Condensed piperidinyl bicyclic compounds and related compounds for use in the treatment of diseases

Abstract

The present invention relates to condensed piperidinyl bicyclic, metasubstituted piperidinyl, and related compounds thereof that modulate the activity of the mammalian C5a receptor by directly binding to it, for use in treating diseases, particularly monosodium urate (MSU) induced diseases, neutrophil-induced inflammatory kidney diseases, cutaneous neutrophil inflammatory diseases, and immune complex diseases.

Description

[Technical Field]

[0001] The present invention relates to condensed piperidinyl bicyclic compounds, metasubstituted piperidinyl compounds, and related compounds thereof that modulate the activity of the mammalian C5a receptor by directly binding to it, for use in treating diseases, particularly monosodium urate (MSU) induced diseases, neutrophil-induced inflammatory kidney diseases, cutaneous neutrophil inflammatory diseases, and immune complex diseases. [Background technology]

[0002] C5a produced by the activation of the complement system The complement system is a vital branch of innate immunity and plays a crucial role in host defense against invading microorganisms. These functions are carried out by functionally related proteins that sequentially detect, label, and eliminate pathogens and cells affected by them. Complement proteins are primarily found in the plasma of the circulating blood to perform their immune surveillance functions. These proteins are inactive under steady state and are activated through an enzyme cascade in response to artificial triggers such as infection, pathogenicity mechanisms, and organ transplantation.

[0003] Complement proteins are activated by three standard pathways, each with a different initial activation mechanism. These three pathways are the classical pathway, the secondary pathway, and the lectin-binding pathway. The classical pathway is activated by antibody complexes. The secondary pathway is initiated by xenobiotic surfaces, such as specific molecules present on microbial membranes, modified 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 ficolin to microbial carbohydrate structures. Once initiated, the progression and amplification of all three pathways utilize the same underlying mechanism, involving a cascade of enzymatic cleavage of complement proteins. All three pathways converge on the formation of C3 convertases, resulting in the proteolysis of C3 into the bioactive fragments C3a and C3b, which then lead to the cleavage of C5 [1].

[0004] C5 is a 190 kDa protein containing an alpha chain (approximately 120 kDa) and a beta chain (approximately 75 kDa). Enzymatic cleavage of the N-terminus of the alpha chain yields C5a. Human C5a is a globular protein with 74 amino acids, containing a core structure and a flexible C-terminus. The glycan attached to the asparagine residue at position 64 exhibits a wide variety of structures, resulting in a molecular weight range of 10 kDa to 15 kDa for human C5a.

[0005] In addition to C5a, proteolysis of C5 also produces C5b, which then forms C5b-9 (MAC, membrane attack complex) with other complement components. C3a, C5a, and MAC are terminal effectors 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 far more potent than C3a.

[0006] C5a function C5a is a key driver of rapid innate immune responses to infection and injury. C5a induces the release of histamine and TNF-alpha. C5a activates granulocytes, particularly stimulating the spectrum of neutrophil activity. At lower concentrations, C5a is a potent chemoattractant for neutrophils. At higher concentrations, C5a induces the release of granulocyte enzymes and the production of oxidants by triggering oxidative bursts. C5a stimulates the production and release of pro-inflammatory cytokines, which then lead to vasodilation, increased vascular permeability, and further increased extravasation of neutrophils. Neutrophils are a double-edged sword; on the one hand, they defend against infection, but on the other hand, in the presence of excessive C5a activity, they directly cause acute or chronic tissue damage.

[0007] 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, C5a-mediated Th-17 cell priming and differentiation, as well as IL-17 production, have been proposed as underlying mechanisms in several autoimmune diseases [2].

[0008] The function of C5a is primarily mediated by C5a receptor 1. C5a exerts its function through its congener receptors, C5a receptor 1 (C5aR1) and the later 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 of many organs, including the kidneys, liver, and lungs. C5aR1 is a G protein-coupled receptor and is linked to several G protein-coupled downstream signaling pathways, including cAMP and calcium-mediated pathways. Loss-of-function approaches, including C5aR1-deficient animal models and pharmacological inhibition, have shown that C5aR1 mediates multifaceted C5a function in various pathophysiological situations, justifying the use of C5aR1 inhibitors, such as antibodies and antagonists, in drug development and clinical practice aimed at treating C5a-related diseases [3].

[0009] C5aR2 is localized both intracellularly and on the cell membrane. Because C5aR2 is not associated with G proteins, it has historically been considered a non-functional decoy receptor and has therefore received far less attention compared to C5aR1. However, accumulated experimental observations suggest that C5aR2 may possess both pro-inflammatory and anti-inflammatory effects depending on the biological context.

[0010] The C5a-C5aR1 axis is a promising therapeutic target for various diseases. C5a has been associated with a wide variety of diseases, including, but is not limited to, renal disorders, cardiovascular disorders, respiratory diseases, skin disorders, arthritis, neurodegenerative diseases (Alzheimer's disease, dementia), ischemia-reperfusion injury, multiple sclerosis, transplant rejection, age-related macular degeneration, neutrophilic dermatosis, and cancer. In line with this view, preclinical and clinical data highlight the potential benefits of inhibiting the C5a-C5aR1 interaction in several diseases [4-7].

[0011] Targeting C5a or the C5a receptor is the opposite of targeting C5 or C3. In principle, there are several ways to block pathogenic C5a function. This can be achieved by direct neutralization of C5a, such as using anti-C5a antibodies, or by C5aR1 inhibitors. It can also be achieved by blocking C5a production by inhibiting C5 cleavage, which can be achieved by targeting C5 itself or its upstream activators, such as C3. However, blocking C5a function by targeting its upstream complement molecules is inherently complicated by the existence of exogenous pathways. Exogenous pathways refer to pathways other than the three standard pathways that lead to C5 cleavage and subsequent C5a production. Exogenous pathways utilize a wide range of proteases outside the complement domain. These proteases include those released by microorganisms, those associated with the coagulation cascade, or those activated during inflammatory responses and tissue damage [8].

[0012] Therefore, modalities targeting C3 or C5 do not block C5 cleavage via exogenous pathways and thus do not completely block C5a production, which may lead to a compromise in therapeutic efficacy.

[0013] Furthermore, targeting C5a or the C5a receptor has other potential clinical benefits compared to targeting C5 and C3. For example, inhibiting C5 or C3 blocks not only C5a but also C5b and subsequent MAC formation. On the other hand, targeting C5a or the C5a receptor can be advantageous because it leaves MAC formation intact, and MAC plays a crucial role in maintaining homeostasis through its bactericidal and tumor-killing effects. Clinical interventions targeting C5a or the C5a receptor may carry a lower risk of infectious complications than interventions targeting C5 or C3.

[0014] Condensed piperidinyl bicyclic, metasubstituted piperidinyl, and related compounds that highly modulate the activity of mammalian C5a receptors by directly binding to them are disclosed in WO2020 / 182384A1.

[0015] Technical problems that form the basis of the present invention As mentioned above, the C5a-C5aR1 axis is considered a promising therapeutic target for treating various diseases, but it remains unclear which specific diseases or disorders can actually be treated using compounds that modulate the activity of the mammalian C5a receptor, and in particular which diseases or disorders can be treated with C5aR1 inhibitors.

[0016] For example, the literature has reported that blocking the C5a receptor 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 by the C5a receptor antagonist PMX53 in the early inflammatory stage did not affect bone regeneration in a model of successful fracture healing (Ehrnthaller, 2016). As another example, it has been reported that complement 5a receptor deficiency did not affect adverse cardiac remodeling after pressure loading in mice (de Haan, 2017). Several more data have been published in the field that demonstrate that blocking the C5a receptor does not necessarily lead to therapeutic success.

[0017] We have now discovered, to our surprise, that certain diseases or disorders can be advantageously treated by specific compounds that directly target the C5a receptor, while avoiding the drawbacks associated with targeting C5 or C3 receptors. In particular, the diseases or disorders that can be treated include monosodium urate (MSU) induced diseases, neutrophil-induced inflammatory kidney diseases, cutaneous neutrophil inflammatory diseases, and immune complex diseases. [Overview of the project]

[0018] In one embodiment, the present invention relates to general formula (XXI): [ka] Compounds having, as well as their pharmaceutically acceptable salts, hydrates, and rotational isomers. [In the formula, C 1 The group is selected from the group consisting of aryl and heteroaryl groups, where the heteroaryl group has 1 to 3 heteroatoms selected from N, O, and S as ring atoms; where the aryl and heteroaryl groups have 1 to 3 R 1 Substitutions may be made as appropriate; C 2is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has 1 to 3 heteroatoms selected from N, O, and S as ring atoms; wherein the aryl and heteroaryl groups may be optionally substituted with 1 to 3 R 2 substituents; C 3 is 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, heterocycloalkyl or heterocycloalkyl-C 1-4 alkyl, wherein the heteroalkyl group has 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocycloalkyl group or moiety has 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group has 1 to 3 heteroatoms selected from N, O, and S as ring atoms, and C3 may each be optionally substituted with 1 to 3 R 3 substituents; R 1 are each independently halogen, -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 [[ID=5&]]-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 bSelected from the group consisting of; where R a and R b Each of them is independently of hydrogen and C 1-8 Alkyl, and C 1-8 If selected from a haloalkyl group or bonded to the same nitrogen atom, it may combine with the nitrogen atom to form a five-membered or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring atoms, which may be appropriately substituted with 1 or 2 oxos; R c Each is independent of C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, where R a , R b and R c The aliphatic and / or cyclic portions are optionally further substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, and dialkylamino groups; optionally, if two R1 substituents are present on adjacent atoms, they combine to form a condensed, 5 or 6-membered carbon ring or heteroring; R 2 These are, independently, halogen, -CN, -NO2, and -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 Selected from the group consisting of; where R d and R e Each of them is independently of hydrogen and C 1-8Alkyl, and C 1-8 selected from haloalkyl, or, when attached to the same nitrogen atom, in combination with said nitrogen atom, having 0 to 2 additional heteroatoms selected from N, O or S as ring atoms, and may be optionally substituted with one or two oxo to form a 5-membered or 6-membered ring; R f are each independently, C 1-8 alkyl or heteroalkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where R d , R e and R f aliphatic and / or cyclic moieties of may optionally be further substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups, and, when two R2 groups are present on adjacent atoms, they may combine to form a 5-membered or 6-membered ring; R 3 are each independently 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 R h , -NRgRh, -ORg, -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 , -X4 -CONR g R h -X 4 -NR h C(O)R g -X 4 -CO2R g , -OX 4 -CO2R g , -NH-X 4 -CO2R g -X 4 -NR h CO2R i , -OX 4 -NR h CO2R i , -NHR j and -NHCH2R j A group consisting of X is selected, where X 4 C 1-4 It is alkylene; R g and R h Each of them is independently of hydrogen and C 1-8 Alkyl or heteroalkyl, C 3-6 Cycloalkyl and C 1-8 If selected from a haloalkyl group or bonded to the same nitrogen atom, it may combine with the nitrogen atom to form a four-membered, five-membered, or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring atoms, which may be appropriately substituted with 1 or 2 oxos; R i Each is independent of C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R j These are C 3-6 Selected from the group consisting of cycloalkyl, imidazolyl, pyrimidinyl, pyrrolinil, pyrrolyl, piperidinyl, morpholinil, tetrahydrofuranil, tetrahydropyranil, and S,S-dioxo-tetrahydrothiopyranil, where R g , R h , R i and R jThe aliphatic and / or cyclic moieties may optionally be further 1-3 halogens, methyl, CF3, hydroxy, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -C(O)OC 1-8 It may be substituted with alkyl, amino, alkylamino, and dialkylamino groups, and optionally two R groups. 3 When groups are present on adjacent atoms, they combine to form a five-membered or six-membered ring; X is either hydrogen or CH3; R 8 and R 9 These are independently selected from the group consisting of hydrogen, halogens, C1-C8 alkyls, C1-C8 haloalkyls, and C1-C8 alkoxys, or R 8 and R 9 These combine to form condensed, saturated or unsaturated monocyclic or polycyclic carbocyclic rings, in which one or more ring carbon atoms may be independently replaced by N, S, or O. and Monosodium urate (MSU) induced diseases, Neutrophil-induced inflammatory kidney diseases, including ischemic nephropathy, ischemic-reperfusion kidney injury, and obstructive nephropathy. Cutaneous neutrophilic inflammatory diseases, and immune complex disease This invention relates to compounds for use in the treatment or prevention of diseases or disorders selected from the group consisting of the following, as well as pharmaceutically acceptable salts, hydrates, and rotational isomers thereof.

