CN113943295A - Pyrrolopyrimidines and their use - Google Patents

Abstract

The invention provides a pyrrolopyrimidine compound and application thereof, and particularly provides a novel compound capable of effectively inhibiting ATX, which is a compound shown in a formula (I), or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound shown in the formula (I):

Description

Pyrrolopyrimidines and their use

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a pyrrolopyrimidine compound, and more particularly relates to a pyrrolopyrimidine compound, a preparation method thereof, and an application thereof in preparation of medicaments.

Background

Autotaxin (abbreviated ATX) is a secreted glycoprotein with Phosphodiesterase (PDE) activity, a member of the extracellular pyrophosphatase/phosphodiesterase (ENPP) family, and is therefore also known as ENPP 2. ATX also has lysophospholipase d (lysopld) activity, and is capable of hydrolyzing Lysophosphatidylcholine (LPC) to bioactive lysophosphatidic acid (LPA). LPA is an intracellular lipid mediator that affects many biological and biochemical processes.

Studies have shown that inhibition of ATX can reduce LPA levels in pathological conditions, thereby providing therapeutic benefit to 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 activation of ATX.

Upregulation of the ATX-LPA signaling pathway is observed in various inflammatory disorders. For example, pro-inflammatory 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 was observed in the mouse carrageenan balloon model (which was used to develop anti-inflammatory agents, including cyclooxygenase inhibitors for arthritis). In addition, a reduction in plasma and in air cell LPA has been observed in the rat carrageenan air cell model with ATX inhibitors, confirming the role of ATX as the major source of LPA during inflammation. As another general role in inflammatory diseases, a "synergistic effect" between LPA and lymphotactin has been demonstrated. High expression of ATX was found at sites of chronic inflammation. Intravenous injection of enzyme-inactive ATX has been shown to inhibit T-cell homing to lymphoid tissues, possibly by competing with endogenous ATX and exerting a dominant negative effect. In some cases, ATX favors lymphocyte entry into lymphoid organs. Thus, ATX inhibitors can block migration of lymphocytes into secondary lymphoid organs and have benefits in autoimmune diseases.

In rheumatoid arthritis, it was confirmed that ATX expression is increased in synovial fibroblasts from Rheumatoid Arthritis (RA) patients, and that elimination of ATX expression in mesenchymal cells (including synovial fibroblasts) leads to reduction of symptoms in a mouse model of rheumatoid arthritis. As such, the role of autotaxin in rheumatoid arthritis is well established.

LPA can also pass through LPA which is one of its cognate receptors₁Upregulation of pain-associated proteins, ATX-mediated targeted inhibition of LPA biosynthesis, may provide a mechanism to prevent neuropathic pain resulting from nerve injury, such as osteoarthritis-associated pain. Autotaxin inhibitors have been observed to reduce LPA and PGE2 and also reduce inflammatory pain. Also, studies have shown that ATX-mediated targeted inhibition of LPA biosynthesis may be a novel mechanism for preventing neuropathic pain resulting from nerve injury.

After resolution of the inflammation and repair of the tissue damage, the tissue generally returns to its original state. Excessive uncontrolled tissue repair can lead to a condition commonly referred to as fibrosis. Fibrosis is characterized by excessive deposition of extracellular matrix components and overgrowth of fibroblasts. Fibrosis can occur in all tissues, but is particularly prevalent in organs that are often chemically and biologically damaged, including the lungs, skin, digestive tract, kidneys, and liver. Fibrosis often severely compromises the normal function of the organ.

In some cases, 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 rabbit blood with different liver lesions, plasma LPA concentration and serum ATX activity were relatively high in carbon tetrachloride-induced liver fibrosis. Plasma LPA concentrations and serum ATX activity were elevated with their severity in different liver injuries.

Pulmonary fibrosis is the terminal change of a large group of lung diseases characterized by fibroblast proliferation and massive extracellular matrix aggregation with inflammatory injury and tissue structure destruction, namely structural abnormality (scar formation) caused by abnormal repair after normal alveolar tissues are damaged. When lung is damaged due to various reasons, the interstitium can secrete collagen for repair, and if the collagen is over-repaired, namely, the fibrocyte is over-proliferated and the extracellular matrix is greatly accumulated, the pulmonary fibrosis is formed.

Specific passage of LPA signals through LPA₁Receptors have a profibrotic effect on epithelial, endothelial and fibroblasts: genetic deletion of this receptor reduces epithelial apoptosis, vascular leakage and fibroblast accumulation in pulmonary fibrosis models.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, fibrotic, interstitial pneumonia characterized by diffuse alveolitis and alveolar structural disorders of unknown etiology, which is manifested primarily as common interstitial pneumonia in imaging and histopathology. As the disease progresses, it causes fibrosis of the lung tissue, the patient's lung tissue becomes thicker and stiffer, resulting in the formation of permanent scars, or the patient's lungs are honeycombed, also referred to visually as "honeycomb lungs" or "loofah lungs". This chronic progressive disease leads to an irreversible and persistent decline in lung function. After definitive diagnosis, the mean survival of 50% of patients is only 2.8 years, and idiopathic pulmonary fibrosis is therefore also referred to as "neoplastic-like disease". The existing drug therapy has the problems of more adverse reactions and poor therapeutic effect; non-drug treatment is mainly lung transplantation, but organ transplantation is expensive and has limited resources and certain clinical risks.

There is evidence that fibroblast proliferation and contraction and extracellular matrix secretion stimulated by LPA promotes fibroproliferation in other airway diseases, such as chronic bronchitis and interstitial lung disease, and the bronchiolar fibrosis found in severe asthma. LPA plays a role in fibrotic interstitial lung disease and bronchiolitis obliterans, where both collagen and myofibroblasts are increased. Studies associated with IPF (idiopathic pulmonary fibrosis) indicate increased LPA levels in patients' bronchoalveolar lavage fluids. Further LPA1 knockout and inhibitor studies revealed a key role for LPA in the fibrotic process in the lung and were complemented by studies using cell-specific knockout mice deficient in bronchial epithelial cells and macrophages. These mice have been shown to be less sensitive to lung fibrosis models. 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), and LPA2 has been shown to play a key role in TGF β activation in epithelial cells under fibrotic conditions. The role of LPA in remodeling and fibrosis is associated with COPD, IPF and asthma, where the disease of pulmonary remodeling as a long-term consequence will limit lung function. Finally, in the interest of lung disease, ATX is one of the three major quantitative trait loci that appear to be associated with differences in lung function in mice.

LPA has been found to be present in elevated concentrations in plasma and ascites in patients with ovarian cancer in early and late stages. Increased LPA levels, altered LPA receptor expression and response may be responsible for the onset, progression or outcome of ovarian cancer. LPA is also associated with prostate, breast, melanoma, head and neck, bowel, brain and thyroid cancers. LPA is involved in the proliferation of tumor cells and invasion of adjacent tissues, leading to metastasis. These biological and pathobiological processes are initiated by LPA activation of G protein-coupled receptors. Tumor patients may be treated by decreasing LPA levels by inhibiting enzymes involved in LPA biosynthesis, such as ATX.

During angiogenesis, ATX, together with other angiogenic factors, leads to angiogenesis. Angiogenesis provides nutrients to tumors during their growth. Therefore, inhibition of angiogenesis can be said to be an important starting point for cancer and tumor therapy.

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 vascularisation, is disclosed in patent application WO2014202458a 1.

There is currently some progress but still a deficiency in the treatment of cancer, fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and/or diseases associated with abnormal angiogenesis. Currently marketed IPF therapeutics are pirfenidone and nintedanib. The pirfenidone has liver function damage (such as liver failure and jaundice), hypersensitivity (such as face swelling, larynx edema, dyspnea, asthmatic suffocation and the like), and severe gastrointestinal tract reaction, and the optogenetic toxicity test shows that the method can cause chromosome structural abnormality and can cause skin carcinogenesis after illumination. The nintedanib has adverse reactions of diarrhea, nausea and abdominal pain, the incidence rate of gastrointestinal tract reaction is as high as 50%, and the common adverse reactions comprise weight loss, anorexia, liver injury, bleeding and the like. The probability of withdrawal from a serious adverse event in patients receiving pirfenidone and nintedanib treatment was 20.9% and 26.3%, respectively. The quality of life of IPF patients can be severely affected, and neither pirfenidone nor nintedanib can improve the quality of life of patients in clinical trials. While both drugs may improve overall outcome, they may only delay the course of the disease but not reverse pulmonary fibrosis, and thus patients with severe specific pulmonary fibrosis may not benefit. Although GLPG-1690, which is the current drug for treating IPF and has a rapid development trend, shows a tendency of reversing the course of disease, the problems of low enzyme activity, large clinical dosage and poor drug compliance are existed. Therefore, the current therapy is not satisfactory, and a large number of patients still need new treatment methods with higher activity and better drug effect, so that the disease process is slowed down or even reversed to a greater extent, the drug compliance is improved, and more patients with idiopathic pulmonary fibrosis benefit.

In view of the above, the present invention provides a compound represented by formula (I), its tautomer, mesomer, racemate, enantiomer, diastereomer, or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate, or prodrug thereof, so as to provide the ATX inhibitor with novel structure, better pharmacokinetic property, better drug effect and strong drug forming property, products useful for treating ATX-related diseases, disorders, including, but not limited to, cancer, metabolic disease, kidney disease, liver disease, fibrotic disease, pulmonary fibrosis, liver fibrosis, proliferative disease, inflammatory disease, pain, osteoarthritis-related pain, autoimmune disease, respiratory disease, cardiovascular disease, neurodegenerative disease, dermatological disorder, and/or abnormal angiogenesis-related disease.

