FUSED BICYCLIC C5aR ANTAGONIST PRODRUGS

Abstract

Claim 1: A compound of any one of formulas (1), (2), (3), (4), (5) or (6), or a pharmaceutically acceptable salt thereof, characterized in that: the vertex of ring a is N or C(R²ᶜ), the vertex of ring b is N or C(R²ᵈ), and the vertex of ring e is N or C(R²ᵉ), wherein no more than one of a, b, and e is N; X¹ is selected from the group consisting of a linkage, C₁₋₈ alkylene, C(O), C(O)-C₁₋₄ alkylene, and S(O)₂; R¹ is selected from the group consisting of: a) a 5- to 10-membered heteroaryl having from 1 to 4 heteroatoms as ring vertices selected from N, O, and S; b) C₆₋₁₀ aryl; c) C₃₋₈ cycloalkyl; d) 4- to 8-membered heterocycloalkyl having from 1 to 2 heteroatoms as ring vertices selected from N, O, and S; and e) C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, -C(O)NR¹ᵃR¹ᵇ, and -CO₂R¹ᵃ; wherein R¹ᵃ and R¹ᵇ are each independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, C₆₋₁₀ aryl,and -C₁₋₆-aryl C₆₋₁₀ alkylene; wherein the -X¹-R¹ group is unsubstituted or substituted with 1 to 5 Rˣ substituents; R²ᵃ and R²ᵉ 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, CN, and halogen, and at least one of R²ᵃ and R²ᵉ is other than hydrogen; 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 hydroxyl, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ hydroxyalkyl, and optionally two R³ groups on the same carbon atom combine to form oxo(=O),and optionally two R³ groups and the carbon atoms to which they are attached to form a 3-6 membered ring with 0-2 heteroatoms as ring members selected from O, N, and S; R⁴ is a member selected from the group consisting of: -NHP¹, -NHC(O)NHP¹, -CH₂NHP¹ and -CH₂NHC(O)NHP¹; 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, halogen, OH, CN, C(O)R⁵⁵⁃ and CO₂R⁵⁵⁃; R⁵' is a member selected from the group consisting of hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ hydroxyalkyl, C(O)R⁵⁵⁃ and CO₂R⁵⁵⁃; wherein each R⁵⁵⁃ is independently selected from the group consisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; R⁶ is a member selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ -O-haloalkyl, C₁₋₆ -S-alkyl, C₁₋₆ -alkyl-C₁₋₆ -O-alkyl, C₁₋₆ -alkyl-C₁₋₆ -S-alkyl, cyano,and halogen; R⁷ is P¹; and R⁸ is -CH₂OP¹; each P¹ is a prodrug component; each Rˣ is independently selected from the group consisting of halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ hydroxyalkyl, C₂₋₄ alkenyl, C₃₋₆ cycloalkyl, C₁₋₄ CO₂-alkyl, and CONH₂; the subscript m is 0, 1, 2, 3, or 4; and the subscript n is 0, 1, 2, or 3. Claim 8: The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, characterized in that P1 is selected from the group consisting of: the group of formulas (7), wherein each R9 is independently selected from the group consisting of H and C1-3 alkyl; and each R10 is independently selected from the group consisting of H, C1-3 alkyl, phenyl, and benzyl. Claim 10: The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof,characterized in that P¹ is selected from the group consisting of -CH₂OH, -P(O)(OR¹⁰)₂, and -CH₂-OP(O)(OR¹⁰)₂, wherein each R¹⁰ is independently selected from the group consisting of H, C₁₋₃ alkyl, phenyl, and benzyl. Claim 11: The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, characterized in that P¹ is selected from the group consisting of an amino acid, a dipeptide, and a tripeptide. Claim 12: The compound of claim 12, characterized in that said amino acid, dipeptide or tripeptide is independently selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, lysine, cysteine, aspartate, glutamate, histidine and phenylalanine, wherein the N atom of each amino acid unit may be methylated or acylated.

Description

PRODRUGS OF FUSIONED BICYCLIC C5aR ANTAGONISTS CROSS REFERENCES TO RELATED REQUESTS This application claims priority benefit under 35 U.S.C. § 119(e) of the U.S. Provisional Application No. 62 / 651,512, filed April 2, 2018, the disclosure of which is incorporated herein by reference in its entirety. DECLARATION REGARDING RIGHTS TO INVENTIONS MADE UNDER GOVERNMENT-FUNDED RESEARCH AND DEVELOPMENT NOT APPLICABLE. REFERENCE TO “LIST OF SEQUENCES”, TABLE, OR LIST OF COMPUTER PROGRAM ANNEX PRESENTED ON COMPACT DISC NOT APPLICABLE. BACKGROUND OF THE INVENTION 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 harmful 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. The complement system is composed of a group of proteins that are normally present in serum in an inactive state. The activation of the complement system involves mainly three different pathways, namely, the classical pathway, the alternative pathway and the lectin pathway (V. M. Holers, In Clinical Immunology: Principles and Practice, ed. R. R. Rich, Mosby Press; 1996, 363 -391): 1) The classical pathway is a calcium / magnesium-dependent cascade, which IF-2019-40565613-APN-ANP#INPI Page 1 of 183 is normally activated by the formation of antigen-antibody complexes. It can also be activated independently of antibodies by binding to C-reactive protein, forming a complex with ligand, and by numerous pathogens, including Gram-negative bacteria. 2) The alternative pathway is a magnesium-dependent cascade that is activated by 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 mannose-binding lectin and 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. etal., J. Immunol. Activation of the complement pathway generates biologically active fragments of complement proteins, for example, anaphylatoxins C3a, C4a and C5a and membrane attack complexes C5b-9 (MAC), all which mediate inflammatory responses by affecting leukocyte chemotaxis; they activate macrophages, neutrophils, platelets, mast cells and endothelial cells; and increase vascular permeability, cytolysis and tissue injury. Complement C5a is one of the most potent proinflammatory mediators of the complement system. (The anaphylactic peptide C5a is 100 times more potent, on a molar basis, in eliciting inflammatory responses than C3a.) C5a is the activated form of C5 (190 kD, molecular weight). C5a is present in human serum at approximately 80 pg / ml (Kohler, P. F. et al., J. Immunol. 99: 1211-1216 (1967)). It is composed of two polypeptide chains, α and β, with approximate molecular weights of 115 kD and 75 kD, respectively (Tack, B. F. 