Pyrrolopyrimidine compounds and uses thereof

Abstract

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

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to pyrrolopyrimidine compounds, and more specifically, the present invention relates to pyrrolopyrimidine compounds and methods for preparing the same, as well as uses thereof in preparing drugs. Background Art

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

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

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

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

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

[0007] After inflammation subsides and tissue damage is repaired, the tissue usually returns to its original state. Excessive, uncontrolled tissue repair can lead to a condition commonly known as fibrosis. Fibrosis is characterized by excessive deposition of extracellular matrix components and excessive growth of fibroblasts. Fibrosis can occur in all tissues, but is particularly prevalent in organs that are often subject to chemical and biological damage, including the lungs, skin, digestive tract, kidneys, and liver. Fibrosis often seriously impairs the normal function of organs.

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

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

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

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

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

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

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

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

[0016] While 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, there are still deficiencies. Currently marketed IPF treatments include pirfenidone and nintedanib. Pirfenidone is associated with liver damage (e.g., liver failure, jaundice), hypersensitivity reactions (e.g., facial swelling, laryngeal edema, dyspnea, wheezing), and severe gastrointestinal reactions. Photogenotoxicity studies have shown potential for chromosomal structural abnormalities and skin carcinogenesis after light exposure. Nintedanib is associated with adverse reactions such as diarrhea, nausea, and abdominal pain, with an incidence of gastrointestinal reactions as high as 50%. Other common adverse reactions include weight loss, loss of appetite, liver damage, and bleeding. The incidence of discontinuation due to serious adverse events in patients receiving pirfenidone and nintedanib was 20.9% and 26.3%, respectively. The quality of life of patients with IPF can be severely impacted, and in clinical trials, neither pirfenidone nor nintedanib has been shown to improve quality of life. Although both drugs may improve overall outcomes, they can only slow the course of the disease but cannot reverse pulmonary fibrosis, so patients with severe idiopathic pulmonary fibrosis may not benefit. GLPG-1690, which is currently developing faster than other IPF drugs, has shown a trend of reversing the course of the disease, but it has problems such as low enzyme activity, large clinical dosage, and poor medication compliance. Therefore, current therapies are not satisfactory, and a large number of patients still need new treatments with higher activity and better efficacy to slow down or even reverse the disease progression to a greater extent, improve medication compliance, and benefit more patients with idiopathic pulmonary fibrosis.

[0017] In view of this, the present invention designs, based on the prior art, a compound represented by formula (I), its tautomers, mesomers, racemates, enantiomers, diastereomers, or pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates or prodrugs, to provide ATX inhibitors with novel structures, better pharmacokinetic properties, better efficacy and strong drugability, which are used to effectively treat ATX-related diseases and conditions, including but not limited to cancer, metabolic diseases, kidney diseases, liver diseases, fibrotic diseases, pulmonary fibrosis, liver fibrosis, proliferative diseases, inflammatory diseases, pain, osteoarthritis-related pain, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders and / or diseases related to abnormal angiogenesis. Summary of the Invention

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

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

[0020]

[0021] in:

[0022] R 1 、R 2 、R 3 or R 4 independently selected from -H, -CN, halogen, unsubstituted or optionally substituted with one or more R a Substituted with the following groups: C 1-6 Alkyl, C 3-6 Cycloalkyl; said R a Selected from halogen, C 1-6 alkyl;

[0023] Each R 5 independently selected from H, -CN, halogen, unsubstituted or optionally substituted with one or more R b Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl; said R b Selected from halogen, C 1-6 alkyl;

[0024] M 1 、M 2 、M 3 、M 4 、M 5 At least one of them is -C(R 6 )= or -CH=, the rest are -N(R 7 )- or -N=, and at least one of them is -N(R 7 )-or-N=;

[0025] R 6 and R 7 Same or different, independently selected from: absent, -H, -CN, halogen, unsubstituted or optionally replaced by one or more R c Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy; said R c Selected from halogen, C 1-6 Alkyl, preferably, the R c Selected from -F, -Cl, methyl, ethyl, propyl;

[0026] Z is selected from -O-, -S-,

[0027] L is a single bond, or is selected from unsubstituted or optionally substituted with one or more R d Substituted with the following groups: C 1-10 Straight chain alkylene, C 3-10 Cycloalkylene, 3-10 membered heterocyclylene; said R d Selected from halogen, methyl, ethyl, cyclopropyl;

[0028] Q is unsubstituted or optionally substituted with one or more R 5 Substituted with the following groups: C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0029] m is selected from an integer of 0-6; n is selected from an integer of 0-6; and p is selected from an integer of 0-5.

[0030] In some embodiments of the present invention, the above R a is selected from -F, -Cl, methyl, ethyl, propyl, and the remaining variables are as defined in the present invention.

[0031] In some embodiments of the present invention, the above R b is selected from -F, -Cl, methyl, ethyl, propyl, and the remaining variables are as defined in the present invention.

[0032] In some embodiments of the present invention, the above R 6 and R 7 are independently selected from absent, -H, -CH3, -CH2CH3, -CH2CH2CH3, -F, -Cl, -Br, -CF3, and other variables are as defined in the present invention.

[0033] In some embodiments of the present invention, the above R 6 and R 7 is independently selected from absent, -H, -CH3, -F, -Cl, -CF3, and the remaining variables are as defined herein.

[0034] In some embodiments of the present invention, the above L is unsubstituted or optionally substituted with one or more R d Substituted: methylene, ethylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, azetidinyl, methylene-cyclopropylene, methylene-cyclobutylene, methylene-cyclopentylene, methylene-cyclohexylene, methylene-azetidinyl, and the remaining variables are as defined herein.

[0035] In some embodiments of the present invention, Q is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl, and the remaining variables are as defined herein.

[0036] In some embodiments of the present invention, the above Q is selected from a benzene ring, and the remaining variables are as defined in the present invention.

[0037] In some embodiments of the present invention, in formula (I), M 1 、M 2 、M 3 、M 4 、M 5 At least 2 or 3 of them are -C(R 6 )= or -CH=, the rest are -N(R 7 )- or -N=, and at least one of them is -N(R 7 )-or-N=, wherein R 6 and R 7 The definitions of are the same as above, and the remaining variables are as defined in the present invention.

[0038] In some embodiments of the present invention, Selected from or Among them, M 3 and M 5 Independently selected from -C(R 6 )=, -CH= or -NH=, wherein R 6 and R 7 The definitions of are the same as above, and the remaining variables are as defined in the present invention.

[0039] In some embodiments of the present invention, Selected from or or or or or The remaining variables are as defined in the present invention.

[0040] In some embodiments of the present invention, in formula (I), m=0, 1 or 2; n=0, 1 or 2, and the remaining variables are as defined in the present invention.

[0041] In some embodiments of the present invention, in formula (I), R 1 、R 2 、R 3 or R 4Independently selected from -H, -CN, unsubstituted or optionally substituted with 1-3 C 1-3 Alkyl R a The following groups are substituted: methyl, ethyl, n-propyl, isopropyl; the R a Selected from -F, -Cl, C 1-3 Alkyl, the remaining variables are as defined in the present invention. In some embodiments of the present invention, in formula (I), each R 1 、R 2 、R 3 or R 4 are independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, and the remaining variables are as defined herein.

[0042] In some embodiments of the present invention, in formula (I), Selected from The remaining variables are as defined in the present invention.

[0043] In some embodiments of the present invention, in formula (I), L is selected from: The remaining variables are as defined in the present invention.

[0044] In some embodiments of the present invention, in formula (I), p=0, 1 or 2, and the remaining variables are as defined herein.

[0045] In some embodiments of the present invention, each R 5 independently selected from H, -CN, -F, -Cl, -Br, -CH3, -CF3, -OCHF2, -OCF3, -CH2CH3, -CH2CH2CH3, The remaining variables are as defined in the present invention.

[0046] In some embodiments of the present invention, each R 5 are independently selected from -H, -CN, -F, -Cl, -Br, -CF3, -OCF3, -OCHF2, and the remaining variables are as defined herein.

[0047] In some embodiments of the present invention, in formula (I), Selected from The remaining variables are as defined in the present invention.

[0048] According to an embodiment of the present invention, the compound of the present invention comprises 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:

[0049]

[0050]

[0051] According to an embodiment of the present invention, the compound of the present invention comprises 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:

[0052]

[0053] The compounds of the present invention may exist in tautomerism. The present invention includes all tautomeric forms of the compounds, whether in equilibrium or one form predominates, the present invention includes each tautomeric form.

[0054] According to another aspect of the present invention, the present invention provides a pharmaceutical composition containing a therapeutically effective dose of at least one compound of formula (I) of the present invention or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate or prodrug thereof.

[0055] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0056] According to another aspect of the present invention, the present invention provides the use of a compound of formula (I), a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate or prodrug thereof, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate or prodrug thereof in the preparation of a medicament for treating ATX-related diseases.

[0057] In some embodiments of the present invention, the ATX-related disease is selected from cancer, metabolic disease, kidney disease, liver disease, fibrotic disease, interstitial lung disease, proliferative disease, inflammatory disease, pain, autoimmune disease, respiratory disease, cardiovascular disease, neurodegenerative disease, dermatological disorder and / or disease associated with abnormal angiogenesis.

[0058] In some embodiments of the present invention, the ATX-related disease is selected from interstitial lung disease, pulmonary fibrosis, liver fibrosis, and renal fibrosis, preferably, idiopathic pulmonary fibrosis. According to embodiments of the present invention, the compounds of the present invention have significant advantages in treating pulmonary fibrosis, particularly idiopathic pulmonary fibrosis.

[0059] In some embodiments of the present invention, the ATX-related disease is selected from metabolic diseases.

[0060] In some embodiments of the present invention, the metabolic disease is selected from type II diabetes and non-alcoholic steatohepatitis. According to embodiments of the present invention, the compounds of the present invention have significant advantages in treating metabolic diseases, particularly type II diabetes and non-alcoholic steatohepatitis.

[0061] In some embodiments of the present invention, the ATX-related disease is selected from neuropathic pain, inflammatory pain, and preferably, osteoarthritis-related pain. According to embodiments of the present invention, the compounds of the present invention have significant advantages in treating osteoarthritis-related pain.

[0062] In some embodiments of the present invention, the ATX-related disease is selected from cancer. According to embodiments of the present invention, the compounds of the present invention have significant advantages in treating cancer.

[0063] Definitions and Explanations of Terms

[0064] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0065] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by persons skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. If multiple definitions of a term are used herein, the definitions in this section shall prevail.

[0066] Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / Vis spectroscopy and pharmacological methods, are used. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, as well as in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purification can be carried out in accordance with methods well known in the art or the description of this application. The above-mentioned techniques and methods can generally be implemented according to conventional methods well known in the art, based on the descriptions in the multiple general and more specific literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2.

[0067] When the numerical ranges described in the specification and claims of this application are understood as “integers”, they should be understood as recording the two endpoints of the range and each integer within the range. For example, “an integer from 1 to 6” should be understood as recording each integer of 0, 1, 2, 3, 4, 5, and 6. When the numerical range is understood as a “number”, it should be understood as recording the two endpoints of the range and each integer within the range and each decimal within the range. For example, “a number from 1 to 10” should be understood as recording not only each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9, respectively.

