Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the invention belongs to the field of medicinal chemistry.
• the present invention relates to a pyridopyrimidine or pyrimidopyrimidine compound or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, a process for the preparation thereof, a pharmaceutical composition thereof and Use in the preparation of mTOR inhibitors.
• Such compounds or pharmaceutical compositions thereof are useful as mTOR inhibitors for the treatment of diseases or conditions resulting from dysfunction of the PBK-AKT-mTOR signaling pathway.
• PBK-Akt-mTOR signaling pathway plays a key role in tumor cell growth, proliferation, invasion and metastasis. Blocking intracellular PBK-Akt-mTOR signaling pathway can inhibit tumor cell proliferation and even promote tumor cell apoptosis. Die.
• PBK-Akt-mTOR signaling pathway multiple key nodal proteins in the PBK-Akt-mTOR signaling pathway are over-activated by mutation or amplification of the coding gene, mutation and amplification of the above-mentioned receptor-type tyrosine kinase, encoding pllOct catalysis
• the subunit's PIK3CA gene is mutated and amplified in a variety of tumors, with over-activation of Akt and PDK1 and a general loss of the negative regulatory factor PTEN.
• the mammalian target of rapamycin is one of the important substrates for Akt and belongs to a non-classical serine/threonine protein kinase of the phosphatidylinositol-3-kinase-associated kinase (PIKK) family.
• the mTOR signaling pathway is a key pathway regulating cell growth and proliferation, which integrates signals from nutrient molecules, energy states, and growth factors to regulate a large number of life processes. Abnormal activation of the mTOR signaling pathway is a common feature of various tumorigenesis and development, and thus has become a hot spot for the development of anti-tumor inhibitors.
• mTOR has at least two functional complexes, mTORCl and mTORC2, which mediate both associated and independent biosignal functions.
• Clinically used rapamycins (including rapamycin and its analogues) bind to the FKBP12-rapamycin binding domain (FRB) near the catalytic site of mTORCl by allosteric, and exert partial inhibition. The role of mTOR protein. These compounds do not directly inhibit mTORC2, nor do they completely block mTORCl-mediated signaling.
• rapamycin has shown some clinical efficacy in some tumors, the mode of action of these drugs does not fully exploit the potential of mTOR to target anti-tumor drugs.
• mTORC2-mediated perphosphate (activation) of AKT is critical for tumor maintenance and growth, but mTORC2 is not inhibited by rapamycins.
• ATP competitive and specific mTOR small molecule inhibitors have made it possible to treat a variety of cancers.
• Some recently reported ATP competitive inhibitors against tumor cell growth and survival, protein binding compared to rapamycin analogues Formation, bioenergy metabolism, etc. have shown stronger inhibition.
• these drugs have strong monotherapy antitumor activity against MDA361 breast cancer, U87MG glioma, A549 and H1975 lung cancer, A498 and 786-0 kidney cancer.
• the inventors of the present invention have determined that the mTOR inhibitor is an ATP competitive inhibitor, and thus its mechanism of action is a non-rapamycin-like compound. Further, on the basis of the previously reported compounds, the inventors of the present invention have obtained a novel class of pyridopyrimidine or pyrimidopyrimidine compounds by rational design and comprehensive consideration of factors such as water solubility and metabolic stability of the compounds. These compounds show good mTOR inhibitory activity at both enzyme and cell levels. After further optimization and screening, it is expected to be developed into a simple and more active anti-tumor drug.
• An object of the present invention is to provide a pyridopyrimidine or pyrimidopyrimidine compound represented by the formula (I) or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof.
• Another object of the invention is to provide a process for the preparation of the compounds provided herein.
• Still another object of the present invention is to provide a pyridopyrimidine or pyrimidopyrimidine compound represented by the formula (I) or an isomer thereof or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof as mTOR inhibition
• a pyridopyrimidine or pyrimidopyrimidine compound represented by the formula (I) or an isomer thereof or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof as mTOR inhibition
• Still another object of the present invention is to provide a pyridylpyrimidine or pyrimidopyrimidine compound represented by the formula (I) or an isomer thereof or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof One or more pharmaceutical compositions.
