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WO2013016999A1 - Dérivés d'hétéroarylpyrimidine et leur procédé de préparation et leur utilisation - Google Patents

Dérivés d'hétéroarylpyrimidine et leur procédé de préparation et leur utilisation Download PDF

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Publication number
WO2013016999A1
WO2013016999A1 PCT/CN2012/078138 CN2012078138W WO2013016999A1 WO 2013016999 A1 WO2013016999 A1 WO 2013016999A1 CN 2012078138 W CN2012078138 W CN 2012078138W WO 2013016999 A1 WO2013016999 A1 WO 2013016999A1
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Prior art keywords
group
mmol
compound
pyrimidin
formula
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PCT/CN2012/078138
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English (en)
Chinese (zh)
Inventor
李心
董庆
陈阳
王斌
白东栋
孙飘扬
张连山
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江苏豪森药业股份有限公司
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Priority to CN201280018231.4A priority Critical patent/CN103582638B/zh
Publication of WO2013016999A1 publication Critical patent/WO2013016999A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a novel heteroarylpyrimidine derivative, a pharmaceutically acceptable salt thereof, a process for the preparation thereof, and a pharmaceutical composition containing the same, and its use as a cancer therapeutic agent, particularly as an mTOR inhibitor.
  • PBK phosphatidylinositol 3-kinase
  • mToR phosphatidylinositol 3-kinase pathway
  • the PBK-AKT-mTOR pathway acts as a key signaling pathway in cells and is involved in the fine-tuning of multiple processes such as cell growth, protein synthesis, energy metabolism, and survival and apoptosis through activation of multiple receptor signals.
  • PBK Phosphatidylinositide 3-kinase
  • the ⁇ 85 regulatory subunit is activated by phosphorylation by interaction with a receptor tyrosine kinase, and the pllO catalytic subunit converts phosphatidylinositol diphosphate (PI2P) to phosphatidylinositol triphosphate (PI3P), Further downstream signaling molecules can be further activated to complete the conduction of extracellular signals (Bader, 2005, Nature Rev., Cancer 5, 921-929; Engelman, 2006, Nature Rev. Genet. 7, 606-619.) .
  • AKT also known as protein kinase B
  • protein kinase B is a serine/threonine protein kinase and is a major downstream effector of PBK.
  • the phosphatidylinositol triphosphate produced by PI3K can induce intracellular AKT and phosphoinositide-dependent protein kinase 1 (PDK1) to be located inside and bound to the cell membrane.
  • PDK1 phosphoinositide-dependent protein kinase 1
  • Activated PDK1 interacts with mTOR complex 2 to phosphorylate A T and maximize activity.
  • AKT As the central link of the entire PBK-AKT-mTOR signal, AKT relies on its kinase activity to regulate multiple downstream signals, and regulates processes such as protein synthesis and cell proliferation, making it one of the important potential targets (Inoki, 2002, Nature Cell Biol, 4, 648-657; Hay, 2004, Genes Dev. 18, 1926-1945.)°
  • mTOR mammalian target of rapamycin
  • mTOR which is an intracellular serine/threonine protein kinase, belongs to four classes of PBk kinases, and The pllO subunit of PI3K has a similar molecular structure.
  • mTOR exists in two different complexes, mTORCl and mTORC2, by binding to different protein molecules.
  • mTORCl is located downstream of AKT; whereas mTORC2 is activated by other mechanisms and is involved in the regulation of AKT activity.
  • AKT attenuates the inhibitory effect of TSC protein on mTORCl by phosphorylating TSC protein (tuberous sclerosis), allowing mTORCl to be activated by GTPase.
  • the activated mTOR further transcribes and translates specific genes through the ribosomal protein kinase p70S6K and the transcriptional regulatory protein 4EBP1, thereby finally completing the conduction process and realizing the response of the cells to extracellular signals (Wullschleger, 2006, Cell 124, 471-484). Sabatini, 2006, Nature Rev. Cancer 6, 729-734.).
  • PBK-AKT-mTOR is a key regulatory pathway for cell function, and its abnormal signal is closely related to the activation of proto-oncogenes, and has a critical impact on the occurrence and development of tumors.
  • PI3K regulatory protein PTEN abnormality As the most common abnormal signaling pathway in tumor cells, PI3K regulatory protein PTEN abnormality, AKT overexpression or overactivation can cause continuous activation of PI3K signal.
