CN111484496A - 2-amino-pyrrolopyrimidine and pyrazolopyrimidine compounds, and preparation method and application thereof - Google Patents
2-amino-pyrrolopyrimidine and pyrazolopyrimidine compounds, and preparation method and application thereof Download PDFInfo
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- CN111484496A CN111484496A CN201910085497.4A CN201910085497A CN111484496A CN 111484496 A CN111484496 A CN 111484496A CN 201910085497 A CN201910085497 A CN 201910085497A CN 111484496 A CN111484496 A CN 111484496A
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- alkyl
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- 238000002360 preparation method Methods 0.000 title claims description 41
- YRAWHADHBYNMDI-UHFFFAOYSA-N N1C(N)=NC=C2N=CC=C21 Chemical compound N1C(N)=NC=C2N=CC=C21 YRAWHADHBYNMDI-UHFFFAOYSA-N 0.000 title abstract description 4
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical class C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- -1 pyrazolopyrimidine compound Chemical class 0.000 claims abstract description 21
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention relates to a 2-aminopyrrolopyrimidine and pyrazolopyrimidine compound, pharmaceutically acceptable salts, prodrugs, crystal forms, stereoisomers, tautomers, hydrates or solvates thereof, a pharmaceutical composition containing the compound, and the compound serving as a receptor tyrosine kinase inhibitor and particularly having excellent inhibitory activity on A L K kinase.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a 2-amino-pyrrolopyrimidine and pyrazolopyrimidine compound, a preparation method and application thereof, wherein the compound can be used as a receptor tyrosine kinase inhibitor, especially as an A L K kinase inhibitor.
Background
Protein Receptor Tyrosine Kinases (RTKs) play an important role in cell signal transduction pathways, transmit extracellular signals into cells, and regulate physiological activities such as proliferation, differentiation, growth, apoptosis and the like of tumor cells through conduction downstream. RTKs are closely related to the development and development of tumors, and therefore, their family members have become the main targets for the development of antitumor drugs.
Anaplastic lymphoma kinase (a L K) is a receptor tyrosine kinase, which belongs to the insulin receptor superfamily, can be fused with a plurality of genes, and once fused, can increase the expression level of a L K, activate a L K and abnormally activate the downstream phosphatidylinositol 3 kinase protein kinase B signaling pathway, cause tumor cell growth, proliferation and anti-apoptosis, such as abnormal proliferation of systemic tissues, inflammatory myofibrocytoma, non-small cell lung cancer and the like, 22 different genes have been found to rearrange with a L K to form fusion protein, which indicates that the a L K locus may be easily translocated for some unknown reasons, but only a few fusion proteins are widely studied, such as NPM-a L K fusion protein in anaplastic large cell lymphoma (AC L C) and EM L-a L K fusion protein in non-small cell lung cancer (NSC L C), mutation of a L K in a plurality of cancers and the activity of a L K as a positive drug for treating a plurality of cancers.
Currently, a number of a L K kinase inhibitors are on the market or are entering clinical trials for treating a L K positive non-small cell lung cancer in 2010, Crizotinib (Crizotinib) developed by feverfew pharmaceuticals was FDA approved for treating a L K positive non-small cell lung cancer, becoming the first a L K kinase inhibitor on the market, subsequently, Ceritinib (Ceritinib) developed by nova pharmaceuticals in 2014 was FDA approved for non-small cell lung cancer patients that are a L K positive, metastatic to cancer cells, and relapsed after using Crizotinib.
Since A L K plays a key role in the process of generating and developing tumors, the development of a novel A L K kinase inhibitor with high inhibitory activity and excellent pharmacokinetic properties becomes a key for the development of novel antitumor drugs.
Disclosure of Invention
The purpose of the invention is as follows: one of the objects of the present invention is to provide a 2-amino-pyrrole/pyrazolopyrimidine compound of the general formula I or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof:
wherein the content of the first and second substances,
x is selected from C or N;
z and W are different and are each independently selected from C, N;
the dotted lines indicate that a single or double bond may be present and one of the dotted lines is a single bond and the other dotted line is a double bond;
R1selected from hydrogen, halogen, alkyl, -CONR7R8、-CONR7(CH2)nNR8、-CONR7(CH2)nOR8、-NR7COR8、-NR7R8、-NR7(CH2)nNR8、-NR7(CH2)nOR8、-CR7R8Aryl or Het, where n ═ 1, 2,3, 4 or 5, R7、R8Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
R2selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;
R3selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl, Het or-YR9；
R4Selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl, Het or-YR9；
Wherein Y is selected from the group consisting of-CR5R6-、-SO2-or-CO-, wherein R5、R6Each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het; r9Selected from alkyl, aryl or Het;
alkyl is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms to which a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms is bonded;
aryl is a carbocyclic ring selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each of which is optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from hydrogen, alkyl, cyano, halo, nitro, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het;
het is a monocyclic heterocycle selected from piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [1,4] dioxinyl or benzo [1,3] dioxolyl; each monocyclic or bicyclic heterocycle is optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from halo, haloalkyl, hydroxy, alkyl or alkoxy;
halogen is a substituent selected from fluorine, chlorine, bromine or iodine.
The compound of the general formula I or the pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof is preferably a compound with the structure of formula IA or formula IB:
wherein R is1、R2、R3、R4、R9X, Y are as defined in formula I.
In some of the preferred embodiments of the present invention,
x is selected from C or N;
y is selected from-CR5R6-、-SO2-or-CO-, wherein R5、R6Each independently represents hydrogen, alkyl;
R1selected from hydrogen, halogen, alkyl, -NR7COR8、-NR7R8、-NR7(CH2)nNR8、-NR7(CH2)nOR8、-CR7R8Aryl or Het, where n ═ 1, 2,3, 4 or 5, R7、R8Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
R2、R3、R4each independently selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;
R9selected from alkyl, aryl or Het.
