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WO2025224179A1 - Inhibiteurs de glutaminyl cyclase destinés à être utilisés dans le traitement d'une maladie rénale - Google Patents

Inhibiteurs de glutaminyl cyclase destinés à être utilisés dans le traitement d'une maladie rénale

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Publication number
WO2025224179A1
WO2025224179A1 PCT/EP2025/061082 EP2025061082W WO2025224179A1 WO 2025224179 A1 WO2025224179 A1 WO 2025224179A1 EP 2025061082 W EP2025061082 W EP 2025061082W WO 2025224179 A1 WO2025224179 A1 WO 2025224179A1
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phenyl
compound
formula
alkyl
substituted
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Christine WENZKOWSKI
Stefan Tasler
Ulrich Heiser
Frank Weber
Michael Schaeffer
Torsten Hoffmann
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Vivoryon Therapeutics NV
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Vivoryon Therapeutics NV
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • the present invention is concerned with the use of the glutaminyl cyclase inhibitors of formula I in methods of treating kidney diseases, wherein R1, R2, R3, X, Y and Z are defined herein.
  • the invention further relates to pharmaceutical compositions comprising a compound of formula I and the therapeutic use thereof in methods of treating kidney diseases in mammals.
  • Glutaminyl cyclase (QC, EC 2.3.2.5) catalyzes the intramolecular cyclization of N-terminal glutamine, and, at a lower rate, also glutamate residues into pyroglutamic acid (pGlu*), liberating ammonia or water.
  • WO 2008/034891 discloses novel glutaminyl-peptide cyclotransferase-like proteins (QPCTLs), which are isoenzymes of glutaminyl cyclase (QC, EC 2.3.2.5), and isolated nucleic acids coding for these isoenzymes. Isoenzymes of glutaminyl cyclase were discovered in several mammalian species including the human isoQC. It was confirmed that the two enzymes, namely QC (also known as QPCT) and the isoenzyme isoQC (also known as QPCTL) are different. QC and isoQC are expressed in several tissues and organs of the body, including brain, lung, heart, liver and kidney.
  • QPCTLs novel glutaminyl-peptide cyclotransferase-like proteins
  • Crystal structures of both QC and isoQC for in silico screening are also known (WO 2012/022804 and WO 2012/059413).
  • QC and isoQC are closely related single-zinc metalloenzymes, which exhibit nearly identical substrate specificity in vitro and the major difference refers to subcellular localization: QC is secreted from expressing cells; isoQC is a resident enzyme of the golgi complex (Cynis et al. (2008), J Mol Biol 379: 966-980).
  • Physiological substrates of QC and isoQC in mammals are, e.g.
  • amyloid beta-peptides (3-40), (3-42), (11-40 and (11-42), ABri, ADan, Gastrin, Neurotensin, FPP, CCL 2, CCL 7, CCL 8, CCL 16, CCL 18, Fractalkine, Orexin A, [Gln3]-glucagon(3-29), [G1n5]-substance P(5-11) and the peptide QYNAD (WO 2008/034891 and WO2010/026209).
  • ECM extracelluar matrix
  • QC-activity can be relevant at two different stages of collagen deposition: either by acting on N-terminally located Glu and Gln on the respective N-propeptides, or, upon extracellular cleavage of the N-propeptide, on an N- terminally located Glu and Gln of the main collagen domain.
  • a post-translational modification has been described in the literature mainly for Col I, but also for Col III as well. Renal fibrosis is characterized by excessive deposition of extracellular matrix (ECM), leading to destruction of normal kidney architecture and loss of renal function.
  • ECM extracellular matrix
  • ⁇ - smooth-muscle-actin-positive (aSMA-positive) myofibroblasts plays a key role in this process.
  • Myofibroblasts are contractile, aSMA-positive cells with multiple roles in pathophysiological processes. Increased production of ECM components like type I and type III fibrillar collagens, hyaluronan, fibronectin, and extra domain A fibronectin distinguish the hallmarks of myofibroblasts.
  • collagen- producing myofibroblasts can be derived from various cellular sources.
  • Bone-marrow-derived fibroblast precursors contribute significantly to the pathogenesis of renal fibrosis.
  • Recruitment of circulating fibroblast precursors into the kidney is driven by chemokine / chemokine receptor interactions like CCL21/CCR7, CXCL16/CXCR6, and via CCR2: respective k.o. mice display 40-50% reduction of fibrosis for either of the first two chemoattractant targets, and 20-30% for the latter (CCR2).
  • chemokine CCL2 MCP-1
  • stability and affinity of which is described to be modulated by inhibition of QC-activity cf. below
  • the chemokines CCL21 and CXCL16 seem not to be equipped with an N-terminally located Glu or Gln residue (Ott et al. (2006), Biochem. Biophys. Res. Commun. 348, 1089-1093; van der Voort et al. (2010), J. Leukoc. Biol. 87: 1029-1039) and are thus no substrates for post-translational variations by QC-activity.
  • CCL21 exerts its chemoattractant activity via CCR7, and this receptor has been described to be unique among the chemokine receptors in being equipped with an N-terminal signal sequence – and cleavage of the latter sets free a Gln residue at the resulting N-terminus which in turn interacts with the C ⁇ terminal peptide of CCL21 to drastically augment CCL21 activity.
  • this receptor has been described to be unique among the chemokine receptors in being equipped with an N-terminal signal sequence – and cleavage of the latter sets free a Gln residue at the resulting N-terminus which in turn interacts with the C ⁇ terminal peptide of CCL21 to drastically augment CCL21 activity.
  • CCL2 (MCP-1), CCL7, CCL8, CCL16, CCL18 and fractalkine are chemotactic cytokines (chemokines) that attract and activate leukocytes and play a fundamental role in inflammation and in pathophysiological conditions, such as suppression of proliferation of myeloid progenitor cells, neoplasia, inflammatory host responses, cancer, psoriasis, rheumatoid arthritis, atherosclerosis, vasculitis, humoral and cell-mediated immunity responses, leukocyte adhesion and migration processes at the endothelium, inflammatory bowel disease, restenosis, pulmonary fibrosis, pulmonary hypertension, liver fibrosis, liver cirrhosis, nephrosclerosis, ventricular remodeling, heart failure, arteriopathy after organ transplantations and failure of vein grafts.
  • chemokines chemotactic cytokines
  • pE-residue protecting against proteolytic degradation in vivo
  • the formation of the N-terminal pE-residue is an important maturation step during synthesis and secretion of not only CCL2 but also hormones such as thyreotropin-releasing hormone and GNRH (Goren et al. (1977), Mol. Pharmacol. 13: 606-614; Abraham & Podell (1981), Mol. Cell. Biochem. 38: 181- 190; Awade et al. (1994), Proteins 20: 34-51).
  • the N-terminal pE of CCL2 can be post- translationally formed by both glutaminyl cyclase (E.C.2.3.2.5, QC) and its isoenzyme, the iso- glutaminyl cyclase (E.C. 2.3.2.-, isoQC) (Schilling et al. (2003), J. Biol. Chem. 278: 49773- 49779; Cynis et al. (2008), J. Mol. Biol. 379: 966-980; Cynis et al. (2011), EMBO Mol. Med. 3: 545-558).
  • N-terminal pE modification makes the protein resistant against N-terminal degradation by aminopeptidases, which is of importance, since chemotactic potency of CCL2 is mediated by its N-terminus (Van Damme, J., et al., (1999) Chem Immunol 72, 42-56). Artificial elongation or degradation leads to a loss of function although CCL2 still binds to its receptor (CCR2) (Proost, P., et al., (1998), J Immunol 160, 4034-4041; Zhang, Y.
  • the compounds of formula I are inhibitors of QC/isoQC and are described in WO 2011/029920.
  • WO 2011/029920 describes a broad range of compounds of formula I and discloses 235 example compounds.
  • WO 2011/029920 further describes the use of said compounds of formula I in the treatment of a disease or disorder selected from the group consisting of Kennedy’s disease, duodenal cancer with or without Helicobacter pylori infections, colorectal cancer, Zolliger-Ellison syndrome, gastric cancer with or without Helicobacter pylori infections, pathogenic psychotic conditions, schizophrenia, infertility, neoplasia, inflammatory host responses, cancer, malign metastasis, melanoma, psoriasis, impaired humoral and cell-mediated immune responses, leukocyte adhesion and migration processes in the endothelium, impaired food intake, impaired sleep-wakefulness, impaired homeostatic regulation of energy metabolism, impaired autonomic function, impaired hormonal balance or impaired regulation of body fluids, multiple sclerosis, the Guillain-Barré syndrome, chronic inflammatory demyelinizing polyradiculoneuropathy, mild cognitive impairment, Alzheimer’s disease, Familial British Dementia, Familial Danish De
  • Kidney disease or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney.
  • Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can be diagnosed by blood tests.
  • Nephrosis is non- inflammatory kidney disease. Nephritis and nephrosis can give rise to nephritic syndrome and nephrotic syndrome respectively.
  • Kidney disease usually causes a loss of kidney function to some degree and can result in kidney failure, the complete loss of kidney function.
  • Kidney failure is known as the end-stage of kidney disease, where dialysis or a kidney transplant is the only treatment option.
  • Chronic kidney disease CKD
  • Acute kidney disease is now termed acute kidney injury (AKI) and is marked by the sudden reduction in kidney function over seven days. In 2007, about one in eight Americans had chronic kidney disease. This rate is increasing over time and was about 1 in 7 Americans estimated to have CKD as of 2021.
  • the kidney has many functions, which a well-functioning kidney realizes by filtering blood in a process known as glomerular filtration. A major measure of kidney function is the glomerular filtration rate (GFR).
  • GFR glomerular filtration rate
  • the glomerular filtration rate is the flow rate of fluid to be filtered through the kidney.
  • the creatinine clearance rate (CCr or CrCl) is the volume of blood plasma that is cleared of creatinine per unit time and is a useful measure for approximating the GFR. Both GFR and CCr may be accurately calculated by comparative measurements of substances in the blood and urine, or estimated by formulas using just a blood test result (eGFR and eCCr) The results of these tests are used to assess the excretory function of the kidneys. Staging of chronic kidney disease is based on categories of GFR as well as albuminuria and cause of kidney disease (Stevens PE, Levin A (2013) Annals of Internal Medicine.158 (11): 825–830).
  • kidney disease causes deposition of the Immunoglobulin A antibodies in the glomerulus, administration of analgesics, xanthine oxidase deficiency, toxicity of chemotherapy agents, and a long-term exposure to lead or its salts.
  • Chronic conditions that can produce nephropathy include systemic lupus erythematosus, diabetes mellitus and high blood pressure (hypertension), which lead to diabetic nephropathy and hypertensive nephropathy, respectively.
  • a first hind towards the involvement of QC/isoQC in kidney diseases was recently published by Kanemitsu et al. (Kanemitsu et al.
  • PQ529 can only be produced as racemate, which is disadvantageous for a possible clinical development of this compound. There is a great need of new therapeutics, which target QC/isoQC, for treating kidney diseases. Description of the Invention It is therefore the purpose of the present invention to provide inhibitors of QC/isoQC for use in methods of treating kidney diseases.
  • said kidney disease is an acute kidney disease (AKI) or a chronic kidney disease (CKD).
  • AKI acute kidney disease
  • CKD chronic kidney disease
  • Persistent, low-grade inflammation has been recognized as an important component of CKD, playing a unique role in its pathophysiology and being accountable in part for cardiovascular and all-cause mortality, as well as contributing to the development of protein-energy wasting.
  • a variety of factors contribute to chronic inflammatory status in CKD, including increased production and decreased clearance of pro-inflammatory cytokines, oxidative stress and acidosis, chronic and recurrent infections, including those related to dialysis access, altered metabolism of adipose tissue, and intestinal dysbiosis.
  • Inflammation directly impacts the glomerular filtration rate (GFR) in CKD and culminates in dialysis patients, where extracorporeal factors, such as impurities in dialysis water, microbiological quality of the dialysate, and bioincompatible factors in the dialysis circuit play an additional role (Akchurin O.M. and Kaskel F. (2015) Blood Purif (2015) 39 (1-3): 84–92).
  • GFR glomerular filtration rate
  • the compounds of formula I are supposed to suppress the progression of inflammation-induced renal dysfunction by inhibiting the CCL2/CCR2 axis.
  • the kidney disease to be treated with a compound of formula I according to the invention is therefore a CKD which is accompanied by a persistent inflammation.