  • These mutations are ubiquitous in a variety of solid tumors, such as breast, lung, colon, pancreatic, liver, and digestive tract, and are closely associated with treatment tolerance and poor prognosis (Wood, 2007, Science 318, 1108- 1113; Thomas, 2007, Nature Genet., 39, 347-351). Therefore, it is expected that the single or multiple inhibition of PI3K, AKT and mTOR by developing small molecule compounds has a good development prospect as a tumor therapeutic drug.
  • the present invention provides a novel structure of mTOR kinase inhibitor, and finds that a compound having such a structure also has good activity and exhibits excellent effects and effects. Summary of the invention
  • R 1 and R 2 together with the N atom to which they are bonded form a heterocyclic group, wherein the heterocyclic group contains one or more hetero atoms selected from N, 0 or S(0) m , and the heterocyclic group Optionally further one or more selected from the group consisting of alkyl, halogen, oxo, alkenyl, aryl, alkoxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)R 7 , -C(0)OR 7 , -S(0) m R 7 , -NR 8 R 9 , -C(0)NR 8 R 9 , -NR 8 C(0)R 9 Substituted by a substituent of -NR 8 S(0) m R 9 or -S(0) m NR 8 R 9 ;
  • R 3 is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is optionally further selected from one or more selected from the group consisting of alkyl, hydroxyalkyl, halogen, oxo, alkenyl, block, alkane Oxy, nitro, cyano, cycloalkyl, haloalkoxy, heterocyclyl, aryl, heteroaryl, -C(0)R 7 , -C(0)OR ⁇ -S(0) m R ⁇ -NR 8 R 9 , -C(0)NR 8 R 9 -NR 8 C(0)R 9 -NR 8 S(0) m R 9 or -S(0) m NR 8 R 9 substituent Replace
  • R 4 is selected from cyano, alkyl, alkenyl, aryl, cycloalkyl, heterocyclyl, -OR 5 , -SR 5 , -NR 5 R 6 , -C(0)NR 8 R 9 or -NHC (0) R 7 , wherein the atom to which the heterocyclic group is bonded to the pyrimidinyl group of the formula (I) is a carbon atom, and the alkyl group, alkenyl group, blocked group, cycloalkyl group or heterocyclic group is optionally further One or more selected from the group consisting of halogen, oxo, hydroxy, alkoxy, cyano, aryl, heterocyclyl, heteroaryl, -C(0)OR 7 or -S(0) m R 7 or Substituted by a substituent of -NR 8 R 9 ;
  • R 5 is selected from heterocyclic groups wherein the heterocyclic group contains one or more heteroatoms selected from N, 0 or S(0) m , and the heterocyclic group is optionally further selected by one or more From alkyl, halogen, oxo, alkenyl, block, alkoxy, haloalkyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)R 7 , -C(0)OR 7 , -S(0) m R 7 , -NR 8 R 9 , -C(0)NR 8 R 9 , -NR 8 C(0)R 9 , -NR 8 S( 0) Substituted by a substituent of m R 9 or -S(0) m NR 8 R 9 ;
  • R 6 is selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group or cycloalkyl group is further further selected from one or more selected from the group consisting of an alkyl group, an alkoxy group, a halogen group, an oxo group, a nitro group, and a cyanogen group.
  • Base cycloalkyl, heterocyclic group, -C(0)R 7 , -C(0)OR 7 , -S(0) m R 7 , -NR 8 R 9 , -C(0)NR 8 R 9 Substituted by a substituent of -NR 8 C(0)R 9 , -NR 8 S(0) m R 9 or -S(0) m NR 8 R 9 ;
  • R 7 , R 8 and R 9 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group Or a heteroaryl group optionally further substituted with one or more substituents selected from alkyl, halo, alkoxy, nitro, cyano, cycloalkyl, oxo, heterocyclyl, aryl or heteroaryl Replace
  • n 0, 1 or 2.
  • a compound of the formula (I) or a pharmaceutically acceptable salt thereof which is a compound of the formula (A) or a pharmaceutically acceptable salt thereof:
  • X to X 3 , R 3 to R 4 are as defined above for the definition of formula (; I );
  • R 1Q is selected from a hydrogen atom or an alkyl group.
