WO2016127949A1 - Pyrimidine derivative as inhibitor for t790 mutation - Google Patents

Pyrimidine derivative as inhibitor for t790 mutation 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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PCT/CN2016/073818
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French (fr)
Chinese (zh)
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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

Disclosed is a pyrimidine derivative for use as a kinase inhibitor. The pyrimidine derivative of the present invention may be used as a kinase inhibitor and is used to treat because drug-resistant tumors caused by T790M mutation.

Description

作为T790变异抑制剂的嘧啶衍生物Pyrimidine derivatives as inhibitors of T790 variation 技术领域Technical field
本发明涉及激酶抑制剂，具体涉及作为由于T790M变异引起的耐药性抑制剂的一种嘧啶衍生物。The present invention relates to kinase inhibitors, and in particular to a pyrimidine derivative as a drug resistance inhibitor due to T790M mutation.
背景技术Background technique
蛋白激酶在细胞信号传导中具有重要作用。它能将磷酸基团从ATP或GTP转移到功能蛋白的特定氨基酸残基上，从而引发一系列生化反应。表皮生长因子(EGFR)是一类研究较多的酪氨酸激酶，它们在多种肿瘤中有高表达。它们的表达与癌细胞增殖，转移等现象有关。因此以表皮生长因子(EGFR)为靶点的抑制剂是近年来抗肿瘤药物研究的重要方向之一。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.
现在市场上有两类EGFR酪氨酸激酶抑制剂，可逆型和不可逆型抑制剂。作为第一代酪氨酸激酶抑制剂的吉非替尼(Gefi tinib)和厄洛替尼(Erlotinib)是非常有效的治疗非小型细胞肺癌的可逆型抑制剂，但它们在临床上的应用都逐渐地表现出耐药性。其中约50％包含由外显子20编码的T790M突变(Kosaka et al.CCR 2006；Balak et al.CCR 2006and Engelmanm et al.Science),其它突变(如D761Y,L747S,T845A)只占不到5％；另外,还有约20％包含MET肿瘤基因扩增导致的耐药,而且,其中一半也并存着T790M突变。以上研究表明,T790M突变是对EGFR-TKIs耐药的主要原因。There are currently two classes of EGFR tyrosine kinase inhibitors on the market, reversible and irreversible inhibitors. 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. Science), and other mutations (such as D761Y, L747S, T845A) account for less than 5 %; In addition, about 20% contain resistance caused by MET tumor gene amplification, and half of them also contain T790M mutation. The above studies indicate that the T790M mutation is the main cause of resistance to EGFR-TKIs.
为了克服因T790M突变导致EGFR对ATP的结合能力恢复所引起的突变,正在研发非ATP竞争性的不可逆抑制剂如B2992，PF0299804等,虽然它们能与EGFR的ATP结合口袋处的Cys797形成共价键,在体内和体外实验中均显示出强于吉非替尼和厄洛替尼的抗T790M突变作用。但是临床试验表明,随即产生的放大或高表达T790M突变将导致对这些不可逆抑制剂的耐药。另一方面,由于受限于药物代谢动力学性质,它们在临床上很难达到可以抑制T790M突变所需的浓度。In order to overcome the mutations caused by the T790M mutation leading to the recovery of EGFR binding to ATP, non-ATP competitive irreversible inhibitors such as B2992, PF0299804, etc., are being developed, although they can form a covalent bond with Cys797 at the ATP binding pocket of EGFR. Both anti-T790M mutations stronger than gefitinib and erlotinib were shown in both in vivo and in vitro experiments. However, clinical trials have shown that the subsequent amplification or high expression of the T790M mutation will result in resistance to these irreversible inhibitors. On the other hand, due to their limited pharmacokinetic properties, they are clinically difficult to achieve the concentration required to inhibit T790M mutations.
因此,尚需一种高药效、高选择性的药物来治疗T790M引起的耐药性肿瘤。Therefore, there is a need for a highly potent and highly selective drug for the treatment of drug-resistant tumors caused by T790M.
发明内容Summary of the invention
本发明的目的在于提供一种高药效、高选择性的药物，能够对抗T790M突变，其能作为具有更好药效和选择性的不可逆抑制剂,能够对抗T790M突变引起的耐药性,同时降低因抑制野生型EGFR而引起的毒副作用。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.
本发明的第一方面，提供一种嘧啶衍生物及其药学上可接受的盐，所述嘧啶衍生物的结构如下式I所示： In a first aspect of the invention, there is provided a pyrimidine derivative having a structure as shown in formula I, and a pharmaceutically acceptable salt thereof:
Figure PCTCN2016073818-appb-000001
Figure PCTCN2016073818-appb-000001
式中，In the formula,
X为H、F、Cl；X is H, F, Cl;
Y为N或CH；Y is N or CH;
R1为C1-C8直链或支链烷基、或取代的C1-C8直链或支链烷基；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;
R2为C1-C8直链或支链烷基、C1-C8直链或支链烷氧基、取代的C1-C8直链或支链烷基、或取代的C1-C8直链或支链烷氧基；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;
R3为H、F、Cl、Br、I、C1-C8直链或支链烷基、或取代的C1-C8直链或支链烷基；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;
R4为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基、或-C(＝O)R7，或R4为N(R8)R9，R8为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基、或-C(＝O)R7，R9为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基，其中R7为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基；R 4 is a C 1 -C 8 linear or branched alkyl group, a substituted C 1 -C 8 straight or branched alkyl group, or -C(=O)R 7 , or R 4 is N(R 8 ) R 9 , R 8 is a C 1 -C 8 straight or branched alkyl group, a substituted C 1 -C 8 straight or branched alkyl group, or -C(=O)R 7 , and R 9 is C 1 - C 8 straight or branched alkyl, substituted C 1 -C 8 straight or branched alkyl wherein R 7 is C 1 -C 8 straight or branched alkyl, substituted C 1 -C 8 straight Chain or branched alkyl group;
R5为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基；R 5 is a C 1 -C 8 linear or branched alkyl group, a substituted C 1 -C 8 straight or branched alkyl group;
R6为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基、或-C(＝O)R7，R7如上所述；R 6 is a C 1 -C 8 linear or branched alkyl group, a substituted C 1 -C 8 linear or branched alkyl group, or -C(=O)R 7 , and R 7 is as defined above;
或者R5与R6连接成环；Or R 5 and R 6 are connected to form a ring;
n为1、2、3、4或0；n is 1, 2, 3, 4 or 0;
其中，各取代是指烷基上的一个或多个H被选自下组的取代基取代：F、Cl、Br、I、羟基。Wherein 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.
在另一优选例中，R5与R6连接形成5-至9-元环，优选为6-元环。当R5与R6连接成环时，R5、R6及分别与其连接的N和Y以及该N和Y之间的C原子一起形成5-至9-元环。In another preferred embodiment, R 5 is bonded to R 6 to form a 5- to 9-membered ring, preferably a 6-membered ring. When 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.
在另一优选例中，当Y为-N-时，R5与R6不连接成环。In another preferred embodiment, when Y is -N-, R 5 and R 6 are not bonded to form a ring.
在另一优选例中，当Y为-N-时，R5与R6连接成环。In another preferred embodiment, when Y is -N-, R 5 and R 6 are bonded to form a ring.
在另一优选例中，当Y为-CH-时，R5与R6连接成环。In another preferred embodiment, when Y is -CH-, R 5 and R 6 are bonded to form a ring.
在另一优选例中，当Y为-CH-时，R4为N(R8)R9，R8为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基、或-C(＝O)R7，R9为C1-C8直链或支链烷基、 取代的C1-C8直链或支链烷基，其中R7为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基。In another preferred embodiment, when Y is -CH-, R 4 is N(R 8 )R 9 , R 8 is a C 1 -C 8 linear or branched alkyl group, and the substituted C 1 -C 8 is straight. a chain or branched alkyl group, or -C(=O)R 7 , 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.
在另一优选例中，R1为C1-C6直链或支链烷基、或取代的C1-C6直链或支链烷基。In another preferred embodiment, 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.
在另一优选例中，R4为C1-C4直链或支链烷基、或-C(＝O)R7，R7为C1-C4直链或支链烷基、取代的C1-C4直链或支链烷基。In another preferred embodiment, R 4 is a C 1 -C 4 linear or branched alkyl group, or -C(=O)R 7 , and R 7 is a C 1 -C 4 linear or branched alkyl group, substituted C 1 -C 4 straight or branched alkyl.
在另一优选例中，R5为C1-C4直链或支链烷基。In another preferred embodiment, R 5 is a C 1 -C 4 linear or branched alkyl group.
在另一优选例中，R6为C1-C4直链或支链烷基。In another preferred embodiment, R 6 is a C 1 -C 4 straight or branched alkyl group.
在另一优选例中，n为1或2。In another preferred embodiment, n is 1 or 2.
在另一优选例中，X为F、或Cl。In another preferred embodiment, X is F, or Cl.
在另一优选例中，R2为C1-C4直链或支链烷基、或取代的C1-C4直链或支链烷基。In another preferred embodiment, 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.
在另一优选例中，R2为F取代的C1-C4直链或支链烷基。In another preferred embodiment, R 2 is an F-substituted C 1 -C 4 straight or branched alkyl group.
在另一优选例中，R2为-CF3。In another preferred embodiment, R 2 is -CF 3 .
在另一优选例中，所述嘧啶衍生物选自：In another preferred embodiment, the pyrimidine derivative is selected from the group consisting of
Figure PCTCN2016073818-appb-000002
Figure PCTCN2016073818-appb-000002
Figure PCTCN2016073818-appb-000003
Figure PCTCN2016073818-appb-000003
Figure PCTCN2016073818-appb-000004
Figure PCTCN2016073818-appb-000004
在另一优选例中，所述药学上可接受的盐选自：氢氟酸盐、盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、甲磺酸盐、三氟甲磺酸盐、苯磺酸盐、萘磺酸盐、乙酸盐、三氟乙酸盐、苹果酸盐、草酸盐、马来酸盐、水杨酸盐。In another preferred embodiment, 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.
本发明的第二方面，提供第一方面所述的嘧啶衍生物的制备方法，According to a second aspect of the present invention, there is provided a method for producing a pyrimidine derivative according to the first aspect,
Figure PCTCN2016073818-appb-000005
Figure PCTCN2016073818-appb-000005
所述方法包括式VI化合物与式VII化合物反应生成式I化合物的步骤。 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.
在另一优选例中，所述式VII化合物的合成包括以下步骤：In another preferred embodiment, the synthesis of the compound of formula VII comprises the steps of:
Figure PCTCN2016073818-appb-000006
Figure PCTCN2016073818-appb-000006
(i)式A化合物与式B化合物反应生成式C化合物；(i) reacting a compound of formula A with a compound of formula B to form a compound of formula C;
(ii)式C化合物脱保护后与丙烯酰氯反应生成式VII化合物。(ii) The compound of formula C is deprotected and reacted with acryloyl chloride to form a compound of formula VII.
本发明的第三方面，提供了本发明第一方面所述的化合物或其药学上可接受的盐的用途，用于制备药物，所述药物：In a third aspect of the invention, there is provided the use of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament,
(i)用作表皮生长因子受体(EGFR)抑制剂；和/或(i) used as an epidermal growth factor receptor (EGFR) inhibitor; and/or
(ii)用作T790M突变的抑制剂；和/或(ii) used as an inhibitor of the T790M mutation; and/or
(iii)用于预防和/或***。(iii) for the prevention and/or treatment of tumors.
在另一优选例中，所述肿瘤为T190M突变引起的耐药性肿瘤。In another preferred embodiment, the tumor is a drug resistant tumor caused by a T190M mutation.
在另一优选例中，所述EGFR为T190M突变的EGFR。In another preferred embodiment, the EGFR is a T190M mutant EGFR.
所述肿瘤选自：肝癌、肺癌(包括纵隔癌)、口腔上皮癌、鼻咽癌、甲状腺癌、食道癌、淋巴癌、胸腔癌、消化道癌、胰腺癌、肠癌、乳腺癌、卵巢癌、子宫癌、肾癌、胆囊癌、胆管癌、中枢神经癌、睾丸癌、膀胱癌、***癌、皮肤癌、黑色素瘤、肉癌、脑癌、血癌(白血病)、***、胶质瘤、胃癌、或腹水瘤。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.
在另一优选例中，所述肿瘤为非小细胞肺癌。In another preferred embodiment, the tumor is non-small cell lung cancer.
本发明的第四方面，提供了种药物组合物，所述药物组合物包含：In a fourth aspect of the invention, there is provided a pharmaceutical composition comprising:
(i)本发明第一方面所述的嘧啶衍生物或其药学上可接受的盐；和(i) the pyrimidine derivative of the first aspect of the invention, or a pharmaceutically acceptable salt thereof;
(ii)药学上可接受的载体。(ii) a pharmaceutically acceptable carrier.
在另一优选例中，所述药物组合物中还包括吉非替尼(Gefitinib)和/或厄洛替尼(Erlotinib)。In another preferred embodiment, Gefitinib and/or Erlotinib are also included in the pharmaceutical composition.
本发明的第五方面，提供了一种体外非治疗性的抑制EGFR的方法，所述方法包括步骤：将本发明第一方面所述的化合物与所述EGFR接触，从而抑制所述EGFR的活性。 According to a fifth aspect of the invention, there is provided a method for non-therapeutic inhibition of EGFR in vitro, the method comprising the steps of: contacting a compound of the first aspect of the invention with the EGFR, thereby inhibiting the activity of the EGFR .
在另一优选例中，所述EGFR为T190M突变的EGFR。In another preferred embodiment, the EGFR is a T190M mutant EGFR.
本发明的第六方面，提供了一种治疗或预防肿瘤的方法，所述方法包括步骤：给肿瘤患者施用治疗或预防有效量的本发明第一方面所述的化合物或本发明第四方面所述的药物组合物。According to a sixth aspect of the invention, a method of treating or preventing a tumor, the method 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.
在另一优选例中，所述肿瘤为T190M突变引起的耐药性肿瘤。In another preferred embodiment, the tumor is a drug resistant tumor caused by a T190M mutation.
本发明的嘧啶衍生物，用作激酶抑制剂，具有高药效、高选择性的特点，能够克服T790突变引起的耐药性，对抗T790M突变。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.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
具体实施方式detailed description
本申请的发明人经过广泛而深入地研究，首次意外研发出一种新型的结构如式I所示的嘧啶衍生物，用作激酶抑制剂，具有高药效、高选择性的特点，能够克服T790突变引起的耐药性，对抗T790M突变。在此基础上，完成了本发明。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.
