CN113024508A - Nitrogen heterocyclic ring derivative and preparation method and application thereof - Google Patents
Nitrogen heterocyclic ring derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN113024508A CN113024508A CN201911351341.2A CN201911351341A CN113024508A CN 113024508 A CN113024508 A CN 113024508A CN 201911351341 A CN201911351341 A CN 201911351341A CN 113024508 A CN113024508 A CN 113024508A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- independently selected
- carrying
- formula
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention relates to nitrogen-containing heterocyclic derivatives, which have the following structures:
a, X, Y, Z, R therein1、R2a、R2b、R3a、R3b、R4a、R4bAnd m is as defined in the specification. The compounds have good inhibition effect on protein tyrosine phosphatase SHP-2, and can be used for preparing antitumor drugs. The invention discloses a preparation method and application thereof.
Description
Technical Field
The invention belongs to the technical field of organic chemical drug synthesis, and relates to nitrogen-containing heterocyclic derivatives, a preparation method thereof, and application thereof in preparation of antitumor drugs.
Technical Field
With the increase of the average life span of human beings, the threat of malignant tumor to human beings is increasingly highlighted. Recent reports from the World Health Organization (WHO) International agency for research on cancer (IARC) show that the number of malignant tumors worldwide is rapidly increasing, and only1810 thousands of cases are newly added in 2018 in one year, and the number of deaths reaches 960 ten thousands. The general term "cancer" is used to generally refer to all malignant tumors. Cancer has biological characteristics of abnormal cell differentiation and proliferation, uncontrolled growth, infiltrative and metastatic properties, and the occurrence of cancer is a complex process with multiple factors and multiple steps. Significant advances in diagnosis and treatment have been made. Tumor surgery, radiation therapy, and chemotherapy are the main strategies for treating cancer. SHP2 is associated with a variety of cancers, such as breast cancer, leukemia, lung cancer, liver cancer, stomach cancer, laryngeal cancer, oral cancer, and the like. Signaling pathways including SHP2 have been discovered and are associated with a variety of diseases. Mutations in the PTPN11 gene can lead to noonan syndrome, LEOPARD syndrome, and childhood leukemia. SHP2 is also associated with several cancer-related cellular processes, such as cancer cell invasion and metastasis, apoptosis, DNA damage, cell proliferation, cell cycle and drug resistance. Based on the structure and function of SHP2, scientists studied specific mechanisms in cancer. SHP2 is embodied in many aspects, and therefore SHP2 is a potent cancer therapeutic target. The research finds that the malignant biological activity of the tumor cells is closely related to SHP-2 tyrosine phosphatase activation mutation. (see:
A，Hellberg C，
F D.Protein-tyrosine phosphatases and cancer[J].Nature Reviews Cancer，2006，6(4)：307；Zhang，Jie，Fei Zhang，and Ruifang Niu.″Functions of Shp2 in cancer.″Journal of cellular and molecular medicine 19.9(2015)：2075-2083.)
SHP2, a tyrosine phosphatase encoded by PTPN11 gene. SHP2 is widely expressed in vertebrate cells. SHP2 comprises one PTP catalytic domain and two SH2 domains. The two SH2 domains are at the nitrogen terminus of SHP2 and the phosphatase domain is at the carbon terminus of SHP 2. SHP-2 is a tyrosine phosphatase that is widely expressed in various tissues and cells, not only plays a role in promoting receptor or cytoplasmic tyrosine protein kinase-mediated signal pathways, but also has a phosphatase-independent linker protein function, and is first defined as an oncogene. The activity of PTPN11 phosphatase is manifested by modulation of intracellular signaling activity. Experimental and clinical data also indicate that SHP2 promotes tumor progression in various types of cancer.
Although SHP-2 has been widely reported as a cancer therapeutic target, no SHP-2 inhibitor small molecule drug is currently on the market. Furthermore, SHP-2 inhibitors are reported to have sulfonic acid, phosphoric acid, carboxylic acid, etc. (see, for example, NSC87877, Song M, Park J E, Park S G, et al NSC-87877, inhibitor of SHP-1/2 PTPs, inhibitor dual-specific phosphate 26(DUSP26) [ J ]. Biochemical and biological research communications, 2009, 381 (4): 491-495), and the phenomenon of poor membrane permeability and, ultimately, poor bioavailability is caused by polar groups present in the form of anions under physiological conditions. In consideration of the defects of the existing inhibitor, a series of nitrogen heterocyclic derivatives with novel structures and good druggability are designed and synthesized by advanced means of computer-aided drug design, such as framework transition, molecular docking, molecular dynamics simulation, pharmacophore, absorption/distribution/metabolism/excretion/toxicity prediction (ADMET prediction) and the like, and the inhibitory activity to SHP-2 is measured. The compounds of the present invention satisfy the need for small molecule inhibitors of SHP 2.
Disclosure of Invention
The invention provides nitrogen-containing heterocyclic derivatives represented by a general formula I and pharmaceutically acceptable salt, solvate or prodrug molecules thereof.
It is another object of the present invention to provide a process for the preparation of compounds having the general formula I.
The invention also aims to provide the application of the compound, the compound usually has protein tyrosine phosphatase SHP-2 inhibitory activity, and SHP-2 is widely reported as an antitumor drug target enzyme, so the compound has the application in preparing antitumor drugs.
