An imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound and its medical use

Abstract

The present invention discloses an imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound and its pharmaceutical use, belonging to the field of pharmaceutical chemistry. The structure of the compound of the present invention is shown below. The compound of the present invention has a significant inhibitory effect on Toll-like receptor (TLR7). The compound can inhibit TLR7 dimerization and prevent TLR7 signal transduction. This inhibitory effect can reduce or prevent immune responses caused by abnormal TLR7 activation, including reducing the production of proinflammatory and antiviral cytokines. It has therapeutic effects on various diseases such as systemic lupus erythematosus, psoriasis, rheumatoid arthritis, multiple sclerosis, and Sjögren's syndrome. The compound of the present invention provides a new option for the treatment of autoimmune diseases or chronic inflammatory diseases. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to an imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound and its medical use. Background Art

[0002] Most autoimmune diseases (AIDs), such as systemic lupus erythematosus (SLE), can severely impact patients' quality of life and even threaten their lives. Existing treatments include steroid pulse therapy and immunosuppressive therapy. However, these existing treatments have significant side effects and can only control disease progression or alleviate symptoms, but cannot cure autoimmune diseases.

[0003] Toll-like receptors (TLRs) are a recently discovered class of pattern recognition receptors that activate innate immunity by recognizing pathogen-associated molecular patterns (PAMPs). After recognizing corresponding ligands on the surfaces of pathogenic microorganisms, TLRs induce immune responses primarily through the MyD88-IRAK-TRAF6 kinase pathway. However, TLR-mediated biological activity also contributes to pathological damage and the development of autoimmune diseases in certain situations. Toll-like receptor 7 (TLR7) is a transmembrane signaling receptor expressed on the surface of mammalian endosomal membranes that activates the innate immune system by recognizing single-stranded RNA. TLR7 is primarily localized to plasmacytoid dendritic cells (pDCs), promoting their secretion of type I interferon α, which in turn activates downstream immune responses. Increased pDC-derived type I interferons (IFNs) are thought to be associated with the progression of many autoimmune diseases, such as systemic lupus erythematosus, psoriasis, rheumatoid arthritis, multiple sclerosis, and Sjögren's syndrome.

[0004] Abnormal activation of TLR7 in vivo can trigger various immune-related diseases. Although TLR7 and its sibling TLR9 exhibit similar tissue expression and share the same signaling pathway, MyD88, TLR7 and TLR9 have opposing inflammatory and regulatory effects in lupus-prone MRL / lpr mice. Studies have found that inhibiting TLR7 can mitigate disease progression, while inhibiting TLR9 promotes it. Therefore, TLR7 is considered a driver of lupus nephritis.

[0005] Most of the small molecules currently developed for TLRs are dual inhibitors of TLR7 / 8. Although studies have shown that overexpression of TLR8 in healthy mice may also trigger autoimmune diseases, the pathogenic mechanism of TLR8 remains controversial. For example, a study used lupus-susceptible female MRL / lpr mice to treat them orally with a TLR8 selective inhibitor. However, compared with the placebo group, the treatment group showed no significant changes in spleen index, skin lesion severity, glomerular diameter, or ANA and anti-ds-DNA antibody levels, and even the mice in the treatment group showed a decrease in survival rate. Therefore, it is emphasized that TLR8 selective inhibitors are ineffective in the treatment of SLE.

[0006] Currently, the fastest-progressing TLR7 inhibitor drug is the small molecule Enpatoran developed by Merck. In 2022, Merck's clinical trial application for Enpatoran (M5049), a TLR7 / 8 auxiliary inhibitor for the treatment of SLE, was approved.

[0007]

[0008] However, M5049, currently in clinical trials, has been shown to affect 5-HT (5-hydroxytryptamine) reuptake and inhibit CAMKK2 at relatively low doses. This may be due to its compact molecular structure, which allows it to pass through the blood-brain barrier. Therefore, the development of effective TLR7 inhibitors for the treatment of diseases such as systemic lupus erythematosus is urgent and necessary. Summary of the Invention

[0009] Purpose of the Invention: To address the above-mentioned technical problems, the present invention provides novel imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compounds with a novel core structure. These compounds or their pharmaceutically acceptable salts can act as TLR7 inhibitors with excellent activity. Furthermore, these compounds are expected to be used to develop targeted drugs for the treatment of autoimmune diseases associated with the TLR7 signaling pathway, such as systemic lupus erythematosus, psoriasis, rheumatoid arthritis, multiple sclerosis, or Sjögren's syndrome.

[0010] The invention also provides a preparation method and medical use of the compound.

[0011] Technical solution: In order to achieve the above-mentioned purpose, the present invention provides an imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof as shown in formula (I):

[0012] ;

[0013] Among them, the dotted line represents a single bond or a double bond;

[0014] R1 is H or C 1-6 Alkyl;

[0015] R2 is H, C 1-6 Alkyl or C 1-6 Alkoxy;

[0016] X is CH, CH2, N or CR4, wherein R4 is C 1-6 Alkyl;

[0017] Y is N or CH;

[0018] R3 is independently selected from any one of the following, and when R2 is H and the dotted line is a double bond, R3 is not an amino group:

[0019] 、 , wherein Z is CH or N, R5 is C 1-5 of alcoholic hydroxyl groups.

[0020] Furthermore, when the dotted line is a double bond, X is CH, N or CR4, Y is N or CH, R1 is H or methyl, and R2 is H, methyl or methoxy; when the dotted line is a single bond, X is CH2, Y is N, R1 is H, and R2 is H; and when R2 is H and the dotted line is a double bond, R3 is not an amino group.

[0021] Further, when the dotted line is a double bond, Y is CH, X is N or CH, R1 is H or methyl, R2 is H or methoxy, and R3 is: or ; When the dotted line is a double bond, Y is N, X is CR4 and R4 is methyl, R1 is H, R2 is H, and R3 is: ;

[0022] When the dotted line is a double bond, Y is N, X is N or CH, R1 is H or methyl, R2 is H, methyl or methoxy, R3 is selected from any one of the following, and when R2 is H, R3 is not amino:

[0023] or , wherein, when Z is CH, R5 is: or ; When Z is N, R5 is: or ; or when the dotted line represents a single bond, R1 is H, R2 is H, X is CH2, Y is N, and R3 is: or , where Z is CH, R5 for .

[0024] Furthermore, the pharmaceutically acceptable salt is an acid addition salt of the compound of formula (I), wherein the acid used for salt formation includes an inorganic acid or an organic acid, the inorganic acid includes any one of hydrochloric acid, sulfuric acid, phosphoric acid or methanesulfonic acid, and the organic acid includes any one of acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid or tartaric acid.

[0025] Preferably, the acid addition salt of the compound of formula (I) is a hydrochloride, and the dotted line represents a double bond; when Y is selected as N, X is N or CH, R1 is methyl, R2 is methoxy, and R3 is:

[0026]

[0027] When Y is CH, X is N or CH, R1 is methyl, R2 is methoxy, and R3 is:

[0028] .

[0029] Furthermore, the compound or a pharmaceutically acceptable salt thereof is selected from any one of Table 1.

[0030] Table 1 Structures and names of compounds I-1 to I-45

[0031]

[0032] Furthermore, the preparation method of the compound of the present invention or its pharmaceutically acceptable salt has the following specific reaction route:

[0033]

[0034] The compound of structural formula (I) is prepared by Suzuki coupling reaction of compound A and compound B in the presence of palladium catalyst.

[0035] Use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a TLR7 antagonist.

[0036] Use of the compound of the present invention or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating TLR7-mediated diseases.

[0037] Furthermore, the TLR7-mediated disease is an autoimmune disease or a chronic inflammatory disease, and the autoimmune disease or chronic inflammatory disease includes: systemic lupus erythematosus, psoriasis, rheumatoid arthritis, multiple sclerosis or Sjögren's syndrome.

[0038] The present invention provides a pharmaceutical composition for preventing or treating TLR7-mediated diseases, comprising the compound or its pharmaceutically acceptable salts, tautomers and stereoisomers, metabolites, metabolic precursors, solvent compounds or prodrugs, and a pharmaceutically acceptable carrier.

[0039] Furthermore, the pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch.

[0040] The compounds of formula (I) prepared in the present invention can be divided into three subcategories: the hydrochloride salt or free amine of the compound of formula (I-1) obtained by deprotection; the compound of formula (I-2) obtained without deprotection; and the compound of formula (I-3) obtained by partial reduction of the compound of formula (I-2). The general synthetic routes for these three categories of compounds are as follows:

[0041]

[0042] Where A is F or Cl, X is CH, N or CR4, where R4 is C 1-6 wherein Y is N or CH, and PG is a protecting group, for example, Boc. L is a substituted group selected from the group consisting of piperazinyl, (1R,4R)-2,5-diazabicyclo, (1S,4S)-2,5-diazabicyclo, 4-aminopiperidine, 4-methyl-4-aminopiperidine, 4-aminomethylpiperidine, (R)-3-aminopiperidine, (S)-3-aminopiperidine, piperidine-4-carboxamide, piperidine-3-carboxamide, 3,8-diazabicyclo[3.2.1]octane, and cis-3,7-diazabicyclo[3.3.0]octane.

[0043] M is selected from the following unsubstituted groups: amino, L-alaninamide, piperidine-4-carboxamide, piperidine-3-carboxamide, 5-(N-ethyl-N-2-hydroxyethylamine)-2-pentylamine, 1-[2-(2-hydroxyethoxy)ethyl]piperazine, N-hydroxyethylpiperazine, 4-hydroxymethylpiperidine, 4-piperidineethanol, 4,4-difluoropiperidine.

[0044] First, the starting material I is reacted with a Boc-protected amine compound (HL-PG) or an unprotected amine compound (HM) via SNAr reaction to obtain compounds of formula (II) and formula (VI). Next, compounds of formula (II) and formula (VI) are treated with pinacol diboron in the presence of a suitable base (e.g., KOAc) and a suitable palladium catalyst (e.g., PdCl2(DPPF)-CH2Cl2 adduct) to obtain compounds of formula (III) and formula (VII), respectively. A Suzuki coupling reaction is performed between compounds of formula (III) and formula (IV) using a suitable palladium catalyst (e.g., tetrakistriphenylphosphine palladium or palladium acetate) and a suitable base (e.g., K2CO3 or Na2CO3) to obtain compounds of formula (V). Compound (V) is then deprotected under acidic conditions (e.g., EA.HCl) to obtain compounds of formula (I-1) or the hydrochloride salt of compound (I-1).

[0045] Suzuki coupling reaction is carried out between the compound of formula (VII) and the compound of formula (IV) using a suitable palladium catalyst (such as tetrakis(triphenylphosphine)palladium) and a suitable base (such as K2CO3) to obtain the compound of formula (I-2).

[0046] A portion of the compound of formula (I-2) is reduced using a suitable reduction method (hydrogen gas palladium carbon) to obtain a compound of formula (I-3).

[0047] The present invention also relates to a method for preparing the hydrochloride of the compound of formula (I-1), which comprises any of the following steps: deprotecting compound (V) with an acid to directly obtain the hydrochloride of the compound of formula (I-1):

[0048]

[0049] R1 is H or methyl, R2 is H or methoxy, X is N or CH; Y is CH or N; L is a substituted group selected from the group consisting of piperazinyl, (1R,4R)-2,5-diazabicyclo, (1S,4S)-2,5-diazabicyclo, 4-methyl-4-aminopiperidine, 4-aminomethylpiperidine, (R)-3-aminopiperidine, (S)-3-aminopiperidine, piperidine-4-carboxamide, piperidine-3-carboxamide, 3,8-diazabicyclo[3.2.1]octane, and cis-3,7-diazabicyclo[3.3.0]octane. PG is a protecting group, such as Boc.

[0050] The present invention also relates to a method for reducing a compound (I-2) containing imidazo[1,2-a]pyridine to a compound (I-3) containing a 5,6,7,8-tetrahydro-imidazole[1,2-a]pyridine structure, the method comprising the following steps:

[0051] Compound (I-2) is reduced with palladium on carbon using hydrogen released by heating ammonium formate to obtain compound (I-3):

[0052]

[0053] Where X is CH, R 1 H, R 2 is H; M is piperidine-4-carboxamide or 4-piperidinylethanol.

[0054] The present invention provides a class of compounds that can be used as TLR7 antagonists. These compounds inhibit the activation of the TLR7-Myd88 signaling pathway and its downstream biological events, reducing the production of cytokines (such as NF-κB) triggered by TLR7 pathway activation, thereby effectively blocking various innate and adaptive immune responses mediated by autoantibodies. In addition, to demonstrate the advantages of the imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrazine structures of the present invention over the cyanoquinoline structure used in the positive drug Enpatoran, the 8-cyanoquinoline of the positive drug Enpatoran was used to replace the 8-methoxy-2-methylimidazo[1,2-a]pyridine (Example 6, I-6) or 8-methoxy-2-methylimidazo[1,2-a]pyrazine (Example 7, I-7) in the mother core structure protected by the present invention, and compound 46 for comparison was prepared. At the same time, an analogue 47 of compound 46 was synthesized to compare and verify the important role of the trifluoromethyl group substituted at the meta position on the pyridine ring retained in the core structure of the present invention in terms of activity. The present invention proves that the designed 8-methoxy-2-methylimidazo[1,2-a]pyridine (Example 6) and 8-methoxy-2-methylimidazo[1,2-a]pyrazine (Example 7) are superior to 8-cyanoquinoline (Example 46) in the antagonistic activity against TLR7. In addition, it is also proved that the introduction of a trifluoromethyl group at the meta position of the pyridine structure (Example 46, I-46) is less than the introduction of a trifluoromethyl group (Example 47, I-47), which can not only significantly improve the antagonistic activity of the compound against TLR7, but also significantly improve the yield of the Suzuki coupling reaction, wherein compound 46 and compound 47 are shown in Table 2.

