Imidazo [1, 2-a] pyrazine or imidazo [1, 2-a] pyridine compound and medical application thereof

Abstract

The invention discloses an imidazo [1, 2-a] pyrazine or imidazo [1, 2-a] pyridine compound and medical application thereof, and belongs to the field of medicinal chemistry. The structure of the compound is shown in the specification, the compound has an obvious inhibiting effect on a Toll-like receptor (TLR7), the compound can prevent signal transduction of the TLR7 by inhibiting TLR7 dimerization, and the inhibiting effect can reduce or prevent immunoreactions caused by abnormal activation of the TLR7, including reduction of generation of pro-inflammatory and antiviral cytokines, so that the compound can be used for preparing an anti-inflammatory drug. The traditional Chinese medicine composition has a treatment effect on various diseases such as systemic lupus erythematosus, psoriasis, rheumatoid arthritis, multiple sclerosis or sicca syndrome. The compound provided by the invention provides a new choice 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 particularly 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, seriously affect the quality of life of patients and even threaten their lives. Existing treatment methods include: pulse hormone therapy, immunosuppressive therapy and other therapies. However, these existing treatment methods have relatively large toxic and side effects, can only control the progression of the disease or relieve symptoms, and cannot cure autoimmune diseases.

[0003] Toll-like receptors (TLRs) are a class of pattern recognition receptors discovered in recent years, which activate innate immunity by recognizing pathogen-associated molecular patterns (PAMPs). After TLRs recognize the corresponding ligands on the surface of pathogenic microorganisms, they mainly induce immune responses through the MyD88-IRAK-TRAF6 kinase pathway. However, the biological activities mediated by TLRs also participate in pathological damage and the occurrence of autoimmune diseases in some cases. Toll-like receptor 7 (TLR7) is a transmembrane signal transduction receptor expressed on the surface of mammalian cell endosomes and can activate the innate immune system by recognizing single-stranded RNA. TLR7 is mainly localized in plasmacytoid DCs (pDCs), promotes pDCs to secrete type I IFNα, and then activates downstream immune responses. The increase in type I interferons (IFNs) derived from pDCs is considered to be related to the progression of many autoimmune diseases, such as: systemic lupus erythematosus, psoriasis, rheumatoid arthritis, multiple sclerosis or Sjogren's syndrome.

[0004] It can be seen that abnormal activation of TLR7 in the body can trigger various immune-related diseases. Although TLR7 and TLR9 of the same family show similar tissue expression and have a common signaling pathway MyD88, TLR7 and TLR9 have opposite inflammatory and regulatory effects in lupus-susceptible MRL / lpr mice. Studies have found that inhibiting TLR7 can alleviate the progression of the disease, while inhibiting TLR9 will promote the progression of the disease. Therefore, TLR7 is considered to be a driving factor for lupus nephritis.

[0005] Most of the small molecules developed for TLR to date 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, some studies have used lupus-susceptible female MRL / lpr mice treated orally with a TLR8-selective inhibitor. However, compared with the placebo group, there were no significant changes in the spleen index, severity of skin lesions, glomerular diameter, or levels of ANA and anti-ds-DNA antibodies in the treatment group. Even the survival rate of the mice in the drug administration group decreased. Therefore, it is emphasized that TLR8-selective inhibitors are ineffective in the treatment of SLE.

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

[0007]

[0008] However, M5049 in clinical research has shown an impact on 5-HT (5-hydroxytryptamine) reuptake and inhibits CAMKK2 at lower doses. This may be due to its overly compact molecular structure that allows it to cross the blood-brain barrier. Therefore, it is urgent and necessary to develop effective TLR7 inhibitors for the treatment of diseases such as systemic lupus erythematosus. Summary of the Invention

[0009] Object of the Invention: Aiming at the above technical problems, the present invention provides imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compounds with a novel parent nucleus. Such compounds or their pharmaceutically acceptable salts can be used as TLR7 inhibitors and have excellent activity. Furthermore, it is expected to develop targeted drugs based on such compounds to treat autoimmune diseases related to the TLR7 signaling pathway, such as systemic lupus erythematosus, psoriasis, rheumatoid arthritis, multiple sclerosis, or Sjogren's syndrome.

[0010] The present invention also provides a preparation method and pharmaceutical use of the above compounds.

[0011] Technical Solution: To achieve the above object, the present invention provides an imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound shown in formula (I) or its pharmaceutically acceptable salt: ;

[0012] Wherein, the dotted line represents a single bond or a double bond; R1 is H or C 1-6an alkyl group; R2 is H, C 1-6 an alkyl group or C 1-6 an alkoxy group; X is CH, CH2, N or CR4, where R4 is C 1-6 an alkyl group; Y is N or CH; R3 is independently selected from any one of the following, and when R2 is H and the dashed line is a double bond, R3 is not an amino group: , , where Z is CH or N, and R5 is C 1-5 an alcohol hydroxyl group.

[0013] Furthermore, when the dashed 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 dashed 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 dashed line is a double bond, R3 is not an amino group.

[0014] Furthermore, when the dashed line is a double bond and Y is CH, X is N or CH, R1 is H or methyl, R2 is H or methoxy, and R3 is: or ; when the dashed line is a double bond, Y is N, X is CR4 and R4 is methyl, R1 is H, R2 is H, and R3 is: ; When the dashed 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 an amino group: or , where, when Z is CH, R5 is: or ; when Z is N, R5 is: or ; or when the dashed line represents a single bond, R1 is H, R2 is H, X is selected as CH2, Y is selected as N, and R3 is: or , where Z is CH, R5 is .

[0015] Furthermore, the pharmaceutically acceptable salt is an acid addition salt of the compound of formula (I), wherein the acid used for salification includes inorganic acids or organic acids. The inorganic acids include any one of hydrochloric acid, sulfuric acid, phosphoric acid or methanesulfonic acid, and the organic acids include 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, di-gluconic acid, aspartic acid or tartaric acid.

[0016] Preferably, the acid addition salt of the compound of formula (I) is 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:

[0017] When Y is selected as CH, X is N or CH, R1 is methyl, R2 is methoxy, and R3 is: 。

[0018] Furthermore, the compound or its pharmaceutically acceptable salt is selected from any one in Table 1.

[0019] Table 1 Structures and names of Compounds I-1 to I-45

[0020] Furthermore, the preparation method of the compound or its pharmaceutically acceptable salt according to the present invention has the following specific reaction route:

[0021] The compound of structural formula (I) is prepared by the Suzuki coupling reaction of compound A and compound B under the action of a palladium catalyst.

[0022] Use of the compound or its pharmaceutically acceptable salt according to the present invention in the preparation of a TLR7 antagonist.

[0023] Use of the compound or its pharmaceutically acceptable salt according to the present invention in the preparation of a drug for preventing or treating TLR7-mediated diseases.

[0024] Furthermore, the TLR7-mediated diseases are autoimmune diseases or chronic inflammatory diseases, and the autoimmune diseases or chronic inflammatory diseases include: systemic lupus erythematosus, psoriasis, rheumatoid arthritis, multiple sclerosis or Sjogren's syndrome.

[0025] The pharmaceutical composition for preparing a medicament for preventing or treating TLR7-mediated diseases according to the present invention comprises the compound or its pharmaceutically acceptable salt, tautomer and stereoisomer, metabolite, metabolic precursor, solvate or prodrug as described above, and a pharmaceutically acceptable carrier.

[0026] Further, the pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository or patch.

[0027] The preparation of the compound of formula (I) according to the present invention can be divided into three subcategories, namely the hydrochloride salt or its 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 reducing a part of the compound of formula (I-2). The general synthetic routes of these three categories of compounds are shown as follows:

[0028] Wherein A is F or Cl, X is CH, N or CR4, wherein R4 is C 1-6 alkyl, Y is N or CH, PG is a protecting group such as Boc. L is a substituted group selected from the following: 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, cis-3,7-diazabicyclo[3.3.0]octane.

[0029] 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.

[0030] First, react starting material I with a Boc-protected amine compound (H-L-PG) or an unprotected amine compound (H-M) via an SNAr reaction to obtain compounds of formula (II) and formula (VI). Then, treat the compounds of formula (II) and formula (VI) with bis(pinacolato)diboron in the presence of a suitable base (such as KOAc) and a suitable palladium catalyst (such as PdCl2(DPPF)-CH2Cl2 adduct) to obtain compounds of formula (III) and formula (VII), respectively. Perform a Suzuki coupling reaction between the compound of formula (III) and the compound of formula (IV) using a suitable palladium catalyst (such as tetrakis(triphenylphosphine)palladium or palladium acetate) and a suitable base (such as K2CO3 or Na2CO3) to obtain the compound of formula (V). Remove the protecting group from the compound of formula (V) under acidic conditions (such as EA.HCl) to obtain the compound of formula (I-1) or the hydrochloride salt of the compound of formula (I-1).

[0031] Perform a Suzuki coupling reaction 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).

[0032] Reduce some of the compound of formula (I-2) using a suitable reduction method (hydrogen / palladium on carbon) to obtain the compound of formula (I-3).

[0033] The present invention also relates to a method for preparing the hydrochloride salt of the compound of formula (I-1), which method comprises any of the following steps: deprotecting the compound (V) with an acid to directly obtain the hydrochloride salt of the compound of formula (I-1):

[0034] 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 following: 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, cis-3,7-diazabicyclo[3.3.0]octane. PG is a protecting group, such as Boc.

[0035] The present invention also relates to a method for reducing a compound (I-2) containing imidazo[1,2-a]pyridine to (I-3) comprising a 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine structure, which method comprises the following steps: React the compound (I-2) with hydrogen released by heating ammonium formate in combination with palladium on carbon reduction to obtain the compound (I-3):

[0036] wherein X is CH, R 1 is H, R 2 is H; M is piperidine-4-carboxamide, 4-piperidylethanol.

