WO2019001379A1 - 用于抑制激酶活性的吲唑类化合物及其组合物及应用 - Google Patents

用于抑制激酶活性的吲唑类化合物及其组合物及应用 Download PDF

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WO2019001379A1
WO2019001379A1 PCT/CN2018/092570 CN2018092570W WO2019001379A1 WO 2019001379 A1 WO2019001379 A1 WO 2019001379A1 CN 2018092570 W CN2018092570 W CN 2018092570W WO 2019001379 A1 WO2019001379 A1 WO 2019001379A1
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compound
mmol
added
cancer
carbazole compound
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PCT/CN2018/092570
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English (en)
French (fr)
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王义汉
李焕银
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深圳市塔吉瑞生物医药有限公司
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Priority to JP2020520705A priority Critical patent/JP6928986B2/ja
Priority to US16/625,009 priority patent/US11267806B2/en
Priority to EP18825179.7A priority patent/EP3626709A4/en
Publication of WO2019001379A1 publication Critical patent/WO2019001379A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention belongs to the field of medical technology, and in particular, the present invention relates to a substituted carbazole compound having an activity of inhibiting protein kinase. More specifically, the present invention relates to certain indole substituted N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-methylpiperazine-1 -yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, these guanidine substituted compounds and compositions thereof can be used to treat mediated by ALK, ROS1, TRK1, TRK2 or TRK3 Related cancers, and these guanidine-substituted compounds have more excellent pharmacokinetic properties.
  • PK protein kinase
  • a large proportion of oncogenes and proto-oncogenes associated with human cancer encode PK.
  • Enhanced PK activity is also associated with many non-malignant diseases such as benign prostatic hyperplasia, familial adenoma, polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, Arthritis, glomerulonephritis, and stenosis and restenosis after surgery.
  • PK is also associated with inflammatory conditions and the proliferation of viruses and parasites. PK may also play an important role in the pathogenesis and development of neurodegenerative diseases.
  • Entrectinib received an FDA-approved breakthrough therapy in May 2017 for the treatment of NTRK gene fusion-positive, locally advanced or metastatic solid tumors in adults and children, who continue to progress after receiving existing therapies. Or there is no standard therapy.
  • Entrectinib is a novel central nervous activity oral tyrosine kinase inhibitor (TKI) targeting tumors containing NTRK1/2/3, ROS1 or ALK gene fusion mutations.
  • TKI oral tyrosine kinase inhibitor
  • Entrectinib is currently the only clinically proven tyrosine kinase inhibitor that is active, targeting primary and metastatic central nervous system cancers, and has no adverse off-target effects.
  • the drug candidate is undergoing Phase 2 clinical trial STARTRK-2.
  • the trial is a global multi-center, open-label, registration-related phase 2 clinical trial using precision medicine's "basket design” to screen for mutations in tumor patient samples, based on tumor type and gene Fusion, patients will be assigned to different “baskets” for treatment. This "basket design” can be incorporated into a range of different tumor types to validate the clinical effects of Entrectinib against molecular targets.
  • ADME ulcerative co-oxidative desorption, distribution, metabolism, and/or excretion
  • Many of the drugs currently on the market also limit their range of applications due to poor ADME properties.
  • the rapid metabolism of drugs can lead to the inability of many drugs that could be effectively treated to treat diseases because they are too quickly removed from the body.
  • Frequent or high-dose medications may solve the problem of rapid drug clearance, but this approach can lead to problems such as poor patient compliance, side effects caused by high-dose medications, and increased treatment costs.
  • rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites.
  • this field has broad therapeutic potential for most tumor types, and currently there is a lack of treatment in this field, and there is a clear unmet clinical need.
  • the present invention discloses a novel anthraquinone-substituted carbazole compound, a pharmaceutical composition and use thereof, which have better kinase inhibitory activity and/or have better pharmacodynamics/pharmacokinetics. performance.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 And R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 and R 31 are each independently selected from hydrogen and hydrazine. , halogen or trifluoromethyl;
  • the shape and volume of the ruthenium in the drug molecule are substantially the same as those of the hydrogen. If the hydrogen in the drug molecule is selectively replaced with hydrazine, the deuterated drug generally retains the original biological activity and selectivity. At the same time, the inventors have confirmed through experiments that the binding of carbon-germanium bonds is more stable than the combination of carbon-hydrogen bonds, which can directly affect the absorption, distribution, metabolism and excretion of some drugs, thereby improving the efficacy, safety and tolerability of the drugs.
  • the strontium 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%, more preferably greater than 75%, and even more preferably greater than 95. %, more preferably greater than 99%.
  • the strontium isotope content in each metamorphic position 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 more than 75%, more preferably more
  • R 1 , R 2 and R 3 are each independently selected from hydrazine or hydrogen.
  • R 1 is ⁇ .
  • R 4 and R 5 are each independently selected from hydrazine or hydrogen.
  • R 4 and R 5 are deuterium.
  • R 6 , R 7 , R 8 are each independently selected from hydrazine or hydrogen.
  • R 6 , R 7 and R 8 are deuterium.
  • R 9 , R 10 and R 11 are each independently selected from hydrazine or hydrogen.
  • R 10 and R 11 are deuterium.
  • R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are each independently selected from hydrazine or hydrogen.
  • R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are ⁇ .
  • R 20 , R 21 and R 22 are each independently selected from hydrazine or hydrogen.
  • R 20 , R 21 , and R 22 are ⁇ .
  • R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 are each independently selected from hydrazine or hydrogen.
  • R 28 , R 29 , R 30 , and R 31 are ⁇ .
  • the compound is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:
  • the compound does not include a non-deuterated compound.
  • the invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a substituted carbazole compound as described above, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof
  • the pharmaceutically acceptable carrier comprises a substance or an additive encapsulated in a capsule, a glidant, a sweetener, a diluent, a preservative, a dye/colorant, a flavor enhancer, a surfactant At least one of a wetting agent, a dispersing agent, a disintegrating agent, a suspending agent, a stabilizer, an isotonic agent, a solvent or an emulsifier.
  • the pharmaceutical composition is a tablet, a pill, a capsule, a powder, a granule, an ointment, an emulsion, a suspension, a solution, a suppository, an injection, an inhalant, a gel, a microsphere or Aerosol.
  • 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 present invention also provides a process for the preparation of a pharmaceutical composition
  • a pharmaceutical composition comprising the steps of: pharmaceutically acceptable carrier with a compound of formula (I) as described above, or a crystalline form thereof, a pharmaceutically acceptable salt, or a hydrate thereof Or a pharmaceutical composition of a solvate, stereoisomer, prodrug or isotopic variation.
  • the present invention further comprises other active compounds which may be selected from the group consisting of antihormonal agents (e.g., antiestrogens, antiandrogens, and aromatase inhibitors), topoisomerase I inhibition.
  • antihormonal agents e.g., antiestrogens, antiandrogens, and aromatase inhibitors
  • topoisomerase I inhibition Agents, topoisomerase II inhibitors, microtubule-targeting drugs, platinum drugs, alkylating agents, DNA damage or intercalators, antineoplastic agents, antimetabolites, other kinase inhibitors, other anti-angiogenic factors, Kinesin inhibitors, therapeutic monoclonal antibodies, inhibitors of mTOR, histone deacetylase inhibitors, farnesyltransferase inhibitors, and inhibitors of hypoxia response.
  • antihormonal agents e.g., antiestrogens, antiandrogens, and aromatase inhibitors
  • topoisomerase I inhibition Agent
  • the active ingredients of the invention may also be used in combination with other active ingredients.
  • the choice of such combination is based on the condition of the treatment, the cross-reactivity of the ingredients, and the combined pharmaceutical properties. It is also possible to administer any of the compounds of the invention in combination with one or more other active ingredients in a single dosage form for simultaneous or sequential administration to a patient.
  • Combination therapies can be administered simultaneously or sequentially. When administered continuously, the combination can be administered in two or more administrations.
  • Combination therapy can provide "synergistic effects" or “synergistic effects”, in other words, when the active ingredients are used together, the effect obtained is greater than the sum of the effects obtained by using the compounds separately.
  • the active ingredient (1) is co-formulated and administered or delivered simultaneously in a combined formulation; (2) administered as a separate formulation or administered in parallel; or (3) obtained by some other dosage regimen Synergy.
  • synergistic effects can be obtained when the compounds are administered or released sequentially, for example, as separate tablets, pills or capsules, or by separate injections of separate syringes.
  • the effective dose of each active ingredient is administered sequentially, i.e., continuously, while in combination therapy, the effective dose of two or more active ingredients is administered together.
  • the invention also provides a method of treating a disease caused by and/or associated with a disorder of protein kinase activity, particularly a PLK family, different isoforms of protein kinase C, Met, PAK-4, PAK-5 , ZC-1, STLK-2, DDR-2, Auroral, Aurora 2, Bub-1, Chk1, Chk2, HER2, raf1, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, FLT3, JAK2, IGF-R, ALK, PI3K, week kinase, Src, Abl, Akt, MAPK, ILK, MK-2, IKK-2, Cdc7, Nek, Cdk/cyclin kinase family, more particularly Aurora2, IGF-1R And ALK activity, and further particularly ALK activity, the method comprising administering to a mammal in need thereof an effective amount of a substituted carbazole compound of formula (I) as defined above.
  • the invention also provides a method of treating a disease caused by and/or associated with a disorder in which protein kinases are selected from the group consisting of ALK, ROS1, TRK1, TRK2, TRK3, etc., the method comprising breast-feeding for such a need
  • the animal is administered an effective amount of a substituted carbazole compound represented by the above formula (I).
  • a preferred method of the invention is the treatment of a disease caused by and/or associated with a disorder in protein kinase activity selected from the group consisting of cancer and cell proliferative diseases.
  • Another preferred method of the invention is the treatment of a particular type of cancer, including cancer, squamous cell carcinoma, hematopoietic tumors of the myeloid or lymphoid lineage, mesenchymal-derived tumors, central and peripheral nervous system tumors, melanoma , seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, thyroid hair follicle carcinoma and Kaposi's sarcoma.
  • cancer squamous cell carcinoma, hematopoietic tumors of the myeloid or lymphoid lineage, mesenchymal-derived tumors, central and peripheral nervous system tumors, melanoma , seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, thyroid hair follicle carcinoma and Kaposi's sarcoma.
  • Another preferred method of the invention is to treat a particular type of cancer, such as, but not limited to, breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer, gastric cancer, clear cell renal cell carcinoma, ocular pigmentation.
  • a particular type of cancer such as, but not limited to, breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer, gastric cancer, clear cell renal cell carcinoma, ocular pigmentation.
  • Melanoma multiple myeloma, rhabdomyosarcoma, Ewing sarcoma, Kaposi's sarcoma and medulloblastoma.
  • Another preferred method of the invention is the treatment of a particular type of cancer, such as, but not limited to, non-small cell lung cancer, neuroblastoma, colorectal cancer, anaplastic large cell lymphoma, cholangiocarcinoma, gastric cancer, glioblasts.
  • a particular type of cancer such as, but not limited to, non-small cell lung cancer, neuroblastoma, colorectal cancer, anaplastic large cell lymphoma, cholangiocarcinoma, gastric cancer, glioblasts.
  • Tumor leiomyosarcoma, melanoma, squamous cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, medullary thyroid carcinoma, papillary thyroid carcinoma.
  • ALK + anaplastic large cell lymphoma ALK + anaplastic large cell lymphoma (ALCL) or other indications in which ALK activity may play a role, such as neuroblastoma, rhabdomyosarcoma, glioblastoma, inflammatory Myofibroblastoma and certain types of melanoma, breast cancer, Ewing's sarcoma, retinoblastoma and non-small cell lung cancer (NSCLC).
  • ALK + anaplastic large cell lymphoma ALK + anaplastic large cell lymphoma (ALCL) or other indications in which ALK activity may play a role, such as neuroblastoma, rhabdomyosarcoma, glioblastoma, inflammatory Myofibroblastoma and certain types of melanoma, breast cancer, Ewing's sarcoma, retinoblastoma and non-small cell lung cancer (NSCLC).
  • NSCLC non-small
  • Another preferred method of the invention is the treatment of cell proliferative disorders such as, but not limited to, benign prostatic hyperplasia, familial adenoma, polyposis, neurofibromatosis, psoriasis, atherosclerosis and proliferation of vascular smooth cells Diseases associated with neointimal formation, such as restenosis after angioplasty or surgery, pulmonary fibrosis, arthritis, glomerular inflammation, retinopathy, including diabetic and neonatal retinopathy and age-related macular degeneration, eg Transplant vascular disease, acromegaly and acromegaly secondary disease that may occur after vascular or organ transplantation, and other hypertrophic diseases in which IGF/IGF-IR signaling is involved, such as fibrotic lung disease, Pathological conditions of chronic or acute oxidative stress or tissue damage induced by hyperoxia, and metabolic disorders in which elevated levels of IGF or IGF-IR activity, such as obesity, are involved.
  • the methods of the invention also provide tumor vascular transmission and metastasis inhibition.
  • the invention also provides a method of inhibiting an active ALK protein comprising contacting the protein with an effective amount of a compound of formula (I).
  • 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 (also referred to as "isotopic variants"), 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.
  • 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. In addition, heavier isotopic substitutions such as guanidine, or 2 H, are preferred in certain therapies due to their good metabolic stability, such as increased half-life or reduced dosage in vivo, and therefore may be preferred in certain circumstances. 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.
  • the compound of the present invention having the formula (I) may exist in the form of an acid addition salt, a base addition salt or a zwitter ion. Salts of the compounds are prepared during or after isolation of the compound.
  • the acid addition salts of the compounds are those derived from the reaction of the compound with an acid.
  • the present invention includes acetates, adipates, alginates, bicarbonates, citrates, aspartates, benzoates, besylate, sulfuric acid of the compounds and prodrugs thereof.
  • Hydrogen salt butyrate, camphorate, camphorsulfonate, digluconate, formate, fumarate, glycerol phosphate, glutamate, hemisulfate, heptanoate, caproic acid Salt, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylene sulfonate, methanesulfonate, naphthalene sulfonate, nicotinate, Oxalate, pamoate, pectate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetate, Tosylate and undecanoate.
  • the base addition salts of the compounds are those derived from the reaction of a compound with a hydroxide, carbonate or bicarbonate of a cation of lithium, sodium, potassium, calcium and magnesium.
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of "stereoisomer" forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the compounds of the invention may also exist in the form of tautomers. Although only one type of non-localized resonant structure may be described, it is contemplated that all such forms fall within the scope of the present invention.
  • olefin-amine tautomers may be present, and all their possible tautomeric forms fall within the scope of the invention.
  • prodrug refers to a compound that is converted in vivo to an active form having its medical effect by, for example, hydrolysis in blood.
  • a prodrug is any covalently bonded carrier which, when administered to a patient, releases the compound of the invention in vivo.
  • Prodrugs are typically prepared by modifying functional groups that cleave the prodrug in vivo to yield the parent compound.
  • Prodrugs include, for example, a compound of the invention wherein a hydroxy, amino or thiol group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amino or sulfhydryl group.
  • prodrugs include, but are not limited to, covalent derivatives of the compounds of the invention formed by the hydroxyl, amino or thiol functional groups thereof with acetic acid, formic acid or benzoic acid.
  • acetic acid formic acid or benzoic acid.
  • an ester such as a methyl ester, an ethyl ester or the like can be used.
  • the ester itself may be active and/or may hydrolyze under conditions in humans.
  • Suitable pharmaceutically acceptable in vivo hydrolysable esters include those which readily decompose in the human body to release the parent acid or its salt.