  • TGF-ß1 transforming growth factor beta 1
  • Innate immune cells are key contributors to kidney inflammation and fibrosis. Infiltration of the renal parenchyma by innate immune cells is governed by multiple signalling pathways. Since the discovery of the chemokine fractalkine (CX3CL1) and its receptor, CX3CR1 over twenty years ago, a wealth of evidence has emerged linking CX3CL1-CX3CR1 signalling to renal pathologies in both acute and chronic kidney diseases (CKD). Although acute autoimmune kidney disease is often successfully treated with immunomodulatory medications, there is a notable lack of treatment options for patients with progressive fibrotic CKD.
  • CX3CL1-CX3CR1 interactions mediate important events in the intra-renal pathophysiology of CKD progression, particularly via recruitment of innate immune cells into the kidney.
  • the compounds of formula I act on the CX3CL1-CX3CR1 system and offers therefore an attractive alternative for the treatment of fibrotic CKD.
  • the compounds of formula I exert anti-fibrotic effects.
  • the kidney disease to be treated with a compound of formula I according to the invention is kidney fibrosis, such as fibrotic CKD.
  • Chemokine CC motif ligand 7 also known as monocyte chemotactic protein (MCP)- 3, is a chemotactic factor for monocytes and neutrophils. Elevated CCL7 expression is observed in cardiovascular disease, diabetes mellitus, and kidney disease. (Chang et al.
  • CCL7 may promote the progression of atherosclerosis and aortic aneurysm and play a significant role in the inflammatory events underlying most vascular diseases, diabetes mellitus, and kidney disease by attracting macrophages and monocytes to amplify inflammatory processes and contribute to the disease progression.
  • target drugs or small molecule drugs against CCL7 there are currently no target drugs or small molecule drugs against CCL7.
  • Activity profile of CCL7 as a substrate for QC/isoQC post-translational modification is vulnerable to enzyme inhibition by the compounds of formula I of the present invention, which thus offer an attractive alternative for the treatment of forms of CKD.
  • chemokines Due to the multiple redundancy system among chemokines and their receptors, further experimental and clinical studies should be interesting to focus not only on direct anti-CCL7 mechanisms but also on combined approaches to target more than one relevant chemokine (e.g. CCL2, CCL7, CX3CL1) as promising therapeutic approach to attenuating the development of cardiovascular disease, diabetes mellitus, and kidney disease.
  • the compounds of formula I act on post-translational modifications on all of e.g. CCL2, CCL7, CX3CL1, which thus offer an attractive alternative for the treatment of forms of CKD. It is known that there are risk factors that may cause and promote the progression of CKD. High blood pressure (hypertension) and diabetes mellitus are the two most common causes of CKD.
  • kidney function and can cause chronic kidney disease include: • Glomerulonephritis. This type of kidney disease involves damage to the glomeruli, which are the filtering units inside your kidneys. • Polycystic kidney disease. This is a genetic disorder that causes many fluid-filled cysts to grow in your kidneys, reducing the ability of your kidneys to function. • Membranous nephropathy. This is a disorder where the body’s immune system attacks the waste-filtering membranes in your kidney. • Obstructions of the urinary tract from kidney stones, an enlarged prostate or cancer. • Vesicoureteral reflux. This is a condition in which pee flows backward back up the ureters to your kidneys. • Nephrotic syndrome.
  • kidney damage This is a collection of symptoms that indicate kidney damage.
  • Recurrent kidney infection pryelonephritis.
  • Diabetes-related nephropathy This is damage or dysfunction of one or more nerves, caused by diabetes mellitus.
  • Lupus and other immune system diseases that cause kidney problems, including polyarteritis nodosa, sarcoidosis, Goodpasture syndrome and Henoch-Schönlein purpura.
  • Connective tissue diseases CTD
  • collagenoses collagenopathies. Therefore, in some embodiments, the (chronic) kidney diseases to be treated with a compound of formula I according to the invention is diabetic nephropathy (DKD).
  • DKD diabetic nephropathy
  • Diabetic nephropathy is typically characterized by damage to the capillaries supplying the kidney glomeruli, which leads to declining filtering efficiency in the kidney and progressive loss in renal function that can lead to end-stage renal disease, with patients requiring dialysis or a kidney transplant.
  • the diabetic nephropathy is caused by diabetes type 1 or diabetes type 2.
  • the (chronic) kidney diseases to be treated with a compound of formula I according to the invention is Focal Segmental Glomerulosclerosis (FSGS).
  • FSGS is a chronic, progressive form of kidney disease characterized by scarring (sclerosis) of the glomeruli.
  • the (chronic) kidney diseases to be treated with a compound of formula I according to the invention is a condition that may cause CKD and is selected from the group consisting of glomerulonephritis, polycystic kidney disease, membranous nephropathy, obstructions of the urinary tract, vesicoureteral reflux, nephrotic syndrome, recurrent kidney infection (pyelonephritis), lupus (Systemic lupus erythematosus; SLE) and, other immune system diseases selected from the group consisting of polyarteritis nodosa, sarcoidosis, Goodpasture syndrome and Henoch-Schönlein purpura.
  • the present invention provides the use of the varoglutamstat, as described herein, for the preparation of a medicament for the alleviation or treatment of a condition that may cause CKD and is selected from the group consisting of Alport syndrome, Fabry disease, and connective tissue diseases (CTD).
  • CTD connective tissue diseases
  • the treatment with compounds of formula I preferably chronic treatment of subjects, increases the GFR when compared to untreated control subjects.
  • said kidney disease to be treated with a compound of formula I according to the invention is preferably a kidney disease which is associated with an impaired glomerular filtration rate (GFR).
  • Creatinine is produced naturally by the body (creatinine is a breakdown product of creatine phosphate, a small molecule, which is found in muscle). It is freely filtered by the glomerulus, but also actively secreted by the peritubular capillaries in very small amounts such that creatinine clearance overestimates actual GFR by 10% to 20%. This margin of error is acceptable, considering the ease with which creatinine clearance is measured.
  • creatinine is already at a steady-state concentration in the blood, and so measuring creatinine clearance is much less cumbersome.
  • creatinine estimates of GFR have their limitations. All of the estimating equations depend on a prediction of the 24-hour creatinine excretion rate, which is a function of muscle mass which is quite variable. As a result, estimated glomerular filtration rate (eGFR) is obtained.
  • eGFR estimated glomerular filtration rate
  • Estimated GFR (eGFR) is now recommended by clinical practice guidelines and regulatory agencies for routine evaluation of GFR whereas measured GFR (mGFR) is recommended as a confirmatory test when more accurate assessment is required.
  • mGFR measured GFR
  • the so-called "4-variable MDRD” (Modification of Diet in Renal Disease) has been used, which estimates GFR using four variables: serum creatinine, age, ethnicity, and gender.
  • the GFR is used to describe the severity of a CKD. For most patients, a GFR over 60 ml/min/1.73m 2 is considered adequate.
  • kidney disease The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and definition of first three also depends on whether there is other evidence of kidney disease (e.g., proteinuria): 0 ) Normal kidney function – GFR above 90 ml/min/1.73 m2 and no proteinuria 1) CKD1 – GFR above 90 ml/min/1.73 m2 with evidence of kidney damage 2) CKD2 (mild) – GFR of 60 to 89 ml/min/1.73 m2 with evidence of kidney damage 3) CKD3 (moderate) – GFR of 30 to 59 ml/min/1.73 m2 4) CKD4 (severe) – GFR of 15 to 29 ml/min/1.73 m2 5) CKD5 (kidney failure) – GFR less than 15 ml/min/1.73 m2 Some people add CKD5D for those stage 5
  • the MDRD formula reads as follows: As a sensitivity analysis, eGFR was calculated not only with MDRD formula, but also with the CKD-EPI Cystatin C formula as defined in Inker, L. A. et al. (2021), N Engl J Med 385: 1737- 1749. See Figures 10 and 11.
  • subjects without risk factors are treated with a compound of formula I.
  • subjects with risk factors are treated with a compound of formula I.
  • the difference between treatment groups in subjects with risk factors for CKD is highly significant and clinically meaningful.
  • Subjects on treatment with a compound of formula I improve above baseline in a dose dependent manner, whereas subjects with risk factors for kidney disease on placebo decline approximately 2.8 ml/min/1.73m2/yr, which represents an expected and credible rate of decline (see Figure 3).
  • the subjects treated with a compound of formula I according to the invention were suffering from type 1 or type 2 diabetes mellitus and/or hypertension as risk factors for CKD.
  • a mean annualized eGFR change (calculated as difference over the placebo group) of about 3.5 ml/min/1.73m2/yr has been observed in the treatment group treated with 300 mg twice daily of a compound of formula I and, of about 6.6 ml/min/1.73m2/yr in the treatment group treated with 600 mg twice daily of a compound of formula I (all values calculated as difference over the placebo group, see Figure 3)
  • a mean annualized eGFR change (calculated as the difference over the placebo group) of about -0.29 ml/min/1.73m2/yr has been observed in the treatment group treated with 300 mg twice daily of a compound of formula I
  • the subjects treated with a compound of formula I were suffering from hypertension or diabetes mellitus (type 1 or type 2) or cardiac disease or an eGFR ⁇ 60 ml/min/1.73m 2 as risk factors for a CKD.
  • the treatment with a compound of formula I leads to an annualized eGFR change (expressed as difference over the placebo group) of 1.5 ml/min/1.73m 2 /yr or higher, preferably 2.0 ml/min/1.73m 2 /yr or higher, more preferably of 2.5 ml/min/1.73m 2 /yr or higher, most preferably 3.0 ml/min/1.73m 2 /yr or higher in a subject without risk factors for CKD, wherein the eGFR is calculated with the MDRD method.
  • the treatment with a compound of formula I leads to an annualized eGFR change (expressed as difference over the placebo group) of 3.0 ml/min/1.73m2/yr or higher or 3.5 ml/min/1.73m2/yr or higher, preferably 4.0 ml/min/1.73m2/yr or higher or 4.5 ml/min/1.73m2/yr or higher, more preferably of 5.0 ml/min/1.73m2/yr or higher or 5.5 ml/min/1.73m 2 /yr or higher, most preferably 6.0 ml/min/1.73m 2 /yr or higher or 6.5 ml/min/1.73m 2 /yr or higher or 7.0 ml/min/1.73m 2 /yr or higher in a subject with risk factors for CKD, wherein the eGFR is calculated with the MDRD method.
  • said risk factors for CKD are selected from type 1 or 2 diabetes mellitus and/or hypertension.
  • the subjects treated with a compound of formula I were suffering from CKD risk factor type 1 or type 2 diabetes mellitus (with or without hypertension) at baseline.
  • the treatment with a compound of formula I led to an annualized eGFR change (expressed as difference over the placebo group) of 10.05 ml/min/1.73m2/yr, when calculated with the MDRD formula ( Figure 10); or 4.87 ml/min/1.73m 2 /yr, when calculated with the 2012 CKD-EPI Cystatin C formula ( Figure 11).
  • the treatment with a compound of formula I leads to an annualized eGFR change (expressed as difference over the placebo group) of 5.0 ml/min/1.73m2/yr or higher or 6.0 ml/min/1.73m2/yr or higher, preferably 7.0 ml/min/1.73m2/yr or higher or 8.0 ml/min/1.73m2/yr or higher, more preferably of 9.0 ml/min/1.73m2/yr or higher, most preferably 10.0 ml/min/1.73m2/yr or higher or 11.0 ml/min/1.73m 2 /yr or higher or 12.0 ml/min/1.73m 2 /yr or higher in a subject with type 1 or type 2 diabetes mellitus (with or without hypertension) as risk factors for CKD, wherein the eGFR is calculated with the MDRD method.
  • the treatment with a compound of formula I leads to an annualized eGFR change (expressed as difference over the placebo group) of 3.0 ml/min/1.73m2/yr or higher, preferably 3.5 ml/min/1.73m2/yr or higher, more preferably of 4.0 ml/min/1.73m2/yr or higher, most preferably 4.5 ml/min/1.73m2/yr or higher or 5.0 ml/min/1.73m2/yr or higher or 5.5 ml/min/1.73m2/yr or higher in a subject with type 1 or type 2 diabetes mellitus (with or without hypertension) as risk factors for CKD, wherein the eGFR is calculated with the 2012 CKD-EPI Cystatin C formula.
  • the treatment of CKD with a compound of formula I is effective in human subjects with and without risk factors for CKD.
  • the treatment effect is higher in human subjects with risk factors for CKD.