术语the term
本发明的上下文中，术语“烷基”表示饱和的线性或支链烃部分，例如-CH3或-CH(CH3)2。In the context of this invention, the term "alkyl" means a saturated linear or branched hydrocarbon moiety, such as -CH 3 or -CH (CH 3) 2.
本发明的上下文中，术语“亚烷基”表示-CnH2n-的线性或支链有机二价官能团，其中n为1-8，也可以为1-6、或1-4，如亚甲基-CH2-、亚乙基-CH2CH2-等。In the context of this invention, the term "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.
本发明的上下文中，术语“烷氧基”表示-O-(C1-8烷基)基团，如-OCH3、-OCH2CH3。In the context of this invention, the term "alkoxy" means -O- (C1-8 alkyl) group, such as -OCH 3, -OCH 2 CH 3.
本发明的上下文中，术语“亚烷氧基”表示-O-(C1-8亚烷基)基团，如-OCH2-、-OCH2CH2-。The context of the present invention, the term "alkoxy" means -O- (C1-8 alkylene) group, such as -OCH 2 -, - OCH 2 CH 2 -.
除非另外说明，本文所述的烷基、亚烷基、烷氧基和亚烷氧基同时包括取代的和未取代的基团。烷基、亚烷基、烷氧基和亚烷氧基上可能的取代基包括，但不限于：C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C10烷氧基、芳基、杂芳基、杂芳氧基、氨基、C1-C10烷基氨基、C1-C20二烷基氨基、芳基氨基、二芳基氨基、C1-C10烷基氨磺酰基、芳基氨磺酰基、C1-C10烷基亚氨基、C1-C10烷基磺基亚氨基、芳基磺基亚氨基、羟基、卤素、巯基、C1-C10烷硫基、C1-C10烷基磺酰基、芳基磺酰基、酰基氨基、氨酰基、氨基硫代酰基、胍基、脲基、氰基、硝基、酰基、硫代酰基、酰氧基、羧基和羧酸酯基。另一方面,环烷基、杂环烷基、杂环烯基、芳基和杂芳基也可互相稠合。Unless otherwise stated, 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 sulfo Amino, arylsulfoimino, hydroxy, halogen, fluorenyl, C1-C10 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, decyl, urea A group, a cyano group, a nitro group, an acyl group, a thioacyl group, an acyloxy group, a carboxyl group, and a carboxylate group. On the other hand, a cycloalkyl group, a heterocycloalkyl group, a heterocycloalkenyl group, an aryl group and a heteroaryl group may also be fused to each other.
本发明中，取代是指被一个或多个取代基取代。优选地，术语取代是指一个或多个氢被选自下组的取代基取代：卤素、烷基、亚烷基、烷氧基、亚烷氧基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、和氨基。更优选地，术语取 代是指一个或多个氢被选自下组的取代基取代：C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C10烷氧基、芳基、杂芳基、杂芳氧基、氨基、C1-C10烷基氨基、C1-C20二烷基氨基、芳基氨基、二芳基氨基、C1-C10烷基氨磺酰基、芳基氨磺酰基、C1-C10烷基亚氨基、C1-C10烷基磺基亚氨基、芳基磺基亚氨基、羟基、卤素、巯基、C1-C10烷硫基、C1-C10烷基磺酰基、芳基磺酰基、酰基氨基、氨酰基、氨基硫代酰基、胍基、脲基、氰基、硝基、酰基、硫代酰基、酰氧基、羧基和羧酸酯基。In the present invention, substitution means substitution by one or more substituents. Preferably, the term 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. More preferably, the term is taken By 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 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, decyl, ureido, cyano, nitro, An acyl group, a thioacyl group, an acyloxy group, a carboxyl group, and a carboxylate group.
术语“烯基”表示包含至少一个双键的直链或支链烃基部分，例如-CH＝CH-CH3。术语“炔基”表示包含至少一个三键的直链或支链烃基部分，例如-C≡C-CH3。术语“环烷基”表示饱和的环状烃基部分，例如环己基。术语“杂环烷基”表示包含至少一个环杂原子(例如N,O或S)的饱和的环状部分，例如4-四氢吡喃基。术语“芳基”表示包含一个或多个芳环的烃基部分。芳基部分的例子包括苯基(Ph)、萘基、芘基、蒽基和菲基。术语“杂芳基”表示包含一个或多个具有至少一个杂原子(例如N,O或S)的芳环的部分。杂芳基部分的例子包括呋喃基、芴基、吡咯基、噻吩基、噁唑基、咪唑基、噻唑基、吡啶基、嘧啶基、喹唑啉基、喹啉基、异喹啉基和吲哚基。术语“氨基”表示-NH2、-NH-(C1-6烷基)或-N(C1-6烷基)2。The term "alkenyl" denotes a straight-chain or branched-chain hydrocarbyl moiety containing at least one double bond, such as -CH = CH-CH 3. The term "alkynyl" denotes a straight-chain or branched-chain hydrocarbyl moiety containing at least one triple bond, such as -C≡C-CH 3. The term "cycloalkyl" denotes a saturated cyclic hydrocarbyl moiety, such as cyclohexyl. The term "heterocycloalkyl" denotes a saturated cyclic moiety comprising at least one ring heteroatom (eg, N, O or S), for example 4-tetrahydropyranyl. The term "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. The term "heteroaryl" denotes a moiety comprising one or more aromatic rings having at least one heteroatom (eg, N, O or S). Examples of the heteroaryl moiety include furyl, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolinyl and anthracene.哚基. The term "amino" means -NH 2 , -NH-(C 1-6 alkyl) or -N(C 1-6 alkyl) 2 .
本发明所述药学上可接受的盐可以是阴离子与式I化合物上带正电荷的基团形成的盐。合适的阴离子包括氯离子、溴离子、碘离子、硫酸根、硝酸根、磷酸根、柠檬酸根、甲基磺酸根、三氟乙酸根、乙酸根、苹果酸根、甲苯磺酸根、酒石酸根、富马酸根、谷氨酸根、葡糖醛酸根、乳酸根、戊二酸根和马来酸根。类似地，可以由阳离子与式I化合物上的带负电荷的基团(例如羧酸根)形成盐。合适的阳离子包括钠离子、钾离子、镁离子、钙离子和铵离子，例如四甲基铵离子。在另一优选例中，“药学上可接受的盐”是指同选自下述酸形成的盐类：氢氟酸、盐酸、氢溴酸、磷酸、乙酸、草酸、硫酸、甲磺酸、水杨酸、三氟甲磺酸、萘磺酸、马来酸、柠檬酸、醋酸、酒石酸、琥珀酸、酢浆草酸、苹果酸、谷氨酸。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. Similarly, 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. In another preferred embodiment, "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.
嘧啶衍生物及其药学上可接受的盐Pyrimidine derivatives and pharmaceutically acceptable salts thereof
本发明提供的嘧啶衍生物及其药学上可接受的盐结构如下式I所示： The pyrimidine derivative and its pharmaceutically acceptable salt structure provided by the present invention are as shown in the following formula I:
Figure PCTCN2016073818-appb-000007
Figure PCTCN2016073818-appb-000007
式中，In the formula,
X为H、F、Cl；X is H, F, Cl;
Y为-N-或-CH-；Y is -N- or -CH-;
R1为C1-C8直链或支链烷基、或取代的C1-C8直链或支链烷基；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;
R2为C1-C8直链或支链烷基、C1-C8直链或支链烷氧基、取代的C1-C8直链或支链烷基、或取代的C1-C8直链或支链烷氧基；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;
R3为H、F、Cl、Br、I、C1-C8直链或支链烷基、或取代的C1-C8直链或支链烷基；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;
R4为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基、或-C(＝O)R7，或R4为N(R8)R9，R8为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基、或-C(＝O)R7，R9为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基，其中R7为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基；R 4 is a C 1 -C 8 linear or branched alkyl group, a substituted C 1 -C 8 straight or branched alkyl group, or -C(=O)R 7 , or R 4 is N(R 8 ) R 9 , R 8 is a C 1 -C 8 straight or branched alkyl group, a substituted C 1 -C 8 straight or branched alkyl group, or -C(=O)R 7 , and R 9 is C 1 - C 8 straight or branched alkyl, substituted C 1 -C 8 straight or branched alkyl wherein R 7 is C 1 -C 8 straight or branched alkyl, substituted C 1 -C 8 straight Chain or branched alkyl group;
R5为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基；R 5 is a C 1 -C 8 linear or branched alkyl group, a substituted C 1 -C 8 straight or branched alkyl group;
R6为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基、或-C(＝O)R7，R7如上所述；R 6 is a C 1 -C 8 linear or branched alkyl group, a substituted C 1 -C 8 linear or branched alkyl group, or -C(=O)R 7 , and R 7 is as defined above;
或者R5与R6连接成环；Or R 5 and R 6 are connected to form a ring;
n为1、2、3、4或0；n is 1, 2, 3, 4 or 0;
其中，各取代是指烷基上的一个或多个H被选自下组的取代基取代：F、Cl、Br、I、羟基。Wherein 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.
在优选地实施方式中，所述嘧啶衍生物选自： In a preferred embodiment, the pyrimidine derivative is selected from the group consisting of
Figure PCTCN2016073818-appb-000008
Figure PCTCN2016073818-appb-000008
Figure PCTCN2016073818-appb-000009
Figure PCTCN2016073818-appb-000009
Figure PCTCN2016073818-appb-000010
Figure PCTCN2016073818-appb-000010
在另一优选例中，所述药学上可接受的盐选自：氢氟酸盐、盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、甲磺酸盐、三氟甲磺酸盐、苯磺酸盐、萘磺酸盐、乙酸盐、三氟乙酸盐、苹果酸盐、草酸盐、马来酸盐、水杨酸盐。In another preferred embodiment, 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.
在另一优选例中，所述药学上可接受的盐选自：氢氟酸盐、盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、甲磺酸盐、三氟甲磺酸盐、苯磺酸盐、萘磺酸盐、乙酸盐、三氟乙酸盐、苹果酸盐、草酸盐、马来酸盐、水杨酸盐。In another preferred embodiment, 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.
除特别说明之处，本发明的所有化合物之中，各手性碳原子(手性中心)可以任选地为R构型或S构型，或R构型和S构型的混合物。Unless otherwise specified, among all compounds of the present invention, each chiral carbon atom (chiral center) may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
制备方法Preparation
本发明还提供了上述嘧啶衍生物的制备方法：The invention also provides a preparation method of the above pyrimidine derivative:
Figure PCTCN2016073818-appb-000011
Figure PCTCN2016073818-appb-000011
所述方法包括式VI化合物与式VII化合物反应生成式I化合物的步骤。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.
在另一优选例中，所述式VII化合物的合成包括以下步骤： In another preferred embodiment, the synthesis of the compound of formula VII comprises the steps of:
Figure PCTCN2016073818-appb-000012
Figure PCTCN2016073818-appb-000012
(i)式A化合物与式B化合物反应生成式C化合物；(i) reacting a compound of formula A with a compound of formula B to form a compound of formula C;
(ii)式C化合物脱保护后形成式D化合物，式D化合物与丙烯酰氯反应生成式VII化合物。(ii) Deprotection of a compound of formula C to form a compound of formula D, which is reacted with acryloyl chloride to form a compound of formula VII.
用途use
本发明的嘧啶衍生物或其药学上可接受的盐的(i)用作T790变异抑制剂；(ii)用于制备预防和/或***的药物；或(iii)用于制备T790变异抑制剂。(i) a pyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof for use as a T790 variant inhibitor; (ii) for the preparation of a medicament for preventing and/or treating a tumor; or (iii) for preparing a T790 variant inhibitor Agent.
在另一优选例中，所述肿瘤为非小细胞肺癌。In another preferred embodiment, the tumor is non-small cell lung cancer.
在另一优选例中，所述嘧啶衍生物或其药学上可接受的盐可用作激酶抑制剂，或用于制备激酶抑制剂。在另一优选例中，所述激酶抑制剂是EGFR酪氨酸激酶抑制剂。In another preferred embodiment, the pyrimidine derivative or a pharmaceutically acceptable salt thereof can be used as a kinase inhibitor or used to prepare a kinase inhibitor. In another preferred embodiment, the kinase inhibitor is an EGFR tyrosine kinase inhibitor.
药物组合物Pharmaceutical composition
本发明提供包含本发明的嘧啶衍生物或其药学上可接受的盐和药学上可接受的载体的药物组合物。The present invention provides a pharmaceutical composition comprising the pyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
在另一优选例中，所述组合物中含有重量比为0.01％-99.95％的嘧啶衍生物或其药学上可接受的盐作为活性成分。In another preferred embodiment, 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%.
该药物组合物优选含有重量比为0.1％-99.9％的嘧啶衍生物或其药学上可接受的盐作为活性成分，较佳地，含有重量比为0.1％-99.5％的嘧啶衍生物或其药学上可接受的盐作为活性成分，更优选含有重量比为0.5％-95％的活性成分。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%.
该药物组合物，含有治疗有效量的本发明嘧啶衍生物或其药学上可接受的盐，可作为一种高效、高选择性的预防和/或***的药物，尤其是非小细胞肺癌，能够克服T790M引起的耐药性，对抗T790M突变。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.
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍 生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂
Figure PCTCN2016073818-appb-000013
润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。"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. By "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. Examples of 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), 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
Figure PCTCN2016073818-appb-000013
Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
可将本发明嘧啶衍生物或其药学上可接受的盐与可药用赋形剂、稀释剂等药学上可接受的载体的混合物以片剂、胶囊、颗粒剂、散剂或糖浆剂的形式口服给药或以注射剂的形式非口服给药。上述制剂可通过常规制药方法制备。可用的药学上可接受的载体的例子包括赋形剂(例如糖类衍生物如乳糖、蔗糖、葡萄糖、甘露糖醇和山梨糖醇；淀粉衍生物如玉米淀粉、土豆淀粉、糊精和羧甲基淀粉；纤维素衍生物如结晶纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠；***胶；右旋糖酐；硅酸盐衍生物如偏硅酸镁铝；磷酸盐衍生物如磷酸钙；碳酸盐衍生物如碳酸钙；硫酸盐衍生物如硫酸钙等)、粘合剂(例如明胶、聚乙烯吡咯烷酮和聚乙二醇)、崩解剂(例如纤维素衍生物如羧甲基纤维素钠、聚乙烯吡咯烷酮)、润滑剂(例如滑石、硬脂酸钙、硬脂酸镁、鲸蜡、硼酸、苯甲酸钠、亮氨酸)、稳定剂(对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等)、矫味剂(例如常用的甜味剂、酸味剂和香料等)、稀释剂和注射液用溶剂(例如水、乙醇和甘油等)。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. Examples of 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, cetyl, boric acid, sodium benzoate, leucine), stable Agents (methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, etc.), flavoring agents (such as commonly used sweeteners, sour agents and perfumes), diluents and solvents for injections (eg water, ethanol and glycerol) Wait).