  • 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 beneficial effects of the present invention are: the compound of the present invention has excellent inhibition to protein kinases such as ALK, ROS1, TRK1, TRK2, TRK3, etc.; the compound is modified in the organism by the technique of deuteration. Metabolism gives compounds better pharmacokinetic parameter properties.
  • the dosage can be changed and a long-acting preparation can be formed to improve the applicability; the substitution of a hydrogen atom in the compound with hydrazine increases the drug concentration of the compound in the animal due to its strontium isotope effect, and improves the therapeutic effect of the drug; Substituting a hydrogen atom in a compound inhibits certain metabolites and increases the safety of the compound.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 And R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 and R 31 are each independently selected from hydrogen and hydrazine. , halogen or trifluoromethyl;
  • the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than the natural strontium isotope content.
  • the ground is greater than 95%, more preferably greater than 99%.
  • Independently selected from hydrogen, deuterium, halogen or trifluoromethyl includes R 1 being selected from hydrogen, deuterium, halogen or trifluoromethyl, R 2 is selected from hydrogen, deuterium, halogen or trifluoromethyl, and R 3 is selected from Hydrogen, hydrazine, halogen or trifluoromethyl, and so on, until R 31 is selected from hydrogen, deuterium, halogen or trifluoromethyl.
  • R 1 is hydrogen, R 1 is deuterium, R 1 is halogen (F, Cl, Br or I) or R 1 is trifluoromethyl
  • R 2 is hydrogen, R 2 is deuterium, and R 2 is Halogen (F, Cl, Br or I) or R 2 is trifluoromethyl
  • R 3 is hydrogen, R 3 is deuterium, R 3 is halogen (F, Cl, Br or I) or R 3 is trifluoromethyl
  • R 31 is hydrogen, R 31 is ⁇ , R 31 is halogen (F, Cl, Br or I) or R 31 is a trifluoromethyl group.
  • the invention relates to a compound of formula (I), wherein R 6 -R 8 are hydrogen, R 1 -R 5 , R 9 -R 31 are each independently selected from hydrogen or hydrazine, appended Provided that the compound contains at least one ruthenium atom.
  • the invention relates to a compound of formula (I), wherein R 2 -R 3 , R 6 -R 9 , R 23 -R 27 are hydrogen, R 1 , R 4 -R 5 , R 10 - R 22 and R 28 - R 31 are each independently selected from hydrogen or hydrazine, with the proviso that the compound contains at least one ruthenium atom.
  • R 4 and R 5 are the same.
  • R 10 and R 11 are the same.
  • R 12 - R 19 are the same.
  • R 20 - R 22 are the same.
  • R 28 - R 31 are the same.
  • the invention relates to a compound of formula (I), wherein R 2 -R 3 , R 6 -R 9 , R 23 -R 27 are hydrogen and R 10 and R 11 are deuterium, R 1 , R 4 -R 5 , R 12 -R 22 , R 28 -R 31 are each independently selected from hydrogen or hydrazine.
  • R 1 is hydrogen; in another specific embodiment, R 1 is deuterium; in another specific embodiment, R 4 -R 5 is hydrogen; in another specific In an embodiment, R 4 -R 5 is deuterium; in another specific embodiment, R 12 -R 19 is hydrogen; in another specific embodiment, R 12 -R 19 is deuterium; In an embodiment, R 20 -R 22 is hydrogen; in another specific embodiment, R 20 -R 22 is deuterium; in another specific embodiment, R 28 -R 31 are hydrogen; In a specific embodiment, R 28 -R 31 is deuterium.
  • the invention relates to a compound of formula (I), wherein R 2 -R 3 , R 6 -R 9 , R 23 -R 27 are hydrogen and R 12 -R 19 are deuterium, R 1 , R 4 -R 5 , R 10 -R 11 , R 20 -R 22 , R 28 -R 31 are each independently selected from hydrogen or hydrazine.
  • R 1 is hydrogen; in another specific embodiment, R 1 is deuterium; in another specific embodiment, R 4 -R 5 is hydrogen; in another specific In an embodiment, R 4 -R 5 is deuterium; in another specific embodiment, R 10 -R 11 is hydrogen; in another specific embodiment, R 10 -R 11 is deuterium; In an embodiment, R 20 -R 22 is hydrogen; in another specific embodiment, R 20 -R 22 is deuterium; in another specific embodiment, R 28 -R 31 are hydrogen; In a specific embodiment, R 28 -R 31 is deuterium.
  • the invention relates to a compound of formula (I), wherein R 2 -R 3 , R 6 -R 9 , R 23 -R 27 are hydrogen and R 20 -R 22 are deuterium, R 1 , R 4 -R 5 , R 10 -R 11 , R 12 -R 19 , R 28 -R 31 are each independently selected from hydrogen or hydrazine.
  • R 1 is hydrogen; in another specific embodiment, R 1 is deuterium; in another specific embodiment, R 4 -R 5 is hydrogen; in another specific In an embodiment, R 4 -R 5 is deuterium; in another specific embodiment, R 10 -R 11 is hydrogen; in another specific embodiment, R 10 -R 11 is deuterium; In an embodiment, R 12 -R 19 is hydrogen; in another specific embodiment, R 12 -R 19 is deuterium; in another specific embodiment, R 28 -R 31 is hydrogen; In a specific embodiment, R 28 -R 31 is deuterium.
  • the compound of the invention is selected from the group consisting of compounds of the formula:
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A mixture of a racemate and a mixture rich in one or more stereoisomers is included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the organic compound can form a complex with the solvent in which it reacts or precipitates or crystallizes from the solvent. These complexes are referred to as "solvates.” When the solvent is water, the complex is referred to as a "hydrate.”
  • the present invention encompasses all solvates of the compounds of the invention.
  • solvate means a form of a compound or a salt thereof which is usually combined with a solvent which is formed by a solvolysis reaction. This physical association can include hydrogen bonding.
  • Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds described herein can be prepared, for example, in crystalline form, and can be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes solvates and isolatable solvates in solution. Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that binds to water. Generally, the ratio of the number of water molecules contained in the hydrate of the compound to the number of molecules of the compound in the hydrate is determined.
  • a hydrate of a compound can be represented, for example, by the formula R.x H 2 O, wherein R is the compound, and x is a number greater than zero.
  • a given compound can form more than one hydrate type, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, for example, a hemihydrate (R ⁇ 0.5H 2 ) O)) and polyhydrate (x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)).
  • the compounds of the invention may be in amorphous or crystalline form (polymorph). Furthermore, the compounds of the invention may exist in one or more crystalline forms. Accordingly, the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • polymorph refers to a crystalline form (or a salt, hydrate or solvate thereof) of a compound in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can result in a crystalline form that predominates. Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the invention also includes isotopically-labeled compounds which are equivalent to those described for formula (I), but one or more of the atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number common in nature.
  • isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18, respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Compounds of the invention, prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs containing such isotopes and/or other isotopes of other atoms are within the scope of the invention.
  • Certain isotopically-labeled compounds of the invention, such as those incorporating radioisotopes (e.g., 3 H and 14 C), are useful in drug and/or substrate tissue distribution assays. Ruthenium, i.e., 3 H and carbon-14, i.e., 14 C isotopes, are particularly preferred because they are easy to prepare and detect.
  • isotopically labeled compounds of the formula (I) of the present invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopes in the following schemes and/or the procedures disclosed in the examples and preparations. Labeled reagents.
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” as used herein refers to a compound which is converted in vivo to an active form thereof having a medical effect by, for example, hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: Solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each introduction This article serves as a reference.
  • a prodrug is any covalently bonded compound of the invention which, when administered to a patient, releases the parent compound in vivo.
  • Prodrugs are typically prepared by modifying functional groups in such a way that the modifications can be cleaved by routine manipulation or in vivo to yield the parent compound.
  • Prodrugs include, for example, a compound of the invention wherein a hydroxy, amino or thiol group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amino or thiol group.
  • representative examples of prodrugs include, but are not limited to, the hydroxy, thiol and amino functional acetate/amide, formate/amide and benzoate/amide derivatives of the compounds of formula (I).
  • an ester such as a methyl ester, an ethyl ester or the like can be used.
  • the ester itself may be active and/or may hydrolyze under conditions in humans.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or a salt thereof.
  • the compounds of the invention can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes, such as those in the schemes below.
  • the reaction for preparing the compound of the present invention can be carried out in a suitable solvent, and a solvent can be easily selected by those skilled in the art of organic synthesis. Suitable solvents can be substantially unreactive with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out (for example, at temperatures ranging from solvent freezing temperatures to solvent boiling temperatures).
  • the given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • the skilled person can select the solvent for the particular reaction step depending on the particular reaction step.
  • the preparation of the compounds of the invention may involve protection and removal protection of different chemical groups.
  • One skilled in the art can readily determine whether protection and removal of protection and the choice of appropriate protecting groups are desired.
  • the chemistry of the protecting group can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.
  • the reaction can be monitored according to any suitable method known in the art.
  • spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (eg 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (eg UV-visible), mass spectrometry (MS) or by chromatography Methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) are used to monitor product formation.
  • NMR nuclear magnetic resonance
  • IR infrared
  • MS mass spectrometry
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • compositions, formulations and kits are provided.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active component.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active component.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active component.
  • a pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin) ), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-e
  • kits e.g., pharmaceutical packs.
  • Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents) Suitable container).
  • first and second containers eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents
  • kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent.
  • a compound of the invention provided in a first container and a second container is combined with other therapeutic agents to form a unit dosage form.
  • the pharmaceutical composition provided by the present invention can be administered by a variety of routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intrasynovial administration, intrasternal administration. , intracerebroventricular administration, intralesional administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of compound actually administered can be determined by the physician. .
  • the compound provided herein is administered to a subject at risk of developing the condition, typically based on a physician's recommendation and administered under the supervision of a physician, at the dosage level as described above.
  • Subjects at risk of developing a particular condition typically include subjects with a family history of the condition, or those subjects that are particularly susceptible to developing the condition by genetic testing or screening.
  • long-term administration can also be administered chronically.
  • Long-term administration refers to administration of a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continuously administered indefinitely, For example, the rest of the subject.
  • chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, for example, within a therapeutic window.
  • a pharmaceutical composition of the present invention can be further delivered using various methods of administration.
  • a pharmaceutical composition can be administered by bolus injection, for example, to rapidly increase the concentration of a compound in the blood to an effective level.
  • the bolus dose will depend on the target systemic level of the active ingredient, for example, an intramuscular or subcutaneous bolus dose will allow the active component to be slowly released, while a bolus delivered directly to the vein (eg, via IV IV drip) can be more Delivered rapidly so that the concentration of the active ingredient in the blood is rapidly increased to an effective level.
  • the pharmaceutical composition can be administered in a continuous infusion form, for example, by IV intravenous drip to provide a steady state concentration of the active ingredient in the subject's body.
  • a bolus dose of the pharmaceutical composition can be administered first, followed by continued infusion.
  • Oral compositions can be in the form of a bulk liquid solution or suspension or bulk powder. More generally, however, the composition is provided in unit dosage form for ease of precise dosing.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active ingredient suitable to produce the desired therapeutic effect with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of the liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions.
  • the compound will generally be a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being useful for forming the desired form of administration.
  • a carrier or excipient and a processing aid is provided in unit dosage form for ease of precise dosing.
  • a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, each preferably providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • a transdermal dose is generally selected in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably about 0.1. To about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the injection dose level ranges from about 1 mg/kg/hr to at least 10 mg/kg/hr from about 1 to about 120 hours, especially 24 to 96 hours.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be administered.
  • the maximum total dose cannot exceed about 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous vehicles as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may include, for example, any of the following components, or a compound having similar properties: a binder, for example, microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as mint, water Methyl salicylate or orange flavoring.
  • a binder for example, microcrystalline cellulose, tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn star
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound will typically be a minor component, often from about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
  • the active component When formulated as an ointment, the active component is typically combined with a paraffin or water miscible ointment base.
  • the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and generally include other ingredients for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of the invention.
  • transdermal administration can be accomplished using a reservoir or a porous membrane type, or a patch of a plurality of solid matrices.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials and processing techniques, etc. are set forth in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, part 8 of which is incorporated herein by reference.
  • the compounds of the invention may also be administered in sustained release form or from a sustained release delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention further relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are alpha-, beta- and gamma-cyclodextrins consisting of 6, 7 and 8 alpha-1,4-linked glucose units, respectively, optionally including one on the attached sugar moiety. Or a plurality of substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, sulfobutylether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation comprises hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • the compounds of the invention are useful for treating cancer caused by dysregulation of human or non-human protein kinases.
  • the protein kinase is selected from the group consisting of ALK, ROS1, TRK1, TRK2, TRK3.
  • the compounds of the invention are inhibitors of at least one mutant of ALK, ROS1, TRK1, TRK2, TRK3 and are therefore suitable for use in the treatment of one or more ALK, ROS1, TRK1, TRK2, TRK3 mutants (eg deletion mutations, Activating mutations, resistance mutations or combinations thereof, specific examples include L1196M, V513M, F598L, G595R, G667C, G667A, G667S, V619M, F633L, G639R, G709C, G709A, G709S, V603M, F617L, G623R, G696C, G696A, G696S One or more disorders associated with the activity.
  • the invention provides a method of treating a mutated ALK, ROS1, TRK1, TRK2, TRK3 mediated disorder comprising administering a compound of the invention to a patient in need thereof, or pharmaceutically acceptable thereof a salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotope derivative, or a step of administering a pharmaceutical composition of the invention.
  • the compounds of the invention will be, but are not limited to, administered to a patient using an effective amount of a compound or composition of the invention to prevent or treat a proliferative disorder in a patient.
  • diseases include cancer, especially non-small cell lung cancer, neuroblastoma, colorectal cancer, anaplastic large cell lymphoma, cholangiocarcinoma, gastric cancer, glioblastoma, leiomyosarcoma, melanoma, squamous cell lung cancer. , ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, medullary thyroid carcinoma, papillary thyroid cancer.
  • the compounds of the present invention are also useful in veterinary treatment of pets, introduced species of animals, and farm animals, including mammals, rodents, and the like. Other examples of animals include horses, dogs, and cats.
  • the compounds of the invention include pharmaceutically acceptable derivatives thereof.
  • 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.
  • Boc 2 O (23.6 g, 108 mmol) and DMAP (2 g, 16.3 mmol) were added sequentially to a solution of 4-fluoro-2-nitrobenzoic acid (10 g, 54 mmol) in dichloromethane (200 mL).
  • the reaction was stirred for 30 minutes, tert-butanol (40 g, 540 mmol) was added, and the mixture was stirred at room temperature overnight. After adding 100 mL of water and extracting with dichloromethane (100 mL ⁇ 3), the organic phase was washed with 1M HCl (40 mL) and brine (40 mL).
  • Trifluoroacetic acid (3 mL) was added to a solution of the compound 13 (1.0 g, 2.11 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature overnight. The solvent and the trifluoroacetic acid were evaporated under reduced pressure. Diethyl ether (20 mL) was added and stirred for 20 min, and a large white solid was precipitated, filtered, and the filter cake was washed with diethyl ether to give a white solid 940 mg (yield: 83.8%).
  • LC-MS (APCI): m / z 419.2 (M + 1) +.
  • Trifluoroacetic acid (3 mL) was added to a solution of Compound 22 (1.0 g, 2.11 mmol) in dichloromethane (10 mL). The solvent and the trifluoroacetic acid were evaporated under reduced pressure. Diethyl ether (20 mL) was added and stirred for 20 min, and a large white solid was precipitated, filtered, and the filter cake was washed with diethyl ether to give a white solid 940 mg (yield: 83.8%).