Disclosure of Invention

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

According to one aspect of the present invention, there is provided a compound which is a compound of formula (I), or a tautomer, stereoisomer, hydrate, solvate, salt or prodrug of a compound of formula (I):

wherein:

R¹、R²、R³or R⁴Independently selected from-H, -CN, halogen, unsubstituted or optionally substituted by one or more R^aSubstituted of the following groups: c_1-6Alkyl radical, C_3-6A cycloalkyl group; the R is^aSelected from halogen, C_1-6An alkyl group;

each R⁵Independently selected from H, -CN, halogen, unsubstituted or optionally substituted by one or more R^bSubstituted of the following groups: c_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6A cycloalkyl group; the R is^bSelected from halogen, C_1-6An alkyl group;

M¹、M²、M³、M⁴、M⁵at least 1 of which is-C (R)⁶) or-CH, the remainder being-N (R)⁷) -or-N ═ and at least 1 is-N (R)⁷) -or-N ═ N;

R⁶and R⁷The same or different, are independently selected from: absent, -H, -CN, halogen, unsubstituted or optionally substituted by one or more R^cSubstituted of the following groups: c_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6A cycloalkoxy group; the R is^cSelected from halogen, C_1-6Alkyl, preferably said R^cSelected from-F, -Cl, methyl, ethyl, propyl;

z is selected from-O-, -S-),

L is a single bond, or is selected from unsubstituted or optionally substituted with one or more R^dSubstituted of the following groups: c_1-10Straight chain alkylene group, C_3-10Cycloalkylene, 3-10 membered heterocyclylene; the R is^dSelected from halogen, methyl, ethyl, cyclopropyl;

q is unsubstituted or optionally substituted by one or more R⁵Substituted of the following groups: c₃-C₁₀Cycloalkyl, 3-10 membered heterocyclyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl;

m is an integer from 0 to 6; n is an integer from 0 to 6; p is selected from an integer of 0 to 5.

In some embodiments of the invention, R is as defined above^aSelected from the group consisting of-F, -Cl, methyl, ethyl, propyl, the remaining variables being as defined herein.

In some embodiments of the invention, R is as defined above^bSelected from the group consisting of-F, -Cl, methyl, ethyl, propyl, the remaining variables being as defined herein.

In some embodiments of the invention, R is as defined above⁶And R⁷Independently selected from the group consisting of absent, -H, -CH₃、-CH₂CH₃、-CH₂CH₂CH₃、

-F、-Cl、-Br、-CF₃The remaining variables are as defined herein.

In some embodiments of the invention, R is as defined above⁶And R⁷Independently selected from the group consisting of absent, -H, -CH₃、-F、-Cl、-CF₃The remaining variables are as defined herein.

In some embodiments of the present invention, L isSubstituted or optionally substituted by one or more R^dSubstituted of the following groups: methylene, ethylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, azetidinylene, methylene-cyclopropylene, methylene-cyclobutylene, methylene-cyclopentylene, methylene-cyclohexylene, methylene-azetidinylene, the remaining variables being as defined in the invention.

In some embodiments of the 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, the remaining variables being as defined herein.

In some embodiments of the invention, Q is selected from the phenyl ring, and the remaining variables are as defined herein.

In some embodiments of the invention, in formula (I), M¹、M²、M³、M⁴、M⁵At least 2 or 3 of which are-C (R)⁶) or-CH, the remainder being-N (R)⁷) -or-N ═ and at least 1 is-N (R)⁷) -or-N ═ wherein R⁶And R⁷As previously described, and the remaining variables are as defined herein.

In some aspects of the present invention, it is preferred,

is selected from

Or

Wherein M is³And M⁵Independently selected from-C (R)⁶) -CH or-NH, wherein R is⁶And R⁷As previously described, and the remaining variables are as defined herein.

In some aspects of the present invention, it is preferred,

is selected from

Or

Or

Or

Or

Or

The remaining variables are as defined herein.

In some embodiments of the invention, in formula (I), m is 0, 1 or 2; n is 0, 1 or 2, and the remaining variables are as defined herein.

In some embodiments of the invention, in formula (I), R¹、R²、R³Or R⁴Independently selected from-H, -CN, unsubstituted or optionally substituted by 1-3C_1-3Alkyl radical R^aSubstituted of the following groups: methyl, ethyl, n-propyl, isopropyl; the R is^aSelected from-F, -Cl, C_1-3Alkyl, the remaining variables being as defined herein. In some embodiments of the invention, in formula (I), each R is¹、R²、R³Or R⁴Independently selected from-H, -CH₃、-CH₂CH₃、-CH₂CH₂CH₃The remaining variables are as defined herein.

In some embodiments of the invention, in formula (I),

is selected from

The remaining variables are as defined herein.

In some embodiments of the invention, in formula (I), L is selected from:

the remaining variables are as defined herein.

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

In some embodiments of the invention, each R is⁵Independently selected from H, -CN, -F, -Cl, -Br, -CH₃、-CF₃、-OCHF₂、-OCF₃、-CH₂CH₃、-CH₂CH₂CH₃、

The remaining variables are as defined herein.

In some embodiments of the invention, each R is⁵Independently selected from-H, -CN, -F, -Cl, -Br, -CF₃、-OCF₃、-OCHF₂The remaining variables are as defined herein.

In some embodiments of the invention, in formula (I),

is selected from

The remaining variables are as defined herein.

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:

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:

tautomerism may occur with the compounds of the present invention. The present invention includes all tautomeric forms of the compounds, whether in equilibrium or one form predominating, each tautomeric form being encompassed by the invention.

According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) of the present invention or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate or prodrug thereof.

"pharmaceutical composition" means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.

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

In some embodiments of the invention, the ATX-related disease is selected from the group consisting of cancer, metabolic disease, renal disease, liver disease, fibrotic disease, interstitial lung disease, proliferative disease, inflammatory disease, pain, autoimmune disease, respiratory disease, cardiovascular disease, neurodegenerative disease, dermatological disorder, and/or abnormal angiogenesis-related disease.

In some embodiments of the present invention, the ATX-related disease is selected from interstitial lung disease, pulmonary fibrosis, liver fibrosis, kidney fibrosis, preferably, idiopathic pulmonary fibrosis. According to embodiments of the present invention, the compounds of the present invention are significantly advantageous in the treatment of pulmonary fibrosis, in particular idiopathic pulmonary fibrosis.

In some embodiments of the invention, wherein the ATX-related disorder is selected from metabolic disorders.

In some embodiments of the invention, the metabolic disease is selected from type II diabetes, non-alcoholic steatohepatitis. According to embodiments of the present invention, the compounds of the present invention are significantly advantageous in the treatment of metabolic diseases, particularly type II diabetes, non-alcoholic steatohepatitis.

In some embodiments of the invention, wherein the ATX-related disorder is selected from neuropathic pain, inflammatory pain, preferably, pain associated with osteoarthritis. According to embodiments of the present invention, the compounds of the present invention are significantly advantageous in the treatment of pain associated with osteoarthritis.

In some embodiments of the invention, wherein the ATX-related disease is selected from cancer. According to embodiments of the invention, the compounds of the invention are significantly advantageous in the treatment of cancer.

Definition and description of terms

Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definition in this section controls.

Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy, and pharmacological methods. Unless a specific definition is set forth, the terms used herein in the pertinent description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner known in the art or as described herein. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds. When writing from left to rightWhen a substituent is described by a conventional formula, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, CH₂O is equivalent to OCH₂。

Where numerical ranges are recited in the specification and claims of this application, and where the numerical ranges are understood to be "integers," they are understood to recite both the endpoints of the ranges and each integer within the range. For example, "an integer of 1 to 6" should be understood to describe each integer of 0, 1,2,3, 4,5, and 6. When a range of values is understood to be "a number," it is understood that the two endpoints of the range, and each integer and each decimal within the range are recited. For example, "a number of 1 to 10" should be understood to not only recite each integer of 1,2,3, 4,5, 6,7, 8, 9, and 10, but also to recite at least the sum of each integer and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which 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 problem or complication, commensurate with a reasonable benefit/risk ratio.

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

In addition to pharmaceutically acceptable salts, other salts are also contemplated by the present invention. They may serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the invention.

The term "stereoisomer" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformers. The stereochemical definitions and conventions used in the present invention are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Depending on the choice of starting materials and process, the compounds according to the invention may be present as one of the possible isomers or as a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, for example as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process. Many geometric isomers of olefins, C ═ N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. When compounds described herein contain olefinic double bonds, such double bonds include both E and Z geometric isomers, unless otherwise specified. If the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis or trans (cis-or trans-) configuration.

When bonds to chiral carbons in the formulae of the present invention are depicted as straight lines, it is to be understood that both the (R) and (S) configurations of the chiral carbons and their enantiomerically pure compounds and mixtures resulting therefrom are included within the scope of this formula. The enantiomers or enantiomerically pure compounds herein are illustrated by Maehr, J.chem.Ed.1985, 62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by wedge bonds and dashed bonds.

Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. The compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids. Suitable resolving agents for use in the fractional recrystallization process are, for example, the D and L forms of 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 β -camphorsulfonic acid. Other resolving agents suitable for fractional crystallization processes include stereoisomerically pure forms of α -methyl-benzylamine (e.g., S and R forms or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like. Resolution of the racemic mixture can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The method can be performed by High Performance Liquid Chromatography (HPLC) or Supercritical Fluid Chromatography (SFC). The choice of the particular method and the conditions of elution, the choice of the chromatography column can be selected by the person skilled in the art according to the structure of the compound and the results of the test. Further, any enantiomer or diastereomer of the compounds described herein may also be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.

The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the invention may exhibit tautomerism. Tautomeric compounds may exist in 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 often result in a mixture whose physicochemical properties are consistent with the 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; whereas in phenol the enol type predominates. The present invention encompasses all tautomeric forms of the compounds.

In the examples of the present invention, protons may occupy cyclic forms at two or more positions 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:

the hydrogen of the nitrogen on the triazole can be on any of the three nitrogens due to resonance, so there is some distinction in nomenclature, but these three forms represent what is really a compound.

The term "pharmaceutical composition" denotes a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.

The terms "effective dose," "effective amount," or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

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.

The term "solvate" means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of solvent bonded with non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.

The term "prodrug" refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds, which modifications may be routinely made or removed in vivo to provide the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy or amino group is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy or a free amino group, respectively.

