CN111484496B

CN111484496B - 2-amino-pyrrolopyrimidine and pyrazolopyrimidine compounds, and preparation method and application thereof

Info

Publication number: CN111484496B
Application number: CN201910085497.4A
Authority: CN
Inventors: 燕立波; 胡诗合; 金永华; 刘宇
Original assignee: Skyrun Pharma Co ltd
Current assignee: Skyrun Pharma Co ltd
Priority date: 2019-01-29
Filing date: 2019-01-29
Publication date: 2022-11-29
Anticipated expiration: 2039-01-29
Also published as: CN111484496A

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 ALK kinase. The invention also relates to a preparation method of the compound and application of the compound in preparing a medicament for preventing and/or treating ALK-related diseases.

Description

2-amino-pyrrolopyrimidine and pyrazolopyrimidine compounds, and preparation method and application thereof

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.

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 downstream conduction. 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 (ALK) is a receptor tyrosine kinase, which belongs to an insulin receptor superfamily, can be fused with a plurality of genes, and can improve the expression level of the ALK once fused, activate the ALK and abnormally activate a downstream phosphatidylinositol 3 kinase protein kinase B signal transduction pathway to cause the growth, proliferation and anti-apoptosis of tumor cells, such as systemic tissue abnormal hyperplasia, inflammatory myofibroblast carcinoma, non-small cell lung cancer and the like. It has now been found that 22 different genes can rearrange with ALK to form fusion proteins, suggesting that the ALK locus may be susceptible to translocation for some unknown reason, but only a few fusion proteins have been extensively studied, such as NPM-ALK fusion protein in anaplastic large cell lymphoma (ACLC) and EML4-ALK fusion protein in non-small cell lung cancer (NSCLC). The mutant and aberrant activity of ALK in various cancers has made it a drug target for the treatment of ALK-positive cancers.

Currently, a number of ALK kinase inhibitors are on the market or are in clinical trials for the treatment of ALK-positive non-small cell lung cancer. In 2010, crizotinib (Crizotinib) developed by feverfew pharmaceuticals was approved by FDA for the treatment of ALK-positive non-small cell lung cancer, becoming the first ALK kinase inhibitor on the market. Subsequently, ceritinib (Ceritinib), developed by nova in 2014, was FDA approved for non-small cell lung cancer patients who were ALK-positive, metastatic to cancer cells, and relapsed after use of crizotinib. In 2015, ai Leti ni (Alectinib) developed by roche was approved by the FDA to be accelerated for non-small cell lung cancer patients with progression of disease after treatment with crizotinib.

Since ALK plays a critical role in the development and progression of tumors, the development of new ALK kinase inhibitors with high inhibitory activity and excellent pharmacokinetic properties has become a key to 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;

R ¹ selected from hydrogen, halogen, alkyl, -CONR ⁷ R ⁸ 、-CONR ⁷ (CH ₂ ) _n NR ⁸ 、-CONR ⁷ (CH ₂ ) _n OR ⁸ 、-NR ⁷ COR ⁸ 、-NR ⁷ R ⁸ 、-NR ⁷ (CH ₂ ) _n NR ⁸ 、-NR ⁷ (CH ₂ ) _n OR ⁸ 、-CR ⁷ R ⁸ Aryl or Het, wherein n =1, 2,3, 4 or 5,R ⁷ 、R ⁸ Each independently represents hydrogen, deuterium, alkyl, aryl or Het;

R ² selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;

R ³ selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl, het or-YR ⁹ ；

R ⁴ Selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl, het or-YR ⁹ ；

Wherein Y is selected from the group consisting of-CR ⁵ R ⁶ -、-SO ₂ -or-CO-, wherein R ⁵ 、R ⁶ Each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het; r ⁹ Selected 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 is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁹ X, 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-CR ⁵ R ⁶ -、-SO ₂ -or-CO-, wherein R ⁵ 、R ⁶ Each independently represents hydrogen, alkyl;

R ¹ selected from hydrogen, halogen, alkyl, -NR ⁷ COR ⁸ 、-NR ⁷ R ⁸ 、-NR ⁷ (CH ₂ ) _n NR ⁸ 、-NR ⁷ (CH ₂ ) _n OR ⁸ 、-CR ⁷ R ⁸ Aryl or Het, wherein n =1, 2,3, 4 or 5,R ⁷ 、R ⁸ Each independently represents hydrogen, deuterium, alkyl, aryl or Het;

