Compounds for treating inflammatory processes

Abstract

The present invention relates to the use of compounds such as compounds of formula (I) or pharmaceutically acceptable salts, solvates and / or prodrugs thereof, for example the use of the compounds in pharmaceutical compositions and in the treatment of diseases, disorders or conditions, wherein the diseases, disorders or conditions include treatable by inhibition of SWAP-70 and / or treatable by inhibition of neutrophil reactive oxygen species (ROS) production, neutrophil extracellular trap formation (NETosis), B lymphocyte plasma mother cell development, B lymphocyte IgE production, mast cell degranulation, eosinophilic granulocyte ROS production, mast cell cytokine release, B lymphocyte IgE production, B lymphocyte IgE production, B lymphocyte IgE production, B lymphocyte IgE production, B lymphocyte IgE production, B lymphocyte IgE production, B lymphocyte IgE production, B lymphocyte IgE production, B lymphocyte IgE production and B lymphocyte IgE production. The composition can be used for treating diseases, symptoms or conditions, such as lung inflammation induced by viruses such as SARS-CoV-2 and the like, which can be treated by virtue of cytokine release of B lymphocytes, cytokine release of endothelial cells, interaction of endothelial cells and immune cells and / or migration of macrophages / monocytes. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to co-pending U.S. Provisional Application No. 63 / 408,305, filed on September 20, 2022, and U.S. Provisional Application No. 63 / 408,624, filed on September 21, 2022, both of which are incorporated herein by reference in their entireties. Technical Field

[0003] The present invention relates to the use of compounds such as 3-(2-chlorophenyl)-5-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)isoxazole-4-carboxamide (B2) in pharmaceutical compositions and in the treatment of diseases, disorders or conditions, including diseases, disorders or conditions treated by inhibiting SWAP-70 to treat and / or inhibit neutrophil reactive oxygen species (ROS) production, neutrophil extracellular trap formation (NETosis), B lymphocyte plasmablast development, B lymphocyte IgE production, mast cell degranulation, eosinophil reactive oxygen species (ROS) production, mast cell cytokine release, B lymphocyte cytokine release, endothelial cell cytokine release, endothelial cell-immune cell interaction and / or macrophage / monocyte migration, such as pulmonary inflammation induced by viruses such as SARS-CoV-2. Background Art

[0004] SWAP-70 was first discovered in 1998 as a protein involved in immunoglobulin isotype switching (Borggrefe, Wabl, et al., 1998) and in 2000 as a protein that supports the specific production of IgE isotype immunoglobulins in mouse B cells and mice (Borggrefe, Keshavarzi, et al., 2001). Subsequent studies have shown that SWAP-70 also supports mast cell degranulation, a key effector process in allergic reactions (Gross, Borggrefe, et al., 2002; Sivalenka and Jessberger, 2004; Sivalenka, Sinha, et al., 2008). Furthermore, this protein was shown to play a key role in the migration and adhesion of hematopoietic cells, which are crucial in many inflammatory processes (Pearce, Angeli, et al., 2006; Chopin, Quemeneur, et al., 2010; Chopin, Chacon-Martinez, et al., 2011; Ocana-Morgner, Reichardt, et al., 2011; Pearce, Audzevich, et al., 2011). The underlying mechanism was subsequently identified: SWAP-70 regulates specific F-actin rearrangements in certain hematopoietic cells, both in the cytoplasm and at the plasma membrane, thereby controlling cell morphogenesis, migration, adhesion, and specific functions that depend on the F-actin network (Chacon-Martinez, Kiessling, et al., 2013; Betaneli and Jessberger, 2020). Furthermore, in B cells, SWAP-70 can enter the nucleus and modulate the antagonism of transcription factors that regulate IgE production (Audzevich, Pearce, et al., 2013). Cell types whose disease-related activities are controlled by SWAP-70 include B lymphocytes at different stages of development (including plasma cells, plasmablasts, mast cells, neutrophils, eosinophils, macrophages, osteoclasts, and endothelial cells).

[0005] U.S. Patent Publication No. 2003 / 0166018 discloses a screening method for identifying substances that modulate the level or activity of SWAP-70 protein in cells capable of degranulation. Canadian Patent No. 2,796,171 discloses a method for identifying substances that inhibit IgE production, comprising contacting at least one candidate substance with SWAP-70, BCL-6, and / or STAT-6, and selecting a candidate substance that specifically inhibits SWAP-70-mediated STAT-6 activation and / or enhances BCL-6-mediated inhibition of SWAP-70-mediated STAT-6 activation. Canadian Patent No. 2,900,798 discloses a method for identifying substances that inhibit SWAP-70 activity, comprising contacting at least one test substance with SWAP-70, detecting the degree of SWAP-70 dimerization, and selecting a test substance that inhibits SWAP-70 dimerization.

[0006] Allergic reactions are a widespread and growing disease with symptoms ranging from mild to severe and even life-threatening. They are caused by the overproduction of IgE, an antibody isotype, that binds to allergens such as hay pollen, nut compounds, and insect venom components. IgE binds to the surface of mast cells via high-affinity receptors. Upon allergen binding, IgE triggers an immediate and intense mast cell response: the sudden release of over 200 preformed bioactive molecules (histamine, cytokines, leukotrienes, etc.), which trigger the allergic reaction. While treatments are available to alleviate symptoms (e.g., histamine antagonists and corticosteroids), there are currently no treatments that target the underlying cause—IgE production. Studies have shown that SWAP-70 promotes IgE production, and the mechanisms involved have been elucidated in mouse splenic B cells and in vivo (Borggrefe, Keshavarzi, et al., 2001; Audzevich, Pearce, et al., 2013). SWAP-70 also supports mast cell degranulation. In the absence of SWAP-70, mouse mast cells are severely impaired in the IgE-triggered degranulation process, and local and systemic IgE-triggered allergic reactions are also significantly reduced in SWAP-70-deficient mice (Gross, Borggrefe, et al., 2002; Sivalenka, Sinha, et al., 2008).

[0007] Lower respiratory tract infections caused by viruses and / or bacteria are the leading cause of infection-related mortality. In the disease caused by the SARS-CoV-2 virus (COVID-19), as well as in other viral infections such as respiratory syncytial virus (RSV) and influenza, life-threatening acute lung inflammation typically develops within a few days of symptom onset (Zaki and Paddock, 2008; Merad, Blish et al., 2022). In COVID-19, this inflammation is characterized by a surge in proinflammatory cytokine levels (a “cytokine storm”), exhaustion of T cells and certain dendritic cell types, excessive expansion of plasmablasts, the development of autoantibodies against type I interferons that reduce their antiviral efficacy, and overactivation of immune cells such as neutrophils, which damage the lung airways through excessive neutrophil extracellular trap formation (NETosis) and / or reactive oxygen species (ROS) production. Other pathological responses include mast cell activation, IgE production, endothelial inflammation and blood coagulation, and macrophage overactivation leading to pulmonary fibrosis (Bastard, Rosen et al., 2020, Fajgenbaum and June, 2020, Kuri-Cervantes, Pampena et al., 2020, Lucas, Wong et al., 2020, Mathew, Giles et al., 2020, Merad and Martin, 2020, Veras, Pontelli et al., 2020, Ferreira-Gomes, Kruglov et al., 2021, Gustine and Jones, 2021, Wendisch, Dietrich et al., 2021, Wu, Liu et al., 2021, Merad, Blish et al., 2022). Although several drugs have been developed that can directly inhibit the proliferation of the COVID-19 virus, these drugs need to be administered early in the infection process to be effective. The use of general immunosuppressants has limited effectiveness [https: / / www.covid19treatmentguidelines.nih.gov]. These drugs (such as corticosteroids such as dexamethasone) carry various risks, such as the development of diabetes and reduced resistance to pathogens. Corticosteroids need to be taken long-term (4-8 weeks), with maximum efficacy achieved after about 2 weeks, and the dose must be slowly reduced, generally over 1-3 weeks. IL6 receptor inhibitors and JAK-STAT pathway inhibitors have also been used to treat patients who show signs of an active cytokine storm and excessive inflammation, but only a relatively small number of these patients have seen improvement.To our knowledge, there are currently no effective and safe immunomodulators reported and used to prevent excessive inflammation for the treatment of COVID-19 and related viral or non-viral inflammatory diseases. Clearly, new drugs are needed to address the severe and variable inflammatory cascade in COVID-19 patients. This is also true for other virally induced pulmonary inflammatory conditions, for which innovative and novel drugs are needed (Zaki and Paddock, 2008). Non-infectious lung diseases such as asthma or chronic obstructive pulmonary disease (COPD) can be exacerbated by certain viral infections, such as RSV, influenza, rhinovirus, parainfluenza, and / or coronavirus (Kennedy, Pham, et al., 2019). For example, these infections can lead to acute respiratory distress syndrome (ARDS), hospitalization, and sometimes death related to the inflammatory process. Acute exacerbations of COPD are also characterized by excessive cytokine production. In addition to lung inflammation, viral-induced inflammation can negatively impact other cells and tissues in the body. These effects, often exacerbated by a cytokine storm, can be systemic, encompassing numerous cell types and tissues, such as the gastrointestinal system, kidneys, heart, nervous system, skin, and liver. In addition to viral infections, infections with other pathogens and other conditions can also lead to severe pulmonary and / or systemic pathology, involving many of the aforementioned cells and processes. Examples include bacterial sepsis and infection with Yersinia pestis (plague), which triggers excessive cytokine production by alveolar macrophages, or the cytokine storm associated with autoimmune diseases (Fajgenbaum and June, 2020).

[0008] In non-virally induced pulmonary inflammatory diseases, the immune system overreacts, leading to life-threatening conditions. Similar to allergic reactions, many manifestations of asthma are triggered by IgE-allergen responses, leading to mast cell degranulation and subsequent inflammatory events, including eosinophil activation and migration. Furthermore, a crucial role for eosinophil migration into the lungs has been demonstrated (Bahaie, Hosseinkhani, et al., 2012). In the absence of SWAP-70, a reduced influx of eosinophils and decreased eosinophil adhesion were observed in asthma-induced mice. In acute asthma, IgE-producing B lymphocytes, Th lymphocytes that trigger Th2 responses, degranulated mast cells, and activated eosinophils play a major role in promoting disease (Martinez and Vercelli, 2013). Current treatments include, for example, inhaled corticosteroids, which are a standard treatment for mild and moderate asthma but have significant side effects, or anti-IgE (omalizumab), anti-IL-5, or anti-IL-13 antibodies for severe asthma, but additional and / or alternative treatment options are clearly needed.

[0009] Urticaria is a common skin disease typically caused by excessive mast cell degranulation (Church, Kolkhir, et al., 2018). Mast cells release histamine in response to physical (heat, cold, pressure) or chemical irritation of the skin, allergens (called pseudoallergic reactions), excessive sun exposure, infection, and / or intolerance to common medications such as aspirin. Many of these stimuli are difficult to avoid. All of these stimuli trigger mast cell degranulation. As mentioned above, SWAP-70 has been shown to play a crucial role in mast cell degranulation in mice. More recently, a role for eosinophils in promoting urticaria has also been reported (Altrichter, Frischbutter, et al., 2020). While mild urticaria can be treated with histamine blockers or leukotriene antagonists, more severe urticaria can spread to the upper respiratory tract and restrict breathing (mucosal swelling), causing significant distress to the patient. IgE has been implicated in pseudoallergic urticaria, and anti-IgE antibody therapy has been used to reduce IgE levels with some success in some patients (Maurer, Altrichter, et al., 2018; Wedi and Traidl, 2021). In severe cases, corticosteroids are often a last resort. Therefore, other treatment options are needed. Urticaria can progress from a spontaneous acute state to a chronic state within approximately 6 weeks (Saini and Kaplan, 2018).

[0010] Osteoporosis affects approximately 15% of the population and is caused by an imbalance between bone formation and bone resorption. Osteoclasts, a type of hematopoietic cell, are the primary regulator of bone resorption, and in osteoporosis, their role predominates. This condition most commonly occurs in postmenopausal women, whose estrogen levels decrease. Bone mass decreases, and bones become brittle and prone to fracture. Osteoclasts resorb bone by firmly adhering to the bone surface and forming a resorption zone beneath their cell bodies. Osteoclasts then secrete acids and proteases to break down the bone. To firmly adhere to bone and create a low-pH, protease-rich environment, osteoclasts need to form a "sealing ring." This ring is based on a specific F-actin structure. Without SWAP-70, osteoclasts cannot form the proper F-actin ring and, consequently, cannot resorb bone in cell culture and in mice (Garbe, Roscher, et al., 2012; Roscher, Hasegawa, et al., 2016). Consequently, SWAP-70-deficient mice develop osteosclerosis, meaning they exhibit a significant increase in bone mass. Increased bone mass is highly beneficial for osteoporosis. Current treatments include bisphosphonates, cytokine / receptor inhibition (RANK system), estrogen receptor agonists, integrin antagonists, Src inhibitors, cathepsin K inhibitors, and calcitonin, but these treatments have significant side effects and / or limited therapeutic efficacy.

[0011] Chronic obstructive pulmonary disease (COPD) is currently incurable and gradually worsens with acute attacks, placing a significant burden on patients. COPD often leads to death. Like asthma, COPD is prone to pneumonia. COPD involves overactivation of multiple immune cell types and enhanced cytokine release, and can therefore be classified as a specific cytokine release syndrome (Brightling and Greening, 2019). Air pollution, smoking, allergens, and pathogens such as bacteria or viruses can all trigger COPD. COPD occurs in many forms and is generally divided into two types: neutrophil-based and eosinophil-based. In addition to these two cell types, other major immune cell types that contribute to COPD are macrophages, mast cells, and plasmablasts.

[0012] In a recent large-scale genome-wide association study, SWAP-70 was identified as a high-risk locus for rheumatoid arthritis (Kwon, Lim, et al., 2020). Generally speaking, in inflammatory arthritis, proinflammatory macrophages, neutrophils, and several types of lymphocytes are overactivated, with more cells recruited to the bone joints (synovium) and activated, thus creating a vicious proinflammatory cycle that the immune system cannot control (Jang, Kwon, et al., 2022). In the context of inflammatory arthritis, osteoclasts are gradually formed and activated to resorb bone, exacerbating joint deterioration. Another hallmark of rheumatoid arthritis (RA) is the production of autoantibodies by plasmablasts, which develop in this highly proinflammatory environment and further exacerbate inflammation. Inflammatory arthritis, broadly defined, also includes gout. In gout, urate crystals activate neutrophils to produce ROS, leading to the formation of neutrophil extracellular traps (NETs) and the secretion of cytokines. RA is an autoimmune disease, and other autoimmune diseases, such as systemic lupus erythematosus, also require novel therapeutic approaches (Touma and Gladman, 2017; Liossis and Staveri, 2021). In these debilitating autoimmune diseases, autoreactive B cells, including plasmablasts, and neutrophil extracellular trap formation play a central role in the pathogenesis (Frangou, Vassilopoulos, et al., 2019). Furthermore, the presence of autoreactive IgE can also elevate IgE levels. Recently, systemic lupus erythematosus, bullous pemphigoid, atopic dermatitis, and other autoimmune diseases have been referred to as auto-IgE-immune diseases or even autoallergic diseases (Maurer, Altrichter, et al., 2018).

[0013] In addition to the known cytokine storms caused by viral-induced lung inflammation (e.g., by various coronaviruses, influenza, and / or RSV strains), other cytokine release syndromes have been reported (Fajgenbaum and June, 2020). This authoritative review states that "cytokine storms and cytokine release syndromes are life-threatening systemic inflammatory syndromes involving elevated circulating cytokine levels and excessive immune cell activation that can be triggered by various therapies, pathogens, cancer, autoimmune diseases, and monogenic disorders" (Fajgenbaum and June, 2020). Immunotherapies, including T-cell therapy, viral and bacterial infections, and sepsis can all cause cytokine storms, which are often accompanied by high fever, headache, rash, diarrhea, respiratory problems, and many other symptoms and can be fatal due to multi-organ failure. Due to the wide range of symptoms, symptomatic treatment is difficult. Instead, the underlying cause should be addressed. Blocking single proinflammatory cytokines (such as IL-6 or its receptor) with antibodies (e.g., tocilizumab) has shown limited efficacy in some cases and needs to be combined with standard or new therapies; due to the long half-life of such therapies, blocking IL-6 may also increase the risk of infection, thus limiting its application (Kang and Kishimoto, 2021).