  • the treatment effect is dose dependent and is higher in treatment groups treated with higher doses, such as 600 mg twice daily, than in the treatment group treated with lower doses, such as 300 mg twice daily.
  • the compound of formula I for use in the treatment of CKD is preferably administered at a dose of > 300 mg twice daily, more preferably at a dose of 450 mg twice daily or higher, and most preferably at a dose of 600 mg twice daily or higher.
  • the results obtained with the treatment of human subjects with a compound of formula I were further confirmed by an in vivo study in mice (see example 3 below).
  • results of the treatment with compounds of formula I were as follows: ⁇ a decrease of FITC-Sinistrin clearance T1/2 and thus an increase of GFR, ⁇ decrease of plasma biomarkers urea, creatinine, and cystatin C, and ⁇ decreases of histomorphometric parameters Col III (slightly), aSMA, and KIM-1. ⁇
  • the invention provides a method for the prophylaxis, prevention and/or treatment of a kidney disease or condition as described herein, in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate or polymorph thereof, or a herein described pharmaceutical composition to the subject.
  • the invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt or solvate or polymorph thereof, or a herein described pharmaceutical composition in the preparation of a medicament for the prophylaxis, prevention and/or treatment of a kidney disease or condition as described herein, in a subject.
  • Said subject is suitably a mammal.
  • Said mammal is preferably a human.
  • the present invention concerns the use of a compound of formula I and pharmaceutical compositions containing the same, as described and claimed herein, in human and veterinary medicine. Therefore, said mammalian subject may also be an animal, such as a cat or dog, which may suffer from a kidney disease to be treated with a compound of formula I as described herein.
  • QC activity as used herein is defined to subsume all intramolecular cyclization reactions of N-terminal glutamine and N-terminal glutamate residues into pyroglutamic acid (pGlu*) by catalytically accelerated transformation through the enzymes QPCT (“QC”) and QPCTL (“isoQC”) (the general course is delineated in Scheme 1).
  • Scheme 1 Cyclization of glutamine or glutamate by QC/isoQC
  • QC activity is also encompassing similarly catalyzed transformations of N- terminal L-homoglutamine or L- ⁇ -homoglutamine into respective cyclic pyro-homoglutamic acid derivatives.
  • QC-inhibitor “glutaminyl cyclase inhibitor” is generally known to a person skilled in the art and means enzyme inhibitors, which inhibit the catalytic activity of both, the QC and/or isoQC enzyme on both general groups of substrates, N-terminal glutamine and glutamate residues.
  • therapeutically effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • the term “pharmaceutically acceptable” embraces both human and veterinary use:
  • the term “pharmaceutically acceptable” embraces a veterinarily acceptable compound or a compound acceptable in human medicine and health care.
  • alkyl denotes a C1-12 alkyl group, suitably a C1-8 alkyl group, e.g. C1-6 alkyl group, e.g. C1-4 alkyl group.
  • Alkyl groups may be straight chain or branched. Suitable alkyl groups include, for example, methyl, ethyl, propyl (e.g.
  • n-propyl and isopropyl e.g n-butyl, iso-butyl, sec- butyl and tert-butyl
  • pentyl e.g. n-pentyl
  • hexyl e.g. n-hexyl
  • heptyl e.g. n-heptyl
  • octyl e.g. n-octyl.
  • Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g. n-propoxy), butoxy (e.g. n-butoxy), pentoxy (e.g. n-pentoxy), hexoxy (e.g. n-hexoxy), heptoxy (e.g. n-heptoxy) and octoxy (e.g. n- octoxy).
  • Exemplary thioalkyl groups include methylthio-.
  • Exemplary haloalkyl groups include fluoroalkyl e.g. CF 3 .
  • alkenyl denotes a C2-12 alkenyl group, suitably a C 2-6 alkenyl group, e.g. a C 2-4 alkenyl group, which contains at least one double bond at any desired location and which does not contain any triple bonds.
  • Alkenyl groups may be straight chain or branched.
  • Exemplary alkenyl groups including one double bond include propenyl and butenyl.
  • Exemplary alkenyl groups including two double bonds include pentadienyl, e.g. (1E, 3E)-pentadienyl.
  • alkynyl denotes a C2-12 alkynyl group, suitably a C2-6 alkynyl group, e.g. a C2-4 alkynyl group, which contains at least one triple bond at any desired location and may or may not also contain one or more double bonds.
  • Alkynyl groups may be straight chain or branched.
  • Exemplary alkynyl groups include propynyl and butynyl.
  • alkylene denotes a chain of formula -(CH2)n- wherein n is an integer e.g. 2-5, unless specifically limited.
  • cycloalkyl denotes a C 3-10 cycloalkyl group (i.e. 3 to 10 ring carbon atoms), more suitably a C3-8 cycloalkyl group, e.g. a C3-6 cycloalkyl group.
  • exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • a most suitable number of ring carbon atoms is three to six.
  • cycloalkenyl denotes a C 5-10 cycloalkenyl group (i.e.5 to 10 ring carbon atoms), more suitably a C 5-8 cycloalkenyl group e.g. a C 5-6 cycloalkenyl group.
  • exemplary cycloalkenyl groups include cyclopropenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • a most suitable number of ring carbon atoms is five to six.
  • Carbocyclyl denotes any ring system in which all the ring atoms are carbon and which contains between three and twelve ring carbon atoms, suitably between three and ten carbon atoms and more suitably between three and eight carbon atoms.
  • Carbocyclyl groups may be saturated or partially unsaturated, but do not include aromatic rings. Examples of carbocyclyl groups include monocyclic, bicyclic, and tricyclic ring systems, in particular monocyclic and bicyclic ring systems. Other carbocylcyl groups include bridged ring systems (e.g. bicyclo[2.2.1]heptenyl).
  • a specific example of a carbocyclyl group is a cycloalkyl group.
  • a further example of a carbocyclyl group is a cycloalkenyl group.
  • a specific example of a heterocyclyl group is a cycloalkyl group (e.g. cyclopentyl or more particularly cyclohexyl) wherein one or more (e.g.1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S or O.
  • heterocyclyl groups containing one hetero atom include pyrrolidine, tetrahydrofuran and piperidine, and exemplary heterocyclyl groups containing two hetero atoms include morpholine and piperazine.
  • a further specific example of a heterocyclyl group is a cycloalkenyl group (e.g. a cyclohexenyl group) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S and O.
  • An example of such a group is dihydropyranyl (e.g.3,4-dihydro-2H-pyran-2-yl-).
  • aryl denotes a C6-12 aryl group, suitably a C6-10 aryl group, more suitably a C 6-8 aryl group.
  • Aryl groups will contain at least one aromatic ring (e.g. one, two or three rings).
  • An example of a typical aryl group with one aromatic ring is phenyl.
  • An example of a typical aryl group with two aromatic rings is naphthyl.
  • heteroaryl unless specifically limited, denotes an aryl residue, wherein one or more (e.g.
  • ring atoms are replaced by heteroatoms selected from N, S and O, or else a 5-membered aromatic ring containing one or more (e.g.1, 2, 3, or 4, suitably 1, 2 or 3) ring atoms selected from N, S and O.
  • Exemplary monocyclic heteroaryl groups having one heteroatom include: five membered rings (e.g. pyrrole, furan, thiophene); and six membered rings (e.g. pyridine, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl).
  • Exemplary monocyclic heteroaryl groups having two heteroatoms include: five membered rings (e.g.
  • Exemplary monocyclic heteroaryl groups having three heteroatoms include: 1,2,3-triazole and 1,2,4-triazole.
  • Exemplary monocyclic heteroaryl groups having four heteroatoms include tetrazole.
  • Exemplary bicyclic heteroaryl groups include: indole (e.g.
  • halogen or “halo” comprises fluorine (F), chlorine (Cl) and bromine (Br).
  • amino refers to the group -NH 2 .
  • phenyl substituted by phenyl refers to biphenyl.
  • benzimidazolyl is shown as benzimidazol-5-yl, which is represented as: , the person skilled in the art will appreciate that benzimidazol-6-yl, which is represented as: , is an equivalent structure.
  • the two forms of benzimidazolyl are covered by the term “benzimidazol-5-yl”.
  • Stereoisomers All possible stereoisomers of the claimed compounds are included in the present invention. There the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers.
  • stereoisomers Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Preparation and isolation of stereoisomers: Where the processes for the preparation of the compounds according to the invention give rise to a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • an optically active acid such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • salts and solvates of the compounds of formula (I) and physiologically functional derivatives thereof which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable.
  • salts and solvates having non- pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds and their pharmaceutically acceptable salts and solvates.
  • Suitable salts according to the invention include e.g.
  • Preferred embodiments of the compounds of formula I for use in the methods of the invention When carbocyclyl and heterocyclyl are substituted, they are typically substituted by 1 or 2 substituents (e.g.1 substitent). Typically the substituent is methyl. More typically carbocyclyl and heterocyclyl groups are unsubstituted. When aryl and heteroaryl are substituted, they are typically substituted by 1, 2 or 3 (e.g.1 or 2) substituents. Substituents for aryl and heteroaryl are selected from C1-6alkyl (e.g. methyl), C2- 6 alkenyl (e.g. buten-3-yl), C 2-6 alkynyl (e.g.
  • C 1-6 haloalkyl e.g. fluoromethyl, trifluoromethyl
  • -C 1-6 thioalkyl e.g. -S-methyl
  • -SOC 1-4 alkyl e.g. -SOmethyl
  • -SO 2 C 1-4 alkyl e.g. -SO2methyl
  • C1-6alkoxy- e.g. methoxy, ethoxy
  • -O-C3-8cycloalkyl e.g. –O-cyclopentyl
  • C3-8cycloalkyl e.g. cyclopropyl, cyclohexyl
  • -SO2C3-8cycloalkyl e.g.
  • -SO2cyclohexyl - SOC3-6cycloalkyl (e.g. -SOcyclopropyl), C3-6alkenyloxy- (e.g. -O-buten-2-yl), C3-6alkynyloxy- (e.g. -O-buten-2-yl), -C(O)C1-6alkyl (e.g. –C(O)ethyl), -C(O)OC1-6alkyl (e.g. -C(O)O-methyl), C1-6alkoxy-C1-6alkyl- (e.g. methoxy-ethyl-), nitro, halogen (e.g.
  • substituents will be selected from C 1-6 alkyl (e.g. methyl), C 1-6 haloalkyl (e.g. C 1- 6 fluoroalkyl, e.g. CF 3 ), C 1-6 alkoxy (e.g. OMe), halogen and hydroxy.
  • R 1 represents heteroaryl
  • examples include monocyclic (e.g. 5 and 6 membered) and bicyclic (e.g. 9 and 10 membered, particularly 9 membered) heteroaryl rings, especially rings containing nitrogen atoms (e.g.1 or 2 nitrogen atoms).
  • a suitable bicyclic heteroaryl ring is a 9-membered heteroaryl ring containing 1 or 2 nitrogen atoms, especially a benzene ring fused to a 5-membered ring containing one or two nitrogen atoms (e.g.1H-benzoimidazolyl). Most suitably the point of attachment is through a benzene ring, e.g. the group is 1H-benzoimidazol- 5-yl.
  • Aforementioned heteroaryl groups may either be unsubstituted (which is more typical) or may suitably be substituted by one or more (e.g.1 or 2) substituents selected from alkyl (e.g. C1-4 alkyl such as Me), alkoxy- (e.g.
  • R 1 represents -C 3-8 carbocyclyl-heteroaryl
  • examples of carbocyclyl include cycloalkyl (e.g. cyclohexyl) and cycloalkenyl (e.g. cyclohexenyl)
  • examples of heteroaryl groups include monocyclic (e.g.5 or 6 membered, particularly 5 membered) rings especially rings containing nitrogen atoms e.g. 1 or 2 nitrogen atoms.
  • Aforementioned heteroaryl groups may either be unsubstituted (which is more typical) or may suitably be substituted by one or more (e.g.1 or 2) substituents selected from alkyl (e.g. C1-4 alkyl such as Me), alkoxy- (e.g. C1-4 alkoxy- such as OMe) and halogen (e.g. F).
  • alkyl e.g. C1-4 alkyl such as Me
  • alkoxy- e.g. C1-4 alkoxy- such as OMe
  • halogen e.g. F
  • a suitable heteroaryl group is imidazol-1-yl.
  • An exemplary - C3-8carbocyclyl-heteroaryl group is 3-imidazol-1-yl-cyclohexyl-.
