WO2020135203A1 - 一种药物化合物及其组合物和应用 - Google Patents

一种药物化合物及其组合物和应用 Download PDF

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WO2020135203A1
WO2020135203A1 PCT/CN2019/126507 CN2019126507W WO2020135203A1 WO 2020135203 A1 WO2020135203 A1 WO 2020135203A1 CN 2019126507 W CN2019126507 W CN 2019126507W WO 2020135203 A1 WO2020135203 A1 WO 2020135203A1
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alkyl
substituted
compound
unsubstituted
ring
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French (fr)
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杨欣
孔锐
袁哲东
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上海度德医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
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    • A61P35/00—Antineoplastic agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a protein kinase TRK kinase inhibitor and the technical field of methods using such compounds.
  • TRK kinase is a class of neurotrophic factor receptors, and its family consists of highly homologous tropomyosin-related kinase A (TRK A), tropomyosin-related kinase B (TRK B), tropomyosin-related kinase C (TRK), which is encoded by NTRK1, NTRK2, and NTRK3 genes, respectively.
  • TRK A tropomyosin-related kinase A
  • TRK B tropomyosin-related kinase B
  • TRK tropomyosin-related kinase C
  • TRK protein overexpression has been found in various cancers such as breast cancer, skin cancer (basal cell carcinoma), lung cancer, neuroblastoma and so on.
  • chromosome mutation occurs, the fusion of NTRK gene and other unrelated genes can lead to abnormal regulation of TRK kinase downstream signaling pathways, resulting in disease.
  • TRK kinase inhibitors can achieve the effect of treating diseases by inhibiting the catalytic activity of kinases.
  • the object of the present invention is to provide a new compound and its pharmaceutical composition, which are used as TRK kinase inhibitors.
  • R 1 represents H, substituted or unsubstituted C 1 -C 6
  • R 1 represents H, substituted or unsubstituted C 1 -C 6 alkyl, alkenyl, alkynyl, substituted or unsubstituted C 1 -C 6 hetero Alkyl, alkenyl, alkynyl;
  • R b represents H, substituted or unsubstituted C 1 -C 6 alkyl
  • R C represents H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted adamantyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, hetero Ar 3 or phenyl, wherein The phenyl group is optionally substituted with one or more substituents independently selected from halogen, CN, CF 3 and O (C 1 -C 6 alkyl),
  • NR b R c forms a 7 to 8 membered bridged heterocyclic ring having a ring nitrogen atom and optionally a second ring heteroatom selected from N and O, wherein the ring is optionally substituted by CO 2 (C 1 -C 6 alkyl) substitution;
  • Hetero Ar 1 represents a 5-membered heteroaromatic ring having 1 to 3 ring nitrogen atoms
  • Hetero Ar 2 represents a 5 to 6 membered heteroaromatic ring having at least one nitrogen ring atom and optionally having a second ring heteroatom independently selected from N and S, wherein the heteroaromatic ring is optionally selected independently C 1 -C 6 alkyl, halogen, (C 1 -C 6 ) alkoxy and one or more substituents of NH (C 1 -C 6 alkyl);
  • Hetero Ar 3 represents a 5 to 6 membered heteroaromatic ring having 1 to 2 ring heteroatoms independently selected from N and O and optionally one or more substituents independently selected from C 1 -C 6 alkyl replace;
  • R e represents H, substituted or unsubstituted C 1 -C 6 alkyl
  • R f represents H, substituted or unsubstituted C 1 -C 6 alkyl or (C 3 -C 6 )cycloalkyl;
  • NR e R f forms a 4- to 6-membered nitrogen heterocycle, which optionally has other ring heteroatoms selected from N and O, wherein the nitrogen heterocycle is optionally substituted with OH;
  • R g is H, substituted or unsubstituted C 1 -C 6 alkyl
  • Y represents phenyl, which is optionally substituted with one or more substituents independently selected from halogen, (C 1 -C 6 )alkoxy, CF 3 and CHF 2 , or represents a 5 to 6 membered heteroaromatic ring, It has a ring heteroatom selected from N and S, wherein the heteroaromatic ring is optionally substituted with one or more halogen atoms;
  • X does not exist, or -CH 2 -, -CH 2 CH 2 -, -CH 2 O- or -CH 2 NR d -;
  • R d represents H, substituted or unsubstituted C 1 -C 6 alkyl
  • R 3 represents H, substituted or unsubstituted C 1 -C 6 alkyl
  • Each R 4 is independently selected from halogen, (C 1 -C 6 )alkyl, OH, (C 1 -C 6 )alkoxy, NH 2 , NH (C 1 -C 6 alkyl), and CH 2 OH;
  • n 0, 1, 2, 3, 4, 5, or 6.
  • the compound of the general formula I, its optical isomers or mixtures thereof, its salts, its solvates, its N-oxides, or their prodrugs are used to treat TRK kinase-related diseases or disorders.
  • the disease or disorder is cancer, proliferative disease, pain disease, skin disease, metabolic disease, muscle disease, neurodegenerative disease, neurological disease, immunodeficiency disease, immunity Mediated diseases, autoimmune diseases, autoimmune-mediated diseases, bone diseases, inflammatory diseases, fibrosis, eye diseases, infectious diseases, viral diseases, wound repair, respiratory diseases, lung diseases, kidney diseases, Kidney disease, liver disease, cardiovascular disease, vascular disease, heart disease, cell death and proliferative inflammatory diseases.
  • the disease or disorder is asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, ulcerative colitis, Crohn's disease, bronchitis, dermatitis, allergic rhinitis, silver Psoriasis, scleroderma, urticaria, rheumatoid arthritis, multiple sclerosis, lymphoma, metastasis, anaplastic large cell lymphoma, osteosarcoma, fibroma, melanoma, breast cancer, kidney cancer, brain cancer, Prostate cancer, colorectal cancer, thyroid cancer, ovarian cancer, pancreatic cancer, neuronal cancer, neuroblastoma, lung cancer, uterine cancer, gastrointestinal cancer, HIV or lupus.
  • such pharmaceutical compositions are formulated for intravenous, oral administration, rectal administration, inhalation administration, intranasal administration, topical administration, intraocular administration Preparation for administration or intra-aural administration.
  • the pharmaceutical composition is a tablet, pill, capsule, liquid formulation, inhaler, nasal spray solution, suppository, solution, emulsion, ointment, eye drops Agent or ear drops.
  • the halogen atom means fluorine, chlorine, bromine and iodine.
  • C 1 -C 6 alkyl refers to linear or branched C 1 -C 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl. .
  • C 1 -C 6 alkylene refers to methylene, ethylene, propylene, butylene and their isomers.
  • the C 1 -C 6 alkoxy group is a straight-chain or branched chain such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc.
  • C l -C 4 alkoxy is a straight-chain or branched chain such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc.
  • the alkyl group includes a linear alkyl group and a branched alkyl group.
  • geometric isomers E-type, Z-type, cis-type, trans-type
  • optical isomers R, S due to the presence of asymmetric carbon atoms, etc.
  • optically active optically active body D, L, d, l type
  • polar substances generated by chromatographic separation high Polars, low polars
  • equilibrium compounds rotamers, mixtures of them in any ratio, racemic mixtures
  • all isomers derived from tautomers are also included in the present invention.
  • optical isomers in the present invention include not only 100% pure but also other optical isomers less than 50%.
  • the compound represented by Formula 1 can be converted into the corresponding salt by a known method.
  • the salt is preferably water-soluble.
  • suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, and pharmaceutically acceptable organic bases (tetramethylammonium, triethylamine) , Methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine, N-methyl- D-glucosamine, etc.) salts, acid adduct salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.)), organic acid salts (B Salt, trifluoroacetate, lactate,
  • the compound represented by Formula 1 and its salt may be converted into a solvate.
  • the solvate is preferably low-toxic and water-soluble.
  • suitable solvates include solvates of water and alcohol solvents (for example, ethanol and the like).
  • the prodrug of the compound represented by the general formula I refers to a compound that can be converted into a compound represented by the general formula I by reacting with enzymes and/or gastric acid in the living body.
  • a prodrug of the compound represented by the general formula I when the compound represented by the general formula I has a hydroxyl group, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or borylated may be mentioned.
  • combined administration or “combination administration” and the like as used herein are meant to include the administration of selected therapeutic drugs to a single patient, which should include those in which the drugs do not need to be administered in the same route or at the same time treatment solutions.
  • composition refers to a mixture of a compound described herein with other chemical ingredients, such as carriers, stabilizers, release agents, dispersants, suspending agents, thickeners or excipients Form agent.
  • cancer refers to abnormal growth of cells, which has a tendency to proliferate in an uncontrolled manner, and in some cases, has a tendency to metastasize (spread).
  • Types of cancer include but are not limited to solid tumors (e.g. bladder, intestine, brain, breast, endometrium, heart, kidney, lung tumors), lymph (lymphoma), ovaries, pancreas or other endocrine organs (thyroid), prostate, Skin (melanoma) or hematological tumors (such as leukemia).
