WO2019149128A1 - Dérivé de 5-chloro-2,4-pyrimidine utilisé en tant que médicament antitumoral - Google Patents

Dérivé de 5-chloro-2,4-pyrimidine utilisé en tant que médicament antitumoral Download PDF

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WO2019149128A1
WO2019149128A1 PCT/CN2019/072915 CN2019072915W WO2019149128A1 WO 2019149128 A1 WO2019149128 A1 WO 2019149128A1 CN 2019072915 W CN2019072915 W CN 2019072915W WO 2019149128 A1 WO2019149128 A1 WO 2019149128A1
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substituted
unsubstituted
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alkyl
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陆柯潮
朱雷
张四平
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the field of biomedicine, and in particular to the 5-chloro-2,4-pyrimidine derivatives as antitumor drugs.
  • ALK Anaplastic lymphoma kinase
  • ACL an oncogene of most anaplastic large cell lymphoma (ALCL) expressed by a variety of molecular mechanisms.
  • ALK translocation or expression leads to tumorigenesis.
  • Activating mutations or translocations of the ALK gene have been identified in several types of cancer, including anaplastic large cell lymphoma, neuroblastoma, inflammatory myofibroblastoma, and non-small cell lung cancer.
  • Some ALK inhibitors have been clinically proven to be effective against a variety of cancers. Specifically, a small number of ALK inhibitors, such as Crizotinib Ceritinib and Brigatinib, which are present in the pharmaceutical market with anti-NSCLC (non-small cell lung cancer).
  • Y is N, or CH
  • L is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted C 1-4 hydrocarbyl;
  • R 1 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 2-8 alkenyl, substituted Or unsubstituted C 2-8 alkynyl, and substituted or unsubstituted C 1-8 alkoxy;
  • R 2 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted a substituted C 3-8 cycloalkyl, a substituted or unsubstituted 3- to 8-membered heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;
  • R 3 and R 6 are independently selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, and substituted or unsubstituted C 1-8 alkoxy;
  • R 4 and R 5 are independently selected from: hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted aryl, and substituted Or unsubstituted heteroaryl; or R 4 and R 5 together with the atom to which they are attached form a 3- to 8-membered ring, which is optionally substituted by one or more Substituent, the substituent being selected from the group consisting of: halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 1-4 alkyl-substituted or unsubstituted 3- to 8-membered heterocyclic group.
  • the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally and independently selected independently from one to three Substituted from the following group of substituents: halogen, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic , aryl, heteroaryl, -CN, -NO 2 , C 1-4 alkoxy; unless otherwise specified, the above aryl is an aryl group having 6 to 12 carbon atoms; the heteroaryl is 5- to 15-membered heteroaryl.
  • the compound structure is as shown in Formula I':
  • R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-4 alkyl.
  • R 2 is a substituted or unsubstituted C 1-4 alkyl group.
  • R 3 is a substituted or unsubstituted C 1-4 alkoxy group.
  • R 6 is hydrogen or a substituted or unsubstituted C 1-4 alkyl group.
  • Y is N.
  • Y is CH
  • R 4 and R 5 are taken together with the carbon atom to which they are attached, optionally containing 0-3 (eg 1, 2, or 3) independently selected from N, O or S.
  • 0-3 eg 1, 2, or 3
  • a 3- to 8-membered ring of a hetero atom preferably a 6-membered ring.
  • Y is N, and R 4 and R 5 together with the N atom to which they are attached form a 3- to 8-membered ring (preferably a 6-membered ring), optionally said 3- to 8-membered
  • the ring further contains 0-3 (eg 1, 2, or 3) heteroatoms independently selected from N, O or S; optionally the 3- to 8-membered ring is substituted by one or more substituents, The substituent is selected from the group consisting of halogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-4 alkyl substituted or unsubstituted 3- to 8-membered heterocyclic.
  • J is N or C;
  • the compound structure is as shown in Formula II':
  • J is C; and K is N.
  • J is N; and K is C.
  • J is N; and K is C; and R 7 is substituted or unsubstituted, optionally containing 0-3 (eg 1, 2, or 3) independently selected from N, O Or a 3- to 8-membered heterocyclic group of a hetero atom of S.