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, Y. M. et al., J. Immunol. 124:2494-2498(1980)). 124: 2494-2498(1980)). C5 is cleaved into fragments C5a and C5b during activation of complement pathways. The convertase enzymes responsible for C5 activation are multisubunit complexes of C4b, C2a and C3b for the classical pathway and (C3b)2, Bb and P for the alternative pathway. IF-2019-40565613-APN-ANP#INPI Page 2 of 183 (Goldlust, Μ. B. et al., J. Immunol. 113: 998-1007 (1974); Schreiber, R. D. et al, Proc. Natl. Acad. Sci. 75: 3948-3952 (1978) ). C5 is activated by cleavage at position 74-75 (Arg-Leu) on the a chain. Upon activation, the 74 amino acid, 11.2 kD C5a peptide is released from the amino-terminal portion of the a 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, J. M. et al., Eur. J. Immunol. 20: 253-257 (1990)). In addition to its anaphylotoxic properties, C5a induces the chemotactic migration of neutrophils (Ward, P. A. et al., J. Immunol. 102: 93-99 (1969)), eosinophils (Kay, A. B. et al., Immunol. 24: 969- 976 (1973)), basophils (Lett-Brown, M. A. 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, K. E. et al., J. Clin. Invest. 94: 1147-1155 ( 1994); Foreman, K. E. et al., Inflammation 20: 1-9 (1996); 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)). Furthermore, C5a modulates hepatic acute phase gene expression and increases the overall immune response by increasing the production of TNF-α, IL-1-β, IL-6, IL-8, prostaglandins and leukotrienes (Lambris, J. D. et al. , In: The Human Complement System in Health and Disease, Volanakis, J. E. ed., Marcel Dekker, New York, pp. 83-118). 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 kD 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, D.E. et al., J. Immunol. 132: 2862-2867 (1984); 44: 183-187 (1995); 1978); The binding site IF-2019-40565613-APN-ANP#INPI Page 3 of 183 C5aR ligand is complex and comprises at least two physically separable binding domains. One binds the amino terminus of C5a (amino acids 1-20) and the disulfide-bonded core (amino acids 21-61), while the second binds to the carboxy-terminal end of C5a (amino acids 62-74) (Wetsel, R. A. , Curr. Immunol. 7: 48-53 (1995)). 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 kidney dialysis machine (Howard, R. J. et al., Arch. Surg. 123. 1496-1501 (1988); 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, B. J. et al., J. Leukoc. Biol. 64: 40- 48 (1998)). Administration of an anti-C5a monoclonal antibody was shown to reduce cardiopulmonary bypass and cardioplegia-induced coronary endothelial dysfunction (Tofukuji, M. et al., J. Thorac. Cardiovasc. Surg. 116: 1060-1068 (1998)). C5a is also involved in acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and multiple organ failure (MIO) (Hack, C. E. et al., Am. J. Med. 1989: 86: 20 -26; Hammerschmidt DE et al. Lancet 1: 947949; 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 lesions, and particularly lung lesions, 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 before treatment with endotoxin or E. coli resulted in a decrease in tissue injury, as well as a decrease in production of IL-6 (Smedegard, G. et al., Am. J. Pathol. 135: 489-497 (1989); Hopken, U. et al., Eur. J. Immunol. 26: 1103-1109 (1996) ; Stevens, J.H. et al., J. Clin. Invest. 77: 1812-1816 (1986). More importantly, blocking or C5a with anti-C5a polyclonal antibodies has been shown to significantly improve rates of 4 IF-2019-40565613-APN-ANP#INPI Page 4 of 183 survival in a cecal ligation / puncture model of sepsis in rats (Czermak, B.J. et al., Nat. Med. 5: 788-792 (1999)). This model shares many aspects of the clinical manifestation of sepsis in humans. (Parker, S.J. et al., Br. J. Surg. 88: 22-30 (2001)). In the same sepsis model, anti-C5a antibodies were shown to inhibit thymocyte apoptosis (Guo, R.F. et al., J. Clin. Invest. 106: 1271-1280 (2000)) and prevent MOF (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, M. S. et al. J. Clin. Invest. 98. 503512 (nineteen ninety six)). The importance of C5a in immune complex-mediated lung injury was later confirmed in mice (Bozic, C. R. et al., Science 26: 1103-1109 (1996)). C5a has been found to be an important mediator in myocardial ischemia-reperfusion injury. Complement depletion reduced myocardial infarct size in mice (Weisman, H. F. et al., Science 249: 146-151 (1990)), and treatment with anti-C5a antibodies reduced injury in a rat model of ischemia. -reperfusion of the hind limbs (Bless, N. M. et al., Am. J. Physiol. 276: L57-L63 (1999)). Reperfusion injury during myocardial infarction was also markedly reduced in pigs that were again treated with a monoclonal anti-C5a IgG (Amsterdam, E. A. 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, R. D. et al., J. Thorac. Cardiovasc. Surg. 120: 350-358 (2000)). C5a-driven neutrophils also contribute to many bullous diseases (e.g., bullous pemphigoid, pemphigus vulgaris, and pemphigus foliaceus). These are chronic and recurrent inflammatory disorders clinically characterized by sterile blisters that appear in the sub-epidermal space of the skin and mucosa. 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, blisters are also characterized by the accumulation of neutrophils in the upper dermal layers and within the cavities of the skin. the blisters. In experimental models, depletion of neutrophils or absence of complement (total or C5-selective) can inhibit the formation of subepidermal blisters, even in the presence of high titers of autoantibodies. IF-2019-40565613-APN-ANP#INPI Page 5 of 183 Complement levels are elevated in patients with rheumatoid arthritis (Jose, P. J. et al., Ann. Rheum. Dis. 49: 747-752 (1990); Grant, E.P., 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 lupus erythematosus systemic (SLE) (Porcel, J. M. et al., Clin. Immunol. Immunopathol. 74: 283-288 (1995)). C5a levels correlate with the severity of the disease state. Collagen-induced arthritis in mice and rats resembles rheumatoid arthritic disease in humans. Mice deficient in the C5a receptor demonstrated complete protection against arthritis induced by injection of anti-collagen monoclonal Abs (Banda, N.K., et al., J. of Immunol., 2003, 171: 2109-2115). Therefore, inhibition of C5a and / or C5a receptor (C5aR) could be useful in the treatment of these chronic diseases.