  • Such cancers and proliferative diseases include, but are not limited to, hematopoietic disorders, hematopoietic malignancies, non-hematopoietic malignancies, benign or malignant tumors, head and neck tumors, brain cancer, kidney cancer, liver cancer, adrenal cancer, neuronal cancer, neurogenic Cell tumor, bladder cancer, breast cancer, secretory breast cancer, stomach cancer, stomach tumor, ovarian cancer, uterine cancer, colon cancer, rectal cancer, colorectal adenoma, prostate cancer, kidney cancer, brain cancer, endometrial cancer, pancreatic cancer , Lung cancer, non-small cell lung cancer, human adenoid cystic cancer, vaginal cancer, thyroid cancer, papillary thyroid cancer, sarcoma, congenital fibroids, osteosarcoma, osteosarcoma, fibroids, myeloma, tumor metastasis to bone , Congenital mesoderm nephroma, glioblastoma, melanom
  • the hematological malignancies include but are not limited to leukemia, myeloid leukemia, hairy cell leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma) and myeloma, including but Not limited to acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic neutrophilic leukemia, acute undifferentiated leukemia, anaplastic large cell lymphoma, hematopoietic stem cells Leukemia, juvenile myelomonocytic leukemia, adult T-cell acute lymphocytic leukemia, acute myeloid leukemia with three-lineage pathological hematopoiesis, mixed lineage leukemia, myelodysplastic syndrome, myeloproliferative disease, multiple bone marrow Tu
  • skin disease refers to skin diseases.
  • skin diseases include, but are not limited to, proliferative or inflammatory diseases of the skin, such as atopic dermatitis, dermatitis, vesicular disease, collagen disease, contact dermatitis, eczema, Kawasaki disease, rosacea, Sjogren-Larsso syndrome and nettle measles.
  • fibrosis or "fibrotic disease” as used herein refers to a disease after acute or chronic inflammation, which is related to abnormal accumulation of cells and/or collagen, including but not limited to fibrosis of thousands of individual organs or tissues, E.g. heart, kidney
  • Fibrosis of the organs, joints, lungs, or skin including, for example, congenital pulmonary fibrosis and cryptogenic fibrotic alveolitis.
  • inhibition refers to alleviating or inhibiting specified symptoms, disorders or diseases, or significantly reducing the baseline activity of a biological activity or process.
  • inflammatory disease refers to those diseases or conditions characterized by one or more of the following symptoms: pain (pain caused by harmful substances and nerve stimulation), fever (fever caused by vasodilation), hair Redness (redness of the skin caused by vasodilation and increased blood flow), swelling (caused by tumors, excessive fluid inflow or restricted outflow), and loss of function (loss of function, which may be partial or complete, temporary or permanent loss).
  • inflammation there are many forms of inflammation, including but not limited to one or more of the following: acute, adhesive, atrophic, catarrhal, chronic, sclerosing, diffuse, infiltrative, exudative, fibrous, focal , Granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, occlusive, substantial, hyperplastic, pseudomembranous, suppurative, serous fibrinous, serous, simple, specific , Subacute, suppurative, toxic, traumatic and/or ulcerative inflammation.
  • Inflammatory diseases also include but are not limited to those that affect the following tissues: blood vessels (polyarteritis, giant cell arteritis); joints (arthritis: crystalline, bone-, psoriasis, reactive, class Rheumatic, Reiter's); gastrointestinal tract (disease); skin (dermatitis); or multiple organs and tissues (systemic lupus erythematosus).
  • tissues blood vessels (polyarteritis, giant cell arteritis); joints (arthritis: crystalline, bone-, psoriasis, reactive, class Rheumatic, Reiter's); gastrointestinal tract (disease); skin (dermatitis); or multiple organs and tissues (systemic lupus erythematosus).
  • neurodegenerative disease or “neurological system disease” refers to a disorder that alters the structure or function of the brain, spinal cord, or peripheral nervous system, including but not limited to Alzheimer's disease, cerebral edema, and local brain deficit Blood, multiple sclerosis, neuropathy, Parkinson's disease, blunt or surgically trauma-discovered diseases (including postoperative cognitive impairment and spinal cord or brainstem injuries), and neurological aspects of the disease, such as degenerative risk diseases and sciatica.
  • Respiratory diseases refers to diseases that affect organs related to respiration, such as the nose, throat, larynx, trachea, bronchi, and lungs. Respiratory diseases include but are not limited to asthma, adult respiratory distress syndrome and allergic (exogenous) asthma, non-allergic (endogenous) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergens Induced asthma, aspirin-sensitive asthma, exercise-induced asthma, carbon dioxide hyperventilation, childhood-onset asthma, adult-onset asthma, cough variant asthma, occupational asthma, hormone-resistant asthma, seasonal asthma, seasonal allergy Rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease (including chronic bronchitis or emphysema), pulmonary hypertension, interstitial lung fibrosis and/or respiratory tract inflammation, and cystic fibrosis and hypoxia.
  • asthma adult respiratory distress syndrome and allergic (exogenous) asthma, non-allergic (endogenous) asthma, acute severe asthma, chronic asthma, clinical
  • the separation position obtained by chromatography and the solvent in parentheses indicated by TLC indicate the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
  • the name of the compound used in this specification is generally based on the computer program for naming based on the IUPAC rule-ACD/Name (registered trademark) of Advanced Development Company, or named according to the IUPAC nomenclature.
  • 2,5-difluorobenzaldehyde (24g, 168.89mmol) was dissolved in dichloromethane (100mL), (R)-(+)-tert-butylsulfinamide (21.59g, 177.33mmol), cesium carbonate ( 38.52g, 59.11mmol), the reaction at room temperature for 3h, the reaction is complete. After filtration, the filter cake was washed with dichloromethane (100 mL), and the filtrates were combined and spin-dried to obtain a crude product of 40.1 g, with a yield of 96.8%.
  • the reaction solution was lowered to -40°C, and a solution of the compound of Example 1 (30.0 g, 0.122 mol) in methylene chloride (150 mL) was slowly added dropwise. During the addition, the temperature was maintained not to exceed -35°C, and the drop was completed at -40°C. The reaction was overnight. After the reaction was completed, saturated ammonium chloride solution (200 mL) was added to quench the reaction, the liquid was separated, and the aqueous phase was extracted with dichloromethane (2 ⁇ 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate and spin-dried to obtain 34.2 g of the crude product of Example 2 in a yield of 80.5%.
  • Example 2 The compound of Example 2 (30 g, 0.083 mol) was dissolved in trifluoroacetic acid/water (4:1, 75 mL) and reacted for 1 h. Then add trifluoroacetic acid (225mL) and triethylsilane (28.95g, 0.25mol), and continue stirring for 20h after the addition. After the reaction was completed, TFA was distilled off under reduced pressure, water (200 mL) and methyl tert-butyl ether (200 mL) were added for dilution, the organic layer was separated, the organic layer was extracted with 1N hydrochloric acid (200 mL), and the aqueous layers were combined.
  • Example 3 Compound (5.04g, 27.5mmol), 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine (5.2g, 26.19mmol) dissolved in ethanol/tetrahydrofuran (4:1, 50mL) in. Triethylamine (12.74 mL, 91.66 mol) was added, and the reaction was heated to 50° C. for 3 h. The reaction was completed, cooled to room temperature, and filtered to obtain 8.2 g of the compound of Example 4 in a yield of 90.7%.
  • Example 4 The compound of Example 4 (8.0 g, 23.17 mmol) was dissolved in methanol (50 mL), and 10 wt% palladium carbon (0.8 g) was added. Under hydrogen atmosphere, the reaction was carried out at 50°C under normal pressure overnight. Filter and spin-dry the solvent to obtain 6.7 g of the compound of Example 5 with a yield of 86.8%.
  • Example 6 The compound of Example 6 (50 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), (S)-3-hydroxypyrrolidine hydrochloride (20.8 mg, 0.17 mmol), triethylamine (28.3 mg, 0.28 mmol) was added ), reaction for 1h, 1N hydrochloric acid was added after the reaction was completed, the organic phase was washed sequentially with water, dried over anhydrous sodium sulfate, and filtered to spin-dry to obtain the compound of Example 7.
  • trans-p-aminocyclohexanol was used instead of (S)-3-hydroxypyrrolidine hydrochloride.
  • Step 1 According to the method for preparing the compound of Example 7, substituting (S)-3-tert-butoxycarbonylaminopyrrolidine for (S)-3-hydroxypyrrolidine hydrochloride to prepare (S)-3-tert-butyl Carbonylaminoamino-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl ) Pyrrolidine-1-thioamide.
  • Step 2 (S)-3-tert-butoxycarbonylaminoamino-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[ 1,5-a]pyrimidin-3-yl)pyrrolidine-1-thioamide was dissolved in dichloromethane/trifluoroacetic acid (4:1, 2.5mL), stirred at room temperature for 30min, and vortexed to give Example 19 Compound.
  • the compound of Example 20 was used instead of the compound of Example 19.
  • Example 1 The compound of Example 1 (21.2 g, 86.43 mmol) was dissolved in HMPA (100 mL), and H 2 O (1.63 g, 90.75 mmol), zinc powder (8.48 g, 129.64 mmol) and allyl bromide (15.68 g, 129.64 mmol). After the mixed solution was stirred at room temperature for 1.5 h, the reaction was completed. Under ice bath, water (250 mL), methyl tert-butyl ether (250 mL), and 10% citric acid (200 mL) were added in portions.
