Preparation process and intermediate of piperazine derivative

Abstract

The invention relates to a preparation process and an intermediate of a piperazine derivative or a stereoisomer or tautomer thereof. The process is simple to operate, low in cost, high in reaction yield, high in product purity and suitable for industrial production.

Description

Preparation process of piperazine derivative and intermediate thereof Technical Field

[0001] The present invention relates to a preparation process of a piperazine derivative or a stereoisomer or tautomer thereof and an intermediate thereof. Background Art

[0002] ADP-ribosylation (ADP-ribosylation) is a post-transcriptional modification of proteins, in which single or multiple adenosine diphosphate ribose (ADP-ribose) groups are incorporated into amino acid residues of proteins. ADP-ribosylation is a reversible process involved in physiological regulation, including cell signal transduction, DNA damage repair, transcription, gene expression regulation, and apoptosis. The enzymes that mediate ADP-ribose insertion and modification are called ADP-ribosylases. ADP-ribosylases can perform two types of modifications: mono-ADP-ribosylation and poly-ADP-ribosylation. When DNA is damaged or cells are subjected to stress, PARP (poly ADP-ribose polymerase) is activated, resulting in an increase in poly ADP-ribose and a decrease in NAD+. To date, scientists have identified 17 different PARPs. MonoPARPs comprise the majority of the PARP family and mediate important biological functions and various stress responses, such as the unfolded protein response, NF-κB signaling, antiviral responses, and cytokine signaling. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly (ADP-ribose) polymerase (PARP-7) is a member of the MonoPARP family. Its expression is regulated by TCDD-activated aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates the toxic activities of many environmental xenobiotics. AHR upregulates PARP-7 expression. PARP-7 interacts with and ADP-ribosylates the kinase TBK1, leading to inhibition of TBK1 activity and downregulation of IFN-I (type I interferon) responses, thereby suppressing antiviral and tumor immune responses.

[0003] The patent (PCT Publication No.: WO2022242750) describes a novel PARP7 inhibitor represented by formula (I'), which has a good inhibitory effect on PARP7 activity and has the potential to prepare anti-tumor drugs.

[0004] Summary of the Invention

[0005] The present invention aims to provide a novel preparation process for piperazine derivatives or their stereoisomers or tautomers and intermediates thereof. The preparation process has the advantages of simple operation, low cost, high yield, high purity, and is more suitable for industrial production.

[0006] One or more embodiments of the present invention provide a process for preparing a piperazine derivative of formula (I-1) or a stereoisomer or tautomer thereof, characterized in that: the compound of formula (I-1) or a stereoisomer or tautomer thereof is prepared by the following reaction steps:

[0007] The compound of formula (Ia-1) is reacted in a reaction solvent under acidic reagent conditions to prepare a compound of formula (I-1);

[0008] The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of them in any proportion;

[0009] The acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, or a mixture of any of the above;

[0010] in:

[0011] R 1a 、R 1b Each independently is H, D or C 1-6 alkyl;

[0012] R 2a 、R 2b Each independently is H, D or C 1-6 alkyl;

[0013] R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0014] R4 and R5 are each independently H or D;

[0015] R6 and R7 are each independently H or D;

[0016] R8 and R9 are each independently H or D;

[0017] R 10 CF3 or SR 10d ;

[0018] R 10d H, D or C 1-6 alkyl;

[0019] B is

[0020] m is 1, 2, or 3;

[0021] n is 0, 1, 2, or 3;

[0022] G is THP, MOM, BOM, MEM, Trt, DMB, PMB or SEM.

[0023] In one or more embodiments, the compound of formula (I-1) of the present invention is selected from the compound of formula (I) or its stereoisomer or tautomer, and the compound of formula (I) or its stereoisomer or tautomer is prepared by the following reaction steps:

[0024] The compound of formula (Ia) is reacted in a reaction solvent under acidic reagent conditions to prepare a compound of formula (I);

[0025] The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of them in any proportion;

[0026] The acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, or a mixture of any of the above.

[0027] One or more embodiments of the present invention provide a process for preparing a compound of formula (Ia-1) or a stereoisomer or tautomer thereof, characterized in that: the compound of formula (Ia-1) or a stereoisomer or tautomer thereof is prepared by the following reaction steps:

[0028] The compound of formula (Ic-1) and compound Ib-1 react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ia-1);

[0029] The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, methyl tert-butyl ether, isopropyl ether, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or a mixture of any of the above in any proportions;

[0030] The alkaline reagent is selected from any one of cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of the above;

[0031] in:

[0032] Compound Ib-1 is

[0033] Alternatively, compound Ib-1 is

[0034] Q is or halogen;

[0035] R 1a 、R 1b 、R 2a 、R 2b , R3, R4, R5, R6, R7, R8, R9, R 10 , B, m, n, and G are defined in the same manner as in claim 1.

[0036] In one or more embodiments, the compound of formula (Ia-1) of the present invention is selected from the compound of formula (Ia) or its stereoisomer or tautomer, and the compound of formula (Ia) or its stereoisomer or tautomer is prepared by the following reaction steps:

[0037] The compound of formula (Ic) and compound Ib react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ia);

[0038] The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, methyl tert-butyl ether, isopropyl ether, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or a mixture of any of the above in any proportions;

[0039] The alkaline reagent is selected from any one of cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of the above;

[0040] in:

[0041] Compound Ib is

[0042] Alternatively, compound Ib is

[0043] Q is or halogen.

[0044] One or more embodiments of the present invention provide a process for preparing a compound of formula (Ic-1) or a stereoisomer or tautomer thereof, characterized in that: the compound of formula (Ic-1) or a stereoisomer or tautomer thereof is prepared by the following reaction steps:

[0045] The compound of formula (If-1) and the compound of formula (Ie-1) react in a reaction solvent under alkaline reagent conditions to prepare the compound of formula (Id-1), and the compound of formula (Id-1) reacts in a reaction solvent under acidic reagent conditions to prepare the compound of formula (Ic-1);

[0046] or

[0047] The compound of formula (If-1) and the compound of formula (I-e1-1) are reacted in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ic-1);

[0048] The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or a mixture of any of the above in any proportions;

[0049] The alkaline reagent is selected from any one of cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of the above;

[0050] The acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, or a mixture of any of the above;

[0051] in:

[0052] R Y1 is Boc, Cbz, PMB, Tos, Fmoc, SEM, Alloc, Pht, or Trt;

[0053] R1a 、R 1b 、R 2a 、R 2b , R3, R4, R5, R6, R7, R8, R9, R 10 , B, m, n are defined in accordance with the definition in claim 1.

[0054] In one or more embodiments, the compound of formula (Ic-1) of the present invention is selected from the compound of formula (Ic) or its stereoisomer or tautomer, and the compound of formula (Ic) or its stereoisomer or tautomer is prepared by the following reaction steps:

[0055] The compound of formula (If) and the compound of formula (Ie) react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Id), and the compound of formula (Id) reacts in a reaction solvent under acidic reagent conditions to prepare a compound of formula (Ic);

[0056] or

[0057] The compound of formula (If) and the compound of formula (I-e1) react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ic);

[0058] The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or a mixture of any of the above in any proportions;

[0059] The alkaline reagent is selected from any one of cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of the above;

[0060] The acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, or a mixture of any of the above.

[0061] One or more embodiments of the present invention provide a process for preparing a compound of formula (If-1) or a stereoisomer or tautomer thereof, characterized in that: the compound of formula (If-1) or a stereoisomer or tautomer thereof is prepared by the following reaction steps:

[0062] The compound of formula (Ig-1) and a bromination reagent react in a reaction solvent to obtain a compound of formula (If-1);

[0063] The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of them in any proportion;

[0064] The bromination reagent is selected from bromine, hydrobromic acid, phosphorus oxybromide, phosphorus tribromide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide, and carbon tetrabromide;

[0065] in:

[0066] R3, R4, R5, R6, R7, R8, R9, R 10 , B, n definitions are consistent with those in claim 1.

[0067] In one or more embodiments, the compound of formula (If-1) of the present invention is selected from the compound of formula (If) or its stereoisomer or tautomer, and the compound of formula (If) or its stereoisomer or tautomer is prepared by the following reaction steps:

[0068] The compound of formula (Ig) and a bromination reagent react in a reaction solvent to obtain a compound of formula (If);

[0069] The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of them in any proportion;

[0070] The bromination reagent is selected from bromine, hydrobromic acid, phosphorus oxybromide, phosphorus tribromide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide, and carbon tetrabromide.