• U and V are N, the others are CH;
• R 2 are each independently 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl or NR A R B , wherein R A and R B are each independently H, unsubstituted or C1-6 alkyl substituted by C1-6 alkoxy or halogen, or C1-6 alkoxy which is unsubstituted or substituted by halogen, Alternatively, R A and R B and the N to which they are bonded form a nitrogen-containing saturated heterocyclic ring having 4 to 8 ring atoms which is unsubstituted or substituted by a C1-6 alkyl group, a C1-6 alkoxy group or a halogen.
• the nitrogen-containing saturated heterocyclic ring includes a piperidine ring, a morpholine ring, a piperazine ring, an N-methyl piperazine ring, a high morpholine ring, a homopiperazine ring, and the like.
• R A and R B are each independently H, unsubstituted or C1-3 alkyl substituted by C1-3 alkoxy or halogen, or C1-3 alkoxy which is unsubstituted or substituted by halogen
• R A and R B and the N-linked thereto form a nitrogen-containing saturated heterocyclic ring having 6 to 7 ring atoms which is unsubstituted or substituted by a C1-3 alkyl group, a C1-3 alkoxy group or a halogen.
• the nitrogen-containing saturated heterocyclic ring is further preferably a morpholine ring.
• R 3 is , , , where Rc is H or
• Rc is preferably H or methyl.
• U is N and V is CH, that is, the compound represented by the formula (I) is preferably a compound represented by the formula (la):
• R 2 are each independently 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl or NR A R B , wherein R A and R B are each independently H, unsubstituted or C1-6 alkyl substituted by C1-6 alkoxy or halogen, or C1-6 alkyl which is unsubstituted or substituted by halogen Oxygen, or, R A and R B and the N to which they are bonded form a nitrogen-containing saturated group having 4 to 8 ring atoms which are unsubstituted or substituted by a C1-6 alkyl group, a C1-6 alkoxy group or a halogen.
• the nitrogen-containing saturated heterocyclic ring includes a piperidine ring, a morpholine ring, a piperazine ring, an N-methyl piperazine ring, a high morpholine ring, a homopiperazine ring, and the like.
• octyl or NR A R B wherein R A and R B are each independently H, unsubstituted or C1-3 alkyl substituted by C1-3 alkoxy or halogen, or Substituted or halogen-substituted C1-3 alkoxy, or R A and R B and N-linked thereto form unsubstituted or substituted by C1-3 alkyl, C1-3 alkoxy or halogen a nitrogen-containing saturated heterocyclic ring having 6 to 7 ring atoms, and the nitrogen-containing saturated heterocyclic ring is further preferably a morpholine ring.
• R 3 is , , , where Rc is H or
• Rc is preferably H or methyl.
• U is CH and V is N, that is, the compound represented by the formula (I) is preferably a compound represented by the formula (lb):
• R 2 are each independently 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl or NR A R B , wherein R A and R B are each independently H, unsubstituted or C1-6 alkyl substituted by C1-6 alkoxy or halogen, or C1-6 alkoxy which is unsubstituted or substituted by halogen, Alternatively, R A and R B and the N to which they are bonded form a nitrogen-containing saturated heterocyclic ring having 4 to 8 ring atoms which is unsubstituted or substituted by a C1-6 alkyl group, a C1-6 alkoxy group or a halogen.
• the nitrogen-containing saturated heterocyclic ring includes a piperidine ring, a morpholine ring, a piperazine ring, an N-methyl piperazine ring, a high morpholine ring, a homopiperazine ring, and the like.