  • the organic layer was separated, and the organic layer was washed sequentially with saturated brine (200 mL+10 mL 10% citric acid), water (2 ⁇ 200 mL), and dried over anhydrous sodium sulfate. After filtration and concentration, a white solid was obtained, which was slurried with n-heptane (200 ml). After filtration, 19.8 g of white solid was obtained with a yield of 80%.
  • Example 25 The compound of Example 25 (18.0 g, 62.64 mmol) was dissolved in dichloromethane (200 mL), and mCPBA (27.02 g, 156.59 mmol) was added in portions under ice bath, keeping the reaction temperature around 0°C. After 20 minutes of reaction, the temperature was raised to room temperature for 40 hours. The reaction solution was cooled to below 10°C, and water (200 mL) and saturated sodium carbonate solution (100 mL) were added.
  • the organic layer was separated, and the organic layer was washed successively with 10% sodium bisulfite (100 mL), a mixed solution of saturated brine (100 mL) and saturated sodium bicarbonate solution (100 mL), and 10% sodium bicarbonate solution (100 mL), anhydrous Dry with sodium sulfate.
  • Example 26 The compound of Example 26 (8.7 g, 27.24 mmol) was dissolved in DMF (80 mL), and potassium iodide (4.52 g, 27.24 mmol) and potassium carbonate (11.29 g, 81.72 mmol) were added. The temperature was raised to 80°C, and the reaction was completed after 0.5 h of reaction. The reaction solution was cooled to room temperature, water (150 mL) was added, and extracted with isopropyl acetate (2 ⁇ 100 mL). The organic phases were combined. The organic phase was washed with water (2 ⁇ 150 mL) and brine (150 mL) in this order, and dried over anhydrous sodium sulfate.
  • Example 27 The compound of Example 27 (3.7 g, 11.59 mmol) was dissolved in dichloromethane (50 mL), and after the reaction liquid was lowered to -40°C, DAST (4.67 mL, 34.76 mmol) was added dropwise. After reacting at -40°C for 20 min, it was raised to room temperature and reacted overnight. After the reaction was completed, saturated sodium bicarbonate solution (30 mL) was added to quench the reaction, and the organic layer was separated. After the organic layer was dried over anhydrous sodium sulfate, it was spin-dried to give a light brown solid. The crude product was recrystallized from ethyl acetate: n-hexane (35 mL, 1:5), and filtered to obtain 2.1 g of off-white solid with a yield of 56.4%.
  • Example 28 The compound of Example 28 (1.0 g, 3.11 mmol) was dissolved in dichloromethane (10 mL), and trifluoromethanesulfonic acid (1.38 mL, 15.56 mmol) and triethylsilane (0.5 g, 4.67 mmol) were added. The reaction was performed at room temperature for 2h, and the reaction was completed. The reaction solution was added with 40% sodium hydroxide solution to adjust the pH to about 13, the organic layer was separated, the aqueous layer was extracted with methylene chloride (3 ⁇ 10 mL), and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate, and spin-dried to give a light brown oily substance 0.58g, yield 93%.
  • Example 30 According to the method for preparing the compound of Example 5, the compound of Example 30 was substituted for the compound of Example 4.
  • Example 32 According to the method for preparing the compound of Example 6, the compound of Example 32 was substituted for the compound of Example 5.
  • Example 7 According to the method for preparing the compound of Example 7, the compound of Example 32 was replaced with the compound of Example 32.
  • Example 36 1-(5-((2R.4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine -3-yl)-3-((1R,4R)-4-hydroxycyclohexyl)thiourea
  • trans-p-aminocyclohexanol was used instead of (S)-3-hydroxypyrrolidine hydrochloride.
  • Step 1 According to the method for preparing the compound of Example 33, (S)-3-tert-butoxycarbonylaminopyrrolidine was used instead of (S)-3-hydroxypyrrolidine hydrochloride to prepare (S)-3-tert-butyl Oxycarbonylamino-N-(5-((2R.4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine -3-yl)pyrrolidine-1-thioamide.
  • Step 2 (S)-3-tert-butoxycarbonylamino-N-(5-((2R.4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl) Pyrazolo[1,5-a]pyrimidin-3-yl)pyrrolidine-1-thioamide was dissolved in dichloromethane/trifluoroacetic acid (4:1,2.5mL), stirred at room temperature for 30min, and vortexed The compound of Example 45 was obtained.
  • Buffer 50mM Hepes, 0.1mM Orthovanadate, 5mM MgCl 2, 0.01% BSA, 1nm DTT;
  • TK-peptide 20mM ATP, 50nM SEB;
  • Color development buffer 50mM Hepes, 0.8M KF, 20mM EDTA, 0.01% BSA;
  • the IC 50 value of the target compound of the present invention is shown in the following table:
  • the tumor cell lines were cultured in an incubator at 37°C and 5% CO 2 according to the respective culture conditions. Passage regularly and take cells in logarithmic growth phase for plating.
