CN117586263A - Piperazine derivatives and their use in medicine - Google Patents

Piperazine derivatives and their use in medicine Download PDF

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CN117586263A
CN117586263A CN202310918399.0A CN202310918399A CN117586263A CN 117586263 A CN117586263 A CN 117586263A CN 202310918399 A CN202310918399 A CN 202310918399A CN 117586263 A CN117586263 A CN 117586263A
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compound
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equiv
pharmaceutically acceptable
methoxybenzyl
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朱钰沁
魏用刚
孙毅
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Kangbaida Sichuan Biopharmaceutical Technology Co ltd
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Chengdu Baiyu Pharmaceutical Co Ltd
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    • 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
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    • A61P35/00—Antineoplastic agents

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Abstract

The application relates to piperazine compounds and compositions thereof and application thereof in preparing antitumor drugs. The piperazine compound can selectively inhibit PARP7, thereby treating cancer.

Description

Piperazine derivatives and their use in medicine
Technical Field
The invention relates to the field of medicines, in particular to a piperazine derivative or pharmaceutically acceptable salt, stereoisomer or deuteride thereof and application thereof in medicines.
Background
Adenosine diphosphate ribosylation (ADP-ribosylation) is a post-transcriptional modification of proteins by inserting single or multiple adenosine diphosphate ribose (ADP-ribose) groups into amino acid residues of the protein. ADP-ribosylation is a reversible process involving physiological regulation of cell signaling, DNA damage repair, transcription, gene expression regulation, apoptosis, etc. ADP-ribose is derived from a redox cofactor: nicotinamide adenine dinucleotide (Nicotinamide adenine dinucleotide, NAD+), the enzyme mediating the ADP-ribose intercalating modification is ADP-ribosylase. In this regulation of the physiological response, the N-glycosidic bond of NAD+ linking the ADP-ribose molecule and the nicotinamide group is cleaved and subsequently captured to the corresponding amino acid residue of the target protein. ADP-ribosyl enzymes can undergo two types of modifications: mono-ADP ribosylation and poly-ADP ribosylation. When DNA damage or cells are stressed by pressure, PARP is activated, resulting in an increase in poly ADP-ribose and a decrease in nad+. PARP1 has been considered for over a decade to be the only poly ADP-ribose polymerase in mammalian cells and therefore the enzyme has been the most studied. To date, scientists have identified 17 different PARPs. MonoPARP occupies a large part of the PARP family and mediates important biological functions and various stress responses, such as: unfolded protein response, NF- κb signaling, antiviral response, and cytokine signaling.
2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) induced poly (ADP-ribose) polymerase (PARP-7) is one of the monoprop family members whose expression is regulated by TCDD-activated Aromatic Hydrocarbon Receptors (AHR), a ligand-activated transcription factor, that mediates the toxic activity of many environmental heterologous organisms. AHR up-regulates the expression of PARP-7, which causes inhibition of TBK1 activity and down-regulation of IFN-I (type I interferon) response by interacting with and ADP-ribosylating the kinase TBK1, thereby resulting in inhibition of the antiviral and tumor immune responses in the body. Thus, selective inhibition of PARP7 can modulate the antiviral and tumor immune responses of the body.
Disclosure of Invention
One or more embodiments of the present application provide selective PARP7 inhibitors or pharmaceutically acceptable salts, stereoisomers or deuterides thereof, and their use in medicine, for example in anticancer therapy.
One or more embodiments of the present application provide a compound, or a pharmaceutically acceptable salt, stereoisomer, or deuterate thereof:
a compound according to the present application, or a pharmaceutically acceptable salt, stereoisomer, or deuterate thereof, wherein the compound is:
one or more embodiments of the present application provide a pharmaceutical composition comprising a compound as described above, a pharmaceutically acceptable salt, stereoisomer, or deuteride thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
One or more embodiments of the present application provide for the use of a pharmaceutical composition of the present application or a compound described, a pharmaceutically acceptable salt, stereoisomer, or deuterate thereof, in the manufacture of a medicament for the treatment and/or prevention of cancer.
One or more embodiments of the present application provide a method for preparing the above compound, including the following steps:
and (3) reacting the compound 3 with the compound 4 in a reaction solvent under the condition of an alkaline reagent at 50-120 ℃ to prepare the compound 1.
The preparation method according to the application, wherein the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane or ethyl acetate; the alkaline reagent is selected from cesium carbonate, sodium acetate, sodium phosphate, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium phosphate, potassium fluoride, DBU, triethylamine, tributylamine, N-diisopropylethylamine or pyridine.
The preparation process according to the present application, wherein the reaction is carried out at 70-110 ℃, preferably 80-100 ℃, e.g. at 90 ℃.
The preparation method according to the present application, wherein the molar ratio of compound 3 to compound 4 is 1:0.9 to 1:1.2, preferably 1:1.
The preparation method according to the present application, wherein the mass-to-volume ratio (g/mL) of the compound 3 to the reaction solvent is 0.050:1 to 0.060:1, preferably 0.055:1.
The preparation method according to the present application, wherein the molar ratio of compound 3 to alkaline agent is 1:3 to 1:5, preferably 1:4.
The preparation method according to the application, wherein the method comprises the following steps: and (3) reacting the compound 3-1 with the compound 4 in a reaction solvent at 50-120 ℃ under the condition of an alkaline reagent to prepare the compound 1-1.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the present application that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.
"pharmaceutical composition" refers to a mixture of one or more compounds described herein, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance that is added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
Experiments show that the piperazine compound can selectively inhibit PARP7, thereby treating cancers such as lung cancer.
Detailed Description
The following examples illustrate the technical aspects of the present invention in detail, but the scope of the present invention is not limited thereto.
The examples are not particularly described, and the reaction temperature is room temperature, and the optimum reaction temperature at room temperature is 20-30 ℃.
MPLC: medium pressure liquid chromatography.
Intermediate 1
5-chloro-2- (4-methoxybenzyl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (intermediate 1)
5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
The first step:
4, 5-dibromo-2- (4-methoxybenzyl) pyridazin-3 (2H) -one (1 b)
4,5-dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one
To a solution of 4, 5-dibromo-2, 3-dihydropyridazin-3-one (1 a,50g,196.94mmol,1.0 equiv.) in N, N-dimethylformamide (500 mL) at 0-10℃was added sodium hydride (11.82 g,295.41mmol,1.5 equiv., 60%) in portions followed by 1- (chloromethyl) -4-methoxybenzene (46.06 g,294.11mmol,1.49 equiv.) at 0 ℃. After the addition, the reaction solution was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was slowly poured into 1.0L of ice-water mixture to quench and extracted with dichloromethane (2X 500 mL). The organic layers were combined and concentrated. The solid was washed with methanol (500 mL. Times.2) to give 1b as a yellow solid (48.4 g, 66% yield).
LC-MS m/z(ESI)＝375.00[M+1]。
And a second step of:
4-bromo-5-methoxy-2- (4-methoxybenzyl) pyridazin-3 (2H) -one (1 c)
4-bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one
