WO2023178928A1 - 2-氨基-4-吲哚基嘧啶类化合物及其制备方法与应用 - Google Patents
2-氨基-4-吲哚基嘧啶类化合物及其制备方法与应用 Download PDFInfo
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- WO2023178928A1 WO2023178928A1 PCT/CN2022/116937 CN2022116937W WO2023178928A1 WO 2023178928 A1 WO2023178928 A1 WO 2023178928A1 CN 2022116937 W CN2022116937 W CN 2022116937W WO 2023178928 A1 WO2023178928 A1 WO 2023178928A1
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- Prior art keywords
- alkyl
- hydrogen
- cancer
- acid
- methyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
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- FDMQDKQUTRLUBU-UHFFFAOYSA-N n-[3-[2-[4-(4-methylpiperazin-1-yl)anilino]thieno[3,2-d]pyrimidin-4-yl]oxyphenyl]prop-2-enamide Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(SC=C2)C2=N1 FDMQDKQUTRLUBU-UHFFFAOYSA-N 0.000 description 1
- HUFOZJXAKZVRNJ-UHFFFAOYSA-N n-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxyanilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound COC1=CC(N2CCN(CC2)C(C)=O)=CC=C1NC(N=1)=NC=C(C(F)(F)F)C=1NC1=CC=CC(NC(=O)C=C)=C1 HUFOZJXAKZVRNJ-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229950000778 olmutinib Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 229950009855 rociletinib Drugs 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
Images
Classifications
-
- 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
- C07D403/14—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 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the invention belongs to the field of chemical medicine, and specifically relates to 2-aminomidine compounds and their preparation methods and applications.
- EGFR epidermal growth factor receptor
- HER epidermal growth factor receptor
- Activation of EGFR can be divided into three steps: (1) Binding of EGFR to ligand can cause the receptor to form homodimers, or it can also form heterodimers with other EGFR families; (2) Dimerization The formation of EGFR promotes the phosphorylation of six specific receptor tyrosine residues in the intracellular region of EGFR, which sequentially transduce various external signals into the cell.
- the signals are mainly transmitted to the nucleus through two pathways, one is Ras-Raf- MAPK pathway; the other is the PI3K-Akt-mTOR pathway; (3) When the signal is transmitted to the nucleus, it causes an increase in the level of gene transcription in the nucleus, causing cell proliferation and transformation, and increased EGFR expression.
- EGFR As a tyrosine kinase type I receptor, EGFR is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes and other cells. EGFR mutation or overexpression generally causes tumors, and its signal transduction pathway plays an important regulatory role in tumor cell proliferation, damage repair, invasion, and neovascularization, and has become one of the hot targets for tumor treatment.
- EGFR inhibitors have greatly improved the survival and quality of life of cancer patients (especially NSCLC patients). So far, a total of 11 EGFR inhibitors of three generations have been launched, including first-generation inhibitors represented by gefitinib, second-generation covalent inhibitors represented by icotinib, and osimertinib. of third-generation inhibitors.
- first-generation inhibitors represented by gefitinib
- second-generation covalent inhibitors represented by icotinib
- osimertinib of third-generation inhibitors.
- the latest third-generation inhibitor osimertinib has also seen serious cases of drug resistance in clinical practice.
- the main reason for resistance to osimertinib is the mutation of amino acid residue 797 of the EGFR protein from cysteine to serine.
- the covalent binding bond of osimertinib cannot bind to the target, resulting in off-target. Solving drug resistance is urgent and has become the most direct means
- the present invention designed and synthesized a series of compounds targeting EGFR gene mutation targets or their pharmaceutically acceptable Salt. This compound solves the clinical resistance problem of osimertinib by inhibiting the EGFR gene mutation target and improves the survival rate of patients.
- the invention also provides a specific preparation method of the compound and its application in anti-tumor drugs.
- Pharmacological experimental results show that this type of compound can inhibit the proliferation of a variety of tumor cells, including brain glioma, pituitary gland tumor, glioma, melanoma, breast cancer, lung cancer, gastric cancer, ovarian cancer, colon cancer, liver cancer, Pancreatic cancer, prostate cancer, testicular cancer, multiple myeloma, leukemia and other solid tumors and hematological tumors.
- the compounds of the present invention are expected to be developed into a new generation of anti-cancer drugs.
- the present invention is a compound represented by general formula (I) and its pharmaceutically acceptable salt.
- X is selected from C, N, O or S
- R 1 is selected from hydrogen, C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl, -S(O) 2 R 5 ;
- R 2 is selected from hydrogen, halogen, hydroxyl, mercapto, cyano, nitro, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkyl, C 3 -C 8 Cycloalkyl;
- R 3 is selected from hydrogen, halogen, amino, -NH-C(O)R 6 ;
- R 4 is selected from hydrogen, -C 1 -C 3 -NR 7 R 8 , -C 1 -C 3 -C(O)NR 9 R 10 ;
- R 5 is selected from hydrogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl;
- R 6 is selected from hydrogen, C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl;
- R 7 , R 8 , R 9 and R 10 are independently selected from hydrogen, C 1 -C 3 alkyl, and halogenated C 1 -C 3 alkyl;
- R 7 and R 8 , R 9 and R 10 can also form a five-membered nitrogen-containing heterocyclic ring or a six-membered nitrogen-containing heterocyclic ring.
- X is selected from C or N;
- R 1 is selected from hydrogen, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, -S(O) 2 R 5 , where R 5 is selected from C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl;
- R 2 is selected from hydrogen, halogen, nitro, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkyl;
- R 3 is selected from hydrogen, halogen, amino, -NH-C(O)R 6 , where R 6 is selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl;
- R 4 is selected from -C 1 -C 3 -NR 7 R 8 , -C 1 -C 3 -C(O)NR 9 R 10 , where R 7 , R 8 , R 9 and R 10 are independently selected from C 1 -C 3 alkyl, R 7 and R 8 , R 9 and R 10 can also form a saturated six-membered nitrogen-containing heterocycle.
- X is selected from C or N;
- R 1 is selected from hydrogen, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, -S(O) 2 R 5 , where R 5 is selected from methyl, ethyl, cyclopropyl;
- R 2 is selected from hydrogen, halogen, nitro, methoxy, halogenated C 1 -C 3 alkyl
- R 3 is selected from hydrogen, halogen, amino, -NH-C(O)R 6 , wherein R 6 is selected from vinyl, propenyl, isobutenyl, methyl, ethyl, isopropyl, and cyclopropyl;
- R 4 is selected from -C 1 -C 3 -NR 7 R 8 , -C 1 -C 3 -C(O)NR 9 R 10 , where R 7 , R 8 , R 9 and R 10 are each independently selected from methyl , ethyl, R 7 and R 8 , R 9 and R 10 can also be morpholine, piperidine, hexahydropyridazine, hexahydropyrimidine, piperazine, N-methylhexahydropyridazine, N-methylhexahydropyridazine Hydropyrimidine, N-methylpiperazine, N-ethylpiperazine, N-isopropylpiperazine.
- X is selected from C or N;
- R 1 is selected from hydrogen, methyl, deuterated methyl, -S(O) 2 R 5 , where R 5 is selected from methyl, ethyl, cyclopropyl;
- R 2 is selected from hydrogen, halogen, nitro, methoxy, trifluoromethyl
- R 3 is selected from hydrogen, halogen, amino, -NH-C(O)R 6 , wherein R 6 is selected from vinyl, propenyl, isobutenyl, methyl, ethyl, isopropyl, and cyclopropyl;
- R 4 is selected from -CH 2 CH 2 -NR 7 R 8 , -CH 2 -C(O)NR 9 R 10 , where R 7 , R 8 , R 9 and R 10 are independently selected from methyl and ethyl, R 7 and R 8 can also be morpholine, piperidine, piperazine, N-methylpiperazine, N-ethylpiperazine or N-isopropylpiperazine.
- X is selected from C or N;
- R 1 is selected from hydrogen, methyl, deuterated methyl, -S(O) 2 R 5 , where R 5 is selected from ethyl;
- R 2 is selected from hydrogen, chlorine, nitro, methoxy, and trifluoromethyl
- R 3 is selected from hydrogen, chlorine, amino, -NH-C(O)R 6 , wherein R 6 is selected from vinyl, propenyl, isobutenyl, methyl, ethyl, isopropyl, and cyclopropyl;
- R 4 is selected from -CH 2 CH 2 -NR 7 R 8 , -CH 2 -C(O)NR 9 R 10 , where R 7 and R 8 are independently selected from methyl and ethyl, and R 7 and R 8 are also It can be morpholine, and R 9 and R 10 are selected from methyl.
- the compounds described herein are selected from I-1 to I-47:
- the above-mentioned pharmaceutically acceptable salts are acid addition salts of compounds of general formula (I), wherein the acids used for salt formation include inorganic acids and organic acids, and the inorganic acids include: hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid, Organic acids include acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, etc. Partic acid and tartaric acid.
- the acids used for salt formation include inorganic acids and organic acids, and the inorganic acids include: hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid, Organic acids include acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenes
- the present invention also discloses a pharmaceutical composition, comprising the above-mentioned compound of general formula (I) or its pharmaceutically acceptable salt or its isomer or its prodrug molecule or its active metabolite, and a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier refers to an excipient or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound.
- the excipients include binders, fillers, disintegrants, lubricants, preservatives, antioxidants, flavoring agents, fragrances, cosolvents, emulsifiers, solubilizers, osmotic pressure regulators, colorants, etc.
- the diluent includes physiological saline, starch, dextrin, sucrose, lactose, etc.
- the EGFR inhibitor drugs can be used to treat cancer or tumor-related diseases.
- Cancer or tumor-related diseases include glioma, pituitary tumor, glioma, melanoma, breast cancer, lung cancer, stomach cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, prostate cancer, testicular cancer, multiple myeloma cancer, leukemia and other solid tumors and hematological tumors.
- the tumor is a malignant tumor with EGFR gene mutation.
- the tumor is a malignant tumor with EGFR L858R/T790M/C797S mutation.
- the compound of general formula (I) or its pharmaceutically acceptable salt according to the present invention has EGFR kinase inhibitory activity and has a therapeutic effect on malignant tumors.
- alkyl used in the present invention refers to saturated straight-chain and branched-chain alkyl groups
- C 1 -C 8 alkyl refers to saturated straight-chain and branched-chain alkyl groups with 1 to 8 carbon atoms, including but not limited to methyl base, ethyl, isopropyl, isobutyl, etc.
- Halogenated C 1 -C 8 alkyl refers to a C 1 -C 8 alkyl group in which the alkyl chain is substituted with one or more halogens.
- Deuterated C 1 -C 8 alkyl group represents a C 1 -C 8 alkyl group substituted with one or more deuterium.
- Unsaturated C 1 -C 8 alkyl represents an alkyl group containing one or more unsaturated bonds, and the unsaturated bonds include alkenyl and alkynyl.
- alkoxy refers to an alkyl group containing an oxygen atom at the end, including but not limited to methoxy, ethoxy, n-propoxy, and isopropoxy.
- cycloalkyl refers to an alkyl group with a cyclic structure, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, etc.
- halogen means fluorine, chlorine, bromine, iodine.
- -S(O) 2 represents sulfonyl group.
- nitrogen-containing heterocycle includes saturated and unsaturated polyvalent nitrogen-containing heterocycles, including but not limited to cycloethylamine, cyclopropylamine, pyrrole, tetrahydropyrrole, imidazole, morpholine, piperazine, pyrazine, N-methyl N-ethylpiperazine, N-ethylpiperazine, etc.