  • a compound of the formula (A) or a pharmaceutically acceptable salt thereof which is a compound of the formula (A) or
  • R 4 is as defined above for the definition of formula (I);
  • R 1Q is selected from a hydrogen atom or an alkyl group
  • R 11 or R 12 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group or -C(0)NR 13 R 14 , wherein the alkyl group or alkoxy group is optionally further selected by one or more Substituted from an alkyl, hydroxyalkyl, hydroxy, alkoxy, halogen, nitro, cyano or -NR 13 R 14 substituent;
  • R 13 or R 14 are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group.
  • a compound of the formula (A) or a pharmaceutically acceptable salt thereof which is a compound of the formula (IV) or
  • R 4 , R 11 or R 12 are as defined above for the definition of the formula ( ⁇ ).
  • a compound of the formula (IV) or a pharmaceutically acceptable salt thereof which is a compound represented by the formula (IV) i or the formula (IV) ii or Its pharmaceutically acceptable salt:
  • R 4 , R 11 or R 12 are as defined above for the definition of formula (IV) ( typical compounds of the invention include, but are not limited to:
  • the invention further relates to a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, the process comprising:
  • the compound of the formula (IA) is subjected to a nucleophilic substitution reaction with R 4 H under basic conditions to obtain a compound of the formula (I);
  • the conditions for providing basicity include an organic base and an inorganic base, and the organic base includes Triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide, the inorganic bases include sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate.
  • a compound of the formula (I) can be reacted with tributyl(R 4 )stannane in the presence of bis(triphenylphosphine)palladium dichloride and cuprous iodide to give a compound of the formula (I).
  • the solvent used includes: dimethyl sulfoxide, 1,4-dioxane or N,N-dimethylformamide.
  • X is selected from halogen; ⁇ 3, ⁇ ⁇ ⁇ is as defined above for the definition of formula (I) in the.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the present invention further relates to the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the preparation of a medicament for inhibiting mTOR and/or PBK kinase.
  • the present invention further relates to the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating a cancer or a tissue hyperplasia disease, wherein the cancer is selected from the group consisting of melanin Tumor, papillary thyroid neoplasm, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, liver cancer, Kidney cancer, bladder cancer, prostate cancer, breast and pancreatic cancer and sarcoma, and primary and recurrent solid tumors or leukemia of malignant glioma, skin cancer, colon cancer, thyroid cancer, lung cancer and ovarian cancer.
  • the cancer is selected from the group consisting of melanin Tumor, papillary thyroid neoplasm, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, liver cancer, Kidney cancer, bladder cancer, prostate cancer, breast and pancreatic cancer
  • the present invention also relates to a method of inhibiting mTOR kinase activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present invention relates to a method for treating a cancer or a tissue hyperplasia comprising administering to a subject a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same , wherein the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoid tumor, liver, kidney, bladder, prostate, breast and pancreatic cancer and sarcoma, and skin Primary and recurrent solid tumors or leukemia of the colon, thyroid, lungs and ovaries.
  • the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoid tumor, liver, kidney, bladder, prostate, breast and pancreatic cancer and sarcoma, and skin Primary and recurrent solid tumors or leukemia of
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing a pharmaceutical composition, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
  • a water-soluble taste masking substance such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or an extended-time substance such as ethylcellulose or cellulose acetate butyrate may be used.
  • hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • Soft gelatin capsules provide oral preparations.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing or wetting agents can be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecyl ethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols
  • the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • preservatives such as ethylparaben or n-propylparaben
  • coloring agents such as ethylparaben or n-propylparaben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • the oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • Oil suspensions may contain thickeners such as beeswax, hard Paraffin or cetyl alcohol.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation.
  • These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or o tocopherol.
  • Dispersible powders and granules suitable for use in the preparation of aqueous suspensions may be employed in the preparation of aqueous dispersions in the presence of a dispersible or wetting agent, a suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweeteners, flavoring agents, and coloring agents can also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate.
  • the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical compositions of the invention may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the patient's bloodstream by local injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous pump.
  • compositions of this invention may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injection solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example, a solution prepared in 1,3-butanediol.
  • sterile fixed oils may be conveniently employed as a solvent or suspending medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
  • fatty acids such as oleic acid can also be prepared as an injection.
