WO2017028810A1 - 一种噻吩并嘧啶化合物 - Google Patents

一种噻吩并嘧啶化合物 Download PDF

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WO2017028810A1
WO2017028810A1 PCT/CN2016/095990 CN2016095990W WO2017028810A1 WO 2017028810 A1 WO2017028810 A1 WO 2017028810A1 CN 2016095990 W CN2016095990 W CN 2016095990W WO 2017028810 A1 WO2017028810 A1 WO 2017028810A1
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cancer
group
compound
pharmaceutically acceptable
acceptable salt
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PCT/CN2016/095990
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English (en)
French (fr)
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易崇勤
许恒
韩方斌
林松文
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北大方正集团有限公司
方正医药研究院有限公司
北大医疗产业集团有限公司
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Publication of WO2017028810A1 publication Critical patent/WO2017028810A1/zh

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present application belongs to the technical field of medicinal chemistry, and in particular, the present application relates to a thienopyrimidine compound.
  • Molecularly targeted drugs are a key mode of action for receptors or transduction processes in the process of cell carcinogenesis, and a therapeutic mode that inhibits tumor growth at the molecular level. Targeting the characteristic molecules of tumor cells, it exerts anti-tumor effects while reducing the toxic side effects on normal cells.
  • Phosphoinositide 3-kinase catalyzes the synthesis of phosphatidylinositol (PI) second messenger PI(3)P, PI(3,4)P2 and PI(3,4,5)P3(PIP3) . Under the proper cellular environment, these three lipids control a variety of physiological processes including cell growth, survival, differentiation, and chemotaxis.
  • the major PI3-kinase isoform in cancer is a class I PI3-K ⁇ consisting of a catalytic (p110 ⁇ ) subunit and a adaptor (p85) subunit.
  • PI3-K/Akt/PTEN pathway Several components of the PI3-K/Akt/PTEN pathway are involved in tumor formation and play an important role in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis, and exercise, and are such as cancer, diabetes, and An important component of the molecular mechanism of diseases such as immune inflammation.
  • PI3-K ⁇ is an attractive and promising target for the development of cancer drugs, which will inhibit the proliferation of cancer cells, and avoid damage to the body by cytotoxic agents, and the tolerance of cancer cells to cytotoxic agents.
  • PI3-K ⁇ inhibitors for use as cancer therapeutics in the field of cancer therapy.
  • the present application provides a thienopyrimidine compound, as well as processes for their preparation and their use as PI3-K and/or mTOR kinase inhibitors.
  • R 1 is selected from hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, and substituted or unsubstituted C 1 -C 4 alkoxy;
  • R 2 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkylcarbonyl and C 3 -C 6 cycloalkylcarbonyl;
  • R 3 is selected from C 1 -C 4 alkyl
  • R 4 is selected from a substituted or unsubstituted phenyl group.
  • the substituted C 1 -C 4 alkyl, substituted C 1 -C 4 alkoxy or substituted phenyl refers to the C 1 -C 4 alkyl group
  • the C 1 -C 4 alkoxy group or the phenyl group are each independently substituted by one or more (for example 1, 2, 3, 4 or 5) substituents selected from the group consisting of halogen, hydroxy, amino, nitro, Cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and C 1 -C 4 alkylcarbonyl.
  • R 4 is a substituted phenyl group, the number of substituents being from 1 to 5, and the substituent is selected from halogen.
  • R 4 is a substituted phenyl group, the number of substituents is 1-2, and the substituent is fluorine. In certain preferred embodiments of the present application, the R 4 is 4-fluorophenyl or 2,4-difluorophenyl.
  • the R 4 is 4-fluorophenyl.
  • the R 4 is 2,4-difluorophenyl.
  • R 1 is selected from the group consisting of halogen, unsubstituted C 1 -C 4 alkyl, and unsubstituted C 1 -C 4 alkoxy.
  • R 1 is selected from halogen.
  • R 1 is chloro
  • R 1 is selected from unsubstituted C 1 -C 4 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec Butyl.
  • R 1 is methyl
  • R 1 is selected from unsubstituted C 1 -C 4 alkoxy groups such as methoxy, ethoxy or isopropoxy.
  • R 1 is methoxy
  • R 1 is selected from the group consisting of methyl, methoxy, and chloro.
  • R 3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and isobutyl.
  • R 3 is methyl
  • R 2 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkylcarbonyl, and C 3 -C 6 cycloalkylcarbonyl.
  • R 2 is hydrogen
  • R 2 is C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl.
  • R 2 is methyl
  • R 2 is C 1 -C 3 alkylcarbonyl, such as methylcarbonyl, ethylcarbonyl, propylcarbonyl or isopropylcarbonyl.
  • R 2 is methylcarbonyl
  • R 2 is C 3 -C 6 cycloalkylcarbonyl, such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl.
  • R 2 is cyclopropylcarbonyl.
  • R 2 is selected from the group consisting of hydrogen, methyl, methylcarbonyl, and cyclopropylcarbonyl.
  • R 1 is selected from the group consisting of halogen, unsubstituted C 1 -C 4 alkyl, and unsubstituted C 1 -C 4 alkoxy;
  • R 2 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkylcarbonyl and C 3 -C 6 cycloalkylcarbonyl;
  • R 3 is selected from C 1 -C 4 alkyl
  • R 4 is a substituted phenyl group, and the number of the substituent is from 1 to 5, and the substituent is selected from a halogen.
  • R 1 is selected from the group consisting of halogen and unsubstituted C 1 -C 4 alkoxy;
  • R 2 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and C 1 -C 3 alkylcarbonyl;
  • R 3 is a methyl group
  • R 4 is a substituted phenyl group, the number of substituents is 1-2, and the substituent is fluorine.
  • R 1 is selected from the group consisting of chloro, methyl, and methoxy
  • R 2 is selected from the group consisting of hydrogen, methyl, methylcarbonyl and cyclopropylcarbonyl;
  • R 3 is a methyl group
  • R 4 is selected from the group consisting of 4-fluorophenyl and 2,4-difluorophenyl.
  • R 1 is selected from the group consisting of chlorine and methoxy
  • R 2 is selected from the group consisting of hydrogen, methyl and methylcarbonyl
  • R 3 is a methyl group
  • R 4 is 2,4-difluorophenyl.