使用药物组合物时，是将安全有效量的本发明嘧啶衍生物或其药学上可接受的盐施用于哺乳动物，“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。其中该安全有效量通常至少约1微克/天，而且在大多数情况下不超过约10毫克/千克体重。较佳地，该剂量是约1微克/天-约3毫克/千克体重。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是在熟练医师技能范围之内的。通常，药物组合物含有1-2000mg活性成分/剂，更佳地，含有10-200mg活性成分/剂。较佳地，所述的“一剂”为一个药片。When a pharmaceutical composition is used, 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. Wherein 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. Preferably, the dosage is from about 1 microgram per day to about 3 milligrams per kilogram of body weight. Of course, 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. In general, 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. Preferably, the "one dose" is a tablet.
此外，本发明嘧啶衍生物或其药学上可接受的盐可以单药使用，也可以与其它药物联合使用。优选的联合使用包括：与外科手术联合使用，与一种或多种西药联合使用，与中草药联合使用，与放射性治疗联合使用。Further, the 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.
本发明的药物组合物的给药途径没有特别限制，其中包括但并不限于：口服给药，注射给药，瘤内给药，植入给药，腔内给药，***给药，透皮给药，内外敷；优选的注射给药包括：静脉注射，肌肉注射，皮下注射，腔内注射、瘤内给药。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.
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments, may be arbitrarily combined. All of the features disclosed in the present specification can be used in combination with any of the compositions, and the various features disclosed in the specification can be replaced by any alternative feature that provides the same, equal or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equal or similar features.
本发明的有益之处在于：The invention is advantageous in that:
(1)本发明提供了一种新型结构的嘧啶衍生物作为激酶抑制剂；(1) The present invention provides a novel structure of a pyrimidine derivative as a kinase inhibitor;
(2)本发明的嘧啶衍生物具有高药效、高选择性的特点； (2) The pyrimidine derivative of the present invention has high drug efficiency and high selectivity;
(3)本发明的嘧啶衍生物能够克服T790M引起的耐药性。(3) The pyrimidine derivative of the present invention can overcome the resistance caused by T790M.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually carried out according to the conditions described in conventional conditions such as Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer. The suggested conditions. Percentages and parts are by weight unless otherwise stated.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described may be employed in the methods of the invention. The preferred embodiments and materials described herein are for illustrative purposes only.
实施例1化合物a的制备Preparation of Compound A of Example 1
Figure PCTCN2016073818-appb-000014
Figure PCTCN2016073818-appb-000014
步骤A：Step A:
Figure PCTCN2016073818-appb-000015
Figure PCTCN2016073818-appb-000015
将4-氟-2-甲氧基硝基苯(0.85g,5mmol)溶在DMF(20ml)中,添加dimethyl-piperidin-4-yl-amine(1g,7.5mmol)和K2CO3(1.5g,10mmol)。然后此 混合物在110℃搅拌24h,倒入水中。混合液用乙酸乙脂萃取(50mlx3)，浓缩得粗产品。硅胶柱层析分离纯化(EtOAc/Heptane，50-100％)得化合物1，(1.1g,78％)1HNMR(400MHz,CDCl3)7.9-8.0(m,1H),6.2-6.4(m,2H),3.9(s,3H),2.8-3.0(m,3H),2.2-2.4(m,8H),1.8-2.0(m,2H),1.5-1.6(m,2H).MS(ESI)m/z:280.0(M+H)+。4-Fluoro-2-methoxynitrobenzene (0.85 g, 5 mmol) was dissolved in DMF (20 mL), dimethyl-piperidin-4-yl-amine (1 g, 7.5 mmol) and K 2 CO 3 (1.5) g, 10 mmol). The mixture was then stirred at 110 ° C for 24 h and poured into water. The mixture was extracted with ethyl acetate (50 ml x 3) and concentrated to give crude. Separation and purification by silica gel column chromatography (EtOAc/Heptane, 50-100%), Compound (1, NMR, EtOAc, EtOAc, EtOAc, EtOAc , 3.9 (s, 3H), 2.8-3.0 (m, 3H), 2.2-2.4 (m, 8H), 1.8-2.0 (m, 2H), 1.5-1.6 (m, 2H). MS (ESI) m / z: 280.0 (M+H)+.
步骤B:Step B:
Figure PCTCN2016073818-appb-000016
Figure PCTCN2016073818-appb-000016
Pd/C(200mg,10％w)添加到化合物1(700mg，2.5mmol)在甲醇(20ml)的溶液中，在15Psi H2搅拌12h。然后把混合物过滤，浓缩得紫色固体化合物，2(650mg)，没有进行进一步的纯化，直接用于下一步反应。MS(ESI)m/z:250.0(M+H)+。Pd / C (200mg, 10% w) was added to compound 1 (700mg, 2.5mmol) in methanol (20ml) and stirred at 15Psi H 2 12h. The mixture was then filtered and concentrated to give a purple solid compound, 2 (650mg), MS (ESI) m / z: 250.0 (M+H)+.
步骤C:Step C:
Figure PCTCN2016073818-appb-000017
Figure PCTCN2016073818-appb-000017
将化合物2(1.6g,6.4mmol),t-BuONa(1.9g,20mmol), Pd2(dba)3(0.38g,0.66mmol)和Xantphos(0.39g,0.66mmol)加入到N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)氨基)苯基)丙烯酰胺(2.3g,6.6mmol)在甲苯(30ml)的溶液中。混合物在N2条件下回流2h。混合物冷却到室温后，过滤，滤液浓缩后得粗品,HPLC进一步纯化得TFA盐,a。1HNMR(400MHz,DMSO)10.3(s,1H),10.1(s,1H),9.5(s,1H),9.2(s,1H),8.5(s,1H),7.0-8.0(m,4H),6.2-6.7(m,4H),5.7-5.8(m,1H),3.8(s,3H),3.2-3.3(m,1H),2.6-2.8(m,10H),2.0-2.1(m,2H),1.6-1.8(m,2H).MS(ESI)m/z:556.2(M+H)+。Compound 2 (1.6 g, 6.4 mmol), t-BuONa (1.9 g, 20 mmol), Pd2 (dba) 3 (0.38 g, 0.66 mmol) and Xantphos (0.39 g, 0.66 mmol) were added to N-(3-( (2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (2.3 g, 6.6 mmol) in toluene (30 mL). The mixture was refluxed for 2 h under N 2 conditions. After the mixture was cooled to room temperature, it was filtered, and the filtrate was concentrated to give a crude material. 1H NMR (400MHz, DMSO) 10.3 (s, 1H), 10.1 (s, 1H), 9.5 (s, 1H), 9.2 (s, 1H), 8.5 (s, 1H), 7.0-8.0 (m, 4H), 6.2-6.7 (m, 4H), 5.7-5.8 (m, 1H), 3.8 (s, 3H), 3.2-3.3 (m, 1H), 2.6-2.8 (m, 10H), 2.0-2.1 (m, 2H) ), 1.6-1.8 (m, 2H). MS (ESI) m/z: 556.2 (M+H)+.
实施例2化合物b的制备Preparation of Compound b of Example 2
Figure PCTCN2016073818-appb-000018
Figure PCTCN2016073818-appb-000018
步骤A：Step A:
Figure PCTCN2016073818-appb-000019
Figure PCTCN2016073818-appb-000019
将4-氟-2-甲氧基硝基苯(0.85g,5mmol)溶在DMF(10ml)中,添加N-methyl-N-piperidin-4-yl-acetamide(1.2g,7.5mmol),K2CO3(1.5g,10mmol)。然后此混合物在110℃搅拌24h,倒入水中。混合液用乙酸乙脂萃取(50mlx3)， 浓缩得粗产品。硅胶柱层析分离纯化(EtOAc/Heptane，10-30％)得化合物3，(1.3g,86％)1HNMR(400MHz,CDCl3)7.8-8.0(m,1H),6.2-6.5(m,2H),3.9(s,3H),2.8-3.2(m,11H),2.0-2.2(m,2H),1.6-1.8(m,2H).MS(ESI)m/z:308.2(M+H)+。4-Fluoro-2-methoxynitrobenzene (0.85 g, 5 mmol) was dissolved in DMF (10 mL). N-methyl-N-piperidin-4-yl-acetamide (1.2 g, 7.5 mmol), K 2 CO 3 (1.5 g, 10 mmol). The mixture was then stirred at 110 ° C for 24 h and poured into water. The mixture was extracted with ethyl acetate (50 ml×3) and concentrated to give crude. Purification by silica gel column chromatography (EtOAc / EtOAc / EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH , 3.9 (s, 3H), 2.8-3.2 (m, 11H), 2.0-2.2 (m, 2H), 1.6-1.8 (m, 2H). MS (ESI) m/z: 308.2 (M+H)+ .
步骤B:Step B:
Figure PCTCN2016073818-appb-000020
Figure PCTCN2016073818-appb-000020
Pd/C(200mg,10％w)添加到化合物3(1g，3.0mmol)在甲醇(20ml)的溶液中，在15Psi H2搅拌12h。然后把混合物过滤，浓缩得紫色固体化合物，4，没有进行进一步的纯化，直接用于下一步反应。MS(ESI)m/z:278.0(M+H)+。Pd / C (200mg, 10% w) was added to compound 3 (1g, 3.0mmol) in methanol (20ml) and stirred at 15Psi H 2 12h. The mixture was then filtered and concentrated to give a purple solid compound, 4, which was used in the next step without further purification. MS (ESI) m / z: 278.0 (M+H)+.
步骤C:Step C:
Figure PCTCN2016073818-appb-000021
Figure PCTCN2016073818-appb-000021
将化合物4(0.67g,2.4mmol),t-BuONa(0.9g,10mmol), Pd2(dba)3(0.38g,0.66mmol)和Xantphos(0.39g,0.66mmol)加入到N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)氨基)苯基)丙烯酰胺(0.9g,2.5mmol)在甲苯(30ml)的溶液中。混合物在N2条件下回流2h。混合物冷却到室温后，过滤，滤液浓缩后得粗品,HPLC进一步纯化得TFA盐,b。1HNMR(400MHz,CD3OD)10.3(s,1H),8.6(s,1H),8.3(s,1H),8.1(s,1H),7.8(s,1H),7.4-7.6(m,2H),7.1-7.3(m,2H),6.2-6.6(m,4H),5.7-5.8(d,1H),3.6-3.8(m,5H),2.5-3.3(m,6H),1.5-2.0(m,7H).MS(ESI)m/z:584.2(M+H)+。Compound 4 (0.67 g, 2.4 mmol), t-BuONa (0.9 g, 10 mmol), Pd2 (dba) 3 (0.38 g, 0.66 mmol) and Xantphos (0.39 g, 0.66 mmol) were added to N-(3-( (2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (0.9 g, 2.5 mmol) in toluene (30 mL). The mixture was refluxed for 2 h under N 2 conditions. After the mixture was cooled to room temperature, it was filtered, and the filtrate was concentrated to give a crude material. 1H NMR (400MHz, CD3OD) 10.3 (s, 1H), 8.6 (s, 1H), 8.3 (s, 1H), 8.1 (s, 1H), 7.8 (s, 1H), 7.4-7.6 (m, 2H), 7.1-7.3 (m, 2H), 6.2-6.6 (m, 4H), 5.7-5.8 (d, 1H), 3.6-3.8 (m, 5H), 2.5-3.3 (m, 6H), 1.5-2.0 (m) , MS (ESI) m/z: 584.2 (M+H)+.
实施例3化合物c的制备Preparation of Compound c of Example 3
Figure PCTCN2016073818-appb-000022
Figure PCTCN2016073818-appb-000022
步骤A：Step A:
Figure PCTCN2016073818-appb-000023
Figure PCTCN2016073818-appb-000023
将4-氟-2-甲氧基硝基苯(0.85g,5mmol)溶在DMF(10ml)中,添加N,N,N’-trimethyl-ethane-1,2-diamine(0.76g,7.5mmol),K2CO3(1.5g,10mmol)。然后此混合物在110℃搅拌24h,倒入水中。混合液用乙酸乙脂萃取(50mlx3)，浓缩得粗产品。硅胶柱层析分离纯化(EtOAc/Heptane，10-100％),得化合物5.4-Fluoro-2-methoxynitrobenzene (0.85 g, 5 mmol) was dissolved in DMF (10 mL). N,N,N'-trimethyl-ethane-1,2-diamine (0.76 g, 7.5 mmol) ), K 2 CO 3 (1.5 g, 10 mmol). The mixture was then stirred at 110 ° C for 24 h and poured into water. The mixture was extracted with ethyl acetate (50 ml x 3) and concentrated to give crude. Separation and purification by silica gel column chromatography (EtOAc/Heptane, 10-100%) to give Compound 5.
1HNMR(400MHz,CDCl3)7.7(s,1H),6.2-6.3(d,2H),3.9(s,3H),3.4-3.5(m,2H),3.0(s,3H),2.5-2.6(m,2H),2.2(s,6H).MS(ESI)m/z:254.0(M+H)+。 1H NMR (400MHz, CDCl3) 7.7 (s, 1H), 6.2-6.3 (d, 2H), 3.9 (s, 3H), 3.4-3.5 (m, 2H), 3.0 (s, 3H), 2.5-2.6 (m) , 2H), 2.2 (s, 6H). MS (ESI) m/z: 254.0 (M+H)+.
步骤B:Step B:
Figure PCTCN2016073818-appb-000024
Figure PCTCN2016073818-appb-000024
Pd/C(200mg,10％w)添加到化合物5(1g，4mmol)在甲醇(20ml)的溶液中，在15Psi H2搅拌12h。然后把混合物过滤，浓缩得紫色固体化合物，6(650mg)，没有进行进一步的纯化，直接用于下一步反应。MS(ESI)m/z:224.0(M+H)+。Pd / C (200mg, 10% w) was added to compound 5 (1g, 4mmol) in methanol (20ml) and stirred at 15Psi H 2 12h. The mixture was filtered and concentrated to give a purple solid compound, 6 (650 mg), MS (ESI) m / z: 224.0 (M+H)+.
