5-5 RING COMPOUNDS FUSED AS C5a INHIBITORS

Abstract

Claim 1: A compound characterized in that it is of formula (1), or a pharmaceutically acceptable salt thereof, wherein: the vertex of ring A1 is selected from the group consisting of N, CH, C(O) and C(R⁴); the vertex of ring A2 is selected from the group consisting of N, CH, and C(R⁴); each of the vertices of ring A3, A⁴, A⁵ and A⁶ is independently selected from the group consisting of CH and C(R⁴); each of the dashed bonds independently indicates a double or single bond;R¹ is selected from the group consisting of -C₁₋₈-alkylene-heteroaryl, -C₁₋₈-alkylene-C₆₋₁₀-aryl, C₁₋₈ alkyl, C₁₋₈ haloalkyl, -C(O)-C₁₋₈ alkyl, -C(O)-aryl C₆₋₁₀, -C(O)-heteroaryl, -C(O)-cycloalkyl C₃₋₆, -C(O)-heterocycloalkyl, -C(O)NR¹ᵃR¹ᵇ, -SO₂-aryl C₆₋₁₀, -SO₂-heteroaryl, -C(O)-alkylene C₁₋₈-O-heteroaryl, -C(O)-alkylene C₁₋₈-O-aryl C₆₋₁₀, -C(O)-alkylene C₁₋₈-O-heterocycloalkyl, -C(O)-alkylene C₁₋₈-O-cycloalkyl -C(O)-alkylene C₁₋₈-C₃₋₆ cycloalkyl and -CO₂R¹ᵃ; The heterocycloalkyl is a 4- to 8-membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S; and the heteroaryl group is a 5- to 10-membered aromatic ring having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S;wherein R¹ᵃ and R¹ᵇ are each independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl; wherein R¹ is optionally substituted with 1 to 5 R⁵ substituents; R²ᵃ and R²ᵉ are each independently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, haloalkyl-O-C₁₋₆, -S-alkyl C₁₋₆, -alkyl C₁₋₆-O-alkyl C₁₋₆, -alkyl C₁₋₆-S-alkyl C₁₋₆, CN, and halogen; R²ᵇ, R²ᶜ, and R²ᵈ are each independently selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, -O-C₁₋₆ haloalkyl, -S-C₁₋₆ alkyl, -O-C₁₋₆ alkyl, -C₁₋₆ alkyl, -S-C₁₋₆ alkyl, cyano, and halogen; Each R³ is independently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, halogen, and hydroxyl, and optionally two R³ groups on the same carbon atom combine to form oxo(=O) or to form a three- to five-membered cycloalkyl ring;each R⁴ is independently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, -O-C₁₋₆ haloalkyl, halogen, cyano, hydroxyl, -S-C₁₋₆ alkyl, -C₁₋₆-O-C₁₋₆ alkyl, -C₁₋₆-S-C₁₋₆ alkyl, -NR⁴ᵃR⁴ᵇ, -CONR⁴ᵃR⁴ᵇ, -CO₂R⁴ᵃ, -COR⁴ᵃ, -OC(O)NR⁴ᵃR⁴ᵇ, -NR⁴ᵃC(O)R⁴ᵇ, -NR⁴ᵃC(O)₂R⁴ᵇ, and -NR⁴ᵃ-C(O)NR⁴ᵃR⁴ᵇ; each R⁴ᵃ and R⁴ᵇ is independently selected from the group consisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl;each R⁵ is independently selected from the group consisting of C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, C₁₋₈ hydroxyalkyl, C₁₋₈ -alkylene-heterocycloalkyl, C₁₋₈ -alkylene-C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl, heterocycloalkyl, halogen, OH, C₂₋₈ alkenyl, C₂₋₈ alkynyl, CN, C(O)R⁵ᵃ, -NR⁵ᵇC(O)R⁵ᵃ, -CONR⁵ᵃR⁵ᵇ, -NR⁵ᵃR⁵ᵇ, -alkylene C₁₋₈-NR⁵ᵃR⁵ᵇ, -S-alkyl C₁₋₆, -alkylene C₁₋₆-O-alkyl C₁₋₆, -alkylene C₁₋₆-S-alkyl C₁₋₆, -OC(O)NR⁵ᵃR⁵ᵇ, -NR⁵ᵃC(O)₂R⁵ᵇ, -NR⁵ᵃ-C(O)NR⁵ᵇR⁵ᵇ, and CO₂R⁵ᵃ; where the heterocycloalkyl group is a 4- to 8-membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S;wherein each R⁵ᵃ and R⁵ᵇ is independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when R⁵ᵃ and R⁵ᵇ are attached to the same nitrogen atom, they combine with the nitrogen atom to form a 5- or 6-membered ring having from 0 to 1 additional heteroatoms as ring vertices selected from N, O, or S; and the subscript n is 0, 1, 2, or 3.

Description

5-5 RING COMPOUNDS FUSED AS C5a INHIBITORS REFERENCES TO RELATED APPLICATIONS

[0001] This application claims a benefit under 35 USC § 119(e) of Provisional US Patent Application No. 62 / 513.025 filed on May 31, 2017, which is incorporated herein in its entirety by reference. DECLARATION CONCERNING RIGHTS TO INVENTIONS MADE UNDER GOVERNMENT-FUNDED RESEARCH AND DEVELOPMENT

[0002] DOES NOT APPLY. REFERENCE TO “LIST OF SEQUENCES”, TABLE, OR LIST OF COMPUTER PROGRAMS ATTACHED ON COMPACT DISC

[0003] DOES NOT APPLY. BACKGROUND OF THE INVENTION

[0004] The complement system plays a central role in the clearance of immune complexes and in immune responses to infectious agents, foreign antigens, virus-infected cells, and tumor cells. Inappropriate or excessive activation of the complement system can lead to detrimental and even life-threatening consequences due to severe inflammation and subsequent tissue destruction. These consequences manifest clinically in various disorders, including septic shock; myocardial injury, as well as intestinal ischemia / reperfusion; graft rejection; organ failure; nephritis; pathological inflammation; and autoimmune diseases.

[0005] The complement system is composed of a group of proteins that are normally present in serum in an inactive state. Activation of the complement system primarily involves three distinct pathways, namely the classical pathway, the alternative pathway, and the lectin pathway (VM Holers, In Clinical Immunology: Principles and Practice, ed. RR Rich, Mosby Press; 1996, 363-391): 1) The classical pathway is a calcium / magnesium-dependent cascade, which The 1935200 of 103 pathway is normally activated by the formation of antigen-antibody complexes. It can also be activated independently of antibodies by the binding of C-reactive protein, forming a complex with the ligand, and by numerous pathogens, including Gram-negative bacteria. 2) The alternative pathway is a magnesium-dependent cascade that is activated by the deposition and activation of C3 on certain susceptible surfaces (e.g., yeast and bacterial cell wall polysaccharides, and certain biopolymeric materials). 3) The lectin pathway involves the initial binding of a mannose-binding lectin and the subsequent activation of C2 and C4, which are common to the classical pathway (Matsushita, M. et al., J. Exp. Med. 176:1497-1502 (1992); Suankratay, C. et al., J. Immunol. 160:3006-3013 (1998)).

[0006] Activation of the complement pathway generates biologically active fragments of complement proteins, e.g., the anaphylatoxins C3a, C4a, and C5a and the membrane attack complexes C5b-9 (MAC), all of which mediate inflammatory responses by affecting leukocyte chemotaxis; activating macrophages, neutrophils, platelets, mast cells, and endothelial cells; and increasing vascular permeability, cytolysis, and tissue injury.

[0007] Complement C5a is one of the most potent pro-inflammatory mediators of the complement system. (Anaphylactic C5a peptide is 100 times more potent, on a molar basis, in eliciting inflammatory responses than C3a.) C5a is the activated form of C5 (190 kDa, molecular weight). C5a is present in human serum at approximately 80 pg / ml (Kohler, PF et al., J. Immunol. 99:1211-1216 (1967)). It is composed of two polypeptide chains, α and β, with approximate molecular weights of 115 kDa and 75 kDa, respectively (Tack, BF et al., Biochemistry 18:1490-1497 (1979)). Biosynthesized as a single-chain molecule, C5 is enzymatically cleaved into a two-chain structure during processing and secretion. After cleavage, the two chains are held together by at least one disulfide bond, as well as non-covalent interactions (Ooi, YM et al., J. Immunol. 124:2494-2498(1980)).

[0008] C5 is cleaved into the fragments C5a and C5b during activation of the complement pathways. The convertase enzymes responsible for C5 activation are multi-subunit complexes of C4b, C2a, and C3b for the classical pathway and of (C3b)2, Bb, and P for the pathway 1935200 of 103 alternative (Goldlust, MB et al., J. Immunol. 113:998-1007 (1974); Schreiber, RD et al, Proc. Natl. Acad. Sci. 75:3948-3952 (1978)). C5 is activated by cleavage at position 74-75 (Arg-Leu) in the α chain. After activation, the 74-amino-acid, 11.2 kD peptide C5a is released from the amino-terminal portion of the α chain. Both C5a and C3a are potent stimulators of neutrophils and monocytes (Schindler, R. et al., Blood 76:1631-1638 (1990); Haeffner-Cavaillon, N. et al., J. Immunol. 138:794-700 (1987); Cavaillon, JM et al., Eur. J. Immunol. 20:253-257 (1990)).

[0009] In addition to its anaphylatoxic properties, C5a induces the chemotactic migration of neutrophils (Ward, PA et al., J. Immunol. 102:93-99 (1969)), eosinophils (Kay, AB et al., Immunol. 24:969-976 (1973)), basophils (Lett-Brown, MA et al., J. Immunol. 117:246-252 1976)), and monocytes (Snyderman, R. et al., Proc. Soc. Exp. Biol. Med. 138:387-390 1971)). Both C5a and C5b-9 activate endothelial cells to express adhesion molecules essential for the sequestration of activated leukocytes, which mediate inflammation and tissue injury (Foreman, KE et al., J. Clin. Invest. 94:1147-1155 (1994); Foreman, KE et al., Inflammation 20:1-9 (1996); Rollins, SA et al., Transplantation 69:1959-1967 (2000)).C5a also mediates inflammatory reactions by causing smooth muscle contraction, increasing vascular permeability, inducing degranulation of basophils and mast cells, and inducing the release of lysosomal proteases and oxidative free radicals (Gerard, C. et al., Ann. Rev. Immunol. 12:775-808 (1994)). In addition, C5a modulates hepatic acute-phase gene expression and enhances the overall immune response by increasing the production of TNF-α, IL-1β, IL-6, IL-8, prostaglandins, and leukotrienes (Lambris, JD et al., In: The Human Complement System in Health and Disease, Volanakis, JE ed., Marcel Dekker, New York, pp. 83-118).

[0010] The anaphylactic and chemotactic effects of C5a are believed to be mediated through its interaction with the C5a receptor. The human C5a receptor (C5aR) is a 52 kDa membrane-bound G protein-coupled receptor, and is expressed on neutrophils, monocytes, basophils, eosinophils, hepatocytes, lung smooth muscle and endothelial cells, and renal glomerular tissues. (Van-Epps, DE et al., J. Immunol. 132:2862-2867 (1984); Haviland, DL et al., J. Immunol. 154:1861-1869 (1995); Wetsel, RA, Immunol. Leff. 44:183-187 (1995); J. Immunol. 155:308-315 (1995); 1935200 of 103 75:3943-3947 (1978); Zwirner, J. et al., Mol. Immunol. 36:877-884 (1999)). The ligand-binding site of C5aR is complex and comprises at least two physically separable binding domains. One binds the C5a amino terminus (amino acids 1-20) and the disulfide-bound core (amino acids 21-61), while the second binds the C5a carboxy-terminal terminus (amino acids 62-74) (Wetsel, RA, Curr. Opin. Immunol. 7:48-53 (1995)).

[0011] C5a plays an important role in inflammation and tissue injury. In cardiopulmonary bypass and hemodialysis, C5a is formed as a result of activation of the alternative complement pathway when human blood comes into contact with the artificial surface of the heart-lung machine or the renal dialysis machine. (Howard, RJ et al., Arch. Surg. 123:1496-1501 (1988); Kirklin, JK et al., J. Cardiovasc. Surg. 86:845-857 (1983); Craddock, PR et al., N. Engl. J. Med. 296:769-774 (1977)). C5a causes increased permeability and capillary edema, bronchoconstriction, pulmonary vasoconstriction, activation of leukocytes and platelets, and infiltration into tissues, particularly the lung (Czermak, BJ et al., J. Leukoc. Biol. 64:40-48 (1998)). Administration of an anti-C5a monoclonal antibody has been shown to reduce cardiopulmonary bypass and cardioplegia-induced coronary endothelial dysfunction (Tofukuji, M. et al., J. Thorac. Cardiovasc. Surg.116:1060-1068 (1998)).

[0012] C5a is also involved in acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and multiple organ failure (MOF) (Hack, CE et al., Am. J. Med. 1989;86:20-26; Hammerschmidt DE et al. Lancet 1980; 1:947949; Heideman M. et al. J. Trauma 1984; 4:1038-1043; Marc, MM, et al., Am. J. Respir. Cell and Mol. Biol., 2004;31:216-219). C5a increases monocyte production of two important proinflammatory cytokines, TNF-α and IL-1. C5a has also been shown to play an important role in the development of tissue injury, and particularly lung injury, in animal models of septic shock. (Smedegard G et al. Am. J. Pathol. 1989; 135:489-497; Markus, S., et al., FASEB Journal (2001), 15:568-570). In sepsis models using rats, pigs, and non-human primates, anti-C5a antibodies administered to the animals prior to treatment with endotoxin or E.coli resulted in a decrease in tissue injury, as well as a decrease in IL-6 production (Smedegard, G. et al., Am. J. Pathol. 135:489-497 (1989); Hopken, U. et al., Eur. J. Immunol. 26:1103-1109 (1996); Stevens, JH et al., J. Clin. Invest. 77:1812-1816 (1986)). More importantly, blockade 4 has been shown. The use of polyclonal anti-C5a antibodies (1935200 of 103 or C5a) significantly improves survival rates in a cecal ligation / puncture model of sepsis in rats (Czermak, BJ et al., Nat. Med. 5:788-792 (1999)). This model shares many aspects of the clinical manifestation of sepsis in humans. (Parker, SJ et al., Br. J. Surg. 88:22-30 (2001)). In the same sepsis model, anti-C5a antibodies were shown to inhibit thymocyte apoptosis (Guo, RF et al., J. Clin. Invest. 106:1271-1280 (2000)) and prevent IOM (Huber-Lang, M. et al., J. Immunol. 166:1193-1199 (2001)). 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, MS et al. J. Clin. Invest. 98:503-512 (1996)). The importance of C5a in immune complex-mediated lung injury was subsequently confirmed in mice (Bozic, CR et al., Science 26:1103-1109 (1996)).

[0013] C5a has been found to be an important mediator of myocardial ischemia-reperfusion injury. Reduction of complement reduced myocardial infarct size in mice (Weisman, HF et al., Science 249:146-151 (1990)), and treatment with anti-C5a antibodies reduced injury in a rat model of hindlimb ischemia-reperfusion (Bless, NM et al., Am. J. Physiol. 276:L57-L63 (1999)). Reperfusion injury during myocardial infarction was also markedly reduced in pigs that were retreated with an anti-C5a monoclonal IgG (Amsterdam, EA et al., Am. J. Physiol. 268:H448-H457 (1995)). A recombinant human C5aR antagonist reduces infarct size in a porcine model of surgical revascularization (Riley, RD et al., J. Thorac. Cardiovasc. Surg. 120:350-358 (2000)).

[0014] C5a-driven neutrophils also contribute to many bullous diseases (e.g., bullous pemphigoid, pemphigus vulgaris, and pemphigus foliaceus). These are chronic, recurrent inflammatory disorders clinically characterized by sterile blisters that appear in the subepidermal space of the skin and mucous membranes. Although autoantibodies against keratinocytes located in the cutaneous basement membranes are thought to underlie the detachment of epidermal basal keratinocytes from the underlying basement membrane, the blisters are also characterized by the accumulation of neutrophils in the upper dermal layers and within the blister cavities. In experimental models, reducing neutrophils or the absence of complement (total or C5-selective) can inhibit the formation of 5 1935200 of 103 subepidermal blisters, even in the presence of high titers of autoantibodies.

[0015] Complement levels are elevated in patients with rheumatoid arthritis (Jose, PJ et al., Ann. Rheum. Dis. 49:747-752 (1990); Grant, EP, et al., J. of Exp. Med., 196(11):1461-1471, (2002)), lupus nephritis (Bao, L., et al., Eur. J. of Immunol., 35(8), 2496-2506, (2005)), and systemic lupus erythematosus (SLE) (Porcel, JM et al., Clin. Immunol. Immunopathol. 74:283-288 (1995)). C5a levels correlate with disease severity. Collagen-induced arthritis in mice and rats resembles rheumatoid arthritis in humans. Mice deficient in the C5a receptor demonstrated complete protection against arthritis induced by injection of anti-collagen monoclonal antibodies. (Banda, NK, et al., J. of Immunol., 2003, 171:2109-2115). Therefore, inhibition of the C5a receptor and / or C5a (C5aR) could be useful in the treatment of these chronic diseases.

[0016] The complement system is believed to be activated in patients with inflammatory bowel disease (IBD) and is thought to play a role in the pathogenesis of the disease. Activated complement products were found on the luminal surface of surface epithelial cells, as well as in the muscularis mucosa and submucosal blood vessels in patients with IBD (Woodruff, TM, et al., J of Immunol., 2003, 171:5514-5520).

[0017] C5aR expression is upregulated in reactive astrocytes, microglia, and endothelial cells in an inflamed human central nervous system (Gasque, P. et al., Am. J. Pathol. 150:31-41 (1997)). C5a may be involved in neurodegenerative diseases, such as Alzheimer's disease (Mukherjee, P. et al., J. Neuroimmunol. 105:124-130 (2000); O'Barr, S. et al., J. Neuroimmunol. (2000) 105:87-94; Farkas, I., et al. J. Immunol. (2003) 170:5764-5771), Parkinson's disease, Pick's disease, and transmissible spongiform encephalopathies. Activation of neuronal C5aR can induce apoptosis (Farkas I et al. J. Physiol. 1998; 507:679-687). Therefore, inhibition of C5a and / or C5aR could also be useful in the treatment of neurodegenerative diseases.

[0018] There is some evidence that C5a production worsens inflammation associated with atopic dermatitis (Neuber, K., et al., Immunology 73:83-87, (1991)), and chronic urticaria (Kaplan, AP, J. Allergy Clin. Immunol. 114; 465-474, (2004).

[0019] Psoriasis is now known to be a T-cell mediated disease (Gottlieb, EL 1935200 of 103 et al., Nat. Med. 1:442-447 (1995)). However, neutrophils and mast cells may also be involved in the pathogenesis of the disease (Terui, T. et al., Exp. Dermatol. 9:1-10; 2000; Werfel, T. et al., Arch. Dermatol. Res. 289:83-86 (1997)). The accumulation of neutrophils under the stratum corneum is observed in the highly inflamed areas of psoriatic plaques, and extracts of psoriatic lesions (scales) contain highly elevated levels of C5a and exhibit potent chemotactic activity toward neutrophils, an effect that can be inhibited by the addition of a C5a antibody. T cells and neutrophils are chemoattracted to C5a (Nataf, S. et al., J. Immunol. 162:4018-4023 (1999); Tsuji, RF et al., J. Immunol. 165:1588-1598 (2000); Cavaillon, JM et al., Eur. J. Immunol. 20:253-257 (1990)).Furthermore, C5aR expression has been demonstrated in plasmacytoid dendritic cells (pDCs) isolated from cutaneous lupus erythematosus lesions, and these cells exhibited chemotactic behavior toward C5a. This suggests that blocking C5aR in pDCs could be effective in reducing pDC infiltration into inflamed skin in both SLE and psoriasis. Therefore, C5a could be an important therapeutic target for the treatment of psoriasis.