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioisotopes, such as deuterium (g) ((R))²H) Tritium (A)³H) Iodine-125 (¹²⁵I) Or C-14(¹⁴C) In that respect All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

The term "C_1-6Alkyl "is understood to preferably mean a straight-chain or branched saturated monovalent hydrocarbon radical having from 1 to 6 carbon atoms. The alkyl group is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-ethylpropyl group, a1, 2-dimethylpropyl group, a neopentyl group, a1, 1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a 3, 3-dimethylbutyl group, a2, 2-dimethylbutyl group, a1, 1-dimethylbutyl group, a2, 3-dimethylbutyl group, a1, 3-dimethylbutyl group or a1, 2-dimethylbutyl group, or the like, or isomers thereof. In particular, the radicals have 1,2 or 3 carbon atoms ("C)₁-C₃Alkyl radicals "), such as methylAlkyl, ethyl, n-propyl or isopropyl.

The term "C_3-6Cycloalkyl "is understood to mean a saturated, monovalent, monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "alkoxy" refers to an alkyl group as defined above having 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.

The term "C_1-6Alkoxy "is to be understood as meaning-O- (C)_1-6Alkyl) in which "C" is_1-6Alkyl "has the above definition.

The term "C_3-6Cycloalkoxy "is understood to mean-O- (C)_3-6Cycloalkyl) in which "C" is_1-6Alkyl "has the above definition.

The term "halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo.

"haloalkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens (e.g., -CvFw, where v is 1 to 3 and w is 1 to (2v + 1)). Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2, 2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

The term "3-10 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5, preferably 1-3 heteroatoms selected from N, O and S. In particular, the heterocyclic group may include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings 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 heterocyclic group may be benzo-fused. The heterocyclyl 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 atom containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, 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, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic radical is non-aromatic.

Advantageous effects

According to the specific examples of the present invention, the compound of formula (I) or the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula (I) according to the present invention can effectively inhibit ATX enzyme activity, and compared with the control compound, the compound of the present invention exhibits superior hepatic metabolic stability and superior pharmacokinetic properties.

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

Detailed Description

The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.

Embodiments of the present invention provide a compound represented by formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof, methods and intermediates for preparing the compound represented by formula (I), the tautomer, the stereoisomer, the hydrate, the solvate, the pharmaceutically acceptable salt, or the prodrug thereof, a pharmaceutical composition, and use of the compound and the pharmaceutical composition in preparation of a medicament.

The reaction solvent used in each reaction step described in the present invention is not particularly limited, and any solvent that can dissolve the starting materials to some extent and does not inhibit the reaction is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). NMR shift in units of 10^-6(ppm). Solvents for NMR measurement were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and an internal standard was Tetramethylsilane (TMS).

Liquid chromatography-mass spectrometry (LC-MS) was performed by a WatersAcquisyt H-classiUplc-QDA mass spectrometer, monitored using an ACQUITYUPLCBEHC18, 2.1 × 50mm, 1.7 μm chromatography column. Gradient elution conditions: 95-5% solvent A1 and 5-95% solvent B1, then 95% B1 and 5% A1 at a flow rate of 1.0mL/min for 0.5min, the percentages being the volume percent of a solvent based on the total solvent volume. Wherein the solvent A1: 0.1% formic acid in water; solvent B1: 0.1% formic acid in acetonitrile. The percentages are the volume percent of solute in solution.

Abbreviations of the present invention are defined as follows:

and (2) CuI: cuprous iodide

DCM: methylene dichloride

DIPEA: also can be written as DIEA, diisopropylethylamine, i.e., N-diisopropylethylamine

DMF: n, N-dimethylformamide

DMSO, DMSO: dimethyl sulfoxide

Et₃N: triethylamine

M: mol/L, for example, n-butyllithium (14.56mL, 29.1mmol, 2.5M solution in n-hexane) means a 2.5mol/L solution of n-butyllithium in n-hexane

N: equivalent concentration, e.g. 2N hydrochloric acid means 2mol/L hydrochloric acid solution

NADPH: reduced coenzyme II

NaH: sodium hydrogen, sodium hydride

NMM: n-methylmorpholine

NMP: n-methyl pyrrolidone

Pd/C: palladium on carbon

PPh₃: triphenylphosphine

SFC: supercritical fluid chromatography

T3P: propylphosphoric acid tricyclic anhydrides, i.e. 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphine-2, 4, 6-trioxide or 1-propylphosphoric anhydride

THF: tetrahydrofuran (THF)

IC₅₀: the median inhibitory concentration is the concentration at which half of the maximal inhibitory effect is achieved.

Unless indicated to the contrary, the compounds exemplified herein are named and numbered using ChemBioDraw Ultra 13.0.

Preparation example 1: synthesis of intermediate B

2- (2- (1H-1,2, 3-triazole-4-yl) ethoxy) acetic acid (intermediate B)

The synthetic route of the target compound intermediate B is shown below:

the first step is as follows: synthesis of methyl 2- (butyl-3-yne-1-oxy) acetate (Compound B-2)

The starting material, 3-butynol (compound B-1) (2.8g,0.4mol), was added to dry tetrahydrofuran (100mL), cooled to 0 deg.C, 60% sodium hydrogen (2.4g, 0.6mmol) was added, stirring was carried out at 0 deg.C for 0.5h, the starting material, methyl 2-bromoacetate (7.3g, 0.48mmol), was added to the reaction mixture, allowed to warm to room temperature naturally, and stirred for 16 h. Water (100mL) was added, and extraction was performed with ethyl acetate (50mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 5:1) to give compound B-2 as a colorless liquid (2.24g, yield 39%).

LC-MSm/z：143.0[M+H]⁺。

The second step is that: synthesis of methyl 2- (2- (1H-1,2, 3-triazole-4-yl) ethoxy) acetate (compound B-3)

Compound B-2(2.24g, 15.7mmol) was added to N, N-dimethylformamide (15mL) and methanol (4mL) at room temperature, azidotrimethylsilane (2.72g,23.6mmol) and cuprous iodide (357mg,1.9mmol) were added under nitrogen, heated to 110 ℃ and stirred for 16 h. Water (150mL) was added, extraction was performed with ethyl acetate (20 mL. times.3), and the aqueous phase was lyophilized to give Compound B-3 as a brown liquid (2.5g, 85.6% yield).

LC-MSm/z：186.1[M+H]⁺。

The third step: synthesis of 2- (2- (1H-1,2, 3-triazole-4-yl) ethoxy) acetic acid (intermediate B)

Compound B-3(2.20g, 11.9mmol) was added to a mixed solution of water (10mL), tetrahydrofuran (10mL) and methanol (10mL) at room temperature, and sodium hydroxide (1.9g,47.6mmol) was added thereto, followed by stirring at room temperature for 16 h. The reaction was concentrated to 15mL, pH was adjusted to 1-2, and the aqueous phase was lyophilized to give intermediate B as a yellow liquid (2.1g, 100% yield).

LC-MSm/z：172.0[M+H]⁺。

Comparative example 1: control Compounds and their preparation

Reference compound was synthesized according to patent application WO2014110000A 1.

The control compounds of the test examples below are all referred to as the compounds described in comparative example 1.

Example 1: synthesis of Compound 1

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)

The synthetic route for the target compound 1 is shown below:

the first step is as follows: synthesis of tert-butyl 2- ((3, 5-dichlorophenethyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 1C)

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

LC-MSm/z：409.1[M+H]⁺。

The second step is that: synthesis of N- (3, 5-dichlorophenethyl) -6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (Compound 1D)

A4M solution of hydrogen chloride in ethyl acetate (10mL) was added to a round bottom flask containing Compound 1C (940mg, 2.297mmol) and stirred at room temperature for 1 h. After completion of the reaction, concentration gave crude compound 1D as a white solid (1.0g, yield 114%). The crude product was used directly in the next step without purification.

The third step: 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)

O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate (84mg, 0.262mmol) was added to N, N-dimethylformamide (5mL) containing 2- (2- (1H-1,2, 3-triazol-5-yl) ethoxy) acetic acid (compound 1E), trifluoroacetic acid (37.3mg, 0.131mmol), N, N-diisopropylethylamine (0.114mL,0.654mmol) at 0 deg.C. After stirring for 5 minutes, Compound 1D (50mg, 0.131mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. Distilled water (20mL) was added for dilution, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated brine (10mL × 2), liquid separation was performed, the organic phase was dried over anhydrous sodium sulfate, filtration and concentration were performed, and the residue was separated by preparative chromatography to give compound 1(4.8mg, yield 7.93%).

¹H 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)。

LC-MSm/z：462.3[M+H]⁺。

Example 2: synthesis of Compound 2

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)

The synthetic route of compound 2 is shown below:

the first step is as follows: synthesis of tert-butyl 2- ((3, 5-bis (trifluoromethyl) phenethyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 2C)

Tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (compound 2B) (0.145g, 0.567mmol) and 2- (3, 5-bis (trifluoromethyl) phenyl) ethylamine hydrochloride (compound 2A) (200mg, 0.68mmol), diisopropylethylamine (0.297mL, 1.701mmol) were dissolved in N-methylpyrrolidinone (5mL) and stirred at 80 ℃ for 16H. Cooling to room temperature, diluting with distilled water (10mL), extracting with ethyl acetate (10mL × 3), combining the organic phases, washing the organic phase with saturated brine (10mL × 2), separating the liquids, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and purifying the residue with a silica gel column (petroleum ether: ethyl acetate (V/V) ═ 10:1 to 1:1) to obtain 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) as a yellow solid (150mg, yield 55.5%).

LC-MSm/z：477.3[M+H]⁺。

The second step is that: synthesis of (N- (3, 5-bis (trifluoromethyl) phenethyl) -6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (Compound 2D)

A4M solution of hydrogen chloride in 1, 4-dioxane (5mL, 20.00mmol) 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) (150mg, 0.315mmol) and stirred at room temperature for 3H. Concentration gave (N- (3, 5-bis (trifluoromethyl) phenethyl) -6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (compound 2D) (145mg) as a pale yellow solid, which was used in the next step without purification.