[0068] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0069] The term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable non-toxic acids or bases, including salts of inorganic acids and bases, and organic acids and bases.

[0070] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts that may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or that may be useful in the identification, characterization, or purification of the compounds of the present invention.

[0071] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformers. The stereochemical definitions and conventions used herein are generally those of SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0072] Depending on the choice of raw materials and methods, the compounds of the present invention may exist in the form of one of the possible isomers or a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric 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 indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are right-handed. With respect to 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 mixtures of the isomers are often referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of alkenes, C=N double bonds, etc. can also exist in the compounds described herein, and all such stable isomers are contemplated by the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in either the cis- or trans- configuration.

[0073] When bonds to chiral carbon atoms in formulae of the present invention are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formulae. The diagrammatic representations of racemates and enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0074] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. Resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active, salified organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by eluting on a column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can also be used to carry out supercritical fluid chromatography (SFC). The selection of specific methods and elution conditions, chromatographic column selection can be selected by those skilled in the art according to the structure of the compound and test results. Further, optically pure starting materials or reagents of known configuration can also be used to obtain any enantiomer or diastereomer of the compound described in the present invention through stereoorganic synthesis.

[0075] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0076] In embodiments of the present invention, protons can occupy two or more positions in the cyclic form of the heterocyclic ring system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically fixed to one form by appropriate substitution. For example:

[0077]

[0078] Due to resonance, the hydrogen of the nitrogen on triazole can be on any of the three nitrogens, so the naming will be different, but these three forms actually represent the same compound.

[0079] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0080] With respect to a drug or pharmacologically active agent, the terms "effective dose," "effective amount," or "therapeutically effective amount" refer to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0081] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0082] The term "solvate" refers to a compound of the present invention or a salt thereof including a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate.

[0083] The term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl or amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or free amino group, respectively.

[0084] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0085] The term "C 1-6 “Alkyl” is understood as meaning preferably a straight-chain or branched, saturated, monovalent hydrocarbon radical having 1 to 6 carbon atoms. Such alkyl radicals are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc., or isomers thereof. In particular, such radicals have 1, 2 or 3 carbon atoms (“C1-C3-alkyl”), for example methyl, ethyl, n-propyl or isopropyl.

[0086] The term "C 3-6 "Cycloalkyl" is understood as meaning a saturated, monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0087] The term "alkoxy" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and sec-pentoxy.

[0088] The term "C 1-6 "Alkoxy" is understood to mean -O-(C 1-6 alkyl), where "C 1-6 "Alkyl" has the above definition.

[0089] The term "C 3-6 "Cycloalkoxy" is understood to mean -O-(C 3-6 cycloalkyl), wherein "C 1-6 "Alkyl" has the above definition.

[0090] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0091] "Haloalkyl" refers to a saturated aliphatic hydrocarbon group, including branched and straight chains, having the specified number of carbon atoms, substituted with one or more halogens (e.g., -CvFw, where v = 1 to 3, w = 1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0092] The term "3-10 membered heterocyclyl" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3, heteroatoms selected from N, O and S. In particular, the heterocyclyl may include, but is not limited to: a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The nitrogen-containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl. According to the present invention, the heterocyclic group is non-aromatic.

[0093] Beneficial effects

[0094] According to a specific example of the present invention, the compound of formula (I) of the present invention or the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I) can effectively inhibit ATX enzyme activity. Compared with the control compound, the compound of the present invention exhibits better liver metabolic stability and better pharmacokinetic properties.

[0095] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. DETAILED DESCRIPTION

[0096] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0097] Embodiments of the present invention provide compounds represented by formula (I), their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, methods and intermediates for preparing compounds represented by formula (I), their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, pharmaceutical compositions, and uses of the compounds and pharmaceutical compositions of the present invention in preparing drugs.

[0098] The reaction solvents used in each reaction step described in the present invention are not particularly limited. Any solvent that can dissolve the starting materials to a certain extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different ratios of solvent combinations equivalent to those described in the present invention are considered to be within the scope of the present invention.

[0099] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 The solvents for NMR measurements are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and tetramethylsilane (TMS) is the internal standard.

[0100] Liquid chromatography-mass spectrometry (LC-MS) was performed on a Waters Acquity H-class UPLC-QDA mass spectrometer using an ACQUITY UPLC BEHC18, 2.1 x 50 mm, 1.7 μm column. Gradient elution conditions were: 95% to 5% solvent A1 and 5% to 95% solvent B1, followed by 95% B1 and 5% A1 for 0.5 min, at a flow rate of 1.0 mL / min. Percentages represent the volume percentage of a particular solvent relative to the total solvent volume. Solvent A1: 0.1% formic acid in water; Solvent B1: 0.1% formic acid in acetonitrile. Percentages represent the volume percentage of the solute relative to the total solvent volume.

[0101] The abbreviations of the present invention are defined as follows:

[0102] CuI: Cuprous iodide

[0103] DCM: dichloromethane

[0104] DIPEA: also written as DIEA, diisopropylethylamine, also known as N,N-diisopropylethylamine

[0105] DMF: N,N-dimethylformamide

[0106] DMSO: dimethyl sulfoxide

[0107] Et3N: triethylamine

[0108] M: mol / L, for example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution) means a n-butyllithium n-hexane solution with a molar concentration of 2.5 mol / L

[0109] N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0110] NADPH: reduced coenzyme II

[0111] NaH: sodium hydride, sodium hydride

[0112] NMM: N-methylmorpholine

[0113] NMP: N-methylpyrrolidone

[0114] Pd / C: Palladium on carbon

[0115] PPh3: triphenylphosphine

[0116] SFC: Supercritical Fluid Chromatography

[0117] T3P: propylphosphonic acid tricyclic anhydride, also known as 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine-2,4,6-trioxide or 1-propylphosphonic anhydride

[0118] THF: Tetrahydrofuran

[0119] IC 50 : Half-maximal inhibitory concentration refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0120] Unless otherwise indicated, compounds exemplified herein are named and numbered using ChemBioDraw Ultra 13.0.

[0121] Preparation Example 1: Synthesis of Intermediate B

[0122] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (Intermediate B)

[0123] The synthetic route of target compound intermediate B is as follows:

[0124]

[0125] Step 1: Synthesis of methyl 2-(butyl-3-yn-1-oxy)acetate (Compound B-2)

[0126] The raw material 3-butynol (Compound B-1) (2.8 g, 0.4 mol) was added to dry tetrahydrofuran (100 mL), cooled to 0°C, and 60% sodium hydroxide (2.4 g, 0.6 mmol) was added. The mixture was stirred at 0°C for 0.5 h. The raw material methyl 2-bromoacetate (7.3 g, 0.48 mmol) was added to the reaction solution, and the mixture was naturally warmed to room temperature and stirred for 16 h. Water (100 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, and concentrated. The residue was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain Compound B-2 as a colorless liquid (2.24 g, 39% yield).

[0127] LC-MS m / z: 143.0 [M+H] + .

[0128] Step 2: Synthesis of methyl 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetate (Compound B-3)

[0129] Compound B-2 (2.24 g, 15.7 mmol) was added to N,N-dimethylformamide (15 mL) and methanol (4 mL) at room temperature. Azidotrimethylsilane (2.72 g, 23.6 mmol) and cuprous iodide (357 mg, 1.9 mmol) were added under nitrogen. The mixture was heated to 110°C and stirred for 16 h. Water (150 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The aqueous phase was lyophilized to obtain compound B-3 as a brown liquid (2.5 g, 85.6% yield).

[0130] LC-MS m / z: 186.1 [M+H] + .

[0131] Step 3: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (Intermediate B)

[0132] Compound B-3 (2.20 g, 11.9 mmol) was added to a mixture of water (10 mL), tetrahydrofuran (10 mL), and methanol (10 mL) at room temperature. Sodium hydroxide (1.9 g, 47.6 mmol) was then added and stirred at room temperature for 16 h. The reaction solution was concentrated to 15 mL, the pH was adjusted to 1-2, and the aqueous phase was lyophilized to obtain intermediate B as a yellow liquid (2.1 g, 100% yield).

[0133] LC-MS m / z: 172.0 [M+H] + .

[0134] Comparative Example 1: Control compound and its preparation

[0135]

[0136] The control compound was synthesized with reference to patent application WO2014110000A1.

[0137] The control compounds in the following test examples all refer to the compounds described in Comparative Example 1.

[0138] Example 1: Synthesis of Compound 1

[0139] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-dichlorophenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 1)

[0140] The synthetic route of target compound 1 is as follows:

[0141]

[0142] Step 1: Synthesis of tert-butyl 2-((3,5-dichlorophenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 1C)

[0143] Tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (0.75 g, 2.93 mmol), 2-(3,5-dichlorophenyl)ethanamine (Compound 1A) (0.557 g, 2.93 mmol), and N,N-diisopropylethylamine (1.025 mL, 5.87 mmol) were dissolved in N-methylpyrrolidone (5 mL) and stirred at 80°C for 16 hours. The mixture was cooled to room temperature, diluted with distilled water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1 to 1:1) to obtain Compound 1C (750 mg, 62.5% yield) as a yellow solid.

[0144] LC-MS m / z: 409.1 [M+H] + .

[0145] Step 2: Synthesis of N-(3,5-dichlorophenethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 1D)

[0146] A 4M solution of hydrogen chloride in ethyl acetate (10 mL) was added to a round-bottom flask containing compound 1C (940 mg, 2.297 mmol) and stirred at room temperature for 1 h. After the reaction was complete, the mixture was concentrated to afford a crude white solid compound 1D (1.0 g, 114% yield). The crude product was used directly in the next step without purification.

[0147] Step 3: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-dichlorophenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 1)

[0148] O-Benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (84 mg, 0.262 mmol) was added to a solution of 2-(2-(1H-1,2,3-triazol-5-yl)ethoxy)acetic acid (Compound 1E), trifluoroacetic acid (37.3 mg, 0.131 mmol), and N,N-diisopropylethylamine (0.114 ml, 0.654 mmol) in N,N-dimethylformamide (5 mL) at 0°C. The mixture was stirred for 5 minutes, and Compound 1D (50 mg, 0.131 mmol) was added to the reaction mixture, which was then stirred at room temperature for 16 hours. Distilled water (20 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative chromatography to obtain compound 1 (4.8 mg, yield 7.93%).

[0149] 1 H NMR(400MHz,MeOD)δ8.22(d,1H),7.73–7.59(m,1H),7.28–7.18(m,3H),4.64(d,2H), 4.56(d,2H),4.30(s,2H),3.85(t,2H),3.65-3.61(m,2H),3.07(t,2H),2.89(t,2H).

[0150] LC-MS m / z: 462.3 [M+H] + .

