Fused piperidinyl bicyclic compounds and related compounds for use in treatment of disease

Abstract

The present invention relates to fused piperidinyl bicyclic compounds, meta-substituted piperidinyl compounds and related compounds that modulate the activity of the mammalian C5a receptor by direct binding to said C5a receptor for use in the treatment of disease, the diseases are in particular monosodium urate (MSU)-induced diseases, neutrophil-driven inflammatory nephropathy, skin neutrophil inflammatory diseases and immune complex diseases.

Description

Technical Field

[0001] This invention relates to fused piperidinyl bicyclic compounds, meta-substituted piperidinyl compounds, and related compounds that modulate the activity of the C5a receptor by directly binding to it in mammals, for use in the treatment of diseases, particularly monosodium urate (MSU)-induced diseases, neutrophil-driven inflammatory nephropathy, cutaneous neutrophilic inflammatory diseases, and immune complex diseases. Background Technology

[0002] C5a generated by activating the complement system

[0003] The complement system is an important branch of innate immunity and plays a crucial role in the host's defense against invading microorganisms. These functions are performed by functionally related proteins that sequentially detect, label, and eliminate pathogens and pathogen-affected cells. Complement proteins are primarily found in circulating blood plasma, performing their immune surveillance functions. These proteins are inactive in a stable state and are activated via enzyme cascades in response to infection, pathogenesis, and artificial triggers such as organ transplantation.

[0004] Complement proteins are activated via three distinct pathways with different initial activation mechanisms. These three pathways are the classical pathway, the alternative pathway, and the lectin-binding pathway. The classical pathway is activated by antibody complexes. The alternative pathway is activated by foreign surfaces, such as certain molecules present on microbial membranes, altered host cell surfaces in lesions, and artificial surfaces encountered during renal dialysis. The lectin-binding pathway is triggered by the binding of mannose-binding lectin proteins or fibrin to microbial carbohydrate structures. After initiation, the progression and amplification of all three pathways utilize the same basic mechanism involving the cleavage cascade of complement proteins. All three pathways converge on the formation of C3 convertase, which leads to the hydrolysis of C3 protein into the bioactive fragments C3a and C3b, which in turn leads to the cleavage of C5[1].

[0005] C5 is a 190 kDa protein consisting of an α chain (approximately 120 kDa) and a β chain (approximately 75 kDa). Enzymatic cleavage of the N-terminus of the α chain yields C5a. Human C5a is a globular protein with 74 amino acids, comprising a core structure and a flexible C-terminus. The sugar chain conjugated to the Asn residue at position 64 has a highly variable structure, resulting in a molecular weight range of 10 kDa to 15 kDa for human C5a.

[0006] In addition to C5a, the proteolysis of C5 also produces C5b, which subsequently forms C5b-9 (MAC, the membrane attack complex) with other complement components. C3a, C5a, and MAC are end-effectants of complement activation. MAC forms transmembrane channels on pathogens or damaged host cells, leading to cell lysis. C3a and C5a are considered anaphylatoxins due to their potent pro-inflammatory effects, with C5a being significantly more potent than C3a.

[0007] C5a Function

[0008] C5a is a key driver of the rapid innate immune response to infection and injury. C5a induces the release of histamine and TNF-α. C5a activates granulocytes. Specifically, C5a stimulates a range of neutrophil activities. At lower concentrations, C5a is a potent chemokine for neutrophils. At higher concentrations, C5a induces the release of granzymes, triggering oxidative bursts that generate oxidants. C5a stimulates the production and release of pro-inflammatory cytokines, which in turn causes vasodilation, increases vascular permeability, and further enhances neutrophil extravasation. Neutrophils are a double-edged sword. On the one hand, they defend against infection; on the other hand, they can directly cause acute or chronic tissue damage when C5a activity is excessive.

[0009] C5a also plays a role in the complex regulation of adaptive immunity. C5a is involved in the interaction between antigen-presenting cells and T cells. C5a can regulate T cell differentiation, survival and proliferation. For example, it has been proposed that C5a-mediated initiation and differentiation of Th-17 cells and IL-17 production are fundamental mechanisms in some autoimmune diseases [2].

[0010] C5a function is primarily mediated by C5a receptor 1.

[0011] C5a functions via its homologous receptor C5a receptor 1 (C5aR1) and subsequently via the identified C5a receptor-like 2 (C5aR2). Both receptors consist of seven helical transmembrane domains and share approximately 35% homology in their primary sequence. C5aR1 is expressed by immune cells, including granulocytes and monocytes, as well as non-myeloid immune cells, such as T cells. C5aR1 is also found in non-immune cells in many organs, such as the kidney, liver, and lung. C5aR1 is a G protein-coupled receptor and is associated with several G protein-coupled downstream signal transduction pathways, such as cAMP and calcium-mediated pathways. Loss-of-function approaches, including C5aR1-deficient animal models and pharmacological inhibition, have demonstrated that C5aR1 mediates multifaceted C5a function in a variety of pathophysiological contexts, which makes it necessary to use C5aR1 inhibitors (such as antibodies and antagonists) in drug development and clinical practice with the goal of treating C5a-related disorders[3].

[0012] C5aR2 is located both intracellularly and on the cell membrane. Because C5aR2 does not associate with G proteins, it has historically been considered a non-functional decoy receptor and has therefore received far less attention than C5aR1. However, accumulated experimental observations suggest that C5aR2 may have both pro-inflammatory and anti-inflammatory effects, depending on the biological context.

[0013] The C5a-C5aR1 axis is a promising therapeutic target for a variety of disorders.

[0014] C5a is associated with a wide range of diseases, including but not limited to: kidney-related disorders, cardiovascular disorders, respiratory diseases, skin disorders, arthritis, neurodegenerative disorders (Alzheimer's disease, dementia), ischemia-reperfusion injury, multiple sclerosis, transplant rejection, age-related macular degeneration, neutrophilic dermatitis, and cancer. Based on this view, preclinical and clinical data have highlighted the potential benefits of inhibiting the C5a-C5aR1 interaction in several disorders [4-7].

[0015] Targeting C5a or C5a receptors is better than targeting C5 or C3.

[0016] In principle, there are several ways to block pathogenic C5a function. It can be blocked by direct neutralization of C5a (e.g., using anti-C5a antibodies) or by C5aR1 inhibitors. It can also be blocked by inhibiting the cleavage of C5 to block C5a generation, which can be achieved by targeting C5 itself or its upstream activators (e.g., C3). However, blocking C5a function by targeting its upstream complement molecules is inherently disrupted by the presence of exogenous pathways. Exogenous pathways are those that lead to the cleavage of C5 and subsequent generation of C5a, which are not the three typical pathways. Exogenous pathways utilize a variety of proteases that are not part of the complement family. These proteases include proteases released by microorganisms, proteases associated with the coagulation cascade, or proteases activated during inflammatory responses and tissue damage [8].

[0017] Therefore, targeting C3 or C5 does not block C5 cleavage via exogenous pathways, thus not completely blocking C5a generation, which may affect the therapeutic effect.

[0018] Furthermore, targeting C5a or the C5a receptor offers other potential clinical benefits compared to targeting C5 and C3. For example, inhibiting C5 or C3 not only blocks C5a but also C5b and subsequent MAC formation. Targeting C5a or the C5a receptor, however, preserves MAC production, which may be advantageous because MAC plays a crucial role in homeostasis through its antimicrobial and antitumor effects. Clinical interventions targeting C5a or the C5a receptor may also carry a lower risk of infectious complications compared to interventions targeting C5 or C3.

[0019] Fused piperidinyl bicyclic compounds, meta-substituted piperidinyl compounds, and related compounds that modulate the activity of the C5a receptor very well by directly binding to the mammalian C5a receptor are disclosed in WO 2020 / 182384 A1.

[0020] Potential technical problems of the present invention

[0021] Although, as explained above, the C5a-C5aR1 axis is considered a promising therapeutic target for the treatment of a variety of disorders, it is unknown which specific diseases or disorders can actually be treated by using compounds that modulate the activity of mammalian C5a receptors, and in particular, it is unknown which diseases or disorders can be treated by C5aR1 inhibitors.

[0022] For example, literature reports that blocking C5a receptors with the C5a receptor antagonist PMX53 did not reduce synovial inflammation in patients with rheumatoid arthritis (Vergunst, 2007). Furthermore, it has been reported that C5aR inhibition with the C5a receptor antagonist PMX53 during the early inflammatory phase did not affect bone regeneration in a complication-free fracture healing model (Ehrnthaller, 2016). As another example, complement 5a receptor deficiency has been reported in mice without affecting adverse cardiac remodeling following stress overload (de Haan, 2017). Several further data in the art demonstrate that blocking C5a receptors does not necessarily lead to therapeutic success.

[0023] The inventors have now surprisingly discovered that certain diseases or disorders can be advantageously treated with specific compounds that directly target the C5a receptor, thereby avoiding the drawbacks associated with targeting C5 or C3. Specifically, the treatable diseases or disorders are monosodium urate (MSU)-induced diseases, neutrophil-driven inflammatory nephropathy, cutaneous neutrophilic inflammatory diseases, and immune complex diseases. Summary of the Invention

[0024] In one aspect, the present invention relates to a compound having the general formula (XXI).

[0025] (XXI)

[0026] and its pharmaceutically acceptable salts, hydrates and rotational isomers;

[0027] in

[0028] C 1 Selected from aryl and heteroaryl groups, wherein the heteroaryl group has 1-3 heteroatoms selected from N, O, and S as ring members; and wherein the aryl and heteroaryl groups are optionally fused with 1 to 3 R atoms. 1 Substituent substitution;

[0029] C 2 Selected from aryl and heteroaryl groups, wherein the heteroaryl group has 1-3 heteroatoms selected from N, O, and S as ring members; and wherein the aryl and heteroaryl groups are optionally fused with 1 to 3 R atoms. 2 Substituent substitution;

[0030] C 3 Selected from C 1-8 Alkyl or heteroalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, heterocyclic alkyl or heterocyclic alkyl-C 1-4 Alkyl groups, wherein the heteroalkyl group has 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic alkyl group or portion has 1-3 heteroatoms selected from N, O, and S, and wherein the heteroaryl group has 1-3 heteroatoms selected from N, O, and S as ring members, and each C 3 Choose any location via 1 to 3 R 3 Substituent substitution;

[0031] Each R 1 Independently selected from halogens, -CN, -R c —CO2R a —CONR a R b —C(O)R a —OC(O)NR a R b —NR b C(O)R a —NR b C(O)2R c —NR a —C(O)NR a R b —NR a C(O)NR a R b —NR a R b —OR a and —S(O)2NR a R b ; where each R a and R b Independently selected from hydrogen and C 1-8 Alkyl and C 1-8A haloalkyl group, or one that, when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring members, and optionally substituted with one or two oxo groups; each R c Selected independently from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R a R b and R c The aliphatic and / or cyclic moiety is optionally further substituted with one to three halogens, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups; and optionally with two R groups. 1 When substituents are located on adjacent atoms, they combine to form fused five- or six-membered carbon rings or heterocycles.

[0032] Each R 2 Independently selected from halogens, -CN, -NO2, -R f —CO2R d —CONR d R e —C(O)R d —OC(O)NR d R e —NR e C(O)R d —NR e C(O)2R f —NR d C(O)NR d R e —NR d R e —OR d and —S(O)2NR d R e ; where each R d and R e Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 A haloalkyl group, or one that, when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring members, and optionally substituted with one or two oxo groups; each R f Selected independently from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R d R e and R fThe aliphatic and / or cyclic moiety is optionally further substituted with one to three halogens, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups, and optionally with two R groups. 2 When groups are located on adjacent atoms, they combine to form five- or six-membered rings;

[0033] Each R 3 Independently selected from halogen, -CN, -R i —CO2R g —CONR g R h —C(O)R g —C(O)R i —OC(O)NR g R h —NR h C(O)R g —NR h CO2R i —NR g C(O)NR g R h —NR g R h —OR g —OR j —S(O)2NR g R h —X 4 —R j —NH—X 4 —R j —O—X 4 —R j —X 4 —NR g R h —X 4 —NHR j —X 4 —CONR g R h —X 4 —NR h C(O)R g —X 4 —CO2R g —O—X 4 —CO2R g —NH—X 4 —CO2R g —X 4 —NR h CO2R i —O—X 4 —NR h CO2R i —NHRj and —NHCH2R j , where X 4 It is C 1-4 Alkylene; each R g and R h Independently selected from hydrogen and C 1-8 Alkyl or heteroalkyl, C 3-6 cycloalkyl and C 1-8 The alkyl halogroup, or, when attached to the same nitrogen atom, can combine with the nitrogen atom to form a four-, five-, or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring members, and optionally substituted with one or two oxo groups; each R i Selected independently from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and each R j Selected from C 3-6 Cycloalkyl, imidazolyl, pyrimidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and S,S-dioxo-tetrahydrothiopyranyl, wherein R g R h R i and R j The aliphatic and / or cyclic moieties may optionally be further oxidized by one to three halogens, methyl groups, CF3 groups, hydroxyl groups, C4 groups, C6 groups, C7 groups, C8 groups, C9 ... 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, —C(O)O—C 1-8 Alkyl, amino, alkylamino, and dialkylamino substitutions, and optionally in both R groups. 3 When groups are located on adjacent atoms, they combine to form five- or six-membered rings;

[0034] X is hydrogen or CH3; and

[0035] R 8 and R 9 Independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 alkoxy, or R 8 and R 9 These can combine to form fused saturated or unsaturated monocyclic or polycyclic carbon rings, wherein one or more of the ring carbon atoms can be independently replaced by N, S, or O.

