WO2019149128A1 - 作为抗肿瘤药物的5-氯-2,4-嘧啶衍生物 - Google Patents

作为抗肿瘤药物的5-氯-2,4-嘧啶衍生物 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
compound
group
alkyl
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PCT/CN2019/072915
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English (en)
French (fr)
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陆柯潮
朱雷
张四平
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陆柯潮
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Priority to CN201980023403.9A priority Critical patent/CN112004809A/zh
Publication of WO2019149128A1 publication Critical patent/WO2019149128A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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

本发明提供了作为ALK抑制剂的5-氯-2,4-嘧啶衍生物。该化合物为式（I）所示化合物或式I所示化合物的可药用盐，前药，水合物，溶剂化合物，代谢产物，其中R 1，R 2，R 3，R 4，R 5如说明书所定义。利用该化合物和药物组合物能够用作ALK抑制剂，用于制备成抑制间变性淋巴瘤激酶的抗肿瘤治疗药物。

Description

作为抗肿瘤药物的5-氯-2,4-嘧啶衍生物 技术领域
本发明属于生物医药领域，具体地本发明涉及作为抗肿瘤药物的5-氯-2,4-嘧啶衍生物。
背景技术
酪氨酸激酶参与大多数癌症的发病机制。然而，很少有酪氨酸激酶被证明在淋巴瘤中具有明确的致病作用。间变性淋巴瘤激酶(ALK)是大多数间变性大细胞淋巴瘤(ALCL)的癌基因通过多种分子机制进行转化表达的。ALK易位或表达异常导致肿瘤发生。ALK基因的激活突变或易位已在几种类型的癌症中鉴定，包括间变性大细胞淋巴瘤、成神经细胞瘤、炎性肌纤维母细胞瘤和非小细胞肺癌。一些ALK抑制剂在临床上已证实对各种癌症有效。具体而言，少数ALK抑制剂，在医药市场上以抗NSCLC(非小细胞肺癌)而存在的药物如Crizotinib Ceritinib和Brigatinib。
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如Crizotinib,Ceritinib等已经上市用于NSCLC的治疗，但是会产生耐药性，不良反应大，存在一定程度的缺陷，并且在中国，目前还没有具有自主知识产权的ALK抑制剂药物上市，因而，开发出更安全，高效的治疗癌症的新型ALK抑制剂药物具有巨大的社会价值和经济效益。
发明内容
本发明的目的在于提供一种作为抗肿瘤药物的5-氯-2,4-嘧啶衍生物及其应用。
在本发明的第一方面，提供了一种如式(I)所示的化合物，或其药学上可接受的盐、前药、代谢产物、水合物、或溶剂合物：
Figure PCTCN2019072915-appb-000001
式(I)中：
X为-(S＝O)-、或-(O＝S＝O)-；
Y为N、或CH；
L选自：氢、卤素、羟基、氰基、取代的或未取代的C 1-4烃基；
R 1选自：氢、卤素、取代的或未取代的C 1-8烷基、取代的或未取代的C 3-8环烷基、取代的或未取代的C 2-8烯基、取代的或未取代的C 2-8炔基、和取代的或未取代的C 1-8烷氧基；
R 2选自：氢、取代的或未取代的C 1-8烷基、取代的或未取代的C 2-8烯基、取代的或未取代的C 2-8炔基、取代的或未取代的C 3-8环烷基、取代的或未取代的3-至8-元杂环基、取代的或未取代的芳基、和取代的或未取代的杂芳基；
R 3和R 6独立地选自：氢、卤素、取代的或未取代的C 1-8烷基、和取代的或未取代的C 1-8烷氧基；
R 4和R 5独立地选自：氢、取代的或未取代的C 1-8烷基、取代的或未取代的C 1-8烷氧基、取代的或未取代的芳基、和取代的或未取代的杂芳基；或者，R 4和R 5和它们所连接的原子一起形成3-至8-元环，所述3-至8-元环任选地被一个或多个取代基取代，所述取代基选自：卤素、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 1-8烷氧基、C 3-8环烷基、C 1-4烷基取代的或未取代的3-至8-元杂环基。
在另一优选例中，所述上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：卤素、羟基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、3-至12-元杂环基、芳基、杂芳基、-CN、-NO 2、C 1-4烷氧基；除非特别说明，上述的芳基为含有6-12个碳原子的芳基；杂芳基为5-至15-元杂芳基。
在另一优选例中，所述化合物结构如式I’所示：
Figure PCTCN2019072915-appb-000002
在另一优选例中，R 1选自：氢、取代的或未取代的C 1-4烷基。
在另一优选例中，R 2为取代的或未取代的C 1-4烷基。
在另一优选例中，R 3为取代的或未取代的C 1-4烷氧基。
在另一优选例中，R 6为氢、或取代的或未取代的C 1-4烷基。
在另一优选例中，X为-(S＝O)-或-(O＝S＝O)-；优选地，X为-(S＝O)-。
在另一优选例中，Y为N。
在另一优选例中，Y为CH，并且R 4和R 5与其相连的碳原子共同形成任选地含有0-3个(如1、2、或3个)独立选自N、O或S的杂原子的3-至8-元环(优选为6元环)。
在另一优选例中，Y为N，并且R 4和R 5与其相连的N原子共同形成3-至8-元环(优选为6元环)，任选地所述3-至8-元环还含有0-3个(如1、2、或3个)独立选自N、O或S的杂原子；任选地所述3-至8-元环被一个或多个取代基取代，所述取代基选自：卤素、C 1-8烷基、C 3-8环烷基、C 1-4烷基取代的或未取代的3-至8-元杂环基。
