CN114380806A - 2-amino-4-indolyl pyrimidine compound and preparation method and application thereof - Google Patents

2-amino-4-indolyl pyrimidine compound and preparation method and application thereof Download PDF

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CN114380806A
CN114380806A CN202210296104.6A CN202210296104A CN114380806A CN 114380806 A CN114380806 A CN 114380806A CN 202210296104 A CN202210296104 A CN 202210296104A CN 114380806 A CN114380806 A CN 114380806A
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CN114380806B (en
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杨鹏
肖易倍
董豪杰
叶秀全
朱亚胜
袁凯
陈伟娇
姬明慧
王晓
王丽萍
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China Pharmaceutical University
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Abstract

The invention discloses a 2-amino-4-indolyl pyrimidine compound and a preparation method and application thereof, belonging to the technical field of drug synthesis. In particular to a pyrimidine compound, a stereoisomer or pharmaceutically acceptable salt thereof, a preparation method thereof and application thereof in antitumor drugs. Pharmacological experiment results show that the compounds can inhibit the proliferation of various tumor cells, and the cancers or tumor-related diseases comprise various solid tumors and blood tumors such as brain glioma, pituitary adenoma, glioma, melanoma, breast cancer, lung cancer, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, prostate cancer, testicular cancer, multiple myeloma, leukemia and the like. The compound of the invention is expected to be developed into a new generation of anti-cancer drugs.

Description

2-amino-4-indolyl pyrimidine compound and preparation method and application thereof
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to a 2-amino piperidine compound, and a preparation method and application thereof.
Background
EGFR (epidermal growth factor receptor, abbreviated as EGFR, ErbB-1 or HER 1) is one of the epidermal growth factor receptor (HER) family members, a transmembrane receptor located on the surface of the cell membrane, with a molecular weight of 170KDa, which is activated by binding to ligands, including EGF and TGF α (transforming growth factor α); furthermore, kinase pathways in cells, including sites such as Y992, Y1045, Y1068, Y1148 and Y1173, are activated, the phosphorylation of downstream MAPK, Akt and JNK pathways is guided, and the cell proliferation is induced. Activation of EGFR can be divided into 3 steps: (1) after EGFR is combined with ligand, receptor can form homodimer, and can also form heterodimer with other EGFR families; (2) the formation of the dimer promotes the phosphorylation of 6 specific receptor tyrosine residues in the intracellular region of EGFR, and respectively and sequentially transduces various external signals into the cell, the signals are mainly transmitted to the cell nucleus through two pathways, and one pathway is a Ras-Raf-MAPK pathway; the other is PI3K-Akt-mTOR pathway; (3) when the signal is transmitted to the nucleus of the cell, the transcription level of the nuclear gene is increased, the cell is proliferated and transformed, and the expression of the EGFR is increased.
EGFR, a type I receptor of tyrosine kinase, is widely distributed on the cell surfaces of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes and the like. EGFR mutation or overexpression generally triggers tumors, and signal transduction pathways of EGFR mutation or overexpression play important regulation and control roles in the aspects of proliferation, damage repair, invasion, neovascularization and the like of tumor cells, and become one of hot targets for tumor treatment.
The successful development of EGFR inhibitors has greatly improved the survival time and quality of life of cancer patients, particularly NSCLC patients. To date, a total of 11 EGFR inhibitors of three generations have been marketed, including the first generation of inhibitors represented by gefitinib, the second generation of covalent inhibitors represented by icotinib, and the third generation of inhibitors represented by oxitinib. However, the latest third generation inhibitor, the oxitinib class, has also clinically developed severe drug resistant cases. The main reason for drug resistance of oxitinib is that the 797 th amino acid residue of the EGFR protein is mutated from cysteine to serine, and the covalent bond of oxitinib cannot be combined with a target spot, so that off-target is caused. Solving the drug resistance is imminent, and the method also becomes the most direct means for improving the survival rate of the non-small cell lung cancer patients.
Disclosure of Invention
The purpose of the invention is as follows: in order to solve the problem of drug resistance caused by EGFR inhibitor axitinib target point mutation in the prior art, the invention designs and synthesizes a series of compounds aiming at EGFR gene mutation target points or pharmaceutically acceptable salts thereof. The compound solves the problem of clinical drug resistance of the oxitinib by inhibiting EGFR gene mutation targets, and improves the survival rate of patients.
The invention also provides a specific preparation method of the compound and application of the compound in antitumor drugs. Pharmacological experiment results show that the compounds can inhibit the proliferation of various tumor cells, including brain glioma, pituitary tumor, glioma, melanoma, breast cancer, lung cancer, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, prostatic cancer, testicular cancer, multiple myeloma, leukemia and other solid tumors and blood tumors. The compound of the invention is expected to be developed into a new generation of anti-cancer drugs.
The technical scheme is as follows: the invention relates to a compound shown in a general formula (I) and a pharmaceutically acceptable salt thereof.
Figure 774243DEST_PATH_IMAGE001
（Ⅰ）
Wherein the content of the first and second substances,
x is selected from C, N, O or S;
R1selected from hydrogen, C1-C3Alkyl, halo C1-C3Alkyl, deuterated C1-C3Alkyl radical, C3-C8Cycloalkyl, -S (O)2R5；
R2Selected from hydrogen, halogen, hydroxy, mercapto, cyano, nitro, C1-C3Alkyl radical, C1-C3Alkoxy, halo C1-C3Alkyl radical, C3-C8A cycloalkyl group;
R3selected from hydrogen, halogen, amino, -NH-C (O) R6；
R4Selected from hydrogen, -C1-C3-NR7R8、-C1-C3-C(O)NR9R10；
R5Selected from hydrogen, C1-C3Alkyl, halo C1-C3Alkyl radical, C3-C8A cycloalkyl group;
R6selected from hydrogen, C1-C8Alkyl, halo C1-C8Alkyl radical, C3-C8Cycloalkyl radical, C2-C8Alkenyl radical, C2-C8An alkynyl group;
R7、 R8、R9and R10Are respectively and independently selected from hydrogen and C1-C3Alkyl, halo C1-C3An alkyl group;
R7and R8，R9And R10Or five-membered nitrogen-containing heterocyclic ring and six-membered nitrogen-containing heterocyclic ring.
Preferably:
x is selected from C or N;
R1selected from hydrogen, C1-C3Alkyl, deuterated C1-C3Alkyl, -S (O)2R5Wherein R is5Is selected from C1-C3Alkyl radical, C3-C8A cycloalkyl group;
R2selected from hydrogen, halogen, nitro, C1-C3Alkoxy, halo C1-C3An alkyl group;
R3selected from hydrogen, halogen, amino, -NH-C (O) R6Wherein R is6Is selected from C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8A cycloalkyl group;
R4is selected from-C1-C3-NR7R8、-C1-C3-C(O)NR9R10Wherein R is7、 R8、R9And R10Are each independently selected from C1-C3Alkyl radical, R7And R8，R9And R10Or a saturated six-membered nitrogen-containing heterocyclic ring.
Preferably:
x is selected from C or N;
R1selected from hydrogen, C1-C3Alkyl, deuterated C1-C3Alkyl, -S (O)2R5Wherein R is5Selected from methyl, ethyl, cyclopropyl;
R2selected from hydrogen, halogen, nitro, methoxy, halogenated C1-C3An alkyl group;
R3selected from hydrogen, halogen, amino, -NH-C (O) R6Wherein R is6Selected from the group consisting of vinyl, propenyl, isobutenyl, methyl, ethyl, isopropyl, cyclopropyl;
R4is selected from-C1-C3-NR7R8、-C1-C3-C(O)NR9R10Wherein R is7、R8、R9And R10Each independently selected from methyl, ethyl, R7And R8，R9And R10Or morpholine, piperidine, hexahydropyridazine, hexahydropyrimidine, piperazine, N-methylhexahydropyridazine, N-methylhexahydropyrimidine, N-methylpiperazine, N-ethylpiperazine, N-isopropylpiperazine.
Preferably:
x is selected from C or N;
R1selected from hydrogen, methyl, deuterated methyl, -S (O)2R5Wherein R is5Selected from methyl, ethyl, cyclopropyl;
R2selected from hydrogen, halogen, nitro, methoxy, trifluoromethyl;
R3selected from hydrogen, halogen, amino, -NH-C (O) R6Wherein R is6Selected from the group consisting of vinyl, propenyl, isobutenyl, methyl, ethyl, isopropyl, cyclopropyl;
R4is selected from-CH2CH2-NR7R8、-CH2-C(O)NR9R10Wherein R is7、R8、R9And R10Each independently selected from methyl, ethyl, R7And R8Or morpholine, piperidine, piperazine, N-methylpiperazine, N-ethylpiperazine and N-isopropylpiperazine.
Preferably:
x is selected from C or N;
R1selected from hydrogen, methyl, deuterated methyl, -S (O)2R5Wherein R is5Is selected from ethyl;
R2selected from hydrogen, chlorine, nitro, methoxy, trifluoromethyl;
R3selected from hydrogen, chlorine, amino, -NH-C (O) R6Wherein R is6Selected from the group consisting of vinyl, propenyl, isobutenyl, methyl, ethyl, isopropyl, cyclopropyl;
R4is selected from-CH2CH2-NR7R8、-CH2-C(O)NR9R10Wherein R is7And R8Each independently selected from methyl, ethyl, R7And R8Or may be morpholine, R9And R10Selected from methyl.
Preferably, the compounds described herein are selected from I-1 to I-47:
Figure 81596DEST_PATH_IMAGE002
Figure 972585DEST_PATH_IMAGE004
Figure 774319DEST_PATH_IMAGE005
Figure 978904DEST_PATH_IMAGE006
Figure 53564DEST_PATH_IMAGE007
Figure 241969DEST_PATH_IMAGE008
Figure 362240DEST_PATH_IMAGE009
Figure 890174DEST_PATH_IMAGE011
Figure 290062DEST_PATH_IMAGE013
the pharmaceutically acceptable salt is an acid addition salt of the compound shown as the general formula (I), wherein the acid for forming the salt comprises an inorganic acid and an organic acid, and the inorganic acid comprises: hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid, and the 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, aspartic acid and tartaric acid.
