Nitrogen heterocyclic compounds and uses thereof

Abstract

The present invention provides nitrogen heterocyclic compounds and uses thereof. Specifically, the present invention provides a new compound that effectively inhibits ATX, which is a compound represented by the following formula, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by the following formula:

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to nitrogen-containing heterocyclic compounds. More specifically, the present invention relates to nitrogen-containing heterocyclic compounds and their use in preparing medicines. Background Art

[0002] Autotaxin (ATX) is a secreted glycoprotein with phosphodiesterase (PDE) activity. It is a member of the extracellular pyrophosphatase / phosphodiesterase (ENPP) family and is therefore also known as ENPP2. ATX also possesses lysophospholipase D (LysoPLD) activity, hydrolyzing lysophosphatidylcholine (LPC) to the biologically active lysophosphatidic acid (LPA). LPA is an intracellular lipid mediator that influences many biological and biochemical processes.

[0003] Studies have shown that under pathological conditions, inhibition of ATX can reduce LPA levels, thereby providing therapeutic benefits for unmet clinical needs, including cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrosis, thrombosis, cholestatic pruritus, or fibrotic diseases induced, mediated and / or propagated by elevated LPA levels and / or ATX activation.

[0004] Upregulation of the ATX-LPA signaling pathway has been observed in various inflammatory conditions. For example, the proinflammatory effects of LPA include mast cell degranulation, smooth muscle cell contraction, and cytokine release from dendritic cells. As a manifestation of its general role in inflammation, upregulation of the ATX-LPA signaling pathway has been observed in the mouse carrageenan air pouch model (a model used for the development of anti-inflammatory drugs, including cyclooxygenase inhibitors for arthritis). Furthermore, reductions in plasma and air pouch LPA have been observed in the rat carrageenan air pouch model using an ATX inhibitor, confirming the role of ATX as a major source of LPA during inflammation. As another general role in inflammatory diseases, a "synergistic effect" has been demonstrated between LPA and lymphocyte migratory chemokines. High ATX expression is found in sites of chronic inflammation. Intravenous administration of enzymatically inactivated ATX has been shown to inhibit T cell homing to lymphoid tissues, likely by competing with endogenous ATX and exerting a dominant-negative effect. In some cases, ATX facilitates the entry of lymphocytes into lymphoid organs. Thus, ATX inhibitors could block lymphocyte migration into secondary lymphoid organs and be beneficial in autoimmune diseases.

[0005] In rheumatoid arthritis, it was demonstrated that ATX expression is increased in synovial fibroblasts from patients with rheumatoid arthritis (RA), and that ablation of ATX expression in interstitial cells (including synovial fibroblasts) leads to attenuated symptoms in a mouse model of rheumatoid arthritis. Thus, the role of autotaxin in rheumatoid arthritis has been well established.

[0006] LPA can also upregulate pain-related proteins through one of its cognate receptors, LPA1. Targeted inhibition of ATX-mediated LPA biosynthesis may provide a mechanism for preventing neuropathic pain caused by nerve injury, such as pain associated with osteoarthritis. Autotaxin inhibitors have been observed to reduce LPA and PGE2 and also alleviate inflammatory pain. Other studies suggest that targeted inhibition of ATX-mediated LPA biosynthesis may be a novel mechanism for preventing neuropathic pain caused by nerve injury.

[0007] After inflammation subsides and tissue damage is repaired, the tissue usually returns to its original state. When no longer needed, excessive, uncontrolled tissue repair can lead to a situation commonly known as fibrosis. Fibrosis is characterized by excessive deposition of extracellular matrix components and excessive growth of fibroblasts. Fibrosis can occur in all tissues, but is particularly prevalent in organs that are often subject to chemical and biological damage, including the lungs, skin, digestive tract, kidneys and liver. Fibrosis often seriously impairs the normal function of organs.

[0008] Under certain circumstances, LPA stimulates hepatic stellate cell proliferation while inhibiting DNA synthesis in hepatocytes. LPA levels and serum ATX activity are elevated in patients with chronic hepatitis C. In the blood of rabbits with varying degrees of liver injury, plasma LPA concentrations and serum ATX activity were relatively high in carbon tetrachloride-induced liver fibrosis. Plasma LPA concentrations and serum ATX activity increased with the severity of different liver injuries.

[0009] Pulmonary fibrosis is a terminal disease characterized by fibroblast proliferation, accumulation of extracellular matrix, inflammatory damage, and structural destruction. This is the result of abnormal repair of damaged alveolar tissue, leading to structural abnormalities (scarring). When lungs are damaged by various factors, the interstitial tissue secretes collagen to repair them. However, if this repair is excessive, resulting in excessive fibroblast proliferation and accumulation of extracellular matrix, pulmonary fibrosis can develop.

[0010] LPA signals specifically through the LPA1 receptor to exert profibrotic effects on epithelial cells, endothelial cells, and fibroblasts: genetic deletion of this receptor reduces epithelial cell apoptosis, vascular leakage, and fibroblast accumulation in a lung fibrosis model.

[0011] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia of unknown etiology, characterized by diffuse alveolitis and alveolar architectural disorganization. Imaging and histopathology primarily present as conventional interstitial pneumonia. As the disease progresses, it causes fibrosis in the lung tissue, resulting in thickening and hardening, leading to permanent scarring or a honeycomb-like appearance, often referred to as "honeycomb lung" or "loofah lung." This chronic, progressive condition leads to irreversible and persistent decline in lung function. With a median survival of only 2.8 years after diagnosis, 50% of patients with IPF have been dubbed a "tumor-like disease." Existing drug treatments are plagued by numerous adverse reactions and poor efficacy. Non-drug treatments primarily rely on lung transplantation, but organ transplantation is expensive, resource-limited, and carries significant clinical risks.

[0012] There is evidence that fibroblast proliferation and contraction and extracellular matrix secretion stimulated by LPA promote fibrosis in other airway diseases, such as peribronchiolar fibrosis present in chronic bronchitis and interstitial lung disease and severe asthma. LPA plays a role in fibrotic interstitial lung disease and bronchiolitis obliterans, in which collagen and myofibroblasts are increased. Studies related to IPF (idiopathic pulmonary fibrosis) have shown that LPA levels are increased in the bronchoalveolar lavage fluid of patients. Further LPA1 knockout and inhibitor studies have revealed the key role of LPA in the fibrotic process in the lungs and are supplemented by studies using cell-specific knockout mice lacking ATX in bronchial epithelial cells and macrophages. These mice have been shown to be less sensitive to models of pulmonary fibrosis. The role of LPA in other fibrotic diseases (kidney and skin) is based on similar types of observations. The role of LPA in lung remodeling is related to the effects of LPA on both lung fibroblasts (via LPA1) and epithelial cells (via LPA2), with LPA2 being shown to play a key role in TGFβ activation in epithelial cells in fibrotic conditions. The role of LPA in remodeling and fibrosis is relevant to COPD, IPF, and asthma, diseases where lung remodeling, as a long-term consequence, limits lung function. Finally, in the context of lung disease, ATX is one of three major quantitative trait loci that appear to be associated with differences in lung function in mice.

[0013] Studies have found elevated levels of LPA in the plasma and ascites of patients with ovarian cancer in both the early and late stages. Elevated LPA levels and altered LPA receptor expression and response may contribute to the onset, progression, or outcome of ovarian cancer. LPA has also been linked to prostate, breast, melanoma, head and neck, intestinal, brain, and thyroid cancers. LPA participates in tumor cell proliferation and invasion of adjacent tissues, leading to metastasis. These biological and pathobiological processes are initiated by LPA activation of G protein-coupled receptors. Inhibiting enzymes involved in LPA biosynthesis, such as ATX, can reduce LPA levels and thus treat cancer patients.

[0014] During angiogenesis, ATX, along with other angiogenic factors, contributes to the formation of blood vessels. Angiogenesis provides nutrients to tumors during their growth. Therefore, inhibiting angiogenesis is an important starting point for cancer and tumor treatment.

[0015] Patent application WO2014202458A1 discloses the role of ATX-LPA signaling in different pathophysiological conditions, such as proliferative diseases, neuropathic pain, inflammation, autoimmune diseases, fibrosis, lymphocyte tracking in lymph nodes, obesity, diabetes or embryonic angiogenesis.

[0016] At present, certain progress has been made in the treatment of cancer, fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders and / or abnormal angiogenesis-related diseases, but there are still shortcomings. Currently available IPF treatment drugs include pirfenidone and nintedanib. Pirfenidone can cause liver damage (such as liver failure, jaundice), hypersensitivity reactions (such as facial swelling, laryngeal edema, dyspnea, wheezing, etc.), and severe gastrointestinal reactions. Photogenotoxicity tests have shown that it may cause chromosomal structural abnormalities and may cause skin cancer after light exposure. Nintedanib has adverse reactions such as diarrhea, nausea, and abdominal pain. The incidence of gastrointestinal reactions is as high as 50%. Common adverse reactions include weight loss, loss of appetite, liver damage, bleeding, etc. Among patients treated with pirfenidone and nintedanib, the rates of drug discontinuation due to serious adverse events were 20.9% and 26.3%, respectively. The quality of life of IPF patients can be severely impacted, and neither pirfenidone nor nintedanib has been shown to improve this quality of life in clinical trials. While both drugs may improve overall outcomes, they can only slow the disease progression but not reverse pulmonary fibrosis. Therefore, patients with severe idiopathic pulmonary fibrosis may not benefit. GLPG-1690, currently a rapidly developing drug for the treatment of IPF, has shown promise in reversing the disease, but suffers from low enzyme activity, high clinical dosage, and poor medication compliance. Therefore, current therapies are unsatisfactory, and a significant number of patients remain in need of new, more active, and effective treatments that can significantly slow or even reverse the disease progression, improve medication compliance, and benefit more patients with idiopathic pulmonary fibrosis.

[0017] In view of this, the present invention designs compounds represented by formulas (I) to (IV) based on the existing technology to provide ATX inhibitors with novel structures, better pharmacokinetic properties, better efficacy, and strong drugability, which are used to effectively treat ATX-related diseases and conditions, including but not limited to cancer, metabolic diseases, kidney diseases, liver diseases, fibrotic diseases, interstitial lung diseases, pulmonary fibrosis, liver fibrosis, proliferative diseases, inflammatory diseases, pain, pain related to osteoarthritis, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders and / or products related to abnormal angiogenesis. Summary of the Invention

[0018] The present invention aims to solve one of the above technical problems to at least some extent or at least provide a useful commercial choice.

[0019] According to one aspect of the present invention, the present invention provides a compound, which is a compound represented by formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I):

[0020]

[0021] Among them, R 1 Selected from hydrogen, halogen, cyano, -OH, -SH, -NO2, unsubstituted or optionally substituted with one or more R a Substituted with the following groups: C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3-10 membered heterocyclic oxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl; C6-C 10 Aryloxy, 5-10 membered heteroaryloxy;

[0022] X and Y are the same or different and are independently selected from -N=, -C(R 4 )=;

[0023] Z is selected from -O-, -S-, -C(R 5 )(R 5 )-、-N(R 7 )-、-N(R 7 )-C(R 5 )(R 6 )-;

[0024] L 1 Selected from -O-, unsubstituted or optionally substituted with one or more R b Substituted C1-C3 alkylene, unsubstituted or optionally substituted with one or more R c Substituted C1-C3 alkyleneoxy;

[0025] Every R a 、R b 、R c The same or different, independently selected from -F, -Cl, -Br, -I, -OH, -CN, =O, -NO2, -NH2, C1-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 Alkenyl, C2-C 10 Alkenyloxy, C2-C 10 Alkynyl, C2-C 10 Alkynyloxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C6-C 20 Aryl, C6-C20 Aryloxy, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy;

[0026] L 2 Selected from -C(R 11 )(R 12 )-or single key;

[0027] Q is selected from C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0028] Every R 2 The same or different, independently selected from hydrogen, halogen, cyano, -OH, -SH, -NO2, unsubstituted or optionally substituted with one or more R c Substituted with the following groups: C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3-10 membered heterocyclyloxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl; C6-C 10 Aryloxy, 5-10 membered heteroaryloxy; preferably, R 3 Selected from -H, -F, -Cl, methyl, ethyl, methoxy, difluoromethoxy;

[0029] m is selected from the integers 0, 1, 2, 3, 4, 5 or 6;

[0030] n 1 、n 2 、n 3 are independently selected from the integers 0, 1, 2 or 3;

[0031] M 1 、M 2 、M 3 、M 4 、M 5 Independently selected from -N=, -N(R 9 )-、-CH=、-C(R 10 )=, where M 1 、M 2 、M 3 、M 4 、M 5 At least one of -N= or -N(R 9 )-, and M 1 、M 2 、M3 、M 4 、M 5 At least one of them is selected from -CH= or -C(R 10 )=; Preferably, M1, M2, M3 are all selected from -N= or -N(R 9 )-,M 4 、M 5 are all selected from -CH= or -C(R 10 )=;

[0032] R 4 、R 5 、R 6 、R 10 、R 11 、R 12 independently selected from hydrogen, halogen, cyano, -OH, -SH, -NO2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3-10 membered heterocyclyloxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl; C6-C 10 Aryloxy, 5-10 membered heteroaryloxy;

[0033] R 7 、R 9 independently selected from hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0034] Furthermore, the compound of formula (I), or the tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs of the compound represented by formula (I) do not include the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0035]

[0036] In some embodiments of the present invention, Z in the compound of formula (I) is selected from -N(R 7 )-or-N(R 7 )-C(R 5 )(R 6 )-, and the remaining variables are as defined in the present invention.

[0037] In some embodiments of the present invention, L in the compound of formula (I)1 The remaining variables are as defined in the present invention.

[0038] In some embodiments of the present invention, Q in the compound of formula (I) is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, 2,3-dihydro-1H-indenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl, and the remaining variables are as defined herein.

[0039] In some embodiments of the present invention, M1, M2, and M3 in the compound of formula (I) are all selected from -N= or -N(R 9 )-,M 4 、M 5 are all selected from -CH= or -C(R 10 )=, and the remaining variables are as defined in the present invention.

