NEW USE OF GLUTAMINYL CYCLASE INHIBITORS Field of the Invention 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. Background of the Invention 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. A QC was first isolated by Messer from the latex of the tropical plant Carica papaya in 1963 (Messer, M. 1963 Nature 4874, 1299). 24 years later, a corresponding enzymatic activity was discovered in animal pituitary (Busby, W. H. J. et al. 1987 J Biol Chem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987 Proc Natl Acad Sci U S A 84, 3628-3632). For the mammalian QC, the conversion of Gln into pGlu by QC could be shown for the precursors of TRH and GnRH (Busby, W. H. J. et al. 1987 J Biol Chem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987 Proc Natl Acad Sci U S A 84, 3628-3632). In addition, initial localization experiments of QC revealed a co-localization with its putative products of catalysis in bovine pituitary, supporting the suggested function in peptide hormone synthesis (Bockers, T. M. et al.1995 J Neuroendocrinol 7, 445-453).
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. 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). Furthermore, several proteins participating in the establishment of extracelluar matrix (ECM) are either proven substrates for QC/isoQC-catalyzed post-translational modifications or can be postulated to be likely subtrates in analogy due to comprising N-terminal Gln or Glu residues – and this seems to be quite conserved for the species human, rat and mouse: e.g. collagens (Bornstein et al. (1970), Biochemistry 9: 4699-4706; Bornstein (1969), Biochemistry 8: 63-71; Kang et al. (1967), Biochemistry 6: 788-795; Rauterberg et al. (1972), Eur. J. Biochem. 27: 231-237; Hoerlein et al. (1979), Eur. J. Biochem.99: 31-38; Weil et al. (1990), J. Biol. Chem.265: 16007- 16011; Cowan et al. (2022), Drug Test Anal. 14: 808-819), fibronectin (Garcia-Pardo et al. (1983), J. Biol. Chem. 258: 12670-12674) and fibromodulin (Oennerfjord et al. (2004), J. Biol. Chem. 279: 26-33). Fibrosis is a progressive and potentially fatal process that can occur in numerous organ systems. Characterized by the excessive deposition of extracellular matrix (ECM) proteins such as collagens and fibronectin, fibrosis affects normal tissue architecture and impedes organ function. Defined by the pathological accumulation of ECM proteins, fibrosis results in scarring and thickening of the affected tissue – in essence it represents an exaggerated wound healing
response which interferes with normal organ function. (Neary et al. (2015), Fibrogenesis Tissue Repair 8: article 35). Collagens are the most abundant protein in the ECM. Fibronectins are glycoproteins that connect cells with collagen fibers in the ECM, allowing cells to move through the ECM. Fibromodulin participates in the assembly of the collagen fibers of the ECM. With collagens as potential substrates for QC-activity, 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. To date, such 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. The activation of α- smooth-muscle-actin-positive (aSMA-positive) myofibroblasts plays a key role in this process. (Yuan et al. (2019), Adv. Exp. Med. Biol.1165: 253-283) 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. (Tai et al. (2021), Biomolecules 11: 1095-1121). Within the kidney, collagen- producing myofibroblasts can be derived from various cellular sources. Resident renal fibroblasts and cells of hematopoietic origin migrating into the kidney seem to be the most important ancestors of myofibroblasts. (Mack et al. (2015), Kidney Int. 87: 297-307) With regard to heterogeneity of kidney myofibroblasts, the total pool of myofibroblasts is split, with ~50% arising from local resident fibroblasts through proliferation. The non-proliferating myofibroblasts derive through differentiation from bone marrow (~35%), the endothelial- tomesenchymal transition program (~10%) and the epithelial-to-mesenchymal transition program (~5%). (LeBleu et al. (2013), Nature Med. 19: 1047-1053) 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). (Yan et al. (2016), Front. Physiol. 7: article 61) Whereas chemoattraction of fibroblast precursors via CCR2 is mediated by the 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. However, 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. (Uetz-von Allmen et al. (2018), J. Leukoc. Biol. 104: 375-389; Jorgensen et al. (2021), Cell. Mol. Life Sci. 78: 6963- 6978) 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. It was found that the isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions (Cynis et al. (2011) EMBO Molecular Medicine 2011, p. 545-558). Cynis reported that isoQC inhibitors are effective against CCL2 and that CCL2 plays a pivotal role in several conditions, including atherosclerosis, pancreatitis, Alzheimer's disease, MS and cancer. It was shown that the chemotactic activity of CCL2 depends on a modified N-terminus of the polypeptide, particularly the formation of a pyroglutamate (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). The 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. J., et al., 1994, J Biol.Chem 269, 15918-15924; Masure, S., et al., 1995, J Interferon Cytokine Res.15, 955-963; Hemmerich, S., et al., (1999) Biochemistry 38, 13013-13025). 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 Dementia, neurodegeneration in Down Syndrome and Huntington’s disease, rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis. Little is known, however, about the involvement of isoQC or QC in kidney diseases, and the suitability of the compounds of formula I for treating kidney diseases. 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) is defined as prolonged kidney abnormalities (functional and/or structural in nature) that last for more than three months. 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). 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). Causes of kidney disease include 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. (2020), Naunyn-Schmiedeberg's Archives of Pharmacology 394: 751–761), who reported that the chronic treatment with the (iso-)glutaminyl cyclase inhibitor PQ529 is a novel and effective approach for treating glomerulonephritis in
chronic kidney disease. Three-week repeated administration of PQ529 (30 and 100 mg/kg, twice daily) significantly reduced the serum and urine CCL2 and urinary protein excretion in a dose-dependent manner. It was suggested that PQ529 suppresses the progression of inflammation-induced renal dysfunction by inhibiting the CCL2/CCR2 axis. It appeared, however, that there is no enantio-selective preparation of PQ529 is available. 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. Accordingly, the invention provides compounds of formula I
or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, or a pharmaceutical composition comprising such a compound for use in methods of treating a kidney disease in a subject, wherein: R1 represents heteroaryl, -carbocyclyl-heteroaryl, -C2-6alkenylheteroaryl, -C1-6alkylheteroaryl, or (CH2)aCR5R6(CH2)bheteroaryl wherein a and b independently represent integers 0-5 provided that a + b = 0-5 and R5 and R6 are alkylene which together with the carbon to which they are attached form a C3-C5 cycloalkyl group; in which any of aforesaid heteroaryl groups may optionally be substituted by one or more groups selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, -C1-6thioalkyl, -
SOC1-4alkyl, -SO2C1-4alkyl, C1-6alkoxy-, -O-C3-8cycloalkyl, C3-8cycloalkyl, -SO2C3- 8cycloalkyl, -SOC3-6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, -C(O)C1-6alkyl, - C(O)OC1-6alkyl, C1-6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, -C(O)OH, -NH2, -NHC1-4alkyl, -N(C1-4alkyl)(C1-4alkyl), -C(O)N(C1-4alkyl)(C1-4alkyl), -C(O)NH2, - C(O)NH(C1-4alkyl) and -C(O)NH(C3-10cycloalkyl); and in which any of aforesaid carbocyclyl groups may optionally be substituted by one or more groups selected from C1-4alkyl, oxo, halogen and C1-4alkoxy; R2 represents H, C1-8alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, -C1-4alkylaryl, -C1- 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 C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, -C1- 6thioalkyl, -SOC1-4alkyl, -SO2C1-4alkyl, C1-6alkoxy-, -O-C3-8cycloalkyl, C3-8cycloalkyl, - SO2C3-8cycloalkyl, -SOC3-6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, -C(O)C1-6alkyl, -C(O)OC1-6alkyl, C1-6alkoxy-C1-6alkyl-, C1-6alkoxy-C1-6alkoxy-, nitro, halogen, haloC1- 6alkyl, haloC1-6alkoxy, cyano, hydroxyl, -C(O)OH, -NH2, -NHC1-4alkyl, -N(C1- 4alkyl)(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl)-N(C1-4alkyl)(C1-4alkyl), -C1-4alkyl-N(C1- 4alkyl)(C1-4alkyl), -C1-4alkoxy-N(C1-4alkyl)(C1-4alkyl), -N(C3-8cycloalkyll)(C3- 8cycloalkyl), -N(-C1-6alkyl-C1-6alkoxy)(-C1-6alkyl-C1-6alkoxy), -C(O)N(C1-4alkyl)(C1- 4alkyl), -C(O)NH2, -C(O)NH(C1-4alkyl) and -C(O)NH(C3-10cycloalkyl); and in which any of aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from C1-4alkyl, oxo, halogen, -C(O)C1-6alkyl and C1-4alkoxy; or R2 represents phenyl substituted by phenyl, phenyl substituted by a monocyclic heteroaryl group, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl, phenyl substituted by heterocyclyl wherein said heterocyclyl is substituted by phenyl, phenyl substituted by –O-C1-4alkyl-heterocyclyl, phenyl substituted by benzyloxy, 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 phenyl, phenyl fused to carbocyclyl, phenyl fused to heterocyclyl, -C1-4alkyl(phenyl substituted by phenyl), -C1-4alkyl(phenyl
substituted by a monocyclic heteroaryl group), -C1-4alkyl(phenyl substituted by a monocyclic heterocyclyl group), -C1-4alkyl(phenyl substituted by an –O-carbocyclyl group), -C1-4alkyl(phenyl substituted by benzyloxy), -C1-4alkyl(optionally substituted phenyl fused to optionally substituted carbocyclyl or -C1-4alkyl(optionally substituted phenyl fused to optionally substituted heterocyclyl); in which any of aforesaid phenyl, benzyloxy and heteroaryl groups may optionally be substituted by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy, and in which any of aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl, phenyl, oxo, halogen, hydroxyl and C1-4alkoxy; R3 represents H, -C1-4alkyl or aryl; in which aforesaid aryl may optionally be substituted by one or more groups selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, -C1-6thioalkyl, -SOC1-4alkyl, - SO2C1-4alkyl, C1-6alkoxy-, -O-C3-8cycloalkyl, C3-8cycloalkyl, -SO2C3-8cycloalkyl, -SOC3- 6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, -C(O)C1-6alkyl, -C(O)OC1-6alkyl, C1- 6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, -C(O)OH, -NH2, -NHC1-4alkyl, - N(C1-4alkyl)(C1-4alkyl), -C(O)N(C1-4alkyl)(C1-4alkyl), -C(O)NH2, -C(O)NH(C1-4alkyl) and, -C(O)NH(C3-10cycloalkyl); or R2 and R3 are joined to form a carbocyclyl ring which is optionally substituted by one or more C1-2alkyl groups; or R2 and R3 are joined to form a carbocyclyl ring which is fused to phenyl, wherein aforesaid carbocyclyl and/or phenyl may optionally be substituted by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy; or R2 and R3 are joined to form a carbocyclyl ring which is fused to monocyclic heteroaryl, wherein aforesaid carbocyclyl and/or heteroaryl may optionally be substituted by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy; X represents C=O, O, S, CR7R8, -O-CH2- or –CH2-CH2-; Y represents CHR9, C=O or C=S; Z represents –N-R4, O or CHR10, such that when X represents O or S, Z must represent CHR10;
or X and Z represent two adjacent carbon atoms of a phenyl ring which is fused in that position and which is optionally substituted by one or more halogen or C1-2alkyl groups; R4 represents H, -C1-8alkyl, -C(O)C1-6alkyl or –NH2; R7 and R8 independently represent H, -C1-4 alkyl or aryl; in which said aforesaid aryl may be optionally substituted by C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C1-6haloalkyl, -C1-6thioalkyl, -SOC1-4alkyl, -SO2C1-4alkyl, C1-6alkoxy-, -O-C3- 8cycloalkyl, C3-8cycloalkyl, -SO2C3-8cycloalkyl, -SOC3-6cycloalkyl, C3-6alkenyloxy-, C3- 6alkynyloxy-, -C(O)C1-6alkyl, -C(O)OC1-6alkyl, C1-6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, -C(O)OH, -NH2, -NHC1-4alkyl, -N(C1-4alkyl)(C1-4alkyl), -C(O)N(C1- 4alkyl)(C1-4alkyl), -C(O)NH2, -C(O)NH(C1-4alkyl) and, -C(O)NH(C3-10cycloalkyl); R9 and R10 independently represent H or methyl; provided that the moiety –Y-Z-X- represents a moiety other than –C(=O)-N(-R4)-C(=O)- or -C(=S)-N(-R4)-C(=O)-. More preferably, said kidney disease is an acute kidney disease (AKI) or a chronic kidney disease (CKD). 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). As one mode-of-action, the compounds of formula I are supposed to suppress the progression of inflammation-induced renal dysfunction by inhibiting the CCL2/CCR2 axis. In a further
embodiment, 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. Chronic inflammation, characteristic of CKD, is often the trigger for a fibrosis process. The inflammatory process is transmitted through epithelial and endothelial cells, which give rise to inflammatory mediators including cytokines and chemokines among others, which in turn lead to the recruitment of inflammatory cells: lymphocytes, polymorphonuclear leukocytes, eosinophils, basophils, mast cells, and macrophages. These inflammatory cells release transforming growth factor beta 1 (TGF-ß1), a potent fibrogenic factor that induces the activation of fibroblasts, increasing the synthesis of extracellular matrix (ECM) proteins (Panizo et al. (2021) Int J Mol Sci.; 22(1): 408). 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. Given a predominance of proven and potential substrates for QC-activity as part of the establishment of extracellular matrix (ECM), including several pro-collagens and collagens like Col I and Col III among others, fibronectin and fibromodulin, and the potential targets for QC- activity in chemoattractant processes for myofibroblast precursors (CCL2/CCR2 and CCL21/CCR7), the compounds of formula I exert anti-fibrotic effects. Accordingly, in a further embodiment, 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 (CCL7), 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. (2022), Cardiovascular Diabetology 21: 185-192) While the detailed pathological role of CCL7 and related signaling pathways in these diseases need further confirmation, it has been suggested that 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. However, 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. 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. Other causes and conditions that affect 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. This is a collection of symptoms that indicate kidney damage. • Recurrent kidney infection (pyelonephritis). • 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. • Hereditary diseases caused by mutation of genes, like Fabry disease and Alport syndrome. • 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). 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. In some embodiments, the diabetic nephropathy is caused by diabetes type 1 or diabetes type 2. In further embodiments, 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 scarring may happen due to an infection, a drug such as anabolic steroids, or a systemic disease such as diabetes mellitus, HIV infection, sickle cell disease or lupus. In further embodiments, 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.
