Patent Application
20200347029
The present invention relates to novel C5a receptor modulators of formula (I) and their use as pharmaceuticals. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and their use as C5a receptor modulators, especially in the treatment of vasculitic diseases or disorders, inflammatory diseases or disorders involving intravascular microvesicle release, immune complex (IC) diseases or disorders, neurodegenerative diseases or disorders, complement related inflammatory diseases or disorders, bullous diseases or disorders, diseases or disorders related to ischemia and/or ischemic reperfusion injury, inflammatory bowel diseases or disorders, and autoimmune diseases or disorders; as well as in contact sensitivity or an inflammation caused by contact with artificial surfaces; increased leukocyte and platelet activation (and infiltration to tissues thereof); pathologic sequelae associated to an intoxication or an injury such as a trauma, an hemorrhage, a shock, or surgery including transplantation, such sequeale including multiple organ failure (MOF), septic shock, shock due to intoxication, or acute lung inflammatory injury; pathologic sequelae associated with insulin-dependent diabetes mellitus; myocardial infarction or thrombosis; edema or an increased capillary permeability; reduction of coronary endothelial dysfunction induced by cardiopulmonary bypass and/or cardioplegia; or cancer.
C5aR1 (CD88) is a seven transmembrane bound G protein coupled receptor (GPCR) belonging to the rhodopsin like family, the gene of which is located on chromosome 19. It couples to pertussis toxin sensitive Gialpha2, Gialpha3 or pertussis toxin insensitive Galpha16 and initiates several downstream signaling pathways. C5aR1 is expressed on a number of immune cell types including monocytes, neutrophils, mast cells, basophils and eosinophils. In addition, it is expressed on many other cell types including hepatocytes, pulmonary and endothelial cells, microglia, neurons and renal glomerular cells. There are a number of ligands described which bind to the C5aR. These include C5a, C5adesArg and C5a+1 kDa. C5a is a central effector molecule of the complement system which itself is a complex enzymatic cascade evolved to crucially complement the immune system against invading pathogens, however, a significant body of evidence shows that inadvertent complement activation leads to many acute inflammatory disorders and autoimmune diseases (Ricklin, D., et al. (2010) “Complement: a key system for immune surveillance and homeostasis.” Nat Immunol 11(9): 785-797) and specifically C5a has been shown to be elevated in a number of these inflammatory and autoimmune disorders. The complement system is activated through four pathways: The classical pathway, and the mannose binding lectin (MBL) pathway which is similar to the classical pathway except for the initial recognition and activation steps which recognize pathogens or antibody complexes. The alternative pathway is activated by binding of spontaneously activated complement C3 protein (C3b fragment) to pathogen surface. These three pathways all lead to the eventual formation of C3 convertases, which is the point where the 3 pathways converge (Guo, R. F. and P. A. Ward (2005) Annu Rev Immunol 23: 821-852). Subsequently C3 convertases lead to the formation of the anaphalatoxins C3a and C5a, together with other complement proteins required to produce the membrane attack complex. A fourth pathway, the extrinsic pathway involves plasma proteases (eg. elastase, thrombin) which act directly on C3 or C5 leading to the subsequent production of C3a and C5a. The anaphylatoxin C5a leads to the recruitment and activation of inflammatory cells of the innate and adaptive system, partly through the enhancement of cell adhesion molecule expression, the release of granule-based enzymes, delayed or enhanced apoptosis, phagocytosis, oxidative burst, histamine secretion and release and chemotaxis. In addition, it elicits the release of other pro inflammatory mediators, such as TNF-a, IL-1, IL-6, IL-8, prostaglandins, and leukotrienes) (N. S. Merle et al. (2015) “Complement System Part II: Role in Immunity.” Front Immunol 6: 257), activation of endothelial cells and vascular permeability which may lead to events in which at the end thrombotic microangiopathy can occur. Therefore, C5a represents one of the most potent inflammatory molecules produced during immune responses and because of its fundamental biology it is potentially implicated in a very wide range of pathologies (Janeway's Immunobiology, 8th edition (2012), Kenneth Murphy, Garland Science, p. 48-72).
C5a is central to the immune system and as such is important in key aspects of inflammation and tissue injury. In addition, there is considerable experimental evidence in the literature that implicates increased levels of C5a with a number of diseases and disorders, in particular in autoimmune and inflammatory diseases and disorders (Ricklin, D., et al. (2010) Nat Immunol 11(9): 785-797).
There is a large body of evidence about C5a and its receptor C5aR in contributing to vasculitic diseases, which demonstrate that C5a levels are elevated and give rise to leukocyte migration and subsequent inflammation which then leads to the eventual destruction of vessel walls (Charles J., et al (2013) Semin Nephrol 33(6): 557-564; Vasculitis, 2nd Edition (2008), Edited by Ball and Bridges, Oxford University Press, pp 47-53; Huang, Y. M., et al. (2015) Arthritis Rheumatol 67(10): 2780-2790; Kallenberg, C. G. and P. Heeringa (2015) Mol Immunol 68(1): 53-56). Inhibition of the C5aR with a C5aR antagonist was effective at ameliorated anti-myeloperoxidase (MPO)-induced NCGN in mice expressing the human C5a receptor (Xiao, H. et al (2014) J Am Soc Nephrol 25(2): 225-231) and was confirmed to be effective in a phase II trial of patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (ClinicalTrials.gov Identifier NCT02222155). Therefore, a C5a antagonist may be useful to treat vasculitic diseases such as ANCA associated vasculitis, leukoclastic vasculitis, Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, Henoch-Schönlein purpura, polyateritis nodosa, rapidly progressive glomerulonephritis (RPGN), cryoglobulinaemia, giant cell arteritis (GCA), Behcet's disease and Takayasu's arteritis (TAK).
C5a is generated when human blood makes contact with artificial surfaces, such as in cardiopulmonary bypass and hemodialysis procedures for instance on the artificial surface of the heart-lung machine in association with vascular surgery such as coronary artery bypass grafting or heart valve replacement or on surfaces of a kidney dialysis machine (Howard, R. J., et al. (1988) Arch Surg 123(12): 1496-1501; Kirklin, J. K., et al. (1983) J Thorac Cardiovasc Surg 86(6): 845-857; Craddock, P. R., et al. (1977) J Clin Invest 60(1): 260-264; Craddock, P. R., et al. (1977) N Engl J Med 296(14): 769-774) or in association with contact with other artificial vessels or container surfaces (e.g. ventricular assist devices, artificial heart machines, transfusion tubing, blood storage bags, plasmapheresis, plateletpheresis, and the like). As such C5aR antagonists could prove useful in preventing deleterious consequences of contact sensitivity and/or inflammation caused by contact with artificial surfaces. In addition, it may be useful in treating inflammatory disorders involving intravascular microvesicle release such as for example thrombotic microangiopathy and sickle cell disease (Zecher, D., et al. (2014) Arterioscler Thromb Vasc Biol 34(2): 313-320). A C5aR antagonist could also prove useful in certain hemotological diseases which are associated with activation of coagulation and fibrinolytic systems, disseminated intravascular coagulation (DIC), pernicious anemia, warm and cold autoimmune hemolytic anemia (AIHA), anti-phospholipid syndrome and its associated complications, arterial and venous thrombosis, pregnancy complications such as recurrent miscarriage and fetal death, preeclampsia, placental insufficiency, fetal growth restriction, cervical remodeling and preterm birth, idiopathic thrombocytopenic purpura (ITP), atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH) and allergic transfusion reactions. The C5-specific humanized antibody, eculizumab is approved for paroxysmal nocturnal hemoglobinuria and atypical haemolytic uraemic syndrome (aHUS) (Wong E K, Kavanagh D, Transl Res. (2015) 165(2):306-20) and has been shown to be efficacious in renal transplant such as acute antibody-mediated kidney allograft rejection and cold agglutinin disease further supporting a potential role for C5aR antagonists in these diseases.
In myocardial ischemia-reperfusion injury C5a has been described to have an important function. Complement depletion reduced myocardial infarct size in mice (Weisman, H. F., T. et al. (1990) Science 249(4965): 146-151; De Hoog, V. C., et al. (2014) Cardiovasc Res 103(4): 521-529) and treatment with anti-C5a antibodies reduced injury in a rat model of hindlimb ischemia-reperfusion (Bless, N. M., et al. (1999) Am J Physiol 276(1 Pt 1): L57-63). Reperfusion injury during myocardial infarction was also markedly reduced in pigs that were re-treated with a monoclonal anti-C5a IgG (Amsterdam, E. A., et al. (1995) Am J Physiol 268(1 Pt 2): H448-457). A recombinant human C5aR antagonist reduces infarct size in a porcine model of surgical revascularization (Riley, R. D., et al. (2000) J Thorac Cardiovasc Surg 120(2): 350-358) providing evidence for the utility of a C5aR antagonist in these diseases. In addition, diseases related to ischemia/reperfusion injury, such as those resulting from transplants, including solid organ transplant, where C5a has been shown to play an important role (Farrar, C. A. and S. H. Sacks (2014) Curr Opin Organ Transplant 19(1): 8-13), could benefit from a C5aR antagonist as could related syndromes such as ischemic reperfusion injury, ischemic colitis and cardiac ischemia (Mueller, M., et al. (2013) Immunobiology 218(9): 1131-1138).
Furthermore, diseases where complement plays a role such as coronary thrombosis (Distelmaier, K., et al. (2009) Thromb Haemost 102(3): 564-572), vascular occlusion, post-surgical vascular reocclusion, atherosclerosis, traumatic central nervous system injury, arrhythmogenic cardiomyopathy (Mavroidis, M., et al. (2015) Basic Res Cardiol 110(3): 27) and Gaucher disease (Pandey et al. (2017) Nature 543: 108-112) could also benefit from a C5aR antagonist. Thus, C5aR modulators may be used preventatively in a patient at risk for myocardial infarction or thrombosis (i.e. a patient who has one or more recognized risk factors for myocardial infarction or thrombosis, such as, but not limited to, obesity, smoking, high blood pressure, hypercholesterolemia, previous or genetic history of myocardial infarction or thrombosis) in order reduce the risk of myocardial infarction or thrombosis. C5a causes increased capillary permeability and edema, leukocyte and platelet activation and infiltration to tissues, as well as bronchoconstriction (Sarma, J. V. and P. A. Ward (2012) Cell Health Cytoskelet 4: 73-82; Czermak, B. J., et al. (1998) J Leukoc Biol 64(1): 40-48). Administration of an anti-C5a monoclonal antibody was shown to reduce cardiopulmonary bypass and cardioplegia-induced coronary endothelial dysfunction (Tofukuji, M., et al. (1998) J Thorac Cardiovasc Surg 116(6): 1060-1068).
C5a and its receptor are also involved in the pathogenesis of acute respiratory distress syndrome (ARDS) (Hammerschmidt, D. E., et al. (1980) Lancet 1(8175): 947-949), Chronic Obstructive Pulmonary Disorder (COPD) (Marc, M. M., et al. (2004) Am J Respir Cell Mol Biol 31(2): 216-219), and multiple organ failure (MOF) (Huber-Lang, M., et al. (2001) “Role of C5a in multiorgan failure during sepsis.” J Immunol 166(2): 1193-1199; Heideman, M. and T. E. Hugli (1984) J Trauma 24(12): 1038-1043). C5a increases monocyte production of two important proinflammatory cytokines TNF-α and IL-I which contribute to pathology in these diseases. C5a has also been shown to play an important role in the development of tissue injury, and particularly pulmonary injury, in animal models of septic shock (Smedegard, G., et al. (1989) Am J Pathol 135(3): 489-497; Unnewehr, H., et al. (2013) J Immunol 190(8): 4215-4225). In sepsis models using rats, pigs and non-human primates, anti-C5a antibodies administered to the animals before treatment with endotoxin or E. coli resulted in decreased tissue injury, as well as decreased production of IL-6 (Hopken, U., et al. (1996) Eur J Immunol 26(5): 1103-1109; Stevens, J. H., et al. (1986) J Clin Invest 77(6): 1812-1816). Inhibition of C5a with anti-C5a polyclonal antibodies has been shown to significantly improve survival rates in a caecal ligation/puncture model of sepsis in rats (Czermak, B. J., et al. (1999) Nat Med 5(7): 788-792). In the same sepsis model, anti-C5a antibodies were shown to inhibit apoptosis of thymocytes (Guo, R. F., et al. (2000) J Clin Invest 106(10): 1271-1280). Anti-C5a antibodies were also protective in a cobra venom factor model of lung injury in rats, and in immune complex-induced lung injury (Mulligan, M. S., et al. (1996) J Clin Invest 98(2): 503-512). The importance of C5a in immune complex-mediated lung injury was also shown in mouse (Bozic, C. R., et al. (1996) Science 273(5282): 1722-1725). Therefore, a C5aR antagonist could be of benefit in many inflammatory disorders and related conditions including neutropenia, sepsis, septic shock, stroke, inflammation associated with severe burns (Hoesel, L. M., et al. (2007) J Immunol 178(12): 7902-7910), osteoarthritis (Yuan, G., et al. (2003) Chin Med J (Engl) 116(9): 1408-1412), as well as acute (adult) respiratory distress syndrome (ARDS), chronic pulmonary obstructive disorder (COPD), bronchial asthma (Pandey, M. K. (2013) Curr Allergy Asthma Rep 13(6): 596-606), systemic inflammatory response syndrome (SIRS), tissue graft rejection, hyperacute rejection of transplanted organs, and the like, and multiple organ dysfunction syndrome (MODS). In addition, C5aR antagonists may be beneficial in treating pathologic sequelae associated with insulin-dependent diabetes mellitus such as diabetic kidney disease (Li, L., et al. (2015) Metabolism 64(5): 597-610), diabetic retinopathy (Cheng, L., et al. (2013). Invest Ophthalmol Vis Sci 54(13): 8191-8198), lupus nephropathy (Bao, L., et al. (2005) Eur J Immunol 35(8): 2496-2506), Heyman nephritis, membranous nephritis, and other forms of glomerulonephritis such as C3 glomerulopathy including dense deposit disease (DDD) (Zhang et al., Clin J Am Soc Nephrol (2014) 9: 1876-1882). Furthermore, the compound eculizumab has been shown to have potential utility for the treatment of neuromyelitis optica.
C5aR antagonists substantially reduced ovalbumin (OVA)-induced total cell (60%), neutrophil (66%) and eosinophil (65%) influxes in lavage fluid sampling suggesting that C5aR blockage might represent a novel therapeutic agent for reducing asthmatic outcomes (Staab, E. B., et al. (2014) Int Immunopharmacol 21(2): 293-300).
The complement system and in particular C5a contribute to the development of many bullous diseases among other things through activation of innate cells including mast cells and neutrophils (e.g. bullous pemphigoid, bullous acquisita, pemphigus foliaceus and pemphigus vulgaris). The detachment of epidermal basal keratinocytes from the underlying basement membrane is thought to be caused by autoantibodies to keratinocytes at the cutaneous basement membrane leading to blisters and a high influx of neutrophils in both the upper dermal layers and within the blister cavities. In experimental models a reduction of neutrophils or absence of complement (total or C5-selective) can inhibit formation of sub-epidermal blisters (Heimbach, L, et al. (2011) J Biol Chem 286(17): 15003-15009; Gammon, W. R. (1989) Immunol Ser 46: 509-525). Recent evidence has emerged to suggest that inhibition of C5a may prove beneficial in the treatment of the skin disorder hidradenitis suppurativa where an antibody against human C5a was shown to improve patient outcome in an open label phase II clinical trial. A C5a receptor antagonist may therefore be useful in bullous diseases.
Complement is believed to be important in inflammatory bowel disease (IBD) pathology and the C5aR is found to be expressed in the epithelial cells of the colon. (Cao, Q., et al. (2012) Am J Physiol Cell Physiol 302(12): C1731-1740). In addition, pharmacological inhibition of C5a activity by PMX205 a peptidic C5aR antagonist is efficacious in preventing DSS-induced colitis, providing further evidence that targeting CD88 in patients with IBD irritable bowel syndrome, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD) (Johswich, K., et al. (2009) Inflamm Bowel Dis 15(12): 1812-1823) could be of therapeutic benefit (Woodruff, T. M., et al. (2003) J Immunol 171(10): 5514-5520; Jain, U., et al. (2013) Br J Pharmacol 168(2): 488-501).
There is a body of evidence suggesting a role for C5a and its receptor in pathologies of the CNS. C5aR expression is upregulated on reactive astrocytes, microglia, and endothelial cells in an inflamed human central nervous system (O'Barr, S. A., et al. (2001) J Immunol 166(6): 4154-4162; Gasque, P., et al. (1997) Am J Pathol 150(1): 31-41) and C5a has been reported to be involved in the pathogenesis of many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) (Mantovani, S., et al. (2014) J Neuroimmunol 276(1-2): 213-218; Humayun, S., et al. (2009) J Neuroimmunol 210(1-2): 52-62; Woodruff, T. M., et al. (2008) J Immunol 181(12): 8727-8734), Alzheimer disease (Fonseca, M. I., et al. (2013) J Neuroinflammation 10: 25; Ager, R. R., et al. (2010) J Neurochem 113(2): 389-401), Parkinson's disease (Wang, X. J., et al. (2007) Neurochem Int 50(1): 39-50) and Huntington's disease (Singhrao et al. (1999) Experimental Neurology 159, 362-376). Furthermore C5a is found to be elevated in the CSF of Guillain-Barre syndrome patients (Hartung, H. P., et al. (1987) Neurology 37(6): 1006-1009; Wakerley, B. R. and N. Yuki (2015) Expert Rev Neurother 15(8): 847-849) and an anti C5 antibody was found to be effective in reducing neuropathy in the mouse (Halstead, S. K., et al. (2008) Brain 131 (Pt 5): 1197-1208; Basta, M. and D. R. Branch (2014) Clin Exp Immunol 178 Suppl 1: 87-88). Also, inhibition of the C5a receptor alleviates experimental CNS lupus (Zwirner, J., et al. (1999) Mol Immunol 36(13-14): 877-884; Jacob, A., B. Hack, et al. (2010) J Neuroimmunol 221(1-2): 46-52). Therefore, C5aR antagonists provided herein may be to treat ALS, Alzheimer's disease, multiple sclerosis, Guillain-Barre syndrome, Parkinson's disease, Huntington's disease and also cognitive function decline associated with cardiopulmonary bypass surgery and related procedures in addition to central nervous system involvement in diseases such as SLE, Sjögren's syndrome and associated immunological profiles.
In many autoimmune diseases Immunoglobulin G-containing immune complex (IC) depositions are found. These contribute to the pathophysiology of the diseases which frequently manifest in different organs of the body including the kidneys, heart, lungs, liver, blood vessels, the nervous system and the skin. There are numerous such IC diseases and examples are systemic lupus erthyematosus (SLE), cryoglobulinemia, rheumatoid arthritis, Sjögren's syndrome (Lawley, T. J., et al. (1979) J Immunol 123(3): 1382-1387), Goodpasture syndrome (antiglomerular basement antibody disease), and hypersensitivity. Immune complexes are known to induce C5 convertases leading to C5a production which subsequently contributes to these diseases (Karsten, C. M. and J. Kohl (2012) Immunobiology 217(11): 1067-1079). In animal models reproducing the mechanisms of IC activation of complement, C5aR has been shown to play an important role. Studies show that C5aR deficient mice and the use of a peptidic C5aR antagonist result in protection from tissue injury induced by ICs. (Strachan, A. J., et al. (2000) J Immunol 164(12): 6560-6565; Kohl, J. and J. E. Gessner (1999) Mol Immunol 36(13-14): 893-903; Baumann, U., et al. (2000) J Immunol 164(2): 1065-1070). Therefore, inhibitors of C5aR could be useful to treat IC diseases including the autoimmune diseases rheumatoid arthritis (Jose, P. J., et al. (1990) Ann Rheum Dis 49(10): 747-752; Grant, E. P., et al. (2002) J Exp Med 196(11): 1461-1471; Yuan, G., et al. (2003) Chin Med J (Engl) 116(9): 1408-1412)), osteoarthritis, systemic lupus erythematosus (Porcel, J. M., et al. (1995) Clin Immunol Immunopathol 74(3): 283-288; Pawaria, S., et al. (2014) J Immunol 193(7): 3288-3295), lupus nephritis (Bao, L, et al. (2005) Eur J Immunol 35(8): 2496-2506), lupus glomerulonephritis and IgA nephropathy (Liu, L, et al. (2014) J Clin Immunol 34(2): 224-232), Heyman nephritis, membranous nephritis and other forms of glomerulonephritis, vasculitis, dermatomyositis (Fiebiger, E., et al. (1998) J Clin Invest 101(1): 243-251), pemphigus, systemic sclerosis (scleroderma) (Sprott, H., et al. (2000) J Rheumatol 27(2): 402-404), bronchial asthma, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage) (Ma, R., et al. (2013) J Clin Immunol 33(1): 172-178), immunovasculitis, and complement mediated thrombotic microangiopathies including atypical haemolytic uremic syndrome (Song, D., et al. (2015) Am J Reprod Immunol 74(4): 345-356; Davin, J. C., N. C. van de Kar (2015) Ther Adv Hematol 6(4): 171-185), mixed cryoglobulinemia, atopic dermatitis (Neuber, K., R. et al. (1991) Immunology 73(1): 83-87; Dang, L., et al. (2015) Mol Med Rep 11(6): 4183-4189), and chronic urticaria (Kaplan, A. P. (2004) J Allergy Clin Immunol 114(3): 465-474; Yan, S., et al. (2014) J Dermatol Sci 76(3): 240-245). Furthermore, the compound eculizumab has been shown to have potential utility for the treatment of myasthenia gravis, and anti-phospholipid syndrome.