[0040] According to an exemplary embodiment of the present invention, the compound represented by formula (I) may further preferably be a compound represented by the following formula (II):

[0041]

[0042] in:

[0043] Q is selected from phenyl, indenyl, 2,3-dihydro-1H-indenyl;

[0044] X and Y are the same or different and are independently selected from -N=, -C(R 4 )=;

[0045] Z is selected from -O-, -S-, -NH-, -NH-CH2-;

[0046] R 1 Selected from hydrogen, fluorine, chlorine, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy;

[0047] R 2 Selected from -H, -F, difluoromethoxy;

[0048] R 4 Independently selected from hydrogen, fluorine, chlorine, methyl, ethyl;

[0049] L 1 Selected from -O-, -CH2-; L 2 is selected from -CH2-, -CH(CH3)- or a single bond;

[0050] n 1 is selected from the integers 0, 1, 2 or 3;

[0051] n 2 、n 3 are independently selected from the integers 1 or 2;

[0052] M 1 、M 2 、M 3 Independently selected from -N=, -N(R 9 )-, where R 9 Selected from hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0053] The compounds do not include the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0054]

[0055] In some embodiments of the present invention, R in formula (II) 1 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, cyclopropyloxy, and the remaining variables are as defined herein.

[0056] In some embodiments of the present invention, R in formula (II) 1 is selected from hydrogen, methyl, and ethyl, and the remaining variables are as defined in the present invention.

[0057] In some embodiments of the present invention, Selected from The remaining variables are as defined in the present invention.

[0058] In some embodiments of the present invention, Selected from The remaining variables are as defined in the present invention.

[0059] In some embodiments of the present invention, Selected from The remaining variables are as defined in the present invention.

[0060] In some embodiments of the present invention, M in formula (II) 1 、M 2 、M 3 are all selected from -N= or -NH-, and the remaining variables are as defined in the present invention.

[0061] In some embodiments of the present invention, for The remaining variables are as defined in the present invention.

[0062] In some embodiments of the present invention, Selected from The remaining variables are as defined in the present invention.

[0063] According to another aspect of the present invention, the present invention provides a compound, which is a compound represented by formula (III), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (III):

[0064]

[0065] in:

[0066] R 1 、R 2 、R 3 independently selected from hydrogen, halogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C1-C 10 alkoxy;

[0067] X and Y are independently selected from -N-, -C(R 4 )=;Z, L are independently selected from -O-, -S-, -C(R 5 )(R 6 )-、-N(R 7 )-;

[0068] Q is selected from C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C7-C 11 Bicyclic, C 11 -C 15 three-membered ring group;

[0069] n, m are independently selected from integers 0, 1, 2, 3, 4, 5 or 6;

[0070] M 1 、M 2 、M 3 、M 4 、M 5 Independently selected from -N=, -N(R 8 )-、-C(R 9 )(R 10 )-, where M 1 、M 2 、M 3 、M 4 、M 5 At least one of -N= or -N(R 8 )-, and M 1 、M2 、M 3 、M 4 、M 5 At least one of them is selected from -C(R 9 )(R 10 )-;

[0071] R 4 、R 5 、R 6 、R 9 、R 10 independently selected from hydrogen, halogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C3-C 10 cycloalkoxy;

[0072] R 7 、R 8 independently selected from hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl.

[0073] In some embodiments of the present invention, Q in formula (III) is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, 2,3-dihydro-1H-indenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl, and the remaining variables are as defined herein.

[0074] According to an exemplary embodiment of the present invention, the compound represented by formula (IV) may further preferably be a compound represented by the following formula (IV):

[0075]

[0076] where R 1 、R 2 The same or different, independently selected from hydrogen, fluorine, chlorine, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy;

[0077] X and Y are the same or different and are independently selected from -N=, -C(R 4 )=;R 4 Independently selected from hydrogen, fluorine, chlorine, methyl, ethyl;

[0078] L is selected from -NH-, -O-, -S-, preferably, L is -NH-;

[0079] n is selected from the integer 0, 1, 2, 3, 4, 5 or 6;

[0080] M 1 、M 2 、M 3 are all selected from -N= or -N(R 8 )-;

[0081] R 8 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; preferably, R 8 is selected from hydrogen, methyl, ethyl; more preferably, for

[0082] In some embodiments of the present invention, R in formula (IV) 1 、R 2 independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, and cyclopropyloxy, and the remaining variables are as defined herein.

[0083] In some embodiments of the present invention, R in formula (IV) 1 、R 2 are independently selected from hydrogen, methyl, and ethyl, and the remaining variables are as defined herein.

[0084] In some embodiments of the present invention, Selected from The remaining variables are as defined in the present invention.

[0085] According to an embodiment of the present invention, the compound of the present invention comprises a compound represented by the following formula, or at least one of a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by the following formula:

[0086]

[0087]

[0088] The compounds of the present invention may exist in tautomerism. The present invention includes all tautomeric forms of the compounds, whether in equilibrium or one form predominates, the present invention includes each tautomeric form.

[0089] According to another aspect of the present invention, the present invention provides a pharmaceutical composition containing a therapeutically effective dose of at least one compound of Formula (I) to Formula (IV) of the present invention or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate or prodrug thereof.

[0090] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0091] According to another aspect of the present invention, the present invention provides the use of compounds represented by Formula (I) to Formula (IV), pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates or prodrugs thereof, or pharmaceutical compositions containing compounds represented by Formula (I) to Formula (IV) or pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates or prodrugs thereof in the preparation of drugs for treating ATX-related diseases.

[0092] In some embodiments of the present invention, the ATX-related disease is selected from cancer, metabolic disease, kidney disease, liver disease, fibrotic disease, interstitial lung disease, proliferative disease, inflammatory disease, pain, autoimmune disease, respiratory disease, cardiovascular disease, neurodegenerative disease, dermatological disorder and / or disease associated with abnormal angiogenesis.

[0093] In some embodiments of the present invention, the ATX-related disease is selected from pulmonary fibrosis, interstitial lung disease, liver fibrosis, and renal fibrosis, preferably, idiopathic pulmonary fibrosis. According to embodiments of the present invention, the compounds of the present invention have significant advantages in treating pulmonary fibrosis, particularly idiopathic pulmonary fibrosis.

[0094] In some embodiments of the present invention, the ATX-related disease is selected from metabolic diseases, preferably, type II diabetes and non-alcoholic steatohepatitis. According to embodiments of the present invention, the compounds of the present invention have significant advantages in treating metabolic diseases, particularly type II diabetes and non-alcoholic steatohepatitis.

[0095] In some embodiments of the present invention, the ATX-related disease is selected from neuropathic pain, inflammatory pain, and preferably, osteoarthritis-related pain. According to embodiments of the present invention, the compounds of the present invention have significant advantages in treating osteoarthritis-related pain.

[0096] In some embodiments of the present invention, the ATX-related disease is selected from cancer. According to embodiments of the present invention, the compounds of the present invention have significant advantages in treating cancer.

[0097] Definitions and Explanations of Terms

[0098] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0099] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by persons skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. If multiple definitions of a term are used herein, the definitions in this section shall prevail.

[0100] Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / Vis spectroscopy and pharmacological methods, are used. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, as well as in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purification can be carried out in accordance with methods well known in the art or the description of this application. The above-mentioned techniques and methods can generally be implemented according to conventional methods well known in the art, based on the descriptions in the multiple general and more specific literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2.

[0101] When the numerical ranges described in the specification and claims of this application are understood as “integers”, they should be understood as recording the two endpoints of the range and each integer within the range. For example, “an integer from 1 to 6” should be understood as recording each integer of 0, 1, 2, 3, 4, 5, and 6. When the numerical range is understood as a “number”, it should be understood as recording the two endpoints of the range and each integer within the range and each decimal within the range. For example, “a number from 1 to 10” should be understood as recording not only each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9, respectively.

[0102] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0103] The term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable non-toxic acids or bases, including salts of inorganic acids and bases, and organic acids and bases.

[0104] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts that may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or that may be useful in the identification, characterization, or purification of the compounds of the present invention.

[0105] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformers. The stereochemical definitions and conventions used herein are generally those of SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0106] According to the selection of raw materials and methods, the compounds of the present invention can exist in the form of one of possible isomers or their mixture, for example as pure optical isomers, or as isomer mixtures, such as as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing a compound with optical activity, prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, where (-) or L represent that the compound is left-handed. Compounds prefixed with (+) or D are dextrorotatory. With respect to a given chemical structure, except that these stereoisomers are mirror images of each other, these stereoisomers are identical. Specific stereoisomers may also be referred to as enantiomers, and the mixture of the isomers is commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of alkenes, C=N double bonds, etc. can also exist in the compounds described herein, and all such stable isomers are contemplated by the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in either the cis- or trans- configuration.

[0107] When bonds to chiral carbon atoms in formulae of the present invention are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formulae. The diagrammatic representations of racemates and enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0108] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. Resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active, salified organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure α-methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. The resolution of the racemic mixture can also be performed by eluting on a column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) can be used. The selection of the specific method, elution conditions, and chromatographic column can be selected by those skilled in the art based on the structure of the compound and test results. Furthermore, any enantiomer or diastereomer of the compounds described in the present invention can also be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.

[0109] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0110] In embodiments of the present invention, protons can occupy two or more positions in the cyclic form of the heterocyclic ring system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically fixed to one form by appropriate substitution. For example:

[0111]

[0112] Due to resonance, the hydrogen of the nitrogen on triazole can be on any of the three nitrogens, so the naming will be different, but these three forms actually represent the same compound.

[0113] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0114] With respect to a drug or pharmacologically active agent, the terms "effective dose," "effective amount," or "therapeutically effective amount" refer to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0115] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0116] The term "solvate" refers to a compound of the present invention or a salt thereof including a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate.

[0117] The term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl group or an amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or a free amino group, respectively.

[0118] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0119] The term "C1-C 10 “Alkyl” is understood as meaning a linear or branched, saturated, monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Such alkyl radicals are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-methylpentyl, 4-methylpentyl ... In some embodiments, the present invention relates to a group having 1, 2, 3, 4, 5 or 6 carbon atoms ("C1-C6 alkyl"), for example, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or tert-butyl. In some embodiments, the present invention relates to a group having 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), for example, methyl, ethyl, n-propyl or isopropyl.

[0120] The term "C3-C 10 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms, including fused or bridged polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon ring such as a decalin ring.

[0121] The term "3-10 membered heterocyclyl" is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 3 to 10 atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from N, O and S, and which may be attached via carbon or nitrogen, unless otherwise indicated, wherein -CH 2-The group is optionally replaced by -C(O)-; and wherein, unless otherwise indicated to the contrary, the ring nitrogen atom or the ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or the ring nitrogen atom is optionally quaternized; wherein the -NH in the ring is optionally substituted by acetyl, formyl, methyl or methylsulfonyl; and the ring is optionally substituted by one or more halogens. It should be understood that when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclic group is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclic group is monocyclic, it must not be aromatic. Examples of heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one, and 2,5-dioxoimidazolidinyl.

[0122] The term "C2-C 10"Alkenyl" is understood to mean a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., C2-C6 alkenyl), having 2 or 3 carbon atoms (i.e., C2-C3 alkenyl). It is understood that in the case where the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z) -2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl yl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z )-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0123] The term "C2-C 10The term "alkynyl" is understood to mean a straight or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, 2, 3, 4, 5 or 6 carbon atoms (i.e., "C2-C6 alkynyl"), 2 or 3 carbon atoms ("C2-C3 alkynyl"). Such alkynyl groups are, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl, or prop-2-ynyl.

[0124] The term "C1-C 10 "Alkoxy" is understood to mean -O-(C1-C 10 alkyl), where "C 1- C 10 "Alkyl" has the above definition.

[0125] The term "C3-C 10 "Cycloalkyloxy" is understood to mean -O-(C3-C 10 Cycloalkyl), wherein "C3-C 10 "Cycloalkyl" has the above definition.

[0126] The term "3-10 membered heterocyclyl" is to be understood as -O-(3-10 membered heterocyclyl), wherein "3-10 membered heterocyclyl" has the above definition.

[0127] The term "C6-C 10 The term "aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 10 carbon atoms, in particular a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. When the C6-C 10 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be at the ortho, para or meta position.

[0128] The term "C6-C 10 "Aryloxy" is understood to mean -O-(C6-C 10 aryl), wherein C6-C 10 Aryl has the above definition.

[0129] The term “5-10 membered heteroaryl” is understood as a monovalent monocyclic, bicyclic or tricyclic aromatic ring radical having 5 to 10 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example “5-14 membered heteroaryl”. The term “5-14 membered heteroaryl” is understood as a monovalent monocyclic, bicyclic or tricyclic aromatic ring radical having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, which contains 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O and S, and which may additionally in each case be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or acininyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.

[0130] The term "5-10 membered heteroaryloxy" is to be understood as -O-(5-10 membered heteroaryl), wherein the 5-10 membered heteroaryl has the above definition.

[0131] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0132] "Haloalkyl" refers to a saturated aliphatic hydrocarbon group, including branched and straight chains, having the specified number of carbon atoms, substituted with one or more halogens (e.g., -CvFw, where v = 1 to 3, w = 1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0133] Beneficial effects

[0134] According to a specific example of the present invention, the compounds represented by formula (I) to (IV) of the present invention or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs have a significant inhibitory effect on ATX enzyme.

[0135] According to a specific example of the present invention, the compound of the present invention has good inhibitory activity against ATX enzyme; the compound of the present invention exhibits better liver metabolic stability, slower metabolism in the human body, and higher exposure; in the hERG test, the compound of the present invention exhibits weak hERG inhibitory activity, combined with the IC of the compound for inhibition of ATX enzyme activity. 50 The values ​​indicate that the compounds of the present invention exhibit a good safety window for inhibiting hERG and have obvious cardiac safety advantages.

[0136] According to specific embodiments of the present invention, the compounds of the present invention exhibit excellent pharmacokinetic properties.

