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WO2010083649A1 - Bisarylurea derivatives and their use - Google Patents

Bisarylurea derivatives and their use Download PDF

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Publication number
WO2010083649A1
WO2010083649A1 PCT/CN2009/070277 CN2009070277W WO2010083649A1 WO 2010083649 A1 WO2010083649 A1 WO 2010083649A1 CN 2009070277 W CN2009070277 W CN 2009070277W WO 2010083649 A1 WO2010083649 A1 WO 2010083649A1
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alkyl
phenyl
group
amino
piperazine
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PCT/CN2009/070277
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French (fr)
Chinese (zh)
Inventor
宫平
赵燕芳
刘亚婧
翟鑫
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Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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Priority to CN200980147890.6A priority Critical patent/CN102216280B/en
Priority to PCT/CN2009/070277 priority patent/WO2010083649A1/en
Publication of WO2010083649A1 publication Critical patent/WO2010083649A1/en
Anticipated expiration legal-status Critical
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/66—Nitrogen atoms

Definitions

  • the present invention relates to a bisarylurea derivative, and a pharmaceutical composition comprising the same as an active ingredient, and a medicament thereof for preparing a receptor protein tyrosine kinase inhibitor and for treating and/or preventing various cancers Use in. Background technique
  • Cancer also known as malignant tumor, is a common type of disease that poses a serious threat to human health.
  • anti-tumor drugs is moving from traditional cytotoxic drugs to new aspects of multiple mechanisms in tumor development. Anti-tumor drug conversion.
  • RTKs selective protein tyrosine kinases
  • multi-target inhibitors are superior to single-target inhibitors in therapy, while drug molecules that inhibit multiple receptor tyrosine kinases simultaneously block multiple signal transductions in cancer cell growth.
  • the pathway can inhibit the growth of tumors more effectively.
  • the multi-target receptor protein tyrosine kinase inhibitor is a new development direction of tumor treatment and drug development.
  • Sorafenib is a bisaryl urea compound. It is an oral multi-target anti-tumor drug jointly developed by Bayer and ONYX in Germany. It was marketed in the US on December 20, 2005 and approved by the FDA for treatment. Advanced renal cell carcinoma, and was listed in China on November 29, 2006. Sorafenib has a dual anti-tumor effect, which directly inhibits tumor growth by blocking the RAF/MEK/ERK signaling pathway; on the other hand, it blocks tumor growth by inhibiting VEGF and platelet-derived growth factor (PDGF) receptors. The formation of blood vessels, indirectly inhibit the growth of tumor cells.
  • PDGF platelet-derived growth factor
  • the present inventors synthesized a series of bisarylurea derivatives, which were screened by in vitro receptor protein tyrosine kinase inhibitory activity and screened for antitumor activity in vitro, indicating strong inhibitory protein tyrosine kinase activity and antitumor activity. . Summary of the invention
  • the present invention relates to a derivative of the formula I or a pharmaceutically acceptable salt thereof, as defined below, among them,
  • ⁇ is phenyl, naphthyl or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from 0, N and S, and optionally 3 substituents;
  • Ar 2 is phenyl, naphthyl or 5-10 membered heteroaryl, the heteroaryl contains 1-3 heteroatoms selected from 0, N and S, and Ar 2 optionally 1 - 3 R 2 is substituted ;
  • n is an integer between 0 and 4;
  • X is hydrogen, d-C 4 alkyl and d-C 4 alkoxy
  • R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ alkyl, (d-C 4 ) alkoxy, N - (C" C 4 ) Alkyl J ⁇ , N, N-di(C "C 4 )alkyl J ⁇ , (d-C 4 ) alkane, (d-C 4 )alkylsulfinyl, (d-C 4 ) Alkylsulfonyl, (C-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N-(d- C 4 Alkyl decanoyl, N, N-di(d-C 4 )alkyl decanoyl, ⁇ sulfonyl, N-(d-C 4 )alkylsulfonyl, N, N-di
  • the limit is: When Ar 2 is a phenyl group, ⁇ is not zero.
  • the present invention preferably relates to a derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein
  • ⁇ is phenyl or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from the group consisting of 0, ⁇ and S, and ⁇ ⁇ optionally 1-1-3 ⁇ ;
  • Ar 2 is a phenyl group or a 5- to 10-membered heteroaryl group, the heteroaryl group contains 1-3 hetero atoms selected from 0, N and S, and Ar 2 is optionally substituted with 1 to 3 R 2 ;
  • n is an integer between 0 and 4; X is hydrogen;
  • R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ alkyl, (d-C 4 ) alkane! L &, N- (d- C 4 Alkyl ⁇ 1 ⁇ 2, N,N-di(d-C 4 )alkyl J ⁇ , (d-C 4 ) alkane, (d-C 4 )alkylsulfinyl, (d-C 4 Alkylsulfonyl, (C-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N- (d- C 4 ) alkyl decanoyl, N, N-di(d-C 4 )alkyl decanoyl, ⁇ sulfonyl, N-(d-C 4 )alkylsulfonyl, N, N-
  • the limit is: When Ar 2 is a phenyl group, ⁇ is not zero.
  • the present invention preferably further relates to a derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein
  • ⁇ is phenyl, and ⁇ ⁇ is optionally substituted with 1 - 3 ⁇ ;
  • Ar 2 is a 5-6 membered heteroaryl group, the heteroaryl group contains 1-3 hetero atoms selected from 0, N and S, and Ar 2 is optionally substituted with 1 to 3 R 2 ;
  • n is an integer between 0 and 4;
  • X is hydrogen
  • R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ alkyl, (d-C 4 ) alkane! L &, N- (d- C 4 Alkyl ⁇ 1 ⁇ 2, N, N-di(d-C 4 )alkyl J ⁇ , (C“C 4 ) alkane, (C “C 4 ) alkylsulfinyl, (d- C 4 ) Alkylsulfonyl, (C-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N- (d- C 4 ) alkyl decanoyl, N, N-di(d-C 4 )alkyl decanoyl, sulfonate Acyl, N-(d-C 4 )alkylsulfonyl, N
  • the invention particularly preferably relates to derivatives of the formula I defined below,
  • ⁇ is phenyl, and ⁇ ⁇ is optionally substituted with 1 - 3 ⁇ ;
  • Ar 2 is a pyrimidinyl group, and the pyrimidinyl group is optionally substituted with 1-3 R 2 ;
  • n is an integer between 0 and 4;
  • X is hydrogen
  • R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ alkyl, (d-C 4 ) alkane! L &, N- (d- C 4 Alkyl ⁇ 1 ⁇ 2, N, N-di(d-C 4 )alkyl J ⁇ , (C“C 4 ) alkane, (C “C 4 ) alkylsulfinyl, (d- C 4 ) Alkylsulfonyl, (C-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N- (d- C 4 ) alkyl decanoyl, N, N-di(d-C 4 )alkyl decanoyl, ⁇ sulfonyl, N-(C "C 4 )alkylsulfonyl, N,
  • the present invention particularly preferably relates to a derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein
  • ⁇ is phenyl, and ⁇ ⁇ is optionally substituted with 1 - 3 ⁇ ;
  • Ar 2 is a pyrimidinyl group, and the pyrimidinyl group is optionally substituted with 1-3 R 2 ;
  • n 1;
  • X is hydrogen
  • R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ Alkyl, (d-C 4 ) alkane! L &, N-(d-C 4 )alkyl ⁇ 1 ⁇ 2, N,N-di(d-C 4 )alkyl J ⁇ , (C"C 4 ) alkane, (d-C 4 ) alkane a sulfinyl group, a (d-C 4 )alkylsulfonyl group, a (C-C 4 ) alkoxyfluorenyl group, a (d-C 4 ) alkoxyethyl group, a (d-C 4 )alkyl acyl group, Aminodecanoyl, N-(d-C 4 )alkyl decanoyl, N,N-di(d-C 4 )alkyl decanoyl, ⁇ sulfonyl, N
  • the invention particularly preferably relates to derivatives of the formula I defined below,
  • ⁇ is phenyl, and ⁇ ⁇ is optionally substituted with 1 - 3 ⁇ ;
  • Ar 2 is 2- 3-trifluoromethyl-6-pyrimidine
  • n 1;
  • X is hydrogen
  • the bisarylurea derivative of the formula I of the present invention can form a pharmaceutically acceptable salt thereof with an acid according to some usual methods in the art to which the present invention pertains.
  • the acid may include a mineral acid or an organic acid, and a salt formed with the following acids is particularly preferred: hydrochloric acid, oxalic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, isethionic acid, tartaric acid, hydrazine Sulfonic acid, ethanesulfonic acid, hydrobromic acid, sulfuric acid, phosphoric acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, benzoic acid or p-toluenesulfonic acid.
  • the invention also includes prodrugs of the derivatives of the invention.
  • the prodrugs are derivatives of the formula I which may themselves have weak or even no activity, but after administration, under physiological conditions (for example by metabolism, solvolysis or otherwise) Converted to the corresponding biologically active form.
  • halogen as used herein, unless otherwise indicated, means fluoro, chloro, bromo or substituted; "alkyl” means a straight or branched alkyl group; “alkylene” means straight or branched.
  • the present invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising a bisarylurea derivative of the formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, and a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical arts.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not cause other adverse effects such as an allergic reaction.
  • compositions of the present invention may be formulated in a number of dosage forms containing some of the excipients commonly used in the pharmaceutical arts; for example, oral preparations (e.g., tablets, capsules, solutions or suspensions); injectable preparations (for example, an injectable solution or suspension, or an injectable dry powder, can be used immediately after the injection of water for injection; a topical preparation (such as an ointment or solution).
  • oral preparations e.g., tablets, capsules, solutions or suspensions
  • injectable preparations for example, an injectable solution or suspension, or an injectable dry powder, can be used immediately after the injection of water for injection
  • a topical preparation such as an ointment or solution.
  • the carrier used in the pharmaceutical composition of the present invention is a common type available in the pharmaceutical field, including: a binder for an oral preparation, a lubricant, a disintegrant, a solubilizer, a diluent, and a stable Preservatives, suspending agents, non-pigmenting, flavoring agents, etc.; preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations.
  • the pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they can be formulated into enteric coated tablets.
  • the compounds of the invention may be used in the treatment of a disease or condition in which a protein tyrosine kinase receptor inhibitor is administered alone or in part, i.e., the compound may be used to produce protein tyrosine kinase receptor inhibition in a mammal in need of such treatment. effect.
  • the compounds of the present invention are useful in the treatment of cancers which provide anti-proliferative effects, particularly in the treatment of cancers susceptible to protein tyrosine kinase receptors such as breast, lung, colon, rectum, stomach, prostate, bladder, pancreas and ovary.
  • the compounds of the invention are also expected to be useful in the treatment of other cell proliferative disorders such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis.
  • the bisarylurea derivatives of the present invention will have activity against leukemia, lymphoid malignant and solid tumors such as cancer and sarcoma in tissues such as liver, kidney, prostate and pancreas.
  • the compounds of the invention are also contemplated for use in the treatment of diseases in which other cells proliferate, including by receptor protein tyrosine kinases, including those of the receptor protein tyrosine kinase that have not yet been identified.
  • diseases include, for example, inflammation, angiogenesis, restenosis, immunological diseases, pancreatic diseases, kidney disease, and embryo maturation and transplantation.
  • the in vitro antitumor activity test indicates that the bisarylurea derivative of the formula I of the present invention has an anticancer effect, and therefore, it can be used as a medicament for the preparation of a medicament for treating and/or preventing cancer.
  • the derivative according to the present invention can be used as an active ingredient for the preparation of a medicament for treating and/or preventing various cancers, and the present invention also provides a method for treating or preventing the above-mentioned diseases, comprising administering a therapeutically effective amount to a patient suffering from or susceptible to the disease.
  • the clinical dose of the bisarylurea derivative of formula I for use in a patient must depend on the subject being treated, the particular route of administration, the severity of the condition being treated, and the optimal dosage will be determined by the physician treating the particular patient. .
  • the active compounds of the invention may be used as the sole anticancer drug or may be used in combination with one or more other antineoplastic agents. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
  • the nuclear magnetic resonance spectrum of the derivative was determined by Bruker ARX-300, and the mass spectrum was determined by Agilent 1100 LC/MSD; the reagents used were either analytically pure or chemically pure.
  • the metal sodium 4. 6 g (0. 20 mol) was gradually added to n-butanol 80 mL, heated until the sodium was completely dissolved, and then added to the ruthenium nitrate 11.6 g (0. 10 mol), refluxed for 15 min, gradually dripped Add 27. 6 g (0.15 mol) of ethyl trifluoroacetoacetate, reflux for about 6 h, after the reaction is completed, cool to room temperature, adjust the pH to 4-5 with 10% hydrochloric acid, precipitate a large amount of solid, suction filtration, cold water The washing cake was washed with a vacuum to give a white powdery solid, 14.9 g, yield: 83. 4%, MS: 180. 2 (M+l).
  • Step D Preparation of 2-amino-4-[4-(4-nitrophenylhydrazino)piperazine-1-yl]-6-trifluorodecylpyrimidine
  • 2-Amino-4-[4-(4-nitrophenylhydrazino)piperazine-1-yl-6-trifluoromethylpyrimidine 8.2 g (0.021 mol) was added to 40 mL of absolute ethanol and stirred. Add DMF 20 mL, polyethylene glycol 400 5 mL, and 0.1 g (0. Oil mol) activated carbon to the reaction solution, stir for 80 min for 5 min, then add 1.7 g (0.006 mol) of ferric chloride hexahydrate to the reaction solution. ), stirring. To the reaction solution, 13.4 g (0.21 mol) of hydrazine hydrate having a content of 80% was added dropwise, and the reaction was carried out for 12 hours.
  • Step G 1-[4-[[4-(2- 6-Trifluoromethylpyrimidin-4-yl)piperazine-1-yl]nonylphenyl]-3-(3-chlorophenyl) Preparation of urea hydrochloride
  • the bisarylurea derivative of the above formula I according to the present invention was subjected to in vitro protein tyrosine kinase inhibitory activity screening and in vitro antitumor activity screening.
  • kinase reaction solution 50 uL was added to each well of a 96-well plate.
  • the test sample lOuL (concentration: 9 ⁇ g/mL) was added to the 2-11 column of the 96-well plate, and the kinase reaction solution 10 uL was added to the columns 1 and 12 by a row of guns.
  • 50 uL of rat brain tissue tyrosine extract [protein content of about 0.4 mg/mL] was added to each well of a 96-well plate, incubated by shaking, incubated for 1 hour, and washed three times with 200 uL of eluate.
  • Inhibition rate % (Control 0D - Sample 0D) I (Control 0D - Blank 0D) X 100%
  • the iiJ ⁇ product is a Sorafenib as an oral multi-kinase inhibitor developed by Bayer and ONYX in Germany.
  • the structural formula is as follows.
  • in vitro anti-tumor activity test (1) Resuscitate MDA-MB-231 (human breast cancer cells), Beb 7402 (human liver cancer cells) and A549 (human non-small cell lung cancer) cells and pass them for 2-3 times to stabilize with trypsin solution (0.25 %) digested from the bottom of the flask.
  • the cell digest is poured into a centrifuge tube and the culture is added to terminate the digestion. Centrifuge the tube at 1300 r/min for 3 min, gently discard the supernatant, add 5 mL of the culture solution, mix and mix the cells, and pipette the lO uL cell suspension into the cell counting plate to adjust the cell concentration to 10 4 . / hole.
  • In the 96-well plate except for the A1 well, which was blank, no cells were added, and the rest were added with 100 uL of cell suspension. The 96-well plate was placed in an incubator for 24 h.
  • Example compounds in vitro antitumor activity are shown in Table 3.
  • Example compounds in vitro antitumor activity are shown in Table 3.
  • Example 6 0.42 1 Example 7 0. 66 1. 1 Example 8 0. 53 0. 3 Example 9 1. 22 1. 5 Example 10 0. 91 1 Example 11 0. 83 1 Example 12 1. 6 0. 90 Example 13 0. 98 1. 1 Example 15 0. 93 0. 88 Example 16 0. 46 1 Example 17 0. 94 0. 86 Example 19 0. 83 1. 1 Example 20 1. 0 1 Example 22 0. 92 1 Example 26 1. 1 1 Sorafenib 1. 1 1. 6 Note: / indicates untested activity.
  • the compound of the formula I to be protected by the present invention has excellent receptor protein tyrosine kinase inhibitory activity and anticancer activity. Therefore, the compounds of the present invention have a good industrial application prospect.