C5a is present in psoriatic plaques and C5aR expression has also been reported in psoriasis where T cells, neutrophils mast cells and dendritic cells are involved in pathogenesis of the disease and are chemotactic to C5a (Diani, M., G. Altomare and E. Reali (2015) Autoimmun Rev 14(4): 286-292). Neutrophil accumulation under the stratum corneum is observed in the highly inflamed areas of psoriatic plaques, and psoriatic lesion (scale) extracts contain highly elevated levels of C5a and exhibit potent chemotactic activity towards neutrophils, an effect that can be inhibited by addition of a C5a antibody. Furthermore, T cells and neutrophils are chemo-attracted by C5a under certain conditions (Nataf, S., et al. (1999) J Immunol 162(7): 4018-4023; Tsuji, R. F., et al. (2000) J Immunol 165(3): 1588-1598; Werfel, T., et al. (1997) Arch Dermatol Res 289(2): 83-86; Mrowietz, U., et al. (2001) Exp Dermatol 10(4): 238-245) meaning C5aR antagonists may be of benefit in treating psoriasis. Furthermore, complement has been implicated in the pathogenesis of glaucoma (Howell et al. (2011), J. Clin. Invest. 121(4): 1429-1444). In addition, there is experimental evidence to suggest a beneficial role of C5aR antagonists in treating cancer with checkpoint blockers. For example, an antibody against the C5aR receptor (IPH5401) has been reported to be efficacious in muring models of cancer (web page Innate Pharma—IPH5401, 2018; https://www.innate-pharma.com/en/pipelineiph5401-first-class-anti-c5ar-mab; Zah H., et al. (2017) Oncoimmunology 6(10): e1349587; Wang Y., et al., (2016) Cancer Discovery 6(9) 1022-1035).
Thus, C5a and C5aR are believed to be clinically implicated in vasculitic diseases or disorders, inflammatory diseases or disorders involving intravascular microvesicle release, immune complex (IC) diseases or disorders, neurodegenerative diseases or disorders, complement related inflammatory diseases or disorders, bullous diseases or disorders, diseases or disorders related to ischemia and/or ischemic reperfusion injury, inflammatory bowel diseases or disorders, and autoimmune diseases or disorders; as well as in contact sensitivity or an inflammation caused by contact with artificial surfaces; increased leukocyte and platelet activation (and infiltration to tissues thereof); pathologic sequelae associated to an intoxication or an injury such as a trauma, an hemorrhage, a shock, or surgery including transplantation, including multiple organ failure (MOF), septic shock, shock due to intoxication, or acute lung inflammatory injury; pathologic sequelae associated with insulin-dependent diabetes mellitus; myocardial infarction or thrombosis; edema or an increased capillary permeability; reduction of coronary endothelial dysfunction induced by cardiopulmonary bypass and/or cardioplegia, or cancer.
There is therefore a requirement for new small organic molecule modulators of the C5a receptor (C5aR), especially antagonists of the C5aR, that could be useful for inhibiting pathogenic events associated with elevated levels of C5a and/or with C5aR activation.
Certain benzimidazolone derivatives as chymase inhibitors are disclosed in WO2008/147697. 4-(Benzimidazol-1-yl)-piperidines as sodium channel inhibitors are disclosed in WO2003/037890. Certain 3-substituted piperidines comprising urea functionality are disclosed as analgesics in WO2001/068604. Benzimidazolone derivatives as phosphodiesterase inhibitors are disclosed in WO2001/005770. 1-Benzyl-1,3-dihydro-2H-benzimidazol-2-one derivatives as vasopressin and/or oxytocin receptor ligands are disclosed in U.S. Pat. No. 5,661,169. D. R. Owen et al., Bioorg. Med. Chem. Lett. 19 (2009) 1702-1706 discloses the compound 3-(1-(4-aminopyridin-2-yl)piperidin-4-yl)-1-benzyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one in a series of 2,4-diaminopyridine S-opioid receptor agonists, which however had pronounced activity in the hERG binding assay.
The present invention provides cyclic urea derivatives of formula (I) which are modulators of the C5a receptor, and are useful for the prevention or treatment of diseases which respond to the C5a receptor.
1) A first aspect of the invention relates to compounds of the formula (I)
wherein
The compounds of formula (I) may contain one or more further stereogenic or asymmetric centers, such as one or more additional asymmetric carbon atoms. The compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
In case a particular compound (or generic structure) is designated as (R)- or (S)-enantiomer/as having an absolute (R)- or (S)-configuration, such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, enantiomeric form. Likewise, in case a specific asymmetric center in a compound is designated as being in (R)- or (S)-configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of said asymmetric center. In analogy, cis- or trans-designations (or (R*,R*) designations) are to be understood as referring to the respective stereoisomer of the respective relative configuration in enriched form, especially in essentially pure form.
The term “enriched”, when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90:10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer/the entirety of the respective other stereoisomers.
The term “essentially pure”, when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer/the entirety of the respective other stereoisomers.
In some instances, the compounds of formula (I) may contain tautomeric forms. Such tautomeric forms are encompassed in the scope of the present invention. For example, in case the present compounds may contain heteroaromatic aromatic rings containing unsubstituted ring nitrogen atoms having a free valency such as pyrazolyl, such rings may be present in tautomeric forms. For example, the group pyrazol-3-yl represents the tautomeric forms 1H-pyrazol-3-yl and 2H-pyrazol-3-yl.
The present invention also includes isotopically labelled, especially 2H (deuterium) labelled compounds of formula (I), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially 2H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life and/or reduced dosage requirements, and/or may lead to a modified metabolism pathway, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
In this patent application, a bond drawn as a dotted line shows the point of attachment of the radical drawn. For example, the radical drawn below
is the 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1,3-diyl group.
In addition, it is well understood that in certain instances the drawn structure of the present compounds may represent several tautomers and such tautomers are comprised in the scope of the present invention: For example compounds of formula (I) wherein Z and Y are CH, X is N, and R4 is hydroxy: i.e. compounds wherein the fragment:
represents
are understood as being one of two possible tautomeric forms. Such compounds, thus, also comprise the compounds wherein said fragment represents the corresponding tautomer:
Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.
Any reference to compounds of formula (I) according to embodiments 1) to 25) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.
The term “pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example “Handbook of Pharmaceutical Salts. Properties, Selection and Use.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and “Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.
Definitions provided herein are intended to apply uniformly to the compounds of formula (I), as defined in any one of embodiments 1) to 25), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.
The term “halogen” means fluorine, chlorine, or bromine, preferably fluorine or chlorine.
The term “alkyl”, used alone or in combination, refers to a saturated straight or branched chain hydrocarbon group containing one to six carbon atoms. The term “(Cx-y)alkyl” (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms. For example a (C1-6)alkyl group contains from one to six carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, 3-methyl-butyl, 2,2-dimethyl-propyl and 3,3-dimethyl-butyl. For example a (C1-4)alkyl group contains from one to four carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert.-butyl. For avoidance of any doubt, in case a group is referred to as e.g. propyl or butyl, it is meant to be n-propyl, respectively n-butyl. Preferred are methyl, ethyl and isopropyl. Most preferred is methyl. Examples of (C1-3)alkyl groups as used for the substituents at ring A (without R1) is methyl. Examples of (C1-4)alkyl groups as used for R1 are methyl and isopropyl. An example of R11 in —CO—R11 is tert-butyl, an example of a (C1-4)alkyl substituent at phenyl in R1 is methyl, an example of (C1-4)alkyl of R14a or R14b is methyl and ethyl. Examples of (C1-4)alkyl groups as used for R2 are methyl and isopropyl. Examples of (C1-3)alkyl groups as used for R3 is methyl. An example of (C1-4)alkyl groups as used for R4, R41, R41a, R41b, R43a and R43b is methyl.
The term “—(Cx-y)alkylene-”, used alone or in combination, refers to bivalently bound alkyl group as defined before containing x to y carbon atoms. Preferably, the points of attachment of a —(C1-y)alkylene group are in 1,1-diyl, in 1,2-diyl, or in 1,3-diyl arrangement. Preferably, the points of attachment of a —(C2-y)alkylene group are in 1,2-diyl or in 1,3-diyl arrangement. Preferred alkylene groups are methylene, ethylene and propylene. A —(C0)alkylene-group is absent and refers to a direct bond.
Alkylene-oxy linker groups —(C1-3)alkylene-O— as used for example in the substituents (C3-6)cycloalkyl-X12— or (C3-6)cycloalkyl-X21— are to be read from left to right, i.e. they refer to the respective (C3-6)cycloalkyl-(C1-3)alkylene-O— groups. An example for (C3-6)cycloalkyl-(C1-3)alkylene-O— is cyclopropyl-methoxy.
Alkylene-amino linker groups R14aR14bN—X14—, wherein X14 represents (C1-3)alkylene, are used for example in the substituents methylamino-methyl, dimethylamino-methyl, (2-hydroxy-ethyl)-methyl-amino]-methyl, (2-methoxy-1-methyl-ethylamino)-methyl, (2-methoxy-ethyl)-methyl-amino]-methyl, [ethyl-(2-hydroxy-ethyl)-amino]-methyl, and [bis-(2-hydroxy-ethyl)-amino]-methyl. Further, alkylene-amino linker groups R14aR14bN—X14—, wherein X14 represents (C1-3)alkylene and R14a and R14b together with the nitrogen to which they are attached to form a 4- to 6-membered saturated ring optionally containing one additional ring heteroatom selected from oxygen and nitrogen, are used for example in the substituents azetidin-1-ylmethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, piperazin-1-ylmethyl, morpholin-4-ylmethyl, morpholin-4-yl-ethyl, morpholin-4-yl-propyl, 1-methyl-piperazin-4-yl)-methyl, 3-methoxy-azetidin-1-ylmethyl, 4-hydroxy-piperidin-1-ylmethyl, 3-methoxy-pyrrolidin-1-ylmethyl, 4-methoxy-piperidin-1-ylmethyl, and 4-dimethylamino-piperidin-1-ylmethyl.
The term “alkoxy”, used alone or in combination, refers to an alkyl-O— group wherein the alkyl group is as defined before. The term “(Cx-y)alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (C1-4)alkoxy group means a group of the formula (C1-4)alkyl-O— in which the term “(C1-4)alkyl” has the previously given significance. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy. Preferred are ethoxy and especially methoxy. Examples of (C1-4)alkoxy groups as used for R11 in —CO—R11 are methoxy, ethoxy, isopropoxy, n-butyloxy and tert-butoxy. An example of a (C1-4)alkoxy substituent at phenyl in R1 is methoxy and n-butyloxy. Examples of (C1-4)alkoxy groups as used for R2 are methoxy and isopropoxy. An example of a (C1-4)alkoxy group as used for R43 is methoxy.
The term “hydroxy-(C1-3)alkyl” relates to an alkyl group wherein a hydroxyl group can be attached to any of the carbon atoms of the alkyl group, for instance 1-hydroxyethyl, 2-hydroxyethyl, hydroxymethyl, 1-hydroxy-1-methyl-ethyl. An example for “hydroxy-(C2-4)alkyl” is 2-hydroxyethyl.
The term “(C1-4)alkoxy-(C1-3)alkyl” relates to an alkyl group wherein an alkoxy group can be attached to any of the carbon atoms of the alkyl group, for instance 1-methoxyethyl, 2-methoxy-1-methyl-ethyl and 2-methoxyethyl.
The term “hydroxyl-(C2-3)alkoxy” relates to an alkoxy group wherein a hydroxyl group can be attached to any of the carbon atoms of the alkoxy group, for instance 2-hydroxy-ethoxy.
The term “(C1-4)alkoxy-(C2-3)alkoxy” relates to a first alkoxy group wherein a second alkoxy group can be attached to any of the carbon atoms of the first alkoxy group, for instance 2-methoxy-ethoxy.
The term “alkynyl”, used alone or in combination, refers to a straight or branched hydrocarbon chain containing two to five carbon atoms and one carbon-carbon triple bond. The term “(Cx-y)alkynyl” (x and y each being an integer), refers to an alkynyl group as defined before containing x to y carbon atoms. For example a (C2-C5)alkynyl group contains from two to five carbon atoms. An example of an alkynyl group is prop-2-yn-1-yl. An example for an alkynyl group as used for the phenyl substituent in R1 is 3-morpholin-4-yl-prop-1-ynyl.
The term “fluoroalkyl”, used alone or in combination, refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term “(Cx-y)fluoroalkyl” (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example a (C1-3)fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred are (C1)fluoroalkyl groups, especially trifluoromethyl.
The term “fluoroalkoxy”, used alone or in combination, refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term “(Cx-y)fluoroalkoxy” (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms. For example a (C1-3)fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred are (C1)fluoroalkoxy groups, especially trifluoromethoxy.
The term “cyano” refers to a group —CN.
The term “cycloalkyl”, used alone or in combination, refers to a saturated monocyclic hydrocarbon ring containing three to six carbon atoms. The term “(Cx-y)cycloalkyl” (x and y each being an integer), refers to a cycloalkyl group as defined before containing x to y carbon atoms. For example a (C3-6)cycloalkyl group contains from three to six carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Preferred are cyclopropyl, cyclopentyl and cyclohexyl; especially cyclopropyl. An example of (C3-6)cycloalkyl groups as used for the group R11 is cyclopropyl. An example for a (C3-6)cycloalkyl group as used for the phenyl substituent in (C3-6)cycloalkyl-X12— is cyclopropyl, examples for a (C3-6)cycloalkyl group as used for the phenyl or heteroaryl substituent in (C3-6)cycloalkyl-X21— are cyclopropyl and cyclobutyl.
The term “(Cx-y)cycloalkyl-(Cx-y)alkyl-O—” refers to a (Cx-y)cycloalkyl group as defined before, which is linked through a (Cx-y)alkylene-O— group as defined before to the rest of the molecule. A particular example of such groups is cyclopropyl-methoxy.
The term “(C3-6)cycloalkyl optionally containing one ring oxygen atom”, used alone or in combination, refers to a cycloalkyl group as defined before. In addition, one ring carbon atom of said cycloalkyl may be replaced by an oxygen atom. Examples of such groups are especially cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; as well as oxygen containing groups such as oxetanyl, tetrahydrofuranyl, and tetrahydro-2H-pyranyl.
The term “heterocyclyl”, used alone or in combination, and if not explicitly defined in a more narrow way, refers to a saturated monocyclic hydrocarbon ring containing one or two ring heteroatoms independently selected from nitrogen and oxygen (especially one nitrogen atom, two nitrogen atoms, one nitrogen atom and one oxygen atom, one oxygen atom, or two oxygen atoms; preferably such heterocyclyl contains one or two ring oxygen atoms, or one nitrogen atom). The term “(Cx-y)heterocyclyl” refers to such a heterocyclyl group containing x to y ring atoms. Heterocyclyl groups are unsubstituted or substituted as explicitly defined. Examples of heterocyclyl groups as used for the group R41 wherein R41 represents (C4)heterocyclyl-X41— are oxetan-3-yl, 1-methyl-pyrrolidin-3-yl, piperidin-4-yl, 2,2-dimethyl-dioxolan-4-yl (notably 2,2-dimethyl-dioxolan-4-yl-methyl), morpholin-4-yl (notably morpholin-4-yl-ethyl) and 1-tert-butoxy-carbonyl-piperidin-4-yl.
The term “(Cx-y) heterocyclyl-(Cx-y)alkyl” refers to a (Cx-y)heterocyclyl group as defined before, which is linked through a (Cx-y)alkylene group as defined before to the rest of the molecule. For the (C4-7)heterocyclyl-(C1-3)alkyl groups as used for R41 examples of —(C1-3)alkylene-groups are methylene, and ethylene. Examples of heterocyclyl groups part of such (C4-7)heterocyclyl-(C1-3)alkylene groups as used for the group R41 wherein R41 represents (C4-7)heterocyclyl-X41— are 2,2-dimethyl-dioxolan-4-yl-methylene and morpholin-4-yl-ethylene.
The substituent phenyl of R1 independently is unsubstituted, mono-, di or trisubstituted. Examples for mono-, di or trisubstituted phenyl as R1 are 2,6-di-methyl-phenyl, 2-methoxy-phenyl, 2-n-butyloxy-phenyl, 2,6-di-methoxy-phenyl, 2-methoxy-ethoxy-phenyl, 2-methoxy-6-methyl-phenyl, 2-bromo-6-fluoro-phenyl, 2,6-di-fluoro-phenyl, 2-fluoro-phenyl, 2-fluoro-6-methoxy-phenyl, 2-fluoro-6-(1-methoxy-ethyl)-phenyl, 2-fluoro-6-methyl-phenyl, 2-Fluoro-6-(3-morpholin-4-yl-prop-1-ynyl)-phenyl, 2-fluoro-6-formyl-phenyl, 2-fluoro-6-cyano-phenyl, 2-fluoro-6-hydroxymethyl-phenyl, 2-fluoro-6-(1-hydroxyethyl)-phenyl, 2-fluoro-6-(1-hydroxy-1-methyl-ethyl)-phenyl, 2-fluoro-6-nitro-phenyl, 2-fluoro-6-acetyl-phenyl, 2-amino-6-fluoro-phenyl, 2-fluoro-6-methylaminomethyl-phenyl, 2-dimethylaminomethyl-6-fluoro-phenyl, 2-fluoro-6-{[(2-hydroxy-ethyl)-methyl-amino]-methyl}-phenyl, 2-fluoro-6-[(2-methoxy-1-methyl-ethylamino)-methyl]-phenyl, 2-Fluoro-6-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-phenyl, 2-{[Ethyl-(2-hydroxy-ethyl)-amino]-methyl}-6-fluoro-phenyl, 2-{[bis-(2-hydroxy-ethyl)-amino]-methyl}-6-fluoro-phenyl, 2-azetidin-1-ylmethyl-5-fluoro-phenyl, 2-fluoro-6-pyrrolidin-1-ylmethyl-phenyl, 2-Fluoro-6-piperidin-1-ylmethyl-phenyl, 2-fluoro-6-morpholin-4-yl-phenyl, 2-Fluoro-6-piperazin-1-ylmethyl-phenyl, 2-Fluoro-6-morpholin-4-ylmethyl-phenyl, 2-Fluoro-6-(2-morpholin-4-yl-ethyl)-phenyl, 2-Fluoro-6-(3-morpholin-4-yl-propyl)-phenyl, 2-Fluoro-6-(1-methyl-piperazin-4-yl)-methyl-phenyl, 2-Fluoro-6-(3-methoxy-azetidin-1-ylmethyl)-phenyl, 2-Fluoro-6-(4-hydroxy-piperidin-1-ylmethyl)-phenyl, 2-Fluoro-6-(3-methoxy-pyrrolidin-1-ylmethyl)-phenyl, 2-Fluoro-6-[1-(3-methoxy-azetidin-1-yl)-ethyl]-phenyl, 2-Fluoro-6-(4-methoxy-piperidin-1-ylmethyl)-phenyl, 2-(4-Dimethylamino-piperidin-1-ylmethyl)-6-fluoro-phenyl, 1-hydroxy-phenyl, 2-hydroxy-ethoxy-phenyl, oxetan-3-yl-oxy-phenyl, cyclopropyl-methoxy-phenyl, cyclobutyl-oxy,-phenyl, 2-(tetrahydro-pyran-4-yloxy)-phenyl, 1-benzyloxy-phenyl or 1-trifluoromethoxy-phenyl.