- the present invention has the following beneficial effects:
- the 2-aminomidine compounds of the present invention or their pharmaceutically acceptable salts or their stereoisomers or their prodrug molecules or their active metabolites can inhibit EGFR family proteases, thereby inhibiting various tumor cells. growth.
- the compound of the present invention can effectively inhibit the activity of drug-resistant mutants of EGFR protein kinase, and can overcome the clinical resistance of non-small cell lung cancer and other tumor patients induced by the existing third-generation selective EGFR T790M small molecule inhibitors Osimertinib, Olmutinib, Rociletinib, etc. medicine.
- Figure 1 is the general structural formula of the 2-aminomidine compound of the present invention.
- N,N-dimethyl-2-(5-nitro-1H-indazol-1-yl)ethylamine (11) (1.6g, 6.8mmol), zinc powder (4.4g, 68mmol) and chlorinated Ammonium (3.6g, 68mmol) was dissolved in 70% ethanol, protected by argon, heated to reflux at 70°C for 3 hours, filtered and concentrated to obtain 1.4g of solid, with a yield of 100%.
- Example 44 7-chloro-1-(2-(dimethylamino)ethyl)-N-(4-(1-methyl-1H-indol-3-yl)-5-(trifluoromethyl )pyrimidin-2-yl)-1H-indazole-5-amine (I-44)
- Compounds were dissolved in 100% DMSO and prepared as a 10mM solution. Prepare 1 ⁇ Kinase buffer. Preparation of compound concentration gradient: compound test starting concentration is 5 ⁇ M, 3-fold dilution, 10 concentrations, single-well detection. Prepare a kinase solution with 2.5 times the final concentration using 1 ⁇ Kinase buffer. Add 10 ⁇ L of 2.5 times the final concentration of kinase solution to the compound wells and positive control wells respectively; add 10 ⁇ L of 1 ⁇ Kinase buffer to the negative control wells. Centrifuge at 1000 rpm for 30 seconds, shake the reaction plate to mix, and incubate at room temperature for 10 minutes.
- Example IC 50 (nM) Example IC50(nM) Example IC50(nM) Example IC50(nM) I-1 100-1000 I-17 10-100 I-33 10-100 I-2 100-1000 I-18 ⁇ 10 I-34 10-100 I-3 100-1000 I-19 10-100 I-35 10-100 I-4 100-1000 I-20 10-100 I-36 10-100 I-5 100-1000 I-21 100-1000 I-37 10-100 I-6 100-1000 I-22 100-1000 I-38 10-100 I-7 100-1000 I-23 100-1000 I-39 100-1000 I-8 1000-2000 I-24 100-1000 I-40 ⁇ 10 I-9 100-1000 I-25 100-1000 I-41 10-100 I-10 1000-2000 I-26 100-1000 I-42 ⁇ 10 I-11 ⁇ 10 I-27 100-1000 I-43 ⁇ 10 I-12 10-100 I-28 ⁇ 20 I-44 10-100 I-13 100-1000 I-29 10-100 I-45 ⁇ 20 I-14 10-100 I-30 10-100 I-46 100-1000 I-15 10-100 I-31 10-100
- the obtained IC 50 values are shown in Table 2. From the results, it can be seen that the compounds of the present invention have strong BaF 3 (EGFR L858R/T790M/C797S ) cell proliferation inhibitory activity.
- H-1975 EGFR L858R/T790M/C797S
- H-1975 cell line H-1975 cell line
- PC-9 cell line PC-9 cell line
- A-549 cell line was tested by the CCK8 method.
- Example compounds inhibit H-1975 (EGFR L858R/T790M/C797S ) cell proliferation IC 50
Abstract
本发明公开了一种2-氨基-4-吲哚基嘧啶类化合物及其制备方法和应用,属于药物合成技术领域。具体涉及一种具有式(I)结构特征的嘧啶类化合物、其立体异构体或其药学上可接受的盐、它们的制备方法以及在抗肿瘤药物中的应用。药理实验结果表明,该类化合物可抑制多种肿瘤细胞的增殖,所述癌症或肿瘤相关疾病包括脑胶质瘤、脑垂体瘤、神经胶质瘤、黑色素瘤、乳腺癌、肺癌、胃癌、卵巢癌、结肠癌、肝癌、胰腺癌、前列腺癌、睾丸癌、多发性骨髓瘤、白血病等多种实体瘤和血液瘤。本发明的化合物有望开发成新一代的抗癌药物。
Description
本发明属于化学医药领域,具体涉及2-氨基密啶类化合物及其制备方法与应用。
EGFR(epidermal growth factor receptor,简称为EGFR、ErbB-1或HER1)是表皮生长因子受体(HER)家族成员之一,位于细胞膜表面的跨膜受体,分子量170KDa,通过与配体结合来激活,包括EGF和TGFα(transforming growth factor α);进而,激活细胞内的激酶通路,包括Y992,Y1045,Y1068,Y1148和Y1173等位点,引导下游MAPK、Akt和JNK通路的磷酸化,诱导细胞增殖。EGFR的活化可分为3个步骤:(1)EGFR与配体结合后可导致受体形成同源二聚体,也可与其他EGFR家族形成异源二聚体;(2)二聚体的形成促使EGFR胞内区6个特异的受体酪氨酸残基磷酸化,分别依次将外界各种信号转导至胞内,主要通过两条途径将信号传递至细胞核,一条是Ras-Raf-MAPK途径;另一条是PI3K-Akt-mTOR途径;(3)当信号传导至细胞核后,引起核内基因转录水平的增加,使细胞增殖、转化,EGFR表达增加。
作为一种酪氨酸激酶I型受体,EGFR广泛分布于哺乳动物上皮细胞、成纤维细胞、胶质细胞、角质细胞等细胞表面。EGFR突变或过表达一般会引发肿瘤,其信号转导途径在肿瘤细胞的增殖、损伤修复、侵袭及新生血管形成等方面发挥重要调控作用,已成为肿瘤治疗的热点靶标之一。
EGFR抑制剂的研发成功,极大地提高了癌症患者(尤其是NSCLC患者)的生存期及生活质量。到目前为止,已有三代共11个EGFR抑制剂上市,包括吉非替尼为代表的第一代抑制剂,埃克替尼为代表的第二代共价抑制剂以及奥希替尼为代表的的第三代抑制剂。但是,最新的第三代抑制剂奥希替尼类药物,也已经在临床上出现了严重的耐药病例。奥希替尼耐药的最主要原因是EGFR蛋白第797位氨基酸残基由半胱氨酸突变为丝氨酸发生突变,奥希替尼的共价结合键无法与靶点结合,从而导致脱靶。解决其耐药性迫在眉睫,也成为提高非小细胞肺癌患者生存率的最直接手段。
发明内容
发明目的:为了解决现有技术中EGFR抑制剂奥希替尼因靶点突变导致的耐药性问题,本发明设计并合成了一系列针对EGFR基因突变靶点的化合物或其药学上可接受的盐。该化合物通过抑制EGFR基因突变靶点来解决临床上奥希替尼耐药问题,提高病人的生存率。
本发明还提供了该化合物的具体制备方法及其在抗肿瘤药物中的应用。药理实验结果表明,该类化合物可抑制多种肿瘤细胞的增殖,包括脑胶质瘤、脑垂体瘤、神经胶质瘤、黑色素瘤、乳腺癌、肺癌、胃癌、卵巢癌、结肠癌、肝癌、胰腺癌、前列腺癌、睾丸癌、多发性骨髓瘤、白血病等多种实体瘤和血液瘤。本发明的化合物有望开发成新一代的抗癌药物。
技术方案:本发明一种通式(Ⅰ)所示的化合物及其药学上可接受的盐。
其中,
X选自C、N、O或S;
R
1选自氢、C
1-C
3烷基、卤代C
1-C
3烷基、氘代C
1-C
3烷基、C
3-C
8环烷基、-S(O)
2R
5;
R
2选自氢、卤素、羟基、巯基、氰基、硝基、C
1-C
3烷基、C
1-C
3烷氧基、卤代C
1-C
3烷基、C
3-C
8环烷基;
R
3选自氢、卤素、氨基、-NH-C(O)R
6;
R
4选自氢、-C
1-C
3-NR
7R
8、-C
1-C
3-C(O)NR
9R
10;
R
5选自氢、C
1-C
3烷基、卤代C
1-C
3烷基、C
3-C
8环烷基;
R
6选自氢、C
1-C
8烷基、卤代C
1-C
8烷基、C
3-C
8环烷基、C
2-C
8链烯基、C
2-C
8炔基;
R
7、R
8、R
9和R
10分别独立选自氢、C
1-C
3烷基、卤代C
1-C
3烷基;
R
7和R
8,R
9和R
10也可以成五元含氮杂环、六元含氮杂环。
优选地:
X选自C或N;
R
1选自氢、C
1-C
3烷基、氘代C
1-C
3烷基、-S(O)
2R
5,其中R
5选自C
1-C
3烷基、C
3-C
8环烷基;
R
2选自氢、卤素、硝基、C
1-C
3烷氧基、卤代C
1-C
3烷基;
R
3选自氢、卤素、氨基、-NH-C(O)R
6,其中R
6选自C
1-C
8烷基、C
2-C
8链烯基、C
2-C
8炔基、C
3-C
8环烷基;
R
4选自-C
1-C
3-NR
7R
8、-C
1-C
3-C(O)NR
9R
10,其中R
7、R
8、R
9和R
10分别独立选自C
1-C
3烷基,R
7和R
8,R
9和R
10也可以成饱和六元含氮杂环。
优选地:
X选自C或N;
R
1选自氢、C
1-C
3烷基、氘代C
1-C
3烷基、-S(O)
2R
5,其中R
5选自甲基、乙基、环丙基;
R
2选自氢、卤素、硝基、甲氧基、卤代C
1-C
3烷基;
R
3选自氢、卤素、氨基、-NH-C(O)R
6,其中R
6选自乙烯基、丙烯基、异丁烯基、甲基、乙基、异丙基、环丙基;
R
4选自-C
1-C
3-NR
7R
8、-C
1-C
3-C(O)NR
9R
10,其中R
7、R
8、R
9和R
10分别独立选自甲基、乙基,R
7和R
8,R
9和R
10也可以成吗啉、哌啶、六氢哒嗪、六氢嘧啶、哌嗪、N-甲基六氢哒嗪、N-甲基六氢嘧啶、N-甲基哌嗪、N-乙基哌嗪、N-异丙基哌嗪。
优选地:
X选自C或N;
R
1选自氢、甲基、氘代甲基、-S(O)
2R
5,其中R
5选自甲基、乙基、环丙基;
R
2选自氢、卤素、硝基、甲氧基、三氟甲基;
R
3选自氢、卤素、氨基、-NH-C(O)R
6,其中R
6选自乙烯基、丙烯基、异丁烯基、甲基、乙基、异丙基、环丙基;