在另一优选例中，所述当X为-(S＝O)-时，所述化合物为R构型、S构型、或R,S混旋型。
在另一优选例中，所述化合物的结构如式(II)所示：
Figure PCTCN2019072915-appb-000003
其中，J为N或C；K为N或C；R 7选自：氢、取代的或未取代的C 1-8烷 基、取代的或未取代的C 2-8烯基、取代的或未取代的C 2-8炔基、取代的或未取代的C 1-8烷氧基、取代的或未取代的C 3-8环烷基、取代的或未取代的3-至8-元杂环基、取代的或未取代的芳基、和取代的或未取代的杂芳基；
X、L、R 1、R 2、R 3、R 6分别如上所述。
在另一优选例中，所述化合物结构如式II’所示：
Figure PCTCN2019072915-appb-000004
其中各取代基如上所述。
在另一优选例中，J为C；并且K为N。
在另一优选例中，J为N；并且K为C。
在另一优选例中，J为N；并且K为C；并且R 7为取代的或未取代的任选地含有0-3个(如1、2、或3个)独立选自N、O或S的杂原子的3-至8-元杂环基。
在另一优选例中，R 7为C 1-4烷基取代的含有2个N杂原子的3-至8-元杂环基，优选为5-至8-元杂环基。
本发明的第二方面，提供了本发明第一方面所述的式(I)化合物的用途，用于：
(a)制备治疗与间变性淋巴瘤激酶(ALK)活性或表达相关的疾病的药物；和/或
(b)制备间变性淋巴瘤激酶(ALK)靶向抑制剂；和/或
(c)体外非治疗性地抑制间变性淋巴瘤激酶(ALK)的活性。
在另一优选例中，所述“间变性淋巴瘤激酶(ALK)活性或表达相关的疾病”包括肿瘤。
在另一优选例中，所述肿瘤包括并不限于：淋巴瘤、肺癌、膀胱癌、乳腺癌、肾癌、胃癌、肝癌、卵巢癌、前列腺癌、宫颈癌、肠癌、上皮细胞癌、多发性骨髓瘤、胰腺癌、白血病等。
在另一优选例中，所述肿瘤包括间变性大细胞淋巴瘤、成神经细胞瘤、炎性肌纤维母细胞瘤和非小细胞肺癌。
本发明的第三方面，提供了一种药物组合物，所述的药物组合物包括：
(i)有效量的本发明第一方面所述的化合物，或其药学上可接受的盐、前药、代谢产物、水合物、或溶剂合物；和
(ii)药学上可接受的载体。
本发明的第四方面，提供了一种治疗肿瘤的方法，所述方法包括步骤：
对需要的对象施用治疗有效量的如本发明第一方面所述的式(I)化合物或其药学上可接受的盐，或对需要的对象施用治疗有效量的如本发明第三方面所述的药物组合物。
本发明的第五方面，提供了一种如本发明第一方面所述的化合物的制备方法，该方法包括步骤：
(a)在惰性溶剂中，化合物A3和化合物A4反应得到式I所示化合物
Figure PCTCN2019072915-appb-000005
在另一优选例中，所述方法还包括步骤：
(b)在惰性溶剂中，化合物A1和化合物A2反应得到化合物A3:
Figure PCTCN2019072915-appb-000006
在另一优选例中，L为氯。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人通过广泛而深入的研究，获得一类对间变性淋巴瘤激酶(ALK)具有显著抑制作用的化合物，这些化合物可以用于制备治疗与间变性淋巴瘤激酶(ALK)活性或表达相关的疾病的药物组合物。在此基础上，完成了本发明。
在描述本发明之前，应当理解本发明不限于所述的具体方法和实验条件，因为这类方法和条件可以变动。还应当理解本文所用的术语其目的仅在于描述具体实施方案，并且不意图是限制性的，本发明的范围将仅由所附的权利要求书限制。
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
虽然在本发明的实施或测试中可以使用与本发明中所述相似或等价的任何方法和材料，本文在此处例举优选的方法和材料。
本发明涉及涉及作为ALK抑制剂的新型5-氯-2,4-取代嘧啶衍生物以及这些化合物在制备用于治疗和预防癌症的药物中的用途。
本发明的目的在于提供通式(I’)所示的化合物或式I’所示化合物的可药用盐，水合物，溶剂化物，代谢产物，或前药：
Figure PCTCN2019072915-appb-000007
式(I)中：
X为-(S＝O)-、或-(O＝S＝O)-；
Y为N、或CH；
R 1选自：氢、卤素、取代的或未取代的C 1-8烷基、取代的或未取代的C 3-8环烷基、取代的或未取代的C 2-8烯基、取代的或未取代的C 2-8炔基、和取代的或未取代的C 1-8烷氧基；
R 2选自：氢、取代的或未取代的C 1-8烷基、取代的或未取代的C 2-8烯基、取代的或未取代的C 2-8炔基、取代的或未取代的C 3-8环烷基、取代的或未取代的3-至8-元杂环基、取代的或未取代的芳基、和取代的或未取代的杂芳基；
R 3和R 6独立地选自：氢、卤素、取代的或未取代的C 1-8烷基、和取代的或未取代的C 1-8烷氧基；
R 4和R 5独立地选自：氢、取代的或未取代的C 1-8烷基、取代的或未取代的C 1-8烷氧基、取代的或未取代的芳基、和取代的或未取代的杂芳基；或者，R 4和R 5和它们所连接的原子一起形成3-至8-元环，所述3-至8-元环任选地被一个或多个取代基取代，所述取代基选自：卤素、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 1-8烷氧基、C 3-8环烷基、C 1-4烷基取代的或未取代的3-至8-元杂环基。
在本发明的一个优选地实施方式中，R 1和R 2可以是独立的取代基，也可以连接成一个环；R 3和R 6可以是两个相同或者不同的取代基；R 4和R 5可以是相同或者不同的取代基，可以连接成一个五元或者六元环。
R 1，R 2，R 3，R 4，R 5，R 6可以含有一个或多个杂原子，例如，但不限于F、Cl、N、O、S。
由此，在本说明书中通篇中，本领域技术人员可对式I所示化合物中所述R 1-R 6的基团及其取代基进行选择，以提供本发明的实施例中所述的，稳定的式I所示化合物或其可药用盐、水合物、溶剂化物、代谢产物。
本发明的典型化合物包括，但不限于：
Figure PCTCN2019072915-appb-000008
Figure PCTCN2019072915-appb-000009
其中*为手性原子，包括R构型，S构型，R,S混旋型化合物。
本发明的化合物中，当X为-(S＝O)-时，化合物为R构型、S构型、或R,S混旋型，此时，本发明的化合物表现出了及其优异的肿瘤抑制活性，具有出乎意料的优异效果。
术语
除特别说明之处，本文中提到的“或”具有与“和/或”相同的意义(指“或”以及“和”)。
除特别说明之处，本发明的所有化合物之中，各手性碳原子(手性中心)可以任选地为R构型或S构型，或R构型和S构型的混合物。
