WO2016127949A1 - Dérivé de pyrimidine utilisé comme inhibiteur agissant sur la mutation t790 - Google Patents

Dérivé de pyrimidine utilisé comme inhibiteur agissant sur la mutation t790 Download PDF

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WO2016127949A1
WO2016127949A1 PCT/CN2016/073818 CN2016073818W WO2016127949A1 WO 2016127949 A1 WO2016127949 A1 WO 2016127949A1 CN 2016073818 W CN2016073818 W CN 2016073818W WO 2016127949 A1 WO2016127949 A1 WO 2016127949A1
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branched alkyl
alkyl group
straight
substituted
compound
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王能辉
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宁波文达医药科技有限公司
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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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to kinase inhibitors, and in particular to a pyrimidine derivative as a drug resistance inhibitor due to T790M mutation.
  • EGFR Epidermal growth factor
  • tyrosine kinase Protein kinases play an important role in cell signaling. It can transfer a phosphate group from ATP or GTP to a specific amino acid residue of a functional protein, thereby triggering a series of biochemical reactions.
  • Epidermal growth factor (EGFR) is a well-studied tyrosine kinase that is highly expressed in a variety of tumors. Their expression is related to the proliferation and metastasis of cancer cells. Therefore, inhibitors targeting epidermal growth factor (EGFR) are one of the important directions in the research of antitumor drugs in recent years.
  • Gefi tinib and erlotinib which are first-generation tyrosine kinase inhibitors, are very effective reversible inhibitors for the treatment of non-small cell lung cancer, but their clinical applications are Gradually showed resistance. About 50% of them contain the T790M mutation encoded by exon 20 (Kosaka et al. CCR 2006; Balak et al. CCR 2006 and Engelmanm et al.
  • T790M mutation is the main cause of resistance to EGFR-TKIs.
  • non-ATP competitive irreversible inhibitors such as B2992, PF0299804, etc.
  • B2992, PF0299804, etc. Both anti-T790M mutations stronger than gefitinib and erlotinib were shown in both in vivo and in vitro experiments.
  • clinical trials have shown that the subsequent amplification or high expression of the T790M mutation will result in resistance to these irreversible inhibitors.
  • due to their limited pharmacokinetic properties they are clinically difficult to achieve the concentration required to inhibit T790M mutations.
  • the object of the present invention is to provide a highly potent and highly selective drug capable of combating T790M mutation, which can be used as an irreversible inhibitor with better efficacy and selectivity, and can resist drug resistance caused by T790M mutation. Reduce the side effects caused by inhibition of wild-type EGFR.
  • a pyrimidine derivative having a structure as shown in formula I, and a pharmaceutically acceptable salt thereof:
  • X is H, F, Cl
  • Y is N or CH
  • R 1 is a C 1 -C 8 linear or branched alkyl group, or a substituted C 1 -C 8 straight or branched alkyl group;
  • R 2 is a C 1 -C 8 straight or branched alkyl group, a C 1 -C 8 straight or branched alkoxy group, a substituted C 1 -C 8 straight or branched alkyl group, or a substituted C 1 -C 8 linear or branched alkoxy;
  • R 3 is H, F, Cl, Br, I, C 1 -C 8 linear or branched alkyl, or substituted C 1 -C 8 straight or branched alkyl;
  • R 5 is a C 1 -C 8 linear or branched alkyl group, a substituted C 1 -C 8 straight or branched alkyl group;
  • R 5 and R 6 are connected to form a ring
  • n 1, 2, 3, 4 or 0;
  • each substitution means that one or more H groups on the alkyl group are substituted with a substituent selected from the group consisting of F, Cl, Br, I, and a hydroxyl group.
  • R 5 is bonded to R 6 to form a 5- to 9-membered ring, preferably a 6-membered ring.
  • R 5 and R 6 are bonded to form a ring, R 5 , R 6 and the N and Y respectively bonded thereto and the C atom between the N and Y form a 5- to 9-membered ring.
  • R 5 and R 6 are not bonded to form a ring.
  • R 5 and R 6 are bonded to form a ring.