  • examples of C2-6 alkenyl include C2-4 alkenyl, in particular propenyl and examples of heteroaryl groups include monocyclic (e.g. 5 or 6 membered, particularly 5 membered) rings especially rings containing nitrogen atoms e.g.1 or 2 nitrogen atoms.
  • Aforementioned heteroaryl groups may either be unsubstituted (which is more typical) or may suitably be substituted by one or more (e.g.1 or 2) substituents selected from alkyl (e.g. C1-4alkyl such as Me), alkoxy- (e.g. C1-4 alkoxy- such as OMe) and halogen (e.g. F).
  • a suitable heteroaryl group is imidazolyl, particularly imidazol-1-yl.
  • An exemplary - alkenylheteroaryl group is 3-imidazol-1-yl-prop-2-enyl-.
  • R 1 represents -C1-6alkylheteroaryl
  • examples of C1-6 alkyl include C1-5alkyl or C1-4alkyl, especially C 2-5 alkyl or C 2-4 alkyl, in particular propyl
  • examples of heteroaryl groups include monocyclic (e.g. 5 or 6 membered, particularly 5 membered) rings especially rings containing nitrogen atoms e.g.1 or 2 nitrogen atoms.
  • Aforementioned heteroaryl groups may either be unsubstituted (which is most typical) or may suitably be substituted by one or more (e.g. 1 or 2) substituents selected from alkyl (e.g. C1-4 alkyl such as Me), alkoxy- (e.g. C1-4 alkoxy- such as OMe) and halogen (e.g. F).
  • alkyl e.g. C1-4 alkyl such as Me
  • alkoxy- e.g. C1-4 alkoxy- such as OMe
  • halogen e.g. F
  • a suitable heteroaryl group is imidazol-1-yl.
  • a particularly suitable -alkylheteroaryl group is 3-imidazol-1-yl-propyl-.
  • R 1 represents -C 1-6 alkylheteroaryl
  • examples wherein alkyl is branched include: .
  • R 1 heteroaryl groups include a 9-membered bicyclic ring containing 2 nitrogen atoms, which ring may optionally be substituted, for example:
  • the heteroaryl groups shown above may also be present as part of a larger R 1 function such as -C3-8carbocyclyl-heteroaryl, -C2-6alkenylheteroaryl or –C1-6alkylheteroaryl.
  • R 2 represents -C1-8alkyl
  • examples include methyl, ethyl, propyl (e.g. n-propyl, isopropyl), butyl (e.g.
  • aryl may typically represent phenyl.
  • Exemplary substituted phenyl groups include 3-methylphenyl-, 2,3-dichlorophenyl-, 2,3-difluorophenyl-, 2,4-dichlorophenyl-, 2,4-difluororophenyl-, 2,4-dimethoxyphenyl-, 2,4-dimethylphenyl-, 2,4- bis(trifluoromethyl)phenyl-, 2,4,6-trifluorophenyl-, 2,4,6-trimethylphenyl-, 2,6- dichlorophenyl-, 2,6-difluorophenyl-, 2,6-dimethoxyphenyl-, 2,6-difluoro-4-(methoxy)phenyl- , 2-isopropyl-6-methylphenyl-, 3-(cyclopentyloxy)-4-methoxyphenyl-, 3,4,5- trimethoxyphenyl-, 3,4-dimethoxyphenyl-, 3,4-dichloropheny
  • R 2 may represent unsubstituted phenyl-.
  • substituted phenyl groups include 2,3,4- trifluorophenyl, 2,3-difluoro-4-methylphenyl, 2-bromo-4-fluorophenyl-, 2-bromo-5- fluorophenyl-, 2-chlorophenyl-, 2-fluorophenyl-, 2-fluoro-5-(trifluoromethyl)phenyl-, 2- hydroxy-3-methoxyphenyl-, 2-hydroxy-5-methylphenyl-, 3-chlorophenyl-, 3-fluorophenyl-, 3- fluoro-4-(trifluoromethyl)phenyl-, 3-fluoro-5-(trifluoromethyl)phenyl-, 2-fluoro-4- (trifluoromethyl)phenyl-, 3-fluoro-4-(methoxy)phenyl-, 3-hydroxy-4-methoxyphenyl-, 4- bromo-2-fluorophenyl, 2,
  • R 2 represents optionally substituted aryl and aryl represents naphthyl
  • examples include unsubstituted naphthyl (e.g. naphthalen-1-yl, naphthalen-2-yl, naphthalen-3-yl) as well as substituted naphthyl (e.g. 4-methyl-naphthalen-2-yl-, 5-methyl-naphthalen-3-yl-, 7-methyl- naphthalen-3-y- and 4-fluoro-naphthalen-2-yl-).
  • examples include monocyclic rings (e.g.
  • Example 5 membered rings include pyrrolyl (e.g. pyrrol-2-yl) and imidazolyl (e.g. 1H-imidazol-2-yl or 1H-imidazol-4-yl), pyrazolyl (e.g. 1H-pyrazol-3-yl), furanyl (e.g. furan-2-yl), thiazolyl (e.g. thiazol-2-yl), thiophenyl (e.g. thiophen-2-yl, thiophen-3-yl).
  • pyrrolyl e.g. pyrrol-2-yl
  • imidazolyl e.g. 1H-imidazol-2-yl or 1H-imidazol-4-yl
  • pyrazolyl e.g. 1H-pyrazol-3-yl
  • furanyl e.g. furan-2-yl
  • thiazolyl e.g. thiazol-2-
  • Example 6 membered rings include pyridinyl (e.g. pyridin-2-yl and pyridin-4-yl). Specific substituents that may be mentioned are one or more e.g.1, 2 or 3 groups selected from halogen, hydroxyl, alkyl (e.g. methyl) and alkoxy- (e.g. methoxy-).
  • Example substituted 5 membered rings include 4,5-dimethyl-furan-2-yl-, 5-hydroxymethyl-furan-2-yl-, 5-methyl-furan-2-yl- and 6-methyl-pyridin-2-yl-.
  • An example substituted 6-membered ring is 1-oxy-pyridin-4-yl-.
  • Example 9 membered rings include 1H-indolyl (e.g. 1H-indol-3-yl, 1H-indol-5-yl), benzothiophenyl (e.g. benzo[b]thiophen-3-yl, particularly 2-benzo[b]thiophen-3-yl), benzo[1,2,5]-oxadiazolyl (e.g. benzo[1,2,5]-oxadiazol-5-yl), benzo[1,2,5]-thiadiazolyl (e.g. benzo[1,2,5]-thiadiazol-5-yl, benzo[1,2,5]thiadiazol-6-yl).
  • benzothiophenyl e.g. benzo[b]thiophen-3-yl, particularly 2-benzo[b]thiophen-3-yl
  • benzo[1,2,5]-oxadiazolyl e.g. benzo[1,2,5]-oxadiazol-5-yl
  • Example 10 membered rings include quinolinyl (e.g.quinolin-3-yl, quinolin-4-yl, quinolin-8-yl). Specific substituents that may be mentioned are one or more e.g.1, 2 or 3 groups selected from halogen, hydroxyl, alkyl (e.g. methyl) and alkoxy- (e.g. methoxy-).
  • Example substituted 9-membered rings include 1- methyl-1H-indol-3-yl, 2-methyl-1H-indol-3-yl, 6-methyl-1H-indol-3-yl.
  • Example substituted 10 membered rings include 2-chloro-quinolin-3-yl, 8-hydroxy-quinolin-2-yl, oxo-chromenyl (e.g.4-oxo-4H-chromen-3-yl) and 6-methyl-4-oxo-4H-chromen-3-yl.
  • R 2 represents carbocyclyl
  • examples include cycloalkyl and cycloalkenyl.
  • cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Examples of cycloalkenyl include cyclohexenyl (e.g.
  • cyclohex-2-enyl cyclohex-3-enyl
  • substituted carbocyclyl examples include 2-methyl-cyclohexyl-, 3-methyl-cyclohexyl-, 4-methyl- cyclohexyl-, 2-methyl-cyclohex-2-enyl, 2-methyl-cyclohex-3-enyl, 3-methyl-cyclohex-3-enyl, 3-methyl-cyclohex-3-enyl.
  • R 2 represents heterocyclyl (which may optionally be substituted)
  • examples include tetrahydrofuranyl, morpholinyl, piperdinyl, 3,4-dihydro-2H-pyranyl, pyrrolidinyl, methyltetrahydrofuranyl- (e.g. 5-methyltetrahydrofuran-2-yl-).
  • examples include —alkyl(substituted phenyl) e.g. in which phenyl is substituted by one or more groups selected from alkyl, fluoroalkyl, halogen and alkoxy (e.g.
  • alkyl is C1-4 alkyl.
  • Another specific group is -alkyl(bicyclic aryl) e.g. wherein bicyclic aryl is optionally substituted naphthyl.
  • a further specific group is benzyl.
  • R 2 represents -C 1-4 alkylheteroaryl in which heteroaryl is optionally substituted, examples include methylheteroaryl and -ethylheteroaryl (e.g.
  • -alkylheteroaryl groups include pyridinylmethyl-, N-methyl-pyrrol-2-methyl- N- methyl-pyrrol-2-ethyl-, N-methyl-pyrrol-3-methyl-, N-methyl-pyrrol-3-ethyl-, 2-methyl- pyrrol-1-methyl-, 2-methyl-pyrrol-1-ethyl-, 3-methyl-pyrrol-1-methyl-, 3-methyl-pyrrol-1- ethyl-, 4-pyridino-methyl-, 4-pyridino-ethyl-, 2-(thiazol-2-yl)-ethyl-, 2-ethyl-indol-1-methyl-, 2-ethyl-indol-1-ethyl-, 3-ethyl-ind
  • R 2 represents -C1-4alkyl-carbocyclyl (which may optionally be substituted)
  • examples include -methyl-cyclopentyl, -methyl-cyclohexyl, -ethyl-cyclohexyl, -propyl-cyclohexyl, - methyl-cyclohexenyl, -ethyl-cyclohexenyl, -methyl(4-methylcyclohexyl) and –propyl (3- methylcyclyohexyl).
  • R 2 represents -C 1-4 alkylheterocyclyl (which may optionally be substituted); examples include -methyl-tetrahydrofuranyl (e.g.
  • R 2 represents phenyl substituted by phenyl or phenyl substituted by a monocyclic heteroaryl group, in which any of aforesaid phenyl and heteroaryl groups may optionally be substituted, typically the phenyl ring connected directly to the nitrogen atom is unsubstituted and the terminal phenyl ring or the monocyclic heteroaryl ring is optionally substituted by one, two or three substitutents (e.g. one or two, e.g. one).
  • the terminal phenyl or monocyclic heteroaryl group is unsubstituted.
  • the terminal phenyl or monocyclic heteroaryl group substitutes the other phenyl group at the 4-position.
  • R 2 represents phenyl substituted by phenyl in which any of aforesaid phenyl groups may optionally be substituted, examples include -biphenyl-4-yl.
  • R 2 represents phenyl substituted by a monocyclic heteroaryl group, in which any of aforesaid phenyl and heteroaryl groups may optionally be substituted, examples include 4- (oxazol-5-yl)phenyl-.
  • R 2 represents phenyl substituted by benzyloxy in which any of aforesaid phenyl and benzyloxy groups may optionally be substituted
  • examples include 4-benzyloxy-phenyl-, 4-(3- methylbenzyloxy)phenyl- and 4-(4-methylbenzyloxy)phenyl-.
  • examples include indanyl (e.g. indan-4-yl-, 2-methyl-indan-4-yl-), indenyl and tetralinyl.
  • R 2 represents optionally substituted phenyl fused to optionally substituted heterocyclyl
  • examples include benzo[1,3]dioxo-4-yl- and 2,3-dihydro-benzo[1,4]dioxin-4-yl-.
  • examples include biphenyl-4-yl- methyl-.
  • examples include 4-(oxazol-5-yl)phenyl-methyl-.
  • R 2 represents -C1-4alkyl(phenyl substituted by benzyloxy) in which any of aforesaid phenyl and benzyloxy groups may optionally be substituted
  • examples include 4-benzyloxy- phenyl-methyl-, 4-(3-methylbenzyloxy)phenyl-methyl- and 4-(4-methylbenzyloxy)phenyl- methyl-.
  • examples include indanyl-methyl- (e.g.