  • the compound of formula I may be selected from the following compounds 1-8:
  • the application also provides a process for the preparation of a compound of formula I selected from the following synthetic methods:
  • Step 1 Methyl 2-aminothiophene-3-carboxylate (Compound 1) and chloroformamidine hydrochloride are reacted in a suitable solvent such as diethylene glycol dimethyl ether at a high temperature ranging from 160 ° C to 200 ° C. Obtaining compound 2;
  • Step 2 Compound 2 is reacted with pivalic anhydride in a suitable solvent such as dimethylformamide in the presence of a base such as triethylamine at a temperature ranging from 60 ° C to 100 ° C to obtain compound 3;
  • a suitable solvent such as dimethylformamide
  • a base such as triethylamine
  • Step 3 Compound 3 is reacted with a chlorinating reagent such as phosphorus oxychloride at a temperature ranging from 20 ° C to 100 ° C to obtain a compound 4;
  • a chlorinating reagent such as phosphorus oxychloride
  • Step 4 converting compound 4 to compound 5 by treatment with methyl boronic acid according to modified Suzuki reaction conditions known to those skilled in the art;
  • Step 5 converting compound 5 to compound 6 by treatment with a brominating reagent such as N-bromosuccinimide;
  • Step 6 Conversion of compound 6 to compound 8 by treatment with compound 7 according to modified Suzuki reaction conditions known to those skilled in the art, followed by hydrolysis with sodium hydroxide;
  • R 1 and R 4 are as defined in the compound of formula I herein;
  • Step 1 Compound 6 is hydrolyzed by sodium hydroxide to obtain compound 9;
  • Step 2 Compound 9 is reacted with an alkyl acid chloride in a suitable solvent such as dimethylformamide in the presence of a base such as triethylamine at a temperature ranging from 0 ° C to 100 ° C to give compound 10;
  • a suitable solvent such as dimethylformamide
  • a base such as triethylamine
  • Step 3 Conversion of compound 10 to compound 11 by treatment with compound 7 according to modified Suzuki reaction conditions known to those skilled in the art;
  • R 5 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl; the remaining substituents are as defined in the compounds of formula I herein;
  • Step 1 Compound 6 is reacted with an alkylating agent in a suitable solvent such as dimethylformamide in the presence of a base such as sodium hydride at a temperature ranging from 0 ° C to 100 ° C to give compound 12;
  • a suitable solvent such as dimethylformamide
  • a base such as sodium hydride
  • Step 2 Compound 12 is hydrolyzed by sodium hydroxide to obtain compound 13;
  • Step 3 Pass according to modified Suzuki reaction conditions known to those skilled in the art Compound 7 is treated to convert compound 13 to compound 14;
  • R 6 is C 1 -C 4 alkyl; the remaining substituents are as defined in the compounds of formula I herein.
  • the compound of formula I described herein is a multi-kinase inhibitor that inhibits a variety of kinases present in cells and on the cell surface, including PI3-K and/or mTOR kinase.
  • the PI3-K is preferably PI3-K ⁇ .
  • the compounds and pharmaceutically acceptable salts thereof are useful in the manufacture of a medicament for the treatment and/or prevention of diseases caused by PI3-K and/or mTOR kinase.
  • the compound and a pharmaceutically acceptable salt thereof can be used for the preparation of a medicament for treating and/or preventing a disease caused by PI3-K kinase; preferably, the PI3-K kinase is PI3-K ⁇ kinase.
  • the compounds and pharmaceutically acceptable salts thereof can be used in the manufacture of a medicament for treating and/or preventing a disease caused by mTOR kinase.
  • the compound and a pharmaceutically acceptable salt thereof can be used for the preparation of a medicament for treating and/or preventing a disease caused by PI3-K and mTOR kinase.
  • the disease caused by the PI3-K and mTOR kinase is cancer.
  • the cancer is selected from the group consisting of brain cancer, glioblastoma, head and neck cancer, lung cancer, melanoma, liver cancer, renal cancer, acute leukemia, chronic leukemia, non-small cell lung cancer, prostate Cancer, thyroid cancer, skin cancer, colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, breast cancer, abnormal bone marrow hyperplasia syndrome, esophageal cancer, sarcoma, osteosarcoma and rhabdomyosarcoma.
  • the pharmaceutically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, triflate , benzenesulfonate, p-toluenesulfonate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate Oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, mandelate, and the like.
  • the present application also provides a pharmaceutical composition for treating and/or preventing a disease caused by PI3-K and/or mTOR kinase, the pharmaceutical composition comprising a compound of the formula I described herein or a pharmaceutically acceptable compound thereof Salt, as well as medicinal excipients.
  • the pharmaceutical composition is an injection, an oral preparation, a transdermal absorbent or a suppository.
  • the compounds of formula I described herein, and pharmaceutically acceptable salts thereof, are useful in the manufacture of a medicament for the treatment and/or prevention of neoplastic diseases.
  • the present application relates to a method of treating and/or preventing a disease caused by PI3-K and/or mTOR kinase, which comprises administering to a subject in need thereof an effective amount of a compound of the formula I described herein or a pharmaceutical thereof The step of accepting the salt.
  • the disease caused by the PI3-K and/or mTOR kinase is cancer.
  • the cancer is selected from the group consisting of brain cancer, glioblastoma, head and neck cancer, lung cancer, melanoma, liver cancer, renal cancer, acute leukemia, chronic leukemia, non-small cell lung cancer, prostate Cancer, thyroid cancer, skin cancer, colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, breast cancer, abnormal bone marrow hyperplasia syndrome, esophageal cancer, sarcoma, osteosarcoma and rhabdomyosarcoma.
  • the present application also relates to the compounds of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of diseases caused by PI3-K and/or mTOR kinase.
  • the disease caused by the PI3-K and/or mTOR kinase is cancer.
  • the cancer is selected from the group consisting of brain cancer, glioblastoma, head and neck cancer, lung cancer, melanoma, liver cancer, renal cancer, acute leukemia, chronic leukemia, non-small cell lung cancer, prostate Cancer, thyroid cancer, skin cancer, colon cancer, rectal cancer, pancreatic cancer, ovarian cancer, breast cancer, abnormal bone marrow hyperplasia syndrome, esophageal cancer, sarcoma, osteosarcoma and rhabdomyosarcoma.
  • N-(4-chlorothieno[2,3-d]pyrimidin-2-yl)pivalamide (2.3 mg, 8.53 mmol), methylboronic acid (1.53 mg, 25.59 mmol) and 2N carbonic acid in a sealed tube a mixture of potassium aqueous solution (12.8 mL, 25.59 mmol) in 1,4-dioxane (65 mL) with argon After bubbling for 5 minutes, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (312 mg, 0.4265 mmol) was then added. The resulting reaction mixture was again bubbled with argon for 5 minutes, sealed and stirred at 105 ° C for 3 hours.
  • Step 6 N-(5-(2-Amino-4-methylthieno[2,3-d]pyrimidin-6-yl)-2-methoxypyridin-3-yl)-2,4-di Fluorobenzenesulfonamide
  • N-(6-Bromo-4-methylthieno[2,3-d]pyrimidin-2-yl)pivalamide (66 mg, 0.2 mmol)
  • N-(2-methoxy-5-(4) ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (102 mg, 0.24 mmol
  • degassing a mixture of 2N aqueous potassium carbonate solution 0.4 mL, 0.8 mmol) in 1,4-dioxane (5 mL) and adding [1,1'-bis(diphenylphosphino)ferrocene Palladium dichloride (15 mg, 0.02 mmol).
  • the resulting reaction mixture was degassed and backfilled with argon (three cycles), and then stirred at 100 ° C for 7.5 hours under an argon atmosphere.
  • the reaction mixture was cooled to room temperature and the volatiles were evaporated in vacuo.
  • Ethanol (3 mL) and 2N sodium hydroxide (0.2 mL, 0.4 mmol) were added to the residue, and the resulting mixture was stirred at 90 ° C for 1.5 hr.
  • the reaction mixture was cooled to room temperature and the volatiles were evaporated in vacuo.
  • the residue was partitioned between ethyl acetate (30 mL) and water (30 mL). The combined organic layers were washed with EtOAcq.
  • the residue was purified by EtOAc EtOAcjjjjjjjjj
  • Step 2 N-(5-(2-Amino-4-methylthieno[2,3-d]pyrimidin-6-yl)-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide synthesis
  • N-(5-Bromo-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (88 mg, 0.24 mmol), boronic acid pinacol ester (67 mg, 0.264 mmol) and anhydrous potassium acetate (47 mg) , 0.48 mmol) of the mixture in dioxane (5 mL) was degassed, then [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride (9 mg, 0.012 mmol, 0.05 eq ) is added to the mixture.
