Amide compounds and their preparation methods

Abstract

The present invention provides amide compounds and a preparation method thereof. Specifically, the present invention provides a new compound that effectively inhibits ATX, which is a compound represented by formula (I) or formula (II), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I) or formula (II): #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to amide compounds, and more specifically, the present invention relates to amide compounds and their preparation methods, as well as 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 biologically active 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 (this model 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 confirmed 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, increased expression of ATX has been demonstrated in synovial fibroblasts from patients with rheumatoid arthritis (RA), and 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 are also studies suggesting that targeted inhibition of ATX-mediated LPA biosynthesis may be a novel mechanism for preventing neuropathic pain caused by nerve injury.

[0007] After inflammation resolves and tissue injury is repaired, tissues generally return to their original state. In cases where it is no longer needed, excessive and uncontrolled tissue repair can lead to a condition commonly referred to as fibrosis. Fibrosis is characterized by the excessive deposition of extracellular matrix components and the overgrowth of fibroblasts. Fibrosis can occur in all tissues, but is particularly prevalent in organs that are frequently exposed 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 class of lung diseases characterized by fibroblast proliferation and massive extracellular matrix accumulation accompanied by inflammatory injury 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, the 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 disrupted alveolar architecture, which mainly presents as usual interstitial pneumonia in imaging and pathological histology. As the disease progresses, it causes fibrosis of lung tissue, and the patient's lung tissue becomes thickened and hardened, resulting in permanent scarring, or the patient's lungs become honeycombed, and it is also vividly called "honeycomb lung" or "stringy 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, the existing drug treatments have problems such as many adverse reactions and poor treatment effects; the non-drug treatment methods are mainly lung transplantation surgeries, but organ transplantation is expensive and resources are limited, and there are 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 the peribronchial fibrosis present in chronic bronchitis, interstitial lung diseases, and severe asthma. LPA plays a role in fibrotic interstitial lung diseases and bronchiolitis obliterans, where both collagen and myofibroblasts increase. Studies related to IPF (idiopathic pulmonary fibrosis) have shown increased levels of LPA 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 major quantitative trait loci that appear 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, and 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, bowel 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 nutrients for tumors during tumor growth. Therefore, inhibiting angiogenesis can be said to be an important starting point for cancer and tumor treatment.

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

[0016] At present, certain progress has been made in the treatment of cancer, fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and / or diseases related to 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 there is a possibility of skin carcinogenesis after light exposure. Nintedanib has adverse reactions such as diarrhea, nausea, and abdominal pain, and the incidence of gastrointestinal reactions is as high as 50%. Common adverse reactions also include weight loss, loss of appetite, liver injury, 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 a compound represented by 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 conditions, including but not limited to cancer, metabolic diseases, kidney diseases, liver diseases, fibrotic diseases, interstitial lung diseases, pulmonary fibrosis, liver fibrosis, proliferative diseases, inflammatory diseases, pain, pain related to osteoarthritis, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and / or products related to abnormal angiogenesis diseases. Summary of the Invention

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

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

[0020]

[0021] Wherein:

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

[0023] Z is selected from -O-, -S-, -N(R 5 ), preferably, Z is selected from -N(R 5 );

[0024] R 1 is independently selected from hydrogen, halogen, cyano, -OH, -SH, -NO2, the following unsubstituted or optionally substituted by one or more R a 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 group, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5-10 membered heteroaryl; C6-C 10 aryloxy, 5-10 membered heteroaryloxy;

[0025] R 2 is selected from hydrogen, the following unsubstituted or optionally substituted by one or more R b groups: C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl;

[0026] Q is the following unsubstituted or optionally substituted by one or more R 3 groups: C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl;

[0027] Each R 3 is the same or different and is independently selected from hydrogen, halogen, cyano, -OH, -SH, -NO2, C1-C 10 alkyl, C3-C 10 cycloalkyl, C1-C 10 alkoxy;

[0028] m is selected from the integers 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

[0029] L is a group without substitution or optionally substituted by one or more R c : C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 20 aryl, 5- to 20-membered heteroaryl,

[0030] Each R a , R b , R c is the same or different and independently selected from each other as -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;

[0031] wherein,

[0032] n is selected from the integers 0, 1, 2 or 3; X1, Y1 are independently selected from -N=, -C(R 6 )=;

[0033] Z1, Z2 are selected from -O-, -S-, -NH-, -N(R 7 )-, -C(R 8 )(R 9 );

[0034] or when Z2 is -N(R 7 )-, Z2 can form a 4- to 7-membered ring with R 2 ;

[0035] M 1 , M 2 , M 3 , M 4 , M 5 are independently selected from -N=, -CH=, -N(R 10 )-, -C(R 11 )=, where M 1 , M 2 , M 3 , M 4 , M 5at least one of which is selected from -N= or -N(R 10 )-, and M 1 、M 2 、M 3 、M 4 、M 5 at least one of which is selected from -CH= or -C(R 11 )=;

[0036] R 4 、R 6 、R 8 、R 9 、R 11 are independently selected from hydrogen, halogen, cyano, -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;

[0037] R 5 、R 7 、R 10 are 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.

[0038] In some embodiments of the present invention, L is the following group which is unsubstituted or optionally substituted by one or more R c : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indanyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl, and the remaining variables are as defined in the present invention.

[0039] In some embodiments of the present invention, L is selected from and the remaining variables are as defined in the present invention.

[0040] In some embodiments of the present invention, R 3 is selected from -H, -F, -Cl, methyl, ethyl, and the remaining variables are as defined in the present invention.

[0041] In some embodiments of the present invention, when Z2 is -N(R 7 )-, Z2 can form a 5-membered ring with R 2 , and the remaining variables are as defined in the present invention.

[0042] In some embodiments of the present invention, when Z2 is -N(R 7 )-, Z2 can combine with R 2 to form The remaining variables are as defined in the present invention.

[0043] In some embodiments of the present invention, 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.

[0044] According to an exemplary embodiment of the present invention, the compound represented by formula (I) can be further preferably a compound represented by the following formula (II):

[0045]

[0046] In formula (II):

[0047] X and Y are each independently selected from -N=, -C(R 4 )=;

[0048] R 1 is independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy;

[0049] R 2 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy;

[0050] L is selected from wherein:

[0051] n is selected from the integers 0, 1, 2, or 3;

[0052] X1 and Y1 are each independently selected from -N=, -C(R 6 )=;

[0053] Z1 and Z2 are selected from -O-, -S-, -N(R 7 )-, -C(R 8 )(R 9 )-;

[0054] or when Z2 is -N(R 7 )-, Z2 can combine with R 2 to form a 4- to 7-membered ring;

[0055] M 1 , M 2 , M 3 are each independently selected from -N= or -N(R10 )-, wherein R 10 is selected from hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; preferably, M 1 , M 2 , M 3 are each independently selected from -N= or -NH-;

[0056] R 4 , R 6 , R 8 , R 9 are independently selected from hydrogen, halogen, C1-C 10 alkyl, C3-C 10 cycloalkyl, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy;

[0057] R 7 , R 10 are independently selected from hydrogen, C1-C 10 alkyl, C3-C 10 cycloalkyl.

