CN111018865B - 1-substituted benzyl pyrazolopyrimidine derivative and preparation method and application thereof - Google Patents

1-substituted benzyl pyrazolopyrimidine derivative and preparation method and application thereof Download PDF

Info

Publication number
CN111018865B
CN111018865B CN202010027321.6A CN202010027321A CN111018865B CN 111018865 B CN111018865 B CN 111018865B CN 202010027321 A CN202010027321 A CN 202010027321A CN 111018865 B CN111018865 B CN 111018865B
Authority
CN
China
Prior art keywords
amino
pyrazolo
pyrimidin
benzamide
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202010027321.6A
Other languages
Chinese (zh)
Other versions
CN111018865A (en
Inventor
赵桂森
徐常青
冉凡胜
禚慧君
段晓明
李玉霞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shandong Kangruijian Medical Technology Co ltd
Original Assignee
Shandong University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong University filed Critical Shandong University
Publication of CN111018865A publication Critical patent/CN111018865A/en
Application granted granted Critical
Publication of CN111018865B publication Critical patent/CN111018865B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Abstract

The invention discloses a 1-substituted benzyl pyrazolopyrimidine derivative and a preparation method and application thereof. The structure of the 1-substituted benzyl pyrazolopyrimidine derivative is shown as a general formula I, a formula II or a formula III
Figure DDA0002362932720000011
Wherein R is1Selected from hydrogen, C1-6 straight chain or branched chain alkyl and trihalomethyl; r2Selected from hydrogen, halogen, nitro, C1-6 straight chain or branched chain alkyl, trifluoromethyl and cyano; r3Selected from amino; r4Selected from substituted amide groups. The compound has certain BTK inhibitory activity.