[0019] Other embodiments will become apparent from the consideration of the detailed description that follows. [Brief explanation of the drawing]

[0020] [Figure 1]In vivo hamster neutropenia models. The inhibition rates (%) of C5a-induced neutropenia (C5a 100 μg / kg) in hamsters are shown 8 hours after administration of INF054 and INF052 (both 10 mg / kg orally). ** indicates p<0.01. [Figure 2] An in vivo model of MSU-induced peritonitis. Quantification of A monocytes (mono), B neutrophils (neut), C leukocytes (WBC), and D lymphocytes (lymph) collected from peritoneal lavage fluid. Group G1 was untreated, Group G2 received monosodium urate (MSU) crystals intraperitoneally and was administered only as a vehicle, and Group G3 received MSU and INF052 (20 mg / kg). ** indicates p<0.01. [Figure 3] Suppression of ischemic-reperfusion kidney injury. This refers to the histopathological state of the kidney after ischemic-reperfusion injury (IRI). Group G1 received INF052 (100 mg / kg) after IRI, Group G2 received only vehicle after IRI, and Group G3 was untreated. * indicates p<0.05. [Figure 4] Unilateral ureteral obstruction (UUO)-induced nephropathy. Blood urea nitrogen (BUN) levels are recorded on days 1, 3, 7, and 14 after UUO surgery. Group G1 was untreated, Group G2 underwent UUO treatment and received vehicle only, and Group G3 underwent UUO treatment and received INF052 (20 mg / kg). [Figure 5] Unilateral ureteral obstruction (UUO)-induced nephropathy. Histopathological condition of the kidney, H&E staining. Group G1 was untreated, Group G2 underwent UUO treatment and received vehicle only, and Group G3 underwent UUO treatment and received INF052 (20 mg / kg). * indicates p<0.05. [Figure 6]Inhibition of immune complex-induced neutrophil activation in human whole blood. Flow cytometry detected neutrophil CD11b expression levels (mean fluorescence intensity (MFI) released by FITC-conjugated anti-CD11b antibody on the surface of neutrophils) under inactivation (HBSS and single primary antibody) and activation (non-PMN-specific or PMN-specific immune complex) conditions. Different upregulated levels of CD11b were efficiently blocked by 0.25 μM (gray bars) and 1 μM (black bars) of INF052. [Figure 7] Blockade of neutrophil-mediated CD11b upregulation induced by plasma from patients with hidradenitis suppurativa. This involved neutrophil activation and subsequent blockade via different concentrations of the C5aR antagonist INF052 to upregulate CD11b expression in whole blood using plasma from an HS patient (pat088). Addition of normal, healthy human plasma supplemented with 15 nM C5a to whole blood was used as controls for activation and blockade, respectively, in the absence and presence of INF052. [Figure 8] Blockade of neutrophil-mediated CD11b upregulation induced by plasma from patients with hidradenitis suppurativa. This involved neutrophil activation and blockade via different concentrations of the C5aR antagonist INF052 to upregulate CD11b expression in whole blood using plasma from three HS patients. Addition of normal, healthy human plasma supplemented with 15 nM C5a to whole blood was used as controls for activation and blockade, respectively, in the absence and presence of INF052. [Modes for carrying out the invention]

[0021] Detailed description of the invention definition Before describing the present invention in detail below, it should be understood that the present invention is not limited to the specific theoretical frameworks, protocols, and reagents described herein, as these may be modified. It should also be understood that the terms used herein are intended solely to describe specific embodiments and are not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention pertains.

[0022] Preferably, the terms used herein are defined as those set forth in "A multilingual glossary of biotechnological terms: (IUPAC Recommended)," edited by Leuenberger, HGW, Nagel, B., and Kolbl, H. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

[0023] Throughout this specification and the subsequent claims, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” are understood to mean that they encompass the integer or process, or group of integers or processes, described, but do not exclude any other integer or process, or group of integers or processes.

[0024] Throughout this specification, several documents (e.g., patents, patent applications, academic publications, manufacturer specifications, instructions, and GenBank accession number filings) are referenced. Nothing in this specification should be construed as acknowledging that the present invention has no prior rights to such disclosures on the grounds of prior art. Some documents referenced herein are characterized as “incorporated by reference.” In the event of any conflict between a definition or teaching in such incorporated reference and a definition or teaching set forth herein, the description herein shall prevail.

[0025] In the context of this invention, C5a specifically refers to human C5a. The amino acid sequence of human C5 can be found at accession number UniProtKB P01031(CO5_HUMAN).

[0026] In the context of the present invention, the expression “C5a receptor” refers to any potential C5a-binding ligand on the surface of any cell, in particular any receptor protein to which C5a may bind and cause a response on that receptor (e.g., activation or inhibition of that receptor). The term “C5a receptor” encompasses, in particular, two receptors, C5aR and C5L2. Alternate names for C5aR are C5aR1 and CD88. Alternate name for C5L2 is C5aR2. Some embodiments of the present invention relate to compounds that modulate C5a receptor activity (e.g., by binding to a C5a receptor). In these contexts, 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 of the C5a receptors (i.e., either C5aR or C5L2), while other compounds modulate the activity of both C5a receptors (i.e., both C5aR and C5L2).

[0027] When used herein, the first compound (e.g., the compound of the present invention) has a dissociation constant K of 1 mM or less, preferably 100 μM or less, preferably 50 μM or less, preferably 30 μM or less, preferably 20 μM or less, preferably 10 μM or less, preferably 5 μM or less, more preferably 1 μM or less, more preferably 900 nM or less, more preferably 800 nM or less, more preferably 700 nM or less, more preferably 600 nM or less, more preferably 500 nM or less, more preferably 400 nM or less, more preferably 300 nM or less, more preferably 200 nM or less, even more preferably 100 nM or less, even more preferably 90 nM or less, even more preferably 80 nM or less, even more preferably 70 nM or less, even more preferably 60 nM or less, even more preferably 50 nM or less, even more preferably 40 nM or less, even more preferably 30 nM or less, even more preferably 20 nM or less, and even more preferably 10 nM or less. d If such a compound is present, the first compound is considered to be "bound" to the second compound.

[0028] The term "binding" in this invention preferably refers to specific binding. "Specific binding" means that a compound (e.g., a protein ligand or nucleic acid aptamer) binds more strongly to a target (e.g., a target protein or target epitope) to which it is specific, compared to binding to other targets. d When a compound binds to the first target at a dissociation constant (K) of the target to which the compound specifically binds, the compound binds more strongly to the first target compared to the second target. Preferably, the dissociation constant (K) of the target to which the compound specifically binds is d ) is the dissociation constant (K) for targets to which the compound does not specifically bind. d It is more than 10 times lower than, preferably more than 20 times lower, more preferably more than 50 times lower, and even more preferably more than 100 times, 200 times, 500 times, or 1000 times lower than ).

[0029] When used herein, "K dThe term (usually measured in "mol / L" and sometimes abbreviated as "M") is intended to refer to the dissociation equilibrium constant of a particular interaction between a compound (e.g., the compound of this invention) and a target molecule.

[0030] The dissociation constant K is used to determine the binding affinity of a compound. d Methods for determining the dissociation constant K are well 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, biolayer interferometry (BLI), enzyme-linked immunosorbent assay (ELISA), flow cytometry, isothermal titration calorimetry (ITC), ultracentrifugation, radioimmunoassay (RIA or IRMA), and enhanced chemiluminescence (ECL). Generally, the dissociation constant K d This is determined by 20°C, 25°C, 30°C, or 37°C. Unless otherwise specified, K as described herein d The value is determined by SPR at 20°C.

[0031] As used herein, the term “naturally occurring” refers, when applied to an object, to the fact that an object can be found in nature. For example, polypeptides or polynucleotide sequences present in living organisms (including viruses) that can be isolated from natural sources and have not been intentionally modified by humans in a laboratory are naturally occurring.

[0032] As used herein, “patient” means any mammal or bird that may benefit from treatment with the compounds described herein (i.e., inhibitors of C5a receptor activity described herein). Preferably, “patient” is selected from the group consisting of laboratory animals (e.g., mice or rats), livestock (e.g., including guinea pigs, rabbits, chickens, turkeys, pigs, sheep, goats, camels, cattle, horses, donkeys, cattle, or dogs), or primates including monkeys and apes (e.g., African green monkeys, chimpanzees, bonobos, gorillas), and humans. It is particularly preferred that “patient” is human. In this specification, the terms “patient” and “treatment subject” (or “subject” for short) are used interchangeably.

[0033] As used herein, “treat,” “treating,” or “treatment” a disease or disorder means achieving one or more of the following: (a) reducing the severity and / or duration of the disorder; (b) limiting or preventing the onset of symptoms that characterize the disorder being treated; (c) preventing the worsening of symptoms that characterize the disorder being treated; (d) limiting or preventing recurrence of the disorder in a patient who has previously had the disorder; and (e) limiting or preventing recurrence of symptoms in a patient who has previously had symptoms of the disorder.

[0034] As used herein, “prevent,” “preventing,” “prevention,” or “prophylaxis” of a disease or disorder means preventing the occurrence of the disorder in a subject for a period of time. For example, if a compound of the present invention (or a pharmaceutical composition containing the compound) is administered to a subject for the purpose of preventing a disease or disorder, the occurrence of the disease or disorder is prevented at least on the day of administration, and preferably for a period of one day or more after 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).

[0035] As used herein, “administer” includes in vivo administration as well as ex vivo direct administration to tissue (e.g., venous graft).

[0036] The "pharmaceutical composition" of the present invention may exist in the form of a composition in which different active ingredients and diluents and / or carriers are mixed with each other, or in the form of a combination formulation in which the active ingredients exist in partially or completely separate forms. An example of such a combination or combination formulation is a kit of parts.

[0037] The "effective dose" is the amount of therapeutic agent sufficient to achieve the intended purpose. The effective dose of a therapeutic agent varies depending on factors such as the properties of the drug, the route of administration, the size and species of the animal receiving the agent, and the purpose of administration. The effective dose in each individual case may be determined empirically by those skilled in the art according to methods established in the art.

[0038] The term "alkyl" means, by itself or as part of other substituents, a linear or branched hydrocarbon radical having a specified number of carbon atoms unless otherwise specified (e.g., C1-C8 alkyl, i.e., C1-C8 meaning 1 to 8 carbon atoms, preferably C1-C6 alkyl, most preferably C1-C4 alkyl). Preferred examples of C1-C4 alkyls mean methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl. More preferably, the C1-C4 alkyl is a methyl group or an ethyl group, particularly a methyl group. In some embodiments, the alkyl is preferably a C2-C6 alkyl, more preferably a 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 number of ring atoms indicated (e.g., C 3-6The term "cycloalkyl" refers to a hydrocarbon ring having a cycloalkyl group and being completely saturated or having one or fewer double bonds between the vertices of the ring. "Cycloalkyl" is also intended to refer to bicyclic and polycyclic hydrocarbon rings. The term "heterocycloalkyl" refers to a cycloalkyl group containing 1 to 5 heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms may be oxidized as appropriate, and the nitrogen atom may be quaternized as appropriate. Heterocycloalkyl groups may be monocyclic, bicyclic, or polycyclic ring systems. Heterocycloalkyl groups may be bonded to the rest of the molecule via ring carbon atoms or heteroatoms.

[0039] The term "alkylene" refers to a divalent radical derived from an alkane, such as -CH2CH2CH2CH2-, either by itself or as part of another substituent. Generally, alkyl (or alkylene) groups have 1 to 24 carbon atoms, and in this invention, those groups with 10 or fewer carbon atoms are preferred. "Lower alkyl" or "lower alkylene" refers to a shorter-chain alkyl or alkylene group, generally having 4 or fewer carbon atoms. Similarly, "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" that have double or triple bonds, respectively.

[0040] The term "heteroalkyl," either by itself or in combination with other terms, means, unless otherwise specified, a stable linear, branched, or cyclic hydrocarbon radical, or a combination thereof, comprising a specified number of carbon atoms and 1 to 3 heteroatoms selected from the group consisting of O, N, and S, where the nitrogen and sulfur atoms may be oxidized as appropriate, and the nitrogen heteroatom may be quaternized as appropriate. The heteroatoms O, N, and S may be located at any internal position of the heteroalkyl group. Similarly, the terms "heteroalkenyl" and "heteroalkynyl," either by themselves or in combination with other terms, mean, unless otherwise specified, an alkenyl group or alkynyl group containing a specified number of carbon atoms and having 1 to 3 heteroatoms selected from the group consisting of O, N, and S, where the nitrogen and sulfur atoms may be oxidized as appropriate, and the nitrogen heteroatom may be quaternized as appropriate. The heteroatoms O, N, and S may be located at any internal position of the heteroalkyl group.

[0041] The term "heteroalkylene" refers to a divalent radical, either saturated, unsaturated, or polyunsaturated, derived from a heteroalkyl group, either by itself or as part of another substituent. For heteroalkylene groups, the heteroatom can occupy one or both ends of the chain (e.g., alkylene oxy, alkylenedioxy, alkylene amino, alkylenediamino, etc.).

[0042] The terms “alkoxy,” “alkylamino,” and “alkylthio” (or thioalkoxy) are used in their conventional sense, referring to the alkyl groups that are bonded to the rest of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Furthermore, for dialkylamino groups, the alkyl portions may be identical or different, and together with the nitrogen atom to which they are bonded, they can form a 3- to 7-membered ring.