[0151] Example 2: Synthesis of Compound 2

[0152] Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-bis(trifluoromethyl)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 2)

[0153] The synthetic route of compound 2 is as follows:

[0154]

[0155] Step 1: Synthesis of tert-butyl 2-((3,5-bis(trifluoromethyl)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 2C)

[0156] Tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 2B) (0.145 g, 0.567 mmol) and 2-(3,5-bis(trifluoromethyl)phenyl)ethanamine hydrochloride (Compound 2A) (200 mg, 0.68 mmol) and diisopropylethylamine (0.297 mL, 1.701 mmol) were dissolved in N-methylpyrrolidone (5 mL) and stirred at 80°C for 16 hours. The mixture was cooled to room temperature, diluted with distilled water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL × 2), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1 to 1:1) to give a yellow solid compound 2-((3,5-bis(trifluoromethyl)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (Compound 2C) (150 mg, yield 55.5%).

[0157] LC-MS m / z: 477.3 [M+H] + .

[0158] Step 2: Synthesis of (N-(3,5-bis(trifluoromethyl)phenethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 2D)

[0159] A 4M solution of hydrogen chloride in 1,4-dioxane (5 mL, 20.00 mmol) was added to a round-bottom flask containing tert-butyl 2-((3,5-bis(trifluoromethyl)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 2C) (150 mg, 0.315 mmol) and stirred at room temperature for 3 h. Concentration afforded (N-(3,5-bis(trifluoromethyl)phenethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 2D) (145 mg) as a pale yellow solid. The crude product was used directly in the next step without purification.

[0160] Step 3: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-bis(trifluoromethyl)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 2)

[0161] At 0 ° C, 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide (294 mg, 0.462 mmol, 50% N,N-dimethylformamide solution) was added dropwise to a mixture containing 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (Intermediate B) (100 mg, 0.578 mmol), triethylamine (0.537 ml, 3.85 mmol), (N-(3,5-bis(trifluoromethyl)phenethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 2D) (145 mg, 0.323 mmol). The mixture was added to a DMF (3 mL) solution of 1H-1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-bis(trifluoromethyl)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (49.2 mg, 24.1% yield).

[0162] 1 H NMR(400MHz,MeOD)δ8.24(d,1H),7.94-7.89(m,3H),7.65(s,1H),7.39(s,1H),4.57(s,1H),4.52-4. 48(m,2H),4.37(s,1H),4.30(s,2H),3.75(t,2H),3.61-3.59(m,2H),3.09(t,2H),2.91-2.89(m,2H).

[0163] LC-MS m / z: 530.3 [M+H] + .

[0164] Example 3: Synthesis of Compound 3

[0165] 2-(2-(1-H-1,2,3-triazol-4-yl)ethoxy)-1-(2-(phenylethylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 3)

[0166] The synthetic route of compound 3 is as follows:

[0167]

[0168] Step 1: Synthesis of tert-butyl 2-(phenylethylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 3C)

[0169] To a single-necked flask, tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (compound 3A) (1 g, 3.92 mmol), 2-phenylethan-1-amine (compound 3B) (0.47 g, 3.92 mmol), diisopropylethylamine (1.01 g, 7.84 mmol), and N-methylpyrrolidone (10 mL) were added and stirred at 80°C for 16 hours. The mixture was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed with saturated brine (50 mL × 2). The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1 to 1:1) to give tert-butyl 2-(phenylethylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 3C) (814 mg, yield 61%) as a light yellow solid.

[0170] LC-MS m / z: 340.4 [M+H] + .

[0171] Step 2: Synthesis of N-phenylethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 3D)

[0172] A 2.5 M solution of hydrogen chloride in 1,4-dioxane (20 mL) and tert-butyl 2-(phenylethylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 3C) (814 mg, 2.39 mmol) were added to a single-necked flask and stirred at room temperature for 1 hour. The mixture was filtered and dried under vacuum at 50°C to afford N-phenylethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 3D) (590 mg, 79% yield) as a white solid.

[0173] Step 3: Synthesis of 2-(2-(1-H-1,2,3-triazol-4-yl)ethoxy)-1-(2-(phenylethylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 3)

[0174] In a single-necked bottle, N-phenylethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 3D) (100 mg, 0.32 mmol), 2-(2-(1H-1,2,3-triazole)-4-yl)ethoxy)acetic acid (Intermediate B) (112.5 mg, 0.65 mmol), diisopropylethylamine (279 mg, 2.16 mmol), N,N-dimethylformamide (2 mL) were added and dissolved at room temperature, cooled to 0 ° C, and 1-propylphosphoric anhydride (343 mg, 0.54 mmol, 50% N,N-dimethylformamide) was added dropwise. Solution), after the addition was complete, the mixture was reacted at room temperature overnight. LCMS showed that the raw material had reacted. The mixture was diluted with water (10 mL) and extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL × 2), separated, and dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative chromatography to obtain compound 2-(2-(1-H-1,2,3-triazol-4-yl)ethoxy)-1-(2-(phenylethylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (compound 3) (30 mg, yield 23.8%).

[0175] 1 HNMR(400MHz, CDCl3)δ8.22(d,1H),7.52(s,1H),7.28-7.33(m,2H),7.19-7.23(m,3H),5.25-5.30 (m,1H),4.50-4.74(m,4H),4.26-4.28(d,2H),3.92(t,2H),3.69(m,2H),3.07(t,2H),2.90(t,2H).

[0176] LC-MS m / z: 394.3 [M+H] + .

[0177] Example 4: Synthesis of Compound 4

[0178] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((4-(trifluoromethoxy)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 4)

[0179] The synthetic route of target compound 4 is as follows:

[0180]

[0181] Step 1: Synthesis of tert-butyl 2-((4-(trifluoromethoxy)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carbonate (Compound 4C)

[0182] Tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 4A) (598 mg, 2.339 mmol), 2-(4-(trifluoromethoxy)phenyl)ethan-1-amine (Compound 4B) (320 mg, 1.560 mmol), and DIEA (806 mg, 6.24 mmol) were dissolved in N-methylpyrrolidone (6 mL) and stirred at 105°C for 18 hours. Water (80 mL) was added to the reaction solution, which was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 3:1) to afford Compound 4C (467 mg, 70.5% yield) as a white solid.

[0183] LC-MS m / z: 425.3 [M+H] + .

[0184] Step 2: Synthesis of N-(4-(trifluoromethoxy)phenethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 4D)

[0185] To compound 4C (700 mg, 1.649 mmol) was added 2.4 N hydrogen chloride in dioxane solution (50 mL), stirred at room temperature for 1.5 hours, concentrated, and the residue was slurried with tert-methyl ether to give a light brown solid compound 4D (650 mg, yield 99.4%).

[0186] LC-MS m / z: 325.2 [M+H] + .

[0187] Step 3: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((4-(trifluoromethoxy)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 4)

[0188] At 0°C, a solution of 1-propanephosphonic acid cyclic anhydride (2.06 g, 6.48 mmol, 50% DMF solution) was added dropwise to a solution of N-(4-(trifluoromethoxy)phenethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 4D) (700 mg, 1.77 mmol), triethylamine (1.747 g, 17.27 mmol), and 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (Intermediate B) (739 mg, 4.32 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 18 hours and the reaction was monitored for completion by TLC. 30 mL of dichloromethane and water (30 mL×3) were added for washing, the organic phase was concentrated, and the residue was purified by silica gel column (dichloromethane:methanol (V / V)=30:1-8-1) to give a crude product (450 mg), which was recrystallized from ethyl acetate / n-heptane to give compound 4 (334.5 mg, yield 39.6%).

[0189] 1 HNMR(400MHz, CDCl3)δ8.23(d,1H),7.53(s,1H),7.26-7.20(m,2H),7.15(d,2H),5.29(d,1H),4.75( s,1H),4.64(d,2H),4.51(s,1H),4.28(d,2H),3.93(t,2H),3.69(dd,2H),3.08(t,2H),2.92(t,2H).

[0190] LC-MS m / z: 478.3 [M+H] + .

[0191] Example 5: Synthesis of Compound 5

[0192] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3-(trifluoromethoxy)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 5)

[0193] The synthetic route of target compound 5 is as follows:

[0194]

[0195] Step 1: Synthesis of tert-butyl 3-(trifluoromethoxy)phenethylcarbamate (Compound 5B)

[0196] 2-(3-(Trifluoromethoxy)phenyl)acetonitrile (Compound 5A) (1 g, 4.92 mmol) was dissolved in methanol (25 mL), and nickel chloride hexahydrate (0.117 g, 0.492 mmol) was added. The reaction solution was stirred and cooled to 0°C. Sodium borohydride (1.862 g, 49.2 mmol) was added portionwise, and the reaction was continued at room temperature for 16 h. Di-tert-butyl dicarbonate (1.611 g, 7.38 mmol) was added, and the reaction was continued at room temperature for 2 h. The reaction solution was quenched by the addition of water (150 mL), and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 100:1 to 20:1) to obtain tert-butyl 3-(trifluoromethoxy)phenethylcarbamate (Compound 5B) (1.1 g, 73.2% yield) as a yellow oil.

[0197] LC-MS m / z: 206.3 [M-Boc+H] + .

[0198] Step 2: Synthesis of 2-(3-(trifluoromethoxy)phenyl)ethylamine hydrochloride (Compound 5C)

[0199] To tert-butyl 3-(trifluoromethoxy)phenethylcarbamate (Compound 5B) (0.997 g, 3.27 mmol) was added a 4M solution of hydrogen chloride in dioxane (5 mL) and stirred at room temperature for 30 min. The solvent was removed under reduced pressure to afford Compound 5C as a yellow solid, which was used directly in the next reaction without further purification.

[0200] Step 3: Synthesis of tert-butyl 2-((3-(trifluoromethoxy)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 5D)

[0201] To the crude compound 5C obtained in the second step were added N-methylpyrrolidone (5 mL), tert-butyl 2-amino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (0.5 g, 1.955 mmol), and N,N-diisopropylethylamine (1.264 g, 9.78 mmol). The reaction was heated to 100°C for 16 h. After cooling to room temperature, water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain tert-butyl 2-((3-(trifluoromethoxy)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 5D) (640 mg, 77% yield) as a yellow solid.

[0202] LC-MS m / z: 425.4 [M+H]+ .

[0203] Step 4: Synthesis of N-(3-(trifluoromethoxy)phenethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 5E)

[0204] To tert-butyl 2-((3-(trifluoromethoxy)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 5D) (640 mg, 1.508 mmol) was added a 2.4 M solution of hydrogen chloride in dioxane (10 mL). The mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure to afford Compound 5E as a yellow viscous solid, which was used in the next step without further purification.

[0205] Step 5: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3-(trifluoromethoxy)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 5)

[0206] To the crude yellow viscous solid N-(3-(trifluoromethoxy)phenethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 5E) obtained in the fourth step were added N,N-dimethylformamide (5 mL), 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (Intermediate B) (387 mg, 2.262 mmol), and triethylamine (1.526 g, 15.08 mmol). The reaction solution was cooled to about 0°C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide (1.152 g, 1.810 mmol, 50% N,N-dimethylformamide solution) was added dropwise. After the addition was complete, the reaction was allowed to react at room temperature for 4 h. Water (25 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 100:1 to 20:1) to obtain compound 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3-(trifluoromethoxy)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 5) (200 mg, yield 27.8%).