[0036] The compound is used to treat or prevent diseases or disorders selected from the following:

[0037] • Monosodium urate (MSU)-induced diseases,

[0038] • Neutrophil-driven inflammatory kidney diseases, including ischemic nephropathy, ischemia-reperfusion kidney injury, and obstructive nephropathy.

[0039] •Skin neutrophilic inflammatory diseases, and

[0040] • Immune complex diseases.

[0041] Other implementation methods will become clear upon review of the detailed description below. Attached Figure Description

[0042] Figure 1 An in vivo model of neutropenia in hamsters. The percentage inhibition of C5a-induced neutropenia (C5a 100 µg / kg) in hamsters was determined 8 h after administration of INF054 and INF052 (both 10 mg / kg orally). **Indication p < 0.01.

[0043] Figure 2 MSU-induced in vivo model of peritonitis. Quantification of the following cell types from peritoneal lavage fluid: A. Monocytes (mono), B. Neutrophils (neutral), C. Leukocytes (WBC), and D. Lymphocytes (lymph). Group G1 was untreated, Group G2 received intraperitoneal injection of monosodium urate (MSU) crystals and received only the medium, and Group G3 received MSU injection and INF052 (20 mg / kg). **Indicative p < 0.01.

[0044] Figure 3 Inhibition of ischemia-reperfusion kidney injury. Histopathological status of the kidney after ischemia-reperfusion injury (IRI). Group G1 received INF052 (100 mg / kg) after IRI, Group G2 received mediator only after IRI, and Group G3 was untreated. *Indicates p < 0.05.

[0045] Figure 4 Unilateral ureteral obstruction (UUO)-induced nephropathy. Blood urea nitrogen (BUN) levels on days 1, 3, 7, and 14 post-UUO surgery. Group G1 was untreated, Group G2 received UUO treatment and received only the mediator, and Group G3 received UUO treatment and INF052 (20 mg / kg).

[0046] Figure 5 Unilateral ureteral obstruction (UUO)-induced nephropathy. Histopathological status of the kidneys after H&E staining. Group G1 was untreated, Group G2 received UUO treatment and received only the mediator, and Group G3 received UUO treatment and INF052 (20 mg / kg). *Indicating p < 0.05.

[0047] Figure 6 Inhibition of immune complex-induced neutrophil activation in human whole blood. Flow cytometry was used to detect neutrophil CD11b expression levels (mean fluorescence intensity (MFI) emitted by FITC-conjugated anti-CD11b antibodies on the neutrophil surface) under non-activation (HBSS and single primary antibody) and activation (non-PMN-specific or PMN-specific immune complexes) conditions. Upregulation of CD11b at different levels was effectively blocked by 0.25 µM (grey bars) and 1 μM (black bars) INF052.

[0048] Figure 7 The upregulation of CD11b on neutrophils induced by plasma from patients with hidradenitis suppurativa was blocked. Neutrophils were activated in whole blood using plasma from HS patients (pat 088) to upregulate CD11b expression, and this upregulation was blocked by different concentrations of the C5aR antagonist INF052. Plasma from healthy individuals in the absence and presence of INF052 was added to whole blood as activation and blockade controls, respectively.

[0049] Figure 8 The upregulation of CD11b on neutrophils induced by plasma from patients with hidradenitis suppurativa was blocked. Neutrophils were activated in whole blood using plasma from three patients with hidradenitis suppurativa to upregulate CD11b expression, and this upregulation was blocked by different concentrations of the C5aR antagonist INF052. Plasma from healthy individuals in the absence and presence of INF052 was added to whole blood as activation and blockade controls, respectively. Detailed Implementation

[0050] definition

[0051] Before describing the invention in detail below, it should be understood that the invention is not limited to the specific methods, schemes, and reagents described herein, as these can be modified. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which will be defined only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0052] Preferably, the terms used herein are defined as described in the following reference: "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, HGW, Nagel, B. and Kölbl, H. (eds.) (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland.

[0053] Throughout this specification and the claims thereafter, unless the context otherwise requires, the word “comprise” and its variations such as “comprises” and “comprising” shall be understood to imply inclusion of the stated whole or step or group of whole or steps, but not to exclude any other whole or step or group of whole or steps.

[0054] Several documents are referenced throughout this specification (e.g., patents, patent applications, scientific publications, manufacturers' specifications, instructions, GenBank accessions, serial submissions, etc.). Nothing herein should be construed as an admission that the invention is not entitled to any prior disclosure due to prior invention. Some of the documents referenced herein are characterized as "incorporated by reference." In the event of a conflict between the definitions or teachings of such incorporated references and those listed in this specification, the text of this specification shall prevail.

[0055] In the context of this invention, C5a specifically refers to human C5a. The amino acid sequence of human C5a can be found with accession number UniProtKB P01031 (CO5_HUMAN).

[0056] In the context of this invention, the term "C5a receptor" refers to any potential C5a-binding ligand on the cell surface, and more particularly to any receptor protein that can bind to C5a and elicit a response (e.g., activate or inhibit the receptor) on said receptor. The term "C5a receptor" specifically covers both receptors, C5aR and C5L2. Alternative names for C5aR are C5aR1 and CD88. Alternative name for C5L2 is C5aR2. Certain embodiments of the invention relate to a compound that modulates the activity of C5a receptors (e.g., by binding to C5a receptors). In these cases, the term "C5a receptor" may refer to (i) C5aR, or (ii) C5L2, or (iii) both C5aR and C5L2. This means that some compounds modulate the activity of only one C5a receptor (i.e., C5aR or C5L2), while other compounds modulate the activity of both C5a receptors (i.e., both C5aR and C5L2).

[0057] As used in this article, if the dissociation constant K of the first compound and the second compound is... d The value is 1 mM or lower, preferably 100 μM or lower, preferably 50 μM or lower, preferably 30 μM or lower, preferably 20 μM or lower, preferably 10 μM or lower, preferably 5 μM or lower, more preferably 1 μM or lower, more preferably 900 nM or lower, more preferably 800 nM or lower, more preferably 700 nM or lower, more preferably 600 nM or lower, more preferably 500 nM or lower, more preferably 400 nM or lower, more preferably 300 nM or lower, more preferably 200 nM or lower, even more preferably 100 nM or lower, even more preferably 90 nM or lower, even more preferably 80 nM or lower, even more preferably 70 nM or lower, even more preferably 60 nM or lower, even more preferably 50 nM or lower, even more preferably 40 nM or lower, even more preferably 30 nM or lower, even more preferably 20 nM or lower, and even more preferably 10 If nM or lower, the first compound (e.g., the compound of the present invention) is considered to "bind" to the second compound (e.g., the target protein).

[0058] According to the invention, the term "binding" preferably refers to specific binding. "Specific binding" means that the compound (e.g., a protein ligand or nucleic acid aptamer) binds more strongly to another target (e.g., a target protein or target epitope, to which the compound is specific) than to a target. If the dissociation constant (K0) of the compound binding to the first target is... d If the dissociation constant (Ki) of the compound is lower than that of the second target, then the compound binds more strongly to the first target compared to the second target. Preferably, the dissociation constant (Ki) of the target to which the compound specifically binds is lower than that of the second target. d The dissociation constant (K) of the target to which the compound binds nonspecifically. d The ratio is less than 10 times, preferably more than 20 times, more preferably more than 50 times, and even more preferably more than 100 times, 200 times, 500 times or 1000 times.

[0059] As used in this article, the term "K" d "(usually measured in "mol / L", sometimes abbreviated as "M")" is intended to refer to the dissociation equilibrium constant of a specific interaction between a compound (such as the compound of the present invention) and a target molecule.

[0060] Used to determine the binding affinity of a compound (i.e., to determine the dissociation constant K). dThe method is known to those skilled in the art and can be selected from, for example, the following methods known in the art: surface plasmon resonance (SPR) based techniques, biofilm layer interferometry (BLI), enzyme-linked immunosorbent assay (ELISA), flow cytometry, isothermal titration calorimetry (ITC), analytical ultracentrifugation, radioimmunoassay (RIA or IRMA), and enhanced chemiluminescence (ECL). Typically, the dissociation constant K... d It is determined at 20ºC, 25ºC, 30ºC, or 37ºC. Unless otherwise explicitly stated, K as described herein... d The value was determined by SPR at 20ºC.

[0061] As used herein, the term "naturally occurring" refers to the fact that an object can be found in nature. For example, polypeptide or polynucleotide sequences that exist in organisms (including viruses) and can be isolated from natural sources and have not been intentionally modified by laboratory personnel are naturally occurring.

[0062] As used herein, “patient” means any mammal or bird that may benefit from treatment with the compounds described herein (i.e., the C5a receptor activity inhibitors described herein). Preferably, “patient” is selected from laboratory animals (e.g., mice or rats), livestock (including, for example, guinea pigs, rabbits, chickens, turkeys, pigs, sheep, goats, camels, cattle, horses, donkeys, cats, or dogs), or primates (including monkeys and apes (e.g., African green monkeys, chimpanzees, bonobos, gorillas) and humans). Particularly preferably, “patient” is a human. The terms “patient” and “subject to be treated” (or simply “subject”) are used interchangeably herein.

[0063] As used herein, “treat,” “treating,” or “treatment” for a disease or disorder means to accomplish one or more of the following: (a) reducing the severity and / or duration of the disorder; (b) limiting or preventing the development of symptoms characteristic of one or more disorders being treated; (c) suppressing the worsening of symptoms characteristic of one or more disorders being treated; (d) limiting or preventing the recurrence of said one or more disorders in a patient who previously had one or more disorders; and (e) limiting or preventing the recurrence of symptoms in a patient who previously had symptoms of one or more disorders.

[0064] As used herein, “prevent,” “preventing,” “prevention,” or “prophylaxis” for a disease or disorder means the prevention of the occurrence of the disorder in a subject for a certain period of time. For example, if a compound of the present invention (or a pharmaceutical composition comprising said compound) is administered to a subject for the purpose of preventing a disease or disorder, the disease or disorder is prevented from occurring at least on the day of administration and preferably also for one or more days after the day of administration (e.g., 1 to 30 days; or 2 to 28 days; or 3 to 21 days; or 4 to 14 days; or 5 to 10 days).

[0065] As used in this article, "application" includes intracellular application as well as direct application to ex vivo tissues (such as intravenous grafts).

[0066] The "pharmaceutical composition" according to the invention can exist in the form of a composition in which different active ingredients and diluents and / or carriers are mixed with each other; or it can be in the form of a combination formulation in which the active ingredients exist in some or completely different forms. An example of such a combination or combination formulation is a kit.

[0067] An "effective amount" of therapeutic agent is sufficient to achieve the intended purpose. The effective amount of a given therapeutic agent will vary depending on factors such as the nature of the agent, the route of administration, the size and species of the animal to be treated, and the purpose of administration. The effective amount in each individual case can be determined empirically by a person skilled in the art using methods recognized in the field.

[0068] Unless otherwise stated, the term "alkyl" itself, or as part of another substituent, refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms (e.g., C1-C8 alkyl, where C1-C8 means one to eight carbons, preferably C1-C6 alkyl, most preferably C1-C4 alkyl). Preferred examples of C1-C4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl. More preferably, C1-C4 alkyl is methyl or ethyl, particularly methyl. In one embodiment, the alkyl group is preferably C2-C6 alkyl, more preferably C2-C4 alkyl. The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. The term "cycloalkyl" refers to a hydrocarbon ring having the indicated number of ring atoms (e.g., C3-6 cycloalkyl) and being fully saturated or having no more than one double bond between the ring vertices. "Cycloalkyl" is also intended to refer to bicyclic and polycyclic hydrocarbon rings. The term "heterocyclic alkyl" refers to a cycloalkyl group containing one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and one or more nitrogen atoms are optionally quaternized. Heterocyclic alkyl groups can be monocyclic, bicyclic, or polycyclic systems. Heterocyclic alkyl groups can be attached to the rest of the molecule via a cyclic carbon or heteroatom.

[0069] The term "alkylene" itself, or as part of another substituent, refers to a divalent group derived from an alkane, such as exemplified as -CH2CH2CH2CH2-. Typically, the alkyl (or alkylene) group will have 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred in this invention. "Lower alkyl" or "lower alkylene" is a shorter-chain alkyl or alkylene group, typically having four or fewer carbon atoms. Similarly, "alkenyl" and "alkynyl" refer to the unsaturated form of an alkylene group having a double or triple bond, respectively.

[0070] Unless otherwise stated, the term "heteroalkyl" itself, or in combination with another term, means a stable straight-chain, branched, or cyclic hydrocarbon group or combination thereof, consisting of the stated number of carbon atoms and one to three heteroatoms selected from O, N, and S, wherein nitrogen and sulfur atoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized. One or more heteroatoms O, N, and S may be located at any internal position of the heteroalkyl group. Similarly, unless otherwise stated, the terms "heteroalkenyl" and "heteroynyl" themselves, or in combination with another term, respectively mean an alkenyl or ynyl group containing the stated number of carbon atoms and having one to three heteroatoms selected from O, N, and S, wherein nitrogen and sulfur atoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized. One or more heteroatoms O, N, and S may be located at any internal position of the heteroalkyl group.

[0071] The term "heteroalkylene" itself, or as part of another substituent, refers to a saturated, unsaturated, or polyunsaturated divalent group derived from a heteroalkylene group. For heteroalkylene groups, the heteroatom can also occupy any one or both chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.).

[0072] The terms "alkoxy", "alkylamino", and "alkathio" (or thioalkoxy) are used in their conventional sense and refer to alkyl groups attached to the remainder of a molecule via an oxygen, amino, or sulfur atom, respectively. Additionally, for dialkylamino groups, the alkyl moiety can be the same or different and can combine to form 3-7 membered rings having a nitrogen atom, each of which is attached to the nitrogen atom.