[0043] The terms "halo" or "halogen" mean, by themselves or as part of other substituents, fluorine, chlorine, bromine, or iodine atoms unless otherwise specified. Furthermore, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, "C 1-4 The term "haloalkyl" is intended to include elements such as trifluoromethyl.

[0044] The term "aryl" refers, unless otherwise specified, to polyunsaturated, generally aromatic hydrocarbon groups, such as C6-C6. 10 The term "aryl group" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, e.g., C4-C4. 10 This refers to a heteroaryl group, where the nitrogen and sulfur atoms may be oxidized as appropriate, and the nitrogen atom may be quaternized as appropriate. The heteroaryl group may be bonded to the rest of the molecule via a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, and non-limiting examples of heteroaryl groups include furyl, thienyl, pyrrolyl, pyridyl, quinolinyl, quinolyl, isoquinolyl, etc. Substituents for each of the aryl and heteroaryl ring systems described above are selected from the group of acceptable substituents listed below.

[0045] For brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthiooxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Therefore, the term "arylalkyl" is intended to include radicals in which an aryl group is bonded to an alkyl group.

[0046] The terms above (e.g., "alkyl," "aryl," and "heteroaryl") include, in some embodiments, both substituted and unsubstituted forms of the radicals shown. Preferred substituents for each type of radical are provided below. For brevity, the terms aryl and heteroaryl refer to the substituted or unsubstituted versions as provided below, while the term alkyl and associated aliphatic radicals are intended to refer to the unsubstituted version unless otherwise indicated.

[0047] Substituents for alkyl groups (including groups often referred to as alkylene, alkenyl, alkynyl, and cycloalkyl) can be a variety of groups selected from -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, the number of which ranges from 0 to (2m'+1), where m' is the total number of carbon atoms in such radicals. R', R'', and R'''' are independently hydrogen and unsubstituted C, 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 group, or unsubstituted aryl-C 1-4 This refers to alkyl groups. If R' and R'' are bonded to the same nitrogen atom, they can combine with that nitrogen atom to form a 3, 4, 5, 6, or 7-membered ring. The term "acyl," when used by itself or as part of another group, refers to an alkyl group in which the two substituents on the carbon closest to the bond site of the radical are replaced by substituents = O.

[0048] Similarly, substituents for aryl and heteroaryl groups are diverse and generally selected from -halogens, -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(NH2)=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, with the number ranging from 0 to the number of unsatisfied valencies on the aromatic ring system (open The range is up to the total number of valences; where R', R'' and R'''' are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenil, C 2-8 Alkynnyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4 Alkyl and unsubstituted aryloxy-C 1-4 Selected from alkyl groups. Other suitable substituents include each of the above aryl substituents bonded to the ring atom by an alkylene deser with 1 to 4 carbon atoms.

[0049] Two of the substituents on adjacent atoms of an aryl or heteroaryl ring are of the formula -TC(O)-(CH2) q The substituents may be replaced as appropriate with -U-, where T and U are independently -NH-, -O-, -CH2- or a single bond, and q is an integer between 0 and 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be of the formula -A-(CH2) rThe substituents -B- may be replaced as appropriate, where A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer from 1 to 3. One of the single bonds in the new ring thus formed may be replaced as appropriate with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be of the formula -(CH2) s -X-(CH2) t The substituents R' in -NR'- and -S(O)2NR'- may be replaced as appropriate, where s and t are independent 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 hydrogen or unsubstituted C 1-6 Selected from alkyl groups.

[0050] As used herein, the term “heteroatom” is intended to include oxygen (O), nitrogen (N), and sulfur (S).

[0051] As used herein, the term “CYCLE” means a saturated or unsaturated monocyclic or polycyclic carbocyclic ring, preferably a 5, 6, or 7-membered ring, where one or more of the ring carbon atoms (e.g., 1, 2, 3, or 4) may be independently replaced 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 encompass all possible isomer forms of the carbocyclic ring (e.g., pyrrolyl includes 1H-pyrrolyl and 2H-pyrrolyl). Examples of cases where CYCLE is a monocyclic or bicyclic aryl group include phenyl and naphthyl. Examples of cases where CYCLE is a monocyclic or bicyclic cycloalkyl group include, but are not limited to, cyclopentyl and cyclohexyl. Examples of cases where the CYCLE is a monocyclic or bicyclic saturated heterocycle include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. Examples of cases where the CYCLE is a monocyclic, bicyclic, or tricyclic partially saturated heterocycle include, but are not limited to, pyrrolidinyl, imidazolinyl, and pyrazolinyl. Examples of cases where the CYCLE is a monocyclic, bicyclic, or tricyclic aromatic heterocycle include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, and triazinyl.

[0052] Throughout this specification, index numbers are used to distinguish different substituents in the compounds of the present invention. Such index numbers are used as superscripts or subscripts, without any particular meaning attached to the use of superscripts or subscripts. In other words, superscript and subscript index numbers 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, and in other formulas and reaction schemes, these substituents are shown as C 1 , C 2 and C 3 It is shown as C 1 C1 and C are the same substituent, 2 C2 and C are the same substituent, 3 C3 and are the same substituent.

[0053] "Pharmacologically acceptable" means that it is approved by a federal or state regulatory authority, or is listed in the United States Pharmacopeia or any other generally accepted pharmacopoeia for use in animals, more specifically in humans.

[0054] The term "pharmaceutically acceptable salt" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. If the compounds of the present invention have relatively acidic functionality, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of the desired base, either in its pure form or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron trivalent, iron divalent, lithium, magnesium, manganese digane, manganese masigane, potassium, sodium, and zinc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperazine, polyamine resins, procaine, purines, theobromine, substituted amines such as triethylamine, trimethylamine, tripropylamine, tromethamine, cyclic amines, and naturally occurring amines. When the compounds of the present invention have relatively basic functionality, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either in pure form 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, monocarbonate, phosphoric acid, monohydrogen-phosphoric acid, dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid.This also includes salts of amino acids such as alginates, 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, Vol. 66, pp. 1-19). Certain compounds of the present invention possess both basic and acidic functionality, enabling the conversion of the compound into either a base or an acid addition salt.

[0055] The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but in other respects, the salt is equivalent to the parent form of the compound for the purposes of the present invention.

[0056] In addition to salt forms, the compounds used in the present invention may also be in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical transformation under physiological conditions to provide the compounds used in the present invention. Furthermore, prodrugs can be converted to the compounds used in the present invention by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be gradually converted to the compounds used in the present invention when placed in a transdermal patch reservoir with appropriate enzymes or chemical reagents.

[0057] Some of the compounds used in this invention may exist in solvated forms, including non-solvent forms and hydrated forms. Generally, the solvated forms are equivalent to the non-solvent forms and are intended to be used within the scope of this invention. Some of the compounds used in this invention may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses intended by this invention and are intended to be within the scope of this invention.

[0058] Some of the compounds used in the present invention have chiral carbon atoms (optical centers) or double bonds, and racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separated enantiomers) are all intended to be included within the scope of the present invention. Compounds used in the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting such compounds (e.g., 1 Instead of H 2 H (i.e., deuterium, D). Compounds include, for example, tritium ( 3 H), Iodine-125( 125 I) or carbon-14 ( 14 The compounds may be radiolabeled with radioactive isotopes such as C). All isotopic variants of the compounds used in this invention, whether radioactive or not, are intended to be included within the scope of this invention.

[0059] Embodiments of the present invention The present invention is further described below. Different aspects of the present invention are defined in more detail in the following description. Unless otherwise explicitly stated, each aspect defined below may be combined with any other aspect. In particular, any feature indicated as preferred or advantageous may be combined with any other feature indicated as preferred or advantageous.

[0060] In one embodiment, the present invention relates to general formula (XXI): [ka] Compounds having, their pharmaceutically acceptable salts, hydrates and rotational isomers [In formula: C 1 The group is selected from the group consisting of aryl and heteroaryl groups, where the heteroaryl group has 1 to 3 heteroatoms selected from N, O, and S as ring atoms; where the aryl and heteroaryl groups have 1 to 3 R 1 Substitutions may be made as appropriate; C 2The group is selected from the group consisting of aryl and heteroaryl groups, where the heteroaryl group has 1 to 3 heteroatoms selected from N, O, and S as ring atoms; where the aryl and heteroaryl groups have 1 to 3 R 2 Substitutions may be made as appropriate; C 3 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, heterocycloalkyl, or heterocycloalkyl-C 1-4 Selected from the group consisting of alkyl groups, where the heteroalkyl group has 1 to 3 heteroatoms selected from N, O, and S, where the heterocycloalkyl group or portion has 1 to 3 heteroatoms selected from N, O, and S, where the heteroaryl group has 1 to 3 heteroatoms selected from N, O, and S as ring atoms, C 3 Each of these has 1 to 3 R 3 Substitutions may be made as appropriate; R 1 These are halogen, -CN, and -R, respectively, independently. 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 Rb Selected from the group consisting of; where Ra and Rb are independently hydrogen and C 1-8 Alkyl, and C 1-8 If selected from a haloalkyl group or bonded to the same nitrogen atom, it may combine with the nitrogen atom to form a five-membered or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring atoms, which may be appropriately substituted with 1 or 2 oxos; R c Each is independent of C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, where R a , R b and R c The aliphatic and / or cyclic moieties may optionally be further substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; optionally with 2 R 1 If substituents are present on adjacent atoms, they combine to form condensed, 5- or 6-membered carbon rings or heterorings; R 2 These are, independently, halogen, -CN, -NO2, and -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 Selected from the group consisting of; where R d and R e Each of them is independently of hydrogen and C 1-8Alkyl, and C 1-8 If selected from a haloalkyl group or bonded to the same nitrogen atom, it may combine with the nitrogen atom to form a five-membered or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring atoms, which may be appropriately substituted with 1 or 2 oxos; R f Each is independent of C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, where R d , R e and R f The aliphatic and / or cyclic moieties may optionally be further substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups, where optionally two R 2 If the groups are located on adjacent atoms, they may combine to form a five-membered ring or a six-membered ring; R 3 These are halogen, -CN, and -R, respectively, independently. 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 R h -NRgRh, -ORg, -OR j -S(O)2NR g R h -X 4 -R j , -NH-X 4 -R j , -OX 4 -R j -X 4 -NR g R h -X 4 -NHRj -X 4 -CONR g R h -X 4 -NR h C(O)R g -X 4 -CO2R g , -OX 4 -CO2R g , -NH-X 4 -CO2R g -X 4 -NR h CO2R i , -OX 4 -NR h CO2R i , -NHR j and -NHCH2R j A group consisting of X is selected, where X 4 C 1-4 It is alkylene; R g and R h Each of them is independently of hydrogen and C 1-8 Alkyl or heteroalkyl, C 3-6 Cycloalkyl and C 1-8 If selected from a haloalkyl group or bonded to the same nitrogen atom, together with the nitrogen atom, it may form a four-membered, five-membered, or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring atoms, which may be appropriately substituted with one or two oxos; R i Independently, C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R j These are C 3-6 Selected from the group consisting of cycloalkyl, imidazolyl, pyrimidinyl, pyrrolinil, pyrrolyl, piperidinyl, morpholinil, tetrahydrofuranil, tetrahydropyranil, and S,S-dioxo-tetrahydrothiopyranil, where R g , R h , R i and R jThe aliphatic and / or cyclic parts may optionally be further enriched with 1-3 halogens, methyl, CF3, hydroxy, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -C(O)OC 1-8 It may be substituted with alkyl, amino, alkylamino, and dialkylamino groups, and optionally two R groups. 3 When groups are present on adjacent atoms, they combine to form a five-membered or six-membered ring; X is either hydrogen or CH3; R 8 and R 9 These are independently selected from the group consisting of hydrogen, halogens, C1-C8 alkyls, C1-C8 haloalkyls, and C1-C8 alkoxys, or R 8 and R 9 These combine to form condensed, saturated or unsaturated monocyclic or polycyclic carbon rings, where one or more ring carbon atoms may be independently replaced by N, S, or O. And, Diseases induced by monosodium urate (MSU) (including peritonitis and gout), Inflammatory kidney diseases caused by neutrophils (including ischemic nephropathy, ischemic-reperfusion kidney injury, and obstructive nephropathy), Neutrophilic inflammatory diseases of the skin (including hidradenitis suppurativa (HS), pyoderma gangrenosum (PG), PASH (PG, acne, and hidradenitis suppurativa), PAPASH (septic arthritis, acne, PG, and hidradenitis suppurativa), chronic spontaneous urticaria, and bullous pemphigoid), and immune complex disease This invention relates to compounds, as well as pharmaceutically acceptable salts, hydrates, and rotational isomers thereof, for use in the treatment or prevention of diseases or disorders selected from the group consisting of the above.

[0061] In some embodiments of this model, R 8 and R 9 At least one of them is not hydrogen, and / or X is hydrogen. Preferably, R 8X is not hydrogen. Preferably, X is hydrogen.

[0062] In some embodiments of this model, the compound is of formula (XXIa): [ka] It has.

