WO2014090147A1 - Dérivés de pyrimidine et leurs sels, leur procédé de préparation et leur utilisation pharmaceutique - Google Patents

Dérivés de pyrimidine et leurs sels, leur procédé de préparation et leur utilisation pharmaceutique Download PDF

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WO2014090147A1
WO2014090147A1 PCT/CN2013/089038 CN2013089038W WO2014090147A1 WO 2014090147 A1 WO2014090147 A1 WO 2014090147A1 CN 2013089038 W CN2013089038 W CN 2013089038W WO 2014090147 A1 WO2014090147 A1 WO 2014090147A1
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group
meso
tautomer
racemate
enantiomer
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PCT/CN2013/089038
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English (en)
Chinese (zh)
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李心
孙飘扬
王少宝
刘宪波
王斌
董庆
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上海恒瑞医药有限公司
江苏恒瑞医药股份有限公司
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Priority to CN201380021201.3A priority Critical patent/CN104245693B/zh
Publication of WO2014090147A1 publication Critical patent/WO2014090147A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to a novel pyrimidine 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 a PBK kinase inhibitor.
  • PBK phosphatidylinositol 3-kinase
  • mTOR rapamycin target
  • mTOR mammalian target of rapamycin
  • mTOR inhibitors themselves are immunosuppressants, one of the side effects. It is the infection that causes great harm to the lungs (Peter Neuhaus et al., Liver Transplantation, 2001, 7(6), 473-384).
  • the PI3K-AKT pathway As one of the most important signaling pathways, the PI3K-AKT pathway has become the preferred target for tumor drug development.
  • PI3K-AKT pathway As a key signaling pathway in the cell, PI3K-AKT pathway is involved in the fine regulation of multiple processes such as cell periodic growth, protein synthesis, energy metabolism and survival and apoptosis through activation of various receptor signals.
  • Phosphatidylinositide 3-kinase belonging to the family of lipid kinases, can be classified into three classes according to their structural characteristics and substrate selectivity. Among them, the most important class 1 PBK is the heterodimeric protein, which is composed of catalytic subunits ( ⁇ 110 ⁇ , ⁇ 110 ⁇ , ⁇ 100 ⁇ and ⁇ ) and subunits with regulatory functions ( ⁇ 85 ⁇ , ⁇ 85 ⁇ , ⁇ 50 ⁇ , ⁇ 55 ⁇ and ⁇ 55 ⁇ ) constitute.
  • the la-type PI3K enzyme subunits ⁇ ⁇ and ⁇ ⁇ are co-expressed in various cell types, while ⁇ expression is more restricted by leukocyte colonies and certain epithelial cells.
  • the lb-type PBK enzyme consists of a pl lO ⁇ catalytic subunit that interacts with the plOl regulatory subunit, and is mainly distributed in leukocytes, platelets, and cardiomyocytes.
  • the ⁇ 85 regulatory subunit is activated by phosphorylation by interaction with a receptor tyrosine kinase, and its amino terminus contains an SH3 domain and a proline-rich region capable of binding to the SH3 domain, and its carboxy terminus contains two
  • the alcohol diphosphate (PI2P) is converted to phosphatidylinositol triphosphate (PI3P), which in turn can further activate multiple downstream signaling molecules
  • the la-type PI3K enzyme can directly or indirectly promote human cancer (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501).
  • the gene PIK3CA is extensively amplified or mutated in various cancers, and the activating mutations in the catalytic sites of the encoded ⁇ ⁇ subtype are associated with various other tumors such as the colorectal site and tumors of the breast and lung.
  • the expression of ⁇ in severe epithelial ovarian cancer, breast cancer, and sputum-deficient tumor cell lines is nearly 5% amplified.
  • ⁇ is associated with immunosuppression and is commonly used in transplant rejection and autoimmune diseases.
  • la-type PBK can indirectly cause tumors to be triggered by a variety of downstream signaling events. For example, by activating Akt, an increase in the effects of PBK-mediated signaling events leads to various cancers. Numerous studies have shown that different PI3K subtypes have different division of labor. The best way to inhibit the growth of malignant cells is to select inhibitors that are more specific for a certain plOO subtype than to inhibit all type I PI3K enzymes (Susan and Kenneth, Cancer Treatment Reviews, 2013 Aug 26. pii: S0305-7372(13) 00171-0).
