Pyrimidine compounds and their uses

Abstract

The present invention provides pyrimidine compounds and their uses. Specifically, the present invention provides a novel 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: #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to pyrimidine compounds, and more specifically, the present invention relates to pyrimidine compounds and their use in the preparation of drugs. Background Art

[0002] Autotaxin (abbreviated as ATX) is a secreted glycoprotein with phosphodiesterase (PDE) activity and is a member of the ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family, and thus is also referred to as ENPP2. ATX also has lysophospholipase D (LysoPLD) activity and can hydrolyze lysophosphatidylcholine (LPC) into bioactive lysophosphatidic acid (LPA). LPA is an intracellular lipid mediator that affects many biological and biochemical processes.

[0003] Studies have shown that under pathological conditions, inhibiting ATX can reduce the level of LPA, 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 disorders. For example, the pro-inflammatory effects of LPA include mast cell degranulation, smooth muscle cell contraction, and cytokine release from dendritic cells. As an indication of its general role in inflammation, upregulation of the ATX-LPA signaling pathway has been observed in the mouse carrageenan air pouch model (which is used for the development of anti-inflammatory drugs, including cyclooxygenase inhibitors for arthritis). In addition, a decrease in LPA in plasma and air pouches has been observed in the rat carrageenan air pouch model using an ATX inhibitor, demonstrating the role of ATX as the main source of LPA during inflammation. As another general role in inflammatory diseases, a "synergistic effect" has been demonstrated between LPA and lymphocyte migration chemokines. High expression of ATX has been found at sites of chronic inflammation. It has been confirmed that intravenous injection of enzymatically inactivated ATX inhibits T-cell homing to lymphoid tissues, possibly by competing with endogenous ATX and exerting a dominant negative effect. In some cases, ATX facilitates lymphocyte entry into lymphoid organs. Therefore, ATX inhibitors can block lymphocyte migration into secondary lymphoid organs and are beneficial in autoimmune diseases.

[0005] In rheumatoid arthritis, it has been demonstrated that the expression of ATX is increased in synovial fibroblasts from patients with rheumatoid arthritis (RA), and the elimination of ATX expression in stromal cells, including synovial fibroblasts, results in attenuation of symptoms in a murine model of rheumatoid arthritis. Accordingly, 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, and 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. It has been observed that autotaxin inhibitors reduce LPA and PGE2 and also alleviate inflammatory pain. There is also research indicating that targeted inhibition of ATX-mediated LPA biosynthesis may be a new mechanism for preventing neuropathic pain caused by nerve injury.

[0007] After inflammation resolution and tissue injury repair, tissues usually return to their initial state. In cases where it is no longer needed, excessive and uncontrolled tissue repair leads to a condition commonly referred to as fibrosis. Fibrosis is characterized by the excessive deposition of extracellular matrix components and the excessive growth of fibroblasts. Fibrosis can occur in all tissues, but it is particularly prevalent in organs that are frequently subjected to chemical and biological damage, including the lung, skin, digestive tract, kidney, and liver. Fibrosis often severely impairs the normal function of organs.

[0008] In certain cases, LPA stimulates the proliferation of hepatic stellate cells 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 different liver injuries, plasma LPA concentration and serum ATX activity are relatively high in carbon tetrachloride-induced liver fibrosis. Plasma LPA concentration and serum ATX activity increase with the severity of different liver injuries.

[0009] Pulmonary fibrosis is the end-stage change of a large category of lung diseases characterized by fibroblast proliferation, massive extracellular matrix accumulation, accompanied by inflammatory damage and destruction of tissue structure, that is, the normal alveolar tissue is damaged and then abnormally repaired, leading to abnormal structure (scar formation). When the lung is damaged by various causes, the interstitium secretes collagen for repair. If the repair is excessive, that is, fibroblasts proliferate excessively and a large amount of extracellular matrix accumulates, pulmonary fibrosis will form.

[0010] LPA signaling specifically has a profibrotic effect on epithelial cells, endothelial cells, and fibroblasts through the LPA1 receptor: genetic deletion of this receptor reduces epithelial cell apoptosis, vascular leakage, and fibroblast accumulation in a pulmonary fibrosis model.

[0011] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia of unknown etiology, characterized by diffuse alveolitis and alveolar structural disorder, and mainly presents as usual interstitial pneumonia in imaging and pathological histology. As the disease progresses, it causes pulmonary fibrosis, with the patient's lung tissue becoming thickened and hardened, resulting in permanent scarring, or the patient's lungs becoming honeycombed, which is vividly called "honeycomb lung" or "sponge lung". This chronic progressive lesion leads to an irreversible and continuous decline in lung function. 50% of patients have an average survival period of only 2.8 years after diagnosis, so idiopathic pulmonary fibrosis is also known as a "tumor-like disease". Currently, existing drug treatments have problems such as many adverse reactions and poor treatment effects; non-drug treatment methods are mainly lung transplantation surgeries, but organ transplantation is expensive, has limited resources, and has certain clinical risks.

[0012] There is evidence that fibroblast proliferation, contraction, and extracellular matrix secretion stimulated by LPA promote fibroproliferation in other airway diseases, such as peribronchiolar fibrosis present in chronic bronchitis, interstitial lung disease, and severe asthma. LPA plays a role in fibrotic interstitial lung disease and bronchiolitis obliterans, where both collagen and myofibroblasts increase. Studies related to IPF (idiopathic pulmonary fibrosis) have shown increased LPA levels 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 lung, and are complemented 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 the lung fibrosis model. 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 (through LPA1) and epithelial cells (through LPA2), and LPA2 has been shown to play a key role in TGFβ activation in epithelial cells under fibrotic conditions. The role of LPA in remodeling and fibrosis is related to COPD, IPF, and asthma, where lung remodeling as a long-term outcome of the disease will limit lung function. Finally, in the context of concerns about lung diseases, in mice, ATX is one of the three main quantitative trait loci that seems to be associated with differences in lung function.

[0013] Previous studies have found that the concentration of LPA is elevated in the plasma and ascites of ovarian cancer patients in the early and late stages. The elevated LPA level, the altered expression and response of LPA receptors may be one of the causes of the onset, progression or outcome of ovarian cancer. LPA is also associated with prostate cancer, breast cancer, melanoma, head and neck cancer, intestinal cancer, brain cancer and thyroid cancer. LPA is involved in the proliferation of tumor cells and the invasion of adjacent tissues, leading to metastasis. These biological and pathophysiological processes are initiated by the activation of LPA of G protein-coupled receptors. Tumor patients can be treated by reducing the LPA level by inhibiting the enzymes related to LPA biosynthesis, such as ATX.

[0014] During angiogenesis, ATX, together with other angiogenic factors, leads to blood vessel formation. Angiogenesis provides nutrition for tumors during tumor growth. Therefore, inhibiting angiogenesis can be said to be an important starting point for cancer and tumor treatment.

[0015] 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, is disclosed in patent application WO2014202458A1.

[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 diseases associated with abnormal angiogenesis, but there are still deficiencies. The currently marketed IPF treatment drugs are pirfenidone and nintedanib. Pirfenidone has liver function impairment (such as liver failure, jaundice), hypersensitivity reactions (such as facial swelling, laryngeal edema, dyspnea, wheezing, etc.), severe gastrointestinal reactions, and photogenotoxicity tests show 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%, and common adverse reactions also include weight loss, loss of appetite, liver damage, bleeding, etc. Among the patients receiving pirfenidone and nintedanib treatment, the probabilities of drug withdrawal due to severe adverse events are 20.9% and 26.3% respectively. The quality of life of IPF patients will be severely affected, and neither pirfenidone nor nintedanib can improve the quality of life of patients in clinical trials. Although both of these drugs may improve the overall outcome, they can only delay the disease course but cannot reverse pulmonary fibrosis, so patients with severe idiopathic pulmonary fibrosis may not benefit. GLPG-1690, which has a relatively fast development progress in the current treatment of IPF drugs, although shows a trend of reversing the disease course, has problems such as low enzyme activity, large clinical drug dosage, and poor drug compliance. Therefore, the current therapies are not satisfactory, and there are still a large number of patients in need of new treatments with higher activity and better efficacy, which can slow down or even reverse the disease process to a greater extent, improve drug compliance, and benefit more patients with idiopathic pulmonary fibrosis.