[0020] Immune complexes, or immune complexes (ICs), containing immunoglobulin G contribute to the pathophysiology of several autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, Sjogren's disease, Goodpasture syndrome, and hypersensitivity pneumonitis. (Madaio, MP, Semin. Nephrol. 19:48-56 (1999); Korganow, AS et al., Immunity 10:451-459 (1999); Bolten, WK, Kidney Int. 50:1754-1760 (1996); Ando, ​​M. et al., Curr. Opin. Pulm. Med. 3:391-399 (1997)). These diseases are highly heterogeneous and generally affect one or more of the following organs: skin, blood vessels, joints, kidneys, heart, lungs, nervous system, and liver (including cirrhosis and hepatic fibrosis). The classic animal model for the inflammatory response in these heart failure diseases is the Arthus reaction, which features polymorphonuclear cell infiltration, hemorrhage, and plasma exudation (Arthus, M., CR Soc. Biol.).55:817-824 (1903)). Recent studies show that C5aR-deficient mice are protected from IC-induced tissue injury (Kohl, J. et al., Mol. Immunol. 36:893-903 (1999); Baumann, U. et al., J. Immunol. 164:1065-1070 (2000)). The results are consistent with the observation that a small anti-C5aR peptide antagonist inhibits the inflammatory response. 1935200 of 103 caused by IC deposition (Strachan, AJ et al., J. Immunol. 164:6560-6565 (2000)). Along with its receptor, C5a plays an important role in the pathogenesis of IC diseases. C5a and C5aR inhibitors could be useful for treating these diseases. Description of related art:

[0021] Non-peptide-based C5a receptor antagonists have been reported to be effective in treating endotoxic shock in rats (Stracham, AJ, et al., J. of Immunol. (2000), 164(12):6560-6565); and in treating IBD in a rat model (Woodruff, TM, et al., J of Immunol., 2003, 171:5514-5520). Non-peptide-based C5a receptor modulators have also been described in patent documents filed by Neurogen Corporation (e.g., WO2004 / 043925, WO2004 / 018460, WO2005 / 007087, WO03 / 082826, WO03 / 08828, WO02 / 49993, WO03 / 084524); Dompe SPA (WO02 / 029187); The University of Queensland (WO2004 / 100975); and ChemoCentryx (WO2010 / 075257).

[0022] Considerable experimental evidence exists in the available literature implicating elevated C5a levels in a number of diseases and disorders, particularly autoimmune and inflammatory diseases and disorders. Therefore, a need remains in the art for novel small organic molecule modulators, e.g., agonists, preferably antagonists, or partial agonists, of the C5a receptor (C5aR) that are useful for inhibiting pathogenic events, e.g., chemotaxis, associated with elevated levels of anaphylatoxin activity. The present invention satisfies this and other needs. BRIEF SUMMARY OF THE INVENTION

[0023] In one aspect, the present invention provides the compounds of Formula (I): 1935200 of 103 (I) or a pharmaceutically acceptable salt thereof, wherein: The vertex of ring A1 is selected from the group consisting of N, CH, C(O) and C(R4); The vertex of ring A2 is selected from the group consisting of N, CH, and C(R4); Each of the vertices of the ring A3, A4, A5 and A6 is independently selected from the group consisting of CH and C(R4); Each of the dashed links independently indicates a double or single link; R1 is selected from the group consisting of -C1-8 alkylene-heteroaryl, -C1-8 alkylene-C6-10 aryl, C1-8 alkyl, C1-8 haloalkyl, -C(O)-C1-8 alkyl, -C(O)-C6-10 aryl, -C(O)heteroaryl, -C(O)-C3-6 cycloalkyl, -C(O)-heterocycloalkyl, -C(O)NR1aR1b, -SO2-C6-10 aryl, SO2-heteroaryl, -C(O)-C1-8 alkylene-O-heteroaryl, -C(O)-C1-8 alkylene-O-C6-10 aryl, -C(O) C1-8 alkylene-O-heterocycloalkyl, -C(O)-C1-8alkylene-O-C3-6cycloalkyl, -C(O)-alkylene C1-8heteroaryl, -C(O)-alkylene C1-8-aryl C6-10, -C(O)-alkylene C1-8-heterocycloalkyl, -C(O)alkylene C1-8-cycloalkyl C3-6 and -CO2R1a; the heterocycloalkyl is a 4- to 8-membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S; and the heteroaryl group is a 5- to 10-membered aromatic ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S; wherein R1ay R1bse are each independently selected from the group consisting of hydrogen, C1-8 alkyl, and C1-8 haloalkyl; where R1 is optionally substituted with 1 to 5 R5 substituents; R2ay R2e are each independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkyl-O-C1-6, C1-6 -S-alkyl, C1-6 -alkyl -C1-6 O-alkyl, C1-6 -alkyl -C1-6 S-alkyl, CN, and halogen; 1935200 of 103 R2b, R2c, and R2d are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, -O-C1-6 haloalkyl, -S-C1-6 alkyl, C1-6 alkyl-O-C1-6 alkyl, -C1-6 alkyl-S-C1-6 alkyl, cyano, and halogen; Each R3 is independently selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, halogen, and hydroxyl, and optionally two R3 groups on the same carbon atom combine to form oxo(=O) or to form a three- to five-membered cycloalkyl ring; Each R4 is independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, -O-C1-6 haloalkyl, halogen, cyano, hydroxyl, -S-C1-6 alkyl, -C1-6 alkyl, -O-C1-6 alkyl, -C1-6 alkyl, -S-C1-6 alkyl, NR4aR4b, -CONR4aR4b, -CO2R4a, -COR4a, -OC(O)NR4aR4b, -NR4aC(O)R4b, -NR4aC(O)2R4b, and NR4a-C(O)NR4aR4b; each R4ay R4bse is independently selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 haloalkyl; Each R5 is independently selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkyl, C1-8 haloalkoxy, C1-8 hydroxyalkyl, C1-8 heterocycloalkyl, C1-8 alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, heterocycloalkyl, halogen, OH, C2-8 alkenyl, C2-8 alkynyl, CN, C(O)R5a, -NR5bC(O)R5a, -CONR5aR5b, NR5aR5b, C1-8 alkylene-NR5aR5b, C1-6 S-alkyl, C1-6 O-alkyl, C1-6 S-alkyl, -OC(O)NR5aR5b, -NR5aC(O)2R5b, -NR5a-C(O)NR5bR5b, and CO2R5a; wherein the heterocycloalkyl group is a 4- to 8-membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S; wherein each R5ay R5b is independently selected from the group consisting of hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when R5ay R5b are attached to the same nitrogen atom, they combine with the nitrogen atom to form a 5- or 6-membered ring having from 0 to 1 additional heteroatoms as ring vertices selected from N, O, or S; and the subscript n is 0, 1, 2, or 3.

[0024] In addition to the compounds provided herein, the present invention also provides pharmaceutical compositions containing one or more of these compounds, as well as 1935200 of 103 methods for the use of these compounds in therapeutic methods, mainly to treat diseases associated with C5a signaling activity.

[0025] In another aspect, the present invention provides methods for diagnosing diseases in an individual. In these methods, the compounds provided herein are administered in labeled form to a subject, followed by diagnostic imaging to determine the presence or absence of C5aR and / or the location of cells expressing a C5aR receptor. In a related aspect, a method for diagnosing diseases is carried out by contacting a tissue or blood sample with a labeled compound as provided herein and determining the presence, absence, quantity, or location of C5aR in the sample. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Not applicable. DETAILED DESCRIPTION OF THE INVENTION I. Abbreviations and definitions

[0027] The term alkyl, by itself or as part of another substituent, means, unless otherwise specified, a linear or branched hydrocarbon radical having the designated number of carbon atoms (i.e., C1-8 means from one to eight carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term alkenyl refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term alkynyl refers to an unsaturated alkyl group having one or more triple bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), isobutenyl, 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers.The term cycloalkyl refers to hydrocarbon rings that have the specified number of atoms in the ring (e.g., C3-6 cycloalkyl) and are fully saturated, or have no more than one double bond between the ring vertices. Cycloalkyl also refers to hydrocarbon rings. 1935200 of 103 bicyclic and polycyclic compounds such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The term heterocycloalkyl refers to a cycloalkyl group containing from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. The heterocycloalkyl may be a monocyclic, bicyclic, or polycyclic ring system. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like.A heterocycloalkyl group can be attached to the rest of the molecule through a carbon ring or a heteroatom.

[0028] The term alkylene, by itself or as part of another substituent, means a divalent radical derived from an alkane, as in -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group shall have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in the present invention. A lower alkyl or lower alkylene is a shorter-chain alkyl or alkylene group, generally having four or fewer carbon atoms. Similarly, alkenylene and alkynylene refer to the unsaturated forms of alkylene having double or triple bonds, respectively.

[0029] The term heteroalkyl, by itself or in combination with another term, means, unless otherwise specified, a stable cyclic or linear or branched-chain hydrocarbon radical, or combinations thereof, comprising the stated number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, Si, and S, wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The O, N, and S heteroatoms may be placed in any interior position of the heteroalkyl group. The Si heteroatom may be placed in any position of the heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule. Examples include -CH2-CH2-O-CH3, -CH2CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2,-S(O)-CH3, -CH2-CH2S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to 12 1935200 of 103 Two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-OSi(CH3)3. Similarly, the terms heteroalkenyl and heteroalkynyl, alone or in combination with another term, mean, unless otherwise indicated, an alkenyl group or alkynyl group, respectively, containing the indicated number of carbons and having from one to three heteroatoms selected from the group consisting of O, N, Si, and S, wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The O, N, and S heteroatoms may be placed in any interior position of the heteroalkyl group.

[0030] The term heteroalkylene, alone or as part of another substituent, means a divalent, saturated, unsaturated, or polyunsaturated radical derived from heteroalkyl, such as -CH2-CH2-S-CH2CH2- and -CH2-S-CH2-CH2-NH-CH2-, -O-CH2-CH=CH-, -CH2CH=C(H)CH2-O-CH2- and -S-CH2-C=C-. For heteroalkylene groups, the heteroatoms may also occupy one or both ends of the chain (e.g., alkylenoxy, alkylenedioxy, alkyleneamino, alkylenediamino and the like).

[0031] The terms alkoxy, alkylamino, and alkylthio (or thioalkoxy) are used in their conventional sense and refer to alkyl groups attached to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. Additionally, for dialkylamino groups, the alkyl portions may be the same or different and may also combine to form a 3- to 7-membered ring with the nitrogen atom to which each is attached. Accordingly, a group represented as -NRaRb is understood to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, and the like.

[0032] The term hydroxyalkyl is used in its conventional sense, and refers to a linear or branched chain alkyl group substituted with at least one hydroxyl group. The hydroxyl group may be in any position on the alkyl group. For example, the term C1-4 hydroxyalkyl includes hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, and the like.

[0033] The terms halo or halogen, by themselves or as part of another substituent, mean, unless otherwise specified, an atom of fluorine, chlorine, bromine, or iodine. Additionally, terms such as haloalkyl are intended to include monohaloalkyl and 1935200 of 103 polyhaloalkyl. For example, the term C1-4 haloalkyl includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0034] Unless otherwise specified, the term aryl means a polyunsaturated hydrocarbon group, typically aromatic, which may be a single ring or multiple rings (up to three rings) fused together or covalently bonded. The term heteroaryl refers to aryl groups (or rings) containing from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. A heteroaryl group may be attached to the rest of the molecule through a heteroatom.Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzooxazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolinyl, isoquinolyl, isothiazolyl, pyrazolyl, and indazolyl. Pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. The substituents for each of the aryl and heteroaryl ring systems listed above are selected from the group of acceptable substituents described below.

[0035] The term pharmaceutically acceptable salts is intended to include salts of the active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient quantity of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and similar salts. Pharmaceutically acceptable salts derived from organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and amines of [unspecified origin].1935200 of 103 natural and similar substances, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, netylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient quantity of the desired acid, either pure or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts include derivatives of inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, carbonic monohydrogen, phosphoric, phosphoric monohydrogen, phosphoric dihydrogen, sulfuric, sulfuric monohydrogen, hydroiodic, or phosphorous acids and the like, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic or galactunoric acids and the like. (see, for example, Berge, SM, et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into addition salts of bases or acids.

[0036] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, although the salts are otherwise equivalent to the parent form of the compound for the purposes of the present invention.

[0037] In addition to the salt forms, the present invention provides compounds in prodrug or propharmaceutical form. The prodrugs or propharmaceuticals of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to yield the compounds of the present invention. Furthermore, the prodrugs can be converted into the compounds of the present invention. 15 1935200 of 103 by chemical or biochemical methods in an ex vivo setting. For example, prodrugs can be slowly converted into the compounds of the present invention when placed in a transdermal patch depot with a suitable enzyme or chemical reagent.

[0038] Certain compounds of the present invention may exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are covered within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and fall within the scope of the present invention.

[0039] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and single isomers (e.g., separate enantiomers) all fall within the scope of the present invention. The compounds of the present invention may also contain non-natural proportions of atomic isotopes in one or more of the atoms constituting such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, fall within the scope of the present invention.

[0040] According to the present, a wavy line, . / wv, intercepting a single, double or triple bond in any chemical structure depicted herein, represents the point of attachment of the single, double or triple bond to the rest of the molecule. II. Description of the forms of implementation A. Compounds

[0041] In one aspect, the present invention provides the compounds of Formula I: 1935200 of 103 R1 R2c(I) or a pharmaceutically acceptable salt thereof, wherein: The vertex of ring A1 is selected from the group consisting of N, CH, C(O) and C(R4); the vertex of ring A2 is selected from the group consisting of N, CH, and C(R4); Each of the vertices of the ring A3, A4, A5 and A6 is independently selected from the group consisting of CH and C(R4); Each of the dashed links independently indicates a double or single link; R1 is selected from the group consisting of -C1-8 alkylene-heteroaryl, -C1-8 alkylene-C6-10 aryl, C1-8 alkyl, C1-8 haloalkyl, -C(O)-C1-8 alkyl, -C(O)-C6-10 aryl, -C(O)heteroaryl, -C(O)-C3-6 cycloalkyl, -C(O)-heterocycloalkyl, -C(O)NR1aR1b, -SO2-C6-10 aryl, SO2-heteroaryl, -C(O)-C1-8 alkylene-O-heteroaryl, -C(O)-C1-8 alkylene-O-C6-10 aryl, -C(O)C1-8 alkylene-O- heterocycloalkyl, -C(O)-C1-8alkylene-O-C3-6cycloalkyl, -C(O)-alkylene C1-8heteroaryl, -C(O)-alkylene C1-8-aryl C6-10, -C(O)-alkylene C1-8-heterocycloalkyl, -C(O)alkylene C1-8-cycloalkyl C3-6 and -CO2R1a; the heterocycloalkyl is a 4- to 8-membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S; and the heteroaryl group is a 5- to 10-membered aromatic ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S; wherein R1ay R1bse are each independently selected from the group consisting of hydrogen, C1-8 alkyl, and C1-8 haloalkyl; where R1 is optionally substituted with 1 to 5 R5 substituents; R2ay R2e are each independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkyl-O-C1-6, C1-6 -S-alkyl, C1-6 -alkyl -C1-6 O-alkyl, C1-6 -alkyl -C1-6 S-alkyl, CN, and halogen; 1935200 of 103 R2b, R2c, and R2d are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, -O-C1-6 haloalkyl, -S-C1-6 alkyl, C1-6 alkyl-O-C1-6 alkyl, -C1-6 alkyl-S-C1-6 alkyl, cyano, and halogen; Each R3 is independently selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, halogen, and hydroxyl, and optionally two R3 groups on the same carbon atom combine to form oxo(=O) or to form a three- to five-membered cycloalkyl ring; Each R4 is independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, -O-C1-6 haloalkyl, halogen, cyano, hydroxyl, -S-C1-6 alkyl, -C1-6 alkyl, -O-C1-6 alkyl, -C1-6 alkyl, -S-C1-6 alkyl, NR4aR4b, -CONR4aR4b, -CO2R4a, -COR4a, -OC(O)NR4aR4b, -NR4aC(O)R4b, -NR4aC(O)2R4b, and NR4a-C(O)NR4aR4b; each R4ay R4bse is independently selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 haloalkyl; Each R5 is independently selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkyl, C1-8 haloalkoxy, C1-8 hydroxyalkyl, C1-8 heterocycloalkyl, C1-8 alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, heterocycloalkyl, halogen, OH, C2-8 alkenyl, C2-8 alkynyl, CN, C(O)R5a, -NR5bC(O)R5a, -CONR5aR5b, NR5aR5b, C1-8 alkylene-NR5aR5b, C1-6 S-alkyl, C1-6 O-alkyl, C1-6 S-alkyl, -OC(O)NR5aR5b, -NR5aC(O)2R5b, -NR5a-C(O)NR5bR5b, and CO2R5a; wherein the heterocycloalkyl group is a 4- to 8-membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S; wherein each R5ay R5b is independently selected from the group consisting of hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when R5ay R5b are attached to the same nitrogen atom, they combine with the nitrogen atom to form a 5- or 6-membered ring having from 0 to 1 additional heteroatoms as ring vertices selected from N, O, or S; and the subscript n is 0, 1, 2, or 3.

[0042] Focusing on the portion of the ring that has A1, A2, A3, A4, A5, and A6, in some embodiments, the portion of the ring that has A1, A2, A3, A4, A5, and A6 as vertices of the 1935200 of 103 ring is a bicyclic heteroaryl selected from: where m is 0, 1, 2 or 3; and where the R4 substituents can be attached to any vertex of the suitable carbon ring of the bicyclic heteroaryl.

[0043] In some embodiments, the portion of the ring that has A1, A2, A3, A4, A5, and A6 as vertices of the ring is NH (Tj (R4)m where m is 0, 1, 2, or 3; wherein the R4 substituents can be attached to any vertex of the suitable carbon ring of the bicyclic heteroaryl.

[0044] In some embodiments, each R4 is independently C1-4 alkyl, C1-4 alkoxy, C1-6 hydroxyalkyl, halogen, cyano, and -CO2R4a, wherein R4a has the definition given above, and wherein the R4 substituents can be attached to any vertex of the suitable carbon ring of the bicyclic heteroaryl.

[0045] A person versed in the art will recognize that the particular carbon atoms of the ring portion having A1, A2, A3, A4, A5, and A6 cannot be substituted with R4. For example, the carbon atom linking the bicyclic heteroaryl moiety (i.e., the ring portion having A1, A2, A3, A4, A5, and A6) to the rest of the molecule and the carbon atoms that are members of both ring systems in the fused bicyclic heteroaryl moiety (i.e., the two carbon atoms that are ring vertices in both benzene and the five-membered ring system) cannot be substituted with R4 because an additional substituent would exceed the valency of these carbon atoms.

[0046] In some embodiments, the portion of the ring having A1, A2, A3, A4, A5, and A6 as vertices of the ring is selected from the group consisting of: 1935200 of 103

[0047] In some embodiments, the portion of the ring having A1, A2, A3, A4, A5, and A6 as vertices of the ring is selected from the group consisting of:

[0048] Returning to R1 and the optional substituent(s), R5, in some embodiments, R1 is -C1-8-heteroaryl alkyl, -C1-8-C6-10 aryl alkyl, C1-8 alkyl, C1-8 haloalkyl, -C(O)-C1-8 alkyl, -C(O)-C6-10 aryl, -C(O)-heteroaryl, -C(O)-C3-8 cycloalkyl, C(O)NR1aR1b, -SO2-C6-10 aryl, -C(O)-C1-8-O-C6-10 alkyl, or -CO2R1a; wherein R1 and R1b, heterocycloalkyl, and heteroaryl have the definition given above, and wherein R1 is optionally substituted with 1 to 5 R5 substituents.

[0049] In some embodiments, the heterocycloalkyl groups of R1 or R5 are 4- to 6-membered rings having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S. In some embodiments, the heteroaryl groups of R1 or R5 are 5- to 6-membered aromatic rings having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S. In some embodiments, group 20 1935200 of 103 C6-10 aryl of R1es phenyl.

[0050] In some embodiments, R1 is -CH2-phenyl optionally substituted by 1 to 3 R5.

[0051] In some embodiments, each R5 is independently selected from C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkyl, C1-8 haloalkoxy, C1-8 hydroxyalkyl, C3-6 cycloalkyl, halogen, OH,-NR5aR5b, or CO?R5a, wherein each R5ay R5b is independently selected from the group consisting of hydrogen, C1-8 alkyl, and C1-8 haloalkyl.

[0052] In some embodiments, R1 is -CH2-phenyl substituted by 1 or 2 R5, wherein each R5 is independently a C1-4 haloalkyl.

[0053] In some embodiments, R1 is -CH2-phenyl substituted by 1 or 2 CF3.