[0063] In some embodiments of the first aspect, the compound is of formula (I) or formula (XI): [ka] has [In the formula, X, C 1 , C 2 , and C 3 It is defined as described above; R in equation (XI) 8 It is defined as described above; R 4 These are cyano, halo, nitro, hydroxyl, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkyl-OH, and (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 Selected from the group consisting of; R 5 and R 6 Each of these is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, and (C3-C6) cycloalkyl; R 7 These are independently hydroxyl, (C1-C6)alkoxy, phenoxy, or -NR 5 R 6 and; m is between 0 and 4; A CYCLE is a saturated or unsaturated monocyclic or polycyclic carbon ring, where one or more ring carbon atoms may be independently replaced by N, S, or O.

[0064] In further embodiments, the compound is of formula (Ia) or formula (XIa): [ka] It has.

[0065] In some embodiments, CYCLE is a saturated or unsaturated, monocyclic or polycyclic, preferably 5, 6, or 7-membered, carbon ring, where 1 to 4 (preferably 1 to 3, more preferably 1 or 2, and even more preferably 1) ring carbon atoms may be independently replaced by N, S, or O.

[0066] In some embodiments, the compound is of formula (II): [ka] It has.

[0067] In further embodiments, the compound is of formula (IIa): [ka] It has.

[0068] In some embodiments, the compounds are (IIIa), (IIIb), (IIIc), and (IIId): [ka] It has an expression selected from the group consisting of the following.

[0069] In further embodiments, the integer m is 0. In these embodiments, the substituent R 4 It does not exist.

[0070] In further embodiments, the compounds are (IIIe), (IIIf), (IIIg), and (IIIh): [ka] It has an expression selected from the group consisting of the following.

[0071] In further embodiments, the integer m is 0, i.e., in these embodiments, substituent R 4 It does not exist.

[0072] In some embodiments, C 1 The structure is as follows: [ka] That is [In the formula, R 1 It is defined as above (each occurrence, R 1 These are independently selected, that is, different residues R on the phenyl ring. 1 (May exist), n is an integer selected from 0, 1, 2, or 3, preferably 2.

[0073] In further embodiments, R 1 These are independently -OH, halogen, and C 1-6 Alkyl, hydroxy(C) 1-6 )alkyl, and halo(C 1-6 ) Selected from the group consisting of alkyl groups. In a preferred embodiment, R 1 Each of these is independently selected from the group consisting of -OH, chloro, methyl, -CH2-OH, and CF3.

[0074] In some embodiments of the first aspect, C 2 The structure is as follows: [ka] That is [In the formula, R 2It is defined as above (each occurrence, R 2 These are independently selected, that is, different residues R on the phenyl ring. 2 (May exist), o is an integer selected from 0, 1, 2, or 3.

[0075] In further embodiments, R 2 Each is independent of C 1-6 Selected from the group consisting of alkyls and halogens. In a preferred embodiment, R 2 Each of these is independently selected from the group consisting of methyl, fluoro, and chloro.

[0076] In some embodiments of the first aspect, C 3 The structure is as follows: [ka] That is [In the formula, R 3 It is defined as above (each occurrence, R 3 These are independently selected, i.e., different R's on the phenyl ring. 3 (The presence of residues is permitted.) p is an integer selected from 0, 1, 2, or 3.

[0077] In a preferred embodiment, p is 1, and R 3 This includes C1-C8 hydroxyalkyl (preferably hydroxypentyl), C1-C8 hydroxyalkoxy (preferably hydroxybutoxy), or NHR as defined above. j In a further preferred embodiment, R j R is selected from the group consisting of C1-C8 alkyl, C1-C8 hydroxyalkyl, C3-C6 cycloalkyl, and tetrahydropyranyl. In a further preferred embodiment, R j The compound is selected from the group consisting of isopropyl, hydroxybutyl, cyclobutyl, cyclopentyl, and tetrahydropyranyl.

[0078] In some embodiments of the first aspect, R 8 R is selected from the group consisting of halogens, C1-C4 alkyls, C1-C4 haloalkyls, and C1-C4 alkoxys. In a preferred embodiment, R 8 The compound is selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl, and methoxy.

[0079] In some embodiments, the compound is selected from the group consisting of 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 below in the "C. Results" section of the Examples section.

[0080] The compounds used in this invention are Ca 2+ In recruitment assays, IC50 is less than 1 μM. 50 It is preferable to have Ca 2+ Mobilization assays are well known in the art. Preferred Ca 2+ The mobilization assay is, for example, U-937 (ATCC(registered trademark) CRL-1593.2 TM Use human monocytes such as IC. 50 Ca suitable for determining 2+ The recruitment assay is described in the examples. Preferably, the compound is Ca 2+ In the recruitment assay, the IC is 500 nM or less, more preferably 200 nM or less, and even more preferably 100 nM or less. 50 It has.

[0081] The compounds used in this invention are Diseases induced by monosodium urate (MSU) (including peritonitis and gout), Inflammatory kidney diseases caused by neutrophils (including ischemic nephropathy, ischemic-reperfusion kidney injury, and obstructive nephropathy), Neutrophilic inflammatory diseases of the skin (including neutrophilic dermatosis (ND), such as hidradenitis suppurativa (HS), pyoderma gangrenosum (PG), PASH (PG, acne, and hidradenitis suppurativa), and PAPASH (septic arthritis, acne, PG, and hidradenitis suppurativa), as well as chronic spontaneous urticaria and bullous pemphigoid), and It is used in the treatment or prevention of diseases or disorders selected from the group consisting of immune complex diseases.

[0082] Uric acid crystals [monosodium urate (MSU)] have emerged as a key factor in both gouty arthritis and immunomodulation. This simple crystalline structure is thought to activate innate host defense mechanisms in multiple ways, leading to potent inflammation and immune activation. The recognition mechanisms of MSU after phase transition from soluble uric acid are diverse, including both protein receptors and nonspecific plasma membrane adhesion. Upon contact with host cells, MSU induces a series of membrane events that trigger Syk and PI3K activation, phagocytosis, and cytokine production. This is further thought to lead to activated C5a formation and IL-1β production, as well as the recruitment of circulating neutrophils to the site of MSU-induced inflammation within 4–6 hours.

[0083] Surprisingly, injection of MSU crystals dramatically increased the number of white blood cells (WBCs) in the peritoneal lavage fluid (not in the blood), but co-administration of the compounds used in this invention resulted in a decrease in the number of WBCs, monocytes, neutrophils, and lymphocytes in the peritoneal lavage fluid. While we do not wish to be bound by theory, it is thought that the presence of the compounds used in this invention may inhibit the recruitment of WBCs, particularly neutrophils, at the site of inflammation. This finding is consistent with the finding that C5aR is expressed on neutrophils. Therefore, this MSU-induced disease model (particularly the peritonitis shown in Example 3) suggests that the compounds used in this invention have the potential to suppress the effects of MSU-induced and neutrophil-driven inflammation in vivo.

[0084] In preferred embodiments, diseases induced by monosodium urate (MSU) include peritonitis and gout. For these conditions, inflammation induced by monosodium urate (MSU) is established as the cause of inflammation, which can be significantly reduced by the compounds used in the present invention, as shown in Example 3.

[0085] Inflammatory kidney diseases, such as glomerulonephritis, are usually caused by bacterial or viral infections, but several additional causes may lead to an inflammatory response in kidney tissue. For example, renal ischemia-reperfusion (I / R) injury is the most common cause of acute renal failure, seen after kidney transplantation, major abdominal and vascular surgery, coronary artery bypass surgery, as well as in trauma and sepsis. The complement system has been shown to mediate renal ischemia-reperfusion (I / R) injury. C5aR was found to be expressed on mesangial cells and tubular epithelial cells in the kidneys of healthy mice. After I / R injury, C5aR expression was upregulated in tubular epithelial cells, and the kidneys were heavily infiltrated with neutrophils.

[0086] Surprisingly, administration of the compounds used in this invention was found to significantly reduce the loss of renal function in an ischemic reperfusion kidney injury model (see Example 4) and a unilateral ureteral obstruction (UUO)-induced nephropathy model (see Example 5).

[0087] While we do not wish to be constrained by theory, this is primarily achieved through neutrophil-dependent pathways, but may also be achieved through neutrophil-independent pathways. This finding suggests that the compounds used in this invention may have the potential to suppress the effects of neutrophil-induced inflammatory kidney diseases in vivo, including ischemic nephropathy, ischemic-reperfusion kidney injury, and obstructive nephropathy.

[0088] Hidradenitis suppurativa (HS) is a chronic, devastating skin disorder affecting areas rich in apocrine glands and is considered one of the neutrophil-associated inflammatory skin diseases. Nodules appear in the affected areas, which gradually swell, release pus, and rupture. This process recurs, leading to fistula formation and scarring. The course of this disease creates a frustrating situation not only for the patient but also for the physician. The prevalence has been reported to be between 1% and 4%. The exact pathophysiology of HS is not well defined. Smoking, dietary habits, and genetic predisposition have all been associated with HS. Compared to healthy controls, an increased percentage of NK cells and a decreased percentage of CD4- lymphocytes likely indicate the presence of an autoimmune tendency against the disorder. IL-1β and IL-17 have been found to be upregulated in HS lesions and are associated with inflammasome activation. Hidradenitis suppurativa (HS) presents with numerous neutrophil infiltrations in the inflamed skin, especially in the late stages of the disease. Activated neutrophils may be a key effector cell type in this disease state, causing tissue damage through direct adverse effects or indirect regulatory effects on other effector cells such as activated T cells and TH17.

[0089] In recent years, hypotheses have been put forward regarding the involvement of some autoimmune or autoinflammatory mechanism in the pathogenesis of HS. These hypotheses have been further strengthened by positive results from prospective placebo-controlled trials with TNF antagonists, which led to the approval of adalimumab (an antibody against tumor necrosis factor α) in patients with moderate to severe HS. One major, yet unresolved, question remains: how are neutrophils recruited to the affected skin lesions, and to what extent do activated neutrophils contribute to the development of the disease?

[0090] The diverse range of possible etiological mechanisms suggested by different studies may indicate that HS is related to host mechanisms rather than exogenous factors. Considering the paradox that both anti-infective therapy (antibiotics) and pro-infective therapy (anti-TNF, corticosteroids, immunosuppressants) may be useful, HS may also manifest as an autoinflammatory disease based on a defect in the innate immunity of hair follicles, 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 lesional and surrounding skin.

[0091] Neutrophilic dermatoses (NDs) are a group of disorders characterized by skin lesions that, upon histological examination, reveal severe inflammatory infiltration, primarily involving neutrophils, without evidence of infection. NDs include pyoderma gangrenosum (PG), Sweet's syndrome, subcorneal pustular dermatosis (SPD), erythema elevata (EED), or neutrophilic urticarial dermatosis (NUD), as well as other well-defined conditions and their atypical or migratory forms. Hidradenitis suppurativa (HS) has recently been assigned to the ND family based on the numerous neutrophil infiltrations observed in the inflamed skin.

[0092] Pyoderma gangrenosum (PG) and hidradenitis suppurativa (HS) are typical neutrophilic dermatoses characterized by neutrophil accumulation in the skin and are considered to be inherently autoinflammatory diseases.

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

[13]

[0093] Neutrophilic urticarial dermatosis (NUD), such as chronic spontaneous urticaria (autoimmune), is a rare form of dermatology. Clinically, it consists of chronic or recurrent rashes, including slightly raised pink to red macules or plaques. The initial lesions last 24–48 hours and disappear without leaving residual pigmentation. Non-cutaneous signs are common, particularly fever and arthralgia. Histopathologically, it involves dense neutrophilic stromal infiltration in the dermis with leukocyte fragmentation but without fibrinoid necrosis of the vascular walls. NUD often occurs in the context of underlying systemic diseases. The most commonly associated diseases are adult-onset Still's disease, Schnitzler syndrome, lupus erythematosus, and cryopyrin-associated periodic syndromes. Treatment of NUD depends on the clinical background. Dapsone and colchicine are often effective, but additional treatment options are desirable.

[0094] Generally, bullous autoimmune dermatological disorders (also known as autoimmune bullous diseases (AIBD)), such as bullous pemphigoid (BP), are a group of clinically and immunopathologically heterogeneous diseases, clinically characterized by blisters or erosions of the skin and / or mucous membranes. In AIBD, autoantibodies target structural proteins of the skin; in pemphigus, they target adhesion plaque proteins that connect adjacent keratinocytes / epithelial cells; and in bullous pemphigoid, they target proteins in the basement membrane that connect the epidermis / epithelium to the dermis / lamina propria. Bullous pemphigoid (BP) is an inflammatory subepidermal bullous disease and is thought to be associated with an IgG autoimmune response to the adhesion plaque protein BP180.