  • 0-3 eg 1, 2, or 3
  • R 7 is a C 1-4 alkyl-substituted 3- to 8-membered heterocyclic group having 2 N heteroatoms, preferably a 5- to 8-membered heterocyclic group.
  • ALK anaplastic lymphoma kinase
  • ALK an anaplastic lymphoma kinase
  • the "anaplastic lymphoma kinase (ALK) activity or expression-related disease” includes a tumor.
  • the tumor includes, but is not limited to, lymphoma, lung cancer, bladder cancer, breast cancer, kidney cancer, gastric cancer, liver cancer, ovarian cancer, prostate cancer, cervical cancer, intestinal cancer, epithelial cancer, multiple sexual myeloma, pancreatic cancer, leukemia, etc.
  • the tumor comprises anaplastic large cell lymphoma, neuroblastoma, inflammatory myofibroblastic tumor, and non-small cell lung cancer.
  • a pharmaceutical composition comprising:
  • a method of treating a tumor comprising the steps of:
  • a process for the preparation of a compound according to the first aspect of the invention which comprises the steps of:
  • the method further includes the steps of:
  • L is chlorine
  • ALK anaplastic lymphoma kinase
  • a pharmaceutical composition for the disease On the basis of this, the present invention has been completed.
  • the present invention relates to novel 5-chloro-2,4-substituted pyrimidine derivatives as ALK inhibitors and to the use of these compounds in the manufacture of a medicament for the treatment and prevention of cancer.
  • Y is N, or CH
  • R 1 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 2-8 alkenyl, substituted Or unsubstituted C 2-8 alkynyl, and substituted or unsubstituted C 1-8 alkoxy;
  • R 2 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted a substituted C 3-8 cycloalkyl, a substituted or unsubstituted 3- to 8-membered heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;
  • R 3 and R 6 are independently selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, and substituted or unsubstituted C 1-8 alkoxy;
  • R 4 and R 5 are independently selected from: hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted aryl, and substituted Or unsubstituted heteroaryl; or R 4 and R 5 together with the atom to which they are attached form a 3- to 8-membered ring, which is optionally substituted by one or more Substituent, the substituent being selected from the group consisting of: halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 1-4 alkyl-substituted or unsubstituted 3- to 8-membered heterocyclic group.
  • R 1 and R 2 may be independent substituents or may be bonded to one ring;
  • R 3 and R 6 may be two identical or different substituents;
  • R 4 and R 5 may be the same or different substituents and may be joined to form a five- or six-membered ring.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 may contain one or more heteroatoms such as, but not limited to, F, Cl, N, O, S.
  • Typical compounds of the invention include, but are not limited to:
  • the tumor suppressing activity has an unexpectedly excellent effect.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • alkyl refers to a straight (ie, unbranched) or branched alkyl group having from 1 to 8 carbon atoms, or a combination thereof.
  • the alkyl group can be saturated, monounsaturated or polyunsaturated, and can include divalent or multivalent radicals.
  • the alkyl group has a carbon number limitation (for example, C 1-8 )
  • a linear or branched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
  • alkenyl when used alone or as part of another substituent, refers to a straight or branched, carbon chain having at least one carbon-carbon double bond.
  • the alkenyl group having one double bond may be represented by -C n H 2n - 1
  • the alkenyl group having 2 double bonds may be represented by -C n H 2n-3 .
  • the alkenyl group has a carbon number limitation (for example, C 2-8 )
  • it means that the alkenyl group has 2 to 8 carbon atoms, for example, a linear or branched alkenyl group having 2 to 8 carbon atoms.
  • alkynyl when used alone or as part of another substituent, refers to an aliphatic hydrocarbon group having at least one carbon to carbon triple bond.
  • the alkynyl group can be straight or branched, or a combination thereof.
  • the alkynyl group has 2-8 (eg, 2-8, 2-6, or 2-4) carbon atoms.
  • the alkynyl group has a carbon number number (for example, C 2-8 alkynyl group), it means that the alkynyl group has 2 to 8 carbon atoms.