  • Step 2 N-(6-(5-(2,4-Difluorobenzenesulfonamido)-6-methoxypyridin-3-yl)-4-methylthieno[2,3-d]pyrimidine -2-yl)acetamide
  • N-(6-Bromo-4-methylthieno[2,3-d]pyrimidin-2-yl)acetamide 50 mg, 0.175 mmol
  • N-(2-methoxy-5-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide 90 mg, 0.21 mmol
  • 2N aqueous potassium carbonate solution 0.263 mL, 0.526 mmol
  • dimethylformamide 4 mL
  • Step 2 N-(6-(5-(2,4-Difluorobenzenesulfonamido)-6-methoxypyridin-3-yl)-4-methylthieno[2,3-d]pyrimidine -2-yl)cyclopropanecarboxamide
  • Step 3 N-(2-Methoxy-5-(4-methyl-2-(methylamino)thieno[2,3-d]pyrimidin-6-yl)pyridin-3-yl) 2,4 -Synthesis of difluorobenzenesulfonamide
  • the potency of the compounds of the present application against PI3K-[alpha] was assessed using an in vitro kinase assay.
  • the kinase activity of PI3K- ⁇ was determined by detecting the level of ADP produced in the kinase reaction using luciferase-based luminescence detection.
  • ADP-Glo TM kinase assay kit was purchased from Promega. All tests were performed at room temperature using a white OptiPlate TM -384 384-well plates.
  • PI3K-alpha kinase is from Crownbio.
  • the substrate was PIP2/PS (Invitrogen).
  • the kinase buffer included 50 mM Hepes (pH 7.5), 3 mM MgCl2, 100 mM NaCl, 1 nM EGTA, 0.03% CHAPS and 2 mM DTT.
  • a PI3K-alpha kinase cocktail was prepared by diluting PI3K-alpha kinase to 0.375 ng/ ⁇ L in kinase buffer.
  • the ATP/substrate mix included 5 ⁇ M PIP 2/PS and 25 ⁇ M ATP.
  • the test compound was diluted to 10 mM in 100% DMSO and then serially diluted 3 times into 10 different concentrations in 100% DMSO.
  • the compound was then diluted in 100% DMSO is diluted 20-fold in ddH 2 O in. 2 ⁇ L of the diluted compound solution and 4 ⁇ L of the ATP/substrate mixture were added to each well of a 384-well plate.
  • the reaction was started by adding 4 ⁇ L of PI3K ⁇ kinase mixture per well, and the final reaction volume was 10 ⁇ L, the ATP concentration was 10 ⁇ M, the PIP 2/PS concentration was 2 ⁇ M, and the PI3K- ⁇ kinase concentration was 0.15 ng/ ⁇ L.
  • the plate was capped and the reaction was allowed to proceed for 1 hour at room temperature, followed by the addition of 10 [mu]L of kinase Glo (TM) reagent per well to stop the reaction.
  • the plates were incubated for 40 minutes and then 20 [mu]L of Kinase Detection Reagent per well was added.
  • the plates were equilibrated in the dark for 30 minutes and then luminescence was read on an EnVision 2104 multi-label microplate reader plate reader.
  • the percent inhibition is calculated based on the following formula:
  • RLU compound is a luminescence reading at a given compound concentration
  • RLU minutes is the luminescence reading in the case of the addition of the highest concentration (2.5 uM) positive control compound
  • RLU max is the luminescence reading in the absence of compound addition.
  • IC 50 is calculated by using the compounds in Excel XLfit program.
  • the compound of the present application has a significant inhibitory effect on PI3K- ⁇ , and the compound of the present application can be used for the preparation of a medicament for treating and preventing cancer and tumor diseases.

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Abstract

本申请公开了一种噻吩并嘧啶化合物，以及它们的制备方法和其作为PI3-K和/或mTOR激酶抑制剂的用途。该取代的噻吩并嘧啶化合物及其药学上可接受的盐可用于制备治疗和/或预防肿瘤疾病的药物。

Description

一种噻吩并嘧啶化合物 技术领域
本申请属于药物化学技术领域，具体地，本申请涉及一种噻吩并嘧啶化合物。
背景技术
抗肿瘤药物的研究与开发是当今生命科学中极富挑战性且意义重大的领域。近年来，随着分子生物学的飞速发展以及人们对癌症发生、发展、作用机制的进一步认识，恶性肿瘤细胞内的信号转导、细胞周期的调控、细胞凋亡的诱导、血管生成以及细胞与胞外基质的相互作用等各种基本过程正在被逐步阐明。因此寻找和发现选择性作用于特定靶点的高效、低毒、特异性强的新型抗肿瘤药物已成为当前药物研究开发的重要领域之一。由此产生了一个新的抗癌药物领域-分子靶向药物。