In even further embodiments, 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). As a result of in vivo studies in animals and in human beings and as shown in the examples hereinbelow, it has been demonstrated that the treatment with compounds of formula I, preferably chronic treatment of subjects, increases the GFR when compared to untreated control subjects. Thus, in a further embodiment, 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). In clinical practice, creatinine clearance or estimates of creatinine clearance based on the serum creatinine level, or serum Cystatin C levels are used to estimate GFR. (cf. e.g. Pei et al. (2013), PLoS ONE 8: e57852, and references cited therein) 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. Unlike precise GFR measurements involving constant infusions of inulin, creatinine is already at a steady-state concentration in the blood, and so measuring creatinine clearance is much less cumbersome. However, 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. 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. There are alternative methods and formulae to calculate the eGFR used in practice. In the examples hereinbelow, 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/1.73m2 is considered adequate. 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 patients requiring dialysis; many patients in CKD5 are not yet on dialysis. Based on measurement of creatinine in µmol/l, 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. The general CKD-EPI Formula is described as follows eGFR = µ × min(Scr/κ, 1)a1 × max(Scr/κ,1)a2 × min(Scys/0.8, 1)b1 × max(Scys/0.8,1)b2 × cAge × d[if female] × e[if Black] κ = 0.7 for female, κ = 0.9 for male for 2012 CKD-EPI cystatine C
µ = 133 a1, a2 = 0 b1 = −0.499, b2 = −1.328 c = 0.9962 d = 0.932 e = 1 eGFR = 133 × min(Scys/0.8, 1)-0.499 × max(Scys/0.8,1)-1.328 × 0.9962Age × 0.932[if female] The data set used for the eGFR slope analysis in Figures 10 and 11 with the CKD-EPI Cystatin C formula is based on Cystatin C measurements from safety as well as biomarker blood samples which were collected at screening, baseline, week 4, 12, 24, 36, 48, 60, 72, 84, EOT and screening, 24, 48, and EOT, respectively. As a result of studies in mice and in human beings and as shown in the examples hereinbelow, it has been demonstrated that the treatment with a compound of formula I, preferably chronic treatment of subjects, has an outstanding and significant effect size on the (e)GFR. In the human study, the annualized eGFR rate is positive in the treatment group, while the annualized eGFR rate is negative in the placebo group. The difference between the treatment group and the placebo group for the annualized eGFR change in the total population tested is highly significant (see Figure 1). It has also been found that the treatment effect on the annualized eGFR change from baseline was dose-dependent (see Figure 2). It was further observed that the effect of the treatment with a compound of formula I on the annualized eGFR change in subjects with risk factors for CKD differs from the effect of the treatment of a compound of formula I in subjects without risk factors (see Figures 3 and 4). Therefore, in some embodiments of the invention, subjects without risk factors are treated with a compound of formula I. In further embodiments, 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). In some embodiments, 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. For subjects suffering from type 1 or type 2 diabetes mellitus and/or hypertension as risk factors for a 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), whereas for subjects without risk factors for a CKD, 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 and, of about 2.4 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 4). In some embodiments, 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/1.73m2 as risk factors for a CKD. Accordingly, in preferred embodiments of the invention, 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/1.73m2/yr or higher, preferably 2.0 ml/min/1.73m2/yr or higher, more preferably of 2.5 ml/min/1.73m2/yr or higher, most preferably 3.0 ml/min/1.73m2/yr or higher in a subject without risk factors for CKD, wherein the eGFR is calculated with the MDRD method. In further preferred embodiments of the invention, 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/1.73m2/yr or higher, most preferably 6.0 ml/min/1.73m2/yr or higher or 6.5 ml/min/1.73m2/yr or higher or 7.0 ml/min/1.73m2/yr or higher in a subject with risk factors for CKD, wherein the eGFR is calculated with the MDRD method. Preferably, said risk factors for CKD are selected from type 1 or 2 diabetes mellitus and/or hypertension. In some embodiments 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/1.73m2/yr, when calculated with the 2012 CKD-EPI Cystatin C formula (Figure 11). Accordingly, in further preferred embodiments of the invention, 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/1.73m2/yr or higher or 12.0 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 MDRD method. Moreover, in preferred embodiments of the invention, 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. In conclusion, 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. Furthermore, 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. Accordingly, 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). In this ADI-CKD animal study, 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. ^ Each of these findings indicates a positive treatment effect on fibrotic events in CKD, which can be caused by anti-fibrotic and anti-inflammatory effects of treatment with compounds of formula I, most like by a combination of both as fibrosis is a general response to inflammation. In a further aspect, 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. In yet a further aspect, 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.
In further embodiments, 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. Definitions The term “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
The general term “QC activity” is also encompassing similarly catalyzed transformations of N- terminal L-homoglutamine or L-^-homoglutamine into respective cyclic pyro-homoglutamic acid derivatives. The term “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. The term “therapeutically effective amount” as used herein, 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.
As used herein, the term “pharmaceutically acceptable” embraces both human and veterinary use: For example the term “pharmaceutically acceptable” embraces a veterinarily acceptable compound or a compound acceptable in human medicine and health care. Throughout the description and the claims the expression "alkyl", unless specifically limited, 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), butyl (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) and octyl (e.g. n-octyl). The expression "alk", for example in the expressions "alkoxy", "haloalkyl" and "thioalkyl” should be interpreted in accordance with the definition of "alkyl". 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. CF3. The expression "alkenyl", unless specifically limited, denotes a C2-12 alkenyl group, suitably a C2-6 alkenyl group, e.g. a C2-4 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. The expression "alkynyl", unless specifically limited, 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. The expression “alkylene” denotes a chain of formula -(CH2)n- wherein n is an integer e.g. 2-5, unless specifically limited. The expression “cycloalkyl”, unless specifically limited, denotes a C3-10 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. The expression “cycloalkenyl”, unless specifically limited, denotes a C5-10 cycloalkenyl group (i.e.5 to 10 ring carbon atoms), more suitably a C5-8 cycloalkenyl group e.g. a C5-6 cycloalkenyl group. Exemplary cycloalkenyl groups include cyclopropenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. A most suitable number of ring carbon atoms is five to six. The expression “carbocyclyl”, unless specifically limited, 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. The expression “heterocyclyl”, unless specifically limited, refers to a carbocyclyl group wherein one or more (e.g.1, 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O. 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. Exemplary 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-). The expression “aryl”, unless specifically limited, denotes a C6-12 aryl group, suitably a C6-10 aryl group, more suitably a C6-8 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.
The expression “heteroaryl”, unless specifically limited, denotes an aryl residue, wherein one or more (e.g. 1, 2, 3, or 4, suitably 1, 2 or 3) 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. pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, such as imidazol-1-yl, imidazol-2-yl imidazol-4-yl); six membered rings (e.g. pyridazine, pyrimidine, pyrazine). 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. indol-6-yl), benzofuran, benzthiophene, quinoline, isoquinoline, indazole, benzimidazole, benzthiazole, quinazoline and purine. The expression “-alkylaryl”, unless specifically limited, denotes an aryl residue which is connected via an alkylene moiety e.g. a C1-4alkylene moiety. The expression “-alkylheteroaryl”, unless specifically limited, denotes a heteroaryl residue which is connected via an alkylene moiety e.g. a C1-4alkylene moiety. The term “halogen” or “halo” comprises fluorine (F), chlorine (Cl) and bromine (Br). The term “amino” refers to the group -NH2. The term ”phenyl substituted by phenyl” refers to biphenyl. When 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. As employed herein, 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. 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. 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. Pharmaceutically acceptable salts:
In view of the close relationship between the free compounds and the compounds in the form of their salts or solvates, whenever a compound is referred to in this context, a corresponding salt, solvate or polymorph is also intended, provided such is possible or appropriate under the circumstances. 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. However, 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. those formed with either organic or inorganic acids or bases All pharmaceutically acceptable acid addition salt forms of the compounds of the present invention are intended to be embraced by the scope of this invention. Polymorph crystal forms: Furthermore, some of the crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. 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- 6alkenyl (e.g. buten-3-yl), C2-6alkynyl (e.g. butyn-3-yl), C1-6haloalkyl (e.g. fluoromethyl, trifluoromethyl), -C1-6thioalkyl (e.g. -S-methyl), -SOC1-4alkyl (e.g. -SOmethyl), -SO2C1-4alkyl (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. fluoro, chloro, bromo), cyano, hydroxyl, -C(O)OH, -NH2, -NHC1-4alkyl (e.g. -NHmethyl), -N(C1-4alkyl)(C1-4alkyl) (e.g. – N(methyl)2), -C(O)N(C1-4alkyl)(C1-4alkyl) (e.g. -C(O)N(methyl)2), -C(O)NH2, -C(O)NH(C1- 4alkyl) (e.g. -C(O)NHmethyl), -C(O)NH(C3-10cycloalkyl) (e.g. -C(O)NHcyclopropyl). More typically, substituents will be selected from C1-6alkyl (e.g. methyl), C1-6haloalkyl (e.g. C1- 6fluoroalkyl, e.g. CF3), C1-6alkoxy (e.g. OMe), halogen and hydroxy. When R1 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. C1-4 alkoxy- such as OMe) and halogen (e.g. F). When R1 represents -C3-8carbocyclyl-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). A suitable heteroaryl group is imidazol-1-yl. An exemplary - C3-8carbocyclyl-heteroaryl group is 3-imidazol-1-yl-cyclohexyl-.
When R1 represents -C2-6alkenyheteroaryl, 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-. When R1 represents -C1-6alkylheteroaryl, examples of C1-6 alkyl include C1-5alkyl or C1-4alkyl, especially C2-5alkyl or C2-4 alkyl, in particular propyl, 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 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). A suitable heteroaryl group is imidazol-1-yl. A particularly suitable -alkylheteroaryl group is 3-imidazol-1-yl-propyl-. When R1 represents -C1-6alkylheteroaryl, examples wherein alkyl is branched include:
. When R1 represents (CH2)aCR5R6(CH2)bheteroaryl wherein a and b independently represent integers 0-5 provided that a + b = 0-5 and R5 and R6 are alkylene which together with the carbon to which they are attached form a C3-C5 cycloalkyl group, examples include:
. Particular examples of R1 heteroaryl groups include a 5-membered ring containing 2 or 3 nitrogen atoms, which ring may optionally be substituted (e.g. in particular by one or two groups, such as methyl, for example:
Other examples of R1 heteroaryl groups include a 9-membered bicyclic ring containing 2 nitrogen atoms, which ring may optionally be substituted, for example:
Clearly, the heteroaryl groups shown above may also be present as part of a larger R1 function such as -C3-8carbocyclyl-heteroaryl, -C2-6alkenylheteroaryl or –C1-6alkylheteroaryl.
When R2 represents -C1-8alkyl, 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. When R2 represents optionally substituted aryl, 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-dichlorophenyl-, 3,4-difluorophenyl-, 3,4- dimethylphenyl-, 3,4,5-trifluorophenyl-, 3,5-bis(trifluororomethyl)phenyl-, 3,5- dimethoxyphenyl-, 2-methoxyphenyl-, 3-methoxyphenyl-, 4-(trifluoromethyl)phenyl-, 4- bromo-2-(trifluoromethyl)phenyl-, 4-bromophenyl-, 4-chloro-3-(trifluoromethyl)phenyl-, 4- chlorophenyl-, 4-cyanophenyl-, 4-ethoxyphenyl-, 4-ethylphenyl-, 4-fluorophenyl-, 4- isopropylphenyl-, 4-methoxyphenyl-, 4-ethoxyphenyl-, 4-propoxyphenyl-, 4-butoxyphenyl-, 4- pentoxyphenyl-, 4-isopropyloxyphenyl-, 4-tetrafluoroethyloxyphenyl-. Alternatively, R2 may represent unsubstituted phenyl-. Further exemplary 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, 4-chloro-3-(trifluoromethyl)phenyl-, 4-chloro-3-methylphenyl, 4- chlorophenyl-, 4-fluorophenyl- and 4-propoxyphenyl-. When R2 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-). When R2 represents optionally substituted heteroaryl, examples include monocyclic rings (e.g. 5 or 6 membered rings) and bicyclic rings (e.g.9 or 10 membered rings) which may optionally
be substituted. 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). 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). 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. When R2 represents carbocyclyl, examples include cycloalkyl and cycloalkenyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of cycloalkenyl include cyclohexenyl (e.g. cyclohex-2-enyl, cyclohex-3-enyl). Examples of substituted carbocyclyl 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. When R2 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-). When R2 represents -C1-4alkylaryl, 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. methyl, trifluoromethyl, tert-butyl, chloro, fluoro and methoxy) and, for example,
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. When R2 represents -C1-4alkylheteroaryl in which heteroaryl is optionally substituted, examples include methylheteroaryl and -ethylheteroaryl (e.g. 1-heteroarylethyl- and 2-heteroarylethyl-), -propylheteroaryl and –butylheteroaryl in which heteroaryl is optionally substituted. Specific examples of -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-indol-1-methyl-, 3-ethyl-indol-1-ethyl-, 4-methyl-pyridin-2- methyl-, 4-methyl-pyridin-2-yl-ethyl-, 4-methyl-pyridin-3-methyl-, 4-methyl-pyridin-3-ethyl-. When R2 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). When R2 represents -C1-4alkylheterocyclyl (which may optionally be substituted); examples include -methyl-tetrahydrofuranyl (e.g. -methyl-tetrahydrofuran-2-yl, -methyl-tetrahydrofuran- 3-yl), -ethyl-tetrahydrofuranyl, -methyl-piperidinyl. When R2 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). Typically the terminal phenyl or monocyclic heteroaryl group is unsubstituted. Typically the terminal phenyl or monocyclic heteroaryl group substitutes the other phenyl group at the 4-position. When R2 represents phenyl substituted by phenyl in which any of aforesaid phenyl groups may optionally be substituted, examples include -biphenyl-4-yl.
When R2 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-. When R2 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-. When R2 represents optionally substituted phenyl fused to optionally substituted carbocyclyl, examples include indanyl (e.g. indan-4-yl-, 2-methyl-indan-4-yl-), indenyl and tetralinyl. When R2 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-. When R2 represents -C1-4alkyl(phenyl substituted by phenyl), examples include biphenyl-4-yl- methyl-. When R2 represents -C1-4alkyl(phenyl substituted by a monocyclic heteroaryl group), examples include 4-(oxazol-5-yl)phenyl-methyl-. When R2 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-. When R2 represents -C1-4alkyl(optionally substituted phenyl fused to optionally substituted carbocyclyl), examples include indanyl-methyl- (e.g. indan-4-yl-methyl-, 2-methyl-indan-4-yl- methyl-), indenyl-methyl- and tetralinyl-methyl-. When R2 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-. When R3 represents -C1-4alkyl, examples include methyl, ethyl, propyl (e.g. n-propyl, isopropyl) and butyl (e.g. n-butyl- sec-butyl, isobutyl and tert-butyl).