  • C 2-8 alkynyl group means having 2 to 8 A linear or branched alkynyl group of one carbon atom, such as ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or the like.
  • cycloalkyl refers to a monocyclic, bicyclic or tricyclic (including cyclo, bridged or spiro) ring system having a saturated or partially saturated.
  • the cycloalkyl group may have 3-16 (e.g., 3-10, or 5-10) carbon atoms.
  • a certain cycloalkyl group has a carbon number limitation (e.g., C 3-10 ), it means that the cycloalkyl group has 3 to 10 carbon atoms.
  • C 3-8 cycloalkyl refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentane. A group, a cycloheptyl group, or the like.
  • alkoxy refers to an alkyl group (eg, -O-alkyl) attached through an oxygen atom, wherein alkyl is as defined above.
  • alkoxy groups are, for example but not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, Or a similar group.
  • the alkoxy group may be substituted by one or more substituents such as a halogen, an amino group, a cyano group, or a hydroxyl group.
  • the alkoxy group can be straight or branched. When the alkoxy group has a carbon number limitation (e.g., C 1-8 ), it means that the cycloalkyl group has 1 to 8 carbon atoms.
  • halogen when used alone or as part of another substituent, refers to F, Cl, Br, and I.
  • aryl when used alone or as part of another substituent, refers to a monocyclic, bicyclic or fused ring aromatic hydrocarbon group.
  • the aryl group may be substituted or unsubstituted.
  • an aryl group has a carbon number limit (e.g., C 6-12 ), it means that the aryl group has 6 to 12 carbon atoms.
  • Examples of aryl groups are, for example but not limited to, phenyl, biphenyl, naphthyl, or the like (each of which may be optionally substituted).
  • the aryl group may contain no or one or more of the same or different (eg, 2, 3, 4) heteroatoms, which may be selected from N, O or S.
  • heteroaryl when used alone or as part of another substituent, refers to a monocyclic, bicyclic or fused ring aromatic group having a particular number of ring carbon atoms (eg, C 4-10 has 4 to 10 ring-forming carbon atoms) and includes at least one same or different hetero atom selected from N, O or S.
  • the atoms on each ring can be arbitrarily substituted.
  • the heteroaryl group may be 5- to 15-membered, having 1 to 5 aromatic ring groups each independently selected from a hetero atom of N, O or S. Examples of heteroaryl groups are, for example but not limited to, pyridine, pyrimidine, pyrrole, oxazole, indole, furan, benzofuran, thiophene, or the like.
  • heterocyclyl refers to a saturated or partially saturated substituent of a monocyclic or fused ring having a particular number of ring-forming carbon atoms (eg, C). 3-11 has 3 to 11 ring-forming carbon atoms) and includes at least one same or different hetero atom selected from N, O or S.
  • the heterocyclic group may be 3- to 15-membered, having 1 to 5 heterocyclic groups each independently selected from a hetero atom of N, O or S.
  • heterocyclic group examples are, for example but not limited to, a nitrogen heterocyclic group, an oxaheterocyclic group, a thioheterocyclic group, a nitrogen oxyheterocyclyl group, a nitrogen thioheterocyclic group, an oxathioheterocyclic group, etc., more preferably The heterocyclic groups appearing in the various examples of the present application.
  • the heterocyclic group may be monocyclic, bicyclic or tricyclic (including a bicyclic ring, a bridged ring or a spiro ring).
  • the term “optionally” or “optionally” means that the moiety is substituted or unsubstituted, and that the substitution occurs only with a chemically achievable position.
  • substituted when with or without “optionally” means that one or more hydrogen atoms on a particular group are replaced by a particular substituent.
  • Particular substituents are the substituents described above in the corresponding paragraphs, or the substituents which appear in the examples.
  • an optionally substituted group may have a substituent selected from a particular group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • a cyclic substituent, such as a heterocycloalkyl group may be attached to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, for example, two rings having a common carbon atom.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are, for example but not limited to, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic , aryl, heteroaryl, halogen, hydroxy, carboxy (-COOH), cyano, C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino.
