CN107556318B - Pyrrolopyrimidine compound containing piperidine as well as preparation method and application thereof - Google Patents
Pyrrolopyrimidine compound containing piperidine as well as preparation method and application thereof Download PDFInfo
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- CN107556318B CN107556318B CN201710726360.3A CN201710726360A CN107556318B CN 107556318 B CN107556318 B CN 107556318B CN 201710726360 A CN201710726360 A CN 201710726360A CN 107556318 B CN107556318 B CN 107556318B
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Abstract
The invention discloses a pyrrolopyrimidine compound containing piperidine and a preparation method and application thereof. The compounds have a structure shown as a general formula (I) or (II). The invention also provides a preparation method and application of the compound. The compound has certain activity of inhibiting AKT1 kinase and anti-cell proliferation activity, and is used for preparing antitumor drugs.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis and medicine, and particularly relates to a pyrrolopyrimidine compound containing piperidine as well as a preparation method and application thereof.
Background
Protein kinase B (also known as AKT) is a serine/threonine kinase and belongs to the AGC kinase family. AKT possesses three subtypes, i.e., AKT1, AKT2, AKT3, which are encoded by different genes, but they have about 80% homology in the entire gene sequence. The three subtypes of AKT have mutually overlapped and different functions, and the activities of inhibiting the three subtypes of AKT1, AKT2 and AKT3 are closely related to the induction of cancer cell apoptosis and the reduction of tumor growth and the reversal of tumor resistance. Studies have shown that abnormally activated AKT is present in a number of solid tumors (prostate, colon, breast, melanoma) and hematological malignancies (lymphoma). (see Yang D, Wang P, Liu J, et al. DesIgn, syntheses and devaluate ion of novel index derivative as AKT In vivo-based assays, 2014,22(1): 366-73; LIU T, Zhan W, Wang Y, et al. Structure-based assays, synthsis and IoblogIcal ion of phosphatidylmethylium derivative as Akt1InhIbItors [ J, European Journal of MedInrather Chem, IsId, 73: 167) T Is phosphatIdylInosItol 3-kInase (phospho-kInase) survival signal (see III) 3523. the growth of tumour cells Is significantly inhibited by the growth of kInase I/mTOR 3. the growth of tumour cells Is significantly inhibited by the growth of tumour cells as AKT/III In vitro kInase (see III) 3. the growth of tumour cells as well as the growth inhibition of growth of tumour cells as well as the growth of tumour growth inhibition of tumour cells as well as the growth of tumour cells as the growth of tumour cells as well as the growth inhibition of tumour growth of tumour cell growth of tumour cells as I/survival signal of III, see Pi 3. Purpork, III .). Therefore, AKT would be a very promising target for tumor therapy, and inhibition of AKT would be a new strategy for molecular targeted therapy. Although various AKT InhIbItors have been introduced into clinical or preclinical studies such as GDC0068, AZD5363, GSK2110183, GSK2141795, MK2206, ARQ-092, BAY1125976, PerifosIne, etc. (see B.R. Huck, I.Mochalkin, Recent progress devices cl Icalcall relevant ATP-completIve Akt InhbItors, [ J ] BIoorganic & MedIcInal ChemIstry letters, 2017,27: 2838-. Therefore, the development of novel high-efficiency, low-toxicity and high-selectivity AKT inhibitors is repeated and far away, and the related reports of the compounds are not found in the prior art.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a piperidine-containing pyrrolopyrimidine compound which has certain PC-3 cell growth inhibitory activity and AKT1 kinase inhibitory activity, and also aims to provide a preparation method and application of the compound.
The technical scheme of the invention is as follows:
piperidine-containing pyrrolopyrimidine compounds
A pyrrolopyrimidine compound containing substituted piperidine or a pharmaceutically acceptable salt thereof has a structure represented by the following general formula (I) or (II):
wherein R is1Hydrogen, mono-halogen substitution, di-halogen substitution, methoxy, alkane;R2hydrogen, chlorine, bromine; r3Hydrogen, amino, substituted piperidine, pyrrole, morpholine, substituted piperazine; n is 0 or 1.
Preferred according to the invention are those R of the general formula (I) or (II)1Is hydrogen, 4-chloro, 4-bromo, 4-fluoro, 4-methoxy, 4-tert-butyl, 3-bromo, 3, 4-dichloro or 2, 4-dichloro; r2Is hydrogen, chlorine or bromine; r3Is hydrogen, amino, dimethylamino, morpholine, piperazine, N-methylpiperazine, 4-hydroxypiperidine, acetylpiperazine, phenylpiperazine, isopropylaminomethylene, piperidine, pyrrole or 4-piperidinyl.
Further preferred, formula (I) or (II) is one of the following compounds:
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2-phenylethanone (I-a1),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone (I-a2),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone (I-a3),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone (I-a4),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone (I-a5),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 6-dichlorophenyl) ethanone (I-a6),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (3, 4-dichlorophenyl) ethanone (I-a7),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (3-bromophenyl) ethanone (I-a8),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methoxyphenyl) ethanone (I-a9),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-tert-butylphenyl) ethanone (I-a10),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methylphenyl) ethanone (I-a11),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-phenylpropan-1-one (I-a12),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3- (4-fluorophenyl) propan-1-one (I-a13),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3- (4-bromophenyl) propan-1-one (I-a14),
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone (I-a15),
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone (I-a16),
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone (I-a17),
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone (I-a18),
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone (I-a19),
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone (I-a20),
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone (I-a21),
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone (I-a22),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2-thiomorpholinone (I-a23),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) ethanone (I-a24),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) ethanone (I-a25),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-acetylpiperazin-1-yl) ethanone (I-a26),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (dimethylamino) ethanone (I-a27),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-ylamino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) ethanone (I-a28),
1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (piperidin-1-yl) ethanone (I-a29),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (piperidin-4-yl) ethanone (I-a30),
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propan-1-one (I-a31),
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propan-1-one (I-a32),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) acetamide (II-a1),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (dimethylamino) acetamide (II-a2),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2-amino-2- (4-chlorophenyl) acetamide (II-a3), N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -3-hydroxy-2-phenylpropanamide (II-a4),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -3- (isopropylamino) propionamide (II-a5),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-bromophenyl) -3- (isopropylamino) propionamide (II-a6),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2-thiomorpholinoacetamide (II-a7),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2-morpholineacetamide (II-a8),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (piperazin-1-yl) acetamide (II-a9),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-hydroxypiperidin-1-yl) acetamide (II-a10),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-acetylpiperazin-1-yl) acetamide (II-a11),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) acetamide (II-a12),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) acetamide (II-a13),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) acetamide (II-a14),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -4- (4-chlorophenyl) piperidine-4-carboxamide (II-a15),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (piperidin-1-yl) acetamide (II-a16),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (pyrrol-1-yl) acetamide (II-a17),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (dimethylamino) acetamide (II-a18),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2-amino-2- (4-chlorophenyl) acetamide (II-a19),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -3-hydroxy-2-phenylpropanamide (II-a20),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -3- (isopropylamino) propionamide (II-a21),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propanamide (II-a22),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) acetamide (II-a23),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (piperazin-1-yl) acetamide (II-a24),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) acetamide (II-a25),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-hydroxypiperidin-1-yl) acetamide (II-a26),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) acetamide (II-a27),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -4- (4-chlorophenyl) piperidine-4-carboxamide (II-a28),
N- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (dimethylamino) acetamide (II-a29),
N- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -3-hydroxy-2-phenylpropanamide (II-a30),
N- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propanamide (II-a31),
N- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) acetamide (II-a32),
N- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) acetamide (II-a33),
N- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) acetamide (II-a 34).
Preparation method of pyrrolopyrimidine compound containing piperidine
The preparation method of the pyrrolopyrimidine compound containing piperidine comprises the following steps: 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine is used as a starting material, bromination or chlorination is carried out through free radicals to obtain an intermediate 2, the intermediate 1 or 2 reacts with p-toluenesulfonyl chloride to obtain an intermediate 3, the intermediate 3 and 1-tert-butyloxycarbonyl-4-aminopiperidine or 4-tert-butyloxycarbonyl-aminopiperidine undergo nucleophilic substitution, Boc protecting groups are removed to obtain an intermediate 5 or 8, the intermediate 5 or 8 and substituted acid undergo amide condensation, and Ts protecting groups are removed to obtain a target product I or II.
The synthetic route is as follows:
wherein R is1、R2、R3As described in general formula (I) or (II).
The reagents and reaction conditions used were as follows:
a) n-bromosuccinimide or N-chlorosuccinimide, N-Dimethylformamide (DMF), room temperature; b) p-toluenesulfonyl chloride (TsCl), sodium hydroxide solution, acetone, room temperature; c) 1-tert-butoxycarbonyl-4-aminopiperidine or 4-tert-butoxycarbonylaminopiperidine, N-Diisopropylethylamine (DIEA), microwave, 150 ℃, d) trifluoroacetic acid (TFA), Dichloromethane (DCM), room temperature, e) (1) a substituted acid, O-benzotriazol-tetramethyluronium Hexafluorophosphate (HBTU), DIEA, DMF, room temperature; (2) TFA, DCM, cesium carbonate at room temperature (3), tetrahydrofuran/methanol in a volume ratio of 3:1 at room temperature; or (1) substituted acid, HBTU, DIEA, DMF, room temperature; (2) cesium carbonate, tetrahydrofuran/methanol, volume ratio 3:1, room temperature.
According to the invention, the preparation method comprises the following steps:
1) dissolving 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine in N, N-Dimethylformamide (DMF), adding N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS) in batches, reacting at room temperature for 10-12H, pouring the reaction solution into 8-10 times of DMF ice water, separating out a large amount of off-white precipitate, filtering, washing a filter cake with purified water, and drying to obtain an intermediate 2 which is directly used in the next step without purification, wherein the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine: the mol ratio of the N-bromosuccinimide or the N-chlorosuccinimide is 1: 1.1.