如本文所用，在单独或作为其他取代基一部分时，术语“烷基”指具有1～8个碳原子的直链(即，无支链)或支链烷基，或其组合。所述的烷基可以是饱和的，单不饱和或多不饱和的，且可以包括二价或多价的原子团。当烷基前具有碳原子数限定(如C 1-8)时，指所述的烷基含有1-8个碳原子，例如，C 1-8烷基可以包括具有1-8个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“烯基”是指直链或支链，具有至少1个碳碳双键的碳链。具有一个双键的烯基可以被表示为 -C nH 2n- 1，具有2个双键的烯基可以被表示为-C nH 2n-3。当烯基前具有碳原子数限定(如C 2-8)时，指所述的烯基含有2-8个碳原子，例如，具有2-8个碳原子的直链或支链烯基，例如乙烯基、丙烯基、1,2-丁烯基、2,3-丁烯基、丁二烯基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“炔基”是指具有至少一个碳碳三键的脂肪族碳氢基团。所述的炔基可以是直链或支链的，或其组合。在一些实施例中，所述的炔基具有2-8(例如，2-8，2-6，或2-4)个碳原子。当炔基前具有碳原子数限定(如C 2-8炔基)时，指所述的炔基含有2-8个碳原子，例如，术语“C 2-8炔基”指具有2～8个碳原子的直链或支链炔基，例如乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、仲丁炔基、叔丁炔基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“环烷基”指具有饱和的或部分饱和的单环、二环或三环(包括并环、桥环或螺环)环系。所述的环烷基可以具有3-16个(例如，3-10个，或5-10个)碳原子。当某个环烷基前具有碳原子数限定(如C 3-10)时，指所述的环烷基含有3-10个碳原子。在一些优选实施例中，术语“C 3-8环烷基”指具有3～8个碳原子的饱和或部分饱和的单环或二环烷基，例如环丙基、环丁基、环戊基、环庚基、或类似基团。
如本文所用，术语“烷氧基”或“烷基氧基”指通过氧原子相连的烷基(例如，-O-烷基)，其中烷基如上所述。特定的烷氧基的例子例如(但并不限于)甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。烷氧基可以被1个或多个取代基取代，所述的取代基例如卤素、氨基、氰基，或羟基。烷氧基可以为直链或支链的。当烷氧基前具有碳原子数限定(如C 1-8)时，指所述的环烷基含有1-8个碳原子。
如本文所用，在单独或作为其他取代基一部分时，术语“卤素”指F、Cl、Br和I。
如本文所用，在单独或作为其他取代基一部分时，术语“芳基”指单环，二环或稠环的芳香族碳氢基团。所述的芳基可以是取代或未取代的。当一个芳基前具有碳原子数限定(如C 6-12)时，指所述的芳基含有6-12个碳原子。芳基的例子例如(但并不限于)：苯基、联苯基、萘基、或类似基团(其中的每个碳原子均可以被任意取代)。所述的芳基可以不含或包含一个或多个相同或不同的(如2、3、4个)杂原子，所述杂原子可以选自N、O或S。
如本文所用，在单独或作为其他取代基一部分时，术语“杂芳基”指单环，二环或稠环的芳香族基团，所述基团具有特定的成环碳原子数(例如，C 4-10即具有4-10个成环碳原子)，且包括至少一个相同或不同的选自N、O或S的杂原子。每个环上原子可以被任意取代。所述的杂芳基可以是5-至15-元的，具有1-5个各自独立地选自N、O或S的杂原子的芳香环基。杂芳基的例子例如(但并不限于)：吡啶、嘧啶、吡咯、吲唑、吲哚、呋喃、苯并呋喃、噻吩，或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“杂环基”指单环或稠环的饱和或部分饱和取代基，所述基团具有特定的成环碳原子数(例如，C 3-11即具有3-11个成环碳原子)，且包括至少一个相同或不同的选自N、O或S的杂原子。所述的杂环基可以是3-至15-元的，具有1-5个各自独立地选自N、 O或S的杂原子的杂环基。杂环基的例子例如(但并不限于)：氮杂环基、氧杂环基、硫杂环基、氮氧杂环基、氮硫杂环基、氧硫杂环基等，更优选的为本申请各实施例中所出现的杂环基。本发明中，杂环基可以为单环、二环或三环(包括并环、桥环或螺环)。
如本文所用，术语“任意地”或“任选地”(例如，“被任意取代的”)指所述的部分为取代的或未取代的，且该取代仅发生与化学上可实现的位置。例如，H、共价键或-C(＝O)-基团不可以被取代基取代。
如本文所用，术语“取代”(在有或无“任意地”修饰时)指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个任意取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环烷基，可以与另一个环相连，例如环烷基，从而形成螺二环系，例如，两个环具有一个共用碳原子。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、氰基、C 1-8醛基、C 2-10酰基、C 2-10酯基、氨基。
为了方便以及符合常规理解，术语“任意取代”或“任选取代”只适用于能够被取代基所取代的位点，而不包括那些化学上不能实现的取代。
化合物的通用合成方法
本本发明通式I所示化合物可通过如下的方法制得，然而该方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易地进行。
在本发明的制备方法中，各反应通常在惰性溶剂中，反应温度-78℃～150℃(优选20～120℃)下进行。各步反应时间通常为0.5～48h，较佳地为2～12h。
反应式A描述了本发明化合物的通用合成方法：
反应式A：
Figure PCTCN2019072915-appb-000010
如本文所用，术语“药学上可接受的盐”指本发明化合物与药学上可接受的无机酸和有机酸所形成的盐，其中，优选的无机酸包括(但并不限于)：盐酸，氢 溴酸，硫酸，硝酸，氨基磺酸和磷酸等；优选的有机酸包括(但并不限于)：柠檬酸，酒石酸，乳酸，丙酮酸，乙酸，苯磺酸，对甲苯磺酸，甲磺酸，萘磺酸，乙磺酸，萘二磺酸，马来酸，苹果酸，丙二酸，富马酸，琥珀酸，丙酸，草酸，三氟乙酸，硬脂酸，扑酸，羟基马来酸，苯乙酸，苯甲酸，水杨酸，谷氨酸，抗坏血酸，对氨基苯磺酸，2-乙酰氧基苯甲酸和羟乙磺酸等。如本文所用，除非特别说明，术语“药学上可接受的盐”指适合与对象(例如，人)的组织接触，而不会产生不适度的副作用的盐。在一些实施例中，本发明的某一化合物的药学上可接受的盐包括具有酸性基团的本发明的化合物的盐(例如，钾盐，钠盐，镁盐，钙盐)或具有碱性基团的本发明的化合物的盐(例如，硫酸盐，盐酸盐，磷酸盐，硝酸盐，碳酸盐)。