分子靶向药物是指针对细胞癌变过程的受体或转导过程中关键的酶，从分子水平抑制肿瘤生长的治疗模式。以肿瘤细胞的特征分子为靶点，在发挥抗肿瘤作用的同时，减少了对正常细胞的毒副作用。
磷酸肌醇3-激酶(PI3-K)催化磷脂酰肌醇(PI)第二信使PI(3)P、PI(3,4)P2及PI(3,4,5)P3(PIP3)的合成。在适当的细胞环境下，这三种脂质控制多种包括细胞生长、存活、分化及趋化性的生理学过程。癌症中的主要PI3-激酶同功异型物为由催化性(p110α)亚单元及转接子(p85)亚单元组成的Ⅰ类PI3-Kα。PI3-K/Akt/PTEN通路的数种组分涉及肿瘤形成，在包括细胞周期调节、增生、存活、细胞凋亡及运动的许多细胞过程的调控中发挥重要作用，且为诸如癌症、糖尿病及免疫性炎症等疾病的分子机制的重要组分。
因此，PI3-Kα为开发癌症药物的具有吸引力和前景的靶标，此类药剂将抑制癌细胞增生，且避免了细胞毒制剂对机体的损伤，及癌细胞对细胞毒制剂的耐受。人们需要新颖的PI3-Kα抑制剂，作为癌症治疗药物应用于癌症治疗领域。
发明内容
本申请提供一种噻吩并嘧啶化合物，以及它们的制备方法和其作为PI3-K和/或mTOR激酶抑制剂的用途。
本申请的技术方案具体如下：
一种噻吩并嘧啶化合物或其药学上可接受的盐，其中所述化合物具有如下式Ⅰ所示的结构：
Figure PCTCN2016095990-appb-000001
其中：
R1选自氢、卤素、取代或未取代的C1-C4烷基和取代或未取代的C1-C4烷氧基；
R2选自氢、C1-C4烷基、C1-C3烷基羰基和C3-C6环烷基羰基；
R3选自C1-C4烷基；
R4选自取代或未取代的苯基。
在本申请的某些优选实施方案中，所述取代的C1-C4烷基、取代的C1-C4烷氧基或取代的苯基是指所述C1-C4烷基、C1-C4烷氧基或苯基各自独立地被一个或多个(例如1、2、3、4或5个)选自下述的取代基取代：卤素、羟基、氨基、硝基、氰基、C1-C4烷基、C1-C4烷氧基和C1-C4烷基羰基。
在本申请的某些优选实施方案中，所述R4为取代的苯基，取代基的个数为1-5个，取代基选自卤素。
在本申请的某些优选实施方案中，所述R4为取代的苯基，取代基的个数为1-2个，取代基为氟。在本申请的某些优选实施方案中，所述R4为4-氟苯基或2，4-二氟苯基。
在本申请的某些优选实施方案中，所述R4为4-氟苯基。
在本申请的某些优选实施方案中，所述R4为2，4-二氟苯基。
在本申请的某些优选实施方案中，R1选自卤素、未取代的C1-C4烷基和未取代的C1-C4烷氧基。
在本申请的某些优选实施方案中，R1选自卤素。
在本申请的某些优选实施方案中，R1为氯。
在本申请的某些优选实施方案中，R1选自未取代的C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或仲丁基。
在本申请的某些优选实施方案中，R1为甲基。
在本申请的某些优选实施方案中，R1选自未取代的C1-C4烷氧基，例如甲氧基、乙氧基或异丙氧基。
在本申请的某些优选实施方案中，R1为甲氧基。
在本申请的某些优选实施方案中，R1选自甲基、甲氧基和氯。
在本申请的某些优选实施方案中，R3选自甲基、乙基、丙基、异丙基、丁基、仲丁基和异丁基。
在本申请的某些优选实施方案中，R3为甲基。
在本申请的某些优选实施方案中，R2选自氢、C1-C4烷基、C1-C3烷基羰基和C3-C6环烷基羰基。
在本申请的某些优选实施方案中，R2为氢。
在本申请的某些优选实施方案中，R2为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或仲丁基。
在本申请的某些优选实施方案中，R2为甲基。
在本申请的某些优选实施方案中，R2为C1-C3烷基羰基，例如甲基羰基、乙基羰基、丙基羰基或异丙基羰基。
在本申请的某些优选实施方案中，R2为甲基羰基。
在本申请的某些优选实施方案中，R2为C3-C6环烷基羰基，例如环丙基羰基、环丁基羰基、环戊基羰基、环己基羰基。
在本申请的某些优选实施方案中，R2为环丙基羰基。
在本申请的某些优选实施方案中，R2选自氢、甲基、甲基羰基和环丙基羰基。
在本申请的某些优选实施方案中，R1选自卤素、未取代的C1-C4烷 基和未取代的C1-C4烷氧基；
R2选自氢、C1-C4烷基、C1-C3烷基羰基和C3-C6环烷基羰基；
R3选自C1-C4烷基；
R4为取代的苯基，取代基的个数为1-5个，取代基选自卤素。
在本申请的某些优选实施方案中，R1选自卤素和未取代的C1-C4烷氧基；
R2选自氢、C1-C4烷基和C1-C3烷基羰基；
R3为甲基；
R4为取代的苯基，取代基的个数为1-2个，取代基为氟。
在本申请的某些优选实施方案中，R1选自氯、甲基和甲氧基；
R2选自氢、甲基、甲基羰基和环丙基羰基；
R3为甲基；
R4选自4-氟苯基和2，4-二氟苯基。
在本申请的某些优选实施方案中，R1选自氯和甲氧基；
R2选自氢、甲基和甲基羰基；
R3为甲基；
R4为2，4-二氟苯基。
在本申请的某些优选实施方案中，所述式I化合物可选自下列化合物1～8：
化合物1、
Figure PCTCN2016095990-appb-000002
化合物2、
Figure PCTCN2016095990-appb-000003
化合物3、
Figure PCTCN2016095990-appb-000004
化合物4、
Figure PCTCN2016095990-appb-000005
化合物5、
Figure PCTCN2016095990-appb-000006
化合物6、
Figure PCTCN2016095990-appb-000007
化合物7、
Figure PCTCN2016095990-appb-000008
和
化合物8、
Figure PCTCN2016095990-appb-000009
本申请还提供了式I所示的化合物的制备方法，其选自以下合成方法：
方法A：
Figure PCTCN2016095990-appb-000010
步骤1：2-氨基噻吩-3-羧酸甲酯(化合物1)与氯甲脒盐酸盐在160℃至200℃范围内的高温下在例如二乙二醇二甲醚的合适溶剂中反应得到化合物2；
步骤2：化合物2在60℃至100℃范围内的温度下在例如三乙胺的碱存在下在例如二甲基甲酰胺的合适溶剂中与特戊酸酐反应得到化合物3；
步骤3：化合物3在20℃至100℃范围内的温度下与例如三氯氧磷的氯代试剂反应得到化合物4；
步骤4：根据经修改的本领域技术人员已知的Suzuki反应条件通过甲基硼酸处理，将化合物4转化为化合物5；
步骤5：通过例如N－溴代丁二酰亚胺的溴代试剂处理，将化合物5转化为化合物6；
步骤6：根据经修改的本领域技术人员已知的Suzuki反应条件通过化合物7处理，然后经氢氧化钠水解，将化合物6转化为化合物8；
其中，R1与R4定义如本申请通式I化合物中所述；
方法B：
Figure PCTCN2016095990-appb-000011
步骤1：化合物6经氢氧化钠水解得到化合物9；
步骤2：化合物9在0℃至100℃范围内的温度下在例如三乙胺的碱存在下在例如二甲基甲酰胺的合适溶剂中与烷基酰氯反应得到化合物10；
步骤3：根据经修改的本领域技术人员已知的Suzuki反应条件通过化合物7处理，将化合物10转化为化合物11；
其中，R5为C1-C3烷基或C3-C6环烷基；其余取代基定义如本申请通式I化合物中所述；
方法C：
Figure PCTCN2016095990-appb-000012
步骤1：化合物6在0℃至100℃范围内的温度下在例如氢化钠的碱存在下在例如二甲基甲酰胺的合适溶剂中与烷基化试剂反应得到化合物12；
步骤2：化合物12经氢氧化钠水解得到化合物13；
步骤3：根据经修改的本领域技术人员已知的Suzuki反应条件通过 化合物7处理，将化合物13转化为化合物14；
其中，R6为C1-C4烷基；其余取代基定义如本申请通式I化合物中所述。