In certain of the more preferred embodiments of the present invention,
x is selected from C or N;
y is selected from-SO2-or-CO-;
R1is selected from-NR7COR8、-NR7R8、-NR7(CH2)nNR8、-NR7(CH2)nOR8Wherein n is 1, 2,3, 4 or 5, R7、R8Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
R2、R3、R4each independently selected from hydrogen, halogen, hydroxy, alkoxy, alkyl;
R9selected from alkyl, aryl or Het.
In certain of the more preferred embodiments of the present invention,
x is selected from C or N;
y is selected from-SO2-or-CO-;
R1is selected from-NR7R8、-NR7(CH2)nNR8Wherein n is 1, 2,3, 4 or 5, R7、R8Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
R2、R3、R4each independently selected from hydrogen, halogen, hydroxy, alkoxy, alkyl;
R9selected from the following aromatic rings, aromatic heterocycles, substituted aromatic rings or substituted aromatic heterocycles: phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyridyl, pyrimidyl, quinolyl and isoquinolyl, wherein the substituent can be 1-3 alkylamino, nitro, cyano, halogen or trifluoromethyl.
In certain of the more preferred embodiments of the present invention,
x is selected from C;
y is selected from-SO2-；
R1Is selected from-NR7R8、-NR7(CH2)nNR8Wherein n is 1, 2,3, 4 or 5, R7、R8Each independently represents hydrogen, alkyl;
R2、R3、R4each independently selected from hydrogen, halogen, alkoxy, alkyl;
R9selected from the following aromatic rings, aromatic heterocycles, substituted aromatic rings or substituted aromatic heterocycles: phenyl, naphthyl, furyl, thienyl, pyridyl, pyrimidyl, quinolyl and isoquinolyl, wherein the substituent can be 1-3 alkylamino, nitro, cyano, halogen or trifluoromethyl.
In some preferred embodiments, the pharmaceutically acceptable salts include, but are not limited to, acid addition salts of the compounds of formula I with: hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, citric, tartaric, lactic, pyruvic, acetic, maleic or succinic, fumaric, salicylic, phenylacetic, mandelic; also included are acid salts of the compounds of formula I with inorganic bases.
In some more preferred embodiments, the pharmaceutically acceptable salts include, but are not limited to, alkali metal cation salts, alkaline earth metal cation salts, and ammonium cation salts.
The compounds of the general formula I according to the invention are preferably the following compounds:
the compounds of the general formula I can also exist in the form of salts, hydrates and solvates thereof, and the compounds can be converted into the compounds of the general formula I in vivo. For example, within the scope of the present invention, the compounds of the present invention are converted into pharmaceutically acceptable salt forms according to procedures known in the art, and they are used in salt form.
Certain compounds of the present invention may exist in polycrystalline or amorphous form.
All tautomeric forms of the compounds of formula I of the invention are included within the scope of the invention. The compounds of the present invention may exist in specific geometric or stereoisomeric forms. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups, and all such isomers and mixtures thereof are included within the scope of the present invention.
As used herein, "prodrug" refers to any covalently bound carrier that releases the active parent drug when administered to a mammalian patient. Prodrugs can be prepared by modifying functional groups present in the compound in a manner that results in the modification of the parent compound by conventional procedures or in vivo. Prodrugs include, when administered to a mammalian patient, for example: compounds in which a hydroxyl, amino, thiol or carboxyl group is linked to any group and is decomposed to form a free hydroxyl, amino, thiol or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols or amine functional methylamine, ethylamine derivatives in the compounds of the invention.
Another object of the present invention is to provide a process for the preparation of a compound having the general formula I, comprising the steps of:
(1) taking acetone as a solvent, and carrying out nucleophilic substitution reaction on the compound II and alkyl sulfonyl chloride, aryl sulfonyl chloride or aryl acyl chloride in the presence of inorganic base to obtain a compound III; or taking DMF as a solvent, and carrying out nucleophilic substitution reaction on the compound II and halogenated alkane or halogenated aromatic hydrocarbon in the presence of inorganic base to obtain a compound III;
the compound II is selected from:
(2) 1, 4-dioxane is used as a solvent, and the compound III and substituted aromatic amine are catalyzed by metal palladium to obtain a compound I;
wherein R1, R2, R3, R4 and R X, Z, W are defined in the general formula I.
The compounds of the general formula I can be prepared by the preparation method or similar preparation methods, and corresponding starting materials are selected according to different substituents and different positions of the substituents. It will be appreciated by those skilled in the art that the above routes are useful for understanding the present invention, but do not limit the content of the invention, and that the variables are defined as mentioned in formula I unless otherwise specified.
Another object of the present invention is to provide a pharmaceutical composition, which comprises a compound of formula I or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
The pharmaceutical compositions of the invention may be administered in various known ways, for example orally, parenterally, by inhalation spray or via an implanted depot. The pharmaceutical composition can be independently administered or combined with other antitumor drugs. Oral compositions may be any orally acceptable dosage form, including, but not limited to, tablets, capsules, emulsions, and suspensions, dispersions, and solutions. Commonly used pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, colorants, fillers, emulsifiers, and the like.
Sterile injectable compositions can be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents. Pharmaceutically acceptable carriers and solvents that may be used include water, mannitol, sodium chloride solution and the like.
The topical compositions may be formulated as oils, lotions, creams and the like. Carriers for the composition include vegetable or mineral oils, animal fats, high molecular weight alcohols, and the like. Pharmaceutically acceptable carriers are carriers in which the active ingredient is soluble.