  • PBKa selective inhibitors are also the most potent inhibitors of tumor suppressive effects.
  • ⁇ 3 ⁇ selective inhibitors can also avoid side effects such as pneumonia, neutropenia, thrombocytopenia, anemia, elevated transaminase, etc. due to ⁇ 3 ⁇ and PI3Kd inhibitors (Brana and Siu, BMC Medicine, 2012, 10: 161).
  • AKT also known as Protein Kinase B
  • AKT is located in the cytoplasm and is in an inactive state.
  • AKT is phosphorylated by PBK activation and recruited to the cytoplasmic membrane and translocated to the cytosol or nucleus. It promotes the phosphorylation of serine and threonine at specific parts of the substrate protein, and completes the regulation of processes such as protein synthesis and cell proliferation.
  • PBK As a key regulatory pathway of cell function, PBK is closely related to the activation of proto-oncogenes and has a critical impact on the occurrence and development of tumors.
  • PBK regulatory protein PTEN abnormality, AKT overexpression or excessive activation can cause persistent activated PBK signal.
  • These mutations are ubiquitous in a variety of solid tumors, such as breast cancer, lung cancer, colon cancer, pancreatic cancer, liver cancer, digestive tract tumors, etc., and are closely related to treatment tolerance and poor prognosis. Therefore, it can be expected that the inhibition of PBK by developing small molecule compounds has a good development prospect as a tumor therapeutic drug.
  • PBK inhibitor BKM-120 developed by Novartis
  • BYL-719 developed by Novartis for the treatment of solid tumors, head and neck cancer
  • a series of patent applications for PI3K inhibitors are currently disclosed, including WO2007084786, WO2009080694, WO2004048365.
  • the present invention provides a novel structure of ⁇ 3 ⁇ kinase inhibitor which has no inhibitory effect on mTOR kinase and which has been found to have excellent activity and exhibit excellent anti-tumor cell proliferation. Summary of the invention
  • the object of the present invention is to provide a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair, and a pharmaceutically acceptable salt thereof:
  • Ring A is a monocyclic heteroaryl group
  • Ring B is a saturated cycloalkyl or heterocyclic group
  • L is a bond or an oxygen atom
  • R 1 is an alkyl group
  • R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyl group, a halogen, an alkoxy group, a nitro group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0)NR 5 R 6 , C(0)R 7 , -C(0)OR 7 , -NHC(0)NR 5 R 6 or -NR 5 R 6 ;
  • R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, a cyano group, an aryl group, a heteroaryl group, -OR 5 or -NR 5 R 6 , wherein the alkyl group, An alkoxy, aryl or heteroaryl group optionally further substituted with one or more substituents selected from alkyl, halo, cyano, amino, hydroxy, alkenyl, alkynyl, carboxy or carboxylate groups; And
  • R 5 , R 6 and R 7 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 hydroxy, alkyl, halo, alkoxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl or heteroaryl .
  • G is an oxygen atom or CCR 9 );
  • Ring A is a monocyclic heteroaryl group
  • R 1 is an alkyl group
  • R 2 is a hydrogen atom or an alkyl group
  • R 3 and R 4 are as described in the general formula (I);
  • R 8 and R 9 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, a cyano group, an aryl group, a heteroaryl group, -OR 5 or -NR 5 R 6 , wherein the alkyl group, The alkoxy, aryl or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of alkyl, halogen, cyano, amino, hydroxy, alkenyl, alkynyl, carboxy or carboxylate groups.
  • G, ring, R 2 to R 4 are as defined by the formula ( ⁇ ).
  • Ring A is a monocyclic heteroaryl group
  • Ring B is a saturated cycloalkyl or heterocyclic group
  • R 1 is an alkyl group
  • R 2 is a hydrogen atom or an alkyl group
  • R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group or an amino group, wherein the alkyl group is optionally further substituted with one or more halogens.
  • Ring, Ring ⁇ R 2 to R 4 are as defined in the formula (III). Further, in a preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form of the construct and a mixture thereof, and a pharmaceutically acceptable salt thereof, wherein R 1 is a methyl group.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention also provides a compound represented by the formula ( ⁇ - ⁇ ) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer
  • the ring 3, L, 1 ⁇ is as defined in the formula (I), and X is a halogen.
  • the present invention also provides a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer and a mixture thereof. And methods of pharmaceutically acceptable salts thereof, the method comprising:
  • the compound of the formula (I) is obtained by coupling a compound of the formula (I-A) with a boron or a boronic acid substituted with a ring A under basic conditions to obtain a compound of the formula (I).
