CN113943275A - Pyrimidine compound and application thereof - Google Patents

Abstract

The invention provides a pyrimidine compound and application thereof, and specifically provides a novel compound for effectively inhibiting ATX, which is a compound shown in the following formula, or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound shown in the following formula:

Description

Pyrimidine compound and application thereof

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a pyrimidine compound, and more particularly relates to a pyrimidine compound and application thereof in preparation of a medicament.

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, when no longer needed, 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 novel ATX inhibitor with superior pharmacokinetic properties, better drug efficacy and strong drug potency for the treatment of ATX-related diseases and disorders, including but not limited to cancer, metabolic diseases, kidney diseases, liver diseases, fibrotic diseases, interstitial lung diseases, pulmonary fibrosis, hepatic fibrosis, proliferative diseases, inflammatory diseases, pain, osteoarthritis-related pain, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders and/or abnormal angiogenesis-related diseases.

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 of formula (I), a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate, or prodrug thereof:

wherein,

R¹、R²、R³、R⁴identical or different, independently of one another, from the group consisting of hydrogen, halogen, -CN, -OH, -SH, -NO₂Unsubstituted or optionally substituted by one or more R^aSubstituted of the following groups: c₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl, 3-10 membered heterocyclyl, C₁-C₁₀Alkoxy radical, C₃-C₁₀Cycloalkyloxy, 3-10 membered heterocyclyloxy, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl; c₆-C₁₀Aryloxy, 5-10 membered heteroaryloxy;

x, Y are identical or different and are each independently selected from-N ═ C (R)⁶) -; z is independently selected from-O-, -S-, -C (R)⁷)(R⁸)-、-N(R⁹)-、-N(R⁹)-C(R⁷)(R⁸)-；

Q is selected from C₃-C₁₀Cycloalkyl, 3-10 membered heterocyclyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl;

each R⁵Are identical or different and are each independently selected from hydrogen, halogen, -CN, C,-OH、-SH、-NO₂Unsubstituted or optionally substituted by one or more R^bSubstituted of the following groups: c₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl, 3-10 membered heterocyclyl, C₁-C₁₀Alkoxy radical, C₃-C₁₀Cycloalkyloxy, 3-10 membered heterocyclyloxy, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl; c₆-C₁₀Aryloxy, 5-10 membered heteroaryloxy;

each R^a、R^bIdentical or different, independently of one another, from the group formed by-F, -Cl, -Br, -I, -OH, -CN, -O, NO₂、--NH₂、C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkenyloxy radical, C₂-C₁₀Alkynyl, C₂-C₁₀Alkynyloxy, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Cycloalkyloxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C₆-C₂₀Aryl radical, C₆-C₂₀Aryloxy, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy;

n¹、n²m is independently selected from the integer 0, 1,2,3, 4, 5 or 6;

M¹、M²、M³、M⁴、M⁵independently selected from-N ═ N (R)¹⁰)-、-CH＝、-C(R¹¹) Wherein M is¹、M²、M³、M⁴、M⁵At least one of which is selected from-N or-N (R)¹⁰) -, and M¹、M²、M³、M⁴、M⁵At least one of which is selected from-CH or-C (R)¹¹)＝；

L is selected from

Wherein p1, p2, p3, p4, q1, q2, q3 and q4 are independently selected from integers of 0, 1,2,3, 4, 5 or 6, and p3 and p4 are not 0 at the same timeQ1 and q2 are not 0 at the same time, and q3 and q4 are not 0 at the same time;

R⁶、R⁷、R⁸、R¹¹、R¹²、R¹³independently selected from hydrogen, halogen, -CN, -OH, -SH, -NO₂、C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl, 3-10 membered heterocyclyl, C₁-C₁₀Alkoxy radical, C₃-C₁₀Cycloalkyloxy, 3-10 membered heterocyclyloxy, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl; c₆-C₁₀Aryloxy, 5-10 membered heteroaryloxy;

R⁹、R¹⁰independently selected from hydrogen, C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl, 3-10 membered heterocyclyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl;

and the compounds do not include the following compounds or tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof:

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

In some embodiments of the invention, in the compound of formula (I), R⁵Selected from the group consisting of-H, -F, -Cl, methyl, ethyl, difluoromethoxy, with the remaining variables as defined herein.

In some aspects of the inventionIn the compounds of the formula (I), M₁、M₂、M₃Are all selected from-N or-N (R)¹⁰)-，M⁴、M⁵Are all selected from-CH or-C (R)¹¹) The remaining variables are as defined herein.

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

in the formula (II), the compound is shown in the specification,

R¹、R²、R³、R⁴independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆A cycloalkyl group;

x, Y are identical or different and are each independently selected from-N ═ C (R)⁶)-；R⁶Independently selected from hydrogen, fluorine, chlorine, methyl, ethyl;

n¹、n²independently selected from the integers 0, 1, 2;

M¹、M²、M³independently selected from-N ═ N (R)¹⁰) -, wherein R¹⁰Selected from hydrogen, C₁-C₆Alkyl or C₃-C₆Cycloalkyl radicals

L is selected from

Wherein p1, p2, p3, p4, q1, q2, q3 and q4 are independently selected from integers of 0, 1 and 2, p3 and p4 are not 00 at the same time, q1 and q2 are not 0 at the same time, and q3 and q4 are not 0 at the same time;

and the compounds do not include the following compounds or tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof:

in some of the present inventionIn the compounds of the formula (II), M¹、M²、M³Are each selected from-N-or-NH-, the remaining variables being as defined herein.

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

in the formula (III), the compound represented by the formula (III),

R¹、R²、R³、R⁴independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆A cycloalkyl group;

R⁵independently selected from hydrogen, -CN, halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen substituted C₁-C₆An alkoxy group;

x, Y are identical or different and are each independently selected from-N ═ C (R)⁶)-；R⁶Independently selected from hydrogen, fluorine, chlorine, methyl, ethyl;

n¹、n²independently selected from the integers 0, 1, 2;

M¹、M²、M³independently selected from-N ═ N (R)¹⁰) -, wherein R¹⁰Selected from hydrogen, C₁-C₆Alkyl or C₃-C₆A cycloalkyl group;

l is selected from

Wherein p1, p2, p3, p4, q1, q2, q3 and q4 are independently selected from integers of 0, 1 and 2, p3 and p4 are not 0 at the same time, q1 and q2 are not 0 at the same time, and q3 and q4 are not 0 at the same time;

and the compounds do not include the following compounds or tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof:

in some embodiments of the invention, in the compound of formula (III), M¹、M²、M³Are each selected from-N-or-NH-, the remaining variables being as defined herein.