  • IR (%) (1-(RLU compound-RLU blank control) / (RLU vehicle control-RLU blank control)) * 100%. Calculate the inhibition rate of different concentration compounds in Excel, and then use GraphPad Prism software to make the inhibition curve and calculate the relevant parameters
  • Blends are produced according to the formulations presented in the table below, and these blends can be used as a tablet form based on direct compression or roller compaction.
  • Drug substance 50 Microcrystalline cellulose Thinner 30.3 lactose Thinner 15.2 Croscarmellose sodium Disintegrant 3 Silica Glidants 1 Magnesium stearate Lubricant 0.5

Abstract

本发明提供的新化合物(I)显示出的生物活性，可用作TRK激酶抑制剂，如用于治疗TRK介导的疾病或病症的药物癌症、皮炎或哮喘等的治疗和预防。

Description

一种药物化合物及其组合物和应用 技术领域
本发明涉及一种蛋白激酶TRK激酶抑制剂以及使用此类化合物的方法技术领域。
背景技术
TRK激酶是一类神经营养因子受体，其家族由高度同源性的原肌球蛋白相关激酶A(TRK A)、原肌球蛋白相关激酶B(TRK B)、原肌球蛋白相关激酶C(TRK C)、分别由NTRK1、NTRK2、NTRK3基因编码。研究表明，NTRK基因主要在神经系统中表达，它在胚胎发育过程和成体中都有表达。当受到信号诱导而活化时，TRK能自身磷酸化，并激活ERK、PLCγ、P13K/AKT等下游通路，影响细胞增殖、分化、代谢、凋亡。目前在乳腺癌、皮肤癌(基底细胞癌)、肺癌、神经母细胞瘤等多种癌症中都发现了TRK蛋白过量表达的情况。而且当染色体变异发生NTRK基因和其他不相关的基因融合，可导致TRK激酶下游信号通路调控失常，从而导致疾病产生。TRK激酶抑制剂可以通过抑制激酶的催化活性，从而达到治疗疾病的效果。
发明内容
本发明的目的是在于提供一种新化合物及其药用组合物，它们用作TRK激酶抑制剂。
为达上述目的，本发明采取的技术方案如下：
如下通式的化合物1，其光学异构体或它们的混合物、其盐、其溶剂合物、其N氧化物、或它们的前药：
Figure PCTCN2019126507-appb-000001
R 1表示H、取代或未取代的C 1-C 6R 1表示H、取代或未取代的C 1-C 6烷基、烯基、炔基，取代或未取代的C 1-C 6杂烷基、烯基、炔基；
R 2表示NR bR c、取代或未取代的C 1-C 6烷基、CF 3、取代或未取代的C 1-C 6杂烷基、-(C 1-C 6烷基)杂Ar 1,-(C 1-C 6烷基)NH 2、-(C 1-C 6烷基)NH(C 1-C 6烷基)、-(C 1-C 6烷基)N(C 1-C 6烷基) 2、杂 Ar 2、杂Cy、任选地被NHSO 2(C 1-C 6烷基)取代的苯基、或任选地被(C 1-C 6烷基)、CN、OH、OMe、NH 2、NHMe、N(CH 3) 2、F、CF 3、CO 2(C 1-C 6烷基)、CO 2H、C(＝O)NR eR f或C(＝O)OR g取代的(C 3-C 6)环烷基；
R b表示H、取代或未取代的C 1-C 6烷基；
R C表示H、取代或未取代的C 1-C 6烷基，取代或未取代的金刚烷基，取代或未取代的C 1-C 6杂烷基、杂Ar 3或苯基，其中所述苯基任选地被独立选自卤素、CN、CF 3和O(C 1-C 6烷基)的一个或多个取代基取代，
或NR bR c形成具有环氮原子的4元杂环，其中所述杂环任选地被独立选自以下的一个或多个取代基取代：卤素、OH、(C 1-C 6烷基)、(C 1-C 6)烷氧基、OC(＝O)(C 1-C 6烷基)、NH 2、NHC(＝O)O(C 1-C 6烷基)和(C 1-C 6)羟基烷基，
或NR bR c形成5至6元杂环，其具有为氮的环杂原子且任选地具有选自N、O和SO 2的第二环杂原子或基团，其中所述杂环任选地被独立选自以下的一个或多个取代基取代：OH、卤素、CF 3、C 1-C 6烷基、CO 2(C 1-C 6烷基)、CO 2H、NH 2、NHC(＝O)O(C 1-C 6烷基)和氧代。
或NR bR c形成7至8元桥联杂环，其具有环氮原子且任选地具有选自N和O的第二环杂原子，其中所述环任选地被CO 2(C 1-C 6烷基)取代；
杂Ar 1表示具有1至3个环氮原子的5元杂芳环；
杂Ar 2表示5至6元杂芳环，其具有至少一个氮环原子且任选地具有独立选自N和S的第二环杂原子，其中所述杂芳环任选地被独立选自C 1-C 6烷基、卤素、(C 1-C 6)烷氧基和NH(C 1-C 6烷基)的一个或多个取代基取代；
杂Cy表示碳连接的4至6元氮杂环，其任选地被独立选自(C 1-C 6)烷氧基、OC(＝O)(C 1-C 6烷基)的一个或多个取代辈取代、或者任选地被选自C 1-C 6烷基的取代基取代的吡啶酮或哒嗪酮环；
杂Ar 3表示5至6元杂芳环，其具有1至2个独立选自N和O的环杂原子且任选地被独立选自C 1-C 6烷基的一个或多个取代基取代；
R e表示H、取代或未取代的C 1-C 6烷基
R f表示H、取代或未取代的C 1-C 6烷基或(C 3-C 6)环烷基；
或NR eR f形成4至6元氮杂环，其任选地具有选自N和O的其它环杂原子，其中所述氮杂环任选地被OH取代；
R g是H、取代或未取代的C 1-C 6烷基；
Y表示苯基，其任选地被独立选自卤素、(C 1-C 6)烷氧基、CF 3和CHF 2的一个或多个取代基取代，或表示5至6元杂芳环，其具有选自N和S的环杂原子，其中所述杂芳环任选地被 一个或多个卤素原子取代；
X不存在，或是-CH 2-、-CH 2CH 2-、-CH 2O-或-CH 2NR d-；
R d表示H，取代或未取代的C 1-C 6烷基；
R 3表示H，取代或未取代的C 1-C 6烷基；
每个R 4独立选自卤素、(C 1-C 6)烷基、OH、(C 1-C 6)烷氧基、NH 2、NH(C 1-C 6烷基)和CH 2OH；
n是0、1、2、3、4、5或6。
一种药物组合物，含有所述的通式化合物、其光学异构体或它们的混合物、其盐、其溶剂合物、其N-氧化物、或它们的前药。
所述的通式化合物I、其光学异构体或它们的混合物、其盐、其溶剂合物、其N-氧化物、或它们的前药用来治疗TRK激酶相关疾病或病症。
在此类用途的某些实施方案中，所述疾病或病症为癌症、增生性疾病、疼痛疾病、皮肤病、代谢性疾病、肌肉疾病、神经退行性疾病、神经性疾病、免疫缺陷疾病、免疫介导的疾病、自身免疫性疾病、自身免疫介导的疾病、骨病、炎性疾病、纤维化、眼睛疾病、传染性疾病、病毒性疾病、创伤修复、呼吸道疾病、肺部疾病、肾病、肾脏疾病、肝病、心血管疾病、血管病、心脏病、细胞死亡和增生性炎性疾病。
在此类用途的某些实施方案中，所述疾病或病症为哮喘、慢性阻塞性肺病、成人呼吸窘迫综合征、溃疡性结肠炎、克罗恩病、支气管炎、皮炎、过敏性鼻炎、银屑病、硬皮病、荨麻疹、类风湿性关节炎、多重硬化症、淋巴瘤、转移、间变性大细胞淋巴瘤、骨肉瘤、纤维瘤、黑素瘤、乳癌、肾癌、脑癌、前列腺癌、结直肠癌、甲状腺癌、卵巢癌、胰腺癌、神经元癌、成神经细胞瘤、肺癌、子宫癌、胃肠癌、HIV或狼疮。
在此类药用组合物的某些实施方案中，此类药用组合物制成用于静脉内、口服给药、直肠给药、吸入给药、鼻内给药、局部给药、眼内给药或耳内给药的制剂。在此类药用组合物的某些实施方案中，所述药用组合物为片剂、丸剂、胶囊、液体制剂、吸入剂、鼻用喷雾溶液、栓剂、溶液剂、乳剂、软膏、滴眼剂或滴耳剂。
本发明中，卤素原子是指氟、氯、溴、碘。
本发明中，C 1-C 6烷基是指甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基等直链或支链的C 1-C 6烷基。
本发明中，C 1-C 6亚烷基是指亚甲基、亚乙基、亚丙基、亚丁基及它们的异构体等。本发明中，C 1-C 6烷氧基是指甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等直链或支链的C l-C 4烷氧基。
本发明中，只要没有特殊说明，还包括所有的异构体。例如，烷基包括直链烷基和支链烷基。进而，双键、环、稠合环中的几何异构体(E型、Z型、顺式体、反式体)、由存在不对称碳原子等而产生的光学异构体(R,S型、α、β构型、对映异构体、非对映异构体)、具有旋光性的光学活性体(D、L、d、l型)、通过色谱分离产生的极性物(高极性物、低极性物)、平衡化合物、旋转异构体、它们的任意比例的混合物、外消旋混合物均包括在本发明中。另外，本发明中，也包括所有的由互变异构体产生的异构体。
另外，本发明中的光学异构体不仅包括100％纯的，而且包括小于50％的其它光学异构体。
本发明中，只要没有特殊说明，如本领域技术人员所熟知的符号
Figure PCTCN2019126507-appb-000002
表示键合至朝向纸面的一侧(即α构型)，
Figure PCTCN2019126507-appb-000003
表示键合至纸面的观察者眼前侧(即β构型)，
Figure PCTCN2019126507-appb-000004
表示α构型、β构型或它们的任意比例的混合物。
通式1表示的化合物可通过公知的方法转化为相应的盐。盐优选为水溶性的。作为适当的盐，可举出碱金属(钾、钠等)的盐、碱土类金属(钙、镁等)的盐、铵盐、药学上可接受的有机碱(四甲基铵、三乙胺、甲胺、二甲胺、环戊胺、苄胺、苯乙胺、哌啶、单乙醇胺、二乙醇胺、三(羟甲基)氨基甲烷、赖氨酸、精氨酸、N-甲基-D-葡糖胺等)的盐、酸加成物盐(无机酸盐(盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、硝酸盐等)、有机酸盐(乙酸盐、三氟乙酸盐、乳酸盐、酒石酸盐、草酸盐、富马酸盐、马来酸盐、苯甲酸盐、柠檬酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、甲苯磺酸盐、羟乙基磺酸盐、葡糖醛酸盐、葡糖酸盐等)等；
通式1表示的化合物及其盐也可以转变为溶剂合物。溶剂合物优选为低毒性且水溶性的。作为适当的溶剂合物，例如可举出水、醇类的溶剂(例如，乙醇等)的溶剂合物。
另外，通式I表示的化合物的前药是指能够在生物体内通过酶和/或胃酸等发生反应，由此转变成通式I表示的化合物。作为通式I表示的化合物的前药，在通式I表示的化合物具有羟基时，可举出该羟基被酰化、烷基化、磷酰化、硼酰化的化合物。
本文中使用的术语“联合给药”或“组合给药”等是指包括将选定的治疗药物给予单一患者，其应当包括其中所述药物不需要以相同给药途径或同一时间给药的治疗方案。
本文中使用的术语“药用组合物”是指本文中所述化合物与其它化学成分的混合物，其 它化学成分例如载体、稳定剂、桸释剂、分散剂、助悬剂、增稠剂或赋形剂。
本文中使用的术语“癌症”是指细胞的异常生长，其具有以不受控制的方式增生的趋势，在某些情况下，有转移(扩散)的趋势。癌症的类型包括但不限于实体瘤(例如膀胱、肠、脑、乳房、子宫内膜、心脏、肾脏、肺肿瘤)、淋巴(淋巴瘤)、卵巢、胰腺或其它内分泌器官(甲状腺)、前列腺、皮肤(黑素瘤)或血液肿瘤(例如白血病)。