The invention also discloses a medicinal composition which comprises the compound shown in the general formula (I) or pharmaceutically acceptable salt thereof or isomer thereof or prodrug molecule thereof or active metabolite thereof and a pharmaceutically acceptable carrier.
Pharmaceutically acceptable carriers refer to excipients or diluents that do not cause significant irritation to the organism and do not interfere with the biological activity and properties of the administered compound. The excipient comprises a binder, a filler, a disintegrating agent, a lubricant, a preservative, an antioxidant, a flavoring agent, an aromatic, a cosolvent, an emulsifier, a solubilizer, an osmotic pressure regulator, a coloring agent and the like, and the diluent comprises normal saline, starch, dextrin, sucrose, lactose and the like.
The compound or the pharmaceutically acceptable salt thereof disclosed by the invention is applied to the preparation of EGFR gene mutation inhibitor medicines.
The EGFR inhibitor medicament is useful for treating cancer or tumor-related diseases.
The application of the compound or the pharmaceutically acceptable salt thereof in preparing the medicine for preventing and/or treating cancer or tumor-related diseases. The cancer or tumor-related diseases include various solid tumors and hematological tumors such as brain glioma, pituitary 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 the like.
In some of these embodiments, the tumor is a malignant tumor in which the EGFR gene is mutated.
In some of these embodiments, the tumor is EGFRL858R/T790M/C797SA mutated malignant tumor.
The compound of the general formula (I) or the pharmaceutically acceptable salt thereof has EGFR kinase inhibition activity and has a treatment effect on malignant tumors.
The term "alkyl" as used herein denotes saturated straight and branched chain alkyl groups, C1-C8Alkyl refers to saturated straight and branched chain alkyl groups having 1 to 8 carbon atoms, including but not limited to methyl, ethyl, isopropyl, isobutyl, and the like. Halogen substituted C1-C8Alkyl means C having one or more halogen substituents on the alkyl chain1-C8An alkyl group. Deuterated C1-C8Alkyl represents C substituted by one or more deuterium1-C8An alkyl group. Unsaturated C1-C8Alkyl refers to alkyl groups containing one or more unsaturated bonds including alkenyl, alkynyl.
The term "alkoxy" denotes an alkyl group containing one oxygen atom at the end, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy.
The term "cycloalkyl" denotes an alkyl group having a cyclic structure including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
The term "halogen" denotes fluorine, chlorine, bromine, iodine.
-S(O)2Represents a sulfuryl group.
-C (O) represents a carbonyl group.
The term "nitrogen-containing heterocycle" includes saturated and unsaturated polyvalent nitrogen-containing heterocycles, including but not limited to, cyclic ethylamine, cyclopropylamine, pyrrole, tetrahydropyrrole, imidazole, morpholine, piperazine, pyrazine, N-methylpiperazine, N-ethylpiperazine and the like.
Compared with the prior art, the invention has the following beneficial effects:
the 2-amino piperidine compound or the pharmaceutically acceptable salt thereof or the stereoisomer thereof or the prodrug molecule thereof or the active metabolite thereof can inhibit the EGFR family protease, thereby inhibiting the growth of various tumor cells. The compound can effectively inhibit the activity of EGFR protein kinase drug-resistant mutants, and can overcome the defects of the prior third-generation selective EGFRT790MSmall molecule inhibitor Osimectinib, Olmutinib, Rociletinib and the like to induce clinical drug resistance of non-small cell lung cancer and other tumor patients.
Drawings
FIG. 1 shows the general structural formula of the 2-amino pyridine compound of the present invention.
Detailed Description
The present application will be described in detail with reference to specific examples.
First, synthesis of example compounds.
Example 1: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) acrylamide (I-1)
Figure 839466DEST_PATH_IMAGE014
The synthetic route is as follows:
Figure 497849DEST_PATH_IMAGE015
step 1.preparation of 5, 7-dinitro-1H-indazole (2):
under ice bath, 5-nitro-1H-indazole (1) (16.32 g,100 mmol) is dissolved in sulfuric acid solution, concentrated nitric acid (40 ml, 400 mmol) is added dropwise in ice bath, after the reaction is finished, the reaction solution is slowly poured into ice water, and after sufficient stirring, the white filter cake of 5, 7-dinitro-1H-indazole (2) is obtained by suction filtration, wherein the white filter cake is 20.61g, and the yield is 99%.1H NMR (400 MHz, DMSO-d 6) δ 14.57 (s, 1H), 9.30 (d, J = 2.0 Hz, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H)。
Step 2.2- (5, 7-dinitro-1H-indazol-1-yl) -N, N-dimethyl-1-ethylamine (3) preparation:
5, 7-dinitro-1H-indazole (2) (10.41 g, 50 mmol) was dissolved in THF, sodium hydride (1.44 g,60 mmol) was added under ice bath, and stirred at room temperature for 0.5H, N-dimethylamino bromoethane hydrobromide (13.98 g,60 mmol) was added. Reacting overnight, quenching, extracting with ethyl acetate, drying with anhydrous sodium sulfate, and performing column chromatography9.77g of a solid was obtained in 70% yield.1H NMR (400 MHz, Chloroform-d) δ 8.95 (d, J = 2.0 Hz, 1H), 8.91 (d, J= 2.1 Hz, 1H), 8.45 (s, 1H), 4.76 (t, J = 5.9 Hz, 2H), 2.62 (t, J = 5.9 Hz, 2H), 2.10 (s, 6H)。
Step 3.1- (2- (dimethylamino) ethyl) -5-nitro-1H-indazol-7-amine (4) preparation:
2- (5, 7-dinitro-1H-indazol-1-yl) -N, N-dimethyl-1-ethylamine (3) (9.49 g, 34 mmol) was dissolved in methanol, ammonium sulfide solution (100 ml, 204 mmol) was added, and the mixture was heated under reflux at 70 ℃ for 3 hours. After the reaction is finished, the solvent is dried by spinning, water is added for suction filtration, the aqueous solution is extracted by ethyl acetate, dried by anhydrous sodium sulfate, and the yellow solid is obtained by column chromatography, wherein the yield is 30 percent.1H NMR (400 MHz, DMSO-d 6) δ 8.23 (s, 1H), 8.05 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 6.00 (s, 2H), 4.73 (t, J = 6.2 Hz, 2H), 2.72 (t, J = 6.2 Hz, 2H), 2.17 (s, 6H)。
Step 4.3- (2-Chloropyrimidin-4-yl) -1-methyl-1H-indole (7) preparation:
2, 4-dichloropyrimidine (5) (1.49 g,10 mmol) and aluminum chloride (4.00 g, 30 mmol) were dissolved in ethylene glycol dimethyl ether, stirred for 5min under the protection of argon, and 1-methyl-1H-indole (6) (1.31 g,10 mmol) was added to the reaction system and reacted at 80 ℃ overnight. The reaction solution was quenched with ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and column chromatographed to give 1.71g of a white solid with a yield of 70%.1H NMR (300 MHz, Chloroform-d) δ 8.41 (dd, J = 5.4, 1.2 Hz, 1H), 8.35 – 8.28 (m, 1H), 7.91 (s, 1H), 7.45 (dd, J = 5.5, 1.3 Hz, 1H), 7.34 (tt, J = 8.0, 1.8 Hz, 3H), 3.85 (s, 3H)。
Step 5. preparation of N, N-di-tert-butoxycarbonyl-1- (2- (dimethylamino) ethyl) -5-nitro-1H-indazol-7-amine (8):
1- (2- (dimethylamino) ethyl) -5-nitro-1H-indazol-7-amine (4) (2.50 g,10 mmol), DMAP (0.25 g, 2 mmol) and triethylamine (2.02 g, 20 mmol) were dissolved in dichloromethane, di-tert-butyl dicarbonate (6.55 g, 30 mmol) was added dropwise to the reaction solution under ice bath, after 8H extraction with a saturated ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated by column chromatography to give a pale yellow solid 4.7g, 98% yield.