  • R 2 represents -C1-4alkyl(optionally substituted phenyl fused to optionally substituted heterocyclyl); examples include benzo[1,3]dioxo-4-yl-methyl- and 2,3-dihydro- benzo[1,4]dioxin-4-yl-methyl-.
  • R 3 represents -C1-4alkyl, examples include methyl, ethyl, propyl (e.g. n-propyl, isopropyl) and butyl (e.g.
  • aryl may typically represent phenyl.
  • exemplary substituted phenyl groups include 2,4-dichlorophenyl-, 2,4-difluororophenyl-, 2,4- dimethoxyphenyl-, 2,4-dimethylphenyl-, 2,4-bis(trifluoromethyl)phenyl-, 2,4,6- trifluorophenyl-, 2,4,6-trimethylphenyl-, 2,6-dichlorophenyl-, 2,6-difluorophenyl-, 2,6- dimethoxyphenyl-, 2-isopropyl-6-methylphenyl-, 3-(cyclopentyloxy)-4-methoxyphenyl-, 3,4,5-trimethoxyphenyl-, 3,4-dimethoxyphenyl-, 3,4-dichlorophenyl-,
  • R 3 may represents unsubstituted phenyl-.
  • Further exemplary substituted phenyl groups include 2-bromo-4-fluorophenyl-, 2-bromo-5-fluorophenyl-, 2-chlorophenyl-, 2-fluoro- 5-(trifluoromethyl)phenyl-, 2-hydroxy-3-methoxyphenyl-, 2-hydroxy-5-methylphenyl-, 3- chlorophenyl-, 3-fluoro-4-(trifluoromethyl)phenyl-, 3-hydroxy-4-methoxyphenyl-, 4-chloro-3- (trifluoromethyl)phenyl-, 4-chlorophenyl-, 4-fluorophenyl- and 4-propoxyphenyl-.
  • R 2 and R 3 are joined to form a carbocyclyl ring, which is optionally substituted by one or more C 1-2 alkyl groups, examples include cycloalkyl (e.g. cyclopropyl, cyclopentyl and cyclohexyl) and cycloalkenyl (e.g. cyclohexenyl).
  • examples include indanyl (e.g. indan-2-yl) and tetralinyl.
  • R 2 and R 3 are joined to form a carbocyclyl ring which is fused to monocyclic heteroaryl; examples include 5-membered carbocyclyl fused to 6-membered heteroaryl, 6-membered carbocyclyl fused to 6-membered heteroaryl, 5-membered carbocyclyl fused to 5-membered heteroaryl and 6-membered carbocyclyl fused to 5-membered heteroaryl.
  • the monocyclic heteroaryl to which carbocyclyl is fused contains at least one heteroatom (e.g. one, two or three heteroatoms, e.g. one or two, e.g. one heteroatom).
  • R 4 represents -C 1-8 alkyl examples include methyl, ethyl, propyl (e.g. n-propyl, isopropyl), butyl (e.g. n-butyl- sec-butyl, isobutyl and tert-butyl), pentyl (e.g. n-pentyl, 3,3,- dimethylpropyl), hexyl, heptyl and octyl.
  • propyl e.g. n-propyl, isopropyl
  • butyl e.g. n-butyl- sec-butyl, isobutyl and tert-butyl
  • pentyl e.g. n-pentyl, 3,3,- dimethylpropyl
  • hexyl heptyl and octyl.
  • R 4 represents -C(O)C1-6alkyl; examples include -C(O)C1-4alkyl such as -C(O)methyl, - C(O)ethyl, -C(O)propyl and -C(O)butyl.
  • R 1 represents heteroaryl or -C 1-6 alkylheteroaryl. In one embodiment, R 1 represents heteroaryl. In a further embodiment, R 1 represents unsubstituted heteroaryl or heteroaryl optionally substituted by one or more C1-6 alkyl (e.g. methyl), halogen (e.g. fluorine) or C1-6 haloalkyl (e.g. trifluoromethyl) groups.
  • R 1 represents -C 1-6 alkylheteroaryl.
  • R 1 suitably represents bicyclic heteroaryl, especially 9- membered bicyclic heteroaryl.
  • R 1 represents a bicyclic heteroaryl ring system and in particular a phenyl ring fused with a 5 membered heteroaryl ring containing one or more (e.g. one or two, suitably one, more suitably two) nitrogen atoms or a pyridine ring fused with a 5-membered heteroaryl ring containing one or more (e.g. one or two, suitably one, more suitably two) nitrogen atoms.
  • R 1 represents bicyclic heteroaryl, preferably the heteroaryl group does not contain S atoms.
  • R 1 represents a phenyl ring fused to a 5-membered heteroaryl ring, preferably R 1 is linked to the core of formula (I) through the phenyl ring.
  • R 1 represents a pyridine ring fused to a 5-membered heteroaryl ring, preferably R 1 is linked to the core of formula (I) through the pyridine ring.
  • R 1 represents unsubstituted heteroaryl.
  • R 1 suitably represents 1H-benzoimidazolyl or imidazo[1,2-a]pyridine, particularly 1H-benzoimidazolyl, especially 1H-benzoimidazol-5-yl.
  • R 1 represents -C 1-6 alkylheteroaryl
  • heteroaryl is suitably monocyclic heteroaryl, especially 5-membered monocyclic heteroaryl.
  • R 1 represents -C1- 6alkylheteroaryl
  • heteroaryl is suitably a 5 membered heteroaryl ring containing one or more (e.g. one or two, suitably one, more suitably two) nitrogen atoms.
  • R 1 represents -C 1- 6 alkylheteroaryl
  • the heteroaryl group does not contain S atoms.
  • heteroaryl represents substituted or unsubstituted imidazolyl.
  • heteroaryl suitably represents substituted or unsubstituted imidazoly-1-yl.
  • R 1 represents -C 1-6 alkylheteroaryl and heteroaryl is substituted imidazoly-1-yl
  • imidazoly-1-yl is suitably substituted by methyl.
  • R 1 represents wherein A represents an unbranched C1-6alkylene chain (e.g.
  • an unbranched C1-5alkylene chain e.g. an unbranched C 1-4 alkylene chain, e.g. an unbranched C 1-3 alkylene chain
  • A represents a branched C1-6alkylene chain (e.g. wherein the one or more (e.g. one or two) branches consist of one or more (e.g. one or two) methyl groups at the same or different positions) or A represents (CH 2 ) a CR 5 R 6 (CH 2 ) b and R 11 , R 12 and R 13 independently represent H or C1-2alkyl.
  • R 1 represents wherein B represents a bond, -CH2-, -CH2-CH2-, -CH(Me)-, -CH(Me)-CH2- or -CH2-CH(Me)- and R 14 and R 15 independently represent H, C1-2alkyl (e.g. methyl), halogen (e.g. fluorine) or C1-6 haloalkyl (e.g. trifluoromethyl).
  • B represents a bond
  • R 14 and R 15 independently represent H, C1-2alkyl (e.g. methyl), halogen (e.g. fluorine) or C1-6 haloalkyl (e.g. trifluoromethyl).
  • R 1 represents wherein C represents a bond, -CH2-, -CH2-CH2-, -CH(Me)-, -CH(Me)-CH2- or -CH2-CH(Me)- and R 16 and R 17 independently represent H, C1-2alkyl (e.g. methyl), halogen (e.g. fluorine) or C1-6 haloalkyl (e.g. trifluoromethyl).
  • C1-2alkyl e.g. methyl
  • halogen e.g. fluorine
  • C1-6 haloalkyl e.g. trifluoromethyl
  • R 1 represents wherein D represents a bond, -CH2-, -CH2-CH2-, -CH(Me)-, -CH(Me)-CH2- or -CH2-CH(Me)- and R 18 and R 19 independently represent H, C 1-2 alkyl (e.g. methyl), halogen (e.g. fluorine) or C 1-6 haloalkyl (e.g. trifluoromethyl); Suitably R 1 represents .
  • R 14 represents H and R 15 represents H.
  • R 14 represents H and R 15 represents C 1-2 alkyl.
  • R 14 represents C 1-2 alkyl and R 15 represents H.
  • R 14 represents methyl and R 15 represents H.
  • R 14 represents H or methyl and R 15 represents C1-2alkyl (e.g. methyl) or halogen (e.g. fluorine).
  • B represents a bond, -CH2- or -CH2CH2-. In one embodiment B represents a bond. In another embodiment, B represents -CH2-. In a third embodiment, B represents -CH2CH2-.
  • R 1 represents .
  • R 11 suitably represents H
  • R 12 suitably represents H or methyl
  • R 13 suitably represents H or methyl.
  • R 12 represents H and R 13 represents methyl.
  • R 12 represents methyl and R 13 represents H.
  • R 12 represents H and R 13 represents H.
  • A represents an unbranched C 2-5 alkylene chain.
  • A represents -(CH2)2-.
  • A represents -(CH2)3-.
  • A represents -(CH 2 ) 4 -.
  • A represents -(CH 2 ) 5 -.
  • A represents -(CH 2 ) 2 -, -(CH2)4- or -(CH2)5-.
  • A represents -(CH2)3-.
  • A represents -(CH2)4-.
  • A represents a branched C2-5 alkylene chain. In one embodiment A does not represent -(CH2)3-.
  • R 1 represents .
  • R 16 represents H and R 17 represents H.
  • R 16 represents H and R 17 represents C 1-2 alkyl.
  • R 16 represents C 1-2 alkyl and R 17 represents H.
  • R 16 represents H or methyl and R 17 represents C1- 2alkyl (e.g. methyl) or halogen (e.g. fluorine).
  • C represents a bond, -CH2- or -CH2CH2-. In one embodiment C represents a bond. In another embodiment, C represents -CH2-. In a third embodiment, C represents -CH2CH2-.
  • R 1 represents In one embodiment R 18 represents H and R 19 represents H. In another embodiment R 18 represents H and R 19 represents C1-2alkyl. In a third embodiment R 18 represents C1-2alkyl and R 19 represents H. In a further embodiment, R 14 represents H or methyl and R 15 represents C1- 2alkyl (e.g. methyl) or halogen (e.g. fluorine).
  • D represents a bond, -CH2- or -CH2CH2-. In one embodiment D represents a bond.
  • D represents -CH 2 -.
  • D represents -CH 2 CH 2 -.
  • R 1 represents .
  • R 1 represents .
  • R2 represents H, C1-8alkyl, C3-8cycloalkyl, -C1-4alkylcarbocyclyl, aryl, heteroaryl, heterocyclyl, -C1-4alkylaryl, phenyl substituted by phenyl, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl wherein said heterocyclyl group is optionally substituted by a methyl or phenyl group, phenyl substituted by carbocyclyl, phenyl substituted by carbocyclyl wherein said carbocyclyl is substituted by heterocyclyl, phenyl substituted by –O-carbocyclyl, heterocyclyl substituted by phenyl, carbocyclyl substituted by
  • R 2 represents H, C 1-8 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, -C 1-4 alkylaryl, phenyl substituted by phenyl, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl wherein said heterocyclyl group is optionally substituted by a methyl or phenyl group, phenyl substituted by –O-C 1-4 alkyl-heterocyclyl or phenyl fused to heterocyclyl, the aforesaid aryl, heteroaryl, phenyl and heterocyclyl groups optionally being substituted.
  • R 2 represents C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, -C1-4alkylaryl, phenyl substituted by phenyl, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl wherein said heterocyclyl group is optionally substituted by a methyl or phenyl group, phenyl substituted by –O-C1-4alkyl-heterocyclyl or phenyl fused to heterocyclyl, the aforesaid aryl, heteroaryl, phenyl and heterocyclyl groups optionally being substituted.
  • R 2 represent H.
  • R 2 represents C1-8alkyl.
  • R 2 When R 2 represents C1-8alkyl, R 2 suitably represents i-propyl or t-butyl. In one embodiment, R 2 represents carbocyclyl. When R 2 represents carbocyclyl, R 2 suitably represents cyclohexyl. In one embodiment, R 2 represents -C 1-4 alkylcarbocyclyl. When R 2 represents -C 1- 4 alkylcarbocyclyl, R 2 suitably represents –CH 2 -cyclohexyl. In one embodiment, R 2 represents optionally substituted aryl. When R 2 represents optionally substituted aryl, R 2 suitably represents optionally substituted phenyl or napthyl.
