, CH 2 ;
  • a 3 is selected from N, CR a , NR a , CH, CR a R b ;
  • a 5 is selected from N or CH, CH 2 ;
  • a 6 is selected from N or CH, CH 2 , CF;
  • a 7 is selected from N or CH, CH 2 , CF; and
  • a 8 is selected from N or CH, CH 2 , CF, CF 2 .
  • one, two or three of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 comprise N atoms.
  • R 1 is selected from the group consisting of:
  • R2 is selected from the group consisting of:
  • R3 is selected from the group consisting of:
  • the invention also provides a pharmaceutical composition comprising a compound according to the invention or a pharmaceutically acceptable salt thereof.
  • the invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of small cell lung cancer.
  • alkyl group of the present invention means a linear, branched or cyclic saturated hydrocarbon group, preferably an alkyl group having 12 or less carbon atoms, more preferably an alkyl group having 6 or less carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl Base, cyclohexyl, n-hexyl, isohexyl, 2,2,-methylbutyl and 2,3-dimethylbutyl.
  • the "C 1-6 alkyl group” of the present invention means a linear, branched or cyclic saturated hydrocarbon group having 1 to 6 carbon atoms.
  • the "C 1-3 alkyl group” of the present invention means a linear, branched or cyclic saturated hydrocarbon group having 1 to 3 carbon atoms.
  • C 2-6 alkenyl group of the present invention means an unsaturated hydrocarbon group having 1 or 2 carbon-carbon double bonds and having 2 to 6 carbon atoms.
  • the " C2-4 alkenyl group” of the present invention means an unsaturated hydrocarbon group having 1 or 2 carbon-carbon double bonds and having 2 to 4 carbon atoms.
  • halogen of the present invention means fluorine, chlorine, bromine or iodine.
  • treatment also includes “prevention” unless indicated to the contrary.
  • treatment as used herein is intended to have the ordinary meaning of treating a disease to completely or partially alleviate one, some or all of its symptoms, or to correct or compensate for a potential pathology.
  • prevention as used herein is intended to have its normal daily meaning and includes primary prevention against the development of the disease and prevention of secondary prevention of the disease that has occurred, temporarily or continuously preventing the progression or worsening of the disease or associated with the disease. The occurrence of new symptoms.
  • salts of the compounds of formula (I), including pharmaceutically acceptable salts may be prepared. These salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • Inorganic acids which can form salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids which can form salts include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, Ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • the pharmaceutically acceptable base addition salt can be formed with an inorganic or organic base.
  • Inorganic bases which can form salts include, for example, ammonium salts and metals of Groups I to XII of the Periodic Table of the Elements.
  • the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts .
  • Organic bases which can form salts include, for example, primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, alkali ion exchange resins and the like. Certain organic amines include isopropylamine, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from basic or acidic moieties by conventional chemical methods.
  • these salts can be obtained by reacting the free acid form of these compounds with a chemical amount of a suitable base (hydrogen, Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, etc.) or by The free base form is prepared by reaction with a chemical amount of a suitable acid.
  • a suitable base hydrogen, Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, etc.
  • the free base form is prepared by reaction with a chemical amount of a suitable acid.
  • These reactions are usually carried out in water or in an organic solvent or a mixture of the two.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • Solvates of the compounds of formula (I), including pharmaceutically acceptable solvates may also be prepared.
  • “Solvate” means a variable stoichiometric complex formed by a solute and a solvent. Such solvents for the purposes of the present invention do not affect the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is a solvent molecule are generally referred to as hydrates. Hydrates include components comprising a stoichiometric amount of water, as well as components comprising variable amounts of water.
  • salts and solvates e.g., hydrates and hydrates of the salts
  • the counterion or binding solvent is pharmaceutically acceptable.
  • salts and solvates having a non-pharmaceutically acceptable counterion or binding solvent are also included within the scope of the invention, for example, as intermediates in the preparation of other compounds of the invention and pharmaceutically acceptable salts and solvates thereof. .
  • the compounds of formula (I), including their salts and solvates, may be present in crystalline form, in amorphous form or as a mixture thereof.
  • the compound or a salt or solvate thereof may also exhibit polymorphism, i.e., the ability to occur in different crystalline forms. These different crystalline forms are generally known as "polymorphs". Polymorphs have the same chemical composition, but the packing, geometric alignment, and other descriptive properties of the crystalline solid state are different. Thus, polymorphs can have different physical properties such as shape, density, hardness, deformability, stability, and solubility properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, all of which can be used for identification. Those skilled in the art will appreciate that, for example, different polymorphs may be produced by altering or adjusting the conditions used in the crystallization/recrystallization of the compound of formula (I).
  • the invention also encompasses different isomers of the compounds of formula (I).
  • “Isomer” refers to a compound that has the same composition and molecular weight but differs in physical and/or chemical properties. The difference in structure can be in the structure (geometric isomers) or in the ability to rotate a plane to polarize light (stereoisomers). With respect to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atoms and may be present as racemates, racemic mixtures, and as individual enantiomers or diastereomers. All such isomeric forms are embraced within the scope of the invention, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis- or trans-configuration. It is also desirable to include all tautomeric forms.
  • any asymmetric atom of the compound of formula (I), such as carbon, etc. can be present in racemic or enantiomeric enrichment, such as the (R)-, (S)- or (R, S)-configuration.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% in the (R)- or (S)-configuration.
  • the substituent on the atom having an unsaturated double bond exists in the cis-(Z)- or trans-(E)- form.
  • a compound of formula (I) can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example as substantially pure geometry Isomer (cis or trans), diastereomer, optical isomer (enantiomer), racemate or mixtures thereof.
  • Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates based on physicochemical differences of the components, for example by chromatography And / or step by step.
  • racemate of any resulting end product or intermediate can be resolved into the optical antipode by known methods, for example by separation of its diastereomeric salts, using optically active acids or The base is obtained and an optically active acidic or basic compound is released.
  • the basic moiety can thus be used to resolve the compounds of the invention into their optical antipodes, for example by reaction with optically active acids such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di- A stepwise crystallization of a salt formed by O, O'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid).
  • the racemic product can also be resolved by chiral chromatography, such as high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • the invention includes both unlabeled forms as well as isotopically labeled forms of the compounds of formula (I).
  • Isotopically labeled compounds have structures described by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes which can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, respectively. , 31 P, 32 P, 35 S, 36 Cl, 125 I.
  • the invention includes various isotopically labeled compounds as defined herein, such as those in which a radioisotope (e.g., 3 H and 14 C) is present or in which non-radioactive isotopes (e.g., 2 H and 13 C) are present.
  • a radioisotope e.g., 3 H and 14 C
  • non-radioactive isotopes e.g., 2 H and 13 C
  • isotopically labeled compounds can be used for metabolic studies (eg using 14 C), reaction kinetic studies (eg with 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission calculations Tomography (SPECT), including analysis of drug substrate tissue distribution, or radiation therapy for patients.
  • PET positron emission tomography
  • SPECT single photon emission calculations Tomography
  • 18 F or labeled compounds may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of formula (I) can generally be substituted for previously used by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparations, using suitable isotopically labeled reagents. Unlabeled reagents were prepared.
  • substitution with heavier isotopes may result in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements or therapeutic indices. Improvement.
  • hydrazine is referred to herein as a substituent of a compound of formula (I).
  • concentration of the heavier isotope, particularly ruthenium may be determined by the isotope enrichment factor.
  • isotopic enrichment factor refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope.
  • a substituent in a compound of the invention is labeled as hydrazine, then for each of the identified ruthenium atoms, the compound has at least 3500 (52.5% ruthenium incorporated at each of the identified ruthenium atoms), at least 4000 (60%) ⁇ Incorporated), at least 4500 (67.5% strontium incorporation), at least 5000 (75% strontium incorporation), at least 5,500 (82.5% strontium incorporation), at least 6,000 (90% hydrazine incorporation), at least 6333.3 (95%) Iridium enrichment factor, at least 6466.7 (97% hydrazine incorporation), at least 6600 (99% hydrazine incorporation), or at least 6633.3 (99.5% hydrazine incorporation).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • the pharmaceutical compositions can be formulated for a particular route of administration, such as oral, parenteral, and rectal administration.
  • the pharmaceutical compositions of the present invention can be in solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including, without limitation, solutions, suspensions or Made of emulsion).
  • the pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricants or buffers, and adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents and buffers, and the like. .
  • the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient and
  • a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;
  • a lubricant such as silica, talc, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; also included for tablets
  • binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired,
  • a disintegrant such as starch, agar, alginic acid or a sodium salt thereof, or an effervescent mixture; and/or
  • the tablets may be film coated or enteric coated according to methods known in the art.
  • compositions for oral administration include an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the form of a tablet, lozenge, water or oil suspension, dispersible powder or granule, In the form of an emulsion, a hard or soft capsule, or a syrup or elixir.
  • a composition for oral use is prepared according to any method known in the art for preparing a pharmaceutical composition, and in order to provide a refined and palatable preparation, the composition can contain one or more selected from sweeteners, flavored Agents for agents, colorants and preservatives. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets.
  • excipients are, for example, inert diluents (for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate); granulating and disintegrating agents (for example corn starch, or alginic acid); binders (for example starch) , gelatin or gum arabic); and lubricants (such as magnesium stearate, stearic acid or talc).
  • inert diluents for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents for example corn starch, or alginic acid
  • binders for example starch
  • lubricants such as magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a lasting effect over a longer period of time.
  • a time delay material
  • Formulations for oral administration can be presented in hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (for example, calcium carbonate, calcium phosphate or kaolin) or presented in a soft gelatin capsule containing the active ingredient with water or oil medium (for example Mix with peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or oil medium for example Mix with peanut oil, liquid paraffin or olive oil.
  • compositions are isotonic aqueous solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions.
  • the compositions may be sterilized and/or contain adjuvants such as preservative, stabilizing, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure and/or buffers. In addition, it may also contain other therapeutically valuable substances.
  • the compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain from about 0.1% to about 75% or from about 1% to about 50% by weight of active ingredient.
  • the present invention also provides anhydrous pharmaceutical compositions and dosage forms comprising the compound of the present invention as an active ingredient.
  • anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low water content ingredients and low water or low humidity conditions.
  • Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous character.
  • anhydrous compositions are packaged using materials known to prevent contact with water so that they can be included in a suitable formulary kit. Examples of suitable packaging include, without limitation, airtight foils, plastics, unit dose containers (eg, vials), blister packs, and strip packs.
  • the invention further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate of decomposition of a compound of the invention as an active ingredient.
  • agent which is referred to herein as a "stabilizer,” includes, without limitation, an antioxidant (eg, ascorbic acid), a pH buffer or a salt buffer, and the like.
  • the pharmaceutical composition or combination of the invention can be a unit dose of from about 1 to 1000 mg of the active ingredient, or from about 1 to 500 mg or from about 1 to 250 mg or from about 1 to 150 mg or from about 0.5 to 100 mg, Or about 1-50 mg of active ingredient.
  • the therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition of the individual, the condition or disease in which it is being treated, or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a condition or disease.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer.
  • the invention provides a method of producing an anti-cancer effect in a warm-blooded animal, such as a human, in need of such treatment, comprising: administering to the animal an effective amount of a compound of formula (I) or a pharmaceutical thereof Acceptable salt.
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an additional anti-tumor substance, for simultaneous, independent or sequential treatment of cancer.
  • the cancer may be selected from the group consisting of ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate Cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic Large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma.
  • AML acute myeloid leukemia
  • the cancer is non-small cell lung cancer.
  • the above compound of the formula (I) or a pharmaceutically acceptable salt thereof can be used as a single therapeutic treatment or in addition to the compound of the present invention to conventional surgery or radiation therapy or chemotherapy or immunotherapy.
  • Such chemotherapy can be administered in parallel, simultaneously, sequentially, or separately with the compounds of the invention, and can comprise one or more of the following types of anti-tumor agents:
  • anti-proliferative/anti-tumor drugs and combinations thereof used in medical oncology such as alkylating agents (eg, cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, benzophenone) Acid mustard, busulfan, temozolomide, nitrosoureas; antimetabolites (eg gemcitabine and antifolates, such as fluoropyrimidines (eg 5-fluorouracil and tegafur), raltitrexed, methotrexate Antimony, anti-tumor antibiotics (eg anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, Mitomycin C, actinomycin, mithramycin; anti-mitotic agents (eg, vinca alkaloids such as vincristine, vinblastine, vindesine,
  • cytostatic agents such as antiestrogens (eg tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, antiandrogens (eg bicalutamide) , flutamide, nilutamide, cyproterone acetate), LHRH antagonists or LHRH agonists (eg goserelin, leuprolide, and buserelin), progestogens (eg, acetate) Progesterone), aromatase inhibitors (eg, anastrozole, letrozole, exemestane), 5 ⁇ -reductase inhibitors (eg finasteride);
  • antiestrogens eg tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, antiandrogens (eg bicalutamide) , flutamide, nilutamide,
  • anti-invasive agents such as c-Src kinase family inhibitors, such as dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors (such as marimastat), urokinase plasmin An inhibitor of prokaryotic receptor function or an antibody to heparanase;
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (eg, anti-erbB2 antibody trastuzumab, anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab Monoclonal antibodies and any growth factor or growth factor receptor antibodies; such inhibitors also include: tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (eg, EGFR family tyrosine kinase inhibitors, such as N- (3-Chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinylpropoxy)-quinazolin-4-amine (gefitinib, ZD1839), N-( 3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774), 6-acrylamido-N-( 3-chloro-4-fluorone, gamma-1-(
  • an anti-angiogenic agent for example, an agent that inhibits the action of vascular endothelial growth factor, such as an anti-human vascular endothelial growth factor antibody bevacizumab and, for example, a VEGF receptor tyrosine kinase inhibitor, such as vandetanib ( ZD6474), vatarani (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034), 4-(4-fluoro-2-methylindole -5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00/47212), for example WO 97/ 22596, WO 97/30035, WO 97/32856 and WO 98/13354;
  • an agent that inhibits the action of vascular endothelial growth factor such as an anti-human
  • vascular damaging agents such as the compounds disclosed in comprestatin A4 and WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • an endothelin receptor antagonist such as ipotetan (ZD4054) or atrasentan;
  • gene therapy methods including, for example, methods for replacing abnormal genes (such as aberrant p53 or abnormal BRCA1 or BRCA2); GDEPT (gene-directed enzyme prodrug therapy) methods, for example, using cytosine deaminase, thymidine kinase or bacteria Those of nitroreductase; methods for increasing the tolerance of a patient to chemotherapy or radiation therapy, such as multidrug resistance gene therapy;
  • Immunotherapeutic methods including, for example, in vitro and in vivo methods for increasing the immunogenicity of a patient's tumor cells, for example, by cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor.
