WO2014090147A1 - 嘧啶类衍生物及其可药用盐、其制备方法及其在医药上的应用 - Google Patents
嘧啶类衍生物及其可药用盐、其制备方法及其在医药上的应用 Download PDFInfo
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- LVAJIFUDNIHRCD-UHFFFAOYSA-N tert-butyl 3-oxo-7-azaspiro[4.5]decane-7-carboxylate Chemical compound O=C1CC2(CC1)CN(CCC2)C(=O)OC(C)(C)C LVAJIFUDNIHRCD-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- KPZYAGQLBFUTMA-UHFFFAOYSA-K tripotassium;phosphate;trihydrate Chemical compound O.O.O.[K+].[K+].[K+].[O-]P([O-])([O-])=O KPZYAGQLBFUTMA-UHFFFAOYSA-K 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000002100 tumorsuppressive effect Effects 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
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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.
Abstract
本发明涉及嘧啶类衍生物及其可药用盐、其制备方法及其在医药上的应用。具体而言,本发明涉及一种通式( I )所示嘧啶类衍生物及其可药用盐,其制备方法以及它们作为癌症治疗剂特别是作为PI3K激酶抑制剂的用途,其中通式( I )中的各取代基的定义与说明书中的定义相同。
Description
嘧啶类衍生物及其可药用盐、 其制备方法及其在医药上的应用
技术领域
本发明涉及一种新型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 PBK激酶抑制剂的用途。 背景技术
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。研究发现, 由磷脂酰肌醇 3激酶 (PBK)— AKT—哺乳动 物雷帕霉素靶点 (mTOR) 介导的传导途径在一些细胞过程,包括增殖和存活中起重 要作用, 并且这些途径的失调是广泛种类的人类癌症和其它疾病谱的致病因素 ( Katso等, Annual Rev. Cell Dev.BioL, 2001 , 17: 615-617)。
哺乳动物雷帕霉素靶点蛋白 (mammalian target of rapamycin, mTOR)的主要作 用是调节蛋白的合成翻译, 因此成为肿瘤治疗的一个靶点, 然而 mTOR抑制剂本 身属于免疫抑制剂,其副作用之一就是引发感染,对肺部的伤害极大 (Peter Neuhaus 等, Liver Transplantation, 2001 ,7(6), 473-384)。
PI3K-AKT 通路作为最主要的信号通路之一, 已成为肿瘤药物开发的优选靶 标。
PI3K-AKT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。
磷脂酰肌醇 3激酶 (Phosphatidylinositide 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 PI3K为异二聚体蛋白,分别由具有催化功能的亚基 (ρ110α、 ρ110β、 ρ100δ 和 ρΙΟΟγ)和具有调节功能的亚基 (ρ85α、 ρ85β、 ρ50α、 ρ55α和 ρ55 γ)构成。 la型 PI3K 酶亚基 ρΐ ΐθα和 ρΐ ΐθβ均共同表达于各种细胞类型中,而 ρΙΟΟδ表达更是受到白细 胞群落和某些上皮细胞的限制。 lb型 PBK酶由与 plOl调节亚基相互作用的 pl lO γ 催化亚基组成, 主要分布在白细胞、 血小板和心肌细胞中。 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, 其氨基端含有 SH3结构域和能 与 SH3结构域结合的脯氨酸富集区, 其羧基端含有 2个 SH2结构域及 1个 plOO 结合的区域, plOO亚基与蛋白激酶具有同源性, 本身既具有丝氨酸 /苏氨酸蛋白激 酶的活性, 又具有磷脂酰肌醇激酶的活性, 可以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。
研究表明, la型 PI3K酶可以直接或间接地促使人类癌症发生 (Vivanco 和 Sawyers, Nature Reviews Cancer, 2002, 2, 489-501 )。 例如, 基因 PIK3CA在各种 癌症中广泛被放大或发生突变, 其编码的 ρΐ ΐθα亚型的催化位点中的激活突变与 各种其它的肿瘤如结肠直肠部位和乳腺和肺的肿瘤有关。 ΡΙΟΟβ在严重的上皮卵巢 癌、 乳腺癌以及 ΡΤΕΝ缺失的肿瘤细胞系中的表达均有近 5%的放大, ρΙΟΟδ与免 疫抑制有关, 常用于移植排斥和自身免疫性疾病当中。 除了直接的作用外, la型 PBK可间接地导致由各种下游信号传导事件从而引发肿瘤。 比如通过激活 Akt, PBK介导的信号传导事件的作用增加导致各种癌症。 大量研究表明, 不同 PI3K 亚型的分工不同, 抑制恶性细胞的生长最好的方法是选择对某种 plOO亚型特异性 更高的抑制剂而不是广泛抑制所有 I型 PI3K酶 (Susan和 Kenneth, Cancer Treatment Reviews, 2013 Aug 26. pii: S0305-7372(13) 00171-0)。 目前临床上非选择性 PBK抑 制剂已经观察到了不可避免的副作用,包括 PI3K抑制剂常见的恶心、呕吐、腹泻、 疲惫、 转氨酶升高、 高血糖症等。 在选择性 PBK抑制剂中, 由于 PIIGCA/pl lOa 是最常见的 PI3K突变亚型,所以 PBKa选择性抑制剂也是最有潜在抑瘤效果的抑 制剂。 同时, ΡΙ3Κα选择性抑制剂也可以最大程度的避免了临床上由于对 ΡΙ3Κβ 及 PI3Kd抑制剂所带来的肺炎、 嗜中性白血球减少症、 血小板减少、 贫血、 转氨 酶升高等副作用 (Brana和 Siu, BMC Medicine, 2012, 10: 161)。
AKT, 又被称为蛋白激酶 B (Protein Kinase B), 属于丝氨酸 (S473位点) /苏氨 酸 (T308位点)蛋白激酶, 是 PI3K主要的下游效应分子。 生理状态下, AKT位于 胞浆内, 处于失活状态, 当其暴露于各种剌激因素时, AKT被 PBK激活发生磷酸 化, 并募集至胞浆膜和转位到胞溶质或胞核, 促进底物蛋白特定部位的丝氨酸、 苏氨酸磷酸化, 完成对诸如蛋白质合成, 细胞增殖等过程的调节。
PBK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 PBK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 PBK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。 因此可以预期, 通过开发小分子化合物实现对 PBK的抑制作为 肿瘤治疗药物具有良好的开发前景。
对于 PBK信号通路而言, 目前已经有多个单独抑制 PBK活性的化合物处于 开发和临床试验阶段。如由 Novartis公司开发的 PBK抑制剂 BKM-120,现处于针 对乳腺癌的临床 ΠΙ期实验阶段。 另一个 PI3K抑制剂 BYL-719, 由 Novartis公司 开发用于治疗实体瘤、 头颈癌, 现也已处于临床 Π期阶段。 目前公开了一系列的 PI3K 抑制剂的专利申请, 其中包括 WO2007084786、 WO2009080694、 WO2004048365。
BKM-120
为了达到更好的肿瘤治疗效果的目的, 更好的满足市场需求, 我们希望能开 发出新一代的高效低毒的针对 PI3K信号通路的抑制剂, 特别作用于 ΡΙ3Κ-α的抑 制剂。本发明将提供一种新型结构的 ΡΙ3Κ激酶抑制剂,对 mTOR激酶无抑制作用, 并发现具有此类结构的化合物具有良好的活性, 并表现出优异的抗肿瘤细胞增殖 的作用。 发明内容
本发明的目的在于提供通式(I )所示的化合物或其互变异构体、 内消旋体、 外 消旋体、 对映异构体、 非对 , 及其可药用盐:
其中:
环 A为单环杂芳基;
环 B为饱和的环烷基或杂环基;
L为一个键或氧原子;
R1为烷基;
R2选自氢原子、 烷基、 羟基、 卤素、 烷氧基、 硝基、 氰基、 环烷基、 杂环基、 芳基、 杂芳基、 -C(0)NR5R6、 -C(0)R7、 -C(0)OR7、 -NHC(0)NR5R6或 -NR5R6;
R3和 R4各自独立地选自氢原子、 烷基、 烷氧基、 卤素、 羟基、 氰基、 芳基、 杂芳基、 -OR5或 -NR5R6, 其中所述烷基、 烷氧基、 芳基或杂芳基任选进一步被一 个或多个选自烷基、 卤素、 氰基、 氨基、 羟基、 烯基、 炔基、 羧基或羧酸酯基的 取代基所取代; 且
R5、 R6和 R7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羟 基、 烷基、 卤素、 烷氧基、 硝基、 氰基、 环烷基、 杂环基、 芳基或杂芳基的取代 基所取代。 在本发明一个优选的实施方案中,一种通式 (Π)所示的化合物或其互变异构体、
内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用 :
其中:
G为氧原子或 CCR 9);
环 A为单环杂芳基;
R1为烷基;
R2为氢原子或烷基;
R3和 R4如通式 (I)中所述; 且
R8和 R9各自独立地选自氢原子、 烷基、 烷氧基、 卤素、 羟基、 氰基、 芳基、 杂芳基、 -OR5或 -NR5R6, 其中所述烷基、 烷氧基、 芳基或杂芳基任选进一步被一 个或多个选自烷基、 卤素、 氰基、 氨基、 羟基、 烯基、 炔基、 羧基或羧酸酯基的 取代基所取代。 进一步,在本发明优选的实施方案中,一种通式 (ΠΑ)所示的化合物或其互变异 构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其 可药用盐,
其中: G、 环 、 R2〜R4如通式 (Π)所述。 在本发明另一优选的实施方案中, 一种通式 (ΠΙ)所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其可 药用盐:
其中:
环 A为单环杂芳基;
环 B为饱和的环烷基或杂环基;
R1为烷基;
R2为氢原子或烷基; 且
R3和 R4各自独立地选自氢原子、 烷基或氨基, 其中所述烷基任选进一步被一 个或多个卤素所取代。 进一步, 在本发明优选的实施方案中, 一种通式 (IIIA)所示的化合物或其互变 异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及 其可药用盐:
其中: 环 、 环^ R2〜R4如通式 (III)所述。 进一步, 在本发明优选的实施方案中, 一种通式(I )所示的化合物或其互变异 构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其 可药用盐, 所述的 R1为甲基。 进一步, 在本发明优选的实施方案中, 一种通式(I )所示的化合物或其互变异 构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其 可药用盐, 所述的环 A为吡啶基或嘧啶基。 进一步, 在本发明优选的实施方案中, 一种通式(I )所示的化合物或其互变异 构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其 可药用盐, 所述的 R2为垸基, 优选为甲基。
进一步, 在本发明优选的实施方案中, 一种通式(I )所示的化合物或其互变异 构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其 可药用盐, 所述的 R3和 R4各自独立地选自氢原子、 烷基、 卤代烷基或氨基。 本发明典型的化合物包括, 但不限于:
形式, 及其可药用盐。 本发明还提供一种通式 (Ι-Α)所示的化合物或其互变异构体、 内消旋体、 外消 旋体、 对映异构体、 非对映异构
( Ι-Α )
可作为合成通式 (I)所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异 构体、 非对映异构体及其混合物形式的中间体, 其中:
环3、 L、 1〜^的定义如通式 (I)中所述, X为卤素。 本发明还提供一种制备通式 (I)所示的化合物或其互变异构体、 内消旋体、 外 消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐的方法, 该 方法包括:
通式 (I-A)化合物与与环 A取代的硼酸酯或硼酸在碱性条件下, 经催化后进行 偶联反应得到通式( I )化合物,
其中: X为卤素; 环 、 环3、 L、 ^〜 4的定义如通式 (I)中所述。 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。
本发明进一步涉及通式 (I)所示的化合物或其互变异构体、 内消旋体、 外消旋
体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 或包含其的药 物组合物在制备治疗蛋白酪氨酸激酶介导的疾病, 特别是 PBK激酶介导的疾病的 药物中的用途。
本发明进一步涉及通式 (I)所示的化合物或其互变异构体、 内消旋体、 外消旋 体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 或包含其的药 物组合物在制备抑制 PI3K-激酶的药物中的用途。
本发明进一步涉及通式 (I)所示的化合物或其互变异构体、 内消旋体、 外消旋 体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 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、 ***状甲状腺肿瘤、 胆管癌、 结肠癌、 卵巢癌、 子宫内膜癌、 子宫颈 癌、 肺癌、 食道癌、 脑癌、 恶性淋巴肿瘤、 肝、 胃、 肾、 膀胱、 ***、 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、 头颈癌、 神经胶质瘤、 成胶质细胞瘤, 优选为乳腺癌。
本发明还涉及一种治疗蛋白酪氨酸激酶介导的疾病, 特别是 PBK激酶介导的 疾病的方法, 其包括给予所需患者治疗有效量的通式 (I) 所示的化合物或其互变 异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及 其可药用盐, 或包含其的药物组合物。
本发明还涉及一种抑制 PI3K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)所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 或包含其的药物组合物。
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) 所示的化合物或其互变异构体、 内消旋体、 外消旋 体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 或包含其的药 物组合物, 其中所述的癌症选自黑素瘤、 ***状甲状腺肿瘤、 胆管癌、 结肠癌、 卵巢癌、 子宫内膜癌、 子***、 肺癌、 食道癌、 脑癌、 恶性淋巴肿瘤、 肝、 胃、 肾、 膀胱、 ***、 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、 头颈癌、 神经胶质瘤、 成胶质细胞瘤, 优 选为乳腺癌。
本发明还涉及作为治疗蛋白酪氨酸激酶介导的疾病, 特别是 PBK激酶介导的 疾病的药物的通式 (I) 所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对 映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 或包含其的药物组合 物。
本发明还涉及作为抑制 PI3K激酶活性的药物的通式 (I) 所示的化合物或其 互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 或包含其的药物组合物。
本发明还涉及作为治疗癌症或组织增生类疾病的药物的通式 (I) 所示的化合
物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合 物形式, 及其可药用盐, 或包含其的药物组合物, 其中所述的癌症选自黑素瘤、 ***状甲状腺肿瘤、 胆管癌、 结肠癌、 卵巢癌、 子宫内膜癌、 子***、 肺癌、 食道癌、 脑癌、 恶性淋巴肿瘤、 肝、 胃、 肾、 膀胱、 ***、 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、 头颈癌、 神经胶质瘤、 成胶质细胞瘤, 优选为乳腺癌。
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***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。
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。
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***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缩合产物例如聚氧乙烯硬脂酸酯, 或环氧乙烷与长链脂肪醇 的缩合产物, 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缩合产物, 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缩合产物, 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、 一种或多种矫味剂和一种或多种甜味剂, 例如蔗糖、 糖精或阿司帕坦。
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矫味剂, 以提供可口的制剂。 可通过加入 抗氧化剂例如丁羟茴醚或 α -生育酚保存这些组合物。
通过加入水可使适用于制备水混悬也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、 矫味剂和着色剂。 通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。 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缩合产物, 例如聚环氧乙烷山梨醇单油酸酯。 乳剂也可以含有甜味剂、 矫味剂、 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。
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。
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。
可按用于直肠给药的栓剂形式给予本发明化合物。 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剌激 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。
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、 ***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, 否则下列用在说明书和权利要求书中的术语具有下述含义。 "烷基 "指饱和的脂族烃基团, 包括 1至 20个碳原子的直链和支链基团。 优
选含有 1至 10个碳原子的烷基, 更优选含有 1至 6个碳原子的烷基。 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、 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、 U-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 代的或未取代的, 当被取代时, 取代基可以在任何可使用的连接点上被取代, 优 选为一个或多个以下基团, 独立地选自烷基、 烯基、 炔基、 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、 氨基、 ¾代烷基、 羟烷 基、 羧基或羧酸酯基。
术语 "烯基"指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。 优选 C2_1Q烯基, 更 优选 C2_6烯基, 最优选 C2_4烯基。 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、 炔基、 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、 氨基、 卤代 烷基、 羟烷基、 羧基或羧酸酯基。
术语 "炔基"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, 例如乙炔基、 1-丙炔基、 2-丙炔基、 1-、 2-或 3-丁炔基等。 优选 C2_1Q炔基, 更优选 C2_6炔基, 最优选 C2_4炔基。 炔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、 炔基、 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、 氨基、 卤代 烷基、 羟烷基、 羧基或羧酸酯基。
"环烷基"指饱和或部分不饱和单环或多环环状烃取代基, 其包括 3至 20个 碳原子, 优选包括 3至 12个碳原子, 更优选环烷基环包含 3至 10个碳原子, 最 优选环烷基环包含 3至 6个碳原子。 单环环烷基的非限制性实施例包含环丙基、 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, 优选环丙基、 环己烯基。 多环环烷基包括螺环、 稠环和桥环的 环烷基。 环烷基可以是任选取代的或未取代的, 当被取代时, 取代基优选为一个 或多个以下基团, 独立地选自烷基、 烯基、 炔基、 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、 氨基、 ¾代烷基、 羟烷基、 羧基 或羧酸酯基。
"杂环基"指饱和或部分不饱和单环或多环环状烃取代基, 其包括 3至 20个 环原子, 其中一个或多个环原子选自氮、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。 优选包括 3至 12 个环原子, 其中 1〜4个是杂原子, 更优选杂环基环包含 3至 10个环原子, 更优 选杂环基环包含 5至 6个环原子。 单环杂环基的非限制性实施例包含吡咯烷基、 哌啶基、 哌嗪基、 吗啉基、 硫代吗啉基、 高哌嗪基、 吡喃基、 四氢呋喃基等。 多 环杂环基包括螺环、 稠环和桥环的杂环基。 杂环基可以是任选取代的或未取代的, 当被取代时, 取代基优选为一个或多个以下基团, 独立地选自烷基、 烯基、 炔基、 烷氧基、 烷硫基、 烷基氨基、 ¾素、 硫醇、 羟基、 硝基、 氰基、 环烷基、 杂环基、 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、 氨基、 卤代烷基、 羟烷基、 羧基或羧酸酯基。
"芳基"指具有共轭的 π电子体系的 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, 优选为 6至 10元, 更优选苯基和萘基, 最优选苯基。 所述芳基环可以稠合于杂芳基、 杂环基或环烷基环上, 其中与母体结构连接在一
芳基可以是取代的或未取代的, 当被取代时, 取代基优选为一个或多个以下基团, 独立地选自烷基、 烯基、 炔基、 烷氧基、 烷硫基、 烷基氨基、 ¾素、 硫醇、 羟基、 硝基、 氰基、 环烷基、 杂环基、 芳基、 杂芳基、 环烷氧基、 杂环烷氧基、 环烷硫 基、 杂环烷硫基、 氨基、 卤代烷基、 羟烷基、 羧基或羧酸酯基。
"单环杂芳基"指包含 1至 4个杂原子, 5至 14个环原子的杂芳族体系, 其 中杂原子包括氧、 硫和氮。 优选为 5至 10元。 杂芳基优选为是 5元或 6元的单环