[0054] In some embodiments, R1 is selected from the group consisting of 1935200 of 103

[0055] In some forms of realization R1es

[0056] Returning to Formula I and the substituents R2a, R2b, R2c, R2d, and R2e, in some embodiments, R2a and R2e are, each independently, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 haloalkyl, or halogen. In some embodiments, R2b, R2c, and R2d are independently H, C1-4 alkyl, C1-4 haloalkyl, or halogen.

[0057] In some forms of realization, R2b, R2c, and R2d are each H.

[0058] In some embodiments, R2ay R2es are, each independently, alkyl C1-6 or C1-6 haloalkyl.

[0059] In some embodiments, R2ay and R2es are, each independently, methyl or ethyl. In some embodiments, R2ay and R2es are both methyl or are both ethyl.

[0060] In some embodiments, the portion of Formula I represented by 1935200 of 103

[0061] Each R3 of Formula I, in some embodiments, is independently C1-6 alkyl, C1-6 haloalkyl, or halogen. In some embodiments, each R3 is independently C1-4 alkyl.

[0062] In some embodiments, n, the subscript of R3, is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 2.

[0063] In some embodiments, the portion of Formula I represented by: R1

[0064] In some embodiments, the compound of Formula I is represented by the (Ib) (Ic).

[0065] In embodiments in which the compound of Formula (I) is represented by Formula (Ia), R1, R3, n, R2a, R2e, and the portion of the ring having A1, A2, A3, A4, A5, and A6 as vertices of the ring have the definition given above for Formula (I).

[0066] In embodiments in which the compound of Formula (I) is represented by Formula (Ib), R1, R2a, R2e, and the portion of the ring having A1, A2, A3, A4, A5, and A6 as vertices of the ring have the definition given above for Formula (I).

[0067] In embodiments in which the compound of Formula (I) is represented by Formula (Ic), R1 and the portion of the ring having A1, A2, A3, A4, A5, and A6 as vertices of the ring have the definition given above for Formula (I). 1935200 of 103

[0068] In some embodiments, the compound of Formula (I) is represented by Formula (Id), (Ie), or (If): (R5)p

[0069] In embodiments in which the compound of Formula (I) is represented by Formula (Id), R1, R4, m, R2a, and R2e have the definition given above for Formula (I).

[0070] In embodiments in which the compound of Formula (I) is represented by Formula (Ie), R1, R4, and m have the definition given above for Formula (I).

[0071] In embodiments in which the compound of Formula (I) is represented by Formula (If), R5, R4, and m have the definition given above for Formula (I), and p is 0, 1, or 2.

[0072] In some embodiments, the compound of Formula (I) is represented by the Formula (Ig) or (Ih) 1935200 of 103

[0073] In embodiments in which the compound of Formula (I) is represented by Formula (Ig) or (Ih), R4 and m have the definition given above for Formula (I).

[0074] In some embodiments, the compound of Formula (I) is a compound described in the Examples section. Preparation of compounds

[0075] Certain compounds of the invention can be prepared following the methodology as described in the Examples section of this document. In addition, the syntheses of certain intermediate compounds that are useful in the preparation of the compounds of the invention are also described. B. Pharmaceutical compositions

[0076] In addition to the compounds provided above, compositions for modulating C5a activity in humans and animals will typically contain a pharmaceutical vehicle or diluent.

[0077] The term composition, as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product resulting, directly or indirectly, from the combination of the specified ingredients in the specified amounts. Pharmaceutically acceptable means that the vehicle, diluent, or excipient must be compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

[0078] Pharmaceutical compositions for the administration of the compounds of the present invention may be conveniently presented in a unit dosage form and may be prepared by any of the methods widely known in the art of pharmacy and drug dispensing. All methods include the step of combining the active ingredient with the vehicle, which constitutes one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately combining the active ingredient with a liquid vehicle or a finely divided solid vehicle, or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active compound in question is included in an amount 25 1935200 of 103 sufficient to produce the desired effect on the disease process or condition.

[0079] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use; for example, as tablets, lozenges, pastilles, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifications as described in U.S. Patent Application 2002-0012680, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gum, chewable tablets, effervescent powder, and effervescent tablets. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group comprising sweeteners, flavorings, colorings, antioxidants, and preservatives to provide pharmaceutically appealing and palatable preparations.The tablets contain the active ingredient mixed with pharmaceutically acceptable, non-toxic excipients suitable for tablet manufacture. These excipients may include, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as maize starch or alginic acid; binding agents such as PVP, cellulose, PEG, starch, gelatin, or gum arabic; and lubricating agents such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or enterically or otherwise coated using techniques known to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period.For example, a retardant material such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated using the techniques described in U.S. Patents Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic controlled-release therapeutic tablets.

[0080] Oral formulations may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, for example, peanut oil, 26 1935200 of 103 liquid paraffin or olive oil. Additionally, emulsions can be prepared with a water-immiscible ingredient, such as oil, and stabilized with surfactants such as mono- and diglycerides, PEG esters, and the like.

[0081] Aqueous suspensions contain the active materials mixed with excipients suitable for the preparation of aqueous suspensions.These excipients are suspending agents; for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; the dispersing or wetting agents may be a natural phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecatonylenoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylsorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate.Aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0082] Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oil suspensions may contain a thickening agent, for example, beeswax, hard paraffin, or cetyl alcohol. Sweetening agents, such as those described above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0083] Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient mixed with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by the agents already mentioned above. Additional excipients may also be present; 1935200 of 103 for example sweeteners, flavorings and colorings.

[0084] The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example, olive oil or peanut oil, or a mineral oil, for example, liquid paraffin, or mixtures thereof. Suitable emulsifying agents may be natural gums, for example, gum arabic or tragacanth gum, natural phosphatides, for example, soybean oil, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of such partial esters with ethylene oxide, for example, polyoxyethylsorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

[0085] Syrups and elixirs may be formulated with sweetening agents; for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. Oral solutions may be prepared in combination with, for example, cyclodextrin, PEG, and surfactants.

[0086] Pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to known technique using the suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic diluent or solvent acceptable for parenteral administration, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any soft fixed oil, including synthetic mono- or diglycerides, may be used. Furthermore, fatty acids such as oleic acid are used in the preparation of injectables.

[0087] The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the 1935200 of 103 drug. These materials include cocoa butter and polyethylene glycols. Additionally, the compounds can be administered by ocular application by means of solutions or ointments. Furthermore, transdermal administration of the compounds of the invention can be carried out by means of iontophoretic patches and the like. For topical use, creams, ointments, jellies, solutions, or suspensions, etc., containing the compounds of the present invention are employed. According to the present invention, topical application is also intended to include the use of mouthwashes and gargles.

[0088] The compounds of the present invention can also be coupled with a carrier that is a suitable polymer, such as addressable pharmaceutical carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylate-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds of the invention can be coupled with a carrier that is a class of biodegradable polymers useful for achieving controlled drug release, for example, polylactic acid, polyglycolic acid, polylactic-polyglycolic acid copolymers, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.Semipermeable polymers and polymer matrices can be formed into molded articles such as valves, cannulas or stents, tubes, prostheses, and the like. In one embodiment of the invention, the compound of the invention is coupled with a semipermeable polymer or polymer matrix that takes the shape of a cannula or cannula-graft device.

[0089] The pharmaceutical compositions of the present invention may be formulated with one or more additional therapeutic agents. These one or more additional therapeutic agents may include corticosteroids, steroids, immunosuppressants, or CD20 inhibitors. In some embodiments, these one or more additional therapeutic agents include obinutuzumab, rituximab, ocrelizumab, cyclophosphamide, prednisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, and hydrocortisone-1729. 1935200 of 103 valerate, halomethasone, alclomethasone dipropionate, beclomethasone, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, ciclesonide, and prednicarbate. Other analyses of the combination treatment are included in the Methods of Use section of this application. C. Methods of use

[0090] The compounds of the invention can be used as agonists, (preferably) antagonists, partial agonists, or inverse agonists of C5a receptors in a variety of contexts, both in vitro and in vivo. In one embodiment, the compounds of the invention are C5aR antagonists that can be used to inhibit the binding of the C5a receptor ligand (e.g., C5a) to the C5a receptor in vitro or in vivo. In general, such methods comprise the step of contacting a C5a receptor with a sufficient quantity of one or more C5a receptor modulators according to the invention herein, in the presence of the C5a receptor ligand in aqueous solution and under conditions suitable for ligand binding to the C5a receptor. The C5a receptor may be present in suspension (e.g., on an isolated membrane or cell preparation), in a cultured or isolated cell, or in a tissue or organ.

[0091] Preferably, the amount of C5a receptor modulator in contact with the receptor should be sufficient to inhibit the binding of C5a to the C5a receptor in vitro as established, for example, using a radioligand binding assay, calcium mobilization assay, or chemotaxis assay in accordance with this document.

[0092] In one embodiment of the invention, the C5a modulators of the invention are used to modulate, preferably inhibit, the signal transduction activity of a C5a receptor, for example, by contacting one or more compounds of the invention with a C5a receptor (either in vitro or in vivo) under conditions suitable for binding of the modulator(s) to the receptor. The receptor may be present in solution or suspension, in a cultured or isolated cell preparation, or within a patient. Any modulation of the signal transduction activity may be evaluated by detecting an effect on calcium mobilization or by detecting an effect on C5a receptor-mediated cell chemotaxis. In general, a 30 1935200 of 103 effective amount of one or more C5a modulators is a sufficient amount to modulate the signal transduction activity of the C5a receptor in vitro within a calcium mobilization assay or C5a receptor-mediated cell chemotaxis within a migration assay.

[0093] When the compounds of the invention are used to inhibit C5a receptor-mediated cellular chemotaxis, preferably leukocyte (e.g., neutrophil) chemotaxis, in an in vitro chemotaxis assay, the methods comprise contacting white blood cells (particularly primate white blood cells, especially human white blood cells) with one or more compounds of the invention. Preferably, the concentration is sufficient to inhibit white blood cell chemotaxis in an in vitro chemotaxis assay, such that the chemotaxis levels observed in a control assay are significantly higher, as described, than the levels observed in an assay in which a compound of the invention has been added.

[0094] In another embodiment, the compounds of the present invention may be further used to treat patients suffering from conditions that are sensitive to modulation of the C5a receptor. According to the present invention, the term "treat" or "treatment" encompasses both disease-modifying treatment and symptomatic treatment, either of which may be prophylactic (i.e., before the onset of symptoms to prevent, delay, or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms to reduce the severity and / or duration of symptoms). According to the present invention, a condition is considered sensitive to modulation of the C5a receptor if modulation of C5a receptor activity results in a reduction of inappropriate C5a receptor activity.According to this document, the term patients includes primates (especially humans), domesticated companion animals (such as dogs, cats, horses and the like) and livestock (such as cows, pigs, sheep and the like), with the doses described herein. Conditions that can be treated by modulation of C5a:

[0095] Autoimmune disorders: for example, rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barré syndrome, pancreatitis, lupus nephritis, lupus, glomerulonephritis, psoriasis, Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis, 1935200 of 103 multiple sclerosis, bronchial asthma, dense deposit disease, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture syndrome (and associated glomerulonephritis and pulmonary hemorrhage), C3 glomerulopathy, C3 glomerulonephritis, membranoproliferative glomerulonephritis, Kawasaki disease, IGA nephropathy, immunovasculitis, tissue graft rejection, graft-versus-host disease, hyperacute rejection of transplanted organs; and the like.

[0096] Inflammatory disorders and related conditions: for example, neutropenia, sepsis, septic shock, Alzheimer's disease, multiple sclerosis, neutrophilia, stroke, inflammatory bowel disease (IBD), inflammation associated with severe burns, lung injury and ischemia-reperfusion injury, osteoarthritis, as well as acute respiratory distress syndrome (adult) (ARDS), chronic obstructive pulmonary disease (COPD), systemic inflammatory response syndrome (SIRS), atopic dermatitis, psoriasis, chronic urticaria and multiple organ dysfunction syndrome (MODS), hemolytic uremic syndrome, atypical hemolytic uremic syndrome (aHUS).Also included are pathological sequelae associated with insulin-dependent diabetes mellitus (including diabetic retinopathy), lupus nephritis, Heyman nephritis, membranous nephritis and other forms of glomerulonephritis, contact sensitivity responses and inflammation resulting from contact of blood with artificial surfaces that can cause complement activation, as occurs, for example, during extracorporeal blood circulation (e.g., during hemodialysis or via a cardiopulmonary machine, e.g., in association with vascular surgery such as coronary artery bypass grafting or heart valve replacement), or in association with contact with other artificial surfaces of receptacles or containers (e.g., ventricular assist devices, artificial heart machines, transfusion tubes, blood storage bags, plasmapheresis, plateletpheresis and the like).Also included are diseases related to ischemia / reperfusion injury, such as those resulting from transplantation, including solid organ transplantation, and syndromes such as ischemic reperfusion injury, ischemic colitis, and cardiac ischemia. The compounds of the present invention may also be useful in the treatment of age-related macular degeneration. (Hageman et al, PNAS 102:7227-7232, 2005).

[0097] Cardiovascular and cerebrovascular disorders: for example, myocardial infarction, 1935200 of 103 coronary thrombosis, vascular occlusion, post-surgical vascular re-occlusion, atherosclerosis, traumatic injury of the central nervous system, and ischemic heart disease. In one embodiment, an effective amount of a compound of the invention may be administered to a patient at risk of 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, hypertension, hypercholesterolemia, prior history, or genetic predisposition to myocardial infarction or thrombosis) to reduce the risk of myocardial infarction or thrombosis.

[0098] Oncological Diseases or Disorders: for example, melanoma, lung cancer, lymphoma, sarcoma, carcinoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, mesothelioma, meningioma, leukemia, lymphoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, pleomorphic adenoma, liver cell papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma and fibroma.

[0099] Vasculitis Diseases: Vasculitic diseases are characterized by inflammation of the blood vessels. Leukocyte infiltration leads to destruction of the vessel walls, and the complement pathway is thought to play an important role in initiating leukocyte migration, as well as in the resulting damage manifested at the site of inflammation. (Vasculitis, Second Edition, Edited by Ball and Bridges, Oxford University Press, pp. 47-53, 2008). The compounds provided in the present invention can be used to treat leukocytic vasculitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune vasculitis, Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, Henoch-Schönlein purpura, polyateritis nodosa, rapidly progressive glomerulonephritis (RPGN), cryoglobulinemia, giant cell arteritis (GCA), Behcet's disease, and Takayasu arteritis (TAK).

[0100] HIV infection and AIDS: The C5a receptor modulators provided in this Document 1935200 of 103 can be used to inhibit HIV infection, delay the progression of AIDS, or decrease the severity of symptoms or HIV infection and AIDS.

[0101] Neurodegenerative disorders and related diseases: In other respects, the C5a antagonists provided herein may be used to treat Alzheimer's disease, multiple sclerosis, and the decline in cognitive function associated with cardiopulmonary bypass surgery and related procedures.

[0102] In one embodiment of the invention, the compounds of the invention can be used for the treatment of selected diseases from the group consisting of sepsis (and associated disorders), COPD, rheumatoid arthritis, lupus nephritis, and multiple sclerosis.

[0103] The treatment methods described herein generally include administering to a patient an effective amount of one or more of the compounds herein. Suitable patients include those patients who suffer from or are susceptible to (i.e., prophylactic treatment) a disorder or disease identified herein. Typical patients for treatment according to the invention include mammals, particularly primates; especially humans. Other suitable patients include companion or domesticated animals such as dogs, cats, horses, and the like, or livestock such as cattle, pigs, sheep, and the like.

[0104] In general, the treatment methods provided herein comprise administering to a patient an effective amount of one or more compounds according to the invention. In a preferred embodiment, the compound(s) of the invention are preferably administered to a patient (e.g., a human) orally or topically. The effective amount may be sufficient to modulate C5a receptor activity and / or sufficient to reduce or alleviate the symptoms presented by the patient. Preferably, the amount administered is sufficient to produce a plasma concentration of the compound (or its active metabolite, if the compound is a prodrug) high enough to detectably inhibit white blood cell (e.g., neutrophil) chemotaxis in vitro. Treatment regimens may vary depending on the compound used and the particular condition being treated.For the treatment of most disorders, a dosing frequency of 4 times a day or less is preferred. In general, it is 1935200 of 103 prefers a twice-daily dosing regimen, with once-daily dosing being particularly preferred. It is understood, however, that the specific dose level and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs (i.e., other drugs administered to the patient), and the severity of the particular disease being treated, as well as the judgment of the attending physician. In general, the use of the lowest dose sufficient to provide effective treatment is preferred.In general, patients can be monitored to determine therapeutic effectiveness using appropriate medical or veterinary criteria for the condition being treated or prevented.

[0105] Dosage levels in the range of approximately 0.1 mg to approximately 140 mg per kilogram of body weight per day are useful in the treatment or prevention of conditions involving C5a pathogenic activity (approximately 0.5 mg to approximately 7 g per human patient per day). The amount of active ingredient that can be combined with vehicles to produce a single dosage form will vary depending on the host being treated and the particular route of administration. Dosage unit forms will generally contain between approximately 1 mg and approximately 500 mg of an active ingredient.For compounds administered orally, transdermally, intravenously, or subcutaneously, it is preferred to administer a sufficient quantity of the compound to achieve a serum concentration of 5 ng / ml to 10 μg / ml of serum; more preferably, a quantity of the compound should be administered to achieve a serum concentration of 20 ng / ml to 1 μg / ml of serum; more preferably, a quantity of the compound sufficient to achieve a serum concentration of 50 ng / ml to 200 ng / ml of serum. For direct injection into the synovial membrane (for the treatment of arthritis), sufficient quantities of the compound should be administered to achieve a local concentration of approximately 1 micromole.

[0106] The dosing frequency may also vary depending on the compound used and the particular disease being treated. However, for the treatment of most disorders, a dosing regimen of 4 times a day, 3 times a day, or less is preferred, with a dosing regimen of once a day or twice a day being particularly preferred. 1935200 of 103 It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e., other medications administered to the patient), the severity of the particular disease being treated, and other factors, including the judgment of the attending physician. Combined treatment

[0107] The compounds described herein may be used in combination with one or more additional therapeutic agents employed in the treatment, prevention, suppression, or improvement of the diseases or conditions for which the compounds and compositions of the present invention are useful. Such one or more additional therapeutic agents may be administered, by a route and in an amount commonly used for this purpose, simultaneously or sequentially with a compound or composition of the present invention. When a compound or composition of the present invention is used concurrently with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound or composition of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound or composition of the present invention.