[0073] Unless otherwise stated, the term "halogen" or "halogen" itself, or as part of another substituent, refers to a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "halogenated alkyl" are intended to include both monohalogenated and polyhalogenated alkyl groups. For example, the term "C1-4 haloalkyl" is intended to include trifluoromethyl, etc.

[0074] Unless otherwise stated, the term "aryl" refers to a polyunsaturated (typically aromatic) hydrocarbon group, such as C6-C. 10 Aryl groups can be monocyclic, fused together, or covalently linked multiple rings (up to three rings). The term "heteroaryl" refers to an aryl group (or ring) containing one to five heteroatomic aryl groups selected from N, O, and S, such as C4-C. 10 A heteroaryl group, wherein nitrogen and sulfur atoms are optionally oxidized, and one or more nitrogen atoms are optionally quaternized. The heteroaryl group may be attached to the remainder of the molecule via a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include furanyl, thiophene, pyrrole, pyridyl, quinolinyl, quinolyl, isoquinolinyl, etc. The substituents in each of the above-described aryl and heteroaryl ring systems are selected from the acceptable substituents described below.

[0075] For the sake of brevity, the term "aryl" in conjunction with other terms (e.g., aryloxy, arylthoxy, arylalkyl) includes both aryl rings and heteroaryl rings as defined above. Therefore, the term "arylalkyl" is intended to include those groups to which an aryl group is attached.

[0076] In some embodiments, the terms above (e.g., "alkyl," "aryl," and "heteroaryl") will include both substituted and unsubstituted forms of the indicated group. Preferred substituents for each type of group are provided below. For brevity, the terms aryl and heteroaryl will refer to the substituted or unsubstituted forms provided below, while the terms "alkyl" and the associated aliphatic group are intended to refer to the unsubstituted form unless otherwise specified.

[0077] The substituents of alkyl groups (including those commonly referred to as alkylene, alkenyl, ynyl, and cycloalkyl) can be selected from a variety of groups including: -halogen, -OR', -NR'R", -SR', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -CN, and -NO2, in quantities ranging from zero to (2 m'+l), where m' is the total number of carbon atoms in this group. R', R" and R'" each independently refer to hydrogen, unsubstituted carbon, and carbon atoms, respectively. 1-6 Alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C 1-6 Alkyl, C 1-8 Alkoxy or C 1-6 Thioalkoxy or unsubstituted aryl-C 1-4 Alkyl groups. When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form 3-, 4-, 5-, 6-, or 7-membered rings. The term "acyl" used either as itself or as part of another group refers to an alkyl group in which the two substituents on the carbon closest to the attachment point of the group are replaced by the substituent =O.

[0078] Similarly, the substituents of aryl and heteroaryl groups are diverse and are generally selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R"', -NH-C(N H2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -N3, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, ranging from zero to the total number of open valence states on the aromatic ring system; and wherein R', R" and R'" are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-8 Alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4 Alkyl and unsubstituted aryloxy-C 1-4 Alkyl groups. Other suitable substituents include each of the above aryl substituents attached to the ring atom via an alkylene chain of 1-4 carbon atoms.

[0079] The two substituents on adjacent atoms of the aryl or heteroaryl ring can optionally be of the formula -TC(O)-(CH2). q The substituents -U- are substituted, where T and U are independently -NH-, -O-, -CH2-, or single bonds, and q is an integer from 0 to 2. Alternatively, the two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by the formula -A-(CH2). r The substituents -B- are substituted, where A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or single bonds, and r is an integer from 1 to 3. One of the single bonds in the newly formed ring may optionally be substituted with a double bond. Alternatively, the two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by the formula -(CH2). s - X-(CH2) t The substituents are substituted, where s and t are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted C. 1-6 alkyl.

[0080] As used in this article, the term "heteroatoms" is intended to include oxygen (O), nitrogen (N), and sulfur (S).

[0081] As used herein, the term "cycle" means a saturated or unsaturated monocyclic or polycyclic carbon ring, preferably a 5-, 6-, or 7-membered ring, wherein one or more (e.g., 1, 2, 3, or 4) of the ring carbon atoms can be independently substituted by N, S, or O. The term "cycle" refers to fully saturated and unsaturated ring systems as well as partially unsaturated ring systems, and is intended to include all possible isomers of the carbon ring (e.g., pyrrolithyl includes 1H-pyrrolithyl and 2H-pyrrolithyl). Examples of monocyclic or bicyclic aryl rings include phenyl and naphthyl. Examples of monocyclic or bicyclic cycloalkyl rings include, but are not limited to, cyclopentyl and cyclohexyl. Examples of monocyclic or bicyclic saturated heterocyclic rings include, but are not limited to, tetrahydrofuranyl, pyrrolithyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, etc. Examples of monocyclic, bicyclic, or tricyclic partially saturated heterocyclic rings include, but are not limited to, pyrrolinyl, imidazolinyl, pyrazolinyl, etc. Examples of aromatic heterocycles with monocyclic, bicyclic, or tricyclic rings include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, etc.

[0082] Throughout this specification, indices are used to distinguish different substituents in the compounds of the present invention. Such indices are used as superscript or subscript numbers and do not imply any specific meaning in the use of superscript or subscript. In other words, superscript and subscript indices are used interchangeably. For example, formulas (I), (XI), and (XXI) all contain substituents C1, C2, and C3. In some formulas and reaction schemes, these substituents are shown as C1, C2, and C3; in others, they are shown as C... 1 C 2 and C 3 But C 1 C1 has the same substituent; C 2 C2 has the same substituent; and C 3 It has the same substituent as C3.

[0083] "Pharmaceutical acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally accepted pharmacopoeia for use in animals, and more particularly in humans.

[0084] The term "pharmaceutically acceptable salt" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases (depending on the specific substituents found on the compounds described herein). When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (pure or in a suitable inert solvent). Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, divalent manganese, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines (including substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.). When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid; and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge, SM et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain both basic and acidic functional groups, which allow the compounds to be converted into basic addition salts or acid addition salts.

[0085] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties (such as solubility in polar solvents), but in other respects, for the purposes of this invention, the salt and the parent form of the compound are equivalent.

[0086] In addition to salt form, the compounds used according to the present invention can be in prodrug form. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds used according to the present invention. Furthermore, prodrugs can be converted into the compounds used according to the present invention in an in vitro environment by chemical or biochemical methods. For example, when placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents, prodrugs can be slowly converted into the compounds used according to the present invention.

[0087] Some compounds used according to the invention may exist in both unsolvable and solvable forms (including hydrated forms). Generally, the solvable form is equivalent to the unsolvable form and is intended to be used within the scope of the invention. Some compounds used according to the invention may exist in various crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses covered by the invention and are intended to fall within the scope of the invention.

[0088] Some compounds used according to the invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and monomeric isomers (e.g., monomeric enantiomers) are all intended to be covered within the scope of the invention. Compounds used according to the invention may also contain atomic isotopes in non-natural proportions (e.g., at one or more atoms constituting such compounds). 2 H (i.e., deuterium, D) replaces 1 H). Compounds can also be made with radioactive isotopes (such as, for example, tritium). 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Radioactive labeling. All isotopic variants of the compounds used according to the present invention (whether or not radioactive) are intended to be covered within the scope of the present invention.

[0089] Embodiments of the present invention

[0090] The invention will now be described further. Different aspects of the invention are defined in more detail in the following paragraphs. Unless explicitly indicated otherwise, each aspect defined below can be combined with any other aspect or combination thereof. In particular, any feature indicated as preferred or advantageous can be combined with any other feature or combination thereof indicated as preferred or advantageous.

[0091] In one aspect, the present invention relates to a compound having the general formula (XXI).

[0092] (XXI)

[0093] and its pharmaceutically acceptable salts, hydrates and rotational isomers;

[0094] in

[0095] C 1 Selected from aryl and heteroaryl groups, wherein the heteroaryl group has 1-3 heteroatoms selected from N, O, and S as ring members; and wherein the aryl and heteroaryl groups are optionally fused with 1 to 3 R atoms. 1 Substituent substitution;

[0096] C 2 Selected from aryl and heteroaryl groups, wherein the heteroaryl group has 1-3 heteroatoms selected from N, O, and S as ring members; and wherein the aryl and heteroaryl groups are optionally fused with 1 to 3 R atoms. 2 Substituent substitution;

[0097] C 3 Selected from C 1-8 Alkyl or heteroalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, heterocyclic alkyl or heterocyclic alkyl-C 1-4 Alkyl groups, wherein the heteroalkyl group has 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic alkyl group or portion has 1-3 heteroatoms selected from N, O, and S, and wherein the heteroaryl group has 1-3 heteroatoms selected from N, O, and S as ring members, and each C 3 Choose any location via 1 to 3 R 3 Substituent substitution;

[0098] Each R 1 Independently selected from halogens, -CN, -R c —CO2R a —CONR a R b —C(O)R a —OC(O)NR a R b —NR b C(O)R a —NR b C(O)2R c —NR a —C(O)NR a R b —NR a C(O)NR a R b —NR a R b —OR a and —S(O)2NR a R b; where each R a and R b Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 A haloalkyl group, or one that, when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring members, and optionally substituted with one or two oxo groups; each R c Selected independently from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R a R b and R c The aliphatic and / or cyclic moiety is optionally further substituted with one to three halogens, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups; and optionally with two R groups. 1 When substituents are located on adjacent atoms, they combine to form fused five- or six-membered carbon rings or heterocycles.

[0099] Each R 2 Independently selected from halogens, -CN, -NO2, -R f —CO2R d —CONR d R e —C(O)R d —OC(O)NR d R e —NR e C(O)R d —NR e C(O)2R f —NR d C(O)NR d R e —NR d R e —OR d and —S(O)2NR d R e ; where each R d and R e Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 A haloalkyl group, or one that, when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring members, and optionally substituted with one or two oxo groups; each R f Selected independently from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R d R e and R f The aliphatic and / or cyclic moiety is optionally further substituted with one to three halogens, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups, and optionally with two R groups. 2 When groups are located on adjacent atoms, they combine to form five- or six-membered rings;

[0100] Each R 3 Independently selected from halogen, -CN, -R i —CO2R g —CONR g R h —C(O)R g —C(O)R i —OC(O)NR g R h —NR h C(O)R g —NR h CO2R i —NR g C(O)NR g R h —NR g R h —OR g —OR j —S(O)2NR g R h —X 4 —R j —NH—X 4 —R j —O—X 4 —R j —X 4 —NR g R h —X 4 —NHR j —X 4 —CONR g R h —X 4 —NR h C(O)R g —X 4 —CO2R g —O—X 4 —CO2R g —NH—X 4 —CO2R g —X 4 —NR h CO2Ri —O—X 4 —NR h CO2R i —NHR j and —NHCH2R j , where X 4 It is C 1-4 Alkylene; each R g and R h Independently selected from hydrogen and C 1-8 Alkyl or heteroalkyl, C 3-6 cycloalkyl and C 1-8 The alkyl halogroup, or, when attached to the same nitrogen atom, can combine with the nitrogen atom to form a four-, five-, or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring members, and optionally substituted with one or two oxo groups; each R i Selected independently from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and each R j Selected from C 3-6 Cycloalkyl, imidazolyl, pyrimidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and S,S-dioxo-tetrahydrothiopyranyl, wherein R g R h R i and R j The aliphatic and / or cyclic moieties may optionally be further oxidized by one to three halogens, methyl groups, CF3 groups, hydroxyl groups, C4 groups, C6 groups, C7 groups, C8 groups, C9 ... 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, —C(O)O—C 1-8 Alkyl, amino, alkylamino, and dialkylamino substitutions, and optionally in both R groups. 3 When groups are located on adjacent atoms, they combine to form five- or six-membered rings;

[0101] X is hydrogen or CH3; and

[0102] R 8 and R 9 Independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 alkoxy, or R 8 and R 9 These can combine to form fused saturated or unsaturated monocyclic or polycyclic carbon rings, wherein one or more of the ring carbon atoms can be independently replaced by N, S, or O.

[0103] The compound is used to treat or prevent diseases or disorders selected from the following:

[0104] • Sodium urate (MSU)-induced diseases, including peritonitis and gout,

[0105] • Neutrophil-driven inflammatory kidney diseases, including ischemic nephropathy, ischemia-reperfusion kidney injury, and obstructive nephropathy.

[0106] • Neutrophilic inflammatory diseases of the skin, including hidradenitis suppurativa (HS), pyoderma gangrenosum (PG), PASH (PG, acne, and hidradenitis suppurativa), PAPASH (suppurative arthritis, acne, PG, and hidradenitis suppurativa), chronic spontaneous urticaria, and bullous pemphigoid, and

[0107] • Immune complex diseases.

[0108] In some implementations of this aspect, R 8 and R 9 At least one of them is not hydrogen and / or X is hydrogen. Preferably, R 8 It is not hydrogen. Preferably, X is hydrogen.

[0109] In some embodiments of this aspect, the compound has the formula (XXIa).

[0110] (XXIa)

[0111] In some embodiments of the first aspect, the compound has formula (I) or formula (XI):

[0112] (I) or (XI),

[0113] in

[0114] X, C 1 C 2 and C 3 As defined above;

[0115] R in equation (XI) 8 As defined above;

[0116] R 4 Selected from cyano, halogen, nitro, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl-OH, (C1-C6)-alkyl-NR 5 R 6 Trifluoromethyl, (C1-C6)alkoxy, (C1-C6)thioalkoxy, phenoxy, COR 7 NR 5 R 6NHCO (C1-C6) alkyl, SO3H, SO2 (C1-C6) alkyl and SO2NR 5 R 6 ;

[0117] R 5 and R 6 Each is independently selected from hydrogen, (C1-C6)alkyl, and (C3-C6)cycloalkyl;

[0118] R 7 Independently hydroxyl, (C1-C6)alkoxy, phenoxy, or -NR 5 R 6 ;

[0119] m is 0-4; and

[0120] A ring is a saturated or unsaturated monocyclic or polycyclic carbon ring in which one or more of the carbon atoms in the ring can be replaced independently by N, S or O.