杂芳基, 例如噻唑基、 吡唑基、 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, 优选吡啶基或嘧啶基。 杂芳基可以是 任选取代的或未取代的, 当被取代时, 取代基优选为一个或多个以下基团, 独立 地选自烷基、 烯基、 炔基、 烷氧基、 烷硫基、 烷基氨基、 卤素、 硫醇、 羟基、 硝 基、 氰基、 环烷基、 杂环基、 芳基、 杂芳基、 环烷氧基、 杂环烷氧基、 环烷硫基、 杂环烷硫基、 氨基、 卤代烷基、 羟烷基、 羧基或羧酸酯基。
"烷氧基"指 -0- (烷基)和 -0- (未取代的环烷基), 其中烷基、 环烷基的定义如 上所述。 非限制性实施例包含甲氧基、 乙氧基、 丙氧基、 丁氧基、 环丙氧基、 环 丁氧基、 环戊氧基、 环己氧基等。 烷氧基可以是任选取代的或未取代的, 当被取 代时, 取代基优选为一个或多个以下基团, 独立地选自为烷基、 烯基、 炔基、 烷 氧基、 烷硫基、 烷基氨基、 卤素、 硫醇、 羟基、 硝基、 氰基、 环烷基、 杂环基、 芳基、 杂芳基、 环烷氧基、 杂环烷氧基、 环烷硫基、 杂环烷硫基、 氨基、 ¾代烷 基、 羟烷基、 羧基或羧酸酯基。
一个 "键"指用 "一"表示的一个共价键。
"卤代烷基"指烷基被一个或多个卤素取代, 其中烷基的定义如上所述。 "羟基"指 -OH基团。
"羟烷基"指被羟基取代的烷基, 其中烷基的定义如上所述。
"卤素"指氟、 氯、 溴或碘。
"氨基"指 -NH2。
"氰基"指 -CN。
"硝基"指 -N02。
"苄基"指 -C¾-苯基。
"氧代基"指 =0。
"羧基"指 -C(0)OH。
"羧酸酯基"指 -C(0)0(焼基)或 (环烷基), 其中烷基、环烷基的定义如上所述。
"氨基保护基"是为了使分子其它部位进行反应时氨基保持不变, 用易于脱 去的基团对氨基进行保护。 非限制性实施例包含甲酰基、 烷基羰基、 烷氧基羰基、 苯甲酰基、 芳烷基羰基、 芳烷氧基羰基、 三苯甲基、 邻苯二甲酰基、 Ν,Ν-二甲基 氨基亚甲基、 取代的甲硅烷基等。 这些基团可任选地被选自卤素、 烷氧基或硝基 中的 1-3个取代基所取代。 氨基保护基优选为叔丁氧羰基。
"任选"或 "任选地"意味着随后所描述地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。
"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。
"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。 本发明的合成方法
为了完成本发明的合成目的, 本发明采用如下的合成技术方案:
一种制备通式 (I)所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映 异构 映异构体及其混合物形式, 及其可药用盐的方法, 该方法包括:
2,4,6-三卤代嘧啶 (a)与环 B 化合物 (b)在碱性条件下溶剂中反应得到二卤代嘧 啶化合物 (c), 二卤代嘧啶化合物 (c)与取代的***啉化合物在碱性条件下溶剂中反 应得到***啉取代的嘧啶化合物 (I-A); 或者***啉取代的二卤代嘧啶化合物 (d)与 环 B化合物 (b)在碱性条件下溶剂中反应得到***啉取代的嘧啶化合物 (I-A); *** 啉取代的嘧啶化合物 (I-A)与环 A取代的硼酸酯或硼酸在碱性条件下, 于溶剂中经 催化剂催化进行偶联反应得到通式(I )化合物。 其中 X为卤素; 环 、 环^ L、 Ri〜R4的定义如通式 (; I )化合物中所述。
碱性条件的试剂包括有机碱和无机碱类, 所述的有机碱类包括但不限于 Ν,Ν- 二异丙基乙胺、 三乙胺、 正丁基锂或叔丁醇钾, 所述的无机碱类包括但不限于碳 酸铯、 碳酸钾、 碳酸钠、 碳酸氢钠、 碳酸氢钾或氢化钠。
催化剂包括但不限于双 (三苯基膦)二氯化钯, [Ι,Γ-双 (二苯基膦)二茂铁]二氯化 钯, 四-三苯基膦钯、 二氯化钯、 醋酸钯或三 (二亚苄基丙酮)二钯。
所用溶剂包括但不限于: N-甲基吡咯烷酮、 四氢呋喃、 甲醇、 乙醇、 乙二醇 二甲醚、 水、 乙腈、 二氯甲烷、 1,4-二氧六环、 二甲基亚砜或 Ν,Ν-二甲基甲酰胺。
一种制备通式 (Π)所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映
异构体、 非对映异构体及其混 药用盐的方法, 该方法包括:
2,4,6-三卤代嘧啶 (a)与氮杂环化合物 (e)在碱性条件下溶剂中反应得到氮杂环 取代的二卤代嘧啶化合物 (f), 氮杂环取代的二卤代嘧啶化合物 (f)与取代的***啉 化合物在碱性条件下溶剂中反应得到***啉取代的嘧啶化合物 (Π-A); 或者***啉 取代的二卤代嘧啶化合物 (d)与氮杂环化合物 (e)在碱性条件下溶剂中反应得到*** 啉取代的嘧啶化合物 (Π-A); ***啉取代的嘧啶化合物 (Π-Α)与环 A取代的硼酸酯 或硼酸在碱性条件下, 于溶剂中经催化剂催化进行偶联反应得到通式( II )化合物。 其中 X为卤素; 环 、 G、 R^R4的定义如通式(Π )化合物中所述。
碱性条件的试剂包括有机碱和无机碱类, 所述的有机碱类包括但不限于 Ν,Ν- 二异丙基乙胺、 三乙胺、 正丁基锂或叔丁醇钾, 所述的无机碱类包括但不限于碳 酸铯、 碳酸钾、 碳酸钠、 碳酸氢钠、 碳酸氢钾或氢化钠。
催化剂包括但不限于双 (三苯基膦)二氯化钯, [Ι,Γ-双 (二苯基膦)二茂铁]二氯化 钯, 四-三苯基膦钯、 二氯化钯、 醋酸钯或三 (二亚苄基丙酮)二钯。
所用溶剂包括但不限于: N-甲基吡咯烷酮、 四氢呋喃、 甲醇、 乙醇、 乙二醇 二甲醚、 水、 乙腈、 二氯甲烷、 1,4-二氧六环、 二甲基亚砜或 Ν,Ν-二甲基甲酰胺。
( d )
2,4,6-三卤代嘧啶 (a)与羟基取代的环 B 化合物 (g)在碱性条件下溶剂中反应得 到二卤代嘧啶化合物 (h), 二卤代嘧啶化合物 (h)与取代的***啉化合物在碱性条件 下溶剂中反应得到***啉取代的嘧啶化合物 (ΠΙ-Α);或者***啉取代的二卤代嘧啶 化合物 (d)与羟基取代的环 B化合物 (g)在碱性条件下溶剂中反应得到***啉取代的 嘧啶化合物 (ΠΙ-Α); ***啉取代的嘧啶化合物 (ΙΠ-Α)与环 A取代的硼酸酯或硼酸在 碱性条件下, 于溶剂中经催化剂催化进行偶联反应得到通式( ΠΙ )化合物。 其中 X 为卤素; 环 、 环3、 1^〜1 4的定义如通式(111 )化合物中所述。
碱性条件的试剂包括有机碱和无机碱类, 所述的有机碱类包括但不限于 Ν,Ν- 二异丙基乙胺、 三乙胺、 正丁基锂或叔丁醇钾, 所述的无机碱类包括但不限于碳 酸铯、 碳酸钾、 碳酸钠、 碳酸氢钠、 碳酸氢钾或氢化钠。
催化剂包括但不限于双 (三苯基膦)二氯化钯, [Ι,Γ-双 (二苯基膦)二茂铁]二氯化 钯, 四-三苯基膦钯、 二氯化钯、 醋酸钯或三 (二亚苄基丙酮)二钯。
所用溶剂包括但不限于: N-甲基吡咯烷酮、 四氢呋喃、 甲醇、 乙醇、 乙二醇 二甲醚、 水、 乙腈、 二氯甲烷、 1,4-二氧六环、 二甲基亚砜或 Ν,Ν-二甲基甲酰胺。 具体实施方式
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。
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。 实施例
化合物的结构是通过核磁共振 (NMR)或 /和质谱 (MS)来确定的。 NMR位移 (δ) 以 10— 6 Cppm)的单位给出。 NMR的测定是用 Bruker AVANCE-400核磁仪, 测定溶 剂为氘代二甲基亚砜 (DMSO-d6), 氘代氯仿 (CDC13), 氘代甲醇 (CD3OD),内标为四 甲基硅烷 (TMS)。
MS的测定用 FINMGAN LCQAd (ESI)质谱仪 (生产商: Thermo, 型号: Finnigan LCQ advantage MAX)0
HPLC的测定使用安捷伦 1200DAD高压液相色谱仪 (Sunfire C18 150 <4.6mm色 谱柱)和 Waters 2695-2996高压液相色谱仪 (Gimini C18 150x4.6mm色谱柱)。
激酶平均抑制率及 IC5Q值的测定用 NovoStar酶标仪 (德国 BMG公司)。
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 (TLC)使用的硅胶板采用的规格是 0.15 mm〜0.2 mm, 薄层层析分离纯化产品采用 的规格是 0.9 mm〜1.0 mm。
柱层析一般使用烟台黄海硅胶 200〜300目硅胶为载体。
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,或可购买 自 ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, 韶远化学 科技 (Accela ChemBio Inc) 、 达瑞化学品等公司。
实施例中无特殊说明, 反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约 1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约 1L容积的氢气气球。
加压氢化反应使用 Parr 3916EK 型氢化仪和清蓝 QL-500 型氢气发生器或 HC2-SS型氢化仪。
氢化反应通常抽真空, 充入氢气, 反复操作 3次。
微波反应使用 CEM Discover-S 908860型微波反应器。
实施例中无特殊说明, 溶液是指水溶液。
实施例中无特殊说明, 反应的温度为室温, 为 20°C〜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: A: 二氯甲烷和甲醇体系, B: 正己烷和乙酸乙酯体系, C: 石油醚和乙 酸乙酯体系, D: 丙酮, 溶剂的体积比根据化合物的极性不同而进行调节。
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, D: 为正己烷和丙酮体系, 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和醋酸等碱性或酸性试剂进行调节。 实施例 1
'-联嘧啶 ]-2'-胺
第一步
(3 & 3'5 4,4'-(6-氯嘧啶 -2,4-二基)双 O甲基吗啉)
将 S 4-(2,6-二氯嘧啶 -4-基) -3-甲基吗啉 (200 mg, 0.81 mmol, 采用 "专利申请 WO2008032064"公开的方法制备而得)溶解于 3 mL乙醇中,加入 (5 3-甲基吗啉 (91 mg, 0.90 mmol)和 N,N-二异丙基乙胺 (0.5 mL, 2.43 mmol),于 65 °C下反应 12小时。 减压浓缩反应液, 加入 10 mL水, 用二氯甲烷萃取 (10 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, 减压浓缩滤液, 用薄层色 谱法以洗脱剂体系 A纯化所得残余物, 得到标题产物 (3 & 3'5 4,4'-(6-氯嘧啶 -2,4- 二基)双 (3-甲基吗啉) la (110 mg, 白色固体), 产率: 43.6%。
MS m/z (ESI): 313.2 [M+l]
第二步
5-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷)嘧啶 -2-胺 将 5-溴代嘧啶 -2-胺 (3.48 g, 20 mmol)溶解于 100 mL二氧六环中, 依次加入 4,4,4',4',5,5,5',5'-八甲基 -2,2'-双 (1,3,2-二氧杂硼烷 )(7.62 g, 30 mmol), [Ι,Γ-双 (二苯 基膦)二茂铁]二氯化钯 (500 mg, 2 mmol)和醋酸钾 (3.91 g, 40 mmol), 氩气置换三 次, 于 85 °C下反应 12小时。 过滤, 减压浓缩滤液, 用石油醚打浆所得残余物, 得 到粗品标题产物 5 4,4,5,5-四甲基 -1,3,2-二氧杂硼烷)嘧啶 -2-胺 lb (5.4 g, 白色固 体)。
MS m/z (ESI): 222.2 [M+l]
第三步
2,6-双《5 3-甲基吗啉) -[4,5'-联嘧啶 ]-2'-胺 将 (3 & 3'5 4,4'-(6-氯嘧啶 -2,4-二基)双 (3-甲基吗啉) la (200 mg, 0.64 mmol)溶解 于 N,N-二甲基甲酰胺和水中,依次加入 5-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷)嘧啶 -2- 胺 lb (212 mg, 0.96 mmol),双 (三苯基膦)二氯化钯 (45 mg, 0.06 mmol)和碳酸钾 (178 mg, 1.28 mmol), 氩气置换三次, 于 90°C下反应 12小时。 向反应液中加入 20 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 (20 mLx2), 无水硫酸钠干燥, 过滤, 减压浓缩滤液, 用薄层色谱法以洗脱剂体系 A纯化所得 残余物, 得到标题产物 2,6-双 C0S)-3-甲基吗啉) -[4,5'-联嘧啶 ]-2'-胺 1 (120 mg, 白色 固体), 产率: 50.6%。