步骤C:Step C:
Figure PCTCN2016073818-appb-000025
Figure PCTCN2016073818-appb-000025
将化合物6(0.54g,2.4mmol),t-BuONa(0.9g,10mmol),Pd2(dba)3(0.38g,0.66mmol)和Xantphos(0.39g,0.66mmol)加入到N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)氨基)苯基)丙烯酰胺(0.86g,2.5mmol)在甲苯(30ml)的溶液中。混合物在N2条件下回流2h。混合物冷却到室温后，过滤，滤液浓缩后得粗品,HPLC进一步纯化得TFA盐,c。1HNMR(400MHz,DMSO)10.3(s,1H),9.8(s,1H),9.2(s,1H),8.7(s,1H),8.4(s,1H),7.0-8.0(m,4H),6.2-6.7(m,4H),5.7-5.8(m,1H),3.8(s,3H),3.6(m,2H),3.2(m,2H),2.8(m,6H),2.5(s,3H).MS(ESI)m/z:530.2(M+H)+。Compound 6 (0.54 g, 2.4 mmol), t-BuONa (0.9 g, 10 mmol), Pd2 (dba) 3 (0.38 g, 0.66 mmol) and Xantphos (0.39 g, 0.66 mmol) were added to N-(3-( (2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (0.86 g, 2.5 mmol) in toluene (30 mL). The mixture was refluxed for 2 h under N 2 conditions. After the mixture was cooled to room temperature, it was filtered, and the filtrate was evaporated to ethylamine. 1H NMR (400MHz, DMSO) 10.3 (s, 1H), 9.8 (s, 1H), 9.2 (s, 1H), 8.7 (s, 1H), 8.4 (s, 1H), 7.0-8.0 (m, 4H), 6.2-6.7 (m, 4H), 5.7-5.8 (m, 1H), 3.8 (s, 3H), 3.6 (m, 2H), 3.2 (m, 2H), 2.8 (m, 6H), 2.5 (s, MS (ESI) m/z: 530.2 (M+H)+.
实施例4化合物d的制备 Preparation of Compound d of Example 4
Figure PCTCN2016073818-appb-000026
Figure PCTCN2016073818-appb-000026
步骤A：Step A:
Figure PCTCN2016073818-appb-000027
Figure PCTCN2016073818-appb-000027
将4-氟-2-甲氧基硝基苯(0.85g,5mmol)溶在DMF(10ml)中,添加7(0.96g,7.5mmol),K2CO3(1.5g,10mmol)。然后此混合物在110℃搅拌24h,倒入水中。混合液用乙酸乙脂萃取(50mlx3)，浓缩得粗产品。硅胶柱层析分离纯化(EtOAc/Heptane，10-30％),得化合物8.2-methoxy-4-fluoro nitrobenzene (0.85g, 5mmol) was dissolved in DMF (10ml), was added 7 (0.96g, 7.5mmol), K 2 CO 3 (1.5g, 10mmol). The mixture was then stirred at 110 ° C for 24 h and poured into water. The mixture was extracted with ethyl acetate (50 ml x 3) and concentrated to give crude. Separation and purification by silica gel column chromatography (EtOAc/Heptane, 10-30%) afforded Compound 8.
1HNMR(400MHz,CDCl3)8.0(d,1H),6.2-6.4(m,2H),3.9(s,3H),3.4-3.8(m,4H),3.0(s,3H),2.9(s,3H),2.0(s,3H).MS(ESI)m/z:282.0(M+H)+。1H NMR (400MHz, CDCl3) 8.0 (d, 1H), 6.2-6.4 (m, 2H), 3.9 (s, 3H), 3.4-3.8 (m, 4H), 3.0 (s, 3H), 2.9 (s, 3H) (MS, ESI) m/z: 282.0 (M+H)+.
步骤B: Step B:
Figure PCTCN2016073818-appb-000028
Figure PCTCN2016073818-appb-000028
Pd/C(200mg,10％w)添加到化合物8(1g，4mmol)在甲醇(20ml)的溶液中，在15Psi H2搅拌12h。然后把混合物过滤，浓缩得紫色固体化合物，9(650mg)，没有进行进一步的纯化，直接用于下一步反应。MS(ESI)m/z:252.0(M+H)+。Pd / C (200mg, 10% w) was added to Compound 8 (1g, 4mmol) in methanol (20ml) and stirred at 15Psi H 2 12h. The mixture was filtered and concentrated to give a purple solid compound, 9 (650 mg), MS (ESI) m / z: 252.0 (M+H)+.
步骤C:Step C:
Figure PCTCN2016073818-appb-000029
Figure PCTCN2016073818-appb-000029
将化合物9(0.64g,2.4mmol),t-BuONa(0.9g,10mmol),Pd2(dba)3(0.38g,0.66mmol)和Xantphos(0.39g,0.66mmol)加入到N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)氨基)苯基)丙烯酰胺(0.86g,2.5mmol)在甲苯(30ml)的溶液中。混合物在N2条件下回流2h。混合物冷却到室温后，过滤，滤液浓缩后得粗品,HPLC进一步纯化得TFA盐,d。1HNMR(400MHz,DMSO)10.1(s,1H),8.6(s,1H),8.2(s,1H),8.1(s,1H),7.0-8.0(m,4H),6.0-6.7(m,4H),5.7-5.8(m,1H),3.7(s,3H),3.3(m,6H),2.6-2.8(m,4H),2.5(s,3H).MS(ESI)m/z:558.2(M+H)+。Compound 9 (0.64 g, 2.4 mmol), t-BuONa (0.9 g, 10 mmol), Pd2 (dba) 3 (0.38 g, 0.66 mmol) and Xantphos (0.39 g, 0.66 mmol) were added to N-(3-( (2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (0.86 g, 2.5 mmol) in toluene (30 mL). The mixture was refluxed for 2 h under N 2 conditions. After the mixture was cooled to room temperature, it was filtered, and the filtrate was evaporated to ethylamine. 1H NMR (400MHz, DMSO) 10.1 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (s, 1H), 7.0-8.0 (m, 4H), 6.0-6.7 (m, 4H) ), 5.7-5.8 (m, 1H), 3.7 (s, 3H), 3.3 (m, 6H), 2.6-2.8 (m, 4H), 2.5 (s, 3H). MS (ESI) m/z: 558.2 (M+H)+.
实施例5化合物e的制备 Preparation of Compound E of Example 5
Figure PCTCN2016073818-appb-000030
Figure PCTCN2016073818-appb-000030
步骤A：Step A:
Figure PCTCN2016073818-appb-000031
Figure PCTCN2016073818-appb-000031
将4-氟-2-甲氧基硝基苯(0.85g,5mmol)溶在DMF(10ml)中,添加N,N,N’-trimethyl-propane-1,3-diamine(0.87g,7.5mmol),K2CO3(1.5g,10mmol)。然后此混合物在110℃搅拌24h,倒入水中。混合液用乙酸乙脂萃取(50mlx3)，浓缩得粗产品。硅胶柱层析分离纯化(EtOAc/Heptane，10-100％),得化合物10.4-Fluoro-2-methoxynitrobenzene (0.85 g, 5 mmol) was dissolved in DMF (10 mL) and N,N,N'-trimethyl-propane-1,3-diamine (0.87 g, 7.5 mmol) was added. ), K 2 CO 3 (1.5 g, 10 mmol). The mixture was then stirred at 110 ° C for 24 h and poured into water. The mixture was extracted with ethyl acetate (50 ml x 3) and concentrated to give crude. Separation and purification by silica gel column chromatography (EtOAc/Heptane, 10-100%) afforded Compound 10.
1HNMR(400MHz,CDCl3)8.0(m,1H),6.0-6.3(m,2H),3.9(s,3H),3.4-3.5(m,2H),3.0(s,3H),2.8-3.0(m,2H),2.2(s,6H),1.7(m，2H).MS(ESI)m/z:268.0(M+H)+。1H NMR (400MHz, CDCl3) 8.0 (m, 1H), 6.0-6.3 (m, 2H), 3.9 (s, 3H), 3.4-3.5 (m, 2H), 3.0 (s, 3H), 2.8-3.0 (m) , 2H), 2.2 (s, 6H), 1.7 (m, 2H). MS (ESI) m/z: 268.0 (M+H)+.
步骤B: Step B:
Figure PCTCN2016073818-appb-000032
Figure PCTCN2016073818-appb-000032
Pd/C(200mg,10％w)添加到化合物10(1g，4mmol)在甲醇(20ml)的溶液中，在15Psi H2搅拌12h。然后把混合物过滤，浓缩得紫色固体化合物，11，没有进行进一步的纯化，直接用于下一步反应。MS(ESI)m/z:238.0(M+H)+。Pd / C (200mg, 10% w) was added to compound 10 (1g, 4mmol) in methanol (20ml) and stirred at 15Psi H 2 12h. The mixture was then filtered and concentrated to give a purple solid compound, <11> MS (ESI) m / z: 238.0 (M+H)+.
步骤C:Step C:
Figure PCTCN2016073818-appb-000033
Figure PCTCN2016073818-appb-000033
将化合物11(0.61g,2.6mmol),t-BuONa(0.9g,10mmol),Pd2(dba)3(0.38g,0.66mmol)和Xantphos(0.39g,0.66mmol)加入到N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)氨基)苯基)丙烯酰胺(0.86g,2.5mmol)在甲苯(30ml)的溶液中。混合物在N2条件下回流2h。混合物冷却到室温后，过滤，滤液浓缩后得粗品,HPLC进一步纯化得TFA盐,e。1HNMR(400MHz,CD3OD)8.3(s,1H),7.3-7.5(m,2H),7.35(m,1H),7.2(m,1H),6.9-7.0(m，2H)，6.6(m,1H),6.0-6.3(m,2H),5.6(d,1H),3.7(s,3H),3.4(m,2H),3.0(s,3H),2.9-3.0(m,2H),2.6(s,3H),1.7(m,1H).MS(ESI)m/z:544.2(M+H)+。 Compound 11 (0.61 g, 2.6 mmol), t-BuONa (0.9 g, 10 mmol), Pd2 (dba) 3 (0.38 g, 0.66 mmol) and Xantphos (0.39 g, 0.66 mmol) were added to N-(3-( (2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (0.86 g, 2.5 mmol) in toluene (30 mL). The mixture was refluxed for 2 h under N 2 conditions. After the mixture was cooled to room temperature, it was filtered, and the filtrate was evaporated to ethylamine. 1H NMR (400MHz, CD3OD) 8.3 (s, 1H), 7.3-7.5 (m, 2H), 7.35 (m, 1H), 7.2 (m, 1H), 6.9-7.0 (m, 2H), 6.6 (m, 1H) ), 6.0-6.3 (m, 2H), 5.6 (d, 1H), 3.7 (s, 3H), 3.4 (m, 2H), 3.0 (s, 3H), 2.9-3.0 (m, 2H), 2.6 ( s, 3H), 1.7 (m, 1 H). MS (ESI) m/z: 544.2 (M+H)+.
实施例6化合物f的制备Preparation of Compound F of Example 6
Figure PCTCN2016073818-appb-000034
Figure PCTCN2016073818-appb-000034
步骤A：Step A:
Figure PCTCN2016073818-appb-000035
Figure PCTCN2016073818-appb-000035
将4-氟-2-甲氧基硝基苯(0.85g,5mmol)溶在DMF(10ml)中,添加12(1g,7.5mmol),K2CO3(1.5g,10mmol)。然后此混合物在110℃搅拌24h,倒入水中。混合液用乙酸乙脂萃取(50mlx3)，浓缩得粗产品。硅胶柱层析分离纯化(EtOAc/Heptane，10-30％),得化合物13.1HNMR(400MHz,CDCl3)8.0(m,1H),6.0-6.2(m,2H),3.9(s,3H),3.2-3.7(m,4H),2.8-3.0(m,6H),2.0(s,3H),1.6-2.0(m,2H).MS(ESI)m/z:296.0(M+H)+。2-methoxy-4-fluoro nitrobenzene (0.85g, 5mmol) was dissolved in DMF (10ml) added 12 (1g, 7.5mmol), K 2 CO 3 (1.5g, 10mmol). The mixture was then stirred at 110 ° C for 24 h and poured into water. The mixture was extracted with ethyl acetate (50 ml x 3) and concentrated to give crude. Purification by silica gel column chromatography (EtOAc / EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH - 3.7 (m, 4H), 2.8-3.0 (m, 6H), 2.0 (s, 3H), 1.6-2.0 (m, 2H). MS (ESI) m/z: 296.0 (M+H)+.
步骤B: Step B:
Figure PCTCN2016073818-appb-000036
Figure PCTCN2016073818-appb-000036
Pd/C(200mg,10％w)添加到化合物13(1g，4mmol)在甲醇(20ml)的溶液中，在15Psi H2搅拌12h。然后把混合物过滤，浓缩得紫色固体化合物，14，没有进行进一步的纯化，直接用于下一步反应。MS(ESI)m/z:266.0(M+H)+。Pd / C (200mg, 10% w) was added to Compound 13 (1g, 4mmol) in methanol (20ml) and stirred at 15Psi H 2 12h. The mixture was then filtered and concentrated to give a purple solid compound, 14, which was used in the next step without further purification. MS (ESI) m / z: 266.0 (M+H)+.