[0017] In view of this, on the basis of the existing technology, the present invention designs the compound shown in formula (I) to provide an ATX inhibitor with novel structure, better pharmacokinetic properties, better efficacy, and strong drug-forming properties, for effectively treating ATX-related diseases and disorders, 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 diseases associated with abnormal angiogenesis. Summary of the Invention

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

[0019] According to one aspect of the present invention, the present invention provides a compound shown in formula (I), its pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, or prodrugs:

[0020]

[0021] in,

[0022] R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, halogen, -CN, -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;

[0023] X and Y are the same or different and are independently selected from -N=, -C(R 6 )-; Z is independently selected from -O-, -S-, -C(R 7 )(R 8 )-、-N(R 9 )-、-N(R 9 )-C(R 7 )(R 8 )-;

[0024] Q is selected from C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0025] Every R 5 are the same or different and are independently selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, unsubstituted or optionally substituted with one or more R b 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;

[0026] Each R a and R b , which are the same or different, are each 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- to 10-membered heterocyclic group, 3- to 10-membered heterocyclic oxy group, C6-C 20 aryl, C6-C 20 aryloxy, 5- to 20-membered heteroaryl, 5- to 20-membered heteroaryloxy;

[0027] n 1 and n 2 , and m are each independently selected from the integers 0, 1, 2, 3, 4, 5 or 6;

[0028] M 1 , M 2 , M 3 , M 4 , M 5 are each independently selected from -N=, -N(R 10 )-, -CH=, -C(R 11 )=, where at least one of M 1 , M 2 , M 3 , M 4 , M 5 is selected from -N= or -N(R 10 )-, and at least one of M 1 , M 2 , M 3 , M 4 , M 5 is selected from -CH= or -C(R 11 )=;

[0029] L is selected from where p1, p2, p3, p4, q1, q2, q3, q4 are each independently selected from the integers 0, 1, 2, 3, 4, 5 or 6, and p3 and p4 are not both 0, q1 and q2 are not both 0, and q3 and q4 are not both 0;

[0030] R 6 , R 7 , R 8 , R 11 , R12 and R 13 is independently selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3- to 10-membered heterocyclic group oxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5- to 10-membered heteroaryl; C6-C 10 aryloxy, 5- to 10-membered heteroaryloxy;

[0031] R 9 and R 10 is independently selected from hydrogen, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl, 5- to 10-membered heteroaryl;

[0032] and the compound does not include the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0033]

[0034] In some embodiments of the present invention, in the compound of formula (I), Q is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, 2,3-dihydro-1H-indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolyl, and the remaining variables are as defined in the present invention.

[0035] In some embodiments of the present invention, in the compound of formula (I), R 5 is selected from -H, -F, -Cl, methyl, ethyl, difluoromethoxy, and the remaining variables are as defined in the present invention.

[0036] In some embodiments of the present invention, in the compound of formula (I), M1, M2, and M3 are each independently selected from -N= or -N(R 10 )-, and M 4 , M 5 are each independently selected from -CH= or -C(R 11 )=, and the remaining variables are as defined in the present invention.

[0037] According to an exemplary embodiment of the present invention, the compound represented by formula (I) may be further preferably the compound represented by the following formula (II):

[0038]

[0039] In formula (II),

[0040] R 1 、R 2 、R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;

[0041] X and Y are the same or different and are independently selected from -N=, -C(R 6 )-; R 6 is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl;

[0042] n 1 、n 2 are independently selected from the integers 0, 1, 2;

[0043] M 1 、M 2 、M 3 are independently selected from -N=, -N(R 10 )-, where R 10 is selected from hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl

[0044] L is selected from where p1, p2, p3, p4, q1, q2, q3, q4 are independently selected from the integers 0, 1, 2, and p3 and p4 are not both 00, q1 and q2 are not both 0, and q3 and q4 are not both 0;

[0045] and the compound does not include the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0046]

[0047] In some embodiments of the present invention, in the compound represented by formula (II), M 1 、M 2 、M 3 are all selected from -N= or -NH-, and the remaining variables are as defined in the present invention.

[0048] According to an exemplary embodiment of the present invention, the compound represented by formula (I) may be further preferably the compound represented by the following formula (III):

[0049]

[0050] In formula (III),

[0051] R 1 、R 2 、R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;

[0052] R 5 is independently selected from hydrogen, -CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy;

[0053] X and Y are the same or different and are independently selected from -N=, -C(R 6 )-; R 6 is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl;

[0054] n 1 、n 2 are independently selected from the integers 0, 1, 2;

[0055] M 1 、M 2 、M 3 are independently selected from -N=, -N(R 10 )-, wherein R 10 is selected from hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0056] L is selected from wherein p1, p2, p3, p4, q1, q2, q3, q4 are independently selected from the integers 0, 1, 2, and p3 and p4 are not both 0, q1 and q2 are not both 0, and q3 and q4 are not both 0;

[0057] and the compound does not include the following compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0058]

[0059] In some embodiments of the present invention, in the compound represented by formula (III), M 1 、M 2 、M 3 are all selected from -N= or -NH-, and the remaining variables are as defined in the present invention.

[0060] 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:

[0061]

[0062]

[0063] According to an embodiment of the present invention, the compounds of the present invention include compounds represented by the following formula, or at least one of tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs of the compounds represented by the following formula:

[0064] Tautomerism may exist in the compounds of the present invention. The present invention includes all tautomeric forms of the compounds. Whether in a state of equilibrium or one form predominates, each tautomeric form is included in the present invention.

[0065] According to another aspect of the present invention, there is provided a pharmaceutical composition containing a therapeutically effective dose of at least one compound represented by formula (I) to formula (III) of the present invention or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate or prodrug thereof.

[0066] "Pharmaceutical composition" refers to a mixture of one or more of the compounds described in the text or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.

[0067] According to another aspect of the present invention, there is provided the use of the compounds represented by formula (I) to formula (III), their pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates or prodrugs, or a pharmaceutical composition containing the compounds represented by formula (I) to formula (III) or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate or prodrug thereof in the preparation of a drug for treating diseases related to ATX.

[0068] In some embodiments of the present invention, the ATX-related diseases are selected from cancer, 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.

[0069] In some embodiments of the present invention, the ATX-related diseases are selected from interstitial lung diseases, pulmonary fibrosis, liver fibrosis, and renal fibrosis.

[0070] In some embodiments of the present invention, the ATX-related disease is selected from idiopathic pulmonary fibrosis. According to the examples of the present invention, the compounds of the present invention have significant advantages in treating pulmonary fibrosis, especially idiopathic pulmonary fibrosis.

[0071] In some embodiments of the present invention, the ATX-related diseases are selected from metabolic diseases.

[0072] In some embodiments of the present invention, the ATX-related diseases are selected from type II diabetes and non-alcoholic steatohepatitis. According to the embodiments of the present invention, the compounds of the present invention have significant advantages in treating metabolic diseases, especially type II diabetes and non-alcoholic steatohepatitis.

[0073] In some embodiments of the present invention, the ATX-related diseases are selected from neuropathic pain and inflammatory pain.

[0074] In some embodiments of the present invention, the ATX-related diseases are selected from the pain associated with osteoarthritis. According to the embodiments of the present invention, the compounds of the present invention have significant advantages in treating the pain associated with osteoarthritis.

[0075] In some embodiments of the present invention, the ATX-related diseases are selected from cancer. According to the embodiments of the present invention, the compounds of the present invention have significant advantages in treating cancer.

[0076] Term Definitions and Explanations

[0077] Unless otherwise specified, the definitions of the groups and terms recited in the specification and claims of this application, including their definitions by way of example, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, etc., can be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination shall fall within the scope described in the specification of this application.

[0078] Unless otherwise defined, all scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and published materials cited herein in their entirety are incorporated herein by reference. If there are multiple definitions of a term herein, the definitions in this chapter shall prevail.

[0079] Unless otherwise specified, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR, and UV / Vis spectroscopy, and pharmacological methods. Unless otherwise specifically defined, the terms employed in the descriptions of analytical chemistry, organic synthetic chemistry, and in relation to pharmaceuticals and medicinal chemistry herein are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and the treatment of patients. For example, the instructions of the manufacturer for the kits can be utilized, or the reactions can be carried out and purification can be performed in a manner known in the art or as described in the present application. Generally, the above-mentioned techniques and methods can be implemented according to the descriptions in a plurality of general and more specific documents cited and discussed in this specification, in accordance with the conventional methods well-known in the art. In this specification, groups and their substituents 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 the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2.

[0080] For the numerical ranges recited in the specification and claims of the present application, when the numerical range is understood as "integers", it should be understood that the two endpoints of the range and each integer within the range are recited. For example, "integers from 1 to 6" should be understood as reciting each of 0, 1, 2, 3, 4, 5, and 6. When the numerical range is understood as "numbers", it should be understood that the two endpoints of the range and each integer within the range, as well as each decimal within the range, are recited. For example, "numbers from 1 to 10" should be understood as not only reciting each of the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sums of each of these integers respectively with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.

[0081] The term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0082] The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.

[0083] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or can be used for the identification, characterization, or purification of the compounds of the present invention.

[0084] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers, and conformational isomers. The stereochemical definitions and conventions used in the present invention generally follow those defined in S.P. 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.

[0085] Depending on the choice of starting materials and methods, the compounds of the present invention may exist in the form of one or a mixture of the possible isomers, for example as pure enantiomers, or as a mixture of isomers, such as a racemic and diastereoisomeric mixture, depending on the number of asymmetric carbon atoms. When describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center(s) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. A compound with the prefix (+) or D is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and a mixture of such isomers is commonly called a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and such a racemic mixture or racemate may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of alkenes, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. When the compounds described herein contain an alkene double bond, unless otherwise stated, such double bonds include E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the substituents on the cycloalkyl group may be in the cis- or trans- configuration.