The actual dosage level of the active ingredient in the pharmaceutical compositions of the invention can be varied to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, and which is non-toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the invention or salt thereof employed, the route of administration, the time of administration, the rate of excretion of the particular composition employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, body weight, general health and medical history of the patient being treated, and like factors well known in the medical arts.
The invention also aims to provide application of the compound in the general formula I or pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof in preparing medicaments for preventing and/or treating A L K related diseases, such as medicaments for preventing and/or treating diseases related to abnormal cell proliferation, morphological change, hyperkinesia and the like related to the gradual change lymphoma enzyme in organisms and medicaments related to angiogenesis or cancer metastasis.
The A L K related disease is selected from, but not limited to, non-small cell lung cancer, liver cancer, papillary renal cell carcinoma, gastric cancer, esophageal cancer, glioblastoma, head and neck squamous cell carcinoma, renal cancer, acute leukemia, prostate cancer, thyroid cancer, skin cancer, colorectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, or mesothelioma.
Has the advantages that:
the compound of the general formula I and pharmaceutically acceptable salts, prodrugs, crystal forms, stereoisomers, tautomers, hydrates or solvates thereof prepared by the invention are used as receptor tyrosine kinase inhibitors, and particularly have excellent inhibitory activity on A L K kinase, so the compound can be used for preparing medicaments for treating clinical symptoms related to A L K, such as medicaments for preventing and/or treating diseases related to abnormal cell proliferation, morphological change, hyperkinesia and the like related to gradual change lymphoma enzyme in organisms and medicaments for preventing diseases related to angiogenesis or cancer metastasis.
Detailed Description
The following examples are given to illustrate the preparation of the compounds of formula I according to the invention, but are not intended to limit the invention in any way. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
The starting materials, reaction reagents and the like used in the examples of the present invention are commercially available. The present invention can be prepared in salified form by salification methods commonly used in the art, such as: dissolving the compound in hydrochloric acid ethanol at room temperature to react to generate hydrochloride; or adding benzene sulfonic acid into the mixture to react to generate benzene sulfonate. Example 32 illustrates the synthesis of the hydrochloride salt of compound I-27, to which other compounds may be referred for their synthesis, or which may be formed by methods commonly used in the art.
Example 1:
5-benzenesulfonyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-5H-pyrrolo [3,2-d ] pyrimidine (I-1)
The synthetic route is as follows:
synthesis of Compound 1:
2-chloro-5H-pyrrolo [3,2-d ] is added to a 100m L single-necked flask]Pyrimidine (0.50g, 3.3mmol), acetone 30M L and benzenesulfonyl chloride (0.69g, 3.9mmol), dripping 2M sodium hydroxide solution at room temperature for 2M L, reacting at room temperature for 3H, directly concentrating the reaction solution to obtain white solid, washing with water, pulping, filtering, washing the filter cake with water for 3 times, drying the filter cake to obtain white solid 0.76g, yield 79%, MS M/z:294.2[ M + H ] in which]+。
Synthesis of 5-benzenesulfonyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-5H-pyrrolo [3,2-d ] pyrimidine (I-1):
into a 100m L single-necked flask were charged compound 1(0.14g, 0.48mmol), compound 2(0.10g, 0.4mmol), cesium carbonate (0.40g, 1.2mmol), BINAP (0.03g, 0.04mmol) and dioxane 10m L, respectively, and Pd (dba) was added under a nitrogen atmosphere2(0.03g, 0.04mmol), and the reaction was carried out at 100 ℃ for 8 hours. Filtering the reaction solution with diatomite, vacuum filtering, concentrating the filtrate, and performing column Chromatography (CH)2Cl2MeOH 10:1) to give 70mg of a yellow solid in 35% yield, MS M/z 507.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.95(s,1H),8.17-8.14(m,1H),8.06(d,J＝8.0Hz,2H),7.95(s,1H),7.76-7.70(m,2H),7.66-7.60(m,2H),6.72-6.70(m,1H),6.66-6.63(m,1H),6.51(s,1H),3.78(s,3H),2.78-2.60(m,3H),2.56-2.50(m,8H),2.02-1.96(m,2H),1.68-1.58(m,2H)。
Example 27-benzenesulfonyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-2)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to give 61mg of yellow solid in 30% yield, MS M/z 507.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.66(s,1H),8.15(s,1H),8.02(d,J＝7.7Hz,2H),7.81(d,J＝8.7Hz,1H),7.72(s,1H),7.55(dd,J＝14.1,6.0Hz,3H),6.71(dd,J＝9.8,3.2Hz,2H),6.66(s,1H),3.83(s,3H),2.70(d,J＝11.2Hz,2H),2.61-2.57(m,3H),2.50(s,6H),2.10-2.07(m,2H),1.75-1.61(m,2H)。