2) the intermediate 2 or 4-chloro-7H-pyrrolo [2,3-d]Dissolving pyrimidine in acetone, adding sodium hydroxide solution, stirring in ice bath for 10-15mIn, and adding in batchesAdding p-toluenesulfonyl chloride, naturally heating to room temperature, reacting for 10-12h, precipitating a large amount of white solid, filtering, and filtering a filter cake by using a volume ratio of 1: 1, washing with acetone/water, and drying to obtain a middle part 3; in intermediate 3, R1Hydrogen, chlorine, bromine; in this reaction, the intermediate 2 or 4-chloro-7H-pyrrolo [2,3-d]The molar ratio of pyrimidine to tosyl chloride to sodium hydroxide is 1: 1.1: 1.2;
3) adding the intermediate 3 into N-methylpyrrolidone (NMP), sequentially adding DIEA, 1-tert-butoxycarbonyl-4-aminopiperidine or 4-tert-butoxycarbonyl aminopiperidine, heating the reaction liquid to 150 ℃ by microwave, reacting for 30-40mIn, quenching the reaction liquid by using 10 times of ice water, extracting by using ethyl acetate, washing an organic phase by using saturated amine chloride and saturated salt water, drying by using anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and performing vacuum distillation by using a solvent in a volume ratio of 1: 2 to obtain an intermediate 4 or an intermediate 7, wherein in the reaction, the molar ratio of the intermediate 2, DIEA, 1-tert-butyloxycarbonyl-4-aminopiperidine or 4-tert-butyloxycarbonyl-aminopiperidine is 1: 1.5: 1.2;
4) and (2) adding the intermediate 4 or the intermediate 7 solvent into dichloromethane, adding trifluoroacetic acid, reacting at room temperature for 4-5h, evaporating the reaction solution to dryness, adjusting the pH to 9 with saturated sodium carbonate aqueous solution, extracting with ethyl acetate, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and performing reaction on the product by using a solvent with a volume ratio of 1: 25 to obtain intermediate 5 or intermediate 8, wherein the volume ratio of trifluoroacetic acid to dichloromethane is 1: 3;
5) dissolving substituted acid in dichloromethane, sequentially adding HBTU and DIEA, stirring at room temperature for 15-20mIn, adding an intermediate 5 or an intermediate 8, reacting at room temperature for 10-12h, washing the reaction solution with saturated ammonium chloride and saturated salt water, and evaporating to obtain an oily substance, wherein in the reaction, the molar ratio of the substituted acid to the HBTU to the DIEA to the intermediate 5 or the intermediate 8 is 1: 1.05: 1.5: dissolving the oily matter in dichloromethane, adding trifluoroacetic acid, reacting at room temperature for 3-4h, evaporating the reaction solution to dryness, adjusting pH to 9 with saturated sodium carbonate, extracting with dichloromethane, washing the organic phase with saturated salt water, evaporating to dryness under reduced pressure to obtain solid, wherein the volume ratio of trifluoroacetic acid to dichloromethane is 1:3, and dissolving the solid in dichloromethane, and dissolving the solid in water to obtain the final productDissolving the mixture by using methanol/tetrahydrofuran in a volume ratio of 1:3, adding cesium carbonate, reacting at room temperature overnight, and directly adding dichloromethane in a volume ratio of 50:1 into a reaction solution: and (3) performing column chromatography purification on methanol to obtain a target product I or II, wherein in the step of reaction, the molar ratio of cesium carbonate to a solid obtained by the reaction is 4: 1; in this step, R in the target product I or II is substituted for acid, intermediate 5 or intermediate 81Is hydrogen, 4-chloro, 4-bromo, 4-fluoro, 4-methoxy, 4-tert-butyl, 3-bromo, 3, 4-dichloro, 2, 4-dichloro; r2Hydrogen, chlorine, bromine; r3Is hydrogen, amino, dimethylamino, morpholine, piperazine, N-methylpiperazine, 4-hydroxypiperidine, acetylpiperazine, phenylpiperazine, isopropylaminomethyl, substituted piperidine, pyrrole or 4-piperidinyl.
The room temperature of the invention is 15-25 ℃.
The substituted acid used in the above preparation method has a structure represented by the following general formula (iii):
wherein R is1、R3N is as described in general formula (I) or (II).
Preferably, according to the invention, the substituted acid of formula (iii) is one of the following:
application of pyrrolopyrimidine compound containing piperidine
The invention designs and synthesizes a series of pyrrolopyrimidine compounds containing piperidine with novel structures, which are shown in general formulas I and II, wherein the introduction of an R3 group (amino or hydroxyl side chain) is a remarkable characteristic of the series of compounds, the introduction of the amino or hydroxyl side chain is based on the summary analysis of the reported structure-activity relationship of AKT1inhibitors, and the amino or hydroxyl side chain structure is most likely to be an active necessary fragment. Through the design and modification mode, the compound with AKT1 kinase inhibitory activity is obtained, and the compound shows inhibitory activity on prostate cancer and lymphoma cell strains.
Therefore, the invention also provides the application of the piperidine-containing pyrrolopyrimidine compound or the medicinal salt thereof in preparing antitumor drugs. Preferably, the anti-tumor drug is an AKT 1-targeted anti-prostate cancer and lymphoma drug.
The invention also provides a pharmaceutical composition suitable for oral or parenteral administration, comprising the piperidine-containing pyrrolopyrimidine compounds of the invention and one or more pharmaceutically acceptable carriers or excipients.
Detailed Description
The present invention will be further described with reference to examples, but the following description is only for the purpose of explaining the present invention and does not limit the contents thereof. The conditions used in the examples can be further adjusted according to the existing equipment conditions, and the implementation conditions not specified are generally the conditions in routine experiments.
Example 1: preparation of Compound I and Compound II
Preparation of intermediate 2:
dissolving 4-chloro-pyrrolo [2,3-d ] pyrimidine (20mmol) in DMF (6mL), adding NBS or NCS (21mmol) in batches in ice bath, reacting at room temperature for 12h, pouring the reaction liquid into 80mL ice water, separating out a large amount of off-white solid, filtering, washing a filter cake with 15mL water, and drying to obtain an intermediate 2.
4, 5-dichloro-pyrrolo [2,3-d ] pyrimidine (2a)
Grey solid, yield 95%,1H NMR(400MHz,DMSO d6):＝12.87(s,1H),8.63(s,1H),7.91(s,1H).MS(ESI)m/z:188[M+H]+.
4-chloro-5-bromo-pyrrolo [2,3-d ] pyrimidine (2b)
Off-white solid, yield 95%,1H NMR(400MHz,DMSO):＝13.00(s,1H),8.64(s,1H),7.97(s,1H).MS(ESI)m/z:232[M+H]+.
preparation of intermediate 3:
4-chloro-pyrrolo [2,3-d ] pyrimidine or intermediate 2(10mmol) was dissolved in acetone (35mL), p-toluenesulfonyl chloride (11mmol) was added while cooling on ice, and 2.0mol/L NaOH solution (12.5mmol,6.25mL) was added, followed by stirring at room temperature overnight. After the reaction is finished, a large amount of white solid is separated out, filtered, and the filter cake is washed by 20mL of acetone/water (1: 1) and dried to obtain an intermediate 3.
4-chloro-7-p-toluenesulfonyl 7H-pyrrolo [2,3-d ] pyrimidine (3a)
Off-white solid, yield 95%,1H-NMR(400MHz,DMSO d6):＝8.83(s,1H),8.13(d,J＝4.0Hz,1H),8.05(d,J＝8Hz 2H),7.48(d,J＝8.0Hz,2H),6.96((d,J＝4.0Hz,1H),3.31(s，3H).MS(ESI)：m/z 308[M+H]+.
4, 5-dichloro-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidine (3b)
White solid, yield 94%, mp:201-,1H NMR(400MHz,DMSO)8.85(s,1H),8.43(s,1H),8.07(d,J＝8.3Hz,2H),7.49(d,J＝8.2Hz,2H),2.38(s,3H).
4-chloro-5-bromo-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidine (3c)
Off-white solid, yield 94%, mp:205-,1H NMR(400MHz,DMSO)8.85(d,J＝2.8Hz,1H),8.43(d,J＝2.5Hz,1H),8.07(t,J＝6.1Hz,2H),7.50(t,J＝6.3Hz,2H),2.38(d,J＝3.4Hz,3H).
preparation of intermediate 4 or 7:
dissolving intermediate 3(10mmol) completely with NMP (15mL), sequentially adding DIEA (15mmol,2.6mL), 1-tert-butoxycarbonyl-4-aminopiperidine or 4-tert-butoxycarbonyl-aminopiperidine (10.5mmol), reacting at 150 deg.C for 30 min with microwave, quenching the reaction solution with ice water (150mL), extracting with ethyl acetate (3X 30mL), washing the organic phase with saturated amine chloride (3X 20mL), saturated saline (3X 20mL), drying over anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and purifying by column chromatography (petroleum ether: ethyl acetate: 9: 1) to obtain intermediate 4 or 7
4- ((7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (4a)
Off-white solid, yield 95%, mp:138- & 141 ℃,1H NMR(400MHz,DMSO)8.23(s,1H),7.96(d,J＝8.3Hz,2H),7.67(d,J＝7.6Hz,1H),7.56(d,J＝3.9Hz,1H),7.43(d,J＝8.2Hz,2H),6.89(d,J＝4.0Hz,1H),4.26–4.14(m,1H),3.94(d,J＝9.8Hz,2H),2.78(d,J＝61.2Hz,2H),2.35(s,3H),1.87(d,J＝10.4Hz,2H),1.40(s,9H),1.37-1.32(m,2H).
4- ((5-chloro-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (4b)
White solid, yield 94%, mp:145-147 ℃,1H NMR(400MHz,DMSO)8.64(s,1H),8.30(s,1H),7.99(d,J＝8.3Hz,2H),7.46(d,J＝8.2Hz,2H),6.50(d,J＝8.0Hz,1H),4.27(dt,J＝11.3,9.4Hz,1H),3.97(d,J＝41.8Hz,2H),2.79(s,2H),1.82(d,J＝9.9Hz,2H),1.53(dd,J＝10.6,7.1Hz,2H),1.40(s,9H).
