Treatment methods using MPO inhibitors

Abstract

This disclosure relates to a method for identifying subjects likely to respond to treatment with myeloperoxidase (MPO) inhibitors based on neutrophil levels and / or concentrations of at least one protein biomarker. This disclosure further relates to a method for selecting subjects for treatment with MPO inhibitors, a method for predicting whether subjects will respond to treatment with MPO inhibitors, and a method for treating subjects likely to respond to treatment with MPO inhibitors. This disclosure further relates to a method for predicting improved clinical response in subjects with MPO-related disorders after treatment with MPO inhibitors.

Description

[Technical Field]

[0001] This disclosure relates to a method for identifying subjects likely to respond to treatment with myeloperoxidase (MPO) inhibitors based on neutrophil levels and / or the concentration of at least one biomarker selected from the group consisting of CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, STK4, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1. This disclosure further relates to a method for selecting subjects for treatment with MPO inhibitors, a method for predicting whether subjects will respond to treatment with MPO inhibitors, and a method for treating subjects that are likely to respond to treatment with MPO inhibitors. [Background technology]

[0002] Myeloperoxidase (MPO) is a heme-containing enzyme found in neutrophils, granulocytes (neutrophils), and monocytes. MPO is a member of a diverse family of mammalian peroxidases, which also includes eosinophil peroxidase (EPO), thyroid peroxidase (TPO), salivary peroxidase (SPS), lactoperoxidase (LPO), and prostaglandin H synthase (PGHS). The mature enzyme is an identical half-dimer. Each half contains covalently bonded heme, which gives MPO its characteristic green color due to its unusual spectral properties. Cleavage of the disulfide bridge linking the two halves of MPO yields a hemienzyme that exhibits spectral and catalytic properties indistinguishable from those of the intact enzyme. This enzyme is activated by hydrogen peroxide, which can be superoxide anions derived from NADPH via superoxide dismutase (SOD) catalysts, superoxide anions derived from xanthine oxidase, and hydrogen peroxide produced by the oxidation of purines. The main physiological substrates of MPO are halides (e.g., chlorides) and pseudohalides (e.g., thiocyanates), which form bactericidal hypohalous acids, such as hypohalous acid (bleach) and hypothiocyanate (J. Clin. Biochem. Nutr., 2011, 48, 8-19).

[0003] Neutrophils play a crucial bactericidal role by phagocytosis (engulfing) and killing microorganisms. The ingested load is taken up into vacuoles called phagosomes, which fuse with granules containing myeloperoxidase to form phagolysosomes. In phagolysosomes, the enzymatic activity of myeloperoxidase leads to the formation of hypochlorous acid, a potent bactericidal compound (Free Radical Biology & Medicine, 2010, 49, 1834-1845). Hypochlorous acid is itself an oxidizing agent, reacting most strongly with thiols and thioethers, but it also converts amines to chloramines and chlorinates aromatic amino acids.

[0004] MPO can also be released extracellularly, where its reaction with chlorides can induce damage to adjacent tissues. In addition to this regulated release of MPO, neutrophils can further cast webs of decondensed DNA, scattered with intracellular proteins such as MPO, into the extracellular space; these are called neutrophil extracellular traps (NETs). These NETs are thought to play a role in host defense against extracellular microorganisms and are suggested to be an important pathophysiological mechanism in acute inflammatory diseases such as immunothrombosis occurring in sepsis (Nature Rev. Immunol, 2013, 13, 34) and autoimmune diseases such as systemic lupus erythematosus (SLE) (Immunol. 2011, 187, 538-552). In particular, MPO is required for NET formation (Blood, 2011, 117, 953).

[0005] Heart failure (HF) is a major and growing syndrome worldwide, with morbidity and mortality rates remaining high despite recent advances in treatment. The rise in HF is partly explained by the aging population, which has a rising prevalence of chronic conditions such as hypertension, renal failure, diabetes, and metabolic syndrome. Furthermore, improvements in the treatment of ischemic heart disease have led to an increase in the number of surviving HFs. This syndrome encompasses a wide range of patients with symptoms and / or signs caused by structural or functional cardiac abnormalities, with left ventricular (LV) function ranging from maintained ejection fraction (HFpEF), mildly reduced ejection fraction (HFmrEF), or reduced ejection fraction (HFrEF) (McDonagh et al 2022).

[0006] The goal of HF treatment is to improve the patient's clinical condition and functional capacity, and to prevent hospitalization and death. Pharmacological treatment recommendations for HFrEF consist of four main classes of drugs: ARBs / ACE inhibitors / ARNIs, beta-blockers, MRAs, and SGLT2 inhibitors. For patients with HFpEF, diagnosis and treatment of comorbidities and the use of diuretics are recommended (McDonagh et al 2022). For patients with HFmrEF and HFpEF, treatments that improve morbidity and mortality are more limited. However, SGLT2 inhibitors have recently been shown to reduce CV death and HF hospitalization in these patients as well (Vaduganathan et al 2022). [Overview of the project]

[0007] The inventors attempted to stratify patients who respond well to treatment with MPO inhibitors.

[0008] Accordingly, this specification provides a method for selecting subjects having myeloperoxidase (MPO)-related disorders for treatment with an MPO inhibitor, comprising: (i) determining the neutrophil level in a blood sample from the subject and selecting the subject for treatment if the neutrophil level is elevated compared to the control neutrophil level; and / or (ii) selecting (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, in a plasma or serum sample from the subject. A method is provided which includes determining the concentration of at least one biomarker selected from the group consisting of HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1, and selecting a subject for treatment if the concentration of at least one biomarker is increased compared to its concentration in a reference sample or reference population.

[0009] This specification provides a method for predicting whether a subject with MPO-related disorder is likely to respond to treatment with an MPO inhibitor, comprising: (i) determining the neutrophil level in a blood sample from the subject and selecting the subject for treatment if the neutrophil level is elevated compared to the control neutrophil level; and / or (ii) determining the presence of (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP in a plasma or serum sample from the subject. A method is provided comprising: 27. Determining the concentration of at least one biomarker selected from the group consisting of IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1, wherein if the concentration of at least one biomarker is increased compared to its concentration in a reference sample or reference population, the subject may respond to treatment with an MPO inhibitor.

[0010] This specification provides a method for identifying subjects with MPO-related disorders who are likely to respond to treatment with an MPO inhibitor, comprising: (i) obtaining a blood sample from the subject and determining the neutrophil level in the blood sample, wherein if the neutrophil level is elevated compared to the control neutrophil level, the subject is likely to respond to treatment with an MPO inhibitor; and / or (ii) obtaining a plasma or serum sample from the subject, and (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dk A method is provided which includes determining the concentration of at least one biomarker selected from the group consisting of k1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 in the plasma or serum sample, wherein if the concentration of at least one biomarker is increased compared to its concentration in a reference sample or reference population, the subject is likely to respond to treatment with an MPO inhibitor.

[0011] This specification indicates that (i) neutrophil levels in a blood sample are higher than control neutrophil levels, and / or (ii) (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, A method is provided for treating or preventing MPO-related disorders in subjects in whom the concentration of at least one biomarker selected from the group consisting of PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b)OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 is shown to be elevated compared to the concentration of at least one biomarker in a reference sample or reference population, the method comprising administering an MPO inhibitor to the subject.

[0012] This specification provides a method for treating or preventing MPO-related disorders in a subject, comprising: (i) determining the neutrophil level in a blood sample from the subject, and / or (ii) determining the levels of (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MM in a plasma or serum sample from the subject. A method is provided comprising determining the concentration of at least one biomarker selected from the group consisting of P1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1, and administering an MPO inhibitor to subjects having a neutrophil level higher than the control neutrophil level and / or an increased concentration of at least one biomarker compared to its concentration in a reference sample or reference population.

[0013] This specification provides a method for treating or preventing MPO-related disorders in a subject, comprising administering an MPO inhibitor to the subject, wherein the subject (i) has a higher neutrophil level in a blood sample compared to a control neutrophil level, and / or (ii) has a higher concentration in a plasma or serum sample of at least one biomarker (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5 A method is provided in which treatment with an MPO inhibitor is selected based on the presence of high concentrations of at least one biomarker selected from the group consisting of (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1.

[0014] A method for identifying and treating subjects suitable for the treatment of MPO-related disorders, a) Obtaining blood samples and / or plasma or serum samples from the subject, b) Measuring neutrophil levels in a blood sample and / or the concentration of at least one biomarker selected from the group consisting of (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 in a plasma or serum sample. c) If the neutrophil level in the blood sample is elevated compared to the control neutrophil level, and / or (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, If the concentration of at least one biomarker selected from the group consisting of OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 is increased compared to the concentration of at least one biomarker in the reference sample or reference population, the subject is identified as suitable for treatment of MPO-related disorders, and d) A method is provided which includes administering an effective amount of an MPO inhibitor to the target.

[0015] This specification provides a method for predicting improved clinical response in subjects with MPO-related disorders after treatment with an MPO inhibitor, wherein a decrease in the concentration of at least one biomarker selected from the group consisting of CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4 after treatment with an MPO inhibitor is provided.

[0016] In this specification, (i) neutrophil levels in a blood sample are higher than control neutrophil levels, and / or (ii) the concentration of at least one biomarker in a plasma or serum sample is higher than that of (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, I MPO inhibitors are provided for use in methods of treating or preventing MPO-related disorders in subjects with elevated concentrations of at least one biomarker selected from the group consisting of L-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1.

[0017] In this specification, (i) a high neutrophil level in a blood sample compared to a control neutrophil level, and / or (ii) a high concentration of at least one biomarker in a plasma or serum sample compared to the concentration of (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, The use of MPO inhibitors in the manufacture of pharmaceuticals for treating or preventing MPO-related disorders in subjects with high concentrations of at least one biomarker selected from the group consisting of IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 is provided.

[0018] This specification provides for MPO inhibitors for use in methods of treating or preventing MPO-related disorders in subjects, wherein the method is: (i) Determine the neutrophil level in the blood sample from the subject, and if the neutrophil level is higher than the control neutrophil level, administer an MPO inhibitor to the subject, and / or (ii) Provided is an MPO inhibitor comprising determining the concentration of at least one biomarker selected from the group consisting of (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 in a plasma or serum sample from the subject, and administering an MPO inhibitor to the subject if the concentration of at least one biomarker is increased compared to its concentration in a reference sample or reference population.

[0019] This specification provides MPO inhibitors for use in methods to treat or prevent MPO-related disorders, the method being (i) neutrophil levels in a blood sample are higher than control neutrophil levels, and / or (ii) (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, I The method involves administering an MPO inhibitor to subjects whose concentration of at least one biomarker selected from the group consisting of L8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 is elevated in a tissue sample compared to the concentration of at least one biomarker in a reference sample or reference population.

[0020] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be selected from the group consisting of CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4.

[0021] In any aspect described above or throughout this specification, or in any disclosure, at least one biomarker may be selected from the group consisting of ANGPT1, CXCL11, CXCL5, Dkk1, IL7, OSM, PDFFA, and PDFFB.

[0022] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be selected from the group consisting of CXCL11, HBEGF, AXIN1, CXCL10, CCL4, CD40L, NEMO, and ITGB1BP2.

[0023] In any aspect described above or throughout this specification, or in any disclosure, at least one biomarker may be CXCL11.

[0024] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be HGF.

[0025] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be 4EBP1.

[0026] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be ACE2.

[0027] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be ANGPT1.

[0028] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be AXIN1.

[0029] In any aspect described above or throughout this specification, or in any disclosure, at least one biomarker may be CASP3.

[0030] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be CCL17.

[0031] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be CCL3.

[0032] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be CCL4.

[0033] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be CD40L.

[0034] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be CST5.

[0035] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be CXCL1.

[0036] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be CXCL10.

[0037] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be CXCL5.

[0038] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be CXCL6.

[0039] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be Dkk1.

[0040] In any aspect described above or throughout this specification, or in any disclosure, at least one biomarker may be HBEGF.

[0041] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be HSP27.

[0042] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be IFNγ.

[0043] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be IL-1Ra.

[0044] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be IL7.

[0045] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be IL8.

[0046] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be ITGB1BP2.

[0047] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be MCP3.

[0048] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be MMP1.

[0049] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be NEMO.

[0050] In any aspect described above or throughout this specification, or in any disclosure, at least one biomarker may be OSM.

[0051] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be PDGF-A.

[0052] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be PDGF-B.

[0053] In any aspect described above or throughout this specification, or in any disclosure, at least one biomarker may be PTX3.

[0054] In any aspect described above or throughout this specification, or in any disclosure, at least one biomarker may be SIRT2.

[0055] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be SRC.

[0056] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be STAMBP.

[0057] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be STK4.

[0058] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be LOX1.

[0059] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be MMP9.

[0060] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be CEACAM8.

[0061] In any aspect or disclosure described above or throughout this specification, at least one biomarker may be MPO.

[0062] In any aspect described above or throughout this specification, or in any disclosure, at least one biomarker may be PGLYRP1.

[0063] In any aspect described above or throughout this specification, or in any disclosure, at least one biomarker may be AZU1.

[0064] This specification provides a method for selecting a subject having myeloperoxidase (MPO)-related disorder for treatment with an MPO inhibitor, comprising: determining the neutrophil level in a blood sample from the subject; and selecting the subject for treatment if the neutrophil level is elevated compared to a control neutrophil level.

[0065] This specification provides a method for predicting whether a subject with MPO-related disorder is likely to respond to treatment with an MPO inhibitor, comprising: determining the neutrophil level in a blood sample from the subject; and selecting the subject for treatment if the neutrophil level is elevated compared to a control neutrophil level.

[0066] A method for identifying subjects with MPO-related disorders who are likely to respond to treatment with an MPO inhibitor is provided herein, comprising obtaining a blood sample from the subject and determining the neutrophil level in the blood sample, wherein if the neutrophil level is elevated compared to the control neutrophil level, the subject is likely to respond to treatment with an MPO inhibitor.

[0067] This specification provides a method for treating or preventing MPO-related disorders in subjects in whom neutrophil levels in a blood sample are shown to be higher than control neutrophil levels, the method comprising administering an MPO inhibitor to the subject.

[0068] This specification provides a method for treating or preventing MPO-related disorders in a subject, comprising determining the neutrophil level in a blood sample from the subject and administering an MPO inhibitor to the subject having a neutrophil level higher than that of a control.

[0069] This specification provides a method for treating or preventing MPO-related disorders in a subject, comprising administering an MPO inhibitor to the subject, wherein the subject is selected for treatment with the MPO inhibitor based on exhibiting higher neutrophil levels in a blood sample compared to control neutrophil levels.

[0070] A method for identifying and treating subjects suitable for the treatment of MPO-related disorders, a) Obtaining a blood sample from the subject, b) Measuring neutrophil levels in blood samples, c) Identifying a subject as suitable for treatment of MPO-related disorder if neutrophil levels in a blood sample are elevated compared to control neutrophil levels, and d) A method is provided which includes administering an effective amount of an MPO inhibitor to the target.

[0071] This specification provides MPO inhibitors for use in methods of treating or preventing MPO-related disorders in subjects with elevated neutrophil levels in blood samples compared to control neutrophil levels.

[0072] This specification provides for the use of MPO inhibitors in the manufacture of pharmaceuticals for treating or preventing MPO-related disorders in subjects with elevated neutrophil levels in blood samples compared to control neutrophil levels.

[0073] This specification provides an MPO inhibitor for use in a method for treating or preventing MPO-related disorders in a subject, the method comprising determining the neutrophil level in a blood sample from the subject, and administering an MPO inhibitor to the subject if the neutrophil level is higher than the control neutrophil level.

[0074] This specification provides an MPO inhibitor for use in methods of treating or preventing MPO-related disorders, comprising administering the MPO inhibitor to a subject in whom the neutrophil level in a blood sample is higher than the control neutrophil level.

[0075] In any of the above embodiments or disclosures, the method may relate to treating MPO-related disorders.

[0076] In some examples of the embodiments or disclosures described above or herein, the MPO-related disorder may be heart failure (e.g., heart failure with reduced ejection fraction or heart failure with maintained ejection fraction), myocardial infarction, coronary artery disease (CAD), peripheral artery disease, AAA, or stroke. For example, the MPO-related disorder may be heart failure with reduced ejection fraction (HFrEF), heart failure with mildly reduced ejection fraction (HFmrEF), or heart failure with maintained ejection fraction (HFpEF). In such cases, treatment may result in improvement from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and / or improvement from baseline in the 6-minute walk distance (6MWD).

[0077] In some examples of the embodiments or disclosures described above or herein, the MPO inhibitor may be mitipelstat.