[0095] Surprisingly, administration of the compounds used in this invention was found to be suitable for improving ND (see Example 7). While we do not wish to be bound by theory, this is primarily achieved through a neutrophil-dependent pathway, although it may also be achieved through a neutrophil-independent pathway. This finding suggests that the compounds used in this invention have the potential to suppress the effects of cutaneous neutrophilic inflammatory diseases, including hidradenitis suppurativa (HS), pyoderma gangrenosum (PG), PASH (PG, acne, and hidradenitis suppurativa), and PAPASH (septic arthritis, acne, PG, and hidradenitis suppurativa), as well as neutrophilic urticarial dermatosis (NUD) and autoimmune bullous disease (AIBD), in vivo.

[0096] Immune complex diseases are a group of conditions resulting from inflammation and tissue damage induced in tissues where immune complexes are formed or deposited. Immune complexes, also called antigen-antibody complexes or antigen-binding antibodies, are molecules formed when multiple antigens bind to antibodies. The bound antigens and antibodies function as a single entity, effectively becoming antigens themselves with specific epitopes. Following the antigen-antibody reaction, immune complexes can undergo one of many responses, including complement deposition, opsonization, phagocytosis, or protease treatment. Immune complex deposition is a prominent feature of several autoimmune diseases, including rheumatoid arthritis, scleroderma, and Sjögren's syndrome. The inability to degrade immune complexes in lysosomes, and their subsequent accumulation on the surface of immune cells, is associated with systemic lupus erythematosus. Furthermore, related immune complex disorders include: IgA nephritis (or IgA nephropathy, named after the deposition of granular immunoglobulin A (IgA) in the mesangium); lupus nephritis (inflammation of the kidneys caused by the autoimmune disease systemic lupus erythematosus (SLE)); ANCA (anti-neutrophil cytoplasmic antibody) vasculitis; anti-C3 glomerulopathy (C3G), characterized by the dominant deposition of complement component 3 (C3) in the renal glomeruli; atypical hemolytic uremic syndrome (aHUS), also known as complement-mediated hemolytic uremic syndrome, which usually involves chronic dysfunction of the complement system. Caused by uncontrolled activation; Goodpasture syndrome (also known as anti-glomerular basement membrane antibody disease, a rare autoimmune disease in which antibodies attack the basement membranes of the lungs and kidneys); crescentic glomerulonephritis; focal segmental glomerulosclerosis (FSGS); rheumatic fever (an inflammatory disease thought to involve the production of autoantibodies); dermatomyositis (DM); chronic inflammatory demyelinating polyneuropathy (CIDP) (also known as chronic relapsing polyneuropathy (CRP) or chronic inflammatory demyelinating polyradiculoneuropathy); chemotherapy-induced peripheral neuropathy (CIPN); and transplant rejection.

[0097] Dermatomyositis (DM) is a subset of specific inflammatory muscle diseases (IIMs) in which skeletal muscle is targeted by the immune system. DM is primarily characterized by muscle inflammation, proximal muscle weakness, and skin lesions. In addition, the disease may present with extramuscular manifestations affecting various organs, including the heart, joints, lungs, and gastrointestinal tract. Recent studies appear to support a link between immune cell infiltration and myocardial injury in dermatomyositis

[14] .

[0098] Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common and heterogeneous immune-mediated neuropathy, characterized by marked demyelination of motor and sensory neurons. CIDP follows a relapsing-remitting or progressive course and causes significant impairment. The pathogenesis of CIDP involves a complex interaction of multiple abnormal immune responses that create a pro-inflammatory environment followed by myelin damage. The complement system appears to play a role in promoting macrophage-mediated demyelination.

[15]

[0099] Chemotherapy-induced peripheral neuropathy (CIPN) is the most common neurological complication of chemotherapy, causing pain, loss of sensation, and numbness in the limbs. Often, acute CIPN leads to discontinuation of chemotherapy, and the condition may persist for months or even years before becoming chronic. Severe pain may necessitate a change in the chemotherapy regimen or discontinuation of treatment, resulting in a risk of reduced treatment effectiveness. Chemotherapy agents are used to halt cancer progression because they have the ability to kill cancer cells. However, these drugs also affect healthy cells, causing side effects such as anemia, diarrhea, and nausea, as well as serious complications such as infertility, infection, and pain. Simultaneously, chemotherapeutic agents can affect the structure of the nervous system, causing various neuropathy, including peripheral neuropathy, depending on the compound and its mechanism of action. Alterations in immune signaling and ion channel expression, neurotoxicity, mitochondrial dysfunction, and axonal degeneration are considered the most relevant mechanisms involved in CIPN, and several studies highlight the importance of immune system and immune-mediated neuroinflammation in its development.

[0100] Surprisingly, administration of the compounds used in this invention was found to significantly reduce immune complex-driven neutrophil activation in an immune complex model in human whole blood (see Example 6).

[0101] Pharmaceutical composition and administration mode In practice, the compounds used in the present invention may be present in a pharmaceutical composition, and the compound, or a pharmaceutical composition containing the compound, may be administered to a patient by any route established in the art that provides a sufficient level of the compound in the patient. It may be administered systemically or topically. Such administration may be non-enteral, transmucosal, e.g., oral, transnasal, transrectal, transvaginal, sublingual, submucosal, transdermal, or inhalation. Preferably, administration is non-enteral, e.g., via intravenous or intraperitoneal injection, and includes, but is not limited to, intra-arterial, intramuscular, intradermal, and subcutaneous administration. When the compounds described herein, or pharmaceutical compositions containing the compounds, are administered topically, they may be injected directly into the organ or tissue being treated.

[0102] Pharmaceutical compositions suitable for oral administration may be provided as capsules or tablets; powders or granules; solutions, syrups, amorphous dispersions in polymers, waxy solids or suspensions (in aqueous or non-aqueous liquids); edible foams or whips; or emulsions. Tablets or hard gelatin capsules may contain lactose, starch or its derivatives, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, stearic acid or its salts. Soft gelatin capsules may contain vegetable oils, waxes, fats, semi-solid or liquid polyols, etc. Solutions and syrups may contain water, polyols, and sugars.

[0103] Activators for oral administration may be coated with or mixed with a material that slows the breakdown and / or absorption of the activator in the gastrointestinal tract (for example, glyceryl monostearate or glyceryl distearate may be used). Thus, sustained release of the activator may be achieved over a long period, and, if necessary, the activator may be protected from degradation in the stomach. Pharmaceutical compositions for oral administration may be formulated to promote the release of the activator at specific gastrointestinal sites due to specific pH or enzymatic conditions.

[0104] Pharmaceutical compositions suitable for transdermal administration may be provided as individual patches intended to remain in close contact with the recipient's epidermis for an extended period. Pharmaceutical compositions suitable for topical administration may be provided as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. For topical administration to the skin, mouth, eyes, or other external tissues, topical ointments or creams are preferably used. When formulated as an ointment, the active ingredient may be selected with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream containing an oil-in-water or water-in-oil base. Pharmaceutical compositions suitable for topical administration to the eyes include eye drops. In these compositions, the active ingredient may be dissolved or suspended in a suitable carrier, such as an aqueous solvent. Pharmaceutical compositions suitable for topical administration to the mouth include lozenges, pastels, and mouthwashes.

[0105] Pharmaceutical compositions suitable for nasal administration may include a solid carrier, such as a powder (preferably having a particle size in the range of 20 to 500 microns). The powder may be administered in the same manner as snuff is ingested, i.e., by rapidly inhaling through the nose from a container of powder held near the nose. Alternatively, compositions employed for nasal administration may include a liquid carrier, such as a nasal spray or nasal drop. These compositions may contain an aqueous or oily solution of the active ingredient. Compositions for inhalation administration may be provided in specially adapted devices (including, but not limited to, pressurized aerosols, nebulizers, or insufflators), 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.

[0106] 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 spray formulations.

[0107] Pharmaceutical compositions suitable for non-enteral administration include aqueous and non-aqueous sterile injection solutions or suspensions, which may contain antioxidants, buffers, bacteriostatic 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, for example, water, alcohol, polyols, glycerin, and vegetable oils. Compositions suitable for non-enteral administration may be supplied in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier, such as sterile saline for injection, immediately before use. Immediately prepared injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0108] In preferred embodiments, the compounds used in the present invention as described herein are formulated according to routine procedures as pharmaceutical compositions suitable for intravenous administration to humans. Generally, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. If necessary, the composition may also contain a solubilizer and a local anesthetic such as lidocaine to relieve pain at the injection site. Generally, the components are supplied separately or mixed together in the form of unit doses, for example, as dry lyophilized powder or anhydrous concentrate in sealed containers such as ampoules or sachets indicating the amount of the activator. When the composition is administered by infusion, it may be dispensed using an infusion bottle containing sterile pharmaceutical-grade water or saline. When the composition is administered by injection, an ampoule of sterile saline may be provided so that the components may be mixed before administration.

[0109] In other embodiments, for example, the compounds used in the present invention as described herein, or pharmaceutical compositions containing such compounds, may be delivered by a controlled-release system. For example, the compounds may be administered by intravenous infusion, implantable osmotic pump, transdermal patch, liposome, or other dosage forms. In some embodiments, 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 other embodiments, the compound may be delivered by 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; US4, 704, 355). In other embodiments, polymer 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; Levy et al. (1985) Science 228:190; During et al. (1989) Ann. Neurol. 25:351; and also Howard et al. (1989) J. Neurosurg. 71:105).

[0110] In further embodiments, the controlled-release system may be positioned near the therapeutic target, i.e., the target cell, tissue, or organ, and therefore require only a small amount of systemic dose (see, for example, Goodson (1984) Medical Applications of Controlled Release, vol. 2, pp. 115–138). Other controlled-release systems are discussed in Langer's review (1990, Science 249:1527–1533).

[0111] In certain embodiments, it may be desirable to administer the compounds used in the present invention as described herein, or pharmaceutical compositions containing such compounds, topically to an area requiring treatment. This may be achieved, for example, by topical infusion during surgery, topical application (e.g., in connection with postoperative wound dressings), injection, by catheter, by suppository, or by implant, for example, by local infusion during surgery, by topical application (e.g., in connection with postoperative wound dressings), by injection, by catheter, by suppository, or by implant. The implant is a silastic TM These are porous, non-porous, or gelatinous materials that include membranes or fibers.

[0112] The selection of a preferred effective amount of a compound used in the present invention, as described herein, will be determined by one of ordinary skill in the art, taking into account several factors known to those of ordinary skill in the art. Such factors include the particular form of the pharmaceutical composition, such as a polypeptide or vector, and its pharmacokinetic parameters (e.g., bioavailability, metabolism, half-life), which are established during normal development procedures typically selected to obtain regulatory approval for a pharmaceutical product. Additional factors to consider when contemplating a dosage include the condition or disease to be prevented and / or treated, or the benefit to be achieved in a normal individual, the patient's weight, the route of administration, whether the administration is acute or chronic, concomitant medications, and other factors that are well known to affect the effectiveness of the administered agent. Accordingly, the exact dosage should be determined according to standard clinical techniques, taking into account the judgment of the physician and the circumstances of each patient, such as the individual patient's condition and immune status. A typical dosage of the compounds used in the present invention is in the range of about 0.1 to 100 mg, preferably about 0.1 to 10 mg, per kg of body weight.

[0113] Methods for preparing various pharmaceutical compositions containing a quantity of an active ingredient are known to those of ordinary skill in the art. For examples of methods for preparing pharmaceutical compositions, see Remington: The Science and Practice of Pharmacy, Lippincott, Williams & Wilkins, 21st Edition (2005). <OO00894>

[0114] In certain embodiments of the present invention, the compounds used in the present invention may be combined with at least one additional therapeutic agent.

[0115] In certain embodiments, the present invention also relates to a method for treating a particular disease as defined above in a patient in need thereof, comprising administering a compound used in the present invention as defined above or a pharmaceutical composition described herein.

[0116] Generally, the compounds used in the present invention can be prepared by the synthetic methods outlined in WO 2020 / 182384 A1, which is incorporated herein by reference.

Example

[0117] The following examples are provided to illustrate the invention described in the claims, but are not intended to limit it. The compounds used in the present invention can be synthesized, as known in the art, for example, from WO2020 / 182384A1 using various reactions known to those skilled in the art. Those skilled in the art will recognize that alternative methods may be selected to synthesize the target compounds used in the present invention. Some of the molecules described herein may exist in different enantiomeric and diastereomeric forms, and the use of all variants of such compounds is claimed.

[0118] Example 1 A. The compounds used in the present invention are inhibitors of C5aR1. The effectiveness of the compounds used in the present invention to modulate the activity of mammalian C5a receptors by directly binding to the C5a receptor is confirmed by the results shown below.