[0058] In some embodiments of the present invention, when Z2 is -N(R 7 ), Z2 can form a 5-membered ring with R 2 , and the remaining variables are as defined in the present invention.

[0059] In some embodiments of the present invention, when Z2 is -N(R 7 ), Z2 can form 2 with R and the remaining variables are as defined in the present invention.

[0060] In some embodiments of the present invention, in the compound of formula (II), X and Y are independently selected from -N=, -CH=, and the remaining variables are as defined in the present invention.

[0061] In some embodiments of the present invention, in the compound of formula (II), when X is -N=, Y is -CH=, or when X is -CH=, Y is -N=, and the remaining variables are as defined in the present invention.

[0062] In some embodiments of the present invention, in the compound of formula (II), is selected from and the remaining variables are as defined in the present invention.

[0063] In some embodiments of the present invention, in the compound of formula (II), R 1 , R 2 are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, cyclopropyloxy, and the remaining variables are as defined in the present invention.

[0064] In some embodiments of the present invention, in the compound of formula (II), R 1 and R 2 are independently selected from hydrogen, methyl, and ethyl, and the remaining variables are as defined in the present invention.

[0065] In some embodiments of the present invention, in the compound of formula (II), L is independently selected from and the remaining variables are as defined in the present invention.

[0066] In some embodiments of the present invention, in the compound of formula (II), Z1 and Z2 are selected from O, N, -CH2-, and the remaining variables are as defined in the present invention.

[0067] In some embodiments of the present invention, in the compound of formula (II), when Z2 is N, Z2 and R2 form a 5-membered ring, and the remaining variables are as defined in the present invention.

[0068] In some embodiments of the present invention, in the compound of formula (II), when Z2 is N, Z2 and R2 form and the remaining variables are as defined in the present invention.

[0069] In some embodiments of the present invention, in the compound of formula (II), is selected from and the remaining variables are as defined in the present invention.

[0070] 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:

[0071]

[0072] 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:

[0073]

[0074] The compounds of the present invention may exhibit tautomerism. The present invention includes all tautomeric forms of the compounds, and whether in a state of equilibrium or one form predominates, each tautomeric form is included in the present invention.

[0075] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising at least one compound represented by formula (I) and / or formula (II) of the present invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate, or prodrug thereof.

[0076] "Pharmaceutical composition" means 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.

[0077] According to yet another aspect of the present invention, the present invention provides a compound represented by formula (I) and / or formula (II), its pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate or prodrug, or a pharmaceutical composition containing the compound represented by formula (I) and / or formula (II) or its pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate or prodrug for use in the preparation of a medicament for treating ATX-related diseases.

[0078] 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.

[0079] In some embodiments of the present invention, the ATX-related diseases are selected from interstitial lung diseases, pulmonary fibrosis, liver fibrosis, kidney fibrosis, preferably 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.

[0080] In some embodiments of the present invention, the ATX-related diseases are selected from metabolic diseases, preferably type II diabetes and non-alcoholic steatohepatitis. According to the examples 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.

[0081] In some embodiments of the present invention, the ATX-related diseases are selected from neuropathic pain and inflammatory pain, preferably pain related to osteoarthritis. According to the examples of the present invention, the compounds of the present invention have significant advantages in treating pain related to osteoarthritis.

[0082] In some embodiments of the present invention, the ATX-related diseases are selected from cancer. According to the examples of the present invention, the compounds of the present invention have significant advantages in treating cancer.

[0083] Term Definitions and Explanations

[0084] Unless otherwise specified, the definitions of 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., may be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination shall fall within the scope recited in the specification of this application.

[0085] Unless otherwise defined, all technical terms 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 specified, 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.

[0086] Unless otherwise specified, conventional methods within the scope of those skilled in the art are employed, such as mass spectrometry, NMR, IR, and UV / Vis spectroscopy and pharmacological methods. Unless a specific definition is provided, the terms used in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceuticals and medicinal chemistry herein are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and the treatment of patients. For example, the instructions of the manufacturer for the use of the kit can be utilized, or the reactions and purifications can be carried out in a manner known in the art or as described in this application. Generally, the above-mentioned techniques and methods can be implemented according to the descriptions in a number 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.

[0087] For the numerical ranges recited in the specification and claims of this 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 to have recited 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 and each decimal within the range are recited. For example, "numbers from 1 to 10" should be understood to have recited not only 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 with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 respectively.

[0088] The term "pharmaceutically acceptable" refers 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.

[0089] 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.

[0090] In addition to pharmaceutically acceptable salts, the present invention contemplates other salts. They can serve as intermediates in the purification of the 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.

[0091] The term "stereoisomer" refers to isomers resulting from different arrangements of atoms in space within 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.

[0092] Depending on the choice of starting materials and methods, the compounds of the invention may exist in the form of one or more of the possible isomers, for example as pure enantiomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, 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 generally called a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which 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 a compound described herein contains an alkene double bond, unless otherwise stated, such double bond includes 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.

[0093] When the bonds to the chiral carbons in the formulas of the invention are depicted as straight lines, it is to be understood that both the (R) and (S) configurations of the chiral carbon and, thus, both the enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The illustration of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62:114 - 120. Unless otherwise stated, wedge and dashed bonds are used to denote the absolute configuration of a stereocenter.

[0094] 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 in racemic form. Resolution of the racemic mixtures of the compounds can be carried out by any of the many 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-phenylglycol, 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 based on 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.

[0095] 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 can exist in two or more interconvertible forms. Prototrophic tautomers result from the migration of a hydrogen atom covalently bonded 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.

[0096] In the examples of the present invention, the proton can occupy two or more positions of a heterocyclic system in cyclic forms, 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 sterically fixed in one form by appropriate substitution. For example:

[0097]

[0098] Due to resonance, the hydrogen of the nitrogen on the triazole can be on any of the three nitrogens, so there will be differences in naming, but these three forms actually represent the same compound.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] The term "solvate" refers to a stoichiometric or non-stoichiometric solvent in which the compounds or salts of the present invention are combined by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.

[0103] The term "prodrug" refers to a compound that can be converted into the 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 this 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.

[0104] 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 transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0105] The term "C1-C 10 alkyl" is to be understood as representing a straight-chain or branched-chain saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl groups are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl etc. or 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.

[0106] The term "C3-C 10 cycloalkyl" is to be understood as representing 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.

[0107] The term "3- to 10-membered heterocyclic group" is to be understood as representing a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 3 to 10 atoms, where 1, 2, 3, 4 or 5 ring atoms are selected from N, O and S, and which, unless otherwise specified, may be linked via carbon or nitrogen, where -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, oxetidinyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroindolyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuryl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5-dioxoimidazolidinyl.