  • Methods of reducing T cell ineffectiveness methods of using transfected immune cells (eg, cytokine-transfected dendritic cells); methods of using cytokine transfected tumor cell lines; methods using anti-idiotypic antibodies a method of reducing the function of immunosuppressive cells (eg, regulatory T cells, myeloid suppressor cells, or dendritic cells expressing IDO (guanamine 2,3-deoxygenase); and using tumor-derived tumor-associated
  • a cancer vaccine consisting of a protein or a peptide of an antigen (for example, NY-ESO-1, mAGE-3, WT1 or Her2/neu).
  • combination therapy As used herein, if the term “combination therapy” is used to describe a combination therapy, it is to be understood that this may mean simultaneous administration, separate administration or sequential administration.
  • the “combination administration” should be similarly understood.
  • “combination therapy” refers to simultaneous administration.
  • “combination therapy” refers to administration alone.
  • “combination therapy” refers to sequential administration. When administered sequentially or separately, the delay in administering the second component should not, for example, lose the benefit of using the effects produced by the combination.
  • the synthetic path is as follows:
  • ring A, ring B, A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 are as defined above.
  • the crude product was purified by prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 48%-78%, 8 min) to give a yellow solid compound 4 ( 79 mg, yield: 19%).
  • reaction mixture was purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 18%-48%, 10 min) to give bright yellow solid compound 6 (37.5 mg) , yield: 4.5%).
  • reaction mixture was subjected to prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 25%-55%, 10 min), and the eluate was lyophilized to obtain Crude product.
  • the crude product was purified by EtOAc (EtOAc:EtOAc:EtOAc
  • the crude product was purified by prep-HPLC (column: Gemini 150*25 5u; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 35%-60%, 12.5 min) to give a white solid compound 15 ( 46 mg, yield: 12%).
  • reaction solution was directly purified by prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 25%-55%, 10 min), after lyophilization
  • the product (190 mg) was obtained.
  • the crude product was purified by EtOAc (EtOAc:MeOH:MeOH:
  • the synthetic route is as follows:
  • N,N,N'-trimethylethylenediamine (1.0 mmol, 1.0 eq.) and N,N-diisopropylethylamine (2.0 mmol, 2.0 eq.) were added to the solution obtained in the above step.
  • the reaction was carried out in a microwave reactor at 140 ° C for 1 h. 50 mL of ethyl acetate was added, and washed with a large amount of saturated brine, the organic phase was kept, dried and concentrated, and used directly for the next reaction.
  • the synthesis method is as follows:
  • Table 1 below is the LC/MS data for each example.
  • Test 1 L858R/T790M EGFR (double mutant) cell phosphorylation test
  • the human lung cell line NCI-H1975 (L858R/T790M double mutant EGFR) was obtained from the American Type Culture Collection. NCI-H1975 cells were cultured in RPMI 1640 medium containing 10% fetal calf serum and 2 mM glutamine. The cells were grown at 37 ° C in a humidified incubator with 5% CO 2 .
  • Detection of endogenous cellular phosphorylation of p-EGFR in cell lysates was performed according to the protocol described in R&D Systems' DuoSet IC Human Phospho-EGFR ELISA (R&D Systems Cat #YLC1095). 90 ⁇ l of cells (8000 cells/well) were cultured in a growth medium in a Corning black clear bottom 96-well plate, and cultured at 37 ° C in a 5% CO 2 humidified incubator overnight, and the cell culture medium was changed to contain The RPMI1640 medium of 1% fetal bovine serum and 2 mM glutamine was further cultured.
  • Table 2 shows representative compounds of the present invention, namely, Compound 6 of Example 2, Compound 11 of Example 4, Compound 26 of Example 12, Compound 27, Compound 28, and Compound 29 of Example 13 in the above-mentioned organism
  • the IC 50 values of the compound 6, the compound 11, the compound 26, the compound 27, the compound 28, and the compound 29 of the present invention in the L858R/T790M EGFR (double mutant) cell phosphorylation test were 0.0151 and 0.0111, respectively.
  • 0.0121, 0.0118, 0.0114 and 0.0106 in contrast, Osimertinib (AZD9291) has an IC 50 value of 0.0459 in the L858R/T790M EGFR (double mutant) cell phosphorylation test, corresponding to the use of compounds 6 and 11 of the present invention. More than three times the IC 50 value.
  • Test 2 Wild-type EGFR cell proliferation test
  • the human lung cell line A431 (wild type EGFR) was obtained from the American Type Culture Collection. NCI-H838 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 2 mM glutamine. The cells were grown at 37 ° C in a humidified incubator with 5% CO 2 .
  • the number of viable cells in the culture was tested according to the protocol described in Promega's Cell Titer-Glo Luminescent cell Viability Assay (Promega Cat. #G7570).
  • 90 ⁇ l of cells (8000 cells/well) were cultured in growth medium in Corning black clear bottom 96-well plates and cultured overnight at 37 ° C in a 5% CO 2 humidified incubator.
  • Serially diluted compounds in 100% DMSO were added to the cells using a pipette and the cells were incubated for an additional 72 hours.
  • 100 ⁇ l of the mixed Cell Titer-Glo reagent was added to cells in a 96-well culture plate to lyse the cells and gently mix.
  • Test 3 L858R/T790M EGFR (double mutant) cell proliferation test
  • the human lung cell line NCI-H1975 (L858R/T790M double mutant EGFR) was obtained from the American Type Culture Collection. NCI-H1975 cells were cultured in RPMI 1640 medium containing 10% fetal calf serum and 2 mM glutamine. The cells were grown at 37 ° C in a humidified incubator with 5% CO 2 .
  • the number of viable cells in the culture was tested according to the protocol described in Promega's Cell Titer-Glo Luminescent cell Viability Assay (Promega Cat. #G7570).
  • 90 ⁇ l of cells (8000 cells/well) were cultured in growth medium in Corning black clear bottom 96-well plates and cultured overnight at 37 ° C in a 5% CO 2 humidified incubator.
  • Serially diluted compounds in 100% DMSO were added to the cells using a pipette and the cells were incubated for an additional 72 hours.
  • 100 ⁇ l of the mixed Cell Titer-Glo reagent was added to cells in a 96-well culture plate to lyse the cells and gently mix.
  • Table 3 shows representative compounds of the present invention, namely Compound 6, Compound 26, Compound 27, Compound 28 and Compound 29, IC 50 values ( ⁇ M) in the above biological experiments, wherein the compound Osimertinib was used as a control. (AZD9291) was synthesized according to the method described in the following literature:
  • the compounds of the present invention with respect to Osimertinib (AZD9291), the L858R / T790M EGFR (double mutant) cell proliferation test IC 50 is relatively small.
  • the IC 50 value obtained with Osimertinib (AZD9291) was about four times higher than the IC 50 value obtained with the compound of the present invention. This indicates that the compound of the present invention is capable of better inhibiting L858R/T790M EGFR (double mutant) cell proliferation relative to Osimertinib (AZD9291).
  • the rightmost column of the table shows the ratio of the IC 50 value of Test 2 to the IC 50 value of Test 3, which characterizes the inhibitory effect of the compound on L858R/T790M EGFR (double mutant) cell proliferation and The greater the selectivity for wild-type EGFR cell proliferation inhibition, the greater the selectivity of the compound for inhibition of L858R/T790M EGFR (double mutant) cell proliferation in wild-type EGFR cells. As shown in Table 3, the compounds of the present invention were much more selective for inhibition of L858R/T790M EGFR (double mutant) cell proliferation than Osimertinib (AZD9291).
  • Test 4 Ba/F3-CAT-EGFR cell proliferation test
  • Ba/F3-CAT-EGFR cell viability assay is based on Development of detection technology.
  • the CAT-EGFR tool cell line was constructed by transforming Ba/F3 cells by overexpressing the intracellular kinase region of wild-type EGFR. This cell depends on the kinase activity of EGFR to grow, and if the small molecule compound inhibits the wild-type EGFR, the cell will apoptosis. Thus, by observing the effect of EGFR small molecules on cell viability, the specificity and activity of wild-type EGFR can be evaluated.
  • Ba/F3-CAT-EGFR (wild type EGFR) cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 2 mM glutamine. The cells were grown at 37 ° C in a humidified incubator with 5% CO 2 .
  • the number of viable cells in the culture was tested according to the protocol described in Promega's Cell Titer-Glo Luminescent cell Viability Assay (Promega Cat. #G7570). 100 ⁇ l of cells (3000 cells/well) were grown in growth medium in Corning black clear bottom 96-well plates and incubated overnight at 37 ° C in a 5% CO 2 humidified incubator. Serially diluted compounds in 100% DMSO were added to the cells using a pipette and the cells were incubated for an additional 72 hours. 100 ⁇ l of the mixed Cell Titer-Glo reagent was added to cells in a 96-well culture plate to lyse the cells and gently mix.
  • Test 5 Ba/F3-DTM-EGFR cell proliferation test
  • Ba/F3-DTM-EGFR cell viability assay is based on Development of detection technology.
  • the DTM-EGFR tool cell line was constructed by transforming Ba/F3 cells by overexpressing the wild-type T790M mutation and the Exon19-deficient EGFR. This cell depends on the kinase activity of EGFR to grow, and if the small molecule compound inhibits the mutant EGFR, the cell will apoptosis. Thus, the specificity and activity of the EGFR small molecule can be evaluated by observing its effect on cell viability.
  • Ba/F3-DTM-EGFR (mutant EGFR) cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 2 mM glutamine. The cells were grown at 37 ° C in a humidified incubator with 5% CO 2 .
  • the number of viable cells in the culture was tested according to the protocol described in Promega's Cell Titer-Glo Luminescent cell Viability Assay (Promega Cat. #G7570). 100 ⁇ l of cells (3000 cells/well) were grown in growth medium in Corning black clear bottom 96-well plates and incubated overnight at 37 ° C in a 5% CO 2 humidified incubator. Serially diluted compounds in 100% DMSO were added to the cells using a pipette and the cells were incubated for an additional 72 hours. 100 ⁇ l of the mixed Cell Titer-Glo reagent was added to cells in a 96-well culture plate to lyse the cells and gently mix.
  • Table 4 shows the IC 50 values ( ⁇ M) of representative compounds of the present invention, that is, the compounds of Examples 4, 9 and 11 in the above biological experiments, wherein the compound Osimertinib (AZD9291) used as a control is according to the following literature The method described is synthesized:
  • the compound of the present invention has a relatively small IC 50 value for the Ba/F3-DTM-EGFR cell proliferation test relative to Osimertinib (AZD9291), indicating that the compound of the present invention is relative to Osimertinib (AZD9291). It can better inhibit the proliferation of Ba/F3-DTM-EGFR cells.
  • the rightmost column of Table 4 shows the ratio of the IC 50 value of Test 4 to the IC 50 value of Test 5, which characterizes the inhibitory effect of the compound on Ba/F3-CAT-EGFR cell proliferation and Ba.
  • the selectivity of /F3-DTM-EGFR cell proliferation the larger the value indicates that the compound has better selectivity for Ba/F3-DTM-EGFR cell proliferation inhibition in Ba/F3 cells.
  • the compounds of the present invention were much more selective for inhibition of proliferation of Ba/F3-DTM-EGFR cells than Osimertinib (AZD9291).
  • Plasma Protein Binding Rate Assay A protein binding assay was performed using a 96-well equilibrium dialysis apparatus from HTDialysis, a human plasma sample or a mouse plasma sample at a concentration of 2 ⁇ M for the test compound and the control compound at 37 ° C for 4 hours. 150 ⁇ L of the test compound plasma sample was added to the drug delivery end of each dialysis well, and 150 ⁇ L of blank dialysis buffer was added to the corresponding receiving end of the dialysis well. The plate was then placed in a humidified, 5% CO 2 incubator and incubated for 4 hours at 37 °C.
  • the dialyzed buffer sample and the dialyzed plasma sample were pipetted into a new 96-well plate (sample receiving plate).
  • a corresponding volume of corresponding blank plasma or buffer is added to the sample.
  • All samples were subjected to protein precipitation and subjected to LC/MS/MS analysis.
  • the concentration of the sample is expressed as the ratio of the peak area of the compound to the internal standard (semi-quantitative).
  • the % unbound ratio (%Unbound), the % binding ratio (%Bound), and the recovery (%Recovery) of the compound were calculated according to the formula.
  • the compound of the present invention has a relatively large ratio of unbound drug in human and mouse plasma relative to Osimertinib (AZD9291), indicating that the compound of the present invention is relative to Osimertinib (AZD9291) is able to increase its plasma unbound drug ratio, the active drug ratio.