When R3 represents optionally substituted aryl, 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-, 3,4-dimethylphenyl-, 3,4,5-trifluorophenyl-, 3,5-bis(trifluororomethyl)phenyl-, 3,5-dimethoxyphenyl-, 3- methoxyphenyl-, 4-(trifluoromethyl)phenyl-, 4-bromo-2-(trifluoromethyl)phenyl-, 4- bromophenyl-, 4-chloro-3-(trifluoromethyl)phenyl-, 4-chlorophenyl-, 4-cyanophenyl-, 4- ethoxyphenyl-, 4-ethylphenyl-, 4-fluorophenyl-, 4-isopropylphenyl-, 4-methoxyphenyl-. Alternatively, R3 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-. When R2 and R3 are joined to form a carbocyclyl ring, which is optionally substituted by one or more C1-2alkyl groups, examples include cycloalkyl (e.g. cyclopropyl, cyclopentyl and cyclohexyl) and cycloalkenyl (e.g. cyclohexenyl). When R2 and R3 are joined to form a carbocyclyl ring which is fused to phenyl; examples include indanyl (e.g. indan-2-yl) and tetralinyl. When R2 and R3 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). When R4 represents -C1-8alkyl 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.
When R4 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. Suitably, R1 represents heteroaryl or -C1-6alkylheteroaryl. In one embodiment, R1 represents heteroaryl. In a further embodiment, R1 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. In another embodiment, R1 represents -C1-6alkylheteroaryl. When R1 represents heteroaryl, R1 suitably represents bicyclic heteroaryl, especially 9- membered bicyclic heteroaryl. More suitably, R1 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. When R1 represents bicyclic heteroaryl, preferably the heteroaryl group does not contain S atoms. When R1 represents a phenyl ring fused to a 5-membered heteroaryl ring, preferably R1 is linked to the core of formula (I) through the phenyl ring. When R1 represents a pyridine ring fused to a 5-membered heteroaryl ring, preferably R1 is linked to the core of formula (I) through the pyridine ring. Suitably R1 represents unsubstituted heteroaryl. In particular, R1 suitably represents 1H-benzoimidazolyl or imidazo[1,2-a]pyridine, particularly 1H-benzoimidazolyl, especially 1H-benzoimidazol-5-yl. When R1 represents -C1-6alkylheteroaryl, heteroaryl is suitably monocyclic heteroaryl, especially 5-membered monocyclic heteroaryl. More suitably, when R1 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. When R1 represents -C1- 6alkylheteroaryl, preferably the heteroaryl group does not contain S atoms. When R1 represents -C1-6alkylheteroaryl, heteroaryl represents substituted or unsubstituted imidazolyl. In particular, when R1 represents -C1-6alkylheteroaryl, heteroaryl suitably represents substituted or unsubstituted imidazoly-1-yl. When R1 represents -C1-6alkylheteroaryl and heteroaryl is substituted imidazoly-1-yl, imidazoly-1-yl is suitably substituted by methyl. In one embodiment R1 represents
wherein A represents an unbranched C1-6alkylene chain (e.g. an unbranched C1-5alkylene chain, e.g. an unbranched C1-4alkylene chain, e.g. an unbranched C1-3alkylene chain) or 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 (CH2)aCR5R6(CH2)b and R11, R12 and R13 independently represent H or C1-2alkyl. In a second embodiment, R1 represents
wherein B represents a bond, -CH2-, -CH2-CH2-, -CH(Me)-, -CH(Me)-CH2- or -CH2-CH(Me)- and R14 and R15 independently represent H, C1-2alkyl (e.g. methyl), halogen (e.g. fluorine) or C1-6 haloalkyl (e.g. trifluoromethyl). In a third embodiment, R1 represents
wherein C represents a bond, -CH2-, -CH2-CH2-, -CH(Me)-, -CH(Me)-CH2- or -CH2-CH(Me)- and R16 and R17 independently represent H, C1-2alkyl (e.g. methyl), halogen (e.g. fluorine) or C1-6 haloalkyl (e.g. trifluoromethyl). In a fourth embodiment, R1 represents
wherein D represents a bond, -CH2-, -CH2-CH2-, -CH(Me)-, -CH(Me)-CH2- or -CH2-CH(Me)- and R18 and R19 independently represent H, C1-2alkyl (e.g. methyl), halogen (e.g. fluorine) or C1-6 haloalkyl (e.g. trifluoromethyl); Suitably R1 represents
.
In one embodiment R14 represents H and R15 represents H. In another embodiment R14 represents H and R15 represents C1-2alkyl. In a third embodiment R14 represents C1-2alkyl and R15 represents H. In a fourth embodiment R14 represents methyl and R15 represents H. In a further embodiment, R14 represents H or methyl and R15 represents C1-2alkyl (e.g. methyl) or halogen (e.g. fluorine). Suitably 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-. Alternatively R1 represents
. R11 suitably represents H, R12 suitably represents H or methyl. R13 suitably represents H or methyl. In one embodiment of the invention, R12 represents H and R13 represents methyl. In another embodiment, R12 represents methyl and R13 represents H. In a third embodiment, R12 represents H and R13 represents H. Suitably A represents an unbranched C2-5 alkylene chain. In one embodiment, A represents -(CH2)2-. In another embodiment, A represents -(CH2)3-. In a third embodiment, A represents -(CH2)4-. In further embodiment, A represents -(CH2)5-. More suitably A represents -(CH2)2-, -(CH2)4- or -(CH2)5-. In one embodiment, A represents -(CH2)3-. In another embodiment, A represents -(CH2)4-.
Alternatively A represents a branched C2-5 alkylene chain. In one embodiment A does not represent -(CH2)3-. When A represents a C2-5 alkylene chain, which is substituted by two alkylene substituents at the same position wherein the two alkylene substituents are joined to each other to form a C3- 5spiro-cycloalkyl group, the spiro-cycloalkyl group is suitably C3spiro-cycloalkyl. Alternatively R1 represents
. In one embodiment R16 represents H and R17 represents H. In another embodiment R16 represents H and R17 represents C1-2alkyl. In a third embodiment R16 represents C1-2alkyl and R17 represents H. In a further embodiment, R16 represents H or methyl and R17 represents C1- 2alkyl (e.g. methyl) or halogen (e.g. fluorine). Suitably 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-. Alternatively R1 represents
In one embodiment R18 represents H and R19 represents H. In another embodiment R18 represents H and R19 represents C1-2alkyl. In a third embodiment R18 represents C1-2alkyl and
R19 represents H. In a further embodiment, R14 represents H or methyl and R15 represents C1- 2alkyl (e.g. methyl) or halogen (e.g. fluorine). Suitably D represents a bond, -CH2- or -CH2CH2-. In one embodiment D represents a bond. In another embodiment, D represents -CH2-. In a third embodiment, D represents -CH2CH2-. More suitably R1 represents
. Yet more suitably R1 represents
. Most suitably, R1 represents
. Suitably 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 phenyl, -C1-4alkyl(phenyl substituted by a monocyclic heterocyclyl group), -C1-4alkyl(phenyl substituted by an –O- carbocyclyl group), phenyl substituted by –O-C1-4alkyl-heterocyclyl or phenyl fused to heterocyclyl, the aforesaid aryl, heteroaryl, phenyl and heterocyclyl groups optionally being substituted. More suitably R2 represents H, 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. Yet more suitably R2 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. In one embodiment, R2 represent H. In one embodiment, R2 represents C1-8alkyl. When R2 represents C1-8alkyl, R2 suitably represents i-propyl or t-butyl.
In one embodiment, R2 represents carbocyclyl. When R2 represents carbocyclyl, R2 suitably represents cyclohexyl. In one embodiment, R2 represents -C1-4alkylcarbocyclyl. When R2 represents -C1- 4alkylcarbocyclyl, R2 suitably represents –CH2-cyclohexyl. In one embodiment, R2 represents optionally substituted aryl. When R2 represents optionally substituted aryl, R2 suitably represents optionally substituted phenyl or napthyl. In one embodiment, R2 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. –O-(CH2)2-OMe), -N(C1-4alkyl)(C1-4alkyl)-N(C1- 4alkyl)(C1-4alkyl) (e.g. –N(Me)-(CH2)2-N(Me)2), -N(C1-4alkyl)(C1-4alkyl) (e.g. – N(ethyl)(ethyl)), -N(C3-8cycloalkyll)(C3-8cycloalkyl) (e.g. –N(cyclopropyl)(cyclopropyl)), -C1- 4alkyl-N(C1-4alkyl)(C1-4alkyl) (e.g. –(CH2)3-N(methyl)(methyl), -C1-4alkoxy-N(C1-4alkyl)(C1- 4alkyl) (e.g. –O(CH2)2-N(methyl)(methyl)), -N(-C1-6alkyl-C1-6alkoxy)(-C1-6alkyl-C1-6alkoxy) (e.g. –N((CH2)2OMe)(CH2)2OMe)). In a further embodiment, R2 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), haloC1-6 alkyl (e.g. trifluoromethyl), haloC1-6 alkoxy (e.g. tetrafluoroethyloxy) or halogen (e.g. chlorine or fluorine). In a yet further embodiment, R2 represents phenyl optionally substituted by one or more groups selected from C1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or isopropyloxy). In a still yet further embodiment, R2 represents phenyl optionally substituted by a propoxy group. When R2 represents optionally substituted phenyl, R2 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-difluorophenyl, 2,3,5-trifluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 3- fluoro-5-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3-fluoro-4- trifluoromethylphenyl, 3-fluoro-4-methoxyphenyl or 2,6-difluoro-4-methoxyphenyl. In an alternative embodiment, R2 represents unsubstituted phenyl. In an alternative embodiment, R2 represents unsubstituted naphthyl. In one embodiment, R2 represents -C1-4alkylaryl, the aforesaid aryl optionally being substituted. When R2 represents -C1-4alkylaryl, R2 suitably represents benzyl optionally substituted by one or more C1-6alkoxy (e.g. methoxy) or halogen (e.g. chlorine or fluorine) groups. When R2 represents optionally substituted benzyl, R2 suitably represents 4-methoxybenzyl, 4- chlorobenzyl or 4-fluorobenzyl. When R2 represents optionally substituted benzyl, R2 also suitably represents 4-propoxybenzyl or 4-isopropoxybenzyl. In an alternative embodiment, R2 represents unsubstituted benzyl. When R2 represents -C1-4alkylaryl, R2 suitably represents – C(H)(Me)-phenyl. When R2 represents -C1-4alkylaryl, R2 suitably represents –(CH2)2-phenyl. In one embodiment, R2 represents optionally substituted heteroaryl. When R2 represents optionally substituted heteroaryl, R2 suitably represents optionally substituted thiophenyl. In an alternative embodiment, R2 represents unsubstituted thiophenyl. In one embodiment, R2 represents optionally substituted heterocyclyl. When R2 represents optionally substituted heteroaryl, R2 suitably represents unsubstituted dihydrobenzodioxinyl or piperidinyl substituted by a -C(O)C1-6alkyl (i.e. –COMe) group. In one embodiment, R2 represents phenyl substituted by phenyl, the aforesaid phenyl groups optionally being substituted. When R2 represents phenyl substituted by phenyl, the aforesaid phenyl groups optionally being substituted, R2 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. In an alternative embodiment, when R2 represents phenyl substituted by phenyl, R2 suitably represents unsubstituted phenyl substituted by unsubstituted phenyl.
In one embodiment, R2 represents optionally substituted phenyl substituted by optionally substituted phenoxy. When R2 represents optionally substituted phenyl substituted by optionally substituted phenoxy, R2 suitably represents phenyl substituted by 4-phenoxy. In one embodiment, R2 represents optionally substituted phenyl substituted by optionally substituted heterocyclyl. When R2 represents optionally substituted phenyl substituted by optionally substituted heterocyclyl, R2 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. In a further embodiment, R2 represents optionally substituted phenyl substituted by optionally substituted heterocyclyl. When R2 represents optionally substituted phenyl substituted by optionally substituted heterocyclyl, R2 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. In one embodiment, R2 represents optionally substituted phenyl substituted by heterocyclyl wherein said heterocyclyl is substituted by phenyl. When R2 represents optionally substituted phenyl substituted by heterocyclyl wherein said heterocyclyl is substituted by phenyl, R2 suitably represents phenyl substituted by 4-piperazinyl substituted by 4N-phenyl, phenyl substituted by 3-piperazinyl substituted by 4N-phenyl. In one embodiment, R2 represents optionally substituted phenyl substituted by optionally substituted carbocyclyl wherein said carbocyclyl is substituted by optionally substituted heterocyclyl. When R2 represents optionally substituted phenyl substituted by optionally substituted carbocyclyl wherein said carbocyclyl is substituted by optionally substituted heterocyclyl, R2 suitably represents phenyl substituted by carbocyclyl (i.e. cyclohexyl) substituted by heterocyclyl (i.e. morpholinyl). In one embodiment, R2 represents optionally substituted phenyl substituted by –O-C1-4alkyl- heterocyclyl. When R2 represents optionally substituted phenyl substituted by –O-C1-4alkyl-
heterocyclyl, R2 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. In one embodiment, R2 represents optionally substituted phenyl substituted by optionally substituted carbocyclyl. When R2 represents optionally substituted phenyl substituted by optionally substituted carbocyclyl, R2 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 C1-4alkoxy (i.e. methoxy) groups. In one embodiment, R2 represents optionally substituted phenyl substituted by –O-carbocyclyl. When R2 represents optionally substituted phenyl substituted by –O-carbocyclyl, R2 suitably represents unsubstituted phenyl substituted by an –O-C3-8 cycloalkyl group (i.e. –O- cyclohexyl). In one embodiment, R2 represents optionally substituted heterocyclyl substituted by optionally substituted phenyl. When R2 represents optionally substituted heterocyclyl substituted by optionally substituted phenyl, R2 suitably represents unsubstituted piperidinyl substituted by unsubstituted phenyl. In one embodiment, R2 represents optionally substituted carbocyclyl substituted by optionally substituted phenyl. When R2 represents optionally substituted carbocyclyl substituted by optionally substituted phenyl, R2 suitably represents unsubstituted C3-8 cycloalkyl (i.e. cyclohexyl) substituted by unsubstituted phenyl. In one embodiment, R2 represents optionally substituted phenyl fused to optionally substituted heterocyclyl. When R2 represents optionally substituted phenyl fused to optionally substituted heterocyclyl, R2 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. In one embodiment, R2 represents -C1-4alkyl(phenyl substituted by a monocyclic heterocyclyl group). When R2 represents -C1-4alkyl(phenyl substituted by a monocyclic heterocyclyl group), R2 suitably represents benzyl substituted by morpholinyl.