Description

1-substituted benzyl pyrazolopyrimidine derivative and preparation method and application thereof
Technical Field
The invention relates to the field of organic compound synthesis and medical application, in particular to a 1-substituted benzyl pyrazolopyrimidine derivative and a preparation method and application thereof.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
BTK (Bruton's tyrosine kinase) belongs to the non-receptor tyrosine kinase Tec family, consisting of 659 amino acids, comprising 5 domains, from the amino terminus a PH domain (pleckstrin homology domain), a TH domain (Tec homology domain), a SH 3domain (Src homology 3domain), a SH 2domain (Src homology 2domain) and a catalytic domain (tyrosine kinase domain), respectively. (see Kawakami Y, Kitaura J, Hata D, Yao L, Kawakami T: Functions of Bruton's tyrosinase in mass and B cells. J Leukoc Biol 1999,65(3): 286) -290) wherein the PH domain recognizes and binds to PIP 3; (see Hyvonen M, Saraste M: Structure of the PH domain and Btk motif from Bruton's tyrosine kinase: molecular extensions for X-linked agammaglobulinemia. EMBO J1997, 16(12): 3396-; (see Vihinen M, Nilsson L, Smith CI: Tec Homology (TH) adjacent to the PH domain. FEBS Lett 1994,350(2-3): 263-265.) the SH 3domain comprises the autophosphorylation site Tyr 223; (see Park H, Wahl MI, Afar DE, Turck CW, Rawlings DJ, Tam C, Scharenberg AM, Kinet JP, Witte ON: Regulation of Btk function by a major autophosphorylation site with the SH3 domain. immunity 1996,4(5):515 and 525. SH) 2domain recognizes phosphorylated tyrosine residues with a specific peptide sequence; the catalytic domain is a hinge-linked double-leaf structure, and the hinge domain (amino acid residue 475-. Src family kinases phosphorylate Tyr551, (see Rawlings DJ, Scharenberg AM, Park H, Wahl MI, Lin S, Kato RM, Fluckiger AC, Witte ON, Kinet JP: Activation of BTK by a phosphorylation mechanism initial by SRC family kinases, science 1996,271(5250), 822-825.Kurosaki T, Kurosaki M: transduction of Bruton' S type kinase ON type 551, critical for B cell antibody receptor function, J Biol M1997, 272(25), 15595. 15598.) Tyr223 is then phosphorylated by itself, leaving BTK in an activated state. (see Satterhwaite AB, Li Z, Witte ON: Btk function in B cell resolution and response. Semin Immunol 1998,10(4): 309-316). Over-activation of the B Cell Receptor (BCR) signaling pathway is an important factor in the development of B cell tumorigenesis. (see Niiro H, Clark EA: Regulation of B-cell wall by antisense-receptors signals Nat Rev Immunol 2002,2(12):945 956.) BTK is an important regulatory molecule in the BCR signaling pathway. (see Buggy JJ, Elias L: Bruton Type Kinase (BTK) and its role in B-cell malignance. int Rev Immunol 2012,31(2): 119-132.) BTK is overexpressed in B-cell lymphomas and it is desirable to provide a BTK inhibitor for treatment of the B-cell lymphomas.
Disclosure of Invention
The invention aims to provide a 1-substituted benzyl pyrazolopyrimidine derivative with BTK (BTK) inhibitory activity, and a preparation method and application of the derivative.
In order to achieve the purpose, the technical scheme of the invention is as follows:
in one aspect of the invention, the structure of the 1-substituted benzyl pyrazolopyrimidine derivative is shown as general formula I, formula II or formula III:
Figure BDA0002362932710000021
wherein R is1Selected from hydrogen, C1-6 straight chain or branched chain alkyl and trihalomethyl; r2Selected from hydrogen, halogen, nitro, C1-6 straight chain or branched chain alkyl, trifluoromethyl and cyano; r3Selected from amino; r4Selected from substituted amide groups.
Further, R1Selected from hydrogen, methyl, trifluoromethyl; r2Selected from fluorine, chlorine, bromine, nitro; r3Selected from amino; r4Selected from the group consisting of chloroacetamide and acrylamide groups.
Further, a compound selected from the group consisting of:
4- (4-amino-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide (I-1)
4- (4-amino-1- (2-chlorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide (I-2)
4- (4-amino-1- (2-bromobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide (I-3)
4- (4-amino-1- (2-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide (I-4)
4- (4-amino-1- (3-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide (I-5)
4- (4-amino-1- (4-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide (I-6)
4- (4-amino-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide (I-7)
4- (4-amino-1- (2-chlorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide (I-8)
4- (4-amino-1- (2-bromobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide (I-9)
4- (4-amino-1- (2-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide (I-10)
4- (4-amino-1- (3-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide (I-11)
4- (4-amino-1- (4-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide (I-12)
4- (4-amino-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-13)
4- (4-amino-1- (2-chlorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-14)
4- (4-amino-1- (2-bromobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-15)
4- (4-amino-1- (2-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-16)
4- (4-amino-1- (3-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-17)
4- (4-amino-1- (4-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (I-18)
4- (4-amino-1- (2-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide (II-1)
4- (4-amino-1- (3-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide (II-2)
4- (4-amino-1- (4-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide (II-3)
4- (4-amino-1- (2-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide (II-4)
4- (4-amino-1- (3-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide (II-5)
4- (4-amino-1- (4-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide (II-6)
4- (4-amino-1- (2-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (II-7)
4- (4-amino-1- (3-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (II-8)
4- (4-amino-1- (4-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (II-9)
4- (4-amino-1- (2-chloroacetylamino-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (III-1)
4- (4-amino-1- (2-allylamido-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (III-2)
4- (4-amino-1- (3-chloroacetylamino-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (III-3)
4- (4-amino-1- (3-allylamido-benzyl (-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (III-4)
4- (4-amino-1- (4-chloroacetylamino-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (III-5)
4- (4-amino-1- (4-allylamido-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (III-6).
The above-mentioned 33 compounds are named after the corresponding reference numbers in parentheses, and for the convenience of description and the simplicity of expression, the above-mentioned reference numbers in parentheses will be directly applied in the following description of the present specification.
In another aspect of the present invention, the process for preparing the above-mentioned 1-substituted benzylpyrazolopyrimidine derivative comprises preparing a compound of formula (I, II, III) by the following reaction scheme starting from compound 1 and compound 3:
Figure BDA0002362932710000041
wherein R is1、R2、R3And R4As defined above, X is hydroxy or halogen.
Further, the method comprises the following steps: carrying out substitution reaction on the compound 1 and N-bromosuccinimide (NBS) to obtain an intermediate 2; condensing the compound 3 and 4-bromobenzoic acid under the conditions of O-benzotriazole-tetramethyluronium Hexafluorophosphate (HBTU) and triethylamine to obtain an intermediate 4; intermediate 4 in Palladium acetate (Pd (OAc)2) 2-dicyclohexyl phosphonium-2, 4, 6-triisopropyl biphenyl (X-PHOS) and potassium acetate (KOAc) to be coupled with pinacol diboron to obtain an intermediate 5; intermediate 5 with intermediate 2 in tetrakis (triphenylphosphine) palladium (Pd (PPh)3)4) Obtaining an intermediate 6 through Suzuki reaction under catalysis; intermediate 6 and
Figure BDA0002362932710000051
nucleophilic substitution is carried out to obtain a compound shown in a general formula I; reducing the nitro-containing compound shown in the general formula I by iron powder to obtain an amino-containing compound shown in the general formula II; condensing part of the amino-containing compound in the general formula II with substituted acyl chloride to obtain the compound in the general formula III.
In a more specific embodiment of the present invention, the preparation method may comprise:
Figure BDA0002362932710000052