步骤C:Step C:
Figure PCTCN2016073818-appb-000037
Figure PCTCN2016073818-appb-000037
将化合物14(0.7g,2.6mmol),t-BuONa(0.9g,10mmol),Pd2(dba)3(0.38g,0.66mmol)和Xantphos(0.39g,0.66mmol)加入到N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)氨基)苯基)丙烯酰胺(0.86g,2.5mmol)在甲苯(30ml)的溶液中。混合物在N2条件下回流2h。混合物冷却到室温后，过滤，滤液浓缩后得粗品,HPLC进一步纯化得TFA盐,f。1HNMR(400MHz,DMSO)10.1(s,1H),8.5(s,1H),8.2(s,1H),8.1(s,1H),7.8(m,1H),7.2-7.5(m,4H),6.0-6.5(m,4H),5.7(m,1H),3.7(s,3H),3.2-3.4(m,4H),2.7-2.9(m,6H),1.9(s,3H),1.6-1.8(m,2H).MS(ESI)m/z:572.2(M+H)+。 Compound 14 (0.7 g, 2.6 mmol), t-BuONa (0.9 g, 10 mmol), Pd2 (dba) 3 (0.38 g, 0.66 mmol) and Xantphos (0.39 g, 0.66 mmol) were added to N-(3-( (2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (0.86 g, 2.5 mmol) in toluene (30 mL). The mixture was refluxed for 2 h under N 2 conditions. After the mixture was cooled to room temperature, it was filtered, and the filtrate was evaporated to ethylamine. 1H NMR (400MHz, DMSO) 10.1 (s, 1H), 8.5 (s, 1H), 8.2 (s, 1H), 8.1 (s, 1H), 7.8 (m, 1H), 7.2-7.5 (m, 4H), 6.0-6.5 (m, 4H), 5.7 (m, 1H), 3.7 (s, 3H), 3.2-3.4 (m, 4H), 2.7-2.9 (m, 6H), 1.9 (s, 3H), 1.6- (MS, ESI) m/z: 572.2 (M+H)+.
实施例7化合物g的制备Preparation of Compound 7 of Example 7
Figure PCTCN2016073818-appb-000038
Figure PCTCN2016073818-appb-000038
步骤A：Step A:
Figure PCTCN2016073818-appb-000039
Figure PCTCN2016073818-appb-000039
[3-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-phenyl]-carbamic acid tert-butyl ester(2g,5.2mmol)溶在DCM(25ml)中,添加TFA(10ml)。然后此混合物在室温搅拌3h,浓缩得一固体。将此固体重新溶解于20ml DCM中,在冰浴中冷却,缓慢地滴加2-氟丙烯酰氯(600mg,5.5mmol).然后此混合物在室温搅拌24h,倒入水中。分离的有机相用食盐水洗涤,浓缩得一固体,硅胶柱层析分离纯化(EtOAc/Hexane，0-10％)得化合物,15.[3-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-phenyl]-carbamic acid tert-butyl ester (2 g, 5.2 mmol) was dissolved in DCM (25 ml). The mixture was then stirred at rt for 3 h and concentrated to a solid. The solid was re-dissolved in 20 mL of DCM, cooled in ice-br., and 2-fluoro acryloyl chloride (600 mg, 5.5 mmol) was slowly added dropwise. The mixture was then stirred at room temperature for 24 h and poured into water. The separated organic phase was washed with brine, EtOAc (EtOAc m.
1HNMR(400MHz,CD3OD)8.3(m,1H),7.7(m,1H),7.4(m,1H),7.1-7.3(m,3H),5.5-5.7(m,1H),5.1-5.3(m,1H).MS(ESI)m/z:361.0(M+H)+。1H NMR (400MHz, CD3OD) 8.3 (m, 1H), 7.7 (m, 1H), 7.4 (m, 1H), 7.1-7.3 (m, 3H), 5.5-5.7 (m, 1H), 5.1-5.3 (m) , 1H). MS (ESI) m/z: 361.0 (M+H)+.
步骤B Step B
Figure PCTCN2016073818-appb-000040
Figure PCTCN2016073818-appb-000040
将化合物6(0.56g,2.5mmol),t-BuONa(0.9g,10mmol),Pd2(dba)3(0.38g,0.66mmol)和Xantphos(0.39g,0.66mmol)加入到15(0.67g,2.5mmol)在甲苯(30ml)的溶液中。混合物在N2条件下回流2h。混合物冷却到室温后，过滤，滤液浓缩后得粗品,HPLC进一步纯化得TFA盐,g。1HNMR(400MHz,CD3OD)8.3(m,1H),7.0-8.0(m,6H),6.2-6.4(m,1H),5.5-6(dd,1H),5.3-5.5(dd,1H),3.9(s,3H),3.5-3.8(m,2H),3.3-3.5(m,5H),2.7(s,6H)..MS(ESI)m/z:548.2(M+H)+。Compound 6 (0.56 g, 2.5 mmol), t-BuONa (0.9 g, 10 mmol), Pd2 (dba) 3 (0.38 g, 0.66 mmol) and Xantphos (0.39 g, 0.66 mmol) were added to 15 (0.67 g, 2.5) Methyl) in a solution of toluene (30 ml). The mixture was refluxed for 2 h under N 2 conditions. After the mixture was cooled to room temperature, it was filtered, and the filtrate was evaporated to ethylamine. 1H NMR (400MHz, CD3OD) 8.3 (m, 1H), 7.0-8.0 (m, 6H), 6.2-6.4 (m, 1H), 5.5-6 (dd, 1H), 5.3-5.5 (dd, 1H), 3.9 (s, 3H), 3.5-3.8 (m, 2H), 3.3-3.5 (m, 5H), 2.7 (s, 6H): MS (ESI) m/z: 548.2 (M+H)+.
实施例8化合物h的制备Preparation of Example 8 Compound h
Figure PCTCN2016073818-appb-000041
Figure PCTCN2016073818-appb-000041
步骤A： Step A:
Figure PCTCN2016073818-appb-000042
Figure PCTCN2016073818-appb-000042
将3，4-二氟苯酚(5.0g,38mmol)和溴化四丁铵(1.3g,3.8mmol)溶于在二氯乙烷(30ml)中，再慢慢地滴加硝酸(7％)(86g,96mmol)。反应在室温下搅拌14h，加入50ml水和50ml二氯甲烷。水相再用20ml二氯甲烷提取一次。合并后的有机相用饱和盐水洗涤，Na2S04干燥和浓缩得粗产品。硅胶柱层析分离纯化(EtOAc/Hexane，0-50％)得化合物2，4、5-二氟-2-硝基苯酚(2.02g,30％)。1HNMR(400MHz,CDCl3)10.6(s,1H),7.9-8.0(m,1H),6.9-7.0(m,1H).3,4-Difluorophenol (5.0 g, 38 mmol) and tetrabutylammonium bromide (1.3 g, 3.8 mmol) were dissolved in dichloroethane (30 ml), and then slowly added nitric acid (7%). (86 g, 96 mmol). The reaction was stirred at room temperature for 14 h and 50 mL water and 50 mL dichloromethane were then. The aqueous phase was extracted once more with 20 ml of dichloromethane. The organic phase was washed with saturated brine, combined, Na 2 S0 4 dried and concentrated to give the crude product. Purification by column chromatography on silica gel (EtOAc /HEtOAc) elute 1H NMR (400MHz, CDCl3) 10.6 (s, 1H), 7.9-8.0 (m, 1H), 6.9-7.0 (m, 1H).
步骤B:Step B:
Figure PCTCN2016073818-appb-000043
Figure PCTCN2016073818-appb-000043
将4、5-二氟-2-硝基苯酚(2.02g,11.54mmol)和碳酸钾(2.39g,17.3mmol)加到DMF(10ml)和碘甲烷(1.1ml，17.3mmol)中,反应混合物在室温搅拌过夜.将混合物倒入水中，搅拌10分钟,沉淀，过滤得化合物17(1.9g,87％).1HNMR(400MHz,CDCl3)7.8-8.0(m,1H),6.8-7.0(m,1H),4.0(s,3H).4,5-Difluoro-2-nitrophenol (2.02 g, 11.54 mmol) and potassium carbonate (2.39 g, 17.3 mmol) were added to DMF (10 mL) and MeOH (1.1 mL, 17.3 mmol). After stirring overnight at room temperature, the mixture was poured into water, stirred for 10 min, and then crystallised to give compound 17 (1.9 g, 87%).1HNMR (400 MHz, CDCl3) 7.8-8.0 (m, 1H), 6.8-7.0 (m, 1H), 4.0 (s, 3H).
步骤C: Step C:
Figure PCTCN2016073818-appb-000044
Figure PCTCN2016073818-appb-000044
将化合物17(2g,10.75mmol)溶在DMF(20ml)中,添加N1,N1,N2-trimethylethane-1,2-diamine(2.2g,21.5mmol),K2CO3(3.0g,21.5mmol)。然后此混合物在110℃搅拌24h,倒入水中。固体被过滤，用水和醚冲洗,在50℃干燥得黄色固体化合物18(2.6g,90％)。1HNMR(400MHz,CDCl3)7.8-7.9(m,1H),6.2-6.4(m,1H),4.0(s,3H),3.5-3.7(m,2H),3.0-3.2(m,3H),2.6-2.7(m,2H),2.2-2.4(m,6H).MS(ESI)m/z:272.0(M+H)+。Compound 17 (2g, 10.75mmol) was dissolved in DMF (20ml), was added N1, N1, N 2 -trimethylethane- 1,2-diamine (2.2g, 21.5mmol), K 2 CO 3 (3.0g, 21.5mmol ). The mixture was then stirred at 110 ° C for 24 h and poured into water. The solid was filtered, washed with water and ethyl ether and dried and evaporated 1H NMR (400MHz, CDCl3) 7.8-7.9 (m, 1H), 6.2-6.4 (m, 1H), 4.0 (s, 3H), 3.5-3.7 (m, 2H), 3.0-3.2 (m, 3H), 2.6 - 2.7 (m, 2H), 2.2-2.4 (m, 6H). MS (ESI) m.
步骤D:Step D:
Figure PCTCN2016073818-appb-000045
Figure PCTCN2016073818-appb-000045
Pd/C(200mg,10％w)添加到化合物18(2g，7.4mmol)在甲醇(20ml)的溶液中，在15Psi H2搅拌12h。然后把混合物过滤，浓缩得紫色固体化合物19(1.7g,95％)。Pd / C (200mg, 10% w) was added to compound 18 (2g, 7.4mmol) in methanol (20ml) and stirred for 12h 15Psi H 2. The mixture was filtered and concentrated to give a purple solid compound 19 (1.7 g, 95%).
1HNMR(400MHz,CDCl3).3-6.6(m,2H),3.6(m,3H),3.0-3.2(m,2H),2.7(m,3H),2.3-2.5(m,2H),2.2(s,6H).MS(ESI)m/z:242.0(M+H)+。1H NMR (400MHz, CDCl3). 3-6.6 (m, 2H), 3.6 (m, 3H), 3.0-3.2 (m, 2H), 2.7 (m, 3H), 2.3-2.5 (m, 2H), 2.2 ( </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt;
步骤E: Step E:
Figure PCTCN2016073818-appb-000046
Figure PCTCN2016073818-appb-000046
将化合物19(1.6g,6.6mmol),t-BuONa(1.9g,20mmol),Pd2(dba)3(0.38g,0.66mmol)和Xantphos(0.39g,0.66mmol)加入到N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)氨基)苯基)丙烯酰胺(2.3g,6.6mmol)在甲苯(30ml)的溶液中。混合物在N2条件下回流2h。混合物冷却到室温后，过滤，滤液浓缩后得粗品,HPLC进一步纯化得TFA盐,h。1HNMR(400MHz,DMSO)10.2(s,1H),9.5(s,1H),9.0(s,1H),8.4(s,1H),8.3(s,1H),7.8(m,1H),7.5-7.7(m,2H),7.2-7.4(m,1H),7.1-7.2(m,1H),6.7-6.8(m,1H),6.4-6.5(m,1H),6.2-6.3(m,1H),5.7-5.8(m,1H),3.8(s,3H),3.2-3.3(m,4H),2.82(s,6H),2.81(s,3H).MS(ESI)m/z:548.0(M+H)+。Compound 19 (1.6 g, 6.6 mmol), t-BuONa (1.9 g, 20 mmol), Pd2 (dba) 3 (0.38 g, 0.66 mmol) and Xantphos (0.39 g, 0.66 mmol) were added to N-(3-( (2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (2.3 g, 6.6 mmol) in toluene (30 mL). The mixture was refluxed for 2 h under N 2 conditions. After the mixture was cooled to room temperature, it was filtered, and the filtrate was evaporated to ethylamine. 1H NMR (400MHz, DMSO) 10.2 (s, 1H), 9.5 (s, 1H), 9.0 (s, 1H), 8.4 (s, 1H), 8.3 (s, 1H), 7.8 (m, 1H), 7.5- 7.7 (m, 2H), 7.2-7.4 (m, 1H), 7.1-7.2 (m, 1H), 6.7-6.8 (m, 1H), 6.4-6.5 (m, 1H), 6.2-6.3 (m, 1H) ), 5.7-5.8 (m, 1H), 3.8 (s, 3H), 3.2-3.3 (m, 4H), 2.82 (s, 6H), 2.81 (s, 3H). MS (ESI) m/z: 548.0 (M+H)+.
实施例9化合物i的制备Preparation of Compound 9 of Example 9
Figure PCTCN2016073818-appb-000047
Figure PCTCN2016073818-appb-000047
步骤A: Step A:
Figure PCTCN2016073818-appb-000048
Figure PCTCN2016073818-appb-000048
将3-氟-4-氯苯酚(5.0g,38.4mmol)和溴化四丁铵(1.3g,3.8mmol)溶解于在二氯乙烷(30ml)中，再慢慢地滴加硝酸(7％)(86g,96mmol)。反应在室温下搅拌14h，加入50ml水和50ml二氯甲烷。水相再用20ml二氯甲烷提取一次。合并后的有机相用饱和盐水洗涤，Na2S04干燥和浓缩得粗品.硅胶柱层析分离纯化(EtOAc/Hexane,0-50％)得化合物20，4-氯-5-氟-2-硝基苯酚(3.0g,41％).1HNMR(400MHz,CDCl3)10.7(s,1H),8.2-8.4(d,1H),6.8-7.0(d,1H).3-Fluoro-4-chlorophenol (5.0 g, 38.4 mmol) and tetrabutylammonium bromide (1.3 g, 3.8 mmol) were dissolved in dichloroethane (30 ml), and then slowly added nitric acid (7) %) (86 g, 96 mmol). The reaction was stirred at room temperature for 14 h and 50 mL water and 50 mL dichloromethane were then. The aqueous phase was extracted once more with 20 ml of dichloromethane. The organic phase was washed with saturated brine, combined, Na 2 S0 4 dried and concentrated to give crude product. Purification by silica gel column chromatography (EtOAc / Hexane, 0-50%) to give Compound 20,4--chloro-5-fluoro-2- Nitrophenol (3.0 g, 41%). 1H NMR (400MHz, CDCl3) 10.7 (s, 1H), 8.2-8.4 (d, 1H), 6.8-7.0 (d, 1H).