[0055] Table 2 Structures and nomenclature of compounds 46 and 47

[0056]

[0057] Therefore, the compounds of the present invention can be used to block TLR7 in all types of cells expressing this receptor, including but not limited to plasmacytoid dendritic cells, B cells, T cells, macrophages, monocytes, neutrophils, keratinocytes, epithelial cells and platelets. Thus, the compounds can be used as therapeutic or preventive agents for systemic lupus erythematosus, lupus nephritis and psoriasis.

[0058] The present invention provides a method for treating or preventing systemic lupus erythematosus and lupus nephritis in a patient in need thereof, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.

[0059] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0060] This invention provides a novel imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound with a novel core structure, incorporating a trifluoromethyl group that significantly enhances its activity. Biochemical activity testing has demonstrated that these compounds exhibit excellent inhibitory activity against TLR7. Therefore, these compounds could serve as effective antagonists for the treatment of diseases regulated by TLR7, potentially leading to the development of targeted drugs for the treatment of diseases associated with the TLR7 signaling pathway, such as systemic lupus erythematosus, psoriasis, rheumatoid arthritis, multiple sclerosis, and Sjögren's syndrome. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1 Figure 44 is the plasma drug concentration-time curve (Ct) of rats after intravenous injection of 2 mg / kg of Example 44 (YP-1);

[0062] Figure 2 Figure 44 is the plasma drug concentration-time curve (Ct) of rats after oral administration of Example 44 (YP-1) (10 mg / kg). DETAILED DESCRIPTION

[0063] The technical solution of the present invention is further described below.

[0064] Unless otherwise specified, the materials and reagents used in the following examples are all commercially available. Experimental methods without specific conditions specified in the examples are generally performed under conventional conditions or the conditions recommended by the manufacturer.

[0065] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having the stated number of carbon atoms.

[0066] The term "C 1-3 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 3 carbon atoms.

[0067] The term "C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms.

[0068] The term "C 1-3 "Alkoxy" means OC 1-3 The alkyl group is an OC 1-3 of alkyl.

[0069] The term "C 1-6 "Alkoxy" means OC 1-6 The alkyl group is an OC 1-6 of alkyl.

[0070] Abbreviations: PE: petroleum ether, EA: ethyl acetate, DCM: dichloromethane, MEOH: methanol, THF: tetrahydrofuran, IC 50 : half-maximal inhibitory concentration; DMSO: dimethyl sulfoxide; DMF: N,N-dimethylformamide; PdCl2(dppf)-CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.

[0071] NMR spectra were obtained using a Bruker Avance 400 MHz.

[0072] Intermediates and final compounds were purified by flash chromatography using the following instruments: i) Biotage Isolera™ Prime flash preparative liquid chromatograph.

[0073] The sources or syntheses of the intermediate compounds used in each example are as follows:

[0074] Intermediate A1 (Int-A1)

[0075] 6-Bromo-imidazo[1,2-a]pyridine, CAS No. 6188-23-4, supplier: Shaoyuan Technology (Shanghai) Co., Ltd., is a light yellow solid.

[0076]

[0077] Intermediate A2 (Int-A2)

[0078] 2-Bromoimidazo[1,2-a]pyrazine, CAS No. 912773-24-1, supplier: Shaoyuan Technology (Shanghai) Co., Ltd., is a white solid.

[0079]

[0080] Intermediate A3 (Int-A3)

[0081] 6-Bromo-8-methyl-imidazo[1,2-a]pyridine, CAS No. 217435-65-9, supplier: Shanghai Haohong Biopharmaceutical Technology Co., Ltd., is a white solid.

[0082]

[0083] Intermediate A4 (Int-A4)

[0084] 6-Bromo-7-methylimidazo[1,2-a]pyridine, CAS No. 116355-18-1, supplier: Shaoyuan Technology (Shanghai) Co., Ltd., is a white solid.

[0085]

[0086] Intermediate A5 (Int-A5)

[0087] 6-Bromo-2-methylimidazo[1,2-a]pyrazine, CAS No. 1159811-97-8, supplier: Shanghai Haohong Biopharmaceutical Technology Co., Ltd., is a white solid.

[0088]

[0089] Intermediate A6 (Int-A6)

[0090] 6-Bromo-8-methoxyimidazo[1,2-a]pyrazine, CAS No. 63744-25-2, supplier: Shanghai Haohong Biopharmaceutical Technology Co., Ltd., is a light yellow solid.

[0091]

[0092] Intermediate A7 (Int-A7)

[0093] 6-Bromo-8-methoxyimidazo[1,2-a]pyridine, CAS No. 1427424-35-8, supplier: Shanghai Haohong Biopharmaceutical Technology Co., Ltd., is a brown solid.

[0094]

[0095] Intermediate A8 (Int-A8)

[0096] 6-Bromo-8-methoxy-2-methylimidazo[1,2-a]pyridine

[0097]

[0098] 2-Amino-3-methoxy-5-bromopyridine (4060 mg, 20 mmol, CAS No.: 42409-58-5, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.) and pyridinium p-toluenesulfonate (0.52 g, 2.0 mmol, CAS No.: 24057-28-1, Supplier: Tianjin Xiens Biochemical Technology Co., Ltd.) were dissolved in 40 mL of isopropanol. 1-Bromo-2,2-dimethoxypropane (4142 mg, 30 mmol, CAS No.: 126-38-5, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.) was then added dropwise to the reaction solution. The reaction mixture was heated at 90°C for 72 hours. The reaction mixture was cooled to room temperature, the solvent was removed by distillation under reduced pressure, and 100 mL of saturated sodium bicarbonate solution was added to quench the reaction. 30 mL of saturated sodium bicarbonate solution was then added. The product was extracted with DCM, the aqueous phase was retained, and the aqueous phase was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (PE / EA = 2:1 constant elution) to obtain 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyridine as a pink solid.

[0099] Intermediate A8-b (Int-A8-b)

[0100] (8-Methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)boronic acid

[0101]

[0102] At room temperature, 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyridine (Int-A8) (2410 mg, 10 mmol), pinacol diboronate (3810 mg, 15.0 mmol, CAS No. 73183-34-3, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.), and potassium acetate (2940 mg, 30.0 mmol) were dissolved in 1,4-dioxane (30 mL). PdCl2(dppf)-CH2Cl2 adduct (816 mg, 1.00 mmol, CAS No. 95464-05-4, Supplier: Tianjin Xiens Biochemical Technology Co., Ltd.) was added. The air was replaced with Ar three times, and the reaction was heated to 95 °C under reflux under Ar atmosphere and stirred for 12 h. After the reaction was cooled, it was filtered through celite, the filter cake was rinsed with methanol, the filtrate was retained, concentrated under reduced pressure, and eluted by silica gel column chromatography (DCM / MEOH=1:1 constant elution) to purify the crude material to give (8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)boronic acid as a brown-black solid.

[0103] Intermediate A9 (Int-A9)

[0104] 6-Bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine

[0105]

[0106] 2-Amino-5-bromo-3-methoxypyrazine (4080 mg, 20 mmol, CAS No. 5900-13-0, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.) and pyridinium p-toluenesulfonate (0.52 g, 2.0 mmol, CAS No. 24057-28-1, Supplier: Tianjin Xiens Biochemical Technology Co., Ltd.) were dissolved in 60 mL of isopropanol. 1-Bromo-2,2-dimethoxypropane (4142 mg, 30 mmol, CAS No. 126-38-5, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.) was then added dropwise to the reaction mixture. The reaction mixture was heated at 65°C for 60 hours. The reaction mixture was cooled to room temperature, and the solvent was removed by distillation under reduced pressure. The reaction mixture was quenched by the addition of 100 mL of saturated sodium bicarbonate solution, followed by extraction with 50 mL of dichloromethane (DCM). This was repeated three times. The organic phase was retained, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3:1 constant elution) to give 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine as a white solid.

[0107] Intermediate A9-b (Int-A9-b)

[0108] (8-Methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)boronic acid

[0109]

[0110] The preparation method for compound Int-A8-b was adopted, replacing Int-A8 with 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine. The reaction mixture was cooled and filtered through celite. The filter cake was rinsed with methanol. The retained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MEOH = 1:2 constant elution ratio) to afford (8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)boronic acid as a brown solid.

[0111] Intermediate B1 (Int-B1)

[0112] 2-Amino-3-trifluoromethyl-5-bromopyridine, CAS No. 79456-34-1, supplier: Shaoyuan Technology (Shanghai) Co., Ltd., is a white solid.

[0113]

[0114] Intermediate B1-b (Int-B1-b)

[0115] 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine

[0116]

[0117] At room temperature, 2-amino-3-trifluoromethyl-5-bromopyridine (2410 mg, 10 mmol, CAS No.: 79456-34-1, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.), pinacol diboron (3.81 g, 15.0 mmol, CAS No. 73183-34-3, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.), and potassium acetate (2.94 g, 30.0 mmol) were dissolved in 1,4-dioxane (30 mL), and PdCl2(dppf)-CH2Cl2 adduct (816 mg, 1.00 mmol, CAS No.: 95464-05-4, Supplier: Tianjin Xiens Biochemical Technology Co., Ltd.) was added. The air was replaced with Ar gas three times, and the reactants were heated to 100 °C under reflux under Ar gas atmosphere and stirred for 8 h. After the reaction was cooled, it was filtered through celite, the filtrate was retained, concentrated under reduced pressure, and eluted by silica gel column chromatography (PE / EA=5:1 constant elution) to purify the crude material to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine.

[0118] Intermediate B2 (Int-B2)

[0119] 1-(5-Bromo-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide

[0120]

[0121] At room temperature, 3-piperidinecarboxamide (1922 mg, 15.0 mmol, CAS No. 4138-26-5, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.) and K2CO3 (4146 mg, 30.0 mmol) were dissolved in 30 ml of DMSO and stirred for 10 minutes. 2-Chloro-5-bromo-3-trifluoromethylpyridine (2600 mg, 10.0 mmol, CAS No. 211122-40-6, Supplier: Tianjin Xiens Biochemical Technology Co., Ltd.) was then added dropwise to the reaction mixture. The reaction mixture was heated at 80°C for 12 hours. The reaction mixture was cooled to room temperature, diluted with 300 ml of water, and extracted three times with 50 ml of EA. The organic phases were combined and concentrated under reduced pressure to obtain a white solid, 1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide.

[0122] Intermediate B2-b (Int-B2-b)

[0123] 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide

[0124]

[0125] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced by 1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide. The product was eluted by silica gel column chromatography (PE / EA=1:2 constant elution) to obtain 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide as a light yellow oil.

[0126] Intermediate B3 (Int-B3)

[0127] 1-(5-Bromo-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0128]

[0129] The preparation method of compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced by 4-piperidinecarboxamide (CAS No.: 39546-32-2, supplier: Tianjin Xiens Biochemical Technology Co., Ltd.) to obtain a light yellow solid.

[0130] Intermediate B3-b (Int-B3-b)

[0131] 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0132]

[0133] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced by 1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide. The product was eluted by silica gel column chromatography (PE / EA=1:2 constant elution) to obtain 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide as a light yellow solid.

[0134] Intermediate B4 (Int-B4)

[0135] (S)-2-((5-Bromo-3-(trifluoromethyl)pyridin-2-yl)amino)propanamide

[0136]

[0137] The preparation method of compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with L-alaninamide (CAS No.: 7324-05-2, supplier: Shanghai Haohong Biopharmaceutical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure and eluted by silica gel column chromatography (PE / EA = 1:1 constant elution) to obtain (S)-2-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)amino)propanamide as a white solid.

[0138] Intermediate B4-b (Int-B4-b)

[0139] (S)-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)amino)propanamide

[0140]

[0141] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced by (S)-2-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)amino)propanamide. The product was eluted by silica gel column chromatography (PE / EA=1:1 constant elution) to obtain (S)-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)amino)propanamide as a light yellow oil.

[0142] Intermediate B5 (Int-B5)

[0143] 2-((4-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)amino)pentyl)(ethyl)amino)ethan-1-ol

[0144]

[0145] The preparation method of compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with 2-[(4-aminopentyl)(ethyl)amino]ethanol (CAS No.: 69559-11-1, supplier: Shaoyuan Technology (Shanghai) Co., Ltd.), and the same amount of triethylamine was used instead of K2CO3 for preparation. After extraction with EA, the organic phase was concentrated under reduced pressure and eluted by silica gel column chromatography (DCM / MEOH=15:1 constant elution) to obtain 2-((4-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)amino)pentyl)(ethyl)amino)ethan-1-ol as a colorless, transparent liquid.