[0137] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. DETAILED DESCRIPTION

[0138] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0139] Embodiments of the present invention provide compounds represented by formula (I) to formula (IV), their tautomers, stereoisomers, hydrates, solvates, salts or prodrugs, methods and intermediates for preparing compounds represented by formula (I) to formula (IV) or their tautomers, stereoisomers, hydrates, solvates, salts or prodrugs, pharmaceutical compositions, and uses of the compounds and pharmaceutical compositions of the present invention in preparing drugs.

[0140] The reaction solvents used in each reaction step described in the present invention are not particularly limited. Any solvent that can dissolve the starting materials to a certain extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different ratios of solvent combinations equivalent to those described in the present invention are considered to be within the scope of the present invention.

[0141] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10-6 The solvents for NMR measurements are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and tetramethylsilane (TMS) is the internal standard.

[0142] Liquid chromatography-mass spectrometry (LC-MS) was performed on a Waters Acquity H-class UPLC-QDA mass spectrometer using an ACQUITY UPLC BEHC18, 2.1 x 50 mm, 1.7 μm column. Gradient elution conditions were: 95% to 5% solvent A1 and 5% to 95% solvent B1, followed by 95% B1 and 5% A1 for 0.5 min, at a flow rate of 1.0 mL / min. Percentages represent the volume percentage of a particular solvent relative to the total solvent volume. Solvent A1: 0.1% formic acid in water; Solvent B1: 0.1% formic acid in acetonitrile. Percentages represent the volume percentage of the solute relative to the total solvent volume.

[0143] Super dry: refers to water content ≤50ppm

[0144] The abbreviations of the present invention are defined as follows:

[0145] aq: aqueous solution

[0146] NMM: N-methylmorpholine

[0147] CuI: Cuprous iodide

[0148] DCM: dichloromethane

[0149] DIAD: diisopropyl azodicarboxylate

[0150] dioxane:1,4-dioxane

[0151] DIPEA: diisopropylethylamine, also known as N, N-diisopropylethylamine

[0152] DMAP: 4-dimethylaminopyridine

[0153] DMF: N,N-dimethylformamide

[0154] DMSO: dimethyl sulfoxide

[0155] EGTA: Ethylene glycol bis(2-aminoethyl ether) tetraacetic acid

[0156] Et3N: triethylamine

[0157] HEPES: (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)

[0158] HPLC: High Performance Liquid Chromatography

[0159] KOH: potassium hydroxide

[0160] MeOH: methanol

[0161] NADPH: reduced coenzyme II

[0162] NaH: sodium hydride

[0163] NMM: N-methylmorpholine

[0164] NMP: N-methylpyrrolidone

[0165] Pd / C: Palladium on carbon

[0166] PPh3: triphenylphosphine

[0167] SFC: Supercritical Fluid Chromatography

[0168] T3P: propylphosphonic acid tricyclic anhydride, also known as 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine-2,4,6-trioxide

[0169] TBTU: O-Benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate

[0170] THF: Tetrahydrofuran

[0171] TMSN3: trimethylsilyl azide

[0172] TsCl: p-Toluenesulfonyl chloride

[0173] IC 50 : Half-maximal inhibitory concentration refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0174] Unless otherwise indicated, compounds exemplified herein are named and numbered using ChemBioDraw Ultra 13.0.

[0175] Example 1: Preparation of target compound 001

[0176] (3-(2-(1H-1,2,3-triazol-4-yl)ethoxy)pyrrolidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (target compound 001)

[0177] The synthetic route of target compound 001 is as follows:

[0178]

[0179] Step 1: Synthesis of tert-butyl 3-((3-ethoxy-3-oxoprop-1-en-1-yl)oxy)pyrrolidine-1-carboxylate (001B)

[0180] Ethyl propiolate (5.24 g, 53.4 mmol) and tert-butyl 3-((3-ethoxy-3-oxoprop-1-en-1-yl)oxy)pyrrolidine-1-carboxylate (5 g, 26.7 mmol) were added to a single-necked flask and dissolved in dichloromethane (50 mL). N-methylmorpholine (1.35 g, 13.4 mmol) was added at room temperature and stirred at room temperature for 1.5 hours. The reaction was stirred at room temperature for 12 hours. TLC (petroleum ether:ethyl acetate (V / V) = 3:1) showed that the reaction was complete. The product was concentrated and the residue was purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 3:1) to give tert-butyl 3-((3-ethoxy-3-oxoprop-1-en-1-yl)oxy)pyrrolidine-1-carboxylate (5 g, 17.52 mmol, yield 65.6%) as a colorless oil.

[0181] Step 2: Synthesis of tert-butyl 3-(3-ethoxy-3-oxopropoxy)pyrrolidine-1-carboxylate (001C)

[0182] To a single-necked flask was added tert-butyl 3-((3-ethoxy-3-oxoprop-1-en-1-yl)oxy)pyrrolidine-1-carboxylate (5 g, 17.52 mmol), palladium carbon and methanol (100 mL). The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. TLC (petroleum ether:ethyl acetate (V / V) = 3:1) showed that the reaction was complete. The mixture was filtered and concentrated to dryness to give a colorless oily crude product of tert-butyl 3-(3-ethoxy-3-oxopropoxy)pyrrolidine-1-carboxylate (6 g).

[0183] Step 3: Synthesis of tert-butyl 3-(3-hydroxypropoxy)pyrrolidine-1-carboxylate (001D)

[0184] In a single-necked flask, tert-butyl 3-(3-ethoxy-3-oxopropoxy)pyrrolidine-1-carboxylate (6 g, 20.88 mmol), sodium borohydride (7.9 g, 209 mmol), lithium chloride (1.77 g, 41.8 mmol) and methanol (100 mL) were added and stirred at room temperature for 12 hours. TLC (petroleum ether:ethyl acetate (V / V) = 3:1) showed that the reaction was complete. Water (2 mL) was added to quench the reaction, and the mixture was concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 3:1) to give oily tert-butyl 3-(3-hydroxypropoxy)pyrrolidine-1-carboxylate (4.5 g, 18.34 mmol, 88% yield).

[0185] Step 4: Synthesis of tert-butyl 3-(3-oxopropoxy)pyrrolidine-1-carboxylate (001E)

[0186] Dimethyl sulfoxide (1.33 g, 16.96 mmol) and ultra-dry dichloromethane (32 mL) were added to a three-necked flask, protected by nitrogen, cooled to -78°C, added oxalyl chloride (1.076 g, 8.48 mmol), reacted at -78°C for 0.5 hour, added tert-butyl 3-(3-hydroxypropoxy)pyrrolidine-1-carboxylate (1.6 g, 6.52 mmol), reacted at -78°C for 2 hours, added triethylamine (3.3 g, 32.6 mmol), warmed to -20°C, quenched by addition of saturated ammonium chloride solution (30 mL), separated, the organic phase was washed twice with saturated ammonium chloride solution (20 mL×2), separated, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a colorless oily crude product of tert-butyl 3-(3-oxopropoxy)pyrrolidine-1-carboxylate (1.6 g).

[0187] Step 5: Synthesis of tert-butyl 3-(but-3-yn-1-yloxy)pyrrolidine-1-carboxylate (001F)

[0188] In a single-necked bottle, tert-butyl 3-(3-oxopropoxy)pyrrolidine-1-carboxylate (1.6 g, 6.58 mmol), potassium carbonate (2.73 g, 19.73 mmol), and ultra-dry methanol (25 mL) were added. The mixture was protected by nitrogen and cooled to 0°C. Dimethyl (1-diazo-2-oxopropyl) phosphonate (1.895 g, 9.86 mmol) was added and reacted at room temperature for 12 hours. The reaction was performed by TLC (petroleum ether:ethyl acetate (V / V)). )=1:1) indicated that the reaction was complete, water (1 mL) was added to quench the reaction, the mixture was concentrated to dryness, ethyl acetate (30 mL for dilution) was added, water (30 mL) was added, the liquids were separated, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column (petroleum ether:ethyl acetate (V / V)=10:1) to give tert-butyl 3-(but-3-yn-1-yloxy)pyrrolidine-1-carboxylate (0.8 g, 3.34 mmol, 50.8% yield) as a colorless oil.

[0189] Step 6: Synthesis of 3-(but-3-yn-1-yloxy)pyrrolidine hydrochloride (001G)

[0190] To a single-necked flask, add tert-butyl 3-(but-3-yn-1-yloxy)pyrrolidine-1-carboxylate (0.8 g, 3.34 mmol) and hydrogen chloride / 1,4-dioxane solution (2.5 M, 2 mL). Stir at room temperature for 3 hours and concentrate to dryness to obtain a colorless oily crude product of 3-(but-3-yn-1-yloxy)pyrrolidine hydrochloride (0.44 g).

[0191] Step 7: Synthesis of 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (Intermediate A)

[0192]

[0193] 2-Chloropyrimidine-5-carboxylic acid (2 g, 12.61 mmol) was dissolved in N-methylpyrrolidone (10 mL), and 2-aminoindan hydrochloride (2.57 g, 15.14 mmol) and N,N-diisopropylethylamine (8.15 g, 63.1 mmol) were added. The reaction mixture was heated to 100°C and reacted for 24 h. The solvent was evaporated under an oil pump, and ethyl acetate (30 mL) was added to the residue for dispersion. The mixture was filtered, and the filter cake was slurried with water (30 mL), filtered, and air-dried at 50°C for 3 h to obtain 2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidine-5-carboxylic acid (2.4 g, 74.5% yield) as a gray solid. Intermediate A used in the following examples can be obtained by referring to this synthetic route and preparation method.

[0194] LC-MS m / z: 256.2 [M+H] + .

[0195] Step 8: Synthesis of (3-(but-3-yn-1-yloxy)pyrrolidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (001H)

[0196] 3-(But-3-yn-1-yloxy)pyrrolidine hydrochloride (0.44 g, 2.504 mmol), 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (0.639 g, 2.504 mmol), diisopropylethylamine (3.24 g, 25.04 mmol), and N,N-dimethylformamide (6 mL) were added to a single-necked bottle and dissolved at room temperature. The mixture was cooled to 0°C and 50% 1-propylphosphoric anhydride / N,N-dimethylformamide solution (1.593 g, 2.504 mmol) was added dropwise. After the addition was complete, the mixture was reacted at room temperature overnight. TLC (methanol:dichloromethane) showed a clear color. The reaction was completed when the mixture was stirred for 2 hours (with 4% paraffin wax and 1% paraffin wax (v / v) = 1:10) and water (20 mL) was added for dilution. The aqueous phase was extracted with dichloromethane (50 mL × 2). The organic phases were combined and washed with saturated brine (50 mL × 2). The organic phase was separated and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (methanol: dichloromethane (V / V) = 1:10) to give a white solid (3-(but-3-yn-1-yloxy)pyrrolidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (600 mg, 1.594 mmol, yield 63.6%).

[0197] LC-MS m / z: 377.46 [M+H] + .

[0198] Step 9: Synthesis of (3-(2-(1H-1,2,3-triazol-4-yl)ethoxy)pyrrolidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (target compound 001)

[0199] L(+) ascorbic acid (281 mg, 1.59 mmol), sodium bicarbonate (134 mg, 1.59 mmol), N,N-dimethylformamide (4 mL), methanol (0.4 mL) were added to a single-necked flask and stirred for 1 hour. (3-(but-3-yn-1-yloxy)pyrrolidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (200 mg, 0.53 mmol), azidotrimethylsilane (245 mg, 2.12 mmol), copper sulfate pentahydrate (53 mg, 0.05 mmol) were added and heated. The mixture was heated to 90°C for 2 hours. LCMS showed that most of the raw materials had reacted. The reaction solution was cooled to room temperature, saturated brine (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phase was washed twice with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative chromatography to give compound (3-(2-(1H-1,2,3-triazol-4-yl)ethoxy)pyrrolidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (23 mg, 0.055 mmol, yield 10.3%).

[0200] 1 H NMR (400MHz, DMSO-d6) δ8.52(s,2H),8.00~8.01(d,1H),7.55~7.62(d,1H),7.19~7.21(m,2H),7.11~7.14(m ,2H),4.61~4.67(m,1H),4.09(s,1H),3.42~3.76(m,6H),3.21~3.26(q,2H),2.82~2.92(m,4H),1.93(s,2H).

[0201] LC-MS m / z: 420.5 [M+H] + .

[0202] Example 2: Preparation of target compound 002

[0203] (3-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)pyrrolidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (target compound 002)

[0204] The synthetic route of compound 002 is as follows:

[0205]

[0206] Step 1: Synthesis of tert-butyl 3-((prop-2-ynyloxy)methyl)pyrrolidine-1-carboxylate (002B)

[0207] tert-Butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (002A) (500 mg, 2.484 mmol) was dissolved in tetrahydrofuran (6 mL), cooled to 0°C, and sodium hydride (99 mg, 2.484 mmol, 60%) was added. The temperature was raised to room temperature and allowed to react for 1 h. 3-Bromopropyne (591 mg, 4.97 mmol) was added dropwise. After addition, the temperature was raised to 60°C and allowed to react for 18 h. The reaction solution was cooled to room temperature and quenched with saturated ammonium chloride solution (50 mL). The solution was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 200:1) to afford tert-butyl 3-((prop-2-ynyloxy)methyl)pyrrolidine-1-carboxylate (002B) (450 mg, 76% yield) as a yellow liquid.

[0208] Step 2: Synthesis of 3-((prop-2-ynyloxy)methyl)pyrrolidine hydrochloride (002C)

[0209] To tert-butyl 3-((prop-2-ynyloxy)methyl)pyrrolidine-1-carboxylate (002B) (450 mg, 1.880 mmol) was added a hydrogen chloride / dioxane solution (5 mL, 12.00 mmol, 2.4 M) and stirred at room temperature for 2 h. The solvent was removed under reduced pressure to yield the crude product, which was used directly in the next step without purification.