The present disclosure will now be described in detail for the purpose of the invention.
A compound having the structure of formula I or a pharmaceutically acceptable salt, solvate or prodrug molecule thereof.
Wherein A represents benzene ring, naphthalene ring, furan, thiophene, pyridine, wherein the benzene ring, naphthalene ring, furan, thiophene, pyridine are optionally substituted by 1, 2, 3 or 4 substituents independently selected from halogen, amino or C1-C3Alkyl substitution;
y is selected from CH or N; x is selected from S or absent; z is selected from CH or N;
m is 0, 1, 2 or 3;
R1is-H, -NH2Or C1-C3An alkyl group;
each R2aAnd R2bAre all independently selected from-H, -NH2or-CH2NH2；
Each R3aAnd R3bAre all independently selected from-H, halogen, -NH2、-OH、-CH2NH2、-CONH2、C1-C3Alkyl, phenyl, benzyl, piperidinyl, morpholinyl, or pyridinyl, wherein said phenyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from fluoro, chloro, or bromo;
each R4aAnd R4bAre all independently selected from-H or-NH2。
Preferred are compounds of formula I or pharmaceutically acceptable salt, solvate or prodrug molecules thereof.
A represents benzene ring, naphthalene ring, furan, thiophene and pyridine, wherein the benzene ring, the naphthalene ring, the furan, the thiophene and the pyridine are optionally selected from 1 or 2 independently from fluorine, chlorine, amino or C1-C3Alkyl substitution;
y is selected from CH or N; x is selected from S or absent; z is N;
m is 0 or 1; r1is-H, -CH3or-NH2；
Each R2aAnd R2bAre all independently selected from-H, -NH2or-CH2NH2；
Each R3aAnd R3bAre all independently selected from-H, -F, -Cl, -NH2、-OH、-CH2NH2、-CONH2、-CH3Phenyl, benzyl, piperidinyl, morpholinyl or pyridinyl, wherein said phenyl is optionally substituted with 1 or 2 chloro;
each R4aAnd R4bAre all-H.
More preferably, the compound represented by the compound of the general formula I or the pharmaceutically acceptable salt thereof is as follows:
the compound of the general formula I in the invention, wherein the pharmaceutically acceptable salt refers to a salt formed by the compound of the general formula I and an acid, and includes various inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids, such as formic acid, acetic acid, trifluoroacetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, amino acids and the like, to form a pharmaceutically acceptable salt.
The compound of the general formula I is synthesized by the following route:
when X is S, Y is N, R1When the compound of formula I becomes I-a:
I-A can be synthesized by the following route:
the compound II is a chemical raw material sold in the market, and the compound II and N-chlorosuccinimide perform chlorination reaction to obtain a compound III; carrying out sandmeyer reaction on the compound III, isoamyl nitrite and copper bromide to obtain a compound IV; carrying out ester ammonolysis reaction on the compound IV and ammonia water to obtain a compound V; compound V and mercapto groupThe substituent is subjected to nucleophilic substitution reaction under alkaline condition to obtain a compound VI; carrying out nucleophilic substitution reaction on the compound VI and a piperidine derivative (without Boc protective group) in N, N-dimethylformamide under the heating condition to obtain a final compound I-A; when the piperidine derivative contains a Boc protecting group, nucleophilic substitution is carried out on the compound VI and the Boc amino (methyl) piperidine derivative to obtain a compound VIII; removing the Boc protecting group of the compound VIII under the trifluoroacetic acid condition to obtain trifluoroacetate I-A-S of I-A; the final compound I-A is obtained by the I-A-S under the alkaline condition; wherein A, m and R2a、R2b、R3a、R3bIn each of claim l, A represents a benzene ring, a naphthalene ring, furan, thiophene, pyridine, wherein the benzene ring, naphthalene ring, furan, thiophene, pyridine is optionally substituted with 1 or 2 groups independently selected from fluorine, chlorine, amino or C1-C3Alkyl substitution; m is 0 or 1; each R2aAnd R2bAre all independently selected from-H, -NH2or-CH2NH2(ii) a Each R3aAnd R3bAre all independently selected from-H, -F, -Cl, -NH2、-OH、-CH2NH2、-CONH2、-CH3Phenyl, benzyl, piperidinyl, morpholinyl or pyridinyl, wherein said phenyl is optionally substituted with 1 or 2 chloro.
When X is S, Y is N, R1＝-CH3or-NH2When the compound of formula I becomes I-B:
I-B can be synthesized by the following route:
performing chlorination reaction on the compound II and N-chlorosuccinimide to obtain a compound III; carrying out sandmeyer reaction on the compound III, isoamyl nitrite and copper bromide to obtain a compound IV; the compound IV and the sulfhydryl substituent generate avidity under the alkaline conditionCarrying out nuclear substitution reaction to obtain a compound VIII; carrying out nucleophilic substitution reaction on the compound VIII and the piperidine derivative in N, N-dimethylformamide under the heating condition to obtain a compound IX; carrying out ester aminolysis reaction on the compound IX and hydrazine hydrate or methylamine to obtain a final compound I-B; wherein A, m and R1、R2a、R2b、R3a、R3bAs respectively stated in claim 1, A represents benzene ring, naphthalene ring, furan, pyridine, wherein the benzene ring, naphthalene ring, furan, thiophene, pyridine are optionally substituted by 1 or 2 groups independently selected from fluorine, chlorine, amino or C1-C3Alkyl substitution; m is 0 or 1; each R2aAnd R2bAre all independently selected from-H, -NH2or-CH2NH2(ii) a Each R3aAnd R3bAre all independently selected from-H, -NH2、-CH2NH2、-CH3Or a piperidinyl group.