[0146] Intermediate B6 (Int-B6)

[0147] 2-(2-(4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethan-1-ol

[0148]

[0149] The preparation method for compound Int-B2 was adopted, replacing 3-piperidinecarboxamide with 1-[2-(2-hydroxyethoxy)ethyl]piperazine (CAS No. 13349-82-1, supplier: Tianjin Xiens Biochemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to provide 2-(2-(4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethan-1-ol as a pale yellow viscous liquid.

[0150] Intermediate B6-b (Int-B6-b)

[0151] 2-(2-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethan-1-ol

[0152]

[0153] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced with 2-(2-(4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethan-1-ol, and eluted by silica gel column chromatography (DCM / MEOH=1:1 constant elution) to obtain 2-(2-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethan-1-ol as a brown oil.

[0154] Intermediate B7 (Int-B7)

[0155] (1-(5-Bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol

[0156]

[0157] The preparation method for compound Int-B2 was adopted, replacing 3-piperidinecarboxamide with 4-hydroxymethylpiperidine (CAS No. 6457-49-4, supplier: Tianjin Xiens Biochemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to provide (1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol as a white viscous solid.

[0158] Intermediate B7-b (Int-B7-b)

[0159] (1-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol

[0160]

[0161] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced by (1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol. The product was eluted by silica gel column chromatography (PE / EA=1:1 constant elution) to obtain (1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol as a brown oil.

[0162] Intermediate B8 (Int-B8)

[0163] 2-(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol

[0164]

[0165] The preparation method of compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with 4-piperidineethanol (CAS No.: 622-26-4, supplier: Shaoyuan Technology (Shanghai) Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to obtain 2-(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol as a white solid.

[0166] Intermediate B8-b (Int-B8-b)

[0167] 2-(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol

[0168]

[0169] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced with 2-(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol, and eluted by silica gel column chromatography (PE / EA=1:1.5 constant elution) to obtain 2-(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol as a light yellow oil.

[0170] Intermediate B9 (Int-B9)

[0171] 2-(4-(5-Bromo-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol

[0172]

[0173] The preparation method for compound Int-B2 was adopted, replacing 3-piperidinecarboxamide with N-hydroxyethylpiperazine (CAS No. 103-76-4, supplier: Tianjin Xiens Biochemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to provide 2-(4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol as a pale yellow liquid.

[0174] Intermediate B9-b (Int-B9-b)

[0175] 2-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol

[0176]

[0177] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced with 2-(4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol, and eluted by silica gel column chromatography (DCM / MEOH=3:1 constant elution) to obtain 2-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol as a brown viscous solid.

[0178] Intermediate B10 (Int-B10)

[0179] 5-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyridine

[0180]

[0181] The preparation method for compound Int-B2 was adopted, replacing 3-piperidinecarboxamide with 4,4-difluoropiperidine (CAS No. 21987-29-1, Supplier: Tianjin Xiens Biochemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to provide 5-bromo-2-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyridine as a light yellow solid.

[0182] Intermediate B10-b (Int-B10-b)

[0183] 2-(4,4-difluoropiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridine

[0184]

[0185] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced by 5-bromo-2-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyridine. The product was eluted by silica gel column chromatography (PE / EA=1:1 constant elution) to obtain 2-(4,4-difluoropiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridine as a colorless oil.

[0186] Intermediate B11 (Int-B11)

[0187] tert-Butyl (R)-(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate

[0188]

[0189] The preparation method for compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with (R)-3-Boc-aminopiperidine (CAS No.: 216854-23-8, Supplier: Tianjin Xiens Biochemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to provide tert-butyl (R)-(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate as a white solid.

[0190] Intermediate B11-b (Int-B11-b)

[0191] tert-Butyl (R)-(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate

[0192]

[0193] The preparation method of compound Int-B1-b was used, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced with (R)-tert-butyl(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate. Silica gel column chromatography (PE / EA = 1.5:1 constant elution) gave (R)-tert-butyl(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate as a brown, viscous solid.

[0194] Intermediate B12 (Int-B12)

[0195] tert-Butyl (1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0196]

[0197] The preparation method of compound Int-B2 was used, and 3-piperidinecarboxamide was replaced with 4-(N-Boc-amino)piperidine (CAS No. 73874-95-0, supplier: Shaoyuan Technology (Shanghai) Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to provide tert-butyl (1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate as a yellow liquid.

[0198] Intermediate B12-b (Int-B12-b)

[0199] tert-Butyl (1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0200]

[0201] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced with tert-butyl (1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate, and eluted by silica gel column chromatography (PE / EA=2:1 constant elution) to obtain tert-butyl (1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate as a yellow translucent solid.

[0202] Intermediate B13 (Int-B13)

[0203] tert-Butyl (1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0204]

[0205] The preparation method of compound Int-B2 was used, and 3-piperidinecarboxamide was replaced with 4-(Boc-amino)-4-methylpiperidine (CAS No. 163271-08-7, supplier: Shaoyuan Technology (Shanghai) Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to provide tert-butyl (1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate as a yellow oily liquid.

[0206] Intermediate B13-b (Int-B13-b)

[0207] tert-Butyl (4-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0208]

[0209] The preparation method of compound Int-B1-b was used, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced with tert-butyl (1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate. Silica gel column chromatography (PE / EA = 3:1 constant elution) was used to obtain tert-butyl (4-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate as a colorless liquid.

[0210] Intermediate B14 (Int-B14)

[0211] tert-Butyl ((1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)carbamate

[0212]

[0213] The preparation method for compound Int-B2 was adopted, replacing 3-piperidinecarboxamide with 4-tert-butyloxycarbonylaminopiperidine (CAS No. 73874-95-0, supplier: Tianjin Xiens Biochemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to provide tert-butyl ((1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)carbamate as a colorless oily liquid.

[0214] Intermediate B14-b (Int-B14-b)

[0215] tert-Butyl ((1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)carbamate

[0216]

[0217] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced with tert-butyl ((1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)carbamate, and eluted by silica gel column chromatography, (PE / EA=1:1 constant elution) to give tert-butyl ((1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)carbamate as a light yellow oil.

[0218] Intermediate B15 (Int-B15)

[0219] tert-Butyl 4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate

[0220]

[0221] The preparation method for compound Int-B2 was adopted, replacing 3-piperidinecarboxamide with 1-(tert-butyloxycarbonyl)piperazine (CAS No. 57260-71-6, supplier: Tianjin Xiens Biochemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to provide tert-butyl 4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate as a light pink viscous solid.

[0222] Intermediate B15-b (Int-B15-b)

[0223] tert-Butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate

[0224]

[0225] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced with 4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester. The mixture was eluted by silica gel column chromatography (PE / EA=1.5:1 constant elution) to obtain 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester as a light yellow oil.

[0226] Intermediate B16 (Int-B16)

[0227] tert-Butyl (1R,4R)-5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0228]

[0229] The preparation method for compound Int-B2 was used, but 3-piperidinecarboxamide was replaced with (1R,4R)-2-Boc-2,5-diazabicyclo[2.2.1]heptane (CAS No. 134003-84-2, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to obtain tert-butyl (1R,4R)-5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as a colorless, transparent oil.

[0230] Intermediate B16-b (Int-B16-b)

[0231] tert-Butyl (1R,4R)-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0232]

[0233] The preparation method for compound Int-B1-b was used, replacing 2-amino-3-trifluoromethyl-5-bromopyridine with (1R,4R)-5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. Silica gel column chromatography (PE / EA = 5:1 constant elution) yielded (1R,4R)-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a colorless, transparent oil.

[0234] Intermediate B17 (Int-B17)

[0235] tert-Butyl 4-((4-bromo-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate

[0236]

[0237] At room temperature, 1-BOC-piperidine-4-carboxamide (3424 mg, 15.0 mmol, CAS No. 91419-48-6, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.) and CS2CO3 (9774 mg, 30.0 mmol) were dissolved in 30 ml of DMSO and stirred for 20 min. 5-Bromo-2-fluorobenzotrifluoride (2430 mg, 10.0 mmol, CAS No. 393-37-3, Supplier: Tianjin Xiens Biochemical Technology Co., Ltd.) was then added to the reaction mixture. The reaction mixture was heated at reflux at 95°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with 300 ml of water, and extracted three times with 50 ml of EA. The organic phases were combined and concentrated under reduced pressure to obtain a light pink solid, tert-butyl 4-((4-bromo-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate.

[0238] Intermediate B17-b (Int-B17-b)

[0239] tert-Butyl 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate

[0240]

[0241] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced with tert-butyl 4-((4-bromo-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate, and eluted by silica gel column chromatography (DCM / MEOH=5:1 constant elution) to obtain tert-butyl 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate as a white solid.

[0242] Intermediate B18 (Int-B18)

[0243] tert-Butyl 3-((4-bromo-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate

[0244]

[0245] Using the preparation method for compound Int-B17, replacing 1-BOC-piperidine-4-carboxamide with 1-Boc-3-carbamoylpiperidine. The reaction mixture was cooled to room temperature, diluted with 300 mL of water, and extracted three times with 50 mL of EA. The organic phases were combined and concentrated under reduced pressure to yield a pale yellow solid, tert-butyl 3-((4-bromo-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate.

[0246] Intermediate B18-b (Int-B18-b)

[0247] tert-Butyl 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate

[0248]

[0249] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced with tert-butyl 3-((4-bromo-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate, and eluted by silica gel column chromatography (DCM / MEOH=4:1 constant elution) to obtain tert-butyl 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate as a light gray solid.

[0250] Intermediate B19 (Int-B19)

[0251] (S)-tert-Butyl(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate

[0252]

[0253] The preparation method for compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with (S)-3-Boc-aminopiperidine (CAS No. 309956-78-3, Supplier: Tianjin Xiens Biochemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to provide tert-butyl (S)-(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate as a white solid.

[0254] Intermediate B19-b (Int-B19-b)

[0255] (S)-tert-Butyl(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate

[0256]

[0257] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced with (S)-(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamic acid tert-butyl ester, and eluted by silica gel column chromatography (PE / EA=1.5:1 constant elution) to obtain (S)-(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamic acid tert-butyl ester as a brown viscous solid.

[0258] Intermediate B20 (Int-B20)

[0259] tert-Butyl (3aR,6aR)-5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0260]

[0261] The preparation method for compound Int-B2 was adopted, replacing 3-piperidinecarboxamide with cis-2-Boc-hexahydropyrrolo[3,4-c]pyrrole (CAS No. 250275-15-1, supplier: Shanghai Haohong Biopharmaceutical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to provide tert-butyl (3aR,6aR)-5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate as a white solid.

[0262] Intermediate B20-b (Int-B20-b)

[0263]

[0264] The preparation method for compound Int-B1-b was used, replacing 2-amino-3-trifluoromethyl-5-bromopyridine with (3aR,6aR)-5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester. Silica gel column chromatography (PE / EA = 1:1 constant elution) afforded (3aR,6aR)-5-(5-(4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)-3-(trifluoromethyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester as a pale yellow oil.

[0265] Intermediate B21 (Int-B21)

[0266] tert-Butyl (1S,4S)-5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0267]

[0268] The preparation method for compound Int-B2 was used, but 3-piperidinecarboxamide was replaced with (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane (CAS No. 113451-59-5, supplier: Shaoyuan Technology (Shanghai) Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to provide tert-butyl (1S,4S)-5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as a colorless, transparent oil.

[0269] Intermediate B21-b (Int-B21-b)

[0270] tert-Butyl (1S,4S)-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0271]

[0272] The preparation method for compound Int-B1-b was used, replacing 2-amino-3-trifluoromethyl-5-bromopyridine with (1S,4S)-5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. Silica gel column chromatography (PE / EA = 5:1 constant elution) yielded (1S,4S)-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a colorless, transparent oil.

[0273] Intermediate B22 (Int-B22)

[0274] tert-Butyl 3-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0275]

[0276] The preparation method for compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with 8-BOC-3,8-diazabicyclo[3.2.1]octane (CAS No.: 149771-44-8, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to obtain tert-butyl 3-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white translucent liquid.

[0277] Intermediate B22-b (Int-B22-b)

[0278] tert-Butyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0279]

[0280] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced with 3-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester. The mixture was eluted by silica gel column chromatography (PE / EA=5:1 constant elution) to obtain 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as a colorless transparent oil.

[0281] Example 1

[0282] 5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-amine

[0283]

[0284] To a reaction vessel, 1 mmol of 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyridine (Int-A8, 241 mg), 1.2 mmol of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (Int-B1-b, 345.7 mg), 3 mmol of K2CO3 (414.6 mg), and 0.1 mmol of tetrakis(triphenylphosphine)palladium (115.6 mg, CAS No. 14221-01-3, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.) were added in sequence. 10 ml of 1,4-dioxane was added as the solvent, along with 1.5 ml of ultrapure water. The air was replaced with Ar three times, and the mixture was heated to 92°C under reflux and stirred for 12 hours under an Ar atmosphere. After the reaction is completed, the reactant is cooled to room temperature, filtered through diatomaceous earth, and the filter cake is rinsed with EA and methanol. The filtrate is retained, concentrated under reduced pressure, and eluted by silica gel column chromatography (PE / EA=1:3 constant elution) to obtain I-1 (compound 1), i.e. 5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-amine (239 mg, 74.2% yield), which is an off-white solid.