[0014] Inflammation associated with endothelial cell activation and cytokine release can trigger a variety of diseases, including coronary artery disease, through the formation of atherosclerotic plaques through monocyte accumulation and adhesion, vascular dysfunction, tissue infiltration of migrating activated leukocytes, and / or overactivation of the coagulation cascade. Excessive secretion of proinflammatory cytokines by endothelial cells, particularly chemokines that stimulate pathological recruitment and accumulation of leukocytes, is a major concern. In sepsis, endothelial cytokines lead to massive recruitment and transendothelial migration of neutrophils, a major cause of mortality (Kilpatrick and Kiani, 2020). Similarly, neutrophils are recruited and accumulated during thromboinflammation. In a large-scale genome-wide analysis, SWAP-70 was identified as a high-risk pathogenic locus for coronary artery disease (Nikpay, Goel, et al., 2015). This protein is thought to promote pathological leukocyte migration and adhesion to the vessel wall. In a recent meta-study, SWAP-70 was identified as a causative gene for coronary artery disease (Zheng, Ma et al., 2020). Summary of the Invention

[0015] The present invention aims to reduce inflammatory processes. These include pro-inflammatory activity in related immune cells, such as mast cells, B lymphocytes, and neutrophils, as well as pro-inflammatory responses in endothelial cells. Studies have shown that B2 can inhibit the activity of specific immune cells. Because B2 does not suppress the activity of the entire immune system, it targets the activity of disease-causing immune cells without eliminating anti-pathogen immune responses. Therefore, B2 and other compounds of the present invention act as immunomodulators rather than systemic immunosuppressants.

[0016] Thus, the present invention includes a method of treating an inflammatory disease, disorder or condition comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:

[0017]

[0018] in,

[0019] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0020] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0021] X 1 selected from N and CH;

[0022] X 2 Selected from O, S and NR 6 ;

[0023] X 3 Selected from O and NR 7 ;

[0024] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0025] X 5 selected from N and CH;

[0026] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0027] m is an integer from 0 to 5; and

[0028] n is an integer from 0 to 4.

[0029] The present invention also includes a method of treating a disease, disorder or condition treatable by inhibiting SWAP-70, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:

[0030]

[0031] in

[0032] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0033] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0034] X 1 selected from N and CH;

[0035] X 2 Selected from O, S and NR 6 ;

[0036] X 3 Selected from O and NR 7 ;

[0037] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0038] X 5 selected from N and CH;

[0039] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0040] m is an integer from 0 to 5; and

[0041] n is an integer from 0 to 4.

[0042] The present invention also includes a method for treating a disease, disorder or condition that can be treated by inhibiting neutrophil reactive oxygen species (ROS) generation, neutrophil extracellular trap formation, B lymphocyte plasmablast development, B lymphocyte IgE production, mast cell degranulation, eosinophil reactive oxygen species (ROS) generation, mast cell cytokine release, B lymphocyte cytokine release, endothelial cell cytokine release, endothelial cell-immune cell interaction and / or macrophage / monocyte migration, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:

[0043]

[0044] in

[0045] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0046] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0047] X 1 selected from N and CH;

[0048] X 2 Selected from O, S and NR 6 ;

[0049] X 3 Selected from O and NR 7 ;

[0050] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0051] X 5 selected from N and CH;

[0052] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0053] m is an integer from 1 to 5; and

[0054] n is an integer of 1 to 4.

[0055] In one embodiment, m is 1.

[0056] In one embodiment, n is 1.

[0057] In one embodiment:

[0058] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0059] R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0060] R 3 is NO2;

[0061] X 1 selected from N and CH;

[0062] X 2 Selected from O, S and NR 6 ;

[0063] X 3 Selected from O and NR 7 ;

[0064] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0065] X 5 selected from N and CH;

[0066] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0067] m is 1; and

[0068] n is an integer of 1 to 4.

[0069] In one embodiment, the compound of formula (I) is a compound of formula I(a):

[0070]

[0071] where R 1 、R 2 、R3 、X 1 、X 2 、X 3 、X 4 and X 5 As defined herein.

[0072] In one embodiment, R 3 For NO2.

[0073] In one embodiment, R 1 C 1-4 In another embodiment, R 1 It is a methyl group.

[0074] In one embodiment, R 2 In another embodiment, R 2 It is a chlorine group.

[0075] In one embodiment, X 1 is N.

[0076] In one embodiment, X 2 It is O.

[0077] In one embodiment, X 3 For NH.

[0078] In one embodiment, X 4 For S.

[0079] In one embodiment, X 5 is N.

[0080] In one embodiment, the compound of formula (I) has the following structure:

[0081]

[0082] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is a compound of formula (I).

[0083] In one embodiment, the subject is a human.

[0084] In one embodiment, the disease, disorder or condition is a microbial infection, asthma, systemic inflammation, endothelial inflammation, allergy, urticaria, osteoporosis, chronic obstructive pulmonary disease (COPD), arthritis, autoimmune disease, cytokine release syndrome, ischemic osteonecrosis and / or sepsis. In another embodiment, the microbial infection is a viral infection, and the treatment is for viral-induced lung inflammation. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat a disease caused by the SARS-CoV-2 virus.

[0085] In one embodiment, the compound of formula (I) is administered by inhalation.

[0086] The present invention also includes the use of a compound of formula I(b), a pharmaceutically acceptable salt, solvate and / or prodrug thereof in medicine:

[0087]

[0088] in,

[0089] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0090] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0091] X 1 selected from N and CH;

[0092] X 2 Selected from O, S and NR 6 ;

[0093] X 3 Selected from O and NR 7 ;

[0094] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0095] X 5 selected from N and CH;

[0096] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0097] m is an integer from 0 to 5; and

[0098] n is an integer from 0 to 4;

[0099] in,

[0100] When m is 0, R 3 Selected from substituted or unsubstituted aryl, heteroaryl, halo, NO2 and SO2R 5 ;

[0101] When m is 1 and R 2 When it is a halogen group, n is an integer from 1 to 4, and R 3 is selected from substituted or unsubstituted aryl, heteroaryl and NO2;

[0102] When m is 2, R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, OR 4 , NO2 and SO2R 5 . .

[0103] In one embodiment, m is 1.

[0104] In one embodiment, n is 1.

[0105] In one embodiment:

[0106] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0107] R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0108] R 3 is NO2;

[0109] X 1 selected from N and CH;

[0110] X 2 Selected from O, S and NR 6 ;

[0111] X 3 Selected from O and NR 7 ;

[0112] X 4Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0113] X 5 selected from N and CH;

[0114] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0115] m is 1; and

[0116] n is an integer of 1 to 4.

[0117] In one embodiment, the compound of formula I(b) is a compound of formula I(c):

[0118]

[0119] where R 1 、R 2 、R 3 、X 1 、X 2 、X 3 、X 4 and X 5 As defined herein.

[0120] In one embodiment, R 3 For NO2.

[0121] In one embodiment, R 1 C 1-4 In another embodiment, R 1 It is a methyl group.

[0122] In one embodiment, R 2 In another embodiment, R 2 It is a chlorine group.

[0123] In one embodiment, X 1 is N.

[0124] In one embodiment, X 2 It is O.

[0125] In one embodiment, X 3 For NH.

[0126] In one embodiment, X 4 For S.

[0127] In one embodiment, X 5 is N.

[0128] In one embodiment: R 1 C 1-5 Alkyl, R 2 is a halogen group, R 3 NO2, X 1 N, X 2 O, X 3 NH, X 4 S, X 5 is N, m is 1 and n is 1.

[0129] In one embodiment, the compound of Formula I(b) has the following structure:

[0130]

[0131] In one embodiment, the compound of formula I(b), pharmaceutically acceptable salts, solvates and / or prodrugs thereof is a compound of formula I(b).

[0132] The present invention also includes a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

[0133] In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0134] Other features and advantages of the present invention will become apparent from the following detailed description. However, it should be understood that although the detailed description and specific examples are intended to illustrate embodiments of the present invention, they are only given by way of example, and the scope of the claims should not be limited by these embodiments, but should be defined based on the broadest interpretation consistent with the overall description. BRIEF DESCRIPTION OF THE DRAWINGS

[0135] The embodiments of the present invention will now be described in more detail with reference to the accompanying drawings, in which:

[0136] Figure 1 The inhibitory effect of 3-(2-chlorophenyl)-5-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)isoxazole-4-carboxamide ("B2") on SWAP-70 dimerization in living cells is shown compared to a control: the left panel shows the inhibitory effect of three different concentrations of B2 on the fluorescence-activated cell sorting-fluorescence resonance energy transfer (FACS-FRET) signal (FRET efficiency), and therefore on SWAP-70 dimerization, measured 20 minutes after stimulation of the cells; the right panel shows the inhibitory effect of 50 μM B2 at an earlier interval after stimulation. B2 was added to the cells 15 minutes before stimulation.

[0137] Figure 2 The figure shows the inhibitory effect of B2 on neutrophil reactive oxygen species (ROS) production compared to the control (far left). The effect of B2 at four different concentrations (from left to right: 100, 50, 20, and 10 μM) is shown. Each symbol represents a single experiment.

[0138] Figure 3 The inhibitory effect of B2 on neutrophil extracellular trap formation (NETosis) is shown. The effects of three different concentrations of B2 (from left to right: 100, 50, and 20 μM) are expressed as the % reduction relative to the untreated control; the data are the average of three experiments.

[0139] Figure 4 %CD38+ / CD19low (upper figure) and %CD138+ (lower figure) curve with B2 concentration change show that B2 is to the inhibitory effect of B lymphocyte plasmablast development.The effect of B2 compared with control (leftmost side) of two kinds of different concentrations (from right to left being followed successively by: 20 and 10 μ M) is shown.Each symbol represents an experiment.

[0140] Figure 5 Shown is the inhibitory effect of B2 on IgE production by B lymphocytes. B2 was applied at 3 different concentrations (from left to right: 50, 20 and 10 μM). Data show the average of >10 experiments.

[0141] Figure 6 The figure shows the inhibitory effect of B2 on mast cell degranulation. The left panel shows the % reduction in degranulation at three different concentrations of B2 (from left to right: 100, 50, and 20 μM). Data are the average of 11 experiments. The right panel shows the measurement of degranulation at three time points (from left to right: 30, 15, and 5 minutes) after the addition of 100 μM B2.

[0142] Figure 7 Figure 2 shows the inhibitory effect of B2 on eosinophil ROS production. The effects of three different concentrations of B2 (from right to left: 100, 50, and 25 μM) are shown compared to the control (far left) and the ROS-induced control (PMA; second from the left); data are the average of three experiments.

[0143] Figure 8 The regulatory effect of B2 on cytokine release from mast cells is shown as a curve of the mean relative intensity of cytokine levels relative to the control. Data are the mean of three experiments.

[0144] Figure 9The regulatory effect of B2 on cytokine release from B lymphocytes is shown. % reduction compared to stimulated controls is shown; data are the mean of 2 experiments.

[0145] Figure 10 The inhibitory effect of B2 on macrophage / monocyte migration is shown. Dark grey: dimethyl sulfoxide (DMSO) only; light grey: 50 μM B2. Shown is one exemplary experiment out of four.

[0146] Figure 11 The inhibitory effect of B2 on neutrophil adhesion to endothelial cells is shown. The number of adherent green fluorescent-labeled neutrophils per field of view is shown, normalized to the area covered by endothelial cells per field of view. Three concentrations of B2 are shown, alongside a solvent (DMSO) control. The figure shows one exemplary experiment out of three. DETAILED DESCRIPTION

[0147] I. Definition

[0148] Unless otherwise stated, the definitions and examples described in this section and other sections are intended to apply to all embodiments and aspects of the present invention, and those skilled in the art will understand these definitions and examples to apply to all embodiments and aspects.

[0149] As used herein, the words "comprising," "having," "including," or "containing" are inclusive or open-ended and do not exclude additional, unrecited elements or process / method steps. As used herein, the term "consisting of" and its derivatives are intended to serve as closed terms, specifying the presence of recited features, elements, components, groups, integers, and / or steps while excluding the presence of other unrecited features, elements, components, groups, integers, and / or steps. As used herein, the term "consisting essentially of" is intended to specify the presence of recited features, elements, components, groups, integers, and / or steps, as well as those features, elements, components, groups, integers, and / or steps that do not materially affect the basic and novel characteristics of such features, elements, components, groups, integers, and / or steps.

[0150] As used herein, terms of degree, such as "substantially," "about," and "approximately" mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed to include a deviation of at least ±5% or at least ±10% of the modified term if such deviation would not negate the meaning of the modified term.

[0151] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0152] As used herein, the term "and / or" means that the listed items are present or used individually or in combination. In practice, the term means that "at least one" or "one or more" of the listed items are present or used.

[0153] As used herein, the term "suitable" means that the selection of specific compounds and / or conditions depends on the specific synthetic operation to be performed and / or the characteristics of the compound to be converted, but such selection is well within the ability of those skilled in the art. All synthetic method steps described herein should be carried out under conditions sufficient to provide the indicated products. It will be understood by those skilled in the art that all reaction conditions, including, for example, the reaction solvent or the lack thereof, reaction time, reaction temperature, reaction pressure, the ratio of reactants, and whether the reaction should be carried out under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product, and that doing so is within their skill.

[0154] As used herein, the expression "to a sufficient extent" with respect to a reaction or process step disclosed herein means that the reaction or process step is carried out to the extent that the conversion of the starting material or substrate to the product is maximized. Conversion can be maximized when more than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% of the starting material or substrate is converted to the product.

[0155] As used herein, the term "subject" includes all members of the animal kingdom, including mammals, and optionally refers to humans. In one embodiment, the subject is a human.

[0156] The term "halo" as used herein refers to a halogen atom, and includes F, Cl, Br, and I. In one embodiment of the present invention, the halo group is a chloro group.

[0157] As used herein, the term "alkyl", whether used alone or as part of another group, refers to a straight or branched chain saturated alkyl group. The number of carbon atoms in the alkyl group is indicated by the numerical prefix "C n1-n2 ". For example, the term C 1-10 Alkyl refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0158] As used herein, the term "aryl", whether used alone or as part of another group, refers to a group containing at least one aromatic ring. When an aryl group contains more than one aromatic ring, the term "aryl" as used herein includes fused aromatic systems. In one embodiment, the aryl group contains 6, 9, 10 or 14 atoms, such as phenyl, naphthyl, indanyl or anthracenyl. The number of carbon atoms in the aryl group is indicated by the numerical prefix "C". n1-n2 ". For example, the term C 6-10 Aryl refers to an aromatic group having 6, 7, 8, 9 or 10 carbon atoms.

[0159] As used herein, the term "heteroaryl," whether used alone or as part of another group, refers to an aromatic ring-containing group having one or more polyvalent heteroatoms (e.g., heteroatoms independently selected from N, O, and S) as part of the ring structure. In one embodiment of the invention, the heteroaryl group includes at least 5 and up to 20 atoms in the ring. A heteroaryl group may contain more than one ring.

[0160] As used herein, the term "substituted" refers to a structure, molecule or group in which one or more available hydrogen atoms are replaced by one or more other chemical groups. It will be readily understood by those skilled in the art that the number of possible substituents depends, for example, on the specific structure, molecule or group and / or the number of available hydrogen atoms therein. For example, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 5, 4, 3, 2 and / or 1 available hydrogen atoms may be replaced by one or more other chemical groups. As used herein, the term "available hydrogen atom" refers to a hydrogen atom that can be replaced by a suitable substituent known to those skilled in the art. In one embodiment, the substituents are independently selected from C 1-4 Alkyl, aryl, heteroaryl, halogen, OR 9 , NO2 and SO2R 9 One or more of which R 9 Selected from H, C 1-4 Alkyl, aryl and heteroaryl.

