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WO2013016999A1 - Heteroaryl-pyrimidine derivatives, and preparation method therefor and use thereof - Google Patents

Heteroaryl-pyrimidine derivatives, and preparation method therefor and use thereof 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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WO
WIPO (PCT)
Prior art keywords
group
mmol
compound
pyrimidin
formula
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PCT/CN2012/078138
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French (fr)
Chinese (zh)
Inventor
李心
董庆
陈阳
王斌
白东栋
孙飘扬
张连山
Original Assignee
江苏豪森药业股份有限公司
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Application filed by 江苏豪森药业股份有限公司 filed Critical 江苏豪森药业股份有限公司
Priority to CN201280018231.4A priority Critical patent/CN103582638B/en
Publication of WO2013016999A1 publication Critical patent/WO2013016999A1/en

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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

The present invention relates to heteroaryl-pyrimidine derivatives, and a preparation method therefor and a use thereof. Specifically, the present invention relates to heteroaryl-pyrimidine derivatives represented by General Formula (I) and pharmaceutically acceptable salts thereof, and the use thereof as a cancer treatment agent especially an mTOR inhibitor, wherein definitions of substituents in General Formula (I) are the same as those in the specification.

Description

杂芳基并嘧啶类衍生物、 其制备方法和用途  Heteroarylpyrimidine derivatives, preparation methods and uses thereof
技术领域 Technical field
本发明涉及一种新型杂芳基并嘧啶类衍生物及其可药用盐、其制备方法及含有 该衍生物的药物组合物以及其作为癌症治疗剂特别是作为 mTOR抑制剂的用途。 背景技术  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. Background technique
在过去的半个世纪中， 针对肿瘤治疗的研究取得了多方面的进展。 随着对肿 瘤基因学和生物学研究的不断深入， 多个细胞内肿瘤相关的关键信号通路被发现。 肿瘤细胞依赖这些通路实现胞外信号的胞内转导， 调节自身持续增殖、 浸润转移 和抗凋亡等活动， 一方面维持其恶性表型特征， 另一方面通过调节特定基因及其 蛋白产物对治疗产生耐受。在这其中磷脂酰肌醇 3激酶 (PBK)— AKT—哺乳动物雷 帕霉素靶点 (mToR)通路作为最主要的信号通路之一成为了肿瘤药物开发的优选靶 标。  In the past half century, research on cancer treatment has made many progress. With the advancement of tumor genetics and biology, a number of intracellular tumor-related key signaling pathways have been discovered. Tumor cells rely on these pathways to achieve intracellular transduction of extracellular signals, regulate their own sustained proliferation, invasion and metastasis, and anti-apoptosis activities, while maintaining their malignant phenotypic characteristics, on the other hand by regulating specific genes and their protein products. Treatment produces tolerance. Among them, the phosphatidylinositol 3-kinase (PBK)-AKT-mammalian rapamycin target (mToR) pathway has become one of the most important signaling pathways and has become a preferred target for tumor drug development.
PBK-AKT-mTOR通路作为细胞内关键的信号通路，通过多种受体信号激活后 参与细胞周期性生长、 蛋白质合成、 能量代谢以及存活凋亡等多个过程的精细调 节。  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.
磷脂酰肌醇 3激酶 Cphosphatidylinositide 3-kinase, PBK), 属于脂激酶家族， 依照其结构特征和底物选择性可以将其划分为 3类。其中对 1类 PBK研究最为深 入。 该类 PBK为异二聚体蛋白， 分别由 pllO和 p85蛋白亚基构成， 每个亚基又 存在有不同的亚型， 如 ρΐΐθα, ρΐΐθβ, ρ85α, ρ85β等。 其中 ρ85调节亚基通过与 受体酪氨酸激酶的相互作用而被磷酸化激活， 进而 pllO催化亚基将磷脂酰肌醇二 磷酸 (PI2P)转化为磷脂酰肌醇三磷酸 (PI3P), 后者则可以进一步激活多个下游信号 分子， 完成胞外信号的继续传导 (Bader, 2005, Nature Rev., Cancer 5， 921-929; Engelman, 2006, Nature Rev. Genet. 7, 606-619.)。  Phosphatidylinositide 3-kinase, PBK), belongs to the family of lipid kinases and can be classified into three classes according to their structural characteristics and substrate selectivity. Among them, the research on Class 1 PBK is the most in-depth. These PBKs are heterodimeric proteins consisting of pllO and p85 protein subunits, respectively, and each subunit has different subtypes, such as ρΐΐθα, ρΐΐθβ, ρ85α, ρ85β and so on. Wherein the ρ85 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, 又被称为蛋白激酶 B (protein Kinase B)， 属于丝氨酸 /苏氨酸蛋白激酶， 是 PBK主要的下游效应分子。 由 PI3K生成的磷脂酰肌醇三磷酸可以诱使胞内的 AKT和磷酸肌醇依赖性蛋白激酶 1 (PDK1) 定位于细胞膜内侧并与之结合。 活化 的 PDK1通过和 mTOR复合物 2共同作用，使 A T磷酸化并达到活性最大化。 AKT 作为整个 PBK-AKT-mTOR信号的中枢性环节， 依靠其激酶活性调节多个下游信 号， 完成对诸如蛋白质合成， 细胞增殖等过程的调节， 使其成为重要的潜在靶点 之一（Inoki, 2002, Nature Cell Biol, 4， 648-657; Hay, 2004, Genes Dev. 18, 1926-1945.)°  AKT, also known as 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. Activated PDK1 interacts with mTOR complex 2 to phosphorylate A T and maximize activity. 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.)°
PBK-AKT-mTOR 信号的另一关键组成是哺乳动物雷帕霉素靶点蛋白 (mammalian target of rapamycin, mTOR), 它于 1990年在研究雷帕霉素作用机制时 被发现并命名。作为胞内丝氨酸 /苏氨酸蛋白激酶的 mTOR属于四类 PBk激酶，与 PI3K的 pllO亚基有着相似的分子结构。 mTOR通过与不同蛋白分子结合以两种不 同的复合物形式存在， mTORCl 和 mTORC2。 mTORCl 位于 AKT 下游； 而 mTORC2则在其他机制作用下激活并参与 AKT活性的调节。 AKT通过磷酸化 TSC 蛋白 (tuberous sclerosis)而弱化 TSC蛋白对 mTORCl 的抑制作用， 使得 mTORCl 通过 GTPase得以活化。激活的 mTOR进一步通过核糖体蛋白激酶 p70S6K和转录 调节蛋白 4EBP1等实现对特定基因的转录和翻译， 从而最终完成传导过程， 实现 细胞对胞外信号的响应 (Wullschleger, 2006, Cell 124, 471-484; Sabatini, 2006, Nature Rev. Cancer 6， 729-734.)。 Another key component of the PBK-AKT-mTOR signal is the mammalian target of rapamycin (mTOR), which was discovered and named in 1990 when studying the mechanism of action 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作为细胞功能的关键调节通路，其异常信号与原癌基因的活 化有着密切的联系， 对肿瘤的发生、 发展过程均有着关键性的影响。 作为肿瘤细 胞中最常见的异常信号通路， 由基因突变造成 PI3K调节蛋白 PTEN异常、 AKT 过量表达或过度活化等均能导致持续活化的 PI3K信号。这些突变在多种实体肿瘤， 如乳腺癌、 肺癌、 结肠癌、 胰腺癌、 肝癌、 消化道肿瘤等都普遍存在， 并且与治 疗耐受和不良预后紧密相关 (Wood, 2007, Science 318, 1108-1113; Thomas,2007, Nature Genet., 39， 347-351)。 因此可以预期， 通过开发小分子化合物实现对 PI3K、 AKT和 mTOR的单独或多重抑制作为肿瘤治疗药物具有良好的开发前景。  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. 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.
目前， 已经有多个单独抑制 PI3K， AKT, mTOR活性或 PBK/mTOR双重抑 制的化合物处于开发和临床试验阶段 (Garcia, 2008, Oncogene 27, 5511-5526; Rhodes, 2008, Cancer Res. 68， 2366-2374; Thoreen, 2009, J. Biol. Chem. 284, 8023-8032.) 目前公开了一系列的 mTOR 激酶抑制剂的专利申请， 其中包括 US20090099174和 WO2008023161。  Currently, there are several compounds that inhibit PI3K, AKT, mTOR activity or PBK/mTOR dual inhibition in development and clinical trials (Garcia, 2008, Oncogene 27, 5511-5526; Rhodes, 2008, Cancer Res. 68, 2366 -2374; Thoreen, 2009, J. Biol. Chem. 284, 8023-8032.) A series of patent applications for mTOR kinase inhibitors are currently disclosed, including US20090099174 and WO2008023161.
尽管目前已公开了一系列的治疗癌症的 mTOR激酶抑制剂， 但开发新的药物 化合物， 以达到更好的肿瘤治疗效果的目的， 从而更好的满足市场需求， 仍然是 十分有必要的。 本发明将提供一种新型结构的 mTOR激酶抑制剂， 并发现具有此 类结构的化合物同样具有良好的活性， 并表现出优异的效果和作用。 发明内容  Although a series of mTOR kinase inhibitors for cancer treatment have been published, it is still necessary to develop new drug compounds for better tumor treatment purposes to better meet market demand. 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
本发明的目的在于提供一种通式（ I )所示的新型杂芳基并嘧啶类衍生物及其 可药用盐，  It is an object of the present invention to provide a novel heteroarylpyrimidine derivative represented by the formula (I) and a pharmaceutically acceptable salt thereof,
Figure imgf000003_0001
其巾 : X1、 X2或 X3其中的一个或两个为 N原子， 其他为 CH;
Figure imgf000003_0001
Its towel : One or two of X 1 , X 2 or X 3 are N atoms, others are CH;
R1和 R2与相连接的 N原子一起形成杂环基，其中所述杂环基内含有一个或多 个选自 N、 0或 S(0)m的杂原子， 并且所述杂环基任选进一步被一个或多个选自烷 基、 卤素、 氧代基、 烯基、 块基、 烷氧基、 硝基、 氰基、 环烷基、 杂环基、 芳基、 杂芳基、 -C(0)R7、 -C(0)OR7、 -S(0)mR7、 -NR8R9、 -C(0)NR8R9、 -NR8C(0)R9、 -NR8S(0)mR9或 -S(0)mNR8R9的取代基所取代； 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 ;
R3选自芳基或杂芳基， 其中所述芳基或杂芳基任选进一步被一个或多个选自 烷基、 羟烷基、 卤素、 氧代基、 烯基、 块基、 烷氧基、 硝基、 氰基、 环烷基、 卤 代烷氧基、 杂环基、 芳基、 杂芳基、 -C(0)R7、 -C(0)OR\ -S(0)mR\ -NR8R9、 -C(0)NR8R9 -NR8C(0)R9 -NR8S(0)mR9或 -S(0)mNR8R9的取代基所取代； 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
R4选自氰基、 烷基、 烯基、 块基、 环烷基、 杂环基、 -OR5、 -SR5、 -NR5R6、 -C(0)NR8R9或 -NHC(0)R7， 其中所述杂环基与通式（ I )的嘧啶基相连接的原子为碳 原子， 所述烷基、 烯基、 块基、 环烷基或杂环基任选进一步被一个或多个选自卤 素、 氧代基、 羟基、 烷氧基、 氰基、 芳基、 杂环基、 杂芳基、 -C(0)OR7或 -S(0)mR7 或 -NR8R9的取代基所取代； 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 ;
R5选自杂环基， 其中所述杂环基内含有一个或多个选自 N、 0或 S(0)m的杂 原子， 并且所述杂环基任选进一步被一个或多个选自烷基、 卤素、 氧代基、 烯基、 块基、烷氧基、 卤代烷基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、 -C(0)R7, -C(0)OR7、 -S(0)mR7、 -NR8R9、 -C(0)NR8R9、 -NR8C(0)R9、 -NR8S(0)mR9 或 -S(0)mNR8R9的取代基所取代； 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 ;
R6选自氢原子、 烷基或环烷基， 其中所述烷基或环烷基任选进一步被一个或 多个选自烷基、 烷氧基、 卤素、 氧代基、 硝基、 氰基、 环烷基、 杂环基、 -C(0)R7、 -C(0)OR7、 -S(0)mR7、 -NR8R9、 -C(0)NR8R9、 -NR8C(0)R9、 -NR8S(0)mR9 或 -S(0)mNR8R9的取代基所取代； 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 ;
R7、 R8和 R9各自独立地选自氢原子、烷基、环烷基、杂环基、 芳基或杂芳基， 其中所述烷基、 环烷基、 杂环基、 芳基或杂芳基任选进一步被一个或多个选自烷 基、 卤素、 烷氧基、 硝基、 氰基、 环烷基、 氧代基、 杂环基、 芳基或杂芳基的取 代基取代； 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
m是 0、 1或 2。 在本发明一个优选的实施方案中， 一种通式（I )所示的化合物或其可药用盐， 其中 R3为芳基。 m is 0, 1 or 2. In a preferred embodiment of the invention, a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 is an aryl group.
在本发明另一优选的实施方案中， 一种通式（I )所示的化合物或其可药用盐， 其为通式 (Π)所示的化合物或其可药用盐：
Figure imgf000005_0001
In another preferred embodiment of the present invention, 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:
Figure imgf000005_0001
( II ) (II)
其巾：  Its towel:
X ~X3, R3〜R4的定义如上对通式 (； I )的定义中所述； X to X 3 , R 3 to R 4 are as defined above for the definition of formula (; I );
R1Q选自氢原子或烷基。 R 1Q is selected from a hydrogen atom or an alkyl group.
在本发明另一优选的实施方案中， 一种通式（ Π )所示的化合物或其可药用盐， 其为通式 (ΠΙ)所示的化合物或其  In another preferred embodiment of the present invention, a compound of the formula (A) or a pharmaceutically acceptable salt thereof, which is a compound of the formula (A) or
Figure imgf000005_0002
Figure imgf000005_0002
其巾：  Its towel:
R4的定义如上对通式（ I )的定义中所述； R 4 is as defined above for the definition of formula (I);
R1Q选自氢原子或烷基； R 1Q is selected from a hydrogen atom or an alkyl group;
R11或 R12各自独立地选自氢原子、 烷基、 烷氧基、 羟基或 -C(0)NR13R14， 其 中所述烷基或烷氧基任选进一步被一个或多个选自烷基、 羟烷基、 羟基、 烷氧基、 卤素、 硝基、 氰基或 -NR13R14的取代基所取代； 且 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;
R13或 R14各自独立地选自氢原子、 烷基或环烷基。 R 13 or R 14 are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group.
在本发明另一优选的实施方案中， 一种通式 (ΠΙ)所示的化合物或其可药用盐， 其为通式 (IV)所示的化合物或其  In another preferred embodiment of the present invention, a compound of the formula (A) or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV) or
Figure imgf000005_0003
Figure imgf000005_0003
其巾：  Its towel:
R4、 R11或 R12定义如上对通式（ΠΙ )的定义中所述。 R 4 , R 11 or R 12 are as defined above for the definition of the formula (ΠΙ).
进一步， 在本发明优选的实施方案中， 一种通式 (IV)所述的化合物或其可药用 的盐， 其为通式 (IV)i或通式 (IV)ii所示的化合物或其可药用盐：
Figure imgf000006_0001
Further, in a preferred embodiment of the present invention, 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:
Figure imgf000006_0001
(IV)i  (IV)i
其巾：  Its towel:
R4、 R11或 R12定义如上对通式（IV)的定义中所述 ( 本发明典型的化合物包括， 但不限于: 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:
Figure imgf000006_0002
Figure imgf000007_0001
Figure imgf000006_0002
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
[5-[2-异丙基 -4-[(3^-3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2- 甲氧基-苯基]甲醇
Figure imgf000017_0001
Figure imgf000018_0001
[5-[2-isopropyl-4-[(3^-3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy Base-phenyl]methanol
〔。 N1, "' [. N1, "'
68 68
( -3-(2-叔丁基 )-4-(3-甲基吗啉)吡啶并 [2，3-d]嘧啶 -7-基) 甲基 苯酰胺 (-3-(2-tert-butyl)-4-(3-methylmorpholine)pyrido[2,3-d]pyrimidin-7-yl)methylbenzamide
或其可药用盐。 本发明进一步涉及一种制备通式（ I )所述的化合物或其可药用盐的方法， 该方 法包括：  Or a pharmaceutically acceptable salt thereof. 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:
Figure imgf000019_0001
Figure imgf000019_0001
( IA ) ( I ) ( IA ) ( I )
将通式 (IA)化合物与 R4H在碱性条件下进行亲核取代反应， 得到通式（ I )化合 物； 提供碱性的条件包括有机碱和无机碱类， 所述的有机碱类包括三乙胺、 N，N- 二异丙基乙胺、 正丁基锂、 叔丁醇钾， 所述的无机碱类包括氢化钠、 碳酸钠、 碳 酸钾或碳酸铯。 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.
或者将通式 (IA)化合物与 R4B(OH)2钯类催化剂催化下， 优选为四 (三苯基膦) 化钯， 双 (三苯基膦)二氯化钯或 [1，1 '-双 (二苯基膦基)二茂铁]二氯化钯进行 Suzuki 偶联反应， 得到通式（I )化合物。 Or catalyzing a compound of the formula (IA) with a R 4 B(OH) 2 palladium catalyst, preferably tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride or [1,1 '-Bis(diphenylphosphino)ferrocene]palladium dichloride is subjected to a Suzuki coupling reaction to give a compound of the formula (I).
或者将通式 (IA)化合物与三丁基 (R4)锡烷在双 (三苯基膦)二氯化钯和碘化亚铜 的存在下进行反应， 得到通式（I )化合物。 Alternatively, 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).
所用溶剂包括： 二甲基亚砜、 1，4-二氧六环或 N，N-二甲基甲酰胺。  The solvent used includes: dimethyl sulfoxide, 1,4-dioxane or N,N-dimethylformamide.
通式 (IA)中， X选自卤素； 〜Χ3、 ^〜^的定义如上对通式（I )的定义中所 述。 In the general formula (IA), X is selected from halogen; ~Χ 3, ^ ~ ^ is as defined above for the definition of formula (I) in the.
本发明进一步涉及一种药物组合物， 其含有治疗有效量的本发明通式 (I)所示 的化合物或其可药用盐以及一种或多种药学上可接受的载体或赋形剂。  The invention further relates to 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.
本发明进一步涉及通式 (I)所示的化合物或其可药用盐或包含其的药物组合物 在制备抑制 mTOR和 /或 PBK激酶的药物中的用途。  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.
本发明进一步涉及通式 (I)所示的化合物或其可药用盐或包含其的药物组合物 在制备治疗癌症或组织增生类疾病的药物中的用途， 其中所述的癌症选自黑素瘤、 乳头状甲状腺肿瘤、 胆管癌、 结肠癌、 卵巢癌、 肺癌、 恶性淋巴肿瘤癌、 肝癌、 肾癌、 膀胱癌、 前列腺癌、 乳腺癌和胰腺癌和肉瘤， 以及恶性胶质瘤、 皮肤癌、 结肠癌、 甲状腺癌、 肺癌和卵巢癌的原发和复发性实体瘤或者白血病。 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.
本发明还涉及一种抑制 mTOR激酶活性的方法， 其包括给予所需患者治疗有 效量的通式 （I) 所示的化合物或其可药用盐， 或包含其的药物组合物。  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.
换言之， 本发明涉及一种治疗癌症或组织增生类疾病的方法， 其包括给予所 需患者治疗有效量的通式 （I) 所示的化合物或其可药用盐， 或包含其的药物组合 物， 其中所述的癌症选自黑素瘤、 乳头状甲状腺肿瘤、 胆管癌、 结肠癌、 卵巢癌、 肺癌、 恶性淋巴肿瘤、 肝、 肾、 膀胱、 前列腺、 乳腺和胰腺的癌和肉瘤、 以及皮 肤、 结肠、 甲状腺、 肺和卵巢的原发和复发性实体瘤或者白血病。  In other words, 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.
含活性成分的药物组合物可以是适用于口服的形式， 例如片剂、 糖锭剂、 锭 剂、 水或油混悬液、 可分散粉末或颗粒、 乳液、 硬或软胶囊， 或糖浆剂或酏剂。 可按照本领域任何已知制备药用组合物的方法制备口服组合物， 此类组合物可含 有一种或多种选自以下的成分： 甜味剂、 矫味剂、 着色剂和防腐剂， 以提供悦目 和可口的药用制剂。 片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药 用的赋形剂。 这些赋形剂可以是惰性赋形剂， 如碳酸钙、 碳酸钠、 乳糖、 磷酸钙 或磷酸钠； 造粒剂和崩解剂， 例如微晶纤维素、 交联羧甲基纤维素钠、 玉米淀粉 或藻酸； 粘合剂， 例如淀粉、 明胶、 聚乙烯吡咯烷酮或阿拉伯胶和润滑剂， 例如 硬脂酸镁、 硬脂酸或滑石粉。 这些片剂可以不包衣或可通过掩盖药物的味道或在 胃肠道中延迟崩解和吸收， 因而在较长时间内提供缓释作用的已知技术将其包衣。 例如， 可使用水溶性味道掩蔽物质， 例如羟丙基甲基纤维素或羟丙基纤维素， 或 延长时间物质例如乙基纤维素、 醋酸丁酸纤维素。  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. These 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. For example, 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.
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、 磷酸钙或高岭土混合的 硬明胶胶囊， 或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、 液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。  It is also possible to use 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.
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。 此类赋形 剂是悬浮剂， 例如羧基甲基纤维素钠、 甲基纤维素、 羟丙基甲基纤维素、 藻酸钠、 聚乙烯吡咯烷酮和阿拉伯胶； 分散剂或湿润剂可以是天然产生的磷脂例如卵磷脂， 或烯化氧与脂肪酸的縮合产物例如聚氧乙烯硬脂酸酯， 或环氧乙烷与长链脂肪醇 的縮合产物， 例如十七碳亚乙基氧基鲸蜡醇 (heptadecaethyleneoxy cetanol), 或环氧 乙烷与由脂肪酸和己糖醇衍生的部分酯的縮合产物， 例如聚环氧乙烷山梨醇单油 酸酯， 或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的縮合产物， 例如聚环氧乙 烷脱水山梨醇单油酸酯。 水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯 或尼泊金正丙酯、 一种或多种着色剂、 一种或多种娇味剂和一种或多种甜味剂， 例如蔗糖、 糖精或阿司帕坦。  The aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such 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 A condensation product of a partial ester such as polyethylene oxide sorbitan monooleate. 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. Flavoring agents such as sucrose, saccharin or aspartame.
油混悬液可通过使活性成分悬浮于植物油如花生油、 橄榄油、 芝麻油或椰子 油， 或矿物油例如液体石蜡中配制而成。 油悬浮液可含有增稠剂， 例如蜂蜡、 硬 石蜡或鲸蜡醇。 可加入上述的甜味剂和娇味剂， 以提供可口的制剂。 可通过加入 抗氧化剂例如丁羟茴醚或 o 生育酚保存这些组合物。 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.
通过加入水可使适用于制备水混悬液的可分散粉末和颗粒提供活性成分和用 于混合的分散剂或湿润剂、 悬浮剂或一种或多种防腐剂。 适宜的分散剂或湿润剂 和悬浮剂可说明上述的例子。 也可加入其他赋形剂例如甜味剂、 娇味剂和着色剂。 通过加入抗氧化剂例如抗坏血酸保存这些组合物。  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.
水包油乳剂的形式， 油相可以是植物油例如橄榄油或花生油， 或矿物油例如 液体石蜡或其混合物。 适宜的乳化剂可以是天然产生的磷脂， 例如大豆卵磷脂和 由脂肪酸和己糖醇酐衍生的酯或偏酯例如山梨坦单油酸酯， 和所述偏酯和环氧乙 烷的縮合产物， 例如聚环氧乙烷山梨醇单油酸酯。 乳剂也可以含有甜味剂、 娇味 剂、 防腐剂和抗氧剂。 可用甜味剂例如甘油、 丙二醇、 山梨醇或蔗糖配制糖浆和 酏剂。 此类制剂也可含有缓和剂、 防腐剂、 着色剂和抗氧剂。  In the form of an oil-in-water emulsion, 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.
本发明药物组合物可以是无菌注射水溶液形式。 可在使用的可接受的溶媒和 溶剂中有水、 林格氏液和等渗氯化钠溶液。 无菌注射制剂可以是其中活性成分溶 于油相的无菌注射水包油微乳。 例如将活性成分溶于大豆油和卵磷脂的混合物中。 然后将油溶液加入水和甘油的混合物中处理形成微乳。 可通过局部大量注射， 将 注射液或微乳注入患者的血流中。 或者， 最好按可保持本发明化合物恒定循环浓 度的方式给予溶液和微乳。 为保持这种恒定浓度， 可使用连续静脉内递药装置。 这种装置的实例是 Deltec CADD-PLUS. TM. 5400型静脉注射泵。  The pharmaceutical compositions of the invention may be in the form of a sterile injectable aqueous solution. Among the 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. For example, 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. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous pump.
本发明药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形 式。 可按已知技术， 用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。 无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶 液或混悬液， 例如 1，3-丁二醇中制备的溶液。此外， 可方便地用无菌固定油作为溶 剂或悬浮介质。 为此目的， 可使用包括合成甘油单或二酯在内的任何调和固定油。 此外， 脂肪酸例如油酸也可以制备注射剂。  The pharmaceutical 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. In addition, 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. In addition, fatty acids such as oleic acid can also be prepared as an injection.
本发明药物组合物可按用于直肠给药的栓剂形式给予。 可通过将药物与在普 通温度下为固体但在直肠中为液体， 因而在直肠中会溶化而释放药物的适宜的无 刺激性赋形剂混合来制备这些药物组合物。 此类物质包括可可脂、 甘油明胶、 氢 化植物油、 各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。  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. Such materials include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
本领域技术人员所熟知的， 药物的给药剂量依赖于多种因素， 包括但并非限 定以下因素： 所用特定化合物的活性、 病人的年龄、 病人的体重、 病人的健康状 况、 病人的行被、 病人的饮食、 给药时间、 给药方式、 排泄的速率、 药物的组合 等； 另外， 最佳的治疗方式如治疗的模式、 通式化合物 (I)的日用量或可药用的盐 的种类可以根据传统的治疗方案来验证。 发明详述 除非有相反陈述， 在说明书和权利要求书中使用的术语具有下述含义。 As is well known to those skilled in the art, 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. Detailed description of the invention Terms used in the specification and claims have the following meanings unless stated to the contrary.
术语 "烷基"指饱和脂肪族烃基团， 其为包含 1至 20个碳原子的直链或支链 基团， 优选含有 1至 12个碳原子的烷基。非限制性实例包括甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 仲丁基、 正戊基、 1，1-二甲基丙基、 1，2-二甲 基丙基、 2，2-二甲基丙基、 1-乙基丙基、 2-甲基丁基、 3-甲基丁基、 正己基、 1-乙基 -2-甲基丙基、 1，1，2-三甲基丙基、 1，1-二甲基丁基、 1，2-二甲基丁基、 2，2-二甲基丁 基、 1，3-二甲基丁基、 2-乙基丁基、 2-甲基戊基、 3-甲基戊基、 4-甲基戊基、 2，3-二 甲基丁基、 正庚基、 2-甲基己基、 3-甲基己基、 4-甲基己基、 5-甲基己基、 2，3-二甲 基戊基、 2，4-二甲基戊基、 2，2-二甲基戊基、 3，3-二甲基戊基、 2-乙基戊基、 3-乙基 戊基、 正辛基、 2，3-二甲基己基、 2，4-二甲基己基、 2，5-二甲基己基、 2，2-二甲基己 基、 3，3-二甲基己基、 4，4-二甲基己基、 2-乙基己基、 3-乙基己基、 4-乙基己基、 2- 甲基 -2-乙基戊基、 2-甲基 -3-乙基戊基、 正壬基、 2-甲基 -2-乙基己基、 2-甲基 -3-乙 基己基、 2，2-二乙基戊基、 正癸基、 3，3-二乙基己基、 2，2-二乙基己基， 及其各种支 链异构体等。 更优选的是含有 1至 6个碳原子的低级烷基， 非限制性实施例包括 甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 仲丁基、 正戊基、 1，1- 二甲基丙基、 1，2-二甲基丙基、 2，2-二甲基丙基、 1-乙基丙基、 2-甲基丁基、 3-甲基 丁基、 正己基、 1-乙基 -2-甲基丙基、 1，1，2-三甲基丙基、 1，1-二甲基丁基、 1，2-二甲 基丁基、 2，2-二甲基丁基、 1，3-二甲基丁基、 2-乙基丁基、 2-甲基戊基、 3-甲基戊基、 4-甲基戊基、 2，3-二甲基丁基等。 烷基可以是取代的或非取代的， 当被取代时， 取 代基可以在任何可使用的连接点上被取代， 所述取代基优选为一个或多个以下基 团， 其独立地选自烷基、 烯基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤素、 硫醇、 羟基、 硝基、 氰基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环烷氧基、 环烷硫基、 杂环烷硫基、 氧代基、 -C(0)R7、 -C(0)OR7、 -S(0)mR7、 -NR8R9、 -C(0)NR8R9、 -NR8C(0)R9、 -NR8S(0)mR9或 -S(0)mNR8R9。 The term "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-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl group, 2-methyl-2-ethylpentyl, 2- 3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3 , 3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. 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 .
术语 "环烷基"指饱和或部分不饱和单环或多环环状烃取代基， 环烷基环包 含 3至 20个碳原子， 优选包含 3至 12个碳原子， 更优选包含 3至 10个碳原子。 单环环烷基的非限制性实例包括环丙基、 环丁基、 环戊基、 环戊烯基、 环己基、 环己烯基、 环己二烯基、 环庚基、 环庚三烯基、 环辛基等； 多环环烷基包括螺环、 稠环和桥环的环烷基。  The term "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.
术语 "螺环烷基"指 5至 20元的单环之间共用一个碳原子 (称螺原子)的多环 基团， 其可以含有一个或多个双键， 但没有一个环具有完全共轭的 π 电子系统。 优选为 6至 14元， 更优选为 7至 10元。 根据环与环之间共用螺原子的数目将螺 环烷基分为单螺环烷基、 双螺环烷基或多螺环烷基， 优选为单螺环烷基和双螺环 烷基。 更优选为 4元 /4元、 4元 /5元、 4元 /6元、 5元 /5元或 5元 /6元单螺环烷基。 螺环烷基的非限制性实例包括：
Figure imgf000023_0001
The term "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 π 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. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
Figure imgf000023_0001
术语 "稠环烷基"指 5至 20元， 系统中的每个环与体系中的其他环共享毗邻 的一对碳原子的全碳多环基团， 其中一个或多个环可以含有一个或多个双键， 但 没有一个环具有完全共轭的 π电子系统。 优选为 6至 14元， 更优选为 7至 10元。 根据组成环的数目可以分为双环、 三环、 四环或多环稠环烷基， 优选为双环或三 。 稠环烷基的非限制性实例包括：  The term "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 π-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. Non-limiting examples of fused cycloalkyl groups include:
Figure imgf000023_0002
Figure imgf000023_0002
术语"桥环烷基"指 5至 20元， 任意两个环共用两个不直接连接的碳原子的 全碳多环基团， 其可以含有一个或多个双键， 但没有一个环具有完全共轭的 π 电 子系统。 优选为 6至 14元， 更优选为 7至 10元。 根据组成环的数目可以分为双 环、 三环、 四环或多环桥环烷基， 优选为双环、 三环或四环， 更有选为双环或三 环。 桥环烷基的  The term "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 π 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
Figure imgf000023_0003
Figure imgf000023_0003
所述环烷基环可以稠合于芳基、 杂芳基或杂环烷基环上， 其中与母体结构连 接在一起的环为环烷基， 非限制性实例包括茚满基、 四氢萘基、 苯并环庚烷基等。 环烷基可以是任选取代的或非取代的， 当被取代时， 取代基优选为一个或多个以 下基团， 其独立地选自烷基、 烯基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤素、 硫醇、 羟基、 硝基、 氰基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环 烷氧基、 环烷硫基、 杂环烷硫基、 氧代基、 -NR8R9、 -C(0)NR8R9, -NR8C(0)R9 -NR8S(0)mR9、 -S(0)mNR8R9、 -C(O)R10 -C(0)OR1()或 -S(O)mR10。 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. 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 Base, heterocycloalkylthio, oxo, -NR 8 R 9 , -C(0)NR 8 R 9 , -NR 8 C(0)R 9 -NR 8 S(0) m R 9 , -S (0) m NR 8 R 9 , -C(O)R 10 -C(0)OR 1() or -S(O) m R 10 .
术语 "烯基"指由至少由两个碳原子和至少一个碳 -碳双键组成的如上定义的 烷基， 例如乙烯基、 1-丙烯基、 2-丙烯基、 1-、 2-或 3-丁烯基等。 烯基可以是取代 的或非取代的， 当被取代时， 取代基优选为一个或多个以下基团， 其独立地选自 烷基、 烯基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤素、 硫醇、 羟基、 硝基、 氰 基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环烷氧基、 环烷硫基、 杂 环烷硫基、 -C(0)R7、 -C(0)OR7、 -S(0)mR7、 -NR8R9、 -C(0)NR8R9、 -NR8C(0)R9、 -NR8S(0)mR9或 -S(0)mNR8R9。 The term "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 .
术语 "块基"指至少由两个碳原子和至少一个碳-碳三键组成的如上所定义的 烷基， 例如乙块基、 1-丙块基、 2-丙块基、 1-、 2-或 3-丁块基等。 块基可以是取代 的或非取代的， 当被取代时， 取代基优选为一个或多个以下基团， 其独立地选自 烷基、 烯基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤素、 硫醇、 羟基、 硝基、 氰 基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环烷氧基、 环烷硫基、 杂 环烷硫基、 -C(0)R7、 -C(0)OR7、 -S(0)mR7、 -NR8R9、 -C(0)NR8R9、 -NR8C(0)R9、 -NR8S(0)mR9或 -S(0)mNR8R9。 The term "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 .
术语 "杂环基"指饱和或部分不饱和单环或多环环状烃取代基， 即包括单环 杂环基和多环杂环基，其包含 3至 20个环原子，其中一个或多个环原子为选自氮、 氧或 S(0)m (其中 m是整数 0至 2)的杂原子， 但不包括 -0-0-、 -0-S-或 -S-S-的环部 分， 其余环原子为碳。 优选包含 3至 12个环原子， 其中 1〜4个是杂原子； 更优 选环烷基环包含 3至 10个环原子； 更优选环烷基环包含 5至 7个环原子； 最优选 环烷 基的非限 The term "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
Figure imgf000024_0001
Figure imgf000024_0001
术语 "与相连接的 N原子一起形成杂环基"指含有至少 1个氮环原子的杂环 基， 优选包含 3至 12个环原子， 更优选包含 3至 8个环原子， 更优选环烷基环包 含 5至 7个环原子， 最优选环烷基环包含 5或 6个环原子， 其中任选进一步含一 个或多个环原子为选自氮、 氧或 S(0)m (其中 m是整数 0至 2)的杂原子； "R1和 R2 与相连接的 N原子一起形成杂环基"用于本发明指含有至少 1个氮环原子的杂环 基， 优选包含 3至 12个环原子， 更优选包含 3至 8个环原子， 更优选环烷基环包 含 5至 7个环原子， 最优选环烷基环包含 5或 6个环原子， 其中任选进一步含有 一个或多个选 g N、 0或 S(0)m的杂原子。 The term "to form a 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 .
多环杂环基包括螺环、 稠环和桥环的杂环基。  The polycyclic heterocyclic group includes a spiro ring, a fused ring, and a heterocyclic group of a bridged ring.
术语 "螺杂环基"指 5至 20元的单环之间共用一个原子 (称螺原子)的多环杂 环基团， 其中一个或多个环原子为选自氮、 氧或 S(0)m (其中 m是整数 0至 2)的杂 原子， 其余环原子为碳。 其可以含有一个或多个双键， 但没有一个环具有完全共 轭的 π电子系统。 优选为 6至 14元， 更优选为 7至 10元。 根据环与环之间共用 螺原子的数目将螺杂环基分为单螺杂环基、 双螺杂环基或多螺杂环基， 优选为单 螺环烷基和双螺环烷基。 更优选为 4元 /4元、 4元 /5元、 4元 /6元、 5元 /5元或 5 元 /6元单螺杂环基。 螺杂环基的非限制性实例包括：
Figure imgf000025_0001
The term "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:
Figure imgf000025_0001
术语 "稠杂环基"指 5至 20元， 系统中的每个环与体系中的其他环共享毗邻 的一对原子的多环杂环基团， 一个或多个环可以含有一个或多个双键， 但没有一 个环具有完全共轭的 π电子系统，其中一个或多个环原子为选自氮、氧或 S(0)m (其 中 m是整数 0至 2)的杂原子， 其余环原子为碳。 优选为 6至 14元， 更优选为 7 至 10元。 根据组成环的数目可以分为双环、 三环、 四环或多环稠杂环基， 优选为 双环或三环， 更优选为 5元 /5元或 5元 /6元双环稠杂环基。 稠杂环基的非限制性 实例包括： The term "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 π-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. Non-limiting examples of fused heterocyclic groups include:
Figure imgf000025_0002
Figure imgf000025_0002
术语 "桥杂环基"指 5至 14元， 任意两个环共用两个不直接连接的原子的多 环杂环基团， 其可以含有一个或多个双键， 但没有一个环具有完全共轭的 π 电子 系统， 其中一个或多个环原子为选自氮、 氧或 S(0)m (其中 m是整数 0至 2)的杂原 子， 其余环原子为碳。 优选为 6至 14元， 更优选为 7至 10元。 7至 10元。 根据 组成环的数目可以分为双环、 三环、 四环或多环桥杂环基， 优选为双环、 三环或 The term "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 π 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
Figure imgf000025_0003
所述杂环基环可以稠合于芳基、 杂芳基或环烷基环上， 其中与母体结构连接 在一起的环为杂环 其非限制性实例包括：
Figure imgf000025_0004
Figure imgf000025_0003
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:
Figure imgf000025_0004
等。 杂环基可以是任选取代的或非取代的， 当被取代时， 取代基优选为一个或多 个以下基团， 其独立地选自烷基、 烯基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤 素、 硫醇、 羟基、 硝基、 氰基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环烷氧基、 环烷硫基、 杂环烷硫基、 氧代基、 -C(0)R7、 -C(0)OR7、 -S(0)mR7、 -NR8R9、 -C(0)NR8R9、 -NR8C(0)R9、 -NR8S(0)mR9或 -S(0)mNR8R9。 Wait. 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. Thio group, alkylamino group, halogen , thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, 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 .
术语"芳基"指 6至 14元全碳单环或稠合多环 (也就是共享毗邻碳原子对的环) 基团， 其为具有共轭的 π电子体系的多环 (即其带有相邻对碳原子的环)基团， 优选 为 6至 10元， 例如苯基和萘基。 所述芳基环可以稠合于杂芳基、 杂环基或环烷基 一起的环为芳基环， 其非限制性实例包括：  The term "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 π-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:
Figure imgf000026_0001
Figure imgf000026_0001
芳基可以是取代的或非取代的， 当被取代时， 取代基优选为一个或多个以下 基团， 其独立地选自烷基、 烯基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤素、 硫 醇、 羟基、 硝基、 氰基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环烷 氧基、环烷硫基、杂环烷硫基、 -C(0)R7、 -C(0)OR7、 -S(0)mR7、 -NR8R9、 -C(0)NR8R9、 -NR8C(0)R9、 -NR8S(0)mR9或 -S(0)mNR8R9。 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 .
术语 "杂芳基"指包含 1至 4个杂原子、 5至 14个环原子的杂芳族体系， 其 中杂原子选自氧、 硫和氮。 杂芳基优选为 5至 10元， 更优选为 5元或 6元， 例如 呋喃基、 噻吩基、 吡啶基、 吡咯基、 N-烷基吡咯基、 嘧啶基、 吡嗪基、 咪唑基、 四唑基等。 所述杂芳基环可以稠合于芳基、 杂环基或环烷基环上， 其中与母体结 构连接 一起的环为杂芳基环， 其非限制性实例包括：  The term "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:
Figure imgf000026_0002
Figure imgf000026_0002
杂芳基可以是任选取代的或非取代的， 当被取代时， 取代基优选为一个或多 个以下基团， 其独立地选自烷基、 烯基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤 素、 硫醇、 羟基、 硝基、 氰基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环烷氧基、 环烷硫基、 杂环烷硫基、 -C(0)R7、 -C(0)OR7、 -S(0)mR7、 -NR8R9、 -C(0)NR8R9、 -NR8C(0)R9、 -NR8S(0)mR9或 -S(0)mNR8R9。 术语 "烷氧基"指 -0- (浣基)和 -0- (非取代的环烷基)， 其中烷基的定义如上所 述。 烷氧基的非限制性实例包括： 甲氧基、 乙氧基、 丙氧基、 丁氧基、 环丙氧基、 环丁氧基、 环戊氧基、 环己氧基。 烷氧基可以是任选取代的或非取代的， 当被取 代时， 取代基优选为一个或多个以下基团， 其独立地选自烷基、 烯基、 块基、 烷 氧基、 烷硫基、 烷基氨基、 ^素、 硫醇、 羟基、 硝基、 氰基、 环烷基、 杂环烷基、 芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、 -C(0)R7 -C(0)OR7 -S(0)mR7、 -NR8R9、 -C(0)NR8R9、 -NR8C(0)R9、 -NR8S(0)mR9或 -S(0)mNR8R9。 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 . The term "alkoxy" refers to -0-(fluorenyl) and -0-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of 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. Thio group, alkylamino group, thiol, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, naphthenic Thio, 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 .
术语 "卤代烷基"指被一个或多个卤素取代的烷基。  The term "haloalkyl" refers to an alkyl group substituted with one or more halogens.
