WO2018157411A1 - 取代的含氮芳环化合物及其应用 - Google Patents

取代的含氮芳环化合物及其应用 Download PDF

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WO2018157411A1
WO2018157411A1 PCT/CN2017/075833 CN2017075833W WO2018157411A1 WO 2018157411 A1 WO2018157411 A1 WO 2018157411A1 CN 2017075833 W CN2017075833 W CN 2017075833W WO 2018157411 A1 WO2018157411 A1 WO 2018157411A1
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Prior art keywords
compound
containing aromatic
pharmaceutical composition
nitrogen
pharmaceutically acceptable
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PCT/CN2017/075833
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English (en)
French (fr)
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王义汉
邢青峰
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深圳市塔吉瑞生物医药有限公司
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Priority to CN201780031986.0A priority Critical patent/CN109311817B/zh
Publication of WO2018157411A1 publication Critical patent/WO2018157411A1/zh

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the invention belongs to the field of medicine.
  • the present invention relates to deuterated nitrogen-containing aromatic ring derivatives and uses thereof, and more particularly to nitrogen-containing aromatic ring compounds and their use as VEGFR inhibitors, or for the treatment and prevention of dysfunction with protein tyrosine kinases Related diseases.
  • Protein tyrosine kinases can be divided into receptor tyrosine kinases (RPTKs) and non-receptor protein tyrosine kinases (nRPTKs).
  • RPTKs receptor tyrosine kinases
  • nRPTKs non-receptor protein tyrosine kinases
  • RPTKs usually have an extracellular domain, a transmembrane domain, and an intracellular kinase domain. According to the structure of the extracellular domain, there are mainly the following types:
  • EGFR Epidermal growth factor receptor family
  • HER1/erbB-1 HER2 (neu/erbB-2), HER3 (erbB-3), HER4 (erbB-4), HERs in many tumors Increased expression, such as colorectal cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, breast cancer, pancreatic cancer, renal cell carcinoma and the like.
  • Vascular endothelial growth factor receptor (VEGFR), whose main members are VEGFR-1 (FLT-1), VEGFR-2 (KDR-FLK-1), VEGFR-3 (FLT-4), etc., are physiological or pathological blood vessels. Important adjustment factors generated.
  • PDGFR Platelet-derived growth factor receptor
  • CSF-1R colony stimulating factor 1 receptor
  • FLK-2 FLK-2
  • c-kit stem cell factor receptor
  • Fibroblast growth factor receptor its main members are FGFR-1, FGFR-2, FGFR-3, FGFR-4, etc. These receptors are closely related to angiogenesis and tumorigenesis; (5) others, such as Insulin receptor (INSR), hepatocyte growth factor receptor (HGFG), nerve growth factor receptor (HGFG) and the like.
  • INSR Insulin receptor
  • HGFG hepatocyte growth factor receptor
  • HGFG nerve growth factor receptor
  • nRPTKs generally have no extracellular structure, they are usually coupled to the cell membrane or exist in the cytoplasm, such as the Src kinase family: Abl, Abl-Brc, etc. Activation of this large class of kinases often promotes tumorigenesis and progression.
  • Src kinase family Abl, Abl-Brc, etc.
  • Activation of this large class of kinases often promotes tumorigenesis and progression.
  • Various tyrosine kinases constitute a cross-over, complex cellular signal transduction pathway, a tyrosine kinase activity inhibition, often compensated by the activity enhancement of another kinase or kinases, a variety of tyrosine Simultaneous inhibition of kinase activity is a new trend in the development of such anti-tumor drugs.
  • the dysregulation of protein tyrosine kinase function triggers a range of diseases in the body.
  • Information shows that more than 50% Both proto-oncogenes and oncogene products have protein tyrosine kinase activity, and their abnormal expression will lead to disorder of cell proliferation regulation, leading to tumorigenesis.
  • the abnormal expression of tyrosine kinase is also closely related to tumor invasion and metastasis, tumor angiogenesis, and tumor chemotherapy resistance.
  • the effective inhibitory protein tyrosine kinase can achieve the purpose of treating tumors, and protein tyrosine kinase has become a new target for anti-tumor drug research.
  • Persistent angiogenesis can be the cause and precondition for various diseases, such as tumor or metastatic growth, psoriasis, arthritis such as rheumatoid arthritis, hemangioma, angiofibroma, eye diseases such as diabetic retinopathy, neovascular glaucoma, Nephropathy such as glomerulonephritis, diabetic nephropathy, malignant renal necrosis, embolic microangiopathy syndrome, graft rejection and glomerular disease, fibrotic diseases such as cirrhosis, mesangial cell proliferative diseases and Arteriosclerosis may cause deterioration of the above diseases.
  • diseases such as tumor or metastatic growth, psoriasis, arthritis such as rheumatoid arthritis, hemangioma, angiofibroma, eye diseases such as diabetic retinopathy, neovascular glaucoma, Nephropathy such as glomerulonephritis, diabetic n
  • Persistent angiogenesis is induced by the factor VEGF through its receptor.
  • VEGF In order for VEGF to exert this effect, VEGF must bind to the receptor and induce tyrosine phosphorylation.
  • VEGF vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • tumor growth can be inhibited by soluble receptors as well as antibodies against VEGF.
  • Lenvatinib chemical name 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, is a Japanese company Developed as an orally effective multi-kinase inhibitor for multiple targets such as c-Kit, Ret and VEGFR-2 for the treatment of gliomas, thyroid tumors, kidney cancer, liver cancer and ovarian cancer tumor. In February 2013, he was recognized by the US FDA orphan drug for clinical treatment of follicular, myeloid, undifferentiated metastatic or locally advanced papillary thyroid carcinoma.
  • Lenvima (lenvatinib) from Eisai, Japan to treat patients with invasive and differentiated thyroid cancer (DTC), and is suitable for patients whose disease is still worsening after radioactive iodine treatment (radioactive iodine-refractory disease).
  • DTC invasive and differentiated thyroid cancer
  • the US FDA approved the combination of the multi-target tyrosine kinase inhibitor Lenvatinib and everolimus for other advanced kidney cancers that failed treatment.
  • Deuterated modification is a potentially attractive strategy for improving the metabolic properties of drugs.
  • Helium is a safe, stable, non-radiative isotope of hydrogen. Compared with the C-H bond, the C-D bond formed by ruthenium and carbon is stronger because of the lower vibration frequency.
  • the "heavy hydrogen" version of the drug may be more stable to degradation and longer in the body. Incorporating hydrazine to replace hydrogen can improve the pharmacodynamics and pharmacokinetic profile of the drug, altering the metabolic fate while maintaining the pharmacological activity and selectivity of the physiologically active compound.
  • Deuterated drugs have a positive impact on safety, efficacy and tolerance, and have excellent research prospects.
  • the present invention discloses a nitrogen-containing aromatic ring compound and a composition comprising the same as an effective vascular endothelial growth factor receptor (VEGFR) inhibitor and/or has better pharmacodynamics /Pharmacokinetic properties.
  • VEGFR vascular endothelial growth factor receptor
  • VEGFR vascular endothelial growth factor receptor
  • a nitrogen-containing aromatic ring compound of the formula (I), or a crystalline form, a pharmaceutically acceptable salt, a prodrug, an isomer, a hydrate or a solvent thereof Compound:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are independently selected from the group consisting of "hydrogen (H), ⁇ (D) "composed group;
  • X is selected from "hydrogen (H), hydrazine (D), methyl, CH 2 D, CHD 2 , CD 3 , CH 2 CH 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 CD 2 CD 3 ”;
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrazine or hydrogen.
  • R 6 , R 7 and R 8 are each independently hydrazine or hydrogen.
  • R 9 , R 10 , R 11 and R 12 are each independently hydrazine or hydrogen.
  • X is a tertiary deuterated methyl group.
  • R 6 is deuterium
  • R 7 and R 8 are deuterium.