[0071] One or more embodiments of the present invention provide a process for preparing a piperazine derivative of formula (I-1) or a stereoisomer or tautomer thereof, characterized in that:

[0072] The first step: reacting a compound of formula (Ii-1) and a compound of formula (Ih-1) in a reaction solvent under alkaline reagent conditions; after the reaction is completed, adding an aqueous solution and stirring to crystallize to prepare a compound of formula (Ig-1); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of them in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of them;

[0073] Step 2: reacting the compound of formula (Ig-1) and a brominating agent in a reaction solvent to obtain a compound of formula (If-1); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportions; the brominating agent is selected from bromine, hydrobromic acid, phosphorus oxybromide, phosphorus tribromide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide, and carbon tetrabromide;

[0074] Step 3: The compound of formula (If-1) and the compound of formula (Ie-1) react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Id-1); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or any mixture of any of them in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, or any mixture of any of them;

[0075] Step 4: The compound of formula (Id-1) is reacted in a reaction solvent under acidic reagent conditions to prepare a compound of formula (Ic-1); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or any mixture of any of them in any proportion; the acidic reagent is selected from hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, or any mixture of any of them;

[0076] Step 5: The compound of formula (Ic-1) and compound Ib-1 react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ia-1); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, methyl tert-butyl ether, isopropyl ether, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or a mixture of any of them in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, or a mixture of any of them;

[0077] Step 6: The compound of formula (Ia-1) is reacted in a reaction solvent under acidic reagent conditions to prepare a compound of formula (I-1); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any two or more thereof in any proportion; the acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, or a mixture of any two or more thereof;

[0078] or

[0079] The first step: reacting a compound of formula (Ii-1) and a compound of formula (Ih-1) in a reaction solvent under alkaline reagent conditions; after the reaction is completed, adding an aqueous solution and stirring to crystallize to prepare a compound of formula (Ig-1); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of them in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of them;

[0080] Step 2: reacting the compound of formula (Ig-1) and a brominating agent in a reaction solvent to obtain a compound of formula (If-1); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportions; the brominating agent is selected from bromine, hydrobromic acid, phosphorus oxybromide, phosphorus tribromide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide, and carbon tetrabromide;

[0081] Step 3: reacting the compound of formula (If-1) and the compound of formula (I-e1-1) in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ic-1); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or any mixture thereof in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, or any mixture thereof;

[0082] Step 4: The compound of formula (Ic-1) and compound Ib-1 react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ia-1); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, methyl tert-butyl ether, isopropyl ether, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or a mixture of any of them in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, or a mixture of any of them;

[0083] Step 5: The compound of formula (Ia-1) is reacted in a reaction solvent under acidic reagent conditions to prepare a compound of formula (I-1); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any several of them in any proportion; the acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, or a mixture of any several of them;

[0084] in:

[0085] Compound Ib-1 is

[0086] Alternatively, compound Ib-1 is

[0087] Q is or halogen;

[0088] R Y1 is Boc, Cbz, PMB, Tos, Fmoc, SEM, Alloc, Pht, or Trt;

[0089] R 1a 、R 1b 、R 2a 、R 2b , R3, R4, R5, R6, R7, R8, R9, R 10 , B, m, n, and G are defined in the same manner as in claim 1.

[0090] In one or more embodiments, the compound of formula (I-1) of the present invention is selected from the compound of formula (I) or its stereoisomer or tautomer, and the compound of formula (I) or its stereoisomer or tautomer is prepared by the following reaction steps:

[0091] The first step: reacting a compound of formula (Ii) and a compound of formula (Ih) in a reaction solvent under alkaline reagent conditions; after the reaction is completed, adding an aqueous solution and stirring to crystallize to prepare a compound of formula (Ig); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of them in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of them;

[0092] Step 2: reacting the compound of formula (Ig) with a brominating agent in a reaction solvent to obtain a compound of formula (If); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportions; the brominating agent is selected from bromine, hydrobromic acid, phosphorus oxybromide, phosphorus tribromide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide, and carbon tetrabromide;

[0093] Step 3: The compound of formula (If) and the compound of formula (Ie) react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Id); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or a mixture of any of them in any proportion; the alkaline reagent is selected from any one of cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of them;

[0094] Step 4: reacting the compound of formula (Id) in a reaction solvent under acidic reagent conditions to prepare a compound of formula (Ic); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, and L-aminopropanol, or a mixture of any two or more thereof in any proportion; the acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, or a mixture of any two or more thereof;

[0095] Step 5: The compound of formula (Ic) and compound Ib react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ia); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, methyl tert-butyl ether, isopropyl ether, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or any mixture of any of them in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or any mixture of any of them;

[0096] Step 6: reacting the compound of formula (Ia) in a reaction solvent under acidic reagent conditions to prepare a compound of formula (I); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any two or more thereof in any proportion; the acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, or a mixture of any two or more thereof;

[0097] or

[0098] The first step: reacting a compound of formula (Ii) and a compound of formula (Ih) in a reaction solvent under alkaline reagent conditions; after the reaction is completed, adding an aqueous solution and stirring to crystallize to prepare a compound of formula (Ig); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of them in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of them;

[0099] Step 2: reacting the compound of formula (Ig) with a brominating agent in a reaction solvent to obtain a compound of formula (If); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportions; the brominating agent is selected from bromine, hydrobromic acid, phosphorus oxybromide, phosphorus tribromide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide, and carbon tetrabromide;

[0100] Step 3: reacting the compound of formula (If) and the compound of formula (I-e1) in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ic); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or any mixture thereof in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, or any mixture thereof;

[0101] Step 4: The compound of formula (Ic) and compound Ib react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ia); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, methyl tert-butyl ether, isopropyl ether, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or a mixture of any of them in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of them;

[0102] Step 5: reacting the compound of formula (Ia) in a reaction solvent under acidic reagent conditions to prepare a compound of formula (I); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any two or more thereof in any proportion; the acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, or a mixture of any two or more thereof;

[0103] Compound Ib is

[0104] Alternatively, compound Ib is

[0105] Q is or halogen.

[0106] One or more embodiments of the present invention provide an intermediate or a stereoisomer or a tautomer thereof for preparing a piperazine derivative of formula (I-1), wherein the intermediate or the stereoisomer or tautomer thereof is selected from:

[0107] in:

[0108] G is THP, MOM, BOM, MEM, Trt or DMB;

[0109] R 1a 、R 1b 、R 2a 、R 2b , R3, R4, R5, R6, R7, R8, R9, R 10The definitions of B, m, and n are consistent with those in claim 1.

[0110] In one or more embodiments, the intermediate of the present invention or its stereoisomer or tautomer is selected from:

[0111] One or more embodiments of the present invention provide an intermediate or a stereoisomer or a tautomer thereof for preparing a piperazine derivative of formula (I-1), wherein the intermediate or the stereoisomer or tautomer thereof is selected from:

[0112] in:

[0113] Q is or halogen;

[0114] The definition of G is consistent with that of claim 1.

[0115] In one or more embodiments, the intermediate of the present invention or its stereoisomer or tautomer is selected from:

[0116] One or more embodiments of the present invention provide a process for preparing a piperazine derivative of formula (I) or an intermediate thereof or a stereoisomer or tautomer thereof, characterized in that:

[0117] The first step: reacting a compound of formula (b1-1) and 3,4-dihydropyran in a reaction solvent in the presence or absence of an acidic reagent to prepare a compound of formula (b1-2); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportions; the acidic reagent is selected from benzenesulfonic acid, p-toluenesulfonic acid, pyridine p-toluenesulfonate, naphthalenesulfonic acid, or camphorsulfonic acid;

[0118] Step 2: reacting the compound of formula (b1-2) and trifluoroethanol in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (b1-3); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any several of them in any proportion; the alkaline reagent is selected from any one of cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any several of them;

[0119] Step 3: The compound of formula (b1-3), cuprous iodide and methyl fluorosulfonyldifluoroacetate react in a reaction solvent under nitrogen protection to prepare a compound of formula (I-b1); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportions.

[0120] One or more embodiments of the present invention provide a process for preparing a piperazine derivative of formula (I) or an intermediate thereof or a stereoisomer or tautomer thereof, characterized in that:

[0121] The first step is the same as the first step of claim 15.

[0122] Step 2: Add a phase transfer catalyst to a reaction solvent to react the compound of formula (b1-2) and sodium methyl mercaptan to prepare a compound of formula (b2-1); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any several of them in any proportion; the phase transfer catalyst is selected from any one of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride, or a mixture of any several of them;

[0123] Step 3: reacting the compound of formula (b2-1), cuprous iodide and methyl fluorosulfonyldifluoroacetate in a reaction solvent under nitrogen protection to prepare a compound of formula (b2-2); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportions;

[0124] Step 4: Add an oxidant to the compound of formula (b2-2) in a reaction solvent to react and prepare a compound of formula (I-b2) and / or formula (I-b3); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any several of them in any proportion; the oxidant is selected from any one of hydrogen peroxide, m-chloroperbenzoic acid, potassium peroxymonosulfonate, sodium periodate, tert-butyl hydroperoxide, oxygen, N-fluorobisbenzenesulfonamide, ammonium molybdate / hydrogen peroxide, and ozone, or a mixture of any several of them.

[0125] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0126] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0127] Halogens include F, Cl, Br and I.