In one embodiment, R2 represents -C1-4alkyl(phenyl substituted by an –O-carbocyclyl group). When R2 represents -C1-4alkyl(phenyl substituted by an –O-carbocyclyl group), R2 suitably represents benzyl substituted by an –O-carbocyclyl group (i.e. –O-cyclohexyl). Suitably R3 represents H or R2 and R3 are joined to form a carbocyclyl ring which is fused to phenyl. Most suitably R3 represents H. Suitably R4 represents H, -C1-8alkyl or -C(O)C1-6alkyl. More suitably R4 represents H or -C1- 8alkyl, e.g. H or methyl. Most suitably R4 represents H. In one embodiment, X represents O, S or CR7R8 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 a further embodiment, X represents O, S or CR7R8. In one embodiment X represents O. In an alternative embodiment X represents S. In an alternative embodiment X represents C=O. In an alternative embodiment, 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 C1-2alkyl groups. In one embodiment, R7 and R8 both represent hydrogen or –C1-4alkyl, or one of R7 and R8 represents hydrogen and the other represents –C1-4alkyl or an optionally substituted aryl group. When one of R7 and R8 represents a –C1-4alkyl group, said group is suitably methyl. When one of R7 and R8 represents an optionally substituted aryl group, said group is suitably unsubstituted phenyl or phenyl substituted by 4-propoxy. In one embodiment, R7 and R8 both represent hydrogen. In an alternative embodiment, R7 and R8 both represent –C1-4alkyl. In an alternative embodiment, one of R7 and R8 represents hydrogen and the other represents –C1-4alkyl (e.g. methyl). In an alternative embodiment, one of R7 and R8 represents hydrogen and the other represents an optionally substituted aryl group (e.g. unsubstituted phenyl or phenyl substituted by a C1-6 alkoxy group).
In one embodiment Y represents C=O, C=S or CH2. In an alternative embodiment, Y represents C=O. In an alternative embodiment Y represents C=S. In an alternative embodiment, Y represents CH2. In one embodiment, Z represents –N-R4 (e.g. -NH or –N-NH2), O or CHR10 (e.g. CH2 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. In an alternative embodiment, Z represents –N-NH2. In an alternative embodiment, Z represents O. In an alternative embodiment, Z represents CH2. In an alternative embodiment, Z represents CH-methyl. In one embodiment, X represents CR7R8, Y represents C=O and Z represents –N-R4. In a further embodiment, X represents CH2, Y represents C=O and Z represents –NH. In a further embodiment, X represents CH-Me, Y represents C=O and Z represents –NH. In a further embodiment, X represents CH2, Y represents C=O and Z represents –N-NH2. When X represents CR7R8, Y represents C=O and Z represents –N-R4, R1 suitably represents 1H-benzo[d]imidazolyl or 1H-imidazo[1,2-a]pyridinyl. When X represents CR7R8, Y represents C=O and Z represents –N-R4, R2 suitably represents: C1-8 alkyl (such as t-butyl); carbocyclyl (such as cyclohexyl); phenyl optionally substituted by one or more C1-6 alkyl (e.g. methyl), C1-6 alkoxy (such as methoxy, ethoxy, propoxy, butoxy, pentoxy or isopropoxy), halogen (such as fluorine or chlorine), haloC1-6 alkyl (such as trifluoromethyl) or haloC1-6 alkoxy groups (such as trifluoromethoxy); optionally substituted 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 optionally substituted phenyl; or optionally substituted phenyl substituted by optionally substituted heterocyclyl (such as optionally substituted phenyl substituted by morpholinyl, optionally substituted phenyl substituted by piperazinyl substituted by phenyl or optionally substituted phenyl substituted by piperazinyl substituted by ethyl). When X represents CR7R8, Y represents C=O and Z represents –N-R4, R3 suitably represents hydrogen. When X represents CR7R8, Y represents C=O and Z represents –N-R4, R3, R7 and R8 each suitably represent hydrogen. In one embodiment, X represents C=O, Y represents CHR9 and Z represents –N-R4. In a further embodiment, X represents C=O, Y represents CH2 and Z represents –NH. When X represents C=O, Y represents CHR9 and Z represents –N-R4, R1 suitably represents 1H-benzo[d]imidazolyl. When X represents C=O, Y represents CHR9 and Z represents –N-R4, R2 suitably represents phenyl optionally substituted by one or more halogen atoms (such as unsubstituted phenyl or 2,3,5-trifluorophenyl). When X represents C=O, Y represents CHR9 and Z represents –N-R4, R3 suitably represents hydrogen. In an alternative embodiment, X represents CR7R8, Y represents C=O and Z represents O. In a further embodiment, X represents CH2, Y represents C=O and Z represents O. In a further embodiment, X represents C(Me)2, Y represents C=O and Z represents O. In a further embodiment, X represents CH-phenyl, Y represents C=O and Z represents O.
When X represents CR7R8, Y represents C=O and Z represents O, R1 suitably represents 1H- benzo[d]imidazolyl or 1H-imidazo[1,2-a]pyridinyl. hen X represents CR7R8, Y represents C=O and Z represents O, R2 suitably represents: C1-8 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); -C1-4 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 phenyl; or optionally substituted phenyl substituted by optionally substituted heterocyclyl (such as optionally substituted phenyl substituted by piperazinyl substituted by phenyl or optionally substituted phenyl substituted by piperazinyl substituted by methyl). When X represents CR7R8, Y represents C=O and Z represents O, R3 suitably represents hydrogen. In an alternative embodiment, X represents CR7R8, Y represents CHR9 and Z represents CHR10. In a further embodiment, X represents CH2, Y represents CH2 and Z represents CH2. When X represents CR7R8, Y represents CHR9 and Z represents CHR10, R1 suitably represents 1H-benzo[d]imidazolyl. When X represents CR7R8, Y represents CHR9 and Z represents CHR10, R2 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 -C1-4 alkylaryl (such as unsubstituted benzyl and benzyl substituted a halogen atom, such as fluorine or chlorine or a C1-6 alkoxy, such as methoxy). When X represents CR7R8, Y represents CHR9 and Z represents CHR10, R3 suitably represents hydrogen. In an alternative embodiment, X represents S, Y represents C=O and Z represents CHR10. In a further embodiment, X represents S, Y represents C=O and Z represents CH2. In a further embodiment, X represents S, Y represents C=O and Z represents CH-methyl. When X represents S, Y represents C=O and Z represents CHR10, R1 suitably represents 1H- benzo[d]imidazolyl. When X represents S, Y represents C=O and Z represents CHR10, R2 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). When X represents S, Y represents C=O and Z represents CHR10, R3 suitably represents hydrogen. In an alternative embodiment, X represents S, Y represents C=S and Z represents CHR10. In a further embodiment, X represents S, Y represents C=S and Z represents CH2. When X represents S, Y represents C=S and Z represents CHR10, R1 suitably represents 1H- benzo[d]imidazolyl.
When X represents S, Y represents C=S and Z represents CHR10, R2 suitably represents optionally substituted phenyl or optionally substituted phenyl substituted by optionally substituted phenoxy. When X represents S, Y represents C=S and Z represents CHR10, R3 suitably represents hydrogen. In an alternative embodiment, X represents CR7R8, Y represents C=O and Z represents CHR10. In a further embodiment, X represents CH2, Y represents C=O and Z represents CH2. When X represents CR7R8, Y represents C=O and Z represents CHR10, R1 suitably represents 1H-benzo[d]imidazolyl. When X represents CR7R8, Y represents C=O and Z represents CHR10, R2 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). When X represents CR7R8, Y represents C=O and Z represents CHR10, R3 suitably represents hydrogen. In an alternative embodiment, X and Z represent two adjacent carbon atoms of a phenyl ring which is fused in that position and Y represents C=O. In a further embodiment, X and Z represent two adjacent carbon atoms of a phenyl ring which is fused in that position and is substituted by one or more halogen or C1-2alkyl groups such as 2,5-dichlorophenyl or 3,4- dichlorophenyl and Y represents C=O. When X and Z represent two adjacent carbon atoms of a phenyl ring which is fused in that position and Y represents C=O, R1 suitably represents 1H-benzo[d]imidazolyl. When X and Z represent two adjacent carbon atoms of a phenyl ring which is fused in that position and Y represents C=O, R2 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. When X and Z represent two adjacent carbon atoms of a phenyl ring which is fused in that position and Y represents C=O, R3 suitably represents hydrogen. In an alternative embodiment, X represents –O-CH2-, Y represents CO and Z represents CHR10. In a further embodiment, X represents –O-CH2-, Y represents CO and Z represents CH2 (see e.g. Example 93). When X represents –O-CH2-, Y represents CO and Z represents CHR10, R1 suitably represents 1H-benzo[d]imidazolyl. When X represents –O-CH2-, Y represents CO and Z represents CHR10, R2 suitably represents phenyl optionally substituted by a C1-6 alkoxy (such as propoxy). When X represents –O-CH2-, Y represents CO and Z represents CHR10, R3 suitably represents hydrogen. In an alternative embodiment, X represents –CH2-CH2-, Y represents CO and Z represents O. When X represents –CH2-CH2-, Y represents CO and Z represents O, R1 suitably represents 1H-benzo[d]imidazolyl or 1H-imidazo[1,2-a]pyridinyl. When X represents –CH2-CH2-, Y represents CO and Z represents O, R2 suitably represents phenyl optionally substituted by a C1-6 alkoxy (such as propoxy). When X represents –CH2-CH2-, Y represents CO and Z represents O, R3 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: R1 represents
; R2 represents C1-8alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, -C1-4alkylaryl, -C1- 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 C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, -C1- 6thioalkyl, -SOC1-4alkyl, -SO2C1-4alkyl, C1-6alkoxy-, -O-C3-8cycloalkyl, C3-8cycloalkyl, -
SO2C3-8cycloalkyl, -SOC3-6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, -C(O)C1-6alkyl, -C(O)OC1-6alkyl, C1-6alkoxy-C1-6alkyl-, C1-6alkoxy-C1-6alkoxy-, nitro, halogen, haloC1- 6alkyl, haloC1-6alkoxy, cyano, hydroxyl, -C(O)OH, -NH2, -NHC1-4alkyl, -N(C1- 4alkyl)(C1-4alkyl), -N(C1-4alkyl)(C1-4alkyl)-N(C1-4alkyl)(C1-4alkyl), -C1-4alkyl-N(C1- 4alkyl)(C1-4alkyl), -C1-4alkoxy-N(C1-4alkyl)(C1-4alkyl), -N(C3-8cycloalkyll)(C3- 8cycloalkyl), -N(-C1-6alkyl-C1-6alkoxy)(-C1-6alkyl-C1-6alkoxy), -C(O)N(C1-4alkyl)(C1- 4alkyl), -C(O)NH2, -C(O)NH(C1-4alkyl) and -C(O)NH(C3-10cycloalkyl); and in which any of aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from C1-4alkyl, oxo, halogen, -C(O)C1-6alkyl and C1-4alkoxy; or R2 represents phenyl substituted by phenyl, phenyl substituted by a monocyclic heteroaryl group, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl, phenyl substituted by heterocyclyl wherein said heterocyclyl is substituted by phenyl, phenyl substituted by –O-C1-4alkyl-heterocyclyl, phenyl substituted by benzyloxy, 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 phenyl, phenyl fused to carbocyclyl, phenyl fused to heterocyclyl, -C1-4alkyl(phenyl substituted by phenyl), -C1-4alkyl(phenyl substituted by a monocyclic heteroaryl group), -C1-4alkyl(phenyl substituted by a monocyclic heterocyclyl group), -C1-4alkyl(phenyl substituted by an –O-carbocyclyl group), -C1-4alkyl(phenyl substituted by benzyloxy), -C1-4alkyl(optionally substituted phenyl fused to optionally substituted carbocyclyl or -C1-4alkyl(optionally substituted phenyl fused to optionally substituted heterocyclyl); in which any of aforesaid phenyl, benzyloxy and heteroaryl groups may optionally be substituted by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy, and in which any of aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl, phenyl, oxo, halogen, hydroxyl and C1-4alkoxy; R3 represents H, -C1-4alkyl or aryl;
in which aforesaid aryl may optionally be substituted by one or more groups selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, -C1-6thioalkyl, -SOC1-4alkyl, - SO2C1-4alkyl, C1-6alkoxy-, -O-C3-8cycloalkyl, C3-8cycloalkyl, -SO2C3-8cycloalkyl, -SOC3- 6cycloalkyl, C3-6alkenyloxy-, C3-6alkynyloxy-, -C(O)C1-6alkyl, -C(O)OC1-6alkyl, C1- 6alkoxy-C1-6alkyl-, nitro, halogen, cyano, hydroxyl, -C(O)OH, -NH2, -NHC1-4alkyl, - N(C1-4alkyl)(C1-4alkyl), -C(O)N(C1-4alkyl)(C1-4alkyl), -C(O)NH2, -C(O)NH(C1-4alkyl) and, -C(O)NH(C3-10cycloalkyl); or R2 and R3 are joined to form a carbocyclyl ring which is optionally substituted by one or more C1-2alkyl groups; or R2 and R3 are joined to form a carbocyclyl ring which is fused to phenyl, wherein aforesaid carbocyclyl and/or phenyl may optionally be substituted by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy; or R2 and R3 are joined to form a carbocyclyl ring which is fused to monocyclic heteroaryl, wherein aforesaid carbocyclyl and/or heteroaryl may optionally be substituted by one or more groups selected from C1-4alkyl, halogen and C1-4alkoxy; X represents C=O, O, S, CR7R8, -O-CH2- or –CH2-CH2-; Y represents CHR9, C=O or C=S; Z represents –N-R4, O or CHR10, such that when X represents O or S, Z must represent CHR10; or X and Z represent two adjacent carbon atoms of a phenyl ring which is fused in that position and which is optionally substituted by one or more halogen or C1-2alkyl groups; R4 represents H, -C1-8alkyl, -C(O)C1-6alkyl or –NH2; R7 and R8 independently represent H or -C1-4 alkyl; R9 and R10 independently represent H or methyl; provided that the moiety –Y-Z-X- represents a moiety other than –C(=O)-N(-R4)-C(=O)- or - C(=S)-N(-R4)-C(=O)-.