[0078] In some of the embodiments or disclosures described above or herein, the neutrophil level is absolute neutrophil count (ANC), and the control neutrophil level is a reference ANC value of approximately 4 million cells / mL. [Brief explanation of the drawing]

[0079] [Figure 1] This study presents neutrophil-related risks in patients with heart failure from the UK Biobank. Heart failure is defined by the ICD-10 codes for dilated cardiomyopathy, heart failure, or ischemic heart disease. The risk of all-cause death (A) or cardiovascular death (B) was determined by univariate Cox regression, using a subgroup with 1 million / mL neutrophils in vials and a reference group with 2-3 million neutrophils / mL. [Figure 2] This study presents neutrophil-to-lymphocyte ratio (NLR)-related risks in patients with heart failure from the UK Biobank. Heart failure is defined by the ICD-10 codes for dilated cardiomyopathy, heart failure, or ischemic heart disease. The risk of all-cause death (A) or cardiovascular death (B) was determined by univariate Cox regression, using a subgroup with one NLR bin and a reference group with one to two NLRs. [Figure 3]The Endeavor study design is shown (Phase 2b portion). a) Participants to complete at home with the provided tablets for 3 consecutive days at weeks 1 and 15 of the study. b) If not possible on the same day as the screening visit, within 1-2 days for screening or within 7 days for a follow-up visit. 6MWT (6-minute walk test) echocardiogram; EoS, end of study; HF, heart failure; hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; KCCQ-TSS, Kansas City Cardiomyopathy Questionnaire - total summary score; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B natriuretic peptide. [Figure 4-1] The SATELLITE study (NCT03756285) shows the baseline-adjusted 90-day efficacy of mitipelstat compared to placebo, stratified at randomization by absolute neutrophil count >4*10⁶ / mL (=Category 1) or <= (=Category 0). Panel A shows NT-proBNP levels, Panel B shows 6-minute walk distance, and Panel C shows Kansas City Cardiomyopathy Questionnaire - Total Symptom Score. [Figure 4-2] The SATELLITE study (NCT03756285) shows the baseline-adjusted 90-day efficacy of mitipelstat compared to placebo, stratified at randomization by absolute neutrophil count >4*10⁶ / mL (=Category 1) or <= (=Category 0). Panel A shows NT-proBNP levels, Panel B shows 6-minute walk distance, and Panel C shows Kansas City Cardiomyopathy Questionnaire - Total Symptom Score. [Figure 4-3] The SATELLITE study (NCT03756285) shows the baseline-adjusted 90-day efficacy of mitipelstat compared to placebo, stratified at randomization by absolute neutrophil count >4*10⁶ / mL (=Category 1) or <= (=Category 0). Panel A shows NT-proBNP levels, Panel B shows 6-minute walk distance, and Panel C shows Kansas City Cardiomyopathy Questionnaire - Total Symptom Score. [Figure 5]This shows the correlation between baseline absolute neutrophil count and total white blood cell count (A) and NLR (B) in two HFpEF cohorts, PROMIS-HfpEF (Shah et al., 2018) and Endeavor (NCT04986202). Each participant is represented by a symbol, and the lines represent straight lines that fit the following equations: "Neutrophils = 0.78 * Total White Blood Cells - 0.8" and "NLR = 0.57 * Neutrophils + 0.5". In A, the horizontal and vertical dotted lines represent 4 * 10⁶ / mL neutrophils and 6.2 * 10⁶ / mL white blood cells, respectively, and in B, they represent 4 * 10⁶ / mL neutrophils and NLR = 2.8, respectively. [Figure 6] This figure shows the baseline characteristics of Endeavor participants stratified by neutrophil count >4 million / mL. In Endeavor, discriminant analysis (OPLS-DA, umetrics.com) was performed on baseline patient characteristics to show how characteristics relate to the neutrophil layer (> or <= 4) and which characteristics map orthogonally to such comparisons. The X-axis (predictive component) in Figure A shows how different characteristics (each symbol) contribute to distinguishing between two groups (higher values ​​along the X-axis indicate better specificity), and the Y-axis (orthogonal component) shows how much variation is unrelated to the group to which one belongs. Key characteristic abbreviations are highlighted (BMI, Body Mass Index; eGFR, Estimated Glomerular Filtration Rate; CrCl, Creatinine Clearance; KCCQ, Quality of Life Score; MCV, Mean Somatic Cell Volume; RBC, Red Blood Cells; Tfsat, Transferrin Saturation; T2D, Type 2 Diabetes; 6MWD, Walking Distance 6 mins). Figure B shows how the 699 participants (all available at the time of analysis) are distributed along these components according to their characteristics. Each symbol (actual neutrophil count size) represents a participant, and darker symbols represent the high neutrophil clustering on the left side of the figure. [Figure 7]A volcano plot showing baseline-adjusted changes in Olink biomarkers at 16 weeks in the Endeavor trial is shown. The Cardiovascular III panel, representing 266 unique Olink-targeted inflammation;Cardiovascular II; and 266 distinctive biomarkers, was applied to baseline and 16-week samples in the Endeavor trial in a preliminary analysis representing paired data from approximately one-third of the cohort of 711 participants. Panel A shows the effect across all participants, while in Panels B and C, the cohort is stratified by baseline neutrophil counts greater than 4 million / mL (Stage 1, Panel B) or less than 4 million / mL (Stage 2, Panel C). Compared to placebo-treated participants, the following 35 biomarkers were significantly reduced (unadjusted p-value < 0.05) in all participants with mitipelstat: 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL11, CXCL5, CXCL6, Dkk1, HBEGF, HGF, HSP27, IFNγ, IL1ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4. [Figure 8]This figure shows the association between the 16-week effects of mitipelstat on biomarkers, function, and symptoms in Endeavor. The figure shows how placebo-adjusted decreases (X-axis) or increases (Y-axis) in 37 biomarkers (listed in Figure 7) are associated with placebo-adjusted changes in A symptoms (KCCQ-TSS) and B function (6MWD). Thus, the lower right quadrant represents placebo-adjusted, baseline-adjusted changes in biomarkers associated with symptom and function changes, resulting in improvement being associated with a decrease in the indicated biomarkers and worsening being associated with an increase in the indicated biomarkers. C is a Venn diagram showing the overlap of eight biomarkers (ANGPT1, CXCL11, CXCL5, Dkk1, IL-7, OSM, PDGF-A, PDGF-B) in the lower right quadrants of panels A and B, namely, their decreases were associated with placebo-adjusted improvement, and their increases were associated with worsening of KCCQ-TSS and 6MWD. The data represents participants for whom Olink data was available for the interim analysis (approximately one-third of the cohort). [Figure 9] This figure shows the association between the 16-week effect of mitipelstat for CXCL11 and the primary endpoint in Endeavor. A subcohort (one-third of the cohort), represented by Olink data, was stratified for participants with 16-week decrease versus increase in CXCL11. The figure shows the change from baseline (CFB) in mitipelstat treatment (A) and placebo treatment (P) in 6MWD (A) and KCCQ-TSS (B). Boxes and whiskers represent Q1-Q3 and maximum / minimum, and the distribution of participants is indicated by a single symbol. Statistics were calculated using the Mann-Whitney U trial. [Figure 10]This figure shows the association between the 16-week effect of mitipelstat on HGF and the primary endpoint in Endeavor. A subcohort (one-third of the cohort) represented by Olink data was stratified for participants with 16-week decrease versus increase in HGF. The figure shows the change from baseline (CFB) in mitipelstat treatment (A) and placebo treatment (P) in 6MWD (A) and KCCQ-TSS (B). Boxes and whiskers represent Q1-Q3 and maximum / minimum, and the distribution of participants is indicated by a single symbol. Statistics were calculated using the Mann-Whitney U trial. [Figure 11] This shows the interaction between the 16-week Olink biomarker effect and baseline neutrophil count in Endeavor. Individual plots show the 10 biomarkers with the greatest effect compared to placebo in the subpopulation (approximately one-third of the cohort) analyzed for these biomarkers. Thin lines and shaded areas represent linear regressions of the change from baseline in neutrophil count and biomarkers between participants treated with mitipelstat (A) or placebo (P). Thick lines represent the corresponding regressions using spline analysis. Dashed arrows and numbers indicate where the confidence intervals for the active and placebo groups diverge, thus approximating the cut-off point of efficacy for the biomarkers. [Modes for carrying out the invention]

[0080] Hereinafter, embodiments and models disclosed herein will be described with reference to the accompanying drawings. Further embodiments and models will be apparent to those skilled in the art. All references used herein are incorporated herein by reference.

[0081] This disclosure relates to a method for identifying subjects more likely to respond to treatment with an MPO inhibitor based on their neutrophil levels and / or the concentration of at least one biomarker selected from the group consisting of (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1. Identifying patients with elevated neutrophil counts represents a patient enrichment strategy, i.e., the identification of patients who are more likely to respond to treatment. This disclosure further relates to methods for selecting subjects for treatment with MPO inhibitors, methods for predicting whether subjects will respond to treatment with MPO inhibitors, and methods for treating subjects who are likely to respond to treatment with MPO inhibitors.

[0082] subject This disclosure relates to identifying subjects with MPO-related disorders as likely to respond to treatment with MPO inhibitors, and / or treating such subjects with MPO inhibitors. MPO-related disorders are described in more detail below. Subjects may be mammals, and in certain embodiments, human subjects.

[0083] MPO-related disorders MPO-related diseases are conditions in which regulation of the enzyme myeloperoxidase (MPO) activity is desirable. In particular, the association between MPO activity and disease has been suggested to be involved in many diseases, including diseases with inflammatory, cardiovascular, respiratory, renal, metabolic, hepatic, and / or neurological components, as well as neutrophil-driven diseases.

[0084] This disclosure may be used for the treatment or prevention of MPO-related disorders involving cardiovascular components. Such disorders (e.g., diseases or conditions) include, but are not limited to, heart failure (e.g., heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with maintained ejection fraction), acute coronary syndrome, myocardial infarction, coronary artery disease (CAD), peripheral artery disease, arrhythmias, cardiomyopathy, dilated and hypertrophic cardiomyopathy, idiopathic dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy / dysplasia (ARVC / D), stress-induced cardiomyopathy, unclassifiable cardiomyopathy, left ventricular uncompressible, valvular heart disease, hypertension, pulmonary hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm (AAA), chemotherapy-induced cardiotoxicity, or stroke. For example, this disclosure may be used in the treatment or prevention of heart failure (e.g., heart failure with reduced ejection fraction or heart failure with maintained ejection fraction), myocardial infarction, coronary artery disease (CAD), peripheral artery disease, AAA, or stroke. For example, MPO-related disorders may be heart failure with reduced ejection fraction (HFrEF), heart failure with mildly reduced ejection fraction (HFmrEF), or heart failure with maintained ejection fraction (HFpEF). In HFrEF, the left ventricular ejection fraction (LVEF) is less than 40%. In HFmrEF, the LVEF is 40-50%. In HFpEF, the LVEF is greater than 50%. The LVEF is calculated by subtracting the end-systolic LV volume from the end-diastolic left ventricular (LV) volume and dividing it by the end-diastolic LV volume. LVEF can be measured by non-invasive methods such as echocardiography, magnetic resonance imaging (MRI), computed tomography (CT), gated equilibrium radionuclide angiography (commonly called multi-gate acquisition [MUGA] scan), and gated myocardial perfusion imaging using either single-photon emission computed tomography (SPECT) or positron emission tomography (PET).

[0085] The disclosed compounds are indicated for use in the treatment or prevention of cardiovascular disease or cardiovascular conditions in mammals, including humans, in response to inhibition of MPO. Such cardiovascular diseases or conditions include coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmias, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, rupture of atherosclerotic plaque, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolongation of the time to recurrence of atrial fibrillation / flutter after electrodefibrillation / prevention of recurrence, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), cessation and / or regression of atherosclerosis, COVID-19 (or SARS) This includes, but is not limited to, CoV2-induced heart failure, COVID-19 (or SARS-CoV2)-induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF), renal crossover, first or recurrent myocardial infarction, peripheral artery disease, restrictive cardiomyopathy, unclassifiable cardiomyopathy, inhibition of plaque rupture, improvement of inflammation associated with plaque rupture, secondary myocardial infarction, ST-elevation myocardial infarction and / or non-ST-elevation myocardial infarction.

[0086] This disclosure may be used for the treatment or prevention of MPO-related disorders having an inflammatory component. Such diseases or conditions include chronic kidney disease (CKD), acute kidney injury (AKI), glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, fatty liver, hepatic fibrosis, gout, sickle cell anemia, cystic fibrosis, vasculitis, and anti-neutrophilic cytoplasmic autoantibodies (ANCA). Examples of conditions that may be treated include, but are not limited to, autoantibody-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein denaturation, and type 2 diabetes. For example, the present invention can be used to treat or prevent COPD, NASH, MASH (metabolic-associated steatohepatitis), or CKD.

[0087] The disclosed compounds are indicated for use in the treatment or prevention of inflammatory diseases or conditions, or diseases or conditions involving inflammatory elements, in mammals, including humans, that respond to inhibition of MPO. Such diseases or conditions include autoimmune diseases, chronic kidney disease (CKD), acute kidney injury (AKI), glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, fatty liver, hepatic fibrosis, gout, sickle cell anemia, cystic fibrosis, vasculitis, and anti-neutrophilic cytoplasmic autoantibodies (ANCA). This includes, but is not limited to, autoantibody-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein denaturation, type 2 diabetes, bronchiectasis, COVID-19 (or SARS-CoV-2) induced renal failure, diabetic kidney disease (DKD), endometriosis, end-stage kidney disease (ESKD), immunoglobulin A vasculitis (Henoch-Schönlein purpura), immunoglobulin A nephropathy (IgAN), lupus nephritis, diabetic CKD, hypertensive CKD, and / or obesity with CKD.

[0088] In some cases, the disclosed compounds are also suitable for use in the treatment or prevention of COPD.

[0089] In some cases, the disclosed compounds are also suitable for use in the treatment or prevention of bronchiectasis.

[0090] The disclosed compounds are further indicated for use in the treatment or prevention of neurological diseases and neurological conditions in mammals, including humans, in response to MPO inhibition. Such diseases and conditions include, but are not limited to, diseases with neuroinflammatory responses. These diseases and conditions include, but are not limited to, Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis (MS), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), epilepsy, acute ischemic stroke and / or subarachnoid hemorrhage.

[0091] The disclosed compounds are further indicated for use in the treatment or prevention of neutrophil-dominant diseases or conditions in mammals, including humans. Such diseases and conditions include, but are not limited to, chronic sinusitis, chronic sinusitis with nasal polyps (CRSwNP), neutrophilic asthma, idiopathic pulmonary fibrosis (IPF), neutrophilic lung disease, and acute respiratory distress syndrome (ARDS).

[0092] The disclosed compounds are indicated for use in the treatment of cancer.

[0093] To avoid misunderstanding, as used herein, the term “treatment” includes treatment for therapeutic purposes and / or treatment for preventive purposes. In some cases, “treatment” may refer only to therapeutic treatment.

[0094] Prevention is expected to be particularly relevant to the treatment of patients who have previously experienced the disease or condition in question, or who are otherwise considered to be at increased risk of developing the disease or condition. Patients at risk of developing a particular disease or condition generally include those with a family history of the disease or condition, those identified by genetic testing or screening, or those identified as particularly susceptible to the disease or condition based on specific biomarker patterns.

[0095] MPO inhibitors An MPO inhibitor for use as described herein may be any compound that inhibits the activity of MPO. Non-limiting examples of such MPO inhibitors are provided below. Further examples of MPO inhibitors are provided in International Publication No. 2016 / 087338, as shown below.

[0096] For example, an MPO inhibitor may be a compound having formula (I), or a pharmaceutically acceptable salt thereof.

[0097] [ka] In the formula, R 1 represents H, F, Cl, or CF3.

[0098] In further embodiments, R 1 represents Cl.

[0099] In one embodiment, R 2 This represents H, CH3, or C2H5.

[0100] R 2 This can represent CH3 or C2H5.

[0101] R 2 This can represent CH3.

[0102] R 3may represent H, CH3, C2H5, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl or cyclopentyl.

[0103] R 3 may represent H.

[0104] R 2 The carbon atom to which R is attached 2 may have the R-configuration when R represents CH3 or C2H5.

[0105] The MPO inhibitor is 1-{2-[(1R)-1-aminopropyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; 1-[2-(1-aminoethyl)-4-chlorobenzyl]-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; 1-{2-[(1R)-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; 1-{2-[(1S)-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; 1-{4-chloro-2-[1-(methylamino)ethyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; 1-{4-chloro-2-[(ethylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; 1-[2-(aminomethyl)-4-chlorobenzyl]-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one; 1-{4-chloro-2-[(methylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-(2-{[(cyclobutylmethyl)amino]methyl}benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(cyclobutylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(cyclopentylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-(2-{[(2-methylpropyl)amino]methyl}benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(propan-2-ylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-[2-(aminomethyl)-4-(trifluoromethyl)benzyl]-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(methylamino)methyl]-4-(trifluoromethyl)benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; and They can be selected from those pharmaceutically acceptable salts.

[0106] In certain embodiments, the MPO inhibitor is mitipelstat (1-{2-[1R-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolyl[3,2-d]pyrimidine-4-one) as shown below.

[0107] [ka]

[0108] Further examples of MPO inhibitors can be found in U.S. Provisional Application No. 63 / 398,939, filed on August 18, 2022. These MPO inhibitors are listed below.