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Abstract

本发明公开了一种三嗪类衍生物及其药学上可接受的盐、药物组合物和用途。具体地，本发明公开了式(I)化合物或其药学上可接受的盐，其中，R1、R2、R3和R4的定义如说明书和权利要求书中所述。本发明所述化合物或其盐可通过调节某些突变形式的表皮生长因子受体而用于治疗或预防疾病或病症。本发明还公开了包含所述化合物或其盐的药物组合物，以及使用所述化合物及其盐治疗由各种不同形式的EGFR所介导的多种疾病的方法，包括非小细胞肺癌。

Description

一种三嗪化合物及其药学上可接受的盐 技术领域
本发明涉及一种治疗癌症的三嗪化合物及其药学上可接受的盐，尤其涉及一种治疗小细胞肺癌的化合物及其药学上可接受的盐。
背景技术
在抗癌药物领域中，对于新的具有更好的活性/选择性的抗癌化合物一直存在需求。已知EGFR是erbB受体家族的跨膜蛋白酪氨酸激酶成员。erbB受体的同源二聚化和/或异源二聚化导致胞内结构域中某些酪氨酸残基的磷酸化，并且激活参与细胞增殖和生存的多种细胞内信号传导通路。erbB家族信号传导的失调可导致细胞增殖、侵入、转移和血管生成，并且已在肺癌、头颈部癌和乳腺癌等癌症中有报道。因此，作为抗癌药物开发的靶点，靶向于EGFR或erbB2的许多药物目前在临床上已得到应用。例如，在新英格兰医学杂志(New England Journal of medicine)，2008年第358期，1160-1174页以及生物化学和生物物理研究通讯(Biochemical and Biophysical Research Communications)，2004年第319卷，1-11页中给出了对erbB受体信号传导及其参与肿瘤发生的综述。
但是，在实际的癌症治疗中存在EGFR激活突变(例如L858R和delE746_A750)，例如，参见科学(Science)，2004年第304期，1497-500页和新英格兰医学杂志，2004年第350期，2129-39页。这些最普遍的EGFR激活突变(L858R和delE746_A750)相对于野生型(WT)EGFR而言，对小分子酪氨酸激酶抑制剂(例如吉非替尼和厄洛替尼)的亲和力增加、同时对三磷酸腺苷(ATP)的亲和力下降。最后，产生对吉非替尼或厄洛替尼治疗的获得性抗性，例如由于看门残基T790M的突变。由于这种突变导致对靶向于EGFR的现有药物的抗性，本领域中仍然需要能抑制包括看门基因突变的EGFR的新化合物。所述的新化合物应当相对于激活突变体形式的EGFR(例如L858R EGFR突变体、或者delE746_A750突变体或Exon19缺失EGFR突变体)和/或抗性突变体形式的EGFR(例如T790M EGFR突变体) 而言，具有对野生型EGFR的有利活性和/或选择性。换言之，本领域需要对某些激活或抗性突变体形式的EGFR显示较高的抑制、同时对野生型EGFR显示相对较低的抑制的化合物，从而不仅能够发挥抗癌效力，而且能够降低与抑制野生型EGFR相关的不良反应和毒理学(例如皮疹和/或腹泻)。
为了解决这一问题，发明人经过研究后，令人惊讶地发现了一类苯胺基-三嗪化合物，其对于EGFR的突变体形式具有较高的抑制效力，同时又具有对野生型EGFR相对较低的抑制。此外，这些化合物具有较好的药理学效果、可接受的毒理学作用以及有利的药代动力学性质。
发明内容
本发明提供了式(I)的化合物或其药学上可接受的盐：
Figure PCTCN2018086929-appb-000001
其中R 1为-NR 5R 6，其中R 5和R 6各自独立地选自C 1-C 6烷基，其中所述烷基为未取代或被-NR 7R 8所取代；
其中R 2选自C 2-C 6烯基，所述烯基为未取代或被-NR 7R 8所取代；
其中R 7和R 8在每次出现时各自独立地选自H或C 1-C 6烷基；
其中R 3选自取代或未取代的稠合二环基团，所述稠合二环为五元环和六元环稠合；
其中R 4选自C 1-C 6烷基。
根据本发明的一个实施方式，其中所述化合物为如下式(II)所示：
Figure PCTCN2018086929-appb-000002
其中A 1、A 4、A 9各自独立地选自N或C；A 2、A 3、A 5、A 6、A 7、A 8各自独立地选自N、NR a、CR a、CR aR b，其中R a和R b各自独立地选自H、C 1-C 6烷基和卤素，或者R a、R b和与它们所连接的同一个碳原子一起形成C 3-C 6环烷基，所述C 1-C 6烷基和C 3-C 6环烷基任选取代有一个或多个卤素原子，所述卤素原子为氟、氯或溴，条件是环A和环B至少一个为不饱和环。
根据本发明的一个实施方式，A 2选自N、CH、CH 2；A 3选自N、CR a、NR a、CH、CR aR b；A 5选自N或CH、CH 2；A 6选自N或CH、CH 2、CF；A 7选自N或CH、CH 2、CF；A 8选自N或CH、CH 2、CF、CF 2。
根据本发明的一个实施方式，其中A 1为N。
根据本发明的一个实施方式，其中A 1、A 2、A 3、A 4、A 5、A 6、A 7、A 8、A 9中有一个、两个或三个包含N原子。
根据本发明的一个实施方式，其中所述R 1选自：
Figure PCTCN2018086929-appb-000003
根据本发明的一个实施方式，其中所述R2选自：
Figure PCTCN2018086929-appb-000004
根据本发明的一个实施方式，其中所述R3选自：
Figure PCTCN2018086929-appb-000005
Figure PCTCN2018086929-appb-000006
根据本发明的一个实施方式，其中所述化合物选自：
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(吡唑[1,5-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物1)
Figure PCTCN2018086929-appb-000007
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(吡唑[1,5-a]嘧啶 -3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物2)
Figure PCTCN2018086929-appb-000008
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(4,5,6,7-四氢吡唑[1,5-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物3)
Figure PCTCN2018086929-appb-000009
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-甲基-1H-吲哚-1-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物4)
Figure PCTCN2018086929-appb-000010
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吡咯[2,3-c]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物5)
Figure PCTCN2018086929-appb-000011
N-(5-((4-(1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物6)
Figure PCTCN2018086929-appb-000012
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(咪唑并[1,2-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物7)
Figure PCTCN2018086929-appb-000013
N-(5-((4-(1H-苯并[d]咪唑-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物8)
Figure PCTCN2018086929-appb-000014
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(吡唑并[1,5-c]嘧啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物9)
Figure PCTCN2018086929-appb-000015
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(咪唑并[1,5-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物10)
Figure PCTCN2018086929-appb-000016
N-(5-((4-(3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物11)
Figure PCTCN2018086929-appb-000017
N-(5-((4-(1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物12)
Figure PCTCN2018086929-appb-000018
N-(5-((4-(1H-吡咯并[3,2-c]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物13)
Figure PCTCN2018086929-appb-000019
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-甲基-1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物14)
Figure PCTCN2018086929-appb-000020
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(5-氟代-3-甲基-1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物15)
Figure PCTCN2018086929-appb-000021
(E)-4-(二甲基氨基)-N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丁-2-烯酰胺(化合物16)
Figure PCTCN2018086929-appb-000022
N-(5-((4-(4,4-二氟-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物17)
Figure PCTCN2018086929-appb-000023
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-甲基-1H-吡咯并[3,2-c]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物18)
Figure PCTCN2018086929-appb-000024
N-(5-((4-(1H-苯并[d][1,2,3]三唑-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物19)
Figure PCTCN2018086929-appb-000025
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(6-氟代-3-甲基-1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物20)
Figure PCTCN2018086929-appb-000026
N-(5-((4-(3,3-二氟-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物21)
Figure PCTCN2018086929-appb-000027
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(螺[环丙烷-1,3'-吡咯[3,2-b]吡啶]-1'(2'H)-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物22)
Figure PCTCN2018086929-appb-000028
N-(5-((4-(3,3-二甲基-5-氟-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物23)
Figure PCTCN2018086929-appb-000029
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(5'-氟代螺[环丙烷-1,3'-吡咯[3,2-b]吡啶]-1'(2'H)-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物24)
Figure PCTCN2018086929-appb-000030
N-(5-((4-(3,3-二甲基-7-氟-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺 (化合物25)
Figure PCTCN2018086929-appb-000031
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(8-甲基咪唑[1,2-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物26)
Figure PCTCN2018086929-appb-000032
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(8-氟代咪唑[1,2-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物27)
Figure PCTCN2018086929-appb-000033
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(8-(三氟代甲基)咪唑并[1,2-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物28)
Figure PCTCN2018086929-appb-000034
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(3-氟代-1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物29)
Figure PCTCN2018086929-appb-000035
本发明还提供了一种药物组合物，其包含根据本发明所述的化合物或其药学上可接受的盐。
本发明还提供了将本发明所述的化合物或其药学上可接受的盐在制备用于治疗小细胞肺癌的药物中的用途。
定义
在本发明中，下列术语具有以下所述的含义：
本发明的“烷基”是指直链、支链或环状的饱和烃基，优选12个碳原子以下的烷基，更优选6个碳原子以下的烷基。烷基的实施例包括甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、新戊基、环己基、正己基、异己基、2,2,-甲基丁基和2,3-二甲基丁基。本发明的“C 1-6烷基”是指含有1-6个碳原子的直链、支链或环状的饱和烃基。本发明的“C 1-3烷基”是指含有1-3个碳原子的直链、支链或环状的饱和烃基。
本发明的“烯基”是指含有一个或多个碳碳双键(C＝C)的直链或支链不饱和烃基。本发明的“C 2-6烯基”是指含有1个或2个碳碳双键且含有2至6个碳原子的不饱和烃基。本发明的“C 2-4烯基”是指含有1个或2个碳碳双键且含有2至4个碳原子的不饱和烃基。例如，乙烯基、丙烯基、正丁烯基、丁二烯基、戊烯基、己烯基。
本发明的“卤素”是指氟、氯、溴、碘。
在本说明书的上下文中，除非有相反的指示，术语“治疗”也包含“预防”。本文中使用的术语“治疗”意在具有其如下的普通含义：处理疾病以完全地或部分地缓解其症状中的一种、部分或全部，或者纠正或补偿潜在的病理。本文中使用的术语“预防”意在具有其正常日常含义，并且包括防止疾病发展的初级预防和防止已发生疾病的二级预防，暂时或持续地防止患者疾病的加剧或恶化或者与疾病相关的新症状的发生。
药学上可接受的盐
本领域技术人员应当理解，可以制备式(I)化合物的盐，包括药学上可接受的盐。这些盐类可以在所述化合物最终分离和纯化过程中原位制备，或者通过独立地分别将以其游离酸或游离碱形式的纯化的化合物与适合的碱或酸反应制备。
可以与无机酸和有机酸形成药学上可接受的酸加成盐，例如，乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘化物/碘化物、羟乙基磺酸盐、乳酸盐、乳糖酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、硬脂酸盐、油酸盐、草酸盐、软脂酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖醛酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以生成盐的无机酸包括，例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以生成盐的有机酸包括，例如，乙酸、丙酸、羟乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、甲苯磺酸、磺基水杨酸等。药学上可接受的碱加成盐可以与 无机或有机碱形成。
可以生成盐的无机碱包括，例如铵盐和元素周期表的I至XII族的金属。在某些实施方案中，所述盐是衍生自钠、钾、铵、钙、镁、铁、银、锌和铜；特别适合的盐包括铵盐、钾盐、钠盐、钙盐和镁盐。
可以生成盐的有机碱包括，例如，伯胺、仲胺和叔胺，取代的胺包括天然产生的取代胺类，环胺、碱离子交换树脂等。某些有机胺类包括异丙胺、二乙醇胺、二乙胺、赖氨酸、葡甲胺、哌嗪及氨基丁三醇。
本发明的药学上可接受的盐能够通过常规的化学方法由碱性或酸性部分合成而来。通常，这些盐能够通过将这些化合物的游离酸形式与化学量的合适的碱(Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应、或者通过将这些化合物的游离碱形式与化学量的合适的酸反应而进行制备。这些反应通常在水中或在有机溶剂中、或在两者的混合物中进行。通常，在适宜时，需要使用非水介质，例如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。其它合适的盐的列表可在“Remington's Pharmaceutical Sciences”,第20版,Mack Publishing Company,Easton,Pa.,(1985)；以及Stahl和Wermuth的“Handbook of Pharmaceutical Salts：Properties,Selection,and Use”(Wiley-VCH,Weinheim,德国,2002)中找到。