2. A compound according to 1, wherein R2 represents aryl, heteroaryl, phenyl substituted by phenyl, phenyl fused to heterocyclyl or R2 and R3 are joined to form a carbocyclyl ring which is fused to phenyl; the aforesaid aryl, heteroaryl, phenyl, heterocyclyl and carbocyclyl optionally being substituted. 3. A compound according to 2, wherein 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, C1-6alkoxy-C1-6alkyl-, C1-6alkoxy-C1-6alkoxy-, -N(C1-4alkyl)(C1-4alkyl)-N(C1- 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- 6alkyl-C1-6alkoxy). 4. A compound according to 3, wherein R2 represents phenyl substituted by one or more C1-6 alkoxy groups. 5. A compound according to 4, wherein R2 represents phenyl optionally substituted by a propoxy group. 6. A compound according to 4, wherein R2 represents phenyl optionally substituted by phenyl. 7. A compound according to any one of 1 to 6, wherein R3 represents H. 8. A compound according to any one of 1 to 7, wherein R4 represents H. 9. A compound according to any one of 1 to 8, wherein X represents CR7R8, Y represents C=O and Z represents –N-R4 or O. 10. A compound according to any one of 1 to 8, wherein X represents C=O, Y represents CHR9 and Z represents –N-R4. 11. A compound according to any one of 1 to 8, wherein X represents CR7R8, Y represents CHR9 or C=O and Z represents CHR10. 12. A compound according to any one of 1 to 8, wherein X represents S, Y represents C=O or C=S and Z represents CHR10.
13. A compound according to any one of 1 to 8, wherein 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, such as 2,5-dichlorophenyl or 3,4 dichlorophenyl, and Y represents C=O. 14. A compound according to any one of 1 to 8, wherein X represents –O-CH2-, Y represents CO and Z represents CHR10. 15. A compound according to any one of 1 to 8, wherein X represents –CH2-CH2-, Y represents CO and Z represents O. The invention further relates to the following, evenly more preferred embodiments: 1. 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: R1 represents a phenyl ring fused to a 5-membered heteroaryl ring wherein R1 is linked to the core of formula (I) through the phenyl ring; R2 represents optionally substituted aryl; R3 represents H or -C1-4alkyl;
in which aforesaid aryl may optionally be substituted by one or more groups selected from C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, -C1-6thioalkyl, -SOC1-4alkyl, -SO2C1-4alkyl, C1- 6alkoxy-, C3-6alkenyloxy-, C3-6alkynyloxy-, -C(O)C1-6alkyl, -C(O)OC1-6alkyl, C1-6alkoxy-C1- 6alkyl-, nitro, halogen, cyano, hydroxyl, -C(O)OH; X represents CR7R8; Z represents –N-R4; Y represents C=O; wherein, R4 represents H, -C1-8alkyl or -C(O)C1-6alkyl; R7 and R8 independently represent H or -C1-4 alkyl; 2. The compound according to 1, wherein R1 represents
wherein: B represents a bond, -CH2-, -CH2-CH2-, -CH(Me)-, -CH(Me)-CH2- or -CH2-CH(Me)- and R14 and R15 independently represent H or C1-2alkyl. 3. The compound according to 1, wherein R1 represents
. 4. The compound according to any one of 1 to 3, wherein R1 represents
. 5. The compound according to any one of 1 to 4, wherein 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-. 6. The compound according to any one of 1 to 5, wherein R2 represents phenyl substituted by one or more groups selected from methyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, isopropyloxy, hydroxyl, trifluoromethyl, tetrafluoroethyloxy, chlorine, fluorine, –(CH2)3-OMe, and –O-(CH2)2-OMe. 7. The compound according to any one of 1 to 5, wherein R2 represents phenyl substituted by one or more C1-6 alkoxy groups. 8. The compound according any one of 1 to 7, wherein 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 R2 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. The compound according to any one of 1 to 13, wherein X represents CH2, Y represents C=O and Z represents NH. The invention further relates to the following, evenly more preferred embodiments: 1. 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: R1 represents
R2 represents optionally substituted aryl; R3 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 CR7R8; Z represents –N-R4; Y represents C=O; wherein, R4 represents H or -C1-8alkyl; R7 and R8 independently represent H or -C1-4 alkyl; 2. The compound according to 1, wherein R2 represents phenyl substituted by C1-6 alkoxy. 3. The compound according to 1 or 2, wherein R2 represents phenyl substituted by one or more groups selected from methyl, methoxy, ethoxy, propoxy, butoxy, pentoxy and isopropyloxy. 4. The compound according to any one of 1 to 3, wherein R2 represents phenyl substituted by a propoxy group. 5. The compound according to 1, wherein R2 represents phenyl substituted by phenyl. 6. The compound according to any one of 1 to 5, wherein R3 represents H. 7. The compound according to any one of 1 to 6, wherein R4 represents H. 8. The compound according to any one of 1 to 7, wherein X represents CR7R8. 9. The compound according to any one of 1 to 8, wherein X represents CH2, Y represents C=O and Z represents NH.
Example compounds of the compounds of formula I Preferably, 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:
Mol Example Chemical Name Structure Formula Weight 5-tert-butyl-1-(1H- 1 benzo[d]imidazol-5- N NH N C14H18N4O 258.319 O yl)imidazolidin-2-one N H 1-(1H-benzo[d]imidazol- 5-yl)-5- 2 C16H20N4O 284.356 cyclohexylimidazolidin-2- one 1-(1H-benzo[d]imidazol- 3 5-yl)-5- NH N N C16H14N4O 278.309 phenylimidazolidin-2-one O N H 1-(1H-benzo[d]imidazol- 4 5-yl)-5-m- NH N C17H16N4 N O 292.335 tolylimidazolidin-2-one O N H O 1-(1H-benzo[d]imidazol- 5-yl)-5-(4- 5 NH N C17H16N4O2 308.335 methoxyphenyl)imidazoli N O din-2-one N H
O 1-(1H-benzo[d]imidazol- 5-yl)-5-(4- NH N N O C17H16N4O2 308.335 methoxyphenyl)imidazoli N H din-2-one enantiomer 1 O 1-(1H-benzo[d]imidazol- 5-yl)-5-(4- NH N N O C17H16N4O2 308.335 methoxyphenyl)imidazoli N H din-2-one enantiomer 2 O (4R,5S)-1-(1H- benzo[d]imidazol-6-yl)-5- NH N C18H18N4O2 322.36 (4-methoxyphenyl)-4- N O methylimidazolidin-2-one N H 1-(1H-benzo[d]imidazol- 5-yl)-5-(3- O NH methoxyphenyl) N N C17H16N4O2 308.335 O imidazolidin-2-one N H 1-(1H-benzo[d]imidazol- O 5-yl)-5-(2- NH N methoxyphenyl) C17H16N4O2 N 308.335 O N imidazolidin-2-one H 1-(1H-benzo[d]imidazol- O 5-yl)-5-(4- NH N C18H18N4O2 322.361 ethoxyphenyl)imidazolidi N O n-2-one N H
1-(1H-benzo[d]imidazol- O 5-yl)-5-(4- N NH C19H20N4O2 336.388 propoxyphenyl) N O imidazolidin-2-one N H (R)-1-(1H- O benzo[d]imidazol-5-yl)-5- C H N O 336.388 (4-propoxyphenyl) NH 19 20 4 2 N N O N imidazolidin-2-one H (S)-1-(1H- O benzo[d]imidazol-5-yl)-5- NH N C19H20N4O 336.388 (4-propoxyphenyl) 2 N O N H imidazolidin-2-one O 1-(1H-benzo[d]imidazol- 5-yl)-5-(4-butoxyphenyl) NH N C20H22N4O2 N 350.414 O imidazolidin-2-one N H 1-(1H-benzo[d]imidazol- 5-yl)-5-(4- (pentyloxy)phenyl) C21H24N4O2 364.441 imidazolidin-2-one 1-(1H-benzo[d]imidazol- O 5-yl)-5-(4- isopropoxyphenyl) NH C19H20N4O2 336.388 N N O imidazolidin-2-one N H
1-(1H-benzo[d]imidazol- O 5-yl)-5-(4- O methoxybenzo[d][1,3] O NH C18H16N4O4 N 352.344 N dioxol-6-yl)imidazolidin- O N H 2-one 1-(1H-benzo[d]imidazol- O 5-yl)-5-(2,3- O dihydrobenzo[b][1,4] N NH C18H16N4O3 336.345 N dioxin-6-yl)imidazolidin- O N H 2-one 5-(4-(1,1,2,2- F O F tetrafluoroethoxy)phenyl) F F NH C18H14F4N4 N 394.323 -1-(1H-benzo[d]imidazol- N O O2 5-yl)imidazolidin-2-one N H 1-(1H-benzo[d]imidazol- F O 5-yl)-5-(2,2- F O C17H12F2N4 difluorobenzo[d][1,3] N NH N 358.299 O3 dioxol-5-yl)imidazolidin- O N H 2-one 1-(1H-benzo[d]imidazol- O 5-yl)-5-(3-fluoro-4- F NH C ethoxyphenyl) 17H1 FN O 326.325 m N 5 4 2 N O imidazolidin-2-one N H
O 1-(1H-benzo[d]imidazol- F 5-yl)-5-(2,6-difluoro-4- C17H14F2N4 NH 344.315 methoxyphenyl) F N N O2 O imidazolidin-2-one N H 5-(4-(2- morpholinoethoxy)phenyl )-1-(1H- 407.466 benzo[d]imidazol-6- C22H25N5O3 yl)imidazolidin-2-one 5-(4-(3- morpholinopropoxy)phen yl)-1-(1H- C23H27N5O3 421.492 benzo[d]imidazol-5- yl)imidazolidin-2-one 5-(2-(2- morpholinoethoxy)phenyl O N )-1-(1H- NH O N N C22H25N5O3 407.466 benzo[d]imidazol-5- O N H yl)imidazolidin-2-one F 1-(1H-benzo[d]imidazol- 5-yl)-5-(4- NH N C16H13FN4O 296.299 fluorophenyl)imidazolidin N O -2-one N H 1-(1H-benzo[d]imidazol- F 5-yl)-5-(2- NH N C16H13FN4O 296.299 fluorophenyl)imidazolidin N O -2-one N H
1-(1H-benzo[d]imidazol- F NH N O 5-yl)-5-(3- C16H13FN4O 296.299 fluorophenyl)imidazolidin N -2-one NH 1-(1H-benzo[d]imidazol- F 5-yl)-5-(2,6- F NH N difluorophenyl) N C16H12F2N4O 314.289 O N imidazolidin-2-one H 1-(1H-benzo[d]imidazol- 5-yl)-5-(3,4- difluorophenyl) C16H12F2N4O 314.289 imidazolidin-2-one F 1-(1H-benzo[d]imidazol- F F 5-yl)-5-(2-fluoro-5- (trifluoromethyl)phenyl) C17H12F4N4 F NH O 364.297 N N O imidazolidin-2-one N H F 1-(1H-benzo[d]imidazol- F F 5-yl)-5-(3-fluoro-5- F (trifluoromethyl)phenyl) NH C17H12F4N4O 364.297 N N imidazolidin-2-one O N H F F 1-(1H-benzo[d]imidazol- F F 5-yl)-5-(2-fluoro-4- (trifluoromethyl)phenyl) C17H12F4N4 NH O 364.297 N N imidazolidin-2-one O N H
F F 1-(1H-benzo[d]imidazol- F 5-yl)-5-(3-fluoro-4- F (trifluoromethyl)phenyl) NH N C17H12F4N4O 364.297 N O imidazolidin-2-one N H 1-(1H-benzo[d]imidazol- Cl 5-yl)-5-(2- NH N N C16H13ClN4O 312.754 chlorophenyl)imidazolidi O N n-2-one H 1-(1H-benzo[d]imidazol- 5-yl)-5-(3- Cl NH N C16H13ClN4O 312.754 chlorophenyl)imidazolidi N O N n-2-one H 1-(1H-benzo[d]imidazol- Cl 5-yl)-5-(2,6- Cl NH N dichlorophenyl) C16H12Cl2N4 N O 347.199 O N imidazolidin-2-one H Cl 1-(1H-benzo[d]imidazol- Cl 5-yl)-5-(2,3- dichlorophenyl) NH C16H12Cl2N4 N O 347.199 N O imidazolidin-2-one N H Cl 1-(1H-benzo[d]imidazol- Cl 5-yl)-5-(3,4- NH dichlorophenyl) N C16H12Cl2N4O 347.199 N O imidazolidin-2-one N H
Cl (S)-1-(1H- Cl benzo[d]imidazol-5-yl)-5- NH (3,4-dichlorophenyl) N C16H12Cl2N4O 347.199 N O imidazolidin-2-one N H 1-(1H-1,3-benzodiazol-5- yl)-5-(4- C H biphenyl)imidazolidin-2- NH 22 18N4O 354.405 N N one O N H (S)-1-(1H-1,3- benzodiazol-5-yl)-5-(4- NH C22H18N4 N O 354.405 biphenyl)imidazolidin-2- N O one N H (R)-1-(1H-1,3- benzodiazol-5-yl)-5-(4- NH C22H18N4O 354.405 biphenyl)imidazolidin-2- N N one O N H 1-(1H-1,3-benzodiazol-5- F yl)-5-(3-fluoro-4- NH C22H17FN4O 372.395 biphenyl)imidazolidin-2- N N O one N H 1-(1H-benzo[d]imidazol- Cl 5-yl)-5-[4-(3- chlorophenyl)phenyl] NH N C22H17ClN4O 388.85 N O imidazolidin-2-one N H
Cl 1-(1H-benzo[d]imidazol- Cl 5-yl)-5-(3’,4’-dichloro-4- henyl)imidazolidin-2- N C22H16Cl2N4O 423.295 bip H N N O one N H 1-(1H-benzo[d]imidazol- 5-yl)-5-(3- NH N N C22H18N4O 354.405 henylphenyl)imidazolidi O N n-2-one H Cl 1-(1H-benzo[d]imidazol- 5-yl)-5-[3-(3- chlorophenyl)phenyl] C22H17ClN4O 388.85 NH N N imidazolidin-2-one O N H 1-(1H-benzo[d]imidazol- O Cl N 5-yl)-5-(3-chloro-4- NH C H ClN O 397. ophenyl) 20 20 5 2 858 morpholin N N O imidazolidin-2-one N H 1-(1H-benzo[d]imidazol- 5-yl)-5-(4-(4- N N phenylpiperazin-1- NH C26H26N6O 438.524 N l)phenyl)imidazolidin-2- N O N one H 1-(1H-benzo[d]imidazol- N N 5-yl)-5-(2-chloro-6-(4- ethylpiperazin-1- NH Cl C22H25ClN6 N O 424.927 l)phenyl)imidazolidin-2- N O one N H