• each is independently 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo
• octyl or NR A R B wherein R A and R B are each independently H, unsubstituted or C1-3 alkyl substituted by C1-3 alkoxy or halogen, or Substituted or halogen-substituted C1-3 alkoxy, or R A and R B and N-linked thereto form unsubstituted or substituted by C1-3 alkyl, C1-3 alkoxy or halogen a nitrogen-containing saturated heterocyclic ring having 6 to 7 ring atoms, and the nitrogen-containing saturated heterocyclic ring is further preferably a morpholine ring.
• R 3 is , , , where Rc is H or
• Rc is preferably H or methyl.
• both U and V are N, that is, the compound represented by the formula (I) is preferably a compound represented by the formula (Ic):
• R 2 are each independently 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl or NR A R B , wherein R A and R B are each independently H, unsubstituted or C1-6 alkyl substituted by C1-6 alkoxy or halogen, or C1-6 alkoxy which is unsubstituted or substituted by halogen, Alternatively, R A and R B and the N to which they are bonded form a nitrogen-containing saturated heterocyclic ring having 4 to 8 ring atoms which is unsubstituted or substituted by a C1-6 alkyl group, a C1-6 alkoxy group or a halogen.
• the nitrogen-containing saturated heterocyclic ring includes a piperidine ring, a morpholine ring, a piperazine ring, an N-methyl piperazine ring, a high morpholine ring, a homopiperazine ring, and the like.
• each is independently 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo
• octyl or NR A R B wherein R A and R B are each independently H, unsubstituted or C1-3 alkyl substituted by C1-3 alkoxy or halogen, or Substituted or halogen-substituted C1-3 alkoxy, or R A and R B and N-linked thereto form unsubstituted or substituted by C1-3 alkyl, C1-3 alkoxy or halogen a nitrogen-containing saturated heterocyclic ring having 6 to 7 ring atoms, and the nitrogen-containing saturated heterocyclic ring is further preferably a morpholine ring.
• R 3 is , , , where Rc is H or
• Rc is preferably H or methyl.
• a particularly preferred specific compound is one of the following compounds:
• the pharmaceutically acceptable salt of the pyridopyrimidine or pyrimidopyrimidine compound represented by the formula (I) provided by the present invention can be dissolved by dissolving a pyridopyrimidine or pyrimidopyrimidine compound represented by the formula (I) Prepared by reacting in a corresponding acid-saturated alcohol solution, for example: dissolving the pyridopyrimidine or pyrimidopyrimidine compound provided by the present invention in a saturated methanol solution of HCl, stirring at room temperature for 30 minutes, and evaporating the solvent to prepare The corresponding hydrochloride salt was obtained.
• the compound in the reaction scheme includes a salt thereof, for example, those salts as defined by the compound having the structural formula (I) and the like.
• reaction schemes shown below provide a possible route for the synthesis of the compounds of the invention as well as key intermediates.
• Examples section below For a more detailed description of the individual reaction steps, please see the Examples section below.
• Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the present invention.
• specific starting materials and reagents are shown in the reaction schemes and described in the following sections, other starting materials and reagents can be readily substituted to provide a variety of derivatives and/or reaction conditions.
• numerous compounds prepared by the methods described herein can be further modified using conventional chemical methods well known to those skilled in the art.
• the substituted pyridine [2,3-d]pyrimidine compound of the formula (la) or an isomer thereof or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof can be produced by the following method, Specific reagents and reaction conditions used in the reaction can be found in Example 1.
• the substituted pyrimidine [4,5-d]pyrimidine compound of the formula (Ic) or an isomer thereof or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof can be produced by the following method, Specific reagents and reaction conditions used in the reaction can be found in Example 32.
• the present invention provides a pyridopyrimidine or pyrimidopyrimidine compound represented by the formula (I) or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvent thereof.
• a pyridopyrimidine or pyrimidopyrimidine compound represented by the formula (I) or an isomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvent thereof Use of the substance, its use as an mTOR inhibitor, and its use in the preparation of a disease or condition, particularly a neoplastic disease, for the treatment of dysfunction by the PBK-AKT-mTOR signaling pathway.