R ² 、R ³ 、R ⁴ each independently selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;

R ⁹ selected 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-SO ₂ -or-CO-;

R ¹ is selected from-NR ⁷ COR ⁸ 、-NR ⁷ R ⁸ 、-NR ⁷ (CH ₂ ) _n NR ⁸ 、-NR ⁷ (CH ₂ ) _n OR ⁸ Wherein n =1, 2,3, 4 or 5,R ⁷ 、R ⁸ Each independently represents hydrogen, deuterium, alkyl, aryl or Het;

R ² 、R ³ 、R ⁴ each independently selected from hydrogen, halogen, hydroxy, alkoxy, alkyl;

R ⁹ selected 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-SO ₂ -or-CO-;

R ¹ is selected from-NR ⁷ R ⁸ 、-NR ⁷ (CH ₂ ) _n NR ⁸ Wherein n =1, 2,3, 4 or 5,R ⁷ 、R ⁸ Each independently represents hydrogen, deuterium, alkyl, aryl or Het;

R ⁹ selected 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, and 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-SO ₂ -；

R ¹ Is selected from-NR ⁷ R ⁸ 、-NR ⁷ (CH ₂ ) _n NR ⁸ Wherein n =1, 2,3, 4 or 5,R ⁷ 、R ⁸ Each independently represents hydrogen, alkyl;

R ² 、R ³ 、R ⁴ each independently selected from hydrogen, halogen, alkoxy, alkyl;

R ⁹ selected from the following aromatic rings, aromatic heterocycles, substituted aromatic rings or substituted aromatic heterocycles: phenyl, naphthyl, furanThe substituent group can be 1 to 3 alkylamino groups, nitro groups, cyano groups, 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 acid, fumaric, salicylic, phenylacetic, mandelic acid; also included are acid salts of 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) Using 1,4-dioxane as a solvent, and obtaining a compound I by catalyzing the compound III and substituted aromatic amine by metal palladium;

wherein R1, R2, R3, R4, X, Z, W are as defined in 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 without limitation 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 shown in the general formula I or pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof in preparing medicines for preventing and/or treating ALK related diseases. Such as: the use thereof for producing a medicament for preventing and/or treating diseases associated with abnormal cell proliferation, morphological changes, hyperkinesia, etc. associated with a progressive lymphoma enzyme in a living body, and a medicament for treating diseases associated with angiogenesis or cancer metastasis.

The ALK-associated 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 beneficial effects 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 especially have excellent inhibitory activity on ALK kinase. Therefore, the compound can be used for preparing a medicament for treating clinical symptoms related to ALK, such as: the use thereof for producing a medicament for preventing and/or treating diseases associated with abnormal cell proliferation, morphological changes, hyperkinesia, etc. associated with a progressive lymphoma enzyme in a living body, and a medicament for treating diseases associated with 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 100mL single-necked bottle]Pyrimidine (0.50g, 3.3 mmol), acetone 30mL and benzene sulfonyl chloride (0.69g, 3.9 mmol), dripping 2mL of 2M sodium hydroxide solution at room temperature, reacting at room temperature for 3h, directly concentrating the reaction solution to obtain a white solid, washing with water, pulping, filtering, washing the filter cake with water for 3 times, drying the filter cake to obtain a white solid 0.76g, yield 79%, MS M/z: 294.2M + H] ⁺ 。

Synthesis of 5-benzenesulfonyl-N- (4- (4- (dimethylamino) -1-piperidinyl) -2-methoxyphenyl) -2-amino-5H-pyrrolo [3,2-d ] pyrimidine (I-1):