[0121] In other embodiments, the compound has formula (Ia) or formula (XIa):

[0122] (Ia) or (XIa).

[0123] In some embodiments, the ring is a saturated or unsaturated monocyclic or polycyclic (preferably quinary, septate or septate) carbon ring, wherein one to four (preferably one to three, more preferably one or two, or even more preferably one) of the carbon atoms in the ring can be independently replaced by N, S or O.

[0124] In some embodiments, the compound has formula (II):

[0125] (II).

[0126] In other embodiments, the compound has formula (IIa):

[0127] (IIa).

[0128] In some embodiments, the compound has a formula selected from the following: (IIIa), (IIIb), (IIIc), and (IIId):

[0129] (IIIa) (IIIb)

[0130] (IIIc) and (IIId).

[0131] In other implementations, the integer m is 0. In these implementations, there is no substituent R. 4 .

[0132] In other embodiments, the compound has a formula selected from the following: (IIIe), (IIIf), (IIIg), and (IIIh):

[0133] (IIIe) (IIIf)

[0134] (IIIg) and (IIIh).

[0135] In other implementations, the integer m is 0, meaning that in these implementations, there is no substituent R. 4 .

[0136] In some implementation schemes, C 1 yes

[0137] ,

[0138] in

[0139] R 1 As defined above (R occurs each time it appears), 1 It is independently selected, meaning that different residues R may exist at the phenyl ring. 1 ),and

[0140] n is an integer selected from 0, 1, 2, or 3, preferably 2.

[0141] In other implementations, each R 1 Independently selected from –OH, halogen, C 1-6 Alkyl, hydroxyl (C 1-6 )alkyl and halogroup (C 1-6 )alkyl. In a preferred embodiment, each R 1 It is independently selected from -OH, chlorine, methyl, -CH2-OH and CF3.

[0142] In some implementations of the first aspect, C 2 yes

[0143] ,

[0144] in

[0145] R 2 As defined above (R occurs each time it appears), 2It is independently selected, meaning that different residues R may exist at the phenyl ring. 2 ),and

[0146] o is an integer selected from 0, 1, 2 or 3.

[0147] In other implementations, each R 2 Selected independently from C 1-6 Alkyl groups and halogens. In a preferred embodiment, each R... 2 It is independently selected from methyl, fluorine and chlorine.

[0148] In some implementations of the first aspect, C 3 yes

[0149] ,

[0150] in

[0151] R 3 As defined above (R occurs each time it appears), 3 It is independently selected, meaning that different residues R may exist at the phenyl ring. 3 ),and

[0152] p is an integer selected from 0, 1, 2 or 3.

[0153] In the preferred embodiment, p is 1 and R 3 It is C 1- C8 hydroxyalkyl (preferably hydroxypentyl), C1-C8 hydroxyalkoxy (preferably hydroxybutoxy), or NHR as defined above j In other preferred embodiments, R j Selected from C1-C8 alkyl, C1-C8 hydroxyalkyl, C3-C6 cycloalkyl, and tetrahydropyranyl. In other preferred embodiments, R j It is selected from isopropyl, hydroxybutyl, cyclobutyl, cyclopentyl and tetrahydropyranyl.

[0154] In some embodiments of the first aspect, R8 is selected from halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups, and C1-C4 alkoxy groups. In a preferred embodiment, R8 is selected from fluorine, chlorine, methyl, trifluoromethyl, and methoxy groups.

[0155] In some embodiments, the compound is selected from INF004, INF011, INF014, INF015, INF022, INF023, INF024, INF025, INF030, INF033, INF034, INF035, INF038, INF039, INF040, INF041, INF045, INF046, INF047, INF048, INF049, INF050, INF051, INF052, INF053, INF054, INF055, INF056, INF058, INF067, INF068, INF069, INF070, INF071, INF072, INF075, INF077 and INF080. The structural formulas and chemical names of these compounds are shown in section “C. Results” of the Examples section below.

[0156] Preferably, in Ca 2+ In the mobilization assay, the IC50 of the compound used according to the present invention 50 1 µM or lower. Ca 2+ Mobilization assays are well-known in the field. Preferred Ca... 2+ Mobilization assays use human monocytes, such as U-937 (ATCC® CRL-1593.2). TM Suitable for determining ICs. 50 Ca 2+ Mobilization measurements are described in the examples. Preferably, in Ca... 2+ In the mobilization assay, the IC50 of the compound 50 It is 500 nM or lower, more preferably 200 nM or lower, and even more preferably 100 nM or lower.

[0158] The compound used according to the invention may be used in the treatment or prevention of the following diseases or disorders:

[0159] • Sodium urate (MSU)-induced diseases, including peritonitis and gout,

[0160] • Neutrophil-driven inflammatory kidney diseases, including ischemic nephropathy, ischemia-reperfusion kidney injury, and obstructive nephropathy.

[0161] • Neutrophilic inflammatory diseases of the skin, including neutrophilic dermatitis (ND) such as hidradenitis suppurativa (HS), pyoderma gangrenosa (PG), PASH (PG, acne, and hidradenitis suppurativa) and PAPASH (suppurative arthritis, acne, PG, and hidradenitis suppurativa), as well as chronic spontaneous urticaria and bullous pemphigoid, and

[0162] • Immune complex diseases.

[0163] Uric acid crystals [monosodium urate (MSU)] emerge as important factors in both gouty arthritis and immune regulation. This simple crystalline structure appears to activate innate host defense mechanisms and trigger robust inflammation and immune activation in multiple ways. The recognition mechanism of MSU after its phase transition from soluble uric acid is diverse, involving both protein receptors and nonspecific plasma membrane attachment. Upon contact with host cells, MSU induces a suite of membrane events, triggering Syk and PI3K activation, phagocytosis, and cytokine production. This is presumably further leading to the formation of active C5a and IL-1β production within 4–6 hours, as well as the recruitment of circulating neutrophils to MSU-induced sites of inflammation.

[0164] It has been surprisingly found that while MSU crystals dramatically increase the number of white blood cells (WBCs) in peritoneal lavage fluid (rather than in blood) upon injection, co-administration of the compounds used according to the invention reduces the cell counts of WBCs, monocytes, neutrophils, and lymphocytes in the peritoneal lavage fluid. Without wishing to be bound by theory, it is assumed that the recruitment of WBCs (especially neutrophils) at sites of inflammation may be inhibited by the presence of the compounds used according to the invention. This finding is consistent with the understanding of C5aR expression on neutrophils. This MSU-induced disease model (particularly peritonitis, as shown in Example 3) thus demonstrates the potential of the compounds used according to the invention to inhibit the effects of MSU-induced and neutrophil-driven inflammation in vivo.

[0165] In a preferred embodiment, monosodium urate (MSU)-induced diseases include peritonitis and gout. For these, it is established that MSU-induced inflammation is the cause of inflammation, which can be significantly reduced by compounds used according to the present invention, as shown in Example 3.

[0166] Although inflammatory kidney diseases (like glomerulonephritis) are usually caused by bacterial or viral infections, several other factors can lead to inflammatory responses in kidney tissue. For example, renal ischemia-reperfusion (I / R) injury is the most common cause of acute renal failure, as seen after kidney transplantation, major abdominal and vascular surgery, coronary artery bypass surgery, and in trauma and sepsis. The complement system has been shown to mediate renal ischemia-reperfusion (I / R) injury. C5aR has been found to be expressed on mesangial cells and renal tubular epithelial cells in the kidneys of healthy mice. Following I / R injury, C5aR expression is upregulated in renal tubular epithelial cells, and the kidneys are heavily infiltrated by neutrophils.

[0167] It has been surprisingly found that, in a model of ischemia-reperfusion kidney injury (see Example 4) and in a model of unilateral ureteral obstruction (UUO)-induced nephropathy (see Example 5), administration of the compound used according to the invention significantly reduces the loss of renal function.

[0168] Without being bound by theory, it is assumed that this is primarily achieved via a neutrophil-dependent pathway, but it can also be achieved via a non-neutrophil-dependent pathway. This finding suggests that the compounds used according to the invention have the potential to inhibit the effects of neutrophil-driven inflammatory kidney diseases (including ischemic nephropathy, ischemia-reperfusion kidney injury, and obstructive nephropathy) in vivo.

[0169] Hidradenitis suppurativa (HS) is a chronic, destructive skin disease affecting areas rich in apocrine glands and is considered one of the neutrophil-associated inflammatory skin diseases. Nodules appear in the affected areas and gradually swell and rupture, releasing pus. This process repeats, leading to sinus tract formation and scarring. The disease process produces frustrating conditions for both patients and physicians. Prevalence has been reported to range from 1% to 4%. The exact pathophysiology of HS is not fully understood. Smoking, dietary habits, and a genetic predisposition are all associated with HS. An increased percentage of NK cells and a decreased percentage of CD4 lymphocytes compared to healthy controls may suggest an autoimmune predisposition to the disorder. IL-1β and IL-17 have been upregulated in HS lesions and are associated with activation of inflammasomes. Hidradenitis suppurativa (HS) presents with abundant neutrophilic infiltration in the inflamed skin, especially in the later stages of the disease. Activated neutrophils may be an important effector cell type in the disease setting that causes tissue damage via direct destructive effects or indirect regulatory effects on other effector cells, such as active T cells and TH17.

[0170] Over the past few years, hypotheses have emerged regarding the pathogenesis of hepatitis B (HS) involving some form of autoimmune or autoinflammatory mechanism. These hypotheses were further reinforced by positive results from prospective, placebo-controlled studies using TNF antagonists, leading to the approval of adalimumab (an antibody against tumor necrosis factor-alpha) for use in patients with moderate to severe HS. An important, yet still unanswered, question remains: how are neutrophils recruited to affected skin lesions, and to what extent do activated neutrophils contribute to disease progression?

[0171] Numerous possible pathogenesis proposed by different studies may suggest that HS is related to host mechanisms rather than exogenous factors. Considering the paradox that both anti-infective therapies (antibiotics) and pro-infective therapies (anti-TNF, corticosteroids, immunosuppressants) may be helpful, HS may present as an autoinflammatory disease based on defects in the hair follicle's innate immunity, supported by the fact that pro-inflammatory cytokines (such as interleukin (IL)-1β and tumor necrosis factor-α (TNF-α)) are significantly increased in the lesion skin and the skin surrounding the lesion.

[0172] Neutrophilic dermatoses (NDs) are a class of skin disorders characterized by skin lesions whose histological examination reveals strongly inflammatory infiltrates composed primarily of neutrophils, without evidence of infection. NDs include pyoderma gangrenosa (PG) and other well-defined entities such as Sweet's syndrome, subkeratotic pustular dermatoses (SPD), persistent raised erythema (EED), or neutrophilic urticarial dermatoses (NUD) and their atypical or transitional forms. Hidradenitis suppurativa (HS) has recently been classified into the ND family based on the presence of abundant neutrophilic infiltrates observed in inflamed skin.

[0173] Pyoderma gangrenosa (PG) and hidradenitis suppurativa (HS) are proto-neutrophilic skin diseases that are considered to originate from autoinflammatory diseases and are characterized by the accumulation of neutrophils in the skin

[12] . Autoinflammatory syndromes represent a new class of inflammatory conditions that are distinct from autoimmune disorders, allergic disorders, and infectious disorders. From a pathophysiological perspective, all autoinflammatory syndromes (such as PAPA (pyogenic arthritis, PG, and acne), PASH (PG, acne, and hidradenitis suppurativa) or PAPASH (pyogenic arthritis, acne, PG, and hidradenitis suppurativa)) share a common mechanism consisting of overactivation of the innate immune system and “sterile” neutrophil-rich skin inflammation

[13] .

[0174] Neutrophilic urticarial dermatitis (NUD) (such as chronic spontaneous urticaria (autoimmune)) is a rare form of skin disease. Clinically, it consists of chronic or recurrent eruptions comprising slightly raised pink to slightly reddish plaques or spots. The underlying lesions last 24 to 48 hours and resolve without leaving any residual pigmentation. Extradermal signs are common, particularly fever or arthralgia. Histopathologically, the dermis contains dense neutrophilic interstitial infiltration and leukopenia, but without fibrotic necrosis of the vascular walls. NUD often occurs in the context of an underlying systemic disease. The most commonly associated diseases are adult-onset Still's disease, Schnitzler syndrome, lupus erythematosus, and cryopyrin-associated periodic syndrome. Treatment of NUD depends on the clinical context. Dapsone and colchicine are often effective, but other treatment options are also desirable.

[0175] Bullous autoimmune skin diseases (also known as autoimmune bullous diseases (AIBDs), such as bullous pemphigoid (BP)) are typically clinically and immunopathologically heterogeneous, characterized by vesicles or erosions of the skin and / or mucous membranes. In AIBDs, autoantibodies target structural proteins of the skin; in pemphigus, they target desmosomes that connect adjacent keratinocytes / epithelial cells; and in pemphigoid, they target proteins in the basement membrane region that connect the epidermis / epithelium and the dermis / lamina propria. Bullous pemphigoid (BP) is an inflammatory subepidermal bullous disease that is thought to be associated with an IgG autoimmune response against the hemidesmosome protein BP180.