[0207] 1H NMR (400MHz, DMSO-d6): δ8.24(d,1H),7.64(bs,1H),7.41-7.13(m,6H),4.55-4.38( m,4H),4.18-4.16(m,2H),3.74-3.71(m,2H),3.51-3.46(m,2H),2.92~2.84(m,4H).

[0208] LC-MS m / z: 478.3 [M+H] + .

[0209] Example 6: Synthesis of Compound 6

[0210] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 6)

[0211] The synthetic route of target compound 6 is as follows:

[0212]

[0213] Step 1: Synthesis of tert-butyl-2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid ethyl ester (Compound 6C)

[0214] At room temperature, tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 6A) (1 g, 3.9 mmol) was added to NMP (10 mL), followed by DIEA (3.9 g, 30 mmol) and (3,5-dichlorophenyl)methanamine (Compound 6B) (1.56 g, 9 mmol). The reaction mixture was heated to 90°C and stirred for 8 hours. The mixture was cooled to room temperature, and water (10 mL) was added in an ice bath. The mixture was extracted with ethyl acetate (15 mL x 2). The organic phase was washed with water (10 mL) and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol (V / V) = 10:1) to give tert-butyl-2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid ethyl ester (Compound 6C) (1.4 g, yield 91%).

[0215] LC-MS m / z: 395.19 [M+H] + .

[0216] Step 2: Synthesis of N-(3,5-dichlorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 6D)

[0217] Tert-butyl-2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid ethyl ester (1.4 g, 3.5 mmol) was added to a solution of hydrogen chloride in dioxane (10 mL) in an ice bath. The mixture was heated to room temperature and stirred for 2 hours. Concentration afforded the product, N-(3,5-dichlorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine hydrochloride (Compound 6D) (1 g, 77.8% yield), which was used directly in the next reaction.

[0218] Step 3: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 6)

[0219] Compound 6D (300 mg, 0.82 mmol) was stirred at room temperature and added with 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (Intermediate B) (209 mg, 1.22 mmol) and DIEA (6 mL). 1-Propanephosphonic acid cyclic anhydride (122 mg, 0.38 mmol, 50% DMF solution) was added under ice-cooling. The mixture was stirred at room temperature overnight. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined and concentrated to obtain compound 6 (22 mg, 6.0% yield).

[0220] 1 H NMR (400MHz, CD3OD) δ8.23(d,1H),7.66(s,1H),7.26(d,3H),4.68-4.49(m,6H),4.27(d,2H),3.83(t,2H),3.04(t,2H).

[0221] LC-MS m / z: 448.00 [M+H] + .

[0222] Example 7: Synthesis of Compound 7

[0223] 2-(2-(1H-imidazol-1-yl)ethoxy)-1-(2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 7)

[0224] The synthetic route of target compound 7 is as follows:

[0225]

[0226] Step 1: Synthesis of methyl 3-imidazolyl-1-propionate (Compound 7B)

[0227] Imidazole (30 g, 0.44 mol) was added to methyl acrylate (45.5 g, 0.53 mol) and potassium phosphate (23.3 g, 0.11 mol) at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction was complete after TLC analysis. The mixture was filtered through silica gel and concentrated to obtain methyl 3-imidazolyl-1-propionate (34.2 g, yield 50.3%).

[0228] Step 2: Synthesis of 2-(1H-imidazol-1-yl)ethan-1-ol (Compound 7C)

[0229] Lithium aluminum tetrahydride (4.04 g, 0.11 mol) was added to dry tetrahydrofuran (130 mL) at room temperature and cooled to -30 degrees Celsius with stirring. At this temperature, methyl 3-imidazolyl-1-propionate (13 g, 0.08 mol) in tetrahydrofuran (20 mL) was slowly added dropwise for 30 minutes, then warmed to room temperature and stirred for 30 minutes. 15% sodium hydroxide (10 mL) was added dropwise to quench the mixture, and ethyl acetate (30 mL × 2) was added for extraction. The organic phases were combined. The crude product was separated and purified by silica gel column (dichloromethane: methanol (V / V) = 10:1) to obtain the product 2-(1H-imidazol-1-yl) ethanol-1-ol (3 g, 24.3% yield).

[0230] Step 3: Synthesis of tert-butyl 2-(2-(1H-imidazol-1-yl)ethoxy)acetate (Compound 7D)

[0231] Sodium hydroxide (0.86 g, 21.5 mmol, 60%) was added to tetrahydrofuran (20 mL) under ice-cooling conditions. After stirring for 20 min, 2-(1H-imidazol-1-yl)ethan-1-ol (2 g, 17.9 mmol) was added. Stirring was continued for 30 min. Tert-butyl bromoacetate (6.99 g, 35.8 mmol) was added under ice-cooling conditions. The mixture was warmed to room temperature and stirred overnight. Water (10 mL) was added and extracted twice with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified on a silica gel column (dichloromethane:methanol (v / v) = 10:1) to obtain tert-butyl 2-(2-(1H-imidazol-1-yl)ethoxy)acetate (Compound 7D) (3 g, 61.7% yield).

[0232] LC-MS m / z:227.15[M+H] + .

[0233] Step 4: Synthesis of 2-(2-(1H-imidazol-1-yl)ethoxy)acetic acid (Compound 7E)

[0234] Tert-butyl 2-(2-(1H-imidazol-1-yl)ethoxy)acetate (3 g, 13.2 mmol) was added to 6 mL of dioxane hydrochloride solution at room temperature and stirred for 5 hours. The concentrated product, 2-(2-(1H-imidazol-1-yl)ethoxy)acetic acid (1.6 g, 71.3% yield), was used directly in the next reaction.

[0235] Step 5: Synthesis of 2-(2-(1H-imidazol-1-yl)ethoxy)-1-(2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 7)

[0236] The raw material 2-(2-(1-(1H-imidazol-1-yl)ethoxy)acetic acid (121 mg, 0.71 mmol) was added to dichloromethane (1 mL) at room temperature, DIEA (1 mL) was added, and the compound N-(3,5-dichlorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 6D) (150 mg, 0.41 mmol) was added under ice bath conditions. ), and 1-propanephosphonic acid cyclic anhydride (71 mg, 0.22 mmol, 50% DMF solution), the reaction was warmed to room temperature and stirred for 3 hours. Concentration was performed to prepare 2-(2-(1H-imidazol-1-yl)ethoxy)-1-(2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 7) (13 mg, yield 6.5%).

[0237] 1H NMR (400MHz, CD3OD) δ8.23(d,1H),7.99(s,1H),7.28(t,4H),7.04(s,1H),4.62-4.50(m,6H),4.33-4.22(m,4H),3.89-3.84(m,2H).

[0238] LC-MS m / z: 224.21 [M / 2+H] + .

[0239] Example 8: Synthesis of Compound 8

[0240] (S)-2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (Compound 8)

[0241] The synthetic route of compound 8 is as follows:

[0242]

[0243] Step 1: Synthesis of (S)-2-(but-3-yn-1-yloxy)propionic acid (Compound 8C)

[0244] To a solution of sodium hydride (2.283 g, 57.1 mmol, 60%) in anhydrous DMF (20 mL) was added but-3-yn-1-ol (2 g, 28.5 mmol) at 0°C. The mixture was stirred at 0°C for 30 minutes, followed by the addition of (R)-2-bromopropionic acid (4.37 g, 28.5 mmol). The mixture was stirred at room temperature for 16 hours. After the reaction, water (200 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 2). 1N dilute hydrochloric acid was added to the aqueous phase to adjust the pH to 1-2, and the mixture was extracted three times with ethyl acetate / tetrahydrofuran (10:1). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford (S)-2-(but-3-yn-1-yloxy)propionic acid (Compound 8C) (2.20 g, 61% yield) as a yellow oil.

[0245] Step 2: Synthesis of (S)-2-(but-3-yn-1-yloxy)-1-(2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (Compound 8D)

[0246] To a DMF solution (3 mL) of N-(3,5-dichlorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (0.1 g, 0.339 mmol) was added (S)-2-(but-3-yn-1-yloxy)propanoic acid (0.072 g, 0.508 mmol) and N-ethyl-N-isopropyl-2-amine (0.219 g, 1.69 mmol) at 0°C. 1-propylphosphonic anhydride (0.14 g, 0.44 mmol, 50% in DMF) was then added at 0°C. The mixture was slowly warmed to room temperature and stirred at room temperature for 12 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL), diluted with water (50 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic layers were concentrated to give the crude product. Purification by preparative plate (DCM:MeOH=10:1) gave a yellow solid product (S)-2-(but-3-yn-1-yloxy)-1-(2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (0.1 g, yield 70.4%).

[0247] Step 3: Synthesis of (S)-2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (Compound 8)

[0248] The reactants (S)-2-(but-3-yn-1-yloxy)-1-(2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (0.1 g, 0.23 mmol), L-ascorbic acid (0.084 g, 0.47 mmol) and sodium bicarbonate (0.040 g, 0.47 mmol) were added to a mixed solution of DMF (2 ml) and methanol (0.2 mL), followed by the addition of copper sulfate pentahydrate (0.014 g, 0.055 mmol) and trimethylsilyl azide (0.096 g, 0.832 mmol) and stirred at 90 ° C for 3 hours. The reactant was diluted with water (20 mL) and then extracted with DCM (10 mL×3). The concentrated organic layers were combined and purified by preparative plate to give (S)-2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (Compound 8) (3.1 mg, yield 3.0%).

[0249] 1 H NMR(400MHz,DMSO-d6)δ8.26-8.21(m,1H),7.84-7.81(m,1H),7.49(s,1H),7.41(s,1H),7.30(s,1H),4.70-4.65(m,2 H),4.64-4.61(m,2H),4.48-4.40(m,1H),4.24-4.21(m,1H),3.65-3.51(m,3H),2.84-2.74(m,2H),1.23-1.20(m,3H).

[0250] LC-MS m / z: 462.3 [M+H] + .

[0251] Example 9: Synthesis of Compound 9

[0252] 2-((1-(1H-1,2,3-triazol-4-yl)propan-2-yl)oxy)-1-(2-(3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 9)

[0253] The synthetic route of compound 9 is as follows:

[0254]

[0255] Step 1: Synthesis of 2-((1-(1H-1,2,3-triazol-4-yl)propan-2-yl)oxy)-1-(2-(3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 9)

[0256] A 50% N,N-dimethylformamide solution of 1-propylphosphonic anhydride (440 mg, 0.692 mmol) was added to a solution of 2-(2-(1H-1,2,3-triazol-5-yl)isopropoxy)acetic acid (150 mg, 0.810 mmol) and diisopropylethylamine (600 mg, 4.65 mmol) in N,N-dimethylformamide (5 mL) at 0°C. The mixture was stirred for 5 minutes, and N-(3,5-dichlorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 6D) (220 mg, 0.597 mmol) was added to the reaction mixture, which was stirred at room temperature for 16 hours. Distilled water (20 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative chromatography to obtain compound 2-((1-(1H-1,2,3-triazol-4-yl)propan-2-yl)oxy)-1-(2-(3,5-dichlorobenzyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (50 mg, yield 18.1%).

[0257] 1 H NMR(400MHz,DMSO-d6)δ8.24(d,1H),7.84(t,1H),7.61(s,1H),7.41(s,1H),7.30(s,2 H),4.54-4.38(m,6H),4.18(q,2H),3.84-3.78(m,1H),2.88-2.78(m,2H),1.09(t,3H).