如本文所用，术语“药学上可接受的溶剂合物”指本发明化合物与药学上可接受的溶剂形成溶剂合物，其中，所述药学上可接受的溶剂包括(但并不限于)：水、乙醇、甲醇、异丙醇、四氢呋喃、二氯甲烷。本发明式I所示化合物的水合物、溶剂化物(如甲醇化物，乙醇化物，DMSO化物)也在本发明的范围内。溶剂化的方法是本领域公知的。
如本文所用，术语“药学上可接受的立体异构体”指本发明化合物所涉及手性原子可以为R构型，也可以为S构型，或其组合。
药物组合物和施用方法
由于本发明化合物具有优异的对ALK激酶的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由与ALK激酶活性或表达量相关的疾病。本发明的化合物可以用于治疗或者预防癌症和抑制癌细胞的增值。
根据现有技术，本发明化合物可用于治疗以下疾病(但并不限于)：各种癌症，列如肺癌、膀胱癌、乳腺癌、肾癌、胃癌、肝癌、卵巢癌、前列腺癌、宫颈癌、肠癌、上皮细胞癌、多发性骨髓瘤、胰腺癌、淋巴瘤、白血病等等。
根据本发明的具体实施例，所述药物用于下列至少之一：用作激酶抑制剂，抑制ALK激酶活性，治疗或者预防癌症和抑制癌细胞的增值。根据本发明的具体示例，本发明对所述化合物在体外对人间变性大细胞淋巴瘤细胞株的增值活性抑制的活性(IC50)做了测试，测试结果表明本发明所述式I所示化合物均具有良好的抑制人间变性大细胞淋巴瘤细胞株增值的活性，本发明所述化合物可用作ALK抑制剂，用于制备成抑制间变性淋巴瘤激酶的抗肿瘤治疗药物。
因此，本发明所述药物能够有效地作为ALK抑制剂，用于治疗一种或一种以上与ALK活性有关的肿瘤疾病，特别是非小细胞肺癌。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和 局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
在下面所描述的具体实施例中，化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定。其中，NMR位移(δ)以百万分之一(ppm)的 单位给出，NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代氯仿(CDCl 3),氘代甲醇(CD 3OD),氘代二甲亚砜(DMSO-d 6),内标为四甲基硅烷(TMS)。液质联用色谱LC-MS的测定用Agilent6120质谱仪，HPLC的测定使用型号为：Agilent 1260(Poroshell 120EC-C18 4.6×50mm色谱柱)
微波反应使用XH-800A微波高压合成仪。
MTT法测式I化合物IC50值用的仪器型号：MD公司的Flexstation 3。
下面实施例中的反应进程的检测采用薄层色谱法(TLC),反应所使用的展开剂的体系有：正己烷/乙酸乙酯体系，二氯甲烷/甲醇体系，溶剂的体积比根据化合物的极性不同而进行调节。薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15-0.2mm,薄层层析分离纯化产品采用的规格是0.4-0.5mm.柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
下面实施例中所使用的起始原料可以采用或者按照本领域已知的方法来合成，或可购买自阿拉丁试剂公司，韶远化学科技，达瑞化学品等公司。
本发明的主要优点在于：
(1)本发明首次公开了一类新的对间变性淋巴瘤激酶(ALK)具有显著抑制作用的化合物；
(2)本发明的化合物对ALK具有显著地及其优异的抑制活性，因而可以用于肿瘤的治疗。
(3)本发明的系列化合物中，某些化合物抑制肿瘤细胞(Karpas299)增值的活性显著优于阳性对照(ceritinib),具有代替阳性对照药物的潜力，因此开发前景巨大。
下面结合具体实施例，进一步详陈本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明详细条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1
5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-(3-甲基-2-甲基磺酰基)苯基)嘧啶-2,4-二胺。
Figure PCTCN2019072915-appb-000011
Figure PCTCN2019072915-appb-000012
第一步
1-甲基-2-甲磺酰基-3-硝基苯
将3-硝基-2-氟甲苯(5.00g,32.2mmol)溶解于15g二甲亚砜中，加入甲基亚磺酸钠(4.94g,48.4mmol),加热至85℃，搅拌反应12小时。将反应液冷却至室温，加入50g水，降温至0-10℃，搅拌40分钟，过滤，真空干燥得到标题产物1-甲基-2-甲磺酰基-3-硝基苯1b(5.89g,灰白色固体)，收率85％。
第二步
2-甲磺酰基-3-甲基苯胺
将1-甲基-2-甲磺酰基-3-硝基苯(5.89g,27.4mmol)溶解于25g无水乙醇中，加入5％钯碳(0.6g)，氢气置换三次，氢气氛下(0.4MPa),搅拌反应48小时。将反应液经过硅藻土过滤，滤液减压浓缩，用硅胶柱色谱法(洗脱液正己烷/乙酸乙酯＝5:1)纯化所得残余物，得到标题产物2-甲磺酰基-3-甲基苯胺1c(4.41g,白色固体)，收率87％。
第三步
2,5-二氯-N-((3-甲基-2-甲磺酰基)苯)嘧啶-4-胺
将DMF/DMSO(50ml/5ml)的混合溶剂降温至0℃，加入NaH(1.37g),搅拌半小时，加入2-甲磺酰基-3-甲基苯胺(4.41g,23.8mmol)的DMF/DMSO(20ml/2ml)溶液，滴完后，在0℃搅拌半小时，慢慢滴加2,4,5-三氯嘧啶(8.73g,47.6mmol)的DMF/DMSO(15ml/1.5ml)溶液，滴完后，升温至室温，搅拌24小时。加入300ml水，搅拌1小时，过滤，得到黄色固体，用硅胶柱色谱法(洗脱液，正己烷/乙酸乙酯＝5:1)纯化此黄色固体，得到标题产物2,5-二氯-N-((3-甲基-2-甲磺酰基)苯)嘧啶-4-胺1e(4.35g,白色固体)，收率55％。
第四步
4-(4-(5-氯-4-(3-甲基-2-甲磺酰基)苯胺)嘧啶-2-氨基)-5-异丙氧基-2-甲基苯基哌啶-1-羧酸叔丁醇醚