  • the compound of the formula I of the present invention can be produced by the following method, however, the conditions of the method, such as the reactant, the solvent, the base, the amount of the compound used, the reaction temperature, the time required for the reaction, and the like are not limited to the following explanations.
  • the compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.
  • each reaction is usually carried out in an inert solvent at a reaction temperature of -78 ° C to 150 ° C (preferably 20 to 120 ° C).
  • the reaction time in each step is usually from 0.5 to 48 h, preferably from 2 to 12 h.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention and a pharmaceutically acceptable inorganic and organic acid, wherein preferred inorganic acids include, but are not limited to, hydrochloric acid, hydrogen Bromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid, etc.; preferred organic acids include, but are not limited to: citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid , naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxy horse Acid, pheny
  • a pharmaceutically acceptable salt of a compound of the invention refers to a salt that is suitable for contact with the tissue of a subject (eg, a human) without causing unpleasant side effects.
  • a pharmaceutically acceptable salt of a compound of the invention includes a salt (eg, a potassium salt, a sodium salt, a magnesium salt, a calcium salt) of a compound of the invention having an acidic group or is basic A salt of a compound of the invention (e.g., a sulfate, a hydrochloride, a phosphate, a nitrate, a carbonate).
  • pharmaceutically acceptable solvate refers to a compound of the invention that forms a solvate with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes, but is not limited to, water , ethanol, methanol, isopropanol, tetrahydrofuran, dichloromethane. Hydrates, solvates (e.g., methanolates, ethanolates, DMSOs) of the compounds of formula I of the present invention are also within the scope of the invention. Methods of solvation are well known in the art.
  • the term "pharmaceutically acceptable stereoisomer” means that the chiral atom to which the compound of the invention relates may be in the R configuration, in the S configuration, or a combination thereof.
  • the compound of the present invention has excellent inhibitory activity against ALK kinase
  • the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are mainly active.
  • the pharmaceutical composition of the ingredients can be used to treat, prevent, and alleviate diseases associated with ALK kinase activity or expression levels.
  • the compounds of the invention may be used to treat or prevent cancer and inhibit the proliferation of cancer cells.
  • the compounds of the present invention can be used for the treatment of diseases (but not limited to): various cancers, such as lung cancer, bladder cancer, breast cancer, kidney cancer, stomach cancer, liver cancer, ovarian cancer, prostate cancer, cervical cancer, Intestinal cancer, epithelial cell carcinoma, multiple myeloma, pancreatic cancer, lymphoma, leukemia, and the like.
  • diseases such as lung cancer, bladder cancer, breast cancer, kidney cancer, stomach cancer, liver cancer, ovarian cancer, prostate cancer, cervical cancer, Intestinal cancer, epithelial cell carcinoma, multiple myeloma, pancreatic cancer, lymphoma, leukemia, and the like.
  • the medicament is for use in at least one of the following: as a kinase inhibitor, inhibiting ALK kinase activity, treating or preventing cancer and inhibiting the proliferation of cancer cells.
  • the present invention tests the activity (IC50) of the compound for inhibiting the proliferation of a human anaplastic large cell lymphoma cell line in vitro, and the test results indicate that the compounds of the formula I of the present invention are all
  • the compound of the present invention can be used as an ALK inhibitor for the preparation of an antitumor therapeutic agent for inhibiting anaplastic lymphoma kinase, having a good activity for inhibiting the proliferation of a human degenerative large cell lymphoma cell line.
  • the medicament of the present invention is effective as an ALK inhibitor for the treatment of one or more neoplastic diseases associated with ALK activity, particularly non-small cell lung cancer.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 5 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
  • NMR nuclear magnetic resonance
  • LC-MS liquid chromatography-mass spectrometry
  • the microwave reaction was performed using an XH-800A microwave high pressure synthesizer.
  • Instrument model for measuring the IC50 value of the compound of formula I by MTT method Flexstation 3 of MD company.
  • the reaction process in the following examples was carried out by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: n-hexane/ethyl acetate system, dichloromethane/methanol system, and the volume ratio of the solvent was based on the compound. Adjust with different polarity.
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15-0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4-0.5.