[0108] The term "C2-C 10"Alkenyl" shall be understood to mean a straight or branched chain 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 or conjugated with each other. 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.

[0109] The term "C2-C 10"Alkynyl" shall be understood to mean a straight-chain or branched monovalent hydrocarbon group which contains one or more triple 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 alkynyl"), having 2 or 3 carbon atoms ("C2-C3 alkynyl"). The alkynyl groups are, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 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 groups are ethynyl, prop-1-ynyl or prop-2-ynyl.

[0110] The term "C1-C 10 alkoxy" shall be understood to be -O-(C1-C 10 alkyl), where "C1-C 10 alkyl" has the definition given above.

[0111] The term "C6-C 10 aryl" shall be understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 10 carbon atoms, in particular a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. When the C6-C 10 aryl is substituted, it may be mono-substituted or multi-substituted. Also, there is no restriction on the substitution site, for example, it may be ortho-substituted, para-substituted or meta-substituted.

[0112] The term "C6-C 10 aryloxy" shall be understood to be -O-(C6-C 10 aryl), where C6-C 10The aryl group has the above definition.

[0113] The term "5- to 10-membered heteroaryl" should be understood as 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 as having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms - especially 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 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, benzisoxazolyl, 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.

[0114] The term "5- to 10-membered heteroaryloxy" should be understood as -O-(5- to 10-membered heteroaryl), where the 5- to 10-membered heteroaryl has the above definition.

[0115] The term "halogen group" or "halogen" means fluorine, chlorine, bromine and iodine.

[0116] "Haloalkyl" refers to a branched or 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.

[0117] Beneficial effects

[0118] According to specific examples of the present invention, the compounds represented by formula (I) and / or formula (II) of the present invention, or their pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates or prodrugs, have a significant inhibitory effect on ATX enzyme.

[0119] According to specific examples of the present invention, the compounds of the present invention have good inhibitory activity against ATX enzyme, the compounds of the present invention show excellent hepatic metabolic stability, are metabolized more slowly in the human body and have a higher exposure level.

[0120] 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 through the practice of the present invention. Detailed implementation manners

[0121] 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 regarded as limiting the scope of the present invention. For those not specified in the embodiments regarding specific techniques or conditions, the techniques or conditions described in the literature in the field or according to the product specifications are followed. For reagents or instruments not specified for the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0122] Embodiments of the present invention provide compounds represented by formula (I) and / or formula (II), their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, methods and intermediates for preparing compounds represented by formula (I) and / or formula (II), their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, pharmaceutical compositions, and the use of the compounds and pharmaceutical compositions of the present invention in the preparation of drugs.

[0123] There is no particular limitation on the reaction solvents used in each reaction step of the present invention. 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.

[0124] 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).

[0125] 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, and 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.

[0126] The abbreviations of the present invention are defined as follows:

[0127] CuI: Copper(I) iodide

[0128] DCM: Dichloromethane

[0129] DIBAL-H: Diisobutylaluminum hydride

[0130] DIPEA: Also written as DIEA, Diisopropylethylamine, i.e., N,N-Diisopropylethylamine

[0131] DMF: N,N-Dimethylformamide

[0132] Et3N: Triethylamine

[0133] HATU: 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0134] MeOH: Methanol

[0135] N: Normality, e.g., 2N hydrochloric acid represents a 2 mol / L hydrochloric acid solution

[0136] NADPH: Reduced nicotinamide adenine dinucleotide phosphate

[0137] NaH: Sodium hydride

[0138] NMM: N-Methylmorpholine, also known as N-Methylmorphine

[0139] NMP: N-Methylpyrrolidone

[0140] SFC: Supercritical fluid chromatography

[0141] T3P: Propylphosphonic anhydride, i.e., 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide or 1-Propylphosphonic anhydride

[0142] THF: Tetrahydrofuran

[0143] TMSN3: Trimethylsilyl azide

[0144] TsCl: p-Toluenesulfonyl chloride

[0145] IC 50 : Half maximal inhibitory concentration, referring to the concentration at which half of the maximum inhibitory effect is achieved.

[0146] Unless otherwise indicated, the compounds exemplified herein are named and numbered using ChemBioDraw Ultra 13.0.

[0147] Example 1: Preparation of Target Compound 001

[0148] N-((2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-3-(2H-1,2,3-triazol-4-yl)cyclopentane-1-carboxamide (Target Compound 001)

[0149] The synthetic route of Target Compound 001 is as follows:

[0150]

[0151] Step 1: (001B) Methyl 3-ethynylcyclopentane-1-carboxylate

[0152] Add the raw material methyl 3-formyl-1-cyclopentanecarboxylate (2.0 g, 12.8 mmol) to 60 mL of methanol, then add dimethyl (1-diazo-2-oxopropyl)phosphonate (4.8 g, 25.6 mmol) and potassium carbonate (5.2 g, 38.5 mmol), stir at room temperature for 16 h, add water (60 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)=10:1) to obtain the title compound methyl 3-ethynylcyclopentane-1-carboxylate as a colorless liquid (0.9 g, yield 45.9%).

[0153] LC-MS m / z: 153.1 [M+H] + 。

[0154] Step 2: (001C) Methyl 3-(2H-1,2,3-triazol-4-yl)cyclopentane-1-carboxylate

[0155] Add methyl 3-ethynylcyclopentane-1-carboxylate (900 mg, 5.96 mmol) to 24 mL of DMF and 3 mL of methanol, add trimethylsilyl azide (1.1 g, 9.5 mmol) and copper(I) iodide (113 mg, 0.59 mmol) under nitrogen protection, heat to 110 °C, and stir for 16 h. Add water (30 mL), extract with ethyl acetate (30 mL×3), dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=3:1) to obtain the title compound methyl 3-(2H-1,2,3-triazol-4-yl)cyclopentane-1-carboxylate as a pale yellow liquid (700 mg, yield 60.6%)

[0156] LC-MS m / z: 196.2 [M+H] + 。

[0157] Step 3: (001D) 3-(2H-1,2,3-triazol-4-yl)cyclopentane-1-carboxylic acid

[0158] At room temperature, methyl 3-(2H-1,2,3-triazol-4-yl)cyclopentane-1-carboxylate (110 mg, 0.56 mmol) was added to 1 mL of water and 5 mL of methanol, and sodium hydroxide (90 mg, 2.26 mmol) was added. The mixture was stirred at room temperature for 5 h. The reaction solution was concentrated to 15 mL, the pH was adjusted to 3 with hydrochloric acid, and it was extracted with methanol:dichloromethane (V / V) = 1:5 (30 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound, 3-(2H-1,2,3-triazol-4-yl)cyclopentane-1-carboxylic acid, as a pale yellow liquid (62 mg, yield 60.0%).