还可以制备式(I)化合物的溶剂化物，包括药学上可接受的溶剂化物。“溶剂化物”是指由溶质和溶剂形成的可变化学量的复合物。为了本发明目的的此类溶剂不影响所述溶质的生物活性。适合溶剂的实例包括但不限于水、MeOH、EtOH和AcOH。其中水是溶剂分子的溶剂化物通常是指水合物。水合物包括包含化学计量的量的水的组分，以及包含可变量的水的组分。
如本文所用，术语“药学上可接受的”的含义是适用于药物用途的化合物。适用于药物的本发明化合物的盐和溶剂化物(例如水合物和盐的水合物)是其中平衡离子或结合溶剂是药学上可接受的那些。但是，具有非药学上可接受的平衡离子或结合溶剂的盐和溶剂化物也包含在本发明范围内，例如，用作制备其它本发明化合物和其药学上可接受的盐和溶剂化物的中间体。
式(I)化合物(包括其盐和溶剂化物)可以以结晶形式、非结晶形式或其混合物存在。所述化合物或其盐或溶剂化物还可以表现出多晶现象，即以不 同结晶形式出现的能力。这些不同的结晶形式通常已知为“多晶型”。多晶型具有相同的化学组成，但是结晶固体状态的堆积、几何排列和其它描述特性不同。因此，多晶型可以具有不同的物理性质，例如形状、密度、硬度、变形性、稳定性和溶解度性质。多晶型通常表现出不同的熔点、IR光谱和X-射线粉末衍射图谱，其全部都可以用于鉴别。本领域技术人员能够了解，例如，通过改变或调整在式(I)化合物的结晶/重结晶中所使用的条件而可能产生不同的多晶型。
本发明还包含式(I)化合物的不同异构体。“异构体”是指具有相同构成和分子量，但是物理和/或化学性质不同的化合物。结构的区别可以是在结构中(几何异构体)或者在旋转平面偏振光的能力上(立体异构体)。关于立体异构体，式(I)化合物可以具有一个或多个不对称碳原子，并可以以外消旋体、外消旋混合物以及以单个对映异构体或非对映异构体出现。全部此类异构体形式都包含在本发明范围内，包括其混合物。如果所述化合物含有双键，取代基可以是E或Z构型。如果所述化合物包含二取代的环烷基，该环烷基的取代基可以具有顺式-或反式-构型。也期望包含全部的互变异构体形式。
式(I)化合物的任意不对称原子(例如碳等)都能够以外消旋或对映异构体富集存在，例如(R)-、(S)-或(R,S)-构型。在某些实施方案中，每一个不对称原子在(R)-或(S)-构型中有至少50％对映异构体过量、至少60％对映异构体过量、至少70％对映异构体过量、至少80％对映异构体过量、至少90％对映异构体过量、至少95％对映异构体过量、或至少99％对映异构体过量。如有可能，在具有不饱和双键的原子上的取代基以顺式-(Z)-或反式-(E)-形式存在。
因此，如本文所用，式(I)化合物能够是可能的异构体、旋转异构体、阻转异构体、互变异构体或其混合物之一的形式，例如作为基本上纯的几何异构体(顺式或反式)、非对映异构体、旋光异构体(对映异构体)、外消旋体或其混合物。
任何所得的异构体的混合物都能够基于组分的物理化学差异被分离成纯的或基本上纯的几何或旋光异构体、非对映异构体、外消旋体，例如通过色谱法和/或分步结晶。
任何所得的终产物或中间体的外消旋体能够通过已知的方法(例如通过 其非对映体盐的分离)被拆分成旋光对映异构体，其用有光学活性的酸或碱获得，并且释放出有光学活性的酸性或碱性化合物。特别地，碱性部分因此可以用于将本发明的化合物拆分成其旋光对映异构体，例如通过与有光学活性的酸(例如酒石酸、二苯甲酰酒石酸、二乙酰酒石酸、二-O,O'-对甲苯酰酒石酸、扁桃酸、苹果酸或樟脑-10-磺酸)形成的盐的分步结晶。外消旋产物也能够通过手性色谱法进行拆分，例如使用手性吸附剂的高压液相色谱法(HPLC)。
本发明包括式(I)化合物的未标记的形式以及同位素标记的形式。同位素标记的化合物具有由本文所给出的化学式描述的结构，除了一个或多个原子被具有所选择的原子量或质量数的原子替换。能够被掺入本发明化合物的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素，分别例如 2H、 3H、 11C、 13C、 14C、 15N、 18F、 31P、 32P、 35S、 36Cl、 125I。本发明包括如本文所定义的各种同位素标记的化合物，例如其中出现放射性同位素(例如 3H和 14C)的那些或其中出现非放射性同位素(例如 2H和 13C)的那些。这些同位素标记的化合物可用于代谢研究(例如使用 14C)、反应动力学研究(例如用 2H或 3H)、检测或成像技术，例如正电子发射断层扫描术(PET)或单光子发射计算体层摄影术(SPECT)，包括药物底物组织分布分析，或者用于患者的放射治疗。特别地，对于PET或SPECT研究可能特别需要 18F或标记的化合物。同位素标记的式(I)化合物通常能够通过本领域的技术人员已知的常规技术或者通过与所附实施例和制备例中所述方法类似的方法、使用合适的同位素标记的试剂代替以前所用的未标记的试剂进行制备。
此外，用较重的同位素、特别是氘(即 2H或D)的取代可能带来由更强的代谢稳定性导致的某些治疗优势，例如增加的体内半衰期或减少的剂量需求或治疗指数的改善。可以理解，在本文中氘被视为式(I)的化合物的取代基。该较重同位素、特别是氘的浓度可能由同位素富集因子决定。如本文所用的术语“同位素富集因子”是指特定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物中的取代基被标为氘，那么对于每一个标出的氘原子，该化合物具有至少3500(在每一个标出的氘原子处52.5％氘掺入)、至少4000(60％氘掺入)、至少4500(67.5％氘掺入)、至少5000(75％氘掺入)、至少5500(82.5％氘掺入)、至少6000(90％氘掺入)、至少6333.3(95％氘掺入)、至少6466.7(97％氘掺入)、至少6600(99％氘掺入)、或至少 6633.3(99.5％氘掺入)的同位素富集因子。
药物组合物
本发明提供了药物组合物，其包含如上所述的式(I)的化合物或其药学上可接受的盐以及药学上可接受的稀释剂或载体。
药物组合物能够针对特定的给药途径进行配制，例如口服给药、肠胃外给药和直肠给药等。此外，本发明的药物组合物能够以固体形式(非限制性地包括胶囊、片剂、丸剂、颗粒剂、粉末剂或栓剂)或以液体形式(非限制性地包括溶液剂、混悬剂或乳剂)制成。药物组合物能够经历常规的制药操作(例如灭菌)和/或能够含有常规的惰性稀释剂、润滑剂或缓冲剂以及辅料，例如防腐剂、稳定剂、润湿剂、乳化剂和缓冲剂等。
通常，药物组合物是片剂或明胶胶囊，其包含活性成分以及
a)稀释剂，例如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素和/或甘氨酸；
b)润滑剂，例如二氧化硅、滑石粉、硬脂酸、其镁或钙盐和/或聚乙二醇；对于片剂也包含
c)粘合剂，例如硅酸镁铝、淀粉糊、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮；如果需要，还有
d)崩解剂，例如淀粉、琼脂、海藻酸或其钠盐、或泡腾混合物；和/或
e)吸收剂、着色剂、调味剂和增甜剂。
根据本领域中已知的方法，片剂可以是薄膜包衣或肠溶包衣的。
用于口服给药的合适的组合物包括有效量的式(I)化合物或其药学上可接受的盐，其为片剂、锭剂、水或油混悬液、可分散的粉末或颗粒、乳剂、硬或软胶囊、或糖浆或酏剂的形式。根据本领域中已知的用于制备药物组合物的任意方法制备用于口服使用的组合物，并且为了提供精制和适口的制剂该组合物能够含有1种或多种选自增甜剂、调味剂、着色剂和防腐剂的试剂。片剂可以含有与适合于制备片剂的无毒的药学上可接受的赋形剂混合在一起的活性成分。这些赋形剂是例如惰性的稀释剂(例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠)；成粒剂和崩解剂(例如玉米淀粉、或海藻酸)；粘合剂(例如淀粉、明胶或阿拉伯胶)；和润滑剂(例如硬脂酸镁、硬脂酸或滑石粉)。片剂是未经包衣的或者通过已知的技术进行包衣从而延缓在 胃肠道的崩解和吸收，从而在较长的时期内提供持久的作用。例如，能够使用延时材料，例如单硬脂酸甘油酯或二硬脂酸甘油酯。用于口服的制剂能够以硬明胶胶囊呈递，其中活性成分与惰性的固体稀释剂(例如碳酸钙、磷酸钙或高岭土)混合，或者以软明胶胶囊呈递，其中活性成分与水或油介质(例如花生油、液体石蜡或橄榄油)混合。
某些可注射的组合物是等渗水溶液或混悬液，栓剂有利地由脂肪乳或混悬液制得。所述的组合物可以进行灭菌和/或含有辅料，例如防腐、稳定、润湿或乳化剂、溶解促进剂、用于调节渗透压的盐和/或缓冲剂。此外，其也可以含有其他的治疗上有价值的物质。所述的组合物分别根据常规的混合、制粒或包衣法进行制备，并且含有大约0.1-75％或含有大约1-50％的活性成分。
由于水可能促进某些化合物的降解，本发明还提供无水的药物组合物和剂型，其包含作为活性成分的本发明化合物。
使用无水或低水含量的成分和低水含量或低湿度的条件能够制备本发明的无水的药物组合物和剂型。可以制备和贮存无水的药物组合物以便保持其无水的性质。因此，使用已知防止与水接触的材料包装无水的组合物以便其能够包含于合适的配方药盒中。合适的包装的实例非限制性地包括气密的箔、塑料、单位剂量容器(例如管形瓶)、泡罩包装和条带包装。
本发明进一步提供药物组合物和剂型，其包含1种或多种降低作为活性成分的本发明化合物的分解速率的试剂。该试剂(其在本文中称作“稳定剂”)非限制性地包括抗氧化剂(例如抗坏血酸)、pH缓冲剂或盐缓冲剂等。
对于大约50-70kg的个体，本发明的药物组合物或组合产品能够是大约1-1000mg活性成分的单位剂量，或者大约1-500mg或大约1-250mg或大约1-150mg或大约0.5-100mg、或大约1-50mg活性成分。化合物、药物组合物或其组合产品的治疗有效剂量取决于个体的物种、体重、年龄和个体情况、其正在接受治疗的病症或疾病或其严重程度。普通技术的内科医生、临床医师或兽医能够容易地确定为了预防、治疗或抑制病症或疾病的发展所需的每一种活性成分的有效量。
治疗用途
另一方面，本发明提供了式(I)的化合物或其药学上可接受的盐，其用 作药物。在另一方面，本发明还提供了式(I)的化合物或其药学上可接受的盐在制备用于治疗癌症的药物中的用途。
另一方面，本发明还提供了在需要这种治疗的温血动物例如人中产生抗癌作用的方法，其包括：向所述动物给药有效量得如式(I)的化合物或其药学上可接受的盐。
另一方面，本发明还提供了式(I)的化合物或其药学上可接受的盐和另外的抗肿瘤物质的用途，用于癌症的同时、独立或序贯治疗。
在上文提及的任一方面或实施方案中，所述癌症可以选自卵巢癌、宫颈癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤,黑色素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝细胞癌、胃癌、胃肠道间质瘤(GIST)、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间变性大细胞淋巴瘤、急性髓细胞白血病(AML)、多发性骨髓瘤、黑色素瘤、间皮瘤。
在一个优选实施方案中，所述癌症为非小细胞肺癌。
上述的式(I)的化合物或其药学上可接受的盐可作为单独治疗应用，或者除了本发明化合物以外还涉及到常规的手术或放射疗法或化学疗法或免疫疗法。这种化学疗法与本发明化合物可以并列地、同时地、序贯地、或分别地给药，并且可包含以下类型的抗肿瘤剂的一种或多种：
(i)医学肿瘤学中所使用的抗增殖/抗肿瘤药物及其组合，例如烷化剂(例如顺铂、奥沙利铂、卡铂、环磷酰胺、氮芥、美法仑、苯丁酸氮芥、白消安、替莫唑胺、亚硝基脲类)；抗代谢药(例如吉西他滨和抗叶酸剂，例如氟嘧啶(如5-氟尿嘧啶和替加氟)、雷替曲塞、甲氨喋呤、阿糖胞苷、羟基脲)；抗肿瘤抗生素(例如蒽环类，如阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素C、放线菌素、光神霉素)；抗有丝分裂药剂(例如长春花生物碱，如长春新碱、长春碱、长春地辛、长春瑞滨；以及紫杉烷类，如紫杉醇、泰索帝)；拓扑异构酶抑制剂(例如表鬼臼毒素(如依托泊苷、替尼泊苷)，安吖啶、托泊替康、喜树碱)；
(ii)细胞生长抑制剂，例如抗雌激素药(例如他莫昔芬、氟维司群、托瑞米芬、雷洛昔芬、屈洛昔芬、抗雄激素药(例如比卡鲁胺、氟他胺、尼鲁米特、醋酸环丙孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林、和布舍瑞林)、孕激素类(例如醋酸甲地孕酮)、芳香酶抑制剂(例如 阿那曲唑、来曲唑、伊西美坦)、5α-还原酶抑制剂(例如非那雄胺)；
(iii)抗侵袭剂，例如c-Src激酶家族抑制剂，例如达沙替尼和波舒替尼(SKI-606)，以及金属蛋白酶抑制剂(如马立马司他)、尿激酶纤溶酶原激活物受体功能的抑制剂或者类肝素酶的抗体；
(iv)生长因子功能的抑制剂：例如这种抑制剂包括生长因子抗体和生长因子受体抗体(例如抗erbB2抗体曲妥珠单抗、抗EGFR抗体帕尼单抗、抗erbB1抗体西妥昔单抗以及任何生长因子或生长因子受体抗体)；这种抑制剂还包括：酪氨酸激酶抑制剂，例如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂，如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉基丙氧基)-喹唑啉-4-胺(吉非替尼，ZD1839)、N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)喹唑啉-4-胺(厄洛替尼，OSI-774)、6-丙烯酰胺基-N-(3-氯-4-氟苯基)-7-(3-吗啉基丙氧基)-喹唑啉-4-胺(CI 1033)、erbB2酪氨酸激酶抑制剂(例如拉帕替尼)；肝细胞生长因子家族的抑制剂；胰岛素生长因子家族的抑制剂；血小板衍生的生长因子家族的抑制剂，例如伊马替尼和/或尼洛替尼(AMN107)；丝氨酸/苏氨酸激酶的抑制剂(例如Ras/Raf信号传导抑制剂，例如法呢基转移酶抑制剂，例如索拉非尼(BAY43-9006)、替匹法尼(R115777)、氯那法尼(SCH66336))、通过mEK和/或AKT激酶的细胞信号传导抑制剂、c-kit抑制剂、abl激酶抑制剂、PI3激酶抑制剂、Plt3激酶抑制剂、CSF-1R激酶抑制剂、IGF受体(胰岛素样生长因子)激酶抑制剂；极光激酶(aurora kinase)抑制剂(例如AZD1152、PH739358、VX-680、MLN8054、R763、MP235、MP529、VX-528、AX39459)，细胞周期蛋白依赖性激酶抑制剂，例如CDK2和/或CDK4抑制剂；
(v)抗血管生成剂，例如抑制血管内皮生长因子作用的药剂，例如抗人血管内皮细胞生长因子抗体贝伐珠单抗以及例如VEGF受体酪氨酸激酶抑制剂，例如凡德他尼(ZD6474)、伐他拉尼(PTK787)、舒尼替尼(SU11248)、阿西替尼(AG-013736)、帕唑帕尼(GW786034)、4-(4-氟-2-甲基吲哚-5-基氧基)-6-甲氧基-7-(3-吡咯烷-1-基丙氧基)喹唑啉(AZD2171；WO 00/47212中的实施例240)，例如WO 97/22596、WO 97/30035、WO 97/32856和WO 98/13354中公开的那些；
(vi)血管损伤剂，例如康普瑞汀A4以及WO 99/02166、WO 00/40529、WO00/41669、WO 01/92224、WO 02/04434和WO 02/08213中公开的化合 物；
(vii)内皮素受体拮抗剂，例如齐泊腾坦(ZD4054)或者阿曲生坦；
(viii)基因治疗方法，包括例如替换异常基因(例如异常p53或者异常BRCA1或BRCA2)的方法；GDEPT(基因定向的酶前药治疗)法，例如使用胞嘧啶脱氨酶、胸苷激酶或者细菌硝基还原酶的那些；提高患者对化学治疗或放射治疗的耐受性的方法，例如多重耐药基因治疗；和
(ix)免疫治疗方法，包括例如提高患者肿瘤细胞的免疫原性的体外和体内方法，例如用细胞因子(例如白细胞介素2、白细胞介素4或者粒细胞巨噬细胞集落刺激因子)进行转染；降低T细胞无效能的方法；使用转染的免疫细胞(例如细胞因子转染的树突状细胞)的方法；使用细胞因子转染的肿瘤细胞系的方法；使用抗独特型抗体的方法；降低免疫抑制性细胞(例如调节性T细胞、髓源性抑制细胞、或表达IDO(吲哚胺2,3-脱氧酶)的树突状细胞)的功能的方法；以及使用衍生自肿瘤相关抗原(例如NY-ESO-1，mAGE-3、WT1或Her2/neu)的蛋白质类或肽类组成的癌症疫苗的方法。
本文中，如果术语“联合治疗”是用来描述组合治疗，则应理解这可以表示同时给药、独立给药或序贯给药。关于“联合给药”应类似地理解。在本发明的一个方面，“联合治疗”是指同时给药。在本发明的另一方面，“联合治疗”是指独立给药。在本发明的另一方面，“联合治疗”是指序贯给药。当序贯给药或独立给药时，给药第二组分的延迟不应例如失去使用组合产生的效果的利益。
本发明化合物的合成方法
本发明的式(I)化合物一般地可以按照以下流程的方法进行合成：
Figure PCTCN2018086929-appb-000036
在所述流程中，由起始原料2,4-二氯-1,3,5-三嗪与适宜的稠环化合物 R 3H偶联得到中间体
Figure PCTCN2018086929-appb-000037
其与中间体
Figure PCTCN2018086929-appb-000038
在催化剂的存在下反应得到式(I)化合物。其中，R 3如上文所定义。
具体地，例如
Figure PCTCN2018086929-appb-000039
的合成路径如下：
Figure PCTCN2018086929-appb-000040
其中，环A、环B、A 2、A 3、A 4、A 5、A 6、A 7、A 8、A 9如上文所定义。
另外，中间体
Figure PCTCN2018086929-appb-000041
的制备合成路线如下：
Figure PCTCN2018086929-appb-000042
具体实施方式
通过以下实施例对本发明的方法进行进一步的说明。应当理解，提供以下实施例的目的仅仅是为了能够更好的理解本发明，而不是以任何方式限定本发明的范围。
中间体III的合成：
在0℃下，向化合物a(50.0g,354mmol)的H 2SO 4(260mL)溶液在搅拌下缓慢加入KNO 3(35.8g,354mmol)，然后搅拌2小时。TLC(石油醚:乙酸乙酯＝5:1,Rf＝0.57)表明反应物转化完全。将反应混合物倒入冰水(3kg)中，用NaOH水溶液调节pH至7，然后用乙酸乙酯(1.5L x 2)萃取。萃取有机相用Na 2SO 4干燥，浓缩得到粗产物。粗产物经硅胶柱纯化(洗脱剂:石油醚:乙酸乙酯＝20:1～5:1)得到黄色固体化合物b(91.0g,产率:69％)。 1H NMR:(ES6131-2-P1A,CDCl 3,400MHz)δ7.45-7.43(d,J＝9.2Hz,1H),6.82-6.79(d,J＝12.0Hz,1H),3.89(s,3H),3.69(br s,2H).