  • X is a halogen
  • the ring, ring 3, L, ⁇ 4 are as defined in the formula (I).
  • 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.
  • the invention further relates to a compound of the formula (I) or a tautomer thereof, a mesogen, a racemic form , pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, in the preparation of a therapeutic protein tyrosine kinase mediated disease, particularly PBK kinase
  • a compound of the formula (I) or a tautomer thereof a mesogen, a racemic form , pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, in the preparation of a therapeutic protein tyrosine kinase mediated disease, particularly PBK kinase
  • PBK kinase a therapeutic protein tyrosine kinase mediated disease
  • drugs that mediate diseases.
  • the present invention further relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof and a mixture thereof, and Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting PI3K-kinase.
  • the present invention further relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof and a mixture thereof, and Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating a cancer or a tissue hyperplasia, wherein the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovary Cancer, endometrial cancer, cervical cancer, lung cancer, esophageal cancer, brain cancer, malignant lymphoma, liver, stomach, kidney, bladder, prostate, breast and pancreatic cancer and sarcoma, as well as skin, colon, thyroid, lung and Primary and recurrent solid tumors of the ovary or leukemia, head and neck cancer, glioma, glioblastoma, preferably breast cancer.
  • the cancer is selected from the group consist
  • the invention also relates to a method of treating a protein tyrosine kinase mediated disease, in particular a PBK kinase mediated disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or Isomers, meso forms, racemates, enantiomers, diastereomers and mixtures thereof, and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.
  • a protein tyrosine kinase mediated disease in particular a PBK kinase mediated disease
  • the invention also relates to a method of inhibiting PI3K kinase activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, a mesogen, a racemate thereof, Enantiomers, diastereomers, and mixtures thereof, and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.
  • the present invention relates to a method for treating a cancer or a tissue hyperplasia comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, or an external a racemate, an enantiomer, a diastereomer, and mixtures thereof, and 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 Cancer, cholangiocarcinoma, colon cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, esophageal cancer, brain cancer, malignant lymphoma, liver, stomach, kidney, bladder, prostate, breast and pancreatic cancer and sarcoma, And primary and recurrent solid tumors of the skin, colon, thyroid, lung and ovary or leukemia, head and neck cancer, glioma, glioblastoma,
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesogen thereof, or a compound thereof, which is a drug for treating a protein tyrosine kinase-mediated disease, particularly a PBK kinase-mediated disease. a racemate, an enantiomer, a diastereomer, and mixtures thereof, and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof as a drug which inhibits the activity of PI3K kinase. And mixtures thereof, and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.
  • the present invention also relates to a compound represented by the general formula (I) as a medicament for treating cancer or a tissue hyperplasia-like disease.
  • the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, esophageal cancer, brain cancer, malignant lymphoma, liver, stomach , kidney, bladder, prostate, breast and pancreatic cancers and sarcomas, as well as primary and recurrent solid tumors of the skin, colon, thyroid, lungs and ovaries or leukemia, head and neck cancer, glioma, glioblastoma, Preferred is breast cancer.
  • 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.
  • the oil suspensions may contain a thickening agent, 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 alpha-tocopherol.
  • Dispersible powders and granules suitable for the preparation of water suspensions can be provided by the addition of water to provide active ingredients and A mixed dispersing 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 sweetening, flavoring, and coloring agents can also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be 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.
  • 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 composition 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.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension 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 injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution prepared in 1,3-butanediol.
  • sterile fixed oils can be conveniently employed as a solvent or suspension 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 compounds of the invention may 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.
  • 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 means a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. Excellent An alkyl group having 1 to 10 carbon atoms is selected, and an alkyl group having 1 to 6 carbon atoms is more preferred.
  • 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,
  • 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, U-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3- Methyl butyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl Base, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 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 alkyl, alkenyl, Alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycle Alkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, 3 ⁇ 4 alkyl, hydroxyalkyl, carboxyl or carboxylate.
  • alkenyl refers to an alkyl radical 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 3- Butyl group and the like.
  • P 2 _ 1Q alkenyl is preferred, C 2 -6 alkenyl is more preferred, and C 2 _ 4 alkenyl is most preferred.
  • 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, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxy or carboxylate groups.