reagents and conditions: (a) NBS, N, N-Dimethylformamide (DMF),80 ℃,3 h; (b) 4-bromobenzoic acid, HBTU, triethylamine, DMF, r.t.,12 h; (c) pd (OAc)2X-PHOS, KOAc, pinacol diboron, 1, 4-dioxane, 90 ℃,12 h; (d) pd (PPh)3)4Potassium phosphate (K)3PO4) 1, 4-dioxane, water (4: 1,135 ℃) and 30 hours; (e) substituted bromobenzyl, potassium carbonate (K)2CO3) DMF, r.t.,10 h; (f) reduced iron powder, ammonium chloride, ethanol: water 3:1, 90 ℃; (g) substituted acyl chloride, N, N-Diisopropylethylamine (DIEA), Tetrahydrofuran (THF), 0-r.t., 5h.
The room temperature in the invention is 20-30 ℃.
Further, dissolving the starting compound 1 in DMF, adding NBS, stirring, reacting at 80 ℃ for 3h, detecting by TLC, reacting basically completely, cooling to room temperature, pouring the reaction solution into ice water, stirring, precipitating a large amount of yellow solid, filtering, washing a filter cake with ice water, and drying to obtain an intermediate 2;
dissolving 4-bromobenzoic acid, HBTU and triethylamine in DMF, reacting at room temperature for 20min, adding the starting material 3, reacting at room temperature for 12h, pouring the reaction solution into water, filtering, drying the filter cake, and performing silica gel column chromatography (petroleum ether: ethyl acetate: 30: 1) to obtain an intermediate 4;
taking Pd (OAc)2X-PHOS, dissolved in 1, 4-dioxane, N2Stirring at room temperature for 20min, dissolving intermediate 4 in 1, 4-dioxane, adding pinacol diborate and KOAc, adding activated ligand solution, N2Protecting, reacting at 90 ℃ for 12h, after the reaction is finished, performing hot filtration by using diatomite, evaporating the solvent under reduced pressure, and performing silica gel column chromatography (petroleum ether: ethyl acetate: 30:1-5:1) to obtain an intermediate 5;
taking intermediate 5, intermediate 2 and Pd (PPh)3)4、K3PO4Adding into a two-necked bottle, dissolving with solvent (1, 4-dioxane: water: 4:1), removing oxygen and N in the solution with ultrasound2Displacing air in the apparatus, N2Protection, refluxing at 135 ℃, reacting for 30h, detecting by TLC, and basically completely reacting. Cooling the reaction solution to room temperature, filtering with diatomite, evaporating the filtrate under reduced pressure, and making silica gel columnChromatography (dichloromethane: methanol 100:1-60:1) to give intermediate 6;
dissolving intermediate 6 in DMF, adding different substituted bromobenzyl, K2CO3Stirring at room temperature for 10h, after the reaction is finished, pouring the reaction liquid into ice water, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, drying, filtering, evaporating the solvent under reduced pressure, and performing silica gel column chromatography (dichloromethane/methanol is 100:1-60:1) to obtain the target compound I.
The synthetic route is as follows:
Figure BDA0002362932710000061
reagents and conditions: (a) NBS, DMF,80 ℃,3 h; (b) 4-bromobenzoic acid, HBTU, triethylamine, DMF, r.t.,12 h; (c) pd (OAc)2X-PHOS, KOAc, pinacol diboron, 1, 4-dioxane, 90 ℃,12 h; (d) pd (PPh)3)4,K3PO41, 4-dioxane, water (4: 1,135 ℃) and 30 hours; (e) substituted bromobenzyls, K2CO3,DMF,r.t.,10h.
Dissolving I-4, I-5, I-6, I-10, I-11, I-12, I-16, I-17 or I-18 in ethanol: adding reducing iron powder and ammonium chloride into the solution with the ratio of water to the solution of 3:1, refluxing for 5h at 90 ℃, filtering by using kieselguhr, evaporating the solvent under reduced pressure, adding water, and filtering to respectively obtain the amino-containing target compound II.
The synthetic route is as follows:
Figure BDA0002362932710000062
reagents and conditions: (f) reduced iron powder, ammonium chloride, ethanol: water 3:1, 90 ℃.
Dissolving II-7, II-8 or II-9 in THF, adding DIEA in ice bath, dropwise adding different substituted acyl chlorides, reacting at room temperature for 5h, evaporating under reduced pressure to remove the solvent, and performing column chromatography (dichloromethane: methanol: 100:1-40:1) to obtain a final product III.
The synthetic route is as follows:
Figure BDA0002362932710000071
reagents and conditions: (g) substituted acyl chloride, DIEA, THF, 0-r.t., 5h.
In a third aspect of the present invention, a pharmaceutical composition comprises the above-mentioned 1-substituted benzylpyrazolopyrimidine derivative or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition of the present invention may be administered in any manner selected from the group consisting of: oral, aerosol inhalation, rectal, nasal, parenteral (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection).
In a fourth aspect of the present invention, a pharmaceutical preparation comprises an active ingredient and a pharmaceutically acceptable adjuvant and/or carrier, wherein the active ingredient comprises the above 1-substituted benzylpyrazolopyrimidine derivative or a pharmaceutically acceptable salt thereof, or comprises the above pharmaceutical composition.
The administration form of the present invention may be a solution form, a colloidal solution form, an emulsion form, a suspension form, a gas dispersion form, a fine particle dispersion form, a solid dispersion form or the like. The solution type is a uniform dispersion system in which the drug is dispersed in a dispersion medium in a molecular or ionic state (particle diameter is less than 1nm), such as aromatic water, solution, syrup, glycerin, spirit, injection, etc. The colloidal solution type is a uniform dispersion system in which a polymer (particle diameter of 1 to 100nm) is dispersed in a dispersion medium, and is also called a polymer solution, such as a mucilage, a collodion, a film coating agent, and the like. The emulsion is a non-uniform dispersion system formed by dispersing oily medicine or medicine oil solution in a dispersion medium in a droplet state, such as oral emulsion, intravenous injection emulsion, partial liniment and the like. The suspension type is a non-uniform dispersion system in which a solid drug is dispersed in a dispersion medium in a particulate state, such as a mixture, a lotion, a suspension, and the like. The gas dispersion type is a dispersion system in which a liquid or solid drug is dispersed in a gas dispersion medium in a particulate state, such as an aerosol. The microparticle dispersion type is that the medicine is dispersed in liquid or solid state by microparticles with different sizes, such as microsphere preparation, microcapsule preparation, nanometer capsule preparation, etc. The solid dispersion type is a dispersion system in which a solid drug exists in an aggregate state, such as a tablet, powder, granule, capsule, pill, and the like.
In a fifth aspect of the invention, the 1-substituted benzyl pyrazolopyrimidine derivative or a pharmaceutically acceptable salt thereof or the pharmaceutical composition is used for preparing a BTK inhibitor drug.
In a sixth aspect of the present invention, an application of the 1-substituted benzyl pyrazolopyrimidine derivative or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing an antitumor drug is provided.
Further, the tumor is a B cell lymphoma.
In a seventh aspect of the present invention, an application of the above 1-substituted benzyl pyrazolopyrimidine derivative or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the preparation of a medicament for treating B-cell lymphoma.
The invention has the beneficial effects that:
experimental example data show that the 1-substituted benzyl pyrazolopyrimidine derivative has certain BTK inhibitory activity, II-8, III-2, III-3 and III-5 have equivalent BTK inhibitory activity, and III-2, III-3 and III-5 have the strongest BTK inhibitory activity.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
In order to make the technical solution of the present invention more clearly understood by those skilled in the art, the technical solution of the present invention will be described in detail below with reference to specific examples and comparative examples.
Example (b):
example 1 preparation of intermediate 2:
dissolving 4-aminopyrazolo [3,4-d ] pyrimidine (5g,37mmol) in 30mL DMF, adding NBS (7.9g, 44.4mmol), reacting at 80 ℃ for 3h, detecting by TLC to ensure that the reaction is basically complete, cooling to room temperature, pouring the reaction liquid into 300mL ice water, stirring to separate out a large amount of yellow solid, filtering, washing a filter cake with ice water, and drying to obtain 6.33g of light yellow solid with the yield of 79.9%.
Example 2 preparation of intermediate 4:
preparation of intermediate 4 a:
4-bromobenzoic acid (2.55g, 12.7mmol), HBTU (4.8g, 12.7mmol), triethylamine (3.5g, 34.5mmol) were dissolved in 20mL of DMF, and the mixture was reacted at room temperature for 20min, then 2-aminopyridine (11.5mmol) was added, and the reaction mixture was reacted at room temperature for 12h, poured into 200mL of water, filtered by suction, the filter cake was dried, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate: 30: 1) to obtain intermediate 4 a.