According to an embodiment of the invention, the compound of the invention comprises a compound of the formula, or at least one of a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound of the formula:

according to an embodiment of the invention, the compound of the invention comprises a compound of the formula, or at least one of a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound of the 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, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formulae (I) to (III) 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) to formula (III), a pharmaceutically acceptable salt, a tautomer, a stereoisomer, a hydrate, a solvate, or a prodrug thereof, or a pharmaceutical composition containing a compound represented by formula (I) to formula (III) or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, a hydrate, a solvate, or a prodrug thereof, for use in the preparation of 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 the group consisting of interstitial lung disease, pulmonary fibrosis, hepatic fibrosis and renal fibrosis.

In some embodiments of the invention, wherein the ATX-related disorder is selected from 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, wherein the ATX-related disease is selected from the group consisting of type II diabetes and nonalcoholic 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.

In some embodiments of the invention, wherein the ATX-related disorder is selected from the group consisting of osteoarthritis-related pain. 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, the person skilled in the art can useThe groups and their substituents are selected to provide stable moieties and compounds. When a substituent is described by a general formula written from left to right, 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 "C₁-C₁₀Alkyl "is understood to mean a straight-chain or branched, saturated monovalent hydrocarbon radical having 1,2,3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutylCyclobutyl and the like or their isomers. In particular, the radicals have 1,2,3, 4, 5, 6 carbon atoms ("C)₁-C₆Alkyl groups) such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly groups having 1,2 or 3 carbon atoms ("C)₁-C₃Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.

The term "C₃-C₁₀Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decaline ring.

The term "3-10 membered heterocyclyl" is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 3 to 10 atoms, wherein 1,2,3, 4 or 5 ring atoms are selected from N, O and S, which may be connected through carbon or nitrogen, unless otherwise indicated, wherein-CH_2-The group is optionally replaced by-C (O) -; and wherein unless otherwise stated to the contrary, the ring nitrogen atom or the ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or the ring nitrogen atom is optionally quaternized; wherein-NH in the ring is optionally substituted with acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted with one or more halogens. It is understood that when the total number of S and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclyl is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclic group is monocyclic, it is not necessarily aromatic. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1, 1-dioxide1H-pyridin-2-one and 2, 5-dioxoimidazolidinyl.

The term "C₂-C₁₀Alkenyl "is understood to mean a straight-chain or branched monovalent hydrocarbon radical comprising one or more double bonds and having 2,3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example having 2,3, 4, 5 or 6 carbon atoms (i.e. C)₂-C₆Alkenyl) having 2 or 3 carbon atoms (i.e., C)₂-C₃Alkenyl). It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, m-n-2-enyl, m-n-1-enyl, m-n-E-4-enyl, m-n-2-enyl, m-n-enyl, m-E-4-enyl, m-2-enyl, m-pent-1-enyl, m-2-methyl-enyl, m-2-methylvinyl, m-2-methyl-2-methylvinyl, m-but-2-enyl, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex-2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E) -1-methylprop-1-enyl, (Z) -1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, (E) -1-methylbut-2-enyl, (Z) -1-methylbut-2-enyl, (E) -3-methylbut-1-enyl, (Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1-enyl, (E) -1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl group and 1-isopropylvinyl group.

The term "C₂-C₁₀Alkynyl "is understood to mean a straight-chain or branched monovalent hydrocarbon radical comprising one or more triple bonds and having 2,3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example having 2,3, 4, 5 or 6 carbon atoms (i.e." C ")₂-C₆Alkynyl ") having 2 or 3 carbon atoms (" C)₂-C₃Alkynyl "). Said alkynyl is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, 1-methylpropan-2-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, pent-3-ynyl, pent-2-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

The term "C₁-C₁₀Alkoxy "is to be understood as meaning-O- (C)₁-C₁₀Alkyl) in which "C" is₁-C₁₀Alkyl "has the above definition.

The term "C₆-C₁₀Aryl is to be understood as meaning a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partially aromatic character of 6 to 10 carbon atoms, in particular a ring having 6 carbon atoms ("C₆Aryl "), such as phenyl; or biphenyl, or is a ring having 9 carbon atoms ("C₉Aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C₁₀Aryl), such as tetralinyl, dihydronaphthyl, or naphthyl. When said C is₆-C₁₀When the aryl group is substituted, it may be mono-or polysubstituted. And, the substitution site thereof is not limited, and may be, for example, ortho-, para-or meta-substitution.

The term "C₆-C₁₀Aryloxy is understood to mean-O- (C)₆-C₁₀Aryl) in which C₆-C₁₀Aryl has the above definition.

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

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

The term "halo" or "halogen" is fluorine, chlorine, bromine and iodine.

"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.

Advantageous effects

According to the specific examples of the present invention, the compounds represented by the formulae (I) to (III) of the present invention, pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates or prodrugs thereof have significant inhibitory effects on ATX enzyme.

According to a specific example of the present invention, the compounds of the present invention are effective in inhibiting ATX enzymatic activity.

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 compounds represented by formulae (I) to (III), pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals, or prodrugs thereof, methods and intermediates for preparing compounds represented by formulae (I) to (III), or pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, co-crystals, or prodrugs thereof, pharmaceutical compositions, and uses of the compounds and pharmaceutical compositions of the present invention in preparing medicaments.

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

DIBAL-H: diisobutylaluminum hydride

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

DMF: n, N-dimethylformamide

DMSO, DMSO: dimethyl sulfoxide

Et₃N: triethylamine

HATU: 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

HPLC: high performance liquid chromatography

MeOH: methanol

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, also known as N-methylmorpholine

NMP: n-methyl pyrrolidone

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)

TMSN₃: azidotrimethylsilane

TsCl: p-toluenesulfonyl chloride

IC₅₀: half inhibitory concentration, meaning maximum inhibitionConcentration at half the effect.