[0161] As used herein, the term "B2" refers to the compound 3-(2-chlorophenyl)-5-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)isoxazole-4-carboxamide, the chemical structure of which is as follows:

[0162]

[0163] As used herein, the terms "compounds of the present invention" and "compounds of the present application" include compounds of formula (I) and pharmaceutically acceptable salts, solvates and / or prodrugs thereof, compounds of formula I(a) and pharmaceutically acceptable salts, solvates and / or prodrugs thereof, compounds of formula I(b) and pharmaceutically acceptable salts, solvates and / or prodrugs thereof, and compounds of formula I(c) and pharmaceutically acceptable salts, solvates and / or prodrugs thereof, as well as B2 and pharmaceutically acceptable salts, solvates and / or prodrugs thereof.

[0164] The term "pharmaceutically acceptable" means compatible with treatment of a subject (eg, a mammal such as a human).

[0165] As used herein, the term "pharmaceutically acceptable salt" refers to acid addition salts or base addition salts that are compatible with treatment of a subject.

[0166] "Acid addition salts compatible with the treatment of a subject" are any non-toxic inorganic or organic salts of any basic compound. For example, basic compounds that form acid addition salts include compounds containing easily protonated amine groups. Inorganic acids that can form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as metal salts such as disodium hydrogen phosphate and potassium hydrogen sulfate. Organic acids that can form suitable salts include monocarboxylic acids, dicarboxylic acids and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Suitable salts can be selected by those skilled in the art. For example, the formation of the desired acid addition salt can be achieved using standard techniques. For example, in one embodiment of the invention, the neutral compound is treated with the desired acid in a suitable solvent, and the salt thus formed is then separated by filtration, extraction and / or any other suitable method.

[0167] "Base addition salts compatible with the treatment of a subject" refers to any non-toxic inorganic or organic salt of any acidic compound. For example, acidic compounds that form base addition salts include compounds containing a sulfonic acid group. Inorganic bases that can form suitable salts include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Organic bases that can form suitable salts include, but are not limited to, aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and picoline or ammonia. Suitable salts can be selected by those skilled in the art. For example, the formation of the desired base addition salt can be achieved using standard techniques. For example, in one embodiment of the invention, the neutral compound is treated with the desired base in a suitable solvent and the salt thus formed is then isolated by filtration, extraction, and / or any other suitable method.

[0168] As used herein with respect to the compounds of the present invention, the term "solvate" refers to a complex formed between the compound and the solvent in which the compound is precipitated or the solvent in which the compound is manufactured. Thus, as used herein, the term "solvate" refers to a compound of the present invention in which molecules of a suitable solvent are incorporated into its crystal lattice. Examples of suitable solvents include ethanol, water, and the like. When water is the solvent, the complex may optionally be referred to as a "hydrate." The formation of solvates varies depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in an appropriate solvent and then separating the solvate by cooling or using an antisolvent and / or reducing and / or evaporating the solvent. Solvates are typically dried or azeotropically prepared under ambient conditions. Those skilled in the art can select appropriate conditions to form a specific solvate.

[0169] As used herein with respect to the compounds of the present invention, the term "prodrug" refers to a derivative of the compound that reacts under biological conditions to produce the compound.

[0170] As used herein, the term "inflammatory disease, disorder or condition" refers to a disease, disorder or condition that comprises one or more inflammatory processes that are inhibited by B2 and / or other compounds of the invention, such as inflammatory processes in which SWAP-70 is expressed in target cells and associated with the activity and properties of SWAP-70.These inflammatory processes may include, for example: (a) macrophages / monocytes: migration, phagocytosis associated with hyperactivation, excessive production of proinflammatory cytokines, adhesion to endothelial cells (important in atherosclerosis - foam cell formation), and / or development of M1 proinflammatory macrophages; (b) basophils: IgE-triggered degranulation leading to allergies, asthma, and other inflammatory processes, and / or excessive production of proinflammatory cytokines; (c) endothelial cells: cytokine release, excessive production of ROS, excessive proliferation and migration, abnormal activation of blood coagulation during inflammation and / or infection, chronic endothelial inflammation in conditions of endothelial dysfunction such as atherosclerosis and COPD, and / or endothelial cell-immunity. Cellular interactions, for example, immune cell adhesion to endothelial cells (other than neutrophils), such as monocytes in atherosclerosis, can also inhibit cell migration into tissues, such as during inflammatory arthritis; (d) Mast cells: degranulation, cytokine release, signaling through FceRI (IgE receptor), signaling through c-kit (the most important differentiation and activation receptor), and / or excessive production of proinflammatory non-cytokine mediators (e.g., prostaglandins and / or leukotrienes); (e) B lymphocytes: plasmablast development, IgE production, cytokine release, Toll-like receptor-triggered excessive and potentially autoreactive plasmablast formation, BT cells in excessive inflammatory processes (f) dendritic cells: excessive activation leading to autoimmune responses; (g) eosinophils: ROS generation, eosinophil migration (an important process in asthma and other inflammatory conditions), degranulation and release of invasive proteins (e.g., hydrolases, peroxidases, ribonucleases, deoxyribonucleases, lipases, and / or elastases), excessive production of proinflammatory cytokines and lipid mediators, and / or eosinophil adhesion to endothelial cells; (h) neutrophils: ROS generation, extracellular trap formation, degranulation of primary, secondary, and tertiary granules, excessive production of proinflammatory cytokines, and / or migration into tissues; (i) ) osteoclasts: fusion of preosteoclasts with multinucleated functional osteoclasts, an important differentiation step; (j) chondrocytes: in diseases such as rheumatoid arthritis, septic arthritis and / or avascular necrosis, these cells, similar to osteoclasts, lead to cartilage degradation; and / or form multinucleated chondroclasts; (k) regulatory T cells (Tregs): downregulate overactivated and functionally reversed Tregs, which promote rather than suppress inflammation; and / or (l) type 2 innate lymphocytes: express proinflammatory cytokines (such as in influenza, RSV infection, allergy and / or asthma), undergo migration and adhesion in pathological environments, and / or platelet-ILC2 adhesion in asthma.In one embodiment, the inflammatory process is neutrophil reactive oxygen species (ROS) generation, neutrophil extracellular trap formation, B lymphocyte plasmablast development, B lymphocyte IgE production, mast cell degranulation, eosinophil ROS generation, mast cell cytokine release, B lymphocyte cytokine release, endothelial cell cytokine release, endothelial cell-immune cell interaction and / or macrophage / monocyte migration, and the compounds of the present invention can inhibit these inflammatory processes.

[0171] As used herein, for example, with respect to the above-mentioned inflammatory processes and / or conditions, diseases and disorders that can be treated by inhibiting SWAP-70 and / or can be treated by inhibiting neutrophil reactive oxygen species (ROS) production, neutrophil extracellular trap formation, B lymphocyte plasmablast development, B lymphocyte IgE production, mast cell degranulation, eosinophil ROS production, mast cell cytokine release, B lymphocyte cytokine release, endothelial cell cytokine release, endothelial cell-immune cell interaction and / or macrophage / monocyte migration, the term "inhibit" refers to an inhibitory effect that results in a therapeutic effect and can be any detectable inhibitory effect in the presence of a compound of the invention compared to the same situation in the absence of the compound. It will be understood by those skilled in the art after considering the present disclosure that certain functions of SWAP-70, such as supporting an appropriate immune response, may not require inhibition - as long as the immune system remains balanced. Conversely, if these functions are overactivated, downregulation may be beneficial, and in such cases, it is best to only moderately downregulate these processes rather than completely abolish them. For example, such inflammatory processes include "excessive" inflammatory processes such as those described above.

[0172] As used herein and as the term "treatment" as known in the art refers to a method for obtaining beneficial or expected results (including clinical results). For example, in the case of treating lung inflammation, beneficial or expected clinical results include but are not limited to alleviating or improving one or more symptoms of lung inflammation, reducing the degree of lung inflammation, stabilizing lung inflammation (i.e., not worsening), delaying or slowing the progression of lung inflammation, improving or alleviating the disease state of lung inflammation, reducing the recurrence of lung inflammation and / or alleviating (whether partially or completely) lung inflammation, whether detectable or undetectable. As used herein, "treatment" also includes prophylactic treatment.

[0173] For example, the compounds of the present invention are administered to a subject or used in an "effective amount". As used herein, the term "effective amount" and similar terms refer to an amount that is effective at the dosage and time necessary to achieve the desired result. For example, in the case of treating lung inflammation, an effective amount of the compound administered or used refers to an amount that can reduce lung inflammation, for example, compared to lung inflammation when the compound is not administered or used. The effective amount can vary depending on factors such as the disease state, age, sex, weight and / or species of the subject. The amount of a given compound corresponding to this effective amount will vary depending on various factors, such as a given compound, pharmaceutical formulation, route of administration or use, type of condition, disease or disorder being treated, characteristics of the subject being treated, etc., but can be determined routinely by those skilled in the art.

[0174] II. Methods of treatment and uses

[0175] Compound B2 was screened in vitro for inhibiting SWAP-70, and it was subsequently demonstrated that compound B2 could block the dimerization of SWAP-70. It has been shown herein that B2 can inhibit corresponding disease-related processes in different human primary leukocyte populations. Therefore, B2 and / or other compounds of the present invention are suitable for treating diseases, disorders or conditions that can be treated by inhibiting SWAP-70 and / or can be treated by inhibiting neutrophil reactive oxygen species (ROS) generation, neutrophil extracellular trap formation, B lymphocyte plasmablast development, B lymphocyte IgE generation, mast cell degranulation, eosinophil ROS generation, mast cell cytokine release, B lymphocyte cytokine release, endothelial cell cytokine release, endothelial cell-immune cell interaction and / or macrophage / monocyte migration, and / or are suitable for treating inflammatory diseases, disorders or conditions.

[0176] Thus, the present invention includes a method of treating an inflammatory disease, disorder or condition comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:

[0177]

[0178] in

[0179] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0180] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0181] X 1 selected from N and CH;

[0182] X 2 Selected from O, S and NR 6 ;

[0183] X 3 Selected from O and NR 7 ;

[0184] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0185] X 5 selected from N and CH;

[0186] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0187] m is an integer from 0 to 5; and

[0188] n is an integer from 0 to 4.

[0189] The present invention also includes the use of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for treating an inflammatory disease, disorder or condition in a subject in need thereof:

[0190]

[0191] in

[0192] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0193] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0194] X 1 selected from N and CH;

[0195] X 2 Selected from O, S and NR 6 ;

[0196] X 3 Selected from O and NR 7 ;

[0197] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0198] X 5 selected from N and CH;

[0199] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0200] m is an integer from 0 to 5; and

[0201] n is an integer from 0 to 4.

[0202] The present invention also includes the use of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for the preparation of a medicament for treating an inflammatory disease, disorder or condition in a subject in need thereof:

[0203]

[0204] in

[0205] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0206] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0207] X 1 selected from N and CH;

[0208] X 2 Selected from O, S and NR 6 ;

[0209] X 3 Selected from O and NR 7 ;

[0210] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0211] X 5 selected from N and CH;

[0212] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0213] m is an integer from 0 to 5; and

[0214] n is an integer from 0 to 4.

[0215] The present invention also includes a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for use in treating an inflammatory disease, disorder or condition:

[0216]

[0217] in

[0218] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0219] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0220] X 1 selected from N and CH;

[0221] X 2 Selected from O, S and NR 6 ;

[0222] X 3 Selected from O and NR 7 ;

[0223] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0224] X 5 selected from N and CH;

[0225] R 4 、R 5 、R 6 、R 7 and R8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0226] m is an integer from 0 to 5; and

[0227] n is an integer from 0 to 4.

[0228] The present invention also includes a method of treating a disease, disorder or condition that is treatable by inhibiting SWAP-70, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:

[0229]

[0230] in

[0231] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0232] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0233] X 1 selected from N and CH;

[0234] X 2 Selected from O, S and NR 6 ;

[0235] X 3 Selected from O and NR 7 ;

[0236] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0237] X 5 selected from N and CH;

[0238] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0239] m is an integer from 0 to 5; and

[0240] n is an integer from 0 to 4.

[0241] The present invention also includes the use of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for treating a disease, disorder or condition in a subject in need thereof, including a disease, disorder or condition that can be treated by inhibiting SWAP-70:

[0242]

[0243] in

[0244] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0245] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0246] X 1 selected from N and CH;

[0247] X 2 Selected from O, S and NR 6 ;

[0248] X 3 Selected from O and NR 7 ;

[0249] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0250] X 5 selected from N and CH;

[0251] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0252] m is an integer from 0 to 5; and

[0253] n is an integer from 0 to 4.

[0254] The present invention also includes the use of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof in the preparation of a medicament for treating a disease, disorder or condition in a subject in need thereof, including a medicament for treating a disease, disorder or condition in a subject in need thereof, including a disease, disorder or condition that can be treated by inhibiting SWAP-70:

[0255]

[0256] in

[0257] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0258] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0259] X 1 selected from N and CH;

[0260] X 2 Selected from O, S and NR 6 ;

[0261] X 3 Selected from O and NR 7 ;

[0262] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0263] X 5 selected from N and CH;

[0264] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0265] m is an integer from 0 to 5; and

[0266] n is an integer from 0 to 4.

[0267] The present invention also includes a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for use in treating a disease, disorder or condition treatable by inhibiting SWAP-70 in a subject in need thereof:

[0268]

[0269] in

[0270] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0271] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0272] X 1 selected from N and CH;

[0273] X 2 Selected from O, S and NR 6 ;

[0274] X 3 Selected from O and NR 7 ;

[0275] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0276] X 5 selected from N and CH;

[0277] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0278] m is an integer from 0 to 5; and

[0279] n is an integer from 0 to 4.

[0280] The present invention also includes a method for treating a disease, disorder or condition that can be treated by inhibiting neutrophil reactive oxygen species (ROS) generation, neutrophil extracellular trap formation, B lymphocyte plasmablast development, B lymphocyte IgE production, mast cell degranulation, eosinophil ROS generation, mast cell cytokine release, B lymphocyte cytokine release, endothelial cell cytokine release, endothelial cell-immune cell interaction and / or macrophage / monocyte migration, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:

[0281]

[0282] in

[0283] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0284] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0285] X 1 selected from N and CH;

[0286] X 2 Selected from O, S and NR 6 ;

[0287] X 3 Selected from O and NR 7 ;

[0288] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0289] X 5 selected from N and CH;

[0290] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0291] m is an integer from 0 to 5; and

[0292] n is an integer from 0 to 4.

[0293] The present invention also includes the use of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for treating a disease, disorder or condition in a subject in need thereof, including diseases, disorders or conditions that can be treated by inhibiting neutrophil reactive oxygen species (ROS) generation, neutrophil extracellular trap formation, B lymphocyte plasmablast development, B lymphocyte IgE production, mast cell degranulation, eosinophil ROS generation, mast cell cytokine release, B lymphocyte cytokine release, endothelial cell cytokine release, endothelial cell-immune cell interaction and / or macrophage / monocyte migration:

[0294]

[0295] in

[0296] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0297] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0298] X 1 selected from N and CH;

[0299] X 2 Selected from O, S and NR 6 ;

[0300] X 3 Selected from O and NR 7 ;

[0301] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0302] X 5 selected from N and CH;

[0303] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0304] m is an integer from 0 to 5; and

[0305] n is an integer from 0 to 4.

[0306] The present invention also includes the use of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof in the preparation of a medicament for treating a disease, disorder or condition in a subject in need thereof, wherein the medicament for treating a disease, disorder or condition in a subject in need thereof includes a medicament for treating a disease, disorder or condition that can be treated by inhibiting neutrophil reactive oxygen species (ROS) generation, neutrophil extracellular trap formation, B lymphocyte plasmablast development, B lymphocyte IgE production, mast cell degranulation, eosinophil ROS generation, mast cell cytokine release, B lymphocyte cytokine release, endothelial cell cytokine release, endothelial cell-immune cell interaction and / or macrophage / monocyte migration:

[0307]

[0308] in

[0309] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0310] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0311] X 1 selected from N and CH;

[0312] X 2 Selected from O, S and NR 6 ;

[0313] X 3 Selected from O and NR 7 ;

[0314] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0315] X 5 selected from N and CH;

[0316] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10alkyl, substituted or unsubstituted aryl and heteroaryl;

[0317] m is an integer from 0 to 5; and

[0318] n is an integer from 0 to 4.