[0037] 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, reduce the production of cytokines (such as NF-κB) triggered by the activation of the TLR7 pathway, and thus effectively block various innate and adaptive immune responses mediated by autoantibodies. In addition, in order to demonstrate the advantages of the imidazo[1,2-a]pyridine structure and imidazo[1,2-a]pyrazine structure of the present invention over the cyanoquinoline structure used in the positive control Enpatoran, 8-cyanoquinoline of the positive control Enpatoran was used to replace 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 core structure protected by the present invention to prepare the comparative compound 46. Meanwhile, an analogue 47 of compound 46 was additionally synthesized to conduct comparison and verify the important role of the meta-substituted trifluoromethyl group on the pyridine ring retained in the core structure of the present invention. The present invention demonstrates 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 both superior to 8-cyanoquinoline (Example 46) in terms of the antagonistic activity against TLR7. In addition, it is also demonstrated that introducing a trifluoromethyl group at the meta-position of the pyridine structure (Example 46, I-46) rather than not introducing a trifluoromethyl group (Example 47, I-47) can not only significantly improve the antagonistic activity of the compound against TLR7 but also significantly improve the yield of the Suzuki coupling reaction. Compounds 46 and 47 are shown in Table 2.

[0038] Table 2 Structures and names of compounds 46 and 47

[0039] Therefore, the compounds of the present invention can be used to block TLR7 in all types of cells expressing such receptors, including but not limited to plasmacytoid dendritic cells, B cells, T cells, macrophages, monocytes, neutrophils, keratinocytes, epithelial cells, and platelets. Thus, the compound can be used as a therapeutic or prophylactic agent for systemic lupus erythematosus, lupus nephritis, and psoriasis.

[0040] 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), its stereoisomers, tautomers, prodrugs or pharmaceutically acceptable salts.

[0041] Beneficial effects: Compared with the prior art, the present invention has the following remarkable advantages: The present invention provides imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compounds with a brand-new parent nucleus, and a trifluoromethyl group that can significantly improve the activity is introduced into the parent nucleus structure. Through biochemical activity tests, these compounds have good inhibitory activity against TLR7. Therefore, these compounds can provide effective antagonists for the treatment of diseases regulated by TLR7, and thus are expected to develop targeted drugs for treating diseases related to the TLR7 signaling pathway such as systemic lupus erythematosus, psoriasis, rheumatoid arthritis, multiple sclerosis or Sjogren's syndrome. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 For the plasma drug concentration-time curve (C-t) of rats after intravenous injection (2 mg / kg) of Example 44 (YP-1); Figure 2 For the plasma drug concentration-time curve (C-t) of rats after intragastric administration (10 mg / kg) of Example 44 (YP-1). DETAILED DESCRIPTION OF THE INVENTION

[0043] The technical solutions of the present invention will be further described below.

[0044] The materials, reagents, etc. used in the following examples can be obtained from commercial sources without special instructions. The experimental methods without specific conditions noted in the examples are usually carried out under conventional conditions or according to the conditions recommended by the manufacturers.

[0045] The term "alkyl" means a straight-chain or branched-chain saturated hydrocarbon group having the stated number of carbon atoms.

[0046] The term "C 1-3 alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group having 1-3 carbon atoms.

[0047] The term "C 1-6 alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group having 1-6 carbon atoms.

[0048] The term "C 1-3 alkoxy" represents O-C 1-3 alkyl, which refers to an alkyl group having O-C 1-3 alkyl.

[0049] The term "C1-6 "Alkoxy" means OC 1-6 The alkyl group is an alkyl having OC 1-6 of alkyl.

[0050] Abbreviations: PE: petroleum ether, EA: ethyl acetate, DCM: dichloromethane, MEOH: methanol, THF: tetrahydrofuran, IC 50 : half inhibitory concentration; DMSO: dimethyl sulfoxide; DMF: N,N-dimethylformamide; PdCl2(dppf)-CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.

[0051] NMR spectra were obtained using a Bruker Avance 400 MHz.

[0052] Intermediates and final compounds were purified by flash chromatography using the following instruments: i) Biotage Isolera™ Prime Flash Prep LC.

[0053] The sources or syntheses of the intermediate compounds used in each example are as follows: Intermediate A1(Int-A1) 6-Bromo-imidazo[1,2-a]pyridine, CAS No.: 6188-23-4, supplier: Shaoyuan Technology (Shanghai) Co., Ltd., is a light yellow solid.

[0054]

[0055] Intermediate A2 (Int-A2) 2-Bromoimidazo[1,2-a]pyrazine, CAS No.: 912773-24-1, supplier: Shaoyuan Technology (Shanghai) Co., Ltd., is a white solid.

[0056]

[0057] Intermediate A3 (Int-A3) 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.

[0058]

[0059] Intermediate A4 (Int-A4) 6-Bromo-7-methylimidazo[1,2-a]pyridine, CAS No.: 116355-18-1, supplier: Shaoyuan Technology (Shanghai) Co., Ltd., is a white solid.

[0060]

[0061] Intermediate A5 (Int-A5) 6-Bromo-2-methylimidazo[1,2-a]pyrazine, CAS No.: 1159811-97-8, supplier: Shanghai Haohong Biopharmaceutical Technology Co., Ltd., is a white solid.

[0062]

[0063] Intermediate A6 (Int-A6) 6-Bromo-8-methoxyimidazo[1,2-a]pyrazine, CAS No.: 63744-25-2, supplier: Shanghai Haohong Biopharmaceutical Technology Co., Ltd., it is a light yellow solid.

[0064]

[0065] Intermediate A7 (Int-A7) 6-Bromo-8-methoxyimidazo[1,2-a]pyridine, CAS No.: 1427424-35-8, supplier: Shanghai Haohong Biopharmaceutical Technology Co., Ltd., it is a brown solid.

[0066]

[0067] Intermediate A8 (Int-A8) 6-Bromo-8-methoxy-2-methylimidazo[1,2-a]pyridine

[0068] First, 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 Xiensi Biochemical Technology Co., Ltd.) were dissolved in 40 mL of isopropanol, and then 1-bromo-2,2-dimethoxypropane (4142 mg, 30 mmol, CAS No.: 126-38-5, supplier: Shaoyuan Technology (Shanghai) Co., Ltd.) was 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 distilled off under reduced pressure, 100 ml of saturated sodium bicarbonate solution was added to quench, and then 30 mL DCM, extract and separate, retain the aqueous phase, concentrate the aqueous phase under reduced pressure, and elute by silica gel column chromatography (PE / EA=2:1 constant elution) to purify the crude material to obtain 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyridine. The product is a pink solid.

[0069] Intermediate A8-b (Int-A8-b) (8-Methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)boronic acid

[0070] At room temperature, 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyridine (Int-A8) (2410 mg, 10 mmol), bis(pinacolato)diboron (3810 mg, 15.0 mmol, CAS No.: 73183-34-3, Supplier: Shanghai Yuanye Bio-Technology Co., Ltd.), potassium acetate (2940 mg, 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 Xiensi Biochemical Technology Co., Ltd.) was added. The air in the reaction system was displaced with Ar gas three times, and the reactants were heated to reflux at 95 °C under an Ar gas atmosphere and stirred for 12 h. After the reaction mixture was cooled, it was filtered through diatomaceous earth, and 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 obtain (8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)boronic acid as a brownish-black solid.

[0071] Intermediate A9 (Int-A9) 6-Bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine

[0072] First, dissolve 2-amino-5-bromo-3-methoxypyrazine (4080 mg, 20 mmol, CAS No.: 5900-13-0, supplier: Shanghai Yuanye Bio-Technology Co., Ltd.) and pyridinium p-toluenesulfonate (0.52 g, 2.0 mmol, CAS No.: 24057-28-1, supplier: Tianjin Xiensi Biochemical Technology Co., Ltd.) in 60 mL of isopropanol. Then, add 1-bromo-2,2-dimethoxypropane (4142 mg, 30 mmol, CAS No.: 126-38-5, supplier: Shanghai Yuanye Bio-Technology Co., Ltd.) dropwise to the reaction solution. Heat the reaction mixture at 65 °C for 60 hours. Cool the reaction mixture to room temperature and remove the solvent by distillation under reduced pressure. Quench with 100 ml of saturated sodium bicarbonate solution, then extract with 50 ml of DCM three times. Retain the organic phase, concentrate it under reduced pressure, and elute by silica gel column chromatography (constant elution with PE / EA = 3:1) to purify the crude material to obtain 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine. The product is a white solid.

[0073] Intermediate A9-b (Int-A9-b) (8-Methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)boronic acid

[0074] Adopt the preparation method of compound Int-A8-b, and replace Int-A8 with 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine. After cooling the reactants, filter through diatomaceous earth, wash the filter cake with methanol, retain the filtrate, concentrate it under reduced pressure, and elute by silica gel column chromatography (constant elution with DCM / MEOH = 1:2) to purify the crude material to obtain (8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)boronic acid, which is a brown solid.

[0075] Intermediate B1 (Int-B1) 2-Amino-3-(trifluoromethyl)-5-bromopyridine, CAS No.: 79456-34-1, supplier: Shanghai Yuanye Bio-Technology Co., Ltd., which is a white solid.

[0076]

[0077] Intermediate B1-b (Int-B1-b) 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine

[0078] At room temperature, 2-amino-3-(trifluoromethyl)-5-bromopyridine (2410 mg, 10 mmol, CAS No.: 79456-34-1, supplier: Shanghai Yuanye Bio-Technology Co., Ltd.), bis(pinacolato)diboron (3.81 g, 15.0 mmol, CAS No. 73183-34-3, supplier: Shanghai Yuanye Bio-Technology Co., Ltd.), 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 Xiensi Biochemical Technology Co., Ltd.) was added. The air was displaced with Ar gas three times, and the reactants were heated to reflux at 100 °C under an Ar gas atmosphere and stirred for 8 h. After the reactants were cooled, they were filtered through diatomaceous earth, the filtrate was retained, concentrated under reduced pressure, and eluted by silica column chromatography (PE / EA = 5:1 constant elution) to purify the crude material to obtain 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine.