[0086] When depicting the bonds to a chiral carbon in the formulae of the present invention as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The graphical representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise stated, the absolute configuration of a stereocenter is represented by a wedge bond and a dashed bond.

[0087] The optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active form or as a racemate. Resolution of the racemic mixtures of the compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional crystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for the fractional crystallization method 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 the fractional crystallization method include stereoisomerically pure forms of α-methyl-benzylamine (e.g., the S and R forms or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of the racemic mixture can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoyl-phenylglycine). High performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) can be employed. The choice of the specific method, as well as the elution conditions and the selection of the column, can be made by those skilled in the art according to the structure of the compound and the test results. Further, any enantiomer or diastereomer of the compounds described in the present invention can be obtained by stereoselective organic synthesis using optically pure starting materials or reagents of known configuration.

[0088] The term "tautomer" refers to functional group isomers resulting from the rapid migration of an atom within a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomers of a compound may exist in two or more interconvertible forms. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in an equilibrium form, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are identical to those of a mixture of the compounds. The position of the equilibrium depends on the chemical characteristics 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.

[0089] In the examples of the present invention, protons can occupy two or more positions in the cyclic forms of the heterocyclic systems, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. The tautomeric forms can be in equilibrium or spatially fixed in one form by appropriate substitution. For example:

[0090]

[0091] Due to resonance, the hydrogen of the nitrogen on the triazole can be on any of the three nitrogens, so the naming will be different, but these three forms actually represent the same compound.

[0092] The term "pharmaceutical composition" refers to a mixture of one or more of the 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 the pharmaceutical composition is to facilitate the administration of the compound to an organism.

[0093] For a drug or a pharmacological active agent, the terms "effective dose", "effective amount" or "therapeutically effective amount" refer to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. For the oral dosage forms in the present invention, the "effective amount" of an active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in a particular case can be determined by those skilled in the art through routine tests.

[0094] The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat a target disorder, disease or condition.

[0095] The term "solvate" refers to a stoichiometric or non-stoichiometric solvent in which the compounds or salts of the present invention are included by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

[0096] The term "prodrug" refers to a compound that can be converted into a biologically active compound of the present invention under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. Prodrugs include compounds formed by connecting a hydroxyl group or an amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group respectively.

[0097] The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound can be labeled with a radioactive isotope, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All isotopic compositions of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0098] The term "C1-C 10 alkyl" shall be understood to mean a straight-chain or branched-chain saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Examples of such alkyl groups are 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, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl and their isomers. In particular, the group has 1, 2, 3, 4, 5, 6 carbon atoms ("C1-C6 alkyl"), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, and more particularly, the group has 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), such as methyl, ethyl, n-propyl or isopropyl.

[0099] The term "C3-C 10 cycloalkyl" shall be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms, including fused or bridged polycyclic systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decahydronaphthalene ring.

[0100] The term "3- to 10-membered heterocyclic group" shall be 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, unless otherwise specified, may be linked through carbon or nitrogen, wherein -CH 2-The group is optionally replaced by -C(O)-; and wherein unless otherwise stated to the contrary, the ring nitrogen atom or ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or the ring nitrogen atom is optionally quaternized; wherein -NH in the ring is optionally substituted by an acetyl group, a formyl group, a methyl group or a mesyl group; 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-methanesulfonylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroindolyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5-dioxoimidazolidinyl.

[0101] The term "C2-C 10"Alkenyl" shall be understood to denote a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 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 should be 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, (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.

[0102] The term "C2-C 10"Alkynyl" shall be understood to mean a straight-chain or branched monovalent hydrocarbon group that contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. For example, it has 2, 3, 4, 5, or 6 carbon atoms (i.e., "C2-C6 alkynyl"), or 2 or 3 carbon atoms ("C2-C3 alkynyl"). The alkynyl group is, 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, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl, or prop-2-ynyl.

[0103] The term "C1-C 10 alkoxy" shall be understood as -O-(C1-C 10 alkyl), where "C1-C 10 alkyl" has the above definition.

[0104] The term "C6-C 10 aryl" shall be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6 to 10 carbon atoms, particularly 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 ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl. When the C6-C 10 aryl is substituted, it can be mono-substituted or multi-substituted. Also, there is no restriction on the substitution site, for example, it can be ortho-substituted, para-substituted, or meta-substituted.

[0105] The term "C6-C 10 aryloxy" shall be understood as -O-(C6-C 10 aryl), where C6-C 10The aryl group has the above definition.

[0106] The term "5- to 10-membered heteroaryl" should be understood to mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring group having 5 to 10 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, such as "5- to 14-membered heteroaryl". The term "5- to 14-membered heteroaryl" should be understood to mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring group 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 - and containing 1 to 5, preferably 1 to 3 - heteroatoms independently selected from N, O and S, and which may additionally be benzo-fused in each case. In particular, the heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0107] The term "5- to 10-membered heteroaryloxy" should be understood to mean -O-(5- to 10-membered heteroaryl), where the 5- to 10-membered heteroaryl has the above definition.

[0108] The term "halogen group" or "halogen" is fluorine, chlorine, bromine and iodine.

[0109] "Haloalkyl" refers to a branched and straight-chain saturated aliphatic hydrocarbon group including a specific number of carbon atoms and substituted by one or more halogens (such as -CvFw, where v = 1 to 3 and 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.

[0110] Beneficial effects

[0111] According to specific examples of the present invention, the compounds represented by formula (I) to formula (III) of the present invention, their pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates or prodrugs have a significant inhibitory effect on ATX enzyme.

[0112] According to specific examples of the present invention, the compounds of the present invention can effectively inhibit the activity of ATX enzyme.

[0113] Additional aspects and advantages of the present invention will be given in part in the following description, become apparent in part from the following description, or be learned by practice of the present invention. Detailed Embodiments

[0114] The solution of the present invention will be explained below in conjunction with embodiments. Those skilled in the art will understand that the following embodiments are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. For those not specified in the embodiments regarding specific techniques or conditions, they shall be carried out according to the techniques or conditions described in the literature in this field or according to the product specifications. For reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained commercially.

[0115] Embodiments of the present invention provide compounds represented by formula (I) to formula (III), pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs thereof, methods and intermediates for preparing compounds represented by formula (I) to formula (III) or pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals or prodrugs thereof, pharmaceutical compositions, and uses of the compounds and pharmaceutical compositions of the present invention in the preparation of drugs.

[0116] There is no particular limitation on the reaction solvents used in each reaction step of the present invention, and 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 equivalent to those described in the present invention, solvent combinations, and different ratios of solvent combinations are regarded as within the scope of the present invention.

[0117] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).

[0118] Liquid chromatography-mass spectrometry (LC-MS) is determined by a Waters Acquity H-class Uplc-QDA mass spectrometer, and monitored using an ACQUITY UPLC BEH C18, 2.1 * 50 mm, 1.7 μm chromatographic column. Gradient elution conditions: at a flow rate of 1.0 mL / min, 95 - 5% solvent A1 and 5 - 95% solvent B1, then 95% B1 and 5% A1 are maintained for 0.5 min. The percentages are the volume percentages of a certain solvent in the total solvent volume. Among them, solvent A1: an aqueous solution of 0.1% formic acid; solvent B1: an acetonitrile solution of 0.1% formic acid. The percentages are the volume percentages of the solute in the solution.

[0119] The abbreviations of the present invention are defined as follows:

[0120] CuI: Copper(I) iodide

[0121] DCM: Dichloromethane

[0122] DIBAL-H: Diisobutylaluminum hydride

[0123] DIPEA: Also written as DIEA, Diisopropylethylamine, i.e., N,N-Diisopropylethylamine

[0124] DMF: N,N-Dimethylformamide

[0125] DMSO: Dimethyl sulfoxide

[0126] Et3N: Triethylamine

[0127] HATU: 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0128] HPLC: High Performance Liquid Chromatography

[0129] MeOH: Methanol

[0130] N: Normality, for example, 2N hydrochloric acid represents a 2 mol / L hydrochloric acid solution

[0131] NADPH: Reduced nicotinamide adenine dinucleotide phosphate

[0132] NaH: Sodium hydride

[0133] NMM: N-Methylmorpholine, also known as N-Methylmorphine

[0134] NMP: N-Methylpyrrolidone

[0135] SFC: Supercritical Fluid Chromatography

[0136] T3P: Propylphosphonic anhydride, i.e., 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide or 1-Propylphosphonic anhydride

[0137] THF: Tetrahydrofuran

[0138] TMSN3: Trimethylsilyl azide

[0139] TsCl: p-Toluenesulfonyl chloride

[0140] IC 50 : Half maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0141] Unless otherwise indicated, the compounds exemplified herein are named and numbered using ChemBioDraw Ultra 13.0.