[0119] B. Biological assay Calcium ++ Mobilization assay U937 cells (ATCC® CRL-1593.2) were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum in a standard cell culture incubator. The day before the assay was performed, dibutyryl-cAMP (a working concentration of 0.5 mM) was added to the cell culture. The next day, the cells were centrifuged and resuspended in RPMI 1640 to a concentration of 40,000 cells per 50 μl. 40,000 cells were seeded into one well of a 96-well poly-D-lysine-coated plate for 2 hours to allow the cells to adhere. After cell adhesion, cytoplasmic calcium ++An indicator (FLIPR Calcium 6 Assay Kit, Molecular Devices) was added to each well and incubated at 37°C for 75 minutes. The test compound was diluted using a robotic liquid handler. The robotic liquid handler tip was replaced after each mixing step. The test compound was added to the cell culture at various concentrations (0.01 nM to 100 μM) for 15 minutes at 37°C. The cell culture plates were then incubated at room temperature for 30 minutes and then placed in a Flexstation-3 plate reader (Molecular Devices). The Flexstation-3 was programmed to add recombinant C5a protein at various concentrations (1 nM to 10 nM) to the cell culture plates and monitor changes in fluorescence intensity correlated with cytoplasmic calcium concentration. The assay was also performed in the presence of human or animal blood components, e.g., human or bovine plasma or serum.

[0120] Chemotivity assay U937 cells were cultured in a standard cell culture incubator in RPMI1640 medium supplemented with 10% fetal bovine serum. The day before performing the assay, dibutyryl-cAMP (working concentration of 0.5 mM) was added to the cell culture. The following day, the cells were centrifuged and resuspended in RPMI1640 to a concentration of 50,000 cells per 20 μl. The cells were incubated with various concentrations of compounds (0.01 nM to 100 μM) at 37°C for 30 minutes. 50,000 cells from 20 μl of RPMI1640 were added to one well of the upper chamber of a 96-well chemotactic plate (chemotactic plate containing a cell filter with 8 micrometer pores was purchased from Neuroprobe). A preferred concentration of C5a or other chemotactic agent in 29 μl of HBSS buffer was added to the lower chamber. Cells that migrated to the lower chamber after 1–3 hours were stained with Cell Titer Glo (Invitrogen) and quantified using FlexStation® 3. The assay was also performed in the presence of human or animal blood components, such as human or bovine plasma or serum.

[0121] Beta-arrestin assay Using the osteosarcoma cell line U2OS (ATCC number HTB-96), we generated genetically modified cell lines that overexpressed two fusion proteins within the same cell: (a) TEV-C5aR1, a fusion protein consisting of tobacco etch virus (TEV) protease fused to wild-type human C5aR1 or a human C5aR1 mutant. The C5aR1 mutant has amino acid mutations that are presumed to mediate the interaction between C5aR1 and the test compound. (b) Luc-arrestin, a fusion protein consisting of β-arrestin-2, an inactive substituted luciferase, and a peptide constituting the TEV protease cleavage site. The peptide was located between β-arrestin-2 and the luciferase.

[0122] Using a modified U2OS cell line, we evaluated the activity of C5aR1 and the extent to which the test compounds could modulate the activity of wild-type or mutant C5aR1. In principle, the binding of C5a to the C5aR1 portion of TEV-C5aR1 on the cell surface activates C5aR1, which leads to binding between the intracellular portion of TEV-C5aR1 and luc-arrestin inside the cell. This allows TEV to cleave the peptide linking beta-arrestin and luciferase. This cleavage converts inactive luciferase into active luciferase, which catalyzes the added luciferase substrate, thereby generating a luminescence signal. The intensity of the luminescence signal correlates with the activity of C5aR1.

[0123] Experimentally, modified U2OS cells were cultured in a standard cell culture incubator in McCoy medium supplemented with 10% fetal bovine serum. The test compound was added to the cell culture medium and incubated for 30 minutes, followed by the addition of C5a and incubation for 1–3 hours. The cells were then lysed with a reagent containing a luciferase substrate, such as One-glo or Bright-glo (Promega). Luminescent units (RLUs) were recorded using a luminescence plate reader such as FlexStation® 3 (Molecular Devices).

[0124] C5a-induced CD11b expression in whole blood assays Fresh peripheral blood samples are obtained from informed human volunteers. 100 μl whole blood is incubated with various concentrations (0.01 nM to 10 μM) of test compounds at 37°C for 20 minutes, and then incubated with preferred concentrations of C5a in the range of 1 nM to 30 nM at 37°C for 20 minutes. The samples are ready for FACS (fluorescence-activated cell sorting) analysis of leukocyte CD11b expression, followed by immunostaining. Samples are incubated with anti-CD11b antibody (BioLegend) on ice, shielded from light, for 30 minutes. 100 μl of blood sample is mixed with 1 mL of erythrocyte lysis buffer (Miltenyi) and incubated at room temperature for 10 minutes. Samples are washed with FACS staining buffer and resuspended in FACS buffer. Samples are analyzed by FACS (Beckman-Coulter) for CD11b expression on the cell surface.

[0125] Animal Neutropenia Assay Animals (mice, rats, or Mongolian gerbils) are acclimated for at least 3 days before use in experiments. A test compound (1 - 30 mg / kg) is administered orally or intravenously. 1 - 3 hours later, the animals are anesthetized using standard procedures such as intraperitoneal administration of ketamine and xylazine. A catheter is inserted into the animals for intravenous administration and blood sampling of C5a. C5a is prepared in physiological saline and injected intravenously at a dose ranging from 30 μg / kg to 120 μg / kg. After C5a administration, blood samples are collected several times over 30 minutes. Blood samples are collected using heparin tubes. Leukocyte fractions such as the abundance of neutrophils in the collected blood samples are analyzed using an automated blood cell counter (Siemens).

[0126] C. Results In biological assays such as calcium mobilization assays, the maximum half - inhibitory concentration, i.e., IC<00A0407>was determined. Using the calcium mobilization assay, the following IC<00A0408>values were determined by the best dose - response curve fitting method. Curves were plotted using the inhibition rate of C5a - induced calcium mobilization against various concentrations of the compound. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [[ID=]]<00A0975> [Table 9] [Table 10] 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 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 INF014: (2R,3S)-1-(2-chlorobenzoyl)-2-(4-(cyclopentylamino)phenyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide 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 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 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 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 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 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 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 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 INF035: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(3-(hydroxymethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide INF038:(2R,3S)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-2-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide 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 INF040: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1-(2-methylbenzoyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide INF041: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluorobenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide 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 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 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 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 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 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 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 INF052: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide INF053: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-dimethylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide INF054: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluor-6-methylbenzol)-N-(4-methyl-3-(triflouromethyl)phenyl)piperidine-3-carboxamide; 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 INF056: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide 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 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 INF068: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-N-(4-hydroxy-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide INF069: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide 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 INF071: (2R,3S,5R)-N-(3-chloro-4-methylphenyl)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-5-(trifluoromethyl)piperidine-3-carboxamide INF072: (2R,3S,5R)-N-(3-chloro-4-hydroxyphenyl)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-5-(trifluoromethyl)piperidine-3-carboxamide INF075: (2R,3S,5R)-1-(2-chloro-6-fluorobenzoyl)-2-(4-(cyclopentylamino)phenyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide INF077: (2R,3S,5R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-5-(trifluoromethyl)piperidine-3-carboxamide INF080: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-N-(3,4-dichlorophenyl)-1-(2,6-difluorobenzoyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0127] Example 2 - Inhibition of C5a-induced neutropenia Hamsters are considered a pharmacologically relevant species possessing analogues to human C5aR. Therefore, similar to humans, neutrophil counts in hamster blood decrease significantly after C5a infusion, leading to neutropenia. While we do not wish to be constrained by theory, it is thought that certain C5a receptor antagonists used in this invention may improve neutrophil infiltration.

[0128] The effect of INF052 and INF054, administered by forced oral (PO) feeding prior to C5a infusion, on inhibiting neutropenia was evaluated in Lakeview Golden (LVG) hamsters. C5a infusion (100 μg / kg, formulated in vehicle 2: physiological saline) was performed 8 and 24 hours after oral administration of the compound (formulated in vehicle 1: 70% PEG-400 / 30% Solutol HS-15). Blood samples were collected via jugular vein catheter at -1 minute (before C5a) and +1 minute (after C5a) before and after C5a infusion. Neutrophil counting and PK analysis were performed on the test animals.

[0129] In this study, the effects of INF052 and INF054 at doses of 10, 20, or 30 mg / kg PO (vehicle 1: formulated in 70% PEG-400 / 30% Solutol HS-15) prior to C5a infusion (vehicle 2: formulated in physiological saline) were evaluated at 4 hours (one 30 mg / kg study), 8 hours, and 24 hours (10, 20, and 30 mg / kg studies). At 8 and 24 hours, INF052 and INF054 at doses of 10, 20, and 30 mg / kg prior to C5a significantly reduced the change in neutrophil count compared to the vehicle 1 + C5a (100 μg / kg) group. The results are summarized in Table 1 below. INF052 at 10 mg / kg showed superior efficacy compared to INF054 in terms of neutrophil count change over 8 hours (see Figure 1). [Table 11] PK: Blood samples were collected in tubes containing EDTA-K2 as an anticoagulant 1 minute after C5a infusion. Plasma samples were kept at -80°C and INF054 / INF052 concentrations were analyzed by HPLC. Inhibition rate (%): Blood samples were collected in tubes containing EDTA-K2 as an anticoagulant at -1 minute (before administration) and 1 minute after C5a infusion, and neutrophils were counted using a blood analyzer (Siemens, ADVIA2120i). % inhibition was calculated by comparing the change in neutrophil count induced by INF054 / INF052 with the change in neutrophil count induced by C5a.

[0130] These results demonstrate that the compounds used in the present invention are effective in blocking C5a-induced neutropenia.

[0131] Example 3 - Inhibition of MSU-induced peritonitis Generally, intraperitoneal injection of monosodium urate (MSU) crystals in hamsters is thought to induce inflammasome complex formation and activate the complement cascade, leading to activated C5a formation and IL-1β production. The latter typically results in the recruitment of circulating neutrophils to MSU-induced inflammatory sites within 4–6 hours. The effect of INF052 was evaluated in a model of monosodium urate (MSU)-induced acute peritonitis in hamsters treated with MSU crystals via intraperitoneal (IP) injection 5 hours after oral administration of either vehicle or 20 mg / kg of INF052 (vehicle: 70% PEG400, 30% Solutol HS15). Saline injection was used as a control. All test animals were sacrificed 6 hours after MSU injection. Blood samples and inflammatory exudate collected from the peritoneal cavity were used for total cell counting and fractionation analysis. The treatment groups were as follows: [Table 12]

[0132] The cell counts, including white blood cells (WBCs), neutrophils (Neut), lymphocytes (Lymph), and monocytes (Mono), in the peritoneal lavage fluid and blood of each group (G) are shown in Table 3 below. [Table 13]

[0133] The volume of peritoneal lavage fluid was as follows: [Table 14]

[0134] As shown in the results above, MSU crystals dramatically increased the number of white blood cells in peritoneal lavage fluid but not in the blood. INF052 significantly reduced the number of MSU-induced white blood cells (WBCs) and neutrophils (Neuts) in peritoneal lavage fluid compared to treatment with MSU + vehicle (see also Figure 2). In addition, no significant effect was found on IL-6 and IL-1β levels in serum (data not shown) and peritoneal lavage fluid (see Table 4 above). These results confirm that the recruitment of WBCs, particularly neutrophils, at the site of inflammation may be inhibited by the presence of INF052.

[0135] In summary, this MSU-induced peritonitis model suggests that the compounds used in this invention may inhibit the effects of neutrophil-driven inflammation, particularly monosodium urate (MSU)-induced inflammation, in vivo.

[0136] Example 4 - Inhibition of ischemic reperfusion kidney injury Golden hamsters were administered Vehicle or INF052 four hours prior to surgery. The animals were anesthetized, the right renal artery, vein, and ureter were ligated, and the right kidney was removed. The left renal pedicle was clipped to stop blood flow to the left kidney. After 45 minutes, the clip was removed and blood flow to the left kidney was resumed. In the Siamese surgery group, the left renal artery was not clipped. The animals were allowed to recover for two days post-surgery. Forty-eight hours after surgery, the animals were sacrificed. Blood and renal tissue samples were collected for analysis. The animal groups are shown in Table 5 below. [Table 15]

[0137] The blood biochemistry results 48 hours after ischemic surgery were as follows: [Table 16]

[0138] INF052 significantly reduced plasma creatinine (CREA) and blood urea nitrogen (BUN) levels after ischemic reperfusion surgery, demonstrating its efficacy in preventing ischemic reperfusion-induced renal injury. C-reactive protein (CRP) was not detected, and fibrin / fibrinogen degradation products (FDP) and D-dimer were detected only at the lowest detectable dose. Three ELISA assays, including those for plasminogen, suPAR (soluble urokinase-type plasminogen activator receptor), and S100A8 / A9 (calprotectin) (data not shown), also failed to detect any signals confirming the absence of inflammation. Platelet counts remained the same regardless of surgery or treatment, suggesting that platelets were not activated.

[0139] The histopathological condition of the kidney is summarized below. [Table 17] [Table 18]

[0140] The results are shown in Figure 3. As confirmed by histopathological markers and periodate Schiff (PAS) staining, administration of INF052 mitigated the negative effects of ischemic reperfusion on the kidney.