[0285] 1 H NMR (400 MHz, Chloroform- d ) d 8.42 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.79 (d,J = 1.5 Hz, 1H), 7.35 (d, J = 1.0 Hz, 1H), 6.50 (d, J = 1.4 Hz, 1H), 5.13 (s, 2H), 4.06 (s, 3H), 2.47 (d, J = 0.8 Hz, 3H).

[0286] Example 2

[0287] 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide

[0288]

[0289] The preparation method of Example 1 was used, except that Int-B1-b was replaced with Int-B2-b and Int-A8 was replaced with Int-A9. Silica gel column chromatography (PE / EA = 1.5:1 constant elution) afforded I-2 (Compound 2), 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide (327 mg, 75.3% yield), as an off-white solid.

[0290] 1 H NMR (400 MHz, Chloroform- d ) d 8.97 (d, J = 2.3 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.05 (s, 1H), 7.43 (d, J = 1.0 Hz, 1H), 6.59 (s, 1H), 5.47 (s,1H), 4.23 (s, 3H), 3.74 – 3.68 (m, 1H), 3.42 (dd, J = 13.0, 7.1 Hz, 1H), 3.36– 3.29 (m, 1H), 3.22 (dd, J = 8.2, 3.3 Hz, 1H), 2.70 (t, J = 4.1 Hz, 1H), 2.51 – 2.47 (m, 3H), 1.95 (dd, J= 8.0, 5.0 Hz, 1H), 1.90 (s, 2H), 1.76 –1.68 (m, 1H).

[0291] Example 3

[0292] 1-(5-(imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0293]

[0294] The preparation method of Example 1 was used, except that Int-B1-b was replaced with Int-B3-b and Int-A8 was replaced with Int-A1. Silica gel column chromatography (DCM / MEOH = 20:1 constant elution) was used to obtain I-3 (Compound 3), 1-(5-(imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (258 mg, 66.3% yield), as a white solid.

[0295] 1 H NMR (400 MHz, Chloroform- d ) d 8.61 (d, J = 2.4 Hz, 1H), 8.33 –8.31 (m, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 9.3 Hz, 1H), 7.70 (d, J = 5.0 Hz, 2H), 7.37 (dd, J = 9.4, 1.8 Hz, 1H), 5.74 (d, J = 8.5 Hz, 2H), 3.86– 3.74 (m, 2H), 3.02 (td, J = 12.3, 2.9 Hz, 2H), 2.46 – 2.36 (m, 1H), 2.00(d, J = 4.3 Hz, 2H), 1.94 (dd, J = 12.5, 3.8 Hz, 2H).

[0296] Example 4

[0297] 1-(5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0298]

[0299] To a reaction vessel, 0.5 mmol of 1-(5-(imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (Compound 3, 154.5 mg), 10% palladium on carbon (154.5 mg, CAS No. 7440-05-3, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.), and 6 mmol of ammonium formate (381 mg) were added. 2.5 ml of anhydrous MEOH and 2.5 ml of anhydrous THF were added as solvents, and the reaction was stirred at room temperature for 18 h. After the reaction is completed, diatomaceous earth is used for filtration, and palladium carbon is quenched. The filtrate is collected, concentrated under reduced pressure, and eluted by silica gel column chromatography (DCM / MEOH=15:1 constant elution) to give I-4 (compound 4), i.e. 1-(5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (128 mg, 65% yield) as a white solid.

[0300] 1 H NMR (400 MHz, Chloroform- d ) d 8.36 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 1.3 Hz, 1H), 6.83 (d, J = 1.3 Hz, 1H), 5.64 (d, J = 22.0 Hz, 2H), 4.23 (ddd, J = 12.4, 5.4, 1.4 Hz, 1H), 3.94 (t, J = 11.6 Hz,1H), 3.68 (dd, J = 12.3, 2.4 Hz, 2H), 3.29 (tdd, J = 11.2, 5.3, 2.8 Hz, 1H),3.15 (ddd, J = 17.1, 5.5, 3.0 Hz, 1H), 2.96 (ddd, J= 15.0, 11.4, 3.4 Hz,3H), 2.37 (ddd, J = 11.5, 7.2, 4.2 Hz, 1H), 2.27 (ddt, J = 11.9, 4.7, 1.5 Hz,1H), 2.21 – 2.13 (m, 1H), 1.97 (d, J = 4.6 Hz, 1H), 1.96 – 1.86 (m, 2H).

[0301] Example 5

[0302] 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-amine

[0303]

[0304] The preparation method of Example 1 was used, except that Int-B1-b was replaced with Int-B12-b, and Int-A8 was replaced with Int-A9. Silica gel column chromatography (PE / EA=3:1) was used to elute 5a, tert-butyl (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate (388 mg, 76.7% yield), as a yellowish-white viscous solid.

[0305] To the reaction flask was added 0.5 mmol of tert-butyl (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate (Compound 5a, 253.2 mg), followed by 6 ml of hydrochloric acid and ethyl acetate solution. The mixture was stirred at room temperature for 12 h. The reactant was concentrated under reduced pressure, and the resulting dry crude product was dissolved in 10 ml of purified water. An appropriate amount of saturated sodium bicarbonate solution was added to adjust the pH to 8.0. The aqueous phase was concentrated under reduced pressure to complete dryness. Eluted by silica gel column chromatography (PE / EA=1:5 constant elution) to give I-5 (Compound 5), ie 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-amine (133 mg, 60.2% yield) as a white solid.

[0306] 1 H NMR (400 MHz, DMSO- d 6) d 9.27 (s, 1H), 9.16 (d,J = 2.3 Hz, 1H),8.58 (d, J = 2.3 Hz, 1H), 8.41 (d, J = 5.8 Hz, 2H), 8.15 – 8.07 (m, 1H), 4.25(s,3H), 3.75 (d, J = 13.3 Hz, 2H), 3.26 (s, 1H), 3.12 – 3.01 (m, 2H), 2.51(dt, J = 3.3, 1.7 Hz, 3H), 2.14 – 2.02 (m, 2H), 1.71 (qd, J = 12.1, 4.1 Hz,2H).

[0307] Example 6

[0308] 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0309]

[0310] The preparation method of Example 1 was used to replace Int-B1-b with Int-B3-b. Silica gel column chromatography (PE / EA = 1:1 constant elution) was used to obtain I-6 (Compound 6), 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (325 mg, 75.1% yield) as a white solid.

[0311] 1 H NMR (400 MHz, Chloroform- d ) d 8.59 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.83 (d, J = 1.5 Hz, 1H), 7.37 (d, J = 1.0 Hz, 1H), 6.53 (d, J = 1.4 Hz, 1H), 5.57 (d, J = 30.6 Hz, 2H), 3.83 – 3.71 (m, 2H), 3.00 (ddd, J=14.2, 11.7, 3.0 Hz, 2H), 2.50 – 2.42 (m, 3H), 2.39 (ddd, J = 11.3, 7.0, 4.3Hz, 1H), 2.05 (s, 3H), 2.00 (dd, J = 13.2, 3.8 Hz, 2H), 1.98 – 1.88 (m, 2H).

[0312] Example 7

[0313] 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0314]

[0315] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B3-b, and Int-A8 was replaced with Int-A9. Silica gel column chromatography was used to elute (PE / EA = 2:1 constant elution) to obtain I-7 (Compound 7), ie, 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (367 mg, 84.9% yield) as a white solid.

[0316] 1 H NMR (400 MHz, DMSO- d 6) d 9.08 (d, J = 2.3 Hz, 1H), 8.89 (s, 1H), 8.50 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 1.0 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 6.86 – 6.79 (m, 1H), 4.12 (s, 3H), 3.64 (d, J = 13.1 Hz, 2H), 2.94 (d, J =2.4 Hz, 1H), 2.37 (d, J = 0.9 Hz, 3H), 2.32 (s, 1H), 1.84 – 1.78 (m, 2H), 1.69 (dd, J = 12.5, 3.6 Hz, 2H).

[0317] Example 8

[0318] (S)-2-((5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)amino)propanamide

[0319]

[0320] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B4-b. Silica gel column chromatography was used to elute (PE / EA = 2:1 constant elution) to give I-8 (Compound 8), i.e., (S)-2-((5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)amino)propanamide (367 mg, 84.9% yield) as a yellow solid.

[0321] 1 H NMR (400 MHz, Chloroform- d ) d 8.47 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.78 (d, J = 1.5 Hz, 1H), 7.38 – 7.32 (m, 1H), 6.49 (d, J =1.4 Hz, 1H), 6.25 (s, 1H), 5.58 (s, 1H), 5.39 (d, J = 5.8 Hz, 1H), 4.80 –4.65 (m, 1H), 4.05 (s, 3H), 2.47 (s, 3H), 1.57 (d, J = 7.1 Hz, 3H).

[0322] Example 9

[0323] 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide

[0324]

[0325] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B2-b. Silica gel column chromatography was used to elute (PE / EA=1:2 constant elution) to give I-9 (Compound 9), 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide (261 mg, 60% yield) as a white solid.

[0326] 1 H NMR (400 MHz, Chloroform- d ) d 8.63 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.84 (d, J = 1.5 Hz, 1H), 7.37 (d, J = 1.0 Hz, 1H), 6.58 (s,1H), 6.53 (d, J = 1.5 Hz, 1H), 5.63 (s, 1H), 4.07 (s, 3H), 3.68 (d, J = 3.6Hz, 1H), 3.38 (dd, J = 12.9, 7.3 Hz, 1H), 3.35 – 3.28 (m, 1H), 3.19 (dd, J =8.6, 3.3 Hz, 1H), 2.69 (dd, J = 6.8, 3.6 Hz, 1H), 2.47 (d, J = 0.9 Hz, 3H), 1.98 – 1.90 (m, 1H), 1.90 – 1.83 (m, 1H), 1.78 – 1.68 (m, 1H).

[0327] Example 10

[0328] 2-(Ethyl(4-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)amino)pentyl)amino)ethan-1-ol

[0329]

[0330] To a reaction flask, 1 mmol of 2-(4-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)amino)pentyl)(ethyl)amino)ethan-1-ol (Int-B5, 398.3 mg), 2 mmol of (8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)boronic acid (Int-A8-b, 416.4 mg), 4 mmol of KCO (552.8 mg), and 0.1 mmol of tetrakis(triphenylphosphine)palladium (115.6 mg, CAS No. 14221-01-3, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.) were added. 12 ml of 1,4-dioxane was added as solvent, and 1.5 ml of purified water was added. The air was replaced with Ar three times, and the mixture was heated to 105°C under an Ar atmosphere and stirred for 24 hours. After the reaction is completed, the reactant is cooled to room temperature, filtered through diatomaceous earth, and the filter cake is rinsed with a large amount of methanol. The filtrate is retained, concentrated under reduced pressure, and eluted by silica gel column chromatography (first using 5 column volumes of pure EA constant elution, then using DCM: MEOH = 5: 1 constant elution) to obtain I-10 (Compound 10), i.e. 2-(ethyl(4-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)amino)pentyl)amino)ethan-1-ol (388 mg, 81.0% yield), which is a colorless oil.

[0331] 1 H NMR (400 MHz, Chloroform- d ) d 8.44 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 1.4 Hz, 1H), 7.35 (d, J = 1.0 Hz, 1H), 6.52 (d, J = 1.4 Hz, 1H), 4.05 (s, 3H), 3.88 – 3.83 (m, 2H), 3.09 – 3.02 (m, 3H), 2.98(t, J = 5.1 Hz, 3H), 2.49 – 2.44 (m, 3H), 2.01 (s, 3H), 1.79 (dt, J = 12.8,8.7 Hz, 2H), 1.72 – 1.59 (m, 2H), 1.30 – 1.24 (m, 6H).

[0332] Example 11

[0333] 2-(Ethyl(4-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)amino)pentyl)amino)ethan-1-ol

[0334]

[0335] The preparation method of Example 10 was adopted, and Int-A8-b was replaced with Int-A9-b. Silica gel column chromatography (first using 5 column volumes of pure EA constant elution, then using DCM:MEOH = 6:1 constant elution) provided I-11 (Compound 11), i.e., 2-(ethyl(4-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)amino)pentyl)amino)ethan-1-ol (355 mg, 73.9% yield) as a brown oil.

[0336] 1 H NMR (400 MHz, Chloroform- d ) d 8.82 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 2.3 Hz, 1H), 7.96 (s, 1H), 7.41 (d, J = 0.9 Hz, 1H), 4.77 (d, J = 7.8 Hz,1H), 4.40 (t, J = 6.5 Hz, 1H), 4.22 (s, 3H), 3.56 (t, J = 5.4 Hz, 2H), 2.61 –2.57 (m, 3H), 2.55 – 2.51 (m, 2H), 2.49 (s,3H), 1.61 – 1.55 (m, 4H), 1.28 (d, J = 6.5 Hz, 4H), 1.24 (d, J = 6.4 Hz, 1H), 1.02 (t, J = 7.1 Hz, 4H).

[0337] Example 12

[0338] 1-(5-(imidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0339]

[0340] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B3-b, and Int-A8 was replaced with Int-A2. Silica gel column chromatography was used to elute (PE / EA = 1:2 constant elution) to obtain I-12 (Compound 12), ie, 1-(5-(imidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (266 mg, 68.2% yield), as a white solid.