将4-(4-氨基-5-异丙氧基-2-甲基苯基)哌啶-1-羧酸叔丁醇醚(2.28g,6.26mmol),2,5-二氯-N-((3-甲基-2-甲磺酰基)苯)嘧啶-4-胺(2.18g,6.26mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.376g,0.626mmol),醋酸钯(73.76mg,0.313mmol),碳酸铯(6.4g,19.64mmol)和40ml四氢呋喃 加入反应瓶中，微波150℃反应20分钟。将反应液冷却至室温，减压蒸馏，蒸干后用硅胶柱色谱法纯化(洗脱液，正己烷/乙酸乙酯＝5:1)所得残余物，得到标题产物4-(4-(5-氯-4-(3-甲基-2-甲磺酰基)苯胺)嘧啶-2-氨基)-5-异丙氧基-2-甲基苯基哌啶-1-羧酸叔丁醇醚1g(1.78g,白色固体)，收率42％。
第五步
5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-((3-甲基-2-甲磺酰基)苯基)嘧啶-2,4-二胺
将4-(4-(5-氯-4-(3-甲基-2-甲磺酰基)苯胺)嘧啶-2-氨基)-5-异丙氧基-2-甲基苯基哌啶-1-羧酸叔丁醇醚(1.78g,2.76mmol)溶于50ml二氯甲烷中，加入三氟乙酸(20g)，室温下搅拌1小时，减压浓缩，加入20ml氢氧化钠水溶液(20％)，70ml乙酸乙酯，搅拌半小时，分液，水相再用70ml乙酸乙酯萃取，合并有机相，有机相依次用水(30ml×1)和饱和氯化钠溶液(30ml×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，并用正己烷/乙酸乙酯(10/1)结晶，得到标题产物5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-((3-甲基-2-甲磺酰基)苯基)嘧啶-2,4-二胺1(1.28g,白色固体)，收率85％。
LCMS:544
1H-NMR(400MHz,CDCl3):δ＝1.38(d,J＝6.1Hz,6H),1.59-1.78(m,5H),2.18(s,3H),2.35(s,3H),2.84(s,3H),2.75-2.82(m,3H),3.20-3.24(M,2H),4.56(sept,J＝6.1Hz),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
实施例2
5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-((3-甲基-2-乙磺酰基)苯基)嘧啶-2,4-二胺
Figure PCTCN2019072915-appb-000013
实施例2的合成方法参照实施例1.
LC-MS:558
1H-NMR(400MHz,CDCl3):δ＝1.24(m,J＝6.5Hz,3H),1.38(d,J＝6.1Hz,6H),1.59-1.78(m,5H),2.18(s,3H),2.35(s,3H),3.45(m,2H),2.75-2.82(m,3H),3.20-3.24(M,2H),4.56(sept,J＝6.1Hz),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
实施例3
(R,S)-5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-(2-异丙基亚磺酰基)苯基)嘧啶-2,4-二胺。
Figure PCTCN2019072915-appb-000014
第一步
2,5-二氯-N-(2-(异丙基硫醚)苯基)嘧啶-4-胺
将2-异丙硫代苯胺盐酸盐(5g,24.4mmol)和2,4,5-三氯嘧啶(4.48g,24.4mmol)溶于50ml甲苯和5ml正丁醇的混合溶剂中，加入N,N-二异丙基乙胺(6.3g,48.8mmol),加热回流反应24小时，降温至室温，加入20ml水，搅拌10分钟，静置分层，得到有机相，有机相依次用水(20ml×1)和饱和氯化钠溶液(20ml×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，并用乙醇结晶，得到标题产物2,5-二氯-N-(2-(异丙基硫醚)苯基)嘧啶-4-胺3b(6.2g,白色固体)，收率81％。
第二步
(R,S)-2,5-二氯-N-(2-(异丙亚磺酰基)苯基)嘧啶-4-胺
将2,5-二氯-N-(2-(异丙亚磺酰基)苯基)嘧啶-4-胺(6.2g,20mmol)溶于100ml二氯甲烷中，降温至0-5℃，慢慢滴加间氯过氧苯甲酸的二氯甲烷溶液(3.14g85％mCPBA/100ml二氯甲烷)，约1小时滴完，滴完后，升温至室温，搅拌5小时，再降温至-5℃--10℃，搅拌1小时，过滤，滤去不溶物，滤液减压浓缩，残留物加正己烷，乙酸乙酯结晶(正己烷/乙酸乙酯＝5:1)，得到标题产物(R,S)-2,5-二氯-N-(2-(异丙亚磺酰基)苯基)嘧啶-4-胺3c(5.2g,白色固体)，收率80％。
第三步
(R,S)-4-(4-(5-氯-4-(2-异丙亚磺酰基)苯胺)嘧啶-2-氨基)-5-异丙氧基-2-甲基苯基哌啶-1-羧酸叔丁醇醚
合成方法参照实施例1第四步的合成方法，得到标题产物(R,S)-4-(4-(5-氯-4-(2-异丙亚磺酰基)苯胺)嘧啶-2-氨基)-5-异丙氧基-2-甲基苯基哌啶-1-羧酸叔丁醇醚(白色固体)，收率40％
第四步
(R,S)-5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-(2-异丙基亚磺酰基)苯基)嘧啶-2,4-二胺。
合成方法参照实施例1第五步的合成方法，得到标题产物(R,S)-5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-(2-异丙基亚磺酰基)苯基)嘧啶-2,4-二胺(白色固体)，收率83％。
LC-MS:542
1H-NMR(400MHz,DMSO-d 6):δ＝1.18(d,J＝6.8Hz,6H),1.24(d,J＝6.1Hz,6H),1.46-1.62(m,4H),2.18(s,3H),2.59-2.65(m,2H),2.69-2.75(m,1H),3.03-3.06(d,2H),3.45-3.51(m,1H),4.51-4.57(m,2H),6.82(s,1H),7.32-7.36(t,J＝7.6Hz,1H),7.51(s,1H),7.59-7.63(t,J＝7.2Hz,1H),7.85(dd,1H),8.05(s,1H),8.23(s,1H),8.45-8.47(m,1H)ppm.