[0079] Intermediate B2 (Int-B2) 1-(5-Bromo-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide

[0080] At room temperature, first 3-piperidinecarboxamide (1922 mg, 15.0 mmol, CAS No.: 4138-26-5, supplier: Shanghai Yuanye Bio-Technology Co., Ltd.) and K2CO3 (4146 mg, 30.0 mmol) were dissolved in 30 ml of DMSO and stirred for 10 min, then 2-chloro-5-bromo-3-(trifluoromethyl)pyridine (2600 mg, 10.0 mmol, CAS No.: 211122-40-6, supplier: Tianjin Xiensi Biochemical Technology Co., Ltd.) was added dropwise to the reaction solution. The reaction mixture was heated at 80 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with 300 ml of water and extracted 3 times with 50 ml of EA. The organic phases were combined and concentrated under reduced pressure to obtain a white solid, which was 1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide.

[0081] Intermediate B2-b (Int-B2-b) 1-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide

[0082] Adopt the preparation method of compound Int-B1-b, replace 2-amino-3-(trifluoromethyl)-5-bromopyridine with 1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide, and elute by silica gel column chromatography (constant elution with PE / EA = 1:2) to obtain 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide, which is a light yellow oil.

[0083] Intermediate B3 (Int-B3) 1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0084] Adopt the preparation method of compound Int-B2, replace 3-piperidinecarboxamide with 4-piperidinecarboxamide (CAS No.: 39546-32-2, supplier: Tianjin Xiensi Biochemical Technology Co., Ltd.) to obtain a light yellow solid.

[0085] Intermediate B3-b (Int-B3-b) 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0086] Adopt the preparation method of compound Int-B1-b, replace 2-amino-3-(trifluoromethyl)-5-bromopyridine with 1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide, and elute by silica gel column chromatography (constant elution with PE / EA = 1:2) to obtain 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide, which is a light yellow solid.

[0087] Intermediate B4 (Int-B4) (S)-2-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)amino)propanamide

[0088] The preparation method of compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with L-alaninamide (CAS No.: 7324-05-2, supplier: Shanghai Aladdin Biochemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure and eluted by silica gel column chromatography (constant elution with PE / EA = 1:1), to obtain (S)-2-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)amino)propanamide, which is a white solid.

[0089] Intermediate B4-b (Int-B4-b) (S)-2-((5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)amino)propanamide

[0090] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-(trifluoromethyl)-5-bromopyridine was replaced with (S)-2-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)amino)propanamide, and eluted by silica gel column chromatography (constant elution with PE / EA = 1:1), to obtain (S)-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)amino)propanamide, which is a light yellow oil.

[0091] Intermediate B5 (Int-B5) 2-((4-((5-Bromo-3-(trifluoromethyl)pyridin-2-yl)amino)pentyl)(ethyl)amino)ethan-1-ol

[0092] 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: Shanghai Yuanye Bio-Technology Co., Ltd.), and the same equivalent of triethylamine was used instead of K2CO3 for the preparation. After extraction with EA, the organic phase was concentrated under reduced pressure and eluted by silica gel column chromatography (constant elution with DCM / MeOH = 15:1), to obtain 2-((4-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)amino)pentyl)(ethyl)amino)ethan-1-ol, which is a colorless transparent liquid.

[0093] Intermediate B6 (Int-B6) 2-(2-(4-(5-Bromo-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethan-1-ol

[0094] The preparation method of compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with 1-[2-(2-hydroxyethoxy)ethyl]piperazine (CAS No.: 13349-82-1, supplier: Tianjin Sine Chemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to obtain 2-(2-(4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethanol, which is a pale yellow viscous liquid.

[0095] Intermediate B6-b (Int-B6-b) 2-(2-(4-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethanol

[0096] 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)ethanol. After elution by silica gel column chromatography (DCM / MEOH = 1:1 constant elution), 2-(2-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethanol was obtained, which is a brown oil.

[0097] Intermediate B7 (Int-B7) (1-(5-Bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol

[0098] The preparation method of compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with 4-hydroxymethylpiperidine (CAS No.: 6457-49-4, supplier: Tianjin Sine Chemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to obtain (1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol, which is a white viscous solid.

[0099] Intermediate B7-b (Int-B7-b) (1-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol

[0100] Adopt the preparation method of compound Int-B1-b, replace 2-amino-3-(trifluoromethyl)-5-bromopyridine with (1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol, and elute by silica gel column chromatography (constant elution with PE / EA = 1:1) to obtain (1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol, which is a brown oil.

[0101] Intermediate B8 (Int-B8) 2-(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol

[0102] Adopt the preparation method of compound Int-B2, replace 3-piperidinecarboxamide with 4-piperidineethanol (CAS No.: 622-26-4, supplier: Shanghai Shaoyuan Technology Co., Ltd.). After extraction with EA, the organic phase is concentrated under reduced pressure to obtain 2-(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol, which is a white solid.

[0103] Intermediate B8-b (Int-B8-b) 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

[0104] Adopt the preparation method of compound Int-B1-b, replace 2-amino-3-(trifluoromethyl)-5-bromopyridine with 2-(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol, and elute by silica gel column chromatography (constant elution with PE / EA = 1:1.5) 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, which is a light yellow oil.

[0105] Intermediate B9 (Int-B9) 2-(4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol

[0106] Adopt the preparation method of compound Int-B2, and replace 3-piperidinecarboxamide with N-hydroxyethylpiperazine (CAS No.: 103-76-4, supplier: Tianjin Siyanshi Biochemical Technology Co., Ltd.). After extraction with EA, the organic phase is concentrated under reduced pressure to obtain 2-(4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol, which is a light yellow liquid.

[0107] Intermediate B9-b (Int-B9-b) 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

[0108] Adopt the preparation method of compound Int-B1-b, and replace 2-amino-3-trifluoromethyl-5-bromopyridine with 2-(4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol. After elution by silica gel column chromatography (DCM / MEOH = 3:1 constant elution), 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 is obtained, which is a brown viscous solid.

[0109] Intermediate B10 (Int-B10) 5-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyridine

[0110] Adopt the preparation method of compound Int-B2, and replace 3-piperidinecarboxamide with 4,4-difluoropiperidine (CAS No.: 21987-29-1, supplier: Tianjin Siyanshi Biochemical Technology Co., Ltd.). After extraction with EA, the organic phase is concentrated under reduced pressure to obtain 5-bromo-2-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyridine, which is a light yellow solid.

[0111] Intermediate B10-b (Int-B10-b) 2-(4,4-Difluoropiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridine

[0112] Adopt the preparation method of compound Int-B1-b, replace 2-amino-3-(trifluoromethyl)-5-bromopyridine with 5-bromo-2-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)pyridine, and elute by silica gel column chromatography (constant elution with PE / EA = 1:1) to obtain 2-(4,4-difluoropiperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridine, which is a colorless oil.

[0113] Intermediate B11 (Int-B11) (R)-(1-(5-Bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)tert-butyl carbamate

[0114] Adopt the preparation method of compound Int-B2, replace 3-piperidinecarboxamide with (R)-3-Boc-aminopiperidine (CAS No.: 216854-23-8, supplier: Tianjin Sine Chemical Technology Co., Ltd.). After extraction with EA, the organic phase is concentrated under reduced pressure to obtain (R)-(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)tert-butyl carbamate, which is a white solid.

[0115] Intermediate B11-b (Int-B11-b) (R)-(1-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)tert-butyl carbamate

[0116] Adopt the preparation method of compound Int-B1-b, replace 2-amino-3-(trifluoromethyl)-5-bromopyridine with (R)-(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)tert-butyl carbamate. And elute by silica gel column chromatography (constant elution with PE / EA = 1.5:1) to obtain (R)-(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)tert-butyl carbamate, which is a brown viscous solid.

[0117] Intermediate B12 (Int-B12) (1-(5-Bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)tert-butyl carbamate

[0118] The preparation method of compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with 4-(N-Boc-amino)piperidine (CAS No.: 73874-95-0, supplier: Shanghai Shaoyuan Chemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to obtain tert-butyl (1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate, which is a yellow liquid.

[0119] Intermediate B12-b (Int-B12-b) tert-butyl (1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0120] 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. After elution by silica gel column chromatography (PE / EA = 2:1 constant elution), tert-butyl (1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)carbamate was obtained, which is a yellow translucent solid.

[0121] Intermediate B13 (Int-B13) tert-butyl (1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0122] The preparation method of compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with 4-(Boc-amino)-4-methylpiperidine (CAS No.: 163271-08-7, supplier: Shanghai Shaoyuan Chemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to obtain tert-butyl (1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate, which is a yellow oily liquid.

[0123] Intermediate B13-b (Int-B13-b) 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

[0124] The preparation method using 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. After elution by silica gel column chromatography (constant elution with PE / EA = 3:1), 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)methyl)carbamate was obtained as a colorless liquid.

[0125] Intermediate B14 (Int-B14) tert-Butyl ((1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)carbamate

[0126] The preparation method using compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with 4-(tert-butoxycarbonylamino)piperidine (CAS No.: 73874-95-0, supplier: Tianjin Xiensi Biochemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to obtain tert-butyl ((1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)carbamate as a colorless oily liquid.