[0142] Preparation Example 1: Preparation of Intermediate 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic Acid

[0143]

[0144] First Step: Methyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate

[0145] Methyl 2-chloropyrimidine-5-carboxylate (2.2 g, 12.7 mmol) as the raw material was added to 50 ml of dioxane. At room temperature, 2,3-dihydro-1H-inden-2-amine hydrochloride (2.27 g, 13.4 mmol) was added, and DIPEA (3.2 g, 31.7 mmol) was added. The mixture was heated to 100 °C and stirred for 15 h. After cooling to room temperature, water (50 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, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain the title compound, pale yellow solid, methyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (A) (2.6 g, yield 75.5%).

[0146] LC-MS m / z: 270.1 [M+H] + 。

[0147] Second Step: 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic Acid

[0148] Methyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (2.25 g, 8.36 mmol) as the raw material was added to 15 ml of THF, 15 ml of methanol, and 15 ml of water. At room temperature, sodium hydroxide (1.34 g, 33.45 mmol) was added, and the mixture was stirred at room temperature for 16 h. The pH of the reaction solution was adjusted to 7 with hydrochloric acid, filtered, and dried to obtain the target compound, white solid, 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (2.1 g, yield 98.4%).

[0149] LC-MS m / z: 256.1 [M+H] + 。

[0150] Example 1: Preparation of Target Compound 001-1

[0151] ((1R,5S,6r)-6-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone. The synthetic route of the target compound 001-1 is as follows:

[0152]

[0153] The first step: Synthesis of tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (001B)

[0154] Add the raw material (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid (500 mg, 2.2 mmol) to 5 ml of THF, add lithium aluminum hydride (125 mg, 3.2 mmol) at room temperature, and stir at room temperature for 24 h. Add water (0.13 ml) to the reaction solution, add 15% aqueous sodium hydroxide solution (0.13 ml), then add 0.36 ml of water, filter, concentrate, and obtain the title compound as a pale yellow liquid, tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (001B) (213 mg, yield 61.6%).

[0155] LC-MS m / z: 158.1 [M+H] + .

[0156] The second step: Synthesis of tert-butyl (1R,5S,6r)-6-((prop-2-yn-1-yloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (001C)

[0157] Add the raw material tert-butyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.0 g, 9.4 mmol) to 35 ml of THF at room temperature, add 60% NaH (560 mg, 14 mmol) at room temperature, stir at 0 °C for 0.5 h, add 3-bromopropyne (1.3 ml, 14.1 mmol), and stir at room temperature for 16 h. Add water (50 ml) to the reaction solution, extract with ethyl acetate (30 ml × 3), combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain the title compound as a pale yellow liquid, tert-butyl (1R,5S,6r)-6-((prop-2-yn-1-yloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (001C) (1.2 g, yield 50.8%).

[0158] LC-MS m / z: 252.1 [M+H] + 。

[0159] Step 3: (1R,5S,6r) 6-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0160] The raw material (1R,5S,6r)-6-((prop-2-yn-1-yloxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.20 g, 4.78 mmol) was added to 10 ml of DMF and 2 ml of methanol. Under nitrogen protection, copper(I) iodide (109 mg, 0.57 mmol) and trimethylsilyl azide (824 mg, 7.17 mmol) were added. The mixture was heated to 110 °C and stirred for 16 h. After cooling to room temperature, water (50 ml) was added. The reaction solution was extracted with ethyl acetate (50 ml × 3), concentrated, and the residue was separated and purified by silica gel column chromatography (methylene chloride:methanol (V / V) = 10:1) to obtain the title compound as a yellow liquid (1R,5S,6r) 6-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (001D), (1.50 g, yield 100%).

[0161] LC-MS m / z: 295.2 [M+H] + 。

[0162] Step 4: (1R,5S,6r) 6-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)-3-azabicyclo[3.1.0]hexane

[0163] At room temperature, the raw material (1R,5S,6r) 6-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.5 g, 5.1 mmol) was added to 20 ml of dichloromethane and 10 ml of methanol. 4 mol / L hydrochloric acid dioxane solution (10 ml) was added, and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated to obtain the title compound as a yellow liquid (1R,5S,6r) 6-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)-3-azabicyclo[3.1.0]hexane (001E) (1.40 g, yield 100%).

[0164] LC-MS m / z: 195.1 [M+H] + 。

[0165] Step 5: ((1R,5S,6r)-6-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone

[0166] The raw material (1R,5S,6r)6-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)-3-azabicyclo[3.1.0]hexane (974 mg, 5.02 mmol) was added to 15 ml of DMF, then 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (800 mg, 3.14 mmol), 1-propylphosphonic anhydride (3.0 g, 4.71 mmol) and N-methylmorpholine (634 mg, 6.26 mmol) were added, and the mixture was stirred at room temperature for 16 h. Water (40 ml) was added, and the mixture was extracted with ethyl acetate (30 ml×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was used to prepare the title compound ((1R,5S,6r)-6-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (230 mg, 17%).

[0167] 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 2H), 7.99 (d, 1H), 7.81 (s, 1H), 7.21 (dt, 2H), 7.16 - 7.13 (m, 2H), 4.65 (dt, 1H), 4.53 (s, 2H), 3.93 (s, 1H), 3.79 (s, 1H), 3.54 (s, 1H), 3.34 (d, 4H), 3.25 (dd, 2H), 2.91 (dd, 2H), 1.52 (s, 2H), 0.81 (dt, 1H).

[0168] LC-MS m / z: 432.0 [M+H] + 。

[0169] Example 2: Preparation of the target compound 002

[0170] ((3aR,5r,6aS)-5-((1H-1,2,3-triazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone

[0171] The synthetic route of the target compound 002-1 is shown as follows:

[0172]

[0173] Step 1: tert-Butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (002B)

[0174] The starting material tert-butyl (3aR,5r,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.0 g, 4.4 mmol) was added to 10 ml of methanol, cooled to 0 °C, and sodium borohydride (336 mg, 8.9 mmol) was added. The mixture was stirred at 0 °C for 24 h. Water (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude title compound tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (002B) as a pale yellow liquid (1 g, yield 99.1%).

[0175] LC-MS m / z: 228.1 [M+H] + 。

[0176] Step 2: tert-Butyl (3aR,5r,6aS)-5-(prop-2-yn-1-yloxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (002C)

[0177] The crude starting material tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (100 mg, 0.44 mmol) was added to 5 ml of DMF at room temperature. 60% NaH (30 mg, 0.9 mmol) was added at room temperature, and the mixture was stirred for 2 h. The mixture was cooled to 10 °C, and 3-bromopropyne (110 mg, 0.9 mmol) was added. The mixture was stirred at 10 °C for 16 h. Water (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to give the title compound tert-butyl (3aR,5r,6aS)-5-(prop-2-yn-1-yloxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (002C) as a pale yellow liquid (80 mg, yield 68.5%).

[0178] LC-MS m / z: 266.1 [M+H] + 。

[0179] Step 3: tert-Butyl (3aR,5r,6aS)-5-((1H-1,2,3-triazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (002D)

[0180] (3aR,5r,6aS)-5-((Prop-2-yn-1-yloxy)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (80 mg, 0.3 mmol) was added to 2.5 ml of DMF and 0.5 ml of methanol. Under nitrogen protection, copper(I) iodide (7 mg, 0.04 mmol) and trimethylsilyl azide (52 mg, 0.45 mmol) were added. The mixture was heated to 110 °C and stirred for 16 h. After cooling to room temperature, water (20 ml) was added. The reaction mixture was extracted with ethyl acetate (20 ml × 3), concentrated to give the crude title compound, (3aR,5r,6aS)-5-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (002D), as a yellow liquid (65 mg, yield 69.9%).

[0181] LC-MS m / z: 309.1 [M+H] + 。

[0182] Step 4: (3aR,5r,6aS)-5-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)octahydrocyclopenta[c]pyrrole (002E)

[0183] The crude product of (3aR,5r,6aS)-5-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (65 mg, 0.21 mmol) was added to 1 ml of dichloromethane and 1 ml of methanol at room temperature. 4 mol / L hydrochloric acid dioxane solution (0.5 ml) was added, and the mixture was stirred at 10 °C for 4 h. The reaction mixture was concentrated to give the title compound, (3aR,5r,6aS)-5-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)octahydrocyclopenta[c]pyrrole (002E), as a yellow solid (60 mg, yield 100%).