Step 6.1 preparation of- (2- (dimethylamino) ethyl) -7- (N, N-di-tert-butoxycarbonyl-amino) -1H-indazol-5-amine (9):
dissolving N, N-di-tert-butoxycarbonyl-1- (2- (dimethylamino) ethyl) -5-nitro-1H-indazol-7-amine (8) (4.8 g,10 mmol), zinc powder (6.5 g,100 mmol) and ammonium chloride (5.4 g,100 mmol) in 70% ethanol solution, refluxing at 70 ℃ for 3H under the protection of argon, and concentrating by suction filtration to obtain a solid 4.4g, wherein the yield is 98%.1H NMR (400 MHz, Chloroform-d) δ 8.69 (d, J = 2.0 Hz, 1H), 8.26 (s, 1H), 8.07 (d, J = 2.0 Hz, 1H), 4.53 – 4.49 (m, 2H), 2.83 – 2.78 (m, 2H), 2.31 (s, 6H), 1.44 (s, 18H)。
Step 7.1- (2- (dimethylamino) ethyl) -N5Preparation of- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1H-indazole-5, 7-diamine (10):
1- (2- (dimethylamino) ethyl) -7- (N, N-di-tert-butoxycarbonyl-amino) -1H-indazol-5-amine (9) (3.19 g,10 mmol), 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (7) (2.68 g,11 mmol) and p-toluenesulfonic acid monohydrate (2.3 g, 12 mmol) were dissolved in N-butanol, heated to 110 ℃ under argon protection, reacted for 8H, filtered with suction and the solid was treated with acetonitrile to give 3.8g of a yellow solid in 90% yield.1H NMR (400 MHz, Chloroform-d) δ 8.49 – 8.44 (m, 1H), 8.27 (d, J = 5.4 Hz, 1H), 7.84 (s, 1H), 7.78 – 7.74 (m, 2H), 7.54 (d, J = 1.8 Hz, 1H), 7.40 – 7.27 (m, 3H), 7.23 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 5.4 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H), 4.85 (t, J = 5.7 Hz, 2H), 3.83 (s, 3H), 3.13 (t, J = 5.7 Hz, 2H), 2.42 (d, J = 4.0 Hz, 6H)。
Step 8. preparation of N- (1- (2- (dimethylamino) ethyl) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) acrylamide (I-1):
1- (2- (dimethylamino) ethyl) -N5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1H-indazole-5, 7-diamine (10) (490 mg, 1.15 mmol) and DIPEA (446 mg, 3.45 mmol) were dissolved in dichloromethane, acryloyl chloride (124.9 mg, 1.38 mmol) was added dropwise in an ice bath, reacted at room temperature for 3 hours, the reaction was extracted with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and column chromatography was concentrated to obtain 220.91mg of a solid in 40% yield.1H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 1.4 Hz, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.16 – 8.03 (m, 3H), 7.93 (d, J = 1.4 Hz, 1H), 7.86 (s, 1H), 7.37 – 7.27 (m, 2H), 7.22 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H), 7.02 – 6.97 (m, 1H), 6.55 – 6.48 (m, 2H), 5.81 (dd, J = 7.7, 4.4 Hz, 1H), 4.79 (t, J = 5.6 Hz, 2H), 3.85 (d, J = 1.5 Hz, 3H), 3.26 (s, 2H), 2.42 (d, J = 1.4 Hz, 6H)。
Example 2: (E) -N- (1- (2- (dimethylamino) ethyl) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) -2-butenamide (I-2)
Figure 693338DEST_PATH_IMAGE016
The synthesis method of reference (I-1) gave a yield of 66%.1H NMR (400 MHz, DMSO-d 6) δ 11.26 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.19 – 7.99 (m, 3H), 7.93 (s, 1H), 7.37 (d, J = 8.2 Hz, 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 = 15.2 Hz, 1H), 4.69 (dd, J = 5.9, 3.6 Hz, 2H), 3.89 (s, 3H), 2.92 (s, 2H), 2.24 (s, 6H), 1.95 (d, J = 6.9 Hz, 3H)。
Example 3: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) -3-methyl-2-butenamide (I-3)
Figure 906538DEST_PATH_IMAGE017
The synthesis method of reference (I-1) was carried out in a yield of 57%.1H NMR (400 MHz, Chloroform-d) δ 11.18 (s, 1H), 8.41 (dt, J = 7.8, 1.0 Hz, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.12 – 7.91 (m, 4H), 7.39 – 7.28 (m, 2H), 7.25 – 7.18 (m, 2H), 7.05 (d, J = 5.4 Hz, 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 = 1.3 Hz, 3H), 2.24 (s, 6H), 1.94 (s, 3H)。
Example 4: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) propionamide (I-4)
Figure 538377DEST_PATH_IMAGE018
The synthesis method of reference (I-1) gave a yield of 63%.1H NMR (300 MHz, Chloroform-d) δ 11.20 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.34 (d, J = 5.4 Hz, 1H), 8.09 (d, J = 11.2 Hz, 2H), 8.01 (d, J = 1.9 Hz, 1H), 7.93 (s, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.25 – 7.21 (m, 1H), 7.07 (d, J = 5.4 Hz, 1H), 4.71 (d, J = 5.6 Hz, 2H), 3.91 (s, 3H), 2.92 (s, 2H), 2.48 (q, J = 7.6 Hz, 2H), 2.23 (s, 7H), 1.33 (t, J = 7.5 Hz, 3H)。
Example 5: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) acetamide (I-5)
Figure 734872DEST_PATH_IMAGE019
The synthesis method of reference (I-1) was carried out in a yield of 54%.1H NMR (300 MHz, Chloroform-d) δ 11.37 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 8.05 (d, J = 1.9 Hz, 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 = 5.4 Hz, 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)。
Example 6: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) isobutyramide (I-6)
Figure 50447DEST_PATH_IMAGE020
The synthesis method of reference (I-1) was carried out in a yield of 71%.1H NMR (300 MHz, Chloroform-d) δ 11.08 (s, 1H), 8.36 (dd, J = 8.1, 6.3 Hz, 2H), 8.09 (d, J = 1.9 Hz, 1H), 8.06 – 8.01 (m, 2H), 7.92 (s, 1H), 7.41 – 7.34 (m, 2H), 7.30 (dd, J = 6.9, 1.3 Hz, 1H), 7.22 (dd, J = 6.9, 1.3 Hz, 1H), 7.05 (d, J = 5.4 Hz, 1H), 4.73 – 4.67 (m, 2H), 3.87 (s, 3H), 2.91 (dd, J = 6.4, 3.5 Hz, 2H), 2.61 (p, J = 6.9 Hz, 1H), 2.19 (s, 6H), 1.32 (d, J = 6.8 Hz, 6H)。
Example 7: 1- (2- (dimethylamino) ethyl) -N- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1H-indazol-5-amine (I-7)
Figure 41405DEST_PATH_IMAGE021
The synthetic route is as follows:
Figure 553683DEST_PATH_IMAGE022
。
step 1. preparation of N, N-dimethyl-2- (5-nitro-1H-indazol-1-yl) ethylamine (11):
5-Nitroindazole (1) (1.63 g,10 mmol) was dissolved in tetrahydrofuran and sodium hydrogen (0.288 g, 12 mmol) was added under ice-bath conditions, oftenAfter stirring at room temperature for 0.5h, N-dimethylamino-bromoethane hydrobromide (2.56 g,11 mmol) was added. The reaction was allowed to stand overnight, quenched, extracted with ethyl acetate, dried over anhydrous sodium sulfate and chromatographed to give 1.64g of a solid in 70% yield.1H NMR (400 MHz, Chloroform-d) δ 8.73 (dd, J = 2.1, 0.7 Hz, 1H), 8.27 (dd, J = 9.2, 2.1 Hz, 1H), 8.22 (d, J = 0.9 Hz, 1H), 7.50 (dt, J = 9.2, 0.8 Hz, 1H), 4.53 (t, J = 6.8 Hz, 2H), 2.85 (t, J = 6.7 Hz, 2H), 2.30 (s, 6H)。
Step 2.1- (2- (dimethylamino) ethyl) -1H-indazol-5-amine (12) preparation:
dissolving N, N-dimethyl-2- (5-nitro-1H-indazol-1-yl) ethylamine (11) (1.6 g, 6.8 mmol), zinc powder (4.4 g, 68 mmol) and ammonium chloride (3.6 g, 68 mmol) in 70% ethanol, heating and refluxing for 3H at 70 ℃ under the protection of argon, and carrying out suction filtration and concentration to obtain 1.4g of solid with the yield of 100%.1H NMR (400 MHz, DMSO-d 6) δ 7.84 (s, 1H), 7.50 (d, J = 8.9 Hz, 1H), 6.90 (dd, J = 8.9, 2.0 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 4.71 (t, J = 6.6 Hz, 2H), 3.52 (t, J = 6.6 Hz, 2H), 2.78 (s, 6H)。
Step 3.1 preparation of- (2- (dimethylamino) ethyl) -N- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1H-indazol-5-amine (I-7):
1- (2- (dimethylamino) ethyl) -1H-indazol-5-amine (12) (204 mg, 1 mmol), 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (7) (243.7 mg, 1 mmol) and p-toluenesulfonic acid monohydrate (228 mg, 1.2 mmol) were dissolved in isopropanol under argon protection and heated at 100 ℃ under reflux for 8H. Cooling and filtering, pulping the solid with acetonitrile to obtain 205.6mg of compound with 50 percent of yield.1H NMR (400 MHz, DMSO-d 6) δ 9.37 (s, 1H), 8.62 (d, J = 7.9 Hz, 1H), 8.32 (d, J = 14.3 Hz, 3H), 7.98 (s, 1H), 7.70 – 7.48 (m, 3H), 7.21 (dt, J = 43.7, 8.2 Hz, 3H), 4.47 (t, J = 6.7 Hz, 2H), 3.88 (s, 3H), 2.72 (t, J = 6.6 Hz, 2H), 2.18 (s, 6H)。
Example 8: n- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1- (2-morpholinoethyl) -1H-indazol-5-amine (I-8)
Figure 881765DEST_PATH_IMAGE023
The synthetic route is as follows:
Figure 38464DEST_PATH_IMAGE024
。