• the tumor diseases include, but are not limited to, melanoma, liver cancer, kidney cancer, acute leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, skin cancer, colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, Breast cancer, myelodysplastic syndrome, esophageal cancer, gastrointestinal cancer, and mesothelioma.
• the present invention provides a therapeutically effective amount of a pyridopyrimidine or pyrimidopyrimidine compound represented by the formula (I) or an isomer thereof or a pharmaceutically acceptable salt thereof
• the above pharmaceutically acceptable carrier means a conventional pharmaceutical carrier in the pharmaceutical field, for example: a diluent such as water; a filler such as starch, sucrose, etc.; a binder such as a cellulose derivative, an alginate, gelatin, poly a vinylpyrrolidone; a wetting agent such as glycerin; a disintegrating agent such as agar, calcium carbonate and sodium hydrogencarbonate; an absorption enhancer such as a quaternary ammonium compound; a surfactant such as cetyl alcohol; an adsorbent carrier such as kaolin and soap clay.
• Lubricants such as talc, calcium stearate and hard Magnesium citrate, and polyethylene glycol.
• other adjuvants such as a flavoring agent and a sweetener may be added to the above pharmaceutical composition.
• the invention also provides a method of treating a disease or condition, in particular a neoplastic disease, caused by a dysfunction of the PBK-AKT-mTOR signaling pathway, comprising administering a therapeutically effective amount of a formula (I) a pyridylpyrimidine or pyrimidopyrimidine compound or a tautomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, or the above-mentioned drug of the present invention
• a formula (I) a pyridylpyrimidine or pyrimidopyrimidine compound or a tautomer thereof, or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, or the above-mentioned drug of the present invention The composition is given to the patient.
• the compounds or compositions provided herein can be administered to a patient in need of such treatment by oral, rectal or parenteral administration.
• a patient in need of such treatment by oral, rectal or parenteral administration.
• it can be prepared into a conventional solid preparation such as a tablet, a powder, a granule, a capsule, etc., or a liquid preparation such as a water or oil suspension, or other liquid preparation such as syrup;
• parenteral administration it may be prepared as a solution for injection, water or an oily suspension, or the like.
• the compounds provided by the present invention all showed good inhibitory activity against mTOR, and also showed strong proliferation inhibition effects on human glioma U87MG and human prostate cancer LNCap cells, among which the most active compounds such as compound 1, compound 3 and Compound 8, which is comparable in activity to similar clinical test compounds such as AZD8055 in the prior art.
• the starting materials are either commercially available or prepared by methods known in the art or prepared according to the methods described herein.
• the structure of the compound is determined by nuclear magnetic resonance (1H-NMR) and/or mass spectrometry (MS). NMR measurement is done with Varian
• AMX-400 nuclear magnetic resonance apparatus the solvent was deuterated chloroform (CDC13) or deuterated dimethyl sulfoxide (DMSO-D6), and TMS was an internal standard.
• the MS was measured using a Thermo Finnigan LCQ-Deca XP (ESI) liquid chromatography-mass spectrometer.
• the column was separated and purified using an ISCO CombiFlash® Rf 75 Rapid Preparative Chromatograph using 200-300 mesh silica gel from Qingdao Ocean Chemical Plant. Microtage heating uses the Biotage Initiator microwave synthesizer.
• Reagents and conditions a) paraformaldehyde, concentrated hydrochloric acid 60 ° C; b) pivalic acid, potassium carbonate, dimethylformamide, 65 ° C; c) tert-butoxy bis (dimethylamino) methane, 54 ° C ; d) 6-aminouracil, glacial acetic acid, water, dimethyl sulfoxide, 99 ° C; e) phosphorus oxychloride, N,N-diisopropylethylamine, anisole, 80 °C ; f) 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride, N,N-diisopropylethylamine, tetrahydrofuran, room temperature; g) 3-oxa-8- Azabicyclo[3.2.1]octane hydrochloride, N,N-diisopropylethylamine, isopropanol, microwave 160
• [2,3-d]pyrimidine-7-yl)-2-methoxybenzyl ester was added with 5 mL of methanol, 3 mL of tetrahydrofuran, and about 80 mg of potassium hydroxide, and allowed to react at room temperature overnight. The solvent was evaporated under reduced pressure. EtOAc (EtOAc m. The title compound was obtained as a yellow solid (yield: 50.0%).