[0128] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0129] "Tautomers" or "tautomeric forms" refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, lactam-lactim isomerization, and the like. The present disclosure includes tautomers of any of the described compounds.

[0130] "Optional" or "optionally" or "selectively" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclyl group is substituted with an alkyl group and instances where the heterocyclyl group is not substituted with an alkyl group.

[0131] Unless otherwise stated, the English abbreviations used in the specification and claims have the following meanings. DETAILED DESCRIPTION

[0132] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0133] It should be noted that the reaction time is appropriately adjusted according to the amount of the reaction raw materials so that the reaction can proceed normally and be completed.

[0134] Example

[0135] Intermediate 1

[0136] 2-(Tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one intermediate I-b1

[0137] 2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0138] first step:

[0139] 4,5-Dibromo-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one b1-2

[0140] 4,5-dibromo-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one

[0141] 58 kg of tetrahydrofuran was pumped into a 100 L reactor, followed by the addition of compound b1-1 (6.5 kg), p-toluenesulfonic acid (1.21 kg), and DHP (4.3 kg). The system was pale yellow upon completion of the addition. After the addition, the temperature was raised to 65-70 ° C. When the internal temperature reached 65-70 ° C, the reaction was incubated for 12 hours. DHP (2.15 kg) was added, and the reaction was continued for 9 hours. DHP (2.15 kg) was added again, and the reaction was continued for 8 hours. The concentration of the raw material compound b1-1 was monitored by HPLC and was less than 17%. After passing the test, the temperature was lowered to 20-30 ° C, and the pH was adjusted to 7-8 with saturated sodium bicarbonate. Stirring was continued for 10 minutes until the pH was still 7-8. Concentrate until no liquid dripped out. 58 kg of ethyl acetate was added to dissolve the mixture, and 32.5 kg of 4N sodium hydroxide was added and stirred for 0.5 hours. The temperature was controlled at 20-30 ° C. The liquid was allowed to stand for separation, and the aqueous phase was discarded. The organic phase was washed twice with 32.5 kg of water, separated, and concentrated. A mixture of 14.6 kg of ethyl acetate and n-heptane (1:10) was added, heated to 50-60°C, and the mixture was dissolved. The mixture was then cooled to -10°C and held for 1 hour. The mixture was filtered, and the filter cake was washed with 6.5 kg of n-heptane. The filter cake was dried under reduced pressure at 45-50°C for 4-6 hours to yield 7.54 kg of crude compound b1-2, with a yield of 87.1% and a purity of 92.5%.

[0142] Step 2:

[0143] 4-Bromo-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethoxy)pyridazin-3(2H)-one b1-3

[0144] 4-bromo-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethoxy)pyridazin-3(2H)-one

[0145] Add 25 kg of DMF and 5 kg of raw material b1-2 to a 100 L reactor and stir to dissolve. Add 4.08 kg of potassium carbonate and 2.23 kg of trifluoroethanol while stirring. After addition, heat to 45-50°C and react for 6 hours. The reaction is considered complete when the concentration of raw material b1-2 is ≤ 2% by HPLC. Filter the reaction mixture through a pad of diatomaceous earth, wash the filter cake with 5 kg of DMF, and combine the filtrates. Add 60 kg of water dropwise to the filtrate at a temperature of 10-30°C. After stirring for 2 hours, filter and wash the filter cake with 10 kg of water to obtain the crude product.

[0146] 5 kg of ethyl acetate and 35 kg of n-heptane were added to the reactor, and the wet filter cake was added under stirring. The mixture was slurried at 20-30 ° C for 2 h, filtered, and the filter cake was washed with 10 kg of n-heptane to obtain a wet filter cake. The filter cake was dried under reduced pressure at 45-50 ° C for 16 h to obtain an off-white solid b1-3 (3.70 kg, yield 70%, purity 98.5%).

[0147] LCMS m / z(ESI)=378.90 / 380.90[M+Na] + .

[0148] Step 3:

[0149] 2-(Tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one intermediate I-b1

[0150] 2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0151] To a 100L reactor, add 47kg DMF and 3.15kg raw material b1-3, stir and dissolve, heat to 100±5°C under nitrogen protection, add 840g cuprous iodide, then mix 5.08kg methyl fluorosulfonyl difluoroacetate with 5kg DMF and add dropwise to the reaction solution. After the addition is complete, keep the reaction warm for 3h. The reaction is considered complete when the raw material b1-3 is ≤0.2% in the HPLC control. After the raw material reaction is complete, the reaction solution is cooled to 30°C, and then 21kg ethyl acetate and 27kg saturated sodium bicarbonate solution are added. Stir for 0.5h, filter the reaction solution through diatomaceous earth, wash the filter cake with 10kg ethyl acetate, combine the filtrate, stand and separate, extract the aqueous phase with 12kg×2 ethyl acetate, combine the organic phases, wash the organic phase twice with 9kg×2 saturated sodium chloride, and concentrate the organic phase under reduced pressure at 50°C until almost no distillate drips out. The residue was dissolved in 6.3 kg of DMF, and 21 kg of water was added dropwise to crystallize for 1 hour. The mixture was filtered and the filter cake was washed with 6.3 kg of water. The filter cake was added to a mixed solvent consisting of 0.63 kg of ethyl acetate and 6.3 kg of n-hexane and slurried for 3-4 hours. The mixture was filtered and the filter cake was washed with 3.15 kg of n-hexane. The filter cake was added with 6 kg of tertiary methyl ether and dissolved at 50-60°C. The mixture was cooled to crystallize and filtered. The filter cake was washed with 0.63 kg of tertiary methyl ether and dried under reduced pressure at 50°C for 16 hours to obtain an off-white solid product I-b1 (1.97 kg, yield 64.5%, purity 98.44%).

[0152] LCMS m / z (ESI) = 369.10 [M+Na] + .

[0153] 1 H NMR (400MHz, DMSO-d6): δ8.36(s,1H), δ5.83~5.88(m,1H), δ5.17~5.26(m,2H), δ3.92~3.9 7(m,1H), δ3.55~3.63(s,1H), δ1.90~2.05(m,2H), δ1.63~1.71(m,2H), δ1.45~1.53(s,2H).

[0154] Intermediate 2

[0155] 5-(Methylsulfinyl)-2-(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one intermediate I-b2

[0156] 5-(methylsulfinyl)-2-(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0157] 5-(Methylsulfonyl)-2-(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one intermediate I-b3

[0158] 5-(methylsulfonyl)-2-(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0159] first step:

[0160] 4,5-Dibromo-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one b1-2

[0161] 4,5-dibromo-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one

[0162] Compound b1-1 (30.00 g, 0.118 mol) and p-toluenesulfonic acid monohydrate (TsOH, 5.61 g, 0.0295 mol) were dissolved in dry tetrahydrofuran (250 mL), and 3,4-dihydro-2H-pyran (DHP, 27 mL, 0.295 mol) was slowly added at room temperature. After stirring for 10 minutes, the mixture was heated to 70°C and refluxed with stirring for 15 hours. After the reaction was almost complete according to TLC, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound b1-2 (36.73 g, yield 92%, purity 91.1%) as a reddish-brown oil.

[0163] LCMS m / z (ESI) = 360.90 [M+Na] + .

[0164] 1 H NMR (400MHz, DMSO-d6): δ7.87(s,1H), δ5.98~6.01(m,1H), δ4.11~4.15(m,1H), δ 3.11~3.77(m,1H), δ2.05~2.17(m,2H), δ1.66~1.77(m,3H), δ1.52~1.62(m,1H).

[0165] Step 2:

[0166] 4-Bromo-5-(methylthio)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one b2-1

[0167] 4-bromo-5-(methylthio)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one

[0168] Compound b1-2 (20.00 g, 0.0592 mol) was dissolved in tetrahydrofuran (200 mL) and stirred to dissolve, then cooled to -10°C, and then tetrabutylammonium bromide (3.82 g, 11.84 mmol) was added, and then a tetrahydrofuran solution of sodium methyl mercaptan (17.10 g of 20% sodium methyl mercaptan dissolved in 50 mL THF, 0.0474 mol) was slowly added dropwise. After the addition was completed, the temperature was raised to room temperature and stirred for 1.5 h. After TLC monitoring, water (200 mL) was added to the reaction solution, stirred for 10 min, and then allowed to stand for stratification. The organic phase was collected, the aqueous phase was extracted twice with ethyl acetate (100 mL), and the organic phases were combined and washed with saturated ammonium chloride solution (200 mL). The organic layer was concentrated under reduced pressure to obtain a light yellow viscous liquid b2-1 (13.39 g, yield 74%, purity 97.2%).

[0169] LCMS m / z(ESI)=327.00 / 329.00[M+Na] + .

[0170] 1 H NMR (400MHz, CDCl3-d): δ7.65(s,1H), δ6.04~6.07(m,1H), δ4.08~4.15(m,1H) ), δ3.72~3.78(m,1H), δ2.58(s,3H), δ2.02~2.05(m,2H), δ1.68~1.77(m,4H).

