WO2016015676A1 - 吡啶取代的2-氨基吡啶类蛋白激酶抑制剂 - Google Patents

吡啶取代的2-氨基吡啶类蛋白激酶抑制剂 Download PDF

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WO2016015676A1
WO2016015676A1 PCT/CN2015/085727 CN2015085727W WO2016015676A1 WO 2016015676 A1 WO2016015676 A1 WO 2016015676A1 CN 2015085727 W CN2015085727 W CN 2015085727W WO 2016015676 A1 WO2016015676 A1 WO 2016015676A1
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Prior art keywords
acid
compound
formula
pharmaceutically acceptable
salt
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PCT/CN2015/085727
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English (en)
French (fr)
Inventor
龚峰
李新路
赵锐
张喜全
许新合
刘希杰
校登明
韩永信
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Centaurus Biopharma Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
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Centaurus Biopharma Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
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Priority to EP15826817.7A priority Critical patent/EP3176160B1/en
Priority to ES15826817T priority patent/ES2762641T3/es
Priority to JP2017505496A priority patent/JP6581180B2/ja
Priority to CN201580039739.6A priority patent/CN106536510B/zh
Priority to US15/329,046 priority patent/US9981946B2/en
Publication of WO2016015676A1 publication Critical patent/WO2016015676A1/zh
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals

Definitions

  • the present invention is in the field of medicinal chemistry, and in particular relates to salts of pharmaceutically acceptable acids of pyridine substituted 2-aminopyridine derivatives.
  • Anaplastic lymphoma kinase is a receptor tyrosine kinase that is a member of the insulin receptor superfamily and plays an important role in tumor cell growth and development.
  • the ALK gene can be fused to a variety of protein genes to express ALK proteins, as well as mutations, amplifications, and the like.
  • ALK gene can be encoded by the fusion gene with the EML4 gene to produce ALK, thereby promoting lung cancer cell growth.
  • EML4-ALK fusion is caused by short arm insertion of chromosome 2, and various variant types have been found so far. All of these fusion genes have been tested for biological function, and their expression products are a chimeric tyrosine kinase. Since 2007, they have gradually appeared in NSCLC related research reports.
  • EML4-ALK fusion gene The discovery of the EML4-ALK fusion gene and the unique effects of ALK inhibitors in its subpopulations allow NSCLC to be divided into different subtypes depending on the molecular pathogenesis, such as EGFR mutant, KRAS mutant, EML4-ALK. Gene fusion type and the like. In patients with general non-small cell lung cancer, the positive rate of EML4-ALK fusion gene is low, about 3% to 7%. The EML4-ALK fusion gene is mainly found in non-smoker patients with lung adenocarcinoma.
  • ALK kinase inhibitors are used to prevent, alleviate and/or treat cancers mediated by protein kinases (eg, ALK), such as ALK-positive non-small cell lung cancer (NSCLC) and the like.
  • ALK protein kinases
  • NSCLC ALK-positive non-small cell lung cancer
  • the application provides 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4'-methoxy-6'-((S)-
  • a pharmaceutically acceptable acid salt of 2-methylpiperazin-1-yl)-3,3'-bipyridin-6-amine (having the structure of formula I below, hereinafter referred to as a compound of formula I).
  • the application provides a method of preparing a salt of a pharmaceutically acceptable acid of the compound of Formula I, which comprises reacting the compound of Formula I with the pharmaceutically acceptable acid.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable acid salt of a compound of formula I and a pharmaceutically acceptable carrier, excipient or diluent.
  • the application provides the use of a pharmaceutically acceptable acid salt of a compound of formula I or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment and/or prevention of a protein kinase-associated disease.
  • the application provides a method for treating and/or preventing a protein kinase-associated disease comprising administering a pharmaceutically acceptable acid salt of a compound of formula I or a pharmaceutical composition thereof to a mammal in need thereof
  • the animal preferably a human, is administered.
  • the application provides a pharmaceutically acceptable acid salt or a pharmaceutical composition thereof for use in the treatment and/or prevention of a protein kinase-associated disease.
  • One embodiment or “implementation” or “in another embodiment” as referred to throughout this specification Or “in certain embodiments” is meant to include in a particular embodiment a particular reference element, structure, or feature that is associated with the embodiment.
  • the appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment.
  • the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • a reaction including a “catalyst” includes a catalyst, or two or more catalysts.
  • the term “or” is generally used in its meaning including “and/or” unless it is specifically defined otherwise.
  • the application provides 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4'-methoxy-6'-((S)-
  • a pharmaceutically acceptable acid salt of 2-methylpiperazin-1-yl)-3,3'-bipyridin-6-amine (having the structure of formula I below, hereinafter referred to as a compound of formula I).
  • the pharmaceutically acceptable acid comprises a mineral acid and an organic acid.
  • examples of the inorganic acid include, but are not limited to, sulfuric acid, carbonic acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and metaphosphoric acid; and the organic acid includes an aliphatic organic acid and an aromatic organic acid, examples thereof Including but not limited to trifluoroacetic acid, lactic acid, fumaric acid, mandelic acid, glycolic acid, toluenesulfonic acid (eg p-toluenesulfonic acid, o-toluenesulfonic acid), citric acid, methanesulfonic acid, formic acid, acetic acid, benzoic acid, phenylacetic acid , malonic acid, cinnamic acid, malic acid, maleic acid, tartaric acid, oxalic acid, fumaric acid, acrylic acid, crotonic acid,
  • the pharmaceutically acceptable acid is selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, citric acid, methanesulfonic acid, malic acid, maleic acid, tartaric acid, and fumaric acid.
  • the pharmaceutically acceptable acid may be in an equimolar ratio (ie a molar ratio of the compound of the formula I to the acid of 1:1) or a different molar ratio
  • the molar ratio of the compound of formula I to the pharmaceutically acceptable acid in the salt can be from 1:0.5 to 4, or from 1:1-3.
  • the molar ratio of the compound of Formula I to the pharmaceutically acceptable acid is 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, or 1:4. .
  • the pharmaceutically acceptable acid salt of the compound of Formula I provided herein is selected from the group consisting of the following salts.
  • the molar ratio of the compound of formula I to hydrochloric acid is 1:0.5, 1:1, 1:1.5, 1 : 2, 1:2.5, 1:3, 1:3.5 or 1:4; in one embodiment, the molar ratio of the compound of the formula I to hydrochloric acid is 1:0.5; in one embodiment, the molar ratio of the compound of the formula I to hydrochloric acid Ratio 1:1; in one embodiment, the molar ratio of the compound of formula I to hydrochloric acid is 1:1.5; in one embodiment, the molar ratio of the compound of formula I to hydrochloric acid is 1:2; in one embodiment, the compound of formula I The molar ratio to hydrochloric acid is 1:2.5;
  • the molar ratio of the compound of formula I to sulfuric acid is 1:0.5, 1:1, 1:1.5, 1: 2, 1:2.5, 1:3, 1:3.5 or 1:4; in one embodiment, the molar ratio of the compound of the formula I to sulfuric acid is 1:0.5; in one embodiment, the molar ratio of the compound of the formula I to the sulfuric acid 1:1; In one embodiment, the molar ratio of the compound of formula I to sulfuric acid is 1:1.5; in one embodiment, the molar ratio of the compound of formula I to sulfuric acid is 1:2; in one embodiment, the compound of formula I is The molar ratio of sulfuric acid is 1:2.5; in one embodiment, the molar ratio of the compound of
  • the molar ratio of the compound of formula i and citric acid 1: 0.5, 1: 1, 1: 1.5 , 1:2, 1:2.5, 1:3, 1:3.5 or 1:4; in one embodiment, the molar ratio of the compound of formula I to citric acid is 1:0.5; in one embodiment, the compound of formula I is The molar ratio of citric acid is 1:1; in one embodiment, the molar ratio of the compound of formula I to citric acid is 1:1.5; in one embodiment, the molar ratio of the compound of formula I to citric acid is 1:2; in one implementation In the scheme, the molar ratio of the compound of formula I to citric acid is 1:2.5; in one embodiment, the molar ratio of the compound of formula I to
  • the molar ratio of the compound of formula i and malic acid 1: 0.5, 1: 1, 1: 1.5 , 1:2, 1:2.5, 1:3, 1:3.5 or 1:4; in one embodiment, the molar ratio of the compound of the formula I to malic acid is 1:0.5; in one embodiment, the compound of the formula I
  • the molar ratio of malic acid is 1:1; in one embodiment, the molar ratio of the compound of formula I to malic acid is 1:1.5; in one embodiment, the molar ratio of the compound of formula I to malic acid is 1:2; in one implementation In the scheme, the molar ratio of the compound of the formula I to malic acid is 1:2.5; in one embodiment, the molar ratio of the compound of
  • the compound of formula i and maleic acid molar ratio of 1: 0.5, 1: 1,1 : 1.5, 1:2, 1:2.5, 1:3, 1:3.5 or 1:4; in one embodiment, the molar ratio of the compound of the formula I to maleic acid is 1:0.5; in one embodiment, The molar ratio of the compound I to the maleic acid is 1:1; in one embodiment, the molar ratio of the compound of the formula I to maleic acid is 1:1.5; in one embodiment, the molar ratio of the compound of the formula I to maleic acid is 1 In one embodiment, the molar ratio of the compound of formula I to maleic acid is 1:2.5; in one embodiment, the molar ratio of the compound of formula I to maleic acid
  • the molar ratio of the compound of formula I to fumaric acid is 1:0.5; in one embodiment, the molar ratio of the compound of formula I to fumaric acid is 1:1; in one embodiment, the compound of formula I is The molar ratio of fumaric acid is 1:1.5; in one embodiment, the molar ratio of the compound of formula I to fumaric acid is 1:2; in one embodiment, the molar ratio of the compound of formula I to fumaric acid is 1:2.5; In one embodiment, the molar ratio of the compound of formula I to fumaric acid is 1:3.