本申请所述通式I化合物是一种多激酶抑制剂，能同时抑制多种存在于细胞内和细胞表面的激酶，包括PI3-K和/或mTOR激酶。所述PI3-K优选为PI3-Kα。因此，所述化合物及其药学上可接受的盐可用于制备治疗和/或预防PI3-K和/或mTOR激酶引起的疾病的药物。例如，所述化合物及其药学上可接受的盐可用于制备治疗和/或预防PI3-K激酶引起的疾病的药物；优选地所述PI3-K激酶为PI3-Kα激酶。例如，所述化合物及其药学上可接受的盐可用于制备治疗和/或预防mTOR激酶引起的疾病的药物。例如，所述化合物及其药学上可接受的盐可用于制备治疗和/或预防PI3-K和mTOR激酶引起的疾病的药物。
在本申请的某些优选实施方案中，所述PI3-K和mTOR激酶引起的疾病为癌症。
在本申请的某些优选实施方案中，所述癌症选自脑癌、成胶质细胞瘤、头颈癌、肺癌、黑色素瘤、肝癌、肾癌、急性白血病、慢性白血病、非小细胞肺癌、前列腺癌、甲状腺癌、皮肤癌、结肠癌、直肠癌、胰腺癌、卵巢癌、乳腺癌、骨髓异常增生综合症、食管癌、肉瘤、骨肉瘤和横纹肌瘤。
在本申请的某些优选实施方案中，所述药学上可接受的盐包括但不限于：盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、甲磺酸盐、三氟甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、1-萘磺酸盐、2-萘磺酸盐、乙酸盐、三氟乙酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、乳酸盐、草酸盐、琥珀酸盐、富马酸盐、马来酸盐、苯甲酸盐、水杨酸盐、苯基乙酸盐、杏仁酸盐等。
本申请还提供了一种治疗和/或预防PI3-K和/或mTOR激酶引起的疾病的药物组合物，所述的药物组合物中含有本申请所述通式I化合物或其药学上可接受的盐，以及药用辅料。优选地，所述的药物组合物为注射剂、口服制剂、透皮吸收剂或栓剂。
本申请所述通式I化合物及其药学上可接受的盐可用于制备治疗和/或预防肿瘤疾病的药物。
本申请涉及一种治疗和/或预防PI3-K和/或mTOR激酶引起的疾病的方法，其包括给有此需要的受试者施用有效量的本申请所述的通式I化合物或其药学上可接受的盐的步骤。
在本申请的某些优选实施方案中，所述PI3-K和/或mTOR激酶引起的疾病为癌症。在本申请的某些优选实施方案中，所述癌症选自脑癌、成胶质细胞瘤、头颈癌、肺癌、黑色素瘤、肝癌、肾癌、急性白血病、慢性白血病、非小细胞肺癌、前列腺癌、甲状腺癌、皮肤癌、结肠癌、直肠癌、胰腺癌、卵巢癌、乳腺癌、骨髓异常增生综合症、食管癌、肉瘤、骨肉瘤和横纹肌瘤。
本申请还涉及所述通式I化合物或其药学上可接受的盐，其用于治疗和/或预防PI3-K和/或mTOR激酶引起的疾病。
在本申请的某些优选实施方案中，所述PI3-K和/或mTOR激酶引起的疾病为癌症。在本申请的某些优选实施方案中，所述癌症选自脑癌、成胶质细胞瘤、头颈癌、肺癌、黑色素瘤、肝癌、肾癌、急性白血病、慢性白血病、非小细胞肺癌、前列腺癌、甲状腺癌、皮肤癌、结肠癌、直肠癌、胰腺癌、卵巢癌、乳腺癌、骨髓异常增生综合症、食管癌、肉瘤、骨肉瘤和横纹肌瘤。
具体实施方式
以下通过具体实施例对本发明作进一步说明。在本发明说明书和权利要求中，化合物的命名都是依据化学结构式，如果表示同一化合物时化合物的命名与化学结构式不符，以化学结构式或化学反应式为准。
实施例1：N-(5-(2-氨基-4-甲基噻吩并[2,3-d]嘧啶-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺的合成
Figure PCTCN2016095990-appb-000013
步骤1：2-氨基噻吩并[2,3-d]嘧啶-4-酚的合成
Figure PCTCN2016095990-appb-000014
将2-氨基噻吩-3-羧酸甲酯(8g，50.96mmol)和氯甲脒盐酸盐(14.65g，127.39mmol)于二乙二醇二甲醚(30mL)中的混合物在200℃下搅拌1.5小时，然后在180℃下再搅拌1.5小时。将反应混合物冷却至室温，弃去溶液部分。向残留物中加入3N氢氧化钠水溶液(45mL)，并将产生的混合物在70℃下搅拌至变为澄清溶液。将产生的溶液冷却至室温，用浓盐酸酸化至pH为2～3，并将产生的混悬液在室温下搅拌3小时。抽滤收集产生的沉淀，用水洗涤，在50℃下干燥得到标题化合物为灰白色固体(6.7g，产率78.64％)。粗标题化合物不经进一步纯化直接用于下一步。
1H NMR(400MHz,DMSO-d6)δ10.89(br s,1H),7.09(d,J＝5.8Hz,1H),6.97(d,J＝5.8Hz,1H),6.52(br s,2H).
MS(ESI+)m/z 168.1[M+H]+.
步骤2：N-(4-羟基噻吩并[2,3-d]嘧啶-2-基)特戊酰胺的合成
Figure PCTCN2016095990-appb-000015
将2-氨基噻吩并[2,3-d]嘧啶-4-酚(941mg，5.63mmol)，特戊酸酐(2.3mL，11.26mmol)，三乙胺(1.6mL，11.26mmol，2.0eq)和4-二甲氨基吡啶(138mg，1.13mmol)于二甲基甲酰胺(4mL)中的混合物在80℃下氩气气氛中搅拌16小时。将反应混合物冷却，用水 (100mL)稀释，用乙酸乙酯(100mL×3)萃取。用水(50mL×2)和食盐水(50mL×2)洗涤合并的有机层，用硫酸钠干燥，过滤，浓缩。残留物经快速柱色谱(硅胶，石油醚/乙酸乙酯＝6:1)纯化得到标题化合物为淡黄色固体(740mg，产率53％)。
1H NMR(400MHz,DMSO-d6)δ12.20(s,1H),11.19(s,1H),7.41(d,J＝5.8Hz,1H),7.33(d,J＝5.8Hz,1H),1.25(s,9H).
MS(ESI+)m/z 252.1[M+H]+.
步骤3：N-(4-氯噻吩并[2,3-d]嘧啶-2-基)特戊酰胺的合成
Figure PCTCN2016095990-appb-000016
将N-(4-羟基噻吩并[2,3-d]嘧啶-2-基)特戊酰胺(2.0g，7.96mmol)于三氯氧磷(12mL)中的混合物回流1小时。在真空中浓缩反应混合物，将残留物倒入冰水(100mL)中。用饱和碳酸氢钠水溶液中和产生的混合物，用乙酸乙酯萃取(50mL×3)。用水(50mL×2)和食盐水(30mL×2)洗涤合并的有机层，用无水硫酸钠干燥，过滤，浓缩。残留物经快速柱色谱(硅胶，石油醚/乙酸乙酯＝8:1然后5:1)纯化得到标题化合物为白色固体(1.4g，产率66.7％)。
1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),7.90(d,J＝6.0Hz,1H),7.48(d,J＝6.0Hz,1H),1.24(s,9H).
MS(ESI+)m/z 270.1[M+H]+.
步骤4：N-(4-甲基噻吩并[2,3-d]嘧啶-2-基)特戊酰胺的合成
Figure PCTCN2016095990-appb-000017
在密封管中将N-(4-氯噻吩并[2,3-d]嘧啶-2-基)特戊酰胺(2.3mg，8.53mmol)，甲基硼酸(1.53mg，25.59mmol)和2N碳酸钾水溶液(12.8mL，25.59mmol)于1,4-二氧六环(65mL)中的混合物以氩气 鼓泡5分钟，然后加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(312mg，0.4265mmol)。将产生的反应混合物再以氩气鼓泡5分钟，密封并在105℃下搅拌3小时。将反应混合物冷却至室温，在真空中蒸发除去挥发物。将残留物分配于乙酸乙酯萃取(50mL)和水(50mL)之间，用乙酸乙酯(50mL×2)萃取水层。用水(50mL)和食盐水(50mL)洗涤合并的有机层，用无水硫酸钠干燥，过滤，浓缩。用残留物经快速柱色谱(硅胶，石油醚/乙酸乙酯＝4:1然后3:1)纯化得到标题化合物为黄色固体(900mg，产率42.3％)。
1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),7.73(d,J＝6.0Hz,1H),7.59(d,J＝6.0Hz,1H),2.73(s,3H),1.24(s,9H).
MS(ESI+)m/z 250.1[M+H]+.