R
4选自-CH
2CH
2-NR
7R
8、-CH
2-C(O)NR
9R
10,其中R
7、R
8、R
9和R
10分别独立选自甲基、乙基,R
7和R
8也可以成吗啉、哌啶、哌嗪、N-甲基哌嗪、N-乙基哌嗪、N-异丙基哌嗪。
优选地:
X选自C或N;
R
1选自氢、甲基、氘代甲基、-S(O)
2R
5,其中R
5选自乙基;
R
2选自氢、氯、硝基、甲氧基、三氟甲基;
R
3选自氢、氯、氨基、-NH-C(O)R
6,其中R
6选自乙烯基、丙烯基、异丁烯基、甲基、乙基、异丙基、环丙基;
R
4选自-CH
2CH
2-NR
7R
8、-CH
2-C(O)NR
9R
10,其中R
7和R
8分别独立选自甲基、乙基,R
7和R
8也可以成吗啉,R
9和R
10选自甲基。
优选地,本申请所述的化合物选自I-1至I-47:
上述药学上可接受的盐为通式(I)化合物的酸加成盐,其中用于成盐的酸包括无机酸及有机酸,所述无机酸包括:盐酸、硫酸、磷酸和甲磺酸,有机酸包括乙酸、三氯乙酸、丙酸、丁酸、马来酸、对甲苯磺酸、苹果酸、丙二酸、肉桂酸、柠檬酸、富马酸、樟脑酸、二葡糖酸、天冬氨酸和酒石酸。
本发明还公开了一种药用组合物,包含上述通式(I)化合物或其药学上可接受的盐或其异构体或其前药分子或其活性代谢产物,以及药学上可接受的载体。
药学上可接受的载体指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的赋形剂或稀释剂。所述赋形剂包括黏合剂、填充剂、崩解剂、润滑剂、防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等,所述稀释剂包括生理盐水、淀粉、糊精、蔗糖、乳糖等。
本发明所述的化合物或其药学上可接受的盐在制备EGFR基因突变抑制剂药物中的应用。
所述EGFR抑制剂药物可用于治疗癌症或肿瘤相关疾病。
本发明所述的化合物或其药学上可接受的盐在制备用于预防和/或治疗癌症或肿瘤相关疾病的药物中的应用。癌症或肿瘤相关疾病包括脑胶质瘤、脑垂体瘤、神经胶质瘤、黑色素瘤、乳腺癌、肺癌、胃癌、卵巢癌、结肠癌、肝癌、胰腺癌、前列腺癌、睾丸癌、多发性骨髓瘤、白血病等多种实体瘤和血液瘤。
在其中一些实施例中,所述肿瘤为EGFR基因突变的恶性肿瘤。
在其中一些实施例中,所述肿瘤为EGFR
L858R/T790M/C797S突变的恶性肿瘤。
本发明所述的通式(I)化合物或其药学上可接受的盐,具有EGFR激酶抑制活性,对恶性肿瘤具有治疗效果。
本发明中所用术语“烷基”表示饱和直链和支链烷基,C
1-C
8烷基是指具有1到8个碳原子的饱和直链和支链烷基,包括但不限于甲基,乙基,异丙基,异丁基等。卤代C
1-C
8烷基是指烷基链有一个及以上卤素取代的C
1-C
8烷基。氘代C
1-C
8烷基表示有一个及以上氘取代的C
1-C
8烷基。不饱和C
1-C
8烷基表示含有一个及多个不饱和键的烷基,不饱和键包括烯基,炔基。
术语“烷氧基”表示末端含有一个氧原子的烷基,包括但不限于甲氧基,乙氧基,正丙氧基,异丙氧基。
术语“环烷基”表示具有环状结构的烷基,包括但不限于环丙基,环丁基,环戊基等。
术语“卤素”表示氟,氯,溴,碘。
-S(O)
2表示硫酰基。
-C(O)表示羰基。
术语“含氮杂环”包括饱和和不饱和的多元含氮杂环,包括但不限于环乙胺,环丙胺,吡咯,四氢吡咯,咪唑,吗啉,哌嗪,吡嗪,N-甲基哌嗪,N-乙基哌嗪等。
与现有技术相比,本发明具有以下有益效果:
本发明的2-氨基密啶类化合物或其药学上可接受的盐或其立体异构体或其前药分子或其活性代谢产物,可以对EGFR家族蛋白酶产生抑制作用,从而抑制多种肿瘤细胞的生长。本发明的化合物能够有效抑制EGFR蛋白激酶耐药突变体的活性,可以克服现有第三代选择性EGFR
T790M小分子抑制剂Osimertinib,Olmutinib,Rociletinib等诱发的非小细胞肺癌等肿瘤病人的临床耐药。
图1是本发明2-氨基密啶类化合物的结构通式。
下面结合具体实施例对本申请作出详细说明。
一、实施例化合物的合成
实施例1:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)丙烯酰胺(I-1)
合成路线如下:
步骤1.5,7-二硝基-1H-吲唑(2)的制备:
冰浴下,将5-硝基-1H-吲唑(1)(16.32g,100mmol)溶于硫酸溶液,并在冰浴下滴加浓硝酸(40ml,400mmol),待反应结束,将反应液缓慢倒入冰水中,充分搅拌后抽滤得5,7-二硝基-1H-吲唑(2)白色滤饼20.61g,产率99%。
1H NMR(400MHz,DMSO-d
6)δ14.57(s,1H),9.30(d,J=2.0Hz,1H),8.95(d,J=2.0Hz,1H),8.70(s,1H)。
步骤2.2-(5,7-二硝基-1H-吲唑-1-基)-N,N-二甲基-1-乙胺(3)的制备:
将5,7-二硝基-1H-吲唑(2)(10.41g,50mmol)溶于THF中,冰浴下,加入钠氢(1.44g,60mmol),常温下搅拌0.5h,加入N,N-二甲胺基溴乙烷氢溴酸盐(13.98g,60mmol)。反应过夜,淬灭后用乙酸乙酯萃取,用无水硫酸钠干燥后经柱层析得固体9.77g,产率70%。
1H NMR(400MHz,Chloroform-d)δ8.95(d,J=2.0Hz,1H),8.91(d,J=2.1Hz,1H),8.45(s,1H),4.76(t,J=5.9Hz,2H),2.62(t,J=5.9Hz,2H),2.10(s,6H)。
步骤3.1-(2-(二甲氨基)乙基)-5-硝基-1H-吲唑-7-胺(4)的制备:
将2-(5,7-二硝基-1H-吲唑-1-基)-N,N-二甲基-1-乙胺(3)(9.49g,34mmol)溶于甲醇,加入硫化铵溶液(100ml,204mmol),70℃下加热回流3h。反应结束后将溶剂旋干,加水抽滤,水溶液用乙酸乙酯萃取,无水硫酸钠干燥,柱层析得黄色固体2.54g,产率30%。
1H NMR(400MHz,DMSO-d
6)δ8.23(s,1H),8.05(d,J=2.2Hz,1H),7.47(d,J=2.1Hz,1H),6.00(s,2H),4.73(t,J=6.2Hz,2H),2.72(t,J=6.2Hz,2H),2.17(s,6H)。
步骤4.3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚(7)的制备:
将2,4-二氯嘧啶(5)(1.49g,10mmol)和氯化铝(4.00g,30mmol)溶于乙二醇二甲醚,氩气保护下搅拌5min,将1-甲基-1H-吲哚(6)(1.31g,10mmol)加入反应体系中,80℃下反应过夜。将反应液加入冰水中淬灭,再用二氯甲烷萃取,无水硫酸钠干燥,柱层析得白色固体1.71g,产率70%。
1H NMR(300MHz,Chloroform-d)δ8.41(dd,J=5.4,1.2Hz,1H),8.35–8.28(m,1H),7.91(s,1H),7.45(dd,J=5.5,1.3Hz,1H),7.34(tt,J=8.0,1.8Hz,3H),3.85(s,3H)。
步骤5.N,N-二叔丁氧羰基-1-(2-(二甲氨基)乙基)-5-硝基-1H-吲唑-7-胺(8)的制备:
将1-(2-(二甲氨基)乙基)-5-硝基-1H-吲唑-7-胺(4)(2.50g,10mmol),DMAP(0.25g,2mmol)和三乙胺(2.02g,20mmol)溶于二氯甲烷,冰浴下,将二碳酸二叔丁酯(6.55g,30mmol)逐滴加入反应液中,8h后用饱和氯化铵溶液萃取,无水硫酸钠干燥,浓缩柱层析得浅黄色固体4.7g,产率98%。
步骤6.1-(2-(二甲氨基)乙基)-7-(N,N-二叔丁氧羰基-氨基)-1H-吲唑-5-胺(9)的制备:
将N,N-二叔丁氧羰基-1-(2-(二甲氨基)乙基)-5-硝基-1H-吲唑-7-胺(8)(4.8g,10mmol),锌粉(6.5g,100mmol)和氯化铵(5.4g,100mmol)溶于70%乙醇溶液中,氩气保护下70℃回流3h,抽滤浓缩得固体4.4g,产率98%。
1H NMR(400MHz,Chloroform-d)δ8.69(d,J=2.0Hz,1H),8.26(s,1H),8.07(d,J=2.0Hz,1H),4.53–4.49(m,2H),2.83–2.78(m,2H),2.31(s,6H),1.44(s,18H)。
步骤7.1-(2-(二甲氨基)乙基)-N
5-(4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)-1H-吲唑-5,7-二胺(10)的制备:
将1-(2-(二甲氨基)乙基)-7-(N,N-二叔丁氧羰基-氨基)-1H-吲唑-5-胺(9)(3.19g,10mmol),3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚(7)(2.68g,11mmol) 和对甲苯磺酸一水合物(2.3g,12mmol)溶于正丁醇,氩气保护下加热至110℃,反应8h,抽滤将固体用乙腈处理得黄色固体3.8g,产率90%。
1H NMR(400MHz,Chloroform-d)δ8.49–8.44(m,1H),8.27(d,J=5.4Hz,1H),7.84(s,1H),7.78–7.74(m,2H),7.54(d,J=1.8Hz,1H),7.40–7.27(m,3H),7.23(ddd,J=8.2,6.9,1.3Hz,1H),7.13(d,J=7.9Hz,1H),6.98(d,J=5.4Hz,1H),6.87(d,J=1.8Hz,1H),4.85(t,J=5.7Hz,2H),3.83(s,3H),3.13(t,J=5.7Hz,2H),2.42(d,J=4.0Hz,6H)。
步骤8.N-(1-(2-(二甲氨基)乙基)-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)丙烯酰胺(I-1)的制备:
将1-(2-(二甲氨基)乙基)-N
5-(4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)-1H-吲唑-5,7-二胺(10)(490mg,1.15mmol)和DIPEA(446mg,3.45mmol)溶于二氯甲烷,冰浴下逐滴加入丙烯酰氯(124.9mg,1.38mmol),常温反应3h,反应液用饱和碳酸氢钠溶液萃取,无水硫酸钠干燥,浓缩柱层析得固体220.91mg,产率40%。
1H NMR(400MHz,Chloroform-d)δ8.46(d,J=1.4Hz,1H),8.24(d,J=7.9Hz,1H),8.16–8.03(m,3H),7.93(d,J=1.4Hz,1H),7.86(s,1H),7.37–7.27(m,2H),7.22(ddd,J=8.2,6.8,1.4Hz,1H),7.02–6.97(m,1H),6.55–6.48(m,2H),5.81(dd,J=7.7,4.4Hz,1H),4.79(t,J=5.6Hz,2H),3.85(d,J=1.5Hz,3H),3.26(s,2H),2.42(d,J=1.4Hz,6H)。
实施例2:(E)-N-(1-(2-(二甲氨基)乙基)-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)-2-丁烯酰胺(I-2)
参照(I-1)的合成方法,产率66%。
1H NMR(400MHz,DMSO-d
6)δ11.26(s,1H),8.38(d,J=8.0Hz,1H),8.35(d,J=5.3Hz,1H),8.19–7.99(m,3H),7.93(s,1H),7.37(d,J=8.2Hz,1H),7.33–7.27(m,1H),7.24–7.21(m,1H),7.13–7.07(m,1H),7.05(s,1H),6.06(d,J=15.2Hz,1H),4.69(dd,J=5.9,3.6Hz,2H),3.89(s,3H),2.92(s,2H),2.24(s,6H),1.95(d,J=6.9Hz,3H)。
实施例3:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)-3-甲基-2-丁烯酰胺(I-3)
参照(I-1)的合成方法,产率57%。
1H NMR(400MHz,Chloroform-d)δ11.18(s,1H),8.41(dt,J=7.8,1.0Hz,1H),8.35(d,J=5.3Hz,1H),8.12–7.91(m,4H), 7.39–7.28(m,2H),7.25–7.18(m,2H),7.05(d,J=5.4Hz,1H),5.86–5.80(m,1H),4.71–4.66(m,2H),3.88(s,3H),2.90(s,2H),2.29(d,J=1.3Hz,3H),2.24(s,6H),1.94(s,3H)。
实施例4:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)丙酰胺(I-4)