  • Mm. column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • the column chromatography eluent system and the thin layer chromatography developer system include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, the volume ratio of the solvent according to the compound
  • the polarity is adjusted to adjust, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.
  • the starting materials used in the following examples may be synthesized by or according to methods known in the art, or may be purchased from Aladdin Reagent, Suiyuan Chemical Technology, Dari Chemicals, and the like.
  • the present invention discloses for the first time a new class of compounds having significant inhibitory effects on anaplastic lymphoma kinase (ALK);
  • the compound of the present invention has remarkable and excellent inhibitory activity against ALK, and thus can be used for the treatment of tumors.
  • the mixed solvent of DMF/DMSO 50 ml/5 ml was cooled to 0 ° C, NaH (1.37 g) was added and stirred for half an hour, and 2-methylsulfonyl-3-methylaniline (4.41 g, 23.8 mmol) of DMF/ DMSO (20ml / 2ml) solution, after the completion of the dropwise addition, stirring at 0 ° C for half an hour, slowly adding 2,4,5-trichloropyrimidine (8.73g, 47.6mmol) DMF / DMSO (15ml / 1.5ml) solution After the completion of the dropwise addition, the temperature was raised to room temperature and stirred for 24 hours.
  • reaction mixture was cooled to room temperature, evaporated, evaporated, evaporated, evaporated, evaporated -Chloro-4-(3-methyl-2-methanesulfonyl)aniline)pyrimidine-2-amino)-5-isopropoxy-2-methylphenylpiperidine-1-carboxylic acid tert-butanol ether 1 g (1.78 g, white solid), yield 42%.
  • Example 2 The synthesis method of Example 2 is referred to Example 1.
  • 2-isopropylthioaniline hydrochloride (5 g, 24.4 mmol) and 2,4,5-trichloropyrimidine (4.48 g, 24.4 mmol) were dissolved in a mixed solvent of 50 ml of toluene and 5 ml of n-butanol, and N was added.
  • N-diisopropylethylamine (6.3 g, 48.8 mmol)
  • heated under reflux for 24 hours cooled to room temperature, added with 20 ml of water, stirred for 10 minutes, and allowed to stand for separation to give an organic phase.
  • the synthesis method was carried out by referring to the synthesis method of the fourth step of Example 1, to obtain the title product (R,S)-4-(4-(5-chloro-4-(2-isopropylsulfinyl)aniline)pyrimidine-2-amino -5-Isopropoxy-2-methylphenylpiperidine-1-carboxylic acid tert-butanol ether (white solid), yield 40%
  • the synthesis method was carried out by referring to the synthesis method of the fifth step of Example 1, to give the title product (R,S)-5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl). Phenyl)-N4-(2-isopropylsulfinyl)phenyl)pyrimidine-2,4-diamine (white solid), yield 83%.
  • the aqueous phase was extracted with dichloromethane (50 ml ⁇ 3).
  • the organic phase was washed with water (30 ml ⁇ 1) and saturated sodium chloride (30 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered,
  • Example 4 The synthesis method of Example 5 is referred to Example 4.
  • the third step 2,5-dichloro-N-(3-methyl 2-(isopropyl sulfide) phenyl)pyrimidine-4-amine
  • Step 5 4-(4-(5-Chloro-4-(3-methyl-2-isopropylsulfonyl)aniline)pyrimidine-2-amino)-5-isopropoxy-2-methylphenyl Piperidine-1-carboxylic acid tert-butanol ether
  • the synthesis method was carried out by referring to the synthesis method of the fourth step 1g of Example 1, to give the title product 4-(4-(5-chloro-4-(3-methyl-2-isopropylsulfonyl)phenylamine)pyrimidine-2-amino) 5-5-Isopropoxy-2-methylphenylpiperidine-1-carboxylic acid tert-butanol ether 6f (white solid), yield 40%.
  • the synthesis method was carried out by referring to the synthesis method of the compound 1 of the fifth step of Example 1, to obtain the target product 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl) -N4-((3-methyl-2-isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine
  • Example 7 The synthesis method of Example 7 is referred to Example 6.
  • Example 8 The synthesis method of Example 8 is referred to Example 1.