[0108] Examples of one or more additional therapeutic agents that may be combined with a compound or composition of the present invention, administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists, (b) steroids and corticosteroids, such as beclomethasone, betamethasone (including betamethasone sodium phosphate, betamethasone valerate, betamethasone dipropionate), prednisone, prenisolone, methylprednisolone, mometasone, dexamethasone (including dexamethasone sodium phosphate), fluticasone, cortisone (including cortisone acetate), hydrocortisone (including hydrocortisone acetate, hydrocortisone-17-valerate, hydrocortisone-17-butyrate, hydrocortisone-17aceponate, hydrocortisone-17-buterate), budesonide, desonide, fluocinonide (including acetonide 1935200 of 103 of fluocinolone), triamcinolone (including triamcinolone acetonide and triamcinolone alcohol), tixocortol (including tixocortol pivalate), fluocortolone (including fluocortolone caproate and fluocortolone pivalate), amcinonide, halcinonide, halometasone, fluprednidenum acetate, salmeterol, salbutamol, ciclesonide, formometerol, alclometasone (including alclometasone dipropionate), prednicarbate, clobetasone (including clobetasone-17butene), clobetasol (including clobetasol-17propionate); (c) immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506 type immunosuppressants, and nicophenolate, for example, mycophenolate mofetil (CellCept8); (d) antihistamines (H1 histamine antagonists) such as brompheniramine, chlorpheniramine, dexchloipheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyralamine, tripelennamine, hydroxyzine, methdilazine,promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine and the like; (e) non-steroidal anti-asthmatics (for example, terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol and pirbuterol), theophylline, cromoline sodium, atropine, ipratropium bromide, leukotriene antagonists (for example, zafmlukast, montelukast, pranlukast, iralucast, pobilukast and SKB-106,203), inhibitors of leukotriene biosynthesis (zileuton, BAY-1005); (f) non-steroidal anti-inflammatory agents (NSAIDs) such as propionic acid derivatives (e.g., aminoprofen, benoxaprofen, bucoxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, riroprofen, naproxen, oxaprozin, pirprofen), pranoprofen, suprofen, tiaprofenic acid and thioxaprofen),Acetic acid derivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozicoic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, thiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (e.g., flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, and tolfenamic acid), biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal), oxicams (e.g., isoxicam, piroxicam, sudoxicam, and tenoxicam), salicylates (e.g., acetylsalicylic acid and sulfasalazine), and pyrazolones (e.g., apazone, bezpiperilon, feprazone, mofebutazone, oxyfenbutazone, and phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (h) phosphodiesterase type IV inhibitors (PDE 37, 1935200 of 103 IV); (i) gold compounds such as auranofin and aurothioglucose, (j) etanercept (EnbrelO), (k) cyclophosphamide, (l) antibody therapies such as orthoclon (OKT3), daclizumab (Zenapax®), basiliximab (Simulect®) and infliximab (Remicade®), (m) CD20-targeted antibody therapies such as obinutuzumab, rituximab or ocrelizumab; (n) chemotherapeutic agents such as anthracyclines (e.g., daunorubicin (daunomycin, rubidomycin), doxorubicin, epirubicin, idarubicin and valrubicin), mitoxantrone and pixantrone; platinum-based agents (e.g., cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin and lipoplatin); tamoxifen and metabolites thereof such as 4-hydroxytamoxifen (afimoxifen) and N-desmethyl-4-hydroxytamoxifen (endoxyfen); taxanes such as paclitaxel (taxol) and docetaxel;alkylating agents (e.g., nitrogen mustards such as mechlorethamine (HN2), cyclophosphamide, ifosfamide, melphalan (L-sarcolysine) and chlorambucil); ethyleneimines and methylmelamines (e.g., hexamethylmelamine, thiotepa, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine (BCNU), lomustine (CCNLJ), semustine (methyl-CCN-U) and streptozoein (streptozotocin) and triazene such as decarbazine (DTIC; dimethyltriazenoimidazolcarboxamide)); antimetabolites (e.g., folic acid analogues such as methotrexate (ametopterin), pyrimidine analogues such as fluorouracil (5-fluorouracil, 5-FU), floxuridine (fluorodeoxyuridine; FUdR), and cytarabine (cytosine arabinoside), and purine analogues and related inhibitors such as mercaptopurine (6-mercaptopurine; 6-MP), thioguanine (6-thioguanine; 6-TG), and pentostatin (2'-deoxyphonincin)); (or) other antagonists of chemokine receptors, in particular CXCR2, CXCR3, CCR2, CCR3, CCR4, CCR7, CX3CR1, and CXCR6.

[0109] The disease or disorder being treated will determine which additional therapeutic agent or agents are most suitable in combination with the compounds of the present invention. Such determination may be made by a person skilled in the art.

[0110] The weight ratio between the compound of the present invention and the second active ingredient may be altered and will depend on the effective dose of each ingredient. In general, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID, the weight ratio between the compound of the present invention and the NSAID will generally range from approximately 1000:1 to approximately 1:1000, preferably from approximately 200:1 to approximately 38:1000. 1935200 of 103 1:200. Generally, combinations of a compound of the present invention and other active ingredients will also be within the range mentioned above, but in each case, an effective dose of each active ingredient must be used. Non-pharmaceutical applications

[0111] In another aspect of the invention, the compounds of the invention can be used in a variety of non-pharmaceutical in vitro and in vivo applications. For example, the compounds of the invention can be labeled and used as probes for the detection and localization of the C5a receptor (cell preparations or tissue section samples). The compounds of the invention can also be used as positive controls in assays for C5a receptor activity; that is, as standards for determining the ability of a candidate agent to bind to the C5a receptor, or as radiotracers for positron emission tomography (PET) or single-photon emission computed tomography (SPECT) imaging. Such methods can be used to characterize C5a receptors in living subjects.For example, a C5a receptor modulator can be labeled using any of a variety of widely known techniques (e.g., radiolabeling with a radionuclide such as tritium) and incubated with a sample for a suitable incubation time (e.g., the binding time determined beforehand). After incubation, the unbound compound is removed (e.g., by washing), and the bound compound is detected using any method suitable for the label employed (e.g., autoradiography or scintillation counting for radiolabeled compounds; spectroscopic methods can be used to detect luminescent and fluorescent clusters). As a control, an adapted sample containing the labeled compound and a larger (e.g., 10-fold) amount of the unlabeled compound can be processed in the same manner.A greater amount of detectable marker remaining in the test sample than in the control indicates the presence of the C5a receptor in the sample. Detection assays, including receptor autoradiography (receptor mapping) of the C5a receptor in cultured cells or tissue samples, can be performed as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons. 1935200 of 103 New York.

[0112] The compounds provided herein can also be used within a variety of widely known cell separation methods. For example, the modulators can be attached to the inner surface of a tissue culture plate or other support for use as affinity ligands to immobilize, and thereby isolate, C5a receptors (e.g., isolate cells expressing the receptor) in vitro. In a preferred application, a modulator attached to a fluorescent marker, such as fluorescein, is brought into contact with cells, which are then analyzed (or isolated) by fluorescence-activated cell sorting (FACS). I. Examples

[0113] The following examples are illustrative and do not limit the claimed invention.

[0114] The reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). ¹H Nuclear Magnetic Resonance (¹H-NMR) spectra were recorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaks relative to TMS are provided and tabulated in the following order: multiplicity (s, singlet, d, doublet, t, triplet, q, quartet, m, multiplet) and number of protons. Mass spectrometry (MS) results are reported as the mass-to-charge ratio, followed by the relative abundance of each ion (in parentheses). In the examples, a single m / e value is reported for the M + H ion (or, as indicated, MH) containing the most common atomic isotopes. Isotope standards correspond to the predicted formula in all cases.Electrospray ionization (ESI) and mass spectrometry were performed on a Hewlett-Packard MSD electrospray mass spectrometer using an HP1100 HPLC for sample elution. Typically, the analyte was dissolved in 0.1 mg / mL methanol, and 1 microliter of the elution solvent was infused into the mass spectrometer, which scanned from 100 to 1500 daltons. All compounds could be analyzed in positive ESI mode, using 1% formic acid in acetonitrile / water as the elution solvent. The compounds listed below could also be analyzed in negative ESI mode, using 2 mM NH4OAc in acetonitrile / water as the elution system. 1935200 of 103

[0115] The following abbreviations are used in the Examples and throughout the description of the invention: EtOH: Ethanol EtONa: Sodium ethoxide THF: Tetrahydrofuran TLC (Thin Layer Chromatography): Thin layer chromatography MeOH: Methanol

[0116] The compounds within the scope of the present invention can be synthesized as described below, using a variety of reactions known to those skilled in the art. Those skilled in the art will also recognize that alternative methods may be employed to synthesize the compounds of the invention, and that the approaches described herein are not exhaustive, but provide practical and widely applicable means for synthesizing the compounds of interest.

[0117] Certain molecules claimed in this description may exist in different enantiomeric and diastereomeric forms, and all variants of these compounds are claimed.

[0118] The detailed description of the experimental procedures used to synthesize the key compounds in this text leads to molecules that are described by the physical data that identify them, as well as by the structural representations associated with them.

[0119] Those skilled in the art will also recognize that acids and bases are frequently used during standard procedures in organic chemistry. Salts of the parent compounds are sometimes produced, if they possess the necessary intrinsic acidity or basicity, during the experimental procedures described in this invention. Example 1 Synthesis of the intermediate 6-fluoro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indole 1935200 of 103 Step b

[0120] Step a: A solution of vinylmagnesium bromide in THF (1.0 M, 70 mL, 70 mmol) was added to a solution of 4-bromo-2-fluoro-6-nitroanisole (5.0 g, 20 mmol) in anhydrous THF (70 mL) under N2 at -50 °C. The reaction mixture was stirred at the same temperature and allowed to warm to -30 °C for 1.5 h. The reaction mixture was stopped with saturated aqueous NH4Cl solution and allowed to cool to room temperature for 1 h. The reaction mixture was diluted with EtOAc, washed with brine, and dried in the presence of Na2SC>4. The solvent was extracted under reduced pressure and the residue was purified by flash silica gel chromatography (0 to 100% EtOAc in hexanes) to obtain 4-bromo-6-fluoro-7-methoxy-U / -indole. MS: (ES) m / z calculated for C9H8BrFNO [M + H]+243.9, found 243.9.

[0121] Step b: A suspension of 4-bromo-6-fluoro-7-methoxy-U / -indole (900 mg, 3.68 mmol), Z»A(pinacolato)diboron (1.21 g, 4.8 mmol) and KOAc (1.08 g, 11 mmol) in dioxane (16 mL) was mixed with Pd(dppf)Ch complex containing dichloromethane (400 mg, 0.49 mmol). The reaction mixture was degassed with N2 for 2 min and stirred at 100 °C for 2 h. The reaction mixture was diluted with EtOAc and filtered through Celite. The solvent was extracted under reduced pressure and the residue was purified by flash silica gel chromatography (0 to 100% EtOAc in hexanes) to obtain 6-fluoro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-U / -indole. MS: (ES) m / z calculated for C15H20BFNO3 [M + H]+292.1, found 292.1. Example 2 Synthesis of 4-(5-(2,4-Z>is(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-6-fluoro-7-methoxy-l¿f-indole 1935200 of 103 either. 1) HCI. NaNO; i Sna2-2H2ü 3) NaOH 4) HCt Et2O Step a1I N-Büc NC''_y Eton reflux 2) tert-butyl nitrite CHJi, MeCN Step b Fdídppf)CI2-CH2Cl2 K2CO3 Dioxane-H2O Step d

[0122] Step a: To a 250 mL flask containing 90 mL of concentrated hydrochloric acid with magnetic stirring, 2,6-Diethylaniline (10 g, 67 mmol) was added. The resulting mixture was stirred for 30 min and cooled with an ice / salt bath until the internal temperature reached -5 °C. A solution of sodium nitrite (5.5 g, 80 mmol) in water (60 mL) was slowly added to the above mixture while maintaining the internal temperature below 5 °C.

[0123] Separately, tin(II) chloride dihydrate (31.6 g, 140 mmol) was added to a 500 mL three-necked round-bottom flask containing concentrated hydrochloric acid (60 mL) with mechanical stirring. The resulting solution was then cooled with an ice bath.

[0124] The diazonium suspension was then filtered into the 500 mL flask containing the 1935200 of 103 vigorously stirred and cooled tin chloride solution. After 90 minutes, the reaction mixture was transferred to a 500 mL Erlenmeyer flask, and the flask was rinsed with water (20 mL) and chloroform (8 mL). The combined mixture was stirred overnight at room temperature. The liquid was decanted to obtain a wet solid. The solid was dried in a vacuum for one day and then transferred to a 500 mL three-necked round-bottom flask fitted with a mechanical stirrer and stirred with ether (180 mL). The resulting mixture was cooled in an ice bath, and 30 mL of 10 N NaOH solution was slowly added to the mixture while maintaining the internal temperature below 12 °C. After the addition, the mixture was allowed to stand for 2 h on ice. The ether layer was decanted into a 500 mL flask and a stream of hydrogen chloride gas was bubbled into the stirred ether solution.The resulting precipitate was collected by filtration to obtain (2,6-diethylphenyl)hydrazine hydrochloride. MS: (ES) m / z calculated for C10H17N2 [M + H]+165.1, found 165.1.

[0125] Step b: Pyridine (4 mL, 49.5 mmol) was added to a mixture of (2,6-diethylphenyl)hydrazine hydrochloride (5 g, 24.91 mmol), tert-butyl 4-cyano-2,2-dimethyl-3-oxopyrrolidine-1-carboxylate (5 g, 20.98 mmol), and EtOH (60 mL) in a 250 mL round-bottom flask under magnetic stirring. The resulting mixture was stirred at 70 °C for 24 h. The solvent was extracted under reduced pressure, and the residue was diluted with EtOAc and washed with aqueous citric acid solution, aqueous NaHCO3 solution, brine, and dried in the presence of MgSO4. The solvent was extracted under reduced pressure and the residue was crystallized from cyclohexane to obtain tert-butyl 3-amino-2-(2,6-diethylphenyl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-carboxylate. MS: (ES) m / z calculated for C22H33N4O2 [M + H]+385.2, found 385.2.

[0126] tert-Butyl nitrite (0.5 mL, 3.8 mmol) was slowly added at room temperature to a mixture of tert-butyl 3-amino-2-(2,6-diethylphenyl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazol5(4H)-carboxylate (1 g, 2.6 mmol), diiodomethane (1.5 mL, 18.6 mmol), and MeCN (15 mL) in a 100 mL round-bottom flask under magnetic stirring. The resulting mixture was stirred at 45 °C for 3 h before being diluted with toluene, washed with saturated NH4Cl / NH4OH (3:1) solution, brine, and dried in the presence of MgSO4. The solvent was extracted under reduced pressure and the residue was purified by flash silica gel chromatography (2 to 25% EtOAc in hexanes) to obtain tert-butyl 2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,6-dihydropyrrolo[3,4c]pyrazol-5(4H)-carboxylate. MS: (ES) m / z calculated for C22H31IN3O2 [M + H]+496.1, 44 1935200 of 103 found 496.2.

[0127] Step c: The above tert-butyl 2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,6-dihydropyrrolo[3,4c]pyrazol-5(4H)-carboxylate was dissolved in dichloromethane (10 mL) and charged with HCl in dioxane (4 N, 5 mL). The resulting mixture was stirred at room temperature for 12 h. Upon completion, the solvent was evaporated in vacuo to obtain 2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride. MS: (ES) m / z calculated for C17H23IN3 [M + H]+396.1, found 396.2.

[0128] N,N-Diisopropylethylamine (0.3 mL, 1.73 mmol) was added to a suspension of 2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride (680 mg, 1.57 mmol) and 2,4-bis(trifluoromethyl)benzaldehyde (800 mg, 3.3 mmol) in 1,2-dichloroethane (10 mL) under magnetic stirring. After stirring at room temperature for 10 min, NaBH(OAc)3 (800 mg, 3.77 mmol) was added in portions. The resulting mixture was stirred at 45 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCO3 solution, brine, and dried in the presence of MgSO4. The solvent was extracted under reduced pressure, and the residue was purified by flash silica gel chromatography (2 to 25% EtOAc in hexanes) to obtain 5-(2,4-bis(trifluoromethyl)benzyl)-2(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole. MS: (ES) m / z calculated for C26H27F6IN3 [M + H]+622.1, found to be 622.1.

[0129] Step d: To a suspension of 5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-3iodo-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (250 mg, 0.40 mmol), 6-fluoro-7-methoxy4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-indole (100 mg, 0.34 mmol) and K2CO3 (445 mg, 1.81 mmol) in dioxane (6 mL) and water (1 mL) Pd(dppf)Cl2 complex was added with dichloromethane (50 mg, 0.06 mmol). The reaction mixture was degassed with N2 for 2 min and stirred under N2 at 100 °C for 2.5 h. The reaction mixture was diluted with EtOAc, washed with aqueous NaHCO3 and dried in the presence of Na2SO4. The solvent was extracted under reduced pressure and the residue was purified by flash silica gel chromatography (3 to 35% EtOAc in hexanes) followed by HPLC (MeCN / H2O, with 1% TFA) to obtain 4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-6-fluoro-7-methoxy-1H-indole.1H NMR (400 MHz, CDCh) δ 8.37 (br s, 1H), 8.19 (d, J = 12 1935200 of 103 Hz, 1H), 7.86 (s, 1H), 7.76 (d, J= 12 Hz, 1H), 7.07–7.33 (m, 4H), 6.41 (dd, J= 2.2, 3.2 Hz, 1H), 6.33 (d, J= 4, 13.8), 4.01 (s, 3H), 3.70 (s, 2H), 2.23–2.37 (m, 4H), 1.55 (s, 6H), 1.02 (t, J= 7.6 Hz, 6H). MS: (ES) m / z calculated for C35H34F7N4O [M + H]+659.2, found 659.2. Example 3 Synthesis of 3-chloro-4-(2-(2,6-diethylphenyl)-6,6-dimethyl-5-(2-(trifluoromethyl)benzyl)-2,4,5,6tetr:hydropyrrole|3.4-c|pyr:isol-3-yl)-7-yluorine-1 / Iΐίΐ( for na e dI al D)d ibero PdídppOClE'CHíClí KOAc i'd(dppit:i2-c;i i2gi2k2co3Dioxane Dioxano Step a 1}NCS. DMF 2) HCI. CH2CI2 Step c 2-CFj- benzaldehyde NaBH(OAc)·! CICH2CH2CI Step d

[0130] Step a: To a suspension of 4-bromo-7-fluoro-U / -indole (1.00 g, 4.67 mmol), Z>zs(pinacolato)diboron (1.31 g, 5.14 mmol) and KOAc (1.15 g, 11.7 mmol) in dioxane (15 mL) Pd(dppf)C12 complex with dichloromethane was added (416 mg, 0.51 mmol). The reaction mixture 46 1935200 of 103 was degassed with N2 for 2 min and stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite. The solvent was extracted under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 30% EtOAc in hexanes) to obtain 7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-indole. MS: (ES) m / z calculated for C14H18BFNO2 [M + H]+262.1, found 262.1.

[0131] Step b: To a suspension of tert-butyl 2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-carboxylate (540 mg, 1.09 mmol), 7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (350 mg, 1.34 mmol), and K2CO3 (830 mg, 6.78 mmol) in dioxane (10 mL) and water (2 mL) Pd(dppf)Cl2 complex with dichloromethane (200 mg, 0.32 mmol) was added. The reaction mixture was degassed with N2 for 2 min and stirred under N2 at 100 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with aqueous NaHCO3, and dried in the presence of Na2SO4. The solvent was extracted under reduced pressure, and the residue was purified by flash silica gel chromatography (5 to 25% EtOAc in hexanes) to obtain tert-butyl 2-(2,6-diethylphenyl)-3-(7-fluoro-1H-indol-4-yl)6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-carboxylate. MS: (ES) m / z calculated for C30H36FN4O2 [M + H]+503.2, found 503.3.

[0132] Step c: The above tert-butyl 2-(2,6-diethylphenyl)-3-(7-fluoro-1H-indol-4-yl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-carboxylate (200 mg, 0.40 mmol) was dissolved in DMF (5 mL) and loaded with N-chlorosuccinimide (100 mg, 0.75 mmol). The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc, washed with aqueous Na2S2O3 solution, brine, and dried in the presence of MgSO4. The solvent was extracted under reduced pressure and the residue was purified by flash silica gel chromatography (2 to 25% EtOAc in hexanes) to obtain tert-butyl 3-(3-chloro-7-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-carboxylate. MS: (ES) m / z calculated for C30H33OFN4O2 [M - H]-535.2, found 535.2.

[0133] The above tert-butyl 3-(3-chloro-7-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-carboxylate was dissolved in dichloromethane (6 mL) and charged with HCl in dioxane (4 N, 5 mL). The resulting mixture was stirred at room temperature. 47 1935200 of 103 for 12 h. Once the reaction was complete, the solvent was evaporated in vacuo to obtain 3-chloro-4-(2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c ]pyrazol-3yl)-7-fluoro-1 H-indole hydrochloride. MS: (ES) m / z calculated for C25H27 ClFN4 [M + H]+437,2, found 437,2.