参照(I-1)的合成方法,产率63%。
1H NMR(300MHz,Chloroform-d)δ11.20(s,1H),8.38(d,J=7.8Hz,1H),8.34(d,J=5.4Hz,1H),8.09(d,J=11.2Hz,2H),8.01(d,J=1.9Hz,1H),7.93(s,1H),7.38(d,J=8.1Hz,1H),7.34–7.27(m,2H),7.25–7.21(m,1H),7.07(d,J=5.4Hz,1H),4.71(d,J=5.6Hz,2H),3.91(s,3H),2.92(s,2H),2.48(q,J=7.6Hz,2H),2.23(s,7H),1.33(t,J=7.5Hz,3H)。
实施例5:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)乙酰胺(I-5)
参照(I-1)的合成方法,产率54%。
1H NMR(300MHz,Chloroform-d)δ11.37(s,1H),8.40(d,J=8.0Hz,1H),8.35(d,J=5.3Hz,1H),8.09(d,J=1.9Hz,1H),8.05(d,J=1.9Hz,1H),8.01(s,1H),7.93(s,1H),7.41–7.36(m,1H),7.34–7.27(m,2H),7.24–7.21(m,1H),7.06(d,J=5.4Hz,1H),4.73–4.67(m,2H),3.89(s,3H),2.94–2.87(m,2H),2.25(s,3H),2.24(s,6H)。
实施例6:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)异丁酰胺(I-6)
参照(I-1)的合成方法,产率71%。
1H NMR(300MHz,Chloroform-d)δ11.08(s,1H),8.36(dd,J=8.1,6.3Hz,2H),8.09(d,J=1.9Hz,1H),8.06–8.01(m,2H),7.92(s,1H),7.41–7.34(m,2H),7.30(dd,J=6.9,1.3Hz,1H),7.22(dd,J=6.9,1.3Hz,1H),7.05(d,J=5.4Hz,1H),4.73–4.67(m,2H),3.87(s,3H),2.91(dd,J=6.4, 3.5Hz,2H),2.61(p,J=6.9Hz,1H),2.19(s,6H),1.32(d,J=6.8Hz,6H)。
实施例7:1-(2-(二甲氨基)乙基)-N-(4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)-1H-吲唑-5-胺(I-7)
合成路线如下:
步骤1.N,N-二甲基-2-(5-硝基-1H-吲唑-1-基)乙胺(11)的制备:
将5-硝基吲唑(1)(1.63g,10mmol)溶于四氢呋喃,冰浴下加入钠氢(0.288g,12mmol),常温搅拌0.5h后加入N,N-二甲胺基溴乙烷氢溴酸盐(2.56g,11mmol)。反应过夜,淬灭后用乙酸乙酯萃取,用无水硫酸钠干燥后经柱层析得固体1.64g,产率70%。
1H NMR(400MHz,Chloroform-d)δ8.73(dd,J=2.1,0.7Hz,1H),8.27(dd,J=9.2,2.1Hz,1H),8.22(d,J=0.9Hz,1H),7.50(dt,J=9.2,0.8Hz,1H),4.53(t,J=6.8Hz,2H),2.85(t,J=6.7Hz,2H),2.30(s,6H)。
步骤2.1-(2-(二甲氨基)乙基)-1H-吲唑-5-胺(12)的制备:
将N,N-二甲基-2-(5-硝基-1H-吲唑-1-基)乙胺(11)(1.6g,6.8mmol),锌粉(4.4g,68mmol)和氯化铵(3.6g,68mmol)溶于70%乙醇,氩气保护,70℃下加热回流3h,抽滤浓缩得固体1.4g,产率100%。
1H NMR(400MHz,DMSO-d
6)δ7.84(s,1H),7.50(d,J=8.9Hz,1H),6.90(dd,J=8.9,2.0Hz,1H),6.83(d,J=2.1Hz,1H),4.71(t,J=6.6Hz,2H),3.52(t,J=6.6Hz,2H),2.78(s,6H)。
步骤3.1-(2-(二甲氨基)乙基)-N-(4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)-1H-吲唑-5-胺(I-7)的制备:
将1-(2-(二甲氨基)乙基)-1H-吲唑-5-胺(12)(204mg,1mmol),3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚(7)(243.7mg,1mmol)和对甲苯磺酸一水合物(228mg,1.2mmol)溶于异丙醇,氩气保护,100℃加热回流8h。冷却抽滤, 固体用乙腈打浆得化合物205.6mg,产率50%。
1H NMR(400MHz,DMSO-d
6)δ9.37(s,1H),8.62(d,J=7.9Hz,1H),8.32(d,J=14.3Hz,3H),7.98(s,1H),7.70–7.48(m,3H),7.21(dt,J=43.7,8.2Hz,3H),4.47(t,J=6.7Hz,2H),3.88(s,3H),2.72(t,J=6.6Hz,2H),2.18(s,6H)。
实施例8:N-(4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)-1-(2-吗啉乙基)-1H-吲唑-5-胺(I-8)
合成路线如下:
(13)的制备参照(11)的合成方法,产率68%。
1H NMR(400MHz,Chloroform-d)δ8.73(d,J=2.0Hz,1H),8.28(dd,J=9.2,2.1Hz,1H),8.22(d,J=0.9Hz,1H),7.50(d,J=9.3Hz,1H),4.55(t,J=6.6Hz,2H),3.63(t,J=4.7Hz,4H),2.90(t,J=6.6Hz,2H),2.50(t,J=4.6Hz,4H)。
(14)的制备参照(12)的合成方法,产率99%。
1H NMR(400MHz,DMSO-d
6)δ7.70(d,J=0.9Hz,1H),7.37(dd,J=8.9,1.0Hz,1H),6.81(dd,J=8.9,2.0Hz,1H),6.74(d,J=1.7Hz,1H),4.39(t,J=6.8Hz,2H),3.54–3.47(m,4H),2.72(t,J=6.8Hz,2H),2.42(dd,J=4.3,2.4Hz,4H)。
(I-14)的制备参照(I-13)的合成方法,产率71%。
1H NMR(400MHz,DMSO-d
6)δ10.57(s,1H),8.70(s,1H),8.34(s,1H),8.24(s,2H),8.10(s,1H),7.93(d,J=8.9Hz,1H),7.65(d,J=8.9Hz,1H),7.60(d,J=8.2Hz,1H),7.38(d,J=6.6Hz,1H),7.31(t,J=7.6Hz,1H),7.10(d,J=9.8Hz,1H),4.99(t,J=6.9Hz,2H),3.99(s,2H),3.93(s,3H),3.83–3.75(m,2H),3.70(t,J=7.0Hz,2H),3.52(s,2H), 3.21(s,2H)。
实施例9:7-氯-1-(2-(二甲氨基)乙基)-N-(4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)-1H-吲唑-5-胺(I-9)
合成路线如下:
步骤1.7-氯-5-硝基-1H-吲唑(16)的制备:
冰浴下,将亚硝酸钠(0.83g,12mmol)的水溶液逐滴加入2-氯-6-甲基-4-硝基苯胺(1.87g,10mmol)的冰醋酸溶液中,室温反应过夜,浓缩加水洗去杂质得棕黄色固体193g,产率98%。
1H NMR(400MHz,DMSO-d
6)δ14.32(s,1H),8.85(d,J=1.9Hz,1H),8.53(s,1H),8.33–8.26(m,1H)。
(17)的制备参照(11)的合成方法,产率65%。
1H NMR(400MHz,Chloroform-d)δ8.61(d,J=2.0Hz,1H),8.27(d,J=2.0Hz,1H),8.24(s,1H),4.91(t,J=7.2Hz,2H),2.88–2.83(m,2H),2.33(s,6H)。
(18)的制备参照(12)的合成方法,产率100%。
1H NMR(400MHz,DMSO-d
6)δ7.92(s,1H),6.96(d,J=1.9Hz,1H),6.78(d,J=1.9Hz,1H),4.99(t,J=6.9Hz,2H),3.46(s,2H),2.76(s,6H)。
(I-9)的制备参照(I-7)的合成方法,产率67%。
1H NMR(400MHz,DMSO-d
6)δ9.53(s,1H),8.60(d,J=8.0Hz,1H),8.38–8.30(m,2H),8.22(d,J=1.8Hz,1H),8.11(s,1H),7.94(d,J=1.8Hz,1H),7.54(d,J=8.2Hz,1H),7.31–7.15(m,3H),4.76(t,J=7.0Hz,2H),3.89(s,3H),2.72(t,J=7.0Hz,2H),2.21(s,6H)。
实施例10:7-氯-N-(4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)-1-(2-吗啉乙基)-1H-吲唑-5-胺(I-10)
合成路线如下:
(19)的制备参照(11)的合成方法,产率55%。
1H NMR(400MHz,Chloroform-d)δ8.62(d,J=2.0Hz,1H),8.28(d,J=2.0Hz,1H),8.24(s,1H),4.93(t,J=7.0Hz,2H),3.67–3.63(m,4H),2.92–2.86(m,2H),2.55–2.51(m,4H)。
(20)的制备参照(12)的合成方法,产率100%。
(I-10)的制备参照(I-7)的合成方法,产率51%。
1H NMR(300MHz,DMSO-d
6)δ9.55(s,1H),8.61(d,J=7.9Hz,1H),8.41–8.31(m,2H),8.23(s,1H),8.12(s,1H),7.94(d,J=1.8Hz,1H),7.54(d,J=8.1Hz,1H),7.23(tt,J=15.9,7.3Hz,3H),4.79(t,J=7.1Hz,2H),3.89(s,3H),3.53(t,J=4.6Hz,4H),2.77(t,J=7.1Hz,2H),2.47–2.39(m,4H)。
实施例11:1-(2-(二甲氨基)乙基)-N-(4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)-1H-吲唑-5-胺(I-11)
合成路线如下:
(22)的制备参照(7)的合成方法,产率35%。
步骤2.3-(2-氯嘧啶-4-基)-1-(乙磺酰基)-1H-吲哚(23)的制备:
将3-(2-氯嘧啶-4-基)-1H-吲哚(22)(4.58g,20mmol)溶于THF溶液中,冰浴下,在反应液中加入钠氢(0.58g,24mmol)。0.5h后将乙基磺酰氯(3.86g,30mmol)加入反应液,反应过夜淬灭,乙酸乙酯萃取,无水硫酸钠干燥浓缩柱层析得3.85g,产率60%。
1H NMR(300MHz,Chloroform-d)δ8.58(d,J=5.3Hz,1H),8.51–8.43(m,1H),8.18(s,1H),7.96–7.88(m,1H),7.57(d,J=5.3Hz,1H),7.48–7.41(m,2H),3.42(q,J=7.4Hz,2H),1.28(d,J=7.4Hz,3H)。
(I-11)的制备参照(I-7)的合成方法,产率78%。
1H NMR(400MHz,Methanol-d
4)δ8.51(d,J=8.1Hz,1H),8.32(d,J=5.3Hz,1H),8.24(s,1H),8.17(dd,J=1.9,0.8Hz,1H),7.95(d,J=0.9Hz,1H),7.90(dt,J=8.4,0.9Hz,1H),7.59(dd,J=9.0,2.0Hz,1H),7.55–7.51(m,1H),7.37(ddd,J=8.4,7.2,1.2Hz,1H),7.24(ddd,J=8.1,7.2,1.1Hz,1H),7.18(d,J=5.3Hz,1H),4.62(t,J=6.5Hz,2H),3.50(q,J=7.4Hz,2H),3.21(t,J=6.5Hz,2H),2.57(s,6H),1.17(t,J=7.4Hz,3H)。
实施例12:N-(4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)-1-(2-吗啉乙基)-1H-吲唑-5-胺(I-12)
(I-12)的制备参照(I-11)的合成方法,产率80%。