The substituent phenyl of R2 independently is unsubstituted, mono-, di or trisubstituted, especially mono- or trisubstituted. Examples for mono or trisubstituted phenyl as R2 are 2-trifluoromethoxy-phenyl, 2-trifluoromethyl-phenyl, 2-methoxy-phenyl, 2-isopropoxy-phenyl, 2-cyclopropyl-phenyl, 2-cyclopropyl-oxy-phenyl, 2-oxetan-3-yl-oxy-phenyl, 2-cyclopropylmethoxy-phenyl, 2-cyclobutyl-oxy-phenyl or 2,4-difluoro-6-isopropoxy-phenyl.
The term “heteroaryl”, used alone or in combination, means a 5- or 6-membered monocyclic aromatic ring containing one to a maximum of three heteroatoms, each independently selected from oxygen, nitrogen and sulfur. Examples of such heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl. Preferred 5- or 6-membered heteroaryl groups are pyrazolyl, oxodiazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. The above-mentioned heteroarl groups are unsubstituted or substituted as explicitly defined. In case 5- or 6-membered heteroaryl group is substituted in ortho-position with regard to the point of attachment of the rest of the molecule, it is understood that such substituent is attached in direct neighbourhood with regard to the point of attachment of the rest of the molecule, i.e. in a relative 1,2-arrangement. In case R1 represents “5- or 6-membered heteroaryl”, the term means the above-mentioned 5- or 6-membered groups, especially pyrazolyl, oxodiazolyl, pyridinyl, pyrimidinyl or pyridazinyl. For the substituent R1, such 5- or 6-membered heteroaryl group is unsubstituted or mono-, di- or tri-substituted (especially mono-, or di-substituted, in particular di-substituted) wherein the substituents are independently selected from (C1-4)alkyl, (C1)alkoxy, cyano, or halogen (especially fluoro or chloro, in particular fluoro). Examples for the 5-membered heteroaryl containing at least one nitrogen atom and optionally one or two further heteroatoms selected from nitrogen or oxygen are 2,5-dimethyl-2H-pyrazol-3-yl, 4-chloro-2,5-dimethyl-2H-pyrazol-3-yl, 2,4,5-trimethyl-2H-pyrazol-3-yl, 5-cyclopropyl-2-methyl-2H-pyrazol-3-yl, 4-formyl-2,5-dimethyl-2H-pyrazol-3-yl, 4-cyano-2,5-dimethyl-2H-pyrazol-3-yl, 4-chloro-5-cyclopropyl-2-methyl-2H-pyrazol-3-yl, 5-cyclopropyl-2,4-dimethyl-2H-pyrazol-3-yl, 5-cyclopropyl-4-formyl-2-methyl-2H-pyrazol-3-yl, 5-isopropyl-[1,3,4]oxodiazol-2-yl, 5-trifluoromethyl-[1,3,4]oxodiazol-2-yl. Examples for the 6-membered heteroaryl group containing one or two nitrogen atoms are 3-methoxy-pyridin-2-yl, 3,5-dimethoxy-pyridin-4-yl, 2,4-dimethoxy-pyridin-3-yl, 3-methyl-pyridin-2-yl, 4-methyl-2-methoxy-pyridin-3-yl, 2-methyl-4-methoxy-pyridin-3-yl, 2-cyano-4-methyl-pyridin-3-yl, 2,4-dimethyl-pyridin-3-yl, 3,5-dimethyl-pyridin-4-yl, 3-fluoro-pyridin-2-yl, 2-fluoro-pyridin-3-yl, 4-fluoro-pyridin-3-yl, 3,5-difluoro-pyridin-4-yl, 3,5-dichloro-pyridazin-4-yl, 3,4-dichloro-pyridazin-2-yl, 4,6-dimethoxy-pyrimidin-5-yl or 4-methyl-6-methoxy-pyrimidin-5-yl.
For the substituent R2, such 5- or 6-membered heteroaryl group is unsubstituted or mono-, di- or tri-substituted (especially mono-substituted) pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, wherein the substituents are independently selected from (C1-3)fluoroalkyl (especially trifluoromethyl), (C1-3)fluoroalkoxy (especially trifluoromethoxy), (C1-4)alkyl (especially methyl and isopropyl), (C1-4)alkoxy (especially methoxy and isopropoxy), halogen (especially chloro). Examples for the 5-membered heteroaryl containing at least one nitrogen atom and optionally one or two further heteroatoms selected from nitrogen or oxygen are 2-trifluoromethyl-thiazol-4-yl and 2-methyl-4-trifluoromethyl-thiazol-5-yl. Examples for the 6-membered heteroaryl group containing one or two nitrogen atoms are 3-methoxy-pyridin-2-yl, 3-isopropoxy-pyridin-2-yl, 4-trifluoromethyl-pyridin-3-yl, 2-trifluoro-pyridin-3-yl, 4-isopropyl-pyridin-3-yl, 3-trifluoromethyl-pyridin-4-yl, 4-methoxy-pyridazin-3-yl, 4-isopropoxy-pyridazin-3-yl, 4-methyl-pyridazin-3-yl, 6-chloro-4-methoxy-pyridazin-3-yl, 6-chloro-4-isopropoxy-pyridazin-3-yl, 4-methoxy-pyrimidin-5-yl, 4-trifluoromethyl-pyrimidin-5-yl, 3-trifluoromethyl-pyrazin-2-yl, 3-methoxy-pyrazin-2-yl, 3-isopropoxy-pyrazin-2-yl or 3-isopropyl-pyrazin-2-yl.
Further embodiments of the invention are presented hereinafter:
2) A second embodiment relates to compounds according to embodiment 1), wherein
3) Another embodiment relates to compounds according to embodiment 1), wherein ring A represents a saturated 4- to 7-membered mono-cyclic carbocyclic ring containing the ring nitrogen atom to which R1 is attached, wherein said ring independently is unsubstituted, or mono-substituted with (C1-3)alkyl (especially methyl), fluoro, or (C1-4)alkoxy-carbonyl (especially ethoxy-carbonyl), or di-substituted wherein the substituents are two (C1-3)alkyl (especially methyl) substituents, or two fluoro substituents [especially such ring A is azetidin-1,3-diyl, pyrrolidin-1,3-diyl, 4-methyl-pyrolidin-1,3-diyl, piperidin-1,3-diyl, piperidin-1,4-diyl, 3-fluoro-piperidin-1,4-diyl, 2-methyl-piperidin-1,4-diyl, 3-methyl-piperidin-1,4-diyl, 3-(ethoxycarbonyl)-piperidin-1,4-diyl, 3,3-dimethyl-piperidin-1,4-diyl, azepan-1,4-diyl].
4) Another embodiment relates to compounds according to embodiment 1), wherein ring A represents unsubstituted, mono- or di-substituted azetidin-1,3-diyl, pyrrolidin-1,3-diyl, piperidin-1,3-diyl, piperidin-1,4-diyl, azepan-1,4-diyl, 2-aza-bicyclo[2.2.1]heptane-2,5-diyl, 3-aza-bicyclo[3.1.1]heptane-3,6-diyl, wherein the substituents are selected from the group of (C1-3)alkyl (especially methyl), fluoro, or (C1-4)alkoxy-carbonyl (especially ethoxy-carbonyl) [especially such ring A is azetidin-1,3-diyl, pyrrolidin-1,3-diyl, 4-methyl-pyrolidin-1,3-diyl, piperidin-1,3-diyl, piperidin-1,4-diyl, 3-fluoro-piperidin-1,4-diyl, 2-methyl-piperidin-1,4-diyl, 3-methyl-piperidin-1,4-diyl, 3-(ethoxycarbonyl)-piperidin-1,4-diyl, 3,3-dimethyl-piperidin-1,4-diyl, azepan-1,4-diyl, 2-aza-bicyclo[2.2.1]heptane-2,5-diyl, 3-aza-bicyclo[3.1.1]heptane-3,6-diyl].
5) Another embodiment relates to compounds according to embodiment 1), wherein ring A represents
6) Another embodiment relates to compounds according to any one of embodiments 1) to 5), wherein
7) Another embodiment relates to compounds according to any one of embodiments 1) to 5), wherein one of X and Z represents CH or N; the other represents CH; and Y represents CR5, wherein R5 represents hydrogen or (C1-3)alkyl (especially R5 represents hydrogen).
8) Another embodiment relates to compounds according to any one of embodiments 1) to 7), wherein R1 represents
9) Another embodiment relates to compounds according to any one of embodiments 1) to 7), wherein R1 represents
10) Another embodiment relates to compounds according to any one of embodiments 1) to 7), wherein R1 represents
11) Another embodiment relates to compounds according to any one of embodiments 1) to 7), wherein R1 represents
12) Another embodiment relates to compounds according to any one of embodiments 1) to 7), wherein R1 represents phenyl which is mono-, or di- or tri-substituted (notably mono- or di-substituted); wherein
13) Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein R2 represents phenyl, or 6-membered heteroaryl (in particular pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl) [especially R2 represents phenyl]; wherein said phenyl or 6-membered heteroaryl independently is mono-, or di-substituted (especially mono-substituted, in particular mono-substituted in ortho position with regard to the point of attachment of the rest of the molecule), wherein the substituents are independently selected from
14) Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein R2 represents phenyl, or 6-membered heteroaryl (in particular pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl) [especially R2 represents phenyl]; wherein said phenyl or 6-membered heteroaryl is mono-substituted in ortho position with regard to the point of attachment of the rest of the molecule, wherein the substituent is independently selected from
15) Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein R2 represents phenyl, which is mono-substituted in ortho position with regard to the point of attachment of the rest of the molecule, wherein the substituent is independently selected from
16) Another embodiment relates to compounds according to any one of embodiments 1) to 15), wherein R3 represents hydrogen, or methyl (especially hydrogen). In a sub-embodiment R3 represents hydrogen.
17) Another embodiment relates to compounds according to any one of embodiments 1) to 16),
R4 represents
18) Another embodiment relates to compounds according to any one of embodiments 1) to 16), wherein R4 represents
19) Another embodiment relates to compounds according to any one of embodiments 1) to 16), wherein R4 represents
20) Another embodiment relates to compounds according to any one of embodiments 1) to 16), wherein R4 represents
21) Another embodiment relates to compounds according to any one of embodiments 1) to 16), wherein R4 represents
22) The invention, thus, relates to compounds of the formula (I) as defined in embodiment 1), or to such compounds further limited by the characteristics of any one of embodiments 2) to 21), under consideration of their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds as medicaments especially in the treatment of disorders relating to diseases and disorders related to pathogenic events associated with elevated levels of C5a and/or with C5aR activation. For avoidance of any doubt, especially the following embodiments relating to the compounds of formula (I) are thus possible and intended and herewith specifically disclosed in individualized form:
1, 2+1, 3+1, 5+1, 6+1, 6+2+1, 6+3+1, 7+1, 7+5+1, 8+1, 8+2+1, 8+3+1, 8+6+1, 8+6+2+1, 8+6+3+1, 9+1, 9+2+1, 9+3+1, 9+6+1, 9+6+2+1, 9+6+3+1, 11+1, 11+5+1, 11+7+1, 11+7+5+1, 12+1, 12+5+1, 12+7+1, 12+7+5+1, 13+1, 13+2+1, 13+3+1, 13+6+1, 13+6+2+1, 13+6+3+1, 13+8+1, 13+8+2+1, 13+8+3+1, 13+8+6+1, 13+8+6+2+1, 13+8+6+3+1, 13+9+1, 13+9+2+1, 13+9+3+1, 13+9+6+1, 13+9+6+2+1, 13+9+6+3+1, 14+1, 14+5+1, 14+7+1, 14+7+5+1, 14+11+1, 14+11+5+1, 14+11+7+1, 14+11+7+5+1, 14+12+1, 14+12+5+1, 14+12+7+1, 14+12+7+5+1, 15+1, 15+5+1, 15+7+1, 15+7+5+1, 15+11+1, 15+11+5+1, 15+11+7+1, 15+11+7+5+1, 15+12+1, 15+12+5+1, 15+12+7+1, 15+12+7+5+1, 16+1, 16+2+1, 16+3+1, 16+5+1, 16+6+1, 16+6+2+1, 16+6+3+1, 16+7+1, 16+7+5+1, 16+8+1, 16+8+2+1, 16+8+3+1, 16+8+6+1, 16+8+6+2+1, 16+8+6+3+1, 16+9+1, 16+9+2+1, 16+9+3+1, 16+9+6+1, 16+9+6+2+1, 16+9+6+3+1, 16+11+1, 16+11+5+1, 16+11+7+1, 16+11+7+5+1, 16+12+1, 16+12+5+1, 16+12+7+1, 16+12+7+5+1, 16+13+1, 16+13+2+1, 16+13+3+1, 16+13+6+1, 16+13+6+2+1, 16+13+6+3+1, 16+13+8+1, 16+13+8+2+1, 16+13+8+3+1, 16+13+8+6+1, 16+13+8+6+2+1, 16+13+8+6+3+1, 16+13+9+1, 16+13+9+2+1, 16+13+9+3+1, 16+13+9+6+1, 16+13+9+6+2+1, 16+13+9+6+3+1, 16+14+1, 16+14+5+1, 16+14+7+1, 16+14+7+5+1, 16+14+11+1, 16+14+11+5+1, 16+14+11+7+1, 16+14+11+7+5+1, 16+14+12+1, 16+14+12+5+1, 16+14+12+7+1, 16+14+12+7+5+1, 16+15+1, 16+15+5+1, 16+15+7+1, 16+15+7+5+1, 16+15+11+1, 16+15+11+5+1, 16+15+11+7+1, 16+15+11+7+5+1, 16+15+12+1, 16+15+12+5+1, 16+15+12+7+1, 16+15+12+7+5+1, 17+1, 17+2+1, 17+3+1, 17+6+1, 17+6+2+1, 17+6+3+1, 17+8+1, 17+8+2+1, 17+8+3+1, 17+8+6+1, 17+8+6+2+1, 17+8+6+3+1, 17+9+1, 17+9+2+1, 17+9+3+1, 17+9+6+1, 17+9+6+2+1, 17+9+6+3+1, 17+13+1, 17+13+2+1, 17+13+3+1, 17+13+6+1, 17+13+6+2+1, 17+13+6+3+1, 17+13+8+1, 17+13+8+2+1, 17+13+8+3+1, 17+13+8+6+1, 17+13+8+6+2+1, 17+13+8+6+3+1, 17+13+9+1, 17+13+9+2+1, 17+13+9+3+1, 17+13+9+6+1, 17+13+9+6+2+1, 17+13+9+6+3+1, 17+16+1, 17+16+2+1, 17+16+3+1, 17+16+5+1, 17+16+6+1, 17+16+6+2+1, 17+16+6+3+1, 17+16+7+1, 17+16+7+5+1, 17+16+8+1, 17+16+8+2+1, 17+16+8+3+1, 17+16+8+6+1, 17+16+8+6+2+1, 17+16+8+6+3+1, 17+16+9+1, 17+16+9+2+1, 17+16+9+3+1, 17+16+9+6+1, 17+16+9+6+2+1, 17+16+9+6+3+1, 17+16+11+1, 17+16+11+5+1, 17+16+11+7+1, 17+16+11+7+5+1, 17+16+12+1, 17+16+12+5+1, 17+16+12+7+1, 17+16+12+7+5+1, 17+16+13+1, 17+16+13+2+1, 17+16+13+3+1, 17+16+13+6+1, 17+16+13+6+2+1, 17+16+13+6+3+1, 17+16+13+8+1, 17+16+13+8+2+1, 17+16+13+8+3+1, 17+16+13+8+6+1, 17+16+13+8+6+2+1, 17+16+13+8+6+3+1, 17+16+13+9+1, 17+16+13+9+2+1, 17+16+13+9+3+1, 17+16+13+9+6+1, 17+16+13+9+6+2+1, 17+16+13+9+6+3+1, 17+16+14+1, 17+16+14+5+1, 17+16+14+7+1, 17+16+14+7+5+1, 17+16+14+11+1, 17+16+14+11+5+1, 17+16+14+11+7+1, 17+16+14+11+7+5+1, 17+16+14+12+1, 17+16+14+12+5+1, 17+16+14+12+7+1, 17+16+14+12+7+5+1, 17+16+15+1, 17+16+15+5+1, 17+16+15+7+1, 17+16+15+7+5+1, 17+16+15+11+1, 17+16+15+11+5+1, 17+16+15+11+7+1, 17+16+15+11+7+5+1, 17+16+15+12+1, 17+16+15+12+5+1, 17+16+15+12+7+1, 17+16+15+12+7+5+1, 19+1, 19+5+1, 19+7+1, 19+7+5+1, 19+11+1, 19+11+5+1, 19+11+7+1, 19+11+7+5+1, 19+12+1, 19+12+5+1, 19+12+7+1, 19+12+7+5+1, 19+14+1, 19+14+5+1, 19+14+7+1, 19+14+7+5+1, 19+14+11+1, 19+14+11+5+1, 19+14+11+7+1, 19+14+11+7+5+1, 19+14+12+1, 19+14+12+5+1, 19+14+12+7+1, 19+14+12+7+5+1, 19+15+1, 19+15+5+1, 19+15+7+1, 19+15+7+5+1, 19+15+11+1, 19+15+11+5+1, 19+15+11+7+1, 19+15+11+7+5+1, 19+15+12+1, 19+15+12+5+1, 19+15+12+7+1, 19+15+12+7+5+1, 19+16+1, 19+16+2+1, 19+16+3+1, 19+16+5+1, 19+16+6+1, 19+16+6+2+1, 19+16+6+3+1, 19+16+7+1, 19+16+7+5+1, 19+16+8+1, 19+16+8+2+1, 19+16+8+3+1, 19+16+8+6+1, 19+16+8+6+2+1, 19+16+8+6+3+1, 19+16+9+1, 19+16+9+2+1, 19+16+9+3+1, 19+16+9+6+1, 19+16+9+6+2+1, 19+16+9+6+3+1, 19+16+11+1, 19+16+11+5+1, 19+16+11+7+1, 19+16+11+7+5+1, 19+16+12+1, 19+16+12+5+1, 19+16+12+7+1, 19+16+12+7+5+1, 19+16+13+1, 19+16+13+2+1, 19+16+13+3+1, 19+16+13+6+1, 19+16+13+6+2+1, 19+16+13+6+3+1, 19+16+13+8+1, 19+16+13+8+2+1, 19+16+13+8+3+1, 19+16+13+8+6+1, 19+16+13+8+6+2+1, 19+16+13+8+6+3+1, 19+16+13+9+1, 19+16+13+9+2+1, 19+16+13+9+3+1, 19+16+13+9+6+1, 19+16+13+9+6+2+1, 19+16+13+9+6+3+1, 19+16+14+1, 19+16+14+5+1, 19+16+14+7+1, 19+16+14+7+5+1, 19+16+14+11+1, 19+16+14+11+5+1, 19+16+14+11+7+1, 19+16+14+11+7+5+1, 19+16+14+12+1, 19+16+14+12+5+1, 19+16+14+12+7+1, 19+16+14+12+7+5+1, 19+16+15+1, 19+16+15+5+1, 19+16+15+7+1, 19+16+15+7+5+1, 19+16+15+11+1, 19+16+15+11+5+1, 19+16+15+11+7+1, 19+16+15+11+7+5+1, 19+16+15+12+1, 19+16+15+12+5+1, 19+16+15+12+7+1, 19+16+15+12+7+5+1, 20+1, 20+5+1, 20+7+1, 20+7+5+1, 20+11+1, 20+11+5+1, 20+11+7+1, 20+11+7+5+1, 20+12+1, 20+12+5+1, 20+12+7+1, 20+12+7+5+1, 20+14+1, 20+14+5+1, 20+14+7+1, 20+14+7+5+1, 20+14+11+1, 20+14+11+5+1, 20+14+11+7+1, 20+14+11+7+5+1, 20+14+12+1, 20+14+12+5+1, 20+14+12+7+1, 20+14+12+7+5+1, 20+15+1, 20+15+5+1, 20+15+7+1, 20+15+7+5+1, 20+15+11+1, 20+15+11+5+1, 20+15+11+7+1, 20+15+11+7+5+1, 20+15+12+1, 20+15+12+5+1, 20+15+12+7+1, 20+15+12+7+5+1, 20+16+1, 20+16+2+1, 20+16+3+1, 20+16+5+1, 20+16+6+1, 20+16+6+2+1, 20+16+6+3+1, 20+16+7+1, 20+16+7+5+1, 20+16+8+1, 20+16+8+2+1, 20+16+8+3+1, 20+16+8+6+1, 20+16+8+6+2+1, 20+16+8+6+3+1, 20+16+9+1, 20+16+9+2+1, 20+16+9+3+1, 20+16+9+6+1, 20+16+9+6+2+1, 20+16+9+6+3+1, 20+16+11+1, 20+16+11+5+1, 20+16+11+7+1, 20+16+11+7+5+1, 20+16+12+1, 20+16+12+5+1, 20+16+12+7+1, 20+16+12+7+5+1, 20+16+13+1, 20+16+13+2+1, 20+16+13+3+1, 20+16+13+6+1, 20+16+13+6+2+1, 20+16+13+6+3+1, 20+16+13+8+1, 20+16+13+8+2+1, 20+16+13+8+3+1, 20+16+13+8+6+1, 20+16+13+8+6+2+1, 20+16+13+8+6+3+1, 20+16+13+9+1, 20+16+13+9+2+1, 20+16+13+9+3+1, 20+16+13+9+6+1, 20+16+13+9+6+2+1, 20+16+13+9+6+3+1, 20+16+14+1, 20+16+14+5+1, 20+16+14+7+1, 20+16+14+7+5+1, 20+16+14+11+1, 20+16+14+11+5+1, 20+16+14+11+7+1, 20+16+14+11+7+5+1, 20+16+14+12+1, 20+16+14+12+5+1, 20+16+14+12+7+1, 20+16+14+12+7+5+1, 20+16+15+1, 20+16+15+5+1, 20+16+15+7+1, 20+16+15+7+5+1, 20+16+15+11+1, 20+16+15+11+5+1, 20+16+15+11+7+1, 20+16+15+11+7+5+1, 20+16+15+12+1, 20+16+15+12+5+1, 20+16+15+12+7+1, 20+16+15+12+7+5+1, 21+1, 21+5+1, 21+7+1, 21+7+5+1, 21+11+1, 21+11+5+1, 21+11+7+1, 21+11+7+5+1, 21+12+1, 21+12+5+1, 21+12+7+1, 21+12+7+5+1, 21+14+1, 21+14+5+1, 21+14+7+1, 21+14+7+5+1, 21+14+11+1, 21+14+11+5+1, 21+14+11+7+1, 21+14+11+7+5+1, 21+14+12+1, 21+14+12+5+1, 21+14+12+7+1, 21+14+12+7+5+1, 21+15+1, 21+15+5+1, 21+15+7+1, 21+15+7+5+1, 21+15+11+1, 21+15+11+5+1, 21+15+11+7+1, 21+15+11+7+5+1, 21+15+12+1, 21+15+12+5+1, 21+15+12+7+1, 21+15+12+7+5+1, 21+16+1, 21+16+2+1, 21+16+3+1, 21+16+5+1, 21+16+6+1, 21+16+6+2+1, 21+16+6+3+1, 21+16+7+1, 21+16+7+5+1, 21+16+8+1, 21+16+8+2+1, 21+16+8+3+1, 21+16+8+6+1, 21+16+8+6+2+1, 21+16+8+6+3+1, 21+16+9+1, 21+16+9+2+1, 21+16+9+3+1, 21+16+9+6+1, 21+16+9+6+2+1, 21+16+9+6+3+1, 21+16+11+1, 21+16+11+5+1, 21+16+11+7+1, 21+16+11+7+5+1, 21+16+12+1, 21+16+12+5+1, 21+16+12+7+1, 21+16+12+7+5+1, 21+16+13+1, 21+16+13+2+1, 21+16+13+3+1, 21+16+13+6+1, 21+16+13+6+2+1, 21+16+13+6+3+1, 21+16+13+8+1, 21+16+13+8+2+1, 21+16+13+8+3+1, 21+16+13+8+6+1, 21+16+13+8+6+2+1, 21+16+13+8+6+3+1, 21+16+13+9+1, 21+16+13+9+2+1, 21+16+13+9+3+1, 21+16+13+9+6+1, 21+16+13+9+6+2+1, 21+16+13+9+6+3+1, 21+16+14+1, 21+16+14+5+1, 21+16+14+7+1, 21+16+14+7+5+1, 21+16+14+11+1, 21+16+14+11+5+1, 21+16+14+11+7+1, 21+16+14+11+7+5+1, 21+16+14+12+1, 21+16+14+12+5+1, 21+16+14+12+7+1, 21+16+14+12+7+5+1, 21+16+15+1, 21+16+15+5+1, 21+16+15+7+1, 21+16+15+7+5+1, 21+16+15+11+1, 21+16+15+11+5+1, 21+16+15+11+7+1, 21+16+15+11+7+5+1, 21+16+15+12+1, 21+16+15+12+5+1, 21+16+15+12+7+1, 21+16+15+12+7+5+1.