  • the compound is selected from the group consisting of the compounds or pharmaceutically acceptable salts thereof, but is not limited for the following compounds:
  • the cerium isotope content of the cerium in the deuterated position is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%.
  • the ground is greater than 95%, more preferably greater than 99%.
  • each of the positions R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and X The strontium isotope content is at least 5%, preferably more than 10%, more preferably more than 15%, more preferably more than 20%, more preferably more than 25%, more preferably more than 30%, more preferably more than 35%, More preferably more than 40%, more preferably more than 45%, more preferably more than 50%, more preferably more than 55%, more preferably more than 60%, more preferably more than 65%, more preferably more than 70%, more Preferably, it is greater than 75%, more preferably greater than 80%, more preferably greater than 85%, more preferably greater than 90%, more preferably greater than 95%, and even more preferably greater than 99%.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and the compound of formula (I) X at least one of R/X contains ruthenium, more preferably two R/X ⁇ , more preferably three R/X ⁇ , more preferably four R/X ⁇ , more preferably five R /X contains ⁇ , preferably six R/X ⁇ , more preferably seven R/X ⁇ , more preferably eight R/X ⁇ , more preferably nine R/X ⁇ , more The best R/X contains ⁇ , preferably 11 R/X ⁇ , more preferably 12 R/X ⁇ , more preferably thirteen R/X ⁇ .
  • the compound does not include a non-deuterated compound.
  • a method of preparing a pharmaceutical composition comprising the steps of: pharmaceutically acceptable carrier and a compound of the first aspect of the invention, or a crystalline form thereof, pharmaceutically acceptable
  • the accepted salt, hydrate or solvate is mixed to form a pharmaceutical composition.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the first aspect of the invention, or a crystalline form thereof, a pharmaceutically acceptable salt, hydrated Or a solvate.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, any glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents A dispersing agent, a disintegrating agent, a suspending agent, a stabilizer, an isotonic agent, a solvent or an emulsifier.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, pills, and gums.
  • Typical routes of administration of the pharmaceutical compositions of the invention include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal , intramuscular, subcutaneous, intravenous administration. Oral administration or injection administration is preferred.
  • the pharmaceutical composition of the present invention can be produced by a method known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a pulverization method, an emulsification method, a freeze-drying method, and the like.
  • the pharmaceutical composition of the present invention is extremely effective as an angiogenesis inhibitor, and therefore, a preventive or therapeutic agent for an effective angiogenesis inhibitory action, an angiogenesis inhibitor, an antitumor agent, an aneurysm therapeutic agent, a cancer metastasis inhibitor, Retinal angiogenesis therapeutic agent, diabetic retinopathy therapeutic agent, inflammatory disease therapeutic agent, deformed arthritis, rheumatoid arthritis, cognac or inflammatory disease therapeutic agent including delayed allergic reaction, powder tumor artery The sclerosis therapeutic agent is effective.
  • Another aspect of the invention provides a method of treating a subject having metastatic cancer or at risk of developing metastatic cancer by administering the compound of the invention alone or in combination with other cytotoxic or therapeutic agents.
  • the cancer may be, for example, one or more of the following cancers: thyroid cancer, pancreatic cancer, gastric cancer, colon cancer, breast cancer, prostate cancer, lung cancer, kidney cancer, brain tumor cancer, blood cancer or ovarian cancer, particularly preferably thyroid Cancer and kidney cancer.
  • the present invention provides a method of treating a subject having metastatic cancer or having a risk of developing metastatic cancer by administering the compound of the present invention alone or in combination with other cytotoxic or therapeutic agents.
  • preferred cytotoxic and therapeutic agents include docetaxel, paclitaxel, doxorubicin, epirubicin, cyclophosphamide, trastuzel monoclonal antibody (trastuzumab) (Herceptin TM), capecitabine (capecitabine), tamoxifen (tamoxifen), toremifene (toremifene), letrozole (letrozole), anastrozole (anastrozole), fulvestrant Fulvestrant, exemestane, goserelin, oxaliplain, carboplatin, cisplatin, dexamethasone, ang peptide (antide), Avastin (bevacizumab) (bevacizumab TM), 5- fluorouracil (5-
  • the therapeutic agent is a platinum agent (e.g., carboplatin, oxaliplatin, cisplatin), a taxane (e.g., paclitaxel, docetaxel), gemcitabine, or camptothecin.
  • a platinum agent e.g., carboplatin, oxaliplatin, cisplatin
  • a taxane e.g., paclitaxel, docetaxel
  • gemcitabine e.g., gemcitabine, or camptothecin.
  • a method of treating a medical condition comprising administering a compound of the invention.
  • the administered compound is an angiogenesis inhibitor.
  • a second agent is also administered.
  • the second agent can be any cytotoxic or therapeutic agent disclosed in the present specification, for example, therapeutic agents selected from the following: Sutent TM (i.e., sunitinib malate (sunitinib malate), described in U.S. Patent No. 6573293, Tykreb TM (i.e., lapatinib (lapatinib), described in U.S. Patent No. 6727256, Nexavar TM (i.e.
  • Temodar TM its use in the treatment of cancer US patent 5,939,098 discloses
  • dasatinib dasatinib
  • Sprycel TM is disclosed in U.S. Patent No. 6,596,746
  • cetuximab Erbitux TM, for example, disclosed in U.S. Patent No. 6,217,866
  • the ixabepilone i.e. ixabepilone,
  • imatinib mesylate i.e. Gleevac TM, is disclosed in U.S. Patent No. 5,521,184
  • trastuzumab Herceptin TM, for example, disclosed in U.S.
  • Patent No. 5,677,171 the taxane and members of a class such as paclitaxel (ie taxol TM, disclosed in US Pat. No. 5,439,686), and docetaxel (ie Taxotere TM, disclosed in US Pat. No. 4,814,470).
  • paclitaxel ie taxol TM, disclosed in US Pat. No. 5,439,686
  • docetaxel ie Taxotere TM, disclosed in US Pat. No. 4,814,470.
  • the present invention provides a method of treating a subject having metastatic cancer or having a risk of metastatic cancer by administering a compound of the present invention in combination with an mTOR inhibitor.
  • preferred mTOR inhibitors include Everolimus, Sirolimus, Temsirolimus, Tacrolimus, Ridaforolimus.
  • halogen means F, Cl, Br, and I unless otherwise specified. More preferably, the halogen atom is selected from the group consisting of F, Cl and Br.
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid.
  • salts of the compounds of the invention with bases such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), ammonium salts (for example lower alkanolammonium).
  • bases such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), ammonium salts (for example lower alkanolammonium).
  • Salts and other pharmaceutically acceptable amine salts such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butyl
  • a base amine salt an ethylenediamine salt, a hydroxyethylamine salt, a dihydroxyethylamine salt, a trihydroxyethylamine salt, and an amine salt formed of morpholine, piperazine, and lysine, respectively.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • the compound of the present invention further includes a prodrug of the nitrogen-containing aromatic ring derivative represented by the formula (I).
  • the term "prodrug” package Including it may be biologically active or inactive, and when it is administered by an appropriate method, it is converted into a compound of the formula (I) by metabolism or chemical reaction in the human body, or the compound of the formula (I) a salt or solution of a compound.
  • the prodrug includes, but is not limited to, a carboxylic acid ester, a carbonate, a phosphate, a nitrate, a sulfate, a sulfone ester, a sulfoxide, an amino compound, a carbamate, an azo compound of the compound. , phosphoramide, glucoside, ether, acetal and the like.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier.
  • the carrier is "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, in a quantity which is not deleterious to the recipient thereof.
  • the compounds of formula (I) and compositions comprising the compounds are VEGFR inhibitors and can be used to treat, prevent or ameliorate various VEGFR related conditions.
  • Pharmaceutical compositions comprising these compounds are useful for treating, preventing, or slowing the progression of the disease or disorder in different therapeutic areas, such as cancer.