  • R 5 and R 6 are bonded to form a ring.
  • R 4 is N(R 8 )R 9
  • R 8 is a C 1 -C 8 linear or branched alkyl group
  • R 9 is a C 1 -C 8 linear or branched alkyl group, a substituted C 1 -C 8 straight or branched alkyl group, wherein R 7 is a C 1 -C 8 linear or branched alkyl group, a substituted C 1 -C 8 linear or branched alkyl group.
  • R 1 is a C 1 -C 6 linear or branched alkyl group, or a substituted C 1 -C 6 linear or branched alkyl group.
  • R 7 is a C 1 -C 4 linear or branched alkyl group, substituted C 1 -C 4 straight or branched alkyl.
  • R 5 is a C 1 -C 4 linear or branched alkyl group.
  • R 6 is a C 1 -C 4 straight or branched alkyl group.
  • n 1 or 2.
  • X is F, or Cl.
  • R 2 is a C 1 -C 4 linear or branched alkyl group, or a substituted C 1 -C 4 linear or branched alkyl group.
  • R 2 is an F-substituted C 1 -C 4 straight or branched alkyl group.
  • R 2 is -CF 3 .
  • the pyrimidine derivative is selected from the group consisting of
  • the pharmaceutically acceptable salt is selected from the group consisting of: hydrofluoride, hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, triflate, Benzene sulfonate, naphthalene sulfonate, acetate, trifluoroacetate, malate, oxalate, maleate, salicylate.
  • the process comprises the step of reacting a compound of formula VI with a compound of formula VII to form a compound of formula I.
  • the synthesis of the compound of formula VII comprises the steps of:
  • a compound of the first aspect of the invention or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament
  • EGFR epidermal growth factor receptor
  • the tumor is a drug resistant tumor caused by a T190M mutation.
  • the EGFR is a T190M mutant EGFR.
  • the tumor is selected from the group consisting of liver cancer, lung cancer (including mediastinal cancer), oral epithelial cancer, nasopharyngeal cancer, thyroid cancer, esophageal cancer, lymphoma, chest cancer, digestive tract cancer, pancreatic cancer, intestinal cancer, breast cancer, ovarian cancer. , uterine cancer, kidney cancer, gallbladder cancer, cholangiocarcinoma, central nervous system cancer, testicular cancer, bladder cancer, prostate cancer, skin cancer, melanoma, meat cancer, brain cancer, blood cancer (leukemia), cervical cancer, glioma, Gastric cancer, or ascites.
  • the tumor is non-small cell lung cancer.
  • a pharmaceutical composition comprising:
  • Gefitinib and/or Erlotinib are also included in the pharmaceutical composition.
  • a method for non-therapeutic inhibition of EGFR in vitro comprising the steps of: contacting a compound of the first aspect of the invention with the EGFR, thereby inhibiting the activity of the EGFR .
  • the EGFR is a T190M mutant EGFR.
  • a method of treating or preventing a tumor comprising the steps of: administering to a tumor patient a therapeutically or prophylactically effective amount of a compound of the first aspect of the invention or a fourth aspect of the invention Said pharmaceutical composition.
  • the tumor is a drug resistant tumor caused by a T190M mutation.
  • the pyrimidine derivative of the present invention which is used as a kinase inhibitor, has the characteristics of high pharmacological action and high selectivity, and can overcome the resistance caused by the T790 mutation and counteract the T790M mutation.
  • the inventors of the present application have extensively and intensively studied, and for the first time, unexpectedly developed a novel pyrimidine derivative having the structure shown in Formula I, which is used as a kinase inhibitor with high pharmacological efficiency and high selectivity, and can be overcome. Resistance to T790 mutations against T790M mutations. On the basis of this, the present invention has been completed.
  • alkyl means a saturated linear or branched hydrocarbon moiety, such as -CH 3 or -CH (CH 3) 2.
  • alkylene denotes -C n H 2n - is a linear or branched divalent organic functional group, wherein n is 1-8, may be 1-6, or 1-4, such as sodium Methyl-CH 2 -, ethylene-CH 2 CH 2 -, and the like.