The third step: 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)

2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriophosphoric acid-2, 4, 6-trioxide (294mg, 0.462mmol, 50% N, N-dimethylformamide solution) is dropped into a DMF (3mL) solution containing 2- (2- (1H-1,2, 3-triazol-4-yl) ethoxy) acetic acid (intermediate B) (100mg, 0.578mmol), triethylamine (0.537mL, 3.85mmol), (N- (3, 5-bis (trifluoromethyl) phenethyl) -6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (compound 2D) (145mg, 0.323mmol) at 0 deg.C, stirred at room temperature for 1H, LCMS monitors the reaction, and then distilled water (30mL) is added for dilution, extraction with ethyl acetate (50mL × 3), combination of the organic phases, washing of the organic phase with saturated brine (10mL × 2), liquid separation, drying of the organic phase over anhydrous sodium sulfate, filtration, concentration and separation of the residue by preparative chromatography gave the compound 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 (49.2mg, 24.1% yield).

¹H 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)。

LC-MSm/z：530.3[M+H]⁺。

Example 3: synthesis of Compound 3

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

The synthetic route for compound 3 is shown below:

the first step is as follows: synthesis of tert-butyl 2- (phenethylamino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 3C)

Tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (compound 3A) (1g, 3.92mmol), 2-phenyleth-1-amine (compound 3B) (0.47g, 3.92mmol), diisopropylethylamine (1.01g,7.84mmol), N-methylpyrrolidone (10mL) were added to a single vial and stirred at 80 ℃ for 16 hours. Cooling to room temperature, diluting with water (10mL), extracting with ethyl acetate (50mL × 3), combining the organic phases, washing the organic phase with saturated brine (50mL × 2), separating the liquids, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and purifying the residue with a silica gel column (petroleum ether: ethyl acetate (V/V) ═ 10:1 to 1:1) to obtain pale yellow solid tert-butyl 2- (phenethylamino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (compound 3C) (814mg, yield 61%).

LC-MSm/z：340.4[M+H]⁺。

The second step is that: synthesis of N-phenethyl-6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (Compound 3D)

A solution of hydrogen chloride in 1, 4-dioxane (2.5M, 20mL), tert-butyl 2- (phenethylamino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (compound 3C) (814mg, 2.39mmol) was added to a single-neck flask and stirred at room temperature for 1 hour. Filtration and drying in vacuo at 50 ℃ gave N-phenethyl-6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (compound 3D) as a white solid (590mg, 79% yield).

The third step: synthesis of 2- (2- (1-H-1,2, 3-triazol-4-yl) ethoxy) -1- (2- (phenethylamino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidin-6-yl) ethan-1-one (Compound 3)

In a single vial was added N-phenethyl-6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (compound 3D) (100mg, 0.32mmol), 2- (2- (1H-1,2, 3-triazolyl) -4-yl) ethoxy) acetic acid (intermediate B) (112.5mg, 0.65mmol), diisopropylethylamine (279mg, 2.16mmol), N, N-dimethylformamide (2mL) dissolved at room temperature, cooled to 0 deg.C, 1-propylphosphoric anhydride (343mg, 0.54mmol, 50% N, N-dimethylformamide solution) was added dropwise, LCMS indicated that the starting material had reacted off, diluted with water (10mL), extracted with dichloromethane (50 mL. times.2), the organic phases combined, washed with saturated brine (50 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to preparative chromatography to give the compound 2- (2- (1-H-1,2, 3-triazol-4-yl) ethoxy) -1- (2- (phenethylamino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidin-6-yl) ethan-1-one (compound 3) (30mg, yield 23.8%).

¹HNMR(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)。

LC-MSm/z：394.3[M+H]⁺。

Example 4: synthesis of Compound 4

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)

The synthesis route of the target compound 4 is shown as follows:

the first step is as follows: synthesis of tert-butyl 2- ((4- (trifluoromethoxy) phenethyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carbonate (Compound 4C)

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

LC-MSm/z：425.3[M+H]⁺。

The second step is that: synthesis of N- (4- (trifluoromethoxy) phenethyl) -6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (Compound 4D)

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

LC-MSm/z：325.2[M+H]⁺。

The third step: 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)

A solution of 1-propanephosphonic acid cyclic anhydride (2.06g, 6.48mmol, 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) (700mg, 1.77mmol), triethylamine (1.747g, 17.27mmol), 2- (2- (1H-1,2, 3-triazol-4-yl) ethoxy) acetic acid (intermediate B) (739mg, 4.32mmol) in dichloromethane (20mL) at 0 deg.C, stirred at room temperature for 18 hours and TLC monitored for completion of the reaction. 30mL of dichloromethane and water (30 mL. times.3) were added and the organic phase was concentrated, and the residue was purified with a silica gel column (dichloromethane: methanol (V/V) ═ 30: 1-8-1) to give a crude product (450mg), which was recrystallized from an ethyl acetate/n-heptane system to give compound 4(334.5mg, yield 39.6%).

¹HNMR(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)。

LC-MSm/z：478.3[M+H]⁺。

Example 5: synthesis of Compound 5

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)

The synthetic route for the target compound 5 is shown below:

the first step is as follows: synthesis of tert-butyl 3- (trifluoromethoxy) phenethylcarbamate (Compound 5B)

2- (3- (trifluoromethoxy) phenyl) acetonitrile (Compound 5A) (1g, 4.92mmol) was dissolved in methanol (25mL), nickel chloride hexahydrate (0.117g, 0.492mmol) was added, the reaction stirred and cooled to 0 deg.C, sodium borohydride (1.862g, 49.2mmol) was added in portions, and the reaction was continued for 16h at room temperature. Di-tert-butyl dicarbonate (1.611g, 7.38mmol) was added and the reaction was continued at room temperature for 2 h. The reaction mixture was quenched with water (150mL), extracted with ethyl acetate (50mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified with a silica gel column (petroleum ether: ethyl acetate (V/V) ═ 100:1 to 20:1) to give tert-butyl 3- (trifluoromethoxy) phenethylcarbamate (compound 5B) as a yellow oil (1.1g, yield 73.2%).

LC-MSm/z：206.3[M-Boc+H]⁺。

The second step is that: synthesis of 2- (3- (trifluoromethoxy) phenyl) ethylamine hydrochloride (Compound 5C)

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

The third step: synthesis of tert-butyl 2- ((3- (trifluoromethoxy) phenethyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-D ] pyrimidine-6-carboxylate (Compound 5D)

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

LC-MSm/z：425.4[M+H]⁺。

The fourth step: synthesis of N- (3- (trifluoromethoxy) phenethyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (Compound 5E)

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

The fifth step: 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)

Adding N, N-dimethylformamide (5mL), 2- (2- (1H-1,2, 3-triazol-4-yl) ethoxy) acetic acid (intermediate B) (387mg, 2.262mmol) and triethylamine (1.526g, 15.08mmol) to the crude N- (3- (trifluoromethoxy) phenethyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (compound 5E) as a yellow viscous solid obtained in the fourth step, cooling the reaction solution to about 0 ℃, dropwise adding 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxotriphosphoric acid-2, 4, 6-trioxide (1.152g, 1.810mmol, 50% N, N-dimethylformamide solution), after the dropwise addition, the reaction was carried out at room temperature for 4 hours. Water (25mL) was added to the reaction solution, dichloromethane was extracted (15mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was separated and purified by a silica gel column (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) (200mg, yield 27.8%).

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)。

LC-MSm/z：478.3[M+H]⁺。

Example 6: synthesis of Compound 6

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)

The synthetic route for the target compound 6 is shown below:

the first step is as follows: synthesis of ethyl tert-butyl-2- ((3, 5-dichlorobenzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 6C)

The compound tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (compound 6A) (1g, 3.9mmol) was added to NMP (10mL) at room temperature followed by DIEA (3.9g, 30mmol), (3, 5-dichlorophenyl) methylamine (compound 6B) (1.56g, 9 mmol). The reaction was warmed to 90 deg.C, stirred for 8 hours, cooled to room temperature, water (10mL) was added under ice-bath conditions, ethyl acetate (15 mL. times.2) was added for extraction, the organic phase was washed with water (10mL), and concentrated to give the crude product. The crude product was purified by silica gel column separation (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) (1.4g, 91% yield).

LC-MSm/z：395.19[M+H]⁺。

The second step is that: synthesis of N- (3, 5-dichlorobenzyl) -6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (Compound 6D)

Ethyl tert-butyl-2- ((3, 5-dichlorobenzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (1.4g, 3.5mmol) was added to hydrogen chloride in dioxane solvent (10mL) under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. Concentration gave the product N- (3, 5-dichlorobenzyl) -6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine hydrochloride (compound 6D) (1g, 77.8% yield) which was used directly in the next reaction.

The third step: 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)

Compound 6D (300mg, 0.82mmol) was added to compound 2- (2- (1H-1,2, 3-triazol-4-yl) ethoxy) acetic acid (intermediate B) (209mg, 1.22mmol), DIEA (6mL) with stirring at room temperature, 1-propanephosphonic acid cyclic anhydride (122mg, 0.38mmol, 50% DMF solution) was added under ice bath conditions and stirred at room temperature overnight. Water (10mL) was added, and extraction was performed with ethyl acetate (10 mL. times.2). The organic phases were combined and concentrated to afford compound 6(22mg, 6.0% yield).

¹H 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)。

LC-MSm/z：448.00[M+H]⁺。

Example 7: synthesis of Compound 7

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)

The synthetic route for the target compound 7 is shown below:

the first step is as follows: synthesis of methyl 3-imidazolyl-1-ylpropionate (Compound 7B)

Imidazole (30g, 0.44mol) was added to methyl acrylate (45.5g, 0.53mol), potassium phosphate (23.3g, 0.11mol) at room temperature. After stirring at room temperature for 3 hours, TLC detection showed complete reaction, silica gel filtration and concentration to give methyl 3-imidazolyl-1-yl propionate (34.2g, 50.3% yield).