  • LC-MS (APCI): m/z 424.2 (M+1) + .
  • Trifluoroacetic acid (1.5 mL) was added to a solution of Compound 29 (0.5 g, 1.06 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature overnight. The solvent and the trifluoroacetic acid were evaporated under reduced pressure. Diethyl ether (20 mL) was then evaporated and evaporated, and then, and the mixture was stirred for 20 minutes, and then filtered and washed with diethyl ether to afford 470 mg of white solid.
  • LC-MS (APCI): m/z 427.2 (M+1) + .
  • Trifluoroacetic acid (3 mL) was added to a solution of Compound 37 (1.0 g, 2.11 mmol) in dichloromethane (3 mL), and the mixture was stirred at room temperature overnight. The solvent and the trifluoroacetic acid were evaporated under reduced pressure. Diethyl ether (20 mL) was added and stirred for 20 min, and a large white solid was precipitated, filtered, and the filter cake was washed with diethyl ether to give a white solid 940 mg (yield: 83.8%).
  • LC-MS (APCI): m / z 416.2 (M + 1) +.
  • N-butanol (275 mL), compound 45 (2.7 g, 15.96 mmol) and hydrazine hydrate (2.74 g, 54.8 mmol) were sequentially added to a 100 mL single-mouth flask equipped with a magnetic stirring and a condenser. The mixture was heated to 120 ° C, and stirred while stirring. The reaction was overnight. The mixture was cooled to room temperature, and the reaction mixture was concentrated. LC-MS (APCI):.
  • Acetic acid (30 mL), compound 35 (3.0 g, 10.31 mmol), compound 48 (2.69 g, 15.46 mmol), and zinc powder (2.68 g, 41.22 mmol) were sequentially added to a 50 mL one-neck flask equipped with a magnetic stirring and condensing tube. The mixture was warmed to 100 ° C, and the reaction was stirred overnight under a nitrogen atmosphere.
  • Triethylamine (111 mg, 1.1 mmol) was added to a solution of compound 52 (260 mg, 0.686 mmol The reaction was stirred for 4 hours. Water (10 mL) was added, and the organic layer was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Potassium carbonate (0.42 g, 3.0 mmol) was added to a methanol/aqueous solution (11 mL, 10/1) of Compound 58 (0.66 g, 1.0 mmol), which was stirred under magnetic stirring, and the mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. After adding water (30 mL), a large amount of a white solid was evaporated, filtered, washed with water (10mL), dissolved in dichloromethane (20mL), dried and concentrated.
  • Test compounds were dissolved in DMSO to make a 20 mM stock solution. Compounds were diluted to 0.1 mM in DMSO (100 times the final concentration of the dilution) before use and diluted in 3 folds at 11 concentrations. Dilute to 4 times the final concentration of the dilution solution with the buffer.
  • the compounds of the present invention provides significant protein kinase inhibitory activity, typically less than 10nM having the IC 50.
  • a compound of the present invention exhibits a superior inhibitory activity against an ALK WT mutant (IC 50 less than 10 nM) compared to a compound without a deuterated Entrectinib, and exhibits an inhibitor activity comparable to Entrectinib to an ALK L119M mutant, particularly It exhibits strong inhibitory activity against TRKA/B/C (IC 50 less than 1 nM).
  • RPMI-1640 medium (GIBCO, catalog number A10491-01), fetal bovine serum (GIBCO, catalog number 10099141), antibiotic (Penicillin-Streptomycin), IL-3 (PeproTech), puromycin; cell line : Ba/F3, Ba/F3Bcr-Abl T315I (purchased from American Standard Biological Collection Center, ATCC), live cell assay kit CellTiter-Glo4 (Promega, catalog number G7572), 96-well black-wall clear flat-bottom cell culture plate ( Corning, catalog number 3340).
  • the compounds of the present invention all exhibited excellent anticancer activity for inhibiting the growth of cancer cells expressing the ALK mutant L1196M.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat 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 metabolic stability of human and rat liver microsomes was evaluated by simultaneously testing the compounds of the present invention and their compounds without deuteration.
  • the half-life and liver intrinsic clearance as indicators of metabolic stability are shown in Table 1.
  • the undeuterated compound Entrectinib was used as a control sample in Table 1.
  • the compounds of the present invention can significantly improve metabolic stability by comparison with the undeuterated compound Entrectinib.
  • SD rat grade SPF grade
  • Weight range 180 ⁇ 220g (actual weight range is 187 ⁇ 197g)
  • the pharmacokinetics of the male SD rats were determined by the non-compartmental statistical moment theory to obtain the test compound (3 mg/kg) after the IgG administration of the non-compartmental statistical moment theory. parameter.

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Abstract

本发明涉及抑制激酶活性的吲唑类化合物，以及涉及它们的制备和用途。具体地，该发明公开了式(I)所示的吲唑类化合物，或其晶型、前药、药学上可接受的盐、立体异构体、互变异构体、溶剂合物或水合物的药物组合物。本发明化合物及包含该化合物的组合物对激酶蛋白具有优异的抑制性，同时具有更好的药代动力学参数特性，能够提高化合物在动物体内的药物浓度，以及提高药物疗效和安全性。

Description

用于抑制激酶活性的吲唑类化合物及其组合物及应用 技术领域
本发明属于医药技术领域，具体地，本发明涉及取代的吲唑类化合物，具有抑制蛋白质激酶的活性。更具体而言，本发明涉及某些氘取代的N-(5-(3,5-二氟苄基)-1H-吲唑-3-基)-4-(4-甲基哌嗪-1-yl)-2-((四氢-2H-吡喃-4-基)氨基)苯甲酰胺，这些氘取代的化合物及其组合物可用于治疗ALK、ROS1、TRK1、TRK2或TRK3等介导的相关癌症，且这些氘取代的化合物具有更优良的药代动力学性质。
背景技术
蛋白激酶(PK)的功能失常是许多疾病的标志。与人类癌症有关的致癌基因和原癌基因有一大部分编码PK。增强的PK活性还与许多非恶性疾病有关，例如良性***增生、家族性腺瘤病、息肉病、神经纤维瘤病、银屑病、与动脉粥样硬化有关的血管平滑细胞增殖、肺纤维化、关节炎、肾小球肾炎和手术后的狭窄和再狭窄。
PK还与炎症性状况以及病毒和寄生虫的增殖有关。PK可能还在神经变形疾病的发病机理和发展中起到重要作用。
关于PK故障或失调的一般参考文献，参见例如Current Opinionin Chemical Biology 1999,3,459-465。
Ignyta公司抗肿瘤新药Entrectinib于2017年5月份获得FDA授予的突破性疗法认定，治疗NTRK基因融合阳性，局部晚期或转移性实体瘤成人和儿童患者，这些患者在接受现有疗法后疾病仍进展，或者没有标准疗法。Entrectinib是一种新型的具有中枢神经活性的口服酪氨酸激酶抑制剂(tyrosine kinase inhibitor，TKI)，靶向含有NTRK1/2/3，ROS1或ALK基因融合突变的肿瘤。
Entrectinib是目前唯一临床证实具有活性、针对原发性和转移性中枢神经***癌症的酪氨酸激酶抑制剂，并且没有不良脱靶效应。该候选药物正在进行2期临床试验STARTRK-2。该试验是一个全球多中心、开放标签、注册相关的2期临床试验，使用精准医学的“篮子设计”(basket design)，入组时会对肿瘤患者样本进行基因突变筛选，根据肿瘤类型和基因融合，患者将被分配到不同的“篮子”进行治疗。这种“篮子设计”可以纳入一系列不同的肿瘤类型，验证Entrectinib针对分子靶标的临床效果。
已知较差的吸收、分布、代谢和/或***(ADME)性质是导致许多候选药物临床试验失败的主要原因。当前上市的许多药物也由于较差的ADME性质限制了它们的应用范围。药物的快速代谢会导致许多本来可以高效治疗疾病的药物由于过快的从体内代谢清除掉而难以成药。频繁或高剂量服药虽然有可能解决药物快速清除的问题，但该方法会带来诸如病人依从性差、高剂量服药引起的副作用及治疗成本上升等问题。另外，快速代谢的药物也可能会使患者暴露于不良的毒性或反应性代谢物中。
因此，该领域对多数肿瘤类型具有广泛治疗潜力，并且目前该领域缺少治疗手段，存在明显的未满足临床需求。
发明内容
针对以上技术问题，本发明公开了一种新型的氘取代的吲唑类化合物、药物组合物及其应用，其具有更好的激酶抑制活性和/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：
一种取代的吲唑类化合物，其特征在于：如式(I)所示的吲唑化合物、或其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物：
Figure PCTCN2018092570-appb-000001
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、 R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30和R 31相互独立地选自氢、氘、卤素或三氟甲基；
附加条件是，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30和R 31中至少一个是氘代的或氘。
采用此技术方案，氘在药物分子中的形状和体积与氢基本上相同，如果药物分子中氢被选择性替换为氘，氘代药物一般还会保留原来的生物活性和选择性。同时发明人经过实验证实，碳氘键的结合比碳氢键的结合更稳定，可直接影响一些药物的吸收、分布、代谢和***等属性，从而提高药物的疗效、安全性和耐受性。
优选的，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R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30和R 31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％。
优选的，式(I)中化合物的R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30和R 31中，至少其中一个R含氘，更佳地两个R含氘，更佳地三个R含氘，更佳地四个R含氘，更佳地五个R含氘，更佳地六个R含氘，更佳地七个R含氘，更佳地八个R含氘，更佳地九个R含氘，更佳地十个R含氘，更佳地十一个R含氘，更佳地十二个R含氘，更佳地十三个R含氘，更佳地十四个R含氘，更佳地十五个R含氘，更佳地十六个R含氘，更佳地十七个R含氘，更佳地十八个R含氘，更佳地十九个R含氘，更佳地二十个R含氘，更佳地二十一个R含氘，更佳地二十二个R含氘，更佳地二十三个R含氘，更佳地二十四个R含氘，更佳地二十五个R含氘，更佳地二十六个R含氘，更佳地二十七个R含氘，更佳地二十八个R含氘，更佳地二十九个R含氘，更佳地三十个R含氘，更佳地三十一个R含氘。
作为本发明的进一步改进，R 1、R 2、R 3各自独立地选自氘或氢。
在另一优选例中，R 1是氘。
作为本发明的进一步改进，R 4、R 5各自独立地选自氘或氢。
在另一优选例中，R 4、R 5是氘。
作为本发明的进一步改进，R 6、R 7、R 8各自独立地选自氘或氢。
在另一优选例中，R 6、R 7、R 8是氘。
作为本发明的进一步改进，R 9、R 10、R 11各自独立地选自氘或氢。
在另一优选例中，R 10、R 11是氘。
作为本发明的进一步改进，R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19各自独立地选自氘或氢。
在另一优选例中，R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19是氘。
作为本发明的进一步改进，R 20、R 21、R 22各自独立地选自氘或氢。
在另一优选例中，R 20、R 21、R 22是氘。
作为本发明的进一步改进，R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31各自独立地选自氘或氢。
在另一优选例中，R 28、R 29、R 30、R 31是氘。
作为本发明的进一步改进，所述化合物选自下述化合物或其药学上可接受的盐：
Figure PCTCN2018092570-appb-000002
Figure PCTCN2018092570-appb-000003
Figure PCTCN2018092570-appb-000004
Figure PCTCN2018092570-appb-000005
Figure PCTCN2018092570-appb-000006
在另一优选例中，所述化合物不包括非氘代化合物。
本发明还公开了一种药物组合物，其含有药学上可接受的载体和如上述所述的取代的吲唑类化合物，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、互变异构体、前药或同位素变体的药物组合物。
作为本发明的进一步改进，所述药学上可接受的载体包括封入胶囊的物质或添加剂、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、溶剂或乳化剂中的至少一种。
作为本发明的进一步改进，所述药物组合物为片剂、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、微球或气溶胶。
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、***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。
本发明还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如上所述的式(I)的化合物，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。
作为本发明的进一步改进，其还包含其他活性化合物，所述活性化合物可选自：抗激素药(例如抗***药、抗雄激素药、和芳香酶抑制剂)、拓扑异构酶I抑制剂、拓扑异构酶II抑制剂、靶向微管的药物、铂类药物、烷化剂、DNA损伤或嵌入剂、抗肿瘤药、抗代谢药、其它激酶抑制剂、其它抗血管生成因子、驱动蛋白抑制剂、治疗用单克隆抗体、mTOR的抑制剂、组蛋白脱乙酰基酶抑制剂、法尼基转移酶抑制剂和缺氧响应的抑制剂。
本发明的活性成分也可与其他活性成分联合使用。这种组合的选择基于治疗的情况、成份的交叉反应性和联合的药学性质。还可能使本发明的任意化合物联合一种或多种其他活性成分，以单一剂型同时或连续对患者给药。联合治疗可以同时或连续给药方案给药。当连续给药时，联合可以两次或更多次给药施用。联合治疗可提供“增效作用”或“协同作用”，换言之，当活性成分一起使用获得的效果大于分开使用化合物所得效果之和。当活性成分：(1)被共同配制和给药或以组合制剂形式同时递送；(2)作为独立的制剂交替给药或平行给药；或(3)通过一些其他给药方案时，可获得协同作用。当以交替治疗递送时，当化合物序贯给药或释放，例如以独立的片剂、丸剂或胶囊剂，或通过单独注射器的不同注射，可获得协同作用。通常，在交替治疗期间，每种活性成分有效剂量被序贯，即连续地给予，而在联合治疗中，两种或更多种活性成分的有效剂量共同给予。
本发明还提供治疗由蛋白激酶活性失调引起的和/或与之相关的疾病的方法，所述蛋白激酶特别是PLK家族、不同同工型的蛋白激酶C、Met，PAK-4，PAK-5，ZC-1，STLK-2，DDR-2，Auroral，Aurora 2，Bub-1，Chk1，Chk2，HER2，raf1，MEK1，MAPK，EGF-R，PDGF-R，FGF-R，FLT3，JAK2，IGF-R，ALK，PI3K，week激酶，Src，Abl，Akt，MAPK，ILK，MK-2，IKK-2，Cdc7，Nek，Cdk/细胞周期蛋白激酶家族，更特别地是Aurora2，IGF-1R和ALK活性，以及进一步特别地是ALK活性，所述方法包括对有此需要的哺乳动物给予有效量的上述定义的式(I)表示的取代吲唑化合物。
本发明还提供治疗由蛋白激酶活性失调引起的和/或与之相关的疾病的方法，所述蛋白激酶选自ALK、ROS1、TRK1、TRK2、TRK3等，所述方法包括对有此需要的哺乳动物给予有效量的上述定义的式(I)表示的取代吲唑化合物。
本发明的优选方法是治疗由蛋白激酶活性失调引起的和/或与之相关的疾病，所述疾病选自癌症和细胞增殖疾病。
本发明的另一种优选方法是治疗具体类型的癌症，包括癌、鳞状细胞癌、骨髓样或淋巴样谱系的造血性肿瘤，间质来源的肿瘤，中枢和外周神经***肿瘤，黑素瘤，***瘤，畸胎癌，骨肉 瘤，着色性干皮病，甲状腺毛囊癌和卡波西肉瘤。
本发明的另一种优选方法是治疗具体类型的癌症，例如，但不限于乳腺癌，肺癌，结直肠癌，***癌，卵巢癌，子宫内膜癌，胃癌，透明细胞肾细胞癌，眼色素层黑素瘤，多发性骨髓瘤，横纹肌肉瘤，尤因肉瘤，卡波西肉瘤和髓母细胞瘤。
本发明的另一种优选方法是治疗具体类型的癌症，例如，但不限于非小细胞肺癌、神经母细胞瘤、结肠直肠癌、间变性大细胞淋巴瘤、胆管癌、胃癌、成胶质细胞瘤、平滑肌肉瘤、黑素瘤、鳞状细胞肺癌、卵巢癌、胰腺癌、***癌、乳腺癌、甲状腺髓样癌、甲状腺***状癌。
本发明的另一种优选方法是治疗ALK+间变性大细胞淋巴瘤(ALCL)或其中ALK活性可起作用的其它适应症，如神经母细胞瘤，横纹肌肉瘤，胶质母细胞瘤，炎性成肌纤维细胞瘤和某些类型的黑素瘤，乳腺癌，尤因肉瘤，视网膜母细胞瘤和非小细胞肺癌(NSCLC).