MS m/z (ESI): 372.2 [M+l]
1H NM (400MHz, DMSO-t 6): δ 8.93 (s, 2H), 7.02(s, 2H), 6.54 (s, 1H), 4.64 (s, 1H), 4.45 (s, 1H), 4.30-4.32 (d, 1H), 4.21-4.23 (d, 1H), 3.91-3.94 (d, 2H), 3.66-3.70 (d, 2H), 3.56-3.59 (m, 2H), 3.42-3.46 (m, 2H), 3.07 (t, 2H), 1.14-1.16 (d, 6H) 实施例 2
5-(2,6-双 ((i?)-3-甲基吗啉)嘧啶 -4-基) -4- (三氟甲基)吡啶 -2-胺
(7?)-4-(2,6-二氯嘧啶 -4-基) -3-甲基吗啉
将 2,4,6-三氯嘧啶 (500 mg, 2.73 mmol)溶解于 30 mL乙醇中,加入 N,N-二异丙 基乙胺 (2 mL, 10.92 mmol)。置于冰水浴中, 缓慢加入 (7?)-3-甲基吗啉 (935 mg, 6.83 mmol), 升至 65 °C下反应 12小时。 减压浓缩反应液, 用薄层色谱法以洗脱剂体系 A 纯化所得残余物, 得到标题产物 (i?)-4-(2,6-二氯嘧啶 -4-基) -3-甲基吗啉 2a (550 mg, 白色固体), 产率: 81.2%。
MS m/z (ESI): 250.1 [M+l]
第二步
(3 ?,3'i?)-4,4'-(6-氯嘧啶 -2,4-二基)双 (3-甲基吗啉) 将 (i?)-4-(2,6-二氯嘧啶 -4-基) -3-甲基吗啉 2a (550 mg, 2.22 mmol)溶解于 10 mL N-甲基吡咯烷酮中, 加入 (i?)-3-甲基吗啉 (270 mg, 2.66 mmol)和碳酸铯 (1.4 g, 4.44 mmol), 升至 95 °C下反应 12小时。 向反应液中加入 20 mL水, 用乙酸乙酯萃取 (30 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, 减压浓缩滤液, 用薄层色谱法以洗脱剂体系 A 纯化所得残余物, 得到标题产物 (3 ?,3'i?)-4,4'-(6-氯嘧啶 -2,4-二基)双 (3-甲基吗啉) 2b (220 mg, 白色固体), 产率: 31.8%。
MS m/z (ESI): 313.2 [M+l]
第三步
5-(2,6-双 ((i?)-3-甲基吗啉)嘧啶 -4-基) -4- (三氟甲基)吡啶 -2-胺 将 (3 ?,3'i?)-4,4'-(6-氯嘧啶 -2,4-二基)双 (3-甲基吗啉) 2b (220 mg, 0.71 mmol)溶 解于 N,N-二甲基甲酰胺和水 (V/V=5: l)中, 依次加入 5-(4,4,5,5-四甲基 -1,3,2-二氧杂 硼烷 -2-基) -4- (三氟甲基)吡啶 -2-胺 2c (306 mg, 1.06 mmol , 采用 "专利申请 WO2007084786"公开的方法制备而得),双 (三苯基膦)二氯化钯 (50 mg, 0.07 mmol) 和碳酸钾 (196 mg, 1.42 mmol), 氩气置换三次, 于 95 °C下反应 12小时。 向反应液 中加入 20 mL水, 用乙酸乙酯萃取 (30 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, 减压浓缩滤液, 用薄层色谱法以洗脱剂体 系 A纯化所得残余物, 得到标题产物 5-(2,6-双 ((i?)-3-甲基吗啉)嘧啶 -4-基) -4- (三氟
甲基)吡啶 -2-胺 2 (80 mg, 白色固体), 产率: 25.8%。
MS m/z (ESI): 439.2 [M+l]
1H NM (400MHz, DMSO-t 6): δ 8.15 (s, IH) 6.80 (s, IH) 6.70 (s, 2H) 6.15 (s, IH) 4.57 (s, IH) 4.31 (s, IH) 4.18-4.21 (d, IH) 4.09-4.22 (d, IH) 3.89 (t, 2H) 3.69 (t, 2H) 3.42-3.47 (m, 2H) 3.33-3.38 (m, 2H) 3.02-3.06 (m, 2H) 1.14-1.16 (d, 6H) 实施例 3
5- 胺
1a 2c 3
第一步
5-(2,6-双 ((5 3-甲基吗啉)嘧啶 -4-基) -4- (三氟甲基)吡啶 -2-胺 将 (3 & 3'5 4,4'-(6-氯嘧啶 -2,4-二基)双 (3-甲基吗啉) la (160 mg, 0.51 mmol)溶解 于 N,N-二甲基甲酰胺和水 (V/V=15:7)中, 依次加入 5-(4,4,5,5-四甲基 -1,3,2-二氧杂 硼烷 -2-基) -4- (三氟甲基)吡啶 -2-胺 2c (221 mg, 0.77 mmol, 采用 "专利申请 WO2007084786"公开的方法制备而得),双 (三苯基膦)二氯化钯 (36 mg, 0.05 mmol) 和碳酸钾 (140 mg, 1.02 mmol), 氩气置换三次, 于 90°C下反应 12小时。 向反应液 中加入 20 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 (20 mLx2), 无水硫酸钠干燥, 过滤, 减压浓缩滤液, 用薄层色谱法以洗脱剂体 系 A纯化所得残余物, 得到标题产物 5-(2,6-双 ((5 3-甲基吗啉)嘧啶 -4-基) -4- (三氟 甲基)吡啶 -2-胺 3 (50 mg, 白色固体), 产率: 22.3%。
MS m/z (ESI): 439.2 [M+l]
1H NM (400MHz, DMSO-t 6): δ 8.15 (s, IH), 6.80 (s, IH), 6.71 (s, 2H), 6.15 (s, IH), 4.59 (s, IH), 4.32 (s, IH), 4.20-4.21 (d, IH), 4.07 (s, IH), 3.92 (t, 2H), 3.68 (t, 2H), 3.52-3.58 (m, 2H), 3.36-3.70 (m, 2H), 3.03-3.07 (m, 2H), 1.14-1.16 (d, 6H) 实施例 4
(5 l-(6-(6-氨基 -4- (三氟甲基)吡啶 -3-基) -2-(3-甲基吗啉)嘧啶 -4-基)哌啶 -4-醇
0S 1-C6-氯 -2-0甲基吗啉)嘧啶 -4-基)哌啶 -4-醇 将 0S)-4-(4,6-二氯嘧啶 -2-基) -3-甲基吗啉 4a(100 mg, 0.40 mmol, 采用 "专利申 请 WO2008032064"公开的方法制备而得), 4-羟基 -哌啶 (45 mg, 0.44 mmol)和碳 酸铯 (263 mg, 0.81 mmol)溶解于 3 mL N,N-二甲基甲酰胺中, 加热至 95°C, 搅拌反 应 12小时。 加入 20 mL 乙酸乙酯, 水相用乙酸乙酯萃取 (10 mLx3), 合并有机相, 用饱和氯化钠溶液洗涤 (30 mL), 无水硫酸镁干燥, 过滤, 减压浓缩滤液, 得到粗 品标题产物 (5 1-(6-氯 -2-(3-甲基吗啉)嘧啶 -4-基)哌啶 -4-醇 4b(0.13 g,黄色油状物), 产物不经纯化直接进行下一步反应。
MS m/z (ESI): 313.2 [M+l]
第二步
(5 l-(6-(6-氨基 -4- (三氟甲基)吡啶 -3-基) -2-(3-甲基吗啉)嘧啶 -4-基)哌啶 -4-醇 将粗品 (5 1-(6-氯 -2-(3-甲基吗啉)嘧啶 -4-基)哌啶 -4-醇 4b(130 mg, 0.40 mmol), 5-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基) -4- (三氟甲基)吡啶 -2-胺 2c(174 mg, 0.61 mmol), [Ι,Γ-双 (二苯基膦)二茂铁]二氯化钯 (29 mg, 0.04 mmol)和碳酸钠 (128 mg, 1.21 mmol)溶解于 6 mL N,N-二甲基甲酰胺和水 (V:V = 5:1)中, 加热至 90°C, 搅拌 反应 12小时。 加入 20 mL 乙酸乙酯, 水相用乙酸乙酯萃取 (10 mLx3), 合并有机 相, 用饱和氯化钠溶液洗涤 (30 mL), 无水硫酸镁干燥, 过滤, 减压浓缩滤液, 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)-1-(6-(6-氨基 -4- (三 氟甲基)吡啶 -3-基) -2-(3-甲基吗啉)嘧啶 -4-基)哌啶 -4-醇 4(10 mg, 黄色油状物), 产 率: 5.6%。
MS m/z (ESI): 439.2 [M+l]
1H NM (400MHz, CDC13): δ 8.17 (s, IH), 7.52-7.55 (m, IH), 6.82 (s, 2H), 6.53 (s, IH), 4.64 (s, IH), 4.45 (s, IH), 4.30-4.32 (m, IH), 4.21-4.23 (m, IH), 3.91-3.94 (m, 2H) 3.80-3.86 (m, 4H), 3.61-3.64 (m, 5H), 3.50-3.53 (m, 2H), 1.37 (d, 3H) 实施例
(5 4-(4-(2- (二氟甲基) -1H-苯并 [d]咪唑 -1-基) -6-吗啉嘧啶 -2-基) -3-甲基吗啉
(S)-4-(4-氯 -6-(2- (二氟甲基) - 1H-苯并 [d]咪唑- 1 -基)嘧啶 -2-基) -3-甲基吗啉 将 (5 4-(4,6-二氯嘧啶 -2-基) -3-甲基吗啉 4a(410 mg, 1.61 mmol), 2- (二氟甲 基) -1H-苯并 [d]咪唑 5a(324 mg, 1.94 mmol)和碳酸钠 (530 mg, 4.96 mmol)溶解于 10 mL二甲基乙酰胺中, 加热至 90°C, 搅拌反应 12小时。 加入 20 mL 乙酸乙酯, 水相用乙酸乙酯萃取 (10 mLx3), 合并有机相, 用饱和氯化钠溶液洗涤 (30 mL), 无 水硫酸镁干燥, 过滤, 减压浓缩滤液, 得到粗品标题产物 (S)-4-(4-氯 -6-(2- (二氟甲 基) -1H-苯并 [d]咪唑 -1-基)嘧啶 -2-基) -3-甲基吗啉 5b(0.70 g, 黄色油状物), 产物不 经纯化直接进行下一步反应。
MS m/z (ESI): 380.1 [M+l]
第二步
(5 4-(4-(2- (二氟甲基) -1H-苯并 [d]咪唑 -1-基) -6-吗啉嘧啶 -2-基) -3-甲基吗啉 将 (S)-4-(4-氯 -6-(2- (二氟甲基) -1H-苯并 [d]咪唑 -1-基)嘧啶 -2-基) -3-甲基吗啉 5b (700 mg, 1.61 mmol)和 5 mL吗啉溶解于 5 mL吡啶中, 加热至 120°C, 搅拌反应 4 小时。 减压浓缩反应液, 加入 20 mL 乙酸乙酯, 用饱和氯化铵溶液洗涤 (30 mL), 无水硫酸镁干燥, 过滤, 减压浓缩滤液, 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 4-(4-(2- (二氟甲基) -1H-苯并 [d]咪唑 -1-基) -6-吗啉嘧啶 -2- 基) -3-甲基吗啉 5(180 mg, 浅黄色固体), 产率: 26.0%。
MS m/z (ESI): 431.3 [M+l]
1H NM (400MHz, CDC13): δ 7.95 (s, 1H), 7.69 (s, 1H), 7.45 (s, 2H), 6.12 (s, 1H), 4.66-4.71 (m, 1H), 4.31-4.37 (dd, 1H), 4.00-4.05 (dd, 1H), 3.86 (m, 5H), 3.64-3.82 (m, 6H), 3.55-3.63 (m, 1H), 3.30-3.58 (m, 2H), 1.37 (d, 3H) 实施例 6
第一步
反式—4-羟基 -N,N-二甲基环己烷甲酰胺
将反式 -4-羟基环己烷甲酸 6a(500 mg, 3.47 mmol), 二甲基胺 (340 mg, 4.17 mmol), 1-乙基 -3-(3'-二甲氨基丙基)碳二亚胺盐酸盐 (1.33 g, 6.94 mmol)和 1-羟基苯 并*** (47 mg, 0.35 mmol)溶解于 11 mL三氟醋酸和二氯甲烷 (V:V = 1 : 10)中, 搅拌 反应 12小时。加入 5 mL水,减压浓缩反应液,得到粗品标题产物反式 -4-羟基 -N,N- 二甲基环己烷甲酰胺 6b(0.70 g, 浅黄色油状物), 产物不经纯化直接进行下一步反 应。
MS m/z (ESI): 172.2 [M+l]