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

Preparation example 1: preparation of intermediate 2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidine-5-carboxylic acid

The first step is as follows: 2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidine-5-carboxylic acid methyl ester

The starting material methyl 2-chloropyrimidine-5-carboxylate (2.2g,12.7mmol) was added to 50ml dioxane, 2, 3-dihydro-1H-indene-2-amine hydrochloride (2.27g,13.4mmol) and DIPEA (3.2g,31.7mmol) were added at room temperature, heated to 100 ℃ and stirred for 15H. After cooling to room temperature, water (50ml) was added to the reaction solution, and extraction was performed with ethyl acetate (50ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 4:1) to give the title compound methyl 2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidine-5-carboxylate (a) (2.6g, yield 75.5%) as a pale yellow solid.

LC-MSm/z：270.1[M+H]⁺。

The second step is that: 2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidine-5-carboxylic acid

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

LC-MSm/z：256.1[M+H]⁺。

Example 1: preparation of object Compound 001-1

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

the first step is as follows: synthesis of (1R,5S,6R) -6- (hydroxymethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (001B)

The starting material (1R,5S,6R) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid (500mg,2.2mmol) was added to 5ml of THF, lithium aluminum hydride (125mg,3.2mmol) was added thereto at room temperature, and the mixture was stirred at room temperature for 24 hours. Water (0.13ml) was added to the reaction solution, and 15% aqueous sodium hydroxide solution (0.13ml) was added to the reaction solution, followed by addition of 0.36ml of water, filtration and concentration to give the title compound tert-butyl (001B) 6- (hydroxymethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate (213mg, 61.6% yield) as a pale yellow liquid.

LC-MSm/z：158.1[M+H]⁺。

The second step is that: synthesis of tert-butyl (1R,5S,6R) -6- ((propan-2-yn-1-yloxy) methyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate (001C)

The starting material tert-butyl (1R,5S,6R) -6- (hydroxymethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate (2.0g,9.4mmol) was added to 35ml THF at room temperature, 60% NaH (560mg,14mmol) was added at room temperature, stirring was carried out at 0 ℃ for 0.5h, 3-bromopropyne (1.3ml,14.1mmol) was added, and stirring was carried out at room temperature for 16 h. The reaction mixture was added with water (50ml), extracted with ethyl acetate (30ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 4:1) to give the title compound tert-butyl (1R,5S,6R) -6- ((propane-2-yn-1-yloxy) methyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate (001C) as a pale yellow liquid (1.2g, 50.8% yield).

LC-MSm/z：252.1[M+H]⁺。

The third step: (1R,5S,6R)6- (((2H-1,2, 3-Triazol-4-yl) methoxy) methyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester

Tert-butyl (1.20g,4.78mmol) of the starting material (1R,5S,6R) -6- ((propan-2-yn-1-yloxy) methyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate was added to 10ml of DMF and 2ml of methanol, cuprous iodide (109mg,0.57mmol) and azidotrimethylsilane (824mg,7.17mmol) were added under nitrogen, heated to 110 ℃ and stirred for 16 h. After cooling to room temperature, water (50ml) was added, and the reaction solution was extracted with ethyl acetate (50ml × 3), concentrated, and the residue was purified by silica gel column separation (dichloromethane: methanol (V/V) ═ 10:1) to give the title compound (1R,5S,6R)6- (((2H-1,2, 3-triazol-4-yl) methoxy) methyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (001D) (1.50g, yield 100%) as a yellow liquid.

LC-MSm/z：295.2[M+H]⁺。

The fourth step: (1R,5S,6R)6- (((2H-1,2, 3-triazol-4-yl) methoxy) methyl) -3-azabicyclo [3.1.0] hexane

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

LC-MSm/z：195.1[M+H]⁺。

The fifth step: ((1R,5S,6R) -6- (((2H-1,2, 3-triazol-4-yl) methoxy) methyl) -3-azabicyclo [3.1.0] hex-3-yl) (2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl) methanone

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

¹H NMR(400MHz,DMSO-d6)δ8.47(s,2H),7.99(d,1H),7.81(s,1H),7.21(dt,2H),7.16-7.13(m,2H),4.65(dt,1H),4.53(s,2H),3.93(s,1H),3.79(s,1H),3.54(s,1H),3.34(d,4H),3.25(dd,2H),2.91(dd,2H),1.52(s,2H),0.81(dt,1H)。

LC-MSm/z：432.0[M+H]⁺。

Example 2: preparation of target Compound 002

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

The synthetic route of the target compound 002-1 is shown below:

the first step is as follows: (3aR,5r,6aS) -5-Hydroxyhexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (002B)

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

LC-MSm/z：228.1[M+H]⁺。

The second step is that: (3aR,5r,6aS) -5- (propane-2-yn-1-yloxy) hexahydrocyclopenta [ C ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (002C)

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

LC-MSm/z：266.1[M+H]⁺。

The third step: (3aR,5r,6aS) -5- ((1H-1,2, 3-triazol-4-yl) methoxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (002D)

The starting material tert-butyl (3aR,5r,6aS) -5- (propan-2-yn-1-yloxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (80mg,0.3mmol) was added to 2.5ml DMF and 0.5ml methanol, cuprous iodide (7mg,0.04mmol) and azidotrimethylsilane (52mg,0.45mmol) were added under nitrogen, heated to 110 ℃ and stirred for 16H. Cooled to room temperature, water (20ml) was added, and the reaction solution was extracted with ethyl acetate (20ml × 3) and concentrated to give the title compound (3aR,5r,6aS) -5- ((1H-1,2, 3-triazol-4-yl) methoxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester crude product (002D) (65mg, yield 69.9%).

LC-MSm/z：309.1[M+H]⁺。

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

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

LC-MSm/z：209.1[M+H]⁺。

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

The starting material (3aR,5r,6aS) -5- ((1H-1,2, 3-triazol-4-yl) methoxy) octahydrocyclopenta [ c ] pyrrole (50mg,0.2mmol) was added to 2ml DMF and 1ml ethyl acetate followed by 2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidine-5-carboxylic acid (73mg,0.3mmol), 1-propylphosphoric anhydride (214mg,0.3mmol) and N-methylmorpholine (121mg,1.2mmol), and stirred at 0 ℃ for 16H. After warming to 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 the title compound ((3aR,5r,6aS) -5- ((1H-1,2, 3-triazol-4-yl) methoxy) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) (2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl) methanone (14mg, yield 13.1%).