[0159] LC-MS m / z: 182.1 [M+H] + 。

[0160] Step 4: N-(2-(2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-3-(2H-1,2,3-triazol-4-yl)cyclopentane-1-carboxamide (Target Compound 001)

[0161] 3-(2H-1,2,3-Triazol-4-yl)cyclopentane-1-carboxylic acid (160 mg, 0.88 mmol) was added to 8 mL of DMF, and then DIPEA (340 mg, 2.64 mmol), HATU (520 mg, 1.32 mmol), and 5-(aminomethyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine hydrochloride (244 mg, 0.88 mmol, the synthesis method is referred to Example 4 below) were added. The mixture was heated to 50 °C and stirred for 16 h. Water (15 mL) was added, and it was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparation to obtain the title compound, N-(2-(2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-3-(2H-1,2,3-triazol-4-yl)cyclopentane-1-carboxamide.

[0162] 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 3H), 7.66 (dd, 2H), 7.21 (dt, 2H), 7.16 - 7.13 (m, 2H), 4.59 (dd, 1H), 4.09 - 4.08 (d, 2H), 3.33 - 3.12 (m, 3H), 2.91 - 2.72 (m, 3H), 2.24 - 1.63 (m, 6H), 1.26 - 0.94 (m, 1H).

[0163] LC-MS m / z: 404.3 [M+H] + 。

[0164] Example 2: Preparation of Target Compound 002

[0165] N-((2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-3-(2H-1,2,3-triazol-4-yl)cyclohexane-1-carboxamide (Target Compound 002)

[0166]

[0167] First Step: (002A) Dimethyl 1,3-cyclohexanedicarboxylate

[0168] Add raw material 1,3-cyclohexanedicarboxylic acid (2.0 g, 11.6 mol) to 30 mL of methanol, then add 0.5 mL of concentrated sulfuric acid, heat to 70 °C, and stir for 16 h. Cool to room temperature, add water (100 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate to obtain the title compound dimethyl 1,3-cyclohexanedicarboxylate (2.20 g, yield 94%).

[0169] LC-MS m / z: 201.1 [M+H] +

[0170] Second Step: (002B) Methyl 3-formyl-1-cyclohexanecarboxylate

[0171] Add raw material dimethyl 1,3-cyclohexanedicarboxylate (2.8 g, 13.98 mmol) to 50 mL of dry tetrahydrofuran, cool to -78 °C, add 1.5 mol / L diisobutylaluminum hydride (9.4 mL, 13.98 mmol) under argon protection, and stir at -78 °C for 0.5 h. Add water (20 mL), allow to warm to room temperature naturally, extract with ethyl acetate (50 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate. Purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain the title compound methyl 3-formyl-1-cyclohexanecarboxylate as a colorless liquid (430 mg, yield 18%).

[0172] LC-MS m / z: 171.1 [M+H] + .

[0173] Third Step: (002C) Methyl 3-ethynylcyclohexane-1-carboxylate

[0174] 3 - formyl - 1 - methyl cyclohexanecarboxylate (400 mg, 2.35 mmol) was added to 12 mL of methanol, then dimethyl (1 - diazo - 2 - oxopropyl)phosphonate (677 mg, 3.5 mmol) and potassium carbonate (972 mg, 7.05 mmol) were added. The mixture was stirred at room temperature for 16 h, 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, 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, methyl 3 - ethynylcyclohexanecarboxylate, as a colorless liquid (230 mg, yield 59%).

[0175] LC - MS m / z: 167.1 [M + H] + 。

[0176] Step 4: Methyl 3-(2H - 1,2,3 - triazol - 4 - yl)cyclohexanecarboxylate

[0177] Methyl 3 - ethynylcyclohexanecarboxylate (200 mg, 1.2 mmol) was added to 15 mL of DMF and 4 mL of methanol. Under nitrogen protection, trimethylsilyl azide (250 mg, 2.17 mmol) and copper(I) iodide (46 mg, 0.24 mmol) were added. The mixture was heated to 110 °C and stirred for 16 h. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3), filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V)=3:1) to obtain the title compound, methyl 3-(2H - 1,2,3 - triazol - 4 - yl)cyclohexanecarboxylate, as a brown liquid (160 mg, yield 63.7%).

[0178] LC - MS m / z: 210.2 [M + H] + 。

[0179] Step 5: 3-(2H - 1,2,3 - triazol - 4 - yl)cyclohexanecarboxylic acid

[0180] Methyl 3-(2H - 1,2,3 - triazol - 4 - yl)cyclohexanecarboxylate (165 mg, 0.78 mmol) was added to 1 mL of water, 3 mL of tetrahydrofuran and 3 mL of methanol at room temperature. Sodium hydroxide (95 mg, 2.37 mmol) was added, and the mixture was stirred at room temperature for 5 h. The reaction solution was concentrated to 15 mL, and the pH was adjusted to 1 - 2 with hydrochloric acid. The aqueous phase was freeze - dried to obtain the title compound, 3-(2H - 1,2,3 - triazol - 4 - yl)cyclohexanecarboxylic acid, as a yellow liquid (168 mg, yield 100%).

[0181] LC - MS m / z: 196.2 [M + H]+ 。

[0182] Step 6: N-((2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-3-(2H-1,2,3-triazol-4-yl)cyclohexane-1-carboxamide (Target Compound 002)

[0183] Add the raw materials 3-(2H-1,2,3-triazol-4-yl)cyclohexane-1-carboxylic acid (84 mg, 0.43 mmol) and 5-(aminomethyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine hydrochloride (119 mg, 0.43 mmol) to 4 mL of DMF and 2 mL of ethyl acetate, then add 1-propylphosphonic anhydride (205 mg, 0.64 mmol) and N-methylmorpholine (130 mg, 1.29 mmol), and stir at room temperature for 16 h. Add water (15 mL), extract with ethyl acetate (15 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (methylene chloride:methanol (V / V) = 5:1) to obtain the title compound N-((2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-3-(2H-1,2,3-triazol-4-yl)cyclohexane-1-carboxamide.

[0184] 1 H NMR (400 MHz, DMSO-d6) δ 8.22 - 8.18 (m, 3H), 7.65 (d, 2H), 7.21 (dd, 2H), 7.16 - 7.12 (m, 2H), 4.60 - 4.57 (m, 1H), 4.06 (d, 2H), 3.24 (dd, 2H), 2.87 (dd, 2H), 2.75 - 2.67 (m, 2H), 2.32 (dd, 1H), 2.03 - 1.95 (m, 2H), 1.91 - 1.76 (m, 2H), 1.58 - 1.23 (m, 4H).

[0185] LC-MS m / z: 418.2 [M+H] + 。

[0186] Example 3: Preparation of Target Compounds 003-1 and 003-2

[0187] (1S,3R)-N-((2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-3-(2H-1,2,3-triazol-4-yl)cyclohexane-1-carboxamide (Target Compound 003-1)

[0188]

[0189] (1R,3S)-N-((2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-3-(2H-1,2,3-triazol-4-yl)cyclohexane-1-carboxamide (Target Compound 003-1)

[0190]

[0191] The starting material N-((2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-3-(2H-1,2,3-triazol-4-yl)cyclohexane-1-carboxamide (Compound 002) was prepared to obtain a ca. 1:1 mixture of Target Compound 003-1 and Target Compound 003-2.