  • R 2 represents phenyl optionally substituted by one or more groups selected from C1-6 alkyl (e.g. methyl), C1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or isopropyloxy), hydroxyl, haloC1-6 alkyl (e.g. trifluoromethyl), haloC1-6 alkoxy (e.g. tetrafluoroethyloxy), halogen (e.g. chlorine or fluorine), C1-6alkoxy-C1-6alkyl- (e.g. –(CH2)3- OMe), C1-6alkoxy-C1-6alkoxy- (e.g.
  • R 2 represents phenyl optionally substituted by one or more groups selected from C1-6 alkyl (e.g. methyl), C1-6 alkoxy (e.g.
  • R 2 represents phenyl optionally substituted by one or more groups selected from C1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or isopropyloxy).
  • R 2 represents phenyl optionally substituted by a propoxy group.
  • R 2 represents optionally substituted phenyl
  • R 2 suitably represents 3-methylphenyl, 2- methoxyphenyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-pentoxyphenyl, 4-isopropyloxyphenyl, 4- tetrafluoroethyloxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,6- dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2,6-difluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3-chloro-5- fluorophenyl, 3,5-difluorophen
  • R 2 represents unsubstituted phenyl. In an alternative embodiment, R 2 represents unsubstituted naphthyl. In one embodiment, R 2 represents -C1-4alkylaryl, the aforesaid aryl optionally being substituted. When R 2 represents -C1-4alkylaryl, R 2 suitably represents benzyl optionally substituted by one or more C 1-6 alkoxy (e.g. methoxy) or halogen (e.g. chlorine or fluorine) groups. When R 2 represents optionally substituted benzyl, R 2 suitably represents 4-methoxybenzyl, 4- chlorobenzyl or 4-fluorobenzyl.
  • R 2 represents optionally substituted benzyl
  • R 2 also suitably represents 4-propoxybenzyl or 4-isopropoxybenzyl.
  • R 2 represents unsubstituted benzyl.
  • R 2 represents -C 1-4 alkylaryl
  • R 2 suitably represents – C(H)(Me)-phenyl.
  • R 2 represents -C1-4alkylaryl
  • R 2 suitably represents –(CH2)2-phenyl.
  • R 2 represents optionally substituted heteroaryl.
  • R 2 represents optionally substituted heteroaryl
  • R 2 suitably represents optionally substituted thiophenyl.
  • R 2 represents unsubstituted thiophenyl.
  • R 2 represents optionally substituted heterocyclyl.
  • R 2 represents optionally substituted heteroaryl
  • R 2 suitably represents unsubstituted dihydrobenzodioxinyl or piperidinyl substituted by a -C(O)C1-6alkyl (i.e. –COMe) group.
  • R 2 represents phenyl substituted by phenyl, the aforesaid phenyl groups optionally being substituted.
  • R 2 represents phenyl substituted by phenyl, the aforesaid phenyl groups optionally being substituted
  • R 2 suitably represents phenyl substituted by 3- phenyl, phenyl substituted by 4-phenyl, phenyl substituted by 3-(3-chlorophenyl), phenyl substituted by 4-(3-chlorophenyl), phenyl substituted by 4-(3,4-dichlorophenyl) or 3- fluorophenyl substituted by 4-phenyl.
  • R 2 when R 2 represents phenyl substituted by phenyl, R 2 suitably represents unsubstituted phenyl substituted by unsubstituted phenyl.
  • R 2 represents optionally substituted phenyl substituted by optionally substituted phenoxy.
  • R 2 suitably represents phenyl substituted by 4-phenoxy.
  • R 2 represents optionally substituted phenyl substituted by optionally substituted heterocyclyl.
  • R 2 represents optionally substituted phenyl substituted by optionally substituted heterocyclyl
  • R 2 suitably represents 3-chlorophenyl substituted by 4- morpholinyl, phenyl substituted by 4-piperazinyl substituted by 4N-methyl, , 2-chlorophenyl substituted by 6-piperazinyl substituted by 4N-ethyl, phenyl substituted by pyrrolidinyl, phenyl substituted by piperidinyl substituted by 4N-methyl, phenyl substituted by tetrahydropyranyl or phenyl substituted by morpholinyl.
  • R 2 represents optionally substituted phenyl substituted by optionally substituted heterocyclyl.
  • R 2 represents optionally substituted phenyl substituted by optionally substituted heterocyclyl
  • R 2 suitably represents 3-chlorophenyl substituted by 4- morpholinyl, phenyl substituted by 4-piperazinyl substituted by 4N-methyl, phenyl substituted by 4-piperazinyl substituted by 4N-phenyl, phenyl substituted by 3-piperazinyl substituted by 4N-phenyl or 2-chlorophenyl substituted by 6-piperazinyl substituted by 4N-ethyl.
  • R 2 represents optionally substituted phenyl substituted by heterocyclyl wherein said heterocyclyl is substituted by phenyl.
  • R 2 represents optionally substituted phenyl substituted by heterocyclyl wherein said heterocyclyl is substituted by phenyl
  • R 2 suitably represents phenyl substituted by 4-piperazinyl substituted by 4N-phenyl, phenyl substituted by 3-piperazinyl substituted by 4N-phenyl.
  • R 2 represents optionally substituted phenyl substituted by optionally substituted carbocyclyl wherein said carbocyclyl is substituted by optionally substituted heterocyclyl.
  • R 2 represents optionally substituted phenyl substituted by optionally substituted carbocyclyl wherein said carbocyclyl is substituted by optionally substituted heterocyclyl
  • R 2 suitably represents phenyl substituted by carbocyclyl (i.e. cyclohexyl) substituted by heterocyclyl (i.e. morpholinyl).
  • R 2 represents optionally substituted phenyl substituted by –O-C1-4alkyl- heterocyclyl.
  • R 2 represents optionally substituted phenyl substituted by –O-C1-4alkyl- heterocyclyl
  • R 2 suitably represents phenyl substituted by 4-O-(CH2)2-morpholinyl, 4-O- (CH2)3-morpholinyl, 2-O-(CH2)2-morpholinyl or 4-O-(CH2)2-piperazinyl.
  • R 2 represents optionally substituted phenyl substituted by optionally substituted carbocyclyl.
  • R 2 represents optionally substituted phenyl substituted by optionally substituted carbocyclyl
  • R 2 suitably represents phenyl substituted by C3-8 cycloalkyl (such as cyclohexyl) wherein said C3-8 cycloalkyl may be optionally substituted by one or more oxo, halogen (i.e. fluorine), hydroxyl or C 1-4 alkoxy (i.e. methoxy) groups.
  • R 2 represents optionally substituted phenyl substituted by –O-carbocyclyl.
  • R 2 represents optionally substituted phenyl substituted by –O-carbocyclyl
  • R 2 suitably represents unsubstituted phenyl substituted by an –O-C 3-8 cycloalkyl group (i.e. –O- cyclohexyl).
  • R 2 represents optionally substituted heterocyclyl substituted by optionally substituted phenyl.
  • R 2 suitably represents unsubstituted piperidinyl substituted by unsubstituted phenyl.
  • R 2 represents optionally substituted carbocyclyl substituted by optionally substituted phenyl.
  • R2 represents optionally substituted carbocyclyl substituted by optionally substituted phenyl
  • R 2 suitably represents unsubstituted C3-8 cycloalkyl (i.e. cyclohexyl) substituted by unsubstituted phenyl.
  • R 2 represents optionally substituted phenyl fused to optionally substituted heterocyclyl.
  • R 2 represents optionally substituted phenyl fused to optionally substituted heterocyclyl
  • R 2 suitably represents benzo-1,3-dioxolanyl, 4-methoxy(benzo-1,3-dioxolanyl), 6-methoxy(benzo-1,3-dioxolanyl), 2,2-difluoro(benzo-1,3-dioxolanyl) or benzo-1,4-dioxanyl.
  • R 2 represents -C 1-4 alkyl(phenyl substituted by a monocyclic heterocyclyl group).
  • R 2 represents -C1-4alkyl(phenyl substituted by a monocyclic heterocyclyl group
  • R 2 suitably represents benzyl substituted by morpholinyl.
  • R 2 represents -C1-4alkyl(phenyl substituted by an –O-carbocyclyl group).
  • R 2 suitably represents benzyl substituted by an –O-carbocyclyl group (i.e. –O-cyclohexyl).
  • R 3 represents H or R 2 and R 3 are joined to form a carbocyclyl ring which is fused to phenyl.
  • R 3 represents H.
  • R 4 represents H, -C1-8alkyl or -C(O)C1-6alkyl. More suitably R 4 represents H or -C1- 8 alkyl, e.g. H or methyl.
  • R 4 represents H.
  • X represents O, S or CR 7 R 8 or X and Z represent two adjacent carbon atoms of a phenyl ring which is fused in that position and is optionally substituted by one or more halogen or C 1-2 alkyl groups.
  • X represents O, S or CR 7 R 8 .
  • X represents O.
  • X represents S.
  • X represents S or CR7R8. In an alternative embodiment X represents –O-CH2- or –CH2-CH2-. In an alternative embodiment X and Z are joined to form a carbocyclic ring, e.g. a five or six membered carbocyclic ring. In an alternative embodiment, X and Z represent two adjacent carbon atoms of a phenyl ring which is fused in that position and is optionally substituted by one or more halogen or C 1-2 alkyl groups. In one embodiment, R 7 and R 8 both represent hydrogen or –C1-4alkyl, or one of R 7 and R 8 represents hydrogen and the other represents –C1-4alkyl or an optionally substituted aryl group.
  • R 7 and R 8 When one of R 7 and R 8 represents a –C 1-4 alkyl group, said group is suitably methyl. When one of R 7 and R 8 represents an optionally substituted aryl group, said group is suitably unsubstituted phenyl or phenyl substituted by 4-propoxy. In one embodiment, R 7 and R 8 both represent hydrogen. In an alternative embodiment, R 7 and R 8 both represent –C 1-4 alkyl. In an alternative embodiment, one of R 7 and R 8 represents hydrogen and the other represents –C 1-4 alkyl (e.g. methyl). In an alternative embodiment, one of R 7 and R 8 represents hydrogen and the other represents an optionally substituted aryl group (e.g.
  • Z represents –N-R 4 (e.g. -NH or –N-NH 2 ), O or CHR 10 (e.g. CH 2 or CH- methyl), or X and Z represent two adjacent carbon atoms of a phenyl ring which is fused in that position and is optionally substituted by one or more halogen or C1-2alkyl groups. In one embodiment, Z represents -NH.
  • R 1 suitably represents 1H-benzo[d]imidazolyl or 1H-imidazo[1,2-a]pyridinyl.
  • R 2 suitably represents: C 1-8 alkyl (such as t-butyl); carbocyclyl (such as cyclohexyl); phenyl optionally substituted by one or more C1-6 alkyl (e.g.
  • phenyl fused to optionally substituted heterocyclyl (such as 4- methoxybenzo[d][1,3]dioxol-6-yl, 2,2-difluorobenzo[d][1,3]dioxol-5-yl or 2,3- dihydrobenzo[b][1,4]dioxin-6-yl); optionally substituted phenyl substituted by optionally substituted heterocyclyl (such as phenyl substituted by -O-(CH2)2-morpholinyl or phenyl substituted by -O-(CH2)3- morpholinyl); optionally substituted phenyl substituted by
  • R 3 suitably represents hydrogen.
  • R 7 and R 8 each suitably represent hydrogen.
  • Y represents CHR 9 and Z represents –N-R 4 .
  • Y represents CH 2 and Z represents –NH.
  • R 1 suitably represents 1H-benzo[d]imidazolyl.
  • R 2 suitably represents phenyl optionally substituted by one or more halogen atoms (such as unsubstituted phenyl or 2,3,5-trifluorophenyl).
  • R 3 suitably represents hydrogen.
  • X represents CR 7 R 8
  • X represents CH 2
  • X represents C(Me) 2
  • X represents CH-phenyl
  • R 1 suitably represents 1H- benzo[d]imidazolyl or 1H-imidazo[1,2-a]pyridinyl.
  • R 2 suitably represents: C 1-8 alkyl (such as i-propyl); phenyl optionally substituted by one or more halogen (such as fluorine or chlorine), C1- 6 alkoxy (such as propoxy) or haloC1-6 alkyl groups (such as trifluoromethyl); -C 1-4 alkylaryl (such as benzyl); optionally substituted phenyl fused to optionally substituted heterocyclyl (such as 2,3- dihydrobenzo[b][1,4]dioxin-6-yl or benzo[d][1,3]dioxol-6-yl); optionally substituted phenyl substituted by optionally substituted heterocyclyl (such as phenyl substituted by -O-(CH2)2-piperazinyl or -O-(CH2)2-morpholinyl); optionally substituted phenyl substituted by optionally substituted
  • R 3 suitably represents hydrogen.