(13) preparation of (4) with reference to the synthesis method of (11), yield 68%.1H NMR (400 MHz, Chloroform-d) δ 8.73 (d, J = 2.0 Hz, 1H), 8.28 (dd, J = 9.2, 2.1 Hz, 1H), 8.22 (d, J = 0.9 Hz, 1H), 7.50 (d, J = 9.3 Hz, 1H), 4.55 (t, J = 6.6 Hz, 2H), 3.63 (t, J = 4.7 Hz, 4H), 2.90 (t, J = 6.6 Hz, 2H), 2.50 (t, J = 4.6 Hz, 4H)。
(14) Preparation of (2) with a yield of 99% according to the synthesis method of (12).1H NMR (400 MHz, DMSO-d 6) δ 7.70 (d, J = 0.9 Hz, 1H), 7.37 (dd, J = 8.9, 1.0 Hz, 1H), 6.81 (dd, J = 8.9, 2.0 Hz, 1H), 6.74 (d, J = 1.7 Hz, 1H), 4.39 (t, J = 6.8 Hz, 2H), 3.54 – 3.47 (m, 4H), 2.72 (t, J = 6.8 Hz, 2H), 2.42 (dd, J = 4.3, 2.4 Hz, 4H)。
(I-14) production according to the synthetic method of (I-13), yield was 71%.1H NMR (400 MHz, DMSO-d 6) δ 10.57 (s, 1H), 8.70 (s, 1H), 8.34 (s, 1H), 8.24 (s, 2H), 8.10 (s, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 6.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 9.8 Hz, 1H), 4.99 (t, J = 6.9 Hz, 2H), 3.99 (s, 2H), 3.93 (s, 3H), 3.83 – 3.75 (m, 2H), 3.70 (t, J = 7.0 Hz, 2H), 3.52 (s, 2H), 3.21 (s, 2H)。
Example 9: 7-chloro-1- (2- (dimethylamino) ethyl) -N- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1H-indazol-5-amine (I-9)
Figure 482215DEST_PATH_IMAGE025
The synthetic route is as follows:
Figure 150962DEST_PATH_IMAGE026
。
step 1.preparation of 7-chloro-5-nitro-1H-indazole (16):
an aqueous solution of sodium nitrite (0.83 g, 12 mmol) was added dropwise to a glacial acetic acid solution of 2-chloro-6-methyl-4-nitroaniline (1.87 g,10 mmol) under ice-bath, reacted overnight at room temperature, concentrated and water was added to wash off impurities to obtain 193g of a brown yellow solid with a yield of 98%.1H NMR (400 MHz, DMSO-d 6) δ 14.32 (s, 1H), 8.85 (d, J = 1.9 Hz, 1H), 8.53 (s, 1H), 8.33 – 8.26 (m, 1H)。
(17) Preparation of (4) with reference to the synthesis method of (11), yield 65%.1H NMR (400 MHz, Chloroform-d) δ 8.61 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.24 (s, 1H), 4.91 (t, J= 7.2 Hz, 2H), 2.88 – 2.83 (m, 2H), 2.33 (s, 6H)。
(18) Preparation of (2) with reference to the synthesis method of (12), the yield was 100%.1H NMR (400 MHz, DMSO-d 6) δ 7.92 (s, 1H), 6.96 (d, J = 1.9 Hz, 1H), 6.78 (d, J = 1.9 Hz, 1H), 4.99 (t, J = 6.9 Hz, 2H), 3.46 (s, 2H), 2.76 (s, 6H)。
(I-9) production according to the synthetic method of (I-7), yield was 67%.1H NMR (400 MHz, DMSO-d 6) δ 9.53 (s, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.38 – 8.30 (m, 2H), 8.22 (d, J = 1.8 Hz, 1H), 8.11 (s, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.31 – 7.15 (m, 3H), 4.76 (t, J = 7.0 Hz, 2H), 3.89 (s, 3H), 2.72 (t, J = 7.0 Hz, 2H), 2.21 (s, 6H)。
Example 10: 7-chloro-N- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1- (2-morpholinoethyl) -1H-indazol-5-amine (I-10)
Figure 257635DEST_PATH_IMAGE027
The synthetic route is as follows:
Figure 16643DEST_PATH_IMAGE028
。
(19) preparation of (4) with reference to the synthesis method of (11), yield 55%.1H NMR (400 MHz, Chloroform-d) δ 8.62 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.24 (s, 1H), 4.93 (t, J= 7.0 Hz, 2H), 3.67 – 3.63 (m, 4H), 2.92 – 2.86 (m, 2H), 2.55 – 2.51 (m, 4H)。
(20) Preparation of (2) with reference to the synthesis method of (12), the yield was 100%.
(I-10) production according to the synthetic method of (I-7), yield was 51%.1H NMR (300 MHz, DMSO-d 6) δ 9.55 (s, 1H), 8.61 (d, J = 7.9 Hz, 1H), 8.41 – 8.31 (m, 2H), 8.23 (s, 1H), 8.12 (s, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.23 (tt, J= 15.9, 7.3 Hz, 3H), 4.79 (t, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.53 (t, J = 4.6 Hz, 4H), 2.77 (t, J = 7.1 Hz, 2H), 2.47 – 2.39 (m, 4H)。
Example 11: 1- (2- (dimethylamino) ethyl) -N- (4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) -1H-indazol-5-amine (I-11)
Figure 801934DEST_PATH_IMAGE029
The synthetic route is as follows:
Figure 492066DEST_PATH_IMAGE030
。
(22) preparation of (4) with reference to the synthetic method of (7), yield was 35%.
Step 2.3- (2-Chloropyrimidin-4-yl) -1- (Ethanesulfonyl) -1H-indole (23) preparation:
3- (2-Chloropyrimidin-4-yl) -1H-indole (22) (4.58 g, 20 mmol) was dissolved in THF solution, and sodium hydrogen (0.58 g, 24 mmol) was added to the reaction under ice bath. After 0.5h, ethyl sulfonyl chloride (3.86 g, 30 mmol) is added into the reaction solution, the reaction is quenched overnight, extracted by ethyl acetate, dried by anhydrous sodium sulfate, concentrated and subjected to column chromatography to obtain 3.85g, and the yield is 60%.1H NMR (300 MHz, Chloroform-d) δ 8.58 (d, J = 5.3 Hz, 1H), 8.51 – 8.43 (m, 1H), 8.18 (s, 1H), 7.96 – 7.88 (m, 1H), 7.57 (d, J = 5.3 Hz, 1H), 7.48 – 7.41 (m, 2H), 3.42 (q, J = 7.4 Hz, 2H), 1.28 (d, J = 7.4 Hz, 3H)。
(I-11) production according to the synthetic method of (I-7), yield was 78%.1H NMR (400 MHz, Methanol-d 4) δ 8.51 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 5.3 Hz, 1H), 8.24 (s, 1H), 8.17 (dd, J = 1.9, 0.8 Hz, 1H), 7.95 (d, J = 0.9 Hz, 1H), 7.90 (dt, J = 8.4, 0.9 Hz, 1H), 7.59 (dd, J = 9.0, 2.0 Hz, 1H), 7.55 – 7.51 (m, 1H), 7.37 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.24 (ddd, J = 8.1, 7.2, 1.1 Hz, 1H), 7.18 (d, J = 5.3 Hz, 1H), 4.62 (t, J = 6.5 Hz, 2H), 3.50 (q, J = 7.4 Hz, 2H), 3.21 (t, J = 6.5 Hz, 2H), 2.57 (s, 6H), 1.17 (t, J = 7.4 Hz, 3H)。
Example 12: n- (4- (1- (ethylsulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) -1- (2-morpholinoethyl) -1H-indazol-5-amine (I-12)
Figure 37317DEST_PATH_IMAGE031
(I-12) production according to the synthetic method of (I-11), yield was 80%.1H NMR (400 MHz, Methanol-d 4) δ 8.52 (d, J = 8.0 Hz, 1H), 8.34 (d, J = 5.3 Hz, 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, 1.2 Hz, 1H), 7.27 – 7.19 (m, 2H), 4.57 (t, J = 6.6 Hz, 2H), 3.64 (t, J = 4.7 Hz, 4H), 3.54 – 3.48 (m, 2H), 2.99 – 2.93 (m, 2H), 2.59 (t, J = 4.6 Hz, 4H), 1.19 (t, J = 7.3 Hz, 3H)。
Example 13: 7-chloro-1- (2- (dimethylamino) ethyl) -N- (4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) -1H-indazol-5-amine (I-13)
Figure 447570DEST_PATH_IMAGE032
(I-13) production according to the synthetic method of (I-11), yield was 88%.1H NMR (400 MHz, DMSO-d 6) δ 9.75 (s, 1H), 8.72 (d, J = 8.0 Hz, 1H), 8.56 (s, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.52 (d, J = 5.3 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 4.80 (t, J = 7.0 Hz, 2H), 3.76 (d, J = 7.3 Hz, 2H), 3.53 (t, J = 4.6 Hz, 4H), 2.77 (t, J = 7.0 Hz, 2H), 2.45 (d, J = 4.9 Hz, 4H), 1.13 (t, J = 7.3 Hz, 3H)。
Example 14: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) acrylamide (I-14)
The synthetic route is as follows:
Figure 124801DEST_PATH_IMAGE033
。
the synthesis method of reference (I-1) was carried out in a yield of 35%.1H NMR (300 MHz, DMSO-d 6) δ 10.39 (s, 1H), 9.71 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.56 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.24 (d, J = 7.0 Hz, 1H), 8.10 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.65 (s, 1H), 7.51 (d, J = 5.3 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 6.55 (dd, J = 17.1, 10.2 Hz, 1H), 6.34 (dd, J = 17.0, 2.0 Hz, 1H), 5.92 – 5.83 (m, 1H), 4.59 (t, J = 6.8 Hz, 2H), 3.76 (d, J = 7.3 Hz, 2H), 3.34 (s, 6H), 2.43 (s, 2H), 1.13 (s, 3H)。
Example 15: (E) -N- (1- (2- (dimethylamino) ethyl) -5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) -2-butenamide (I-15)
Figure 722136DEST_PATH_IMAGE034
The synthesis method of reference (I-1) was carried out in a yield of 75%.1H NMR (300 MHz, DMSO-d 6) δ 10.21 (s, 1H), 9.67 (s, 1H), 8.76 (d, J = 7.8 Hz, 1H), 8.60 – 8.43 (m, 2H), 8.21 (s, 1H), 8.02 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.62 (s, 1H), 7.47 (dd, J = 12.2, 6.3 Hz, 2H), 7.38 (d, J = 7.8 Hz, 1H), 6.87 (dd, J = 15.1, 7.5 Hz, 1H), 6.21 (d, J = 15.4 Hz, 1H), 4.49 (t, J = 7.1 Hz, 2H), 3.76 (q, J = 7.4 Hz, 2H), 2.59 (t, J = 6.8 Hz, 2H), 2.14 (s, 6H), 1.90 (d, J = 6.9 Hz, 3H), 1.13 (t, J = 7.3 Hz, 3H)。