步骤B:Step B:
Figure PCTCN2016073818-appb-000049
Figure PCTCN2016073818-appb-000049
将4-氯-5-氟-2-硝基苯酚(2.22g,11.54mmol)和K2CO3(2.39g,17.3mmol)加到DMF(10ml)和碘甲烷(1.1ml，17.3mmol)中,反应混合物在室温搅拌过夜.将混合物倒入水中，搅拌10分钟,沉淀,过滤得化合物21(2.3g,96％).1HNMR(400MHz,CDCl3)8.0-8.1(d,1H),6.8-7.0(d,1H),4.0(s,3H).4-Chloro-5-fluoro-2-nitrophenol (2.22 g, 11.54 mmol) and K 2 CO 3 (2.39 g, 17.3 mmol) were added to DMF (10 mL) and MeOH (1.1 mL, 17.3 mmol) The reaction mixture was stirred at room temperature overnight. The mixture was poured into water, and the mixture was stirred for 10 min, and then filtered to give compound 21 (2.3 g, 96%). 1H NMR (400 MHz, CDCl3) 8.0-8.1 (d, 1H), 6.8-7.0 (d, 1H), 4.0 (s, 3H).
步骤C: Step C:
Figure PCTCN2016073818-appb-000050
Figure PCTCN2016073818-appb-000050
将化合物21(2.2g,10.75mmol)溶在DMF(20ml)中,添加N1,N1,N2-trimethylethane-1,2-diamine(2.2g,21.5mmol),K2CO3(3.0g,21.5mmol)。然后此混合物在110℃搅拌24小时后,倒入水中。固体被过滤，用水和醚冲洗,在50℃干燥得黄色固体化合物22(2.8g,91.3％).1HNMR(400MHz,CDCl3)8.0(s,1H),6.5(s,1H),3.9(s,3H),3.3-3.4(m,2H),3.0(s,3H),2.5-2.6(m,2H),2.2(s,6H).MS(ESI)m/z:288.0(M+H)+。Compound 21 (2.2g, 10.75mmol) was dissolved in DMF (20ml), was added N1, N1, N 2 -trimethylethane- 1,2-diamine (2.2g, 21.5mmol), K 2 CO 3 (3.0g, 21.5 Mm). The mixture was then stirred at 110 ° C for 24 hours and poured into water. The solid was filtered, washed with water and EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 3H), 3.3-3.4 (m, 2H), 3.0 (s, 3H), 2.5-2.6 (m, 2H), 2.2 (s, 6H). MS (ESI) m/z: 288.0 (M+H)+ .
步骤D:Step D:
Figure PCTCN2016073818-appb-000051
Figure PCTCN2016073818-appb-000051
Pd/C(200mg,10％w)添加到化合22(2.1g,7.4mmol)在甲醇(20ml)的溶液中，在15Psi H2搅拌12h。然后把混合物过滤，浓缩得紫色固体化合物23(1.76g,94％)1HNMR(400MHz,CDCl3)6.6-6.7(d,2H),3.8(s,3H),3.0-3.2(m,2H),2.7(s,3H),2.4-2.6(m,2H),2.2(s,6H).MS(ESI)m/z:258.0(M+H)+。Pd / C (200mg, 10% w) was added to compound 22 (2.1g, 7.4mmol) in methanol (20ml) and stirred at 15Psi H 2 12h. The mixture was then filtered and concentrated to give a crystal crystal crystals (yield: sd, s, s, s, s, s, s, s, s, s, s, s, s, s. (s, 3H), 2.4-2.6 (m, 2H), 2.2 (s, 6H). MS (ESI) m/z: 258.0 (M+H)+.
步骤E: Step E:
Figure PCTCN2016073818-appb-000052
Figure PCTCN2016073818-appb-000052
将化合物23(1.7g,6.6mmol),t-BuONa(1.9g,20mmol),Pd2(dba)3(0.38g,0.66mmol)和Xantphos(0.39g,0.66mmol)加入到N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)氨基)苯基)丙烯酰胺(2.3g,6.6mmol)在甲苯(30ml)的溶液中。混合物在N2气氛下回流2h，混合物冷却到室温后，过滤，滤液浓缩后得粗品,HPLC进一步纯化得TFA盐,i。1HNMR(400MHz,DMSO)10.2(s,1H),9.5(s,1H),8.9(s,1H),8.3-8.4(m,2H),7.8(m,2H),7.5-7.7(m,1H),7.2-7.4(m,1H),7.1-7.2(m,1H),6.7-6.8(m,1H),6.4-6.5(m,1H),6.2-6.3(m,1H),5.7-5.8(m,1H),3.8(s,3H),3.2-3.3(m,4H),2.82(m,6H),2.7(s,3H).MS(ESI)m/z:564.0(M+H)+。Compound 23 (1.7 g, 6.6 mmol), t-BuONa (1.9 g, 20 mmol), Pd2 (dba) 3 (0.38 g, 0.66 mmol) and Xantphos (0.39 g, 0.66 mmol) were added to N-(3-( (2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (2.3 g, 6.6 mmol) in toluene (30 mL). The mixture was refluxed for 2 h under N 2 EtOAc. EtOAc was evaporated. 1H NMR (400MHz, DMSO) 10.2 (s, 1H), 9.5 (s, 1H), 8.9 (s, 1H), 8.3-8.4 (m, 2H), 7.8 (m, 2H), 7.5-7.7 (m, 1H) ), 7.2-7.4 (m, 1H), 7.1-7.2 (m, 1H), 6.7-6.8 (m, 1H), 6.4-6.5 (m, 1H), 6.2-6.3 (m, 1H), 5.7-5.8 (m, 1H), 3.8 (s, 3H), 3.2-3.3 (m, 4H), 2.82 (m, 6H), 2.7 (s, 3H). MS (ESI) m/z: 564.0 (M+H) +.
实施例10化合物j的制备Preparation of Compound j of Example 10
Figure PCTCN2016073818-appb-000053
Figure PCTCN2016073818-appb-000053
步骤A： Step A:
Figure PCTCN2016073818-appb-000054
Figure PCTCN2016073818-appb-000054
将4-氟-2-甲氧基硝基苯(0.85g,5mmol)溶在DMF(10ml)中,添加S-dimethyl-pyrrolidin-3-yl-amine(0.86g,7.5mmol),K2CO3(1.5g,10mmol)。然后此混合物在110℃搅拌24h,倒入水中。混合液用乙酸乙脂萃取(50mlx3)，浓缩得粗产品。硅胶柱层析分离纯化(EtOAc/Heptane，10-40％),得化合物24.1HNMR(400MHz,CDCl3)8.0(d,1H),5.7-6.0(m,2H),3.9(s,3H),3.5-3.6(m,2H),3.2-3.5(m,2H),2.8-3.0(m,1H),2.2-2.4(m,6H),1.8-2.0(m,2H).MS(ESI)m/z:266.0(M+H)+。4-Fluoro-2-methoxynitrobenzene (0.85 g, 5 mmol) was dissolved in DMF (10 mL). S-dimethyl-pyrrolidin-3-yl-amine (0.86 g, 7.5 mmol), K 2 CO 3 (1.5 g, 10 mmol). The mixture was then stirred at 110 ° C for 24 h and poured into water. The mixture was extracted with ethyl acetate (50 ml x 3) and concentrated to give crude. Purification by silica gel column chromatography (EtOAc/Heptane, EtOAc, EtOAc (EtOAc) EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -3.6 (m, 2H), 3.2-3.5 (m, 2H), 2.8-3.0 (m, 1H), 2.2-2.4 (m, 6H), 1.8-2.0 (m, 2H). MS (ESI) m/ z: 266.0 (M+H)+.
步骤B:Step B:
Figure PCTCN2016073818-appb-000055
Figure PCTCN2016073818-appb-000055
Pd/C(200mg,10％w)添加到化合物24(1g，4mmol)在甲醇(20ml)的溶液中，在15Psi H2搅拌12h。然后把混合物过滤，浓缩得紫色固体化合物，25，没有进行进一步的纯化，直接用于下一步反应。MS(ESI)m/z:236.0(M+H)+。步骤C: Pd/C (200 mg, 10% w) was added to a solution of Compound 24 (1 g, 4 <RTIgt ; The mixture was then filtered and concentrated to give a purple solid compound, 25, which was used in the next step without further purification. MS (ESI) m / z: 236.0 (M+H)+. Step C:
Figure PCTCN2016073818-appb-000056
Figure PCTCN2016073818-appb-000056
将化合物25(0.62g,2.6mmol),t-BuONa(0.9g,10mmol),Pd2(dba)3(0.38g,0.66mmol)和Xantphos(0.39g,0.66mmol)加入到N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)氨基)苯基)丙烯酰胺(0.86g,2.5mmol)在甲苯(30ml)的溶液中。混合物在N2条件下回流2h。混合物冷却到室温后，过滤，滤液浓缩后得粗品,HPLC进一步纯化得TFA盐,j。1HNMR(400MHz,DMSO)10.4(s,1H),10.2(s,1H),9(s,1H),8.6(s,1H),8.3(s,1H),7.2-7.7(m,5H),6.5(m,1H),6.25(m,2H),5.7(m,1H),3.4-4(m,7H),3.2(m,1H),2.8(s,62.4(m,1H),2.2(m,1H).MS(ESI)m/z:542.2(M+H)+。Compound 25 (0.62 g, 2.6 mmol), t-BuONa (0.9 g, 10 mmol), Pd2 (dba) 3 (0.38 g, 0.66 mmol) and Xantphos (0.39 g, 0.66 mmol) were added to N-(3-( (2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (0.86 g, 2.5 mmol) in toluene (30 mL). The mixture was refluxed for 2 h under N 2 conditions. After the mixture was cooled to room temperature, it was filtered, and the filtrate was concentrated to give a crude material. 1H NMR (400MHz, DMSO) 10.4 (s, 1H), 10.2 (s, 1H), 9 (s, 1H), 8.6 (s, 1H), 8.3 (s, 1H), 7.2-7.7 (m, 5H), 6.5 (m, 1H), 6.25 (m, 2H), 5.7 (m, 1H), 3.4-4 (m, 7H), 3.2 (m, 1H), 2.8 (s, 62.4 (m, 1H), 2.2 ( m, 1H). MS (ESI) m.
实施例11化合物k的制备Preparation of Compound k of Example 11
Figure PCTCN2016073818-appb-000057
Figure PCTCN2016073818-appb-000057
步骤A： Step A:
Figure PCTCN2016073818-appb-000058
Figure PCTCN2016073818-appb-000058
将4-氟-2-甲氧基硝基苯(0.85g,5mmol)溶在DMF(10ml)中,添加R-dimethyl-pyrrolidin-3-yl-amine(0.86g,7.5mmol),K2CO3(1.5g,10mmol)。然后此混合物在110℃搅拌24h,倒入水中。混合液用乙酸乙脂萃取(50mlx3)，浓缩得粗产品。硅胶柱层析分离纯化(EtOAc/Heptane，10-40％),得化合物26.1HNMR(400MHz,CDCl3)7.8-8(m,1H),5.7-6.0(m,2H),3.9(s,3H),2.6-3.6(m,5H),2.2-2.4(m,6H),1.8-2.0(m,2H).MS(ESI)m/z:266.0(M+H)+。4-Fluoro-2-methoxynitrobenzene (0.85 g, 5 mmol) was dissolved in DMF (10 mL). R-dimethyl-pyrrolidin-3-yl-amine (0.86 g, 7.5 mmol), K 2 CO 3 (1.5 g, 10 mmol). The mixture was then stirred at 110 ° C for 24 h and poured into water. The mixture was extracted with ethyl acetate (50 ml x 3) and concentrated to give crude. Purification by silica gel column chromatography (EtOAc/Heptane, EtOAc, EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH , 2.6-3.6 (m, 5H), 2.2-2.4 (m, 6H), 1.8-2.0 (m, 2H). MS (ESI) m/z: 266.0 (M+H)+.
步骤B:Step B:
Figure PCTCN2016073818-appb-000059
Figure PCTCN2016073818-appb-000059
Pd/C(200mg,10％w)添加到化合物26(1g，4mmol)在甲醇(20ml)的溶液中，在15Psi H2搅拌12h。然后把混合物过滤，浓缩得紫色固体化合物，27，没有进行进一步的纯化，直接用于下一步反应。MS(ESI)m/z:236.0(M+H)+。步骤C: Pd / C (200mg, 10% w) was added to compound 26 (1g, 4mmol) in methanol (20ml) and stirred at 15Psi H 2 12h. The mixture was then filtered and concentrated to give a purple solid compound, 27, which was used in the next step without further purification. MS (ESI) m / z: 236.0 (M+H)+. Step C:
Figure PCTCN2016073818-appb-000060
Figure PCTCN2016073818-appb-000060
将化合物27(0.58g,2.6mmol),t-BuONa(0.9g,10mmol),Pd2(dba)3(0.38g,0.66mmol)和Xantphos(0.39g,0.66mmol)加入到N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)氨基)苯基)丙烯酰胺(0.86g,2.5mmol)在甲苯(30ml)的溶液中。混合物在N2条件下回流2h。混合物冷却到室温后，过滤，滤液浓缩后得粗品,HPLC进一步纯化得TFA盐,k。1HNMR(400MHz,DMSO)10.4(s,1H),10.2(s,1H),8.9(s,1H),8.4(s,1H),8.3(s,1H),7.2-7.8(m,5H),6.5(m,1H),6.25(m,2H),5.7(m,1H),3.8(s,3H),3.2-3.8(m,5H),2.9(s,6H),2.4-2.5(m,1H),2.1-2.3(m,1H).MS(ESI)m/z:542.2(M+H)+。Compound 27 (0.58 g, 2.6 mmol), t-BuONa (0.9 g, 10 mmol), Pd2 (dba) 3 (0.38 g, 0.66 mmol) and Xantphos (0.39 g, 0.66 mmol) were added to N-(3-( (2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (0.86 g, 2.5 mmol) in toluene (30 mL). The mixture was refluxed for 2 h under N 2 conditions. After the mixture was cooled to room temperature, it was filtered, and the filtrate was concentrated to give a crude material. 1H NMR (400MHz, DMSO) 10.4 (s, 1H), 10.2 (s, 1H), 8.9 (s, 1H), 8.4 (s, 1H), 8.3 (s, 1H), 7.2-7.8 (m, 5H), 6.5 (m, 1H), 6.25 (m, 2H), 5.7 (m, 1H), 3.8 (s, 3H), 3.2-3.8 (m, 5H), 2.9 (s, 6H), 2.4-2.5 (m, 1H), 2.1-2.3 (m, 1 H). MS (ESI) m/z: 542.2 (M+H)+.