¹H NMR(400MHz,DMSO-d6)δ8.46(s,2H),7.98(d,1H),7.78(s,1H),7.22(dd,2H),7.16-7.13(m,2H),4.66(dt,1H),4.51(d,2H),4.02-3.99(m,1H),3.71(s,2H),3.49(d,2H),3.34-3.22(m,3H),2.91(dd,2H),2.62(s,2H),2.07-1.99(m,2H),2.14(s,2H)。

LC-MSm/z：446.3[M+H]⁺。

Example 3: preparation of target Compound 002-2

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

the first step is as follows: (3aR,5s,6aS) -5- ((4-nitrobenzoyl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (002-2B)

The starting material (3aR,5s,6aS) -5-Hydroxyhexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (500mg,2.2mmol) was added to 10ml THF, 4-nitrobenzoic acid (735mg,4.4mmol), triphenylphosphine (1.1g,4.4mmol) were added, cooled to 0 deg.C, stirred for 0.5H, DEAD (766mg,4.4mmol) was added, and stirred at 0 deg.C for 24H. Water (40ml) was added to the reaction solution, extracted with ethyl acetate (40ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 10:1) to give the title compound (3aR,5s,6aS) -5- ((4-nitrobenzoyl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (003B) aS a pale yellow liquid (470mg, 56.7% yield).

LC-MSm/z：377.1[M+H]⁺。

The second step is that: (003C) (3aR,5s,6aS) -5-Hydroxyhexahydrocyclopenta [ C ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (002-2C)

The starting material tert-butyl (3aR,5s,6aS) -5- ((4-nitrobenzoyl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (470mg,1.25mmol) was added to 15ml methanol and 5ml water, potassium carbonate (345mg,2.5mmol) was added and stirred at room temperature for 16H. The reaction mixture was filtered, concentrated, water (20ml) was added, extraction was performed with ethyl acetate (20ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) ═ 1:1) to give the title compound (3aR,5s,6aS) -5-hydroxyhexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester aS a pale yellow liquid (265mg, yield 93.4%)

LC-MSm/z：228.1[M+H]⁺。

The third step: (3aR,5s,6aS) -5- (propane-2-yn-1-yloxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (002-2D)

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

LC-MSm/z：266.1[M+H]⁺。

The fourth step: (3aR,5s,6aS) -5- ((1H-1,2, 3-triazol-4-yl) methoxy) hexahydrocyclopentan [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (002-2E)

The starting material tert-butyl (3aR,5s,6aS) -5- (propan-2-yn-1-yloxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (200mg,0.7mmol) was added to 5ml DMF and 1ml methanol, copper iodide (17mg,0.1mmol) and azidotrimethylsilane (130mg,0.45mmol) were added under nitrogen, heated to 110 ℃ and stirred for 16H. Cooled to room temperature, water (20ml) was added, and the reaction solution was extracted with ethyl acetate (20ml × 3) and concentrated to give the title compound (3aR,5s,6aS) -5- ((1H-1,2, 3-triazol-4-yl) methoxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester crude product (003E) (200mg, yield 86.0%) aS a yellow liquid.

LC-MSm/z：309.1[M+H]⁺。

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

Crude (200mg,0.65mmol) of crude (3aR,5s,6aS) -5- ((1H-1,2, 3-triazol-4-yl) methoxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester is added to 2ml dichloromethane and 2ml methanol at room temperature, 4mol/L dioxane hydrochloride solution (1ml) is added, and the mixture is stirred at 10 ℃ for 4H. The reaction was concentrated to give the title compound (3aR,5s,6aS) -5- ((1H-1,2, 3-triazol-4-yl) methoxy) octahydrocyclopenta [ c ] pyrrole crude product (003E) aS a yellow solid (190mg, 100% yield).

LC-MSm/z：209.1[M+H]⁺。

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

The starting material (3aR,5s,6aS) -5- ((1H-1,2, 3-triazol-4-yl) methoxy) octahydrocyclopenta [ c ] pyrrole (100mg,0.2mmol) was added to 4ml DMF and 2ml ethyl acetate followed by 2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidine-5-carboxylic acid (147mg,0.6mmol), 1-propylphosphoric anhydride (428mg,0.7mmol) and N-methylmorpholine (243mg,2.4mmol), and stirred at 0 ℃ for 16H. Water (30ml) was added to warm to room temperature, extracted with ethyl acetate (30ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and the residue was prepared to give the title compound ((3aR,5s,6aS) -5- ((1H-1,2, 3-triazol-4-yl) methoxy) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) (2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl) methanone (26mg, 12.1%).

¹H NMR(400MHz,DMSO-d6)δ8.49(s,2H),8.00(d,1H),7.79(s,1H),7.21(dt,2H),7.16-7.13(m,2H),4.70-4.61(m,1H),4.48(s,2H),4.11(s,1H),3.69(s,2H),3.36(s,2H),3.25(dd,3H),2.91(dd,2H),2.74(s,2H),1.90(d,2H),1.63(s,2H)。

LC-MSm/z：446.3[M+H]⁺。

Example 4: preparation of target Compound 003

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

The synthetic route for the target compound 003 is shown below:

the first step is as follows: synthesis of 2- ((3- (difluoromethoxy) benzyl) amino) pyrimidine-5-carboxylic acid (003B)

2-Chloropyrimidine-5-carboxylic acid (2g, 12.61mmol), (3- (difluoromethoxy) phenyl) methylamine (3.28g, 18.92mmol), N, N-diisopropylethylamine (4.89g, 37.8mmol) was dissolved in N-methylpyrrolidone (10mL) and heated to 100 ℃ for 20 h. Cooled to room temperature, the reaction was concentrated, the residue was slurried with isopropyl acetate (30mL), filtered, the cake rinsed with water (30mL) and dried at 45 ℃ for 2h to give 2- ((3- (difluoromethoxy) benzyl) amino) pyrimidine-5-carboxylic acid (003B) as a yellow solid (3g, 81% yield).