[0258] LC-MS m / z: 462.3 [M+H] + .

[0259] Example 10: Synthesis of Compound 10

[0260] (R)-2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (Compound 10)

[0261] The synthetic route of compound 10 is as follows:

[0262]

[0263] The specific operation was similar to that of the preparation of Example 8 (Compound 8), except that (S)-2-bromopropionic acid was used instead of the (R)-2-bromopropionic acid in Example 8. After the same three-step reaction, (R)-2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-dichlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (Compound 10) (26.0 mg, 0.056 mmol) was finally purified.

[0264] 1 H NMR (400MHz, DMSO-d6) δ8.26-8.21(m,1H),7.85-7.82(m,1H),7.62(br,1H),7.41(s,1H),7.30-7.27(m,2H),4.70-4.56(m,2H),4. 49-4.47(m,2H),4.40-4.39(m,1H),4.27-4.21(m,1H),3.64-3.57(m,2H),3.11-3.09(m,1H),2.88-2.84(m,2H),1.23-1.14(m,3H).

[0265] LC-MS m / z: 462.3 [M+H] + .

[0266] Example 11: Synthesis of Compound 11

[0267] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3-(difluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 11)

[0268] The synthetic route of compound 11 is as follows:

[0269]

[0270] Step 1: Synthesis of tert-butyl 2-((3-(difluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 11C)

[0271] Tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 11B) (1 g, 3.92 mmol), (3-difluoromethoxyphenyl)methanamine (Compound 11A) (1.35 g, 7.80 mmol), and diisopropylethylamine (2.5 g, 19.40 mmol) were dissolved in N-methylpyrrolidone (10 mL) and stirred at 100°C for 16 hours. The mixture was cooled to room temperature, diluted with distilled water (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 2), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 10:1 to 1:1) to give tert-butyl 2-((3-(difluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 11C) (1.2 g, yield 77.9%).

[0272] Step 2: Synthesis of N-(3-(difluoromethoxy)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 11D)

[0273] At room temperature, tert-butyl 2-((3-(difluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 11C) (1.2 g, 3.06 mmol) was added to a 100 mL solution of hydrogen chloride in 1,4-dioxane and stirred at room temperature for 8 hours. After monitoring the completion of the reaction, it was filtered and the solid was dried to obtain N-(3-(difluoromethoxy)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-amine dihydrochloride (Compound 11D) (950 mg, yield 85.3%).

[0274] Step 3: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3-(difluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 11)

[0275] 1-Propylphosphonic anhydride (326 mg, 1.025 mmol, 50% N,N-dimethylformamide solution) was added to a solution of 2-(2-(1H-1,2,3-triazol-5-yl)ethoxy)acetic acid (175 mg, 1.023 mmol) and diisopropylethylamine (530 mg, 4.109 mmol) in N,N-dimethylformamide (2 mL) at 0°C. The mixture was stirred for 5 minutes, and N-(3-(difluoromethoxy)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (200 mg, 0.55 mmol) was added to the reaction mixture, which was then stirred at room temperature for 16 hours. Distilled water (5 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (2 mL × 2), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative chromatography to give 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3-(difluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 11) (160 mg, yield 65.3%).

[0276] 1 H NMR(400MHz, CDCl3)δ8.25(d,1H),7.53(s,1H),7.32(t,1H),7.25(s,1H),7.19(d,1H),7.11(s,1H),7.02(d,1H), 6.50(td,1H),5.69(brs,1H),4.75(s,1H),4.68-4.63(m,4H),4.51(s,1H),4.27(d,2H),3.92(t,2H),3.08(t,2H).

[0277] LC-MS m / z: 446.36 [M+H] + .

[0278] Example 12: Synthesis of Compound 12

[0279] 5-(((6-(2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)isophthalonitrile (Compound 12)

[0280] The synthetic route of compound 12 is as follows:

[0281]

[0282] Step 1: Synthesis of tert-butyl 2-((3,5-dicyanobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 12C)

[0283] The raw material, tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 12B) (100 mg, 0.39 mmol), was added to DMF (3 mL), followed by 3,5-dicyanobenzylamine (92 mg, 0.59 mmol) and cesium carbonate (255 mg, 0.78 mmol). The mixture was heated to 85°C and stirred for 16 h. The mixture was filtered, water (30 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, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain tert-butyl 2-((3,5-dicyanobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 12C) (17 mg, 11.5% yield) as a yellow solid.

[0284] LC-MS m / z: 377.1 [M+H] + .

[0285] Step 2: Synthesis of 5-(((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)isophthalonitrile dihydrochloride (Compound 12D)

[0286] At room temperature, tert-butyl 2-((3,5-dicyanobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (500 mg, 1.33 mmol) was added to dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added and stirred for 4 h. Ethyl acetate (20 mL) was added and the mixture was washed with saturated sodium bicarbonate solution (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) and concentrated to obtain 5-(((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)isophthalonitrile dihydrochloride (Compound 12D) (125 mg, 27.0% yield) as a yellow solid.

[0287] LC-MS m / z: 277.1 [M+H] + .

[0288] Step 3: Synthesis of 5-(((6-(2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)isophthalonitrile (Compound 12)

[0289] The raw material 5-(((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)isophthalonitrile dihydrochloride (Compound 12D) (14 mg, 0.04 mmol) was added to DMF (2 mL) at room temperature, and 1-propylphosphonic anhydride (40 mg, 0.061 mmol, 50% ethyl acetate solution), N-methylmorpholine (11 mg, 0.106 mmol) and 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (10 mg, 0.061 mmol) were added and stirred for 15 h. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used to obtain 5-(((6-(2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)isophthalonitrile (Compound 12) (2.8 mg, yield 16.3%).

[0290] 1 H NMR (400MHz, CD3OD) δ8.30(d,1H),8.06(s,1H),8.00(s,2H),7.72(s,1H),4.69(s,4H),4.60(d,2H),4.32(d,2H),3.87(s,2H),3.10(t,2H).

[0291] LC-MS m / z: 430.1 [M+H] + .

[0292] Example 13: Synthesis of Compound 13

[0293] 3-(((6-(2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile (Compound 13)

[0294] The synthetic route of compound 13 is as follows:

[0295]

[0296] Step 1: Synthesis of tert-butyl 2-((3-cyanobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 13B)

[0297] The starting material, 3-(aminomethyl)benzonitrile (310 mg, 2.35 mmol), was added to DMF (5 mL), followed by tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (500 mg, 1.96 mmol) and cesium carbonate (1.27 g, 3.92 mmol). The mixture was heated to 85°C and stirred for 16 h. Water (50 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, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain tert-butyl 2-((3-cyanophenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 13B) (180 mg, 26.1% yield) as a yellow solid.

[0298] LC-MS m / z: 352.1 [M+H] + .

[0299] Step 2: Synthesis of 3-(((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile dihydrochloride 13C)

[0300] The starting material, tert-butyl 2-((3-cyanophenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 13B) (180 mg, 0.51 mmol), was added to dichloromethane (3 mL) at room temperature, followed by trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated to afford 3-(((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile dihydrochloride (Compound 13C) (150 mg, 91% yield) as a yellow solid.

[0301] LC-MS m / z: 252.1 [M+H] + .

[0302] Step 3: Synthesis of 3-(((6-(2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile (Compound 13)

[0303] The raw material 3-(((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile dihydrochloride (Compound 13C) (50 mg, 0.16 mmol) was added to N,N-dimethylformamide (2 mL), and 1-propylphosphonic anhydride (146 mg, 0.23 mmol, 50% ethyl acetate solution), N-methylmorpholine (38 mg, 0.38 mmol) and 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (40 mg, 0.37 mmol) were added and stirred at room temperature for 16 h. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used to prepare compound 3-(((6-(2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile (Compound 13) (10 mg, yield 15.4%).

[0304] 1 H NMR (400MHz, DMSO-d6) δ8.30(d,1H),7.95(s,1H),7.72-7.64(m,4H),7.54(t,1H),4.60-4.43(m,6H),4.22(d,2H),3.78-3.74(m,2H),2.95(t,2H).

[0305] LC-MS m / z: 405.0 [M+H] + .

[0306] Example 14: Synthesis of Compound 14

[0307] 3-(((6-(2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)-5-(trifluoromethoxy)benzonitrile (Compound 14)

[0308] The synthetic route of compound 14 is as follows:

[0309]

[0310] Step 1: Synthesis of tert-butyl 2-((3-bromo-5-(trifluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 14B)

[0311] The raw material 3-bromo-5-(trifluoromethoxy)benzylamine (0.9 g, 3.3 mmol) was added to N-methylpyrrolidone (5 mL), and tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (1.2 g, 4.95 mmol) and diisopropylethylamine (1.24 g, 9.9 mmol) were added, heated to 90 ° C, and stirred for 16 h. Water (50 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, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give a yellow liquid 2-((3-bromo-5-(trifluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (Compound 14B) (1.2 g, yield 74.5%).

[0312] LC-MS m / z: 489.1 [M+H] + .

[0313] Step 2: Synthesis of tert-butyl 2-((3-cyano-5-(trifluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 14C)

[0314] The raw material tert-butyl 2-((3-bromo-5-(trifluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 14B) (1.4 g, 2.86 mmol) was added to N,N-dimethylacetamide (15 mL) at room temperature, and zinc cyanide (1.4 g, 11.96 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (210 mg, 0.29 mmol) were added. The mixture was heated to 160°C in a microwave under nitrogen protection and stirred for 1 h. Water (50 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, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give tert-butyl 2-((3-cyano-5-(trifluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 14C) (0.8 g, yield 64.1%) as a white solid.

[0315] LC-MS m / z: 436.1 [M+H] + .

[0316] Step 3: Synthesis of 3-(((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)-5-(trifluoromethoxy)benzonitrile dihydrochloride (Compound 14D)

[0317] The starting material, tert-butyl 2-((3-cyano-5-(trifluoromethoxy)phenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 14C) (100 mg, 0.23 mmol), was added to ethyl acetate (15 mL) at room temperature. A 4M solution of hydrogen chloride in 1,4-dioxane (2 mL) was then added and stirred at room temperature for 2 h. The mixture was concentrated to afford 3-(((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)-5-(trifluoromethoxy)benzonitrile dihydrochloride (Compound 14D) (36 mg, 38.5% yield) as a white solid.

[0318] LC-MS m / z: 336.1 [M+H] + .

[0319] Step 4: Synthesis of 3-(((6-(2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)-5-(trifluoromethoxy)benzonitrile (Compound 14)

[0320] The raw material 3-(((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)-5-(trifluoromethoxy)benzonitrile dihydrochloride (Compound 14D) (220 mg, 0.54 mmol) was added to N,N-dimethylformamide (5 mL), and 1-propylphosphonic anhydride (706 mg, 1.86 mmol, 50% ethyl acetate solution), N-methylmorpholine (310 mg, 3.1 mmol) and 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (210 mg, 1.24 mmol) were added and stirred at room temperature for 16 h. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (35 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used to prepare compound 3-(((6-(2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)-5-(trifluoromethoxy)benzonitrile (Compound 14) (18 mg, yield 6.8%).