In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas “+” indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. In other words, “20+15+12+1” for example refers to embodiment 20) depending on embodiment 15), depending on embodiment 12), depending on embodiment 1), i.e. embodiment “20+15+12+1” corresponds to the compounds of formula (I) according to embodiment 1) further limited by all the features of the embodiments 12), 15), and 20).
23) A second aspect of the invention relates to compounds of the formula (I) according to embodiment 1) which are also compounds of the formula (II)
wherein X is CH and Z is CH, X is N and Z is CH, or X is CH and Z is N;
In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas “+” indicates the limitations as outlined above.
24) A third aspect of the invention relates to compounds of the formula (I) according to embodiment 1) which are also compounds of the formula (III)
wherein X is CH and Z is CH, X is N and Z is CH, or X is CH and Z is N;
In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas “+” indicates the limitations as outlined above.
25) Another embodiment relates to compounds according to embodiment 1) which are selected from the following compounds:
The compounds of formula (I), (II) and (III) according to embodiments 1) to 25) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (including topical application or inhalation).
The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula (I), (II) or (III), or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
The present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I), (II) or (III) as defined in any one of embodiments 1) to 25).
In a preferred embodiment of the invention, the administered amount is comprised between 1 mg and 1000 mg per day, particularly between 5 mg and 500 mg per day, more particularly between 25 mg and 400 mg per day, especially between 50 mg and 200 mg per day.
Whenever the word “between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40° C. and 80° C., this means that the end points 40° C. and 80° C. are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1, 2, 3, or 4.
Unless used regarding temperatures, the term “about” placed before a numerical value “X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10° C. to Y plus 10° C., and preferably to an interval extending from Y minus 5° C. to Y plus 5° C.
For avoidance of any doubt, if compounds are described as useful for the prevention or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention or treatment of said diseases.
The compounds of formula (I), (II) and (III) as defined in any one of embodiments 1) to 25) are useful for the prevention/prophylaxis or treatment of diseases and disorders related to pathogenic events associated with elevated levels of C5a and/or with C5aR activation.
Such diseases and disorders related to pathogenic events associated with elevated levels of C5a and/or with C5aR activation are especially:
In addition to the above-listed diseases and disorders, further diseases and disorders related to pathogenic events associated with elevated levels of C5a and/or with C5aR activation are:
The present compounds may in addition be useful for
Vasculitic diseases or disorders include especially vasculitis, ANCA associated vasculitis and glomerulonephritis (GN, especially rapidly progressive GN) associated with ANCA associated vasculitis, leukoclastic vasculitis, granulomatosis with polyangiitis (GPA, also referred to as Wegener's granulomatosis), microscopic polyangiitis, Churg-Strauss syndrome, Henoch-Schönlein purpura, polyateritis nodosa, cryoglobulinaemia, giant cell arteritis (GCA), Behcet's disease, and Takayasu's arteritis (TAK).
Inflammatory diseases or disorders involving intravascular microvesicle release include especially thrombotic microangiopathy, and sickle cell disease.
Immune complex (IC) diseases or disorders include especially cryoglobulinemia, Sjögren's syndrome (and associated immunological profiles), Goodpasture syndrome (antiglomerular basement antibody disease) and glomerulonephritis (GN, especially rapidly progressive GN) or pulmonary hemorrhage associated with Goodpasture syndrome, and hypersensitivity;
Neurodegenerative diseases and disorders include especially amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Guillain-Barre syndrome, neuropathy, and cognitive function decline associated with cardiopulmonary bypass surgery and related procedures.
Complement related inflammatory diseases or disorders include especially coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, atherosclerosis, traumatic central nervous system injury, arrhythmogenic cardiomyopathy, bronchoconstriction, acute respiratory distress syndrome (ARDS), Chronic Obstructive Pulmonary Disorder (COPD), complement mediated thrombotic microangiopathies including atypical haemolytic uremic syndrome, and Gaucher disease.
Bullous diseases or disorders include especially bullous pemphigoid, bullous acquisita, pemphigus foliaceus, pemphigus vulgaris, and sub-epidermal blisters.
Diseases or disorders related to ischemia and/or ischemic reperfusion injury include especially ischemic reperfusion injury (including myocardial ischemia-reperfusion injury, and ischemic/reperfusion injury resulting from transplantation, including solid organ transplant), ischemic colitis, and cardiac ischemia.
Inflammatory bowel diseases or disorders include especially irritable bowel syndrome, ulcerative colitis, Crohn's disease, and inflammatory bowel disease (IBD).
Autoimmune diseases or disorders include especially rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus (SLE) and glomerulonephritis (GN, especially rapidly progressive GN) associated with lupus erythematosus (lupus nephritis), central nervous system (CNS) lupus, dermatomyositis, pemphigus, systemic sclerosis (scleroderma), autoimmune hemolytic and thrombocytopenic states, immunovasculitis, mixed cryoglobulinemia, atopic dermatitis, chronic urticaria, psoriasis, myasthenia gravis, and anti-phospholipid syndrome.
Further inflammatory diseases or disorders associated with elevated levels of C5a and/or with C5aR activation include especially neutropenia, sepsis, septic shock, stroke, inflammation associated with severe burns, osteoarthritis, acute (adult) respiratory distress syndrome (ARDS), chronic pulmonary obstructive disorder (COPD), asthma, especially bronchial asthma, systemic inflammatory response syndrome (SIRS), tissue graft rejection, hyperacute rejection of transplanted organs, multiple organ dysfunction syndrome (MODS), diabetic retinopathy, neuromyelitis optica, and glomerulonephritis including Heyman nephritis/membranous glomerulonephritis, Berger's disease (IgA nephropathy), and other forms of glomerulonephritis including C3 glomerulopathy.
The term “cancer” notably refers to skin cancer including melanoma including metastatic melanoma; lung cancer including non-small cell lung cancer; bladder cancer including urinary bladder cancer, urothelial cell carcinoma; renal carcinomas including renal cell carcinoma, metastatic renal cell carcinoma, metastatic renal clear cell carcinoma; gastro-intestinal cancers including colorectal cancer, metastatic colorectal cancer, familial adenomatous polyposis (FAP), oesophageal cancer, gastric cancer, gallbladder cancer, cholangiocarcinoma, hepatocellular carcinoma, and pancreatic cancer such as pancreatic adenocarcinoma or pancreatic ductal carcinoma; endometrial cancer; ovarian cancer; cervical cancer; neuroblastoma; prostate cancer including castrate-resistant prostate cancer; brain tumors including brain metastases, malignant gliomas, glioblastoma multiforme, medulloblastoma, meningiomas; breast cancer including triple negative breast carcinoma; oral tumors; nasopharyngeal tumors; thoracic cancer; head and neck cancer; leukemias including acute myeloid leukemia, adult T-cell leukemia; carcinomas; adenocarcinomas; thyroid carcinoma including papillary thyroid carcinoma; choriocarcinoma; Ewing's sarcoma; osteosarcoma; rhabdomyosarcoma; Kaposi's sarcoma; lymphoma including Burkitt's lymphoma, Hodgkin's lymphoma, MALT lymphoma; multiple myelomas; or virally induced tumors.
When used for the prevention/prophylaxis or treatment of a cancer, such use includes use of the present compounds as single therapeutic agents and their use in combination with one or more chemotherapy agents and/or radiotherapy and/or targeted therapy (especially in combination with targeted therapy).
The terms “radiotherapy” or “radiation therapy” or “radiation oncology”, refer to the medical use of ionizing radiation in the prevention/prophylaxis (adjuvant therapy) and/or treatment of cancer; including external and internal radiotherapy.
The term “targeted therapy” refers to the prevention/prophylaxis (adjuvant therapy) and/or treatment of cancer with one or more anti-neoplastic agents such as small molecules or antibodies which act on specific types of cancer cells or stromal cells. Some targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells. Other types of targeted therapies help the immune system kill cancer cells (immunotherapies); or inhibit angiogenesis, the growth and formation of new blood vessels in the tumor; or deliver toxic substances directly to cancer cells and kill them. An example of a targeted therapy which is in particular suitable to be combined with the compounds of the present invention is immunotherapy, especially immunotherapy targeting the programmed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1.
When used in combination with the present compounds, the term “targeted therapy” especially refers to agents such as:
When used in combination with the present compounds, immune checkpoint inhibitors, and especially those targeting the PD-1 receptor or its ligand PD-L1, are preferred.
The invention further relates to a method of modulating (especially downregulating) the consequences of the complement activation (especially by activating innate cells) in a subject in need thereof [especially in a subject having a disease or disorder related to pathogenic events associated with elevated levels of C5a and/or with C5aR activation; in particular in a subject having a vasculitic disease or disorder, an inflammatory disease or disorder involving intravascular microvesicle release, an immune complex (IC) disease or disorder, a neurodegenerative disease or disorder, a complement related inflammatory disease or disorder, a bullous disease or disorder, a disease or disorder related to ischemia and/or ischemic reperfusion injury, an inflammatory bowel disease or disorder, or an autoimmune disease or disorder; or in a subject having a contact sensitivity or an inflammation caused by contact with artificial surfaces; an increased leukocyte and platelet activation (and infiltration to tissues thereof); a pathologic sequelae associated to an intoxication or an injury such as a trauma, an hemorrhage, a shock, or surgery including transplantation, including multiple organ failure (MOF), septic shock, shock due to intoxication (such as shock due to snake venom), or acute lung inflammatory injury; a pathologic sequelae associated with insulin-dependent diabetes mellitus; a myocardial infarction or thrombosis; an edema or an increased capillary permeability; or a reduction of coronary endothelial dysfunction induced by cardiopulmonary bypass and/or cardioplegia], comprising administering to said subject a pharmaceutically active amount of a compound of formula (I), (II) and (III) as defined in any one of embodiments 1) to 25). For avoidance of doubt, the term “modulating the complement activation” is to be understood as downregulating/reducing the amplification of the immune response and downregulating/reducing the activation of the cell-killing membrane attack complex, especially by activating innate cells.
The compounds of formula (I), (II) and (III) can be prepared by the methods given below, by the methods given in the experimental part below or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures. In the schemes below, the generic groups Ring A, R1, R1a, R14a, R14b, X14, R2, R2a, X21, R3, R4, R41R41a, R41b, X41, R42a, R42b, R43a, R43b are as defined for the compounds of formula (I), (II) and (III). In some instances, the generic groups Ring A, R1, R1a, R14a, R14b, X14, R2, R2a, X21, R3, R4, R41, R41a, R41b, X41, R42a, R42b, R43a, R43b may be incompatible with the assembly illustrated in the schemes, or will require the use of protecting groups (PG). The use of protecting groups is well known in the art (see for example “Protective Groups in Organic Synthesis”, T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place. In some cases, the final product may be further modified, for example, by manipulation of substituents to give a new final product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. The compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts in a manner known per se.
Compounds of structure Ia can be prepared according to the synthetic route given in scheme A below.
Compounds of structure A-1 can be prepared by aromatic nucleophilic substitution of amine of structure BB-1 on halides of structure BB-2 wherein X represents fluorine or chlorine in the presence of a suitable base such as DIPEA and heating in a suitable solvent such as DMSO at temperatures between 80° C. and 100° C. (Scheme A, step a).
Diamino compounds of structure A-2 can be prepared by reduction of the nitro group in compounds of structure A-1 using standard conditions such as catalytic hydrogenation with a suitable catalyst such as Pd/C and in the presence of a suitable solvent such as EtOAc and under a hydrogen atmosphere. Alternatively, reduction of the nitro group in compounds of structure A-1 may be performed by treatment with zinc dust and ammonium formate in solvents such as MeOH at temperatures around 0° C. (Scheme A, step b).
Cyclic ureas of structure A-3 can be prepared by cyclisation of diamines of structure A-2 by treatment with a suitable carbonyl transfer agent such as CDI in the presence of a suitable non protic solvent such as MeCN at temperatures between RT and 45° C. (Scheme A, step c).
Alkylation of the nitrogen atom having a free valency in compounds of structure A-3 with a suitable halide of structure BB-3 wherein X represents chlorine or bromine, in the presence of a suitable base such as NaH or K2CO3 and in solvents such as THF, DMF or a mixture of both at temperatures between 0° C. and 50° C. may afford compounds of structure Ia (Scheme A, step d).
Alternatively, compounds of structure Ia can be prepared according to the synthetic route given in scheme B below.
Compounds of structure B-1 can be prepared by aromatic nucleophilic substitution of amine of structure BB-5 on halides of structure BB-6 wherein X represents fluorine or chlorine in the presence of a suitable base such as DIPEA and heating at temperatures between 150° C. and 180° C. (Scheme B, step a).
Reduction of the nitro group in compounds of structure B-1 using standard conditions such as treatment by zinc dust and ammonium formate in solvents such as MeOH at temperatures around 0° C. may afford diamines of structure B-2. Alternatively, reduction of the nitro group in compounds of structure B-1 may be performed by catalytic hydrogenation with a suitable catalyst such as Pd/C in the presence of a suitable solvent such as EtOAc and under a hydrogen atmosphere (Scheme B, step b).
Cyclisation of diamines of structure B-2 to form cyclic urea of structure B-3 (Scheme B, step c) can be performed following conditions as those previously described for the synthesis of compounds of structure A-3 (Scheme A, step c).
Alkylation of the nitrogen atom having a free valency in compounds of structure B-3 can be achieved using Mitsunobu conditions by treatment with a suitable alcohol of structure BB-7 and for instance a (cyanomethylene)trialkylphosphorane reagent in the presence of a suitable solvent such as toluene at temperatures around 110° C. (Scheme B, step d).
Compounds of structure Ib, Ic, Ig, Ih, Ii, Iq and Iag can be prepared according to the synthetic route given in scheme C below.
Cleavage of the Boc protecting group in compounds of formula Ia can be performed using a suitable acid such as HCl or TFA in the presence of a suitable solvent such as dioxane, MeOH or DCM at temperatures around RT (Scheme C, step a).