4- ((5-bromo-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (4c)
White solid, yield 93%, mp:170-,1H NMR(400MHz,DMSO)8.31(s,1H),8.00(d,J＝8.3Hz,2H),7.88(s,1H),7.46(d,J＝8.2Hz,2H),6.38(d,J＝7.8Hz,1H),4.23(br,1H),3.89(d,J＝11.4Hz,2H),2.91(br,2H),2.37(s,3H),1.91-1.84(m,2H),1.59-1.45(m,2H),1.40(s,9H).
(1- (7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) carboxylic acid tert-butyl ester (7a)
White solid, yield 89%,1H NMR(400MHz,DMSO)8.30–8.19(m,1H),7.98(d,J＝8.4Hz,2H),7.64(d,J＝4.1Hz,1H),7.43(d,J＝8.2Hz,2H),6.95(d,J＝4.2Hz,1H),4.47(d,J＝13.4Hz,2H),3.57(br,1H),3.19(t,J＝11.5Hz,2H),2.36(s,3H),1.82(d,J＝10.3Hz,2H),1.38(s,9H),1.36–1.28(m,2H).
(1- (5-chloro-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) carboxylic acid tert-butyl ester (7b)
White solid, yield 83%,1H NMR(400MHz,DMSO)8.36(s,1H),8.01(d,J＝8.0Hz,2H),7.97(s,1H),7.44(d,J＝8.0Hz,2H),4.14–4.00(m,2H),3.48(d,J＝31.7Hz,1H),3.10(t,J＝11.4Hz,2H),2.38(d,J＝5.7Hz,3H),1.82(d,J＝10.7Hz,2H),1.55–1.44(m,2H),1.37(s,9H).
(1- (5-bromo-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) carboxylic acid tert-butyl ester (7c)
White solid, yield 91%,1H NMR(400MHz,DMSO)8.37(s,1H),8.04(d,J＝8.0Hz,2H),8.02(s,1H),7.44(d,J＝8.4Hz,2H),4.11–3.97(m,2H),3.60–3.41(m,1H),3.08(t,J＝11.5Hz,2H),2.37(s,3H),1.83(d,J＝10.6Hz,2H),1.57-1.47(m,2H),1.37(s,9H).
synthesis of intermediate 5 and intermediate 8:
intermediate 4 or intermediate 7(4.0g) was dissolved in dichloromethane (10mL), and trifluoroacetic acid (3.5mL) was added to react at room temperature for 4 h. After the reaction, the solvent was evaporated to dryness under reduced pressure, the pH was adjusted to 9 with saturated sodium carbonate, and the mixture was extracted with dichloromethane (3 × 20mL), the organic layers were combined, the organic layer was washed with saturated brine (3 × 20mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give an oil, and intermediate 5 or intermediate 8 was isolated and purified by column chromatography, and the elution solvent was dichloromethane/methanol ═ 30: 1.
n- (piperidin-4-yl) -7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (5a)
Off-white solid, yield 93%, mp:214-216 ℃,1H NMR(400MHz,DMSO)9.02(br,2H),8.25(s,1H),7.98(dd,J＝12.7,7.9Hz,3H),7.57(d,J＝3.9Hz,1H),7.43(d,J＝8.2Hz,2H),7.03(d,J＝4.0Hz,1H),4.28(s,1H),3.31(d,J＝12.9Hz,2H),3.00(t,J＝11.2Hz,2H),2.36(s,3H),2.03(d,J＝13.3Hz,2H),1.78(d,J＝11.8Hz,2H).
5-chloro-N- (piperidin-4-yl) -7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (5b)
Off-white solid, yield 89%, mp:235-,1H NMR(400MHz,DMSO)8.76(br 2H),8.33(s,1H),8.27(s,1H),8.00(d,J＝8.4Hz,2H),7.46(d,J＝8.3Hz,2H),6.58(t,J＝10.1Hz,1H),4.38(dd,J＝11.2,7.4Hz,1H),4.21(d,J＝13.0Hz,2H),3.13(dd,J＝23.7,11.9Hz,2H),2.37(s,3H),2.06–1.93(m,2H),1.94–1.78(m,2H).
5-bromo-N- (piperidin-4-yl) -7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (5c)
Brown solid, yield 88%, mp:188-,1H NMR(400MHz,DMSO)8.71(br,2H),8.33(s,1H),8.00(d,J＝8.4Hz,2H),7.91(s,1H),7.46(d,J＝8.2Hz,2H),6.40(d,J＝7.4Hz,1H),4.27(br,1H),3.35(br,2H),2.99(t,J＝13.8Hz,2H),2.39(s,3H),2.11-2.05(m,2H),1.73-1.65(m,2H).
1- (7-p-toluenesulfonyl-7H-pyrrolo [2,3-b ] pyrimidin-4-yl) piperidin-4-amine (8a)
Off-white solid, yield 90%,1H NMR(400MHz,DMSO)8.23(s,1H),7.98(d,J＝8.3Hz,2H),7.63(d,J＝4.1Hz,1H),7.43(d,J＝8.2Hz,2H),6.94(d,J＝4.1Hz,1H),4.41(t,J＝16.0Hz,2H),3.19(t,J＝16.0Hz,2H),2.85(td,J＝9.6,4.8Hz,1H),2.35(s,3H),1.78(d,J＝9.5Hz,2H),1.30-1.13(m,2H).
1- (5-chloro-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-amine (8b)
Off-white solid, yield 92%,1H NMR(400MHz,DMSO)8.36(s,1H),8.01(d,J＝8.0Hz,2H),7.97(s,1H),7.44(d,J＝8.0Hz,2H),4.14–4.00(m,2H),3.48(d,J＝31.7Hz,1H),3.10(t,J＝11.4Hz,2H),2.38(d,J＝5.7Hz,3H),1.82(d,J＝10.7Hz,2H),1.55–1.44(m,2H).
1- (5-bromo-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-amine (8c)
Off-white solid, yield 91%,1H NMR(400MHz,DMSO)8.37(s,1H),8.04(d,J＝8.0Hz,2H),8.02(s,1H),7.44(d,J＝8.4Hz,2H),4.11–3.97(m,2H),3.60–3.41(m,1H),3.08(t,J＝11.5Hz,2H),2.37(s,3H),1.83(d,J＝10.6Hz,2H),1.57-1.47(m,2H).
preparation of target compounds I and II:
the preparation route of the target compounds I and II will follow two schemes a and B:
A) the substituted acid (1mmol) was dissolved in dichloromethane (6mL) in a25 mL eggplant-shaped bottle, HBTU (1.05mmol) and DIEA (1.5mmol) were added in this order, and the mixture was stirred at room temperature for 15 minutes, and then intermediate 5 or intermediate 8(1mmol) was added and reacted at room temperature overnight. After the reaction, the reaction mixture was washed with saturated ammonium chloride (3 × 20mL) and saturated brine (3 × 20mL), dichloromethane was evaporated under reduced pressure to obtain an oil, the oil was dissolved with dichloromethane (4), trifluoroacetic acid (1.3mL) was added to the solution, the reaction was carried out at room temperature for 4 hours, the solvent was evaporated under reduced pressure, the pH was adjusted to 9 with saturated sodium carbonate solution, dichloromethane (3 × 20mL) was used for extraction, the organic phases were combined, washed with saturated brine (3 × 20mL), dichloromethane was evaporated under reduced pressure to obtain a solid, and the solid was dissolved in methanol/tetrahydrofuran (1: and (3), (6) dissolving, adding cesium carbonate (4mmol), reacting at room temperature overnight, and separating and purifying the reaction liquid by direct column chromatography to obtain a target product I or II, wherein an elution solvent is dichloromethane/methanol (50): 1.
B) the substituted acid (1mmol) was dissolved in dichloromethane (6mL) in a25 mL eggplant-shaped bottle, HBTU (1.05mmol) and DIEA (1.5mmol) were added in this order, and the mixture was stirred at room temperature for 15 minutes, and then intermediate 5 or intermediate 8(1mmol) was added and reacted at room temperature overnight. After completion of the reaction, the reaction mixture was washed with saturated ammonium chloride (3 × 20mL) and saturated brine (3 × 20mL), and dichloromethane was distilled off under reduced pressure to obtain an oil, which was purified by methanol/tetrahydrofuran (1: 3(6mL), adding cesium carbonate (4mmol), reacting at room temperature overnight, and separating and purifying the reaction liquid by direct column chromatography to obtain a target product I or II, wherein an elution solvent is dichloromethane/methanol (50: 1.