此类癌症和增生性疾病包括但不限于造血障碍、造血系统恶性肿瘤、非造血系统恶性瘤、良性或恶性肿瘤、头颈肿瘤、脑癌、肾癌、肝癌、肾上腺癌、神经元癌、成神经细胞瘤、膀胱癌、乳癌、分泌性乳癌、胃癌、胃肿瘤、卵巢癌、子宫癌、结肠癌、直肠癌、结直肠腺瘤、前列腺癌、肾癌、脑癌、子宫内膜癌、胰腺癌、肺癌、非小细胞肺癌、人腺样囊性癌、阴道癌、甲状腺癌、乳头状甲状腺癌、肉瘤、先天性纤维瘤、融骨肉瘤、骨肉瘤、纤维瘤、骨髓瘤、肿瘤向骨转移、先天性中胚叶肾瘤、成胶质细胞瘤、黑素瘤、多发性骨髓瘤、胃肠癌、胃肠道间质瘤、肥大细胞增多症、成神经细胞瘤、纤维化癌症、肿瘤转移生长、表皮过度增生、银屑病、转移、前列腺增生、瘤形成、上皮样瘤形成、淋巴瘤、弥漫性大B细胞淋巴瘤、B细胞淋巴瘤、乳腺癌、肾母细胞瘤、错构瘤综合征、小脑皮质弥漫性神经节细胞瘤和Bannayan-Zonana综合征。
所述恶性血液病包括但不限于白血病、骨髓性白血病、毛细胞白血病、淋巴瘤(非霍奇金淋巴瘤)、霍奇金病(也称为霍奇金淋巴瘤)和骨髓瘤，包括但不限于急性淋巴细胞白血病、急性髓性白血病、急性早幼粒细胞白血病、慢性淋巴细胞白血病、慢性髓性白血病、慢性中性粒细胞白血病、急性未分化白血病、间变性大细胞淋巴瘤、造血干细胞白血病、幼年型粒-单核细胞白血病、成人T-细胞急性淋巴细胞白血病、急性髓性白血病伴骨髓三系病态造血、混合谱系白血病、骨髓增生异常综合征、髓性增生性疾病、多发性骨髓瘤、髓性肉瘤和急性早幼粒细胞白血病。
本文中使用的术语“皮肤病”是指皮肤疾病。此类皮肤病包括但不限于皮肤的增生性或炎性疾病，例如异位性皮炎、皮炎、水泡症、胶原病、接触性皮炎、湿疹、川崎病、红斑痤疮、Sjogren—Larsso综合征和荨麻疹。
本文中使用的术语“纤维化”或“纤维化疾病”是指急性或慢性炎症后的疾病，与细胞和/或胶原蛋白的异常积聚有关，包括但不限千个体器官或组织的纤维化，例如心脏、肾
脏、关节、肺或皮肤的纤维化，包括例如先天性肺纤维化和隐源性纤维化肺泡炎。
本文中使用的术语抑制是指减轻或抑制指定的症状、病症或疾病，或者显著降低生物学活性或过程的基线活性。
本文中使用的术语“炎性疾病”是指特征在于具有一或多个下列症状的那些疾病或病症： 疼痛(有害物质以及神经刺激所产生的疼痛)、发热(血管舒张产生的发热)、发红(血管舒张以及血流增加导致的皮肤发红)、肿胀(肿瘤，体液过度流入或流出受限导致的)以及功能丧失(机能丧失，可能是部分或全部、暂时或永久丧失)。炎症有多种形式，包括但不限于下列一或多种炎症：急性、粘连性、萎缩性、卡他性、慢性、硬化性、扩散性、浸润性、渗出性、纤维性、局灶性、肉芽肿性、增生性、肥厚性、间质性、转移性、坏死性、闭塞性、实质性、增生性、假膜性、化脓性、浆液纤维蛋白性、浆液性、单纯性、特异性、亚急性、化脓性、中毒性、外伤性和/或溃疡性炎症。炎性疾病还包括但不限于那些影响下列组织的炎性疾病：血管(多动脉炎、巨细胞性动脉炎)；关节(关节炎：结晶性、骨-、银屑病性、反应性、类风湿性、Reiter's)；胃肠道(疾病)；皮肤(皮炎)；或多器官和组织(系统性红斑狼疮)。
本文中使用的术语“神经退行性疾病”或“神经系统疾病”是指改变脑、脊髓或外周神经系统结构或功能的病症，包括但不限千阿尔茨海默病、脑水肿、脑局部缺血、多重硬症、神经病、帕金森病、钝击或手术创伤后发现的疾病(包括手术后认知障碍以及脊髓或脑干伤害)以及疾病的神经方面，例如退行性风险疾病和坐骨神经痛。
本文中使用的术语“呼吸道疾病”是指影响与呼吸有关的器官的疾病，所述器官例如鼻、咽喉、喉、气管、支气管和肺。呼吸道疾病包括但不限千哮喘、成人呼吸窘迫综合征和过敏性(外源性)哮喘、非过敏性(内源性)哮喘、急性严重哮喘、慢性哮喘、临床性哮喘、夜间哮喘、过敏原诱导的哮喘、阿司匹林敏感性哮喘、运动诱发的哮喘、二氧化碳换气过度、儿童发作型哮喘、成人发作型哮喘、咳嗽变异性哮喘、职业性哮喘、激素抵抗性哮喘、季节性哮喘、季节性过敏性鼻炎、长年性过敏性鼻炎、慢性阻塞性肺病(包括慢性的支气管炎或肺气肿)、肺高血压、间质性肺纤维化和/或呼吸道炎症以及囊性纤维化和缺氧。
具体实施方式
由色谱得到的分离的位置和由TLC表示的括号内的溶剂表示所使用的洗脱溶剂或展开溶剂，比例表示体积比。
本说明书中使用的化合物的名称，一般采用基于IUPAC法则进行命名的计算机程序--Advanced Chemistry Development公司的ACD/Name(注册商标)，或者根据IUPAC命名法来命名。
实施例1：(R,E)-N-(2,5-二氟亚苄基)-2-甲基丙烷-2-亚磺酰胺
Figure PCTCN2019126507-appb-000005
2,5-二氟苯甲醛(24g，168.89mmol)溶于二氯甲烷(100mL)中，加入(R)-(+)-叔丁基亚磺酰胺(21.59g，177.33mmol)，碳酸铯(38.52g，59.11mmol)，室温反应3h，反应完全。过滤，滤饼用二氯甲烷(100mL)洗涤，合并滤液，旋干得粗品40.1g，收率96.8％，直接投入下一步反应。
实施例2：(R)-N-((R)-1-(2,5-二氟苯基)-3-(1,3-二噁烷-2-)丙基)-2-甲基丙烷-2-亚磺酰胺
Figure PCTCN2019126507-appb-000006
镁条(5.95g，0.245mol)和碘(催化量)悬浮于四氢呋喃(50mL)中，悬浮液中滴加2-(2-溴乙基)-1,3-二噁烷(4.43g，0.0245mol)的四氢呋喃溶液(20ml)。反应液温度升至65℃左右。滴毕冷却至室温后，继续滴加2-(2-溴乙基)-1,3-二噁烷(39.87g，0.221mol)的四氢呋喃溶液(180ml)，滴毕室温反应30min。将该反应液降至-40℃，缓慢滴加实施例1化合物(30.0g，0.122mol)的二氯甲烷(150mL)溶液，加入过程中维持温度不超过-35℃，滴毕在-40℃下反应过夜。反应结束后，加入饱和氯化铵溶液(200mL)淬灭反应，分液，水相用二氯甲烷(2×200mL)萃取。合并有机相，无水硫酸钠干燥后旋干得实施例2化合物粗品34.2g，收率80.5％。
实施例3：R-2-(2,5-二氟苯基)吡咯烷
Figure PCTCN2019126507-appb-000007
实施例2化合物(30g，0.083mol)溶于三氟乙酸/水(4:1，75mL)中，反应1h后。再加入三氟乙酸(225mL)以及三乙基硅烷(28.95g，0.25mol)，加毕继续搅拌20h。反应结 束后减压蒸馏除去TFA，加入水(200mL)和甲基叔丁基醚(200mL)稀释，分离有机层，有机层用1N盐酸(200mL)萃取，合并水层。水层用40％的氢氧化钠溶液调节pH至13后，用二氯甲烷(3×200mL)萃取。合并有机相，无水硫酸钠干燥后，旋干得实施例3化合物10.2g，收率64.5％。
实施例4：R-5-(2-(2,5-二氟苯基)吡咯烷-1-基)-3-硝基吡唑并[1,5-a]嘧啶
Figure PCTCN2019126507-appb-000008
实施例3化合物(5.04g，27.5mmol)，5-氯-3-硝基吡唑并[1,5-a]嘧啶(5.2g,26.19mmol)溶于乙醇/四氢呋喃(4:1，50mL)中。加入三乙胺(12.74mL，91.66mol)，加热至50℃反应3h，反应结束，冷却至室温，过滤得到实施例4化合物8.2g，收率90.7％。
实施例5：R-5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-胺
Figure PCTCN2019126507-appb-000009
实施例4化合物(8.0g，23.17mmol)溶于甲醇(50mL)中，加入10wt％钯碳(0.8g)。在氢气环境下，50℃常压反应过夜。过滤，旋干溶剂得实施例5化合物6.7g，收率86.8％。
实施例6：R-5-(2-(2,5-二氟苯基)吡咯烷-1-基)-3-异硫氰基吡唑并[1,5-a]嘧啶
Figure PCTCN2019126507-appb-000010
实施例5化合物(2.0g，6.34mmol)溶于二氯甲烷(20mL)中，加入碳酸钾(1.75g，12.69mL)和硫光气(0.88g，0.6mL)，室温反应过夜。反应结束后，加水淬灭反应，水层用二氯甲烷(3×20mL)萃取。合并有机相，无水硫酸钠干燥后旋干，粗品用硅胶柱层析(石油 醚：乙酸乙酯＝3：1)分离纯化，得到实施例6化合物1.7g，收率79.4％。
实施例7：(S)-N-(5-R-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-羟基吡咯烷-1-硫代酰胺
Figure PCTCN2019126507-appb-000011
实施例6化合物(50mg，0.14mmol)溶于二氯甲烷(5mL)中，加入(S)-3-羟基吡咯烷盐酸盐(20.8mg，0.17mmol)，三乙胺(28.3mg，0.28mmol)，反应1h，反应结束后加入1N盐酸，有机相再依次用水洗涤，无水硫酸钠干燥，过滤旋干得实施例7化合物。
实施例8：(R)-1-(5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(四氢呋喃-4基)硫脲
Figure PCTCN2019126507-appb-000012
根据制备实施例7化合物的方法，用4-氨基四氢呋喃代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例9：(R)-1-苄基-3-(5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)硫脲
Figure PCTCN2019126507-appb-000013
根据制备实施例7化合物的方法，用苄胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例10：1-(5-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-((1R,4R)-4-羟基环己基)硫脲
Figure PCTCN2019126507-appb-000014
根据制备实施例7化合物的方法，用反式对氨基环己醇代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例11：(R)-1-(环己基甲基)-3-(5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)硫脲
Figure PCTCN2019126507-appb-000015
根据制备实施例7化合物的方法，用环己甲胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例12：(R)-1-环己基-3-(5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)硫脲
Figure PCTCN2019126507-appb-000016
根据制备实施例7化合物的方法，用环己胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例13：(R)-N-(5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-羟基氮杂环丁烷基-1-硫代酰胺