[0171] Step 3:

[0172] 5-(Methylthio)-2-(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one b2-2

[0173] 5-(methylthio)-2-(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0174] Compound b2-1 (13.00 g, 0.0426 mol) and cuprous iodide (4.06 g, 0.0213 mol) were dissolved in N,N-dimethylformamide (DMF, 130 mL), and methyl fluorosulfonyldifluoroacetate (24.56 g, 0.128 mol) was slowly added at room temperature. After the addition, the temperature was raised to 100°C and the mixture was stirred for 3 h. After the reaction was completed as monitored by HPLC, the reaction solution was cooled to room temperature and filtered through celite. The filter cake was washed with ethyl acetate (100 mL). The filtrate was collected and added with water (100 mL). After stirring for 10 min, the mixture was allowed to stand for separation. The organic layer was collected, and the aqueous layer was extracted twice with ethyl acetate (50 mL). The organic layers were combined and concentrated under reduced pressure to obtain crude compound b2-2 (12.95 g, brown solid). The crude compound b2-2 was dissolved in methanol (40 mL). The methanol solution was slowly added to water (200 mL) at room temperature and stirred for crystallization for 30 min. The mixture was then filtered and the filter cake was rinsed with water (30 mL). The filter cake was dried under reduced pressure to obtain b2-2 (9.00 g, yield 71.5%, purity 97.5%).

[0175] LCMS m / z (ESI) = 317.00 [M+Na] + .

[0176] Step 4:

[0177] 5-(Methylsulfinyl)-2-(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one intermediate I-b2

[0178] 5-(methylsulfinyl)-2-(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0179] 5-(Methylsulfonyl)-2-(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one intermediate I-b3

[0180] 5-(methylsulfonyl)-2-(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0181] Compound b2-2 (6.35 g, 0.0216 mol) was added to a reaction flask and stirred to dissolve in dichloromethane (60 mL) at room temperature. Meta-chloroperbenzoic acid (8.77 g, 0.0432 mol) was then slowly added. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was filtered, and the filter cake was rinsed once with dichloromethane (15 mL). The filtrate was collected and quenched with aqueous sodium thiosulfate solution. The mixture was allowed to stand for stratification. The organic layer was collected and washed with saturated aqueous sodium bicarbonate solution (30 mL). The mixture was concentrated under reduced pressure to give a crude product (6.74 g). The crude product was slurried with Hex / EA (30 mL / 0.5 mL) at room temperature for 1 h, filtered, and the filter cake was rinsed once with Hex / EA (12 mL / 0.2 mL). The filter cake was dried under reduced pressure at 40°C to give off-white solids I-b2 and / or I-b3 (5.20 g, yield 78%, purity 98.3%).

[0182] I-b2: LCMS m / z(ESI)=333.00.

[0183] I-b3: LCMS m / z(ESI)=349.00.

[0184] Example 1

[0185] (S)-4-(Trifluoromethyl)-5-((1-((5-(5-(trifluoroethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Compound I

[0186] (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0187] first step:

[0188] (5-(5-(Trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-methyl)methanol I-g

[0189] (5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol

[0190] The temperature of the 200L reactor was controlled at <40°C, and N,N-dimethylformamide (40.39kg), (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol I-i (8.60kg, 1.3eq), and N,N-diisopropylethylamine (15.19kg, 4.0eq) were added in sequence. Stirring was continued for 10 minutes. 2-chloro-5-(trifluoromethyl)pyrimidine I-h (5.35kg, 1.0eq) was added while controlling the temperature at <30°C. After addition, the reaction was continued at 40±5°C for 2 hours. The reaction was completed by HPLC. The reaction solution was controlled at a temperature of less than 20°C and slowly added to purified water in batches. 1 (128.37 kg), continue stirring for 0.5 h, filter, and wash the filter cake with purified water. 2 The mixture was slurried for 0.5 h, filtered with suction, and the filter cake was rinsed with purified water (42.80 kg). The filter cake was dried at 60±5°C for 16 h to obtain (5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-methyl)methanol I-g (8.17 kg, yield 93%, purity 99.8%).

[0191] LCMS m / z (ESI) = 300.05 [M+1].

[0192] 1H NMR (400MHz, DMSO-d6): δ8.78(s,2H),6.14(s,1H),4.98-5.02(m,3H),4.37-4.38(s,2H),4.31-4.33(t,2H),4.13-4.16(t,2H).

[0193] Step 2:

[0194] 2-(Bromomethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine Ⅰ-f

[0195] 2-(bromomethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

[0196] Under nitrogen, a 200L reactor was charged with (5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-methyl)methanol I-g (7.47 kg, 1.0 eq) and dichloromethane (99.01 kg). Phosphorus tribromide (10.14 kg, 1.5 eq) was added, maintaining the temperature at 20±5°C. After addition, the mixture was heated to 35±5°C and allowed to react for 2 h. HPLC confirmed the reaction was complete. The reaction was quenched with ice water (50.44 kg); the aqueous phase was extracted with dichloromethane (26.73 kg), and the organic phases were combined. The organic phase was washed sequentially with water (9.72 kg) and then with sodium bicarbonate solution (NaHCO3 (3.74 kg) added to water (38.85 kg)). The organic phase was filtered through a pad of silica gel (14.94 kg), and the filter cakes were washed with DCM (198.01 kg). The filtrate was added with anhydrous sodium sulfate (14.94 kg) and dried. The product was concentrated to obtain an off-white solid crude product. The product was slurried with n-heptane (30.66 kg) for 30 min, filtered, and the filter cake was washed with n-heptane (10.22 kg). The product was dried at 55 ± 5 ° C to obtain an off-white solid, and an off-white solid Ⅰ-f (7.32 kg, yield 81%, purity 99.8%) was obtained.

[0197] LCMS m / z(ESI)=362.10 / 364.10[M+H] + .

[0198] 1 H NMR (400MHz, CDCl3): δ8.568~8.570(d,2H),6.202(s,1H),5.056(s,2H),4.482(s,2H),4.390~4.418(t,2H),4.250~4.278(t,2H).

[0199] Step 3:

[0200] tert-Butyl-(1-((5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethoxy)propyl-2-carbamate I-d

[0201] tert-butyl(S)-(1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)carbamate

[0202] Under nitrogen protection, add Ⅰ-f (12.94 kg, 1.0 eq), N,N-dimethylformamide (122.02 kg), and N-Boc-L-alaninol (7.51 kg, 1.2 eq) to a 500L reactor in sequence. Cool to -10-0°C, control the temperature at -10±5°C, and slowly add sodium tert-butoxide (3.75 kg, 1.1 eq) in batches. After the addition, control the temperature at -10-0°C and continue the reaction for 1 hour. Stop the reaction when Ⅰ-f ≤ 1.0% by HPLC monitoring. Control the temperature below 10°C and slowly add purified water. 1 (388.20kg, 30m) quench the reaction and crystallize, control the temperature at 25±5℃ and continue stirring for 0.5h, centrifuge and filter; the filter cake is placed in a 200L reactor with purified water 2 (142.34kg) 25±5℃ beating for 0.5h, centrifugal filtration, purified water 3 and purified water 4 (14.80kg×2) elution. The filter cake was washed with mixed solution (V 乙酸乙酯 :V 正庚烷 =1:8, a total of 90.75 kg) was slurried at 25±5°C for 1 h, centrifuged and filtered, and the mixed solution (V 乙酸乙酯 :V 正庚烷 =1:8, a total of 18.12 kg) and the filter cake was washed and dried at 55±5°C for 10 h to give an off-white solid I-d (13.07 kg, yield 80%, purity 98.6%).

[0203] LCMS m / z (ESI) = 457.20 [M+H] + 、479.20[M+Na] + .

[0204] 1H NMR (400MHz, DMSO-d6): δ8.793(s,2H),6.649~6.669(d,1H),6.167(s,1),5.024(s,2H),4.362(s,2H),4.318~4.345(t,2H) ,4.156~4.183(t,2H),3.571~3.620(m,1H),3.314~3.352(m,1H),3.176~3.215(m,1H),1.360(s,9H),0.987~1.004(d,3H).

[0205] Step 4:

[0206] (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethoxy)propan-2-amine hydrochloride I-c

[0207] (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine hydrochloride

[0208] Under nitrogen protection, toluene (11.38 kg) and concentrated hydrochloric acid (4.38 kg) were added to the reactor, and I-d (6.54 kg, 1.0 m) was slowly added in batches at a temperature of 20-30 ° C. After the addition was completed, the temperature was raised to 50 ± 5 ° C and the reaction was continued for 2 h. The temperature was lowered to 20 ± 5 ° C, and the mixture was allowed to stand for 15 min to separate the liquids. The organic phase was extracted with water (6.54 kg), the aqueous phase was combined, and dichloromethane was added. 1 and dichloromethane 2 The aqueous layer was extracted twice with 17.33 kg (2 times) to obtain an aqueous solution of I-c (yield 95%, purity 95.2%).