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2-phenylethanone (I-a1)
White solid, yield 69%, mp: 197 ℃ and 200 ℃,1H NMR(400MHz,DMSO)11.51(s,1H),8.09(s,1H),7.27-7.23(m,6H),7.06(s,1H),6.57(s,1H),4.40(d,J＝13.1Hz,1H),4.29-4.26(m,1H),4.07–3.94(m,1H),3.74(d,J＝5.7Hz,2H),3.16(t,J＝12.0Hz,1H),2.76(t,J＝11.8Hz,1H),1.92(t,J＝11.6Hz,2H),1.39–1.24(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone (I-a2)
White solid, yield 64%, mp: 197 at the temperature of 201 ℃,1H NMR(400MHz,DMSO)11.47(s,1H),8.08(s,1H),7.29(dd,J＝8.2,5.8Hz,2H),7.15(dd,J＝15.6,6.7Hz,3H),7.09–7.02(m,1H),6.55(s,1H),4.38(d,J＝12.7Hz,1H),4.29(br,1H),4.02(d,J＝13.4Hz,1H),3.74(q,J＝15.1Hz,2H),3.17(dd,J＝14.5,9.5Hz,1H),2.75(t,J＝11.6Hz,1H),1.92(br,2H),1.29(dd,J＝22.2,12.2Hz,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone (I-a3)
White solid, yield 75%, mp: at the temperature of 270 ℃ and 273 ℃,1H NMR(400MHz,DMSO)11.49(s,1H),8.08(s,1H),7.38(d,J＝8.0Hz,2H),7.22(t,J＝8.0Hz,1H),7.19(d,J＝8.0Hz,1H),7.05(dd,J＝4.0Hz,1H),6.55(t,J＝4.0Hz,1H),4.38(t,J＝11.4Hz,1H),4.27(m,1H),3.75(dd,J＝8.0Hz 1H),3.16(t,J＝12.8Hz,1H),2.75(t,J＝12.8Hz,1H),1.94(m,2H),1.37(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone (I-a4)
White solid, yield 74%, mp: 267-271 ℃,1H NMR(400MHz,DMSO)11.47(s,1H),8.09(s,1H),7.51(d,J＝7.6Hz,2H),7.22(d,J＝7.7Hz,3H),7.05(s,1H),6.55(s,1H),4.38(d,J＝12.4Hz,1H),4.28(br,1H),4.00(d,J＝13.6Hz,1H),3.73(q,J＝15.5Hz,2H),3.17(t,J＝12.4Hz,1H),2.76(t,J＝11.5Hz,1H),2.02–1.87(m,2H),1.31-1.25(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone (I-a5)
White solid, yield 77%, mp: 202-205 deg.c,1H NMR(400MHz,DMSO)11.50(s,1H),8.11(s,1H),7.58(s,1H),7.37(dd,J＝20.3,5.1Hz,2H),7.26(d,J＝7.7Hz,1H),7.06(s,1H),6.59(s,1H),4.36(m,2H),4.05(m,1H),3.85(q,J＝16.3Hz,2H),3.24(t,J＝12.0Hz,1H),2.82(t,J＝11.7Hz,1H),2.03-1.99(m,2H),1.61–1.29(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 6-dichlorophenyl) ethanone (I-a6)
White solid, yield 75%, mp: 271, 273 ℃ of the temperature control agent,1H NMR(400MHz,DMSO)11.49(s,1H),8.11(s,1H),7.46(d,J＝8.0Hz,2H),7.35–7.23(m,2H),7.08(s,1H),6.57(s,1H),4.37(m,2H),4.15(d,J＝13.7Hz,1H),4.03(q,J＝16.6Hz,2H),2.80(t,J＝11.6Hz,1H),2.65(b.r.,1H),2.06(d,J＝11.2Hz,1H),1.96(d,J＝10.8Hz,1H),1.63–1.49(m,1H),1.47-1.39(m,1H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (3, 4-dichlorophenyl) ethanone (I-a7)
White solid, yield 68%, mp: 222-224 deg.c,1H NMR(400MHz,DMSO)11.49(s,1H),8.09(s,1H),7.63–7.44(m,2H),7.23(dd,J＝12.5,8.0Hz,2H),7.06(s,1H),6.53(s,1H),4.39-4.28(m,2H),4.03(d,J＝13.4Hz,1H),3.79(q,J＝15.6Hz,2H),3.19(t,J＝12.6Hz,1H),2.77(t,J＝12.6Hz,1H),1.96(b.r.,2H),1.37(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (3-bromophenyl) ethanone (I-a8)
White solid, yield 79%, mp: 211-213 deg.c of water for the first time,1H NMR(400MHz,DMSO)11.49(s,1H),8.09(s,1H),7.58(d,J＝8.2Hz,1H),7.53(s,1H),7.23(dd,J＝12.5,8.0Hz,2H),7.06(s,1H),6.56(s,1H),4.39-4.31(m,2H),4.02(d,J＝10.8Hz,1H),3.90–3.71(m,2H),3.28–3.13(m,1H),2.77(t,J＝13.2Hz,1H),1.94(s,2H),1.41-1.36(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methoxyphenyl) ethanone (I-a9)
White solid, yield 68%, mp: 210-212 deg.c,1H NMR(400MHz,DMSO)11.48(s,1H),8.10(s,1H),7.21(s,1H),7.18(d,J＝8.6Hz,2H),7.05(s,1H),6.88(d,J＝8.6Hz,2H),6.56(s,1H),4.40(d,J＝13.2Hz,1H),4.35–4.22(m,1H),4.01(d,J＝13.7Hz,1H),3.73(s,3H),3.72–3.60(m,2H),3.14(t,J＝13.1Hz,1H),2.74(t,J＝11.7Hz,1H),1.95-1.85(m,2H),1.41–1.22(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-tert-butylphenyl) ethanone (I-a10)
White solid, yield 65%, mp: 213-215 ℃ of the mixed gas,1H NMR(400MHz,DMSO)11.49(s,1H),8.10(s,1H),7.33(d,J＝8.2Hz,2H),7.22(d,J＝7.7Hz,1H),7.17(d,J＝8.2Hz,2H),7.09–7.03(m,1H),6.57(s,1H),4.39(d,J＝13.2Hz,1H),4.34–4.24(m,1H),4.02(d,J＝13.2Hz,1H),3.69(s,2H),3.16(t,J＝12.1Hz,1H),2.76(t,J＝11.8Hz,1H),1.94(d,J＝10.3Hz,2H),1.37(ddd,J＝15.3,12.7,4.2Hz,2H),1.27(s,9H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methylphenyl) ethanone (I-a11)
White solid, yield 67%, mp: 236-238 ℃,1H NMR(400MHz,DMSO)11.50(s,1H),8.09(s,1H),7.23(d,J＝7.6Hz,1H),7.18–7.09(m,4H),7.05(s,1H),6.56(s,1H),4.40(d,J＝13.2Hz,1H),4.29-4.26(m,1H),3.99(d,J＝13.3Hz,1H),3.79–3.60(m,2H),3.14(t,J＝12.1Hz,1H),2.74(t,J＝11.7Hz,1H),2.27(s,3H),1.91(t,J＝12.7Hz,2H),1.39–1.23(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-phenylpropan-1-one (I-a12)
White solid, yield 84%, mp:167-,1H NMR(400MHz,DMSO)11.47(s,1H),8.09(s,1H),7.36–7.12(m,6H),7.05(s,1H),6.55(s,1H),4.39(d,J＝13.0Hz,1H),4.35–4.21(m,1H),3.91(d,J＝14.1Hz,1H),3.12(t,J＝12.0Hz,1H),2.83(t,J＝7.7Hz,2H),2.73(t,J＝11.6Hz,1H),2.68–2.61(m,2H),1.94(s,2H),1.47–1.28(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3- (4-fluorophenyl) propan-1-one (I-a13)
White solid, yield 67%, mp: 210-214 deg.c,1H NMR(400MHz,DMSO)11.48(s,1H),8.10(s,1H),7.35–7.24(m,2H),7.19(d,J＝7.6Hz,1H),7.08(dd,J＝15.7,6.5Hz,3H),6.56(s,1H),4.39(d,J＝12.8Hz,1H),4.28(s,1H),3.92(d,J＝16.3Hz,1H),3.12(t,J＝12.0Hz,1H),2.82(t,J＝7.5Hz,2H),2.73(t,J＝12.1Hz,1H),2.64(t,J＝7.5Hz,2H),1.94(s,2H),1.38(dd,J＝21.7,10.6Hz,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3- (4-bromophenyl) propan-1-one (I-a14)
White solid, yield 64%, mp: 271, 274 ℃,1H NMR(400MHz,DMSO)12.10(s,1H),8.23(s,1H),7.56(s,1H),7.27(br,4H),7.18(s,1H),6.79(s,1H),4.43(br,1H),4.21(br,1H),3.94(br,1H),3.18–3.07(m,1H),2.95–2.77(m,2H),2.82–2.55(m,3H),2.08–1.82(m,2H),1.53-1.35(m,2H).
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone (I-a15)
White solid, yield: 58%, mp: 185-187 ℃ in sequence,1H NMR(400MHz,DMSO)11.99(s,1H),8.16(s,1H),7.31(s,1H),7.30–7.24(m,2H),7.13(t,J＝8.8Hz,2H),6.16(d,J＝6.8Hz,1H),4.36(d,J＝11.5Hz,2H),3.99(d,J＝13.5Hz,1H),3.82–3.65(m,2H),3.18(t,J＝12.3Hz,1H),2.77(t,J＝12.0Hz,1H),1.95-1.85(m,2H),1.54-.145(m,2H).
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone (I-a16)
White solid, yield 54%, mp: 191-193 ℃ of the temperature of the reaction kettle,1H NMR(400MHz,DMSO)11.91(s,1H),8.15(s,1H),7.37(d,J＝8.4Hz,2H),7.30(d,J＝2.4Hz,1H),7.27(d,J＝8.4Hz,2H),6.09(d,J＝7.9Hz,1H),4.35(d,J＝13.7Hz,2H),3.98(d,J＝13.9Hz,1H),3.84–3.60(m,2H),3.18(t,J＝12.6Hz,1H),2.77(t,J＝11.5Hz,1H),1.95-1.92(m,2H),1.55–1.42(m,2H).
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone (I-a17)
Off-white solid, yield 64%, mp: 182-184 ℃, the temperature of the reaction kettle is changed,1H NMR(400MHz,DMSO)11.98(s,1H),8.19(d,J＝28.2Hz,1H),7.50(d,J＝8.2Hz,2H),7.36–7.24(m,1H),7.21(d,J＝8.1Hz,2H),6.09(d,J＝7.8Hz,1H),4.35(d,J＝11.3Hz,2H),3.98(d,J＝13.1Hz,1H),3.81–3.63(m,2H),3.18(t,J＝12.1Hz,1H),2.77(t,J＝11.9Hz,1H),1.95-1.92(m,2H),1.57-1.44(m,2H).
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone (I-a18)
White solid, yield 57%, mp: 217-219 deg.c,1H NMR(400MHz,DMSO)11.94(s,1H),8.16(s,1H),7.59(d,J＝1.9Hz,1H),7.39(dd,J＝8.2,2.0Hz,1H),7.35(s,1H),7.34–7.29(m,1H),6.14(d,J＝7.9Hz,1H),4.40-4.33(m,2H),4.02(d,J＝14.2Hz,1H),3.85(s,2H),3.26(t,J＝12.0Hz,1H),2.81(t,J＝11.7Hz,1H),2.07–1.87(m,2H),1.69-1.47(m,2H).
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone (I-a19)
Light yellow solid, yield: 56%, mp: 155 ℃ at 157 ℃ in addition to the temperature,1H NMR(400MHz,DMSO)12.02(s,1H),8.17(s,1H),7.36(s,1H),7.28(q,J＝8.0Hz,5H),6.03(d,J＝7.8Hz,1H),4.32-4.29(m,2H),3.99-3.94(m,1H),3.79–3.64(m,2H),3.21(t,J＝13.9Hz,1H),2.84(t,J＝11.1Hz,1H),1.98-1.96(m,2H),1.48-1.40(m,2H).