[0210] Step 3: Synthesis of (2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)(3-((prop-2-ynyloxy)methyl)pyrrolidin-1-yl)methanone (002D)

[0211] To the crude product of the previous step, 3-((prop-2-ynyloxy)methyl)pyrrolidine hydrochloride (002C) (330 mg, 1.879 mmol), were added N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (2.428 g, 18.79 mmol), and 2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidine-5-carboxylic acid (480 mg, 1.879 mmol). The reaction solution was cooled to about 0°C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide (1.435 g, 2.254 mmol, 50% N,N-dimethylformamide solution) was added dropwise. After the addition was complete, the mixture was reacted at 5-10°C for 20 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel plate (petroleum ether: ethyl acetate (V / V) = 1:2) to give a white solid (2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)(3-((prop-2-ynyloxy)methyl)pyrrolidin-1-yl)methanone (002D) (500 mg, yield 70.7%).

[0212] LC-MS m / z: 377.4 [M+H] + .

[0213] Step 4: Synthesis of (3-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)pyrrolidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (target compound 002)

[0214] Under nitrogen protection, (2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)(3-((prop-2-ynyloxy)methyl)pyrrolidin-1-yl)methanone (002D) (200 mg, 0.531 mmol) was dissolved in N,N-dimethylformamide (4 mL) and methanol (2 mL), and sodium L-ascorbate (210 mg, 1.06 mmol) was added. The mixture was stirred at 30-40 ° C for 30 min, and then trimethylsilane azide (612 mg, 5.31 mmol) and copper sulfate pentahydrate (53.1 mg, 0.213 mmol) were added. The temperature was raised to 90 ° C for 3 h. The reaction solution was cooled to room temperature, water (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel plate (ethyl acetate:methanol (V / V) = 10:1, appropriate amount of aqueous ammonia) to obtain compound (3-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)pyrrolidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (target compound 002) (105 mg, yield 47.1%).

[0215] 1 H NMR (400MHz, DMSO-d6): δ8.48(s, 2H), 7.95~7.96(d,1H), 7.79(t,1H), 7.10~7.19(m,4H), 4.5 0~4.65(m,3H), 3.19~3.55(m,8H), 2.85~2.90(dd,2H), 2.41(m,1H), 1.90(m,1H), 1.58(m,1H).

[0216] LC-MS m / z: 420.3 [M+H] + .

[0217] Example 3: Preparation of target compound 003

[0218] (3-((2-(1H-1,2,3-triazol-4-yl)ethoxy)methyl)pyrrolidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (target compound 003)

[0219] The synthetic route of compound 003 is as follows:

[0220]

[0221] Step 1: Synthesis of tert-butyl 3-((toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylate (003B)

[0222] tert-Butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (003A) (500 mg, 2.484 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (503 mg, 4.97 mmol) and 4-dimethylaminopyridine (152 mg, 1.242 mmol) were added. The temperature was lowered to 0°C, and p-toluenesulfonyl chloride (568 mg, 2.98 mmol) was added portionwise. The temperature was raised to room temperature and the reaction was allowed to react for 20 h. Water (30 mL) was added to quench the reaction. The layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 20:1) to afford tert-butyl 3-((tosyloxymethyl)pyrrolidine-1-carboxylate (003B) (800 mg, 91% yield) as a white solid.

[0223] Step 2: Synthesis of tert-butyl 3-((but-3-ynyloxy)methyl)pyrrolidine-1-carboxylate (003C)

[0224] Under nitrogen, 3-butyn-1-ol (100 mg, 1.426 mmol) was dissolved in N,N-dimethylformamide (5 mL), cooled to 0°C, and sodium hydride (57 mg, 1.426 mmol, 60%) was added. The mixture was stirred at room temperature for 30 min. Tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (003B) (507 mg, 1.426 mmol) was added, and the temperature was raised to 80°C for 18 h. The reaction solution was cooled to room temperature and quenched by the addition of saturated ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 100:1) to afford tert-butyl 3-((but-3-ynyloxy)methyl)pyrrolidine-1-carboxylate (003C) (140 mg, 38.7% yield) as a colorless liquid.

[0225] Step 3: Synthesis of 3-((but-3-ynyloxy)methyl)pyrrolidine hydrochloride (003D)

[0226] To tert-butyl 3-((but-3-ynyloxy)methyl)pyrrolidine-1-carboxylate (003C) (100 mg, 0.395 mmol) was added a hydrogen chloride / dioxane solution (2 mL, 4.80 mmol, 2.4 M) and stirred at room temperature for 1 h. The solvent was removed under reduced pressure to yield the crude product, which was used directly in the next reaction without purification.

[0227] Step 4: Synthesis of (3-((but-3-ynyloxy)methyl)pyrrolidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (003E)

[0228] To the crude 3-((but-3-ynyloxy)methyl)pyrrolidine hydrochloride (003D) of the previous step were added N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (510 mg, 3.95 mmol), and 2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidine-5-carboxylic acid (101 mg, 0.395 mmol). The reaction solution was cooled to about 0°C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide (302 mg, 0.474 mmol, 50% N,N-dimethylformamide solution) was added dropwise. After the addition was complete, the mixture was reacted at room temperature for 4 h. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel plate (petroleum ether: ethyl acetate (V / V) = 1:2) to give a white solid (3-((but-3-ynyloxy)methyl)pyrrolidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (003E) (90 mg, yield 58.4%).

[0229] LC-MS m / z: 391.5 [M+H] + .

[0230] Step 5: Synthesis of (3-((2-(1H-1,2,3-triazol-4-yl)ethoxy)methyl)pyrrolidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (target compound 003)

[0231] Under nitrogen protection, (3-((but-3-ynyloxy)methyl)pyrrolidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (003E) (90 mg, 0.230 mmol) was dissolved in N,N-dimethylformamide (3 mL) and methanol (1 mL), and sodium L-ascorbate (91.3 mg, 0.460 mmol) was added. The mixture was stirred at room temperature for 30 min, and then trimethylsilyl azide (266 mg, 2.305 mmol) and copper sulfate pentahydrate (23 mg, 0.092 mmol) were added. The temperature was raised to 90 ° C and the reaction was carried out for 2 h. The reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel plate (ethyl acetate: methanol (V / V) = 10:1, ammonia water) to obtain compound (3-((2-(1H-1,2,3-triazol-4-yl)ethoxy)methyl)pyrrolidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (target compound 003) (10 mg, yield 10%).

[0232] 1 H NMR (400MHz, DMSO-d6): δ8.49(s,2H), 7.95~7.97(d,1H), 7.56(t,1H), 7.10~7.19(m,4H), 4.58~4.67(m,1H), 3.96~3.97(d ,1H), 3.43~3.59(m,5H), 3.17~3.26(m,3H), 2.85~2.91(dd,4H), 2.39~2.40(m,1H), 1.90(m,1H), 1.58(m,1H), 1.33(m,1H).

[0233] LC-MS m / z: 434.3 [M+H] + .

[0234] Example 4: Preparation of target compound 004

[0235] (3-((1H-1,2,3-triazol-4-yl)methoxy)azetidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (target compound 004)

[0236] The synthetic route of compound 004 is as follows:

[0237]

[0238] Step 1: Synthesis of tert-butyl 3-(prop-2-ynyloxy)azetidine-1-carboxylate (004B)

[0239] Under nitrogen, tert-butyl 3-hydroxyazetidine-1-carboxylate (004A) (680 mg, 3.93 mmol) was dissolved in N,N-dimethylformamide (10 mL), cooled to 0-5°C, and sodium hydride (157 mg, 3.93 mmol, 60%) was added. The mixture was stirred at room temperature for 30 min. 3-Bromo-1-propyne (700 mg, 5.89 mmol) was added, and the temperature was raised to 50°C for 20 h. The reaction solution was cooled to room temperature and quenched with saturated ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 10:1) to afford tert-butyl 3-(prop-2-ynyloxy)azetidine-1-carboxylate (004B) (560 mg, 67.5% yield) as a yellow liquid.

[0240] Step 2: Synthesis of 3-(prop-2-ynyloxy)azetidine hydrochloride (004C)

[0241] To tert-butyl 3-(prop-2-ynyloxy)azetidine-1-carboxylate (004B) (560 mg, 2.65 mmol) was added a hydrogen chloride / dioxane solution (10 mL, 40.0 mmol, 4 M) and stirred at room temperature for 1 h. The solvent was removed under reduced pressure to obtain a crude product, which was used directly in the next reaction without purification.

[0242] Step 3: Synthesis of (2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)(3-(prop-2-ynyloxy)azetidin-1-yl)methanone (004D)

[0243] To the crude 3-(prop-2-ynyloxy)azetidine hydrochloride (004C) of the previous step were added N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (1.712 g, 13.25 mmol), and 2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidine-5-carboxylic acid (676 mg, 2.65 mmol). The reaction solution was cooled to about 0°C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide (2.023 g, 3.18 mmol, 50% N,N-dimethylformamide solution) was added dropwise. After the addition was complete, the mixture was reacted at 10-15°C for 18 h. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel plate (petroleum ether: ethyl acetate (V / V) = 1:2) to give a white solid (2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)(3-(prop-2-ynyloxy)azetidin-1-yl)methanone (004D) (260 mg, yield 28.2%).

[0244] LC-MS m / z: 349.4 [M+H] + .

[0245] Step 4: Synthesis of (3-((1H-1,2,3-triazol-4-yl)methoxy)azetidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (004)

[0246] Under nitrogen protection, (2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)(3-(prop-2-ynyloxy)azetidin-1-yl)methanone (004D) (260 mg, 0.746 mmol) was dissolved in N,N-dimethylformamide (5 mL) and methanol (2 mL), and sodium L-ascorbate (296 mg, 1.49 mmol) was added. The mixture was stirred at 30-40 ° C for 30 min, and copper sulfate pentahydrate (74.5 mg, 0.299 mmol) and trimethylsilyl azide (860 mg, 7.46 mmol) were added. The temperature was raised to 90 ° C for 2 h. The reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with dichloromethane (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel plate (ethyl acetate:methanol (V / V) = 10:1, ammonia water) to obtain compound (3-((1H-1,2,3-triazol-4-yl)methoxy)azetidine-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (004) (37 mg, yield 12.7%).

[0247] 1 H NMR (400MHz, DMSO-d6): δ8.55~8.51 (d, 2H), 8.11~8.09 (d, 1H), 7.85 (s, 1H), 7.19~7.09 (m, 4H), 4.68~4 .59 (m, 1H), 4.54~4.38 (m, 4H), 4.18 (brs, 2H), 3.77 (brs, 1H), 3.25~3.19 (dd, 2H), 2.91~2.85 (dd, 2H).

[0248] LC-MS m / z: 392.3 [M+H] + .

[0249] Example 5: Preparation of target compound 005

[0250] (3-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)azetidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (target compound 005)

[0251] The synthetic route of target compound 005 is as follows:

[0252]

[0253] Step 1: Synthesis of tert-butyl 3-((prop-2-yn-1-oxy)methyl)azetidine-1-carboxylate (005C)

[0254] 3-(Hydroxymethyl)azetidine-1-carboxylic acid tert-butyl ester (1 g, 5.34 mmol) was added to a single-necked flask and dissolved in tetrahydrofuran (10 mL). 60% sodium hydride (0.24 g, 5.87 mmol) was added at room temperature and stirred at room temperature for 0.5 hours. Propyl bromide (3.2 g, 26.7 mmol) was added and stirred at room temperature for 12 hours. TLC (petroleum ether: ethyl acetate (V / V) = 3:1) showed that the reaction was complete. Methanol (10 mL) was added to quench the reaction and concentrate. The residue was purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 3:1) to give tert-butyl 3-((prop-2-yn-1-oxy)methyl)azetidine-1-carboxylate (1.1 g, 4.88 mmol, 91% yield) as a colorless oil.

[0255] Step 2: Synthesis of 3-((prop-2-yn-1-oxy)methyl)azetidine hydrochloride (005D)

[0256] To a single-necked flask, tert-butyl 3-((prop-2-yn-1-oxy)methyl)azetidine-1-carboxylate (1.1 g, 4.88 mmol) and a hydrogen chloride / 1,4-dioxane solution (2.5 M, 20 mL) were added. The mixture was stirred at room temperature for 3 hours and concentrated to dryness to obtain a crude colorless oil (0.8 g).

[0257] Step 3: Synthesis of (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(3-((prop-2-yn-1-oxy)methyl)azetidin-1-yl)methanone (005F)

[0258] In a single-necked flask, tert-butyl 3-((prop-2-yn-1-oxy)methyl)azetidine-1-carboxylate (284 mg, 1.76 mmol), 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (300 mg, 1.18 mmol), diisopropylethylamine (1.52 g, 11.75 mmol), and N,N-dimethylformamide (3 mL) were added and dissolved at room temperature. The mixture was cooled to 0°C, and a 50% 1-propylphosphoric anhydride / N,N-dimethylformamide solution (747 g, 1.18 mmol) was added dropwise. After the addition was complete, the mixture was reacted at room temperature overnight. TLC (methanol: dichloromethane) indicated the reaction mixture had a high yield. The reaction was completed after 1:10 saturated sodium chloride (50 mL × 2) and 3-((2,3-dihydro-1H-indene-2-yl)amino)pyrimidin-5-yl)(3-((prop-2-yn-1-oxy)methyl)azetidin-1-yl)methanone (120 mg, 0.33 mmol, 28.2% yield) was obtained.

[0259] Step 4: Synthesis of (3-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)azetidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (target compound 005)

[0260] L(+) ascorbic acid (146 mg, 0.83 mmol), sodium bicarbonate (70 mg, 0.83 mmol), N,N-dimethylformamide (2 mL), methanol (0.4 mL) were added to a single-necked flask and stirred for 1 hour. (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(3-((prop-2-yn-1-oxy)methyl)azetidin-1-yl)methanone (100 mg, 0.28 mmol), azidotrimethylsilane (0.13 g, 1.1 mmol), copper sulfate pentahydrate (28 mg, 0.11 mmol) were added and heated to 90°C for reaction. After 2 hours, LCMS showed that most of the raw materials had reacted. The reaction solution was cooled to room temperature, and saturated brine (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phase was washed twice with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative chromatography to give compound (3-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)azetidine-1-yl)(2-((2,3-dihydro-1H-indene-2-yl)amino)pyrimidin-5-yl)methanone (target compound 005) (6.3 mg, 0.016 mmol, yield 5.6%).