[0109] MPO inhibitors are given by formula (II)

[0110] [ka] It may be a compound having, During the ceremony, X=CH or N Y 1 =CZ 1 Or N, Y 2 =CZ 2 Or N, Y 3 =CZ 3 Or N, Y 4 =CZ 4 Or N and Y 5 =CZ 5 Or it is N, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 If present, these are independently H, Halo, CF3, Q, or T. However, Y 1 , Y 2 , Y 3 , Y 4 Or Y 5 One or less of these is N, and Y 1 , Y 2 , Y 3 , Y 4 Or Y 5 At least two of them are CH and Z 1 , Z 2 , Z 3 , Z 4 and Z 5 One or fewer of these are Halo or CF3 and 1, Z 1 , Z 2 , Z 3 , Z 4 and Z5 Only one of them is either Q or T. Q is

[0111] [ka] In the formula, m is 0, 1, 2, or 3. T is

[0112] [ka] And, p is either 0 or 1, s is 0, 1, or 2. n is 0, 1, or 2. A is CH2, CF2, CHF, CHR 2 , CFR 2 , NR 3 Or it is O, During the ceremony, R 1 and R 2 If present, these are independently CH2F, CHF2, or CF3. R 3 If present, it is independently H or CH3. or any stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0113] The term "halo" means fluoro, chloro, bromine, or iodine. In some examples, "halo" may be fluoro or chloro in any of the relevant MPO inhibitors disclosed herein.

[0114] MPO inhibitors have a structure:

[0115] [ka] A compound having, or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, where X, Y 1 , Y 2 , Y3 , Y 4 、 A, R 1 n, p, and s are defined above for equation (II).

[0116] MPO inhibitors are compounds:

[0117] [ka] A compound having, or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, where X, Y 1 , Y 2 , Y 3 , Y 4 、 A, R 1 n, p, and s are defined above for equation (II).

[0118] MPO inhibitors have a structure:

[0119] [ka] A compound having, or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, where X, Y 1 , Y 2 , Y 3 , Y 4 、 A, R 1 n, p, and s are defined above for equation (II).

[0120] MPO inhibitors may be compounds of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or pharmaceutically acceptable salts thereof, Y 1 is N, and Y 2 , Y 3 , and Y 4 It is CH.

[0121] MPO inhibitors may be compounds of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or pharmaceutically acceptable salts thereof, Y2 is N, and Y 1 , Y 3 , and Y 4 It is CH.

[0122] MPO inhibitors may be compounds of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or pharmaceutically acceptable salts thereof, Y 3 is N, and Y 1 , Y 2 , and Y 4 It is CH.

[0123] MPO inhibitors may be compounds of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or pharmaceutically acceptable salts thereof, Y 4 is N, and Y 1 , Y 2 , and Y 3 It is CH.

[0124] The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where n is 0.

[0125] The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where n is 1.

[0126] The MPO inhibitor may be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where n is 2.

[0127] MPO inhibitors may be compounds of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or pharmaceutically acceptable salts thereof, where A is NR 3 That is the case.

[0128] The MPO inhibitor can be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where A is NR 3 and R 3 is CH 3 .

[0129] The MPO inhibitor can be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where A is NR 3 and R 3 is H. [[ID=1​​​​​​​​​​​​​​​​​​​​​​​​​​​The MPO inhibitor can be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CHR 2 and R 2 is CH2F.

[0136] The MPO inhibitor can be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CHR 2 and R 2 is CHF2.

[0137] The MPO inhibitor can be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein A is CHR 2 and R 2 is CF3.

[0138] The MPO inhibitor can be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and s is 0.

[0139] The MPO inhibitor can be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and s is 1.

[0140] The MPO inhibitor can be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and s is 2.

[0141] The MPO inhibitor can be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and p is 0.

[0142] The MPO inhibitor can be a compound of formula (II), formula (III), or formula (IV), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and p is 1.

[0143] MPO inhibitors may be compounds of formula (II), any stereoisomer thereof, or pharmaceutically acceptable salts, Y 5 That is CZ5, Z 5 It is either T or Q.

[0144] MPO inhibitors may be compounds of formula (II), any stereoisomer thereof, or pharmaceutically acceptable salts thereof, Y 5 CZ 5 And Z 5 It is T.

[0145] MPO inhibitors may be compounds of formula (II), any stereoisomer thereof, or pharmaceutically acceptable salts thereof, Y 5 CZ 5 And Z 5 is T, and T is

[0146] [ka] That is the case.

[0147] In some cases, p can be 0.

[0148] MPO inhibitors may be compounds of formula (II), any stereoisomer thereof, or pharmaceutically acceptable salts thereof, Y 5 CZ 5 And Z 5 is T or Q, and Y 1 , Y 2 , Y 3 and Y 4 It is CH.

[0149] In some cases, Z 5 It can be T.

[0150] In some cases, T is

[0151] [ka] It is possible.

[0152] In some cases, p can be 0.

[0153] An MPO inhibitor may be a compound of formula (II), any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where Y 5 CZ 5 And Z 5 is T or Q, and Y 1 , Y 2 , Y 3 and Y 4 One of them is N.

[0154] An MPO inhibitor may be a compound of formula (II), any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where Y 5 CZ 5 And Z 5 is T or Q, and Y 1 , Y 2 , Y 3 and Y 4 Two of them are CH, and Y 1 , Y 2 , Y 3 and Y 4 One of them is N, and Y 1 , Y 2 , Y 3 and Y 4 One of them is CCl.

[0155] An MPO inhibitor may be a compound of formula (II), any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where Z 1 and Z 5 These, together with the atoms to which they are bonded, form a 5-membered or 6-membered N-heterocyclic ring. In some examples, Y 2 , Y 3 , and Y 4 It can be CH.

[0156] The term "N-heterocyclic" refers to a partially or fully saturated hydrocarbon ring system, i.e., a non-aromatic system in which at least one of the ring carbon atoms is replaced by nitrogen.

[0157] An MPO inhibitor may be a compound of formula (II), any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where Z 2 and Z 3 These, together with the atoms to which they are bonded, form a 5-membered or 6-membered N-heterocyclic ring. In further embodiments, Y 1 , Y 4 , and Y 5 It is CH.

[0158] An MPO inhibitor may be a compound of formula (II), any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where Y 2 Q is the value of m. In some examples, m=1.

[0159] An MPO inhibitor may be a compound of formula (II), any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where Y 3 Q is the value of m. In some examples, m=1.

[0160] An MPO inhibitor may be a compound of formula (II), any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where Y 4 Q is the value of m. In some examples, m=1.

[0161] An MPO inhibitor may be a compound of formula (II), any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where X is CH.

[0162] An MPO inhibitor may be a compound of formula (II), any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where X is N.

[0163] A compound MPO inhibitor selected from the following, or its stereoisomer or pharmaceutically acceptable salt: 1-(2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(4-chloro-2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(4-chloro-2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(4-chloro-2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(4-chloro-2-(pyrroridine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(4-chloro-2-(pyrroridine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(4-chloro-2-(pyrroridine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(4-chloro-2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(4-chloro-2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(4-chloro-2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 3-(4-chloro-2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purine-6-one, 1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-3-(2-(azepan-2-yl)-4-chlorobenzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, (S)-3-(2-(azepan-2-yl)-4-chlorobenzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, (R)-1-(2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-(4-methylpiperazin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-(2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-(5-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-(4,4-difluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(2-(4,4-difluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(2-(4,4-difluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-3-(2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-3-(2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-3-(2-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, 3-(2-(4,4-difluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purine-6-one, 3-(2-(5-fluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-1-((2-(-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-((2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((cis)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-(2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((trans)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((2S,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-3-(2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-3-(2-((trans)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-3-(2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-3-(2-((2S,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, rac-1-(2-((2R,4S)-4-(difluoromethyl)piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-((2R,4S)-4-(difluoromethyl)piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-((2S,4R)-4-(difluoromethyl)piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-((2-(piperidine-2-yl)pyridine-3-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((cis)-4-(trifluoromethyl)piperidine-2-yl)pyridine-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)pyridine-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((cis)-4-(trifluoromethyl)piperidine-2-yl)pyridine-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)pyridine-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(4-(1-aminocyclobutyl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(3-(1-aminocyclobutyl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-(piperidine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-(morpholine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(2-(Morpholin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, (S)-1-(2-(Morpholin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(2-(Piperidin-4-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, rac-2-Thioxo-1-((2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-Thioxo-1-((2-((trans)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-Thioxo-1-((2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 2-Thioxo-1-((2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, and its pharmaceutically acceptable salts.

[0164] The MPO inhibitor can be a compound having the formula (IIa)

[0165]

Chemical formula

[0166] MPO inhibitors are given by formula (IIb)

[0167] [ka] It may be a compound having, During the ceremony, X 1 =CH or N, each X 2 These are independently CH, CF, or CCl, r and q are 0, 1, or 2, provided that r+q=2 or 3. or any stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0168] MPO inhibitors may be compounds having formula (IIa) or (IIb), any stereoisomer thereof, or pharmaceutically acceptable salts thereof, where each X 2 It is CH.

[0169] An MPO inhibitor may be a compound having formula (IIa) or (IIb), any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where r is 1 and q is 1.

[0170] An MPO inhibitor may be a compound having formula (IIa) or (IIb), any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where r is 1 and q is 2, or r is 2 and q is 1.

[0171] An MPO inhibitor may be a compound having formula (IIa) or (IIb), any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, where r is 0 and q is 2, or r is 2 and q is 0.

[0172] The MPO inhibitor can be a compound having formula (IIa) or (IIb), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 is CH.

[0173] The MPO inhibitor can be a compound having formula (IIa) or (IIb), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 is N.

[0174] The MPO inhibitor can be a compound selected from the following: 1-((1,2,3,4-Tetrahydroisoquinolin-8-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(Isoindolin-5-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, 1-(Isoindolin-4-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, and any stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0175] The MPO inhibitor has the structure:

[0176]

Chemical formula

[0177] The MPO inhibitor has the structure:

[0178]

Chemical formula

[0179] MPO inhibitors have a structure:

[0180] [ka] It may be a compound having, in the formula, Y 1 , Y 2 , Y 3 , Y 4 , A, R 1 n, p, and s are defined above for equation (IV).

[0181] When an MPO inhibitor or salt thereof described herein is administered as a therapeutic treatment for a disorder, it is administered in a “therapeutic effective dose,” which is an amount sufficient to reduce or completely alleviate the symptoms or other adverse effects of the disorder, to cure the disorder, to reverse, completely halt or slow the progression of the disorder, or to reduce the risk of the disorder worsening.

[0182] The dosage of MPO inhibitors for use as described herein varies depending on the compound used, the mode of administration, and the desired treatment. However, generally, sufficient results are obtained when the compound is administered in solid doses of 1 mg to 2000 mg per day. For example, the MPO inhibitor mitipelstat may be administered once daily at a dose of 2.5 mg or 5 mg. In one embodiment, MPO is administered orally.

[0183] The MPO inhibitors and their pharmaceutically acceptable derivatives as defined herein may be used alone or in the form of a suitable pharmaceutical composition in which the compound or derivative is mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier. Accordingly, MPO inhibitors may be present in pharmaceutical compositions containing an MPO inhibitor or a pharmaceutically acceptable salt thereof mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier. Administration may, but is not limited to, enteral (including oral, sublingual, or rectal), intranasal, inhalation, intravenous, topical, or other parenteral routes. For conventional procedures for selecting and preparing suitable pharmaceutical formulations, see, for example, Pharmaceuticals—The Science of Dosage Form Designs, MEAulton, Churchill Livingstone, 2 nd It is described in ED.2002.

[0184] The MPO inhibitors defined herein may further be administered together with other compounds used to treat MPO-related disorders as defined herein.

[0185] Other compounds that may be used in combination with MPO inhibitors (by simultaneous administration, sequential administration, or in combination) include the following: • Cardiac medications, • Antihypertensive drugs, • Diuretics, • Peripheral vasodilators, • Lipid denaturing drugs, • Antidiabetic drugs, • Anti-inflammatory drugs, or • Anticoagulant.

[0186] Examples of the above include, but are not limited to, digitalis glycosides, antiarrhythmic drugs, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers (e.g., valsartan), endothelin receptor blockers, β-blockers, thiazide diuretics, loop diuretics, cholesterol synthesis inhibitors such as statins (e.g., rosuvastatin), cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, antidiabetic drugs such as insulin and its analogues, GLP-1 analogues, sulfonamides, dipeptidyl peptidase 4 inhibitors, thiazolidinediones, SGLT-2 inhibitors, anti-inflammatory drugs such as NSAIDs and CCR2 antagonists, anticoagulants such as heparin, thrombin inhibitors and factor Xa inhibitors, platelet aggregation inhibitors, P2X7 antagonists, and neprilysin inhibitors (e.g., sacubitril).

[0187] Neutrophil levels As described above, elevated neutrophil counts (e.g., in patients with HFpEF) are associated with an increased tendency for neutrophils to degranulate, cast extracellular traps, and thus release MPO (Bai et al., 2021; Bjornsdottir et al, 2015). In this disclosure, elevated neutrophil levels are used as a patient enrichment strategy, i.e., to identify subjects more likely to respond to treatment with MPO inhibitors.

[0188] The neutrophil level in a subject can be determined by various methods, for example, by determining the subject's (i) absolute neutrophil count (ANC), (ii) neutrophil-to-lymphocyte ratio (NLR), and / or (iii) total white blood cell (WBC) count. Each of the subject's ANC, NLR, and / or WBC count can be determined in a blood sample taken from the subject.

[0189] ANC is the total number of neutrophils in the target white blood cell (WBC) count, and can be calculated by multiplying the total WBC count by the percentage of neutrophils (i.e., neutrophils) and dividing by 100 (see Coates, 2000).

[0190] The ANC of the subject can be determined by routine hematological analysis of the subject's complete blood count using a blood analyzer. Blood analyzers are used to count and identify blood cells quickly and accurately. They perform complete blood counts, including counting red blood cells (RBCs), white blood cells (WBCs), hemoglobin, and platelets, as well as hematocrit levels. Other analyses include: RBC distribution width, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, WBC difference number in percentage and absolute (including ANC), platelet distribution width, mean platelet volume, large platelet cell ratio, and platelet reference. The blood analyzers used for analysis may vary between hospitals depending on the specific manufacturer. Examples of manufacturers include Abbott Diagnostics, Beckman Coulter, Erba Diagnostics, Horiba, Idexx, Siemens, Sysmex, Diagnostica Stago, and Clinical Diagnostics Solutions (CDS).

[0191] NLR is the neutrophil-to-lymphocyte ratio in a blood sample from a subject, and is calculated by dividing the number of neutrophils by the number of lymphocytes in the blood sample. The number of neutrophils and lymphocytes in a blood sample from a subject can be determined by routine hematological analysis of the subject's complete blood count using a blood analyzer as described above.

[0192] Neutrophils are the most abundant type of white blood cell in the blood (i.e., white blood cells), and the neutrophil count correlates well with the total WBC count, so the total WBC count can be used as a surrogate measure of neutrophil levels. Typically, neutrophil count

[0193]

number

[0194] In certain embodiments, a subject is identified as more likely to respond to treatment with an MPO inhibitor if their neutrophil levels in a blood sample are higher than their control neutrophil levels. The control neutrophil level may be the mean or median neutrophil level in a population, for example, the mean or median neutrophil level in a population of the same ethnicity as the subject. For example, the control neutrophil level may be the mean or median neutrophil level in a population of healthy subjects, for example, the mean or median neutrophil level in a population of healthy subjects of the same ethnicity as the subject. The population may be, for example, an adult population or an adolescent population, for example, 12-18 years old.

[0195] When measuring neutrophil levels in a blood sample derived from a subject as ANC, the control neutrophil level is the reference ANC value. The reference ANC value may be the mean or median ANC in a population, for example, the mean or median ANC in a population of the same ethnicity as the subject. For example, the reference ANC value may be the mean or median ANC in a population of healthy subjects, for example, the mean or median ANC in a population of healthy subjects of the same ethnicity as the subject. Mean ANC values ​​in various ethnic populations are shown in Table 1 below. Further median ANC values ​​in various ethnic populations are shown in Table 2 of Lim et al., 2010. The reference ANC value may be 4 million cells / mL ±20%, ±10%, ±5%, ±4%, ±3%, ±2%, or ±1%. The reference ANC value may also be approximately 4 million cells / mL or 4 million cells / mL.

[0196] When measuring neutrophil levels in plasma samples derived from a subject as NLR, the control neutrophil level is the reference NLR value. The reference NLR value may be the mean or median NLR value in a population, for example, the mean or median NLR value in a population of the same ethnicity as the subject. For example, the reference NLR value may be the mean or median NLR value in a population of healthy subjects, for example, the mean or median NLR value in a population of healthy subjects of the same ethnicity as the subject. The reference NLR value may be approximately 2.21 (Table 1, Bai et al., 2010) or approximately 2.3 (based on ANC of 4 million cells / mL; see correlation in Figure 5). The reference NLR value may be 3 ± 20%, ± 10%, ± 5%, ± 4%, ± 3%, ± 2%, or ± 1%. The reference NLR value may be approximately 3 or 3.