步骤5：N-(6-溴-4-甲基噻吩并[2,3-d]嘧啶-2-基)特戊酰胺的合成
Figure PCTCN2016095990-appb-000018
向N-(4-甲基噻吩并[2,3-d]嘧啶-2-基)特戊酰胺(900mg，3.6mmol)于二甲基甲酰胺(4mL)中的溶液中加入N-溴代丁二酰亚胺(770mg，4.32mmol)，将产生的混合物在室温下搅拌4小时。用水(30mL)稀释反应混合物，用乙酸乙酯(30mL×3)萃取水层。用水(30mL×2)和食盐水(30mL×2)洗涤合并的有机层，用无水硫酸钠干燥，过滤，浓缩。用残留物经快速柱色谱(硅胶，石油醚/乙酸乙酯＝6:1)纯化得到标题化合物为黄色固体(900mg，产率76.3％)。
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),7.88(s,1H),2.68(s,3H),1.23(s,9H).
步骤6：N-(5-(2-氨基-4-甲基噻吩并[2,3-d]嘧啶-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺
Figure PCTCN2016095990-appb-000019
将N-(6-溴-4-甲基噻吩并[2,3-d]嘧啶-2-基)特戊酰胺(66mg，0.2mmol)，N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶-3-基)-2,4-二氟苯磺酰胺(102mg，0.24mmol)和2N碳酸钾水溶液(0.4mL，0.8mmol)于1,4-二氧六环(5mL)中的混合物脱气，并加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(15mg，0.02mmol)。将产生的反应混合物脱气并回充氩气(三个循环)，然后在100℃下氩气气氛中搅拌7.5小时。将反应混合物冷却至室温，在真空中除去挥发物。向残留物中加入乙醇(3mL)和2N氢氧化钠(0.2mL，0.4mmol)，并将产生的混合物在90℃下搅拌1.5小时。将反应混合物冷却至室温，在真空中除去挥发物。将残留物分配于乙酸乙酯萃取(30mL)和水(30mL)之间，用乙酸乙酯(30mL×2)萃取水层。用水(30mL)和食盐水(30mL)洗涤合并的有机层，用无水硫酸钠干燥，过滤，浓缩。残留物经快速柱色谱(硅胶，二氯甲烷/10％氨水甲醇溶液＝100:1)纯化得到标题化合物为黄色固体(40mg，两步产率47.5％)。
1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.32(d,J＝1.6Hz,1H),7.91(d,J＝1.6Hz,1H),7.81–7.70(m,2H),7.59(t,J＝10.4Hz,1H),7.22(td,J＝8.8,2.0Hz,1H),6.82(s,2H),3.63(s,3H),2.57(s,3H).
MS(ESI+)m/z 464.0[M+H]+.
实施例2：N-(5-(2-氨基-4-甲基噻吩并[2,3-d]嘧啶-6-基)-2-甲氧基吡啶-3-基)-4-氟苯磺酰胺的合成
Figure PCTCN2016095990-appb-000020
按照实施例1步骤6的方法制备标题化合物为白色固体(产率37.9％)。
1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.30(d,J＝2.3Hz,1H),7.85(d,J＝2.3Hz,1H),7.82(dd,J＝8.8,5.2Hz,2H),7.72(s,1H),7.42(t,J＝8.8Hz,2H),6.81(s,2H),3.64(s,3H),2.57(s,3H).
MS(ESI+)m/z 446.0[M+H]+.
实施例3：N-(5-(2-氨基-4-甲基噻吩并[2,3-d]嘧啶-6-基)-2-氯吡啶-3-基)-4-氟苯磺酰胺的合成
Figure PCTCN2016095990-appb-000021
步骤1：6-溴-4-甲基噻吩并[2,3-d]嘧啶-2-胺的合成
Figure PCTCN2016095990-appb-000022
将N-(6-溴-4-甲基噻吩并[2,3-d]嘧啶-2-基)特戊酰胺(470mg，1.44mmol)，2N氢氧化钠水溶液(1.44mL，2.88mmol)在乙醇(10mL)中的混合物在90℃下搅拌1.5小时。将反应混合物冷却至室温，在真空中除去挥发物。将残留物分配于乙酸乙酯萃取(30mL)和水(30mL)之间，用乙酸乙酯(30mL×2)萃取水层。用水(30mL)和食盐水(30mL)洗涤合并的有机层，用无水硫酸钠干燥，过滤，浓缩。残留物经 快速柱色谱(硅胶，二氯甲烷/甲醇＝120:1)纯化得到标题化合物为白色固体(288mg，产率81.9％)。
1H NMR(400MHz,DMSO-d6)δ7.56(s,1H),6.82(s,2H),2.48(s,3H).
MS(ESI+)m/z 243.9,245.9[M+H]+.
步骤2：N-(5-(2-氨基-4-甲基噻吩并[2,3-d]嘧啶-6-基)-2-氯吡啶-3-基)-4-氟苯磺酰胺的合成
Figure PCTCN2016095990-appb-000023
将N-(5-溴-2-氯吡啶-3-基)-4-氟苯磺酰胺(88mg,0.24mmol)，联硼酸频哪醇酯(67mg,0.264mmol)和无水醋酸钾(47mg,0.48mmol)在二氧六环(5mL)中的混合物脱气，然后将[1,1'-双(二苯基膦基)二茂铁]二氯化钯(9mg,0.012mmol,0.05eq)加到混合物中。将产生的反应混合物脱气并回充氩气(三个循环)，在100℃下氩气气氛中搅拌3.5小时。冷却至室温后，向产生的反应混合物中加入6-溴-4-甲基噻吩并[2,3-d]嘧啶-2-胺(49mg,0.2mmol)，2N碳酸钾水溶液(300μL,0.6mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(9mg,0.012mmol)。将产生反应混合物脱气并回充氩气(三个循环)，在100℃下氩气气氛中搅拌3.5小时。将反应混合物冷却至室温，用水(30mL)稀释，用乙酸乙酯萃取(30mL×3)。用食盐水(30mL)洗涤合并的有机层，用无水硫酸钠干燥，过滤，浓缩。残留物经快速柱色谱(硅胶，二氯甲烷/10％氨水甲醇溶液＝80:1)纯化得到标题化合物为白色固体(40mg，产率为46.6％)。
1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.65(d,J＝2.4Hz,1H),7.99(s,1H),7.88(d,J＝2.4Hz,1H),7.82(dd,J＝8.8,5.2Hz,2H),7.45(t,J＝8.8Hz,2H),6.94(s,2H),2.58(s,3H).
MS(ESI+)m/z 450.0[M+H]+.
实施例4：N-(5-(2-氨基-4-甲基噻吩并[2,3-d]嘧啶-6-基)-2-甲基吡啶-3-基)-4-氟苯磺酰胺的合成
Figure PCTCN2016095990-appb-000024
按照实施例3中步骤2的方法制备标题化合物为白色固体(产率为46.6％)。
1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.70(d,J＝2.0Hz,1H),7.82(s,1H),7.76(dd,J＝8.8,5.2Hz,2H),7.49(d,J＝2.0Hz,1H),7.46(t,J＝8.8Hz,2H),6.87(s,2H),2.57(s,3H),2.17(s,3H).
MS(ESI+)m/z 430.0[M+H]+.