Example 35-Cyclopropanesulfonyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-5H-pyrrolo [3,2-d ] pyrimidine (I-3)
Preparation method referring to example 1, with 2-chloro-5H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 28mg in 15% yield, MS M/z 471.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.83(s,1H),7.95(d,J＝3.6Hz,1H),7.90(s,1H),7.83(d,J＝8.7Hz,1H),6.71(d,J＝3.6Hz,1H),6.64(d,J＝2.3Hz,1H),6.51(dd,J＝8.8,2.4Hz,1H),3.81(s,3H),3.25-3.16(m,2H),2.64(t,J＝11.3Hz,2H),2.29(s,6H),1.90-1.88(m,2H),1.59-1.51(m,2H),1.30-1.25(m,2H),1.23-1.20(m,2H),1.17-1.07(m,2H)。
Example 45- (4-tert-butylbenzyl) -N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-5H-pyrrolo [3,2-d ] pyrimidine (I-4)
Preparation method referring to example 1, with 2-chloro-5H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 10mg in 5% yield, MS M/z 513.3[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.94(s,1H),8.14(d,J＝3.7Hz,1H),8.00-7.92(m,2H),7.71(d,J＝8.7Hz,1H),7.64(d,J＝8.7Hz,1H),7.52(d,J＝8.4Hz,1H),7.40-7.28(m,1H),6.69(d,J＝3.6Hz,1H),6.63(d,J＝2.5Hz,1H),6.49(dd,J＝8.8,2.4Hz,1H),3.78(s,3H),3.71(s,2H),2.64-2.59(m,2H),2.51(s,6H),2.40-2.35(m,3H),2.05-1.94(m,2H),1.59-1.50(m,2H),1.24(s,9H)。
Example 55- (4-chloro-3-trifluoromethylbenzenesulfonyl) -N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-5H-pyrrolo [3,2-d ] pyrimidine (I-5)
Preparation method referring to example 1, with 2-chloro-5H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain 21mg of yellow solid with 9% yield, MS M/z 609.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):9.28(s,1H),8.54-8.53(m,1H),8.15-8.08(m,2H),8.02-7.94(m,1H),7.87(d,J＝8.8Hz,1H),7.72(d,J＝8.1Hz,1H),6.64(s,1H),6.52(d,J＝8.0Hz,1H),6.42(d,J＝9.1Hz,1H),3.66(s,3H),2.79-2.57(m,3H),2.30-2.15(m,8H),2.10-1.99(s,2H),1.50-1.45(m,2H)。
Example 65-benzyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-5H-pyrrolo [3,2-d ] pyrimidine (I-6)
Preparation method referring to example 1, with 2-chloro-5H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 10mg in 5% yield, MS M/z 457.4[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.68(s,1H),8.16(d,J＝8.8Hz,1H),7.84(d,J＝3.0Hz,1H),7.52-7.22(m,6H),6.65(s,1H),6.52(d,J＝8.7Hz,1H),6.33(d,J＝2.9Hz,1H),5.43(s,2H),3.84(s,3H),2.65-2.59(m,3H),2.58-2.55(m,2H),2.43(s,6H),1.98-1.91(m,2H),1.64-1.61(m,2H)。
Example 75- (1-phenylethyl) -N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-5H-pyrrolo [3,2-d ] pyrimidine (I-7)
Preparation method referring to example 1, with 2-chloro-5H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 10mg in 5% yield, MS M/z 471.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.60(s,1H),8.12(d,J＝8.7Hz,1H),7.99(d,J＝3.2Hz,1H),7.43-7.21(m,5H),6.62(d,J＝2.4Hz,1H),6.49(dd,J＝8.8,2.6Hz,1H),6.35(d,J＝3.1Hz,1H),5.86-5.84(m,1H),5.33-5.30(m,0H),3.82(s,3H),2.63-2.58(m,3H),2.10-2.16(m,8H),2.02-2.00(m,2H),1.92-1.86(m,3H),1.51-1.48(m,2H)。
Example 85-cyclopentyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-5H-pyrrolo [3,2-d ] pyrimidine (I-8)
Preparation method referring to example 1, with 2-chloro-5H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 10mg in 6% yield, MS M/z 438.4[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.76(s,1H),8.19(d,J＝8.7Hz,1H),7.77(d,J＝3.1Hz,1H),7.38(s,1H),6.64(d,J＝2.4Hz,1H),6.51(dd,J＝8.8,2.5Hz,1H),6.28(d,J＝3.0Hz,1H),3.84(s,3H),2.64-2.58(m,3H),2.22(s,6H),2.22-2.17(m,3H),2.07-1.93(m,2H),1.58-1.46(m,2H),1.34-1.22(m,8H)。
Example 95-isopropyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-5H-pyrrolo [3,2-d ] pyrimidine (I-9)
Preparation method referring to example 1, with 2-chloro-5H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 105mgThe rate is 64%, MS M/z is 409.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.79(s,1H),8.22(d,J＝8.7Hz,1H),7.80(d,J＝3.1Hz,1H),7.38(s,1H),6.66(d,J＝2.4Hz,1H),6.53(dd,J＝8.8,2.5Hz,1H),6.29(d,J＝3.0Hz,1H),4.85-4.65(m,1H),3.86(s,3H),2.70-2.63(m,3H),2.53-2.51(m,8H),2.04-2.01(m,2H),1.74-1.61(m,2H),1.47(d,J＝6.7Hz,6H)。
Example 105-p-toluenesulfonyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-5H-pyrrolo [3,2-d ] pyrimidine (I-10)
Preparation method referring to example 1, with 2-chloro-5H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain 159mg of yellow solid with yield of 76%, MS M/z:521.4[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.94(s,1H),8.18-8.13(m,1H),8.06(d,J＝7.8Hz,2H),7.99(s,1H),7.78-7.71(m,2H),7.66-7.60(m,1H),6.72-6.71(m,1H),6.68-6.65(m,1H),6.51(s,1H),3.78(s,3H),2.78-2.60(m,3H),2.56-2.50(m,8H),2.10(s,3H),2.03-1.95(m,2H),1.68-1.59(m,2H)。
Example 117- (2-Thienylsulfonyl) -N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-11)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 69mg in 34% yield, MS M/z 513.6[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.68(s,1H),8.15(s,1H),8.11(d,J＝4.1Hz,1H),7.99(d,J＝8.6Hz,1H),7.90(d,J＝3.2Hz,1H),7.49(d,J＝4.0Hz,1H),7.23-7.14(m,1H),6.71(d,J＝3.9Hz,2H),6.62(dd,J＝8.8,2.2Hz,1H),3.84(s,3H),3.34-3.09(m,3H),2.77-2.56(m,8H),2.11-2.08(m,2H),1.79-1.71(m,2H)。