第二步
反式 -4-(6-氯 -2-((5 3-甲基吗啉)嘧啶 -4-基氧基) -N,N-二甲基环己烷甲酰胺 将氢化钠 (24 mg, 0.60 mmol)溶解于 5 mL四氢呋喃中,冷却至 0°C,加入 2 mL 粗品反式 -4-羟基 -N,N-二甲基环己烷甲酰胺 6b(103 mg, 0.60 mmol)的四氢呋喃溶 液,搅拌 1小时,加入 (5 4-(4,6-二氯嘧啶 -2-基) -3-甲基吗啉 4a(100 mg, 0.40 mmol), 搅拌反应 12小时。 加入 5 mL水, 减压浓缩反应液, 得到粗品标题产物反式 -4-(6- 氯 -2-((5 3-甲基吗啉)嘧啶 -4-基氧基) -N,N-二甲基环己烷甲酰胺 6c(0.20 g, 黄色油 状物), 产物不经纯化直接进行下一步反应。
MS m/z (ESI): 383.2 [M+l]
第三步
反式 -4-(6-(6-氨基 -4- (三氟甲基)吡啶 -3-基) -2-((5 3-甲基吗啉)嘧啶 -4-基氧基) -N,N- 二甲基环己烷甲酰胺
将粗品反式 -4-(6-氯 -2-((5 3-甲基吗啉)嘧啶 -4-基氧基) -N,N-二甲基环己烷甲酰 胺 6c(200 mg, 0.40 mmol), 5-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基) -4- (三氟甲基) 吡啶 -2-胺 2c(174 mg, 0.61 mmol), [Ι,Γ-双 (二苯基膦)二茂铁]二氯化钯 (29 mg, 0.04 mmol)和碳酸钠(128 mg, 1.21 mmol)溶解于 6 mL N,N-二甲基甲酰胺和水 (V:V = 5: 1) 中, 加热至 90°C, 搅拌反应 12小时。 减压浓缩反应液, 用制备分离法纯化所得残 余物, 得到标题产物反式 -4-(6-(6-氨基 -4- (三氟甲基)吡啶 -3-基) -2-((5 3-甲基吗啉)
嘧啶 -4-基氧基) -N,N-二甲基环己烷甲酰胺 6(20 mg, 黄色油状物), 产率: 9.8 %。 MS m/z (ESI): 509.5 [M+l]
1H NM (400MHz, CDC13): δ 8.09 (s, 1H), 6.83 (s, 1H), 6.67 (s, 2H), 6.21 (s, 1H) 3.82-3.87 (m, 2H), 3.77 (s, 1H), 3.63-3.66 (m, 5H), 3.45 (s, 6H), 2.84-2.86 (m, 2H) 2.41 (s, 1H), 2.24 (s, 2H), 1.89 (s, 2H), 1.72-1.75 (m, 2H), 1.37 (d, 3H) 实施例 7
(5 5-( 啶 -2-
第一步
(5 4-(4-氯 -6- ((四氢 -2H-吡喃 -4-基)氧基)嘧啶 -2基) -3-甲基***啉 氩气保护下, 将钠氢 (24 mg, 0.60 mmol)悬浮于 5 mL的四氢呋喃中, 冰浴到 0 °C下, 慢慢滴加 2H-四氢吡喃 -4-醇 (62 mg, 0.60 mmol)的四氢呋喃溶液, 并在此温 度下持续搅拌 1小时, 然后加入 0S 4-C4,6-二氯嘧啶 -2-基) -3-甲基吗啉 4aC100 mg, 0.40 mmol, 采用 "专利申请 WO2008032064"公开的方法制备而得), 并在室温条 件下过夜, 次日, 加入冰水 5 mL淬灭反应, 加入 20 mL 乙酸乙酯, 水相用乙酸 乙酯萃取 (10 mLx3), 合并有机相, 用饱和氯化钠溶液洗涤 (30 mL), 无水硫酸镁干 燥, 过滤, 减压浓缩滤液, 得到粗品标题产物 (5 4-(4-氯 -6- ((四氢 -2H-吡喃 -4-基) 氧基)嘧啶 -2基) -3-甲基***啉 7a(0.2 g, 浅黄色油状物),产物不经纯化直接进行下 一步反应。
MS m/z (ESI): 314.12 [M+l]
第二步
(5 5-(2-(3-甲基***啉) -6- ((四氢 -2H-吡喃 -4-基)氧基)嘧啶 -4-基) -4-三氟甲基吡啶 -2- 将粗品 (5 4-(4-氯 -6-((四氢 -2H-吡喃 -4-基)氧基)嘧啶 -2 基) -3-甲基***啉 7a(0.2 g, 0.4 mmol), 5-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基) -4- (三氟甲基)吡啶 -2- 胺 2c(174 mg, 0.60 mmol), [Ι,Γ-双 (二苯基膦)二茂铁]二氯化钯 (29 mg, 0.04 mmol) 和碳酸钠 (128 mg, 1.21 mmol)溶解于 6 mL N,N-二甲基甲酰胺和水V:V = 5:1)中,
加热至 90°C, 搅拌反应 12小时。 加入 20 mL 乙酸乙酯, 水相用乙酸乙酯萃取 (10 mLx3), 合并有机相, 用饱和氯化钠溶液洗涤 (30 mL), 无水硫酸镁干燥, 过滤, 减压浓缩滤液, 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 5-(2-(3-甲基***啉) -6- ((四氢 -2H-吡喃 -4-基)氧基)嘧啶 -4-基) -4-三氟甲基吡啶 -2- 7(60 mg, 黄色固体), 产率: 34 %。
MS m/z (ESI): 440.4 [M+l]
1H NM (400MHz, CDC13): δ 8.15 (s, 1H), 6.88 (s, 1H), 6.69 (s, 2H), 6.20 (s, 1H), 3.82-3.87 (m, 2H), 3.76-3.80 (m, 2H), 3.55-3.68 (m, 5H), 2.84-2.86 (m, 1H), 2.41 (s, 2H), 2.24 (s, 2H), 1.82-1.85 (m, 2H), 1.37 (d, 3H) 实施例 8
(5 -5 -2-胺
4a 8a
第一步
0S 4-C4-氯 -6-环丙烷嘧啶 -2-基) -3-甲基***啉 氩气保护下, 将 0S 4-C4,6-二氯嘧啶 -2-基) -3-甲基吗啉 4aC100 mg, 0.40 mmol, 采用 "专利申请 WO2008032064"公开的方法制备而得), 环丙烷硼酸 (42 mg, 0.48 mmol), 醋酸钯 (5 mg, 0.02 mmol), 三苯基膦 (11.3mg, 0.04 mmol), 磷酸钾三水合 物 (319 mg, 1.2 mmol)混悬于 5 mL的甲苯中,在 110°C反应 6小时,加入冰水 5 mL 淬灭反应, 加入 30 mL 乙酸乙酯, 水相用乙酸乙酯萃取 (15 mLx3), 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, 减压浓缩滤液, 得到粗 品标题产物 (5 4-C4-氯 -6-环丙烷嘧啶 -2-基) -3-甲基***啉 8aC0.12 g, 黑色油状物), 产物不经纯化直接进行下一步反应。
第二步
(5 5-(6-环丙烷 -2-(3-甲基***啉)嘧啶 -4-基) -4-三氟甲基吡啶 -2-胺 氩气保护下, 将粗品 0S 4 4-氯 -6-环丙烷嘧啶 -2-基) -3-甲基***啉 8a (0.12 g, 0.4 mmol), 5-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基) -4- (三氟甲基)吡啶 -2-胺 2c (174 mg, 0.60 mmol), [Ι,Γ-双 (二苯基膦)二茂铁]二氯化钯 (29 mg, 0.04 mmol)和碳酸钠
(128 mg, 1.21 mmol)混悬于 6 mL N,N-二甲基甲酰胺和水 (V:V = 5: 1)中, 加热至 90 °C, 搅拌反应 12小时。 加入 20 mL 乙酸乙酯, 水相用乙酸乙酯萃取 (10 mLx3), 合并有机相, 用饱和氯化钠溶液洗涤 (30 mL), 无水硫酸镁干燥, 过滤, 减压浓缩 滤液, 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 5-(6-环丙 烷 -2-(3-甲基***啉)嘧啶 -4-基) -4-三氟甲基吡啶 -2-胺 8 (10 mg, 白色固体), 产率: Ί %。
MS m/z (ESI): 380.3 [M+l]
1H NM (400MHz, CDC13): δ 8.15 (s, IH), 7.70 (s, 2H), 7.55 (s, IH), 6.55 (s, IH), 4.33-4.40 (m, IH), 4.01-4.08 (m, IH), 3.81-3.86 (m, IH), 3.74-3.78 (m, IH), 3.56-3.66 (m, 2H), 3.36-3.43 (m, IH), 3.01 (s, IH), 1.37 (d, 3H), 1.28-1.31 (m, 2H), 1.22-1.26 (m, 2H) 实施例 9
(5 -胺
第一步
(5 4-(4-氯 -6-***啉嘧啶 -2-基) -3-甲基***啉 氩气保护下, 将 0S 4-(4,6-二氯嘧啶 -2-基) -3-甲基吗啉 4a(300 mg, 1.21 mmol, 采用 "专利申请 WO2008032064 "公开的方法制备而得), ***啉 (116 mg, 1.33 mmol), 碳酸铯 (789 mg, 2.42 mmol), 混悬于 5 mL的 N,N-二甲基甲酰胺中, 在 95 °C反应 12小时, 加入冰水 5 mL淬灭反应, 加入 30 mL 乙酸乙酯, 水相用乙酸乙 酯萃取 (15 mLx3),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, 减压浓缩滤液, 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 0S 4-C4-氯 -6-***啉嘧啶 -2-基) -3-甲基***啉 9aC0.2 g, 白色固体), 产率: 55 %。
MS m/z (ESI): 299.1 [M+l]
第二步
(5 5-(2-(3-甲基***啉) -6-***啉嘧啶 -4-基) -4-三氟甲基吡啶 -2-胺 氩气保护下, 将 S 4- 4-氯 -6-***啉嘧啶 -2-基) -3-甲基***啉 9a (0.2 g, 0.67
mmol), 5-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基) -4- (三氟甲基)吡啶 -2-胺 2c (290 mg, 1.0 mmol), [Ι,Γ-双 (二苯基膦)二茂铁]二氯化钯 (50 mg, 0.067 mmol)和碳酸钾 (185 mg, 1.34 mmol)混悬于 13 mL N,N-二甲基甲酰胺和水 (V:V = 10:3)中, 加热至 100°C, 搅拌反应 12小时。 加入冰水 20 mL淬灭反应, 加入 30 mL 乙酸乙酯, 水 相用乙酸乙酯萃取 (30 mLx3), 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, 减压浓缩滤液, 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 5-(2-(3-甲基***啉) -6-***啉嘧啶 -4-基) -4-三氟甲基吡啶 -2- 胺 9 (25 mg, 白色固体), 产率: 8.8 %。
MS m/z (ESI): 425.2 [M+l]
1H NM (400MHz, CDC13): δ 8.30 (s, 1H), 6.85 (s, 1H), 6.01 (s, 1H), 4.94 (s, 2H), 4.74 (s, 1H), 4.34-4.36 (d, 1H), 3.97 (s, 1H), 3.80-3.86 (m, 6H), 3.61-3.64 (m, 5H), 3.5 (d, 1H), 1.30 (s, 3H) 实施例 10
6-(6-氨基 -4- (三氟甲基)吡啶 -3-基) -2-***啉 -N-(l- (四氢 -2H-吡喃 -4-基)哌啶 -4-基)嘧
第一步
6-氯 -2-***啉 -N-C1-C四氢 -2H-吡喃 -4-基)哌啶 -4-基)嘧啶 -4-胺 氩气保护下, 将 4 4,6-二氯嘧啶 -2-基)***啉 10a 680 mg, 2.92 mmol, 采用 "专利申请 WO2005007646"公开的方法制备而得), 1-(四氢-2 吡喃-4-基)哌啶-4- 胺 (650 mg, 3.5 mmol, 采用 "专利申请 WO2007036711 "公开的方法制备而得), 碳酸铯 (1.4 g, 4.38 mmol), 混悬于 5 mL的 N-甲基吡咯烷酮中, 在 90°C反应 1.5 小时, 加入冰水 10 mL淬灭反应, 加入 30 mL 乙酸乙酯, 水相用乙酸乙酯萃取 (30 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, 减压浓缩滤液,得到标题产物粗品 6-氯 -2-***啉 -N-(l- (四氢 -2H-吡喃 -4-基)哌啶 -4- 基)嘧啶 -4-胺 10b(750 mg, 黄色固体), 产率: 67.6 %。