实施例12化合物l的制备Preparation of Compound 1 of Example 12
Figure PCTCN2016073818-appb-000061
Figure PCTCN2016073818-appb-000061
步骤A: Step A:
Figure PCTCN2016073818-appb-000062
Figure PCTCN2016073818-appb-000062
化合物28(4.0g,21.5mmol)溶在DMF(50ml)中,添加N1,N1,N2-trimethylethane-1,2-diamine(8.8g,86mmol)和K2CO3(12.0g,43mmol)。然后此混合物在110℃搅拌24h,倒入水中。固体被过滤，用水和醚冲洗,在50℃干燥得黄色固体化合物29(1.3g,45％).1HNMR(400MHz,CDCl3)7.8(m,1H),6.5(m,1H),4.0(s,3H),3.2-3.3(m,2H),2.8(s,3H),2.5-2.6(m,2H),2.2-2.3(m,9H).MS(ESI)m/z:267.9(M+H)+。Compound 28 (4.0g, 21.5mmol) was dissolved in DMF (50ml) were added N1, N1, N 2 -trimethylethane- 1,2-diamine (8.8g, 86mmol) and K 2 CO 3 (12.0g, 43mmol ). The mixture was then stirred at 110 ° C for 24 h and poured into water. The solid was filtered, washed with water and EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 3H), 3.2-3.3 (m, 2H), 2.8 (s, 3H), 2.5-2.6 (m, 2H), 2.2-2.3 (m, 9H). MS (ESI) m/z: 267.9 (M+H )+.
步骤B:Step B:
Figure PCTCN2016073818-appb-000063
Figure PCTCN2016073818-appb-000063
Pd/C(200mg,10％w)添加到化合物29(1.2g,4.5mmol)在甲醇(20ml)的溶液中，在15Psi H2搅拌12h。然后把混合物过滤，浓缩得紫色固体化合物30(1.0g,94％).1HNMR(400MHz,CDCl3)6.6(s,1H),6.5(s,1H),3.8(s,3H),2.8-3.0(m,2H),2.5(s,3H),2.4-2.5(m,2H),2.2-2.3(s,6H)，2.2(s，3H).MS(ESI)m/z:238.0(M+H)+。Pd / C (200mg, 10% w) was added to compound 29 (1.2g, 4.5mmol) in methanol (20ml) and stirred at 15Psi H 2 12h. The mixture was filtered and concentrated to give a purple solid compound 30 (1.0 g, 94%). 1H NMR (400 MHz, CDCl3) 6.6 (s, 1H), 6.5 (s, 1H), 3.8 (s, 3H), 2.8-3.0 ( m, 2H), 2.5 (s, 3H), 2.4-2.5 (m, 2H), 2.2-2.3 (s, 6H), 2.2 (s, 3H). MS (ESI) m/z: 238.0 (M+H )+.
步骤C: Step C:
Figure PCTCN2016073818-appb-000064
Figure PCTCN2016073818-appb-000064
将化合物30(1.0g,4.2mmol),t-BuONa(1.2g,13mmol),Pd2(dba)3(0.24g,0.42mmol)和Xantphos(0.25g,0.42mmol)加入到N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)氨基)苯基)丙烯酰胺(1.5g,4.2mmol)在甲苯(30ml)的溶液中。混合物在N2气氛下回流2h，混合物冷却到室温后，过滤,滤液浓缩后得粗品,HPLC进一步纯化得TFA盐,l.1HNMR(400MHz,DMSO)10.2(s,1H),9.5(s,1H),9.1(s,1H),8.4-8.6(m,2H),7.7-7.8(s,1H),7.6-7.7(m,1H),7.5(s,1H),7.25-7.35(m,1H),7.1-7.2(m,1H),6.8(s,1H),6.4-6.5(m,1H),6.2-6.3(m,1H),5.7-5.8(m,1H),3.8(s,3H),3.2-3.3(m,4H),2.82(m,6H),2.5(s,3H),1.9-2.0(s，3H).MS(ESI)m/z:543.9(M+H)+。Compound 30 (1.0 g, 4.2 mmol), t-BuONa (1.2 g, 13 mmol), Pd2 (dba) 3 (0.24 g, 0.42 mmol) and Xantphos (0.25 g, 0.42 mmol) were added to N-(3-( (2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (1.5 g, 4.2 mmol) in toluene (30 mL). The mixture was refluxed under an atmosphere of N 2 2h, the mixture was cooled to room temperature, filtered, the filtrate was concentrated to give a crude product, HPLC to give the TFA salt was further purified, l.1HNMR (400MHz, DMSO) 10.2 (s, 1H), 9.5 (s, 1H ), 9.1 (s, 1H), 8.4-8.6 (m, 2H), 7.7-7.8 (s, 1H), 7.6-7.7 (m, 1H), 7.5 (s, 1H), 7.25-7.35 (m, 1H) ), 7.1-7.2 (m, 1H), 6.8 (s, 1H), 6.4-6.5 (m, 1H), 6.2-6.3 (m, 1H), 5.7-5.8 (m, 1H), 3.8 (s, 3H) , (3), 2.
实施例13化合物m的制备Preparation of Compound m of Example 13
Figure PCTCN2016073818-appb-000065
Figure PCTCN2016073818-appb-000065
步骤A: Step A:
Figure PCTCN2016073818-appb-000066
Figure PCTCN2016073818-appb-000066
化合物31(15.14g,100mmol)和锌粉(19.61g,300mmol)悬浮在50ml的水中，浓HCI(37％,50ml,610mmol)被缓慢地添加到搅拌的混合物中，混合物加热至回流六小时。反应冷却到室温，添加***，和食盐。并通过硅藻土过滤，用***洗涤。滤液再用饱和盐水洗涤，MgS04干燥，过滤,浓缩得粗品。硅胶柱层析分离纯化得化合物32(7.24g，52％).Compound 31 (15.14 g, 100 mmol) and zinc powder (19.61 g, 300 mmol) were suspended in 50 ml of water, and concentrated HCI (37%, 50 ml, 610 mmol) was slowly added to the stirred mixture and the mixture was heated to reflux for six hours. The reaction was cooled to room temperature and diethyl ether and brine were added. It was filtered through celite and washed with diethyl ether. The filtrate was washed with saturated brine, dried (MgSO4), filtered and evaporated. The compound 32 (7.24 g, 52%) was obtained by silica gel column chromatography.
1HNMR(400MHz,CDCl3)7.0-7.1(m,1H),6.5-6.6(m,2H),2.5-2.6(m,2H),1.1-1.2(m,3H)。1H NMR (400 MHz, CDCl3) 7.0-7.1 (m, 1H), 6.5-6.6 (m, 2H), 2.5-2.6 (m, 2H), 1.1-1.2 (m, 3H).
步骤B:Step B:
Figure PCTCN2016073818-appb-000067
Figure PCTCN2016073818-appb-000067
化合物32(7.24g,51.6mmol)溶解在100ml的二氯甲烷中，加入溴化四丁铵(1.7g,5.2mmol)。再慢慢地滴加硝酸(7％，66ml)。反应在室温下搅拌14h，加入50ml水和50ml二氯甲烷。水相再用20ml二氯甲烷提取一次。合并后的有机相用饱和盐水洗涤，Na2S04干燥和浓缩得粗品。硅胶柱层析分离纯化(EtOAc/Hexane,0-50％)得化合物33,4-乙基-5-氟-2-硝基苯酚(5.76g,60％)。1HNMR(400MHz,CDCl3)10.7(s,1H),8.0(d,1H),6.8(d,1H),2.5-2.7(m,2H),1.2-1.3(m,3H)。Compound 32 (7.24 g, 51.6 mmol) was dissolved in 100 mL of dichloromethane and tetrabutylammonium bromide (1.7 g, 5.2 mmol). Nitric acid (7%, 66 ml) was slowly added dropwise. The reaction was stirred at room temperature for 14 h and 50 mL water and 50 mL dichloromethane were then. The aqueous phase was extracted once more with 20 ml of dichloromethane. The organic phase was washed with saturated brine, combined, dried Na 2 S0 4 and concentrated to obtain a crude product. Purification by silica gel column chromatography (EtOAc /HEtOAc) 1H NMR (400MHz, CDCl3) 10.7 (s, 1H), 8.0 (d, 1H), 6.8 (d, 1H), 2.5-2.7 (m, 2H), 1.2-1.3 (m, 3H).
步骤C:Step C:
Figure PCTCN2016073818-appb-000068
Figure PCTCN2016073818-appb-000068
将4-乙基-5-氟-2-硝基苯酚,33(5.72g,30.9mmol)和K2CO3 (6.4g,46.4mmol)加到DMF(60ml)和碘甲烷(2.5ml，40mmol)中,反应混合物在室温搅拌过夜.将混合物倒入水(60ml)和***(200ml)中。有机相用饱和盐水洗涤，MgS04干燥，过滤，浓缩得粗品。硅胶柱层析分离纯化(二氯甲烷,100％)得化合物34，1-乙基-2-氟-4-甲氧基-5-硝基苯(5.1g,83％).1HNMR(400MHz,CDCl3)7.8(m,1H),6.7(m,1H),3.9(s,3H),2.6(m,2H),1.2(m,3H).4-Ethyl-5-fluoro-2-nitrophenol, 33 (5.72 g, 30.9 mmol) and K 2 CO 3 (6.4 g, 46.4 mmol) were added to DMF (60 ml) and methylene chloride (2.5 ml, 40 mmol The reaction mixture was stirred at room temperature overnight. The mixture was poured into water (60 ml) and diethyl ether (200 ml). The organic phase was washed with saturated brine, dried EtOAc m. Purification by silica gel column chromatography (dichloromethane (100%) CDCl3) 7.8 (m, 1H), 6.7 (m, 1H), 3.9 (s, 3H), 2.6 (m, 2H), 1.2 (m, 3H).
步骤D:Step D:
Figure PCTCN2016073818-appb-000069
Figure PCTCN2016073818-appb-000069
化合物34(2.5g,12.5mmol)溶解在DMF(25ml)中,添加N1,N1,N2-trimethylethane-1,2-diamine(25.0g,50mmol),K2CO3(7g,50mmol)。然后混合物在110℃下搅拌48h。倒入水中，固体过滤，用水和醚冲洗，在50℃干燥得黄色固体化合物35(1.8g,52.3％).1HNMR(400MHz,CDCl3)7.8(s,1H),6.6(s,1H),3.9(s,3H),3.1-3.2(m,2H),2.8(s,3H),2.5-2.6(m,2H),2.4-2.5(m,2H),2.2(s,6H),1.2-1.3(m,3H).MS(ESI)m/z:282.0(M+H)+。Compound 34 (2.5g, 12.5mmol) was dissolved in DMF (25ml), was added N1, N1, N 2 -trimethylethane- 1,2-diamine (25.0g, 50mmol), K 2 CO 3 (7g, 50mmol). The mixture was then stirred at 110 ° C for 48 h. Pour into water, the solid was filtered, washed with H2HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (s, 3H), 3.1-3.2 (m, 2H), 2.8 (s, 3H), 2.5-2.6 (m, 2H), 2.4-2.5 (m, 2H), 2.2 (s, 6H), 1.2-1.3 (m, 3H). MS (ESI) m.
步骤E:Step E:
Figure PCTCN2016073818-appb-000070
Figure PCTCN2016073818-appb-000070
Pd/C(200mg,10％w)添加到化合物35(1.8g,6.6mol)在甲醇(30ml)的溶液中，在15Psi H2搅拌12h，然后把混合物过滤，浓缩得紫色固体化合物 36(1.5g,95％),1HNMR(400MHz,CDCl3)6.6(s,1H),6.5(s,1H),3.8(s,3H),2.8-3(m,5H),2.5-2.6(m,2H),2.3-2.4(m,2H),2.2(s,6H),1.1-1.2(m,3H).MS(ESI)m/z:252.0(M+H)+。Pd / C (200mg, 10% w) was added to compound 35 (1.8g, 6.6mol) in methanol (30ml) and stirred at 15Psi H 2 12h, and then the mixture was filtered and concentrated to give a purple solid compound 36 (1.5 g, 95%), 1H NMR (400MHz, CDCl3) 6.6 (s, 1H), 6.5 (s, 1H), 3.8 (s, 3H), 2.8-3 (m, 5H), 2.5-2.6 (m, 2H) , 2.3-2.4 (m, 2H), 2.2 (s, 6H), 1.1-1.2 (m, 3H). MS (ESI) m/z: 252.0 (M+H)+.
步骤F:Step F:
Figure PCTCN2016073818-appb-000071
Figure PCTCN2016073818-appb-000071
将化合物36(1.5g,6.0mmol),t-BuONa(1.7g,18mmol),Pd2(dba)3(0.43g,0.75mmol)和Xantphos(0.44g,0.75mmol)加入到N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)氨基)苯基)丙烯酰胺(2.2g,6.0mmol)在甲苯(30ml)的溶液中。混合物在N2气氛下回流2h，混合物冷却到室温后，过滤，滤液浓缩后得粗品,HPLC进一步纯化得TFA盐,m。1HNMR(400MHz,DMSO)10.2(s,1H),9.5(s,1H),9.1(s,1H),8.6(s,1H),8.4(s,1H),7.6-7.7(m,1H),7.5-7.6(m,1H),7.5(s,1H),7.2-7.3(m,1H),7.1-7.2(m,1H),6.8(s,1H),6.3-6.5(m,1H),6.2-6.3(m,1H),5.7-5.8(m,1H),3.9(s,3H),3.1-3.2(m,4H)2.6-2.8(m,6H),2.54(s,3H),2.3-2.5(m,2H),0.8-0.9(m,3H).MS(ESI)m/z:557.9(M+H)+。Compound 36 (1.5 g, 6.0 mmol), t-BuONa (1.7 g, 18 mmol), Pd2 (dba) 3 (0.43 g, 0.75 mmol) and Xantphos (0.44 g, 0.75 mmol) were added to N-(3-( (2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (2.2 g, 6.0 mmol) in toluene (30 mL). The mixture was refluxed for 2 h under N 2 EtOAc. EtOAc was evaporated. 1H NMR (400MHz, DMSO) 10.2 (s, 1H), 9.5 (s, 1H), 9.1 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 7.6-7.7 (m, 1H), 7.5-7.6 (m, 1H), 7.5 (s, 1H), 7.2-7.3 (m, 1H), 7.1-7.2 (m, 1H), 6.8 (s, 1H), 6.3-6.5 (m, 1H), 6.2-6.3 (m, 1H), 5.7-5.8 (m, 1H), 3.9 (s, 3H), 3.1-3.2 (m, 4H) 2.6-2.8 (m, 6H), 2.54 (s, 3H), 2.3 - 2.5 (m, 2H), 0.8-0.9 (m, 3H). MS (ESI) m/z: 557.9 (M+H)+.