The second step is that: synthesis of 2- (1H-imidazol-1-yl) ethan-1-ol (Compound 7C)

Lithium aluminum hydride (4.04g, 0.11mol) was added to dry tetrahydrofuran (130mL) at room temperature and cooled to-thirty degrees Celsius with stirring. At this temperature, methyl 3-imidazolyl-1-ylpropionate (13g, 0.08mol) in tetrahydrofuran (20mL) was slowly added dropwise for 30 minutes, then warmed to room temperature, stirred for 30 minutes, quenched by adding 15% sodium hydroxide (10mL), extracted with ethyl acetate (30 mL. times.2), and combined organically. The crude product was purified by silica gel column separation (dichloromethane: methanol (V/V) ═ 10:1) to give 2- (1H-imidazol-1-yl) ethan-1-ol (3g, 24.3% yield) as a product.

The third step: synthesis of tert-butyl 2- (2- (1H-imidazol-1-yl) ethoxy) acetate (Compound 7D)

Sodium hydride (0.86g, 21.5mmol, 60%) was added to tetrahydrofuran (20mL) under ice-bath conditions, after stirring for 20min, the compound 2- (1H-imidazol-1-yl) ethan-1-ol (2g, 17.9mmol) was added, stirring was continued for 30min, tert-butyl bromoacetate (6.99g, 35.8mmol) was added under ice-bath conditions, warmed to room temperature, and stirred overnight. Water (10mL) was added, ethyl acetate (20mL × 2) was extracted twice, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by separation with a silica gel column (dichloromethane: methanol (V/V) ═ 10:1) to give tert-butyl 2- (2- (1H-imidazol-1-yl) ethoxy) acetate (compound 7D) (3g, yield 61.7%).

LC-MS m/z：227.15[M+H]⁺。

The fourth step: synthesis of 2- (2- (1H-imidazol-1-yl) ethoxy) acetic acid (Compound 7E)

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

The fifth step: 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)

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

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)。

LC-MSm/z：224.21[M/2+H]⁺。

Example 8: synthesis of Compound 8

(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)

The synthetic route for compound 8 is shown below:

the first step is as follows: synthesis of (S) -2- (but-3-yn-1-yloxy) propionic acid (Compound 8C)

To a solution of sodium hydride (2.283g, 57.1mmol, 60%) in anhydrous DMF (20mL) at 0 deg.C was added but-3-yn-1-ol (2g, 28.5mmol), the mixture was stirred at 0 deg.C for 30min, then (R) -2-bromopropionic acid (4.37g, 28.5mmol) was added. The mixture was stirred at room temperature for 16 hours, and after completion of the reaction, water (200mL) was added, extraction was performed with ethyl acetate (20mL × 2), pH 1-2 was adjusted by adding 1N diluted hydrochloric acid to the aqueous phase, extraction was performed three times with ethyl acetate/tetrahydrofuran (10:1), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give (S) -2- (but-3-yn-1-yloxy) propionic acid (compound 8C) (2.20g, yield 61%) as a yellow oily product.

The second step is that: 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)

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

The third step: 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)

The reaction mass (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 (0.1g, 0.23mmol), L-ascorbic acid (0.084g, 0.47mmol) and sodium bicarbonate (0.040g, 0.47mmol) were added to a mixed solution of DMF (2mL) and methanol (0.2mL), followed by copper sulfate pentahydrate (0.014g, 0.055mmol) and azidotrimethylsilane (0.096g, 0.832mmol) and stirred at 90 ℃ for 3 hours. The reaction was diluted with water (20mL) and then extracted with DCM (10mL × 3), the combined concentrated organic layers were 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) (3.1mg, 3.0% yield).

¹H 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,2H),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)。

LC-MSm/z：462.3[M+H]⁺。

Example 9: synthesis of Compound 9

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)

The synthetic route for compound 9 is shown below:

the first step is as follows: 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)

A50% solution of 1-propylphosphoric anhydride in N, N-dimethylformamide (440mg, 0.692mmol) was added to a solution of 2- (2- (1H-1,2, 3-triazol-5-yl) isopropoxy) acetic acid (150mg, 0.810mmol), diisopropylethylamine (600mg, 4.65mmol) in N, N-dimethylformamide (5mL) at 0 ℃. After stirring for 5 minutes, N- (3, 5-dichlorobenzyl) -6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (compound 6D) (220mg, 0.597mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. Distilled water (20mL) was added for dilution, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, the organic phase was washed with saturated brine (10mL × 2), separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to preparative chromatography to give the 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 (50mg, yield 18.1%).

¹H NMR(400MHz,DMSO-d6)δ8.24(d,1H),7.84(t,1H),7.61(s,1H),7.41(s,1H),7.30(s,2H),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).

LC-MSm/z：462.3[M+H]⁺。

Example 10: synthesis of Compound 10

(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)

The synthetic route for compound 10 is shown below:

the procedure was carried out in the same manner as in the preparation of example 8 (Compound 8) except that (S) -2-bromopropionic acid was used in place of (R) -2-bromopropionic acid in example 8, and through 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) (26.0mg, 0.056mmol) was finally purified.

¹H 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)。

LC-MSm/z：462.3[M+H]⁺。

Example 11: synthesis of Compound 11

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)

The synthetic route for compound 11 is shown below:

the first step is as follows: synthesis of tert-butyl 2- ((3- (difluoromethoxy) benzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 11C)

Tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (compound 11B) (1g, 3.92mmol) and (3-difluoromethoxy) phenyl) methylamine (compound 11A) (1.35g, 7.80mmol), diisopropylethylamine (2.5g, 19.40mmol) were dissolved in N-methylpyrrolidone (10mL) and stirred at 100 ℃ for 16 hours. Cooling to room temperature, diluting with distilled water (20mL), extracting with ethyl acetate (20mL × 3), combining the organic phases, washing the organic phase with saturated brine (20mL × 2), separating the liquids, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and purifying the residue with a silica gel column (petroleum ether: ethyl acetate (V/V) ═ 10:1 to 1:1) to obtain tert-butyl 2- ((3- (difluoromethoxy) benzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (compound 11C) (1.2g, yield 77.9%).

The second step is that: synthesis of N- (3- (difluoromethoxy) benzyl) -6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (Compound 11D)

Tert-butyl 2- ((3- (difluoromethoxy) benzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-D ] pyrimidine-6-carboxylate (compound 11C) (1.2g, 3.06mmol) was added to a solution of 100mL hydrogen chloride in 1, 4-dioxane at room temperature and stirred at room temperature for 8 hours to monitor completion of the reaction, after filtration and drying of the solid, N- (3- (difluoromethoxy) benzyl) -6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (compound 11D) (950mg, 85.3% yield) was obtained.

The third step: 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)

1-Propylphosphoric anhydride (326mg, 1.025mmol, 50% N, N-dimethylformamide solution) was added to a solution of 2- (2- (1H-1,2, 3-triazol-5-yl) ethoxy) acetic acid (175mg,1.023mmol), diisopropylethylamine (530mg,4.109mmol) in N, N-dimethylformamide (2mL) at 0 ℃. After stirring for 5 minutes, N- (3- (difluoromethoxy) benzyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (200mg, 0.55mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. Distilled water (5mL) was added for dilution, extraction was performed with ethyl acetate (5mL × 3), the organic phases were combined, the organic phase was washed with saturated brine (2mL × 2), separated, dried over anhydrous sodium sulfate, filtered, concentrated, and 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) (160mg, yield 65.3%).

¹H 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)。

LC-MSm/z：446.36[M+H]⁺。

Example 12: synthesis of Compound 12

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)

The synthetic route for compound 12 is shown below:

the first step is as follows: synthesis of tert-butyl 2- ((3, 5-dicyanobenzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 12C)

The starting material tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (compound 12B) (100mg, 0.39mmol) was added to DMF (3mL), 3, 5-dicyanobenzylamine (92mg, 0.59mmol) and cesium carbonate (255mg, 0.78mmol) were added, heated to 85 ℃ and stirred for 16H. Filtration was performed, water (30mL) was added, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) ═ 4:1) to give 2- ((3, 5-dicyanobenzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (compound 12C) as a yellow solid (17mg, yield 11.5%).

LC-MSm/z：377.1[M+H]⁺。

The second step is that: synthesis of 5- (((6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-yl) amino) methyl) isophthalonitrile dihydrochloride (Compound 12D)

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

LC-MSm/z：277.1[M+H]⁺。

The third step: 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)

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

¹H 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)。

LC-MSm/z：430.1[M+H]⁺。

Example 13: synthesis of Compound 13

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)

The synthetic route for compound 13 is shown below:

the first step is as follows: synthesis of tert-butyl 2- ((3-cyanobenzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 13B)

The starting material, 3- (aminomethyl) benzonitrile (310mg, 2.35mmol), was added to DMF (5mL), tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (500mg, 1.96mmol) and cesium carbonate (1.27g, 3.92mmol) were added, heated to 85 ℃ and stirred for 16H. Water (50mL) was added, and extraction was performed with ethyl acetate (20mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 3:1) to give 2- ((3-cyanophenyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (compound 13B) as a yellow solid (180mg, yield 26.1%).

LC-MSm/z：352.1[M+H]⁺。

The second step is that: synthesis of 3- (((6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-yl) amino) methyl) benzonitrile dihydrochloride 13C)

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

LC-MSm/z：252.1[M+H]⁺。

The third step: 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)

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

¹H 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)。

LC-MSm/z：405.0[M+H]⁺。

Example 14: synthesis of Compound 14

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)

The synthetic route for compound 14 is shown below:

the first step is as follows: synthesis of tert-butyl 2- ((3-bromo-5- (trifluoromethoxy) benzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 14B)

The starting material, 3-bromo-5- (trifluoromethoxy) benzylamine (0.9g, 3.3mmol) was added to N-methylpyrrolidone (5mL), tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (1.2g, 4.95mmol) and diisopropylethylamine (1.24g, 9.9mmol) were added, heated to 90 ℃ and stirred for 16H. Water (50mL) was added, and extraction was performed with ethyl acetate (20mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 3:1) to give 2- ((3-bromo-5- (trifluoromethoxy) benzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (compound 14B) as a yellow liquid (1.2g, yield 74.5%).