术语 "卤代烷氧基"指在烷基上被一个或多个卤素取代的烷氧基。  The term "haloalkoxy" refers to an alkoxy group substituted on the alkyl group with one or more halogens.
术语 "羟基"指 -OH基团。  The term "hydroxy" refers to an -OH group.
术语 "羟烷基"指被羟基取代的烷基。  The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.
术语 "卤素"指氟、 氯、 溴或碘。  The term "halogen" means fluoro, chloro, bromo or iodo.
术语 "氨基"指 -NH2。 The term "amino" refers to -NH 2 .
术语 "氰基"指 -CN。  The term "cyano" refers to -CN.
术语 "硝基"指 -N02。 The term "nitro" refers to -N0 2 .
术语 "苄基"指 -CH2-苯。 The term "benzyl" refers to -CH 2 - benzene.
术语 "氧代基"指 =0。  The term "oxo" refers to =0.
术语 "羧基"指 -C(0)OH。  The term "carboxy" refers to -C(0)OH.
术语 "羧酸酯基"指 -C(0)0(烷基)或 -C(0)0 (环烷基） ， 其中烷基、 环烷基的 定义如上所述。  The term "carboxylate group" means -C(0)0(alkyl) or -C(0)0(cycloalkyl) wherein alkyl, cycloalkyl are as defined above.
"任选"或 "任选地"意味着随后所描述的事件或环境可以但不必发生， 该 说明包括该事件或环境发生或不发生地场合。例如， "任选被烷基取代的杂环基团" 意味着烷基可以但不必须存在， 该说明包括杂环基团被烷基取代的情形和杂环基 团不被烷基取代的情形。  "Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "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. .
"取代的"指基团中的一个或多个氢原子， 优选为最多 5个， 更优选为 1〜3 个氢原子彼此独立地被相应数目的取代基取代。 不言而喻， 取代基仅处在它们的 可能的化学位置， 本领域技术人员能够在不付出过多努力的情况下确定 (通过实验 或理论)可能或不可能的取代。例如， 具有游离氢的氨基或羟基与具有不饱和 (如烯 属)键的碳原子结合时可能是不稳定的。  "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.
"药物组合物"表示含有一种或多种本文所述化合物或其生理学上 /可药用的 盐或前体药物与其他化学组分的混合物， 以及其他组分例如生理学 /可药用的载体 和赋形剂。 药物组合物的目的是促进对生物体的给药， 利于活性成分的吸收进而 发挥生物活性。  "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.
"可药用盐"是指本发明化合物的盐， 这类盐用于哺乳动物体内时具有安全 性和有效性， 且具有应有的生物活性。  "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.
R7〜R9的定义如通式 化合物中所述， m是 0， 1或 2。 具体实施方式 R 7 to R 9 are as defined in the compound of the formula, and m is 0, 1 or 2. detailed description
以下结合实施例用于进一步描述本发明， 但这些实施例并非限制本发明的范 围。  The invention is further described below in conjunction with the examples, but these examples are not intended to limit the scope of the invention.
本发明实施例中未注明具体条件的实验方法， 通常按照常规条件， 或按照原 料或商品制造厂商所建议的条件。 未注明具体来源的试剂， 为市场购买的常规试 剂。  The experimental methods in the examples of the present invention which do not specify the specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions recommended by the original material or the manufacturer of the article. Reagents without specific source are routinely purchased from the market.
化合物的结构是通过核磁共振 (1H NMR)和 /或质谱 (MS)来确定的。 iHNMR位 移 (δ)以百万分之一 (ppm)的单位给出。 1H NMR的测定是用 Bruker AVANCE-400核 磁仪， 测定溶剂为氘代甲醇 (CD3OD)、 氘代氯仿 (CDC13)， 六氘代二甲基亚砜 (OMSO-d6), 内标为四甲基硅烷 (TMS)。 The structure of the compound is determined by nuclear magnetic resonance (1H NMR) and/or mass spectrometry (MS). The iHNMR shift (δ) 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).
MS的测定用 FINMGAN LCQAd (ESI)质谱仪 (生产商： Thermo,型号： Finnigan LCQ advantage MAX)。  The MS was measured using a FINMGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
HPLC的测定使用安捷伦 1200DAD高压液相色谱仪 (Sunfire C18 150x4.6mm 色谱柱)和 Waters 2695-2996高压液相色谱仪 (Gimini C 18 150x4.6mm色谱柱）。  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).
IC5o值的测定用 NovoStar酶标仪 (德国 BMG公司）。 The IC 5 o value was determined using a NovoStar plate reader (BMG, Germany).
薄层层析硅胶板使用烟台黄海 HSGF254或青岛 GF254硅胶板， 薄层色谱法 Thin layer chromatography silica gel plate using Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, thin layer chromatography
(TLC)检测反应使用的硅胶板采用的规格是 0.15 mm〜0.2 mm, 薄层色谱法分离纯 化产品使用的硅胶板采用的规格是 0.4 mm〜0.5 mm。 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.
硅胶柱一般使用烟台黄海硅胶 200〜300目硅胶为载体。  The silica gel column generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as a carrier.
碱性氧化铝柱一般使用国药层析用 FCP200〜300目碱性氧化铝为载体。  The alkaline alumina column is generally used as a carrier for FCP200~300 mesh basic alumina using the national medicine chromatography.
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成， 或可以 于 ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, 韶远化学 科技 (； Accela ChemBio Inc) 和达瑞化学品等公司处购买。  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.
实施例中无特殊说明， 反应均在氮气或氩气氛下进行。  Unless otherwise stated in the examples, the reactions were all carried out under a nitrogen or argon atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约 1 L容积的氩气或氮气气球。  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.
氢气氛是指反应瓶连接一个约 1 L容积的氢气气球。  The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
加压氢化反应使用 Parr 3916EKX型氢化仪和清蓝 QL-500 型氢气发生器或 HC2-SS型氢化仪。  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.
氢化反应通常抽真空， 充入氢气， 反复操作 3次。  The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
实施例中无特殊说明， 溶液是指水溶液。  There is no particular description in the examples, and the solution means an aqueous solution.
实施例中无特殊说明， 反应的温度为室温， 为 20°C〜30°C。  Unless otherwise specified in the examples, the reaction temperature is room temperature and is 20 ° C to 30 ° C.
实施例中的反应进程的监测采用薄层色谱法 (TLC)， 反应所使用的展开剂的体 系有： 二氯甲烷和甲醇体系， 正己烷和乙酸乙酯体系， 石油醚和乙酸乙酯体系， 丙酮体系， 溶剂的体积比根据化合物的极性不同而进行调节。  The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). 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.
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包 括： A: 二氯甲烷和甲醇体系， B: 正己烷和乙酸乙酯体系， C : 二氯甲烷和丙酮 体系， 溶剂的体积比根据化合物的极性不同而进行调节， 也可以加入少量的三乙 胺等碱性或醋酸等酸性试剂进行调节。 实施例 1 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 In the system, 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. Example 1
7  7
Figure imgf000029_0001
Figure imgf000029_0001
第一步  First step
7-氯 -1H-吡啶并 [2，3-d]嘧啶 -2,4-二酮  7-chloro-1H-pyrido[2,3-d]pyrimidine-2,4-dione
将 2-氨基 -6-氯-吡啶-甲酰胺 la (5.90 g， 34 mmol, 采用公知的方法 "专利 WO2007060404"制备而得)溶解于 120 mL甲苯中， 加入草酰氯 (5.6 mL, 68 mmol), 回流反应 4小时。 过滤， 滤饼用甲苯洗涤 (20 mLx2)， 真空干燥， 得到标题产物粗 品 7-氯 -1H-吡啶并 [2，3-d]嘧啶 -2,4-二酮 lb (6 g， 乳白色固体)，产物不经纯化直接进 行下步反应。  2-Amino-6-chloro-pyridine-carboxamide la (5.90 g, 34 mmol, prepared by the known method "WO2007060404") was dissolved in 120 mL of toluene, and oxalyl chloride (5.6 mL, 68 mmol) was added. , reflux reaction for 4 hours. Filtration, the filter cake was washed with toluene (20 mL×2) and dried in vacuo to give the title product crude product 7-chloro-1H-pyrido[2,3-d]pyrimidine-2,4-dione lb (6 g, milky white solid) The product was directly subjected to the next step without purification.
MS m/z (ESI): 198.2 [M+l]  MS m/z (ESI): 198.2 [M+l]
第二步  Second step
2，4，7-三氯吡啶并 [2，3-d]嘧啶  2,4,7-trichloropyrido[2,3-d]pyrimidine
将粗品 7-氯 -1H-吡啶并 [2，3-d]嘧啶 -2,4-二酮 lb (6 g， 30.40 mmol)溶解于 80 mL 甲苯中， 加入 N，N-二异丙基乙胺 (11.80 g， 91.40 mmol), 70°C下搅拌 40分钟， 加入 三氯氧磷 (15.50 g， 91.40 mmol), 回流反应 3小时。 减压浓縮， 加入 50 mL乙酸乙 酯， 分液， 有机相用饱和氯化钠溶液洗涤 (20 mL)， 无水硫酸钠干燥， 过滤， 滤液 减压浓縮， 用硅胶柱色谱法以洗脱剂体系 C纯化所得残余物， 得到标题产物 2，4，7- 三氯吡啶并 [2，3-d]嘧啶 lc (5 g， 白色固体)， 产率： 69.4%。  The crude 7-chloro-1H-pyrido[2,3-d]pyrimidine-2,4-dione lb (6 g, 30.40 mmol) was dissolved in 80 mL of toluene and N,N-diisopropyl B was added. The amine (11.80 g, 91.40 mmol) was stirred at 70 ° C for 40 min, and phosphorus oxychloride (15.50 g, 91.40 mmol) was added and refluxed for 3 hours. Concentrate under reduced pressure, add 50 mL of ethyl acetate, EtOAc (EtOAc)EtOAc. The obtained residue was purified to give the titled product 2,4,7-trichloropyrido[2,3-d]pyrimidine lc (5 g, white solid), yield: 69.4%.
MS m/z (ESI): 234.1 [M+l] MS m/z (ESI): 234.1 [M+l]
第三步  third step
4-(；2，7-二氯吡啶并 [2，3-d]嘧啶 -4-基)吗啉 将 2，4，7-三氯吡啶并 [2，3-d]嘧啶 lc (3 g， 12.80 mmol)溶解于 60 mL二氯甲烷中， 滴加吗啉 (2.23 g， 25.60 mmol), 搅拌反应 19小时。 减压浓縮， 加入 50 mL乙酸乙 酯和 50 mL水， 分液， 有机相用饱和氯化钠溶液洗涤 (50 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱剂体系 C纯化所得残余物， 得到标 题产物 4-(2，7-二氯吡啶并 [2，3-d]嘧啶 -4-基)吗啉 Id (2.90 g， 白色固体 产率： 79.7%。 4-(;2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)morpholine 2,4,7-Trichloropyrido[2,3-d]pyrimidine lc (3 g, 12.80 mmol) was dissolved in 60 mL of dichloromethane, and morpholine (2.23 g, 25.60 mmol) was added dropwise. 19 hours. The organic layer was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated. Chromatography. The obtained residue was purified with EtOAc EtOAc (EtOAc) Rate: 79.7%.
MS m/z (ESI): 285.1 [M+l]  MS m/z (ESI): 285.1 [M+l]
第四步  the fourth step
[5-(2-氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲醇 将 4-(2，7-二氯吡啶并 [2，3-d]嘧啶 -4-基)吗啉 Id (3.27 g， 11.50 mmol)溶解于 100 mL乙腈和水 (V/V = 1 :1)的混合溶剂中，加入 [2-甲氧基 -5-(4，4，5，5-四甲基 -1，3，2-二氧 杂戊硼烷 -2-基）苯基]甲醇 le (4.24 g， 13.80 mmol, 采用公知的方法"专利 WO2007084786"制备而得)， 碳酸钾 (4.80 g， 34.50 mmol)和双 (三苯基膦)合二氯化钯 (1.60 g, 2.30 mmol), 90°C下反应 3小时。 冷却后加入 400 mL乙酸乙酯， 分层， 有 机相用饱和氯化钠溶液洗涤 (100 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用 硅胶柱色谱法以洗脱剂体系 A纯化所得残余物， 得到标题产物 [5-(2-氯 -4-吗啉-吡 啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲醇 lf (2 g， 淡黄色固体 产率： 45.5%。 MS m/z (ESI): 387.1 [M+l]  [5-(2-Chloro-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol 4-(2,7-di The chloropyrido[2,3-d]pyrimidin-4-yl)morpholine Id (3.27 g, 11.50 mmol) was dissolved in 100 mL of a mixed solvent of acetonitrile and water (V/V = 1:1). -Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol le (4.24 g, 13.80 mmol, A well-known method "prepared by the patent WO2007084786", potassium carbonate (4.80 g, 34.50 mmol) and bis(triphenylphosphine)palladium dichloride (1.60 g, 2.30 mmol) were reacted at 90 ° C for 3 hours. After cooling, 400 mL of ethyl acetate was added, and the organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained is purified to give the title product [5-(2-chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol lf ( 2 g, pale yellow solid yield: 45.5% MS m/z (ESI): 387.1 [M+l]
第五步  the fifth step
7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-甲腈 将 [5-(2-氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲醇 If (50 mg， 0.13 mmol)和氰化钠 (7 mg， 0.14 mmol)溶解于 2 mL二甲基亚砜中， 140°C下反应 2小时。 冷却后加入 20 mL水，用乙酸乙酯萃取 (20 mLx2),合并有机相，依次用水 (40 mLx3) 和饱和氯化钠溶液洗涤 (40 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层 色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 7-[3- (羟甲基) -4-甲氧基- 苯基] -4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-甲腈 l (10 mg， 黄色固体 产率： 20.4%。  7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-B-pyrido[2,3-d]pyrimidine-2-carbonitrile [5-(2- Chloro-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol If (50 mg, 0.13 mmol) and sodium cyanide (7 mg , 0.14 mmol) was dissolved in 2 mL of dimethyl sulfoxide and reacted at 140 ° C for 2 hours. After cooling, add 20 mL of water, and extract with ethyl acetate (20 mL×2). The organic phase is combined, washed with water (40 mL×3) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered Concentration, the residue obtained was purified by EtOAc EtOAc (EtOAc) And [2,3-d]pyrimidine-2-carbonitrile 1 (10 mg, yellow solid yield: 20.4%.
MS m/z (ESI): 378.0 [M+l] MS m/z (ESI): 378.0 [M+l]
iHNMR (400 MHz, CD3OD): δ 8.57 (d, 1H), 8.33 (s, 1H), 8.25 (d， 1H), 8.13 (d， 1H)， 7.19 (d, 1H), 5.37 (s, 1H), 4.75 (s, 2H), 4.13-4.09 (m, 4H), 3.98 (s, 3H), 3.89-3.88 (m, 4H) 实施例 2 iHNMR (400 MHz, CD 3 OD): δ 8.57 (d, 1H), 8.33 (s, 1H), 8.25 (d, 1H), 8.13 (d, 1H), 7.19 (d, 1H), 5.37 (s, (1, H)
743- (羟甲基) -4-甲氧基 - 并「2,3-dl嘧啶 -2-甲酰胺  743-(Hydroxymethyl)-4-methoxy- and "2,3-dl-pyrimidine-2-carboxamide
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000030_0001
Figure imgf000031_0001
将 7-[3- (；羟甲基 4-甲氧基 -苯基 ]-4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-甲腈 1 (130 mg， 0.33 mmol), 过氧化氢溶液 (112 mg， 0.99 mmol)和碳酸钾 (92 mg， 0.66 mmol)溶解于 5 mL二甲基亚砜中， 反应 12小时。 加入 20 mL水， 用乙酸乙酯萃取 (20 mLx3)， 合并有机相， 用饱和氯化钠溶液洗涤 (40 mL)， 无水硫酸钠干燥， 过滤， 滤液减压 浓縮，用 HPLC制备色谱法以洗脱剂体系 A纯化所得残余物，得到标题产物 7-[3- (羟 甲基) -4-甲氧基 -苯基 ]-4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-甲酰胺 2 (20 mg， 黄色固体)， 产 率 15.3%。  7-[3-(; hydroxymethyl 4-methoxy-phenyl]-4-morpholine-B-pyrido[2,3-d]pyrimidine-2-carbonitrile 1 (130 mg, 0.33 mmol Hydrogen peroxide solution (112 mg, 0.99 mmol) and potassium carbonate (92 mg, 0.66 mmol) were dissolved in 5 mL of dimethyl sulfoxide for 12 hours. Add 20 mL of water and extract with ethyl acetate (20) The organic phase is combined, washed with a saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure, and purified by HPLC to eluent. The title product 7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-B-pyrido[2,3-d]pyrimidine-2-carboxamide 2 (20 mg, Yellow solid), yield 15.3%.
MS m/z (ESI): 396.2 [M+l]  MS m/z (ESI): 396.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.32 (s， 1H), 7.92-7.90 (m， 2H), 7.56 (d， 1H), 7.04 (d， 1H), 5.39 (s， 1H), 4.86 (s， 2H), 4.00 (s， 3H), 3.90-3.85 (m， 8H) 实施例 3 iHNMR (400 MHz, DMSO-J 6 ): δ 8.32 (s, 1H), 7.92-7.90 (m, 2H), 7.56 (d, 1H), 7.04 (d, 1H), 5.39 (s, 1H), 4.86 (s, 2H), 4.00 (s, 3H), 3.90-3.85 (m, 8H) Example 3
3-「「7-「3- (羟甲基) -4-甲氧基 -苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧啶 -2-  3-""7-"3-(Hydroxymethyl)-4-methoxy-phenyll-4-"(3 -3-methylmorpholin-4-yl 1 pyridine and 2,3-dl Pyrimidine-2-
Figure imgf000031_0002
Figure imgf000031_0002
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (100 mg， 0.25 mmol, 采用公知的方法 "专利 WO2008023161 "制备而得)， 3-氨基氮杂卓 -2-酮 (47.36 mg， 0.37 mmol), N，N-二异 丙基乙胺 (0.2 mL, 0.75 mmol)禾 B 5 mL 1,4-二氧六环， 90°C下反应 12小时。 减压浓 縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 3-[[7-[3- (羟甲 基) -4-甲氧基 -苯基 ]-4-[C3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2-基]氨基]氮杂卓 -2-酮 3 (80 mg， 黄色固体)， 产率： 65.0%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (100 mg, 0.25 mmol, prepared by the known method "WO2008023161", 3-aminoazepin-2-one (47.36 mg, 0.37 mmol), N,N- Diisopropylethylamine (0.2 mL, 0.75 mmol) and B 5 mL 1,4-dioxane, reacted at 90 ° C for 12 hours. Concentrated under reduced pressure, purified by thin layer chromatography with solvent system A The residue obtained gave the title product 3-[[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-[C3-3-methylmorpholin-4-yl] Pyrido[2,3-d]pyrimidin-2-yl]amino]azan-2-one 3 (80 mg, yellow solid), Yield: 65.0%.
MS m/z (ESI): 493.1 [M+l] MS m/z (ESI): 493.1 [M+l]
iHNMR (400 MHz, CDC13): δ 8.23-8.01 (m， 3H), 7.56-7.49 (m， 1H)， 7.01-6.91 (m， 1H) 5.37 (s， 1H), 4.82-4.79 (m， 2H), 3.95 (s， 3H), 3.72-3.68 (m， 4H)， 3.56-3.54 (m， 1H)， 3.44-3.32 (m， 3H), 3.22-3.19 (m， 2H), 1.88-1.63 (m， 2H), 1.56-1.24 (m， 4H)， 1.10 (d, 3H) 实施例 4 iHNMR (400 MHz, CDC1 3 ): δ 8.23-8.01 (m, 3H), 7.56-7.49 (m, 1H), 7.01-6.91 (m, 1H) 5.37 (s, 1H), 4.82-4.79 (m, 2H) ), 3.95 (s, 3H), 3.72-3.68 (m, 4H), 3.56-3.54 (m, 1H), 3.44-3.32 (m, 3H), 3.22-3.19 (m, 2H), 1.88-1.63 (m, 2H), 1.56-1.24 (m, 4H), 1.10 (d, 3H) Example 4
Γ5-Γ2-环丙基 -4-「( -甲氧基 -苯基 1甲醇  Γ5-Γ2-cyclopropyl-4-"(-methoxy-phenyl 1 methanol
Figure imgf000032_0001
Figure imgf000032_0001
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (30 mg， 0.07 mmol), 5 mL 1,4-二氧六环和水 (V/V = 3: 1) 的混合溶剂，环丙基硼酸 (8 mg， 0.09 mmol),碳酸钾 (31 mg， 0.23 mmol)和 [1，Γ-双 (；二 苯基膦基)二茂铁]二氯化钯 (3 mg， 0.004 mmol), 100°C下反应 18小时。 反应液减压 浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 [5-[2-环丙基 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲醇 4 (6 mg， 白 色固体)， 产率： 20.0%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (30 mg, 0.07 mmol), 5 mL of a mixed solvent of 1,4-dioxane and water (V/V = 3:1), cyclopropylboronic acid (8 mg, 0.09) Methyl), potassium carbonate (31 mg, 0.23 mmol) and [1, bis-bis(;diphenylphosphino)ferrocene]palladium dichloride (3 mg, 0.004 mmol), reacted at 100 ° C for 18 hours The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj -Based B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 4 (6 mg, white solid), yield: 20.0%.
MS m/z (ESI): 407.2 [M+l] MS m/z (ESI): 407.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.27-8.25 (m， 2H), 8.15 (d, 1H)， 7.75 (d, 1H)， 7.03 (d: 1H), 4.82 (s， 2H), 4.51 (s， 1H), 4.08 (m， 2H), 3.98 (s， 3H), 3.83-3.73 (m， 5H)， 1.55-1.53 (m， 3H), 1.25-1.23 (m， 1H)， 1.13-1.11 (m， 2H), 0.92-0.90 (m， 2H) 实施例 5 iHNMR (400 MHz, DMSO-J 6 ): δ 8.27-8.25 (m, 2H), 8.15 (d, 1H), 7.75 (d, 1H), 7.03 (d : 1H), 4.82 (s, 2H), 4.51 (s, 1H), 4.08 (m, 2H), 3.98 (s, 3H), 3.83-3.73 (m, 5H), 1.55-1.53 (m, 3H), 1.25-1.23 (m, 1H), 1.13-1.11 (m, 2H), 0.92-0.90 (m, 2H) Example 5
2-Γ743- (羟甲基) -4-甲氧基 -苯 ,3-dl嘧啶 -2-基 1丙基 -1,3-二醇  2-Γ743- (hydroxymethyl)-4-methoxy-benzene, 3-dl pyrimidine-2-yl 1-propyl-1,3-diol
Figure imgf000032_0002
Figure imgf000033_0001
Figure imgf000032_0002
Figure imgf000033_0001
第一步  First step
叔丁基 [[5-(2-氯 -4-吗啉-吡啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲醇] -二甲基硅烷 将 [5-(2-氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲醇 If (300 mg， 0.78 mmol), 叔丁基二甲基氯硅烷 (140 mg， 0.93 mmol)和三乙胺 (0.2 mL, 1.55 mmol) 溶解于 10 mL四氢呋喃中， 60°C下反应 12小时。 减压浓縮， 用硅胶柱色谱法以洗 脱剂体系 B纯化所得残余物， 得到标题产物叔丁基 [[5-(2-氯 -4-吗啉-吡啶并 [2，3-d] 嘧啶 -7-基) -2-甲氧基-苯基]甲醇] -二甲基硅烷 5a C150 mg， 黄色固体)，产率： 38.6%。 MS m/z (ESI): 502.1 [M+l]  tert-Butyl[[5-(2-chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol]-dimethylsilane [5-(2-Chloro-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol If (300 mg, 0.78 mmol), tert-Butyldimethylchlorosilane (140 mg, 0.93 mmol) and triethylamine (0.2 mL, 1.55 mmol) were dissolved in 10 mL of tetrahydrofuran and reacted at 60 ° C for 12 hours. The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut Pyrimidin-7-yl)-2-methoxy-phenyl]methanol]-dimethylsilane 5a C 150 mg (yellow solid), yield: 38.6%. MS m/z (ESI): 502.1 [M+l]
第二步  Second step
2-[7-[3- [(叔丁基 (二甲基)硅基)氧甲基 ]-4-甲氧基 -苯基 ]-4-吗啉-吡啶并 [2，3-d]嘧 啶 -2-基]丙二酸二乙酯  2-[7-[3-[(tert-butyl(dimethyl)silyl)oxymethyl]-4-methoxy-phenyl]-4-morpholine-pyrido[2,3-d] Pyrimidin-2-yl]malonic acid diethyl ester
将氢化钠 (28.80 mg， 1.20 mmol)和丙二酸二乙酯 (192 mg， 1.20 mmol)溶解于 10 mL乙腈中， 搅拌 30分钟， 加入叔丁基 [[5-0氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基) -2- 甲氧基-苯基]甲醇] -二甲基硅烷 5a (300 mg， 0.60 mmol), 回流反应 3小时。 倒入 30 mL冰水中， 用乙酸乙酯萃取 (40 mLx3)， 合并有机相， 用饱和氯化钠溶液洗涤 (50 mLx2), 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用 HPLC制备色谱法以洗脱剂体 系 A纯化所得残余物，得到标题产物 2-[7-[3- [(叔丁基 (二甲基)硅基)氧甲基 ]-4-甲氧 基-苯基] -4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-基]丙二酸二乙酯 5b (240 mg, 红棕色固体)， 产率： 64.2%。  Sodium hydride (28.80 mg, 1.20 mmol) and diethyl malonate (192 mg, 1.20 mmol) were dissolved in 10 mL of acetonitrile and stirred for 30 min to add tert-butyl [[5-0 chloro-4-morpholine -B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol]-dimethylsilane 5a (300 mg, 0.60 mmol). Pour into 30 mL of ice water, and extract with ethyl acetate (40 mL×3). The organic phase is combined, washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and filtered. Chromatography The residue obtained was purified using eluent A to give the title product 2-[7-[3-[(t-butyl(dimethyl)silyl)oxymethyl]-4-methoxy-phenyl ] 4-morpholine-B-pyrido[2,3-d]pyrimidin-2-yl]malonate 5b (240 mg, reddish brown solid), Yield: 64.2%.
MS m/z (ESI): 625.1 [M+l] MS m/z (ESI): 625.1 [M+l]
第三步  third step
2-[7-[3- (；羟甲基) -4-甲氧基 -苯基 ]-4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-基]丙基 -1，3-二醇 将 2-[7-[3- [(叔丁基 (二甲基)硅基)氧甲基 ]-4-甲氧基 -苯基 ]-4-吗啉-吡啶并 [2，3-d] 嘧啶 -2-基]丙二酸二乙酯 5b (120 mg, 0.20 mmol)溶解于 10 mL四氢呋喃中，加入硼 氢化锂 (17 mg, 0.80 mmol), 60°C下反应 2小时。 减压浓縮， 用 HPLC制备色谱法 以洗脱剂体系 A纯化所得残余物，得到标题产物 2-[7-[3- (羟甲基) -4-甲氧基-苯基] -4- 吗啉-吡啶并 [2，3-d]嘧啶 -2-基]丙基 -1,3-二醇 5 (8 mg， 黄色固体)， 产率： 9.7%。 MS m/z (ESI): 428.1 [M+l]  2-[7-[3-(;hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-B-pyrido[2,3-d]pyrimidin-2-yl]propyl- 1,3-diol will be 2-[7-[3-[(tert-butyl(dimethyl)silyl)oxymethyl]-4-methoxy-phenyl]-4-morpholine-pyridine [2,3-d] Pyrimidin-2-yl]malonate 5b (120 mg, 0.20 mmol) was dissolved in 10 mL of tetrahydrofuran, and lithium borohydride (17 mg, 0.80 mmol) was added at 60 ° C Reaction for 2 hours. Concentration under reduced pressure, the residue obtained was purified by chromatography eluting with EtOAc EtOAc (EtOAc) Morpholine-pyrido[2,3-d]pyrimidin-2-yl]propyl-1,3-diol 5 (8 mg, yellow solid), Yield: 9.7%. MS m/z (ESI): 428.1 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.33 (s, 1H)， 8.01-7.96 (m， 2H), 7.51 (d, 1H)， 7.10 (d, 1H), 5.02 (s, 1H)， 4.97 (s, 2H), 4.78 (s, 2H), 3.87-3.85 (m， 7H), 3.71-3.55 (m， 8H)， 2.97-2.96 (m， 1H) 实施例 6 Γ2-甲氧基 -5-「 -基 1苯基 1甲醇 iHNMR (400 MHz, DMSO-J 6 ): δ 8.33 (s, 1H), 8.01-7.96 (m, 2H), 7.51 (d, 1H), 7.10 (d, 1H), 5.02 (s, 1H), 4.97 (s, 2H), 4.78 (s, 2H), 3.87-3.85 (m, 7H), 3.71-3.55 (m, 8H), 2.97-2.96 (m, 1H) Example 6 Γ2-methoxy-5-"-yl 1 phenyl 1 methanol
Figure imgf000034_0001
Figure imgf000034_0001
将 [5-(2-氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲醇 If (150 mg， 0.39 mmol), 1-甲基哌啶 -4-胺 (53 mg， 0.46 mmol)和 N，N-二异丙基乙胺 （100 mg， 0.78 mmol)依次溶解于 5 mL 1，4-二氧六环中， 微波 140°C下反应 35分钟。 减压浓縮， 用 HPLC 制备色谱法以洗脱剂体系 A纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-吗啉 -2-C4-哌啶基氨基) B比啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 6 (10 mg， 黄色固 体)， 产率： 5.7%。  [5-(2-Chloro-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol If (150 mg, 0.39 mmol) , 1-methylpiperidin-4-amine (53 mg, 0.46 mmol) and N,N-diisopropylethylamine (100 mg, 0.78 mmol) were dissolved in 5 mL of 1,4-dioxane. The reaction was carried out in a microwave at 140 ° C for 35 minutes. Concentration under reduced pressure, and the residue obtained was purified by HPLC to elute to afford the title product [2-methoxy-5-[4-morpholin-2-C4-piperidinylamino). Pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 6 (10 mg, yellow solid), yield: 5.7%.
MS m/z (ESI): 451.1 [M+l] MS m/z (ESI): 451.1 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.32 (s, 1H), 8.21 (d, 1H), 8.08 (d, 1H), 7.62 (d， 1H)， 7.10 (d, 1H)， 5.26 (s, 1H)， 4.85 (s, 1H)， 4.82 (s, 1H)， 4.58 (s, 2H), 3.87 (s, 3H), 3.78-3.68 (m, 8H)， 3.31-3.29 (m, 3H), 3.04-2.98 (m, 2H), 2.03-2.00 (m, 2H), 1.51-1.48 (m， 2H) 实施例 7 iHNMR (400 MHz, DMSO-J 6 ): δ 8.32 (s, 1H), 8.21 (d, 1H), 8.08 (d, 1H), 7.62 (d, 1H), 7.10 (d, 1H), 5.26 (s , 1H), 4.85 (s, 1H), 4.82 (s, 1H), 4.58 (s, 2H), 3.87 (s, 3H), 3.78-3.68 (m, 8H), 3.31-3.29 (m, 3H), 3.04-2.98 (m, 2H), 2.03-2.00 (m, 2H), 1.51-1.48 (m, 2H) Example 7
「542- (氨基甲基 -4-吗啉-吡啶并「2,3-dl嘧啶 -7-基 1-2-甲氧基 -苯基 1甲醇  "542-(Aminomethyl-4-morpholine-pyridyl"2,3-dlpyrimidin-7-yl 1-2-methoxy-phenyl 1methanol
Figure imgf000034_0002
Figure imgf000034_0002
将 7-[3- (；羟甲基) -4-甲氧基 -苯基 ]-4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-甲腈 1 (；6 mg， 0.02 mmol)溶解于 2 mL甲醇中， 加入 0.1 mL氨水和钯 /碳 (3 mg， 10%), 氢气置换 三次， 反应 1小时。 反应液过滤， 减压浓縮， 用硅胶柱色谱法以洗脱剂体系 A纯 化所得残余物， 得到标题产物 [5-[2- (氨基甲基) -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基] -2- 甲氧基-苯基]甲醇 7 (5 mg， 黄色固体)， 产率： 83.3% 7-[3-(;hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-B-pyrido[2,3-d]pyrimidine-2-carbonitrile 1 (;6 mg , 0.02 mmol) was dissolved in 2 mL of methanol, and 0.1 mL of ammonia water and palladium/carbon (3 mg, 10%) were added, and the hydrogen was replaced three times for 1 hour. The reaction solution was filtered, and concentrated under reduced pressure. The residue was obtained to give the title product [5-[2-(aminomethyl)-4- morpholine-B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzene Methyl]methanol 7 (5 mg, yellow solid), Yield: 83.3%
MS m/z (ESI): 382.2 [M+l] MS m/z (ESI): 382.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.32 (s， 1H), 7.99-7.97 (m， 2H), 7.56 (d， 1H), 7.04 (d， 1H), 5.39 (s, 2H), 4.85 (s, 1H)， 4.72 (s, 2H), 4.04-3.93 (m， 4H)， 3.89 (s, 3H), 3.77-3.72 (m， 4H)， 2.28-2.26 (m， 2H) 实施例 8 iHNMR (400 MHz, DMSO-J 6 ): δ 8.32 (s, 1H), 7.99-7.97 (m, 2H), 7.56 (d, 1H), 7.04 (d, 1H), 5.39 (s, 2H), 4.85 (s, 1H), 4.72 (s, 2H), 4.04-3.93 (m, 4H), 3.89 (s, 3H), 3.77-3.72 (m, 4H), 2.28-2.26 (m, 2H) Example 8
「5-「2-( ,6-二氢 -2H-吡喃 -4-基) -4 l嘧啶 -7-基 1-2-甲氧基 -苯基 1甲醇  "5-"2-( ,6-Dihydro -2H-pyran-4-yl) -4 l pyrimidine -7-yl 1-2-methoxy-phenyl 1 methanol
Figure imgf000035_0001
Figure imgf000035_0001
于微波管中依次加入 [5-(2-氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基] 甲醇 If (100 mg， 0.26 mmol), 三丁基 (3,6-二氢 -2Η-吡喃 -4-基)锡烷 8a (144 mg， 0.39 mmol, 采用公知的方法 "专利 WO2010014939"制备而得)， 双 (；三苯基膦)合二氯 化钯 (17 mg， 0.025 mmol), N，N-二异丙基乙胺 (66 mg， 0.52 mmol),碘化亚酮 (4.70 mg: 0.025 mmol)和 5 mL N，N-二甲基甲酰胺， 130°C下反应 20分钟， 加入 20 mL乙酸 乙酯， 用水萃取 (20 mLx3)， 合并有机相， 用饱和氯化钠溶液洗涤 (50 mLx2)， 无水 硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余 物， 得到标题产物 [5-[2-(3，6-二氢 -2H-吡喃 -4-基 4-吗啉-吡啶并 [2，3-d]嘧啶 -7-基] -2- 甲氧基-苯基]甲醇 8 (55 mg， 黄色固体)， 产率： 49.1%。 [5-(2-Chloro-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol If (100) was added in a microwave tube. Mg, 0.26 mmol), tributyl(3,6-dihydro-2Η-pyran-4-yl)stannane 8a (144 mg, 0.39 mmol, prepared by the known method "WO2010014939"), double (triphenylphosphine) palladium dichloride (17 mg, 0.025 mmol), N,N-diisopropylethylamine (66 mg, 0.52 mmol), iodide iodide (4.70 mg : 0.025 mmol) and 5 mL of N,N-dimethylformamide, reacted at 130 ° C for 20 minutes, added 20 mL of ethyl acetate, extracted with water (20 mL×3), combined organic phase and washed with saturated sodium chloride solution (50 mL×2). The residue was dried over anhydrous sodium sulfate (MgSO4), filtered,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 4-yl 4-morpholine-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 8 (55 mg, yellow solid), yield: 49.1%.
MS m/z (ESI): 435.2 [M+l] MS m/z (ESI): 435.2 [M+l]
iHNMR (400 MHz, CDC13): δ 8.30 (m， 2H), 7.82 (d， 1H), 7.46 (d, 1H), 7.07 (d, 1H)， 4.84 (s, 2H), 4.49 (s, 2H), 4.00 (s, 3H), 3.98-3.95 (m, 4H), 3.88-3.09 (m, 4H), 2.94-2.93 (m, 2H), 1.69-1.67 (m, 2H), 1.43-1.39 (m, 2H) 实施例 9 iHNMR (400 MHz, CDC1 3 ): δ 8.30 (m, 2H), 7.82 (d, 1H), 7.46 (d, 1H), 7.07 (d, 1H), 4.84 (s, 2H), 4.49 (s, 2H ), 4.00 (s, 3H), 3.98-3.95 (m, 4H), 3.88-3.09 (m, 4H), 2.94-2.93 (m, 2H), 1.69-1.67 (m, 2H), 1.43-1.39 (m , 2H) Example 9
Γ2-甲氧基 -5-「2- (甲磺酰基甲基) -4-吗啉-吡啶并「2,3-dl嘧啶 -7-基 1苯基 1甲醇 2-methoxy-5-"2-(methylsulfonylmethyl)-4-morpholine-pyridine and 2,3-dlpyrimidin-7-yl 1phenyl 1 methanol
Figure imgf000036_0001
Figure imgf000036_0001
第一步  First step
叔丁基 -[[5-(2-氯 -4-吗啉-吡啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲基氧基]-二甲基 tert-Butyl-[[5-(2-chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methyloxy]-di Methyl
-娃院  -Dal
将 [5-(2-氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲醇 If (1 g， 2.58 mmol),叔丁基二甲基氯硅烷 (779 mg， 5.16 mmol)和三乙胺 (1 mL, 7.74 mmol)溶解于 10 mL四氢呋喃中， 回流反应 4小时， 50°C下反应 12小时。 减压浓縮， 用硅胶柱 色谱法以洗脱剂体系 B 纯化所得残余物， 得到标题产物叔丁基 -[[5-(2-氯 -4-吗啉- 吡啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲氧基]-二甲基 -硅烷 9a (500 mg， 白色固 体)， 产率 38.5%。  [5-(2-Chloro-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol If (1 g, 2.58 mmol) tert-Butyldimethylchlorosilane (779 mg, 5.16 mmol) and triethylamine (1 mL, 7.74 mmol) were dissolved in 10 mL of tetrahydrofuran, refluxed for 4 hours, and reacted at 50 ° C for 12 hours. The organic layer was concentrated under reduced pressure. Pyrimidin-7-yl)-2-methoxy-phenyl]methoxy]-dimethyl-silane 9a (500 mg, white solid), yield 38.5%.
MS m/z (ESI): 502.1 [M+l] MS m/z (ESI): 502.1 [M+l]
第二步  Second step
叔丁基 -[[2-甲氧基 -5-[2- (甲磺酰基甲基) -4-吗啉-吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲 氧基] -二甲基 -硅烷  tert-Butyl-[[2-methoxy-5-[2-(methylsulfonylmethyl)-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methoxy -dimethyl-silane
将磺酰基二甲烷 (282 mg， 3 mmol)溶解于 5 mL四氢呋喃中，滴加正丁基锂 (0.18 mL, 0.45 mmol), 搅拌 30分钟， 加入叔丁基 -[[5-(2-氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7- 基) -2-甲氧基-苯基]甲氧基] -二甲基 -硅烷 9a (150 mg， 0.30 mmol)，搅拌反应 12小时。 反应液减压浓縮， 用 HPLC制备色谱法以洗脱剂体系 A纯化所得残余物， 得到标 题产物叔丁基 -[[2-甲氧基 -5-[2- (甲磺酰基甲基) -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基]苯 基]甲氧基] -二甲基 -硅烷 9b (10 mg， 黄色固体)， 产率： 5.9%。  Sulfonyl dimethane (282 mg, 3 mmol) was dissolved in 5 mL of tetrahydrofuran, n-butyllithium (0.18 mL, 0.45 mmol) was added dropwise, stirred for 30 min, and tert-butyl-[[5-(2-chloro) -4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methoxy]-dimethyl-silane 9a (150 mg, 0.30 mmol ), the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. 4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methoxy]-dimethyl-silane 9b (10 mg, yellow solid), Yield: 5.9% .
MS m/z (ESI): 559.2 [M+l] MS m/z (ESI): 559.2 [M+l]
第三步  third step
[2-甲氧基 -5-[2- (甲磺酰基甲基) -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 将叔丁基 -[[2-甲氧基 -5-[2- (甲磺酰基甲基) -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基]苯 基]甲氧基] -二甲基 -硅烷 9b (10 mg， 0.02 mmol)和乙酰氯 (5 mg， 0.05 mmol)溶解于 5 mL甲醇中， 40°C下反应 12小时。 减压浓縮， 加入 20 mL乙酸乙酯， 依次用饱和 碳酸氢钠溶液 (20 mLx2)和饱和氯化钠溶液洗涤 (20 mLx2),无水硫酸钠干燥，过滤， 滤液减压浓縮， 用 HPLC制备色谱法以洗脱剂体系 A纯化所得残余物， 得到标题 产物 [2-甲氧基 -5-[2- (甲磺酰基甲基) -4-吗啉-吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 9 (5 mg， 黄色固体)， 产率： 62.5%。 [2-Methoxy-5-[2-(methylsulfonylmethyl)-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol tert-butyl -[[2-methoxy-5-[2-(methylsulfonylmethyl)-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methoxy ]-Dimethyl-silane 9b (10 mg, 0.02 mmol) and acetyl chloride (5 mg, 0.05 mmol) were dissolved in 5 mL of methanol and reacted at 40 ° C for 12 hours. The organic layer was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. HPLC preparative chromatography purification of the resulting residue with eluent system A to give the title Product [2-Methoxy-5-[2-(methylsulfonylmethyl)-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 9 (5 mg, Yellow solid), Yield: 62.5%.