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone (I-a20)
Light yellow solid, yieldRate 56%, mp: 202-205 deg.c,1H NMR(400MHz,DMSO)12.03(s,1H),8.16(s,1H),7.37(t,J＝5.4Hz,2H),7.27(d,J＝8.4Hz,2H),6.04(d,J＝7.7Hz,1H),4.35-4.29(m,2H),3.97-3.94(m,1H),3.81–3.67(m,2H),3.22(t,J＝11.7Hz,1H),2.84(t,J＝11.3Hz,1H),1.99-1.91(m,2H),1.54–1.33(m,2H).
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone (I-a21)
Brown solid, yield 52%, mp: 192 deg.c and 195 deg.c,1H NMR(400MHz,DMSO)12.04(s,1H),8.16(s,1H),7.51(d,J＝8.4Hz,2H),7.36(s,1H),7.21(d,J＝8.4Hz,2H),6.03(d,J＝7.7Hz,1H),4.38–4.25(m,2H),3.97-3.94(m,1H),3.78(s,2H),3.22(t,J＝11.6Hz,1H),2.85(t,J＝11.3Hz,1H),2.05–1.93(m,2H),1.57–1.34(m,2H).
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone (I-a22)
White solid, yield 58%, mp:170 ℃ and 173 ℃ below zero,1H NMR(400MHz,DMSO)12.05(s,1H),8.18(s,1H),7.58(d,J＝2.0Hz,1H),7.37-7.34(m,3H),6.08(d,J＝7.7Hz,1H),4.47–4.22(m,2H),4.01-3.97(m,1H),3.85(s,2H),3.29(d,J＝11.5Hz,1H),2.88(t,J＝11.3Hz,1H),2.07-1.99(,2H),1.70–1.42(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2-thiomorpholinone (I-a23)
White solid, yield 74%, mp: the temperature of the mixture is 98-102 ℃,1H NMR(400MHz,DMSO)11.46(s,1H),8.08(s,1H),7.43(d,J＝7.3Hz,4H),7.18(d,7.7Hz,1H),7.05(d,J＝13.8Hz,1H),6.54(d,J＝13.2Hz,1H),4.80(s,1H),4.43(d,J＝11.6Hz,1H),4.22(m,2H),3.01(t,J＝12.0Hz,1H),2.87–2.62(m,5H),2.60-2.55(m,4H),2.03-1.78(m,2H),1.56–1.13(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) ethanone (I-a24)
Light yellow solid, yield 67%, mp: 132-135 deg.c,1H NMR(400MHz,DMSO)11.47(s,1H),8.07(s,1H),7.44(dt,J＝22.4,7.5Hz,4H),7.11(d,J＝7.8Hz,1H),7.04(d,J＝11.6Hz,1H),6.53(d,J＝20.6Hz,1H),4.56(d,J＝11.8Hz,1H),4.44–4.18(m,3H),3.25–3.15(m,1H),3.04(t,J＝12.2Hz,1H),2.67(br,4H),2.39(br,4H),2.14(s,3H),1.99–1.79(m,2H),1.48–1.29(m,1H),1.23–1.10(m,1H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) ethanone (I-a25)
White solid, yield 74%,1H NMR(400MHz,DMSO)11.53(br,1H),8.09(d,J＝4.9Hz,1H),7.53(s,4H),7.21(t,J＝7.8Hz,2H),7.07(d,J＝12.4Hz,1H),6.91(d,J＝7.9Hz,2H),6.79(t,J＝7.0Hz,1H),6.55(d,J＝25.3Hz,1H),4.78(s,1H),4.42(d,J＝11.3Hz,1H),4.27(br,2H),3.32–2.97(m,5H),2.92–2.55(m,4H),2.06–1.74(m,2H),1.51-1.38(m,1H),1.34–1.05(m,1H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-acetylpiperazin-1-yl) ethanone (I-a26)
White solid, yield 75%,1H NMR(400MHz,DMSO)11.48(d,J＝10.0Hz,1H),8.08(d,J＝4.9Hz,1H),7.46(p,J＝8.6Hz,4H),7.24(d,J＝7.7Hz,0.5H),7.13(d,J＝7.6Hz,0.5H),7.09–7.02(m,1H),6.54(d,J＝19.6Hz,1H),4.71(d,J＝10.9Hz,1H),4.41(d,J＝12.7Hz,1H),4.21(dd,J＝26.8,16.4Hz,2H),3.39(br,4H),3.21(t,J＝12.1Hz,0.5H),3.02(t,J＝12.1Hz,0.5H),2.82–2.65(m,1H),2.42(br,4H),2.03–1.73(m,5H),1.55–1.27(m,1H),1.25-1.14(m,1H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (dimethylamino) ethanone (I-a27)
Off-white solid, yield 61%, mp: 134 deg.c, 137 deg.c,1H NMR(400MHz,DMSO)11.47(d,J＝8.0Hz,1H),8.09(t,J＝8.8Hz,1H),7.46(dq,J＝16.8,8.3Hz,4H),7.12(d,J＝7.8Hz,1H),7.04(d,J＝11.4Hz,1H),6.53(d,J＝16.8Hz,1H),4.52(s,1H),4.41(d,J＝10.2Hz,1H),4.28-4.16(m,2H),3.01(t,J＝12.3Hz,1H),2.84–2.60(m,1H),2.27–2.07(m,6H),1.99–1.74(m,2H),1.49–1.27(m,1H),1.29-1.11(d,J＝9.3Hz,1H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-ylamino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) ethanone (I-a28)
White solid, yield 69%, mp: 121-124 deg.c,1H NMR(400MHz,DMSO)11.48(d,J＝8.6Hz,1H),8.08(d,J＝3.9Hz,1H),7.47(dt,J＝15.2,8.4Hz,4H),7.19(7.7Hz,1H),7.05(d,J＝12.5Hz,1H),6.54(d,J＝23.8Hz,1H),4.69(d,J＝13.5Hz,1H),4.40(d,J＝12.8Hz,1H),4.24(dd,J＝20.2,13.5Hz,2H),3.46(d,J＝13.3Hz,1H),3.21(d,J＝9.5Hz,2H),3.05(t,J＝12.3Hz,1H),2.80-2.65(m,1H),2.19(s,3H),2.01-1.81(m,2H),1.55-1.33(m,1H),1.18-1.10(m,1H).HRMS(ESI):m/z for C23H27BrCl2N6O[M+H]+,calculated 553.0807,found553.0884
1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (piperidin-1-yl) ethanone (I-a29)
White solid, yield 59%, mp: 142-146 deg.C,1H NMR(400MHz,DMSO)11.49(s,1H),8.08(d,J＝4.5Hz,1H),7.43(dd,J＝18.5,7.1Hz,4H),7.19(7.7Hz,1H),7.05(d,J＝10.2Hz,1H),6.54(d,J＝17.5Hz,1H),4.57(s,1H),4.42-4.25(m,3H),3.22-3.03(m,1H),2.84–2.61(m,1H),2.37(br,4H),2.01-1.84(m,2H),1.56-1.27(m,7H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (piperidin-4-yl) ethanone (I-a30)
White solid, yield 64%, mp: the temperature of the mixture is 96-99 ℃,1H NMR(400MHz,DMSO)11.94(br,1H),8.11(s,1H),7.50(d,J＝8.4Hz,2H),7.29(d,J＝6.5Hz,3H),5.99(d,J＝7.6Hz,1H),4.19(br,1H),3.28(d,J＝12.4Hz,2H),3.05(t,J＝12.1Hz,2H),2.98–2.93(m,2H),2.76(t,J＝12.0Hz,2H),2.33(d,J＝13.4Hz,2H),2.13(s,2H),1.74(br,2H),1.30(br,2H).
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propan-1-one (I-a31)
White solid, yield 51%, mp: at the temperature of between 88 and 92 ℃,1H NMR(400MHz,DMSO)11.94(br,1H),8.13(d,J＝4.3Hz,1H),7.66(d,J＝3.5Hz,1H),7.49–7.39(m,1H),7.40–7.27(m,2H),6.03(d,J＝7.7Hz,1H),4.42-4.31(m,4H),3.78(t,J＝13.0Hz,1H),3.03(dt,J＝24.4,11.8Hz,2H),2.83–2.63(m,3H),2.02-1.83(m,2H),1.71–1.32(m,2H),0.96(br,6H).