  • the present application provides 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4'-methoxy-6'-((S)
  • a process for the preparation of a pharmaceutically acceptable acid salt of 2-methylpiperazin-1-yl)-3,3'-bipyridyl-6-amine which comprises; 5-((R)-1-( 2,6-Dichloro-3-fluorophenyl)ethoxy)-4'-methoxy-6'-((S)-2-methylpiperazin-1-yl)-3,3'- Bipyridyl-6-amine (having the structure of formula I below, hereinafter referred to as a compound of formula I) is reacted with the pharmaceutically acceptable acid.
  • the pharmaceutically acceptable acid comprises a mineral acid and an organic acid.
  • the inorganic acid include, but are not limited to, sulfuric acid, carbonic acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and metaphosphoric acid.
  • the organic acid includes an aliphatic organic acid and an aromatic organic acid, and examples thereof include, but are not limited to, trifluoroacetic acid, lactic acid, fumaric acid, mandelic acid, glycolic acid, toluenesulfonic acid (for example, p-toluenesulfonic acid, o-toluenesulfonic acid).
  • citric acid, methanesulfonic acid formic acid, acetic acid, benzoic acid, phenylacetic acid, malonic acid, cinnamic acid, malic acid, maleic acid, tartaric acid, oxalic acid, fumaric acid, acrylic acid, crotonic acid, oleic acid and linoleic acid acid.
  • the pharmaceutically acceptable acid is selected from the group consisting of sulfuric acid, hydrochloric acid, and phosphorus. Acid, p-toluenesulfonic acid, citric acid, methanesulfonic acid, malic acid, maleic acid, tartaric acid and fumaric acid.
  • the compound of Formula I in the preparation of the pharmaceutically acceptable acid salt of the compound of Formula I, can be dissolved in a suitable single solvent or mixed solvent containing the corresponding acid.
  • the reaction is carried out to obtain the salt, or the compound of the formula I is dissolved in a suitable single solvent or a mixed solvent, and then the corresponding acid is added thereto to carry out a reaction to obtain the salt.
  • the pharmaceutically acceptable acid in the method of preparing a pharmaceutically acceptable acid salt of the compound of Formula I, can be in an equimolar ratio (ie, the mole of the compound of Formula I and the acid) The ratio is 1:1) or reacts with the compound of formula I in different molar ratios, depending on whether the acid is a monobasic or polybasic acid, and the desired salt.
  • the molar ratio of the compound of formula I to the acid can be from 1:0.5 to 4, or from 1:1-3.
  • the pharmaceutically acceptable acid salt of the compound of formula I can be prepared by adjusting the amount of the pharmaceutically acceptable acid, for example, using a stoichiometric amount or an excess of a pharmaceutically acceptable acid relative to the compound of formula I.
  • the molar ratio of the compound of Formula I to the pharmaceutically acceptable acid is 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1 :3, 1:3.5 or 1:4.
  • the reaction temperature may range from 0 ° C to the boiling point of the solvent system, preferably from 0 ° C to 50 ° C, more preferably It is preferably 0 ° C to 35 ° C.
  • the reaction in the method of preparing a pharmaceutically acceptable acid salt of the compound of Formula I, can be carried out under the protection of an inert gas such as nitrogen.
  • the reaction time can be from 0.5 to 5 h.
  • suitable solvents include ethers, alcohols, ketones, nitriles, esters, alkanes, halogenated alkanes, and any combination thereof.
  • suitable solvents include ethers, alcohols, ketones, nitriles, esters, alkanes, halogenated alkanes, and any combination thereof. Examples thereof include, but are not limited to, tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, ethyl formate, hexane, dichloromethane, chloroform and Any combination of them.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable acid salt of a compound of formula I and a pharmaceutically acceptable carrier, excipient or diluent.
  • the "pharmaceutically acceptable carrier and excipient” means an inert substance which facilitates administration of the active ingredient, including but not limited to the acceptable use by the State Food and Drug Administration for human or animal (eg livestock). Any of the glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents Agent, solvent or emulsifier.
  • Non-limiting examples of such carriers and excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules Agents, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, and the like.
  • 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, peritoneal Internal, intramuscular, subcutaneous, intravenous administration.
  • a preferred route of administration is oral administration.
  • the application provides a method of modulating protein kinase activity comprising contacting the protein kinase with a salt of a pharmaceutically acceptable acid of the compound of Formula I.
  • the protein kinase is selected from the group consisting of ALK.
  • the protein kinase comprises a mutated kinase, wherein the mutated kinase is selected from the group consisting of a mutated ALK kinase.
  • the application provides the use of a pharmaceutically acceptable acid salt of a compound of formula I or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment and/or prophylaxis of a disease, wherein the disease is with a protein kinase (eg, ALK) activity-related diseases, such as abnormal cell proliferation, wherein abnormal cell proliferation includes cancer.
  • a protein kinase eg, ALK
  • the present application also provides the use of a pharmaceutically acceptable acid salt of a compound of Formula I, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment and/or prevention of a disease mediated by ALK .
  • ALK-mediated diseases include, but are not limited to, ALK-positive non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoid Tumors, systemic histiocytosis, neuroblastoma, and the like, preferably include ALK-positive non-small cell lung cancer.
  • the present application also provides a method of treating and/or preventing a disease in a mammal (e.g., a human), wherein the disease is a disease associated with protein kinase (e.g., ALK) activity, the method comprising administering to a mammal (e.g., a human) A therapeutically effective amount of a pharmaceutically acceptable acid salt of the compound of formula I or a pharmaceutical composition thereof.
  • a mammal e.g., a human
  • a therapeutically effective amount of a pharmaceutically acceptable acid salt of the compound of formula I or a pharmaceutical composition thereof
  • the protein kinase is selected from the group consisting of ALK.
  • the protein kinase comprises a mutated kinase, wherein the mutated kinase is selected from the group consisting of a mutated ALK kinase.
  • the present application also provides methods of treating and/or preventing a disease in a mammal (eg, a human), wherein the disease is a disease associated with ALK activity, the method comprising administering to a mammal (eg, a human) A therapeutically effective amount of a pharmaceutically acceptable acid salt of the compound of formula I or a pharmaceutical composition thereof.