Compounds of structure Ib wherein R1 represents an unsubstituted, mono-, di- or tri-substituted phenyl or 5- or 6-membered heteroaryl can be prepared by Buchwald-Hartwig cross coupling of halides of structure R1—X wherein X represents iodine, bromine or chloride and R1 represents an unsubstituted, mono-, di- or tri-substituted phenyl or 5- or 6-membered heteroaryl with an amine of structure C-1 in the presence of a suitable palladium catalyst such as Pd2(dba)3 and a ligand such as BINAP, in the presence of a suitable base such as sodium tert-butoxide and heating in a suitable solvent such as toluene at temperatures between 100° C. and 110° C. (Scheme C, step b).
Compounds of structure Ib wherein R1 represents an unsubstituted, mono- or di-substituted benzyl can be prepared by reductive amination of benzaldehyde of structure R1a—CHO wherein R1a represents a mono- or di-substituted phenyl with an amine of structure C-1 using standard conditions such as treatment with NaBH(OAc)3 in the presence of AcOH and a suitable solvent such as DCM or THF at temperatures around RT (Scheme C, step b).
Compounds of structure Ic wherein R1 represents an unsubstituted, mono-, di- or tri-substituted phenyl or 5- or 6-membered heteroarl can be prepared by aromatic nucleophilic substitution of amines of structure C-1 on activated halides of structure R1—X wherein X represents fluorine or chlorine and R1 represents a suitable unsubstituted, mono-, di- or tri-substituted phenyl or 5- or 6-membered heteroaryl in the presence of a suitable base such as CsF or K2CO3 and heating in a suitable solvent such as DMSO at temperatures between 60° C. and 110° C. (Scheme C, step b).
Alternatively, compounds of structure Ic wherein R1 represents a 5- or 6-membered heteroaryl can be prepared by aromatic nucleophilic substitution of amines of structure C-1 on alcohol of structure R1—X wherein X represents hydroxy and R1 represents a suitable 5- or 6-membered heteroaryl by activation of the corresponding alcohol with PyBOP in the presence of a suitable base such as DIPEA in solvents such as DMF at temperatures around RT (Scheme C, step b).
Compounds of structure Ig wherein R1 represents a (C1-4)alkoxy-carbonyl, phenoxy-carbonyl or (C3-6)cycloalkoxy-carbonyl can be prepared by treatment of amines of structure C-1 with chloroformate (or pentafluorophenylcarbonate, respectively) of structure R1—X wherein R1 represents (C1-4)alkoxy-carbonyl, phenoxy-carbonyl or (C3-6)cycloalkoxy-carbonyl and X represents chlorine (or X represents pentafluorophenoxy, respectively) in the presence of a suitable base such as TEA and in a suitable solvent such as DCM or DMF at temperatures between RT and 110° C. (Scheme C, step b).
Compounds of structure Ih wherein R1 represents a (C1-4)alkyl-carbonyl, phenyl-carbonyl or (C3-6)cycloalkyl-carbonyl optionally containing one ring oxygen and optionally mono-substituted with methyl or trifluoromethyl can be prepared by treatment of amines of structure C-1 with acid chlorides of structure R1—X wherein R1 represents (C1-4)alkyl-carbonyl, phenyl-carbonyl or (C3-6)cycloalkyl-carbonyl optionally containing one ring oxygen and optionally mono-substituted with methyl or trifluoromethyl and X represents chlorine in the presence of a suitable base such as TEA and in a suitable solvent such as DCM at temperatures between 0° C. and RT (Scheme C, step b).
Compounds of structure Ii wherein R1 represents (C1-4)alkyl can be prepared by reductive amination of a suitable aldehyde of structure R1a—CHO wherein R1a represents hydrogen or (C1-3)alkyl, acetone or butanone with amines of structure C-1 using standard conditions such as treatment with NaBH(OAc)3 in the presence of AcOH and a suitable solvent such as DCM, MeOH, THF or mixture thereof at temperatures around RT (Scheme C, step b). Alternatively, triethylsilane in solvents such as MeOH in the presence of catalytic amount of indium chloride (III) at temperatures around RT can be used as reductive conditions. Alternatively, alkylation of amines of structure C-1 with halides of structure R1—X wherein X represents chlorine, bromine or iodine in the presence of a suitable base such as K2CO3 and a suitable solvent such as MeCN at temperatures between RT and 65° C. may afford compounds of structure Ii (Scheme C, step b).
Compounds of structure C-2 can be prepared by alkylation of carbamates of structure BB-10 by treatment with an appropriate halide of formula BB-3 wherein X represents chlorine or bromine in the presence of a suitable base such as K2CO3 and carrying out the rxn in a suitable solvent such as MeCN at temperatures around 80° C. (Scheme C, step c).
Compounds of formula Iag can be prepared by Buchwald-Hartwig cross coupling of halides of formula C-2 with amines of formula BB-4 by treatment with a suitable palladium catalyst such as BrettPhos precatalyst and a suitable ligand such as BrettPhos, in the presence of a suitable base such as sodium tert-butoxide and heating in a suitable solvent such as dioxane at temperatures around 80° C. Using those conditions, the consecutive cyclisation to form the cyclic urea occurred and afforded the compounds of formula Iag (Scheme C, step d).
Compounds of structure C-3 can be prepared by aromatic nucleophilic substitution of amine of structure BB-4 on halides of structure BB-2 wherein X represents fluorine or chlorine in the presence of a suitable base such as DIPEA and heating in a suitable solvent such as DMSO at temperatures between 50° C. and 105° C. (Scheme C, step e).
Diamino compounds of structure C-4 can be prepared by reduction of the nitro group in compounds of structure C-3 using standard conditions such as catalytic hydrogenation with a suitable catalyst such as Pd/C and in the presence of a suitable solvent such as EtOAc and under a hydrogen atmosphere. Alternatively, the reduction of the nitro group can be performed by treatment with ammonium formate and zinc dust in the presence of a suitable solvent such as MeOH at temperatures around RT (Scheme C, step f).
Cyclic urea of structure C-6 can be prepared by cyclisation of diamines of structure C-4 by treatment with a suitable carbonyl transfer agent such as CDI in the presence of a suitable non protic solvent such as MeCN at temperatures between RT and 45° C. (Scheme C, step g).
Alternatively, compounds of structure C-6 can be prepared by aromatic nucleophilic substitution of amines of structure C-5 on halides of structure BB-8 wherein X represents fluorine or chlorine in the presence of a suitable base such as K2CO3 and heating in a suitable solvent such as DMSO at temperatures around 100° C. (Scheme C, step i). Compounds of structure C-5 can be prepared by cleavage of the Boc protecting group in compounds of formula A-3 using a suitable acid such as HCl or TFA in the presence of a suitable solvent such as dioxane, MeOH or DCM at temperatures around RT (Scheme C, step h).
Compounds of structure Id to If, Ij to Ip, Iu to Iz and Iae can be prepared according to the synthetic route given in scheme D below.
Alkylation of the nitrogen atom having a free valency in compounds of structure C-6 with a suitable halide of structure BB-3 wherein X represents chlorine or bromine, in the presence of a suitable base such as NaH or K2CO3 and in solvents such as THF, DMF or a mixture of both at temperatures between 0° C. and 50° C. may afford compounds of structure Iq (Scheme C, step j). Alternatively, alkylation of the nitrogen atom having a free valency in compounds of structure C-6 can be achieved using Mitsunobu conditions by treatment with a suitable alcohol of structure BB-3 wherein X represents hydroxy and for instance a (cyanomethylene)trialkylphosphorane reagent in the presence of a suitable solvent such as toluene at temperatures around 110° C. (Scheme C, step j).
Compounds of structure Id wherein R1 represents a 5- or 6-membered heteroaryl with at least one unsubstituted position can be prepared by decarbonylation of compounds of formula Ib or Ic wherein R1 represents a 5- or 6-membered heteroaryl which is substituted by a formyl group by treatment with a suitable acid such as toluene-4-sulfonic acid and in the presence of a suitable solvent such as MeOH under microwave conditions at temperatures around 120° C. (Scheme D, step a).
Compounds of structure If wherein R1 represents a 5- or 6-membered heteroaryl with at least one methyl substituent can be prepared by Wolff-Kishner type reduction of compounds of formula Ib or Ic wherein R1 represents a 5- or 6-membered heteroaryl which is substituted by one formyl group. The treatment with 4-toluene-sulfonyl hydrazide in the presence of toluene-4-sulfonic acid monohydrate with a suitable solvent such as a mixture of DMF and tetramethylene sulfone at temperatures around 100° C. affords the hydrazone intermediate which is consecutively reduced by treatment with sodium cyanoborohydride at temperatures around 100° C. (Scheme D, step a).
Compounds of structure Ij wherein R4 represents hydroxy can be prepared by treatment of suitable compounds of formula Ib and Ic wherein R4 represents methoxy with a suitable Lewis acid such as boron tribromide in the presence of a suitable solvent such as DCM at temperatures between −10° C. and RT (Scheme D, step a).
Compounds of structure Im wherein R1 represents a hydroxymethyl substituted phenyl or 5- or 6-membered heteroaryl can be prepared by treatment of compounds of formula Ib and Ic wherein R1 represents a formyl substituted phenyl or 5- or 6-membered heteroaryl by treatment with a suitable reducing reagent such as NaBH4 in the presence of a suitable solvent such as MeOH or THF at temperatures between 0° C. and RT (Scheme D, step a).
Compounds of structure In wherein R1 represents a 1-hydroxy-(C2-C3)-alkyl substituted phenyl or 5- or 6-membered heteroaryl can be prepared by treatment of compounds of formula Ib and Ic wherein R1 represents a formyl substituted phenyl or 5- or 6-membered heteroaryl by treatment with a suitable Grignard reagent in the presence of a suitable solvent such as THF at temperatures between 0° C. and RT (Scheme D, step a).
Compounds of structure Iu wherein R1 represents a R14aR14bN—X14— substituted phenyl, 5- or 6-membered heterocycle wherein X14 represents a methylene and R1 and R14 independently represent hydrogen, (C1-4)alkyl, hydroxy-(C2-4)alkyl, (C1-3)alkoxy-(C2-4)alkyl; or R14a and R14b together with the nitrogen to which they are attached to form a 4- to 6-membered saturated ring optionally containing one additional ring heteroatom selected from oxygen and nitrogen; and wherein said ring is optionally mono-substituted with (C1-4)alkyl can be prepared by reductive amination of compounds of formula Ib or Ic wherein R1 represents a formyl substituted phenyl or 5- or 6-membered heteroaryl using standard conditions such as treatment with NaBH(OAc)3 in the optional presence of AcOH and a suitable solvent such as DCM or THF at temperatures around RT (Scheme D, step a).
Compounds of structure Ie wherein R1 represents a chlorine substituted 5- or 6-membered heteroaryl can be prepared by chlorination of compounds of formula Id wherein R1 represents a 5- or 6-membered heteroaryl with one unsubstituted position by treatment with a chlorinating reagent such as NCS in the presence of a suitable solvent such as THF at temperatures around RT (Scheme D, step b).
Compounds of structure Ik wherein X and Z represents CH and R4 represents —O—R41 wherein R41 represents (C1-4)alkyl, (C2-4)alkyl which is substituted with one or two hydroxyl, R41aR41bN—(C2-3)alkylene-, wherein R41a and R41b independently represent hydrogen or (C1-4)alkyl; or (C4a)heterocyclyl-X41—, wherein X41 represents a direct bond or (C1-3)alkylene, and wherein the (C4-7)heterocyclyl independently contains one or two ring heteroatoms independently selected from nitrogen and oxygen; wherein said (C4-7)heterocyclyl independently is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl or (C1-4)alkoxy-carbonyl attached to a ring nitrogen atom having a free valency can be prepared by alkylation of compounds of formula Ij wherein X and Z represents CH and R4 represents hydroxyl by treatment with an appropriate halide such as R41—W wherein W represents chlorine or bromine in the presence of a suitable base such as K2CO3 and carrying out the rxn in a suitable solvent such as DMSO at temperatures between 50 and 105° C. (Scheme D, step b).
Compounds of structure Io wherein R1 represents a 1-oxo-(C2-C5)-alkyl substituted phenyl or 5- or 6-membered heteroaryl can be prepared by oxidation of compounds of formula In wherein R1 represents a (C1-C4)-alkyl-hydroxymethyl substituted phenyl or 5- or 6-membered heteroaryl by treatment with an oxidizing reagent such as DMP in the presence of a suitable solvent such as DCM at temperatures around RT (Scheme D, step b).
Compounds of structure Ie can be prepared by Suzuki cross coupling of chlorides of structure Ie wherein R1 represents a chlorine substituted 5- or 6-membered heteroaryl with a (C1-C4)-alkyl boronic acid or boroxine in the presence of a suitable palladium catalyst such as PEPPSI-IPr, in the presence of a suitable base such as K2CO3 and heating in a suitable solvent such as dioxane at temperatures between 115° C. (Scheme D, step c).
Compounds of structure Ip wherein R1 represents a 1-hydroxy-1-methyl-ethyl substituted phenyl or 5- or 6-membered heteroaryl can be prepared by treatment of compounds of formula Io wherein R1 represents an acetyl substituted phenyl or 5- or 6-membered heteroaryl by treatment with a suitable Grignard reagent in the presence of a suitable solvent such as THF at temperatures between 0° C. and RT (Scheme D, step c).
Compounds of structure Ix wherein X and Z represents CH and R4 represents a diol containing substituent (respectively a substituent containing a nitrogen atom having a free valency) can be prepared by acidic deprotection of compounds of structure Ik wherein R4 represents a substituent which contains a ketal protected diol (respectively a substituent containing a Boc protected nitrogen) in the presence of a suitable acid such as aqueous HCl (respectively TFA) and a suitable solvent such as THF (respectively DCM) at temperatures between 0° C. and RT (Scheme D, step c).
Alkylation of the free hydroxyl group in compounds of structure Im wherein R1 represents a hydroxymethyl substituted phenyl or 5- or 6-membered heteroaryl or in compounds of structure In wherein R1 represents a 1-hydroxy-(C2-C3)-alkyl substituted phenyl or 5- or 6-membered heteroaryl with a suitable (C1-C4)-alkyl halide, in the presence of a suitable base such as NaH and in solvents such as THF, DMF or a mixture of both at temperatures between 0° C. and 50° C. may afford compounds of structure Iz (Scheme D, step d).
Compounds of structure Iae wherein R1 represents a R14aR14bN—CH(Me)-, R14aR14bN—CH(Et)-, or R14aR14bN—C(Me)2-substituted phenyl or 5- or 6-membered heteroaryl wherein R14a and R14b independently represent hydrogen, (C1-4)alkyl, hydroxy-(C2-4)alkyl, (C1-3)alkoxy-(C2-4)alkyl; or R14a and R14b together with the nitrogen to which they are attached to form a 4- to 6-membered saturated ring optionally containing one additional ring heteroatom selected from oxygen and nitrogen; and wherein said ring is optionally mono-substituted with (C1-4)alkyl (especially methyl), hydroxy, (C1-4)alkoxy (especially methoxy), or dimethylamino can be prepared following a two-step procedure: (i) chlorination by treatment of compounds of formula In wherein R1 represents a 1-hydroxy-(C2-C3)-alkyl substituted phenyl or 5- or 6-membered heteroaryl with a chlorinating reagent such as SOCl2 in the presence of a suitable solvent such as DCM at temperatures around RT and (ii) consecutive nucleophilic substitution with amines of formula R14aR14bNH wherein R14a and R14b independently represent hydrogen, (C1-4)alkyl, hydroxy-(C2-4)alkyl, (C1-3)alkoxy-(C2-4)alkyl; or R14a and R14b together with the nitrogen to which they are attached to form a 4- to 6-membered saturated ring optionally containing one additional ring heteroatom selected from oxygen and nitrogen; and wherein said ring is optionally mono-substituted with (C1-4)alkyl (especially methyl), hydroxy, (C1-4)alkoxy (especially methoxy), or dimethylamino in the presence of a base such as TEA and a suitable solvent such as DCM at temperatures between 0° C. and RT (Scheme D, step e).
Compounds of structure D-1 can be prepared by chlorination of compounds of structure Ij wherein R4 represents hydroxyl, Y represents CR5 wherein R5 represents hydrogen or (C1-C3)alkyl and one of X and Z or both represents N and the possible other one represents CR5 wherein R5 represents hydrogen or (C1-C3)alkyl, using a neat chlorinating reagent such as POCl3 and heating at temperatures around 85° C. (Scheme D, step f).
Compounds of structure Iv wherein R5 represents hydrogen or (C1-C3)alkyl, one of X and Z or both represents N and the possible other one represents CR5 wherein R5 represents hydrogen or (C1-C3)alkyl and R4 represents —NR42aR42b wherein R42a and R42b independently represent hydrogen, (C1-4)alkyl, (C1-3)alkoxy-(C2-3)alkyl, hydroxy-(C2-3)alkyl, or R42a and R42b together with the nitrogen to which they are attached form a 4- to 7-membered saturated ring optionally containing one further ring heteroatom selected from oxygen and nitrogen, wherein said ring is unsubstituted or mono-substituted with (C1-3)alkyl (especially methyl), or (C1-3)alkoxy (especially methoxy) can be prepared by aromatic nucleophilic substitution of neat amines of structure HNR42aR42b wherein R42a and R42b are defined above on compounds of structure D-1 at temperatures between 100 and 140° C. Alternatively, Buchwald-Hartwig cross coupling conditions can be used by treatment with a suitable palladium catalyst such as RuPhos precatalyst and a suitable ligand such as RuPhos, in the presence of a suitable base such as Cs2C03 and heating in a suitable solvent such as t-BuOH at temperatures around 110° C. (Scheme D, step g).
Compounds of structure Iv wherein R5 represents hydrogen or (C1-C3)alkyl, one of X and Z or both represents N and the possible other one represents CR5 wherein R5 represents hydrogen or (C1-C3)alkyl and R4 represents —O—R41 wherein R41 represents (C1-4)alkyl (especially methyl); (C2-4)alkyl which is substituted with one or two hydroxy (especially 2-hydroxyethyl, 2,3-dihydroxypropyl); R41aR41bN—(C2-3)alkylene- wherein R41a and R41b independently represent hydrogen or (C1-4)alkyl (especially such group is 2-dimethylamino-ethyl); or (C4-7)heterocyclyl-X41—, wherein X41 represents a direct bond or (C1-3)alkylene, and wherein the (C4-7)heterocyclyl independently contains one or two ring heteroatoms independently selected from nitrogen and oxygen; wherein said (C4-7)heterocyclyl independently is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl (especially methyl); and/or (C1-4)alkoxy-carbonyl attached to a ring nitrogen atom having a free valency can be prepared by aromatic nucleophilic substitution of alcohol of structure HOR41 wherein R41 is defined above on compounds of structure D-1 in the presence of a suitable base such as KOH and heating in a suitable solvent such as DMSO at temperatures around 50 (Scheme D, step g).
Compounds of structure Ix wherein R5 represents hydrogen or (C1-C3)alkyl, one of X and Z or both represents N and the possible other one represents CR5 wherein R5 represents hydrogen or (C1-C3)alkyl and R4 represents a diol containing substituent (respectively a substituent containing a nitrogen atom having a free valency) can be prepared by acidic deprotection of compounds of structure Iv wherein R4 represents a substituent which contains a ketal protected diol (respectively a substituent containing a Boc protected nitrogen) in the presence of a suitable acid such as aqueous HCl (respectively TFA) and a suitable solvent such as THF (respectively DCM) at temperatures between 0° C. and RT (Scheme D, step h).
Compounds of structure D-2 can be prepared by Wittig type rxn between compounds of formula Ic wherein R1 represents a formyl substituted phenyl and (methoxymethyl)triphenylphosphonium chloride by treatment with a strong base such as n-butyllithium in the presence of a suitable solvent such as THF at temperatures around −78° C. (Scheme D, step i).
Compounds of structure Iw can be prepared by acidic hydrolysis of enol ether of structure D-2 in the presence of a suitable acid such as aqueous HCl and heating in a suitable solvent such as THF at temperatures around 70° C. (Scheme D, step j).