[0192] Preparation conditions: Welch, Ultimate C18 column, 10 nm, 21.2 nm × 250 mm.

[0193] Mobile phase A was a 1‰ pure aqueous solution of trifluoroacetic acid, and mobile phase B was a 1‰ acetonitrile solution of trifluoroacetic acid. Gradient conditions: 0 - 3 minutes, mobile phase A was maintained at 90%, gradient elution from 3 - 18 minutes, changing from 90% to 5%, and maintained at 5% from 18 - 22 minutes.

[0194] 1 H NMR (400 MHz, DMSO-d6) δ 8.22 - 8.21 (m, 3H), 7.62 (d, 2H), 7.20 (d, 2H), 7.14 (d, 2H), 4.58 (d, 1H), 4.06 (d, 2H), 3.24 (dd, 2H), 2.87 (dd, 2H), 2.73 - 2.67 (m, 2H), 2.32 (d, 1H), 2.01 - 1.97 (m, 2H), 1.82 - 1.76 (m, 2H), 1.50 - 1.24 (m, 4H).

[0195] LC-MS m / z: 418.2 [M + H] + .

[0196] Example 4: Preparation of Target Compound 004

[0197] 2-(2-(1H-1,2,3-Triazol-4-yl)ethoxy)-N-((2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)acetamide (Target Compound 004)

[0198] The synthetic route of Target Compound 004 is shown below:

[0199]

[0200] Step 1: Synthesis of 5-cyano-N-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine (004C)

[0201] Add 2-chloropyrimidine-5-carbonitrile (4 g, 15.64 mmol), 2,3-dihydro-1H-inden-2-amine (3.18 g, 18.77 mmol), diisopropylethylamine (4.04 g, 31.3 mmol), and N-methylpyrrolidone (40 mL) into a single-necked flask, and stir at 80 °C for 16 hours. Cool to room temperature, dilute with water (40 mL), extract with ethyl acetate (200 mL × 3), combine the organic phases, wash the organic phase with saturated brine (200 mL × 2), separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1 - 3:1) to obtain a grayish-white solid 5-cyano-N-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine (4 g, yield 72.6%).

[0202] Step 2: Synthesis of 5-(aminomethyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine hydrochloride (004D)

[0203] Add 5-cyano-N-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine (0.7 g, 2.96 mmol), methanol (20 mL), Raney nickel (1.74 g, 29.6 mmol), and concentrated ammonia water (30%, 2 mL) into a single-necked flask, and hydrogenate at room temperature with a hydrogen balloon for 15 hours. Filter, concentrate the filtrate to dryness, add hydrochloric acid / ethyl acetate (50 mL, 4N) to the residue, stir at room temperature for 0.5 hour, and concentrate. Purify the residue by trituration with dichloromethane to obtain a light brown solid 5-(aminomethyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine hydrochloride (700 mg, 2.54 mmol, yield 86%).

[0204] Step 3: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-N-((2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)acetamide (target compound 004)

[0205] At 0 °C, 5-(aminomethyl)-N-((2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine hydrochloride (276 mg, 1.0 mmol), 2-(2-(1H-1,2,3-triazol-5-yl)ethoxy)acetic acid hydrochloride (0.31 g, 1.5 mmol, the synthesis method refers to pages 20 - 21 of patent literature WO2014110000A1, where the synthesis of carboxylic acid uses 1,4-dioxane solution of hydrogen chloride to replace trifluoroacetic acid / dichloromethane system), and N,N-diisopropylethylamine (0.77 g, 6.0 mmol) in N,N-dimethylformamide (3 mL) solution. 50% 1-propylphosphoric anhydride / N,N-dimethylformamide solution (0.96 g, 1.5 mmol) was added dropwise. After the addition, the reaction was carried out overnight at room temperature. TLC (methanol:dichloromethane (V / V) = 1:10) showed the reaction was complete. Water (10 mL) was added for dilution. The aqueous phase was extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL × 2), separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by preparative chromatography to obtain 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-N-((2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)acetamide.

[0206] 1H NMR (400 MHz, DMSO-d6) δ 8.30 (t, 1H), 8.20 (s, 2H), 7.64 (s, 1H), 7.39 - 7.41 (d, 1H), 7.07 - 7.18 (m, 4H), 4.50 - 4.59 (m, 1H), 4.07 - 4.11 (m, 2H), 3.88 (s, 2H), 3.66 (t, 2H), 3.13 - 3.22 (m, 2H), 2.80 - 2.92 (m, 4H).

[0207] LC-MS m / z: 394.3 [M + H] + 。

[0208] Example 5: Preparation of target compound 005

[0209] N-((2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-N-methylacetamide (target compound 005)

[0210] The synthetic route of target compound 005 is as follows:

[0211]

[0212] Step 1: Synthesis of Ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (005B)

[0213] Add ethyl 2-chloropyrimidine-5-carboxylate (2 g, 10.7 mmol), 2,3-dihydro-1H-inden-2-amine hydrochloride (3.64 g, 21.4 mmol), N,N-diisopropylethylamine (6.93 g, 53.6 mmol), and N-methylpyrrolidone (20 mL) into a single-necked flask. Stir at 80 °C for 16 h. Cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (100 mL × 3), combine the organic phases, wash the organic phases with saturated brine (100 mL × 2), separate the layers, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain solid ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (2.5 g, 8.82 mmol, yield 82%).

[0214] Step 2: Synthesis of (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanol (005C)

[0215] Add ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (2 g, 10.7 mmol) into a three-necked flask, add THF (25 mL) and stir to dissolve. Cool to -15 °C, add diisobutylaluminum hydride / tetrahydrofuran solution (15 mL, 25%), continue to react at -15 °C for 1 h. TLC (petroleum ether:ethyl acetate (V / V) = 1:1) shows no remaining raw materials. Add water (0.5 mL) to quench, then add 15% sodium hydroxide (2 mL) solution, add 1 mL of water, filter, concentrate to dryness, and purify the residue by silica gel column chromatography (ethyl acetate) to obtain white solid (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanol (0.8 g, 3.32 mmol, yield 94%).

[0216] Step 3: Synthesis of 5-(Chloromethyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (005D)

[0217] Add (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanol (0.8 g, 3.32 mmol), dichloromethane (8 mL), and thionyl chloride (3.94 g, 33.2 mmol) into a single-necked flask. Stir at room temperature for 2 h. TLC (petroleum ether:ethyl acetate (V / V) = 1:1) shows no remaining raw materials. Concentrate the reaction solution to dryness to obtain crude solid 5-(chloromethyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (0.9 g).