[0321] 1 H NMR (400MHz, CDCl3) δ8.31(d,1H),7.58(d,2H),7.44(d,2H),5.83(s,1H),4.78-4.66(m,5H),4.54(s,1H),4.31(d,2H),3.95(t,2H)3.10(t,2H).

[0322] LC-MS m / z: 489.1 [M+H] + .

[0323] Example 15: Synthesis of Compound 15

[0324] Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-benzylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 15)

[0325] The synthetic route of compound 15 is as follows:

[0326]

[0327] Step 1: Synthesis of tert-butyl 2-benzylamino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 15B)

[0328] 2-Chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (0.5 g, 1.96 mmol), benzylamine (0.25 g, 2.35 mmol), and diisopropylethylamine (1.025 mL, 5.87 mmol) were dissolved in N-methylpyrrolidone (5 mL) and stirred at 80°C for 16 hours. The mixture was cooled to room temperature, diluted with distilled water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1 to 1:1) to obtain tert-butyl 2-benzylamino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (350 mg, 54.8% yield) as a yellow solid.

[0329] Step 2: Synthesis of N-benzyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 15C)

[0330] A 4M solution of hydrogen chloride in 1,4-dioxane (10 mL) was added to a round-bottom flask containing tert-butyl 2-benzylamino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carbonate (350 mg, 0.922 mmol) and stirred at room temperature for 1 hour. Concentration afforded N-benzyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 15C) (270 mg, 98% yield) as a white solid. The crude product was used directly in the next step without purification.

[0331] Step 3: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-benzylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 15)

[0332] A 50% N,N-dimethylformamide solution of 1-propylphosphonic anhydride (871 mg, 1.370 mmol) was added to a solution of 2-(2-(1H-1,2,3-triazol-5-yl)ethoxy)acetic acid (373 mg, 1.310 mmol) and diisopropylethylamine (442 mg, 3.426 mmol) in N,N-dimethylformamide (5 mL) at 0°C. The mixture was stirred for 5 minutes, and N-benzyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (270 mg, 0.906 mmol) was added to the reaction mixture, which was then stirred at room temperature for 16 hours. Distilled water (20 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative chromatography to give a light yellow solid 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-benzylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (64 mg, yield 18.6%).

[0333] 1 H NMR(400MHz,DMSO-d6)δ8.23(d,1H),7.51(s,1H),7.33-7.27(m,5H),5.62(b,1H),4 .74(s,1H),4.66-4.61(m,4H),4.49(s,1H),4.26(d,2H),3.91(t,2H),3.07(t,2H).

[0334] LC-MS m / z: 380.2 [M+H] + .

[0335] Example 16: Synthesis of Compound 16

[0336] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-difluorophenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 16)

[0337] The synthetic route of compound 16 is as follows:

[0338]

[0339] Step 1: Synthesis of tert-butyl 2-((3,5-difluorophenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 16C)

[0340] The raw material, tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (800 mg, 3.14 mmol), was added to N,N-dimethylformamide (3 mL), followed by 3,5-difluorobenzylamine (538 mg, 3.76 mmol) and cesium carbonate (2.05 g, 6.28 mmol). The mixture was heated to 90°C and stirred for 16 h. The mixture was filtered, water (30 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, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain tert-butyl 2-((3,5-difluorophenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 16C) (500 mg, 43.9% yield) as a yellow solid.

[0341] LC-MS m / z: 363.2 [M+H] + .

[0342] Step 2: Synthesis of N-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 16D)

[0343] The starting material, 2-((3,5-difluorophenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid (500 mg, 1.38 mmol), was added to a 4M solution of hydrogen chloride in 1,4-dioxane (4 mL) at room temperature and stirred for 2 h. The mixture was concentrated to afford N-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 16D) (360 mg, 72% yield) as a yellow solid.

[0344] LC-MS m / z: 263.2 [M+H] + .

[0345] Step 3: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-difluorophenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 16)

[0346] The raw material N-(3,5-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 16D) (150 mg, 0.45 mmol) was added to N,N-dimethylformamide (4 mL) and ethyl acetate (2 mL) at room temperature, and 1-propylphosphonic anhydride (544 mg, 0.86 mmol, 50% ethyl acetate solution), N-methylmorpholine (115 mg, 1.14 mmol) and 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (132 mg, 0.63 mmol) were added and stirred for 5 h. Water (15 mL) was added, and the mixture 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 give 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-difluorophenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 16) (40 mg, yield 21.3%).

[0347] 1 H NMR(400MHz,DMSO-d6)δ8.31(d,1H),7.91(s,1H),7.70(d,1H),7.08-6.99(m,3H ),4.60-4.52(m,5H),4.43(s,1H),4.22(d,2H),3.78-3.74(m,2H),2.94(t,2H).

[0348] LC-MS m / z: 416.2 [M+H] + .

[0349] Example 17: Synthesis of Compound 17

[0350] 3-(((6-(2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)-5-chlorobenzonitrile (Compound 17)

[0351] The synthetic route of compound 17 is as follows:

[0352]

[0353] Step 1: Synthesis of 3-(azidomethyl)-5-chlorobenzonitrile (Compound 17B)

[0354] The raw material, 3-chloro-5-(hydroxymethyl)benzonitrile (2.0 g, 11.9 mmol), was added to toluene (60 mL) at room temperature. 1,8-diazabicycloundec-7-ene (2.18 g, 14.4 mmol) was added under nitrogen and stirred for 16 h. Water (90 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 10:1) to afford 3-(azidomethyl)-5-chlorobenzonitrile (Compound 17B) (1.53 g, 66% yield) as a colorless liquid.

[0355] LC-MS m / z: 193.2 [M+H] + .

[0356] Step 2: Synthesis of 3-aminomethyl-5-chlorobenzonitrile (Compound 17C)

[0357] The raw material 3-(azidomethyl)-5-chlorobenzonitrile (compound 17B) (1.38 g, 7.23 mmol) was added to tetrahydrofuran (30 mL) and water (5 mL), and then triphenylphosphine (2.08 g, 7.95 mmol) was added and stirred at room temperature for 16 h. 1 M HCl (20 mL) was added and extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain the title compound 3-aminomethyl-5-chlorobenzonitrile as a light yellow solid (0.7 g, yield 58%).

[0358] LC-MS m / z: 167.2 [M+H] + .

[0359] Step 3: Synthesis of tert-butyl 2-((3-chloro-5-cyanobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 17D)

[0360] The raw material, tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (550 mg, 2.15 mmol), was added to N,N-dimethylformamide (8 mL), followed by the addition of 3-aminomethyl-5-chlorobenzonitrile (430 mg, 2.59 mmol) and potassium carbonate (742 mg, 5.37 mmol). 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 (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain tert-butyl 2-((3-chloro-5-cyanobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 17D) (150 mg, 21.7% yield) as a pale yellow solid.

[0361] LC-MS m / z: 386.2 [M+H] + .

[0362] Step 4: Synthesis of 3-chloro-5-(((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile dihydrochloride (Compound 17E)

[0363] The starting material, tert-butyl 2-((3-chloro-5-cyanobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 17D) (150 mg, 0.38 mmol), was added to methanol (5 mL) and dichloromethane (5 mL) at room temperature. A 4M solution of hydrogen chloride in 1,4-dioxane (5 mL) was added, and the mixture was stirred at room temperature for 15 h. The reaction solution was concentrated, the pH adjusted to 9-10 with saturated aqueous sodium carbonate, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-chloro-5-(((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile dihydrochloride (Compound 17E) (100 mg, 73.7% yield) as a pale yellow solid.

[0364] LC-MS m / z: 286.2 [M+H] + .

[0365] Step 5: Synthesis of 3-(((6-(2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)-5-chlorobenzonitrile (Compound 17)

[0366] The raw material 3-chloro-5-(((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile dihydrochloride (Compound 17E) (100 mg, 0.28 mmol) was added to N,N-dimethylformamide (4 mL), followed by 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (65 mg, 0.42 mmol), 1-propylphosphonic anhydride (225 mg, 0.7 mmol, 50% ethyl acetate solution) and N-methylmorpholine (70 mg, 0.7 mmol), and the mixture was stirred at room temperature for 16 h. Water (15 mL) was added, and the mixture 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) = 10:1) to give compound 3-(((6-(2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)methyl)-5-chlorobenzonitrile (Compound 17) (40 mg, yield 32%).

[0367] 1 H NMR (400MHz, DMSO-d6) δ8.31(d,1H),7.92(d,2H),7.72-7.69(m,3H),4.60-4.51(m,5H),4.44(s,1H),4.21(d,2H),3.78-3.74(m,2H),2.95(t,2H).

[0368] LC-MS m / z: 439.0 [M+H] + .

[0369] Example 18: Synthesis of Compound 18

[0370] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3-(trifluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 18)

[0371] The synthetic route of compound 18 is as follows:

[0372]

[0373] Step 1: Synthesis of tert-butyl 2-((3-(trifluoromethoxy)benzyl)-1-amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 18B)

[0374] The raw material 3-trifluoromethoxybenzylamine (675 mg, 3.5 mmol) was added to N,N-dimethylformamide (10 mL), followed by tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (811 mg, 3.2 mmol) and cesium carbonate (2.3 g, 7 mmol). The mixture was heated to 90°C and stirred for 16 h. Water (50 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, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain tert-butyl 2-((3-(trifluoromethoxy)benzyl)-1-amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 18B) (380 mg, 29% yield) as a yellow solid.

[0375] LC-MS m / z: 411.1 [M+H] + .

[0376] Step 2: Synthesis of N-(3-(trifluoromethoxy)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 18C)

[0377] The starting material, tert-butyl 2-((3-(trifluoromethoxy)benzyl)-1-amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 18B) (135 mg, 0.37 mmol), was added to dichloromethane (38 mL) at room temperature. A 4M solution of hydrogen chloride in 1,4-dioxane (3 mL) was then added and stirred for 2 h. The mixture was concentrated to afford N-(3-(trifluoromethoxybenzyl))-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 18C) (116 mg, 82% yield) as a yellow solid.

[0378] LC-MS m / z: 311.1 [M+H] + .

[0379] Step 3: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3-(trifluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 18)

[0380] The raw material N-(3-(trifluoromethoxybenzyl))6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 18C) (116 mg, 0.30 mmol) was added to N,N-dimethylformamide (4 mL) and ethyl acetate (2 mL), and 1-propylphosphonic anhydride (176 mg, 0.56 mmol, 50% ethyl acetate solution), N-methylmorpholine (187 mg, 1.85 mmol) and 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (63 mg, 0.37 mmol) were added. The mixture was cooled to 0°C and stirred for 0.5 h. The mixture was naturally warmed to room temperature and stirred for 16 h. Water (15 mL) was added, and the mixture 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 compound 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3-(trifluoromethoxybenzyl))amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 18) (107 mg, yield 77%).

[0381] 1 H NMR(400MHz,DMSO-d6)δ8.30(d,1H),7.96-7.91(m,1H),7.70(d,1H),7.46(t,1H),7.35(d,1H ),7.28(s,1H),7.22(d,1H),4.60-4.43(m,6H),4.22(d,2H),3.78-3.74(m,2H),2.95(t,2H).