  • alkynyl 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 ethynyl, 1-propynyl, 2-propynyl, 1-, 2- Or 3-butynyl and the like.
  • C 2 _ 1Q alkynyl group more preferably C 2 _ 6 alkynyl group, most preferably C 2 _ 4 alkynyl group.
  • the alkynyl 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, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxy or carboxylate groups.
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises from 3 to 10 The carbon atom, most preferably the cycloalkyl ring contains from 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • 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 alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, oxo, amino, 3 ⁇ 4 alkyl, hydroxyalkyl, carboxy or carboxylate.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(0) m ( Wherein m is a hetero atom of the integer 0 to 2), but does not include a ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon. It preferably includes 3 to 12 ring atoms, of which 1 to 4 are hetero atoms, more preferably the heterocyclic ring contains 3 to 10 ring atoms, and more preferably the heterocyclic ring contains 5 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
  • the polycyclic heterocyclic group includes a spiro ring, a fused ring, and a heterocyclic group of a bridged ring.
  • 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 alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, 3 ⁇ 4, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxy or carboxylate.
  • the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, 3 ⁇ 4, thiol, hydroxy, nitro, cyano, cycloal
  • Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring sharing a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, more preferably benzene.
  • the phenyl group is most preferred.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the parent structure is attached to
  • 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, alkynyl, alkoxy, alkylthio, alkane. Amino, 3 ⁇ 4, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, an amino group, a halogenated alkyl group, a hydroxyalkyl group, a carboxyl group or a carboxylate group.
  • “Monocyclic heteroaryl” refers to a heteroaromatic system containing from 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 5 to 10 yuan.
  • the heteroaryl group is preferably a 5- or 6-membered single ring.
  • a heteroaryl group such as thiazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc., preferably pyridyl or Pyrimidinyl.
  • 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, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxy or carboxylate groups.
  • the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl
  • Alkoxy means -0-(alkyl) and -0-(unsubstituted cycloalkyl), wherein alkyl, cycloalkyl are as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • 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, an alkynyl group, an alkoxy group, and an alkane group.
  • a “key” refers to a covalent bond represented by "one”.
  • Haloalkyl means an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • Hydrogens means an -OH group.
  • Hydroalkyl means an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Amino means -NH 2 .
  • Neitro means -N0 2 .
  • Benzyl means -C3 ⁇ 4-phenyl.
  • Carboxy means -C(0)OH.
  • the "carboxylate group” means -C(0)0(fluorenyl) or (cycloalkyl), wherein the alkyl group and the cycloalkyl group are as defined above.
  • amino protecting group is such that the amino group remains unchanged in the reaction of other parts of the molecule, and the amino group is protected by a group which is easily removed.
  • Non-limiting examples include formyl, alkylcarbonyl, alkoxycarbonyl, benzoyl, aralkylcarbonyl, aralkoxycarbonyl, trityl, phthaloyl, anthracene, fluorene-dimethyl Aminoaminomethylene, substituted silyl, and the like. These groups may be optionally substituted with from 1 to 3 substituents selected from halogen, alkoxy or nitro.
  • the amino protecting group is preferably a tert-butoxycarbonyl group.
  • 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 refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their The possible chemical positions, 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. Synthetic method of the present invention
  • a preparation of a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer and a mixture thereof, and a pharmaceutically acceptable salt thereof Method includes:
  • 2,4,6-trihalopyrimidine (a) and ring B compound (b) are reacted in a solvent under basic conditions to obtain a dihalopyrimidine compound (c), a dihalopyrimidine compound (c) and a substituted morphine
  • the porphyrin compound is reacted in a solvent under basic conditions to obtain a morpholine-substituted pyrimidine compound (IA); or the morpholine-substituted dihalopyrimidine compound (d) is reacted with the ring B compound (b) in a solvent under basic conditions.
  • a morpholine-substituted pyrimidine compound (IA); a morpholine-substituted pyrimidine compound (IA) and a cyclic A-substituted borate or boric acid are subjected to a catalyst-catalyzed coupling reaction in a solvent under basic conditions to obtain a formula (I). ) compound.
  • X is a halogen; the ring, ring L, Ri ⁇ R 4 are as defined in the compound of formula (;I).
  • the alkaline condition reagent includes an organic base and an inorganic base, and the organic base includes, but not limited to, hydrazine, hydrazine-diisopropylethylamine, triethylamine, n-butyllithium or potassium t-butoxide.