[0218] Step 4: Synthesis of N-(2,3-dihydro-1H-inden-2-yl)-5-((methylamino)methyl)pyrimidin-2-amine (005E) Add 5-(chloromethyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (0.4 g, 1.66 mmol) and methylamine / methanol solution (40%, 4 mL) to a single-necked flask, stir the reaction at room temperature for 2 hours. TLC (petroleum ether:ethyl acetate (V / V) = 1:1) shows that there is no raw material remaining. Concentrate the reaction solution to dryness to obtain a crude off-white solid N-(2,3-dihydro-1H-inden-2-yl)-5-((methylamino)methyl)pyrimidin-2-amine (0.4 g).

[0219] Step 5: Synthesis of N-((2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-N-methylacetamide (Target compound 005)

[0220] Add N-(2,3-dihydro-1H-inden-2-yl)-5-((methylamino)methyl)pyrimidin-2-amine (60 mg, 0.24 mmol), 2-(2-(1H-1,2,3-triazol-5-yl)ethoxy)acetic acid hydrochloride (0.15 g, 0.94 mmol), triethylamine (0.36 g, 3.54 mmol) and N,N-dimethylformamide (3 mL) to a single-necked flask, dissolve at room temperature, cool to 0 °C, and dropwise add 50% 1-propylphosphonic anhydride / N,N-dimethylformamide solution (0.45 g, 0.71 mmol). After the addition, react at room temperature for 2 hours. 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 phases with saturated brine (50 mL × 2), separate the layers, dry the organic phases with anhydrous sodium sulfate, filter, concentrate, and separate the residue by preparative chromatography to obtain N-((2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-N-methylacetamide.

[0221] 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 2H), 7.60 (s, 1H), 7.44 - 7.46 (d, 1H), 7.09 - 7.18 (m, 4H), 4.51 - 4.59 (m, 1H), 4.11 - 4.25 (m, 5H), 3.62 - 3.72 (m, 3H), 3.17 - 3.22 (dd, 2H), 2.81 - 2.88 (m, 5H).

[0222] LC-MS m / z: 408.2 [M+H] + 。

[0223] Example 6: Preparation of the target compound 006

[0224] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)ethyl)acetamide (target compound 006)

[0225] The synthetic route of the target compound 006 is as follows:

[0226]

[0227] First step: Synthesis of 1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)ethan-1-one (006A)

[0228] Add the raw material 1-(2-chloropyrimidin-5-yl)ethan-1-one (500 mg, 3.19 mmol) to 10 mL of N-methylpyrrolidone, add 2,3-dihydro-1H-inden-2-amine (560 mg, 4.15 mmol) and potassium carbonate (880 mg, 6.38 mmol), heat to 100 °C, and stir for 16 h. Filter, add water (60 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 title compound as a pale yellow solid, 1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)ethan-1-one (240 mg, yield 30%).

[0229] LC-MS m / z: 254.1 [M+1] + 。

[0230] Second step: Synthesis of (E)-N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)ethylidene)-2-methylpropane-2-thioamide (006B)

[0231] The raw material 1-(2-(2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)ethan-1-one (200 mg, 0.78 mmol) was added to 5 mL of tetraethyl titanate, and 2-methylpropyl-2-thiolamine (287 mg, 2.37 mmol) and potassium carbonate (880 mg, 6.38 mmol) were added. The mixture was heated to 100 °C and stirred for 16 h. After filtration, 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 separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain the title compound as a pale yellow solid (E)-N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)ethylidene)-2-methylpropane-2-thioamide (100 mg, yield 35%).

[0232] LC-MS m / z: 357.2 [M+H] + 。

[0233] Step 3: Synthesis of N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)ethyl)-2-methylpropane-2-thioamide (006C)

[0234] The raw material (E)-N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)ethylidene)-2-methylpropane-2-thioamide (200 mg, 0.56 mmol) was added to tetrahydrofuran (4 mL) and methanol (4 mL), and sodium borohydride (43.0 mg, 1.12 mmol) was added. The mixture was stirred at room temperature for 16 h. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product of the title compound as a pale yellow oil, N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)ethyl)-2-methylpropane-2-thioamide (260 mg, yield 100%) was obtained.

[0235] LC-MS m / z: 359.2 [M+H] +

[0236] Step 4: Synthesis of 5-(1-aminoethyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (006D)

[0237] At room temperature, the raw material N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)ethyl)-2-methylpropane-2-thioamide (260 mg, 0.72 mmol) was added to 5 mL of tetrahydrofuran, and a 1,4-dioxane solution (10 mL) of 4 mol / L hydrogen chloride was added. The mixture was stirred at room temperature for 15 h. The reaction solution was concentrated, the pH was adjusted to 9 - 10 with saturated aqueous sodium carbonate solution, and it was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound, 5-(1-aminoethyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, as a pale yellow solid (190 mg, yield 90%).

[0238] LC-MS m / z: 255.2[M+H] + 。

[0239] Step 5: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)ethyl)acetamide (Target Compound 006)

[0240] The raw material 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (107 mg, 0.63 mmol) was added to 4 mL of DMF, and then 5-(1-aminoethyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (160 mg, 0.63 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (359 mg, 0.94 mmol), and N,N-diisopropylethylamine (406 mg, 3.14 mmol) were added. The mixture was stirred at room temperature for 16 h. Water (15 mL) was added, and it was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 5:1) to obtain the title compound 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)ethyl)acetamide.

[0241] 11H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 2H), 8.17 (d, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7.21 (dd, 2H), 7.16 - 7.12 (m, 2H), 4.89 - 4.83 (m, 1H), 4.61 - 4.57 (m, 1H), 3.91 (s, 2H), 3.71 (t, 2H), 3.23 (dd, 3H), 2.94 (t, 2H), 2.87 (dd, 2H), 1.40 (d, 3H)

[0242] LC-MS m / z: 408.5 [M+H] + 。

[0243] Example 7: Preparation of Target Compound 007

[0244] 1-(3-(1H-1,2,3-Triazol-4-yl)propyl)-3-((2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)imidazolidin-2-one (Target Compound 007)

[0245] The synthetic route of target compound 007 is as follows:

[0246]

[0247] The First Step: Synthesis of Pent-4-yn-1-yl 4-methylbenzenesulfonate (007B)

[0248] Add pent-4-yn-1-ol (1 g, 11.9 mmol), dichloromethane (20 mL), triethylamine (1.45 g, 14.3 mmol), 4-dimethylaminopyridine (0.15 g, 1.2 mmol) into a single-neck flask, cool to 0 °C, add p-toluenesulfonyl chloride (2.4 g, 12.5 mmol), stir at room temperature overnight. TLC (petroleum ether: ethyl acetate (V / V) = 3:1) shows a small amount of raw material remaining. Add NaOH (1 M, 15 mL), stir for 15 minutes, separate the layers, extract the aqueous phase with dichloromethane (20 mL), combine the organic phases, wash with saturated brine (20 mL), separate the layers, filter, dry over anhydrous sodium sulfate, concentrate to dryness, and purify the residue by silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1) to obtain pale yellow solid pent-4-yn-1-yl 4-methylbenzenesulfonate (1.5 g, 6.29 mmol, yield 53%).