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propan-1-one (I-a32)
White solid, yield 52%, mp:106-,1H NMR(400MHz,DMSO)11.99(s,1H),8.14(d,J＝5.1Hz,1H),7.66(d,J＝6.9Hz,1H),7.50–7.41(m,1H),7.40–7.32(m,2H),5.84(d,J＝7.5Hz,1H),4.46–4.21(m,3H),3.74(dd,J＝29.6,13.9Hz,1H),3.30–3.15(m,1H),3.17–2.97(m,2H),2.87(dd,J＝24.4,14.8Hz,1H),2.79–2.61(m,2H),2.05–1.95(m,1H),1.87(dd,J＝12.7,4.5Hz,1H),1.71–1.59(m,1H),1.49(dd,J＝20.9,9.3Hz,1H),0.97(s,6H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) acetamide (II-a1)
White solid, yield 85%,1H NMR(400MHz,DMSO)11.70(s,1H),8.14(s,1H),8.10(d,J＝7.6Hz,1H),7.35(d,J＝8.4Hz,2H),7.27(d,J＝8.4Hz,2H),7.18(s,1H),6.58(s,1H),4.55(d,J＝13.4Hz,2H),3.87(s,1H),3.39(s,2H),3.23(t,J＝11.4Hz,2H),1.84(d,J＝12.4Hz,2H),1.43-1.34(m,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (dimethylamino) acetamide (II-a2)
White solid, yield 74%, mp: 209 at 212 c,1H NMR(400MHz,DMSO)11.69(s,1H),8.12(d,J＝14.9Hz,2H),7.41(d,J＝8.4Hz,4H),7.18(s,1H),6.57(s,1H),4.59(br,2H),3.89(s,1H),3.15(br,2H),2.10(s,6H),1.76(br,2H),1.45(br,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2-amino-2- (4-chlorophenyl) acetamide (II-a3)
White solid, yield 56%, mp: at 229-,1H NMR(400MHz,DMSO)11.68(s,1H),8.13(s,1H),8.06(s,1H),7.38(d,J＝10.1Hz,4H),7.18(s,1H),6.58(s,1H),4.55(t,J＝13.9Hz,2H),4.32(s,1H),3.88(s,1H),3.20(br,2H),1.86-1.74(m,2H),1.45-1.34(m,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -3-hydroxy-2-phenylpropanamide (II-a4)
White solid, yield 59%,1H NMR(400MHz,DMSO)11.68(s,1H),8.13(s,1H),8.00(d,J＝7.7Hz,1H),7.32–7.25(m,4H),7.21(ddd,J＝6.3,4.3,2.2Hz,1H),7.18–7.15(m,1H),6.57(dd,J＝3.5,1.6Hz,1H),4.79(s,1H),4.53(dd,J＝28.7,13.6Hz,2H),4.00–3.83(m,2H),3.61–3.45(m,2H),3.20(dd,J＝25.8,12.3Hz,2H),1.88(d,J＝10.0Hz,1H),1.73(d,J＝10.0Hz,1H),1.48–1.36(m,1H),1.31–1.24(m,1H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -3- (isopropylamino) propionamide (II-a5)
White solid, yield 63%, mp: 162-165 deg.c,1H NMR(400MHz,DMSO)11.69(s,1H),8.22–8.05(m,2H),7.35(q,J＝8.5Hz,4H),7.17(s,1H),6.56(s,1H),4.53(dd,J＝29.1,13.5Hz,2H),3.89(s,1H),3.64(s,1H),3.26–3.12(m,3H),2.79(dd,J＝20.8,9.0Hz,2H),1.89(d,J＝13.2Hz,1H),1.73(d,J＝10.6Hz,1H),1.43(dd,J＝21.7,12.1Hz,1H),1.32–1.20(m,1H),0.99(d,J＝6.1Hz,6H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-bromophenyl) -3- (isopropylamino) propionamide (II-a6)
White solid, yield 58%, mp: 193 deg.c, 196 deg.c,1H NMR(400MHz,DMSO)11.70(s,1H),8.23–8.14(m,1H),8.13(s,1H),7.49(d,J＝8.3Hz,2H),7.27(d,J＝8.3Hz,2H),7.22–7.12(m,1H),6.56(d,J＝2.1Hz,1H),4.52(dd,J＝25.2,13.5Hz,2H),3.88(s,1H),3.65–3.50(m,1H),3.22(dd,J＝26.2,12.0Hz,2H),3.13–3.00(m,1H),2.71(dd,J＝10.6,5.1Hz,2H),1.88(d,J＝10.7Hz,1H),1.72(d,J＝10.6Hz,1H),1.49–1.29(m,2H),0.94(d,J＝6.1Hz,6H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2-thiomorpholinoacetamide (II-a7)
White solid, yield 74%, mp: 254-256 deg.c,1H NMR(400MHz,DMSO)11.69(s,1H),8.14(s,1H),8.10(d,J＝8.0Hz,1H),7.44–7.33(m,4H),7.21–7.15(m,1H),6.59(s,1H),4.58(br,2H),3.99(s,1H),3.92(s,1H),3.18(dd,J＝19.0,11.5Hz,2H),2.60(s,8H),1.85-1.71(m,2H),1.54–1.35(m,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2-morpholinoacetamide (II-a8)
Light yellow solid, yieldRate 65%, mp: 118 at a temperature of 121 c,1H NMR(400MHz,DMSO)11.68(s,1H),8.17–8.07(m,2H),7.42(q,J＝8.5Hz,4H),7.18(s,1H),6.57(s,1H),4.57(t,J＝12.3Hz,2H),3.97–3.82(m,1H),3.77(s,1H),3.57(s,4H),3.17(dd,J＝21.6,10.4Hz,2H),2.31-2.25(m,4H),1.82(d,J＝10.5Hz,1H),1.72(d,J＝10.5Hz,1H),1.55–1.31(m,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (piperazin-1-yl) acetamide (II-a9)
Light yellow solid, yield 64%, mp: 125 ℃ and 129 ℃,1H NMR (400MHz, DMSO)11.69(s,1H),8.18(d, J ═ 8.0Hz,1H),8.14(s,1H),7.41(s,4H),7.18(s,1H),6.57(s,1H),4.57(t, J ═ 11.1Hz,2H),3.92(br,2H),3.18(br,2H),3.00(br,4H),2.47(br,4H),1.79-1.68(m,2H), 1.53-1.34 (m,2H).
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-hydroxypiperidin-1-yl) acetamide (II-a10)
Off-white solid, yield 73%, mp: 116-119 deg.c,1H NMR(400MHz,DMSO)11.69(s,1H),8.13(d,J＝9.4Hz,1H),8.07(dd,J＝22.5,8.1Hz,1H),7.43–7.33(m,4H),7.21–7.15(m,1H),6.62–6.53(m,1H),4.66–4.50(m,3H),3.96–3.88(m,1H),3.84(d,J＝18.0Hz,1H),3.39–3.26(m,2H),3.20(br,2H),2.63–2.53(m,2H),1.98-1.89(m,1H),1.81–1.55(m,4H),1.54–1.34(m,3H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-acetylpiperazin-1-yl) acetamide (II-a11)
White solid, yield 71%, mp: 226-,1H NMR(400MHz,DMSO)11.69(s,1H),8.15(d,J＝7.2Hz,2H),7.51–7.34(m,4H),7.25–7.02(m,1H),6.57(s,1H),4.58(t,J＝12.5Hz,2H),3.90(br,1H),3.84(s,1H),3.39(dd,J＝14.3,9.0Hz,4H),3.18(dd,J＝21.5,10.3Hz,2H),2.39–2.16(m,4H),1.95(s,3H),1.85-1.71(m,2H),1.53–1.33(m,2H).13C NMR(101MHz,DMSO)169.20,168.51,156.66,152.42,151.10,136.71,132.76(2C),130.84(2C),128.67,121.89,102.64,101.36,73.39,51.28,50.79,46.43,45.98,44.80(2C),41.17,31.79,31.46,21.59.
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) acetamide (II-a12)
White solid, yield 54%, mp:>270℃，1H NMR(400MHz,DMSO)11.68(s,1H),8.14(s,2H),7.49-7.40(m,3H),7.15(d,J＝18.1Hz,2H),6.57(s,1H),4.56(br,2H),4.00–3.63(m,2H),3.19(br,2H),2.23(br,8H),2.17(s,3H),1.93–1.71(m,2H),1.47(br,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) acetamide (II-a13)
White solid, yield 71%, mp: at 229-,1H NMR(400MHz,DMSO)11.77(s,1H),8.36(br,1H),8.15(s,1H),7.48(dd,J＝18.1,7.7Hz,4H),7.20(t,J＝7.7Hz,3H),6.90(d,J＝8.1Hz,2H),6.78(t,J＝7.1Hz,1H),6.60(s,1H),4.56(t,J＝15.7Hz,2H),4.11(br,1H),3.93(s,1H),3.29–3.05(m,6H),2.65(br,4H),1.87(d,J＝11.6Hz,1H),1.73(d,J＝11.2Hz,1H),1.55–1.35(m,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) acetamide (II-a14)
White solid, yield 61%, mp: 216-128 deg.c,1H NMR(400MHz,DMSO)11.62(s,1H),8.13(d,J＝7.9Hz,1H),8.07(s,1H),7.40(d,J＝8.5Hz,2H),7.33(d,J＝8.5Hz,2H),7.13–7.08(m,1H),6.50(dd,J＝3.3,1.5Hz,1H),4.49(t,J＝14.5Hz,2H),3.87(s,1H),3.79(s,1H),3.28(s,2H),3.13(d,J＝2.1Hz,1H),3.09(d,J＝10.7Hz,2H),2.13(s,3H),1.74(d,J＝10.4Hz,1H),1.61(d,J＝10.5Hz,1H),1.46–1.24(m,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -4- (4-chlorophenyl) piperidine-4-carboxamide (II-a15)
White solid, yield 46%, mp: 142-145 deg.c of the raw materials,1H NMR(400MHz,DMSO)11.69(s,1H),8.13(s,1H),7.35(q,J＝8.9Hz,5H),7.17(d,J＝3.6Hz,1H),6.56(d,J＝3.6Hz,1H),4.63(d,J＝13.3Hz,2H),3.98(s,1H),3.07(t,J＝12.0Hz,2H),2.80(d,J＝12.1Hz,2H),2.59(t,J＝11.3Hz,2H),2.40(dt,J＝16.6,10.2Hz,4H),1.71-1.58(m,4H),1.46–1.32(m,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (piperidin-1-yl) acetamide (II-a16)
White solid, yield 56%, mp: 240-,1H NMR(400MHz,DMSO)11.69(s,1H),8.15(s,1H),8.04(d,J＝8.0Hz,1H),7.43–7.30(m,4H),7.26–7.05(m,1H),6.59(ddd,J＝11.8,3.5,1.7Hz,1H),4.58(s,2H),3.91(s,1H),3.74(s,1H),3.18(dd,J＝20.4,9.8Hz,2H),2.26(s,4H),1.78(dd,J＝34.6,12.2Hz,2H),1.58-1.41(m,6H),1.33(t,J＝13.3Hz,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (pyrrol-1-yl) acetamide (II-a17)