[0197] When neutrophil levels in a blood sample derived from a subject are measured as total WBC count, the control neutrophil level is the reference total WBC count. The reference total WBC count may be the mean or median total WBC count in a population, for example, the mean or median total WBC count in a population of the same ethnicity as the subject. For example, the reference total WBC count may be the mean or median total WBC count in a population of healthy subjects, for example, the mean or median total WBC count in a population of healthy subjects of the same ethnicity as the subject. The mean WBC counts in various ethnic populations are shown in Table 1 below. Further median WBCs in various ethnic populations are shown in Table 1 of Lim et al., 2010 and Table 2 of Lim et al., 2015. The reference total WBC count may be 6.25 million cells / mL ±20%, ±10%, ±5%, ±4%, ±3%, ±2%, or ±1%. The reference WBC count may be approximately 6.25 million cells / mL or 6.25 million cells.

[0198] [Table 1] Data obtained from Table 3 of Lim et al., 2010.

[0199] Predictive and predictive response biomarkers In some cases, subjects with MPO-related disorders are identified as more likely to respond to treatment with MPO inhibitors if they have elevated concentrations of biomarkers selected from the group consisting of CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4.

[0200] In some cases, subjects are identified as being more likely to respond to treatment with MPO inhibitors when their CXCL11 levels are elevated.

[0201] In some cases, subjects are identified as being more likely to respond to treatment with MPO inhibitors when HGF levels are elevated.

[0202] In some cases, subjects with elevated 4EBP1 levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0203] In some cases, subjects with elevated ACE2 levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0204] In some cases, subjects with elevated ANGPT1 levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0205] In some cases, subjects with elevated AXIN1 levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0206] In some cases, subjects with elevated CASP3 levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0207] In some cases, subjects are identified as being more likely to respond to treatment with MPO inhibitors when their CCL17 levels are elevated.

[0208] In some cases, subjects with elevated CCL3 levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0209] In some cases, subjects with elevated CCL4 levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0210] In some cases, subjects with increased CD40L concentrations are identified as being more likely to respond to treatment with MPO inhibitors.

[0211] In some cases, subjects with elevated CST5 levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0212] In some cases, subjects with elevated CXCL1 levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0213] In some cases, subjects are identified as being more likely to respond to treatment with MPO inhibitors when their CXCL10 levels are elevated.

[0214] In some cases, subjects are identified as being more likely to respond to treatment with MPO inhibitors when their CXCL5 levels are elevated.

[0215] In some cases, subjects with elevated CXCL6 levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0216] In some cases, subjects were identified as being more likely to respond to treatment with MPO inhibitors when their Dkk1 levels were elevated.

[0217] In some cases, subjects with elevated HBEGF levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0218] In some cases, subjects with elevated HSP27 levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0219] In some cases, subjects with elevated IFNγ levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0220] In several cases, subjects were identified as being more likely to respond to treatment with MPO inhibitors if they had elevated IL-1Ra levels.

[0221] In some cases, subjects with elevated IL7 levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0222] In some cases, subjects with elevated IL-8 levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0223] In some cases, subjects with elevated ITGB1BP2 levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0224] In some cases, subjects are identified as being more likely to respond to treatment with MPO inhibitors when their MCP3 levels are elevated.

[0225] In some cases, subjects with elevated MMP1 concentrations are identified as being more likely to respond to treatment with MPO inhibitors.

[0226] In some cases, subjects with increased NEMO concentrations are identified as being more likely to respond to treatment with MPO inhibitors.

[0227] In some cases, subjects are identified as being more likely to respond to treatment with MPO inhibitors if they have elevated OSM concentrations.

[0228] In some cases, subjects were identified as being more likely to respond to treatment with MPO inhibitors when their PDGF-A levels were elevated.

[0229] In some cases, subjects were identified as being more likely to respond to treatment with MPO inhibitors when their PDGF-B levels were elevated.

[0230] In some cases, subjects are identified as more likely to respond to treatment with MPO inhibitors when PTX3 levels are elevated.

[0231] In some cases, subjects are identified as being more likely to respond to treatment with MPO inhibitors when SIRT2 concentrations are elevated.

[0232] In some cases, subjects are identified as being more likely to respond to treatment with MPO inhibitors when SRC concentrations are elevated.

[0233] In some cases, subjects with elevated STAMBP levels are identified as being more likely to respond to treatment with MPO inhibitors.

[0234] In some cases, subjects were identified as being more likely to respond to treatment with MPO inhibitors when their STK4 levels were elevated.

[0235] In some cases, subjects with MPO-related disorders are more likely to have an improved clinical response after treatment with an MPO inhibitor if the concentration of at least one biomarker selected from the group consisting of CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4 decreases after treatment with an MPO inhibitor.

[0236] In some cases, subjects are identified as more likely to have an improved clinical response if their CXCL11 levels decrease after treatment with MPO inhibitors.

[0237] In some cases, subjects are identified as more likely to have an improved clinical response if their HGF levels decrease after treatment with MPO inhibitors.

[0238] In some cases, if the subject's 4EBP1 concentration decreases after treatment with an MPO inhibitor, the subject is identified as more likely to have an improved clinical response.

[0239] In some cases, subjects are identified as more likely to have an improved clinical response if their ACE2 levels are reduced after treatment with MPO inhibitors.

[0240] In some cases, subjects are identified as more likely to have an improved clinical response if their ANGPT1 levels decrease after treatment with MPO inhibitors.

[0241] In some cases, if the subject's AXIN1 concentration decreases after treatment with an MPO inhibitor, the subject is identified as more likely to have an improved clinical response.

[0242] In some cases, subjects are identified as more likely to have an improved clinical response if their CASP3 levels decrease after treatment with MPO inhibitors.

[0243] In some cases, subjects are identified as more likely to have an improved clinical response if their CCL17 levels decrease after treatment with MPO inhibitors.

[0244] In some cases, subjects are identified as more likely to have an improved clinical response if their CCL3 levels decrease after treatment with MPO inhibitors.

[0245] In some cases, subjects with decreased CCL4 levels after treatment with MPO inhibitors are identified as more likely to have an improved clinical response.

[0246] In some cases, subjects are identified as more likely to have an improved clinical response if their CD40L levels decrease after treatment with MPO inhibitors.

[0247] In some cases, subjects are identified as more likely to have an improved clinical response if their CST5 levels decrease after treatment with MPO inhibitors.

[0248] In some cases, subjects are identified as more likely to have an improved clinical response if their CXCL1 levels decrease after treatment with MPO inhibitors.

[0249] In some cases, subjects are identified as more likely to have an improved clinical response if their CXCL10 levels decrease after treatment with MPO inhibitors.

[0250] In some cases, if a subject shows a decrease in CXCL5 levels after treatment with an MPO inhibitor, that subject is likely to have an improved clinical response.

[0251] In some cases, subjects are identified as more likely to have an improved clinical response if their CXCL6 levels decrease after treatment with MPO inhibitors.

[0252] In some cases, subjects with decreased Dkk1 levels after treatment with MPO inhibitors are identified as being more likely to have an improved clinical response.

[0253] In some cases, subjects are identified as more likely to have an improved clinical response if their HBEGF levels decrease after treatment with MPO inhibitors.

[0254] In some cases, subjects are identified as more likely to have an improved clinical response if their HSP27 levels decrease after treatment with MPO inhibitors.

[0255] In some cases, subjects who exhibit a decrease in IFNγ concentration after treatment with MPO inhibitors are identified as being more likely to have an improved clinical response.

[0256] In some cases, subjects who exhibit a decrease in IL-1Ra concentration after treatment with MPO inhibitors are identified as being more likely to have an improved clinical response.

[0257] In some cases, subjects are identified as more likely to have an improved clinical response if their IL7 levels are reduced after treatment with MPO inhibitors.

[0258] In some cases, subjects are identified as more likely to have an improved clinical response if their IL8 levels are reduced after treatment with MPO inhibitors.

[0259] In some cases, subjects are identified as more likely to have an improved clinical response if their ITGB1BP2 levels decrease after treatment with MPO inhibitors.

[0260] In some cases, subjects are identified as more likely to have an improved clinical response if their MCP3 levels are reduced after treatment with MPO inhibitors.

[0261] In some cases, if the subject's MMP1 concentration decreases after treatment with an MPO inhibitor, the subject is identified as more likely to have an improved clinical response.

[0262] In some cases, subjects are identified as more likely to have an improved clinical response if their NEMO levels decrease after treatment with an MPO inhibitor.

[0263] In some cases, subjects are identified as more likely to have an improved clinical response if their OSM levels decrease after treatment with MPO inhibitors.

[0264] In some cases, subjects are identified as more likely to have an improved clinical response if their PDGF-A levels are reduced after treatment with MPO inhibitors.

[0265] In some cases, subjects are identified as more likely to have an improved clinical response if their PDGF-B levels are reduced after treatment with MPO inhibitors.

[0266] In some cases, if the subject's PTX3 concentration decreases after treatment with an MPO inhibitor, the subject is identified as likely to have an improved clinical response.

[0267] In some cases, subjects are identified as more likely to have an improved clinical response if their SIRT2 levels decrease after treatment with MPO inhibitors.

[0268] In some cases, subjects are identified as more likely to have an improved clinical response if their SRC levels decrease after treatment with MPO inhibitors.

[0269] In some cases, subjects were identified as more likely to have an improved clinical response if their STAMBP levels decreased after treatment with MPO inhibitors.

[0270] In some cases, subjects with decreased STK4 levels after treatment with MPO inhibitors are identified as being more likely to have an improved clinical response.

[0271] [Table 2]

[0272] The concentrations of these biomarkers in a sample derived from the target, such as plasma or serum, may be evaluated at the protein level and measured by any suitable method known in the art, such as ELISA.

[0273] The concentration of any of the above biomarkers can be determined in a sample obtained from a subject such as a plasma sample, serum sample, urine sample, or sputum sample.

[0274] In some cases, if the concentration of at least one biomarker selected from the group consisting of CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4 is elevated compared to its concentration in a reference sample or reference population, the subject is identified as more likely to respond to treatment with an MPO inhibitor.

[0275] The reference sample may be a corresponding sample type (e.g., the same type of tissue) from a normal, healthy individual, for example, an individual that does not have MPO-related disorder or is not suspected of having MPO-related disorder. For example, the reference sample may be a corresponding sample type (e.g., the same type of tissue) from a normal, healthy individual of the same ethnicity as the subject. The reference population may be a population of healthy subjects. The reference population may be subjects of the same ethnicity as the subject, for example, a population of healthy subjects.

[0276] Inflammation risk biomarkers In certain embodiments, if a subject has elevated concentrations of inflammatory risk biomarkers and / or biomarkers annotated with neutrophil degranulation, such as OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and / or AZU1 (see Table 3), the subject is identified as more likely to respond to treatment with an MPO inhibitor. Of these, OSM correlates highly with neutrophil count, and LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 are all markers annotated with neutrophil degranulation (https: / / reactome.org / content / detail / R-HSA-6798695), and therefore can be used as surrogates for neutrophil levels and degranulation, respectively.

[0277] [Table 3]

[0278] The concentrations of these biomarkers in a sample derived from the target, such as plasma or serum, may be evaluated at the protein level and measured by any suitable method known in the art, such as ELISA. Methods for measuring the levels of these biomarkers are shown in Table 4 below.

[0279] [Table 4]

[0280] The concentration of any of the above biomarkers can be determined in a sample obtained from a subject such as a plasma sample, serum sample, urine sample, or sputum sample.

[0281] In one embodiment, if the concentration of at least one of the biomarkers described above is increased compared to its concentration in a reference sample or reference population, the subject is identified as more likely to respond to treatment with an MPO inhibitor. The reference sample may be a corresponding sample type (e.g., the same type of tissue) from a normal, healthy individual, for example, an individual that does not have or is not suspected of having an MPO-related disorder. For example, the reference sample may be a corresponding sample type (e.g., the same type of tissue) from a normal, healthy individual of the same ethnicity as the subject. The reference population may be a population of healthy subjects. The reference population may be subjects of the same ethnicity as the subject, for example, a population of healthy subjects.

[0282] Outcomes after treatment The treatments described herein using MPO inhibitors may result in an improvement in the symptoms experienced by the subject, i.e., an improved clinical response. For example, if the MPO-related disease is a cardiovascular disease, treatment may result in an improvement from baseline in the Kansas City Cardiomyopathy Questionnaire Comprehensive Symptom Score (KCCQ-OSS) and / or an improvement from baseline in the 6-minute walk distance (6MWD). Improvement from baseline in the Kansas City Cardiomyopathy Questionnaire Comprehensive Symptom Score (KCCQ-OSS) and / or an improvement from baseline in the 6-minute walk distance (6MWD) represents an improvement in clinical response.

[0283] Improvement in KCCQ-OSS or 6MWD is measured against baseline. Typically, baseline is the subject's KCCQ-OSS or 6MWD before treatment with an MPO inhibitor or at the time of randomization to treatment.

[0284] The KCCQ is a psychometrically validated questionnaire developed for patients with congestive HF (Green et al., 2000). It is a 23-item self-managed health status scale that quantifies physical limitations, symptoms, social interference, self-effects, and quality of life. Results from each domain are summarized and converted to a score from 0 to 100. A higher score indicates better health status. Improvement may be, for example, an increase of at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, or at least 10 points from baseline in the KCCQ-OSS. In some cases, improvement may be an increase of at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% from baseline in the KCCQ-OSS.

[0285] The 6MWD test involves the subject walking as far as they can in 6 minutes. Improvement may be, for example, an increase of at least 5m, at least 10m, at least 20m, at least 30m, at least 40m, at least 50m, at least 60m, or at least 70m in 6MWD from baseline. In some cases, improvement may be an increase of at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% in 6MWD from baseline.

[0286] In some cases, KCCQ-OSS or 6MWD may be determined 16, 24, or 48 weeks after baseline, i.e., 16, 24, or 48 weeks after the initiation of treatment with an MPO inhibitor. Therefore, improvement from baseline in KCCQ-OSS or 6MWD may be observed at 16, 24, or 48 weeks.

[0287] Treatment with MPO inhibitors described herein may result in a reduction from baseline in plasma levels of N-terminal pro-B natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP), and / or interleukin-6 (IL-6). Typically, baseline is the plasma levels of NT-proBNP, hsCRP, and / or IL-6 of the subject before treatment with the MPO inhibitor or at randomization to treatment. Plasma levels of NT-proBNP, hsCRP, and / or IL-6 can be measured by any suitable technique known in the art. Typically, plasma levels of NT-proBNP, hsCRP, and / or IL-6 are measured by ELISA or by proteomic methods such as mass spectrometry or SOMAscan. In some cases, a reduction of at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% from baseline in plasma levels of NT-proBNP, hsCRP, and / or IL-6 may represent an improvement.

[0288] In some cases, plasma levels of NT-proBNP, hsCRP, and / or IL-6 may be determined at 16, 24, or 48 weeks after baseline, i.e., 16, 24, or 48 weeks after the initiation of treatment with an MPO inhibitor. Therefore, a decrease in plasma levels of NT-proBNP, hsCRP, and / or IL-6 from baseline may be observed at 16, 24, or 48 weeks.

[0289] Treatment with MPO inhibitors described herein may result in improvements from baseline in left ventricular total longitudinal strain (LV-GLS), left atrial volume index (LAVI), and / or left ventricular mass index (LVMI). LV / GLS, LAVI, and / or LNMI may be assessed by echocardiography. Typically, baseline LV-GLS, LAVI, and / or LVMI are those of the subject prior to treatment with MPO inhibitors. In some cases, an increase of at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% in LV-GLS from baseline may represent improvement. In some cases, a decrease of at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% in LAVI and / or LVMI from baseline may represent improvement.

[0290] In some cases, LV-GLS, LAVI, and / or LVMI may be determined 16, 24, or 48 weeks after baseline, i.e., 16, 24, or 48 weeks after the initiation of treatment with an MPO inhibitor. Therefore, improvements in LV-GLS, LAVI, and / or LVMI from baseline may be seen at 16, 24, or 48 weeks.

[0291] Treatment with the MPO inhibitors described herein may result in a reduced risk of hospitalization, a reduced risk of emergency heart failure visits to a hospital requiring additional loop diuretic therapy, a reduced risk of myocardial infarction, a reduced risk of major adverse cardiovascular events (MACE), and / or a reduced risk of cardiovascular death, compared to no treatment being administered to the subject. MACE may be determined as the time to any of the five components of MACE (death, myocardial infarction, stroke, heart failure hospitalization, or vascular regeneration).