本发明的另一种优选方法是治疗细胞增殖疾病，例如，但不限于良性***增生，家族性腺瘤病，息肉病，神经纤维瘤病，银屑病，动脉粥样硬化和与血管平滑细胞增殖和新生内膜形成有关的疾病，例如血管成形术或手术后的再狭窄，肺纤维化，关节炎，肾小球炎症，视网膜病变，包括糖尿病性和新生儿视网膜病变和老年性黄斑变性，例如可能在血管或器官移植后发生的移植血管疾病，肢端肥大症和肢端肥大症继发性病症，以及其中涉及IGF/IGF-IR信号传导的其它肥大性疾病，例如纤维化肺疾病，涉及慢性或急性氧化性应激的病理学情况或高氧症诱发的组织损伤，和其中涉及升高的IGF水平或IGF-IR活性的代谢障碍，例如肥胖。
另外，本发明的方法还提供了肿瘤血管发送和转移抑制。
本发明还提供了抑制活性ALK蛋白的方法，包括使所述蛋白质接触有效量的式(I)的化合物。
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(也称为“同位素变体”)，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。其中含有上述同位素或其他同位素原子的 本发明的式(I)的化合物或其多晶型、药学上可接受的盐、前药、立体异构体、同位素变体、水合物或溶剂合物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。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。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。
本发明具有式(I)的化合物可以以酸加成盐、碱加成盐或两性离子形态存在。化合物的盐是在化合物的分离期间或纯化之后制备的。化合物的酸加成盐是衍生自化合物与酸反应的那些盐。例如，本发明包括化合物和其前体药物的乙酸盐、己二酸盐、藻酸盐、碳酸氢盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甲酸盐、富马酸盐、甘油磷酸盐、谷氨酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、乳糖酸盐、乳酸盐、马来酸盐、均三甲苯磺酸盐、甲磺酸盐、萘磺酸盐、烟酸盐、草酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、磷酸盐、苦味酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、三氯乙酸盐、对甲苯磺酸盐和十一烷酸盐。化合物的碱加成盐是衍生自化合物与锂、钠、钾、钙和镁等的阳离子的氢氧化物、碳酸盐或碳酸氢盐反应的那些盐。
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种“立体异构体”形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
在某些情况中，本发明化合物也可能以互变异构体的形式存在。尽管仅有一种非定域共振结构可能被描述，但设想所有的这类形式都落在本发明的保护范围内。例如，对于嘌呤、嘧啶、咪唑、胍、脒和四唑***而言，烯-胺互变异构体可能存在，并且所有它们可能的互变异构形式都落在本发明保护范围内。
术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。前药为任何共价键合的载体，当将这种前药给予患者时，其在体内释放本发明化合物。通常通过修饰官能团来制备前药，该修饰使得前药在体内裂解产生母体化合物。前药包括，例如，其中羟基、氨 基或巯基与任意基团键合的本发明化合物，当将其给予患者时，可以裂解形成羟基、氨基或巯基。因此，前药的代表性实例包括但不限于，本发明化合物通过其中的羟基、氨基或巯基官能团与乙酸、甲酸或苯甲酸形成的共价衍生物。另外，在羧酸(-COOH)的情况下，可以使用酯，例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯包括容易在人体中分解而释放母体酸或其盐的那些。
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。
与现有技术相比，本发明的有益效果为：本发明的化合物对ALK、ROS1、TRK1、TRK2、TRK3等蛋白激酶具有优异的抑制性；通过氘化这一技术改变化合物在生物体中的代谢，使化合物具有更好的药代动力学参数特性。在这种情况下，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，提高化合物在动物体内的药物浓度，提高了药物疗效；用氘取代化合物中的氢原子，可以抑制某些代谢产物，提高了化合物的安全性。
具体实施方式
化合物
本发明提供式(I)化合物，或其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物：
Figure PCTCN2018092570-appb-000007
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30和R 31相互独立地选自氢、氘、卤素或三氟甲基；
附加条件是，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30和R 31中至少一个是氘代的或氘。
作为本发明的优选实施方案，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％。
在具体实施方案中，“R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30和R 31相互独立地选自氢、氘、卤素或三氟甲基”包括R 1选自氢、氘、卤素或三氟甲基，R 2选自氢、氘、卤素或三氟甲基，R 3选自氢、氘、卤素或三氟甲基，以此类推，直至R 31选自氢、氘、卤素或三氟甲基。更具体地，包括R 1为氢、R 1为氘、R 1为卤素(F、Cl、Br或I)或R 1为三氟甲基，R 2为氢、R 2为氘、R 2为卤素(F、Cl、Br或I)或R 2为三氟甲基，R 3为氢、R 3为氘、R 3为卤素(F、Cl、Br或I)或R 3为三氟甲基，以此类推，直至R 31为氢、R 31为氘、R 31为卤素(F、Cl、Br或I)或R 31为三氟甲基的技术方案。
在优选地实施方案中，本发明涉及一种式(I)的化合物，其中，R 6-R 8为氢，R 1-R 5、R 9-R 31各自独立地选自氢或氘，附加条件是所述化合物至少含有一个氘原子。
在优选地实施方案中，本发明涉及一种式(I)的化合物，其中，R 2-R 3、R 6-R 9、R 23-R 27是氢，R 1、R 4-R 5、R 10-R 22、R 28-R 31各自独立地选自氢或氘，附加条件是所述化合物至少含有一个氘原子。
在优选地实施方案中，R 4和R 5是相同的。
在优选地实施方案中，R 10和R 11是相同的。
在优选地实施方案中，R 12-R 19是相同的。
在优选地实施方案中，R 20-R 22是相同的。
在优选地实施方案中，R 28-R 31是相同的。
在优选地实施方案中，本发明涉及一种式(I)的化合物，其中，R 2-R 3、R 6-R 9、R 23-R 27是氢，R 10和R 11是氘，R 1、R 4-R 5、R 12-R 22、R 28-R 31各自独立地选自氢或氘。在另一具体的实施方案中，R 1是氢；在另一具体的实施方案中，R 1是氘；在另一具体的实施方案中，R 4-R 5是氢；在另一具体的 实施方案中，R 4-R 5是氘；在另一具体的实施方案中，R 12-R 19是氢；在另一具体的实施方案中，R 12-R 19是氘；在另一具体的实施方案中，R 20-R 22是氢；在另一具体的实施方案中，R 20-R 22是氘；在另一具体的实施方案中，R 28-R 31是氢；在另一具体的实施方案中，R 28-R 31是氘。
在优选地实施方案中，本发明涉及一种式(I)的化合物，其中，R 2-R 3、R 6-R 9、R 23-R 27是氢，R 12-R 19是氘，R 1、R 4-R 5、R 10-R 11、R 20-R 22、R 28-R 31各自独立地选自氢或氘。在另一具体的实施方案中，R 1是氢；在另一具体的实施方案中，R 1是氘；在另一具体的实施方案中，R 4-R 5是氢；在另一具体的实施方案中，R 4-R 5是氘；在另一具体的实施方案中，R 10-R 11是氢；在另一具体的实施方案中，R 10-R 11是氘；在另一具体的实施方案中，R 20-R 22是氢；在另一具体的实施方案中，R 20-R 22是氘；在另一具体的实施方案中，R 28-R 31是氢；在另一具体的实施方案中，R 28-R 31是氘。
在优选地实施方案中，本发明涉及一种式(I)的化合物，其中，R 2-R 3、R 6-R 9、R 23-R 27是氢，R 20-R 22是氘，R 1、R 4-R 5、R 10-R 11、R 12-R 19、R 28-R 31各自独立地选自氢或氘。在另一具体的实施方案中，R 1是氢；在另一具体的实施方案中，R 1是氘；在另一具体的实施方案中，R 4-R 5是氢；在另一具体的实施方案中，R 4-R 5是氘；在另一具体的实施方案中，R 10-R 11是氢；在另一具体的实施方案中，R 10-R 11是氘；在另一具体的实施方案中，R 12-R 19是氢；在另一具体的实施方案中，R 12-R 19是氘；在另一具体的实施方案中，R 28-R 31是氢；在另一具体的实施方案中，R 28-R 31是氘。
在优选地实施方案中，本发明化合物选自下式结构的化合物：
Figure PCTCN2018092570-appb-000008
Figure PCTCN2018092570-appb-000009
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
本领域技术人员将理解，有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括包括水、甲醇、乙醇、乙酸、DMSO、THF、***等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R·x H 2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R·0.5H 2O))和多水合物(x为大于1的数，例如，二水合物(R·2H 2O)和六水合物(R·6H 2O))。
本发明化合物可以是无定形或结晶形式(多晶型)。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。
本发明还包括同位素标记的化合物，它们等同于式(I)所述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如 3H和 14C)的那些可用于药物和/或底物组织分布测定。氚、即 3H和碳-14、即 14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即 2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(I)化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
此外，前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的前药描述于T.Higuchi和V.Stella，Prodrugs as Novel Delivery Systems，A.C.S.Symposium Series的Vol.14，Edward B.Roche，ed.，Bioreversible Carriers in Drug Design，American Pharmaceutical Association and Pergamon Press，1987，以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery：solubility limitations overcome by the use of prodrugs”，Advanced Drug Delivery Reviews(1996)19(2)115-130，每篇引入本文作为参考。
前药为任何共价键合的本发明化合物，当将这种前药给予患者时，其在体内释放母体化合物。通常通过修饰官能团来制备前药，修饰是以使得该修饰可以通过常规操作或在体内裂解产生母体化合物的方式进行的。前药包括，例如，其中羟基、氨基或巯基与任意基团键合的本发明化合物，当将其给予患者时，可以裂解形成羟基、氨基或巯基。因此，前药的代表性实例包括(但不限于)式(I)化合物的羟基、巯基和氨基官能团的乙酸酯/酰胺、甲酸酯/酰胺和苯甲酸酯/酰胺衍生物。另外，在羧酸(-COOH)的情况下，可以使用酯，例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯基包括容易在人体中分解而释放母体酸或其盐的那些基团。
合成
本发明化合物(包括其盐)可使用已知有机合成技术来制备，且可按照多种可能合成途径中的任一种(诸如下文方案中的那些)来合成。用于制备本发明化合物的反应可在合适的溶剂中进行，有机合成领域的技术人员可容易地选择溶剂。合适的溶剂可在进行反应的温度(例如，在溶剂结冻温度至溶剂沸点温度范围内的温度)下与起始物质(反应物)、中间体或产物实质上不反应。既定反应可在一种溶剂或一种以上溶剂的混合物中进行。技术人员可依据具体反应步骤来选择用于具体反应步骤的溶剂。
本发明化合物的制备可涉及不同化学基团的保护和去除保护。本领域技术人员可容易地判定是否需要保护和去除保护以及适当保护基的选择。保护基的化学性质可参见例如Wuts和Greene，Protective Groups in Organic Synthesis，第4版，John Wiley&Sons：New Jersey，(2006)，其通过引用整体并入本文中。
可按照本领域已知任何合适的方法来监测反应。例如，可通过光谱手段(诸如核磁共振(NMR)光谱法(例如 1H或 13C)、红外(IR)光谱法、分光光度法(例如，UV-可见光)、质谱(MS))或通过 色谱方法(诸如高效液相色谱法(HPLC)或薄层色谱法(TLC))来监测产物形成。
药物组合物、制剂和试剂盒
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的活性组分。在一些实施方案中，所述药物组合物包含治疗有效量的活性组分。在一些实施方案中，所述药物组合物包含预防有效量的活性组分。
用于本发明的药学上可接受的赋形剂是指不会破坏一起配制的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括但不限于，离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、***给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之 中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定水平，例如，在治疗窗内。
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度快速提高至有效水平。推注剂量取决于活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组合物，而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中，本文以引用的方式引入该文献。
本发明化合物还可以以持续释放形式给予，或从持续释放给药***中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。
适应症
本发明化合物可用于治疗人类或非人类蛋白激酶失调导致的癌症。在具体的实施方案中，所述的蛋白激酶选自ALK、ROS1、TRK1、TRK2、TRK3。
本发明化合物是ALK、ROS1、TRK1、TRK2、TRK3的至少一种突变体的抑制剂并且因此适用于治疗与一种或一种以上ALK、ROS1、TRK1、TRK2、TRK3突变体(例如缺失突变、活化突变、抗性突变或其组合，具体实例包括L1196M、V513M、F598L、G595R、G667C、G667A、G667S、V619M、F633L、G639R、G709C、G709A、G709S、V603M、F617L、G623R、G696C、G696A、G696S)的活性相关的一种或一种以上病症。因此，在具体实施方案中，本发明提供一种治疗突变ALK、ROS1、TRK1、TRK2、TRK3介导的病症的方法，其包含向有需要的患者给药本发明化合物，或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素衍生物，或给药本发明所述的药物组合物的步骤。
本发明的化合物将应用于，但绝不限于，使用本发明的化合物或组合物的有效量对患者给药来预防或治疗患者增殖性疾病。这样的疾病包括癌症，尤其是非小细胞肺癌、神经母细胞瘤、结肠直肠癌、间变性大细胞淋巴瘤、胆管癌、胃癌、成胶质细胞瘤、平滑肌肉瘤、黑素瘤、鳞状细胞肺癌、卵巢癌、胰腺癌、***癌、乳腺癌、甲状腺髓样癌、甲状腺***状癌。
本发明的化合物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物，包括哺乳动物，啮齿类动物等等。另外一些动物的实例包括马、狗和猫。在此，本发明的化合物包括其药学上可接受的衍生物。
实施例
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。
合成方法
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。
本文所用的缩写具有以下含义：
APCI 大气压力化学游离法
Boc 2O 二碳酸二叔丁酯
Tol 甲苯
DMAP 4-二甲氨基吡啶
DCM 二氯甲烷
TsOMe 对甲苯磺酸甲酯
DMF N,N-二甲基甲酰胺
TFA 三氟乙酸
TFAA 三氟乙酸酐
TEA 三乙胺
DIPEA N,N-二异丙基乙胺
THF 四氢呋喃
TMSBr 三甲甲硅烷基溴
TsCl 对甲苯磺酰氯
DMSO 二甲亚砜
实施例1制备N-(5-(3,5-二氟苄基)-1H-吲唑-3-基)-4-(4-(甲基-d 3)哌嗪-1-基)-2-((四氢-2H-吡喃-4-基)氨基)苯甲酰胺，即化合物T-1，分子式如下：
Figure PCTCN2018092570-appb-000010
采用以下路线进行合成：
Figure PCTCN2018092570-appb-000011
Figure PCTCN2018092570-appb-000012
步骤1 化合物3的合成
向配有磁力搅拌、冷凝管的250mL三口瓶中依次加入甲苯(100mL)、化合物1(5g，30.30mmol)、化合物2(6.9g，33.33mmol)和K 3PO 4(12.8g，60.60mmol)，抽真空并氮气置换，加入Pd(PPh 3) 4(770mg，0.67mmol)，再次抽真空并氮气置换三次，升温到110℃，保温搅拌反应5h。冷却到室温，加入乙酸乙酯(200mL)生成的固体过滤，滤液浓缩，残留物过硅胶柱得白色固体5.4g，收率72.2％。 1H NMR(400MHz,CDCl 3)δ7.43-7.39(m,2H),7.18(t,J＝8.8Hz,1H),6.73-6.66(m,3H),3.96(s,2H).