  • the diseases associated with ALK activity include, but are not limited to, ALK-positive non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoid Tumors, systemic histiocytosis, neuroblastoma, and the like, preferably include ALK-positive non-small cell lung cancer.
  • the present application also provides a pharmaceutically acceptable acid salt of the compound of formula I for use in modulating protein kinase activity or for treating and/or preventing a disease associated with protein kinase activity in a mammal (eg, a human) or Their pharmaceutical compositions.
  • the protein kinase is preferably ALK.
  • the protein kinase comprises a mutated kinase, wherein the mutated kinase is selected from the group consisting of a mutated ALK kinase.
  • the present application also provides a pharmaceutically acceptable acid of the compound of Formula I for use in modulating ALK activity or for treating and/or preventing a disease associated with ALK activity in a mammal (eg, a human) Salts or their pharmaceutical compositions.
  • the diseases associated with ALK activity include, but are not limited to, ALK-positive non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoid Tumors, systemic histiocytosis, neuroblastoma, and the like, preferably include ALK-positive non-small cell lung cancer.
  • Step 1 Dissolve (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (20.9 g, 0.10 mol) in 200 mL of anhydrous tetrahydrofuran, and sequentially add 3-hydroxy-2 under nitrogen atmosphere. -Nitropyridine (16.0 g, 0.11 mol) and triphenylphosphine (40.0 g, 0.15 mol), and the reaction mixture was stirred at room temperature for 1 hour. After cooling to 0 ° C, diisopropyl azodicarboxylate (40 mL, 0.15 mol) was added dropwise, and after stirring, stirring was continued at 0 ° C for 12 hours. The solvent was evaporated to give an oily crystal. 20.2 g), yield: 61%.
  • Step 2 (R)-3-(1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (20.0 g, 60 mmol) at 0 ° C with stirring
  • To the ethanol solution (300 mL) 15 mL of 2M hydrochloric acid and reduced iron powder (27 g, 480 mmol) were added. After the addition, the mixture was heated to reflux for 12 hours. After cooling to room temperature, filtration and concentration of the filtrate, (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine (17.0 g) was obtained. Directly used in the next step, yield: 94%. MS m/z [ESI]: 301.0 [M + 1].
  • Step 3 To a solution of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine (15.0 g, 50 mmol) at 0 ° C. Bromosuccinimide (10 g, 56 mmol) was added portionwise in acetonitrile (200 mL). The addition was carried out at 0 ° C for 1 hour. Then, the solvent was evaporated, the methylene chloride was added, and the organic layer was washed with saturated aqueous sodium hydrogen sulfate, and dried over anhydrous sodium sulfate. -(2,6-Dichloro-3-fluorophenyl)ethoxy)-5-bromo-2-aminopyridine (9.88 g), yield: 52%. MS m/z [ESI]: 380.9 [M + 1].
  • Step 4 (R)-3-(1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-5-bromo-2-aminopyridine (7.6 g, 20 mmol), boronic acid Which alcohol ester (7.56g, 30mmol), Pd(dppf)Cl 2 (732mg, 1mmol) and anhydrous potassium acetate (4.90g, 50mmol) were added to dry dioxane (200mL), replaced with nitrogen at 100 ° C Reaction for 4 hours.
  • Step 1 2-Chloro-4-methoxypyridine (2.58 g, 18 mmol), (S)-3-methyl-1-tert-butoxycarbonylpiperazine (5.4 g, 27 mmol), Pd 2 (dba) 3 (824 mg, 0.9 mmol), BINAP (1.12 g, 1.8 mmol) and potassium tert-butoxide (5.01 g, 45 mmol) were added to dry toluene (200 mL) and refluxed for 16 hr under nitrogen atmosphere. Then, the reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. MS m/z [ESI]: 308.2 [M + 1].
  • Step 2 To a solution of (S)-4-(4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (2.46 g, 8 mmol). Bromosuccinimide (1.57 g, 8.8 mmol) was added portionwise in acetonitrile (50 mL). The reaction was carried out for 2 hours at room temperature. The solvent was evaporated under reduced pressure. dichloromethane was evaporated, evaporated, evaporated, evaporated, evaporated. 75%. MS m/z [ESI]: 386.1 [M + 1].
  • Step 1 tert-Butyl (S)-4-(5-bromo-4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylate (106 mg, 0.275 mmol), (R) )-3-(1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentane-2-yl)-2-aminopyridine (140 mg, 0.33 mmol), tetrakis(triphenylphosphine)palladium (32 mg, 0.0275 mmol) and cesium carbonate (179 mg, 0.55 mmol) were added to dioxane ( 10 mL) and water (1.5 mL) were replaced with nitrogen and reacted at 100 ° C overnight.
  • Step 2 To 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4'-methoxy-6'-(( Add a solution of S)-2-methyl-4-tert-butoxycarbonylpiperazin-1-yl)-3,3'-bipyridin-6-amine (67 mg, 0.11 mmol) in dichloromethane (10 mL) The fluoroacetic acid (1 mL) was stirred for 1 hour, then the pH of the reaction mixture was adjusted to more than 13 with 10 mol/L sodium hydroxide solution, then extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • the inhibitory activity of IC 50 uses the indicators to represent, i.e., IC 50 activity of ALK kinase, is inhibited by 50% of the compound.
  • the homogeneous activity time-resolved fluorescence (HTRF, Cisbio) method was used to establish and optimize the kinase activity detection platform of ALK (purchased from Millipore) for the determination of compound activity.
  • HEPES buffer Prepare 50ml 0.05M HEPES buffer with 1M HEPES buffer (Invitrogen, Catalog No. 15630-080), take 1M HEPES buffer 2.5ml, add appropriate amount of distilled water (ddH 2 O), with NaOH The pH was adjusted to 7.0 and finally ddH 2 O (re-distilled water) was added to 50 ml.
  • Test compound a compound of formula I
  • the compound was diluted 3 times with 100% DMSO starting from 1 mM, 4 ⁇ l of each concentration was added to 96 ⁇ l of reaction buffer, 2.5 ⁇ l was added to a 384-well plate (OptiPlate-384, PerkinElmer), and then added. 5 ⁇ l of the kinase was mixed by centrifugation, and then 2.5 ⁇ l of ATP was added to the TK peptide mixture (the final concentration of ATP was Km) to initiate the reaction.
  • the compound inhibits generation of ALK enzyme IC 50: IC 50 values calculated using compound GraFit6.
  • IC above compound of formula I 50 measured value of 1.96nM. This data indicates that the compound of formula I has excellent ALK inhibitory activity.
  • Table 1 lists the ALK kinase inhibitory activity of the compound of formula I against the mutation.
  • ALK kinases in which L1196M and G1269S mutations are commercially available are commercially available.
  • the experimental method was as follows: nude mice were subcutaneously inoculated with human non-small cell lung cancer NCI-H2228 cells, and after the tumors were grown to 80-200 mm 3 , the animals were randomly divided into groups (D0) and administered, and the dosage and administration schedule were specifically See Table 2. The tumor volume was measured twice a week, the rats were weighed, and data were recorded. The tumor volume (V) is calculated as:
  • V 1/2 ⁇ a ⁇ b 2 , where a and b represent length and width, respectively.
  • T/C(%) (TT 0 )/(CC 0 ) ⁇ 100, where T and C are the tumor volumes at the end of the experiment, respectively; T 0 and C 0 are the tumor volumes at the beginning of the experiment, respectively.
  • T/C (%) (TT 0 ) / T 0 ⁇ 100, where T is the tumor volume at the end of the experiment; T 0 is the tumor volume at the beginning of the experiment.
  • the tumor inhibition rate (%) 100-T/C (%), partial regression means that the tumor becomes small but does not disappear, and complete regression means that the tumor disappears.
  • solvent distilled water containing 0.1% Tween-80
  • treatment group was prepared with distilled water containing 0.1% Tween-80.
  • D0-20 indicates that continuous administration was performed once a day for 21 days from 0 days (D0); D0-13 indicates that administration was continued once every day for 14 days from 0 days.