  • the beneficial effects of the present invention are that the substituted nitrogen-containing aromatic ring compound disclosed by the present invention and the composition comprising the same have excellent inhibition to VEGFR and have better pharmacokinetics. Parameter characteristics.
  • the dosage can be varied and a long acting formulation can be formed to improve suitability.
  • Replacing a hydrogen atom in a compound with hydrazine can increase the drug concentration of the compound in an animal to improve the efficacy of the drug due to its strontium isotope effect.
  • Substitution of a hydrogen atom in a compound with hydrazine may increase the safety of the compound due to inhibition of certain metabolites.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are independently selected from the group consisting of "hydrogen (H), ⁇ (D) "composed group;
  • X is selected from the group consisting of "hydrogen (H), hydrazine (D), methyl, CH 2 D, CHD 2 , CD 3 , CH 2 CH 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 CD 2 CD 3 ”.
  • the base may be selected from the group consisting of potassium t-butoxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethyl. Amine, 4-N,N-lutidine or pyridine.
  • Step 14 Synthesis of chloro-7-hydroxy-6-quinolinecarboxamide (Compound 2).
  • Step 1 Synthesis of the compound 4-amino-3-chlorophenol-2,6-d 2 .
  • Step 2 Synthesis of the compound 1-(2-chloro-4-phenol-2,6-d 2 )-3-cyclopropylurea.
  • Step 3 Synthesis of the compound 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy-2,6-d 2 ]-7-methoxy-6-quinolinecarboxamide.
  • Step 3 Synthesis of the compound ⁇ 3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy-5-d ⁇ -7-methoxy-6-quinolinecarboxamide.
  • Step 5 Synthesis of the compound 4-(3-chloro-4-(3-cyclopropylaminocarbonyl)aminophenoxy)-7-methoxyquinoline-8-d-6-carboxamide.
  • control group 4-[3-chloro- 4-(Cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide
  • Test group Examples, comparing their pharmacokinetic differences.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were separated from the red blood cells by centrifugation at 5000 rpm for 5 minutes at 4 °C. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • the experimental results show that the compound of the present invention has better pharmacokinetics in animals relative to the control compound, and thus has better pharmacodynamics and therapeutic effects.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; mouse liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the compound of the present invention has a longer half-life and a smaller clearance rate, and exhibits superior metabolic stability in small rat liver microsome experiments, and thus It is suitable as a drug for diseases associated with dysfunction of protein tyrosine kinases.

Abstract

本发明涉及了一种取代的含氮芳环化合物及包含该化合物的组合物及其应用。具体地，该发明公开了式(I)所示的含氮芳化合物，或其晶型、药学上可接受的盐、前药、立体异构体、水合物或溶剂合物的药物组合物。本发明所述化合物可作为血管内皮生长因子受体(VEGFR)抑制剂，进而可适用于制备治疗与蛋白酪氨酸激酶功能失调相关的疾病(如甲状腺癌等)的药物。

Description

取代的含氮芳环化合物及其应用 技术领域
本发明属于医药领域。具体地，本发明涉及氘代含氮芳环衍生物及其用途，更具体地是，涉及含氮芳环化合物及其作为VEGFR抑制剂，或用于治疗和预防与蛋白酪氨酸激酶功能失调相关疾病。
背景技术
蛋白酪氨酸激酶可分为受体酪氨酸激酶(RPTKs)和非受体蛋白酪氨酸激酶(nRPTKs)。RPTKs通常具有一个细胞外结构域、一个跨膜区以及一个细胞内激酶域，根据其细胞外区域结构的不同，主要有以下几类：
表皮生长因子受体(EGFR)家族，其主要成员有EGFR(HER1/erbB-1)、HER2(neu/erbB-2)、HER3(erbB-3)、HER4(erbB-4)，许多肿瘤中HERs表达增强，如结肠直肠癌、头颈鳞状上皮细胞癌、非小细胞肺癌、乳腺癌、胰腺癌、肾细胞癌等。
血管内皮生长因子受体(VEGFR)，其主要成员有VEGFR-1(FLT-1)，VEGFR-2(KDR-FLK-1)，VEGFR-3(FLT-4)等，是生理或病理性血管生成的重要调节因子。
血小板衍生生长因子受体(PDGFR)，其主要成员有PDGFR-α，PDGFR-β，集落刺激因子1受体(CSF-1R)，FLK-2，干细胞因子受体(c-kit)等，这类受体的激活与肿瘤相关。
成纤维生长因子受体(FGFR)，其主要成员有FGFR-1、FGFR-2、FGFR-3、FGFR-4等，这类受体与血管生成、肿瘤发生密切相关；(5)其它，如胰岛素受体(INSR)，肝细胞生长因子受体(HGFG)，神经生长因子受体(HGFG)等。(丁健，《蛋白酪氨酸激酶——前景光明的抗肿瘤靶点》，第三届中国肿瘤学术大会论文；2004，11，130-140)。
nRPTKs一般没有细胞外结构，它们通常与细胞膜耦联或存在于细胞质中，如Src激酶家族：Abl、Abl-Brc等等，这大类激酶的激活往往促进肿瘤的发生和发展。各种酪氨酸激酶构成相互交叉的、复杂的细胞信号转导通路，一种酪氨酸激酶的活性抑制，往往可通过另一种或多种激酶的活性增强来弥补，多种酪氨酸激酶活性同时被抑制是目前这类抗肿瘤药物研发的新趋势。