[0001] The complement system is believed to be activated in patients with inflammatory bowel disease (IBD) and is believed to play a role in the pathogenesis of the disease. Activated complement products were found in the luminal side of superficial epithelial cells as well as in the muscularis mucosa and submucosal blood vessels in patients with Eli (Woodruff, T.M., et al., J of Immunol., 2003, 171: 5514 -5520). 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 could 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 be useful in the treatment of these neurodegenerative diseases. There is some evidence that C5a production worsens the inflammation associated with atopic dermatitis (Neuber, K„ et al., Immunology 73:83-87, (1991)), and chronic urticaria (Kaplan, A.P., J. Allergy Clin. Immunol. 114; 465-474, (2004). Psoriasis is now known to be a T cell-mediated disease (Gottlieb, E. L. et al., Nat. Med. 1: 442-447 (1995)). However, neutrophils and mast cells can also IF-2019-40565613-APN-ANP#INPI Page 6 of 183 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)). Accumulation of neutrophils under the stratum corneum is observed in the highly inflamed areas of psoriatic plaques, and extracts from psoriatic lesions (scales) contain highly elevated levels of C5a and exhibit potent chemotactic activity toward neutrophils, an effect that can be inhibited by adding a C5a antibody. T cells and neutrophils are chemoattracted to C5a (Nataf, S. et al., J. Immunol. 162: 4018-4023 (1999); Tsuji, R. F. et al., J. Immunol. 165: 1588-1598 (2000) ; Cavaillon, J. M. 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 showed chemotactic behavior toward C5a, suggesting that blocking C5aR in pDC 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. Immune complexes, or immune complexes (IC), containing immunoglobulin G contribute to the pathophysiology of several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, Sjogren's disease, Goodpasture syndrome, and hypersensitivity pneumonitis (Madaio, Μ P., Semin. Nephrol. 19: 48-56 (1999), Korganow, A. S. et al., Immunity 10: 451-459 (1999); Ando, ​​M. et al., Curr. 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 liver fibrosis). The classic animal model for the inflammatory response in these HF diseases is the Arthus reaction, which presents the infiltration of polymorphonuclear cells, hemorrhage and plasma exudation (Arthus, M., C.R. 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 caused by IC deposition (Strachan, A. J. et al., J. Immunol. 164: 6560-6565 (2000)). IF-2019-40565613-APN-ANP#INPI Page 7 of 183 Together with its receptor, C5a plays an important role in the pathogenesis of HF diseases. C5a and C5aR inhibitors could be useful in treating these diseases. Related Art Description: Non-peptide-based C5a receptor antagonists have been reported to be effective in treating endotoxic shock in rats (Stracham, A.J., et al., J. of Immunol. (2000), 164(12). 6560-6565) ; and to treat Eli in a rat model (Woodruff, T.M., 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., W02004 / 043925, W02004 / 018460, W02005 / 007087, WO03 / 082826, W003 / 08828, WO02 / 49993, WO03 / 084524); Dompe S.P.A. (W002 / 029187); The University of Queensland (W02004 / 100975); and ChemoCentryx (W02010 / 075257). There is considerable experimental evidence in the available literature implicating increased levels of C5a with a number of diseases and disorders, particularly in autoimmune and inflammatory diseases and disorders. Therefore, there remains a need in the art for new small organic molecule modulators, e.g., agonists, preferably antagonists, partial agonists, of the C5a receptor (C5aR) that are useful for inhibiting pathogenic events, e.g., chemotaxis, associated with increased levels of anaphylatoxin activity. The present invention meets this and other needs. BRIEF SUMMARY OF THE INVENTION In one aspect, the present invention provides the compounds of Formulas (IA), (IB), (IC), (IIA), (IIB), and (IIC): IF-2019-40565613-APN-ANP#INPI Page 8 of 183 I.C. ΙΑ IB I ΙΑ IIB IIC or a pharmaceutically acceptable salt thereof, wherein the symbols, letters and subscripts n m, a, b, e, X1, R1, R2a, R2b, R3, R4, R5, R5', R6, R7 and R8 have the meanings given in the description that follows. In addition to the compounds provided herein, the present invention also provides pharmaceutical compositions containing one or more of these compounds, as well as methods for the use of these compounds in therapeutic methods, primarily to treat diseases associated with the signaling activity of C5a. In yet another aspect, the present invention provides methods of diagnosing diseases in an individual. In these methods, the compounds provided herein are administered in labeled form to a subject, followed by imaging to determine the presence or absence of C5aR and / or the localization of cells expressing a C5aR receptor. In a related aspect, a disease diagnosis method is carried out by putting into IF-2019-40565613-APN-ANP#INPI Page 9 of 183 contact a tissue or blood sample with a labeled compound as provided herein and determine the presence, absence, amount or location of C5aR in the sample. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the release of active compound intermediate 4 from the compound of Example 1 (0.5 mg / kg mol equiv., AUC = 4,160 ng.hr / mL). Figure 2 shows the release of active compound intermediate 1 from the compound of Example 4 (0.5 mg / kg mol equiv., AUC = 753 ng.hr / mL). DETAILED DESCRIPTION OF THE INVENTION Abbreviations and definitions The term alkyl, alone or as part of another substituent, means, unless otherwise indicated, a straight-chain or branched hydrocarbon radical, having the designated number of carbon atoms (i.e. Ci-8 means one to eight carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, secbutyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. The term alchemyl refers to an unsaturated alkyl group that has 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 homologs and isomers. The term cycloalkyl refers to hydrocarbon rings that have the indicated number of ring atoms (for example, C3.6 cycloalkyl) and that are completely saturated or that have no more than one double bond between the ring vertices. Cycloalkyl also refers to bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The term heterocycloalkyl refers to a cycloalkyl group containing 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 quatemized. He IF-2019-40565613-APN-ANP#INPI Page 10 of 183 heterocycloalkyl can 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, thiomorphohne-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. The term alkylene, alone or as part of another substituent, means a divalent radical derived from an alkane, such as -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those 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 unsaturated forms of alkylene that have double or triple bonds, respectively. The term heteroalkyl, alone or in combination with another term, means, unless otherwise indicated, a stable cyclic or straight-chain or branched hydrocarbon radical, or combinations thereof, comprising the indicated number of atoms of carbon and one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen heteroatom can be optionally quatemized. The heteroatom(s) O, N and S can be placed in any position inside the heteroalkyl group. The Si heteroatom can be placed at any position on the heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule. Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2,-S(O )-CH3, -CH2-CH2-S(O)2-CH3, CH=CH-O-CH3, -Yes(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3 )-CH3. Up to two heteroatoms can 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, that contains the indicated number of carbons and that 11 IF-2019-40565613-APN-ANP#INPI Page 11 of 183 has one to three heteroatoms selected from the group consisting of O, N, Si and S, and in which the nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quatemized. The heteroatom(s) O, N and S can be placed in any position inside the heteroalkyl group. The term heteroalkylene alone or as part of another substituent means a divalent, saturated, or unsaturated, or polyunsaturated radical derived from heteroalkyl, such as -CH2-CH2-S-CH2CH2- and -CH2-S-CH2-CH2 -NH-CH2-, -O-CH2-CH=CH-, -CH2-CH=C(H)CH2-O-CH2- and -S-CH2-OC-. For heteroalkylene groups, heteroatoms can also occupy one or both ends of the chain (for example, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamine and the like). The terms alkoxy, alkylamino and alkylthio (or thioalkoxy) are used in their conventional sense, and refer to those 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 moieties can be the same or different and can also combine to form a 3-7 membered ring with the nitrogen atom to which each is attached. Accordingly, a group represented as -NRaRb is intended to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like. The term hydroxyalkyl is used in its conventional sense, and refers to a straight-chain or branched alkyl group substituted with at least one hydroxyl group. The hydroxyl group can be in any position on the alkyl group. For example, the term hydroxylalkyl Cm includes hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl and the like. The terms halo or halogen, by themselves or as part of another substituent, mean, unless otherwise indicated, a fluorine, chlorine, bromine or iodine atom. Additionally, terms such as haloalkyl are intended to include monohaloalkyl and polyhaloalkyl. For example, the term Cm haloalkyl includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like. The term aryl means, unless otherwise indicated, a polyunsaturated hydrocarbon group, typically aromatic, which may be a single ring or multiple rings (up to three rings) that are fused together or covalently linked. The term heteroaryl is IF-2019-40565613-APN-ANP#INPI Page 12 of 183 refers to aryl groups (or rings) containing one to five heteroatoms selected from N, O and S, where the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quatemized. A heteroaryl group can 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, pyrimindinyl, triazinyl, quinolinyl, quinoxalimlo, quinazolinyl, cinolinyl, phthalazinium, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzooxazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizimlo, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, is oquinohlo, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, tindo and the like. The substituents for each of the aryl and heteroaryl ring systems indicated above are selected from the group of acceptable substituents described below. The term pharmaceutically acceptable salts is intended to include salts of the active compounds that are 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 said compounds with a sufficient amount of the desired base, pure or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc salts, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines and the like, such as arginine, betaine, caffeine, choline, Ν,Ν'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, 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 IF-2019-40565613-APN-ANP#INPI Page 13 of 183 invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from 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, italic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic acids 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, S.M., 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 to base or acid addition salts. 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. In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention 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 reservoir with a suitable enzyme or chemical reagent. IF-2019-40565613-APN-ANP#INPI Page 14 of 183 Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, which include hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are contemplated 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. Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) all fall within the scope of the present invention. The compounds of the present invention may also contain unnatural ratios of atomic isotopes in one or more of the atoms that constitute said compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example 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. The term prodrug component refers to a group that provides desired properties to a compound that improve, for example, the stability of the compound, in vivo circulation time or solubility. A compound carrying a prodrug component is metabolized (usually by hydrolysis or enzymatically) after administration to a subject, resulting in an active compound. Compounds with a prodrug component can only be activated upon cleavage, but compounds with a prodrug component can have activity in their unreacted forms. Furthermore, a prodrug component may itself be active. Examples of prodrug components contemplated in this invention include, but are not limited to, phosphate, phosphomethyl, hydroxymethyl, amino acids, dipeptide and tripeptide moieties. Other contemplated embodiments are further described herein. The term amino acid refers to natural and non-natural amino acids. Non-natural amino acids refer to compounds that have the same basic chemical structure as a natural amino acid, that is, a carbon a that is bonded to a hydrogen, a carboxyl group, a IF-2019-40565613-APN-ANP#INPI Page 15 of 183 amino group and an R group, such as, but not limited to, homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogues have modified R groups (such as 2,5-diaminopentanoic acid) or modified peptide backbones, but retain the same basic chemical structure as a natural amino acid. The amino acids of the present disclosure include N-methylated and N-acylated residues. When the terminal group of the amino acid is an N atom, it can be di-methylated. Accordingly, a wavy line, ·««, that intersects a single, double or triple bond in any chemical structure represented herein, represents the point of attachment of the single, double or triple bond to the rest of the molecule. Description of embodiments Compounds In one aspect, the present invention provides the compounds of Formulas (IA), (IB), (IC), (IIA), (IIB), and QIC): IF-2019-40565613-APN-ANP#INPI Page 16 of 183 ΙΑ I.C. HAIIB IICo a pharmaceutically acceptable salt thereof, wherein: the vertex of ring a is N or C(R2c), the vertex of ring b is N or C(R2d), and the vertex of ring e is N or C(R2e), where no more than one of a, b and e is N; X1 is selected from the group consisting of a bond, Ci-e alkylene, C(O), C(O)-alkylene Ci-4, and S(O)2; ' Ri is selected from the group consisting of: a) 5 to 10 membered heteroaryl having from 1 to 4 heteroatoms as ring vertices selected from N, O and S; b) Có-io aryl; c) C3-8 cycloalkyl; d) 4 to 8 membered heterocycloalkyl having from 1 to 2 heteroatoms as ring vertices selected from N, O and S; and IF-2019-40565613-APN-ANP#INPI Page 17 of 183 e) Cm alkyl, Cm alkoxy, Ci-8 haloalkyl, -C(O)NRlaR'b, and -CO2Rla; wherein R and Rlb are selected, each independently, from the group consisting of hydrogen, Ci-8 alkyl, Có-io aryl, and -Ci-6 alkylene-Có-io aryl, wherein the group -X'-R1 is optionally substituted with 1 to 5 Rx substituents; R2a and R2es are selected, each independently, from the group consisting of hydrogen, Cm alkyl, Ci-ó alkoxy, Ci-6 haloalkyl, -O-Cm haloalkyl, -S-Ci-6 alkyl, -Ci-6 alkyl-Oalkyl Ci-6, -alkyl Ci-6-S-alkyl Cm, CN, and halogen, and at least one of R2a and R2ees other than hydrogen; R2b, R2c, and R2d are each independently selected from the group consisting of hydrogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, -O-Cm haloalkyl, -S-Ci-6 alkyl, - Ci-6-O-alkyl Cm alkyl, -Cm alkyl -S-Ci-ó alkyl, cyano, and halogen; each R3 is independently selected from the group consisting of hydroxyl, Cm alkyl, Cm haloalkyl and Cm hydroxyalkyl, and optionally two R3 groups on the same carbon atom combine to form oxo (=0), and optionally two R3 groups and the carbon atoms to which they are joined to form a 3-6 membered ring with 0-2 heteroatoms as ring members selected from O, N, and S; r4 is a member selected from the group consisting of: -NHP1, -NHC(O)NHP', -CH2NHP1 and -CH2NHC(0)NHP'; each R5 is independently selected from the group consisting of Ci-8 alkyl, Ci-8 alkoxy, Ci-8 haloalkyl, Ci-8 haloalkoxy, Cm hydroxyalkyl, halogen, OH, CN, C(O)R and CO2R, . R5' is a member selected from the group consisting of hydrogen, Ci-8 alkyl, Ci-8 haloalkyl, Ci-8 hydroxyalkyl, C(O)R5a and CO2R5a; wherein each R5ase independently selects from the group consisting of hydrogen, Cm alkyl, and Cm haloalkyl; R6 is a member selected from the group consisting of hydrogen, Cj-6 alkyl, Ci6 alkoxy, Cm haloalkyl, -O-C1-6 haloalkyl, -S-Cm alkyl, -Ci-6 alkyl, -O-Cm alkyl, -alkyl CmS-alkyl Ci-ó, cyano, and halogen; R7is P1; and IF-2019-40565613-APN-ANP#INPI Page 18 of 183 R8es-CH2OP'; each P1 is a prodrug component; each Rx is independently selected from the group consisting of halogen, CN, Ci-4 alkyl, Cm alkoxy, Cm haloalkyl, Cm haloalkoxy, Cm hydroxyalkyl, C2-4 alkenyl, C3.6 cycloalkyl, CO2-Cm alkyl, and CONH2; the subscript m is 0, 1, 2, 3 or 4; and the subscript n is 0, 1, 2 or 3. In one group of embodiments, the compounds provided herein have the Formula (ΙΑ)* In another group of embodiments, the compounds provided herein have the Formula (IB). In yet another group of embodiments, the compounds provided herein have the Formula (IC). In yet another group of embodiments, the compounds provided herein have the Formula (ΠΑ). In another group of embodiments, the compounds provided herein have the Formula (ΠΒ). In yet another group of embodiments, the compounds provided herein have the Formula (IIC). In some embodiments for the compounds of formula (IA), (IB), (IC), (HA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups In previous embodiments, P1 is selected from the group consisting of: IF-2019-40565613-APN-ANP#INPI Page 19 of 183 wherein each R9 is independently selected from the group consisting of H and C1-3 alkyl; and each R10 is independently selected from the group consisting of H, C1.3 alkyl, femlo, and benzyl. In some embodiments for the compounds of formula (IA), (IB), (IC), (HA), (ΠΒ), (HC), or a pharmaceutically acceptable salt thereof, as well as any of the groups of previous embodiments, P1 is selected from the group consisting of. wherein each Ryse independently selects from the group consisting of -OP(O)(ORyl)2, -OC(O)CH2N(Ry2)2, -N(Ry2)2, and piperazine; each Rylse independently selects from the group consisting of H, alkyl Ci-3, and benzyl; each Ry2is independently H or C1-3 alkyl; and each phenyl ring bearing a Ryo -CH2Ry substituent is further substituted with 0 to 3 members independently selected from the group consisting of nitro, halogen, CN, CF3, Cm alkyl, C1.4 alkoxy, Cm haloalkyl, Ci4 haloalkoxy, e hydroxyalkyl Cm. . In some embodiments for the compounds of formula (IA), (IB), (IC), (HA), (ΠΒ), (HC), or a pharmaceutically acceptable salt thereof, as well as any of the groups Of the above embodiments, P1 is selected from the group consisting of CH2OH, . IF-2019-40565613-APN-ANP#INPI Page 20 of 183 -P(0)(0R'°)2, and -CH2-O-P(O)(OR10)2, wherein each R10 is independently selected from the group consisting of H, C1-3 alkyl, phenyl, and benzyl. In some embodiments for the compounds of formula (IA), (IB), (IC), (HA), (ΠΒ), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups In previous embodiments, P1 is selected from the group consisting of an amino acid, a dipeptide, and a tripeptide. In some embodiments, the amino acid, dipeptide or tripeptide are naturally occurring amino acids. In some embodiments, the amino acid, dipeptide or tripeptide is independently selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, lysine, cisterna, aspartate, glutamate, histidine and phenylalanine, wherein the N atom of each amino acid unit can be methylated or acylated. The amino acids of the present invention can be covalently linked to the remainder of the molecule through any suitable means. Suitable linkages include, but are not limited to, amide formation between an amine group and a hydroxyl group, ester formation between a carboxylic acid group and a hydroxyl group, and sulfonamide (NS-bond) formation between a thio group and a hydroxyl group. Not me. Typically, amino acids are covalently linked to the remainder of the molecule through the alpha amino group or the alpha carboxylic acid; However, when the R group of the amino acid includes a functional group, this can also serve as a linking point. For example, the carboxylic acid of a glutamate can serve as a binding point with the remainder of the molecule. Similarly, the thiol of a cysteine ​​can also serve as a binding point to the remainder of the molecule. In some embodiments for the compounds of formula (IA), (IB), (IC), (HA), (ΠΒ), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups In previous embodiments, P1 is selected from the group consisting of: IF-2019-40565613-APN-ANP#INPI Page 21 of 183 With reference to the compounds of formula (IA), (IB), (IC), (HA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups of forms of above embodiments, in certain selected embodiments, X1 is a link; in other selected embodiments, X1 is C(O); In still other selected embodiments, X1 is C.-8 alkylene; In still other selected embodiments, IIC), or a pharmaceutically acceptable salt thereof, as well as any of the above groups of embodiments, in some additional embodiments, wherein R1 is a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms as ring vertices selected from N, O and S, the -X'-R1 group is optionally substituted with 1 to 4 Rx substituents. In still other embodiments, R1 is selected from the group consisting of pyrazolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, thiadiazolyl and pyrazinyl, and wherein the group -X'-R1 is optionally substituted with 1 to 4 Rx substituents. With reference to the compounds of formula (IA), (IB), (IC), (HA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups of forms of previous embodiments, in some additional embodiments, R1 is Có-io aryl, and the group -X'-R1 is optionally substituted with 1 to 4 Rx substituents. In still other embodiments, R1 is phenyl; and wherein the group -X'-R1 is optionally substituted with 1 to 4 Rx substituents. With reference to the compounds of formula (IA), (IB), (IC), (ΠΑ), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups of forms of above embodiments, in some additional embodiments, R1 is C3.8 cycloalkyl, and the group -X'-R1 is optionally substituted with 1 to 4 Rx substituents. In still other embodiments, R1 is selected from the group consisting of cyclobutyl, cyclopentyl and cyclohexyl; and wherein the group -X'-R1 is optionally substituted with 1 to 4 Rx substituents. With reference to the compounds of formula (IA), (IB), (IC), (IIA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups of IF-2019-40565613-APN-ANP#INPI Page 22 of 183 above embodiments, in some additional embodiments, R' is a 4- to 8-membered heterocycloalkyl having 1 to 2 heteroatoms as ring vertices selected from N, O and S, the group -X' -R1 is optionally substituted with 1 to 4 Rx substituents. In still other selected embodiments, R1 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl; and wherein the group -X'-R1 is optionally substituted with 1 to 4 Rx substituents. With reference to the compounds of formula (IA), (IB), (IC), (HA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups of forms of above embodiments, in some additional embodiments, R1 is selected from the group consisting of Ci-s alkyl, Ci-8 alkoxy, Ci-8 haloalkyl, -C(O)NRaR, and CChR13; wherein R and Rlb are selected, each independently, from the group consisting of hydrogen, Ci-8 alkyl, Có-io aryl, and -Ci-6 alkylene-Có-io aryl; and wherein the group -X'-R1 is optionally substituted with 1 to 4 Rx substituents. With reference to the compounds of formula (IA), (IB), (IC), (HA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups of forms of above embodiments, in some additional embodiments, R' is selected from the group consisting of phenyl, pyridyl, pyrimidinyl and pyrazinyl; wherein the X'-R' group is optionally substituted with 1 to 4 Rx substituents. With reference to the compounds of formula (IA), (IB), (IC), (HA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups of forms of previous embodiments, in some additional embodiments, the ring vertices a and b are CH; R2bes H; the vertex of the ring e is C(R2e), and R2a and R2ese are selected from the group consisting of Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, -O-Ci-6 haloalkyl, -S-Ci6 alkyl, -Ci-6-alkyl-O-Ci-6 alkyl, -Ci-or-S-alkyl-Ci-6 alkyl, CN, and halogen. With reference to the compounds of formula (IA), (IB), (IC), (ΠΑ), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups of forms of previous embodiments, in some additional embodiments, the ring vertices a and b are CH; R2bes H; The vertex of the e ring is C(R2e), and R2a and R2ese are selected from the group consisting of Ci-6 alkyl, Ci-6 alkoxy, and halogen. IF-2019-40565613-APN-ANP#INPI Page 23 of 183 With reference to the compounds of formula (IA), (IB), (IC), (IIA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups of forms of above embodiments, in some additional embodiments, the subscript n is 0, 1 or 2 and each R5, when present, is selected from the group consisting of F, Cl, CN, Cm alkyl and Cm alkoxy. In still other selected embodiments, the subscript n is 0, 1 or 2 and each R5, when present, is selected from the group consisting of F, Cl, CN, CH3 and OCH3. With reference to the compounds of formula (IA), (IB), (IC), (ΠΑ), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups of forms of above embodiments, in some additional embodiments, the subscript n is 0, 1 or 2 and each R3, when present, is Cm alkyl. In a particular group of embodiments of the compounds of formula (IA), (IB), (IC), (ΠΑ), (ΠΒ), (IIC), or a pharmaceutically acceptable salt thereof, R1 is selected from the group consisting of phenyl or pyridyl, wherein the group -X'-R1 is optionally substituted with 1 to 4 Rx substituents; the vertices of ring a and b are CH; R2bes H; the apex of the e ring is C(R2e), and R2a and R2ese are independently selected from the group consisting of Cm alkyl, Cm alkoxy and halogen; m is 0, 1 or 2 and each R3, when present, is CH3;n is 0, 1 or 2 and each R5, when present, is selected from the group consisting of F, Cl, CN, CH3 and OCH3 . In some embodiments of the compounds of formula (IA), (IB), (IC), (IIA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, R1 is selected from the group consisting in: IF-2019-40565613-APN-ANP#INPI Page 24 of 183 In some embodiments of the compounds of formula (IA), (IB), (IC), (HA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, -X'-R1 is selected from the group consisting of: IF-2019-40565613-APN-ANP#INPI Page 25 of 183 IF-2019-40565613-APN-ANP#INPI Page 26 of 183 In some embodiments of the compounds of formula (IA), (IB), (IC), (HA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, R1 is selected from the group consisting in: In some embodiments of the compounds of formula (IA), (IB), (IC), (HA), (ΠΒ), (IIC), or a pharmaceutically acceptable salt thereof, R1 is selected from the group consisting in: IF-2019-40565613-APN-ANP#INPI Page 27 of 183 In some embodiments of the compounds of formula (IA), (IB), (IC), (HA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, R1 is selected from the group consisting in: IF-2019-40565613-APN-ANP#INPI Page 28 of 183 With reference to the compounds of formula (IA), (IB), (IC), (IIA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups of forms of above embodiments, in some additional embodiments, the group is selected from the group consisting of With reference to the compounds of formula (IA), (IB), (IC), (ΠΑ), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups of forms of above embodiments, in some additional embodiments, where n is 0. With reference to the compounds of formula (IA), (IB), (IC), (HA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well as any of the groups of forms of previous embodiments, in some additional embodiments, the subscript n is 2 and the two R3 groups are on the same carbon atom and combine to form oxo (=0). IF-2019-40565613-APN-ANP#INPI Page 29 of 183 In some embodiments, the compound of the present invention is a compound described in the Examples section and the accompanying Tables. Preparation of the Compounds Certain compounds of the invention can be prepared following the methodology as described in the Examples section of this document. Furthermore, the syntheses of certain intermediate compounds that are useful in the preparation of the compounds of the invention are also described. Pharmaceutical compositions In addition to the compounds provided above, compositions for modulating C5a activity in humans and animals will typically contain a pharmaceutical carrier or diluent. The term composition, as used herein, is intended to encompass a product comprising the specified ingredients in the specified quantities, as well as any product that is formed, directly or indirectly, from the combination of the specified ingredients in the specified quantities. By pharmaceutically acceptable it is understood that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not harmful to its recipient. Pharmaceutical compositions for administration of the compounds of the present invention may conveniently be presented in a unit dosage form and may be prepared by any of the methods widely known in the art of pharmacy and drug delivery. All methods include the step of bringing the active ingredient into association with the vehicle that constitutes one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately associating the active ingredient with a liquid carrier or a finely divided solid carrier, 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 sufficient to produce the desired effect on the disease process or condition. Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use; for example, such as tablets, wafers, lozenges, IF-2019-40565613-APN-ANP#INPI Page 30. of 183 aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsions as described in U.S. Patent Application. 2002-0012680, hard or soft capsules, syrups, elixirs, solutions, oral patch, oral gel, 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 consisting of sweetening agents, flavoring agents, coloring agents, antioxidants and preservatives to provide pharmaceutically elegant and palatable preparations. The tablets contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients that are suitable for tablet manufacturing. These excipients may be, for example, inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mamtol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example PVP, cellulose, PEG, starch, gelatin or gum arabic, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated, enteric or otherwise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide sustained action over a longer period. For example, a retarding material such as glyceryl monostearate or glyceryl distearate may be employed. They can also be coated using the techniques described in Pat. US No. 4,256,108; 4,166,452; and 4,265,874 to form controlled release osmotic therapeutic tablets. 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, liquid paraffin or olive oil. Additionally, emulsions can be prepared with a water-immiscible ingredient, such as oil, and stabilized with surfactants such as monodiglycerides, PEG esters and the like. IF-2019-40565613-APN-ANP#INPI Page 31 of 183 Aqueous suspensions contain the active materials mixed with suitable excipients for the preparation of aqueous suspensions. Said excipients are suspending agents; for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth 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 example heptadecatonileneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylenesorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of hexitol, for example monooleate of polyethylenesorbitan. Aqueous suspensions may also contain one or more preservatives, for example, ethyl or npropyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. Oil suspensions can 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. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by adding an antioxidant such as ascorbic acid. Dispersed 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, 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, for example sweeteners, flavorings and colorings. 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 IF-2019-40565613-APN-ANP#INPI Page 32 of 183 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 gum tragacanth, natural phosphatides, for example soybean, lecithin and esters or partial esters derived from fatty acids and anhydrides of hexitol, for example sorbitan monooleate, and products of condensation of said partial esters with ethylene oxide; for example, polyoxyethylenesorbitan monooleate. Emulsions may also contain sweetening and flavoring agents. Syrups and elixirs can 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 can be prepared in combination with, for example, cyclodextrin, PEG and surfactants. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art 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 parental administration, for example a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any soft fixed oil can be used including synthetic mono- or diglycerides. Additionally, fatty acids like oleic acid find use in the preparation of injectables. 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 usual temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. Additionally, the compounds can be administered by ocular application through solutions or ointments. Furthermore, transdermal administration of the compounds of the invention can be IF-2019-40565613-APN-ANP#INPI Page 33 of 183 carried out by means of iontophoretic patches and similar. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are used. Accordingly, topical application is also intended to include the use of mouthwashes and gargling rinses. 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, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the invention can be coupled with a carrier which is a class of biodegradable polymers useful for achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid , polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. Polymers and semipermeable 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 polymeric matrix that takes the form of a cannula or cannulagraft device. The pharmaceutical compositions of the present invention may be formulated with one or more additional therapeutic agents. Said one or more additional therapeutic agents are selected from the group consisting of corticosteroids, steroids, immunosuppressants, Immunoglobulin G agonists, dipeptidyl peptidase IV inhibitors, lymphocyte function antigen 3 receptor antagonists, ligand inhibitors. of interleukin-1 beta, IL-2 receptor alpha subunit inhibitors, HGF gene stimulators, IL-6 antagonists, IL-5 antagonists, IL-5 antagonists, alpha antitrypsin stimulators 1, cannabinoid receptor antagonists, histone deacetylase inhibitors, AKT protein kinase inhibitors, CD20 inhibitors, Abl tyrosine kinase inhibitors, JAK tyrosine kinase inhibitors, TNF alpha ligand inhibitors, hemoglobin modulators , TNF antagonists, proteasome inhibitors, CD3 modulators, Hsp 70 family inhibitors, immunoglobulin agonists, '34 antagonists IF-2019-40565613-APN-ANP#INPI Page 34 of 183 CD30, tubulin antagonists, sphingosine-1-phosphate receptor 1 agonists, connective tissue growth factor ligand inhibitors, caspase inhibitors, adrenocorticotropic hormone liver, Btk tyrosine kinase inhibitors, Btk subcomponent inhibitors Cls complement, erythropoietin receptor agonists, B-cell stimulatory ligand inhibitors, cyclin-dependent kinase-2 inhibitors, P-selectin glycoprotein ligand-1 stimulators, mTOR inhibitors, elongation factor 2 inhibitors , cell adhesion molecule inhibitors, factor of cytotoxic T lymphocytes, angiotensin II receptor antagonists, angiotensin II receptor modulators, TNF superfamily 12A receptor antagonists, CD52 antagonists, adenosine deaminase inhibitors, CD6 inhibitors of the differentiation antigen T cells, FGF-7 ligands, dihydroorotate dehydrogenase inhibitors, Syk tyrosine kinase inhibitors, type I interferon receptor antagonists, interferon alpha ligand inhibitors, macrophage migration inhibitory factor inhibitors, antagonists alpha-V / beta-6 integrin, cisterna protease stimulators, p38 MAP kinase inhibitors, TP53 gene inhibitors, Shiga toxin I inhibitors, fucosyltransferase 6 stimulators, interleukin 22 ligands, IRS1 gene, protein kinase C stimulators, protein kinase C alpha inhibitors, CD74 antagonists, immunoglobulin gamma Fe receptor IIB antagonists, T cell antigen CD7 inhibitors, CD95 antagonists, N acetylmannosamine kinase stimulators, cardiotrophin1 ligands, leukocyte elastase inhibitors, CD40 ligand receptor antagonists, CD40 ligand modulators, IL-17 antagonists, TLR-2 antagonists, lectin serine binding protease-2 (MASP-2) inhibitors amannan, factor B inhibitors, factor D inhibitors, C3aR modulators, C5aR2 modulators, T cell receptor antagonists, PD-1 inhibitors, PD-L1 inhibitors, TIGIT inhibitors, TIM-3 inhibitors , LAG-3 inhibitors, VISTA inhibitors, STING agonists, IDO inhibitors, adenosine receptor modulators, CD39 inhibitors, CD73 inhibitors, chemokine receptor antagonists, especially CXCR1, CXCR2, CXCR3, IF-2019-40565613-APN-ANP#INPI Page 35 of 183 CXCR4, CXCR7, CCR1, CCR2, CCR3, CCR4, CCR5, CCR7, CCR7, CCR9, CX3CR1 and CXCR6, and combinations thereof. In some embodiments, said 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, hydrocortisone-17valerate, halometasone, alclomethasone dipropionate, beclomethasone, betamethas valerate one, dipropionate betamethasone, prednicarbate, clobetasone-17-butyrate, clobetasol17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, ciclesonide and prednicarbate, GB-0998, immuglo , begelomab, alefacept, aldesleukin, gevokizumab, daclizumab, basiliximab, inolimomab, beperminogen perplasmid, sirukumab, tocilizumab, clazakizumab, mepolizumab, fmgolimod, panobinostat, triciribine, nilotinib, imatinib, tofacitinib, momelotinib, peflcitinib, itacitinib, infliximab, Hb- CO, etanercept, ixazomib, bortezomib, muromonab, otelixizumab, gusperimus, brentuximab vedotin, Ponesimod, KRP-203, FG-3019, emricasan, corticotropin, ibrutinib, cinryze, conestat, methoxy polyethylene glycol-epoietin beta, belimumab, blisibimod, atacicept, seliciclib , Neihulizumab, Everolimus, Sirolimus, Denileuquina Diftitox, LMB-2, Natalizumab, Catridecacog, Cyclosporine, Tacrolimus, Volaporin, Numporin, Canakinumab, Mycophenolate, Mizoribina, CE-1145, TKDLI, ABATACEPT, BELATACEPT, BELATACEPT, BELATACEPT, BELATACEPT , Txa-127 , BIIB-023, alemtuzumab, pentostatin, itolizumab, palifermin, leflunomide, PRO-140, cemcnviroc, fostamatinib, anifrolumab, sifalimumab, BAX-069, BG-00011, losmapimod, QPI-1002, ShigamAbs, TZ-101, F-652 , reparixin, ladarixin, PTX-9908, aganirsen, APH-703, sotrastaurin, sotrastaurin, milatuzumab, SM-101, T-Guard, APG-101, DEX-M74, cardiotropin1, tiprelestat, ASKP-1240, BMS-986004, HPH -116, KD-025, OPN-305, TOL-101, defibrotide, pomalidomide, Thymoglobulin, laquinimod, remestemcel-L, equine antithymocyte immunoglobulin, Stempeucel, LIV-Gamma, Octagam 10%, t2c-001, 99mTc-sestamibi, Clairyg , Prosorba, pomalidomide, laquinimod, teplizumab, FCRx, solnatide, foralumab, ATIR-101, BPX-501, 36 IF-2019-40565613-APN-ANP#INPI Page 36 of 183 ACP-01, ALLO-ASC-DFU, irbesartan + propagermanium, ApoCell, cannabidiol, RGI-2001, saratin, diphtheria toxin-bivalent anti-CD3 antibody conjugate, NOX-lOO, LT-1951, OMS721, ALN-CC5, ACH- 4471, AMY-101, Acthar gel, and CD4+CD25+ regulatory T cells, MEDI7814, P32, P59, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, CCX354, CCX721, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX587, 4 , CCX282, CCX025, CCX507, CCX430, CCX765, CCX758, CCX771, CCX662, CCX650, and combinations thereof. Other discussions of combination treatment are included in the Methods of Use section of this application. Methods of use The compounds of the invention can be used as agonists, (preferably) antagonists, partial agonists, 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 amount of one or more C5a receptor modulators according to the present, in the presence of the C5a receptor ligand in aqueous solution and under suitable conditions. for ligand binding to the C5a receptor. The C5a receptor may be present in suspension (for example, in an isolated membrane or cell preparation), in a cultured or isolated cell, or in a tissue or organ. 