[0319] The present invention also includes a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for use in treating a disease, disorder or condition that can be treated by inhibiting neutrophil reactive oxygen species (ROS) generation, neutrophil extracellular trap formation, B lymphocyte plasmablast development, B lymphocyte IgE production, mast cell degranulation, eosinophil ROS generation, mast cell cytokine release, B lymphocyte cytokine release, endothelial cell cytokine release, endothelial cell-immune cell interaction and / or macrophage / monocyte migration in a subject in need thereof:

[0320]

[0321] in

[0322] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0323] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0324] X 1 selected from N and CH;

[0325] X 2 Selected from O, S and NR 6 ;

[0326] X 3 Selected from O and NR 7 ;

[0327] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0328] X 5 selected from N and CH;

[0329] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0330] m is an integer from 0 to 5; and

[0331] n is an integer from 0 to 4.

[0332] In one embodiment, m is an integer from 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In another embodiment, m is 4, 3, 2, or 1. In one embodiment, m is not 0. In one embodiment, m is not 2. In one embodiment, m is 1. In one embodiment, when m is 0, R 3 Selected from substituted or unsubstituted aryl, heteroaryl, halo, NO2 and SO2R 5 In another embodiment, when m is 1 and R 2 When it is a halogen group, n is an integer from 1 to 4, and R 3 is selected from substituted or unsubstituted aryl, heteroaryl and NO2. In another embodiment, when m is 2, R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, OR 4 , NO2 and SO2R 5 .

[0333] In one embodiment, n is an integer from 1 to 4, 1 to 3, or 1 to 2. In another embodiment, n is 3, 2, or 1. In yet another embodiment, n is 1.

[0334] In one embodiment:

[0335] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0336] R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0337] R 3 is NO2;

[0338] X 1 selected from N and CH;

[0339] X 2 Selected from O, S and NR 6 ;

[0340] X 3 Selected from O and NR 7 ;

[0341] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0342] X 5 selected from N and CH;

[0343] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0344] m is 1; and

[0345] n is an integer of 1 to 4.

[0346] In one embodiment, the compound of formula (I) is a compound of formula I(a):

[0347]

[0348] in

[0349] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0350] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0351] X 1 selected from N and CH;

[0352] X 2 Selected from O, S and NR 6 ;

[0353] X 3 Selected from O and NR 7 ;

[0354] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0355] X 5 is selected from N and CH; and

[0356] R 4 、R5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl; or

[0357] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0358] R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0359] R 3 is NO2;

[0360] X 1 selected from N and CH;

[0361] X 2 Selected from O, S and NR 6 ;

[0362] X 3 Selected from O and NR 7 ;

[0363] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0364] X 5 is selected from N and CH; and

[0365] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl.

[0366] In one embodiment, R 1 is H. In another embodiment, R 1 Selected from C 1-10 In another embodiment, R 1 C 1-10 In another embodiment, R 1 C 1-5 In another embodiment, R 1 C1-4 In another embodiment, R 1 It is a methyl group.

[0367] In one embodiment, R 2 In another embodiment, R 2 It is a chlorine group.

[0368] In one embodiment, R 3 In one embodiment, R 3 Not for SO2R 5 .

[0369] In one embodiment, R 4 is H. In another embodiment, R 4 Selected from C 1-10 In another embodiment, R 4 C 1-10 In another embodiment, R 4 is a substituted or unsubstituted aryl group. In one embodiment, R 4 It is a heteroaryl group.

[0370] In one embodiment, R 5 is H. In another embodiment, R 5 Selected from C 1-10 In another embodiment, R 5 C 1-10 In another embodiment, R 5 is a substituted or unsubstituted aryl group. In one embodiment, R 5 It is a heteroaryl group.

[0371] In one embodiment, R 6 is H. In another embodiment, R 6 Selected from C 1-10 In another embodiment, R 6 C 1-10 In another embodiment, R 6 is a substituted or unsubstituted aryl group. In one embodiment, R 6 It is a heteroaryl group.

[0372] In one embodiment, R 7 is H. In another embodiment, R 7 Selected from C 1-10 In another embodiment, R7 C 1-10 In another embodiment, R 7 is a substituted or unsubstituted aryl group. In one embodiment, R 7 It is a heteroaryl group.

[0373] In one embodiment, R 8 is H. In another embodiment, R 8 Selected from C 1-10 In another embodiment, R 8 C 1-10 In another embodiment, R 8 is a substituted or unsubstituted aryl group. In one embodiment, R 8 It is a heteroaryl group.

[0374] In one embodiment, X 1 is N.

[0375] In one embodiment, X 2 It is O.

[0376] In one embodiment, X 3 NR 7 In another embodiment, X 3 For NH.

[0377] In one embodiment, X 4 For S.

[0378] In one embodiment, X 5 is N.

[0379] In one embodiment, X 1 N, X 2 O, X 3 NH, X 4 S and / or X 5 is N.

[0380] In one embodiment, the compound of formula (I) has the following structure:

[0381]

[0382] In one embodiment, the compound of formula (I) is a compound of formula I(b), a pharmaceutically acceptable salt, solvate and / or prodrug thereof:

[0383]

[0384] in,

[0385] m is an integer from 0 to 5;

[0386] n is an integer from 0 to 4;

[0387] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0388] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0389] X 1 selected from N and CH;

[0390] X 2 Selected from O, S and NR 6 ;

[0391] X 3 Selected from O and NR 7 ;

[0392] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0393] X 5 is selected from N and CH; and

[0394] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0395] The restrictions are:

[0396] When m is 0, R 3 Selected from substituted or unsubstituted aryl, heteroaryl, halo, NO2 and SO2R 5 ;

[0397] When m is 1 and R 2 When it is a halogen group, n is an integer from 1 to 4, and R 3 is selected from substituted or unsubstituted aryl, heteroaryl and NO2; and

[0398] When m is 2, R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, OR 4 , NO2 and SO2R5 .

[0399] In one embodiment, m is an integer from 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In another embodiment, m is 4, 3, 2, or 1. In one embodiment, m is not 0. In one embodiment, m is not 2. In one embodiment, m is 1.

[0400] In one embodiment, n is an integer from 1 to 4, 1 to 3, or 1 to 2. In another embodiment, n is 3, 2, or 1. In yet another embodiment, n is 1.

[0401] In one embodiment:

[0402] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0403] R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0404] R 3 is NO2;

[0405] X 1 selected from N and CH;

[0406] X 2 Selected from O, S and NR 6 ;

[0407] X 3 Selected from O and NR 7 ;

[0408] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0409] X 5 selected from N and CH;

[0410] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0411] m is 1; and

[0412] n is an integer of 1 to 4.

[0413] In one embodiment, the compound of formula I(b) is a compound of formula I(c):

[0414]

[0415] in

[0416] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0417] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0418] X 1 selected from N and CH;

[0419] X 2 Selected from O, S and NR 6 ;

[0420] X 3 Selected from O and NR 7 ;

[0421] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0422] X 5 is selected from N and CH; and

[0423] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0424] The restrictions are:

[0425] When m is 0, R 3 Selected from substituted or unsubstituted aryl, heteroaryl, halo, NO2 and SO2R 5 ;

[0426] When m is 1 and R 2 When it is a halogen group, n is an integer from 1 to 4, and R 3 is selected from substituted or unsubstituted aryl, heteroaryl and NO2; and

[0427] When m is 2, R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, OR 4 , NO2 and SO2R 5 ;or

[0428] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0429] R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0430] R 3 is NO2;

[0431] X 1 selected from N and CH;

[0432] X 2 Selected from O, S and NR 6 ;

[0433] X 3 Selected from O and NR 7 ;

[0434] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0435] X 5 is selected from N and CH; and

[0436] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl.

[0437] In one embodiment, R 1 is H. In another embodiment, R 1 Selected from C 1-10 In another embodiment, R 1 C 1-10 In another embodiment, R 1 C 1-5 In another embodiment, R 1 C 1-4In another embodiment, R 1 It is a methyl group.

[0438] In one embodiment, R 2 In another embodiment, R 2 It is a chlorine group.

[0439] In one embodiment, R 3 In one embodiment, R 3 Not for SO2R 5 .

[0440] In one embodiment, R 4 is H. In another embodiment, R 4 Selected from C 1-10 In another embodiment, R 4 C 1-10 In another embodiment, R 4 is a substituted or unsubstituted aryl group. In one embodiment, R 4 It is a heteroaryl group.

[0441] In one embodiment, R 5 is H. In another embodiment, R 5 Selected from C 1-10 In another embodiment, R 5 C 1-10 In another embodiment, R 5 is a substituted or unsubstituted aryl group. In one embodiment, R 5 It is a heteroaryl group.

[0442] In one embodiment, R 6 is H. In another embodiment, R 6 Selected from C 1-10 In another embodiment, R 6 C 1-10 In another embodiment, R 6 is a substituted or unsubstituted aryl group. In one embodiment, R 6 It is a heteroaryl group.

[0443] In one embodiment, R 7 is H. In another embodiment, R 7 Selected from C 1-10 In another embodiment, R 7 C1-10 In another embodiment, R 7 is a substituted or unsubstituted aryl group. In one embodiment, R 7 It is a heteroaryl group.

[0444] In one embodiment, R 8 is H. In another embodiment, R 8 Selected from C 1-10 In another embodiment, R 8 C 1-10 In another embodiment, R 8 is a substituted or unsubstituted aryl group. In one embodiment, R 8 It is a heteroaryl group.

[0445] In one embodiment, X 1 is N.

[0446] In one embodiment, X 2 It is O.

[0447] In one embodiment, X 3 NR 7 In another embodiment, X 3 For NH.

[0448] In one embodiment, X 4 For S.

[0449] In one embodiment, X 5 is N.

[0450] In one embodiment, R 1 C 1-5 Alkyl; R 2 is a halogen group; R 3 NO2; X 1 N; X 2 O; X 3 NH; X 4 S; X 5 is N; m is 1; and n is 1.

[0451] The present invention also includes the use of a compound of formula I(b), a pharmaceutically acceptable salt, solvate and / or prodrug thereof in medicine:

[0452]

[0453] in

[0454] R 1 Selected from H, C 1-10alkyl, substituted or unsubstituted aryl and heteroaryl;

[0455] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0456] X 1 selected from N and CH;

[0457] X 2 Selected from O, S and NR 6 ;

[0458] X 3 Selected from O and NR 7 ;

[0459] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0460] X 5 selected from N and CH;

[0461] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0462] m is an integer from 0 to 5;

[0463] n is an integer from 0 to 4;

[0464] in,

[0465] When m is 0, R 3 Selected from substituted or unsubstituted aryl, heteroaryl, halo, NO2 and SO2R 5 ;

[0466] When m is 1 and R 2 When it is a halogen group, n is an integer from 1 to 4, and R 3 is selected from substituted or unsubstituted aryl, heteroaryl and NO2;

[0467] When m is 2, R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, OR 4 , NO2 and SO2R 5 .

[0468] In one embodiment, m is an integer from 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In another embodiment, m is 4, 3, 2, or 1. In one embodiment, m is not 0. In one embodiment, m is not 2. In one embodiment, m is 1.

[0469] In one embodiment, n is an integer from 1 to 4, 1 to 3, or 1 to 2. In another embodiment, n is 3, 2, or 1. In yet another embodiment, n is 1.

[0470] In one embodiment:

[0471] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0472] R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0473] R 3 is NO2;

[0474] X 1 selected from N and CH;

[0475] X 2 Selected from O, S and NR 6 ;

[0476] X 3 Selected from O and NR 7 ;

[0477] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0478] X 5 selected from N and CH;

[0479] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0480] m is 1; and

[0481] n is an integer of 1 to 4.

[0482] In one embodiment, the compound of formula I(b) is a compound of formula I(c):

[0483]

[0484] in

[0485] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0486] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0487] X 1 selected from N and CH;

[0488] X 2 Selected from O, S and NR 6 ;

[0489] X 3 Selected from O and NR 7 ;

[0490] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0491] X 5 is selected from N and CH; and

[0492] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0493] The restrictions are:

[0494] When m is 0, R 3 Selected from substituted or unsubstituted aryl, heteroaryl, halo, NO2 and SO2R 5 ;

[0495] When m is 1 and R 2 When it is a halogen group, n is an integer from 1 to 4, and R 3 is selected from substituted or unsubstituted aryl, heteroaryl and NO2; and

[0496] When m is 2, R2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, OR 4 , NO2 and SO2R 5 ;or

[0497] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0498] R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0499] R 3 is NO2;

[0500] X 1 selected from N and CH;

[0501] X 2 Selected from O, S and NR 6 ;

[0502] X 3 Selected from O and NR 7 ;

[0503] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0504] X 5 is selected from N and CH; and

[0505] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl.

[0506] In one embodiment, R 1 is H. In another embodiment, R 1 Selected from C 1-10 In another embodiment, R 1 C 1-10 In another embodiment, R 1 C 1-5 In another embodiment, R 1 C 1-4In another embodiment, R 1 It is a methyl group.

[0507] In one embodiment, R 2 In another embodiment, R 2 It is a chlorine group.

[0508] In one embodiment, R 3 In one embodiment, R 3 Not for SO2R 5 .

[0509] In one embodiment, R 4 is H. In another embodiment, R 4 Selected from C 1-10 In another embodiment, R 4 C 1-10 In another embodiment, R 4 is a substituted or unsubstituted aryl group. In one embodiment, R 4 It is a heteroaryl group.

[0510] In one embodiment, R 5 is H. In another embodiment, R 5 Selected from C 1-10 In another embodiment, R 5 C 1-10 In another embodiment, R 5 is a substituted or unsubstituted aryl group. In one embodiment, R 5 It is a heteroaryl group.

[0511] In one embodiment, R 6 is H. In another embodiment, R 6 Selected from C 1-10 In another embodiment, R 6 C 1-10 In another embodiment, R 6 is a substituted or unsubstituted aryl group. In one embodiment, R 6 It is a heteroaryl group.

[0512] In one embodiment, R 7 is H. In another embodiment, R 7 Selected from C 1-10 In another embodiment, R 7 C1-10 In another embodiment, R 7 is a substituted or unsubstituted aryl group. In one embodiment, R 7 It is a heteroaryl group.

[0513] In one embodiment, R 8 is H. In another embodiment, R 8 Selected from C 1-10 In another embodiment, R 8 C 1-10 In another embodiment, R 8 is a substituted or unsubstituted aryl group. In one embodiment, R 8 It is a heteroaryl group.

[0514] In one embodiment, X 1 is N.

[0515] In one embodiment, X 2 It is O.

[0516] In one embodiment, X 3 NR 7 In another embodiment, X 3 For NH.

[0517] In one embodiment, X 4 For S.

[0518] In one embodiment, X 5 is N.

[0519] In one embodiment, R 1 C 1-5 Alkyl; R 2 is a halogen group; R 3 NO2; X 1 N; X 2 O; X 3 NH; X 4 S; X 5 is N; m is 1; and n is 1.

[0520] In one embodiment, the compound of formula (I) has the following structure:

[0521]

[0522] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is a compound of formula (I); that is, it is not a pharmaceutically acceptable salt, solvate and / or prodrug of a compound of formula (I).

[0523] In one embodiment, the subject is a human.

[0524] The disease, disorder or condition can be any suitable inflammatory disease, disorder or condition, and / or can be treated by inhibiting SWAP-70 and / or can be treated by inhibiting neutrophil reactive oxygen species (ROS) generation, neutrophil extracellular trap formation, B lymphocyte plasmablast development, B lymphocyte IgE production, mast cell degranulation, eosinophil ROS generation, mast cell cytokine release, B lymphocyte cytokine release, endothelial cell cytokine release, endothelial cell-immune cell interactions and / or macrophage / monocyte migration.