蛋白酪氨酸激酶功能的失调会引发生物体内的一系列疾病。资料显示，超过50％ 的原癌基因和癌基因产物都具有蛋白酪氨酸激酶活性，它们的异常表达将导致细胞增殖调节发生紊乱，进而导致肿瘤发生。此外，酪氨酸激酶的异常表达还与肿瘤的侵袭和转移，肿瘤新生血管的生成，肿瘤的化疗抗性密切相关。有效抑蛋白制酪氨酸激酶，可以达到治疗肿瘤的目的，蛋白酪氨酸激酶已成为抗肿瘤药物研究的新靶点。
持续性血管生成可以是各种疾病的诱因和前提条件，例如肿瘤或转移生长，牛皮癣，关节炎如类风湿关节炎，血管瘤，血管纤维瘤，眼疾病如糖尿病视网膜病、新血管性青光眼，肾病如肾小球性肾炎、糖尿病性肾病、恶性肾坏死、栓塞性微血管病综合症、移植物排异反应和肾小球病，纤维变性疾病如肝硬化、肾小球膜细胞增殖性疾病和动脉硬化，或者可导致上述疾病的恶化。
持续性血管生成是由因子VEGF通过其受体诱发的。为使VEGF可发挥该作用，VEGF必须结合至该受体上，并诱发酪氨酸磷酸化。
直接或者间接抑制VEGF受体(VEGF＝血管内皮生长因子)可用于治疗此等疾病以及其他由VEGF诱发的病理性血管生成和血管渗透性病症如肿瘤血管生成。例如，已知肿瘤的生长可用可溶性受体以及抗VEGF的抗体来抑制。
兰伐替尼(Lenvatinib)，化学名为4-[3-氯-4-(环丙胺基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺，是日本卫材公司开发的一种口服有效的多激酶抑制剂，主要作用于c-Kit、Ret和VEGFR-2等多个靶点，用于治疗神经胶质瘤、甲状腺瘤、肾癌、肝癌和卵巢癌等实体瘤。2013年2月获得美国FDA孤儿药认定，临床用于治疗滤泡状、髓样、未分化的转移性或局部晚期甲状腺乳头状癌。2015年2月，美国FDA批准日本Eisai公司的Lenvima(lenvatinib)治疗侵袭性、分化型甲状腺癌(DTC)患者，适用于在接受放射性碘治疗后疾病仍恶化(放射性碘难治性疾病)的患者。2016年5月13日，美国FDA批准多靶点酪氨酸激酶抑制剂Lenvatinib和依维莫司联合，用于其他治疗失败的晚期肾癌。
氘代修饰是改进药物代谢性质的一种有潜在吸引力的策略。氘是氢的安全、稳定、非辐射性的同位素。与C-H键相比，氘与碳形成的C-D键因为振动频率较低，所以较强。此外，药物的“重氢”型式可能对降解更稳定且在生物体内维持更长时间。并入氘来代替氢可改善药物的药效学和药代动力学概况，改变代谢归宿，同时保持生理学活性化合物的药理活性和选择性。氘化药物可对安全性、功效及耐受性都有正面影响，具有优良的研究前景。
发明内容
针对以上技术问题，本发明公开了一种含氮芳环化合物及包含该化合物的组合物，其作为一种有效的血管内皮生长因子受体(VEGFR)抑制剂和/或具有更好药效学/药代动力学性能。
对此，本发明采用的技术方案为：
本发明的目的是提供一类新型有效的血管内皮生长因子受体(VEGFR)抑制剂和/或具有更好药效学/药代动力学性能的化合物。
本发明的第一方面中，提供了一种式(I)所示的含氮芳环化合物，或其晶型、药学上可接受的盐、前药、同分异构体、水合物或溶剂化合物：
Figure PCTCN2017075833-appb-000001
式中：
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12相互独立地选自由“氢(H)、氘(D)”组成的组；
X选自“氢(H)、氘(D)、甲基、CH2D、CHD2、CD3、CH2CH3、CHDCH3、CHDCH2D、CHDCHD2、CHDCD3、CD2CH3、CD2CH2D、CD2CHD2CD2CD3”；
及其生理学上可接受的盐、前药、水合物、溶剂化物、互变异构体和立体异构体，包括这些化合物以所有比例形成的混合物。
作为本发明的进一步改进，R1、R2、R3、R4和R5各自独立地为氘或氢。
作为本发明的进一步改进，R6、R7、R8各自独立地为氘或氢。
作为本发明的进一步改进，R9、R10、R11和R12各自独立地为氘或氢。
在另一优选例中，X是三次氘代的甲基。
在另一优选例中，R6是氘。
在另一优选例中，R7、R8是氘。
在另一优选例中，所述化合物选自下组化合物或其药学上可接受的盐，但不局限 于下列化合物：
Figure PCTCN2017075833-appb-000002
Figure PCTCN2017075833-appb-000003
Figure PCTCN2017075833-appb-000004
在另一优选例中，氘在氘代位置的氘同位素含量至少是大于天然氘同位素含量(0.015％)，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。
具体地说，在本发明中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12和X各氘代位置中氘同位素含量至少是5％，较佳地大于10％，更佳地大于15％，更佳地大于20％，更佳地大于25％，更佳地大于30％，更佳地大于35％，更佳地大于40％，更佳地大于45％，更佳地大于50％，更佳地大于55％，更佳地大于60％，更佳地大于65％，更佳地大于70％，更佳地大于75％，更佳地大于80％，更佳地大于85％，更佳地大于90％，更佳地大于95％，更佳地大于99％。
在另一优选例中，式(I)中化合物的R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12和X，至少其中一个R/X含氘，更佳地两个R/X含氘，更佳地三个R/X含氘，更佳地四个R/X含氘，更佳地五个R/X含氘，更佳地六个R/X含氘，更佳地七个R/X含氘，更佳地八个R/X含氘，更佳地九个R/X含氘，更佳地十个R/X含氘，更佳地十一个R/X含氘，更佳地十二个R/X含氘，更佳地十三个R/X含氘。
在另一优选例中，所述化合物不包括非氘代化合物。
在本发明的第二方面中，提供了一种制备药物组合物的方法，包括步骤：将药学上可接受的载体与本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。
在本发明的第三方面中，提供了一种药物组合物，它含有药学上可接受的载体和本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物。
可用于本发明药物组合物中的药学上可接受的载体包括但不限于任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明药物组合物可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶 囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本发明药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选口服给药或注射给药。
本发明的药物组合物可以采用本领域周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
本发明的药物组合物，作为血管新生抑制剂极其有效，所以，作为血管新生抑制作用有效的疾病的预防或治疗剂、血管新生抑制剂、抗肿瘤剂、血管瘤治疗剂、癌转移抑制剂、视网膜血管新生症治疗剂、糖尿病性视网膜症治疗剂、炎症性疾病治疗剂、变形性关节炎、风湿性关节炎、干藓或包括迟发性过敏反应的炎症性疾病治疗剂、粉瘤性动脉硬化症治疗剂有效。
本发明的另一方面提供通过单独施用或者与其他细胞毒剂或治疗剂联合施用本发明的化合物，来治疗患有转移癌或有转移癌发病风险的受试者的方法。所述癌症可为例如以下癌症中的一种或多种：甲状腺癌、胰腺癌、胃癌、大肠癌、乳癌、前列腺癌、肺癌、肾癌、脑瘤癌、血液癌或卵巢癌，特别优选甲状腺癌和肾癌。
本发明提供通过单独施用或者与其他细胞毒剂或治疗剂联合施用本发明的化合物，来治疗患有转移癌或具有转移癌发病风险的受试者的方法。特别地，优选的细胞毒剂和治疗剂包括多西他赛(docetaxel)、紫杉醇(paclitaxel)、多柔比星(doxorubicin)、表柔比星(epirubicin)、环磷酰胺(cyclophosphamide)、曲妥珠单抗(trastuzumab)(HerceptinTM)、卡培他滨(capecitabine)、他莫昔芬(tamoxifen)、托瑞米芬(toremifene)、来曲唑(letrozole)、阿那曲唑(anastrozole)、氟维司群(fulvestrant)、依西美坦(exemestane)、戈舍瑞林(goserelin)、奥沙利铂(oxaliplain)、卡铂(carboplatin)、顺铂(cisplatin)、地塞米松(dexamethasone)、安肽(antide)、贝伐单抗(bevacizumab)(bevacizumabTM)、5-氟尿嘧啶(5-fluorouracil)、亚叶酸钙(leucovorin)、左旋咪唑(levamisole)、伊立替康(irinotecan)、依托泊苷(etoposide)、托泊替康(topotecan)、吉西他滨(gemcitabine)、长春瑞滨(vinorelbine)、雌莫司汀(estramustine)、米托蒽醌(mitoxantrone)、阿巴瑞克(abarelix)、唑来膦酸(zoledronate)、链佐星(streptozocin)、利妥昔单抗(rituximab)(RituxanTM)、伊达比星(idarubicin)、白消安(busulfan)、苯丁酸氮芥(chlorambucil)、氟达拉滨(fludarabine)、伊马替尼(imatinib)、阿 糖胞苷(cytarabine)、替伊莫单抗(ibritumomab)(ZevalinTM)、托西莫单抗(tositumomab)(BexxarTM)、干扰素α-2b、美法仑(melphalam)、硼替佐米(bortezomib)(VelcadeTM)、六甲蜜胺(altretamine)、天冬酰胺酶(asparaginase)、吉非替尼(gefitinib)(IressaTM)、厄洛替尼(erlonitib)(TarcevaTM)、抗-EGF受体抗体(CetuximabTM、Abx-EGF)及埃博霉素。更优选地，所述治疗剂为铂剂(例如卡铂、奥沙利铂、顺铂)、紫杉烷(例如紫杉醇、多西他赛)、吉西他滨或喜树碱。