  • X represents CR 7 R 8
  • Y represents CHR 9 and Z represents CHR 10 .
  • X represents CH2, Y represents CH2 and Z represents CH2.
  • R 1 suitably represents 1H-benzo[d]imidazolyl.
  • R 2 suitably represents: hydrogen; phenyl optionally substituted by one or more halogen (such as fluorine or chlorine), C1- 6 alkoxy (such as methoxy); or optionally substituted -C 1-4 alkylaryl (such as unsubstituted benzyl and benzyl substituted a halogen atom, such as fluorine or chlorine or a C 1-6 alkoxy, such as methoxy).
  • R 3 suitably represents hydrogen.
  • X represents S
  • R 2 suitably represents: phenyl optionally substituted by one or more halogen (such as fluorine or chlorine); optionally substituted naphthyl (such as unsubstituted naphthyl); optionally substituted phenyl substituted by optionally substituted phenoxy; or optionally substituted heteroaryl (such as unsubstituted thiophenyl).
  • R 3 suitably represents hydrogen.
  • R 1 suitably represents 1H- benzo[d]imidazolyl.
  • R 2 suitably represents optionally substituted phenyl or optionally substituted phenyl substituted by optionally substituted phenoxy.
  • R 3 suitably represents hydrogen.
  • X represents CR 7 R 8
  • X represents CH 2
  • R 1 suitably represents 1H-benzo[d]imidazolyl.
  • R 2 suitably represents: phenyl optionally substituted by one or more halogen (such as fluorine), C1-6 alkoxy (such as methoxy or propoxy); or optionally substituted phenyl fused to optionally substituted heterocyclyl (such as 2,3- dihydrobenzo[b][1,4]dioxin-6-yl).
  • R 3 suitably represents hydrogen.
  • R 1 suitably represents 1H-benzo[d]imidazolyl.
  • R 2 suitably represents: phenyl optionally substituted by one or more halogen (such as fluorine or chlorine), C1- 6 alkoxy (such as methoxy or propoxy); optionally substituted phenyl substituted by optionally substituted phenyl; optionally substituted phenyl fused to optionally substituted heterocyclyl (such as benzo[d][1,3]dioxol-6-yl); or optionally substituted phenyl substituted by optionally substituted phenoxy.
  • halogen such as fluorine or chlorine
  • C1- 6 alkoxy such as methoxy or propoxy
  • optionally substituted phenyl substituted by optionally substituted phenyl optionally substituted phenyl fused to optionally substituted heterocyclyl (such as benzo[d][1,3]dioxol-6-yl); or optionally substituted phenyl substituted by optionally substituted phenoxy.
  • R 3 suitably represents hydrogen.
  • X represents –O-CH2-
  • Y represents CO and Z represents CHR 10 .
  • X represents –O-CH 2 -
  • Y represents CO and Z represents CH 2 (see e.g. Example 93).
  • R 1 suitably represents 1H-benzo[d]imidazolyl.
  • R 2 suitably represents phenyl optionally substituted by a C1-6 alkoxy (such as propoxy).
  • R 3 suitably represents hydrogen.
  • X represents –CH2-CH2-
  • Y represents CO and Z represents O.
  • R 1 suitably represents 1H-benzo[d]imidazolyl or 1H-imidazo[1,2-a]pyridinyl.
  • R 2 suitably represents phenyl optionally substituted by a C1-6 alkoxy (such as propoxy).
  • R 3 suitably represents hydrogen. More preferred embodiments of the compounds of formula I for use in the methods of the invention The invention further relates to the following more preferred embodiments: 1.
  • a compound of formula I or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof or a pharmaceutical composition comprising said compound of formula I for use in the methods according to the invention, wherein: R 1 represents ; R 2 represents C 1-8 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, -C 1-4 alkylaryl, -C 1- 4alkylheteroaryl, -C1-4alkylcarbocyclyl or -C1-4alkylheterocyclyl; in which any of aforesaid aryl and heteroaryl groups may optionally be substituted by one or more groups selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -C 1- 6thioalkyl, -SOC1-4alkyl, -SO2C1-4alkyl, C1-6alkoxy-, -O-C3-8cycl
  • R2 represents aryl, heteroaryl, phenyl substituted by phenyl, phenyl fused to heterocyclyl or R 2 and R 3 are joined to form a carbocyclyl ring which is fused to phenyl; the aforesaid aryl, heteroaryl, phenyl, heterocyclyl and carbocyclyl optionally being substituted.
  • R2 represents phenyl optionally substituted by one or more groups selected from C1-6 alkyl, C1-6 alkoxy, hydroxyl, haloC1-6 alkyl, haloC1-6 alkoxy, halogen, C 1-6 alkoxy-C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkoxy-, -N(C 1-4 alkyl)(C 1-4 alkyl)-N(C 1- 4alkyl)(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl), -N(C3-8cycloalkyll)(C3-8cycloalkyl), -C1-4alkyl- N(C1-4alkyl)(C1-4alkyl), -C1-4alkoxy-N(C1-4alkyl)(C1-4alkyl), -N(-C1-6alkyl-C1-6alkoxy)(-C1- 6 alkyl-C 1-6 alkoxy).
  • the invention further relates to the following, evenly more preferred embodiments: 1.
  • R1 represents wherein: B represents a bond, -CH2-, -CH2-CH2-, -CH(Me)-, -CH(Me)-CH2- or -CH2-CH(Me)- and R14 and R 15 independently represent H or C1-2alkyl. 3.
  • R1 represents . 4.
  • R1 represents . 5.
  • R2 represents phenyl substituted by one or more groups selected from phenyl, C1-6 alkyl, C1-6 alkoxy, hydroxyl, haloC1-6 alkyl, haloC1-6 alkoxy, halogen, C1-6alkoxy-C1-6alkyl- and C1-6alkoxy-C1-6alkoxy-.
  • R2 represents phenyl substituted by one or more groups selected from methyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, isopropyloxy, hydroxyl, trifluoromethyl, tetrafluoroethyloxy, chlorine, fluorine, –(CH 2 ) 3 -OMe, and –O-(CH2)2-OMe. 7.
  • R2 represents phenyl substituted by one or more C1-6 alkoxy groups.
  • R2 represents phenyl substituted by one or more groups selected from methoxy, ethoxy, propoxy, butoxy, pentoxy or isopropyloxy. 9. The compound according to any one of 1 to 8, wherein R2 represents phenyl substituted by a propoxy group. 10. The compound according to any one of 1 to 5, wherein R 2 represents phenyl substituted by phenyl. 11. The compound according to any one of 1 to 10, wherein R3 represents H. 12. The compound according to any one of 1 to 11, wherein R4 represents H. 13. The compound according to any one of 1 to 12, wherein X represents CR7R8. 14.
  • a compound of formula (I), wherein said compound of formula (I) is the compound: or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, or a pharmaceutical composition comprising said compound, pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein: R 1 represents R 2 represents optionally substituted aryl; R 3 represents H or -C1-4alkyl; in which aforesaid aryl may optionally be substituted by one or more groups selected from phenyl, C1-6alkyl, and C1-6alkoxy-; X represents CR 7 R 8 ; Z represents –N-R 4 ; Y represents C O; wherein, R 4 represents H or -C 1-8 alkyl; R 7 and R 8 independently represent H
  • R2 represents phenyl substituted by C1-6 alkoxy. 3.
  • R2 represents phenyl substituted by one or more groups selected from methyl, methoxy, ethoxy, propoxy, butoxy, pentoxy and isopropyloxy. 4.
  • R2 represents phenyl substituted by a propoxy group. 5.
  • R 2 represents phenyl substituted by phenyl. 6.
  • R3 represents H. 7.
  • R4 represents H.
  • X represents CR7R8. 9.
  • the compound for use in methods of treating a kidney disease in a subject of the present invention is selected from a compound according to examples 1 to 235 shown in table below, or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, or a pharmaceutical composition comprising such a compound:
  • the compound of formula I is a compound selected from example compounds 12 to 14. In a yet further embodiment, the compound of formula I is a compound selected from example compounds 42 to 44. In a most preferred embodiment, the compound of formula I is Varoglutamstat.
  • Varoglutamstat ((S)-1-(1H-benzo[d]imidazol-5-yl)-5-(4- propoxyphenyl)imidazolidin-2-one), which is also known as PQ912, can be represented by the structural formula of example 14: . In some embodiments of the invention, Varoglutamstat is used as free base. In some embodiments of the invention, Varoglutamstat is used as a pharmaceutically acceptable salt.
  • Varoglutamstat is used as hydrochloride salt in the methods of treating a kidney disease according to the invention.
  • Varoglutamstat hydrochloride as discussed herein has the chemical formula:
  • the compound of formula I for use in the methods of the invention is (S)-1-(1H-1,3-benzodiazol-5-yl)-5-(4-biphenyl)imidazolidin-2-one, which is also named PQ1083 herein, and which is represented by the structural formula of example 43: .
  • PQ1083 is used as free base.
  • PQ1083 is used as a pharmaceutically acceptable salt.
  • compositions To prepare the pharmaceutical compositions of this invention, a compound of formula I is used as the active ingredient.
  • the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral, or parenteral such as intramuscular.
  • a pharmaceutical carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral, or parenteral such as intramuscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient(s) necessary to deliver an effective dose as described above.
  • compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful, and the like, from about 10 mg to 1.500 mg per day (preferred 50 – 1.200 mg per day)
  • dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated, and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
  • compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol, or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the composition may be presented in a form suitable for once-weekly or once- monthly administration.
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 10 to about 1.000 mg of the active ingredient of the present invention.
  • the tablets or pills of the compositions of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
  • the pharmaceutical composition may contain between about 10 mg and 1.000 mg, preferably about 25 to 800 mg, more preferably 50 to 600 mg of a compound of formula I, and may be constituted into any form suitable for the mode of administration selected.
  • Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions.
  • compositions useful for parenteral administration include sterile solutions, emulsions, and suspensions.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the liquid forms in suitable flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methylcellulose and the like.
  • suitable suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methylcellulose and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • the compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compound of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamid-ephenol, or polyethyl eneoxidepolyllysine substituted with palmitoyl residue.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross- linked or amphipathic block copolymers of hydrogels.
  • the compound of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of the addressed disorders is required.
  • the daily dosage of the products may be varied over a wide range from 10 mg to 1.500 mg per mammal per day.
  • compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 300, 500, 600, 800 or 1.000 milligrams of of a compound of formula I for the symptomatic adjustment of the dosage to the patient to be treated.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • the invention also provides a process for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula (I), optionally in combination with at least one of the other aforementioned agents and a pharmaceutically acceptable carrier.
  • the compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.
  • Suitable dosages, including especially unit dosages, of the compounds of the present invention include the known dosages including unit doses for these compounds as described or referred to in reference text such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein) or the above mentioned publications.
  • Figure 1 shows the results of the eGFR slope analysis after 96 weeks treatment of human subjects with Varoglutamstat vs. placebo. eGFR was calculated with the MDRD formula. The results are shown for the total population of the investigated subjects (Placebo groups vs. treatment groups).
  • Figure 2 shows the results of the eGFR slope analysis after 96 weeks treatment of human subjects with Varoglutamstat vs. placebo. eGFR was calculated with the MDRD formula. The results are shown for the different dose groups investigated (Placebo groups vs. the treatments groups that received 300 mg Varoglutamstat twice daily or 600 mg Varoglutamstat twice daily).
  • Figure 3 shows the results of the eGFR slope analysis over up to 96 weeks treatment of human subjects that suffer from the CKD risk factors type 1 or type 2 diabetes mellitus and/or hypertension at baseline, with Varoglutamstat vs. placebo.
  • eGFR was calculated with the MDRD formula.
  • the results are shown for the different dose groups investigated (Placebo groups vs. the treatments groups that received 3 00 mg Varoglutamstat twice daily or 600 mg Varoglutamstat twice daily).
  • Figure 4 shows the results of the eGFR slope analysis after 96 weeks treatment of human subjects that showed no CKD risk factors at baseline, with Varoglutamstat vs. placebo.
  • eGFR was calculated with the MDRD formula.
  • FIG. 5 shows the plasma urine concentration change from baseline resulting from the treatment of patients with Varoglutamstat vs. placebo.