Compounds of structure Iy wherein R1 represents a R14aR14bN—X14— substituted phenyl, wherein X14 represents a ethylene; and wherein R14a and R14b independently represent hydrogen, (C1-4)alkyl, hydroxy-(C2-4)alkyl, (C1-3)alkoxy-(C2-4)alkyl; or R14a and R14b together with the nitrogen to which they are attached to form a 4- to 6-membered saturated ring optionally containing one additional ring heteroatom selected from oxygen and nitrogen; and wherein said ring is optionally mono-substituted with (C1-4)alkyl (especially methyl), hydroxy, (C1-4)alkoxy (especially methoxy), or dimethylamino can be prepared by reductive amination of compounds of structure Iw with amines of structure R14aR14bNH wherein R14a and R14b are defined above using standard conditions such as treatment with NaBH(OAc)3 in the presence of AcOH and a suitable solvent such as DCM or THF at temperatures around RT (Scheme D, step k).
Compounds of structure Ir to It and Iaf can be prepared according to the synthetic route given in scheme E below.
The chlorine or bromine atom on either R1 or R2 which represent a phenyl or 5- or 6-membered heteroaryl or when X, Y or Z represents C—Cl or C—Br in compounds of structure Iq can be replaced by one hydrogen atom (respectively by one deuterium atom) by catalytic hydrogenation (respectively deuteration) using a suitable catalyst such as Pd/C in the presence of a suitable solvent such as EtOAc, MeOH or a mixture of both and under a hydrogen (respectively a deuterium) atmosphere at temperatures around RT. That transformation provides compounds of structure Ir. Catalytic transfer hydrogenation conditions using for instance ammonium formate can be an alternative procedure (Scheme E, step a).
Compounds of structure Iq wherein R4 represents methoxycarbonyl can be transformed to compounds of formula E-1 by hydrolysis with a suitable base such as LiOH, NaOH or KOH in the presence of water and a suitable organic solvent such as THF, MeOH or EtOH or a mixture of them at temperatures between RT and 50° C. (Scheme E, step b).
Compounds of structure Is can be prepared by amide coupling of carboxylic acids of structure E-1 with amines of structure R43aR43bNH wherein R43a and R43b independently represents hydrogen, (C1-4)alkyl, (C1-3)alkoxy-(C2-3)alkyl, or hydroxy-(C2-3)alkyl using standard amide coupling reagent such as EDC.HCl/HOBt, HATU or PyBOP in the presence of a suitable base such as DIPEA or Et3N and in a suitable solvent such as DCM or DMF at temperatures around RT (Scheme E, step c).
Compounds of structure It can be prepared by reduction of compounds of structure Iq wherein R4 represents methoxycarbonyl by treatment with a suitable reducing reagent such as CaBH4 (formed in situ from NaBH4 and CaCl2) in the presence of a suitable solvent such as EtOH at temperatures between 0° C. and RT (Scheme E, step d).
Compounds of structure Iq wherein R2 represents an acetoxy substituted phenyl or 5- or 6-membered heteroaryl can be transformed to compounds of formula E-2 wherein R2 represents an hydroxy substituted phenyl or 5- or 6-membered heteroaryl by hydrolysis with a suitable base such as LiOH, NaOH or KOH in the presence of water and a suitable organic solvent such as THF, MeOH or EtOH or a mixture of them at temperatures around RT (Scheme E, step e).
Compounds of structure Iaf wherein R2 represents a (C1-4)alkoxy or (C3-6)cycloalkyl-X21— substituted phenyl, wherein X21 represents a —O—, or —(C1-3)alkylene-O—, and wherein the (C3-6)cycloalkyl independently contains one optional ring oxygen can be prepared by O-alkylation of compounds of structure E-2 wherein R2 represents an hydroxy substituted phenyl with halogenide of formula R2a—X wherein X represents chlorine or bromine and R2a represents (C1-4)alkyl, (C3-6)cycloalkyl or (C3-6)cycloalkyl-(C1-3)alkylene-, in the presence of a suitable base such as NaH or K2CO3 and in solvents such as THF, DMF or a mixture of both at temperatures between 0° C. and 100° C. (Scheme E, step f).
Compounds of structure Iaa, Iab, Iac, Iad, Iah, Iai and Iaj can be prepared according to the synthetic route given in scheme F below.
Compounds of structure Iah wherein R1 represents a hydroxy substituted phenyl or 5- or 6-membered heteroaryl can be prepared by hydrolysis of the acetyl protecting group (respectively by cleavage of the benzyl protecting group) on compounds of formula Ic wherein R1 represents a suitable acetoxy (respectively benzyloxy) substituted phenyl or 5- or 6-membered heteroaryl with a suitable base such as LiOH, NaOH or KOH in the presence of water and a suitable organic solvent such as THF, MeOH or EtOH or a mixture of them (respectively by catalytic hydrogenation using a suitable catalyst such as palladium hydroxide on carbon under a hydrogen atmosphere in the presence of a suitable solvent such as EtOAc) at temperatures around RT (Scheme F, step a).
Alkylation of the free hydroxyl group in compounds of structure Iah wherein R1 represents a hydroxy substituted phenyl or 5- or 6-membered heteroaryl with a suitable halide of structure R15—X wherein X represents bromine or chlorine and R15 represents (C1-C4)-alkyl, hydroxy-(C2-3)alkyl, (C1-4)alkoxy-(C2-3)alkyl, (C3-6)cycloalkyl, or (C3-6)cycloalkyl-(C1-3)alkyl in the presence of a suitable base such as NaH or K2CO3 and in solvents such as THF, DMF or a mixture of both at temperatures between 0° C. and 80° C. may afford compounds of structure Iai wherein R1 represents a (C1-4)alkoxy, hydroxy-(C2-3)alkoxy, or (C3-6)cycloalkyl-X12— substituted phenyl or 5- or 6-membered heteroaryl, wherein X12 represents a —O—, or —(C1-3)alkylene-O—, and wherein the (C3-6)cycloalkyl independently contains one optional ring oxygen (Scheme F, step b). Alternatively, alkylation of the free hydroxyl group in compounds of structure Iah wherein R1 represents a hydroxy substituted phenyl or 5- or 6-membered heteroaryl can be achieved using Mitsunobu conditions by treatment with a suitable alcohol of structure R15—OH wherein R15 represents (C1-C4)-alkyl, hydroxy-(C2-3)alkyl, (C1-4)alkoxy-(C2-3)alkyl, (C3-6)cycloalkyl, or (C3-6)cycloalkyl-(C1-3)alkyl and for instance a (cyanomethylene)trialkyl phosphorane reagent in the presence of a suitable solvent such as toluene at temperatures around 110° C. (Scheme F, step b). A possible protective group on the substituent R15 can be consecutively cleaved by standard deprotection conditions to provide compounds of structure Iaj. Treatment for instance by TBAF in THF at temperatures around RT can lead to deprotection of TBDMS protected alcohol.
Compounds of structure Iaa wherein R1 represents an amino substituted phenyl can be prepared by reduction of compounds of formula Ic wherein R1 represents a nitro substituted phenyl by catalytic hydrogenation for instance using a suitable catalyst such as Pd/C under a hydrogen atmosphere in the presence of a suitable solvent such as EtOAc at temperatures around RT (Scheme F, step c).
Compounds of structure Iab wherein R1 represents a bromine substituted phenyl can be prepared by a Sandmeyer type rxn of compounds of formula Iaa wherein R1 represents an amino substituted phenyl using standard conditions such as treatment with NaNO2 in aq. HBr at temperatures around −20° C. and consecutive treatment with CuBr at temperatures around 60° C. (Scheme F, step d).
Compounds of structure Iac wherein R1 represents a R14aR14bN—X14— substituted phenyl wherein X14 represents 1,3-prop-1-ynylene; and wherein R14a and R14b independently represent (C1-4)alkyl, (C1-3)alkoxy-(C2-4)alkyl; or R14a and R14b together with the nitrogen to which they are attached to form a 4- to 6-membered saturated ring optionally containing one additional ring heteroatom selected from oxygen and nitrogen; and wherein said ring is optionally mono-substituted with (C1-4)alkyl (especially methyl), (C1-4)alkoxy (especially methoxy), or dimethylamino can be prepared by Sonogashira type cross-coupling of bromides of formula Iab wherein R1 represents a bromine substituted phenyl with R14aR14bN—CH2—C—CH wherein R14a and R14b are defined above, in the presence of a suitable palladium catalyst such as bis(tri-tert-butylphosphine)paladium(0), in the presence of a suitable copper catalyst such as copper iodide, in the presence of a suitable base such as DBU and heating in a suitable solvent such as THF at temperatures around 70° C. (Scheme F, step e).
Compounds of structure Iad wherein R1 represents a R14aR14bN—X4— substituted phenyl wherein X14 represents 1,3-propylene; and wherein R14a and R14b independently represent (C1-4)alkyl, (C1-3)alkoxy-(C2-4)alkyl; or R14a and R14b together with the nitrogen to which they are attached to form a 4- to 6-membered saturated ring optionally containing one additional ring heteroatom selected from oxygen and nitrogen; and wherein said ring is optionally mono-substituted with (C1-4)alkyl (especially methyl), (C1-4)alkoxy (especially methoxy), or dimethylamino can be prepared by reduction of the acethylenic group in compounds of formula Iac wherein R1 represents a R14aR14bN—X14— substituted phenyl wherein X14 represents 1,3-prop-1-ynylene; and wherein R14a and R14b are defined above using standard conditions such as catalytic hydrogenation with a suitable catalyst such as Pd/C and in the presence of a suitable solvent such as EtOAc and under a hydrogen atmosphere (Scheme F, step f).
If not commercially available, amines of structure BB-4 can be prepared according to the synthetic route given in scheme G below.
Compounds of structure G-2 wherein R1 represents an unsubstituted, mono-, di- or tri-substituted phenyl or 5- or 6-membered heteroaryl can be prepared by Buchwald-Hartwig cross coupling of halides of structure R1—X wherein X represents iodine, bromine or chloride and R1 represents an unsubstituted, mono-, di- or tri-substituted phenyl or 5- or 6-membered heteroaryl with an amine of structure G-1 in the presence of a suitable palladium catalyst such as Pd2(dba)3 and a ligand such as BINAP, in the presence of a suitable base such as sodium tert-butoxide and heating in a suitable solvent such as toluene at temperatures between 100° C. and 110° C. (Scheme G, step a).
Alternatively, compounds of structure G-2 wherein R1 represents an unsubstituted, mono-, di- or tri-substituted phenyl or 5- or 6-membered heteroaryl can be prepared by aromatic nucleophilic substitution of amines of structure G-1 on activated halides of structure R1—X wherein X represents fluorine or chlorine and R1 represents a suitable mono-, di- or tri-substituted phenyl or 5- or 6-membered heteroaryl in the presence of a suitable base such as K2CO3 and heating in a suitable solvent such as DMSO at temperatures between 60° C. and 110° C. (Scheme G, step a).
Cleavage of the ketal protecting group in compounds of structure G-2 by acidic hydrolysis in the presence of a suitable acid such as aq. HCl and heating in a suitable solvent such as THF at temperatures around 70° C. may afford ketones of structure G-3 (Scheme G, step b).
Transformation of ketones of structure G-3 to amines of structure BB-4 can be achieved by reductive amination with for instance aq. ammonia under catalytic hydrogenation conditions using a suitable catalyst such as Pd/C in the presence of a suitable solvent such as dioxane under a hydrogen atmosphere at temperatures around RT (Scheme G, step c).
Compounds of structure G-5 wherein R1 represents an unsubstituted, mono-, di- or tri-substituted phenyl or 5- or 6-membered heteroaryl can be prepared by aromatic nucleophilic substitution of amines of structure G-4 on activated halides of structure R1—X wherein X represents fluorine or chlorine and R1 represents a suitable mono-, di- or tri-substituted phenyl or 5- or 6-membered heteroaryl in the presence of a suitable base such as K2CO3 and heating in a suitable solvent such as DMSO at temperatures between 60° C. and 110° C. (Scheme G, step d).
Compounds of structure G-5 wherein R1 represents a mono-, di- or tri-substituted phenyl which is substituted by one methyl group can be prepared following a four-step procedure: (i) aromatic nucleophilic substitution of amines of structure G-4 on halides of structure R1—X wherein X represents fluorine or chlorine and R1 represents a suitable mono-, di- or tri-substituted phenyl which is substituted by one formyl group in the presence of a suitable base such as K2CO3 and heating in a suitable solvent such as DMSO at temperatures between 60° C. and 110° C. and (ii) consecutive reduction of the benzaldehyde derivative by treatment with a suitable reducing reagent such as NaBH4 in the presence of a suitable solvent such as MeOH at temperatures between 0° C. and RT and (iii) consecutive acetylation of the resulting benzyl alcohol by treatment with acetyl chloride in the presence of a suitable base such as TEA and in a suitable solvent such as DCM at temperatures between 0° C. and RT and (iv) final catalytic hydrogenation of the resulting benzyl ester with a suitable catalyst such as Pd/C in the presence of a suitable solvent such as EtOAc, MeOH or mixture thereof and under a hydrogen atmosphere at temperatures around RT (Scheme G, step d).
Cleavage of the Boc protecting group in compounds of structure G-5 can be performed using a suitable acid such as HCl or TFA in the presence of a suitable solvent such as dioxane, MeOH or DCM at temperatures around RT to afford amines of structure BB-4 (Scheme G, step e).
All temperatures are stated in ° C. Commercially available starting materials were used as received without further purification. If not explicitly indicated as having a specific absolute configuration, example compounds or intermediates that are chiral are in general prepared as a racemic mixture of two enantiomers, even if the corresponding example compound's name or precursor's name is not preceded with the mention rac. Relative configuration is indicated for example as (R*,R*) meaning that the two respective absolute configurations are either (R,R) or (S,S); likewise, (R*,S*) indicates a relative configuration of either (R,S) or (S,R).
Compounds described in the invention are characterized by LC-MS data (retention time tR is given in min) and/or NMR using the conditions described below.
Dionex Ultimate 3000 system with Dionex HPG-3200RS binary pump, Thermo MSQ Plus MS detector and Dionex DAD-3000RS PDA detector.
Eluents (acidic conditions): A: H2O+0.04% TFA; B: MeCN; gradient: 5% B→95% B; runtime: 1.5 min; flow: 4.5 mL/min; detection: UV/Vis+MS
Column Agilent Zorbax SB-aq, 4.6×50 mm, 3.5 μm
Bruker Avance HD spectrometer equipped with a 500 MHz Ultrashield™ Magnet and a 5 mm DCH cryoprobe or Bruker Avance II spectrometer equipped with a 400 MHz Ultrashield™ Magnet and a BBO 5 mm probehead. Chemical shifts (δ) are reported in parts per million (ppm) relative to proton resonances resulting from incomplete deuteration of the NMR solvent, e.g. for dimethylsulfoxide δ(H) 2.49 ppm, for chloroform δ(H) 7.24 ppm. The abbreviations s, d, t, q and m refer to singlet, doublet, triplet, quartet, multiplet, respectively and br to broad. Coupling constants J are reported in Hz.
The compounds were purified by either column chromatography on silica-gel and/or prep. LC-MS using the conditions described below.
Column chromatography (CC) was performed using prepacked cartridges (SNAP Ultra™, SNAP KP-SIL™, SNAP KP-NH™, Isolute™ Silica II or Isolute™ NH2) from Biotage.
Gilson 333/334 Prep-Scale HPLC pump equipped with Gilson LH215 autosampler, Dionex SRD-3200 degasser, Dionex ISO-3100A make-up pump, Dionex DAD-3000 DAD detector and Thermo MSQ Plus Single Quadrupole MS detector. Flow: 75 mL/min. Detection: UV/Vis and/or MS.
Additional informations for the purification are summerized in the table below using following explanations:
XBridge: column Waters XBridge C18, 10 μm, 30×75 mm
Acidic: eluant: A=H2O with 0.5% HCOOH, B=MeCN
Basic: eluant: A=H2O with 0.125% NH4OH, B=MeCN
Very lipophilic gradient: 50% B→95% B over 4 min then 95% B over 2 min
Lipophilic gradient: 30% B→95% B over 4 min then 95% B over 2 min
Normal gradient: 20% B→95% B over 4 min then 95% B over 2 min
Polar gradient: 10% B→95% B over 4 min then 95% B over 2 min
Very polar gradient: 5% B→50% B over 3 min then 50% B→95% B over 1 min and finally 95% B over 2 min
To a suspension of 4-chloro-3-nitro-2-pyridone (1.0 g, 5.7 mmol) and silver carbonate (1.9 g, 6.9 mmol) in hexane (17 mL) was added Mel (0.72 mL, 11.5 mmol). The rxn mixture was heated to 80° C. for 1h and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc to give the title compound as white solid.
LC-MS: tR=0.82 min
1H NMR (400 MHz, DMSO-d6) δ:8.41 (d, J=5.6 Hz, 1H), 7.50 (d, J=5.6 Hz, 1H), 4.02 (s, 3H)
To a suspension of 4-chloro-3-nitro-2-pyridone (1.0 g, 5.7 mmol) and K2CO3 (1.6 g, 11.5 mmol) in DMA (5 mL) was added Mel (0.72 mL, 11.5 mmol). The rxn mixture was heated to 45° C. and stirred for 1h. It was quenched with H2O, acidified to pH 5 with a 25% aq. soln. of HCl and extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo.
LC-MS: tR=0.60 min; [M+H]+: 189.15
1H NMR (400 MHz, DMSO-d6) δ:8.10 (d, J=7.4 Hz, 1H), 6.70 (d, J=7.4 Hz, 1H), 3.55 (s, 3H)
A suspension of 4,6-dichloro-5-nitropyrimidine (2.0 g, 10.2 mmol) in anh. MeOH (37 mL) was cooled to 0° C. and NaOMe (579 mg, 10.2 mmol) was portionwise added over 10 min. The rxn mixture was stirred for 30 min and filtered. The filtrate was concentrated in vacuo and the crude was purified by CC using Hept/EtOAc.
LC-MS: tR=0.75 min
1H NMR (400 MHz, DMSO-d6) δ:8.93 (s, 1H), 4.14 (s, 3H)
A suspension of methyl-heteroarene (1 eq) in chlorobenzene (4 mL/mmol) was heated to 50° C. and NBS (1.3 eq) was dropwise added at 50° C. The flask was purged with argon and AIBN (0.1 eq) was added in one portion. The rxn mixture was heated to 80° C. and stirred for 5h (see Table 1). After cooling to RT, the mixture was diluted with Et2O and washed with a 1M aq. soln. of HCl (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
1H NMR (400 MHz,
To a soln. of 4-trifluoromethyl-pyridin-3-yl-methanol (419 mg, 2.3 mmol) in DCM (7 mL) was added SOCl2 (0.84 mL, 11.6 mmol). The rxn mixture was stirred for 1h at RT, quenched with a 10% aq. soln. of Na2CO3 and extracted with DCM (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
LC-MS: tR=0.79 min, [M+MeCN+H]+: 237.05
1H NMR (400 MHz, DMSO-d6) δ: 9.00 (s, 1H), 8.86 (dd, J1=0.5 Hz, J2=5.1 Hz, 1H), 7.81 (d, J=5.1 Hz, 1H), 4.95 (s, 2H)
The appropriate methylpyridine (1 eq) was dissolved in a 1M soln. of bromine in acetic acid (1 mL/mmol) and the solution was stirred ON at RT and for 6h at 80° C. (see Table 2). The mixture was basified with a 1M aq. soln. of NaOH and extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude dibromo product was dissolved in THF (4 mL/mmol) and DIPEA (1.05 eq) and diethyl phosphite (1.05 eq) were sequentially added at 0° C. The mixture was stirred for 10 min at 0° C. and ON at RT. It was quenched with water and extracted with EtOAc (3×). The combined org. phases were washed with a sat. aq. soln. of NH4Cl and brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
1H NMR (400 MHz,
To a suspension of carboxylic acid (1 eq) in anh. THF (5 mL/mmol) was added at −10° C. 4-methylmorpholine (1.8 eq) and ethyl chloroformate (1.5 eq). The mixture was stirred for 30 min at −10° C. and NaBH4 (3 eq) was added in one portion. It was warmed to 0° C. and MeOH (3 mL/mmol) was added dropwise (see Table 3). The rxn mixture was stirred for 1h at 0° C. and for 1h at RT. It was quenched with water, acidified with a 1M aq. soln. of HCl until pH 4 and extracted with n-BuOH (3×). The combined org. phases were dried and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc/MeOH.