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Abstract

Bisarylurea derivatives of formula I or the pharmaceutically acceptable salts are provided. The compounds of formula I are used for the manufacture of inhibitors of receptor protein tyrosine kinases and medicament for treating and/or preventing a tumor.

Description

双芳基脲类衍生物及用途  Bisylurea derivatives and uses thereof

技术领域 Technical field

本发明涉及双芳基脲类衍生物，以及以该衍生物为活性成分的药 物组合物，以及其在制备受体蛋白酪氨酸激酶抑制剂以及用于治疗和 /或预防各种癌症的药物中的用途。 背景技术  The present invention relates to a bisarylurea derivative, and a pharmaceutical composition comprising the same as an active ingredient, and a medicament thereof for preparing a receptor protein tyrosine kinase inhibitor and for treating and/or preventing various cancers Use in. Background technique

癌症， 又称为恶性肿瘤， 是严重威胁人类健康的一类常见病。近 年来，随着分子生物学技术的发展和对发病机制以及细胞分子水平的 进一步认识，抗肿瘤药物的研究正在从传统的细胞毒药物向靶向作用 于肿瘤发生发展机制中多个环节的新型抗肿瘤药物转变。  Cancer, also known as malignant tumor, is a common type of disease that poses a serious threat to human health. In recent years, with the development of molecular biology technology and further understanding of pathogenesis and cell molecular level, research on anti-tumor drugs is moving from traditional cytotoxic drugs to new aspects of multiple mechanisms in tumor development. Anti-tumor drug conversion.

随着对肿瘤发生机制研究的深入，发现实体瘤的信号传导是一个 复杂的、多因素的蛋白网络系统， 抑制单一信号传导往往不足以遏制 肿瘤的发展。 将多种作用于不同靶点的选择性蛋白酪氨酸激酶 (Protein Tyros ine Kinases, RTKs)抑制剂联合用药， 可以从多个环 节抑制肿瘤的生长。但是在临床应用中， 多种不同结构的药物分子同 时使用， 会出现药物交叉作用， 使药物的吸收、 代谢和排泄复杂化， 并加重药物的毒副作用，降低药物的抗肿瘤疗效。临床试验结果显示， 多靶点抑制剂在治疗方面优于单靶点抑制剂，同时对多个受体酪氨酸 激酶具有抑制作用的药物分子可以同时阻断癌细胞生长中多个信号 转导通路，可更为有效地抑制肿瘤的生长， 多靶点受体蛋白酪氨酸激 酶抑制剂是目前肿瘤治疗和药物开发的新的发展方向。  With the deepening of research on the mechanism of tumorigenesis, it is found that the signal transduction of solid tumors is a complex, multi-factor protein network system, and inhibition of single signal transmission is often insufficient to curb the development of tumors. A combination of a variety of selective protein tyrosine kinases (RTKs) inhibitors acting on different targets can inhibit tumor growth from multiple loops. However, in clinical applications, drug molecules of different structures are used at the same time, and drug cross-effects may occur, complicating the absorption, metabolism and excretion of drugs, aggravating the side effects of drugs, and reducing the anti-tumor effect of drugs. Clinical trials have shown that multi-target inhibitors are superior to single-target inhibitors in therapy, while drug molecules that inhibit multiple receptor tyrosine kinases simultaneously block multiple signal transductions in cancer cell growth. The pathway can inhibit the growth of tumors more effectively. The multi-target receptor protein tyrosine kinase inhibitor is a new development direction of tumor treatment and drug development.

索拉非尼（Sorafenib )为双芳基脲类化合物， 是由德国拜耳公 司和 ONYX公司共同研制的口服多靶点抗肿瘤药物， 2005年 12月 20 日在美国上市， 被 FDA批准用于治疗晚期肾细胞癌， 并于 2006年 11 月 29日在中国上市。索拉非尼具有双重的抗肿瘤作用，一方面通阻断 RAF/MEK/ERK信号传导通路直接抑制肿瘤生长； 另一方面通过抑制 VEGF 和血小板衍生生长因子（PDGF)受体而阻断肿瘤新生血管的形 成， 间接地抑制肿瘤细胞的生长。  Sorafenib is a bisaryl urea compound. It is an oral multi-target anti-tumor drug jointly developed by Bayer and ONYX in Germany. It was marketed in the US on December 20, 2005 and approved by the FDA for treatment. Advanced renal cell carcinoma, and was listed in China on November 29, 2006. Sorafenib has a dual anti-tumor effect, which directly inhibits tumor growth by blocking the RAF/MEK/ERK signaling pathway; on the other hand, it blocks tumor growth by inhibiting VEGF and platelet-derived growth factor (PDGF) receptors. The formation of blood vessels, indirectly inhibit the growth of tumor cells.

本发明人合成了一系列的双芳基脲类衍生物，经体外受体蛋白酪 氨酸激酶抑制活性筛选和体外抗肿瘤活性筛选，表明具有强的抑制蛋 白酪氨酸激酶活性和抗肿瘤活性。 发明内容 The present inventors synthesized a series of bisarylurea derivatives, which were screened by in vitro receptor protein tyrosine kinase inhibitory activity and screened for antitumor activity in vitro, indicating strong inhibitory protein tyrosine kinase activity and antitumor activity. . Summary of the invention

本发明涉及定义如下的通式 I的衍生物或其药学上可接受的盐，

Figure imgf000003_0001
其中， The present invention relates to a derivative of the formula I or a pharmaceutically acceptable salt thereof, as defined below,
Figure imgf000003_0001
among them,

人！^为苯基、萘基或 5-10元杂芳基，所述杂芳基含有 1-3个选自 0、 N和 S的杂原子， 且人^任选 3个 ^取代；  people! ^ is phenyl, naphthyl or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from 0, N and S, and optionally 3 substituents;

Ar2为苯基、 萘基或 5-10元杂芳基， 所述杂芳基含有 1-3个选 自 0、 N和 S的杂原子， 且 Ar2任选 1- 3个 R2取代； Ar 2 is phenyl, naphthyl or 5-10 membered heteroaryl, the heteroaryl contains 1-3 heteroatoms selected from 0, N and S, and Ar 2 optionally 1 - 3 R 2 is substituted ;

n为 0-4之间的整数；  n is an integer between 0 and 4;

X为氢、 d- C4烷基和 d- C4烷氧基； X is hydrogen, d-C 4 alkyl and d-C 4 alkoxy;

为氢、 卤素、 三氟曱基、 三氟曱氧基、 羟基、 ^&、 硝基、 氰 基、 （d- C4)烷基、 （d- C4)烷氧基、 N - (d- C4)烷基 J^、 N, N-二（d- C4) 烷基 J^、 （d- C4)烷基硫基、 （d- C4)烷基亚磺酰基、 （d- C4)烷基磺酰 基、 （d- C4)烷氧基曱基、 （d- C4)烷氧基乙基、 （d- C4)烷基酰基、氨基 曱酰基、 N- (d- C4)烷基 ^曱酰基、 N, N-二（d- C4)烷基 ^曱酰基、 ^磺酰基、 N- (d- C4)烷基 ^磺酰基、 N, N-二（^- C4烷基 ^磺酰 基、 d- C3亚烷基二氧基； Is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, ^&, nitro, cyano, (d-C 4 )alkyl, (d-C 4 )alkoxy, N - (d - C 4 )alkyl J^, N, N-di(d-C 4 ) alkyl J^, (d-C 4 )alkylthio, (d-C 4 )alkylsulfinyl, (d - C 4 ) alkylsulfonyl, (d-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N- ( D-C 4 )alkyl-nonanoyl, N,N-di(d-C 4 )alkyl-decanoyl, ^sulfonyl, N-(d-C 4 )alkylsulfonyl, N, N- Di(^-C 4 alkylsulfonyl, d-C 3 alkylenedioxy;

R2为氢、三氟曱基、三氟曱氧基、氨基、羟基、羧基、氰基、 (C -CJ 烷基、 （d- C4)烷氧基、 N - (C「 C4)烷基 J^、 N, N-二（C「 C4)烷基 J^、 (d- C4)烷^ ¾基、 （d- C4)烷基亚磺酰基、 （d- C4)烷基磺酰基、 (C -C4) 烷氧基曱基、 （d- C4)烷氧基乙基、 （d- C4)烷基酰基、 氨基曱酰基、 N- (d- C4)烷基 ^曱酰基、 N, N-二（d- C4)烷基 ^曱酰基、 ^磺 酰基、 N- (d- C4)烷基 ^磺酰基、 N, N-二（d- C4)烷基 ^磺酰基、 d- C3亚烷基二氧基； R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ alkyl, (d-C 4 ) alkoxy, N - (C" C 4 ) Alkyl J^, N, N-di(C "C 4 )alkyl J^, (d-C 4 ) alkane, (d-C 4 )alkylsulfinyl, (d-C 4 ) Alkylsulfonyl, (C-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N-(d- C 4 Alkyl decanoyl, N, N-di(d-C 4 )alkyl decanoyl, ^sulfonyl, N-(d-C 4 )alkylsulfonyl, N, N-di (d- C 4 ) alkyl sulfonyl, d-C 3 alkylenedioxy;

限制 为： 当 Ar2为苯基时， η不为 0。 The limit is: When Ar 2 is a phenyl group, η is not zero.