  • alkoxy means -O- (C1-8 alkyl) group, such as -OCH 3, -OCH 2 CH 3.
  • alkoxy means -O- (C1-8 alkylene) group, such as -OCH 2 -, - OCH 2 CH 2 -.
  • alkyl, alkylene, alkoxy, and alkyleneoxy groups described herein include both substituted and unsubstituted groups.
  • Possible substituents on alkyl, alkylene, alkoxy and alkyleneoxy groups include, but are not limited to, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl , C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C10 alkoxy, aryl, heteroaryl, heteroaryloxy, amino, C1-C10 alkyl Amino, C1-C20 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfamoyl, arylsulfamoyl, C1-C10 alkylimino, C1-C10 alkyl sul
  • substitution means substitution by one or more substituents.
  • substitution means that one or more hydrogens are substituted with a substituent selected from the group consisting of halogen, alkyl, alkylene, alkoxy, alkyleneoxy, alkenyl, alkynyl, cycloalkyl, Heterocycloalkyl, aryl, heteroaryl, and amino.
  • substituted means that one or more hydrogens are substituted by a substituent selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C10 alkoxy, aryl, heteroaryl, heteroaryloxy, amino, C1-C10 alkylamino, C1-C20 dialkyl Amino, arylamino, diarylamino, C1-C10 alkylsulfamoyl, arylsulfamoyl, C1-C10 alkylimino, C1-C10 alkylsulfoimino, arylsulfonimido , hydroxy, halogen, fluorenyl, C1-C10 alkyl, C2-C10 alken
  • alkynyl denotes a straight-chain or branched-chain hydrocarbyl moiety containing at least one triple bond, such as -C ⁇ C-CH 3.
  • cycloalkyl denotes a saturated cyclic hydrocarbyl moiety, such as cyclohexyl.
  • heterocycloalkyl denotes a saturated cyclic moiety comprising at least one ring heteroatom (eg, N, O or S), for example 4-tetrahydropyranyl.
  • aryl refers to a hydrocarbyl moiety containing one or more aromatic rings. Examples of the aryl moiety include phenyl (Ph), naphthyl, anthryl, fluorenyl and phenanthryl.
  • heteroaryl denotes a moiety comprising one or more aromatic rings having at least one heteroatom (eg, N, O or S).
  • heteroaryl moiety examples include furyl, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolinyl and anthracene. ⁇ .
  • amino means -NH 2 , -NH-(C 1-6 alkyl) or -N(C 1-6 alkyl) 2 .
  • the pharmaceutically acceptable salts of the present invention may be salts of anions with a positively charged group on the compound of formula I.
  • Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fuma Acid, glutamate, glucuronide, lactate, glutarate and maleate.
  • a salt can be formed from a cation with a negatively charged group (e.g., a carboxylate) on a compound of formula I.
  • Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium ions, such as tetramethylammonium ions.
  • pharmaceutically acceptable salt refers to a salt formed from an acid selected from the group consisting of hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, Salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, tartaric acid, succinic acid, oxalic acid, malic acid, glutamic acid.
  • X is H, F, Cl
  • Y is -N- or -CH-
  • R 1 is a C 1 -C 8 linear or branched alkyl group, or a substituted C 1 -C 8 straight or branched alkyl group;
  • R 2 is a C 1 -C 8 straight or branched alkyl group, a C 1 -C 8 straight or branched alkoxy group, a substituted C 1 -C 8 straight or branched alkyl group, or a substituted C 1 -C 8 linear or branched alkoxy;
  • R 3 is H, F, Cl, Br, I, C 1 -C 8 linear or branched alkyl, or substituted C 1 -C 8 straight or branched alkyl;
  • R 5 is a C 1 -C 8 linear or branched alkyl group, a substituted C 1 -C 8 straight or branched alkyl group;
  • R 5 and R 6 are connected to form a ring
  • n 1, 2, 3, 4 or 0;
  • each substitution means that one or more H groups on the alkyl group are substituted with a substituent selected from the group consisting of F, Cl, Br, I, and a hydroxyl group.