LC-MSm/z：296.2[M+H]⁺。

The second step is that: synthesis of tert-butyl 6- (prop-2-yn-1-yloxy) -2-azaspiro [3.3] heptane-2-carboxylate (003D)

Tert-butyl 6-hydroxy-2-azaspiro [3.3] heptane-2-carboxylate (1g, 4.69mmol) was dissolved in tetrahydrofuran (5mL), cooled to 0 deg.C, sodium hydride (188mg, 4.69mmol, 60%) was added, followed by dropwise addition of 3-bromopropyne (0.837g, 7.03mmol), and after completion of the addition, the reaction was carried out at room temperature for 18 hours. Quenched with saturated ammonium chloride solution (30mL), extracted with ethyl acetate (20 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 6- (prop-2-yn-1-yloxy) -2-azaspiro [3.3] heptane-2-carboxylate (003D) (1.2g) as a yellow liquid.

The third step: synthesis of 6- (prop-2-yn-1-yloxy) -2-azaspiro [3.3] heptane hydrochloride (003E)

To tert-butyl 6- (prop-2-yn-1-yloxy) -2-azaspiro [3.3] heptane-2-carboxylate (003D) (1.2g, 4.77mmol) was added hydrogen chloride dioxane solution (10mL), and the reaction was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to give a crude product which was used in the next reaction without purification.

The fourth step: synthesis of (2- ((3- (difluoromethoxy) benzyl) amino) pyrimidin-5-yl) (6- (prop-2-yn-1-yloxy) -2-azaspiro [3.3] hept-2-yl) methanone (003F)

To crude 6- (prop-2-yn-1-yloxy) -2-azaspiro [3.3] heptane hydrochloride (003E) (636mg, 3.39mmol) in the previous step was added N, N-dimethylformamide (10mL), N, N-diisopropylethylamine (1.094g, 8.47mmol), 2- ((3- (difluoromethoxy) benzyl) amino) pyrimidine-5-carboxylic acid (003B) (500mg, 1.694mmol), the reaction was cooled to about 0 deg.C, 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphate-2, 4, 6-trioxide (1.617g, 2.54mmol, 50% N, N-dimethylformamide solution) was added dropwise, and the reaction was completed at room temperature for 18 h. The reaction solution was quenched with water (100mL), extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 1:1) to give (2- ((3- (difluoromethoxy) benzyl) amino) pyrimidin-5-yl) (6- (prop-2-yn-1-yloxy) -2-azaspiro [3.3] hept-2-yl) methanone (003F) (400mg, 55.1% yield) as a white solid.

LC-MSm/z：429.4[M+H]⁺。

The fifth step: synthesis of (6- ((1H-1,2, 3-triazol-4-yl) methoxy) -2-azaspiro [3.3] hept-2-yl) (2- ((3- (difluoromethoxy) benzyl) amino) pyrimidin-5-yl) methanone (003)

(2- ((3- (difluoromethoxy) benzyl) amino) pyrimidin-5-yl) (6- (prop-2-yn-1-yloxy) -2-azaspiro [3.3] hept-2-yl) methanone (003F) (400mg, 0.934mmol) was dissolved in N, N-dimethylformamide (8mL) and methanol (2mL) under nitrogen, sodium L-ascorbate (370mg, 1.867mmol) was added, azidotrimethylsilane (1.08g, 9.34mmol) and copper sulfate pentahydrate (93mg, 0.373mmol) were added, and the mixture was heated to 90 ℃ for reaction for 4 hours. The reaction was cooled to room temperature, water (40mL) was added, extraction was performed with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was isolated and purified by silica gel plate to give (6- ((1H-1,2, 3-triazol-4-yl) methoxy) -2-azaspiro [3.3] hept-2-yl) (2- ((3- (difluoromethoxy) benzyl) amino) pyrimidin-5-yl) methanone (compound 003) (62.9mg, yield 14.3%).

¹H NMR(400MHz,DMSO-d6)δ8.30(s,2H),8.14(t,1H),7.76(s,1H),7.32–7.26(m,1H),7.11(d,2H),7.04(s,1H),7.00–6.91(m,1H),4.54(s,2H),4.48(d,2H),3.78–3.55(m,3H),3.21–3.14(m,2H),1.78(s,2H),1.49–1.37(m,2H)。

LC-MSm/z：472.3[M+H]⁺。

Example 5: preparation of target Compound 004

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

The route of the synthesis of 004 is shown below:

the first step is as follows: synthesis of 6- (tosyloxy) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (004B)

6-hydroxy-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (004A) (2g, 9.38mmol) was dissolved in dichloromethane (30mL), triethylamine (1.898g, 18.76mmol), 4-dimethylaminopyridine (573mg, 4.69mmol) were added, the temperature was reduced to 0 ℃ and p-toluenesulfonyl chloride (2.145g, 11.25mmol) was added in portions, and the mixture was warmed to room temperature for 18 h. After quenching with water (50mL), the layers were separated, the aqueous phase was extracted with dichloromethane (30mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 5:1) to give tert-butyl 6- (toluenesulfonyloxy) -2-azaspiro [3.3] heptane-2-carboxylate (004B) as a white solid (3.2g, 93% yield).

The second step is that: synthesis of 6- (but-3-yn-1-yloxy) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (004C)

Under nitrogen, 3-butyn-1-ol (610mg, 8.71mmol) was dissolved in N, N-dimethylformamide (5mL), cooled to 0 deg.C, and sodium hydride (348mg, 8.71mmol, 60%) was added and stirred at room temperature for 30 min. 6- (tosyloxy) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (004B) (3.2g, 8.71mmol) was added and the reaction was allowed to warm to 80 ℃ for 20 h. The reaction solution was cooled to room temperature, quenched by addition of saturated ammonium chloride solution (30mL), 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 with a silica gel column (petroleum ether: ethyl acetate (V/V) ═ 20: 1) to give 6- (but-3-yn-1-yloxy) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (004C) as a yellow liquid (400mg, yield 17.3%).

The third step: synthesis of 6- (but-3-yn-1-yloxy) -2-azaspiro [3.3] heptane hydrochloride (004D)

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

The fourth step: synthesis of (6- (but-3-yn-1-yloxy) -2-aza-spiro [3.3] heptan-2-yl) (2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl) methanone (004E)

To the crude 6- (but-3-yn-1-yloxy) -2-azaspiro [3.3] heptane hydrochloride (004D) in the previous step was added N, N-dimethylformamide (5mL), N, N-diisopropylethylamine (974mg, 7.54mmol), 2- (2, 3-dihydro-1H-inden-2-ylamino) pyrimidine-5-carboxylic acid (308mg, 1.206mmol), the reaction mixture was cooled to about 0 deg.C, and 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphoric acid-2, 4, 6-trioxa-oxide (1.151g, 1.809mmol, 50% N, N-dimethylformamide solution) was added dropwise and reacted at 20-25 deg.C for 18H. The reaction solution was added with water (50mL), extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was isolated and purified with a silica gel plate (petroleum ether: ethyl acetate (V/V) ═ 1:1) to give (6- (but-3-yn-1-yloxy) -2-aza-spiro [3.3] heptan-2-yl) (2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl) methanone (004E) (230mg, yield 37.9%) as a white solid.