[0141] In summary, this ischemic-reperfusion kidney injury model suggests that the compounds used in the present invention may have the potential to suppress neutrophil-induced inflammatory kidney disease in vivo, particularly the negative effects of ischemia-reperfusion on the kidney.

[0142] Example 5 - Efficacy in unilateral ureteral obstruction (UUO)-induced nephropathy The unilateral ureteral obstruction (UUO) model is a model of renal interstitial fibrosis. C5aR expression in renal tubular cells was sparse in normal renal cortex but was significantly upregulated after UUO. C5 deficiency or inhibition of C5aR has been found to result in a significant reduction in extracellular matrix deposition and associated inflammation in fibrotic kidneys. This study evaluated the efficacy of INF052 in the UUO model.

[0143] To ensure similar average weight, golden hamsters (8-10 weeks old) were randomly divided into three groups. Animals in groups 2 and 3 underwent UUO (unilateral ureteral obstruction) surgery on day 1. The animals were anesthetized with 2-5% isoflurane. The left kidney was exposed by a lateral abdominal incision, and the left ureter was tied off at the lower pole level with two 3.0 silk sutures. Postoperatively, the animals received analgesics, buprenorphine hydrochloride (0.05 mg / kg), and gentamicin (20 mg / kg, im). All animals were monitored until consciousness was restored. The animals' general condition was monitored daily. The animals were administered the vehicle or active ingredient for a total of 14 days (see Table 8 below). [Table 19] UUO = Unilateral ureteral obstruction

[0144] After treatment with INF052, no significant difference in left obstructed kidney weight / body weight was observed compared to group 2. No deaths were observed up to 14 days postoperatively.

[0145] Serum creatinine levels were slightly elevated in groups 2 and 3 around 3 days post-surgery, but were normal in all groups by 7 days. Serum creatinine levels typically do not rise until substantial loss of renal function occurs. In the UUO model used, changes in creatinine were not expected because only one kidney was obstructed with progressive fibrosis, while the other remained functional.

[0146] As shown in Figure 4, blood urea nitrogen (BUN) levels were significantly increased in group 2 on days 7 and 14 after UUO surgery. Treatment with INF052 was able to maintain BUN levels at low levels very similar to those of animals that had not undergone surgery, suggesting that INF052 interfered with the UUO process and avoided inducing higher metabolic or inflammatory activity. The histopathological conditions of the kidneys are summarized in Table 9 below. [Table 20]

[0147] In group 3, INF052 treatment significantly reduced the total H&E staining score compared to group 2 (UUO-vehicle) (see Figure 5). INF052 further reduced the fibrosis score determined by Masson staining and the score of α-SMA-positive cells (see Table 9).

[0148] In summary, the results from the unilateral ureteral obstruction model suggest that the compounds used in this invention have the potential to suppress the negative effects of neutrophil-induced inflammatory kidney disease, particularly unilateral ureteral obstruction, in vivo, and therefore have the potential to treat obstructive nephropathy.

[0149] Example 6 - Efficacy in reducing neutrophil activation caused by immune complexes in an immune complex model using human whole blood. The objectives of this study were to evaluate the pro-inflammatory effects, such as complement activation and neutrophil stimulation, generated by different immune complexes (ICs), and to demonstrate the inhibitory function of the C5aR antagonist used in this invention in these rapid immune responses in a human whole blood model.

[0150] The intracellular interactions (ICs) involved in this study were formed by co-incubating primary rabbit IgG (either anti-human PMN IgG or unrelated rabbit IgG) with goat secondary anti-rabbit IgG prior to whole blood stimulation, thereby forming polymorphonuclear neutrophil (PMN)-specific and non-PMN-specific ICs, respectively. Neutrophil activation after mixing each IC with whole blood was indicated by elevated C5a levels in the blood and upregulation of CD11b expression on the neutrophil surface. As a C5aR antagonist, INF052 does not affect the immediate innate immune response to C5a release. Therefore, its anti-inflammatory effect in this whole blood model can only be demonstrated by inhibiting the upregulation of CD11b. C5a levels were determined by C5a ELISA, and CD11b was measured by flow cytometry via fluorescein isothiocyanate (FITC)-conjugated anti-CD11b antibody.

[0151] method a. Preparation of immune complexes and their application to human whole blood in the presence or absence of C5a / C5aR axis blockers.

[0152] Primary antibodies, PMN-specific and non-PMN-specific rabbit IgG, were diluted to a pre-preparation concentration of 500 μg / mL. Secondary anti-rabbit IgG was diluted to two different pre-preparation concentrations of 1 mg / mL and 0.5 mg / mL to form two primary-to-secondary antibody ratios (1:2 and 1:1) for IC. The primary and secondary antibodies, as well as buffer HBSS, were mixed in a 1:1:1 volume ratio. Several control samples were also prepared, including a blank control without antibodies and each single-antibody control. 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 components and to form IC as needed. Subsequently, 75 μL of the mixture was co-incubated with 175 μL of freshly collected human whole blood (with ACD as anticoagulant) at 37°C for 30 minutes in the presence of either 28 μL of HBSS, 0.5% DMSO, or INF052 for upcontrol of CD11b and release of C5a. The final concentrations in the whole blood mixture were 45 μg / mL for the primary antibody and 45 μg / mL for the secondary antibody (primary-to-secondary antibody ratio 1:1) or 90 μg / mL (ratio 1:2).

[0153] b. Detection of IC-induced CD11b upregulation on the neutrophil surface

[0154] 100 μL of the whole blood sample described above was placed on ice for 5 minutes. CD11b on the cell surface was captured with 2 μL of FITC-conjugated anti-CD11b antibody during a 30-minute incubation on ice in the dark. Red blood cells were hemolyzed at room temperature for 10 minutes using 1 mL of 1× FACS lysis solution. The cells were then washed twice with 2 mL of staining buffer by centrifugation at 2500 rpm for 3 minutes at room temperature. The 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.

[0155] result As shown in Figure 6, both PMN-specific and non-PMN-specific IgG immune complexes strongly upregulated CD11b expression levels. PMN-specific IgG-IC induced significantly higher levels of CD11b than non-PMN-specific IgG-IC (3.4–5.3-fold increase in CD11b signaling compared to 2.5–4.8-fold increase from baseline). The antigen-to-antibody ratio determines the size and shape of the immune complex, which is then crucial in the effect of IC. A primary-to-secondary antibody ratio of 1:2 showed a much stronger activation effect 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 Figure 6). The different upregulated levels of CD11b were efficiently blocked by 0.25 μM (second gray bar from the right) and 1 μM (black bar) of INF052 in Figure 6.

[0156] Example 7 - Blockade of CD11b upregulation on neutrophils induced by plasma from patients with hidradenitis suppurativa. This embodiment describes the successful induction of neutrophil activation (upregulation of CD11b) in human whole blood by plasma samples collected from four patients with hidradenitis suppurativa (HS) in two clinical studies, and the blockade of this activation by the C5aR antagonist INF052. It demonstrates that C5aR-targeting agents used in this invention, such as INF052, are suitable for blocking uncontrolled neutrophil activation in neutrophilic dermatosis (ND).

[0157] The objectives of the following studies were to demonstrate: i) that plasma collected from patients with hidradenitis suppurativa (HS) can activate neutrophils in human whole blood (as demonstrated by the upregulation of CD11b on neutrophils); and ii) that the C5aR antagonist INF052 is highly potent in blocking inappropriate or uncontrolled neutrophil activation.

[0158] Neutrophil accumulation at inflammatory sites depends on the expression of adhesion molecules, including CD11b. Upregulation and recruitment of CD11b from the intracellular pool to the neutrophil surface are essential for the rolling and migration of human neutrophils. Therefore, enhanced CD11b expression reflects an inflammatory triggering event. Activated complement products, particularly elevated C5a in the blood of HS patients, can strongly upregulate CD11b expression through the binding of C5a to its receptor C5aR on neutrophils. Consequently, blocking the C5a-C5aR axis is expected to eliminate or attenuate the upregulation of CD11b on the neutrophil surface.

[0159] 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 from FITC-conjugated anti-CD11b antibodies bound to neutrophils compared to the activation condition.

[0160] experiment sample Following the consensus definition, one plasma sample from an HS patient at the Pathology Clinic of Attico University General Hospital in Athens, and three plasma samples from the Phase IIb trial SHINE (ClinicalTrials.gov ID: NCT03487276) were applied to this study. The complement system was activated in the pathogenesis of HS, as indicated by elevated levels of C3a, C5a, and C5b-9. The C5a levels of the four HS patients are listed below. These are significantly higher than the levels of normal healthy individuals. [Table 21]

[0161] Healthy human citrate (dextrose citrate) plasma from a single donor was purchased from Biomex GmbH and used as a control under inactivation / non-inflammatory conditions. The C5aR antagonist INF052 was used dissolved in DMSO as a 10 mM stock solution and stored at -70°C.

[0162] procedure a) Preparation of human whole blood with added INF052 Human whole blood was collected fresh from healthy donors in the presence of 12% dextrose citrate solution (ACD). INF052 stock solution (10 mM in 100% DMSO) was serially diluted with DMSO, then with HBSS, to obtain the target 10-fold concentrated working solution in HBSS / 2.5% DMSO. These working solutions were then diluted 10-fold in whole blood to obtain the final INF052-added human whole blood. As a control, 100% DMSO was similarly diluted and added to whole blood. The added blood samples were incubated at 37°C for 30 minutes to allow sufficient time for INF052 to bind to C5aR.

[0163] b) Human CD11b efficacy assay (flow cytometry assay) Blockade of INF052-mediated neutrophil CD11b upregulation was performed ex vivo in either INF052 (0.25% DMSO) or human whole blood supplemented with 0.25% DMSO. Recombinant human C5a (rhC5a) at a final concentration of 15 nM was used as a positive control to confirm neutrophil activation. Each sample was measured in a double-dip spectroscopy.

[0164] 12 μL of healthy human plasma (huP), plasma from an HS patient, or 150 nM rhC5a was added to 80 μL of whole blood supplemented with INF052 / DMSO. The final volume of each test sample was filled to 120 μL with HBSS. The following is the simplest example of samples tested in a single assay. In practice, samples from several patients and several different concentrations of INF052 may be added to a single assay. [Table 22]

[0165] All samples were incubated at 37°C for 20 minutes, taking into account the time required for CD11b expression, followed by exposure to ice for 5 minutes to further stop protein expression. To detect CD11b expression on neutrophils, 2 μL of FITC-conjugated anti-CD11b antibody was then added to each sample and incubated on ice in the dark for 30 minutes. Red blood cells (RBCs) were lysed at room temperature for 10 minutes using 1 mL of 1× FACS lysis solution. After RBC lysis, the remaining blood cells were washed twice with 2 mL of staining buffer (SB), centrifuged at 1300 g for 3 minutes at room temperature, and resuspended in 500 μL of SB. The resuspended cells were analyzed by flow cytometry within 1 hour. Granulocytes were gated on an FSC vs. SSC dot plot, and the mean fluorescence intensity (MFI) of FITC-labeled (via anti-CD11b antibody) granulocytes was recorded. The blockade rate (%) of C5aR antagonists was calculated as follows:

[0166] Blockage rate (%) = (MFI(patient plasma) - MFI(patient plasma + INF052)) / (MFI(patient plasma) - MFI(healthy human plasma)) × 100

[0167] result Plasma from HS patients upregulated CD11b expression on neutrophils. CD11b expression on neutrophils was evaluated using plasma samples from healthy donors and several diagnosed HS patients (pat088, 160-0004, 160-0006, and 160-0010). The mean fluorescence intensity (MFI) of healthy controls was 5412 ± 301.2 (mean ± standard deviation) in the first assay using study samples from SHINE and 4523.5 ± 41.7 in the second assay. These were the baseline expression levels of CD11b in the unstimulated state. In the presence of plasma from individual HS patients, a 2.3–2.6-fold increase in CD11b expression was achieved, which was well comparable to the positive control 15nM rhC5a (2.2–2.4-fold) (Tables 10 and 11, Figures 7 and 8). These data indicated significantly upregulated CD11b expression on neutrophils mediated by inflammatory factors in the plasma of HS patients.

[0168] INF052 successfully blocked the CD11b upcontrol induced by HS and C5a. As described above, both HS patient plasma and 15 nM rhC5a strongly upregulated CD11b expression on blood neutrophils. Activation could be efficiently blocked in a dose-dependent manner by incubating whole blood with the C5aR antagonist INF052 prior to contact with the stimulant (i.e., HS patient plasma or C5a). In the initial experiment using plasma samples from an HS patient (pat088), all three concentrations of INF052, namely 50 nM, 250 nM, and 1 μM, showed blocking effects of over 120%. Blockade exceeding 100% suggests that INF052 not only inhibited the stimulating effect attributable to HS plasma or C5a, but also prevented other indirect or nonspecific neutrophil activation during the long incubation period (Table 10 and Figure 7). Similar results were obtained in a second experiment using samples from three other HS patients from the SHINE study, where 100 nM and 250 nM INF052 alone reduced “baseline” CD11b signaling by 20.5% and 51.6%, respectively. Regarding the elevation of CD11b caused by patient plasma, 100 nM and 250 nM INF052 achieved blockade of 64.4%–94.8% and 92.6%–118.8%, respectively (Table 11 and Figure 8).