[0134] Step d: N,N-Diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspension of 3-chloro-4-(2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole hydrochloride (75 mg, 0.16 mmol) and 2-trifluoromethylbenzaldehyde (120 mg, 0.69 mmol) in 1,2-dichloroethane (6 mL) under magnetic stirring. After stirring at room temperature for 10 min, NaBH(OAc)3 (150 mg, 0.71 mmol) was added to the reaction mixture. The resulting mixture was stirred at 40 °C for 1 h, then cooled to room temperature, diluted with EtOAc, washed with brine, and dried in the presence of MgSO4. The solvent was extracted under reduced pressure and the residue was purified by preparative TLC (40% EtOAc in hexanes) followed by HPLC (MeCN / H2O, with 1% TFA) to obtain 3-chloro-4-(2-(2,6-diethylphenyl)-6,6-dimethyl-5-(2-(trifluoromethyl)benzyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1 H-indole.1H NMR (400 MHz, CD3OD) δ 7.92-7.99 (m, 1H), 7.52-7.66 (m, 2H), 7,347.38 (m, 2H), 7.24-7.29 (m, 2H), 6.94-6.98 (m, 1H), 6.66 (dd, J = 8.2, 10.8 Hz, 1H), 6.50 (dd, J = 4.5, 8.2 Hz, 1H), 4.88 (br, 1H), 4.09 (s, 2H), 3.82 (d, J = 11.5 Hz, 1H), 3.43 (d, J = 11.5 Hz, 1H), 2.53 (dq, J = 7,5, 15 Hz, 1H), 2.37-2.46 (m, 2H), 2.07 (dq, J = 7.5, 15 Hz, 1H), 1.54 (s, 3H), 1.51 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H), 0.76 (t, J = 7.6 Hz, 3H). MS: (ES) m / z calculado para C33H32OT4N4 [M + H]+595,2, encontrado 595,2. Example 4 Synthesis of 4-(5-(2,4-bis(trifluorometil)bencil)-2-(2,6-dietilfenil)-6,6-dimetil-2,4,5,6tetrahydropirrolo[3,4-c ]pirazol-3-il)-7-fluoro-1 H-indol 1935200 de 103

[0135] A mixture of 5-(2,4-bis(trifluoromethyl)benzyl)-3-iodo-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (200 mg, 0.32 mmol), 7-fluoro-4-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)-U7-indole (150 mg, 0.57 mmol), K2CO3 (276 mg, 2.0 mmol), and Pd(dppf)C12 complex with dichloromethane (60 mg, 0.07 mmol) in dioxane (6 mL) and water (1 mL) It was stirred at 100 °C for 5 h under N2. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through a Celite stopper. The filtrate was collected, concentrated in vacuo, and the residue was purified by flash silica gel chromatography (0 to 50% EtOAc in hexanes) to obtain 4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-U / -indole.Ί, 2H), 6.61 (m, 1H), 6.47 (m, 2H), 4.15 (s, 2H), 3.71 (s, 2H), 2.37 (m, 2H), 2.22 (m, 2H), 1.56 (s, 6H), 1.00 (t, J= Ί,β Hz, 6H). MS: (ES) m / z calculado para C34H32F7N4 [M + H]+629,2, encontrado 629,2. Example 5 Synthesis of 4-(5-(3,5-Z> / s(trifluorometil)bencil)-2-(2,6-dietilfenil)-6,6-dimetil-2,4,5,6tetrahydropirrolo[3,4-c]pirazol-3-il)-7-fluoro-1¿f-indol 1935200 de 103 i

[0136] Step a: A mixture of 2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride (2.20 g, 5.1 mmol), 3,5-ozs(trifluoromethyl)benzaldehyde (1.85 g, 7.6 mmol), NaBH(OAc)3 (3.24 g, 15.3 mmol), z'PrNEt2 (0.84 mL, 5.1 mmol) and acetic acid (0.49 mL, 7.6 mmol) in DCM (30 mL) was stirred at room temperature for 1.5 h. It was then stopped with aqueous NaHCCh and extracted with EtOAc. The organic layer was separated, dried in the presence of Na2SC>4, concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (0 to 30% EtOAc in hexanes) to obtain 5-(3,5bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4c]pyrazole. MS: (ES) zzz / z calculated for C26H27FIN3 [M + H]+622,1, found 622,1.

[0137] Step b: A mixture of 5-(3,5-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (1.50 g, 2.4 mmol), 7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-U7-indole (817 mg, 3.1 mmol), K2CO3 (0.830 g, 6.0 mmol), and Pd(dppf)C12 complex with dichloromethane (30 mg, 0.36 mmol) in dioxane (12 mL) and water (1.5 mL) was stirred at 100 °C for 2 h under N2. The reaction mixture was cooled to room temperature and 50 1935200 of 103 divided between EtOAc and NaHCCh. The organic head separated, separated in the presence of NazSCh, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0 to 50% EtOAc in hexane) followed by HPLC (MeCN / EEO, with 1% TFA) to obtain 4-(5-(3,5-Z>zXtrifluoromethyl)bencyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahidropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-U7-indole. 'H NMR (400 MHz, CDCh) δ 8.48 (s, 1H), 7.92 (s, 2H), 7.14 (s, 1H), 7.24 (dd, J= Ί,β, Ί,β Hz, 1H), 7.20 (d, J= 2.8 Hz, 1H), 7.07 (dd, J= 7.6, 7.6 Hz, 2H), 6.61 (m, 1H), 6.47 (m, 2H), 4.03 (s, 2H), 3.65 (s, 2H), 2.37 (m, 2H), 2.22 (m, 2H), 1.56 (s, 6H), 1.00 (t, J= Ί,β Hz, 6H). MS: (ES) m / z calculated for C34H32F7N4 [M + H]+629.2, set at 629.2. Example 6 Synthesis of the intermediary methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Z / -indole-7carboxylate Bís(pin acolat o id ibo ro lJd{dp[]f)CI2-CI laÜI2 Dioxane

[0138] Step a: To a suspension of methyl 4-bromo-U7-indole-7-carboxylate (300 mg, 1.18 mmol), Z»A(pinacolato)diboron (330 mg, 1.30 mmol), and KOAc (290 mg, 2.96 mmol) in dioxane (8 mL) was added Pd(dppf)C12 complex with dichloromethane (100 mg, 0.12 mmol). The reaction mixture was degassed with N2 for 2 min and stirred at 100 °C for 1 h. The reaction mixture was diluted with EtOAc and filtered through Celite. The solvent was extracted under reduced pressure and the residue was purified by flash silica gel chromatography (5 to 30% EtOAc in hexanes) to obtain methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-U7-indol 7-carboxylate. MS: (ES) m / z calculated for C16H21BNO4 [M + H]+302.2, found 302.2. Example 7 Synthesis of (4-(5-(2,4-Z>zs(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-1 / / -indol-7-yl jinet anol 1935200 of 103

[0139] Step a: A mixture of 5-(2,4-Z>zs(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (100 mg, 0.16 mmol), methyl 4-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)-U7-indol-7-carboxylate (78 mg, 0.26 mmol), K2CO3 (150 mg, 1.1 mmol) and Pd(dppf)C12 complex with dichloromethane (90 mg, 0.11 mmol) in dioxane (4 mL) and water (0.7 mL) was stirred at 100 °C for 2 h under N2. The reaction mixture was cooled to room temperature and divided between aqueous EtOAc and NaHCCh. The organic layer was separated, dried in the presence of Na2SC>4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0 to 40% EtOAc in hexanes) to obtain methyl 4-(5-(2,4Z>z5(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-U7-indole-7-carboxylate. MS: (ES) zzz / z calculated for C36H35F6N4O2 [M + H]+669.3, found 669.3.

[0140] Step b: To a solution of methyl 4-(5-(2,4-Z>zs(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-U7-indole-7-carboxylate (25 mg, 0.037 mmol) in THF (1.5 mL) at 0 °C, a solution of LiAlEL in ether (1.0 M, 0.20 mL, 0.20 52 1935200 of 103 mmol). After 1 h at 0 °C, the reaction mixture was neutralized with water and divided between EtOAc and aqueous NaHCCb. The organic layer was separated, dried in the presence of Na2SC>4, and concentrated in vacuo. The residue was purified by HPLC (MeCN / EEO, with 1% TFA) followed by flash silica gel chromatography (0 to 60% EtOAc in hexanes) to obtain (4-(5-(2,4Z>z5(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-1#-indol-7-yl)methanol. 'H NMR (400 MHz, CDCh) δ 8.99 (s, 1H), 8.18 (d, J= 8.0 Hz, 1H), 7.86 (s, 1H), 7.74 (d, J= 8.4 Hz, 1H), 7.24 (m, 2H), 7.06 (d, J= Ί,β Hz, 2H), 6.70 (d, J= 7.4 Hz, 1H), 6.49 (d, J= 7.4 Hz, 1H), 6.48 (d, J= 2.6 Hz, 1H), 4.92 (d, J= 5.6 Hz, 2H), 4.15 (s, 2H), 3.72 (s, 2H), 2.39 (m, 2H), 2.26 (m, 2H), 1.83 (t, J= 5.8 Hz, 1H), 1.56 (s, 6H), 1.02 (t, J= 7.6, 6H). MS: (ES) m / z calculated for C35H35F6N4O [M + H]+641.3, found 641.3. Example 8 Synthesis of the intermediate 3,3,3-trifluoro-2,2-dimethylpropanoyl chloride (COCI)2

[0141] A mixture of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (0.312 g, 2.0 mmol), oxalyl chloride (0.17 mL, 2.0 mmol) and DMF (2 drops) in DCM (6.7 mL) was stirred at room temperature for 30 min. The reaction mixture containing 3,3,3-trifluoro-2,2-dimethylpropanoyl chloride was used directly in the next step without further purification. Example 9 Synthesis of 4-(2-(2,6-diethylphenyl)-6,6-dimethyl-5-(3,3,3-trifluoro-2,2-dimethylpropyl)-2,4,5,6tetrahydropyrrolo|3.4-c|pyrazol-3-yl)-7-yluoro-1 / / -indole 1935200 of 103

[0142] Step a: A mixture of 4-(2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-U / -indole hydrochloride (78 mg, 0.18 mmol), 3,3,3-trifluoro-2,2-dimethylpropanoyl chloride (~2 mmol) and NEts (0.13 mL, 0.89 mmol) in DCM (3 mL) was stirred for 1h at room temperature. The mixture was then divided between EtOAc and aqueous NaHCCh. The organic layer was separated, dried in the presence of Na2SC>4, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0 to 15% EtOAc in DCM) to obtain 1-(2-(2,6-diethylphenyl)-3-(7-fluoro-U / -indol-4-yl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4c]pyrazol-5(4J7)-yl)-3,3,3-trifluoro-2,2-dimethylpropan-l-one. MS: (ES) m / z calculated for C30H33F4N4O [M + H]+541.3, found 541.2.

[0143] Step b: A solution of l-(2-(2,6-diethylphenyl)-3-(7-fluoro-U / -indol-4-yl)-6,6-dimethyl2,6-dihydropyrrolo[3,4-c]pyrazol-5(4J7)-yl)-3,3,3-trifluoro-2,2-dimethylpropan-l-one (35 mg, 0.064 mmol) in THF (2 mL) was mixed with a solution of DIBAL-H in DCM (1.0 M, 1.5 mL, 1.5 mmol). After 1 h at room temperature, the reaction mixture was stopped with aqueous NaHCO3 and divided between EtOAc and aqueous NaHCO3. The organic layer was separated, dried in the presence of Na2SO4, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0 to 10% EtOAc in DCM) to obtain 4-(2-(2,6-diethylphenyl)-6,6-dimethyl-5-(3,3,3trifluoro-2,2-dimethylpropyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-U / -indole.H NMR (400 MHz, CDCI3) δ 8.49 (s, 1H), 7.27 (dd, J= 2.4, 2.4 Hz, 1H), 7.23 (dd, J= 8.0, 8.0 Hz, 1H), 7.06 (d, J= 7, 2.2), m 6.56 (m, 1H), 6.47 (m, 1H), 3.93 (s, 2H), 2.84 (s, 2H), 2.35 (m, 2H), 2.20 (m, 2H), 1.41 (s, 6H), 1.19 (β (H, = 6Ί). MS: (ES) m / z calculated for C30H35F4N4 [M + H]+527.3, found 527.2. Example 10 Synthesis of 4-(5-(2,4-Z> / s(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahydropyrrole [3,4-c] pyrazol-3-yl)-3-fluorol- 1 / / -indo S.ísípinacolatojdiboro Η(ί{[ίρμί)ϋ|2-ϋΝ;Π2 KOAc Dioxanecr Step a 1935200 of 103 Hi{[ip[]í)GI2-GH;GI2 K3CO3Dioxane - HZO Step b

[0144] Step a: A suspension of 4-bromo-3-fluoro-Uf-indole (240 mg, 1.1 mmol), Z>zs(pinacolato)diboron (420 mg, 1.7 mmol) and KOAc (320 mg, 3.3 mmol) in dioxane (5 mL) was mixed with Pd(dppf)Ch complex containing dichloromethane (140 mg, 0.17 mmol). The reaction mixture was degassed with N2 for 2 min and stirred at 90 °C for 2 h. The reaction mixture was adsorbed onto silica gel and purified by flash silica gel chromatography (0 to 100% EtOAc in hexanes) to obtain 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Z7indole. MS: (ES) m / z calculated for C14H18BFNO2 [M + H]+262.1, found 261.2.

[0145] Step b: To a suspension of 5-(2,4-Z>zXtrifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-3iodo-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (74 mg, 0.12 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lZ / -indole (64 mg, 0.25 mmol) and K2CO3 (169 mg, 1.2 mmol) in dioxane (6 mL) and water (1 mL) Pd(dppf)C12 complex with dichloromethane (49 mg, 0.060 mmol) was added. The reaction mixture was degassed with N2 for 2 min and stirred under N2 at 90 °C for 16 h. The reaction mixture was adsorbed onto silica gel and purified by flash silica gel chromatography (0 to 30% MTBE in hexanes) followed by HPLC (MeCN / ELO, with 1% TFA), and preparative TLC (EtOAc in toluene) to obtain 4-(5-(2,4Z>z5(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-3-fluoro-1#-indole.'H NMR (400 MHz, CD3OD) δ 8.25 (d, J= 8.4 Hz, 1H), 7.89-7.94 (m, 2H), 7.28 (t, J= Ί,β Hz, 1H), 7.20 (dd, J= 8.77, 1, 2.6 3H), 6.85 (t, J= 8.4 Hz, 1H), 6.51 (d, J= 7.2 Hz, 1H), 4.19 (s, 2H), 3.65 (s, 2H), 2.19–2.50 (m, 4H), 1.74–H2, 0, 6). MS: (ES) m / z calculated for C34H32F7N4 [M + H]+629.3, found 629.3. 1935200 of 103 Example 11 Synthesis of 4-(5-(2,4-Z>z's(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahydropyrrole|3.4-c|pyrazol-3-yl)-3-inethyl-1 / / -indole 8is(pinaculate)diburo Pd{dppf)Glz-CHzCI? KOAc Dioxane Step a Pd(dppf)CI2'CH2Clsk2c;o3Dioxane - HjO Step b

[0146] Step a: To a suspension of 4-bromo-3-methyl-U / -indole (240 mg, 1.1 mmol), Z>zs(pinacolato)diboron (910 mg, 3.6 mmol) and KOAc (710 mg, 7.2 mmol) in dioxane (6 mL) Pd(dppf)C12 complex with dichloromethane (290 mg, 0.36 mmol) was added. The reaction mixture was degassed (N2) for 2 min and stirred at 90 °C for 4 h. The reaction mixture was adsorbed onto silica gel and purified by flash silica gel chromatography (0 to 25% MTBE in hexanes) to obtain 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-17 / -indole. MS: (ES) m / z calculated for C15H21BNO2 [M + H]+258.2, found 258.1.

[0147] Step b: To a suspension of 5-(2,4-Z>zXtrifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (65 mg, 0.10 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-17 / -indole (127 mg, 0.49 mmol), and K2CO3 (256 mg, 1.9 mmol) in dioxane (6 mL) and water (1 mL), Pd(dppf)C12 complex with dichloromethane (51 mg, 0.062 mmol) was added. The reaction mixture was degassed with N2 for 2 min and stirred under N2 at 90°C. 1935200 at 103 °C for 2 h. The reaction mixture was adsorbed onto silica gel and purified by flash silica gel chromatography (0 to 100% MTBE in hexanes) followed by HPLC (MeCN / EEO, with 1% TFA) and preparative TLC (40% acetone in hexanes) to obtain 4-(5(2,4-Z>A(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4c]pyrazol-3-yl)-3-methyl-l#-indole. 'HNMR (400 MHz, CD3OD) δ 8.25-8.18 (m, 1H), 7.92 (d, J = 9.0 Hz, 2H), 7.29-7.17 (m, 3H), 7.04 (d, J= 1.2 Hz, 1H), 6.97-6.90 (m, 1H), 6.77 (dd, J= 8.2, 7.3 Hz, 1H), 6.44 (dd, J= 7.4, 0.9 Hz, 1H), 4.25-4.10 (m, 2H), 3.66 (d, J= 11.6 Hz, 1H), 3.51 (d, J= 11.6 Hz, 1H), 2.28-2.58 (m, 3H), 2.17 (s, 3H), 2.00-2.11 (m, 1H), 1.55 (s, 3H), 1.53 (s, 3H), 1.34 (t, J= Ί,β Hz, 3H), 0.77 (t, J= Ί,β Hz, 3H). MS: (ES) m / z calculated for C35H35F6N4 [M + H]+625.3, found 625.3. Example 12 Synthesis of tert-butyl 2-(2,6-dimethylphenyl)-3-(lZ / -indol-5-yl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5carboxylate 1935200 of 103

[0148] Step a: To tert-butyl 3-cyano-4-oxo-pyrrolidine-1-carboxylate (19.5 g, 92.54 mmol) and (2,6-dimethylphenyl)hydrazine hydrochloride (16 g, 92.65 mmol) EtOH (160 mL) and AcOH (40 mL) were added. The resulting suspension was stirred at 50 °C overnight. Upon completion, the reaction mixture was stopped with 1N aqueous NaOH solution and extracted with EtOAc (2 x 100 mL), dried (MgSO4), and concentrated in vacuo. The crude product was then purified by flash silica gel chromatography (50% EtOAc in hexanes) to obtain tert-butyl 3-amino-2-(2,6-dimethylphenyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5-carboxylate. MS: (ES) m / z calculated for C18H25N4O2 [M + H]+329.2, found 329.2.

[0149] Step b: Isoamyl nitrite (11.74 mL, 87.5 mmol) was slowly added at room temperature to a mixture of tert-butyl 3-amino-2-(2,6-dimethylphenyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxylate (14.35 g, 43.75 mmol), diiodomethane (14 mL, 175 mmol), and MeCN (180 mL). The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was adsorbed onto silica gel and purified by flash silica gel chromatography (30% EtOAc in hexanes) to obtain tert-butyl 2-(2,6-dimethylphenyl)-3-iodo-4,6-dihydropyrrolo[3,4c]pyrazole-5-carboxylate. MS: (ES) m / z calculated for C18H23IN3O2 [M + H]+440,1, found 440,2.