  • n is the number of mice, the number of experimental mice is 12 for the control group, and n for the treatment group.

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Abstract

本发明公开了作为蛋白激酶抑制剂的吡啶取代的2-氨基吡啶衍生物的药学上可接受酸的盐、其制备方法、其药物组合物及其在治疗和/或与蛋白激酶有关疾病中的用途。

Description

吡啶取代的2-氨基吡啶类蛋白激酶抑制剂 技术领域
本发明属于药物化学领域，具体而言涉及吡啶取代的2-氨基吡啶衍生物的药学上可接受酸的盐。
背景技术
近年来的分子生物学研究表明酪氨酸激酶(Protein Tyrosine Kinases，PTKs)作用的细胞信号转导通路在肿瘤的形成和发展中起着极其重要的作用。抑制酪氨酸激酶的活性，能降低细胞信号转导通路的激活，从而抑制肿瘤细胞诱导生存和增殖，达到治疗肿瘤的效果。
间变性淋巴瘤激酶(ALK)是一种受体酪氨酸激酶，属于胰岛素受体超家族中的一员，它在肿瘤细胞生长和发展过程中起着重要作用。ALK基因可以与多种蛋白基因发生融合，表达产生ALK蛋白，也可产生突变、扩增等变异。在1997年，首次描述了异生性大细胞淋巴瘤上染色体2短臂上的致癌性ALK基因重组，之后在其他恶性肿瘤也有发现，包括弥漫性大B细胞淋巴瘤以及恶性组织细胞增多症，以及在多种实体肿瘤也有发现，包括炎性肌纤维母细胞瘤、食道鳞状上皮细胞癌、神经母细胞瘤以及最近提出的非小细胞肺癌(NSCLC)。
2007年首次报道ALK基因可通过与EML4基因形成融合基因来编码产生ALK，从而促进肺癌细胞生长。EML4-ALK融合由2号染色体短臂插入引起，迄今已发现多种变异类型。经检测，所有这些融合基因均有生物学功能，其表达产物为一种嵌合酪氨酸激酶，于2007年开始逐渐见诸于NSCLC相关研究报道。
EML4-ALK融合基因的发现及ALK抑制剂在其亚组人群中显示的独特效果使得NSCLC根据分子发病机制的不同，可分为不同的亚型，如EGFR突变型、KRAS突变型、EML4-ALK基因融合型等。在一般的非小细胞肺癌患者中，EML4-ALK融合基因阳性率较低，约为3％～7％左右。EML4-ALK融合基因主要见于患有肺腺癌的不吸烟患者。2010年报告的一项研究显示，在中国肺腺癌患者中，EML4-ALK融合基因阳性率明显高于欧美患者，为16.13％；患有肺腺癌的不吸烟患者中，其阳性率为19.23％；缺乏EGFR和KRAS突变的肺腺癌中，其突变率高达42.8％。
虽然人们已经研究了大量的对蛋白激酶有抑制活性的化合物，且一些蛋白激酶抑制剂已经上市用于抗肿瘤的治疗，但是会产生耐药性。因而，亟需开发新的蛋白激酶抑制剂， 例如ALK激酶抑制剂，用于预防、缓解和/或治疗由蛋白激酶(例如ALK)介导的癌症，如ALK阳性的非小细胞肺癌(NSCLC)等。
发明内容
一方面，本申请提供了5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺(具有如下式Ⅰ的结构，下称式Ⅰ化合物)的药学上可接受酸的盐。
Figure PCTCN2015085727-appb-000001
另一方面，本申请提供了制备所述式Ⅰ化合物的药学上可接受酸的盐的方法，其包括将所述式Ⅰ化合物和所述药学上可接受酸反应。
另一方面，本申请提供了药物组合物，其含有治疗有效量的所述式Ⅰ化合物的药学上可接受酸的盐和药学上可接受的载体、赋形剂或稀释剂。
再一方面，本申请提供了所述式Ⅰ化合物的药学上可接受酸的盐或其药物组合物在制备用于治疗和/或预防与蛋白激酶相关的疾病的药物中的用途。
再一方面，本申请提供了用于治疗和/或预防与蛋白激酶相关的疾病的方法，其包括将所述式Ⅰ化合物的药学上可接受酸的盐或其药物组合物对有需要的哺乳动物、优选人进行给药。
再一方面，本申请提供了用于治疗和/或预防与蛋白激酶相关的疾病的所述式Ⅰ化合物的药学上可接受酸的盐或其药物组合物。
发明详述
在以下的说明中，包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而，相关领域的技术人员会认识到，不采用一个或多个这些具体的细节，而采用其它方法、部件、材料等的情况下可实现实施方案。
除非本申请中另外要求，在整个说明书和其后的权利要求书中，词语“包括(comprise)”及其英文变体例如“包括(comprises)”和“包括(comprising)”应解释为开放式的、含括式的意义，即“包括但不限于”。
在整个本说明书中提到的“一实施方案”或“实施方案”或“在另一实施方案中” 或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
应当理解，在本申请说明书和附加的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。因此，例如提到的包括“催化剂”的反应包括一种催化剂，或两种或多种催化剂。还应当理解，术语“或”通常以其包括“和/或”的含义而使用，除非文中另外明确地规定。
一方面，本申请提供了5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺(具有如下式Ⅰ的结构，下称式Ⅰ化合物)的药学上可接受酸的盐。
Figure PCTCN2015085727-appb-000002
在某些实施方案中，所述药学上可接受酸包括无机酸和有机酸。其中，所述无机酸的实例包括但不限于硫酸、碳酸、硝酸、盐酸、氢溴酸、氢碘酸、磷酸和偏磷酸；所述有机酸包括脂肪族有机酸和芳香族有机酸，其实例包括但不限于三氟乙酸、乳酸、延胡索酸、扁桃酸、乙醇酸、甲苯磺酸(例如对甲苯磺酸、邻甲苯磺酸)、柠檬酸、甲磺酸、甲酸、乙酸、苯甲酸、苯乙酸、丙二酸、肉桂酸、苹果酸、马来酸、酒石酸、草酸、富马酸、丙烯酸、巴豆酸、油酸和亚油酸。在一些优选的实施方案中，所述药学上可接受酸选自硫酸、盐酸、磷酸、对甲苯磺酸、柠檬酸、甲磺酸、苹果酸、马来酸、酒石酸和富马酸。
在所述式Ⅰ化合物的药学上可接受酸的盐中，所述药学上可接受酸可以以等摩尔比(即式Ⅰ化合物与所述酸的摩尔比为1:1)或以不同摩尔比用于所述盐的制备，这取决于所述酸是一元酸还是多元酸，以及所需要的盐。例如，所述盐中式Ⅰ化合物与药学上可接受酸的摩尔比可为1:0.5-4，或者1:1-3。在一些实施方案中，式Ⅰ化合物与药学上可接受酸的摩尔比为1:0.5、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5或1:4。
在一些具体的实施方案中，本申请提供的式Ⅰ化合物的药学上可接受酸的盐选自如下盐。
(1)5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶 -6-胺盐酸盐；在一些实施方案中，式Ⅰ化合物与盐酸的摩尔比1:0.5、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5或1:4；在一个实施方案中，式Ⅰ化合物与盐酸的摩尔比1:0.5；在一个实施方案中，式Ⅰ化合物与盐酸的摩尔比1:1；在一个实施方案中，式Ⅰ化合物与盐酸的摩尔比1:1.5；在一个实施方案中，式Ⅰ化合物与盐酸的摩尔比1:2；在一个实施方案中，式Ⅰ化合物与盐酸的摩尔比1:2.5；在一个实施方案中，式Ⅰ化合物与盐酸的摩尔比1:3。
(2)5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶 -6-胺硫酸盐；在一些实施方案中，式Ⅰ化合物与硫酸的摩尔比1:0.5、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5或1:4；在一个实施方案中，式Ⅰ化合物与硫酸的摩尔比1:0.5；在一个实施方案中，式Ⅰ化合物与硫酸的摩尔比1:1；在一个实施方案中，式Ⅰ化合物与硫酸的摩尔比1:1.5；在一个实施方案中，式Ⅰ化合物与硫酸的摩尔比1:2；在一个实施方案中，式Ⅰ化合物与硫酸的摩尔比1:2.5；在一个实施方案中，式Ⅰ化合物与硫酸的摩尔比1:3。