White solid, yield 54%, mp: 195 deg.c, 198 deg.c,1H NMR(400MHz,DMSO)11.68(s,1H),8.14(s,1H),8.02(d,J＝8.1Hz,1H),7.46(d,J＝8.4Hz,2H),7.37(d,J＝8.5Hz,2H),7.20–7.14(m,1H),6.57(d,J＝2.0Hz,1H),4.59(d,J＝13.2Hz,2H),3.87(s,1H),3.69(s,1H),3.14(t,J＝13.2Hz,2H),2.41(s,2H),2.30(s,2H),1.81–1.70(m,2H),1.69(br,4H),1.55–1.35(m,2H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (dimethylamino) acetamide (II-a18)
Light yellow solid, yield 60%, mp: 198-201 ℃ of the raw materials,1H NMR(400MHz,DMSO)12.17(s,1H),8.26(s,1H),8.18(d,J＝7.9Hz,1H),7.49(s,1H),7.42(dd,J＝20.0,8.6Hz,4H),4.11(br,2H),3.83(br,1H),3.67(s,1H),3.03(br,2H),2.44(dd,J＝14.1,7.0Hz,2H),2.11(s,6H),1.84-1.73(m,2H),1.71–1.55(m,2H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2-amino-2- (4-chlorophenyl) acetamide (II-a19)
White solid, yield 55%, mp: 197 ℃ and 199 ℃ are adopted,1H NMR(400MHz,DMSO)12.14(s,1H),8.26(s,1H),8.11(d,J＝7.8Hz,1H),7.48(s,1H),7.43(d,J＝8.5Hz,2H),7.37(d,J＝8.5Hz,2H),4.34(s,1H),4.10(t,J＝13.2Hz,2H),3.82(br,1H),3.09(q,J＝12.4Hz,2H),1.88(d,J＝10.1Hz,1H),1.79(d,J＝10.9Hz,1H),1.71–1.49(m,2H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -3-hydroxy-2-phenylpropanamide (II-a20)
White solid, yield 53%, mp:205 at a temperature of 208 deg.c,1H NMR(400MHz,DMSO)12.15(s,1H),8.25(s,1H),8.06(s,1H),7.47(s,1H),7.30(d,J＝7.1Hz,4H),7.22(s,1H),4.79(s,1H),4.08(dd,J＝26.5,12.6Hz,2H),3.89(d,J＝48.1Hz,2H),3.55(d,J＝30.6Hz,2H),3.08(dd,J＝28.2,12.4Hz,2H),1.91(d,J＝10.5Hz,1H),1.75(d,J＝10.8Hz,1H),1.60(d,J＝9.9Hz,1H),1.47(d,J＝9.8Hz,1H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -3- (isopropylamino) propionamide (II-a21)
White solid, yield 57%, mp: 198-202 deg.c,1H NMR(400MHz,DMSO)12.14(s,1H),8.25(s,1H),8.22(d,J＝7.7Hz,1H),7.48(s,1H),7.36(q,J＝8.7Hz,4H),4.07(br,2H),3.83(s,1H),3.69–3.58(m,1H),3.11(t,J＝14.2Hz,3H),2.77(td,J＝12.0,5.9Hz,2H),1.91(d,J＝10.0Hz,1H),1.76(d,J＝13.7Hz,1H),1.68–1.53(m,1H),1.46(dd,J＝21.7,12.8Hz,1H),0.97(d,J＝6.2Hz,6H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propanamide (II-a22)
Yellow solid, yield 57%, mp: 179-182 deg.C,1H NMR(400MHz,DMSO)12.17(br,1H),8.39(d,J＝7.7Hz,1H),8.26(s,1H),7.60(d,J＝2.0Hz,1H),7.49(d,J＝10.3Hz,2H),7.41(dd,J＝8.5,2.1Hz,1H),4.08(br,3H),3.90(s,1H),3.12(br,3H),2.87(br,2H),1.92-1.81(m,2H),1.47-1.66(m,2H),1.02(s,6H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) acetamide (II-a23)
White solid, yield 66%,1H NMR(400MHz,DMSO)12.15(s,1H),8.25(d,J＝6.0Hz,1H),8.24(d,J＝7.5Hz,1H),7.54–7.45(m,3H),7.42(d,J＝8.5Hz,2H),7.19(t,J＝7.9Hz,2H),6.90(d,J＝8.1Hz,2H),6.76(t,J＝7.2Hz,1H),4.11(t,J＝12.3Hz,2H),3.93–3.77(m,2H),3.13(s,4H),3.11–3.01(m,2H),2.48-2.41(m,4H),1.88(d,J＝10.4Hz,1H),1.76(d,J＝10.3Hz,1H),1.62-1.51(m,2H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (piperazin-1-yl) acetamide (II-a24)
A pale yellow solid, yield 67%,1H NMR(400MHz,DMSO)12.16(s,1H),8.33–8.18(m,2H),7.53–7.33(m,5H),4.11(t,J＝12.6Hz,2H),3.99(s,1H),3.87(br,1H),3.20–2.82(m,6H),2.51–2.39(m,4H),1.89-1.75(m,2H),1.71–1.51(m,2H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) acetamide (II-a25)
White solid, yield 56%,1H NMR(400MHz,DMSO)12.16(s,1H),8.26(s,1H),8.17(d,J＝7.8Hz,1H),7.48(s,1H),7.42(dd,J＝18.4,8.3Hz,4H),4.10(t,J＝12.5Hz,2H),3.81(br,2H),3.06(dd,J＝22.2,10.9Hz,2H),2.33(br,8H),2.17(s,3H),1.86(d,J＝10.7Hz,1H),1.74(d,J＝11.8Hz,1H),1.60(dd,J＝24.9,12.1Hz,2H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-hydroxypiperidin-1-yl) acetamide (II-a26)
White solid, yield 64%,1H NMR(400MHz,DMSO)12.16(s,1H),8.26(s,1H),8.15(dd,J＝22.4,8.1Hz,1H),7.49(s,1H),7.40(d,J＝6.1Hz,4H),4.12(br,2H),3.87(d,J＝16.0Hz,2H),3.36(br,2H),3.08(br,2H),2.46(q,J＝7.1Hz,4H),2.03–1.76(m,4H),1.73–1.57(m,4H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) acetamide (II-a27)
Light cyan solid, yield 61%, mp: at the temperature of between 87 and 91 ℃,1H NMR(400MHz,DMSO)12.15(s,1H),8.28(s,1H),8.25(s,1H),7.49(s,1H),7.48(d,J＝8.0Hz,2H),7.41(d,J＝8.5Hz,2H),4.09(t,J＝14.4Hz,2H),3.97(s,1H),3.80(s,1H),3.21(br,1H),3.13(d,J＝15.1Hz,1H),3.09-2.99(m,2H),2.22(s,3H),1.84(d,J＝10.2Hz,1H),1.69(d,J＝12.1Hz,1H),1.61–1.45(m,2H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -4- (4-chlorophenyl) piperidine-4-carboxamide (II-a28)
Light yellow solid, yield: 53%, mp: the temperature of the mixture is 96-99 ℃,1H NMR(400MHz,MeOD)8.19(s,1H),7.48–7.30(m,5H),7.23(s,1H),4.28(d,J＝13.1Hz,2H),3.99(br,1H),3.23(d,J＝13.8Hz,2H),3.08(br,4H),2.63(d,J＝14.0Hz,2H),2.06(d,J＝11.1Hz,2H),1.86(d,J＝13.4Hz,2H),1.69–1.58(m,2H).HRMS(ESI):m/z for C23H26ClN6O[M+H]+,calculated 473.1545,found473.1620.
n- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (dimethylamino) acetamide (II-a29)
Yellow solid, yield 62%, mp: 124-127 deg.C,1H NMR(400MHz,DMSO)12.26(s,1H),8.27(s,1H),8.19(d,J＝8.0Hz,1H),7.55(s,1H),7.42(dd,J＝19.7,8.6Hz,4H),4.13–3.99(m,2H),3.81(s,1H),3.67(s,1H),3.02(dd,J＝18.9,10.7Hz,2H),2.09(s,6H),1.88–1.57(m,4H).
n- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -3-hydroxy-2-phenylpropanamide (II-a30)
Off-white solid, yield 58%, mp: 185-188 ℃ of the reaction kettle,1H NMR(400MHz,DMSO)12.24(s,1H),8.26(s,1H),8.07(d,J＝7.0Hz,1H),7.53(s,1H),7.39–7.14(m,5H),4.78(s,1H),4.11–3.89(m,3H),3.83(s,1H),3.55(d,J＝32.3Hz,2H),3.05(d,J＝10.2Hz,2H),1.90(br,1H),1.74(br,1H),1.63-1.50(m,2H).
n- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propanamide (II-a31)
Yellow solid, yield 58%, mp: 136 deg.c and 139 deg.c,1H NMR(400MHz,DMSO)12.25(s,1H),8.42(d,J＝7.7Hz,1H),8.27(s,1H),7.58(d,J＝2.0Hz,1H),7.54(s,1H),7.51(d,J＝8.5Hz,1H),7.40(dd,J＝8.5,2.2Hz,1H),4.07–3.98(m,3H),3.93–3.83(m,1H),3.14–2.98(m,3H),2.79–2.70(m,2H),1.90(d,J＝10.4Hz,1H),1.82(d,J＝10.2Hz,1H),1.65(dd,J＝18.3,9.2Hz,1H),1.60–1.53(m,1H),0.96(d,J＝2.5Hz,6H).
n- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) acetamide (II-a32)
Yellow solid, yield 57%, mp: 181-184 deg.c,1H NMR(400MHz,DMSO)12.25(s,1H),8.27(s,1H),8.18(d,J＝7.8Hz,1H),7.54(s,1H),7.41(dd,J＝18.5,8.6Hz,4H),4.05(t,J＝12.4Hz,2H),3.79(br,2H),3.03(dd,J＝22.2,10.9Hz,2H),2.79(br,4H),2.31(br,4H),2.15(s,3H),1.85(d,J＝12.1Hz,1H),1.74-1.55(m,3H).
n- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) acetamide (II-a33)
White solid, yield 64%, mp: 135-138 deg.c,1H NMR(400MHz,DMSO)12.25(s,1H),8.28(s,1H),8.25(d,J＝8.0Hz,1H),7.54(d,J＝2.3Hz,1H),7.46(dd,J＝27.8,8.5Hz,4H),7.19(t,J＝7.9Hz,2H),6.90(d,J＝8.1Hz,2H),6.76(t,J＝7.2Hz,1H),4.06(t,J＝12.2Hz,2H),3.92–3.82(m,2H),3.14-3.01(m,6H),2.49-2.39(m,4H),1.88(d,J＝10.0Hz,1H),1.81–1.54(m,3H).
n- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) acetamide (II-a34)
Light yellow solid, yield 63%, mp: 188-191 ℃,1H NMR(400MHz,DMSO)12.20(s,1H),8.31–8.23(m,2H),7.53(dd,J＝7.1,2.4Hz,1H),7.49(d,J＝8.5Hz,2H),7.41(d,J＝8.4Hz,2H),4.11–3.92(m,3H),3.77(dd,J＝15.5,11.8Hz,1H),3.21(s,1H),3.18–2.92(m,3H),2.22(s,3H),1.84(d,J＝10.3Hz,1H),1.74–1.50(m,3H).