compound 1 (0.14g, 0.48mmol), compound 2 (0.10g, 0.4mmol), cesium carbonate (0.40g, 1.2mmol), BINAP (0.03g, 0.04mmol) and 10mL of dioxane were each charged into a 100mL single-necked flask, and Pd (dba) was added under a nitrogen atmosphere ₂ (0.03g, 0.04mmol), and the reaction was allowed to warm to 100 ℃ for 8h. Filtering the reaction solution with diatomite, vacuum filtering, concentrating the filtrate, and performing column Chromatography (CH) ₂ Cl ₂ MeOH = 10) to give 70mg of yellow solid in 35% yield, MS m/z:507.2, [ M ] +H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 2-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 is used as a starting material to obtain 61mg of yellow solid, the yield is 30%, MS m/z is 507.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 3-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 is used as starting material to obtain yellow solid 28mg with yield of 15%, MS m/z:471.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 4- (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 is used as starting material to obtain yellow solid 10mg with yield of 5%, MS m/z:513.3[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 5- (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-pyrroleAnd [3,2-d]Pyrimidine is used as starting material to obtain yellow solid 21mg with yield of 9%, MS m/z 609.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 6-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 is used as starting material to obtain yellow solid 10mg, yield 5%, MS m/z 457.4[ M ] +H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 7- (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 is used as starting material to obtain yellow solid 10mg with yield of 5%, MS m/z:471.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 8-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 is used as starting material to obtain yellow solid 10mg with yield 6%, MS m/z 438.4[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 9-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 is used as starting material to obtain yellow solid 105mg with yield 64%, MS m/z:409.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 10-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 is used as starting material to obtain yellow solid 159mg, yield 76%, MS m/z:521.4[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 11- (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 is used as starting material to obtain yellow solid 69mg with yield 34%, MS m/z:513.6[ M ] +H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 12- (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 is used as a starting material to obtain 13mg of yellow solid,yield 6%, MS m/z 543.2[ m ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 13- (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 is used as starting material to obtain yellow solid 37mg, yield is 16%, MS m/z is 575.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 14- (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 is used as starting material to obtain yellow solid 22mg with yield 10%, MS m/z:575.4[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 15- (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 is used as starting material to obtain yellow solid 93mg with yield of 46%, MS m/z:508.2[ m ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 16- (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 is used as starting material to obtain yellow solid 64mg with yield 29%, MS m/z:557.5[ M ] +H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 17-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 is used as a starting material to obtain yellow solid 63mg with yield of 34%, MS m/z:471.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 18- (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 is used as starting material to obtain yellow solid 60mg with yield 32%, MS m/z:471.3[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 19-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 is used as starting material to obtain yellow solid 87mg, yield is 50%, MS m/z is 435.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 20-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 is used as starting material to obtain yellow solid 33mg, yield is 15%, MS m/z is 541.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 21-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 is used as starting material to obtain yellow solid 2mg with yield 1%, MS m/z 510.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 22-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 is used as starting material to obtain yellow solid 7mg, yield is 3%, MS m/z is 510.3[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 23-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 is used as a starting material to obtain 22mg of yellow solid, the yield is 12 percent, and MS m/z is 479.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 24-benzenesulfonyl-N- (4- (morpholin-1-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-24)

The preparation method is as in example 1, to2-chloro-7H-pyrrolo [3,2-d]Pyrimidine is used as starting material to obtain yellow solid 176mg with yield of 95%, MS m/z:466.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 25-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 is used as starting material to obtain yellow solid 80mg with yield of 36%, MS m/z of 562.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 26-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 is used as starting material to obtain yellow solid 70mg, yield 31%, MS m/z 564.3[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 27-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 is used as starting material to obtain yellow solid 45mg, yield 24%, MS m/z 464.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 28-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 is used as starting material to obtain yellow solid 76mg, yield 38%, MS m/z 506.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 29-benzenesulfonyl-N- (4- (tetrahydropyrrol-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 is used as starting material to obtain yellow solid 150mg, yield 84%, MS m/z 450.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 30-benzenesulfonyl-N- (4- (1-tert-butoxycarbonyl-3,6-dihydropyridin-4-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine (I-30)

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 31-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 is used as starting material to obtain yellow solid 50mg, yield 27%, MS m/z, 463.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 32-benzenesulfonyl-N- (4- (piperidin-4-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d ] pyrimidine hydrochloride (I-32)

20mg of 7-benzenesulfonyl-N- (4- (1-tert-butoxycarbonylpiperidin-4-yl) -2-methoxyphenyl) -2-amino-7H-pyrrolo [2,3-d was taken]The pyrimidine is dissolved in 5mL ethanol hydrochloride (1 mol/L), the reaction is carried out at room temperature for 3h, and the TLC detects that the raw material reaction is complete. 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 yellow solid 15mg with yield of 79%, MS m/z of 537.2[ M ] +H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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 33-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 is used as starting material to obtain yellow solid 43mg with yield 46%, MS m/z: 471.2M + H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(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) ALK inhibitory Activity assay for target Compounds