LC-MSm/z：489.1[M+H]⁺。

The second step is that: synthesis of tert-butyl 2- ((3-cyano-5- (trifluoromethoxy) benzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 14C)

The starting material tert-butyl 2- ((3-bromo-5- (trifluoromethoxy) benzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (compound 14B) (1.4g, 2.86mmol) was added to N, N-dimethylacetamide (15mL) at room temperature, zinc cyanide (1.4g, 11.96mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (210mg, 0.29mmol) were added, and microwave heated to 160 ℃ under nitrogen protection and stirred for 1H. Water (50mL) was added, and extraction was performed with ethyl acetate (20mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 3:1) to give 2- ((3-cyano-5- (trifluoromethoxy) benzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (compound 14C) as a white solid (0.8g, 64.1% yield).

LC-MSm/z：436.1[M+H]⁺。

The third step: synthesis of 3- (((6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-yl) amino) methyl) -5- (trifluoromethoxy) benzonitrile dihydrochloride (Compound 14D)

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) (100mg, 0.23mmol) was added to ethyl acetate (15mL) at room temperature, followed by 4M hydrogen chloride in 1, 4-dioxane (2mL) and stirring at room temperature for 2H. Concentration gave 3- (((6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-yl) amino) methyl) -5- (trifluoromethoxy) benzonitrile dihydrochloride (compound 14D) as a white solid (36mg, 38.5% yield).

LC-MSm/z：336.1[M+H]⁺。

The fourth step: 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)

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

¹H 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)。

LC-MSm/z：489.1[M+H]⁺。

Example 15: synthesis of Compound 15

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)

The synthetic route for compound 15 is shown below:

the first step is as follows: synthesis of 2-benzylamino-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (Compound 15B)

Tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (0.5g, 1.96mmol), benzylamine (0.25g, 2.35mmol), diisopropylethylamine (1.025mL, 5.87mmol) was dissolved in N-methylpyrrolidone (5mL) and stirred at 80 ℃ for 16 hours. Cooling to room temperature, diluting with distilled water (10mL), extracting with ethyl acetate (10mL × 3), combining the organic phases, washing the organic phase with saturated brine (10mL × 2), separating the liquids, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and purifying the residue with a silica gel column (petroleum ether: ethyl acetate (V/V) ═ 10:1 to 1:1) to obtain 2-benzylamino-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (350mg, yield 54.8%) as a yellow solid.

The second step is that: synthesis of N-benzyl-6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (Compound 15C)

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

The third step: 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)

A50% solution of 1-propylphosphoric anhydride in N, N-dimethylformamide (871mg, 1.370mmol) was added to a solution of 2- (2- (1H-1,2, 3-triazol-5-yl) ethoxy) acetic acid (373mg, 1.310mmol), diisopropylethylamine (442mg, 3.426mmol) in N, N-dimethylformamide (5mL) at 0 ℃. After stirring for 5 minutes, N-benzyl-6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (270mg, 0.906mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. Distilled water (20mL) was added for dilution, extraction was performed with ethyl acetate (20 mL. times.3), the organic phases were combined, the organic phase was washed with saturated brine (10 mL. times.2), separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to preparative chromatography to give 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 (64mg, yield 18.6%) as a pale yellow solid.

¹H 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)。

LC-MSm/z：380.2[M+H]⁺。

Example 16: synthesis of Compound 16

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)

The synthetic route for compound 16 is shown below:

the first step is as follows: synthesis of tert-butyl 2- ((3, 5-difluorophenyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 16C)

The starting material, tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (800mg, 3.14mmol), was added to N, N-dimethylformamide (3mL), 3, 5-difluorobenzylamine (538mg, 3.76mmol) and cesium carbonate (2.05g, 6.28mmol) were added, heated to 90 deg.C, and stirred for 16H. Filtration, addition of water (30mL), extraction with ethyl acetate (20mL × 3), combination of organic phases, drying over anhydrous sodium sulfate, filtration, concentration, and separation and purification of the residue on a silica gel column (petroleum ether: ethyl acetate (V/V) ═ 4:1) gave 2- ((3, 5-difluorophenyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (compound 16C) as a yellow solid (500mg, 43.9% yield).

LC-MSm/z：363.2[M+H]⁺。

The second step is that: synthesis of N- (3, 5-difluorophenyl) -6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (Compound 16D)

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

LC-MSm/z：263.2[M+H]⁺。

The third step: 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)

The starting material, N- (3, 5-difluorophenyl) -6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (compound 16D) (150mg, 0.45mmol), was added to N, N-dimethylformamide (4mL) and ethyl acetate (2mL) at room temperature, 1-propylphosphoric anhydride (544mg, 0.86mmol, 50% ethyl acetate solution), N-methylmorpholine (115mg, 1.14mmol) and 2- (2- (1H-1,2, 3-triazol-4-yl) ethoxy) acetic acid (132mg, 0.63mmol) were added and stirred for 5H. Water (15mL) was added, extraction was performed with ethyl acetate (15mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column separation (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) (40mg, yield 21.3%).

¹H 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)。

LC-MSm/z：416.2[M+H]⁺。

Example 17: synthesis of Compound 17

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)

The synthetic route for compound 17 is shown below:

the first step is as follows: synthesis of 3- (azidomethyl) -5-chlorobenzonitrile (Compound 17B)

The starting material, 3-chloro-5- (hydroxymethyl) benzonitrile (2.0g, 11.9mmol), was added to toluene (60mL) at room temperature, 1, 8-diazabicycloundec-7-ene (2.18g, 14.4mmol) was added under nitrogen and stirred for 16 h. Water (90mL) was added, and extraction was performed with ethyl acetate (50mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 10:1) to give 3- (azidomethyl) -5-chlorobenzonitrile (compound 17B) as a colorless liquid (1.53g, yield 66%).

LC-MSm/z：193.2[M+H]⁺。

The second step is that: synthesis of 3-aminomethyl-5-chlorobenzonitrile (Compound 17C)

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

LC-MSm/z：167.2[M+H]⁺。

The third step: synthesis of tert-butyl 2- ((3-chloro-5-cyanobenzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-D ] pyrimidine-6-carboxylate (Compound 17D)

The starting material, tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (550mg, 2.15mmol), was added to N, N-dimethylformamide (8mL), followed by addition of 3-aminomethyl-5-chlorobenzonitrile (430mg, 2.59mmol) and potassium carbonate (742mg, 5.37mmol), heated to 100 deg.C, and stirred for 16H. Filtration was performed, water (30mL) was added, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) ═ 1:1) to give 2- ((3-chloro-5-cyanobenzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-D ] pyrimidine-6-carboxylic acid tert-butyl ester (compound 17D) as a pale yellow solid (150mg, yield 21.7%).

LC-MSm/z：386.2[M+H]⁺。

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

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

LC-MSm/z：286.2[M+H]⁺。

The fifth step: 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)

The starting material, 3-chloro-5- (((6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-yl) amino) methyl) benzonitrile dihydrochloride (compound 17E) (100mg, 0.28mmol) was added to N, N-dimethylformamide (4mL), followed by 2- (2- (1H-1,2, 3-triazol-4-yl) ethoxy) acetic acid (65mg, 0.42mmol), 1-propylphosphoric anhydride (225mg, 0.7mmol, 50% ethyl acetate solution), and N-methylmorpholine (70mg, 0.7mmol), and stirred at room temperature for 16H. Water (15mL) was added, and extraction was performed with ethyl acetate (15mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column separation (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) (40mg, yield 32%).

¹H 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)。

LC-MSm/z：439.0[M+H]⁺。

Example 18: synthesis of Compound 18

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)

The synthetic route for compound 18 is shown below:

the first step is as follows: synthesis of tert-butyl 2- ((3- (trifluoromethoxy) benzyl) -1-amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 18B)

The starting material, 3-trifluoromethoxybenzylamine (675mg, 3.5mmol), was added to N, N-dimethylformamide (10mL), tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (811mg, 3.2mmol) and cesium carbonate (2.3g, 7mmol) were added, heated to 90 ℃ and stirred for 16H. Water (50mL) was added, and extraction was performed with ethyl acetate (20mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 3:1) to give 2- ((3- (trifluoromethoxy) benzyl) -1-amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (compound 18B) as a yellow solid (380mg, yield 29%).

LC-MSm/z：411.1[M+H]⁺。

The second step is that: synthesis of N- (3- (trifluoromethoxy) benzyl)) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (Compound 18C)

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

LC-MSm/z：311.1[M+H]⁺。

The third step: 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)

The starting material, N- (3- (trifluoromethoxybenzyl)) 6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (compound 18C) (116mg, 0.30mmol), was added to N, N-dimethylformamide (4mL) and ethyl acetate (2mL), 1-propylphosphoric anhydride (176mg, 0.56mmol, 50% ethyl acetate solution), N-methylmorpholine (187mg, 1.85mmol) and 2- (2- (1H-1,2, 3-triazol-4-yl) ethoxy) acetic acid (63mg, 0.37mmol) were added, cooled to 0 ℃, stirred for 0.5H, allowed to spontaneously warm to room temperature, and stirred for 16H. Water (15mL) was added, extraction was performed with ethyl acetate (15mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column separation (dichloromethane: methanol (V/V) ═ 5:1) to give 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) (107mg, yield 77%).

¹H 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)。

LC-MSm/z：464.1[M+H]⁺。

Example 19: synthesis of Compound 19

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)

The synthetic route for compound 19 is shown below:

the first step is as follows: synthesis of tert-butyl 2- ((3-chlorobenzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 19B)

The starting material, 3-chlorobenzylamine (338mg, 2.4mmol), was added to N-methylpyrrolidinone (10mL), tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (500mg, 2.0mmol) and N, N-diisopropylethylamine (774mg, 6mmol) were added, heated to 90 ℃ and stirred for 16H. Water (50mL) was added, and extraction was performed with ethyl acetate (20mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 3:1) to give 2- ((3-chlorobenzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (compound 19B) as a yellow solid (570mg, yield 80.8%).