将化合物b(79.0g,424mmol)，N,N',N'-三甲基乙烷-1,2-二胺(65.1g,637mmol,82mL)和碳酸钾(88.0g,637mmol)的DMF(150mL)混合物在90℃下搅拌25小时。TLC(石油醚:乙酸乙酯＝3:1)表明反应物已经消耗完全。向反应液中加入水(1.5L)，二氯甲烷萃取(800mLx3)，饱和食盐水(1L)洗涤，Na 2SO 4干燥，浓缩得到粗产物。粗产物经硅胶柱纯化(洗脱剂:二氯甲烷:甲醇＝100:1～20:1)得到黄色油状物化合物c(66.0g,产率:58％)。
1H NMR:(ES6131-2-P1A,CDCl 3,400MHz)δ＝7.31(s,1H),6.63(s,1H),3.90(s,3H),3.06-3.03(t,J＝6.0Hz,2H),2.79(s,3H),2.51-2.48(t,J＝6.0Hz,2H),2.31(s,6H).LCMS:269.1[M+H] +,Rt＝1.240。
在0℃下向化合物c(18.0g,67.1mmol)的二氯甲烷(200mL)溶液中加入三乙胺(18.0g,178mmol,25mL)，然后滴加烯丙酰氯(8.0g,88.6mmol,7.2mL)。反应混合物在0℃下搅拌16小时。TLC(二氯甲烷:甲醇＝20:1)表明反应物基本反应完全。反应混合物用水(400mL)淬灭，二氯甲烷(200mLx3)萃取。有机相用Na 2SO 4干燥,过滤,浓缩得到粗产物。粗产物经硅胶柱层析(二氯甲烷:甲醇＝100:1～20:1)纯化得到棕色油状物化合物d(8.10g,产率:39％)。
1H NMR:(ES6131-4-p1a,CDCl 3,400MHz)δ＝10.12(s,1H),9.19(s,1H),6.79(s,1H),6.49-6.44(d,J＝17.2Hz,1H),6.32-6.25(dd,J 1＝10.0Hz,J 2＝16.8Hz,2H),5.75–5.72(d,J＝10.0Hz),3.93(s,3H),2.92-2.90(t,J＝5.2Hz,2H),2.79(s,3H),2.49-2.46(m,2H),2.33(s,6H).LCMS:323.2[M+H] +。
向化合物d(9.0g,27.9mmol),Fe(7.8g,139mmol)andNH 4Cl(7.5g,140mmol)的混合物中加入乙醇(100mL)和水(50mL)，然后在50℃下搅拌16小时。TLC(二氯甲烷:甲醇＝10:1)表明反应物反应完全。反应液过滤后浓缩得到粗产物。粗产物经硅胶柱层析(二氯甲烷:甲醇＝20:1)纯化，洗脱液浓缩得到灰白色固体中间体III(7.6g,产率:93％)。 1H NMR:(ES6131-12-p1a,CDCl 3,400MHz)δ7.08(br s,1H),6.85(s,1H),6.65-6.58(dd,J 1＝10.0Hz,J＝16.8Hz,1H),6.45-6.41(m,1H),5.86-5.83(dd,J 1＝10.0Hz,J＝16.8Hz,1H),3.93(s,3H),3.37-3.31(m,2H),3.08(s,2H),2.75(s,6H),2.68(s,3H)。
实施例1
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-甲基-1H-吲哚-1-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物4)
合成路线
[根据细则26改正16.07.2018]　
Figure WO-DOC-FIGURE-27
在0℃下向化合物B1_1(500mg,3.75mmol)和二异丙基乙胺(533mg,4.13mmol)的二氯甲烷(3mL)溶液中加入2,4-二氯-1,3,5-三嗪(562mg,3.75mmol)，然后搅拌1小时。TLC(石油醚:乙酸乙酯＝10:1,Rf＝0.48)表明反应物反应完全。反应混合物浓缩得到粗产物。粗产物经硅胶柱层析(石油醚:乙酸乙酯＝100:1～25:1)纯化得到灰白色固体化合物B1_2(720mg,产率:70％)。
1H NMR:(ES6208-30-P1A,CDCl 3,400MHz)δ8.51(s,0.5H),8.47(s,0.5H),8.3(d,J＝8.0Hz,0.5H),8.27(d,J＝8.0Hz,0.5H),7.26-7.15(m,2H),7.06(t,J＝7.6Hz,1H),4.39(t,J＝12.0Hz,1H),3.74-3.70(m,1H),3.50-3.42(m,1H),1.33(d,J＝6.8Hz,3H)。
向B1_2(600mg,2.4mmol)的二氯甲烷(15mL)溶液中加入DDQ(1.1g,4.9mmol)。反应液在氮气保护下于25℃搅拌5小时。TLC(石油醚:乙酸乙酯＝10:1)表明反应物反应完全.反应液经硅胶柱层析(石油醚:乙酸乙酯＝25:1)纯化得到白色固体化合物B1_3(560mg,产率:94％)。
1H NMR:(ES6176-26-P1A,CDCl 3,400MHz)δ8.81(br s,1H),8.69-8.67(d,J＝9.2Hz,1H),7.91(s,1H),7.56-7.54(d,J＝8.0Hz,1H),7.43-7.39(t,J＝7.6Hz,1H),7.36-7.33(t,J＝7.6Hz,1H),2.34(s,3H)。
向中间体III(239mg,0.82mmol)的四氢呋喃(10mL)溶液中加入化合物B1_3(200mg,0.82mmol)，然后加入吡啶(129mg,1.6mmol)。反应混合物在氮气保护下于25℃搅拌6小时。TLC(石油醚:乙酸乙酯＝5:1)表明反应物反应完全。反应混合物浓缩得到粗产品。粗产品经prep-HPLC(column:Waters Xbridge 150*25 5u；mobile phase:[water(10mM NH 4HCO 3)-ACN]；B％:48％-78％,8min)纯化得到黄色固体化合物4(79mg,产率:19％)。
1H NMR:(ES6176-27-P1A,CDCl 3,400MHz)δ10.13(s,1H),9.81-9.76(br s,1H),8.79-8.77(d,J＝8.4Hz,1H),8.63(s,1H),7.92-7.88(br s,1H),7.54-7.52(d,J＝7.6Hz,1H),7.35-7.24(m,3H),6.82(s,1H),6.55-6.51(m,1H),6.41-6.36(m,1H),5.75-5.72(d,J＝10.4Hz,1H),3.90(s,3H),2.91(s,2H),2.73(s,3H),2.49(s,3H),2.31(s,8H).LCMS:501.4[M+H] +,Rt＝0.771.HPLC:96.41％purity(220nm),Rt＝5.06。
实施例2
N-(5-((4-(1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物6)
合成路线
Figure PCTCN2018086929-appb-000044
在0℃下向2,4-二氯-1,3,5-三嗪(257mg,1.70mmol)的DMF(12mL)溶液中加入化合物B2(202mg,1.70mmol)和二异丙基乙胺(234mg,1.80mmol)，然后搅拌0.5小时。在0℃下中间体III(500mg,1.70mmol)和二异丙基乙胺(234mg,1.80mmol)依次加入反应液。该反应混合物在25℃下搅拌20小时。TLC(石油醚:乙酸乙酯＝1:2,Rf＝0.35)表明反应物反应完全。反应混合物经prep-HPLC(column:Waters Xbridge 150*25 5u；mobile phase:[water(10mM NH4HCO3)-ACN]；B％:18％-48％,10min)纯化得到亮黄色固体化合物6(37.5mg,产率:4.5％)。
1H NMR:(ES6045-14-P1A,CDCl 3,400MHz)δ10.21(br s,1H),9.01(d,J＝8.0Hz,1H),8.65(s,1H),8.52(d,J＝2.8Hz,1H),7.87(s,1H),7.20-7.28(m,1H),6.95(s,1H),6.84(s,1H),6.50(d,J＝16.0Hz,1H),6.37-6.33(m,1H),5.75(d,J＝10.0Hz,1H),3.92(s,3H),2.91(s,2H),2.75(s,3H),2.33(d,J＝4.0Hz,2H),2.18(s.6H)。
LCMS:488.1[M+H] +,Rt＝3.615.HPLC:98.31％purity(220nm),Rt＝3.52。
实施例3
N-(5-((4-(1H-苯并[d]咪唑-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基) 乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物8)
合成路线
Figure PCTCN2018086929-appb-000045
在0℃下向2,4-二氯-1,3,5-三嗪(257mg,1.70mmol)的DMF(8mL)溶液中加入化合物B3(202mg,1.70mmol)和二异丙基乙胺(234mg,1.80mmol)，然后搅拌1小时。在0℃下二异丙基乙胺(234mg,1.80mmol)和中间体III(500mg,1.70mmol)依次加入反应液。该反应混合物在25℃下搅拌16小时。LCMS(es6131-8-p1a)表明反应物反应完全。反应混合物经prep-HPLC(column:Waters Xbridge 150*25 5u；mobile phase:[water(10mM NH 4HCO 3)-ACN]；B％:25％-55％,10min)，洗脱液冻干得到粗产物。粗产物经prep-TLC(二氯甲烷:甲醇＝15:1)纯化得到白色固体化合物8(59mg,产率:7％)。
1H NMR:(ES6131-28-P1A1,CDCl 3,400MHz)δ10.20(s,1H),9.72(s,2H),8.72(s,1H),8.60-8.58(m,1H),7.95(s,1H),7.93-7.84(m,1H),7.42(s,2H),6.84(s,1H),6.59-6.53(m,1H),7.42(s,2H),6.84(s,1H),6.59-6.53(m,1H),6.37-6.32(m,1H),5.76-5.73(d,J＝10.8Hz,1H),3.92(s,3H),2.91(s,2H),2.75(s,3H),2.31(s,8H)。
LCMS:488.3[M+H] +,Rt＝0.687.HPLC:97.53％purity(220nm),Rt＝3.70。
实施例4
N-(5-((4-(3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物11)
合成路线
[根据细则26改正16.07.2018]　
Figure WO-DOC-FIGURE-31
氮气保护下于0℃向化合物B9_1(500mg,3.08mmol)的四氢呋喃(10mL)溶液中加入硼氢化钠(583mg,15.4mmol)，然后滴加BF 3.Et 2O(6.82g,21.6mmol,5.93mL,45％纯度)。然后反应混合物在20℃搅拌6小时。TLC(石油醚:乙酸乙酯＝1:1,Rf＝0.45)表明反应物反应完全。反应混合物用饱和氯化铵淬灭(5mL)，乙酸乙酯(10mL)萃取。水相用乙酸乙酯(5mL x3)萃取。合并的有机相用饱和食盐水(5mL)洗涤，硫酸钠干燥，浓缩得到黄色固体化合物B9(400mg,产率:88％)。
1H NMR:(ES6174-5-P1A 400MHz CDCl 3)δ7.86(dd,J＝1.2Hz,4.8Hz,1H)，6.98(dd,J＝4.8Hz,8.0Hz,1H)，6.93(dd,J＝5.2Hz,8.0Hz,1H)，3.42(s,2H)，1.39(s,6H)。
向2,4-二氯-1,3,5-三嗪(202mg,1.40mmol)的四氢呋喃(10mL)溶液中加入化合物B9(200mg,1.40mmol)和吡啶(213mg,2.70mmol)，然后在氮气保护下于25℃搅拌5小时。TLC(石油醚:乙酸乙酯＝2:1)表明反应物反应完全。反应混合物减压浓缩得到粗产物。粗产物经硅胶柱层析(石油醚:乙酸乙酯＝30:1～25:1)纯化得到白色固体化合物B9_2(35mg,产率:10％)。
向中间体III(39mg,0.13mmol)的四氢呋喃3mL溶液中加入化合物B9_2(35mg,0.13mmol)和吡啶(21mg,0.27mmol)，然后在氮气保护下于25℃搅拌5小时。TLC(石油醚:乙酸乙酯＝2:1)表明反应物反应完全。反应混合物减压浓缩得到粗产物。粗产物经prep-HPLC(column:Waters Xbridge 150*25 5u；mobile phase:[water(10mM NH 4HCO 3)-ACN]；B％:31％-51％,8min)纯化得到黄色固体化合物11(9.5mg,产率:14％)。