Example 16: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) -3-methyl-2-butenamide (I-16)
Figure 602236DEST_PATH_IMAGE035
The synthesis method of reference (I-1) gave a yield of 80%.1H NMR (400 MHz, Methanol-d 4) δ 8.54 (d, J= 8.2 Hz, 1H), 8.33 (d, J = 5.3 Hz, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 7.96 – 7.88 (m, 2H), 7.64 (s, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 5.4 Hz, 1H), 6.00 (s, 1H), 4.59 (t, J = 6.9 Hz, 2H), 3.50 (q, J = 7.3 Hz, 2H), 2.88 (t, J = 6.8 Hz, 2H), 2.34 (s, 5H), 2.22 (s, 3H), 1.96 (s, 3H), 1.18 (t, J = 7.3 Hz, 3H)。
Example 17: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) propionamide (I-17)
Figure 588034DEST_PATH_IMAGE036
The synthesis method of reference (I-1) was carried out in a yield of 90%.1H NMR (300 MHz, DMSO-d 6) δ 10.15 (s, 1H), 9.65 (s, 1H), 8.77 (d, J = 8.1 Hz, 1H), 8.55 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.48 (dd, J = 9.2, 6.5 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 4.52 (t, J= 7.0 Hz, 2H), 3.76 (q, J = 7.2 Hz, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.43 (q, J= 7.6 Hz, 2H), 2.16 (s, 6H), 1.17 (d, J = 7.5 Hz, 3H), 1.12 (d, J = 7.2 Hz, 3H)。
Example 18: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) acetamide (I-18)
Figure 590494DEST_PATH_IMAGE037
The synthesis method of reference (I-1) was carried out in a yield of 88%.1H NMR (300 MHz, DMSO-d 6) δ 10.23 (s, 1H), 9.66 (s, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.55 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.00 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.51 – 7.44 (m, 2H), 7.37 (t, J = 7.6 Hz, 1H), 4.53 (t, J = 7.0 Hz, 2H), 3.76 (q, J = 7.3 Hz, 2H), 2.61 (t, J = 7.0 Hz, 2H), 2.18 (s, 6H), 2.14 (s, 3H), 1.13 (t, J = 7.3 Hz, 3H)。
Example 19: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) isobutyramide (I-19)
Figure 862075DEST_PATH_IMAGE038
The synthesis method of reference (I-1) gave a yield of 85%.1H NMR (400 MHz, DMSO-d 6) δ 10.09 (s, 1H), 9.65 (s, 1H), 8.79 (d, J = 7.9 Hz, 1H), 8.56 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.54 – 7.44 (m, 3H), 7.37 (t, J = 7.6 Hz, 1H), 4.51 (t, J = 6.9 Hz, 2H), 3.76 (q, J = 7.2 Hz, 2H), 2.73 – 2.66 (m, 1H), 2.60 (t, J = 7.0 Hz, 2H), 2.15 (s, 6H), 1.18 (d, J= 6.8 Hz, 6H), 1.12 (t, J = 7.3 Hz, 3H)。
Example 20: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) cyclopropanecarboxamide (I-20)
Figure 373015DEST_PATH_IMAGE039
The synthesis method of reference (I-1) was carried out in a yield of 91%.1H NMR (400 MHz, DMSO-d 6) δ 10.38 (s, 1H), 9.64 (s, 1H), 8.76 (d, J = 8.1 Hz, 1H), 8.55 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.47 (dd, J = 11.1, 6.4 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 4.52 (t, J = 7.1 Hz, 2H), 3.76 (q, J = 7.3 Hz, 2H), 2.60 (t, J = 7.1 Hz, 2H), 2.19 (s, 6H), 1.92 – 1.79 (m, 1H), 1.13 (t, J = 7.3 Hz, 3H), 0.85 (d, J = 6.0 Hz, 4H)。
Example 21: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1- (trideuteromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) acrylamide (I-21)
Figure 226701DEST_PATH_IMAGE040
The synthetic route is as follows:
Figure 337746DEST_PATH_IMAGE041
。
the synthesis method of reference (I-1) gave a yield of 41%.1H NMR (400 MHz, DMSO-d 6) δ 10.42 (s, 1H), 9.46 (s, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.37 – 8.30 (m, 2H), 8.20 (d, J = 1.9 Hz, 1H), 8.03 (s, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.21 – 7.15 (m, 2H), 6.54 (dd, J = 17.1, 10.2 Hz, 1H), 6.33 (dd, J = 17.0, 2.0 Hz, 1H), 5.85 (dd, J = 10.1, 1.9 Hz, 1H), 4.49 (t, J= 7.2 Hz, 2H), 2.57 (t, J = 7.2 Hz, 2H), 2.13 (s, 6H)。
Example 22: (E) -N- (1- (2- (dimethylamino) ethyl) -5- ((4- (1- (trideuteromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) -2-butenamide (I-22)
Figure 158940DEST_PATH_IMAGE042
The synthesis method of reference (I-1) gave a yield of 56%.1H NMR (400 MHz, DMSO-d 6) δ 10.22 (d, J = 11.8 Hz, 1H), 9.46 (d, J = 3.1 Hz, 1H), 8.60 (d, J = 7.8 Hz, 1H), 8.34 (d, J= 5.8 Hz, 2H), 8.19 (s, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.68 (d, J = 9.7 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.18 (dd, J = 10.3, 6.3 Hz, 2H), 6.88 (dq, J = 14.0, 6.8 Hz, 1H), 6.22 (d, J = 15.3 Hz, 1H), 4.54 – 4.45 (m, 2H), 3.24 (d, J = 7.0 Hz, 1H), 2.57 (t, J = 7.1 Hz, 2H), 2.14 (d, J= 9.0 Hz, 6H), 1.90 (d, J = 6.8 Hz, 2H)。
Example 23: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1- (trideuteromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) -3-methyl-2-butenamide (I-23)
Figure 397154DEST_PATH_IMAGE043
The synthesis method of reference (I-1) gave a yield of 67%.1H NMR (400 MHz, DMSO-d 6) δ 10.08 (s, 1H), 9.45 (s, 1H), 8.61 (d, J = 8.0 Hz, 1H), 8.37 – 8.31 (m, 2H), 8.24 – 8.16 (m, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.30 – 7.23 (m, 1H), 7.18 (dd, J = 9.7, 6.2 Hz, 2H), 5.98 (s, 1H), 4.50 (t, J = 7.1 Hz, 2H), 2.59 (t, J = 7.0 Hz, 2H), 2.22 – 2.16 (m, 3H), 2.14 (s, 6H), 1.90 (s, 3H)。
Example 24: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1- (trideuteromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) propionamide (I-24)
Figure 557877DEST_PATH_IMAGE044
The synthesis method of reference (I-1) was carried out at a yield of 70%.1H NMR (300 MHz, DMSO-d 6) δ 10.12 (s, 1H), 9.43 (s, 1H), 8.60 (d, J = 7.9 Hz, 1H), 8.34 (d, J = 4.4 Hz, 2H), 8.17 (s, 1H), 8.00 (s, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.22 – 7.12 (m, 2H), 4.52 (t, J = 7.0 Hz, 2H), 2.59 (t, J = 7.0 Hz, 2H), 2.43 (q, J = 7.6 Hz, 2H), 2.16 (s, 6H), 1.16 (t, J = 7.6 Hz, 3H)。
Example 25: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1- (trideuteromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) acetamide (I-25)
Figure 780436DEST_PATH_IMAGE045
The synthesis method of reference (I-1) was carried out in a yield of 69%.1H NMR (300 MHz, DMSO-d 6) δ 10.22 (s, 1H), 9.45 (s, 1H), 8.60 (d, J = 7.9 Hz, 1H), 8.34 (d, J = 6.1 Hz, 2H), 8.17 (d, J= 1.9 Hz, 1H), 8.01 (s, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.33 – 7.24 (m, 1H), 7.19 (dd, J = 6.2, 2.8 Hz, 2H), 4.53 (t, J = 7.0 Hz, 2H), 2.61 (t, J = 7.0 Hz, 2H), 2.18 (s, 6H), 2.14 (s, 3H)。
Example 26: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1- (trideuteromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) isobutyramide (I-26)
Figure 557768DEST_PATH_IMAGE046
The synthesis method of reference (I-1) was carried out in a yield of 45%.1H NMR (300 MHz, DMSO-d 6) δ 10.05 (s, 1H), 9.42 (s, 1H), 8.61 (d, J = 7.9 Hz, 1H), 8.38 – 8.29 (m, 2H), 8.21 (s, 1H), 8.00 (s, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.27 (t, J= 7.5 Hz, 1H), 7.21 – 7.14 (m, 2H), 4.51 (t, J = 7.0 Hz, 2H), 2.76 – 2.64 (m, 1H), 2.60 (t, J = 6.9 Hz, 2H), 2.15 (s, 6H), 1.19 (d, J = 6.8 Hz, 6H)。
Example 27: n- (1- (2- (dimethylamino) ethyl) -5- ((4- (1- (trideuteromethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) cyclopropanecarboxamide (I-27)
Figure 114520DEST_PATH_IMAGE047
The synthesis method of reference (I-1) was carried out in a yield of 73%.1H NMR (300 MHz, DMSO-d 6) δ 10.37 (s, 1H), 9.42 (s, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.37 – 8.30 (m, 2H), 8.19 (s, 1H), 8.00 (s, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.27 (t, J= 7.6 Hz, 1H), 7.21 – 7.14 (m, 2H), 4.52 (t, J = 7.1 Hz, 2H), 2.60 (t, J = 7.1 Hz, 2H), 2.19 (s, 6H), 1.88 (s, 1H), 0.85 (d, J = 5.4 Hz, 4H)。
Example 28: 1- (2- (dimethylamino) ethyl) -N- (4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) -1H-indazol-5-amine (I-28)
Figure 395328DEST_PATH_IMAGE048
The synthetic route is as follows:
Figure 788788DEST_PATH_IMAGE049
the synthesis method of reference (I-1) was carried out at a yield of 70%.1H NMR (400 MHz, DMSO-d 6) δ 9.57 (s, 1H), 8.73 (d, J = 8.1 Hz, 1H), 8.53 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.24 (d, J= 1.4 Hz, 1H), 7.98 (s, 1H), 7.96 – 7.90 (m, 1H), 7.63 (d, J = 1.3 Hz, 2H), 7.50 – 7.43 (m, 2H), 7.33 (t, J = 7.6 Hz, 1H), 4.43 (t, J = 6.6 Hz, 2H), 3.76 (q, J = 7.3 Hz, 2H), 2.85 (t, J = 6.6 Hz, 2H), 2.52 – 2.50 (m, 4H), 1.13 (t, J = 7.3 Hz, 3H), 0.87 (t, J = 7.1 Hz, 6H)。