通过手性制备柱拆分，可以得到(R)-5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-(2-异丙基亚磺酰基)苯基)嘧啶-2,4-二胺和(S)-5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-(2-异丙基亚磺酰基)苯基)嘧啶-2,4-二胺。
实施例4
5-氯-N2-(2-甲氧基-4-(4-(4-甲基-1-哌嗪基)-1-哌啶基)苯基)-N4-((3-甲基-2-甲磺酰基)苯基)嘧啶-2,4-二胺
Figure PCTCN2019072915-appb-000015
将2,5-二氯-N-((3-甲基-2-甲磺酰基)苯基)嘧啶-4-胺(1.56g,4.70mmol)和2-甲氧基-4-(4-(4-甲基哌嗪基)哌啶基)苯胺(2g,6.59mmol)溶于2-甲氧基乙醇(25ml)中，加入2.5M盐酸乙醇(5ml),将此混合物倒入到一个厚壁玻璃瓶中，加热到120℃，反应6小时，降温至室温，减压浓缩，向残留物中加入50ml水，50ml乙酸乙酯，搅拌分层，去掉乙酸乙酯层，收集水层，水层中滴加20％氢氧化钠水溶液调PH值至12。用二氯 甲烷(50ml×3)萃取水相，有机相依次用水(30ml×1)和饱和氯化钠溶液(30ml×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，浓缩物用硅胶柱色谱法纯化(洗脱液，二氯甲烷/甲醇＝10:1)所得残余物，得到标题产物5-氯-N2-(2-甲氧基-4-(4-(4-甲基-1-哌嗪基)-1-哌啶基)苯基)-N4-((3-甲基-2-甲磺酰基)苯基)嘧啶-2,4-二胺4(1.41g,灰白色固体)，收率50％。
LC-MS:600
1H-NMR(400MHz,CD 3OD):δ＝1.66(dq,J＝3.89,12.09Hz,2H),1.97-2.08(m,2H),2.29(s,3H),2.35(s,3H),2.89(s,3H),2.33-2.42(m,1H),2.43-2.62(m,4H),2.62-2.86(m,6H),3.69(d,J＝12.30Hz,2H),3.84(s,3H),6.65(d,J＝2.51Hz,1H),7.25(ddt,J＝1.00,2.26,7.53Hz,1H),7.47-7.54(m,1H),7.60(m,1H),7.66(d,J＝8.78Hz,1H),8.02(s,1H),8.33(dd,J＝4.52,8.03Hz,1H)ppm.
实施例5
(R,S)-5-氯-N2-(2-甲氧基-4-(4-(4-甲基-1-哌嗪基)-1-哌啶基)苯基)-N4-((2-异丙亚磺酰基)苯基)嘧啶-2,4-二胺
Figure PCTCN2019072915-appb-000016
实施例5的合成方法参照实施例4。
LC-MS:598
1H-NMR(400MHz,CD 3OD):δ＝1.30(d,J＝7.0Hz,6H),1.66(dq,J＝3.89,12.09Hz,2H),1.97-2.08(m,2H),2.29(s,3H),2.33-2.42(m,1H),2.43-2.62(m,4H),2.62-2.86(m,6H),3.18(m,J＝6.7Hz,1H)3.69(d,J＝12.30Hz,2H),3.84(s,3H),6.45(dd,J＝2.51,8.78Hz,1H),6.65(d,J＝2.51Hz,1H),7.25(ddt,J＝1.00,2.26,7.53Hz,1H),7.47-7.54(m,1H),7.60(m,1H),7.66(d,J＝8.78Hz,1H),8.02(s,1H),8.33(dd,J＝4.52,8.03Hz,1H)ppm.
通过手性制备柱拆分，可以制备出(R)-5-氯-N2-(2-甲氧基-4-(4-(4-甲基-1-哌嗪基)-1-哌啶基)苯基)-N4-((2-异丙亚磺酰基)苯基)嘧啶-2,4-二胺和(S)-5-氯-N2-(2-甲氧基-4-(4-(4-甲基-1-哌嗪基)-1-哌啶基)苯基)-N4-((2-异丙亚磺酰基)苯基)嘧啶-2,4-二胺。
R,S对应物中有一个具有更大活性，所以其中一个纯手性异构体的活性会更大。
实施例6
5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-((3-甲基-2-异丙磺酰基)苯基)嘧啶-2,4-二胺
Figure PCTCN2019072915-appb-000017
第一步 3-硝基-2-异丙巯基甲苯
将3-硝基-2-氟甲苯(5.00g,32.2mmol)和异丙硫醇(2.7g,35.5mmol)溶解于30gDMF中，加入K 2CO 3(6.7g,48.5mmol),加热至85℃，搅拌反应12小时。将反应液冷却至室温，加入50g水，100ml乙酸乙酯，搅拌半小时，分液，水相再用100ml乙酸乙酯萃取，合并有机相，有机相依次用水(50ml×1)和饱和氯化钠溶液(50ml×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，蒸干后用硅胶柱色谱法纯化(洗脱液，正己烷/乙酸乙酯＝5:1)所得残余物，得到标题产物3-硝基-2-异丙巯基甲苯6b(4.90g,黄色液体)，收率72％。
第二步 2-异丙巯基-3-甲基苯胺盐酸盐
将3-硝基-2-异丙巯基甲苯(4.90g,23.2mmol)溶解于25g无水乙醇中，加入5％钯碳(0.49g)，氢气置换三次，氢气氛下(0.4MPa),搅拌反应48小时。将反应液经过硅藻土过滤，滤液减压浓缩，蒸干后，加入50ml乙酸乙酯，2ml盐酸异丙醇，降温至0-5℃，过滤得到标题产物2-异丙巯基-3-甲基苯胺盐酸盐6c(4.65g,白色固体)，收率92％。
第三步 2,5-二氯-N-(3-甲基2-(异丙基硫醚)苯基)嘧啶-4-胺
合成方法参照实施例3第一步3b的合成方法，得到标题产物2,5-二氯-N-(3-甲基2-(异丙基硫醚)苯基)嘧啶-4-胺6d(5.96g,白色固体)，收率 85％。
第四步 2,5-二氯-N-(3-甲基-2-(异丙磺酰基)苯基)嘧啶-4-胺将2,5-二氯-N-(3-甲基-2-(异丙基硫醚)苯基)嘧啶-4-胺(5.96g,20mmol)溶于100ml二氯甲烷中，降温至0-5℃，慢慢滴加间氯过氧苯甲酸的二氯甲烷溶液(6.1g85％mCPBA/200ml二氯甲烷)，约1小时滴完，滴完后，升温至室温，搅拌5小时，再降温至-5℃--10℃，搅拌1小时，过滤，滤去不溶物，滤液减压浓缩，残留物加正己烷，乙酸乙酯结晶(正己烷/乙酸乙酯＝5:1)，得到标题产物2,5-二氯-N-(3-甲基-2-(异丙磺酰基)苯基)嘧啶-4-胺6e(5.6g,白色固体)，收率84％。
第五步 4-(4-(5-氯-4-(3-甲基-2-异丙磺酰基)苯胺)嘧啶-2-氨基)-5-异丙氧基-2-甲基苯基哌啶-1-羧酸叔丁醇醚
合成方法参照实施例1第四步1g的合成方法，得到标题产物4-(4-(5-氯-4-(3-甲基-2-异丙磺酰基)苯胺)嘧啶-2-氨基)-5-异丙氧基-2-甲基苯基哌啶-1-羧酸叔丁醇醚6f(白色固体)，收率40％。