(3)5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡 啶-6-胺柠檬酸盐；在一些实施方案中，式Ⅰ化合物与柠檬酸的摩尔比1:0.5、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5或1:4；在一个实施方案中，式Ⅰ化合物与柠檬酸的摩尔比1:0.5；在一个实施方案中，式Ⅰ化合物与柠檬酸的摩尔比1:1；在一个实施方案中，式Ⅰ化合物与柠檬酸的摩尔比1:1.5；在一个实施方案中，式Ⅰ化合物与柠檬酸的摩尔比1:2；在一个实施方案中，式Ⅰ化合物与柠檬酸的摩尔比1:2.5；在一个实施方案中，式Ⅰ化合物与柠檬酸的摩尔比1:3。
(4)5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡 啶-6-胺苹果酸盐；在一些实施方案中，式Ⅰ化合物与苹果酸的摩尔比1:0.5、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5或1:4；在一个实施方案中，式Ⅰ化合物与苹果酸的摩尔比1:0.5；在一个实施方案中，式Ⅰ化合物与苹果酸的摩尔比1:1；在一个实施方案中，式Ⅰ化合物与苹果酸的摩尔比1:1.5；在一个实施方案中，式Ⅰ化合物与苹果酸的摩尔比1:2；在一个实施方案中，式Ⅰ化合物与苹果酸的摩尔比1:2.5；在一个实施方案中，式Ⅰ化合物与苹果酸的摩尔比1:3。
(5)5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡 啶-6-胺马来酸盐；在一些实施方案中，式Ⅰ化合物与马来酸的摩尔比1:0.5、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5或1:4；在一个实施方案中，式Ⅰ化合物与马来酸的摩尔比1:0.5；在一个实施方案中，式Ⅰ化合物与马来酸的摩尔比1:1；在一个实施方案中，式Ⅰ化合物与马来酸的摩尔比1:1.5；在一个实施方案中，式Ⅰ化合物与马来酸的摩尔比1:2；在一个 实施方案中，式Ⅰ化合物与马来酸的摩尔比1:2.5；在一个实施方案中，式Ⅰ化合物与马来酸的摩尔比1:3。
(6)5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡 啶-6-胺酒石酸盐；在一些实施方案中，式Ⅰ化合物与酒石酸的摩尔比1:0.5、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5或1:4；在一个实施方案中，式Ⅰ化合物与酒石酸的摩尔比1:0.5；在一个实施方案中，式Ⅰ化合物与酒石酸的摩尔比1:1；在一个实施方案中，式Ⅰ化合物与酒石酸的摩尔比1:1.5；在一个实施方案中，式Ⅰ化合物与酒石酸的摩尔比1:2；在一个实施方案中，式Ⅰ化合物与酒石酸的摩尔比1:2.5；在一个实施方案中，式Ⅰ化合物与酒石酸的摩尔比1:3。
(7)5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡 啶-6-胺富马酸盐；在一些实施方案中，式Ⅰ化合物与富马酸的摩尔比1:0.5、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5或1:4。在一个实施方案中，式Ⅰ化合物与富马酸的摩尔比1:0.5；在一个实施方案中，式Ⅰ化合物与富马酸的摩尔比1:1；在一个实施方案中，式Ⅰ化合物与富马酸的摩尔比1:1.5；在一个实施方案中，式Ⅰ化合物与富马酸的摩尔比1:2；在一个实施方案中，式Ⅰ化合物与富马酸的摩尔比1:2.5；在一个实施方案中，式Ⅰ化合物与富马酸的摩尔比1:3。
另一方面，本申请提供了5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺的药学上可接受酸的盐的制备方法，其包括；将5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺(具有如下式Ⅰ的结构，下称式Ⅰ化合物)与所述药学上可接受酸反应。
Figure PCTCN2015085727-appb-000003
在某些实施方案中，所述药学上可接受酸包括无机酸和有机酸。所述无机酸的实例包括但不限于硫酸、碳酸、硝酸、盐酸、氢溴酸、氢碘酸、磷酸和偏磷酸。所述有机酸包括脂肪族有机酸和芳香族有机酸，其实例包括但不限于三氟乙酸、乳酸、延胡索酸、扁桃酸、乙醇酸、甲苯磺酸(例如对甲苯磺酸、邻甲苯磺酸)、柠檬酸、甲磺酸、甲酸、乙酸、苯甲酸、苯乙酸、丙二酸、肉桂酸、苹果酸、马来酸、酒石酸、草酸、富马酸、丙烯酸、巴豆酸、油酸和亚油酸。在一些优选的实施方案中，所述药学上可接受酸选自硫酸、盐酸、磷 酸、对甲苯磺酸、柠檬酸、甲磺酸、苹果酸、马来酸、酒石酸和富马酸。
在某些实施方案中，在所述式Ⅰ化合物的药学上可接受酸的盐的制备方法中，可通过将所述式Ⅰ化合物溶于含有相应的酸的合适的单一溶剂或混合溶剂中来进行反应以获得所述盐，或者将所述式Ⅰ化合物溶于合适的单一溶剂或混合溶剂中，随后向其中加入相应的酸来进行反应以获得所述盐。
在某些实施方案中，在所述式Ⅰ化合物的药学上可接受酸的盐的制备方法中，所述药学上可接受酸可以以等摩尔比(即所述式Ⅰ化合物与该酸的摩尔比为1:1)或以不同摩尔比与所述式Ⅰ化合物反应，这取决于酸是一元酸还是多元酸，以及所需要的盐。例如，在制备所述盐时，所述式Ⅰ化合物与所述酸的摩尔比可为1:0.5-4，或者1:1-3。
可通过调整药学上可接受酸的用量，例如，采用相对于式Ⅰ化合物的化学计算量或过量的药学上可接受酸，制备得到所述式Ⅰ化合物的药学上可接受酸的盐。在一些实施方案中，制备所述盐时，所述式Ⅰ化合物与所述药学上可接受酸的摩尔比为1:0.5、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5或1:4。
在某些实施方案中，在所述式Ⅰ化合物的药学上可接受酸的盐的制备方法中，反应温度可为0℃至溶剂系统的沸点，优选的反应温度为0℃-50℃，更优选0℃-35℃。
在某些实施方案中，在所述式Ⅰ化合物的药学上可接受酸的盐的制备方法中，反应可在诸如氮气等惰性气体的保护下进行。在某些实施方案中，反应时间可为0.5-5h。
在某些实施方案中，合适的溶剂包括醚类、醇类、酮类、腈类、酯类、烷烃类、卤代烷烃类及它们的任意组合。其实例包括但不限于四氢呋喃、二氧六环、异丙醚、乙醚、甲醇、乙醇、异丙醇、丙酮、乙腈、乙酸乙酯、甲酸乙酯、己烷、二氯甲烷、三氯甲烷及它们的任意组合。
再一方面，本申请提供药物组合物，其含有治疗有效量的所述式Ⅰ化合物的药学上可接受酸的盐和药学上可接受的载体、赋形剂或稀释剂。
所述“药学上可接受的载体和赋形剂”是指有利于活性成分给药的惰性物质，包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述载体和赋形剂的非限制性实例包括但不限于碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
本发明的药物组合物可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊 剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。
给予本发明的药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选的给药途径是口服给药。
再一方面，本申请提供调节蛋白激酶活性的方法，其包括将所述蛋白激酶与所述式Ⅰ化合物的药学上可接受酸的盐接触。优选地，所述蛋白激酶选自ALK。此外，所述蛋白激酶包括突变的激酶，其中突变的激酶选自突变的ALK激酶。
再一方面，本申请提供所述式Ⅰ化合物的药学上可接受酸的盐或它们的药物组合物在制备用于治疗和/或预防疾病的药物中的用途，其中所述疾病是与蛋白激酶(例如ALK)活性相关的疾病，例如异常细胞增殖，其中异常细胞增殖包括癌症。