• the title compound was prepared by the method of Example 1.
• the a, b, c, d, e and h steps were the same except that the 3-oxa-8-azabicyclo ring in the two steps f and g [3.2.1 ] Octane hydrochloride was replaced by 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride.
• the title compound was obtained as a yellow solid (yield: 38.0%).
• the title compound was prepared by the method of Example 1.
• the a, b, c, d, e, f, and h steps were the same, except that the 3-oxa-8-azabicyclo ring in the g step [3.2.1]
• the octane hydrochloride was replaced by (S)-3-methylmorpholine.
• the title compound was obtained as a yellow solid, yield 64%.
• Example 4 5-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-yl)-2-morpholinepyridine [2,3-d]pyrimidine-7- Preparation of -2-methoxyphenylmethanol (Compound 4)
• the title compound was prepared by the method of Example 1.
• the a, b, c, d, e, f, and h steps were the same, except that the 3-oxa-8-azabicyclo ring in the g step [3.2.1]
• the octane hydrochloride is replaced by morpholine.
• the title compound was obtained as a yellow solid, yield 47%.
• the title compound was prepared by the method of Example 1.
• the a, b, c, d, e, f, and h steps were the same, except that the 3-oxa-8-azabicyclo ring in the g step [3.2.1]
• the octane hydrochloride was replaced by (2S,6R)-2,6-dimethylmorpholine.
• the title compound was obtained as a yellow solid (yield: 79%).
• the title compound was prepared by the method of Example 1.
• the a, b, c, d, e, f, and h steps were the same, except that the 3-oxa-8-azabicyclo ring in the g step [3.2.1]
• the octane hydrochloride was replaced by 2-methoxy-N-methylethylamine.
• the title compound was obtained as a yellow solid, yield 80%.
• the title compound was prepared by the method of Example 1.
• the a, b, c, d, e, f, and h steps were the same, except that the 3-oxa-8-azabicyclo ring in the g step [3.2.1]
• the octane hydrochloride was replaced by 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride.
• the title compound was obtained as a yellow solid, yield 60%.
• the title compound was prepared by the method of Example 1.
• the a, b, c, d, e, g, and h steps were the same, except that the 3-oxa-8-azabicyclo ring in the f step [3.2.1]
• the octane hydrochloride was replaced by (S)-3-methylmorpholine.
• the title compound was obtained as a yellow solid, yield 82%.
• the title compound was prepared by the method of Example 1.
• the a, b, c, d, e, g, and h steps were the same, except that the 3-oxa-8-azabicyclo ring in the f step [3.2.1]
• the octane hydrochloride is replaced by morpholine.
• the title compound was obtained as a yellow solid, yield 82%.
• the title compound was prepared by the method of Example 1.
• the a, b, c, d, e, g, and h steps were the same, except that the 3-oxa-8-azabicyclo ring in the f step [3.2.1]
• the octane hydrochloride was replaced by (2S,6R)-2,6-dimethylmorpholine.
• the title compound was obtained as a yellow solid, yield 48%.
• the title compound was prepared by the method of Example 1.
• the a, b, c, d, e, g, and h steps were the same, except that the 3-oxa-8-azabicyclo ring in the f step [3.2.1]
• the octane hydrochloride was replaced by 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride.
• the title compound was obtained as a yellow solid, yield 75%.
• the title compound was prepared by the method of Example 1.
• the a, b, c, d, e, g, and h steps were the same, except that the 3-oxa-8-azabicyclo ring in the f step [3.2.1]
• the octane hydrochloride was replaced by 2-methoxy-N-methylethylamine.
• the title compound was obtained as a yellow solid, yield 75%.