[0209] LCMS m / z (ESI) = 357.20 [M+H] + 、379.10[M+Na] + .

[0210] 1H NMR (400MHz, DMSO-d6): δ8.810(s,2H),6.183(s,1H),5.029(s,2H),4.361(s,2H),4.319~4 .346(t,2H),4.156~4.183(t,2H),3.137~3.182(m,2H),2.896~2.911(m,1H),1.447(s,2H), 0.896~0.913(d,3H).

[0211] Step 5:

[0212] 2-(Tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)-5-((S)-1-((5-(pentafluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-alkyl)amino)pyridazin-3(2H)-one I-a

[0213] 2-(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)-5-(((S)-1-((5-(5-

[0214] (trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0215] Under nitrogen protection, add Ⅰ-c aqueous solution and tetrahydrofuran (12.90kg) to a 100L reactor in sequence, control the temperature to ≤35℃, slowly add cesium carbonate (17.75kg) in batches, and continue stirring for 10-15min. Control the temperature to less than 40℃ and add Ⅰ-b1 (5.04kg) and tetrabutylammonium bromide (0.49kg) in sequence. After the addition, replace the nitrogen three times, raise the temperature to 30-35℃, and continue the reaction for 4-8h. The reaction is completed when the peak area of ​​Ⅰ-b1 is ≤2% by HPLC monitoring. Cool the reaction solution to 25-35℃ and add ethyl acetate 1 (43.75kg) was stirred and allowed to stand for 15 minutes to separate the liquids. The aqueous phase was treated with ethyl acetate. 2 and ethyl acetate 3 ((21.87kg×2) extraction, combined organic phase, purified water 1 (24.25kg) and purified water 2 (24.25kg) washed the organic phase (stirred for 5min and allowed to stand for 15min) twice. The organic phase was filtered through silica gel (4.85kg) and ethyl acetate was added. 4(43.75 kg) was washed until almost no product remained (TLC), and concentrated at 50 ± 5 ° C until almost no fraction flowed out to obtain the crude product Ⅰ-a. The crude product was kept at 45 ± 5 ° C and washed with ethanol. 1 (2.28kg) and n-heptane 1 (19.89kg) mixed solution was slurried at 50±5℃ for about 3h. Centrifuged and filtered, and ethanol was used. 2 (0.78kg) and n-heptane 2 The filter cake was washed with 1% ethanol (6.69 kg) and dried at 45±5°C for 8 h to obtain pure product Ⅰ-a (7.01 kg, yield 87.4%, purity 97.2%).

[0216] LCMS m / z (ESI) = 603.30 [M+H] + .

[0217] 1 H NMR (400MHz, DMSO-d6): δ8.78-8.80(d,2H), δ8.00-8.01(d,1H), δ8.00-8.01(d ,1H),δ6.47-6.48(d,1H),δ6.06-6.09(d,1H),δ5.73-5.78(m,1H),δ5.00(s,1H ),δ4.41(d,2H),δ4.30-4.37(m,2H),δ4.16-4.18(m,3H),δ3.90-3.93(m,1H),δ 3.42-3.56(m,3H), δ1.89-2.05(m,2H), δ1.42-1.65(m,4H), δ1.16-1.17(d,3H).

[0218] 19 F NMR(400MHz,DMSO-d6)δ-59.40,-55.72.

[0219] Step 6:

[0220] (S)-4-(Trifluoromethyl)-5-((1-((5-(5-(trifluoroethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Compound I

[0221] (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0222] Under nitrogen protection, Ⅰ-a (6.97 kg), acetonitrile and 1 (10.94Kg). Control the temperature below 15℃ and add 4M HCl / EA (37.71kg). After the addition is complete, heat to 30±5℃ and stir for 5h. Monitor the reaction by HPLC. Control the temperature below 15℃ and add purified water to the reaction solution. 1 (20.91 kg), ammonia water was used to adjust the pH value to 6-7, and the aqueous phase was treated with ethyl acetate. 1 and ethyl acetate 2 ((15.75kg, 2.26m)×2) extraction, combined organic phase, 20% sodium chloride aqueous solution 1 (13.94 kg) and 20% sodium chloride aqueous solution 2 (13.94 kg) washed twice, dried with anhydrous sodium sulfate (5.97 kg), and washed with ethyl acetate 3 Rapid silica gel column chromatography (10.46 kg) until there is almost no product, and then concentrated to near dryness under reduced pressure. The oily substance is purified by acetonitrile. 2 and acetonitrile 3 The crude product of compound I was obtained by belt (5.51 kg) × 2 times.

[0223] Under nitrogen protection, acetonitrile 4 (10.94 kg) was added to the crude product of compound I, heated to 60-65 ° C and dissolved for 0.5 h; purified water was added 2 (20.91kg), cool to 25±5℃ and continue stirring for 18h, then add acetonitrile 5 :water 3 =2:3 (total 5V; acetonitrile (10.94kg); water (20.91kg)), continue crystallization at 25±5℃ for 8h, centrifuge and filter, the filter cake is washed with a mixture of acetonitrile (4.39kg); water (8.36kg) to obtain a wet product of compound I, which is dried at 55±5℃ for 16h to obtain compound I (3.6kg, yield 60%, purity 98.5%).

[0224] LCMS m / z (ESI) = 519.20 [M+H] + and 541.20[M+Na] + .

[0225] 1 H NMR (400MHz, DMSO-d6): δ12.496(s,1H),8.814~8.816(s,2H),7.926(s,1H),6.287~6.317(m,1H),6.128(s,1H),5.02 8(s,2H),4.440~4.469(d,2H),4.331~4.359(m,2H),4.170~4.197(m,3H),3.513~3.527(m,2H),1.169~1.185(d,3H).

[0226] 19 F NMR(400MHz,DMSO-d6)δ-55.47,-59.48.

[0227] 13 C NMR (400MHz, DMSO-d6) δ161.7,157.86,155.94~155.97,148.52,146.00,135.81 ,128.53,125.54~126.17,122.86~123.46,112.1~113.09,100.87,95.04~95.86 72.55,66.14,48.41,46.06,41.09~41.22,17.49.

[0228] Example 2

[0229] (S)-4-(Trifluoromethyl)-5-((1-((5-(5-(trifluoroethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Compound I

[0230] (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0231] The difference between Example 2 and Example 1 mainly lies in the fifth step. The implementation process of the fifth step in Example 2 is as follows:

[0232] Step 5:

[0233] 2-(Tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)-5-((S)-1-((5-(pentafluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-alkyl)amino)pyridazin-3(2H)-one I-a

[0234] 2-(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)-5-(((S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0235] Compound Ic (0.12 g, 0.98 mmol) was placed in a reaction flask, and DMF (4 mL) was added. The temperature was cooled to 0°C, followed by the addition of DIPEA (0.167 g, 1.292 mmol) and the mixture was stirred for 10 min. I-b2 and / or I-b3 (0.400 g, 1.227 mmol) were then added, and the mixture was stirred at low temperature for 2 h. After completion of the reaction, the reaction solution was quenched by adding water, extracted with ethyl acetate, and the organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography to afford Compound Ia (0.4 g, 56% yield, 98.2% purity) as an off-white solid.

[0236] Example 3

[0237] (S)-4-(Trifluoromethyl)-5-((1-((5-(5-(trifluoroethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Compound I

[0238] (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0239] The difference between Example 3 and Example 1 mainly lies in the fourth step. The implementation process of the fourth step in Example 3 is as follows:

[0240] Step 4:

[0241] (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethoxy)propan-2-amine hydrochloride I-c

[0242] (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine hydrochloride

[0243] To a 100-L reactor, I-d (3.6 kg, 1.0 eq), ethyl acetate (14.4 L), and n-heptane (3.6 L) were added sequentially and stirred for 10 min. 4N HCl / dioxane (7.4 L) was slowly added dropwise at 45-55°C and the reaction continued for 2 h. The reaction was complete upon disappearance of I-d by TLC monitoring. The mixture was centrifuged and the filter cake was rinsed with 5 L of ethyl acetate. The filter cake was dried at 60±5°C for 8 h to yield 3.4 kg of an off-white solid I-c in a yield >100%. The HPLC purity was 98.2%.