实施例5：N-(5-(2-氨基-4-甲基噻吩并[2,3-d]嘧啶-6-基)-2-甲基吡啶-3-基)-2,4-二氟苯磺酰胺的合成
Figure PCTCN2016095990-appb-000025
按照实施例3中步骤2的方法制备标题化合物为淡黄色固体(产率为27.9％)。
1H NMR(400MHz,DMSO-d6)δ10.49(br s,1H),8.68(s,1H),7.85–7.74(m,2H),7.65–7.56(m,2H),7.26(td,J＝8.6,2.1Hz,1H),6.87(s,2H),2.57(s,3H),2.29(s,3H).
MS(ESI+)m/z 448.0[M+H]+.
实施例6：N-(6-(5-(2,4-二氟苯磺酰胺基)-6-甲氧基吡啶-3-基)-4-甲基噻吩并[2,3-d]嘧啶-2-基)乙酰胺的合成
Figure PCTCN2016095990-appb-000026
步骤1：N-(6-溴-4-甲基噻吩并[2,3-d]嘧啶-2-基)乙酰胺的合成
Figure PCTCN2016095990-appb-000027
室温下将乙酰氯(83mg，1.05mmol)加到6-溴-4-甲基噻吩并[2,3-d]嘧啶-2-胺(85mg,0.35mmol)，吡啶(138mg，1.75mmol)于二甲基甲酰胺(4mL)中的混合物中。将产生的反应混合物在室温下搅拌4小时。用水(30mL)稀释反应混合物，用乙酸乙酯(30mL×3)萃取。用水(30mL×2)和食盐水(30mL)洗涤合并的有机层，用无水硫酸钠干燥，过滤，浓缩。残留物经快速色谱柱(硅胶，二氯甲烷/甲醇＝200:1)纯化得到标题化合物为淡黄色固体(52mg，51.9％)。
1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),7.85(s,1H),2.66(s,3H),2.17(s,3H).
MS(ESI+)m/z 286.0,288.0[M+H]+.
步骤2：N-(6-(5-(2,4-二氟苯磺酰胺基)-6-甲氧基吡啶-3-基)-4-甲基噻吩并[2,3-d]嘧啶-2-基)乙酰胺
Figure PCTCN2016095990-appb-000028
将N-(6-溴-4-甲基噻吩并[2,3-d]嘧啶-2-基)乙酰胺(50mg,0.175mmol)，N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶-3-基)-2,4-二氟苯磺酰胺(90mg,0.21mmol)和2N碳酸钾水溶液(0.263mL,0.526mmol)于二甲基甲酰胺(4mL)中的混合物脱气，然后加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(13mg,0.0175mmol)。将产生的反应混合物脱气并回充氩气(三个循环)，然后在100℃下氩气气氛中搅拌6小时。将反应混合物冷却至室温，用水(30mL)稀释，用乙酸乙酯萃取(30mL×3)。用水(30mL)和食盐水(30mL)洗涤合并的有机层，用无水硫酸钠干燥，过滤，浓缩。残留物经快速柱色谱(硅胶，二氯甲烷/甲醇＝80:1)纯化得到标题化合物为白色固体(37mg，产率为41.6％)。
1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),10.40(s,1H),8.44(d,J＝2.4Hz,1H),8.03(d,J＝2.4Hz,1H),8.02(s,1H),7.78(td,J＝8.6,6.4Hz,1H),7.66–7.52(m,1H),7.23(td,J＝8.4,2.2Hz,1H),3.65(s,3H),2.74(s,3H),2.20(s,3H).
MS(ESI+)m/z 506.0[M+H]+.
实施例7：N-(6-(5-(2,4-二氟苯磺酰胺基)-6-甲氧基吡啶-3-基)-4-甲基噻吩并[2,3-d]嘧啶-2-基)环丙烷甲酰胺的合成
Figure PCTCN2016095990-appb-000029
步骤1：N-(6-溴-4-甲基噻吩并[2,3-d]嘧啶-2-基)环丙烷甲酰胺的合成
Figure PCTCN2016095990-appb-000030
按照实施例6中步骤1的方法制备标题化合物为淡黄色固体(90mg，57.7％)。
1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),7.86(s,1H),2.66(s,3H),2.14–2.05(m,1H),0.85–0.77(m,4H).
MS(ESI+)m/z 311.9,313.9[M+H]+.
步骤2：N-(6-(5-(2,4-二氟苯磺酰胺基)-6-甲氧基吡啶-3-基)-4-甲基噻吩并[2,3-d]嘧啶-2-基)环丙烷甲酰胺
Figure PCTCN2016095990-appb-000031
按照实施例6中步骤2的方法制备标题化合物为白色固体(37mg，产率为37.4％)。
1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),10.42(s,1H),8.45(d,J＝2.4Hz,1H),8.04(s,1H),8.03(d,J＝2.4Hz,1H),7.77(td,J＝8.4,6.4Hz,1H),7.64–7.56(m,1H),7.23(td,J＝8.4,2.0Hz,1H),3.65(s,3H),2.75(s,3H),2.17–2.07(m,1H),0.88–0.76(m,4H).
MS(ESI+)m/z 531.9[M+H]+.
实施例8：N-(2-甲氧基-5-(4-甲基-2-(甲氨基)噻吩并[2,3-d]嘧啶-6-基)吡啶-3-基)-2,4-二氟苯磺酰胺的合成
Figure PCTCN2016095990-appb-000032
步骤1：N-(6-溴-4-甲基噻吩并[2,3-d]嘧啶-2-基)-N-甲基特戊酰胺的合成
Figure PCTCN2016095990-appb-000033
在0℃下向将N-(6-溴-4-甲基噻吩并[2,3-d]嘧啶-2-基)特戊酰胺(328mg，1.0mmol)于二甲基甲酰胺(8mL)中的溶液中加入氢化钠(70％矿物油分散物，58mg,1.7mmol)，并将产生的反应混合物在0℃下搅拌10分钟。加入碘甲烷(0.125mL，0.2mmol)，将产生的反应混合物在0℃下搅拌1小时，然后用水(30mL)淬灭，用乙酸乙酯(20mL×3)萃取。用水(30mL)和食盐水(30mL)洗涤合并的有机层，用无水硫酸钠干燥，过滤，浓缩。残留物经快速柱色谱(硅胶，石油醚/乙酸乙酯＝6:1)纯化得到标题化合物为白色固体(80mg，产率23.4％)。
1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),3.25(s,3H),2.72(s,3H),1.06(s,9H).
MS(ESI+)m/z 342.0,344.0[M+H]+.
步骤2：6-溴-N,4-二甲基噻吩并[2,3-d]嘧啶-2-胺
Figure PCTCN2016095990-appb-000034
将N-(6-溴-4-甲基噻吩并[2,3-d]嘧啶-2-基)-N-甲基特戊酰胺(81mg，0.24mmol)，2N氢氧化钠水溶液(0.24mL，0.48mmol)在乙醇(3mL)中的混合物在90℃下搅拌1.5小时。将反应混合物冷却至室温，在真空中除去挥发物。将残留物分配于乙酸乙酯萃取(30mL)和水(30mL)之间，用乙酸乙酯(30mL×2)萃取水层。用水(30mL)和食盐水(30mL)洗涤合并的有机层，用无水硫酸钠干燥，过滤，浓缩。残留物经快速柱色谱(硅胶，石油醚/乙酸乙酯＝12:1)纯化得到标题化合物为白色固体(41mg，产率67.1％)。
1H NMR(400MHz,DMSO-d6)δ7.57(s,1H),7.33(br s,1H),2.80(d,J＝4.8Hz,3H),2.49(s,3H).
MS(ESI+)m/z 257.9,259.9[M+H]+.