• the synthetic route is:
• Reagents and conditions a) morpholine, 0 ° C, 2 hours; b) pivalic acid-5-ethyl bromide-2-methoxybenzyl ester, bistriphenylphosphine palladium dichloride, iodide Copper, triethylamine, dimethylformamide, 45 ° C; c) tert-butylamine, 120 ° C; d) i. m-chloroperoxybenzoic acid, dichloromethane, room temperature; ii. morpholine, dimethyl Sulfone, 75 ° C; e) Potassium hydroxide, tetrahydrofuran, room temperature.
• the title compound was prepared by the method of Example 13, and the a, b, 0, and 6 steps were the same except that the morpholine in the d step was replaced with (S)-3-methylmorpholine.
• the title compound was obtained as a yellow solid, yield 50%.
• the title compound was prepared by the method of Example 13, and the a, b, 0, and 6 steps were the same except that the morpholine in the d step was replaced with (2S,6R)-2,6-dimethylmorpholine.
• the title compound was obtained as a yellow solid, yield 52%.
• the title compound was prepared by the method of Example 13.
• the reactions of b, 0 and 6 were the same except that the morpholine in step a was replaced by (2S,6R)-2,6-dimethylmorpholine in d step.
• the morpholine was replaced with (S)-3-methylmorpholine.
• the title compound was obtained as a white solid.
• the title compound was prepared by the method of Example 13, and b, c and e were reacted in the same manner except that the morpholine in the a and d steps was changed to (2S,6R)-2,6-dimethylmorpholine.
• the title compound was obtained as a white solid, yield 55%.
• Example 18 (5-(2,4-bis((S)-3-methylmorpholine)pyr! 3 ⁇ 4[4,3-d]pyrimidine! 3 ⁇ 4-7-yl)-2-methoxy Preparation of phenyl)methanol (compound 18)
• the title compound was prepared by the method of Example 13, and b, c and e were reacted in the same manner except that the morpholine in steps a and d was replaced by (S)-3-methylmorpholine.
• the title compound was obtained as a white solid, yield 56%.
• the title compound was prepared by the method of Example 13, and b, c, d, and e were reacted in the same manner except that the morpholine in step a was changed to (S)-3-methylmorpholine.
• the title compound was obtained as a white solid, yield 30%.
• the title compound was prepared by the method of Example 13, and b, c, d and e were reacted in the same manner except that the morpholine in step a was replaced by 8-oxa-3-azabicyclo[3.2.1]octane. Hydrochloride. The title compound was obtained as a white solid.
• the title compound was prepared by the method of Example 13, and the reactions of b, 0 and 6 were the same except that the morpholine in step a was replaced by 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride. Salt, morpholine in step d is replaced with (S)-3-methylmorpholine. The title compound was obtained as a yellow solid.
• the title compound was prepared by the method of Example 13, and b, c and e were reacted in the same manner except that the morpholine in step a and step d was replaced by 3-oxa-8-azabicyclo[3.2.1] octane. Alkane hydrochloride. The title compound was obtained as a white solid, yield 50%.
• the title compound was prepared by the method of Example 13, and b, c, d and e were reacted in the same manner except that the morpholine in step a was replaced by 3-oxa-8-azabicyclo[3.2.1]octane. Hydrochloride. The title compound was obtained as a white solid.
• the title compound was prepared by the method of Example 13, and the steps b, 0 and 6 were the same except that the morpholine in step a was replaced by 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride. Salt, morpholine in step d is replaced with (S)-3-methylmorpholine. The title compound was obtained as a yellow solid.
• the title compound was prepared by the method of Example 13.
• the a, 0 and 6 steps were the same except that the p-pentanoic acid-5-ethyl-bromo-2-methoxybenzyl ester in step b was replaced with a benzene block.
• the morpholine in step d is replaced with (S)-3-methylmorpholine.
• the title compound was obtained in a yield of 42%.
• the title compound was prepared by the method of Example 13.