[0261] 1 H NMR (400MHz, DMSO-d6) δ8.50~8.53(d,2H),8.07~8.09(d,1H),7.81(s,1H),7.09~7.19(m,4H),4.61~4.65(m,1H) ), 4.56(s,1H), 4.38(s,1H), 4.02(s,2H), 3.67(s,1H), 3.55~3.57(d,2H), 3.19~3.25(m,2H), 2.85~2.90(m,2H).

[0262] LC-MS m / z: 406.4 [M+H] + .

[0263] Example 6: Preparation of target compound 006

[0264] (3-((2-(1H-1,2,3-triazol-4-yl)ethoxy)methyl)azetidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (target compound 006)

[0265] The synthetic route of compound 006 is as follows:

[0266]

[0267] Step 1: Synthesis of tert-butyl 3-((toluenesulfonyloxy)methyl)azetidine-1-carboxylate (006B)

[0268] tert-Butyl 3-(hydroxymethyl)azetidine-1-carboxylate (006A) (2 g, 10.68 mmol) was dissolved in dichloromethane (30 mL). Triethylamine (2.162 g, 21.36 mmol) and 4-dimethylaminopyridine (0.652 g, 5.34 mmol) were added. The temperature was lowered to 0°C, and p-toluenesulfonyl chloride (2.444 g, 12.82 mmol) was added portionwise. The temperature was raised to room temperature and the reaction was allowed to react for 48 h. Water (30 mL) was added to quench the reaction. The layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 15:1) to afford tert-butyl 3-((tosyloxymethyl)azetidine-1-carboxylate (006B) (3.3 g, 90% yield) as a white solid.

[0269] Step 2: Synthesis of tert-butyl 3-((but-3-ynyloxy)methyl)azetidine-1-carboxylate (006C)

[0270] Under nitrogen, 3-butyn-1-ol (677 mg, 9.67 mmol) was dissolved in N,N-dimethylformamide (15 mL), cooled to 0°C, and sodium hydride (387 mg, 9.67 mmol, 60%) was added. The mixture was stirred at room temperature for 30 min. Tert-butyl 3-((tosyloxy)methyl)azetidine-1-carboxylate (006B) (3.3 g, 9.67 mmol) was added, and the temperature was raised to 80°C for 20 h. The reaction solution was cooled to room temperature and quenched by adding saturated ammonium chloride solution (75 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:1) to give colorless liquid tert-butyl 3-((but-3-ynyloxy)methyl)azetidine-1-carboxylate (006C) (1.21 g, yield 52.3%).

[0271] Step 3: Synthesis of 3-((but-3-ynyloxy)methyl)azetidine hydrochloride (006D)

[0272] To tert-butyl 3-((but-3-ynyloxy)methyl)azetidine-1-carboxylate (006C) (500 mg, 2.089 mmol) was added a hydrogen chloride / dioxane solution (8 mL, 32.0 mmol, 4 M) and stirred at room temperature for 1 h. The solvent was removed under reduced pressure to yield the crude product, which was used directly in the next reaction without purification.

[0273] Step 4: Synthesis of (3-((but-3-ynyloxy)methyl)azetidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (006E)

[0274] To the crude 3-((but-3-ynyloxy)methyl)azetidine hydrochloride (006D) from the previous step were added N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (2.7 g, 20.89 mmol), and 2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidine-5-carboxylic acid (533 mg, 2.089 mmol). The reaction solution was cooled to about 0°C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide (1.595 g, 2.507 mmol, 50% N,N-dimethylformamide solution) was added dropwise. After the addition was complete, the mixture was reacted at 5-10°C for 20 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel plate (petroleum ether: ethyl acetate (V / V) = 1:2) to give a white solid (3-((but-3-ynyloxy)methyl)azetidin-1-yl)(2-((2,3-dihydro-1H-indene-2-yl)amino)pyrimidin-5-yl)methanone (006E) (295 mg, yield 37.5%).

[0275] LC-MS m / z: 377.3 [M+H] + .

[0276] Step 5: Synthesis of (3-((2-(1H-1,2,3-triazol-4-yl)ethoxy)methyl)azetidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (target compound 006)

[0277] Under nitrogen protection, (3-((but-3-ynyloxy)methyl)azetidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (006E) (180 mg, 0.478 mmol) was dissolved in N,N-dimethylformamide (4 mL) and methanol (2 mL), and sodium L-ascorbate (189 mg, 0.956 mmol) was added. The mixture was stirred at 30-40 ° C for 30 min, and then trimethylsilane azide (551 mg, 4.78 mmol) and copper sulfate pentahydrate (47.8 mg, 0.191 mmol) were added. The temperature was raised to 90 ° C for 3 h. The reaction solution was cooled to room temperature, water (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel plate (ethyl acetate:methanol (V / V) = 10:1, appropriate amount of aqueous ammonia) to give a light yellow solid (3-((2-(1H-1,2,3-triazol-4-yl)ethoxy)methyl)azetidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (target compound 006) (15.4 mg, yield 7.7%).

[0278] 1 H NMR (400MHz, DMSO-d6): δ8.59 (s, 2H), 8.12~8.13 (d, 1H), 7.62 (s, 1H), 7.14~7.25 (m, 4H), 4.63~4 .72(m, 1H), 4.43(s, 1H), 4.05(s, 2H), 3.58~3.72(m, 5H), 3.24~3.29(dd, 2H), 2.79~2.95(m, 5H).

[0279] LC-MS m / z: 420.3 [M+H] + .

[0280] Example 7: Preparation of target compound 007

[0281] (3-((2-(1H-1,2,3-triazol-4-yl)ethoxy)methyl)azetidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (target compound 007)

[0282] The synthetic route of compound 007 is as follows:

[0283]

[0284] Step 1: Synthesis of tert-butyl 3-((toluenesulfonyloxy)methyl)azetidine-1-carboxylate (007B)

[0285] Dissolve tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (007A) (1 g, 5.34 mmol), triethylamine (1.081 g, 10.68 mmol) and 4-dimethylaminopyridine (0.326 g, 2.67 mmol) in dichloromethane (15 mL), cool to 0-5°C, add 4-methylbenzenesulfonyl chloride (1.222 g, 6.41 mmol) in portions, and after addition, warm to room temperature and react for 20 h. Water (50 mL) was added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with dichloromethane (25 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 20:1) to obtain a yellow oily product tert-butyl 3-((tosyloxy)methyl)azetidine-1-carboxylate (007B) (1.8 g, yield 99%).

[0286] Step 2: Synthesis of tert-butyl 3-((but-3-ynyloxy)methyl)azetidine-1-carboxylate (007C)

[0287] Dissolve 3-butyn-1-ol (0.37 g, 5.27 mmol) in N,N-dimethylformamide (5 mL), cool to 0-5°C, add sodium hydride (211 mg, 5.27 mmol, 60%), and warm to room temperature with stirring for 30 min. Dissolve tert-butyl 3-((tosyloxy)methyl)azetidine-1-carboxylate (007B) (1.8 g, 5.27 mmol) in N,N-dimethylformamide (5 mL) and add dropwise to the reaction mixture. After addition, heat to 80°C and react for 20 h. The reaction solution was cooled to room temperature and quenched by adding saturated ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10:1) to give a yellow liquid tert-butyl 3-((but-3-ynyloxy)methyl)azetidine-1-carboxylate (007C) (690 mg, yield 54.7%).

[0288] Step 3: Synthesis of tert-butyl 3-((2-(1H-1,2,3-triazol-4-yl)ethoxy)methyl)azetidine-1-carboxylate (007D)

[0289] Tert-butyl 3-((but-3-ynyloxy)methyl)azetidine-1-carboxylate (007C) (500 mg, 2.089 mmol) and cuprous iodide (39.8 mg, 0.209 mmol) were dissolved in N,N-dimethylformamide (5 mL) and methanol (1 mL), and trimethylsilyl azide (1.204 g, 10.45 mmol) was added dropwise to the reaction solution. The reaction system was purged with nitrogen three times and the temperature was raised to 100 ° C for 18 h. The reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give a colorless oily substance, tert-butyl 3-((2-(1H-1,2,3-triazol-4-yl)ethoxy)methyl)azetidine-1-carboxylate (007D) (250 mg, yield 42.4%).

[0290] LC-MS m / z: 183.3 (M-Boc+H).

[0291] Step 4: Synthesis of 4-(2-(azetidin-3-ylmethoxy)ethyl)-1H-1,2,3-triazole hydrochloride (007E)

[0292] To tert-butyl 3-((2-(1H-1,2,3-triazol-4-yl)ethoxy)methyl)azetidine-1-carboxylate (007D) (220 mg, 0.779 mmol) was added a hydrogen chloride / dioxane solution (5 mL, 20.0 mmol, 4 M) and the mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to yield the crude product, which was used directly in the next reaction without purification.

[0293] Step 5: Synthesis of 6-(2,3-dihydro-1H-inden-2-ylamino)nicotinate (007G)

[0294] Palladium acetate (327 mg, 1.457 mmol) and triphenylphosphine (764 mg, 2.91 mmol) were dissolved in 1,4-dioxane (100 mL). The reaction mixture was stirred at room temperature for 30 min. Methyl 6-chloronicotinate (007F) (5 g, 29.1 mmol), 2-aminoindan hydrochloride (5.93 g, 35.0 mmol), and cesium carbonate (18.99 g, 58.3 mmol) were then added. The mixture was heated to 100°C and allowed to react for 18 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain methyl 6-(2,3-dihydro-1H-inden-2-ylamino)nicotinate (007G) (1.36 g, 17.4% yield) as a green solid.

[0295] LC-MS m / z: 269.3 [M+H] + .

[0296] Step 6: Synthesis of potassium 6-(2,3-dihydro-1H-inden-2-ylamino)nicotinate (007H)

[0297] Methyl 6-(2,3-dihydro-1H-inden-2-ylamino)nicotinate (007G) (1.36 g, 5.07 mmol) was dissolved in methanol (40 mL) and potassium hydroxide (427 mg, 7.60 mmol) was added. The temperature was raised to 50°C and the reaction was allowed to react for 4 h. The reaction solution was concentrated to dryness to obtain potassium 6-(2,3-dihydro-1H-inden-2-ylamino)nicotinate (007H) (1.45 g, 98% yield) as a yellow solid.

[0298] Step 7: Synthesis of (3-((2-(1H-1,2,3-triazol-4-yl)ethoxy)methyl)azetidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (target compound 007)

[0299] To the crude product of the fourth step, 4-(2-(azetidin-3-ylmethoxy)ethyl)-1H-1,2,3-triazole hydrochloride (007E) (170 mg, 0.777 mmol), were added N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (502 mg, 3.89 mmol), and potassium 6-(2,3-dihydro-1H-inden-2-ylamino)nicotinate (007H) (227 mg, 0.777 mmol). The reaction solution was cooled to about 0°C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide (742 mg, 1.166 mmol, 50% N,N-dimethylformamide solution) was added dropwise. After the addition was complete, the mixture was reacted at 15-20°C for 20 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel plate (dichloromethane: methanol (V / V) = 20:1, ammonia water) to obtain compound (3-((2-(1H-1,2,3-triazol-4-yl)ethoxy)methyl)azetidin-1-yl)(2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl)methanone (target compound 007) (10.2 mg, yield 3.14%).

[0300] 1H NMR (400MHz, DMSO-d6): δ8.30~8.30 (d, 1H), 7.61~7.55 (m, 2H), 7.40~7.38 (d, 1H), 7.23~7.20 (m, 2H), 7.15~7.10 (m, 2H), 6.48~6.4 6(d, 1H), 4.66~4.58(m, 1H), 4.35(brs, 1H), 3.99(brs, 2H), 3.65(t, 2H), 3.57~3.55(d, 2H), 3.29~3.24(dd, 4H), 2.89~2.79(m, 4H).

[0301] LC-MS m / z: 419.4 [M+H] + .

[0302] Example 8: Preparation of target compound 008

[0303] (4-((2H-1,2,3-triazol-4-yl)methoxy)piperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (target compound 008)

[0304] The synthetic route of compound 008 is as follows:

[0305]

[0306] Step 1: Synthesis of tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (008B)

[0307] tert-Butyl 4-hydroxypiperidine-1-carboxylate (008A) (2 g, 9.94 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0°C. Sodium hydride (437 mg, 10.93 mmol, 60%) was added, followed by the dropwise addition of 3-bromopropyne (1.77 g, 14.91 mmol). The mixture was allowed to react at room temperature for 16 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 100:1) to afford tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (008B) (2.0 g, 84% yield) as a liquid.

[0308] Step 2: Synthesis of 4-(prop-2-yn-1-yloxy)piperidine hydrochloride (008C)

[0309] To tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (008B) (2.0 g, 8.36 mmol) was added a 4M solution of hydrogen chloride in dioxane (20 mL), and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to obtain a crude product, which was used directly in the next reaction without purification.

[0310] Step 3: Synthesis of (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(4-(prop-2-yn-1-yloxy)piperidin-1-yl)-methanone (008D)

[0311] To the crude product 4-(prop-2-yn-1-yloxy)piperidine hydrochloride (008C) (300 mg, 1.708 mmol) of the previous step were added N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (1.104 g, 8.54 mmol), and 2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidine-5-carboxylic acid (458 mg, 1.793 mmol). The reaction solution was cooled to about 0°C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide (1.413 g, 2.220 mmol, 50% N,N-dimethylformamide solution) was added dropwise. After the addition was complete, the mixture was reacted at room temperature for 16 h. The reaction solution was quenched by adding water (60 mL), extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified on a silica gel plate (petroleum ether: ethyl acetate (V / V) = 5:1) to give a white solid (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(4-(prop-2-yn-1-yloxy)piperidin-1-yl)-methanone (008D) (410 mg, yield 63.8%).