  • the pharmaceutical composition of the present invention can be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • the dosage of the drug depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, The patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; alternatively, the preferred mode of treatment such as the mode of treatment, the daily dose of the compound of formula (I) or the type of pharmaceutically acceptable salt It can be verified according to traditional treatment options.
  • the preferred mode of treatment such as the mode of treatment, the daily dose of the compound of formula (I) or the type of pharmaceutically acceptable salt
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpent
  • lower alkyl groups having 1 to 6 carbon atoms More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of alkane Base, alkenyl, block, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -C(0)R 7 , -C(0)OR 7 , -S(0) m R 7 , -NR 8 R 9 , -C(0)NR 8 R 9 , -NR 8 C(0)R 9 , -NR 8 S(0) m R 9 or -S(0) m NR 8 R 9 .
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 10 One carbon atom.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring.
  • Bridged cycloalkyl preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, a block group, an alkoxy group, and an alkane group.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -C(0)R 7 , -C(0)OR 7 , -S(0) m R 7 , -NR 8 R 9 , -C(0)NR 8 R 9 , -NR 8 C (0)R 9 , -NR 8 S(0) m R 9 or -S(0) m NR 8 R 9 .
  • block group refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as an ethyl group, a 1-propyl block, a 2-propyl block, a 1-, 2 - or 3-butyl base, etc.
  • the block group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -C(0)R 7 , -C(0)OR 7 , -S(0) m R 7 , -NR 8 R 9 , -C(0)NR 8 R 9 , -NR 8 C (0) R 9 , -NR 8 S(0) m R 9 or -S(0) m NR 8 R 9 .
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block,
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, that is, includes a monocyclic heterocyclic group and a polycyclic heterocyclic group, which contains 3 to 20 ring atoms, one or more of which a ring atom is a hetero atom selected from nitrogen, oxygen or S(0) m (where m is an integer from 0 to 2), but does not include a ring moiety of -0-0-, -0-S- or -SS-, The remaining ring atoms are carbon.
  • It preferably contains 3 to 12 ring atoms, of which 1 to 4 are hetero atoms; more preferably the cycloalkyl ring contains 3 to 10 ring atoms; more preferably the cycloalkyl ring contains 5 to 7 ring atoms; most preferably cycloalkane Base limit
  • heterocyclic group together with the N atom to be bonded means a heterocyclic group containing at least one nitrogen ring atom, preferably containing 3 to 12 ring atoms, more preferably 3 to 8 ring atoms, more preferably cycloalkane.
  • the base ring contains 5 to 7 ring atoms, and most preferably the cycloalkyl ring contains 5 or 6 ring atoms, wherein optionally further one or more ring atoms are selected from nitrogen, oxygen or S(0) m (where m Is a hetero atom of the integer 0 to 2); "R 1 and R 2 together with the N atom to which they are bonded form a heterocyclic group" used in the present invention means a heterocyclic group containing at least one nitrogen ring atom, preferably 3 to 12 More preferably, the ring atom contains from 3 to 8 ring atoms, more preferably the cycloalkyl ring contains from 5 to 7 ring atoms, and most preferably the cycloalkyl ring contains 5 or 6 ring atoms, optionally further comprising one or more Select a hetero atom of g N, 0 or S(0) m .
  • the polycyclic heterocyclic group includes a spiro ring, a fused ring, and a heterocyclic group of a bridged ring.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (0).
  • m (where m is an integer 0 to 2) of a hetero atom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • Non-limiting examples of spiroheterocyclyl groups include:
  • fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more a double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(0) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group may be classified according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5- to 5- or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic groups include:
  • bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total The ⁇ electron system of the yoke, wherein one or more of the ring atoms is a hetero atom selected from nitrogen, oxygen or S(0) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic or tricyclic or
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic ring, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, a block group, an alkoxy group, and an alkane group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) which is a polycyclic ring having a conjugated ⁇ -electron system (ie, The ring group adjacent to a carbon atom is preferably 6 to 10 members, such as a phenyl group and a naphthyl group.