LC-MSm/z：403.4[M+H]⁺。

The fifth step: synthesis of (6- (2- (1H-1,2, 3-triazol-4-yl) ethoxy) -2-aza-spiro [3.3] heptan-2-yl) (2- ((2, 3-dihydro-1H-inden-pyridin-2-yl) amino) pyrimidin-5-yl) methanone (004)

Under the protection of nitrogen, (6- (but-3-yn-1-yloxy) -2-aza-spiro [3.3] heptan-2-yl) (2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl) methanone (004E) (230mg, 0.571mmol) was dissolved in N, N-dimethylformamide (4mL) and methanol (2mL), sodium L-ascorbate (226mg, 1.143mmol) was added, azidotrimethylsilane (329mg, 2.86mmol) and copper sulfate pentahydrate (57.1mg, 0.229mmol) were added, and the temperature was raised to 90 ℃ for 3H. The reaction solution was cooled to room temperature, water (40mL) was added, dichloromethane was extracted (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a silica gel plate (ethyl acetate: methanol (V/V) ═ 10:1, aqueous ammonia) to give (6- (2- (1H-1,2, 3-triazol-4-yl) ethoxy) -2-aza-spiro [3.3] heptan-2-yl) (2- ((2, 3-dihydro-1H-indenpyridin-2-yl) amino) pyrimidin-5-yl) methanone (004) (10mg, 3.93% yield).

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

LC-MSm/z：446.3[M+H]⁺。

Example 6: preparation of target Compound 005

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

The synthetic route for target compound 005 is shown below:

the first step is as follows: synthesis of tert-butyl 9- (prop-2-yn-1-yloxy) -3-azaspiro [5.5] undecane-3-carboxylate (005B)

Tert-butyl 9-hydroxy-3-azaspiro [5.5] undecane-3-carboxylic acid ester (0.5g, 5.34mmol) and tetrahydrofuran (5mL) were added to a single vial to dissolve, 60% sodium hydride (0.089g, 2.23mmol) was added thereto at room temperature, the mixture was stirred at room temperature for 0.5 hour, bromopropyne (0.662g, 5.57mmol) was added thereto, the reaction was stirred at room temperature for 72 hours, TLC (petroleum ether: ethyl acetate (V/V) ═ 3:1) showed completion, methanol (10mL) was added to quench the reaction, the reaction was concentrated, and the residue was purified with a silica gel column (petroleum ether: ethyl acetate (V/V) ═ 3:1) to give 9- (prop-2-yn-1-yloxy) -3-azaspiro [5.5] undecane-3-carboxylic acid tert-butyl ester (200mg, 0.651mmol, 35.0% yield) as a colorless oil.

The second step is that: synthesis of 9- (prop-2-yn-1-yloxy) -3-azaspiro [5.5] undecane hydrochloride (005C)

Tert-butyl 9- (prop-2-yn-1-yloxy) -3-azaspiro [5.5] undecane-3-carboxylate (200mg, 0.651mmol), hydrogen chloride/1, 4 dioxane solution (2.5M, 2mL) was added to a single vial, stirred at room temperature for 3 hours, and concentrated to dryness to give crude 9- (prop-2-yn-1-yloxy) -3-azaspiro [5.5] undecane hydrochloride as a white solid (0.158g, 0.651mmol, 100% yield).

The third step: synthesis of (2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl) (9- (prop-2-yn-1-yloxy) -3-azaspiro [5.5] undecane-pyridin-3-yl) methanone (005D)

In a single vial was added crude 9- (prop-2-yn-1-yloxy) -3-azaspiro [5.5] undecane hydrochloride (0.158g, 0.651mmol), 2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidine-5-carboxylic acid (166mg, 0.651mmol), diisopropylethylamine (0.839g, 6.51mmol), N-dimethylformamide (4mL) dissolved at room temperature, cooled to 0 ℃, 50% 1-propylphosphoric anhydride/N, N-dimethylformamide solution (0.620g, 0.974mmol) was added dropwise, after completion of the addition, the reaction was allowed to proceed overnight at room temperature, TLC (methanol: dichloromethane (V/V) ═ 1:10) showed completion of the reaction, diluted with water (10mL), the aqueous phase was extracted with dichloromethane (50mL × 2), the organic phases were combined, washed with saturated brine (50mL × 2), separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified over a silica gel column (methanol: dichloromethane (V/V) ═ 1:10) to give (2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl) (9- (prop-2-yn-1-yloxy) -3-azaspiro [5.5] undecane-pyridin-3-yl) methanone (200mg, 0.45mmol, 69.3% yield) as a white solid.

LC-MSm/z：445.58[M+H]⁺。

The fourth step: synthesis of (9- ((1H-1,2, 3-triazol-4-yl) methoxy) -3-azaspiro [5.5] undecan-3-yl) (2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl) methanone (005)

Into a single-necked flask was added sodium L (+) ascorbate (178mg, 0.90mmol), (2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl) (4- (1- (prop-2-yn-1-yloxy) ethyl) piperidin-1-yl) methanone (200mg, 0.45mmol), trimethylsilyl azide (0.155g, 1.35mmol), copper sulfate pentahydrate (22mg, 0.09mmol), N, N-dimethylformamide (4mL), methanol (0.4mL), heated to 90 ℃ for 2 hours, LCMS showed most of the reaction of the starting materials, the reaction solution was cooled to room temperature, saturated saline (10mL) was added to the reaction solution, ethyl acetate (50 mL. times.2) was extracted, the organic phase was washed twice with saturated saline (20 mL. times.2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue chromatographed to give (9- ((1H-1,2, 3-triazol-4-yl) methoxy) -3-azaspiro [5.5] undecan-3-yl) (2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl) methanone (30mg, 0.062mmol, 13.68% yield).