When X is absent, Y is N, R1＝-H、-CH3or-NH2When the compound of formula I becomes I-C:
I-C can be synthesized by the following route:
performing chlorination reaction on the compound II and N-chlorosuccinimide to obtain a compound III; carrying out sandmeyer reaction on the compound III, isoamyl nitrite and copper bromide to obtain a compound IV; carrying out Suzuki reaction on the compound IV and aryl boric acid to obtain a compound X; carrying out nucleophilic substitution reaction on the compound X and the piperidine derivative in N, N-dimethylformamide under the heating condition to obtain a compound XI; carrying out an ester aminolysis reaction on the compound XI and ammonia water, hydrazine hydrate or methylamine to obtain a final compound I-C; a, R therein1、R2a、R2b、R3a、R3bAs in claim 1, respectively, A represents a benzene ringWherein the phenyl rings are optionally substituted with 1 or 2 substituents independently selected from chloro or amino; m is 0 or 1; r1Is selected from-H, -CH3or-NH2；R2a＝R2b-H; each R3aAnd R3bAre all independently selected from-H, -CH3。
When Y is CH, R1＝-CH3or-NH2When the compound of formula I becomes I-D:
I-D can be synthesized by the following route:
carrying out esterification reaction on a compound XII and methanol under the catalysis of thionyl chloride to obtain a compound XIII; nucleophilic substitution or Suzuki reaction is carried out on the compound XIII and a sulfhydryl substituent or aryl boric acid respectively to obtain a compound XIV; carrying out nucleophilic substitution reaction on the compound XIV and the piperidine derivative in N, N-dimethylformamide under the heating condition to obtain a compound XV; carrying out ester ammonolysis reaction on the compound XV and hydrazine hydrate or methylamine to obtain a final compound I-D; a, X, R therein1、R2a、R2b、R3a、R3bAs respectively recited in claim 1, a represents a benzene ring, the benzene ring being optionally substituted with 1 or 2 chloro; x is selected from S or absent; r2a＝R2b-H; each R3aAnd R3bAre all independently selected from-H, -CH3。
The specific implementation mode is as follows:
the invention is further illustrated by the following examples, which are illustrative only and are not meant to limit the scope of the invention in any way. Variations of the teachings of the present invention may be made by those skilled in the art without departing from the scope of the claims of the present application.
EXAMPLE 1 Synthesis of Compound I-A-1
Step one, synthesis of compound III
Commercial compound II (15.3g, 100mmol) was dissolved in DMF (200mL) and stirred at room temperature, followed by addition of N-chlorosuccinimide (16.1g, 120 mmol). The resulting reaction was heated and stirred at 80 ℃ until TLC indicated completion of the reaction.
The reaction mixture was poured into ice water (500mL), stirred, and extracted with dichloromethane (200 mL. times.3). The organic phases were combined, washed successively with saturated sodium carbonate solution (500mL) and 5% brine (200mL), and dried over anhydrous sodium sulfate. The dried organic phase was evaporated on a rotary evaporator and the residue obtained was purified by column chromatography to give product III, 17.2g, 92% yield. MS: m/z 189(M + H)+.
Step two, synthesis of Compound IV
Compound III (15.0g, 80mmol) and copper bromide (35.7g, 160mmol) were added to DMF (300mL) and stirred for 10 min; isoamyl nitrite (18.7g, 160mmol) was slowly added dropwise with cooling in an ice water bath. After the addition was complete, the mixture was stirred under nitrogen at 65 ℃ until TLC indicated completion of the reaction.
After the reaction mixture was cooled to room temperature, it was poured into ice-water (500mL), stirred, and extracted with dichloromethane (200 mL. times.3). The organic phases were combined, washed with water (500 mL. times.5) and dried over anhydrous sodium sulfate. The dried organic phase was evaporated on a rotary evaporator and the residue obtained was purified by column chromatography to give product IV, 10.5g, 52% yield. MS: m/z 252(M + H)+.
Step three, synthesis of compound V
Compound IV (10.1g, 40mmol) was added to methanol (20mL), followed by ammonia (200mL) and the reaction stirred at room temperature until TLC indicated completion.
The reaction mixture was filtered and the filter cake was washed successively with water, methanol and dried to give product V, 8.3g, 88% yield. MS: m/z 237(M + H)+.
Step four, synthesis of compound VI-1
Taking compound V (1.2g, 5mmol), 2, 3-dichlorothiophenol (1.1g, 6mmol), K2CO3(1.4g, 10mmol) was added to DMF (20mL) and stirred at 50 ℃ until TLC indicated completion of the reaction.
After the reaction mixture was cooled to room temperature, it was poured into ice-water (50mL), stirred, and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, washed with water (50 mL. times.5) and dried over anhydrous sodium sulfate. The dried organic phase was evaporated off the solvent on a rotary evaporator and the residue obtained was purified by column chromatography to give the product VI-1, 1.4g, 86% yield. MS: m/z 335(M + H)+.