1H NMR(400MHz,Methanol-d
4)δ8.52(d,J=8.0Hz,1H),8.34(d,J=5.3Hz,1H),8.27(s,1H),8.19–8.14(m,1H),7.95–7.89(m,2H),7.61–7.52(m,2H),7.38(ddd,J=8.4,7.1,1.2Hz,1H),7.27–7.19(m,2H),4.57(t,J=6.6Hz,2H),3.64(t,J=4.7Hz,4H),3.54–3.48(m,2H),2.99–2.93(m,2H),2.59(t,J=4.6Hz,4H),1.19(t,J=7.3Hz,3H)。
实施例13:7-氯-1-(2-(二甲氨基)乙基)-N-(4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)-1H-吲唑-5-胺(I-13)
(I-13)的制备参照(I-11)的合成方法,产率88%。
1H NMR(400MHz,DMSO-d
6)δ9.75(s,1H),8.72(d,J=8.0Hz,1H),8.56(s,1H),8.51(d,J=5.3Hz,1H),8.18(s,1H),8.12(s,1H),7.94(s,1H),7.92(s,1H),7.52(d,J=5.3Hz,1H),7.48(t,J=7.9Hz,1H),7.38(t,J=7.7Hz,1H),4.80(t,J=7.0Hz,2H),3.76(d,J=7.3Hz,2H),3.53(t,J=4.6Hz,4H),2.77(t,J=7.0Hz,2H),2.45(d,J=4.9Hz,4H),1.13(t,J=7.3Hz,3H)。
实施例14:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)丙烯酰胺(I-14)
合成路线如下:
参照(I-1)的合成方法,产率35%。
1H NMR(300MHz,DMSO-d
6)δ10.39(s,1H),9.71(s,1H),8.76(d,J=8.0Hz,1H),8.56(s,1H),8.49(d,J=5.2Hz,1H),8.24 (d,J=7.0Hz,1H),8.10(s,1H),7.93(d,J=8.3Hz,1H),7.65(s,1H),7.51(d,J=5.3Hz,1H),7.45(d,J=7.9Hz,1H),7.38(d,J=7.6Hz,1H),6.55(dd,J=17.1,10.2Hz,1H),6.34(dd,J=17.0,2.0Hz,1H),5.92–5.83(m,1H),4.59(t,J=6.8Hz,2H),3.76(d,J=7.3Hz,2H),3.34(s,6H),2.43(s,2H),1.13(s,3H)。
实施例15:(E)-N-(1-(2-(二甲氨基)乙基)-5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)-2-丁烯酰胺(I-15)
参照(I-1)的合成方法,产率75%。
1H NMR(300MHz,DMSO-d
6)δ10.21(s,1H),9.67(s,1H),8.76(d,J=7.8Hz,1H),8.60–8.43(m,2H),8.21(s,1H),8.02(s,1H),7.93(d,J=8.3Hz,1H),7.62(s,1H),7.47(dd,J=12.2,6.3Hz,2H),7.38(d,J=7.8Hz,1H),6.87(dd,J=15.1,7.5Hz,1H),6.21(d,J=15.4Hz,1H),4.49(t,J=7.1Hz,2H),3.76(q,J=7.4Hz,2H),2.59(t,J=6.8Hz,2H),2.14(s,6H),1.90(d,J=6.9Hz,3H),1.13(t,J=7.3Hz,3H)。
实施例16:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)-3-甲基-2-丁烯酰胺(I-16)
参照(I-1)的合成方法,产率80%。
1H NMR(400MHz,Methanol-d
4)δ8.54(d,J=8.2Hz,1H),8.33(d,J=5.3Hz,1H),8.26(s,1H),8.09(s,1H),7.96–7.88(m,2H),7.64(s,1H),7.37(t,J=7.7Hz,1H),7.27(t,J=7.6Hz,1H),7.20(d,J=5.4Hz,1H),6.00(s,1H),4.59(t,J=6.9Hz,2H),3.50(q,J=7.3Hz,2H),2.88(t,J=6.8Hz,2H),2.34(s,5H),2.22(s,3H),1.96(s,3H),1.18(t,J=7.3Hz,3H)。
实施例17:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)丙酰胺(I-17)
参照(I-1)的合成方法,产率90%。
1H NMR(300MHz,DMSO-d
6)δ10.15(s,1H),9.65(s,1H),8.77(d,J=8.1Hz,1H),8.55(s,1H),8.48(d,J=5.2Hz,1H),8.19(s,1H),8.01(s,1H),7.93(d,J=8.3Hz,1H),7.60(d,J=1.9Hz,1H),7.48(dd,J=9.2,6.5Hz,2H),7.37(t,J=7.6Hz,1H),4.52(t,J=7.0Hz,2H),3.76(q,J=7.2Hz,2H),2.60(t,J=7.0Hz,2H),2.43(q,J=7.6Hz,2H),2.16(s,6H),1.17(d,J=7.5Hz,3H),1.12(d,J=7.2Hz,3H)。
实施例18:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)乙酰胺(I-18)
参照(I-1)的合成方法,产率88%。
1H NMR(300MHz,DMSO-d
6)δ10.23(s,1H),9.66(s,1H),8.75(d,J=8.0Hz,1H),8.55(s,1H),8.48(d,J=5.3Hz,1H),8.17(d,J=1.9Hz,1H),8.00(s,1H),7.93(d,J=8.3Hz,1H),7.62(d,J=2.0Hz,1H),7.51–7.44(m,2H),7.37(t,J=7.6Hz,1H),4.53(t,J=7.0Hz,2H),3.76(q,J=7.3Hz,2H),2.61(t,J=7.0Hz,2H),2.18(s,6H),2.14(s,3H),1.13(t,J=7.3Hz,3H)。
实施例19:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)异丁酰胺(I-19)
参照(I-1)的合成方法,产率85%。
1H NMR(400MHz,DMSO-d
6)δ10.09(s,1H),9.65(s,1H),8.79(d,J=7.9Hz,1H),8.56(s,1H),8.48(d,J=5.3Hz,1H),8.25(s,1H),8.01(s,1H),7.93(d,J=8.3Hz,1H),7.54–7.44(m,3H),7.37(t,J=7.6Hz,1H),4.51(t,J=6.9Hz,2H),3.76(q,J=7.2Hz,2H),2.73–2.66(m,1H),2.60(t,J=7.0Hz,2H),2.15(s,6H),1.18(d,J=6.8Hz,6H),1.12(t,J=7.3Hz,3H)。
实施例20:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)环丙甲酰胺(I-20)
参照(I-1)的合成方法,产率91%。
1H NMR(400MHz,DMSO-d
6)δ10.38(s,1H),9.64(s,1H),8.76(d,J=8.1Hz,1H),8.55(s,1H),8.48(d,J=5.2Hz,1H),8.20(s,1H),8.00(s,1H),7.93(d,J=8.3Hz,1H),7.56(d,J=1.9Hz,1H),7.47(dd,J=11.1,6.4Hz,2H),7.37(t,J=7.6Hz,1H),4.52(t,J=7.1Hz,2H),3.76(q,J=7.3Hz,2H),2.60(t,J=7.1Hz,2H),2.19(s,6H),1.92–1.79(m,1H),1.13(t,J=7.3Hz,3H),0.85(d,J=6.0Hz,4H)。
实施例21:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-(三氘代甲基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)丙烯酰胺(I-21)
合成路线如下:
参照(I-1)的合成方法,产率41%。
1H NMR(400MHz,DMSO-d
6)δ10.42(s,1H),9.46(s,1H),8.59(d,J=8.0Hz,1H),8.37–8.30(m,2H),8.20(d,J=1.9Hz,1H),8.03(s,1H),7.73(d,J=1.9Hz,1H),7.53(d,J=8.1Hz,1H),7.29–7.23(m, 1H),7.21–7.15(m,2H),6.54(dd,J=17.1,10.2Hz,1H),6.33(dd,J=17.0,2.0Hz,1H),5.85(dd,J=10.1,1.9Hz,1H),4.49(t,J=7.2Hz,2H),2.57(t,J=7.2Hz,2H),2.13(s,6H)。
实施例22:(E)-N-(1-(2-(二甲氨基)乙基)-5-((4-(1-(三氘代甲基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)-2-丁烯酰胺(I-22)
参照(I-1)的合成方法,产率56%。
1H NMR(400MHz,DMSO-d
6)δ10.22(d,J=11.8Hz,1H),9.46(d,J=3.1Hz,1H),8.60(d,J=7.8Hz,1H),8.34(d,J=5.8Hz,2H),8.19(s,1H),8.01(d,J=2.7Hz,1H),7.68(d,J=9.7Hz,1H),7.53(d,J=8.2Hz,1H),7.29–7.23(m,1H),7.18(dd,J=10.3,6.3Hz,2H),6.88(dq,J=14.0,6.8Hz,1H),6.22(d,J=15.3Hz,1H),4.54–4.45(m,2H),3.24(d,J=7.0Hz,1H),2.57(t,J=7.1Hz,2H),2.14(d,J=9.0Hz,6H),1.90(d,J=6.8Hz,2H)。
实施例23:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-(三氘代甲基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)-3-甲基-2-丁烯酰胺(I-23)
参照(I-1)的合成方法,产率67%。
1H NMR(400MHz,DMSO-d
6)δ10.08(s,1H),9.45(s,1H),8.61(d,J=8.0Hz,1H),8.37–8.31(m,2H),8.24–8.16(m,1H),8.01(d,J=1.9Hz,1H),7.65(d,J=2.1Hz,1H),7.53(d,J=8.1Hz,1H),7.30–7.23(m,1H),7.18(dd,J=9.7,6.2Hz,2H),5.98(s,1H),4.50(t,J=7.1Hz,2H),2.59(t,J=7.0Hz,2H),2.22–2.16(m,3H),2.14(s,6H),1.90(s,3H)。
实施例24:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-(三氘代甲基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)丙酰胺(I-24)
参照(I-1)的合成方法,产率70%。
1H NMR(300MHz,DMSO-d
6)δ10.12(s,1H),9.43(s,1H),8.60(d,J=7.9Hz,1H),8.34(d,J=4.4Hz,2H),8.17(s,1H),8.00(s,1H),7.66(d,J=1.9Hz,1H),7.53(d,J=8.1Hz,1H),7.27(t,J=7.6Hz,1H),7.22–7.12(m,2H),4.52(t,J=7.0Hz,2H),2.59(t,J=7.0Hz,2H),2.43(q,J=7.6Hz,2H),2.16(s,6H),1.16(t,J=7.6Hz,3H)。
实施例25:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-(三氘代甲基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)乙酰胺(I-25)