本发明优选涉及定义如下的通式 I的衍生物，或其药学上可接受 的盐， 其中，  The present invention preferably relates to a derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein

人！^为苯基或 5-10元杂芳基， 所述杂芳基含有 1-3个选自 0、 Ν 和 S的杂原子， 且 ΑΓι任选 1- 3个 ^取代； people! ^ is phenyl or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from the group consisting of 0, Ν and S, and Α Γι optionally 1-1-3 ^;

Ar2为苯基或 5- 10元杂芳基， 所述杂芳基含有 1-3个选自 0、 N 和 S的杂原子， 且 Ar2任选 1- 3个 R2取代； Ar 2 is a phenyl group or a 5- to 10-membered heteroaryl group, the heteroaryl group contains 1-3 hetero atoms selected from 0, N and S, and Ar 2 is optionally substituted with 1 to 3 R 2 ;

n为 0-4之间的整数； X为氢； n is an integer between 0 and 4; X is hydrogen;

为氢、 卤素、 三氟曱基、 三氟曱氧基、 羟基、 ^&、 硝基、 氰 基、 （d- C4)烷基、 （d- C4)烷氧基、 N - (d- C4)烷基 J^、 N, N-二（d- C4) 烷基 J^、 （d- C4)烷基硫基、 （d- C4)烷基亚磺酰基、 （d- C4)烷基磺酰 基、 （d- C4)烷氧基曱基、 （d- C4)烷氧基乙基、 （d- C4)烷基酰基、氨基 曱酰基、 N- (d- C4)烷基 ^曱酰基、 N, N-二（d- C4)烷基 ^曱酰基、 ^磺酰基、 N- (d- C4)烷基 ^磺酰基、 N, N-二（^- C4烷基 ^磺酰 基、 d- C3亚烷基二氧基； Is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, ^&, nitro, cyano, (d-C 4 )alkyl, (d-C 4 )alkoxy, N - (d - C 4 )alkyl J^, N, N-di(d-C 4 ) alkyl J^, (d-C 4 )alkylthio, (d-C 4 )alkylsulfinyl, (d - C 4 ) alkylsulfonyl, (d-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N- ( D-C 4 )alkyl-nonanoyl, N,N-di(d-C 4 )alkyl-decanoyl, ^sulfonyl, N-(d-C 4 )alkylsulfonyl, N, N- Di(^-C 4 alkylsulfonyl, d-C 3 alkylenedioxy;

R2为氢、三氟曱基、三氟曱氧基、氨基、羟基、羧基、氰基、 (C -CJ 烷基、 （d- C4)烷！ L &、 N- (d- C4)烷基 ·½、 N, N-二（d- C4)烷基 J^、 (d- C4)烷^ ¾基、 （d- C4)烷基亚磺酰基、 （d- C4)烷基磺酰基、 (C -C4) 烷氧基曱基、 （d- C4)烷氧基乙基、 （d- C4)烷基酰基、 氨基曱酰基、 N- (d- C4)烷基 ^曱酰基、 N, N-二（d- C4)烷基 ^曱酰基、 ^磺 酰基、 N- (d- C4)烷基 ^磺酰基、 N, N-二（d- C4)烷基 ^磺酰基、 d- C3亚烷基二氧基。 R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ alkyl, (d-C 4 ) alkane! L &, N- (d- C 4 Alkyl·1⁄2, N,N-di(d-C 4 )alkyl J^, (d-C 4 ) alkane, (d-C 4 )alkylsulfinyl, (d-C 4 Alkylsulfonyl, (C-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N- (d- C 4 ) alkyl decanoyl, N, N-di(d-C 4 )alkyl decanoyl, ^sulfonyl, N-(d-C 4 )alkylsulfonyl, N, N-di (d - C 4 ) alkyl sulfonyl, d-C 3 alkylenedioxy.

限制 为： 当 Ar2为苯基时， η不为 0。 The limit is: When Ar 2 is a phenyl group, η is not zero.

本发明优选还涉及定义如下的通式 I的衍生物，或其药学上可接 受的盐， 其中，  The present invention preferably further relates to a derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein

人！^为苯基， 且 ΑΓι任选 1- 3个 ^取代； people! ^ is phenyl, and Α Γι is optionally substituted with 1 - 3 ^;

Ar2为 5-6元杂芳基， 所述杂芳基含有 1-3个选自 0、 N和 S的 杂原子， 且 Ar2任选 1- 3个 R2取代； Ar 2 is a 5-6 membered heteroaryl group, the heteroaryl group contains 1-3 hetero atoms selected from 0, N and S, and Ar 2 is optionally substituted with 1 to 3 R 2 ;

n为 0-4之间的整数；  n is an integer between 0 and 4;

X为氢；  X is hydrogen;

为氢、 卤素、 三氟曱基、 三氟曱氧基、 羟基、 ^&、 硝基、 氰 基、 （d- C4)烷基、 （d- C4)烷氧基、 N - (d- C4)烷基 J^、 N, N-二（d- C4) 烷基氨基、 （d- C4)烷基硫基、 （d- C4)烷基亚磺酰基、 （d- c4)烷基磺酰 基、 （d- C4)烷氧基曱基、 （d- C4)烷氧基乙基、 （d- c4)烷基酰基、氨基 曱酰基、 N- (d- C4)烷基 ^曱酰基、 N, N-二（d- C4)烷基 ^曱酰基、 ^磺酰基、 N- (d- C4)烷基 ^磺酰基、 N, N-二（^- C4烷基 ^磺酰 基、 d- C3亚烷基二氧基； Is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, ^&, nitro, cyano, (d-C 4 )alkyl, (d-C 4 )alkoxy, N - (d - C 4 )alkyl J^, N, N-di(d-C 4 ) alkylamino, (d-C 4 )alkylthio, (d-C 4 )alkylsulfinyl, (d- c 4 ) alkylsulfonyl, (d-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d- c 4 )alkyl acyl, aminodecanoyl, N- (d - C 4 ) alkyl decanoyl, N, N-di(d-C 4 )alkyl decanoyl, ^sulfonyl, N-(d-C 4 )alkylsulfonyl, N, N-di (^-C 4 alkyl sulfonyl, d-C 3 alkylenedioxy;

R2为氢、三氟曱基、三氟曱氧基、氨基、羟基、羧基、氰基、 (C -CJ 烷基、 （d- C4)烷！ L &、 N- (d- C4)烷基 ·½、 N, N-二（d- C4)烷基 J^、 (C「 C4)烷^ ¾基、 （C「 C4)烷基亚磺酰基、 （d- C4)烷基磺酰基、 (C -C4) 烷氧基曱基、 （d- C4)烷氧基乙基、 （d- C4)烷基酰基、 氨基曱酰基、 N- (d- C4)烷基 ^曱酰基、 N, N-二（d- C4)烷基 ^曱酰基、 ^磺 酰基、 N- (d- C4)烷基 ^磺酰基、 N, N-二（d- C4)烷基 ^磺酰基、 d- C3亚烷基二氧基。 R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ alkyl, (d-C 4 ) alkane! L &, N- (d- C 4 Alkyl·1⁄2, N, N-di(d-C 4 )alkyl J^, (C“C 4 ) alkane, (C “C 4 ) alkylsulfinyl, (d- C 4 ) Alkylsulfonyl, (C-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N- (d- C 4 ) alkyl decanoyl, N, N-di(d-C 4 )alkyl decanoyl, sulfonate Acyl, N-(d-C 4 )alkylsulfonyl, N,N-di(d-C 4 )alkylsulfonyl, d-C 3 alkylenedioxy.

本发明特别优选涉及定义如下的通式 I的衍生物， 其中，  The invention particularly preferably relates to derivatives of the formula I defined below,

人！^为苯基， 且 ΑΓι任选 1- 3个 ^取代； people! ^ is phenyl, and Α Γι is optionally substituted with 1 - 3 ^;

Ar2为嘧啶基， 所述嘧啶基任选 1-3个 R2取代； Ar 2 is a pyrimidinyl group, and the pyrimidinyl group is optionally substituted with 1-3 R 2 ;

n为 0-4之间的整数；  n is an integer between 0 and 4;

X为氢；  X is hydrogen;

为氢、 卤素、 三氟曱基、 三氟曱氧基、 羟基、 ^&、 硝基、 氰 基、 （C「 C4)烷基、 （C「 C4)烷氧基、 N- (C「 C4)烷基 J^、 N, N-二（C「 C4) 烷基 J^、 （d- C4)烷基硫基、 （d- C4)烷基亚磺酰基、 （d- C4)烷基磺酰 基、 （d- C4)烷氧基曱基、 （d- C4)烷氧基乙基、 （d- C4)烷基酰基、氨基 曱酰基、 N- (d- C4)烷基 ^曱酰基、 N, N-二（d- C4)烷基 ^曱酰基、 ^磺酰基、 N- (d- C4)烷基 ^磺酰基、 N, N-二（^- C4烷基 ^磺酰 基、 d- C3亚烷基二氧基； Is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, ^&, nitro, cyano, (C "C 4 ) alkyl, (C "C 4 ) alkoxy, N- (C "C 4 )alkyl J^, N, N-di(C"C 4 ) alkyl J^, (d-C 4 )alkylthio, (d-C 4 )alkylsulfinyl, (d - C 4 ) alkylsulfonyl, (d-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N- ( D-C 4 )alkyl-nonanoyl, N,N-di(d-C 4 )alkyl-decanoyl, ^sulfonyl, N-(d-C 4 )alkylsulfonyl, N, N- Di(^-C 4 alkylsulfonyl, d-C 3 alkylenedioxy;

R2为氢、三氟曱基、三氟曱氧基、氨基、羟基、羧基、氰基、 (C -CJ 烷基、 （d- C4)烷！ L &、 N- (d- C4)烷基 ·½、 N, N-二（d- C4)烷基 J^、 (C「 C4)烷^ ¾基、 （C「 C4)烷基亚磺酰基、 （d- C4)烷基磺酰基、 (C -C4) 烷氧基曱基、 （d- C4)烷氧基乙基、 （d- C4)烷基酰基、 氨基曱酰基、 N- (d- C4)烷基 ^曱酰基、 N, N-二（d- C4)烷基 ^曱酰基、 ^磺 酰基、 N- (C「 C4)烷基 ^磺酰基、 N, N-二（C「 C4)烷基 ^磺酰基、 d- C3亚烷基二氧基。 R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ alkyl, (d-C 4 ) alkane! L &, N- (d- C 4 Alkyl·1⁄2, N, N-di(d-C 4 )alkyl J^, (C“C 4 ) alkane, (C “C 4 ) alkylsulfinyl, (d- C 4 ) Alkylsulfonyl, (C-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N- (d- C 4 ) alkyl decanoyl, N, N-di(d-C 4 )alkyl decanoyl, ^sulfonyl, N-(C "C 4 )alkylsulfonyl, N, N-di (C "C 4 ) alkyl sulfonyl, d-C 3 alkylenedioxy.

本发明特别优选涉及定义如下的通式 I的衍生物，或其药学上可 接受的盐， 其中，  The present invention particularly preferably relates to a derivative of the formula I, or a pharmaceutically acceptable salt thereof, wherein

人！^为苯基， 且 ΑΓι任选 1- 3个 ^取代； people! ^ is phenyl, and Α Γι is optionally substituted with 1 - 3 ^;

Ar2为嘧啶基， 所述嘧啶基任选 1-3个 R2取代； Ar 2 is a pyrimidinyl group, and the pyrimidinyl group is optionally substituted with 1-3 R 2 ;

n为 1;  n is 1;

X为氢；  X is hydrogen;

为氢、 卤素、 三氟曱基、 三氟曱氧基、 羟基、 ^&、 硝基、 氰 基、 （C「 C4)烷基、 （C「 C4)烷氧基、 N- (C「 C4)烷基 J^、 N, N-二（C「 C4) 烷基 J^、 （d- C4)烷基硫基、 （d- C4)烷基亚磺酰基、 （d- C4)烷基磺酰 基、 （d- C4)烷氧基曱基、 （d- C4)烷氧基乙基、 （d- C4)烷基酰基、氨基 曱酰基、 N- (d- C4)烷基 ^曱酰基、 N, N-二（d- C4)烷基 ^曱酰基、 ^磺酰基、 N- (d- C4)烷基 ^磺酰基、 N, N-二（^- C4烷基 ^磺酰 基、 d- C3亚烷基二氧基； Is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, ^&, nitro, cyano, (C "C 4 ) alkyl, (C "C 4 ) alkoxy, N- (C "C 4 )alkyl J^, N, N-di(C"C 4 ) alkyl J^, (d-C 4 )alkylthio, (d-C 4 )alkylsulfinyl, (d - C 4 ) alkylsulfonyl, (d-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N- ( D-C 4 )alkyl-nonanoyl, N,N-di(d-C 4 )alkyl-decanoyl, ^sulfonyl, N-(d-C 4 )alkylsulfonyl, N, N- Di(^-C 4 alkylsulfonyl, d-C 3 alkylenedioxy;

R2为氢、三氟曱基、三氟曱氧基、氨基、羟基、羧基、氰基、 (C -CJ 烷基、 （d- C4)烷！ L &、 N- (d- C4)烷基 ·½、 N, N-二（d- C4)烷基 J^、 (C「 C4)烷^ ¾基、 （d- C4)烷基亚磺酰基、 （d- C4)烷基磺酰基、 (C -C4) 烷氧基曱基、 （d- C4)烷氧基乙基、 （d- C4)烷基酰基、 氨基曱酰基、 N- (d- C4)烷基 ^曱酰基、 N, N-二（d- C4)烷基 ^曱酰基、 ^磺 酰基、 N- (d- C4)烷基 ^磺酰基、 N, N-二（d- C4)烷基 ^磺酰基、 d- C3亚烷基二氧基。 R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-CJ Alkyl, (d-C 4 ) alkane! L &, N-(d-C 4 )alkyl·1⁄2, N,N-di(d-C 4 )alkyl J^, (C"C 4 ) alkane, (d-C 4 ) alkane a sulfinyl group, a (d-C 4 )alkylsulfonyl group, a (C-C 4 ) alkoxyfluorenyl group, a (d-C 4 ) alkoxyethyl group, a (d-C 4 )alkyl acyl group, Aminodecanoyl, N-(d-C 4 )alkyl decanoyl, N,N-di(d-C 4 )alkyl decanoyl, ^sulfonyl, N-(d-C 4 )alkyl^ Sulfonyl, N,N-di(d-C 4 )alkylsulfonyl, d-C 3 alkylenedioxy.