[0312] LC-MS m / z: 377.4 [M+H] + .

[0313] Step 4: Synthesis of (4-((2H-1,2,3-triazol-4-yl)methoxy)piperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (target compound 008)

[0314] Under nitrogen protection, (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(4-(prop-2-yn-1-yloxy)piperidin-1-yl)-methanone (008D) (200 mg, 0.531 mmol) was dissolved in N,N-dimethylformamide (4 mL) and methanol (2 mL), and sodium L-ascorbate (210 mg, 1.063 mmol) was added. Then, trimethylsilyl azide (612 mg, 5.31 mmol) and copper sulfate pentahydrate (53.1 mg, 0.213 mmol) were added, and the temperature was raised to 90 ° C for 4 hours. The reaction solution was cooled to room temperature, water (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel plate (ethyl acetate: methanol (V / V) = 10:1, ammonia water) to obtain compound (4-((2H-1,2,3-triazol-4-yl)methoxy)piperidin-1-yl)(2-((2,3-dihydro-1H-indene-2-yl)amino)pyrimidin-5-yl)methanone (target compound 008) (20.6 mg, yield 9.24%).

[0315] 1 H NMR (400MHz, DMSO-d6): δ8.39(s,2H),7.97(d,1H),7.25-7.19(m,2H),7.17-7.11(m,2H),5.75(d,1H), 4.72-4.58(m,3H),3.72(d,3H),3.30-3.20(m,4H),2.97(dd,2H),1.93-1.82(m,2H),1.56-1.46(m,2H).

[0316] LC-MS m / z: 420.5 [M+H] + .

[0317] Example 9: Preparation of target compound 009

[0318] Synthesis of (4-(2-(1H-1,2,3-triazol-5-yl)ethoxy)piperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amine)pyrimidin-5-yl)methanone (target compound 009)

[0319] The synthetic route of compound 009 is as follows:

[0320]

[0321] Step 1: Synthesis of tert-butyl 4-((3-ethoxy-3-oxopropyl-1-en-1-yl)oxy)piperidine-1-carboxylate (009B)

[0322] tert-Butyl 4-hydroxypiperidine-1-carboxylate (5.0 g, 24.8 mmol), ethyl propiolate (2.9 g, 29.6 mmol), and N-methylmorpholine (3.8 g, 37.6 mmol) were added to dichloromethane (100 mL). The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated. The resulting product was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain tert-butyl 4-((3-ethoxy-3-oxopropyl-1-en-1-yl)oxy)piperidine-1-carboxylate (009B) (7.2 g, 24.1 mmol, 97.2% yield).

[0323] Step 2: Synthesis of tert-butyl 4-(3-ethoxy-3-oxopropoxy)piperidine-1-carboxylate (009C)

[0324] tert-Butyl 4-((3-ethoxy-3-oxopropyl-1-en-1-yl)oxy)piperidine-1-carboxylate (009B) (7.2 g, 24.1 mmol) and palladium on carbon (10%, 0.5 g) were added to methanol (100 mL) and stirred at room temperature overnight under a hydrogen atmosphere. The solid was removed by filtration, and the mother liquor was concentrated to obtain tert-butyl 4-(3-ethoxy-3-oxopropyloxy)piperidine-1-carboxylate (009C) (7.0 g, 23.2 mmol, 96.3% yield), which was used directly in the next reaction.

[0325] Step 3: Synthesis of tert-butyl 4-(3-hydroxyoxypropoxy)piperidine-1-carboxylate (009D)

[0326] tert-Butyl 4-(3-ethoxy-3-oxopropoxy)piperidine-1-carboxylate (009C) (7.0 g, 23.2 mmol) and LiCl (2.0 g, 47.2 mmol) were added to ethanol (100 mL), and NaBH4 (8.8 g, 231.6 mmol) was slowly added. The mixture was stirred at room temperature overnight and concentrated. The resultant was purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 5:1) to obtain tert-butyl 4-(3-hydroxyoxypropoxy)piperidine-1-carboxylate (009D) (3.0 g, 11.6 mmol, yield 50.0%).

[0327] Step 4: Synthesis of tert-butyl 4-(3-formyloxypropoxy)piperidine-1-carboxylate (009E)

[0328] A solution of DMSO (0.59 g, 7.6 mmol) in dichloromethane (20 mL) was cooled to -78°C and oxalyl chloride (1.9 g, 15.0 mmol) was added dropwise, maintaining the internal temperature below -60°C. After 30 minutes at -78°C, a solution of tert-butyl 4-(3-hydroxyoxypropoxy)piperidine-1-carboxylate (009D) (1.3 g, 5.0 mmol) in DCM (5 mL) was added over 30 minutes, maintaining the temperature below -70°C. Stirring was continued for 2 hours, and the mixture was gradually warmed to -55°C, followed by the addition of freshly distilled triethylamine (2.54 g, 25.1 mmol) over 15 minutes. The reaction was allowed to warm to room temperature and saturated aqueous ammonium chloride was added, followed by brine (50 mL). The organic layer was separated and washed with brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude tert-butyl 4-(3-formyloxypropoxy)piperidine-1-carboxylate (009E) (1.0 g), which was used directly in the next step.

[0329] Step 5: Synthesis of tert-butyl 4-(butyl-3-alkynyl-1-oxy)piperidine-1-carboxylate (009F)

[0330] tert-Butyl 4-(3-formyloxypropoxy)piperidine-1-carboxylate (009E) (0.5 g, 1.9 mmol) was dissolved in methanol (5 mL), potassium carbonate (263 mg, 5.7 mmol) was added, and then dimethyl (1-diazo-2-oxopropyl) phosphonate (0.55 g, 2.85 mmol) was added dropwise. The mixture was then stirred at room temperature (25°C) for 12 hours. The reaction mixture was diluted with methyl tert-butyl ether, washed with saturated sodium bicarbonate solution, water, and brine, and the organic phase was dried over anhydrous sodium sulfate. After concentration, the resulting crude product was purified by silica gel column chromatography to obtain the product tert-butyl 4-(butyl-3-alkynyl-1-oxy)piperidine-1-carboxylate (009F) (100 mg, 0.4 mmol, 21.1% yield).

[0331] Step 6: Synthesis of 4-(butyl-3-alkynyl-1-oxy)piperidine hydrochloride (009G)

[0332] To tert-butyl 4-(butyl-3-alkynyl-1-oxy)piperidine-1-carboxylate (009F) (100 mg, 0.4 mmol) was added a solution of hydrogen chloride in 1,4-dioxane (5 mL, 4 M) and allowed to react at room temperature for 1 hour. The solvent was removed under reduced pressure to yield 4-(butyl-3-alkynyl-1-oxy)piperidine hydrochloride (009G) as a yellow solid. The crude product was used directly in the next reaction without purification.

[0333] Step 7: Synthesis of (4-(butyl-3-alkynyl-1-oxy)piperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amine)pyrimidin-5-yl)methanone (009H)

[0334] A 50% N,N-dimethylformamide solution of 1-propylphosphonic anhydride (300 mg, 0.5 mmol) was added to a solution of 4-(butyl-3-ynyl-1-oxyl)piperidine hydrochloride (009G) and diisopropylethylamine (10 mg, 0.7 mmol) in N,N-dimethylformamide (1 mL) at 0°C. The mixture was stirred for 5 minutes, and 2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidine-5-carboxylic acid (101 mg, 0.4 mmol) was added to the reaction mixture, which was then stirred at room temperature for 16 hours. Distilled water (10 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative chromatography to give a light yellow solid (4-(butyl-3-alkynyl-1-oxy)piperidin-1-yl)(2-((2,3-dihydro-1H-indene-2-yl)amine)pyrimidin-5-yl)methanone (009H) (130 mg, 0.33 mmol, two-step yield 82.5%).

[0335] Step 8: Synthesis of (4-(2-(1H-1,2,3-triazol-5-yl)ethoxy)piperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amine)pyrimidin-5-yl)methanone (target compound 009)

[0336] Under nitrogen protection, (4-(butyl-3-alkynyl-1-oxy)piperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)amine)pyrimidin-5-yl)methanone (009H) (130 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (3 mL) and methanol (1 mL), and sodium L-ascorbate (117 mg, 0.59 mmol) was added. The mixture was stirred at room temperature for 30 min, and then trimethylsilane azido (192 mg, 1.67 mmol) and copper sulfate pentahydrate (33 mg, 0.132 mmol) were added. The temperature was raised to 90 ° C and the reaction was carried out for 2 h. The reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel plate (ethyl acetate: methanol (V / V) = 10:1, ammonia water) to obtain compound (4-(2-(1H-1,2,3-triazol-5-yl)ethoxy)piperidin-1-yl)(2-((2,3-dihydro-1H-indene-2-yl)amine)pyrimidin-5-yl)methanone (target compound 009) (25 mg, yield 17.3%).

[0337] 1H NMR (400MHz, DMSO-d6): δ8.49(b,2H),7.97(d,1H),7.63(b,1H),7.23~7.20(m,2H),7.15~7.13(m,2H),4.68~4.6 2(m,1H),3.68(t,3H),3.60~3.57(m,1H),3.32~3.26(m,5H),2.94~2.88(m,4H),1.81(b,2H),1.47~1.45(m,2H).

[0338] LC-MS m / z: 434.4 [M+H] + .

[0339] Example 10: Preparation of target compound 010

[0340] (4-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-1-yl)(5-((2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)methanone (target compound 010)

[0341] The synthetic route of compound 010 is as follows:

[0342]

[0343] Step 1: Synthesis of 5-(2,3-dihydro-1H-inden-2-ylamino)pyrazine-2-carboxylic acid (010B)

[0344] Under nitrogen, 5-chloropyrazine-2-carboxylic acid (500 mg, 3.15 mmol), 2-aminoindane hydrochloride (642 mg, 3.78 mmol), palladium acetate (35.4 mg, 0.158 mmol), triphenylphosphine (83 mg, 0.315 mmol), and cesium carbonate (3083 mg, 9.46 mmol) were dissolved in 1,4-dioxane (10 mL) and water (10 mL) in sequence. The mixture was heated to 100°C and reacted for 20 h. The reaction solution was cooled, the organic solvent was evaporated, and the mixture was filtered. The solid was slurried with ethyl acetate (30 mL), filtered, and dried under air at 40°C for 2 h to obtain crude 5-(2,3-dihydro-1H-inden-2-ylamino)pyrazine-2-carboxylic acid (010B) (805 mg).

[0345] LC-MS m / z: 256.3 [M+H] + .

[0346] Step 2: Synthesis of tert-butyl 4-((prop-2-ynyl-1-oxy)methyl)piperidine-1-carboxylate (010D)

[0347] tert-Butyl 4-(hydroxymethyl)piperidine-1-carboxylate (010C) (15 g, 69.7 mmol) was dissolved in tetrahydrofuran (150 mL), cooled to 0°C, and sodium hydride (3.07 g, 77 mmol, 60%) was added. The mixture was stirred at room temperature for 30 min. 3-Bromopropyne (12.43 g, 105 mmol) was added dropwise and allowed to react at room temperature for 20 h. The reaction mixture was quenched by adding saturated ammonium chloride solution (300 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to afford tert-butyl 4-((prop-2-ynyl-1-oxy)methyl)piperidine-1-carboxylate (010D) (14 g, 79.3% yield) as a yellow liquid.

[0348] Step 3: Synthesis of 4-((prop-2-ynyl-1-oxy)methyl)piperidine hydrochloride (010E)

[0349] To tert-butyl 4-((prop-2-ynyloxy)methyl)piperidine-1-carboxylate (010D) (800 mg, 3.16 mmol) was added a solution of hydrogen chloride in dioxane (10 mL, 40.0 mmol, 4 M). The mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure to obtain the crude product, which was used directly in the next step without purification.

[0350] Step 4: Synthesis of (5-((2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)(4-((prop-2-ynyl-1-oxy)methyl)piperidin-1-yl)methanone (010F)

[0351] To the crude 4-((prop-2-ynyl-1-oxy)methyl)piperidine hydrochloride (010E) from the previous step were added N,N-dimethylformamide (8 mL), N,N-diisopropylethylamine (2038 mg, 15.77 mmol), and 5-(2,3-dihydro-1H-inden-2-ylamino)pyrazine-2-carboxylic acid (010B) (805 mg, 3.15 mmol). The reaction solution was cooled to about 0°C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide (3010 mg, 4.73 mmol, 50% N,N-dimethylformamide solution) was added dropwise. After the addition was complete, the mixture was reacted at 25-30°C for 2 h. Water (80 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified on a silica gel plate (petroleum ether: ethyl acetate (V / V) = 1:1) to give a light yellow solid (5-((2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)(4-((prop-2-ynyl-1-oxy)methyl)piperidin-1-yl)methanone (010F) (110 mg, yield 8.93%).

[0352] LC-MS m / z: 391.4 [M+H] + .

[0353] Step 5: Synthesis of (4-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-1-yl)(5-((2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)methanone (target compound 010)

[0354] Under nitrogen protection, (5-(2,3-dihydro-1H-inden-2-ylamino)pyrazin-2-yl)(4-((prop-2-ynyloxy)methyl)piperidin-1-yl)methanone (010F) (110 mg, 0.282 mmol) was dissolved in N,N-dimethylformamide (4 mL) and methanol (1 mL), and sodium L-ascorbate (112 mg, 0.563 mmol) was added. Then, trimethylsilyl azide (162 mg, 1.409 mmol) and copper sulfate pentahydrate (28.1 mg, 0.113 mmol) were added, and the temperature was raised to 100 ° C for 3 h. The reaction solution was concentrated, and dichloromethane:methanol (V / V) = 10:1 (50 mL) was added to the residue to dissolve it. The mixture was filtered and concentrated, and the residue was separated on a silica gel plate (ethyl acetate:methanol (V / V) = 20:1, ammonia water) to obtain compound (4-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-1-yl)(5-((2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)methanone (target compound 010) (25.9 mg, yield 21.21%).