[0292] Treatment with MPO inhibitors described herein may result in improvements in the patient's overall impression of severity of heart failure symptoms (PGIS-HF), the patient's overall impression of severity of dyspnea (PGIS-WD), patient assessment of dyspnea, acute version (PRD-acute version), EuroQol 5-dimensional 5-level questionnaire (EQ-5D-5L), and / or New York Heart Association (NYHA) class compared to baseline. Typically, baseline PGIS-HF, PGIS-WD, PRD-acute version, EQ-5D-5L, and / or New York Heart Association class are the same as the subject's PGIS-HF, PGIS-WD, PRD-acute version, EQ-5D-5L, and / or NYHA class before treatment with MPO inhibitors.

[0293] The PGIS-HF assesses how participants perceive the overall severity of their HF symptoms over the past two weeks and is used to enable anchor-based assessment of clinically meaningful changes within participants. Participants select from six response options ranging from “no symptoms” to “very severe.”

[0294] The PGIS-WD assesses how participants perceive their current overall limitations in walking ability and allows for anchor-based assessment of clinically meaningful changes within participants regarding 6MWD. Participants choose from six response options ranging from “no limitation” to “very severe limitation.”

[0295] The PRD-Acute Edition is a single question item that asks participants to rate their shortness of breath immediately on a scale of 0 to 10, where 0 indicates "no shortness of breath" and 10 indicates "imaginably bad."

[0296] The EQ-5D-5L, developed by the EuroQol Group, is a self-report questionnaire used to derive a standardized measure of health status (also known as a utility score). The EQ-5D-5L utility score is widely accepted by reimbursement authorities and used to support health economic assessments.

[0297] This detailed description and its specific examples are illustrative and illustrate only embodiments. Therefore, it is not limited to the exemplary embodiments described herein. Furthermore, for clarity, various features described in the context of separate embodiments can be combined to form a single embodiment. Conversely, for brevity, various features described in the context of a single embodiment can be combined to form subcombinations thereof.

[0298] To avoid misunderstanding, where a base is limited by "as defined above" in this specification, it should be understood that the base includes the broadest definition that first arises, as well as each and all other definitions relating to that base. It should be understood that any definition, claim, aspect, or embodiment of a variable base of a formula disclosed herein can be combined (to the extent contextually possible) with any other definition, claim, aspect, or embodiment herein to provide further embodiments of this specification.

[0299] Features disclosed in the foregoing description, the following claims, or the accompanying drawings, expressed in a particular form or relating to means for performing the disclosed functions, or methods or processes for obtaining the disclosed results, may be used, as necessary, separately or in any combination of such features, to implement the present disclosure in a variety of forms.

[0300] The embodiments disclosed herein are described in conjunction with the exemplary embodiments described above, but many equivalent modifications and changes will be apparent to those skilled in the art upon reading this disclosure. Therefore, the exemplary embodiments described above are illustrative and not limiting. Various modifications to the embodiments described can be made without departing from the spirit and scope of this disclosure.

[0301] To avoid any doubt, any theoretical explanations provided herein are provided for the purpose of improving the reader's understanding. The inventors do not wish to be bound by any of these theoretical explanations.

[0302] Any section headings used herein are for structural purposes only and should not be construed as limiting the subject matter described herein.

[0303] Throughout this Spec., including the claims, unless the context requires otherwise, the words “comprise” and “include,” as well as variations such as “comprises,” “comprising,” and “including,” will be understood to mean the inclusion of the integer or step or group of integers or steps described, but not the exclusion of any other integer or step or group of integers or steps.

[0304] Where used herein and in the appended claims, the singular forms “a,” “an,” and “the” refer to multiple objects unless the context clearly indicates otherwise. Ranges may be expressed herein as “about” one particular value and / or “about” another particular value. Where such ranges are expressed, an alternative embodiment includes one particular value and / or the other particular value. Similarly, where a value is expressed as an approximation by the use of the antecedent “about,” it will be understood that a particular value forms an alternative embodiment. The term “about” with respect to numbers is optional and means, for example, ±10%. [Examples]

[0305] A binomial analysis of UK Biobank heart failure patients with neutrophil counts >4 million / mL yielded a hazard ratio of 1.46 for all-cause mortality and a hazard ratio of 1.49 for cardiovascular (CV) mortality (p<2E-16) (see Figure 1).

[0306] A two-way analysis of UK Biobank heart failure patients with an NLR > 2.27 yielded hazard ratios of 1.52 for all-cause mortality and 1.55 for cardiovascular mortality (p < 2E-16) (see Figure 2).

[0307] Neutrophil concentration in SATELLITE studies SATELLITE (NCT03756285) was a randomized, double-blind, placebo-controlled phase 2a trial evaluating the target engagement and safety of SATELLITE in patients with heart failure and ejection fraction ≥40%. Furthermore, the effects of mitipelstat on cardiac wall stress (assessed by plasma NT-proBNP levels), exercise capacity (assessed by 6-minute walk distance, 6MWD), and quality of life (assessed by the Kansas City Cardiomyopathy Questionnaire total score, KCCQ-OSS) were evaluated as exploratory endpoints at 1 and 3 months post-treatment. In a post-hoc analysis, baseline-adjusted effects on these variables were evaluated in subgroups stratified by baseline absolute neutrophil count (> or <= 4 million neutrophils / mL). Figure 4 shows the 3-month effects (maximum, minimum, median, and Q1-Q3) of mitipelstat versus placebo on baseline-adjusted NT-proBNP, 6MWD, and KCCQ-OSS. The median absolute change in the neutrophil subgroups >4 vs <=4 in placebo was -204 vs 28 pg / mL NT-proBNP. In the KCCQ-OSS score, this was +17 vs 41m 6MWD and +4.9 vs 0 points. The corresponding placebo-adjusted data was -439 vs +2 pg / mL NTproBNP. For the neutrophil subgroups >4 vs <=4, the KCCQ-OSS score was +27 vs -3m 6MWD and 9.1 vs -6.5 points, respectively.

[0308] Endeavour Research Here, we present the Part A design of Endeavor (NCT04986202), a sequential Phase 2b-3 randomized clinical trial to evaluate the effects of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with maintained or mildly reduced ejection fraction. Endeavor is the first Phase 2b-3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF / HFmrEF.

[0309] overview Endeavor is a randomized, double-blind, parallel-group, placebo-controlled, multicenter, consecutive Phase 2b and Phase 3 study of the efficacy and safety of mitipelstat in addition to optimal background therapy for up to 48 weeks in patients with heart failure and LVEF >40%. The study consists of two parts: Part A is a Phase 2b efficacy, safety / tolerability, and dose-finding study with planned randomization of approximately 660 patients. The results from Part A will determine the dose of mitipelstat for Part B, a Phase 3 study with planned randomization of approximately 820 patients.

[0310] Patient inclusion and exclusion criteria Eligible patients are those aged 40-85 years with a body mass index of 18.0-45 kg / m². 2 Eligible patients also have a stable symptomatic heart failure with an LVEF greater than 40% for at least one month (New York Heart Association Class IIIV). Eligible patients further have a KCCQ Total Symptom Score (TSS) of ≤90 points, as well as a 6MWD of at least 30m and a maximum of 400m, with a difference of less than 50m between two 6MWD measurements. Eligible patients further have a structural heart disease, signs of increased left ventricular filling pressure, signs of significant diastolic dysfunction, or a recent hospitalization for decompensated heart failure (Table 5).

[0311] The main exclusion criterion is an estimated glomerular filtration rate of 30 mL / min / 1.73 m² at the time of screening. 2The criteria for inclusion are: a systolic blood pressure of less than 90 mmHg at randomization (or 160 mmHg or greater if not receiving treatment with three or more antihypertensive drugs, or greater than 180 mmHg regardless of treatment), a heart rate greater than 110 bpm or less than 50 bpm at randomization, a life expectancy of less than 3 years for reasons other than cardiovascular disease, or a recorded LVEF of less than 40% (Table 5).

[0312] Randomization and treatment Eligible patients will be randomized in a 1:1:1 ratio to receive one orally once daily dose of mitipelstat 2.5 mg, mitipelstat 5 mg, or the corresponding placebo tablet for 48 weeks. Patients will be randomized using interactive response techniques to assign and conceal their assignment (Figure 3). Randomization will be based on capping rules using neutrophil count, motility (6MWD), and symptomatic status (KCCQ-TSS), with baseline absolute neutrophil count (>4 × 10⁻¹⁰) being the basis for randomization. 6 / mL vs ≤4 × 10 6 The study is stratified by ( / mL). The 48-week double-blind treatment period includes a 16-week period followed by a 32-week safety extension period.

[0313] endpoint Effectiveness The dual primary endpoints were changes from baseline to 16 weeks in KCCQ-TSS and 6MWD (Table 7). The KCCQ is a patient-reported and effective tool for quantifying heart failure symptoms, heart failure-related physical limitations, and health-related quality of life, while the KCCQ-TSS is a 0-100 scale (higher scores indicate worse symptoms) that measures only heart failure symptoms (Spertus et al., 2020). The KCCQ-TSS was chosen because myeloperoxidase inhibition is the principle behind symptom improvement, and the results of Phase 2a SATELLITE preceding Endeavor suggested that the trend of improvement in KCCQ-OSS was facilitated by improvements in KCCQ-TSS (Lam et al., 2021). The 6MWD is a standardized, self-paced measure of exercise capacity that reflects the usual daily activities of people with moderate to severe heart disease (Holland et al, 2014).

[0314] Secondary endpoints include changes in KCCQ-TSS and 6MWD from baseline to 24 and 48 weeks, changes in plasma concentrations of biomarkers N-terminal pro-B natriuretic peptide, high-sensitivity C-reactive protein, and interleukin-6 to 16, 24, and 48 weeks, and changes in echocardiographic parameters such as whole-ventricular longitudinal strain, left atrial volume index, and left ventricular mass index to 16 and 24 weeks.

[0315] safety Safety and tolerability outcomes include adverse events, vital signs, laboratory tests, and electrocardiograms. Adverse events of particular interest include infections and skin reactions, including maculopapular rash. Maculopapular rash is graded using the Common Terminology Criteria for Adverse Events (Table 7). Vital sign parameters include blood pressure, pulse rate, body temperature, and orthostatic blood pressure (Table 6).

[0316] statistical methods Sample size estimation Approximately 660 patients are expected to be randomized, with an estimated 600 having complete efficacy data (allowing for a 10% dropout rate). A sample size of 200 patients per group (1:1:1) with an overall significance level of α=0.05 and 85% power allows for the detection of a 6.0-point difference in mean change from baseline in the KCCQ-TSS when comparing mitipelstat with placebo. For 6MWD, this sample size allows for the detection of a 21m difference. The calculations were based on analysis of covariance (ANCOVA), assuming that the changes from baseline in the KCCQ-TSS and 6MWD are approximately normally distributed with standard deviations of 20 points and 70m, respectively.

[0317] interim analysis One or more interim analyses will be conducted in the Phase 2b portion of the study to inform further development of the clinical research program (including, but not limited to, dose selection for the Phase 3 portion of the study). The final interim analysis will be conducted when all patients in the Phase 2b portion of the study have completed the visits or evaluations specified in the final protocol. All members of the research team will remain blinded throughout Phase 2b. If Phase 3 is not initiated or progressed, the final interim 2b analysis will be the final analysis.

[0318] Effectiveness analysis Efficacy endpoints are analyzed in a complete analysis set including all randomized participants who received at least one dose of mitipelstat or placebo. Endpoints are analyzed by randomized treatment assignment comparing mitipelstat to placebo. The nominal significance level is 5%, all trials are two-sided, and all confidence intervals are 95%. An ANCOVA model is used with treatment group, neutrophil count, and baseline values ​​of efficacy variables as covariates. The null hypothesis is zero difference in the mean change from baseline between mitipelstat (pooled dose) and placebo for the dual primary endpoint, and the alternative hypothesis is a non-zero difference. Missing data are not imputed. Trial multiplicity across primary and secondary endpoints is accounted for using a pre-specified trial procedure with alpha recycling. This strategy controls for a type I error rate of 5% for false rejection of the null hypothesis.

[0319] Subgroup analysis We plan subgroup analyses of the primary endpoint based on baseline demographics and disease characteristics to assess the consistency of the effect (Table 8).

[0320] Consideration Endeavor is the first sequential Phase 2b-3 clinical trial in patients with heart failure and, to the best of the inventors' knowledge, a LVEF of more than 40%. This study aims to compare the efficacy of mitipelstat versus placebo using dual primary endpoints: physical function (6MWD) and patient-reported heart failure symptoms (KCCQ-TSS).

[0321] Mitiperustat has been previously evaluated in healthy volunteers (Gan et al., 2019; Nelander et al, 2021) and in patients with HFpEF / HFmrEF in the SATELLITE study (Lam et al, 2021). In SATELLITE, compared to the placebo group (n=14), the mitiperustat 5 mg group (n=27) inhibited plasma myeloperoxidase activity by 75% (95% confidence interval [CI]: 48-88, nominal p<0.001) from baseline to the end of treatment, and was generally well-tolerated, except for one patient who developed maculopapular rash (Lam et al, 2021). Patients treated with mitipelstat showed a tendency towards improved KCCQ-OSS compared to placebo, with a placebo-adjusted change of +6.283 points (95% CI: -0.461, +13.027, nominal p=0.067). However, no placebo-adjusted improvement was observed in coronary flow reserve or 6MWD. However, due to early termination of the study because of COVID-19, this study was insufficient to assess these efficacy outcomes.

[0322] Despite recent advances, new therapies for patients with HFpEF / HFmrEF remain in need. The EMPEROR-Preserved and DELIVER trials demonstrated the efficacy of sodium-glucose cotransporter-2 inhibitors in a broad range of patients with HFpEF / HFmrEF (Vaduganathan et al, 2022). However, the absolute risk reduction in both of these large randomized controlled trials was only about 3%, and the residual risk of cardiovascular death and hospitalization due to heart failure remained high. Improvement in the KCCQ-TSS was moderate at best, with a placebo-adjusted increase of only 1.5–2.5 points (on a 0–100 scale). Greater improvements have been reported in only one trial conducted in the US, PRESERVED-HF, which reported a placebo-adjusted improvement of 5.8 points in the KCCQ-TSS and 20.8 points in the 6MWDWD (Nassif et al, 2021). Conversely, other studies have not reported improvements in health status or exercise capacity in patients with HFpEF and HFmrEF (Abraham et al., 2021). The PARALLAX trial of sacubitril / valsartan in patients with heart failure and LVEF >40% did not show improvement in KCCQ score or 6MWD (Pieske et al., 2021). Furthermore, mineralocorticoid receptor antagonists are not associated with improved exercise capacity in patients with HFpEF (Edelmann et al., 2013). Therefore, there remains a significant unmet need for therapies that can improve health status (symptoms and / or health-related quality of life) and exercise capacity in patients with HFpEF and HFmrEF.

[0323] Endeavor was designed to investigate a novel therapeutic pathway independent of blood pressure reduction, heart rate reduction, and congestion relief. Inhibition of myeloperoxidase with mitipelstat specifically targets the pathophysiology hypothesized to be associated with HFpEF and HFmrEF. Interstitial myeloperoxidase modulates myofibroblast function and fibrosis, and elevated circulating myeloperoxidase levels are associated with chronic heart failure and poor clinical outcomes (Hawkins et al., 2021; Tang et al, 2006; Tang et al, 2007). Endeavor is designed to test the hypothesis that improving myeloperoxidase-related microvascular dysfunction and fibrosis will yield clinical benefits, which will be evaluated using KCCQ-TSS and 6MWD as dual primary efficacy endpoints, in addition to biomarkers and echocardiography as secondary endpoints, and is quite powerful.

[0324] The advantages of the Endeavor study design include careful selection of patients with HFpEF and HFmrEF by excluding patients with conditions that can mimic heart failure when LVEF exceeds 40%. The selection criteria further ensure that the majority of the study population has a high absolute neutrophil count, which is important because neutrophils are the primary source of myeloperoxidase. Neutrophil count is a viable method for enriching patients with more pronounced neutrophil degranulation, and patients with an increased neutrophil-to-lymphocyte ratio are at higher risk of poor outcome (Bai et al., 2021). Furthermore, an increased neutrophil-to-lymphocyte ratio has been associated with a decrease in 6MWD, but this was in the context of pulmonary hypertension (Harbaum et al., 2017). Repeating 6MWD before randomization aims to reduce both heterogeneity in the enrollment population and variability in assessment. Furthermore, the seamless design of Endeavor between Phase 2b and Phase 3 allows for a rapid transition from dose-selection studies to central trials, potentially enabling early regulatory approval of myeloperoxidase inhibition in patients with HFpEF and HFmrEF if mitipelstat proves effective.