¹H NMR(400MHz,DMSO-d6)δ8.34(s,2H),7.92～7.93(d,1H),7.76(s,1H),7.17～7.19(m,2H),7.09～7.12(m,2H),4.59～4.64(m,1H),4.52(s,2H),3.31～3.43(m,5H),3.19～3.24(q,2H),2.85～2.90(q,2H),1.58～1.70(m,4H),1.32～1.41(m,6H),1.12～1.19(m,2H)。

LC-MSm/z：488.61[M+H]⁺。

Example 7: preparation of target compound 006

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

The synthetic route for compound 006 is shown below:

the first step is as follows: synthesis of tert-butyl 2- (prop-2-yn-1-yloxy) -7-azaspiro [3.5] nonane-7-carboxylate (006B)

Tert-butyl 2-hydroxy-7-azaspiro [3.5] nonane-7-carboxylate (006A) (2g, 8.29mmol) was dissolved in tetrahydrofuran (20mL), cooled to 0 deg.C, sodium hydride (365mg, 9.12mmol, 60%) was added, 3-bromopropyne (1.479g, 12.43mmol) was added dropwise, and after completion of the addition, the reaction was allowed to proceed at room temperature for 16 hours. Quenched with water (50mL), extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) ═ 50: 1) to give 2- (prop-2-yn-1-yloxy) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (006B) as a yellow liquid (2.1g, 91% yield).

The second step is that: synthesis of 2- (prop-2-yn-1-yloxy) -7-azaspiro [3.5] nonane hydrochloride (006C)

To tert-butyl 2- (prop-2-yn-1-yloxy) -7-azaspiro [3.5] nonane-7-carboxylate (006B) (2.1g,7.52mmol) was added a solution of hydrogen chloride in dioxane (20mL) and the reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give a crude product which was used in the next reaction without purification.

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

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

LC-MSm/z：417.4[M+H]⁺。

The fourth step: synthesis of (2- ((1H-1,2, 3-triazol-4-yl) methoxy) -7-azaspiro [3.5] non-7-yl) (2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl) methanone (006)

(2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl) (2- (prop-2-yn-1-yloxy) -7-azaspiro [3.5] nonan-7-yl) methanone (006D) (440mg, 0.964mmol) was dissolved in N, N-dimethylformamide (8mL) and methanol (4mL) under nitrogen, sodium L-ascorbate (382mg, 1.928mmol) was added, azidotrimethylsilane (1110mg, 9.64mmol) and copper sulfate pentahydrate (96mg, 0.386mmol) were added, and the mixture was heated to 90 ℃ for 4 hours. The reaction solution was cooled to room temperature, water (40mL) was added, ethyl acetate was extracted (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a silica gel plate (ethyl acetate: methanol (V/V) ═ 10:1, aqueous ammonia) to give (2- ((1H-1,2, 3-triazol-4-yl) methoxy) -7-azaspiro [3.5] non-7-yl) (2- ((2, 3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl) methanone (006) (70.9mg, yield 14.73%).

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

LC-MSm/z：474.3[M+H]⁺。

Example 8: preparation of target compound 007

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

the first step is as follows: synthesis of 7- (prop-2-yn-1-yloxy) -2-azaspiro [3-4] nonane-2-carboxylic acid tert-butyl ester (007B)

Adding NaH ((489mg,12.22mmol, 60%) to a solution of tert-butyl 7-hydroxy-2-azaspiro [3-4] nonane-2-carboxylate (007A) (590mg,2.445mmol) in tetrahydrofuran (30mL) at 0 deg.C, stirring at room temperature for 30min, adding 3-bromoprop-1-yne (1454mg,12.22mmol), stirring the reaction mixture at 25 deg.C overnight, TLC (petroleum ether: ethyl acetate: 5:1) indicating the formation of new spots, diluting with distilled water (30mL), extracting with ethyl acetate (50 mL. times.3), combining the organic phases, washing the organic phase with saturated brine (10 mL. times.2), separating, 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): 1-5: 1) to obtain 7- (prop-2-yn-1-yloxy) -2-yne) as a yellow oily compound -azaspiro [3-4] nonane-2-carboxylic acid tert-butyl ester (007B) (550mg,1.969mmol, 81% yield).

The second step is that: synthesis of 7- (prop-2-yn-1-yloxy) -2-aza-spiro [3.5] nonane (007C)

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

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

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

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

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

1H NMR(400MHz,DMSO-d6)δ8.58(d,2H),8.11(d,1H),7.79(s,1H),7.13-7.22(m,4H),4.62-4.73(m,1H),4.55(s,2H),4.05(d,2H),3.67(d,2H),3.35-3.40(m,1H),3.22-3.28(m,2H),2.88-2.94(m,2H),1.75-1.80(m,4H),1.49(t,2H),1.34-1.37(m,2H)。

LC-MS m/z：460.3[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 inhibitor screening and detecting kit (Cayman, 700580). Test compounds were first prepared as 10mM stock solutions in DMSO solvent, then 8 concentration points were diluted using DMSO gradient, followed by dilution of the 8 concentration points into 19 × compound working solution (DMSO content 1.9%) with Autotaxin assay buffer (1 ×) provided in the kit. The Autotaxin assay reagent (10X) was removed and diluted 10-fold with Autotaxin assay buffer (1X). The substrate of Autotaxin was taken out, dissolved in 1.2mL of Autotaxin detection buffer (1X), mixed well and allowed to stand at room temperature. In a 96-well plate, 150. mu.L of Lautotaxin assay buffer (1X), 10. mu.L of diluted 19X compound working solution, 10. mu.L of Lautotaxin assay reagent (1X), 20. mu.L of dissolved Autotaxin substrate were added to each well at each concentration point, and mixedMixing, shaking table at constant temperature of 37 deg.C, and incubating in dark for 30 min; 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

Test compounds	IC50(nM)
		Compound 001-1	2.50
Compound 002-1	7.8
		Compound 002-2	1.14
Compound 003	7.12
		Compound 004	6.3
Compound 005	0.979
		Compound 006	1.17
Compound 007	7.05

Experimental results show that the compound has good inhibitory activity on ATX enzyme and can effectively inhibit the activity of ATX enzyme.