  • Inorganic bases include, but are not limited to, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or sodium hydride.
  • Catalysts include, but are not limited to, bis(triphenylphosphine)palladium dichloride, [ ⁇ , ⁇ -bis(diphenylphosphino)ferrocene] palladium dichloride, tetra-triphenylphosphine palladium, palladium dichloride , palladium acetate or tris(dibenzylideneacetone) dipalladium.
  • Solvents used include, but are not limited to: N-methylpyrrolidone, tetrahydrofuran, methanol, ethanol, ethylene glycol dimethyl ether, water, acetonitrile, dichloromethane, 1,4-dioxane, dimethyl sulfoxide or hydrazine , ⁇ -dimethylformamide.
  • a compound represented by the formula ( ⁇ ) or a tautomer, a mesogen, a racemate, an enantiomer A method of isomers, diastereomers, and mixed salts thereof, the method comprising:
  • the alkaline condition reagent includes an organic base and an inorganic base, and the organic base includes, but not limited to, hydrazine, hydrazine-diisopropylethylamine, triethylamine, n-butyllithium or potassium t-butoxide.
  • Inorganic bases include, but are not limited to, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or sodium hydride.
  • Catalysts include, but are not limited to, bis(triphenylphosphine)palladium dichloride, [ ⁇ , ⁇ -bis(diphenylphosphino)ferrocene] palladium dichloride, tetra-triphenylphosphine palladium, palladium dichloride , palladium acetate or tris(dibenzylideneacetone) dipalladium.
  • Solvents used include, but are not limited to: N-methylpyrrolidone, tetrahydrofuran, methanol, ethanol, ethylene glycol dimethyl ether, water, acetonitrile, dichloromethane, 1,4-dioxane, dimethyl sulfoxide or hydrazine , ⁇ -dimethylformamide.
  • a preparation of a compound of the formula (A) or a tautomer, a mesogen, a racemate, an enantiomer, a conformation, and a mixture thereof, and a pharmaceutically acceptable salt thereof Method includes:
  • the alkaline condition reagent includes an organic base and an inorganic base, and the organic base includes, but not limited to, hydrazine, hydrazine-diisopropylethylamine, triethylamine, n-butyllithium or potassium t-butoxide.
  • Inorganic bases include, but are not limited to, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or sodium hydride.
  • Catalysts include, but are not limited to, bis(triphenylphosphine)palladium dichloride, [ ⁇ , ⁇ -bis(diphenylphosphino)ferrocene] palladium dichloride, tetra-triphenylphosphine palladium, palladium dichloride , palladium acetate or tris(dibenzylideneacetone) dipalladium.
  • Solvents used include, but are not limited to: N-methylpyrrolidone, tetrahydrofuran, methanol, ethanol, ethylene glycol dimethyl ether, water, acetonitrile, dichloromethane, 1,4-dioxane, dimethyl sulfoxide or hydrazine , ⁇ -dimethylformamide. detailed description
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the measurement of the MS was performed using a FINMGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX) 0
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the average inhibition rate of the kinase and the IC 5Q value were determined using a NovoStar plate reader (BMG, Germany).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm ⁇ 0.2 mm, and the thin layer chromatography separation and purification product adopts a specification of 0.9 mm. ⁇ 1.0 mm.
  • reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.
  • 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 3916EK hydrogenation apparatus and a clear blue QL-500 hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction was carried out using a CEM Discover-S Model 908860 microwave reactor.
  • 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 system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • Purification compounds using column chromatography eluent systems and thin layer chromatography developers include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone The system, D: is a n-hexane and acetone system, and the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.
  • A dichloromethane and methanol systems
  • B n-hexane and ethyl acetate systems
  • C dichloromethane and acetone
  • D is a n-hexane and acetone system
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine
  • 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane)pyrimidine-2-amine dissolves 5-bromopyrimidin-2-amine (3.48 g, 20 mmol)
  • 4-4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxo) was added in sequence.
  • 2,6-bis "5 3-methylmorpholine"-[4,5'-bipyrimidine]-2'-amine will (3 & 3'5 4,4'-(6-chloropyrimidine-2,4 -diyl) bis(3-methylmorpholine) la (200 mg, 0.64 mmol) dissolved in N,N-dimethylformamide and water, followed by 5-(4,4,5,5-tetramethyl Base-1,3,2-dioxaborane)pyrimidine-2-amine lb (212 mg, 0.96 mmol), bis(triphenylphosphine)palladium dichloride (45 mg, 0.06 mmol) and potassium carbonate ( 178 mg, 1.28 mmol), three times with argon, and reacted at 90 ° C for 12 hours.