[0150] Step c: To a suspension of tert-butyl 2-(2,6-dimethylphenyl)-3-iodo-4,6-dihydropyrrolo[3,4-c]pyrazol-5-carboxylate (878 mg, 2 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-indole (729 mg, 3 mmol), and Na2CO3 (530 g, 5 mmol) in dioxane (8 mL) and water (2 mL), Pd(dppf)Cl2 complex with dichloromethane (163 mg, 0.2 mmol) was added. The reaction mixture was degassed with N2 for 2 min and stirred at 90 °C for 2 h. The reaction mixture was diluted with EtOAc and filtered through Celite. The solvent was extracted under reduced pressure and the residue was purified by flash silica gel chromatography (0 to 100% EtOAc in hexanes) to obtain tert-butyl 2-(2,6-dimethylphenyl)-3-(1H-indol-5-yl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5-carboxylate. MS: (ES) m / z calculated for C26H29N4O2 [M + H]+429.2, found 429.2. Example 13

[0151] The compounds in Table 2 below were prepared using the methods described above. Error! Reference source not found. 1935200 of 103 characterization (MS and / or NMR) are provided for each compound on the list. Table 1: Structure & Characterization Data (Nuclear Magnetic Resonance / Mass Spectrometry or NMR / MS) of the specific embodiments Estructura Ή NMR MS Ej. 13.001 O i 0 N O ' j h W NH 1H NMR (400 MHz, CD3OD) δ 7,44 (d, J= 3,1 Hz, 1H), 7,32 (t, J= 8,0 Hz, 1H), 7,16 (d, J= 7,6 Hz, 2H), 6,59-6,65 (m, 1H), 6,53-6,56 (m, 1H), 6,45-6,50 (m, 1H), 4,72 (s, 2H), 3,88 (s, 2H), 2,19-2,37 (m, 4H), 1,87 (s, 6H), 1,46 (s, 9H), 0,99 (t, J= 7,6 Hz, 6H). MS: (ES) m / z calculado para C32H39FN5O3 [M + H]+560,3, encontrado 560,3. Ej. 13.002 0^> W NH 'H NMR (400 MHz, CD3OD) δ 7,89 (brs, 1Η), 7,37 (d, J = 3,2 Hz, 1H), 7,31 (t, . / =8,0 Hz, 1H), 7,12-7,15 (m, 3H), 6,54-6,60 (m, 1H), 6,50-6,53 (m, 1H), 6,39-6,43 (m, 1H), 4,12 (s, 2H), 3,90 (s, 2H), 2,15-2,37 (m, 4H), 1,50 (s, 6H), 0,97 (t, J= 7,6 Hz, 6H). MS: (ES) m / z calculado para C29H31FN5O [M + H]+ 484,3, encontrado 484,3. 1935200 de 103 Ej. 13.003 i Z°H \XN N V' -L 1H NMR (400 MHz, CDCh) δ 8,53 (s, 1H), 7,27 (dd, 7=2,6, 2,6 Hz, 1H), 7,23 (dd, 7=7,6, 7,6 Hz, 1H), 7,06 (d,7=7,6, 2H), 6,63 (m, 1H), 6,56 (m, 1H), 6,48 (m, 1H), 3,99 (s, 2H), 2,70 (s, 2H), 2,39 (m, 2H), 2,23 (m, 2H), 1,62 (br s, 1H), 1,43 (s, 6H), 1,25 (s, 6H), 0,99 (t, 7= 7,6 Hz, 6H). MS: (ES) m / z calculado para C29H36FN4O [M + H]+ 475,3, encontrado 475,3. Ej. 13.004 F3C-^\ / CF3 xy \ N H K / NHN , XXX 1H NMR (400 MHz, CD3OD) δ 8,20-8,27 (m, 1H), 7,89-7,92 (m, 2H), 7,38 (s, 1H), 7,227,32 (m, 2H), 6,95-6,98 (m, 1H), 6,66 (dd, 7=8,2, 10,8 Hz, 1H), 6,50 (dd, 7= 4,5, 8,2 Hz, 1H), 4,88 (br, 1H), 4,18 (s, 2H), 3,84 (d, 7 = 11,4 Hz, 1H), 3,49 (d, 7 = 11,4 Hz, 1H), 2,47 (dq, 7=7,5, 15 Hz, 1H), 2,372,46 (m, 2H), 2,07 (dq, 7= 7,5, 15 Hz, 1H), 1,54 (s, 3H), 1,52 (s, 3H), 1,33 (t, 7= 7,6 Hz, 3H), 0,76 (t, 7= 7,6 Hz, 3H). MS: (ES) m / z calculado para C34H31CIF7N4 [M + H]+663,2, encontrado 663,2. Ej. 13.005 Cl F Tj] \,-N. W Xanh N'>nl .-1. ..F^'F X Ή NMR (400 MHz, CD3OD) δ 7,56-7,61 (m, 1H), 7,34 (d, 7 = 3,0 Hz, 1H), 7,30 (t, 7= 7,6 Hz, 1H), 7,18-7,22 (m, 1H), 7,14 (d, 7= 8,0 Hz, 2H), 7,017,07 (m, 1H), 6,53-6,58 (m, 1H), 6,45 (t, 7=3,1 Hz, 1H), 6,38-6,42 (m, 1H), 4,04 (s, 2H), 3,73 (s, 2H), 2,15-2,38 (m, 4H), 1,57 (s, 6H), 0,98 (t, 7 = 7,2 Hz, 6H). MS: (ES) m / z calculado para C32H32CIF2N4 [M + H]+ 545,2, encontrado 545,2. 1935200 de 103 Yes. 13.006 TjT W NH N'm 1H NMR (400 MHz, CD3OD) δ 7.50 (m, 1H), 7.37 - 7.26 (m, 2H), 7.14 (d, 7= 7.7 Hz, 2H), 6.7=6, 8.2 (t (dd, J= 10.9, 8.2 Hz, 1H), 6.48 −6.36(m, 2H), 3.96 (s, 2H), 3.73 (s, 2H), 2.26 (m, 4H), 1.56 (s, 6H), 0.7=6 (t)., 0.7=6 H7)., MS: (ES) m / z calculated for C32H32F3N4 [M + H]+ 529.3, found 529.3. Yes. 13,007 Ljj \ NH OH NV \ Ϊ F 'H NMR salt of TFA (400 MHz, CD3OD) δ 11.41 (s, 1H), 8.75 (d, 7= 5.6 Hz, 2H), 7.94 (d, 7= 5.6 Hz, 2H), 7.94 (dd, 7, 7= 62.4), 2.6, 2.6 Hz, 1H), 7.34 (dd, 7 = 7.6, 7.6 Hz, 1H), 7.16 (d, 7 = 7.6 Hz, 2H), 6.60 (m, 1H), 6.45 (m, 2H, 4, 29H), 4.67 (s, s (m, 4H), 1.88 (s, 6H), 0.98 (t, 7= 7.6 Hz, 6H). MS: (ES) m / z calculated for C31H33FN5 [M + H]+ 494.3, found 494.3. Yes. 13.008 TJ \ n —V ^ci.^ Μ Γ..ΝΗ N.L-z'L N v 1 1 '0''' 1H NMR (400 MHz, CD3OD) δ 7,47-7,57 (m, 1H), 7,39 (s, 1H), 7,23-7,28 (m, 2H), 7,127,16 (m,2H), 6,95-6,98 (m, 1H), 6,66 (dd, 7=8,2, 10,8 Hz, 1H), 6,50 (dd, 7= 4,5, 8,2 Hz, 1H), 4,88 (br, 1H), 4,00 (d,7 = 11,4 Hz, 1H), 3,81-3,90 (m, 2H), 3,50 (d, 7= 11,4 Hz, 1H), 2,33-2,46 (m, 3H), 2,00-2,13 (m, 1H), 1,56 (s, 3H), 1,49 (s, 3H), 1,31 (t, 7= 7,6 Hz, 3H), 0,75 (t, 7= 7,6 Hz, 3H). MS: (ES) m / z calculado para C32H31CI2F2N4 [M + H]+ 579,2, encontrado 579,2. 1935200 de 103 Ej. 13.009 \ N ΛΑ £ NH n v X T £Xf 'H NMR sal de TFA (400 MHz, CD3OD) δ 11,46 (s, 1H), 8,87 (d, J= 1,0 Hz, 1H), 8,71 (d, 7=5,2 Hz, 1H), 8,26 (d, J = 7,6 Hz, 1H), 7,68 (m, 1H), 7,41 (dd, 7=2,8, 2,8 Hz, 1H), 7,35 (dd, 7=7,8, 7,8 Hz, 1H), 7,18 (d, 7= 8,0 Hz, 2H), 6,61 (m, 1H), 6,45 (m, 2H), 4,75 (s, 2H), 4,53 (s, 2H), 2,25 (m, 4H), 1,97 (s, 6H), 0,97 (t, 7 = 7,6 Hz, 6H). MS: (ES) m / z calculado para C31H33FN5 [M + H]+ 494,3, encontrado 494,3. Ej. 13.010 TJ \ N-, —V W £ NH N TXA 1H NMR (400 MHz, CD3OD) δ 7,46-7,52 (m, 1H), 7,39 (s, 1H), 7,23-7,28 (m, 2H), 6,827,00 (m, 3H), 6,66 (dd, 7= 8,2, 10,8 Hz, 1H), 6,50 (dd, 7= 4,5, 8,2 Hz, 1H), 4,88 (br, 1H), 4,00 (d, 7 = 11,6 Hz, 1H), 3,81-3,90 (m, 2H), 3,50 (d, 7 = 11,6 Hz, 1H), 2,30-2,58 (m, 3H), 2,00-2,12 (m, 1H), 1,57 (s, 3H), 1,49 (s, 3H), 1,31 (t, 7 = 7,6 Hz, 3H), 0,75 (t,7=7,6 Hz, 3H). MS: (ES) m / z calculado para C32H31CIF3N4 [M + H]+563,2, encontrado 563,2. Ej. 13.011 X^^F \.-N...£X XaNH XxX 1 1H NMR (400 MHz, CD3OD) δ 7,26-7,34 (m, 3H), 7,167,25 (m, 2H), 7,13 (d, 7= 7,2 Hz, 2H), 6,90-7,00 (m, 1H), 6,55 (dd, 7 = 10,9, 8,1 Hz, 1H), 6,36-6,46 (m, 2H), 5,46-5,51 (m, 1H), 3,93 (s, 2H), 3,67 (s, 2H), 2,05-2,45 (m, 4H), 1,54 (s, 6H), 0,98 (t, 7= 7,6 Hz, 6H). MS: (ES) m / z calculado para C32H33F2N4 [M + H]+ 511,3, encontrado 511,3. 1935200 de 103 Yes. 13.012 Xji \ N XNHN V' 1 'H NMR salt of TFA (400 MHz, CD3OD) δ 11.46 (s, 1H), 8.68 (d, J =4.8 Hz, 1H), 7.92 (dd, J= 1.6, 76=H0, Hz), 1H), 7.45 (m, 2H), 7.38 (dd, 7=7.6, 7.6 Hz, 1H), 7.18 (d, 7= 7.6 Hz, 2H), 6.62 (m, 1H), 6.53 (m, 1H), 6.45 (s), 1795 (m, 4 (s, 2H), 2.27 (m, 4H), 1.92 (s, 6H), 0.98 (t, 7= 7.6 Hz, 6H). MS: (ES) m / z calculated for C31H33FN5 [M + H]+ 494.3, found 494.3. Yes. 13.013 CK .Cl YjT \χΝχ W Γ^νη n. Λ Γ 1H NMR (400 MHz, CD3OD) δ 7.57 (d, 7= 8.2 Hz, 1H), 7.44 (d, 7=2.1 Hz, 1H), 7.26-7.37 (m, 3H), 7.14, 7.6 (dd, 7= Hz 7= 8.2, 10.8 Hz, 1H), 6.39–6.46 (m, 2H), 4.88 (br, 1H), 4.04 (s, 2H), 3.74 (s, 2H), 2.03–2.33 (m, 4H, 7, 1.56 (0,6=H Hz, 6H). MS: (ES) m / z calculated for C32H32CI2FN4 [M + H]+561.2, found 561.2. Yes. 13.014 W NH Νλα XX^ 1H NMR (400 MHz, CD3OD) δ 7,42 (d, 7= 8,4 Hz, 2H), 7,28-7,34 (m, 4H), 7,20-7,26 (m, 1H), 7,14 (d, 7= 7,7 Hz, 2H), 6,55 (dd, 7=8,2, 11,0 Hz, 1H), 6,47-6,35 (m, 2H), 3,93 (s, 2H), 3,68 (s, 2H), 2,12-2,39 (m, 4H), 1,56 (s, 6H), 0,97 (t, 7 = 7,6 Hz, 6H). MS: (ES) m / z calculado para C32H34FN4 [M + H]+ 493,3, encontrado 493,3. 1935200 de 103 Yes. 13.015 Tj \ Νχ HL NH NVL 1H NMR (400 MHz, CD3OD) δ 7.32–7.49 (m, 1H), 7.257.34 (m, 3H), 7.04–7.14 (m, 4H–), 1.5.5 6.386.46 (m, 2H), 4.88 (br, 1H), 3.99 (s, 2H), 3.74 (s, 2H), 2.17-2.36 (m, 4H), 1.57 (s, 6H), 0.97 (t, J= 6.6). MS: (ES) m / z calculated for C32H33F2N4 [M + H]+ 511.3, found 511.3. Yes. 13.016 rj \ Νχ HL NH NVL 1 1H NMR (400 MHz, CD3OD) δ 7.39-7.45 (m, 2H), 7.267.36 (m, 2H), 7.14 (d, J =8.2 Hz, 6, 2H), 2H 6.55 (dd, 7=8.2, 11.0 Hz, 1H), 6.35–6.46 (m, 2H), 4.88 (br, 1H), 3.91 (s, 2H), 3.66 (s, 2H), 2.17–2.36 (t, 9), 1, 4H J= 7.6 Hz, 6H). MS: (ES) m / z calculated for C32H33F2N4 [M + H]+ 511.3, found 511.3. Yes. 13.017 F3ZAzCF3 TJ \ N / W £ NH NNV Á [ 'Az'Ci 1H NMR (400 MHz, CD3OD) δ 8.23 ​​(d, J =8.2 Hz, 1H), 7.92-7.93 (m, 27-7), 7.2,2 (d, J =7.7 Hz, 2H), 6.83 (d, J =7.7 Hz, 1H), 6.42-6.48 (m, 2H), 4.88 (br, 1H), 4.22 (s, 2H), 3.66 (s, 2H), 2.6 (s, 2H), 2.6 (H, 2.2). 1.00 (t, J =7.6 Hz, 6H).MS: (ES) m / z calculated for C34H32CIF6N4 [M + H]+ 645,2, found 645,2. 1935200 of 103 Yes. 13.018 f3c^_cf3 TJ W NH NnXX 1H NMR (400 MHz, CD3OD) 6 8.24 (d, 7= 8.6 Hz, 1H), 7.89 - 7.95 (m, 2H), 7.24 - J7, 7,2.34 (m Hz, 2H), 6.60 (d, 7= 7.2 Hz, 1H), 6,336.42 (m, 2H), 4.22 (s, 2H), 3.73 (s, 2H), 2.16–2.42 (m, 7H), 1.57 (t, 0, 6), 1.56 (s, =H 6H). MS: (ES) m / z calculated for C35H35F6N4 [M + H]+ 625.3, found 625.3. Yes. 13.019 f3C-^\^CF3 Xj Y..N... FA N. ΚΑΎ % NH 'XX F Ή NMR (400 MHz, CD3OD) 6 8,25-8.29 (m, 1H), 7,957.97 (d, 2H, 7, 7,21), 7 = 1.4 Hz, 1H), 6.47 (dd, 7 = 1.4, 12.6 Hz, 1H), 6.33-6.35 (m, 1H), 4.88 (br, 1H), 4.25 (s, 2H-1), 3.93, 5.5 (s, 2, 25 (H), 2H (s, 6H), 1.04 (t, 7= 7.6 Hz, 6H). MS: (ES) m / z calculated for C34H32F7N4 [M + H]+ 629.2, found 629.3. Yes. 13.020 oX) N \ N zOH N, K / A N V' 1 Ϊ XX F 'H NMR sal de TFA (400 MHz, CD3OD) 6 11,31 (s, 1H), 8,56 (d, 7= 4,4 Hz, 1H), 7,99 (dd, 7 = 1,6, 7,2 Hz, 1H), 7,73 (d, 7= 7,6 Hz, 1H), 7,50 (m, 1H), 7,32 (m, 2H), 7,15 (d, 7= 7,6 Hz, 2H), 6,58 (m, 1H), 6,44 (m, 1H), 6,39 (m, 1H), 4,71 (s, 2H), 2,28 (m, 4H), 2,03 (s, 6H), 0,99 (t, 7= 7,6 Hz, 6H). MS: (ES) m / z calculado para C3iH3iFN5O[M + H]+ 508,2, encontrado 508,2. 1935200 de 103 Yes. 13.021 Tj \ N JJ JU nv X. Ϊ Xto'F 1H NMR (400 MHz, CDCh) δ 8.30 (s, 1H), 7.91 (d, 7=7.6 Hz, 1H), 7.51 (d, 7, 7, 7, 7, 8, 1, Hz), 7.6 Hz, 1H), 7.14 (m, 3H), 6.97 (d,7 = 7.6 Hz, 2H), 6.51 (m, 1H), 6.41 (m, 1H), 6.36 (m, 1H), 4.00 (s, 2H), 3,2, 3,6 2.12 (m, 2H), 1.47 (s, 6H), 0.90 (t, 7 = 7.4 Hz, 6H). MS: (ES) m / z calculated for C33H33F4N4 [M + H]+ 561.3, found 561.3. Yes. 13.022 CK / , τ T \ N 1 / F~\ Γ NH N LU NVX Ϊ XXu~F UQi Ή NMR (400 MHz, CDCI3) δ 8.54 (s, 1H), 7.26 (dd,7=2.8, 7, 2.8), 7.6, 7.6 Hz, 1H), 6.99 (d,7=7.6 Hz, 2H), 6.59 (m, 1H), 6.43 (m, 2H), 4.53 (s, 2H), 2.20 (m, 6H), 1.84 (m, 13H). MS: (ES) m / z calculated for C30H36FN4O [M + H]+ 487.3, found 487.3. Yes. 13.023 FaC-^s^CFa Tj _X\ VJ J / nh N, XXJ Vj f Ή NMR (400 MHz, CDCI3) δ 8,19 (s, 1H), 8,11 (d, 7=8,0 Hz, 1H), 7,78 (s, 1H), 7,67 (d, 7= 8,4 Hz, 1H), 7,17 (dd, 7 = 7,8, 7,8 Hz, 1H), 7,09 (dd,7 = 2,8, 2,8 Hz, 1H), 7,01 (d,7 = 7,6 Hz, 2H), 6,81 (dd,7=2,0, 8,8 Hz, 1H), 6,35 (m, 1H), 6,25 (dd, 7=2,0, 10,8 Hz, 1H), 4,06 (s, 2H), 3,64 (s, 2H), 2,28 (m, 2H), 2,15 (m, 2H), 1,48 (s, 6H), 0,92 (t, 7 = 7,6 Hz, 6H). MS: (ES) m / z calculado para C34H32F7N4 [M + H]+ 629,2, encontrado 629,2. 1935200 de 103 Ej. 13.024 \ N FJ Γ NH 1H NMR (400 MHz, CDC13) δ 8,54 (s, 1H), 7,34 (dd, 7= 2,8, 2,8 Hz, 1H), 7,26 (m, 1H), 7,07 (d, J =7,6 Hz, 2H), 6,68 (m, 1H), 6,49 (m, 2H), 4,85 (s, 2H), 2,84 (s, 2H), 2,32 (m, 2H), 2,20 (m, 2H), 1,91 (s, 6H), 1,54 (s, 6H), 1,00 (t, 7 = 7,6 Hz, 6H). MS: (ES) m / z calculado para C30H33F4N4O [M + H]+541,3, encontrado 541,2. Ej. 13.025 f3c_^_cf3 TJ >N)CF W NII ' Γ''-·' 1H NMR (400 MHz, CD3OD) 6 8,21 (d, 7= 8,4 Hz, 1H), 7,90 (br s, 2H), 7,24 - 7,31 (m, 4H), 6,92 - 6,95 (m, 1H), 6,88 (t, 7 = 8,4 Hz), 6,55 (dd, 7= 0,76, 7,6 Hz, 1H), 4,18 (s, 2H), 3,86 (d, 7 = 12 Hz, 1H), 3,48 (d,7 = 11,6 Hz, 1H), 2,03-2,61 (m, 4H), 1,54 (s, 3H), 1,53 (s, 3H), 1,35 (t, 7= 7,6 Hz, 3H), 0,75 (t, 7= 7,6 Hz, 3H). MS: (ES) m / z calculado para C34H32CIF6N4 [M + H]+ 645,2, encontrado 645,2. Ej. 13.026 F3C_^XF3 rrj \,N, -Y ' / NC._ Η Γ NH n'n Y¿Y' 1H NMR (400 MHz, CD3OD) 6 8,38 (d, 7= 8,7 Hz, 1H), 8,06 (s, 1H), 7,88 (d, 7= 4,5 Hz, 2H), 7,41 (dd, 7= 8,3, 0,8 Hz, 1H), 7,23 - 7,33 (m, 2H), 6,93-7,08 (m, 2H), 6,68-6,75 (m, 1H), 4,21 (s, 2H), 3,99 (d, 7= 11,3 Hz, 1H), 3,51 (d,7 = 11,4 Hz, 1H), 2,46-2,68 (m, 2H), 2,30-2,40 (m, 1H), 1,98 -2,06 (m, 1H), 1,57 (s, 3H), 1,55 (s, 3H), 1,36 (t, 7= 7,5 Hz, 3H), 0,77 (t, 7= 7,6 Hz, 3H). MS: (ES) m / z calculado para C35H32F6N5 [M + H]+ 636,3, encontrado 636,3. 1935200 de 103 Ej. 13.027 F3C^ ^xCF3 XI \ N π Oh N. < 'X0j 1H NMR (400 MHz, CDCh) δ 8,42 (s, 1H), 8,20 (d, 7=8,4 Hz, 1H), 7,86 (s, 1H), 7,77 (d, J= 8,0 Hz, 1H), 7,21 (m, 2H), 7,03 (br s, 2H), 6,51 (t, J= 10,4 Hz, 1H), 6,38 (m, 1H), 4,14 (s, 2H), 3,63 (s, 2H), 2,38 (br s, 4H), 1,56 (s, 6H), 1,00 (br s, 6H). MS: (ES) m / z calculado para C34H31F8N4 [M + H]+ 647,2, encontrado 647,2. Ej. 13.028 F3C^\ X 1 X^xf3 VNY W NH n'nKO ΊΧχ· z 1H NMR (400 MHz, CD3OD) δ 8,34 (s, 1H), 7,89 (d, 7=8,2 Hz, 1H), 7,69 -7,77(m, 1H), 7,22- 7,35 (m, 3H), 7,14 (d, 7 = 7,7 Hz, 2H), 6,80 (t, 7= 7,8 Hz, 1H), 6,49 (m, 1H), 6,34 (m, 1H), 4,22 (s, 2H), 3,71 (s, 2H), 2,20-2,50 (m, 4H), 1,56 (s, 6H), 0,99 (m, 6H). MS: (ES) m / z calculado para C34H33F6N4 [M + H]+ 611,3, encontrado 611,3. Ej. 13.029 f3c_^ X 1 X^cf3 VNY W NH nn: 1 1H NMR (400 MHz, CD3OD) δ 7,38 (d, 7= 3,0 Hz, 1H), 7,24-7,35 (m, 4H), 7,15 (d, 7 = 7,6 Hz, 2H), 6,90-7,01 (m, 3H), 6,85 (t, 7= 7,6 Hz, 1H), 6,54 (d, 7= 7,2 Hz, 1H), 6,48 (d, 7= 3,1 Hz, 1H), 4,82 (s, 2H), 2,18-2,42 (m, 4H), 1,91 (s, 6H), 0,99 (t, 7= 7,6 Hz, 6H). MS: (ES) m / z calculado para C33H35N4O2 [M + H]+ 519,3, encontrado 519,3. 1935200 de 103 Yes. 13.030 X 1 VN\ W NH nn : ζχζ 1H NMR (400 MHz, CD3OD) 6 7.63 (d, J =2.7 Hz, 1H), 7.20-7.40 (m, 5H), 7.13 (d, J8, 7 = 76m-Hz), 1H), 6.49 (dt, 7=7.5, 0.7 Hz, 1H), 6.40 (dd, 7=3.2, 0.8 Hz, 1H), 4.06 (s, 2H), 3.76 (s, 2H), 3.31),51 (s, 5.7 (2H), 4.4 6H), 0.94 (t, 7 = 7.6 Hz, 6H). MS: (ES) m / z calculated for C32H33CI2N4 [M + H]+ 543.2, found 543.2. Yes. 13.031 XJ Znx Η XX N . zz^x NX / > Λ 1 F'XZ u 1H NMR (400 MHz, CD3OD) 6 8.23 ​​(d, 7= 8.2 Hz, 1H), 7.92-7.93 (m, 2H), 7.22-7.39 (m, 3H), 7.6,07 7=8.2, 10.8, 1H), 6.236.27 (m, 1H), 4.87 (br, 1H), 4.21 (s, 2H), 3.67 (s, 2H), 2.20–2.36 (br, 4H), 6 (8–H), 1.81 (s). MS: (ES) m / z calculated for C34H32F7N4 [M + H]+ 629.2, found 629.3. Yes. 13.032 F3C^<\ TJ \xNx H XX n.zz^z Ϊ vz 1H NMR (400 MHz, CD3OD) 6 8.24 (d, 7= 7.9 Hz, 1H), 7.54-7.64 (m, 2H), 7.23-7.42 (m, 4H), 7.13 (d, 7.7 Hz), 8, 7.7 7.7 Hz, 1H), 6.35–6.49 (m, 2H), 4.86 (br, 1H), 4.13 (s, 2H), 3.70 (s, 2H), 2.17–2.42 (m, 4H), 1.55 (s, 7.7=6H), 0.5. MS: (ES) m / z calculated for C33H34F3N4 [M + H]+ 543.3, found 543.6. 1935200 of 103 Yes. 13.033 F3C-^í^CF3 XJ Vn... η Γ'νη N. XXX NXJ 1H NMR (400 MHz, CD3OD) 5 8.24 (d, J =8.2 Hz, 1H), 7.90-7.93 (m, 27 (7m-), (d, 7= 7.7 Hz, 2H), 6.80 (t, 7= 7.7 Hz, 1H), 6.35-6.49 (m, 2H), 4.88 (br, 1H), 4.22 (s, 2H), 3.6), 71 (s, 2m-2H), 2,3,3 6H), 0.99 (t, J= 7.6 Hz, 6H). MS: (ES) m / z calculated for C34H33F6N4 [M + H]+ 611.3, found 611.6. Yes. 13.034 Ck^ x Vn... / / i\ N._ XZYX ' L·· ' Ή NMR (400 MHz, CD3OD) 5 7.68 (s, 1H), 7.37-7.46 (m, 2H), 7.14-7.32 (m, 5H (d), 7.4 6.84–6.86 (m, Hz, 1H), 6.25–6.26 (m, 1H), 4.86 (br, 1H), 4.08 (s, 2H), 3.94 (s, 2H), 2.26–2.35 (m, 4H, 1, 3.53 (s Hz, 6H). MS: (ES) m / z calculated for C32H33CI2N4 [M + H]+ 543.2, found 543.5. Yes. 13.035 F3C-^\ Xj Vn... / / ΐ\ N._ DN \ A / 1 X,-' NH1 Ή NMR (400 MHz, CD3OD) 5 8.01 (d, J =8.0 Hz, 1H), 7.58-7.73 (m, 2H), 7.42 (t, J= 7.7 Hz, 2H-7), 8.21 (dd, 7=1.7, 8.0 Hz, 1H), 6.23–6.24 (m, 1H), 4.88 (br, 1H), 4.16 (s, 2H), 3.88 (s, 2H), 2.020–2.36 (m, 4.6), J (s = 1, 52), 1,62 Hz, 6H). MS: (ES) m / z calculated for C33H34F3N4 [M + H]+ 543.3, found 543.5. 1935200 of 103 Ej. 13.036 \ N N. KzA 7 XXnh XX 1H NMR (400 MHz, CDCh) δ δ 8,13 (br, 1H), 7,32-7,37 (m, 1H), 7,15-7,22 (m, 4H), 7,06 (d, J =7,6 Hz, 1H), 6,91 (dd, 7=1,7, 8,5 Hz, 1H), 6,436,44 (m, 1H), 4,08 (s, 2H), 2,50 (s, 2H), 2,00 (s, 6H), 1,36 (s,6H), 1,00 (s,9H). MS: (ES) m / z calculado para C28H35N4 [M + H]+ 427,3, encontrado 427,5. Ej. 13.037 Λ 0H \,Nx XXXh XlX 1H NMR (400 MHz, CD3OD) δ 7,55-7,63 (m, 2H), 7,107,39 (m, 9H), 6,82-6,90 (m, 1H), 6,23-6,24 (m, 1H), 4,82 (br, 2H), 4,64 (d, J= 11,5 Hz, 1H), 4,33 (d, J= 11,5 Hz, 1H), 3,87 (s, 1H), 2,06-2,39 (m, 4H), 1,59 (s, 3H), 1,35 (s, 3H), 1,19 (s, 3H), 1,05 (s, 3H), 0,83-1,03 (m, 6H). MS: (ES) m / z calculado para C35H41N4O [M + H]+ 533,3, encontrado 533,7. Ej. 13.038 A jf) Vn,.(XX u Ή NMR (400 MHz, CDCI3) δ 8.15 (br, 1H), 7.48-7.56 (m, 2H), 7.24-7.44 (m, 5H), 7.087.20 (m, 4H), 6.83 (dd, 7=1.7, 8.6 Hz, 1H), 6.36-6.37 (m, 1H), 4.93 (s, 1H), 4.69 (d, J= 11.4 Hz, 1H), 4.18-4.35 (m, 4H), 3.94 (d, J= 11.4 Hz, 1H), 2.14-2.43 (m, 4H), 1.58 (s, 3H), 1.51 (s, 3H), 1.19-1.34 (m, 6H), 0.96-1.07 (m, 6H). MS: (ES) m / z calculated for C35H39N4O2 [M + H]+ 547.3, encontrado 547.5. 1935200 of 103 Hey. 13,039 N no. K / Y % J vJUh XX 1H NMR (400 MHz, CDCh) δ δ 8.17 (br, 1H), 7.13-7.37 (m, 4H), 7.03-7.06 (m, 2H), 6.89 (dd, J= 1.1, 8.5 Hz, 1H), 6.42-6.44 (m, 1H), 4.18 (s, 2H), 4.06 (s, 2H), 2.69 (s, 2H), 2.00 (s, 6H), 1.01 (s, 9H). MS: (ES) m / z calculated for C26H31N4 [M + H]+ 399.3, set at 399.5. Table 2: Structure & Characteristic Data (MS) of specific implementation forms 1935200 of 103 Hey. 13.042 0 Nll? \,NW NH Ν'1ΠΤ F MS: (ES) m / z calculated for C27H31FN5O [M + H]+ 460.3, set at 460.3. Hey. 13.043 F3C^<\XF3 Vj \ NO Γ NH n^kJx N \ > MS: (ES) m / z calculated for C34H33F6N4O [M + H]+ 627.3, set at 627.3. 1935200 of 103 Hey. 13.044 F3c 0.. / 1 ΐ \ n W ANH / Aj 1 MS: (ES) m / z calculated for C32H34F3N6O [M + H]+ 575.3, set at 575.3. Hey. 13.045 TJ \ NNL / ' \-0 N \ A f | ..... .NH 1 MS: (ES) m / z calculated for C34H33F6N4O [M + H]+ 627.3, set at 627.3. Hey. 13.046 Ox 0.. / i TA JUJAh χχχ MS: (ES) m / z calculated for C30H37N4O2 [M + H]+ 485.3, set at 485.5. 1935200 of 103 Hey. 13.047 r- N ΓΧ - ,- N n. KXf v 7 Hey. 13.048 °χ0— N vz 7 Hey. 13.049 O;^O °x> ? XXnh XX MS: (ES) m / z calculated for C26H27N4O3 [M + H]+ 443.2, set at 443.2. 1935200 of 103 Eg. 13.050 τγ 0 Λ-Μ T ' Ν - 7 Υγ-ΝΗ χχ MS: (ES) m / z calculated for C29H33N4O [M + H]+ 453.2, found 453.2. Eg. 13.051 °V^rY Ν V / . υυ MS: (ES) m / z calculated for C28H31N4O [M + H]+ 439.2, found to be 439.2. Eg. 13.052 °γ° Ν Ν. j' γγ-ΝΗ χχ MS: (ES) m / z calculated for C25H28N5O2 [M + H]+ 430.2, found to be 430.2. 1935200 of 103 Eg. 13.053 °yO N 7 Ky-NH XX MS: (ES) m / z calculated for C27H29N4O [M + H]+ 425.2, found to be 425.2. Eg. 13.054 Λ N XX _____ Ϊ XM MS: (ES) m / z calculated for C30H35N4O [M + H]+ 467.3, found to be 467.5. Eg. 13.055 0 ,-.. / Ί N 1NXC 7 xy^NH XX MS: (ES) m / z calculated for C27H31N4O [M + H]+ 427.2, found to be 427.2. 1935200 of 103 1935200 of 103 Ex. 13.059 (X ,NH Ϊ N nCλ·..,.·'-Λ 7 Va NH XX MS: (ES) m / z calculated for C26H30N5O [M + H]+ 428.2, found 428.2. Ex. 13.060 °χθ N Nn '· NV \ 7 7 nh XX MS: (ES) m / z calculated for C28H25N4O [M + H]+ 433.2, found 433.2. Example 14