[0249] The Second Step: Synthesis of 1-(Pent-4-yn-1-yl)imidazolidin-2-one (007D)

[0250] Add 4-pent-4-yn-1-yl benzenesulfonate (1.1 g, 12.6 mmol) and N,N-dimethylformamide (10 mL) to a single-necked flask, stir and dissolve at room temperature. Add 60% sodium hydride (0.55 g, 13.9 mmol), stir at room temperature for 1 hour, then stir at 45 °C for 0.5 hour. Cool to room temperature, add carbonyldiimidazole (1.5 g, 6.29 mmol), and stir overnight at room temperature. TLC (dichloromethane:methanol (V / V) = 10:1) shows a new spot. Add methanol (5 mL) to quench the reaction, concentrate to dryness, add dichloromethane (20 mL) to dilute, add saturated sodium chloride solution (20 mL), separate the layers. Extract the aqueous phase twice with dichloromethane (20 mL × 2). Combine the organic phases and wash twice with saturated sodium chloride solution (20 mL × 2), separate the layers. Dry the organic phase over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain 1-(pent-4-yn-1-yl)imidazolidin-2-one as a white oil (0.5 g, 3.29 mmol, yield 52%).

[0251] Step 3: Synthesis of 1-((2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-3-(pent-4-yn-1-yl)imidazolidin-2-one (007E)

[0252] Add 1-(pent-4-yn-1-yl)imidazolidin-2-one (0.31 g, 2 mmol) and tetrahydrofuran (5 mL) to a three-necked flask. Add 60% sodium hydride (0.24 g, 6 mmol) under stirring at room temperature, stir for 0.5 hour, then stir at 45 °C for 0.5 hour. Cool to room temperature and add 5-(chloromethyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (0.26 g, 1 mmol). Stir at room temperature for 0.5 hour. TLC (dichloromethane:methanol (V / V) = 10:1) shows no remaining starting material. Add saturated ammonium chloride (10 mL) to the reaction mixture, extract with ethyl acetate (20 mL × 2). Dry the organic phase over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain 1-((2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-3-(pent-4-yn-1-yl)imidazolidin-2-one as a white solid (0.26 g, 0.69 mmol, yield 35%).

[0253] Step 4: Synthesis of 1-(3-(1H-1,2,3-triazol-4-yl)propyl)-3-((2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)imidazolidin-2-one (Target compound 007)

[0254] Add L(+)-ascorbic acid (0.14 g, 0.8 mmol), sodium bicarbonate (67 mg, 0.8 mmol), DMF (2 mL), methanol (0.4 mL) to a single-necked flask, stir and react for 1 hour. Then add 1-((2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)-3-(pent-4-yn-1-yl)imidazolidin-2-one (0.26 g, 0.27 mmol), azidotrimethylsilane (0.12 g, 1.1 mmol), copper sulfate pentahydrate (27 mg, 0.11 mmol), heat to 90 °C and react for 2 hours. LCMS shows that most of the raw materials have reacted. Cool the reaction solution to room temperature, add saturated brine (10 mL) to the reaction solution, extract with ethyl acetate (50 mL × 2), wash the organic phase twice with saturated brine (20 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate, and separate the residue by preparative chromatography to obtain 1-(3-(1H-1,2,3-triazol-4-yl)propyl)-3-((2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methyl)imidazolidin-2-one.

[0255] 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 2H), 7.58 (s, 1H), 7.44~7.46 (d, 1H), 7.30 (s, 2H), 7.08~7.17 (m, 4H), 4.51~4.60 (m, 1H), 4.05 (s, 2H), 3.07~3.24 (m, 7H), 2.81~2.86 (dd, 2H), 2.58 (t, 2H), 1.70~1.77 (m, 2H).

[0256] LC-MS m / z: 419.5 [M+H] + 。

[0257] Example 8: Preparation of the target compound 008

[0258] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-N-((5-((2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)methyl)acetamide (target compound 008)

[0259] The synthetic route of the target compound 008 is as follows:

[0260]

[0261] The first step: Synthesis of 5-((2,3-dihydro-1H-inden-2-yl)amino)pyrazine-2-carbonitrile (008B)

[0262] 2-Aminoindane hydrochloride (600 mg, 3.56 mmol) and 5-chloropyrazine-2-carbonitrile (496 mg, 3.56 mmol), DIEA (1.8 g, 13.93 mmol) were dissolved in N-methylpyrrolidone (30 mL), and stirred at 80 °C for 18 h. The reaction was monitored by TLC until completion. Heating was stopped, and the mixture was stirred to room temperature. Water (150 mL) was added, and the mixture was extracted with ethyl acetate (70 mL×5). The organic phases were combined, washed with saturated aqueous Na2CO3 solution (100 mL×2), dried over MgSO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to give a pale yellow solid 5-((2,3-dihydro-1H-inden-2-yl)amino)pyrazine-2-carbonitrile (800 mg, yield 95%).

[0263] LC-MS m / z: 237.2 [M+H] + 。

[0264] Step 2: Synthesis of 5-(aminomethyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine hydrochloride (008C)

[0265] 5-((2,3-Dihydro-1H-inden-2-yl)amino)pyrazine-2-carbonitrile (700 mg, 2.96 mmol) was added to methanol (25 mL), and 15% aqueous NaOH solution (25 mL) and Raney nickel catalyst (1.0 g) were slowly added with stirring in an ice-water bath. Under a hydrogen atmosphere, the mixture was stirred at room temperature for 4 h. The supernatant was filtered, and the filtrate was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated aqueous Na2CO3 solution (100 mL×2), dried over MgSO4, filtered, and the filtrate was concentrated. The residue was added to hydrochloric acid / ethyl acetate (50 mL, 4N), stirred at room temperature for 0.5 h, and concentrated. The residue was purified by trituration with dichloromethane to give a light brown solid 5-(aminomethyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine hydrochloride (700 mg, 2.54 mmol, yield 86%).

[0266] LC-MS m / z: 224.2 [M+H] + 。

[0267] Step 3: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-N-(((5-((2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)methyl)acetamide (target compound 008)

[0268] At 0 °C, a solution of 1-propane phosphonic anhydride (1.038 g, 3.26 mmol, 50% DMF solution) was added dropwise to a solution of 5-(aminomethyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrazine-2-amine hydrochloride (300 mg, 1.088 mmol), triethylamine (900 mg, 8.89 mmol), and 2-(2-(1H-1,2,3-triazol-5-yl)ethoxy)acetic acid (452 mg, 2.176 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 18 h and monitored by TLC until the reaction was complete. Dichloromethane (30 mL) was added, and the mixture was washed with saturated aqueous sodium bicarbonate (30 mL × 3). The organic phase was concentrated, and the residue was separated by preparative chromatography to obtain a pale yellow solid, 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-N-((5-((2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)methyl)acetamide (130 mg, 0.33 mmol, yield 14.7%).