  • the ring in which the aryl ring may be fused to a heteroaryl group, a heterocyclic group or a cycloalkyl group is an aryl ring, and non-limiting examples thereof include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -C(0)R 7 , -C(0)OR 7 , -S(0) m R 7 , -NR 8 R 9 , -C(0)NR 8 R 9 , -NR 8 C (0) R 9 , -NR 8 S(0) m R 9 or -S(0) m NR 8 R 9 .
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, more preferably 5 members or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetra Azolyl and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkane Thio group, alkylamino group, halogen, thiol, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkyl sulfide Alkyl, heterocycloalkylthio, -C(0)R 7 , -C(0)OR 7 , -S(0) m R 7 , -NR 8 R 9 , -C(0)NR 8 R 9 , NR 8 C(0)R 9 , -NR 8 S(0) m R 9 or -S(0) m NR 8 R 9 .
  • alkoxy refers to -0-(fluorenyl) and -0-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, a block group, an alkoxy group, and an alkane group.
  • haloalkyl refers to an alkyl group substituted with one or more halogens.
  • haloalkoxy refers to an alkoxy group substituted on the alkyl group with one or more halogens.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -N0 2 .
  • benzyl refers to -CH 2 - benzene.
  • carboxylate group means -C(0)0(alkyl) or -C(0)0(cycloalkyl) wherein alkyl, cycloalkyl are as defined above.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
  • Substituted means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity.
  • “Pharmaceutically-acceptable salt” means a salt of a compound of the present invention which is safe and effective for use in a mammal and which has the desired biological activity.
  • R 7 to R 9 are as defined in the compound of the formula, and m is 0, 1 or 2. detailed description
  • the structure of the compound is determined by nuclear magnetic resonance (1H NMR) and/or mass spectrometry (MS).
  • the iHNMR shift ( ⁇ ) is given in parts per million (ppm).
  • the 1H NMR measurement was performed on a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDC1 3 ), hexamethyl dimethyl sulfoxide (OMSO-d 6 ), internal standard. It is tetramethylsilane (TMS).
  • the MS was measured using a FINMGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150 x 4.6 mm column).
  • the IC 5 o value was determined using a NovoStar plate reader (BMG, Germany).
  • the specification of the silica gel plate used for the (TLC) detection reaction is 0.15 mm to 0.2 mm, and the silica gel plate used for the separation of the purified product by thin layer chromatography is 0.4 mm to 0.5 mm.
  • the silica gel column generally uses Yantai Huanghai silica gel 200 ⁇ 300 mesh silica gel as a carrier.
  • the alkaline alumina column is generally used as a carrier for FCP200 ⁇ 300 mesh basic alumina using the national medicine chromatography.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be used by ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc and Companies such as Dare Chemicals buy.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the systems used for the reaction were: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, petroleum ether and ethyl acetate systems, In the acetone system, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and Acetone
  • A dichloromethane and methanol systems
  • B n-hexane and ethyl acetate systems
  • C dichloromethane and Acetone
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline reagent such as triethylamine or an acidic reagent such as acetic acid may be added for adjustment.
  • an alkaline reagent such as triethylamine or an acidic reagent such as acetic acid
  • Tetrahydropyran-4-ol 60 mg, 0.59 mmol
  • 3 mL of N,N-dimethylformamide and sodium hydride (10 mg, 0.26 mmol) were added to the sealed tube, and stirred at 50 °C.
  • Porphyrin-pyrido[2,3-d]pyrimidin-2-yl]acetonitrile 19 (9 mg, yellow solid), yield: 10.0%; 2-cyano-2-[7-[3-(hydroxymethyl) -4-Methoxy-phenyl]-4-morpholine-B-pyrido[2,3-d]pyrimidin-2-yl]acetate tert-butyl ester 20 (10 mg, yellow solid), yield: 11.0%.
  • Tetrahydropyran-4-ol (31 mg, 0.31 mmol) was dissolved in 5 mL of tetrahydrofuran, sodium hydride (13 mg, 0.34 mmol) was added with stirring, and stirred for 3 hr, [5-[2-chloro-4] -[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 3a (150 mg, 0.37 The reaction was stirred for 1 hr, EtOAc (3 mL), EtOAc (EtOAc) Filtration, and the filtrate was concentrated under reduced pressure. -yl]-2-tetrahydropyran-4-yl-oxy-B-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 23 (20 mg, yellow solid), yield : 12.5%.