To a soln. of alcohol (1 eq) in DCM (5 mL/mmol) was added SOCl2 (1.5 to 2.5 eq) at 0° C. The rxn mixture was stirred for 2h at RT (see Table 4) and partitioned between EtOAc and a sat. aq. soln. of NaHCO3. The org. phase was washed with a sat. aq. soln. of NaHCO3 (1×) and brine (1×), dried over MgSO4 and concentrated in vacuo.
1H NMR (400 MHz,
To a soln. of methyl 4,6-dichloropyridazine-3-carboxylate (550 mg, 2.66 mmol) in anh. THF (13 mL) was added dropwise at 0° C. a 25% soln. of NaOMe in MeOH (0.638 mL, 2.79 mmol). The rxn mixture was stirred ON at RT and poured onto a 1M aq. soln. of HCl. The soln. was neutralized with a sat. aq. soln. of NaHCO3 and extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
LC-MS: tR=0.54 min. [M+H]+: 203.14
To a soln. of 6-chloro-4-methoxy-pyridazine-3-carboxylic acid methyl ester (120 mg, 0.592 mmol) in anh. EtOH (4.7 mL) was added CaCl2 (20 mg, 0.178 mmol) and the rxn mixture was cooled to −10° C. NaBH4 (56 mg, 1.48 mmol) was added portionwise and the mixture was stirred for 1.5 h at −10° C. and for 30 min at RT. It was quenched at 0° C. with water and EtOH was evaporated off. The residue was partitioned between EtOAc and water and the aq. phase was further extracted with EtOAc (2×). The combined org. phases were washed with brine (lx), dried over MgSO4 and concentrated in vacuo.
LC-MS: tR=0.40 min, [M+H]+: 175.20
To a soln. of (6-Chloro-4-methoxy-pyridazin-3-yl)-methanol (73 mg, 0.393 mmol) in DCM (1.97 mL) was added SOCl2 (0.043 mL, 0.59 mmol) at 0° C. The rxn mixture was stirred for 2h at RT and partitioned between EtOAc and a sat. aq. soln. of NaHCO3. The org. phase was washed with a sat. aq. soln. of NaHCO3 (1×) and brine (lx), dried over MgSO4 and concentrated in vacuo.
LC-MS: tR=0.63 min, [M+H]+: 193.13
To a soln. of 4,6-dichloropyridazine-3-carboxylic acid methyl ester (500 mg, 2.42 mmol) in anh. THF (12 mL) was added dropwise at 0° C. a 2M soln. of lithium isopropoxide in THF (1.27 mL, 2.54 mmol). The rxn mixture was stirred for 30 min at 0° C. and poured into a 1M aq. soln. of HCl. The aq. soln. was neutralized with a sat. aq. soln. of NaHCO3 and extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
LC-MS: tR=0.82 min, [M+H]+: 259.12
To a soln. of 6-chloro-4-isopropoxy-pyridazine-3-carboxylic acid isopropyl ester (80 mg, 0.309 mmol) in anh. EtOH (4.6 mL) was added CaCl2) (10 mg, 0.093 mmol) and the rxn mixture was cooled to −10° C. NaBH4 (29 mg, 0.773 mmol) was added portionwise and the mixture was stirred for 30 min at −10° C. and for 1h min at RT. It was quenched at 0° C. with water and EtOH was evaporated off. The residue was partitioned between EtOAc and water and the aq. phase was further extracted with EtOAc (2×). The combined org. phases were washed with brine (lx), dried over MgSO4 and concentrated in vacuo.
LC-MS: tR=0.55 min, [M+H]+: 203.14
To a soln. of carboxylic acid (1 eq) in anh. MeOH (4 mL/mmol) was added AcCl (3 eq) and the rxn mixture was stirred for 2.5 h at 80° C. (see Table 5). MeOH was evaporated off and the residue was partitioned between a sat. aq. soln. of NaHCO3 and EtOAc. The org. phase was washed with a 10% aq. soln. of Na2CO3 (1×) and with brine (1×), dried over MgSO4 and concentrated in vacuo.
An oven dried flask was charged with 3-chloropyrazine-2-carboxylic acid ethyl ester (500 mg, 2.63 mmol), PEPPSI-IPr (18 mg, 0.026 mmol) and CPhos (12 mg, 0.026 mmol). The flask was evacuated and refilled with argon (3×) and toluene (5 mL) was added. The rxn mixture was cooled to 0° C. and a 0.5M soln. of 2-propyl zinc bromide in THF (6.83 mL, 3.41 mmol) was added dropwise. The rxn mixture was stirred for 72h at RT and partitioned between half sat. brine and DCM. The org. phase was dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
LC-MS: tR=0.74 min, [M+H]+: 195.18
To a soln. of methyl 2,4-difluoro-6-hydroxybenzoic acid methyl ester (200 mg, 1.01 mmol) and 2-propanol (0.116 mL, 1.51 mmol) in toluene (1.5 mL) was added a 1M soln. of (tributylphosphoranylidene)acetonitrile in toluene (2.02 mL, 2.02 mmol) under argon. The rxn mixture was heated to 110° C. and stirred for 2h. It was quenched with water and extracted with DCM (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
LC-MS: tR=0.89 min, [M+H]+: 231.10
To a soln. of methyl ester (BB-3A) (1 eq) in anh. EtOH (15 mL/mmol) was added CaCl2 (0.3 eq) and the rxn mixture was cooled to −10° C. NaBH4 (2.5 eq) was added portionwise and the mixture was stirred for 30 min at −10° C. and for a given time at a given temperature (see Table 6). It was quenched at 0° C. with water and EtOH was evaporated off. The residue was partitioned between EtOAc and water and the aq. phase was further extracted with EtOAc (2×). The combined org. phases were washed with brine (lx), dried over MgSO4 and concentrated in vacuo.
To a of methyl or ethyl ester (1eq) in anh. THF (4.5 to 7 mL/mmol) was added dropwise at 0° C. a 2.4 M soln. of LiAlH4 in THF (1 eq). The n mixture was stirred for 1.5 h at 000(see Table 6), quenched with a sat. aq. soln. of NH4Cl and extracted with EtOAc (3×). The combined org. phases were dried over MgSO4 and concentrated in vacuo. When necessary the crude was purified by CC using EtOAc.
1H NMR (400 MHz,
To a solution of the appropriate amine (1eq) and the appropriate fluoroarene (1.1 eq) in DMSO (0.9 mL/mmol) was added K2CO3(2 eq) and the mixture was heated to 105° C. and stirred for 18h (see Table 7). It was quenched with water and extracted with DCM. The org. phase was washed with water (5×) and brine (1×), dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH.
A suspension of intermediate BB-4A (1 eq) in anh. MOH (2 mL/mmol) was cooled to 0° C. and NaBH4(1.3- to 1.5 eq) was added portionwise at 0° C. (see Table 8). Then mixture was stirred for 1h at 0° C. to reach completion. It was carefully quenched by dropwise addition of water at 0° C. and extracted with EtOAc. The org. phase was washed with water and brine, dried over MgSO4 and concentrated in vacuo.
A solution of intermediate BB31-4(1 eq) and TEA (1.5 eq) in DCM (0.5 mL/mmol) was cooled to 0° C. and AcCl (1.5 eq) was added dropwise at 0° C. (see Table 9). The rxn mixture was stirred for 1 h at 0° C. to reach completion. It was diluted with DCM and washed with a 10% solution of citric acid (2×), with a sat. solution of NaHCO3 (2×) and with brine (1×). The org. phase was dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
Intermediate BB-40(1 eq) was dissolved in a mixture of MeOH (6 mL/mmol) and EtOAc (2 mL/mmol) and the flask was evacuated three times and refilled with nitrogen. Wet Pd/C (0.08 eq) was added and the flask was evacuated and refilled three times with hydrogen. The suspension was stirred under a hydrogen atmosphere for 3h (see Table 10) and filtered over a pad of Celite. The cake was washed with EtOAc and MeOH and the filtrate was concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a solution of intermediate BB-4D or BB-4A (1 eq) in DCM (4 mL/mmol) was added dropwise TFA (1 mL/mmol) and the rxn mixture was stirred for 1h to 18h at RT (see Table 11). It was basified with a 1M solution of NaOH until pH 12-13 and extracted with DCM (3×). The combined org. phases were dried over MgSO4 and concentrated in vacuo.
To a mixture of the appropriate amine G-1 (1 eq), the appropriate halide (1.2 eq) and sodium tert-butoxide (2 eq) in toluene (3 mL/mmol) under N2, was added BINAP (0.2 eq) and Pd2(dba)3 (0.1 eq) (see Table 12). The rxn mixture was flushed with N2, heated to 100° C. in a sealed vial and stirred for 24h. It was partitioned between water and EtOAc and the org. phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
Toa soln. of ketal intermediate G-2 (1 eq) in anh. THF (3 mL/mmol) was added a 1M aq. sol. of HCl (2 mL/mmol) at RT (see Table 13). The rxn mixture was heated to 70° C. and stirred for 24h. It was quenched with a sat. aq. soln. of NaHCO3 and extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a soln. of ketone intermediate G-3 (1 eq) in dioxane (9.1 mL/mmol) was added a 25% aq. soln. of NH4OH (38 eq) and H2O (0.35 mL/mmol). The flask was evacuated three times and refilled with nitrogen. Wet Pd/C (0.06 eq) was added and the flask was evacuated and refilled three times with hydrogen. The suspension was stirred under a hydrogen atmosphere for 24h (see Table 14) and filtered over a pad of Celite. The cake was washed with dioxane and MeOH and the filtrate was concentrated in vacuo. The crude was purified by CC using DCM/MeOH.
A soln. of the appropriate alcohol (1 eq) and bis(pentafluorophenyl)carbonate (1.2 eq) in MeCN (0.55 mL/mmol) was cooled to 0° C. and Et3N (3.2 eq) was added dropwise. The rxn mixture was stirred ON allowing the temperature to reach RT (see Table 15). The mixture was concentrated in vacuo and the residue was purified by CC using DCM/MeOH.
1H NMR (400 MHz,
The carbonic acid pentafluorophenyl ester 3-trifluoromethyl-oxetan-3-yl ester (BB-8-3) was prepared according to Med. Chem. Commun., 2013, 4, 95.
To a soln. of 2-fluoro-6-morpholinoaniline (100 mg, 0.51 mmol) in anh. MeCN was added tert-butyl nitrite (0.121 mL, 1.02 mmol) and copper (II) bromide (137 mg, 0.612 mmol). The rxn mixture was stirred for 30 min at RT and partitioned between water and EtOAc. The aq. phase was washed with EtOAc (2×) and the combined org. phases were washed with brine (1×), dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc and additionally by prep. LC-MS using method 2.
LC-MS: tR=0.97 min, [M+H]+: 260.05
CDI (1228 mg, 7.34 mmol) was added to a soln. of isobutyric acid hydrazide (500 mg, 4.9 mmol) in anh. dioxane (21 mL) and the rxn mixture was heated at 85° C. and stirred ON. Dioxane was evaporated off and the residue was partitioned between water and EtOAc. The org. phase was washed with brine (1×), dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
LC-MS: tR=0.49 min, [M+MeCN+H]+: 170.27
1H NMR (400 MHz, DMSO-d6) δ:12.05 (m, 1H), 2.86 (m, 1H), 1.19 (d, J=6.9 Hz, 6H)
To a soln. of 3,4-dichloro-2-methylpyridine (228 mg, 1.3 mmol) in MeOH (6.7 mL) was added a 25% soln. of NaOMe in MeOH (3.5 mL, 15.3 mmol) and the soln. was heated to 65° C. for 18h. It was partitioned between DCM and water and the org. phase was washed with brine (lx), dried over MgSO4 and concentrated in vacuo to give the title compound as white solid.
LC-MS: tR=0.38 min, [M+H]+: 158.43
1H NMR (500 MHz, DMSO) δ: 8.28 (d, J=5.6 Hz, 1H), 7.07 (d, J=5.7 Hz, 1H), 3.92 (s, 3H), 2.51 (s, 3H)
To a soln. of 4-amino-3-methoxypyridine (905 mg, 7 mmol) in MeCN (20 mL) was added N-bromosuccinimide (1384 mg, 7.7 mmol) and the soln. was stirred for 1h at RT. It was quenched with a sat. aq. soln. of Na2S2O3 and extracted with EtOAc. The org. phase was washed with a sat. aq. soln. of NaHCO3 (5×) and brine (lx), dried over MgSO4 and concentrated in vacuo to give the title compound as brown oil.
LC-MS: tR=0.38 min, [M+H]+: 203.17
1H NMR (500 MHz, DMSO) δ: 7.98 (s, 1H), 7.89 (s, 1H), 5.87 (s, 2H), 3.86 (s, 4H)
To a soln. of 3-bromo-5-methoxy-pyridin-4-ylamine (1140 mg, 5.61 mmol) and 2,6-lutidine (1.33 mL, 11.20 mmol) in DCM (40 mL) was added dropwise a soln. of methyl chloroformate (0.482 mL, 6.18 mmol) in DCM (5 mL) at 0° C. The rxn mixture was allowed to warm to RT and stirred for 18h. Additional amount of 2,6-lutidine (2.67 mL, 22.5 mmol) and methylchloroformate (0.876 mL, 11.2 mmol) was added at 0° C. and the rxn mixture stirred for 1h at RT. It was quenched with a sat. aq. soln. of NaHCO3 and extracted with DCM (2×). The combined org. phases were dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
LC-MS: tR=0.62 min, [M+H]+: 261.14
1H NMR (400 MHz, DMSO) δ: 9.23 (s, 1H), 8.40 (s, 1H), 8.39 (s, 1H), 3.91 (s, 3H), 3.63 (s, 3H)
To a soln. of 1-fluoro/chloro-2-nitro-(hetero)arene (BB-2, 1 eq) and Boc-protected diamine (BB-1, 1 to 1.2 eq) in DMSO (1.5 mL/mmol) was added DIPEA (2 eq) and the soln. was heated at a given temperature for a given time (see Table 16). The rxn mixture was partitioned between EtOAc and water. The org. phase was washed with water (4×) and with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc and/or DCM/MeOH.
To a soln. of intermediate A-1 (1eq) in EtOAc (3 to 3.3 mL/mmol) was added 10% Pd/C moistened with ˜50% water (0.01 to 0.05 eq) and the rxn mixture was hydrogenated under atmospheric pressure for a given time (see Table 17). It was filtered over a pad of celite and the filtrate was concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH.
Toa soln. of intermediate A-2 (1 eq) in MeCN (3.7 mL/mmol) was added CDI (1.2 eq) and the rxn mixture was stirred at a given temperature for a given time (see Table 18). The solvent was evaporated off and the residue was partitioned between EtOAc or DCM and water. The org. phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH.
To a soln. of intermediate A-3 (1eq) in anh. DMF (3.5 to 6 mL/mmol) was added K2CO3(3eq) at RT then reactant BB-3 (1.1 to 2eq) at 0° C. The rxn mixture was allowed to reach RT and stirred at a given temperature for given time (see Table 19). It was quenched with water and extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH or by trituration in a mixture of Hept/EtOAc 1/1 and filtration.
To a soln. of intermediate A-3(1eq) in anh. THF (3 mL/mmol) was added NaH (2eq, as a 60% dispersion in mineral oil) at RT followed by BB-3 (1.2 eq). When necessary in term of solubility, anh. DMF (0.1 to 2 mL/mmol) could be added. The rxn mixture was stirred at a given temperature for a given time (see Table 19), quenched with a sat. soln. of NaHCO3 and extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH
A mixture of BB1-6 (1eq) and BB1-5 (8.3 eq) in DIPEA (2 eq) was heated to 180° C. and stirred for a given temperature (see Table 20). It was partitioned between DCM and water and the org. phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a suspension of intermediate B-1 (1eq) and zinc dust (10eq) in MOH (10 mL/mmol) was added ammonium formate (10 eq) at 000. The rxn mixture was stirred at a given temperature for a given time (see Table 2), filtered over a pad of celite and the filtrate was concentrated in vacuo. The crude was purified by CC using DCM/MeOH.
Intermediates B-3 were prepared using a similar protocol as for the synthesis of intermediates A-3 replacing intermediates A-2 by intermediates B-2 (see Table 22).
Toa soln. of intermediate B-3 (1 eq) and BB-7 (1.5 eq) in toluene (6.8 mL/mmol) was added a 1M soln. of (tributylphosphoranylidene)acetonitrile in toluene (2 eq) under argon. The rxn mixture was heated to 110° C. and stirred for a given time (see Table 23). It was quenched with water and extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc and/or DCM/MeOH. When necessary, an additional purification by prep. LC-MS Method 1 can be performed.
To a soln. of intermediate Ia (1 eq) in DCM (2 to 10 mL/mmol) was added TEA (1.5 to 5 mL/mmol) and the rxn mixture was stirred at RT for a given time (see Table 24). It was quenched with a 1M soln. of NaOH until pH reached 12 to 13 and extracted with DCM (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH.
To a mixture of C-1 (1 eq), BB-8 (1.3 eq) and sodium tert-butoxide (2 eq) in toluene (3 to 10 mL/mmol) under N2, was added BINAP (0.2 eq) and Pd2(dba)3 (0.1 eq). The rxn mixture was flushed with N2, heated at a given temperature and stirred for a given time (see Table 25). It was partitioned between water and EtOAc and the org. phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc. When necessary an additional purification by prep. LC-MS was performed.
To a soln. of C-1 (1 eq) in THF (10 mL/mmol) was added BB-8 (3 eq) and the rxn mixture was stirred for 1h. AcOH (1.1 eq) and NaBH(OAc)3 (3 eq) were added and the rxn mixture was stirred at RT for a given time (see Table 25). It was quenched with a 1M aq. soln. of NaOH and extracted with DCM (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a soln. of C-1 (1 eq) and BB-8 (to 1.1 eq) in DMSO (3 mL/mmol) was added CsF (2 eq). The rxn mixture was heated at a given temperature for a given time (see Table 26) and was partitioned between EtOAc and water. The org. phase was washed with water (3×) and with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
C-1 (1 eq), BB-8 (1.5 eq) and DIPEA (3 eq) were dissolved in anh. DMF (5 mL/mmol) and the mixture was stirred for 5 min at RT. PyBOP (1.8 eq) was added portionwise and the rxn mixture was further stirred at RT for a given time (see Table 26). It was partitioned between EtOAc and a 5% aq. soln. of KHSO4 and the org. phase was washed with a sat. aq. soln. of NaHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
The procedure is similar to method A replacing CsF by K2CO3(2 eq).
The procedure is similar to method B but the resulting open form product is additionally submitted to a cyclodehydration as follows:
The open form product (1 eq) was dissolved in anh. THF and Burgess' reagent (2.5 eq) was added portionwise at RT (see Table 26). The rxn mixture was stirred at 150° C. for 30 min under microwave condition and partitioned between EtOAc and H2. The org. phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
Toa soln. of Ic (1 eq) in MeOH (8 mL/mmol) was added toluene-4-sulfonic acid monohydrate (0.2 eq) and the rxn mixture was heated at 120° C. under microwave condition for a given time (see Table 27). It was concentrated in vacuo and partitioned between EtOAc and a sat. aq. soln. of NaHCO3. The org. phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
Toa soln. of Id (1 eq) in THF (4.5 mL/mmol) was added NCS (1.4 eq) and the rxn mixture was stirred at RT for a given time (see Table 28). It was partitioned between EtOAc and water and the org. phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a stirred soln. of Ic (1eq) in a mixture of DMF (0.5 mL) was added toluene-4-sulfonic acid monohydrate (0.13 eq) and 4-toluenesulfonyhydrazide (1.3eq) followed by sulfolane (0.5 mL) (see Table 29). The mixture was stirred at 100° C. for 1h and cooled to RT. Sodium cyanoborohydride (4eq) was added portionwise and the mixture was stirred at 100° C. for 24h. It was quenched with a sat. aq. soln. of NaHCO3 and extracted 3× with EtOAc. The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by prep. LC-MS using method 3.