[0244] Example 4

[0245] (S)-4-(Trifluoromethyl)-5-((1-((5-(5-(trifluoroethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Compound I

[0246] (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0247] The difference between Example 4 and Example 1 mainly lies in the fifth step. The implementation process of the fifth step in Example 4 is as follows:

[0248] Step 5:

[0249] 2-(Tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)-5-((S)-1-((5-(pentafluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-alkyl)amino)pyridazin-3(2H)-one I-a

[0250] 2-(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)-5-(((S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0251] Under nitrogen protection, 1-c (5.0 g), 1-b1 (4.0 g), and DMF (40 mL) were added to the reaction flask in sequence to dissolve the mixture. The temperature was controlled at ≤35°C. DBU (6.6 g, 3.0 eq) was slowly added in batches. After the addition was completed, the temperature was controlled at 50°C and the reaction was carried out for 4 h. The reaction solution was added to 300 ml of water and filtered. The filter cake was dissolved with ethyl acetate, washed with water and saturated ammonium chloride in sequence, concentrated, and crystallized with methanol and water to give an off-white solid Ⅰ-a (4.98 g, yield 57.2%, purity 98.3%).

[0252] Example 5

[0253] (S)-4-(Trifluoromethyl)-5-((1-((5-(5-(trifluoroethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Compound I

[0254] (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0255] first step:

[0256] (5-(5-(Trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-methyl)methanol I-g

[0257] (5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol

[0258] The temperature of a 200L reactor was controlled at <40°C, and N,N-dimethylformamide (40.39 kg), (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol I-i (8.60 kg, 1.3 eq), and N,N-diisopropylethylamine (15.19 kg, 4.0 eq) were added in sequence. Stirring was continued for 10 min. 2-Chloro-5-(trifluoromethyl)pyrimidine I-h (5.35 kg, 1.0 eq) was added, the temperature was controlled at <30°C, and after the addition was completed, the reaction was continued at 40±5°C for 2 h. The reaction was completed as detected by HPLC. The reaction solution was temperature-controlled below 20°C and slowly added into purified water (128.37 kg) in batches. The mixture was stirred for 0.5 h and filtered. The filter cake was slurried with purified water (69.54 kg) for 0.5 h and filtered with suction. The filter cake was rinsed with purified water (42.80 kg). The filter cake was dried at 60±5°C for 16 h to obtain (5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-methyl)methanol I-g (8.17 kg, yield 93%, purity 99.8%).

[0259] LCMS m / z (ESI) = 300.05 [M+1].

[0260] 1 H NMR (400MHz, DMSO-d6): δ8.78(s,2H),6.14(s,1H),4.98-5.02(m,3H),4.37-4.38(s,2H),4.31-4.33(t,2H),4.13-4.16(t,2H).

[0261] Step 2:

[0262] 2-(Bromomethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine Ⅰ-f

[0263] 2-(bromomethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

[0264] Under nitrogen, a 200L reactor was charged sequentially with (5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-methyl)methanol I-g (7.47 kg, 1.0 eq) and dichloromethane (99.01 kg). Phosphorus tribromide (10.14 kg, 1.5 eq) was added, maintaining the temperature at 20±5°C. After addition, the temperature was raised to 35±5°C and the reaction was allowed to proceed for 2 h. HPLC confirmed the reaction was complete. The reaction was quenched with ice water (50.44 kg); the aqueous phase was extracted with dichloromethane (26.73 kg), and the organic phases were combined. The organic phases were washed sequentially with water (9.72 kg) and then with 42.59 kg of sodium bicarbonate solution. The organic phase was filtered through a silica gel pad (14.94 kg). The filter cakes were washed with DCM until no product flowed out. The filtrate was added with anhydrous sodium sulfate (14.94 kg) and dried. The filtrate was concentrated to obtain an off-white solid crude product. The product was purified by heptane distillation. 1 (30.66kg) slurry for 30min, filter, n-heptane 2 The filter cake was washed with 10.22 kg of filtrate and dried at 55±5°C to obtain an off-white solid, obtaining an off-white solid Ⅰ-f (7.32 kg, yield 81%, purity 99.8%).

[0265] LCMS m / z(ESI)=362.10 / 364.10[M+H] + .

[0266] 1 H NMR (400MHz, CDCl3): δ8.568~8.570(d,2H),6.202(s,1H),5.056(s,2H),4.482(s,2H),4.390~4.418(t,2H),4.250~4.278(t,2H).

[0267] Step 3:

[0268] (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine I-c

[0269] (S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine

[0270] Under nitrogen, tetrahydrofuran (20 ml) and L-aminopropanol (1.04 g, 13.8 mmol) were added to a 100 L reaction flask. The temperature was lowered to -5°C and potassium tert-butoxide (1.55 g, 13.8 mmol) was slowly added while maintaining a temperature of -5±3°C. After the addition, the reaction was stirred at -5±3°C for 1 h. 2-(Bromomethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine I-f (1.0 g, 2.76 mmol) was added. The reaction was removed from the refrigerator and allowed to warm to room temperature with stirring for 2 h to terminate the reaction. The reaction was quenched by slowly adding 200 ml of water while maintaining a temperature below 10°C. The reaction was extracted with EA (100 mL x 4). The organic phases were combined and washed with saturated brine (100 mL x 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the organic solvent removed under reduced pressure. The residue was purified by medium pressure preparation (acetonitrile / water = 3 / 7) to give I-c as an off-white solid (700 mg, yield 71.2%, purity 95.6%).

[0271] LCMS m / z (ESI) = 357.20 [M+H] + .

[0272] 1 H NMR (400MHz, DMSO-d6): δ8.816(s,2H),6.183(s,1H),5.029(s,2H),4.361(s,2H),4.319~4.346(t,2H ),4.156~4.183(t,2H),3.137~3.182(m,2H),2.896~2.911(m,1H),1.447(s,2H),0.896~0.913(d,3H).

[0273] Step 4:

[0274] 2-(Tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)-5-((S)-1-((5-(pentafluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-alkyl)amino)pyridazin-3(2H)-one I-a

[0275] 2-(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)-5-(((S)-1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0276] Under nitrogen, add I-c (20.0 g, 5.6 mmol), water (40 ml), and tetrahydrofuran (60 ml) to a 100 mL reaction flask. Slowly add cesium carbonate (7.3 g, 22.4 mmol) in batches while maintaining the temperature at ≤35°C. Stir for 10-15 min. Add I-b1 (20.7 g, 5.99 mmol) and tetrabutylammonium bromide (200 mg) while maintaining the temperature below 40°C. Replace the mixture with nitrogen three times, raise the temperature to 30-35°C, and continue the reaction for 4-8 h. Monitor the reaction for completion by LCMS. The reaction solution was poured into 100 mL of water, extracted with ethyl acetate (200 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 10:1 to 2:1) to obtain compound Ⅰ-a as an off-white solid (27 g, yield 80%, purity 97.8%).

[0277] LCMS m / z (ESI) = 603.30 [M+H] + .

[0278] 1 H NMR (400MHz, DMSO-d6): δ8.78-8.80(d,2H), δ8.00-8.01(d,1H), δ8.00-8.01(d ,1H),δ6.47-6.48(d,1H),δ6.06-6.09(d,1H),δ5.73-5.78(m,1H),δ5.00(s,1H ),δ4.41(d,2H),δ4.30-4.37(m,2H),δ4.16-4.18(m,3H),δ3.90-3.93(m,1H),δ 3.42-3.56(m,3H), δ1.89-2.05(m,2H), δ1.42-1.65(m,4H), δ1.16-1.17(d,3H).

[0279] 19 F NMR(400MHz,DMSO-d6)δ-59.40,-55.72.

[0280] Step 5:

[0281] (S)-4-(Trifluoromethyl)-5-((1-((5-(5-(trifluoroethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Compound I

[0282] (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0283] Under nitrogen protection, Ⅰ-a (6.97 kg), acetonitrile and 1 (10.94Kg). Control the temperature below 15℃ and add 4M HCl / EA (37.71kg). After the addition is complete, heat to 30±5℃ and stir for 5h. Monitor the reaction by HPLC. Control the temperature below 15℃ and add purified water to the reaction solution. 1 (20.91 kg), ammonia water was used to adjust the pH value to 6-7, and the aqueous phase was treated with ethyl acetate. 1 and ethyl acetate 2 ((15.75kg) × 2) extraction, combined organic phase, 20% sodium chloride aqueous solution 1 (13.94 kg) and 20% sodium chloride aqueous solution 2 (13.94 kg) washed twice, dried with anhydrous sodium sulfate (5.97 kg), and washed with ethyl acetate 3 Rapid silica gel column chromatography (10.46 kg) until there is almost no product, and then concentrated to near dryness under reduced pressure. The oily substance is purified by acetonitrile. 2 and acetonitrile 3 The crude product of compound I was obtained by belt (5.51 kg) × 2 times.

[0284] Under nitrogen protection, acetonitrile 4 (10.94 kg) was added to the crude product of compound I, heated to 60-65 ° C and dissolved for 0.5 h; purified water was added 2 (20.91kg), cool to 25±5℃ and continue stirring for 18h, then add acetonitrile 5 :water 3 =2:3 (total 5V; acetonitrile (10.94kg); water (20.91kg)), continue crystallization at 25±5℃ for 8h, centrifuge and filter, the filter cake is washed with a mixture of acetonitrile (4.39kg); water (8.36kg) to obtain a wet product of compound I, which is dried at 55±5℃ for 16h to obtain compound I (3.6kg, yield 60%, purity 98.5%).