LC-MSm/z：361.4[M+H]⁺。

The second step is that: synthesis of N- (3- (chlorobenzyl)) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (Compound 19C)

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

LC-MSm/z：261.4[M+H]⁺。

The third step: 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)

The starting material N- (3-chlorobenzyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine (compound 19C) (110mg, 0.42mmol) was added to N, N-dimethylformamide (4mL) and ethyl acetate (2mL), 1-propylphosphoric anhydride (200mg, 0.63mmol, 50% ethyl acetate solution), N-methylmorpholine (212mg, 2.1mmol) and 2- (2- (1H-1,2, 3-triazol-4-yl) ethoxy) acetic acid (72mg, 0.42mmol) were added, cooled to 0 deg.C, stirred for 0.5H, allowed to spontaneously warm to room temperature, and stirred for 16H. Water (15mL) was added, extraction was performed with ethyl acetate (15mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column separation (dichloromethane: methanol (V/V) ═ 5:1) to give 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) (40mg, yield 23%).

¹H 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)。

LC-MSm/z：414.2[M+H]⁺。

Example 20: synthesis of Compound 20

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)

The synthetic route for compound 20 is shown below:

the first step is as follows: synthesis of 1- (3, 5-dichlorophenyl) ethane-1-amine (Compound 20B)

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

LC-MSm/z：190.1[M+H]⁺。

The second step is that: synthesis of tert-butyl 2- ((1- (3, 5-dichlorophenyl) ethyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 20C)

The starting material 1- (3, 5-dichlorophenyl) ethane-1-amine (compound 20B) (235mg, 1.2mmol) was added to N-methylpyrrolidone (3mL), tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (300mg, 1.2mmol) and N, N-diisopropylethylamine (453mg, 3.5mmol) were added, heated to 90 ℃ and stirred for 16H. Water (15mL) was added, and extraction was performed with ethyl acetate (20mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 3:1) to give 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) as a yellow liquid (117mg, yield 28.8%).

LC-MSm/z：409.1[M+H]⁺。

The third step: synthesis of N- (1- (3, 5-dichlorophenyl) ethyl) -6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (Compound 20D)

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

LC-MSm/z：309.1[M+H]⁺。

The fourth step: 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)

The starting material, N- (1- (3, 5-dichlorophenyl) ethyl) -6, 7-dihydro-5H-pyrrolo [3,4-D ] pyrimidin-2-amine dihydrochloride (compound 20D) (200mg, 0.52mmol), was added to N, N-dimethylformamide (4mL) and ethyl acetate (2mL), 1-propylphosphoric anhydride (515mg, 0.8mmol, 50% ethyl acetate solution), N-methylmorpholine (293mg, 2.9mmol) and 2- (2- (1H-1,2, 3-triazol-4-yl) ethoxy) acetic acid (119mg, 0.7mmol) were added, cooled to 0 deg.C, stirred for 0.5H, allowed to spontaneously warm to room temperature and stirred for 16H. Water (15mL) was added, and extraction was performed with ethyl acetate (15mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column separation (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) (6mg, yield 2.5%).

¹H NMR(400MHz,DMSO-d6)δ8.25(d,1H),7.88(dd,1H),7.64(s,1H),7.42(dt,3H),5.11-5.04(m,1H),4.50(dd,4H),4.17(d,2H),3.74(tt,2H),2.93(t,2H)1.42(d,3H)。

LC-MSm/z：462.1[M+H]⁺。

Example 21: synthesis of Compound 21

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)

The synthetic route for compound 21 is shown below:

the first step is as follows: synthesis of tert-butyl 2- ((4-chlorobenzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 21B)

The starting 4-chlorobenzylamine (282mg, 2.0mmol) was added to N-methylpyrrolidinone (10mL), tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (510mg, 2.0mmol) and N, N-diisopropylethylamine (1.03g, 8mmol) were added, heated to 90 ℃ and stirred for 16H. Water (50mL) was added, and extraction was performed with ethyl acetate (20mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 3:1) to give 2- ((4-chlorobenzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (compound 21B) as a yellow solid (300mg, yield 41.7%).

LC-MSm/z：361.4[M+H]⁺。

The second step is that: synthesis of N- (4-chlorobenzyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (Compound 21C)

The starting material tert-butyl 2- ((4-chlorobenzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (compound 21B) (105mg, 0.29mmol) was added to dichloromethane (6mL) at room temperature, followed by addition of a 4M solution of hydrogen chloride in 1, 4-dioxane (2mL) and stirring for 2H. Concentration gave N- (4-chlorobenzyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (compound 21C) as a yellow solid (90mg, 93% yield).

LC-MSm/z：261.4[M+H]⁺。

The third step: 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)

The starting material, N- (4-chlorobenzyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (compound 21C) (140mg, 0.42mmol), was added to N, N-dimethylformamide (4mL) and ethyl acetate (2mL), 1-propylphosphoric anhydride (262mg, 0.82mmol, 50% ethyl acetate solution), N-methylmorpholine (278mg, 2.75mmol) and 2- (2- (1H-1,2, 3-triazol-4-yl) ethoxy) acetic acid (90mg, 0.55mmol) were added, cooled to 0 ℃, stirred for 0.5H, allowed to spontaneously warm to room temperature, and stirred for 16H. Water (15mL) was added, extraction was performed with ethyl acetate (15mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column separation (dichloromethane: methanol (V/V) ═ 5:1) to give 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) (50mg, yield 29%).

¹H 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)。

LC-MSm/z：414.2[M+H]⁺。

Example 22: synthesis of Compound 22

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)

The synthetic route for compound 22 is shown below:

the first step is as follows: synthesis of tert-butyl 2- ((4- (trifluoromethoxy) benzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 22B)

The starting 4-trifluoromethoxybenzylamine (compound 22A) (100mg, 0.52mmol) was added to N, N-dimethylformamide (3mL), tert-butyl 2-chloro-5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (100mg, 0.45mmol) and cesium carbonate (255mg, 0.78mmol) were added, heated to 90 deg.C, and stirred for 16H. Water (50mL) was added, and extraction was performed with ethyl acetate (20mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 3:1) to give 2- ((4- (trifluoromethoxy) benzyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylic acid tert-butyl ester (compound 22B) as a yellow solid (12mg, yield 7.5%).

LC-MSm/z：411.1[M+H]⁺。

The second step is that: synthesis of N- (4- (trifluoromethoxy) benzyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (Compound 22C)

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

LC-MSm/z：311.1[M+H]⁺。

The third step: 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)

The starting material, N- (4- (trifluoromethoxybenzyl)) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (compound 22C) (113mg, 0.29mmol), was added to N, N-dimethylformamide (4mL) and ethyl acetate (2mL), 1-propylphosphoric anhydride (175mg, 0.55mmol, 50% ethyl acetate solution), N-methylmorpholine (185mg, 1.82mmol) and 2- (2- (1H-1,2, 3-triazol-4-yl) ethoxy) acetic acid (63mg, 0.37mmol) were added, cooled to 0 ℃, stirred for 0.5H, allowed to spontaneously warm to room temperature and stirred for 16H. Water (15mL) was added, and extraction was performed with ethyl acetate (15mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by silica gel column separation (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) (95mg, yield 70.7%).

¹H 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)。

LC-MSm/z：464.1[M+H]⁺。

Example 23: synthesis of Compound 23, Compound 24 and Compound 25

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)

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)

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)

The synthetic routes for compound 23, compound 24 and compound 25 are shown below:

the first step is as follows: synthesis of tert-butyl (2-phenylcyclopropyl) carbamate (Compound 23B)

Diphenyl azide phosphate (4.12g, 16.96mmol) was added to a solution of 2-phenylcyclopropanecarboxylic acid (2.5g, 15.41mmol) and triethylamine (1.716g, 16.96mmol) in t-butanol (19.42g, 262mmol) at 0 deg.C, the gas was replaced and the reaction was allowed to proceed overnight at 90 deg.C under nitrogen. After the reaction was monitored by TLC, distilled water (50mL) was added to dilute the solution, the solution was extracted with ethyl acetate (100mL × 3), the organic phases were combined, washed with saturated brine (10mL × 2), separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column (petroleum ether: ethyl acetate (V/V) ═ 10:1 to 1:1) to obtain (2-phenylcyclopropyl) carbamic acid tert-butyl ester (compound 23B) (2.28g, yield 63.4%) as a yellow solid.

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).

The second step is that: synthesis of 2-phenylcyclopropane-1-amine-2, 2, 2-trifluoroacetic acid (Compound 23C)

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

The third step: synthesis of tert-butyl 2- ((2-phenylcyclopropyl) amino) -5, 7-dihydro-6H-pyrrolo [3,4-d ] pyrimidine-6-carboxylate (Compound 23E)

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

LC-MSm/z：353.2[M+H]⁺。

The fourth step: synthesis of N- (2-phenylcyclopropyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (Compound 23F)

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

The fourth step: 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)

2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriophosphoric acid-2, 4, 6-trioxide (888mg,1.395mmol, 50% N, N-dimethylformamide solution) is added dropwise to a solution of N, N-dimethylformamide (10mL) containing N- (2-phenylcyclopropyl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-2-amine dihydrochloride (compound 23F) (378mg, 1.16mmol), 2- (2- (1H-1,2, 3-triazol-4-yl) ethoxy) acetic acid (239mg, 1.395mmol), N, N-diisopropylethylamine (2.030mL, 11.62mmol) at 0 ℃ and stirred at room temperature for 16 hours. After the reaction was completed by LCMS, distilled water (50mL) was added to dilute the solution, the solution was extracted with dichloromethane (100 mL. times.3), the organic phases were combined, the organic phase was washed with saturated brine (10 mL. times.2), separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was chromatographed 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) (96.0mg, yield 20.4%).