  • 2,4,6-Trichloropyrimidine 500 mg, 2.73 mmol was dissolved in 30 mL of ethanol and N,N-diisopropylethylamine (2 mL, 10.92 mmol) was added. Place in an ice water bath, slowly add (7?)-3-methylmorpholine (935 mg, 6.83 mmol), and raise to 65 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj Morpholine 2a (550 mg, white solid), Yield: 81.2%.
  • EtOAc EtOAc
  • Test Example 1 Determination of PI3K kinase activity by the compounds of the present invention
  • PI3K kinase used in this experiment: PI3K-alpha ( ⁇ 3 ⁇ - ⁇ , Invitrogen, Cat. No. PV4788), PBK-beta ( ⁇ 3 ⁇ - ⁇ , Carna, Cat. No. 11-102), PBK-delta (PI3K-, Invitrogen, Cat. No. PV 5273) , PBK-gamma (PI3K-, Invitrogen, item number PV4786).
  • the in vitro cell assay described below can determine the proliferation inhibitory activity of the test compound against PBK kinase, and the test compound is dissolved in dimethyl sulfoxide according to the concentration required for the experiment.
  • ATP was diluted with lx buffer to give a 10 ⁇ ATP solution.
  • biochemical inhibitory activities of the PI3K kinases ( ⁇ - ⁇ , ⁇ - ⁇ , ⁇ 3 ⁇ - ⁇ , and ⁇ 3 ⁇ - ⁇ ) of the compounds of the present invention were determined by the above tests, and the IC 5Q values measured are shown in Table 1.
  • the inhibitory effect on the activity of ⁇ 3 ⁇ kinase is weak, and the preferred compound of the present invention is selective for the inhibition of ⁇ 3 ⁇ -kinase ( ⁇ 3 ⁇ - ⁇ ).
  • the different isomers of the preferred compounds of the invention have a greater inhibitory activity against ⁇ kinase ( ⁇ 3 ⁇ -01), and the inhibitory activity of the compound of Example 3 on ⁇ - ⁇ is significantly higher than that of the compounds of Examples 2, 14 and 15;
  • the number of substituents on the morpholine ring of the inventive compound has a great influence on the selectivity of ⁇ kinase ( ⁇ - ⁇ ) inhibition, and the S-configuration of the two morpholine rings which are substituted by a methyl group to the ⁇ 3 ⁇ kinase ( ⁇ -
  • the selectivity of ⁇ ) inhibition was higher than that of a compound in which only one morpholine ring was substituted by a methyl group, and the compounds of Examples 3, 14 and 15 were significantly more selective for inhibition of ⁇ 3 ⁇ kinase ( ⁇ 3 ⁇ - ⁇ ) than the compound of Example 9.
  • Test Example 2 Determination of inhibition of mTOR kinase activity by the compound of the present invention
  • This experiment uses K-LISATM mTOR (Recombinant) Activity Kit, item number: CBA104, purchased from MERCK.
  • the in vitro cell assay described below can determine the inhibitory activity of the test compound on mTOR kinase.
  • the test compound is dissolved in dimethyl sulfoxide according to the concentration required for the experiment, and the substrate is coated on a microplate.
  • the appropriate amount of mTOR enzyme was mixed with lx buffer to a final concentration of 2 ng ⁇ L.
  • 50 ATP and DTT solutions were added to each microplate, 1 test compound DMSO solution (only 1 DMSO was added to the control and blank) and 50 ⁇ l of the above enzyme solution (only 50 ⁇ 1 buffer was added to the control).
  • the cells were incubated at 30 ° C for 45 minutes, washed with a washing solution, dried, and repeated 3 times.
  • the primary antibody was added and incubated for 1 hour. Wash the plate with washing solution, control dry, repeat 3 times, add secondary antibody, and incubate for 1 hour. Wash the plate with washing solution, control dry, repeat 3 times, add TMB, and develop color for 5 ⁇ 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 microplate reader.
  • the IC 5Q value of the compound can be calculated from the inhibition of the mTO activity of the test compound at various concentrations.