1H NMR:(ES6176-31-P1B,CDCl 3,400MHz)δ10.11-10.06(br s,1H),9.72(s,1H),8.60-8.58(d,J＝8.4Hz,1H),8.54(s,1H),8.44(s,1H),7.79-7.76(br s,1H),7.13(s,1H),6.80(s,1H),6.48-6.44(m,1H),6.37-6.31(m,1H),5.73-5.69(d,J＝11.6Hz,1H),4.44-4.40(br s,1H),3.88(s,3H),2.90(s,2H),2.72(s,3H),2.25(s,8H),1.50(s,6H),1.43(s,2H).LCMS:518.4[M+H] +,Rt＝0.655.HPLC:89.62％purity(220nm),Rt＝3.76。
实施例5
N-(5-((4-(1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物12)
合成路线
Figure PCTCN2018086929-appb-000047
在0℃下向2,4-二氯-1,3,5-三嗪(206mg,1.40mmol)的乙腈(12mL)溶液中加入化合物B4(162mg,1.40mmol)和碳酸氢钠(127mg,1.50mmol)，然后在0℃下搅拌6小时。中间体III(400mg,1.40mmol)加入，然后反应混合物在25℃下搅拌20小时。TLC(二氯甲烷:甲醇＝20:1,Rf＝0.40)表明反应物反应完全。反应混合物用水(12mL)，二氯甲烷(12mL x 3)萃取。有机相用饱和食盐水洗涤，硫酸钠干燥,过滤浓缩得到粗产物。粗产物经prep-HPLC纯化，洗脱液冻干得到黄色固体化合物12(110mg,产率:16％)。
1H NMR:(ES6131-28-P1A1,CDCl 3,400MHz)δ10.28-10.23(m,2H),9.96(s,1H),8.80(s,1H),8.24-8.21(m,1H),7.79-7.77(m,1H),7.34-7.30(m,1H),7.11-7.07(m,1H),6.84(s,1H),6.66-6.62(d,J＝16.8Hz,1H),6.45-6.41(m,1H),5.83-5.80(d,J＝9.6Hz,1H),3.93(s,3H),2.90-2.89(m,2H),2.74(s,3H),2.34-2.31(m,8H)。
LCMS:488.3[M+H] +,Rt＝0.688。
HPLC:98.33％purity(220nm),Rt＝4.52。
实施例6
N-(5-((4-(1H-吡咯并[3,2-c]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲 基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物13)
合成路线
Figure PCTCN2018086929-appb-000048
在0℃下向2,4-二氯-1,3,5-三嗪(257mg,1.70mmol)的DMF(10mL)溶液中加入中间体III(500mg,1.71mmol)和二异丙基乙胺(234mg,1.80mmol)，然后在0℃下搅拌1小时。二异丙基乙胺(234mg,1.80mmol)和化合物B5(202mg,1.71mmol)依次加入.然后反应混合物在25℃下搅拌15小时。LCMS表明反应物反应完全。反应混合物经prep-HPLC(column:Waters Xbridge 150*25 5u；mobile phase:[water(10mM NH 4HCO 3)-ACN]；B％:23％-53％,10min)纯化，洗脱液冻干，然后再经prep-TLC(二氯甲烷:甲醇＝15:1)纯化得到灰白色固体化合物13(60mg,产率:7％)。
1H NMR:(ES6131-13-P2A,CDCl 3,400MHz)δ10.23(s,1H),9.66-9.60(m,1H),8.93-8.88(m,1H),8.67-8.60(m,2H),8.43-8.42(m,1H),7.92-7.89(m,1H),6.84(s,2H),6.51-6.46(d,J＝17.6Hz,1H),6.38-6.31(dd,J 1＝10.0Hz,J 2＝16.8Hz,1H),5.75-5.73(d,J＝13.0Hz,1H),3.90(s,3H),2.92-2.89(t,J＝6.0Hz,2H),2.75(s,3H),2.35-2.33(t,J＝5.6Hz,2H),2.30(s,6H).LCMS:488.4[M+H] +,Rt＝0.660。
HPLC:97.75％purity(220nm),Rt＝3.47。
实施例7
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-甲基-1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物14)
合成路线
Figure PCTCN2018086929-appb-000049
在25℃下向化合物B6(300mg,2.30mmol)的乙腈(5mL)溶液中加入2,4-二氯-1,3,5-三嗪(340mg,2.30mmol)，然后在50℃下搅拌3小时。LCMS检测到产物。反应混合物过滤,浓缩得到黄色固体粗产物B6_1(410mg)，该粗产物没有经过纯化直接用于下一步反应。
在25℃下向化合物B6_1(300mg,1.20mmol)的DMF(10mL)溶液中加入中间体III(357mg,1.20mmol)，然后在25℃下搅拌3小时。LCMS检测到产物。反应混合物经prep-HPLC(column:Waters Xbridge 150*255u；mobile phase:[water(10mM NH 4HCO 3)-ACN]；B％:25％-55％,10min)，洗脱液冻干得到粗产物。粗产物在乙酸乙酯(3mL)中重结晶，过滤得到黄色固体化合物14(127mg,产率:21％)。
1H NMR:(ES6131-31-p1b,CDCl 3,400MHz)δ9.63(s,1H),9.09(s,1H),8.95(s,1H),8.17(s,1H),7.74-7.72(d,J＝8.8Hz,1H),7.60-7.58(d,J＝8.0Hz,1H),7.33-7.30(m,1H),7.06-7.03(m,1H),6.94-6.90(m,1H),6.72(s,1H),6.51-6.47(d,J＝16.8Hz,1H),5.77-5.74(d,J＝11.2Hz,1H),3.89(s,3H),3.29-3.27(t,J＝5.2Hz,2H),3.19(s,2H),3.08(s,3H),2.84(s,6H),2.64(s,3H).LCMS:502.4[M+H] +,Rt＝0.692。
HPLC:99.48％purity(220nm),Rt＝3.38。
实施例8
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(5-氟代-3-甲基-1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物15)
合成路线
Figure PCTCN2018086929-appb-000050
在0℃搅拌下向化合物B8_1(4.0g,26.1mmol)的浓盐酸(20mL)溶液中滴加亚硝酸钠(1.9g,27.9mmol)水(9.6mL)溶液，然后继续搅拌1小时。SnCl 2.2H 2O(13.2g,58.5mmol)的浓盐酸(9.6mL)溶液在0℃下滴加到反应液中，然后继续搅拌2小时。TLC(石油醚:乙酸乙酯＝8:1)表明反应物反应完全。向反应液中加入饱和碳酸钾溶液至pH＝8。用乙酸乙酯(200mL x4)萃取。有机相用饱和食盐水(150mL)洗涤，硫酸钠干燥,过滤,减压浓缩得到黄色化合物B8(3.9g,产率:51％)。
1H NMR:(ES6176-15-P1A,CDCl 3,400MHz)δ10.01(br s,1H),7.39-7.36(m,1H),7.32-7.29(dd,J 1＝2.0Hz,J 2＝8.8Hz,1H),7.19-7.14(td,J 1＝2.4Hz,J 2＝8.8Hz,1H),2.57(s,3H)。
在0℃下向化合物2,4-二氯-1,3,5-三嗪(500mg,3.33mmol)的乙腈(10mL)溶液中加入化合物B8(501mg,3.33mmol)和碳酸氢钠(308mg,3.66mmol)。然后反应混合物在氮气保护下于25℃搅拌16小时。TLC(二氯甲烷:石油醚＝5:1)表明反应物反应完全。反应混合物过滤，滤液减压浓缩得到粗产物。粗产物经硅胶柱层析(二氯甲烷:石油醚＝1:1～4:1)纯化得到黄色化合物B8_2(400mg,产率:46％)。
1H NMR:(ES6176-21-P1A2,CDCl 3,400MHz)δ9.12(s,1H),7.72-7.69(m,1H),7.18-7.10(m,2H),3.02(s,3H)。
在25℃下向中间体III(222mg,0.76mmol)的四氢呋喃(10mL)溶液中加入化合物B8_2(200mg,0.76mmol)，然后吡啶(120mg,1.50mmol)加入到反应液.该反应混合物在氮气的保护下于25℃搅拌6小时。TLC(石油醚: 乙酸乙酯＝4:1)表明反应物反应完全。反应混合物减压浓缩得到粗产物。
粗产物经prep-HPLC(column:Gemini 150*25 5u；mobile phase:[water(10mM NH 4HCO 3)-ACN]；B％:35％-60％,12.5min)纯化得到白色固体化合物15(46mg,产率:12％)。
1H NMR:(ES6176-23-P1A,CDCl 3,400MHz)δ10.19(s,1H),9.60(s,1H),8.14(s,1H),7.72(br s,1H),7.15-7.11(m,2H),6.82(s,1H),6.49-6.45(m,1H),6.35-6.29(m,1H),5.73-5.70(d,J＝9.6Hz,1H),3.88(s,3H),3.02(s,2H),2.84(s,2H),2.73(s,3H),2.66(s,1H),2.33(s,3H),2.29(s,6H)。
LCMS:520.4[M+H] +,Rt＝0.695.HPLC:98.4％purity(220nm),Rt＝3.75。
实施例9
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-甲基-1H-吡咯并[3,2-c]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物18)
合成路线
Figure PCTCN2018086929-appb-000051
向化合物B10_1(1.0g,4.50mmol)的DMF(15mL)溶液中加入trimethyl(prop-1-ynyl)silane(1.5g,13.6mmol)，氯化锂(192.9mg,4.50mmol)，碳酸钠(964.5mg,9.10mmol)和Pd(dppf)Cl 2.CH 2Cl 2(186mg,0.23mmol)，然后反应混合物在氮气的保护下于25℃搅拌16小时。TLC(石油醚:乙酸乙 酯＝1:1)表明反应物反应完全。向反应液中加入水(80mL)，用乙酸乙酯(100mL x 3)萃取。有机相用饱和食盐水洗涤，硫酸钠干燥,过滤,减压浓缩得到粗产物。粗产物经硅胶柱层析(石油醚:乙酸乙酯＝20:1～1:1)纯化得到棕色固体B10_2(780mg,产率:84％)。
1H NMR:(ES6176-36-P1A,CDCl 3,400MHz)δ8.89(s,1H),8.70(br s,1H),8.27-8.26(d,J＝5.6Hz,1H),7.24-7.22(d,J＝6.0Hz,1H),2.47(s,3H),0.40(s,9H)。
向化合物B10_2(780mg,3.80mmol)的乙醇(35mL)溶液中加入氢氧化钠(4.7g,117mmol)，然后反应混合物在80℃下搅拌16小时。TLC(二氯甲烷:甲醇＝20:1)表明反应物反应完全。反应液冷却到25℃，倒入水(50mL)中，用乙酸乙酯(60mL x 3)萃取。有机相用饱和食盐水溶液(50mL)洗涤，硫酸钠干燥,过滤,减压浓缩得到粗产物。粗产物经硅胶柱层析(二氯甲烷:甲醇＝100:1～20:1)纯化得到棕色固体B10(400mg,产率:79％)。
1H NMR:(ES6176-39-P1A,CDCl 3,400MHz)δ9.49(br s,1H),8.70(s,1H),8.09-8.07(d,J＝5.6Hz,1H),7.07-7.06(d,J＝6.0Hz,1H),6.83(s,1H),2.19(s,3H)。
在0℃下向中间体III(664mg,2.3mmol)的DMF(10mL)溶液中加入化合物2,4-二氯-1,3,5-三嗪(340mg,2.30mmol)，然后反应混合物在氮气保护下于0℃搅拌1小时。化合物B10(300mg,2.30mmol)加入到反应液中，然后反应混合物在氮气保护下于0℃搅拌2小时.LCMS检测到目标产物。反应混合物减压浓缩得到粗产物。粗产物经prep-HPLC(column:Waters Xbridge 150*25 5u；mobile phase:[water(10mM NH4HCO3)-ACN]；B％:18％-48％,8min)and then was purified by prep-HPLC(column:Waters Xbridge150*25 5u；mobile phase:[water(10mM NH 4HCO 3)-ACN]；B％:32％-62％,10min)纯化得到白色固体化合物18(58mg,产率:5％)。