[0176] It has been surprisingly found that the application of the compounds used according to the invention is suitable for improving ND (see Example 7). Without wishing to be bound by theory, it is assumed that this is primarily achieved via a neutrophil-dependent pathway, but it can also be achieved via a non-neutrophil-dependent pathway. This finding suggests that the compounds used according to the invention have the potential to inhibit in vivo the effects of neutrophilic inflammatory diseases of the skin, including hidradenitis suppurativa (HS), pyoderma gangrenosum (PG), PASH (PG, acne, and hidradenitis suppurativa) and PAPASH (suppurative arthritis, acne, PG, and hidradenitis suppurativa), as well as neutrophilic urticarial dermatitis (NUD) and autoimmune bullous diseases (AIBD)).

[0177] Immune complex diseases are a group of conditions arising from inflammation and tissue damage induced in tissues where immune complexes are formed or deposited. Immune complexes (sometimes called antigen-antibody complexes or antibodies that bind to antigens) are molecules formed by the binding of multiple antigens to multiple antibodies. The bound antigens and antibodies function as a single entity (actually as independent antigens with specific epitopes). Following an antigen-antibody reaction, immune complexes can undergo any of a variety of reactions, including complement deposition, opsonization, phagocytosis, or processing by proteases. Immune complex deposition is a major feature of several autoimmune diseases, including rheumatoid arthritis, scleroderma, and Sjögren's syndrome. Immune complexes that cannot be degraded in lysosomes and subsequently accumulate on the surface of immune cells are associated with systemic lupus erythematosus. Other related immune complex disorders include IgA nephritis (or IgA nephropathy, named for the deposition of immunoglobulin A (IgA) in the mesangium in a granular pattern); lupus nephritis (an inflammation of the kidneys caused by systemic lupus erythematosus (SLE), an autoimmune disease); ANCA (anti-neutrophilic cytoplasmic antibody) vasculitis; C3 glomerulonephropathy (C3G), characterized by significant deposition of the third component of complement (C3) in the glomeruli; and atypical hemolytic uremic syndrome (aHUS), also known as complement-mediated hemolytic uremic syndrome, which is usually caused by chronic irritation of the complement system. Control activation-induced; Goodpassuia syndrome (also known as anti-glomerular basement membrane disease, a rare autoimmune disease in which antibodies attack the basement membrane in the lungs and kidneys); crescentic glomerulonephritis; focal segmental glomerulosclerosis (FSGS); rheumatic fever (an inflammatory disease believed to involve the production of autoantibodies); dermatomyositis (DM); chronic inflammatory demyelinating polyneuropathy (CIDP) (also known as chronic relapsing polyneuropathy (CRP) or chronic inflammatory demyelinating polyradiculopathy); chemotherapy-induced peripheral neuropathy (CIPN); and transplant rejection.

[0178] Dermatomyositis (DM) is an acquired autoimmune disease in which skeletal muscle becomes a target of the immune system, and the disease is a subtype of idiopathic inflammatory myopathy (IIM). DM is characterized primarily by muscle inflammation, proximal muscle weakness, and skin involvement. In addition, the disease may present with extramuscular symptoms affecting various organs, including the heart, joints, lungs, and gastrointestinal tract. Recent studies appear to confirm the association between immune cell infiltration and myocardial damage in dermatomyositis

[14] .

[0179] Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common, heterogeneous, immune-mediated neuropathy characterized by significant demyelination of motor and sensory nerves. CIDP follows a relapsing-remitting or progressive course and causes significant disability. The pathogenesis of CIDP involves a complex interplay of multiple aberrant immune responses that create a pro-inflammatory environment that subsequently damages the myelin sheath. The complement system appears to play a role in promoting macrophage-mediated demyelination.

[15]

[0180] Chemotherapy-induced peripheral neuropathy (CIPN) is the most common neurological complication of chemotherapy, causing pain, loss of sensation, and numbness in the hands and feet. In many cases, acute CIPN leads to the cessation of chemotherapy, and the symptoms can persist for months or years until they become chronic. When the pain becomes too severe, changes to the chemotherapy regimen or discontinuation of treatment are necessary, leading to the risk of reduced treatment efficacy. Chemotherapy drugs are used to block cancer progression due to their ability to kill cancer cells. However, these drugs also affect healthy cells, causing side effects such as anemia, diarrhea, and nausea, and also leading to serious complications such as infertility, infections, and pain. Simultaneously, chemotherapeutic agents can affect the structure of the nervous system, and depending on the compound and its mechanism of action, they can cause a variety of neuropathy, such as peripheral neuropathy. Changes in immune signaling and ion channel expression, neurotoxicity, mitochondrial dysfunction, and axonal degeneration are considered among the most relevant mechanisms involved in CIPN, and several studies have highlighted that the immune system and immune-mediated neuroinflammation are key events in the development of CIPN.

[0181] It has been surprisingly found that, in a human whole blood immune complex model, administration of the compound used according to the invention significantly reduces immune complex-driven neutrophil activation (see Example 6).

[0182] Pharmaceutical composition and administration

[0183] In practice, the compounds used according to the invention can be in pharmaceutical compositions, and the compounds or pharmaceutical compositions containing the compounds can be administered to a patient via any route recognized in the art, thereby providing a sufficiently high level of the compounds in the patient. It can be administered systemically or locally. Such administration can be parenteral, transmucosal (e.g., oral, nasal, rectal, vaginal, sublingual, submucosal), transdermal, or by inhalation. Preferably, administration is parenteral, such as via intravenous or intraperitoneal injection, and also includes, but is not limited to, intra-arterial, intramuscular, intradermal, and subcutaneous administration. If the compounds described herein or pharmaceutical compositions containing the compounds are administered locally, they can be injected directly into the organ or tissue to be treated.

[0184] Pharmaceutical compositions suitable for oral administration may be provided in the following forms: capsules or tablets; powders or granules; solutions, syrups, amorphous dispersions in polymers, waxy solids, or suspensions (in aqueous or non-aqueous liquids); edible foaming agents or whipped preparations; or emulsions. Tablets or hard gelatin capsules may contain lactose, starch or derivatives thereof, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, stearic acid or salts thereof. Soft gelatin capsules may contain vegetable oils, waxes, fats, semi-solid or liquid polyols, etc. Solutions and syrups may contain water, polyols, and sugars.

[0185] Active agents intended for oral administration can be coated with or mixed with a material that delays the disintegration and / or absorption of the active agent in the gastrointestinal tract (e.g., glyceryl monostearate or glyceryl distearate can be used). Thus, sustained release of the active agent can be achieved over several hours, and, if desired, the active agent can be protected from degradation in the stomach. Pharmaceutical compositions for oral administration can be formulated to facilitate the release of the active agent at specific gastrointestinal locations due to specific pH or enzymatic conditions.

[0186] Pharmaceutical compositions suitable for transdermal application can be provided as discrete patches intended to maintain close contact with the recipient's epidermis over an extended period of time. Pharmaceutical compositions suitable for topical application can be provided as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. For topical application to the skin, mouth, eyes, or other exposed tissues, topical ointments or creams are preferred. When formulated as an ointment, the active ingredient can be used with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream using an oil-in-water emulsion or water-in-oil base. Pharmaceutical compositions suitable for topical application to the eyes include eye drops. In these compositions, the active ingredient can be dissolved or suspended in a suitable carrier, such as an aqueous solvent. Pharmaceutical compositions suitable for topical application in the oral cavity include lozenges, pasties, and mouthwashes.

[0187] Pharmaceutical compositions suitable for nasal administration may comprise a solid carrier, such as a powder (preferably having a particle size in the range of 20 to 500 micrometers). The powder can be administered by inhalation (i.e., rapid inhalation through the nose from a container holding the powder near the nose). Alternatively, compositions suitable for nasal administration may comprise a liquid carrier, such as a nasal spray or nasal drops. These compositions may comprise an aqueous or oil solution of the active ingredient. Compositions for inhalation administration may be provided in particularly suitable devices, including but not limited to pressurized aerosols, nebulizers, or inhalers, which may be configured to deliver a predetermined dose of the active ingredient. Pharmaceutical compositions may also be administered to the lungs via the nasal cavity.

[0188] Pharmaceutical compositions suitable for rectal administration may be provided as suppositories or enemas. Pharmaceutical compositions suitable for vaginal administration may be provided as vaginal suppositories, tampons, creams, gels, pastes, foams, or sprays.

[0189] Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions or suspensions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the composition substantially isotonic with the blood of the intended recipient. Other components that may be present in such compositions include water, alcohols, polyols, glycerol, and vegetable oils. Compositions suitable for parenteral administration may be available in single-dose or multi-dose containers (e.g., sealed ampoules and vials) and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier (e.g., sterile injectable saline solution) just before use. Temporary injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0190] In a preferred embodiment, the compounds used according to the invention as described herein are formulated into pharmaceutical compositions suitable for intravenous administration to humans according to conventional procedures. Typically, the compositions for intravenous administration are solutions in sterile isotonic buffer solutions. If necessary, the compositions may also include solubilizers and local anesthetics (such as lidocaine) to relieve pain at the injection site. Generally, the components are provided separately or mixed together in unit dosage forms, for example, as dried lyophilized powders or anhydrous concentrates in hermetically sealed containers, such as ampoules or capsules indicating the amount of active agent. When the composition is to be administered by infusion, it can be dispensed using an infusion bottle containing sterile pharmaceutical-grade water or saline. When the composition is administered by injection, a sterile saline ampoule can be provided so that the components can be mixed prior to administration.

[0191] In another embodiment, for example, a compound or pharmaceutical composition comprising said compound, as described herein and used according to the invention, may be delivered in a controlled-release system. For example, the compound may be administered via intravenous infusion, implantable osmotic pump, transdermal patch, liposome, or other administration methods. In one embodiment, a pump may be used (see Sefton (1987) CRC Crit. Ref. Biomed. Eng. 14: 201; Buchwald et al. (1980) Surgery 88:507; Saudek et al. (1989) N. Eng. J. Med. 321: 574). In another embodiment, the compound can be delivered in vesicles (particularly liposomes) (see Langer (1990) Science 249:1527-1533; Treat et al. (1989) in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, NY, 353-365; WO 91 / 04014; US 4,704,355). In another implementation, polymeric materials may be used (see Medical Applications of Controlled Release (1974) Langer and Wise (eds.), CRC Press: Boca Raton, Fla.; Controlled Drug Bioavailability, Drug Product Design and Performance, (1984) Smolen and Ball (eds.), Wiley: NY; Ranger and Peppas (1953) J. Macromol. Sci. Rev. Macromol. Chem. 23: 61; see also Levy et al. (1985) Science 228:190; During et al. (1989) Ann. Neurol. 25: 351; Howard et al. (1989) J. Neurosurg. 71: 105).

[0192] In yet another implementation, the controlled-release system can be placed near the therapeutic target (i.e., target cells, tissues, or organs), thus requiring only a fraction of the systemic dose (see, for example, Goodson (1984) 115-138 Medical Applications of Controlled Release, Vol. 2). Other controlled-release systems are discussed in a review by Langer (1990, Science 249: 1527-1533).

[0193] In specific implementations, it may be desirable to apply topically to the area requiring treatment a compound as described herein or a pharmaceutical composition comprising said compound. This can be achieved, for example, but not limited to, local infusion during surgery, topical application (e.g., in conjunction with postoperative wound dressings), by injection, via catheter, via suppository, or by means of an implant that is a porous, non-porous, or gel-like material, including membranes (such as silastic™ membranes) or fibers.

[0194] The selection of the preferred effective dose of the compound used according to the invention as described herein will be determined by a person skilled in the art based on consideration of several factors known to them. Such factors include the specific form of the pharmaceutical composition (e.g., a peptide or carrier) and its pharmacokinetic parameters, such as bioavailability, metabolism, half-life, etc., which are typically determined in the routine development procedures used to obtain regulatory approval for pharmaceutical compounds. Other factors to consider for the dose include the condition or disease to be prevented and / or treated, or the benefit to be obtained in a normal individual, the patient's weight, the route of administration, whether the administration is acute or chronic, concomitant drug therapy, and other well-known factors affecting the efficacy of the administered agent. Therefore, the accurate dose should be determined based on the practitioner's judgment and the individual patient's condition, for example, according to standard clinical techniques, based on the individual patient's condition and immune status. Typical doses of the compounds used according to the invention are in the range of about 0.1 to 100 mg / kg body weight, preferably about 0.1 to 10 mg / kg body weight.

[0195] Methods for preparing various pharmaceutical compositions having a certain amount of active ingredient are known to those skilled in the art. For examples of methods for preparing pharmaceutical compositions, see Remington: The Science and Practice of Pharmacy , Lippincott, Williams & Wilkins, 21st ed. (2005).

[0196] In one embodiment of the invention, the compound used according to the invention may also be combined with at least one other therapeutic agent.

[0197] In one embodiment, the invention also relates to a method for treating a patient requiring such treatment for a specific disease as defined above, the method comprising administering a compound as defined above for use according to the invention or a pharmaceutical composition as described herein.

[0198] Generally, the compounds used according to the present invention can be prepared by the synthetic methods outlined in WO 2020 / 182384 A1, which is incorporated herein by reference.

[0199] Example

[0200] The following examples are provided to illustrate, and not to limit, the claimed invention. The compounds used within the scope of this invention can be synthesized using a variety of reactions known to those skilled in the art (e.g., according to WO 2020 / 182384 A1). Those skilled in the art will also appreciate that alternative methods can be employed to synthesize the target compounds used in this invention. Certain molecules described herein may exist in different enantiomeric and diastereomeric forms, and use of all such variants of these compounds is claimed.

[0201] Example 1

[0202] A. The compound used in this invention is an inhibitor of C5aR1.

[0203] The results shown below confirm the efficacy of the compound used according to the present invention in regulating the activity of the C5a receptor by directly binding to the mammalian C5a receptor.