1-(H-imidazo[1,2- N a]pyridin-7-yl)-5- N C16H14N4 N O 278.309 phenylimidazolidin-2-one NH O 1-(H-imidazo[1,2- N a]pyridin-7-yl)-5-(4- N O N C19H20N4O2 336.388 propoxyphenyl) O N H imidazolidin-2-one 5-(4-butoxyphenyl)-1-(H- imidazo[1,2-a]pyridin-7- C20H22N4O2 350.414 yl)imidazolidin-2-one 5-(2,6-difluoro-4- O methoxyphenyl)-1-(H- F N C17H14F2N4O2 344.315 imidazo[1,2-a]pyridin-7- F N N yl)imidazolidin-2-one NH O 1-(H-imidazo[1,2- O a]pyridin-7-yl)-5-(4- O O methoxybenzo[d][1,3] N C18H16N4O4 352.344 N N dioxol-6-yl)imidazolidin- NH O 2-one 5-(4-(2- morpholinoethoxy)phenyl )-1-(H-imidazo[1,2- C22H25N5O3 407.466 a]pyridin-7- yl)imidazolidin-2-one
5-(2,6-difluorophenyl)-1- N F N C 16 H 12 F 2 N 4 (H-imidazo[1,2-a]pyridin- N F 314.28 O N O 7-yl)imidazolidin-2-one H 5-(biphenyl)-1-(H- N N imidazo[1,2-a]pyridin-7- C22H18N4 N O 354.405 yl)imidazolidin-2-one O HN 5-(3-fluorobiphenyl)-1- N N (H-imidazo[1,2-a]pyridin- F C22H17FN4 O O 372.395 N 7-yl)imidazolidin-2-one HN 1-(H-imidazo[1,2- a]pyridin-7-yl)-5-(4-(4- N N phenylpiperazin-1- C26H26N6O 438.22 NH yl)phenyl)imidazolidin-2- N N O one N O NH 1-(1H-benzo[d]imidazol- N 5-yl)-5- C16H14N4O 278.30 phenylimidazolidin-4-one N NH F 1-(1H-benzo[d]imidazol- F O C 16 H 11 F 3 N 4 5-yl)-5-(2,3,5- F O trifluorophenyl) 332.27 N NH N imidazolidin-4-one N H
1-Amino-3-(1H- O benzo[d]imidazol-5-yl)-4- N NH2 N C H N O (4-methoxyphenyl) 17 17 5 2 323.34 N O imidazolidin-2-one N H (S)-3-(1H- O benzo[d]imidazol-6-yl)-4- N C16H13N3O2 279.293 phenyloxazolidin-2-one O N NH (R)-3-(1H- O benzo[d]imidazol-6-yl)-4- N C16H13N3O2 279.293 O phenyloxazolidin-2-one N NH O O (S)-3-(1H- N benzo[d]imidazol-5-yl)-4- C13H15N3O2 245.27 isopropyloxazolidin-2-one N NH O (S)-3-(1H- O N benzo[d]imidazol-5-yl)-4- C17H15N3O2 293.31 benzyloxazolidin-2-one N NH (4S,5R)-3-(1H- benzo[d]imidazol-6-yl)- O N C22H17N3O2 355.389 4,5-diphenyloxazolidin-2- O one N NH
(4S,5S)-3-(1H- benzo[d]imidazol-6-yl)-5- O N C17H15N3O2 293.32 methyl-4- O phenyloxazolidin-2-one N NH (S)-3-(1H- benzo[d]imidazol-6-yl)- N O C18H17N3O2 307.346 5,5-dimethyl-4- O phenyloxazolidin-2-one N NH (S)-3-(1H- O benzo[d]imidazol-6-yl)-4- (4- O N C19H19N3O3 337.372 O propoxyphenyl)oxazolidin N NH -2-one (S)-3-(1H- O O benzo[d]imidazol-6-yl)-4- (2,3-dihydrobenzo[b][1,4] O N C18H15N3O4 337.11 O dioxin-7-yl)oxazolidin-2- N one NH (S)-4- O O (benzo[d][1,3]dioxol-6- yl)-3-(1H- O N C17H13N3O4 323.09 benzo[d]imidazol-6- O yl)oxazolidin-2-one N NH
(4S,5R)-3-(1H- O O benzo[d]imidazol-6-yl)- 4,5-bis(4- O N C28H29N3O4 471.22 propoxyphenyl)oxazolidin O N NH -2-one diastereomer 1 (4S,5R)-3-(1H- O O benzo[d]imidazol-6-yl)- 4,5-bis(4- O N C28H29N3O4 471.22 propoxyphenyl)oxazolidin O N NH -2-one diastereomer 2 O 3-(1H-benzo[d]imidazol- 6-yl)-5-phenyl-4-(4- O N C25H23N3O3 O 413.17 propoxyphenyl)oxazolidin N -2-one NH diastereomer 1 O -(1H-benzo[d]imidazol-6- yl)-5-phenyl-4-(4- O N O C25H23N3O3 413.17 propoxyphenyl)oxazolidin N -2-one NH diastereomer 2
H N (S)-4-(4-(2-(piperazin-1- N yl)ethoxy)phenyl)-3-(1H- O C22H25N5O3 407.2 benzo[d]imidazol-6- O N yl)oxazolidin-2-one O N NH (S)-4-(4-(2- O N morpholinoethoxy)phenyl O )-3-(1H- C22H24 O N4O4 408.18 N benzo[d]imidazol-6- O yl)oxazolidin-2-one N NH (S)-3-(1H- F F benzo[d]imidazol-6-yl)-4- (2,3- O N C16H11F2N3O2 315.08 difluorophenyl)oxazolidin O -2-one N NH (S)-3-(1H- F benzo[d]imidazol-6-yl)-4- (3- O N C16H12FN3O2 297.09 fluorophenyl)oxazolidin- O 2-one N NH (S)-3-(1H- F benzo[d]imidazol-6-yl)-4- (3-fluoro-5- F3C O N C17H11F4N3O2 365.08 (trifluoromethyl)phenyl) O N oxazolidin-2-one NH
(S)-3-(1H- benzo[d]imidazol-6-yl)-4- Cl O (3- N C16H12ClN3O2 313.06 O chlorophenyl)oxazolidin- N 2-one NH (S)-3-(1H- Cl benzo[d]imidazol-6-yl)-4- (4- O N C16H12ClN3O2 313.06 O chlorophenyl)oxazolidin- N 2-one NH (S)-3-(1H- benzo[d]imidazol-6-yl)-4- Cl [4-(3- O N C22H16ClN3O2 389.09 chlorophenyl)phenyl] O N NH oxazolidin-2-one (S)-3-(1H- benzo[d]imidazol-6-yl)-4- O [3-(3- N O C22H16ClN3O2 389.09 Cl chlorophenyl)phenyl] N NH oxazolidin-2-one (S)-3-(1H- benzo[d]imidazol-6-yl)-4- N N (4-(4-phenylpiperazin-1- O N C26H25N5O2 439.2 yl)phenyl)oxazolidin-2- O N NH one
(S)-3-(1H- N benzo[d]imidazol-6-yl)-4- N (4-(4-methylpiperazin-1- O N C21H23N5O2 377.19 O yl)phenyl)oxazolidin-2- N NH one (S)-3-(1H- benzo[d]imidazol-6-yl)-4- N N (3-(4-phenylpiperazin-1- N O C26H25N5O2 439.50 N yl)phenyl)oxazolidin-2- O NH one (S)-3-(2-methyl-1H- O N benzo[d]imidazol-6-yl)-4- O C17H15N3O2 293.31 phenyloxazolidin-2-one N NH (S)-4-(1H- O benzo[d]imidazol-6-yl)-5- N O (4- O C20H21N3O3 351.39 propoxyphenyl)morpholin NH -3-one N 3-(1H-benzo[d]imidazol- O 6-yl)-4-(4- N O O C20H21N3O3 351.39 propoxyphenyl)-1,3- NH oxazinan-2-one N
(S)-3-(H-imidazo[1,2- O a]pyridin-7-yl)-4- N C16H13N3O2 279.293 phenyloxazolidin-2-one O N N (4S,5R)-3-(H- imidazo[1,2-a]pyridin-7- O N C22H17N3O2 355.389 yl)-4,5- O diphenyloxazolidin-2-one N N (4S,5R)-3-(imidazo[1,2- a]pyridin-6-yl)-4,5- N O C22H17N3O2 355.38 diphenyloxazolidin-2-one O N N O (S)-3-(H-imidazo[1,2- a]pyridin-7-yl)-4-(4- O N C19H19N3O3 337.372 propoxyphenyl)oxazolidin O N -2-one N Cl (S)-4-(4-chlorophenyl)-3- (H-imidazo[1,2-a]pyridin- O N C16H12ClN3O2 313.06 7-yl)oxazolidin-2-one O N N
3-(imidazo[1,2-a]pyridin- O 7-yl)-4-(4- O N O C20H21N3O3 351.39 propoxyphenyl)-1,3- oxazinan-2-one N N 5-(2-phenylpyrrolidin-1- N N C17H17N3 263.33 yl)-1H-benzo[d]imidazole N H 5-(2-(4- N N methoxyphenyl)pyrrolidin N H C18H19N3O 293.36 -1-yl)-1H- benzo[d]imidazole O 5-(2-(4- N N fluorophenyl)pyrrolidin- N C17H16FN3 281.32 1-yl)-1H- H benzo[d]imidazole F 5-(2-(4- N N chlorophenyl)pyrrolidin- N H C17H16ClN3 297.78 1-yl)-1H- benzo[d]imidazole Cl 5-(2-benzylpyrrolidin-1- N N C18H19N3 277.36 yl)-1H-benzo[d]imidazole N H
5-(2-(4- chlorobenzyl)pyrrolidin- N N C18H18ClN3 311.80 1-yl)-1H- N H Cl benzo[d]imidazole 5-(2-(4- N N fluorobenzyl)pyrrolidin-1- C18H18FN3 N 295.35 H yl)-1H-benzo[d]imidazole F 5-(pyrrolidin-1-yl)-1H- N N C11H13N3 187.24 benzo[d]imidazole N H 5-(2-(4- methoxybenzyl)pyrrolidin N N C19H21N3O 307.38 -1-yl)-1H- N H O benzo[d]imidazole O 3-(1H-benzo[d]imidazol- H N S N 6-yl)-2-(4- C16H12ClN3O N 329.80 chlorophenyl)thiazolidin- S 4-one Cl O 3-(1H-benzo[d]imidazol- N N S 5-yl)-2-phenylthiazolidin- HN C16H13N3OS 295.35 4-one
O 3-(1H-benzo[d]imidazol- H N S N 6-yl)-2-(4- N C16H12FN3OS 313.34 fluorophenyl)thiazolidin- 4-one F O 3-(1H-benzo[d]imidazol- H S N N 6-yl)-2-(naphthalen-1- C20H15N3OS 345.41 N yl)thiazolidin-4-one 3-(1H-benzo[d]imidazol- O H N S N 6-yl)-2-(4- N C22H17N3O2S 387.45 phenoxyphenyl)thiazolidi O n-4-one 3-(1H-benzo[d]imidazol- O H 6-yl)-2-(2,6- N S N C16H11F2N3O F 331.33 difluorophenyl)thiazolidin N F S -4-one O 3-(1H-benzo[d]imidazol- H S N N 6-yl)-2-(thiophen-3- C14H11N3OS2 301.38 N yl)thiazolidin-4-one S O 3-(1H-benzo[d]imidazol- H S N N 6-yl)-5-methyl-2- C17H15N3OS 309.38 phenylthiazolidin-4-one N
3-(1H-benzo[d]imidazol- 5-yl)-2- N S C16H13N3S2 311.42 phenylthiazolidine-4- N HN thione S S 3-(1H-benzo[d]imidazol- H N S N 6-yl)-2-(4- N phenoxyphenyl) C22H17N3OS2 403.51 O thiazolidine-4-thione 1-(1H-benzo[d]imidazol- O N 5-yl)-5-(4- F C17H14FN3O 295.31 fluorophenyl)pyrrolidin- 2-one N NH 1-(1H-benzo[d]imidazol- O N 5-yl)-5-(4- O C18H17N3O2 307.34 methoxyphenyl)pyrrolidin N -2-one NH 1-(1H-benzo[d]imidazol- O 5-yl)-5-(4- N O C20H21N3O2 335.39 propoxyphenyl)pyrrolidin N -2-one NH 1-(1H-benzo[d]imidazol- O 5-yl)-5-(2,3- O N O dihydrobenzo[b][1,4] C19H17N3O3 335.35 dioxin-6-yl)pyrrolidin-2- N NH one
1-(1H-benzo[d]imidazol- O N 5-yl)-5-phenylpyrrolidin- C17H15N3O 277.32 2-one N NH 2-(1H-benzo[d]imidazol- O N 5-yl)-3-phenylisoindolin- C21H15N3O 325.36 1-one N NH 2-(1H-benzo[d]imidazol- O 5-yl)-3-(4- N C27H19N3O 401.45 biphenyl)isoindolin-1-one N NH 2-(1H-benzo[d]imidazol- 5-yl)-3-(4- O N F C21H14FN3O 343.35 fluorophenyl)isoindolin- 1-one N NH 2-(1H-benzo[d]imidazol- 5-yl)-3-(3- O N C 21 H 14 FN 3 O 343.35 fluorophenyl)isoindolin- F 1-one N NH
2-(1H-benzo[d]imidazol- F 5-yl)-3-(3,5- O N C21H13F2N3O 361.34 difluorophenyl)isoindolin- F 1-one N NH 2-(1H-benzo[d]imidazol- 5-yl)-3-(4- O N Cl C21H14ClN3O 359.80 chlorophenyl)isoindolin- 1-one N NH 2-(1H-benzo[d]imidazol- 5-yl)-3-(3,4- O N C 21 H 13 Cl 2 N Cl 394.25 dichlorophenyl)isoindolin Cl 3 O -1-one N NH 2-(1H-benzo[d]imidazol- F 5-yl)-3-(3-chloro-5- O N C 21 H 13 ClFN 377.79 fluorophenyl)isoindolin- Cl 3 O 1-one N NH 2-(1H-benzo[d]imidazol- 5-yl)-3-(4- O N O C22H17N3O2 355.38 methoxyphenyl)isoindolin -1-one N NH
2-(1H-benzo[d]imidazol- O 5-yl)-3-(4- N C24H21N3O2 383.44 propoxyphenyl)isoindolin N O N -1-one H O 2-(1H-benzo[d]imidazol- 5-yl)-3-(3-fluoro-4- F N C 22 H 16 FN 3 O 373.37 methoxyphenyl)isoindolin N O 2 -1-one N H 2-(1H-benzo[d]imidazol- O 5-yl)-3-(3,4- O N C oxyphenyl) 23H19N O 385.41 dimeth O 3 3 isoindolin-1-one N NH 3-(benzo[d][1,3]dioxol-6- yl)-2-(1H- O N O C22H15N3O3 369.37 benzo[d]imidazol-5- O yl)isoindolin-1-one N NH 2-(1H-benzo[d]imidazol- 5-yl)-3-(4- O N O C27H19N3O2 417.45 phenoxyphenyl)isoindolin N -1-one NH O Cl 2-(1H-benzo[d]imidazol- 5-yl)-4,7-dichloro-3-(4- 22 15 2 N Cl C H Cl N 424.27 methoxyphenyl)isoindolin N O 3 O 2 -1-one N H
2-(1H-benzo[d]imidazol- Cl O 5-yl)-5,6-dichloro-3-(4- Cl C 22 H 15 Cl 2 N N 424.27 methoxyphenyl)isoindolin N O 3 O 2 N -1-one H Cl Cl 2-(1H-benzo[d]imidazol- C 24 H 19 Cl 2 N 5-yl)-5,6-dichloro-3-(4- N O O 3O2 452.33 propoxyphenyl)isoindolin -1-one N NH (S)-2-(1H- benzo[d]imidazol-5-yl)-3- C H N O (3,4-dimethoxyphenyl) 23 19 3 3 385.41 isoindolin-1-one (R)-2-(1H- benzo[d]imidazol-5-yl)-3- O O N O C H N (3,4-dimethoxyphenyl) 23 19 3O3 385.41 N isoindolin-1-one NH (R)-2-(1H- benzo[d]imidazol-5-yl)-3- O N (4-propoxyphenyl) O C24H21N3O2 383.44 N isoindolin-1-one NH (S)-2-(1H- benzo[d]imidazol-5-yl)-3- O N (4-propoxyphenyl) O C24H21N3O2 383.44 N isoindolin-1-one NH
(R)-2-(1H- benzo[d]imidazol-5-yl)-3- O N C 21 H 14 ClN 3 (4-chlorophenyl) Cl 359.80 O isoindolin-1-one N NH (S)-2-(1H- benzo[d]imidazol-5-yl)-3- O N C 21 H 14 ClN 3 (4-chlorophenyl) Cl 359.80 O isoindolin-1-one N NH 1-(1H-benzo[d]imidazol- HN O 5-yl)-5-(4- N C22H24N4O 360.45 phenylcyclohexyl) N imidazolidin-2-one NH 1-(1H-benzo[d]imidazol- N 6-yl)-5-(1- HN N C21H23N5O 361.44 phenylpiperidin-4- N O yl)imidazolidin-2-one N H H 1-(1H-benzo[d]imidazol- O N N 5-yl)-5-(4-(3- N C20H22N4O2 350.41 methoxypropyl)phenyl) N H imidazolidin-2-one O H 1-(1H-benzo[d]imidazol- N HO 5-yl)-5-(4- N C16H N O 294.30 N 14 4 2 hydroxyphenyl) O imidazolidin-2-one N H
H 1-(1H-benzo[d]imidazol- N O HO 5-yl)-5-(2- N C16H14N4O2 294.30 hydroxyphenyl) N imidazolidin-2-one N H 1-(1H-benzo[d]imidazol- H N O HO 5-yl)-5-(2,4- N C16H14N4O3 310.30 dihydroxyphenyl) N HO imidazolidin-2-one N H H 1-(1H-benzo[d]imidazol- N OH 5-yl)-5-(3,4- N OH C1 H N O 310.30 N 6 14 4 3 dihydroxyphenyl) imidazolidin-2-one O N H H 1-(1H-benzo[d]imidazol- N 5-yl)-5-(3- N OH C16H14N4O2 294.30 hydroxyphenyl) N imidazolidin-2-one O N H 1-(1H-benzo[d]imidazol- HN O 5-yl)-5-(4- N O C22H24N4O2 376.45 (cyclohexyloxy)phenyl) N imidazolidin-2-one NH H 5-(4-(2- O N N methoxyethoxy)phenyl)- N C19H20N4O3 352.38 1-(1H-benzo[d]imidazol- N H O 5-yl)imidazolidin-2-one O