Example 127- (2, 6-difluorobenzenesulfonyl) -N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-12)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 13mg in 6% yield, MS M/z 543.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.66(s,1H),8.16(s,1H),8.09(d,J＝4.2Hz,1H),7.97(d,J＝8.6Hz,1H),7.91(d,J＝3.2Hz,1H),7.46(d,J＝4.2Hz,1H),7.25-7.17(m,1H),6.71(d,J＝3.2Hz,2H),6.65-6.62(m,1H),3.83(s,3H),3.33-3.10(m,3H),2.78-2.56(m,8H),2.12-2.08(m,2H),1.75-1.71(m,2H)。
Example 137- (2, 6-Dichlorobenzenesulfonyl) -N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-13)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain 37mg of yellow solid with yield of 16%, MS M/z 575.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.86(s,1H),8.24(s,1H),8.11(d,J＝4.1Hz,1H),8.01(d,J＝8.6Hz,1H),7.92(d,J＝3.2Hz,1H),7.47(d,J＝4.1Hz,1H),7.25-7.17(m,1H),6.72(d,J＝3.2Hz,2H),6.66-6.62(m,1H),3.85(s,3H),3.34-3.10(m,3H),2.79-2.58(m,8H),2.12-2.08(m,2H),1.75-1.70(m,2H)。
Example 147- (2-trifluoromethylbenzenesulfonyl) -N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-14)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as initial material to obtain yellow solid 22mg in 10% yield, MS M/z 575.4[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.61(s,1H),8.49(d,J＝7.9Hz,1H),7.94(dd,J＝12.6,8.2Hz,2H),7.81(t,J＝7.7Hz,1H),7.60-7.54(m,2H),7.52-7.48(m,1H),6.77-6.65(m,3H),3.89(s,3H),3.20-3.14(m,3H),2.88-2.83(m,2H),2.78(s,6H),2.25-2.15(m,3H),1.92-1.81(m,2H)。
Example 157- (3-Pyridinesulfonyl) -N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-15)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 93mg in 46% yield, MS M/z 508.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.85(s,1H),7.97(d,J＝3.6Hz,1H),7.90(s,1H),7.83(d,J＝8.7Hz,1H),6.73(d,J＝3.6Hz,1H),6.64-6.51(m,5H),3.80(s,3H),3.26-3.18(m,3H),2.64-2.61(m,2H),2.27(s,6H),1.90-1.88(m,2H),1.59-1.51(m,2H)。
Example 167- (1-Naphthalenesulfonyl) -N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-16)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 64mg in 29% yield, MS M/z 557.5[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.61(s,1H),8.52(dd,J＝19.5,7.4Hz,2H),8.32(d,J＝7.8Hz,1H),8.08(d,J＝7.1Hz,1H),7.97(s,1H),7.91(s,1H),7.78-7.53(m,4H),6.72(d,J＝17.1Hz,3H),3.79(s,3H),2.92-2.72(m,3H),2.59-2.51(s,8H),2.05-2.03(m,2H),1.72-1.69(m,2H)。
Example 177-Cyclopropanesulfonyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-17)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 63mg in 34% yield and MS M/z 471.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.84(s,1H),7.96(d,J＝3.6Hz,1H),7.92(s,1H),7.85(d,J＝8.8Hz,1H),6.71(d,J＝3.6Hz,1H),6.65(d,J＝2.3Hz,1H),6.51(dd,J＝8.8,2.3Hz,1H),3.83(s,3H),3.25-3.17(m,2H),2.65-2.61(m,2H),2.29(s,6H),1.92-1.88(m,2H),1.59-1.53(m,2H),1.30-1.26(m,2H),1.24-1.20(m,2H),1.17-1.08(m,2H)。
Example 187- (1-phenylethyl) -N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-18)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 60mg in 32% yield and MS M/z 471.3[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.62(s,1H),8.44(d,J＝9.4Hz,1H),7.56(s,1H),7.38-7.30(m,4H),6.98(d,J＝3.7Hz,1H),6.57(d,J＝6.9Hz,2H),6.41(d,J＝3.6Hz,1H),6.09(t,J＝7.1Hz,1H),3.89(s,3H),3.52-3.47(m,1H),3.02-2.99(m,1H),2.80-2.74(m,2H),2.70-2.62(m,8H),2.25-2.22(m,2H),1.91(d,J＝7.2Hz,3H),1.30-1.27(m,2H)。
Example 197-cyclopentyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-19)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain 87mg of yellow solid with yield of 50%, MS M/z 435.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.60(s,1H),8.52(d,J＝8.6Hz,1H),7.71(s,1H),7.01(d,J＝3.2Hz,1H),6.69-6.55(m,2H),6.41(d,J＝3.6Hz,1H),3.91(d,J＝9.6Hz,3H),2.64-2.58(m,3H),2.22(s,6H),2.22-2.17(m,3H),2.07-1.93(m,2H),1.59-1.45(m,2H),1.34-1.21(m,8H)。
Example 205-chloro-7-benzenesulfonyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-20)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 33mg in 15% yield, MS M/z 541.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.64(s,1H),8.47(s,1H),8.00(d,J＝7.6Hz,2H),7.78-7.71(m,2H),7.65(d,J＝8.7Hz,1H),7.55(t,J＝7.8Hz,2H),6.72(d,J＝2.0Hz,1H),6.65(d,J＝8.9Hz,1H),3.81(s,3H),2.76-2.59(m,3H),2.49-2.40(m,8H),2.03-1.89(m,2H),1.67-1.59(m,2H)。
Example 211-benzenesulfonyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -6-amino-1H-pyrazolo [3,4-d ] pyrimidine (I-21)
Preparation method referring to example 1, with 6-chloro-1H-pyrazolo [3,4-d]Pyrimidine as starting material to obtain yellow solid 2mg in 1% yield, MS M/z 510.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.65(s,1H),8.49(s,1H),8.01(d,J＝7.6Hz,2H),7.79-7.73(m,2H),7.66(d,J＝8.7Hz,1H),7.56(t,J＝7.8Hz,2H),6.70(d,J＝2.0Hz,1H),6.66(d,J＝8.9Hz,1H),3.82(s,3H),2.76-2.60(m,3H),2.49-2.42(m,8H),2.03-1.91(m,2H),1.67-1.62(m,2H)。
Example 221-benzenesulfonyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -5-amino-1H-pyrazolo [4,3-d ] pyrimidine (I-22)