[0285] LCMS m / z (ESI) = 519.20 [M+H] + and 541.20[M+Na] + .

[0286] 1 H NMR (400MHz, DMSO-d6): δ12.496(s,1H),8.814~8.816(s,2H),7.926(s,1H),6.287~6.317(m,1H),6.128(s,1H),5.02 8(s,2H),4.440~4.469(d,2H),4.331~4.359(m,2H),4.170~4.197(m,3H),3.513~3.527(m,2H),1.169~1.185(d,3H).

[0287] 19 F NMR(400MHz,DMSO-d6)δ-55.47,-59.48.

[0288] 13 C NMR (400MHz, DMSO-d6) δ161.7,157.86,155.94~155.97,148.52,146.00,135.81 ,128.53,125.54~126.17,122.86~123.46,112.1~113.09,100.87,95.04~95.86 72.55,66.14,48.41,46.06,41.09~41.22,17.49.

[0289] Example 6

[0290] (S)-4-(Trifluoromethyl)-5-((1-((5-(5-(trifluoroethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]methoxy)propan-2-yl)amino)pyridazin-3(2H)-one Compound I

[0291] (S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one

[0292] The difference between Example 6 and Example 1 mainly lies in the second step. The implementation process of the second step in Example 6 is as follows:

[0293] Step 2:

[0294] 2-(Bromomethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine Ⅰ-f

[0295] 2-(bromomethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

[0296] Under nitrogen protection, Ⅰ-g (220g, 1.0eq) and toluene (1905.2g) were added to the reaction flask in sequence, and the temperature was lowered to 15°C. Phosphorus tribromide (238.9g, 1.2eq) was added while controlling the temperature to less than 25°C. After the addition was completed, the temperature was raised to 90±5°C and stirred for 3h. TLC and HPLC were controlled to show that there was no raw material. The reaction solution was slowly added to 0-5°C ice water (1485g) while controlling the temperature to <18°C to quench, and the mixture was allowed to stand. The filter cake was washed with diatomaceous earth and ethyl acetate (440g). The mixture was allowed to stand for stratification, and the aqueous phase was extracted with ethyl acetate (992.2g). The organic phase was washed with water (1100g) and 10% sodium bicarbonate solution in sequence. The organic phase was dried over anhydrous sodium sulfate (440g) for 0.5h, filtered, and the filter cake was washed with ethyl acetate (220g). The mixture was concentrated to obtain an off-white solid crude product, and n-heptane was added. 1 (902g) was slurried at 20±5℃ for 30min, filtered, and then added with n-heptane. 2 The filter cake was washed with water (301.4 g) and dried at 55±5°C for 8 h to obtain an off-white solid Ⅰ-f (215.7 g, yield 81.3%, purity 99.5%).

[0297] The present invention specification describes specific embodiments in detail, and those skilled in the art will recognize that the above embodiments are exemplary and cannot be construed as limiting the present invention. At the same time, the above embodiments presented in this application can be freely combined within a reasonable range understood by those skilled in the art, and these combinations will also fall within the scope of protection of the present invention. For those skilled in the art, without departing from the principles of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A process for preparing a piperazine derivative of formula (I-1) or a stereoisomer or tautomer thereof, characterized in that: The compound of formula (I-1) or its stereoisomer or tautomer is prepared by the following reaction steps: The compound of formula (Ia-1) is reacted in a reaction solvent under acidic reagent conditions to prepare a compound of formula (I-1); The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportion; The acidic reagent is selected from any one or a mixture of any of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid; in: R 1a , R 1b Each independently is H, D or C 1-6 alkyl; R 2a , R 2b Each independently is H, D or C 1-6 alkyl; R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H or D; R6 and R7 are each independently H or D; R8 and R9 are each independently H or D; R 10 CF3 or SR 10d ; R 10d H, D or C 1-6 alkyl; B is m is 1, 2 or 3; n is 0, 1, 2 or 3; G is THP, MOM, BOM, MEM, Trt, DMB, PMB or SEM.

2. The preparation process according to claim 1, characterized in that: The compound of formula (I-1) is selected from the compound of formula (I) or its stereoisomer or tautomer, and the compound of formula (I) or its stereoisomer or tautomer is prepared by the following reaction steps: The compound of formula (Ia) is reacted in a reaction solvent under acidic reagent conditions to prepare a compound of formula (I); The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportion; The acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid or a mixture of any of them.

3. A process for preparing a compound of formula (Ia-1) or a stereoisomer or tautomer thereof, characterized in that: The compound of formula (Ia-1) or its stereoisomer or tautomer is prepared by the following reaction steps: The compound of formula (Ic-1) and compound Ib-1 react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ia-1); The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, methyl tert-butyl ether, isopropyl ether, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or a mixture of any of the above in any proportions; The alkaline reagent is selected from any one of cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of the above; in: Compound Ib-1 is Or compound Ib-1 is Q is or halogen; R 1a , R 1b , R 2a , R 2b , R3, R4, R5, R6, R7, R8, R9, R 10 The definitions of B, m, n, and G are consistent with those in claim 1.

4. The preparation process according to claim 3, characterized in that: The compound of formula (Ia-1) is selected from the compound of formula (Ia) or its stereoisomer or tautomer, and the compound of formula (Ia) or its stereoisomer or tautomer is prepared by the following reaction steps: The compound of formula (Ic) and compound Ib react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ia); The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, methyl tert-butyl ether, isopropyl ether, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or a mixture of any of the above in any proportions; The alkaline reagent is selected from any one of cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of the above; in: Compound Ib is Alternatively, compound Ib is Q is or halogen.

5. A process for preparing a compound of formula (Ic-1) or a stereoisomer or tautomer thereof, characterized in that: The compound of formula (Ic-1) or its stereoisomer or tautomer is prepared by the following reaction steps: The compound of formula (If-1) and the compound of formula (Ie-1) react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Id-1), and the compound of formula (Id-1) reacts in a reaction solvent under acidic reagent conditions to prepare a compound of formula (Ic-1); or The compound of formula (If-1) and the compound of formula (I-e1-1) react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ic-1); The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or a mixture of any of the above in any proportions; The alkaline reagent is selected from any one or a mixture of any of cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine; The acidic reagent is selected from any one or a mixture of any of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid; in: R Y1 is Boc, Cbz, PMB, Tos, Fmoc, SEM, Alloc, Pht or Trt; R 1a , R 1b , R 2a , R 2b , R3, R4, R5, R6, R7, R8, R9, R 10 , B, m, and n are defined in accordance with those in claim 1.

6. The preparation process according to claim 5, characterized in that: The compound of formula (Ic-1) is selected from the compound of formula (Ic) or its stereoisomer or tautomer, and the compound of formula (Ic) or its stereoisomer or tautomer is prepared by the following reaction steps: The compound of formula (If) and the compound of formula (Ie) react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Id), and the compound of formula (Id) reacts in a reaction solvent under acidic reagent conditions to prepare a compound of formula (Ic); or The compound of formula (If) and the compound of formula (I-e1) react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ic); The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or a mixture of any of the above in any proportions; The alkaline reagent is selected from any one or a mixture of any of cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine; The acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid or a mixture of any of them.

7. A process for preparing a compound of formula (If-1) or a stereoisomer or tautomer thereof, characterized in that: The compound of formula (If-1) or its stereoisomer or tautomer is prepared by the following reaction steps: The compound of formula (Ig-1) and a bromination reagent react in a reaction solvent to obtain a compound of formula (If-1); The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportion; The bromination reagent is selected from bromine, hydrobromic acid, phosphorus oxybromide, phosphorus tribromide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide, and carbon tetrabromide; in: R3, R4, R5, R6, R7, R8, R9, R 10 , B, and n are defined in accordance with those in claim 1.

8. The preparation process according to claim 7, characterized in that: The compound of formula (If-1) is selected from the compound of formula (If) or its stereoisomer or tautomer, and the compound of formula (If) or its stereoisomer or tautomer is prepared by the following reaction steps: The compound of formula (Ig) and a bromination reagent react in a reaction solvent to obtain a compound of formula (If); The reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportion; The bromination reagent is selected from bromine, hydrobromic acid, phosphorus oxybromide, phosphorus tribromide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide, and carbon tetrabromide.