[0525] In one embodiment, the disease, disorder or condition can be treated by inhibiting neutrophil reactive oxygen species (ROS) production. In another embodiment, the disease, disorder or condition can be treated by inhibiting neutrophil extracellular trap formation. In another embodiment, the disease, disorder or condition can be treated by inhibiting B lymphocyte plasmablast development. In another embodiment, the disease, disorder or condition can be treated by inhibiting B lymphocyte IgE production. In another embodiment, the disease, disorder or condition can be treated by inhibiting mast cell degranulation. In another embodiment, the disease, disorder or condition can be treated by inhibiting eosinophil reactive oxygen species (ROS) production. In another embodiment, the disease, disorder or condition can be treated by inhibiting mast cell cytokine release. In another embodiment, the disease, disorder or condition can be treated by inhibiting B lymphocyte cytokine release. In another embodiment, the disease, disorder or condition can be treated by inhibiting endothelial cell cytokine release. In another embodiment, the disease, disorder or condition is an endothelial cell-immune cell interaction that can be treated by inhibition. In another embodiment, the disease, disorder or condition can be treated by inhibiting macrophage / monocyte migration. In another embodiment, the disease, disorder or condition can be treated by inhibiting neutrophil reactive oxygen species (ROS) generation, neutrophil extracellular trap formation, B lymphocyte plasmablast development, B lymphocyte IgE generation, mast cell degranulation, eosinophil ROS generation, mast cell cytokine release, B lymphocyte cytokine release, endothelial cell cytokine release, endothelial cell-immune cell interaction and macrophage / monocyte migration.

[0526] In one embodiment, the disease, disorder or condition is a microbial infection, asthma, systemic inflammation, endothelial inflammation, allergy, urticaria, osteoporosis, chronic obstructive pulmonary disease (COPD), arthritis, an autoimmune disease, cytokine release syndrome, avascular necrosis and / or sepsis.

[0527] In one embodiment, the disease, disorder or condition is a microbial infection. In one embodiment, the microbial infection is a viral infection or a bacterial infection. In another embodiment, the microbial infection is a viral infection. In one embodiment, the viral infection is caused by SARS-CoV-2 virus, respiratory syncytial virus (RSV) or influenza virus (e.g., influenza A). In another embodiment, the viral infection is caused by SARS-CoV-2 virus. Therefore, in one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat a disease caused by the SARS-CoV-2 virus. In another embodiment, the microbial infection is a bacterial infection. In one embodiment, the bacterium is Yersinia pestis.

[0528] In one embodiment, treatment is for lung inflammation. Pulmonary inflammation may be viral-induced lung inflammation or non-viral lung inflammation. In one embodiment, lung inflammation is viral-induced lung inflammation. In another embodiment, lung inflammation is bacterial-induced lung inflammation. For example, in one embodiment, microbial infection is viral infection, and treatment is for viral-induced lung inflammation. In one embodiment, treatment of lung inflammation prevents subsequent opportunistic pneumonia. In another embodiment, opportunistic pneumonia is caused by a virus (e.g., rhinovirus or influenza virus), a bacterium (e.g., Streptococcus pneumoniae) or a combination thereof.

[0529] In one embodiment, the disease, disorder or condition is systemic inflammation. Systemic inflammation can be virally induced systemic inflammation or non-viral systemic inflammation. Systemic inflammation can be, for example, a consequence of lung inflammation or a direct inflammatory process. In one embodiment, systemic inflammation includes inflammation of the gastrointestinal system, kidneys, heart, nervous system, skin and / or liver.

[0530] In one embodiment, the disease, disorder or condition is endothelial inflammation. In another embodiment, the treatment is for atherosclerosis and / or coronary artery disease.

[0531] In one embodiment, the disease, disorder or condition is sepsis. In another embodiment, the sepsis is bacterial sepsis.

[0532] In one embodiment, the disease, disorder or condition is allergy. In another embodiment, the allergy is an IgE-mediated allergy selected from contact allergy, atopic dermatitis, food allergy (such as nut allergy), hay fever and venom allergy.

[0533] In one embodiment, the disease, disorder, or condition is asthma. In one embodiment, asthma is triggered by an IgE-allergen reaction. In another embodiment, asthma is chronic asthma. In another embodiment, asthma is acute asthma. In yet another embodiment, the treatment is for the prevention of an acute asthma attack.

[0534] In one embodiment, the disease, disorder, or condition is urticaria. In one embodiment, the urticaria is pseudoallergic urticaria. In another embodiment, the urticaria is acute. In yet another embodiment, the urticaria is chronic.

[0535] In one embodiment, the disease, disorder or condition is osteoporosis.

[0536] In one embodiment, the disease, disorder or condition is chronic obstructive pulmonary disease (COPD). In one embodiment, treatment is for acute COPD attacks. In another embodiment, treatment is for chronic COPD. In another embodiment, treatment is to prevent the development of progressive COPD disease in chronic COPD subjects.

[0537] In one embodiment, the disease, disorder or condition is arthritis (e.g., inflammatory arthritis). In one embodiment, the arthritis is septic arthritis and / or rheumatoid arthritis (RA). In another embodiment, the arthritis is rheumatoid arthritis (RA). In yet another embodiment, the treatment is for an acute attack of RA. In another embodiment, the treatment is to prevent RA from worsening. In another embodiment, the inflammatory arthritis is gout.

[0538] In one embodiment, the disease, disorder or condition is an autoimmune disease. In another embodiment, the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, bullous pemphigoid, psoriasis or atopic dermatitis.

[0539] In one embodiment, the disease, disorder, or condition is cytokine release syndrome. In one embodiment, the treatment is for thrombosis associated with a cytokine storm. In one embodiment, the thrombosis is associated with a soluble adhesion molecule inhibited by the compounds of the present invention. In one embodiment, the treatment is for venous thromboembolism. In another embodiment, the treatment is for arterial thrombosis, an inflammatory disease.

[0540] In one embodiment, the disease, disorder or condition is avascular necrosis.

[0541] In one embodiment, the subject is suffering from a combination of two or more diseases, disorders or conditions, and the disease, disorder or condition are selected from microbial infection, asthma, systemic inflammation, endothelial inflammation, allergy, urticaria, osteoporosis, chronic obstructive pulmonary disease (COPD), arthritis, autoimmune disease, cytokine release syndrome, ischemic osteonecrosis and sepsis. For example, in one embodiment, treatment is for a subject suffering from a non-infectious lung disorder (e.g., asthma or COPD) aggravated by a viral infection (such as, but not limited to RSV, influenza virus, rhinovirus, parainfluenza virus and / or coronavirus). In one embodiment, the subject to be treated suffers from respiratory distress syndrome (ARDS) caused by a viral infection.

[0542] The present invention also includes a composition comprising one or more compounds of the present invention and an optional carrier. The compounds of the present invention are optionally formulated into pharmaceutical compositions for administration to a subject or for use in a biocompatible form suitable for in vivo administration or use. Therefore, the present invention further includes a pharmaceutical composition comprising one or more compounds of the present invention and optionally a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier. In another embodiment of the present invention, the pharmaceutical composition comprises a pharmaceutically acceptable diluent or carrier and at least another component selected from a diluent, a filler, a binder and other excipients or stabilizers.

[0543] In one embodiment, the pharmaceutical composition comprises a compound of Formula I(b), a pharmaceutically acceptable salt, solvate and / or prodrug thereof:

[0544]

[0545] in

[0546] m is an integer from 0 to 5;

[0547] n is an integer from 0 to 4;

[0548] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0549] R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0550] X 1 selected from N and CH;

[0551] X 2 Selected from O, S and NR 6 ;

[0552] X 3 Selected from O and NR 7 ;

[0553] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0554] X 5 is selected from N and CH; and

[0555] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0556] The restrictions are:

[0557] When m is 0, R 3 Selected from substituted or unsubstituted aryl, heteroaryl, halo, NO2 and SO2R 5 ;

[0558] When m is 1 and R 2 When it is a halogen group, n is an integer from 1 to 4, and R 3 is selected from substituted or unsubstituted aryl, heteroaryl and NO2; and

[0559] When m is 2, R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, OR 4 , NO2 and SO2R 5 .

[0560] In one embodiment, m is an integer from 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In another embodiment, m is 4, 3, 2, or 1. In one embodiment, m is not 0. In one embodiment, m is not 2. In one embodiment, m is 1.

[0561] In one embodiment, n is an integer from 1 to 4, 1 to 3, or 1 to 2. In another embodiment, n is 3, 2, or 1. In yet another embodiment, n is 1.

[0562] In one embodiment:

[0563] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0564] R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0565] R 3 is NO2;

[0566] X 1 selected from N and CH;

[0567] X 2 Selected from O, S and NR 6 ;

[0568] X 3 Selected from O and NR 7 ;

[0569] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0570] X 5 selected from N and CH;

[0571] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0572] m is 1; and

[0573] n is an integer of 1 to 4.

[0574] In one embodiment, the compound of formula I(b) is a compound of formula I(c):

[0575]

[0576] in

[0577] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0578] R 2 and R 3 Each independently selected from C 1-10Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ;

[0579] X 1 selected from N and CH;

[0580] X 2 Selected from O, S and NR 6 ;

[0581] X 3 Selected from O and NR 7 ;

[0582] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0583] X 5 is selected from N and CH; and

[0584] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0585] The restrictions are:

[0586] When m is 0, R 3 Selected from substituted or unsubstituted aryl, heteroaryl, halo, NO2 and SO2R 5 ;

[0587] When m is 1 and R 2 When it is a halogen group, n is an integer from 1 to 4, and R 3 is selected from substituted or unsubstituted aryl, heteroaryl and NO2; and

[0588] When m is 2, R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, OR 4 , NO2 and SO2R 5 ;or

[0589] R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl;

[0590] R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4, NO2 and SO2R 5 ;

[0591] R 3 is NO2;

[0592] X 1 selected from N and CH;

[0593] X 2 Selected from O, S and NR 6 ;

[0594] X 3 Selected from O and NR 7 ;

[0595] X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ;

[0596] X 5 is selected from N and CH; and

[0597] R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl.

[0598] In one embodiment, R 1 is H. In another embodiment, R 1 Selected from C 1-10 In another embodiment, R 1 C 1-10 In another embodiment, R 1 C 1-5 In another embodiment, R 1 C 1-4 In another embodiment, R 1 It is a methyl group.

[0599] In one embodiment, R 2 In another embodiment, R 2 It is a chlorine group.

[0600] In one embodiment, R 3 In one embodiment, R 3 Not for SO2R 5 .

[0601] In one embodiment, R 4is H. In another embodiment, R 4 Selected from C 1-10 In another embodiment, R 4 C 1-10 In another embodiment, R 4 is a substituted or unsubstituted aryl group. In one embodiment, R 4 It is a heteroaryl group.

[0602] In one embodiment, R 5 is H. In another embodiment, R 5 Selected from C 1-10 In another embodiment, R 5 C 1-10 In another embodiment, R 5 is a substituted or unsubstituted aryl group. In one embodiment, R 5 It is a heteroaryl group.

[0603] In one embodiment, R 6 is H. In another embodiment, R 6 Selected from C 1-10 In another embodiment, R 6 C 1-10 In another embodiment, R 6 is a substituted or unsubstituted aryl group. In one embodiment, R 6 It is a heteroaryl group.

[0604] In one embodiment, R 7 is H. In another embodiment, R 7 Selected from C 1-10 In another embodiment, R 7 C 1-10 In another embodiment, R 7 is a substituted or unsubstituted aryl group. In one embodiment, R 7 It is a heteroaryl group.

[0605] In one embodiment, R 8 is H. In another embodiment, R 8 Selected from C 1-10 In another embodiment, R 8 C 1-10 In another embodiment, R 8is a substituted or unsubstituted aryl group. In one embodiment, R 8 It is a heteroaryl group.

[0606] In one embodiment, X 1 is N.

[0607] In one embodiment, X 2 It is O.

[0608] In one embodiment, X 3 NR 7 In another embodiment, X 3 For NH.

[0609] In one embodiment, X 4 For S.

[0610] In one embodiment, X 5 is N.

[0611] In one embodiment, R 1 C 1-5 Alkyl; R 2 is a halogen group; R 3 NO2; X 1 N; X 2 O; X 3 NH; X 4 S; X 5 is N; m is 1; and n is 1.

[0612] In one embodiment, the compound of Formula I(b) has the following structure:

[0613]

[0614] In one embodiment, the compound of Formula I(b), pharmaceutically acceptable salt, solvate and / or prodrug thereof is a compound of Formula I(b); that is, it is not a pharmaceutically acceptable salt, solvate and / or prodrug of that compound.

[0615] The present invention also includes a pharmaceutical composition as described herein, which is used in any of the methods of treatment or uses as described herein. For example, the present invention includes a method for treating an inflammatory disease, disorder or condition as described herein, comprising administering an effective amount of a pharmaceutical composition as described herein to a subject in need thereof; a method for treating a disease, disorder or condition that can be treated by inhibiting SWAP-70 as described herein, comprising administering an effective amount of a pharmaceutical composition as described herein to a subject in need thereof; and a method for treating a disease, disorder or condition that can be treated by inhibiting neutrophil reactive oxygen species (ROS) generation, neutrophil extracellular trap formation, B lymphocyte plasmablast development, B lymphocyte IgE generation, mast cell degranulation, eosinophil ROS generation, mast cell cytokine release, B lymphocyte cytokine release, endothelial cell cytokine release, endothelial cell-immune cell interaction and / or macrophage / monocyte migration as described herein, comprising administering an effective amount of a pharmaceutical composition as described herein to a subject in need thereof, and corresponding uses. It will be appreciated by those skilled in the art that the embodiments of these methods and uses may be varied as described herein based on the above-described methods and uses of the compounds of the invention.

[0616] As will be appreciated by those skilled in the art, the compounds of the present invention can be administered to a subject or used in various forms according to the selected route of administration or use. In one embodiment, one or more compounds of the present invention are administered orally (orally) or parenterally (including injection (e.g., intravenous (iv), intramuscular (im), intraperitoneal (ip), subcutaneous (sc) and intrathecal (it) administration or use forms), infusion, implantation, inhalation, intranasal, sublingual, oral, rectal, vaginal, topical, transdermal, ocular and otic administration or use forms to a subject or use, and the compound is formulated accordingly. For example, the compounds of the present invention are administered or used in the form of injections, sprays, tablets / capsules, powders, topical medications, gels, drops, patches, implants, sustained-release pumps or any other suitable administration or use methods, and those skilled in the art can select suitable administration or use methods.

[0617] In one embodiment, one or more compounds of the present invention are administered orally, for example, with an inert diluent or with an assimilable edible carrier, or encapsulated in a hard or soft shell gelatin capsule, or compressed into a tablet, or mixed directly into the food of the diet. In one embodiment, for oral therapeutic administration or use, one or more compounds of the present invention are mixed with an excipient and administered or used in the form of an ingestible tablet, buccal tablet, lozenge, capsule, elixir, suspension, syrup, wafer, or the like. Oral dosage forms also include modified release formulations, such as immediate release formulations and sustained release formulations. In another embodiment of the present invention, one or more compounds of the present invention are administered or used parenterally. Pharmaceutical forms suitable for administration or use by injection include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Those skilled in the art know how to prepare suitable formulations. In one embodiment, one or more compounds of the present invention are administered by inhalation.

[0618] The method of treatment or use comprises administering or using an effective amount of one or more compounds of the present invention to the subject, optionally including a single administration or use, or optionally including a series of administrations or uses. For example, the compound of the present invention is administered or used at least once a week. However, in another embodiment, in a given treatment or use, the compound is administered or used to the subject once every three weeks, or from once a week to once a day. In another embodiment, the compound is administered or used 2, 3, 4, 5 or 6 times a day. The length of the treatment period or use period depends on a variety of factors, such as the characteristics of the disease, disorder or condition, the severity of the disease, disorder or condition, the age of the subject, the concentration of one or more compounds in the formulation, the activity of the compounds of the present invention, and / or a combination thereof. It should also be understood that the effective amount of the compound used for treatment or use may increase or decrease during a specific treatment regimen or use. Changes in dosage may be revealed by standard diagnostic detection methods known in the art. In some cases, long-term administration or use is required. For example, one or more compounds of the present invention are administered or used in an amount and duration sufficient to treat the subject.