Step five. Synthesis of Compound VII-1
Taking compound VI-1(1.0g, 3mmol), 4-Boc-aminomethyl piperidine (0.8g, 3.6mmol), K2CO3(0.8g, 6mmol) was added to DMF (15mL) and stirred at 100 deg.C until TLC indicated completion of the reaction.
After the reaction mixture was cooled to room temperature, it was poured into ice-water (50mL), stirred, and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, washed with water (50 mL. times.5) and dried over anhydrous sodium sulfate. The dried organic phase was subjected to evaporation of the solvent on a rotary evaporator and the residue obtained was purified by column chromatography to give the product VII-1, 1.2g, in 77% yield. MS: m/z 513(M + H)+.
Step six. Synthesis of Compound I-A-1
Compound VII-1(1.0g, 2mmol) was dissolved in dichloromethane (10mL) and added to trifluoroacetic acid (5mL) with cooling in an ice water bath and stirred at room temperature until TLC indicated completion of the reaction.
The reaction mixture was evaporated on a rotary evaporator to give the product I-a-S, 10mL of water was added, pH was adjusted to 9-10 with sodium hydroxide solution, extraction was performed with dichloromethane (20mL × 5), and the organic phases were combined and dried over anhydrous sodium sulfate. The dried organic phase was subjected to evaporation of the solvent on a rotary evaporator and the residue obtained was purified by column chromatography to give the product I-A-1, 0.6g, 73% yield. MS: m/z 413(M + H)+.
EXAMPLE 2 Synthesis of Compound I-B-1
Step one, synthesis of compound VIII-1
Taking compound IV (1.3g, 5mmol), 2, 3-dichlorothiophenol (1.1g, 6mmol), K2CO3(1.4g, 10mmol) was added to DMF (20mL) and stirred at 50 ℃ until TLC indicated completion of the reaction.
After the reaction mixture was cooled to room temperature, it was poured into ice-water (50mL), stirred, and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, washed with water (50 mL. times.5) and dried over anhydrous sodium sulfate. The dried organic phase was subjected to evaporation of the solvent on a rotary evaporator and the residue obtained was purified by column chromatography to give the product VIII-1, 1.4g, in 79% yield. MS: m/z 350(M + H)+.
Step two, synthesis of compound IX-1-Boc
Taking the compound VIII-1(1.0g, 3mmol), 3-Boc-aminopiperidine (0.7g, 3.6mmol), K2CO3(0.8g, 6mmol) was added to DMF (15mL) and stirred at 100 deg.C until TLC indicated completion of the reaction.
After the reaction mixture was cooled to room temperature, it was poured into ice-water (50mL), stirred, and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, washed with water (50 mL. times.5) and dried over anhydrous sodium sulfate. The dried organic phase was subjected to evaporation of the solvent on a rotary evaporator and the resulting residue was purified by column chromatography to give the product IX-1-Boc, 1.2g, 81% yield. MS: m/z 513(M + H)+.
Step three, synthesis of compound IX-1
Compound IX-1-Boc (1.0g, 2mmol) was dissolved in dichloromethane (10mL) and added to trifluoroacetic acid (5mL) with cooling in an ice water bath and stirred at room temperature until TLC indicated completion of the reaction.
The reaction mixture was evaporated on a rotary evaporator to remove the solvent, 10mL of water was added, the pH was adjusted to 9-10 with sodium hydroxide solution, and the mixture was extracted with dichloromethane (20mL × 5)And the organic phases are combined and dried over anhydrous sodium sulfate. The dried organic phase was evaporated on a rotary evaporator and the residue obtained was purified by column chromatography to give product IX-1, 0.6g, 70% yield. MS: m/z 414(M + H)+.
Step four, synthesis of compound I-B-1
Compound IX-1(0.4g, 1mmol) was dissolved in ethanol (10mL), 80% hydrazine hydrate solution (10mL) was added, and the mixture was heated with stirring at 80 ℃ under nitrogen until TLC indicated completion of the reaction.
After the reaction mixture was cooled to room temperature, it was poured into ice-water (20mL), stirred, and extracted with dichloromethane (20 mL. times.5). The organic phases were combined and dried over anhydrous sodium sulfate. The dried organic phase was evaporated in a rotary evaporator and the residue obtained was purified by column chromatography to give the product I-B-1 in 0.4g, 90% yield. MS: m/z 414(M + H)+.
EXAMPLE 3 Synthesis of Compound I-C-1
Step one, synthesis of compound X-1
Taking compound IV (1.3g, 5mmol), 2, 3-dichlorobenzene boric acid (1.1g, 6mmol), K2CO3(1.4g，10mmol)，Pd[P(C6H5)3]4(0.3g, 0.25mmol) was dissolved in dioxane (18 mL)/water (2mL) mixed solution and stirred under nitrogen at 100 ℃ until TLC indicated completion of the reaction.
After the reaction mixture was cooled to room temperature, it was poured into ice-water (20mL), stirred, and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, washed with water (50 mL. times.3) and dried over anhydrous sodium sulfate. The dried organic phase was evaporated in a rotary evaporator and the residue obtained was purified by column chromatography to give the product X-1, 1.1g in 70% yield. MS: m/z 318(M + H)+.