Figure PCTCN2019126507-appb-000017
根据制备实施例7化合物的方法，用3-羟基氮杂环丁胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例14：(R)-1-(5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(2-羟基乙基)硫脲
Figure PCTCN2019126507-appb-000018
根据制备实施例7化合物的方法，用乙醇胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例15：(R)-3-(5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-1,1-二(2-羟基乙基)硫脲
Figure PCTCN2019126507-appb-000019
根据制备实施例7化合物的方法，用二乙醇胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例16：(R)-1-(5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(3-甲氧基丙基)硫脲
Figure PCTCN2019126507-appb-000020
根据制备实施例7化合物的方法，用3-甲氧基丙胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例17：(R)-1-(5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(2-甲氧基乙基)硫脲
Figure PCTCN2019126507-appb-000021
根据制备实施例7化合物的方法，用2-甲氧基乙胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例18：(R)-1-(5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(2,2-二甲氧基乙基)硫脲
Figure PCTCN2019126507-appb-000022
根据制备实施例7化合物的方法，用氨基乙醛缩二甲醇代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例19：(S)-3-氨基-N-(5-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)吡咯烷-1-硫代酰胺
Figure PCTCN2019126507-appb-000023
步骤1：根据制备实施例7化合物的方法，用(S)-3-叔丁氧碳基氨基吡咯烷代替(S)-3-羟基吡咯烷盐酸盐来制备(S)-3-叔丁氧碳基氨基氨基-N-(5-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)吡咯烷-1-硫代酰胺。
步骤2：(S)-3-叔丁氧碳基氨基氨基-N-(5-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)吡咯烷-1-硫代酰胺溶于二氯甲烷/三氟乙酸(4:1,2.5mL)中，室温搅拌30min，旋干即得实施例19化合物。
实施例20：(R)-3-氨基-N-(5-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)吡咯烷-1-硫代酰胺
Figure PCTCN2019126507-appb-000024
根据制备实施例19化合物的方法，用(R)-3-叔丁氧羰基氨基吡咯烷代替(S)-3-叔丁氧碳 基氨基吡咯烷来制备。
实施例21：(R)-1-(5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(2,2,2-三氟乙基)硫脲
Figure PCTCN2019126507-appb-000025
根据制备实施例7化合物的方法，用三氟甲磺胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例22：(R)-1-(5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(3-羟基金刚烷基)硫脲
Figure PCTCN2019126507-appb-000026
根据制备实施例7化合物的方法，用3-羟基-1-金刚烷胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例23：(S)-N-(5-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(3,3-二甲基脲基)吡咯烷-1-硫代酰胺
Figure PCTCN2019126507-appb-000027
实施例19化合物溶于二氯甲烷中，加入二甲基甲酰氯(1.2eq)和三乙胺(2.5eq)，室温反应1h后，用硅胶柱层析(石油醚：乙酸乙酯＝3：1)分离纯化，得到实施例23化合物。
实施例24：(R)-N-(5-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(3,3-二甲基脲基)吡咯烷-1-硫代酰胺
Figure PCTCN2019126507-appb-000028
根据制备实施例23化合物的方法，用实施例20化合物代替实施例19化合物来制备。
实施例25：(R)-N-((R)-1-(2,5-二氟苯基)丁-3-烯-1-基)-2-甲基丙烷-2-亚磺酰胺
Figure PCTCN2019126507-appb-000029
实施例1化合物(21.2g,86.43mmol)溶于HMPA(100mL)中，依次加入H 2O(1.63g,90.75mmol),锌粉(8.48g，129.64mmol)以及烯丙基溴(15.68g，129.64mmol)。混合溶液于室温搅拌1.5h后反应结束。冰浴下分批加入水(250mL)，甲基叔丁基醚(250mL)，10％柠檬酸(200mL)。分离有机层，有机层依次用饱和食盐水(200mL+10mL 10％柠檬酸)，水(2×200mL)洗涤，无水硫酸钠干燥。过滤浓缩得白色固体，用正庚烷(200ml)打浆，过滤后得白色固体19.8g，收率80％。
实施例26：N-((1R)-1-(2,5-二氟苯基)-2-(环氧乙基-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺
Figure PCTCN2019126507-appb-000030
实施例25化合物(18.0g，62.64mmol)溶于二氯甲烷(200mL)中，冰浴下分批加入mCPBA(27.02g，156.59mmol)，保持反应温度在0℃左右。反应20分钟后，升温至室温反应40h。将反应液冷却至10℃以下，加入水(200mL)，饱和碳酸钠溶液(100mL)。分离有机层，有机层依次用10％亚硫酸氢钠(100mL)，饱和食盐水(100mL)和饱和碳酸氢钠溶液(100mL)混合溶液，以及10％碳酸氢钠溶液(100mL)洗涤、无水硫酸钠干燥。
过滤、旋干，得到无色油状物(立马固化)，用正己烷(50mL)打浆，过滤得白色固体 17.2g,收率86％。
实施例27：(3R,5R)-1-(叔丁基磺酰基)-5-(2,5-二氟苯基)-3-羟基吡咯烷
Figure PCTCN2019126507-appb-000031
实施例26化合物(8.7g,27.24mmol)溶于DMF(80mL)中，加入碘化钾(4.52g,27.24mmol)以及碳酸钾(11.29g,81.72mmol)。升温至80℃，反应0.5h后，原料反应完全。反应液冷却至室温，加入水(150mL)，用乙酸异丙酯(2×100mL)萃取，合并有机相，有机相依次用水(2×150mL)以及盐水(150mL)洗涤、无水硫酸钠干燥。过滤，旋干得淡棕色固体,用乙酸乙酯：正庚烷(1:1)80mL进行两次次重结晶，两次都取滤液，最后旋干滤液得固体3.7g,收率43％。
实施例28：(2R,4S)-1-(叔丁基磺酰基)-2-(2,5-二氟苯基)-4-氟-吡咯烷
Figure PCTCN2019126507-appb-000032
实施例27化合物(3.7g,11.59mmol)溶于二氯甲烷(50mL)中，反应液降至-40℃后滴加DAST(4.67mL,34.76mmol)。在-40℃下反应20min后，升至室温反应过夜。反应结束后加入饱和碳酸氢钠溶液(30mL)淬灭反应，分离有机层。有机层用无水硫酸钠干燥后，旋干得淡棕色固体。粗品用乙酸乙酯：正己烷(35mL，1:5)重结晶，过滤得类白色固体2.1g，收率56.4％。
实施例29：(2R,4S)-2-(2,5-二氟苯基)-4-氟-吡咯烷
Figure PCTCN2019126507-appb-000033
实施例28化合物(1.0g，3.11mmol)溶于二氯甲烷(10mL)中，加入三氟甲磺酸(1.38mL,15.56mmol)以及三乙基硅烷(0.5g，4.67mmol)。室温反应2h，反应结束。反应液加入40％的氢氧化钠溶液调节pH至13左右，分离有机层，水层再用二氯甲烷(3×10mL)萃取，合并有机层。有机层用无水硫酸钠干燥，旋干得淡棕色油状物0.58g，收率93％。
实施例30：5-((2R,4S)-2-(2,5-二氟苯基)-4-氟-吡咯烷-1-基)-3-硝基吡唑并[1,5-a]嘧啶
Figure PCTCN2019126507-appb-000034
根据制备实施例4化合物的方法，用(2R,4S)-2-(2,5-二氟苯基)-4-氟-吡咯烷代替R-2-(2,5-二氟苯基)吡咯烷来制备。
实施例31：5-((2R,4S)-2-(2,5-二氟苯基)-4-氟-吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-胺
Figure PCTCN2019126507-appb-000035
根据制备实施例5化合物的方法，用实施例30化合物代替实施例4化合物。
实施例32：5-((2R,4S)-2-(2,5-二氟苯基)-4-氟-吡咯烷-1-基)-3-异硫氰基吡唑并[1,5-a]嘧啶
Figure PCTCN2019126507-appb-000036
根据制备实施例6化合物的方法，用实施例32化合物代替实施例5化合物。
实施例33：(S)-N-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-羟基吡咯烷-1-硫代酰胺
Figure PCTCN2019126507-appb-000037
根据制备实施例7化合物的方法，用实施例32化合物代替实施例5化合物。
实施例34：(R)-1-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(四氢呋喃-4基)硫脲
Figure PCTCN2019126507-appb-000038
根据制备实施例33化合物的方法，用4-氨基四氢呋喃代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例35：(R)-1-苄基-3-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)硫脲
Figure PCTCN2019126507-appb-000039