Example 29: 7-chloro-1- (2- (dimethylamino) ethyl) -N- (4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) -1H-indazol-5-amine (I-29)
Figure 53416DEST_PATH_IMAGE050
The synthetic route is as follows:
Figure 633433DEST_PATH_IMAGE051
the synthesis method of reference (I-7) was carried out in a yield of 75%.1H NMR (300 MHz, DMSO-d 6) δ 9.73 (s, 1H), 8.72 (d, J = 8.0 Hz, 1H), 8.55 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.98 – 7.87 (m, 2H), 7.49 (dd, J = 18.7, 6.6 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 4.72 (t, J = 7.0 Hz, 2H), 3.76 (q, J = 7.3 Hz, 2H), 2.83 (t, J = 7.0 Hz, 2H), 1.13 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.1 Hz, 6H)。
Example 30: n- (1- (2- (diethylamino) ethyl) -5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) acrylamide (I-30)
Figure 299907DEST_PATH_IMAGE052
The synthetic route is as follows:
Figure 923655DEST_PATH_IMAGE053
(32) preparation of (4) with reference to the synthesis method of (3), yield 72%.1H NMR (400 MHz, Chloroform-d) δ 8.93 (d, J = 2.0 Hz, 1H), 8.92 (d, J = 2.1 Hz, 1H), 8.44 (s, 1H), 4.74 (t, J= 5.8 Hz, 2H), 2.71 (t, J = 5.9 Hz, 2H), 2.33 (t, J = 7.1 Hz, 4H), 0.68 (t, J= 7.1 Hz, 6H)。
（33）Preparation of (5) with reference to the synthesis method of (4), yield 50%.1H NMR (400 MHz, Chloroform-d) δ 8.10 (d, J = 2.0 Hz, 1H), 8.09 (s, 1H), 7.40 (d, J = 2.0 Hz, 1H), 4.76 – 4.70 (m, 2H), 2.95 – 2.91 (m, 2H), 2.46 (q, J = 7.2 Hz, 4H), 0.84 (t, J = 7.1 Hz, 6H)。
(34) Preparation of (5) with reference to the synthesis method of (8), yield 98%.1H NMR (400 MHz, Chloroform-d) δ 8.68 (d, J = 2.0 Hz, 1H), 8.24 (s, 1H), 8.06 (d, J = 2.0 Hz, 1H), 4.49 – 4.44 (m, 2H), 2.97 – 2.93 (m, 2H), 2.59 (q, J = 7.1 Hz, 4H), 1.44 (s, 18H), 1.02 (t, J = 7.1 Hz, 6H)。
(I-36) production according to the synthetic method of (I-7), yield was 33%.1H NMR (300 MHz, DMSO-d 6) δ 10.35 (s, 1H), 9.68 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.56 (s, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.21 (s, 1H), 8.03 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 1.7 Hz, 1H), 7.51 – 7.43 (m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 6.53 (dd, J = 17.1, 10.1 Hz, 1H), 6.32 (dd, J = 16.9, 2.0 Hz, 1H), 5.90 – 5.81 (m, 1H), 4.44 (t, J = 7.2 Hz, 2H), 3.76 (q, J = 7.3 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.43 (q, J = 7.1 Hz, 4H), 1.13 (t, J = 7.3 Hz, 3H), 0.87 (t, J = 7.1 Hz, 6H)。
Example 31: (E) -N- (1- (2- (diethylamino) ethyl) -5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) -2-butenamide (I-31)
Figure 193356DEST_PATH_IMAGE054
The synthesis method of reference (I-1) gave a yield of 67%.1H NMR (400 MHz, DMSO-d 6) δ 10.15 (d, J = 6.4 Hz, 1H), 9.66 (d, J = 3.7 Hz, 1H), 8.77 (s, 1H), 8.55 (d, J = 1.0 Hz, 1H), 8.48 (d, J = 5.3 Hz, 1H), 8.20 (dd, J = 5.3, 1.8 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.97 – 7.89 (m, 1H), 7.63 – 7.56 (m, 1H), 7.51 – 7.43 (m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 6.93 – 6.81 (m, 1H), 6.21 (d, J = 15.3 Hz, 1H), 4.45 (dt, J = 14.2, 7.1 Hz, 2H), 3.79 – 3.73 (m, 2H), 3.23 (dt, J = 6.8, 1.5 Hz, 1H), 2.71 (dt, J = 11.7, 7.2 Hz, 2H), 2.48 – 2.41 (m, 4H), 1.90 (d, J = 6.8 Hz, 2H), 1.13 (t, J = 7.3 Hz, 3H), 0.88 (t, J = 7.1 Hz, 6H)。
Example 32: n- (1- (2- (diethylamino) ethyl) -5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) -3-methyl-2-butenamide (I-32)
Figure 967277DEST_PATH_IMAGE055
The synthesis method of reference (I-1) was carried out in a yield of 76%.1H NMR (400 MHz, DMSO-d 6) δ 10.08 (d, J = 50.4 Hz, 1H), 9.65 (s, 1H), 8.77 (d, J = 7.9 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.48 (d, J = 5.3 Hz, 1H), 8.19 (d, J = 1.9 Hz, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.58 (dd, J = 16.7, 1.9 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.37 (d, J = 7.7 Hz, 1H), 5.97 (s, 1H), 4.47 (q, J = 7.2, 6.1 Hz, 2H), 3.79 – 3.72 (m, 2H), 2.73 (s, 2H), 2.46 (d, J = 7.3 Hz, 4H), 2.17 (d, J= 1.2 Hz, 2H), 1.90 (s, 2H), 1.84 (s, 1H), 1.13 (t, J = 7.3 Hz, 3H), 0.89 (t, J = 7.2 Hz, 6H)。
Example 33: n- (1- (2- (diethylamino) ethyl) -5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) propionamide (I-33)
Figure 541785DEST_PATH_IMAGE056
The synthesis method of reference (I-1) gave a yield of 83%.1H NMR (400 MHz, Chloroform-d) δ 10.81 (s, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 5.2 Hz, 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, 1.3 Hz, 1H), 7.38 – 7.33 (m, 1H), 7.31 (s, 1H), 7.08 (d, J = 5.2 Hz, 1H), 4.68 (s, 2H), 3.42 (q, J = 7.4 Hz, 2H), 2.97 (s, 2H), 2.49 (q, J = 7.5 Hz, 6H), 1.29 (d, J = 7.3 Hz, 6H), 0.89 (d, J = 6.0 Hz, 6H)。
Example 34: n- (1- (2- (diethylamino) ethyl) -5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) acetamide (I-34)
Figure 602013DEST_PATH_IMAGE057
The synthesis method of reference (I-1) was carried out in a yield of 76%.1H NMR (400 MHz, DMSO-d 6) δ 10.15 (s, 1H), 9.66 (s, 1H), 8.81 – 8.71 (m, 1H), 8.55 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.01 (s, 1H), 7.97 – 7.91 (m, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.52 – 7.44 (m, 2H), 7.37 (t, J = 7.6 Hz, 1H), 4.48 (t, J = 7.0 Hz, 2H), 3.76 (q, J = 7.2 Hz, 2H), 2.73 (t, J = 7.0 Hz, 2H), 2.47 (t, J = 7.1 Hz, 4H), 2.14 (s, 3H), 1.13 (t, J = 7.3 Hz, 3H), 0.90 (t, J = 7.1 Hz, 6H)。
Example 35: n- (1- (2- (diethylamino) ethyl) -5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) isobutyramide (I-35)
Figure 575655DEST_PATH_IMAGE058
The synthesis method of reference (I-1) gave a yield of 65%.1H NMR (400 MHz, Chloroform-d) δ 10.70 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 5.2 Hz, 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, 1.3 Hz, 1H), 7.38 – 7.32 (m, 2H), 7.07 (d, J = 5.2 Hz, 1H), 4.68 (t, J = 4.7 Hz, 2H), 3.41 (q, J = 7.4 Hz, 2H), 2.97 (d, J = 5.7 Hz, 2H), 2.62 (s, 1H), 2.46 (q, J = 7.1 Hz, 4H), 1.31 (d, J = 6.7 Hz, 4H), 1.28 (t, J = 7.4 Hz, 6H), 0.89 (t, J = 7.1 Hz, 6H)。
Example 36: n- (1- (2- (diethylamino) ethyl) -5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-7-yl) cyclopropanecarboxamide (I-36)
Figure 952934DEST_PATH_IMAGE059
The synthesis method of reference (I-1) was carried out in a yield of 78%.1H NMR (400 MHz, DMSO-d 6) δ 10.35 (s, 1H), 9.64 (s, 1H), 8.77 (d, J = 7.6 Hz, 1H), 8.55 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 8.01 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.51 – 7.44 (m, 2H), 7.37 (t, J = 7.7 Hz, 1H), 4.47 (t, J = 7.1 Hz, 2H), 3.76 (q, J = 7.2 Hz, 2H), 2.73 (t, J = 7.2 Hz, 2H), 1.86 (d, J = 6.3 Hz, 1H), 1.13 (t, J = 7.3 Hz, 3H), 0.92 (t, J = 7.1 Hz, 6H), 0.85 (d, J = 5.9 Hz, 4H)。
Example 37: 2- (5- ((4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -1H-indazol-1-yl) -N, N-dimethylacetamide (I-37)
Figure 610311DEST_PATH_IMAGE060
The synthetic route is as follows:
Figure 44704DEST_PATH_IMAGE061
the synthesis method of reference (I-7) was carried out in a yield of 76%.1H NMR (400 MHz, DMSO-d 6) δ 9.59 (s, 1H), 8.74 (d, J = 8.0 Hz, 1H), 8.54 (s, 1H), 8.47 (d, J = 5.3 Hz, 1H), 8.26 (d, J= 1.9 Hz, 1H), 7.99 (d, J = 0.9 Hz, 1H), 7.95 – 7.90 (m, 1H), 7.61 (dd, J = 9.0, 2.0 Hz, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.49 – 7.43 (m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 5.40 (s, 2H), 3.76 (q, J = 7.3 Hz, 2H), 3.12 (s, 3H), 2.87 (s, 3H), 1.13 (t, J = 7.3 Hz, 3H)。
Example 38: n- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1- (2- (dimethylamino) ethyl) -1H-indazol-5-amine (I-38)
Figure 771220DEST_PATH_IMAGE062
The synthesis method of reference (I-7) gave a yield of 79%. 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.57 (s, 2H), 8.45 (s, 1H), 8.21-8.19 (m, 1H), 7.93 (d, J = 0.8 Hz, 1H), 7.67-7.58 (m, 2H), 7.54 (dd, J = 8.3, 0.9 Hz, 1H), 7.28 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 4.48 (t, J = 6.6 Hz, 2H), 3.93 (s, 3H), 2.72 (t, J = 6.6 Hz, 2H), 2.18 (s, 6H).