  • Cyclopropyl-(4-methylamino-1-piperidinyl)methanone 1-(;cyclopropylcarbonyl)piperidin-4-one 42a (555 mg, 3.32 mmol, prepared by the known method "US Patent 4,312,876") was dissolved in 20 mL of methanol, and 3.3 mL of 2 M methylamine was added. A solution of tetrahydrofuran was stirred for 1 hour, sodium triacetoxyborohydride (1.41 g, 6.64 mmol) was added, and the mixture was stirred for 12 hr, concentrated under reduced pressure, ethyl acetate (50 mL).
  • N-Methyl-1-tetrahydropyran-4-yl-piperidin-4-amine 60 mg, 0.30 mmol
  • [5-[2-it-4-[(35)-3-methyl Morpholin-4-yl] B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 3a 100 mg, 0.25 mmol
  • N,N-diiso Propylethylamine 78 mg, 0.60 mmol was dissolved in 5 mL of N,N-dimethylacetamide, and reacted at 90 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure.
  • EtOAc EtOAc m. -(2-tert-butyl)-4-(3-methylmorpholine)-p-pyrido[2,3-d]pyrimidin-7-yl)methylbenzamide 68 (420 mg, white solid yield: 24.1%.
  • Test Example 1 Determination of inhibition of mTOR kinase activity by a compound of the present invention
  • This experiment used K-LISATM mTOR (Recombinant) Activity Kit (Activity Kit), article number: CBA104, purchased from MERCK.
  • the in vitro cell assay described below can determine the inhibitory activity of the test compound on mTOR kinase, and the test compound is dissolved in dimethyl sulfoxide according to the concentration required for the experiment.
  • ATP and DTT were diluted with lx buffer to obtain 200 ⁇ ATP and 2000 ⁇ DTT solution, and the final concentration of mTOR enzyme was 2 ng ⁇ L.
  • the biochemical activity of the compound of the present invention was measured by the above test, and the IC 5 was measured. See the table below
  • MCF-7 breast cancer cells
  • the in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound against tumor cells highly expressing mTOR/PI3k, and the activity can be expressed by an IC 5Q value.
  • the general protocol for such an experiment is as follows: First, MCF-7 cells (purchased in Institute of biochemistry and cell biology) are seeded on a 96-well culture plate at a suitable cell concentration of 4000 cells/mL, and then the cells are placed in a carbon dioxide incubator. Incubate at 37 ° C, let them grow to overnight, change the medium to add a series of concentration (10000, 1000, 100, 10, 1, O.lnm) The culture medium of the test compound solution, the culture plate was returned to the incubator for continuous culture for 72 hours.
  • test compound was assayed for inhibition of cell proliferation activity using CCK8 (Cell Counting Kit-8, Cat. No.: CK04, purchased from Dojindo).
  • CCK8 Cell Counting Kit-8, Cat. No.: CK04, purchased from Dojindo.
  • the IC 5Q value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations.
  • the in vitro cell assay described below can determine the proliferation inhibitory activity of the test compound on tumor cells, and the inhibitory activity of the compound can be expressed by the IC 5Q value.
  • the experimental protocol is briefly described as follows: First, PC-3 cells (supplied in Institute of biochemistry and cell biology) with DMEM-F12 supplemented with 10% FBSC as Gibco) were purchased at a suitable cell concentration of 2000 cells/mL. The medium was seeded on a 96-well culture plate, and then cultured overnight in a constant temperature incubator at 37 ° C, 5% CO 2 . After the cells were attached, the medium was changed to a fresh medium containing a gradient of the test compound (10000, 1000, 100, 10, 1, 0.1 nm).
  • the cell culture plate was continuously cultured for 72 hours under the aforementioned conditions. After 72 hours, the inhibitory activity of the compound on cell proliferation was measured by the CCK8 method. The IC 5Q value of the compound can be calculated from the inhibition of cell proliferation by the test compound at various concentrations.
  • the concentration of the drug in plasma at different times after administration of the compound of Example 4, the compound of Example 31, the compound of Example 46 and the compound of Example 57 by intragastric administration was determined by LC/MS/MS method.
  • the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
  • Example 4 The compound of Example 4, the compound of Example 31, the compound of Example 46 and the compound of Example 57.