[0341] 1 H NMR (400 MHz, Chloroform- d ) d 9.20 (s, 1H), 8.92 (s, 1H), 8.48 (t, J = 2.8 Hz, 2H), 7.87 (s, 1H), 7.81 (s, 1H), 5.66 (s, 2H), 3.86 (d, J = 12.9Hz, 2H), 3.12 – 2.96 (m, 2H), 2.47 – 2.35 (m, 1H), 1.99 (dd, J = 8.1, 3.8 Hz,2H), 1.94 (dd, J = 12.3, 3.6 Hz, 2H).

[0342] Example 13

[0343] 2-(2-(4-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethan-1-ol

[0344]

[0345] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B6-b, and Int-A8 was replaced with Int-A9. Silica gel column chromatography was used as the eluting agent (PE / EA=1:2 constant elution) to give I-13 (Compound 13), 2-(2-(4-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethane-1-ol (371 mg, 77.3% yield) as a light yellow translucent solid.

[0346] 1 H NMR (400 MHz, Chloroform- d ) d 8.94 (d, J = 2.3 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.04 (s, 1H), 7.44 (d, J = 1.0 Hz, 1H), 4.29 (s, 1H), 4.23 (s, 3H), 3.76 – 3.72 (m, 4H), 3.66 (dd, J = 5.5, 3.1 Hz, 2H), 3.48 (t, J = 4.8Hz, 4H), 2.74 – 2.70 (m, 4H), 2.68 (t, 2H), 2.50 (s, 3H).

[0347] Example 14

[0348] 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-amine hydrochloride

[0349]

[0350] The preparation method of Example 1 is adopted, and Int-B1-b is replaced with Int-B13-b. By silica gel column chromatography elution, (PE / EA=2:1), 14a, i.e. (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)t-butyl carbamate (405 mg, 78.2% yield) is obtained as a light yellow oil.

[0351] 0.5 mmol of tert-butyl (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (Compound 14a, 259.8 mg) was added to the reaction flask, followed by 3 ml of hydrochloric acid and ethyl acetate solution. Stirring was carried out at room temperature for 12 h. After completion of the reaction, the reactant was concentrated under reduced pressure, and then 10 ml of DCM and 10 ml of PE were added twice, each time concentrated under reduced pressure to complete dryness. Finally, solid powder was uniformly precipitated to obtain I-14 (Compound 14), i.e., 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-amine hydrochloride (182 mg, 80.6% yield) as a white solid.

[0352] 1 H NMR (400 MHz, DMSO- d 6) d 8.98 (d, J = 2.7 Hz, 1H), 8.48 (d, J = 2.4Hz, 1H), 8.38 (s, 2H), 8.32 (s, 1H), 8.10 – 8.05 (m, 1H), 7.79 (d, J = 1.3Hz, 1H), 4.19 (s, 23H), 3.58 (d, J = 13.0 Hz, 2H), 3.26 (t, J = 10.7 Hz, 2H), 2.49 (s, 3H), 2.00 – 1.92 (m, 2H), 1.86 – 1.75 (m, 2H), 1.40 (s, 3H).

[0353] Example 15

[0354] 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-amine hydrochloride

[0355]

[0356] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B13-b, and Int-A8 was replaced with Int-A9. Silica gel column chromatography was used to elute (PE / EA=2.5:1) to give 15a, i.e., tert-butyl (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazine-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (432 mg, 83.1% yield) as a colorless viscous oil.

[0357] The preparation method of Example 14 was used, and 14a was replaced by 15a to obtain compound I-15 (Compound 15), ie, 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-amine hydrochloride (202 mg, 88.6% yield) as a white solid.

[0358] 1 H NMR (400 MHz, Chloroform-d) d 9.18 (s, 1H), 9.14 (d, J = 2.2 Hz,1H), 8.57 (d, J = 2.3 Hz, 1H), 8.37 (s, 2H), 8.07 – 8.03 (m, 1H), 4.22 (s,3H), 3.61 (d, J = 14.0 Hz, 2H), 3.27 (s, 2H), 2.47 (s, 3H), 1.93 (d, J = 3.9Hz, 2H), 1.80 (dt, J = 9.5, 4.2 Hz, 2H), 1.40 (s, 3H).

[0359] Example 16

[0360] (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol

[0361]

[0362] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B7-b. Silica gel column chromatography was used to elute (PE / EA = 1:1.5 constant elution) to give I-16 (Compound 16), i.e., (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol (260 mg, 61.9% yield) as a light yellow solid.

[0363] 1 H NMR (400 MHz, Chloroform- d ) d 8.58 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.83 (d, J = 1.5 Hz, 1H), 7.37 (d, J = 1.0 Hz, 1H), 6.53 (d, J = 1.4 Hz, 1H), 4.06 (s, 3H), 3.76 (dt, J = 12.6, 2.4 Hz, 2H), 3.59 (d, J =6.4 Hz, 2H), 2.97 (td, J = 12.5, 2.3 Hz, 2H), 2.47 (d, J = 0.9 Hz, 3H), 1.86(dd, 2H), 1.80 – 1.70 (m, 1H), 1.51 – 1.38 (m, 2H).

[0364] Example 17

[0365] 1-(5-(2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0366]

[0367] The preparation method of Example 1 was used, and Int-B1-b was replaced with Int-B3-b, and Int-A8 was replaced with Int-A5. Silica gel column chromatography was used to elute (PE / EA = 1:2 constant elution) to give I-17 (Compound 17), 1-(5-(2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (291 mg, 72.0% yield), as a light yellow solid.

[0368] 1 H NMR (400 MHz, Chloroform- d ) d 9.06 (s, 1H), 8.90 (d, J = 2.4 Hz,1H), 8.46 (d,J = 2.3 Hz, 1H), 8.40 – 8.36 (m, 1H), 7.56 (s, 1H), 5.61 (s,2H), 3.84 (d, J = 13.4 Hz, 2H), 3.03 (td, J = 12.4, 2.7 Hz, 2H), 2.56 (s,3H), 2.46 – 2.36 (m, 1H), 2.00 (d, J = 3.6 Hz, 2H), 1.98 – 1.85 (m, 2H).

[0369] Example 18

[0370] 1-(5-(8-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0371]

[0372] The preparation method of Example 1 was used, and Int-B1-b was replaced with Int-B3-b, and Int-A8 was replaced with Int-A3. Silica gel column chromatography was used to elute (PE / EA = 1:1 constant elution) to give I-18 (Compound 18), 1-(5-(8-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (291 mg, 72.0% yield), as a light yellow solid.

[0373] 1 H NMR (400 MHz, Chloroform- d ) d 8.62 (d, J = 2.4 Hz, 1H), 8.22 –8.18 (m, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.69 (dd, 2H), 7.19 (t, J = 1.4 Hz,1H), 5.54 (d, J = 42.5 Hz, 2H), 3.84 – 3.76 (m, 2H), 3.09 – 2.96 (m, 2H), 2.72 (t, J = 0.9 Hz, 3H), 2.48 – 2.35 (m, 1H), 2.02 – 1.99 (m, 2H), 1.95 (td,2H).

[0374] Example 19

[0375] 1-(5-(8-methoxyimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0376]

[0377] The preparation method of Example 1 was used, and Int-B1-b was replaced with Int-B3-b, and Int-A8 was replaced with Int-A7. Silica gel column chromatography was used to elute (PE / EA = 1:2 constant elution) to give I-19 (Compound 19), 1-(5-(8-methoxyimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (319 mg, 76.1% yield) as a white-yellow solid.

[0378] 1 H NMR (400 MHz, Chloroform- d ) d 8.62 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.64 (d, J = 2.5 Hz, 2H), 6.59 (d, J = 1.5 Hz, 1H), 5.67 – 5.47 (m, 2H), 4.10 (s, 3H), 3.80 (d, J = 13.0 Hz, 2H),3.09 – 2.97 (m, 2H), 2.45 – 2.36 (m, 1H), 2.00 (d, J = 4.0 Hz, 2H), 1.96 (td,2H).

[0379] Example 20

[0380] 5-(8-methoxyimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-amine

[0381]

[0382] The preparation method of Example 1 was adopted, and Int-A8 was replaced with Int-A7. Silica gel column chromatography was used to elute (PE / EA=1.5:1 constant elution) to give I-20 (Compound 20), 5-(8-methoxyimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-amine (215 mg, 69.8% yield), as a yellow solid.

[0383] 1 H NMR (400 MHz, Chloroform- d ) d 8.44 (d, J = 2.2 Hz, 1H), 7.88 (dd, J = 7.6, 1.8 Hz, 2H), 7.61 (s, 2H), 6.54 (d, J = 1.4 Hz, 1H), 5.15 (s, 2H), 4.08 (s, 3H).

[0384] Example 21

[0385] 6-(6-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine

[0386]

[0387] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B10-b, and Int-A8 was replaced with Int-A9. Silica gel column chromatography was used to elute (PE / EA=5:1 constant elution) to obtain I-21 (Compound 21), i.e., 6-(6-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine (227 mg, 53.2% yield) as a light pink solid.

[0388] 1 H NMR (400 MHz, Chloroform- d ) d 8.97 (d, J = 2.3 Hz, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.07 (s, 1H), 7.45 (s, 1H), 4.25 (s, 3H), 3.50 (t, J= 5.7 Hz,4H), 2.51 (s, 3H), 2.17 (tt, J = 13.8, 5.7 Hz, 4H).

[0389] Example 22

[0390] (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol

[0391]

[0392] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B7-b, and Int-A8 was replaced with Int-A9. Silica gel column chromatography was used to elute (PE / EA = 3:1 constant elution) to give I-22 (Compound 22), i.e., (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol (285 mg, 67.6% yield) as a white solid.

[0393] 1 H NMR (400 MHz, Chloroform- d ) d 8.95 (d, J = 2.3 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.03 (s, 1H), 7.44 (d, J = 0.9 Hz, 1H), 4.23 (s, 3H), 3.82(dt, J = 12.7, 2.5 Hz, 2H), 3.60 (d, J = 6.4 Hz, 2H), 2.99 (td, J = 12.5, 2.3Hz, 2H), 2.50 (d, J = 0.9 Hz, 3H), 1.87 (dd, J = 12.9, 2.8 Hz, 2H), 1.76(tdt, J = 11.8, 6.5, 2.7 Hz, 1H), 1.45 (qd, J = 12.2, 3.9 Hz, 2H).

[0394] Example 23

[0395] (1-(5-(imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol

[0396]

[0397] The preparation method of Example 1 was used, and Int-B1-b was replaced with Int-B7-b, and Int-A8 was replaced with Int-A1. Silica gel column chromatography (pure EA constant elution) gave I-23 (Compound 23), (1-(5-(imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol (218 mg, 57.9% yield) as a gray solid.

[0398] 1 H NMR (400 MHz, Chloroform- d ) d 8.61 (d, J = 2.4 Hz, 1H), 8.31 (d, J = 1.8 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 9.4 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.37 (dd, J = 9.3, 1.8 Hz, 1H), 3.85 – 3.77 (m, 2H), 3.61 (d, J = 6.4 Hz, 2H), 3.00 (td, J = 12.5, 2.3 Hz, 2H), 1.88 (dd, J = 13.4, 3.5 Hz,2H), 1.77 (ddt, J = 11.9, 8.2, 5.1 Hz, 1H), 1.46 (qd, J = 12.3, 3.9 Hz, 2H).

[0399] Example 24

[0400] 2-(1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol

[0401]

[0402] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B8-b, and Int-A8 was replaced with Int-A9. Silica gel column chromatography was used to elute (PE / EA=1:1 constant elution) to give I-24 (Compound 24), 2-(1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazine-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol (369 mg, 84.7% yield) as a white solid.

[0403] 1 H NMR (400 MHz, Chloroform- d ) d 8.94 (d, J = 2.3 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.02 (s, 1H), 7.43 (d, J = 1.0 Hz, 1H), 4.23 (s, 3H), 3.81 (p, J = 2.0 Hz, 1H), 3.77 (t, J = 6.5 Hz, 3H), 2.97 (td, J = 12.6, 2.3 Hz, 2H),2.50 (d, J = 0.9 Hz, 3H), 1.88 – 1.79 (m, 2H), 1.75 – 1.66 (m, 1H), 1.61 (q, J = 6.6 Hz, 2H), 1.51 – 1.36 (m, 2H).

[0404] Example 25

[0405] 1-(5-(8-methoxyimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0406]

[0407] The preparation method of Example 1 was used, and Int-B1-b was replaced with Int-B3-b, and Int-A8 was replaced with Int-A6. Silica gel column chromatography was used to elute (PE / EA = 1:1 constant elution) to give I-25 (Compound 25), 1-(5-(8-methoxyimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (331 mg, 78.9% yield) as a white solid.

[0408] 1 H NMR (400 MHz, Chloroform- d ) d 8.98 (d, J = 2.3 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.14 (s, 1H), 7.70 (d, J = 1.6 Hz, 2H), 5.56 (s, 1H), 5.40 (s,1H), 4.27 (s, 3H), 3.84 (d, J = 13.0 Hz, 2H), 3.12 – 2.96 (m, 2H), 2.42 (tt, J = 11.4, 4.2 Hz, 1H), 2.03 – 1.99 (m, 2H), 1.95 (td, 2H).