Preparation of intermediate 4 b:
compound 3 was prepared from 2-amino-4-methylpyridine, in the same manner as for the preparation of intermediate 4 a.
Preparation of intermediate 4 c:
compound 3 was prepared from 2-amino-4-trifluoromethylpyridine as starting material in the same manner as for the preparation of intermediate 4 a.
Example 3 preparation of intermediate 5:
preparation of intermediate 5 a:
taking Pd (OAc)2(315mg,1.4mmol), X-PHOS (1.3g,2.8mmol), dissolved in 14mL of 1, 4-dioxane, N2Stirring at room temperature for 20min, dissolving intermediate 4a (28.1mmol) in 100mL of 1, 4-dioxane, adding pinacol diboron (14.42g,56mmol) and KOAc (8.4g, 84mmol), and adding the activated ligand solution, N2Protection, reaction at 90 ℃ for 12h, and finishing the reactionHot-filtering with diatomite, evaporating the solvent under reduced pressure, and performing silica gel column chromatography (petroleum ether: ethyl acetate: 30:1-5:1) to obtain an intermediate 5 a.
Preparation of intermediates 5b, 5c and intermediate 5a, intermediate 4a was replaced with intermediates 4b, 4c, respectively.
Example 4 preparation of intermediate 6:
preparation of intermediate 6 a:
intermediate 5a (18.69mmol), intermediate 5(2g,9.34mmol) and Pd (PPh) were collected3)4(531mg,0.46mmol)、K3PO4(5.95g,28.02mmol) was added to a 250mL two-necked flask, and 100mL of a solvent (1, 4-dioxane: water 4:1) was added to dissolve the mixture, and oxygen and N in the solution were removed by sonication2Displacing air in the apparatus, N2And (4) protection, heating and refluxing in an oil bath at 135 ℃, reacting for 30 hours, detecting by TLC, and basically completely reacting. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was evaporated under reduced pressure and subjected to silica gel column chromatography (dichloromethane: methanol: 100:1-60:1) to give intermediate 6 a.
Preparation of intermediates 6b, 6c and intermediate 6a, intermediate 5a was replaced with intermediates 5b, 5c, respectively.
Example 5 preparation of the object compound I:
preparation of I-1:
intermediate 6a (1mmol) was dissolved in 3mL DMF and 2-fluorobenzyl bromide (1.2mmol), K was added2CO3(0.21g,1.5mmol), stirring at room temperature for 10h, after the reaction is completed, pouring the reaction solution into 30mL ice water, extracting with ethyl acetate (30mL × 3), combining the organic phases, washing with saturated brine, drying, filtering, evaporating the solvent under reduced pressure, and performing silica gel column chromatography (dichloromethane/methanol ═ 80:1) to obtain a part of the target compound I-1.
The preparation of I-2-1-18 is the same as the preparation process of I-1, and the intermediate 6 is obtained by performing the preparation steps of I-1 on an intermediate 6a, an intermediate 6b and an intermediate 6c respectively with 2-fluorobenzyl bromide, 2-chlorobenzyl bromide, 2-bromobenzyl bromide, 2-nitrobenzyl bromide, 3-nitrobenzyl bromide and 4-nitrobenzyl bromide.
II-1 preparation:
dissolve I-4(1mmol) in EtOH: adding reducing iron powder (2mmol) and ammonium chloride (3mmol) into the solution with the ratio of water to the solution of 3:1, refluxing for 5h at 90 ℃, filtering by using kieselguhr, evaporating the solvent under reduced pressure, adding water, and filtering to obtain the target compound II-1 containing amino.
The preparation of II-2-II-9 is the same as the preparation process of II-1, and the preparation steps of II-1 are carried out on I-4, I-5, I-6, I-10, I-11, I-12, I-16, I-17 and I-18.
Preparation of III-1:
dissolving II-7(0.5mmol) in THF, adding DIEA (1mmol) in ice bath, dropwise adding chloroacetyl chloride (0.6mmol), reacting at room temperature for 5h, removing the solvent by evaporation under reduced pressure, and performing column chromatography (dichloromethane: methanol ═ 60:1) to obtain the final product III-1.
The preparation of III-2 to III-6 is the same as the preparation process of III-1, and II-7, II-8 and II-9 are respectively obtained by the step of preparing III-1 with chloroacetyl chloride and acryloyl chloride.
I. The structures of II and III are characterized as follows:
i-1:4- (4-amino-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide
White solid, yield 67%, Mp:204-,1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.41(d,J＝3.9Hz,1H),8.33(s,1H),8.21(t,J＝9.0Hz,3H),7.86(t,J＝7.7Hz,1H),7.79(d,J＝8.1Hz,2H),7.44–6.97(m,7H),5.65(s,2H).13C NMR(100MHz,DMSO-d6)δ166.02,161.56,159.11,158.69,156.61,155.13,152.61,148.46,143.96,138.64,136.38,134.33,130.67,130.64,130.47,130.39,129.31,128.61,125.15,125.12,124.30,124.15,120.38,116.04,115.83,115.26,97.88,44.12,44.08.ESI-MS:m/z 440.27[M+H]+
i-2:4- (4-amino-1- (2-chlorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide
White solid, yield 70%, Mp:224-,1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.42(s,1H),8.31(s,1H),8.22(t,J＝8.2Hz,3H),7.87(t,J＝7.2Hz,1H),7.80(d,J＝8.1Hz,2H),7.51(d,J＝7.8Hz,1H),7.36-7.28(m,3H),7.21–7.16(m,1H),7.02(d,J＝7.2Hz,1H),5.69(s,2H).13C NMR(100MHz,DMSO-d6)δ166.01,158.74,156.65,155.37,152.62,148.46,144.14,138.64,136.37,134.78,134.35,132.38,129.96,129.91,129.85,129.32,128.62,128.01,120.38,115.26,97.90,47.92.ESI-MS:m/z 456.14[M+H]+
i-3:4- (4-amino-1- (2-bromobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide
White solid, yield 61%, Mp:240-,1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.41(d,J＝4.5Hz,1H),8.31(s,1H),8.22(t,J＝8.2Hz,3H),7.89–7.84(m,1H),7.81(d,J＝8.2Hz,2H),7.68(d,J＝7.8Hz,1H),7.37–7.23(m,3H),7.19(dd,J＝7.0,5.1Hz,1H),6.93(d,J＝7.4Hz,1H),5.66(s,2H).13C NMR(100MHz,DMSO-d6)δ166.02,158.74,156.66,155.41,152.61,148.46,144.18,138.64,136.37,134.37,133.17,130.16,129.68,129.31,128.63,128.55,122.45,120.39,115.26,97.92,50.34.ESI-MS:m/z 500.22[M+H]+
i-4:4- (4-amino-1- (2-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide
Off-white solid, yield 59%, Mp:236-238 deg.C,1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.41(d,J＝3.9Hz,1H),8.29(s,1H),8.21(t,J＝8.0Hz,3H),8.14(d,J＝8.1Hz,1H),7.90–7.83(m,1H),7.79(d,J＝8.2Hz,2H),7.68(t,J＝7.5Hz,1H),7.59(t,J＝7.8Hz,1H),7.19(dd,J＝7.2,5.0Hz,1H),6.98(d,J＝7.6Hz,1H),5.97(s,2H).13C NMR(100MHz,DMSO-d6)δ166.01,158.77,156.74,155.54,152.62,148.45,148.18,144.40,138.63,136.27,134.65,134.43,132.24,129.86,129.57,129.32,128.62,125.46,120.38,115.26,97.98,47.42.ESI-MS:m/z 467.05[M+H]+
i-5:4- (4-amino-1- (3-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide
White solid, yield 69%, Mp:225-,1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.42(d,J＝4.7Hz,1H),8.34(s,1H),8.24-8.20(m,5H),8.17(d,J＝8.1Hz,1H),7.92–7.78(m,4H),7.75(d,J＝7.7Hz,1H),7.65(t,J＝7.9Hz,1H),7.19(dd,J＝7.1,5.1Hz,1H),5.77(s,2H).13C NMR(100MHz,DMSO-d6)δ166.01,158.75,156.77,155.19,152.61,148.46,148.32,144.25,139.68,138.64,136.29,134.78,134.40,130.80,129.33,128.62,123.17,122.80,120.39,115.26,97.98,49.52.ESI-MS:m/z 467.13[M+H]+
i-6:4- (4-amino-1- (4-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide
White solid, yield 68%, Mp:247-,1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.42(d,J＝4.7Hz,1H),8.33(s,1H),8.22(t,J＝7.6Hz,6H),7.93–7.80(m,4H),7.54(d,J＝8.7Hz,2H),7.19(dd,J＝7.0,5.1Hz,1H),5.77(s,2H).13C NMR(100MHz,DMSO-d6)δ166.01,158.74,156.75,155.24,152.61,148.46,147.42,145.08,144.28,138.64,136.28,134.39,129.32,129.17,128.63,124.32,120.39,115.26,97.97,49.72.ESI-MS:m/z 467.11[M+H]+
i-7: 4- (4-amino-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide
White solid, yield 74%, Mp:212-,1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.32(s,1H),8.26(d,J＝5.0Hz,1H),8.19(d,J＝8.2Hz,2H),8.08(s,1H),7.78(d,J＝8.2Hz,2H),7.37(q,J＝6.1Hz,1H),7.26-7.14(m,4H),7.11-6.63(m,2H),5.65(s,2H),2.37(s,3H).13C NMR(100MHz,DMSO-d6)δ165.92,161.56,159.11,158.69,156.60,155.13,152.65,149.33,148.07,143.97,136.34,134.39,130.68,130.64,130.48,130.40,129.25,128.60,125.15,125.12,124.30,124.15,121.40,116.04,115.83,115.64,97.87,44.12,44.08,21.42.ESI-MS:m/z 454.10[M+H]+
i-8:4- (4-amino-1- (2-chlorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide
White solid, yield 79%, Mp:226-,1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.31(s,1H),8.26(d,J＝5.0Hz,1H),8.19(d,J＝8.3Hz,2H),8.09(s,1H),7.79(d,J＝8.3Hz,2H),7.52(d,J＝7.8Hz,1H),7.40–7.26(m,3H),7.04-7.01(m,3H),5.69(s,2H),2.37(s,3H).13C NMR(100MHz,DMSO-d6)δ165.92,158.73,156.65,155.37,152.65,149.33,148.08,144.14,136.32,134.78,134.42,132.38,129.96,129.92,129.86,129.26,128.62,128.01,121.40,115.64,97.89,47.92,21.43.ESI-MS:m/z 470.14[M+H]+
i-9:4- (4-amino-1- (2-bromobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide
White solid, yield 66%, Mp:224-,1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.30(s,1H),8.26(d,J＝5.0Hz,1H),8.19(d,J＝8.3Hz,2H),8.08(s,1H),7.80(d,J＝8.3Hz,2H),7.68(d,J＝7.8Hz,1H),7.35-7.24(m,3H),7.03(d,J＝4.9Hz,1H),6.93(d,J＝7.5Hz,1H),5.66(s,2H),2.37(s,3H).13C NMR(100MHz,DMSO-d6)δ170.82,165.91,158.72,156.64,155.39,149.33,148.07,144.17,136.36,136.30,134.41,133.16,130.17,129.68,129.25,128.62,128.56,122.44,121.40,115.63,97.90,50.33,21.43.ESI-MS:m/z 513.97[M+H]+