[0127] Intermediate B14-b (Int-B14-b) 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

[0128] The preparation method using 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. After elution by silica gel column chromatography (constant elution with PE / EA = 1:1), 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 was obtained as a light yellow oil.

[0129] Intermediate B15 (Int-B15) tert-Butyl 4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate

[0130] The preparation method of compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with 1-(tert-butoxycarbonyl)piperazine (CAS No.: 57260-71-6, supplier: Tianjin Sine Chemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to obtain tert-butyl 4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate, which was a light pink viscous solid.

[0131] Intermediate B15-b (Int-B15-b) tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate

[0132] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced with tert-butyl 4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate. After elution by silica gel column chromatography (PE / EA = 1.5:1 constant elution), tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate was obtained, which was a light yellow oil.

[0133] Intermediate B16 (Int-B16) (1R,4R)-tert-butyl 5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0134] The preparation method of compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with (1R,4R)-2-Boc-2,5-diazabicyclo[2.2.1]heptane (CAS No.: 134003-84-2, supplier: Shoyuan Technology (Shanghai) Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to obtain (1R,4R)-tert-butyl 5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, which was a colorless transparent oil.

[0135] Intermediate B16-b (Int-B16-b) (1R,4R)-tert-butyl 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

[0136] Adopt the preparation method of compound Int-B1-b, and replace 2-amino-3-(trifluoromethyl)-5-bromopyridine with tert-butyl (1R,4R)-5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. And elute by silica gel column chromatography (PE / EA = 5:1 constant elution) to obtain 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, which is a colorless transparent oil.

[0137] Intermediate B17 (Int-B17) tert-Butyl 4-((4-bromo-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate

[0138] At room temperature, first dissolve 1-BOC-piperidine-4-carboxamide (3424 mg, 15.0 mmol, CAS No.: 91419-48-6, supplier: Shanghai Shaoyuan Technology Co., Ltd.) and Cs2CO3 (9774 mg, 30.0 mmol) in 30 ml of DMSO and stir for 20 min. Then add 5-bromo-2-fluorobenzotrifluoride (2430 mg, 10.0 mmol, CAS No.: 393-37-3, supplier: Tianjin Xiensi Biochemical Technology Co., Ltd.) to the reaction solution, and heat the reaction mixture under reflux at 95 °C for 16 hours. Cool the reaction mixture to room temperature, dilute it with 300 ml of water and extract it 3 times with 50 ml of EA. Combine the organic phases and concentrate under reduced pressure to obtain a light pink solid, which is tert-butyl 4-((4-bromo-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate.

[0139] Intermediate B17-b (Int-B17-b) tert-Butyl 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)carbamoyl)piperidine-1-carboxylate

[0140] 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)amino)carbonyl)piperidine-1-carboxylate. After elution by silica gel column chromatography (constant elution with DCM / MeOH = 5:1), tert-butyl 4-(((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)amino)carbonyl)piperidine-1-carboxylate was obtained as a white solid.

[0141] Intermediate B18 (Int-B18) tert-butyl 3-(((4-bromo-2-(trifluoromethyl)phenyl)amino)carbonyl)piperidine-1-carboxylate

[0142] The preparation method of compound Int-B17 was adopted, and 1-BOC-piperidine-4-carboxamide was replaced with 1-Boc-3-aminocarbonylpiperidine. The reaction mixture was cooled to room temperature, diluted with 300 ml of water and extracted 3 times with 50 ml of EA. The organic phases were combined and concentrated under reduced pressure to obtain a pale yellow solid, which was tert-butyl 3-(((4-bromo-2-(trifluoromethyl)phenyl)amino)carbonyl)piperidine-1-carboxylate.

[0143] Intermediate B18-b (Int-B18-b) tert-butyl 3-(((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)amino)carbonyl)piperidine-1-carboxylate

[0144] 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)amino)carbonyl)piperidine-1-carboxylate. After elution by silica gel column chromatography (constant elution with DCM / MeOH = 4:1), tert-butyl 3-(((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)amino)carbonyl)piperidine-1-carboxylate was obtained as a light gray solid.

[0145] Intermediate B19 (Int-B19) (S)-tert-butyl (1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate

[0146] The preparation method of compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with (S)-3-Boc-aminopiperidine (CAS No.: 309956-78-3, supplier: Tianjin Sine Chemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to obtain tert-butyl (S)-(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate, which is a white solid.

[0147] Intermediate B19-b (Int-B19-b) (S)-(1-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate

[0148] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-trifluoromethyl-5-bromopyridine was replaced with tert-butyl (S)-(1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate. After elution by silica gel column chromatography (PE / EA = 1.5:1 constant elution), tert-butyl (S)-(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate was obtained, which is a brown viscous solid.

[0149] Intermediate B20 (Int-B20) (3aR,6aR)-5-(5-Bromo-3-(trifluoromethyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

[0150] The preparation method of compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with cis-2-Boc-hexahydropyrrolo[3,4-c]pyrrole (CAS No.: 250275-15-1, supplier: Shanghai Aladdin Biochemical Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to obtain (3aR,6aR)-5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester, which is a white solid.

[0151] Intermediate B20-b (Int-B20-b)

[0152] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-(trifluoromethyl)-5-bromopyridine was replaced with tert-butyl (3aR,6aR)-5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. After elution by silica gel column chromatography (constant elution with PE / EA = 1:1), tert-butyl (3aR,6aR)-5-(5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was obtained as a pale yellow oil.

[0153] Intermediate B21 (Int-B21) (1S,4S)-tert-butyl 5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0154] The preparation method of compound Int-B2 was adopted, and 3-piperidinecarboxamide was replaced with (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane (CAS No.: 113451-59-5, supplier: Shanghai Shaoyuan Technology Co., Ltd.). After extraction with EA, the organic phase was concentrated under reduced pressure to obtain (1S,4S)-tert-butyl 5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as a colorless transparent oil.

[0155] Intermediate B21-b (Int-B21-b) (1S,4S)-tert-butyl 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

[0156] The preparation method of compound Int-B1-b was adopted, and 2-amino-3-(trifluoromethyl)-5-bromopyridine was replaced with (1S,4S)-tert-butyl 5-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. After elution by silica gel column chromatography (constant elution with PE / EA = 5:1), (1S,4S)-tert-butyl 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 was obtained as a colorless transparent oil.

[0157] Intermediate B22 (Int-B22) tert-Butyl 3-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0158] Using the preparation method of compound Int-B2, and replacing 3-piperidinecarboxamide with 8-BOC-3,8-diazabicyclo[3.2.1]octane (CAS No.: 149771-44-8, supplier: Shanghai Shaoyuan Technology 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, which is a white semi-transparent liquid.

[0159] Intermediate B22-b (Int-B22-b) 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

[0160] Using the preparation method of compound Int-B1-b, and replacing 2-amino-3-trifluoromethyl-5-bromopyridine with tert-Butyl 3-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, and eluting by silica gel column chromatography (PE / EA = 5:1 constant elution), to obtain 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, which is a colorless transparent oil.

[0161] Example 1

[0162] 5-(8-Methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-amine

[0163] 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: Shanghai Shaoyuan Technology Co., Ltd.) were successively added to the reaction vessel. 10 ml of 1,4-dioxane was added as a solvent, and 1.5 ml of ultrapure water was added. The air was displaced three times with Ar gas, and the mixture was heated to reflux at 92 °C under an Ar gas atmosphere and stirred for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, 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 (constant elution with PE / EA = 1:3) to obtain I-1 (Compound 1), namely 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.

[0164] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0165] Example 2

[0166] 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide

[0167] Using the preparation method of Example 1, replace Int-B1-b with Int-B2-b and Int-A8 with Int-A9. Elute by silica gel column chromatography (constant elution with PE / EA = 1.5:1) to obtain I-2 (Compound 2), namely 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), which is an off-white solid.

[0168] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0169] Example 3

[0170] 1-(5-(Imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0171] Using the preparation method of Example 1, replace Int-B1-b with Int-B3-b and Int-A8 with Int-A1. Elute by silica gel column chromatography (DCM / MEOH = 20:1 constant elution) to obtain I-3 (Compound 3), namely 1-(5-(imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (258 mg, 66.3% yield), which is a white solid.

[0172] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0173] Example 4

[0174] 1-(5-(5,6,7,8-Tetrahydroimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0175] Add 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: Shanghai Shaoyuan Technology Co., Ltd.), and 6 mmol of ammonium formate (381 mg) into the reaction vessel. Add 2.5 ml of anhydrous MEOH and 2.5 ml of anhydrous THF as solvents, and stir the reactants at room temperature for 18 h. After the reaction is completed, filter by suction using diatomaceous earth, quench the palladium on carbon, collect the filtrate, concentrate it under reduced pressure, and elute it by silica gel column chromatography (DCM / MEOH = 15:1 constant elution) to obtain I-4 (Compound 4), namely 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), which is a white solid.

[0176] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0177] Example 5

[0178] 1-(5-(8-Methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-amine

[0179] Using the preparation method of Example 1, replace Int-B1-b with Int-B12-b and Int-A8 with Int-A9. Elute by silica gel column chromatography (PE / EA = 3:1) to obtain 5a, namely 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), which is a yellowish-white viscous solid.

[0180] Add 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) to the reaction flask, then add 6 ml of hydrochloric acid ethyl acetate solution, stir at room temperature for 12 h, concentrate the reactants under reduced pressure, dissolve the obtained dry crude product in 10 ml of purified water, and add an appropriate amount of saturated sodium bicarbonate solution to adjust the pH to 8.0. Concentrate the aqueous phase to complete dryness under reduced pressure. Elute by silica gel column chromatography (PE / EA = 1:5 constant elution) to obtain I-5 (Compound 5), namely 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), which is a white solid.

[0181] 1 H NMR (400 MHz, DMSO- d 6) δ 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).