Preparation method referring to example 1, with 5-chloro-1H-pyrazolo [4,3-d]Pyrimidine as starting material to obtain yellow solid 7mg in 3% yield, MS M/z 510.3[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.64(s,1H),8.50(s,1H),8.00(d,J＝7.6Hz,2H),7.78-7.73(m,2H),7.67(d,J＝8.7Hz,1H),7.57(t,J＝7.8Hz,2H),6.71(d,J＝2.0Hz,1H),6.64(d,J＝8.9Hz,1H),3.80(s,3H),2.77-2.61(m,3H),2.48-2.40(m,8H),2.05-1.93(m,2H),1.68-1.60(m,2H)。
Example 237-benzenesulfonyl-N- (4- (4-methylpiperazin-1-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-23)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 22mg in 12% yield, MS M/z 479.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.66(s,1H),8.14(s,1H),8.02(d,J＝7.8Hz,2H),7.83(d,J＝8.7Hz,1H),7.72(t,J＝7.4Hz,1H),7.57-7.53(m,3H),6.71(dd,J＝8.0,3.1Hz,2H),6.64(dd,J＝8.8,2.3Hz,1H),3.83(s,3H),3.27-3.21(m,4H),2.75-2.60(m,4H),2.42(s,3H)。
Example 247-benzenesulfonyl-N- (4- (morpholin-1-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-24)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain 176mg of yellow solid with 95% yield, MS M/z 466.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.66(s,1H),8.15(s,1H),8.02(d,J＝7.9Hz,2H),7.84(d,J＝8.7Hz,1H),7.72(s,1H),7.55(dd,J＝12.1,5.5Hz,3H),6.74-6.67(m,2H),6.63(d,J＝8.8Hz,1H),3.82(s,3H),3.81-3.74(m,4H),3.21-3.12(m,4H)。
Example 257-benzenesulfonyl-N- (4- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-25)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 80mg in 36% yield, MS M/z 562.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.65(s,1H),8.14(s,1H),8.02(d,J＝7.7Hz,2H),7.79(d,J＝8.7Hz,1H),7.72(t,J＝7.5Hz,1H),7.54(dd,J＝13.8,5.9Hz,3H),6.69(d,J＝3.9Hz,2H),6.63(d,J＝8.8Hz,1H),3.82(s,3H),3.37-3.23(m,4H),2.73-2.67(m,9H),2.38(s,3H),1.91-1.89(m,2H),1.63-1.56(m,2H)。
EXAMPLE 267-benzenesulfonyl-N- (4- (1-tert-Butoxycarbonylpiperidin-4-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-26)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to give 70mg of yellow solid in 31% yield, MS M/z 564.3[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.76(s,1H),8.25(d,J＝8.6Hz,1H),8.23(s,1H),8.09(d,J＝7.6Hz,2H),7.75-7.72(m,1H),7.65-7.53(m,3H),7.15(d,J＝7.5Hz,2H),6.77(d,J＝4.0Hz,1H),4.04-4.01(m,2H),3.91(s,3H),2.55-2.50(m,3H),2.38-2.32(m,2H),1.91-1.89(m,2H),1.43(s,9H)。
Example 277-benzenesulfonyl-N- (4- (piperidin-4-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-27)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 45mg in 24% yield, MS M/z 464.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.83(s,1H),8.58(s,1H),8.31(t,J＝10.0Hz,1H),8.07(d,J＝7.6Hz,2H),7.77-7.64(m,2H),7.60(t,J＝7.9Hz,2H),7.24-7.19(m,2H),6.82(d,J＝4.0Hz,1H),3.93(s,3H),2.55-2.51(m,3H),2.38-2.33(m,2H),1.93-1.90(m,2H)。
Example 287-benzenesulfonyl-N- (4- (1-acetylpiperidin-4-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-28)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 76mg in 38% yield, MS M/z 506.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.74(s,1H),8.22(d,J＝8.6Hz,1H),8.20(s,1H),8.09(d,J＝7.6Hz,2H),7.75-7.72(m,1H),7.65-7.55(m,3H),7.15(d,J＝7.5Hz,2H),6.77(d,J＝4.0Hz,1H),4.04-4.01(m,2H),3.91(s,3H),2.55-2.50(m,3H),2.38-2.32(m,5H),1.91-1.89(m,2H)。
Example 297-benzenesulfonyl-N- (4- (tetrahydro-pyrrol-1-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-29)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 150mg in 84% yield, MS M/z 450.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.60(s,1H),8.10(s,1H),8.01(d,J＝7.8Hz,2H),7.75-7.68(m,1H),7.62(d,J＝8.5Hz,1H),7.54(s,2H),7.48(d,J＝4.0Hz,1H),6.66(d,J＝4.0Hz,1H),6.28(s,1H),6.24(d,J＝8.7Hz,1H),3.80(s,3H),3.31-3.25(m,4H),1.98-1.97(m,4H)。
EXAMPLE 307-benzenesulfonyl-N- (4- (1-tert-butoxycarbonyl-3, 6-dihydropyridin-4-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-30)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 80mg in 36% yield, MS M/z 562.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.75(s,1H),8.26(d,J＝8.6Hz,1H),8.22(s,1H),8.07(d,J＝7.6Hz,2H),7.71(q,J＝7.6Hz,1H),7.65-7.53(m,3H),7.15(d,J＝7.5Hz,2H),6.76(d,J＝4.0Hz,1H),6.22(s,1H),4.04-4.01(m,2H),3.91(s,3H),3.57-3.52(m,2H),2.55-2.50(m,2H),1.44(s,9H)。
Example 317-benzenesulfonyl-N- (4- (3, 6-dihydropyridin-4-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-31)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 50mg in 27% yield, MS M/z 463.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.81(s,1H),8.56(s,1H),8.30(t,J＝10.0Hz,1H),8.07(d,J＝7.6Hz,2H),7.78-7.65(m,2H),7.58(t,J＝7.9Hz,2H),7.21(dd,J＝12.0,3.5Hz,2H),6.80(d,J＝4.0Hz,1H),6.30(s,1H),3.92(s,3H),3.77-3.70(m,2H),3.35-3.31(m,2H),2.78-2.72(m,2H)。
Example 327-benzenesulfonyl-N- (4- (piperidin-4-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine hydrochloride (I-32)
Collecting 20mg of 7-benzenesulfonyl-N- (4- (1-tert-butoxycarbonylpiperidin-4-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d]Dissolving pyrimidine in 5M L hydrochloric acid ethanol (1 mol/L), reacting at room temperature for 3H, detecting that the reaction of raw materials is complete by T L C, directly concentrating the reaction solution to obtain yellow solid, washing with methanol, pulping, filtering, washing the filter cake with methanol for 3 times, drying the filter cake to obtain 15mg of yellow solid with yield of 79%, MS M/z:537.2[ M + H ] M]+。