在某些实施方案中，本申请还提供所述式Ⅰ化合物的药学上可接受酸的盐或它们的药物组合物在制备用于治疗和/或预防由ALK介导的疾病的药物中的用途。所述的ALK介导的疾病包括但不限于ALK阳性的非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B细胞淋巴瘤、全身组织细胞增生症和神经母细胞瘤等，优选地包括ALK阳性的非小细胞肺癌。
另外，本申请还提供治疗和/或预防哺乳动物(例如人)的疾病的方法，其中所述疾病是与蛋白激酶(例如ALK)活性相关的疾病，该方法包括向哺乳动物(例如人)给予治疗有效量的所述式Ⅰ化合物的药学上可接受酸的盐或它们的药物组合物。优选地，所述蛋白激酶选自ALK。此外，所述蛋白激酶包括突变的激酶，其中突变的激酶选自突变的ALK激酶。
在某些实施方案中，本申请还提供治疗和/或预防哺乳动物(例如人)的疾病的方法，其中所述疾病是与ALK活性相关的疾病，该方法包括向哺乳动物(例如人)给予治疗有效量的所述式Ⅰ化合物的药学上可接受酸的盐或它们的药物组合物。所述与ALK活性相关的疾病包括但不限于ALK阳性的非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B细胞淋巴瘤、全身组织细胞增生症和神经母细胞瘤等，优选地包括ALK阳性的非小细胞肺癌。
此外，本申请还提供了用于调节蛋白激酶活性或者用于治疗和/或预防哺乳动物(例如人)的与蛋白激酶活性相关的疾病的所述式Ⅰ化合物的药学上可接受酸的盐或它们的药物组合物。所述蛋白激酶优选为ALK。所述蛋白激酶包括突变的激酶，其中突变的激酶选自突变的ALK激酶。
在某些实施方案中，本申请还提供用于调节ALK活性或者用于治疗和/或预防哺乳动物(例如人)的与ALK活性相关的疾病的所述式Ⅰ化合物的药学上可接受酸的盐或它们的药物组合物。所述与ALK活性相关的疾病包括但不限于ALK阳性的非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B细胞淋巴瘤、全身组织细胞增生症和神经母细胞瘤等，优选地包括ALK阳性的非小细胞肺癌。
实施例
下面的具体实施例，其目的是使本领域的技术人员能更清楚地理解和实施本发明。它们不应该被认为是对本发明范围的限制，而只是本发明的示例性说明和典型代表。凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明，本发明使用的原料都是直接商购的且未经进一步纯化直接使用的。
实施例1式Ⅰ化合物的制备
中间体1的制备
Figure PCTCN2015085727-appb-000004
步骤1：把(S)-1-(2,6-二氯-3-氟苯基)乙醇(20.9g,0.10mol)溶于200mL无水四氢呋喃中，氮气氛下依次加入3-羟基-2-硝基吡啶(16.0g,0.11mol)和三苯基膦(40.0g，0.15mol)，反应混合物在室温下搅拌1小时。冷至0℃，滴加偶氮二甲酸二异丙酯(40mL,0.15mol)，加毕后在0℃下继续搅拌12小时。蒸去溶剂，得到油状物，经硅胶柱色谱法分离，得到(R)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-2-硝基吡啶(20.2g)，收率：61％。
步骤2：在0℃，搅拌条件下，向(R)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-2-硝基吡啶(20.0g，60mmol)的乙醇溶液(300mL)中加入2M盐酸15mL、还原铁粉(27g，480mmol)。加毕，加热回流12小时。随后冷却至室温，过滤，滤液浓缩，得(R)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-2-氨基吡啶(17.0g)，将其直接用于下一步，收率：94％。MS m/z[ESI]:301.0[M+1]。
步骤3：在0℃，搅拌条件下，向(R)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-2-氨基吡啶(15.0g,50mmol)的乙腈溶液(200mL)中分批加入溴代丁二酰亚胺(10g，56mmol)。加毕在0℃下反应1小时。随后蒸去溶剂，加入二氯甲烷，用饱和碳酸氢钠水溶液洗涤有机相，经无水硫酸钠干燥，减压浓缩后，经硅胶柱色谱法分离残留物，得到(R)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-5-溴-2-氨基吡啶(9.88g)，收率：52％。MS m/z[ESI]:380.9[M+1]。
步骤4：将(R)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-5-溴-2-氨基吡啶(7.6g,20mmol)、联硼酸频哪醇酯(7.56g，30mmol)、Pd(dppf)Cl2(732mg,1mmol)和无水醋酸钾(4.90g，50mmol)加到干燥的二噁烷(200mL)中，氮气置换，于100℃反应4小时。冷却后，减压蒸除溶剂，经硅胶柱色谱法分离残留物，得到(R)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-氨基吡啶(5.46g)，收率：64％。MS m/z[ESI]:427.1[M+1]。
中间体2的制备
Figure PCTCN2015085727-appb-000005
步骤1：将2-氯-4-甲氧基吡啶(2.58g,18mmol)、(S)-3-甲基-1-叔丁氧羰基哌嗪(5.4g，27mmol)、Pd2(dba)3(824mg，0.9mmol)、BINAP(1.12g，1.8mmol)和叔丁醇钾(5.01g，45mmol)加入干燥的甲苯(200mL)中，在氮气氛下，回流16小时。随后，将反应混合物冷却至室温，过滤，减压浓缩后，经硅胶柱色谱法分离残留物，得到目标化合物，收率：50％。MS m/z[ESI]:308.2[M+1]。
步骤2：0℃，搅拌条件下，向(S)-4-(4-甲氧基吡啶-2-基)-3-甲基哌嗪-1-羧酸叔丁酯(2.46g，8mmol)的乙腈溶液(50mL)中分批加入溴代丁二酰亚胺(1.57g，8.8mmol)。加毕在室温反应2小时。减压蒸去溶剂，加入二氯甲烷，用饱和碳酸氢钠水溶液洗涤有机相，经无水硫酸钠干燥，减压浓缩后，经硅胶柱色谱法分离残留物，得到中间体2，收率：75％。MS m/z[ESI]:386.1[M+1]。
式Ⅰ化合物的制备
Figure PCTCN2015085727-appb-000006
步骤1：将(S)-4-(5-溴-4-甲氧基吡啶-2-基)-3-甲基哌嗪-1-羧酸叔丁酯(106mg，0.275mmol)、(R)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-氨基吡啶(140mg,0.33mmol)、四(三苯基膦)钯(32mg,0.0275mmol)和碳酸铯(179mg，0.55mmol)加到二噁烷(10mL)和水(1.5mL)中，氮气置换，100℃反应过夜。冷却后，经硅胶柱色谱法分离，得到5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基-4-叔丁氧羰基哌嗪-1-基)-3,3'-联吡啶-6-胺(70mg)，收率：42％。MS m/z[ESI]:606.2[M+1]。
步骤2：在室温和搅拌条件下向5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基-4-叔丁氧羰基哌嗪-1-基)-3,3'-联吡啶-6-胺(67mg，0.11mmol)的二氯甲烷溶液中(10mL)加入三氟乙酸(1mL)，搅拌1小时，随后用10mol/L氢氧化钠溶液调节反应混合物的pH值大于13，然后用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩，经硅胶柱色谱法分离纯化(以二氯甲烷:甲醇＝8:1为洗脱剂)，得到5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺(30mg)，收率：55％。