9. A process for preparing a piperazine derivative of formula (I-1) or a stereoisomer or tautomer thereof, characterized in that: The first step: reacting a compound of formula (Ii-1) and a compound of formula (Ih-1) in a reaction solvent under alkaline reagent conditions; after the reaction is completed, adding an aqueous solution and stirring to crystallize to prepare a compound of formula (Ig-1); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportion; the alkaline reagent is selected from any one of cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of the above; Step 2: reacting the compound of formula (Ig-1) and a brominating agent in a reaction solvent to obtain a compound of formula (If-1); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportion; the brominating agent is selected from bromine, hydrobromic acid, phosphorus oxybromide, phosphorus tribromide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide, and carbon tetrabromide; Step 3: The compound of formula (If-1) and the compound of formula (Ie-1) react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Id-1); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, any one or a mixture of any several in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, any one or a mixture of any several; Step 4: The compound of formula (Id-1) reacts in a reaction solvent under acidic reagent conditions to prepare a compound of formula (Ic-1); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, Any one of H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol or any mixture of any proportion; the acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid or any mixture of any proportion; Step 5: The compound of formula (Ic-1) and compound Ib-1 react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ia-1); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, methyl tert-butyl ether, isopropyl ether, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, any one or a mixture of any several in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, any one or a mixture of any several; Step 6: reacting the compound of formula (Ia-1) in a reaction solvent under acidic reagent conditions to prepare a compound of formula (I-1); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or any mixture of any of them in any proportion; the acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, or any mixture of any of them; or The first step: reacting the compound of formula (Ii-1) and the compound of formula (Ih-1) in a reaction solvent under alkaline reagent conditions; after the reaction is completed, adding an aqueous solution and stirring for crystallization to prepare a compound of formula (Ig-1); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, any one of n-heptane or a mixture of any of the above in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, tert-butyl alcohol, sodium ... Any one or a mixture of any of potassium butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine; Step 2: reacting the compound of formula (Ig-1) and a brominating agent in a reaction solvent to obtain a compound of formula (If-1); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportion; the brominating agent is selected from bromine, hydrobromic acid, phosphorus oxybromide, phosphorus tribromide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide, and carbon tetrabromide; Step 3: The compound of formula (If-1) and the compound of formula (I-e1-1) react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ic-1); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, any one or a mixture of any several in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, any one or a mixture of any several; Step 4: reacting the compound of formula (Ic-1) and compound Ib-1 in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ia-1); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, methyl tert-butyl ether, isopropyl ether, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, any one or a mixture of any several in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, any one or a mixture of any several; Step 5: reacting the compound of formula (Ia-1) in a reaction solvent under acidic reagent conditions to prepare a compound of formula (I-1); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or any mixture of any several of them in any proportion; the acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, or any mixture of any several of them; in: Compound Ib-1 is Or compound Ib-1 is Q is or halogen; R Y1 is Boc, Cbz, PMB, Tos, Fmoc, SEM, Alloc, Pht or Trt; R 1a , R 1b , R 2a , R 2b , R3, R4, R5, R6, R7, R8, R9, R 10 The definitions of B, m, n, and G are consistent with those in claim 1.

10. The preparation process according to claim 9, characterized in that: The compound of formula (I-1) is selected from the compound of formula (I) or its stereoisomer or tautomer, and the compound of formula (I) or its stereoisomer or tautomer is prepared by the following reaction steps: The first step: reacting a compound of formula (Ii) and a compound of formula (Ih) in a reaction solvent under alkaline reagent conditions; after the reaction is completed, adding an aqueous solution and stirring to crystallize to prepare a compound of formula (Ig); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportion; the alkaline reagent is selected from any one of cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of the above; Step 2: reacting the compound of formula (Ig) and a brominating agent in a reaction solvent to obtain a compound of formula (If); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or any mixture of any of the above in any proportion; the brominating agent is selected from bromine, hydrobromic acid, phosphorus oxybromide, phosphorus tribromide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide, and carbon tetrabromide; Step 3: The compound of formula (If) and the compound of formula (Ie) react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Id); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, any one or a mixture of any several in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, any one or a mixture of any several; Step 4: reacting the compound of formula (Id) in a reaction solvent under acidic reagent conditions to prepare a compound of formula (Ic); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, or any mixture of any of them in any proportion; the acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, or any mixture of any of them; Step 5: The compound of formula (Ic) and compound Ib react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ia); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, methyl tert-butyl ether, isopropyl ether, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, any one or a mixture of any several in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, any one or a mixture of any several; Step 6: reacting the compound of formula (Ia) in a reaction solvent under acidic reagent conditions to prepare a compound of formula (I); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or any mixture of any of them in any proportion; the acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, or any mixture of any of them; or The first step: reacting a compound of formula (Ii) and a compound of formula (Ih) in a reaction solvent under alkaline reagent conditions; after the reaction is completed, adding an aqueous solution and stirring to crystallize to prepare a compound of formula (Ig); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportion; the alkaline reagent is selected from any one of cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of the above; Step 2: reacting the compound of formula (Ig) and a brominating agent in a reaction solvent to obtain a compound of formula (If); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or any mixture of any of the above in any proportion; the brominating agent is selected from bromine, hydrobromic acid, phosphorus oxybromide, phosphorus tribromide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide, and carbon tetrabromide; Step 3: The compound of formula (If) and the compound of formula (I-e1) react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ic); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, any one or a mixture of any several in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, any one or a mixture of any several; Step 4: The compound of formula (Ic) and compound Ib react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (Ia); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, n-heptane, methyl tert-butyl ether, isopropyl ether, H2O, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, L-aminopropanol, any one or a mixture of any of the above in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, Any one of sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of them; Step 5: reacting the compound of formula (Ia) in a reaction solvent under acidic reagent conditions to prepare a compound of formula (I); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or any mixture of any of them in any proportion; the acidic reagent is selected from any one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, difluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, or any mixture of any of them; Compound Ib is Alternatively, compound Ib is Q is or halogen.

11. An intermediate or a stereoisomer or a tautomer thereof for preparing a piperazine derivative of formula (I-1), wherein the intermediate or a stereoisomer or a tautomer thereof is selected from: in: G is THP, MOM, BOM, MEM, Trt or DMB; R 1a , R 1b , R 2a , R 2b , R3, R4, R5, R6, R7, R8, R9, R 10 , B, m, and n are defined in accordance with those in claim 1.

12. The intermediate according to claim 11 or its stereoisomer or tautomer, wherein the intermediate or its stereoisomer or tautomer is selected from:

13. An intermediate or a stereoisomer or a tautomer thereof for preparing a piperazine derivative of formula (I-1), wherein the intermediate or a stereoisomer or a tautomer thereof is selected from: in: Q is or halogen; The definition of G is consistent with that of claim 1.

14. The intermediate according to claim 13, or its stereoisomer or tautomer, wherein the intermediate or its stereoisomer or tautomer is selected from:

15. A process for preparing a piperazine derivative of formula (I) or an intermediate of a stereoisomer or tautomer thereof or a preparation process of a stereoisomer or tautomer thereof, characterized in that: The first step: reacting a compound of formula (b1-1) and 3,4-dihydropyran in a reaction solvent in the presence or absence of an acidic reagent to prepare a compound of formula (b1-2); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportion; the acidic reagent is selected from benzenesulfonic acid, p-toluenesulfonic acid, pyridine p-toluenesulfonate, naphthalenesulfonic acid, or camphorsulfonic acid; Step 2: The compound of formula (b1-2) and trifluoroethanol react in a reaction solvent under alkaline reagent conditions to prepare a compound of formula (b1-3); the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, any one of n-heptane or any mixture of any of the above in any proportion; the alkaline reagent is selected from cesium carbonate, sodium carbonate, Any one of sodium acetate, sodium phosphate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium acetate, potassium phosphate, potassium hydroxide, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine, or a mixture of any of them; Step 3: reacting the compound of formula (b1-3), cuprous iodide and methyl fluorosulfonyl difluoroacetate in a reaction solvent under nitrogen protection to prepare a compound of formula (I-b1); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportion.

16. A process for preparing a piperazine derivative of formula (I) or an intermediate of a stereoisomer or tautomer thereof or a preparation process of a stereoisomer or tautomer thereof, characterized in that: The first step is the same as the first step of claim 15. Step 2: Add a phase transfer catalyst to a reaction solvent to react the compound of formula (b1-2) and sodium methyl mercaptan to prepare a compound of formula (b2-1); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or any mixture of any of them in any proportion; the phase transfer catalyst is selected from any one of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride, or any mixture of any of them; Step 3: reacting the compound of formula (b2-1), cuprous iodide and methyl fluorosulfonyl difluoroacetate in a reaction solvent under nitrogen protection to prepare a compound of formula (b2-2); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportion; Step 4: Add an oxidant to the compound of formula (b2-2) in a reaction solvent to react and prepare a compound of formula (I-b2) and / or formula (I-b3); the reaction solvent is selected from any one of acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, ethyl acetate, and n-heptane, or a mixture of any of the above in any proportion; the oxidant is selected from any one of hydrogen peroxide, m-chloroperbenzoic acid, potassium peroxymonosulfonate, sodium periodate, tert-butyl hydroperoxide, oxygen, N-fluorobisbenzenesulfonamide, ammonium molybdate / hydrogen peroxide, and ozone, or a mixture of any of the above.