本发明特别优选涉及定义如下的通式 I的衍生物， 其中，  The invention particularly preferably relates to derivatives of the formula I defined below,

人！^为苯基， 且 ΑΓι任选 1- 3个 ^取代； people! ^ is phenyl, and Α Γι is optionally substituted with 1 - 3 ^;

Ar2为 2- 3-三氟曱基- 6-嘧^; Ar 2 is 2- 3-trifluoromethyl-6-pyrimidine;

为氢、 卤素、 三氟曱基、 三氟曱氧基、 （d- C4)烷基、 (C -C4) 烷氧基； Is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, (d-C 4 )alkyl, (C-C 4 ) alkoxy;

n为 1;  n is 1;

X为氢；  X is hydrogen;

本发明非常特别优选下列通式 I的衍生物，或其药学上可接受的  Very particular preference is given to derivatives of the following formula I, or pharmaceutically acceptable thereof

1- [4- [ [4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基] -3- (3-氯苯基)脲； 1-[4-[[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-3-(3-chlorobenzene Urea

1- [4- [ [4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基] -3- (3, 5-双三氟曱基苯基)脲；  1-[4-[[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl] -3- (3, 5- Ditrifluorodecylphenyl)urea;

1- [4- [ [4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基] -3- (3-氯 -4-氟苯基)脲；  1-[4-[[4-(2-Amino- 6-tris-ylpyrimidinyl-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-3-(3-chloro- 4-fluorophenyl)urea;

1- [4- [ [4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基] -3- (3-三氟曱基 -4-氟苯基)脲；  1-[4-[[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-3-(3-trifluoro Mercapto-4-fluorophenyl)urea;

1- [4- [ [4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基] -3- (3-氟苯基)脲；  1-[4-[[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-3-(3-fluorobenzene Urea

1- [4- [ [4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基] -3- (3, 4 -二氯苯基)脲；  1-[4-[[4-(2-Amino- 6-tris-l-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl] -3- (3, 4 - Dichlorophenyl)urea;

1- [4- [ [4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基] -3- (3, 5 -二氯苯基)脲；  1-[4-[[4-(2-Amino- 6-tri-l-decylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl] -3- (3, 5 - Dichlorophenyl)urea;

1- [4- [ [4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基] -3- (3, 5 -二氟苯基)脲；  1-[4-[[4-(2-Amino- 6-tri-l-decylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl] -3- (3, 5 - Difluorophenyl)urea;

1- [4- [ [4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基] -3- (2-氟苯基)脲；  1-[4-[[4-(2-Amino- 6-tris-ylpyrimidinyl-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-3-(2-fluorobenzene Urea

1- [4- [ [4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基] -3- (4-氯苯基)脲； 1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶- 4-基)哌嗪- 1-基〗曱基]苯 基] - 3- (3-三氟曱基苯基)脲。 1- [4- [ [4-(2-Amino- 6-tri- 1 - ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl phenyl] -3- (4-chlorobenzene Urea 1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(3-trifluorodecylbenzene Base) urea.

而且，按照本发明所属领域的一些通常方法，本发明的通式 I的 双芳基脲类衍生物可以与酸生成它的药学上可接受的盐。酸可以包括 无机酸或有机酸， 与下列酸形成的盐是特别优选的： 盐酸、草酸、 马 来酸、 富马酸、 柠檬酸、 洒石酸、 苹果酸、 羟乙磺酸、 酒石酸、 曱磺 酸、 乙磺酸、 氢溴酸、 硫酸、 磷酸、 萘二磺酸、 乙酸、 丙酸、 乳酸、 三氟乙酸、 苯曱酸或对曱苯磺酸等。  Moreover, the bisarylurea derivative of the formula I of the present invention can form a pharmaceutically acceptable salt thereof with an acid according to some usual methods in the art to which the present invention pertains. The acid may include a mineral acid or an organic acid, and a salt formed with the following acids is particularly preferred: hydrochloric acid, oxalic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, isethionic acid, tartaric acid, hydrazine Sulfonic acid, ethanesulfonic acid, hydrobromic acid, sulfuric acid, phosphoric acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, benzoic acid or p-toluenesulfonic acid.

此外， 本发明还包括本发明衍生物的前药。依据本发明， 前药是 通式 I的衍生物， 它们自身可能具有较弱的活性或甚至没有活性，但 是在给药后，在生理条件下（例如通过代谢、溶剂分解或另外的方式） 被转化成相应的生物活性形式。  Furthermore, the invention also includes prodrugs of the derivatives of the invention. According to the invention, the prodrugs are derivatives of the formula I which may themselves have weak or even no activity, but after administration, under physiological conditions (for example by metabolism, solvolysis or otherwise) Converted to the corresponding biologically active form.

除非另外指出， 本发明所用的术语 "卤素"是指氟、 氯、 溴或 代； "烷基"是指直链或支链的烷基； "亚烷基"是指直链或支链的亚 烷基； "环烷基" 是指取代或未取代的环烷基； 杂芳基包括含有一个 或多个选自 0、 N和 S的杂原子， 可以是单环或多环的， 环状体系是 芳香性的， 可以举出例如咪唑基、 吡1^、 嘧1^、 （1, 2, 3) -和（1, 2, 4) -三唑基、 吡嗪基、 四唑基、 呋喃基、 噻吩基、 异噁唑基、 噁唑 基、 吡唑基、 吡咯基、 唑基、 苯并 哈基、 苯并呋喃基、 苯并咪唑 基、 苯并噻唑基、 吲哚基、 喹啉基等； 饱和杂环基包括含有一个或多 个选自 0、 N和 S的杂原子， 环状体系可以是单环或多环的， 可以举 出例如吡咯烷基、 吗啉基、 哌嗪基、 哌1^、 吡唑烷基、 咪唑烷基和 噻唑啉基等。 The term "halogen" as used herein, unless otherwise indicated, means fluoro, chloro, bromo or substituted; "alkyl" means a straight or branched alkyl group; "alkylene" means straight or branched. An alkylene group; "cycloalkyl" means a substituted or unsubstituted cycloalkyl group; a heteroaryl group includes a hetero atom containing one or more selected from 0, N and S, which may be monocyclic or polycyclic, ring shaped system is aromatic, include for example imidazolyl, pyrazolyl, 1 ^, 1 ^ ethyl, (1, 2, 3) - and (1, 2, 4) - triazolyl, pyrazinyl, tetrazolyl , furanyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, oxazolyl, benzoheptyl, benzofuranyl, benzimidazolyl, benzothiazolyl, fluorenyl, a quinolyl group or the like; a saturated heterocyclic group includes one or more hetero atoms selected from 0, N and S, and the cyclic system may be monocyclic or polycyclic, and examples thereof include pyrrolidinyl group, morpholinyl group, piperazinyl, 1 ^ piperazine, pyrazolidinyl, imidazolidinyl, and the like thiazolinyl.

本发明包括药物组合物，该组合物含有通式 I的双芳基脲类衍生 物或其药学上可接受的盐、水合物或溶剂化物作为活性成分， 以及药 学上可接受的赋型剂。所述药学上可接受的赋型剂是指任何可用于药 学领域的稀释剂、 辅助剂和 /或载体。 本发明的衍生物可以与其他活 性成分组合使用， 只要它们不产生其他不利的作用， 例如过敏反应。  The present invention includes a pharmaceutical composition comprising a bisarylurea derivative of the formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical arts. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not cause other adverse effects such as an allergic reaction.

本发明的药物组合物可配制成若干种剂型，其中含有药学领域中 常用的一些赋形剂； 例如， 口服制剂（如片剂， 胶嚢剂， 溶液或混悬 液）；可注射的制剂（如可注射的溶液或混悬液，或者是可注射的干燥 粉末，在注射前加入注射用水可立即使用）；局部制剂（例如软膏或溶 液）。  The pharmaceutical compositions of the present invention may be formulated in a number of dosage forms containing some of the excipients commonly used in the pharmaceutical arts; for example, oral preparations (e.g., tablets, capsules, solutions or suspensions); injectable preparations ( For example, an injectable solution or suspension, or an injectable dry powder, can be used immediately after the injection of water for injection; a topical preparation (such as an ointment or solution).

用于本发明药物组合物的载体是药学领域中可得到的常见类型， 包括： 口服制剂用的粘合剂、 润滑剂、 崩解剂、 助溶剂、 稀释剂、 稳 定剂、 悬浮剂、无色素、矫味剂等； 可注射制剂用的防腐剂、加溶剂、 稳定剂等； 局部制剂用的基质、 稀释剂、 润滑剂、 防腐剂等。 药物制 剂可以经口服或胃肠外方式（例如静脉内、皮下、腹膜内或局部）给药， 如果某些药物在胃部条件下是不稳定的， 可将其配制成肠衣片剂。 The carrier used in the pharmaceutical composition of the present invention is a common type available in the pharmaceutical field, including: a binder for an oral preparation, a lubricant, a disintegrant, a solubilizer, a diluent, and a stable Preservatives, suspending agents, non-pigmenting, flavoring agents, etc.; preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations. The pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they can be formulated into enteric coated tablets.

我们已发现本发明化合物具有抑制蛋白酪氨酸激酶活性，因此本 发明化合物具有抗增生性质。本发明化合物可以用于蛋白酪氨酸激酶 受体抑制剂单独或部分间介的疾病或病症的治疗，即化合物可以在需 要这类治疗的哺乳动物体内用于产生蛋白酪氨酸激酶受体抑制作用。  We have found that the compounds of the invention have inhibitory protein tyrosine kinase activity, and thus the compounds of the invention have anti-proliferative properties. The compounds of the invention may be used in the treatment of a disease or condition in which a protein tyrosine kinase receptor inhibitor is administered alone or in part, i.e., the compound may be used to produce protein tyrosine kinase receptor inhibition in a mammal in need of such treatment. effect.

本发明化合物可以用于提供抗增生作用的癌症的治疗，尤其治疗 蛋白酪氨酸激酶受体敏感的癌症如乳腺、 肺、 结肠、 直肠、 胃、 前列 腺、膀胱、胰腺和卵巢的癌。本发明化合物也被期望可以用于治疗其 他细胞增生疾病如牛皮癣、良性前列腺肥大、动脉粥样硬化和再狭窄。 另外预期本发明的双芳基脲类衍生物将具有抗白血病、淋巴恶性和固 体肿瘤如在组织如肝、 肾、 前列腺和胰腺中的癌和肉瘤范围的活性。  The compounds of the present invention are useful in the treatment of cancers which provide anti-proliferative effects, particularly in the treatment of cancers susceptible to protein tyrosine kinase receptors such as breast, lung, colon, rectum, stomach, prostate, bladder, pancreas and ovary. The compounds of the invention are also expected to be useful in the treatment of other cell proliferative disorders such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis. It is further contemplated that the bisarylurea derivatives of the present invention will have activity against leukemia, lymphoid malignant and solid tumors such as cancer and sarcoma in tissues such as liver, kidney, prostate and pancreas.

另外，也预期本发明化合物可用于治疗其它细胞增生的疾病，其 中包括通过受体蛋白酪氨酸激酶标记，包括还未确定的受体蛋白酪氨 酸激酶的畸变细胞。 这类疾病包括， 例如， 炎症、血管生成、 血管再 狭窄， 免疫学疾病、 胰腺病、 肾病和胚成熟和移植。  In addition, the compounds of the invention are also contemplated for use in the treatment of diseases in which other cells proliferate, including by receptor protein tyrosine kinases, including those of the receptor protein tyrosine kinase that have not yet been identified. Such diseases include, for example, inflammation, angiogenesis, restenosis, immunological diseases, pancreatic diseases, kidney disease, and embryo maturation and transplantation.

体外抗肿瘤活性试验表明本发明的通式 I的双芳基脲类衍生物 具有抗癌作用， 因此， 它可以用作制备治疗和 /或预防癌症的药物。  The in vitro antitumor activity test indicates that the bisarylurea derivative of the formula I of the present invention has an anticancer effect, and therefore, it can be used as a medicament for the preparation of a medicament for treating and/or preventing cancer.

根据本发明的衍生物可作为活性成分用于制备治疗和 /或预防各 种癌症，本发明也提供治疗或预防上述疾病的方法， 包括给予患有或 易患有此病的病人治疗有效量的根据本发明的衍生物。通式 I的双芳 基脲类衍生物用于患者的临床剂量必需依赖被治疗的主体、给药的具 体途径、被治疗疾病的严重性而变化， 而最佳剂量由治疗具体患者的 医生确定。  The derivative according to the present invention can be used as an active ingredient for the preparation of a medicament for treating and/or preventing various cancers, and the present invention also provides a method for treating or preventing the above-mentioned diseases, comprising administering a therapeutically effective amount to a patient suffering from or susceptible to the disease. A derivative according to the invention. The clinical dose of the bisarylurea derivative of formula I for use in a patient must depend on the subject being treated, the particular route of administration, the severity of the condition being treated, and the optimal dosage will be determined by the physician treating the particular patient. .

本发明活性化合物可作为唯一的抗癌药物使用，或者可以与一种 或多种其它抗肿瘤药物联合使用。 联合治疗通过将各个治疗组分同 时、 顺序或隔开给药来实现。  The active compounds of the invention may be used as the sole anticancer drug or may be used in combination with one or more other antineoplastic agents. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.

下文中提供的实施例和制备例进一步阐明和举例说明本发明化 合物及其制备方法。应当理解， 下述实施例和制备例的范围并不以任 何方式限制本发明的范围。  The examples and preparations provided hereinafter further illustrate and exemplify the compounds of the invention and methods for their preparation. It is to be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention.