MS m/z (ESI): 445.1 [M+l] MS m/z (ESI): 445.1 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.55 (s， 1H)， 8.45 (d， 1H)， 8.15 (d， 1H)， 7.67 (d， 1H)， 7.05 (d, 1H), 5.39 (s， 1H), 4.86 (s， 2H), 4.83 (s， 2H), 4.14-4.10 (m， 4H)， 3.97 (s， 3H), 3.88-3.83 (m, 4H), 3.15 (s, 3H) 实施例 10 iHNMR (400 MHz, DMSO-J 6 ): δ 8.55 (s, 1H), 8.45 (d, 1H), 8.15 (d, 1H), 7.67 (d, 1H), 7.05 (d, 1H), 5.39 (s , (1, H) Example 10
Γ2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 1-2-個氢吡喃 -4-基-氨基)吡啶并「2,3-dl嘧啶 -7-  2-methoxy-5-"4-"(3 -3-methylmorpholin-4-yl1-2-hydropyran-4-yl-amino)pyridine and 2,3-dl pyrimidine- 7-
Figure imgf000037_0001
Figure imgf000037_0001
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (140 mg， 0.35 mmol), 四氢吡喃 -4-氨基 (60 mg， 0.52 mmol), 3 mLl，4-二氧六环和 N，N-二异丙基乙胺 (225 mg， 1.75 mmol), 90°C下反应 12小时。 减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产 物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2- (四氢吡喃 -4-基-氨基) B比啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 10 (17mg， 黄色固体)， 产率： 11.8%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (140 mg, 0.35 mmol), tetrahydropyran-4-amino (60 mg, 0.52 mmol), 3 mL of 1,2-dioxane and N,N-diisopropyl Ethylamine (225 mg, 1.75 mmol) was reacted for 12 hours at 90 ° C. The residue was purified eluting with EtOAc (EtOAc) [4-[(3 -3-methylmorpholin-4-yl)-2-(tetrahydropyran-4-yl-amino) B-pyrido[2,3-d]pyrimidin-7-yl] Phenyl]methanol 10 (17 mg, yellow solid), Yield: 11.8%.
MS m/z (ESI): 466.2 [M+l] MS m/z (ESI): 466.2 [M+l]
iHNMR (400 MHz, CDC13): δ 8.15 (d， 2H), 7.96 (d， 1H), 7.49 (s, 1H), 6.94 (d, 1H)， 4.76 (s, 2H), 4.47-4.45 (m, 1H), 4.02 (d, 3H), 3.92 (s, 3H), 3.81-3.80 (m, 3H), 3.75 (m, 3H), 3.71 (t， 2H), 2.90-2.80 (m， 2H), 2.04-2.02 (m， 2H), 1.50-1.48 (m， 4H) 实施例 11 iHNMR (400 MHz, CDC1 3 ): δ 8.15 (d, 2H), 7.96 (d, 1H), 7.49 (s, 1H), 6.94 (d, 1H), 4.76 (s, 2H), 4.47-4.45 (m , 1H), 4.02 (d, 3H), 3.92 (s, 3H), 3.81-3.80 (m, 3H), 3.75 (m, 3H), 3.71 (t, 2H), 2.90-2.80 (m, 2H), 2.04-2.02 (m, 2H), 1.50-1.48 (m, 4H) Example 11
Γ2-甲氧基 -5-(4-吗啉 -2-四氢吡喃 -4-基-吡啶并「2,3-dl嘧啶 -7-基)苯基 1甲醇 2-methoxy-5-(4-morpholin-2-tetrahydropyran-4-yl-pyrido-2,3-dlpyrimidin-7-yl)phenyl 1methanol
Figure imgf000038_0001
Figure imgf000038_0001
将 [5-[2-(3，6-二氢 -2H-吡喃 -4-基 )-4-吗啉-吡啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯 基]甲醇 8 (80 mg， 0.18 mmol)溶解于 5 mL甲醇中，加入钯 /碳 (16 mg， 10%)和 0.2 mL 乙酸， 氢气置换三次， 搅拌反应 12小时。 过滤， 滤液减压浓縮， 用薄层色谱法以 展开剂体系 A纯化所得残余物， 得到标题产物 [2-甲氧基 -5-(4-吗啉 -2-四氢吡喃 -4- 基-吡啶并 [2，3-d]嘧啶 -7-基)苯基]甲醇 ll (23 mg， 黄色固体)， 产率： 28.8%。  [5-[2-(3,6-Dihydro-2H-pyran-4-yl)-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy The base-phenyl]methanol 8 (80 mg, 0.18 mmol) was dissolved in 5 mL of methanol, and then palladium/carbon (16 mg, 10%) and 0.2 mL of acetic acid were added, and the mixture was replaced with hydrogen three times, and the reaction was stirred for 12 hours. Filtration, and the filtrate was concentrated under reduced pressure. Base-pyrido[2,3-d]pyrimidin-7-yl)phenyl]methanol (23 mg, yellow solid), yield: 28.8%.
MS m/z (ESI): 437.2 [M+l] MS m/z (ESI): 437.2 [M+l]
iHNMR (400 MHz, CDC13): 8.28 (d, 1H), 8.26 (s， 1H), 8.19 (d, 1H), 7.77 (d, 2H), 7.01 (d， 1H)， 4.80 (s, 2H), 4.10 (d， 2H), 3.96 (s, 3H), 3.88-3.80 (m， 8H)， 3.78 (s, 1H), 3.61 (t， 2H), 2.14-1.98 (m, 4H) 实施例 12 iHNMR (400 MHz, CDC1 3 ): 8.28 (d, 1H), 8.26 (s, 1H), 8.19 (d, 1H), 7.77 (d, 2H), 7.01 (d, 1H), 4.80 (s, 2H) , 4.10 (d, 2H), 3.96 (s, 3H), 3.88-3.80 (m, 8H), 3.78 (s, 1H), 3.61 (t, 2H), 2.14-1.98 (m, 4H) Example 12
34「7-「3- (羟 -4-甲氧基 -苯基 1-4-吗啉-吡啶并「2,3-dl嘧啶 -2-基 1氨基愾杂卓 34" 7- "3-(Hydroxy-4-methoxy-phenyl1-4-morpholine-pyridine and 2,3-dl-pyrimidin-2-yl-1aminoindole
Figure imgf000038_0002
Figure imgf000038_0002
将 [5-(2-氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲醇 If (200 mg, 0.52 mmol), 3-氨基氮杂卓 -2-酮 (100 mg, 0.62 mmol)和 N，N-二异丙基乙胺 (0.1 mL, 0.37 mmol)溶解于 5 mL 1，4-二氧六环中， 回流反应 7小时。 反应液减压浓縮， 用 HPLC制备色谱法以洗脱剂体系 A纯化所得残余物， 得到标题产物 3-[[7-[3- (羟甲 基) -4-甲氧基 -苯基 ]-4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-基]氨基]氮杂卓 -2-酮 12 (80 mg， 黄 色固体)， 产率： 32.4%。 [5-(2-Chloro-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol If (200 mg, 0.52 mmol) , 3-aminoazepine-2-one (100 mg, 0.62 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.37 mmol) were dissolved in 5 mL of 1,4-dioxane. The reaction was refluxed for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by HPLC to elute to afford the title product 3-[[7-[3- (hydroxymethyl) -4-Methoxy-phenyl]-4-morpholine-B-pyrido[2,3-d]pyrimidin-2-yl]amino]azepin-2-one 12 (80 mg, yellow Solid), Yield: 32.4%.
MS m/z (ESI): 479.1 [M+l] MS m/z (ESI): 479.1 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.45 (s， 1H)， 8.33 (d, 1H)， 8.16-8.15 (m， 1H)， 8.13 (d， 1H)， 7.89 (d, 1H), 7.15 (d, 1H), 5.33 (s， 1H), 4.67 (s， 1H), 4.57 (s， 2H), 3.88 (s， 3H), 3.79-3.70 (m， 9H)， 3.32-3.30 (m， 2H), 2.10-2.07 (m， 2H), 1.80-1.75 (m， 2H), 1.48-1.45 (m， 2H) 实施例 13 iHNMR (400 MHz, DMSO-J 6 ): δ 8.45 (s, 1H), 8.33 (d, 1H), 8.16-8.15 (m, 1H), 8.13 (d, 1H), 7.89 (d, 1H), 7.15 (d, 1H), 5.33 (s, 1H), 4.67 (s, 1H), 4.57 (s, 2H), 3.88 (s, 3H), 3.79-3.70 (m, 9H), 3.32-3.30 (m, 2H) ), 2.10-2.07 (m, 2H), 1.80-1.75 (m, 2H), 1.48-1.45 (m, 2H) Example 13
Figure imgf000039_0001
Figure imgf000039_0001
第一步  First step
3-[(3-氨基甲酰 -6-氯 -2-吡啶)氨基] -3-氧代-丙酸甲酯 将 2-氨基 -6-氯-吡啶-甲酰胺 la (500 mg， 2.91 mmol), N，N-二异丙基乙胺 (537 mL， 2.91 mmol)和 4-二甲氨基吡啶 (3.57 mg， 0.03 mmol)溶解于 16 mL二氯甲烷和 N，N-二甲基甲酰胺 (V/V = 1 : 1)的混合溶剂中， 0°C下滴加 3-氯 -3-氧代-丙酸甲酯 (477 mg， 3.50 mmol),室温搅拌反应 18小时。加入 30 mL水，用乙酸乙酯萃取 (30 mLx2), 合并有机相， 依次用水 (50 mLx3)和饱和氯化钠溶液洗涤 (50 mLx2)， 无水硫酸钠干 燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱剂体系 A纯化所得残余物， 得 到标题产物 3-[C3-氨基甲酰 -6-氯 -2-吡啶)氨基] -3-氧代-丙酸甲酯 13a (420 mg， 黄色 固体)， 产率： 50.5%。  3-[(3-carbamoyl-6-chloro-2-pyridyl)amino]-3-oxo-propionic acid methyl ester 2-amino-6-chloro-pyridine-carboxamide la (500 mg, 2.91 mmol , N,N-diisopropylethylamine (537 mL, 2.91 mmol) and 4-dimethylaminopyridine (3.57 mg, 0.03 mmol) dissolved in 16 mL of dichloromethane and N,N-dimethylformamide In a mixed solvent of (V/V = 1:1), methyl 3-chloro-3-oxo-propionate (477 mg, 3.50 mmol) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 18 hours. After adding 30 mL of water and extracting with ethyl acetate (30 mL×2), the organic phase was combined, washed with water (50 mL×3) and saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and filtered. The residue obtained was purified by silica gel column chromatography eluting eluting elut elut (420 mg, yellow solid), Yield: 50.5%.
MS m/z (ESI): 272.0 [M+l] MS m/z (ESI): 272.0 [M+l]
第二步  Second step
2-(7-氯 -4-氧代 -3H-吡啶并 [2，3-d]嘧啶 -2基)乙酸乙酯 将 3-[(3-氨基甲酰 -6-氯 -2-吡啶)氨基] -3-氧代-丙酸甲酯 13a (30 mg， 0.11 mmol) 和碳酸钠 C59 mg， 0.55 mmol)溶解于 2 mL乙醇和水 (V/V = 1 : 1)的混合溶剂中， 搅拌 反应 34小时。 加入 10 mL水， 用乙酸乙酯萃取 (20 mIX3)， 合并有机相， 用饱和 氯化钠溶液洗涤 (40 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用硅胶柱色 谱法以洗脱剂体系 A纯化所得残余物， 得到标题产物 2-(7-氯 -4-氧代 -3H-吡啶并 [2，3-d]嘧啶 -2基)乙酸乙酯 13b (15 mg， 白色固体)， 产率： 53.6%。 Ethyl 2-(7-chloro-4-oxo-3H-pyrido[2,3-d]pyrimidin-2-yl)acetate 3-[(3-carbamoyl-6-chloro-2-pyridine) Amino]-3-oxo-propionic acid methyl ester 13a (30 mg, 0.11 mmol) and sodium carbonate C59 mg, 0.55 mmol) were dissolved in a mixture of 2 mL of ethanol and water (V/V = 1:1). Stir Reaction for 34 hours. After adding 10 mL of water, and extracting with ethyl acetate (20 mIX3), the organic phase is combined, washed with a saturated sodium chloride solution (40 mL×2), dried over anhydrous sodium sulfate, filtered, The obtained residue was purified with EtOAc EtOAc (EtOAc) White solid), Yield: 53.6%.
MS m/z (ESI): 268.1 [M+l] MS m/z (ESI): 268.1 [M+l]
第三步  third step
2-(4，7-二氯吡啶并 [2，3-d]嘧啶 -2-基)乙酸乙酯 将 2-(7-氯 -4-氧代 -3H-吡啶并 [2，3-d]嘧啶 -2-基）乙酸乙酯 13b (340 mg， 1.27 mmol)和 N，N-二异丙基乙胺 (493 mg， 3.82 mmol)溶解于 20 mL甲苯中， 0°C下加入三 氯氧磷 (52 mg， 0.34 mmol), 搅拌反应 1小时， 反应液减压浓縮， 真空干燥， 得到 标题产物粗品 2-(4，7-二氯吡啶并 [2，3-d]嘧啶 -2基)乙酸乙酯 13c (160 mg， 白色固 体)， 产物不经纯化直接用于下步反应。  Ethyl 2-(4,7-dichloropyrido[2,3-d]pyrimidin-2-yl)acetate 2-(7-chloro-4-oxo-3H-pyrido[2,3-d Pyrimidine-2-yl)acetate 13b (340 mg, 1.27 mmol) and N,N-diisopropylethylamine (493 mg, 3.82 mmol) were dissolved in 20 mL of toluene and trichlorobenzene was added at 0 °C. Phosphorus (52 mg, 0.34 mmol), the reaction was stirred for 1 hr. Ethyl acetate 13c (160 mg, white solid), product was used in the next step without purification.
MS m/z (ESI): 286.1 [M+l] MS m/z (ESI): 286.1 [M+l]
第四步  the fourth step
2-(7-氯 -4-吗啉-吡啶并 [2，3-d]嘧啶 -2基)乙酸乙酯 将粗品 2-(4，7-二氯吡啶并 [2，3-d]嘧啶 -2基)乙酸乙酯 13c (160 mg， 0.56 mmol) 和三乙胺 (113 mg， 1.12 mmol)溶解于 10 mL二氯甲烷中， 0°C下加入吗啉 (55 mg， 0.62 mmol), 室温反应 18小时， 加入 20 mL水， 用乙酸乙酯萃取 (20 mLx3)， 合并 有机相， 用饱和氯化钠溶液洗涤 (40 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓 縮， 用硅胶柱色谱法以洗脱剂体系 A纯化所得残余物， 得到标题产物 2-(7-氯 -4- 吗啉-吡啶并 [2，3-d]嘧啶 -2基)乙酸乙酯 13d (160 mg， 白色固体)， 产率： 85.1%。 MS m/z (ESI): 337.0 [M+l] Ethyl 2-( 7 -chloro-4-morpholine-pyrido[2,3-d]pyrimidin-2-yl)acetate as a crude 2-(4,7-dichloropyrido[2,3-d]pyrimidine Ethyl acetate 13c (160 mg, 0.56 mmol) and triethylamine (113 mg, 1.12 mmol) were dissolved in 10 mL of dichloromethane and morpholine (55 mg, 0.62 mmol). The reaction was carried out at room temperature for 18 hours, EtOAc (EtOAc) (EtOAc) The obtained residue was purified to silica gel column chromatography elut elut elut elut elut elut 160 mg, white solid), Yield: 85.1%. MS m/z (ESI): 337.0 [M+l]
第五步  the fifth step
2-[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-基]乙酸乙酯 将 2-(7-氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -2基)乙酸乙酯 13d (20 mg， 0.06 mmol), [2- 甲氧基 -5-(4，4，5，5-四甲基 -1，3，2-二氧杂戊硼烷 -2-基)苯基]甲醇 le (17 mg， 0.06 mmol) 和碳酸氢钠 (15 mg， 0.18 mmol)溶解于 2 mL乙腈和水 (V/V = 1 : 1)的混合溶剂中， 加 入四 (三苯基膦)钯 (6.93 mg， 0.006 mmol), 90°C下反应 3小时， 加入 10 mL水， 用 乙酸乙酯萃取 (10 mLx3)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫 酸钠干燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱剂体系 A纯化所得残余 物，得到标题产物 2-[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-吗啉-吡啶并 [2，3-d]嘧啶 -2-基] 乙酸乙酯 13 (13 mg， 黄色固体)， 产率： 50.0%。  Ethyl 2-[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-B-pyrido[2,3-d]pyrimidin-2-yl]acetate Ethyl 2-(7-chloro-4-morpholine-B-pyrido[2,3-d]pyrimidin-2-yl)acetate 13d (20 mg, 0.06 mmol), [2-methoxy-5- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol le (17 mg, 0.06 mmol) and sodium bicarbonate (15 mg, 0.18) Ment) dissolved in 2 mL of a mixed solvent of acetonitrile and water (V/V = 1:1), added tetrakis(triphenylphosphine)palladium (6.93 mg, 0.006 mmol), reacted at 90 ° C for 3 hours, added 10 </ br> </ br> </ br> </ br> </ br> </ br> </ br> The obtained residue was purified by a solvent-off system A to give the title product 2-[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3-d] Pyrimidin-2-yl]ethyl acetate 13 (13 mg, yellow solid), yield: 50.0%.
MS m/z (ESI): 439.1 [M+l] MS m/z (ESI): 439.1 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.28 (d, 1H), 8.26 (s， 1H), 8.19 (d， 1H), 7.77 (d， 2H), 7.01 (d， 1H), 4.80 (s， 2H), 4.10 (d, 2H), 3.96 (s， 3H), 3.61 (m， 2H), 3.32-3.30 (m， 2H), 2.78 (s， 2H), 2.10-2.07 (m， 2H), 1.80-1.75 (m， 2H)， 1.35 (t， 3H) 实施例 14 iHNMR (400 MHz, DMSO-J 6 ): δ 8.28 (d, 1H), 8.26 (s, 1H), 8.19 (d, 1H), 7.77 (d, 2H), 7.01 (d, 1H), 4.80 (s , 2H), 4.10 (d, 2H), 3.96 (s, 3H), 3.61 (m, 2H), 3.32-3.30 (m, 2H), 2.78 (s, 2H), 2.10-2.07 (m, 2H), 1.80-1.75 (m, 2H), 1.35 (t, 3H) Example 14
「542-「(1,1-二氧代硫代吡喃-4-基)氨基卜4-吗啉-吡啶并「2,3-(11嘧啶-7-基1-2-甲氧基-  "542-"(1,1-dioxothiopyran-4-yl)aminobu-4-morpholine-pyridine and "2,3-(11-pyrimidin-7-yl)1-2-methoxy-
Figure imgf000041_0001
Figure imgf000041_0001
第一步  First step
1，1-二氧代硫代吡喃 -4-胺  1,1-dioxothiopyran-4-amine
将 1,1-二氧代硫代吡喃 -4-酮 14a (6.60 g， 44.70 mmol)和甲酸铵 (28 g， 0.45 mmol) 溶解于 70 mL甲醇和水 (V/V = 6:1)的混合溶剂中， 加入钯 /碳 (2.80 g， 10%)， 氢气置 换三次， 搅拌反应 12小时， 过滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱剂体系 A纯化所得残余物， 得到标题产物 1，1-二氧代硫代吡喃 -4-胺 14b (4.20 g， 白色固 体)， 产率： 63.6%。  Dissolve 1,1-dioxothiopyran-4-one 14a (6.60 g, 44.70 mmol) and ammonium formate (28 g, 0.45 mmol) in 70 mL of methanol and water (V/V = 6:1) To the mixed solvent, palladium on carbon (2.80 g, 10%) was added, and the hydrogen was replaced three times. The reaction was stirred for 12 hours, filtered, and the filtrate was concentrated under reduced pressure. The title product 1,1-dioxothiopyran-4-amine 14b (4.20 g, white solid) was obtained, yield: 63.6%.
MS m/z (ESI): 149.1 [M+l] MS m/z (ESI): 149.1 [M+l]
第二步  Second step
7-[3- [(叔丁基 (二甲基)硅烷基)氧基甲基] -4-甲氧基-苯基] -N-(l，l-二氧代硫代吡喃 -4 基 4-吗啉-吡啶并 [2，3-d]嘧啶 -2-胺  7-[3-[(tert-Butyl(dimethyl)silyl)oxymethyl]-4-methoxy-phenyl]-N-(l,l-dioxothiopyran-4 4-morpholine-pyrido[2,3-d]pyrimidin-2-amine
于封管中依次加入叔丁基 [[5-(2-氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基- 苯基]甲醇] -二甲基硅烷 5a (100 mg， 0.20 mmol), 1,1-二氧代硫代吡喃 -4-胺 14b (60 mg， 0.40 mmol), N，N-二异丙基乙胺 (80 mg， 0.60 mmol)和 15 mL 1,4-二氧六环， 120°C下反应 12小时。 反应液减压浓縮， 用 HPLC制备色谱法以洗脱剂体系 A纯 化所得残余物， 得到标题产物 7-[3- [(叔丁基 (二甲基)硅烷基)氧基甲基] -4-甲氧基- 苯基] -N-CU-二氧代硫代吡喃 -4基 4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-胺 14c (53 mg， 黄 色固体)， 产率： 43.4%。  Add tert-butyl [[5-(2-chloro-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl] in turn in a sealed tube Methanol]-dimethylsilane 5a (100 mg, 0.20 mmol), 1,1-dioxothiopyran-4-amine 14b (60 mg, 0.40 mmol), N,N-diisopropylethylamine (80 mg, 0.60 mmol) and 15 mL of 1,4-dioxane were reacted at 120 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. 4-methoxy-phenyl]-N-CU-dioxothiopyran-4-yl 4-morpholine-B-pyrido[2,3-d]pyrimidin-2-amine 14c (53 mg, Yellow solid), Yield: 43.4%.
MS m/z (ESI): 614.2 [M+l] MS m/z (ESI): 614.2 [M+l]
第三步  third step
[5-[2-[G，l-二氧代硫代吡喃 -4-基)氨基] -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基- 苯基]甲醇  [5-[2-[G,1-dioxothiopyran-4-yl)amino]-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl]-2 -methoxy-phenyl]methanol
将 7-[3- [(叔丁基 (二甲基)硅烷基)氧基甲基] -4-甲氧基-苯基] -Ν-(1，1-二氧代硫代 吡喃 -4基) -4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-胺 14c (122 mg， 0.20 mmol)溶解于 5 mL甲 醇中， 滴加 10 mL盐酸甲醇溶液， 搅拌 30分钟， 减压浓縮， 真空干燥， 得到标题 产物 [5-[2-[(1，1-二氧代硫代吡喃 -4-基)氨基] -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧 基-苯基]甲醇 14 (6 mg， 黄色固体)， 产率： 6.0% 7-[3-[(tert-Butyl(dimethyl)silyl)oxymethyl]-4-methoxy-phenyl]-indole-(1,1-dioxothio) Pyran-4-yl)-4-morpholine-B-pyrido[2,3-d]pyrimidin-2-amine 14c (122 mg, 0.20 mmol) was dissolved in 5 mL of methanol, and 10 mL hydrochloric acid in methanol was added dropwise. , stirred for 30 minutes, concentrated under reduced pressure and dried in vacuo to give the title product [5-[2-[(1,1-dioxothiopyran-4-yl)amino]-4-morpholine-B ratio Pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 14 (6 mg, yellow solid), yield: 6.0%
MS m/z (ESI): 500.1 [M+l] MS m/z (ESI): 500.1 [M+l]
iHNMR (400 MHz, CDC13): δ 8.17 (s， 1H), 8.14 (s， 1H), 8.02 (d, 1H), 7.50 (d, 2H), 6.99 (d, 2H), 4.79 (s， 2H), 4.50 (br.， 1H), 3.95 (s， 3H), 3.89-3.88 (m， 4H)， 3.74 (s， 2H), 3.18-3.15 (m, 4H)， 2.52-2.48 (m， 2H), 2.29-2.27 (m， 3H) 实施例 15 iHNMR (400 MHz, CDC1 3 ): δ 8.17 (s, 1H), 8.14 (s, 1H), 8.02 (d, 1H), 7.50 (d, 2H), 6.99 (d, 2H), 4.79 (s, 2H ), 4.50 (br., 1H), 3.95 (s, 3H), 3.89-3.88 (m, 4H), 3.74 (s, 2H), 3.18-3.15 (m, 4H), 2.52-2.48 (m, 2H) , 2.29-2.27 (m, 3H) Example 15
「2-甲氧基 -5- -7-基 1苯基 1甲  "2-methoxy-5--7-yl 1 phenyl 1 A
Figure imgf000042_0001
Figure imgf000042_0001
于封管中依次加入 (3R)-四氢呋喃 -3-醇 (45 mg， 0.51 mmol), 3 mLN，N-二甲基甲 酰胺和氢化钠(；31 1¾，0.78 1^^0， 50°C下搅拌 1小时，加入 [5-( 氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲醇 If (lOO mg, 0.26 mmol), 50°C下反应 12小时， 加入 50 mL乙酸乙酯和 20mL水， 分层， 有机相用饱和氯化钠溶液洗涤， 无水硫 酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-吗啉 -2-[ 3R)-四氢呋喃 -3-基]氧基-吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 15 (15 mg， 黄色固体)， 产率： 13.3%。  (3R)-tetrahydrofuran-3-ol (45 mg, 0.51 mmol), 3 mL of N,N-dimethylformamide and sodium hydride (31 13⁄4, 0.78 1^^0, 50 ° C) were added to the sealed tube. After stirring for 1 hour, [5-(chloro-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol If (100 mg, 0.26 mmol), the reaction was carried out at 50 ° C for 12 hours, 50 mL of ethyl acetate and 20 mL of water were added, and the layers were separated. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated. The resulting residue was purified by EtOAc EtOAc (EtOAc): 2,3-d]pyrimidin-7-yl]phenyl]methanol 15 (15 mg, yellow solid), yield: 13.3%.
MS m/z (ESI): 439.1 [M+l] MS m/z (ESI): 439.1 [M+l]
iHNMR (400 MHz, CDC13): δ 8.11 (s, 1H), 7.91 (d， 1H), 7.78 (d， 1H), 7.05 (d, 1H)， 6.86 (d, 1H), 4.80 (s, 2H), 4.07-4.00 (m, 8H)， 3.95 (s, 3H), 3.89 (s, 4H), 2.31 (s, 3H) 实施例 16 iHNMR (400 MHz, CDC1 3 ): δ 8.11 (s, 1H), 7.91 (d, 1H), 7.78 (d, 1H), 7.05 (d, 1H), 6.86 (d, 1H), 4.80 (s, 2H) ), 4.07-4.00 (m, 8H), 3.95 (s, 3H), 3.89 (s, 4H), 2.31 (s, 3H) Example 16
l-「4-「「7-「3- (羟甲基) -4-甲氧基 -苯基 1-4-吗啉-吡啶并「2,3-dl嘧啶 -2-基 1氨基 1-1-哌 啶基 1乙酮 L-"4-""7-"3-(Hydroxymethyl)-4-methoxy-phenyl1-4-morpholine-pyridine and "2,3-dl-pyrimidin-2-yl 1amino 1- 1-piperidinyl 1 ethyl ketone
Figure imgf000043_0001
Figure imgf000043_0001
将 [5-(2-氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲醇 If (200 mg， 0.52 mmol), 1-(4-氨基 -1-哌啶基)乙酮 （88 mg， 0.62 mmol)和 N，N-二异丙基乙胺 (0.1 mL， 0.37 mmol)溶解于 5 mL 1，4-二氧六环， 回流反应 7小时。 反应液减压浓縮， 用 HPLC制备色谱法以洗脱剂体系 A纯化所得残余物， 得到标题产物 1-[4-[[7-[3- (羟 甲基) -4-甲氧基 -苯基 ]-4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-基]氨基] -1-哌啶基]乙酮 16 (90 mg， 黄色固体)， 产率： 35.1%。  [5-(2-Chloro-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol If (200 mg, 0.52 mmol) , 1-(4-Amino-1-piperidyl)ethanone (88 mg, 0.62 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.37 mmol) dissolved in 5 mL 1,4- Oxycyclohexane, reflux reaction for 7 hours. The reaction mixture was concentrated under reduced pressure and purified to purified crystals eluted elut elut elut elut elut elut elut eluting Phenyl]-4-morpholine-B-pyrido[2,3-d]pyrimidin-2-yl]amino]-1-piperidinyl]ethanone 16 (90 mg, yellow solid), Yield: 35.1 %.
MS m/z (ESI): 493.1 [M+l] MS m/z (ESI): 493.1 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.30 (s, 1H), 8.17 (d, 1H), 8.07 (d, 1H), 7.72 (d， 1H)， 7.09 (d， 1H)， 5.21 (t， 1H)， 4.56 (d, 2H), 4.33 (br.， 1H)， 4.17 (br.， 2H), 3.92 (s， 2H), 3.87 (s， 3H), 3.77 (s, 2H), 3.65 (s, 3H), 3.24-3.21 (m， 2H), 2.03 (s, 3H), 1.99-1.87 (m， 4H)， 1.48-1.30 (m, 2H) 实施例 17 iHNMR (400 MHz, DMSO-J 6 ): δ 8.30 (s, 1H), 8.17 (d, 1H), 8.07 (d, 1H), 7.72 (d, 1H), 7.09 (d, 1H), 5.21 (t , 1H), 4.56 (d, 2H), 4.33 (br., 1H), 4.17 (br., 2H), 3.92 (s, 2H), 3.87 (s, 3H), 3.77 (s, 2H), 3.65 ( s, 3H), 3.24-3.21 (m, 2H), 2.03 (s, 3H), 1.99-1.87 (m, 4H), 1.48-1.30 (m, 2H) Example 17
Γ2-甲氧基 -5-( -基)苯基 1甲醇  Γ2-methoxy-5-(-yl)phenyl 1 methanol
Figure imgf000043_0002
Figure imgf000043_0002
于封管中依次加入四氢吡喃 -4-醇 （60 mg， 0.59 mmol), 3 mL N，N-二甲基甲酰 胺和氢化钠 (10 mg， 0.26 mmol), 50°C下搅拌 1小时， 加入 [5-(2-氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲醇 If (lOO mg, 0.26 mmol), 50°C下反应 12小时， 加入 50 mL乙酸乙酯和 20mL水， 分层， 有机相用饱和氯化钠溶液洗涤， 无水硫 酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 [2-甲氧基 -5-(4-吗啉 -2-四氢吡喃 -4-基 -氧基 -B比啶并 [2，3-d]嘧啶 -7-基) 苯基]甲醇 17 (15 mg， 黄色固体)， 产率： 12.8%。 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. In hours, add [5-(2-chloro-4-morpholine-B-pyridinium and [2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol If (100 mg, 0.26 mmol), reacted at 50 ° C for 12 hours, added 50 mL of ethyl acetate and 20 mL of water The organic phase is washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. Oxy-5-(4-morpholin-2-tetrahydropyran-4-yl-oxy-B-pyrido[2,3-d]pyrimidin-7-yl)phenyl]methanol 17 (15 mg , yellow solid), Yield: 12.8%.
MS m/z (ESI): 453.1 [M+l] MS m/z (ESI): 453.1 [M+l]
iHNMR (400 MHz, CDC13): δ 8.34 (d， 1H), 8.26 (s, 1H), 7.97 (d, 1H), 7.70 (d, 1H)， 6.62 (d， 1H), 4.76 (s, 2H), 4.03-4.01 (m， 5H)， 3.90-3.88 (m， 3H), 3.87 (s, 3H), 3.81-3.79 (m, 1H), 3.64-3.62 (m, 2H), 2.20-2.10 (m, 2H), 2.00-1.85 (m, 4H) 实施例 18 iHNMR (400 MHz, CDC1 3 ): δ 8.34 (d, 1H), 8.26 (s, 1H), 7.97 (d, 1H), 7.70 (d, 1H), 6.62 (d, 1H), 4.76 (s, 2H ), 4.03-4.01 (m, 5H), 3.90-3.88 (m, 3H), 3.87 (s, 3H), 3.81-3.79 (m, 1H), 3.64-3.62 (m, 2H), 2.20-2.10 (m , 2H), 2.00-1.85 (m, 4H) Example 18
2-甲氧基 - -基 1苯基 1甲醇  2-methoxy-based 1 phenyl 1 methanol
Figure imgf000044_0001
Figure imgf000044_0001
于封管中依次加入 [5-(2-氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲 醇 If (100 mg， 0.25 mmol), 1-甲基哌啶 -4-醇盐酸盐 (76 mg， 0.50 mmol), 碳酸铯 (82 mg， 0.25 mmol)和 5 mL 1,4-二氧六环， 120°C下反应 4小时， 反应液减压浓縮， 用 薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 2-甲氧基 -5-[4-吗啉 -2-(4-哌啶氧基) -吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 18 (25 mg， 黄色固体)， 产率： 22.1%。  [5-(2-Chloro-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol If (100) was added to the sealed tube. Mg, 0.25 mmol), 1-methylpiperidin-4-ol hydrochloride (76 mg, 0.50 mmol), cesium carbonate (82 mg, 0.25 mmol) and 5 mL 1,4-dioxane, 120° The reaction was carried out for 4 hours at C, and the reaction mixture was evaporated to dryness. Piperidinyloxy)-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 18 (25 mg, yellow solid), yield: 22.1%.
MS m/z (ESI): 452.1 [M+l]  MS m/z (ESI): 452.1 [M+l]
iHNMR (400 MHz, CDC13): δ 8.30 (s, 1H)， 8.18 (d, 1H)， 8.05 (d, 1H)， 7.56 (d, 1H)， 7.07 (d, 1H)， 5.19 (t， 1H)， 4.72 (d, 1H)， 4.56 (d, 2H), 4.38 (d, 2H), 3.86 (s, 3H), 3.77-3.70 (m， 4H)， 3.67-3.66 (m， 4H)， 3.36-3.34 (m， 1H)， 1.96-1.80 (m， 2H), 1.38-1.36 (m， 2H) 实施例 19,20 iHNMR (400 MHz, CDC1 3 ): δ 8.30 (s, 1H), 8.18 (d, 1H), 8.05 (d, 1H), 7.56 (d, 1H), 7.07 (d, 1H), 5.19 (t, 1H) ), 4.72 (d, 1H), 4.56 (d, 2H), 4.38 (d, 2H), 3.86 (s, 3H), 3.77-3.70 (m, 4H), 3.67-3.66 (m, 4H), 3.36- 3.34 (m, 1H), 1.96-1.80 (m, 2H), 1.38-1.36 (m, 2H) Example 19, 20
2-Γ743- (羟甲基) -4-甲氧基 -苯基 1-4-吗啉-吡啶并「2,3-dl嘧啶 -2-基 1乙腈 2-氰基 -2-「7-「3- (羟甲基) -4-甲氧基 - 4-吗啉-吡啶并「2,3-dl嘧啶 -2-基 1乙酸叔 2-Γ743-(Hydroxymethyl)-4-methoxy-phenyl1-4-morpholine-pyridine and 2,3-dl-pyrimidin-2-yl-1acetonitrile 2-cyano-2-"7- "3-(Hydroxymethyl)-4-methoxy-4-morpholine-pyridine and "2,3-dl-pyrimidin-2-yl 1 acetic acid
Figure imgf000045_0001
Figure imgf000045_0001
第一步  First step
2-[7-[3- [(叔丁基 (二甲基)硅基)氧甲基 ]-4-甲氧基 -苯基 ]-4-吗啉-吡啶并 [2，3-d]嘧 啶 -2-基] -2-氰基 -乙酸叔丁酯  2-[7-[3-[(tert-butyl(dimethyl)silyl)oxymethyl]-4-methoxy-phenyl]-4-morpholine-pyrido[2,3-d] Pyrimidin-2-yl]-2-cyano-t-butyl acetate
将 2-氰基 -乙酸叔丁酯 (140 mg， 1.00 mmol)溶解于 5 mL四氢呋喃中， 加入叔丁 基醇钾 (40 mg， 0.35 mmol),搅拌 30分钟，加入叔丁基 -[[5-(2-氯 -4-吗啉 -B比啶并 [2，3-d] 嘧啶 -7-基) -2-甲氧基-苯基]甲氧基] -二甲基 -硅烷 9a (50 mg， 0.10 mmol), 反应 12小 时， 减压浓縮， 加入 30 mL水， 用乙酸乙酯萃取 (30 mLx3)， 合并有机相， 用无水 硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物粗品 2-[7-[3- [(叔丁基 (二甲基） 硅基)氧甲基 ]-4-甲氧基 -苯基 ]-4-吗啉-吡啶并 [2，3-d]嘧啶 -2-基] -2-氰基 -乙酸叔丁酯 19a (50 mg, 黄色固体)， 产物不经纯化直接用于下步反应。  2-Cyano-acetic acid tert-butyl ester (140 mg, 1.00 mmol) was dissolved in 5 mL of tetrahydrofuran, potassium tert-butylate (40 mg, 0.35 mmol) was added, stirred for 30 min, and tert-butyl-[[5 -(2-chloro-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methoxy]-dimethyl-silane 9a ( 50 mg, 0.10 mmol), EtOAc (3 mL), EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The title product was obtained as the crude 2-[7-[3-[(tert-butyl(dimethyl)silyl)oxymethyl]-4-methoxy-phenyl]-4-morpholine-pyridine[2, 3-d]pyrimidin-2-yl]-2-cyano-acetic acid tert-butyl ester 19a (50 mg, yellow solid), product was used for the next step without purification.
MS m/z (ESI): 606.2 [M+l] MS m/z (ESI): 606.2 [M+l]
第二步  Second step
2-[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-基]乙腈 2-氰基 -2-[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-吗啉-吡啶并 [2，3-d]嘧啶 -2-基]乙酸叔 丁酯  2-[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-B-pyrido[2,3-d]pyrimidin-2-yl]acetonitrile 2-cyano Tert-butyl 2-[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3-d]pyrimidin-2-yl]acetate
将粗品 2-[7-[3- [(叔丁基 (二甲基)硅基)氧甲基 ]-4-甲氧基 -苯基 ]-4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-基] -2-氰基 -乙酸叔丁酯 19a (100 mg, 0.16 mmol)溶解于 5 mL 甲苯中， 加入对甲苯磺酸 (10 mg， 0.03 mmol), 反应 12小时， 再于 65 °C下反应 3小时， 减压 浓縮， 加入 50 mL乙酸乙酯， 用饱和氯化铵溶液洗涤 (15 mLx2)， 合并有机相， 用 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得 残余物， 得到标题产物 2-[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-吗啉-吡啶并 [2，3-d]嘧啶 -2-基]乙腈 19 (9 mg， 黄色固体)， 产率： 10.0%; 2-氰基 -2-[7-[3- (羟甲基) -4-甲氧基- 苯基] -4-吗啉 -B比啶并 [2，3-d]嘧啶 -2-基]乙酸叔丁酯 20 (10 mg, 黄色固体)， 产率： 11.0%。  The crude 2-[7-[3-[(tert-butyl(dimethyl)silyl)oxymethyl]-4-methoxy-phenyl]-4-morpholine-B is pyridine-[2, 3-d]pyrimidin-2-yl]-2-cyano-acetic acid tert-butyl ester 19a (100 mg, 0.16 mmol) was dissolved in 5 mL of toluene, p-toluenesulfonic acid (10 mg, 0.03 mmol), reaction 12 </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> Concentration under reduced pressure, and the residue obtained was purified by silica gel eluting to afford the title product 2-[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-? 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%.
MS m/z (ESI): 392.1 [M+l]  MS m/z (ESI): 392.1 [M+l]
iHNMR (400 MHz, CDC13): δ 8.48 (s, 1H)， 8.26 (d, 1H)， 8.02 (d, 2H), 6.97 (d, 1H)， 4.81 (s， 2H), 4.45 (s， 2H), 4.15 (s， 3H), 4.06 (s， 1H)， 3.97 (s， 3H), 3.89 (s， 4H) iHNMR (400 MHz, CDC1 3 ): δ 8.48 (s, 1H), 8.26 (d, 1H), 8.02 (d, 2H), 6.97 (d, 1H), 4.81 (s, 2H), 4.45 (s, 2H), 4.15 (s, 3H), 4.06 (s, 1H), 3.97 (s, 3H), 3.89 (s, 4H)
MS m/z (ESI): 492.1 [M+l] MS m/z (ESI): 492.1 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 12.62 (s, 1H), 8.09 (d， 2H), 7.90 (d， 1H), 7.54 (d， 1H) 6.98 (d， 1H), 4.80 (s， 2H), 4.06 (s， 1H), 3.96 (s， 4H)， 3.94 (s， 2H), 3.82 (s， 4H)， 3.59 (s， 9H) 实施例 21 iHNMR (400 MHz, DMSO-J 6 ): δ 12.62 (s, 1H), 8.09 (d, 2H), 7.90 (d, 1H), 7.54 (d, 1H) 6.98 (d, 1H), 4.80 (s, 2H), 4.06 (s, 1H), 3.96 (s, 4H), 3.94 (s, 2H), 3.82 (s, 4H), 3.59 (s, 9H) Example 21
「542-「(1,1-二氧代硫代吡喃-4-基)氨基卜4-「( -3-甲基吗啉-4-基1吡啶并「2,3-(11嘧啶  "542-"(1,1-dioxothiopyran-4-yl)aminobu 4-"(-3-methylmorpholin-4-yl 1pyridine and 2,3-(11-pyrimidine)
Figure imgf000046_0001
Figure imgf000046_0001
将 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲 醇 3a (150 mg, 0.37 mmol)溶解于 5 mL N，N-二甲基乙酰胺中， 加入 1,1-二氧代硫代 吡喃 -4-胺 14b (112 mg, 0.74 mmol)和 N，N-二异丙基乙胺 (143 mg, 1.11 mmol), 90 °C 下反应 48小时， 倒入 20 mL水中， 用乙酸乙酯萃取 (20 mL><3)， 合并有机相， 用 饱和氯化钠溶液洗涤 (50 mL), 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用 HPLC 制备色谱法以洗脱剂体系 A纯化所得残余物，得到标题产物 [5-[2-[(1，1-二氧代硫代 吡喃 -4-基)氨基] -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基] 甲醇 21 (30 mg， 黄色固体)， 产率： 15.6%。  [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 mmol) was dissolved in 5 mL of N,N-dimethylacetamide, and 1,1-dioxothiopyran-4-amine 14b (112 mg, 0.74 mmol) And N,N-diisopropylethylamine (143 mg, 1.11 mmol), reacted at 90 °C for 48 hours, poured into 20 mL of water, extracted with ethyl acetate (20 mL><3), combined organic phase It was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, filtered, evaporated, evaporated. 2-[(1,1-dioxothiopyran-4-yl)amino]-4-[(3-3-methylmorpholin-4-yl]B-pyridyl[2,3-d Pyrimidine-7-yl]-2-methoxy-phenyl]methanol 21 (30 mg, yellow solid), yield: 15.6%.