• the a, 0 and 6 steps were the same except that the p-pentanoic acid-5-ethyl-bromo-2-methoxybenzyl ester in step b was replaced with a benzene block.
• the morpholine in step d is replaced with 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride.
• the title compound was obtained in a yield of 42%.
• the title compound was prepared by the method of Example 13, and c, d and e were reacted in the same manner except that the p-pentanoic acid-5-ethyl-bromo-2-methoxybenzyl ester in step b was replaced with a benzene block. , the morpholine in step a is replaced with (S)-3-methylmorpholine. The title compound was obtained in a yield of 42%.
• the title compound was prepared by the method of Example 13, and c and e were reacted in the same manner except that the p-pentanoic acid-5-ethyl-bromo-2-methoxybenzyl ester in step b was replaced with phenylacetylene, a step. And morpholine in step d was replaced with (S)-3-methylmorpholine. The title compound was obtained in a yield of 42%.
• Reagents and conditions a) potassium phosphate, palladium acetate, 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium, dioxane, reflux; b) methyl chloroformate, sodium Hydrogen, tetrahydrofuran, room temperature; c) 30 wt% hydrogen peroxide, sodium hydroxide, ethanol, reflux; d) phosphorus oxychloride, N,N-diisopropylethylamine, reflux; e) morpholine, N, N-diisopropylethylamine, tetrahydrofuran, room temperature.
• Example 33 (3S,3'S)-4,4'-(7-Phenylpyrimidine[4,5-d]pyrimidine-2,4-diyl)-bis(3-methylmorpholine) (compound) Preparation of 33)
• the title compound was prepared by the method of Example 32, and a, b, c, and d were reacted in the same manner except that the morpholine in the e step was replaced with (S)-3-methylmorpholine.
• the title compound was obtained in a yield of 66%.
• the title compound was prepared by the method of Example 32, and a, b, c and d were reacted in the same manner except that the morpholine in the e step was replaced with 8-oxa-3-azabicyclo[3.2.1]octane. Hydrochloride. The title compound was obtained in a yield of 64%.
• the synthetic route is:
• Reagents and conditions a) N,N-dimethylformamide dimethyl acetal, toluene, reflux; b) 6-aminouracil, glacial acetic acid, water, dimethyl sulfoxide, 99 ° C; c) Phosphorus oxychloride, N,N-diisopropylethylamine, anisole, 80 ° C; d) 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride, N, N -diisopropylethylamine, tetrahydrofuran, room temperature; e) 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride, N,N-diisopropylethylamine, isopropanol, Microwave 160 ° C, 80 minutes.
• the title compound rice was prepared by the method of Example 35, and a, b and c were reacted in the same manner except for the 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in the d and e steps.
• the salt was replaced with 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride.
• the title compound was obtained in a yield of 64%.
• the title compound was prepared by the method of Example 35, and a, b and c were reacted in the same manner except that the 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in step d was replaced ( S)-3-methylmorpholine, 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in step e is replaced by 8-oxa-3-azabicyclo[3.2.1 Octane hydrochloride. The title compound was obtained in a yield of 64%.
• the title compound was prepared by the method of Example 35, and a, b and c were reacted in the same manner except that the 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in step d was replaced. Morpholine, 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in step e was replaced by 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride. The title compound was obtained in a yield of 60%.
• the title compound rice was prepared by the method of Example 35, and the a, b, 0 and 6 steps were the same except that the 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in the d step was obtained. Change to (2S,6R)-2,6-dimethylmorpholine. The title compound was obtained in a yield of 64%.
• the title compound was prepared by the method of Example 35, and a, b and c were reacted in the same manner except that the 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in step d was replaced ( 2S,6R)-2,6-dimethylmorpholine, 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in step e is replaced by 8-oxa-3-aza Bicyclo [3.2.1] octane hydrochloride. The title compound was obtained in a yield of 66%.