参照(I-1)的合成方法,产率69%。
1H NMR(300MHz,DMSO-d
6)δ10.22(s,1H),9.45(s,1H),8.60(d,J=7.9Hz,1H),8.34(d,J=6.1Hz,2H),8.17(d,J=1.9Hz,1H),8.01(s,1H),7.70(d,J=1.9Hz,1H),7.53(d,J=8.1Hz,1H),7.33–7.24(m,1H),7.19(dd,J=6.2,2.8Hz,2H),4.53(t,J=7.0Hz,2H),2.61(t,J=7.0Hz,2H),2.18(s,6H),2.14(s,3H)。
实施例26:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-(三氘代甲基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)异丁酰胺(I-26)
参照(I-1)的合成方法,产率45%。
1H NMR(300MHz,DMSO-d
6)δ10.05(s,1H),9.42(s,1H),8.61(d,J=7.9Hz,1H),8.38–8.29(m,2H),8.21(s,1H),8.00(s,1H),7.60(d,J=1.9Hz,1H),7.53(d,J=8.1Hz,1H),7.27(t,J=7.5Hz,1H),7.21–7.14(m,2H),4.51(t,J=7.0Hz,2H),2.76–2.64(m,1H),2.60(t,J=6.9Hz,2H),2.15(s,6H),1.19(d,J=6.8Hz,6H)。
实施例27:N-(1-(2-(二甲氨基)乙基)-5-((4-(1-(三氘代甲基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)环丙甲酰胺(I-27)
参照(I-1)的合成方法,产率73%。
1H NMR(300MHz,DMSO-d
6)δ10.37(s,1H),9.42(s,1H),8.60(d,J=8.0Hz,1H),8.37–8.30(m,2H),8.19(s,1H),8.00(s,1H),7.62(d,J=1.9Hz,1H),7.53(d,J=8.1Hz,1H),7.27(t,J=7.6Hz,1H),7.21–7.14(m,2H),4.52(t,J=7.1Hz,2H),2.60(t,J=7.1Hz,2H),2.19(s,6H),1.88(s,1H),0.85(d,J=5.4Hz,4H)。
实施例28:1-(2-(二甲氨基)乙基)-N-(4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)-1H-吲唑-5-胺(I-28)
合成路线如下:
参照(I-1)的合成方法,产率70%。
1H NMR(400MHz,DMSO-d
6)δ9.57(s,1H),8.73(d,J=8.1Hz,1H),8.53(s,1H),8.47(d,J=5.2Hz,1H),8.24(d,J=1.4Hz,1H),7.98(s,1H),7.96–7.90(m,1H),7.63(d,J=1.3Hz,2H),7.50–7.43(m,2H),7.33(t,J=7.6Hz,1H),4.43(t,J=6.6Hz,2H),3.76(q,J=7.3Hz,2H),2.85(t,J=6.6Hz,2H),2.52–2.50(m,4H),1.13(t,J=7.3Hz,3H),0.87(t,J=7.1Hz,6H)。
实施例29:7-氯-1-(2-(二甲氨基)乙基)-N-(4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)-1H-吲唑-5-胺(I-29)
合成路线如下:
参照(I-7)的合成方法,产率75%。
1H NMR(300MHz,DMSO-d
6)δ9.73(s,1H),8.72(d,J=8.0Hz,1H),8.55(s,1H),8.50(d,J=5.3Hz,1H),8.17(s,1H),8.11(s,1H),7.98–7.87(m,2H),7.49(dd,J=18.7,6.6Hz,2H),7.37(t,J=7.6Hz,1H),4.72(t,J=7.0Hz,2H),3.76(q,J=7.3Hz,2H),2.83(t,J=7.0Hz,2H),1.13(t,J=7.2Hz,3H),0.90(t,J=7.1Hz,6H)。
实施例30:N-(1-(2-(二乙氨基)乙基)-5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)丙烯酰胺(I-30)
合成路线如下:
(32)的制备参照(3)的合成方法,产率72%。
1H NMR(400MHz,Chloroform-d)δ8.93(d,J=2.0Hz,1H),8.92(d,J=2.1Hz,1H),8.44(s,1H),4.74(t,J=5.8Hz,2H),2.71(t,J=5.9Hz,2H),2.33(t,J=7.1Hz,4H),0.68(t,J=7.1Hz,6H)。
(33)的制备参照(4)的合成方法,产率50%。
1H NMR(400MHz,Chloroform-d)δ8.10(d,J=2.0Hz,1H),8.09(s,1H),7.40(d,J=2.0Hz,1H),4.76–4.70(m,2H),2.95–2.91(m,2H),2.46(q,J=7.2Hz,4H),0.84(t,J=7.1Hz,6H)。
(34)的制备参照(8)的合成方法,产率98%。
1H NMR(400MHz,Chloroform-d)δ8.68(d,J=2.0Hz,1H),8.24(s,1H),8.06(d,J=2.0Hz,1H),4.49–4.44(m,2H),2.97–2.93(m,2H),2.59(q,J=7.1Hz,4H),1.44(s,18H),1.02(t,J=7.1Hz,6H)。
(I-36)的制备参照(I-7)的合成方法,产率33%。
1H NMR(300MHz,DMSO-d
6)δ10.35(s,1H),9.68(s,1H),8.76(d,J=8.0Hz,1H),8.56(s,1H),8.49(d,J=5.3Hz,1H),8.21(s,1H),8.03(s,1H),7.92(d,J=8.3Hz,1H),7.64(d,J=1.7Hz,1H),7.51–7.43(m,2H),7.36(t,J=7.6Hz,1H),6.53(dd,J=17.1,10.1Hz,1H),6.32(dd,J=16.9,2.0Hz,1H),5.90–5.81(m,1H),4.44(t,J=7.2Hz,2H),3.76(q,J=7.3Hz,2H),2.69(t,J=7.2Hz,2H),2.43(q,J=7.1Hz,4H),1.13(t,J=7.3Hz,3H),0.87(t,J=7.1Hz,6H)。
实施例31:(E)-N-(1-(2-(二乙氨基)乙基)-5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)-2-丁烯酰胺(I-31)
参照(I-1)的合成方法,产率67%。
1H NMR(400MHz,DMSO-d
6)δ10.15(d,J=6.4Hz,1H),9.66(d,J=3.7Hz,1H),8.77(s,1H),8.55(d,J=1.0Hz,1H),8.48(d,J=5.3Hz,1H),8.20(dd,J=5.3,1.8Hz,1H),8.02(d,J=2.0Hz,1H),7.97–7.89(m,1H),7.63–7.56(m,1H),7.51–7.43(m,2H),7.36(t,J=7.6Hz,1H),6.93–6.81(m,1H),6.21(d,J=15.3Hz,1H),4.45(dt,J=14.2,7.1Hz,2H),3.79–3.73(m,2H),3.23(dt,J=6.8,1.5Hz,1H),2.71(dt,J=11.7,7.2Hz,2H),2.48–2.41(m,4H),1.90(d,J=6.8Hz,2H),1.13(t,J=7.3Hz,3H),0.88(t,J=7.1Hz,6H)。
实施例32:N-(1-(2-(二乙氨基)乙基)-5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)-3-甲基-2-丁烯酰胺(I-32)
参照(I-1)的合成方法,产率76%。
1H NMR(400MHz,DMSO-d
6)δ10.08(d,J=50.4Hz,1H),9.65(s,1H),8.77(d,J=7.9Hz,1H),8.55(d,J=1.9Hz,1H),8.48(d,J=5.3Hz,1H),8.19(d,J=1.9Hz,1H),8.01(d,J=2.1Hz,1H),7.93(d,J=8.3Hz,1H),7.58(dd,J=16.7,1.9Hz,1H),7.50–7.43(m,2H),7.37(d,J=7.7Hz,1H),5.97(s,1H),4.47(q,J=7.2,6.1Hz,2H),3.79–3.72(m,2H),2.73(s,2H),2.46(d,J=7.3Hz,4H),2.17(d,J=1.2Hz,2H),1.90(s,2H),1.84(s,1H),1.13(t,J=7.3Hz,3H),0.89(t,J=7.2Hz,6H)。
实施例33:N-(1-(2-(二乙氨基)乙基)-5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)丙酰胺(I-33)
参照(I-1)的合成方法,产率83%。
1H NMR(400MHz,Chloroform-d)δ10.81(s,1H),8.52(d,J=8.0Hz,1H),8.46(d,J=5.2Hz,1H),8.21(s,1H),8.11(s,1H),7.98–7.93(m,2H),7.88(s,1H),7.43(ddd,J=8.4,7.2,1.3Hz,1H),7.38–7.33(m,1H),7.31(s,1H),7.08(d,J=5.2Hz,1H),4.68(s,2H),3.42(q,J=7.4Hz,2H),2.97(s,2H),2.49(q,J=7.5Hz,6H),1.29(d,J=7.3Hz,6H),0.89(d,J=6.0Hz,6H)。
实施例34:N-(1-(2-(二乙氨基)乙基)-5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)乙酰胺(I-34)
参照(I-1)的合成方法,产率76%。
1H NMR(400MHz,DMSO-d
6)δ10.15(s,1H),9.66(s,1H),8.81–8.71(m,1H),8.55(s,1H),8.48(d,J=5.3Hz,1H),8.17(d, J=1.9Hz,1H),8.01(s,1H),7.97–7.91(m,1H),7.61(d,J=1.9Hz,1H),7.52–7.44(m,2H),7.37(t,J=7.6Hz,1H),4.48(t,J=7.0Hz,2H),3.76(q,J=7.2Hz,2H),2.73(t,J=7.0Hz,2H),2.47(t,J=7.1Hz,4H),2.14(s,3H),1.13(t,J=7.3Hz,3H),0.90(t,J=7.1Hz,6H)。
实施例35:N-(1-(2-(二乙氨基)乙基)-5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)异丁酰胺(I-35)
参照(I-1)的合成方法,产率65%。
1H NMR(400MHz,Chloroform-d)δ10.70(s,1H),8.53(d,J=8.0Hz,1H),8.46(d,J=5.2Hz,1H),8.25(s,1H),8.10(s,1H),7.97–7.92(m,2H),7.83(s,1H),7.42(ddd,J=8.4,7.2,1.3Hz,1H),7.38–7.32(m,2H),7.07(d,J=5.2Hz,1H),4.68(t,J=4.7Hz,2H),3.41(q,J=7.4Hz,2H),2.97(d,J=5.7Hz,2H),2.62(s,1H),2.46(q,J=7.1Hz,4H),1.31(d,J=6.7Hz,4H),1.28(t,J=7.4Hz,6H),0.89(t,J=7.1Hz,6H)。
实施例36:N-(1-(2-(二乙氨基)乙基)-5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-7-基)环丙甲酰胺(I-36)
参照(I-1)的合成方法,产率78%。
1H NMR(400MHz,DMSO-d
6)δ10.35(s,1H),9.64(s,1H),8.77(d,J=7.6Hz,1H),8.55(s,1H),8.48(d,J=5.3Hz,1H),8.19(d,J=1.8Hz,1H),8.01(s,1H),7.93(d,J=8.3Hz,1H),7.56(d,J=1.8Hz,1H),7.51–7.44(m,2H),7.37(t,J=7.7Hz,1H),4.47(t,J=7.1Hz,2H),3.76(q,J=7.2Hz,2H),2.73(t,J=7.2Hz,2H),1.86(d,J=6.3Hz,1H),1.13(t,J=7.3Hz,3H),0.92(t,J=7.1Hz,6H),0.85(d,J=5.9Hz,4H)。