¹H 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)。

LC-MSm/z：406.4[M+H]⁺。

The fifth step: synthesis of Compound 24 and Compound 25

Compound 24 and compound 25 were obtained by SFC resolution.

Separation conditions are as follows: a column of Cellucoat 50 multiplied by 4.6mm I.D.,3 um; the mobile phase consists of mobile phase A and mobile phase B: mobile phase a was carbon dioxide and mobile phase B was methanol containing 0.05% diethylamine; gradient elution conditions: 40% mobile phase B, 60% mobile phase a; flow rate: 3 mL/min; wavelength: 220nm, column temperature: 35 ℃; column pressure: 100 Bar.

Peak 1:

¹H 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)。

LC-MSm/z：406.2[M+H]⁺。

peak 2:

¹H 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)。

LC-MSm/z：406.2[M+H]⁺。

examples of biological Activity and related Properties

Test example 1: autotaxin (ATX) enzyme activity inhibition assay

The inhibitory activity of the compound on the Autotaxin enzyme is detected by adopting an Autotaxin inhibition Screening Assay Kit (Cayman, 700580). Firstly, preparing a compound to be tested in a DMSO solvent10mM stock solution, then use DMSO gradient dilution 8 concentration points, then with kit provided Autotaxin Assay buffer (1 ×) will be 8 concentration points diluted into 19 x compound working solution (DMSO content of 1.9%). Autotaxin Assay Reagent (10X) was removed and diluted 10-fold with Autotaxin Assay Buffer (1X). The Autotaxin Substrate was removed, dissolved in 1.2mL Autotaxin Assay Buffer (1X), mixed, and allowed to stand at room temperature. In a 96-well plate, 150 μ L of Autotaxin Assay Buffer (1 ×), 10 μ L of diluted 19 × compound working solution, 10 μ L of Autotaxin Assay Reagent (1 ×), 20 μ L of dissolved Autotaxin Substrate, mixing, shaking at a constant temperature of 37 ℃ for 30min in a light-shielding manner; taking out the 96-well plate, and placing the 96-well plate on an enzyme labeling instrument to read OD 405; inputting the experimental result into GraphPad Prism software, and obtaining the IC of each compound through fitting calculation₅₀。

TABLE 1 results of the inhibitory Activity of the test Compounds on ATX enzymatic Activity

Experimental results show that the compound has good inhibitory activity on ATX enzyme.

Test example 2: human liver microsome stability test

The stability test of human liver microsome adopts compound and human liver microsome to incubate in vitro for detection. Test compounds were first formulated in DMSO solvent as 10mM stock solutions, followed by dilution of the compounds to 0.5mM using acetonitrile. Human liver microsomes (Corning) were diluted with PBS to a microsome/buffer solution, and 0.5mM compound was diluted with this solution to a working solution at a compound concentration of 1.5. mu.M and a human liver microsome concentration of 0.75 mg/ml. The reaction was initiated by adding 30. mu.L of the working solution to each well of a deep-well plate, and then 15. mu.L of a preheated 6mM NADPH solution, and incubated at 37 ℃. At 0 part of incubation,5. At 15, 30, 45 minutes, the reaction was stopped by adding 135. mu.L of acetonitrile to the corresponding well. After terminating the reaction with acetonitrile at the last 45 minute time point, the deep well plate was vortexed for 10 minutes (600rpm/min) and then centrifuged for 15 minutes. Centrifuging, taking the supernatant, adding purified water at a ratio of 1:1, performing LC-MS/MS detection to obtain the peak area of the compound at each time point and the peak area of an internal standard, comparing the peak area ratios of the compound at 5, 15, 30 and 45 minutes with the peak area ratio at 0 minute, calculating the residual percentage of the compound at each time point, and calculating T by using Excel_1/2。

Table 2 human liver microsome stability test results

The experimental result shows that the compound of the invention shows more excellent liver metabolic stability, is metabolized more slowly in human body and has higher exposure.

Test example 3: pharmacokinetic testing

In vivo pharmacokinetic experiments in mice, male mice, 6, 25-30g, were fasted overnight. 3 rats were orally administered with 10mg/kg by gavage, and blood was collected before and 15, 30 minutes and 1,2, 4, 8, 24 hours after administration. Another 3 mice were administered 1mg/kg by intravenous injection and blood was collected before administration and at 5, 15, 30 minutes and 1,2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 8000 rpm for 6 minutes at 4 ℃ and plasma was collected and stored at-20 ℃. And (3) adding 3-5 times of acetonitrile solution containing an internal standard into the plasma at each time point, mixing, carrying out vortex mixing for 1 minute, centrifuging at 4 ℃ for 10 minutes at 13000 rpm, taking supernatant, adding 3 times of water, mixing, and taking a proper amount of mixed solution to carry out LC-MS/MS analysis. The major pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model.

TABLE 3 results of in vivo pharmacokinetic experiments in mice

The experimental result shows that the compound of the invention shows more excellent pharmacokinetic properties.

Claims (12)

1. A compound which is a compound of formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of formula (I):

wherein:

R¹、R²、R³or R⁴Independently selected from-H, -CN, halogen, unsubstituted or optionally substituted by one or more R^aSubstituted of the following groups: c_1-6Alkyl radical, C_3-6A cycloalkyl group; the R is^aSelected from halogen, C_1-6Alkyl, preferably said R^aSelected from-F, -Cl, methyl, ethyl, propyl;

each R⁵Independently selected from H, -CN, halogen, unsubstituted or optionally substituted by one or more R^bSubstituted of the following groups: c_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6A cycloalkyl group; the R is^bSelected from halogen, C_1-6Alkyl, preferably said R^bSelected from-F, -Cl, methyl, ethyl, propyl;

M¹、M²、M³、M⁴、M⁵at least 1 of which is-C (R)⁶) or-CH, the remainder being-N (R)⁷) -or-N ═ and at least 1 is-N (R)⁷) -or-N ═ N;

R⁶and R⁷The same or different, are independently selected from: absent, -H, -CN, halogen, unsubstituted or optionally substituted by one or more R^cSubstituted of the following groups: c_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6A cycloalkoxy group; the R is^cSelected from halogen, C_1-6Alkyl, preferably said R^cSelected from-F, -Cl, methyl, ethyl, propyl;

preferably, R⁶And R⁷Independently selected from the group consisting of absent, -H, -CH₃、-CH₂CH₃、-CH₂CH₂CH₃、

-F、-Cl、-Br、-CF₃(ii) a More preferably, R⁶And R⁷Independently selected from the group consisting of absent, -H, -CH₃、-F、-Cl、-CF₃；

Z is selected from-O-, -S-),

L is a single bond, or is selected from unsubstituted or optionally substituted with one or more R^dSubstituted of the following groups: c_1-10Straight chain alkylene group, C_3-10Cycloalkylene, 3-10 membered heterocyclylene; the R is^dSelected from halogen, methyl, ethyl, cyclopropyl;

preferably, L is unsubstituted or optionally substituted with one or more R^dSubstituted of the following groups: methylene, ethylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, azetidinylene, methylene-cyclopropylene, methylene-cyclobutylene, methylene-cyclopentylene, methylene-cyclohexylene, methylene-azetidinylene;

q is unsubstituted or optionally substituted by one or more R⁵Substituted of the following groups: c₃-C₁₀Cycloalkyl, 3-10 membered heterocyclyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl; preferably, Q is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, t,Piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl; more preferably, Q is selected from the group consisting of benzene rings;

m is an integer from 0 to 6; n is an integer from 0 to 6; p is selected from an integer of 0 to 5.

2. The compound of claim 1, wherein:

M¹、M²、M³、M⁴、M⁵at least 2 or 3 of which are-C (R)⁶) or-CH, the remainder being-N (R)⁷) -or-N ═ and at least 1 is-N (R)⁷) -or-N ═ N;

preferably, the first and second electrodes are formed of a metal,

is selected from

Wherein M is³And M⁵Independently selected from-C (R)⁶) -CH ═ or-NH ═ or;

more preferably still, the first and second liquid crystal compositions are,

is selected from

3. The compound of claim 1, wherein:

m is 0, 1 or 2; n is 0, 1 or 2;

R¹、R²、R³or R⁴Independently selected from-H, -CN, unsubstituted orOptionally substituted by 1-3C_1-3Alkyl radical R^aSubstituted of the following groups: methyl, ethyl, n-propyl, isopropyl; the R is^aSelected from-F, -Cl, C_1-3An alkyl group;

more preferably, each R¹、R²、R³Or R⁴Independently selected from-H, -CH₃、-CH₂CH₃、-CH₂CH₂CH₃。

4. The compound of claim 1, wherein:

is selected from

5. The compound of claim 1, wherein L is selected from:

6. the compound of claim 1, wherein:

p is 0, 1 or 2;

each R⁵Independently selected from H, -CN, -F, -Cl, -Br, -CH₃、-CF₃、-OCHF₂、-OCF₃、-CH₂CH₃、-CH₂CH₂CH₃、

Preferably, each R⁵Independently selected from-H, -CN, -F, -Cl, -Br, -CF₃、-OCF₃、-OCHF₂。

7. The compound of claim 1, wherein:

is selected from

8. A compound of the formula, a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate, or prodrug thereof:

9. a compound of the formula, a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate, or prodrug thereof:

10. a pharmaceutical composition comprising a compound of any one of claims 1 to 9, a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate, or prodrug thereof.

11. Use of a compound according to any one of claims 1 to 9, a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition according to claim 10, for the manufacture of a medicament for the treatment of a disease associated with ATX.

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

optionally, wherein said ATX-related disease is selected from interstitial lung disease, pulmonary fibrosis, liver fibrosis, kidney fibrosis, preferably, from idiopathic pulmonary fibrosis;

optionally, wherein said ATX-related disorder is selected from metabolic disorders, preferably, from type II diabetes, non-alcoholic steatohepatitis;

optionally, wherein said ATX-related disorder is selected from neuropathic pain, inflammatory pain, preferably, from osteoarthritis-related pain;

optionally, wherein the ATX-related disease is selected from cancer.