[0325] The strengths of all study designs are mitigated by their limitations. The Phase 3 portion of Endeavor may not be continued if the efficacy or safety results of Phase 2b are unfavorable, or conversely, if the results show a significant benefit that suggests a direct transition to a larger cardiovascular outcome trial. The 6MWD is a measure of exercise capacity, but not of general daily activity or maximal capacity (assessed using cardiopulmonary exercise testing). Furthermore, the 6MWD does not provide insight into the mechanisms of exercise limitation because the results can be influenced by age, sex, height, weight, and orthopedic problems. The KCCQ-TSS captures clinically meaningful changes in patient-reported symptoms of heart failure, but is not sensitive to changes in physical, social, and emotional functioning and health-related quality of life, which are captured through other KCCQ domains (Spertus et al., 2020). These domains are evaluated as exploratory efficacy outcomes. Endeavor does not test for major adverse cardiac events or other event-driven outcomes as a primary or secondary measure of efficacy (death and serious adverse events are considered safety outcomes). While the FDA has indicated that treatments for HFpEF may be approved based on improvement in symptoms or functional capacity, it is unclear whether such treatments are covered by payers and therefore may not be available to patients.

[0326] In summary, Endeavor is designed for the most rapidly achievable central efficacy evaluation of mitipelstat to enable potential early approval for the treatment of patients with HFpEF / HFmrEF based on improved physical function and self-reported heart failure symptoms. This approach is favorable for novel selective myeloperoxidase inhibitors targeting previously untested pathophysiological pathways.

[0327] interim analysis Figure 6 shows the baseline characteristics of Endeavor participants stratified by neutrophil count >4 million / mL, confirming associations with pathological neutrophil states, i.e., hypofunction (shorter 6MWD) and symptoms (lower KCCQ), body mass index (BMI), signs of anemia (lower transferrin saturation, Tfsat), as well as high levels of acute-phase proteins and neutrophil and obesity-related cytokines (adipokines), some of which are related to clinical events in the observational cohort.

[0328] A preliminary analysis of approximately one-third of the cohort of 711 participants in the Endeavor trial identified 35 biomarkers that were significantly reduced by mitipelstat compared to placebo-treated participants after stratification for baseline neutrophil counts above 4 million / mL (see Figure 7). These were 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL11, CXCL5, CXCL6, Dkk1, HBEGF, HGF, HSP27, IFNγ, IL1ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4. For example, among participants with decreased CXCL11, mitipelstat treatment was associated with a 3.7-point increase in KCCQ-TSS and a 24m longer 6MWD. Among participants with increased CXCL11, mitipelstat treatment was associated with a 1.2-point decrease in KCCQ-TSS and a 6.4m shorter 6MWD (see Figures 8A and B). Eight biomarkers (ANGPT1, CXCL11, CXCL5, Dkk1, IL-7, OSM, PDGF-A, PDGF-B) were associated with placebo-adjusted improvement, and increases in these eight biomarkers were associated with worsening KCCQ-TSS and 6MWD.

[0329] These findings are confirmed for CXCL11 by the data provided in Figure 9. As shown in Figure 9A, mitipelstat-induced decline in CXCL11 resulted in a significant increase in 6MWD. Figure 9B shows a similar effect for KCCQ-TSS. Mitipelstat-induced decline in CXCL11 resulted in an increase in KCCQ-TSS. Similarly, mitipelstat-induced decline in HGF resulted in increases in both 6MWD and KCCQ-TSS (see Figures 10A and B).

[0330] For the 10 biomarkers that showed the greatest effect compared to placebo, the mean cutpoint for eight of the biomarkers (CXCL11, HBEGF, AXIN1, CXCL10, CCL4, CD40L, NEMO, and ITGB1BP2) was 4.1 million neutrophils / ml (see Figure 11). For two of the biomarkers, STAMBP and HGF, no separation of confidence intervals was observed.

[0331] [Table 5-1]

[0332] [Table 5-2]

[0333] [Table 5-3]

[0334] 6MWD, 6-minute walk distance; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AZ, AstraZeneca; BP, blood pressure; bpm, beats per minute; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CYP3A4, cytochrome P450 3A4; E / e', ratio of initial mitral valve inflow velocity to initial mitral annular dilation velocity. ePRO, Electronic Patient Report Outcome; Hb, Hemoglobin; HF, Heart Failure; hsCRP, High Sensitivity C-Reactive Protein; IL-6, Interleukin-6; IV, Intravenous; KCCQ-TSS, Kansas City Cardiomyopathy Questionnaire All-Symptom Score; eGFR, Estimated Glomerular Filtration Rate; HFpEF, Heart Failure with Preserved Ejection Fraction; LAVI, Left Atrial Volume Index; LVMI, Left Ventricular Mass Index; MI, Myocardial Infarction; NT-proBNP, N-Terminal Pro-B Natriuretic Peptide; PASP, Pulmonary Systolic Pressure; PI, Researcher; TRmax, Tricuspid Valve Maximum Regurgitation; TSS, Total Symptom Score; ULN, Upper Limit of Normal.

[0335] [Table 6]

[0336] 6MWD (6-minute walk distance); AE (adverse event); AEoSI (adverse event of special interest); CTCAE (Common Terminology Criteria for Adverse Events); ECG (electrocardiogram); hsCRP (high-sensitivity C-reactive protein); KCCQ (Kansas City Cardiomyopathy Questionnaire); HF (heart failure); IL6 (interleukin-6); LAVI (left atrial volume index); LV-GLS (left ventricular vertical strain); LVMI (left ventricular mass index); NT-proBNP (N-terminal pro-brain natriuretic peptide); TSS (total symptom score).

[0337] [Table 7]

[0338] Note: Maculopapular rash, also known as morbilli rash, is one of the most common adverse skin conditions. It is defined as a disorder characterized by the presence of macules (flat) and papules (raised) that often affect the upper trunk, spread afferently, and are itchy.

[0339] National Cancer Institute CTCAE v5.0, November 27, 2017 (https: / / ctep.cancer.gov / protocoldevelopment / electronic_applications / ctc.htm#ctc_50) CTCAE (Common Terminology Criteria for Adverse Events).

[0340] [Table 8]

[0341] 6MWD (6-minute walk distance); CKD-EPI (Collaborative Epidemiological Study of Chronic Kidney Disease); HF (Heart Failure); eGFR (Estimated Glomerular Filtration Rate); HF (Heart Failure); LVEF (Left Ventricular Ejection Fraction); NT-proBNP (N-terminal pro-B type natriuretic peptide); NYHA (New York Heart Association); T2DM (Type 2 Diabetes Mellitus).

[0342] The following numbered clauses describing aspects of the present invention are part of the description. 1. A method for selecting a subject with myeloperoxidase (MPO)-related disorder for treatment with an MPO inhibitor, comprising: (i) determining the neutrophil level in a blood sample from the subject and selecting the subject for treatment if the neutrophil level is elevated compared to the control neutrophil level; and / or (ii) determining the concentration of at least one biomarker selected from the group consisting of OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 in a plasma or serum sample from the subject and selecting the subject for treatment if the concentration of at least one biomarker is elevated compared to its concentration in a reference sample or reference population. 2. A method for predicting whether a subject with MPO-related disorder is likely to respond to treatment with an MPO inhibitor, comprising: (i) determining the neutrophil level in a blood sample from the subject and selecting the subject for treatment if the neutrophil level is elevated compared to the control neutrophil level; and / or (ii) determining the concentration of at least one biomarker selected from the group consisting of OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 in a plasma or serum sample from the subject, wherein if the concentration of at least one biomarker is elevated compared to its concentration in a reference sample or reference population, the subject is likely to respond to treatment with an MPO inhibitor. 3. A method for identifying subjects with MPO-related disorders who are likely to respond to treatment with an MPO inhibitor, comprising: (i) obtaining a blood sample from the subject and determining the neutrophil level in the blood sample, wherein if the neutrophil level is elevated compared to the control neutrophil level, the subject is likely to respond to treatment with an MPO inhibitor; and / or (ii) obtaining a plasma or serum sample from the subject and determining the concentration in the plasma or serum sample of at least one biomarker selected from the group consisting of OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1, wherein if the concentration of at least one biomarker is elevated compared to its concentration in a reference sample or reference population, the subject is likely to respond to treatment with an MPO inhibitor. 4. A method for treating or preventing MPO-related disorders in a subject in which (i) neutrophil levels in a blood sample have been shown to be higher than control neutrophil levels, and / or (ii) the concentration of at least one biomarker selected from the group consisting of OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 in a plasma or serum sample has been shown to be increased compared to the concentration of at least one biomarker in a reference sample or reference population, the method comprising administering an MPO inhibitor to the subject. 5. A method for treating or preventing MPO-related disorders in a subject, comprising: (i) determining the neutrophil level in a blood sample from the subject; and / or (ii) determining the concentration of at least one biomarker selected from the group consisting of OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 in a plasma or serum sample from the subject; and administering an MPO inhibitor to a subject having a neutrophil level higher than the control neutrophil level and / or an increased concentration of at least one biomarker compared to its concentration in a reference sample or reference population. 6. A method for treating or preventing MPO-related disorders in a subject, comprising administering an MPO inhibitor to the subject, wherein the subject is selected for treatment with an MPO inhibitor based on the following: (i) a higher neutrophil level in a blood sample compared to a control neutrophil level, and / or (ii) a higher concentration in a plasma or serum sample of at least one biomarker selected from the group consisting of OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 compared to the concentration of at least one biomarker in a reference sample or reference population. 7. A method for identifying and treating subjects suitable for the treatment of MPO-related disorders, the method being: a) Obtaining blood samples and / or plasma or serum samples from the subject, b) Measuring neutrophil levels in a blood sample, and / or the concentration of at least one biomarker selected from the group consisting of OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 in a plasma or serum sample, c) If the neutrophil level in the blood sample is elevated compared to the control neutrophil level, and / or the concentration of at least one biomarker selected from the group consisting of OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 is elevated compared to the concentration of at least one biomarker in the reference sample or reference population, the subject is identified as suitable for treatment of MPO-related disorder, and d) A method comprising administering an effective amount of an MPO inhibitor to the target. 8. An MPO inhibitor for use in a method of treating or preventing MPO-related disorders in a subject, wherein (i) the neutrophil level in the blood sample is elevated compared to the control neutrophil level, and / or (ii) the concentration of at least one biomarker selected from the group consisting of OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 is elevated compared to the concentration of at least one biomarker in a reference sample or reference population. 9. An MPO inhibitor for use in a method for treating or preventing MPO-related disorders in a subject, wherein the method is: (i) Determine the neutrophil level in the blood sample from the subject, and if the neutrophil level is higher than the control neutrophil level, administer an MPO inhibitor to the subject, and / or (ii) An MPO inhibitor comprising determining the concentration of at least one biomarker selected from the group consisting of OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 in a plasma or serum sample from the subject, and administering an MPO inhibitor to the subject if the concentration of at least one biomarker is increased compared to its concentration in a reference sample or reference population. 10. An MPO inhibitor for use in a method for treating or preventing MPO-related disorders, the method comprising administering the MPO inhibitor to a subject in which (i) neutrophil levels in a blood sample are higher than control neutrophil levels, and / or (ii) the concentration of at least one biomarker selected from the group consisting of OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 in a tissue sample is increased compared to the concentration of at least one biomarker in a reference sample or reference population. 11. An MPO inhibitor for use as described in any one of Clauses 1 to 7 or any one of Clauses 8 to 10, wherein (i) the neutrophil level is absolute neutrophil count (ANC) and the control neutrophil level is a reference ANC value, (ii) the neutrophil level is neutrophil-to-lymphocyte ratio (NLR) and the control neutrophil level is a reference NLR value, and / or (iii) the neutrophil level is determined by total white blood cell (WBC) count and the control neutrophil level is a reference total WBC count. 12. An MPO inhibitor for use as described in or for use in Clause 11, wherein (i) the reference ANC value is the median or mean of ANC in the same ethnic group of the subject, (ii) the reference NLR value is the median or mean of NLR in the same ethnic group of the subject, and / or (iii) the reference total WBC count is the median or mean of total WBC count in the same ethnic group of the subject. 13. An MPO inhibitor for use according to the method described in Clause 11 or Clause 12, wherein the reference ANC value is 4 million cells / mL ±20%, ±10%, ±5%, ±4%, ±3%, ±2%, or ±1%. 14. An MPO inhibitor for use according to the method described in Clause 13, wherein the reference ANC value is approximately 4 million cells / mL. 15. An MPO inhibitor for use or as described in any one of the clauses 11 to 14, wherein the reference NLR value is 3 ± 20%, ± 10%, ± 5%, ± 4%, ± 3%, ± 2%, or ± 1%. 16. A method for use of an MPO inhibitor as described in Clause 15, wherein the reference NLR value is approximately 3. 17. An MPO inhibitor for use according to any one of the provisions of Clauses 11 to 16, wherein the reference total WBC count is 6.25 million cells / mL ±20%, ±10%, ±5%, ±4%, ±3%, ±2%, or ±1%. 18. The method of use of an MPO inhibitor as described in Clause 17, wherein the reference total WBC count is approximately 6.25 million cells / mL. 19. An MPO inhibitor for use or according to any one of the methods described in any one of the clauses 1 to 18, wherein the reference sample is derived from a normal, healthy individual. 20. An MPO inhibitor for use in the manner described in or for use in the manner described in Clause 19, wherein the reference sample is derived from the same ethnic group of the subject as the subject. 21. An MPO inhibitor for use as described in any one of the paragraphs 1 to 20, wherein the reference population is a population of subjects of the same ethnicity as the subject, and the concentration of at least one biomarker in the reference population is the median or mean concentration of at least one biomarker in a population of healthy subjects of the same ethnicity as the subject. 22. An MPO inhibitor for use according to any one of the paragraphs 1 to 21, wherein the MPO-related disorder has inflammatory, cardiovascular, respiratory, renal, metabolic, hepatic and / or neurological components and / or neutrophil-driven impairment. 23. MPO-related diseases include chronic kidney disease (CKD), acute kidney injury (AKI), glomeruloarthritis, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), alcoholic and non-alcoholic steatohepatitis (ASH / NASH), alcoholic and non-alcoholic fatty liver disease (AFLD / NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, and irritable bowel syndrome. MPO inhibitors for use or according to the method described in Clause 22, for conditions including IBS syndrome, rheumatoid arthritis, systemic lupus erythematosus, hepatic steatosis, hepatic fibrosis, gout, sickle cell disease, cystic fibrosis, vasculitis, antineutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), noncystic fibrotic bronchiectasis (NCFB), vascular dysfunction, lipoprotein denaturation, and / or type 2 diabetes. 24. MPO inhibitors for use in the manner described in or for use in the manner described in Clause 23, wherein the MPO-related disorder is COPD, NASH, or CKD. 25. An MPO inhibitor for use according to or as described in Clause 22, wherein the MPO-related disorder is a cardiovascular disorder, e.g., heart failure (e.g., heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with maintained ejection fraction), acute coronary syndrome, myocardial infarction, coronary artery disease (CAD), peripheral artery disease, arrhythmia, cardiomyopathy, dilated and hypertrophic cardiomyopathy, idiopathic dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy / dysplasia (ARVC / D), stress-induced cardiomyopathy, unclassifiable cardiomyopathy, left ventricular uncompressible, valvular heart disease, hypertension, pulmonary hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm (AAA), chemotherapy-induced cardiotoxicity, or stroke. 26. An MPO inhibitor for use as described in or for use in the manner described in Clause 25, wherein the MPO-related disorder is heart failure (e.g., heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with maintained ejection fraction), myocardial infarction, coronary artery disease (CAD), peripheral artery disease, AAA, or stroke. 27. An MPO inhibitor for use according to the method described in Clause 26, wherein the MPO-related disorder is heart failure with reduced ejection fraction (HFrEF), heart failure with mildly reduced ejection fraction (HFmrEF), or heart failure with maintained ejection fraction (HFpEF). 28. An MPO inhibitor for use as described in any one of clauses 25-27, wherein the treatment results in improvement from baseline in the Kansas City Cardiomyopathy Questionnaire Comprehensive Symptom Score (KCCQ-OSS) and / or improvement from baseline in the 6-minute walk distance (6MWD). 29. An MPO inhibitor for use as described in or for use in Clause 28, wherein improvement of KCCQ-OSS and / or 6MWD is observed from baseline to 16 weeks, 24 weeks, or 48 weeks. 30. An MPO inhibitor for use as described in any one of Clauses 1 to 29, wherein the treatment results in a reduction from baseline in plasma levels of N-terminal pro-B natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP), and / or interleukin-6 (IL-6). 31. An MPO inhibitor for use according to the method described in Clause 30, wherein the reduction in plasma levels of NT-proBNP, hsCRP, and / or IL-6 is from baseline to 16, 24, or 48 weeks. 32. An MPO inhibitor for use as described in any one of Clauses 1 to 31, wherein the treatment results in an improvement from baseline in the total longitudinal strain of the left ventricle (LV-GLS), left atrial volume index (LAVI), and / or left ventricular mass index (LVMI). 33. An MPO inhibitor for use according to the method described in Clause 32, wherein improvement in LV-GLS, LAVI, and / or LVMI is from baseline to 16 or 24 weeks. 34. An MPO inhibitor for use as described in any one of Clauses 1 to 33, which results in a reduced risk of hospitalization, a reduced risk of emergency heart failure visits to a hospital requiring additional loop diuretic therapy, a reduced risk of myocardial infarction, a reduced risk of major adverse cardiovascular events (MACE), and / or a reduced risk of cardiovascular death, compared to no treatment being administered to the subject. 35. An MPO inhibitor is a compound of formula (I),