[0619] The extent and / or adverse clinical manifestations of the disease, disorder or condition are optionally reduced (remitted) and / or the time course of progression is slowed or prolonged, compared to not treating the disease, disorder or condition.

[0620] One or more compounds of the present invention can be administered or used alone, or administered or used in combination with other therapeutic agents suitable for treating the disease, disorder or condition. When administered or used in combination with other known therapeutic agents, one embodiment is that one or more compounds of the present invention are administered or used simultaneously with those therapeutic agents. As used herein, the term "simultaneously" when administering or using two substances to a subject refers to providing each of the two substances so that it has biological activity in an individual at the same time. The exact details of administration or use will depend on the pharmacokinetics of the two substances when they are present in each other, and may include administering or using the two substances within a few hours of each other, or even administering or using another substance within 24 hours after administering or using a substance (if pharmacokinetics are suitable). Designing a suitable dosing regimen is routine for those skilled in the art. In a specific embodiment, the two substances will be administered or used substantially simultaneously, that is, within a few minutes of each other, or administered or used in a single composition comprising the two substances. Another embodiment is that the combination of the two substances is administered to the subject or used in a non-simultaneous manner.

[0621] The dosage of the compound of the present invention may vary according to a variety of factors, such as the pharmacodynamic properties of the compound, the mode of administration or use, the age, health status and weight of the subject, the characteristics of the disease, disorder or condition, the nature and extent of the symptoms of the disease, disorder or condition, the frequency of treatment or use and the type of simultaneous treatment or use (if any), and the clearance rate of the compound in the subject. Those skilled in the art can determine the appropriate dosage based on the above factors. In one embodiment, the compound of the present invention is initially administered or used in a suitable dose, which optionally can be adjusted as needed based on the clinical response. As a representative example, for adults or animals, the oral dosage range of one or more compounds of the present invention is less than 1 mg per day to 1000 mg per day. In one embodiment, the compound of the present invention is administered or used in a single daily dose, or the total daily dose can be divided into two, three or four daily doses.

[0622] III. Preparation of the Compounds of the Invention

[0623] Compound of the present invention can be prepared by a variety of methods, and those skilled in the art can easily select. Those skilled in the art can also select suitable technology to process and / or purify intermediates and final products. The compound for synthesizing the compounds of this invention can be obtained from commercial sources, such as but not limited to Sigma-Aldrich, AcrosOrganics, Lach-Ner or TCI, or can also be prepared by suitable methods well known to those skilled in the art.

[0624] For example, in the compounds of the present invention, X 1N, X 2 O and X 3 In embodiments where A is NH, the compounds are generally prepared according to the methods shown in Scheme 1. Unless otherwise indicated, the variables in Scheme 1 and the following exemplary preparation examples are as defined herein for the compounds of the invention, and A + is a suitable alkali metal ion, such as sodium ion (Na + ). Those skilled in the art can readily adapt the method to prepare, for example, compounds having X as defined herein for the compounds of the invention. 1 、X 2 and / or X 3 of compounds.

[0625]

[0626] Solution 1

[0627] In one embodiment, as shown in Scheme 1, the process comprises reacting an optionally substituted benzaldehyde of formula (I)I with a suitable reagent to prepare an oxime of formula (I)II, followed by chlorination of the oxime of formula (I)II to prepare a chlorooxime of formula (I)V, cyclization of the chlorooxime of formula (I)V with a suitable alkali metal salt (e.g., sodium salt) of an acetoacetate of formula V, followed by hydrolysis of the methyl ester to prepare a carboxylic acid of formula VI, and amide coupling of the carboxylic acid of formula VI with a compound of formula VII (e.g., a 2-amino-benzothiazole derivative) to prepare a compound of formula (I).

[0628] In one embodiment, the reaction of the optionally substituted benzaldehyde of formula (I)I with a suitable reagent to prepare the oxime of formula (I)II comprises reacting the optionally substituted benzaldehyde of formula (I)I with hydroxylamine hydrochloride in the presence of a suitable base (such as sodium hydroxide) in a suitable solvent or a mixture thereof (such as a mixture of water and ethanol), and the reaction time and temperature should be sufficient to fully convert the optionally substituted benzaldehyde of formula (I)I into the oxime of formula (I)II.

[0629] In one embodiment, the chlorination of the oxime of formula (I) II to the chlorooxime of formula (I) V comprises reacting the oxime of formula (I) II with a suitable chlorinating agent (e.g., N-chlorosuccinimide) in a suitable solvent or mixture thereof (such as, N,N-dimethylformamide, DMF), and the reaction time and temperature should be sufficient to fully convert the oxime of formula (I) II to the chlorooxime of formula (I) V. In one embodiment, N-chlorosuccinimide is added to a solution of the oxime of formula (I) II in a suitable solvent or mixture thereof (such as DMF) in portions, for example, 10, 9, 8, 7, 6, 5, 4, 3 or 2 portions. In another embodiment, the reaction comprises induction with HCl (g).

[0630] In one embodiment, the cyclization of the chlorooxime of formula (I) V with the suitable alkali metal salt of the acetoacetate of formula V comprises reacting the chlorooxime of formula (I) V with the suitable alkali metal salt of the acetoacetate of formula V in the presence of a suitable base (e.g., NaOH) in a suitable solvent or mixture thereof (such as methanol) for a time and temperature sufficient to fully convert the chlorooxime of formula (I) V and the suitable alkali metal salt of the acetoacetate of formula V into the methyl ester of the carboxylic acid of formula VI. In one embodiment, the alkali metal salt of the acetoacetate of formula V is a sodium salt. In one embodiment, the suitable alkali metal salt of the acetoacetate of formula V is added to a solution of the chlorooxime of formula (I) V in a suitable solvent or mixture thereof (such as methanol) in portions, for example, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2 portions. In one embodiment, the hydrolysis comprises reacting the methyl ester of the carboxylic acid of Formula VI with a suitable hydrolyzing agent (e.g., an aqueous solution of a suitable base such as NaOH) for a time and temperature sufficient to fully convert the methyl ester of the carboxylic acid of Formula VI into the carboxylic acid of Formula VI. In one embodiment, the hydrolysis is performed in situ; e.g., the methyl ester of the carboxylic acid of Formula VI is not treated, separated, and / or purified prior to the hydrolysis.

[0631] In one embodiment, the amide coupling of the carboxylic acid of Formula VI with the compound of Formula VII (e.g., a 2-amino-benzothiazole derivative) comprises adding triethylamine and diisopropylcarbodiimide (DIC) to a mixture of the carboxylic acid of Formula VI, the compound of Formula VII, and ethyl cyanohydroxyiminoacetate (Oxyma) in a suitable solvent or mixture thereof (such as dimethylformamide) and reacting for a time and temperature sufficient to fully react the carboxylic acid of Formula VI with the compound of Formula VII, followed by a suitable workup.

[0632] The following are non-limiting examples of the present invention:

[0633] Example

[0634] Example 1: Preparation of 3-(2-chlorophenyl)-5-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)isoxazole-4-carboxamide ("B2")

[0635] I. Synthesis

[0636] a) Synthesis of 2-chlorobenzaldehyde oxime

[0637]

[0638] To a stirred mixture of 2-chlorobenzaldehyde (100 g, 0.711 mol) in water (100 mL) and 96% ethanol (250 mL) cooled to 5°C in an ice bath was added hydroxylamine hydrochloride (54.5 g, 0.784 mol). The solution was stirred at 5°C and 50% NaOH (95 mL) was slowly added; the mixture became strongly basic as indicated by litmus paper. The mixture was warmed to room temperature, stirred for 1 hour, acidified with concentrated HCl (25 mL) until strongly acidic on litmus paper, and extracted with CHCl (3 x 250 mL). The combined organic extracts were washed with water (2 x 250 mL) and brine (2 x 250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a crystalline oil. Yield: 109.0 g (98%). Liquid chromatography-mass spectrometry (LC-MS): MS (electrospray ionization; ESI) calculated: CHClNO [M+H] + 156.01; experimental value: 155.99, retention time (t R )=2.67min.

[0639] b) Synthesis of 2-chloro-N-hydroxybenzimidoyl chloride

[0640]

[0641] To a stirred solution of 2-chlorobenzaldehyde oxime (100 g, 0.64 mol) in N,N-dimethylformamide (DMF; 630 mL) was added one-fifth (17.1 g, 0.13 mol) of N-chlorosuccinimide (NCS). To initiate the reaction, HCl (gas) from an HCl generator was passed through the reaction mixture while stirring vigorously until the temperature began to rise. The solution temperature rose to 35°C and was maintained below this temperature by periodic ice bath cooling. The remaining NCS (68.4 g, 0.51 mol) was added in four portions, each separated by 15 minutes, after which the reaction mixture was stirred for 0.5 hours. The solution was concentrated in vacuo, and the residue was dissolved in methyl tert-butyl ether (MTBE; 600 mL), washed with water (2 x 500 mL), brine (1 x 500 mL), dried over anhydrous sodium sulfate (25 g), filtered, and concentrated in vacuo to afford a pale yellow oil. Yield: 116.8 g (96%). LC-MS: MS (ESI) calculated value: C7H6Cl2NO[M+H] + 189.97; experimental value: 190.00, t R =3.14min.

[0642] c) Synthesis of 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylic acid

[0643]

[0644] A solution of 2-chloro-N-hydroxybenzimidoyl chloride (121.76 g, 0.64 mol) in methanol (900 mL) was cooled to -15 to -20°C, and NaOH (1.3 g, 0.032 mol) was added. Methyl acetoacetate (88.44 g, 0.64 mol) was then added in 10 portions at -15°C, with a 10-minute interval between each portion. The reaction mixture was then heated to 20°C and stirred for an additional 30 minutes. The reaction mixture was then cooled to 0°C, and a solution of NaOH (51.0 g, 1.28 mol) in water (150 mL) was added. The reaction mixture was then stirred at 50°C for 2 hours. The methanol was removed in vacuo, and the remaining suspension was diluted with water (1500 mL) and the pH adjusted to 2.0-2.5 with 20% H2SO4 (250 mL). The compound was filtered, washed with water (2 x 500 mL), and dried in vacuo to afford the product as a yellow solid. Yield: 129.33 g (85%). LC-MS: MS (ESI) calculated value: C 11 H9ClNO3[M+H] + 238.02; experimental value: 237.97, t R =3.60min. Nuclear magnetic resonance (NMR): 1 HNMR (DMSO-d6, 500MHz, δ, ppm): 2.72 (s, 3H), 7.42-7.48 (m, 2H), 7.50-7.54 (m, 1H), 7.57-7.59 (m, 1H), 12.98 (br.s, 1H). 13 C NMR (DMSO-d6, 125MHz, δ, ppm): 12.85, 109.98, 127.01, 128.43, 129.27, 131.15, 131.26, 132.93, 160.62, 162.30, 175.06.

[0645] d) Synthesis of 3-(2-chlorophenyl)-5-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)isoxazole-4-carboxamide

[0646]

[0647] To a solution of 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylic acid (100 g, 0.42 mol), 2-amino-6-nitrobenzothiazole (90.75 g, 0.46 mol, 1.1 eq), and ethyl cyanohydroxyiminoacetate (Oxyma; 68.25 g, 0.48 mol, 1.1 eq) in DMF (900 mL) were added triethylamine (70.0 mL, 0.50 mol, 1.2 eq) and diisopropylcarbodiimide (DIC) (85.0 mL, 0.55 mol, 1.3 eq). The reaction mixture was stirred at 50° C. under a nitrogen atmosphere for 16 hours, cooled to room temperature, and then placed in a 5° C. refrigerator for 2 hours. The resulting suspension was filtered, the filter cake washed with DMF (2×50 ml), and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (3000 mL), extracted with 2% aqueous K2CO3 solution (2×1000 mL), 0.2 M HCl (2×1000 mL), brine (2×1000 mL), dried over anhydrous sodium sulfate (50 g), filtered and concentrated. The product was dissolved in ethyl acetate (20 mL / g) under reflux and activated carbon powder (1 g per 10 g of product) was added. The resulting suspension was heated to reflux with vigorous stirring for 10 minutes and then filtered by hot filtration. The filtrate was heated to reflux and heptane (10 mL / g) was slowly added. The solution was allowed to cool to room temperature and stirred gently overnight. Yield: 121.7 g (70%). LC-MS: MS (ESI) calculated value: C 18 H 12 ClN4O4S[M+H] + 415.02; experimental value: 414.84, t R =4.26min. 1 HNMR (CDCl3, 500MHz, δ, ppm): 2.89 (s, 3H), 7.49-7.65 (m, 4H), 7.69 (d, J = 9.0Hz, 1H), 8.28 (dd, J = 9.0, 2.3Hz, 1H), 8.73 (d, J = 2.3Hz, 1H). 13 C NMR(CDCl3,125MHz,δ,ppm):13.72,110.21,118.29,120.92,122.34,126.36,128.32,13 1.02,131.93,132.42,133.02,133.96,144.35,152.02,158.08,159.46,161.66,177.08.

[0648] II. Discussion

[0649] 3-(2-Chlorophenyl)-5-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)isoxazole-4-carboxamide was obtained according to Scheme 2.

[0650]

[0651] Scheme 2. i) NH2OH·HCl, NaOH, EtOH / water, 20°C, 2h; ii) NCS, DMF, 20°C, 0.5h; iii) sodium methyl acetoacetate, NaOH, MeOH, -20°C to +50°C, 6h; iv) 2-amino-6-nitrobenzothiazole, DIC, Oxyma, Et3N, DMF, 50°C, 16h.

[0652] Briefly, 2-chlorobenzaldehyde oxime is prepared by treating 2-chlorobenzaldehyde with hydroxylamine hydrochloride in the presence of ethanolic sodium hydroxide. 2-Chlorobenzaldehyde oxime is then converted to 2-chloro-N-hydroxybenzimidoyl chloride by chlorination with N-chlorosuccinimide (NCS) in DMF. Next, 2-chloro-N-hydroxybenzimidoyl chloride undergoes cyclization with sodium methyl acetoacetate and hydrolysis with NaOH to yield 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylic acid. Finally, amide coupling of 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylic acid with 2-amino-6-nitrobenzothiazole in the presence of diisopropylcarbodiimide (DIC) and Oxyma affords 3-(2-chlorophenyl)-5-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)isoxazole-4-carboxamide.

[0653] Example 2: Biological Activity

[0654] I. Materials and Methods

[0655] FACS-FRET of SWAP-70 in living cells: This method is consistent with that previously described by Betaneli and Jessberger (2020). Briefly, two SWAP-70 strains labeled with different fluorescent dyes, Cerulean and Venus, are stably expressed in 293T cells. Upon cell activation, for example with sodium vanadate, SWAP-70 dimerizes. The two fluorophores then combine to produce a fluorescence resonance energy transfer (FRET) signal, which is measured by FACS. FACS-FRET allows for the simultaneous analysis of large numbers of cells. Figure 1 The left panel in Figure 2 shows the inhibitory effect of B2 on the FACS-FRET signal (FRET efficiency), and therefore on SWAP-70 dimerization, at 50, 25, and 10 μM, compared to the control (far left), measured after 20 minutes of stimulation of the cells.

[0656] Neutrophil ROS generation: using MACSexpress TM Neutrophil reactive oxygen species (ROS) generation was measured on human primary neutrophils isolated from fresh blood samples using the Neutrophil Kit as described by the manufacturer's instructions (Miltenyi Biotec Inc.). Neutrophils were treated with 20 μM of the bacterial peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) as a physiologically relevant stimulant in RPMI containing 50 μM dihydrorhodamine 123 (DHR-123) to produce ROS. ROS were measured by FACS based on the conversion of DHR-123 to rhodamine-123.