[0355] 1 H NMR (400MHz, DMSO-d6): δ8.21~8.20(d,1H), 7.84~7.76(m,3H), 7.21~7.19(m,2H), 7.14~7.10(m,2H), 4.6 2~4.54(m,1H), 4.49(s,2H), 3.32~3.24(m,4H), 2.85~2.79(dd,2H), 1.84~1.63(m,4H), 1.32~1.04(m,6H).

[0356] LC-MS m / z: 434.4 [M+H] + .

[0357] Example 11: Preparation of target compound 011

[0358] (4-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-1-yl)(2-((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone (target compound 011)

[0359] The synthetic route of target compound 011 is as follows:

[0360]

[0361] Step 1: Synthesis of 2-((3-(difluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid (011B)

[0362] 2-Chloropyrimidine-5-carboxylic acid (2 g, 12.61 mmol), (3-(difluoromethoxy)phenyl)methanamine (3.28 g, 18.92 mmol), and N,N-diisopropylethylamine (4.89 g, 37.8 mmol) were dissolved in N-methylpyrrolidone (10 mL) and heated to 100°C for 20 h. After cooling to room temperature, the reaction solution was concentrated, and the residue was slurried with isopropyl acetate (30 mL). The residue was filtered, and the filter cake was rinsed with water (30 mL) and dried at 45°C for 2 h to obtain 2-((3-(difluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid (Compound 011B) (3 g, 81% yield) as a yellow solid.

[0363] LC-MS m / z: 296.2 [M+H] + .

[0364] Step 2: Synthesis of tert-butyl 4-((prop-2-yn-1-yloxy)methyl)piperidine-1-carboxylate (011D)

[0365] tert-Butyl 4-(hydroxymethyl)piperidine-1-carboxylate (011C) (2 g, 9.29 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0°C, and sodium hydride (409 mg, 10.22 mmol, 60%) was added, followed by dropwise addition of 3-bromopropyne (1.66 g, 14 mmol). The mixture was allowed to react at room temperature for 18 hours. Water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 100:1) to afford tert-butyl 4-((prop-2-yn-1-yloxy)methyl)piperidine-1-carboxylate (011D) (1.6 g, 68% yield) as a yellow liquid.

[0366] Step 3: Synthesis of 4-((prop-2-yn-1-yloxy)methyl)piperidine hydrochloride (011E)

[0367] To tert-butyl 4-((prop-2-yn-1-yloxy)methyl)piperidine-1-carboxylate (011D) (1.6 g, 6.32 mmol) was added a solution of hydrogen chloride in dioxane (20 mL). The mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to obtain the crude product, which was used directly in the next reaction without purification.

[0368] Step 4: Synthesis of (2-((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)(4-((propan-2-yl-1-yloxy)methyl)piperidin-1-yl)methanone (011F)

[0369] To the crude product of the previous step, 4-((prop-2-yn-1-yloxy)methyl)piperidine hydrochloride (011D) (300 mg, 1.582 mmol), were added N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (1.022 g, 7.91 mmol), and 2-((3-(difluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid (490 mg, 1.661 mmol). The reaction solution was cooled to about 0°C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide (1.308 g, 2.056 mmol, 50% N,N-dimethylformamide solution) was added dropwise. After the addition was complete, the mixture was reacted at room temperature for 16 h. The reaction solution was quenched by adding water (60 mL), extracted with ethyl acetate (30 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel plate to give a white solid (2-((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)(4-((propan-2-yl-1-yloxy)methyl)piperidin-1-yl)methanone (011F) (500 mg, yield 73.4%).

[0370] LC-MS, M / Z (ESI): 431.4 [M+H] + .

[0371] Step 5: Synthesis of (4-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-1-yl)(2-((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone (Compound 011)

[0372] Under nitrogen protection, (2-((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)(4-((propyl-2-yl-1-yloxy)methyl)piperidin-1-yl)methanone (011F) (500 mg, 1.162 mmol) was dissolved in N,N-dimethylformamide (15 mL) and methanol (8 mL), and sodium L-ascorbate (460 mg, 2.323 mmol) was added. Then, trimethylsilyl azide (1.34 g, 11.62 mmol) and copper sulfate pentahydrate (116 mg, 0.465 mmol) were added, and the temperature was raised to 90 ° C for 4 hours. The reaction solution was cooled to room temperature, water (40 mL) was added, and the product was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified using a silica gel plate to obtain compound (4-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-1-yl)(2-((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone (Compound 011) (66.6 mg, yield 12.1%).

[0373] 1 H NMR(400MHz,DMSO-d6)δ8.31(s,2H),8.17(t,1H),7.78(s,1H),7.32(t,1H),7.15(d,1H),7.07(s,1H),7.03-6.96(m,1 H),4.56-4.45(m,4H),3.26(d,2H),2.85(s,2H),2.49-2.44(m,2H),1.84-1.73(m,1H),1.64(d,2H),1.15-1.02(m,2H).

[0374] LC-MS m / z: 474.3 [M+H] + .

[0375] Example 12: Preparation of target compound 012

[0376] (4-(((2H-1,2,3-triazol-4-yl)methoxy)piperidin-1-yl)(2-((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone (target compound 012)

[0377] The synthetic route of target compound 012 is as follows:

[0378]

[0379] The specific synthesis steps were as shown in Example 11 to prepare the target compound 012.

[0380] 1 H NMR (400MHz, DMSO-d6) δ8.46(s,2H),8.28(t,1H),7.73(s,1H),7.32-7.27(m,1H),7.14-7.08(m,2H),7.03(s,1H) ),6.98-6.93(m,1H),4.49(d,2H),4.36(s,2H),4.26(d,2H),3.90(d,3H),2.42-2.35(m,2H),2.01-1.94(m,2H).

[0381] LC-MS, M / Z (ESI): 460.4 [M+H] + .

[0382] Example 13: Preparation of target compound 013

[0383] N-(4-(1H-1,2,3-triazol-4-yl)butyl)-2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxamide (target compound 013)

[0384] The synthetic route of target compound 013 is as follows:

[0385]

[0386] Step 1: Synthesis of 5-hexyn-1-amine (013B)

[0387] 6-Chloro-1-hexyne (1 g, 8.58 mmol), potassium phthalimide (1.906 g, 10.29 mmol), and potassium iodide (7.12 g, 42.9 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the temperature was raised to 80° C. for reaction for 20 h. The mixture was cooled to room temperature, water (70 mL) was added, and the mixture was extracted with methyl tert-butyl ether (40 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. Anhydrous ethanol (20 mL) and hydrazine hydrate (2.040 g, 32.6 mmol, 80% aqueous solution) were added to the residue. The mixture was heated to 70 ° C and reacted for 2 h. A large amount of white solid precipitated. The mixture was cooled to room temperature, hydrochloric acid solution (60 mL, 1N) and water (70 mL) were added, filtered, and the filtrate was extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow liquid 5-hexyn-1-amine (013B) (0.8 g, yield 96%).

[0388] Step 2: Synthesis of tert-butyl hexane-5-alkynylcarbamate (013C)

[0389] 5-Hexyn-1-amine hydrochloride (500 mg, 3.74 mmol) and triethylamine (757 mg, 7.48 mmol) were dissolved in tetrahydrofuran (10 mL), and di-tert-butyl dicarbonate (1.225 g, 5.61 mmol) was added. The reaction solution was stirred at room temperature for 4 h. Water (50 mL) was added to quench the reaction, and ethyl acetate (20 mL × 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:1 to 20:1) to obtain tert-butyl hexane-5-ynylcarbamate (013C) (620 mg, 84% yield) as a yellow liquid.

[0390] Step 3: Synthesis of tert-butyl 4-(1H-1,2,3-triazol-4-yl)butylcarbamate (013D)

[0391] Under nitrogen, tert-butyl hexane-5-ynylcarbamate (013C) (570 mg, 2.89 mmol), N,N-dimethylformamide (5 mL), methanol (1 mL), and cuprous iodide (27.5 mg, 0.144 mmol) were added. The reaction mixture was cooled to 0-5°C, and trimethylsilyl azide (666 mg, 5.78 mmol) was added dropwise. After the addition was complete, the temperature was raised to 100°C and the reaction was allowed to react for 18 h. The mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 3:1 to 2:1) to afford tert-butyl 4-(1H-1,2,3-triazol-4-yl)butylcarbamate (013D) (220 mg, 32% yield) as a yellow oil.

[0392] Step 4: Synthesis of 4-(1H-1,2,3-triazol-4-yl)butan-1-amine hydrochloride (013E)

[0393] To tert-butyl 4-(1H-1,2,3-triazol-4-yl)butylcarbamate (013D) (220 mg, 0.916 mmol) was added a solution of hydrogen chloride in dioxane (5 mL, 2.4 M) and stirred at room temperature for 1 h. The solvent was removed under reduced pressure to afford a yellow solid, which was used directly in the next reaction without further purification.

[0394] Step 5: Synthesis of N-(4-(1H-1,2,3-triazol-4-yl)butyl)-2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxamide (target compound 013)

[0395] To the crude product of the previous step, 4-(1H-1,2,3-triazol-4-yl)butan-1-amine hydrochloride (013E), were added N,N-dimethylformamide (5 mL), triethylamine (926 mg, 9.16 mmol), and 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (351 mg, 1.373 mmol). The reaction solution was cooled to about 0°C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide (1.165 g, 1.831 mmol, 50% N,N-dimethylformamide solution) was added dropwise. After the addition was complete, the mixture was reacted at room temperature for 3 h. The reaction solution was added with water (50 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (ethyl acetate: methanol (V / V) = 10:1) to obtain compound N-(4-(1H-1,2,3-triazol-4-yl)butyl)-2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxamide (target compound 013) (25 mg, yield 7.2%).

[0396] 1 H NMR (400MHz, DMSO-d6): δ8.68 (s, 2H), 8.24 (t, 1H), 8.02~8.03 (d, J=4.0Hz, 1H), 7.56 (bs, 1H), 7.10~7.19 (m, 4H), 4.59~4.6 8(m, 1H), 3.19~3.43(m, 4H), 2.84~2.90(dd, J1=16.0Hz, J2=8.0Hz, 2H), 2.64(t, 2H), 1.57~1.64(m, 2H), 1.45~1.53(m, 2H).

[0397] LC-MS m / z: 378.2 [M+H] + .

[0398] Example 14: Preparation of target compound 014

[0399] Synthesis of N-(5-(1H-1,2,3-triazol-4-yl)pentyl)-2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxamide (target compound 014) The synthetic route of target compound 014 is as follows:

[0400]

[0401] Step 1: Synthesis of 7-chlorohept-1-yne (014B)

[0402] 6-Heptynol (1.35 g, 12.04 mmol) and pyridine (1.61 g, 20.46 mmol) were dissolved in dichloromethane (10 mL). Thionyl chloride (2.43 g, 20.46 mmol) was added dropwise with stirring in an ice-water bath. The mixture was stirred at room temperature for 4.5 hours. The reaction was monitored for completion by TLC. Dichloromethane (10 mL) was added, and the mixture was washed sequentially with water (20 mL × 2) and saturated ammonium chloride (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 7-chlorohept-1-yne (1.3 g, 9.95 mmol, 83% yield) as a colorless liquid.

[0403] Step 2: Synthesis of 2-(hept-6-yn-1-yl)isoindoline-1,3-dione (014C)

[0404] To 7-chlorohept-1-yne (1.3 g, 9.95 mmol) was added phthalimide (1.76 g, 11.94 mmol), potassium carbonate (1.37 g, 9.95 mmol), potassium iodide (82.6 mg, 0.4975 mmol), and DMF (15 mL). The mixture was heated and stirred at 70°C for 18 hours. The reaction was monitored for completion by TLC. Heating was discontinued, the mixture was cooled with stirring, and ethyl acetate (75 mL) and petroleum ether (45 mL) were added. The mixture was washed sequentially with water (60 mL × 3) and saturated ammonium chloride solution (60 mL × 2). The organic phase was dried over anhydrous ammonium sulfate, filtered, and concentrated. The residue was purified on a silica gel column to obtain 2-(hept-6-yn-1-yl)isoindoline-1,3-dione as a white solid (880 mg, 3.65 mmol, 36.6% yield).

[0405] Step 3: Synthesis of hept-6-yn-1-amine (014D)

[0406] To 2-(hept-6-yn-1-yl)isoindoline-1,3-dione (880 mg, 3.65 mmol) was added hydrazine hydrate (2.01 g, 40.12 mmol) and anhydrous ethanol (20 mL). The mixture was heated and stirred at 90°C for 2 hours. The reaction was complete after TLC monitoring. Heating was stopped, the mixture was cooled with stirring, and the filtrate was filtered. The filtrate was concentrated, and the residue was dissolved in ethyl acetate (20 mL). The mixture was washed with water (20 mL x 3). The organic phase was concentrated to afford hept-6-yn-1-amine (500 mg, 4.5 mmol, 123% yield) as a yellow liquid.

[0407] Step 4: Synthesis of tert-butylhept-6-yn-1-ylcarbamate (014E)

[0408] To hept-6-yn-1-amine (500 mg, 4.5 mmol) was added dichloromethane (5 mL) and triethylamine (4.55 g, 45 mmol). Di-tert-butyl dicarbonate (7.8 g, 36 mmol) was added dropwise with stirring. The mixture was stirred at room temperature for 18 hours. The reaction was monitored for completion by TLC. The mixture was washed with water (5 mL x 3), the organic phase was concentrated, and the residue was purified on a silica gel column to afford tert-butyl hept-6-yn-1-ylcarbamate (1.1 g, 5.2 mmol, 115% yield) as a white solid.

[0409] Step 5: Synthesis of tert-butyl (5-(1H-1,2,3-triazol-4-yl)pentyl)carbamate (014F)

[0410] Dissolve tert-butylhept-6-yn-1-ylcarbamate (1.1 g, 5.2 mmol) in DMF (18 mL). Add anhydrous methanol (2 mL), cuprous iodide (79 mg, 0.42 mmol), and trimethylsilyl azide (1.08 g, 9.36 mmol) with stirring. Heat and stir at 100°C for 18 hours. The reaction is complete, monitored by TLC. Heating is discontinued, the mixture is cooled with stirring, and water (100 mL) is added. Extraction is performed with ethyl acetate (50 mL x 3). The organic phases are combined and concentrated. The residue is purified on a silica gel column to obtain an oily product, tert-butyl (5-(1H-1,2,3-triazol-4-yl)pentyl)carbamate (200 mg, 0.79 mmol, 15% yield).