i-10: 4- (4-amino-1- (2-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide
White solid, yield 72%, Mp:228-,1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.29(s,1H),8.26(d,J＝5.0Hz,1H),8.20(d,J＝8.3Hz,2H),8.14(d,J＝7.7Hz,1H),8.09(s,1H),7.79(d,J＝8.2Hz,2H),7.63(dt,J＝34.4,7.3Hz,2H),7.01(dd,J＝16.2,6.3Hz,2H),5.97(s,2H),2.37(s,3H).13C NMR(100MHz,DMSO-d6)δ165.91,158.76,156.74,155.53,152.66,149.32,148.18,148.07,144.40,136.22,134.66,134.48,132.23,129.85,129.57,129.26,128.61,125.46,121.39,115.63,97.95,47.40,21.42.ESI-MS:m/z 481.15[M+H]+
i-11: 4- (4-amino-1- (3-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide
White solid, yield 75%, Mp:210-,1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.34(s,1H),8.26(d,J＝5.0Hz,1H),8.21-8.08(m,4H),8.08(s,1H),7.80(d,J＝8.3Hz,2H),7.74(d,J＝7.7Hz,1H),7.65(t,J＝7.9Hz,1H),7.03(d,J＝5.0Hz,1H),5.77(s,2H),2.37(s,3H).13C NMR(100MHz,DMSO-d6)δ165.91,158.75,156.76,155.19,152.65,149.32,148.32,148.07,144.25,139.68,136.24,134.78,134.46,130.79,129.27,128.62,123.16,122.80,121.39,115.64,97.98,49.52,21.42.ESI-MS:m/z 481.11[M+H]+
i-12: 4- (4-amino-1- (4-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide
White solid, yield 71%, Mp:222-,1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.32(s,1H),8.26(d,J＝5.0Hz,1H),8.22-8.19(m,4H),8.08(s,1H),7.80(d,J＝8.2Hz,2H),7.53(d,J＝8.6Hz,2H),7.02(d,J＝4.9Hz,1H),5.76(s,2H),2.37(s,3H).13C NMR(100MHz,DMSO-d6)δ165.91,158.74,156.75,155.24,152.64,149.33,148.07,147.42,145.07,144.29,136.24,134.45,129.26,129.16,128.63,124.31,121.40,115.64,97.97,49.71,21.42.ESI-MS:m/z 481.18[M+H]+
i-13: 4- (4-amino-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
White solid, yield 73%, Mp:248- & 250 ℃,1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),8.70(d,J＝5.1Hz,1H),8.58(s,1H),8.32(s,1H),8.22(d,J＝8.3Hz,2H),7.81(d,J＝8.3Hz,2H),7.57(d,J＝5.0Hz,1H),7.40-7.34(m,1H),7.32-6.73(m,5H),5.65(s,2H).13C NMR(100MHz,DMSO-d6)δ166.67,161.56,159.12,158.70,156.61,155.16,153.72,150.39,143.89,139.30,138.97,138.64,138.31,136.74,133.80,130.67,130.63,130.46,130.38,129.46,128.65,127.50,125.14,125.10,124.78,124.29,124.15,122.07,119.35,116.03,115.82,115.67,115.64,110.36,110.32,110.28,110.24,97.91,44.13,44.09.ESI-MS:m/z 508.09[M+H]+
i-14: 4- (4-amino-1- (2-chlorobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
Light yellow solid, yield 71%, Mp:210-,1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),8.70(d,J＝5.1Hz,1H),8.58(s,1H),8.31(s,1H),8.22(d,J＝8.2Hz,2H),7.82(d,J＝8.2Hz,2H),7.56(d,J＝4.4Hz,1H),7.51(d,J＝7.8Hz,1H),7.44-7.15(m,3H),7.12-6.66(m,2H),5.69(s,2H).13C NMR(100MHz,DMSO-d6)δ166.68,158.70,156.60,155.37,153.72,150.42,144.08,138.97,138.66,136.71,134.76,133.83,132.39,129.97,129.92,129.88,129.47,128.68,128.01,124.79,122.07,115.75,115.71,115.68,115.63,110.37,110.33,110.28,110.24,97.92,47.94.ESI-MS:m/z 524.08[M+H]+
i-15: 4- (4-amino-1- (2-bromobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
Light yellow solid, yield 65%, Mp:218-220 ℃,1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),8.71(d,J＝5.1Hz,1H),8.58(s,1H),8.31(s,1H),8.22(d,J＝8.2Hz,2H),7.83(d,J＝8.2Hz,2H),7.69(d,J＝7.8Hz,1H),7.57(d,J＝5.1Hz,1H),7.33(t,J＝7.5Hz,1H),7.27(t,J＝7.0Hz,1H),6.94(d,J＝6.9Hz,1H),5.67(s,2H).13C NMR(100MHz,DMSO-d6)δ166.68,158.74,156.66,155.42,153.71,150.41,144.11,139.30,138.97,138.64,138.31,136.71,136.35,133.83,133.17,130.17,129.69,129.47,128.68,128.55,127.51,124.78,122.46,122.06,119.34,115.73,115.70,115.66,115.64,110.36,110.32,110.28,110.24,97.93,50.35.ESI-MS:m/z 568.02[M+H]+
i-16:4- (4-amino-1- (2-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
Off-white solid, yield 55%, Mp:105- & 108 ℃,1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),8.70(d,J＝5.0Hz,1H),8.58(s,1H),8.29(s,1H),8.22(d,J＝8.3Hz,2H),8.14(d,J＝7.3Hz,1H),7.81(d,J＝8.3Hz,2H),7.68(t,J＝7.2Hz,1H),7.61-7.56(m,2H),6.98(d,J＝7.7Hz,1H),5.97(s,2H).13C NMR(100MHz,DMSO-d6)δ166.66,158.76,156.74,155.55,153.72,150.39,148.18,144.32,139.31,138.98,138.65,138.32,136.62,134.64,133.89,132.21,129.85,129.57,129.47,128.66,127.49,125.45,124.78,122.06,119.34,115.67,115.64,115.62,110.35,110.31,110.27,110.23,97.98,47.42.ESI-MS:m/z 533.23[M-H]-
i-17- (4-amino-1- (3-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
White solid, yield 69%, Mp:248-,1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),8.69(d,J＝4.7Hz,1H),8.57(s,1H),8.34(s,1H),8.24(s,1H),8.22(s,2H),8.15(d,J＝7.9Hz,1H),7.83(d,J＝7.8Hz,2H),7.74(d,J＝7.4Hz,1H),7.64(t,J＝7.8Hz,1H),7.54(d,J＝4.4Hz,1H),7.44-6.20(s,2H),5.77(s,2H).13C NMR(100MHz,DMSO-d6)δ166.64,158.75,156.75,155.21,153.71,150.35,148.30,144.18,139.64,139.30,138.97,138.64,138.31,136.64,134.75,133.87,130.74,129.48,128.66,127.48,124.76,123.12,122.80,122.05,119.33,115.68,115.63,115.60,115.57,110.31,110.27,110.23,98.01,49.54.ESI-MS:m/z 533.40[M-H]-
i-18- (4-amino-1- (4-nitrobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
White solid, yield 68%, Mp:224-,1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),8.70(d,J＝5.1Hz,1H),8.58(s,1H),8.32(s,1H),8.22(dd,J＝8.6,2.4Hz,4H),7.83(d,J＝8.3Hz,2H),7.58-7.52(m,3H),5.77(s,2H).13C NMR(100MHz,DMSO-d6)δ166.65,158.75,156.75,155.27,153.72,150.37,147.43,145.04,144.22,139.30,138.98,138.65,136.65,133.86,129.47,129.16,128.68,127.40,124.78,124.29,122.06,119.44,115.65,115.63,110.32,110.27,110.24,98.01,49.73.ESI-MS:m/z 533.57[M-H]-
II-1:4- (4-amino-1- (2-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide
White solid, yield 63%, Mp:250-,1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.41(d,J＝4.1Hz,1H),8.33(s,1H),8.22(t,J＝8.2Hz,3H),7.86(t,J＝7.3Hz,1H),7.80(d,J＝8.1Hz,2H),7.21–7.16(m,1H),7.00(t,J＝7.6Hz,1H),6.95(d,J＝7.3Hz,1H),6.67(d,J＝7.9Hz,1H),6.52(t,J＝7.3Hz,1H),5.42(s,2H),5.39(s,2H).13C NMR(100MHz,DMSO-d6)δ166.02,158.74,156.49,154.69,152.62,148.46,146.90,143.54,138.63,136.40,134.31,130.21,129.32,129.22,128.57,120.52,120.38,116.70,115.74,115.27,97.78,47.63.ESI-MS:m/z 437.07[M+H]+
II-2:4- (4-amino-1- (3-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide
White solid, yield 61%, Mp:226-,1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.41(d,J＝3.9Hz,1H),8.31(s,1H),8.22(t,J＝8.4Hz,3H),7.87(t,J＝7.8Hz,1H),7.80(d,J＝8.3Hz,2H),7.22–7.16(m,1H),6.95(t,J＝7.8Hz,1H),6.46(t,J＝7.1Hz,3H),5.42(s,2H),5.10(s,2H).13C NMR(100MHz,DMSO-d6)δ166.03,158.66,156.48,154.93,152.63,149.36,148.46,143.46,138.63,138.08,136.57,134.22,129.49,129.30,128.59,120.37,115.46,115.27,113.61,113.21,97.88,50.68.ESI-MS:m/z 437.12[M+H]+
II-3:4- (4-amino-1- (4-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (pyridin-2-yl) benzamide
White solid, yield 72%, Mp:224-,1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.41(d,J＝4.7Hz,1H),8.31(s,1H),8.21(dd,J＝10.9,8.6Hz,3H),7.86(t,J＝8.6Hz,1H),7.78(d,J＝8.2Hz,2H),7.21–7.16(m,1H),7.05(d,J＝8.3Hz,2H),6.49(d,J＝8.3Hz,2H),5.38(s,2H),5.07(s,2H).13C NMR(100MHz,DMSO-d6)δ166.03,158.62,156.38,154.61,152.63,148.79,148.46,143.23,138.63,136.63,134.17,129.43,129.29,128.56,124.30,120.37,115.27,114.14,97.92,50.38.ESI-MS:m/z 437.05[M+H]+
II-4:4- (4-amino-1- (2-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide
White solid, yield 68%, Mp:205-,1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.33(s,1H),8.26(d,J＝5.0Hz,1H),8.20(d,J＝8.2Hz,2H),8.09(s,1H),7.79(d,J＝8.2Hz,2H),7.03-6.98(m,2H),6.94(d,J＝7.2Hz,1H),6.67(d,J＝7.9Hz,1H),6.51(t,J＝7.4Hz,1H),5.41(s,4H).13C NMR(100MHz,DMSO-d6)δ165.91,158.75,156.48,154.69,152.66,149.30,148.06,146.91,143.54,136.36,134.38,130.23,129.28,129.22,128.57,121.38,120.54,116.70,115.76,115.65,97.78,45.84,21.41.ESI-MS:m/z 451.07[M+H]+
II-5:4- (4-amino-1- (3-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide
Off-white solid, yield 68%, Mp:224- & 226 ℃,1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.32(s,1H),8.26(d,J＝4.8Hz,1H),8.20(d,J＝7.9Hz,2H),8.09(s,1H),7.80(d,J＝8.0Hz,2H),7.03(d,J＝4.5Hz,1H),6.96(t,J＝7.7Hz,1H),6.47-6.44(m,3H),5.42(s,2H),5.11(s,2H),2.37(s,3H).13C NMR(100MHz,DMSO-d6)δ165.94,158.66,156.47,154.92,152.66,149.36,149.32,148.07,143.46,138.08,136.53,134.28,129.50,129.24,128.59,121.40,115.65,115.47,113.61,113.22,97.87,50.67,21.43.ESI-MS:m/z 451.12[M+H]+
II-6:4- (4-amino-1- (4-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4-methylpyridin-2-yl) benzamide
Orange solid, yield 58%, Mp:188-,1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.31(s,1H),8.26(d,J＝5.0Hz,1H),8.19(d,J＝8.3Hz,2H),8.08(s,1H),7.77(d,J＝8.3Hz,2H),7.06-7.02(m,3H),6.49(d,J＝8.3Hz,2H),5.37(s,2H),5.11(s,2H),2.37(s,3H).13C NMR(100MHz,DMSO-d6)δ165.93,158.61,156.38,154.61,152.66,149.30,148.80,148.08,143.23,136.58,134.23,129.42,129.24,128.55,124.28,121.39,115.65,114.13,97.90,50.37,21.43.ESI-MS:m/z 451.11[M+H]+
II-6- (4-amino-1- (2-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