The inhibitory activity of the synthesized compound on ALK is measured by a Fluorescence Resonance Energy Transfer (FRET) method (for specific implementation methods, lebakken CS, kang HC, vogel KW, afluorescence lifetime-based analysis to characteristics of fluorescence kinase inhibitors JBiomol Screen.2007.12 (6): 828-841), and a compound with better activity is screened compared with a positive control drug. ALK was obtained by direct purchase of the kit.

(2) The following table shows the results of in vitro ALK kinase activity and in vitro cancer cell activity assays 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 compound and the medically acceptable salt thereof have ALK inhibitory effect and can provide basis for preparing medicines for treating/preventing ALK-related diseases; experiments preliminarily confirm that the activity of the 5H-pyrrolopyrimidine parent nucleus compound is lower than that of the 7H-pyrrolopyrimidine parent nucleus compound, while the activity of the 7H-pyrrolopyrimidine parent nucleus compound is relatively better, and verify the specificity of the sulfonamide connection position.

Pharmacological test results show that the 2-amino-7H-pyrrolo [2,3-d ] pyrimidine compound has better ALK kinase inhibitory activity, the single concentration inhibition rate of part of the compound is equivalent to or superior to that of a positive control drug Brigatinib, and the compound can be used for preventing or treating clinical diseases related to ALK kinase inhibitors.

The above compound and its pharmaceutically acceptable salt of the present invention have ALK inhibitory activity and are useful as active ingredients in pharmaceuticals. Therefore, the medicine containing the compound as an effective component can be used for preparing a medicine for treating clinical symptoms related to ALK, such as: the use thereof for producing a medicament for preventing and/or treating diseases associated with abnormal cell proliferation, morphological changes, hyperkinesia, etc. associated with a progressive lymphoma enzyme in a living body, and a medicament for treating diseases associated with 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

1. A compound of formula I or a pharmaceutically acceptable salt thereof:

wherein, the first and the second end of the pipe are connected with each other,

x is selected from CH or N;

R ¹ is selected from-NR ⁷ (CH ₂ ) _n NR ⁸ Wherein n =1, 2,3, 4 or 5,R ⁷ 、R ⁸ Each independently represents hydrogen, alkyl;

R ² is selected from alkoxy;

R ⁴ selected from hydrogen;

wherein Y is selected from the group consisting of-CR ⁵ R ⁶ -or-SO ₂ -, wherein R ⁵ 、R ⁶ Each independently represents hydrogen or an aryl group;

R ⁹ selected from alkyl or aryl;

aryl is a carbocyclic ring selected from phenyl, each of which is optionally substituted with 1 or 2 substituents, each substituent independently selected from hydrogen, alkyl, halo, or haloalkyl;

halogen is a substituent selected from fluorine, chlorine, bromine or iodine;

the alkyl groups appearing in the upper Wen Wanji, alkoxy groups, haloalkyl groups are straight or branched chain saturated hydrocarbon groups 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.

2. The compound of claim 1, wherein:

x is selected from N;

R ² is selected from alkoxy;

R ⁴ selected from hydrogen;

y is selected from-SO ₂ -；

R ⁹ selected from phenyl.

3. 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 acid, fumaric, salicylic, phenylacetic, mandelic acid; also included are acid salts of the compounds of formula I with inorganic bases.

4. A compound according to claim 3, characterized in that: the pharmaceutically acceptable salts include alkaline metal cation salts, alkaline earth metal cation salts and ammonium cation salts.

5. The compound according to claim 1, characterized by being selected from:

6. 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:

(2) Using 1,4-dioxane as a solvent, and carrying out palladium catalysis on the compound III and substituted aromatic amine to obtain a compound I; wherein R is ¹ 、R ² 、R ⁴ 、R ⁹ X is as defined in formula I.

7. A pharmaceutical composition characterized by: comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

8. Use of a compound according to any one of claims 1 to 5 for the preparation of a medicament for the prevention and/or treatment of ALK-associated diseases.

9. Use according to claim 8, characterized in that: the ALK-associated disease is selected from 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.