在一个实施方案中，提供了一种治疗医学状况(medical condition)的方法，包括施用本发明的化合物。在另外一个实施方案中，施用的化合物是血管生成抑制剂。在另一个实施方案中，还施用第二种试剂。所述第二种试剂可以是本说明书中公开的任一种细胞毒剂或治疗剂，举例来说可选自下列治疗剂：SutentTM(即苹果酸舒尼替尼(sunitinib malate)，描述于美国专利6573293，TykrebTM(即拉帕替尼(lapatinib)，描述于美国专利6727256，NexavarTM(即Bayer BAY 43-9006/索拉非尼)，AZD2171(即RecentinTM，在PCT国际申请公开号WO 00/47212中公开)，贝伐单抗，mTOR抑制剂如雷帕霉素(rapamycin)及其衍生物(雷帕霉素羟基酯，包括CC1-779即temsirolimus，的制备和应用在美国专利5362718中公开)，作用于所述激酶的细胞质部分的激酶抑制剂，吉西他滨(即GemzarTM，在美国专利4808614中公开)，替莫唑胺(temozolomide)(即TemodarTM，其在癌症治疗中的应用在美国专利5939098中公开)，达沙替尼(dasatinib)(即SprycelTM，在美国专利6596746中公开)，西妥昔单抗(ErbituxTM，例如在美国专利6217866中公开)，伊沙匹隆(ixabepilone)(BMS-247550)，甲磺酸伊马替尼(imatinib mesylate)(即GleevacTM，在美国专利5521184中公开)，曲妥珠单抗(HerceptinTM，例如在美国专利5677171中公开)，以及紫杉烷类的成员如紫杉醇(即TaxolTM，在美国专利5439686中公开)和多西他赛(即TaxotereTM，在美国专利4814470中公开)。
本发明提供通过mTOR抑制剂联合施用本发明的化合物，来治疗患有转移癌或具有转移癌发病风险的受试者的方法。特别地，优选的mTOR抑制剂包括依维莫司(Everolimus)、雷帕霉素(Sirolimus)、替西罗莫司(Temsirolimus)、他克莫司(Tacrolimus)、Ridaforolimus。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
本文中，如无特别说明，“卤素”指F、Cl、Br、和I。更佳地，卤原子选自F、Cl和Br。
本文中，如无特别说明，“氘代”指化合物或基团中的一个或多个氢被氘所取代；氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
本文中，如无特别说明，“非氘代的化合物”是指含氘原子比例不高于天然氘同位素含量(0.015％)的化合物。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如2H，3H，13C，14C，15N，17O，18O，31P，32P，35S，18F以及36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如3H和14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即3H和碳-14，即14C，它们的制备和检测比较容易，是同位素中的首选。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用示例中的方案可以制备。
药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
此外，本发明化合物还包括式(I)所示的含氮芳环衍生物的前药。术语“前药”包 括其本身可以是具有生物学活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式(I)的一类化合物，或式(I)的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
本发明还提供了包含式(I)的化合物或其药学上可接受的盐或所述化合物的药学上可接受的盐以及药学上可接受的载体的药物组合物。所述载体在与制剂的其他成分相容以及，在药学上可接受的载体的情况下，在用于药物中的量下不会对其接受者有害的意义上是“可接受的”。
式(I)化合物和包含所述化合物的组合物是VEGFR抑制剂，并且可以用于治疗、预防或消除各种VEGFR的相关病症。包含这些化合物的药物组合物用于在不同治疗领域诸如癌症中治疗、预防疾病或障碍或减慢所述疾病或障碍进程。
与现有技术相比，本发明的有益效果为：本发明公开的取代的含氮芳环类化合物及包含该化合物的组合物对VEGFR具有优异的抑制性，同时具有更好的药代动力学参数特性。可以改变剂量并形成长效制剂，改善适用性。用氘取代化合物中的氢原子，由于其氘同位素效应，能够提高化合物在动物体内的药物浓度，以提高药物疗效。用氘取代化合物中的氢原子，由于某些代谢产物被抑制，可能提高化合物的安全性。
具体实施方式
下面更具体地描述本发明式I结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～100℃，优选0℃～80℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-24小时。
下面的通用制备路线可以用于合成本发明式(I)化合物。
Figure PCTCN2017075833-appb-000005
式中：
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12相互独立地选自由“氢(H)、氘(D)”组成的组；
在一些实施实例中，X选自“氢(H)、氘(D)、甲基、CH2D、CHD2、CD3、CH2CH3、CHDCH3、CHDCH2D、CHDCHD2、CHDCD3、CD2CH3、CD2CH2D、CD2CHD2CD2CD3”。
在一些实施实例中，碱可选自叔丁醇钾、碳酸钾、碳酸钠、碳酸氢钠、碳酸铯、氢氧化钠、氢氧化钾、氢氧化锂、三乙胺、二异丙基乙基胺、4-N，N-二甲基吡啶或吡啶。
实施例1制备4-[3-氯-4-(环丙胺基羰基)氨基苯氧基]-7-d3-甲氧基-6-喹啉甲酰胺 (化合物A-1)
Figure PCTCN2017075833-appb-000006
步骤14-氯-7-羟基-6-喹啉甲酰胺(化合物2)的合成。
氮气保护下，向4-氯-7-甲氧基-6-喹啉甲酰胺(1.18g，5mmol)的DCM(15mL)溶液中，缓慢滴加BBr3(3.12g，12.5mmoL)，控制温度在-10℃以下。滴加完毕后在0℃下反应3小时，再冷却至-10℃，缓慢滴加20mL甲醇淬灭反应。将反应液升至室温搅拌过夜，减压蒸除溶剂，将固体用10mL甲醇溶解并旋干(重复3次)，将粗品加入5mL蒸馏水，70搅拌2小时，冷至室温，过滤干燥得类白色固体4-氯-7-羟基-6-喹啉甲酰胺(0.66g，收率60％)。LC-MS(APCI):m/z＝223(M+1)+。
步骤24-氯-7-d3-甲氧基-6-喹啉甲酰胺(化合物3)的合成。
氮气保护下，向4-氯-7-羟基喹啉-6-甲酰胺(0.60g，2.7mmol)和碳酸钾(1.12g，8.1mmol)的DMF(10mL)溶液中，缓慢滴加CD3I(0.97g，6.75mmol)，控制温度 在0℃以下。滴加完毕后自然升至升温反应3小时。加入20mL水淬灭，用乙酸乙酯萃取(30mL x 3)，有机相用20mL水和20mL饱和食盐水各洗涤一次，无水硫酸钠干燥，过滤，蒸干，经硅胶柱分离得淡黄色固体4-氯-7-d3-甲氧基-6-喹啉甲酰胺(0.39g，收率60％)。LC-MS(APCI):m/z＝240(M+1)+；1H NMR(300MHz,DMSO-d6)δ8.82(d,J＝4.8Hz,1H),8.49(s,1H),7.86(d,J＝26.7Hz,2H),7.65(d,J＝4.8Hz,1H),7.59(s,1H)。