[0184] LC-MS m / z: 209.1 [M+H] + 。

[0185] Step 5: ((3aR,5r,6aS)-5-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (002-1)

[0186] (3aR,5r,6aS)-5-((1H-1,2,3-triazol-4-yl)methoxy)octahydrocyclopenta[c]pyrrole (50 mg, 0.2 mmol) was added to 2 ml of DMF and 1 ml of ethyl acetate, followed by the addition of 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (73 mg, 0.3 mmol), 1-propylphosphonic anhydride (214 mg, 0.3 mmol) and N-methylmorpholine (121 mg, 1.2 mmol). The mixture was stirred at 0 °C for 16 h. After warming to room temperature, water (15 ml) was added, and the mixture was extracted with ethyl acetate (15 ml × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was used to prepare the title compound ((3aR,5r,6aS)-5-((1H-1,2,3-triazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (14 mg, yield 13.1%).

[0187] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 2H), 7.98 (d, 1H), 7.78 (s, 1H), 7.22 (dd, 2H), 7.16 - 7.13 (m, 2H), 4.66 (dt, 1H), 4.51 (d, 2H), 4.02 - 3.99 (m, 1H), 3.71 (s, 2H), 3.49 (d, 2H), 3.34 - 3.22 (m, 3H), 2.91 (dd, 2H), 2.62 (s, 2H), 2.07 - 1.99 (m, 2H), 2.14 (s, 2H).

[0188] LC-MS m / z: 446.3 [M + H] + 。

[0189] Example 3: Preparation of the target compound 002-2

[0190] The synthetic route of ((3aR,5s,6aS)-5-((1H-1,2,3-triazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone, the target compound 002-2, is shown below:

[0191]

[0192] First step: tert-Butyl (3aR,5s,6aS)-5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (002-2B)

[0193] (3aR,5s,6aS)-tert-Butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (500 mg, 2.2 mmol) was added to 10 ml of THF. 4-Nitrobenzoic acid (735 mg, 4.4 mmol) and triphenylphosphine (1.1 g, 4.4 mmol) were added. The mixture was cooled to 0 °C and stirred for 0.5 h. Then DEAD (766 mg, 4.4 mmol) was added and the mixture was stirred at 0 °C for 24 h. Water (40 ml) was added to the reaction mixture. The mixture was extracted with ethyl acetate (40 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain the title compound, pale yellow liquid, (3aR,5s,6aS)-tert-Butyl 5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (003B) (470 mg, yield 56.7%).

[0194] LC-MS m / z: 377.1 [M+H] + 。

[0195] Step 2: (003C) (3aR,5s,6aS)-tert-Butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (002-2C)

[0196] (3aR,5s,6aS)-tert-Butyl 5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (470 mg, 1.25 mmol) was added to 15 ml of methanol and 5 ml of water. Potassium carbonate (345 mg, 2.5 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and concentrated. Water (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain the title compound, pale yellow liquid, (3aR,5s,6aS)-tert-Butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (265 mg, yield 93.4%)

[0197] LC-MS m / z: 228.1 [M+H] + 。

[0198] Step 3: (3aR,5s,6aS)-tert-Butyl 5-(prop-2-yn-1-yloxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (002-2D)

[0199] At room temperature, the raw material (3aR,5s,6aS)-tert-butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (265 mg, 1.2 mmol) was added to 6 ml of DMF. 60% NaH (96 mg, 2.4 mmol) was added at room temperature, and the mixture was heated to 60 °C, stirred for 2 h, cooled to 0 °C, 3-bromopropyne (357 mg, 2.4 mmol) was added, and the mixture was stirred at 0 °C for 16 h. The reaction mixture was added to water (20 ml), extracted with ethyl acetate (20 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product of the title compound, (3aR,5s,6aS)-tert-butyl 5-(prop-2-yn-1-yloxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (003D) (210 mg, yield 67.9%) was obtained as a pale yellow liquid.

[0200] LC-MS m / z: 266.1 [M+H] + 。

[0201] Step 4: (3aR,5s,6aS)-tert-butyl 5-((1H-1,2,3-triazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (002-2E)

[0202] The raw material (3aR,5s,6aS)-tert-butyl 5-(prop-2-yn-1-yloxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (200 mg, 0.7 mmol) was added to 5 ml of DMF and 1 ml of methanol. Copper(I) iodide (17 mg, 0.1 mmol) and trimethylsilyl azide (130 mg, 0.45 mmol) were added under nitrogen protection, and the mixture was heated to 110 °C and stirred for 16 h. After cooling to room temperature, water (20 ml) was added, and the reaction mixture was extracted with ethyl acetate (20 ml × 3), concentrated, and the crude product of the title compound, (3aR,5s,6aS)-tert-butyl 5-((1H-1,2,3-triazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (003E), (200 mg, yield 86.0%) was obtained as a yellow liquid.

[0203] LC-MS m / z: 309.1 [M+H] + 。

[0204] Step 5: (3aR,5s,6aS)-5-((1H-1,2,3-triazol-4-yl)methoxy)octahydrocyclopenta[c]pyrrole (002-2F)

[0205] At room temperature, the crude product of tert-butyl (3aR,5s,6aS)-5-((1H-1,2,3-triazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (200 mg, 0.65 mmol) was added to 2 ml of dichloromethane and 2 ml of methanol. 4 mol / L hydrochloric acid dioxane solution (1 ml) was added, and the mixture was stirred at 10 °C for 4 h. The reaction solution was concentrated to obtain the crude product of the title compound (3aR,5s,6aS)-5-((1H-1,2,3-triazol-4-yl)methoxy)octahydrocyclopenta[c]pyrrole (003E) (190 mg, yield 100%).

[0206] LC-MS m / z: 209.1 [M+H] + 。

[0207] Step 6: ((3aR,5s,6aS)-5-((1H-1,2,3-triazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (002-2)

[0208] The raw material (3aR,5s,6aS)-5-((1H-1,2,3-triazol-4-yl)methoxy)octahydrocyclopenta[c]pyrrole (100 mg, 0.2 mmol) was added to 4 ml of DMF and 2 ml of ethyl acetate, then 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (147 mg, 0.6 mmol), 1-propylphosphonic anhydride (428 mg, 0.7 mmol) and N-methylmorpholine (243 mg, 2.4 mmol) were added. The mixture was stirred at 0 °C for 16 h. The temperature was raised 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, concentrated, and the residue was prepared to obtain the title compound ((3aR,5s,6aS)-5-((1H-1,2,3-triazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (26 mg, 12.1%).

[0209] 11H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 2H), 8.00 (d, 1H), 7.79 (s, 1H), 7.21 (dt, 2H), 7.16 - 7.13 (m, 2H), 4.70 - 4.61 (m, 1H), 4.48 (s, 2H), 4.11 (s, 1H), 3.69 (s, 2H), 3.36 (s, 2H), 3.25 (dd, 3H), 2.91 (dd, 2H), 2.74 (s, 2H), 1.90 (d, 2H), 1.63 (s, 2H).

[0210] LC-MS m / z: 446.3 [M + H] + 。

[0211] Example 4: Preparation of Target Compound 003

[0212] (6 - ((1H-1,2,3-Triazol-4-yl)methoxy)-2-azaspiro[3.3]hept-2-yl)(2 - ((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone (003)

[0213] The synthetic route of the target compound 003 is as follows:

[0214]

[0215] First Step: Synthesis of 2 - ((3-(difluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid (003B)

[0216] Dissolve 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) in N-methylpyrrolidone (10 mL), heat to 100 °C and react for 20 h. Cool to room temperature, concentrate the reaction solution, add the residue to isopropyl acetate (30 mL) for pulping, filter, wash the filter cake with water (30 mL), and dry at 45 °C for 2 h to obtain the yellow solid 2 - ((3-(difluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid (003B) (3 g, yield 81%).

[0217] LC-MS m / z: 296.2 [M + H] + 。

[0218] Second Step: Synthesis of tert-butyl 6-(prop-2-yn-1-yloxy)-2-azaspiro[3.3]heptane-2-carboxylate (003D)

[0219] Dissolve tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 4.69 mmol) in tetrahydrofuran (5 mL), cool to 0 °C, add sodium hydride (188 mg, 4.69 mmol, 60%), and then dropwise add 3-bromopropyne (0.837 g, 7.03 mmol). After addition, react at room temperature for 18 hours. Quench with saturated ammonium chloride solution (30 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the yellow liquid tert-butyl 6-(prop-2-yn-1-yloxy)-2-azaspiro[3.3]heptane-2-carboxylate (003D) (1.2 g).

[0220] Step 3: Synthesis of 6-(prop-2-yn-1-yloxy)-2-azaspiro[3.3]heptane hydrochloride (003E)

[0221] To tert-butyl 6-(prop-2-yn-1-yloxy)-2-azaspiro[3.3]heptane-2-carboxylate (003D) (1.2 g, 4.77 mmol), add a solution of hydrogen chloride in dioxane (10 mL), and stir at room temperature for 1 h. Remove the solvent under reduced pressure to obtain the crude product, which is directly used in the next step without purification.