MS m/z (ESI): 514.2 [M+l] MS m/z (ESI): 514.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.30 (s, 1H), 8.16-8.07 (m， 2H), 7.62 (d， 1H), 7.11 (d， 1H), 4.57 (s, 2H), 4.30 (s, 1H), 3.87 (s, 3H), 3.73-3.11 (m， 13H), 2.22-2.11 (m， 4H)， 1.30-1.27 (m, 3H) 实施例 22 iHNMR (400 MHz, DMSO-J 6 ): δ 8.30 (s, 1H), 8.16-8.07 (m, 2H), 7.62 (d, 1H), 7.11 (d, 1H), 4.57 (s, 2H), 4.30 (s, 1H), 3.87 (s, 3H), 3.73-3.11 (m, 13H), 2.22-2.11 (m, 4H), 1.30-1.27 (m, 3H) Example 22
「542- (环丙基 (四氢吡喃 -4-基)氨基) -4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧啶  "542-(Cyclopropyl(tetrahydropyran-4-yl)amino)-4-"(3 -3-methylmorpholin-4-yl 1pyridine and 2,3-dl pyrimidine
-7-基 1-2-甲氧基 -苯基 1甲醇 -7-yl 1-2-methoxy-phenyl 1 methanol
Figure imgf000047_0001
Figure imgf000047_0001
将 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲 醇 3a (150 mg， 0.37 mmol)溶解于 5 mL N，N-二甲基乙酰胺中， 加入 N-环丙基四氢 吡喃 -4-胺 (80 mg， 0.56 mmol)和 N，N-二异丙基乙胺 (13 mL, 0.74 mmol), 90°C下反应 48小时， 倒入 20 mL水中， 用乙酸乙酯萃取 (20 mIX3)， 合并有机相， 用饱和氯化 钠溶液洗涤 (50 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用 HPLC制备色谱 法以洗脱剂体系 A 纯化所得残余物， 得到标题产物 [5-[2- (环丙基 (四氢吡喃 -4-基) 氨基 4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲醇 22 (10 mg， 黄色固体)， 产率： 5.3%。  [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 mmol) was dissolved in 5 mL of N,N-dimethylacetamide and N-cyclopropyltetrahydropyran-4-amine (80 mg, 0.56 mmol) and N , N-diisopropylethylamine (13 mL, 0.74 mmol), reacted at 90 ° C for 48 hours, poured into 20 mL water, extracted with ethyl acetate (20 mIX3), combined organic phase with saturated sodium chloride The solution was washed (50 mL), dried over anhydrous sodium sulfate, EtOAcjjjjjjjjjjjjjjjj (tetrahydropyran-4-yl)amino 4-[(3 -3-methylmorpholin-4-yl] B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy Base-phenyl]methanol 22 (10 mg, yellow solid), yield: 5.3%.
MS m/z (ESI): 506.2 [M+l] MS m/z (ESI): 506.2 [M+l]
iHNMR (400 MHz, CDC13): δ 8.66-8.62 (m， 1H)， 8.29-8.27 (m， 1H)， 8.23-8.21 (m， 1H) 7.79-7.77 (m， 1H), 7.08-7.03 (m， 1H), 4.85 (s, 2H), 4.66-4.64 (m， 1H), 4.19-4.08 (m， 4H)， 4.02 (s， 3H), 4.00-3.85 (m， 4H)， 3.50-3.48 (m， 4H)， 1.73-1.70 (m， 5H)， 1.61-1.59 (m， 3H), 1.32-1.28 (m, 4H) 实施例 23 iHNMR (400 MHz, CDC1 3 ): δ 8.66-8.62 (m, 1H), 8.29-8.27 (m, 1H), 8.23-8.21 (m, 1H) 7.79-7.77 (m, 1H), 7.08-7.03 (m , 1H), 4.85 (s, 2H), 4.66-4.64 (m, 1H), 4.19-4.08 (m, 4H), 4.02 (s, 3H), 4.00-3.85 (m, 4H), 3.50-3.48 (m , 4H), 1.73-1.70 (m, 5H), 1.61-1.59 (m, 3H), 1.32-1.28 (m, 4H) Example 23
「2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 1-2-四氢吡喃 -4-基-氧基-吡啶并「2,3-dl嘧啶  "2-Methoxy-5-"4-"(3 -3-methylmorpholin-4-yl1-2-tetrahydropyran-4-yl-oxy-pyridyl"2,3-dl Pyrimidine
Figure imgf000047_0002
Figure imgf000048_0001
Figure imgf000047_0002
Figure imgf000048_0001
将四氢吡喃 -4-醇 (31 mg， 0.31 mmol)溶解于 5 mL四氢呋喃中，搅拌下加入氢化 钠 (13 mg， 0.34 mmol), 搅拌 3小时， 加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲醇 3a (150 mg， 0.37 mmol), 搅拌反应 1小时， 加入 10 mL水， 减压浓縮， 用二氯甲烷萃取 (10 mIX3)， 合并有机相， 用饱和氯化 钠溶液洗涤 (20 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展 开剂体系 A 纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4- 基] -2-四氢吡喃 -4-基 -氧基 -B比啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 23 (20 mg， 黄色固 体)， 产率： 12.5%。  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%.
MS m/z (ESI): 467.1 [M+l] MS m/z (ESI): 467.1 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.33 (s, 1H)， 7.99-7.97 (m， 2H), 7.47 (d, 1H)， 7.00 (d, 1H), 4.58 (s， 2H), 3.83 (s， 3H), 3.75-3.55 (m， 9H)， 2.90-2.88 (m， 1H), 2.87-2.85 (m， 2H) 2.11-1.86 (m, 4H)， 1.15 (d， 3H) 实施例 24 iHNMR (400 MHz, DMSO-J 6 ): δ 8.33 (s, 1H), 7.99-7.97 (m, 2H), 7.47 (d, 1H), 7.00 (d, 1H), 4.58 (s, 2H), 3.83 (s, 3H), 3.75-3.55 (m, 9H), 2.90-2.88 (m, 1H), 2.87-2.85 (m, 2H) 2.11-1.86 (m, 4H), 1.15 (d, 3H) Example 24
「2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 l-2-「(3R)-四氢呋喃 -3-基 1氧基-吡啶并「2,3-dl嘧  "2-Methoxy-5-"4-"(3 -3-methylmorpholin-4-yl l-2-"(3R)-tetrahydrofuran-3-yloxy-pyridine" 2,3 -dl
Figure imgf000048_0002
Figure imgf000048_0002
于封管中依次加入 (3R)-四氢呋喃 -3-醇 (88 mg， 1 mmol), 3 mL N，N-二甲基甲酰 胺和氢化钠 (60 mg， 1.50 mmol), 50°C下搅拌 3小时， 加入 [5-[2-氯 -4-[(3 -3-甲基吗 啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲醇 3a (100 mg， 0.25 mmol), 50 °C 下反应 12小时， 加入 50 mL乙酸乙酯和 15 mL水， 分层， 有机相用饱和氯化钠溶 液洗涤 (30 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂 体系 A 纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4- 基] -2-[C3R)-四氢呋喃 -3-基]氧基-吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 24 (18 mg， 黄色 固体)， 产率： 16.4%。 (3R)-Tetrahydrofuran-3-ol (88 mg, 1 mmol), 3 mL of N,N-dimethylformamide and sodium hydride (60 mg, 1.50 mmol) were added to the sealed tube and stirred at 50 °C. 3 hours, adding [5-[2-chloro-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]-2-yl Oxy-phenyl]methanol 3a (100 mg, 0.25 mmol), reacted at 50 °C for 12 hours, added 50 mL of ethyl acetate and 15 mL of water, layered, and the organic phase was washed with saturated sodium chloride (30 mL) Drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, using thin layer chromatography as a developing solvent The obtained residue was purified to give the title product [2-methoxy-5-[4-[(3-3-methylmorpholin-4-yl)-2-[C3R)-tetrahydrofuran-3-yl] Oxy-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 24 (18 mg, yellow solid), yield: 16.4%.
MS m/z (ESI): 453.2 [M+l] MS m/z (ESI): 453.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.36 (s， 1H)， 8.27 (d， 1H)， 8.19-8.17 (m， 1H)， 7.80 (d， 1H), 7.13 (d， 1H), 5.70-5.67 (m， 1H), 4.72 (s， 2H), 4.69-4.67 (m， 1H), 4.14-4.08 (m， 3H), 4.06-3.95 (m， 3H), 3.94 (s, 3H), 3.85-3.70 (m， 4H)， 2.37-2.32 (m， 1H), 2.25-2.22 (m， 1H)， 1.17-1.15 (m， 3H) 实施例 25 iHNMR (400 MHz, DMSO-J 6 ): δ 8.36 (s, 1H), 8.27 (d, 1H), 8.19-8.17 (m, 1H), 7.80 (d, 1H), 7.13 (d, 1H), 5.70 -5.67 (m, 1H), 4.72 (s, 2H), 4.69-4.67 (m, 1H), 4.14-4.08 (m, 3H), 4.06-3.95 (m, 3H), 3.94 (s, 3H), 3.85 -3.70 (m, 4H), 2.37-2.32 (m, 1H), 2.25-2.22 (m, 1H), 1.17-1.15 (m, 3H) Example 25
4-「「7-「3- (羟甲基) -4-甲氧基 -苯基 l-4-「(3 -3-甲基吗啉 -4-基 1-吡啶并「2,3-dl嘧啶  4-""7-"3-(Hydroxymethyl)-4-methoxy-phenyll-4-"(3 -3-methylmorpholin-4-yl 1-pyridine and "2,3- Pyrimidine
Figure imgf000049_0001
Figure imgf000049_0001
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (100 mg， 0.25 mmol), 4-氨基哌啶 -1-甲酸叔丁酯 (100 mg， 0.50 mmol), 碳酸铯 (98 mg， 0.30 mmol)和 5 mL N，N-二甲基乙酰胺， 90°C下反应 12小时， 加入 30 mL水， 过滤， 滤饼真空干燥， 得到标题产物 4-[[7-[3- (羟甲基) -4- 甲氧基 -苯基 ]-4-[C3 -3-甲基吗啉 -4-基] -吡啶并 [2，3-d]嘧啶 -2-基]氨基]哌啶 -2-甲酸 叔丁酯 25 (100 mg， 黄色固体)， 产率： 71.4%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (100 mg, 0.25 mmol), 4-aminopiperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.50 mmol), cesium carbonate (98 mg, 0.30 mmol) and 5 mL N, N-dimethylacetamide, reacted at 90 ° C for 12 hours, added 30 mL of water, filtered, and dried under vacuum to give the title product 4-[[7-[3-(hydroxymethyl)-4-methoxy Tert-butyl ester of phenyl-phenyl]-4-[C3-3-methylmorpholin-4-yl]-pyrido[2,3-d]pyrimidin-2-yl]amino]piperidine-2-carboxylate (100 mg, yellow solid), Yield: 71.4%.
MS m/z (ESI): 565.3 [M+l] MS m/z (ESI): 565.3 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.21 (s, 1H)， 8.16-8.10 (m， 2H), 7.56 (d, 1H)， 7.10 (d, 1H), 5.49 (s， 1H), 4.70 (s， 2H), 4.60-4.30 (m， 1H), 4.07-3.90 (m， 5H)， 3.85-3.69 (m， 6H) 2.99-2.84 (m， 2H), 2.82-2.80 (m， 4H)， 2.20-2.03 (m， 1H)， 1.89-1.85 (m， 2H), 1.32 (s， 9H) 实施例 26 iHNMR (400 MHz, DMSO-J 6 ): δ 8.21 (s, 1H), 8.16-8.10 (m, 2H), 7.56 (d, 1H), 7.10 (d, 1H), 5.49 (s, 1H), 4.70 (s, 2H), 4.60-4.30 (m, 1H), 4.07-3.90 (m, 5H), 3.85-3.69 (m, 6H) 2.99-2.84 (m, 2H), 2.82-2.80 (m, 4H), 2.20-2.03 (m, 1H), 1.89-1.85 (m, 2H), 1.32 (s, 9H) Example 26
「2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 l-2-(4-哌啶基氨基)吡啶并「2,3-dl嘧啶 -7-基 1苯 基 1甲醇 "2-Methoxy-5-"4-"(3 -3-methylmorpholin-4-yl l-2-(4-piperidinylamino)pyridine and 2,3-dl pyrimidine-7- Base 1 phenyl 1 methanol
Figure imgf000050_0001
Figure imgf000050_0001
将 4-[[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-[(3 -3-甲基吗啉 -4-基] -吡啶并 [2，3-d]嘧 啶 -2-基]氨基]哌啶 -2-甲酸叔丁酯 25 (425 mg， 0.75 mmol)溶解于 20 mL盐酸 1，4-二 氧六环溶剂中， 反应 12小时， 反应液减压浓縮， 用 HPLC制备色谱法以洗脱剂体 系 A纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2-(4- 哌啶基氨基)吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 26 (300 mg， 黄色固体)， 产率： 85.7%。  4-[[7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-[(3 -3-methylmorpholin-4-yl)-pyrido[2,3 -d]pyrimidin-2-yl]amino]piperidine-2-carboxylic acid tert-butyl ester 25 (425 mg, 0.75 mmol) dissolved in 20 mL of 1,4-dioxane hydrochloride for 12 hours, reaction solution Concentration under reduced pressure, and the residue obtained was purified by chromatography eluting to elute to afford the title product [2-methoxy-5-[4-[(3-3-methylmorpholin-4-yl) 2-(4-piperidinylamino)pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 26 (300 mg, yellow solid), yield: 85.7%.
MS m/z (ESI): 465.2 [M+l]  MS m/z (ESI): 465.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.32 (s, 1H), 8.21 (d, 1H), 8.08 (d, 1H), 7.62 (d， 1H)， 7.10 (d, 1H), 5.26 (s， 1H), 4.85 (s， 1H), 4.58 (s， 2H), 3.87 (s， 3H), 3.78-3.68 (m， 4H)， 3.45-3.43 (m， 1H), 3.11-2.90 (m， 3H), 2.79-2.69 (m， 4H)， 1.89-1.79 (m， 4H)， 1.20 (d， 3H) 实施例 27 iHNMR (400 MHz, DMSO-J 6 ): δ 8.32 (s, 1H), 8.21 (d, 1H), 8.08 (d, 1H), 7.62 (d, 1H), 7.10 (d, 1H), 5.26 (s , 1H), 4.85 (s, 1H), 4.58 (s, 2H), 3.87 (s, 3H), 3.78-3.68 (m, 4H), 3.45-3.43 (m, 1H), 3.11-2.90 (m, 3H ), 2.79-2.69 (m, 4H), 1.89-1.79 (m, 4H), 1.20 (d, 3H) Example 27
Γ2-甲氧基 -5-「4-「( -3-甲基吗啉 -4-基 1-2-乙烯基-吡啶并「2,3-dl嘧啶 -7-基 1苯基 1  Γ2-methoxy-5-"4-"(-3-methylmorpholin-4-yl-1-2-vinyl-pyridyl"2,3-dlpyrimidin-7-yl 1phenyl 1
Figure imgf000050_0002
于微波管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -7- 基] -2-甲氧基-苯基]甲醇 3a (100 mg， 0.25 mmol), 三丁基 (乙烯基)锡烷 (120 mg， 0.38 mmol),双 (三苯基膦)二氯化钯 (18 mg， 0.025 mmol), N，N-二异丙基乙胺 (65 mg， 0.50 mmol), 碘化亚酮 (5 mg， 0.025 mmol)和 5 mL N，N-二甲基甲酰胺， 130°C下反应 30 分钟， 加入 20 mL乙酸乙酯， 用水萃取 (20 mLx3)， 合并有机相， 用饱和氯化钠溶 液洗涤 (50 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂 体系 A纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2-乙 烯基-吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 27 (80 mg， 黄色固体)， 产率： 81.6%。 MS m/z (ESI): 393.2 [M+l]
Figure imgf000050_0002
[5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-7-yl]-2-yl was added sequentially to a microwave tube Oxy-phenyl]methanol 3a (100 mg, 0.25 mmol), tributyl(vinyl)stannane (120 mg, 0.38 mmol), bis(triphenylphosphine)palladium dichloride (18 mg, 0.025 mmol , N,N-diisopropylethylamine (65 mg, 0.50 mmol), iodide iodide (5 mg, 0.025 mmol) and 5 mL of N,N-dimethylformamide, reaction at 130 ° C 30 </ br></br></br></br></br></br></br></br></br></br></br> The residue obtained was purified by EtOAc EtOAc (EtOAc) (md. 2,3-d]pyrimidin-7-yl]phenyl]methanol 27 (80 mg, yellow solid), yield: 81.6%. MS m/z (ESI): 393.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.37-8.32 (m， 2H), 8.23 (d, 1H), 7.92 (d， 1H), 7.12 (d: 1H), 6.84-6.80 (m, 1H), 6.72-6.67 (m, 1H), 5.79-5.77 (m, 1H), 4.72-4.69 (m, 3H), 4.19-4.16 (m， 1H), 4.00-3.92 (m， 4H)， 3.87-3.75 (m， 4H)， 1.54-1.52 (m， 3H) 实施例 28 iHNMR (400 MHz, DMSO-J 6 ): δ 8.37-8.32 (m, 2H), 8.23 (d, 1H), 7.92 (d, 1H), 7.12 (d : 1H), 6.84-6.80 (m, 1H) , 6.72-6.67 (m, 1H), 5.79-5.77 (m, 1H), 4.72-4.69 (m, 3H), 4.19-4.16 (m, 1H), 4.00-3.92 (m, 4H), 3.87-3.75 ( m, 4H), 1.54-1.52 (m, 3H) Example 28
Γ2-甲氧基 -5-「4-「( -3-甲基吗啉 -4-基 1-2-「2-( -吡啶基)乙炔基 1吡啶并「2,3-dl嘧  Γ2-methoxy-5-"4-"(-3-methylmorpholin-4-yl 1-2-"2-(-pyridyl)ethynyl 1 pyridine and 2,3-dl-pyrimidine
Figure imgf000051_0001
Figure imgf000051_0001
将 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲 醇 3a (100 mg， 0.25 mmol)和 3-乙块基吡啶 (30 mg， 0.30 mmol)溶解于 5 mL N，N-二甲 基甲酰胺中，加入双 (三苯基膦)二氯化钯 (10 mg， 0.015 mmol),碘化亚酮 (10 mg， 0.05 mmol)和三乙胺 (300 mg， 0.30 mmol), 80°C下反应 4小时， 反应液减压浓縮， 用薄 层色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-[(3 -3- 甲基吗啉—4-基] -2-[2-(3-吡啶基)乙块基]吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 28 (20 mg， 黄色固体)， 产率： 17.2%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy- Phenyl]methanol 3a (100 mg, 0.25 mmol) and 3-ethylphenylpyridine (30 mg, 0.30 mmol) were dissolved in 5 mL of N,N-dimethylformamide and bis(triphenylphosphine) Palladium chloride (10 mg, 0.015 mmol), iodide (10 mg, 0.05 mmol) and triethylamine (300 mg, 0.30 mmol), reacted at 80 ° C for 4 hours, and concentrated under reduced pressure. The resulting residue was purified by EtOAc (EtOAc) elut elut (3-Pyridinyl)ethylidene]pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 28 (20 mg, yellow solid), yield: 17.2%.
MS m/z (ESI): 468.2 [M+l] MS m/z (ESI): 468.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.87 (s, 1H), 8.69-8.68 (m， 1H), 8.44-8.40 (m， 2H), 8.19-8.17 (m， 1H), 8.14-8.13 (m， 1H), 8.04-8.02 (d, 2H), 7.55-7.52 (m， 1H), 7.16 (d， 1H), 5.25-5.20 (m， 1H), 4.71-4.70 (m， 1H), 4.59 (s， 2H), 4.09-4.07 (m， 1H), 3.94-3.92 (m， 1H)， 3.89 (s, 3H), 3.77-3.69 (m， 2H), 3.59-3.57 (m， 1H), 1.45-1.43 (m， 3H) 实施例 29 iHNMR (400 MHz, DMSO-J 6 ): δ 8.87 (s, 1H), 8.69-8.68 (m, 1H), 8.44-8.40 (m, 2H), 8.19-8.17 (m, 1H), 8.14-8.13 ( m, 1H), 8.04-8.02 (d, 2H), 7.55-7.52 (m, 1H), 7.16 (d, 1H), 5.25-5.20 (m, 1H), 4.71-4.70 (m, 1H), 4.59 ( s, 2H), 4.09-4.07 (m, 1H), 3.94-3.92 (m, 1H), 3.89 (s, 3H), 3.77-3.69 (m, 2H), 3.59-3.57 (m, 1H), 1.45- 1.43 (m, 3H) Example 29
「4-Γ「7-「3- (羟甲基) -4-甲氧基 -苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧啶  "4-Γ"7-"3-(Hydroxymethyl)-4-methoxy-phenyll-4-"(3 -3-methylmorpholin-4-yl 1pyridine and 2,3- Pyrimidine
Figure imgf000052_0001
Figure imgf000052_0001
第一步  First step
2-[4- (苄基氨基)哌啶 -1-幾基]吡咯 -1-甲酸叔丁酯 将 2-(4-氧代哌啶 -1-羰基) B比咯 -1-甲酸叔丁酯 29a (2.40 g， 8.11 mmol, 采用公知 的方法 "专利 US2004134019"制备而得)， 苄胺 (870 mg， 8.13 mmol)和三 (乙酰基) 硼氢化钠 (4.30 g， 0.02 mmol)溶解于 30 mL N，N-二甲基乙酰胺中，搅拌反应 12小时， 加入 50 mL二氯甲烷， 分层， 有机相依次用 2 M氢氧化钠溶液 (50 mL)， 饱和碳酸 钠溶液 (50 mL)和饱和氯化钠溶液洗涤 (50 mL)， 无水硫酸钠干燥， 过滤， 滤液减压 浓縮， 得到标题产物粗品 2-[4- (苄基氨基)哌啶 -1-羰基]吡咯 -1-甲酸叔丁酯 29b (2 g， 黄色油状物)， 产物不经纯化直接用于下步反应。  2-[4-(Benzylamino)piperidin-1-yl]pyrrole-1-carboxylic acid tert-butyl ester 2-(4-oxopiperidin-1-carbonyl) B-pyrrol-1-carboxylic acid tert-butyl Ester 29a (2.40 g, 8.11 mmol, prepared by the known method "Patent US2004134019"), benzylamine (870 mg, 8.13 mmol) and tris(acetyl)sodium borohydride (4.30 g, 0.02 mmol) were dissolved in 30 In mL N,N-dimethylacetamide, stir the reaction for 12 hours, add 50 mL of dichloromethane, separate the layers, and organic phase with 2 M sodium hydroxide solution (50 mL), saturated sodium carbonate solution (50 mL) It was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate - tert-butyl formate 29b (2 g, yellow oil), product was used in the next step without purification.
MS m/z (ESI): 388.2 [M+l] MS m/z (ESI): 388.2 [M+l]
第二步  Second step
2-(4-氨基哌啶 -1-羰基]吡咯 -1-甲酸叔丁酯  2-(4-Aminopiperidine-1-carbonyl)pyrrole-1-carboxylic acid tert-butyl ester
将粗品 2-[4- (节基氨基)哌啶小羰基]吡咯小甲酸叔丁酯 29b (2 g， 5.20 mmol)溶 解于 30 mL甲醇中， 加入钯 /碳 (200 mg， 10%)， 氢气置换三次， 搅拌反应 48小时， 过滤，滤液减压浓縮，得到标题产物粗品 2-(4-氨基哌啶 -1-羰基]吡咯 -1-甲酸叔丁酯 29c (1.50 g, 黄色油状物)， 产物不经纯化直接用于下步反应。  The crude 2-[4-(nodal amino)piperidines small carbonyl]pyrrole carboxylic acid tert-butyl ester 29b (2 g, 5.20 mmol) was dissolved in 30 mL of methanol and then palladium/carbon (200 mg, 10%). The hydrogen was replaced three times, the reaction was stirred for 48 hrs, filtered, and the filtrate was evaporated tolululululululululululululululululululu The product was used in the next step without purification.
MS m/z (ESI): 298.2 [M+l] MS m/z (ESI): 298.2 [M+l]
第三步  third step
2-[4-[[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2-基]氨基]哌啶 -1-羰基]吡咯 -1-甲酸叔丁酯 2-[4-[[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-[(3 -3-methylmorpholin-4-yl) B-pyridin[ 2,3-d]pyrimidine -2-yl]amino]piperidine-1-carbonyl]pyrrole-1-carboxylic acid tert-butyl ester
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (200 mg， 0.50 mmol),粗品 2-(4-氨基哌啶 -1-羰基] B比咯 -1- 甲酸叔丁酯 29c (225 mg， 0.75 mmol),碳酸铯 (489 mg， 1.50 mmol)和 5 mL N，N-二甲 基乙酰胺， 120°C下反应 12小时， 加入 20 mL水， 用二氯甲烷萃取 (20 mLx3)， 合 并有机相， 用饱和氯化钠溶液洗涤 (50 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓 縮， 用 HPLC 制备色谱法以洗脱剂体系 A 纯化所得残余物， 得到标题产物 2-[4-[[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2- 基]氨基]哌啶小羰基]吡咯小甲酸叔丁酯 29 d (15 mg， 黄色固体)， 产率： 5.0%。 MS m/z (ESI): 662.3 [M+l] [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (200 mg, 0.50 mmol), crude 2-(4-aminopiperidine-1-carbonyl) B-pyrrol-1-carboxylic acid tert-butyl ester 29c (225 mg, 0.75 mmol),铯 (489 mg, 1.50 mmol) and 5 mL of N,N-dimethylacetamide, reacted at 120 ° C for 12 hours, added 20 mL of water, extracted with dichloromethane (20 mL×3), combined organic phase, saturated The sodium chloride solution was washed (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by HPLC to afford the title product 2 -[4-[[ 7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidine -2-yl]amino]piperidines small carbonyl]pyrrole carboxylic acid tert-butyl ester 29 d (15 mg, yellow solid), yield: 5.0%. MS m/z (ESI): 662.3 [M+l]
第四步  the fourth step
[4-[[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶  [4-[[7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-[(3 -3-methylmorpholin-4-yl) B) is pyridine [2, 3-d]pyrimidine
-2-基]氨基] -1-哌啶基] -吡咯 -2-基 -甲酮  -2-yl]amino]-1-piperidinyl]-pyrrole-2-yl-ketone
将 2-[4-[[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d] 嘧啶 -2-基]氨基]哌啶 -1-羰基] B比咯 -1-甲酸叔丁酯 29 d (20 mg， 0.03 mmol)溶解于 20 mL盐酸 1，4-二氧六环溶剂中， 反应 12小时， 反应液减压浓縮， 用 HPLC制备色 谱法以洗脱剂体系 A纯化所得残余物， 得到标题产物 [4-[[7-[3- (羟甲基) -4-甲氧基- 苯基] -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2-基]氨基] -1-哌啶基] -吡咯 -2-基- 甲酮 29 (10 mg， 黄色固体)， 产率： 58.8%。  2-[4-[[7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-[(3 -3-methylmorpholin-4-yl) B) [2,3-d]pyrimidin-2-yl]amino]piperidine-1-carbonyl] B-tert-l-carboxylic acid tert-butyl ester 29 d (20 mg, 0.03 mmol) dissolved in 20 mL of HCl In the dioxane solvent, the reaction is carried out for 12 hours, and the reaction mixture is concentrated under reduced pressure. The obtained residue is purified by HPLC to elute to afford the title product [4-[[7-[3- (hydroxyl) -4-methoxy-phenyl]-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-2-yl]amino] - 1-piperidinyl]-pyrrol-2-yl-methanone 29 (10 mg, yellow solid), yield: 58.8%.
MS m/z (ESI): 562.3 [M+l] MS m/z (ESI): 562.3 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.21-8.11 (m， 2H), 8.07 (d, 1H), 7.90-7.87 (m， 1H)， 6.94-6.81 (m, 1H), 4.57-4.46 (m, 1H), 4.45-4.40 (m, 3H), 4.06-3.69 (m, 8H)， 3.66-3.36 (m， 7H), 3.10-3.01 (m， 5H)， 3.00-2.40 (m， 1H), 2.46-2.41 (m， 1H), 1.85-1.77 (m， 5H) 实施例 30 iHNMR (400 MHz, DMSO-J 6 ): δ 8.21-8.11 (m, 2H), 8.07 (d, 1H), 7.90-7.87 (m, 1H), 6.94-6.81 (m, 1H), 4.57-4.46 ( m, 1H), 4.45-4.40 (m, 3H), 4.06-3.69 (m, 8H), 3.66-3.36 (m, 7H), 3.10-3.01 (m, 5H), 3.00-2.40 (m, 1H), 2.46-2.41 (m, 1H), 1.85-1.77 (m, 5H) Example 30
「5-Γ2-(Ζ2-二甲氧基乙基 )-4-「( -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧啶 -7-基 1-2-甲  "5-Γ2-(Ζ2-dimethoxyethyl)-4-"(-3-methylmorpholin-4-yl 1pyridine and 2,3-dlpyrimidin-7-yl 1-2-A
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000053_0001
Figure imgf000054_0001
第一步  First step
[2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2-(2-三甲基硅基乙块基) B比啶并 [2，3-d]嘧啶  [2-methoxy-5-[4-[(3 -3-methylmorpholin-4-yl]-2-(2-trimethylsilyl)-yl) B-pyridyl[2,3 -d]pyrimidine
-7-基]苯基]甲醇  -7-yl]phenyl]methanol
于微波管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (150 mg， 0.37 mmol), 乙块基 (三甲基)硅烷 (74 mg， 0.75 mmol), 碘化亚酮 (8 mg， 0.037 mmol), 四 (三苯基膦)钯 (15 mg， 0.037 mmol), 三乙胺 (114 mg， 1.10 mmol)和 5 mL N，N-二甲基甲酰胺， 100°C下反应 12小时， 反应液减 压浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2-(2-三甲基硅基乙块基) B比啶并 [2，3-d]嘧啶 -7-基]苯基] 甲醇 30a (120 mg， 黄色固体)， 产率： 70.0%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-yl was added sequentially to a microwave tube Oxy-phenyl]methanol 3a (150 mg, 0.37 mmol), ethyl bromide (trimethyl) silane (74 mg, 0.75 mmol), iodide iodide (8 mg, 0.037 mmol), tetrakis(triphenyl) Palladium (15 mg, 0.037 mmol), triethylamine (114 mg, 1.10 mmol) and 5 mL of N,N-dimethylformamide, reacted at 100 ° C for 12 hours. The resulting residue was purified by EtOAc (EtOAc) elut elut Trimethylsilylethylidene) B-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 30a (120 mg, yellow solid), yield: 70.0%.
MS m/z (ESI): 463.2 [M+l] MS m/z (ESI): 463.2 [M+l]
第二步  Second step
[5-[2-(2，2-二甲氧基乙基 )-4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲 氧基-苯基]甲醇  [5-[2-(2,2-Dimethoxyethyl)-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidine-7 -yl]-2-methoxy-phenyl]methanol
将 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2-(2-三甲基硅基乙块基) B比啶并 [2，3-d] 嘧啶 -7-基]苯基]甲醇 30b (100 mg， 0.21 mmol)和氢氧化钠（17 mg， 0.42 mmol)溶解于 5 mL甲醇中， 反应 12小时， 减压浓縮， 加入 50 mL乙酸乙酯， 分层， 有机相用 饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层 色谱法以展开剂体系 A 纯化所得残余物， 得到标题产物 [5-[2-(2，2-二甲氧基乙 基) -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲醇 30 (10 mg， 黄色固体)， 产率： 12.5%。  [2-Methoxy-5-[4-[(3 -3-methylmorpholin-4-yl)-2-(2-trimethylsilylethyl) B) is pyridine [2, 3-d]pyrimidin-7-yl]phenyl]methanol 30b (100 mg, 0.21 mmol) and sodium hydroxide (17 mg, 0.42 mmol) were dissolved in 5 mL of methanol, and reacted for 12 hr. Ethyl acetate (50 mL), EtOAc (EtOAc)EtOAc. To give the title product [5-[2-(2,2-dimethoxyethyl)-4-[(3-3-methylmorpholin-4-yl)B-pyridyl[2,3- d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 30 (10 mg, yellow solid), yield: 12.5%.
MS m/z (ESI): 455.2 [M+l] MS m/z (ESI): 455.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 6.91 (d, 1H)， 6.81 (s， 1H)， 6.71 (d， 1H)， 6.48 (d， 1H)， 5.62 (d, 1H), 3.59-3.56 (m， 1H), 3.18 (s, 3H), 3.17 (m， 1H), 2.77-2.73 (m， 1H)， 2.48-2.46 (m， 1H), 2.32 (s， 3H), 2.28-2.17 (m， 4H)， 1.85 (s， 6H)， 1.77 (m， 2H), 1.65 (m， 2H) 实施例 31 iHNMR (400 MHz, DMSO-J 6 ): δ 6.91 (d, 1H), 6.81 (s, 1H), 6.71 (d, 1H), 6.48 (d, 1H), 5.62 (d, 1H), 3.59-3.56 (m, 1H), 3.18 (s, 3H), 3.17 (m, 1H), 2.77-2.73 (m, 1H), 2.48-2.46 (m, 1H), 2.32 (s, 3H), 2.28-2.17 (m , 4H), 1.85 (s, 6H), 1.77 (m, 2H), 1.65 (m, 2H) Example 31
Γ2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 1-2- (甲基 (四氢吡喃 -4-基)氨基)吡啶并「2,3-dl  Γ2-methoxy-5-"4-"(3 -3-methylmorpholin-4-yl1-2-(methyl(tetrahydropyran-4-yl)amino)pyridine"2,3 -dl
嘧啶 -7-基 1苯基 1甲醇 Pyrimidine-7-yl 1 phenyl 1 methanol
Figure imgf000055_0001
Figure imgf000055_0001
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (150 mg, 0.37 mmol), N-甲基四氢吡喃 -4-胺 (47 mg， 0.41 mmol), N，N-二异丙基乙胺 (24 mg，0.19 mmol)和 5 mL N，N-二甲基乙酰胺， 90°C下 反应 12小时， 倒入 10 mL水中， 过滤， 滤饼真空干燥， 用 HPLC制备色谱法以洗 脱剂体系 A 纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4- 基] -2- (甲基 (四氢吡喃 -4-基)氨基) B比啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 31 (5 mg, 黄色 固体)， 产率： 3.0%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (150 mg, 0.37 mmol), N-methyltetrahydropyran-4-amine (47 mg, 0.41 mmol), N,N-diisopropylethylamine (24 mg, 0.19 mmol) and 5 mL of N,N-dimethylacetamide, reacted at 90 ° C for 12 hours, poured into 10 mL of water, filtered, and the filter cake was dried in vacuo and purified by HPLC preparative chromatography using eluent system A. The residue gave the title product [2-methoxy-5-[4-[(3-3-methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl)amino) B-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 31 (5 mg, yellow solid), yield: 3.0%.
MS m/z (ESI): 480.2 [M+l] MS m/z (ESI): 480.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.29 (s, 1H), 8.14 (d, 1H), 8.06 (d, 1H), 7.57 (d， 1H)， 7.09 (d, 1H), 5.21-5.19 (m, 1H), 4.58-4.56 (m, 2H), 4.40-4.39 (m, 1H), 4.02-3.97 (m, 2H), 3.91-3.85 (m， 2H), 3.86 (s, 3H), 3.75-3.74 (m， 1H)， 3.66-3.63 (m， 2H), 3.52-3.42 (m， 3H), 3.07 (s, 3H), 2.53-2.52 (m， 1H), 2.01-1.83 (m， 4H)， 1.37-1.36 (m， 3H) 实施例 32 iHNMR (400 MHz, DMSO-J 6 ): δ 8.29 (s, 1H), 8.14 (d, 1H), 8.06 (d, 1H), 7.57 (d, 1H), 7.09 (d, 1H), 5.21-5.19 (m, 1H), 4.58-4.56 (m, 2H), 4.40-4.39 (m, 1H), 4.02-3.97 (m, 2H), 3.91-3.85 (m, 2H), 3.86 (s, 3H), 3.75 -3.74 (m, 1H), 3.66-3.63 (m, 2H), 3.52-3.42 (m, 3H), 3.07 (s, 3H), 2.53-2.52 (m, 1H), 2.01-1.83 (m, 4H) , 1.37-1.36 (m, 3H) Example 32
Γ2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 1-2-「(3-甲基四氢吡喃 -4-基)氨基)吡啶并「2,3-dl  Γ2-methoxy-5-"4-"(3 -3-methylmorpholin-4-yl1-2-"(3-methyltetrahydropyran-4-yl)amino)pyridine and "2 , 3-dl
Figure imgf000055_0002
Figure imgf000056_0001
Figure imgf000055_0002
Figure imgf000056_0001
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (150 mg, 0.37 mmol), 3-甲基四氢吡喃 -4-胺 (100 mg， 0.75 mmol), 0.1 mL N，N-二异丙基乙胺和 5 mL 1,4-二氧六环， 100°C下反应 16小时， 减压浓縮， 用 HPLC制备色谱法以洗脱剂体系 A纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2-[(3-甲基四氢吡喃 -4-基)氨基) B比啶并 [2，3-d] 嘧啶 -7-基]苯基]甲醇 32 (5 mg， 黄色固体)， 产率： 2.9%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (150 mg, 0.37 mmol), 3-methyltetrahydropyran-4-amine (100 mg, 0.75 mmol), 0.1 mL N,N-diisopropylethylamine and 5 </RTI> </RTI> 1,4-dioxane, reaction at 100 ° C for 16 hours, concentrating under reduced pressure, EtOAc EtOAc. -[4-[(3 -3-methylmorpholin-4-yl)-2-[(3-methyltetrahydropyran-4-yl)amino) B-pyrido[2,3-d] Pyrimidine-7-yl]phenyl]methanol 32 (5 mg, yellow solid), yield: 2.9%.
MS m/z (ESI): 480.2 [M+l] MS m/z (ESI): 480.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.20 (s, 1H)， 8.15-8.13 (d, 1H)， 7.54 (d, 1H)， 7.35-7.33 (m， 1H), 7.08 (d, 1H), 4.71 (s, 2H), 4.50 (br.， 2H), 3.93 (s, 6H)， 3.92-3.90 (m， 1H), 3.85-3.83 (m， 2H), 3.77-3.75 (m， 8H)， 1.96 (br.， 2H), 1.46 (d， 3H) 实施例 33 iHNMR (400 MHz, DMSO-J 6 ): δ 8.20 (s, 1H), 8.15-8.13 (d, 1H), 7.54 (d, 1H), 7.35-7.33 (m, 1H), 7.08 (d, 1H) , 4.71 (s, 2H), 4.50 (br., 2H), 3.93 (s, 6H), 3.92-3.90 (m, 1H), 3.85-3.83 (m, 2H), 3.77-3.75 (m, 8H), 1.96 (br., 2H), 1.46 (d, 3H) Example 33
Γ2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 1-2- (四氢吡喃 -3-基-氨基)吡啶并「2,3-dl嘧啶 -7-  Γ2-methoxy-5-"4-"(3 -3-methylmorpholin-4-yl1-2-(tetrahydropyran-3-yl-amino)pyridine and 2,3-dl pyrimidine -7-
Figure imgf000056_0002
Figure imgf000056_0002
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (50 mg, 0.13 mmol), 四氢吡喃 -3-胺 (15 mg, 0.15 mmol), N，N-二异丙基乙胺 (32 mg, 0.25 mmol)和 5 mL 1,4-二氧六环， 100°C下反应 12小时， 减压浓縮， 用 HPLC制备色谱法以洗脱剂体系 A纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2- (四氢吡喃 -3-基-氨基)吡啶并 [2，3-d]嘧啶 -7- 基]苯基]甲醇 33 (10 mg， 黄色固体)， 产率： 17.2%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (50 mg, 0.13 mmol), tetrahydropyran-3-amine (15 mg, 0.15 mmol), N,N-diisopropylethylamine (32 mg, 0.25 mmol) 5 mL of 1,4-dioxane, which was reacted at 100 ° C for 12 hours, concentrated under reduced pressure, and purified by HPLC to elute to afford the title compound [2-methoxy- 5-[4-[(3 -3-methylmorpholin-4-yl)-2-(tetrahydropyran-3-yl-amino)pyrido[2,3-d]pyrimidin-7-yl] Phenyl]methanol 33 (10 mg, yellow solid), yield: 17.2%.