实施例37:2-(5-((4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-1H-吲唑-1-基)-N,N-二甲基乙酰胺(I-37)
合成路线如下:
参照(I-7)的合成方法,产率76%。
1H NMR(400MHz,DMSO-d
6)δ9.59(s,1H),8.74(d,J=8.0Hz,1H),8.54(s,1H),8.47(d,J=5.3Hz,1H),8.26(d,J=1.9Hz,1H),7.99(d,J=0.9Hz,1H),7.95–7.90(m,1H),7.61(dd,J=9.0,2.0Hz,1H),7.51(d,J=9.0Hz,1H),7.49–7.43(m,2H),7.36(t,J=7.6Hz,1H),5.40(s,2H),3.76(q,J=7.3Hz,2H),3.12(s,3H),2.87(s,3H),1.13(t,J=7.3Hz,3H)。
实施例38:N-(5-氯-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)-1-(2-(二甲氨基)乙基)-1H-吲唑-5-胺(I-38)
参照(I-7)的合成方法,产率79%。1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.57(s,2H),8.45(s,1H),8.21–8.19(m,1H),7.93(d,J=0.8Hz,1H),7.67–7.58(m,2H),7.54(dd,J=8.3,0.9Hz,1H),7.28(ddd,J=8.2,7.0,1.2Hz,1H),7.08(t,J=7.6Hz,1H),4.48(t,J=6.6Hz,2H),3.93(s,3H),2.72(t,J=6.6Hz,2H),2.18(s,6H)。
实施例39:N-(5-氯-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)-1-(2-(二甲氨基) 乙基)-1H-吲唑-5-胺(I-39)
参照(I-7)的合成方法,产率80%。
1H NMR(400MHz,DMSO-d
6)δ9.16(s,1H),8.87(d,J=7.9Hz,1H),8.39(s,1H),8.29(t,J=1.3Hz,1H),8.25(s,1H),7.93(s,1H),7.61(d,J=1.3Hz,2H),7.55–7.51(m,1H),7.27(ddd,J=8.2,7.0,1.2Hz,1H),7.12(ddd,J=8.1,7.0,1.0Hz,1H),4.47(t,J=6.6Hz,2H),3.98(s,3H),3.90(s,3H),2.73(t,J=6.6Hz,2H),2.20(s,6H)。
实施例40:N-(5-氯-4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)-1-(2-(二甲氨基)乙基)-1H-吲唑-5-胺(I-40)
参照(I-7)的合成方法,产率80%。
1H NMR(400MHz,DMSO-d
6)δ9.86(s,1H),8.63(s,1H),8.47(s,2H),8.16(d,J=1.8Hz,1H),7.93(d,J=9.1Hz,2H),7.66(d,J=9.0Hz,1H),7.59(dd,J=9.0,1.9Hz,1H),7.48(ddd,J=8.4,7.2,1.3Hz,1H),7.30(s,1H),4.48(t,J=6.5Hz,2H),3.80(q,J=7.3Hz,2H),2.74(t,J=6.5Hz,2H),2.19(s,6H),1.13(t,J=7.3Hz,3H)。
实施例41:7-氯-1-(2-(二甲氨基)乙基)-N-(4-(1-甲基-1H-吲哚-3-基)-5-硝基嘧啶-2-基)-1H-吲唑-5-胺(I-41)
参照(I-7)的合成方法,产率56%。
1H NMR(400MHz,DMSO-d
6)δ10.53(s,1H),9.05(s,1H),8.18(d,J=1.8Hz,1H),8.14(s,1H),8.05(s,1H),7.88(d,J=1.8Hz,1H),7.57(d,J=8.3Hz,1H),7.34–7.04(m,3H),4.77(t,J=7.0Hz,2H),3.91(s,3H),2.71(t,J=6.9Hz,2H),2.20(s,6H)。
实施例42:1-(2-(二甲氨基)乙基)-N-(4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)-1H-吲哚-5-胺(I-42)
参照(I-7)的合成方法,产率82%。
1H NMR(300MHz,DMSO-d
6)δ9.40(s,1H),8.75(d,J=8.0Hz,1H),8.52(s,1H),8.42(d,J=5.2Hz,1H),8.02(d,J=1.8Hz,1H),7.92(dd,J=8.4,0.9Hz,1H),7.48–7.44(m,1H),7.44–7.40(m,2H),7.38(dd,J=8.2,2.5Hz,2H),7.31(t,J=7.6Hz,1H),6.36(dd,J=3.0,0.7Hz,1H),4.25(t,J=6.6Hz,2H),3.75(q,J=7.3Hz,2H),2.63(t,J=6.6Hz,2H),2.20(s,6H),1.12(t,J=7.3Hz,3H)。
实施例43:N-(5-氯-4-(1-(乙磺酰基)-1H-吲哚-3-基)嘧啶-2-基)-1-(2-(二甲氨基)乙基)-1H-吲哚-5-胺(I-43)
参照(I-7)的合成方法,产率85%。
1H NMR(400MHz,DMSO-d
6)δ9.64(s,1H),8.57(s,1H),8.46(s,2H),7.96–7.89(m,2H),7.45(dd,J=13.1,8.2Hz,2H),7.38–7.32(m,2H),7.25(s,1H),6.33(d,J=3.1Hz,1H),4.25(t,J=6.6Hz,2H),3.79(q,J=7.3Hz,2H),2.63(t,J=6.6Hz,2H),2.20(s,6H),1.13(t,J=7.3Hz,3H)。
实施例44:7-氯-1-(2-(二甲氨基)乙基)-N-(4-(1-甲基-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)-1H-吲唑-5-胺(I-44)
参照(I-7)的合成方法,产率75%。
1H NMR(400MHz,DMSO-d
6)δ10.20(s,1H),8.78(s,1H),8.19(s,2H),8.04(s,1H),7.94–7.87(m,2H),7.56(d,J=8.2Hz,1H),7.32–7.27(m,1H),7.13(s,1H),4.76(t,J=7.0Hz,2H),3.93(s,3H),2.71(t,J=7.0Hz,2H),2.20(s,6H)。
实施例45:1-(2-(二甲氨基)乙基)-N-(4-(1-(乙磺酰基)-1H-吲哚-3-基)-5-(三氟甲基)嘧啶-2-基)-1H-吲哚-5-胺(I-45)
参照(I-7)的合成方法,产率87%。
1H NMR(400MHz,DMSO-d
6)δ10.17(s,1H),8.84(s,1H),8.06(s,1H),7.96–7.93(m,1H),7.91(d,J=8.3Hz,1H),7.89(s,1H),7.51–7.34(m,5H),6.32(s,1H),4.23(t,J=6.6Hz,2H),3.75(q,J=7.2Hz,2H),2.59(t,J=6.5Hz,2H),2.18(s,6H),1.07(t,J=7.3Hz,3H)。
实施例46:1-(2-(二甲氨基)乙基)-N-(4-(1-甲基-1H-吲哚-3-基)-5-硝基嘧啶-2-基)-1H-吲哚-5-胺(I-46)
参照(I-7)的合成方法,产率56%。
1H NMR(400MHz,DMSO-d
6)δ10.30(s,1H),9.00(s,1H),8.00(d,J=12.4Hz,3H),7.54(d,J=8.3Hz,1H),7.48(d,J=8.8Hz,1H),7.44–7.37(m,2H),7.26(s,1H),7.02(s,1H),6.39(s,1H),4.28(t,J=6.6Hz,2H),3.89(s,3H),2.66(d,J=6.9Hz,2H),2.23(s,6H)。
实施例47:N
5-(4-(1H-吲哚-3-基)嘧啶-2-基)-1-(2-(二甲氨基)乙基)-1H-吲唑-5,7-二胺(I-47)
参照(I-7)的合成方法,产率50%。
1H NMR(400MHz,Chloroform-d)δ8.77(s,1H),8.49(dd,J=7.1,1.8Hz,1H),8.33(d,J=5.3Hz,1H),7.88–7.85(m,2H),7.51(d,J=1.7Hz,1H),7.43–7.39(m,1H),7.29–7.27(m,1H),7.25–7.21(m,1H),7.14(s,1H),7.03(d,J=5.3Hz,1H),6.88(d,J=1.8Hz,1H),4.73–4.70(m,2H),2.84–2.81(m,2H),2.23(s,6H)。
二、生物学评价
(1)EGFR
L858R/T790M/C797S激酶活性分析测试方法
将化合物用100%DMSO溶解并配制成10mM溶液。配制1×Kinase buffer。化合物浓度梯度的配制:化合物测试起始浓度为5μM,3倍稀释,10个浓度,单孔检测。用1×Kinase buffer配制2.5倍终浓度的激酶溶液。在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶液;在阴性对照孔中加10μL的1×Kinase buffer。用1000rpm离心30秒,反应板振荡混匀后室温孵育10分钟。 用1×Kinase buffer配制25/15倍终浓度的ATP和Kinase substrate 22混合溶液。加入15μL的25/15倍终浓度的ATP和底物的混合溶液,起始反应。将384孔板1000rpm离心30秒,振荡混匀后室温孵育60分钟。停止激酶反应后,1000rpm离心30秒,振荡混匀。用Caliper EZ Reader读取转化率。采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线,从而得出各个化合物对酶活性的IC
50值。
所得IC
50值如表1所示,从结果可以看出,本发明实施例化合物具有很强的EGFR
L858R/T790M/C797S激酶抑制活性。
表1实施例化合物对EGFR
L858R/T790M/C797S激酶活性的IC
50测量值
实施例 | IC 50(nM) | 实施例 | IC50(nM) | 实施例 | IC50(nM) |
I-1 | 100-1000 | I-17 | 10-100 | I-33 | 10-100 |
I-2 | 100-1000 | I-18 | <10 | I-34 | 10-100 |
I-3 | 100-1000 | I-19 | 10-100 | I-35 | 10-100 |
I-4 | 100-1000 | I-20 | 10-100 | I-36 | 10-100 |
I-5 | 100-1000 | I-21 | 100-1000 | I-37 | 10-100 |
I-6 | 100-1000 | I-22 | 100-1000 | I-38 | 10-100 |
I-7 | 100-1000 | I-23 | 100-1000 | I-39 | 100-1000 |
I-8 | 1000-2000 | I-24 | 100-1000 | I-40 | <10 |
I-9 | 100-1000 | I-25 | 100-1000 | I-41 | 10-100 |
I-10 | 1000-2000 | I-26 | 100-1000 | I-42 | <10 |
I-11 | <10 | I-27 | 100-1000 | I-43 | <10 |
I-12 | 10-100 | I-28 | <20 | I-44 | 10-100 |
I-13 | 100-1000 | I-29 | 10-100 | I-45 | <20 |
I-14 | 10-100 | I-30 | 10-100 | I-46 | 100-1000 |
I-15 | 10-100 | I-31 | 10-100 | I-47 | 10-100 |
I-16 | 10-100 | I-32 | 10-100 | Osimertinib | 100-1000 |
(2)细胞增殖抑制测试方法
化合物对BaF
3(EGFR