To a soln. of C-1 (1 eq) and TEA (3eq) in a given solvent (5 mL/mmol) (see) was added at 0° C. alkyl choroformate or pentafluorophenylcarbonate-8 (1.2eq). The rxn mixture was allowed to warm to RT and stirred at a given temperature for a given time (see Table 30). It was partitioned between DCM and a sat. aq. soln. of NaHCO3. The org. phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH or Hept/EtOAc. If necessary a second purification by prep. L-MS using method 2, 3 or 6 can be performed.
To a soln. of C-1(1 eq) and TEA (3eq) in DCM (5 mL/mmol) was added at 0° C. acid chloride BB1-8 (1 to 1.2 eq). The rxn mixture was stirred at RT for a given time (see Table 31) and partitioned between DCM and a sat. aq. soln. of NaHCO3. The org. phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a soln. of C-1 (1eq) in a mixture of DM (25 mL/mmol) and MOH (50 mL/mmol) were added AcOH (1.2 eq) and aldehyde BB-8 (1.3 eq) followed by NaBH(OAc)3 (1.4 eq) portionwise. The rxn mixture was stirred at RT for a given time (see Table 32). It was quenched with a sat. aq. soln. of NaHCO3 and extracted with DCM (3×). The combined org. phases were dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH.
To a soln. of C-1 (1eq) in MOH (5 mL/mmol) was added BB1-8 (1.1 eq) and the rxn mixture was stirred for 15 min. Triethylsilane (2eq) and indium(III) chloride (0.3 eq) were added and the rxn mixture was stirred at RT for a given time (see Table 32). It was quenched with a sat. aq. soln. of K2CO3 and extracted with DCM (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by prep. LC-MS using method 6.
To a soln. of C-1 (1eq) in MCN (5 mL/mmol) was added K2CO3(4 eq) and BB-8 (5 eq) and the rxn mixture was stirred at 65° C. for a given time (see Table 32). It was partitioned between EtOAc and water and the org. phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH.
To soln. of Ib (1eq) in DCM (4 mL/mmol) was added dropwise at 0° C. a 1M soln. of BBr3 in DCM (3eq). The rxn mixture was allowed to warm to RT and stirred for a given time (see Table 33). The mixture was quenched with chilled H2O and extracted with DCM (3×). The combined org. phases were dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a soln. of Ib (1 eq) in DCM (20 to 35 mL/mmol) was added dropwise at −10° C. a 1M soln. of BBr3 in DCM (2 eq). The rxn mixture was stirred at −10° C. for 30 min, allowed to warm to RT and stirred for a given time (see Table 33). The mixture was quenched with chilled H2, basified with a sat. aq. soln. of NaHCO3 and extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH.
To a stirred soln. of Ij (1 eq) in DMSO (10 mL/mmol) was added K2C3 (2 eq) followed by the corresponding halide (1.1 eq). The rxn mixture was stirred at a given temperature for a given time (see Table 34). It was partitioned between EtOAc and H2. The org. phase was washed with water (3×) and brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or by prep. LC-MS using method 3.
To a mixture of Ie (1 eq), boron species (3 eq) and K2C3(5 eq) in dioxane (4 mL/mmol) under N2, was added PEPPSI-Pr (0.1 eq). The rxn mixture was flushed with N2, heated at a given temperature and stirred for a given time (see Table 35). It was partitioned between water and EtOAc and the org. phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc. When necessary an additional purification by prep. LC-MS was performed.
To a stirred soln. of Ic (1 eq) in MeOH (4 mL/mmol) was added portionwise at 0° C. NaBH4 (2 eq). The rxn mixture was stirred at RT for a given time (see Table 36) and quenched with H2O. It was extracted with DCM (3×) and the combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a stirred soln. of Ic (1 eq) in THF (20 mL/mmol) under argon was added dropwise at 0° C. a 3M soln. of MeMgBr in Et2O (2 eq). The rxn mixture was stirred for a given time (see Table 37) allowing temperature to reach RT. The mixture was cooled to 0° C., quenched with a sat. aq. soln. of NH4C and extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a stirred soln. of In (1eq) in DCM (3 mL/mmol) was added a 15% soln. of DMP in DCM (1.5 eq). The rxn mixture was stirred at RT for a given time (see Table 38). The mixture was quenched with a sat. aq. soln. of NaHCO3 and extracted with DCM (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
The procedure was similar to the one synthesizing compounds of formula In except that reactant Ic were replaced by reactant Io (see Table 39).
Intermediates C-3 were prepared using a similar protocol as for the synthesis of intermediates A-1 replacing amine building blocks BB-1 by amine building blocks BB-4 (see Table 40).
Intermediates C-4 were prepared using a similar protocol (method A) as for the synthesis of intermediates A-2 replacing intermediates A-1 by intermediates C-3 (see Table 41).
Alternatively, intermediates C-4 were prepared using the protocol described below (method B).
To a suspension of intermediate C-3(1 eq) in MeOH (18.7 mL/mmol) was added Zn dust (10 eq) and the rxn mixture was cooled to 0° C. Ammonium formate (10 eq) was added and the rxn mixture was stirred at RT for a given time (see Table 41). It was filtered over a pad of celite and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc and washed with a sat. aq. soln. of NaHCO3. The org. phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
Intermediates C-6 were prepared using a similar protocol as for the synthesis of intermediates A-3 replacing intermediates A-2 by intermediates C-4 (see Table 42).
Intermediates C-5 were prepared using a similar protocol as for the synthesis of intermediates C-1 replacing intermediates Ia by intermediates A-3 (see Table 43).
To a soln. of C-5 (1 eq) in DMSO (1.5 mL/mmol) was added K2CO3(2 eq) and BB-8 (1.2 eq). The rxn mixture was heated at a given temperature for a given time (see Table 44) and was partitioned between DCM and water. The org. phase was washed with water (3×) and with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using EtOAc/MeOH.
Compounds of formula Iq were prepared using similar protocols (method A or B) as for the synthesis of intermediates or examples Ia replacing intermediates A-3 by intermediates C-6 (see Table 45). Alternatively, intermediates or examples Iq were prepared using the protocol described below (method C).
To a soln. of intermediate C-6 (1eq) and BB-3(to 1.5eq) in toluene (3.4 to 6.8 mL/mmol) was added a 1M soln. of (tributylphosphoranylidene)acetonitrile in toluene (2 eq) under argon. The rxn mixture was heated to 110° C. and stirred for a given time (see Table 45). It was quenched with water and extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc and/or DCM/MeOH. When necessary, an additional purification by prep. LC-MS using method 1 or 2 can be performed.
To a soln. of intermediate Iq (1 eq) in EtOH (5 to 12 mL/mmol) was added ammonium formate (2 eq) and 10% Pd/C moistened with ˜50% water (0.05 eq) and the rxn mixture was heated to 65° C. for a given time (see Table 46). It was filtered over a pad of celite and the filtrate was concentrated in vacuo. The crude was purified by CC using EtOAc/MeOH or DCM/MeOH.
To a soln. of intermediate Iq (1 eq) in a mixture of EtOAc (65 mL/mmol) and MOH (89 mL/mmol) was added 10% Pd/C moistened with ˜50% water (0.1 eq) and the rxn mixture was hydrogenated under an atmospheric pressure of deuterium for a given time (see Table 46). It was filtered over a pad of celite and the filtrate was concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
Toa soln. of intermediates Iq (1 eq) in a 1/1/1 mixture of TH/MeOH/water (9 mL/mmol) was added lithium hydroxide hydrate (4 eq). The rxn mixture was heated to 50° C. and stirred for a given time (see Table 47). It was diluted with water and extracted with Et2 (3×). The aq. phase was acidified until pH 2-3 with a 1 M soln. of HCl and extracted with DCM (3×). The combined org. phases were dried over MgSO4 and concentrated in vacuo.
To a soln. of acids of formula E-1 (1 eq) in DMF (4 mL/mmol) was added DIPEA (3 eq) and HATU (1 eq). The rxn mixture was stirred for 5 min at RT and the appropriate amine (1.2 eq) pure or as soln. was added. The rxn mixture was further stirred ON at RT (see Table 48) and diluted with DCM. The org. phase was washed with water and brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a soln. of compounds of formula Iq (1 eq) and CaCl2 (0.3 eq) in EtOH (15 mL/mmol) was added at 0° C. a suspension of NaBH4 (2.5 eq) in EtOH (8 mL/mmol). The rxn mixture was allowed to warm to RT and stirred at that temperature for a given time (see Table 49). It was quenched with water and extracted with DCM (3×). The combined org. phases were dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a stirred soln. of Ic (1eq) in a mixture of DCM (25 mL/mmol), MOH (50 mL/mmol) and AcOH (1.2 eq) was added the appropriate amine (1.3 eq) followed by NaBH(OAc)3 (1.4 eq). The rxn mixture was stirred at RT for a given time (see Table 50) and the volatiles were evaporated in vacuo. The residue was partitioned between DCM and a sat. aq. soln. of NaHCO3. The org. phase was dried over MgSO4 and concentrated in vacuo. The crude was purified by prep. LC-MS using method 4 and 5.
To a stirred soln. of aldehyde Ic (1eq) and the appropriate amine (1.1eq) in THF (4 mL/mmol) was added NaBH(OAc)3(1.5eq). The rxn mixture was stirred at RT for a given time (see Table 50) and partitioned between DCM and a 1M aq. soln. of NaOH. The org. phase was dried over MgSO4 and concentrated in vacuo. The crude was purified by prep. LC-MS using method 2.
A suspension of Ij (1eq) in POCl3(2 mL/mmol) was heated to 85° C. and stirred ON (see Table 51). The rxn mixture was carefully quenched with a ice cold 2M aq. soln. of NaOH and extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
A soln. of D-1(1 eq) in the appropriate amine (mL/mmol) was heated to a given temperature and stirred for a given time (see Table 52). The rxn mixture was diluted with EtOAc and washed with a sat. aq. soln. of NaHCO3 (2×) and with brine. The org. phase was dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To stirred soln. of D-1 (1eq) in DMSO (8 mL/mmol) was added the appropriate alcohol (5 to 10eq) and KOH (2.5 eq). The rxn mixture was heated to a given temperature for a given time (see Table 52). It was diluted with EtOAc and washed with H2O (3×) and brine. The org. phase was dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH.
An oven dried flask was charged with intermediate D-1 (1 eq), the appropriate amine (1.2 eq), Cs2CO3 (2.5 eq) RuPhos precatalyst (0.1 eq) and RuPhos (0.1 eq). The flask was evacuated and refilled with argon (3×) and t-BuOH (17 mL/mmol) was added. The rxn mixture was degassed under vacuum, refilled with argon (3×) and heated to a given temperature and stirred for a given time (see Table 52). It was partitioned between water and EtOAc and the org. phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by prep. LC-MS using method 2 and 5.
A suspension of (methoxymethyl)triphenylphosphonium chloride (1.2 eq) in anh. THF (12.5 mL/mmol) was cooled to −78° C. A1.6 M soln. of n-butyllithium in hexanes (1.2 eq) was dropwise added at −78° C. and the mixture was stirred for 30 min at −78° C. A solution of aldehyde Ic (1eq) in anh. THF (6.25 mL/mmol) was dropwise added at −7800 and the rxn mixture was stirred for a given time (see Table 53) at RT. It was quenched with a sat. aq. soln. of NH4Cl and extracted with DCM (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH and/or by prep. LC-MS using method 1.
To a soln. of enol ether D-2 (1 eq) in anh. THF (8.7 mL/mmol) was added a 5M aq. soln. of HCl (1.8 mL/mmol) and the rxn mixture was heated to 70° C. and stirred for a given time (see Table 54). The mixture was diluted with Et2O and washed with H2O and a sat. aq. soln. of NaHCO3. The org. phase was dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using DCM/MeOH.
To a solution of intermediate Iv (1 eq) in DCM (4 mL/mmol) was added dropwise TFA (1 mL/mmol) and the rxn mixture was stirred at RT for a given time (see Table 55). It was basified with a 1M solution of NaOH until pH 12-13 and extracted with DCM (3×). The combined org. phases were dried over MgSO4 and concentrated in vacuo. The crude was purified by prep. LC-MS using method 4.
To a soln. of ketal Iv or Ik (1 eq) in anh. THF (9 mL/mmol) was added a 25% aq. soln. of HCl (3 mL/mmol) at 0° C. and the rxn mixture was stirred for a given time (see Table 55) at RT. The rxn mixture was quenched with a sat. aq. soln. of NaHCO3 and extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a stirred soln. of Iw (1 eq) in DCM (4 mL/mmol) was added AcOH (1.5 eq) and the appropriate amine (1.1 eq) followed by NaBH(OAc)3 (1.5 eq). The n mixture was stirred at RT for a given time (see Table 56) and partitioned between DCM and a sat. aq. soln. of NaHCO3. The org. phase was dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using EtOAc/MeOH.
To a stirred suspension of alcohol In (1eq) in THF (15 mL/mmol) was added at 0° C. NaH (5 eq). The mixture was stirred for 10 min and the corresponding halide (1.5 eq) was added. The rxn mixture was allowed to reach RT and stirred at a given temperature for a given time (see Table 57). It was quenched with water and extracted with DCM (3×). The combined org. phases were dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH.
To a soln. of intermediate Ic (1 eq) in EtOAc (3 mL/mmol) was added 10% Pd/C moistened with ˜50% water (0.01 eq) and the rxn mixture was hydrogenated under atmospheric pressure for a given time (see Table 58). It was filtered over a pad of celite and the filtrate was concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
A stirred soln. of aniline Iaa (1 eq) in a 48% aq. soln. of HBr (2.7 mL/mmol) was cooled to −20° C. and a soln. of NaNO2 (1 eq) in H2O (0.4 mL/mmol) was dropwise added. The mixture was stirred for 30 min at 0° C. and a soln. of CuBr (0.55 eq) in a 48% aq. soln. of HBr (0.8 mL/mmol) was dropwise added. The rxn mixture was heated to 60° C. and stirred for a given time (see Table 59). The pH was adjusted to around 7 by the addition of a 2M aq. soln. of NaOH and the mixture was extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by prep. LC-MS using method 1.
To a degassed mixture of bromide Iaa (1 eq) and alkyne (1.6 eq) in anh. THF (24 mL/mmol) was added under argon CuI (0.06 eq), bis(tri-tert-butyl phosphine)palladium(0) (0.05 eq) and DBU (1.3 eq). The mixture was heated to 70° C. and stirred for 2h (see Table 60). The volatiles were evaporated off and the residue was purified by prep. L-MS using method 3.
To a soln. of alkyne Iac (1eq) in EtOAc (3 mL/mmol) was added 10% Pd/C moistened with ˜50% water (0.01 eq) and the rxn mixture was hydrogenated under atmospheric pressure for a given time (see Table 61). It was filtered over a pad of celite and the filtrate was concentrated in vacuo. The crude was purified by prep. LC-MS using method 5.
A soln. of alcohol In (1 eq) in DCM (3 mL/mmol) was cooled to 0° C. and thionyl chloride (1.1 eq) was dropwise added. The rxn mixture was stirred for 30 min at RT and the volatiles were evaporated off. The residue was taken in DCM (5 mL/mmol) and TEA (5 eq) followed by the appropriate amine (1.1 eq) were added at 0° C. The mixture was allowed to warm to RT and stirred for a given time (see Table 62). It was diluted with DCM and washed with a 1M aq. soln. of NaOH. The org. phase was dried over MgSO4 and concentrated in vacuo. The crude was purified by prep. LC-MS using method 2 and 5.
To a soln. of carboxylic ester Iq (1 eq) in THF (7.2 mL/mmol) was added a 2M aq. soln. of NaOH (10 eq) and the rxn mixture was stirred at RT for a given time (see Table 63). It was acidified with a 1M aq. soln. of HCl until pH-4-5 and extracted with EtOAc (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a stirred suspension of phenol E-2 (1eq) in THF (15 mL/mmol) was added at 0° C. NaH (5eq). The mixture was stirred for 10 min and the corresponding halide (1.5 eq) was added. The rxn mixture was stirred at a given temperature for a given time (see Table 64). It was quenched with water and extracted with EtOAc (3×). The combined org. phases were dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a stirred soln. of phenol E-2 (1 eq) in anh. DMF (8 mL/mmol) was added K2CO3(2 eq) and the corresponding halide (2eq). The rxn mixture was stirred for a given time and a given temperature (see Table 64). Additional amount of halide (3×2eq) were added to bring the rxn to completion. It was partitioned between EtOAc and H2O and the org. phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified
To a soln. of methyl carbamate BB-10 (1 eq) in MeCN (4.3 mL/mmol) was added K2CO3 (2.2 eq) and the corresponding halide (1.05 eq). The rxn mixture was heated to a given temperature and stirred for a given time (see Table 65). It was filtered and the filtrate was concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
Sodium tert-butoxide (6 eq), BrettPhos precatalyst (0.3 eq) and BrettPhos (0.3 eq) were placed in a sealed cap vial and a soln. of intermediate-2 (3 eq) and amine BB-4 (1eq) in anh. dioxane were added. The rxn mixture was flushed with N2, heated at a given temperature and stirred for a given time (see Table 66). It was quenched with water and extracted with DCM (3×). The combined org. phases were dried over MgSO4 and concentrated in vacuo. The crude was purified by prep. LC-MS using method 1.
To a soln. of intermediate Ib (1 eq) in EtOH (20 mL/mmol) was added 20% palladium hydroxide on carbon (0.1 eq) and the rxn mixture was hydrogenated under atmospheric pressure for a given time (see Table 67). It was filtered over a pad of celite and the filtrate was concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
To a soln. of intermediate Iah (1 eq) and alcohol R15—OH (1 to 1.5eq) in toluene (10 mL/mmol) was added a 1M soln. of (tributylphosphoranylidene)acetonitrile in toluene (2eq) under argon. The rxn mixture was heated to 110° C. and stirred for a given time (see Table 68). It was quenched with water and extracted with DCM (3×). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or DCM/MeOH. When necessary, an additional purification by prep. LC-MS using method 5 can be performed.
To a soln. of Iai (1 eq) in THF (20 mL/mmol) was added dropwise a 1M soln. of TBAF in THF (1.2 eq) and the rxn mixture was stirred at RT for a given time (see Table 69). It was partitioned between EtOAc and a sat. aq. soln. of NaHCO3. The org. phase was dried over MgSO4 and concentrated in vacuo. The crude was purified by prep. LC-MS using method 6.
hC5a DISCO IC50 Assay
Adherent cells (CHO-K1 C5AR1 beta-arrestin cell line, DiscoverX, CA USA) are washed with PBS, detached by incubation with Dissociation Buffer (Gibco Cat #13151-014, 2 ml per 165 cm2 dish) for 3 minutes, then washed with 10 ml PBS (without Mg++ and Ca++) and counted. 7500 cells/384-well are seeded out in 384-well plates (Cell culture plate MTP384 white Polystyrene, Corning, Cat #3570) in 20 μl/well Cell plating medium (F12 HAMs/10% FCS/1% P/S) and incubated at 37° C./5% CO2/24h.
5 μl Antagonist at 6-fold end concentration or DMSO control is added to assay medium and subsequently 5 μl 1-10 nM C5a agonist at 6 fold end concentration. Cells are centrifuged for 1 min at 1000 rpm and incubated for 1.5 hour in at 37° C. Plates are equilibrated at room temperature for several minutes before adding 12 μl/well Detection Reagent (PathHunter Detection Kit, DiscoverX, Cat #93-0001). Plates are centrifuged for 1 min at 1000 rpm and incubated for 45 minutes at RT before being measured on a Fluostar Optima, BMG Labtech. IC50 values are calculated from a serial dilution range of antagonist using inhouse software and given in nmol/l.
The calculated IC50 values may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art. Average IC50 values from several measurements are given as geometric mean values.
Antagonistic activities of exemplified compounds are displayed in Table 70 below.
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/EP2018/051278 | Jan 2018 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2019/051230 | 1/18/2019 | WO | 00 |