MS m/z (ESI): 466.2 [M+l] MS m/z (ESI): 466.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.87 (s, 1H), 8.30 (s, 1H), 8.16-8.14 (m， 1H)， 8.07-8.05 (m， 1H)， 7.61-7.58 (m， 1H)， 5.27-5.24 (m， 1H)， 4.96 (m， 1H)， 4.75 (m， 1H)， 4.57-4.56 (m， 1H), 4.41-4.39 (m， 2H), 4.14-4.12 (m， 1H), 3.87-3.86 (m， 3H), 3.74 (m， 2H), 3.66 (s， 2H), 3.60-3.54 (m， 3H), 1.37-1.33 (m， 2H), 1.29-1.28 (m， 2H), 1.23 (s， 3H) 实施例 34 iHNMR (400 MHz, DMSO-J 6 ): δ 8.87 (s, 1H), 8.30 (s, 1H), 8.16-8.14 (m, 1H), 8.07-8.05 (m, 1H), 7.61-7.58 (m, 1H), 5.27-5.24 (m, 1H), 4.96 (m, 1H), 4.75 (m, 1H), 4.57-4.56 (m, 1H), 4.41-4.39 (m, 2H), 4.14-4.12 (m, 1H), 3.87-3.86 (m, 3H), 3.74 (m, 2H), 3.66 (s, 2H), 3.60-3.54 (m, 3H), 1.37-1.33 (m, 2H), 1.29-1.28 (m, 2H), 1.23 (s, 3H) Example 34
Γ2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 1-2- (四氢呋喃 -3-基-氨基)吡啶并「2,3-dl嘧啶 -7-  2-methoxy-5-"4-"(3 -3-methylmorpholin-4-yl1-2-(tetrahydrofuran-3-yl-amino)pyridine and 2,3-dl pyrimidine-7-
Figure imgf000057_0001
Figure imgf000057_0001
将 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲 醇 3a (150 mg， 0.37 mmol), 四氢呋喃 -3-胺 (50 mg， 0.56 mmol)和 N，N-二异丙基乙胺 (0.15 mL, 0.75 mmol)溶解于 5 mL 1,4-二氧六环中， 90°C下反应 12小时，倒入 20 mL 水中， 用乙酸乙酯萃取 (20 mLx3)， 合并有机相， 用饱和氯化钠溶液洗涤 (50 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得 残余物， 得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2- (四氢呋喃 -3-基-氨 基)吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 34 (10 mg， 黄色固体)， 产率： 5.9%。  [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 mmol), tetrahydrofuran-3-amine (50 mg, 0.56 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.75 mmol) dissolved in 5 mL 1,4 - dioxane, react at 90 ° C for 12 hours, pour into 20 mL of water, extract with ethyl acetate (20 mL x 3), combine the organic phase, wash with saturated sodium chloride solution (50 mL), anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was evaporated to dryness. Benzyl-4-yl]-2-(tetrahydrofuran-3-yl-amino)pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 34 (10 mg, yellow solid), yield: 5.9 %.
MS m/z (ESI): 452.2 [M+l] MS m/z (ESI): 452.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.32-8.31 (m, 2H), 8.10-8.09 (m, 1H)， 7.84-7.74 (m， 1H), 7.14-7.13 (m， 1H), 5.24 (s， 1H), 4.58 (s， 2H), 3.88 (s， 3H), 3.93-3.65 (m， 12H), 2.24-2.20 (m， 1H), 1.96-1.94 (m， 1H), 1.28-1.24 (m， 3H) 实施例 35 iHNMR (400 MHz, DMSO-J 6 ): δ 8.32-8.31 (m, 2H), 8.10-8.09 (m, 1H), 7.84-7.74 (m, 1H), 7.14-7.13 (m, 1H), 5.24 ( s, 1H), 4.58 (s, 2H), 3.88 (s, 3H), 3.93-3.65 (m, 12H), 2.24-2.20 (m, 1H), 1.96-1.94 (m, 1H), 1.28-1.24 ( m, 3H) Example 35
3-「「7-「3- (羟甲基 4-甲氧基苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧啶 -2-基 1 氨基 1哌啶 -2-酮 3 - ""7-"3-(Hydroxymethyl 4-methoxyphenyl l-4-"(3 -3-methylmorpholin-4-yl 1 pyridine and 2,3-dl pyrimidine-2 -yl 1 amino 1 piperidin-2-one
Figure imgf000057_0002
Figure imgf000058_0001
Figure imgf000057_0002
Figure imgf000058_0001
将 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲 醇 3a (150 mg， 0.37 mmol), 3-氨基哌啶 -2-酮 (50 mg， 0.41 mmol)和 N，N-二异丙基乙 胺 (0.1 mL, 0.56 mmol)溶解于 5 mL 1,4-二氧六环中， 90°C下反应 12小时，，倒入 20 mL冰水中， 用乙酸乙酯萃取 (20 mLx3)， 合并有机相， 用饱和氯化钠溶液洗涤 (50 mL), 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用 HPLC制备色谱法以洗脱剂体系 A纯化所得残余物， 得到标题产物 3-[[7-[3- (羟甲基) -4-甲氧基苯基] -4-[(3 -3-甲基 吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2-基]氨基]哌啶 -2-酮 35 (10 mg， 黄色固体)， 产率： 5.6%。  [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 mmol), 3-aminopiperidin-2-one (50 mg, 0.41 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.56 mmol) dissolved in 5 In mL 1,4-dioxane, react at 90 ° C for 12 hours, pour into 20 mL of ice water, extract with ethyl acetate (20 mL×3), combine the organic phases, and wash with saturated sodium chloride solution (50 The title compound is 3-[[7-[3-(hydroxymethyl)). The title compound is obtained from the titled product. 4-methoxyphenyl]-4-[(3 -3-methylmorpholin-4-yl] B-pyrido[2,3-d]pyrimidin-2-yl]amino]piperidine-2 - Ketone 35 (10 mg, yellow solid), Yield: 5.6%.
MS m/z (ESI): 479.3 [M+l]  MS m/z (ESI): 479.3 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.30 (s, 1H), 8.18-8.06 (m， 2H), 7.63 (d， 1H), 7.11 (d， 1H), 5.21-5.19 (m， 1H)， 4.58 (d, 2H), 3.98-3.92 (m， 1H)， 3.87 (s, 3H), 3.74-3.61 (m， 5H)， 3.25-2.20 (m， 5H)， 2.02-1.87 (m， 4H)， 1.24 (s， 3H) 实施例 36 iHNMR (400 MHz, DMSO-J 6 ): δ 8.30 (s, 1H), 8.18-8.06 (m, 2H), 7.63 (d, 1H), 7.11 (d, 1H), 5.21-5.19 (m, 1H) , 4.58 (d, 2H), 3.98-3.92 (m, 1H), 3.87 (s, 3H), 3.74-3.61 (m, 5H), 3.25-2.20 (m, 5H), 2.02-1.87 (m, 4H) , 1.24 (s, 3H) Example 36
Ν-Γ743- (羟甲基) -4-甲氧基苯基 l-4-「( -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧啶 -2-
Figure imgf000058_0002
Ν-Γ743-(Hydroxymethyl)-4-methoxyphenyl l-4-"(-3-methylmorpholin-4-yl1pyridinium-2,3-dlpyrimidin-2-
Figure imgf000058_0002
将 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲 醇 3a (50 mg， 0.13 mmol)和 N，N-二异丙基乙胺 (33 mg， 0.26 mmol)溶解于 5 mL二氯 甲烷中， 冰浴下滴加环丙基酰氯 (20 mg， 0.19 mmol), 反应 12小时， 反应液减压浓 縮， 加入 20 mL水， 用二氯甲烷萃取 (20 mLx3)， 合并有机相， 用饱和氯化钠溶液 洗涤 (50 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用 HPLC制备色谱法以展 开剂体系 A 纯化所得残余物， 得到标题产物 N-[7-[3- (羟甲基) -4-甲氧基苯 基] -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2-基]环丙基酰胺 36 (6 mg， 乳白色 固体)， 产率： 10.3%. [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy- Phenyl]methanol 3a (50 mg, 0.13 mmol) and N,N-diisopropylethylamine (33 mg, 0.26 mmol) were dissolved in 5 mL of dichloromethane. Mg, 0.19 mmol), reaction for 12 hours, the reaction mixture is concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) Dry over sodium sulfate, filter, concentrate the filtrate under reduced pressure, and prepare the chromatographic method by HPLC. The residue obtained was purified by the title compound A to give the title product N-[7-[3-(hydroxymethyl)-4-methoxyphenyl]-4-[(3-3-methylmorpholin-4- B]pyrido[2,3-d]pyrimidin-2-yl]cyclopropylamide 36 (6 mg, milky white solid), yield: 10.3%.
MS m/z (ESI): 450.2 [M+l] MS m/z (ESI): 450.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.87 (s, 1H)， 8.30 (s, 1H)， 8.15-8.13 (m， 1H)， 7.67-7.65 (m， 1H)， 7.01 (d, 1H)， 4.67 (s, 2H), 3.95-3.93 (m， 2H), 3.75-3.73 (m， 2H), 3.71-3.70 (m， 2H), 3.68 (s, 3H), 3.50-3.48 (m， 1H)， 1.23 (s, 3H), 1.16-1.14 (m， 1H)， 0.91-0.88 (m， 2H), 0.63-0.59 (m， 2H) 实施例 37 iHNMR (400 MHz, DMSO-J 6 ): δ 8.87 (s, 1H), 8.30 (s, 1H), 8.15-8.13 (m, 1H), 7.67-7.65 (m, 1H), 7.01 (d, 1H) , 4.67 (s, 2H), 3.95-3.93 (m, 2H), 3.75-3.73 (m, 2H), 3.71-3.70 (m, 2H), 3.68 (s, 3H), 3.50-3.48 (m, 1H) , 1.23 (s, 3H), 1.16-1.14 (m, 1H), 0.91-0.88 (m, 2H), 0.63-0.59 (m, 2H) Example 37
(3 -3-「「7-「3- (羟甲基) -4-甲氧基 -苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧  (3 -3-""7-"3-(Hydroxymethyl)-4-methoxy-phenyll-4-"(3 -3-methylmorpholin-4-yl 1 pyridine and "2, 3-dl
Figure imgf000059_0001
Figure imgf000059_0001
将 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲 醇 3a (200 mg， 0.50 mmol), 氨基氮杂卓 -2-酮 (70 mg， 0.55 mmol)和 N，N-二异 丙基乙胺 (97 mg，0.75mol)溶解于 5 mL N，N-二甲基乙酰胺中， 90°C下反应 12小时， 倒入冰水中， 过滤， 滤饼用 5 mL水洗涤， 用 HPLC制备色谱法以展开剂体系 A纯 化所得残余物， 得到标题产物 (3 -3-[[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-[(3 -3-甲基 吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2-基]氨基]氮杂卓 -2-酮 37 C30 mg， 黄色固体)， 产率： 12.2%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy- Phenyl]methanol 3a (200 mg, 0.50 mmol), aminoazepine-2-one (70 mg, 0.55 mmol) and N,N-diisopropylethylamine (97 mg, 0.75 mol) dissolved in 5 mL In N,N-dimethylacetamide, the reaction was carried out at 90 ° C for 12 hours, poured into ice water, filtered, and the filter cake was washed with 5 mL of water, and the obtained residue was purified by HPLC to prepare the residue obtained by HPLC. The title product (3 -3-[[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-[(3-3-methylmorpholin-4-yl) B-pyridinium And [2,3-d]pyrimidin-2-yl]amino]azan-2-one 37 C 30 mg, yellow solid), Yield: 12.2%.
MS m/z (ESI): 493.2 [M+l]  MS m/z (ESI): 493.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.30 (s, 1H), 8.17-8.16 (m, 1H), 8.06-8.05 (m, 1H), 7.92-7.90 (m， 1H)， 7.11-7.09 (d， 1H)， 5.21-5.18 (m， 1H)， 4.58 (d， 2H), 4.61-4.60 (m， 1H), 3.87 (s， 3H), 3.73-3.62 (m， 5H)， 3.17-3.10 (m， 5H)， 2.10-1.81 (m， 6H)， 1.23 (s， 3H) 实施例 38 iHNMR (400 MHz, DMSO-J 6 ): δ 8.30 (s, 1H), 8.17-8.16 (m, 1H), 8.06-8.05 (m, 1H), 7.92-7.90 (m, 1H), 7.11-7.09 ( d, 1H), 5.21-5.18 (m, 1H), 4.58 (d, 2H), 4.61-4.60 (m, 1H), 3.87 (s, 3H), 3.73-3.62 (m, 5H), 3.17-3.10 ( m, 5H), 2.10-1.81 (m, 6H), 1.23 (s, 3H) Example 38
「4-Γ「7-「3-ί羟甲基 4-甲氧基苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧啶 -2- 基 1氨基 1-1-哌啶基 1-(3-吡啶基)甲酮 "4-Γ"7-"3-ί-hydroxymethyl 4-methoxyphenyl l-4-" (3 -3-methylmorpholin-4-yl 1 pyridine and 2,3-dl pyrimidine- 2-yl 1amino-1-phenylpiperidinyl 1-(3-pyridyl)methanone
Figure imgf000060_0001
Figure imgf000060_0001
将 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲 醇 3a (80 mg， 0.20 mmol), (4-氨基 -1-哌啶基 )-(3-吡啶基）甲酮 (58 mg， 0.24 mmol), N，N-二异丙基乙胺 (65 mg， 0.50mol)和 5 mL N，N-二甲基乙酰胺， 90°C下反应 4小时， 减压浓縮， 用 HPLC制备色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 [4-[[7-[3- (羟甲基) -4-甲氧基苯基] -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2-基] 氨基] -1-哌啶基： K3-吡啶基)甲酮 38 (20 mg， 黄色固体)， 产率： 11.7%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy- Phenyl]methanol 3a (80 mg, 0.20 mmol), (4-amino-1-piperidinyl)-(3-pyridyl)methanone (58 mg, 0.24 mmol), N,N-diisopropyl The amine (65 mg, 0.50 mol) and 5 mL of N,N-dimethylacetamide were reacted at 90 ° C for 4 hours, concentrated under reduced pressure, and purified by HPLC preparative chromatography to afford The title product [4-[[7-[3-(hydroxymethyl)-4-methoxyphenyl]-4-[(3-3-methylmorpholin-4-yl) B) is pyridine [2 , 3-d]pyrimidin-2-yl]amino]-1-piperidinyl: K3-pyridyl)methanone 38 (20 mg, yellow solid), yield: 11.7%.
MS m/z (ESI): 570.2 [M+l] MS m/z (ESI): 570.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.87 (s, 1H)， 8.72-8.70 (d, 1H)， 8.32 (s, 1H)， 8.23-8.19 (m, 1H), 8.09-7.96 (m, 2H), 7.56-7.54 (m, 1H), 7.52-7.47 (m, 1H), 7.04-7.01 (m， 1H)， 4.63 (s， 2H), 3.88 (s， 3H), 3.61-3.50 (m， 7H), 3.37-3.26 (m， 4H)， 2.65-2.63 (m， 1H), 1.85-1.54 (m， 4H)， 1.24 (s， 3H) 实施例 39 iHNMR (400 MHz, DMSO-J 6 ): δ 8.87 (s, 1H), 8.72-8.70 (d, 1H), 8.32 (s, 1H), 8.23-8.19 (m, 1H), 8.09-7.96 (m, 2H), 7.56-7.54 (m, 1H), 7.52-7.47 (m, 1H), 7.04-7.01 (m, 1H), 4.63 (s, 2H), 3.88 (s, 3H), 3.61-3.50 (m, 7H), 3.37-3.26 (m, 4H), 2.65-2.63 (m, 1H), 1.85-1.54 (m, 4H), 1.24 (s, 3H) Example 39
「4-Γ「7-「3-ί羟甲基 4-甲氧基苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧啶 -2-  "4-Γ"7-"3-ί-hydroxymethyl 4-methoxyphenyl l-4-" (3 -3-methylmorpholin-4-yl 1 pyridine and 2,3-dl pyrimidine- 2-
Figure imgf000060_0002
Figure imgf000060_0002
将 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] Β比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲 醇 3a (80 mg， 0.20 mmol), 4-氨基 -N，N-二甲基 -哌啶 -1-甲酰胺 (40 mg， 0.24 mmol), N，N-二异丙基乙胺 (65 mg， 0.50 mmol)和 5 mL N，N-二甲基乙酰胺， 90°C下反应 4小 时， 减压浓縮， 用 HPLC制备色谱法以展开剂体系 A纯化所得残余物， 得到标题 产物 [4-[[7-[3- (羟甲基) -4-甲氧基苯基] -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2-基]氨基] -N，N-二甲基 -哌啶 -1-甲酰胺 39 C30 mg， 黄色固体)， 产率： 30.0%。 MS m/z (ESI): 536.2 [M+l] [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)indolepyrido[2,3-d]pyrimidin-7-yl]-2-methoxy- Phenyl]methanol 3a (80 mg, 0.20 mmol), 4-amino-N,N-dimethyl-piperidine-1-carboxamide (40 mg, 0.24 mmol) N,N-diisopropylethylamine (65 mg, 0.50 mmol) and 5 mL of N,N-dimethylacetamide, reacted at 90 ° C for 4 hours, concentrated under reduced pressure, and purified by HPLC. The residue obtained was purified to give the title product [4-[[7-[3-(hydroxymethyl)-4-methoxyphenyl]-4-[(3-3-methylmorpholin-4) -yl]B-pyrido[2,3-d]pyrimidin-2-yl]amino]-N,N-dimethyl-piperidine-1-carboxamide 39 C30 mg, yellow solid), Yield: 30.0 %. MS m/z (ESI): 536.2 [M+l]
iHNMR (400 MHz, DMSO- ): δ 8.26 (s， 1H), 8.12 (d, 1H), 7.94 (m， 1H), 7.56 (m， 1H) 7.09 (d, 1H), 4.57 (s， 2H), 3.85-3.76 (m， 4H)， 3.76-3.74 (m， 2H), 3.64-3.59 (m， 5H)， 2.85 (s, 3H), 2.70 (s, 6H)， 1.90 (m， 3H), 1.78-1.71 (m， 2H), 1.49 (s, 3H) 实施例 40 iHNMR (400 MHz, DMSO-): δ 8.26 (s, 1H), 8.12 (d, 1H), 7.94 (m, 1H), 7.56 (m, 1H) 7.09 (d, 1H), 4.57 (s, 2H) , 3.85-3.76 (m, 4H), 3.76-3.74 (m, 2H), 3.64-3.59 (m, 5H), 2.85 (s, 3H), 2.70 (s, 6H), 1.90 (m, 3H), 1.78 -1.71 (m, 2H), 1.49 (s, 3H) Example 40
(3RV3-「「7-「3-i羟甲基 4-甲氧基 -苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧  (3RV3-""7-"3-ihydroxymethyl 4-methoxy-phenyl l-4-" (3 -3-methylmorpholin-4-yl 1 pyridine and 2,3-dl-pyrimidine
Figure imgf000061_0001
Figure imgf000061_0001
将 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲 醇 3a (200 mg， 0.50 mmol), (3R)-3-氨基氮杂卓 -2-酮 (77 mg， 0.60 mmol)和 N，N-二异 丙基乙胺 (0.15 mL， 1 mmol)溶解于 5 mL N，N-二甲基乙酰胺中， 90 °C下反应 12小时， 减压浓縮， 用 HPLC制备色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 (3R)-3-[[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2-基]氨基]氮杂卓 -2-酮 40 (10 mg， 黄色固体)， 产率： 4.1%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy- Phenyl]methanol 3a (200 mg, 0.50 mmol), (3R)-3-aminoazepin-2-one (77 mg, 0.60 mmol) and N,N-diisopropylethylamine (0.15 mL, 1 Methyl acetate was dissolved in 5 mL of N,N-dimethylacetamide, and the reaction was carried out at 90 ° C for 12 hours, and concentrated under reduced pressure. )-3-[[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-[(3 -3-methylmorpholin-4-yl) B-pyridyl[2] , 3-d]pyrimidin-2-yl]amino]azan-2-one 40 (10 mg, yellow solid), Yield: 4.1%.
MS m/z (ESI): 493.3 [M+l] MS m/z (ESI): 493.3 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.31 (s， 1H), 8.17-8.07 (m， 2H), 7.92-7.90 (m， 1H)， 7.64-7.62 (m, 1H), 7.12 (d, 1H), 6.62-6.59 (m, 1H), 5.22-5.19 (m, 1H), 4.19-4.17 (m, 2H), 3.87 (s， 3H), 3.75-3.62 (m， 5H)， 3.20-3.14 (m， 3H), 2.11-1.82 (m， 4H)， 1.45-1.34 (m， 2H), 1.24 (s， 3H) 实施例 41 iHNMR (400 MHz, DMSO-J 6 ): δ 8.31 (s, 1H), 8.17-8.07 (m, 2H), 7.92-7.90 (m, 1H), 7.64-7.62 (m, 1H), 7.12 (d, 1H), 6.62-6.59 (m, 1H), 5.22-5.19 (m, 1H), 4.19-4.17 (m, 2H), 3.87 (s, 3H), 3.75-3.62 (m, 5H), 3.20-3.14 ( m, 3H), 2.11-1.82 (m, 4H), 1.45-1.34 (m, 2H), 1.24 (s, 3H) Example 41
Γ2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 1-2- (甲基 (四氢呋喃 -3-基)氨基)吡啶并「2,3-dl 嘧啶 -7-基 1苯基 1甲醇 Γ2-methoxy-5-"4-"(3 -3-methylmorpholin-4-yl1-2-(methyl(tetrahydrofuran-3-yl)amino)pyridine"2,3-dl pyrimidine -7-yl 1 phenyl 1 methanol
Figure imgf000062_0001
Figure imgf000062_0001
将 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲 醇 3a (80 mg， 0.20 mmol), N-甲基四氢呋喃 -3-胺 (24 mg， 0.24 mmol)和 N，N-二异丙基 乙胺 (65 mg， 0.40 mol)溶解于 5 mL N，N-二甲基乙酰胺中， 90°C下反应 12小时， 减 压浓縮， 用 HPLC制备色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 [2- 甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2- (甲基 (四氢呋喃 -3-基)氨基)吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 41 (5 mg， 黄色固体)， 产率： 5.4%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy- Phenyl]methanol 3a (80 mg, 0.20 mmol), N-methyltetrahydrofuran-3-amine (24 mg, 0.24 mmol) and N,N-diisopropylethylamine (65 mg, 0.40 mol) dissolved in 5 The reaction was carried out at 90 ° C for 12 hours in mL N,N-dimethylacetamide, and concentrated under reduced pressure. 5-[4-[(3 -3-methylmorpholin-4-yl)-2-(methyl(tetrahydrofuran-3-yl)amino)pyrido[2,3-d]pyrimidin-7-yl] Phenyl]methanol 41 (5 mg, yellow solid), yield: 5.4%.
MS m/z (ESI): 466.2 [M+l] MS m/z (ESI): 466.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.32 (s, 1H)， 8.17 (d, 1H)， 8.08 (d, 1H)， 7.61 (d， 1H)， 7.01 (d, 1H)， 4.58 (d， 2H), 4.43-4.41 (m， 2H), 4.15-4.13 (m， 1H)， 4.02-3.87 (m， 6H)， 3.76-3.67 (m， 3H), 3.62-3.61 (m， 4H)， 2.61-2.41 (m， 1H), 1.63 (s， 3H), 0.90-0.86 (m， 3H) 实施例 42 iHNMR (400 MHz, DMSO-J 6 ): δ 8.32 (s, 1H), 8.17 (d, 1H), 8.08 (d, 1H), 7.61 (d, 1H), 7.01 (d, 1H), 4.58 (d , 2H), 4.43-4.41 (m, 2H), 4.15-4.13 (m, 1H), 4.02-3.87 (m, 6H), 3.76-3.67 (m, 3H), 3.62-3.61 (m, 4H), 2.61 -2.41 (m, 1H), 1.63 (s, 3H), 0.90-0.86 (m, 3H) Example 42
环丙基 -「4-「「7-「3- (羟甲基) -4-甲氧基苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl Cyclopropyl-"4-"" 7- "3-(hydroxymethyl)-4-methoxyphenyl l-4-"(3 -3-methylmorpholin-4-yl 1 pyridine and "2 , 3-dl
Figure imgf000062_0002
Figure imgf000062_0002
第一步  First step
环丙基—(4-甲基氨基 -1-哌啶基)甲酮 将 1- (；环丙基羰基)哌啶 -4-酮 42a (555 mg， 3.32 mmol, 采用公知的方法 "专利 US4312876"制备而得)溶解于 20 mL甲醇中， 加入 3.3 mL 2M甲胺的四氢呋喃溶 液， 搅拌 1小时， 加入三乙酰氧基硼氢化钠 (1.41 g， 6.64 mmol), 反应 12小时， 减 压浓縮， 加入 50 mL乙酸乙酯， 用水洗涤 (50 mL)， 无水硫酸钠干燥， 过滤， 滤液 减压浓縮， 得到标题产物粗品环丙基 -(4-甲基氨基 -1-哌啶基)甲酮 42b (250 mg， 浅 黄色油状物)， 产物不经纯化直接用于下步反应。 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). Drying, filtration, and EtOAcqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH In the next step of the reaction.
MS m/z (ESI): 183.1 [M+l] MS m/z (ESI): 183.1 [M+l]
第二步  Second step
环丙基—[4-[[7-[3- (羟甲基) -4-甲氧基苯基] -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d] 嘧啶 -2-基]-甲基-氨基]小哌 ¾基]甲酮  Cyclopropyl-[4-[[7-[3-(hydroxymethyl)-4-methoxyphenyl]-4-[(3-3-methylmorpholin-4-yl) B-pyridyl) [2,3-d]pyrimidin-2-yl]-methyl-amino]piperidine 3⁄4yl]methanone
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (150 mg, 0.37 mmol),粗品环丙基 -(4-甲基氨基 -1-哌啶基) 甲酮 42b (82 mg, 0.45 mmol), N，N-二异丙基乙胺 (145 mg, 1.12 mol)禾卩 5 mL N，N-二 甲基乙酰胺， 90°C下反应 12小时， 加入 10 mL二氯甲烷和 6 mL水， 分层， 水相 用二氯甲烷萃取 (20 mL)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mL)， 无水硫酸 钠干燥， 过滤， 滤液减压浓縮， 用 HPLC制备色谱法以展开剂体系 A纯化所得残 余物，得到标题产物环丙基 -[4-[[7-[3- (羟甲基) -4-甲氧基苯基] -4-[(3 -3-甲基吗啉 -4- 基]吡啶并 [2，3-d]嘧啶 -2-基] -甲基 -氨基 ]-1-哌啶基]甲酮 42 (2.5 mg, 黄色固体)， 产 率： 1.2%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (150 mg, 0.37 mmol), crude cyclopropyl-(4-methylamino-1-piperidinyl)methanone 42b (82 mg, 0.45 mmol), N, N- Isopropylethylamine (145 mg, 1.12 mol) and 5 mL N,N-dimethylacetamide, reacted at 90 ° C for 12 hours, added 10 mL of dichloromethane and 6 mL of water, layered, aqueous phase The mixture was extracted with dichloromethane (20 mL), EtOAc (EtOAc)EtOAc. The obtained residue was purified to give the title product, <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; [4-[[7-[3-(hydroxymethyl)-4-methoxyphenyl]-4-[(3-3-methylmorpholine- 4-Phenyl]pyrido[2,3-d]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl]methanone 42 (2.5 mg, yellow solid), Yield: 1.2%.
MS m/z (ESI): 547.3 [M+l]  MS m/z (ESI): 547.3 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.22 (s, 2H), 8.11 (d， 1H)， 7.51-7.41 (m， 1H)， 7.10 (d， 1H), 4.73 (s， 2H), 3.82 (s， 3H), 3.80-3.60 (m， 10H), 2.81-2.61 (m， 4H)， 2.21-2.11 (m， 5H)， 1.53-1.45 (m， 1H), 1.35-1.26 (m， 3H), 1.12-0.91 (m， 2H), 0.95-0.90 (m， 1H)， 0.82-0.74 (m， 2H) 实施例 43 iHNMR (400 MHz, DMSO-J 6 ): δ 8.22 (s, 2H), 8.11 (d, 1H), 7.51-7.41 (m, 1H), 7.10 (d, 1H), 4.73 (s, 2H), 3.82 (s, 3H), 3.80-3.60 (m, 10H), 2.81-2.61 (m, 4H), 2.21-2.11 (m, 5H), 1.53-1.45 (m, 1H), 1.35-1.26 (m, 3H) , 1.12-0.91 (m, 2H), 0.95-0.90 (m, 1H), 0.82-0.74 (m, 2H) Example 43
(3RV3-「「7-「3-i羟甲基 4-甲氧基 -苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧  (3RV3-""7-"3-ihydroxymethyl 4-methoxy-phenyl l-4-" (3 -3-methylmorpholin-4-yl 1 pyridine and 2,3-dl-pyrimidine
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000063_0001
Figure imgf000064_0001
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (110 mg， 0.27 mmol), (3R)-1-甲基 -3-甲基氨基-氮杂卓 -2- 酮 (60 mg， 0.41 mmol), N，N-二异丙基乙胺 (106 mg， 0.82 mmol)禾卩 5 mL N，N-二甲基 乙酰胺， 90°C下反应 12小时， 减压浓縮， 用 HPLC制备色谱法以展开剂体系 A纯 化所得残余物， 得到标题产物 (3R)-3-[[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-[(3 -3-甲基 吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2-基] -甲基 -氨基 ]-1-甲基氮杂卓 -2-酮 43 (10 mg, 黄色 固体)， 产率： 7.2%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (110 mg, 0.27 mmol), (3R)-1-methyl-3-methylamino-azoxa-2-one (60 mg, 0.41 mmol), N, N- Diisopropylethylamine (106 mg, 0.82 mmol) and 5 mL of N,N-dimethylacetamide, reacted at 90 ° C for 12 hours, concentrated under reduced pressure, and chromatographed by HPLC to develop solvent system A The obtained residue was purified to give the title product (3,3,3-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-[(3-3-methylmorpholine- 4-yl]B-pyrido[2,3-d]pyrimidin-2-yl]-methyl-amino]-1-methylazepin-2-one 43 (10 mg, yellow solid), yield : 7.2%.
MS m/z (ESI): 521.2 [M+l] MS m/z (ESI): 521.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.35 (s, 1H), 8.12 (d, 1H), 7.36 (d, 1H), 7.23 (d， 1H)， 7.10 (d, 1H), 4.58 (s, 2H), 3.88 (s, 3H), 3.90-3.63 (m, 8H)， 3.52 (s, 3H), 3.25-3.16 (m, 3H), 2.89 (s， 3H), 2.02-1.75 (m， 6H)， 1.26-1.24 (m， 3H) 实施例 44 iHNMR (400 MHz, DMSO-J 6 ): δ 8.35 (s, 1H), 8.12 (d, 1H), 7.36 (d, 1H), 7.23 (d, 1H), 7.10 (d, 1H), 4.58 (s , 2H), 3.88 (s, 3H), 3.90-3.63 (m, 8H), 3.52 (s, 3H), 3.25-3.16 (m, 3H), 2.89 (s, 3H), 2.02-1.75 (m, 6H) ), 1.26-1.24 (m, 3H) Example 44
「4-Γ「7-「3- (羟甲基) -4-甲氧基苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧啶 -2-  "4-Γ"7-"3-(Hydroxymethyl)-4-methoxyphenyl l-4-"(3 -3-methylmorpholin-4-yl 1 pyridine and 2,3-dl Pyrimidine-2-
Figure imgf000064_0002
Figure imgf000064_0002
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (100 mg, 0.25 mmol), 4-甲基氨基哌啶 -1-甲酸异丙酯 (87 mg, 0.30 mmol), N，N-二异丙基乙胺 (130 mL, 0.75 mmol)禾卩 5 mL N，N-二甲基乙酰 胺， 90°C下反应 12小时， 加入 20 mL饱和氯化铵溶液， 乙酸乙酯萃取 (20 mIX3)， 合并有机相， 用饱和氯化钠溶液洗涤 (15 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮， 用 HPLC 制备色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 [4-[[7-[3- (羟甲基) -4-甲氧基苯基] -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2-基] - 甲基-氨基]哌啶 -1-甲酸异丙酯 44 (35 mg， 黄色固体)， 产率： 24.8%。 [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (100 mg, 0.25 mmol), 4-methylaminopiperidine-1-carboxylic acid isopropyl ester (87 mg, 0.30 mmol), N,N-diisopropylethylamine (130 mL, 0.75 mmol) and 5 mL of N,N-dimethylacetamide, reacted at 90 ° C for 12 hours, added 20 mL of saturated ammonium chloride solution, extracted with ethyl acetate (20 mIX3), combined organic phase, The mixture was washed with a saturated sodium chloride solution (15 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. [4-[[7-[3-(Hydroxymethyl)-4-methoxyphenyl]-4-[(3-3-methylmorpholin-4-yl] B-pyridyl[2,3 -d]pyrimidin-2-yl]-methyl-amino]piperidine-1-carboxylic acid isopropyl ester 44 (35 mg, yellow solid), yield: 24.8%.
MS m/z (ESI): 566.2 [M+l] MS m/z (ESI): 566.2 [M+l]
iHNMR (400 MHz, CDC13): δ 8.22 (s, 1H)， 8.17 (d, 1H)， 8.00 (d, 1H)， 7.46 (d, 1H)， 6.99 (d, 1H)， 4.94-4.92 (m， 2H), 4.78 (s, 2H), 3.98-3.96 (m， 1H)， 3.87 (s, 3H), 3.86-3.84 (m， 4H)， 3.77-3.76 (m， 4H)， 3.08-3.02 (m， 6H)， 1.75 (s, 3H), 1.51 (d, 6H)， 1.26 (s, 3H) 实施例 45 iHNMR (400 MHz, CDC1 3 ): δ 8.22 (s, 1H), 8.17 (d, 1H), 8.00 (d, 1H), 7.46 (d, 1H), 6.99 (d, 1H), 4.94-4.92 (m , 2H), 4.78 (s, 2H), 3.98-3.96 (m, 1H), 3.87 (s, 3H), 3.86-3.84 (m, 4H), 3.77-3.76 (m, 4H), 3.08-3.02 (m , 6H), 1.75 (s, 3H), 1.51 (d, 6H), 1.26 (s, 3H) Example 45
Γ2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 1-2-「甲基 -「(3R)-四氢呋喃 -3-基 1氨基 1吡啶  Γ2-methoxy-5-"4-"(3 -3-methylmorpholin-4-yl 1-2-"methyl-"(3R)-tetrahydrofuran-3-yl 1amino 1pyridine
Figure imgf000065_0001
Figure imgf000065_0001
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (150 mg， 0.37 mmol), (3R)-N-甲基四氢呋喃 -3-胺 (91 mg， 0.45 mmol), N，N-二异丙基乙胺 (195 mL, 1.12 mmol)禾卩 5 mL N，N-二甲基乙酰胺， 90°C下反应 12小时， 加入 15 mL饱和氯化铵溶液， 乙酸乙酯萃取 (15 mIX3)， 合 并有机相， 用饱和氯化钠溶液洗涤 (15 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压 浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2- [甲基 -[(3R)-四氢呋喃 -3-基]氨基]吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 45 (31 mg， 黄色固体)， 产率： 17.8%。 [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (150 mg, 0.37 mmol), (3R)-N-methyltetrahydrofuran-3-amine (91 mg, 0.45 mmol), N,N-diisopropylethylamine (195 mL , 1.12 mmol) and 5 mL of N,N-dimethylacetamide, reacted at 90 ° C for 12 hours, added 15 mL of saturated ammonium chloride solution, extracted with ethyl acetate (15 mIX3), combined organic phase, saturated washed with sodium chloride solution (15 mLx2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product [2-methoxy --5 -[4-[(3 -3-methylmorpholin-4-yl)-2-[methyl-[(3R)-tetrahydrofuran-3-yl]amino]pyrido[2,3-d]pyrimidine- 7-yl]phenyl]methanol 45 (31 mg, yellow solid), yield: 17.8%.
MS m/z (ESI): 466.2 [M+l] MS m/z (ESI): 466.2 [M+l]
iHNMR (400 MHz, CDC13): δ 8.18 (s, 1H), 8.15 (d, 1H), 7.98 (d, 1H), 7.43 (d, 1H)， 7.00 (d, 1H), 4.78 (s, 2H), 4.40 (s, 1H), 4.12-4.10 (m, 1H), 3.94-3.92 (m, 1H), 3.90 (s, 3H), 3.88-3.86 (m， 2H), 3.72-3.70 (m， 3H), 3.23 (s, 3H), 2.37 (s, 1H), 1.95 (br.， 5H)， 1.50 (d, 3H) 实施例 46 iHNMR (400 MHz, CDC1 3 ): δ 8.18 (s, 1H), 8.15 (d, 1H), 7.98 (d, 1H), 7.43 (d, 1H), 7.00 (d, 1H), 4.78 (s, 2H) ), 4.40 (s, 1H), 4.12-4.10 (m, 1H), 3.94-3.92 (m, 1H), 3.90 (s, 3H), 3.88-3.86 (m, 2H), 3.72-3.70 (m, 3H) ), 3.23 (s, 3H), 2.37 (s, 1H), 1.95 (br., 5H), 1.50 (d, 3H) Example 46
Γ5-Γ2-叔丁基 -4-「(3 -3-甲基吗啉 1吡啶并「2,3- 嘧啶 -7-基 1-2-甲氧基 -苯基 1甲醇 Γ5-Γ2-tert-butyl-4-"(3 -3-methylmorpholine 1 pyridine and 2,3-pyrimidin-7-yl 1-2-methoxy-phenyl 1 methanol
Figure imgf000066_0001
Figure imgf000066_0001
第一步  First step
2- (；叔丁基) -7-氯 -2，3-二氢吡啶并 [2，3-d]嘧啶 -4(1H 酮 于反应瓶中依次加入 2-氨基 -6-氯-吡啶-甲酰胺 la (500 mg， 2.90 mmol), 三甲 基乙醛 (754 mg， 8.80 mmol), 氯化铜 (1.20 g， 8.80 mmol)和 5 mL乙醇， 75 °C反应 12 小时， 反应液过滤， 滤饼用二氯甲烷洗涤 (5 mLx2)， 滤液减压浓縮， 用硅胶柱色谱 法以展开剂体系 A纯化所得残余物， 得到标题产物 2- (叔丁基) -7-氯 -2,3-二氢吡啶 并 [2，3-d]嘧啶 -4(1H 酮 46a (96 mg， 白色固体)， 产率： 13.9%。  2-(; tert-butyl)-7-chloro-2,3-dihydropyrido[2,3-d]pyrimidine-4 (1H ketone was added to the reaction flask sequentially with 2-amino-6-chloro-pyridine- Formamide la (500 mg, 2.90 mmol), trimethylacetaldehyde (754 mg, 8.80 mmol), copper chloride (1.20 g, 8.80 mmol) and 5 mL ethanol, reacted at 75 °C for 12 hours, and filtered. The filter cake was washed with dichloromethane (5 mL×2), and the filtrate was evaporated to dryness. 3-Dihydropyrido[2,3-d]pyrimidine-4 (1H ketone 46a (96 mg, white solid), yield: 13.9%.
第二步  Second step
2- (；叔丁基) -7-氯-吡啶并 [2，3-d]嘧啶 -4(3H)-酮 将 2- (叔丁基) -7-氯 -2,3-二氢吡啶并 [2，3-d]嘧啶 -4(1H 酮 46a (110 mg， 0.46 mmol)溶解于 5 mL二氯甲烷中， 加入 2，3-二氯 -5,6-二氰基 -1,4-苯醌 (210 mg， 0.92 mmol), 反应 1小时， 加入 10 mL水， 用二氯甲烷萃取 (；10 mIX3)， 合并有机相， 用饱和碳酸氢钠溶液洗涤 (10 mLx2)， 无水硫酸镁干燥， 过滤， 滤液减压浓縮， 用 硅胶柱色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 2- (叔丁基) -7-氯-吡 啶并 [2，3-d]嘧啶 -4(3H 酮 46b (80 mg， 灰色固体)， 产率： 73.4%。  2-(; tert-butyl)-7-chloro-pyrido[2,3-d]pyrimidin-4(3H)-one 2-(tert-butyl)-7-chloro-2,3-dihydropyridine And [2,3-d]pyrimidine-4 (1H ketone 46a (110 mg, 0.46 mmol) was dissolved in 5 mL of dichloromethane, and 2,3-dichloro-5,6-dicyano-1,4 was added. -Phenylhydrazine (210 mg, 0.92 mmol), 1 hour, 10 mL of water, extracted with dichloromethane (10 m IX3), combined organic phase, washed with saturated sodium bicarbonate (10 mL×2), anhydrous sulfuric acid The magnesium was dried, filtered, and the filtrate was evaporated to dryness. Pyrimidine-4 (3H ketone 46b (80 mg, gray solid), yield: 73.4%.
MS m/z (ESI): 238.2 [M+l] MS m/z (ESI): 238.2 [M+l]
第三步  third step
叔丁基 )-7-氯-吡啶并 [2，3-d]嘧啶 -4-基) -3-甲基吗啉  Tert-butyl)-7-chloro-pyrido[2,3-d]pyrimidin-4-yl)-3-methylmorpholine
于反应瓶中依次加入 2- (叔丁基) -7-氯-吡啶并 [2，3-d]嘧啶 -4(3H 酮 46b (80 mg， 0.33 mmol)和 2 mL三氯氧磷， 回流反应 30分钟， 反应液减压浓縮， 真空干燥， 加 入 5 mL二氯甲烷和 ( -3-甲基吗啉 (100 mg， 1.00 mmol), 搅拌反应 1小时， 反应液 减压浓縮，用硅胶柱色谱法以展开剂体系 B纯化所得残余物，得到标题产物 ( -4-(2- 叔丁基 7-氯-吡啶并 [2，3-d]嘧啶 -4-基 )-3-甲基吗啉 46c ( 0 mg， 黄色油状物 产率： 66.6%。 2-(tert-butyl)-7-chloro-pyrido[2,3-d]pyrimidine-4 (3H ketone 46b (80 mg, 0.33 mmol) and 2 mL of phosphorus oxychloride were added to the reaction flask in turn. After reacting for 30 minutes, the reaction solution was concentrated under reduced vacuo. and evaporated in vacuo. 5 mL dichloromethane and (3-methylmorpholine (100 mg, 1.00 mmol), and the reaction was stirred for 1 hour. The residue was purified by silica gel column chromatography eluting eluting 3-methylmorpholine 46c (0 mg, yellow oily yield: 66.6%).