L858R/T790M/C797S)细胞增殖抑制活性通过CTG方法进行测试:
实验步骤:
将化合物用100%DMSO溶解并配制成1mM溶液,把2μL溶液溶于98μL培养基中稀释至20μM/L,将悬浮细胞离心,换培养液然后计数。用培养基将化合物稀释至所需浓度。在96孔板中加入95μL细胞悬浮液,并在每个孔中依次加入5μL相应浓度化合物,吹打均匀。将96孔板放置于细胞培养箱中培养72h。三天后,在96孔板每个孔中加入
试剂,将孔板放置在震动器上震动两分钟使细胞裂解释放细胞中ATP,室温孵育10分钟,使发光信号稳定,用酶标仪读取荧光值。采用分析软件GraphPad Prism 7的inhibitor vs.response-Variable slope(four parameters)拟合量效曲线,从而得出各个化合物对酶活性的IC
50值。
所得IC
50值如表2所示,从结果可以看出,本发明实施例化合物具有很强的BaF
3(EGFR
L858R/T790M/C797S)细胞增殖抑制活性。
表2实施例化合物对BaF
3(EGFR
L858R/T790M/C797S)细胞增殖抑制IC
50
化合物 | IC 50(nM) |
I-18 | 100-1000 |
I-40 | <50 |
I-42 | 100-1000 |
I-43 | <50 |
I-45 | <50 |
Osimertinib | >1000 |
Brigatinib | 100-1000 |
化合物对H-1975(EGFR
L858R/T790M/C797S)细胞系,H-1975细胞系,PC-9细胞系,A-549细胞系细胞增殖抑制活性通过CCK8方法进行测试。
实验步骤:
将细胞计数之后在96孔板中接种100μL细胞悬浮液。在培养箱培养一天,等细胞贴壁后加入相应浓度化合物,将化合物用100%DMSO溶解并配制成1mM溶液,然后用培养基将化合物稀释至所需浓度。在96孔板中加入100μL化合物溶液,吹打均匀。将96孔板放置于细胞培养箱中培养72h。三天后,在96孔板每个孔中加入10μL Cell Count Kit 8试剂,将96孔板放置于细胞培养箱中培养4h,用酶标仪读取荧光值。采用分析软件GraphPad Prism 7的inhibitor vs.response-Variable slope(four parameters)拟合量效曲线,从而得出各个化合物对酶活性的IC
50值。
表3实施例化合物对H-1975(EGFR
L858R/T790M/C797S)细胞增殖抑制IC
50
化合物 | IC 50(nM) |
I-40 | 20-100 |
I-43 | 20-100 |
I-45 | <20 |
Osimertinib | >3000 |
表4实施例化合物对H-1975细胞增殖抑制IC
50
化合物 | IC 50(nM) |
I-40 | 100-1000 |
I-43 | 100-1000 |
I-45 | <100 |
表5实施例化合物对PC-9细胞增殖抑制IC
50
化合物 | IC 50(nM) |
I-40 | 100-1000 |
I-43 | 100-1000 |
I-45 | <100 |
Osimertinib | <100 |
表6实施例化合物对A-549细胞增殖抑制IC
50
化合物 | IC 50(nM) |
I-40 | >10000 |
I-43 | >20000 |
I-45 | >20000 |
Osimertinib | >5000 |
Claims (10)
- 一种通式(I)所示的化合物或其药学上可接受的盐,其特征在于:其中,X选自C、N、O或S;R 1选自氢、C 1-C 3烷基、卤代C 1-C 3烷基、氘代C 1-C 3烷基、C 3-C 8环烷基、-S(O) 2R 5;R 2选自氢、卤素、羟基、巯基、氰基、硝基、C 1-C 3烷基、C 1-C 3烷氧基、卤代C 1-C 3烷基、C 3-C 8环烷基;R 3选自氢、卤素、氨基、-NH-C(O)R 6;R 4选自氢、-C 1-C 3-NR 7R 8、-C 1-C 3-C(O)NR 9R 10;R 5选自氢、C 1-C 3烷基、卤代C 1-C 3烷基、C 3-C 8环烷基;R 6选自氢、C 1-C 8烷基、卤代C 1-C 8烷基、C 3-C 8环烷基、C 2-C 8链烯基、C 2-C 8炔基;R 7、R 8、R 9和R 10分别独立选自氢、C 1-C 3烷基、卤代C 1-C 3烷基;R 7和R 8,R 9和R 10也可以成五元含氮杂环、六元含氮杂环。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:X选自C或N;R 1选自氢、C 1-C 3烷基、氘代C 1-C 3烷基、-S(O) 2R 5,其中R 5选自C 1-C 3烷基、C 3-C 8环烷基;R 2选自氢、卤素、硝基、C 1-C 3烷氧基、卤代C 1-C 3烷基;R 3选自氢、卤素、氨基、-NH-C(O)R 6,其中R 6选自C 1-C 8烷基、C 2-C 8链烯基、C 2-C 8炔基、C 3-C 8环烷基;R 4选自-C 1-C 3-NR 7R 8、-C 1-C 3-C(O)NR 9R 10,其中R 7、R 8、R 9和R 10分别独立选自C 1-C 3烷基或者R 7和R 8,R 9和R 10成饱和六元含氮杂环。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:X选自C或N;R 1选自氢、C 1-C 3烷基、氘代C 1-C 3烷基、-S(O) 2R 5,其中R 5选自甲基、乙基、环丙基;R 2选自氢、卤素、硝基、甲氧基、卤代C 1-C 3烷基;R 3选自氢、卤素、氨基、-NH-C(O)R 6,其中R 6选自乙烯基、丙烯基、异丁烯基、甲基、乙基、异丙基、环丙基;R 4选自-C 1-C 3-NR 7R 8、-C 1-C 3-C(O)NR 9R 10,其中R 7、R 8、R 9和R 10分别独立选自甲基、乙基,R 7和R 8,R 9和R 10也可以成吗啉、哌啶、六氢哒嗪、六氢嘧啶、哌嗪、N-甲基六氢哒嗪、N-甲基六氢嘧啶、N-甲基哌嗪、N-乙基哌嗪、N-异丙基哌嗪。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:X选自C或N;R 1选自氢、甲基、氘代甲基、-S(O) 2R 5,其中R 5选自甲基、乙基、环丙基;R 2选自氢、卤素、硝基、甲氧基、三氟甲基;R 3选自氢、卤素、氨基、-NH-C(O)R 6,其中R 6选自乙烯基、丙烯基、异丁烯基、甲基、乙基、异丙基、环丙基;R 4选自-CH 2CH 2-NR 7R 8、-CH 2-C(O)NR 9R 10,其中R 7、R 8、R 9和R 10分别独立选自甲基、乙基,R 7和R 8也可以成吗啉、哌啶、哌嗪、N-甲基哌嗪、N-乙基哌嗪、N-异丙基哌嗪。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:X选自C或N;R 1选自氢、甲基、氘代甲基、-S(O) 2R 5,其中R 5选自乙基;R 2选自氢、氯、硝基、甲氧基、三氟甲基;R 3选自氢、氯、氨基、-NH-C(O)R 6,其中R 6选自乙烯基、丙烯基、异丁烯基、甲基、乙基、异丙基、环丙基;R 4选自-CH 2CH 2-NR 7R 8、-CH 2-C(O)NR 9R 10,其中R 7和R 8分别独立选自甲基、乙基,R 7和R 8也可以成吗啉,R 9和R 10选自甲基。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:所述药学上可接受的盐为通式(I)化合物的酸加成盐,其中用于成盐的酸包括无机酸及有机酸,所述无机酸包括盐酸、硫酸、磷酸和甲磺酸,所述有机酸包括乙酸、三氯乙酸、丙酸、丁酸、马来酸、对甲苯磺酸、苹果酸、丙二酸、肉桂酸、柠檬酸、富马酸、樟脑酸、二葡糖酸、天冬氨酸和酒石酸。
- 一种药用组合物,其特征在于:包含权利要求1的通式(I)化合物或其药学上可接受的盐或其异构体或其前药分子或其活性代谢产物,以及药学上可接受的载体。
- 根据权利要求1所述的化合物或其药学上可接受的盐在制备用于预防和/或治疗癌症或肿瘤相关疾病的药物中的应用,所述癌症或肿瘤相关疾病包括脑胶质瘤、脑垂体瘤、神经胶质瘤、黑色素瘤、乳腺癌、肺癌、胃癌、卵巢癌、结肠癌、肝癌、胰腺癌、前列腺癌、睾丸癌、多发性骨髓瘤、白血病多种实体瘤和血液瘤。
- 根据权利要求9所述的应用,所述肿瘤为EGFR基因突变的恶性肿瘤。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104903312A (zh) * | 2013-10-07 | 2015-09-09 | 卡德门企业有限公司 | Rho激酶抑制剂 |
CN105646454A (zh) * | 2016-01-19 | 2016-06-08 | 浙江大学 | 含异羟肟酸片段的2-芳胺基嘧啶类衍生物及制备和应用 |
CN105884699A (zh) * | 2016-05-11 | 2016-08-24 | 中国药科大学 | 4-取代苯胺喹唑啉类衍生物及其制备方法和用途 |
CN108218838A (zh) * | 2016-12-13 | 2018-06-29 | 青岛海洋生物医药研究院股份有限公司 | 嘧啶基吲哚衍生物及其制备方法和在制备抗肿瘤药物中的应用 |
CN109689645A (zh) * | 2016-06-30 | 2019-04-26 | 杨森制药有限公司 | 作为nik抑制剂的氰基吲哚啉衍生物 |
WO2020211839A1 (en) * | 2019-04-19 | 2020-10-22 | Dizal (Jiangsu) Pharmaceutical Co., Ltd. | Jak1 selective kinase inhibitor |
CN112292378A (zh) * | 2019-05-22 | 2021-01-29 | 上海翰森生物医药科技有限公司 | 含吲哚类衍生物抑制剂、其制备方法和应用 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CA2881993C (en) * | 2011-07-27 | 2017-05-09 | Astrazeneca Ab | Substituted 4-methoxy-n3-(pyrimidin-2-yl)benzene-1,3-diamine compounds, and salts thereof |
WO2014155300A2 (en) * | 2013-03-28 | 2014-10-02 | Aurigene Discovery Technologies Limited | Substitued pyrimidine amine derivatives as tak-1 inhibitors |
CN106458990B (zh) * | 2014-04-04 | 2019-06-07 | 希洛斯医药品股份有限公司 | 细胞周期蛋白依赖性激酶7(cdk7)的抑制剂 |
CN104844580B (zh) * | 2015-04-17 | 2017-10-20 | 中国药科大学 | 嘧啶类化合物、其制备方法及医药用途 |
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104903312A (zh) * | 2013-10-07 | 2015-09-09 | 卡德门企业有限公司 | Rho激酶抑制剂 |
CN105646454A (zh) * | 2016-01-19 | 2016-06-08 | 浙江大学 | 含异羟肟酸片段的2-芳胺基嘧啶类衍生物及制备和应用 |
CN105884699A (zh) * | 2016-05-11 | 2016-08-24 | 中国药科大学 | 4-取代苯胺喹唑啉类衍生物及其制备方法和用途 |
CN109689645A (zh) * | 2016-06-30 | 2019-04-26 | 杨森制药有限公司 | 作为nik抑制剂的氰基吲哚啉衍生物 |
CN108218838A (zh) * | 2016-12-13 | 2018-06-29 | 青岛海洋生物医药研究院股份有限公司 | 嘧啶基吲哚衍生物及其制备方法和在制备抗肿瘤药物中的应用 |
WO2020211839A1 (en) * | 2019-04-19 | 2020-10-22 | Dizal (Jiangsu) Pharmaceutical Co., Ltd. | Jak1 selective kinase inhibitor |
CN112292378A (zh) * | 2019-05-22 | 2021-01-29 | 上海翰森生物医药科技有限公司 | 含吲哚类衍生物抑制剂、其制备方法和应用 |
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