第六步 5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-((3-甲基-2-异丙磺酰基)苯基)嘧啶-2,4-二胺
合成方法参照实施例1第五步化合物1的合成方法，得到目标产物5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-((3-甲基-2-异丙磺酰基)苯基)嘧啶-2,4-二胺
LC-MS:572
1H-NMR(400MHz,CDCl3):δ＝1.18(d,J＝6.8Hz,6H),1.24(d,J＝6.1Hz,6H),1.46-1.62(m,4H),2.18(s,3H),2.35(s,3H)2.59-2.65(m,2H),2.69-2.75(m,1H),3.03-3.06(d,2H),3.45-3.51(m,1H),4.51-4.57(m,1H),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
实施例7
5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-((3-羟甲基-2-异丙磺酰基)苯基)嘧啶-2,4-二胺
Figure PCTCN2019072915-appb-000018
Figure PCTCN2019072915-appb-000019
实施例7的合成方法参照实施例6
LC-MS:588
1H-NMR(400MHz,CDCl3,):δ＝1.18(d,J＝6.8Hz,6H),1.24(d,J＝6.1Hz,6H),1.46-1.62(m,4H),2.0(s,1H),2.18(s,3H),2.59-2.65(m,2H),2.69-2.75(m,1H),3.03-3.06(d,2H),3.45-3.51(m,1H),4.51-4.57(m,2H),4.79(S,2H),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
实施例8
5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-((3-羟甲基-2-乙磺酰基)苯基)嘧啶-2,4-二胺
Figure PCTCN2019072915-appb-000020
Figure PCTCN2019072915-appb-000021
实施例8的合成方法参照实施例1
LC-MS:574
1H-NMR(400MHz,CDCl3,):δ＝1.28(m,J＝6.8Hz,3H),1.38(d,J＝6.1Hz,6H),1.46-1.62(m,4H),2.0(s,1H),2.18(s,3H),2.59-2.65(m,2H),2.69-2.75(m,1H),3.03-3.06(d,2H),3.45(m,2H),4.51-4.57(m,2H),4.79(S,2H),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
实施例9
5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-((3-羟甲基-2-甲磺酰基)苯基)嘧啶-2,4-二胺
Figure PCTCN2019072915-appb-000022
实施例9的合成方法参照实施例1
LC-MS:560
1H-NMR(400MHz,CDCl3,):δ＝1.38(d,J＝6.1Hz,6H),1.46-1.62(m,4H),2.0(s,1H),2.18(s,3H),2.59-2.65(m,2H),2.69-2.75(m,1H),2.84(s,3H)3.03-3.06(d,2H),4.51-4.57(m,2H),4.79(S,2H),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
实施例10
(R,S)-5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-(3-甲基-2-异丙基亚磺酰基)苯基)嘧啶-2,4-二胺。
Figure PCTCN2019072915-appb-000023
实施例10的合成方法参照实施例3
LC-MS:556
1H-NMR(400MHz,CDCl3):δ＝1.18(d,J＝6.8Hz,6H),1.24(d,J＝6.1Hz,6H),1.46-1.62(m,4H),2.18(s,3H),2.35(s,3H),2.59-2.65(m,2H),2.69-2.75(m,1H),2.89(m,1H),3.03-3.06(d,2H),,4.51-4.57(m,1H),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
实施例11
(R,S)-5-氯-N2-(2-异丙氧基-5-甲基-4-(哌啶-4-基)苯基)-N4-((3-羟甲基-2-异丙亚磺酰基)苯基)嘧啶-2,4-二胺
Figure PCTCN2019072915-appb-000024
实施例11的合成方法参照实施例3
LC-MS:572
1H-NMR(400MHz,CDCl3,):δ＝1.18(d,J＝6.8Hz,6H),1.24(d,J＝6.1Hz,6H),1.46-1.62(m,4H),2.0(s,1H),2.18(s,3H),2.59-2.65(m,2H),2.69-2.75(m,1H),3.03-3.06(d,2H),2.89(m,1H),4.51-4.57(m,1H),4.79(S,2H),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
实施例12
(R,S)-5-氯-N2-(2-甲氧基-4-(4-(4-甲基-1-哌嗪基)-1-哌啶基)苯基)-N4-((3-甲基2-异丙亚磺酰基)苯基)嘧啶-2,4-二胺
Figure PCTCN2019072915-appb-000025
Figure PCTCN2019072915-appb-000026
实施例12的合成方法参照实施例3和实施例4.
LC-MS:612
1H-NMR(400MHz,CD 3OD):δ＝1.30(d,J＝7.0Hz,6H),1.66(dq,J＝3.89,12.09Hz,2H),1.97-2.08(m,2H),2.29(s,3H),2.30(s,3H)2.33-2.42(m,1H),2.43-2.62(m,4H),2.62-2.86(m,6H),3.18(m,J＝6.7Hz,1H)3.69(d,J＝12.30Hz,2H),3.84(s,3H),6.65(d,J＝2.51Hz,1H),7.25(ddt,J＝1.00,2.26,7.53Hz,1H),7.47-7.54(m,1H),7.60(m,1H),7.66(d,J＝8.78Hz,1H),8.02(s,1H),8.33(dd,J＝4.52,8.03Hz,1H)ppm.