MS m/z (ESI): 382.2 [M+l]
第二步
6-(6-氨基 -4- (三氟甲基)吡啶 -3-基) -2-***啉 -N-(l- (四氢 -2H-吡喃 -4-基)哌啶 -4-基)嘧 啶 -4-胺
氩气保护下, 将 6-氯 -2-***啉 -N-(l- (四氢 -2H-吡喃 -4-基)哌啶 -4-基)嘧啶 -4-胺 10b (380 mg, 1 mmol), 5-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基) -4- (三氟甲基)吡啶 -2-胺 2c (432 mg, 1.5 mmol), [Ι,Γ-双 (二苯基膦)二茂铁]二氯化钯 (70 mg, 0.1 mmol) 和碳酸钾 (276 mg, 2 mmol)混悬于 6 mL N,N-二甲基甲酰胺和水 (V:V = 5:1)中, 加 热至 90°C, 搅拌反应 12小时。 加入冰水 20 mL淬灭反应, 加入 30 mL 乙酸乙酯, 水相用乙酸乙酯萃取 (30 mLx3), 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, 减压浓缩滤液, 用制备 HPLC纯化所得残余物, 得到标题 产物 6-(6-氨基 -4- (三氟甲基)吡啶 -3-基) -2-***啉 -ΛΚ1- (四氢 -2H-吡喃 -4-基)哌啶 -4- 基)嘧啶 -4-胺 10 (20 mg, 白色固体), 产率: 5 %。
MS m/z (ESI): 508.3 [M+l]
1H NM (400MHz, DMSO-t 6): δ 8.07 (s, 1H),6.79 (s, 1H), 6.66 (s, 2H), 5.87 (s, 1H), 3.82-3.87 (d, 2H), 3.77 (s, 1H), 3.63-3.66 (m, 10H), 2.84-2.86 (d, 2H), 2.43 (s, 1H), 2.24 (t, 2H), 1.89 (s, 2H), 1.61-1.63 (d, 2H), 1.39-1.42 (m, 4H), 1.24 (s, 1H) 实施例 11
5 -胺
2-氧杂 -7-氮杂螺 [4.5]癸烷
将 2-氧杂 -7-氮杂螺 [4.5]癸烷 -7-羧酸叔丁酯 lla C1.2 g, 5.0 mmol)加入到氯化 氢的 1,4-二氧六环溶液 (4 N, 20 mL)中, 加毕, 搅拌反应 4小时。 滴加饱和碳酸氢 钠溶液至反应液 pH为 7~8, 加入 20 mL水, 用乙酸乙酯萃取 (50 mLX 3), 合并有
机相, 用无水硫酸钠干燥, 过滤, 滤液减压浓缩, 得到标题产物 2-氧杂 -7-氮杂螺 [4.5]癸烷 llb (700 mg, 黄色油状物), 直接进行下步反应。
第二步
7_(6-氯 -2-吗啉代嘧啶 -4-基) -2-氧杂 -7-氮杂螺 [4.5]癸烷
将 4-(4,6-二氯嘧啶 -2-基)吗啉 10a (300 mg, 1.3 mmol)、 2-氧杂 -7-氮杂螺 [4.5] 癸烷 lib (343 mg, 1.9 mmol)和碳酸铯 (1.3 g, 3.9 mmol)加入到 15 mL的 N-甲基吡 咯烷酮中, 搅拌均勾, 反应液加热至 95 °C, 继续搅拌反应 2小时。 反应液倒入 30 mL水中, 用乙酸乙酯萃取 (50 mLx3), 合并有机相, 有机相用饱和氯化钠溶液洗 涤, 无水硫酸钠干燥, 过滤, 滤液减压浓缩, 得到标题产物 7-(6-氯 -2-吗啉代嘧啶 -4-基) -2-氧杂 -7-氮杂螺 [4.5]癸烷 llc (440 mg, 棕色油状物), 产率: 100%。
MS m/z (ESI): 339.2 [M+l]
第三步
5 2-吗啉代 -6 2-氧杂 -7-氮杂螺 [4.5]癸烷 -7-基)嘧啶 -4-基 )-4- (三氟甲基)吡啶 -2-胺 氩气氛下,将 7 6-氯 -2-吗啉代嘧啶 -4-基) -2-氧杂 -7-氮杂螺 [4.5]癸烷 11c (400 mg, 1.2 mmol)、5-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基) -4- (三氟甲基)吡啶 -2-胺 2c (510 mg, 1.8 mmol)、 [Ι,Γ-双 (二苯基膦)二茂铁]二氯化钯 (87 mg, 0.12 mmol)和碳 酸钠 (250 mg, 2.4 mmol)依次加入到 24 mL 的 1,4-二氧六环和水的混合溶剂中 (V:V=5: 1), 加热至 90°C, 搅拌反应 16小时。 反应液减压浓缩, 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 5-(2-吗啉代 -6-(2-氧杂 -7-氮杂螺 [4.5] 癸烷 -7-基)嘧啶 -4-基) -4- (三氟甲基)吡啶 -2-胺 ll (5 mg, 浅灰色固体), 产率: 1.0%。 MS m/z (ESI): 463.4 [M-l]
1H NM (400MHz, CDC13): δ 8.28 (s, 1H), 6.86 (s, 1H), 6.05 (s, 1H), 5.02 (s, 2H), 4.00-3.87 (m, 2H), 3.82-3.80 (m, 8H), 3.76-3.61 (m, 4H), 3.46-3.42 (m, 2H), 1.92-1.86 (m, 2H), 1.76-1.64 (m, 4H) 实施例 12
5_(2-吗啉代 -6 2-氧杂 -8-氮杂螺 [4.5]癸烷 -8-基)嘧啶 -4-基 )-4- (三氟甲基)吡啶 -2-胺
8_(6-氯 -2-吗啉代嘧啶 -4-基) -2-氧杂 -8-氮杂螺 [4.5]癸烷 将 4-(4,6-二氯嘧啶 -2-基)吗啉 10a (330 mg, 1.4 mmol)、 2-氧杂 -8-氮杂螺 [4.5] 癸烷 12a (300 mg, 2.0 mmol, 采用公知的方法 " 'ο^^α« ά M£¾fc «a/ 而'^ 7 Letters, 2002, 12(13), 1759-1762 "制备而得)和碳酸铯 (925 mg, 2.8 mmol)加入到
15 mL的 N-甲基吡咯烷酮中, 搅拌均勾, 反应液加热至 95 °C, 继续搅拌反应 2小 时。 反应液倒入 30 mL水中, 用乙酸乙酯萃取 (50 mLx3), 合并有机相, 有机相用 饱和氯化钠溶液洗涤,无水硫酸钠干燥, 过滤,滤液减压浓缩,得到标题产物 8-(6- 氯 -2-吗啉代嘧啶 -4-基) -2-氧杂 -8-氮杂螺 [4.5]癸烷 12b (400 mg, 棕色液体), 产率: 83.2%。
MS m/z (ESI): 339.2 [M+l]
第二步
5_(2-吗啉代 -6 2-氧杂 -8-氮杂螺 [4.5]癸烷 -8-基)嘧啶 -4-基 )-4- (三氟甲基)吡啶 -2-胺 氩气氛下, 将 8 6-氯 -2-吗啉代嘧啶 -4-基) -2-氧杂 -8-氮杂螺 [4.5]癸烷 12b (100 mg, 0.3 mmol)、5-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基) -4- (三氟甲基)吡啶 -2-胺 2c (127 mg, 0.4 mmol)、 [Ι,Γ-双 (二苯基膦)二茂铁]二氯化钯 (21 mg, 0.03 mmol)和碳 酸钠 (70 mg, 0.6 mmol)依次加入到 12 mL 的 1,4-二氧六环和水的混合溶剂中 (V:V=5: 1), 加热至 85 °C, 搅拌反应 16小时。 反应液减压浓缩, 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 5-(2-吗啉代 -6-(2-氧杂 -8-氮杂螺 [4.5] 癸烷 -8-基)嘧啶 -4-基) -4- (三氟甲基)吡啶 -2-胺 12 (5 mg, 黄色固体), 产率: 3.6%。 MS m/z (ESI): 465.2 [M+l]
1H NM (400MHz, CDC13): δ 8.33 (s, 1H), 6.91(s, 1H), 6.07 (s, 1H), 5.10 (s, 2H), 3.87-3.67 (m, 12H), 3.21-2.90 (m, 4H), 1.87-1.84 (m, 2H), 1.77-1.67 (m, 4H) 实施例 13
5—(2-吗啉代 -6-(5H-吡咯并 [3,4- 啶 -4-基) -4- (三氟甲基)吡啶 -2-胺
4- 4-氯 -6- 5H-吡咯并 [3,4-6]吡啶 -6 7H)-基)嘧啶 -2-基)吗啉 得 4-(4,6-二氯嘧啶 -2-基)吗啉 10a (400 mg, 1.7 mmol)、 6,7-二氢 -5H-吡咯并
[3,4-b]口比 二盐酸盐 13a (400 mg, 2.1 mmol)和碳酸铯 (2.2 g, 6.9 mmol)加入到 15 mL的 N-甲基吡咯烷酮中, 搅拌均勾, 反应液加热至 95 °C, 继续搅拌反应 2小时。 反应液倒入 30 mL水中, 用乙酸乙酯萃取 (50 mLx3), 合并有机相, 有机相用饱和 氯化钠溶液洗涤, 无水硫酸钠干燥, 过滤, 滤液减压浓缩, 得到标题产物 4-(4-氯 -6-C5H-吡咯并 [3,4-6]吡啶 -6C7H)-基)嘧啶 -2-基)吗啉 13b (240 mg,黄色固体),产率: 44.0%。
MS m/z (ESI): 318.1 [M+l]
第二步
5-(2-吗啉代 -6-(5H-吡咯并 [3,4-6]吡啶 -6(7H)-基)嘧啶 -4-基) -4- (三氟甲基)吡啶
-2-胺
氩气氛下, 将 4 4-氯 -6-C5H-吡咯并 [3,4-6]吡啶 -6C7H)-基)嘧啶 -2-基)吗啉 13b (240 mg, 0.8 mmol)、 5-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基) -4- (三氟甲基)吡啶 -2- 胺 2c (326 mg, 1.1 mmol)、 [Ι,Γ-双 (二苯基膦)二茂铁]二氯化钯 (26 mg, 0.08 mmol) 和碳酸钠 (160 mg, 1.5 mmol)依次加入到 24 mL的 1,4-二氧六环和水的混合溶剂中 (V:V=5: 1), 加热至 100°C, 搅拌反应 7小时。 反应液减压浓缩, 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 5-(2-吗啉代 -6-(5H-吡咯并 [3,4-6]吡 啶 -6C7H)-基)嘧啶 -4-基) -4- (;三氟甲基)吡啶 -2-胺 13 (10 mg, 浅黄色固体), 产率: 3.0%。
MS m/z (ESI): 444.4 [M+l]
1H NM (400MHz, CDC13): 58.64 (s, 1H), 8.11-8.0 (m, 2H), 7.81 (d, 1H), 7.39 (s, 1H), 7.04-7.00 (m, 2H), 6.09 (s, 1H), 5.06 (s, 2H), 4.92 (s, 2H), 3.92-3.83 (m, 8H) 实施例 14
5-(2 2-胺
第一步
(5 4-(6-氯 -2-((7?)-3-甲基吗啉)嘧啶 -4-基) -3-甲基吗啉 将 0S 4-(2,6-二氯嘧啶 -4-基) -3-甲基吗啉 (2.27 g, 9.15 mmol, 采用专利申请 WO2008032064"公开的方法制备而得)溶解于 18 mL N,N-二甲基甲酰胺中, 氩
气置换三次, 冰浴冷却至 0°C, 加入碳酸钾 (2.53 g, 18.30 mmol), 滴加 (i?)-3-甲基 吗啉 (1.37 g, 13.72 mmol), 升温至 99°C下反应 18小时。 加入 180 mL乙酸乙酯, 有机相用水 (80 mLx3)和饱和氯化钠溶液 (80 mLx l)洗涤, 无水硫酸钠干燥, 过滤, 减压浓缩滤液, 用硅胶柱色谱法以洗脱剂体系 B纯化所得残余物, 粗产物用石油 醚打浆 16 小时, 得到标题产物 (5 4-(6-氯 -2-((i?)-3-甲基吗啉)嘧啶 -4-基) -3-甲基吗 啉 14a (2.04 g, 白色固体), 产率: 71.3%。
MS m/z (ESI): 313.2 [M+l]
第二步