步骤3 4-[3-氯-4-(环丙胺基羰基)氨基苯氧基]-7-d3-甲氧基-6-喹啉甲酰胺(化合物A-1)的合成。
将4-氯-7-d3-甲氧基-6-喹啉甲酰胺(0.195g，0.83mmol)和1-(2-氯-4-羟基苯基)3-环丙基脲(0.188g，0.83mmol)溶于5mL DMSO中，氮气保护下加入叔丁醇钾(0.186g，1.66mmol)，加热到100℃，反应过夜。冷却至室温，加入20mL水，用乙酸乙酯(30mL x 3)萃取，有机相用2 0mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得淡黄色固体4-[3-氯-4-(环丙胺基羰基)氨基苯氧基]-7-d3-甲氧基-6-喹啉甲酰胺(0.28g，收率80％)。LC-MS(APCI):m/z＝430(M+1)+；1H NMR(300MHz,DMSO-d6)δ8.67(t,J＝2.7Hz,2H),8.28(d,J＝9.1Hz,1H),7.99(s,1H),7.87(s,1H),7.75(s,1H),7.51(d,J＝5.7Hz,2H),7.29–7.19(m,2H),6.53(d,J＝5.3Hz,1H),0.67(d,J＝6.4Hz,2H),0.43(s,2H)。
实施例2制备4-[2,6-d2-3-氯-4-(环丙胺基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰 胺(化合物A-2)
Figure PCTCN2017075833-appb-000007
步骤1.化合物4-氨基-3-氯苯酚-2,6-d2的合成。
向20mL微波管中加入4-氨基-3-氯苯酚(0.5g，3.48mmol)，氘氧化钠(0.143g，3.48mmol)和重水10mL，氮气鼓泡1分钟，密封放入微波反应仪。于120℃微波反应30分钟，待降至室温后取出，用乙酸乙酯(10mL*3)萃取，有机相用10mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得淡红色油状物4-氨基-3-氯苯酚-2,6-d2约0.43g，收率84.8％。LC-MS(APCI):m/z＝146(M+1)+；1H NMR(300MHz,DMSO-d6)δ8.78(s,1H),6.64(s,1H),4.63(s,2H)。
步骤2.化合物1-(2-氯-4-苯酚-2,6-d2)-3-环丙基脲的合成。
冰浴下向4-氨基-3-氯苯酚-2,6-d2(0.43g，2.95mmol)的DMF(10mL)溶液中加入吡啶，然后缓慢滴加氯甲酸苯酯(0.46g，2.95mmol)，控制温度不超过20℃，撤去冰浴，室温下搅拌30分钟，加入40mL水，40mL乙酸乙酯和10mL 6N盐酸，搅拌5分钟，分层，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得淡黄色固体0.55g。将该固体溶于10mL DMF，冰浴下缓慢滴加环丙胺(118.2mg，2.07mmol)，滴毕室温反应过夜。向反应液中加入40mL水，40mL乙酸乙酯，10mL 6N盐酸，搅拌5分钟，分层，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得淡黄色固体1-(2-氯-4-苯酚-2,6-d2)-3-环丙基脲0.43g，收率63.7％。LC-MS(APCI):m/z＝229(M+1)+；1H NMR(300MHz,DMSO-d6)δ9.51(s,1H),7.68(s,1H),7.58(s,1H),6.85(d,J＝2.8Hz,1H),2.52(d,J＝3.3Hz,1H),0.61(td,J＝6.9,4.7Hz,2H),0.42–0.33(m,2H)。
步骤3.化合物4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基-2,6-d2]-7-甲氧基-6-喹啉甲酰胺的合成。
将4-氯-7-甲氧基喹啉-6-甲酰胺(0.2g，0.85mmol)和1-(2-氯-4-苯酚-2,6-d2)-3-环丙基脲(0.193g，0.85mmol)溶于5mL DMSO中，氮气保护下加入叔丁醇钾(0.189g，1.70mmol)，加热到100℃，反应过夜。冷却至室温，加入20mL水，用乙酸乙酯(20mL*3)萃取，有机相用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得淡黄色固体4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基-2,6-d2]-7-甲氧基-6-喹啉甲酰胺0.24g，收率66.2％。LC-MS(APCI):m/z＝429(M+1)+；1H NMR(300MHz,DMSO-d6)δ8.67(t,J＝2.7Hz,2H),8.28(s,1H),7.99(s,1H),7.81(d,J＝33.4Hz,2H),7.52(s,1H),7.21(d,J＝2.9Hz,1H),6.53(d,J＝5.2Hz,1H),4.03(s,3H),2.58(tq,J＝6.4,3.3Hz,1H),0.67(td,J＝6.9,4.7Hz,2H),0.43(p,J＝5.0,4.6Hz,2H)。
实施例3制备4-[3-氯-4-(环丙胺基羰基)氨基-5-d-苯氧基]-7-甲氧基-6-喹啉甲酰胺 (化合物A-3)
Figure PCTCN2017075833-appb-000008
步骤1.化合物4-氨基-3-氯-苯酚-5-d的合成。
向20mL微波管中加入4-氨基-3-氯苯酚(0.5g，3.48mmol)，36％氘代盐酸0.36mL和重水10mL，氮气鼓泡1分钟，密封放入微波反应仪。于180℃微波反应0.5小时，待降至室温后取出，加入20mL饱和碳酸钠溶液，搅拌5分钟，用乙酸乙酯(10mL*3)萃取，有机相用10mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得淡红色油状物4-氨基-3-氯-苯酚-5-d约0.46g，收率91.4％。LC-MS(APCI):m/z＝145(M+1)+；1H NMR(300MHz,DMSO-d6)δ8.81(s,1H),6.68–6.62(m,1H),6.53(td,J＝11.3,4.4,2.8Hz,1H),4.63(s,2H)。
步骤2.化合物1-(2-氯-4-苯酚-6-d)-3-环丙基脲的合成。
冰浴下向4-氨基-3-氯-苯酚-5-d(0.46g，3.18mmol)的DMF(10mL)溶液中加入吡啶，然后缓慢滴加氯甲酸苯酯(0.5g，3.18mmol)，控制温度不超过20℃，撤去冰浴，室温下搅拌30分钟，加入40mL水，40mL乙酸乙酯，10mL 6N盐酸，搅拌5分钟，分层，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得淡黄色固体0.58g。将该固体溶于10mL DMF，冰浴下缓慢滴加环丙胺(0.13g，2.19mmol)，滴毕室温反应过夜。向反应液中加入40mL水，40mL乙酸乙酯，10mL 6N盐酸，搅拌5分钟，分层，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得淡黄色固体1-(2-氯-4-苯酚-6-d)-3-环丙基脲0.46g，收率63.5％。LC-MS(APCI):m/z＝228(M+1)+；1H NMR(300MHz,DMSO-d6)δ9.51(s,1H),7.58(s,1H),6.85(d,J＝2.8Hz,1H),6.78(d,J＝2.8Hz,1H),6.66(dd,J＝2.6,1.4Hz,1H),2.53(d,J＝3.3Hz,1H),0.62(td,J＝6.9,4.7Hz,2H),0.44–0.32(m,2H)。
步骤3.化合物{3-氯-4-(环丙基氨基羰基)氨基苯氧基-5-d}-7-甲氧基-6-喹啉甲酰胺的合成。
将4-氯-7-甲氧基喹啉-6-甲酰胺(0.2g，0.85mmol)和1-(2-氯-4-苯酚-6-d)-3-环丙基脲(0.193g，0.85mmol)溶于5mL DMSO中，氮气保护下加入叔丁醇钾(0.189g，1.70mmol)，加热到100℃，反应过夜。冷却至室温，加入20mL水，用乙酸乙酯(20mL*3)萃取，有机相用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得淡黄色固体[3-氯-4-(环丙基氨基羰基)氨基苯氧基-5-d}-7-甲氧基-6-喹啉甲酰胺0.28g，收率74.5％。LC-MS(APCI):m/z＝428(M+1)+；1H NMR(300MHz,DMSO-d6)δ8.67(t,J＝2.7Hz,2H),7.99(s,1H),7.81(d,J＝33.3Hz,2H),7.61–7.42(m,2H),7.32 –7.14(m,2H),6.53(d,J＝5.2Hz,1H),4.03(s,3H),2.58(dq,J＝7.0,3.3Hz,1H),0.72–0.61(m,2H),0.43(p,J＝4.5Hz,2H)。
实施例4制备4-[3-氯-4-(环丙胺基羰基)氨基苯氧基]-7-甲氧基-8-d-6-喹啉甲酰胺 (化合物A-4)