Example 39: n- (5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1- (2- (dimethylamino) ethyl) -1H-indazol-5-amine (I-39)
Figure 888210DEST_PATH_IMAGE063
The synthesis method of reference (I-7) showed a yield of 80%.1H NMR (400 MHz, DMSO-d 6) δ 9.16 (s, 1H), 8.87 (d, J = 7.9 Hz, 1H), 8.39 (s, 1H), 8.29 (t, J = 1.3 Hz, 1H), 8.25 (s, 1H), 7.93 (s, 1H), 7.61 (d, J = 1.3 Hz, 2H), 7.55 – 7.51 (m, 1H), 7.27 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.12 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 4.47 (t, J = 6.6 Hz, 2H), 3.98 (s, 3H), 3.90 (s, 3H), 2.73 (t, J = 6.6 Hz, 2H), 2.20 (s, 6H)。
Example 40: n- (5-chloro-4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) -1- (2- (dimethylamino) ethyl) -1H-indazol-5-amine (I-40)
Figure 118203DEST_PATH_IMAGE064
The synthesis method of reference (I-7) showed a yield of 80%.1H NMR (400 MHz, DMSO-d 6) δ 9.86 (s, 1H), 8.63 (s, 1H), 8.47 (s, 2H), 8.16 (d, J = 1.8 Hz, 1H), 7.93 (d, J = 9.1 Hz, 2H), 7.66 (d, J = 9.0 Hz, 1H), 7.59 (dd, J = 9.0, 1.9 Hz, 1H), 7.48 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.30 (s, 1H), 4.48 (t, J = 6.5 Hz, 2H), 3.80 (q, J = 7.3 Hz, 2H), 2.74 (t, J = 6.5 Hz, 2H), 2.19 (s, 6H), 1.13 (t, J = 7.3 Hz, 3H)。
Example 41: 7-chloro-1- (2- (dimethylamino) ethyl) -N- (4- (1-methyl-1H-indol-3-yl) -5-nitropyrimidin-2-yl) -1H-indazol-5-amine (I-41)
Figure 5388DEST_PATH_IMAGE065
The synthesis method of reference (I-7) gave a yield of 56%.1H NMR (400 MHz, DMSO-d 6) δ 10.53 (s, 1H), 9.05 (s, 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.34 – 7.04 (m, 3H), 4.77 (t, J = 7.0 Hz, 2H), 3.91 (s, 3H), 2.71 (t, J = 6.9 Hz, 2H), 2.20 (s, 6H)。
Example 42: 1- (2- (dimethylamino) ethyl) -N- (4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) -1H-indol-5-amine (I-42)
Figure 219200DEST_PATH_IMAGE066
The synthesis method of reference (I-7) was carried out in a yield of 82%.1H NMR (300 MHz, DMSO-d 6) δ 9.40 (s, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.52 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.02 (d, J= 1.8 Hz, 1H), 7.92 (dd, J = 8.4, 0.9 Hz, 1H), 7.48 – 7.44 (m, 1H), 7.44 – 7.40 (m, 2H), 7.38 (dd, J = 8.2, 2.5 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 6.36 (dd, J = 3.0, 0.7 Hz, 1H), 4.25 (t, J = 6.6 Hz, 2H), 3.75 (q, J = 7.3 Hz, 2H), 2.63 (t, J = 6.6 Hz, 2H), 2.20 (s, 6H), 1.12 (t, J = 7.3 Hz, 3H)。
Example 43: n- (5-chloro-4- (1- (ethanesulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) -1- (2- (dimethylamino) ethyl) -1H-indol-5-amine (I-43)
Figure 997669DEST_PATH_IMAGE067
The synthesis method of reference (I-7) gave a yield of 85%.1H NMR (400 MHz, DMSO-d 6) δ 9.64 (s, 1H), 8.57 (s, 1H), 8.46 (s, 2H), 7.96 – 7.89 (m, 2H), 7.45 (dd, J = 13.1, 8.2 Hz, 2H), 7.38 – 7.32 (m, 2H), 7.25 (s, 1H), 6.33 (d, J = 3.1 Hz, 1H), 4.25 (t, J= 6.6 Hz, 2H), 3.79 (q, J = 7.3 Hz, 2H), 2.63 (t, J = 6.6 Hz, 2H), 2.20 (s, 6H), 1.13 (t, J = 7.3 Hz, 3H)。
Example 44: 7-chloro-1- (2- (dimethylamino) ethyl) -N- (4- (1-methyl-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) -1H-indazol-5-amine (I-44)
Figure 364060DEST_PATH_IMAGE068
The synthesis method of reference (I-7) was carried out in a yield of 75%.1H NMR (400 MHz, DMSO-d 6) δ 10.20 (s, 1H), 8.78 (s, 1H), 8.19 (s, 2H), 8.04 (s, 1H), 7.94 – 7.87 (m, 2H), 7.56 (d, J = 8.2 Hz, 1H), 7.32 – 7.27 (m, 1H), 7.13 (s, 1H), 4.76 (t, J = 7.0 Hz, 2H), 3.93 (s, 3H), 2.71 (t, J = 7.0 Hz, 2H), 2.20 (s, 6H)。
Example 45: 1- (2- (dimethylamino) ethyl) -N- (4- (1- (ethanesulfonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) -1H-indol-5-amine (I-45)
Figure 939922DEST_PATH_IMAGE069
The synthesis method of reference (I-7) was carried out in a yield of 87%.1H NMR (400 MHz, DMSO-d 6) δ 10.17 (s, 1H), 8.84 (s, 1H), 8.06 (s, 1H), 7.96 – 7.93 (m, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.89 (s, 1H), 7.51 – 7.34 (m, 5H), 6.32 (s, 1H), 4.23 (t, J = 6.6 Hz, 2H), 3.75 (q, J = 7.2 Hz, 2H), 2.59 (t, J = 6.5 Hz, 2H), 2.18 (s, 6H), 1.07 (t, J= 7.3 Hz, 3H)。
Example 46: 1- (2- (dimethylamino) ethyl) -N- (4- (1-methyl-1H-indol-3-yl) -5-nitropyrimidin-2-yl) -1H-indol-5-amine (I-46)
Figure 578714DEST_PATH_IMAGE070
The synthesis method of reference (I-7) gave a yield of 56%.1H NMR (400 MHz, DMSO-d 6) δ 10.30 (s, 1H), 9.00 (s, 1H), 8.00 (d, J = 12.4 Hz, 3H), 7.54 (d, J = 8.3 Hz, 1H), 7.48 (d, J= 8.8 Hz, 1H), 7.44 – 7.37 (m, 2H), 7.26 (s, 1H), 7.02 (s, 1H), 6.39 (s, 1H), 4.28 (t, J = 6.6 Hz, 2H), 3.89 (s, 3H), 2.66 (d, J = 6.9 Hz, 2H), 2.23 (s, 6H)。
Example 47: n is a radical of5- (4- (1H-indol-3-yl) pyrimidin-2-yl) -1- (2- (dimethylamino) ethyl) -1H-indazole-5, 7-Diamine (I-47)
Figure 754349DEST_PATH_IMAGE071
The synthesis method of reference (I-7) showed a yield of 50%.1H NMR (400 MHz, Chloroform-d) δ 8.77 (s, 1H), 8.49 (dd, J = 7.1, 1.8 Hz, 1H), 8.33 (d, J = 5.3 Hz, 1H), 7.88 – 7.85 (m, 2H), 7.51 (d, J = 1.7 Hz, 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 = 5.3 Hz, 1H), 6.88 (d, J = 1.8 Hz, 1H), 4.73 – 4.70 (m, 2H), 2.84 – 2.81 (m, 2H), 2.23 (s, 6H)。
Second, biological evaluation
（1）EGFRL858R/T790M/C797SKinase activity assay
Compounds were dissolved in 100% DMSO and formulated into 10mM solutions. A1 XKinase buffer was prepared. Preparation of compound concentration gradient: compound assay starting concentration was 5 μ M, 3-fold dilution, 10 concentrations, single well assay. A2.5 fold final concentration of Kinase solution was prepared using a 1 XKinase buffer. 10 mu L of kinase liquid with 2.5 times final concentration is added into the compound hole and the positive control hole respectively; mu.L of 1 XKinase buffer was added to the negative control wells. The plate was centrifuged at 1000rpm for 30 seconds, shaken and mixed and incubated at room temperature for 10 minutes. A25/15-fold final concentration of ATP and Kinase substrate 22 mixed solution was made up with 1 XKinase buffer. The reaction was initiated by adding 15. mu.L of a mixed solution of ATP and substrate at 25/15-fold final concentration. The 384 well plates were centrifuged at 1000rpm for 30 seconds, shaken well and incubated for 60 minutes at room temperature. After stopping the kinase reaction, the mixture was centrifuged at 1000rpm for 30 seconds and shaken to mix. The conversion was read using a Caliper EZ Reader. The dose-effect curves were fitted using the analysis software GraphPad Prism 5 log (inhibitor) vs. response-Variable slope to obtain the IC of each compound for enzyme activity50 The value is obtained.