1b (48.4 g,129.40mmol,1.0 equiv) was dissolved in methanol (417 mL) and the reaction stirred at room temperature for 2h. The resulting reaction mixture was concentrated to 80mL and filtered to give crude product. The resulting filter cake was slurried in water (160 mL) for 1h and filtered to give 1c as a white solid (38.72 g, 92% yield).
LC-MS m/z(ESI)＝326.30[M+1]。
And a third step of:
5-methoxy-2- (4-methoxybenzyl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (1 d)
5-methoxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
1c (14 g,43.04mmol,1.0 equiv) and CuI (4.10 g,21.52mmol,0.50 equiv) were weighed into a 250mL reaction flask and dissolved in N-methylpyrrolidone (72 mL) followed by slow addition of methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (16.4 mL,129.11mmol,3.0 equiv). After the addition, the reaction was stirred in an oil bath at 100℃for 3 hours. After the reaction was completed, 90mL of water was added to the reaction solution for quenching. The resulting solution was extracted with dichloromethane (3X 60 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give 1d as a white solid (12.1 g, 89% yield).
LC-MS m/z(ESI)＝315.10[M+1]。
Fourth step:
5-hydroxy-2- (4-methoxybenzyl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (1 e)
5-hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
To a solution of 1d (12.1 g,38.52mmol,1.0 equiv.) in N, N-dimethylformamide (60 mL) was added dropwise trimethyliodosilane (9.97 g,50.07mmol,1.3 equiv.) at room temperature. The resulting reaction solution was stirred at 85℃for 20h. After the reaction was completed, 60mL of water was added to the reaction mixture to quench the reaction, followed by extraction of the resulting solution with methylene chloride (3X 60 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give 1e as a white solid (10.4 g, 90% yield).
LC-MS m/z(ESI)＝301.07[M+1]。
Fifth step:
5-chloro-2- (4-methoxybenzyl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (intermediate 1)
5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
Oxalyl chloride (8.79 g,69.32mmol,2.0 equiv.) is slowly added dropwise to a solution of compound 1e (10.4 g,34.66mmol,1.0 equiv.) in N, N-dimethylformamide (52 mL) at 0deg.C. After the addition, the reaction mixture was stirred at room temperature for 8 hours. After the reaction was completed, 550mL of water was added to the reaction mixture to quench. The mixture was filtered to give intermediate 1 as a white solid (11.04 g, 99%).
LC-MS m/z(ESI)＝319.68[M+1]。
Intermediate 2
(S) -1- ((5- (4-methoxybenzyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) methoxy) propan-2-amine (intermediate 2)
(S)-1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)m ethoxy)propan-2-amine
The first step:
5- (4-methoxybenzyl) -4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine-2-carboxylic acid ethyl ester (2 b)
ethyl-5-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate
Ethyl 4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine-2-carboxylate (2 a,5.0g,24mmol,1.0 equiv) was weighed out, p-methoxybenzyl bromide (4.2 mL,28.8mmol,1.2 equiv) was dissolved in N, N-dimethylformamide (50 mL), sodium hydride (1.15 g,28.8mmol,1.2 equiv) was slowly added under ice bath, and the addition was completed, and the reaction was carried out at room temperature for 3 hours. The reaction was completed, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was dried by spinning. The crude product was purified by flash column chromatography (dichloromethane: methanol=20:1) to give 2b as a white solid (7.5 g, 92% yield).
1 H NMR(400MHz,DMSO-d 6 ):δ7.33-7.23(m,2H),7.14(s,1H),6.94-
6.87(m,2H),4.62(s,2H),4.50-4.38(m,2H),4.28(q,2H),3.76-3.69(m,5H),1.29(t,3H)。
LC-MS m/z(ESI)＝330.10[M+1]。
And a second step of:
(5- (4-methoxybenzyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) methanol (2 c)
(5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol
2b (4.1 g,12.5mmol,1.0 equiv) was weighed and dissolved in tetrahydrofuran (100 mL). Under nitrogen, a solution of lithium aluminum hydride in tetrahydrofuran (50 mL,50mmol,4.0 equiv) was slowly added dropwise under an ice bath. After the dripping, the mixture is heated to 70 ℃ for reaction for 10min. The reaction was complete, cooled to room temperature, quenched in an ice-water bath, filtered with suction, and the filtrate was dried by rotary evaporation, and the crude product was purified by flash column chromatography (dichloromethane: methanol=10:1) to give 2c as a yellow solid (2.45 g, 71% yield).