  • the pyrimidine derivative is selected from the group consisting of
  • the pharmaceutically acceptable salt is selected from the group consisting of: hydrofluoride, hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, triflate, Benzene sulfonate, naphthalene sulfonate, acetate, trifluoroacetate, malate, oxalate, maleate, salicylate.
  • the pharmaceutically acceptable salt is selected from the group consisting of: hydrofluoride, hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, triflate, Benzene sulfonate, naphthalene sulfonate, acetate, trifluoroacetate, malate, oxalate, maleate, salicylate.
  • 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.
  • the invention also provides a preparation method of the above pyrimidine derivative:
  • the process comprises the step of reacting a compound of formula VI with a compound of formula VII to form a compound of formula I.
  • the synthesis of the compound of formula VII comprises the steps of:
  • a pyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof for use as a T790 variant inhibitor for use as a T790 variant inhibitor
  • a pyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof for use as a T790 variant inhibitor for use as a T790 variant inhibitor
  • a pyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof for use as a T790 variant inhibitor for use as a T790 variant inhibitor
  • for the preparation of a medicament for preventing and/or treating a tumor or
  • preparing a T790 variant inhibitor Agent for preparing a T790 variant inhibitor Agent.
  • the tumor is non-small cell lung cancer.
  • the pyrimidine derivative or a pharmaceutically acceptable salt thereof can be used as a kinase inhibitor or used to prepare a kinase inhibitor.
  • the kinase inhibitor is an EGFR tyrosine kinase inhibitor.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the pyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the composition contains, as an active ingredient, a pyrimidine derivative or a pharmaceutically acceptable salt thereof in a weight ratio of 0.01% to 99.95%.
  • the pharmaceutical composition preferably contains, as an active ingredient, a pyrimidine derivative or a pharmaceutically acceptable salt thereof in a weight ratio of 0.1% to 99.9%, preferably a pyrimidine derivative or a pharmaceutical thereof in a weight ratio of 0.1% to 99.5%.
  • the above acceptable salt is used as the active ingredient, and more preferably contains the active ingredient in a weight ratio of 0.5% to 95%.
  • the pharmaceutical composition comprising a therapeutically effective amount of the pyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof, can be used as a highly effective and highly selective drug for preventing and/or treating tumors, especially non-small cell lung cancer, Overcome the resistance caused by T790M against the T790M mutation.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • “compatibility” it is meant herein that the components of the composition are capable of intermingling with the active ingredients of the present invention and with respect to each other without significantly reducing the efficacy of the active ingredients.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
  • the mixture of the pyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or the like can be orally administered in the form of a tablet, a capsule, a granule, a powder or a syrup. It is administered or administered parenterally in the form of an injection.
  • the above formulations can be prepared by conventional pharmaceutical methods.
  • useful pharmaceutically acceptable carriers include excipients (e.g., saccharide derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, dextrin, and carboxymethyl Starch; cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose; gum arabic; dextran; silicate derivatives such as silicon Magnesium aluminate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc., binders such as gelatin, polyvinylpyrrolidone and polyethylene glycol, disintegration Agents (such as cellulose derivatives such as sodium carboxymethylcellulose, polyvinylpyrrolidone), lubricants (such as talc, calcium stearate, magnesium stearate, magnesium
  • a safe and effective amount of a pyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof is administered to a mammal, and a "safe and effective amount" means that the amount of the active ingredient is sufficient to significantly improve the condition without As for serious side effects.
  • the safe and effective amount is usually at least about 1 microgram per day, and in most cases no more than about 10 milligrams per kilogram of body weight.
  • the dosage is from about 1 microgram per day to about 3 milligrams per kilogram of body weight.
  • the specific dose should also consider the route of administration, the health of the patient and other factors, which are within the skill of the skilled physician.
  • the pharmaceutical compositions contain from 1 to 2000 mg of active ingredient per dose, more preferably from 10 to 200 mg of active ingredient per dose.
  • the "one dose" is a tablet.
  • pyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof may be used singly or in combination with other drugs.