步骤3：N-(2-甲氧基-5-(4-甲基-2-(甲氨基)噻吩并[2,3-d]嘧啶-6-基)吡啶-3-基)2,4-二氟苯磺酰胺的合成
Figure PCTCN2016095990-appb-000035
将6-溴-N,4-二甲基噻吩并[2,3-d]嘧啶-2-胺(41mg，0.16mmol)，N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶-3-基)-4-氟苯磺酰胺(82mg，0.19mmol)和2N碳酸钾水溶液(0.24mL，0.48mmol)于1,4-二氧六环(3.5mL)中的混合物脱气，并加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(11.6mg，0.016mmol)。将产生的反应混合物脱气并回充氩气(三个循环)，然后在100℃下氩气气氛中搅拌4.5小时。将反应混合物冷却至室温，在真空中除去挥发物。将残留物分配于乙酸乙酯萃取(30mL)和水(30mL)之间，用乙酸乙酯(30mL×2)萃取水层。用水(30mL)和食盐水(30mL)洗涤合并的有机层，用无水硫酸钠干燥，过滤，浓缩。残留物经快速柱色谱(硅胶，二氯甲烷/甲醇＝160:1)纯化得到标题化合物为黄色固体(30mg，产率39.5％)。
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.32(d,J＝2.2Hz,1H),7.91(d,J＝2.2Hz,1H),7.82–7.72(m,2H),7.64–7.53(m,1H),7.30(br s,1H),7.22(td,J＝8.7,2.5Hz,1H),3.63(s,3H),2.85(d,J＝4.8Hz,3H),2.58(s,3H).
MS(ESI+)m/z 477.9[M+H]+.
实验例：
实验方法：生物化学检测PI3K-α活性
使用体外激酶检测评估本申请的化合物对PI3K-α的效能。使用基于荧光素酶的冷光检测，通过检测激酶反应中所产生的ADP水平来测 定PI3K-α的激酶活性。ADP-GloTM激酶检测试剂盒购自Promega公司。所有检测均在室温下进行，使用OptiPlateTM-384白色384孔板。PI3K-α激酶来自Crownbio。底物为PIP2/PS(Invitrogen)。激酶缓冲液包括50mM Hepes(pH 7.5)，3mM MgCl2，100mM NaCl，1nM EGTA，0.03％CHAPS和2mM DTT。通过在激酶缓冲液将PI3K-α激酶稀释为0.375ng/μL配制PI3K-α激酶混合液。ATP/底物混合液包括5μM PIP2/PS和25μM ATP。将待测化合物在100％DMSO中稀释至10mM，然后在100％DMSO中按3倍连续稀释成10个不同浓度。然后将稀释于100％DMSO中的化合物在ddH2O中稀释20倍。将2μL稀释的化合物溶液和4μL的ATP/底物混合液加到384孔板的各孔中。通过加入每孔4μL的PI3Kα激酶混合液开始反应，最终反应体积为10μL，ATP浓度为10μM，PIP2/PS浓度为2μM，PI3K-α激酶浓度为0.15ng/μL。将板盖住并将反应在室温进行1小时，随后加入每孔10μL的激酶GloTM试剂终止反应。将板孵育40分钟，然后加入每孔20μL激酶检测试剂。将板在暗处平衡30分钟，随后在EnVision 2104多标记微孔板检测仪读板器上读取冷光。
抑制百分率基于以下公式计算：
抑制％＝[1-(RLU化合物-RLU分钟)/(RLUmax-RLU分钟)]×100
其中RLU化合物为给定化合物浓度下的冷光读数，RLU分钟为加入最高浓度(2.5uM)阳性对照化合物的情况下的冷光读数，RLUmax为不加入化合物的情况下的冷光读数。通过使用Excel中XLfit程序中来计算化合物的IC50。
实验结果见表1:
Figure PCTCN2016095990-appb-000036
Figure PCTCN2016095990-appb-000037
Figure PCTCN2016095990-appb-000038
从上述实验中可以看出，本申请化合物对PI3K-α具有明显的抑制作用，本申请化合物可用于制备治疗和预防癌症、肿瘤疾病的药物。
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解。根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (11)

  1. 式I所示的化合物或其药学上可接受的盐：
    Figure PCTCN2016095990-appb-100001
    其中，
    R1选自氢、卤素、取代或未取代的C1-C4烷基和取代或未取代的C1-C4烷氧基；
    R2选自氢、C1-C4烷基、C1-C3烷基羰基和C3-C6环烷基羰基；
    R3选自C1-C4烷基；
    R4选自取代或未取代的苯基；
    优选地，所述取代的C1-C4烷基、取代的C1-C4烷氧基或取代的苯基是指所述C1-C4烷基、C1-C4烷氧基或苯基各自独立地被一个或多个(例如1、2、3、4或5个)选自下述的取代基取代：卤素、羟基、氨基、硝基、氰基、C1-C4烷基、C1-C4烷氧基和C1-C4烷基羰基。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，所述R4为取代的苯基，其中，取代基的个数为1-5个，取代基选自卤素。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，所述R4为取代的苯基，其中，取代基的个数为1-2个，取代基选自氟。
  4. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐，R1选自卤素、未取代的C1-C4烷基和未取代的C1-C4烷氧基。
  5. 根据权利要求1-4任一项所述的化合物或其药学上可接受的盐， R1选自甲基、甲氧基和氯。
  6. 根据权利要求1-5任一项所述的化合物或其药学上可接受的盐，R3为甲基。
  7. 根据权利要求1-6任一项所述的化合物或其药学上可接受的盐，其特征在于，R2选自氢、甲基、甲基羰基和环丙基羰基。
  8. 根据权利要求1所述的化合物或其药学上可接受的盐，所述式I所示的化合物选自下列化合物：
    Figure PCTCN2016095990-appb-100002
    Figure PCTCN2016095990-appb-100003
  9. 药物组合物，其含有权利要求1-8任一项所述的通式I化合物或其药学上可接受的盐，以及药用辅料。
  10. 权利要求1-8任一项所述的通式I化合物或其药学上可接受的盐或权利要求9的药物组合物在制备治疗和/或预防PI3-K和/或mTOR激酶引起的疾病的药物中的用途；优选地，所述PI3-K和/或mTOR激 酶引起的疾病为癌症；优选地，所述癌症选自脑癌、成胶质细胞瘤、头颈癌、肺癌、黑色素瘤、肝癌、肾癌、急性白血病、慢性白血病、非小细胞肺癌、前列腺癌、甲状腺癌、皮肤癌、结肠癌、直肠癌、胰腺癌、卵巢癌、乳腺癌、骨髓异常增生综合症、食管癌、肉瘤、骨肉瘤和横纹肌瘤。
  11. 一种治疗和/或预防PI3-K和/或mTOR激酶引起的疾病的方法，其包括向有此需要的受试者施用有效量的权利要求1-8任一项所述的通式I化合物或其药学上可接受的盐或权利要求9的药物组合物的步骤；优选地，所述PI3-K和/或mTOR激酶引起的疾病为癌症；优选地，所述癌症选自脑癌、成胶质细胞瘤、头颈癌、肺癌、黑色素瘤、肝癌、肾癌、急性白血病、慢性白血病、非小细胞肺癌、前列腺癌、甲状腺癌、皮肤癌、结肠癌、直肠癌、胰腺癌、卵巢癌、乳腺癌、骨髓异常增生综合症、食管癌、肉瘤、骨肉瘤和横纹肌瘤。
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