  • the biochemical activity of the compound of the present invention was measured by the above test, and the measured IC 5Q values are shown in Table 2.
  • the in vitro mutant ⁇ 3 ⁇ - ⁇ kinase activity was tested by the following method.
  • the mutant ⁇ 3 ⁇ - ⁇ kinase used in this experiment was PI3-Kinase (pll0a(H1047)/p85 a ), Cat. No.: 14-792; PI3 Kinase ( ⁇ 110 ⁇ ( ⁇ 545 ⁇ )/ ⁇ 85 ⁇ ), Cat. No.: 14-783; PI3-Kinase ( ⁇ 110 ⁇ ( ⁇ 542 ⁇ )/ ⁇ 85 ⁇ ), Item No.: 14-782, all purchased from millipore.
  • the in vitro cell assay described below can determine the proliferation inhibitory activity of the test compound against the mutant ⁇ - ⁇ kinase, and the test compound is dissolved in dimethyl sulfoxide according to the concentration required for the experiment.
  • Appropriate amount of PIP2:PS Lipid substrate (Invitrogen, Cat. No.
  • PV5100 mutant PI3K kinase ((pll0a(H1047R)/p85a), ( ⁇ 110 ⁇ ( ⁇ 545 ⁇ )/ ⁇ 85 ⁇ ), ⁇ 110 ⁇ ( ⁇ 542 ⁇ )/ ⁇ 85 ⁇ )) enzyme and lx buffer Liquid mixing.
  • 50 ⁇ of ATP solution was added to each EP tube, 1 test compound DMSO solution (only 1 pure DMSO was added to the control and blank) and 50 ⁇ of the above enzyme-substrate mixture (only 50 lx buffer was added to the control). After thoroughly mixing the tubes, they were incubated at 37 ° C for 45 minutes and then at 4 ° C for 10 minutes. For each concentration of the test compound and the control, two parallel holes were provided for each blank.
  • Preferred compounds of the invention have a significant inhibitory effect on mutant PBK-a kinase activity.
  • Test Example 4 Inhibition of proliferation of breast cancer cell line MCF-7 by the compound of the present invention
  • the in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound on a breast cancer cell line, and its 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.
  • 0.1 mL of blood was collected before administration and 0.5, 1, 2, 4, 6, 8, 11, 24, 48 hours after administration, placed in an EDTA anticoagulation tube, centrifuged at 3500 rpm for 10 minutes, and plasma was separated, at -20 °C save. Eat 2 hours after administration.
  • the content of the test compound in the plasma of rats after intragastric administration was determined by LC/MS/MS method.
  • the analytical method has a linear range of 1.00-2000 ng/mL and a lower limit of quantification of 1.00 ng/mL; plasma samples are pre-treated with precipitated proteins for analysis.
  • the pharmacokinetic parameters of the compounds of the invention are as follows:
  • the preferred compounds of the present invention have good pharmacological absorption and have obvious pharmacological absorption effects.

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Abstract

La présente invention concerne des dérivés de pyrimidine et leurs sels, un procédé de préparation et une utilisation pharmaceutique associés. Plus précisément, la présente invention concerne des dérivés de pyrimidine de formule générale (I), des sels pharmaceutiquement acceptables de ceux-ci, et les procédés de préparation de ceux-ci, ainsi que leur utilisation en tant qu'agent thérapeutique anticancéreux, en particulier leur utilisation en tant qu'inhibiteur de P13K kinase, chaque substitut de formule générale (I) étant défini tel que dans la description.
PCT/CN2013/089038 2012-12-14 2013-12-11 Dérivés de pyrimidine et leurs sels, leur procédé de préparation et leur utilisation pharmaceutique WO2014090147A1 (fr)

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WO2016095833A1 (fr) * 2014-12-17 2016-06-23 上海海雁医药科技有限公司 Dérivé de pyrimidine disubstitué en 2-morpholin-4,6 et procédé de préparation et utilisation pharmaceutique associés
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WO2017198347A1 (fr) * 2016-05-18 2017-11-23 Piqur Therapeutics Ag Traitement de lésions cutanées
CN108430987A (zh) * 2016-06-02 2018-08-21 上海海雁医药科技有限公司 Pi3k抑制剂及其药学上可接受的盐和多晶型物及其应用
IL263076A (en) * 2016-05-18 2018-12-31 Piqur Therapeutics Ag Treatment of skin lesions
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

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