Step two, synthesis of compound XI-1-Boc
Taking compound X-1(1.0g, 3mmol), (4-methylpiperidine)-4-yl) carbamic acid tert-butyl ester (0.8g, 3.6mmol), K2CO3(0.8g, 6mmol) was added to DMF (15mL) and stirred at 100 deg.C until TLC indicated completion of the reaction.
After the reaction mixture was cooled to room temperature, it was poured into ice-water (50mL), stirred, and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, washed with water (50 mL. times.5) and dried over anhydrous sodium sulfate. The dried organic phase was subjected to evaporation of the solvent on a rotary evaporator and the resulting residue was purified by column chromatography to give the product XI-1-Boc, 1.1g, 75% yield. MS: m/z 496(M + H)+.
Step three, synthesis of compound XI-1
Compound XI-1-Boc (1.0g, 2mmol) was dissolved in dichloromethane (10mL) and added to trifluoroacetic acid (5mL) with cooling in an ice water bath and stirred at room temperature until TLC indicated completion of the reaction.
The reaction mixture was evaporated on a rotary evaporator to remove the solvent, then 10mL of water was added, the pH was adjusted to 9-10 with sodium hydroxide solution, extracted with dichloromethane (20mL × 5), and the organic phases were combined and dried over anhydrous sodium sulfate. The dried organic phase was evaporated on a rotary evaporator and the residue obtained was purified by column chromatography to give the product XI-1, 0.6g, 73% yield. MS: m/z 396(M + H)+.
Step four, synthesis of compound I-C-1
Compound XI-1(0.4g, 1mmol) was dissolved in ethanol (10mL), 80% hydrazine hydrate solution (10mL) was added, and the mixture was heated with stirring at 80 ℃ under nitrogen until TLC indicated completion of the reaction.
After the reaction mixture was cooled to room temperature, it was poured into ice-water (20mL), stirred, and extracted with dichloromethane (20 mL. times.5). The organic phases were combined and dried over anhydrous sodium sulfate. The dried organic phase was subjected to evaporation of the solvent on a rotary evaporator and the residue obtained was purified by column chromatography to give the product I-C-1, 0.3g, in 88% yield. MS: m/z 396(M + H)+.
EXAMPLE 4 Synthesis of Compound I-D-1
Step one Synthesis of Compound XIII
Compound XII (7.1g, 30mmol) was dissolved in ethanol (100mL) and 100mL of thionyl chloride was slowly added dropwise with cooling in an ice-water bath. After the addition was complete, the mixture was stirred with heating at 60 ℃ until TLC indicated completion of the reaction.
After the reaction mixture was cooled to room temperature, the solvent was evaporated on a rotary evaporator and the resulting residue was slurried with ethanol/water (v: v ═ 9: 1), filtered, the filter cake washed with ethanol and dried to give product XIII, 6.5g, 87% yield. MS: m/z 251(M + H)+.
Step two, synthesis of Compound XIV-1
The compound XIII (1.3g, 5mmol), 2, 3-dichlorophenylboronic acid (1.1g, 6mmol) and K were taken2CO3(1.4g，10mmol)，Pd[P(C6H5)3]4(0.3g, 0.25mmol) was dissolved in dioxane (18 mL)/water (2mL) mixed solution and stirred under nitrogen at 100 ℃ until TLC indicated completion of the reaction.
After the reaction mixture was cooled to room temperature, it was poured into ice-water (20mL), stirred, and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, washed with water (50 mL. times.3) and dried over anhydrous sodium sulfate. The dried organic phase was evaporated on a rotary evaporator and the residue obtained was purified by column chromatography to give the product XIV-1, 1.2g, 75% yield. MS: m/z 317(M + H)+.
Step three, synthesis of compound XV-1-Boc
Taking compound XIV-1(1.0g, 3mmol), (4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (0.8g, 3.6mmol), K2CO3(0.8g, 6mmol) was added to DMF (15mL) and stirred at 100 deg.C until TLC indicated completion of the reaction.
After the reaction mixture was cooled to room temperature, it was poured into ice-water (50mL), stirred, and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, washed with water (50 mL. times.5) and dried over anhydrous sodium sulfate. Evaporating the dried organic phase to remove the solvent on a rotary evaporator, and purifying the obtained residue by column chromatography to obtainThe product XV-1-Boc, 1.0g, yield 70%. MS: m/z 495(M + H)+.
Step four, synthesis of compound XV-1
Compound XV-1-Boc (1.0g, 2mmol) was dissolved in dichloromethane (10mL) and added to trifluoroacetic acid (5mL) with cooling in an ice water bath and stirred at room temperature until TLC indicated completion of the reaction.
The reaction mixture was evaporated on a rotary evaporator to remove the solvent, then 10mL of water was added, the pH was adjusted to 9-10 with sodium hydroxide solution, extracted with dichloromethane (20mL × 5), and the organic phases were combined and dried over anhydrous sodium sulfate. The dried organic phase was evaporated in a rotary evaporator and the residue purified by column chromatography to give the product XV-1, 0.6g, 75% yield. MS: m/z 395(M + H)+.
Step five. Synthesis of Compound I-D-1
Compound XV-1(0.4g, 1mmol) was dissolved in ethanol (10mL), 80% hydrazine hydrate solution (10mL) was added, and the mixture was heated under nitrogen at 80 ℃ with stirring until TLC indicated completion of the reaction.