1H NMR:(ES6176-42-P1A,CDCl 3,400MHz)δ10.19(s,1H),9.76-9.74(br s,1H),8.85(s,2H),8.65-8.59(m,2H),8.47(s,1H),7.97-7.96(br,1H),6.83(s,1H),6.54-6.39(m,2H),5.76-5.74(d,J＝10.4Hz,1H),3.91(s,3H),2.94-2.91(m,2H),2.74(s,3H),2.49(s,3H),2.38(s,2H),2.33(s,6H).LCMS:502.3[M+H] +,Rt＝0.632。
HPLC:100.0％purity(220nm),Rt＝3.85。
实施例10
N-(5-((4-(1H-苯并[d][1,2,3]三唑-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物19)
合成路线
Figure PCTCN2018086929-appb-000052
在0℃下向化合物2,4-二氯-1,3,5-三嗪(257mg,1.70mmol)的DMF(10mL)溶液中加入中间体III(204mg,1.70mmol)和二异丙基乙胺(234mg,1.80mmol)，然后反应混合物在0℃下搅拌1小时。二异丙基乙胺(234mg,1.80mmol)和化合物B11(204mg,1.70mmol)依次加入到反应液中。然后反应混合物在25℃下搅拌15小时。LCMS表明反应物反应完全。该反应液直接经prep-HPLC(column:Waters Xbridge 150*25 5u；mobile phase:[water(10mM NH 4HCO 3)-ACN]；B％:25％-55％,10min)纯化，冻干后得到处产物(190mg)。粗产物再经prep-TLC(二氯甲烷:甲醇＝20:1)纯化得到黄色固体化合物19(79mg,产率:13％)。
1H NMR:(ES6131-11-P1A,CDCl 3,400MHz)δ10.22(s,1H),9.03(s,1H),9.02(s,1H),8.66-8.64(d,J＝7.6Hz,1H),8.19-8.17(d,J＝8.8Hz,2H),7.69(s,1H),7.51(s,1H),6.84(s,1H),6.55-6.33(m,2H),5.73-7.70(m,1H),3.91(s,3H),6.79(s,1H),2.89(s,2H),2.74(s,3H),2.29(s,8H)。
LCMS:489.2[M+H] +,Rt＝0.673.HPLC:95.63％purity(220nm),Rt＝3.27。
实施例11
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(6-氟代-3-甲基-1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物20)
合成路线
[根据细则26改正16.07.2018]　
Figure WO-DOC-FIGURE-39
在25℃下向水合肼(6.4g,128mmol)的DMF(50mL)溶液中加入化合物B7_1(10.0g,64.1mmol)。然后反应混合物在氮气保护下于120℃搅拌18小时。TLC(石油醚:乙酸乙酯＝5:1)表明反应物反应完全。反应液冷却到室温，用水(200mL)稀释，乙酸乙酯(150mL x 3)萃取。有机相用饱和食盐水(200mL)洗涤,硫酸钠干燥,过滤,减压浓缩得到粗产物。粗产物经硅胶柱层析(石油醚:乙酸乙酯＝5:1to 1:1)纯化得到白色固体化合物B7(3.0g,产率:31％)。
1H NMR:(ES6176-3-P1A1,CDCl 3,400MHz)δ10.35(br s,3H),7.64-7.60(m,1H),7.09-7.06(dd,J 1＝2.0Hz,J 2＝9.2Hz,1H),6.95-6.92(td,J 1＝8.8Hz,J 2＝11.2Hz,1H),2.59(s,3H)。
在0℃下向化合物2,4-二氯-1,3,5-三嗪(500mg,3.33mmol)的乙腈(10mL)溶液中加入化合物B7(501mg,3.33mmol)和碳酸氢钠(308mg,3.66mmol)，然后反应混合物在氮气保护下于25℃搅拌16小时。TLC(二氯甲烷:石油醚＝4:1)表明反应物反应完全。反应液过滤，滤液减压浓缩得到粗产物。粗产物经硅胶柱层析(二氯甲烷:石油醚＝1:1to 3:1)纯化得到黄色固体化合物B7_2(410mg,产率:47％)。
1H NMR:(ES6176-3-P1A1,CDCl 3,400MHz)δ8.97(s,1H),8.42-8.39(dd,J 1＝1.6Hz,J 2＝9.6Hz,1H),7.70-7.67(m,1H),7.21-7.17(td,J 1＝2.0Hz,J 2＝4.4Hz,1H),2.68(s,3H)。
在25℃下向中间体III(222mg,0.76mmol)的四氢呋喃(10mL)溶液中加入B7_2(200mg,0.76mmol)和吡啶(120mg,1.5mmol)。然后反应混合物在氮气保护下于25℃搅拌6小时。TLC(石油醚:乙酸乙酯＝4:1)表明反应物反应完全。反应液减压浓缩得到粗产物。粗产物经prep-HPLC(column:Gemini 150*25 5u；mobile phase:[water(10mM NH 4HCO 3)-ACN]；B％:35％-60％,12.5min)纯化得到白色固体化合物20(76mg,产率:19％)。
1H NMR:(ES6176-24-P1A1,CDCl 3,400MHz)δ10.20-10.13(m,1H),9.59(s, 1H),8.90(s,1H),8.15(s,1H),7.63-7.58(br s,1H),7.31(s,1H),6.88-6.82(m,2H),6.48-6.44(m,1H),6.35-6.29(m,1H),5.73-5.70(d,J＝10.8Hz,1H),3.88(s,3H),3.06(s,2H),2.90(s,2H),2.73(s,3H),2.66(s,1H),2.34(s,2H),2.29(s,6H)。
LCMS:520.4[M+H] +,Rt＝0.689.HPLC:97.8％purity(220nm),Rt＝3.67。
实施例12
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(8-甲基咪唑[1,2-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物26)，
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(8-氟代咪唑[1,2-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物27)，
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(8-(三氟代甲基)咪唑并[1,2-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物28)
合成路线如下：
Figure PCTCN2018086929-appb-000054
将氨基吡啶(50mmol,1.0eq.)，氯乙醛(55mmol,1.1eq.)和碳酸氢钠(60mmol,1.2mmol)加入圆底烧瓶中，加入乙醇60mL及水15mL，于80℃下反应5h(R＝CF3时过夜)，TLC监测反应完全。加入饱和食盐水100mL，二氯甲烷(100mL×3)萃取，取有机相，干燥浓缩，经柱层析纯化(洗脱剂为EA：PE＝1：3)，收率：95％。
Figure PCTCN2018086929-appb-000055
将化合物12-2(10mmol,1.0eq.)溶于二氯甲烷20mL中，分批加入NBS(10.5mmol,1.05mmol)，室温下搅拌10min即反应完全，饱和食盐 水淬灭。经柱层析纯化(洗脱剂为EA：PE＝1：4)，收率：95％。
Figure PCTCN2018086929-appb-000056
氩气保护下，将化合物12-3(10mmol,1.0eq.)和异丙醇频哪醇硼酸酯(10mmol,1.0eq.)溶于20mL四氢呋喃中。冰浴下，逐滴加入异丙基氯化镁四氢呋喃溶液(2.0M，5.5mL，1.1eq.)，反应3h。饱和食盐水淬灭反应，加入乙酸乙酯(50mL×3)萃取，取有机相，干燥浓缩。经柱层析纯化(洗脱剂为EA：MeOH＝12：1)，收率：25％。
Figure PCTCN2018086929-appb-000057
将2,4-二氯-1,3,5-三嗪(10mmol,1.0eq.)溶于20mL丙酮中，冰浴下逐滴加入4-氟-2-甲氧基-5-硝基苯胺(9.5mmol,0.95eq.)的丙酮溶液(10mL)，反应3h。经柱层析纯化(洗脱剂为EA：PE＝1：4)，收率：50％。
Figure PCTCN2018086929-appb-000058
氩气保护下，将化合物12-4(1.0mmol,1.0eq.)和化合物12-5(1.0mmol,1.0eq.)溶于2.0mL DMSO中，加入四三苯基膦钯(0.15mmol,0.15eq.)和碳酸钠溶液(1.0M,2.0eq.)，将其置于微波反应器中120℃下反应1h，过滤浓缩，直接用于下一步反应。
Figure PCTCN2018086929-appb-000059
向上步所得溶液中加入N,N,N'-三甲基乙二胺(1.0mmol,1.0eq.)及N,N-二异丙基乙胺(2.0mmol,2.0eq.)，将其置于微波反应器中140℃下反应1h。加入50mL乙酸乙酯，并用大量饱和食盐水洗涤，保留有机相，干燥浓缩，直接用于下一步反应。
Figure PCTCN2018086929-appb-000060
向上步浓缩物中加入乙醇(5mL)和水(1mL)中，加入铁粉(10.0mmol,10.0eq.)，氯化铵(10.0mmol,10.0eq.)，室温下搅拌过夜。用饱和碳酸氢钠溶液调节pH至8～9，用乙酸乙酯萃取，保留有机相，干燥浓缩，直接用于下一步反应。
Figure PCTCN2018086929-appb-000061
氩气保护下，将化合物12-8(1.0mmol,1.0eq.)溶于二氯甲烷中，加入丙烯酰氯(1.0mmol,1.0eq.)和N,N-二异丙基乙胺(1.0mmol,1.0eq.)，室温下搅拌20min，用饱和食盐水淬灭反应，并以二氯甲烷(20mL×3)萃取，保留有机相，干燥浓缩，制备高效液相纯化。
实施例13
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(3-氟代-1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物29)
合成方法如下：
将下式中的化合物13-1(200mg,1.47mmol)和化合物13-2(420mg,1.40mmol)溶于CH3CN(20ml)中，加入K 2CO 3(386.7mg,2.80mmol)常温下搅拌过夜。LC-MS检测反应进程，反应完毕后加水淬灭，乙酸乙酯萃取(50ml×3),无水硫酸钠干燥，旋干得到粗产物化合物13-3。
[根据细则26改正16.07.2018]　
Figure WO-DOC-FIGURE-43-1
将上步得到的化合物13-3和化合物13-4(123.5mg,1.2mmol)溶于DMA(10ml)中，加入DIPEA(260.4mg,2.0mmol)，在微波条件下，80℃反应1小时。LC-MS检测反应进程，反应完毕后加水淬灭，乙酸乙酯萃取(3ml×3),无水硫酸钠干燥，旋干得到粗产物化合物13-5。
[根据细则26改正16.07.2018]　
Figure WO-DOC-FIGURE-43-2
将上步得到的化合物13-5溶于CH 3OH(20ml)中，加入Pd/C(50mg)，在1标准大气压H2氛围下过夜还原，LC-MS检测反应进程，反应完毕后抽滤掉Pd/C，乙酸乙酯洗涤(5ml×3)，旋干得到粗产物化合物13-6。
[根据细则26改正16.07.2018]　
Figure WO-DOC-FIGURE-43-3
将上步得到的粗产物13-6和DIPEA(219.7mg,1.7mmol)溶于DCM(20ml)中，加入13-7(67.7mg,0.75mmol)，室温下反应30min,LC-MS检测反应进程，反应完毕后用饱和碳酸氢钠溶液淬灭，乙酸乙酯萃取(30ml×3)，旋干后得到粗产物13-8，用制备液相色谱分离得到白色固体13-8 (10mg)。1H NMR(500MHz,DMSO-d6)δ9.84(br,1H),9.58(br,1H),9.38(br,1H),8.66(br,1H),8.02(s,1H),7.88(br,1H),7.46(m,2H),7.08(m,1H),6.66(m,1H),6.28(d,J＝17Hz,1H),5.78(d,J＝12Hz,1H),3.82(s,3H),3.33(m,7H),2.83(s,3H),2.82(s,3H),2.64(m,4H). 19F NMR(376MHz,DMSO-d 6)δ-73.7.HRMS(ESI)calcd.for[C 25H 28FN 9O 2H] +(M+H) +:m/z 506.24228.