5-(2-((i?)-3-甲基吗啉) -6-((5 3-甲基吗啉)嘧啶 -4基) -4- (三氟甲基)吡啶 -2-胺 将 (5 4-(6-氯 -2-((i?)-3-甲基吗啉)嘧啶 -4-基) -3-甲基吗啉 14a (1.83 g,5.86 mmol) 溶解于 30 mL 乙二醇二甲醚中, 加入 5-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2- 基) -4- (三氟甲基)吡啶 -2-胺 2c (4.22 g, 14.65 mmol)和 15 mL 2 M 碳酸钠溶液, 搅 拌 5分钟,氩气置换三次,加入 (Ι,Γ-双 (二苯基膦基)二茂铁)二氯化钯 (214 mg, 0.29 mmol),氩气置换三次,于 90°C下反应 1小时。 向反应液中加入 100 mL乙酸乙酯, 有机相用水 (50 mLx2)和饱和氯化钠溶液 (50 mLx l)洗涤, 无水硫酸钠干燥, 过滤, 减压浓缩滤液, 用硅胶柱色谱法以洗脱剂体系 D纯化所得残余物, 粗产物用丙酮 和正己烷 (V/V=l:40)的混合溶剂打浆 16 小时, 得到标题产物 5-(2-((^)-3-甲基吗 啉) -6-C0S 3-甲基吗啉)嘧啶 -4-基) -4- (;三氟甲基)吡啶 -2-胺 14 (1.45 g, 白色固体), 产 率: 56.4%。
MS m/z (ESI): 439.2 [M+l]
1H NM (400MHz, CDC13): δ 8.28 (s, 1H), 6.79 (s, 1H), 5.93 (s, 1H), 4.82 (s, 2H), 4.71 (dd, 1H), 4.29 (d, 2H), 3.75-3.95 (m, 3H), 3.71-3.74 (m, 4H), 3.54-3.58 (m, 2H), 3.23-3.27 (m, 2H), 1.28 (t, 6H). 实施例 15
5-(6 -胺
第一步
(7?)-4-(6-氯 -2-((5)-3-甲基吗啉)嘧啶 -4-基) -3-甲基吗啉
将 (i?)-4-(2,6-二氯嘧啶 -4-基) -3-甲基吗啉 2a (2.48 g, 10 mmol)溶解于 20 mL N,N-二甲基甲酰胺中, 氩气置换三次, 冰浴冷却至 0°C, 加入碳酸钾 (2.76 g, 20 mmol), 滴加 (5 3-甲基吗啉 (1.50 g, 15 mmol), 升温至 99°C下反应 18小时。 加入 150 mL乙酸乙酯, 有机相用水 (50 mLx3)和饱和氯化钠溶液 (50 mLx l)洗涤, 无水 硫酸钠干燥, 过滤, 减压浓缩滤液, 用硅胶柱色谱法以洗脱剂体系 B纯化所得残 余物, 粗产物用石油醚打浆 16小时, 得到标题产物 (i?)-4-(6-氯 -2-((5 3-甲基吗啉) 嘧啶 -4-基) -3-甲基吗啉 15a (2 g, 白色固体), 产率: 64.0%。
MS m/z (ESI): 313.2 [M+l]
第二步
5-(6-((i?)-3-甲基吗啉) -2-((5 3-甲基吗啉)嘧啶 -4基) -4- (三氟甲基)吡啶 -2-胺 将 (i?)-4-(6-氯 -2-((5 3-甲基吗啉)嘧啶 -4-基) -3-甲基吗啉 15a (2 g, 6.39 mmol) 溶解于 34 mL 乙二醇二甲醚中, 加入 5-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2- 基) -4- (三氟甲基)吡啶 -2-胺 2c (4.60 g, 15.98 mmol)和 17 mL 2 M碳酸钠溶液, 搅 拌 5分钟,氩气置换三次,加入 (Ι,Γ-双 (二苯基膦基)二茂铁)二氯化钯 (234 mg, 0.32 mmol),氩气置换三次,于 90°C下反应 1小时。 向反应液中加入 100 mL乙酸乙酯, 有机相用水 (50 mLx2)和饱和氯化钠溶液 (50 mLx l)洗涤, 无水硫酸钠干燥, 过滤, 减压浓缩滤液, 用硅胶柱色谱法以洗脱剂体系 D纯化所得残余物, 粗产物用丙酮 和正己烷 (V/V=l :40)的混合溶剂打浆 16 小时, 得到标题产物 5-(6-((^)-3-甲基吗 啉) -2-(0S 3-甲基吗啉)嘧啶 -4-基) -4- (;三氟甲基)吡啶 -2-胺 15 (250 mg, 白色固体), 产率: 8.9%。
MS m/z (ESI): 439.2 [M+l]
1H NM (400MHz, CDC13): δ 8.28 (s, 1H), 6.79 (s, 1H), 5.93 (s, 1H), 4.82 (s, 2H), 4.71 (dd, 1H), 4.29 (d, 2H), 3.75-3.95 (m, 3H), 3.71-3.74 (m, 4H), 3.54-3.58 (m, 2H), 3.23-3.27 (m, 2H), 1.28 (t, 6H). 测试例:
生物学评价
测试例 1、 本发明化合物对 PI3K激酶活性的测定
体外 PI3K激酶活性通过以下的方法进行测试。
本实验使用的 PI3K激酶: PI3K-alpha (ΡΙ3Κ-α, Invitrogen, 货号 PV4788 ), PBK-beta (ΡΙ3Κ-β, Carna, 货号 11-102) , PBK-delta (PI3K- , Invitrogen, 货号 PV 5273 ) , PBK-gamma (PI3K- , Invitrogen, 货号 PV4786) 。
以下所述的体外细胞实验可测定受试化合物对 PBK激酶的增殖抑制活性, 测 试化合物根据实验所需浓度溶解于二甲基亚砜。 配制 i x缓冲液, 每 10 mL i x缓冲 液加 10 DTT。用 l x缓冲液稀释 ATP得到 10 μΜ ATP溶液。将适量 PIP2:PS Lipid 底物(Invitrogen, 货号 PV5100) , PI3K(PI3K-alpha , PBK-beta , PBK-delta , PBK-gamma)酶与 l x缓冲液混合。 往各 EP管中分别加入 50 μΙ ΑΤΡ溶液, 1 测
试化合物 DMSO溶液 (对照和空白中只加 1 纯 DMSO) 及 50 μL上述酶 -底物 混合液(对照中只加 50 l x缓冲液)。 各管充分混勾后, 于 37°C孵育 45分钟后, 再于 4°C放置 10分钟。 各测试化合物不同浓度及对照, 空白各设 2个平行孔。 各 孔加 50 μL 上述反应体系及 50 μL Kinase-Glo®反应液 (购买于 Promega, 货号 V3772),混合后室温振荡 1小时后用 BIOTEK FLX800荧光分析仪测定各孔化学发 光读值。
本发明化合物的活性
本发明化合物的 PI3K激酶 (ΡΒΚ-α, ΡΒΚ-β, ΡΙ3Κ-δ和 ΡΙ3Κ-γ) 生化抑制活 性通过以上的试验进行测定, 测得的 IC5Q值见表 1。
表 1本发明化合物对 PI3K激酶(ΡΒΚ-α、 ΡΙ3Κ-β ΡΒΚ-δ 、 ΡΙ3Κ-γ) 的活性 抑制的 IC:
对 ΡΙ3Κ激酶(ΡΒΚ-β、 ΡΒΚ-δ 、 ΡΒΚ-γ)活性的抑制作用较弱, 本发明优选化合 物对 ΡΙ3Κ激酶 (ΡΙ3Κ-α) 的抑制具有选择性。
本发明优选化合物的不同的异构体对 ΡΒΚ激酶(ΡΙ3Κ-01 ) 的抑制活性差异较 大, 实施例 3化合物对 ΡΒΚ-α的抑制活性显著高于实施例 2、 14和 15化合物; 同时本发明化合物的吗啉环上的取代基个数对 ΡΒΚ激酶(ΡΒΚ-α)抑制的选择性 影响很大, 两个吗啉环上均被甲基取代的 S构型化合物对 ΡΙ3Κ激酶(ΡΒΚ-α)抑 制的选择性高于只有一个吗啉环被甲基取代的化合物, 如实施例 3、 14和 15化合 物对 ΡΙ3Κ激酶 (ΡΙ3Κ-α) 抑制的选择性显著强于实施例 9化合物。 测试例 2、 本发明化合物对 mTOR激酶的活性抑制的测定
体外 mTOR激酶活性的抑制通过以下的方法进行测试。
本实验用 K-LISA™ mTOR (重组体)活性试剂盒 (Activity Kit), 货号: CBA104, 购于 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, 将底物包被在微孔板上。 配制 lx 缓冲液, 用 lx缓冲液稀释 ATP和 DTT得到 200 μΜ ATP和 2000 μΜ DTT溶液,
将适量 mTOR酶与 lx缓冲液混合, 终浓度 2 ng^L。 向每个微孔板中分别加入 50 ATP和 DTT溶液, 1 测试化合物 DMSO溶液 (对照和空白中只加 1 纯 DMSO)及 50 μί上述酶溶液 (对照中只加 50 μί 1χ缓冲液)。 各管充分混勾后, 于 30°C孵育 45分钟后, 用洗液洗板, 控干, 重复 3次, 加入一抗, 孵育 1小时。 用 洗液洗板, 控干, 重复 3次, 加入二抗, 孵育 1小时。 用洗液洗板, 控干, 重复 3 次, 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 IC5Q值可通过不同浓度下受试化合物对于 mTO 活性的抑制数值计算得出。
本发明化合物的活性
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 IC5Q值见表 2。
表 2本发明化合物对 m-TOR激酶的活性抑制的 IC:
结论: 本发明优选化合物对 mTOR激酶活性的抑制作用较弱。 测试例 3、 本发明化合物对突变型 ΡΙ3Κ-α激酶活性的测定
体外突变型 ΡΙ3Κ-α激酶活性通过以下的方法进行测试。
本实验使用的突变型 ΡΙ3Κ-α激酶为 PI3-Kinase (pll0a(H1047 )/p85 a ),货号: 14-792 ; PI3 Kinase (ρ110α(Ε545Κ)/ρ85α) , 货 号 : 14-783 ; PI3-Kinase (ρ110α(Ε542Κ)/ρ85α), 货号: 14-782, 均购于 millipore公司。
以下所述的体外细胞实验可测定受试化合物对突变型 ΡΒΚ-α激酶的增殖抑制 活性,测试化合物根据实验所需浓度溶解于二甲基亚砜。配制 ix缓冲液,每 10 mL lx缓冲液加 10 L DTT。用 lx缓冲液稀释 ATP得到 10 μΜ ATP溶液。将适量 PIP2:PS Lipid底物 (Invitrogen, 货号 PV5100), 突变型 PI3K激酶 ((pll0a(H1047R)/p85a), (ρ110α(Ε545Κ)/ρ85α), ρ110α(Ε542Κ)/ρ85α))酶与 lx缓冲液混合。往各 EP管中分别 加入 50 μΐ ATP溶液, 1 测试化合物 DMSO溶液 (对照和空白中只加 1 纯 DMSO)及 50 μί上述酶 -底物混合液(对照中只加 50 lx缓冲液)。 各管充分混 勾后, 于 37°C孵育 45分钟后, 再于 4°C放置 10分钟。 各测试化合物不同浓度及 对照, 空白各设 2个平行孔。 各孔加 50 μL上述反应体系及 50 μL Kinase-Glo®反 应液 (购买于 Promega,货号 V3772),混合后室温振荡 1小时后用 BIOTEK FLX800 荧光分析仪测定各孔化学发光读值。
本发明化合物的活性
本发明化合物的对突变型 ΡΙ3Κ-α激酶生化抑制活性通过以上的试验进行 定, 测得的 IC5Q值见表 3。
表 3 本发明优选化合物对突变型 ΡΙ3Κ-α激酶的活性抑制的 IC
结论: 本发明优选化合物对突变型 PBK-a激酶活性具有明显的抑制作用。 测试例 4、 本发明化合物对乳腺癌细胞株 MCF-7的增殖抑制测定
下面的体外试验是用来测定本发明化合物对乳腺癌细胞株细胞株 -MCF-7的增 殖抑制活性。
以下所述的体外细胞试验可测定受试化合物对乳腺癌细胞株的增殖抑制活 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 nM、 1000 nM、 100 nM、 10 nM、 1 ηΜ、 0.1 nM)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。
本发明化合物活性本发明化合物生物活性由上述分析所得, 计算所得的 IC50 值如下表 4:
表 4本发明化合物对 MCF-7细胞的增殖抑制的 IC
结论: 本发明优选化合物均对 MCF-7细胞具有明显的增殖抑制活性。 药代动力学评价
测试例 5、 本发明实施例 3的药代动力学测试
1、 摘要
以 SD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 3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。
2、 试验方案
2.1 试验药品
实施例 3化合物。
2.2 试验动物
健康成年 SD大鼠 4只, 雌雄各半, 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。
2.3 药物配制
称取适量样品, 加入 0.5% CMC-Na, 超声制成 0.5 mg/mL混悬液。
2.4 给药
SD大鼠 4只, 雌雄各半, 禁食一夜后分别灌胃给药, 剂量为 5.0 mg/kg, 给药体 积 lO mL/kgo
3、 操作
于给药前及给药后 0.5、 1、 2、 4、 6、 8、 11、 24、 48小时采血 0.1 mL, 置于 EDTA抗凝试管中, 3500 rpm离心 10分钟, 分离血浆, 于 -20°C保存。 给药后 2 小时进食。