[0182] Example 6

[0183] 1-(5-(8-Methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0184] Using the preparation method of Example 1, replace Int-B1-b with Int-B3-b. Elute by silica gel column chromatography (constant elution with PE / EA = 1:1) to obtain I-6 (Compound 6), namely 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), which is a white solid.

[0185] 1 H NMR (400 MHz, Chloroform- d ) δ 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, 4.3 Hz, 1H), 2.05 (s, 3H), 2.00 (dd, J = 13.2, 3.8 Hz, 2H), 1.98 – 1.88 (m, 2H).

[0186] Example 7

[0187] 1-(5-(8-Methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0188] Using the preparation method of Example 1, and replacing Int-B1-b with Int-B3-b and Int-A8 with Int-A9. Eluting by silica gel column chromatography (PE / EA = 2:1 constant elution), I-7 (Compound 7) was obtained, namely 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), which is a white solid.

[0189] 1 H NMR (400 MHz, DMSO- d 6) δ 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).

[0190] Example 8

[0191] (S)-2-((5-(8-Methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)amino)propanamide

[0192] Using the preparation method of Example 1 and replacing Int-B1-b with Int-B4-b. Elution by silica gel column chromatography (PE / EA = 2:1 constant elution) gave I-8 (Compound 8), namely (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), which was a yellow solid.

[0193] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0194] Example 9

[0195] 1-(5-(8-Methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide

[0196] Using the preparation method of Example 1 and replacing Int-B1-b with Int-B2-b. Elution by silica gel column chromatography (PE / EA = 1:2 constant elution) gave I-9 (Compound 9), namely 1-(5-(8-Methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide (261 mg, 60% yield), which was a white solid.

[0197] 1 H NMR (400 MHz, Chloroform- d ) δ 8.63 (d, J J = 2.4 Hz, 1H), 8.02 (d, J J = 2.5 Hz, 1H), 7.84 (d, J J = 1.5 Hz, 1H), 7.37 (d, J J = 1.0 Hz, 1H), 6.58 (s,1H), 6.53 (d, J J = 1.5 Hz, 1H), 5.63 (s, 1H), 4.07 (s, 3H), 3.68 (d, J J = 3.6Hz, 1H), 3.38 (dd, J J = 12.9, 7.3 Hz, 1H), 3.35 – 3.28 (m, 1H), 3.19 (dd, J J =8.6, 3.3 Hz, 1H), 2.69 (dd, J J = 6.8, 3.6 Hz, 1H), 2.47 (d, J J = 0.9 Hz, 3H),1.98 – 1.90 (m, 1H), 1.90 – 1.83 (m, 1H), 1.78 – 1.68 (m, 1H).

[0198] Example 10

[0199] 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

[0200] 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 K2CO3 (552.8 mg) and 0.1 mmol of tetrakis(triphenylphosphine)palladium (115.6 mg, CAS No.: 14221-01-3, Supplier: Shanghai Shaoyuan Technology Co., Ltd.) were added to a reaction flask. 12 ml of 1,4-dioxane was added as a solvent, and 1.5 ml of purified water was added. The air was displaced with Ar gas three times, and the mixture was heated to 105 °C and stirred for 24 hours under an Ar gas atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was rinsed with a large amount of methanol. The filtrate was retained, concentrated under reduced pressure, and eluted by silica gel column chromatography (first eluted with 5 column volumes of pure EA constantly, and then eluted with DCM:MEOH = 5:1 constantly) to obtain I-10 (Compound 10), namely 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 was a colorless oil.

[0201] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0202] Example 11

[0203] 2-(ethyl(4-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)amino)pentyl)amino)ethanol

[0204] Using the preparation method of Example 10 and replacing Int-A8-b with Int-A9-b. Elution was carried out by silica gel column chromatography (first eluting with 5 column volumes of pure EA constantly, and then eluting with DCM:MEOH = 6:1 constantly), to obtain I-11 (Compound 11), namely 2-(ethyl(4-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)amino)pentyl)amino)ethanol (355 mg, 73.9% yield), which is a brown oil.

[0205] 1 H NMR (400 MHz, Chloroform- d ) δ 8.82 (d, J J = 2.2 Hz, 1H), 8.19 (d, J J = 2.3 Hz, 1H), 7.96 (s, 1H), 7.41 (d, J J = 0.9 Hz, 1H), 4.77 (d, J J = 7.8 Hz,1H), 4.40 (t, J J = 6.5 Hz, 1H), 4.22 (s, 3H), 3.56 (t, J 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 J = 6.5 Hz, 4H), 1.24 (d, J J = 6.4 Hz, 1H), 1.02 (t, J J = 7.1 Hz, 4H).

[0206] Example 12

[0207] 1-(5-(imidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0208] The preparation method of Example 1 was adopted, and Int-B1-b was replaced by Int-B3-b, and Int-A8 was replaced by Int-A2. Elution was carried out by silica gel column chromatography (constant elution with PE / EA = 1:2), and I-12 (Compound 12), that is, 1-(5-(imidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (266 mg, 68.2% yield), was obtained as a white solid.

[0209] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0210] Example 13

[0211] 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

[0212] The preparation method of Example 1 was adopted, and Int-B1-b was replaced by Int-B6-b, and Int-A8 was replaced by Int-A9. Elution was carried out by silica gel column chromatography (constant elution with PE / EA = 1:2), and I-13 (Compound 13), that is, 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 (371 mg, 77.3% yield), was obtained as a pale yellow translucent solid.

[0213] 11H NMR (400 MHz, Chloroform- d ) δ 8.94 (d, J J = 2.3 Hz, 1H), 8.37 (d, J J = 2.4 Hz, 1H), 8.04 (s, 1H), 7.44 (d, J J = 1.0 Hz, 1H), 4.29 (s, 1H), 4.23 (s,3H), 3.76 – 3.72 (m, 4H), 3.66 (dd, J J = 5.5, 3.1 Hz, 2H), 3.48 (t, J J = 4.8Hz, 4H), 2.74 – 2.70 (m, 4H), 2.68 (t, 2H), 2.50 (s, 3H).

[0214] Example 14

[0215] Hydrochloride of 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-amine

[0216] Using the preparation method of Example 1 and replacing Int-B1-b with Int-B13-b. Elution by silica gel column chromatography (PE / EA = 2:1) gave 14a, namely tert-butyl (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (405 mg, 78.2% yield), which was a pale yellow oil.

[0217] 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 a reaction flask, and then 3 ml of hydrochloric acid ethyl acetate solution was added. Stir at room temperature for 12 h. After the reaction was completed, the reactants were concentrated under reduced pressure. Then, 10 ml of DCM was added twice and 10 ml of PE was added twice, and each time it was concentrated under reduced pressure until completely dry. Finally, solid powder precipitated uniformly to obtain I-14 (Compound 14), namely hydrochloride of 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-amine (182 mg, 80.6% yield), which was a white solid.

[0218] 1 H NMR (400 MHz, DMSO- d 6) δ 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).

[0219] Example 15

[0220] Hydrochloride of 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-amine

[0221] The preparation method of Example 1 was adopted, and Int-B1-b was replaced by Int-B13-b, and Int-A8 was replaced by Int-A9. Elution was carried out by silica gel column chromatography (PE / EA = 2.5:1) to obtain 15a, namely tert-butyl (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate (432 mg, 83.1% yield), which was a colorless viscous oil.

[0222] The preparation method of Example 14 was adopted, and 14a was replaced by 15a to obtain Compound I-15 (Compound 15), namely hydrochloride of 1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-amine (202 mg, 88.6% yield), which was a white solid.

[0223] 1 H NMR (400 MHz, Chloroform-d) δ 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).

[0224] Example 16

[0225] (1-(5-(8-Methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol

[0226] The preparation method of Example 1 was adopted, and Int-B1-b was replaced by Int-B7-b. Elution was carried out by silica gel column chromatography (constant elution with PE / EA = 1:1.5) to obtain I-16 (Compound 16), namely (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), which was a pale yellow solid.

[0227] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0228] Example 17

[0229] 1-(5-(2-Methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0230] Using the preparation method of Example 1, and replacing Int-B1-b with Int-B3-b and Int-A8 with Int-A5. Elution by silica gel column chromatography (constant elution with PE / EA = 1:2) gave I-17 (Compound 17), namely 1-(5-(2-Methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (291 mg, 72.0% yield), which was a pale yellow solid.

[0231] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0232] Example 18

[0233] 1-(5-(8-Methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0234] Using the preparation method of Example 1, and replacing Int-B1-b with Int-B3-b and Int-A8 with Int-A3. Eluting by silica gel column chromatography (constant elution with PE / EA = 1:1), I-18 (Compound 18), namely 1-(5-(8-Methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (291 mg, 72.0% yield), was obtained as a pale yellow solid.

[0235] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0236] Example 19

[0237] 1-(5-(8-Methoxyimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0238] Using the preparation method of Example 1, and replacing Int-B1-b with Int-B3-b and Int-A8 with Int-A7. Eluting by silica gel column chromatography (constant elution with PE / EA = 1:2), I-19 (Compound 19), namely 1-(5-(8-Methoxyimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (319 mg, 76.1% yield), was obtained as a white-yellow solid.

[0239] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0240] Example 20

[0241] 5-(8-Methoxyimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-amine

[0242] The preparation method of Example 1 was adopted, and Int-A8 was replaced by Int-A7. Through elution by silica gel column chromatography (constant elution with PE / EA = 1.5:1), I-20 (Compound 20) was obtained, namely 5-(8-methoxyimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-amine (215 mg, 69.8% yield), which is a yellow solid.