[0411] Step 6: Synthesis of 5-(1H-1,2,3-triazol-4-yl)pentan-1-amine (014G)

[0412] To tert-butyl (5-(1H-1,2,3-triazol-4-yl)pentyl)carbamate (200 mg, 0.79 mmol) was added a solution of hydrogen chloride in 1,4-dioxane (120 mL, 2.4 N), stirred at room temperature for 2 hours, and concentrated to give 5-(1H-1,2,3-triazol-4-yl)pentan-1-amine hydrochloride (200 mg, 1.05 mmol, yield 132%) as an oil.

[0413] Step 7: Synthesis of N-(5-(1H-1,2,3-triazol-4-yl)pentyl)-2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxamide (target compound 014)

[0414] To 5-(1H-1,2,3-triazol-4-yl)pentan-1-amine hydrochloride (200 mg, 1.05 mmol) were added DMF (2 mL), 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (402 mg, 1.575 mmol), N,N-diisopropylethylamine (679 mg, 5.25 mmol) and TBTU (674 mg, 2.1 mmol) and stirred at room temperature for 18 hours. The reaction was completed after monitoring by TLC. The product was concentrated and methanol (20 mL) was added to the residue. The insoluble material was filtered off and the filtrate was separated by preparative chromatography to obtain compound N-(5-(1H-1,2,3-triazol-4-yl)pentyl)-2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxamide (5 mg, 12.77 μmol, yield 1.22%).

[0415] 1 HNMR (400MHz, DMSO-d6) δ8.71 (s, 2H), 8.28 (s, 1H), 8.07 (d, 1H), 7.57 (s, 1H), 7.29-7.04 (m, 4H ), 4.70-4.62(m,1H), 3.25(dd,4H), 2.90(dd,2H), 2.64(t,2H), 1.70-1.44(m,4H),1.34(d,2H).

[0416] LC-MS m / z: 392.4 [M+H] + .

[0417] Example 15: Preparation of target compound 015

[0418] N-(6-(1H-1,2,3-triazol-4-yl)butyl)-2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidine-5-carboxamide (target compound 015)

[0419] The synthetic route of target compound 015 is as follows:

[0420]

[0421] Step 1: Synthesis of 2-(7-octynyl)isoindoline-1,3-dione (015B)

[0422] 7-Octyn-1-ol (015A) (1 g, 7.92 mmol), tetrahydrofuran (40 mL), phthalimide (1.749 g, 11.89 mmol), and triphenylphosphine (3.12 g, 11.89 mmol) were added sequentially to a reaction flask. The reaction mixture was stirred and cooled to 0-5°C. Diisopropyl azodicarboxylate (3.53 g, 17.43 mmol) was added dropwise, maintaining the temperature below 20°C. After the addition was complete, the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 100:1 to 20:1) to afford 2-(7-octynyl)isoindoline-1,3-dione (015B) as a yellow oil (2.0 g, 99% yield).

[0423] Step 2: Synthesis of 2-(6-(1H-1,2,3-triazol-4-yl)hexyl)isoindoline-1,3-dione (015C)

[0424] Under nitrogen, 2-(7-octynyl)isoindoline-1,3-dione (015B) (500 mg, 1.958 mmol), N,N-dimethylformamide (9 mL), methanol (1 mL), and cuprous iodide (19 mg, 0.098 mmol) were added sequentially to a reaction flask. The reaction solution was stirred and cooled to 0-5°C. Azidotrimethylsilane (451 mg, 3.92 mmol) was added dropwise to the reaction system, and the reaction was heated to 100°C in a microwave oven for 3 h. The mixture was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 5:1 to 2:1) to give a yellow solid 2-(6-(1H-1,2,3-triazol-4-yl)hexyl)isoindoline-1,3-dione (015C) (230 mg, 39.4% yield).

[0425] LC-MS m / z: 299.2 [M+H] +

[0426] Step 3: Synthesis of 6-(1H-1,2,3-triazol-4-yl)hexan-1-amine (015D)

[0427] To 2-(6-(1H-1,2,3-triazol-4-yl)hexyl)isoindoline-1,3-dione (015C) (230 mg, 0.771 mmol) were added anhydrous ethanol (5 mL) and hydrazine hydrate (0.154 g, 3.85 mmol, 80%). The reaction mixture was heated to 70°C for 2 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to dryness to afford crude 6-(1H-1,2,3-triazol-4-yl)hexan-1-amine (015D), which was used directly in the next reaction.

[0428] Step 4: Synthesis of N-(6-(1H-1,2,3-triazol-4-yl)butyl)-2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidine-5-carboxamide (target compound 015)

[0429] To the crude product of the previous step, 6-(1H-1,2,3-triazol-4-yl)hexan-1-amine (015D), N,N-dimethylformamide (3 mL), triethylamine (722 mg, 7.13 mmol), and 2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidine-5-carboxylic acid (218 mg, 0.856 mmol) were added. The reaction solution was cooled to about 0°C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide (908 mg, 1.427 mmol, 50% N,N-dimethylformamide solution) was added dropwise. After the addition was complete, the mixture was reacted at room temperature for 3 h. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (ethyl acetate: methanol (V / V) = 10:1) to obtain compound N-(6-(1H-1,2,3-triazol-4-yl)butyl)-2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidine-5-carboxamide (target compound 015) (15 mg, yield 5.2%).

[0430] 1 H NMR (400MHz, DMSO-d6): δ8.67~8.69(d,2H), 8.25(t,1H), 8.04~8.06(d,1H), 7.55(s,1H), 7.10~7.19(m,4H), 4.58~4.6 7(m,1H), 3.15~3.25(m,4H), 2.83~2.89(dd,2H), 2.59(t,2H), 1.53~1.60(m,2H), 1.42~1.49(m,2H), 1.27~1.30(m,4H).

[0431] LC-MS m / z: 406.3 [M+H] + .

[0432] Biological activity and related properties test examples

[0433] Test Example 1: Autotaxin (ATX) enzyme activity inhibition test

[0434] The inhibitory activity of the compounds against the Autotaxin enzyme was tested using the Autotaxin Inhibitor Screening Assay Kit (Cayman, 700580). First, the test compound was prepared into a 10mM stock solution in DMSO solvent, and then gradiently diluted with DMSO to 8 concentration points. Subsequently, the 8 concentration points were diluted to a 19× compound working solution (DMSO content is 1.9%) using the Autotaxin Assay Buffer (1×) provided by the kit. The Autotaxin Assay Reagent (10×) was taken out and diluted 10 times with the Autotaxin Assay Buffer (1×). The Autotaxin substrate was taken out and dissolved in 1.2mL of Autotaxin Assay Buffer (1×), mixed and allowed to stand at room temperature. In a 96-well plate, 150 μL of Autotaxin assay buffer (1×), 10 μL of diluted 19× compound working solution, 10 μL of Autotaxin assay reagent (1×), and 20 μL of dissolved Autotaxin substrate were added to each well of each concentration point. The mixture was mixed and incubated in a 37°C constant temperature shaking in the dark for 30 min. The 96-well plate was removed and placed on a microplate reader to read the OD405. The experimental results were input into GraphPad Prism software, and the IC of each compound was obtained by fitting and calculation. 50 .

[0435] Table 1 Results of the inhibitory activity of the test compounds on ATX enzyme activity

[0436] Test compound <![CDATA[IC 50 (nM)]]> Compound 014 2.92 Compound 013 5.95 Compound 015 2.82 Compound 001 4.09 Compound 003 10.1 Compound 002 4.97 Compound 005 1.75 Compound 006 2.24 Compound 004 18.1 Compound 008 3.15 Compound 009 2.09 Compound 007 5.61 Compound 011 2.47 Compound 012 120 Compound 010 1.95

[0437] The experimental results show that the compound of the present invention has good inhibitory activity on ATX enzyme and can effectively inhibit ATX enzyme activity.

[0438] Test Example 2: Human liver microsome stability test

[0439] The stability test for human liver microsomes was performed by incubating the compound with human liver microsomes in vitro. The test compound was first prepared as a 10 mM stock solution in DMSO solvent, and then diluted to 0.5 mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS to form a microsome / buffer solution, and this solution was used to dilute 0.5 mM of the compound to form a working solution. The working solution contained 1.5 μM compound and 0.75 mg / ml human liver microsomes. A deep-well plate was prepared, and 30 μL of the working solution was added to each well. The reaction was then initiated by adding 15 μL of preheated 6 mM NADPH solution and incubated at 37°C. The reaction was terminated by adding 135 μL of acetonitrile to the corresponding wells at 0, 5, 15, 30, and 45 minutes of incubation. After terminating the reaction with acetonitrile at the final 45-minute time point, the deep-well plate was vortexed for 10 minutes (600 rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected and purified water was added in a 1:1 ratio. LC-MS / MS was then performed to obtain the ratio of the compound peak area to the internal standard peak area at each time point. The peak area ratios of the compound at 5, 15, 30, and 45 minutes were compared with the peak area ratio at 0 minute. The remaining percentage of the compound at each time point was calculated. T was calculated using Excel. 1 / 2 .

[0440] Table 2 Human liver microsome stability test results

[0441]

[0442]

[0443] The experimental results show that the compound of the present invention exhibits excellent liver metabolic stability, is metabolized more slowly in the human body, and has a higher exposure amount.

Claims

1. A compound, which is a compound represented by formula (I), or a tautomer of the compound represented by formula (I), or a pharmaceutically acceptable salt thereof: in, R 1 Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy; Selected from Z is selected from -NH-, -NH-CH2-; L 1 Selected from -O-, C1-C3 alkylene, C1-C3 alkyleneoxy; L 2 is selected from -CH2- or a single bond; Q is selected from phenyl, indenyl; R 2 selected from hydrogen, halogen, unsubstituted or optionally substituted by one or more halogens: C1-C3 alkyl, C1-C3 alkoxy; m is selected from an integer 0 or 1; n 1 is selected from the integers 0, 1, 2 or 3; n 2 Selected from the integers 1, 2 or 3; n 3 is selected from the integers 0, 1, 2 or 3; M 1 、M 2 、M 3 independently selected from -N=, -NH-; M 4 、M 5 independently selected from -CH=; The compound does not include the following compounds or their tautomers, or pharmaceutically acceptable salts:

2. The compound according to claim 1, characterized in that L 1 is -O-; and / or, R 2 Selected from -H, -F, -Cl, methyl, ethyl, methoxy, difluoromethoxy.

3. The compound according to claim 1, characterized in that for 4. A compound represented by formula (II), or a tautomer or a pharmaceutically acceptable salt of the compound represented by formula (II): in: Q is selected from phenyl, indenyl; Selected from Z is selected from -NH-, -NH-CH2-; R 1 Selected from hydrogen, fluorine, chlorine, C1-C6 alkyl, C1-C6 alkoxy; R 2 Selected from -H, -F, difluoromethoxy; L 1 Selected from -O-, -CH2-; L 2 is selected from -CH2-, -CH(CH3)- or a single bond; n 1 is selected from the integers 0, 1, 2 or 3; n 2 、n 3 are independently selected from the integers 1 or 2; M 1 、M 2 、M 3 independently selected from -N=, -NH-; The compound does not include the following compounds or their tautomers, or pharmaceutically acceptable salts:

5. The compound according to claim 4, characterized in that R 1 Selected from hydrogen.

6. The compound according to claim 4, characterized in that In formula (II) Selected from 7. The compound according to claim 4, characterized in that In formula (II) Selected from 8. The compound according to claim 4, characterized in that In formula (II) for 9. The compound according to claim 4, characterized in that In formula (II) Selected from 10. A compound represented by formula (III), or a tautomer or a pharmaceutically acceptable salt of the compound represented by formula (III): in: R 1 、R 2 independently selected from hydrogen; R 3 is selected from hydrogen and halogen; Selected from Z and L are selected from -NH-; Q is selected from indenyl; m is selected from the integer 0; n is selected from the integers 1, 2, 3, 4, 5 or 6; M 1 、M 2 、M 3 independently selected from -N=, -NH-, M 4 、M 5 is selected from -CH=.

11. A compound represented by formula (IV), or a tautomer or a pharmaceutically acceptable salt of the compound represented by formula (IV): where R 1 、R 2 selected from hydrogen; Selected from L is selected from -NH-; n is selected from the integers 4, 5 or 6; M 1 、M 2 、M 3 are all selected from -N= or -N(R 8 )-; R 8 Selected from hydrogen.

12. The compound according to claim 11, characterized in that for 13. The compound according to any one of claims 1 to 12, selected from:

14. A pharmaceutical composition, characterized in that The method comprises the compound according to any one of claims 1 to 13.

15. Use of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating ATX-related diseases.

16. The use according to claim 15, wherein the ATX-related disease is selected from metabolic diseases, kidney diseases, liver diseases, fibrotic diseases, interstitial lung diseases, proliferative diseases, inflammatory diseases, pain, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders and / or diseases related to abnormal angiogenesis.

17. The use according to claim 15, wherein the ATX-related disease is selected from interstitial lung disease, pulmonary fibrosis, liver fibrosis, and renal fibrosis.

18. The use according to claim 15, wherein the ATX-related disease is selected from idiopathic pulmonary fibrosis.

19. The use according to claim 15, wherein the ATX-related disease is selected from metabolic diseases.

20. The use according to claim 19, wherein the ATX-related disease is selected from type II diabetes and non-alcoholic steatohepatitis.

21. The use according to claim 15, wherein the ATX-related disease is selected from neuropathic pain and inflammatory pain.

22. The use according to claim 21, wherein the ATX-related disease is selected from osteoarthritis-related pain.

23. The use according to claim 15, wherein the ATX-related disease is selected from cancer.

Images