[0269] 1 HNMR (400 MHz, CD3OD) δ 8.45 (brs, 2H), 7.95 (s, 1H), 7.85 (s, 1H), 7.68 (s, 1H), 7.22 - 7.20 (m, 2H), 7.14 - 7.12 (m, 2H), 4.62 (dd, 2H), 4.39 (s, 2H), 4.03 (s, 2H), 3.81 (t, 2H), 3.33–3.31 (m, 2H), 3.06 (t, 2H), 2.87 (dd, 2H).

[0270] LC-MS m / z: 394.3 [M+H] + 。

[0271] Test Examples of Biological Activity and Related Properties

[0272] Test Example 1: Autotaxin (ATX) Enzyme Activity Inhibition Assay

[0273] The inhibitory activity of the compound against Autotaxin enzyme was detected using an Autotaxin inhibitor screening assay kit (Cayman, 700580). First, the compound to be tested was prepared into a 10 mM stock solution in DMSO solvent, and then 8 concentration points were diluted in a DMSO gradient. Subsequently, the 8 concentration points were diluted into a 19× compound working solution (with 1.9% DMSO content) using the Autotaxin assay buffer (1×) provided by the kit. The Autotaxin assay reagent (10×) was taken out and diluted 10 times with the Autotaxin assay buffer (1×). The Autotaxin substrate was taken out, 1.2 mL of the Autotaxin assay buffer (1×) was added to dissolve it, and after mixing, it was left standing at room temperature. In a 96-well plate, in each well corresponding to each concentration point, 150 μL of the Autotaxin assay buffer (1×), 10 μL of the diluted 19× compound working solution, 10 μL of the Autotaxin assay reagent (1×), and 20 μL of the dissolved Autotaxin substrate were added, mixed well, and incubated in a constant temperature shaking incubator at 37 °C 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 GraphPad Prism software, and the IC 50 .

[0274] Table 1 Results of the inhibitory activity of the test compounds against ATX enzyme activity

[0275]

[0276] The experimental results show that the compounds of the present invention have good inhibitory activity against the ATX enzyme and can effectively inhibit the activity of the ATX enzyme.

[0277] Test Example 2: Human liver microsome stability test

[0278] The human liver microsome stability test was performed by in vitro co-incubation of the compound with human liver microsomes. First, the test compound was prepared as a 10 mM stock solution in DMSO solvent, and then the compound was diluted to 0.5 mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS to form a microsome / buffer solution, and this solution was used to dilute the 0.5 mM compound to form a working solution with a compound concentration of 1.5 μM and a human liver microsome concentration of 0.75 mg / mL in the working solution. Take a deep well plate, add 30 μL of the working solution to each well, then add 15 μL of pre-warmed 6 mM NADPH solution to initiate the reaction, and incubate at 37 °C. At 0, 5, 15, 30, and 45 minutes of incubation, add 135 μL of acetonitrile to the corresponding wells to terminate the reaction. After terminating the reaction with acetonitrile at the last 45-minute time point, the deep well plate was vortexed for 10 minutes (600 rpm / min), and then centrifuged for 15 minutes. After centrifugation, take the supernatant, add purified water in a 1:1 ratio, and then perform LC-MS / MS detection to obtain the ratio of the compound peak area to the internal standard peak area at each time point. Compare the peak area ratios of the compound at 5, 15, 30, and 45 minutes with the peak area ratio at 0 minute, calculate the remaining percentage of the compound at each time point, and use Excel to calculate T 1 / 2 .

[0279] Table 2 Results of human liver microsome stability test

[0280]

[0281] The experimental results show that the compound of the present invention exhibits excellent liver metabolic stability, is metabolized more slowly in the human body, and has a higher exposure level.

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: X and Y are the same or different and are independently selected from -N=, -CH=; Z is selected from -NH-; R 1 independently selected from hydrogen, halogen, C1-C6 alkyl; R 2 selected from hydrogen, C1-C6 alkyl; Q is an unsubstituted or optionally substituted by one or more R 3 substituted with the following groups: indenyl, 2,3-dihydro-1H-indenyl; R 3 selected from -H, -F, -Cl, methyl, ethyl; m is selected from the integer 0 or 1; L is selected from C3-C 10 cycloalkyl or Z1 and Z2 are selected from -O-, -NH-, -C(R 8 )(R 9 )-; 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 )=; R 8 、R 9 、R 11 are independently selected from hydrogen, C1-C6 alkyl; R 10 Independently selected from hydrogen, C1-C6 alkyl groups.

2. The compound according to claim 1, characterized in that: L is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3. The compound according to claim 1, wherein: L is selected from 4. 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: X and Y are independently selected from -N=, -CH=; R 1 independently selected from hydrogen, halogen, C1-C6 alkyl; R 2 independently selected from hydrogen, C1-C6 alkyl; L is selected from Wherein: Z1 and Z2 are selected from -O-, -NH-, -C(R 8 )(R 9 )-; M 1 、M 2 、M 3 independently selected from -N= or -N(R 10 )-, wherein R 10 is selected from hydrogen, C1-C6 alkyl; R 8 、R 9 are independently selected from hydrogen, C1-C6 alkyl groups.

5. The compound according to claim 4, wherein: M 1 、M 2 、M 3 are each independently selected from -N= or -NH-.

6. The compound according to claim 4, wherein: selected from R 1 、R 2 are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, butyl, cyclopropyl, cyclobutyl; L is independently selected from Z1 and Z2 are selected from O, N, -CH2-; selected from 7. The compound according to claim 4, wherein: R 1 、R 2 independently selected from hydrogen, methyl, and ethyl.

8. The compound according to claim 1 or 4, which is selected from at least one of the following compounds:

9. The compound according to claim 1 or 4, which is selected from at least one of the following compounds:

10. A pharmaceutical composition, characterized in that, Comprising the compound according to any one of claims 1 to 9.

11. Use of the compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10 in the preparation of a drug for treating a disease related to ATX.

12. The use according to claim 11, wherein the ATX-related disease is selected from cancer, metabolic disease, kidney disease, liver disease, fibrotic disease, interstitial lung disease, proliferative disease, inflammatory disease, pain, autoimmune disease, respiratory disease, cardiovascular disease, neurodegenerative disease, dermatological disorder and / or abnormal angiogenesis-related disease.

13. The use according to claim 11, wherein the ATX-related disease is selected from interstitial lung disease, pulmonary fibrosis, liver fibrosis, renal fibrosis.

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

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

16. The use according to claim 11, wherein the ATX-related disease is selected from type II diabetes, non-alcoholic steatohepatitis.

17. The use according to claim 11, wherein the ATX-related disease is selected from neuropathic pain, inflammatory pain.

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

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

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