本发明人采用实施例1中的方法，使用携带不同的R1－R6取代基的中间体，分别制备了化合物a-j，根据上述实施例中所披露的方法，结合具体的结构，本领域技术人员完全能够实现上述化合物a-j的制备和结构确认。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.
实施例14活性检测Example 14 Activity Detection
采用常规方法对上述实施例制备的化合物进行检测，结果表明本发明的嘧啶衍生物(本发明的化合物)可用于抑制肝癌、肺癌、淋巴癌、乳腺癌、卵巢癌、胃癌等肿瘤细胞的生长，尤其是可抑制非小细胞肺癌细胞的生长。The compound prepared in the above examples was tested by a conventional method, and the results showed that 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.
经检测，结果表明本发明的化合物可作为一种高效、高选择性的预防和/ 或***的药物，尤其是非小细胞肺癌，能够克服T790M引起的耐药性，对抗T790M突变。Upon examination, 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.
实验方法简介如下。The experimental method is described as follows.
1实验材料1 experimental material
1.1试剂1.1 reagent
1.试剂的贮存：用DMSO将化合物配置成50mM的母液，溶解后保存于-20℃。1. Storage of reagent: The compound was placed in a mother liquor of 50 mM in DMSO, dissolved and stored at -20 °C.
2.RPMI-1640液体培养基：GIBCO，Cat.C11875500BT2. RPMI-1640 liquid medium: GIBCO, Cat.C11875500BT
DMEM液体培养基：GIBCO，Cat.C11995500BTDMEM liquid medium: GIBCO, Cat.C11995500BT
胎牛血清FBS：Hyclone，Cat.C2027050Fetal bovine serum FBS: Hyclone, Cat.C2027050
Penicillin-Streptomycin，GIBCO，Cat.15070063Penicillin-Streptomycin, GIBCO, Cat.15070063
Promega CellTiter-
Figure PCTCN2016073818-appb-000072
检测试剂：Cat.G7573Promega CellTiter-
Figure PCTCN2016073818-appb-000072
Detection reagent: Cat.G7573
PBS磷酸盐缓冲液,Splarbio，10*，PH7.2-7.4PBS phosphate buffer, Splarbio, 10*, pH 7.2-7.4
Trypsin，GIBCO，Cat.25200056Trypsin, GIBCO, Cat.25200056
1.2仪器及耗材1.2 Instruments and consumables
康宁96孔白色细胞培养板，Corning，Cat.3917Corning 96-well white cell culture plate, Corning, Cat.3917
细胞培养瓶，25cm(Cat.430639)，75cm(Cat.430641)Cell culture flask, 25cm (Cat.430639), 75cm (Cat.430641)
RAININ 12道排枪：Cat.2-20μl LTS，20-200μl LTSRAININ 12-row gun: Cat. 2-20μl LTS, 20-200μl LTS
15ml尖底离心管，Corning，Cat.43079115ml tipped centrifuge tube, Corning, Cat.430791
10ml移液管，Corning，Cat.448810ml pipette, Corning, Cat.4488
Thermo生物安全柜，1300Series A2，Class II,Type A2Thermo Biosafety Cabinet, 1300Series A2, Class II, Type A2
Thermo二氧化碳培养箱Thermo carbon dioxide incubator
多功能读板仪PerkinElmer，Envi sionMulti-function plate reader PerkinElmer,Envi sion
Optec倒置显微镜Optec inverted microscope
1.3数据分析软件1.3 data analysis software
GraphPad Prism 5.0GraphPad Prism 5.0
2实验方法2 experimental methods
2.1待测试剂的配制2.1 Preparation of the test agent
按照各化合物所标识的质量与分子量，将相应体积的DMSO加入到试剂瓶中，震荡混匀配置成25mM的储液。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.
2.2采用Promega公司的CellTiter-
Figure PCTCN2016073818-appb-000073
检测试剂建立了贴壁细胞增殖抑制筛选方法。 2.2 Using Promega's CellTiter-
Figure PCTCN2016073818-appb-000073
The detection reagent establishes a screening method for adherent cell proliferation inhibition.
人肺癌细胞株用RPIM-1640(NCI-H1975细胞，ATCC)或DMEM(A431细胞，ATCC)液体培养基加10％胎牛血清(FBS)及100units/ml青霉素和0.1mg/ml链霉素在细胞培养箱(37℃，5％CO2)中进行培养。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 ).
在待测试剂的检测中，将细胞消化、计数并铺于96孔白板中，每孔195μl细胞悬液，37℃过夜培养。第二天加入待测试剂，具体操作如下：待测试剂从原液或DMSO 10倍稀释液用DMSO进行3倍梯度稀释，每个浓度取8μl稀释到92μl无血清培养基中，然后取5μl加入到受试细胞中。处理3天后，弃掉培养基，加入25μl CellTiter-
Figure PCTCN2016073818-appb-000074
试剂，室温混匀2mins，静止10mins后在Envisin上读取luminescence荧光信号，使用GraphPad Prism 5.0计算待测试剂对细胞增殖抑制的IC50值。实验所用细胞基因型、培养基及铺板细胞数详见表1。In the detection of the test agent, the cells were digested, counted and plated in a 96-well white plate, and 195 μl of the cell suspension per well was cultured overnight at 37 °C. Add the test agent the next day, the specific operation is as follows: the test agent is diluted from the stock solution or DMSO 10 times dilution with DMSO in 3 fold, each concentration is diluted 8 μl into 92 μl serum-free medium, then 5 μl is added to In the test cells. After 3 days of treatment, the medium was discarded and 25 μl of CellTiter- was added.
Figure PCTCN2016073818-appb-000074
The reagent was mixed at room temperature for 2 mins. After quiescence for 10 mins, the luminescence fluorescence signal was read on Envisin, and the IC50 value of the test agent for cell proliferation inhibition was calculated using GraphPad Prism 5.0. The cell genotypes, medium and plating cells used in the experiment are shown in Table 1.
表1.实验用细胞的详细信息Table 1. Details of experimental cells
Figure PCTCN2016073818-appb-000075
Figure PCTCN2016073818-appb-000075
表2生物活性检测结果Table 2 biological activity test results
化合物编号Compound number NCI-H1975IC50(nM)NCI-H1975IC50(nM) A431IC50(nM)A431IC50(nM)
aa 2.72.7 4242
bb 1313 5252
cc 5.65.6 100.8100.8
dd 4747 537537
ee 24twenty four 476476
ff 2929 319319
gg 207207 >3000>3000
hh 3232 320320
ii 2929 232232
jj 2525 321321
kk 3030 350350
ll 4747 6868
mm 278278 470470
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。 All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (15)

  1. 一种嘧啶衍生物及其药学上可接受的盐，所述嘧啶衍生物的结构如下式I所示：A pyrimidine derivative and a pharmaceutically acceptable salt thereof, the pyrimidine derivative having the structure shown in the following formula I:
    Figure PCTCN2016073818-appb-100001
    Figure PCTCN2016073818-appb-100001
    式中，In the formula,
    X为H、F、Cl；X is H, F, Cl;
    Y为N或CH；Y is N or CH;
    R1为C1-C8直链或支链烷基、或取代的C1-C8直链或支链烷基；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;
    R2为C1-C8直链或支链烷基、C1-C8直链或支链烷氧基、取代的C1-C8直链或支链烷基、或取代的C1-C8直链或支链烷氧基；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;
    R3为H、F、Cl、Br、I、C1-C8直链或支链烷基、或取代的C1-C8直链或支链烷基；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;
    R4为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基、或-C(＝O)R7，或R4为N(R8)R9，R8为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基、或-C(＝O)R7，R9为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基，其中R7为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基；R 4 is a C 1 -C 8 linear or branched alkyl group, a substituted C 1 -C 8 straight or branched alkyl group, or -C(=O)R 7 , or R 4 is N(R 8 ) R 9 , R 8 is a C 1 -C 8 straight or branched alkyl group, a substituted C 1 -C 8 straight or branched alkyl group, or -C(=O)R 7 , and R 9 is C 1 - C 8 straight or branched alkyl, substituted C 1 -C 8 straight or branched alkyl wherein R 7 is C 1 -C 8 straight or branched alkyl, substituted C 1 -C 8 straight Chain or branched alkyl group;
    R5为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基；R 5 is a C 1 -C 8 linear or branched alkyl group, a substituted C 1 -C 8 straight or branched alkyl group;
    R6为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基、或-C(＝O)R7，R7如上所述；R 6 is a C 1 -C 8 linear or branched alkyl group, a substituted C 1 -C 8 linear or branched alkyl group, or -C(=O)R 7 , and R 7 is as defined above;
    或者R5与R6连接成环；Or R 5 and R 6 are connected to form a ring;
    n为1、2、3、4或0；n is 1, 2, 3, 4 or 0;
    其中，各取代是指烷基上的一个或多个H被选自下组的取代基取代：F、Cl、Br、I、羟基。Wherein 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.
  2. 如权利要求1所述的嘧啶衍生物，其特征在于，当Y为N时，R5与R6不连接成环。The pyrimidine derivative according to claim 1, wherein when Y is N, R 5 and R 6 are not bonded to form a ring.
  3. 如权利要求1所述的嘧啶衍生物，其特征在于，当Y为CH时，R4为N(R8)R9， R8为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基、或-C(＝O)R7，R9为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基，其中R7为C1-C8直链或支链烷基、取代的C1-C8直链或支链烷基。The pyrimidine derivative according to claim 1, wherein, when Y is CH, R 4 is N(R 8 )R 9 , and R 8 is a C 1 -C 8 linear or branched alkyl group, substituted a C 1 -C 8 linear or branched alkyl group, or -C(=O)R 7 , R 9 is a C 1 -C 8 straight or branched alkyl group, a substituted C 1 -C 8 straight chain or a branch An alkyl group, wherein R 7 is a C 1 -C 8 straight or branched alkyl group, a substituted C 1 -C 8 straight or branched alkyl group.
  4. 如权利要求1所述的嘧啶衍生物，其特征在于，R1为C1-C6直链或支链烷基、或取代的C1-C6直链或支链烷基。The pyrimidine derivative according to claim 1, wherein 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.
  5. 如权利要求1所述的嘧啶衍生物，其特征在于，R4为C1-C4直链或支链烷基、或-C(＝O)R7，R7为C1-C4直链或支链烷基、取代的C1-C4直链或支链烷基。The pyrimidine derivative according to claim 1, wherein R 4 is a C 1 - C 4 linear or branched alkyl group, or -C(=O)R 7 , and R 7 is a C 1 - C 4 straight A chain or branched alkyl group, a substituted C 1 -C 4 straight or branched alkyl group.
  6. 如权利要求1所述的嘧啶衍生物，其特征在于，R5为C1-C4直链或支链烷；和/或The pyrimidine derivative according to claim 1, wherein R 5 is a C 1 -C 4 linear or branched alkane; and/or
    R6为C1-C4直链或支链烷基。R 6 is a C 1 -C 4 linear or branched alkyl group.
  7. 如权利要求1所述的嘧啶衍生物，其特征在于，R5与R6连接形成5-至9-元环。The pyrimidine derivative according to claim 1, wherein R 5 is bonded to R 6 to form a 5- to 9-membered ring.
  8. 如权利要求1所述的嘧啶衍生物，其特征在于，n为1或2。The pyrimidine derivative according to claim 1, wherein n is 1 or 2.
  9. 如权利要求1所述的嘧啶衍生物，其特征在于，所述嘧啶衍生物选自：The pyrimidine derivative according to claim 1, wherein the pyrimidine derivative is selected from the group consisting of:
    Figure PCTCN2016073818-appb-100002
    Figure PCTCN2016073818-appb-100002
    Figure PCTCN2016073818-appb-100003
    Figure PCTCN2016073818-appb-100003
    Figure PCTCN2016073818-appb-100004
    Figure PCTCN2016073818-appb-100004
  10. 如权利要求1所述的嘧啶衍生物的制备方法，其特征在于，The method for producing a pyrimidine derivative according to claim 1, wherein
    Figure PCTCN2016073818-appb-100005
    Figure PCTCN2016073818-appb-100005
    所述方法包括式VI化合物与式VII化合物反应生成式I化合物的步骤。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.
  11. 如权利要求1所述的化合物或其药学上可接受的盐的用途，其特征在于，用于制备药物，所述药物：Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament, said medicament:
    (i)用作表皮生长因子受体(EGFR)抑制剂；和/或(i) used as an epidermal growth factor receptor (EGFR) inhibitor; and/or
    (ii)用作T790M突变的抑制剂；和/或(ii) used as an inhibitor of the T790M mutation; and/or
    (iii)用于预防和/或***。 (iii) for the prevention and/or treatment of tumors.
  12. 如权利要求11所述的用途，其特征在于，所述肿瘤为T190M突变引起的耐药性肿瘤。The use according to claim 11, wherein the tumor is a drug resistant tumor caused by a T190M mutation.
  13. 一种药物组合物，其特征在于，所述药物组合物包含：A pharmaceutical composition, characterized in that the pharmaceutical composition comprises:
    (i)权利要求1所述的嘧啶衍生物或其药学上可接受的盐；和(i) the pyrimidine derivative of claim 1 or a pharmaceutically acceptable salt thereof;
    (ii)药学上可接受的载体。(ii) a pharmaceutically acceptable carrier.
  14. 一种体外非治疗性的抑制EGFR的方法，其特征在于，所述方法包括步骤：将权利要求1所述的化合物与所述EGFR接触，从而抑制所述EGFR的活性。A method for non-therapeutic inhibition of EGFR in vitro, the method comprising the steps of: contacting the compound of claim 1 with the EGFR to inhibit the activity of the EGFR.
  15. 一种治疗或预防肿瘤的方法，所述方法包括步骤：给肿瘤患者施用治疗或预防有效量的权利要求1所述的化合物或权利要求13所述的药物组合物。 A method of treating or preventing a tumor, the method comprising the step of administering to a tumor patient a therapeutically or prophylactically effective amount of the compound of claim 1 or the pharmaceutical composition of claim 13.
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