步骤2 化合物4的合成
向配有磁力搅拌、冷凝管的100mL单口瓶中依次加入正丁醇(550mL)、化合物3(5.4g，21.86 mmol)和水合肼(5.47g，109.3mmol)，混合物升温到120℃，保温搅拌反应过夜。冷却到室温，反应液浓缩，残留物过硅胶柱得白色固体3.4g，收率60.1％。LC-MS(APCI):m/z＝260.1(M+1) +. 1H NMR(400MHz,CDCl 3)δ11.32(s,1H),7.53(s,1H),7.18-7.11(m,2H),7.05-7.00(m,1H),6.95-6.92(m,2H),5.25(br s,2H),4.00(s,2H).
步骤3 化合物6的合成
向磁力搅拌下的4-氟-2-硝基苯甲酸(10g，54mmol)的二氯甲烷(200mL)溶液中依次加入Boc 2O(23.6g,108mmol)和DMAP(2g，16.3mmol)，室温下搅拌反应30分钟，加入叔丁醇(40g，540mmol)，混合物室温搅拌反应过夜。加入水100mL，二氯甲烷萃取(100mLx3)，有机相依次1M HCl(40mL)、饱和食盐水(40mL)洗，无水硫酸钠干燥，过滤，浓缩得白色固体7g，收率53.7％。LC-MS(APCI):m/z＝242.1(M+1) +.
步骤4 化合物8的合成
向磁力搅拌下的化合物6(2g，8.3mmol)的DMF(10mL)溶液中加入哌嗪(928mg,10.8mmol)，混合物室温搅拌反应过夜。加入水50mL，搅拌20分钟，析出大量固体，过滤，水洗(20mL)，干燥得黄色固体1.9g，收率74.5％。LC-MS(APCI):m/z＝208.1(M+1-100) +，308.1(M+1) +.
步骤5 化合物9的合成
向磁力搅拌下的化合物8(1.9g，6.19mmol)的乙腈溶液(10mL)中依次加入TsOMe-d 3(1.75g,9.28mmol)和K 2CO 3(2.56g，18.6mmol)，混合物室温搅拌反应过夜。减压蒸除乙腈，加水(20mL)和乙酸乙酯(30mL)，分出有机层，水层乙酸乙酯萃取(30mLx2)，合并有机相，无水硫酸钠干燥，过滤，浓缩，过硅胶柱得黄色固体1.6g，收率79.8％。LC-MS(APCI):m/z＝225.1(M+1-100) +，325.1(M+1) +。 1H NMR(400MHz,CDCl 3)δ7.71(d,J＝8.8Hz,1H),6.99(d,J＝2.4Hz,1H),6.94(dd,J＝8.8Hz,J＝2.4Hz,1H),3.35(t,J＝4.2Hz,4H),2.54(t,J＝4.2Hz,4H),1.51(s,9H).
步骤6 化合物10的合成
向磁力搅拌下的化合物9(1.6g，4.94mmol)的甲醇溶液(20mL)中加入Pd-C(160mg,10％wt)，抽真空并氢气置换三次，氢气球下室温搅拌反应过夜。滤掉催化剂，无水甲醇洗涤(10mL)，滤液浓缩得无色油状物1.4g，收率96.3％。LC-MS(APCI):m/z＝195.1(M+1-100) +，295.1(M+1) +.
步骤7 化合物12的合成
向磁力搅拌下的化合物10(1.4g，4.76mmol)的二氯甲烷溶液(20mL)中依次加入化合物11(571mg，5.71mmol)和三氟醋酸(1mL)，N 2氛下室温搅拌反应1.5小时，再加入三醋酸硼氢化四甲基铵(1.88g，7.14mmol)，室温搅拌反应过夜。加入水(20mL)，分出有机层，水相二氯 甲烷萃取(20mLx2)，无水硫酸钠干燥，过滤，滤液浓缩，过硅胶柱得无色油状物1.4g，收率77.7％。LC-MS(APCI):m/z＝279.1(M+1-100) +，379.1(M+1) +. 1H NMR(400MHz,CDCl 3)δ7.91(d,J＝7.0Hz,1H),7.75(d,J＝9.0Hz,1H),6.15(dd,J＝9.0Hz,J＝3.0Hz,1H),6.02(d,J＝3.0Hz,1H),4.02-3.98(m,2H),3.59-3.54(m,3H),3.29(t,J＝5.0Hz,4H),2.54(t,J＝5.0Hz,4H),2.06-2.03(m,2H),1.68-1.61(m,2H),1.55(sa,9H).
步骤8 化合物13的合成
0℃下，向磁力搅拌下的化合物12(1.4g，3.7mmol)的二氯甲烷溶液(20mL)中加入三乙胺(0.85mL，5.92mmol)，缓慢滴加入TFAA(1.4mL，4.81mmol)，室温下搅拌反应4h。加入水(20mL)，分出有机层，水相二氯甲烷萃取(20mLx2)，无水硫酸钠干燥，过滤，滤液浓缩，过硅胶柱得无色油状物1.0g，收率57.0％。LC-MS(APCI):m/z＝375.1(M+1-100) +，475.1(M+1) +.
步骤9 化合物14的合成
0℃下，向磁力搅拌下的化合物13(1.0g，2.11mmol)的二氯甲烷溶液(10mL)中加入三氟醋酸(3mL)，氮气氛下室温下搅拌反应过夜。减压蒸出溶剂及三氟醋酸，加入***(20mL)，搅拌20分钟，析出大量白色固体，过滤，***洗涤滤饼，干燥得白色固体940mg，收率83.8％。LC-MS(APCI):m/z＝419.2(M+1) +.
步骤10 化合物16的合成
N 2氛及0℃下，向磁力搅拌下的化合物14(940mg，1.77mmol)的干燥二氯甲烷溶液(10mL)中加入干燥的DMF(3滴)，缓慢滴加入草酰氯(4.4mL，8.8mmol，2M二氯甲烷溶液)，氮气氛下室温下搅拌反应3小时。减压蒸除溶剂及多余的草酰氯，并用干燥的二氯甲烷带两次，溶于干燥四氢呋喃中(3mL)，待用。另一50mL双口烧瓶中加入化合物4(219mg，0.85mmol)及干燥四氢呋喃(5mL)，搅拌溶解，N 2氛下加入DIPEA(437mg，3.38mmol)，冷却到0℃，缓慢滴加入上述酰氯溶液，滴完后拆去冰浴，室温下搅拌反应过夜。减压蒸除溶剂，残留物过硅胶柱得白色固体0.66g，收率56.5％。LC-MS(APCI):m/z＝660.3(M+1) +.
步骤11 化合物T-1的合成
向磁力搅拌下的16(0.66g，1.0mmol)的甲醇/水溶液(11mL，10/1)中加入碳酸钾(0.42g，3.0mmol)，氮气氛下室温下搅拌反应3小时。加入水(30mL)，析出大量灰色固体，过滤，水洗(10mL)，溶于二氯甲烷(20mL)，干燥，浓缩，残留物过硅胶柱得白色固体0.4g，收率71.0％。LC-MS(APCI):m/z＝564.2(M+1) +. 1H NMR(400MHz,CDCl 3)δ8.52(s,1H),8.14(d,J＝8.0Hz,1H),7.76(s,1H),7.56(d,J＝8.8Hz,1H),7.31(d,J＝8.8Hz,1H),7.16(dd,J＝8.8Hz,J＝2.0Hz,1H),6.72-6.69(m, 2H),6.64-6.59(m,1H),6.23(dd,J＝8.8Hz,J＝2.0Hz,1H),6.10(s,1H),4.05(s,2H),4.01-3.95(m,2H),3.60-3.52(m,3H),3.35(t,J＝4.8Hz,4H),2.62(t,J＝4.8Hz,4H),2.05-2.01(m,2H).
实施例2制备N-(5-(3,5-二氟苄基)-1H-吲唑-3-基)-4-(4-甲基哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-((四氢-2H-吡喃-4-基)氨基)苯甲酰胺，即化合物T-2，分子式如下：
Figure PCTCN2018092570-appb-000013
采用以下合成路线：
Figure PCTCN2018092570-appb-000014
Figure PCTCN2018092570-appb-000015
步骤1 化合物18的合成。
向磁力搅拌下的化合物6(2g，8.3mmol)的DMF(10mL)溶液中加入化合物17(928mg,10.8mmol)，混合物室温搅拌反应过夜。加入水50mL，搅拌20分钟，析出大量固体，过滤，水洗(20mL)，干燥得黄色固体1.9g，收率74.5％。LC-MS(APCI):m/z＝213.1(M+1-100) +,313.1(M+1) +.
步骤2 化合物19的合成
向磁力搅拌下的化合物18(1.9g，6.19mmol)的乙腈溶液(10mL)中依次加入TsOMe(1.75g,9.28mmol)和K 2CO 3(2.56g，18.6mmol)，混合物室温搅拌反应过夜。减压蒸除乙腈，加水(20mL)和乙酸乙酯(30mL)，分出有机层，水层乙酸乙酯萃取(30mLx2)，合并有机相，无水硫酸钠干燥，过滤，浓缩，过硅胶柱得黄色固体1.6g，收率79.8％。LC-MS(APCI):m/z＝230.1(M+1-100) +,330.1(M+1) +. 1H NMR(400MHz,CDCl 3)δ7.71(d,J＝8.8Hz,1H),6.99(d,J＝2.4Hz,1H),6.94(dd,J＝8.8Hz,J＝2.4Hz,1H),2.35(s,3H),1.51(s,9H).
步骤3 化合物20的合成
向磁力搅拌下的化合物19(1.6g，4.94mmol)的甲醇溶液(20mL)中加入Pd-C(160mg,10％wt)，抽真空并氢气置换三次，氢气球下室温搅拌反应过夜。滤掉催化剂，无水甲醇洗涤(10mL)，滤液浓缩得无色油状物1.4g，收率96.3％。LC-MS(APCI):m/z＝200.1(M+1-100) +,300.1(M+1) +.
步骤4 化合物21的合成
向磁力搅拌下的化合物20(1.4g，4.76mmol)的二氯甲烷溶液(20mL)中依次加入化合物 11(571mg，5.71mmol)和三氟醋酸(1mL)，N 2氛下室温搅拌反应1.5小时，再加入三醋酸硼氢化四甲基铵(1.88g，7.14mmol)，室温搅拌反应过夜。加入水(20mL)，分出有机层，水相二氯甲烷萃取(20mLx2)，无水硫酸钠干燥，过滤，滤液浓缩，过硅胶柱得无色油状物1.4g，收率77.7％。LC-MS(APCI):m/z＝284.1(M+1-100) +，384.1(M+1) +. 1H NMR(500MHz,CDCl 3)δ:7.91(d,J＝7.0Hz,1H),7.75(d,J＝9.0Hz,1H),6.15(dd,J＝9.0Hz,J＝3.0Hz,1H),6.02(d,J＝3.0Hz,1H),4.02-3.98(m,2H),3.59-3.54(m,3H),2.35(s,3H),2.06-2.03(m,2H),1.68-1.61(m,2H),1.55(s,9H).
步骤5 化合物22的合成
0℃下，向磁力搅拌下的化合物21(1.4g，3.7mmol)的二氯甲烷溶液(20mL)中加入三乙胺(0.85mL，5.92mmol)，缓慢滴加入TFAA(1.4mL，4.81mmol)，室温下搅拌反应4h。加入水(20mL)，分出有机层，水相二氯甲烷萃取(20mLx2)，无水硫酸钠干燥，过滤，滤液浓缩，过硅胶柱得无色油状物1.0g，收率57.0％。LC-MS(APCI):m/z＝380.1(M+1-100) +，480.1(M+1) +.
步骤6 化合物23的合成
0℃下，向磁力搅拌下的化合物22(1.0g，2.11mmol)的二氯甲烷溶液(10mL)中加入三氟醋酸(3mL)，氮气氛下室温下搅拌反应过夜。减压蒸出溶剂及三氟醋酸，加入***(20mL)，搅拌20分钟，析出大量白色固体，过滤，***洗涤滤饼，干燥得白色固体940mg，收率83.8％。LC-MS(APCI):m/z＝424.2(M+1) +.
步骤7 化合物25的合成
N 2氛及0℃下，向磁力搅拌下的化合物23(940mg，1.77mmol)的干燥二氯甲烷溶液(10mL)中加入干燥的DMF(3滴)，缓慢滴加入草酰氯(4.4mL，8.8mmol，2M二氯甲烷溶液)，氮气氛下室温下搅拌反应3小时。减压蒸除溶剂及多余的草酰氯，并用干燥的二氯甲烷带两次，溶于干燥四氢呋喃中(3mL)，待用。另一50mL双口烧瓶中加入化合物4(219mg，0.85mmol)及干燥四氢呋喃(5mL)，搅拌溶解，N 2氛下加入DIPEA(437mg，3.38mmol)，冷却到0℃，缓慢滴加入上述酰氯溶液，滴完后拆去冰浴，室温下搅拌反应过夜。减压蒸除溶剂，残留物过硅胶柱得白色固体0.66g，收率56.5％。LC-MS(APCI):m/z＝665.3(M+1) +.
步骤8 T-2的合成
向磁力搅拌下的化合物25(0.66g，1.0mmol)的甲醇/水溶液(11mL，10/1)中加入碳酸钾(0.42g，3.0mmol)，氮气氛下室温下搅拌反应3小时。加入水(30mL)，析出大量灰色固体，过滤，水洗(10mL)，溶于二氯甲烷(20mL)，干燥，浓缩，残留物过硅胶柱得白色固体0.4g，收率71.0％。LC-MS(APCI):m/z＝569.2(M+1) +. 1H NMR(400MHz,DMSO-D 6)δ:12.66(s,1H),10.11(s,1H),8.30(d, J＝8.0Hz,1H),7.80(d,J＝8.8Hz,1H),7.49(s,1H),7.42(d,J＝8.8Hz,1H),7.26(dd,J＝8.8Hz,J＝1.6Hz,1H),7.02-6.98(m,3H),6.24(dd,J＝8.8Hz,J＝2.4Hz,1H),6.14(d,J＝2.8Hz,1H),4.05(s,2H),3.84-3.80(m,2H),3.73-3.68(m,1H),3.50(t,J＝9.6Hz,2H),2.30(s,3H),1.98-1.93(m,2H),1.40-1.33(m,2H).
实施例3制备N-(5-(3,5-二氟苄基)-1H-吲唑-3-基)-4-(4-(甲基-d 3)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-((四氢-2H-吡喃-4-基)氨基)苯甲酰胺，即化合物T-3，分子式如下：
Figure PCTCN2018092570-appb-000016
采用以下合成路线：
Figure PCTCN2018092570-appb-000017
Figure PCTCN2018092570-appb-000018
步骤1 化合物26的合成。
向磁力搅拌下的化合物18(0.85g，3.1mmol)的乙腈溶液(10mL)中依次加入TsOMe-d 3(0.88g,4.62mmol)和K 2CO 3(1.28g，9.3mmol)，混合物室温搅拌反应过夜。减压蒸除乙腈，加水(20mL)和乙酸乙酯(30mL)，分出有机层，水层乙酸乙酯萃取(30mLx2)，合并有机相，无水硫酸钠干燥，过滤，浓缩，过硅胶柱得黄色固体0.8g，收率79.8％。LC-MS(APCI):m/z＝233.1(M+1-100) +，333.1(M+1) +. 1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.8Hz,1H),6.99(d,J＝2.4Hz,1H),6.94(dd,J＝8.8Hz,J＝2.4Hz,1H),1.51(s,9H).