LC-MS m/z(ESI)＝274.10[M+1]。
And a third step of:
(S) -1- ((5- (4-methoxybenzyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) methoxy) propan-2-amine (intermediate 2)
(S)-1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine
To a 25mL reaction flask, 2c (864 mg,3.16mmol,1.0 equiv) was added and anhydrous N, N-dimethylformamide (18 mL) was dissolved. N (N) 2 Sodium hydride (300 mg,7.51mmol,2.5 eq) was added in portions at 0deg.C and stirring was continued for 30min at that temperature. Subsequently, a solution of (S) -4-methyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide in N, N-dimethylformamide (18 mL) was slowly added dropwise to the reaction system, the temperature during the dropwise addition was kept at 0℃and stirring was continued for 2 hours. After the reaction was completed, the reaction system ph=3 was adjusted and stirred at room temperature for 0.5h. Extraction of the reaction mixture with EA (3X 120 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product which was purified by column chromatography (dichloromethane: methanol=40:1) to give intermediate 2 as a white solid (252 mg, 24% yield).
LC-MS m/z(ESI)＝331.50[M+1]。
Intermediate 3
(S) -5- ((1- ((4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) methoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin 3 (2H) -one (intermediate 3)
(S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
The first step:
(S) -2- (4-methoxybenzyl) -5- ((1- ((5- (4-methoxybenzyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) methoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (3 a)
(S)-2-(4-methoxybenzyl)-5-((1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Intermediate 2 (252 mg,0.764mmol,1.0 eq) and intermediate 1 (291.4 mg,0.916mmol,1.1 eq) were weighed into a 10mL reaction flask and dissolved by adding N, N-dimethylformamide (3.0 mL). Subsequently, N-diisopropylethylamine (0.5 mL,3.06mmol,4.0 equiv) was added sequentially. The mixture was stirred at 100deg.C for 4h. After completion of the reaction, concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=1:1.5) to give 3a as a white solid (359.8 mg, yield 77%).
LC-MS m/z(ESI)＝613.62[M+1]。
And a second step of:
(S) -5- ((1- (((4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) methoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin 3 (2H) -one (intermediate 3)
(S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
To a 10mL reaction flask weighed 3a (359.8 mg,0.588mmol,1.0 equiv) was added trifluoroacetic acid (3.4 mL) and trifluoromethanesulfonic acid (0.42 mL,4.7mmol,8.0 equiv) in sequence. After the addition, the reaction was stirred at 25℃for 1h. Subsequently, the reaction solution was stirred under an oil bath at 70 ℃. After the reaction was completed, 15mL of water was added to the reaction mixture to quench. The resulting solution was extracted with ethyl acetate (3X 15 mL). The pH of the organic layer was adjusted to 8 to 9 by aqueous potassium carbonate. The combined organic layers were concentrated in vacuo and the residue purified by MPLC (water/acetonitrile=1:1) to give intermediate 3 as a white solid (48 mg, 22% yield).
1 H NMR(400MHz,DMSO-d 6 )δ12.46(s,1H),8.81(s,2H),7.90(s,1H),6.28(dd,1H),6.11(s,1H),5.01(s,2H),4.41(d,2H),4.32(t,2H),4.16(t,3H),3.55-3.45(m,2H),1.15(d,3H)。
LC-MS m/z(ESI)＝373.1[M+1]。
Intermediate 4
2-chloro-5- (2-fluorophenyl) pyrimidine (intermediate 4)
2-chloro-5-(2-fluorophenyl)pyrimidine
4a (1.93 g,10mmol,1.0 equiv) was added to a toluene/water (50 mL/2.5 mL) mixture followed by 2-fluorobenzeneboronic acid (1.68 g,12mmol,1.2 equiv), pd (dppf) Cl 2 (0.408 g,0.5mmol,0.05 equiv.) cesium carbonate (9.78 g,30mmol,3.0 equiv.) is reacted at 80℃for 5.0h after addition. After the reaction was completed, 30mL of water was added to the reaction solution, and the reaction mixture was extracted with 3X 40mL of ethyl acetate (3X 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=10:1) to give intermediate 4 as a white solid (1.71 g, 82% yield).
LC-MS m/z(ESI)＝209.62[M+1]。
Example 1
(S) -5- ((1- ((5- (5- (2-fluorophenyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-ylmethoxy) propyl-2-amino) -4- (trifluoromethyl) pyrazin-3 (2H) -one (compound 1)