Claims (10)

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、R³、R⁴identical or different, independently of one another, from the group consisting of hydrogen, halogen, -CN, -OH, -SH, -NO₂Unsubstituted or optionally substituted by one or more R^aSubstituted of the following groups: c₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl, 3-10 membered heterocyclyl, C₁-C₁₀Alkoxy radical, C₃-C₁₀Cycloalkyloxy, 3-10 membered heterocyclyloxy, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl; c₆-C₁₀Aryloxy, 5-10 membered heteroaryloxy;

x, Y are identical or different and are each independently selected from-N ═ C (R)⁶) -; z is independently selected from-O-, -S-, -C (R)⁷)(R⁸)-、-N(R⁹)-、-N(R⁹)-C(R⁷)(R⁸)-；

Q is selected from C₃-C₁₀Cycloalkyl, 3-10 membered heterocyclyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl; preferably, Q is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, 2, 3-dihydro-1H-indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolylA group selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl and quinolinyl;

each R⁵Identical or different, independently of one another, from the group consisting of hydrogen, halogen, -CN, -OH, -SH, -NO₂Unsubstituted or optionally substituted by one or more R^bSubstituted of the following groups: c₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl, 3-10 membered heterocyclyl, C₁-C₁₀Alkoxy radical, C₃-C₁₀Cycloalkyloxy, 3-10 membered heterocyclyloxy, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl; c₆-C₁₀Aryloxy, 5-10 membered heteroaryloxy;

each R^a、R^bIdentical or different, independently of one another, from the group formed by-F, -Cl, -Br, -I, -OH, -CN, -O, NO₂、--NH₂、C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkenyloxy radical, C₂-C₁₀Alkynyl, C₂-C₁₀Alkynyloxy, C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Cycloalkyloxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C₆-C₂₀Aryl radical, C₆-C₂₀Aryloxy, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy;

preferably, R⁵Selected from-H, -F, -Cl, methyl, ethyl, difluoromethoxy;

n¹、n²m is independently selected from the integer 0, 1,2,3, 4, 5 or 6;

M¹、M²、M³、M⁴、M⁵independently selected from-N ═ N (R)¹⁰)-、-CH＝、-C(R¹¹) Wherein M is¹、M²、M³、M⁴、M⁵At least one of which is selected from-N or-N (R)¹⁰) -, and M¹、M²、M³、M⁴、M⁵At least one of which is selected from-CH or-C (R)¹¹) Is as follows; preferably, M₁、M₂、M₃Are all selected from-N or-N (R)¹⁰)-，M⁴、M⁵Are all selected from-CH or-C (R)¹¹)＝；

L is selected from

Wherein p1, p2, p3, p4, q1, q2, q3 and q4 are independently selected from integers of 0, 1,2,3, 4, 5 or 6, p3 and p4 are not 0 at the same time, q1 and q2 are not 0 at the same time, and q3 and q4 are not 0 at the same time;

R⁶、R⁷、R⁸、R¹¹、R¹²、R¹³independently selected from hydrogen, halogen, -CN, -OH, -SH, -NO₂、C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl, 3-10 membered heterocyclyl, C₁-C₁₀Alkoxy radical, C₃-C₁₀Cycloalkyloxy, 3-10 membered heterocyclyloxy, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl; c₆-C₁₀Aryloxy, 5-10 membered heteroaryloxy;

R⁹、R¹⁰independently selected from hydrogen, C₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl, 3-10 membered heterocyclyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl;

and the compounds do not include the following compounds or tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof:

2. a compound that is a compound of formula (II), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of formula (II):

wherein,

R¹、R²、R³、R⁴independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆A cycloalkyl group;

x, Y are identical or different and are each independently selected from-N ═ C (R)⁶)-；R⁶Independently selected from hydrogen, fluorine, chlorine, methyl, ethyl;

n¹、n²independently selected from the integers 0, 1, 2;

M¹、M²、M³independently selected from-N ═ N (R)¹⁰) -, wherein R¹⁰Selected from hydrogen, C₁-C₆Alkyl or C₃-C₆A cycloalkyl group; preferably, M¹、M²、M³Are each selected from-N ═ or-NH-;

l is selected from

Wherein p1, p2, p3, p4, q1, q2, q3 and q4 are independently selected from integers of 0, 1 and 2, p3 and p4 are not 0 at the same time, q1 and q2 are not 0 at the same time, and q3 and q4 are not 0 at the same time;

and the compounds do not include the following compounds or tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof:

3. a compound that is a compound of formula (III), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of formula (III):

wherein,

R¹、R²、R³、R⁴independently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₆A cycloalkyl group;

R⁵independently selected from hydrogen, -CN, halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen substituted C₁-C₆An alkoxy group;

x, Y are identical or different and are each independently selected from-N ═ C (R)⁶)-；R⁶Independently selected from hydrogen, fluorine, chlorine, methyl, ethyl;

n¹、n²independently selected from the integers 0, 1, 2;

M¹、M²、M³independently selected from-N ═ N (R)¹⁰) -, wherein R¹⁰Selected from hydrogen, C₁-C₆Alkyl or C₃-C₆A cycloalkyl group; preferably, M¹、M²、M³Are each selected from-N ═ or-NH-;

l is selected from

Wherein p1, p2, p3, p4, q1, q2, q3 and q4 are independently selected from integers of 0, 1 and 2, p3 and p4 are not 0 at the same time, q1 and q2 are not 0 at the same time, and q3 and q4 are not 0 at the same time;

and the compounds do not include the following compounds or tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof:

4. a compound according to any one of claims 1 to 3, a stereoisomer, a tautomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof, wherein the compound is selected from one of the following structures:

5. a compound according to any one of claims 1 to 3, a stereoisomer, a tautomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof, wherein the compound is selected from one of the following structures:

6. a pharmaceutical composition comprising a compound according to any one of claims 1 to 4.

7. Use of a compound according to any one of claims 1 to 5, or a pharmaceutical composition according to claim 6, in the manufacture of a medicament for the treatment of a disease associated with ATX.

8. The use according to claim 7, 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.

9. Use according to claim 7, wherein the ATX-related disease is selected from interstitial lung disease, lung fibrosis, liver fibrosis, kidney fibrosis, preferably from idiopathic lung fibrosis.

10. Use according to claim 7, wherein the ATX-related disease is selected from metabolic diseases, 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.