[0409] Example 26

[0410] 1-(5-(7-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0411]

[0412] The preparation method of Example 1 was used, and Int-B1-b was replaced with Int-B3-b, and Int-A8 was replaced with Int-A4. Silica gel column chromatography was used to elute (PE / EA = 2:1 constant elution) to give I-26 (Compound 26), 1-(5-(7-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (264 mg, 65.5% yield), as a white solid.

[0413] 1 H NMR (400 MHz, Chloroform- d ) d8.41 (d, J = 2.3 Hz, 1H), 8.01 (s,1H), 7.86 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.58 – 7.55 (m, 1H), 7.54 – 7.52 (m, 1H), 5.60 (d, J = 37.7 Hz, 2H), 3.89 – 3.77 (m, 2H), 3.03(td, J = 12.3, 2.9 Hz, 2H), 2.46 – 2.38 (m, 1H), 2.29 (s, 3H), 2.01 (d, J =4.3 Hz, 2H), 1.96 (dd, J = 11.6, 3.9 Hz, 2H).

[0414] Example 27

[0415] 6-(6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine hydrochloride

[0416]

[0417] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B16-b, and Int-A8 was replaced with Int-A9. Silica gel column chromatography was used to elute (PE / EA = 4:1 constant elution) to obtain compound 27a, i.e., (1R, 4R)-5-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (392 mg, 77.8% yield), as a light yellow oil.

[0418] The preparation method of Example 14 was adopted, and 14a was replaced by 27a to obtain I-27 (Compound 27), ie, 6-(6-((1R, 4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine hydrochloride (138 mg, 61.4% yield) as a yellow-white solid.

[0419] 1H NMR (400 MHz, DMSO-d6) d 9.92 (s, 1H), 9.44 (s, 1H), 9.16 (s, 1H), 9.08 (d, J = 2.2 Hz, 1H), 8.54 (d, J = 2.2 Hz, 1H), 8.07 (s, 1H), 4.97 (s,1H), 4.45 (s, 1H), 4.23 (s, 3H), 3.81 (dd, 2H), 3.43 (s, 1H), 3.38 – 3.30 (m,1H), 2.48 (s, 3H), 2.14 (d, J = 11.0 Hz, 1H), 1.99 (d, J = 11.0 Hz, 1H).

[0420] Example 28

[0421] N-(4-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxamide hydrochloride

[0422]

[0423] To a reaction vessel, 1 mmol of 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyridine (Compound Int-A8, 241 mg), 1.2 mmol of tert-butyl 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate (Compound Int-B17-b, 597.6 mg), 0.2 mmol of triphenylphosphine (52.5 mg, CAS No. 603-35-0, Supplier: Shanghai Aladdin Biochemical Technology Co., Ltd.), 0.05 mmol of palladium acetate (11.3 mg, CAS No. 3375-31-3, Supplier: Shaoyuan Technology (Shanghai) Co., Ltd.), and 3 mL of 1 M sodium carbonate solution were added. 9 mL of DMF was added as solvent. The air was replaced with Ar gas three times, and the mixture was heated to 95 ° C under reflux under an Ar atmosphere and stirred for 10 hours. After the reaction was completed, the reactant was cooled to room temperature, filtered through celite, and the filter cake was rinsed with EA and methanol. The filtrate was retained, concentrated under reduced pressure, and eluted by silica gel column chromatography (PE / EA=1:2 constant elution) to obtain compound 28a, i.e. tert-butyl 4-(4-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate (405 mg, 76.1% yield), which is a yellow translucent solid.

[0424] The preparation method of Example 14 was used, and 14a was replaced by 28a to obtain I-28 (Compound 28), ie, N-(4-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxamide hydrochloride (196 mg, 83.7% yield) as a white solid.

[0425] 1 H NMR (400 MHz, DMSO- d 6) d 9.97 (s, 1H), 9.00 (s, 1H), 8.13 (s, 2H), 8.09 (s, 1H), 7.75 (s, 1H), 7.42 (s, 1H), 6.92 (s, 1H), 4.20 (s, 2H), 3.22(d, J = 12.8 Hz, 2H), 2.83 (d, J = 11.8 Hz, 2H), 2.50 (s, 3H), 2.43 – 2.35(m, 1H), 1.90 – 1.81 (m, 3H), 1.73 (dd, J = 13.2, 9.7 Hz, 3H).

[0426] Example 29

[0427] 8-Methoxy-2-methyl-6-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridine hydrochloride

[0428]

[0429] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B15-b. Silica gel column chromatography was used to elute (PE / EA = 1.5:1 constant elution) to obtain compound 29a, tert-butyl 4-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (334 mg, 68.0% yield), as a colorless oil.

[0430] The preparation method of Example 14 was used, and 14a was replaced by 29a to obtain I-29 (Compound 29), 8-methoxy-2-methyl-6-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridine hydrochloride (172 mg, 80.5% yield) as a dark yellow solid.

[0431] 1 H NMR (400 MHz, DMSO- d 6) d 9.05 (d, J = 2.4 Hz, 1H), 8.99 (d, J = 2.4Hz, 1H), 8.53 (dd, J = 21.3, 2.5 Hz, 1H), 8.11 (d, J = 10.8 Hz, 1H), 7.81 (d, J = 5.7 Hz, 1H), 4.20 (d, J = 2.0 Hz, 3H), 3.52 (d, J = 15.4 Hz, 4H), 3.28(d, J = 4.8 Hz, 2H), 3.22 (s, 2H), 1.91 (d, J = 1.0 Hz, 3H).

[0432] Example 30

[0433] N-(4-(imidazo[1,2-a]pyrazin-6-yl)-2-(trifluoromethyl)phenyl)piperidine-3-carboxamide hydrochloride

[0434]

[0435] Using the preparation method of Example 28 and replacing Int-A8 with Int-A2 and Int-B17-b with Int-B18-b, compound 30a, i.e., tert-butyl 3-((4-(imidazo[1,2-a]pyrazin-6-yl)-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate (342 mg, 69.9% yield), was obtained as a white solid.

[0436] The preparation method of Example 14 was used, and 14a was replaced by 30a to obtain I-30 (Compound 30), the hydrochloride salt of N-(4-(imidazo[1,2-a]pyrazin-6-yl)-2-(trifluoromethyl)phenyl)piperidine-3-carboxamide (191 mg, 89.9% yield), as a white solid.

[0437] 1 H NMR (400 MHz, DMSO- d 6) d 10.17 (s, 1H), 9.70 – 9.65 (m, 1H), 9.49(d, J = 10.3 Hz, 1H), 9.42 (s, 1H), 9.20 (d, J = 10.9 Hz, 1H), 8.39 (dd, J =15.4, 1.8 Hz, 2H), 8.23 ​​(d, J = 1.5 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 3.34 –3.27 (m, 1H), 3.19 (d, J = 12.3 Hz, 1H), 3.14 – 3.05 (m, 1H), 2.98 (q, J =10.8 Hz, 1H), 2.87 (s, 1H), 2.15 – 2.07 (m, 1H), 1.84 (d, J = 5.6 Hz, 2H),1.71 – 1.55 (m, 1H).

[0438] Example 31

[0439] (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanamine hydrochloride

[0440]

[0441] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B14-b, and Int-A8 was replaced with Int-A9. Silica gel column chromatography was used to elute (PE / EA=2:1 constant elution) to give compound 31a, i.e., tert-butyl (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazine-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)carbamate (425 mg, 81.6% yield) as a light yellow solid.

[0442] The preparation method of Example 14 was used, and 14a was replaced by 31a to obtain compound I-31 (compound 31), i.e., (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanamine hydrochloride (198 mg, 86.8% yield) as a white solid.

[0443] 1 H NMR (400 MHz, DMSO- d 6) d 9.29 (s, 1H), 9.14 (d, J = 2.3 Hz, 1H),8.56 (d, J = 2.3 Hz, 1H), 8.27 (s, 1H), 8.16 – 8.13 (m, 1H), 4.25 (s, 3H), 3.76 (d, J = 12.9 Hz, 2H), 2.97 (t, J = 12.3 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.50 (s, 3H), 1.92 – 1.84 (m, 3H), 1.38 – 1.27 (m, 2H).

[0444] Example 32

[0445] N-(4-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxamide hydrochloride

[0446]

[0447] Using the preparation method of Example 28 and replacing Int-A8 with Int-A9, compound 32a, i.e., tert-butyl 4-((4-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate (408 mg, 76.5% yield), was obtained as a white translucent solid.

[0448] Using the preparation method of Example 14 and replacing 14a with 32a, I-32 (Compound 32), N-(4-(imidazo[1,2-a]pyrazin-6-yl)-2-(trifluoromethyl)phenyl)piperidine-3-carboxamide hydrochloride (201 mg, 85.7% yield) was obtained as a white solid.

[0449] 1 H NMR (400 MHz, DMSO- d 6) d 9.88 (s, 1H), 9.20 (s, 2H), 8.86 (d, J =11.1 Hz, 1H), 8.38 – 8.31 (m, 2H), 8.04 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 4.23 (s, 3H), 3.36 – 3.25 (m, 2H), 2.94 (q, J = 11.6 Hz, 2H), 2.80 (t, J =3.9 Hz, 1H), 2.47 (s, 3H), 2.03 – 1.96 (m, 2H), 1.87 (s, 2H).

[0450] Example 33

[0451] 6-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridine hydrochloride

[0452]

[0453] The preparation method of Example 1 was adopted, and Int-A8 was replaced by Int-A1, and Int-B1-b was replaced by Int-B15-b. Silica gel column chromatography was performed (PE / EA = 1:2 constant elution) to afford 33a, tert-butyl 4-(5-(imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (313 mg, 70.0% yield), as a white translucent solid.

[0454] Using the preparation method of Example 14 and replacing 14a with 33a, I-33 (Compound 33), ie, the hydrochloride salt of 6-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridine (166 mg, 86.7% yield), was obtained as a white solid.

[0455] 1 H NMR (400 MHz, DMSO- d 6) d 9.66 (s, 2H), 9.51 (d, J = 4.0 Hz, 1H),9.01 (d, J = 2.3 Hz, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.42 (d, J = 9.4 Hz, 1H),8.39 – 8.26 (m, 2H), 8.11 (d, J = 9.4 Hz, 1H), 3.53 (d, J = 5.2 Hz, 4H), 3.22(s, 4H).

[0456] Example 34

[0457] 8-Methoxy-2-methyl-6-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyrazine

[0458]

[0459] The preparation method of Example 1 was adopted, and Int-A8 was replaced with Int-A9, and Int-B1-b was replaced with Int-B15-b. Silica gel column chromatography was used to elute (PE / EA = 1:1 constant elution) to give compound 34a, tert-butyl 4-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (385 mg, 78.2% yield), as a white oil.

[0460] Using the preparation method of Example 5 and replacing 5a with 34a, I-34 (Compound 34), 8-methoxy-2-methyl-6-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyrazine (127 mg, 64.8% yield), was obtained as a white solid.

[0461] 1H NMR (400 MHz, Chloroform- d ) d 8.97 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.04 (s, 1H), 7.45 (d, J = 0.9 Hz, 1H), 4.24 (s, 3H), 3.51 (s, 3H), 3.41 – 3.37 (m, 4H), 3.08 – 3.03 (m, 3H).

[0462] Example 35

[0463] 2-Methyl-6-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyrazine

[0464]

[0465] The preparation method of Example 1 was adopted, and Int-A8 was replaced with Int-A5, and Int-B1-b was replaced with Int-B15-b. Silica gel column chromatography was used to elute (PE / EA = 1.5:1 constant elution) to give 35a, i.e., tert-butyl 4-(5-(2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (352 mg, 76.1% yield), as a white solid.

[0466] Using the preparation method of Example 5 and replacing 5a with 35a, I-35 (Compound 35), 2-methyl-6-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyrazine (129 mg, 71.3% yield), was obtained as a white solid.

[0467] 1 H NMR (400 MHz, DMSO- d 6) d 9.66 (d, J = 6.4 Hz, 1H), 9.62 (s, 1H), 9.36 (d, J = 4.1 Hz, 1H), 9.20 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H),8.20 (d, J= 3.8 Hz, 1H), 3.55 (t, J = 4.7 Hz, 4H), 3.22 (s, 4H), 2.56 (d, J = 3.0 Hz, 3H).

[0468] Example 36

[0469] 2-(1-(5-(imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol

[0470]

[0471] The preparation method of Example 1 was used, and Int-A8 was replaced with Int-A1, and Int-B1-b was replaced with Int-B8-b. Silica gel column chromatography was used to elute (DCM / MEOH = 15:1 constant elution) to give I-36 (Compound 36), 2-(1-(5-(imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol (237 mg, 60.7% yield) as a white solid.

[0472] 1 H NMR (400 MHz, Chloroform- d ) d 8.61 (d, J = 2.4 Hz, 1H), 8.31 (t, J = 1.4 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 9.4 Hz, 1H), 7.72 –7.68 (m, 2H), 7.37 (dd, J = 9.4, 1.8 Hz, 1H), 3.80 (d, J = 5.7 Hz, 2H), 3.78– 3.75 (m, 2H), 3.05 – 2.91 (m, 2H), 1.84 (d, J = 12.9 Hz, 2H), 1.75 – 1.69(m, 1H), 1.62 (q, J = 6.6 Hz, 2H), 1.51 – 1.39 (m, 2H), 1.38 (s, 1H).