下面合成路线 A描述了本发明的通式 I衍生物的制备，所有的原 料都是通过这些示意图中描述的方法、通过有机化学领域普通技术人 员熟知的方法制备的或者可商购。本发明的全部最终衍生物都是通过 这些示意图中描述的方法或通过与其类似的方法制备的，这些方法是 有机化学领域普通技术人员熟知的。这些示意图中应用的全部可变因 数如下文的定义或如权利要求中的定义。 Scheme A below describes the preparation of the derivatives of the general formula I of the present invention, all of which are prepared by the methods described in these schematics, by methods well known to those of ordinary skill in the art of organic chemistry or are commercially available. All of the final derivatives of the invention are passed The methods described in these schematics are prepared by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All of the variable factors applied in these schematics are as defined below or as defined in the claims.

按照本发明的通式 I衍生物， 在路线 A中， ΑΓι、 Ar2、 X和 η如发 明内容所定义。 Derivatives of the formula I according to the invention, in Scheme A, Α Γ , Ar 2 , X and η are as defined in the Summary of the Invention.

Figure imgf000009_0001
Figure imgf000009_0001

I 路线 A 通式 I化合物的合成路线 在化合物 A- 1为起始原料， 在碱性条件下， 与过量的哌嗪进行取 代反应， 制得化合物 A- 2， 继而与 Ar2Cl进行取代反应， 得到化合物 A- 3。 在乙醇中， A- 3经水合肼还原制得 A- 4， 化合物 A- 4与人！^取代 的异氰酸酯缩合， 得到双芳脲类衍生物 I 。 具体实施方式 I Route A The synthesis route of the compound of the formula I is carried out in the compound A-1 as a starting material, and under basic conditions, a substitution reaction with an excess of piperazine to obtain a compound A-2, followed by substitution with Ar 2 Cl , Compound A-3 was obtained. In ethanol, A-3 is reduced by hydrazine hydrate to produce A-4, compound A-4 and human! ^ Substituted isocyanate condensation to give the bis-arylurea derivative I. detailed description

实施例旨在阐述而不是限制本发明的范围。衍生物的核磁共振氢 谱用 Bruker ARX- 300测定， 质谱用 Agi lent 1100 LC/MSD测定； 所 用试剂均为分析纯或化学纯。

Figure imgf000009_0002
The examples are intended to illustrate and not to limit the scope of the invention. The nuclear magnetic resonance spectrum of the derivative was determined by Bruker ARX-300, and the mass spectrum was determined by Agilent 1100 LC/MSD; the reagents used were either analytically pure or chemically pure.
Figure imgf000009_0002

r 2' 表 1. 实施例 1-26的结构式 r 2' Table 1. Structural Formulas of Examples 1-26

Figure imgf000010_0001
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Figure imgf000010_0001
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Figure imgf000011_0001
Figure imgf000011_0001

26 2'-CH HC1 26 2'-CH HC1

实施例 1: 1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基] 曱基]苯基] -3- (3-氯苯基)脲盐酸盐 Example 1: 1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(3-chloro Phenyl)urea hydrochloride

步骤 A: 2-氨基- 4-羟基- 6-三氟曱基嘧啶的制备  Step A: Preparation of 2-amino-4-hydroxy-6-trifluoromethylpyrimidine

将金属钠 4. 6 g (0. 20 mol)逐渐加入正丁醇 80 mL中， 加热至 钠完全溶解后， 加入硝酸胍 11. 6 g (0. 10 mol) , 回流 15 min后， 逐渐滴加 27. 6 g (0. 15mol)三氟乙酰乙酸乙酯， 回流反应约 6 h， 反 应完毕后，冷却至室温，用 10%盐酸调节 pH至 4 ~ 5，析出大量固体， 抽滤，冷水洗涤滤饼，真空干燥得白色粉末固体 14. 9 g，收率： 83. 4%, MS: 180. 2 (M+l)。  The metal sodium 4. 6 g (0. 20 mol) was gradually added to n-butanol 80 mL, heated until the sodium was completely dissolved, and then added to the ruthenium nitrate 11.6 g (0. 10 mol), refluxed for 15 min, gradually dripped Add 27. 6 g (0.15 mol) of ethyl trifluoroacetoacetate, reflux for about 6 h, after the reaction is completed, cool to room temperature, adjust the pH to 4-5 with 10% hydrochloric acid, precipitate a large amount of solid, suction filtration, cold water The washing cake was washed with a vacuum to give a white powdery solid, 14.9 g, yield: 83. 4%, MS: 180. 2 (M+l).

步骤 B: 2- 4-氯- 6-三氟曱基嘧啶的制备  Step B: Preparation of 2- 4-chloro-6-trifluoromethylpyrimidine

将 2-氨基- 4-羟基- 6-三氟曱基嘧啶 18. 0 (0. 10 mol)分批逐渐加 入无水乙腈 200 mL与三氯氧磷 100 mL的混合溶液中， 搅拌升温至 75 C 滴加 100 mL含有三乙胺 4 g (0. 04 mol)的乙腈溶液， 回流反 应 12 h。 反应完毕后， 将反应液冷却至室温， 减压浓缩， 向残余液 中加入水水 600 mL， 501C下搅拌 3 h。 抽滤， 冷水洗涤滤饼， 干燥得 灰白色固体 15. 5 g， 收率： 78. 5%， MS: 198. 7 (M+1)。  2-amino-4-hydroxy-6-trifluoromethylpyrimidine 18.0 (0. 10 mol) was gradually added to a mixed solution of anhydrous acetonitrile 200 mL and phosphorus oxychloride 100 mL, and the temperature was raised to 75. C 100 mL of a solution containing 4 g of triethylamine (0.04 mol) in acetonitrile was added dropwise and refluxed for 12 h. After completion of the reaction, the reaction solution was cooled to room temperature, and concentrated under reduced pressure. Water (600 mL) was added to the residue and stirred at 501 C for 3 h. The filter cake was washed with cold water, and dried to give a white solid. 15. g, yield: 78. 5%, MS: 198. 7 (M+1).

步骤 C: 1- (4-硝基苯曱基)哌嗪的制备  Step C: Preparation of 1-(4-nitrophenylhydrazino)piperazine

将无水碳酸钟 12. 8 g (0. 093 mol) , 无水乙醇 250 mL加入到三 颈瓶 500 mL中， 加入无水哌嗪 80 g (0. 93 mol)， 0- 下分批逐渐 加入对硝基溴苄 20 g (0. 093 mol) , 加毕， 0-5 反应 1 h。 反应完 毕后， 将反应液倾入 300 mL水中， 二氯曱烷提取， 合并提取液， 水 洗， 无水硫酸钠干燥。 蒸干得 17. 3 g淡黄色固体， 收率： 84. 2%， MS: 222. 0 (M+1)。  Add 12. 8 g (0. 093 mol) of anhydrous carbonic acid clock, 250 mL of absolute ethanol to 500 mL of a three-necked flask, add 80 g (0. 93 mol) of anhydrous piperazine, and gradually add batches of 0- Add p-nitrobenzyl bromide 20 g (0. 093 mol), add, and react 0-5 for 1 h. After the completion of the reaction, the reaction solution was poured into 300 mL of water, extracted with dichloromethane, and the combined extracts were washed with water and dried over anhydrous sodium sulfate. Evaporation of 17.3 g of a pale yellow solid. Yield: 84. 2%, MS: 222.

步骤 D: 2-氨基- 4- [4- (4-硝基苯曱基)哌嗪- 1-基] - 6-三氟曱基 嘧啶的制备  Step D: Preparation of 2-amino-4-[4-(4-nitrophenylhydrazino)piperazine-1-yl]-6-trifluorodecylpyrimidine

将 2- 4-氯- 6-三氟曱基嘧啶 8. 3 g (0. 031mol)及 1- (4-硝 基苯基）哌嗪 7. 0 g (0. 031mol)加入到无水乙醇 85 mL中， 升温至 50 , 逐渐向反应液中加入三乙胺 3. 2 g (0. 031mol) , 滴加完毕后， 回流反应 8 h。 反应完毕后， 将反应液冷却， 水箱过夜静置析晶。 抽 滤，滤饼水洗，少量乙醚洗，干燥得白色粉末固体 8. 2 g，收率： 69. 5%， MS: 383· 1 (Μ+1)。  2- chloro-6-trifluoromethylpyrimidine 8. 3 g (0. 031 mol) and 1-(4-nitrophenyl)piperazine 7. 0 g (0. 031 mol) were added to absolute ethanol In 85 mL, the temperature was raised to 50, and triethylamine 3. 2 g (0. 031 mol) was gradually added to the reaction solution, and after the completion of the dropwise addition, the reaction was refluxed for 8 hours. After the reaction was completed, the reaction solution was cooled, and the water tank was allowed to stand overnight for crystallization. After filtration, the filter cake was washed with water, a little diethyl ether and dried to give a white powdery solid 8. 2 g, yield: 69. 5%, MS: 383·1 (Μ+1).

步骤 Ε: 2-氨基- 4- [4- (4-氨基苯曱基)哌嗪- 1-基] - 6-三氟曱基 嘧啶的制备 Step Ε: 2-Amino-4-[4-(4-aminophenylhydrazino)piperazine-1-yl]-6-trifluorodecyl Preparation of pyrimidine

取 2-氨基- 4- [4- (4-硝基苯曱基)哌嗪- 1-基〗 -6-三氟曱基嘧啶 8.2 g (0.021 mol)加入到无水乙醇 40 mL中， 搅拌， 向反应液中加 入 DMF 20 mL、 聚乙二醇 400 5 mL和 0.1 g (0. Oil mol)活性炭， 80 搅拌 5 min, 然后向反应液中加入六水合三氯化铁 1.7 g (0.006 mol), 搅拌。 向反应液中逐滴加入 13.4 g (0.21 mol)含量为 80%的 水合肼， 滴毕后于 反应 12 h。 反应完毕后， 趁热抽滤， 蒸出滤 液中的乙醇， 向残留液体加入 200 mL水， 析出大量固体， 抽滤， 水 洗， 干燥得淡粉色粉末固体 6.0 g (收率： 78.7%)。 MS: 353.4 (M+1)。  2-Amino-4-[4-(4-nitrophenylhydrazino)piperazine-1-yl-6-trifluoromethylpyrimidine 8.2 g (0.021 mol) was added to 40 mL of absolute ethanol and stirred. Add DMF 20 mL, polyethylene glycol 400 5 mL, and 0.1 g (0. Oil mol) activated carbon to the reaction solution, stir for 80 min for 5 min, then add 1.7 g (0.006 mol) of ferric chloride hexahydrate to the reaction solution. ), stirring. To the reaction solution, 13.4 g (0.21 mol) of hydrazine hydrate having a content of 80% was added dropwise, and the reaction was carried out for 12 hours. After completion of the reaction, the mixture was filtered while hot, and the ethanol in the filtrate was distilled off. To the residual liquid, 200 mL of water was added to precipitate a large amount of solid, which was filtered, washed with water, and dried to give a pale pink powder solid (yield: 78.7%). MS: 353.4 (M + 1).

步骤 F: 3-氯苯基异氰酸酯的制备  Step F: Preparation of 3-chlorophenyl isocyanate

将间氯苯胺 30 g (0.24 mol)加入到干燥的二氧六环 200 mL中， 升温至 50C 分批次加入固体光气 68.7 g (0.24 mol)， 加毕， 80 反应 24 h。 反应毕， 减压蒸馏， 收集馏分 b.p.125- 128 /30- 40 mmHg, 得无色液体 14.9 g， 收率： 45.2%。  30 g (0.24 mol) of m-chloroaniline was added to 200 mL of dry dioxane, and the temperature was raised to 50 C. 68.7 g (0.24 mol) of solid phosgene was added in portions, and the reaction was carried out for 80 hours. After completion of the reaction, the mixture was distilled under reduced pressure, and fractions b.p. 125- 128 / 30 - 40 mmHg were obtained to obtain a colorless liquid, 14.9 g, yield: 45.2%.

步骤 G: 1- [4- [[4- (2- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基] 曱基〗苯基〗 -3- (3-氯苯基)脲盐酸盐的制备  Step G: 1-[4-[[4-(2- 6-Trifluoromethylpyrimidin-4-yl)piperazine-1-yl]nonylphenyl]-3-(3-chlorophenyl) Preparation of urea hydrochloride

取 2-氨基- 4- [4- (4-氨基苯曱基)哌嗪- 1-基] -6-三氟曱基嘧啶 0.35 g (0.001 mol)加入到 5 mL干燥的四氢呋喃中，搅拌下加入 0.23 g (0.0015 mol) 3-氯苯基异氰酸酯， 5- 10 反应 8 h。 反应完毕后， 将反应液倾入水 15 mL中， 析出固体， 抽滤， 水洗， 干燥得白色粉末 固体。 将白色固体加入到 5 mL丙酮中， 室温搅拌下滴加盐酸乙醚调 H 1-2, 继续搅拌 0.5 h， 抽滤， 少量乙醚洗， 干燥得实施例 1化 合物 0.39g， 收率： 72.0%， m. p. 206-210^, MS: 506·2(Μ+1)。  Add 2-amino-4-[4-(4-aminophenylhydrazino)piperazine-1-yl]-6-trifluoromethylpyrimidine 0.35 g (0.001 mol) to 5 mL of dry tetrahydrofuran and stir 0.23 g (0.0015 mol) of 3-chlorophenyl isocyanate was added, and 5-10 was reacted for 8 h. After completion of the reaction, the reaction mixture was poured into 15 mL of water to precipitate a solid, which was filtered, washed with water and dried to give a white powder solid. The white solid was added to 5 mL of acetone, and H 1-2 was added dropwise with stirring at room temperature, and the mixture was stirred for 0.5 h, filtered, filtered, washed with diethyl ether and dried to give the compound of the compound of Example 1 (0.39 g, yield: 72.0%, Mp 206-210^, MS: 506·2 (Μ+1).