[0222] Step 4: Synthesis of (2-((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(prop-2-yn-1-yloxy)-2-azaspiro[3.3]hept-2-yl)methanone (003F)

[0223] To the crude product 6-(prop-2-yn-1-yloxy)-2-azaspiro[3.3]heptane hydrochloride (003E) (636 mg, 3.39 mmol) from the previous step, add N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (1.094 g, 8.47 mmol), 2-((3-(difluoromethoxy)benzyl)amino)pyrimidine-5-carboxylic acid (003B) (500 mg, 1.694 mmol). Cool the reaction solution to about 0 °C, and dropwise add 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorin-2,4,6-trioxide (1.617 g, 2.54 mmol, 50% solution in N,N-dimethylformamide). After dropping, react at room temperature for 18 h. Quench the reaction solution with water (100 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain the white solid (2-((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(prop-2-yn-1-yloxy)-2-azaspiro[3.3]hept-2-yl)methanone (003F) (400 mg, yield 55.1%).

[0224] LC-MS m / z: 429.4 [M+H] + 。

[0225] Step 5: Synthesis of (6-((1H-1,2,3-triazol-4-yl)methoxy)-2-azaspiro[3.3]hept-2-yl)(2-((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone (003)

[0226] Under nitrogen protection, dissolve (2-((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)(6-(prop-2-yn-1-yloxy)-2-azaspiro[3.3]hept-2-yl)methanone (003F) (400 mg, 0.934 mmol) in N,N-dimethylformamide (8 mL) and methanol (2 mL), add sodium L-ascorbate (370 mg, 1.867 mmol), then add trimethylsilyl azide (1.08 g, 9.34 mmol) and copper(II) sulfate pentahydrate (93 mg, 0.373 mmol), and heat to 90 °C for reaction for 4 hours. Cool the reaction solution to room temperature, add water (40 mL), extract with ethyl acetate (30 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel plate chromatography to obtain (6-((1H-1,2,3-triazol-4-yl)methoxy)-2-azaspiro[3.3]hept-2-yl)(2-((3-(difluoromethoxy)benzyl)amino)pyrimidin-5-yl)methanone (Compound 003) (62.9 mg, yield 14.3%).

[0227] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 2H), 8.14 (t, 1H), 7.76 (s, 1H), 7.32–7.26 (m, 1H), 7.11 (d, 2H), 7.04 (s, 1H), 7.00–6.91 (m, 1H), 4.54 (s, 2H), 4.48 (d, 2H), 3.78–3.55 (m, 3H), 3.21–3.14 (m, 2H), 1.78 (s, 2H), 1.49–1.37 (m, 2H).

[0228] LC-MS m / z: 472.3 [M+H] + 。

[0229] Example 5: Preparation of the target compound 004

[0230] (6-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-2-aza-spiro[3.3]heptan-2-yl)(2-((2,3-dihydro-1H-indenopyridin-2-yl)amino)pyrimidin-5-yl)methanone (004)

[0231] The synthetic route of 004 is as follows:

[0232]

[0233] The first step: Synthesis of tert-butyl 6-(tosyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (004B)

[0234] Dissolve tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (004A) (2 g, 9.38 mmol) in dichloromethane (30 mL), add triethylamine (1.898 g, 18.76 mmol), 4-dimethylaminopyridine (573 mg, 4.69 mmol), cool to 0 °C, and add p-toluenesulfonyl chloride (2.145 g, 11.25 mmol) in portions. Warm to room temperature and react for 18 h. Quench with water (50 mL), separate the layers, extract the aqueous phase with dichloromethane (30 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 5:1) to obtain white solid tert-butyl 6-(tosyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (004B) (3.2 g, yield 93%).

[0235] The second step: Synthesis of tert-butyl 6-(but-3-yn-1-yloxy)-2-azaspiro[3.3]heptane-2-carboxylate (004C)

[0236] Under nitrogen protection, dissolve 3-butyn-1-ol (610 mg, 8.71 mmol) in N,N-dimethylformamide (5 mL), cool to 0 °C, add sodium hydride (348 mg, 8.71 mmol, 60%), and stir at room temperature for 30 min. Add tert-butyl 6-(tosyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (004B) (3.2 g, 8.71 mmol), warm to 80 °C and react for 20 h. Cool the reaction solution to room temperature, quench with saturated ammonium chloride solution (30 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 20:1) to obtain yellow liquid tert-butyl 6-(but-3-yn-1-yloxy)-2-azaspiro[3.3]heptane-2-carboxylate (004C) (400 mg, yield 17.3%).

[0237] Step 3: Synthesis of 6-(but-3-yn-1-yloxy)-2-azaspiro[3.3]heptane hydrochloride (004D)

[0238] Hydrogen chloride dioxane solution (5 mL, 20.0 mmol, 4 M) was added to tert-butyl 6-(but-3-yn-1-yloxy)-2-azaspiro[3.3]heptane-2-carboxylate (004C) (400 mg, 1.507 mmol), and the mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure to obtain the crude product, which was directly used in the next step without purification.

[0239] Step 4: Synthesis of (6-(but-3-yn-1-yloxy)-2-aza-spiro[3.3]heptan-2-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (004E)

[0240] To the crude product 6-(but-3-yn-1-yloxy)-2-azaspiro[3.3]heptane hydrochloride (004D) from the previous step, N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (974 mg, 7.54 mmol), and 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (308 mg, 1.206 mmol) were added. The reaction solution was cooled to about 0 °C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorin-2,4,6-trioxide (1.151 g, 1.809 mmol, 50% N,N-dimethylformamide solution) was added dropwise. After the addition was complete, the reaction was carried out at 20 - 25 °C for 18 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, concentrated, and the residue was separated and purified by silica gel plate (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain the white solid (6-(but-3-yn-1-yloxy)-2-aza-spiro[3.3]heptan-2-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (004E) (230 mg, yield 37.9%).

[0241] LC-MS m / z: 403.4 [M+H] + 。

[0242] Step 5: Synthesis of (6-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-2-aza-spiro[3.3]heptan-2-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (004)

[0243] Under nitrogen protection, dissolve (6-(but-3-yn-1-yloxy)-2-aza-spiro[3.3]heptan-2-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (004E) (230 mg, 0.571 mmol) in N,N-dimethylformamide (4 mL) and methanol (2 mL), add sodium L-ascorbate (226 mg, 1.143 mmol), then add trimethylsilyl azide (329 mg, 2.86 mmol) and copper sulfate pentahydrate (57.1 mg, 0.229 mmol), and heat to 90 °C for reaction for 3 h. Cool the reaction solution to room temperature, add water (40 mL), extract with dichloromethane (30 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel plate separation (ethyl acetate:methanol (V / V)=10:1, ammonia water) to obtain (6-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-2-aza-spiro[3.3]heptan-2-yl)(2-((2,3-dihydro-1H-indenpyridin-2-yl)amino)pyrimidin-5-yl)methanone (004) (10 mg, yield 3.93%).

[0244] 1 H NMR(400MHz,DMSO-d6): δ8.53(d,2H), 8.13(d,1H), 7.59(brs,1H), 7.35(t,1H), 7.21~7.18(m,2H), 7.14~7.11(m,2H), 4.67~4.59(m,1H), 4.32(d,2H), 3.91(t,3H),3.49(t,2H), 3.26~3.20(m,2H), 2.91~2.86(m,2H), 2.82(t,2H), 2.45~2.42(m,2H), 2.02~1.97(m,2H).

[0245] LC-MSm / z: 446.3[M+H] + 。

[0246] Example 6: Preparation of target compound 005

[0247] (9-((1H-1,2,3-triazol-4-yl)methoxy)-3-azaspiro[5.5]undecan-3-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (target compound 005)

[0248] The synthetic route of the target compound 005 is as follows:[[]]

[0249]

[0250] Step 1: Synthesis of tert-butyl 9-(prop-2-yn-1-yloxy)-3-azaspiro[5.5]undecane-3-carboxylate (005B)

[0251] Add tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (0.5 g, 5.34 mmol) to a single-necked flask, dissolve it in tetrahydrofuran (5 mL), add 60% sodium hydride (0.089 g, 2.23 mmol) at room temperature, stir at room temperature for 0.5 h, add propargyl bromide (0.662 g, 5.57 mmol), stir the reaction at room temperature for 72 h. TLC (petroleum ether:ethyl acetate (V / V) = 3:1) shows that the reaction is complete. Quench the reaction with methanol (10 mL), concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain colorless oily tert-butyl 9-(prop-2-yn-1-yloxy)-3-azaspiro[5.5]undecane-3-carboxylate (200 mg, 0.651 mmol, yield 35.0%).

[0252] Step 2: Synthesis of 9-(prop-2-yn-1-yloxy)-3-azaspiro[5.5]undecane hydrochloride (005C)

[0253] Add tert-butyl 9-(prop-2-yn-1-yloxy)-3-azaspiro[5.5]undecane-3-carboxylate (200 mg, 0.651 mmol) to a single-necked flask, add hydrogen chloride / 1,4-dioxane solution (2.5 M, 2 mL), stir at room temperature for 3 h, concentrate to dryness to obtain crude 9-(prop-2-yn-1-yloxy)-3-azaspiro[5.5]undecane hydrochloride (0.158 g, 0.651 mmol, yield 100%).