根据制备实施例33化合物的方法，用苄胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例36：1-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-((1R,4R)-4-羟基环己基)硫脲
Figure PCTCN2019126507-appb-000040
根据制备实施例33化合物的方法，用反式对氨基环己醇代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例37：(R)-1-(环己基甲基)-3-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)硫脲
Figure PCTCN2019126507-appb-000041
根据制备实施例33化合物的方法，用环己甲胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例38：(R)-1-环己基-3-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)硫脲
Figure PCTCN2019126507-appb-000042
根据制备实施例33化合物的方法，用环己胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例39：(R)-N-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-羟基氮杂环丁烷基-1-硫代酰胺
Figure PCTCN2019126507-appb-000043
根据制备实施例33化合物的方法，用3-羟基氮杂环丁胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例40：(R)-1-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(2-羟基乙基)硫脲
Figure PCTCN2019126507-appb-000044
根据制备实施例33化合物的方法，用乙醇胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例41：(R)-3-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-1,1-二(2-羟基乙基)硫脲
Figure PCTCN2019126507-appb-000045
根据制备实施例33化合物的方法，用二乙醇胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例42：(R)-1-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(3-甲氧基丙基)硫脲
Figure PCTCN2019126507-appb-000046
根据制备实施例33化合物的方法，用3-甲氧基丙胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例43：(R)-1-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(2-甲氧基乙基)硫脲
Figure PCTCN2019126507-appb-000047
根据制备实施例33化合物的方法，用2-甲氧基乙胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例44：(R)-1-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(2，2-二甲氧基乙基)硫脲
Figure PCTCN2019126507-appb-000048
根据制备实施例33化合物的方法，用氨基乙醛缩二甲醇代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例45：(S)-3-氨基-N-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)吡咯烷-1-硫代酰胺
Figure PCTCN2019126507-appb-000049
步骤1：根据制备实施例33化合物的方法，用(S)-3-叔丁氧碳基氨基吡咯烷代替(S)-3-羟基吡咯烷盐酸盐来制备(S)-3-叔丁氧羰基氨基-N-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)吡咯烷-1-硫代酰胺。
步骤2：(S)-3-叔丁氧羰基氨基-N-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)吡咯烷-1-硫代酰胺溶于二氯甲烷/三氟乙酸(4:1,2.5mL)中，室温搅拌30min，旋干即得实施例45化合物。
实施例46：(R)-3-氨基-N-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)吡咯烷-1-硫代酰胺
Figure PCTCN2019126507-appb-000050
根据制备实施例45化合物的方法，用(R)-3-叔丁氧羰基氨基吡咯烷代替(S)-3-叔丁氧碳基氨基吡咯烷来制备。
实施例47：(R)-1-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(2，2，2-三氟乙基)硫脲
Figure PCTCN2019126507-appb-000051
根据制备实施例33化合物的方法，用三氟甲磺胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
实施例49：(R)-1-(5-((2R.4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-(3-羟基金刚烷基)硫脲
Figure PCTCN2019126507-appb-000052
根据制备实施例33化合物的方法，用3-羟基-1-金刚烷胺代替(S)-3-羟基吡咯烷盐酸盐来制备。
目标化合物列表：
Figure PCTCN2019126507-appb-000053
Figure PCTCN2019126507-appb-000054
Figure PCTCN2019126507-appb-000055
Figure PCTCN2019126507-appb-000056
Figure PCTCN2019126507-appb-000057
Figure PCTCN2019126507-appb-000058
Figure PCTCN2019126507-appb-000059
Figure PCTCN2019126507-appb-000060
生物学实验例1：
TRK A酶抑制活性的测定
激酶反应：
缓冲液:50mM Hepes,0.1mM Orthovanadate,5mM MgCl 2,0.01％BSA,1nm DTT；
0.5nM TRKA；
0.3μM TK-peptide,20mM ATP,50nM SEB；
23℃反应90minutes；
显色反应：
显色缓冲液:50mM Hepes,0.8M KF,20mM EDTA,0.01％BSA；
0.67nM TK-Antibody,50nM XL665；
23℃反应60minutes；
检测设备：
Envision(PerkinElmer#2104)
由基于受试化合物的各浓度下的抑制率的抑制曲线，计算受试化合物的50％抑制率的值(IC 50值)。
对于本发明目标化合物的IC 50值，如下表所示：
实施例编号 IC 50(nM)
7 1.95
8 23.73
9 3.54
10 11.03
11 27.44
12 6.32
13 27.75
14 20.79
15 81.68
16 55.69
17 31.39
18 8.83
19 140.22
20 100.34
21 31.13
22 4.32
23 6.09
24 12.6
33 0.75
34 4.46
35 3.34
36 3.95
37 4.43
38 1.26
39 1.24
40 6.98
41 6.54
42 6.36
43 12.39
44 7.27
45 15.7
46 12.39
47 5.45
48 4.07
Larotrectinib(LOXO-101) 1.96
Entrectinib(RXDX-101) 0.43
生物学实验例2：
研究活性化合物抑制体外肿瘤细胞增殖的作用
1.细胞系及培养方法
细胞系 肿瘤类型 生长特点 培养方法
KM-12 结肠癌 贴壁 DMEM+FBS10％
2.培养基及试剂
培养基及试剂 生产商 货号
DMEM GIBCO 11995-065
Dulbecco's PBS Thermo SH30028.02B
FBS Hyclone SH30084.03
Antibiotic-antimycotic GIBCO 15240-062
DMSO SIGMA D2650
L-glutamine Invitrogen 25030164
3.细胞活性实验所用试剂及仪器
(1).Promega CellTiter-Glo发光法细胞活性检测试剂盒(Promega-G7573).
(2).2104 EnVision读板器，PerkinElmer
4.实验方法及步骤
4.1细胞培养
将肿瘤细胞系按各自的培养条件在37℃，5％CO 2的培养箱中进行培养。定期传代，取处于对数生长期的细胞用于铺板。
4.1.1细胞铺板
1)用台盼兰进行细胞染色并计数活细胞。
2)将细胞浓度调整至合适浓度。
3)在培养板中每孔加入90μL细胞悬液，在空白对照空中加入不含细胞的培养液。
4)将培养板在37℃,5％CO 2,及100％相对湿度的培养箱中培养过夜。
4.2化合物存储板制备
制备400X化合物存储板：将化合物用DMSO从最高浓度梯度稀释至最低浓度。
4.3 10X化合物工作液的配制及化合物处理细胞
1)10X化合物工作液的配制：在V形底的96孔板中加入76μL细胞培养液，从400X化合物存储板中吸取4μL化合物加入96孔板的细胞培养液中。在溶媒对照和空白对照中加入4μL DMSO。加入化合物或DMSO后用排枪吹打混匀。
2)加药：取10μL的10X化合物工作液加入到细胞培养板中。在溶媒对照和空白对照中加入10μL DMSO-细胞培养液混合液。DMSO终浓度为0.50％。
3)将96孔细胞板放回培养箱中培养72h。
4.4 CellTiter-Glo发光法细胞活性检测
以下步骤按照Promega CellTiter-Glo发光法细胞活性检测试剂盒(Promega-G7573)的说明书来进行。
1)将CellTiter-Glo缓冲液融化并放置至室温。
2)将CellTiter-Glo底物放置至室温。
3)在一瓶CellTiter-Glo底物中加入CellTiter-Glo缓冲液以溶解底物，从而配制CellTiter-Glo工作液。
4)缓慢涡旋震荡使充分溶解。
5)取出细胞培养板放置30分钟使其平衡至室温。
6)在每孔中加入50μL(等于每孔中细胞培养液一半体积)的CellTiter-Glo工作液。用铝箔纸包裹细胞板以避光。
7)将培养板在轨道摇床上振摇2分钟以诱导细胞裂解。
8)培养板在室温放置10分钟以稳定发光信号。
9)在2104 EnVision读板器上检测发光信号。