[0152] This Example illustrates the evaluation of the biological activity associated with the specific compounds of the invention. MATERIALS AND METHODS A. Cells 1. Cells that express the C5a receptor a) U937 cells

[0153] U937 cells are a monocytic cell line that expresses C5aR and are available from ATCC (VA). These cells were cultured as a suspension in RPMI medium 1935200 of 103 Cells were supplemented with 2 mM L-glutamine, 1.5 g / L sodium bicarbonate, 4.5 g / L glucose, 10 mM HEPES, 1 mM sodium pyruvate, and 10% FBS. Cells were cultured in 5% CO2 / 95% air, 100% humidity at 37°C and subcultured twice weekly at a 1:6 ratio (cells were cultured at densities ranging from 1 x 10⁵ to 2 x 10⁶ cells / mL) and harvested at 1 x 10⁶ cells / mL. Prior to the assay, cells were treated overnight with 0.5 mM cyclic AMP (Sigma, OH) and washed once before use. The cAMP-treated U937 cells can be used in C5aR ligand-binding and functional assays. b) Isolated human neutrophils

[0154] Optionally, human or murine neutrophils may be used to assay the activity of the compound. Neutrophils can be isolated from fresh human blood using density separation and centrifugation. Briefly, whole blood is incubated with equal parts of 3% dextran and allowed to separate for 45 minutes. After separation, the top layer is superimposed on 15 mL of Ficoll (15 mL of Ficoll per 30 mL of blood suspension) and centrifuged for 30 minutes at 400 x g without a brake. The pellet at the bottom of the tube is isolated and resuspended in PharmLyse RBC lysis buffer (BD Biosciences, San Jose, CA), after which the sample is centrifuged again for 10 minutes at 400 x g with a brake. The remaining cell pellet is resuspended as appropriate and consists of isolated neutrophils. B. Essays 1. Inhibition of C5aR ligand binding

[0155] C5aR-expressing cAMP-treated U937 cells were centrifuged and resuspended in assay buffer (20 mM HEPES, pH 7.1, 140 mM NaCl, 1 mM CaCl2, 5 mM MgCl2, and 0.1% bovine serum albumin) to a concentration of 3 x 10⁶ cells / ml. Binding assays were set up as follows. 0.1 mL of cells were added to assay plates containing 5 μL of the compound, giving a final concentration of ~2–10 μM of each compound for screening (or part of a dose response for IC50 determinations of the compound). Then, 0.1 mL of 125I-labeled C5a (obtained from Perkin Elmer Life Sciences, Boston, MA) diluted in assay buffer was added to a 1935200 of 103 to a final concentration of ~50 pM, producing ~30,000 cpm per well. The plates were sealed and incubated for approximately 3 hours at 4 °C on a vibrating platform. The reactions were aspirated onto GF / B glass filters pre-soaked in 0.3% polyethyleneimine (PEI) solution in a vacuum cell collector (Packard Instruments, Meriden, CT). Scintillation fluid (40 μA; Microscint 20, Packard Instruments) was added to each well, the plates were sealed, and the radioactivity was measured using a Topcount scintillation counter (Packard Instruments). Control wells containing either diluent only (for total counts) or excess C5a (1 μg / ml, for non-specific binding) were used to calculate the total percent inhibition for the compound. The Prism software program from GraphPad, Inc. (San Diego, CA) was used to calculate the IC50 values.IC50 values ​​are the concentrations required to reduce the binding of radiolabeled C5a to the receptor by 50%. (For a more detailed description of ligand binding and other functional assays, see Dairaghi et al., J. Biol. Chem. 274:21569-21574 (1999), Penfold et al., Proc. Natl. Acad. Sci. USA. 96:9839-9844 (1999), and Dairaghi et al., J. Biol. Chem. 272:28206-28209 (1997)). 2. Calcium mobilization

[0156] Optionally, the compounds can be further analyzed to determine their ability to inhibit calcium influx in cells. To detect the release of intracellular calcium stores, cells (e.g., cAMP-stimulated U937s or neutrophils) are incubated with 3 μM INDO-1AM dye (Molecular Probes; Eugene, OR) in cell medium for 45 minutes at room temperature and washed with phosphate-buffered saline (PBS). After INDO-1AM loading, the cells are resuspended in flow buffer (Hank's equilibrated saline (HBSS) and 1% FBS). Calcium mobilization is measured using a Photon Technology International spectrophotometer (Photon Technology International, New Jersey) with excitation at 350 nm and simultaneous dual recording of fluorescence emission at 400 nm and 490 nm. The relative levels of intracellular calcium are expressed as the 400 nm / 490 nm emission ratio.Experiments are performed at 37 °C with constant mixing in cuvettes, each containing 10⁶ cells in 2 ml of flow buffer. Chemokine ligands can be used in the range of 1 to 100 nM. The emission ratio is plotted over time (typically 2–3). 1935200 of 103 minutes). The candidate ligand blocking compounds (up to 10 μM) are added at 10 seconds, followed by the chemokines at 60 seconds (i.e., C5a, R&D Systems, Minneapolis, MN) and the control chemokine (i.e., SDF-1a; R&D Systems; Minneapolis, MN) at 150 seconds. 3. Chemotaxis trials

[0157] Optionally, compounds may be further analyzed to determine their ability to inhibit chemotaxis in cells. Chemotaxis assays are performed using 5-μm pore polycarbonate-coated filters and polyvinylpyrrolidone in 96-well chemotaxis chambers (Neuroprobe, Gaithersburg, MD) using chemotaxis buffer (Hank's balanced salt solution (HBSS) and 1% FBS). C5aR ligands (i.e., C5a, R&D Systems, Minneapolis, MN) are used to assess compound-mediated inhibition of C5aR-mediated migration. Other chemokines (namely, SDF-1a, R&D Systems, Minneapolis, MN) are used as specificity controls. The lower chamber is loaded with 29 μl of chemokine (i.e., 0.03 nM C5a) and varying amounts of compound; The upper chamber contains 100,000 U937 cells or neutrophils in 20 pl.The chambers are incubated for 1.5 hours at 37°C and the number of cells in the lower chamber is quantified by direct cell counts in five high-power fields per well or by the CyQuant (Molecular Probes) assay, a fluorescent dye method that measures nucleic acid content and microscopic observation. C. Identification of C5aR inhibitors 1. Essay

[0158] To evaluate small organic molecules that prevent the C5a receptor from binding to its ligand, an assay was used that detected radioactive ligand (i.e., C5a) binding to cells expressing C5aR on the cell surface (e.g., cAMP-stimulated U937 cells or isolated human neutrophils). For compounds that inhibit binding, whether competitive or not, lower radioactive counts were observed compared to uninhibited controls. 1935200 of 103

[0159] Equal numbers of cells were added to each well in the plate. The cells were then incubated with radiolabeled C5a. Unbound ligand was removed by washing the cells, and bound ligand was determined by quantifying radioactive counts. Cells incubated without any organic compound yielded total counts; nonspecific binding was determined by incubating cells with unlabeled and labeled ligand. The percentage of inhibition was determined by the equation: % inhibition = (1 - [(sample cpm) - (non-specific cpm)] / [(total cpm) - (non-specific cpm)]) x 100. 2. Dose-response curves

[0160] To determine the affinity of the candidate compound for C5aR and confirm its ability to inhibit ligand binding, inhibitory activity was titrated over a range of compound concentrations from 1 x 10-10 to 1 x 10-4 M. In the assay, the amount of compound was varied, while the number of cells and the ligand concentration were kept constant. D. In vivo efficacy models

[0161] Compounds of interest can be evaluated for potential efficacy in treating C5a-mediated conditions by determining the compound's efficacy in an animal model. In addition to the models described below, other suitable animal models for studying the compound of interest can be found in Mizuno, M. et al., Expert Opin. Investig. Drugs (2005), 14(7), 807-821, which is incorporated herein by reference. 1. Models of C5a-induced leukopenia a) C5a-induced leukopenia in a human C5aR knock-in mouse model

[0162] To study the effectiveness of the compounds of the present invention in a model In 1935200 of 103 animals, a recombinant mouse can be created using standard techniques, where the genetic sequence encoding mouse C5aR is replaced with the sequence encoding human C5aR, to create an hC5aR-KI mouse. In this mouse, administration of hC5a leads to the upregulation of adhesion molecules on blood vessel walls that bind to leukocytes in the blood, sequestering them from the bloodstream. The animals are administered 20 μg / kg of hC5a, and 1 minute later, the leukocytes are quantified in peripheral blood using standard techniques. Pretreatment of mice with varying doses of the compounds presented here can almost completely block hC5a-induced leukopenia. b) C5a-induced leukopenia in a Cynomolgus model

[0163] To study the efficacy of the compounds of the present invention in a non-human primate model, C5a-induced leukopenia is studied in a Cynomolgus model. In this model, administration of hC5a leads to the upregulation of adhesion molecules on the walls of blood vessels that bind to leukocytes in the blood, thereby sequestering them from the bloodstream. The animals receive 10 μg / kg of hC5a, and 1 minute later, the leukocytes are counted in the peripheral blood. Mouse model of ANCA-induced vasculitis

[0164] On day 0, hC5aR-KI mice receive 50 mg / kg of purified antibody against myeloperoxidase intravenously (Xiao et al, J. Clin. Invest. 110:955-963 (2002)). The mice also receive daily oral doses of the compounds of the invention or vehicle for seven days, after which they are sacrificed and their kidneys are removed for histological examination. Analysis of kidney sections may show a significantly lower number and severity of crescentic and necrotic lesions in the glomeruli compared to vehicle-treated animals. 2. Mouse model of choroidal neovascularization

[0165] To study the efficacy of the compounds of the present invention in the treatment of age-related macular degeneration (AMD), the Bruch membrane in the eyes of hC5aR-KI mice is disrupted by laser photocoagulation (Nozika et al, PNAS 103: 2328-2333 (2006). Mice are treated 84 1935200 of 103 with vehicle or with an appropriate daily oral or intravitreal dose of a compound of the invention for one to two weeks. Laser-induced damage repair and neovascularization are assessed by histology and angiography. 3. Models of rheumatoid arthritis a) Rabbit model of destructive joint inflammation

[0166] To study the effects of candidate compounds on inhibiting the inflammatory response of rabbits to intra-articular injection of the bacterial membrane component lipopolysaccharide (LPS), a rabbit model of destructive joint inflammation is used. The design of this study mimics the destructive joint inflammation seen in arthritis. Intra-articular injection of LPS causes an acute inflammatory response characterized by the release of cytokines and chemokines, many of which have been identified in rheumatoid arthritis. Marked increases in leukocytes occur in the synovial fluid and synovial membrane in response to the elevation of these chemotactic mediators. Selective chemokine receptor antagonists have shown efficacy in this model (see Podolin, et al., J. Immunol. 169(11):6435-6444 (2002)).