(S)-5-((1-((5-(5-(2-fluorophenyl)pyrimidin-2-yl)-4,5,6,7tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Intermediate 3 (221 mg,0.6mmol,1.0 equiv) and intermediate 4 (125 mg,0.6mmol,1.0 equiv) were each weighed into a 10mL reaction flask and dissolved in N, N-dimethylformamide (4.0 mL). N, N-diisopropylethylamine (0.4 mL,0.52mmol,4 equiv) was added to the mixture, and the reaction was stirred at 90℃for 1h. After the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was purified by MPLC (water/acetonitrile=1:1) to give compound 1 as a white solid (176.4 mg, yield 54%).
LCMS m/z＝545.50[M+l]。
Biological assay
PARP enzymatic Biochemical assay
The experiment uses PARP1, TNKS2, PARP7 and PARP14 chemiluminescence detection kit (BPS, catNo.80551/80552/80573/80578/79729/80568) to carry out PARP enzymatic biochemical detection. The specific scheme is as follows: the 1 Xhistone mixture was added to a 96-well plate at 50. Mu.L per well and incubated overnight at 4 ℃. The next day, after washing with PBST, 200. Mu.L of blocking buffer was added to each well and incubated for 90min. After washing again with PBST, 5. Mu.L of inhibitor, 20. Mu.L of 1 XPNP buffer and 25. Mu.L of streptavidin-HRP were added per well and incubated for 30min at room temperature. After washing with PBST, 100. Mu.L of the mixture of Elisa ECL substrates A and B was added to each well, and immediately chemiluminescent values were read using an ELISA reader, and IC was calculated 50 Values.
The results show that: the compounds of the present invention have significant biological inhibitory activity against PARP 7.
NCI-H1373 cell proliferation inhibition experiment
Human lung adenocarcinoma cells NCI-H1373 (ATCC, CRL-5866) were cultured in RPMI-1640 medium containing 10% FBS and 1% diabody TM ) Culturing at 37deg.C, 5% CO 2 Is provided. Cell digestions were counted in the logarithmic growth phase and inoculated into 96-well plates at 1500 NCI-H1373 per well and placed in an incubator for overnight culture. The following day, test compounds were formulated as 10mM stock solution using DMSO, starting at a maximum dose of 10. Mu.M, and 3-fold gradient dilutions were performed using RPMI-1640 medium, setting a total of 10 gradient concentrations, 2 parallel wells per well. After 6 days of incubation, 100. Mu.LCell Titer Blue working solution was added to each well and chemiluminescent readings were performed on the microplate reader. Calculation of IC using graphpadprism7.0 software 50 。
The results show that: the compound has remarkable inhibition effect on NCI-H1373 cell proliferation.
While the specification describes in detail specific embodiments of the present invention, those skilled in the art will recognize that the foregoing embodiments are illustrative and not to be construed as limiting the invention, and that many variations and modifications of the invention may be made without departing from the spirit of the invention, which is intended to fall within the scope of the appended claims.

Claims (5)

1. A compound, or a pharmaceutically acceptable salt, stereoisomer, or deuterate thereof, wherein the compound is selected from the following structures:
2. a pharmaceutical composition comprising a compound of claim 1 or a stereoisomer thereof and one or more pharmaceutically acceptable carriers and/or excipients.
3. Use of a compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or deuterate thereof, or a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
4. A process for the preparation of a compound as claimed in claim 1, comprising the steps of:
and (3) reacting the compound 3 with the compound 4 in a reaction solvent under the condition of an alkaline reagent at 50-120 ℃ to prepare the compound 1.
5. The method of manufacturing according to claim 4, wherein: the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane or ethyl acetate; the alkaline reagent is selected from cesium carbonate, sodium acetate, sodium phosphate, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium phosphate, potassium fluoride, DBU, triethylamine, tributylamine, N-diisopropylethylamine or pyridine.
CN202310918399.0A 2022-08-09 2023-07-25 Piperazine derivatives and their use in medicine Pending CN117586263A (en)

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CN2022109366747 2022-08-09

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