(S)-5-(4-(2- NH (dimethylamino)ethoxy)p N O N henyl)-1-(1H- N C20H23N5O2 365.42 benzo[d]imidazol-5- O N H yl)imidazolidin-2-one N HN 3-(1H-benzo[d]imidazol- O 5-yl)-1-phenethyl-4-(4- N N C27H28N4O2 440.53 propoxyphenyl) O imidazolidin-2-one 3-(1H-benzo[d]imidazol- 5-yl)-1-((naphthalen-2- O yl)methyl)-4-(4- C30H28N4O2 476.56 propoxyphenyl) N N HN imidazolidin-2-one O N 3-(1H-benzo[d]imidazol- O 5-yl)-1-(3-phenylpropyl)- C28H30N4O2 454.56 4-(4-propoxyphenyl) N N imidazolidin-2-one NH O N 3-(1H-benzo[d]imidazol- O 5-yl)-1-benzyl-4-(4- C26H26N4O2 426.51 propoxyphenyl) N N imidazolidin-2-one HN O N
1-(1H-benzo[d]imidazol- H F N 5-yl)-5-(4-fluoro-3- N O C 17 H 15 FN 4 O N 326.32 methoxyphenyl) 2 imidazolidin-2-one O N H 1-(1H-benzo[d]imidazol- HN O N F 5-yl)-5-(3-fluoro-4- C 19 H 19 FN 4 O O 354.37 propoxyphenyl) N 2 imidazolidin-2-one NH H 1-(1H-benzo[d]imidazol- O N 5-yl)-5-(2-fluoro-4- N F 19 19 4 N C H FN O 354.37 propoxyphenyl) N 2 imidazolidin-2-one H O H (S)-1-(1H- O N N benzo[d]imidazol-5-yl)-5- N C H N (4-(diethylamino)phenyl) 20 23 5O 349.42 N H N imidazolidin-2-one 1-(1H-benzo[d]imidazol- H N O 5-yl)-5-(4- N C 16 H 13 ClN 4 N 312.75 chlorophenyl)imidazolidi O n-2-one N Cl H 1-(1H-benzo[d]imidazol- H N 5-yl)-5-(4- N C22H24N4O 360.45 cyclohexylphenyl) N O imidazolidin-2-one N H
1-(1H-benzo[d]imidazol- 5-yl)-5-(4-(4- HN N O O N morpholinocyclohexyl) C26H31N5O2 445.55 phenyl)imidazolidin-2- N NH one (S)-1-(1H- N NH benzo[d]imidazol-5-yl)-5- (4-(1-methylpiperidin-4- C22H25N5O 375.46 O N yl)phenyl)imidazolidin-2- N HN one 1-(1H-benzo[d]imidazol- N NH 5-yl)-5-(4-(tetrahydro-2H- pyran-4- C H N O O 21 22 4 2 362.42 N yl)phenyl)imidazolidin-2- O HN one 1-(1H-benzo[d]imidazol- HN O 5-yl)-5-(4-(4- O N C22H22N4O2 374.43 oxocyclohexyl)phenyl) N imidazolidin-2-one NH (S)-1-(1H- HN O N benzo[d]imidazol-5-yl)-5- F C 22 H 22 F 2 N 4 (4-(4,4- N F 396.43 O difluorocyclohexyl)pheny NH l)imidazolidin-2-one H 1-(1H-benzo[d]imidazol- N O 5-yl)-5-(3-(pyrrolidin-1- N N C20H21N5O 347.41 yl)phenyl)imidazolidin-2- N one N H
1-(1H-benzo[d]imidazol- H N N 5-yl)-5-(4-(piperidin-1- N C21H23N5O 361.44 yl)phenyl)imidazolidin-2- N O one N H 1-(1H-benzo[d]imidazol- H N O 5-yl)-5-(3-(piperidin-1- N N C21H23N5O 361.44 yl)phenyl)imidazolidin-2- N one N H O 1-(1H-benzo[d]imidazol- H N N 5-yl)-5-(4- N C20H21N5O2 363.41 morpholinophenyl) N O imidazolidin-2-one N H H N 5-(4-cyclohexylphenyl)-1- O N (H-imidazo[1,2-a]pyridin- N C22H24N4O 360.45 7-yl)imidazolidin-2-one N 1-(H-imidazo[1,2- H N O a]pyridin-7-yl)-5-(4- N (pyrrolidin-1- C H N O N 20 21 5 347.41 yl)phenyl)imidazolidin-2- N N one 1-(H-imidazo[1,2- H N a]pyridin-7-yl)-5-(3- O N (pyrrolidin-1- N C20H21N5O 347.41 yl)phenyl)imidazolidin-2- N N one
1-(H-imidazo[1,2- H N O a]pyridin-7-yl)-5-(4- N (piperidin-1- N C21H23N5O 361.44 yl)phenyl)imidazolidin-2- N N one 1-(H-imidazo[1,2- H a]pyridin-7-yl)-5-(3- N O N (piperidin-1- N C21H23N5O 361.44 N yl)phenyl)imidazolidin-2- N one 1-(H-imidazo[1,2- H N O a]pyridin-7-yl)-5-(1- N C21H23N5O 361.44 phenylpiperidin-4- N N N yl)imidazolidin-2-one (S)-3-(1H- O O benzo[d]imidazol-5-yl)-4- N N (4-(3- C20H21N3O3 351.39 N methoxypropyl)phenyl) H O oxazolidin-2-one 3-(1H-benzo[d]imidazol- NH N 5-yl)-4-(4-(3- N C21H24N4O2 364.44 (dimethylamino)propyl) N O phenyl)oxazolidin-2-one O H N (S)-3-(7-methyl-1H- N benzo[d]imidazol-5-yl)-4- C17H15N3O2 293.31 N phenyloxazolidin-2-one O O
O F (S)-3-(6-fluoro-1H- O N NH C 16 H 12 FN 3 O benzo[d]imidazol-5-yl)-4- 297.28 N 2 phenyloxazolidin-2-one F H N (S)-3-(7-fluoro-1H- N C 16 H 12 FN 3 O benzo[d]imidazol-5-yl)-4- 297.28 N 2 phenyloxazolidin-2-one O O (S)-3-(1H- O O N benzo[d]imidazol-5-yl)-4- N HN C17H21N3O2 299.36 (cyclohexylmethyl) oxazolidin-2-one (S)-3-(1H- benzo[d]imidazol-5-yl)-4- NH C16H19N3O2 285.34 cyclohexyloxazolidin-2- N N one O O (S)-3-(1H- O O benzo[d]imidazol-5-yl)-4- N C22H23N3O2 361.41 (4-phenylcyclohexyl) N oxazolidin-2-one NH (S)-3-(1H- O O benzo[d]imidazol-5-yl)-4- N N C21H22N4O2 362.42 (1-phenylpiperidin-4- N yl)oxazolidin-2-one NH
O (S)-4-(1-acetylpiperidin- H N N 4-yl)-3-(1H- N C17H20N4O3 328.36 benzo[d]imidazol-5- N yl)oxazolidin-2-one O O 3-(1H-benzo[d]imidazol- O O N 5-yl)-4-(1- N HN C18H17N3O2 307.34 phenylethyl)oxazolidin-2- one O O (S)-4-(4-propoxybenzyl)- O N 3-(1H-benzo[d]imidazol- C20H21N3O3 351.39 5-yl)oxazolidin-2-one N NH O O (S)-4-(4- O isopropoxybenzyl)-3-(1H- N C20H21N3O3 351.39 benzo[d]imidazol-5- N yl)oxazolidin-2-one NH (S)-4-(4- O O O (cyclohexyloxy)benzyl)- N C23H25N3O3 391.46 3-(1H-benzo[d]imidazol- N 5-yl)oxazolidin-2-one NH O N O 4-(4-morpholinobenzyl)- N HN 3-(1H-benzo[d]imidazol- C21H22N4O3 378.42 5-yl)oxazolidin-2-one N O
(S)-3-(1H- O O benzo[d]imidazol-5-yl)-4- N C H N O N 18 17 3 2 307.34 phenethyloxazolidin-2- one N H 3-(1H-benzo[d]imidazol- O O 5-yl)-4-(4- N O C22H23N3O3 377.43 (cyclohexyloxy)phenyl) N oxazolidin-2-one NH (S)-3-(7-methyl-1H- O O benzo[d]imidazol-5-yl)-4- N (4- N C20H21N3O3 351.39 propoxyphenyl)oxazolidin N H O -2-one (S)-3-(6,7-dimethyl-1H- O HN N benzo[d]imidazol-5-yl)-4- C21H23N3O3 365.42 (4-propoxyphenyl) N oxazolidin-2-one O O (S)-4-(4-(2- O O N methoxyethoxy)phenyl)- N C H N O N 19 19 3 4 353.37 3-(1H-benzo[d]imidazol- H O 5-yl)oxazolidin-2-one O (S)-4-(4-(2- NH (dimethylamino)ethoxy) N O N phenyl)-3-(1H- C H N O 366.41 N 20 22 4 3 benzo[d]imidazol-5- O O yl)oxazolidin-2-one
O 3-(1H-benzo[d]imidazol- O F 5-yl)-4-(2,6-difluoro-4- N C 17 H 13 F 2 N 3 345.30 methoxyphenyl)oxazolidi F N O 3 n-2-one O N H O O (S)-3-(1H- N benzo[d]imidazol-5-yl)-4- N C20H22N4O2 350.41 (4-(diethylamino)phenyl) N H N oxazolidin-2-one (S)-3-(1H- N NH benzo[d]imidazol-5-yl)-4- (4-(bis(2- O O N C22H26N4O4 410.46 methoxyethyl)amino) N O phenyl)oxazolidin-2-one O O O (S)-3-(1H- N benzo[d]imidazol-5-yl)-4- N C22H22N4O2 374.43 (4-(dicyclopropylamino) N H N phenyl)oxazolidin-2-one (S)-3-(1H- HN N benzo[d]imidazol-6-yl)-4- C22H17N3O2 355.38 (biphenyl-4- O N yl)oxazolidin-2-one O 3-(1H-benzo[d]imidazol- O O 5-yl)-4-(4-(4- O N C22H21N3O3 375.42 oxocyclohexyl)phenyl) N oxazolidin-2-one NH
3-(1H-benzo[d]imidazol- O O O N 5-yl)-4-(4-(4- C23H25N3O3 391.46 methoxycyclohexyl)phen N yl)oxazolidin-2-one NH 3-(1H-benzo[d]imidazol- O OH 5-yl)-4-(4-(4- O N C22H23N3O3 377.43 hydroxycyclohexyl)pheny N l)oxazolidin-2-one NH 3-(1H-benzo[d]imidazol- O N O 5-yl)-4-(4-(4- O N C26H30N4O3 446.54 morpholinocyclohexyl) N NH phenyl)oxazolidin-2-one 3-(1H-benzo[d]imidazol- O O 5-yl)-4-(4-(pyrrolidin-1- N N C20H20N4O2 348.39 yl)phenyl)oxazolidin-2- N one NH (S)-3-(1H- O benzo[d]imidazol-5-yl)-4- N O N (4-(piperidin-1- C21H22N4O2 362.46 yl)phenyl)oxazolidin-2- N NH one (S)-3-(1H- O benzo[d]imidazol-5-yl)-4- O N N (3-(piperidin-1- C21H22N4O2 362.46 yl)phenyl)oxazolidin-2- N NH one
(S)-3-(1H- O N O O N benzo[d]imidazol-5-yl)-4- C20H20N4O3 364.39 (4-morpholinophenyl) oxazolidin-2-one N NH (S)-3-(1H- O O O N benzo[d]imidazol-5-yl)-4- N C20H20N4O3 364.39 (3-morpholinophenyl) N oxazolidin-2-one NH 3-(1H-benzo[d]imidazol- N NH 5-yl)-4-(4-(tetrahydro-2H- pyran-4- C2 H N O 363.40 O 1 21 3 3 N yl)phenyl)oxazolidin-2- O O one 3-(1H-benzo[d]imidazol- N NH 5-yl)-4-(4-(1- methylpiperidin-4- C22H24N4O2 376.45 O N yl)phenyl)oxazolidin-2- N O one (S)-3-(1H- O N benzo[d]imidazol-6-yl)-4- O N N (3-(4-methylpiperazin-1- C21H23N5O2 377.43 yl)phenyl)oxazolidin-2- HN N one (S)-3-(3-methylH- imidazo[1,2-a]pyridin-7- N C H N O N N 17 15 3 2 293.31 yl)-4-phenyloxazolidin-2- one O O
(S)-3-(3- F F (trifluoromethyl)H- F N C 17 H 12 F 3 N 3 imidazo[1,2-a]pyridin-7- 347.29 N N O 2 yl)-4-phenyloxazolidin-2- O O one (S)-4-(2,3- O dihydrobenzo[b][1,4] N O dioxin-6-yl)-3-(H- N C18H15N3O4 337.32 N imidazo[1,2-a]pyridin-7- O O yl)oxazolidin-2-one (S)-4-(4- N cyclohexylphenyl)-3-(H- N C22H23N3O2 361.43 imidazo[1,2-a]pyridin-7- N yl)oxazolidin-2-one O O (S)-3-(H-imidazo[1,2- a]pyridin-7-yl)-4-(4- N N N (piperidin-1- C21H22N4O2 362.42 yl)phenyl)oxazolidin-2- N O one O (S)-3-(H-imidazo[1,2- N N a]pyridin-7-yl)-4-(4- C20H20N4O3 364.39 morpholinophenyl) O N oxazolidin-2-one N O O
(S)-3-(H-imidazo[1,2- a]pyridin-7-yl)-4-(4-(4- N N phenylpiperazin-1- O C H N O N 26 25 5 2 439.50 yl)phenyl)oxazolidin-2- N O N one H O N (S)-1-(1H- N benzo[d]imidazol-5-yl)-5- N (4-(bis(2- N C H 22H27N5O3 409.48 N methoxyethyl)amino)phen O yl)imidazolidin-2-one O H O N 5-(4-(N-(2- N (dimethylamino)ethyl)-N- N methylamino)phenyl)-1- N C H N O H 21 26 6 378.47 N (1H-benzo[d]imidazol-5- yl)imidazolidin-2-one N 3-(1H-benzo[d]imidazol- O F 5-yl)-4-(4-(4,4- N F O C 22 H 21 F 2 N 3 397.41 difluorocyclohexyl)pheny O 2 N l)oxazolidin-2-one NH 2-(1H-benzo[d]imidazol- F F 5-yl)-4,7-difluoro-3-(4- O N C 24 H 19 F 2 N 3 O 419.42 propoxyphenyl)isoindolin O 2 -1-one N NH
2-(H-imidazo[1,2- O a]pyridin-7-yl)-3-(3,4- 233 O N O C23H19N3O3 385.41 dimethoxyphenyl)isoindol in-1-one N N (S)-2-(H-imidazo[1,2- O a]pyridin-7-yl)-3-(3,4- 234 O N O C23H19N3O3 385.41 dimethoxyphenyl)isoindol in-1-one N N (S)-3-(3,4- dimethoxyphenyl)-2-(3- O O N 235 methylH-imidazo[1,2- O C24H21N3O3 399.44 a]pyridin-7-yl)isoindolin- N N 1-one In one embodiment, the compound of formula I is a compound selected from example compounds 1 to 235. In a further embodiment, 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. Preferably, Varoglutamstat is used as hydrochloride salt in the methods of treating a kidney disease according to the invention. As per definition, Varoglutamstat hydrochloride as discussed herein has the chemical formula:
In a further most preferred embodiment, 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:
. In some embodiments of the invention, PQ1083 is used as free base. In some embodiments of the invention, PQ1083 is used as a pharmaceutically acceptable salt. Pharmaceutical 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. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, gelcaps and tablets, 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. For parenterals, 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. The pharmaceutical 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) The dosages, however, 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. Preferably these 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. Alternatively, the composition may be presented in a form suitable for once-weekly or once- monthly administration. For preparing solid compositions such as tablets, 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. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills, and capsules. 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. For example, 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. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. This liquid forms in which the compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. 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. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions. Advantageously, 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. Furthermore, 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. To be administered in the form of transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable
binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. 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. For parenteral administration, 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. Furthermore, 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. For oral administration, the 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. In a further aspect, the invention also provides a process for preparing 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. The present invention is further illustrated by the following Figures and non-limiting Examples. With reference to the Figures, these are as follows: 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 300 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. 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 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 Varoglutamstat 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 Varoglutamstat 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. It will thus be readily apparent to one skilled in the art that e.g., variations in scale of experiments might have an impact on optimized concentrations and/or time scales for certain parts of the processes. Thus, although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention. Examples Example 1 – Synthesis of the compounds of formula I The synthesis of the compounds of formula I is described in WO 2011/029920 as follows: ^ General processes to prepare the compounds of formula I are described on pp. 45 to 49. ^ General methods for the synthesis of the compounds of formula I are described on pp. 130 to 145.
^ The individual synthesis of the 235 example compounds of formula I is described on pp.145 to 291. WO 2011/029920 is incorporated herein by reference in its entirety and, specifically, in regard to the processes and synthesis methods to prepare compounds of formula I as described on pp. 45 to 49 and 130 to 291. 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. 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. Randomization after DSMB decision of further subjects occurred 1:1 for 600 mg BID or placebo. Duration of treatment/ Observation per patient: Minimum of 48 weeks (+6 weeks screening and 4 weeks FU: 58 weeks), maximum of 96 weeks • Visit 1/ Screening (week -6 to 0) • Visit 2/ Baseline (Day 0) - Day 1: Start IMP application • Visit 3/ Week 4 (±1 week) • Visit 4/ Week 12 (±1 week) • Visit 5/ Week 16 (by phone) (±1 week) • Visit 6/ Week 24 (±1 week) • Visit 7/ Week 36 (±1 week) • Visit 8/ Week 48 (±1 week) • Visit 9/10/11// Week 60, 72, 84 (±1 week) Visit windows as noted above are calculated with the baseline visit (V2) as reference. 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. Assay Principle: 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. In the presence of 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 µmol/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/1.73m2 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). In keeping with the pre-specified primary endpoint analysis, terms were also included for sex, education level and the trial stratification factors (drug-naïve versus non drug-naïve for approved AD treatment and MMSE, <=24 and 25-30). The estimated annualized rate of change was extracted from the model by treatment arm, along with the associated standard error; and the difference between treatment arms in the annualized rate of change was also extracted, along with its standard error, 95% confidence interval and 2-sided p-value. Further analysis examined the influence of 300 mg and 600 mg exposures and also executed analyses in (i) patients with hypertension or diabetes at baseline (T2D) and (ii) patients with hypertension or diabetes or cardiac disease or eGFR<60 mL/min/1.73m2 at baseline. SAS 9.4 software was used for all analyses. Results The results for the calculation of the annualized eGFR changes from baseline are shown in Figures 1 to 4. Figures 1 to 4 show the eGFR annualised rate of change mL/min/1.73m2/yr with 95 % confidence intervals indicated. “yr” means year.
*, **, or *** mean different levels of significant difference (cf. below; with p-value indicated in the respective figure) between the treatment group and placebo, ns means not significant difference. SEM means Standard error of the mean. BUN changes from baseline are shown in Figure 5. It has been demonstrated that the treatment with Varoglutamstat, preferably chronic treatment of subjects, has a significant effect size on the eGFR. The annualized eGFR change from baseline significantly increases in the treatment group, while the annualized eGFR change falls under the baseline in the placebo group. The difference between the treatment group and the placebo group for the annualized eGFR change in the total population tested is highly significant. (see Figure 1). It has also been found that the treatment effect on the annualized eGFR change from baseline was dose-dependent (see Figure 2). It was further observed that the effect of the treatment with Varoglutamstat on the annualized eGFR change in subjects with risk factors for CKD differs from the effect of the treatment of subjects without risk factors with Varoglutamstat (see Figures 3 and 4). 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, 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). For subjects suffering from hypertension and/or type 2 diabetes mellitus as risk factors for a CKD, 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 as difference over the placebo group, see Figure 4). In conclusion, 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. Furthermore, 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. 2.2 Patient selection by 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. In the subgroup at risk “Diabetes” (with or without hypertension), the overall treatment effect on the annualized rate of change of eGFR (MDRD formula) (mL/min/1.73m2/year) was -4.96 for placebo, 5.09 for varoglutamstat and +10.05 difference between the groups in favor of varoglutamstat, statistically significant treatment effect with a p-value of 0.0226. Details of the analysis are shown in Figures 10 and 11.
Sensitivity analysis of eGFR calculation As a sensitivity analysis, eGFR was calculated not only with MDRD formula, but also with the CKD-EPI Cystatin C formula as defined as follows: Inker, L. A. et al. (2021), N Engl J Med 385: 1737-1749. General CKD-EPI Formula eGFR = µ × min(Scr/κ, 1)a1 × max(Scr/κ,1)a2 × min(Scys/0.8, 1)b1 × max(Scys/0.8,1)b2 × cAge × d[if female] × e[if Black] κ = 0.7 for female, κ = 0.9 for male for 2012 CKD-EPI cystatine C µ = 133 a1, a2 = 0 b1 = −0.499, b2 = −1.328 c = 0.9962 d = 0.932 e = 1 eGFR = 133 × min(Scys/0.8, 1)-0.499 × max(Scys/0.8,1)-1.328 × 0.9962Age × 0.932[if female] Data set included Cystatin C measurements from safety as well as biomarker blood samples which were collected at screening, baseline, week 4,12, 24, 36, 48, 60, 72, 84, EOT and screening, 24, 48, and EOT, respectively.
Human serum samples / 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. This is a mixed model applied to repeated eGFR measures over time with subject-specific random effects for intercept and slope, and the same model was used as described above for eGFR calculation by MDRD formula. The overall treatment effect (all subjects) on the annualized rate of change (mL/min/1.73m2/year) was -2.31 for placebo, -0.46 for varoglutamstat and +1.84 difference between the groups in favor of varoglutamstat treatment, statistically significant with a p-value of 0.0191. In the subgroup at risk “Diabetes” (with or without hypertension), the overall treatment effect on the annualized rate of change (mL/min/1.73m2/year) was -5.03 for placebo, -0.16 for varoglutamstat and +4.87 difference between the groups in favor of varoglutamstat treatment, statistically significant with a p-value of 0.0324. Example 3 – Varoglutamstat (PQ912) and PQ1083 as representative examples in ADI- CKD mouse model (adenine-diet induced chronic kidney disease) Male C57BL/6JRj mice (11 weeks old) were randomized into 4 groups (n=10 per group) based on body weight at day -3: 1) Control – vehicle (PO, BID), 2) CKD – vehicle (PO, BID), 3) CKD – PQ912 (200 mg/kg, PO, BID), 4) CKD – PQ1083 (100 mg/kg, PO, QD). 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. On study day -3, 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. In study week 3 spot urine was sampled for quantification of albumin, creatinine, urine albumin-to-creatinine ratio (uACR) and cystatin C levels. GFR was measured for assessment of renal function. At termination, plasma was collected for evaluation of urea, creatinine, and cystatin C levels. Furthermore, both kidneys were weighed, and the left kidney was further processed for histomorphometric assessment of fibrosis (Col III), myofibroblast activation (α-SMA), tubular injury (KIM-1) and kidney inflammation (F4/80). Glomerular filtration rate (GFR) measurements Transcutaneous measurements of FITC-Sinistrin clearance for GFR estimation in mouse: Under light isoflurane anesthesia, Medibeacon transdermal GFR monitors are mounted to the back of the animal according to manufacturer’s instructions. Baseline autofluorescence is measured for minimum 5 minutes before a bolus of FITC-Sinistrin (40 mg/ml, 0.15 mg/g BW) is injected into the tail vein. 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 T½ 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. Next, the primary antibody is visualized with DAB as chromogen. Finally, sections are counterstained in hematoxylin and cover slipped. Slides are scanned under a 20x objective in a ScanScope AT slide scanner (Aperio). Antigen Primary antibody Vendor
Col3a1 Goat anti-Type III Collagen Southern Biotech, Cat. 1330-01 α-SMA Rabbit anti-alpha smooth muscle actin Abcam, Cat. ab124964 [EPR5368] F4/80 Rat anti-F4/80 [C1:A3-1] Abcam, Cat. ab6640 KIM-1 Goat anti-Kim-1 RnD systems, Cat. AF1817 Quantitative image analysis of kidney (Quantitative assessment of immunoreactivity) IHC-positive staining is quantified by image analysis using the VIS software (Visiopharm, Denmark). 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). Statistics ANOVA with Dunnett’s test one-factor linear model, each Group compared to Group 2 (CKD – vehicle). *: p < 0.05, **: p < 0.01, ***: P < 0.001, ****: P < 0.0001 Results: Between Group 1 and Group 2, adenine-diet induced a significant alteration of the following parameters: bodyweight, GFR, plasma parameters urea, creatinine and cystatin C, urine albumin-to-creatinine ratio (uACR) and histomorphometric parameters Col III, aSMA, KIM1, F4/80).
Both treatment groups had a beneficial effect on bodyweight (BW) development over Group 2 (Figure 6), which was even significant for Group 4 (PQ1083). 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. 95% Confidence intervals are shown, 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).