[0167] An LPS study was conducted in rabbits essentially as described in Podolin et al. ibid. Female New Zealand rabbits (approximately 2 kg) were treated intra-articularly in one knee with LPS (10 ng) along with vehicle alone (1% DMSO phosphate-buffered saline) or with the addition of the candidate compound (dose 1 = 50 μM or dose 2 = 100 μM) in a total volume of 1.0 mL. Sixteen hours after LPS injection, the knees were washed and cell counts were performed. The beneficial effects of treatment were determined by histopathological evaluation of synovial inflammation. Inflammation values ​​were used for histopathological evaluation: 1 minimal, 2 mild, 3 moderate, 4 moderate to marked. b) Evaluation of a compound in a rat model of collagen-induced arthritis

[0168] A 17-day collagen type II arthritis study was conducted to evaluate the effects 1935200 of 103 of a candidate compound on clinical arthritis-induced ankle inflammation. Collagen-induced arthritis in rats is an experimental model of polyarthritis that has been widely used for the preclinical testing of numerous antiarthritic agents (see Trentham et al., J. Exp. Med. 146(3):857-868 (1977), Bendele et al., Toxicologic Pathol. 27:134-142 (1999), Bendele et al., Arthritis Rheum. 42:498-506 (1999)). The distinguishing features of this model are a reliable onset and progression of robust and readily measurable polyarticular inflammation, marked cartilage destruction in association with pannus formation and mild-to-moderate bone resorption and periosteal bone proliferation.

[0169] Female Lewis rats (approximately 0.2 kg) are anesthetized with isoflurane and injected with Freund's incomplete adjuvant containing 2 mg / ml of bovine type II collagen at the base of the tail and two sites on the back on days 0 and 6 of this 17-day study. A candidate compound is applied subcutaneously daily from day 0 to day 17 at an effective dose. Measurements of ankle joint diameter were taken, and reduction in joint swelling was used as a measure of efficacy. 4. Rat model of sepsis

[0170] To study the effect of compounds of interest on the inhibition of the generalized inflammatory response associated with sepsis-like illness, the Cecal Ligation and Puncture (CLP) rat model of sepsis is used. A CLP study in rats is essentially performed as described in Fujimura N, et al. (American Journal of Respiratory Critical Care Medicine 2000; 161:440-446). Briefly, albino Wistar rats of both sexes weighing between 200 and 250 g are fasted for twelve hours prior to the experiments. The animals are maintained on normal 12-hour light-dark cycles and fed ordinary rat food until 12 hours before the experiment. Subsequently, the animals are divided into four groups: (i) two sham groups and (ii) two CLP groups.Each of these two groups (i.e., (i) and (ii)) is divided into a control vehicle group and a test compound group. Sepsis is induced by the CLP method. Under brief anesthesia, a midline laparotomy is performed with minimal dissection, and the cecum is ligated just below the ileocecal valve with 3-0 suture, thus maintaining intestinal continuity. The antimesineric surface of the cecum is perforated with a needle. A 18-gauge needle was inserted at two sites 1 cm apart, and the cecum was gently squeezed until fecal matter was extruded. The intestine was then returned to the abdomen, and the incision was closed. At the end of the operation, all rats were resuscitated with saline solution, 3 ml / 100 g body weight, administered subcutaneously. After the operation, the rats were not fed but had free access to water for the next 16 hours until they were euthanized. The sham groups underwent a laparotomy, and the cecum was manipulated but not ligated or perforated. The beneficial effects of the treatment were measured by histopathological classification of tissues and organs, as well as by measuring several key indicators of liver function, kidney function, and lipid peroxidation. To assess liver function, aspartate transaminase (AST) and alanine transaminase (ALT) were measured.Blood urea nitrogen and creatinine levels are measured to assess kidney function. Pro-inflammatory cytokines such as TNF-alpha and IL-1beta are also analyzed using ELISA to determine serum levels. 5. SLE mouse model of experimental lupus nephritis

[0171] To study the effect of compounds of interest on systemic lupus erythematosus (SLE), the MRL / Ipr murine SLE model is used. The MRL / Mp-Tmfrsf6'pl- (MRL / Ipr) strain is a commonly used mouse model of human SLE. To test the efficacy of compounds in this model, male MRL / Ipr mice are divided equally between control and C5aR antagonist groups at 13 weeks of age. The compound or vehicle is then administered to the animals via osmotic pumps for the next 6 weeks to maintain coverage and minimize stress. Serum and urine samples are collected every two weeks during the six weeks of disease onset and progression. In a minority of these mice, glomerulosclerosis develops, leading to death from renal failure.Monitoring mortality as an indicator of renal failure is one of the measurement criteria, and successful treatment will generally result in a delay in sudden death among the trial groups. Furthermore, the presence and severity of renal disease can also be continuously monitored with blood urea nitrogen (BUN) and albuminuria measurements. Tissue and organ samples were also obtained at 19 weeks and subjected to histopathology. 1935200 of 103 immunohistochemistry and were classified based on tissue damage and cellular infiltration. 6. Rat model of COPD

[0172] Smoke-induced airway inflammation in rodent models can be used to evaluate the efficacy of compounds in chronic obstructive pulmonary disease (COPD). Selective chemokine antagonists have demonstrated efficacy in this model (see Stevenson et al., Am. J. Physiol. Lung Cell Mol. Physiol. 288 L514-L522, 2005). An acute rat COPD model is implemented as described by Stevenson et al. A compound of interest is administered systemically orally or intravenously, or locally as a nebulized compound. Male Sprague-Dawley rats (350-400 g) are placed in Perspex chambers and exposed to cigarette smoke inhaled by a pump (50 mL every 30 seconds with fresh air in between). The rats are exposed for a total period of 32 minutes. The rats are sacrificed up to 7 days after initial exposure.Any beneficial effect of the treatment is evaluated by a decrease in the infiltration of inflammatory cells, and decreases in chemokine and cytokine levels.

[0173] In a chronic model, mice or rats are exposed to daily tobacco smoke for up to 12 months. The compound is administered systemically via once-daily oral administration, or potentially locally via a nebulized compound. In addition to the inflammation observed in the acute model (Stevensen et al.), the animals may also exhibit other pathologies similar to those seen in human COPD, such as emphysema (as indicated by the increased mean linear intercept), as well as altered lung chemistry (see Martorana et al., Am. J. Respir. Crit Care Med. 172(7):848-53). 7. EAE mouse model of multiple sclerosis

[0174] Experimental autoimmune encephalomyelitis (EAE) is a model of human multiple sclerosis. Variations of the model have been published and are well known in the field. In a typical protocol, C57BL / 6 mice (Charles River Laboratories) are used for the EAE model. The mice are immunized with 200 μg of myelin oligodendrocyte glycoprotein (MOG) 35-55 (Peptide 88). 1935200 of 103 International) emulsified in Complete Freund's Adjuvant (CFA) containing 4 mg / ml of Mycobacterium tuberculosis (Sigma-Aldrich) sc on day 0. In addition, on day 0 and day 2, the animals received 200 ng of pertussis toxin (Calbiochem) iv. Clinical scoring is based on a 0-5 scale: 0, no signs of disease; 1, floppy tail; 2, hind limb weakness; 3, hind limb paralysis; 4, forelimb weakness or paralysis; 5, moribund. The administration of the compounds of interest to be evaluated can be initiated on day 0 (prophylactic) or day 7 (therapeutic, when there is histological evidence of the disease but few animals show clinical signs) and are administered once or more times a day at the concentrations appropriate for their activity and pharmacokinetic properties, for example 100 mg / kg scThe efficacy of the compounds can be assessed by comparing severity (peak average clinical score in the presence of the compound compared to the vehicle) or by measuring a decrease in the number of F4 / 80-positive macrophages isolated from spinal cords. Spinal mononuclear cells can be isolated using a discontinuous Percoll gradient. The cells can be labeled using rat anti-mouse F4 / 80-PE or rat IgG2bPE (Caltag Laboratories) and quantified by FACS analysis using 10 μA of Polybeads per sample (Polysciences). 8. Mouse model of kidney transplantation

[0175] Transplantation models can be performed in mice; for example, an allogeneic kidney transplantation model from C57BL / 6 to BALB / c mice is described in Faikah Gueler et al., JASN Express, August 27, 2008. Briefly, the mice are anesthetized, and the donor's left kidney is connected to an aortic cuff and the renal vein to a small vena cava cuff, and the ureters are removed en bloc. After the recipient's left nephrectomy, the vascular cuffs are anastomosed to the recipient's abdominal aorta and vena cava, respectively, below the level of the native renal vessels. The ureter is anastomosed directly into the bladder. The cold ischemia time is 60 minutes, and the warm ischemia time is 30 minutes. The native right kidney can be removed at the time of allograft transplantation or on day 4 post-transplant for long-term survival studies.The overall physical condition of the mice is monitored for evidence of rejection. Treatment of the animals with the compound can be initiated before surgery or immediately afterward.89 1935200 of 103 after transplantation; for example, by subcutaneous injection once a day. Renal function and survival of mice are assessed. Serum creatinine levels are measured using an automated method (Beckman Analyzer, Krefeld, Germany). 9. Mouse model of ischemia / reperfusion

[0176] A mouse model of ischemia / reperfusion injury can be performed as described in Xiufen Zheng et al., Am. J. Pathol., Vol. 173:4, Oct. 2008. Briefly, 6- to 8-week-old CD1 mice are anesthetized and placed on a heating pad to maintain warmth during surgery. After abdominal incisions, the renal pedicles are dissected, and a microvascular clamp is placed on the left renal pedicle for 25–30 minutes. After ischemia, the clamps are removed along with the right kidney, the incisions are sutured, and the animals are allowed to recover. Blood samples are taken for serum creatinine and BUN analysis as an indicator of renal health. Alternatively, animal survival is monitored over time.The compound can be administered to animals before and / or after surgery, and the effects on serum creatinine, BUN, or animal survival are used as indicators of the compound's efficacy. 10. Mouse model of tumor growth

[0177] 1x10⁵ TC-1 cells (ATCC, VA) are injected subcutaneously into 6- to 16-week-old C57BL / 6 mice in the right or left hind flank. Beginning approximately 2 weeks after cell injection, tumors are measured in calibers every 2 to 4 days until tumor size necessitates euthanasia of the mice. At euthanasia, the animals undergo complete necropsy, and the spleens and tumors are removed. Excised tumors are measured and weighed. Compounds may be administered before and / or after tumor injections, and the retardation or inhibition of tumor growth may be used to evaluate compound efficacy.

[0178] Error! Reference source not found. The structures and activity for the representative compounds described herein are provided below. The activity is provided below for inhibition in the chemotaxis assay (See Example). 1935200 of 103 B 3) according to this: +, 500 nM < IC50; ++, 50 nM < IC50 < 500 nM; +++, 5 nM < IC50 < 50 nM; and ++++, IC50 < 5 nM. Table 3: Structure & Biological Activity of the Specific Forms of Realization Compound Structure IC50 (nM) 1.001 cf3 H nh n flL H 3 CH 3 +++ 1.002 F3C_^CF3 xy H,C lí Η,ώγ'Ν ίΛ-ΖΧ 7 \\ J___CHS ++++ 1.003 H3C^CH3 O <s / NH H,C J Ha x' / XjíNH 1 H3C / YjCH3 + 1.004 >αΓ o ?yb γ / Z ω1 / ZOZ ++++ 1.005 FsC^^^CFa Xj H J0NH Η3Ο^ψΑ^0Η3 OH +< / s> 1935200 of 103 ​1.006 0. Y^NH, HC J. j^xX-F h3 c^\Z^>^ch3 + 1.007 0 CH- η £> yxX HsC / xpP cHj ++ 1.008 X hc. Η3<*γΚ H JONH χΧ ++ 1.009 z J tí i xn Μ. 7θ Ü}--( oY >=\ ^pCz ~O 0-7 z / —f Xno < x X ++ 1.010 I LL? Z x frx x +++ 1935200 of 103 1,011 f3c_. cf3 TJ H3C i Η,ώγΝχ ci TO, +++ 1.012 z qz \ "nz / =( ^An / znz +++ 1.013 χ H, C ¿ H,<V\ h Oh TO, jCTOTT +++ 1.014 z "n A ) p-1 > / T o ivT 1 / XZ ++ 1.015 ¿Aw -svrt A / z -ri 1 +++ 1.016 Y?i H3C i H3cANk m J0NH N Κ / Ί xVAf H 3c H 3 ++ 1935200 of 103 1.017 z Q Tl 1 ++++ 1.018 z y- / =< Cry T +++ 1.019 fj H3C A H3ctUN> JU: H 3 c H 3 +++ 1.020 wZ O wZ / P»1 / —( z A"o >XT Q Γ + z T1-SM zl. z Z^_] A>„ < X °„ z ++++ 1.022 1 / Cry w A / $=, " OO v / ST / z / — zo ¿ z” o zn +++ 1935200 of 103 1.023 IF OR / Ρω1 ! Z TI 1 ++++ 1.024 F3C^^ / CF3 Xj XÍNH 1 Η3°χχχ°Η3 ++++ 1.025 ^4 / x zx J1 o 1 jr ++++ 1.026 ^VA > / ++++ 1.SF'J F'J F 7 +++ 1,028 / zx -nz ++ 1935200 of 103 1.029 ο / ή-Λ 1 2 / -ή 1 +++ 1.030 T uM <\ X-'Vv O Vj 7 \ x J5 &Χ-8 oy—' ml / IO \ zom Z +++ 1.031 ¿XQ +c^ h$3 LH3C Zc JONH ?VAf H 3C H 3 ++++ 1.033 z uz__ / - „ QXi "XpXS xd < rt \ I o T +++ 1.034 F3C^^-^CF3 TJ H c Γ H3t~VNS ci__ H Xnh iV +++ 1935200 of 103 1.035 F3C^^^CF3 Xj H,CJH XNHH3°XXXCH3 +++ 1.036 X « Z Í X +++ 1.037 F3C^^CF3 XX HC ¿ H CNHH3°Xmj CH' ++++ 1.038^ T 3C <h$NH +++ 1.039 IL· Z J v. iry zz x” +++ 1.040 f3c \X~ch. °v η,3°ν Mj£nh flj Η3ο^χχ^ + 1935200 of 103 1.041 H,C Μ Η Χ> Hs<A-AAcH3 ++ 1.042 Cl / \ Ζ1 η c 1 Η χ> λθ njA'AT'M +++ 1.043 faf V ζζ h3c ¿ H,C— \ z zh n, zz iXw H 3 C-^γΖγ^· c H3 +++ 1.044 Z: z +++ nz: z +++ 1.045 F ,Xn hZf / HZf M fZ 3 Cz γΖΧ C H3 +++ 1.046 (Q hX Sz^Z^ IZ= / ~N +++ 1935200 of 103 1.047 F / CO H,ZO «Z / Z HjEvAch, h +++ 1.048 I ω OI \ w ) pi / 1w / —( zo \=< Q ) ( o- / / / / X i / \ o / / M woo ω1 \·^ / cF cF +++ 1.049 Oi X ++ 1.050 H3C '0 0-UU η3° I Η3ΟΖ_ / N' λ \)—Ν - 1 Η Η3°ΧΧΧ°Ν3 +++ 1.051 CH. ΑΗ3 f^CH3 Ν Μ / -Α<χ ν Ζ ΖΝ H3CZzCV η + 1.052 CH- | / ?Η3 <^η3H3C Ν 3H3C \ / γτΡ cxz +++ 1935200 of 103 1.053 ÍL--L ° nF wV / y WW ++ 1.054 h3c ch3 CL yc y oxxch3 Rro 1 V ZZ—N fETOV H + 1.055 CH. H3apsdH3 ° on L Ln h3c^í cfij^ H + 1.056 N Uv IL An HV + 1.057 I ω X?L "O <y + 1.058 CH, H3c¿p¿H3 °<γ'° N νΧ> ~~ <τ~ίχν ? l xn h3c^l cv h +100 1935200 100 of 103 1.059 ХжХХ Д з + 1.060 I i ' ++ 1.061 I ω w7 / / woo \ II XX 'y-'-'\ ω « + 1.062 z 4Xa o__ / oo X^X i ωζ iz^ + 1.063 CH, ύ*Η3 <!--?, L J N ? LAn sAyCV H + 1.064 CH. LXH3 N n A X Η3=γΑ<=Ιν H +<br--> 101 1935200 101 of 103 1.065 CH, h3c ¿h3 O NH N 1 1 JN + 1.066 z o__< <z v "o 1 + 1.067 ch. h3c^¿h3 o n v xn η3ογλγ-οα: h ++

[0179] Although certain embodiments of the present invention have been described herein, those skilled in the art will recognize the possibility of introducing variations to the embodiments set forth, and it is expected that such variations may be implemented as appropriate. Accordingly, the invention may be implemented in a manner other than that specifically described herein, and it contemplates all modifications and equivalents of the object in accordance with the following claims as permitted by applicable law. Furthermore, any combination of the elements described above in all their possible variations is contemplated by the invention unless otherwise indicated or the context clearly indicates otherwise.

[0180] All publications, patent applications, accession numbers, and other references cited in this description are incorporated by reference, as if each individual publication or patent application were specifically and individually indicated as incorporated in such capacity. 102 1935200 102 of 103 CLARKE MODET & CO. (ARGENTINA) SA - 30540437455 Digitally signed by PORTALTRAMITES - INPI Date: 2022.08.26 15:20:29 -03:00 Reason: Digitally Signed by the INPI Location: Buenos Aires, Argentina 1935200 103 of 103< / z>

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the portion of the ring having A1, A2, A3, A4, A5, and A6 as ring vertices is a bicyclic heteroaryl represented by structure FORMULA 2, wherein m is 0, 1, 2, or 3; and wherein the R4 substituents can be attached to any suitable carbon ring vertex of the bicyclic heteroaryl; R1 is -CH2-phenyl substituted by 1 or 2 R5, wherein each R5 is independently C1-4 haloalkyl; R2a and R2e are each independently selected from the group consisting of C1-6 alkyl and C1-6 haloalkyl; R2b, R2c, and R2d are each H; each R 3 is independently selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, halogen and hydroxyl; each R 4 is independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, C1-6 hydroxyalkyl, halogen, cyano and -CO2R 4a ;and wherein the R4 substituents can be attached to any vertex of the suitable carbon ring of the bicyclic heteroaryl; and the subscript n is 0, 1, 2, or 3, characterized in that the compound is selected from the group consisting of: tables with formulas follow. Four claims follow;