[0243] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0244] Example 21

[0245] 6-(6-(4,4-Difluoropiperidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine

[0246] The preparation method of Example 1 was adopted, and Int-B1-b was replaced by Int-B10-b, and Int-A8 was replaced by Int-A9. Through elution by silica gel column chromatography (constant elution with PE / EA = 5:1), I-21 (Compound 21) was obtained, namely 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), which is a light pink solid.

[0247] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0248] Example 22

[0249] (1-(5-(8-Methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol

[0250] Using the preparation method of Example 1, and replacing Int-B1-b with Int-B7-b and Int-A8 with Int-A9. Elution by silica gel column chromatography (PE / EA = 3:1 constant elution) gave I-22 (Compound 22), namely (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), which was a white solid.

[0251] 1 H NMR (400 MHz, Chloroform- d ) δ 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, 2.3 Hz, 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).

[0252] Example 23

[0253] (1-(5-(Imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol

[0254] Using the preparation method of Example 1, and replacing Int-B1-b with Int-B7-b and Int-A8 with Int-A1. Elution was carried out by silica gel column chromatography (constant elution with pure EA) to obtain I-23 (Compound 23), namely (1-(5-(Imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanol (218 mg, 57.9% yield), which is a gray solid.

[0255] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0256] Example 24

[0257] 2-(1-(5-(8-Methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol

[0258] 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. Elution was carried out by silica gel column chromatography (constant elution with PE / EA = 1:1), and I-24 (Compound 24), that is, 2-(1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol (369 mg, 84.7% yield), was obtained as a white solid.

[0259] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0260] Example 25

[0261] 1-(5-(8-Methoxyimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0262] 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-A6. Elution was carried out by silica gel column chromatography (constant elution with PE / EA = 1:1), and I-25 (Compound 25), that is, 1-(5-(8-methoxyimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (331 mg, 78.9% yield), was obtained as a white solid.

[0263] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0264] Example 26

[0265] 1-(5-(7-Methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0266] Using the preparation method of Example 1, and replacing Int-B1-b with Int-B3-b and Int-A8 with Int-A4. Eluting by silica gel column chromatography (constant elution with PE / EA = 2:1), I-26 (Compound 26), namely 1-(5-(7-Methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (264 mg, 65.5% yield), was obtained as a white solid.

[0267] 1 H NMR (400 MHz, Chloroform- d ) δ 8.41 (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).

[0268] Example 27

[0269] Hydrochloride of 6-(6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine

[0270] Using the preparation method of Example 1, and replacing Int-B1-b with Int-B16-b and Int-A8 with Int-A9. Eluting by silica gel column chromatography (PE / EA = 4:1 constant elution), compound 27a, namely tert-butyl (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-carboxylate (392 mg, 77.8% yield), was obtained as a pale yellow oil.

[0271] Using the preparation method of Example 14, and replacing 14a with 27a, I-27 (compound 27), namely hydrochloride of 6-(6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine (138 mg, 61.4% yield), was obtained as a yellowish-white solid.

[0272] 1H NMR (400 MHz, DMSO-d6) δ9.92 (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).

[0273] Example 28

[0274] Hydrochloride of N-(4-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxamide

[0275] Add 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 1M sodium carbonate solution to the reaction vessel. Add 9 mL of DMF as the solvent. Replace the air with Ar gas three times, and under an Ar gas atmosphere, heat the mixture to reflux at 95 °C and stir for 10 hours. After the reaction is completed, cool the reactant to room temperature, filter it through diatomaceous earth, and wash the filter cake with EA and methanol. Retain the filtrate, concentrate it under reduced pressure, and elute it by silica gel column chromatography (constant elution with PE / EA = 1:2) to obtain Compound 28a, namely 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.

[0276] Using the preparation method of Example 14 and replacing 14a with 28a, I-28 (Compound 28), namely hydrochloride of N-(4-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxamide (196 mg, 83.7% yield), was obtained as a white solid.

[0277] 1 H NMR (400 MHz, DMSO- d 6) δ 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).

[0278] Example 29

[0279] Hydrochloride of 8-methoxy-2-methyl-6-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridine

[0280] Using the preparation method of Example 1 and replacing Int-B1-b with Int-B15-b. By eluting with silica gel column chromatography (PE / EA = 1.5:1 constant elution), Compound 29a, namely 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), was obtained as a colorless oil.

[0281] Using the preparation method of Example 14 and replacing 14a with 29a. I-29 (Compound 29), namely hydrochloride of 8-methoxy-2-methyl-6-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridine (172 mg, 80.5% yield), was obtained as a dark yellow solid.

[0282] 1 H NMR (400 MHz, DMSO- d 6) δ 9.05 (d, J J = 2.4 Hz, 1H), 8.99 (d, J J = 2.4Hz, 1H), 8.53 (dd, J J = 21.3, 2.5 Hz, 1H), 8.11 (d, J J = 10.8 Hz, 1H), 7.81 (d, J J = 5.7 Hz, 1H), 4.20 (d, J J = 2.0 Hz, 3H), 3.52 (d, J J = 15.4 Hz, 4H), 3.28(d, J J = 4.8 Hz, 2H), 3.22 (s, 2H), 1.91 (d, J J = 1.0 Hz, 3H).

[0283] Example 30

[0284] Hydrochloride of N-(4-(imidazo[1,2-a]pyrazin-6-yl)-2-(trifluoromethyl)phenyl)piperidine-3-carboxamide

[0285] Using the preparation method of Example 28, and replacing Int-A8 with Int-A2 and Int-B17-b with Int-B18-b, compound 30a, namely 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.

[0286] Using the preparation method of Example 14, and replacing 14a with 30a. I-30 (compound 30), namely hydrochloride of N-(4-(imidazo[1,2-a]pyrazin-6-yl)-2-(trifluoromethyl)phenyl)piperidine-3-carboxamide (191 mg, 89.9% yield), was obtained as a white solid.

[0287] 1 H NMR (400 MHz, DMSO- d 6) δ 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).

[0288] Example 31

[0289] (1-(5-(8-Methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methanamine hydrochloride

[0290] Using the preparation method of Example 1, and replacing Int-B1-b with Int-B14-b and Int-A8 with Int-A9. Elution by silica gel column chromatography (PE / EA = 2:1 constant elution) gave compound 31a, namely tert-butyl (1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)carbamate (425 mg, 81.6% yield), which was a pale yellow solid.

[0291] Using the preparation method of Example 14, and replacing 14a with 31a, gave compound I-31 (compound 31), namely (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), which was a white solid.

[0292] 1 H NMR (400 MHz, DMSO- d 6) δ9.29 (s, 1H), 9.14 (d, J J = 2.3 Hz, 1H),8.56 (d, J J = 2.3 Hz, 1H), 8.27 (s, 1H), 8.16 – 8.13 (m, 1H), 4.25 (s, 3H),3.76 (d, J J = 12.9 Hz, 2H), 2.97 (t, J J = 12.3 Hz, 2H), 2.74 (t, J J = 6.0 Hz,2H), 2.50 (s, 3H), 1.92 – 1.84 (m, 3H), 1.38 – 1.27 (m, 2H).

[0293] Example 32

[0294] Hydrochloride of N-(4-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxamide

[0295] Using the preparation method of Example 28 and replacing Int-A8 with Int-A9, compound 32a, namely tert-butyl 4-(((4-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-2-(trifluoromethyl)phenyl)amino)carbonyl)piperidine-1-carboxylate (408 mg, 76.5% yield), was obtained as a white translucent solid.

[0296] Using the preparation method of Example 14 and replacing 14a with 32a, I-32 (compound 32), namely hydrochloride of N-(4-(imidazo[1,2-a]pyrazin-6-yl)-2-(trifluoromethyl)phenyl)piperidine-3-carboxamide (201 mg, 85.7% yield), was obtained as a white solid.

[0297] 1 H NMR (400 MHz, DMSO- d 6) δ 9.88 (s, 1H), 9.20 (s, 2H), 8.86 (d, J 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).

[0298] Example 33

[0299] Hydrochloride of 6-(6-(Piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridine

[0300] Using the preparation method of Example 1, and replacing Int-A8 with Int-A1 and Int-B1-b with Int-B15-b. Elution by silica gel column chromatography (constant elution with PE / EA = 1:2) gave 33a, namely tert-butyl 4-(5-(imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (313 mg, 70.0% yield), which was a white translucent solid.

[0301] Using the preparation method of Example 14, and replacing 14a with 33a, I-33 (Compound 33) was obtained, namely hydrochloride of 6-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridine (166 mg, 86.7% yield), which was a white solid.

[0302] 1 H NMR (400 MHz, DMSO- d 6) δ 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).

[0303] Example 34

[0304] 8-Methoxy-2-methyl-6-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyrazine

[0305] Using the preparation method of Example 1, and replacing Int-A8 with Int-A9 and Int-B1-b with Int-B15-b. Eluting by silica gel column chromatography (constant elution with PE / EA = 1:1), compound 34a, namely 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), was obtained as a white oil.

[0306] Using the preparation method of Example 5, and replacing 5a with 34a, I-34 (compound 34), namely 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.

[0307] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0308] Example 35

[0309] 2-Methyl-6-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyrazine

[0310] The preparation method of Example 1 was adopted, and Int-A8 was replaced by Int-A5, and Int-B1-b was replaced by Int-B15-b. Elution was carried out by silica gel column chromatography (constant elution with PE / EA = 1.5:1), and 35a, that is, 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), was obtained as a white solid.

[0311] The preparation method of Example 5 was adopted, and 5a was replaced by 35a to obtain I-35 (Compound 35), that is, 2-methyl-6-(6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyrazine (129 mg, 71.3% yield), as a white solid.

[0312] 1 H NMR (400 MHz, DMSO- d 6) δ 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).