[0254] Step 3: Synthesis of (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(9-(prop-2-yn-1-yloxy)-3-azaspiro[5.5]undecan-3-yl)methanone (005D)

[0255] Add the crude product of 9-(prop-2-yn-1-yloxy)-3-azaspiro[5.5]undecane hydrochloride (0.158 g, 0.651 mmol), 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (166 mg, 0.651 mmol), diisopropylethylamine (0.839 g, 6.51 mmol) into a single-necked flask, dissolve them in N,N-dimethylformamide (4 mL) at room temperature, cool to 0 °C, and dropwise add 50% 1-propylphosphonic anhydride / N,N-dimethylformamide solution (0.620 g, 0.974 mmol). After the addition, react overnight at room temperature. TLC (methanol:dichloromethane (V / V) = 1:10) shows that the reaction is complete. Dilute with water (10 mL), extract the aqueous phase with dichloromethane (50 mL × 2), combine the organic phases, wash the organic phase with saturated brine (50 mL × 2), separate the layers, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (methanol:dichloromethane (V / V) = 1:10) to obtain a white solid (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(9-(prop-2-yn-1-yloxy)-3-azaspiro[5.5]undecan-3-yl)methanone (200 mg, 0.45 mmol, 69.3% yield).

[0256] LC-MS m / z: 445.58 [M+H] + 。

[0257] Step 4: Synthesis of (9-((1H-1,2,3-triazol-4-yl)methoxy)-3-azaspiro[5.5]undecan-3-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (005)

[0258] Add sodium L(+)-ascorbate (178 mg, 0.90 mmol), (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(4-(1-(prop-2-yn-1-yloxy)ethyl)piperidin-1-yl)methanone (200 mg, 0.45 mmol), azidotrimethylsilane (0.155 g, 1.35 mmol), copper(II) sulfate pentahydrate (22 mg, 0.09 mmol), N,N-dimethylformamide (4 mL), and methanol (0.4 mL) to a single-necked flask. Heat the mixture to 90 °C and react for 2 hours. LCMS shows that most of the starting materials have reacted. Cool the reaction mixture to room temperature, add saturated brine (10 mL), and extract with ethyl acetate (50 mL × 2). Wash the organic phase with saturated brine (20 mL × 2) twice, dry over anhydrous sodium sulfate, filter, concentrate, and separate the residue by preparative chromatography to obtain (9-((1H-1,2,3-triazol-4-yl)methoxy)-3-azaspiro[5.5]undecan-3-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (30 mg, 0.062 mmol, yield 13.68%).

[0259] 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 2H), 7.92 - 7.93 (d, 1H), 7.76 (s, 1H), 7.17 - 7.19 (m, 2H), 7.09 - 7.12 (m, 2H), 4.59 - 4.64 (m, 1H), 4.52 (s, 2H), 3.31 - 3.43 (m, 5H), 3.19 - 3.24 (q, 2H), 2.85 - 2.90 (q, 2H), 1.58 - 1.70 (m, 4H), 1.32 - 1.41 (m, 6H), 1.12 - 1.19 (m, 2H).

[0260] LC-MS m / z: 488.61 [M+H] + 。

[0261] Example 7: Preparation of the target compound 006

[0262] (2-((1H-1,2,3-triazol-4-yl)methoxy)-7-azaspiro[3.5]nonan-7-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (006)

[0263] The synthetic route of compound 006 is as follows:

[0264]

[0265] Step 1: Synthesis of tert-butyl 2-(prop-2-yn-1-yloxy)-7-azaspiro[3.5]nonane-7-carboxylate (006B)

[0266] Dissolve tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (006A) (2 g, 8.29 mmol) in tetrahydrofuran (20 mL), cool to 0 °C, add sodium hydride (365 mg, 9.12 mmol, 60%), and then dropwise add 3-bromopropyne (1.479 g, 12.43 mmol). After addition, react at room temperature for 16 h. Quench with water (50 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 50:1) to obtain yellow liquid tert-butyl 2-(prop-2-yn-1-yloxy)-7-azaspiro[3.5]nonane-7-carboxylate (006B) (2.1 g, yield 91%).

[0267] Step 2: Synthesis of 2-(prop-2-yn-1-yloxy)-7-azaspiro[3.5]nonane hydrochloride (006C)

[0268] Add hydrogen chloride dioxane solution (20 mL) to tert-butyl 2-(prop-2-yn-1-yloxy)-7-azaspiro[3.5]nonane-7-carboxylate (006B) (2.1 g, 7.52 mmol), and stir at room temperature for 2 h. Remove the solvent under reduced pressure to obtain the crude product, which is directly used in the next step without purification.

[0269] Step 3: Synthesis of (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-(prop-2-yn-1-yloxy)-7-azaspiro[3.5]non-7-yl)methanone (006D)

[0270] To the crude product 2-(prop-2-yn-1-yloxy)-7-azaspiro[3.5]nonane hydrochloride (006C) (300 mg, 1.391 mmol), N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (899 mg, 6.95 mmol), and 2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidine-5-carboxylic acid (373 mg, 1.460 mmol) were added. The reaction solution was cooled to about 0 °C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (1.150 g, 1.808 mmol, 50% solution in N,N-dimethylformamide) was added dropwise. After the addition was complete, the reaction was carried out at room temperature for 16 h. The reaction solution was quenched by adding water (60 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel plate (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain the white solid (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-(prop-2-yn-1-yloxy)-7-azaspiro[3.5]non-7-yl)methanone (006D) (440 mg, yield 76%).

[0271] LC-MS m / z: 417.4 [M+H] + 。

[0272] Step 4: Synthesis of (2-((1H-1,2,3-triazol-4-yl)methoxy)-7-azaspiro[3.5]non-7-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (006)

[0273] Under nitrogen protection, dissolve (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(2-(prop-2-yn-1-yloxy)-7-azaspiro[3.5]nonan-7-yl)methanone (006D) (440 mg, 0.964 mmol) in N,N-dimethylformamide (8 mL) and methanol (4 mL), add sodium L-ascorbate (382 mg, 1.928 mmol), then add trimethylsilyl azide (1110 mg, 9.64 mmol) and copper(II) sulfate pentahydrate (96 mg, 0.386 mmol), and heat the mixture to 90 °C for 4 hours. Cool the reaction mixture to room temperature, add water (40 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (ethyl acetate:methanol (V / V) = 10:1, ammonia water) to obtain (2-((1H-1,2,3-triazol-4-yl)methoxy)-7-azaspiro[3.5]non-7-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (006) (70.9 mg, yield 14.73%).

[0274] 1 H NMR(400MHz,DMSO-d6): δ8.39(s,2H),7.95(d,1H),7.81(s,1H),7.24-7.18(m,2H),7.17-7.11(m,2H),4.70-4.56(m,1H),4.44(s,2H),4.11-4.02(m,1H),3.48-3.35(m,4H),3.25(dd,2H),2.92(d,1H),2.88(d,1H),2.21-2.13(m,2H),1.69-1.61(m,2H),1.57-1.46(m,4H).

[0275] LC-MSm / z: 474.3[M+H] + 。

[0276] Example 8: Preparation of the target compound 007

[0277] The synthetic route of the target compound 007 is as follows:

[0278]

[0279] The first step: Synthesis of tert-butyl 7-(prop-2-yn-1-yloxy)-2-azaspiro[3.4]nonane-2-carboxylate (007B)

[0280] At 0 °C, NaH ((489 mg, 12.22 mmol, 60%) was added to a solution of tert-butyl 7-hydroxy-2-azaspiro[3.4]nonane-2-carboxylate (007A) (590 mg, 2.445 mmol) in tetrahydrofuran (30 mL). After stirring at room temperature for 30 min, 3-bromoprop-1-yne (1454 mg, 12.22 mmol) was added, and the reaction mixture was stirred at 25 °C overnight. TLC (petroleum ether:ethyl acetate = 5:1) showed the formation of a new spot. Distilled water (30 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1 - 5:1) to obtain tert-butyl 7-(prop-2-yn-1-yloxy)-2-azaspiro[3.4]nonane-2-carboxylate (007B) (550 mg, 1.969 mmol, yield 81%).

[0281] Step 2: Synthesis of 7-(prop-2-yn-1-yloxy)-2-aza-spiro[3.5]nonane (007C)

[0282] Hydrochloric acid / ethyl acetate (10 mL, 4 M) was added to a solution of tert-butyl 7-(prop-2-yn-1-yloxy)-2-azaspiro[3.4]nonane-2-carboxylate in dioxane (10 mL), and the mixture was stirred at room temperature for 3 h. After completion of the reaction, it was concentrated to obtain white solid 7-(prop-2-yn-1-yloxy)-2-aza-spiro[3.5]nonane (420 mg, 1.947 mmol, 99% yield, hydrochloride). The crude product was used directly in the next step without purification.