The resulting IC50The values are shown in Table 1, and it can be seen from the results that the compounds of the examples of the present invention have strong EGFRL858R/T790M/C797SKinase inhibitory activity.
Table 1 example compounds versus EGFRL858R/T790M/C797SIC of kinase Activity50Measured value
Figure 961864DEST_PATH_IMAGE072
(2) Cell proliferation inhibition assay
Compound pair BaF3 (EGFRL858R/T790M/C797S) Cell proliferation inhibitory activity was tested by the CTG method:
the experimental steps are as follows:
compounds were dissolved in 100% DMSO and formulated into 1mM solution, 2. mu.L of the solution was diluted to 20. mu.M/L in 98. mu.L of medium, the suspension cells were centrifuged, the medium was changed and counted. The compound was diluted to the desired concentration with the culture medium. Add 95. mu.L of cell suspension to 96-well plate and add 5. mu.L of the corresponding concentration compound to each well in turn, and blow down to uniformity. The 96-well plate was placed in a cell incubator for 72 h. After three days, adding 50 mu LCellTiter-Glo reagent into each hole of a 96-hole plate, placing the hole plate on a vibrator to vibrate for two minutes to crack cells to release ATP in the cells, incubating for 10 minutes at room temperature to stabilize a luminescent signal, and reading a fluorescence value by using an enzyme-labeling instrument. The dose-effect curves were fitted using the analytical software GraphPad Prism 7, inhibitor vs. response-Variable slope (four parameters) to derive the IC of each compound for enzyme activity50 The value is obtained.
The resulting IC50The values are shown in Table 2, and it can be seen from the results that the compounds of the examples of the present invention have strong BaF3(EGFRL858R/T790M/C797S) Cell proliferation inhibitory activity.
Table 2 example compounds vs BaF3 (EGFRL858R/T790M/C797S) Cell proliferation inhibition IC50
Figure 377802DEST_PATH_IMAGE073
。
Compound pair H-1975 (EGFR)L858R/T790M/C797S) Cell line, H-1975 cell line, PC-9 cell line, A-549 cell line cell proliferation inhibitory activity was tested by the CCK8 method.
The experimental steps are as follows:
after counting the cells, 100 μ L of the cell suspension was seeded in a 96-well plate. After the cells are attached to the surface, the compound with the corresponding concentration is added, the compound is dissolved in 100% DMSO to prepare a 1mM solution, and then the compound is diluted to the required concentration by using a culture medium. Add 100. mu.L of compound solution to 96-well plate and blow and beat well. The 96-well plate was placed in a cell incubator for 72 h. Three days later, 10. mu.L of Cell Count Kit 8 reagent was added to each well of the 96-well plate, the 96-well plate was placed in a Cell incubator for 4 hours, and the fluorescence value was read with a microplate reader. The dose-effect curves were fitted using the analytical software GraphPad Prism 7, inhibitor vs. response-Variable slope (four parameters) to derive the IC of each compound for enzyme activity50 The value is obtained.
TABLE 3 example Compound Pair H-1975 (EGFR)L858R/T790M/C797S) Cell proliferation inhibition IC50
Figure 300627DEST_PATH_IMAGE074
TABLE 4 inhibition of cell proliferation IC of H-1975 by the compounds of the examples50
Figure 155320DEST_PATH_IMAGE075
TABLE 5 inhibition of PC-9 cell proliferation IC by the compounds of the examples50
Figure DEST_PATH_IMAGE076
TABLE 6 inhibition of A-549 cell proliferation IC by the compounds of the examples50
Figure DEST_PATH_IMAGE077

Claims (10)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:
Figure 829174DEST_PATH_IMAGE001
（I）
wherein the content of the first and second substances,
x is selected from C, N, O or S;
R1selected from hydrogen, C1-C3Alkyl, halo C1-C3Alkyl, deuterated C1-C3Alkyl radical, C3-C8Cycloalkyl, -S (O)2R5；
R2Selected from hydrogen, halogen, hydroxy, mercapto, cyano, nitro, C1-C3Alkyl radical, C1-C3Alkoxy, halo C1-C3Alkyl radical, C3-C8A cycloalkyl group;
R3selected from hydrogen, halogen, amino, -NH-C (O) R6；
R4Selected from hydrogen, -C1-C3-NR7R8、-C1-C3-C(O)NR9R10；
R5Selected from hydrogen, C1-C3Alkyl, halo C1-C3Alkyl radical, C3-C8A cycloalkyl group;
R6selected from hydrogen, C1-C8Alkyl, halo C1-C8Alkyl radical, C3-C8Cycloalkyl radical, C2-C8Alkenyl radical, C2-C8An alkynyl group;
R7、 R8、R9and R10Are respectively and independently selected from hydrogen and C1-C3Alkyl, halo C1-C3An alkyl group, a carboxyl group,
or, R7And R8，R9And R10Forming five-membered nitrogen-containing heterocyclic ring and six-membered nitrogen-containing heterocyclic ring.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
x is selected from C or N;
R1selected from hydrogen, C1-C3Alkyl, deuterated C1-C3Alkyl, -S (O)2R5Wherein R is5Is selected from C1-C3Alkyl radical, C3-C8A cycloalkyl group;
R2selected from hydrogen, halogen, nitro, C1-C3Alkoxy, halo C1-C3An alkyl group;
R3selected from hydrogen, halogen, amino, -NH-C (O) R6Wherein R is6Is selected from C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8A cycloalkyl group;
R4is selected from-C1-C3-NR7R8、-C1-C3-C(O)NR9R10Wherein R is7、 R8、R9And R10Are each independently selected from C1-C3Alkyl, or R7And R8，R9And R10To form saturated six-membered nitrogen-containing heterocyclic ring.
3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
x is selected from C or N;
R1selected from hydrogen, C1-C3Alkyl, deuterated C1-C3Alkyl, -S (O)2R5Wherein R is5Selected from methyl, ethyl, cyclopropyl;
R2selected from hydrogen, halogen, nitro, methoxy, halogenated C1-C3An alkyl group;
R3selected from hydrogen, halogen, amino,-NH-C(O)R6Wherein R is6Selected from the group consisting of vinyl, propenyl, isobutenyl, methyl, ethyl, isopropyl, cyclopropyl;
R4is selected from-C1-C3-NR7R8、-C1-C3-C(O)NR9R10Wherein R is7、R8、R9And R10Each independently selected from methyl, ethyl, or, R7And R8，R9And R10Morpholine, piperidine, hexahydropyridazine, hexahydropyrimidine, piperazine, N-methylhexahydropyridazine, N-methylhexahydropyrimidine, N-methylpiperazine, N-ethylpiperazine and N-isopropylpiperazine.
4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
x is selected from C or N;
R1selected from hydrogen, methyl, deuterated methyl, -S (O)2R5Wherein R is5Selected from methyl, ethyl, cyclopropyl;
R2selected from hydrogen, halogen, nitro, methoxy, trifluoromethyl;
R3selected from hydrogen, halogen, amino, -NH-C (O) R6Wherein R is6Selected from the group consisting of vinyl, propenyl, isobutenyl, methyl, ethyl, isopropyl, cyclopropyl;
R4is selected from-CH2CH2-NR7R8、-CH2-C(O)NR9R10Wherein R is7、R8、R9And R10Each independently selected from methyl, ethyl, or, R7And R8Morpholine, piperidine, piperazine, N-methylpiperazine, N-ethylpiperazine and N-isopropylpiperazine.
5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
x is selected from C or N;
R1selected from hydrogen, methyl, deuterated methyl, -S(O)2R5Wherein R is5Is selected from ethyl;
R2selected from hydrogen, chlorine, nitro, methoxy, trifluoromethyl;
R3selected from hydrogen, chlorine, amino, -NH-C (O) R6Wherein R is6Selected from the group consisting of vinyl, propenyl, isobutenyl, methyl, ethyl, isopropyl, cyclopropyl;
R4is selected from-CH2CH2-NR7R8、-CH2-C(O)NR9R10Wherein R is7And R8Each independently selected from methyl, ethyl, or, R7And R8Morpholine, R9And R10Selected from methyl.
6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: the compound is selected from compounds with structural formulas shown as formulas (I-1) to (I-47):
Figure 700309DEST_PATH_IMAGE002
Figure 745626DEST_PATH_IMAGE003
Figure 354550DEST_PATH_IMAGE004
Figure 795021DEST_PATH_IMAGE005
Figure 742117DEST_PATH_IMAGE006
Figure 900828DEST_PATH_IMAGE007
Figure 224362DEST_PATH_IMAGE008
Figure 519339DEST_PATH_IMAGE009
Figure 840599DEST_PATH_IMAGE010
Figure 480747DEST_PATH_IMAGE011
Figure 342393DEST_PATH_IMAGE012
Figure 491877DEST_PATH_IMAGE013
。
7. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salt is an acid addition salt of the compound of formula (I), wherein the acid used for salt formation includes inorganic acids including hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid, and organic acids including 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, aspartic acid and tartaric acid.
8. A pharmaceutical composition characterized by: comprising a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof or an isomer thereof or a prodrug molecule thereof or an active metabolite thereof, and a pharmaceutically acceptable carrier.
9. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of cancer or tumor-related diseases including brain gliomas, pituitary tumors, gliomas, melanomas, breast cancers, lung cancers, stomach cancers, ovarian cancers, colon cancers, liver cancers, pancreatic cancers, prostate cancers, testicular cancers, multiple myeloma, leukemia multiple solid tumors, and hematological tumors.
10. The use of claim 9, wherein the tumor is a malignant tumor in which the EGFR gene is mutated.
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