第四步  the fourth step
[5-[2-叔丁基 -4-[(3 -3-甲基吗啉]吡啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲醇 于反应瓶中依次加入 ( -4-(2-叔丁基 )-7-氯-吡啶并 [2，3-d]嘧啶 -4-基) -3-甲基吗 啉 46c (60 mg， 0.19 mmol), [2-甲氧基 -5-(4，4，5，5-四甲基 -1，3，2-二氧杂戊硼烷 -2-基) 苯基]甲醇 le (59 mg， 0.22 mmol), 四三苯基磷钯 (6 mg， 10%), 碳酸钾 (78 mg， 0.56 mmol)禾 B 1.25 mL 1,4-二氧六环和水 (V/V = 4: 1)混合溶剂， 80°C反应 12小时， 反应 液减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 [5-[2- 叔丁基 -4-[C3 -3-甲基吗啉]吡啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲醇 46 (51 mg， 浅黄色固体)， 产率： 64.5%。  [5-[2-tert-Butyl-4-[(3 -3-methylmorpholine]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol (-4-(2-tert-Butyl)-7-chloro-pyrido[2,3-d]pyrimidin-4-yl)-3-methylmorpholine 46c (60 mg, 0.19 mmol) was added to the reaction flask , [2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol le (59 mg, 0.22 mmol), tetratriphenylphosphine palladium (6 mg, 10%), potassium carbonate (78 mg, 0.56 mmol) and B 1.25 mL 1,4-dioxane and water (V/V = 4: 1) The solvent was mixed and reacted at 80 ° C for 12 hours, and the reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjj 3-Methylmorpholine]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 46 (51 mg, pale yellow solid), yield: 64.5%.
MS m/z (ESI): 423.2 [M+l] MS m/z (ESI): 423.2 [M+l]
iHNMR (400 MHz, CDC13): δ 8.27-8.25 (m， 1H)， 8.23-8.22 (m， 1H)， 8.18-8.16 (m， 1H) 7.77-7.75 (m， 1H), 7.03-7.01 (m， 1H), 4.80 (s， 2H), 4.47-4.45 (m， 1H) 4.06-4.98 (m， 2H), 3.96 (s， 3H), 3.84-3.69 (m， 4H)， 1.66-1.64 (m， 3H), 1.49 (s， 9H) 实施例 47 iHNMR (400 MHz, CDC1 3 ): δ 8.27-8.25 (m, 1H), 8.23-8.22 (m, 1H), 8.18-8.16 (m, 1H) 7.77-7.75 (m, 1H), 7.03-7.01 (m , 1H), 4.80 (s, 2H), 4.47-4.45 (m, 1H) 4.06-4.98 (m, 2H), 3.96 (s, 3H), 3.84-3.69 (m, 4H), 1.66-1.64 (m, 3H), 1.49 (s, 9H) Example 47
环丙基 -「4-「7-「3- (轻甲基 4-甲氧基苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl Cyclopropyl-"4-" 7- "3-(light methyl 4-methoxyphenyl l-4-"(3 -3-methylmorpholin-4-yl 1 pyridine and 2,3- Dl
Figure imgf000067_0001
Figure imgf000067_0001
将环丙基 -(4-羟基 -1-哌啶基)甲酮 (95 mg， 0.56 mmol)溶解于 5 mL N，N-二甲基 甲酰胺中， 冰浴下加入氢化钠 (41 mg， 1.12 mmol), 搅拌 30 分钟， 加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲醇 3a (150 mg， 0.37 mmol), 室温反应 12小时， 倒入 20 mL冰水中， 用乙酸乙酯萃取 (20 mLx3)， 合并有机相， 用饱和氯化钠溶液洗涤 (50 mL)， 无水硫酸钠干燥， 过滤， 滤液减压 浓縮， 用 HPLC制备色谱法以展开剂体系 A纯化所得残余物， 得到标题产物环丙 基—[4-[7-[3- (羟甲基) -4-甲氧基苯基] -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2- 基]氧基 -1-哌啶基]甲酮 47 (5 mg， 黄色固体)， 产率： 2.5%。 Dissolve cyclopropyl-(4-hydroxy-1-piperidyl)methanone (95 mg, 0.56 mmol) in 5 mL of N,N-dimethylformamide and add sodium hydride (41 mg, 1.12 mmol), stir for 30 minutes, add [5-[2-chloro-4-[(3 -3-methylmorpholin-4-yl) B-pyridyl[2,3-d]pyrimidin-7-yl ] 2-methoxy-phenyl]methanol 3a (150 mg, 0.37 mmol), mp. mp. The sodium salt solution was washed (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. -[4-[7-[3-(Hydroxymethyl)-4-methoxyphenyl]-4-[(3-3-methylmorpholin-4-yl) B-pyridyl[2, 3-d]pyrimidin-2-yl]oxy-1-piperidinyl]methanone 47 (5 mg, yellow solid), yield: 2.5%.
MS m/z (ESI): 434.2 [M+l] MS m/z (ESI): 434.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.35-8.33 (m， 2H), 8.12 (d， 1H), 7.83 (d, 1H), 7.13 (d: 1H), 4.70 (s， 2H), 3.88 (s， 3H), 3.73-3.56 (m， 10H), 3.00-2.94 (m， 3H), 2.12-2.00 (m， 4H), 1.54-1.52 (m, 1H), 1.42-1.39 (m, 3H), 1.24-1.23 (m, 4H) 实施例 48 iHNMR (400 MHz, DMSO-J 6 ): δ 8.35-8.33 (m, 2H), 8.12 (d, 1H), 7.83 (d, 1H), 7.13 (d : 1H), 4.70 (s, 2H), 3.88 (s, 3H), 3.73-3.56 (m, 10H), 3.00-2.94 (m, 3H), 2.12-2.00 (m, 4H), 1.54-1.52 (m, 1H), 1.42-1.39 (m, 3H) , 1.24-1.23 (m, 4H) Example 48
「2-甲氧基 -5-「4-「( -3-甲基吗啉 -4-基 1-2-四氢吡喃 -4-基硫基-吡啶并「2,3-dl嘧啶  "2-Methoxy-5-"4-"(-3-methylmorpholin-4-yl-1-2-tetrahydropyran-4-ylthio-pyridyl"2,3-dl pyrimidine
Figure imgf000068_0001
Figure imgf000068_0001
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (130 mg， 0.32 mmol), 四氢吡喃 -4-硫醇 (56 mg， 0.39 mmol), N，N-二异丙基乙胺 (126 mg， 0.92 mmol),碳酸钾 (100 mg， 0.72 mmol)和 5 mL N，N-二甲基乙酰胺， 110°C下反应 12小时， 加入 20 mL饱和氯化铵溶液， 用乙酸 乙酯萃取 (20 mLx3)， 合并有机相， 用饱和氯化钠溶液洗涤 (50 mL)， 无水硫酸钠干 燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到 标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2-四氢吡喃 -4-基硫基 -B比啶并 [2，3-d] 嘧啶 -7-基]苯基]甲醇 48 (20 mg， 黄色固体)， 产率： 12.8%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (130 mg, 0.32 mmol), tetrahydropyran-4-thiol (56 mg, 0.39 mmol), N,N-diisopropylethylamine (126 mg, 0.92 mmol) , potassium carbonate (100 mg, 0.72 mmol) and 5 mL of N,N-dimethylacetamide, reacted at 110 ° C for 12 hours, added 20 mL of saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL×3). The organic phase was combined, washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, filtered, evaporated. -Methoxy-5-[4-[(3 -3-methylmorpholin-4-yl)-2-tetrahydropyran-4-ylthio-B-pyrido[2,3-d] Pyrimidine-7-yl]phenyl]methanol 48 (20 mg, yellow solid), yield: 12.8%.
MS m/z (ESI): 483.2 [M+l] MS m/z (ESI): 483.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.22 (s, 1H), 8.18 (d, 1H), 7.99 (d, 1H), 7.46 (d， 1H)， 6.78 (d, 1H), 4.80 (s, 2H), 4.43 (s, 1H), 4.02-4.00 (m, 1H), 3.95 (s, 3H), 3.85-3.83 (m, 2H), 3.75-3.73 (m， 3H), 3.35 (s， 4H)， 1.71 (br.， 6H)， 1.48 (d， 2H) 实施例 49 iHNMR (400 MHz, DMSO-J 6 ): δ 8.22 (s, 1H), 8.18 (d, 1H), 7.99 (d, 1H), 7.46 (d, 1H), 6.78 (d, 1H), 4.80 (s , 2H), 4.43 (s, 1H), 4.02-4.00 (m, 1H), 3.95 (s, 3H), 3.85-3.83 (m, 2H), 3.75-3.73 (m, 3H), 3.35 (s, 4H ), 1.71 (br., 6H), 1.48 (d, 2H) Example 49
「4-Γ「7-「3- (羟甲基) -4-甲氧基苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧啶 -2- 基 1-甲基 -氨基 1-1-哌啶基 1-(3-吡啶基)甲酮 "4-Γ"7-"3-(Hydroxymethyl)-4-methoxyphenyl l-4-"(3 -3-methylmorpholin-4-yl 1 pyridine and 2,3-dl Pyrimidin-2-yl 1-methyl-amino1-1-piperidinyl 1-(3-pyridyl)methanone
Figure imgf000069_0001
Figure imgf000069_0001
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (100 mg， 0.25 mmol), (4-甲基氨基 -1-哌啶基 )-(3-吡啶基) 甲酮 (60 mg， 0.27 mmol), N，N-二异丙基乙胺 (64 mg， 0.49 mmol)禾卩 5 mL N，N-二甲基 乙酰胺， 90°C下反应 4小时， 减压浓縮， 用 HPLC制备色谱法以展开剂体系 A纯 化所得残余物， 得到标题产物 [4-[[7-[3- (羟甲基) -4-甲氧基苯基] -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2-基] -甲基 -氨基 ]-1-哌啶基 ]-(3-吡啶基)甲酮 49 (20 mg， 黄 色固体)， 产率： 13.8%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (100 mg, 0.25 mmol), (4-methylamino-1-piperidinyl)-(3-pyridyl)methanone (60 mg, 0.27 mmol), N, N- Diisopropylethylamine (64 mg, 0.49 mmol) and 5 mL N,N-dimethylacetamide, reacted at 90 ° C for 4 hours, concentrated under reduced pressure, and chromatographed by HPLC to develop solvent system A The obtained residue was purified to give the title product [4-[[7-[3-(hydroxymethyl)-4-methoxyphenyl]-4-[(3-3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl]-(3-pyridyl)methanone 49 (20 mg, yellow solid), yield : 13.8%.
MS m/z (ESI): 584.2 [M+l] MS m/z (ESI): 584.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.67-8.63 (m, 3H), 8.29-8.28 (m, 1H), 8.14-8.13 (m， 1H), 7.57 (d， 1H), 7.51-7.48 (m， 2H), 7.09-7.07 (m， 1H), 4.55 (d, 2H), 3.76 (s， 3H), 3.65-3.63 (m， 2H), 3.60-3.40 (m， 5H)， 3.39-3.31 (m， 1H)， 3.20 (s, 3H), 3.08 (m， 2H), 1.79-1.60 (m， 6H)， 1.22 (m， 3H) 实施例 50 iHNMR (400 MHz, DMSO-J 6 ): δ 8.67-8.63 (m, 3H), 8.29-8.28 (m, 1H), 8.14-8.13 (m, 1H), 7.57 (d, 1H), 7.51-7.48 ( m, 2H), 7.09-7.07 (m, 1H), 4.55 (d, 2H), 3.76 (s, 3H), 3.65-3.63 (m, 2H), 3.60-3.40 (m, 5H), 3.39-3.31 ( m, 1H), 3.20 (s, 3H), 3.08 (m, 2H), 1.79-1.60 (m, 6H), 1.22 (m, 3H) Example 50
「2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 1-2- (四氢吡喃 -4-基-甲基)吡啶并「2,3-dl嘧啶 -7-  "2-Methoxy-5-"4-"(3 -3-methylmorpholin-4-yl1-2-(tetrahydropyran-4-yl-methyl)pyridine and 2,3- Dl pyrimidine-7-
Figure imgf000069_0002
Figure imgf000069_0002
第一步  First step
2-甲氧基 -5-[4-氧代 -2- (四氢吡喃 -4基-甲基) -3H-吡啶并 [2，3-d]嘧啶 -7-基]苯基甲 酸甲酯 2-methoxy-5-[4-oxo-2-(tetrahydropyran-4-yl-methyl)-3H-pyrido[2,3-d]pyrimidin-7-yl]phenyl Methyl ester
将 2-甲氧基 -5-[4-氧代 -2- (四氢吡喃 -4 基-甲基) -3H-吡啶并 [2，3-d]嘧啶 -7-基]苯 基甲酸 50a (395 mg， 1 mmol, 采用公知的方法 "专利 CN101983199A"制备而得) 溶解于 5 mL甲醇中， 加入 3 mL氯化亚砜， 回流反应 3小时， 减压浓縮， 用薄层 色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 2-甲氧基 -5-[4-氧代 -2- (四 氢吡喃 -4基-甲基) -3H-吡啶并 [2，3-d]嘧啶 -7-基]苯基甲酸甲酯 50b (180 mg, 黄色固 体)， 产率： 44.0%。  2-methoxy-5-[4-oxo-2-(tetrahydropyran-4-yl-methyl)-3H-pyrido[2,3-d]pyrimidin-7-yl]phenylcarboxylic acid 50a (395 mg, 1 mmol, prepared by the known method "patent CN101983199A") dissolved in 5 mL of methanol, added with 3 mL of thionyl chloride, refluxed for 3 hours, concentrated under reduced pressure, using thin layer chromatography The obtained residue was purified to give the title product 2-methoxy-5-[4-oxo-2-(tetrahydropyran-4-yl-methyl)-3H-pyridine and [2,3] -d]pyrimidin-7-yl]methyl benzoate 50b (180 mg, yellow solid), yield: 44.0%.
MS m/z (ESI): 410.1 [M+l] MS m/z (ESI): 410.1 [M+l]
第二步  Second step
2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2- (四氢吡喃 -4-基-甲基) B比啶并 [2，3-d]嘧啶  2-methoxy-5-[4-[(3 -3-methylmorpholin-4-yl)-2-(tetrahydropyran-4-yl-methyl) B-pyridyl[2,3 -d]pyrimidine
-7-基]苯基甲酸甲酯  Methyl-7-yl]phenylcarboxylate
将 2-甲氧基 -5-[4-氧代 -2- (四氢吡喃 -4 基-甲基) -3H-吡啶并 [2，3-d]嘧啶 -7-基]苯 基甲酸甲酯 50b (50 mg, 0.13 mmol)和 甲基吗啉盐酸盐溶解于 1.5 mL三氯氧 磷中， 加入 N，N-二异丙基乙胺 (82 mg， 0.63 mmol), 90°C下反应 3小时， 减压浓縮， 加入 10 mL水，用二氯甲烷萃取 (5 mLx3)，合并有机相，用饱和氯化钠溶液洗涤 (10 mLx2), 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 A 纯化所得残余物， 得到标题产物 2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2- (四氢吡喃 _4-基-甲基) B比啶并 [2，3-d]嘧啶 -7-基]苯基甲酸甲酯 50b (18 mg, 黄色固体)， 产率： 29.0%。  2-methoxy-5-[4-oxo-2-(tetrahydropyran-4-yl-methyl)-3H-pyrido[2,3-d]pyrimidin-7-yl]phenylcarboxylic acid Methyl ester 50b (50 mg, 0.13 mmol) and methylmorpholine hydrochloride dissolved in 1.5 mL of phosphorus oxychloride and added N,N-diisopropylethylamine (82 mg, 0.63 mmol), 90 ° C The reaction was carried out for 3 hours, concentrated under reduced pressure, EtOAc (EtOAc) (EtOAc (EtOAc m. The residue was purified by EtOAc (EtOAc) eluting 2-(tetrahydropyran-4-yl-methyl) B-pyrido[2,3-d]pyrimidin-7-yl]phenylcarboxylate 50b (18 mg, yellow solid), yield: 29.0 %.
MS m/z (ESI): 493.2 [M+l]  MS m/z (ESI): 493.2 [M+l]
第三步  third step
[2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2- (四氢吡喃 -4-基-甲基) B比啶并 [2，3-d]嘧啶 -7- 基]苯基]甲醇  [2-Methoxy-5-[4-[(3 -3-methylmorpholin-4-yl)-2-(tetrahydropyran-4-yl-methyl) B is pyridine [2, 3-d]pyrimidin-7-yl]phenyl]methanol
将 2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2- (四氢吡喃 -4-基-甲基) B比啶并 [2，3-d] 嘧啶 -7-基]苯基甲酸甲酯 50b (18 mg, 0.04 mmol)和 0.5 mL乙醇溶解于 0.5 mL四氢 呋喃中， 加入硼氢化钠 (2 mg， 0.05 mmol), 反应 12小时， 减压浓縮， 用薄层色谱 法以展开剂体系 A纯化所得残余物，得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2- (四氢吡喃 -4-基-甲基) B比啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 50 (11 mg, 黄色固 体)， 产率： 64.7%。  2-methoxy-5-[4-[(3 -3-methylmorpholin-4-yl)-2-(tetrahydropyran-4-yl-methyl) B is pyridine [2, 3-d]pyrimidin-7-yl]methyl benzoate 50b (18 mg, 0.04 mmol) and 0.5 mL of ethanol were dissolved in 0.5 mL of tetrahydrofuran, and sodium borohydride (2 mg, 0.05 mmol) was added for 12 hours. The residue was purified by EtOAc (EtOAc) eluting -2- (tetrahydropyran-4-yl-methyl) B-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 50 (11 mg, yellow solid), yield: 64.7 %.
MS m/z (ESI): 465.1 [M+l] MS m/z (ESI): 465.1 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.32 (s, 1H), 7.97-7.92 (m， 2H), 7.47 (s, 1H), 7.01 (s, 1H), 4.61 (s， 2H), 3.65 (s， 3H), 3.57-3.40 (m， 8H)， 3.01-3.00 (m， 1H), 2.75-2.70 (m， 2H): 2.51-2.48 (m， 2H), 1.98-1.96 (s， 1H), 1.69-1.67 (m， 2H), 1.44-1.42 (m， 2H), 1.12 (s， 3H) 实施例 51 iHNMR (400 MHz, DMSO-J 6 ): δ 8.32 (s, 1H), 7.97-7.92 (m, 2H), 7.47 (s, 1H), 7.01 (s, 1H), 4.61 (s, 2H), 3.65 (s, 3H), 3.57-3.40 (m, 8H), 3.01-3.00 (m, 1H), 2.75-2.70 (m, 2H) : 2.51-2.48 (m, 2H), 1.98-1.96 (s, 1H) , 1.69-1.67 (m, 2H), 1.44-1.42 (m, 2H), 1.12 (s, 3H) Example 51
「5-Γ2-( ,6-二氢 -2H-吡喃 -4-基) -4-「( -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧啶 -7-基 1-2- 甲氧基 -苯基 1甲醇 "5-Γ2-( ,6-Dihydro-2H-pyran-4-yl)-4-"(-3-methylmorpholin-4-yl 1pyridine and 2,3-dl pyrimidine-7- Base 1-2-methoxy-phenyl 1 methanol
Figure imgf000071_0001
Figure imgf000071_0001
于微波管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -7- 基] -2-甲氧基-苯基]甲醇 3a (250 mg， 0.67 mmol), 三丁基 (3,6-二氢 -2H-吡喃 -4-基)锡 烷 8a (300 mg， 0.80 mmol), 双 (三苯基膦)二氯化钯 (47 mg， 0.067 mmol), N，N-二异 丙基乙胺 (233 mL, 1.34 mmol), 碘化亚酮 (15 mg， 0.07 mmol)和 0.5 mL N，N-二甲基 甲酰胺， 130°C下反应 20分钟， 加入 25 mL水， 用乙酸乙酯萃取 (30 mLx2)， 合并 有机相， 用饱和氯化钠溶液洗涤 (50 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 [5-[2-(3，6-二氢 -2H- 吡喃 -4-基) -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲醇 51 (28 mg, 黄色固体)， 产率： 9.3%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-7-yl]-2-yl was added sequentially to a microwave tube Oxy-phenyl]methanol 3a (250 mg, 0.67 mmol), tributyl(3,6-dihydro-2H-pyran-4-yl)stannane 8a (300 mg, 0.80 mmol), double (3) Phenylphosphine)palladium dichloride (47 mg, 0.067 mmol), N,N-diisopropylethylamine (233 mL, 1.34 mmol), iodide iodide (15 mg, 0.07 mmol) and 0.5 mL of N, N-dimethylformamide, reacted at 130 ° C for 20 minutes, added 25 mL of water, extracted with ethyl acetate (30 mL×2), combined organic phase, washed with saturated sodium chloride solution (50 mL), anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was evaporated to dryness. -4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 51 ( 28 mg, yellow solid), Yield: 9.3%.
MS m/z (ESI): 449.2 [M+l] MS m/z (ESI): 449.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.27-8.26 (m， 2H), 8.22-8.20 (d， 1H), 7.80 (d， 1H)， 7.07-7.05 (d, 1H), 5.96-5.94 (m， 1H), 4.86 (s， 2H), 4.56-4.54 (m， 1H), 4.48-4.46 (m， 2H), 4.06-4.04 (m， 2H), 4.00 (s， 3H), 3.98-3.96 (m， 1H), 3.83-3.80 (m， 3H), 3.78-3.76 (m， 1H)， 2.92-2.90 (m， 2H), 2.35 (s， 2H), 1.52 (d， 2H) 实施例 52 iHNMR (400 MHz, DMSO-J 6 ): δ 8.27-8.26 (m, 2H), 8.22-8.20 (d, 1H), 7.80 (d, 1H), 7.07-7.05 (d, 1H), 5.96-5.94 ( m, 1H), 4.86 (s, 2H), 4.56-4.54 (m, 1H), 4.48-4.46 (m, 2H), 4.06-4.04 (m, 2H), 4.00 (s, 3H), 3.98-3.96 ( m, 1H), 3.83-3.80 (m, 3H), 3.78-3.76 (m, 1H), 2.92-2.90 (m, 2H), 2.35 (s, 2H), 1.52 (d, 2H) Example 52
「2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 1-2-「甲基 -「 3-吡啶基甲基) -4-哌啶基 1氨 基 1吡 醇  "2-Methoxy-5-"4-"(3 -3-methylmorpholin-4-yl1-2-"methyl-"3-pyridylmethyl)-4-piperidyl 1amino 1 pyridyl alcohol
Figure imgf000071_0002
Figure imgf000072_0001
Figure imgf000071_0002
Figure imgf000072_0001
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (100 mg， 0.25 mmol), N-甲基 -1-(3-吡啶基甲基)哌啶 -4- 胺(100 1¾，0.49 1^^1 0.5 二异丙基乙胺和2 ^二甲基乙酰胺， 110 °C下反应 12小时， 加入 10 mL乙酸乙酯和 6 mL水， 分层， 有机相用饱和氯化钠 溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展 开剂体系 A 纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4- 基] -2- [甲基 -[1-(3-吡啶基甲基) -4-哌啶基]氨基]吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 52 (68 mg, 黄色固体)， 产率： 47.9%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (100 mg, 0.25 mmol), N-methyl-1-(3-pyridylmethyl)piperidin-4-amine (100 13⁄4, 0.49 1^^1 0.5 diisopropyl Ethylamine and 2 ^ dimethylacetamide, reacted at 110 ° C for 12 hours, added 10 mL of ethyl acetate and 6 mL of water, layered, and the organic phase was washed with saturated sodium chloride solution (30 mL×2), anhydrous Drying over sodium sulfate, filtration, EtOAc EtOAc (EtOAc) Morpholin-4-yl]-2-[methyl-[1-(3-pyridylmethyl)-4-piperidinyl]amino]pyrido[2,3-d]pyrimidin-7-yl]benzene Methyl]methanol 52 (68 mg, yellow solid), yield: 47.9%.
MS m/z (ESI): 570.6 [M+l] MS m/z (ESI): 570.6 [M+l]
iHNMR (400 MHz, DMSO- ): δ 8.61-8.51 (m， 2H), 8.25-8.11 (m， 2H), 7.97 (d, 1H 7.82 (d， 1H 7.41 (d, 1H 7.33-7.31 (m， 1H 6.99 (d, 1H 4.61 (s, 2H), 4.36 (br.， 1H 4.03-3.61 (m, 9H), 3.42-2.90 (m, 8H), 2.25-1.76 (m, 4H), 1.48 (d, 3H), 1.26 (s, 3H) 实施例 53iHNMR (400 MHz, DMSO-): δ 8.61-8.51 (m, 2H), 8.25-8.11 (m, 2H), 7.97 (d, 1H 7.82 (d, 1H 7.41 (d, 1H 7.33-7.31 (m, 1H) 6.99 (d, 1H 4.61 (s, 2H), 4.36 (br., 1H 4.03-3.61 (m, 9H), 3.42-2.90 (m, 8H), 2.25-1.76 (m, 4H), 1.48 (d, 3H ), 1.26 (s, 3H) Example 53
2-甲氧基 -5- 4- 3 -3-甲基吗啉 -4-基 1-2-四氢呋喃 -4-基-吡啶并「2,3-dl嘧啶 -7-基 1苯  2-methoxy-5- 4-3-methylmorpholin-4-yl 1-2-tetrahydrofuran-4-yl-pyridyl 2,3-dlpyrimidin-7-yl 1benzene
Figure imgf000072_0002
Figure imgf000072_0002
将 [5-[2-(3，6-二氢 -2H-吡喃 -4-基) -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7- 基] -2-甲氧基-苯基]甲醇 54 (25 mg, 0.05 mmol)溶解于 20 mL甲醇中， 加入钯 /碳 (ΙΟ mg, 10%), 氢气置换三次， 搅拌反应 3小时， 过滤， 滤液减压浓縮， 用薄层色谱 法以展开剂体系 A纯化所得残余物，得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2-四氢呋喃 -4-基 -B比啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 53 (15 mg,浅黄色固体)， 产率： 60.0% [5-[2-(3,6-Dihydro-2H-pyran-4-yl)-4-[(3 -3-methylmorpholin-4-yl] B-pyridyl[2,3 -d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 54 (25 mg, 0.05 mmol) dissolved in 20 mL of methanol, palladium/carbon (ΙΟ mg, 10%) The reaction was stirred for 3 hours, filtered, and the filtrate was evaporated to dryness. Methylmorpholin-4-yl]-2-tetrahydrofuran-4-yl-B-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 53 (15 mg, pale yellow solid) Yield: 60.0%
MS m/z (ESI): 451.2 [M+l]  MS m/z (ESI): 451.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.29 (d， 1H)， 8.25 (d, 1H)， 8.18 (d， 1H)， 7.78 (d， 1H)， 7.04 (d， 1H), 4.80 (s， 2H), 4.56-4.54 (m， 1H), 4.17 (d, 2H), 3.99 (d, 1H), 3.96 (s， 3H), 3.82-3.80 (m， 1H), 3.75 (d, 3H), 3.58-3.56 (m， 2H), 3.22 (s， 1H), 2.14-2.12 (m， 3H), 2.02-2.00 (m， 2H), 1.56 (d， 3H) 实施例 54 iHNMR (400 MHz, DMSO-J 6 ): δ 8.29 (d, 1H), 8.25 (d, 1H), 8.18 (d, 1H), 7.78 (d, 1H), 7.04 (d, 1H), 4.80 (s , 2H), 4.56-4.54 (m, 1H), 4.17 (d, 2H), 3.99 (d, 1H), 3.96 (s, 3H), 3.82-3.80 (m, 1H), 3.75 (d, 3H), 3.58-3.56 (m, 2H), 3.22 (s, 1H), 2.14-2.12 (m, 3H), 2.02-2.00 (m, 2H), 1.56 (d, 3H) Example 54
4-「「7-「3- (轻甲基 4-甲氧基 -苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧啶 -2- 4-"" 7- "3-(Light methyl 4-methoxy-phenyll-4-"(3 -3-methylmorpholin-4-yl 1 pyridine and 2,3-dl pyrimidine- 2-
Figure imgf000073_0001
Figure imgf000073_0001
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (100 mg， 0.25 mmol)， 4-甲基氨基哌啶小甲酸甲酯 (50 mg, 0.30 mmol), N，N-二异丙基乙胺 (96 mg， 0.75 mmol)和 5 mL N，N-二甲基乙酰胺， 90 °C下反应 4小时， 减压浓縮， 用 HPLC制备色谱法以展开剂体系 A纯化所得残余 物， 得到标题产物 4-[[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-[(3 -3-甲基吗啉 -4-基] B比啶 并 [2，3-d]嘧啶 -2-基] -甲基-氨基]哌啶 -1-甲酸甲酯 54 (20 mg， 黄色固体)， 产率： 15.3%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (100 mg, 0.25 mmol), methyl 4-methylaminopiperidinecarboxylate (50 mg, 0.30 mmol), N,N-diisopropylethylamine (96 mg, 0.75 Methyl) and 5 mL of N,N-dimethylacetamide, reacted at 90 ° C for 4 hours, concentrated under reduced pressure, and purified by HPLC to give the titled 7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidine Methyl-2-methyl]-methyl-amino]piperidine-1-carboxylate 54 (20 mg, yellow solid), yield: 15.3%.
MS m/z (ESI): 537.2 [M+l]  MS m/z (ESI): 537.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.28 (s, 1H), 8.13 (d, 1H), 8.04 (d, 1H), 7.56 (d， 1H)， 7.08 (d， 1H), 4.56 (d， 2H), 4.24-4.05 (m， 3H), 3.82 (s， 3H), 3.74-3.72 (m， 2H), 3.64 (s, 3H), 3.03 (s， 3H), 3.02-2.68 (m， 4H)， 2.40-2.31 (m， 3H), 1.76-1.60 (m， 4H)， 1.36 (d， 3H) 实施例 55 iHNMR (400 MHz, DMSO-J 6 ): δ 8.28 (s, 1H), 8.13 (d, 1H), 8.04 (d, 1H), 7.56 (d, 1H), 7.08 (d, 1H), 4.56 (d) , 2H), 4.24-4.05 (m, 3H), 3.82 (s, 3H), 3.74-3.72 (m, 2H), 3.64 (s, 3H), 3.03 (s, 3H), 3.02-2.68 (m, 4H ), 2.40-2.31 (m, 3H), 1.76-1.60 (m, 4H), 1.36 (d, 3H) Example 55
「5-Γ2-「「1-ί2-氟 -2-甲基 -丙基 4-哌啶基 1-甲基 -氨基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并 "5-Γ2-""1-ί2-Fluoro-2-methyl-propyl 4-piperidinyl 1-methyl-amino l-4-"(3 -3-methylmorpholin-4-yl 1 Pyridine
「2,3-dl嘧啶 -7-基 1-2-甲氧基 -苯基 1甲醇 "2,3-dl pyrimidine-7-yl1-2-methoxy-phenyl 1 methanol
Figure imgf000074_0001
Figure imgf000074_0001
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (100 mg， 0.25 mmol), 1 -(2-氟 -2-甲基-丙基) -N-甲基 -哌啶 基 -4-胺 (300 mg， 1.60 mmol), N，N-二异丙基乙胺 (370 mg， 2.88 mmol)禾卩 3 mL Ν,Ν- 二甲基乙酰胺， 110°C下反应 12小时， 加入 10 mL乙酸乙酯和 6 mL水， 分层， 有 机相用饱和氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 [5-[2-[[1-(2-氟 -2-甲 基-丙基) -4-哌啶基] -甲基 -氨基 ]-4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2- 甲氧基-苯基]甲醇 55 (35 mg， 黄色固体)， 产率： 7.2%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (100 mg, 0.25 mmol), 1-(2-fluoro-2-methyl-propyl)-N-methyl-piperidinyl-4-amine (300 mg, 1.60 mmol ), N,N-diisopropylethylamine (370 mg, 2.88 mmol) and 3 mL hydrazine, hydrazine-dimethylacetamide, reacted at 110 ° C for 12 hours, added 10 mL of ethyl acetate and 6 mL The organic layer was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Product [5-[2-[[1-(2-Fluoro-2-methyl-propyl)-4-piperidinyl]-methyl-amino]-4-[(3-3-methylmorpholine) 4-yl]B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 55 (35 mg, yellow solid), yield: 7.2%.
MS m/z (ESI): 551.3 [M+l] MS m/z (ESI): 551.3 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.23 (s, 1H), 8.15 (d, 1H), 8.02 (d, 1H), 7.46 (d， 1H)， 7.03 (d, 1H)， 4.82 (s, 2H), 4.10-3.71 (m， 6H)， 3.21 (s, 3H), 2.51-1.55 (m， 12H), 1.53-1.37 (m, 4H)， 1.29 (s， 9H) 实施例 56 iHNMR (400 MHz, DMSO-J 6 ): δ 8.23 (s, 1H), 8.15 (d, 1H), 8.02 (d, 1H), 7.46 (d, 1H), 7.03 (d, 1H), 4.82 (s , 2H), 4.10-3.71 (m, 6H), 3.21 (s, 3H), 2.51-1.55 (m, 12H), 1.53-1.37 (m, 4H), 1.29 (s, 9H) Example 56
醇  Alcohol
Figure imgf000074_0002
Figure imgf000074_0002
第一步  First step
2-[7-[3-(2，2-二甲基丙酰氧基甲基 )-4-甲氧基 -苯基 ]-4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -2-基]丙二酸二乙酯 2-[7-[3-(2,2-Dimethylpropanoyloxymethyl)-4-methoxy-phenyl]-4-[(3 -3-methylmorpholin-4-yl) Pyridine [2,3-d]pyrimidin-2-yl]malonate diethyl ester
将氢化钠 (133 mg， 3.27 mmol)溶解于 35 mL四氢呋喃中， 滴加丙二酸二乙酯 (525 mg， 3.27 mmol), 搅拌 30分钟， 滴加 20 mL [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] 吡啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基] -甲基 -2,2-二甲基丙酸酯 56a (700 mg， 1.49 mmol, 采用公知的方法"专利 US20090318434A1 "制备而得)的四氢呋喃溶液， 回 流 12小时， 减压浓縮， 加入 50 mL乙酸乙酯和 50 mL水， 分层， 有机相用饱和氯 化钠溶液洗涤 (50 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以 展开剂体系 C纯化所得残余物，得到标题产物 2-[7-[3-(2，2-二甲基丙酰氧基甲基 )-4- 甲氧基 -苯基 ]-4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2-基]丙二酸二乙酯 56b (860 mg, 黄色固体)， 产率： 97.8%。  Dissolve sodium hydride (133 mg, 3.27 mmol) in 35 mL of tetrahydrofuran, add diethyl malonate (525 mg, 3.27 mmol), stir for 30 minutes, add 20 mL [5-[2-chloro-4] -[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]-methyl-2,2-di Methyl propionate 56a (700 mg, 1.49 mmol, prepared by a known method), US Pat. No. 2,090,318, 434 A1, prepared in tetrahydrofuran, refluxed for 12 hours, concentrated under reduced pressure, 50 mL of ethyl acetate and 50 mL of water. The organic phase was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated. [7-[3-(2,2-Dimethylpropionyloxymethyl)-4-methoxy-phenyl]-4-[(3 -3-methylmorpholin-4-yl] B Bisuccinyl [2,3-d]pyrimidin-2-yl]malonate 56b (860 mg, yellow solid), Yield: 97.8%.
MS m/z (ESI): 609.2 [M+l] MS m/z (ESI): 609.2 [M+l]
第二步  Second step
[2-甲氧基 -5-[2-甲基 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基]苯基]甲基  [2-Methoxy-5-[2-methyl-4-[(3 -3-methylmorpholin-4-yl] B-pyrido[2,3-d]pyrimidin-7-yl]benzene Methyl
-2,2-二甲基丙酸酯  -2,2-dimethylpropionate
将 2-[7-[3-(2，2-二甲基丙酰氧基甲基 )-4-甲氧基 -苯基 ]-4-[(3 -3-甲基吗啉 -4-基] 吡啶并 [2，3-d]嘧啶 -2-基]丙二酸二乙酯 56b (860 mg, 1.41 mmol)溶解于 15 mL二甲 基亚砜中， 加入氯化锂 (60 mg， 1.41 mmol), 150°C下反应 2小时， 加入 30 mL乙酸 乙酯和 30 mL水， 分层， 水相用乙酸乙酯萃取 (30 mLx2)， 合并有机相， 无水硫酸 钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 C纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[2-甲基 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基: 苯基]甲基 -2,2-二甲基丙酸酯 56c (430 mg， 淡黄色油状物)， 产率： 65.5%。 2 - [7 - [3 - (2, 2-dimethyl-propionyloxy methyl) -4-methoxy - phenyl] -4 - [(3-methyl-morpholin-4 Diethyl pyrido[2,3-d]pyrimidin-2-yl]malonate 56b (860 mg, 1.41 mmol) was dissolved in 15 mL of dimethyl sulfoxide and lithium chloride (60 mg, After the reaction was carried out at 150 ° C for 2 hours, 30 mL of ethyl acetate and 30 mL of water were added, and the mixture was evaporated. The filtrate was concentrated under reduced pressure, and the obtained residue was purified to purified crystals to afford the title product [2-methoxy-5-[2-methyl-4-[(3-3-methyl) Benzyl-4-yl] B-pyrido[2,3-d]pyrimidin-7-yl: phenyl]methyl-2,2-dimethylpropanoate 56c (430 mg, pale yellow oil) Yield: 65.5%.
MS m/z (ESI): 465.2 [M+l] MS m/z (ESI): 465.2 [M+l]
第三步  third step
[2-甲氧基 -5-[2-甲基 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 将 [2-甲氧基 -5-[2-甲基 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基]苯基] 甲基 -2,2-二甲基丙酸酯 56c (30 mg, 0.06 mmol)溶解于 6 mL四氢呋喃和水 (V/V = 5:1)混合溶剂中， 加入氢氧化锂 (28 mg， 0.65 mmol), 反应 4小时， 减压浓縮， 用薄 层色谱法以展开剂体系 A 纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[2-甲基 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 56 (19 mg, 淡黄色固 体)， 产率： 76.9%。  [2-Methoxy-5-[2-methyl-4-[(3 -3-methylmorpholin-4-yl] B-pyrido[2,3-d]pyrimidin-7-yl]benzene [2-methoxy-5-[2-methyl-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidine-7 -yl]phenyl]methyl-2,2-dimethylpropionate 56c (30 mg, 0.06 mmol) was dissolved in 6 mL of tetrahydrofuran and water (V/V = 5:1) in a mixed solvent. Lithium (28 mg, 0.65 mmol), mp EtOAc (EtOAc) -4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 56 (19 mg, pale yellow solid) Rate: 76.9%.
MS m/z (ESI): 381.2 [M+l] MS m/z (ESI): 381.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.29 (d， 1H), 8.26 (s， 1H), 8.17 (d， 1H), 7.77 (d， 1H)， 7.03 (d， 1H), 4.79 (s， 2H), 4.56-4.55 (m， 1H), 4.09-4.06 (m， 1H), 4.01-3.99 (m， 1H)， 3.96 (s, 3H), 3.86-3.83 (m， 1H)， 3.76-3.73 (m， 3H), 2.71 (s, 3H), 1.52 (d, 3H) 实施例 57 iHNMR (400 MHz, DMSO-J 6 ): δ 8.29 (d, 1H), 8.26 (s, 1H), 8.17 (d, 1H), 7.77 (d, 1H), 7.03 (d, 1H), 4.79 (s , 2H), 4.56-4.55 (m, 1H), 4.09-4.06 (m, 1H), 4.01-3.99 (m, 1H), 3.96 (s, 3H), 3.86-3.83 (m, 1H), 3.76-3.73 (m, 3H), 2.71 (s, 3H), 1.52 (d, 3H) Example 57
「2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 1-2-「甲基 -「 2,2,2-三氟乙基) -4-哌啶基 1氨
Figure imgf000076_0001
"2-Methoxy-5-"4-"(3 -3-methylmorpholin-4-yl1-2-"methyl-"2,2,2-trifluoroethyl)-4-piperider Acridine 1 ammonia
Figure imgf000076_0001
将 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲 醇 3a (150 mg， 0.37 mmol)，N-甲基 -1-(2，2，2-三氟乙基)哌啶 -4-胺 (110 mg， 0.56 mmol) 和 N，N-二异丙基乙胺 (0.2 mL, 1.12 mmol)溶解于 5 mL N，N-二甲基乙酰胺中， 90°C 下反应 12小时， 反应液减压浓縮， 用 HPLC制备色谱法以展开剂体系 A纯化所得 残余物，得到标题产物 [2-甲氧基 -5-[4-[C3 -3-甲基吗啉 -4-基] -2- [甲基 -[1-(2，2，2-三氟 乙基) -4-哌啶基]氨基] B比啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 57 (15 mg， 黄色固体)， 产 率： 7.2%。  [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 mmol), N-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-amine (110 mg, 0.56 mmol) and N,N- Diisopropylethylamine (0.2 mL, 1.12 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 and purified by HPLC. The residue obtained was purified to give the title product [2-methoxy-5-[4-[C3-3-methylmorpholin-4-yl]-2-[methyl-[1-(2, 2,2-Trifluoroethyl)-4-piperidinyl]amino] B-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 57 (15 mg, yellow solid), yield : 7.2%.