EXAMPLE 2 determination of AKT1 kinase inhibitory Activity, anti-proliferative Activity of the Compounds on prostate cancer PC-3 cells and mantle lymphoma (Rec-1, Jeko-R, Maver, Z138, Mino) cells
The compounds I-a1 to I-a32 and II-a1 to II-a34 of example 1 were tested for biological activity as follows, and the results are shown in tables 1 and 2.
The AKT1 kinase inhibitory activity and the anti-proliferative activity of PC-3 and lymphoma cells of the compounds are performed by the methods reported in the literature, and the specific references are as follows: LIu Y, YIN Y, Zhang J, NomIe K, Zhang L, Yang D, Wang ML, ZhaoG.2016.DIscovery of 4- (PIPerazm-1-yl) -7H-pyrrolo [2,3-D ] pyrImIdeDerivatives as Akt InhIbItors. Arch Pharm (WeInheim)349:356-362.LIU Y, YIN Y, Zhang Z, LIC.J, Zhang H, Zhang D, JIang C, NomIe K, Zhang L, Wang M.L, ZhaoG.2017. Structrul OptIzatIon antibodies sheets pot terminal InhIhIhItors Ak J543: 138 EuvJ.
TABLE 1 inhibitory Activity of Compounds on AKT1 kinase and antiproliferative Activity of PC-3 cells
aMedian Inhibitory Concentration (IC) of compounds on AKT1 kinase50)
bND＝not detected
TABLE 2 antiproliferative activity of the compounds on lymphoma cells
aND＝not detected
The experimental result shows that most compounds have weak inhibiting activity on AKT1 kinase under the concentration of 1 mu M, wherein the inhibiting activity of the compounds I-a32, II-a21, II-a22, II-a28 and II-a31 on AKT1 is 69%, 88%, 78%, 79% and 68%, respectively, and the half inhibiting concentrations of the compounds on AKT1 kinase are 0.60 mu M, 0.29 mu M, 0.69 mu M, 0.23 mu M and 0.36 mu M. The inhibitory activity of the compounds I-a20, I-a32 and II-a28 on lymphoma cells is equivalent to that of the marketed drug of Imatinib (IBN), so that the compounds of the invention can be used as drugs for targeting AKT1 to prostate cancer and lymphoma.
Claims (9)
1. A substituted piperidine-containing pyrrolopyrimidine compound or a pharmaceutically acceptable salt thereof, characterized by having a structure represented by the following general formula (I):
wherein R is1Is single halogen substituted, multiple halogen substituted, methoxy; r2Hydrogen, chlorine, bromine; r3Is amino, dimethylamino, piperidine, pyrrole, morpholine, piperazine, N-methylpiperazine, acetyl piperazine, phenyl piperazine; n is 0 or 1.
2. The substituted piperidine-containing pyrrolopyrimidine compound according to claim 1, wherein R in the general formula (I)1Is 4-chloro, 4-bromo, 4-fluoro, 4-methoxy or 2, 4-dichloro; r2Is hydrogen, chlorine or bromine; r3Is dimethylamino, morpholine, N-methylpiperazine, acetylpiperazine, phenylpiperazine or 4-piperidyl.
3. A substituted piperidine-containing pyrrolopyrimidine compound, which is one of the following compounds:
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methoxyphenyl) ethanone,
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone,
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone,
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone,
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone,
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone,
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone,
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone,
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2-thiomorpholinone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-acetylpiperazin-1-yl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (dimethylamino) ethanone,
1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (piperidin-1-yl) ethanone.
4. The preparation method of the substituted piperidine-containing pyrrolopyrimidine compound according to claim 1, wherein 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine is used as a starting material, bromination or chlorination is carried out through a free radical reaction to obtain an intermediate 2, the intermediate 2 reacts with p-toluenesulfonyl chloride to obtain an intermediate 3, the intermediate 3 and 1-tert-butoxycarbonyl-4-aminopiperidine undergo nucleophilic substitution, then a protecting group is removed to obtain an intermediate 5, the intermediate 5 and a substituted acid undergo amide condensation, and then the protecting group is removed to obtain a target product I;
the synthetic route is as follows:
wherein R is1、R2、R3As described in general formula (I);
the substituted acid has a structure shown in the following general formula (III):
wherein R is1、R3N is as described in formula (I);
the reagents and reaction conditions used were as follows:
a) n-bromosuccinimide or N-chlorosuccinimide, N-Dimethylformamide (DMF), room temperature; b) p-toluenesulfonyl chloride, sodium hydroxide solution, acetone, room temperature; c) 1-tert-butoxycarbonyl-4-aminopiperidine, N-Diisopropylethylamine (DIEA), microwave, 150 ℃, d) trifluoroacetic acid (TFA), Dichloromethane (DCM), room temperature, e) (1) substituted acid, HBTU, DIEA, DMF, room temperature; (2) TFA, DCM, cesium carbonate at room temperature (3), tetrahydrofuran/methanol in a volume ratio of 3:1 at room temperature; or (1) substituted acid, HBTU, DIEA, DMF, room temperature; (2) cesium carbonate, tetrahydrofuran/methanol, volume ratio 3:1, room temperature.
5. The process for producing a substituted piperidine-containing pyrrolopyrimidine compound according to claim 4, which comprises the steps of:
1) dissolving 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine in N, N-Dimethylformamide (DMF), adding N-bromosuccinimide or N-chlorosuccinimide in batches, reacting at room temperature for 10-12H, pouring the reaction solution into 8-10 times of DMF ice water, separating out a large amount of off-white precipitate, filtering, washing a filter cake with purified water, and drying to obtain an intermediate 2, wherein the intermediate 2 is not purified and is directly used in the next step, and the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine: the mol ratio of the N-bromosuccinimide or the N-chlorosuccinimide is 1: 1.1;
2) reacting the intermediate 2 or 4-chloro-7H-pyrrolo [2,3-d]Dissolving pyrimidine in acetone, adding a sodium hydroxide solution, stirring for 10-15mIn in an ice bath, adding p-toluenesulfonyl chloride in batches, naturally heating to room temperature, reacting for 10-12h, separating out a large amount of white solid, filtering, and filtering a filter cake by using a filter mass in a volume ratio of 1: 1, washing with acetone/water, and drying to obtain a middle part 3; in intermediate 3, R1Hydrogen, chlorine, bromine; in this reaction, the intermediate 2 or 4-chloro-7H-pyrrolo [2,3-d]The molar ratio of pyrimidine to tosyl chloride to sodium hydroxide is 1: 1.1: 1.2;
3) adding the intermediate 3 into NMP, sequentially adding DIEA, 1-tert-butyloxycarbonyl-4-aminopiperidine, heating the reaction liquid to 150 ℃ by microwave, reacting for 30-40mIn, quenching the reaction liquid by using 10 times of ice water, extracting by using ethyl acetate, washing an organic phase by using saturated amine chloride and saturated salt water, drying by using anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and reacting by using a solvent prepared by the volume ratio of 1: 2 to obtain an intermediate 4, wherein in the reaction, the molar ratio of the intermediate 2, DIEA and 1-tert-butyloxycarbonyl-4-aminopiperidine is 1: 1.5: 1.2;
4) and (2) adding the intermediate 4 solvent into dichloromethane, adding trifluoroacetic acid, reacting at room temperature for 4-5h, evaporating the reaction solution to dryness, adjusting the pH to 9 by using saturated sodium carbonate aqueous solution, extracting by using ethyl acetate, washing an organic phase by using saturated salt, drying by using anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and reacting the solvent with a solvent prepared by a volume ratio of 1: 25 to give intermediate 5, which was purified by column chromatography using dichloromethane/methanol in which the ratio by volume of trifluoroacetic acid to dichloromethane was 1: 3;
5) dissolving substituted acid in dichloromethane, sequentially adding HBTU and DIEA, stirring at room temperature for 15-20mIn, adding an intermediate 5, reacting at room temperature for 10-12h, washing the reaction solution with saturated ammonium chloride and saturated salt water, and evaporating to obtain an oily substance, wherein in the reaction, the molar ratio of the substituted acid to the HBTU to the DIEA to the intermediate 5 is 1: 1.05: 1.5: dissolving the oily matter in dichloromethane, adding trifluoroacetic acid, reacting at room temperature for 3-4h, evaporating the reaction solution to dryness, adjusting pH to 9 with saturated sodium carbonate, extracting with dichloromethane, washing the organic phase with saturated saline, evaporating to dryness under reduced pressure to obtain a solid, wherein the volume ratio of trifluoroacetic acid to dichloromethane is 1:3, dissolving the solid with methanol/tetrahydrofuran at the volume ratio of 1:3, adding cesium carbonate, reacting at room temperatureOvernight, the reaction was run with 50:1 dichloromethane: and (3) carrying out column chromatography purification on methanol to obtain a target product I, wherein in the step of reaction, the molar ratio of cesium carbonate to a solid obtained by the reaction is 4: 1; in this step, the substituted acid, intermediate 5, in the target product I, R1Is 4-chloro, 4-bromo, 4-fluoro, 4-methoxy, 2, 4-dichloro; r2Hydrogen, chlorine, bromine; r3Is dimethylamino, morpholine, N-methylpiperazine, acetylpiperazine, phenylpiperazine or 4-piperidyl.
6. The process for preparing a substituted piperidine-containing pyrrolopyrimidine compound according to claim 4, wherein the substituted acid is one of:
7. use of the substituted piperidine-containing pyrrolopyrimidine compounds or pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 3 for the preparation of antitumor agents.
8. The use according to claim 7, characterized in that the antineoplastic drug is an anti-prostate cancer and anti-lymphoma drug targeting AKT 1.
9. A pharmaceutical composition suitable for oral or parenteral administration comprising a compound according to any one of claims 1 to 3 and one or more pharmaceutically acceptable carriers or excipients.
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