After the reaction mixture was cooled to room temperature, it was poured into ice-water (20mL), stirred, and extracted with dichloromethane (20 mL. times.5). The organic phases were combined and dried over anhydrous sodium sulfate. The dried organic phase was evaporated in a rotary evaporator and the residue obtained was purified by column chromatography to give the product I-D-1, 0.3g, 76% yield. MS: m/z 395(M + H)+.
Examples 5 to 51
Referring to the methods of examples 1-4, the following compounds having the general formula I were synthesized.
Example 52: enzyme inhibiting activity of compound
The experiment adopts a pNPP method to determine the enzyme inhibiting activity of the compound, the pNPP, namely 4-nitrophenyl disodium phosphate, can be hydrolyzed into p-nitrophenol (pNP) by SHP-2, the pNP is converted into a strongly yellow quinoid structure under the alkaline condition, an absorbance value at 405nm is determined by a spectrophotometric method, and the activity level of phosphatase can be calculated by colorimetric analysis. Add 100. mu.L of the system to a 96-well microplate: mu.L (300ng) of SHP-2 phosphatase was added, incubated at 37 ℃ for 2min, the absorbance (OD) at 405nm was measured, 40. mu.L of pNPP (purchased from Shanghai Aladdin Biotech Co., Ltd.) was added to initiate the reaction, and then shaken in a microplate reader (Botryn, USA, model C5MVDG) for 1min and incubated at 37 ℃ for half an hour. The reaction was stopped with 100. mu.L of 3M sodium hydroxide and the absorbance at 405nm was measured. The experiment was set up with a negative control group, a positive control group and a blank group. Sodium vanadate is used as a positive control, an equal amount of buffer solution is used for replacing the SHP-2 protein solution to be used as a negative control group so as to eliminate the influence of the color of the sample, and an equal amount of DMSO is used for replacing an inhibitor to be used as a blank group. The samples to be tested are diluted by three times and four gradients, 3 groups of parallel tests are carried out, the inhibition rate of each compound on the activity of the SHP-2 protein is respectively calculated, and the results are summarized in the following table 1. The results show that: the partial nitrogenous heterocyclic derivative has good inhibitory activity on protein tyrosine phosphatase SHP-2, and can be used for preparing anti-tumor drugs.
TABLE 1 partial compounds of general formula I inhibit the activity of SHP-2 at 50. mu.g/ml
| Test compound | Inhibition ratio (%) | Test compound | Inhibition ratio (%) |
| Example 28 Compounds | 53 | Example 36 Compounds | 97 |
| Example 31 Compounds | 75 | Example 37 Compounds | 96 |
| Example 32 Compounds | 60 | Example 38 Compounds | 90 |
| Example 33 Compounds | 56 | Example 44 Compounds | 87 |
Claims (10)
1. The nitrogen-containing heterocyclic derivative is characterized by having the following structural general formula I:
wherein A represents benzene ring, naphthalene ring, furan, thiophene, pyridine, wherein the benzene ring, naphthalene ring, furan, thiophene, pyridine are optionally substituted by 1, 2, 3 or 4 substituents independently selected from halogen, amino or C1-C3Alkyl substitution;
y is selected from CH or N; x is selected from S or absent; z is selected from CH or N; m is 0, 1, 2 or 3;
R1is-H, -NH2Or C1-C3An alkyl group;
each R2aAnd R2bAre all independently selected from-H, -NH2or-CH2NH2；
Each R3aAnd R3bAre all independently selected from-H, halogen, -NH2、-OH、-CH2NH2、-CONH2、C1-C3Alkyl, phenyl, benzyl, piperidinyl, morpholinyl, or pyridinyl, wherein said phenyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from fluoro, chloro, or bromo;
each R4aAnd R4bAre all independently selected from-H or-NH2。
2. A nitrogen-containing heterocyclic derivative according to claim 1, wherein:
a represents benzene ring, naphthalene ring, furan, thiophene and pyridine, wherein the benzene ring, the naphthalene ring, the furan, the thiophene and the pyridine are optionally selected from 1 or 2 independently from fluorine, chlorine, amino or C1-C3Alkyl substitution;
y is selected from CH or N; x is selected from S or absent; z is N; m is 0 or 1;
R1is-H, -CH3or-NH2；
Each R2aAnd R2bAre all independently selected from-H, -NH2or-CH2NH2；
Each R3aAnd R3bAre all independently selected from-H, -F, -Cl, -NH2、-OH、-CH2NH2、-CONH2、-CH3Phenyl, benzyl, piperidinyl, morpholinyl or pyridinyl, wherein said phenyl is optionally substituted with 1 or 2 chloro;
each R4aAnd R4bAre all-H.
3. A compound of the structure of formula I as defined in claim 1 or 2 is selected from the following compounds:
4. a nitrogen-containing heterocyclic derivative according to claims 1-3 wherein said compound further comprises a pharmaceutically acceptable salt, solvate or prodrug molecule of formula I.