Off-white solid, yield 69%, Mp:240-,1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),8.71(d,J＝5.0Hz,1H),8.58(s,1H),8.33(s,1H),8.22(d,J＝8.1Hz,2H),7.81(d,J＝8.1Hz,2H),7.57(d,J＝4.7Hz,1H),7.00(t,J＝7.6Hz,1H),6.93(d,J＝7.2Hz,1H),6.66(d,J＝7.8Hz,1H),6.51(t,J＝7.4Hz,1H),5.41(s,2H),5.39(s,2H).13C NMR(100MHz,DMSO-d6)δ166.69,158.75,156.49,154.71,153.73,150.41,146.90,143.47,139.30,138.97,138.64,138.32,136.76,133.78,130.21,129.48,129.22,128.62,127.50,124.79,122.07,120.52,116.70,116.70,115.75,115.68,115.66,110.36,110.33,110.29,110.25,97.80,47.64.ESI-MS:m/z 503.30[M-H]-
II-8- (4-amino-1- (3-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
Light pink solid with a yield of 73 percent and Mp:240-,1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),8.63(d,J＝4.8Hz,1H),8.51(s,1H),8.25(s,1H),8.16(d,J＝7.9Hz,2H),7.76(d,J＝7.9Hz,2H),7.48(d,J＝4.5Hz,1H),7.31–6.65(m,3H),6.40(s,3H),5.35(s,2H),5.03(s,2H).13C NMR(100MHz,DMSO-d6)δ166.70,158.67,156.48,154.95,153.73,150.40,149.36,143.39,139.30,138.97,138.65,138.32,138.07,136.93,133.70,129.49,129.46,128.65,124.79,122.07,119.36,115.70,115.67,115.64,115.61,115.48,113.63,113.23,110.37,110.33,110.29,110.25,97.91,50.69.ESI-MS:m/z 503.41[M-H]-
II-9- (4-amino-1- (4-aminobenzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
White solid, yield 75%, Mp 266-,1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),8.70(d,J＝5.1Hz,1H),8.57(s,1H),8.31(s,1H),8.21(d,J＝8.3Hz,2H),7.80(d,J＝8.2Hz,2H),7.56(d,J＝5.2Hz,1H),7.05(d,J＝8.3Hz,2H),6.49(d,J＝8.3Hz,2H),5.37(s,2H),5.08(s,2H).13C NMR(100MHz,DMSO-d6)δ166.74,158.63,156.39,154.64,153.94,150.40,148.79,143.18,139.26,138.93,138.60,136.94,133.79,129.45,129.43,128.60,124.81,124.30,122.09,115.56,115.53,114.15,110.41,110.37,110.33,110.29,97.94,50.40.ESI-MS:m/z 503.43[M-H]-
III-1:4- (4-amino-1- (2-chloroacetylamino-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
Off-white solid, yield 69%, Mp:158-,1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.34(s,1H),8.70(d,J＝4.8Hz,1H),8.57(s,1H),8.34(s,1H),8.22(d,J＝7.7Hz,2H),7.81(d,J＝7.8Hz,2H),7.56(d,J＝5.0Hz,1H),7.43(d,J＝7.9Hz,1H),7.32(t,J＝7.6Hz,1H),7.18(t,J＝7.5Hz,1H),7.07(d,J＝7.7Hz,1H),5.58(s,2H),4.40(s,2H).13C NMR(100MHz,DMSO-d6)δ166.66,165.78,158.69,156.45,154.84,153.72,150.38,143.91,139.29,138.98,138.65,138.32,136.65,135.46,133.82,131.45,129.47,129.41,128.75,128.66,126.60,126.26,124.78,122.06,119.34,115.67,115.64,110.33,110.29,97.89,47.09,43.79.
III-2- (4-amino-1- (2-allylamido-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
Off-white solid, yield 56%, Mp:136-,1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.18(s,1H),8.70(d,J＝5.0Hz,1H),8.58(s,1H),8.33(s,1H),8.22(d,J＝7.8Hz,2H),7.81(d,J＝7.8Hz,2H),7.56(d,J＝6.0Hz,2H),7.31(t,J＝7.6Hz,1H),7.15(t,J＝7.5Hz,1H),7.06(d,J＝7.7Hz,1H),6.56(dd,J＝16.9,10.2Hz,1H),6.31(d,J＝17.0Hz,1H),5.82(d,J＝10.2Hz,1H),5.59(s,2H).13C NMR(100MHz,DMSO-d6)δ166.67,164.04,158.76,156.52,154.87,153.72,150.38,143.82,139.30,138.98,138.65,138.32,136.68,135.95,133.80,132.21,130.80,129.45,129.27,128.65,127.42,126.01,125.59,124.78,122.06,115.70,115.67,115.63,110.32,110.28,110.24,97.89,47.25.ESI-MS:m/z 557.33[M-H]-
III-3- (4-amino-1- (3-chloroacetylamino-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
White solid, yield 60%, Mp:166-,1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.31(s,1H),8.70(d,J＝4.9Hz,1H),8.58(s,1H),8.32(s,1H),8.22(d,J＝8.1Hz,2H),7.83(d,J＝8.0Hz,2H),7.57(d,J＝5.5Hz,2H),7.46(s,1H),7.31(t,J＝7.7Hz,1H),7.08(d,J＝7.6Hz,1H),5.58(s,2H),4.21(s,2H).13C NMR(100MHz,DMSO-d6)δ166.69,165.13,158.50,156.33,154.96,153.73,150.42,143.81,139.30,139.23,138.98,138.65,138.21,136.76,133.80,129.64,129.48,128.68,124.79,123.66,122.08,119.07,118.75,115.70,115.67,110.37,110.33,110.29,110.25,97.92,50.38,44.01.ESI-MS:m/z 579.44[M-H]-
III-4- (4-amino-1- (3-allylamido-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
White solid, yield 56%, Mp:278-,1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.19(s,1H),8.69(d,J＝5.0Hz,1H),8.57(s,1H),8.54–8.46(m,3H),8.12(d,J＝8.4Hz,2H),7.64(d,J＝9.8Hz,2H),7.55(d,J＝4.9Hz,1H),7.32(t,J＝7.7Hz,1H),7.06(d,J＝7.6Hz,1H),6.40(dd,J＝16.9,10.2Hz,1H),6.24(dd,J＝17.0,1.7Hz,1H),5.74(dd,J＝10.3,1.4Hz,1H),5.61(s,2H).13C NMR(100MHz,DMSO-d6)δ166.69,163.66,158.68,156.58,155.02,153.72,150.40,143.70,139.81,139.29,138.96,138.64,138.31,138.10,136.83,133.76,132.31,129.50,129.47,128.68,127.33,124.78,123.30,122.06,119.08,118.79,115.67,115.64,110.32,110.28,97.94,50.42.ESI-MS:m/z 557.55[M-H]-
III-5- (4-amino-1- (4-chloroacetylamino-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
Grey solid, yield 59%, Mp:140-,1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.34(s,1H),8.70(d,J＝4.9Hz,1H),8.58(s,1H),8.33(s,1H),8.23(d,J＝8.0Hz,2H),7.83(d,J＝8.0Hz,2H),7.56(d,J＝7.2Hz,3H),7.32(d,J＝8.2Hz,2H),7.26-6.20(s,2H),5.56(s,2H),4.24(s,2H).13C NMR(100MHz,DMSO-d6)δ166.68,165.09,158.62,156.47,154.91,153.73,150.40,143.65,139.30,138.97,138.64,138.40,138.32,136.83,133.75,132.86,129.46,128.84,128.66,124.78,122.07,120.01,119.36,115.67,115.64,110.37,110.33,110.29,110.25,97.96,50.06,43.99.ESI-MS:m/z 579.34[M-H]-
III-6- (4-amino-1- (4-allylamido-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide
White solid, yield 54%, Mp:125-,1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.17(s,1H),8.70(d,J＝5.0Hz,1H),8.58(s,1H),8.32(s,1H),8.22(d,J＝8.2Hz,2H),7.81(d,J＝8.2Hz,2H),7.62(d,J＝8.3Hz,2H),7.57(d,J＝5.1Hz,1H),7.30(d,J＝8.4Hz,2H),6.41(dd,J＝17.0,10.1Hz,1H),6.24(d,J＝17.0Hz,1H),5.74(d,J＝9.9Hz,1H),5.54(s,2H).13C NMR(100MHz,DMSO-d6)δ166.68,163.58,158.69,156.55,154.92,153.73,150.39,143.60,139.17,138.97,138.93,138.64,138.31,136.86,133.73,132.49,132.27,129.46,128.79,128.66,127.37,124.79,122.07,119.95,115.66,115.64,110.33,110.29,110.25,97.97,50.10.ESI-MS:m/z 557.17[M-H]-
experimental example: the compound is used for BTK inhibitory activity test and kinase selectivity determination experiment.
1) Compound activity assay for inhibition of BTK kinase:
the experimental method comprises the following steps: all compounds tested were formulated in DMSO as 50-fold final assay concentration working solution. The compound working solution was first added as a first component to the test wells, followed by the addition of a kinase buffer (containing 8mM MOPS pH 7.0, 0.2mM EDTA, 250. mu. MKVEKIGEGTYGVVYK (Cdc2 peptide), 10mM magnesium acetate and [ gamma-33P ] -ATP) diluted BTK kinase solution. The addition of Mg/ATP initiates the kinase reaction. Subsequently, the reaction was incubated at room temperature for 40 minutes, and a 0.5% phosphoric acid solution was added to terminate the reaction. 10 μ L of the reaction was spotted onto a pad of P30 filter paper, washed 4 times with 0.425% phosphoric acid for 4 minutes each, then washed once with methanol, followed by drying and scintillation counting.
The test was set up with a compound test group (C), a positive control group (P) and a blank control group (B). The positive control group contained no test compound, DMSO was used instead (final concentration 2%), and the other components were identical to the test group (residual kinase activity 100%); staurosporine (staurosporine) was used in place of test compound in the blank control group to eliminate kinase activity and establish a baseline (residual kinase activity 0%).
Figure BDA0002362932710000201
IC was calculated by fitting a curve using Gragopd prism6.0 software with the logarithm of concentration as the abscissa and the inhibition ratio as the center50The value is obtained. Target compound pair BTK kinaseThe results of the inhibitory activity assay are shown in Table 1.
TABLE 1 inhibitory Activity of the Compounds of interest on BTK
Figure BDA0002362932710000202
IC50a: half maximal inhibitory concentration
NDb: not determined
The experimental data in Table 1 show that most compounds have certain inhibitory activity on BTK, and the half inhibitory concentration of some compounds is less than 100 nM. Compounds III-2, III-3 and III-5 showed the strongest inhibitory activity against BTK with half inhibitory concentration values of 64, 52 and 45nM, respectively.
2) Assay of compound for kinase selectivity experiments:
the experimental method is the same as that of the BTK kinase inhibitory activity experiment.
The inhibitory activity of the compounds III-5 and IBN (ibrutinib) on 20 kinases is determined, and the experimental results are shown in Table 2.
TABLE 2.1. mu.M inhibition of different kinases by III-5 and IBN
Figure BDA0002362932710000211
The results of the kinase selectivity determination of the compound show that the compound III-5 has better selectivity than IBN, and the III-5 has higher inhibitory activity (the inhibition rate is more than 80%) to the Tec kinase family (Tec, Bmx, Blk and Txk) and weak inhibitory activity (the inhibition rate is less than 40%) to Brk, Csk, EGFR, ErbB2, ErbB4, Fgr, Fyn, Hck, Itk, JAK3, Lck, Lyn, PTK5, Src, SRM and Yes kinase.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (11)