[0657] Neutrophil extracellular trap formation: Neutrophil production of extracellular traps, i.e., NETosis, was measured on primary human neutrophils isolated as described above or from fresh blood samples by Pancoll gradient centrifugation. 2 × 10 neutrophils per well were added to 96-well plates. 5 The total cell number was 4 × 10 cells per ml in RPMI. 6 The concentration of 100 cells / mL induced the formation of extracellular traps in neutrophils. Cells were treated with the ionophore phorbol myristate acetate (100 nM PMA) or the bacterial product pyocyanin (10 μM) for 3 hours. TM Extracellular DNA is measured by fluorescence assay of ELISA Green and / or by fluorescence microscopy.

[0658] B lymphocyte plasmablast development: For the development of human B lymphocyte plasmablasts, primary human B cells were isolated from the buffy coat using the MACSxpress Buffy Coat Pan B Cell Isolation Kit (Miltenyi Biotec) according to the manufacturer's instructions. 5 × 10 cells / ml were cultured in RPMI in the presence of human transferrin (20 μg / ml), IL-21 (100 ng / ml), recombinant hCD40L (100 μg / ml), anti-HA (50 μg / ml), and 4% paraformaldehyde (50 μg / ml). 4 Cells were cultured at a cell density of 100 cells / mL. Plasmablast formation was measured after 5 days using two sets of markers: CD38+ / CD19low and CD138+, targeting the two stages of plasmablast development.

[0659] B lymphocyte IgE production: B lymphocyte IgE production was measured as previously described by Audzevich et al. (2013). Briefly, primary human B cells isolated from the buffy coat using the MACSxpress Buffy Coat Pan B Cell Isolation Kit (Miltenyi Biotec) were cultured at 5 × 10 cells / ml. 4 Cells were cultured at a cell density of 10 cells and stimulated with recombinant hCD40L (100 μg / ml) and IL-4 (50 ng / ml) for 6 days. On day 6, the frequency of IgE+ B lymphocytes was determined by FACS using anti-CD19 and anti-IgE antibodies.

[0660] Mast cell degranulation: Human primary mast cells were cultured in StemSpan containing 125 ng / ml SCF and 20 ng / ml IL-3. TM CD34 + Hematopoietic progenitor cells developed and their purity was measured after 4 to 5 weeks by FACS analysis of c-kit and FcεRI expression. This was measured by FACS using the appearance of Lamp-1 (CD107a), consistent with the method previously described by Klewer et al. (2021), and applied here to human primary mast cells. Degranulation was triggered by preincubating mast cells with 1.3 μg / ml of IgE overnight and then treating them with 0.2 μg / ml of anti-IgE for 30 minutes.

[0661] Eosinophil ROS production: Human primary eosinophils were purified from the buffy coat by first isolating total peripheral blood mononuclear cells (PBMCs) by density gradient centrifugation on ficoll, followed by negative selection using the Miltenyi Inc. Eosinophil Purification Kit according to the manufacturer's instructions. Eosinophils were then isolated at 1 × 10 per ml. 6 The cell density of 10 cells was resuspended in preheated tissue culture medium that had been placed in an incubator overnight to reach equilibrium and contained 25 μM dihydrorhodamine 123 (DHR-123). The cells were then stimulated with 1 μM phorbol 12-myristate 13-acetate (PMA) for 20 minutes in the incubator in the presence or absence of B2 or DMSO (for controls) and then immediately placed on ice to stop the reaction. As described above for neutrophil ROS generation, the level of oxidized DHR in the samples was measured by flow cytometry.

[0662] Mast cell cytokine release: Primary human mast cells developed from CD34+ precursors in culture as described above for mast cell degranulation were cultured at 0.8 × 10 6The cell density of 10 cells was stimulated with 0.12 mg / ml IgE and 0.1 μg / ml anti-IgE in mast cell culture medium (StemSpan SFEM, including 100 ng / ml SCF, 50 ng / ml IL6, 2 & FBS and 1% Pen / Strep). Cells were simultaneously treated with 100 μM B2 and the cytokine levels present in the culture supernatant were measured after 24 hours. The levels of 105 cytokines were measured by the human XL cytokine array of R&D Systems according to the manufacturer's instructions. Signals were measured by fluorescence-based photometric readings in the Li-COR Odyssey fluorescence imaging system, and spots were quantified using Fiji software.

[0663] B lymphocyte cytokine release: Primary human B lymphocytes isolated from fresh buffy coat were cultured at 5 × 10 cells / ml in 24-well plates. 5 Cells were stimulated with CD40L and IL-4 for 5 days, and the levels of 105 cytokines in the cell culture supernatants were measured using the R&D Systems Human XL Cytokine Antibody Array according to the manufacturer's instructions. Signals were measured using a fluorescence-based photometric readout on a Li-COR Odyssey fluorescence imaging system, and spots were quantified using Fiji software.

[0664] Macrophage / monocyte migration: To purify monocytes / macrophages from the buffy coat, total PBMCs were first isolated by density gradient centrifugation on ficoll, followed by negative selection using a monocyte purification kit from Miltenyi Inc. according to the manufacturer's instructions. Subsequently, monocytes were isolated at 5 × 10 6 The cells were resuspended in tissue culture medium at a concentration of 100 cells / mL. The migration of monocytes to CCL2 was then measured using a Boyden chamber assay equipped with an 8 μM pore size membrane. The procedure was as follows: 200 μl of cells were transferred to the upper chamber in the presence or absence of B2 or DMSO control. 1 ml of chemokine solution at concentrations of 10 ng / mL and 100 ng / mL was added to the lower chamber, along with the same amount of B2 or DMSO as in the upper chamber. The cells were then allowed to migrate for 6 hours, and the number of cells that migrated to the lower chamber was determined by standard cell counting.

[0665] Neutrophil Adhesion to Endothelial Cells: Primary human pulmonary microvascular endothelial cells (HPMEC) were purchased from Promocell and cultured in Promocell's endothelial cell culture medium according to the company's protocol. Endothelial cells were seeded at a concentration of 50,000 cells per well in flat-bottom 96-well plastic plates. After 24 hours, endothelial cells were stimulated with TNF-α (100 ng / ml) and inhibitors overnight. Neutrophils were isolated from whole blood using the MACSxpress Neutrophil Isolation Kit. Neutrophils were isolated at a concentration of 1 × 10 per ml. 6 Neutrophils of 10 cells were cultured at 37°C with 1 μM CellTracker TM Dye CMFDA was used for fluorescence labeling for 40 minutes. The labeled cells were resuspended in HBS solution (0.14M NaCl, 5mM KCl, 1mM CaCl2, 0.4mM MgSO4, 0.5mM MgCl2, 0.3mM Na2HPO4, 6mM glucose and 4mM NaHCO3). The stimulated endothelial cells were washed once with culture medium and 100 μl of labeled neutrophils and B2 or DMSO of specified concentration were added. The plate was incubated at 37°C for 30 minutes and carefully washed twice with PBS to remove non-adherent cells. The adherent cells were fixed in 100% methanol for 10 minutes and then observed under a 10-fold magnification by an inverted microscope. The sample was analyzed three times and 3 visual fields were taken in each well. The cells in each visual field were quantified using FiJi software.

[0666] Endothelial cell cytokine release: Primary human pulmonary microvascular endothelial cells (HPMEC) were purchased from Promocell and cultured in Promocell's endothelial cell culture medium according to the company's protocol. To measure the release of inflammatory mediators, HPMECs were cultured in 12-well plates in 1 ml of endothelial cell culture medium until confluence. The cells were then stimulated overnight with 100 ng / ml of TNFα in the presence or absence of B2 or control DMSO. The supernatant was then collected and the levels of inflammatory mediators in the supernatant were measured using the Cytokine XXL Array from R&D systems as described above according to the manufacturer's instructions.

[0667] II. Results

[0668] B2 inhibits SWAP-70 dimerization in living cells ( Figure 1Two SWAP-70 proteins labeled with different fluorescent dyes, Cerulean and Venus, were stably expressed in 293T cells. Upon cell activation (e.g., with sodium vanadate), SWAP-70 dimerizes. The two fluorophores then combine to produce a fluorescence resonance energy transfer (FRET) signal, which is measured using FACS. FACS-FRET allows for simultaneous analysis of large numbers of cells. Figure 1 The left panel in Figure 2 shows the inhibitory effect of B2 on the FACS-FRET signal (FRET efficiency), and therefore on SWAP-70 dimerization, at 50, 25, and 10 μM, compared to the control (far left), measured after 20 minutes of stimulation of the cells. Figure 1 The right panel shows the inhibitory effect of 50 μM B2 compared to the control (leftmost column, 5-10 minutes; second column from the right: 10-15 minutes) at earlier intervals after stimulation (second column from the left: 5-10 minutes, rightmost column: 10-15 minutes). B2 was added to the cells 15 minutes before stimulation.

[0669] To investigate the effect of B2 on neutrophil ROS production, human primary neutrophils isolated from fresh blood samples were treated with the bacterial peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) as a physiologically relevant stimulator of reactive oxygen species (ROS) production, and ROS were measured by FACS based on the conversion of dihydrorhodamine 123 to rhodamine 123. The effects of four different concentrations of B2 are shown ( Figure 2 50μM and 100μM B2 had a significant inhibitory effect on ROS generation.

[0670] To investigate the effect of B2 on neutrophil extracellular trap formation, human primary neutrophils isolated from fresh blood samples were treated for 3 hours with the ionophore phorbol myristate acetate (PMA) or the bacterial product pyocyanin to form extracellular traps (to remove DNA from the environment). TM Green measures extracellular DNA by photometry. The results are shown in Figure 3 middle.

[0671] To investigate the inhibitory effect of B2 on the development of B lymphocyte plasmablasts, primary human B cells isolated from the buffy coat were cultured in the presence of CD40, IL21, and anti-IgM, and two sets of markers were used for the two stages of plasmablast development: CD38+ / CD19low ( Figure 4 , upper panel) and CD138+( Figure 4 , lower panel) Plasmablast formation was measured by FACS.

[0672] To investigate the inhibitory effect of B2 on IgE production by B lymphocytes, the frequency of IgE+ B lymphocytes was determined by FACS on day 6 of culture of primary human B cells isolated from fresh buffy coat and stimulated with CD40L and IL4. The results are shown in Figure 5 Some toxicity was observed at 50 μM, but no toxicity was observed at lower concentrations.

[0673] To investigate the inhibitory effect of B2 on mast cell degranulation, degranulation was measured by FACS using the appearance of Lamp-1 (CD107a) on the surface of human primary mast cells after degranulation. Degranulation was triggered by IgE / anti-IgE, and B2 was applied 30 minutes before the addition of IgE. Three different concentrations of B2 were tested; Figure 6 From left to right in (left panel): 100, 50 and 20 μM. The mean of 11 experiments is shown as the % reduction in degranulation. Degranulation was also measured at 3 time points after addition of 100 μM B2 ( Figure 6 , right).

[0674] To investigate the inhibitory effect of B2 on ROS production in eosinophils, human primary eosinophils isolated from fresh blood samples were treated with PMA to induce ROS production, and ROS were measured by FACS based on the conversion of dihydrorhodamine 123 to rhodamine 123. Figure 7 ).

[0675] To investigate the regulatory effects of B2 on mast cell cytokine release, primary human mast cells were stimulated with IgE / anti-IgE, treated with 100 μM B2, and the levels of cytokines present in the culture supernatant were measured 24 hours later. The levels of 105 cytokines were measured using the R&D Systems Human XL Cytokine Array and fluorescence-based photometric readings. The levels of exemplary cytokines relative to the control are shown in Table 1. Figure 8 shown.

[0676] To investigate the regulatory effects of B2 on cytokine release from B lymphocytes, primary human B lymphocytes isolated from fresh buffy coat were stimulated with CD40L and IL4 for 24 h, and the levels of 105 cytokines in the cell culture supernatants were measured using the R&D Systems Human XL Cytokine Array and fluorescence-based photometric readout. The percentage reduction in levels compared to controls was shown in Table 1. Figure 9 shown.

[0677] To investigate the inhibitory effect of B2 on macrophage / monocyte migration, primary peripheral blood mononuclear cells were isolated from the buffy coat and subsequently negatively selected. TMThe device tested cell migration towards the chemokine CCL2, which is known to play an important role in the pathology of Covid-19. Migrated cells were quantified after 5 hours in the presence of vehicle (DMSO) alone or in the presence of 50 μM B2 in DMSO. Figure 10 ).

[0678] To study neutrophil adhesion to endothelial cells, primary human neutrophils were fluorescently labeled with 1 μM CellTracker dye and resuspended in HBS solution before adding B2 or DMSO. Green fluorescent adherent cells were counted, the area covered by endothelial cells was measured, and the number of neutrophils adhered to endothelial cells was normalized to the area covered by endothelial cells. Figure 11 Data are shown for a control (DMSO) and three concentrations of B2 (10, 20, and 50 μM B2 in DMSO).

[0679] Table 1 summarizes the results of studies investigating the effects of B2 on the regulation of cytokine production in stimulated pulmonary endothelial cells. Human primary pulmonary endothelial cells were primed for cytokine production by the proinflammatory cytokine TNFα. Levels of 105 cytokines were measured in cell culture supernatants using the R&D Systems Human XL Cytokine Array and fluorescence-based photometric readout. The table lists cytokines whose production was reduced by more than 50% (left) or by 20% to 50% (right) following treatment with 50 μM B2.

[0680] Table 1

[0681]

[0682] *Poor dose response, with only a slight increase in response to TNF.

[0683] Table 2 shows the inhibitory effect of B2 on endothelial cell cytokine release. Human primary coronary artery endothelial cells (HCAEC) were primed for cytokine production by the proinflammatory cytokine TNFα. The levels of 105 cytokines in the cell culture supernatant were measured using the R&D Systems Human XL Cytokine Array and fluorescence-based photometric readout. The table lists the cytokines whose production was reduced by more than 50% (left) or by 20% to 50% (right) after treatment with 50 μM B2.

[0684] Table 2

[0685]

[0686]

[0687] III. Discussion

[0688] Compound B2 was screened in vitro for inhibition of SWAP-70 and subsequently demonstrated to block the dimerization of SWAP-70, which is key to its activity ( Figure 1 ). Here, B2 has been shown to inhibit corresponding disease-related processes in different human primary leukocyte populations. For example, B2 may be useful in reducing overreactions, pathological immune responses, and inflammatory responses while leaving the underlying immune system intact. Therefore, B2 is not considered an immunosuppressant (like corticosteroids, which can have serious side effects), but rather an effective immunomodulator. Therefore, the inflammatory / immune processes targeted by B2 are not completely eliminated, but rather significantly attenuated.

[0689] B2 can inhibit the production of IgE by human primary peripheral blood B lymphocytes ( Figure 5 ). Therefore, B2 and the compounds of the present invention can be used as inhibitors of IgE production. Human primary mast cells developed from progenitor cells isolated from blood are also inhibited by B2 in IgE-mediated degranulation ( Figure 6 Thus, inhibition of SWAP-70 mediated by B2 and / or other compounds of the present invention may be useful for synergistically inhibiting two core processes of allergic reactions: IgE production and mast cell degranulation. This could be used to treat various types of IgE-mediated allergies, such as contact allergies, atopic dermatitis, food allergies, hay fever, venom allergies, and the like.