5. A process for the preparation of a compound having the structure of formula I as defined in any one of claims 1 to 3, wherein X ═ S, Y ═ N, R1When the compound of formula I becomes I-a:
performing chlorination reaction on the compound II and N-chlorosuccinimide to obtain a compound III; carrying out sandmeyer reaction on the compound III, isoamyl nitrite and copper bromide to obtain a compound IV; carrying out ester ammonolysis reaction on the compound IV and ammonia water to obtain a compound V; carrying out nucleophilic substitution reaction on the compound V and a sulfhydryl substituent under an alkaline condition to obtain a compound VI; carrying out nucleophilic substitution reaction on the compound VI and a piperidine derivative (without Boc protective group) in N, N-dimethylformamide under the heating condition to obtain a final compound I-A; when the piperidine derivative contains a Boc protecting group, nucleophilic substitution is carried out on the compound VI and the Boc amino (methyl) piperidine derivative to obtain a compound VIII; removing the Boc protecting group of the compound VIII under the trifluoroacetic acid condition to obtain trifluoroacetate I-A-S of I-A; the final compound I-A is obtained by the I-A-S under the alkaline condition; wherein A, m and R2a、R2b、R3a、R3bAs respectively stated in claim 1, A represents a benzene ring, a naphthalene ring, furan, thiophene, pyridine, wherein the benzene ring, the naphthalene ring, the furan, the thiophene, the pyridine are optionally substituted by 1 or 2 groups independently selected from fluorine, chlorine, amino or C1-C3Alkyl substitution; m is 0 or 1; each R2aAnd R2bAre all independently selected from-H, -NH2or-CH2NH2(ii) a Each R3aAnd R3bAre all independently selected from-H, -F, -Cl, -NH2、-OH、-CH2NH2、-CONH2、-CH3Phenyl, benzyl, piperidinyl, morpholinyl or pyridinyl, wherein said phenyl is optionally substituted with 1 or 2 chloro.
6. A process for the preparation of a compound having the structure of formula I as defined in any one of claims 1 to 3, wherein X ═ S, Y ═ N, R1＝-CH3or-NH2When the compound of formula I becomes I-B:
compounds II and N-Performing chlorination reaction on chlorosuccinimide to obtain a compound III; carrying out sandmeyer reaction on the compound III, isoamyl nitrite and copper bromide to obtain a compound IV; carrying out nucleophilic substitution reaction on the compound IV and a sulfhydryl substituent under an alkaline condition to obtain a compound VIII; carrying out nucleophilic substitution reaction on the compound VIII and the piperidine derivative in N, N-dimethylformamide under the heating condition to obtain a compound IX; carrying out ester aminolysis reaction on the compound IX and hydrazine hydrate or methylamine to obtain a final compound I-B; wherein A, m and R1、R2a、R2b、R3a、R3bAs respectively stated in claim 1, A represents benzene ring, naphthalene ring, furan, pyridine, wherein the benzene ring, naphthalene ring, furan, thiophene, pyridine are optionally substituted by 1 or 2 groups independently selected from fluorine, chlorine, amino or C1-C3Alkyl substitution; m is 0 or 1; each R2aAnd R2bAre all independently selected from-H, -NH2or-CH2NH2(ii) a Each R3aAnd R3bAre all independently selected from-H, -NH2、-CH2NH2、-CH3Or a piperidinyl group.
7. A process for the preparation of a compound having the structure of formula I as defined in any one of claims 1 to 3, wherein X is absent, Y is N, R1＝-H、-CH3or-NH2When the compound of formula I becomes I-C:
performing chlorination reaction on the compound II and N-chlorosuccinimide to obtain a compound III; carrying out sandmeyer reaction on the compound III, isoamyl nitrite and copper bromide to obtain a compound IV; carrying out Suzuki reaction on the compound IV and aryl boric acid to obtain a compound X; carrying out nucleophilic substitution reaction on the compound X and the piperidine derivative in N, N-dimethylformamide under the heating condition to obtain a compound XI; carrying out an ester aminolysis reaction on the compound XI and ammonia water, hydrazine hydrate or methylamine to obtain a final compound I-C; a, R therein1、R2a、R2b、R3a、R3bEach as claimed in claim 1, wherein a represents a phenyl ring, wherein the phenyl ring is optionally substituted with 1 or 2 substituents independently selected from chloro or amino; m is 0 or 1; r1Is selected from-H, -CH3or-NH2；R2a＝R2b-H; each R3aAnd R3bAre all independently selected from-H, -CH3。
8. A process for the preparation of a compound having the structure of formula I as defined in any one of claims 1 to 3, wherein Y ═ CH, R1＝-CH3or-NH2When the compound of formula I becomes I-D:
carrying out esterification reaction on a compound XII and methanol under the catalysis of thionyl chloride to obtain a compound XIII; nucleophilic substitution or Suzuki reaction is carried out on the compound XIII and a sulfhydryl substituent or aryl boric acid respectively to obtain a compound XIV; carrying out nucleophilic substitution reaction on the compound XIV and the piperidine derivative in N, N-dimethylformamide under the heating condition to obtain a compound XV; carrying out ester ammonolysis reaction on the compound XV and hydrazine hydrate or methylamine to obtain a final compound I-D; a, X, R therein1、R2a、R2b、R3a、R3bAs respectively recited in claim 1, a represents a benzene ring, the benzene ring being optionally substituted with 1 or 2 chloro; x is selected from S or absent; r2a＝R2b-H; each R3aAnd R3bAre all independently selected from-H, -CH3。
9. Use of nitrogen-containing heterocyclic ring derivatives according to claims 1-4 for the preparation of antitumor drugs against lung cancer, colon cancer, neuroblastoma, melanoma, breast cancer, stomach cancer, blood cancer, etc.