1.1-substituted benzyl pyrazolopyrimidine derivative, which is characterized in that the structure of the compound is shown as formula III:
Figure FDA0002796525560000011
wherein R is1Selected from hydrogen, C1-6 straight chain or branched chain alkyl and trihalomethyl; r4Selected from the group consisting of chloroacetamide and acrylamide groups.
2. The 1-substituted benzyl-4-aminopyrazolopyrimidine derivative according to claim 1, characterized in that R is1Selected from hydrogen, methyl, trifluoromethyl.
3. The 1-substituted benzylpyrazolopyrimidine derivative according to claim 2, which is selected from the group consisting of:
4- (4-amino-1- (2-chloroacetylamino-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4- (4-amino-1- (2-allylamido-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4- (4-amino-1- (3-chloroacetylamino-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4- (4-amino-1- (3-allylamido-benzyl (-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4- (4-amino-1- (4-chloroacetylamino-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide;
4- (4-amino-1- (4-allylamido-benzyl) -1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide.
4. A process for the preparation of a 1-substituted benzylpyrazolopyrimidine derivative according to any of claims 1 to 3, which comprises the preparation of a compound of formula III:
Figure FDA0002796525560000021
wherein R is1And R4As defined in any one of claims 1 to 3, X is hydroxy or halogen, R2Selected from hydrogen, halogen, nitro, C1-6 straight chain or branched chain alkyl, trifluoromethyl and cyano; r3Selected from amino groups.
5. The process for producing a 1-substituted benzylpyrazolopyrimidine derivative according to claim 4, which comprises the steps of: carrying out substitution reaction on the compound 1 and N-bromosuccinimide to obtain an intermediate 2; condensing the compound 3 and 4-bromobenzoic acid under the conditions of O-benzotriazole-tetramethylurea hexafluorophosphate and triethylamine to obtain an intermediate 4; the intermediate 4 is coupled with pinacol diboron under the conditions of palladium acetate, 2-dicyclohexyl phosphorus-2, 4, 6-triisopropyl biphenyl and potassium acetate to obtain an intermediate 5; the intermediate 5 and the intermediate 2 are subjected to Suzuki reaction under the catalysis of palladium tetrakis (triphenylphosphine) to obtain an intermediate 6; intermediate 6 and
Figure FDA0002796525560000022
nucleophilic substitution is carried out to obtain a compound shown in a general formula I; reducing the nitro-containing compound shown in the general formula I by iron powder to obtain an amino-containing compound shown in the general formula II; and condensing the amino-containing compound shown in the general formula II with substituted acyl chloride to obtain the compound shown in the general formula III.
6. A pharmaceutical composition comprising the 1-substituted benzylpyrazolopyrimidine derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical preparation, which comprises an active ingredient and a pharmaceutically acceptable adjuvant and/or carrier, wherein the active ingredient comprises the 1-substituted benzyl pyrazolopyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, or comprises the pharmaceutical composition according to claim 6.
8. Use of the 1-substituted benzylaminopyrazolopyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 6 for preparing a BTK inhibitor drug.
9. Use of the 1-substituted benzylpyrazolopyrimidine derivative of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 6 in the preparation of an antitumor drug.
10. The use of claim 9, wherein the tumor is a B cell lymphoma.
11. Use of a 1-substituted benzylpyrazolopyrimidine derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 6 for the preparation of a medicament for the treatment of B-cell lymphoma.
CN202010027321.6A 2019-10-17 2020-01-10 1-substituted benzyl pyrazolopyrimidine derivative and preparation method and application thereof Active CN111018865B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910988183 2019-10-17
CN2019109881835 2019-10-17