步骤2 化合物27的合成
向磁力搅拌下的化合物26(0.8g，2.48mmol)的甲醇溶液(10mL)中加入Pd-C(80mg,10％wt)，抽真空并氢气置换三次，氢气球下室温搅拌反应过夜。滤掉催化剂，无水甲醇洗涤(10mL)，滤液浓缩得无色油状物0.7g，收率96.3％。LC-MS(APCI):m/z＝200.1(M+1-100) +，300.1(M+1) +.
步骤3 化合物28的合成
向磁力搅拌下的化合物27(0.7g，2.88mmol)的二氯甲烷溶液(10mL)中依次化合物11(236mg，2.36mmol)和三氟醋酸(0.5mL)，N 2氛下室温搅拌反应1.5小时，再加入三醋酸硼氢化四甲基铵(0.94g，3.57mmol)，室温搅拌反应过夜。加入水(20mL)，分出有机层，水相二氯甲烷萃取(20mLx2)，无水硫酸钠干燥，过滤，滤液浓缩，过硅胶柱得无色油状物0.7g，收率77.7％。LC-MS(APCI): m/z＝287.1(M+1-100) +，387.1(M+1) +. 1H NMR(500MHz,CDCl 3)δ7.91(d,J＝7.0Hz,1H),7.75(d,J＝9.0Hz,1H),6.15(dd,J＝9.0Hz,J＝3.0Hz,1H),6.02(d,J＝3.0Hz,1H),4.02-3.98(m,2H),3.59-3.54(m,3H),2.06-2.03(m,2H),1.68-1.61(m,2H),1.55(s,9H).
步骤4 化合物29的合成
冰水浴下，向磁力搅拌下的化合物21(0.7g，1.85mmol)的二氯甲烷溶液(10mL)中加入三乙胺(0.47mL，2.97mmol)，缓慢滴加入TFAA(0.7mL，2.42mmol)，室温下搅拌反应4小时。加入水(20mL)，分出有机层，水相二氯甲烷萃取(20mLx2)，无水硫酸钠干燥，过滤，滤液浓缩，过硅胶柱得无色油状物0.5g，收率57.0％。LC-MS(APCI):m/z＝383.1(M+1-100) +,483.1(M+1) +.
步骤5 化合物30的合成
0℃下，向磁力搅拌下的化合物29(0.5g，1.06mmol)的二氯甲烷溶液(5mL)中加入三氟醋酸(1.5mL)，氮气氛下室温下搅拌反应过夜。减压蒸出溶剂及三氟醋酸，加入***(20mL)，搅拌20分钟，析出大量白色固体，过滤，***洗涤滤饼，干燥得白色固体470mg，收率83.8％。LC-MS(APCI):m/z＝427.2(M+1) +.
步骤6 化合物32的合成
N 2氛及冰水浴下，向磁力搅拌下的化合物30(470mg，0.88mmol)的干燥二氯甲烷溶液(6mL)中加入干燥的DMF(2滴)，缓慢滴加入草酰氯(2.2mL，4.4mmol，2M二氯甲烷溶液)，氮气氛下室温下搅拌反应3小时。减压蒸除溶剂及多余的草酰氯，并用干燥的二氯甲烷带两次，溶于干燥四氢呋喃中(2mL)，待用。另一50mL双口烧瓶中加入化合物4(110mg，0.43mmol)及干燥四氢呋喃(5mL)，搅拌溶解，N 2氛下加入DIPEA(220mg，1.70mmol)，冰水浴冷却，缓慢滴加入上述酰氯溶液，滴完后拆去冰浴，室温下搅拌反应过夜。减压蒸除溶剂，残留物过硅胶柱得白色固体0.33g，收率56.5％。LC-MS(APCI):m/z＝668.3(M+1) +.
步骤8 化合物T-3的合成
向磁力搅拌下的化合物32(0.33g，0.5mmol)的甲醇/水溶液(6mL，10/1)中加入碳酸钾(0.21g，1.5mmol)，氮气氛下室温下搅拌反应3小时。加入水(30mL)，析出大量灰色固体，过滤，水洗(10mL)，溶于二氯甲烷(20mL)，干燥，浓缩，残留物过硅胶柱得白色固体0.2g，收率71.0％。LC-MS(APCI):m/z＝572.3(M+1) +. 1H NMR(400MHz,DMSO-D 6)δ12.66(s,1H),10.11(s,1H),8.30(d,J＝8.0Hz,1H),7.80(d,J＝8.8Hz,1H),7.49(s,1H),7.42(d,J＝8.8Hz,1H),7.26(dd,J＝8.8Hz,J＝1.6Hz,1H),7.02-6.98(m,3H),6.24(dd,J＝8.8Hz,J＝2.4Hz,1H),6.14(d,J＝2.8Hz,1H),4.05(s,2H),3.84-3.80(m,2H),3.73-3.68(m,1H),3.50(t,J＝9.6Hz,2H),1.98-1.93(m,2H),1.40-1.33(m,2H).
实施例4制备N-(5-(3,5-二氟苄基)-1H-吲唑-3-基)-4-(4-甲基哌嗪-1-基)-2-((四氢-2H-吡喃-4-基)氨基)苯甲酰胺-3,5-d，即化合物T-4，分子式如下：
Figure PCTCN2018092570-appb-000019
采用以下合成路线：
Figure PCTCN2018092570-appb-000020
步骤1 化合物34的合成。
向配有磁力搅拌的50mL单口烧瓶中加入化合物6(10g，42.32mmol)和N-甲基哌嗪(12.8g，124.43mmol)，混合物室温下搅拌反应过夜。LC-MS(APCI):m/z＝322.1(M+1) +。 1H NMR(400MHz,CDCl 3)δ7.71(d,J＝8.8Hz,1H),6.99(d,J＝2.4Hz,1H),6.94(dd,J＝8.8Hz,J＝2.4Hz,1H),3.35(t,J＝4.2Hz,4H),2.54(t,J＝4.2Hz,4H),2.35(s,3H),1.51(s,9H).
步骤2 化合物35的合成
向磁力搅拌下的化合物34(6.0g，18.7mmol)的甲醇溶液(20mL)中加入Pd-C(600mg,10％wt)，抽真空并氢气置换三次，氢气球下室温搅拌反应过夜。滤掉催化剂，无水甲醇洗涤(10mL)，滤液浓缩得无色油状物4.9g，收率90.0％。LC-MS(APCI):m/z＝292.1(M+1) +。
步骤3 化合物36的合成
向磁力搅拌下的化合物35(1.4g，4.76mmol)的二氯甲烷溶液(20mL)中依次化合物11(571mg，5.71mmol)和三氟醋酸(1mL)，N2氛下室温搅拌反应1.5小时，再加入三醋酸硼氢化四甲基铵(1.88g，7.14mmol)，室温搅拌反应过夜。加入水(20mL)，分出有机层，水相二氯甲烷萃取(20mLx2)，无水硫酸钠干燥，过滤，滤液浓缩，过硅胶柱得无色油状物1.4g，收率77.7％。LC-MS(APCI):m/z＝376.1(M+1) +。 1H NMR(500MHz,CDCl 3)δ7.91(d,J＝7.0Hz,1H),7.75(d,J＝9.0Hz,1H),6.15(dd,J＝9.0Hz,J＝3.0Hz,1H),6.02(d,J＝3.0Hz,1H),4.02-3.98(m,2H),3.59-3.54(m,3H),3.29(t,J＝5.0Hz,4H),2.54(t,J＝5.0Hz,4H),2.35(s,3H),2.06-2.03(m,2H),1.68-1.61(m,2H),1.55(s,9H).
步骤4 化合物37的合成
冰水浴下，向磁力搅拌下的化合物36(1.4g，3.7mmol)的二氯甲烷溶液(20mL)中加入三乙胺(0.85mL，5.92mmol)，缓慢滴加入TFAA(1.4mL，4.81mmol)，室温下搅拌反应4小时。加入水(20mL)，分出有机层，水相二氯甲烷萃取(20mLx2)，无水硫酸钠干燥，过滤，滤液浓缩，过硅胶柱得无色油状物1.0g，收率57.0％。LC-MS(APCI):m/z＝472.1(M+1) +。
步骤5 化合物38的合成
0℃下，向磁力搅拌下的化合物37(1.0g，2.11mmol)的二氯甲烷溶液(10mL)中加入三氟醋酸(3mL)，氮气氛下室温下搅拌反应过夜。减压蒸出溶剂及三氟醋酸，加入***(20mL)，搅拌20分钟，析出大量白色固体，过滤，***洗涤滤饼，干燥得白色固体940mg，收率83.8％。LC-MS(APCI):m/z＝416.2(M+1) +。
步骤6 化合物40的合成
N 2氛及0℃下，向磁力搅拌下的化合物38(940mg，1.77mmol)的干燥二氯甲烷溶液(10mL) 中加入干燥的DMF(3滴)，缓慢滴加入草酰氯(4.4mL，8.8mmol，2M二氯甲烷溶液)，氮气氛下室温下搅拌反应3小时。减压蒸除溶剂及多余的草酰氯，并用干燥的二氯甲烷带两次，溶于干燥四氢呋喃中(3mL)，待用。另一50mL双口烧瓶中加入化合物4(219mg，0.85mmol)及干燥四氢呋喃(5mL)，搅拌溶解，N 2氛下加入DIPEA(437mg，3.38mmol)，冰水浴冷却，缓慢滴加入上述酰氯溶液，滴完后拆去冰浴，室温下搅拌反应过夜。减压蒸除溶剂，残留物过硅胶柱得白色固体0.66g，收率56.5％。LC-MS(APCI):m/z＝657.3(M+1) +。
步骤7 化合物41的合成
向磁力搅拌下的化合物40(0.66g，1.0mmol)的甲醇/水溶液(11mL，10/1)中加入碳酸钾(0.42g，3.0mmol)，氮气氛下室温下搅拌反应3小时。加入水(30mL)，析出大量灰色固体，过滤，水洗(10mL)，溶于二氯甲烷(20mL)，干燥，浓缩，残留物过硅胶柱得白色固体0.4g，收率71.0％。LC-MS(APCI):m/z＝561.2(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.52(s,1H),8.14(d,J＝8.0Hz,1H),7.76(s,1H),7.56(d,J＝8.8Hz,1H),7.31(d,J＝8.8Hz,1H),7.16(dd,J＝8.8Hz,J＝2.0Hz,1H),6.72-6.69(m,2H),6.64-6.59(m,1H),6.23(dd,J＝8.8Hz,J＝2.0Hz,1H),6.10(s,1H),4.05(s,2H),4.01-3.95(m,2H),3.60-3.52(m,3H),3.35(t,J＝4.8Hz,4H),2.62(t,J＝4.8Hz,4H),2.40(s,3H),2.05-2.01(m,2H).
步骤8 化合物T-4的合成
向配有磁力搅拌及冷凝管的50mL单口烧瓶中依次加入化合物41(112mg，0.2mmol)、CH 3COOD(8mL)，搅拌下加入锌粉(56mg，1mmol)，抽真空并N 2置换三次，升温到70℃并保温搅拌反应2小时。冷却到室温，加入乙酸乙酯(20mL)，滤掉未反应完全的锌粉，滤液浓缩至干，加入饱和NaHCO 3溶于(10mL)，乙酸乙酯萃取(15mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得白色固体80mg，收率71.4％。LC-MS(APCI):m/z＝563.2(M+1) +。 1H NMR(400MHz,DMSO-D6)δ12.64(s,1H),10.09(s,1H),8.28(d,J＝8.0Hz,1H),7.79(d,J＝8.8Hz,1H),7.48(s,1H),7.40(d,J＝8.8Hz,1H),7.25(dd,J＝8.8Hz,J＝1.6Hz,1H),7.02-6.98(m,3H),4.04(s,2H),3.84-3.80(m,2H),3.73-3.68(m,1H),3.50(t,J＝9.6Hz,2H),3.26(t,J＝4.8Hz,4H),2.44(t,J＝4.8Hz,4H),2.30(s,3H),1.98-1.93(m,2H),1.40-1.33(m,2H).
实施例5制备N-(5-(3,5-二氟苄基)-1H-吲唑-3-基)-4-(4-(甲基-d3)哌嗪-1-基)-2-((四氢-2H-吡喃-4-基)氨基)苯甲酰胺-3,5-d 2，即化合物T-5，分子式如下：
Figure PCTCN2018092570-appb-000021
采用以下合成路线：
Figure PCTCN2018092570-appb-000022
向配有磁力搅拌及冷凝管的50mL单口烧瓶中依次加入化合物T-1(112mg，0.2mmol)、-CH 3COOD(8mL)，搅拌下加入锌粉(56mg，1mmol)，抽真空并N 2置换三次，升温到70℃并保温搅拌反应2小时。冷却到室温，加入乙酸乙酯(20mL)，滤掉未反应完全的锌粉，滤液浓缩至干，加入饱和NaHCO 3溶于(10mL)，乙酸乙酯萃取(15mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得白色固体80mg，收率71.4％。LC-MS(APCI):m/z＝566.2(M+1) +。 1H NMR(400MHz,DMSO-D6)δ12.64(s,1H),10.09(s,1H),8.28(d,J＝8.0Hz,1H),7.79(d,J＝8.8Hz,1H),7.48(s,1H),7.40(d,J＝8.8Hz,1H),7.25(dd,J＝8.8Hz,J＝1.6Hz,1H),7.02-6.98(m,3H),4.04(s,2H),3.84-3.80(m,2H),3.73-3.68(m,1H),3.50(t,J＝9.6Hz,2H),3.26(t,J＝4.8Hz,4H),2.44(t,J＝4.8Hz,4H),1.98-1.93(m,2H),1.40-1.33(m,2H).
实施例6制备N-(5-(3,5-二氟苄基)-1H-吲唑-3-基)-4-(4-(甲基-d 3)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-((四氢-2H-吡喃-4-基)氨基)苯甲酰胺-3,5-d 2，即化合物T-6，分子式如下：
Figure PCTCN2018092570-appb-000023
采用以下合成路线：
Figure PCTCN2018092570-appb-000024
配有磁力搅拌及冷凝管的50mL单口烧瓶中依次加入化合物T-3(112mg，0.2mmol)、CH 3COOD(8mL)，搅拌下加入锌粉(56mg，1mmol)，抽真空并N 2置换三次，升温到70℃并保温搅拌反应2h。冷却到室温，加入乙酸乙酯(20mL)，滤掉未反应完全的锌粉，滤液浓缩至干，加入饱和NaHCO 3溶于(10mL)，乙酸乙酯萃取(15mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得白色固体80mg，收率71.4％。LC-MS(APCI):m/z＝574.2(M+1) +. 1H NMR(400MHz,DMSO-d 6)δ12.64(s,1H),10.09(s,1H),8.28(d,J＝8.0Hz,1H),7.79(d,J＝8.8Hz,1H),7.48(s,1H),7.40(d,J＝8.8Hz,1H),7.25(dd,J＝8.8Hz,J＝1.6Hz,1H),7.02-6.98(m,3H),4.04(s,2H),3.84-3.80(m,2H),3.73-3.68(m,1H),3.50(t,J＝9.6Hz,2H),1.98-1.93(m,2H),1.40-1.33(m,2H).