  • Figure 6 shows results from ADI-CKD model in mice, bodyweight at termination relative to starting bodyweight (which was the parameter by which randomization into groups was performed).
  • Figure 7 shows results from ADI-CKD model in mice, T1/2 of FITC-Sinistrin clearance at termination, and GFR as calculated therefrom and normalized to BW.
  • Figure 8 shows results from ADI-CKD model in mice, plasma parameters Urea, Creatinine and Cystatin C levels at termination.
  • Figure 9 shows results from ADI-CKD model in mice, histomorphometric parameters Collagen III, aSMA and KIM-1, as fractional area percentage of the left kidney.
  • Figure 10 shows the results of the eGFR slope analysis over up to 96 weeks treatment of human subjects that suffer from the CKD risk factor type 1 or type 2 diabetes (with or without hypertension) at baseline (this represents a subset of the population outlined in Figure 3, which had “diabetes and/or hypertension” at baseline), with V aroglutamstat vs. placebo treatment.
  • eGFR was calculated with the MDRD formula.
  • Figure 11 shows the results of the eGFR slope analysis over up to 96 weeks treatment of human subjects, comparing the “total population” and the “Diabetes” sub- population, in which subjects suffer from the CKD risk factor type 1 or type 2 diabetes (with or without hypertension) at baseline (together representing same (sub)populations as analyzed in Figure 1 and Figure 10, respectively), with V aroglutamstat vs. placebo treatment.
  • eGFR was calculated with the 2012 CKD- EPI Cystatin C formula.
  • the following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
  • Example 2 –Treatment study in human subjects with Varoglutamstat as representative example 2.1 Overall study description In a multicenter, randomized, double-blind, placebo-controlled, parallel group dose finding study, 259 human subjects selected for Mild Cognitive Impairment and Mild Dementia due to Alzheimer’s Disease were treated with Varoglutamstat hydrochloride versus placebo.
  • Varoglutamstat or placebo tablets were administered orally once daily in weeks 1 and 2 and twice daily orally from week 3 onwards. The total treatment duration was between 48 and 96 weeks. Subjects were randomized 1:1:1 (placebo, 300 mg, 600 mg all BID; indicated dose refers to Varoglutamstat free base selected for Mild Cognitive Impairment and Mild Dementia due to Alzheimer’s Disease) for the first 90 included, and 1:1 (placebo and dose decided by Data Safety Monitoring Board (DSMB)) from patient 91 onwards. All tablets will were taken after a meal.
  • DSMB Data Safety Monitoring Board
  • Dosis regimen Dose in weeks 1 and 2 50 mg once daily (evening) or placebo Dose in weeks 3 and 4: 50 mg BID or placebo Dose in weeks 5-8: 150 mg BID or placebo Dose in weeks 9-12: 300 mg BID or placebo Dose in weeks 13 onwards (until DSMB dose decision): First 90 subjects, 300 mg BID or 600 mg BID or placebo 1:1:1. Subjects randomized between the 90th randomized subject and the DSMB: 300 mg BID or placebo 1:1. After the DSMB decision, all subjects randomized to Varoglutamstat and having completed at least 12 weeks uptitration were switched to the chosen dose (600 mg BID) until study completion (week 48 to 96). Subjects randomized to placebo stayed on placebo.
  • Biomarker monitored during the study The effect of Varoglutamstat on serum biomarkers of renal tissue turnover and the change from baseline in serum biomarkers of renal tissue turnover were monitored.
  • Blood (serum and plasma) samples for assessing kidney biomarkers creatinine, blood urea nitrogen (BUN) have been taken regularily.
  • eGFR, creatinine and BUN were assessed at visits, typically 3 months periods.
  • Laboratory methods Creatinine Serum creatine was quantified using a commercial enzymatic kit (ECRE_2, Siemens Medical Solutions, Denmark) on an ADVIA 1800 instrument (Siemens Healthcare Diagnostics, Denmark) according to manufacturer’s instructions.
  • Creatinine is converted to creatine by creatininase and further hydrolyzed to sarcosine which in turn is further decomposed by sarcosine oxidase to form glycine, formaldehyde and hydrogen peroxide.
  • peroxidase the product of the oxidative condensation with N-(3- sulfopropyl)-3-methoxy-5-methylaniline (HMMPS) and 4-aminoantipyrine can be quantified by photometric readout.
  • Urea Serum urea was quantified using a commercial enzymatic IVD kit of (Siemens Medical Solutions, Denmark) on an ADVIA 1800 instrument (Siemens Healthcare Diagnostics, Denmark) according to manufacturer’s instructions.
  • Assay Principle Urea is hydrolyzed in the presence of water and urease to ammonia and carbon dioxide. The ammonia reacts with alpha-Ketoglutarate in the presence of Glutamate dehydrogenase and NADPH and the oxidation of NAD can be quantified by photometric readout.
  • Assessment of eGFR The eGFR was estimated using the "4-variable MDRD" method, which estimates GFR using four variables: serum creatinine, age, ethnicity, and gender. For measuring creatinine in ⁇ mol/l, this formula reads as follows: A baseline eGFR was determined at the beginning of the clinical trial representing the mean value of the eGFR of all subjects of the treatment group and the placebo group.
  • the progression of the eGFR was monitored during the trial duration in about 12 week intervals and visualized as annualized change from baseline, expressed ml/min/1.73m2/yr over time.
  • the BSA adjusted eGFR in mL/min/1.73m 2 was determined via measured creatinine level using the by MDRD formula.
  • Annualized Rate of change of eGFR over time (expressed as ml/min/1.73m2/yr) was estimated via random co-efficients analysis. This is a mixed model applied to repeated eGFR measures over time with subject-specific random effects for intercept and slope (DeVries et al., 2024 Pharm Stat, 2024, doi: 10.1002/pst.2381).
  • Subjects on treatment with a compound of formula I improve above baseline in a dose dependent manner, a finding that has not been observed before with other therapies currently on the market, whereas subjects with risk factors for kidney disease on placebo decline approximately 2.7 ml/min/1.73m2/yr, which represents an expected and credible rate of decline (see Figure 3).
  • a mean annualized eGFR change (calculated as difference over the placebo group) of 3.53 ⁇ 2.380 ml/min/1.73m2/yr has been observed in the treatment group treated with 300 mg twice daily of Varoglutamstat and, of 6.61 ⁇ 1.920 ml/min/1.73m2/yr in the treatment group treated with 600 mg twice daily of Varoglutamstat (all values calculated as difference over the placebo group, see Figure 3), whereas for subjects without risk factors for a CKD, a mean annualized eGFR change (calculated as the difference over the placebo group) of -0.29 ⁇ 2.430 ml/min/1.73m2/yr has been observed in the treatment group treated with 300 mg twice daily of Varoglutamstat and, of 2.36 ⁇ 1.390 ml/min/1.73m2/yr in the treatment group treated with 600 mg twice daily of Varoglutamstat (all values calculated
  • Varoglutamstat treatment of CKD is effective in human subjects with and without risk factors for CKD.
  • the treatment effect is higher in in human subjects with and without risk factors for CKD.
  • the treatment effect is dose dependent and is higher in the treatment group treated with 600 mg twice daily than in the treatment group treated with 300 mg twice daily.
  • CKD risk factor “Diabetes” Patients at risk for CKD due to diabetes mellitus were defined as patients having at baseline either medical history of diabetes (type 1 or 2) and/or co-medication with drugs used in diabetes and/or are untreated with a baseline HbA1c >6.5% (corresponds to >48 mmol HbA1c per mol hemoglobin [mmol/mol]).
  • This subgroup contains 32 patients: 12 randomized to placebo, 20 randomized to Varoglutamstat.
  • Slope analysis for subgroup “Diabetes” A slope analysis resulted in the annualized rate of change of eGFR with all available data over up to 96 weeks (average treatment duration was 77 weeks in total population and about 70 weeks in patients with diabetes as defined above) revealing an increase in eGFR on drug treatment in the overall population but even more in patients at risk for CKD and even more in patients with diabetes as defined above, compared to a general annual decline of eGFR in all these (sub)populations on placebo treatment.
  • Cystatin C-Assay Blood samples were collected in heparinized tubes and plasma was separated and stored at - 70 ⁇ C until analysis. Samples were measured using commercial kits for Cystatin C_2 (CYSC_2) (Atellica CH Analyzer, Siemens Healthineers) following instructions in product data sheet. This assay is based on Latex particles coated with anti-cystatin C antibody (Catalog no. 9116FX01). Assessment of eGFR by CDK-EPI Cystatin C 2012 The eGFR was determined using the CDK-EPI Cystatin C 2012 calculation model. Annualized Rate of change of eGFR over time (expressed as ml/min/1.73m2/yr) was determined via random co-efficients analysis.
  • Example 3 Varoglutamstat (PQ912) and PQ1083 as representative examples in ADI- CKD mouse model (adenine-diet induced chronic kidney disease)
  • Vehicle used comprised 0.8% (w/v) Methylcellulose (400 cP) and 0.25% (v/v) Tween80 in water.
  • PQ912 was used as a hydrochloride salt, the dose level is indicated for the free base, though.
  • all groups were switched to control diet (S9352-E064, Ssniff, Germany), and from study day 1 and throughout the study, groups 2 and 3 were switched to a diet containing 0.2% adenine (S9352-E060, Ssniff, Germany) to induce CKD.
  • S9352-E060, Ssniff, Germany 0.2% adenine
  • GFR was measured for assessment of renal function.
  • plasma was collected for evaluation of urea, creatinine, and cystatin C levels.
  • GFR Glomerular filtration rate
  • Plasma clearance of FITC-Sinistrin is then monitored transcutaneous for up to 90 minutes post-injection during which time the animals are conscious and allowed to move freely. Finally, an exponential function is fitted to the data and the GFR is estimated based on the T1 ⁇ 2 of the FITC-Sinistrin clearance.
  • Histological staining procedures In brief, glass slides with paraffin embedded sections are deparaffinated in xylene and rehydrated in series of graded ethanol. Immunohistochemistry using single chromogen: Immunohistochemistry (IHC) is performed using standard procedures. Briefly, after antigen retrieval and blocking of endogenous peroxidase activity, slides are incubated with primary antibody. The primary antibody is detected using a polymeric HRP-linker antibody conjugate.
  • VIS protocols are designed to analyze the virtual slides in two steps: Plasma assays Urea and Creatinine Blood samples are collected in heparinized tubes and plasma is separated and stored at -70 ⁇ C until analysis. Samples are measured using commercial kits (Roche Diagnostics), on the Cobas c 501 autoanalyzer. Cystatin C Blood samples are collected in heparinized tubes and plasma is separated and stored at -70 ⁇ C until analysis. Cystatin C is measured using a commercial ELISA kit (R&D Systems).
  • Figures are also provided for T1/2 of FITC-Sinistrin clearance at termination, and relative GFR as calculated therefrom (normalized to 100 BW; Figure 7), plasma parameters Urea, Creatinine and Cystatin C levels (Figure 8), histomorphometric parameters Collagen III, aSMA and KIM-1 ( Figure 9), all determined towards the end of study week 3 or at termination.
  • Varoglutamstat treatment (Group 3) analyzed versus Group 2 showed the following results: - increase of bodyweight - decrease of FITC-Sinistrin clearance T1/2 (highly significant) and thus increase of GFR (significant) - decreases of plasma biomarkers urea, creatinine (significant), and cystatin C (highly significant) - decreases of histomorphometric parameters Col III (highly significant), aSMA (highly significant), and KIM-1 (significant) PQ1083 treatment (Group 4) analyzed versus Group 2 showed the following results: - increase of bodyweight (significant) - decrease of FITC-Sinistrin clearance T1/2 (significant) and thus increase of GFR - decreases of plasma biomarkers urea, creatinine (slightly), and cystatin C (significant) - decreases of histomorphometric parameters Col III (slightly), aSMA, and KIM-1 (slightly).

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Abstract

La présente invention concerne l'utilisation des inhibiteurs de glutaminyl cyclase de formule (I) dans des méthodes de traitement de maladies rénales, où R1, R2, R3, X, Y et Z sont tels que définis dans la description. L'invention concerne en outre des compositions pharmaceutiques comprenant un composé de formule (I) et leur utilisation thérapeutique dans des méthodes de traitement de maladies rénales chez des mammifères.
PCT/EP2025/061082 2024-04-23 2025-04-23 Inhibiteurs de glutaminyl cyclase destinés à être utilisés dans le traitement d'une maladie rénale Pending WO2025224179A1 (fr)

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