[0204] B. Biological assay

[0205] calcium ++ Mobilization Measurement

[0206] U937 cells (ATCC) were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum in a standard cell culture incubator. ® CRL-1593.2). One day prior to the assay, bibutyryl-cAMP (0.5 mM working concentration) was added to the cell culture. The next day, the cells were rotated and resuspended in RPMI 1640 to a concentration of 40,000 cells / 50 µl. 40,000 cells were seeded into one well of a 96-well poly-D-lysine coated plate and held for two hours to allow cell adhesion. After cell adhesion, cytoplasmic calcium was added. ++Indicator (FLIPR Calcium 6 Assay Kit, Molecular Devices) was added to each well and incubated at 37ºC for 75 min. The test compound was diluted using a robotic liquid processor. The pipette tip of the robotic liquid processor was replaced after each mixing step. The test compound was added to cell cultures at different concentrations (0.01 nM to 100 µM) and held at 37ºC for 15 min. The cell culture plates were then incubated at room temperature for 30 min before being placed in a Flexstation-3 reader (Molecular Devices). The Flexstation-3 was programmed to add recombinant C5a protein to cell culture plates at different concentrations (1 nM to 10 nM) and monitor changes in fluorescence intensity related to cytoplasmic calcium concentration. The assay was also performed in the presence of human or animal blood components (such as human or bovine plasma or serum).

[0207] Chemotaxis assay

[0208] U937 cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum in a standard cell culture incubator. One day prior to the assay, bibutyryl-cAMP (0.5 mM working concentration) was added to the cell culture. The next day, the cells were rotated and resuspended in RPMI 1640 to a concentration of 50,000 cells / 20 µl. The cells were incubated with different concentrations (0.01 nM to 100 µM) of the compound at 37ºC for 30 min. 50,000 cells in 20 µl of RPMI 1640 were added to one well of the upper chamber of a 96-well chemokine plate (a chemokine plate with a cell filter having 8 μm pores, purchased from Neuroprobe). 29 µl of HBSS buffer at a preferred concentration of C5a or other chemokine was added to the lower chamber. Cells that migrated to the lower chamber one to three hours later were stained with Cell Titer Glo (Invitrogen) and treated with FlexStation. ® 3. Quantification is performed. The determination is also performed in the presence of human or animal blood components (such as human or bovine plasma or serum).

[0209] β-blocking protein assay

[0210] Using U2OS (ATCC designation HTB-96), an osteosarcoma cell line, genetically engineered cell lines overexpressing two types of fusion proteins were generated in the same cells: (a) the fusion protein TEV-C5aR1, which consists of a tobacco etch virus (TEV) protease fused to wild-type human C5aR1 or a human C5aR1 mutant. The C5aR1 mutant carries one or more amino acid mutations that are presumed to mediate the interaction between C5aR1 and the test compound. (b) the fusion protein Luc-blocking protein, which consists of β-blocking protein-2 (an inactive substitutional luciferase) and a peptide constituting the TEV protease cleavage site. The peptide is located between β-blocking protein-2 and the luciferase.

[0211] The activity of C5aR1 was investigated using engineered U2OS cell lines, and the extent to which test compounds could modulate the activity of wild-type or mutant C5aR1 was examined. In principle, C5a binds to the C5aR1 moiety of TEV-C5aR1 at the cell surface, activating C5aR1. This leads to the binding of the intracellular portion of TEV-C5aR1 to the luciferase-blocking protein within the cell, allowing TEV to cleave the peptide linking the β-blocking protein to luciferase. This cleavage converts inactive luciferase into active luciferase, which catalyzes the addition of the luciferase substrate, thereby generating a luminescent signal. The intensity of the luminescent signal is correlated with the activity of C5aR1.

[0212] In the experiment, engineered U2OS cells were cultured in McCoy medium supplemented with 10% fetal bovine serum in a standard cell culture incubator. The test compound was added to the cell culture medium and incubated for 30 minutes, followed by the addition of C5a and incubation for one to three hours. Cells were then lysed using a reagent containing a luciferase substrate (such as One-glo or Bright-glo (Promega)). A luminescent plate reader (such as FlexStation) was used. ® 3 (Molecular Devices) Recording Light Emitting Unit (RLU).

[0213] C5a-induced CD11b expression in whole blood assay

[0214] Fresh peripheral blood samples were obtained from consenting human volunteers. 100 µl of whole blood was incubated for 20 minutes at 37ºC with test compounds at varying concentrations (0.01 nM to 10 µM), followed by incubation for 20 minutes at 37ºC with C5a at a preferred concentration ranging from 1 nM to 30 nM. Samples were prepared for immunostaining, followed by FACS (fluorescence-activated cell sorting) analysis of CD11b expression in leukocytes. Samples were incubated on ice for 30 minutes in the dark with an anti-CD11b antibody (BioLegend). One mL of erythrocyte lysis buffer (Miltenyi) was added to 100 µl of blood sample and incubated at room temperature for 10 minutes. Samples were washed with FACS staining buffer and resuspended in FACS buffer. Cell surface CD11b expression in the samples was analyzed using FACS (Beckman Coulter).

[0215] Animal neutropenia assay

[0216] Allow animals (mice, rats, or Mongolian gerbils) to acclimate for at least three days prior to use in experiments. Administer the test compound orally or intravenously (1 to 30 mg / kg). One to three hours later, anesthetize the animal using standard procedures (e.g., intraperitoneal administration of ketamine and mebenzylthiazide). Insert a catheter into the animal for intravenous administration of C5a and blood collection. Construct C5a in saline and administer intravenously at doses ranging from 30 µg / kg to 120 µg / kg. Collect several blood samples within 30 minutes of C5a administration. Collect blood samples using heparinized tubing. Analyze the white blood cell differentials (e.g., neutrophil abundance) in the collected blood samples using an automated hematology analyzer (Siemens).

[0217] C. result

[0218] In biological assays (such as calcium mobilization assays), the half-maximal inhibition concentration (IC50) is determined. 50 Using calcium mobilization assays, the following IC50 values ​​were determined by optimal dose-response curve fitting. 50 The curves were plotted using the percentage inhibition of C5a-induced calcium mobilization relative to various concentrations of the compound.

[0219]

[0220] INF004: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0221] INF011: (2R,3S)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-2-(4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0222] INF014: (2R,3S)-1-(2-chlorobenzoyl)-2-(4-(cyclopentylamino)phenyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0223] INF015: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0224] INF022: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-6-fluoro-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0225] INF023: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-6-methyl-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0226] INF024: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-6-methoxy-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0227] INF025: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-6,7-difluoro-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0228] INF030: (2R,3S)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-2-(4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0229] INF033: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0230] INF034: (2R,3S)-1-(2-fluoro-6-methylbenzoyl)-2-(4-(3-hydroxy-3-methylbutyl)phenyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0231] INF035: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(3-(hydroxymethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0232] INF038: (2R,3S)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-2-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0233] INF039: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-6-fluoro-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0234] INF040: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1-(2-methylbenzoyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0235] INF041: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluorobenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0236] INF045: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-5-fluoro-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0237] INF046: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-7-fluoro-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0238] INF047: (2R,3S)-6-chloro-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0239] INF048: (2R,3S)-1-(2-fluoro-6-methylbenzoyl)-2-(4-(3-hydroxy-3-methylbutyl)phenyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0240] INF049: (2R,3S)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-2-(4-(isopropylamino)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0241] INF050: (2R,3S)-2-(4-(cyclobutylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0242] INF051: (2R,3S)-1-(2-fluoro-6-methylbenzoyl)-2-(4-((2-hydroxy-2-methylpropyl)amino)phenyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0243] INF052: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0244] INF053: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-dimethylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0245] INF054: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide;

[0246] INF055: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0247] INF056: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0248] INF058: (2R,3S)-1-(2-fluoro-6-methylbenzoyl)-2-(4-(2-hydroxy-2-methylpropoxy)phenyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0249] INF067: (2R,3S,5R)-2-(4-((cyclopentyl-1-d)amino)phenyl)-1-(2,6-difluorobenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0250] INF068: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-N-(4-hydroxy-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0251] INF069: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0252] INF070: (2R,3S,5R)-1-(2,6-difluorobenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-2-(4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0253] INF071: (2R,3S,5R)-N-(3-chloro-4-methylphenyl)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0254] INF072: (2R,3S,5R)-N-(3-chloro-4-hydroxyphenyl)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0255] INF075: (2R,3S,5R)-1-(2-chloro-6-fluorobenzoyl)-2-(4-(cyclopentylamino)phenyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0256] INF077: (2R,3S,5R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0257] INF080: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-N-(3,4-dichlorophenyl)-1-(2,6-difluorobenzoyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0258] Example 2 - Inhibition of C5a-induced neutropenia

[0259] Hamsters are considered a pharmacologically relevant species possessing analogues of human C5aR. Therefore, as in humans, the number of neutrophils in hamster blood significantly decreases after C5a injection-induced neutropenia. Without wishing to be bound by theory, it is assumed that the specific C5a receptor antagonist used according to the present invention can improve neutrophil infiltration.

[0260] The effects of INF052 and INF054 administered orally (PO) prior to C5a injection on the inhibition of neutropenia were evaluated in Lakeview Golden (LVG) hamsters. C5a injections (100 μg / kg, prepared in saline, medium 2) were administered 8 and 24 hours after oral administration of the compounds (reconstituted in medium 1: 70% PEG-400 / 30% Solutol HS-15). Blood samples were collected via a jugular catheter before and after C5a injection at -1 min (before C5a) and +1 min (after C5a). Neutrophil counts and p-kJ analysis were performed to study the animals.

[0261] The study evaluated the effects of INF052 and INF054 at 10, 20, or 30 mg / kg PO doses (reconstituted in media 1: 70% PEG-400 / 30% Solutol HS-15) before C5a injection (prepared in media 2: saline) in LVG hamsters at 4 h (one 30 mg / kg study), 8 h, and 24 h. Compared with the media 1 + C5a (100 μg / kg) group, doses of INF052 and INF054 at 10, 20, and 30 mg / kg before C5a at 8 h and 24 h significantly reduced changes in neutrophil count. The results are summarized in Table 1 below. Regarding changes in neutrophil count at 8 h, 10 mg / kg INF052 showed better potency than INF054 (see Table 1). Figure 1 ).

[0262] Table 1

[0263]

[0264] PK: Blood samples were collected 1 min after C5a injection into tubes containing EDTA-K2 as an anticoagulant. Plasma samples were maintained at -80ºC and the INF054 / INF052 concentrations were analyzed by HPLC.

[0265] Inhibition %: Blood samples were collected at -1 min (before dose) and 1 min after C5a injection into tubes containing EDTA-K2 as an anticoagulant, and neutrophils were counted using a hematology analyzer (Siemens, ADVIA2120i). Inhibition % was calculated by comparing the changes in neutrophil count induced by INF054 / INF052 with the changes in neutrophil count induced by C5a.

[0266] These results show that the compounds used according to the present invention are effective in blocking C5a-induced neutropenia.

[0267] Example 3 - Inhibition of MSU-induced peritonitis

[0268] Typically, injection of monosodium urate (MSU) crystals into the peritoneal cavity of hamsters triggers the formation of inflammasome complexes and activates the complement cascade, presumably leading to the formation of active C5a and the production of IL-1β. The latter results in the recruitment of circulating neutrophils to the MSU-induced site of inflammation, usually occurring within 4 to 6 hours. The effect of INF052 on a model of MSU-induced acute peritonitis was evaluated in hamsters orally administered either the medium or 20 mg / kg of INF052 (medium: 70% PEG400, 30% Solutol HS15), followed by intraperitoneal (IP) injection of MSU crystals 5 h post-administration. Saline injection served as a control. All study animals were sacrificed 6 hours post-MSU injection. Total cell counts and differential analyses were performed using blood samples and inflammatory exudates recovered from the peritoneal cavity. Treatment groups were as follows:

[0269] Table 2

[0270]

[0271] Cell counts, including white blood cells (WBC), neutrophils (Neut), lymphocytes (Lymph), and monocytes (Mono), in peritoneal lavage fluid and blood of each group (G) are shown in Table 3 below:

[0272] Table 3

[0273]

[0274] ** p < 0.01

[0275] The volume of peritoneal lavage fluid is as follows:

[0276] Table 4

[0277]

[0278] As the results above show, MSU crystals dramatically increased the number of white blood cells in peritoneal lavage fluid, but not in blood. Compared to MSU + mediator treatment, INF052 significantly reduced MSU-induced white blood cell (WBC) and neutrophil (Neut) counts in peritoneal lavage fluid (see also...). Figure 2 Furthermore, no significant effect was found on serum (data not shown) and peritoneal lavage fluid levels of IL-6 and IL-1β (see Table 4 above). These results confirm that the recruitment of WBCs (especially neutrophils) to sites of inflammation may be inhibited by the presence of INF052.

[0279] In summary, this MSU-induced peritonitis model demonstrates that the compounds used according to the present invention have the potential to inhibit the effects of neutrophil-driven inflammation, particularly MSU-induced inflammation, in vivo.

[0280] Example 4 - Inhibition of ischemia-reperfusion kidney injury

[0281] Four hours prior to surgery, golden hamsters were given a mediator or INF052. Animals were anesthetized, and the right renal artery, vein, and ureter were ligated. The right kidney was removed. The left renal pedicle was clamped to interrupt blood flow to the left kidney. After 45 minutes, the clamp was removed, and blood flow to the left kidney was restored. In the sham-operated group, the left renal artery was not clamped. Animals were allowed two days to recover post-surgery. Animals were euthanized 48 hours post-surgery. Blood and kidney tissue samples were collected for analysis. Animal groups are shown in Table 5 below.