5.数据分析
用下列公式来计算检测化合物的抑制率(Inhibition rate，IR)：IR(％)＝(1–(RLU化合 物–RLU空白对照)/(RLU溶媒对照–RLU空白对照))*100％。在Excel中计算不同浓度化合物的抑制率，然后用GraphPad Prism软件作抑制曲线图和计算相关参数
化合物33以及Larotrectinib(LOXO-101)
对体外肿瘤细胞增殖的抑制作用
Figure PCTCN2019126507-appb-000061
药物制剂实施例1：
根据下表中所呈现的配方产生共混物，这些共混物可作为基于直接压缩或碾压的片剂剂型。首先，将API、微晶纤维素及乳糖添加至混合器中25rpm混合3min。然后，将剩余的稀释剂、崩解剂、助流剂、润滑剂至混合器中25rpm继续混合3min。
组分 目的 百分比
API 药物物质 50
微晶纤维素 稀释剂 30.3
乳糖 稀释剂 15.2
交联羧甲基纤维素钠 崩解剂 3
二氧化硅 助流剂 1
硬脂酸镁 润滑剂 0.5
最后应说明的是：以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (18)

  1. 如下的通式化合物1，其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药：
    Figure PCTCN2019126507-appb-100001
    R 1表示H、取代或未取代的C 1-C 6R 1表示H、取代或未取代的C 1-C 6烷基、烯基、炔基，取代或未取代的C 1-C 6杂烷基、烯基、炔基；
    R 2表示NR bR c、取代或未取代的C 1-C 6烷基、CF 3、取代或未取代的C 1-C 6杂烷基、-(C 1-C 6烷基)杂Ar 1,-(C 1-C 6烷基)NH 2、-(C 1-C 6烷基)NH(C 1-C 6烷基)、-(C 1-C 6烷基)N(C 1-C 6烷基) 2、杂Ar 2、杂Cy、任选地被NHSO 2(C 1-C 6烷基)取代的苯基、或任选地被(C 1-C 6烷基)、CN、OH、OMe、NH 2、NHMe、N(CH 3) 2、F、CF 3、CO 2(C 1-C 6烷基)、CO 2H、C(＝O)NR eR f或C(＝O)OR g取代的(C 3-C 6)环烷基；
    R b表示H、取代或未取代的C 1-C 6烷基；
    R C表示H、取代或未取代的C 1-C 6烷基，取代或未取代的金刚烷基，取代或未取代的C 1-C 6杂烷基、杂Ar 3或苯基，其中所述苯基任选地被独立选自卤素、CN、CF 3和O(C 1-C 6烷基)的一个或多个取代基取代，
    或NR bR c形成具有环氮原子的4元杂环，其中所述杂环任选地被独立选自以下的一个或多个取代基取代：卤素、OH、(C 1-C 6烷基)、(C 1-C 6)烷氧基、OC(＝O)(C 1-C 6烷基)、NH 2、NHC(＝O)O(C 1-C 6烷基)和(C 1-C 6)羟基烷基，
    或NR bR c形成5至6元杂环，其具有为氮的环杂原子且任选地具有选自N、O和SO 2的第二环杂原子或基团，其中所述杂环任选地被独立选自以下的一个或多个取代基取代：OH、卤素、CF 3、C 1-C 6烷基、CO 2(C 1-C 6烷基)、CO 2H、NH 2、NHC(＝O)O(C 1-C 6烷基)和氧代。
    或NR bR c形成7至8元桥联杂环，其具有环氮原子且任选地具有选自N和O的第二环杂原子，其中所述环任选地被CO 2(C 1-C 6烷基)取代；
    杂Ar 1表示具有1至3个环氮原子的5元杂芳环；
    杂Ar 2表示5至6元杂芳环，其具有至少一个氮环原子且任选地具有独立选自N和S的第二环杂原子，其中所述杂芳环任选地被独立选自C 1-C 6烷基、卤素、(C 1-C 6)烷氧基和NH(C 1-C 6烷基)的一个或多个取代基取代；
    杂Cy表示碳连接的4至6元氮杂环，其任选地被独立选自(C 1-C 6)烷氧基、OC(＝O)(C 1-C 6烷基)的一个或多个取代辈取代、或者任选地被选自C 1-C 6烷基的取代基取代的吡啶酮或 哒嗪酮环；
    杂Ar 3表示5至6元杂芳环，其具有1至2个独立选自N和O的环杂原子且任选地被独立选自C 1-C 6烷基的一个或多个取代基取代；
    R e表示H、取代或未取代的C 1-C 6烷基
    R f表示H、取代或未取代的C 1-C 6烷基或(C 3-C 6)环烷基；
    或NR eR f形成4至6元氮杂环，其任选地具有选自N和O的其它环杂原子，其中所述氮杂环任选地被OH取代；
    R g是H、取代或未取代的C 1-C 6烷基；
    Y表示苯基，其任选地被独立选自卤素、(C 1-C 6)烷氧基、CF 3和CHF 2的一个或多个取代基取代，或表示5至6元杂芳环，其具有选自N和S的环杂原子，其中所述杂芳环任选地被一个或多个卤素原子取代；
    X不存在，或是-CH 2-、-CH 2CH 2-、-CH 2O-或-CH 2NR d-；
    R d表示H，取代或未取代的C 1-C 6烷基；
    R 3表示H，取代或未取代的C 1-C 6烷基；
    每个R 4独立选自卤素、(C 1-C 6)烷基、OH、(C 1-C 6)烷氧基、NH 2、NH(C 1-C 6烷基)和CH 2OH；
    n是0、1、2、3、4、5或6。
  2. 如权利要求1所述的通式化合物1，其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药，其特征在于：所述的R 2表示NR bR c、取代或未取代的C 1-C 6烷基、CF 3、取代或未取代的C 1-C 6杂烷基、-(C 1-C 6烷基)杂Ar 1、-(C 1-C 6烷基)NH 2、-(C 1-C 6烷基)NH(C 1-C 6烷基)、-(C 1-C 6烷基)N(C 1-C 6烷基) 2、杂Ar 2、杂Cy、任选的被NHSO 2(C 1-C 6烷基)取代的苯基、或任选的被(C 1-C 6烷基)、CN、OH、OMe、NH 2、NHMe、N(CH 3) 2、F、CF 3、-CO 2(C 1-C6烷基)、-CO 2H取代的(C 3-C 6)环烷基、C(＝O)NR eR f或C(＝O)OR g。
  3. 如权利要求2所述的通式化合物1，其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药，其特征在于：所述的R 2表示NR bR c。
  4. 如权利要求1-3任一所述的通式化合物1，其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药，其特征在于：所述的NR bR c形成具有环氮原子的4元杂环，其中所述杂环任选地被独立选自以下的一个或多个取代基取代：卤素、OH、(C1-C6烷基)、(C1-C6)烷氧基、-OC(＝O)(C1-C6烷基)、NH2、-NHC(＝O)O(C1-C6烷基)和(C1-C6)羟基烷基，或NRbRc形成5至6元杂环，其具有为氮的环杂原子且任选地具有选自N、O和SO2的第二环杂原子或基团，其中所述杂环任选地被独立选自以下的 一个或多个取代基取代：OH、卤素、CF3、C1-C6烷基、-OC(＝O)(C1-C6烷基)、CO2H、NH2、-NHC(＝O)O(C1-C6烷基)和氧代。
  5. 如权利要求1-3任一所述的通式化合物1，其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药，其特征在于：R c是H、取代或未取代的C 1-C 6烷基，取代或未取代的金刚烷基，取代或未取代的C 1-C 6杂烷基、杂Ar 3或苯基，其中所述苯基任选地被独立选自卤素、CN、CF 3和-O(C 1-C 6烷基)的一个或多个取代基取代。
  6. 如权利要求1-3任一所述的通式化合物1，其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药，其特征在于：其中X不存在，或是-CH 2-或-CH 2CH 2-。
  7. 如权利要求6所述的通式化合物1，其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药，其特征在于：X是-CH 2-。
  8. 如权利要求1-3任一所述的通式化合物1，其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药，其特征在于：Y是任意被独立选自卤素、(C 1-C 6)烷氧基、CF 3和CHF 2中的一个或多个取代基取代的苯基。
  9. 如权利要求8所述的通式化合物1，其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药，其特征在于：其中Y是2,5-二氟苯基。
  10. 如权利要求1-3任一所述的通式化合物1，其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药，其特征在于：Y具有下图1a的构型
    Figure PCTCN2019126507-appb-100002
  11. 如权利要求1-3任一所述的通式化合物1，其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药，其特征在于：其中R 3是H。
  12. 如权利要求1-3任一所述的通式化合物1，其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药，其特征在于：每个R 4独立选自卤素、(C 1-C 6)烷基、OH、(C 1-C 6)烷氧基、NH 2、NH(C 1-C 6烷基)和CH 2OH；n是0、1或2。
  13. 如权利要求12所述的通式化合物1，其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药，其特征在于：R 4是氟，n是0或1。
  14. 一种药用组合物，其特征在于：所述药用组合物包含治疗有效量的权利要求1-13中任一 项所述的通式化合物1、其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药和可药用的载体。
  15. 权利要求1-13中任一项所述的通式化合物1、其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药在生产用于治疗TRK介导的疾病或病症的药物中的用途，其中所述疾病或病症为癌症、皮炎或哮喘。
  16. 权利要求1-13中任一项所述的通式化合物1、其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药在生产用于治疗TRK介导的疼痛或恶病质的药物中的用途。
  17. 权利要求1-13中任一项所述的通式化合物1、其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药在生产用于治疗其中与TRK激酶活性有关的疾病，其中所述疾病选自癌症、皮炎和哮喘。
  18. 权利要求1-13中任一项所述的通式化合物1、其光学异构体或它们的混合物、其药学上可接受的盐、其溶剂合物、其N氧化物、或它们的前药在生产用于治疗其中与IRK激酶活性有关的疼痛或恶病质。
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