[0169] All these results indicate that the C5a / C5aR axis plays a dominant role in CD11b expression on neutrophils. Therefore, C5aR-targeting agents used in this invention, such as INF052, are suitable for blocking uncontrolled neutrophil activation in neutrophilic dermatosis (ND). [Table 23] [Table 24] References 1. Merle, N.S., et al., Complement System Part I - Molecular Mechanisms of Activation and Regulation. Front Immunol, 2015. 6: p. 262. 2. Schatz-Jakobsen, J.A., et al., Structural and functional characterization of human and murine C5a anaphylatoxins. Acta Crystallogr D Biol Crystallogr, 2014. 70(Pt 6): p. 1704-17. 3. Klos, A., et al., International Union of Basic and Clinical Pharmacology. LXXXVII. Complement peptide C5a, C4a, and C3a receptors. Pharmacol Rev, 2013. 65(1): p. 500-43. 4. Ricklin, D., et al., The renaissance of complement therapeutics. Nat Rev Nephrol, 2018. 14(1): p. 26-47. 5. Tesar, V. and Z. Hruskova, Avacopan in the treatment of ANCA-associated vasculitis. Expert Opin Investig Drugs, 2018. 27(5): p. 491-496. 6. Li, G., et al., Neuroprotective effects of argatroban and C5a receptor antagonist (PMX53) following intracerebral haemorrhage. Clin Exp Immunol, 2014. 175(2): p. 285-95. 7. Nunez-Cruz, S., et al., Genetic and pharmacologic inhibition of complement impairs endothelial cell function and ablates ovarian cancer neovascularization. Neoplasia, 2012. 14(11): p. 994-1004. 8. Riedemann, N.C., et al., Controlling the anaphylatoxin C5a in diseases requires a specifically targeted inhibition. Clin Immunol, 2017. 180: p. 25-32. 9. de Haan, J.J. et al (2017). Complement 5a Receptor deficiency does not influence adverse cardiac remodeling after pressure-overload in mice. Scientific Reports, 7: 17045 | DOI:10.1038 / s41598-017-16957-3. 10. Ehrnthaller, C et al (2016). C5aR inhibition in the early. Eur J Med Res, 21, 42. 11. Vergunst, CE. et al (2007). C5a receptor blocker fails to show clinical benefit in patients with RA. Rheumatology, 46, 1773-1778. 12. Marzano AV, Ceccherini I, Gattorno M, Fanoni D, Caroli F, Rusmini M, Grossi A, De Simone C, Borghi OM, Meroni PL and others. 2014. Association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) shares genetic and cytokine profiles with other autoinflammatory diseases. Medicine (Baltimore) 93(27):e187. 13. Cugno M, Borghi A, Marzano AV. 2017. PAPA, PASH and PAPASH Syndromes: Pathophysiology, Presentation and Treatment. Am J Clin Dermatol. 2017 Aug;18(4):555-562. doi: 10.1007 / s40257-017-0265-1. 14. Zhang et al. Arthritis Research & Therapy (2023) 25:69 https: / / doi.org / 10.1186 / s13075-023-03052-4. 15. Querol L.A. et al. Neurotherapeutics (2022) 19:864-873 https: / / doi.org / 10.1007 / s13311-022-01221-y

Claims

1. General formula (XXI) 【Chemistry 1】 Compounds having, as well as their pharmaceutically acceptable salts, hydrates, and rotational isomers. [In the formula, C １ The group is selected from the group consisting of aryl and heteroaryl groups, where the heteroaryl group has 1 to 3 heteroatoms selected from N, O, and S as ring atoms; where the aryl and heteroaryl groups have 1 to 3 R １ Substitutions may be made as appropriate; C ２ The group is selected from the group consisting of aryl and heteroaryl groups, where the heteroaryl group has 1 to 3 heteroatoms selected from N, O, and S as ring atoms; where the aryl and heteroaryl groups have 1 to 3 R ２ Substitutions may be made as appropriate; C ３ is 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, heterocycloalkyl or heterocycloalkyl-C １－４ alkyl, and is selected from the group consisting of, wherein the heteroalkyl group has 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocycloalkyl group or moiety has 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl group has 1 to 3 heteroatoms selected from N, O, and S as ring atoms, each C ３ may optionally be substituted with 1 to 3 R ３ substituents; R １ These are, independently, halogen, -CN, and -R. ｃ , -CO ２ R 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) ２ R 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) ２ NR ａ R ｂ Selected from the group consisting of; where R ａ and R ｂ Each of them is independently of hydrogen and C １－８ Alkyl and C １－８ If selected from a haloalkyl group or bonded to the same nitrogen atom, it may combine with the nitrogen atom to form a five-membered or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring atoms, which may be appropriately substituted with one or two oxos; R ｃ Each is independent of C １－８ Alkyl or heteroalkyl, C １－８ Haloalkyl, C ３－６ Selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, where R ａ , R ｂ and R ｃ The aliphatic and / or cyclic moieties are optionally further substituted with one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; optionally two R １ If substituents are present on adjacent atoms, they combine to form condensed, five- or six-membered carbon rings or heterorings; R ２ These are, independently, halogen, -CN, and -NO. ２ , -R ｆ , -CO ２ R 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) ２ R ｆ , -NR ｄ C(O)NR ｄ R ｅ , -NR ｄ R ｅ , -OR ｄ , and -S(O) ２ NR ｄ R ｅ Selected from the group consisting of; where R ｄ and R ｅ Each of them is independently of hydrogen and C １－８ Alkyl and C １－８ If selected from a haloalkyl group or bonded to the same nitrogen atom, it may combine with the nitrogen atom to form a five-membered or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring atoms, which may be appropriately substituted with one or two oxos; R ｆ Each is independent of C １－８ Alkyl or heteroalkyl, C １－８ Haloalkyl, C ３－６ Selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, where R ｄ , R ｅ and R ｆ The aliphatic and / or cyclic moieties are optionally further substituted with 1 to 3 halogen, hydroxy, methyl, amino, alkylamino, and dialkylamino groups, and optionally with 2 R ２ When groups are present on adjacent atoms, they combine to form a five-membered or six-membered ring; R ３ is each independently halogen, -CN, -R ｉ , -CO ２ R 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 CO ２ R ｉ , -NR ｇ R ｈ , -NR ｇ R ｈ , -OR ｇ , -OR ｊ , -S(O) ２ NR ｇ R ｈ , -X ４ [[ID=q50]]-R ｊ , -NH-X ４ -R ｊ , -O-X<* ４ [[ID=*58]]-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 [[ID=*84]]-CO ２ R<0*000132>, -O-X ４ -CO ２ R ｇ , -NH-X ４ -CO ２ R ｇ , -X ４ -NR<* ｈ CO ２ R ｉ , -O-X ４ -NR<00*00144>CO ２ R ｉ , -NHR ｊ and -NHCH<0*000148>R Note: There seem to be some tags that might be incorrect in the original (e.g., ４ , ｇ , ｈ , ｈ , ２ with an asterisk added for the suspected incorrect part). This translation is done based on the provided rules while trying to make sense of the text as it is. If these are actual correct tags, the translation should be adjusted accordingly. ｊ A group consisting of X is selected, where X ４ C １－４ It is alkylene; R ｇ and R ｈ Each of them is independently of hydrogen and C １－８ Alkyl or heteroalkyl, C ３－６ Cycloalkyl and C １－８ If selected from a haloalkyl group or bonded to the same nitrogen atom, it may combine with the nitrogen atom to form a four-membered, five-membered, or six-membered ring having 0 to 2 additional heteroatoms selected from N, O, or S as ring atoms, which may be appropriately substituted with one or two oxos; R ｉ Each is independent of C １－８ Alkyl or heteroalkyl, C １－８ Haloalkyl, C ３－６ Selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R ｊ These are C ３－６ Selected from the group consisting of cycloalkyl, imidazolyl, pyrimidinyl, pyrrolinil, pyrrolyl, piperidinyl, morpholinil, tetrahydrofuranil, tetrahydropyranil, and S,S-dioxo-tetrahydrothiopyranil, where R ｇ , R ｈ , R ｉ and R ｊ The aliphatic and / or cyclic portions may optionally be further one to three halogens, methyl, CF ３ , hydroxy, C １－４ Alkoxy, C １－４ Alkoxy-C １－４ Alkyl, -C(O)O-C １－８ Substituted with alkyl, amino, alkylamino, and dialkylamino groups, and optionally two R groups ３ When groups are present on adjacent atoms, they combine to form a five-membered or six-membered ring; X is hydrogen or CH ３ And; R ８ and R ９ They are independent of each other: hydrogen, halogen, and C １ -C ８ Alkyl, C １ -C ８ Haloalkyl and C １ -C ８ Selected from the group consisting of alkoxys, or R ８ and R ９ These combine to form condensed, saturated or unsaturated monocyclic or polycyclic carbon rings, in which one or more ring carbon atoms may be independently replaced by N, S, or O. And, Diseases induced by monosodium urate (MSU), Inflammatory kidney disease caused by neutrophils, Cutaneous neutrophilic inflammatory diseases, and immune complex disease Compounds, as well as pharmaceutically acceptable salts, hydrates, and rotational isomers thereof, for use in the treatment or prevention of diseases or disorders selected from the group consisting of the above.

2. R ８ and R ９ The compound for use according to claim 1, wherein at least one of is not hydrogen, and / or hereby X is hydrogen.

3. The aforementioned compound is of formula (XXIa): 【Chemistry 2】 A compound for use according to claim 1 or 2, having the properties of:

4. The compound is of formula (I) or formula (XI): 【Transformation 3】 It has, preferably formula (Ia) or formula (XIa): 【Chemistry 4】 A compound for use according to any one of claims 1 to 3, having [In the formula, R ４ (C) １ -C ６ ) alkyl, (C ３ -C ６ ) Cycloalkyl, (C １ -C ６ ) alkyl-OH, (C １ -C ６ )-alkyl-NR ５ R ６ , trifluoromethyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Thioalkoxy, phenoxy, COR ７ NR ５ R ６ , NHCO (C １ -C ６ ) alkyl, SO ３ H, SO ２ (C １ -C ６ )alkyl and SO ２ NR ５ R ６ Selected from the group consisting of; R ５ and R ６ Each is independently of hydrogen, (C １ -C ６ ) alkyl and (C ３ -C ６ ) Selected from the group consisting of cycloalkyl groups; R ７ These are independently hydroxyl, (C １ -C ６ ) Alkoxy, phenoxy or -NR ５ R ６ And; m is between 0 and 4; A CYCLE is a saturated or unsaturated monocyclic or polycyclic carbon ring in which one or more ring carbon atoms may be independently replaced by N, S, or O.

5. The compounds are (II), (IIIa), (IIIb), (IIIc), and (IIId): 【Transformation 5】 The formula is selected from the group consisting of (IIa), (IIIe), (IIIf), (IIIg), and (IIIh): 【Transformation 6】 A compound for use according to any one of claims 1 to 4, having a formula selected from the group consisting of the following:

6. C １ However, the structure is as follows: 【Transformation 7】 [In the formula, n is an integer selected from 0, 1, 2, or 3.] A compound for use according to any one of claims 1 to 5.

7. C ２ However, the structure is as follows: 【Transformation 8】 [In the formula, o is an integer selected from 0, 1, 2, or 3.] A compound for use according to any one of claims 1 to 6.

8. C ３ However, the structure is as follows: 【Chemistry 9】 [In the formula, p is an integer selected from 0, 1, 2, or 3.] A compound for use according to any one of claims 1 to 7.

9. R ８ However, halogen, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl and C １ -C ４ A compound for use according to any one of claims 1 to 4, 6, 7, or 8, selected from the group consisting of alkoxys; preferably selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl, and methoxy.

10. The compound for use according to any one of claims 1 to 8 is selected from the group consisting of the following: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】

11. The compound for use according to any one of claims 1 to 4, 6, 7, 8, or 9 is selected from the group consisting of the following: 【Chemistry 15】 【Chemistry 16】

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 11, Diseases induced by monosodium urate (MSU), Inflammatory kidney disease caused by neutrophils, Cutaneous neutrophilic inflammatory diseases, and immune complex disease A pharmaceutical composition for use in the treatment or prevention of a disease or disorder selected from the group consisting of the following.

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

14. A compound for use according to any one of claims 1 to 11, or a pharmaceutical composition for use according to claim 12, wherein the disease or disorder is selected from the group consisting of inflammatory kidney diseases caused by neutrophils, including ischemic nephropathy, ischemic-reperfusion kidney injury, and obstructive nephropathy, or the disease or disorder is selected from the group consisting of cutaneous neutrophilic inflammatory diseases, 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.

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

Images