[0282] Table 5

[0283]

[0284] IRI = Ischemia-reperfusion injury

[0285] The blood biochemistry results 48 hours after the ischemic surgery are as follows:

[0286] Table 6

[0287]

[0288] IRI = Ischemia-reperfusion injury

[0289] INF052 significantly reduced plasma levels of creatine (CREA) and blood urea nitrogen (BUN) after ischemia-reperfusion surgery, demonstrating its role in preventing ischemia-reperfusion-induced kidney injury. C-reactive protein (CRP) was not detected, and fibrin / fibrinogen degradation products (FDP) and D-dimer were detected only at the minimum detectable dose. Three ELISA assays, including plasminogen, suPAR (soluble urokinase-type plasminogen activating receptor), and S100A8 / A9 (calcium defense protein) (data not shown), also failed to detect any signal, confirming the absence of inflammation. Platelet counts remained unchanged with or without surgery or treatment, indicating that platelets were not activated.

[0290] The histopathological condition of the kidneys is summarized below:

[0291] Table 7

[0292]

[0293] IRI = Ischemia-reperfusion injury

[0294] Histopathological scoring criteria

[0295]

[0296] The results are shown in Figure 3 In China, the administration of INF052 reduced the negative effects of ischemia-reperfusion on the kidneys, as confirmed by histopathological markers and periodic acid-Schiff (PAS) staining.

[0297] In summary, this ischemia-reperfusion kidney injury model demonstrates that the compounds used according to the present invention have the potential to inhibit the negative effects of neutrophil-driven inflammatory nephropathy (especially ischemia-reperfusion) on the kidneys in vivo.

[0298] Example 5 - Efficacy in unilateral ureteral obstruction (UUO)-induced nephropathy

[0299] Unilateral ureteral obstruction (UUO) is a model of renal interstitial fibrosis. C5aR expression in renal tubular cells is sparse in normal renal cortex but is significantly upregulated after UUO. C5 deficiency or inhibition of C5aR was found to significantly reduce extracellular matrix deposition and associated inflammation in the fibrotic kidney. In this study, the efficacy of INF052 in the UUO model was evaluated.

[0300] Golden hamsters (8–10 weeks old) were randomly assigned to three groups to achieve similar average body weight. Animals in groups 2 and 3 were induced to undergo unilateral ureteral obstruction (UUO) surgery on day 1. Animals were anesthetized with 2–5% isoflurane. The left kidney was exposed via a lumbar incision, and the left ureter was ligated at the lower pole level with two 3.0mm ribbons. Animals were given pain medication postoperatively, namely buprenorphine hydrochloride (0.05 mg / kg) and gentamicin (20 mg / kg, IM). All animals were monitored until they regained consciousness. General health of the animals was monitored daily. The animal was administered the mediator or active ingredient over a total period of 14 days (see Table 8 below).

[0301] Table 8

[0302]

[0303] * Administer the first dose 5 hours before the UUO procedure on day 1.

[0304] UUO = Unilateral ureteral obstruction

[0305] Compared with group 2, no significant difference in the weight / body weight of the obstructed left kidney was observed after INF052 treatment. No deaths were observed up to 14 days post-surgery.

[0306] Approximately 3 days post-surgery, serum creatinine levels were slightly elevated in groups 2 and 3, but returned to normal in all groups by day 7. Serum creatinine levels typically do not increase until severe renal function loss occurs. In the UUO model used, only one kidney was obstructed by progressive fibrosis, while the other kidney remained functional; therefore, no change in creatinine was expected.

[0307] like Figure 4 As shown, blood urea nitrogen (BUN) levels were significantly increased in group 2 on days 7 and 14 post-UUO surgery. Treatment with INF052 was able to maintain BUN levels at low levels very similar to those in animals that did not undergo surgery, indicating that INF052 interferes with the UUO program and avoids inducing higher metabolic or inflammatory activity.

[0308] The histopathological condition of the kidneys is summarized in Table 9 below:

[0309] Table 9

[0310]

[0311] UUO = Unilateral ureteral obstruction

[0312] Compared to UUO-media group 2, INF052 treatment in group 3 significantly reduced the total score of H&E staining (see [link]). Figure 5 INF052 further reduced fibrosis scores and α-SMA-positive cell scores as determined by Masson staining (see Table 9).

[0313] In summary, the results of the unilateral ureteral obstruction model indicate that the compounds used according to the present invention have the potential to inhibit the negative effects of neutrophil-driven inflammatory nephropathy (especially unilateral ureteral obstruction) in vivo, and thus have the potential to treat obstructive nephropathy.

[0314] Example 6 - Efficacy in reducing reduced immune complex-driven neutrophil activation in a human whole blood immune complex model

[0315] The aim of this study is to evaluate the pro-inflammatory effects (such as complement activation and neutrophil stimulation) of different immune complexes (ICs) in a human whole blood model, and to confirm the inhibitory function of the C5aR antagonist used in this invention in these rapid immune responses.

[0316] The ICs involved in this study were formed by co-incubating primary anti-rabbit IgG (anti-human PMN IgG or unrelated rabbit IgG) with goat secondary anti-rabbit IgG prior to whole blood stimulation to form polymorphonuclear neutrophil (PMN)-specific ICs and non-PMN-specific ICs, respectively. Neutrophil activation upon mixing the corresponding ICs with whole blood was manifested as an increase in C5a levels in the blood and an upregulation of CD11b expression on the neutrophil surface. As a C5aR antagonist, INF052 had no effect on the immediate innate immune response against C5a release. Therefore, its anti-inflammatory effect in this whole blood model could only be confirmed by inhibiting CD11b upregulation. C5a levels were determined by C5a ELISA, and CD11b was measured by flow cytometry via a FITC-conjugated anti-CD11b antibody.

[0317] method

[0318] a. Preparation of immune complexes and their application in human whole blood with or without C5a / C5aR axis blockers.

[0319] The primary antibody (rabbit IgG specific to PMN and non-PMN specific rabbit IgG) was diluted to a pre-final concentration of 500 μg / mL. Secondary anti-rabbit IgG was diluted to two different pre-final concentrations of 1 mg / mL and 0.5 mg / mL to form ICs with two primary-to-secondary antibody ratios (1:2 and 1:1). The primary and secondary antibodies, along with buffer HBSS, were mixed at a 1:1:1 volume ratio. Several control samples were also prepared, such as an antibody-free blank control and corresponding monoclonal antibody controls. Each missing component in the mixture was replaced with an equal volume of HBSS. The mixture was incubated at room temperature (RT) for 30 minutes to allow sufficient contact between each component and IC formation as needed. Subsequently, 75 μL of the mixture was co-incubated with 175 μL of freshly drawn human whole blood (ACD as anticoagulant) at 37ºC for 30 minutes in the presence of 28 μL of HBSS, 0.5% DMSO, or INF052 to upregulate CD11b and release C5a. The final concentration of the primary antibody in the whole blood mixture was 45 μg / mL, and the secondary antibody was 45 μg / mL (primary antibody to secondary antibody ratio 1:1) or 90 μg / mL (ratio 1:2).

[0320] b. Detection of IC-induced upregulation of CD11b on the surface of neutrophils

[0321] 100 μL of the above whole blood sample was placed on ice for 5 minutes. During the 30-minute incubation on ice in the dark, CD11b on the cell surface was captured with 2 μL of FITC-conjugated anti-CD11b antibody. Red blood cells were lysed at RT for 10 minutes with 1 mL of 1× FACS lysis buffer. Cells were then washed twice with 2 mL of staining buffer by rotating at 2500 rpm for 3 minutes at RT. Cells were resuspended in 500 μL of staining buffer. All samples were analyzed within 1 hour. Granulocytes were gated in a scatter plot, and the mean fluorescence intensity (MFI) of antibody-bound cells was measured.

[0322] result

[0323] like Figure 6 As shown, both PMN-specific and non-PMN-specific IgG immune complexes significantly upregulated CD11b expression levels. PMN-specific IgG-IC induced significantly higher CD11b levels than non-PMN-specific IgG-IC (a 3.4- to 5.3-fold increase in baseline CD11b signaling compared to a 2.5- to 4.8-fold increase). The antigen-to-antibody ratio determines the size and shape of the immune complex. This, in turn, plays a role in the effectiveness of IC. A primary antibody to secondary antibody ratio of 1:2 showed significantly stronger activation than a ratio of 1:1 (1.9-fold and 1.5-fold higher for non-PMN-specific IC and PMN-specific IC, respectively). See also Figure 6 ).exist Figure 6 In the study, upregulation of CD11b at different levels was effectively blocked by 0.25 µM (gray bar, second from the right) and 1 μM (black bar) INF052.

[0324] Example 7 - Blocking CD11b upregulation on neutrophils induced by plasma from patients with hidradenitis suppurativa

[0325] This embodiment describes the activation (CD11b upregulation) of neutrophils in human whole blood induced by plasma samples collected from four patients with hidradenitis suppurativa (HS) in two clinical studies, and the successful blocking of this activation by the C5aR antagonist INF052. It demonstrates that C5aR-targeting drugs (such as INF052) used according to the present invention are suitable for blocking uncontrolled neutrophil activation in neutrophilic dermatitis (ND).

[0326] The aim of the following study was to confirm that: i) plasma collected from patients with hidradenitis suppurativa (HS) can activate neutrophils in human whole blood, manifested as upregulation of CD11b on neutrophils; ii) the C5aR antagonist INF052 is highly effective in blocking inappropriate or uncontrolled neutrophil activation.

[0327] Neutrophil accumulation at sites of inflammation depends on the expression of adhesion molecules, including CD11b. Upregulation of CD11b and the mobilization of CD11b from the intracellular pool to the neutrophil surface are essential for the rolling behavior and migration of human neutrophils. Therefore, enhanced CD11b expression reflects inflammatory triggering events. Activated complement products (especially C5a, which is elevated in the blood of patients with hepatitis B) can significantly upregulate CD11b expression via the binding of C5a to its receptor C5aR on neutrophils. Consequently, blocking the C5a-C5aR axis is expected to eliminate or attenuate CD11b upregulation on the neutrophil surface.

[0328] Human CD11b assays were performed using flow cytometry to detect FITC-conjugated anti-CD11b antibodies on the surface of neutrophils. The blocking activity of the C5aR antagonist was determined by the decrease in fluorescence intensity emitted by FITC-conjugated anti-CD11b antibodies bound to neutrophils compared to the activation condition.

[0329] experiment

[0330] sample

[0331] According to the consensus definition, this study used plasma samples from one HS patient at the Pathology Clinic of Attiko University General Hospital and three plasma samples from the Phase IIb trial SHINE (ClinicalTrials.gov ID: NCT03487276). The pathogenesis of HS involves activation of the complement system, manifested as elevated levels of C3a, C5a, and C5b-9. The C5a levels of the four HS patients are listed below; they were significantly higher than those in healthy individuals.

[0332]

[0333] Single-donor citrate (citrate-citrate-glucose) plasma from healthy individuals was purchased from Biomex GmbH and used as a control for unactivated / non-inflammatory conditions.

[0334] The C5aR antagonist INF052 was dissolved in DMSO as a 10 mM stock solution and stored at -70ºC.

[0335] program

[0336] a) Preparation of human whole blood with added INF052

[0337] Fresh human whole blood was drawn from healthy donors in the presence of 12% citrate-glucose solution (ACD). INF052 stock solution (10 mM, in 100% DMSO) was stepwise diluted in DMSO, then stepwise diluted in HBSS to obtain a target working solution 10-fold concentrated in HBSS / 2.5% DMSO. These working solutions were then diluted 10-fold in whole blood to obtain the final INF052-infused human whole blood. As a control, 100% DMSO was diluted in the same manner and infused into whole blood. The infused blood samples were incubated at 37ºC for 30 minutes to allow sufficient time for INF052 to bind to C5aR.

[0338] b) Human CD11b potency assay (flow cytometry)

[0339] In vitro upregulation of neutrophil CD11b by INF052 was performed in human whole blood infused with either INF052 (0.25% DMSO) or 0.25% DMSO. Neutrophil activation was confirmed using recombinant human C5a (rhC5a) at a final concentration of 15 nM as a positive control. Each sample was measured in duplicate.

[0340] 12 µL of healthy human plasma (huP), HS patient plasma, or 150 nM rhC5a was added to 80 µL of whole blood mixed with INF052 / DMSO. The final volume of each test sample was then filled to a maximum of 120 µL using HBSS. The following is a simplified example of a sample tested in one assay. In real-world scenarios, samples from several patients and several different concentrations of INF052 could be added to a single assay.

[0341]

[0342] All samples were then incubated at 37ºC for 20 min to allow time for CD11b expression, followed by exposure on ice for 5 min to stop further protein expression. To detect CD11b expression on neutrophils, 2 µL of FITC-conjugated anti-CD11b antibody was added to each sample and incubated on ice in the dark for 30 min. Red blood cells (RBCs) were lysed using 1 mL of 1×FACS lysis buffer for 10 min at room temperature. After RBC lysis, the remaining blood cells were washed twice with 2 mL of staining buffer (SB), centrifuged at 1300 g for 3 min at RT, and resuspended in 500 µL of SB. The resuspended cells were analyzed by flow cytometry within 1 h. Granulocytes were gated on FSC and SSC dot plots, and the mean fluorescence intensity (MFI) of FITC-labeled granulocytes (via anti-CD11b antibody) was recorded. The blocking percentage of the C5aR antagonist was calculated as follows:

[0343]

[0344] result

[0345] HS patients have upregulated CD11b expression on neutrophils in their plasma

[0346] CD11b expression on neutrophils was evaluated using plasma samples from healthy blood donors and several confirmed HS patients (pat 088, 160-0004, 160-0006, and 160-0010). The mean fluorescence intensity (MFI) of healthy controls was 5412 ± 301.2 (mean ± SD) in the first assay and 4523.5 ± 41.7 in the second assay using study samples from SHINE. These are unstimulated baseline expression levels of CD11b. A 2.3–2.6-fold increase in CD11b expression was achieved in the presence of plasma from isolated HS patients, which was fully comparable to CD11b expression in the positive control 15 nM rhC5a (2.2–2.4-fold) (Tables 10 and 11). Figure 7 and Figure 8 These data show a significant upregulation of CD11b expression on neutrophils mediated by inflammatory factors in the plasma of HS patients.