[0473] Example 37

[0474] 2-(1-(5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol

[0475]

[0476] The preparation method of Example 4 was adopted, and compound 3 was replaced with compound 36. Eluted by silica gel column chromatography (DCM / MEOH=9:1 constant elution) to give compound I-37, 2-(1-(5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol (138 mg, 70.1% yield) as a white solid.

[0477] 1 H NMR (400 MHz, Chloroform- d ) d 8.34 (d, J = 2.4 Hz, 1H), 7.73 (s,1H), 7.09 – 7.01 (m, 1H), 6.83 (s, 1H), 4.22 (dd, J = 12.5, 5.3 Hz, 1H), 3.94(t, J = 11.6 Hz, 1H), 3.76 (t, J = 6.5 Hz, 2H), 3.65 (dt, J = 13.1, 3.1 Hz,2H), 3.27 (tdd, J = 11.3, 5.4, 2.8 Hz, 1H), 3.17 (ddd, J = 17.2, 5.5, 2.9 Hz,1H), 2.99 (dt, J = 11.6, 5.9 Hz, 1H), 2.91 (td, J = 12.4, 2.3 Hz, 2H), 2.27(ddd, J = 13.0, 6.5, 3.1 Hz, 1H), 2.13 (ddt, J = 18.0, 10.2, 5.6 Hz, 3H),1.81 (dd, J = 13.4, 3.3 Hz, 2H), 1.61 (t, J= 6.5 Hz, 2H), 1.43 (td, J =12.1, 3.8 Hz, 2H).

[0478] Example 38

[0479] 2-(4-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol

[0480]

[0481] The preparation method of Example 1 was used, and Int-A8 was replaced by Int-A9, and Int-B1-b was replaced by Int-B9-b. Silica gel column chromatography was used as the eluting agent (pure EA as the constant elution) to give compound I-38 (Compound 38), 2-(4-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol (346 mg, 79.3% yield), as a white solid.

[0482] 1 H NMR (400 MHz, Chloroform- d ) d 8.96 (d, J = 2.3 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.04 (s, 1H), 7.44 (d, J = 0.9 Hz, 1H), 4.24 (s, 3H), 3.70 (s,2H), 3.49 – 3.42 (m, 4H), 2.71 (t, J = 4.9 Hz, 4H), 2.66 (t, J = 5.4 Hz, 2H), 2.51 – 2.48 (m, 3H).

[0483] Example 39

[0484] 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyridine hydrochloride

[0485]

[0486] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B21-b. Silica gel column chromatography was used to elute (PE / EA=2:1 constant elution) to give 39a, i.e., (1S,4S)-5-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (389 mg, 77.3% yield) as a colorless, transparent oil.

[0487] The preparation method of Example 14 was used, and 14a was replaced by 39a to obtain compound I-39 (compound 39), i.e., 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyridine hydrochloride (179 mg, 88.8% yield) as a white solid.

[0488] 1 H NMR (400 MHz, DMSO- d 6) d 10.08 (s, 1H), 9.73 (s, 1H), 9.00 (d, J =1.2 Hz, 1H), 8.89 (d, J = 2.4 Hz, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.08 (d, J =1.4 Hz, 1H), 7.77 (d, J = 1.2 Hz, 1H), 4.97 (s, 1H), 4.45 (s, 1H), 4.19 (s,3H), 3.90 (d, J = 10.6 Hz, 1H), 3.79 (s, 1H), 3.46 – 3.33 (m, 2H), 2.50 –2.48 (m, 3H), 2.11 (s, 1H), 2.04 – 1.97 (m, 1H).

[0489] Example 40

[0490] (R)-1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-amine hydrochloride

[0491]

[0492] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B11-b, and Int-A8 was replaced with Int-A9. Silica gel column chromatography was used to elute (PE / EA=3:1 constant elution) to give compound 40a, i.e., (R)-tert-butyl(1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate (372 mg, 73.5% yield), as a colorless, transparent oil.

[0493] The preparation method of Example 14 was used, and 14a was replaced by 40a to obtain I-40 (Compound 40), i.e., (R)-1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-amine hydrochloride (188 mg, 85.1% yield) as a yellow-white solid.

[0494] 1 H NMR (400 MHz, DMSO- d 6) d 9.30 (s, 1H), 9.18 (d, J = 2.2 Hz, 1H),8.60 (d, J = 2.2 Hz, 1H), 8.53 (d, J = 5.4 Hz, 2H), 8.15 (s, 1H), 4.24 (s, 3H), 3.48 (d, J = 12.5 Hz, 1H), 3.24 (d, J = 12.2 Hz, 1H), 3.08 (t, J = 11.1Hz, 1H), 2.89 (t, J = 11.1 Hz, 1H), 2.50 (d, J = 2.6 Hz, 3H), 2.18 – 2.08 (m,1H), 1.91 (s, 1H), 1.88 – 1.80 (m, 1H), 1.60 (td, J = 11.9, 10.4, 5.9 Hz, 2H), 1.22 (s, 1H).

[0495] Example 41

[0496] Hydrochloride of 6-(6-((3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine

[0497]

[0498] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B20-b, and Int-A8 was replaced with Int-A9. Silica gel column chromatography was used to elute (PE / EA=3:1 constant elution) to give compound 41a, i.e., (3aR,6aR)-5-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (353 mg, 72.9% yield), as a white solid.

[0499] The preparation method of Example 14 was used, and 14a was replaced by 41a. I-41 (Compound 41), 6-(6-((3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine hydrochloride (192 mg, 89.1% yield), was obtained as a white solid.

[0500] 1 H NMR (400 MHz, DMSO- d 6) d 9.80 (d, J = 20.2 Hz, 2H), 9.24 (s, 1H), 9.07 (d, J = 2.2 Hz, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 4.26 (s, 3H), 3.82 (dd, J = 11.5, 6.1 Hz, 2H), 3.65 (dd, J = 11.6, 3.2 Hz,2H), 3.49 – 3.38 (m, 2H), 3.13 – 3.08 (m, 2H), 3.05 (dd, J = 11.2, 5.6 Hz, 2H), 2.50 (s, 2H).

[0501] Example 42

[0502] (R)-1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-amine hydrochloride

[0503]

[0504] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B11-b. Silica gel column chromatography was used to elute (PE / EA=3:1 constant elution) to give compound 42a, i.e., (R)-tert-butyl(1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate (365 mg, 77.2% yield), as a yellow oil.

[0505] The preparation method of Example 14 was used, and 14a was replaced by 42a to obtain I-42 (Compound 42), i.e., (R)-1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-amine hydrochloride (155 mg, 73.4% yield) as a yellow-white solid.

[0506] 1 H NMR (400 MHz, DMSO- d 6) d 9.05 (d, J = 1.2 Hz, 1H), 9.01 (d, J = 2.3Hz, 1H), 8.54 (d, J = 5.1 Hz, 2H), 8.51 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 1.3Hz, 1H), 7.82 (d, J = 1.2 Hz, 1H), 4.19 (s, 3H), 3.87 (dd, J = 12.3, 3.7 Hz,1H), 3.50 – 3.42 (m, 1H), 3.29 – 3.19 (m, 1H), 3.06 (t, 1H), 2.88 (t, J =10.7 Hz, 1H), 2.50 (s, 3H), 2.12 (d, J= 10.5 Hz, 1H), 1.89 – 1.80 (m, 1H), 1.68 – 1.54 (m, 2H).

[0507] Example 43

[0508] (S)-1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-amine hydrochloride

[0509]

[0510] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B19-b, and Int-A8 was replaced with Int-A9. Silica gel column chromatography was used to elute (PE / EA = 5:1 constant elution) to give compound 43a, i.e., (S)-tert-butyl (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate (381 mg, 74.7% yield), as a yellow oil.

[0511] The preparation method of Example 14 was used, and 14a was replaced by 43a to obtain compound I-43 (compound 43), i.e., (S) -1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-amine hydrochloride (166 mg, 67.6% yield) as a yellow-white solid.

[0512] 1 H NMR (400 MHz, DMSO- d 6) d 9.28 (s, 1H), 9.19 (d, J = 2.3 Hz, 1H),8.60 (d, J = 2.3 Hz, 1H), 8.52 (d, J = 5.4 Hz, 2H), 8.12 (s, 1H), 4.24 (s, 3H), 3.90 (dd, J = 12.1, 3.8 Hz, 1H), 3.49 (d, J = 12.9 Hz, 1H), 3.24 (s,1H), 3.12 – 3.04 (m, 1H), 2.89 (t, J = 10.8 Hz, 1H), 2.50 (s, 3H), 2.12 (d,J = 9.3 Hz, 1H), 1.89 – 1.81 (m, 1H), 1.68 – 1.55 (m, 2H).

[0513] Example 44

[0514] 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine hydrochloride

[0515]

[0516] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B21-b, and Int-A8 was replaced with Int-A9. Silica gel column chromatography was used to elute (PE / EA = 1.5:1 constant elution) to give compound 44a, i.e., (1S,4S)-5-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (353 mg, 69.4% yield), as a yellow oil.

[0517] The preparation method of Example 14 was used, and 14a was replaced by 44a to obtain compound I-44 (compound 44), i.e., 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine hydrochloride (152 mg, 67.1% yield) as a white solid.

[0518] 1 H NMR (400 MHz, DMSO- d 6) d 9.94 (s, 1H), 9.46 (s, 1H), 9.16 (s, 1H), 9.08 (d, J = 2.2 Hz, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.06 (d, J = 1.1 Hz, 1H), 4.97 (s, 1H), 4.45 (d, J = 2.8 Hz, 1H), 4.23 (s, 3H), 3.82 (dd, 2H), 3.49 –3.31 (m, 2H), 2.48 (d,J = 0.9 Hz, 3H), 2.14 (d, J = 11.0 Hz, 1H), 1.99 (d, J = 10.9 Hz, 1H).

[0519] Example 45

[0520] 6-(6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine hydrochloride

[0521]

[0522] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B22-b, and Int-A8 was replaced with Int-A9. Silica gel column chromatography was used to elute (PE / EA=3:1 constant elution) to give compound 45a, tert-butyl 3-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazine-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (393 mg, 77.8% yield), as a yellow oil.

[0523] The preparation method of Example 14 was used, and 14a was replaced by 45a to obtain I-45 (Compound 45), ie, 6-(6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine hydrochloride (171 mg, 70.1% yield) as a white solid.

[0524] 1 H NMR (400 MHz, DMSO-d6) d 9.71 (d, 2H), 9.23 (d, J = 9.1 Hz, 2H), 8.63 (s, 1H), 8.07 (s, 1H), 4.23 (s, 3H), 4.13 (s, 2H), 3.54 (dd, 4H), 2.48(s, 3H), 2.00 (s, 4H).

[0525] Example 46

[0526] 1-(5-(8-cyanoquinolin-5-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0527]

[0528] The preparation method of Example 1 was adopted, and Int-B1-b was replaced with Int-B3-b, and Int-A8 was replaced with 5-bromoquinoline-8-carbonitrile (CAS: 507476-70-2, supplier: Shaoyuan Technology (Shanghai) Co., Ltd.). Eluted by silica gel column chromatography, (PE / EA=1.5:1 constant elution), to obtain I-46 (Compound 46), i.e. 1-(5-(8-cyanoquinolin-5-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (325 mg, 75.1% yield) as a white solid.

[0529] 1 H NMR (400 MHz, Chloroform- d ) d 9.16 (dd, J = 4.2, 1.6 Hz, 1H), 8.49(d, J = 2.3 Hz, 1H), 8.25 (dd, J = 8.6, 1.7 Hz, 1H), 8.21 (d, J = 7.5 Hz,1H), 7.95 (d, J = 2.3 Hz, 1H), 7.63 – 7.53 (m, 2H), 5.47 (d, J = 46.0 Hz,2H), 3.95 (d, J = 13.1 Hz, 2H), 3.09 (td, J = 13.4, 12.4, 3.0 Hz, 2H), 2.50 –2.39 (m, 1H), 2.03 (d, 2H), 2.02 – 1.91 (m, 2H).

[0530] Example 47

[0531] 1-(5-(8-cyanoquinolin-5-yl)pyridin-2-yl)piperidine-4-carboxamide

[0532]

[0533] The detailed synthesis steps of compound 47 and intermediates Int-1 and Int-2 are as follows:

[0534]

[0535] At room temperature, 4-piperidinecarboxamide (CAS No. 39546-32-2, 1922 mg, 15.0 mmol, Supplier: Tianjin Xiens Biochemical Technology Co., Ltd.) and K2CO3 (5528 mg, 40.0 mmol) were dissolved in 30 ml of DMSO and stirred for 10 minutes. 2-Fluoro-5-bromopyridine (1760 mg, 10.0 mmol, CAS No. 766-11-0, Supplier: Tianjin Xiens Biochemical Technology Co., Ltd.) was then added dropwise to the reaction mixture. The reaction mixture was refluxed at 85°C for 8 hours. The reaction mixture was cooled to room temperature, diluted with 300 ml of water, and extracted three times with 50 ml of EA. The organic phases were combined and concentrated under reduced pressure to obtain Int-1, 1-(5-bromopyridin-2-yl)piperidine-4-carboxamide, as a white solid (2660 mg, 93.9% yield).