实施例7制备N-(5-((3,5-二氟苯基)甲基-d 2)-1H-吲唑-3-基)-4-(4-甲基哌嗪-1-基)-2-((四氢-2H-吡喃-4-基)氨基)苯甲酰胺，即化合物T-7，分子式如下：
Figure PCTCN2018092570-appb-000025
采用以下合成路线：
Figure PCTCN2018092570-appb-000026
步骤1 化合物43的合成
向配有磁力搅拌的50mL单口烧瓶中加入化合物42(1.73g，10mmol)和无水四氢呋喃(20mL)，氮气保护下冷却到0℃，缓慢加入氘代四氢铝锂(0.42g，10mmol)，0℃下搅拌反应1h。缓慢加入固体十水硫酸钠淬灭反应，直到不冒气泡，加入二氯甲烷(40mL)，过滤，滤液无水硫酸钠干燥，过滤，旋干得白色固体1.2g，收率82.2％。LC-MS(APCI):m/z＝147.1(M+1) +.1H NMR(400MHz,CDCl3)δ(ppm)6.90-6.85(m,2H),6.74-6.68(m,1H),2.12(s,1H).
步骤2 化合物44的合成
向磁力搅拌下的50mL单口烧瓶依次加入化合物43(3.93g，26.9mmol)和三甲基溴硅烷(4.53g，29.6mmol)，氮气氛下室温搅拌反应2小时。加入乙酸乙酯(50mL)，水洗(10mL)，饱和食盐水洗(10mL)，无水硫酸钠干燥，浓缩得无色油状物4.4g，收率78.6％。LC-MS(APCI):m/z＝209.0(M+1) +.
步骤3 化合物45的合成
向配有磁力搅拌、冷凝管的250mL三口瓶中依次加入甲苯(50mL)、化合物1(2.5g，15.15mmol)、化合物44(3.9g，16.65mmol)和K 3PO4(6.4g，30.30mmol)，抽真空并氮气置换，加入Pd(PPh 3) 4(385mg，0.33mmol)，再次抽真空并氮气置换三次，升温到110℃，保温搅拌反应5小时。冷却到室温，加入乙酸乙酯(100mL)生成的固体过滤，滤液浓缩，残留物过硅胶柱得白色固体2.7g，收率72.2％。 1H NMR(400MHz,CDCl 3)δ(ppm)7.43-7.39(m,2H),7.18(t,J＝8.8Hz,1H),6.73-6.66(m,3H).
步骤4 化合物46的合成
向配有磁力搅拌、冷凝管的100mL单口瓶中依次加入正丁醇(275mL)、化合物45(2.7g，15.96mmol)和水合肼(2.74g，54.8mmol)，混合物升温到120℃，保温搅拌反应过夜。冷却到室温，反应液浓缩，残留物过硅胶柱得白色固体1.7g，收率60.1％。LC-MS(APCI):m/z＝262.1(M+1) +. 1H NMR(400MHz,DMSO-d 6)δ(ppm)11.32(s,1H),7.53(s,1H),7.18-7.11(m,2H),7.05-7.00(m,1H),6.95-6.92(m,2H),5.25(br s,2H).
步骤5 化合物47的合成
N 2氛及0℃下，向磁力搅拌下的化合物39(940mg，1.77mmol)的干燥二氯甲烷溶液(10mL)中加入干燥的DMF(3滴)，缓慢滴加入草酰氯(4.4mL，8.8mmol，2M二氯甲烷溶液)，氮气氛下室温下搅拌反应3小时。减压蒸除溶剂及多余的草酰氯，并用干燥的二氯甲烷带两次，溶于干燥四氢呋喃中(3mL)，待用。另一50mL双口烧瓶中加入化合物46(219mg，0.85mmol)及干燥四氢呋喃(5mL)，搅拌溶解，N 2氛下加入DIPEA(437mg，3.38mmol)，冷却到0℃，缓慢滴加入上述酰氯溶液，滴完后拆去冰浴，室温下搅拌反应过夜。减压蒸除溶剂，残留物过硅胶柱得白色固体0.66g，收率56.5％。LC-MS(APCI):m/z＝659.3(M+1) +.
步骤6 T-7的合成
向磁力搅拌下的化合物47(0.66g，1.0mmol)的甲醇/水溶液(11mL，10/1)中加入碳酸钾(0.42g，3.0mmol)，氮气氛下室温下搅拌反应3小时。加入水(30mL)，析出大量灰色固体，过滤，水洗(10mL)，溶于二氯甲烷(20mL)，干燥，浓缩，残留物过硅胶柱得白色固体0.4g，收率71.0％。LC-MS(APCI):m/z＝561.2(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm)8.52(s,1H),8.14(d,J＝8.0Hz,1H),7.76(s,1H),7.56(d,J＝8.8Hz,1H),7.31(d,J＝8.8Hz,1H),7.16(dd,J＝8.8Hz,J＝2.0Hz,1H),6.72-6.69(m,2H),6.64-6.59(m,1H),6.23(dd,J＝8.8Hz,J＝2.0Hz,1H),6.10(s,1H),4.01-3.95(m,2H),3.60-3.52(m,3H),3.35(t,J＝4.8Hz,4H),2.62(t,J＝4.8Hz,4H),2.40(s,3H),2.05-2.01(m,2H).
实施案例8制备N-(5-(3,5-二氟苄基)-1H-吲唑-3-基)-4-(4-甲基哌嗪-1-基)-2-((四氢-2H-吡喃-4-基-2,2,6,6-d 4)氨基)苯甲酰胺，即化合物T-8，其分子式如下：
Figure PCTCN2018092570-appb-000027
采用以下合成路线：
Figure PCTCN2018092570-appb-000028
步骤1 化合物49的合成
向配有磁力搅拌和冷凝管的50mL单口烧瓶中依次加入醋酸(30mL)、化合物35(3.0g，10.31mmol)、化合物48(2.69g，15.46mmol)和锌粉(2.68g，41.22mmol)，混合物升温到100℃， 氮气氛下保温搅拌反应过夜。冷却到室温，加入乙酸乙酯(40mL)，过滤，乙酸乙酯(10mL)洗涤滤饼，合并有机相，浓缩至干，加入饱和碳酸氢钠水溶液(20mL)，乙酸乙酯萃取(40mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得无水油状物2.0g，收率44.32％。LC-MS(APCI):m/z＝450.3(M+1) +.
步骤2 化合物50的合成
向配有磁力搅拌和冷凝管的50mL单口烧瓶中加入无水四氢呋喃(20mL)和化合物49(2.0g，4.45mmol)，氮气保护下冷却到0℃，缓慢加入氘代四氢铝锂(0.37g，8.91mmol)，0℃下搅拌反应10分钟。缓慢加入固体十水硫酸钠淬灭反应，直到不冒气泡，加入二氯甲烷(40mL)，过滤，滤液无水硫酸钠干燥，过滤，旋干得无色油状物847mg，收率45.6％。LC-MS(APCI):m/z＝398.3(M+1) +. 1H NMR(400MHz,CDCl 3)δ7.75-7.70(m,2H),6.31(d,J＝2.0Hz,1H),6.14(dd,J＝8.4Hz,J＝2.0Hz,1H),3.97-3.89(m,1H),3.32(t,J＝4.2Hz,3H),2.55(t,J＝4.2Hz,4H),2.35(s,3H),1.85-1.81(m,4H),1.55(s,9H).
步骤3 化合物51的合成
向配有磁力搅拌的50mL单口瓶中依次加入化合物50(847mg，2.03mmol)、二氯甲烷(5mL)、DMF(5mL)和三乙胺(308mg，3.04mmol)，冷水浴冷却，缓慢滴加入对甲苯磺酰氯((387mg，2.03mmol))的二氯甲烷溶液(5mL)，滴完后，拆去冰浴，氮气氛下室温搅拌反应过夜。旋干，残留物过硅胶柱得无色油状物770mg，收率70.2％。LC-MS(APCI):m/z＝552.3(M+1) +.
步骤4 化合物52的合成
向配有磁力搅拌的25mL单口瓶中依次加入化合物51(770mg，1.4mmol)和无水THF(10mL)，氮气氛下冷却到0℃，缓慢加入NaH(84mg，2.1mmol，60％矿物油)，加完后缓慢升至室温，反应3h。加入水(10mL)淬灭反应，乙酸乙酯萃取(15mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得白色固体260mg，收率49.0％。LC-MS:m/z＝380.3(M+1) +. 1H NMR(500MHz,CDCl 3)δ7.91(d,J＝7.0Hz,1H),7.75(d,J＝9.0Hz,1H),6.15(dd,J＝9.0Hz,J＝3.0Hz,1H),6.02(d,J＝3.0Hz,1H),3.29(t,J＝5.0Hz,4H),2.54(t,J＝5.0Hz,4H),2.35(s,3H),2.05-2.01(m，2H),1.68-1.61(m,2H),1.55(s,9H).
步骤5 化合物53的合成
0℃下，向磁力搅拌下的化合物52(260mg，0.686mmol)的二氯甲烷溶液(8mL)中加入三乙胺(111mg，1.1mmol)，缓慢滴加入TFAA(0.25mL，0.892mmol)，室温下搅拌反应4小时。加入水(10mL)，分出有机层，水相二氯甲烷萃取(10mLx2)，无水硫酸钠干燥，过滤，滤液浓缩，过硅胶柱得无色油状物420mg，收率98.2％。LC-MS(APCI):m/z＝476.1(M+1) +.
步骤6 化合物54的合成
0℃下，向磁力搅拌下的化合物53(420mg，0.884mmol)的二氯甲烷溶液(10mL)中加入三氟醋酸(3mL)，氮气氛下室温下搅拌反应过夜。减压蒸出溶剂及三氟醋酸，加入***(20mL)，搅拌20分钟，析出大量白色固体，过滤，***洗涤滤饼，干燥得白色固体330mg，收率70.0％。LC-MS(APCI):m/z＝420.2(M+1) +.
步骤7 化合物56的合成
N 2氛及0℃下，向磁力搅拌下的化合物54(330mg，0.62mmol)的干燥二氯甲烷溶液(6mL)中加入干燥的DMF(2滴)，缓慢滴加入草酰氯(1.6mL，3.2mmol，2M二氯甲烷溶液)，氮气氛下室温下搅拌反应3小时。减压蒸除溶剂及多余的草酰氯，并用干燥的二氯甲烷带两次，溶于干燥四氢呋喃中(3mL)，待用。另一50mL双口烧瓶中加入化合物4(145mg，0.59mmol)及干燥四氢呋喃(3mL)，搅拌溶解，N 2氛下加入DIPEA(320mg，2.48mmol)，冷却到0℃，缓慢滴加入上述酰氯溶液，滴完后拆去冰浴，室温下搅拌反应过夜。减压蒸除溶剂，残留物过硅胶柱得白色固体0.28g，收率67.7％。LC-MS(APCI):m/z＝661.3(M+1) +.
步骤8 T-8的合成
向磁力搅拌下的化合物56(0.28g，0.42mmol)的甲醇/水溶液(11mL，10/1)中加入碳酸钾(0.18g，1.27mmol)，氮气氛下室温下搅拌反应3小时。加入水(30mL)，析出大量灰色固体，过滤，水洗(10mL)，溶于二氯甲烷(20mL)，干燥，浓缩，残留物过硅胶柱得白色固体165mg，收率69.6％。LC-MS(APCI):m/z＝565.2(M+1) +. 1H NMR(400MHz,CDCl 3)δ8.52(s,1H),8.14(d,J＝8.0Hz,1H),7.76(s,1H),7.56(d,J＝8.8Hz,1H),7.31(d,J＝8.8Hz,1H),7.16(dd,J＝8.8Hz,J＝2.0Hz,1H),6.72-6.69(m,2H),6.64-6.59(m,1H),6.23(dd,J＝8.8Hz,J＝2.0Hz,1H),6.10(s,1H),4.05(s,2H),3.35(t,J＝4.8Hz,4H),2.62(t,J＝4.8Hz,4H),2.40(s,3H),2.05-2.01(m,2H).
实施案例9制备N-(5-(二氟苄基)-1H-吲唑-3-基)-4-(4-甲基哌嗪-1-基)-2-((四氢-2H-吡喃-4-基)氨基)苯甲酰胺，即化合物T-9，其分子式如下：
Figure PCTCN2018092570-appb-000029
采用以下合成路线：
Figure PCTCN2018092570-appb-000030
向配有磁力搅拌及冷凝管的50mL单口烧瓶中依次加入化合物41(200mg，0.35mmol)、D 2O(5mL)、DMSO-D 6(5mL)和40％NaOD重水溶液(180mg，0.178mL)，混合物升温到70℃，氮气氛下保温搅拌反应过夜。冷却到室温，乙酸乙酯萃取(20mLx3)，合并有机相，水洗(40mLx3)，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得白色固体120mg，收率60％。LC-MS(APCI):m/z＝562.4(M+1) +. 1H NMR(DMSO-d 6,300MHz)δ12.64(s,1H),10.09(s,1H),8.29(d,J＝5.7Hz,1H),7.79(d,J＝6.9Hz,1H),7.48(s,1H),7.40(d,J＝6.6Hz,1H),7.25(d,J＝6.6Hz,1H),6.98(d,J＝6.0Hz,2H),6.23(d,J＝6.6Hz,1H),6.13(s,1H),4.04(s,2H),3.83-3.78(m,2H),3.68(s,1H),3.49(t,J＝7.5Hz,2H),3.26(s,4H),2.44(s,4H),2.23(s,3H),1.93(d,J＝8.7Hz,2H),1.38-1.29(m,2H).
实施案例10制备N-(5-((3,5-二氟苯基)甲基-d 2)-1H-吲唑-3-基)-4-(4-甲基哌嗪-1-基)-2-((四氢-2H-吡喃-4-基)氨基)苯甲酰胺-3,5-d 2，即化合物T-10，其分子式如下：
Figure PCTCN2018092570-appb-000031
采用以下合成路线：
Figure PCTCN2018092570-appb-000032
向配有磁力搅拌及冷凝管的50mL单口烧瓶中依次加入化合物T-7(112mg，0.2mmol)、CH 3COOD(8mL)，搅拌下加入锌粉(56mg，1mmol)，抽真空并N 2置换三次，升温到70℃并保温搅拌反应2小时。冷却到室温，加入乙酸乙酯(20mL)，滤掉未反应完全的锌粉，滤液浓缩至干，加入饱和NaHCO 3溶于(10mL)，乙酸乙酯萃取(15mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得白色固体80mg，收率71.4％。LC-MS(APCI):m/z＝566.2(M+1) +.1H NMR(400MHz,DMSO-D 6)δ12.64(s,1H),10.09(s,1H),8.28(d,J＝8.0Hz,1H),7.79(d,J＝8.8Hz,1H),7.48(s,1H),7.40(d,J＝8.8Hz,1H),7.25(dd,J＝8.8Hz,J＝1.6Hz,1H),7.02-6.98(m,3H),3.84-3.80(m,2H),3.73-3.68(s，1H),3.50(t,J＝9.6Hz,2H),3.26(t,J＝4.8Hz,4H),2.44(t,J＝4.8Hz,4H),1.98-1.93(m,2H),1.40-1.33(m,2H).