1H-NMR(400MHz,DMSO-d6)(ppm):9.35(s,1H),9.02(s,1H),8.83(s,1H),8.58(s,1H),8.31(t,J＝10.0Hz,1H),8.07(d,J＝7.6Hz,2H),7.77-7.64(m,2H),7.60(t,J＝7.9Hz,2H),7.24-7.19(m,2H),6.82(d,J＝4.0Hz,1H),3.93(s,3H),2.55-2.51(m,3H),2.38-2.33(m,2H),1.93-1.90(m,2H)。
Example 337-benzoyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-33)
Preparation method referring to example 1, with 2-chloro-7H-pyrrolo [3,2-d]Pyrimidine as starting material to obtain yellow solid 43mg in 46% yield, MS M/z 471.2[ M + H ]]+。
1H-NMR(400MHz,DMSO-d6)(ppm):8.72(s,1H),8.17(s,1H),8.05(d,J＝7.8Hz,2H),7.84(d,J＝8.7Hz,1H),7.78(s,1H),7.56(dd,J＝14.1,6.0Hz,3H),6.70(dd,J＝9.8,3.2Hz,2H),6.68(s,1H),3.86(s,3H),2.71(d,J＝11.2Hz,2H),2.61-2.58(m,3H),2.51(s,6H),2.10-2.08(m,2H),1.75-1.63(m,2H)。
Example 34: biological activity
(1) Determination of A L K inhibitory Activity of target Compound
The synthesized compound was measured for inhibition activity against A L K by Fluorescence Resonance Energy Transfer (FRET) method (for specific implementation: L ebakken CS, Kang HC, Vogel KW, Afluorescence life-based inhibition to characteristics kinase inhibition. JBiomol Screen.2007.12(6): 828-.
(2) The following table shows the in vitro a L K kinase activity and in vitro cancer cell activity assay results for some of the compounds:
(the compound symbols in the table correspond to the preceding compound symbols)
From the above table, it can be seen that the above compounds and pharmaceutically acceptable salts thereof of the present invention have a L K inhibitory effect and can provide a basis for the preparation of a medicament for the treatment/prevention of a disease associated with a L K, and experiments preliminarily determined that the activity of the 5H-pyrrolopyrimidine nucleus compound is relatively low compared with the activity of the 7H-pyrrolopyrimidine nucleus compound, and the activity of the 7H-pyrrolopyrimidine nucleus compound is relatively good, and confirmed the specificity of the sulfonamide linkage site.
Pharmacological test results show that the 2-amino-7H-pyrrolo [2,3-d ] pyrimidine compound has better A L K kinase inhibitory activity, the single concentration inhibition rate of part of compounds is equivalent to or better than that of a positive control drug Brigatinib, and the compound can be used for preventing or treating clinical diseases related to an A L K kinase inhibitor.
Therefore, the medicine containing the compound as the active ingredient can be used for preparing medicines for treating clinical symptoms related to A L K, such as medicines for preventing and/or treating diseases related to abnormal cell proliferation, morphological change, hyperkinetic function and the like related to the gradual-change lymphoma enzyme in organisms and medicines related to angiogenesis or cancer metastasis.
As noted above, while the present invention has been shown and described with reference to certain preferred embodiments, it is not to be construed as limited thereto. Various changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (13)
1. A compound of formula I or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof:
wherein the content of the first and second substances,
x is selected from C or N;
z and W are different and are each independently selected from C, N;
the dotted lines indicate that a single or double bond may be present and one of the dotted lines is a single bond and the other dotted line is a double bond;
R1selected from hydrogen, halogen, alkyl, -CONR7R8、-CONR7(CH2)nNR8、-CONR7(CH2)nOR8、-NR7COR8、-NR7R8、-NR7(CH2)nNR8、-NR7(CH2)nOR8、-CR7R8Aryl or Het, where n ═ 1, 2,3, 4 or 5, R7、R8Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
R2selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;
R3selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl, Het or-YR9；
R4Selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl, Het or-YR9；
Wherein Y is selected from the group consisting of-CR5R6-、-SO2-or-CO-, wherein R5、R6Each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het; r9Selected from alkyl, aryl or Het;
alkyl is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms to which a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms is bonded;
aryl is a carbocyclic ring selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each of which is optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from hydrogen, alkyl, cyano, halo, nitro, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het;
het is a monocyclic heterocycle selected from piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [1,4] dioxinyl or benzo [1,3] dioxolyl; each monocyclic or bicyclic heterocycle is optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from halo, haloalkyl, hydroxy, alkyl or alkoxy;
halogen is a substituent selected from fluorine, chlorine, bromine or iodine.