10. A pharmaceutical composition comprising a therapeutically effective amount of a nitrogen-containing heterocyclic derivative according to any one of claims 1-4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911351341.2A CN113024508A (en) | 2019-12-25 | 2019-12-25 | Nitrogen heterocyclic ring derivative and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911351341.2A CN113024508A (en) | 2019-12-25 | 2019-12-25 | Nitrogen heterocyclic ring derivative and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113024508A true CN113024508A (en) | 2021-06-25 |
Family
ID=76452285
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911351341.2A Pending CN113024508A (en) | 2019-12-25 | 2019-12-25 | Nitrogen heterocyclic ring derivative and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113024508A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022235866A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
| WO2022235864A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2022235870A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors for the treatment of cancer |
| CN115340530A (en) * | 2022-07-01 | 2022-11-15 | 广东药科大学-香港大学中山生物医药创新平台 | Method for preparing nitrogen-containing heterocyclic derivative and application thereof |
| WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
| WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009068321A1 (en) * | 2007-11-26 | 2009-06-04 | Forschungsverbund Berlin E.V. | Site-directed high throughput screening |
| CN110143949A (en) * | 2018-05-09 | 2019-08-20 | 北京加科思新药研发有限公司 | It can be used as the new type heterocycle derivative of SHP2 inhibitor |
-
2019
- 2019-12-25 CN CN201911351341.2A patent/CN113024508A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009068321A1 (en) * | 2007-11-26 | 2009-06-04 | Forschungsverbund Berlin E.V. | Site-directed high throughput screening |
| CN110143949A (en) * | 2018-05-09 | 2019-08-20 | 北京加科思新药研发有限公司 | It can be used as the new type heterocycle derivative of SHP2 inhibitor |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022235866A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
| WO2022235864A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2022235870A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors for the treatment of cancer |
| WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
| WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
| CN115340530A (en) * | 2022-07-01 | 2022-11-15 | 广东药科大学-香港大学中山生物医药创新平台 | Method for preparing nitrogen-containing heterocyclic derivative and application thereof |
| CN115340530B (en) * | 2022-07-01 | 2024-01-26 | 广东药科大学-香港大学中山生物医药创新平台 | Method for preparing nitrogen-containing heterocyclic derivative and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113024508A (en) | Nitrogen heterocyclic ring derivative and preparation method and application thereof | |
| CN114761408B (en) | KRAS G12C inhibitor and application thereof in medicine | |
| CN112920131A (en) | 1,2, 4-triazole derivatives and preparation method and application thereof | |
| CN110698461B (en) | Preparation method of third-generation EGFR inhibitor | |
| CN104003988A (en) | CDK2 (cyclin-dependent kinase 2) kinase inhibitor based on 3-amino-beta-carboline and derivatives thereof, as well as preparation method and application of CDK2 kinase inhibitor | |
| CN107383004B (en) | 2-amino imidazopyridine derivative and preparation and application thereof | |
| Liao et al. | Design and optimization of novel 4-(2-fluorophenoxy) quinoline derivatives bearing a hydrazone moiety as c-Met kinase inhibitors | |
| CN114957162B (en) | Preparation and application of thiadiazole parent nucleus compound | |
| CN110818609A (en) | Preparation method and application of 3-acetyl indole BRPF1 inhibitor | |
| CN111704646A (en) | Steroid compound and preparation method and application thereof | |
| WO2009049492A1 (en) | N-substituted aromatic hydrocarbon aniline and multi-substituted diarylether compounds, the preparation and the use of antitumor thereof | |
| CN114014814A (en) | N-benzyl-4-phenylphthalazin-1-amine derivative, preparation method thereof and medicine for treating RECQL4 specific expression | |
| CN103922992B (en) | A kind of antitumour activity indolone derivatives, preparation method and use | |
| CN110240598B (en) | Process for preparing carboxamide derivatives and intermediate compounds thereof | |
| CN115304603A (en) | Preparation and application of quinazoline inhibitor | |
| CN111943885A (en) | Synthetic method of Laolatinib intermediate 2-amino-5-bromo-3-hydroxypyridine | |
| CN108727377A (en) | 3- cyano pyrazoles simultaneously [1,5-a] pyrimidine derivatives and its preparation method and application | |
| CN103910643B (en) | Anti-cancer activity ketone derivative as well as synthetic method and application thereof | |
| CN105017145B (en) | 7-chloro-4-oxo-quinoline derivative with antitumor activity | |
| WO2022184119A1 (en) | Tyrosine kinase inhibitor and pharmaceutical use thereof | |
| CN115490689B (en) | Irreversible KRAS G12C Preparation and application of inhibitor | |
| CN112174958B (en) | Pyrido [2,3-d ] pyrimidine compound and preparation method and application thereof | |
| CN112441970A (en) | 2, 5-disubstituted-3-aminopyridine compound and preparation method and application thereof | |
| CN104586842A (en) | Anti-cancer activity indole derivative, synthesis method and uses thereof | |
| CN108358841B (en) | 4- ((2-substituted quinoline-4-yl) amino) benzoyl hydrazine derivatives, and preparation method and application thereof |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20210625 |