Figure PCTCN2017075833-appb-000009
步骤1.化合物4-氨基-2-甲氧基苯腈-3,5-d2的合成。
向20mL微波管中加入4-氨基-2-甲氧基苯腈(1.48g，10mmol)，36％氘代盐酸1mL和重水15mL，氮气鼓泡1分钟，密封放入微波反应仪。于120℃微波反应2小时，待降至室温后取出，加入20mL饱和碳酸钠溶液，搅拌5分钟，用乙酸乙酯萃取，有机相用10mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得淡黄色固体1.1g，收率73％。LC-MS(APCI):m/z＝151(M+1)+；1H NMR(400MHz,DMSO-d6)δ7.24(s,1H),6.17(s,2H)。
步骤2.化合物4-(((2,2-二甲基-4,6-二氧代-1,3-二氧杂环己烷-5-亚甲基)甲基)氨基)-2-甲氧基苯腈-3,5-d2的合成。
将4-氨基-2-甲氧基苯腈-3,5-d2(1.06g，7.1mmol)溶于15mL异丙醇中，油浴加热到50℃，分批加入5-(甲氧亚甲基)-2,2-二甲基-1,3-二氧杂环已烷-4,6-二酮(1.4g，7.5mmol)，加料完毕，升温至回流反应1小时。冷却至室温，过滤，滤饼用少量石油醚洗涤，干燥得淡黄色固体1.5g，收率70％。LC-MS(APCI):m/z＝305(M+1)+；1H NMR(500MHz,DMSO-d6)δ11.27(d,J＝14.2Hz,1H),8.73(d,J＝14.2Hz,1H),7.75(s,1H),3.96(s,3H),1.69(s,6H)。
步骤3.化合物7-甲氧基-4-氧代-1,4-二氢喹啉-6-甲腈-8-d的合成。
将4-(((2,2-二甲基-4,6-二氧代-1,3-二氧杂环己烷-5-亚甲基)甲基)氨基)-2-甲氧基苯腈-3,5-d2(1.46g，4.8mmol)加入到10mL二苯醚中，油浴升温到200℃反应0.5小时。自然冷却至室温，过滤，滤饼用少量石油醚洗涤，干燥得棕色固体0.58g，收率60％。LC-MS(APCI):m/z＝202(M+1)+；1H NMR(500MHz,DMSO-d6)δ11.84(s,1H),8.32(s,1H),7.92–7.88(m,1H),6.04(d,J＝7.5Hz,1H),3.98(s,3H)。
步骤4.化合物4-氯-7-甲氧基喹啉-6-甲腈-8-d的合成。
将7-甲氧基-4-氧代-1,4-二氢喹啉-6-甲腈-8-d(0.58g，2.9mmol)加入到10mL氯化亚砜中，滴一滴DMF，升温至回流反应2小时。旋蒸浓缩至干，甲苯拖带两次，残留物经硅胶柱分离得淡黄色色固体约0.52g，收率82％。LC-MS(APCI):m/z＝220(M+1)+。
步骤5.化合物4-氯-7-甲氧基喹啉-8-d-6-甲酰胺的合成。
将4-氯-7-甲氧基喹啉-6-甲腈-8-d(0.52g，2.4mmol)和碳酸钾(1.0g，7.2mmol)溶于10mL DMSO中，冰浴下缓慢滴加30％双氧水1.5mL，滴毕于室温下反应3小时。反应完全后加入20mL水稀释，乙酸乙酯萃取，浓缩，干燥得淡黄色固体0.47g，收率83％。LC-MS(APCI):m/z＝238(M+1)+；1H NMR(400MHz,DMSO-d6)δ8.82(d,J＝4.7Hz,1H),8.50(s,1H),7.90(s,1H),7.81(s,1H),7.65(d,J＝4.8Hz,1H),4.03(s,3H)。
步骤5.化合物4-(3-氯-4-(3-环丙基氨基羰基)氨基苯氧基)-7-甲氧基喹啉-8-d-6-甲酰胺的合成。
将4-氯-7-甲氧基喹啉-8-d-6-甲酰胺(100mg，0.42mmol)和1-(2-氯-4-羟基苯基)-3-环丙基脲(95mg，0.42mmol)溶于5mL DMSO中，氮气保护下加入叔丁醇钾(94mg，0.84mmol)，加热到100℃，反应过夜。冷却至室温，加入20mL水，用乙酸乙酯萃取，有机相用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得淡黄色固体125mg，收率70％。LC-MS(APCI):m/z＝428(M+1)+；1H NMR(400MHz,DMSO-d6)δ8.67(t,J＝2.6Hz,2H),8.28(d,J＝9.1Hz,1H),7.99(s,1H),7.86(s,1H),7.74(s,1H),7.49(d,J＝2.8Hz,1H),7.25(dd,J＝9.1,2.8Hz,1H),7.21(d,J＝2.9Hz,1H),6.53(d,J＝5.2Hz,1H),2.58(dq,J＝6.9,3.4Hz,1H),0.70–0.62(m,2H),0.44(dd,J＝4.5,2.2Hz,2H)。
实施例5制备4-[3-氯-4-(环丙胺基羰基)氨基-2,6-d2-苯氧基]-7-d3-甲氧基-6-喹啉 甲酰胺(化合物A-5)
Figure PCTCN2017075833-appb-000010
将4-氯-7-(甲氧基喹啉-d3)-6-甲酰胺(100mg，0.42mmol)和1-(2-氯-4-羟基苯基-3,5-d2)-3-环丙基脲(95mg，0.42mmol)溶于5mL DMSO中，氮气保护下加入叔丁醇钾(94mg，0.84mmol)，加热到100℃，反应过夜。冷却至室温，加入20mL水， 用乙酸乙酯萃取，有机相用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得淡黄色固体112mg，收率62％。LC-MS(APCI):m/z＝432(M+1)+；1H NMR(400MHz,DMSO-d6)δ8.67(t,J＝2.7Hz,2H),8.28(s,1H),7.99(s,1H),7.86(s,1H),7.74(s,1H),7.51(s,1H),7.20(d,J＝2.8Hz,1H),6.53(d,J＝5.2Hz,1H),2.62-2.56(m,1H),0.89-0.80(m,2H),0.70-0.63(m,2H)。
实施例6制备4-[3-氯-4-(环丙胺基羰基)氨基-5-d-苯氧基]-7-d3-甲氧基-6-喹啉甲 酰胺(化合物A-6)
Figure PCTCN2017075833-appb-000011
将4-氯-7-(甲氧基喹啉-d3)-6-甲酰胺(100mg，0.42mmol)和1-(2-氯-4-羟基苯基-6-d)-3-环丙基脲(95mg，0.42mmol)溶于5mL DMSO中，氮气保护下加入叔丁醇钾(94mg，0.84mmol)，加热到100℃，反应过夜。冷却至室温，加入20mL水，用乙酸乙酯萃取，有机相用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得淡黄色固体110mg，收率61％。LC-MS(APCI):m/z＝431(M+1)+；1H NMR(400MHz,DMSO-d6)δ8.67(t,J＝2.7Hz,2H),7.99(s,1H),7.86(s,1H),7.74(s,1H),7.51(s,1H),7.50–7.49(m,1H),7.26–7.23(m,1H),7.20(d,J＝2.9Hz,1H),6.53(d,J＝5.2Hz,1H),2.60-2.55(m,1H),0.70-0.63(m,2H),0.46-0.40(m,2H)。
实施例7制备4-[3-氯-4-(环丙胺基羰基)氨基-2,6-d2-苯氧基]-7-甲氧基-8-d-6-喹啉 甲酰胺(化合物A-7)
Figure PCTCN2017075833-appb-000012
将4-氯-7-甲氧基喹啉-8-d-6-甲酰胺(100mg，0.42mmol)和1-(2-氯-4-羟基苯基-3,5-d2)-3-环丙基脲(95mg，0.42mmol)溶于5mL DMSO中，氮气保护下加入叔丁醇钾(94mg，0.84mmol)，加热到100℃，反应过夜。冷却至室温，加入20mL水，用乙酸乙酯萃取，有机相用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得淡黄色固体118mg，收率65％。LC-MS(APCI):m/z＝430(M+1)+；1H NMR(400MHz,DMSO-d6)δ8.67(t,J＝2.6Hz,2H),8.28(s,1H),7.99(s,1H),7.88– 7.83(m,1H),7.74(s,1H),7.20(d,J＝3.0Hz,1H),6.53(d,J＝5.3Hz,1H),4.03(s,3H),3.17(d,J＝4.5Hz,0H),2.58(dq,J＝7.0,3.4Hz,1H),0.70-0.63(m,2H),0.46–0.40(m,2H)。
实施例8制备4-[3-氯-4-(环丙胺基羰基)氨基-5-d-苯氧基]-7-甲氧基-8-d-6-喹啉甲 酰胺(化合物A-8)
Figure PCTCN2017075833-appb-000013