[根据细则26改正16.07.2018]　
Figure WO-DOC-FIGURE-44
下表1是各实施例LC/MS数据
表1
实施例编号 化合物编号 [M+H] +
1 化合物4 501.4
2 化合物6 488.1
3 化合物8 488.3
4 化合物11 518.4
5 化合物12 488.3
6 化合物13 488.4
7 化合物14 502.4
8 化合物15 520.4
9 化合物18 502.3
10 化合物19 489.2
11 化合物20 520.4
12 化合物26 502.3
12 化合物27 506.2
12 化合物28 556.2
13 化合物29 506.2
测试1：L858R/T790M EGFR(双突变体)细胞磷酸化测试
人肺细胞系NCI-H1975(L858R/T790M双突变EGFR)是从美国典型培养物保藏中心获得。将NCI-H1975细胞培养在含有10％胎牛血清和2mM谷氨酰胺的RPMI1640培养基中。使细胞在有5％CO 2的加湿培养箱中于37℃生长。
依照R&D Systems公司的DuoSet IC Human Phospho-EGFR ELISA(R&D Systems目录号#DYC1095)中所描述的方案，来进行细胞裂解液中内源性细胞磷酸化p-EGFR的检测。将90μl细胞(8000细胞/孔)培养在Corning黑色透明底96孔板里的生长培养基中，并于37℃下在5％CO 2加湿培养箱中培养过夜后，将细胞培养液换成含有1％胎牛血清和2mM谷氨酰胺的RPMI1640培养基继续培养。使用移液器将100％DMSO中连续稀释的化合物加至细胞，轻柔混合培养基之后，并将细胞再培养2小时。将100μl 1X裂解缓冲液添加到各孔中。将Greiner高结合力96孔板用捕获抗体覆盖，然后用3％BSA进行封闭。去除封闭液之后，将100μl裂解液转移到Greiner高结合力96孔板中，孵育2小时。轻柔混合并用PBS清洗培养板之后，添加100μl检测抗体，并孵育2小时。轻柔混合并用PBS清洗培养板之后，添加100μl TMB底物(Cell Signaling Technology目录号7004)，孵育1小时。将100μl终止溶液添加到培养板中，并检测各孔对450nm波长的吸光度。最后将数据输入合适的软件包(例如Prism)以进行曲线拟合分析。基于此数据并通过计算获得50％抑制效果所需的化合物浓度来确定IC 50值。
下表2显示了本发明的代表性化合物，即实施例2的化合物6，实施例4的化合物11，实施例12的化合物26、化合物27、化合物28，实施例13的化合物29在上述的生物学实验中的IC 50值(μM)，其中用作对照的化合物Osimertinib(AZD9291)是按照以下文献所述的方法合成：
Discovery of a Potent and Selective EGFR Inhibitor(AZD9291)of Both Se nsitizing and T790M Resistance Mutations That Spares the Wild Type Form of th e Receptor，J.Med.Chem.,2014,57(20),pp 8249–8267。
表2
Figure PCTCN2018086929-appb-000066
如上表2所示，本发明的化合物6、化合物11、化合物26、化合物27、化合物28、化合物29在L858R/T790M EGFR(双突变体)细胞磷酸化测试中IC 50值分别是0.0151、0.0111、0.0121、0.0118、0.0114和0.0106，与之相比，Osimertinib(AZD9291)在L858R/T790M EGFR(双突变体)细胞磷酸化测试中IC 50值为0.0459，相当于采用本发明化合物6和化合物11情况下IC 50值的三倍以上。
测试2：野生型EGFR细胞增殖测试
人肺细胞系A431(野生型EGFR)是从美国典型培养物保藏中心获得。将NCI-H838细胞培养在含有10％胎牛血清和2mM谷氨酰胺的RPMI1640培养基中。使细胞在有5％CO 2的加湿培养箱中于37℃生长。
依照Promega公司的Cell Titer-Glo Luminescent cell Viability Assay(Promega目录号#G7570)中所描述的方案，来进行检测培养物中活细胞的数目。将90μl细胞(8000细胞/孔)培养在Corning黑色透明底96孔板里的生长培养基中，并于37℃下在5％CO2加湿培养箱中培养过夜。使用移液器将100％DMSO中连续稀释的化合物加至细胞，并将细胞再培养72小时。将100μl混合好的Cell Titer-Glo试剂加入到96孔培养板中的细胞中裂解细胞，并轻柔混合。随后，在Envision微孔板检测仪上进行自发荧光的检测，得到化合物的数据。最后将数据输入合适的软件包(例如Prism)以进行曲线拟合分析。基于此数据并通过计算获得50％抑制效果所需的化 合物浓度来确定IC 50值。
测试3：L858R/T790M EGFR(双突变体)细胞增殖测试
人肺细胞系NCI-H1975(L858R/T790M双突变EGFR)是从美国典型培养物保藏中心获得。将NCI-H1975细胞培养在含有10％胎牛血清和2mM谷氨酰胺的RPMI1640培养基中。使细胞在有5％CO 2的加湿培养箱中于37℃生长。
依照Promega公司的Cell Titer-Glo Luminescent cell Viability Assay(Promega目录号#G7570)中所描述的方案，来进行检测培养物中活细胞的数目。将90μl细胞(8000细胞/孔)培养在Corning黑色透明底96孔板里的生长培养基中，并于37℃下在5％CO 2加湿培养箱中培养过夜。使用移液器将100％DMSO中连续稀释的化合物加至细胞，并将细胞再培养72小时。将100μl混合好的Cell Titer-Glo试剂加入到96孔培养板中的细胞中裂解细胞，并轻柔混合。随后，在Envision微孔板检测仪上进行自发荧光的检测，得到化合物的数据。最后将数据输入合适的软件包(例如Prism)以进行曲线拟合分析。基于此数据并通过计算获得50％抑制效果所需的化合物浓度来确定IC 50值。
下表3显示了本发明的代表性化合物，即化合物6、化合物26、化合物27、化合物28和化合物29，在上述的生物学实验中的IC 50值(μM)，其中用作对照的化合物Osimertinib(AZD9291)是按照以下文献所述的方法合成：
Discovery of a Potent and Selective EGFR Inhibitor(AZD9291)of Both Se nsitizing and T790M Resistance Mutations That Spares the Wild Type Form of th e Receptor，J.Med.Chem.,2014,57(20),pp 8249–8267。
表3
Figure PCTCN2018086929-appb-000067
参见表3所示，本发明的化合物相对于Osimertinib(AZD9291)，在L858R/T790M EGFR(双突变体)细胞增殖测试中，IC 50值相对较小。采用Osimertinib(AZD9291)所获得的IC 50值约为采用本发明化合物所获得IC 50值的四倍以上。这表明本发明的化合物相对于Osimertinib(AZD9291)能够更好地抑制L858R/T790M EGFR(双突变体)细胞增殖。另外，如表3所示，表最右栏表示的是测试2的IC 50值与测试3的IC 50值的比值，其表征了化合物对于L858R/T790M EGFR(双突变体)细胞增殖抑制作用和对于野生型EGFR细胞增殖抑制作用的选择性，该值越大表明化合物在野生型EGFR细胞中对L858R/T790M EGFR(双突变体)细胞增殖作用抑制的选择性更好。如表3所示本发明化合物对L858R/T790M EGFR(双突变体)细胞增殖作用抑制的选择性远远好于Osimertinib(AZD9291)。
测试4：Ba/F3-CAT-EGFR细胞增殖测试
Ba/F3-CAT-EGFR细胞活力检测是基于
Figure PCTCN2018086929-appb-000068
开发的检测技术。通过过表达野生态EGFR的胞内激酶区域转化Ba/F3细胞，构建CAT-EGFR工具细胞株。这株细胞依赖EGFR的激酶活性才能生长，如果通过小分子化合物抑制野生态的EGFR，细胞就会凋亡。从而可以通过观察EGFR小分子对细胞活力的影响，评估其对野生态EGFR的特异性和活性。
Ba/F3-CAT-EGFR(野生型EGFR)细胞培养在含有10％胎牛血清和2mM谷氨酰胺的RPMI1640培养基中。使细胞在有5％CO 2的加湿培养箱中于37℃生长。
依照Promega公司的Cell Titer-Glo Luminescent cell Viability Assay(Promega目录号#G7570)中所描述的方案，来进行检测培养物中活细胞的数目。将100μl细胞(3000细胞/孔)培养在Corning黑色透明底96孔板里的生长培养基中，并于37℃下在5％CO 2加湿培养箱中培养过夜。使用移液器将100％DMSO中连续稀释的化合物加至细胞，并将细胞再培养72小时。将100μl混合好的Cell Titer-Glo试剂加入到96孔培养板中的细胞中裂解细胞，并轻柔混合。随后，在Envision微孔板检测仪上进行自发荧光的检测，得到化合物的数据。最后将数据输入合适的软件包(例如Prism)以进行曲线拟合分析。基于此数据并通过计算获得50％抑制效果所需的化合物浓度来确定IC 50值。
测试5：Ba/F3-DTM-EGFR细胞增殖测试
Ba/F3-DTM-EGFR细胞活力检测是基于
Figure PCTCN2018086929-appb-000069
开发的检测技术。通过过表达野生态T790M突变和Exon19缺失的EGFR转化Ba/F3细胞，构建DTM-EGFR工具细胞株。这株细胞依赖EGFR的激酶活性才能生长，如果通过小分子化合物抑制突变态的EGFR，细胞就会凋亡。从而可以通过观察EGFR小分子对细胞活力的影响，评估其对突变EGFR的特异性和活性。
Ba/F3-DTM-EGFR(突变型EGFR)细胞培养在含有10％胎牛血清和2mM谷氨酰胺的RPMI1640培养基中。使细胞在有5％CO 2的加湿培养箱中于37℃生长。
依照Promega公司的Cell Titer-Glo Luminescent cell Viability Assay(Promega目录号#G7570)中所描述的方案，来进行检测培养物中活细胞的数目。将100μl细胞(3000细胞/孔)培养在Corning黑色透明底96孔板里的生长培养基中，并于37℃下在5％CO 2加湿培养箱中培养过夜。使用移液器将100％DMSO中连续稀释的化合物加至细胞，并将细胞再培养72小时。将100μl混合好的Cell Titer-Glo试剂加入到96孔培养板中的细胞中裂解细胞，并轻柔混合。随后，在Envision微孔板检测仪上进行自发荧光的检测，得到化合物的数据。最后将数据输入合适的软件包(例如Prism)以进行曲线拟合分析。基于此数据并通过计算获得50％抑制效果所需的化合物浓度来确定IC 50值。
表4显示了本发明的代表性化合物，即实施例4、9和11的化合物在上述的生物学实验中的IC 50值(μM)，其中用作对照的化合物Osimertinib(AZD9291)是按照以下文献所述的方法合成：
Discovery of a Potent and Selective EGFR Inhibitor(AZD9291)of Both Se nsitizing and T790M Resistance Mutations That Spares the Wild Type Form of th e Receptor，J.Med.Chem.,2014,57(20),pp 8249–8267。
表4
Figure PCTCN2018086929-appb-000070
参见表4所示，本发明的化合物相对于Osimertinib(AZD9291)来说，针对Ba/F3-DTM-EGFR细胞增殖测试，其IC 50值相对较小，表明本发明的化合物相对于Osimertinib(AZD9291)能够更好地抑制Ba/F3-DTM-EGFR细胞增殖。另外，如表4所示，表4最右栏表示的是测试4的IC 50值与测试5的IC 50值的比值，其表征了化合物对于Ba/F3-CAT-EGFR细胞增殖抑制作用和Ba/F3-DTM-EGFR细胞增殖作用的选择性，该值越大表明化合物在Ba/F3细胞中对Ba/F3-DTM-EGFR细胞增殖作用抑制的选择性更好。如表4所示本发明化合物对Ba/F3-DTM-EGFR细胞增殖作用抑制的选择性远远好于Osimertinib(AZD9291)。
测试6：血浆蛋白结合率(Plasma ProteinBinding rate)测试
血浆蛋白结合率测试采用HTDialysis公司的96孔平衡透析装置，将浓度为2μM供试品和对照化合物的人血浆样品或小鼠血浆样品在37℃平衡透析4小时，来进行蛋白结合的研究。将150μL供试化合物血浆样品加入到每个透析孔的给药端，在透析孔对应的接收端中加入150μL空白透析缓冲液。然后将透析板置于湿润的、5％CO 2的培养箱中，在37℃下孵育4小时。透析结束后，移取50μL透析后的缓冲液样品和透析后的血浆样品到新的96孔板中(样品接收板)。在样品中加入相应体积的对应空白血浆或缓冲液。所有样品经过蛋白沉淀后进行LC/MS/MS分析。样品的浓度用化合物与内标的峰面积比值表示(半定量)。最后根据公式计算出化合物的％未结合率(％Unbound)、％结合率(％Bound)和回收率(％Recovery)。
表5
Figure PCTCN2018086929-appb-000071
在正常情况下，各种药物以一定的比率与血浆蛋白结合，在血浆中常同时存在结合型与未结合型(游离型)，而只有未结合型药物才具有药物活性。参见表5所示，针对血浆蛋白结合率测试，本发明的化合物相对于Osimertinib(AZD9291)来说，其在人和小鼠血浆中的未结合药物比率相对较大，表明本发明的化合物相对于Osimertinib(AZD9291)能够增大其血浆未结合药物比率，即活性药物比率。
本文所公开的量纲和值不旨在被理解为严格地限于所述的精确值。相反，除非另外指明，每个这样的量纲是指所引用的数值和围绕该数值的功能上等同的范围。
除非明确排除或换句话讲有所限制，本文中引用的每一个文献，包括任何交叉引用或相关专利或专利申请，均据此以引用方式全文并入本文。 对任何文献的引用均不是承认其为本文公开的或受权利要求书保护的任何发明的现有技术、或承认其独立地或以与任何其它一个或多个参考文献的任何组合的方式提出、建议或公开任何此类发明。进一步讲，如果此文献中术语的任何含义或定义与以引用方式并入本文的文献中相同术语的任何含义或定义相冲突，将以此文献中赋予那个术语的含义或定义为准。
尽管已用具体实施方案来说明和描述了本发明，但对于本领域的技术人员显而易见的是，在不背离本发明的精神和保护范围的情况下可作出许多其它的改变和变型。因此，随附权利要求书中旨在涵盖本发明范围内的所有这些改变和变型。

Claims (10)

  1. 式(I)的化合物或其药学上可接受的盐：
    Figure PCTCN2018086929-appb-100001
    其中R 1为-NR 5R 6，其中R 5和R 6各自独立地选自C 1-C 6烷基，其中所述烷基为未取代或被-NR 7R 8所取代；
    其中R 2选自C 2-C 6烯基，所述烯基为未取代或被-NR 7R 8所取代；
    其中R 7和R 8在每次出现时各自独立地选自H或C 1-C 6烷基；
    其中R 3选自取代或未取代的稠合二环基团，所述稠合二环为五元环和六元环稠合；
    其中R 4选自C 1-C 6烷基。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中所述化合物为如下式(II)所示：
    Figure PCTCN2018086929-appb-100002
    其中，
    A 1、A 4、A 9各自独立地选自N或C；
    A 2、A 3、A 5、A 6、A 7、A 8各自独立地选自N、NR a、CR a、CR aR b，
    其中R a和R b各自独立地选自H、C 1-C 6烷基和卤素，或者R a、R b和与它们所连接的同一个碳原子一起形成C 3-C 6环烷基，所述C 1-C 6烷基和C 3-C 6环烷基任选取代有一个或多个卤素原子，
    条件是环A和环B至少一个为不饱和环。
  3. 根据权利要求1至2任一项所述的化合物或其药学上可接受的盐，其中A 1为N。
  4. 根据权利要求1至3任一项所述的化合物或其药学上可接受的盐，其中A 1、A 2、A 3、A 4、A 5、A 6、A 7、A 8、A 9中有一个、两个或三个包含N原子。
  5. 根据权利要求1至4任一项所述的化合物或其药学上可接受的盐，其中所述R 1选自：
    Figure PCTCN2018086929-appb-100003
  6. 根据权利要求1至5任一项所述的化合物或其药学上可接受的盐，其中所述R 2选自：
    Figure PCTCN2018086929-appb-100004
  7. 根据权利要求1至6任一项所述的化合物或其药学上可接受的盐，其中所述R 3选自：
    Figure PCTCN2018086929-appb-100005
    Figure PCTCN2018086929-appb-100006
    Figure PCTCN2018086929-appb-100007
  8. 根据权利要求1所述的化合物或其药学上可接受的盐，其中所述化合物选自：
    Figure PCTCN2018086929-appb-100008
    Figure PCTCN2018086929-appb-100009
    Figure PCTCN2018086929-appb-100010
    Figure PCTCN2018086929-appb-100011
    Figure PCTCN2018086929-appb-100012
    Figure PCTCN2018086929-appb-100013
    Figure PCTCN2018086929-appb-100014
    Figure PCTCN2018086929-appb-100015
    Figure PCTCN2018086929-appb-100016
  9. 一种药物组合物，其包含根据权利要求1至8任一项所述的化合物或其药学上可接受的盐。
  10. 权利要求1至8任一项所述的化合物或其药学上可接受的盐在制备用于治疗小细胞肺癌的药物中的用途。
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