实施案例11制备N-(5-((3,5-二氟苯基)甲基-d 2)-1H-吲唑-3-基)-4-(4-(甲基-d 3)哌嗪-1-基)-2-((四氢-2H-吡喃-4-基)氨基)苯甲酰胺，即化合物T-11，其结构式如下：
Figure PCTCN2018092570-appb-000033
采用以下合成路线：
Figure PCTCN2018092570-appb-000034
步骤1 化合物57的合成
N 2氛及0℃下，向磁力搅拌下的化合物14(940mg，1.77mmol)的干燥二氯甲烷溶液(10mL)中加入干燥的DMF(3滴)，缓慢滴加入草酰氯(4.4mL，8.8mmol，2M二氯甲烷溶液)，氮气氛下室温下搅拌反应3小时。减压蒸除溶剂及多余的草酰氯，并用干燥的二氯甲烷带两次，溶于干燥四氢呋喃中(3mL)，待用。另一50mL双口烧瓶中加入化合物46(219mg，0.85mmol)及干燥四氢呋喃(5mL)，搅拌溶解，N 2氛下加入DIPEA(437mg，3.38mmol)，冷却到0℃，缓慢滴加入上述酰氯溶液，滴完后拆去冰浴，室温下搅拌反应过夜。减压蒸除溶剂，残留物过硅胶柱得白色固体0.66g，收率56.5％。LC-MS(APCI):m/z＝662.3(M+1) +.
步骤2 T-11的合成
向磁力搅拌下的化合物57(0.66g，1.0mmol)的甲醇/水溶液(11mL，10/1)中加入碳酸钾(0.42g，3.0mmol)，氮气氛下室温下搅拌反应3小时。加入水(30mL)，析出大量灰色固体，过滤，水洗(10mL)，溶于二氯甲烷(20mL)，干燥，浓缩，残留物过硅胶柱得白色固体0.4g，收率71.0％。LC-MS(APCI):m/z＝566.2(M+1) +. 1H NMR(400MHz,CDCl 3)δ8.52(s,1H),8.14(d,J＝8.0Hz,1H),7.76(s,1H),7.56(d,J＝8.8Hz,1H),7.31(d,J＝8.8Hz,1H),7.16(dd,J＝8.8Hz,J＝2.0Hz,1H),6.72-6.69(m,2H),6.64-6.59(m,1H),6.23(dd,J＝8.8Hz,J＝2.0Hz,1H),6.10(s,1H),4.01-3.95(m,2H),3.60-3.52(m,3H),3.35(t,J＝4.8Hz,4H),2.62(t,J＝4.8Hz,4H),2.05-2.01(m,2H).
实施案例12制备N-(5-((3,5-二氟苯基)甲基-d 2)-1H-吲唑-3-基)-4-(4-甲基哌啶-1-基)-2-((四氢 -2H-吡喃-4-基-2,2,6,6-d 4)氨基)苯甲酰胺-3,5-d 2，即化合物T-12，其分子式如下：
Figure PCTCN2018092570-appb-000035
采用以下合成路线：
Figure PCTCN2018092570-appb-000036
向配有磁力搅拌及冷凝管的50mL单口烧瓶中依次加入化合物T-8(112mg，0.2mmol)、CH 3COOD(8mL)，搅拌下加入锌粉(56mg，1mmol)，抽真空并N 2置换三次，升温到70℃并保温搅拌反应2小时。冷却到室温，加入乙酸乙酯(20mL)，滤掉未反应完全的锌粉，滤液浓缩至干，加入饱和NaHCO 3溶于(10mL)，乙酸乙酯萃取(15mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得白色固体80mg，收率71.4％。LC-MS(APCI):m/z＝571.2(M+1) +.1H NMR(400MHz,DMSO-d 6)δ12.64(s,1H),10.09(s,1H),8.28(d,J＝8.0Hz,1H),7.79(d,J＝8.8Hz,1H),7.48(s,1H),7.40(d,J＝8.8Hz,1H),7.25(dd,J＝8.8Hz,J＝1.6Hz,1H),7.02-6.98(m,3H),3.73-3.68(s，1H),3.26(t,J＝4.8Hz,4H),2.44(t,J＝4.8Hz,4H),1.98-1.93(m,2H),1.40-1.33(m,2H).
实施案例13制备N-(5-((3,5-二氟苯基)甲基-d 2)-1H-吲唑-3-基)-4-(4-甲基哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-((四氢-2H-吡喃-4-基)氨基)苯甲酰胺，即化合物T-13，其分子式如下：
Figure PCTCN2018092570-appb-000037
采用以下合成路线：
Figure PCTCN2018092570-appb-000038
步骤1 化合物58的合成
N 2氛及0℃下，向磁力搅拌下的化合物24(940mg，1.77mmol)的干燥二氯甲烷溶液(10mL)中加入干燥的DMF(3滴)，缓慢滴加入草酰氯(4.4mL，8.8mmol，2M二氯甲烷溶液)，氮气氛下室温下搅拌反应3小时。减压蒸除溶剂及多余的草酰氯，并用干燥的二氯甲烷带两次，溶于干燥四氢呋喃中(3mL)，待用。另一50mL双口烧瓶中加入化合物46(219mg，0.85mmol)及干燥四氢呋喃(5mL)，搅拌溶解，N 2氛下加入DIPEA(437mg，3.38mmol)，冷却到0℃，缓慢滴加入上述酰氯溶液，滴完后拆去冰浴，室温下搅拌反应过夜。减压蒸除溶剂，残留物过硅胶柱得白色固体0.66g，收率56.5％。LC-MS(APCI):m/z＝667.3(M+1) +.
步骤2 T-13的合成
向磁力搅拌下的化合物58(0.66g，1.0mmol)的甲醇/水溶液(11mL，10/1)中加入碳酸钾(0.42g，3.0mmol)，氮气氛下室温下搅拌反应3小时。加入水(30mL)，析出大量灰色固体，过滤，水 洗(10mL)，溶于二氯甲烷(20mL)，干燥，浓缩，残留物过硅胶柱得白色固体0.4g，收率71.0％。LC-MS(APCI):m/z＝566.2(M+1)+.1H NMR(400MHz,CDCl3)δ8.52(s,1H),8.14(d,J＝8.0Hz,1H),7.76(s,1H),7.56(d,J＝8.8Hz,1H),7.31(d,J＝8.8Hz,1H),7.16(dd,J＝8.8Hz,J＝2.0Hz,1H),6.72-6.69(m,2H),6.64-6.59(m,1H),6.23(dd,J＝8.8Hz,J＝2.0Hz,1H),6.10(s,1H),4.01-3.95(m,2H),3.60-3.52(m,3H),2.44(s,3H),2.05-2.01(m,2H),1.65-1.60(m,2H).
生物活性测试
(1)激酶抑制实验。
化合物配制：受试化合物溶于DMSO配成20mM母液。使用前将化合物在DMSO中稀释成0.1mM(100倍终浓度的稀释液)，并做3倍梯度稀释，11个浓度。加药时用缓冲液稀释成4倍终浓度的稀释液。
激酶检测：配制缓冲液后，将酶与预先稀释配制的不同浓度化合物混合，室温放置30分钟，每个浓度双复孔。加入对应底物及ATP，室温反应60分钟(其中设置阴阳性对照)。反应完毕加入抗体检测，室温孵育60分钟后Evnvision检测，采集数据。通过Evnvision酶标仪检测，测定在各浓度的本发明化合物存在下的酶活力，并计算不同浓度的化合物对酶活力的抑制活性，之后根据四参数方程，根据Graphpad 5.0软件对不同浓度化合物下酶活力的抑制活性进行拟合，计算出IC 50值。
按照上述方法，测试本发明化合物对ALK WT、ALK L1196M、TRK A、TRK B、TRK C激酶的抑制活性。实施实例中的激酶抑制作用结果如表1所示，其中A表示IC 50≤1nM，B表示IC 50为1-10nM，C表示IC 50是10-100nM，D表示IC 50是100-200nM，并且E表示IC 50≥200nM。
如表1所示，本发明化合物具有显著的蛋白激酶抑制活性，一般具有低于10nM的IC 50。例如，同现没有氘代的化合物Entrectinib比较，本发明化合物对ALK WT突变体表现出更优良的抑制活性(IC 50小于10nM)，对ALK L119M突变体表现出与Entrectinib相当的抑制剂活性，特别是对TRKA/B/C表现出强的抑制活性(IC 50小于1nM)。
表1激酶抑制作用对比表
Figure PCTCN2018092570-appb-000039
Figure PCTCN2018092570-appb-000040
(2)细胞毒性实验
检测实施例化合物对Ba/F3，Ba/F3EML-ALK，Ba/F3EML-ALK L1196M、KM12(TPM3-TRKA)、HCC-78(SLC34A2-ROS1)细胞活性的抑制效应。
耗材及试剂：RPMI-1640培养基(GIBCO，目录号A10491-01)、胎牛血清(GIBCO，目录号10099141)、抗生素(Penicillin-Streptomycin)，IL-3(PeproTech)，嘌呤霉素；细胞系：Ba/F3，Ba/F3Bcr-Abl T315I(购自美国标准生物品收藏中心，ATCC)，活细胞检测试剂盒CellTiter-Glo4(Promega，目录号G7572)，96孔黑壁透明平底细胞培养板(Corning，目录号3340)。
实验方法：1.制备细胞板将Ba/F3，Ba/F3Bcr-Abl T315I细胞分别种于96孔板中，并在Ba/F3细胞中加入8ng/ml IL-3，细胞板置于二氧化碳培养箱中过夜培养。2.用DMSO溶解被测化合物并进行3.16倍梯度稀释，9个化合物浓度，设置三复孔实验。3.化合物处理细胞将化合物转移到细胞板中，化合物起始浓度为10μM。细胞板置于二氧化碳培养箱中培养3天。4.检测向细胞板中加入CellTiter-Glo试剂，室温孵育30分钟使发光信号稳定。采用PerkinElmer Envision多标记分析仪读数。
实验结果如表2所示，其中A表示IC 50为1-10nM，B表示IC 50是10-50nM，C表示IC 50是50-150nM，D表示IC 50是150-200nM，E表示IC 50≥200nM。
表2细胞毒性对比表
化合物编号 Ba/F3EML-ALK Ba/F3EML-ALK L1196M KM12 HCC-78
   IC 50(nM) IC 50(nM) IC 50(nM) IC 50(nM)
Entrectinib C E A B
T-1 C E A B
T-2 C E A B
T-3 C E    
T-4 C E    
T-5 C E    
T-6 C E    
T-7 C E    
T-8 C E    
T-9 C E    
T-11 B E    
T-12 B E    
如表2所示，本发明化合物都表现出抑制表达ALK突变体L1196M癌细胞生长的优良抗癌活性。
(3)肝微粒代谢实验
微粒体实验：人肝微粒体：0.5mg/mL，Xenotech；大鼠肝微粒体：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的粉末，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***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***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***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***溶液，作为0min样品。再向孵育板每孔加入80μL的NADPH再生***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***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t 1/2和CL int，其中V/M即等于1/蛋白浓度。
Figure PCTCN2018092570-appb-000041
对本发明化合物及其没有氘代的化合物同时测验比较，评价其在人和大鼠肝微粒体的代谢稳定性。作为代谢稳定性的指标的半衰期及肝固有清除率如表1所示。表1中采用未经氘代的化合物Entrectinib作为对照样品。如表3所示，通过与未经氘代的化合物Entrectinib对照，本发明化合物可以显著改善代谢稳定性。
表3代表性的实施例化合物与Entrectinib对照样的代谢稳定性对比表
Figure PCTCN2018092570-appb-000042
Figure PCTCN2018092570-appb-000043
(4)大鼠药代动力学实验
实验目的：研究大鼠给予实验的化合物后，考察本发明化合物的药代动力学行为。
实验动物：
种类及品系：SD大鼠等级：SPF级
性别及数量：雄性，6只
体重范围：180～220g(实际体重范围为187～197g)
来源：上海西普尔必凯实验动物有限公司
实验及动物合格证号：SCXK(沪)2013-0016
实验过程：
在血样采集之前，预先在EDTA-K2抗凝管中加入20L的2M氟化钠溶液(酯酶抑制剂)，于80度烘箱内烘干后，置于4度冰箱存放。
大鼠，雄性，体重187～197g，随机分为2组，于实验前一天下午开始禁食过夜但可自由饮水，给药后4h给食物。A组给予Entrectinib(3mg/kg)，B组给予实施例化合物(3mg/kg)，分别于给药后15min、30min、1、2、3、5、8、10h从大鼠眼眶静脉取血100-200L左右，置于经EDTA-K2抗凝的0.5mL的Eppendorf管中，立即混匀，抗凝后，尽快将试管轻轻颠倒混匀5-6次后,血取好后放置在冰盒中，30min内把血样本在4000rpm，10min，4℃条件下离心分离血浆，收集全部血浆后立即于-20℃保存。所有时间点样品采集后测定每个时间点的血浆中的血药浓度。
根据上述所得的给药后平均血药浓度-时间数据，采用Winnonin软件，按非房室统计矩理论求算雄性SD大鼠分别i.g给予待测化合物(3mg/kg)后的药代动力学相关参数。
实验表明结果见下表4，与未氘代的化合物Entrectinib相比，本发明化合物具有更优的活性，并且具有优异的药代动力学性质。
表4代表性的实施例化合物与Entrectinib对照样的PK参数对比表
Figure PCTCN2018092570-appb-000044
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 (13)

  1. 一种取代的吲唑类化合物，其特征在于：如式(I)所示的吲唑化合物、或其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物：
    Figure PCTCN2018092570-appb-100001
    其中，
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30和R 31相互独立地选自氢、氘、卤素或三氟甲基；
    附加条件是，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30和R 31中至少一个是氘代的或氘。
  2. 根据权利要求1所述的取代的吲唑类化合物，其特征在于：R 2、R 3、R 9、R 23、R 24、R 25、R 26和R 27是氢。
  3. 根据权利要求2所述的取代的吲唑类化合物，其特征在于：R 1是氘。
  4. 根据权利要求2所述的取代的吲唑类化合物，其特征在于：R 4和R 5是氘。
  5. 根据权利要求2所述的取代的吲唑类化合物，其特征在于：R 28、R 29、R 30和R 31是氘。
  6. 根据权利要求2-5中任意一项所述的取代的吲唑类化合物，其特征在于：R 10和R 11是氘。
  7. 根据权利要求2-6中任意一项所述的取代的吲唑类化合物，其特征在于：R 20、R 21和R 22是氘。
  8. 根据权利要求2-7中任意一项所述的取代的吲唑类化合物，其特征在于：R 12、R 13、R 14、R 15、R 16、R 17、R 18和R 19为氘。
  9. 根据权利要求1所述的取代的吲唑类化合物，其可选自下式化合物：
    Figure PCTCN2018092570-appb-100002
    Figure PCTCN2018092570-appb-100003
    Figure PCTCN2018092570-appb-100004
    Figure PCTCN2018092570-appb-100005
  10. 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权利要求1-9中任意一项所述的取代的吲唑类化合物，或其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物的药物组合物。
  11. 选自权利要求1-9中任意一项所述的吲唑类化合物或其药学上可接受的盐，或权利要求10所述的药物组合物在制备用于治疗由蛋白激酶活性失调引起的相关癌症的方法。
  12. 根据权利要求11所述的方法，其特征在于：所述的蛋白激酶至少选自ALK、ROS1、TRK1、TRK2或TRK3中的一种。
  13. 根据权利要求11所述的方法，其特征在于：其中所述的癌症选自非小细胞肺癌、神经母细胞瘤、结肠直肠癌、间变性大细胞淋巴瘤、胆管癌、胃癌、成胶质细胞瘤、平滑肌肉瘤、黑素瘤、鳞状细胞肺癌、卵巢癌、胰腺癌、***癌、乳腺癌、甲状腺髓样癌、甲状腺***状癌。
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