[0343] [ka] During the ceremony, R 1 These are H, F, Cl, or CF3. R 2 These are H, CH3, or C2H5. R 3 These are H, CH3, C2H5, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, or cyclopentyl. An MPO inhibitor for use or the method described in any one of clauses 1 to 34, or a pharmaceutically acceptable salt thereof. 36. 1-{2-[(1R)-1-aminopropyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-[2-(1-aminoethyl)-4-chlorobenzyl]-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(1R)-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(1S)-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{4-chloro-2-[1-(methylamino)ethyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{4-chloro-2-[(ethylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-[2-(aminomethyl)-4-chlorobenzyl]-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{4-chloro-2-[(methylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-(2-{[(cyclobutylmethyl)amino]methyl}benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(cyclobutylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(cyclopentylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-(2-{[(2-methylpropyl)amino]methyl}benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(propan-2-ylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-[2-(aminomethyl)-4-(trifluoromethyl)benzyl]-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(methylamino)methyl]-4-(trifluoromethyl)benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; An MPO inhibitor for use as described in or for use in the manner described in Clause 35, or selected from pharmaceutically acceptable salts thereof. 37. MPO inhibitors, formula (II)

[0344] [ka] It is a compound of, During the ceremony, X=CH or N Y 1 =CZ 1 Or N, Y 2 =CZ 2 Or N, Y 3 =CZ 3 Or N, Y 4 =CZ 4 Or N and Y 5 =CZ 5 Or it is N, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 If present, these are independently H, Halo, CF3, Q, or T. However, Y 1 , Y 2 , Y 3 , Y 4 Or Y 5 One or less of these is N, and Y 1 , Y 2 , Y 3 , Y 4 Or Y 5At least two of them are CH and Z 1 , Z 2 , Z 3 , Z 4 and Z 5 One or fewer of these are Halo or CF3 and 1, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Only one of them is either Q or T. Q is

[0345] [ka] In the formula, m is 0, 1, 2, or 3. T is

[0346] [ka] And, p is either 0 or 1, s is 0, 1, or 2. n is 0, 1, or 2. A is CH2, CF2, CHF, CHR 2 , CFR 2 , NR 3 Or it is O, During the ceremony, R 1 and R 2 If present, these are independently CH2F, CHF2, or CF3. R 3 If present, it is independently H or CH3. An MPO inhibitor for use or the method described in any one of Clauses 1 to 34, or any stereoisomer thereof or a pharmaceutically acceptable salt thereof. 38. MPO inhibitors, structure:

[0347] [ka] An MPO inhibitor having the method or use described in Clause 37. 39. MPO inhibitors, 1-(2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(4-chloro-2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(4-chloro-2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(4-chloro-2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(4-chloro-2-(pyrroridine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(4-chloro-2-(pyrroridine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(4-chloro-2-(pyrroridine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(4-chloro-2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(4-chloro-2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(4-chloro-2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 3-(4-chloro-2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purine-6-one, 1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-3-(2-(azepan-2-yl)-4-chlorobenzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, (S)-3-(2-(azepan-2-yl)-4-chlorobenzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, (R)-1-(2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-(4-methylpiperazin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-(2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-(5-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-(4,4-difluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(2-(4,4-difluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(2-(4,4-difluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-3-(2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-3-(2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-3-(2-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, 3-(2-(4,4-difluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purine-6-one, 3-(2-(5-fluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-1-((2-(-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-((2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((cis)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-(2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((trans)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((2S,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-3-(2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-3-(2-((trans)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-3-(2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-3-(2-((2S,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, rac-1-(2-((2R,4S)-4-(difluoromethyl)piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-((2R,4S)-4-(difluoromethyl)piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-((2S,4R)-4-(difluoromethyl)piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-((2-(piperidine-2-yl)pyridine-3-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((cis)-4-(trifluoromethyl)piperidine-2-yl)pyridine-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)pyridine-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((cis)-4-(trifluoromethyl)piperidine-2-yl)pyridine-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)pyridine-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(4-(1-aminocyclobutyl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(3-(1-aminocyclobutyl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-(piperidine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-(morpholine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(2-(morpholine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(2-(morpholine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-(piperidine-4-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-((2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((trans)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((2S,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, and An MPO inhibitor for use as described in or for use in the manner described in Clause 37, selected from the pharmaceutically acceptable salts thereof. 40. MPO inhibitors, formula (IIa)

[0348] [ka] It is a compound having the following properties: During the ceremony, X 1 =CH or N, each X 2 These are independently CH, CF, or CCl. r and q are 0, 1, or 2, provided that r+q=2 or 3. An MPO inhibitor for use or the method described in any one of Clauses 1 to 34, or any stereoisomer thereof or a pharmaceutically acceptable salt thereof. 41. MPO inhibitors, formula (IIb),

[0349] [ka] It is a compound having the following properties: During the ceremony, X 1 =CH or N, each X 2 These are independently CH, CF, or CCl. r and q are 0, 1, or 2, provided that r+q=2 or 3. An MPO inhibitor for use or the method described in any one of Clauses 1 to 34, or any stereoisomer thereof or a pharmaceutically acceptable salt thereof. 42. MPO inhibitors, 1-((1,2,3,4-tetrahydroisoquinoline-8-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(isoindoline-5-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(isoindoline-4-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, and An MPO inhibitor for use as described in or for use in the manner described in Clause 37, selected from the pharmaceutically acceptable salts thereof. 43. An MPO inhibitor for use or according to any one of the provisions of Clauses 1 to 34, wherein the MPO inhibitor is mitipelstat.

[0350] References Abraham WT,Lindenfeld J,Ponikowski P,Agostoni P,Butler J,Desai AS,Filippatos G,Gniot J,Fu M,Gullestad L,Howlett JG,Nicholls SJ,Redon J,Schenkenberger I,Silva-Cardoso J,Stork S,Krzysztof Wranicz J,Savarese G,Brueckmann M,Jamal W,Nordaby M,Peil B,Ritter I,Ustyugova A,Zeller C,Salsali A,Anker SD.Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction,with and without type 2 diabetes.Eur Heart J 42,700-710 (2021). Bai, B., et al.High Neutrophil to Lymphocyte Ratio and Its Gene Signatures Correlate With Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction.Front Cardiovasc Med 8:614757 (2021). Bjornsdottir,H.,et al.Neutrophil NET formation is regulated from the inside by myeloperoxidase-processed reactive oxygen species.Free Radic Biol Med 89,1024-1035 (2015). Coates,T.D.(2020,April 15)。Laboratory evaluation of neutrophil disorders. UpToDate https: / / www.uptodate.com / contents / laboratory-evaluation-of-neutrophil-disorders. Edelmann F,Wachter R,Schmidt AG,Kraigher-Krainer E,Colantonio C,Kamke W,Duvinage A,Stahrenberg R,Durstewitz K,Loffler M,Dungen HD,Tschope C,Herrmann-Lingen C,Halle M,Hasenfuss G,Gelbrich G,Pieske B,Aldo DHFI.Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction:the Aldo-DHF randomized controlled trial.JAMA 309,781-791 (2013) Gan LM,Lagerstrom-Fermer M,Ericsson H,Nelander K,Lindstedt EL,Michaelsson E,Kjaer M,Heijer M,Whatling C,Fuhr R.Safety,tolerability,pharmacokinetics and effect on serum uric acid of the myeloperoxidase inhibitor AZD4831 in a randomized,placebo-controlled,phase I study in healthy volunteers.Br J Clin Pharmacol 85,762-770 (2019). Green CP、Porter CB、Bresnahan DR、Spertus JA。Development and evaluation of the Kansas City Cardiomyopathy Questionnaire:a new health status measure for heart failure.J Am Coll Cardiol.2000;35(5):1245-55. Harbaum L,Baaske KM,Simon M,Oqueka T,Sinning C,Glatzel A,Luneburg N,Sydow K,Bokemeyer C,Klose H.Exploratory analysis of the neutrophil to lymphocyte ratio in patients with pulmonary arterial hypertension.BMC Pulm Med 17,72 (2017). Hawkins CL,Davies MJ.Role of myeloperoxidase and oxidant formation in the extracellular environment in inflammation-induced tissue damage.Free Radic Biol Med 172,633-651 (2021). Holland AE,Spruit MA,Troosters T,Puhan MA,Pepin V,Saey D,McCormack MC,Carlin BW,Sciurba FC,Pitta F,Wanger J,MacIntyre N,Kaminsky DA,Culver BH,Revill SM,Hernandes NA,Andrianopoulos V,Camillo CA,Mitchell KE,Lee AL,Hill CJ,Singh SJ.An official European Respiratory Society / American Thoracic Society technical standard:field walking tests in chronic respiratory disease.Eur Respir J 44,1428-1446 (2014). Lam CSP,CVoors AA,Shah SJ,Erlinge D,Saraste A,Pirazzi C,Grove EL,Barasa A,Schou M,Aziz A,Gustavsson A,Garkaviy O,Gan LM,Gabrielsen A,Lund LH.Myeloperoxidase inhibitor AZD4831 target engagement and safety in a phase2a study in patients with heart failure with preserved ejection fraction (SATELLITE).European Journal of Heart Failure 23,129 (2021). Lim,E.M.,et al.Race-specific WBC and neutrophil count reference intervals.Int Jnl Lab Hem 32,590-597 (2010). Lim,E.M.,et al.Racial / Ethnic-Specific Reference Intervals for Common Laboratory Tests:A Comparison among Asians,Blacks,Hispanics,and White.Hawai’i Journal of Medicine & Public Health,74 (9),302-310. Markousis-Mavrogenis G,et al.,Multimarker profiling identifies protective and harmful immune processes in heart failure:findings from BIOSTAT-CHF.Cardiovasc Res 118,1964-1977 (2022). McDonagh TA,et al.,2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure.Eur J Heart Fail 24,4-131 (2022). Nassif ME,Windsor SL,Borlaug BA,Kitzman DW,Shah SJ,Tang F,Khariton Y,Malik AO,Khumri T,Umpierrez G,Lamba S,Sharma K,Khan SS,Chandra L,Gordon RA,Ryan JJ,Chaudhry SP,Joseph SM,Chow CH,Kanwar MK,Pursley M,Siraj ES,Lewis GD,Clemson BS,Fong M,Kosiborod MN.The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction:a multicenter randomized trial.Nat Med 27,1954-1960 (2021). Nelander K,Lagerstrom-Fermer M,Amilon C,Michaelsson E,Heijer M,Kjaer M,Russell M,Han D,Lindstedt EL,Whatling C,Gan LM,Ericsson H.Early clinical experience with AZD4831,a novel myeloperoxidase inhibitor,developed for patients with heart failure with preserved ejection fraction.Clin Transl Sci 14,812-819 (2021). Pieske B,Wachter R,Shah SJ,Baldridge A,Szeczoedy P,Ibram G,Shi V,Zhao Z,Cowie MR,Investigators P,Committee m.Effect of sacubitril / valsartan vs standard medical therapies on plasma NT-proBNP concentration and submaximal exercise capacity in patients with heart failure and preserved ejection fraction:the PARALLAX randomized clinical trial.JAMA 326,1919-1929 (2021). Shah AD,et al.,Neutrophil Counts and Initial Presentation of 12 Cardiovascular Diseases:A CALIBER Cohort Study.J Am Coll Cardiol 69,1160-1169 (2017). Shah SJ,et al.,Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction:PROMIS-HFpEF.Eur Heart J 39,3439-3450 (2018). Spertus JA,Jones PG,Sandhu AT,Arnold SV.Interpreting the Kansas City Cardiomyopathy Questionnaire in clinical trials and clinical care:JACC state-of-the-art review.J Am Coll Cardiol.76,2379-2390(2020). Tang WH,Brennan ML,Philip K,Tong W,Mann S,Van Lente F,Hazen SL.Plasma myeloperoxidase levels in patients with chronic heart failure.Am J Cardiol 98,796-799 (2006). Tang WH,Tong W,Troughton RW,Martin MG,Shrestha K,Borowski A,Jasper S,Hazen SL,Klein AL.Prognostic value and echocardiographic determinants of plasma myeloperoxidase levels in chronic heart failure.J Am Coll Cardiol 49,2364-2370 (2007). Vaduganathan M, Docherty KF, Claggett BL, Jhund PS, de Boer RA, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, Shah SJ, Desai AS, McMurray JJV, Solomon SD.SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomized controlled trials.Lancet 400,757–767 (2022).

Claims

1. A method for selecting subjects with myeloperoxidase (MPO)-related disorders for treatment with an MPO inhibitor, comprising: (i) determining the neutrophil level in a blood sample from the subject, and selecting the subject for treatment if the neutrophil level is elevated compared to the control neutrophil level; and / or (ii) (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF in a plasma or serum sample from the subject. A method comprising: determining the concentration of at least one biomarker selected from the group consisting of HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1; and selecting the subject for treatment if the concentration of the at least one biomarker is increased compared to its concentration in a reference sample or reference population.

2. A method for predicting whether a subject with MPO-related disorder is likely to respond to treatment with an MPO inhibitor, comprising: (i) determining the neutrophil level in a blood sample from the subject, and selecting the subject for treatment if the neutrophil level is elevated compared to the control neutrophil level; and / or (ii) (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27 in a plasma or serum sample from the subject A method comprising: (b) determining the concentration of at least one biomarker selected from the group consisting of IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1, wherein if the concentration of the at least one biomarker is increased compared to its concentration in a reference sample or reference population, the subject may respond to treatment with an MPO inhibitor.

3. A method for identifying subjects with MPO-related disorders that are likely to respond to treatment with an MPO inhibitor, comprising: (i) obtaining a blood sample from the subject and determining the neutrophil level in the blood sample, wherein if the neutrophil level is increased compared to the control neutrophil level, the subject is likely to respond to treatment with an MPO inhibitor; and / or (ii) obtaining a plasma or serum sample from the subject, wherein (a) the plasma or serum sample contains CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, A method comprising determining the concentration of at least one biomarker selected from the group consisting of CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1, wherein if the concentration of the at least one biomarker is increased compared to its concentration in a reference sample or reference population, the subject is likely to respond to treatment with an MPO inhibitor.

4. (i) Neutrophil levels in blood samples are shown to be higher than control neutrophil levels, and / or (ii) (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, DKK1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDG A method for treating or preventing MPO-related disorders in subjects in which the concentration of at least one biomarker selected from the group consisting of F-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 is shown to be increased compared to the concentration of the at least one biomarker in a reference sample or reference population, the method comprising administering an MPO inhibitor to the subject.

5. A method for treating or preventing MPO-related disorders in a subject, comprising: (i) determining the neutrophil level in a blood sample from the subject, and / or (ii) determining the following in a plasma or serum sample from the subject: (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, DKK1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, A method comprising: determining the concentration of at least one biomarker selected from the group consisting of NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1; and administering an MPO inhibitor to a subject having a neutrophil level higher than the control neutrophil level and / or an increased concentration of the at least one biomarker compared to its concentration in a reference sample or reference population.

6. A method for treating or preventing MPO-related disorders in a subject, the method comprising administering an MPO inhibitor to the subject, wherein the subject (i) has a higher neutrophil level in a blood sample compared to a control neutrophil level, and / or (ii) has a higher concentration in a plasma or serum sample of (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL1 in a reference sample or reference population compared to the concentration of at least one biomarker in a reference sample or reference population. A method selected for treatment with an MPO inhibitor based on the presence of high concentrations of at least one biomarker selected from the group consisting of (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1.

7. A method for identifying and treating subjects suitable for the treatment of MPO-related disorders, wherein the method is: a) Obtaining blood samples and / or plasma or serum samples from the subject, b) The neutrophil levels in the blood sample and / or the (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, I Measuring the concentration of at least one biomarker selected from the group consisting of L7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1 and AZU1, c) If the neutrophil level in the blood sample is increased compared to the control neutrophil level, and / or (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OS Identifying a subject as suitable for the treatment of MPO-related disorders if the concentration of at least one biomarker selected from the group consisting of M, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 is increased compared to the concentration of the at least one biomarker in a reference sample or reference population, and d) A method comprising administering an effective amount of an MPO inhibitor to the subject.

8. A method for predicting improved clinical response in subjects with MPO-related disorders after treatment with an MPO inhibitor, wherein a decrease in the concentration of at least one biomarker selected from the group consisting of CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, DKK1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4 after treatment with an MPO inhibitor predicts improved clinical response.

9. (i) Higher neutrophil levels in the blood sample compared to control neutrophil levels, and / or (ii) Higher concentrations in the plasma or serum sample compared to the concentration of at least one biomarker in the reference sample or reference population: (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, DKK1, HBEGF, HSP27, IFNγ, I An MPO inhibitor for use in a method of treating or preventing MPO-related disorders in subjects with elevated concentrations of at least one biomarker selected from the group consisting of L-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1.