2. The compound of claim 1, having the structure of formula IA or formula IB:
wherein R is1、R2、R3、R4、R9X, Y are as defined in formula I.
3. The compound of claim 2, wherein:
x is selected from C or N;
y is selected from-CR5R6-、-SO2-or-CO-, wherein R5、R6Each independently represents hydrogen, alkyl;
R1selected from hydrogen, halogen, alkyl, -NR7COR8、-NR7R8、-NR7(CH2)nNR8、-NR7(CH2)nOR8、-CR7R8Aryl or Het, where n ═ 1, 2,3, 4 or 5, R7、R8Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
R2、R3、R4each independently selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;
R9selected from alkyl, aryl or Het.
4. A compound according to claim 3, characterized in that:
x is selected from C or N;
y is selected from-SO2-or-CO-;
R1is selected from-NR7COR8、-NR7R8、-NR7(CH2)nNR8、-NR7(CH2)nOR8Wherein n is 1, 2,3, 4 or 5, R7、R8Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
R2、R3、R4each independently selected from hydrogen, halogen, hydroxy, alkoxy, alkyl;
R9selected from alkyl, aryl or Het.
5. The compound of claim 4, wherein:
x is selected from C or N;
y is selected from-SO2-or-CO-;
R1is selected from-NR7R8、-NR7(CH2)nNR8Wherein n is 1, 2,3, 4 or 5, R7、R8Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
R2、R3、R4each independently selected from hydrogen, halogen, hydroxy, alkoxy, alkyl;
R9selected from the following aromatic rings, aromatic heterocycles, substituted aromatic rings or substituted aromatic heterocycles: phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, pyridyl, pyrimidyl, quinolyl and isoquinolyl, wherein the substituent can be 1-3 alkylamino, nitro, cyano, halogen or trifluoromethyl.
6. The compound of claim 5, wherein:
x is selected from C;
y is selected from-SO2-；
R1Is selected from-NR7R8、-NR7(CH2)nNR8Wherein n is 1, 2,3, 4 or 5, R7、R8Each independently represents hydrogen, alkyl;
R2、R3、R4each independently selected from hydrogen, halogen, alkoxy, alkyl;
R9selected from the following aromatic rings, aromatic heterocycles, substituted aromatic rings or substituted aromatic heterocycles: phenyl, naphthyl, furyl, thienyl, pyridyl, pyrimidyl, quinolyl and isoquinolyl, wherein the substituent can be 1-3 alkylamino, nitro, cyano, halogen or trifluoromethyl.
7. The compound of claim 1, wherein: the pharmaceutically acceptable salts include acid addition salts of the compounds of formula I with the following acids: hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, citric, tartaric, lactic, pyruvic, acetic, maleic or succinic, fumaric, salicylic, phenylacetic, mandelic; also included are acid salts of the compounds of formula I with inorganic bases.
8. The compound of claim 7, wherein: the pharmaceutically acceptable salts include alkaline metal cation salts, alkaline earth metal cation salts and ammonium cation salts.
9. The compound according to claim 1, characterized by being selected from:
10. a process for the preparation of compounds of the general formula I according to claim 1, characterized in that: the method comprises the following steps:
(1) taking acetone as a solvent, and carrying out nucleophilic substitution reaction on the compound II and alkyl sulfonyl chloride, aryl sulfonyl chloride or aryl acyl chloride in the presence of inorganic base to obtain a compound III; or taking DMF as a solvent, and carrying out nucleophilic substitution reaction on the compound II and halogenated alkane or halogenated aromatic hydrocarbon in the presence of inorganic base to obtain a compound III;
the compound II is selected from:
(2) 1, 4-dioxane is used as a solvent, and the compound III and substituted aromatic amine are catalyzed by metal palladium to obtain a compound I;
wherein R is1、R2、R3、R4X, Z, W are as defined in formula I.
11. A pharmaceutical composition characterized by: comprising a compound of any one of claims 1-9, or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
12. Use of a compound according to any one of claims 1 to 9 for the preparation of medicaments for the prophylaxis and/or treatment of diseases which are associated with a L K.
13. The use according to claim 12, wherein the A L K related disease is selected from the group consisting of, but not limited to, non-small cell lung cancer, liver cancer, papillary renal cell carcinoma, gastric cancer, esophageal cancer, glioblastoma, head and neck squamous cells, renal cancer, acute leukemia, prostate cancer, thyroid cancer, skin cancer, colorectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, and mesothelioma.
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| CN101981036A (en) * | 2008-02-06 | 2011-02-23 | 诺瓦提斯公司 | Pyrrolo [2, 3-D] pyridines and use thereof as tyrosine kinase inhibitors |
| US20160222014A1 (en) * | 2013-09-10 | 2016-08-04 | Asana Biosciences, Llc | Compounds for regulating fak and/or src pathways |
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| CN101981036A (en) * | 2008-02-06 | 2011-02-23 | 诺瓦提斯公司 | Pyrrolo [2, 3-D] pyridines and use thereof as tyrosine kinase inhibitors |
| US20160222014A1 (en) * | 2013-09-10 | 2016-08-04 | Asana Biosciences, Llc | Compounds for regulating fak and/or src pathways |
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