按照实施例 1的方法，选择合适的原料和试剂，分别制得实施例 2- 28化合物：  According to the method of Example 1, the appropriate starting materials and reagents were selected to prepare the compounds of Examples 2-28:

实施例 2: Example 2:

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基〗曱基]苯 基] -3- (4-三氟曱氧基苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(4-trifluorodecyloxy) Phenyl) urea hydrochloride;

MS: 556.5 (M+l)。  MS: 556.5 (M+l).

实施例 3: Example 3:

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶- 4-基)哌嗪- 1-基〗曱基]苯 基]- 3- (3, 5-双三氟曱基苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]fluorenyl]phenyl]- 3-(3,5-difluoro Nonylphenyl) urea hydrochloride;

MS: 608.0 (M+1)；  MS: 608.0 (M+1);

'H-NMR (DMS0-d6) δ (ppm)： 10.4 (s, 1 H) , 9.79 (s, 1 H) , 8.10 (s, 2 H) , 7.65 (s, 1 H) , 7.47 - 7.56 (m, 4 H, 7=8.7 Hz) , 6. 57 (s, 1 H) , 4. 50 (brs, 2 H) , 4. 25 (s, 2 H) , 3. 37 (m, 4 H) , 3. 02 (m, 2 H)。 'H-NMR (DMS0-d 6 ) δ (ppm): 10.4 (s, 1 H) , 9.79 (s, 1 H) , 8.10 (s, 2 H) , 7.65 (s, 1 H) , 7.47 - 7.56 (m, 4 H, 7=8.7 Hz), 6. 57 (s, 1 H) , 4. 50 (brs, 2 H) , 4. 25 (s, 2 H) , 3. 37 (m, 4 H) , 3. 02 (m, 2 H).

实施例 4: Example 4:

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基〗曱基]苯 基〗 -3- (4-三氟曱基苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]fluorenyl]phenyl]-3-(4-trifluorodecylbenzene Urea hydrochloride

MS: 540. 5 (M+l)。  MS: 540. 5 (M+l).

实施例 5: Example 5

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶- 4-基)哌嗪- 1-基〗曱基]苯 基] - 3- (3, 4-二氟苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(3,4-difluorobenzene Urea hydrochloride

MS: 508. 5 (M+l)。  MS: 508. 5 (M+l).

实施例 6: Example 6:

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基〗曱基]苯 基] - 3- (2, 5-二曱基苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(2,5-didecyl) Phenyl) urea hydrochloride;

MS: 500. 5 (M+l)。  MS: 500. 5 (M+l).

实施例 7: Example 7

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶- 4-基)哌嗪- 1-基〗曱基]苯 基] -3- (3-氯- 4-氟苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indenyl]phenyl]-3-(3-chloro-4-fluoro Phenyl) urea hydrochloride;

MS: 624. 9 (M+1)；  MS: 624. 9 (M+1);

'H-NMR (DMS0-d6) δ (ppm)： 9. 68 (s, 1 H) , 9. 56 (s, 1 H) , 7. 78 (dd, 1 H, =1. 8 Hz, 72=2. 1 Hz) , 7. 45 - 7. 53 (m, 4 H) , 7. 32 (m, 2 H) , 6. 58 (s, 1 H) , 4. 54 (brs, 2 H) , 4. 24 (s, 2 H) , 3. 38 (m, 4 H) , 3. 00 (m, 2 H)。 'H-NMR (DMS0-d 6 ) δ (ppm): 9. 68 (s, 1 H) , 9. 56 (s, 1 H) , 7. 78 (dd, 1 H, =1. 8 Hz, 7 2 =2. 1 Hz) , 7. 45 - 7. 53 (m, 4 H) , 7. 32 (m, 2 H) , 6. 58 (s, 1 H) , 4. 54 (brs, 2 H) , 4. 24 (s, 2 H) , 3. 38 (m, 4 H) , 3. 00 (m, 2 H).

实施例 8: Example 8

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基〗曱基]苯 基〗 -3- (3-三氟曱基- 4-氟苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(3-trifluoromethyl)- 4-fluorophenyl)urea hydrochloride;

MS: 558. 5 (M+1) ;  MS: 558. 5 (M+1);

'H-NMR (DMS0-d6) δ (ppm)： 9. 89 (s, 1 H) , 9. 64 (s, 1 H) , 8. 00 (dd, 1 H, 7=2. 4 Hz) , 7. 64 (m, 1 H) , 7. 41 - 7. 56 (m, 5 H) , 6. 59 (s, 1 H) , 4. 56 (brs, 2 H) , 4. 26 (s, 2 H) , 3. 39 (m, 4 H) , 3. 00 (m, 2 H)。 'H-NMR (DMS0-d 6 ) δ (ppm): 9. 89 (s, 1 H) , 9. 64 (s, 1 H) , 8. 00 (dd, 1 H, 7=2. 4 Hz ), 7. 64 (m, 1 H) , 7. 41 - 7. 56 (m, 5 H) , 6. 59 (s, 1 H) , 4. 56 (brs, 2 H) , 4. 26 ( s, 2 H) , 3. 39 (m, 4 H) , 3. 00 (m, 2 H).

实施例 9: Example 9

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基〗曱基]苯 基〗 -3- (3-氟苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(3-fluorophenyl)urea Hydrochloride;

MS: 490. 5 (M+1) ;  MS: 490. 5 (M+1);

'H-NMR (DMS0-d6) δ (ppm)： 9. 71 (s, 1 H) , 9. 63 (s, 1 H) , 7. 34 - 7. 55 (m, 5 H) , 7. 29 (m, 1 H) , 7. 11 (d, 1 H, 7=8. 7 Hz) , 6. 77 (m, 1 H) , 6. 61 (s, 1 H) , 4. 56 (brs, 2 H) , 4. 26 (s, 2 H) , 3. 37 (m, 4 H) , 3. 00 (m, 2 H)。 'H-NMR (DMS0-d 6 ) δ (ppm): 9. 71 (s, 1 H) , 9. 63 (s, 1 H) , 7. 34 - 7. 55 (m, 5 H) , 7. 29 (m, 1 H) , 7. 11 (d, 1 H, 7=8. 7 Hz) , 6. 77 (m, 1 H) , 6. 61 (s, 1 H) , 4. 56 (brs, 2 H) , 4. 26 (s, 2 H) , 3. 37 (m, 4 H) , 3. 00 (m, 2 H) .

实施例 10: Example 10

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基〗曱基]苯 基] -3- (3, 4-二曱基苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(3,4-didecyl) Phenyl) urea hydrochloride;

MS: 500· 5 (Μ+1)。  MS: 500· 5 (Μ+1).

实施例 11 : Example 11:

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基〗曱基]苯 基〗 -3- (3, 4-二氯苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(3,4-dichlorobenzene Urea hydrochloride

MS: 541. 4 (M+1)  MS: 541. 4 (M+1)

'H-NMR (DMS0-d6) δ (ppm) ： 9. 79 (s, 1 H) , 9. 61 (s, 1 H) , 7. 88 (d, 1 H, 7=2. 4 Hz) , 7. 47 - 7. 56 (m, 5 H) , 7. 34 (dd, 1 H, 7=2. 4 Hz) , 6. 61 (s, 1 H) , 4. 56 (brs, 2 H) , 4. 26 (s, 2 H) , 3. 37 (m, 4 H) , 3. 05 (m, 2 H)。 'H-NMR (DMS0-d 6 ) δ (ppm): 9. 79 (s, 1 H) , 9. 61 (s, 1 H) , 7. 88 (d, 1 H, 7=2. 4 Hz ), 7. 47 - 7. 56 (m, 5 H) , 7. 34 (dd, 1 H, 7=2. 4 Hz) , 6. 61 (s, 1 H) , 4. 56 (brs, 2 H) , 4. 26 (s, 2 H) , 3. 37 (m, 4 H) , 3. 05 (m, 2 H).

实施例 12: Example 12:

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基〗曱基]苯 基] -3- (3, 5-二氯苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(3,5-dichlorobenzene Urea hydrochloride

MS: 541. 4 (M+1)；  MS: 541. 4 (M+1);

'H-NMR (DMS0-d6) δ (ppm) ： 9. 93 (s, 1 H) , 9. 64 (s, 1 H) ,'H-NMR (DMS0-d 6 ) δ (ppm): 9. 93 (s, 1 H) , 9. 64 (s, 1 H) ,

7. 46 ~ 7. 54 (m, 6 H) , 7. 15 (dd, 1 H, 7=1. 8 Hz) , 6. 56 (s, 1 H) , 4. 50 (brs, 2 H) , 4. 25 (s, 2 H) , 3. 34 (m, 4 H) , 3. 01 (m, 2 H)。 7. 46 ~ 7. 54 (m, 6 H) , 7. 15 (dd, 1 H, 7=1. 8 Hz) , 6. 56 (s, 1 H) , 4. 50 (brs, 2 H) , 4. 25 (s, 2 H) , 3. 34 (m, 4 H) , 3. 01 (m, 2 H).

实施例 13: Example 13

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基〗曱基]苯 基] -3- (3, 5-二氟苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(3,5-difluorobenzene) Urea hydrochloride

MS: 508. 5 (M+l)。  MS: 508. 5 (M+l).

实施例 14: Example 14

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶- 4-基)哌嗪- 1-基〗曱基]苯 基〗 -3- (2, 6-二氯苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]fluorenyl]phenyl]-3-(2,6-dichlorobenzene Urea hydrochloride

MS: 541. 4 (M+l)。  MS: 541. 4 (M+l).

实施例 15: Example 15

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶- 4-基)哌嗪- 1-基〗曱基]苯 基〗 -3- (2-氟苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(2-fluorophenyl)urea Hydrochloride;

MS: 490. 5 (M+1)； 'H-NMR (DMS0-d6) δ (ppm) ： 9. 70 (s, 1 H) , 8. 80 (s, 1 H)， 8. 11 (t, 1 H, 7=8. 1 Hz) , 7. 47 - 7. 55 (m, 4 H, 7=8. 7 Hz) , 7. 23 (t, 1 H, 7=8. 4 Hz) , 7. 13 (t, 1 H, 7=7. 8 Hz) , 7. 04 (m, 1 H) , 6. 56 (s, 1 H) , 4. 50 (brs, 2 H)， 4. 24 (s, 2 H)， 3. 37 (m, 4 H)， 3. 01 (m, 2 H)。 MS: 490. 5 (M+1); 'H-NMR (DMS0-d 6 ) δ (ppm): 9. 70 (s, 1 H) , 8. 80 (s, 1 H), 8. 11 (t, 1 H, 7=8. 1 Hz ), 7. 47 - 7. 55 (m, 4 H, 7=8. 7 Hz) , 7. 23 (t, 1 H, 7=8. 4 Hz) , 7. 13 (t, 1 H, 7 =7. 8 Hz) , 7. 04 (m, 1 H) , 6. 56 (s, 1 H) , 4. 50 (brs, 2 H), 4. 24 (s, 2 H), 3. 37 (m, 4 H), 3. 01 (m, 2 H).

实施例 16 : Example 16:

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基〗曱基]苯 基〗 -3- (5-三氟曱基- 2-氯苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]fluorenyl]phenyl]-3-(5-trifluorodecyl- 2-chlorophenyl)urea hydrochloride;

MS: 574· 9 (Μ+1)。  MS: 574· 9 (Μ +1).

实施例 17: Example 17

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶- 4-基)哌嗪- 1-基〗曱基]苯 基〗 -3- (4-氯苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(4-chlorophenyl)urea Hydrochloride;

MS: 506. 9 (M+1) ;  MS: 506. 9 (M+1);

'H-NMR (DMS0-d6) δ (ppm)： 9. 52 (s, 2 H) , 8. 11 (t, 1 H, 7=8. 1 Hz) , 7. 45 - 7. 54 (m, 6 H) , 7. 33 (s, 1 H) , 7. 30 (s, 1 H) , 6. 56 (s, 1 H) , 4. 50 (brs, 2 H)， 4. 24 (s, 2 H)， 3. 36 (m, 4 H, )， 3. 01 (m, 2 H)。 'H-NMR (DMS0-d 6 ) δ (ppm): 9. 52 (s, 2 H) , 8. 11 (t, 1 H, 7=8.1 Hz), 7. 45 - 7. 54 ( m, 6 H) , 7. 33 (s, 1 H) , 7. 30 (s, 1 H) , 6. 56 (s, 1 H) , 4. 50 (brs, 2 H), 4. 24 ( s, 2 H), 3. 36 (m, 4 H, ), 3. 01 (m, 2 H).

实施例 18: Example 18

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基〗曱基]苯 基〗 -3- (3-三氟曱氧基苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(3-trifluorodecyloxy) Phenyl) urea hydrochloride;

MS: 556· 5 (Μ+1)。  MS: 556· 5 (Μ+1).

实施例 19 : Example 19:

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶- 4-基)哌嗪- 1-基〗曱基]苯 基〗 -3- (2-三氟曱基苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]indolyl]phenyl]-3-(2-trifluorodecylbenzene) Urea hydrochloride

MS: 540· 5 (Μ+1)。  MS: 540· 5 (Μ+1).