[0313] Example 36

[0314] 2-(1-(5-(Imidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol

[0315] The preparation method of Example 1 was adopted, and Int-A8 was replaced by Int-A1, and Int-B1-b was replaced by Int-B8-b. Elution was carried out by silica gel column chromatography (DCM / MEOH = 15:1 constant elution), and I-36 (Compound 36), that is, 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), was obtained as a white solid.

[0316] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0317] Example 37

[0318] 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

[0319] The preparation method of Example 4 was adopted, and Compound 3 was replaced with Compound 36. Through elution by silica gel column chromatography (DCM / MEOH = 9:1 constant elution), Compound I-37, namely 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), was obtained as a white solid.

[0320] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0321] Example 38

[0322] 2-(4-(5-(8-Methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol

[0323] Using the preparation method of Example 1, and replacing Int-A8 with Int-A9 and Int-B1-b with Int-B9-b. Eluting by silica gel column chromatography (constant elution with pure EA), compound I-38 (compound 38), namely 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), was obtained as a white solid.

[0324] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0325] Example 39

[0326] Hydrochloride of 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyridine

[0327] The preparation method of Example 1 was adopted, and Int-B1-b was replaced by Int-B21-b. Through silica gel column chromatography elution (PE / EA = 2:1 constant elution), 39a was obtained, namely tert-butyl (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-carboxylate (389 mg, 77.3% yield), which was a colorless transparent oil.

[0328] The preparation method of Example 14 was adopted, and 14a was replaced by 39a to obtain Compound I-39 (Compound 39), namely the hydrochloride of 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyridine (179 mg, 88.8% yield), which was a white solid.

[0329] 1 H NMR (400 MHz, DMSO- d 6) δ 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).

[0330] Example 40

[0331] (R)-1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-amine hydrochloride

[0332] 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. Elution was carried out by silica gel column chromatography (constant elution with PE / EA = 3:1), and compound 40a, namely tert-butyl (R)-(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), was obtained as a colorless transparent oil.

[0333] The preparation method of Example 14 was adopted, and 14a was replaced with 40a to obtain Compound I-40 (Compound 40), namely hydrochloride of (R)-1-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-amine (188 mg, 85.1% yield), which was a yellowish-white solid.

[0334] 1 H NMR (400 MHz, DMSO- d 6) δ 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).

[0335] Example 41

[0336] 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

[0337] Using the preparation method of Example 1, and replacing Int-B1-b with Int-B20-b and Int-A8 with Int-A9. Elution by silica gel column chromatography (PE / EA = 3:1 constant elution) gave Compound 41a, namely tert-butyl (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)-carboxylate (353 mg, 72.9% yield), which was a white solid.

[0338] Using the preparation method of Example 14, and replacing 14a with 41a. I-41 (Compound 41) was obtained, namely 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 (192 mg, 89.1% yield), which was a white solid.

[0339] 1 H NMR (400 MHz, DMSO- d 6) δ 9.80 (d, J J = 20.2 Hz, 2H), 9.24 (s, 1H),9.07 (d, J J = 2.2 Hz, 1H), 8.53 (d, J J = 2.3 Hz, 1H), 8.15 (d, J J = 1.2 Hz, 1H),4.26 (s, 3H), 3.82 (dd, J J = 11.5, 6.1 Hz, 2H), 3.65 (dd, J J = 11.6, 3.2 Hz,2H), 3.49 – 3.38 (m, 2H), 3.13 – 3.08 (m, 2H), 3.05 (dd, J J = 11.2, 5.6 Hz,2H), 2.50 (s, 2H).

[0340] Example 42

[0341] (R)-1-(5-(8-Methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-amine hydrochloride

[0342] Using the preparation method of Example 1 and replacing Int-B1-b with Int-B11-b. Elution by silica gel column chromatography (PE / EA = 3:1 constant elution) gave compound 42a, namely tert-butyl (R)-(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), which was a yellow oil.

[0343] Using the preparation method of Example 14 and replacing 14a with 42a gave I-42 (compound 42), namely (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), which was a yellowish-white solid.

[0344] 1 H NMR (400 MHz, DMSO- d 6) δ 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).

[0345] Example 43

[0346] (S)-1-(5-(8-Methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-amine hydrochloride

[0347] Using the preparation method of Example 1, and replacing Int-B1-b with Int-B19-b and Int-A8 with Int-A9. Elution by silica gel column chromatography (PE / EA = 5:1 constant elution) gave compound 43a, namely tert-butyl (S)-(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), which was a yellow oil.

[0348] Using the preparation method of Example 14, and replacing 14a with 43a, gave compound I-43 (compound 43), namely (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), which was a yellowish-white solid.

[0349] 1 H NMR (400 MHz, DMSO- d 6) δ 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).

[0350] Example 44

[0351] Hydrochloride of 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine

[0352] Using the preparation method of Example 1, and replacing Int-B1-b with Int-B21-b and Int-A8 with Int-A9. Eluting by silica gel column chromatography (PE / EA = 1.5:1 constant elution), compound 44a was obtained, namely tert-butyl (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-carboxylate (353 mg, 69.4% yield), which is a yellow oil.

[0353] Using the preparation method of Example 14, and replacing 14a with 44a, compound I-44 (compound 44) was obtained, namely hydrochloride of 6-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine (152 mg, 67.1% yield), which is a white solid.

[0354] 1 H NMR (400 MHz, DMSO- d 6) δ 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).

[0355] Example 45

[0356] Hydrochloride of 6-(6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine

[0357] Using the preparation method of Example 1, and replacing Int-B1-b with Int-B22-b and Int-A8 with Int-A9. Eluting by silica gel column chromatography (PE / EA = 3:1 constant elution), compound 45a was obtained, namely tert-butyl 3-(5-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-3-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (393 mg, 77.8% yield), which is a yellow oil.

[0358] Using the preparation method of Example 14, and replacing 14a with 45a, I-45 (compound 45) was obtained, namely hydrochloride of 6-(6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-methoxy-2-methylimidazo[1,2-a]pyrazine (171 mg, 70.1% yield), which is a white solid.

[0359] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0360] Example 46

[0361] 1-(5-(8-cyanoquinolin-5-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide

[0362] The preparation method of Example 1 was adopted, and Int-B1-b was replaced by Int-B3-b, and Int-A8 was replaced by 5-bromoquinoline-8-carbonitrile (CAS: 507476-70-2, supplier: Shanghai Shaoyuan Technology Co., Ltd.). Through silica gel column chromatography elution (constant elution with PE / EA = 1.5:1), I-46 (Compound 46), that is, 1-(5-(8-cyanoquinolin-5-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (325 mg, 75.1% yield) was obtained, which is a white solid.

[0363] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0364] Example 47

[0365] 1-(5-(8-cyanoquinolin-5-yl)pyridin-2-yl)piperidine-4-carboxamide

[0366] The detailed synthesis steps of Compound 47 and intermediates Int-1 and Int-2 are as follows:

[0367] At room temperature, first dissolve 4-piperidinecarboxamide (CAS No.: 39546-32-2, 1922 mg, 15.0 mmol, supplier: Tianjin Xiensi Biochemical Technology Co., Ltd.) and K2CO3 (5528 mg, 40.0 mmol) in 30 ml of DMSO and stir for 10 min. Then, add 2-fluoro-5-bromopyridine (1760 mg, 10.0 mmol, CAS No.: 766-11-0, supplier: Tianjin Xiensi Biochemical Technology Co., Ltd.) dropwise into the reaction solution. Reflux the reaction mixture at 85 °C for 8 hours. Cool the reaction mixture to room temperature, dilute it with 300 ml of water and extract it 3 times with 50 ml of EA. Combine the organic phases, concentrate under reduced pressure to obtain a white solid, which is Int-1, namely 1-(5-bromopyridin-2-yl)piperidine-4-carboxamide (2660 mg, 93.9% yield).

[0368] At room temperature, dissolve Int-1 (1415 mg, 5 mmol), bis(pinacolato)diboron (1523 mg, 6 mmol, CAS No. 73183-34-3, supplier: Shanghai Shaoyuan Science and Technology Co., Ltd.), potassium acetate (1470 mg, 15.0 mmol) in 1,4-dioxane (15 mL), and add PdCl2(dppf)-CH2Cl2 adduct (408 mg, 0.5 mmol, CAS No.: 95464-05-4, supplier: Tianjin Xiensi Biochemical Technology Co., Ltd.). Replace the air with Ar gas three times, heat the reactants to 105 °C under an Ar gas atmosphere, and stir the reaction for 16 h. After cooling the reactants, filter them through diatomaceous earth, retain the filtrate, concentrate under reduced pressure, and elute by silica gel column chromatography (constant elution with pure EA) to purify the crude material to obtain Int-2, namely 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidine-4-carboxamide (1270 mg, 76.7% yield).

[0369] Adopt the preparation method of Example 1, and replace Int-B1-b with Int-2 and Int-A8 with 5-bromoquinoline-8-carbonitrile (CAS: 507476-70-2, supplier: Shanghai Shaoyuan Science and Technology Co., Ltd.). Elute by silica gel column chromatography (constant elution with DCM / MEOH = 15:1) to obtain I-47 (Compound 47), namely 1-(5-(8-cyanoquinolin-5-yl)-3-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxamide (39 mg, 11% yield), which is an off-white solid.

[0370] 1 H NMR (400 MHz, Chloroform-d ) δ 9.05 (dd, J J = 4.2, 1.6 Hz, 1H), 8.30(dd, J J = 8.6, 1.7 Hz, 1H), 8.22 (d, J J = 2.4 Hz, 1H), 8.10 (d, J J = 7.5 Hz,1H), 7.54 (dd, J 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 J = 13.5 Hz, 2H), 2.99 (t, J J = 12.6 Hz, 2H),2.48 – 2.37 (m, 1H), 1.96 (d, J J = 13.3 Hz, 2H), 1.85 – 1.70 (m, 2H).