[0690] To the best of our knowledge, no effective and safe immunomodulators that can prevent excessive inflammation have been reported and applied in the treatment of COVID-19 and related viral or non-viral inflammatory diseases. Since SWAP-70 is expressed in B cells, mast cells, neutrophils, eosinophils and endothelial cells, inhibition of SWAP-70 is expected to prevent severe COVID-19 disease. As mentioned above, the role of SWAP-70 in IgE production, mast cell degranulation and eosinophil activation in mice has been reported. In addition, the data in this article also show that B2 treatment can inhibit the production of IgE ( Figure 5 ), mast cell degranulation ( Figure 6 ) and eosinophil activation ( Figure 7 ). In addition, we here determined the inhibitory effect of B2 on human B cell plasmablast development ( Figure 4 ), which is consistent with the role of SWAP-70 in mouse plasmablast development (Chopin, Chacon-Martinez, et al., 2011). In addition, neutrophil activity associated with COVID-19 and other viral lung inflammation was also inhibited by B2. ROS generation and extracellular trap formation, which are drivers of COVID-19 disease, were significantly reduced (respectively). Figure 2 and Figure 3 In addition, COVID-19, like other viral infections of the lungs, results in a massive release of pro-inflammatory cytokines (cytokine release syndrome, often referred to as a “cytokine storm”). We observed that B2 modulates the cytokine release profiles of mast cells, B cells, and human lung endothelial cells (respectively). Figure 8 、 9 and Table 1), thereby reducing specific pro-inflammatory cytokines. As mentioned above, during COVID-19, macrophages or monocytes (macrophages develop from monocytes) migrate to the infected lungs and trigger pulmonary fibrosis. B2 reduces macrophage migration ( Figure 10 ), thereby preventing the formation of fibrosis. Therefore, B2 and other compounds of the present invention can be used to treat COVID-19 and other viral or non-viral inflammatory diseases. Because B2 or similar compounds reduce the key activities of B cells, plasmablasts, mast cells, neutrophils, eosinophils and monocytes / macrophages, a six-fold synergistic effect is expected in COVID-19 patients. Similar effects are expected for other viral infections of the upper respiratory tract and lungs (such as RSV or influenza virus) because these viruses have overlapping characteristics. Preventing more severe lung damage may reduce the risk of subsequent opportunistic pneumonia, which may be caused by viruses such as rhinoviruses and influenza viruses or bacteria such as Streptococcus pneumoniae.

[0691] In addition to lung inflammation, viral-induced inflammation can also negatively impact other cells and tissues in the body. This effect is often amplified by a cytokine storm, which can spread throughout the body, encompassing many cell types and tissues, including but not limited to the gastrointestinal system, kidneys, heart, nervous system, skin, and / or liver. In addition to viral infections, infections with other pathogens and other conditions can also lead to severe lung and / or systemic pathology, involving many of the cells and processes mentioned above. For example, bacterial sepsis, infection with Yersinia pestis (plague), which can trigger excessive cytokine production by alveolar macrophages, or cytokine storms associated with autoimmune diseases (Fajgenbaum and June, 2020). Given B2's inhibitory effects on immune cell activation and its regulatory effects on cytokine release, we anticipate that treatment with B2 and / or other compounds of the present invention will be beneficial for many of these diseases.

[0692] Similar to allergic reactions, many manifestations of asthma are triggered by IgE-allergen reactions, leading to mast cell degranulation and subsequent inflammatory events, including eosinophil activation and migration. Following the logic described above regarding allergies, the inhibitory effects of B2 and / or other compounds of the present invention on IgE production and mast cell degranulation are expected to significantly reduce asthma symptoms. In addition, as described above, we observed that when treated with B2, human primary eosinophils isolated from blood produced less pro-inflammatory, potentially tissue-damaging reactive oxygen species (ROS) ( Figure 7 ). Therefore, we also expect that B2 and / or other compounds of the present invention can reduce the migration and activation of eosinophils in the lung environment of asthmatic patients. In addition, B2 was found to mediate the reduction of secretion of certain cytokines (including chemokines) by human mast cells, B lymphocytes and lung endothelial cells (see respectively). Figure 8 、 Figure 9 The results of the present study (Table 1 and Table 2) strongly suggest that this treatment could have additional benefits for asthmatics, as the inflammatory milieu would be improved and the reduced chemokine levels would reduce the influx of harmful immune cells into the asthmatic lungs. Thus, B2 or similar compounds could potentially produce a four-fold synergistic beneficial effect in asthmatics during acute asthma attacks, and treatment with B2 and / or other compounds of the invention could also help prevent such attacks.

[0693] Urticaria is a common skin disease that is usually caused by excessive mast cell degranulation. As mentioned above, SWAP-70 has been reported to play an important role in mouse mast cell degranulation, and B2 has been shown to inhibit degranulation in human primary mast cells ( Figure 6 ). IgE is involved in pseudoallergic urticaria, and anti-IgE antibody therapy has been used to reduce IgE levels with some success in some patients (Maurer, Altrichter et al., 2018; Wedi and Traidl, 2021). This suggests that the effect of B2 on IgE production is also beneficial here. Corticosteroids are usually the last resort in severe cases. It is expected that B2 and / or other compounds of the present invention will be beneficial not only in patients with acute attacks, but also in chronic patients, mainly by reducing mast cell degranulation, but also by reducing eosinophil activation, thereby creating an environment with reduced sensitivity to stimuli. B2 and / or other compounds of the present invention may prevent the formation of chronic urticaria. In the autoimmune variant of chronic urticaria, plasmablasts that produce autoantibodies play a major role, and their production is also inhibited by B2 ( Figure 4 ), and are expected to be inhibited by other compounds of the invention.

[0694] Without SWAP-70, osteoclasts cannot form proper F-actin rings and, therefore, cannot resorb bone in cell culture or in mice. Consequently, SWAP-70-deficient mice develop osteosclerosis, meaning they exhibit a significant increase in bone mass. Therefore, blocking SWAP-70 by treatment with B2 and / or other compounds of the invention could reduce osteoclast activity and increase bone mass, thereby improving bone health in patients with osteoporosis.

[0695] COPD involves overactivation of several immune cell types targeted by B2 and enhanced cytokine release, and can therefore also be classified as a specific cytokine release syndrome (Brightling and Greening, 2019). In addition to these two cell types, other major immune cell types that promote COPD include macrophages, mast cells, and plasmablasts. Since B2 can reduce the activity of all these cell types ( Figure 2 、 4 , 6 and 7), we therefore expect that B2 and / or other compounds of the present invention will have significant synergistic effects in treating both acute exacerbations and chronic phases of COPD patients, with the aim of preventing the progression of the disease in the chronic phase.

[0696] Among the various forms of arthritis, inflammatory arthritis may also be a target for treatment using B2 and / or other compounds of the present invention. Another characteristic of rheumatoid arthritis (RA) is the production of autoantibodies by plasmablasts, which develop in this highly pro-inflammatory environment and further exacerbate inflammation. B2 will inhibit the formation of plasmablasts, the activation of neutrophils, the migration of macrophages, and the formation and activity of osteoclasts, and will therefore benefit RA patients in a four-fold synergistic manner. This makes B2 different from the single cytokine blockers currently under investigation. The use of B2 and / or other compounds of the present invention can not only treat acute attacks of RA, but also chronic exacerbations of RA, thus hopefully breaking the vicious cycle. Inflammatory arthritis in a broad sense also includes gout. In gout, urate crystals activate neutrophils to produce ROS, resulting in extracellular trap formation and cytokine secretion. As shown in the figure, B2 can at least reduce ROS generation and extracellular trap formation in human primary neutrophils (respectively). Figure 2 and 3 RA is an autoimmune disease, and other autoimmune diseases can also be treated with B2 and / or other compounds of the present invention. B2 and similar compounds may work synergistically to address at least three pathogenic mechanisms: IgE production, plasmablast development, and extracellular trap formation. Similar considerations apply to other autoantibody-driven autoimmune diseases.

[0697] Cells centrally involved and overactivated during a cytokine storm include those implicated by B2: macrophages, mast cells, eosinophils, neutrophils, and endothelial cells. These cells produce a range of proinflammatory cytokines, including chemokines, which contribute to the onset of the cytokine storm. Reducing the production of these proinflammatory cytokines, particularly chemokines, through B2 and / or other compounds of the present invention could significantly help manage acute cytokine release syndromes (CRSs) triggered by various stimuli. B2 has been shown herein to reduce cytokine secretion by endothelial cells, with a significant reduction in the secretion of several chemokines (Table 1). Furthermore, B2 reduced the secretion of several soluble adhesion molecules by endothelial cells (Table 1). Because these soluble adhesion molecules have been implicated in certain forms of thrombosis, such as venous thromboembolism (Torres, Matos, et al., 2017), their reduction could be beneficial in these and similar cases. As with other inflammatory conditions, a vicious cycle occurs in which increased coagulation (thrombin) triggers increased endothelial cell cytokine production, which in turn triggers more coagulation, a cycle that urgently needs to be broken (Jackson, Darbousset, et al., 2019). Table 2 shows the results from primary human coronary artery endothelial cells (HCAEC). B2 and other compounds of the present invention are expected to weaken or stop this cycle by reducing endothelial cell cytokine production and immune cell recruitment (without increasing bleeding, a major side effect of anticoagulants), thereby treating inflammatory arterial thrombosis and other systemic inflammatory diseases with thrombotic tendencies.

[0698] In a recent meta-study, SWAP-70 was identified as a causative gene for coronary artery disease. Therefore, inhibition of SWAP-70 through treatment with B2 and / or other compounds of the present invention is expected to benefit such patients, as such treatment would inhibit leukocyte migration and accumulation, as well as endothelial cell activation and cytokine release. For high-risk patients (with a heritability of 40-60% and the presence of multiple other risk factors), treatment with B2 and / or other compounds of the present invention could also be considered a preventative measure to reduce leukocyte accumulation.

[0699] While the present invention has been described with reference to the embodiments, it should be understood that the scope of the claims should not be limited by the embodiments set forth in the embodiments, but should be given the broadest interpretation consistent with the entire specification.

[0700] All publications, patents, and patent applications are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference in its entirety. If a term is defined differently in a document incorporated herein by reference, the definition in this document shall control.

[0701] Take a slightly less expensive dress code

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Claims

1. A method for treating an inflammatory disease, disorder or condition in a subject in need thereof comprising administering to the subject an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof: in, R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl; R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ; X 1 selected from N and CH; X 2 Selected from O, S and NR 6 ; X 3 Selected from O and NR 7 ; X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ; X 5 selected from N and CH; R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl; m is an integer from 0 to 5; and n is an integer from 0 to 4.

2. A compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for use in treating a disease, disorder or condition treatable by inhibiting SWAP-70 in a subject in need thereof, wherein an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is administered to the subject, in, R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl; R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ; X 1 selected from N and CH; X 2 Selected from O, S and NR 6 ; X 3 Selected from O and NR 7 ; X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ; X 5 selected from N and CH; R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl; m is an integer from 0 to 5; and n is an integer from 0 to 4.

3. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for treating a disease, disorder or condition treatable by inhibiting neutrophil reactive oxygen species generation, neutrophil extracellular trap formation, B lymphocyte plasmablast development, B lymphocyte IgE production, mast cell degranulation, eosinophil reactive oxygen species generation, mast cell cytokine release, B lymphocyte cytokine release, endothelial cell cytokine release, endothelial cell-immune cell interaction and / or macrophage / monocyte migration in a subject in need thereof, wherein an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is administered to the subject, in R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl; R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ; X 1 selected from N and CH; X 2 Selected from O, S and NR 6 ; X 3 Selected from O and NR 7 ; X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ; X 5 selected from N and CH; R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl; m is an integer from 1 to 5; and n is an integer of 1 to 4.

4. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 3, wherein: m is 1.

5. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 4, wherein: n is 1.

6. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 3, wherein: R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl; R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ; R 3 is NO2; X 1 selected from N and CH; X 2 Selected from O, S and NR 6 ; X 3 Selected from O and NR 7 ; X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ; X 5 selected from N and CH; R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl; m is 1; and n is an integer of 1 to 4.

7. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 3, wherein: The compound of formula (I) is a compound of formula I(a): where R 1 、R 2 、R 3 、X 1 、X 2 、X 3 、X 4 and X 5 As defined in any one of claims 1 to 3 and 6.

8. Use of the compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to claim 7, wherein: R 3 For NO2.

9. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 8, wherein R 1 C 1-4 alkyl.

10. Use of the compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to claim 9, wherein: R 1 It is a methyl group.

11. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 10, wherein: R 2 It is a halogen group.

12. Use of the compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to claim 11, wherein: R 2 It is a chlorine group.

13. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 12, wherein: X 1 is N.

14. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 13, wherein: X 2 It is O.

15. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 14, wherein: X 3 For NH.

16. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 15, wherein: X 4 For S.

17. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 16, wherein: X 5 is N.

18. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 3, wherein: The compound of formula (I) has the following structure:

19. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 18, wherein The compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is the compound of formula (I).

20. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 19, wherein The subject is a human.

21. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 20, wherein: The disease, disorder or condition is a microbial infection, asthma, systemic inflammation, endothelial inflammation, allergy, urticaria, osteoporosis, chronic obstructive pulmonary disease, arthritis, an autoimmune disease, cytokine release syndrome, avascular necrosis and / or sepsis.

22. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to claim 21, wherein: The microbial infection is a viral infection, and the treatment is for viral-induced lung inflammation.

23. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to claim 21 or 22, wherein: The compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat diseases caused by the SARS-CoV-2 virus.

24. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof according to any one of claims 1 to 23, wherein The compound of formula (I) is administered by inhalation.

25. A compound of formula I(b) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof for use in medicine, in, R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl; R 2 and R 3 Each independently selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ; X 1 selected from N and CH; X 2 Selected from O, S and NR 6 ; X 3 Selected from O and NR 7 ; X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ; X 5 selected from N and CH; R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl; m is an integer from 0 to 5; and n is an integer from 0 to 4; in, When m is 0, R 3 Selected from substituted or unsubstituted aryl, heteroaryl, halo, NO2 and SO2R 5 ; When m is 1 and R 2 When it is a halogen group, n is an integer from 1 to 4, and R 3 is selected from substituted or unsubstituted aryl, heteroaryl and NO2; When m is 2, R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, OR 4 , NO2 and SO2R 5 .

26. The use of the compound according to claim 25, wherein m is 1.

27. The use of a compound according to claim 25 or 26, wherein n is 1.

28. The use of the compound according to claim 25, wherein R 1 Selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl; R 2 Selected from C 1-10 Alkyl, substituted or unsubstituted aryl, heteroaryl, halogen, OR 4 , NO2 and SO2R 5 ; R 3 is NO2; X 1 selected from N and CH; X 2 Selected from O, S and NR 6 ; X 3 Selected from O and NR 7 ; X 4 Selected from O, S, CH2, SO, SO2 and NR 8 ; X 5 selected from N and CH; R 4 、R 5 、R 6 、R 7 and R 8 Each independently selected from H, C 1-10 alkyl, substituted or unsubstituted aryl and heteroaryl; m is 1; and n is an integer of 1 to 4.

29. The use of the compound according to claim 25, wherein The compound of formula I(b) is a compound of formula I(c): where R 1 、R 2 、R 3 、X 1 、X 2 、X 3 、X 4 and X 5 As defined in claim 25 or 28.

30. The use of a compound according to claim 29, wherein R 3 For NO2.

31. The use of a compound according to any one of claims 25 to 30, wherein R 1 C 1-4 alkyl.

32. The use of a compound according to claim 31, wherein R 1 It is a methyl group.

33. The use of a compound according to any one of claims 25 to 32, wherein R 2 It is a halogen group.

34. The use of a compound according to claim 33, wherein R 2 It is a chlorine group.

35. Use of a compound according to any one of claims 25 to 34, wherein X 1 is N.

36. Use of a compound according to any one of claims 25 to 35, wherein X 2 It is O.

37. Use of a compound according to any one of claims 25 to 36, wherein X 3 For NH.

38. Use of a compound according to any one of claims 25 to 37, wherein X 4 For S.

39. Use of a compound according to any one of claims 25 to 38, wherein X 5 is N.

40. The use of a compound according to claim 25 or 29, wherein R 1 C 1-5 Alkyl, R 2 is a halogen group, R 3 NO2, X 1 N, X 2 O, X 3 NH, X 4 S, X 5 is N, m is 1 and n is 1.

41. The use of a compound according to claim 25, wherein The compound of formula I(b) has the following structure:

42. Use of a compound according to any one of claims 25 to 41, wherein The compound of formula I(b) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is the compound of formula I(b).

43. A pharmaceutical composition comprising a compound according to any one of claims 25 to 42, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

44. The pharmaceutical composition of claim 43, further comprising a pharmaceutically acceptable carrier.

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