• the title compound was prepared by the method of Example 35, and a, b, c and d were reacted in the same manner except that the 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in the e step was changed. Formed morpholine. The title compound was obtained in a yield of 64%.
• the title compound was prepared by the method of Example 35, and a, b, c and d were reacted in the same manner except that the 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in the e step was changed. (2S,6R)-2,6-dimethylmorpholine. The title compound was obtained in a yield of 66%.
• the title compound rice was prepared by the method of Example 35, and a, b, c and d were reacted in the same manner except for the 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in the e step. Change to 2-(methoxyethyl)methylamine. The title compound was obtained in a yield of 60%.
• the title compound was prepared by the method of Example 35, and a, b, c and d were reacted in the same manner except that the 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in the e step was changed. To 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride. The title compound was obtained in a yield of 60%. MS (ESI): m/z, 495 [M+H]+.
• the title compound was prepared by the method of Example 35, and a, b and c were reacted in the same manner except that the 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in step d was changed to 8. -oxa-3-azabicyclo[3.2.1]octane hydrochloride, replacing 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in step e with morpholine. The title compound was obtained in a yield of 64%.
• the title compound was prepared by the method of Example 35, and a, b and c were reacted in the same manner except that the 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in step d was changed to 8. -oxa-3-azabicyclo[3.2.1]octane hydrochloride, replacing 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in step e (S) -3-methylmorpholine. The title compound was obtained in a yield of 64%.
• the title compound was prepared by the method of Example 35, and a, b and c were reacted in the same manner except that the 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in step d was changed to 8. -oxa-3-azabicyclo[3.2.1]octane hydrochloride, replacing 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in step e (2S, 6R)-2,6-dimethylmorpholine. The title compound was obtained in a yield of 64%.
• the title compound was prepared by the method of Example 35, and a, b and c were reacted in the same manner except that the 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in step d was replaced. 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride, replacing 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in step e (2 -Methoxyethyl)methylammonium. The title compound was obtained in a yield of 60%.
• the title compound was prepared by the method of Example 35, and the a, b, 0 and 6 steps were the same except that the 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride in the d step was changed. To 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride. The title compound was obtained in a yield of 66%.
• the mTOR kinase activity assay was performed using 1.7 M mTOR (Millipore, 14-770M), 50 M ULight-4EBPl (Perkin-Elmer, TRF0128M), 100 ⁇ ATP, and the detection system LANCE® f//tra (PerkinElmer).
• mTOR relative activity% (addition hole Lance light value - blank group (without mTOR) light value) / (DMSO group light value - blank group light value) x 100%.
• the test data was processed using Microsoft Office Excel software and Graphpad PRISM 5 software to calculate IC 5Q values.
• the mTOR inhibition rate is expressed by Mean ⁇ SD. The test results are shown in Table 1.
• the cell proliferation assay was based on two types of cell lines, human glioma U87MG and human prostate cancer LNCap, all derived from ATCC.
• U87MG and LNCap contain a PTEN gene deletion, which belongs to mTOR signal-dependent tumor cells.
• the cell culture medium and related reagents were all from GIBCO.
• U87MG cells were cultured in MEM complete medium (containing 10% fetal bovine serum, 100 U/mL penicillin, 100 g/mL streptomycin).
• LNCap cells were cultured in RPMI-1640 complete medium (containing 10% fetal bovine serum, 100 U/mL penicillin, 100 g/mL streptomycin).
• MTS and PMS were purchased from sigma company, mother liquor MTS/PMSC20: 1) 20 ⁇ 7 wells were added to the test cells, and the proliferation test results were recorded in a 96-well plate microplate after appropriate incubation.
• Cell relative viability % (medical group ⁇ 4 90 value - blank group light value) / (DMSO group light value - blank group light value) x l00%.
• the test data was processed using Microsoft Office Excel software and Graphpad PRISM 5 software to calculate IC 5Q values.
• the cell proliferation inhibition rate was expressed by Mean ⁇ SD. See Table 2 for test results.

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