测试例：
生物学评价
测试例1，本发明化合物对人间变性大细胞淋巴瘤细胞株Karpas299的增值抑制测定。
本实验使用的细胞株来源：Karpas299(科佰生物科技南京有限公司)
以下所述的体外细胞实验可测定受试化合物对人间变性大细胞淋巴瘤细胞株的增值抑制活性，其活性可用IC50值来表示。此类试验的一般方案如下：首先将待测细胞株(科佰生物科技南京有限公司)以事宜细胞浓度5000细胞/ml介质接种在96孔培养板上，每孔接种80μL细胞悬液，然后将细胞在5％二氧化碳恒温箱内37℃进行培养，让它们生长至过夜，更换培养基为加有一系列浓度梯度(3μM,1μM，0.3μM，0.1μM，30nM，10nM,3nM，1nM,0.3nM)受试化合物溶液的培养基，将培养基板重新放回培养箱，连续孵育72小时，结束孵育后，往细胞板中加入13.5μl的CCK-8溶液，置于37℃培养箱中孵育大约2-4小时，轻轻震荡后，在SpectraMax M5 Microplate Reader上测定450nm波长处的吸光度，以650nm处吸光度作为参比，计算抑制率。
按下式计算药物对肿瘤细胞生长的抑制率：肿瘤细胞生长抑制率％＝[Ac-As)/(Ac-Ab)]×100％
As:样品的OA(细胞+CCK-8+待测化合物)
Ac:阴性对照的OA(细胞+CCK-8+DMSO)
Ab:阳性对照的OA(培养基+CCK-8+DMSO)
运用软件Graphpad Prism 6并采用计算公式log(inhibitor)vs.normalized response–variable slope进行IC50曲线拟合并计算出IC50值.
本发明化合物生物活性由上述分析所得，计算所得的IC 50值如表2：
表2：目标化合物对肿瘤细胞Karpas299的抑制率
实施例编号 IC 50/(nM)
1 52.3
2 35.4
3(R,S混旋化合物) 3.51
4 38.7
5(R，S混旋化合物) 1.34
6 104.1
7 64.5
8 42.3
9 50.2
10(R，S混旋化合物) 16.04
11(R，S混旋化合物) 5.12
12(R，S混旋化合物) 7.84
阳性对照(色瑞替尼) 23.7
结论：本发明优选化合物均对Karpas299细胞具有明显的增值抑制活性。其中化合物3,5,10,11,12显示出了显著更佳的抑制活性，化合物3的活性达到了阳性对照活性的约7倍；化合物5的活性达到了阳性对照的17倍以上。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种如式(I)所示的化合物，或其药学上可接受的盐、前药、代谢产物、水合物、或溶剂合物：
    Figure PCTCN2019072915-appb-100001
    其中，式(I)中：
    X为-(S＝O)-、或-(O＝S＝O)-；
    Y为N、或CH；
    L选自：氢、卤素、羟基、氰基、取代的或未取代的C 1-4烃基；
    R 1选自：氢、卤素、取代的或未取代的C 1-8烷基、取代的或未取代的C 3-8环烷基、取代的或未取代的C 2-8烯基、取代的或未取代的C 2-8炔基、和取代的或未取代的C 1-8烷氧基；
    R 2选自：氢、取代的或未取代的C 1-8烷基、取代的或未取代的C 2-8烯基、取代的或未取代的C 2-8炔基、取代的或未取代的C 3-8环烷基、取代的或未取代的3-至8-元杂环基、取代的或未取代的芳基、和取代的或未取代的杂芳基；
    R 3和R 6独立地选自：氢、卤素，取代的或未取代的C 1-8烷基、和取代的或未取代的C 1-8烷氧基；
    R 4和R 5独立地选自：氢、取代的或未取代的C 1-8烷基、取代的或未取代的C 1-8烷氧基、取代的或未取代的芳基、和取代的或未取代的杂芳基；或者，R 4和R 5和它们所连接的原子一起形成3-至8-元环，所述3-至8-元环任选地被一个或多个取代基取代，所述取代基选自：卤素、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 1-8烷氧基、C 3-8环烷基、C 1-4烷基取代的或未取代的3-至8-元杂环基。
  2. 如权利要求1所述的化合物，其特征在于，R 1选自：氢、和取代的或未取代的C 1-4基。
  3. 如权利要求1所述的化合物，其特征在于，R 2为取代的或未取代的C 1-4基。
  4. 如权利要求1所述的化合物，其特征在于，R 3为取代的或未取代的C 1-4烷氧基。
  5. 如权利要求1所述的化合物，其特征在于，R 6为氢、或取代的或未取代的C 1-4烷基。
  6. 如权利要求1所述的化合物，其特征在于，X为-(S＝O)-。
  7. 如权利要求1所述的化合物，其特征在于，所述化合物的结构如式(II)所示：
    Figure PCTCN2019072915-appb-100002
    其中，J为N或C；K为N或C；R 7选自：氢、取代的或未取代的C 1-8烷基、取代的或未取代的C 2-8烯基、取代的或未取代的C 2-8炔基、取代的或未取代的C 1-8烷氧基、取代的或未取代的C 3-8环烷基、取代的或未取代的3-至8-元杂环基、取代的或未取代的芳基、和取代的或未取代的杂芳基；
    X、L、R 1、R 2、R 3、R 6分别如权利要求1中所述。
  8. 如权利要求1所述的化合物，其特征在于，L为卤素，优选为氯。
  9. 如权利要求1所述的化合物，其特征在于，当X为-(S＝O)-时，所述化合物为R构型、S构型、或R,S混旋型。
  10. 如权利要求1所述的化合物，其特征在于，R 7为C 1-4烷基取代的含有2个N杂原子的3-至8-元杂环基。
  11. 如权利要求1所述的化合物，其特征在于，所述的式(I)化合物具有选自下组的结构：
    Figure PCTCN2019072915-appb-100003
    Figure PCTCN2019072915-appb-100004
    其中*为手性原子。
  12. 如权利要求1所述的式(I)化合物的用途，其特征在于，用于：
    (a)制备治疗与间变性淋巴瘤激酶(ALK)活性或表达相关的疾病的药物；和/或
    (b)制备间变性淋巴瘤激酶(ALK)靶向抑制剂；和/或
    (c)体外非治疗性地抑制间变性淋巴瘤激酶(ALK)的活性。
  13. 一种药物组合物，其特征在于，所述的药物组合物包括：
    (i)有效量的本发明第一方面所述的化合物，或其药学上可接受的盐、前药、代谢产物、水合物、或溶剂合物；和
    (ii)药学上可接受的载体。
  14. 一种如权利要求1所述的化合物的制备方法，其特征在于，该方法包括步骤：
    (a)在惰性溶剂中，化合物A3和化合物A4反应得到式I所示化合物：
    Figure PCTCN2019072915-appb-100005
    其中，X、Y、R 1、R 2、R 3、R 4、R 5、R 6分别如权利要求1所述。
  15. 一种治疗肿瘤的方法，其特征在于，所述方法包括步骤：
    对需要的对象施用治疗有效量的如权利要求1所述的式(I)化合物或其药学上可接受的盐，或对需要的对象施用治疗有效量的如权利要求8所述的药物组合物。
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