[0347] INF052 successfully blocked HS and C5a-induced CD11b upregulation.

[0348] As described above, both HS patient plasma and 15 nM rhC5a significantly upregulated CD11b expression on blood neutrophils. This activation could be effectively blocked in a dose-dependent manner by incubating whole blood with the C5aR antagonist INF052 prior to exposure to the stimuli (i.e., HS patient plasma or C5a). In the first experiment using plasma samples from HS patients (pat 088), all three concentrations (i.e., 50 nM, 250 nM, and 1 µM) of INF052 showed >120% blocking effect. >100% blocking indicates that INF052 not only inhibited the stimulatory effects induced by HS plasma or C5a but also prevented nonspecific activation of neutrophils during prolonged incubation (Table 10 and...). Figure 7 Similar results were obtained in the second experiment using samples from three other HS patients from the SHINE study, where 100 nM and 250 nM INF052 alone reduced “baseline” CD11b signal to 20.5% and 51.6%, respectively. Regarding patient plasma-driven CD11b elevation, 100 nM and 250 nM INF052 achieved blockade of 64.4%–94.8% and 92.6%–118.8%, respectively (Table 11 and...). Figure 8 ).

[0349] All these results confirm that the C5a / C5aR axis plays a major role in CD11b expression on neutrophils. Therefore, drugs targeting C5aR, such as INF052, as used according to the present invention, are suitable for blocking uncontrolled neutrophil activation in neutrophilic dermatitis (ND).

[0350]

[0351]

[0352] References

[0353] 1.Merle, NS, et al., Complement System Part I - MolecularMechanisms of Activation and Regulation. Front Immunol, 2015. 6: p. 262.

[0354] 2.Schatz-Jakobsen, JA, et al., Structural and functional characterization of human and murine C5a anaphylatoxins. Acta Crystallogr DBiol Crystallogr, 2014. 70(Pt 6): p. 1704-17.

[0355] 3.Klos, A., et al., International Union of Basic and ClinicalPharmacology. LXXXVII. Complement peptide C5a, C4a, and C3a receptors.Pharmacol Rev, 2013. 65(1): p. 500-43.

[0356] 4.Ricklin, D., et al., The renaissance of complement therapeutics. Nat Rev Nephrol, 2018. 14(1): p. 26-47.

[0357] 5.Tesar, V. and Z. Hruskova, Avacopan in the treatment of ANCA-associated vasculitis. Expert Opin Investig Drugs, 2018. 27(5): p. 491-496.

[0358] 6.Li, G., et al., Neuroprotective effects of argatroban and C5areceptor antagonist (PMX53) following intracerebral haemorrhage. Clin ExpImmunol, 2014. 175(2): p. 285-95.

[0359] 7.Nunez-Cruz, S., et al., Genetic and pharmacologic inhibition ofcomplement impairs endothelial cell function and ablates ovarian cancerneovascularization. Neoplasia, 2012. 14(11): p. 994-1004.

[0360] 8.Riedemann, N.C., et al., Controlling the anaphylatoxin C5a indiseases requires a specifically targeted inhibition. Clin Immunol, 2017.180: p. 25-32.

[0361] 9.de Haan, J.J. et al (2017). Complement 5a Receptor deficiency doesnot influence adverse cardiac remodeling after pressure-overload in mice.Scientific Reports, 7: 17045 | DOI:10.1038 / s41598-017-16957-3.

[0362] 10.Ehrnthaller, C et al (2016). C5aR inhibition in the early. Eur JMed Res, 21, 42.

[0363] 11.Vergunst, CE. et al (2007). C5a receptor blocker fails to showclinical benefit in patients with RA. Rheumatology, 46, 1773–1778.

[0364] 12.Marzano AV, Ceccherini I, Gattorno M, Fanoni D, Caroli F, RusminiM, Grossi A, De Simone C, Borghi OM, Meroni PL and others. 2014. Associationof pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) sharesgenetic and cytokine profiles with other autoinflammatory diseases. Medicine(Baltimore) 93(27):e187.

[0365] 13.Cugno M, Borghi A, Marzano AV. 2017. PAPA, PASH and PAPASHSyndromes: Pathophysiology, Presentation and Treatment. Am J Clin Dermatol.2017 Aug;18(4):555-562. doi: 10.1007 / s40257-017-0265-1.

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Claims

1. A compound having the general formula (XXI) (XXI) and its pharmaceutically acceptable salts, hydrates and rotational isomers; in C 1 Selected from aryl and heteroaryl groups, wherein the heteroaryl group has 1-3 heteroatoms selected from N, O, and S as ring members; and wherein the aryl and heteroaryl groups are optionally fused with 1 to 3 R atoms. 1 Substituent substitution; C 2 Selected from aryl and heteroaryl groups, wherein the heteroaryl group has 1-3 heteroatoms selected from N, O, and S as ring members; and wherein the aryl and heteroaryl groups are optionally fused with 1 to 3 R atoms. 2 Substituent substitution; C 3 Selected from C 1-8 Alkyl or heteroalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, heterocyclic alkyl or heterocyclic alkyl-C 1-4 Alkyl groups, wherein the heteroalkyl group has 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclic alkyl group or portion has 1-3 heteroatoms selected from N, O, and S, and wherein the heteroaryl group has 1-3 heteroatoms selected from N, O, and S as ring members, and each C 3 Choose any location via 1 to 3 R 3 Substituent substitution; Each R 1 Independently selected from halogens, -CN, -R c —CO2R a —CONR a R b —C(O)R a —OC(O)NR a R b —NR b C(O)R a —NR b C(O)2R c —NR a —C(O)NR a R b —NR a C(O)NR a R b —NR a R b —OR a and —S(O)2NR a R b ; where each R a and R b Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 A haloalkyl group, or one that, when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring members, and optionally substituted with one or two oxo groups; each R c Selected independently from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R a R b and R c The aliphatic and / or cyclic moiety is optionally further substituted with one to three halogens, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups; and optionally with two R groups. 1 When substituents are located on adjacent atoms, they combine to form fused five- or six-membered carbon rings or heterocycles. Each R 2 Independently selected from halogens, -CN, -NO2, -R f —CO2R d —CONR d R e —C(O)R d —OC(O)NR d R e —NR e C(O)R d —NR e C(O)2R f —NR d C(O)NR d R e —NR d R e —OR d and —S(O)2NR d R e ; where each R d and R e Independently selected from hydrogen and C 1-8 Alkyl and C 1-8 A haloalkyl group, or one that, when attached to the same nitrogen atom, can combine with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring members, and optionally substituted with one or two oxo groups; each R f Selected independently from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R d R e and R f The aliphatic and / or cyclic moiety is optionally further substituted with one to three halogens, hydroxyl, methyl, amino, alkylamino, and dialkylamino groups, and optionally with two R groups. 2 When groups are located on adjacent atoms, they combine to form five- or six-membered rings; Each R 3 Independently selected from halogen, -CN, -R i —CO2R g —CONR g R h —C(O)R g —C(O)R i —OC(O)NR g R h —NR h C(O)R g —NR h CO2R i —NR g C(O)NR g R h —NR g R h —OR g —OR j —S(O)2NR g R h —X 4 —R j —NH—X 4 —R j —O—X 4 —R j —X 4 —NR g R h —X 4 —NHR j —X 4 —CONR g R h —X 4 —NR h C(O)R g —X 4 —CO2R g —O—X 4 —CO2R g —NH—X 4 —CO2R g —X 4 —NR h CO2R i —O—X 4 —NR h CO2R i —NHR j and —NHCH2R j , where X 4 It is C 1-4 Alkylene; each R g and R h Independently selected from hydrogen and C 1-8 Alkyl or heteroalkyl, C 3-6 cycloalkyl and C 1-8 The alkyl halogroup, or, when attached to the same nitrogen atom, can combine with the nitrogen atom to form a four-, five-, or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring members, and optionally substituted with one or two oxo groups; each R i Selected independently from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and each R j Selected from C 3-6 Cycloalkyl, imidazolyl, pyrimidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and S,S-dioxo-tetrahydrothiopyranyl, wherein R g R h R i and R j The aliphatic and / or cyclic moieties may optionally be further oxidized by one to three halogens, methyl groups, CF3 groups, hydroxyl groups, C4 groups, C6 groups, C7 groups, C8 groups, C9 ... 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, —C(O)O—C 1-8 Alkyl, amino, alkylamino, and dialkylamino substitutions, and optionally in both R groups. 3 When groups are located on adjacent atoms, they combine to form five- or six-membered rings; X is hydrogen or CH3; and R 8 and R 9 Independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 alkoxy, or R 8 and R 9 These can combine to form fused saturated or unsaturated monocyclic or polycyclic carbon rings, wherein one or more of the ring carbon atoms can be independently replaced by N, S, or O. The compound is used to treat or prevent diseases or disorders selected from the following: • Monosodium urate (MSU)-induced diseases, • Neutrophil-driven inflammatory kidney disease, •Skin neutrophilic inflammatory diseases, and • Immune complex diseases.

2. The compound for the said use according to claim 1, wherein R 8 and R 9 At least one of them is not hydrogen and / or where X is hydrogen.

3. The compound for the said use according to claim 1 or claim 2, wherein the compound has the formula (XXIa). (XXIa)。 4. The compound for the said use according to any one of claims 1 to 3, wherein the compound has formula (I) or formula (XI): (I) or (XI), Preferably, it has formula (Ia) or formula (XIa): (Ia) or (XIa), in R 4 Selected from cyano, halogen, nitro, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl-OH, (C1-C6)-alkyl-NR 5 R 6 Trifluoromethyl, (C1-C6)alkoxy, (C1-C6)thioalkoxy, phenoxy, COR 7 NR 5 R 6 NHCO (C1-C6) alkyl, SO3H, SO2 (C1-C6) alkyl and SO2NR 5 R 6 ; R 5 and R 6 Each is independently selected from hydrogen, (C1-C6)alkyl, and (C3-C6)cycloalkyl; R 7 Independently hydroxyl, (C1-C6)alkoxy, phenoxy, or -NR 5 R 6 ; m is 0-4; and A ring is a saturated or unsaturated monocyclic or polycyclic carbon ring in which one or more of the carbon atoms in the ring can be replaced independently by N, S or O.

5. The compound for the purpose according to any one of claims 1 to 4, wherein the compound has a formula selected from the following: (II), (IIIa), (IIIb), (IIIc), and (IIId): (II)、 (IIIa)、 (IIIb)、 (IIIc) and (IIId), Preferably, it has a formula selected from the following: (IIa), (IIIe), (IIIf), (IIIg), and (IIIh): (IIa)、 (IIIe)、 (IIIf)、 (IIIg) and (IIIh).

6. The compound for the said use according to any one of claims 1 to 5, wherein C 1 yes ， in n is an integer selected from 0, 1, 2 or 3.

7. The compound for the said use according to any one of claims 1 to 6, wherein C 2 yes ， in o is an integer selected from 0, 1, 2 or 3.

8. The compound for the said use according to any one of claims 1 to 7, wherein C 3 yes ， in p is an integer selected from 0, 1, 2 or 3.

9. The compound for the purpose according to any one of claims 1 to 4, 6, 7 or 8, wherein R8 is selected from halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups and C1-C4 alkoxy groups; preferably selected from fluorine, chlorine, methyl, trifluoromethyl and methoxy groups.

10. The compound for the said use according to any one of claims 1 to 8, wherein the compound is selected from... 、 、 、 、 11. The compound for the purpose according to any one of claims 1 to 4, 6, 7, 8 or 9, wherein the compound is selected from...

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 11, the pharmaceutical composition being used to treat or prevent diseases or disorders selected from: • Monosodium urate (MSU)-induced diseases, • Neutrophil-driven inflammatory kidney disease, •Skin neutrophilic inflammatory diseases, and • Immune complex diseases.

13. The compound for the use according to any one of claims 1 to 11 or the pharmaceutical composition for the use according to claim 12, wherein the disease or disorder is selected from monosodium urate (MSU)-induced diseases, including peritonitis and gout.

14. The compound for the use according to any one of claims 1 to 11 or the pharmaceutical composition for the use according to claim 12, wherein the disease or disorder is selected from neutrophil-driven inflammatory nephropathy, including ischemic nephropathy, ischemia-reperfusion kidney injury, and obstructive nephropathy, or wherein the disease or disorder is selected from cutaneous neutrophilic inflammatory diseases, including hidradenitis suppurativa (HS), pyoderma gangrenosa (PG), PASH (PG, acne, and hidradenitis suppurativa), PAPASH (suppurative arthritis, acne, PG, and hidradenitis suppurativa), chronic spontaneous urticaria, and bullous pemphigoid.

15. The compound for the use according to any one of claims 1 to 11 or the pharmaceutical composition for the use according to claim 12, wherein the disease or disorder is selected from immune complex diseases, including rheumatoid arthritis, systemic lupus erythematosus (SLE), immune complex-mediated glomerulonephritis, IgA nephritis, lupus nephritis, ANCA (anti-neutrophilic cytoplasmic antibody) vasculitis, anti-C3 glomerulonephropathy, atypical hemolytic uremic syndrome (aHUS), Goodpassuia syndrome, crescentic glomerulonephritis, focal segmental glomerulosclerosis (FSGS), rheumatic fever, dermatomyositis, chronic inflammatory demyelinating polyneuropathy, chemotherapy-induced peripheral neuropathy, and transplant rejection.

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