[0371] Example 48

[0372] The inhibitory effect of the compound of formula (I) on TLR7 consists of two experiments, including: evaluating the activation of TLR7 signaling by detecting the level of secreted embryonic alkaline phosphatase (SEAP) in HEK-Blue TM -hTLR7 cells; detecting the viability levels of HEK-Blue TM -hTLR7 cells in the blank group and the dosing groups (administered with different concentrations of the compound of formula (I)) by CCK-8. According to the ratio of the CCK-8 experimental results of the dosing groups to the blank group, the change in SEAP level caused by cell proliferation / death is corrected to obtain a more accurate TLR7 inhibitory effect of each compound. The IC 50 curves of each compound are fitted using GraphPad Prism and the IC 50 values are calculated.

[0373] Stable HEK-Blue TMThe -hTLR7 cell line was purchased from (InvivoGen, San Diego, CA, USA). Among them, 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 the IFN-β minimal promoter fused with 5 NF-κB and AP-1 binding sites, and the activation of NF-κB will lead to the expression of SEAP. The activity of SEAP can be conveniently measured with the alkaline phosphatase detection reagent - QUANTI-Blue. HEK-Blue TM The -hTLR7 cell line serves as a reporter cell for detecting TLR7 activity. When stimulated by a ligand (R848), the TLR7-NF-κB signaling pathway is activated, causing NF-κB to enter the nucleus and bind to the SEAP reporter gene to initiate transcription, ultimately producing SEAP and secreting it outside the cell. Since the treatment with different compounds can have different effects on TLR7 activity and the amount of SEAP produced also varies, the content of SEAP can be evaluated using the alkaline phosphatase detection reagent QUANTI-Blue-TM and converted into the inhibitory effect of each compound on TLR7 activity.

[0374] Determination of secreted embryonic alkaline phosphatase: Preparation of HEK-Blue cell medium: 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.

[0375] Preparation of HEK-Blue cell detection medium: Inactivate FBS in a 56 °C water bath for 30 min, then supplement the DMEM medium with inactivated FBS at a concentration of 10%, and supplement 50 U / mL penicillin, 50 mg / mL streptomycin, 100 mg / mL Zeocin (solution), 10 μg / mL Blasticidin (solution), and 2 mM L-glutamine.

[0376] The specific steps are as follows: Seed the HEK-Blue TM -hTLR7 cells into a 96-well plate, with 3.5×10 cells seeded in each well 4Cells were cultured in a cell incubator preset at 37 °C and containing 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). The cell culture supernatant was collected for testing at different time points; QUANTI-Blue TM working solution was prepared by mixing 1 ml of QB reagent and 1 ml of QB buffer, adding 98 ml of sterile water, and mixing well. After incubating at room temperature for 10 min, 20 μL of cell supernatant and 180 μL of QUANTI-Blue TM working solution were added to each well of a 96-well plate, and then incubated in the incubator at 37 °C for 30 min. The OD value was read at a wavelength of 620 - 655 nm using an enzyme-linked immunosorbent assay (ELISA) reader, and the SEAP secretion level and TLR7 signal activation were evaluated based on the change in OD value.

[0377] Cell viability assay (CCK8): 100 μl of cell suspension was added to each well of a 96-well plate; different concentrations of specific drugs were added and incubated in the incubator at 37 °C for 24 h. The CCK8 detection reagent (10% of the culture volume was added to each well) was added to the 96-well plate and incubated in the 37 °C incubator for 1 h again; the OD value was measured at a wavelength of 450 nm using an ELISA reader.

[0378] The inhibitory activity (IC 50 value) of the compound of formula (I) against human TLR7 was divided into five ranges: "A1", "A2", "B", "C", and "D". Among them, "A1" represents the IC 50 value of the compound < 10 nM; "A2" represents the IC 50 value of the compound between 10 nM and 100 nM; "B" represents the IC 50 value of the compound between 100 nM and 300 nM; "C" represents the IC 50 value of the compound between 300 nM and 1 μM; "D" represents the IC 50 value of the compound > 1 μM. Table 3 shows the activity range of the compounds of the present invention in the HEK-Blue TM -hTLR7 cell assay.

[0379] Table 3 Inhibitory activity of the compounds prepared in each example of the present invention against HTLR7

[0380] Note: 46 and 47 are the synthesized compounds for comparison, and Enpatoran (M5049) and HCQ (hydroxychloroquine) are the positive drugs.

[0381] Among compounds 1 - 45, the activities of compounds 14, 32, and 44 are all less than 1 nM, showing excellent inhibitory effects.

[0382] Example 49 The pharmacokinetic properties of the preferred compound YP - 1, which is compound 44, were evaluated through a single - dose PK study in male Sprague - Dawley (SD) rats.

[0383] Six male SD rats were divided into two groups of three rats each. Compound YP - 1 (Example 44) was administered by intravenous injection at 2 mg / kg and by gavage at 10 mg / kg, respectively. Whole blood (150 μL) was collected from the ophthalmic venous plexus of the rats at 0 min, 2 min (only for intravenous injection), 5 min, 10 min, 20 min, 30 min, 60 min, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after dosing into tubes containing sodium heparin. The blood samples were centrifuged at 8000 rpm for 5 min at 4 °C to separate plasma. After centrifugation, the obtained plasma was transferred to a clean tube and stored at - 20 °C for further analysis. When used, it was thawed naturally at room temperature before use. Meanwhile, an LC - MS / MS method was established to determine the concentration of compound YP - 1 in rat plasma. The plasma drug concentration - time curve was plotted using Graphpad Prism software, and the pharmacokinetic parameters were calculated using WinNonlin software.

[0384] The pharmacokinetic study of YP - 1 (compound 44) in SD rats, the data are shown in Tables 4, 5, and 6.

[0385] Results: After intravenous injection of Example 44 (2 mg / kg), C C₀ was approximately 176.90 ± 26.46 ng / mL, the in - vivo exposure ( AUC 0-t ) was approximately 326.84 ± 50.67 h·ng / mL, AUC 0-∞ AUC₀ - ∞ was approximately 343.04 ± 39.81 h·ng / mL, the half - life ( t 1 / 2 ) was approximately 4.22 ± 0.50 h, the clearance rate ( CL ) was approximately 5.88 ± 0.68 L / h / kg, and the volume of distribution ( V ) was approximately 35.53 ± 2.46 L / kg. As Figure 1As shown, after intravenous injection of Compound 44, it showed an obvious distribution phase in rats. Considering its apparent volume of distribution value, it is suggested that the compound may have a relatively wide tissue distribution; other pharmacokinetic parameters obtained by fitting showed that the half-life ( t 1 / 2 ) of Compound 44 was approximately 4.22 ± 0.50 h, and the clearance rate ( CL ) was approximately 5.88 ± 0.68 L / h / kg, indicating good metabolic behavior of the compound in rats after intravenous injection.

[0386] After intragastric administration of Example 44 (10 mg / kg), the maximum plasma concentration ( C max ) was approximately 155.67 ± 34.02 ng / mL, the time to reach the peak plasma concentration ( T max ) was approximately 5.33 ± 1.15 h, and the in vivo exposure ( AUC 0-t ) was approximately 1895.39 ± 375.55 h·ng / mL, AUC 0-∞ approximately 1925.23 ± 385.68 h·ng / mL, and the bioavailability ( F ) was 115.98%. As Figure 2 shown, after intragastric administration, the absorption rate of 44 was slow, but the absorption extent was high, indicating a high in vivo exposure of the compound in rats after intragastric administration.

[0387] Table 4 Plasma concentration of Example 44 in rats after intravenous injection (2 mg / kg) (n = 3)

[0388] Table 5 Plasma concentration of Example 44 in rats after intragastric administration (10 mg / kg) (n = 3)

[0389] Table 6 Key pharmacokinetic parameters of Example 44 in rats after administration (n = 3)

[0390] Note: -- means meaningless here.

[0391] Based on the above results, it can be seen that after intravenous injection of Example 44, it was rapidly and widely distributed in rats; after intragastric administration, the absorption rate of Example 44 was slow and the bioavailability was high.

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: ； Among them, The dotted line represents a single bond or a double bond; 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, where R4 is an alkyl group of C 1-6 ; 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 amino: and wherein Z is CH or N, and R5 is C 1-5 alcohol hydroxyl group.

2. The imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein When the dotted line is a double bond, X is CH, N or CR4, Y is N or CH, R1 is H or C 1-3 alkyl, R2 is H, C 1-3 alkyl or C 1-3 alkoxy; when the dotted line is a single bond, X is CH2, Y is N, R1 is H, R2 is H; and when R2 is H and the dotted line is a double bond, 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 dashed line represents 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 dashed line is 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 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: 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 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), and the acid used for salting includes inorganic acids or organic acids. The inorganic acids include any one of hydrochloric acid, sulfuric acid, phosphoric acid or methanesulfonic acid; the organic acids include 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, di-gluconic 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 its pharmaceutically acceptable salt 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 its pharmaceutically acceptable salt according to any one of claims 1-5 in the preparation of a TLR7 antagonist.

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

8. The use according to claim 7, wherein The TLR7-mediated diseases are autoimmune diseases or chronic inflammatory diseases, and the autoimmune diseases or chronic inflammatory diseases include systemic lupus erythematosus, psoriasis, rheumatoid arthritis, multiple sclerosis or Sjogren's syndrome.

9. A pharmaceutical composition for preventing or treating TLR7-mediated diseases, characterized in that, Comprising the imidazo[1,2-a]pyrazine or imidazo[1,2-a]pyridine compound or its pharmaceutically acceptable salt according to any one of claims 1-5, tautomers and stereoisomers, metabolites, metabolic precursors, solvate compounds or prodrugs, and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, wherein The pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository or patch.

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