10. An MPO inhibitor for use in a method for treating or preventing MPO-related disorders in a subject, wherein the method is: (i) Determine the neutrophil level in a blood sample from the subject, and if the neutrophil level is higher than the control neutrophil level, administer the MPO inhibitor to the subject, and / or (ii) Plasma or serum samples from the subject, (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX 3. An MPO inhibitor comprising determining the concentration of at least one biomarker selected from the group consisting of SIRT2, SRC, STAMBP and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1 and AZU1, and administering the MPO inhibitor to a subject if the concentration of the at least one biomarker is increased compared to its concentration in a reference sample or reference population.

11. An MPO inhibitor for use in a method for treating or preventing MPO-related disorders, wherein the method is characterized by (i) a neutrophil level in a blood sample being higher than a control neutrophil level, and / or (ii) (a) a tissue sample containing CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, An MPO inhibitor comprising administering the MPO inhibitor to a subject whose concentration of at least one biomarker selected from the group consisting of ITGB1BP2, MCP3, MMP1, NEMO, OSM, PDGF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP, and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1, and AZU1 is increased compared to the concentration of the at least one biomarker in a reference sample or reference population.

12. (i) Neutrophil levels in the blood sample are higher than control neutrophil levels, and / or (ii) (a) CXCL11, HGF, 4EBP1, ACE2, ANGPT1, AXIN1, CASP3, CCL17, CCL3, CCL4, CD40L, CST5, CXCL1, CXCL10, CXCL5, CXCL6, Dkk1, HBEGF, HSP27, IFNγ, IL-1Ra, IL7, IL8, ITGB1BP2, MCP3, MMP1, NEMO, OSM, PD in the plasma or serum sample. Use of an MPO inhibitor in the manufacture of a pharmacopoeia for the treatment or prevention of an MPO-related disorder in a subject in which the concentration of at least one biomarker selected from the group consisting of GF-A, PDGF-B, PTX3, SIRT2, SRC, STAMBP and STK4, and / or (b) OSM, LOX1, MMP9, CEACAM8, MPO, PGLYRP1 and AZU1 is increased compared to the concentration of the at least one biomarker in a reference sample or reference population.

13. (i) the neutrophil level is the absolute neutrophil count (ANC) and the control neutrophil level is a reference ANC value, (ii) the neutrophil level is the neutrophil-to-lymphocyte ratio (NLR) and the control neutrophil level is a reference NLR value, and / or (iii) the neutrophil level is determined by the total white blood cell (WBC) count and the control neutrophil level is a reference total WBC count, the method according to any one of claims 1 to 8, an MPO inhibitor for use according to any one of claims 9 to 11, or the use according to claim 12.

14. (i) the reference ANC value is the median or mean ANC in a group of subjects of the same ethnicity as the subject, (ii) the reference NLR value is the median or mean NLR in a group of subjects of the same ethnicity as the subject, and / or (iii) the reference total WBC count is the median or mean total WBC count in a group of subjects of the same ethnicity as the subject, the method according to claim 13, an MPO inhibitor for use, or use.

15. The method according to claim 13 or 14, an MPO inhibitor for use, or use, wherein the reference ANC value is 4 million cells / mL ±20%, ±10%, ±5%, ±4%, ±3%, ±2%, or ±1%.

16. The method according to claim 15, an MPO inhibitor for use, or use, wherein the reference ANC value is approximately 4 million cells / mL.

17. The method according to any one of claims 13 to 16, an MPO inhibitor for use, or use, wherein the reference NLR value is 3 ± 20%, ± 10%, ± 5%, ± 4%, ± 3%, ± 2%, or ± 1%.

18. The method according to claim 17, an MPO inhibitor for use, or use, wherein the reference NLR value is approximately 3.

19. The method according to any one of claims 13 to 18, an MPO inhibitor for use, or use, wherein the reference total WBC count is 6.25 million cells / mL ±20%, ±10%, ±5%, ±4%, ±3%, ±2%, or ±1%.

20. The method according to claim 19, an MPO inhibitor for use, or use, wherein the reference total WBC count is approximately 6.25 million cells / mL.

21. The method according to any one of claims 1 to 20, an MPO inhibitor for use, or use, wherein the reference sample is derived from a normal, healthy individual.

22. The method according to claim 21, an MPO inhibitor for use, or use, wherein the reference sample is derived from a target population of the same ethnicity as the subject.

23. The method according to any one of claims 1 to 22, an MPO inhibitor for use, or use, wherein the reference population is a population of subjects of the same ethnicity as the subject, and the concentration of the at least one biomarker in the reference population is the median or mean concentration of the at least one biomarker in a population of healthy subjects of the same ethnicity as the subject.

24. The method according to any one of claims 1 to 23, an MPO inhibitor for use, or use, wherein the MPO-related disorder has inflammatory, cardiovascular, respiratory, renal, metabolic, hepatic and / or neurological components, and / or neutrophil drive disorder.

25. The aforementioned MPO-related disorders include chronic kidney disease (CKD), acute kidney injury (AKI), glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), alcoholic and non-alcoholic steatohepatitis (NASH), alcoholic and non-alcoholic fatty liver disease (AFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, fatty liver, hepatic fibrosis, gout, sickle cell anemia, cystic fibrosis, vasculitis, and anti-neutrophilic cytoplasmic autoantibodies (ANCA). The method according to claim 24, an MPO inhibitor for use, or use of autoantibody-associated vasculitis, asthma, chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis (NCFB), vascular dysfunction, lipoprotein denaturation and / or type 2 diabetes.

26. The aforementioned MPO-related disorders include chronic kidney disease (CKD), acute kidney injury (AKI), glomerular injury, nephritis, glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis, diabetic nephropathy, cardiorenal syndrome (CRS), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, fatty liver, hepatic fibrosis, gout, sickle cell anemia, cystic fibrosis, vasculitis, and anti-neutrophilic cytoplasmic autoantibodies (ANCA). The method according to claim 24, an MPO inhibitor for use, or use of the method for use of the MPO inhibitor for

27. The method according to claim 25 or 26, an MPO inhibitor for use, or use, wherein the MPO-related disorder is COPD, bronchiectasis, NASH, or CKD.

28. The method according to claim 27, an MPO inhibitor for use, or use, wherein the MPO-related disorder is COPD.

29. The method according to claim 27, an MPO inhibitor for use, or use, wherein the MPO-related disorder is bronchiectasis.

30. The method according to claim 24, an MPO inhibitor for use, or use, wherein the MPO-related disorder is a cardiovascular disorder, such as heart failure (e.g., heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with maintained ejection fraction), acute coronary syndrome, myocardial infarction, coronary artery disease (CAD), peripheral artery disease, arrhythmia, cardiomyopathy, dilated and hypertrophic cardiomyopathy, idiopathic dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy / dysplasia (ARVC / D), stress-induced cardiomyopathy, unclassifiable cardiomyopathy, left ventricular uncompressible, valvular heart disease, hypertension, pulmonary hypertension (PAH), vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, plaque rupture, abdominal aortic aneurysm (AAA), chemotherapy-induced cardiotoxicity, or stroke.

31. The aforementioned MPO-related disorders include coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), arrhythmias, cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocardial infarction, hypertension, pulmonary arterial hypertension (PAH), pulmonary hypertension, vascular dysfunction, atherosclerosis, ischemic heart disease, atrial fibrillation, pericarditis, diastolic dysfunction, rupture of atherosclerotic plaque, abdominal aortic aneurysm, chemotherapy-induced cardiotoxicity, prolongation of the time to recurrence of atrial fibrillation / flutter after electrical cardiomyopathy / deficiency, arrhythmogenic right ventricular cardiomyopathy, atherosclerotic cardiovascular disease (ASCVD), cessation and / or regression of atherosclerosis, COVID-19 (or SARS) The method according to claim 24, an MPO inhibitor for use, or use, which is CoV2-induced heart failure, COVID-19 (or SARS CoV2)-induced cardiomyopathy, cardiovascular disease, heart failure with preserved ejection fraction (HFpEF), renal crossover, first-time or recurrent myocardial infarction, peripheral artery disease, restrictive cardiomyopathy, unclassifiable cardiomyopathy, inhibition of plaque rupture, improvement of inflammation associated with plaque rupture, secondary myocardial infarction, ST-elevation myocardial infarction and / or non-ST-elevation myocardial infarction.

32. The method according to claim 30, an MPO inhibitor for use, or use, wherein the MPO-related disorder is heart failure (e.g., heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with maintained ejection fraction), myocardial infarction, coronary artery disease (CAD), peripheral artery disease, AAA, or stroke.

33. The method according to claim 32, an MPO inhibitor for use, or use, wherein the MPO-related disorder is heart failure with reduced ejection fraction (HFrEF), heart failure with mildly reduced ejection fraction (HFmrEF), or heart failure with maintained ejection fraction (HFpEF).

34. The method according to any one of claims 30 to 33, an MPO inhibitor for use, or use, wherein the treatment results in improvement from baseline in the Kansas City Cardiomyopathy Questionnaire Comprehensive Symptom Score (KCCQ-OSS) and / or improvement from baseline in the 6-minute walk distance (6MWD).

35. The method according to claim 34, an MPO inhibitor for use, or use, wherein the improvement of KCCQ-OSS and / or 6MWD is from baseline to 16 weeks, 24 weeks, or 48 weeks.

36. The method according to any one of claims 1 to 35, an MPO inhibitor for use, or use thereof, wherein the treatment results in a reduction from baseline in plasma levels of N-terminal pro-B natriuretic peptide (NT-proBNP), highly sensitive C-reactive protein (hsCRP), and / or interleukin-6 (IL-6).

37. The method according to claim 36, an MPO inhibitor for use, or use, wherein the reduction in plasma levels of NT-proBNP, hsCRP, and / or IL-6 is from baseline to 16 weeks, 24 weeks, or 48 weeks.

38. The method according to any one of claims 1 to 37, an MPO inhibitor for use, or use thereof, wherein the treatment results in an improvement from baseline in left ventricular total longitudinal strain (LV-GLS), left atrial volume index (LAVI), and / or left ventricular mass index (LVMI).

39. The method according to claim 38, an MPO inhibitor for use, or use, wherein the improvement of LV-GLS, LAVI and / or LVMI is from baseline to 16 or 24 weeks.

40. The method, MPO inhibitor for use, or use according to any one of claims 1 to 39, wherein the treatment results in a reduced risk of hospitalization, a reduced risk of emergency heart failure visits to a hospital requiring additional loop diuretic treatment, a reduced risk of myocardial infarction, a reduced risk of major adverse cardiovascular events (MACEs), and / or a reduced risk of cardiovascular death, compared to the case in which the treatment is not administered to the subject.

41. The MPO inhibitor is a compound of formula (I), 【Chemistry 1】 During the ceremony, R １ is H, F, Cl or CF ３ And, R ２ H, CH ３ or C ２ H ５ And, R ３ is H, CH ３ , C ２ H ５ , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl or cyclopentyl, The method according to any one of claims 1 to 40, an MPO inhibitor for use, or a pharmaceutically acceptable salt thereof.

42. 1-{2-[(1R)-1-aminopropyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-[2-(1-aminoethyl)-4-chlorobenzyl]-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(1R)-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(1S)-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{4-chloro-2-[1-(methylamino)ethyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{4-chloro-2-[(ethylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-[2-(aminomethyl)-4-chlorobenzyl]-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{4-chloro-2-[(methylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-(2-{[(cyclobutylmethyl)amino]methyl}benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(cyclobutylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(cyclopentylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-(2-{[(2-methylpropyl)amino]methyl}benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(propan-2-ylamino)methyl]benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-[2-(aminomethyl)-4-(trifluoromethyl)benzyl]-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; 1-{2-[(methylamino)methyl]-4-(trifluoromethyl)benzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one; The method according to claim 41, an MPO inhibitor for use, or a salt selected from the pharmaceutically acceptable salt thereof.

43. The aforementioned MPO inhibitor is given by formula (II) 【Chemistry 2】 It is a compound of, During the ceremony, X = CH or N Y １ = CZ １ Or N, Y ２ = CZ ２ Or N, Y ３ = CZ ３ Or N, Y ４ = CZ ４ Or N and Y ５ = CZ ５ Or it is N, Z １ Z ２ Z ３ Z ４ and Z ５ If present, H, Halo, CF are independent. ３ , Q or T, However, Y １ , Y ２ , Y ３ , Y ４ Or Y ５ One or less of these is N, and Y １ , Y ２ , Y ３ , Y ４ Or Y ５ At least two of them are CH and Z １ Z ２ Z ３ Z ４ and Z ５ One or fewer of these are either halo or CF ３ and 1, Z １ Z ２ Z ３ Z ４ and Z ５ Only one of them is either Q or T. Q is 【Transformation 3】 In the formula, m is 0, 1, 2, or 3. T is 【Chemistry 4】 And, p is 0 or 1, s is 0, 1, or 2. n is 0, 1, or 2. A is CH ２ CF ２ CHF, CHR ２ CFR ２ , NR ３ Or it is O, During the ceremony, R １ and R ２ If present, independently, CH ２ F, CHF ２ Or CF ３ And, R ３ If present, H or CH are independent. ３ And, The method according to any one of claims 1 to 40, an MPO inhibitor for use, or use thereof, which is any stereoisomer thereof or a pharmaceutically acceptable salt thereof.

44. The MPO inhibitor has a structure 【Transformation 5】 The method according to claim 43, having : an MPO inhibitor for use, or for use.

45. The aforementioned MPO inhibitor 1-(2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(4-chloro-2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(4-chloro-2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(4-chloro-2-(piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(4-chloro-2-(pyrroridine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(4-chloro-2-(pyrroridine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(4-chloro-2-(pyrroridine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(4-chloro-2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(4-chloro-2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(4-chloro-2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 3-(4-chloro-2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purine-6-one, 1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(2-(azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-3-(2-(azepan-2-yl)-4-chlorobenzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purine-6-one, (S)-3-(2-(azepan-2-yl)-4-chlorobenzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one, (R)-1-(2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(2-(morpholine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-(4-methylpiperazine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-(2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-(5-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-(4,4-difluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(2-(4,4-difluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(2-(4,4-difluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-3-(2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-3-(2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-Thioxo-3-(2-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 3-(2-(4,4-difluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purine-6-one, 3-(2-(5-fluoropiperidine-2-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-1-((2-(-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-((2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((cis)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-(2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((trans)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-(2-((2S,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-3-(2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purine-6-one, 2-Thioxo-3-(2-((trans)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-Thioxo-3-(2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, 2-Thioxo-3-(2-((2S,4S)-4-(trifluoromethyl)piperidine-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one, rac-1-(2-((2R,4S)-4-(difluoromethyl)piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-((2R,4S)-4-(difluoromethyl)piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-((2S,4R)-4-(difluoromethyl)piperidine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-((2-(piperidine-2-yl)pyridine-3-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((cis)-4-(trifluoromethyl)piperidine-2-yl)pyridine-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)pyridine-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((cis)-4-(trifluoromethyl)piperidine-2-yl)pyridine-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((3-((2S,4R)-4-(trifluoromethyl)piperidine-2-yl)pyridine-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(4-(1-aminocyclobutyl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(3-(1-aminocyclobutyl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-(piperidine-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-(morpholine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (R)-1-(2-(morpholine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, (S)-1-(2-(morpholine-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(2-(piperidine-4-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, rac-2-thioxo-1-((2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((trans)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((2R,4R)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 2-Thioxo-1-((2-((2S,4S)-4-(trifluoromethyl)piperidine-2-yl)pyridine-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, and The method according to claim 43, an MPO inhibitor for use, or use, selected from the pharmaceutically acceptable salts thereof.

46. The aforementioned MPO inhibitor is defined by formula (IIa): 【Transformation 6】 It is a compound having the following properties: During the ceremony, X １ = CH or N, Each X ２ These are independently CH, CF, or CCl, r and q are 0, 1, or 2, provided that r + q = 2 or 3. The method according to any one of claims 1 to 40, an MPO inhibitor for use, or use thereof, which is any stereoisomer thereof or a pharmaceutically acceptable salt thereof.

47. The aforementioned MPO inhibitor is given by formula (IIb): 【Transformation 7】 It is a compound having the following properties: During the ceremony, X １ = CH or N, Each X ２ These are independently CH, CF, or CCl, r and q are 0, 1, or 2, provided that r + q = 2 or 3. The method according to any one of claims 1 to 40, an MPO inhibitor for use, or use thereof, which is any stereoisomer thereof or a pharmaceutically acceptable salt thereof.

48. The aforementioned MPO inhibitor 1-((1,2,3,4-tetrahydroisoquinoline-8-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(isoindoline-5-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, 1-(isoindoline-4-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidine-4-one, and The method according to claim 43, an MPO inhibitor for use, or use, selected from the pharmaceutically acceptable salts thereof.

49. The method according to any one of claims 1 to 40, an MPO inhibitor for use, or use, wherein the MPO inhibitor is mitipelstat.

Images