MS m/z (ESI): 561.6 [M+l]  MS m/z (ESI): 561.6 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.30 (s， 1H), 8.15 (d， 1H), 8.07 (d， 1H), 7.57 (d， 1H)， 7.10 (d, 1H), 5.23-5.20 (m， 1H), 4.59-4.57 (m， 2H), 3.90-3.89 (m， 2H), 3.87 (s, 3H), 3.75-3.59 (m， 4H)， 3.30-3.28 (m， 4H)， 3.27-2.21 (m， 2H), 3.07 (s, 3H), 3.06-3.03 (m， 2H), 1.85-1.82 (m， 2H), 1.63-1.61 (m， 2H), 1.58-1.37 (m， 3H) 实施例 58 iHNMR (400 MHz, DMSO-J 6 ): δ 8.30 (s, 1H), 8.15 (d, 1H), 8.07 (d, 1H), 7.57 (d, 1H), 7.10 (d, 1H), 5.23-5.20 (m, 1H), 4.59-4.57 (m, 2H), 3.90-3.89 (m, 2H), 3.87 (s, 3H), 3.75-3.59 (m, 4H), 3.30-3.28 (m, 4H), 3.27 -2.21 (m, 2H), 3.07 (s, 3H), 3.06-3.03 (m, 2H), 1.85-1.82 (m, 2H), 1.63-1.61 (m, 2H), 1.58-1.37 (m, 3H) Example 58
Γ2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 1-2-「甲基 -il-四氢吡喃 -4-基 -4-哌啶基)氨基  Γ2-methoxy-5-"4-"(3 -3-methylmorpholin-4-yl1-2-"methyl-il-tetrahydropyran-4-yl-4-piperidinyl) Amino
Figure imgf000076_0002
将 N-甲基 -1-四氢吡喃 -4-基 -哌啶 -4-胺 (60 mg， 0.30 mmol), [5-[2-it-4-[(35)-3- 甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲醇 3a (100 mg， 0.25 mmol) 和 N，N-二异丙基乙胺 (78 mg， 0.60 mmol)溶解于 5 mL N，N-二甲基乙酰胺中， 90°C下 反应 12小时， 反应液减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2- [甲基 -(1-四氢吡喃 -4-基 -4- 哌啶基)氨基]吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 58 (15 mg，黄色固体)，产率： 10.7%。 MS m/z (ESI): 563.2 [M+l]
Figure imgf000076_0002
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) and 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. The residue obtained is purified to give the title product [2-methoxy-5-[4-[(3-3-methylmorpholin-4-yl)-2-[methyl-(1-tetrahydropyran) 4--4--4-piperidinyl)amino]pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 58 (15 mg, yellow solid), yield: 10.7%. z (ESI): 563.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.30 (d， 1H)， 8.15 (d， 1H)， 8.05 (d， 1H)， 7.58 (d， 1H)， 7.09 (d, 1H), 4.58 (d, 1H), 4.48-4.45 (m， 2H), 3.95-3.89 (m， 4H)， 3.87-3.81 (m， 3H), 3.82-3.74 (m， 1H), 3.72-3.54 (m， 4H)， 3.31-3.27 (m， 2H), 3.17 (d, 1H), 3.07 (s， 3H), 2.54-2.52 (m， 4H)， 1.96-1.56 (m， 6H)， 1.38 (d, 3H), 1.30-1.27 (m， 1H) 实施例 59 iHNMR (400 MHz, DMSO-J 6 ): δ 8.30 (d, 1H), 8.15 (d, 1H), 8.05 (d, 1H), 7.58 (d, 1H), 7.09 (d, 1H), 4.58 (d , 1H), 4.48-4.45 (m, 2H), 3.95-3.89 (m, 4H), 3.87-3.81 (m, 3H), 3.82-3.74 (m, 1H), 3.72-3.54 (m, 4H), 3.31 -3.27 (m, 2H), 3.17 (d, 1H), 3.07 (s, 3H), 2.54-2.52 (m, 4H), 1.96-1.56 (m, 6H), 1.38 (d, 3H), 1.30-1.27 (m, 1H) Example 59
Γ2-甲氧基 -5-「2- (甲基 (四氢吡喃 -4-基)氨基) -4-(8-氧杂 -3-氮杂二环「3.2.1谇垸 -3- -dl嘧啶 -7-基 1苯基 1甲醇  Γ2-methoxy-5-"2-(methyl(tetrahydropyran-4-yl)amino)-4-(8-oxa-3-azabicyclo"3.2.1谇垸-3- -dl pyrimidine-7-yl 1 phenyl 1 methanol
Figure imgf000077_0001
Figure imgf000077_0001
第一步  First step
3-(2，7-二氯吡啶并 [2，3-d]嘧啶 -4-基) -8-氧杂 -3-氮杂二环 [3.2.1]辛烷 将 2，4，7-三氯吡啶并 [2，3-d]嘧啶 lc (235 mg, 1 mmol), 8-氧杂 -3-氮杂二环 [3.2.1] 辛烷 (150 mg, 1 mmol)和 N，N-二异丙基乙胺 (258 mg, 2 mmol)溶解于 10 mL四氢呋 喃中， 反应 12小时， 减压浓縮， 加入 25 mL水和 25 mL乙酸乙酯， 分层， 水相用 乙酸乙酯萃取 (30 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (50 mL)， 无水硫酸 钠干燥， 过滤， 滤液减压浓縮， 得到标题产物粗品 3-(2，7-二氯吡啶并 [2，3-d]嘧啶 -4- 基) -8-氧杂 -3-氮杂二环 [3.2.1]辛烷 59a (320 mg, 浅黄色固体)， 产物不经纯化直接 用于下步反应。  3-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane will be 2,4,7- Trichloropyrido[2,3-d]pyrimidine lc (235 mg, 1 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (150 mg, 1 mmol) and N,N -Diisopropylethylamine (258 mg, 2 mmol) was dissolved in 10 mL of THF. The mixture was evaporated, evaporated, evaporated, evaporated. The mixture was extracted (30 mL×2), EtOAcjjjjjjjjjj And [2,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane 59a (320 mg, pale yellow solid). The next step is the reaction.
MS m/z (ESI): 312.1 [M+l] MS m/z (ESI): 312.1 [M+l]
第二步  Second step
[5-[2-氯 -4-(8-氧杂 -3-氮杂二环 [3.2.1]辛烷 -3-基)吡啶并 [2，3-d]嘧啶 -7-基] -2-甲氧 基苯基]甲醇 [5-[2-Chloro-4-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrido[2,3-d]pyrimidin-7-yl]- 2-methoxy Phenyl]methanol
将粗品 3-(2，7-二氯吡啶并[2，3-(1]嘧啶-4-基)-8-氧杂-3-氮杂二环[3.2.1]辛烷 59a (311 mg， 1 mmol), [2-甲氧基 -5-(4，4，5，5-四甲基 -1，3，2-二氧杂戊硼烷 -2-基)苯基]甲醇 le (396 mg， 1.50 mmol),双 (三苯基膦)合二氯化钯 (115 mg， 0.10 mmol)和碳酸钠 (212 mg， 2 mmol)溶解于 10 mL 1,4-二氧六环和水 (V/V = 2:1)混合溶剂中， 90°C下反应 4 小时， 减压浓縮， 加入 20 mL水， 用二氯甲烷萃取 (30 mLx2)， 合并有机相， 用饱 和氯化钠溶液洗涤 (50 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用 HPLC制 备色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 [5-[2-氯 -4-(8-氧杂 -3-氮 杂二环 [3.2.1]辛烷 -3-基)吡啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基苯基]甲醇 59b (300 mg， 黄色固体)， 产率： 72.7%。  The crude 3-(2,7-dichloropyrido[2,3-(1]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane 59a (311 mg , 1 mmol), [2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol le ( 396 mg, 1.50 mmol), bis(triphenylphosphine)palladium dichloride (115 mg, 0.10 mmol) and sodium carbonate (212 mg, 2 mmol) dissolved in 10 mL of 1,4-dioxane and water (V/V = 2:1) in a mixed solvent, react at 90 ° C for 4 hours, concentrate under reduced pressure, add 20 mL of water, extract with dichloromethane (30 mL×2), combine the organic phase with saturated sodium chloride The solution was washed (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated. 8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrido[2,3-d]pyrimidin-7-yl]-2-methoxyphenyl]methanol 59b ( 300 mg, yellow solid), Yield: 72.7%.
MS m/z (ESI): 413.4 [M+l] MS m/z (ESI): 413.4 [M+l]
第三步  third step
[2-甲氧基 -5-[2- (甲基 (四氢吡喃 -4-基)氨基) -4-(8-氧杂 -3-氮杂二环 [3.2.1]辛烷 -3- 基)吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇  [2-Methoxy-5-[2-(methyl(tetrahydropyran-4-yl)amino)-4-(8-oxa-3-azabicyclo[3.2.1]octane- 3-yl)pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol
将 [5-[2-氯 -4-(8-氧杂 -3-氮杂二环 [3.2.1]辛烷-3-基)吡啶并[2，3-(1]嘧啶-7-基]-2-甲 氧基苯基]甲醇 59b (300 mg， 0.73 mmol), N-甲基四氢吡喃 -4-胺 (167 mg， 1.45 mmol) 和 N，N-二异丙基乙胺 (0.4 mL, 2.20 mmol)溶解于 5 mL N，N-二甲基乙酰胺中， 90 °C 下反应 12小时， 反应液减压浓縮， 用 HPLC制备色谱法以展开剂体系 A纯化所得 残余物， 得到标题产物 [2-甲氧基 -5-[2- (甲基 (四氢吡喃 -4-基)氨基 4-(8-氧杂 -3-氮杂 二环 [3.2.1]辛烷 -3-基)吡啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 59 (10 mg， 黄色固体 产 率： 5.5%。  [5-[2-Chloro-4-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrido[2,3-(1]pyrimidin-7-yl ]-2-methoxyphenyl]methanol 59b (300 mg, 0.73 mmol), N-methyltetrahydropyran-4-amine (167 mg, 1.45 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.20 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 and purified by HPLC. To give the title product [2-methoxy-5-[2-(methyl(tetrahydropyran-4-yl)amino 4-(8-oxa-3-azabicyclo[3.2.1] Octane-3-yl)pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 59 (10 mg, yellow solid yield: 5.5%.
MS m/z (ESI): 492.6 [M+l]  MS m/z (ESI): 492.6 [M+l]
iHNMR (400 MHz, CDC13): δ 8.29 (s, 1H)， 8.18 (d, 1H)， 8.07 (d, 1H)， 7.57 (d, 1H)， 7.11 (d, 1H)， 5.22-5.19 (m， 1H)， 4.59-4.57 (m， 2H), 4.42 (s， 2H), 4.13-4.10 (m， 2H), 3.99-3.98 (m， 2H), 3.93 (s, 1H), 3.87 (s, 3H), 3.53-3.46 (m， 4H)， 3.07 (s, 3H), 1.89-1.75 (m， 6H)， 1.61-1.59 (m, 2H) 实施例 60 iHNMR (400 MHz, CDC1 3 ): δ 8.29 (s, 1H), 8.18 (d, 1H), 8.07 (d, 1H), 7.57 (d, 1H), 7.11 (d, 1H), 5.22-5.19 (m , 1H), 4.59-4.57 (m, 2H), 4.42 (s, 2H), 4.13-4.10 (m, 2H), 3.99-3.98 (m, 2H), 3.93 (s, 1H), 3.87 (s, 3H ), 3.53-3.46 (m, 4H), 3.07 (s, 3H), 1.89-1.75 (m, 6H), 1.61-1.59 (m, 2H) Example 60
6-「4-「(3 -3-甲基吗啉 -4-基) -2- (甲基 (四氢吡喃 -4-基)氨基)吡啶并「2,3-dl嘧啶 -7- 基 lchroman-4-醇  6-"4-"(3 -3-Methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl)amino)pyridine and "2,3-dl pyrimidine-7- Lchroman-4-ol
Figure imgf000078_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000079_0001
第一步  First step
(3 -4-(2，7-二氯吡啶并 [2，3-d]嘧啶 -4-基) -3-甲基 -吗啉 将 2，4，7-三氯吡啶并 [2，3-d]嘧啶 lc (1.50 g， 6.41 mmol)溶解于 10 mL二氯甲烷 中， 0°C下加入 N，N-二异丙基乙胺 (827 mg， 6.41 mmol)和 (3 -3-甲基吗啉 (647 mg， 6.41 mmol), 室温反应 1小时， 加入 20 mL水和 40 mL乙酸乙酯， 分层， 有机相 用饱和氯化钠溶液洗涤 (50 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用硅胶 柱色谱法以展开剂体系 B 纯化所得残余物， 得到标题产物 (3 -4-(2，7-二氯吡啶并 [2，3-d]嘧啶 -4-基) -3-甲基 -吗啉 60a (1.80 g， 黄色固体)， 产率： 94.2%。  (3 -4-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-3-methyl-morpholine 2,4,7-trichloropyridin[2,3 -d]pyrimidine lc (1.50 g, 6.41 mmol) was dissolved in 10 mL of dichloromethane, and N,N-diisopropylethylamine (827 mg, 6.41 mmol) and (3 -3- The morpholine (647 mg, 6.41 mmol) was reacted at room temperature for 1 hour, 20 mL of water and 40 mL of ethyl acetate were added, and the organic layer was washed with saturated sodium chloride (50 mL) and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified to silica gel column chromatography to afford to afford the title product (3 -4-(2,7-dichloropyrido[2,3-d]pyrimidine-4 -yl)-3-methyl-morpholine 60a (1.80 g, yellow solid), Yield: 94.2%.
MS m/z (ESI): 299.0 [M+l] MS m/z (ESI): 299.0 [M+l]
第二步  Second step
7-氯 -N-甲基 -4-[(3 -3-甲基吗啉 -4-基] -N-四氢吡喃 -4-基 -B比啶并 [2，3-d]嘧啶 -2胺 将 (3 —4-(2，7-二氯吡啶并 [2，3-d]嘧啶 -4-基) -3-甲基 -吗啉 60a (329 mg， 1.10 mmol)溶解于 2 mL N，N-二甲基乙酰胺中， 加入 N，N-二异丙基乙胺 (142 mg， 1.10 mmol)和 N-甲基四氢吡喃 -4-胺 (126 mg， 1.10 mmol), 90 °C下反应 12小时，加入 5 mL 水和 20 mL乙酸乙酯， 分层， 有机相用饱和氯化钠溶液洗涤 (20 mL)， 无水硫酸钠 干燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱法以展开剂体系 B纯化所得残余物， 得到标题产物 7-氯 -N-甲基 -4-[(3 -3-甲基吗啉 -4-基] -N-四氢吡喃 -4-基 -吡啶并 [2，3-d]嘧啶 -2-胺 60b (70 mg， 黄色固体)， 产率： 16.8%。  7-Chloro-N-methyl-4-[(3 -3-methylmorpholin-4-yl]-N-tetrahydropyran-4-yl-B-pyrido[2,3-d]pyrimidine -2 amine dissolved (3 - 4-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-3-methyl-morpholine 60a (329 mg, 1.10 mmol) in 2 Add N,N-diisopropylethylamine (142 mg, 1.10 mmol) and N-methyltetrahydropyran-4-amine (126 mg, 1.10 mmol) to mL N,N-dimethylacetamide The reaction was carried out at 90 °C for 12 hours, 5 mL of water and 20 mL of ethyl acetate were added, and the mixture was separated. The organic phase was washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate The residue obtained was purified by silica gel column chromatography eluting to afford to afford the title product 7-chloro-N-methyl-4-[(3-3-methylmorpholin-4-yl)-N-tetrahydro Pyran-4-yl-pyrido[2,3-d]pyrimidin-2-amine 60b (70 mg, yellow solid), yield: 16.8%.
MS m/z (ESI): 378.1 [M+l] MS m/z (ESI): 378.1 [M+l]
第三步  third step
6-[4-[(3^3-甲基吗啉 -4-基) -2- (甲基 (四氢吡喃 -4-基)氨基) B比啶并 [2，3-d]嘧啶 -7- 基] chroman-4-酮  6-[4-[(3^3-methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl)amino)B-pyrido[2,3-d]pyrimidine -7-yl]chromn-4-ketone
将 6-(4，4，5，5-四甲基 -1，3，2-二氧杂戊硼烷 -2-基) chroman-4-酮 60c (101 mg， 0.37 mmol, 采用公知的方法 "专利 WO2007084786"制备而得)和 7-氯 -N-甲基 -4-[(3 -3- 甲基吗啉 -4-基] -N-四氢吡喃 -4-基 -B比啶并 [2，3-d]嘧啶 -2-胺 60b (70 mg， 0.18 mmol)溶 解于 2 mL 1，4-二氧六环和水 (V/V = 4:1)混合溶剂中，加入四 (三苯基膦)钯 (20.70 mg， 0.018 mmol)和碳酸钾 (46 mg， 0.32 mmol), 搅拌 10分钟， 100°C下微波反应 20分 钟， 过滤， 滤液中加入 2 mL水和 10 mL乙酸乙酯， 分层， 有机相用饱和氯化钠溶 液洗涤 (20 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱法以展开 剂体系 B纯化所得残余物， 得到标题产物 6-[4-[(3 3-甲基吗啉 -4-基) -2- (甲基 (四氢 吡喃 -4-基)氨基) B比啶并 [2，3-d]嘧啶 -7-基] chroman-4-酮 60d (80 mg， 黄色固体 产 率： 88.5%。 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-one 60c (101 mg, 0.37 mmol, using a known method "Prepared by WO2007084786" and 7-chloro-N-methyl-4-[(3 -3-methylmorpholin-4-yl]-N-tetrahydropyran-4-yl-B-pyridinium And [2,3-d]pyrimidin-2-amine 60b (70 mg, 0.18 mmol) was dissolved in 2 mL of 1,4-dioxane and water (V/V = 4:1) mixed solvent, and added to (triphenylphosphine)palladium (20.70 mg, 0.018 mmol) and potassium carbonate (46 mg, 0.32 mmol), stirred for 10 minutes, microwave reaction at 100 ° C for 20 minutes The mixture was filtered, and the filtrate was combined with 2 mL of water and 10 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate Column chromatography was carried out to purify the obtained residue to give the title product 6-[4-[(3 3-methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl) Amino) B-pyrido[2,3-d]pyrimidin-7-yl]chroman-4-one 60d (80 mg, yellow solid yield: 88.5%.
MS m/z (ESI): 490.2[M+1]  MS m/z (ESI): 490.2 [M+1]
第四步  the fourth step
6-[4-[(3^3-甲基吗啉 -4-基) -2- (甲基 (四氢吡喃 -4-基)氨基) B比啶并 [2，3-d]嘧啶 -7- 基] chroman-4-醇  6-[4-[(3^3-methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl)amino)B-pyrido[2,3-d]pyrimidine -7-yl]chromn-4-ol
将 6-[4-[(3 3-甲基吗啉 -4-基) -2- (甲基 (四氢吡喃 -4-基)氨基) B比啶并 [2，3-d]嘧啶 -7-基] chroman-4-酮 60d (75 mg， 0.19 mmol)溶解于 2 mL甲醇中， 加入硼氢化钠 (21.30 mg, 0.56 mmol), 反应 2小时， 加入 2 mL水和 5 mL乙酸乙酯， 分层， 有机 相用饱和氯化钠溶液洗涤 (20 mL),无水硫酸钠干燥，过滤，滤液减压浓縮，用 HPLC 制备色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 6-[4-[(3 3-甲基吗啉 -4-基) -2-(甲基（四氢吡喃 -4-基)氨基)吡啶并 [2，3-d]嘧啶 -7-基] chroman-4-醇 60 (36 mg, 浅黄色固体)， 产率： 39.0%。  6-[4-[(3 3-Methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl)amino)B-pyrido[2,3-d]pyrimidine -7-yl]chromn-4-one 60d (75 mg, 0.19 mmol) was dissolved in 2 mL of methanol, sodium borohydride (21.30 mg, 0.56 mmol) was added, and reacted for 2 hours, 2 mL of water and 5 mL of acetic acid B were added. The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Product 6-[4-[(3 3-Methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl)amino)pyrido[2,3-d]pyrimidine-7 -yl]chromn-4-ol 60 (36 mg, pale yellow solid), Yield: 39.0%.
MS m/z (ESI): 492.2 [M+l] MS m/z (ESI): 492.2 [M+l]
iHNMR (400 MHz, CDC13): δ 8.31 (s, 1H), 7.95 (d, 2H), 7.36 (d, 1H), 6.92 (d, 1H)， 4.91 (s, 1H)， 4.36-4.31 (m， 4H)， 4.08-3.67 (m， 11H), 3.15 (s, 2H), 2.11 (m， 2H), 1.94-1.90 (m， 2H), 1.69 (m， 2H), 1.46 (d， 3H) 实施例 61 iHNMR (400 MHz, CDC1 3 ): δ 8.31 (s, 1H), 7.95 (d, 2H), 7.36 (d, 1H), 6.92 (d, 1H), 4.91 (s, 1H), 4.36-4.31 (m , 4H), 4.08-3.67 (m, 11H), 3.15 (s, 2H), 2.11 (m, 2H), 1.94-1.90 (m, 2H), 1.69 (m, 2H), 1.46 (d, 3H) Example 61
(2-甲氧基 -5-(2- (甲基 嘧啶 -2-基)哌啶 -4-基)氨基) -4-((3 -3-甲基吗啉)吡啶并  (2-methoxy-5-(2-(methylpyrimidin-2-yl)piperidin-4-yl)amino)-4-((3-3-methylmorpholine)pyridine
Figure imgf000080_0001
Figure imgf000080_0001
第一步  First step
1- (嘧啶 -2-基)哌啶 -4-酮  1-(pyrimidin-2-yl)piperidin-4-one
于封管中依次加入 2-氯嘧啶 61a (100 mg, 0.87 mmol), 哌啶 -4-酮 61b (140 mg: 1.05 mmol), 三乙胺 (435 mg, 4.35 mmol)和 5 mL 1,4-二氧六环， 90°C反应 12小时， 反应液过滤， 滤液减压浓縮， 得到标题产物粗品 1- (嘧啶 -2-基)哌啶 -4-酮 61c (160 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。 2-Chloropyrimidine 61a (100 mg, 0.87 mmol), piperidin-4-one 61b (140 mg : 1.05 mmol), triethylamine (435 mg, 4.35 mmol) and 5 mL 1,4 were added to the sealed tube. - dioxane, reacted at 90 ° C for 12 hours, The reaction mixture was filtered, and then evaporated tolulululululululululululululululu
MS m/z (ESI): 178.2 [M+l] MS m/z (ESI): 178.2 [M+l]
第二步  Second step
甲基 - 1 - (嘧啶 -2-基)哌啶 -4-胺  Methyl-1 - (pyrimidin-2-yl)piperidin-4-amine
将粗品 1- (嘧啶 -2-基)哌啶 -4-酮 61c (400 mg， 2.26 mmol)和甲胺盐酸盐 (305 mg， 4.52 mmol)溶解于 20 mL 1，2-二氯乙烷中， 搅拌反应 1小时， 加入三醋酸硼氢化钠 (1.40 g, 6.78 mmol), 反应 12小时， 加入 30 mL二氯甲烷， 分液， 有机相依次用饱 和碳酸氢钠溶液 (30 mLx3)和饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过 滤，滤液减压浓縮，得到标题产物粗品 N-甲基 -1- (嘧啶 -2-基)哌啶 -4-胺 61d (210 mg， 白色油状物)， 产物不经纯化直接用于下步反应。  The crude 1-(pyrimidin-2-yl)piperidin-4-one 61c (400 mg, 2.26 mmol) and methylamine hydrochloride (305 mg, 4.52 mmol) were dissolved in 20 mL of 1,2-dichloroethane The reaction was stirred for 1 hour, sodium borohydride triacetate (1.40 g, 6.78 mmol) was added, and the reaction was carried out for 12 hours, 30 mL of dichloromethane was added, and the organic phase was successively saturated with sodium hydrogen carbonate (30 mL×3) and saturated. The sodium chloride solution was washed (20 mL×2), dried over anhydrous sodium sulfate. 210 mg, white oil), product was used in the next step without purification.
MS m/z (ESI): 193.2 [M+l] MS m/z (ESI): 193.2 [M+l]
第三步  third step
(2-甲氧基 -5-(2- (甲基 (1- (嘧啶 -2-基)哌啶 -4-基)氨基) -4-((3 -3-甲基吗啉)吡啶并  (2-methoxy-5-(2-(methyl(1-(pyrimidin-2-yl)piperidin-4-yl)amino)-4-((3-3-methylmorpholine)pyridine)
[2，3-d]嘧啶 -7-基]苯基]甲醇 [ 2 ,3-d]pyrimidin- 7 -yl]phenyl]methanol
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2-甲氧基-苯基]甲醇 3a (100 mg， 0.25 mmol), 粗品 N-甲基 -1- (嘧啶 -2-基)哌啶 -4- 胺 61d (87 mg， 0.30 mmol), N，N-二异丙基乙胺 (0.3 mL, 0.75 mmol)和 4 mL N，N-二 甲基乙酰胺， 90°C反应 12小时， 加入 15 mL水， 用乙酸乙酯萃取 (15 mLx2), 合 并有机相， 用饱和氯化钠溶液洗涤 (10 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压 浓縮， 用硅胶柱色谱法以展开剂体系 A纯化所得残余物， 得到标题产物 (2-甲氧基 -5-(2-(甲基 0(嘧啶 -2-基)哌啶 -4-基)氨基 )-4-((3^-3-甲基吗啉)吡啶并 [2，3-d]嘧啶 -7- 基]苯基]甲醇 61 (21 mg， 黄色固体)， 产率： 19.1%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-yl-yl]-2-A was sequentially added to the sealed tube. Oxy-phenyl]methanol 3a (100 mg, 0.25 mmol), crude N-methyl-1-(pyrimidin-2-yl)piperidin-4-amine 61d (87 mg, 0.30 mmol), N,N- Diisopropylethylamine (0.3 mL, 0.75 mmol) and 4 mL of N,N-dimethylacetamide, reacted at 90 ° C for 12 hours, added 15 mL of water, extracted with ethyl acetate (15 mL×2), combined organic The mixture was washed with a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated. Oxy-5-(2-(methyl 0(pyrimidin-2-yl)piperidin-4-yl)amino)-4-((3^-3-methylmorpholine)pyrido[2,3- d]pyrimidin-7-yl]phenyl]methanol 61 (21 mg, yellow solid), yield: 19.1%.
MS m/z (ESI): 557.5 [M+l] MS m/z (ESI): 557.5 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.37 (d, 2H), 8.36 (s， 1H), 8.24 (s， 1H), 8.08 (d, 1H)， 7.71 (s, 1H), 7.12 (d， 1H), 6.62 (t， 1H), 5.31 (s, 1H), 4.84 (d， 2H), 4.56 (s, 2H), 3.90 (d， 1H), 3.86 (s， 3H), 3.58-3.75 (m， 4H)， 3.06 (s， 4H)， 1.92-2.08 (m， 2H), 1.75 (s， 3H), 1.41 (d， 3H), 0.84 (t， 2H) 实施例 62 iHNMR (400 MHz, DMSO-J 6 ): δ 8.37 (d, 2H), 8.36 (s, 1H), 8.24 (s, 1H), 8.08 (d, 1H), 7.71 (s, 1H), 7.12 (d , 1H), 6.62 (t, 1H), 5.31 (s, 1H), 4.84 (d, 2H), 4.56 (s, 2H), 3.90 (d, 1H), 3.86 (s, 3H), 3.58-3.75 ( m, 4H), 3.06 (s, 4H), 1.92-2.08 (m, 2H), 1.75 (s, 3H), 1.41 (d, 3H), 0.84 (t, 2H) Example 62
Γ2-甲氧基 -5-「4-「(3 -3-甲基吗啉 -4-基 1-2-「甲基 (四氢吡喃 -4-基)氨基 1吡啶并 2-methoxy-5-"4-"(3 -3-methylmorpholin-4-yl 1-2-"methyl(tetrahydropyran-4-yl)amino 1pyridine
「2 醇 "2 alcohol
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000081_0001
Figure imgf000082_0001
将 [5-0氯 -4-吗啉 -B比啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基]甲醇 If (100 mg， 0.26 mmol), N-甲基四氢吡喃 -4-胺 (29 mg， 0.26 mmol)和 N，N-二异丙基乙胺 (66 mg， 0.51 mmol)溶解于 5 mL N，N-二甲基乙酰胺中， 90°C下反应 12小时， 反应液减压浓縮， 用薄层色谱法以展开剂体系 A 纯化所得残余物， 得到标题产物 [2-甲氧基 -5-[4-[(3 -3-甲基吗啉 -4-基] -2- [甲基 (四氢吡喃 -4-基)氨基] B比啶并 [2，3-d]嘧啶 -7-基] 苯基]甲醇 62 (10 mg， 黄色固体)， 产率： 8.3%。 [5-0 chloro-4-morpholine-B-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol If (100 mg, 0.26 mmol), N -Methyltetrahydropyran-4-amine (29 mg, 0.26 mmol) and N,N-diisopropylethylamine (66 mg, 0.51 mmol) dissolved in 5 mL of N,N-dimethylacetamide and reacted at 90 ° C 12 hours, the reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product [2-methoxy --5-- [4 - [(3 - 3-methylmorpholin-4-yl]-2-[methyl(tetrahydropyran-4-yl)amino]B-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 62 (10 mg, yellow solid), Yield: 8.3%.
MS m/z (ESI): 563.2 [M+l] MS m/z (ESI): 563.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.29 (s, 1H), 8.19 (d, 1H), 8.06 (d, 1H), 7.58 (d， 1H)， 7.09 (d， 1H), 4.57 (s, 2H), 4.01-3.82 (m， 2H), 3.86 (s, 3H), 3.78-3.50 (m， 4H)， 3.49-3.40 (m， 2H), 3.39-3.18 (m， 6H)， 3.07 (s, 3H), 1.85-1.78 (m， 3H) 实施例 63 iHNMR (400 MHz, DMSO-J 6 ): δ 8.29 (s, 1H), 8.19 (d, 1H), 8.06 (d, 1H), 7.58 (d, 1H), 7.09 (d, 1H), 4.57 (s , 2H), 4.01-3.82 (m, 2H), 3.86 (s, 3H), 3.78-3.50 (m, 4H), 3.49-3.40 (m, 2H), 3.39-3.18 (m, 6H), 3.07 (s , 3H), 1.85-1.78 (m, 3H) Example 63
Γ2- (二氟甲氧基 )-5-「4-「(3 -3-甲基吗啉 -4-基 1-2- (甲基 (四氢吡喃 -4-基)氨基)吡啶  Γ2-(Difluoromethoxy)-5-"4-"(3 -3-methylmorpholin-4-yl 1-2-(methyl(tetrahydropyran-4-yl)amino)pyridine
Figure imgf000082_0002
Figure imgf000082_0002
第一步  First step
[5—[2-氯—4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2- (二氟甲氧基)苯基] 甲醇 [ 5- [2-Chloro-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]-2-(difluoromethoxy) Phenyl]methanol
将 (3 -4-(2，7-二氯吡啶并 [2，3-d]嘧啶 -4-基) -3-甲基 -吗啉 60a (380 mg， 1.67 mmol), [2- (二氟甲氧基 )-5-(4，4，5，5-四甲基 -1，3，2-二氧杂戊硼烷 -2-基)苯基]甲醇 (500 mg， 1.67 mmol, 采用公知的方法 "专利 WO2007084786"制备而得)， [1，1'-双 (；二苯 基膦基)二茂铁]二氯化钯 (61 mg， 0.083 mmol)和碳酸钠 (530 mg， 5 mmol)溶解于 6 mL l，4-二氧六环和水 (V/V = 5: l)混合溶剂中， 90°C下反应 12小时， 反应液减压浓 縮， 加入 10 mL乙酸乙酯和 10 mL水， 分层， 水相用乙酸乙酯萃取 (5 mL><2)， 合 并有机相， 用饱和氯化钠溶液洗涤 (20 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓 縮， 用薄层色谱法以展开剂体系 A 纯化所得残余物， 得到标题产物 [5-[2-氯 -4-[(35)-3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2- (二氟甲氧基)苯基]甲醇 63a (80 mg, 浅褐色固体)， 产率： 11.0%。 (3 -4-(2,7-Dichloropyrido[2,3-d]pyrimidin-4-yl)-3-methyl-morpholine 60a (380 mg, 1.67 mmol), [2- (two Fluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (500 mg, 1.67 mmol, A well-known method "prepared by patent WO2007084786", [1,1'-bis(;diphenylphosphino)ferrocene]palladium dichloride (61 mg, 0.083 mmol) and sodium carbonate (530 mg, 5) Mm) dissolved in 6 In a mixed solvent of mL 1 , 4-dioxane and water (V/V = 5: l), the reaction was carried out at 90 ° C for 12 hours, and the reaction solution was concentrated under reduced pressure, and 10 mL of ethyl acetate and 10 mL of water were added. The layers were separated and the aqueous phase was extracted with ethyl acetate (5 mL &lt; 2). The organic phase was combined and washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The resulting residue was purified by EtOAc to EtOAc (EtOAc). -d]pyrimidin-7-yl]-2-(difluoromethoxy)phenyl]methanol 63a (80 mg, light brown solid), yield: 11.0%.
MS m/z (ESI): 437.1 [M+l] MS m/z (ESI): 437.1 [M+l]
第二步  Second step
[2- (二氟甲氧基 )-5-[4-[(3 -3-甲基吗啉 -4-基] -2- (甲基 (四氢吡喃 -4-基)氨基) B比啶 并 [2，3-d]嘧啶 -7-基]苯基]甲醇  [2-(Difluoromethoxy)-5-[4-[(3 -3-methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl)amino)B Bis-[2,3-d]pyrimidin-7-yl]phenyl]methanol
于封管中依次加入 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -Ί- 基] -2- (二氟甲氧基)苯基]甲醇 63a (80 mg, 0.18 mmol), N-甲基吗啉 -4-胺 (100 mg, 0.87 mmol), N，N-二异丙基乙胺 (70 mg, 0.54 mmol)和 3 mL N，N-二甲基乙酰胺， 110 °C下反应 12小时， 加入 9 mL水和 15 mL乙酸乙酯， 分层， 有机相用饱和氯化钠 溶液洗涤 (5 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开 剂体系 A纯化所得残余物，得到标题产物 [2- (二氟甲氧基 )-5-[4-[(3 -3-甲基吗啉 -4- 基] -2 甲基 (四氢吡喃 -4-基)氨基) B比啶并 [2，3-d]嘧啶 -7-基]苯基]甲醇 63 (7 mg, 浅褐 色固体)， 产率： 7.4%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-indenyl]-2- (in the sealed tube) Difluoromethoxy)phenyl]methanol 63a (80 mg, 0.18 mmol), N-methylmorpholin-4-amine (100 mg, 0.87 mmol), N,N-diisopropylethylamine (70 mg , 0.54 mmol) and 3 mL of N,N-dimethylacetamide, reacted at 110 °C for 12 hours, added 9 mL of water and 15 mL of ethyl acetate, layered, and the organic phase was washed with saturated sodium chloride solution (5) The residue was purified by EtOAc (EtOAc m.). -[(3 -3-methylmorpholin-4-yl] -2 methyl(tetrahydropyran-4-yl)amino) B-pyrido[2,3-d]pyrimidin-7-yl]benzene Methyl]methanol 63 (7 mg, light brown solid), yield: 7.4%.
MS m/z (ESI): 516.2 [M+l] MS m/z (ESI): 516.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 7.85 (d， 1H)， 7.75-7.65 (br.， 1H)， 7.38 (t， 1H)， 7.25 (d: 1H), 6.62-6.52 (m， 1H), 5.75-5.65 (m， 1H), 5.34 (s， 2H), 4.40-4.25 (m， 1H), 4.15-3.98 (m， 2H), 3.91-3.50 (m， 8H)， 3.30-3.10 (m， 1H)， 2.21 (s, 3H), 2.13-1.90 (m， 2H), 1.56-1.46 (m, 2H), 1.29 (s, 3H) 实施例 64 iHNMR (400 MHz, DMSO-J 6 ): δ 7.85 (d, 1H), 7.75-7.65 (br., 1H), 7.38 (t, 1H), 7.25 (d : 1H), 6.62-6.52 (m, 1H) ), 5.75-5.65 (m, 1H), 5.34 (s, 2H), 4.40-4.25 (m, 1H), 4.15-3.98 (m, 2H), 3.91-3.50 (m, 8H), 3.30-3.10 (m , 1H), 2.21 (s, 3H), 2.13-1.90 (m, 2H), 1.56-1.46 (m, 2H), 1.29 (s, 3H) Example 64
「2—氟 -5-「4-「(3 -3-甲基吗啉 -4-基 1-2- (甲基 (四氢吡喃 -4-基)氨基)吡啶并「2,3-dl嘧 "2-Fluoro- 5- " 4 -"(3-3-methylmorpholin-4-yl1-2-(methyl(tetrahydropyran-4-yl)amino)pyridine"2,3- Dyrazine
Figure imgf000083_0001
第一步
Figure imgf000083_0001
first step
[5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-氟-苯基]甲醇 将 [4-氟 -3- (羟甲基)苯基]硼酸 (293 mg， 1.72 mmol, 采用公知的方法 "专利 WO2004000814"制备而得)， （3 -4-(2，7-二氯吡啶并 [2，3-d]嘧啶 -4-基) -3-甲基 -吗啉 60a (430 mg， 1.44 mmol), [1，Γ-双 (二苯基膦基)二茂铁]二氯化钯 (104 mg， 0.144 mmol)和碳酸钠 (305 mg， 2.88 mmol)溶解于 10 mL 1,4-二氧六环和水 (V/V = 5:1)混 合溶剂中， 90°C下反应 12小时， 反应液减压浓縮， 加入 20 mL乙酸乙酯和 10 mL 水， 分层， 水相用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (30 mL), 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 A 纯化所得残余物，得到标题产物 [5-[2-氯 -4-[ ¾)-3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-氟-苯基]甲醇 64a (110 mg， 黄色固体)， 产率： 19.6%。  [5-[2-Chloro-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-phenyl] [4-Fluoro-3-(hydroxymethyl)phenyl]boronic acid (293 mg, 1.72 mmol, prepared by the known method "WO2004000814"), (3 -4-(2,7-dichloro) Pyrido[2,3-d]pyrimidin-4-yl)-3-methyl-morpholine 60a (430 mg, 1.44 mmol), [1, fluorene-bis(diphenylphosphino)ferrocene] Palladium chloride (104 mg, 0.144 mmol) and sodium carbonate (305 mg, 2.88 mmol) were dissolved in 10 mL of a mixture of 1,4-dioxane and water (V/V = 5:1) at 90 °C. After the reaction was carried out for 12 hours, the reaction mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 30 mL), dried over anhydrous sodium sulfate, filtered, EtOAcjjjjjjjjjjjjjjjjjjjj 3-methylmorpholin-4-yl] B-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-phenyl]methanol 64a (110 mg, yellow solid), Yield: 19.6 %.
MS m/z (ESI): 390.1 [M+l] MS m/z (ESI): 390.1 [M+l]
第二步  Second step
[2-氟 -5-[4-[(3 -3-甲基吗啉 -4-基] -2- (甲基 (四氢吡喃 -4-基)氨基) B比啶并 [2，3-d]嘧 啶 -7-基]苯基]甲醇 [2-Fluoro- 5- [4-[(3 -3-methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl)amino) B) is pyridine [2, 3-d]pyrimidin-7-yl]phenyl]methanol
将 [5-[2-氯 -4-[(3^-3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-氟-苯基]甲醇 64a (100 mg， 0.26 mmol), N-甲基吗啉 -4-胺 (44.40 mg， 0.39 mmol)和 N，N-二异丙基乙 胺 (100 mg，0.77 mmol)溶解于 5 mL N，N-二甲基乙酰胺中， 90°C下反应 12小时， 反 应液减压浓縮， 用 HPLC制备色谱法以展开剂体系 A纯化所得残余物， 得到标题 产物 [2-氟 -5-[4-[(3 -3-甲基吗啉 -4-基] -2-(甲基(四氢吡喃 -4-基)氨基)吡啶并 [2，3-d] 嘧啶 -7-基]苯基]甲醇 64 (4 mg， 黄色固体)， 产率： 3.3%。  [5-[2-Chloro-4-[(3^-3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzene Methyl]methane 64a (100 mg, 0.26 mmol), N-methylmorpholin-4-amine (44.40 mg, 0.39 mmol) and N,N-diisopropylethylamine (100 mg, 0.77 mmol) dissolved in 5 The reaction was carried out at 90 ° C for 12 hours in mL N,N-dimethylacetamide, and the reaction mixture was concentrated under reduced pressure. 5-[4-[(3 -3-methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl)amino)pyrido[2,3-d]pyrimidine-7 -yl]phenyl]methanol 64 (4 mg, yellow solid), yield: 3.3%.