[0283] Step 3: Synthesis of (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(7-(prop-2-yn-1-yloxy)-2-aza-spiro[3.5]non-2-yl)methanone (007D)

[0284] At 0 °C, T3P (1880 mg, 2.96 mmol, 50% in DMF) was added to a solution of 7-(prop-2-yn-1-yloxy)-2-aza-spiro[3.5]nonane (425 mg, 1.970 mmol), 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (453 mg, 1.773 mmol), and DIEA (1.720 ml, 9.85 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to remove most of the DMF. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the yellow solid compound (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(7-(prop-2-yn-1-yloxy)-2-aza-spiro[3.5]nonan-2-yl)methanone (450 mg, 1.080 mmol, yield 54.8%).

[0285] Step 4: Synthesis of (7-((1H-1,2,3-triazol-4-yl)methoxy)-2-aza-spiro[3.5]non-2-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (007)

[0286] At 0 °C, TMSN3 (166 mg, 1.441 mmol) was added to a solution of (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)(7-(prop-2-yn-1-yloxy)-2-aza-spiro[3.5]nonan-2-yl)methanone (200 mg, 0.480 mmol), copper(II) sulfate pentahydrate (23.98 mg, 0.096 mmol), and sodium ascorbate (190 mg, 0.960 mmol) in DMF (10 ml) and methanol (1 mL), and the mixture was stirred at 100 °C for 3 h. After cooling to room temperature and monitoring the reaction by TLC until completion, the reaction solution was concentrated under reduced pressure to remove most of the DMF. The residue was purified by preparative liquid chromatography to obtain (7-((1H-1,2,3-triazol-4-yl)methoxy)-2-aza-spiro[3.5]non-2-yl)(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanone (20.4 mg, 0.040 mmol, yield 8.34%).

[0287] 1H NMR(400MHz, DMSO-d6) δ 8.58 (d, 2H), 8.11 (d, 1H), 7.79 (s, 1H), 7.13 - 7.22 (m, 4H), 4.62 - 4.73 (m, 1H), 4.55 (s, 2H), 4.05 (d, 2H), 3.67 (d, 2H), 3.35 - 3.40 (m, 1H), 3.22 - 3.28 (m, 2H), 2.88 - 2.94 (m, 2H), 1.75 - 1.80 (m, 4H), 1.49 (t, 2H), 1.34 - 1.37 (m, 2H).

[0288] LC-MS m / z: 460.3 [M + H] + 。

[0289] Biological Activity and Related Property Test Examples

[0290] Test Example 1: Autotaxin (ATX) Enzyme Activity Inhibition Test

[0291] The inhibitory activity of the compound against the Autotaxin enzyme was detected using the Autotaxin Inhibitor Screening Assay Kit (Cayman, 700580). First, the test compound was prepared as a 10 mM stock solution in DMSO solvent, and then diluted to 8 concentration points using a DMSO gradient. Subsequently, the 8 concentration points were diluted to a 19× compound working solution (with 1.9% DMSO content) using the Autotaxin detection buffer (1×) provided by the kit. The Autotaxin detection reagent (10×) was taken out and diluted 10 times using the Autotaxin detection buffer (1×). The Autotaxin substrate was taken out, dissolved in 1.2 mL of the Autotaxin detection buffer (1×), and left to stand at room temperature after mixing. In a 96-well plate, in each well corresponding to each concentration point, 150 μL of the Autotaxin detection buffer (1×), 10 μL of the diluted 19× compound working solution, 10 μL of the Autotaxin detection reagent (1×), and 20 μL of the dissolved Autotaxin substrate were added, mixed well, and incubated at 37°C in a constant-temperature shaking incubator in the dark for 30 min; the 96-well plate was taken out and the OD405 was read on an enzyme-linked immunosorbent assay (ELISA) reader; the experimental results were input into the GraphPad Prism software, and the IC of each compound was obtained through fitting calculation. 50 。

[0292] Table 1 Results of the Inhibitory Activity of the Test Compounds against the ATX Enzyme Activity

[0293] Test Compound <![CDATA[IC 50 (nM)]]> Compound 001-1 2.50 Compound 002-1 7.8 Compound 002-2 1.14 Compound 003 7.12 Compound 004 6.3 Compound 005 0.979 Compound 006 1.17 Compound 007 7.05

[0294] The experimental results show that the compound of the present invention has good inhibitory activity against ATX enzyme and can effectively inhibit the activity of ATX enzyme.

Claims

1. A compound, which is a compound represented by formula (I), or a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound represented by formula (I): Wherein, R 1 、R 2 、R 3 、R 4 are the same or different and are each independently selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy; n 1 、n 2 are independently selected from the integers 0, 1, 2 or 3; X and Y are the same or different and are each independently selected from -N=, -C(R 6 )-; Z is independently selected from -N(R 9 )-, -N(R 9 )-C(R 7 )(R 8 ); Q is selected from C6-C 10 aryl, 2,3-dihydro-1H-indenyl; Each R 5 is the same or different and is independently selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, and the following groups which are unsubstituted or optionally substituted by one or more R b groups: C1-C6 alkyl, C1-C6 alkoxy; R b selected from -F, -Cl, -Br, -I; m is independently selected from the integers 0, 1, 2 or 3; M 1 and M 2 and M 3 are independently selected from -N= or -N(R 10 )-, M 4 is selected from -CH=, M 5 is selected from -C=; L is selected from , where p1, p2, p3, p4 are independently selected from the integers 0, 1 or 2, and p3 and p4 are not both 0; q1, q2, q3, q4 are independently selected from the integers 0, 1 or 2, and p3 and p4 are not both 0, q1 and q2 are not both 0, and q3 and q4 are not both 0; R 6 independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 12 、R 13 are independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy; R 9 and R 10 are independently selected from hydrogen, C1-C6 alkyl; And the compound does not include the following compounds or their tautomers, stereoisomers, or pharmaceutically acceptable salts: 。 2. The compound according to claim 1, wherein R 5 Selected from -H, -F, -Cl, methyl, ethyl, difluoromethoxy.

3. A compound, which is a compound represented by formula (II), or a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound represented by formula (II): Wherein, R 1 、R 2 、R 3 、R 4 independently selected from hydrogen, C1-C6 alkyl; X and Y are the same or different and are each independently selected from -N=, -C(R 6 )-; R 6 is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl; n 1 、n 2 independently selected from the integers 0, 1, 2; M 1 、M 2 、M 3 independently selected from -N=, -N(R 10 )-, wherein R 10 is selected from hydrogen, C1-C6 alkyl; L is selected from , where p1, p2, p3, p4 are independently selected from the integers 0 or 1, and p3 and p4 are not both 0; q1, q2, q3, q4 are independently selected from the integers 1 or 2; And the compound does not include the following compounds or their tautomers, stereoisomers, or pharmaceutically acceptable salts: 。 4. The compound according to claim 3, wherein: M 1 、M 2 、M 3 are each selected from -N= or -NH-.

5. A compound, which is a compound represented by formula (III), or a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound represented by formula (III): Wherein, R 1 、R 2 、R 3 、R 4 independently selected from hydrogen, C1-C6 alkyl; R 5 Independently selected from hydrogen, -CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy; X and Y are the same or different and each independently selected from -N=, -C(R 6 )-; R 6 is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl; n 1 and n 2 are independently selected from the integers 0, 1, 2; M 1 、M 2 、M 3 are independently selected from -N=, -N(R 10 ), where R 10 is selected from hydrogen, C1-C6 alkyl; L is selected from , where p1, p2, p3, p4 are independently selected from the integers 0 or 1, and p3 and p4 are not both 0; q1, q2, q3, q4 are independently selected from the integers 1 or 2.

6. The compound according to claim 5, wherein: M 1 、M 2 、M 3 are each independently selected from -N= or -NH-.

7. The compound according to any one of claims 1 to 6, its stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein the compound is selected from one of the following structures: 。 8. The compound according to any one of claims 1 to 6, its stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein the compound is selected from one of the following structures: 。 9. A pharmaceutical composition, characterized in that, Comprising the compound according to any one of claims 1 to 8.

10. Use of the compound according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 9, in the preparation of an ATX enzyme inhibitor.

11. Use of the compound according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 9, in the preparation of a drug for treating ATX-related diseases, wherein the ATX-related diseases are selected from cancer, type II diabetes, non-alcoholic steatohepatitis, fibrotic diseases, interstitial lung diseases, neuropathic pain, inflammatory pain, autoimmune diseases, and / or respiratory diseases.

12. The use according to claim 11, wherein the ATX-related diseases are selected from interstitial lung diseases, pulmonary fibrosis, liver fibrosis, and renal fibrosis.

13. The use according to claim 11, wherein The ATX-related disease is selected from idiopathic pulmonary fibrosis.

14. The use according to claim 11, wherein the ATX-related disease is selected from pain related to osteoarthritis.

15. The use according to claim 11, wherein the ATX-related disease is selected from cancer.

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