  • Example 9 The synthesis method of Example 9 is referred to Example 1.
  • Example 3 The synthesis method of Example 10 is referred to Example 3.
  • Example 11 The synthesis method of Example 11 is referred to Example 3.
  • Example 12 The synthesis method of Example 12 is referred to Example 3 and Example 4.
  • Test Example 1 a compound of the present invention for the inhibition of proliferation of the human anaplastic large cell lymphoma cell line Karpas 299.
  • the in vitro cell assay described below can determine the additive inhibitory activity of a test compound on a human anaplastic large cell lymphoma cell line, and its activity can be expressed by an IC50 value.
  • the general protocol for such a test is as follows: First, the cell strain to be tested (Kelong Biotechnology Nanjing Co., Ltd.) is seeded on a 96-well culture plate at a cell concentration of 5000 cells/ml, and 80 ⁇ L of the cell suspension is inoculated into each well, and then The cells were cultured at 37 ° C in a 5% carbon dioxide incubator and allowed to grow overnight.
  • the medium was changed to a series of concentration gradients (3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM).
  • the culture medium of the test compound solution was returned to the incubator for 72 hours.
  • 13.5 ⁇ l of CCK-8 solution was added to the cell plate, and the mixture was incubated in a 37 ° C incubator for about 2 - 2
  • the absorbance at a wavelength of 450 nm was measured on a SpectraMax M5 Microplate Reader, and the absorbance at 650 nm was used as a reference to calculate the inhibition rate.
  • tumor cell growth inhibition rate % [Ac-As)/(Ac-Ab)] ⁇ 100%
  • the IC50 curve was fitted and the IC50 value was calculated using the software Graphpad Prism 6 and using the calculation formula log(inhibitor) vs.normalized response–variable slope.
  • Example number IC 50 /(nM) 1 52.3 2 35.4 3 (R, S mixed compound) 3.51 4 38.7 5 (R, S mixed compound) 1.34 6 104.1 7 64.5 8 42.3 9 50.2 10 (R, S mixed compound) 16.04 11 (R, S mixed compound) 5.12 12 (R, S mixed compound) 7.84 Positive control (chromatinib) 23.7
  • the preferred compounds of the present invention all have significant value-added inhibitory activity against Karpas299 cells.
  • the compounds 3, 5, 10, 11, 12 showed significantly better inhibitory activity, the activity of the compound 3 reached about 7 times the activity of the positive control; the activity of the compound 5 reached 17 times or more of the positive control.

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Abstract

La présente invention concerne un dérivé de 5-chloro-2,4-pyrimidine utilisé en tant qu'inhibiteur de la kinase du lymphome anaplasique (ALK). Le dérivé est un composé représenté par la formule I ou un sel pharmaceutiquement acceptable, un promédicament, un hydrate, un composé solvant, un métabolite du composé représenté par la formule (I), dans laquelle R1, R2, R3, R4 et R5 sont tels que définis dans la description. Le composé et la composition pharmaceutique peuvent être utilisés en tant qu'inhibiteur d'ALK et pour préparer un médicament thérapeutique antitumoral pour l'inhibition d'ALK.
PCT/CN2019/072915 2018-01-31 2019-01-24 Dérivé de 5-chloro-2,4-pyrimidine utilisé en tant que médicament antitumoral Ceased WO2019149128A1 (fr)

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CN103641816A (zh) * 2006-12-08 2014-03-19 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
WO2017158619A1 (fr) * 2016-03-15 2017-09-21 Natco Pharma Limited Procédé modifié pour la préparation de céritinib et de forme amorphe de céritinib

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EP2311807B1 (fr) * 2006-12-08 2015-11-11 Novartis AG Composés et compositions inhibant la protéine kinase
CN106699743B (zh) * 2015-11-05 2020-06-12 湖北生物医药产业技术研究院有限公司 嘧啶类衍生物及其用途

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CN103641816A (zh) * 2006-12-08 2014-03-19 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
WO2017158619A1 (fr) * 2016-03-15 2017-09-21 Natco Pharma Limited Procédé modifié pour la préparation de céritinib et de forme amorphe de céritinib

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