[0382] LC-MS m / z: 464.1 [M+H] + .

[0383] Example 19: Synthesis of Compound 19

[0384] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3-chlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 19)

[0385] The synthetic route of compound 19 is as follows:

[0386]

[0387] Step 1: Synthesis of tert-butyl 2-((3-chlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 19B)

[0388] The raw material 3-chlorobenzylamine (338 mg, 2.4 mmol) was added to N-methylpyrrolidone (10 mL), followed by tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (500 mg, 2.0 mmol) and N,N-diisopropylethylamine (774 mg, 6 mmol). The mixture was heated to 90°C and stirred for 16 h. Water (50 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, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain tert-butyl 2-((3-chlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 19B) (570 mg, 80.8% yield) as a yellow solid.

[0389] LC-MS m / z: 361.4 [M+H] + .

[0390] Step 2: Synthesis of N-(3-(chlorobenzyl))-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 19C)

[0391] The starting material, tert-butyl 2-((3-chlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 19B) (150 mg, 0.42 mmol), was added to dichloromethane (10 mL) at room temperature. A 4M solution of hydrogen chloride in 1,4-dioxane (3 mL) was then added and stirred for 2 h. The mixture was concentrated to afford N-(3-chlorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 19C) (124 mg, 89% yield) as a yellow solid.

[0392] LC-MS m / z: 261.4 [M+H] + .

[0393] Step 3: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3-chlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 19)

[0394] The raw material N-(3-chlorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine (Compound 19C) (110 mg, 0.42 mmol) was added to N,N-dimethylformamide (4 mL) and ethyl acetate (2 mL), and 1-propylphosphonic anhydride (200 mg, 0.63 mmol, 50% ethyl acetate solution), N-methylmorpholine (212 mg, 2.1 mmol) and 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (72 mg, 0.42 mmol) were added. The mixture was cooled to 0°C and stirred for 0.5 h. The mixture was naturally warmed to room temperature and stirred for 16 h. Water (15 mL) was added, and the mixture 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 compound 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3-chlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 19) (40 mg, yield 23%).

[0395] 1 H NMR (400MHz, DMSO-d6) δ8.30(d,1H),7.90(s,1H),7.69(s,1H),7.34-7.26(m,4H),4.59-4.43(m,6H),4.21(d,2H),3.76(d,2H),2.95(t,2H).

[0396] LC-MS m / z: 414.2 [M+H] + .

[0397] Example 20: Synthesis of Compound 20

[0398] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((1-(3,5-dichlorophenyl)ethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 20)

[0399] The synthetic route of compound 20 is as follows:

[0400]

[0401] Step 1: Synthesis of 1-(3,5-dichlorophenyl)ethane-1-amine (Compound 20B)

[0402] 3,5-Dichloroacetophenone (400 mg, 2.1 mmol) was added to methanol (2 mL) at room temperature, followed by tetraethyl titanate (958 mg, 4.2 mmol) and concentrated aqueous ammonia (1.5 mL). The mixture was stirred at room temperature for 16 h. Sodium borohydride (160 mg, 4.2 mmol) was added at room temperature and stirred for 3 h. Methanol (2 mL) and water (5 mL) were added, filtered, and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 1:4) to afford 1-(3,5-dichlorophenyl)ethane-1-amine (Compound 20B) (258 mg, 64% yield) as a yellow liquid.

[0403] LC-MS m / z: 190.1 [M+H] + .

[0404] Step 2: Synthesis of tert-butyl 2-((1-(3,5-dichlorophenyl)ethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 20C)

[0405] The raw material 1-(3,5-dichlorophenyl)ethane-1-amine (Compound 20B) (235 mg, 1.2 mmol) was added to N-methylpyrrolidone (3 mL), and tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (300 mg, 1.2 mmol) and N,N-diisopropylethylamine (453 mg, 3.5 mmol) were added. The mixture was heated to 90 ° C and stirred for 16 h. Water (15 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, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give a yellow liquid 2-((1-(3,5-dichlorophenyl)ethyl-1-amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (Compound 20C) (117 mg, yield 28.8%).

[0406] LC-MS m / z: 409.1 [M+H] + .

[0407] Step 3: Synthesis of N-(1-(3,5-dichlorophenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 20D)

[0408] The raw material tert-butyl 2-((1-(3,5-dichlorophenyl)ethyl-1-amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 20C) (250 mg, 0.61 mmol) was added to a 4M solution of hydrogen chloride in 1,4-dioxane (4 mL) at room temperature and stirred for 2 h. After concentration, N-(1-(3,5-dichlorophenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-amine dihydrochloride (Compound 20D) (200 mg, 86% yield) was obtained as a yellow solid.

[0409] LC-MS m / z: 309.1 [M+H] + .

[0410] Step 4: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((1-(3,5-dichlorophenyl)ethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 20)

[0411] The raw material N-(1-(3,5-dichlorophenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 20D) (200 mg, 0.52 mmol) was added to N,N-dimethylformamide (4 mL) and ethyl acetate (2 mL), and 1-propylphosphonic anhydride (515 mg, 0.8 mmol, 50% ethyl acetate solution), N-methylmorpholine (293 mg, 2.9 mmol) and 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (119 mg, 0.7 mmol) were added. The mixture was cooled to 0°C and stirred for 0.5 h. The mixture was naturally warmed to room temperature and stirred for 16 h. Water (15 mL) was added, and the mixture 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 give 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((1-(3,5-dichlorophenyl)ethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 20) (6 mg, 2.5% yield).

[0412] 1H NMR(400MHz,DMSO-d6)δ8.25(d,1H),7.88(dd,1H),7.64(s,1H),7.42(dt,3H),5.1 1-5.04(m,1H),4.50(dd,4H),4.17(d,2H),3.74(tt,2H),2.93(t,2H)1.42(d,3H).

[0413] LC-MS m / z: 462.1 [M+H] + .

[0414] Example 21: Synthesis of Compound 21

[0415] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((4-chlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 21)

[0416] The synthetic route of compound 21 is as follows:

[0417]

[0418] Step 1: Synthesis of tert-butyl 2-((4-chlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 21B)

[0419] The raw material 4-chlorobenzylamine (282 mg, 2.0 mmol) was added to N-methylpyrrolidone (10 mL), followed by tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (510 mg, 2.0 mmol) and N,N-diisopropylethylamine (1.03 g, 8 mmol). The mixture was heated to 90°C and stirred for 16 h. Water (50 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, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain tert-butyl 2-((4-chlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 21B) (300 mg, 41.7% yield) as a yellow solid.

[0420] LC-MS m / z: 361.4 [M+H] + .

[0421] Step 2: Synthesis of N-(4-chlorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 21C)

[0422] The starting material, tert-butyl 2-((4-chlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 21B) (105 mg, 0.29 mmol), was added to dichloromethane (6 mL) at room temperature. A 4M solution of hydrogen chloride in 1,4-dioxane (2 mL) was then added and stirred for 2 h. The mixture was concentrated to afford N-(4-chlorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 21C) (90 mg, 93% yield) as a yellow solid.

[0423] LC-MS m / z: 261.4 [M+H] + .

[0424] Step 3: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((4-chlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 21)

[0425] The raw material N-(4-chlorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 21C) (140 mg, 0.42 mmol) was added to N,N-dimethylformamide (4 mL) and ethyl acetate (2 mL), and 1-propylphosphonic anhydride (262 mg, 0.82 mmol, 50% ethyl acetate solution), N-methylmorpholine (278 mg, 2.75 mmol) and 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (90 mg, 0.55 mmol) were added. The mixture was cooled to 0°C and stirred for 0.5 h. The mixture was naturally warmed to room temperature and stirred for 16 h. Water (15 mL) was added, and the mixture 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 compound 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((4-chlorobenzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 21) (50 mg, yield 29%).

[0426] 1 H NMR (400MHz, DMSO-d6) δ8.28(d,1H),7.86(d,1H),7.69(s,1H),7.36-7.30(m,4H),4.59-4.42(m,6H),4.21(d,2H),3.76(d,2H),2.95(t,2H).

[0427] LC-MS m / z: 414.2 [M+H]+ .

[0428] Example 22: Synthesis of Compound 22

[0429] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((4-(trifluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 22)

[0430] The synthetic route of compound 22 is as follows:

[0431]

[0432] Step 1: Synthesis of tert-butyl 2-((4-(trifluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 22B)

[0433] The raw material 4-trifluoromethoxybenzylamine (Compound 22A) (100 mg, 0.52 mmol) was added to N,N-dimethylformamide (3 mL), followed by tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (100 mg, 0.45 mmol) and cesium carbonate (255 mg, 0.78 mmol). The mixture was heated to 90°C and stirred for 16 h. Water (50 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, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain tert-butyl 2-((4-(trifluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 22B) (12 mg, 7.5% yield) as a yellow solid.

[0434] LC-MS m / z: 411.1 [M+H] + .

[0435] Step 2: Synthesis of N-(4-(trifluoromethoxy)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 22C)

[0436] The starting material, tert-butyl 2-((4-(trifluoromethoxy)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 22B) (150 mg, 0.37 mmol), was added to dichloromethane (8 mL) at room temperature. A 4M solution of hydrogen chloride in 1,4-dioxane (3 mL) was then added and stirred for 2 h. The mixture was concentrated to afford N-(4-(trifluoromethoxybenzyl))-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 22C) (113 mg, 80% yield) as a yellow solid.

[0437] LC-MS m / z: 311.1 [M+H] + .

[0438] Step 3: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((4-(trifluoromethoxybenzyl))amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 22)

[0439] The raw material N-(4-(trifluoromethoxybenzyl))-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 22C) (113 mg, 0.29 mmol) was added to N,N-dimethylformamide (4 mL) and ethyl acetate (2 mL), and 1-propylphosphonic anhydride (175 mg, 0.55 mmol, 50% ethyl acetate solution), N-methylmorpholine (185 mg, 1.82 mmol) and 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (63 mg, 0.37 mmol) were added. The mixture was cooled to 0°C and stirred for 0.5 h. The mixture was naturally warmed to room temperature and stirred for 16 h. Water (15 mL) was added, and the mixture 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 give 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((4-(trifluoromethoxybenzyl))amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 22) (95 mg, yield 70.7%).

[0440] 1 H NMR(400MHz,DMSO-d6)δ8.31(d,1H),7.97(s,1H),7.71(d,1H),7.44(d,2H), 7.31(d,2H),4.60-4.44(m,6H),4.22(d,2H),3.78-3.74(m,2H),2.96(t,2H).

[0441] LC-MS m / z: 464.1 [M+H] + .