MS m/z[ESI]:506.1[M+1]；
1H-NMR(400MHz,CDCl3):δ＝7.94(1H,s),7.71(1H,s),7.28-7.32(1H,m),7.07(1H,t,J＝8.4Hz),6.97(1H,s),6.04-6.13(2H,m),4.86(2H,s),4.57-4.59(1H,m),4.03(1H,d,J＝14Hz),3.76(3H,s),3.07-3.33(4H,m),2.88-3.00(1H,m),1.84(3H,d,J＝6.8Hz),1.34(3H,d,J＝6.8Hz)。
实施例2式Ⅰ化合物的药学上可接受酸的盐的制备
1、式Ⅰ化合物的柠檬酸盐的制备
取0.01mol的式Ⅰ化合物溶于乙醇中，室温搅拌下加入柠檬酸-乙醇溶液(10ml，1.2mol/L)，反应1小时后，减压浓缩至干，得类白色固体，X射线粉末衍射显示为无定形物，mp：225.3-226.8℃。
2、式Ⅰ化合物的柠檬酸盐的制备
取0.01mol的式Ⅰ化合物溶于丙酮中，室温搅拌下加入柠檬酸-丙酮溶液(10ml，1.2mol/L)，反应1小时后，减压浓缩至干，得到固体，X射线粉末衍射显示为无定形物。
3、式Ⅰ化合物的柠檬酸盐的制备
取0.01mol的式Ⅰ化合物溶于乙酸乙酯中，20℃搅拌下加入柠檬酸-丙酮溶液(10ml，1.2mol/L)，反应1小时后，减压浓缩至干，得到固体，X射线粉末衍射显示为无定形物。
4、式Ⅰ化合物的柠檬酸盐的制备
取0.01mol的式Ⅰ化合物溶于1,4-二氧六环中，20℃搅拌下加入柠檬酸-丙酮溶液(10ml，1.2mol/L)，反应1小时后，减压浓缩至干，得到固体，X射线粉末衍射显示为无定形物。
5、式Ⅰ化合物的盐酸盐的制备
取0.01mol的式Ⅰ化合物溶于乙醇中，室温搅拌下加入5ml盐酸-乙醇溶液(10％，w/w)，反应1小时后，反应液析出固体，过滤、滤饼经真空干燥，得到类白色固体，mp：179.6-179.8℃。
6、式Ⅰ化合物的硫酸盐的制备
取0.01mol的式Ⅰ化合物溶于乙醇中，室温搅拌下加入硫酸-乙醇溶液(10ml，1.2mol/L)，反应1小时后，反应液析出固体，过滤、滤饼经真空干燥，得到浅黄色固体，mp：186.5-189.4℃。
7、式Ⅰ化合物的苹果酸盐的制备
取0.01mol的式Ⅰ化合物溶于乙醇中，室温搅拌下加入苹果酸-1,4-二氧六环溶液(10ml，1.2mol/L)，反应1小时后，反应液析出固体，过滤、滤饼经真空干燥，得到类白色固体，mp：190.4-191.1℃。
8、式Ⅰ化合物的马来酸盐的制备
取0.01mol的式Ⅰ化合物溶于乙醇中，室温搅拌下加入马来酸-乙酸乙酯溶液(10ml，1.2mol/L)，反应1小时后，反应液析出固体，过滤、滤饼经真空干燥，得到类白色固体，mp：179.9-180.1℃。
9、式Ⅰ化合物的酒石酸盐的制备
取0.01mol的式Ⅰ化合物溶于乙醇中，室温搅拌下加入酒石酸-丙酮溶液(10ml，1.2mol/L)，反应1小时后，反应液析出固体，过滤、滤饼经真空干燥，得到类白色固体，mp：225.8-226.0℃。
10、式Ⅰ化合物的富马酸盐的制备
取0.01mol的式Ⅰ化合物溶于乙醇中，室温搅拌下加入富马酸-乙醇溶液(10ml，1.2mol/L)，反应1小时后，反应液析出固体，过滤、滤饼经真空干燥，得到类白色固体，mp：185.3-187.7℃。
实施例3药理学实验
下述实验测定了式Ⅰ化合物对ALK激酶和突变的ALK激酶的抑制活性，以及测定了对人非小细胞肺癌NCI-H2228裸小鼠移植瘤的疗效。可以理解，式Ⅰ化合物的药学上可接受酸的盐(例如盐酸盐、硫酸盐、柠檬酸盐、苹果酸盐、马来酸盐、酒石酸盐、富马酸盐)在体内具有与式Ⅰ化合物相同的药理学活性。
1、ALK激酶抑制活性的测定
采用以下方法来测定本申请的式Ⅰ化合物对ALK激酶的抑制活性，该抑制活性采用IC50这一指标来表示，IC50即ALK激酶的活性被抑制50％时的化合物的浓度。采取匀相 时间分辨荧光(HTRF，Cisbio)方法建立并优化了ALK(购买于Millipore)的激酶活性检测平台，进行化合物活性的测定。
材料和方法：
材料：
a.白色384孔板(Perkin Elmer，Catalog No.607290/99)
b.HEPES缓冲液：用1M HEPES缓冲液(Invitrogen，Catalog No.15630-080)配制50ml0.05M HEPES缓冲液，取1M HEPES缓冲液2.5ml，加适量重蒸水(ddH2O)，用NaOH调节pH至7.0，最后加ddH2O(重蒸水)至50ml。
c.ALK激酶(Millipore)
d.0.1M Na3VO4
e.1M MgCl2
f.0.2M DTT
g.10％BAS
h.DMSO
i.ddH2O
j.待测化合物：式Ⅰ化合物
按以下操作顺序进行：
1.配制ALK酶反应缓冲液：50mM HEPES(pH＝7.0)，0.1mM Na3VO4，0.01％BAS，5mM MgCl2，1mM DTT，放置于冰上备用；
2.将化合物从1mM开始用100％DMSO进行3倍的梯度稀释，每个浓度取4μl加入到96μl的反应缓冲液中，取2.5μl加入到384孔板(OptiPlate-384,PerkinElmer)，然后加入5μl的激酶，离心混匀，再加入2.5μl的ATP与TK peptide混合液(ATP终浓度为Km值)启动反应。
3.将384孔板放于孵育箱中在23℃下反应120分钟。
4.加入5μl的TK Antibody-Cryptate抗体，5μl的链霉亲和素标记的XL-665停止反应。
5.在孵育箱(22-23℃)中孵育1小时；
6.使用酶标仪Envision(PerkinElmer)读取反应的荧光信号：320nm激发，读取665nm波长的发射光谱；
7.化合物对ALK酶抑制IC50的生成：使用GraFit6计算化合物的IC50值。
上述方法测得式Ⅰ化合物的IC50值为1.96nM。该数据表明式Ⅰ化合物具有优异的 ALK抑制活性。
2、对突变的ALK激酶的抑制活性的测定
表1列出了式Ⅰ化合物对突变后的ALK激酶抑制活性。其中L1196M、G1269S突变的ALK激酶可通过商业途径购买获得。
表1式Ⅰ化合物对突变ALK激酶的抑制活性
Figure PCTCN2015085727-appb-000007
3、对人非小细胞肺癌NCI-H2228裸小鼠移植瘤的疗效的测定
采用的实验方法为：裸小鼠皮下接种人非小细胞肺癌NCI-H2228细胞，待肿瘤生长至80-200mm3后，将动物随机分组(D0)并给药，给药剂量和给药方案具体见表2。每周测2次瘤体积，称鼠重，记录数据。肿瘤体积(V)计算公式为：
V＝1/2×a×b2，其中a、b分别表示长、宽。
T/C(％)＝(T-T0)/(C-C0)×100，其中T、C分别为实验结束时的肿瘤体积；T0、C0分别为实验开始时的肿瘤体积。
当肿瘤出现消退时，T/C(％)＝(T-T0)/T0×100，其中T为实验结束时的肿瘤体积；T0为实验开始时的肿瘤体积。
抑瘤率(％)＝100-T/C(％)，部分消退是指肿瘤变小但未消失，完全消退是指肿瘤消失。
表2式Ⅰ化合物对人非小细胞肺癌NCI-H2228裸小鼠移植瘤的疗效
Figure PCTCN2015085727-appb-000008
Figure PCTCN2015085727-appb-000009
其中：溶剂(含0.1％Tween-80的蒸馏水)组为对照组，治疗组化合物用含0.1％Tween-80的蒸馏水配制。
D0-20表示从0天(D0)起，每天给药1次连续给药21天；D0-13表示从0天起，每天给药一次连续给药14天。
P值为与对照相比，经student’s t检验所得。
n为小鼠数目，实验小鼠数目为对照组n为12，治疗组n均为6。

Claims (25)

  1. 式Ⅰ化合物的药学上可接受酸的盐，其中式Ⅰ化合物具有如下结构：
    Figure PCTCN2015085727-appb-100001
  2. 如权利要求1所述的式Ⅰ化合物的药学上可接受酸的盐，其中所述药学上可接受酸包括无机酸和有机酸。