[0536] At room temperature, Int-1 (1415 mg, 5 mmol), pinacol diboronate (1523 mg, 6 mmol, CAS No. 73183-34-3, supplier: Shaoyuan Technology (Shanghai) Co., Ltd.), and potassium acetate (1470 mg, 15.0 mmol) were dissolved in 1,4-dioxane (15 mL), and PdCl2(dppf)-CH2Cl2 adduct (408 mg, 0.5 mmol, CAS No. 95464-05-4, supplier: Tianjin Xiens Biochemical Technology Co., Ltd.) was added. The air was replaced with Ar gas three times, and the reactants were heated to 105°C under Ar atmosphere and stirred for 16 h. After the reaction was cooled, it was filtered through celite, the filtrate was retained, concentrated under reduced pressure, and eluted by silica gel column chromatography (pure EA constant elution) to purify the crude material to give Int-2, i.e. 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidine-4-carboxamide (1270 mg, 76.7% yield).

[0537] The preparation method of Example 1 is adopted, and Int-B1-b is replaced with Int-2, and Int-A8 is replaced with 5-bromoquinoline-8-carbonitrile (CAS: 507476-70-2, supplier: Shaoyuan Technology (Shanghai) Co., Ltd.). Eluted by silica gel column chromatography, (DCM / MEOH=15:1 constant elution), I-47 (Compound 47), i.e. 1-(5-(8-cyanoquinolin-5-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (39 mg, 11% yield) is obtained as an off-white solid.

[0538] 1 H NMR (400 MHz, Chloroform-d ) d 9.05 (dd, J = 4.2, 1.6 Hz, 1H), 8.30(dd, J = 8.6, 1.7 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 7.5 Hz,1H), 7.54 (dd, J = 8.8, 2.5 Hz, 1H), 7.49 – 7.38 (m, 2H), 6.78 (s, 1H), 5.45(s, 1H), 5.31 (s, 1H), 4.42 (d, J = 13.5 Hz, 2H), 2.99 (t, J = 12.6 Hz, 2H),2.48 – 2.37 (m, 1H), 1.96 (d, J = 13.3 Hz, 2H), 1.85 – 1.70 (m, 2H).

[0539] Example 48

[0540] The inhibitory effect of the compound of formula (I) on TLR7 consists of two experiments, including: detecting HEK-Blue TM -The level of secretory embryonic alkaline phosphatase (SEAP) in hTLR7 cells was used to evaluate TLR7 signal activation; the blank group and the treatment group (administered with different concentrations of the compound of formula (I)) were detected by CCK-8. HEK-Blue TM -hTLR7 cell viability level. The changes in SEAP levels caused by cell proliferation / death were corrected based on the ratio of the CCK-8 test results of the drug-treated group to the blank group to obtain a more accurate TLR7 inhibitory effect of each compound. GraphPad Prism was used to fit the IC values ​​of each compound. 50 Curve and calculate IC 50 value.

[0541] Stable HEK-Blue TMThe hTLR7 cell line was purchased from InvivoGen, San Diego, CA, USA. HEK-Blue cells are human embryonic kidney (HEK) cells transfected with the SEAP (secreted embryonic alkaline phosphatase) gene. The SEAP reporter gene is under the control of a minimal IFN-β promoter fused to five NF-κB and AP-1 binding sites. NF-κB activation leads to SEAP expression. SEAP activity can be conveniently measured using the alkaline phosphatase detection reagent, QUANTI-Blue. HEK-Blue TM The -hTLR7 cell line serves as a reporter cell for TLR7 activity detection. Upon ligand (R848) stimulation, the TLR7-NF-κB signaling pathway is activated, leading to NF-κB translocation to the nucleus, binding to the SEAP reporter gene, and initiating transcription, ultimately producing SEAP, which is secreted into the cell. Because different compounds can have varying effects on TLR7 activity and the amount of SEAP produced, SEAP levels can be assessed using the alkaline phosphatase assay reagent QUANTI-Blue™, and this level can be converted into the inhibitory effect of each compound on TLR7 activity.

[0542] Secreted embryonic alkaline phosphatase assay:

[0543] HEK-Blue cell culture medium preparation: 10% fetal bovine serum (FBS), 50 U / mL penicillin, 50 mg / mL streptomycin, 100 μg / mL Zeocin (solution), 10 μg / mL Blasticidin (solution), 2 mM L-glutamine and DMEM medium.

[0544] Preparation of HEK-Blue cell assay medium: FBS was inactivated in a 56°C water bath for 30 min, and then the inactivated FBS was used to supplement DMEM medium at a concentration of 10%, and supplemented with 50 U / mL penicillin and 50 mg / mL streptomycin, 100 mg / mL Zeocin (solution), 10 μg / mL Blasticidin (solution) and 2 mM L-glutamine.

[0545] The specific steps are as follows:

[0546] HEK-Blue TM hTLR7 cells were seeded in 96-well plates at a rate of 3.5 × 10 4Cells were cultured in a cell culture incubator set at 37°C and 5% CO2, and stimulated with different concentrations of R848 (40 μM), HCQ (16 μM), Enpatoran (1 μM, 5 μM), and the synthetic test compound (1 μM). Cell culture supernatants were collected at different time points for testing; QUANTI-Blue was prepared. TM Working solution: 1 ml QB reagent and 1 ml QB buffer were mixed and then added to 98 ml sterile water to mix thoroughly. After incubation at room temperature for 10 min, 20 μL cell supernatant and 180 μL QUANTI-Blue were added to each well of a 96-well plate. TM The cells were then incubated in an incubator at 37°C for 30 min. OD values ​​were read at a wavelength of 620-655 nm using a microplate reader, and SEAP secretion levels and TLR7 signaling activation were assessed by changes in OD values.

[0547] Cell viability assay (CCK8): 100 μl of cell suspension was added to each well of a 96-well plate. The specific drug was added at various concentrations and incubated in a 37°C incubator for 24 hours. CCK8 assay reagent (10% of the culture volume per well) was added to the 96-well plate and incubated again in a 37°C incubator for 1 hour. OD values ​​were measured at 450 nm using a microplate reader.

[0548] The inhibitory activity of the compound of formula (I) on human TLR7 (IC 50 The values ​​are divided into five ranges: "A1", "A2", "B", "C", and "D". "A1" represents the IC value of the compound. 50 Values ​​<10 nM; "A2" represents the IC of the compound 50 The values ​​are between 10 nM and 100 nM; "B" represents the IC of the compound. 50 The values ​​range from 100 nM to 300 nM; "C" represents the IC of the compound. 50 The values ​​range from 300 nM to 1 μM; “D” represents the IC of the compound. 50 The value is greater than 1 μM. Table 3 shows the activity of the compounds of the present invention in HEK-Blue TM - Range of activity in hTLR7 cell assays.

[0549] Table 3 Inhibitory activity of the compounds prepared in various examples of the present invention against HTLR7

[0550]

[0551] Note: 46 and 47 are compounds synthesized for comparison, and Enpatoran (M5049) and HCQ (hydroxychloroquine) are positive drugs.

[0552] Among compounds 1-45, compounds 14, 32, and 44 all had activities less than 1 nM, demonstrating excellent inhibitory effects.

[0553] Example 49

[0554] The pharmacokinetic properties of the preferred compound YP-1, also known as compound 44, were evaluated by a single-dose PK study in male Sprague-Dawley (SD) rats.

[0555] Six male SD rats were divided into two groups, three rats in each group, and administered Compound YP-1 (Example 44) at 2 mg / kg intravenous injection and 10 mg / kg oral gavage, respectively. Whole blood (150 μL) was collected from the rats' retinal venous plexus at 0, 2 minutes (intravenous injection only), 5 minutes, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration, and transferred into tubes containing sodium heparin. The blood samples were centrifuged at 8000 rpm for 5 minutes at 4°C to separate the plasma. After centrifugation, the resulting plasma was transferred to a clean tube and stored at -20°C until analysis. When used, the plasma was thawed at room temperature before use. An LC-MS / MS method was also established to determine the concentration of Compound YP-1 in rat plasma. Plasma concentration-time curves were plotted using Graphpad Prism software, and pharmacokinetic parameters were calculated using WinNonlin software.

[0556] Pharmacokinetic study of YP-1 (Compound 44) ​​in SD rats. Detailed data are shown in Tables 4, 5, and 6.

[0557] Results: After intravenous administration of Example 44 (2 mg / kg), C 0 is approximately 176.90±26.46 ng / mL, and the in vivo exposure ( AUC 0-t ) about 326.84±50.67 h·ng / mL, AUC 0-∞ About 343.04±39.81 h·ng / mL, half-life ( t 1 / 2 ) was approximately 4.22±0.50 h, and the clearance rate ( CL ) is approximately 5.88±0.68 L / h / kg, and the distribution volume ( V ) is approximately 35.53±2.46 L / kg. Figure 1As shown in Figure 2, compound 44 showed an obvious distribution phase in rats after intravenous injection, and its apparent distribution volume value suggested that the compound may have a relatively wide tissue distribution; other pharmacokinetic parameters obtained by fitting showed that the half-life of compound 44 ( t 1 / 2 ) was approximately 4.22±0.50 h, and the clearance rate ( CL ) was approximately 5.88±0.68 L / h / kg, indicating that the compound had a good metabolic behavior in rats after intravenous administration.

[0558] After oral administration of Example 44 (10 mg / kg), the maximum plasma concentration ( C max ) was approximately 155.67±34.02 ng / mL, and the peak blood concentration time ( T max ) is about 5.33±1.15 h, and the in vivo exposure ( AUC 0-t ) is approximately 1895.39±375.55h·ng / mL, AUC 0-∞ It is about 1925.23±385.68 h·ng / mL, and the bioavailability ( F ) is 115.98%. Figure 2 As shown in the data, after oral administration, the absorption rate of 44 was slow, but the absorption degree was high, indicating that the exposure of the compound in rats was high after oral administration.

[0559] Table 4 Blood drug concentration of Example 44 in rats after intravenous injection (2 mg / kg) (n=3)

[0560]

[0561] Table 5 Blood drug concentration of Example 44 in rats after oral administration (10 mg / kg) (n=3)

[0562]

[0563] Table 6 Key pharmacokinetic parameters of Example 44 in rats after administration (n=3)

[0564]

[0565] Note: -- means it has no meaning here.

[0566] Based on the above results, it can be seen that Example 44 is quickly and widely distributed in the rat body after intravenous injection; after oral administration, Example 44 is absorbed slowly and has a high bioavailability.

Claims

1. An imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound represented by formula (I) or a pharmaceutically acceptable salt thereof: ； in, Dashed lines indicate simultaneous single bonds or simultaneous double bonds; R1 is H or C 1-6 Alkyl; R2 is H, C 1-6 Alkyl or C 1-6 Alkoxy; X is CH, CH2, N or CR4, wherein R4 is C 1-6 Alkyl; Y is N or CH; R3 is independently selected from any one of the following, and when R2 is H and the dotted line is a double bond, R3 is not an amino group: 、 , wherein Z is CH or N, R5 is C 1-5 of alcoholic hydroxyl groups.

2. The imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: When the dotted line is a double bond, X is CH, N or CR4, Y is N or CH, and R1 is H or C 1-3 Alkyl, R2 is H, C 1-3 Alkyl or C 1-3 when the dotted line is a single bond at the same time, X is CH2, Y is N, R1 is H, and R2 is H; and when R2 is H and the dotted line is a double bond at the same time, R3 is not an amino group.

3. The imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The dotted line is also a double bond, when Y is CH, X is N or CH, R1 is H or methyl, R2 is H or methoxy, and R3 is: or ; Or when the dotted line is also a double bond, Y is N, X is CR4 and R4 is methyl, R1 is H, R2 is H, and R3 is: ; Or when the dotted lines are double bonds, Y is N, X is N or CH, R1 is H or methyl, R2 is H, methyl or methoxy, R3 is selected from any one of the following, and when R2 is H, R3 is not amino: or , wherein, when Z is CH, R5 is: or , when Z is N, R5 is: or ; Or when the dotted line represents a single bond at the same time, R1 is H, R2 is H, X is CH2, Y is N, and R3 is: or , where Z is CH and R5 is .

4. The imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The pharmaceutically acceptable salt is an acid addition salt of the compound of formula (I), wherein the acid used for salt formation includes an inorganic acid or an organic acid, the inorganic acid includes any one of hydrochloric acid, sulfuric acid, phosphoric acid or methanesulfonic acid; the organic acid includes any one of acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid or tartaric acid.

5. The imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound or a pharmaceutically acceptable salt thereof is selected from any one of the following I-1 to I-45: 。 6 . Use of the imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of a TLR7 antagonist.

7. Use of the imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating TLR7-mediated diseases.

8. The use according to claim 7, characterized in that The TLR7-mediated disease is an autoimmune disease or a chronic inflammatory disease, and the autoimmune disease or the chronic inflammatory disease includes systemic lupus erythematosus, psoriasis, rheumatoid arthritis, multiple sclerosis or Sjögren's syndrome.

9. A pharmaceutical composition for preventing or treating TLR7-mediated diseases, characterized in that: The invention comprises the imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, characterized in that The pharmaceutical composition is in the form of capsules, powders, tablets, granules, pills, injections, syrups, oral solutions, inhalants, ointments, suppositories or patches.

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