实施例 20: Example 20

1- [4- [4- (2-氨基- 6-三氟曱基嘧啶 -4-基）哌嗪- 1-基]苯 基〗 -3- (4-氯苯基)脲盐酸盐；  1-[4-[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]phenyl]-3-(4-chlorophenyl)urea hydrochloride;

MS: 492· 2 (Μ+1)。  MS: 492· 2 (Μ+1).

实施例 21 : Example 21:

1- [4- [4- (4-苯基哌嗪- 1-基) -2-曱氧基]苯基] -3- (3-异丙基苯 基)脲盐酸盐；  1-[4-[4-(4-Phenylpiperazine-1-yl)-2-indolyl]phenyl]-3-(3-isopropylphenyl)urea hydrochloride;

MS: 445· 3 (Μ+1)。  MS: 445· 3 (Μ +1).

实施例 22: Example 22

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基〗乙基]苯 基〗 -3- (2-氟苯基)脲盐酸盐； 1- [4- [ [4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]ethyl]benzene -3-(2-fluorophenyl)urea hydrochloride;

MS: 504· 5 (Μ+1)。  MS: 504· 5 (Μ+1).

实施例 23: Example 23

1- [4- [ [2- (4-呋喃基 -2-基)哌嗪- 1-基〗乙基〗苯基〗 -3- (2-三氟 曱基苯基)脲盐酸盐；  1-[4-[[2-(4-furyl-2-yl)piperazine-1-yl]ethyl]phenyl]-3-(2-trifluorodecylphenyl)urea hydrochloride;

MS: 489· 2 (Μ+1)。  MS: 489· 2 (Μ+1).

实施例 24: Example 24

1- [4- [4- (4-苯基哌嗪- 1-基) -丁基〗苯基〗 -3- (2, 5-二曱基苯基） 脲盐酸盐；  1-[4-[4-(4-Phenylpiperazine-1-yl)-butylphenyl)-3-(2,5-didecylphenyl)urea hydrochloride;

MS: 457· 6 (Μ+1)。  MS: 457. 6 (Μ +1).

实施例 25: Example 25:

1- [4- [ [4- (2-氨基- 6-三氟曱基嘧啶 -4-基)哌嗪- 1-基〗丁基]苯 基] -3- (2, 6-二氯苯基)脲盐酸盐；  1-[4-[[4-(2-Amino-6-trifluoromethylpyrimidin-4-yl)piperazine-1-yl]butyl]phenyl]-3-(2,6-dichlorobenzene Urea hydrochloride

MS: 683· 4 (Μ+1)。  MS: 683· 4 (Μ+1).

实施例 26: Example 26

1- [3-曱基- 4- [ [4- (吡啶 -2-基)哌嗪- 1-基]曱基]苯基] -3- (3-三 氟曱基 -4-氟苯基)脲盐酸盐；  1-[3-indolyl-4-[ [4-(pyridin-2-yl)piperazine-1-yl]indolyl]phenyl]-3-(3-trifluorodecyl-4-fluorophenyl) Urea hydrochloride;

MS: 688· 5 (Μ+1)。  MS: 688. 5 (Μ+1).

本发明产物的药理研究 Pharmacological study of the product of the invention

对按照本发明的上式 I的双芳基脲类衍生物进行了体外蛋白酪氨 酸激酶抑制活性筛选和体外抗肿瘤活性筛选。  The bisarylurea derivative of the above formula I according to the present invention was subjected to in vitro protein tyrosine kinase inhibitory activity screening and in vitro antitumor activity screening.

一、 蛋白酪氨酸激酶抑制活性筛选  I. Screening of protein tyrosine kinase inhibitory activity

(1)在 96孔板的每孔中加入 50uL的激酶反应液。 在 96孔板的 2-11列加入受试样品 lOuL (浓度为 9 μ g/mL )， 用排枪在 1和 12列 加入激酶反应液 10uL。 在 96孔板的每孔中加入 50uL的大鼠脑组织 酪氨酸提取液 [蛋白质含量约为 0. 4mg/mL]， 振荡混匀， 孵育 1 小时， 以 200uL的洗脱液洗 3次。  (1) 50 uL of the kinase reaction solution was added to each well of a 96-well plate. The test sample lOuL (concentration: 9 μg/mL) was added to the 2-11 column of the 96-well plate, and the kinase reaction solution 10 uL was added to the columns 1 and 12 by a row of guns. 50 uL of rat brain tissue tyrosine extract [protein content of about 0.4 mg/mL] was added to each well of a 96-well plate, incubated by shaking, incubated for 1 hour, and washed three times with 200 uL of eluate.

(2) 用 persona l pipettor在 96孔板的每孔中加入 lOOuL的用 洗脱液 2000倍稀释的连有辣根过氧化物酶（ HRP )的抗磷酸多肽抗体 液， 振荡混匀， 室温孵育 30分钟。  (2) Add 100uL of anti-phosphopeptide antibody solution with horseradish peroxidase (HRP) diluted with 2000 times of eluate in each well of 96-well plate with persona l pipettor, shake and mix, incubate at room temperature 30 minutes.

(3) 以洗脱液洗 3次。  (3) Wash 3 times with eluent.

(4) 每孔加入 l OOuL邻苯二胺溶液。室温下避光孵育 7- 10分钟。  (4) Add lOOuL o-phenylenediamine solution to each well. Incubate in the dark for 7-10 minutes at room temperature.

(5) 每孔中加入 lOOuL lmol/L硫酸以终止反应。 (6) 在 30分钟内用酶标仪测定在 492 nm处的吸光度。 (5) Add lOOuL of lmol/L sulfuric acid to each well to terminate the reaction. (6) The absorbance at 492 nm was measured with a microplate reader within 30 minutes.

(7) 由酶标仪测定的样品吸光度和同板测定的未加药物的对照 吸光度计算药物对蛋白酪氨酸激酶的抑制率。 计算方法如下：  (7) The absorbance of the sample measured by the microplate reader and the unadsorbed control of the same plate. The absorbance of the drug was used to calculate the inhibition rate of the protein tyrosine kinase. The calculation method is as follows:

抑制率％= (对照 0D -样品 0D) I (对照 0D -空白 0D) X 100% 所 iiJ ^照品是由德国拜耳公司和 ONYX公司共同研制的作为口服 多激酶抑制剂的 Sorafenib, 结构式如下，  Inhibition rate %= (Control 0D - Sample 0D) I (Control 0D - Blank 0D) X 100% The iiJ ^ product is a Sorafenib as an oral multi-kinase inhibitor developed by Bayer and ONYX in Germany. The structural formula is as follows.

Figure imgf000018_0001
Figure imgf000018_0001

随机选择的部分化合物抑制蛋白酪氨酸激酶活性结果见表 2。  The results of inhibition of protein tyrosine kinase activity by partially selected compounds are shown in Table 2.

表 2·  Table 2·

Figure imgf000018_0002
二、 体外抗肿瘤活性测试 (1) 将 MDA- MB- 231 (人乳腺癌细胞）、 Be卜 7402 (人肝癌细胞）和 A549 (人非小细胞肺癌）细胞复苏并传代 2-3次稳定后，用胰蛋白酶溶 液（0.25%)使其从培养瓶底部消化下来。 将细胞消化液倒入离心管 中而后加入培养液以终止消化。将离心管在 1300r/min下离心 3min， 轻轻弃去上清液后加入 5 mL培养液， 吹打混匀细胞， 吸取 lO uL 细 胞混悬液加入细胞计数板中计数， 调整细胞浓度为 104个 /孔。 96孔 板中除 A1孔为空白孔不加细胞外， 其余皆加入 100 uL细胞混悬液。 将 96孔板放入培养箱中培养 24 h。
Figure imgf000018_0002
Second, in vitro anti-tumor activity test (1) Resuscitate MDA-MB-231 (human breast cancer cells), Beb 7402 (human liver cancer cells) and A549 (human non-small cell lung cancer) cells and pass them for 2-3 times to stabilize with trypsin solution (0.25 %) digested from the bottom of the flask. The cell digest is poured into a centrifuge tube and the culture is added to terminate the digestion. Centrifuge the tube at 1300 r/min for 3 min, gently discard the supernatant, add 5 mL of the culture solution, mix and mix the cells, and pipette the lO uL cell suspension into the cell counting plate to adjust the cell concentration to 10 4 . / hole. In the 96-well plate, except for the A1 well, which was blank, no cells were added, and the rest were added with 100 uL of cell suspension. The 96-well plate was placed in an incubator for 24 h.

(2) 用 50 μ ΐ 二曱基亚砜溶解受试样品， 然后加入适量培养 液， 使样品溶解成 2 mg/mL药液。 然后在 24孔板中将样品稀释为 (2) Dissolve the test sample with 50 μM decyl sulfoxide, then add an appropriate amount of the culture solution to dissolve the sample into 2 mg/mL solution. Then dilute the sample to a 24-well plate

100， 20， 4， 0.8， 0.16 μ g/mL。 每个浓度加入 3孔， 其中周围两行 两列细胞长势受环境影响较大， 只作为空白细胞孔使用。 将 96孔板 ^^培养箱中培养 72h。 100, 20, 4, 0.8, 0.16 μg/mL. Each concentration was added to 3 wells, and the growth of the surrounding two rows and two columns was greatly affected by the environment and was only used as a blank cell well. The cells were cultured in a 96-well plate for 72 hours.

(3) 将 96孔板中带药培养液弃去，用磷酸緩冲溶液 (PBS)将细胞 冲洗两遍， 在每孑 Li中加入 MTT (四氮唑）（0.5 mg/mL) lOOuL^b 培 养箱中 4 h后， 弃去 MTT溶液， 加入二曱基亚砜 100 uL。 在磁力振 荡器上振荡使存活细胞与 MTT反应产物曱臜充分溶解，放入酶标仪中 测定结果， 通过 Bliss法可求出药物 IC5。值。 (3) Discard the drug-containing medium in the 96-well plate, rinse the cells twice with phosphate buffer solution (PBS), and add MTT (tetrazole) (0.5 mg/mL) per 孑Li. lOOuL^b After 4 h in the incubator, the MTT solution was discarded and 100 uL of dimethyl sulfoxide was added. The magnetic oscillator was shaken to completely dissolve the viable cells and the MTT reaction product, and the results were measured in a microplate reader. The drug IC 5 was obtained by the Bliss method. value.

化合物的体外抗肿瘤细胞活性结果见表 3。 实施例化合物体外抗肿瘤活性  The in vitro antitumor cell activity of the compounds is shown in Table 3. Example compounds in vitro antitumor activity

IC50 ^g/mL) IC 50 ^g/mL)

化合物  Compound

MDA- MB- 231 Be卜 7402 实施例 1 0.009 1  MDA- MB- 231 Be Bu 7402 Example 1 0.009 1

实施例 2 0.48 1  Example 2 0.48 1

实施例 3 1.22 1.2  Example 3 1.22 1.2

实施例 4 0.62 1  Example 4 0.62 1

实施例 5 0.81 1  Example 5 0.81 1

实施例 6 0.42 1 实施例 7 0. 66 1. 1 实施例 8 0. 53 0. 3 实施例 9 1. 22 1. 5 实施例 10 0. 91 1 实施例 11 0. 83 1 实施例 12 1. 6 0. 90 实施例 13 0. 98 1. 1 实施例 15 0. 93 0. 88 实施例 16 0. 46 1 实施例 17 0. 94 0. 86 实施例 19 0. 83 1. 1 实施例 20 1. 0 1 实施例 22 0. 92 1 实施例 26 1. 1 1 索拉非尼 1. 1 1. 6 注： /表示未测活性。 Example 6 0.42 1 Example 7 0. 66 1. 1 Example 8 0. 53 0. 3 Example 9 1. 22 1. 5 Example 10 0. 91 1 Example 11 0. 83 1 Example 12 1. 6 0. 90 Example 13 0. 98 1. 1 Example 15 0. 93 0. 88 Example 16 0. 46 1 Example 17 0. 94 0. 86 Example 19 0. 83 1. 1 Example 20 1. 0 1 Example 22 0. 92 1 Example 26 1. 1 1 Sorafenib 1. 1 1. 6 Note: / indicates untested activity.

从上述试验结果可以清楚地看出，本发明所要保护的通式 I的化 合物，具有优异的受体蛋白酪氨酸激酶抑制活性和抗癌活性。 因此本 发明的化合物具有艮好的工业应用前景。  As is apparent from the above test results, the compound of the formula I to be protected by the present invention has excellent receptor protein tyrosine kinase inhibitory activity and anticancer activity. Therefore, the compounds of the present invention have a good industrial application prospect.