  3. 如权利要求1所述的式Ⅰ化合物的药学上可接受酸的盐，其中所述药学上可接受酸选自硫酸、碳酸、硝酸、盐酸、氢溴酸、氢碘酸、磷酸、偏磷酸、三氟乙酸、乳酸、延胡索酸、扁桃酸、乙醇酸、对甲苯磺酸、邻甲苯磺酸、柠檬酸、甲磺酸、甲酸、乙酸、苯甲酸、苯乙酸、丙二酸、肉桂酸、苹果酸、马来酸、酒石酸、草酸、富马酸、丙烯酸、巴豆酸、油酸和亚油酸。
  4. 如权利要求1所述的式Ⅰ化合物的药学上可接受酸的盐，其选自：
    5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺盐酸盐，
    5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺硫酸盐，
    5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺柠檬酸盐，
    5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺苹果酸盐，
    5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺马来酸盐，
    5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺酒石酸盐，和
    5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺富马酸盐。
  5. 制备权利要求1-4中任一项所述的式Ⅰ化合物的药学上可接受酸的盐的方法，其包括将 所述式Ⅰ化合物和所述药学上可接受酸反应。
  6. 如权利要求5所述的制备方法，其中所述药学上可接受酸选自硫酸、碳酸、硝酸、盐酸、氢溴酸、氢碘酸、磷酸、偏磷酸、三氟乙酸、乳酸、延胡索酸、扁桃酸、乙醇酸、对甲苯磺酸、邻甲苯磺酸、柠檬酸、甲磺酸、甲酸、乙酸、苯甲酸、苯乙酸、丙二酸、肉桂酸、苹果酸、马来酸、酒石酸、草酸、富马酸、丙烯酸、巴豆酸、油酸和亚油酸，优选盐酸、硫酸、柠檬酸、苹果酸、马来酸、酒石酸和富马酸。
  7. 如权利要求5或6所述的制备方法，其中通过将所述式Ⅰ化合物溶于含有相应的药学上可接受酸的单一溶剂或混合溶剂中来进行反应以获得所述盐，或者将所述式Ⅰ化合物溶于单一溶剂或混合溶剂中，随后向其中加入相应的药学上可接受酸来进行反应以获得所述盐。
  8. 如权利要求5-7中任一项所述的制备方法，其中所述式Ⅰ化合物与所述药学上可接受酸的摩尔比可为1:0.5-4或1:1-3，例如1:0.5、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5或1:4。
  9. 如权利要求5-8中任一项所述的制备方法，其中实施反应的温度可为0℃至溶剂系统的沸点，优选0℃-50℃，更优选0℃-35℃。
  10. 如权利要求5-9中任一项所述的制备方法，其中所述反应在诸如氮气氛的惰性气氛中实施。
  11. 如权利要求5-10中任一项所述的制备方法，其中所述反应的时间为0.5-5h。
  12. 如权利要求7-11中任一项所述的制备方法，其中所述溶剂选自四氢呋喃、二氧六环、异丙醚、乙醚、甲醇、乙醇、异丙醇、丙酮、乙腈、乙酸乙酯、甲酸乙酯、己烷、二氯甲烷、三氯甲烷及它们的任意组合。
  13. 药物组合物，其含有治疗有效量的权利要求1-4中任一项所述的式Ⅰ化合物的药学上可接受酸的盐和药学上可接受的载体、赋形剂或稀释剂。
  14. 权利要求1-4中任一项所述的式Ⅰ化合物的药学上可接受酸的盐或权利要求13所述的药物组合物在制备用于治疗和/或预防与蛋白激酶相关的疾病的药物中的用途。
  15. 权利要求1-4中任一项所述的式Ⅰ化合物的药学上可接受酸的盐或权利要求13所述的药物组合物在制备用于治疗和/或预防与突变的蛋白激酶相关的疾病的药物中的用途。
  16. 权利要求1-4中任一项所述的式Ⅰ化合物的药学上可接受酸的盐或权利要求13所述的药物组合物在制备用于治疗和/或预防由ALK介导的疾病的药物中的用途。
  17. 如权利要求16所述的用途，其中所述由ALK介导的疾病包括ALK阳性的非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B 细胞淋巴瘤、全身组织细胞增生症和神经母细胞瘤。
  18. 用于治疗和/或预防与蛋白激酶相关的疾病的方法，其包括将权利要求1-4中任一项所述的式Ⅰ化合物的药学上可接受酸的盐或权利要求13所述的药物组合物对有需要的哺乳动物、优选人进行给药。
  19. 用于治疗和/或预防与突变的蛋白激酶相关的疾病的方法，其包括将权利要求1-4中任一项所述的式Ⅰ化合物的药学上可接受酸的盐或权利要求13所述的药物组合物对有需要的哺乳动物、优选人进行给药。
  20. 用于治疗和/或预防由ALK介导的疾病的方法，其包括将权利要求1-4中任一项所述的式Ⅰ化合物的药学上可接受酸的盐或权利要求13所述的药物组合物对有需要的哺乳动物、优选人进行给药。
  21. 如权利要求20所述的方法，其中所述由ALK介导的疾病包括ALK阳性的非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B细胞淋巴瘤、全身组织细胞增生症和神经母细胞瘤。
  22. 用于治疗和/或预防与蛋白激酶相关的疾病的权利要求1-4中任一项所述的式Ⅰ化合物的药学上可接受酸的盐或权利要求13所述的药物组合物。
  23. 用于治疗和/或预防与突变的蛋白激酶相关的疾病的权利要求1-4中任一项所述的式Ⅰ化合物的药学上可接受酸的盐或权利要求13所述的药物组合物。
  24. 用于治疗和/或预防由ALK介导的疾病的权利要求1-4中任一项所述的式Ⅰ化合物的药学上可接受酸的盐或权利要求13所述的药物组合物。
  25. 如权利要求24所述的式Ⅰ化合物的药学上可接受酸的盐或药物组合物，其中所述由ALK介导的疾病包括ALK阳性的非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B细胞淋巴瘤、全身组织细胞增生症和神经母细胞瘤。
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CN110330483A (zh) * 2015-07-30 2019-10-15 正大天晴药业集团股份有限公司 吡啶取代的2-氨基吡啶类蛋白激酶抑制剂的结晶
CN110283161B (zh) * 2015-07-30 2021-09-03 正大天晴药业集团股份有限公司 吡啶取代的2-氨基吡啶类蛋白激酶抑制剂的结晶
WO2021018310A1 (zh) * 2019-08-01 2021-02-04 正大天晴药业集团股份有限公司 用于治疗非小细胞肺癌的氨基吡啶衍生物
WO2021219137A1 (zh) * 2020-04-30 2021-11-04 正大天晴药业集团股份有限公司 用于治疗met基因异常疾病的氨基吡啶衍生物
CN115484955A (zh) * 2020-04-30 2022-12-16 正大天晴药业集团股份有限公司 用于治疗met基因异常疾病的氨基吡啶衍生物
CN113754579A (zh) * 2020-06-01 2021-12-07 正大天晴药业集团股份有限公司 一种吡啶衍生物的制备方法
CN113754579B (zh) * 2020-06-01 2025-08-01 正大天晴药业集团股份有限公司 一种吡啶衍生物的制备方法

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JP2017521475A (ja) 2017-08-03
CN106536510B (zh) 2019-04-26
ES2762641T3 (es) 2020-05-25
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US20170226084A1 (en) 2017-08-10
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