  • the compound of Example 4, the compound of Example 31, the compound of Example 46 and the compound of Example 57 were administered by gavage to rats 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 11.0 before and after administration. Blood was collected in 24.0 hours, placed in heparinized tubes, centrifuged at 3500 rpm for 5 min, and stored at 20 °C. Eat 2 hours after administration.
  • the content of the test compound in the plasma of rats after intragastric administration of different concentrations of the drug was determined by LC/MS/MS method.
  • the linear range of the method was 1.00 ⁇ 2000 ng/ml; plasma samples were analyzed by methanol precipitation protein analysis.
  • the pharmacokinetic parameters of the compounds of the invention are as follows:
  • the compound of the present invention has good pharmacological absorption and has obvious pharmacokinetic advantages.

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Abstract

La présente invention porte sur des dérivés d'hétéroarylpyrimidine et sur leur procédé de préparation et leur utilisation. Précisément, la présente invention porte sur des dérivés d'hétéroarylpyrimidine représentés par la formule générale (I) et des sels pharmaceutiquement acceptables de ceux-ci et sur leur utilisation comme agent de traitement anticancéreux en particulier comme inhibiteur de mTOR, les définitions des substituants dans la formule générale (I) étant les mêmes que celles dans la description.
PCT/CN2012/078138 2011-08-04 2012-07-03 Dérivés d'hétéroarylpyrimidine et leur procédé de préparation et leur utilisation WO2013016999A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103588792A (zh) * 2013-03-04 2014-02-19 中国科学院上海药物研究所 吡啶并嘧啶或嘧啶并嘧啶类化合物、其制备方法、药物组合物及其用途
WO2016150396A1 (fr) * 2015-03-25 2016-09-29 中国科学院上海药物研究所 Procédé de synthèse de dérivé de pyridine et de pyrimidine substitué
WO2022058344A1 (fr) 2020-09-18 2022-03-24 Bayer Aktiengesellschaft Pyrido[2,3-d]pyrimidin-4-amines en tant qu'inhibiteurs de sos1
EP4074317A1 (fr) 2021-04-14 2022-10-19 Bayer AG Dérivés de phosphore en tant que nouveaux inhibiteurs de sos1
US11771716B2 (en) 2019-06-12 2023-10-03 King Fahd University Of Petroleum And Minerals Nanoclays for the control of melanoma cell proliferation and cell viability
WO2024056782A1 (fr) 2022-09-16 2024-03-21 Bayer Aktiengesellschaft Dérivés de pyrido[3,4-d]pyrimidine substitués par sulfone pour le traitement du cancer
WO2024079252A1 (fr) 2022-10-13 2024-04-18 Bayer Aktiengesellschaft Inhibiteurs de sos1
EP4161926A4 (fr) * 2020-06-03 2024-06-19 Yumanity Therapeutics, Inc. Pyridopyrimidines et leurs méthodes d'utilisation
WO2025202022A1 (fr) 2024-03-27 2025-10-02 Bayer Aktiengesellschaft Inhibiteurs de l'interaction entre ras et sos1 à base de quinazoline, macrocycliques et anticancéreux

Families Citing this family (2)

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Publication number Priority date Publication date Assignee Title
CN104557913B (zh) * 2013-10-28 2017-02-08 上海汇伦生命科技有限公司 吡啶并嘧啶类化合物，其制备方法和用途
US20250255868A1 (en) * 2021-04-09 2025-08-14 Hangzhou Innogate Pharma Co., Ltd. Heterocyclic compound acting as kras g12d inhibitor

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005025574A2 (fr) * 2003-09-12 2005-03-24 4 Aza Bioscience Nv Derives de pteridine pour le traitement du choc septique et de maladies liees au tnf-$g(a)
WO2006135993A1 (fr) * 2005-06-24 2006-12-28 Gilead Sciences, Inc. Pyrido(3,2-d)pyrimidines et compositions pharmaceutiques destinees au traitement de l'hepatite c