Claims

权 利 要 求 Rights request 1、 通式 I的衍生物或其药学上可接受的盐，
Figure imgf000021_0001
其中， A derivative of formula I or a pharmaceutically acceptable salt thereof,
Figure imgf000021_0001
among them, 人！^为苯基、 萘基或 5-10元杂芳基， 所述杂芳基含有 1-3个选自 0、 N和 S的杂原子， 且人^任选 3个 ^取代；  people! ^ is phenyl, naphthyl or 5-10 membered heteroaryl, the heteroaryl containing 1-3 heteroatoms selected from 0, N and S, and optionally 3 substituents; Ar2为苯基、 萘基或 5-10元杂芳基， 所述杂芳基含有 1-3个选自 0、 Ν和 S的杂原子， 且 Ar2任选 1- 3个 R2取代； Ar 2 is a phenyl group, a naphthyl group or a 5-10 membered heteroaryl group, the heteroaryl group having 1 to 3 hetero atoms selected from the group consisting of 0, fluorene and S, and Ar 2 optionally having 1 to 3 R 2 substituents ; n为 0-4之间的整数；  n is an integer between 0 and 4; X为氢、 d- C4烷基和 d- C4烷氧基； X is hydrogen, d-C 4 alkyl and d-C 4 alkoxy; 为氢、 卤素、 三氟曱基、 三氟曱氧基、 羟基、 ^&、 硝基、 氰 基、 （C「 C4)烷基、 （C「 C4)烷氧基、 N- (C「 C4)烷基 J^、 N, N-二（C「 C4) 烷基 J^、 （d- C4)烷基硫基、 （d- C4)烷基亚磺酰基、 （d- C4)烷基磺酰 基、 （d- C4)烷氧基曱基、 （d- C4)烷氧基乙基、 （d- C4)烷基酰基、氨基 曱酰基、 N— (d— C4)烷基 ^曱酰基、 N, N—二（d— C4)烷基 ^曱酰基、 ^磺酰基、 N- (d- C4)烷基 ^磺酰基、 N, N-二（^- C4烷基 ^磺酰 基、 d- C3亚烷基二氧基； Is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, ^&, nitro, cyano, (C "C 4 ) alkyl, (C "C 4 ) alkoxy, N- (C "C 4 )alkyl J^, N, N-di(C"C 4 ) alkyl J^, (d-C 4 )alkylthio, (d-C 4 )alkylsulfinyl, (d - C 4 ) alkylsulfonyl, (d-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d-C 4 )alkyl acyl, aminodecanoyl, N— ( D—C 4 )alkyl-decanoyl, N,N-di(d-C 4 )alkyl-decanoyl, ^sulfonyl, N-(d-C 4 )alkylsulfonyl, N, N- Di(^-C 4 alkylsulfonyl, d-C 3 alkylenedioxy; R2为氢、三氟曱基、三氟曱氧基、氨基、羟基、羧基、氰基、 (C -C4) 烷基、 （d- C4)烷！ L &、 N- (d- C4)烷基 ·½、 N, N-二（d- C4)烷基 J^、 (C「 C4)烷^ ¾基、 （C「 C4)烷基亚磺酰基、 （d- C4)烷基磺酰基、 (C -C4) 烷氧基曱基、 （d- C4)烷氧基乙基、 （d- C4)烷基酰基、 氨基曱酰基、 N- (d- C4)烷基 ^曱酰基、 N, N-二（d- C4)烷基 ^曱酰基、 ^磺 酰基、 N- (d- C4)烷基 ^磺酰基、 N, N-二（d- C4)烷基 ^磺酰基、 d- C3亚烷基二氧基； R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-C 4 )alkyl, (d-C 4 ) alkane! L &, N-(d-C 4 )alkyl·1⁄2, N,N-di(d-C 4 )alkyl J^, (C"C 4 ) alkane, (C"C 4 ) alkane a sulfinyl group, a (d-C 4 )alkylsulfonyl group, a (C-C 4 ) alkoxyfluorenyl group, a (d-C 4 ) alkoxyethyl group, a (d-C 4 )alkyl acyl group, Aminodecanoyl, N-(d-C 4 )alkyl decanoyl, N,N-di(d-C 4 )alkyl decanoyl, ^sulfonyl, N-(d-C 4 )alkyl^ Sulfonyl, N,N-di(d-C 4 )alkylsulfonyl, d-C 3 alkylenedioxy; 限制条件为： 当 Ar2为苯基时， η不为 0。 The limiting conditions are: When Ar 2 is a phenyl group, η is not zero. 2、 权利要求 1的通式 I的衍生物， 或其药学上可接受的盐， 2. A derivative of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, 其中，  among them, 人^为苯基或 5- 10元杂芳基，所述杂芳基含有 1-3个选自 0、 Ν和 S的杂原子， 且 ΑΓι任选 1- 3个 ^取代； The human ^ is a phenyl group or a 5- to 10-membered heteroaryl group, the heteroaryl group having 1-3 hetero atoms selected from the group consisting of 0, fluorene and S, and Α Γι optionally 1-1-3 ^; Ar2为苯基或 5-10元杂芳基， 所述杂芳基含有 1-3个选自 0、 N 和 S的杂原子， 且 Ar2任选 1- 3个 R2取代； n为 0-4之间的整数； Ar 2 is a phenyl group or a 5-10 membered heteroaryl group, the heteroaryl group contains 1-3 hetero atoms selected from 0, N and S, and Ar 2 is optionally substituted with 1 to 3 R 2 ; n is an integer between 0 and 4; X为氢；  X is hydrogen; 为氢、 卤素、 三氟曱基、 三氟曱氧基、 羟基、 ^&、 硝基、 氰 基、 （C「 C4)烷基、 （C「 C4)烷氧基、 N- (C「 C4)烷基 J^、 N, N-二（C「 C4) 烷基 J^、 （d- C4)烷基硫基、 （d- C4)烷基亚磺酰基、 （d- C4)烷基磺酰 基、 （d- C4)烷氧基曱基、 （d- C4)烷氧基乙基、 （d- c4)烷基酰基、氨基 曱酰基、 N- (d- C4)烷基 ^曱酰基、 N, N-二（d- C4)烷基 ^曱酰基、 ^磺酰基、 N- (d- C4)烷基 ^磺酰基、 N, N-二（^- C4烷基 ^磺酰 基、 d- C3亚烷基二氧基； Is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, ^&, nitro, cyano, (C "C 4 ) alkyl, (C "C 4 ) alkoxy, N- (C "C 4 )alkyl J^, N, N-di(C"C 4 ) alkyl J^, (d-C 4 )alkylthio, (d-C 4 )alkylsulfinyl, (d - C 4 ) alkylsulfonyl, (d-C 4 ) alkoxyfluorenyl, (d-C 4 )alkoxyethyl, (d- c 4 )alkyl acyl, aminodecanoyl, N- ( D-C 4 )alkyl-nonanoyl, N,N-di(d-C 4 )alkyl-decanoyl, ^sulfonyl, N-(d-C 4 )alkylsulfonyl, N, N- Di(^-C 4 alkylsulfonyl, d-C 3 alkylenedioxy; R2为氢、三氟曱基、三氟曱氧基、氨基、羟基、羧基、氰基、 (C -C4) 烷基、 （d- C4)烷！ L &、 N- (d- C4)烷基 ·½、 N, N-二（d- C4)烷基 J^、 (C「 C4)烷^ ¾基、 （C「 C4)烷基亚磺酰基、 （d- C4)烷基磺酰基、 (C -C4) 烷氧基曱基、 （d- C4)烷氧基乙基、 （d- C4)烷基酰基、 氨基曱酰基、 N- (d- C4)烷基 ^曱酰基、 N, N-二（d- C4)烷基 ^曱酰基、 ^磺 酰基、 N- (C「 C4)烷基 ^磺酰基、 N, N-二（C「 C4)烷基 ^磺酰基、 d- C3亚烷基二氧基。 R 2 is hydrogen, trifluoromethyl, trifluoromethoxy, amino, hydroxy, carboxy, cyano, (C-C 4 )alkyl, (d-C 4 ) alkane! L &, N-(d-C 4 )alkyl·1⁄2, N,N-di(d-C 4 )alkyl J^, (C"C 4 ) alkane, (C"C 4 ) alkane a sulfinyl group, a (d-C 4 )alkylsulfonyl group, a (C-C 4 ) alkoxyfluorenyl group, a (d-C 4 ) alkoxyethyl group, a (d-C 4 )alkyl acyl group, Aminodecanoyl, N-(d-C 4 )alkyl decanoyl, N,N-di(d-C 4 )alkyl decanoyl, ^sulfonyl, N-(C"C 4 )alkyl^ sulfonyl, N, N- di (C "C 4) alkyl ^ alkylsulfonyl, d- C 3 alkylenedioxy group. 3、 权利要求 2的通式 I的衍生物， 或其药学上可接受的盐， 3. A derivative of formula I according to claim 2, or a pharmaceutically acceptable salt thereof, 其中，  among them, 人^为苯基， 且 ΑΓι任选 1- 3个 ^取代； The person ^ is phenyl, and Α Γι is optionally substituted with 1 - 3 ^; Ar2为 5-6元杂芳基， 所述杂芳基含有 1-3个选自 0、 N和 S的杂 原子， 且 Ar2任选 1- 3个 R2取代。 Ar 2 is a 5-6 membered heteroaryl group, the heteroaryl group contains 1-3 heteroatoms selected from 0, N and S, and Ar 2 is optionally substituted with 1 to 3 R 2 . 4、 权利要求 3的通式 I的衍生物， 或其药学上可接受的盐， 4. A derivative of formula I according to claim 3, or a pharmaceutically acceptable salt thereof, 其中，  among them, 人！^为苯基， 且 ΑΓι任选 1- 3个 ^取代； people! ^ is phenyl, and Α Γι is optionally substituted with 1 - 3 ^; Ar2为嘧啶基， 所述嘧啶基任选 1-3个 R2取代。 Ar 2 is a pyrimidinyl group, and the pyrimidinyl group is optionally substituted with 1 to 3 R 2 groups. 5、 权利要求 4的通式 I的衍生物， 或其药学上可接受的盐， 5. A derivative of formula I according to claim 4, or a pharmaceutically acceptable salt thereof, 其中，  among them, 人！^为苯基， 且 ΑΓι任选 1- 3个 ^取代； people! ^ is phenyl, and Α Γι is optionally substituted with 1 - 3 ^; Ar2为嘧啶基， 所述嘧啶基任选 1-3个 R2取代； Ar 2 is a pyrimidinyl group, and the pyrimidinyl group is optionally substituted with 1-3 R 2 ; n为 1。  n is 1. 6、 权利要求 5的通式 I的衍生物， 或其药学上可接受的盐， 其中， 6. A derivative of formula I according to claim 5, or a pharmaceutically acceptable salt thereof, among them, 人！^为苯基， 且 ΑΓι任选 1- 3个 ^取代； people! ^ is phenyl, and Α Γι is optionally substituted with 1 - 3 ^; Ar2为 2- J^- 3-三氟曱基- 6-嘧^; Ar 2 is 2-J^- 3-trifluoromethyl- 6-pyrimidine; 为氢、 卤素、 三氟曱基、 三氟曱氧基、 （d- C4)烷基、 （d- C4)烷 氧基； Is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, (d-C 4 )alkyl, (d-C 4 ) alkoxy; n为 1。  n is 1. 7、 下列通式 I的化合物， 或其药学上可接受的盐: 7. A compound of the formula I below, or a pharmaceutically acceptable salt thereof: ] L-[4- [[4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基]-： 3- (3-氯苯基)脲；  L-[4- [[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-: 3- (3- Chlorophenyl)urea; ] L-[4- [[4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基]-： 3- (3, 5-双三氟曱基苯基)脲；  L-[4- [[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-: 3- (3, 5-bistrifluoromethylphenyl)urea; ] L-[4- [[4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基]-： 3- (3-氯 -4-氟苯基)脲；  L-[4- [[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-: 3- (3- Chloro-4-fluorophenyl)urea; ] L-[4- [[4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基]-： J-(3-三氟曱基 -4-氟苯基)脲；  L-[4- [[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-ylyl] phenyl]-: J-(3- Trifluoromethyl-4-fluorophenyl)urea; ] L-[4- [[4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基]-： 3- (3-氟苯基)脲；  L-[4- [[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-: 3- (3- Fluorophenyl)urea; ] L-[4- [[4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基]-： 3- (3, 4 -二氯苯基)脲；  L-[4- [[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-: 3- (3, 4-dichlorophenyl)urea; ] L-[4- [[4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基]-： 3- (3, 5 -二氯苯基)脲；  L-[4- [[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-: 3- (3, 5-dichlorophenyl)urea; ] L-[4- [[4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基]-： 3- (3, 5 -二氟苯基)脲；  L-[4- [[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-: 3- (3, 5-difluorophenyl)urea; ] L-[4- [[4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基]-： J-(2-氟苯基)脲；  L-[4- [[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-: J-(2- Fluorophenyl)urea; ] L-[4- [[4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基]-： 3-(4-氯苯基)脲；  L-[4-[[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-: 3-(4- Chlorophenyl)urea; ] L-[4- [[4- (2-氨基- 6-三 1曱基嘧啶- -4- -基)哌嗪-〗 L-基〗曱基〗苯 基]-： 3- (3-三氟曱基苯基)脲。  L-[4- [[4-(2-Amino- 6-tris-ylpyrimidin-4-yl)piperazine-] L-yl] fluorenyl]phenyl]-: 3- (3- Trifluoromethylphenyl)urea. 8、 一种药用组合物， 包含权利要求 1-7中任何一项的衍生物或其药 学上可接受的盐作为活性成分以及药学上可接受的赋型剂。 A pharmaceutical composition comprising the derivative according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable excipient. 9、 权利要求 1-7中任何一项的衍生物或其药学上可接受的盐在制备 受体蛋白酪氨酸激酶抑制剂中的应用。 9. A derivative according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, prepared Application in receptor protein tyrosine kinase inhibitors. 10、权利要求 1-7中任何一项的衍生物或其药学上可接受的盐在制备 治疗和 /或预防各种癌症疾病的药物中的应用。 Use of a derivative according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of various cancer diseases.
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