MS m/z (ESI): 468.2 [M+l] MS m/z (ESI): 468.2 [M+l]
iHNMR (400 MHz, CDC13): δ 8.41 (s, 1H)， 8.09 (d， 1H)， 7.67-7.44 (m， 2H), 7.17 (d， 1H), 5.41-5.39 (m， 1H), 4.89 (s, 2H), 4.17-3.70 (m， 8H)， 3.53 (s, 3H), 3.28-3.21 (m， 4H) 2.01-1.98 (m， 2H), 1.56-1.52 (m， 2H), 1.35-1.30 (m， 3H) 实施例 65 iHNMR (400 MHz, CDC1 3 ): δ 8.41 (s, 1H), 8.09 (d, 1H), 7.67-7.44 (m, 2H), 7.17 (d, 1H), 5.41-5.39 (m, 1H), 4.89 (s, 2H), 4.17-3.70 (m, 8H), 3.53 (s, 3H), 3.28-3.21 (m, 4H) 2.01-1.98 (m, 2H), 1.56-1.52 (m, 2H), 1.35- 1.30 (m, 3H) Example 65
「4-Γ「7-「3- (羟甲基) -4-甲氧基 -苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧啶  "4-Γ"7-"3-(Hydroxymethyl)-4-methoxy-phenyll-4-"(3 -3-methylmorpholin-4-yl 1pyridine and 2,3- Pyrimidine
-2-基 1-甲 )甲酮  -2-yl 1-methyl)methanone
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000084_0001
Figure imgf000085_0001
将 (4-甲基氨基 -1-哌啶基 )-(2-吡啶基）甲酮 (60 mg， 0.27 mmol)、 [5-[2-氯 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲醇 3a (100 mg， 0.25 mmol)和 N，N-二异丙基乙胺 (64 mg， 0.49 mmol) 溶解于 3 mL N，N-二甲基乙酰 胺中， 90°C下反应 12小时， 反应液减压浓縮， 用 HPLC制备色谱法以展开剂体系 A纯化所得残余物，得到标题产物 [4-[[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-[(3 -3-甲基 吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -2-基] -甲基 -氨基 ]-1-哌啶基 ]-(2-吡啶基）甲酮 65 (30 mg， 黄色固体)， 产率： 20.6%。  (4-Methylamino-1-piperidinyl)-(2-pyridyl)methanone (60 mg, 0.27 mmol), [5-[2-chloro-4-[(3 -3-methyl)?啉-4-yl] B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol) and N,N-diisopropyl Ethylethylamine (64 mg, 0.49 mmol) was dissolved in 3 mL of N,N-dimethylacetamide, and reacted at 90 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified to give the title product [4-[[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-[(3-3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl]-(2-pyridyl)methanone 65 (30 mg, yellow solid), Rate: 20.6%.
MS m/z (ESI): 468.2 [M+l] MS m/z (ESI): 468.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.68 (s, 1H)， 8.22 (s, 1H)， 8.11-7.93 (m， 3H), 7.66-7.60 (m， 2H), 7.52-7.47 (m， 1H), 6.91 (d, 1H), 4.85-4.75 (m， 2H), 4.08-4.05 (m， 1H), 3.88 (s， 3H), 3.84-3.65 (m， 5H)， 3.48-3.25 (m， 2H), 3.20-2.75 (m， 3H), 2.67-2.65 (m， 1H)， 2.10-1.76 (m， 7H), 1.63-1.61 (m， 3H) 实施例 66 iHNMR (400 MHz, DMSO-J 6 ): δ 8.68 (s, 1H), 8.22 (s, 1H), 8.11-7.93 (m, 3H), 7.66-7.60 (m, 2H), 7.52-7.47 (m, 1H), 6.91 (d, 1H), 4.85-4.75 (m, 2H), 4.08-4.05 (m, 1H), 3.88 (s, 3H), 3.84-3.65 (m, 5H), 3.48-3.25 (m, 2H), 3.20-2.75 (m, 3H), 2.67-2.65 (m, 1H), 2.10-1.76 (m, 7H), 1.63-1.61 (m, 3H) Example 66
「4-Γ「7-「3- (羟甲基) -4-甲氧基 -苯基 l-4-「(3 -3-甲基吗啉 -4-基 1吡啶并「2,3-dl嘧啶  "4-Γ"7-"3-(Hydroxymethyl)-4-methoxy-phenyll-4-"(3 -3-methylmorpholin-4-yl 1pyridine and 2,3- Pyrimidine
Figure imgf000085_0002
Figure imgf000085_0002
将 (4-甲基氨基 -1-哌啶基) -苯基甲酮 (60 mg， 0.28 mmol)、 [5-[2-氯 -4-[(3 -3-甲基 吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲醇 3a (100 mg， 0.25 mmol)和 N，N-二异丙基乙胺 (64 mg， 0.49 mmol)溶解于 3 mL N，N-二甲基乙酰胺中， 90°C下 反应 12小时， 反应液减压浓縮， 用 HPLC制备色谱法以展开剂体系 A纯化所得残 余物， 得到标题产物 [4-[[7-[3- (羟甲基) -4-甲氧基 -苯基 ]-4-[(3S)-3-甲基吗啉 -4-基]吡 啶并 [2，3-d]嘧啶 -2-基] -甲基 -氨基 ]-1-哌啶基] -苯基甲酮 66 (40 mg，黄色固体)，产率： 27.5%。 (4-Methylamino-1-piperidinyl)-phenylmethanone (60 mg, 0.28 mmol), [5-[2-chloro-4-[(3-3-methylmorpholin-4-) B]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol) and N,N-diisopropylethylamine ( 64 mg, 0.49 mmol) was dissolved in 3 mL of N,N-dimethylacetamide, and reacted at 90 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by HPLC. , the title product [4-[[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-[(3S)-3-methylmorpholin-4-yl]pyridine) [2,3-d]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl]-phenylmethanone 66 (40 mg, yellow solid), yield: 27.5%.
MS m/z (ESI): 468.2 [M+l]  MS m/z (ESI): 468.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.29 (s， 1H), 8.15 (d， 1H), 8.05 (d， 1H), 7.57-7.55 (d， 1H), 7.49-7.32 (m， 4H)， 7.09-7.07 (m， 1H), 4.56 (s， 2H), 4.47-4.43 (m， 1H), 3.86 (s， 3H) 3.76-3.59 (m， 5H)， 3.08 (s, 3H), 1.77-1.56 (m， 4H)， 1.66-1.62 (m， 6H)， 1.37-1.35 (m， 2H), 1.25-1.20 (m, 2H) 实施例 67 iHNMR (400 MHz, DMSO-J 6 ): δ 8.29 (s, 1H), 8.15 (d, 1H), 8.05 (d, 1H), 7.57-7.55 (d, 1H), 7.49-7.32 (m, 4H) , 7.09-7.07 (m, 1H), 4.56 (s, 2H), 4.47-4.43 (m, 1H), 3.86 (s, 3H) 3.76-3.59 (m, 5H), 3.08 (s, 3H), 1.77- 1.56 (m, 4H), 1.66-1.62 (m, 6H), 1.37-1.35 (m, 2H), 1.25-1.20 (m, 2H) Example 67
Γ5- 醇  Γ5- alcohol
Figure imgf000086_0001
Figure imgf000086_0001
第一步  First step
5 2-异丙基 -4-氧代 -3H-吡啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基甲酸甲酯 将 5-(2-异丙基 -4-氧代 -3H-吡啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基-苯基甲酸 67a (200 mg， 0.60 mmol, 采用公知的方法"文献 Journal of Medicinal chemistry, 2009(25): 7946-7949"制备而得)和 1 mL二氯亚砜溶解于 5 mL甲醇中， 回流反应 12小时， 减压浓縮，加入 5 mL水和 5 mL二氯甲烷，分层，水相用二氯甲烷萃取 (10 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mL)， 无水硫酸镁干燥， 过滤， 滤液减压 浓縮，得到标题产物粗品 5-(2-异丙基 -4-氧代 -3H-吡啶并 [2，3-d]嘧啶 -7-基) -2-甲氧基 -苯基甲酸甲酯 67b (120 mg， 黄色固体)， 产物不经纯化直接用于下步反应。  5-2-Isopropyl-4-oxo-3H-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenylcarboxylic acid methyl ester 5-(2-isopropyl 4-oxo-3H-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenylcarboxylic acid 67a (200 mg, 0.60 mmol, using a known method) "Journal of Medicinal" Chemistry, 2009 (25): 7946-7949 "prepared" and 1 mL of thionyl chloride dissolved in 5 mL of methanol, refluxed for 12 hours, concentrated under reduced pressure, and added 5 mL of water and 5 mL of dichloromethane. The layers were separated and the aqueous phase was extracted with methylene chloride (10 mL). -(2-Isopropyl-4-oxo-3H-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenylcarboxylic acid methyl ester 67b (120 mg, yellow solid) The product was used in the next step without purification.
MS m/z (ESI): 354.2 [M+l] MS m/z (ESI): 354.2 [M+l]
第二步  Second step
5-[2-异丙基 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基甲酸 甲酯  5-[2-isopropyl-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl Methyl formate
于反应瓶中依次加入 5-(2-异丙基 -4-氧代 -3H-吡啶并 [2，3-d]嘧啶 -7-基) -2-甲氧 基-苯基甲酸甲酯 67b (120 mg， 0.34 mmol)和 2 mL三氯氧磷， 回流反应 6小时， 减 压浓縮， 加入 5 mL N，N-二甲基乙酰胺、 （3 -3-甲基吗啉 (100 mg， 1 mmol)禾 B 1 mL N，N-二异丙基乙胺， 120°C反应 12小时，加入 20 mL水，用乙酸乙酯萃取 (10 mLx3), 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸镁干燥， 过滤， 滤液减 压浓縮，得到标题产物粗品 5-[2-异丙基 -4-[C3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 _7_基 ]-2-甲氧基-苯基甲酸甲酯 67c (40 mg， 黄色固体)， 产物不经纯化直接用于下 步反应。 Add 5-(2-isopropyl-4-oxo-3H-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenylcarboxylic acid methyl ester 67b to the reaction flask (120 mg, 0.34 mmol) and 2 mL of phosphorus oxychloride, refluxed for 6 hours, concentrated under reduced pressure, and added 5 mL of N,N-dimethylacetamide, (3-3-methylmorpholine (100 mg) , 1 mmol) Wo 1 1 mL N,N-diisopropylethylamine, reacted at 120 ° C for 12 hours, added 20 mL of water, extracted with ethyl acetate (10 mL×3), combined organic phase with saturated sodium chloride Wash the solution (20 mLx2), dry over anhydrous magnesium sulfate, filter, filtrate minus Concentration by pressure gave the title product crude 5-[2-isopropyl-4-[C3-3-methylmorpholin-4-yl]B-pyrido[2,3-d]pyrimidin- 7 -yl] Methyl 2 -methoxy-phenylcarboxylate 67c (40 mg, yellow solid), product was used in the next step without purification.
MS m/z (ESI): 437.2 [M+l]  MS m/z (ESI): 437.2 [M+l]
第三步  third step
[5-[2-异丙基 -4-[(3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基-苯基]甲醇 将粗品 5-[2-异丙基 -4-[(3 -3-甲基吗啉 -4-基]吡啶并 [2，3-d]嘧啶 -7-基] -2-甲氧基 -苯基甲酸甲酯 67c (40 mg， 0.09 mmol)溶解于 2 mL四氢呋喃中， 0°C下加入氢化铝 锂 (5 mg， 0.11 mmol), 反应 12小时， 减压浓縮， 用薄层色谱法以展开剂体系 A纯 化所得残余物， 得到标题产物 [5-[2-异丙基 -4-[C3 -3-甲基吗啉 -4-基] B比啶并 [2，3-d] 嘧啶 -7-基] -2-甲氧基-苯基]甲醇 67 (7 mg， 黄色固体)， 产率： 18.9%。  [5-[2-Isopropyl-4-[(3 -3-methylmorpholin-4-yl) B-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy -Phenyl]methanol to crude 5-[2-isopropyl-4-[(3 -3-methylmorpholin-4-yl)pyrido[2,3-d]pyrimidin-7-yl]-2 Methyl methoxy-phenylcarboxylate 67c (40 mg, 0.09 mmol) was dissolved in 2 mL of THF. EtOAc (5 mg, 0.11 mmol). The resulting residue was purified by EtOAc (EtOAc) eluting , 3-d] pyrimidin-7-yl]-2-methoxy-phenyl]methanol 67 (7 mg, yellow solid), yield: 18.9%.
MS m/z (ESI): 408.2 [M+l] MS m/z (ESI): 408.2 [M+l]
iHNMR (400 MHz, DMSO-J6): δ 8.30-8.25 (m， 2H), 8.17 (d, 1H)， 7.78 (d, 1H)， 7.03 (d: 1H), 4.79 (s， 2H), 4.52-4.50 (m， 1H), 4.10-4.02 (m， 1H), 3.96 (s， 3H), 3.78-3.73 (m， 2H): 3.44-3.38 (m， 2H), 2.91-2.89 (m， 2H), 1.69 (s， 6H)， 1.53-1.51 (m， 3H) 实施例 68iHNMR (400 MHz, DMSO-J 6 ): δ 8.30-8.25 (m, 2H), 8.17 (d, 1H), 7.78 (d, 1H), 7.03 (d : 1H), 4.79 (s, 2H), 4.52 -4.50 (m, 1H), 4.10-4.02 (m, 1H), 3.96 (s, 3H), 3.78-3.73 (m, 2H) : 3.44-3.38 (m, 2H), 2.91-2.89 (m, 2H) , 1.69 (s, 6H), 1.53-1.51 (m, 3H) Example 68
)-3-(2-叔丁基 )-4-( -7-基) -N-甲基苯酰胺  )-3-(2-tert-butyl)-4-(-7-yl)-N-methylbenzamide
Figure imgf000087_0001
Figure imgf000087_0001
依次将 ( -4-(2-叔丁基 )-7-氯-吡啶并 [2，3-d]嘧啶 -4-基) -3-甲基吗啉 46c (1.3 g， 4.15 mmol) N-甲基 -3-(4，4，5，5-四甲基 -1，3，2-二氧杂戊硼烷 -2-基)苯胺 68a (1.3 g， 5 mmol), 四三苯基膦钯 (0.48 g， 0.42 mmol), 碳酸钾（1.7 g， 12.45 mmol)溶解于 25 mL 二氧六环和水 (V/V = 4: 1)混合溶剂中， 80°C下反应 5小时， 反应液减压浓縮， 用硅 胶柱色谱法以洗脱剂体系 A纯化所得残余物， 减压浓縮至少量溶剂， 自然冷却， 析出固体， 再用乙酸乙酯重结晶， 得到标题产物 ( -3-(2-叔丁基 )-4-(3-甲基吗啉)口比 啶并 [2，3-d]嘧啶 -7-基) 甲基苯酰胺 68 (420 mg， 白色固体 产率： 24.1%。  (-4-(2-tert-Butyl)-7-chloro-pyrido[2,3-d]pyrimidin-4-yl)-3-methylmorpholine 46c (1.3 g, 4.15 mmol) N- Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine 68a (1.3 g, 5 mmol), tetratriphenylphosphine Palladium (0.48 g, 0.42 mmol), potassium carbonate (1.7 g, 12.45 mmol) was dissolved in 25 mL of a mixture of dioxane and water (V/V = 4:1) and reacted at 80 ° C for 5 hours. The liquid 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%.
MS m/z (ESI): 420.4 [M+l] MS m/z (ESI): 420.4 [M+l]
iHNMR (400 MHz, CDC ): δ 8.80 (s, 1H)， 8.27-8.22 (m， 2H), 8.03-8.01 (m， 1H)， 7.86-7.84 (m， 1H), 7.59-7.55 (m， 1H), 6.55 (s, 1H), 4.57-4.56 (m， 1H), 4.30-4.20 (m， 1H), 4.05-4.01 (m， 1H), 3.85-3.77 (m， 4H)， 3.09-3.08 (m， 3H), 1.60-1.56 (m， 3H), 1.51 (s， 9H) 测试例： iHNMR (400 MHz, CDC): δ 8.80 (s, 1H), 8.27-8.22 (m, 2H), 8.03-8.01 (m, 1H), 7.86-7.84 (m, 1H), 7.59-7.55 (m, 1H), 6.55 (s, 1H), 4.57-4.56 (m, 1H), 4.30-4.20 (m, 1H), 4.05-4.01 (m, 1H) ), 3.85-3.77 (m, 4H), 3.09-3.08 (m, 3H), 1.60-1.56 (m, 3H), 1.51 (s, 9H) Test example:
生物学评价  Biological evaluation
测试例 1 本发明化合物对 mTOR激酶的活性抑制的测定  Test Example 1 Determination of inhibition of mTOR kinase activity by a compound of the present invention
体外 mTOR激酶活性的抑制通过以下的方法进行测试。  Inhibition of mTOR kinase activity in vitro was tested by the following method.
本实验用 K-LISA™ mTOR (重组体)活性试剂盒（Activity Kit), 货号： CBA104, 购于 MERCK。  This experiment used K-LISATM mTOR (Recombinant) Activity Kit (Activity Kit), article number: CBA104, purchased from MERCK.
以下所述的体外细胞实验可测定受试化合物对 mTOR激酶的抑制活性， 测试 化合物根据实验所需浓度溶解于二甲基亚砜中。 用 lx缓冲液稀释 ATP和 DTT得 到 200 μΜ ATP和 2000 μΜ DTT溶液， mTOR酶终浓度为 2 ng^L。 向微孔板中 分别加入 50 μL· AΎF和 DTT溶液， 1 测试化合物 DMSO溶液 （对照和空白中只 加 1 μΐ纯 DMSO)及 50 μL上述酶溶液 （对照中只加 50 μL lx缓冲液)。各管充分混 匀后， 于 30°C孵育 45分钟后， 用洗液洗 3次， 加入一抗， 孵育 1小时。 用洗液洗 3次， 加入二抗， 孵育 1小时。 加入 TMB， 显色 5〜15分钟。 加入终止液终止反 应。 在 NOVOstar酶标仪上， 以 450 nm波长测吸光值。 化合物的 IC5。值可通过不 同浓度下受试化合物对于 mTOR活性的抑制数值计算得出。 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 μΜ ATP and 2000 μΜ DTT solution, and the final concentration of mTOR enzyme was 2 ng^L. Add 50 μL·AΎF and DTT solution to the microplate, 1 test compound DMSO solution (only 1 μΐ pure DMSO in control and blank) and 50 μL of the above enzyme solution (only 50 μL lx buffer in the control). After thoroughly mixing the tubes, they were incubated at 30 ° C for 45 minutes, washed three times with a washing solution, and added with a primary antibody, and incubated for 1 hour. Wash 3 times with washing solution, add secondary antibody, and incubate for 1 hour. Add TMB and develop color for 5 to 15 minutes. The reaction was terminated by the addition of a stop solution. The absorbance was measured at a wavelength of 450 nm on a NOVOstar plate reader. Compound IC 5 . The value can be calculated from the inhibition value of the test compound for mTOR activity at different concentrations.
本发明化合物的活性  Activity of the compounds of the invention
本发明化合物的生化学活性通过以上的试验进行测定， 测得的 IC5。值见下表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
1。 1.
表 1 本发明化合物对 mTOR激酶的活性抑制的 IC:  Table 1 Inhibition of mTOR kinase activity by compounds of the invention:
Figure imgf000088_0001
38 21
Figure imgf000088_0001
38 21
39 23  39 23
40 4.7  40 4.7
41 9.8  41 9.8
42 4.5  42 4.5
43 5.4  43 5.4
44 0.7  44 0.7
45 5.6  45 5.6
46 3  46 3
47 33.6  47 33.6
48 16.7  48 16.7
49 0.4  49 0.4
52 2.2  52 2.2
53 32  53 32
54 3.9  54 3.9
55 66  55 66
57 1.6  57 1.6
58 9.8  58 9.8
59 9  59 9
61 14  61 14
65 11  65 11
66 24  66 24
68 53  68 53
结论： 本发明实施例化合物对 mTOR激酶增殖均有明显地抑制作用。 测试例 2 本发明化合物对细胞 MCF-7的增殖抑制测定  Conclusion: The compounds of the examples of the present invention have a significant inhibitory effect on the proliferation of mTOR kinase. Test Example 2 Determination of proliferation inhibition of cells MCF-7 by the compound of the present invention
下面的体外试验是用来测定本发明化合物对细胞株一 MCF-7 (乳腺癌细胞） 的增殖抑制活性。  The following in vitro assay was used to determine the proliferation inhibitory activity of the compounds of the invention against a cell line, MCF-7 (breast cancer cells).
以下所述的体外细胞试验可测定受试化合物对高表达 mTOR/PI3k的肿瘤细胞 的增殖抑制活性， 其活性可用 IC5Q值来表示。 此类试验的一般方案如下： 首先将 MCF-7细胞 (购于 Institute of biochemistry and cell biology)以适宜细胞浓度 4000 个 细胞 /mL 介质接种在 96孔培养板上，然后将细胞在二氧化碳恒温箱内 37°C进行培 养， 让它们生长至过夜， 更换培养基为加有一系列浓度递度 (10000、 1000、 100、 10、 1、 O.lnm)受试化合物溶液的培养基， 将培养板重新放回培养箱， 连续培养 72 个小时。 72小时后， 可用 CCK8(细胞计算试剂盒 8 (Cell Counting Kit-8), 货号： CK04, 购于 Dojindo)方法进行测试化合物对于抑制细胞增殖活性。 IC5Q值可通过 一系列不同浓度下， 受试化合物对于细胞的抑制数值进行计算。 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. After 72 hours, the test compound was assayed for inhibition of cell proliferation activity using 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.
本发明化合物活性  Compound activity of the present invention
本发明化合物生物活性由上述分析所得， 计算所得的 IC5Q值如下表 2: The biological activity of the compound of the present invention was obtained by the above analysis, and the calculated IC 5Q value is shown in Table 2 below:
表 2本发明化合物对 MCF-7细胞的增殖抑制的 IC:  Table 2 Inhibition of proliferation of MCF-7 cells by the compounds of the present invention IC:
Figure imgf000090_0001
测试例 3 本发明化合物对细胞 PC-3的增殖抑制测定
Figure imgf000090_0001
Test Example 3 Determination of Proliferation Inhibition of Cellular PC-3 by Compounds of the Invention
下面的体外试验是用来测定本发明化合物对细胞株一 PC-3 (人前列腺癌细胞） 的增殖抑制活性。  The following in vitro test was conducted to determine the proliferation inhibitory activity of the compound of the present invention against a cell line of PC-3 (human prostate cancer cells).
以下所述的体外细胞实验可测定受试化合物对肿瘤细胞的增殖抑制活性， 化 合物的抑制活性可用 IC5Q值来表示。实验方案简述如下： 首先将以 DMEM-F12 附 加 10% FBSC购于 Gibco)作为完全培养基的 PC-3细胞 (；购于 Institute of biochemistry and cell biology), 以适宜的细胞浓度 2000个 /mL介质接种在 96孔培养板上， 然后 在 37°C， 5% C02条件下， 于恒温培养箱内培养过夜。 待细胞贴壁后， 将培养基更 换为含有受试化合物梯度浓度 (10000、 1000、 100、 10、 1、 O.lnm)溶液的新鲜培养 基。此后，将细胞培养板在前述条件下连续培养 72个小时。 72小时后，采用 CCK8 方法测定化合物对于细胞增殖的抑制活性。 化合物的 IC5Q值可通过不同浓度下受 试化合物对于细胞增殖的抑制数值计算得出。 本发明化合物活性 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). Thereafter, 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. Compound activity of the present invention
本发明化合物生物活性由上述分析所得， 计算所得的 IC5Q值如下表 3 : The biological activity of the compound of the present invention was obtained by the above analysis, and the calculated IC 5Q value is shown in Table 3 below:
表 3本发明化合物对 PC-3细胞的增殖抑制的 IC5o Table 3 IC 5 o inhibition of proliferation of PC-3 cells by the compounds of the present invention
Figure imgf000091_0001
Figure imgf000091_0001
结论： 本发明化合物均对 PC-3细胞具有明显的增殖抑制活性。 药代动力学评价  Conclusion: The compounds of the present invention all have significant proliferation inhibitory activity against PC-3 cells. Pharmacokinetic evaluation
测试例 4、 本发明化合物的药代动力学测试  Test Example 4. Pharmacokinetic test of the compound of the present invention
1、 摘要  1, abstract
以大鼠为受试动物， 应用 LC/MS/MS法测定了大鼠灌胃给予实施例 4化合物、 实施例 31化合物、 实施例 46化合物和实施例 57化合物后不同时刻血浆中的药物浓 度。 研究本发明的化合物在大鼠体内的药代动力学行为， 评价其药动学特征。  Using rat as a test animal, 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.
2、 试验方案  2. Test plan
2.1 试验药品  2.1 Test drugs
实施例 4化合物、 实施例 31化合物、 实施例 46化合物和实施例 57化合物。 2.2 试验动物 健康成年 SD大鼠 16只， 雌雄各半， 平均分成 4组， 每组 4只， 购自上海西普尔- 必凯实验动物有限公司， 动物生产许可证号： SCXK (沪) 2008-0016。 The compound of Example 4, the compound of Example 31, the compound of Example 46 and the compound of Example 57. 2.2 Test animals Healthy adult SD rats, 16 males and females, divided into 4 groups, 4 in each group, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.
2.3 药物配制  2.3 Drug preparation
称取适量样品， 加入 0.5% CMC-Na， 超声制成 0.5 mg/ml混悬液。  An appropriate amount of the sample was weighed, 0.5% CMC-Na was added, and a 0.5 mg/ml suspension was prepared by ultrasonication.
2.4 给药  2.4 Administration
SD大鼠 16只， 雌雄各半， 平均分成 4组， 禁食一夜后分别灌胃给药， 剂量为 5.0 mg/kg或 10.0 mg/kg， 给药体积 10 ml/kg。  Sixteen SD rats, half male and half female, were divided into 4 groups. They were intragastrically administered overnight after fasting. The dose was 5.0 mg/kg or 10.0 mg/kg, and the dosage volume was 10 ml/kg.
3、 操作  3, operation
大鼠灌胃给药实施例 4化合物、 实施例 31化合物、 实施例 46化合物和实施 例 57化合物， 于给药前及给药后 0.5， 1.0, 2.0, 3.0, 4.0， 6.0, 8.0， 11.0, 24.0 小时采血 0.1 ml, 置于肝素化试管中， 3500 rpm离心 5 min分离血浆， 乎 20°C保存。 给药后 2 小时进食。  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.
用 LC/MS/MS法测定不同浓度的药物灌胃给药后大鼠血浆中的待测化合物含 量。 方法的线性范围均为 1.00〜2000 ng/ml; 血浆样品经甲醇沉淀蛋白处理后进行 分析。  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.
4、 药代动力学参数结果  4, pharmacokinetic parameters results
本发明化合物的药代动力学参数如下:  The pharmacokinetic parameters of the compounds of the invention are as follows:
Figure imgf000092_0001
结论： 本发明化合物的药代吸收良好， 具有明显的药代动力学优势。
Figure imgf000092_0001
Conclusion: The compound of the present invention has good pharmacological absorption and has obvious pharmacokinetic advantages.

Claims

权利要求书： Claims:
1、 一种通式（I )所示的化合物或其可药用盐， A compound of the formula (I) or a pharmaceutically acceptable salt thereof,
Figure imgf000093_0001
Figure imgf000093_0001
( I ) (I)
其巾：  Its towel:
X1、 X2或 X3其中的一个或两个为 N原子， 其他为 CH; One or two of X 1 , X 2 or X 3 are N atoms, others are CH;
R1和 R2与相连接的 N原子一起形成杂环基，其中所述的杂环基内含有一个或 多个选自 N、 0或 S(0)m的杂原子， 并且所述杂环基任选进一步被一个或多个选自 烷基、 卤素、 氧代基、 烯基、 块基、 烷氧基、 硝基、 氰基、 环烷基、 杂环基、 芳 基、 杂芳基、 -C(0)R7、 -C(0)OR7、 -S(0)mR7、 -NR8R9、 -C(0)NR8R9、 -NR8C(0)R9、 -NR8S(0)mR9或 -S(0)mNR8R9的取代基所取代； 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 ring Further optionally further selected from 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, -NR 8 S (0) m R 9 , or -S (0) m NR 8 R 9 substituents of;
R3选自芳基或杂芳基， 其中所述芳基或杂芳基任选进一步被一个或多个选自 烷基、 羟烷基、 ^素、 氧代基、 烯基、 块基、 烷氧基、 ^代烷氧基、 硝基、 氰基、 环烷基、杂环基、芳基、杂芳基、 -C(0)R7、 -C(0)OR7、 -S(0)mR7、 -NR8R9、 -C(0)NR8R9、 -NR8C(0)R9、 -NR8S(0)mR9或 -S(0)mNR8R9的取代基所取代； R 3 is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is optionally further further selected from one or more selected from the group consisting of alkyl, hydroxyalkyl, thiol, oxo, alkenyl, block, Alkoxy, ^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 , -NR 8 S(0) m R 9 or -S(0) m NR Substituted by a substituent of 8 R 9 ;
R4选自氰基、 烷基、 烯基、 块基、 环烷基、 杂环基、 -OR5、 -SR5、 -NR5R6、 -C(0)NR8R9或 -NHC(0)R7， 其中所述杂环基与通式（ I )的嘧啶基相连接的原子为碳 原子， 所述烷基、 烯基、 块基、 环烷基或杂环基任选进一步被一个或多个选自卤 素、 氧代基、 羟基、 烷氧基、 氰基、 芳基、 杂环基、 杂芳基、 -C(0)OR7或 -S(0)mR7 或 -NR8R9的取代基所取代； 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 ;
R5选自杂环基， 其中所述杂环基内含有一个或多个选自 N、 0或 S(0)m的杂 原子， 并且所述杂环基任选进一步被一个或多个选自烷基、 卤素、 氧代基、 烯基、 块基、 卤代烷基、烷氧基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、 -C(0)R -C(0)OR7、 -S(0)mR7、 -NR8R9、 -C(0)NR8R9、 -NR8C(0)R9、 -NR8S(0)mR9 或 -S(0)mNR8R9的取代基所取代； 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, haloalkyl, alkoxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)R -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 ;
R6选自氢原子、 烷基或环烷基， 其中所述烷基或环烷基任选进一步被一个或 多个选自烷基、 烷氧基、 卤素、 氧代基、 硝基、 氰基、 环烷基、 杂环基、 -C(0)R7、 -C(0)OR7、 -S(0)mR7、 -NR8R9、 -C(0)NR8R9、 -NR8C(0)R9、 -NR8S(0)mR9 或 -S(0)mNR8R9的取代基所取代； 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 ;
R7、 R8和 R9各自独立地选自氢原子、烷基、环烷基、杂环基、 芳基或杂芳基， 其中所述烷基、 环烷基、 杂环基、 芳基或杂芳基任选进一步被一个或多个选自烷 基、 卤素、 烷氧基、 硝基、 氰基、 环烷基、 氧代基、 杂环基、 芳基或杂芳基的取 代基所取代； 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 selected from one or more selected from the group consisting of alkane Substituted with a substituent of a halogen, an alkoxy group, a nitro group, a cyano group, a cycloalkyl group, an oxo group, a heterocyclic group, an aryl group or a heteroaryl group;
m是 0、 1或 2。  m is 0, 1, or 2.
2、 根据权利要求 1所述的通式（ I )所示的化合物或其可药用盐， 其中所述 R3 为芳基。 The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the R 3 is an aryl group.
3、 根据权利要求 1所述的通式（I )所示的化合物或其可药用盐， 其为通式 (II) 所示的化合物或其可药用盐： The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of the formula (II) or a pharmaceutically acceptable salt thereof:
Figure imgf000094_0001
其巾：
Figure imgf000094_0001
Its towel:
X ~X3, R3〜R4的定义如权利要求 1中所述； X to X 3 , R 3 to R 4 are as defined in claim 1;
R1Q选自氢原子或烷基。 R 1Q is selected from a hydrogen atom or an alkyl group.
4、 根据权利要求 3所述的通式 (I)所示的化合物或其可药用盐， 其为通式 (III) 所示的化合物或其可药用盐： The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, which is a compound of the formula (III) or a pharmaceutically acceptable salt thereof:
Figure imgf000094_0002
其巾：
Figure imgf000094_0002
Its towel:
R4的定义如权利要求 1中所述； R 4 is as defined in claim 1;
R1Q选自氢原子或烷基； R 1Q is selected from a hydrogen atom or an alkyl group;
R11或 R12各自独立地选自氢原子、 烷基、 烷氧基、 羟基或 -C(0)NR13R14， 其 中所述烷基或烷氧基任选进一步被一个或多个选自烷基、 羟烷基、 羟基、 烷氧基、 卤素、 硝基、 氰基或 -NR13R14的取代基所取代； 且 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;
R13或 R14各自独立地选自氢原子、 烷基或环烷基。 R 13 or R 14 are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group.
5、 根据权利要求 4所述的通式 (I)所示的化合物或其可药用盐， 其为通式 (IV) 所示的化合物或其可药用的盐：
Figure imgf000095_0001
The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, which is a compound of the formula (IV) or a pharmaceutically acceptable salt thereof:
Figure imgf000095_0001
其中， R4、 R11或 R12的定义如权利要求 4中所述。 Wherein R 4 , R 11 or R 12 are as defined in claim 4.
6、 根据权利要求 5所述的通式 (I)所示的化合物或其可药用盐， 其为通式 (IV)i 或通式 (IV)ii所
Figure imgf000095_0002
The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 5, which is of the formula (IV) i or the formula (IV) ii
Figure imgf000095_0002
(IV)i  (IV)i
其中， R4、 R11或 R12定义如权利要求 4中所述。 Wherein R 4 , R 11 or R 12 are as defined in claim 4.
7、 根据权利要求 1所述的通式（ I )所示的化合物或其可药用盐， 其中所述化  The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound
Figure imgf000095_0003
Figure imgf000095_0003
Figure imgf000096_0001
CT8.0/ZlOZN3/X3d 6669蒙 IOZ OAV
Figure imgf000096_0001
CT8.0/ZlOZN3/X3d 6669 Meng IOZ OAV
Figure imgf000097_0001
Figure imgf000097_0001
8、 一种根据权利要求 1所述的通式（ I )所示的化合物或其可药用盐的制备方 法， 其包括将通式 (IA)化合物与 R4H在碱性条件下进行反应， 得到通式（I)化合物 的步骤， A process for producing a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which comprises reacting a compound of the formula (IA) with R 4 H under basic conditions. a step of obtaining a compound of the formula (I),
Figure imgf000097_0002
Figure imgf000097_0002
(IA) (I) 其中， X选自卤素； 〜 3， 1^〜14的定义如权利要求 1中所述 (IA) (I) wherein X is selected from halogen; 〜 3 , 1^~1 4 is as defined in claim 1
9、 一种根据权利要求 1所述的通式（ I )所示的化合物或其可药用盐的制备方 法， 其包括将通式 (I A)化合物与 R4B(OH)2进行 Suzuki 偶联反应， 得到通式（ I )化 合物的步骤，
Figure imgf000098_0001
A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which comprises subjecting a compound of the formula (IA) to R 4 B(OH) 2 for Suzuki coupling. a step of obtaining a compound of the formula (I),
Figure imgf000098_0001
( IA ) ( I )  ( IA ) ( I )
其中， X选自卤素； 〜 3， Ri〜R4的定义如权利要求 1中所述 Wherein X is selected from halogen; 〜 3 , Ri~R 4 is as defined in claim 1.
10、 一种根据权利要求 1所述的通式（ I )所示的化合物或其可药用盐的制备方 法，其包括将通式 (IA)化合物与三丁基 (R4)锡烷进行反应，得到通式（I )化合物的步 骤， A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which comprises subjecting a compound of the formula (IA) with tributyl(R 4 )stannane. a step of obtaining a compound of the formula (I),
Figure imgf000098_0002
Figure imgf000098_0002
( IA ) ( I ) ( IA ) ( I )
其中， X选自卤素； X3, Ri〜R4的定义如权利要求 1中所述。 Wherein X is selected from halogen; X 3 , Ri~R 4 are as defined in claim 1.
11、 一种药物组合物， 所述药物组合物含有治疗有效量的根据权利要求 1 所 述的通式（ I )所示的化合物或其可药用盐， 以及一种或多种药学上可接受的载体或 赋形剂。 A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable salts Accepted carrier or excipient.
12、 根据权利要求 1所述的通式（I )所示的化合物或其可药用盐， 或根据权利 要求 11所述的药物组合物在制备抑制 mTOR和 /或 PI3K激酶的药物中的用途。 The use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 11, for the preparation of a medicament for inhibiting mTOR and/or PI3K kinase .
13、 根据权利要求 1所述的通式（I )所示的化合物或其可药用盐， 或根据权利 要求 11所述的药物组合物在制备治疗癌症或组织增生类疾病的药物中的用途， 其 中所述的癌症选自黑素瘤、 乳头状甲状腺肿瘤、 胆管癌、 结肠癌、 卵巢癌、 肺癌、 恶性淋巴肿瘤、 肝癌、 肾癌、 膀胱癌、 前列腺癌、 乳腺癌和胰腺癌和肉瘤， 以及 恶性胶质瘤、 皮肤癌、 结肠癌、 甲状腺癌、 肺癌和卵巢癌的原发和复发性实体瘤 或者白血病。 The use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 11, for the preparation of a medicament for the treatment of cancer or tissue hyperplasia The cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, liver cancer, kidney cancer, bladder cancer, prostate cancer, breast cancer, 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.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103588792A (en) * 2013-03-04 2014-02-19 中国科学院上海药物研究所 Pyridopyrimidine or pyrimidopyrimidine compound, its preparation method, pharmaceutical composition and use thereof
WO2016150396A1 (en) * 2015-03-25 2016-09-29 中国科学院上海药物研究所 Process of synthesizing substituted pyridine and pyrimidine compound
WO2022058344A1 (en) 2020-09-18 2022-03-24 Bayer Aktiengesellschaft Pyrido[2,3-d]pyrimidin-4-amines as sos1 inhibitors
EP4074317A1 (en) 2021-04-14 2022-10-19 Bayer AG Phosphorus derivatives as novel sos1 inhibitors
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 (en) 2022-09-16 2024-03-21 Bayer Aktiengesellschaft Sulfone-substituted pyrido[3,4-d]pyrimidine derivatives for the treatment of cancer
WO2024079252A1 (en) 2022-10-13 2024-04-18 Bayer Aktiengesellschaft Sos1 inhibitors
EP4161926A4 (en) * 2020-06-03 2024-06-19 Yumanity Therapeutics, Inc. Pyridopyrimidines and methods of their use
WO2025202022A1 (en) 2024-03-27 2025-10-02 Bayer Aktiengesellschaft Anticancer macrocyclic quinazoline-based inhibitors of the ineraction between ras and sos1

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104557913B (en) * 2013-10-28 2017-02-08 上海汇伦生命科技有限公司 Pyridopyrimidine compounds as well as preparation method and application thereof
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 (en) * 2003-09-12 2005-03-24 4 Aza Bioscience Nv PTERIDINE DERIVATIVES FOR THE TREATMENT OF SEPTIC SHOCK AND TNF-α-RELATED DISEASES.
WO2006135993A1 (en) * 2005-06-24 2006-12-28 Gilead Sciences, Inc. Pyrido(3,2-d)pyrimidines and pharmaceutical compositions useful for treating hepatitis c.
US20080194546A1 (en) * 2005-11-22 2008-08-14 Kudos Pharmaceuticals Limited Pyrido-, Pyrazo- and Pyrimido-Pyrimidine Derivatives as mTOR Inhibitors
WO2009107767A1 (en) * 2008-02-29 2009-09-03 大日本住友製薬株式会社 Novel bicyclic pyrimidine derivative having antagonistic activity on h4 receptor

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5667086B2 (en) * 2009-02-12 2015-02-12 メルク セローノ ソシエテ アノニム 2-morpholino-pyrido [3,2-d] pyrimidine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005025574A2 (en) * 2003-09-12 2005-03-24 4 Aza Bioscience Nv PTERIDINE DERIVATIVES FOR THE TREATMENT OF SEPTIC SHOCK AND TNF-α-RELATED DISEASES.
WO2006135993A1 (en) * 2005-06-24 2006-12-28 Gilead Sciences, Inc. Pyrido(3,2-d)pyrimidines and pharmaceutical compositions useful for treating hepatitis c.
US20080194546A1 (en) * 2005-11-22 2008-08-14 Kudos Pharmaceuticals Limited Pyrido-, Pyrazo- and Pyrimido-Pyrimidine Derivatives as mTOR Inhibitors
WO2009107767A1 (en) * 2008-02-29 2009-09-03 大日本住友製薬株式会社 Novel bicyclic pyrimidine derivative having antagonistic activity on h4 receptor

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014135028A1 (en) * 2013-03-04 2014-09-12 中国科学院上海药物研究所 Pyridopyrimidine or pyrimidopyrimidine compound, preparation method, pharmaceutical composition and use thereof
JP2016510042A (en) * 2013-03-04 2016-04-04 中国科学院上▲海▼▲藥▼物研究所 Pyridopyrimidine or pyrimidopyrimidine compounds, production method thereof, pharmaceutical composition and use thereof
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 (en) * 2013-03-04 2018-07-27 Шанхай Инститьют Оф Материа Медика, Чайниз Академи Оф Сайенсиз Pyridopyrimidine compound, method for production, pharmaceutical composition and application of indicated compounds
CN103588792A (en) * 2013-03-04 2014-02-19 中国科学院上海药物研究所 Pyridopyrimidine or pyrimidopyrimidine compound, its preparation method, pharmaceutical composition and use thereof
WO2016150396A1 (en) * 2015-03-25 2016-09-29 中国科学院上海药物研究所 Process of synthesizing substituted pyridine and pyrimidine compound
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 (en) * 2020-06-03 2024-06-19 Yumanity Therapeutics, Inc. Pyridopyrimidines and methods of their use
WO2022058344A1 (en) 2020-09-18 2022-03-24 Bayer Aktiengesellschaft Pyrido[2,3-d]pyrimidin-4-amines as sos1 inhibitors
WO2022219035A1 (en) 2021-04-14 2022-10-20 Bayer Aktiengesellschaft Phosphorus derivatives as novel sos1 inhibitors
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