  • Preferred combinations include: in combination with surgery, in combination with one or more Western medicines, in combination with Chinese herbal medicines, in combination with radiotherapy.
  • the administration route of the pharmaceutical composition of the present invention is not particularly limited, and includes, but is not limited to, oral administration, injection administration, intratumoral administration, implantation administration, intraluminal administration, anal administration, and transdermal administration.
  • Administration, internal and external application; preferred injection administration includes: intravenous injection, intramuscular injection, subcutaneous injection, intraluminal injection, intratumoral administration.
  • the present invention provides a novel structure of a pyrimidine derivative as a kinase inhibitor
  • the pyrimidine derivative of the present invention has high drug efficiency and high selectivity
  • the pyrimidine derivative of the present invention can overcome the resistance caused by T790M.
  • EtOAc EtOAc
  • the present inventors prepared the compound aj by using the method of Example 1 using intermediates carrying different R 1 -R 6 substituents, according to the method disclosed in the above examples, combined with the specific structure, the prior art The person is fully capable of achieving the preparation and structural confirmation of the above compound aj.
  • the pyrimidine derivative (the compound of the present invention) of the present invention can be used for inhibiting the growth of tumor cells such as liver cancer, lung cancer, lymphoma, breast cancer, ovarian cancer, and gastric cancer. In particular, it can inhibit the growth of non-small cell lung cancer cells.
  • the results show that the compound of the present invention can be used as an efficient and highly selective prevention and / Or drugs that treat tumors, especially non-small cell lung cancer, can overcome the resistance caused by T790M against T790M mutations.
  • DMEM liquid medium GIBCO, Cat.C11995500BT
  • Fetal bovine serum FBS Hyclone, Cat.C2027050
  • Penicillin-Streptomycin GIBCO, Cat.15070063
  • RAININ 12-row gun Cat. 2-20 ⁇ l LTS, 20-200 ⁇ l LTS
  • a corresponding volume of DMSO was added to the reagent bottle according to the mass and molecular weight identified by each compound, and the mixture was shaken and mixed to prepare a 25 mM stock solution.
  • the detection reagent establishes a screening method for adherent cell proliferation inhibition.
  • Human lung cancer cell line was treated with RPIM-1640 (NCI-H1975 cells, ATCC) or DMEM (A431 cells, ATCC) liquid medium plus 10% fetal bovine serum (FBS) and 100 units/ml penicillin and 0.1 mg/ml streptomycin.
  • the cells were cultured in a cell culture incubator (37 ° C, 5% CO 2 ).
  • the cells were digested, counted and plated in a 96-well white plate, and 195 ⁇ l of the cell suspension per well was cultured overnight at 37 °C.

Abstract

L'invention concerne un dérivé de pyrimidine s'utilisant comme inhibiteur de kinase. Le dérivé de pyrimidine selon la présente invention peut être utilisé comme inhibiteur de kinase et dans le traitement de tumeurs pharmacorésistantes induites par la mutation T790M.
PCT/CN2016/073818 2015-02-15 2016-02-15 Dérivé de pyrimidine utilisé comme inhibiteur agissant sur la mutation t790 WO2016127949A1 (fr)

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WO2012064706A1 (fr) * 2010-11-10 2012-05-18 Avila Therapeutics, Inc. Inhibiteurs d'egfr sélectifs d'un mutant et leurs utilisations
CN104860922A (zh) * 2014-02-24 2015-08-26 宁波文达医药科技有限公司 作为间变性淋巴瘤激酶抑制剂的嘧啶衍生物
CN104860921A (zh) * 2014-02-24 2015-08-26 宁波文达医药科技有限公司 作为t790变异抑制剂的嘧啶衍生物

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Publication number Priority date Publication date Assignee Title
CN110526915A (zh) * 2018-05-25 2019-12-03 首药控股(北京)有限公司 一种间变性淋巴瘤激酶抑制剂的制备方法
CN110526915B (zh) * 2018-05-25 2022-02-01 首药控股(北京)股份有限公司 一种间变性淋巴瘤激酶抑制剂的制备方法

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