将4-氯-7-甲氧基喹啉-8-d-6-甲酰胺(100mg，0.42mmol)和1-(2-氯-4-羟基苯基-6-d)-3-环丙基脲(95mg，0.42mmol)溶于5mL DMSO中，氮气保护下加入叔丁醇钾(94mg，0.84mmol)，加热到100℃，反应过夜。冷却至室温，加入20mL水，用乙酸乙酯萃取，有机相用20mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得淡黄色固体120mg，收率66％。LC-MS(APCI):m/z＝429(M+1)+；1H NMR(400MHz,DMSO-d6)δ8.69–8.64(m,2H),7.99(s,1H),7.89–7.82(m,1H),7.75(s,1H),7.51–7.47(m,1H),7.26–7.23(m,1H),7.21(d,J＝2.9Hz,1H),6.52(d,J＝5.3Hz,1H),4.03(s,3H),2.57(tt,J＝6.9,3.4Hz,1H),0.70–0.62(m,2H),0.47–0.39(m,2H)。
生物活性测试。
大鼠中的药代动力学评价。
8只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，分成2组，每组4只，单次口服给予5mg/kg剂量的(a)对照组：4-[3-氯-4-(环丙胺基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺；(b)试验组：实施例，比较其药代动力学差异。
大鼠采用标准饲料饲养，给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血，采血的时间点为给药后0.083小时，0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时和24小时。
大鼠吸入乙醚后短暂麻醉，眼眶采集300μL血样于试管。试管内有30μL1％肝素盐溶液。使用前，试管于60℃烘干过夜。在随后一个时间点血样采集完成之后，大鼠乙醚麻醉后处死。
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血样 在4℃5000rpm离心5分钟，将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中，标明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进计算。
实验结果表明，相对于对照化合物，本发明化合物在动物体内具有更好的药物动力学，因而具有更好的药效学和治疗效果。
代谢稳定性评价。
微粒体实验：人肝微粒体：0.5mg/mL，Xenotech；小鼠肝微粒体：0.5mg/mL，Xenotech；辅酶(NADPH/NADH)：1mM，Sigma Life Science；氯化镁：5mM，100mM磷酸盐缓冲剂(pH为7.4)。
储备液的配制：精密称取一定量的化合物实施例1-7粉末，并用DMSO分别溶解至5mM。
磷酸盐缓冲液(100mM，pH7.4)的配制：取预先配好的0.5M磷酸二氢钾150mL和700mL的0.5M磷酸氢二钾溶液混合，再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4，使用前用超纯水稀释5倍，加入氯化镁，得到磷酸盐缓冲液(100mM)，其中含100mM磷酸钾，3.3mM氯化镁，pH为7.4。
配制NADPH再生系统溶液(含有6.5mM NADP，16.5mM G-6-P，3U/mL G-6-P D，3.3mM氯化镁)，使用前置于湿冰上。
配制终止液：含有50ng/mL盐酸普萘洛尔和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL人肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL SD大鼠肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。
样品的孵育：用含70％乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM，作为工作液，备用。分别取398μL的人肝微粒体或者大鼠肝微粒体稀释液加入96孔孵育板中(N＝2)，分别加入2μL 0.25mM的的工作液中，混匀。
代谢稳定性的测定：在96孔深孔板的每孔中加入300μL预冷的终止液，并置于冰上，作为终止板。将96孔孵育板和NADPH再生系统置于37℃水浴箱中，100转/分钟震荡，预孵5min。从孵育板每孔取出80μL孵育液加入终止板，混匀，补充20μL  NADPH再生系统溶液，作为0min样品。再向孵育板每孔加入80μL的NADPH再生系统溶液，启动反应，开始计时。相应化合物的反应浓度为1μM，蛋白浓度为0.5mg/mL。分别于反应10、30、90min时，各取100μL反应液，加入终止板中，涡旋3min终止反应。将终止板于5000×g，4℃条件下离心10min。取100μL上清液至预先加入100μL蒸馏水的96孔板中，混匀，采用LC-MS/MS进行样品分析。
数据分析：通过LC-MS/MS系统检测相应化合物及内标的峰面积，计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率，并根据以下公式计算t1/2和CLint，其中V/M即等于1/蛋白浓度。
Figure PCTCN2017075833-appb-000014
表1实施例化合物的肝微粒代谢评价
Figure PCTCN2017075833-appb-000015
实验结果如上表1所示，同兰伐替尼相比，本发明化合物的半衰期较长，清除率较小，在小大鼠肝微粒体实验中都表现出较优的代谢稳定性，因而更适合作为与蛋白酪氨酸激酶功能失调相关疾病的药物。
应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围，实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比为重量份和重量百分比。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。

Claims (11)

  1. 一种取代的含氮芳环化合物，其特征在于：如式(I)所示的含氮芳环化合物，或其晶型、药学上可接受的盐、水合物或溶剂化合物，
    Figure PCTCN2017075833-appb-100001
    式中：
    R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12相互独立地选自由“氢(H)、氘(D)”组成的组；
    X选自“氢(H)、氘(D)、甲基、CH2D、CHD2、CD3、CH2CH3、CHDCH3、CHDCH2D、CHDCHD2、CHDCD3、CD2CH3、CD2CH2D、CD2CHD2CD2CD3”；
    及其生理学上可接受的盐、前药、水合物、溶剂化物、互变异构体和立体异构体，包括这些化合物以所有比例形成的混合物。
  2. 根据权利要求1所述的化合物，其特征在于：R1、R2、R3、R4和R5各自独立地为氘或氢。
  3. 根据权利要求1所述的化合物，其特征在于：R6、R7、R8各自独立地为氘或氢。
  4. 根据权利要求1所述的化合物，其特征在于：R9、R10、R11和R12各自独立地为氘或氢。
  5. 根据权利要求1所述的化合物，其特征在于：X是三次氘代的甲基。
  6. 根据权利要求1所述的含氮芳环化合物，其特征在于：所述化合物选自下组化合物或其药学上可接受的盐，但不局限于下列化合物：
    Figure PCTCN2017075833-appb-100002
    Figure PCTCN2017075833-appb-100003
    Figure PCTCN2017075833-appb-100004
  7. 一种药物组合物，其特征在于：其含有药学上可接受的载体和如权利要求1～6任意一项所述的取代的含氮芳环化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物、立体异构体、前药或同位素变体的药物组合物作为有效成分，并含有常规药用载体。
  8. 如权利要求7所述的药物组合物，其特征在于，所述的药物组合物可以用于治疗、预防或消除与蛋白酪氨酸激酶功能失调相关疾病，包含这些化合物的药物组合物用于在不同治疗领域诸如癌症中治疗、预防疾病或障碍或减慢所述疾病或障碍进程。
  9. 一种如权利要求1～6任意一项所述的含氮芳环化合物的用途，其特征在于：用于制备治疗、预防或消除与蛋白酪氨酸激酶功能失调相关疾病的药物。
  10. 一种在受试者中治疗和/或预防与蛋白酪氨酸激酶功能失调相关的疾病的方法，所述方法包括向所述受试者给药如权利要求1～6任意一项所述的式(I)化合物或其多晶型、药学上可接受的盐、前药、立体异构体、同位素变体、水合物或溶剂化合物，或者权利要求7或8中任一项的药物组合物。
  11. 如权利要求9或10所述的的用途，其特征在于，所述疾病可选自甲状腺癌或肾癌。
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