用 LC/MS/MS法测定灌胃给药后大鼠血浆中的待测化合物含量。 分析方法的 线性范围为 1.00-2000 ng/mL, 定量下限为 1.00 ng/mL; 血浆样品经沉淀蛋白预处 理后进行分析。
4、 药代动力学参数结果
本发明化合物的药代动力学参数如下:
结论: 本发明优选化合物的药代吸收良好, 具有明显的药代吸收效果。
Claims
1、 一种通式( I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映 异构体、 非对映异构体及其 盐:
其中:
环 A为单环杂芳基;
环 B为饱和的环烷基或杂环基;
L为一个键或氧原子;
R1为烷基;
R2选自氢原子、 烷基、 羟基、 卤素、 烷氧基、 硝基、 氰基、 环烷基、 杂环基、 芳基、 杂芳基、 -C(0)NR5R6、 -C(0)R7、 -C(0)OR7、 -NHC(0)NR5R6或 -NR5R6;
R3和 R4各自独立地选自氢原子、 烷基、 烷氧基、 卤素、 羟基、 氰基、 芳基、 杂芳基、 -OR5或 -NR5R6, 其中所述烷基、 烷氧基、 芳基或杂芳基任选进一步被一 个或多个选自烷基、 卤素、 氰基、 氨基、 羟基、 烯基、 炔基、 羧基或羧酸酯基的 取代基所取代; 且
R5、 R6和 R7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羟 基、 烷基、 卤素、 烷氧基、 硝基、 氰基、 环烷基、 杂环基、 芳基或杂芳基的取代 基所取代。
2、 根据权利要求 1所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对 映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 其为通式 (Π)所示的化 合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混 合物形式, 及其可药用盐:
G为氧原子或 CCR 9);
环 A为单环杂芳基;
R1为烷基;
R2为氢原子或烷基;
R3和 R4如权利要求 1所述; 且
R8和 R9各自独立地选自氢原子、 烷基、 烷氧基、 卤素、 羟基、 氰基、 芳基、 杂芳基、 -OR5或 -NR5R6, 其中所述烷基、 烷氧基、 芳基或杂芳基任选进一步被一 个或多个选自烷基、 卤素、 氰基、 氨基、 羟基、 烯基、 炔基、 羧基或羧酸酯基的 取代基所取代。
3、 根据权利要求 2所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对 映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 其为通式 (ΠΑ)所示的 化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其 混合物形式, 及其可药用盐:
其中: G、 环 、 R2〜R4如权利要求 2所述。
4、 根据权利要求 1所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对 映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 其为通式 (ΠΙ)所示的化 合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混 合物形式, 及其可药用盐:
其中:
环 A为单环杂芳基;
环 B为饱和的环烷基或杂环基;
R1为烷基;
R2为氢原子或烷基; 且
R3和 R4各自独立地选自氢原子、 烷基或氨基, 其中所述烷基任选进一步被一 个或多个卤素所取代。
5、 根据权利要求 4所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对 映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 其为通式 (ΠΙΑ)所示的 化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其 混合物形式, 及其可药用盐:
其中: 环 、 环8、 R2〜R4如权利要求 4所述。
6、 根据权利要求 1、 2、 4任一项所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 其中 R1 为甲基。
7、 根据权利要求 1〜6任一项所述的化合物或其互变异构体、 内消旋体、 外消 旋体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 其中环 A为 吡啶基或嘧啶基。
8、 根据权利要求 1〜7任一项所述的化合物或其互变异构体、 内消旋体、 外 消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 其中 R2为 烷基, 优选为甲基。
9、 根据权利要求 1〜8任一项所述的化合物或其互变异构体、 内消旋体、 外 消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 其中 R3和 R4各自独立地选自氢原子、 烷基、 卤代烷基或氨基。
10、 根据权利要求 1〜9任一项所述的化合物或其互变异构体、 内消旋体、 外 消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 其中所述 化合物选自:
12、 一种通式 (I-A)所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对 映异构体、 非对映异构体及其混合物形式:
( I-A )
其中:
环3、 L、 1〜^的定义如权利要求 1中所述, X为卤素。
13、 一种制备根据权利要求 1 所述的化合物或其互变异构体、 内消旋体、 外 消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐的方法, 该 方法包括:
通式 (I-A)化合物与与环 A取代的硼酸酯或硼酸在碱性条件下, 经催化后进行 偶联反应得到通式( I )化合物,
其中: X为卤素; 环 、 环^ L、 ^〜 4的定义如权利要求 1中所述。
14、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 1〜11 任一项所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对 映异构体及其混合物形式, 及其可药用盐, 以及一种或多种药学上可接受的载体 或赋形剂。
15、 根据权利要求 1〜11 任一项所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 或根据 权利要求 14 所述的药物组合物在制备治疗蛋白酪氨酸激酶介导的疾病, 特别是 PBK激酶介导的疾病的药物中的用途。
16、 根据权利要求 1〜11 任一项所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 或根据 权利要求 14所述的药物组合物在制备抑制 PBK激酶的药物中的用途。
17、 根据权利要求 1〜11 任一项所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体及其混合物形式, 及其可药用盐, 或根据
权利要求 14 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、 ***状甲状腺肿瘤、 胆管癌、 结肠癌、 卵巢癌、 子宫内膜癌、 子***、 肺癌、 食道癌、 脑癌、 恶性淋巴肿瘤、 肝、 胃、 肾、 膀 胱、 ***、 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、 头颈癌、 神经胶质瘤、 成胶质细胞瘤, 优选为乳 腺癌。
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WO2016095833A1 (zh) * | 2014-12-17 | 2016-06-23 | 上海海雁医药科技有限公司 | 2-吗啉-4,6-二取代的嘧啶衍生物、其制法与医药上的用途 |
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WO2017198347A1 (en) * | 2016-05-18 | 2017-11-23 | Piqur Therapeutics Ag | Treatment of skin lesions |
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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JP2017533246A (ja) * | 2014-11-11 | 2017-11-09 | ピクール セラピューティクス アーゲー | ジフルオロメチル−アミノピリジンおよびジフルオロメチル−アミノピリミジン |
WO2016095833A1 (zh) * | 2014-12-17 | 2016-06-23 | 上海海雁医药科技有限公司 | 2-吗啉-4,6-二取代的嘧啶衍生物、其制法与医药上的用途 |
CN107001348A (zh) * | 2014-12-17 | 2017-08-01 | 上海海雁医药科技有限公司 | 2‑吗啉‑4,6‑二取代的嘧啶衍生物、其制法与医药上的用途 |
CN107001348B (zh) * | 2014-12-17 | 2019-10-11 | 上海海雁医药科技有限公司 | 2-吗啉-4,6-二取代的嘧啶衍生物、其制法与医药上的用途 |
AU2015366357B2 (en) * | 2014-12-17 | 2018-07-19 | Shanghai Haiyan Pharmaceutical Technology Co. Ltd. | 2-morpholin-4,6-disubstituted pyrimidine derivative, and preparation method and pharmaceutical use thereof |
US10227324B2 (en) | 2014-12-17 | 2019-03-12 | Shanghai Haiyan Pharmaceutical Technology Co., Ltd. | 2-morpholin-4,6-disubstituted pyrimidine derivative, and preparation method and pharmaceutical use thereof |
CN104788482A (zh) * | 2015-01-23 | 2015-07-22 | 沧州普瑞东方科技有限公司 | 一种制备2-氨基嘧啶-5-硼酸频那醇酯的方法 |
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CN109414415A (zh) * | 2016-05-18 | 2019-03-01 | 皮奎尔治疗公司 | 皮肤病变的治疗 |
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US10993947B2 (en) | 2016-05-18 | 2021-05-04 | Torqur | Treatment of skin lesions |
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US11918586B2 (en) | 2016-05-18 | 2024-03-05 | Torqur Ag | Treatment of skin lesions |
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 |
CN108430987B (zh) * | 2016-06-02 | 2021-06-18 | 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 |
US11926616B2 (en) | 2018-03-08 | 2024-03-12 | Incyte Corporation | Aminopyrazine diol compounds as PI3K-γ inhibitors |
US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
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CN104245693B (zh) | 2016-08-24 |
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