[0442] Example 23: Synthesis of Compound 23, Compound 24 and Compound 25

[0443] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((2-phenylcyclopropyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 23)

[0444] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((1S,2R)-2-phenylcyclopropyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-D]pyrimidin-6-yl)ethan-1-one (Compound 24)

[0445] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((1R,2S)-2-phenylcyclopropyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-D]pyrimidin-6-yl)ethan-1-one (Compound 25)

[0446] The synthetic routes of compound 23, compound 24 and compound 25 are as follows:

[0447]

[0448] Step 1: Synthesis of tert-butyl (2-phenylcyclopropyl)carbamate (Compound 23B)

[0449] Diphenylphosphoryl azide (4.12 g, 16.96 mmol) was added to a solution of 2-phenylcyclopropanecarboxylic acid (2.5 g, 15.41 mmol) and triethylamine (1.716 g, 16.96 mmol) in tert-butanol (19.42 g, 262 mmol) at 0°C. After replacement of the gas, the mixture was reacted at 90°C under nitrogen protection overnight. After cooling to room temperature and monitoring the reaction by TLC, the mixture was diluted with distilled water (50 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 10:1 to 1:1) to obtain tert-butyl (2-phenylcyclopropyl)carbamate (Compound 23B) (2.28 g, 63.4% yield) as a yellow solid.

[0450] 1H NMR (400MHz, DMSO-d6) δ7.26-7.15(m,3H),7.17-7.11(m,1H),7.10-7.05(m,2H),2.60(bs,1H),1.91-1.86(m,1H),1.38(s,9H),1.13-1.04(m,2H).

[0451] Step 2: Synthesis of 2-phenylcyclopropane-1-amine-2,2,2-trifluoroacetic acid (Compound 23C)

[0452] Trifluoroacetic acid (11.59 mL, 150 mmol) was added to tert-butyl (2-phenylcyclopropyl)carbamate (Compound 23B) (1.95 g, 8.36 mmol) in dichloromethane (5 mL) and stirred at room temperature for 3 h. The reaction solution was directly concentrated to afford 2-phenylcyclopropane-1-amine-2,2,2-trifluoroacetic acid (Compound 23C) (2.1 g) as a yellow oil.

[0453] Step 3: Synthesis of tert-butyl 2-((2-phenylcyclopropyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 23E)

[0454] Cesium carbonate (5.27 g, 16.18 mmol) was added to a solution of tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (1.379 g, 5.39 mmol) and 2-phenylcyclopropane-1-amine (Compound 23C) (2.0 g, 8.09 mmol) in N,N-dimethylformamide (20 mL), and stirred at 90° C. for 16 hours. The mixture was cooled to room temperature and monitored by TLC. After completion of the reaction, distilled water (100 mL) was added for dilution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), separated, and dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10:1 to 1:1) to give tert-butyl 2-((2-phenylcyclopropyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Compound 23E) (800 mg, 42.08% yield) as a yellow solid.

[0455] LC-MS m / z: 353.2 [M+H] + .

[0456] Step 4: Synthesis of N-(2-phenylcyclopropyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 23F)

[0457] A solution of tert-butyl 2-((2-phenylcyclopropyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (530 mg, 15 mmol) (Compound 23E) in a 4M solution of hydrogen chloride in 1,4-dioxane (15 mL, 36.0 mmol) was stirred at room temperature for 2 h. After monitoring the reaction, the mixture was concentrated to afford a yellow solid, N-(2-phenylcyclopropyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 23F) (380 mg, 78% yield), which was used directly in the next step.

[0458] Step 4: Synthesis of 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((2-phenylcyclopropyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 23)

[0459] At 0°C, 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide (888 mg, 1.395 mmol, 50% N,N-dimethylformamide solution) was added dropwise to a solution of N-(2-phenylcyclopropyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride (Compound 23F) (378 mg, 1.16 mmol), 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)acetic acid (239 mg, 1.395 mmol), and N,N-diisopropylethylamine (2.030 ml, 11.62 mmol) in N,N-dimethylformamide (10 mL) and stirred at room temperature for 16 h. After the reaction was completed, monitored by LCMS, distilled water (50 mL) was added for dilution, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative chromatography to give 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((2-phenylcyclopropyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (Compound 23) (96.0 mg, yield 20.4%).

[0460] 1 H NMR(400MHz,DMSO-d6)δ8.28(d,1H),7.71–7.69(m,2H),7.26(t,2H),7.15(d,3H),4.59-4.42(m ,4H),4.21(d,2H),3.77-3.73(m,2H),2.94-2.89(m,3H),1.96-1.94(m,1H),1.28–1.19(m,2H).

[0461] LC-MS m / z: 406.4 [M+H] + .

[0462] Step 5: Synthesis of Compound 24 and Compound 25

[0463] Compound 24 and compound 25 were separated and obtained by SFC.

[0464] Separation conditions: Column: Cellucoat 50×4.6mm ID, 3um; mobile phase consisting of mobile phase A and mobile phase B: mobile phase A is carbon dioxide, mobile phase B is methanol containing 0.05% diethylamine; gradient elution conditions: 40% mobile phase B, 60% mobile phase A; flow rate: 3 mL / min; wavelength: 220 nm, column temperature: 35°C; column pressure: 100 Bar.

[0465] Peak 1:

[0466] 1 H NMR(400MHz, CDCl3)δ8.29(d,1H),7.53(d,1H),7.34–7.28(m,2H),7.23-7.19(m,3H),5.60(d,1H) ,4.76-4.51(m,4H),4.28(d,2H),3.93-3.90(m,2H),3.09-2.98(m,3H),2.09(s,1H),1.40(t,2H).

[0467] LC-MS m / z: 406.2 [M+H] + .

[0468] Peak 2:

[0469] 1 H NMR(400MHz, CDCl3)δ8.29(d,1H),7.53(d,1H),7.30(t,2H),7.21(t,3H),5.61(d,1H),4.76-4.52(m, 4H),4.28(d,2H),3.92(d,2H),3.11–2.95(m,3H),2.09(s,1H),1.47–1.41(m,1H),1.35-1.34(m,1H).

[0470] LC-MS m / z: 406.2 [M+H] + .

[0471] Biological activity and related properties test examples

[0472] Test Example 1: Autotaxin (ATX) enzyme activity inhibition test

[0473] The inhibitory activity of the compounds against the autotaxin enzyme was tested using the Autotaxin Inhibitor Screening Assay Kit (Cayman, 700580). First, prepare the test compound in DMSO to a 10 mM stock solution. Then, serially dilute the solution to eight concentrations using DMSO. Then, dilute the eight concentrations using the Autotaxin Assay Buffer (1×) provided in the kit to a 19× working solution (DMSO content is 1.9%). Remove the Autotaxin Assay Reagent (10×) and dilute it 10-fold using Autotaxin Assay Buffer (1×). Dissolve the Autotaxin Substrate in 1.2 mL of Autotaxin Assay Buffer (1×), mix thoroughly, and let stand at room temperature. In a 96-well plate, 150 μL of Autotaxin Assay Buffer (1×), 10 μL of diluted 19× compound working solution, 10 μL of Autotaxin Assay Reagent (1×), and 20 μL of dissolved Autotaxin Substrate were added to each well of each concentration point. The mixture was mixed and incubated in a 37°C constant temperature shaking in the dark for 30 min. The 96-well plate was removed and placed on a microplate reader to read the OD405. The experimental results were input into GraphPad Prism software, and the IC of each compound was obtained by fitting and calculation. 50 .

[0474] Table 1 Results of the inhibitory activity of the test compounds on ATX enzyme activity

[0475]

[0476]

[0477] The experimental results show that the compound of the present invention has good inhibitory activity on ATX enzyme.

[0478] Test Example 2: Human liver microsome stability test

[0479] The stability test for human liver microsomes was performed by incubating the compound with human liver microsomes in vitro. The test compound was first prepared as a 10 mM stock solution in DMSO solvent, and then diluted to 0.5 mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS to form a microsome / buffer solution, and this solution was used to dilute 0.5 mM of the compound to form a working solution. The working solution contained 1.5 μM compound and 0.75 mg / ml human liver microsomes. A deep-well plate was prepared, and 30 μL of the working solution was added to each well. The reaction was then initiated by adding 15 μL of preheated 6 mM NADPH solution and incubated at 37°C. The reaction was terminated by adding 135 μL of acetonitrile to the corresponding wells at 0, 5, 15, 30, and 45 minutes of incubation. After terminating the reaction with acetonitrile at the final 45-minute time point, the deep-well plate was vortexed for 10 minutes (600 rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected and purified water was added in a 1:1 ratio. LC-MS / MS was then performed to obtain the ratio of the compound peak area to the internal standard peak area at each time point. The peak area ratios of the compound at 5, 15, 30, and 45 minutes were compared with the peak area ratio at 0 minute. The remaining percentage of the compound at each time point was calculated. T was calculated using Excel. 1 / 2 .

[0480] Table 2 Human liver microsome stability test results

[0481]

[0482]

[0483] The experimental results show that the compound of the present invention exhibits better liver metabolic stability, is metabolized more slowly in the human body, and has a higher exposure amount.

[0484] Test Example 3: Pharmacokinetic Test

[0485] In vivo pharmacokinetic studies in mice were performed using six male mice (25-30 g) fasted overnight. Three rats were orally administered 10 mg / kg, and blood was collected before dosing and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Three other mice were intravenously administered 1 mg / kg, and blood was collected before dosing and 5, 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Blood samples were centrifuged at 8000 rpm for 6 minutes at 4°C, and plasma was collected and stored at -20°C. Plasma was collected at each time point and mixed with 3-5 times the volume of acetonitrile containing an internal standard, vortexed for 1 minute, and centrifuged at 13,000 rpm for 10 minutes at 4°C. The supernatant was mixed with 3 times the volume of water, and the appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

[0486] Table 3 Pharmacokinetic test results in mice

[0487]

[0488] The experimental results show that the compound of the present invention exhibits better pharmacokinetic properties.

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): in: R 1 、R 2 、R 3 or R 4 are independently selected from -H, halogen, unsubstituted or optionally substituted with one or more R a Substituted C 1-6 Alkyl; the R a Selected from -F, -Cl, methyl, ethyl, propyl; Each R 5 independently selected from H, -CN, -F, -Cl, -Br, -CH3, -CF3, -OCHF2, -OCF3, -CH2CH3, -CH2CH2CH3; Selected from Z is selected from -O-, or -S-; L is Q is unsubstituted or optionally substituted with one or more R 5 Substituted with the following groups: phenyl; m=2; n=1; p is selected from 0, 1, 2 or 3.

2. The compound according to claim 1, wherein: R 1 、R 2 、R 3 or R 4 Independently selected from -H, unsubstituted or optionally substituted with 1-3 R a The following groups are substituted: methyl, ethyl, n-propyl, isopropyl; the R a Selected from -F, -Cl, methyl, ethyl, propyl.

3. The compound according to claim 1, wherein: Each R 1 、R 2 、R 3 or R 4 Independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3.

4. The compound according to claim 1, wherein: Selected from 5. The compound according to claim 1, wherein: p=0, 1 or 2.

6. The compound according to claim 1, wherein: Each R 5 Independently selected from -H, -CN, -F, -Cl, -Br, -CF3, -OCF3, -OCHF2.

7. The compound according to claim 1, wherein: Selected from 8. A compound represented by the following formula, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

9. A compound represented by the following formula, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

10. A pharmaceutical composition, characterized in that The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

11. Use of the compound according to any one of claims 1 to 9, a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating ATX-related diseases.

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 disease related to abnormal angiogenesis.

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

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

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

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

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