Publications (2)

Publication Number Publication Date
CN111018865A CN111018865A (en) 2020-04-17
CN111018865B true CN111018865B (en) 2021-01-15

Family

ID=70198879

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010027321.6A Active CN111018865B (en) 2019-10-17 2020-01-10 1-substituted benzyl pyrazolopyrimidine derivative and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN111018865B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111662296B (en) * 2020-06-02 2021-12-31 山东大学 Hydroxamic acid derivative containing pyrazolopyrimidine and preparation method and application thereof
CN114573586B (en) * 2020-11-28 2023-11-03 杭州和正医药有限公司 Polycyclic compound for inhibiting Bruton tyrosine kinase activity, pharmaceutical composition and application thereof
CN112574216B (en) * 2020-12-16 2022-03-08 天津济坤医药科技有限公司 Compound, preparation method thereof and application thereof in preparing anti-cancer drugs
CN114181160A (en) * 2021-12-28 2022-03-15 南通大学 2, 4-dianilinopyrimidine-containing hydrazide derivative and preparation method and application thereof
CN114031559A (en) * 2021-12-28 2022-02-11 南通大学 Aryl nitrogen-containing heterocycle modified 5-fluoro-pyrimidinediamine benzoate and preparation method and application thereof

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016019237A2 (en) * 2014-07-31 2016-02-04 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
CN105764896A (en) * 2013-09-30 2016-07-13 药品循环有限责任公司 Inhibitors of Bruton's tyrosine kinase
CN106999494A (en) * 2014-08-01 2017-08-01 药品循环有限公司 The inhibitor of bruton's tyrosine kinase
WO2017134685A2 (en) * 2016-02-02 2017-08-10 Sun Pharma Advanced Research Company Limited Novel hydrazino compounds as btk inhibitors
WO2018002958A1 (en) * 2016-06-30 2018-01-04 Sun Pharma Advanced Research Company Limited Novel hydrazide containing compounds as btk inhibitors
WO2018009017A1 (en) * 2016-07-07 2018-01-11 Daewoong Pharmaceutical Co., Ltd. NOVEL 4-AMINOPYRAZOLO[3,4-d]PYRIMIDINYLAZABICYCLO DERIVATIVES AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
CN107759602A (en) * 2016-08-17 2018-03-06 中国科学院上海药物研究所 Compound, its pharmaceutical composition and purposes containing conjugation connection alkene structure
CN109111446A (en) * 2017-06-22 2019-01-01 上海度德医药科技有限公司 A kind of heteroaryl compound with pharmaceutical activity
CN109369654A (en) * 2018-11-20 2019-02-22 山东大学 1,3- bis- substituted-4-amino Pyrazolopyrimidines and its preparation method and application

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105764896A (en) * 2013-09-30 2016-07-13 药品循环有限责任公司 Inhibitors of Bruton's tyrosine kinase
WO2016019237A2 (en) * 2014-07-31 2016-02-04 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
CN106999494A (en) * 2014-08-01 2017-08-01 药品循环有限公司 The inhibitor of bruton's tyrosine kinase
WO2017134685A2 (en) * 2016-02-02 2017-08-10 Sun Pharma Advanced Research Company Limited Novel hydrazino compounds as btk inhibitors
WO2018002958A1 (en) * 2016-06-30 2018-01-04 Sun Pharma Advanced Research Company Limited Novel hydrazide containing compounds as btk inhibitors
WO2018009017A1 (en) * 2016-07-07 2018-01-11 Daewoong Pharmaceutical Co., Ltd. NOVEL 4-AMINOPYRAZOLO[3,4-d]PYRIMIDINYLAZABICYCLO DERIVATIVES AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
CN107759602A (en) * 2016-08-17 2018-03-06 中国科学院上海药物研究所 Compound, its pharmaceutical composition and purposes containing conjugation connection alkene structure
CN109111446A (en) * 2017-06-22 2019-01-01 上海度德医药科技有限公司 A kind of heteroaryl compound with pharmaceutical activity
CN109369654A (en) * 2018-11-20 2019-02-22 山东大学 1,3- bis- substituted-4-amino Pyrazolopyrimidines and its preparation method and application

Also Published As

Publication number Publication date
CN111018865A (en) 2020-04-17

Similar Documents

Publication Publication Date Title
CN111018865B (en) 1-substituted benzyl pyrazolopyrimidine derivative and preparation method and application thereof
CN110062761B (en) Substituted 1H-imidazo [4,5-b ] pyridin-2 (3H) -ones and uses thereof
CN106661000B (en) EGFR inhibitor and its preparation and application
CA2413134C (en) Quinazoline ditosylate salt compounds
CN102858765B (en) Pyrazolyl quinazoline kinase inhibitors
CN105837576B (en) BTK inhibitor
CN100448874C (en) N-aroyl cyclic amines
CN106061966B (en) Bicyclic heterocycle derivatives as bromodomain inhibitor
CN1713907B (en) N-substituted pyrrolidin derivatives as dipeptidyl peptidase IV inhibitors
CN105189515B (en) Furopyridine class as bromine structural domain inhibitor
TW202026271A (en) Small molecule pd-1/pd-l1 inhibitor, pharmaceutical composition thereof with pd-l1 antibody and application thereof
CN103517896B (en) (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide
CN101878031A (en) The inhibitors of kinases that is used for the treatment of myeloproliferative disease and other proliferative diseases
CN101389335A (en) Thiadiazole compounds and methods of use.
CN107001339A (en) Noval chemical compound
JP6321821B2 (en) 2,3,4,6-4-substituted benzene-1,5-diamine derivatives, their production and use in pharmaceuticals
CN104024257A (en) Novel quinoxaline inhibitors of PI3K
CN106456582A (en) TrkA kinase inhibitors, compositions and methods thereof
CN101827848A (en) 2- [ (2-{phenylamino}-1H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino] benzamide derivatives as iIGF-1R inhibitors for the treatment of cancer
KR20110088960A (en) Bicyclic heteroaryl derivatives having inhibitory activity for protein kinases
JP2007519753A (en) Compound
TW200829558A (en) Quinazolines for PDK1 inhibition
CN101119996A (en) Chemical compouns
CN104926788B (en) Substituted piperidine analog derivative, the pharmaceutical composition containing it and its application in antitumor
CN106928219A (en) Nitrogenous fused heterocyclic compound, preparation method, intermediate, composition and application

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20220222

Address after: 250100 rooms 5a-110 and 3a-110, building 2, No. 286, Yuyang Road, Huashan street, Licheng District, Jinan City, Shandong Province

Patentee after: Shandong kangruijian Medical Technology Co.,Ltd.

Address before: 250012 No. 44 West Wenhua Road, Lixia District, Shandong, Ji'nan

Patentee before: SHANDONG University

TR01 Transfer of patent right