US20080194546A1 (en) * 2005-11-22 2008-08-14 Kudos Pharmaceuticals Limited Pyrido-, Pyrazo- and Pyrimido-Pyrimidine Derivatives as mTOR Inhibitors
WO2009107767A1 (fr) * 2008-02-29 2009-09-03 大日本住友製薬株式会社 Nouveau dérivé de pyrimidine bicyclique qui présente une activité antagoniste sur le récepteur h4

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5667086B2 (ja) * 2009-02-12 2015-02-12 メルク セローノ ソシエテ アノニム ２−モルホリノ−ピリド［３，２−ｄ］ピリミジン

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005025574A2 (fr) * 2003-09-12 2005-03-24 4 Aza Bioscience Nv Derives de pteridine pour le traitement du choc septique et de maladies liees au tnf-$g(a)
WO2006135993A1 (fr) * 2005-06-24 2006-12-28 Gilead Sciences, Inc. Pyrido(3,2-d)pyrimidines et compositions pharmaceutiques destinees au traitement de l'hepatite c
US20080194546A1 (en) * 2005-11-22 2008-08-14 Kudos Pharmaceuticals Limited Pyrido-, Pyrazo- and Pyrimido-Pyrimidine Derivatives as mTOR Inhibitors
WO2009107767A1 (fr) * 2008-02-29 2009-09-03 大日本住友製薬株式会社 Nouveau dérivé de pyrimidine bicyclique qui présente une activité antagoniste sur le récepteur h4

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014135028A1 (fr) * 2013-03-04 2014-09-12 中国科学院上海药物研究所 Composé de pyridopyrimidine ou de pyrimidopyrimidine, procédé de préparation, composition pharmaceutique et utilisation de celui-ci
JP2016510042A (ja) * 2013-03-04 2016-04-04 中国科学院上▲海▼▲藥▼物研究所 ピリドピリミジンまたはピリミドピリミジン系化合物、その製造方法、薬剤組成物及びその用途
US9796732B2 (en) 2013-03-04 2017-10-24 Shandong Luoxin Pharmaceutical Group Stock Co., Ltd. Pyridopyrimidine or pyrimidopyrimidine compound, prepration method, pharmaceutical composition, and use thereof
AU2014225155B2 (en) * 2013-03-04 2017-11-23 Fudan University Pyridopyrimidine or pyrimidopyrimidine compound, preparation method, pharmaceutical composition and use thereof
RU2662713C2 (ru) * 2013-03-04 2018-07-27 Шанхай Инститьют Оф Материа Медика, Чайниз Академи Оф Сайенсиз Пиридопиримидиновое соединение, способ получения, фармацевтическая композиция и применение указанных соединений
CN103588792A (zh) * 2013-03-04 2014-02-19 中国科学院上海药物研究所 吡啶并嘧啶或嘧啶并嘧啶类化合物、其制备方法、药物组合物及其用途
WO2016150396A1 (fr) * 2015-03-25 2016-09-29 中国科学院上海药物研究所 Procédé de synthèse de dérivé de pyridine et de pyrimidine substitué
US10316033B2 (en) 2015-03-25 2019-06-11 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Process of synthesizing substituted pyridine and pyrimidine compound
US11771716B2 (en) 2019-06-12 2023-10-03 King Fahd University Of Petroleum And Minerals Nanoclays for the control of melanoma cell proliferation and cell viability
EP4161926A4 (fr) * 2020-06-03 2024-06-19 Yumanity Therapeutics, Inc. Pyridopyrimidines et leurs méthodes d'utilisation
WO2022058344A1 (fr) 2020-09-18 2022-03-24 Bayer Aktiengesellschaft Pyrido[2,3-d]pyrimidin-4-amines en tant qu'inhibiteurs de sos1
WO2022219035A1 (fr) 2021-04-14 2022-10-20 Bayer Aktiengesellschaft Utilisation de dérivés de phosphore en tant que nouveaux inhibiteurs de sos1
EP4074317A1 (fr) 2021-04-14 2022-10-19 Bayer AG Dérivés de phosphore en tant que nouveaux inhibiteurs de sos1
WO2024056782A1 (fr) 2022-09-16 2024-03-21 Bayer Aktiengesellschaft Dérivés de pyrido[3,4-d]pyrimidine substitués par sulfone pour le traitement du cancer
WO2024079252A1 (fr) 2022-10-13 2024-04-18 Bayer Aktiengesellschaft Inhibiteurs de sos1
WO2025202022A1 (fr) 2024-03-27 2025-10-02 Bayer Aktiengesellschaft Inhibiteurs de l'interaction entre ras et sos1 à base de quinazoline, macrocycliques et anticancéreux

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