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 according to this. In one embodiment of the invention, the C5a modulators of the invention are used to modulate, preferably inhibit, the signal transducing 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 the 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 IF-2019-40565613-APN-ANP#INPI Page 37 of 183 signal transduction activity detecting an effect on calcium mobilization or detecting an effect on cellular chemotaxis mediated by the C5a receptor. In general, an effective amount of one or more C5a modulators is an amount sufficient to modulate the signal transducing activity of the C5a receptor in vitro within a C5a receptor-mediated calcium mobilization or cellular chemotaxis assay within a migration essay. When the compounds of the invention are used to inhibit C5a receptor-mediated cellular chemotaxis, preferably chemotaxis of leukocytes (e.g., neutrophils), in an in vitro chemotaxis assay, said methods comprise contacting white blood cells of the blood (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 levels of chemotaxis observed in a control assay are significantly higher, as described above, than the levels observed in a test in which a compound of the invention has been added. In another embodiment, the compounds of the present invention may additionally be used to treat patients suffering from conditions that are sensitive to C5a receptor modulation. As used herein, 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 (that is, after the onset of symptoms, in order to reduce the severity and / or duration of symptoms). Accordingly, a condition is considered sensitive to C5a receptor modulation if modulation of C5a receptor activity results in reduction of inappropriate activity of a C5a receptor. Accordingly, 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), at the doses described herein. Conditions that can be treated by C5a modulation: IF-2019-40565613-APN-ANP#INPI Page 38 of 183 Autoimmune disorders: for example, rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barre syndrome, pancreatitis, lupus nephritis, lupus, glomerulonephntis, psoriasis, Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, disease of dense deposits, 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. 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, injury pulmonary and ischemia-reperfusion injury, osteoarthritis, as well as acute respiratory distress syndrome (ARDS, or ARDS), chronic obstructive pulmonary disease (COPD), systemic inflammatory response syndrome (SIRS, Systemic Inflammatory Response Syndrome), atopic dermatitis, psoriasis, chronic urticaria and multiple organ dysfunction syndrome (MODS), hemolytic uremic syndrome, atypical hemolytic uremic syndrome (aHUS) atypical Hemolytic Uremic Syndrome). Also included are pathological sequelae associated with insulin-dependent diabetes mellitus (including diabetic retinopathy), lupus nephropathy, 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 circulation of blood (for example, during hemodialysis or through a cardiopulmonary machine, for example, in association with vascular surgery such as coronary artery bypass grafting or valve replacement cardiac), or in association with contact with other artificial surfaces of vessels or containers (for example, ventricular assist devices, artificial heart machines, transfusion tubes, blood storage bags, plasmapheresis, plateletpheresis and the like). Diseases related to the injury are also included. IF-2019-40565613-APN-ANP#INPI Page 39 of 183 ischemia / reperfusion, such as those resulting from transplants, 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, P.N.A.SA02. 7227-7232, 2005). Cardiovascular and cerebrovascular disorders: for example, myocardial infarction, coronary thrombosis, vascular occlusion, postsurgical vascular reocclusion, atherosclerosis, traumatic injury to 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, previous history or genetic history of myocardial infarction or thrombosis) to reduce the risk of myocardial infarction or thrombosis. 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, cell carcinoma squamous, basal cell carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, pleomorphic adenoma, hepatic cell papilloma, adenoma renal tubular, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma and fibroma. Vasculitis Diseases: Vasculitic diseases are characterized by inflammation of the vessels. Leukocyte infiltration leads to destruction of the vessel walls, and the complement pathway is thought to play an important role in the initiation of leukocyte migration as well as 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-associated vasculitis (ANCA, Anti. 40 IF-2019-40565613-APN-ANP#INPI Page 40 of 183 Neutrophil Cytoplasmic Antibody), immune vasculitis, Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, Henoch-Schonlein purpura, pohatentis nodosa, Rapidly Progressive Glomerulonephritis (RPGN), cryoglobulinemia, giant cell arteritis (GCA), or GCA, Giant Cell Arteritis), Behcet's disease, and Takayasu's arteritis (TAK). HIV Infection and AIDS: The C5a receptor modulators provided herein may be used to inhibit HIV infection, delay the progression of AIDS, or decrease the severity of HIV and AIDS symptoms or infection. Neurodegenerative disorders and related diseases: In other aspects, the C5a antagonists provided herein can be used to treat Alzheimer's disease, multiple sclerosis, and the decline in cognitive function associated with cardiopulmonary bypass surgery, and related procedures. In one embodiment of the invention, the compounds of the invention can be used for the treatment of diseases selected from the group consisting of sepsis (and associated disorders), COPD, rheumatoid arthritis, lupus nephritis and multiple sclerosis. The treatment methods described herein generally include administering to a patient an effective amount of one or more compounds herein. Suitable patients include those patients who suffer from or are susceptible to suffering from (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 cows, pigs, sheep and the like. 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 an amount sufficient to modulate the activity of the C5a receptor and / or an amount sufficient to reduce or alleviate the symptoms presented by the patient. IF-2019-40565613-APN-ANP#INPI Page 41 of 183 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 the chemotaxis of white blood cells (e.g., neutrophils) 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, a twice-daily dosing regimen is preferred, with once-daily dosing being particularly preferred. It will be understood, however, that the specific dosage 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, drug combination (i.e., other drugs administered to the patient), and the severity of the particular disease being treated, as well as the GP discretion. In general, the use of the minimum dose sufficient to provide effective treatment is preferred. In general, patients can generally be monitored for therapeutic effectiveness using medical or veterinary criteria appropriate for the condition being treated or prevented. Dosage levels on the order of about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment or prevention of conditions involving pathogenic activity of C5a (about 0.5 mg to about 7 g per human patient per day). The amount of active ingredient that can be combined with the carriers to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Dosage unit forms will generally contain between about 1 mg and about 500 mg of an active ingredient. For compounds administered orally, transdermally, intravenously or subcutaneously, it is preferred to administer a sufficient amount of the compound to achieve a serum concentration of 5 ng (nanograms) / ml-10 μg (micrograms) / ml serum, more preferably, A compound should be administered to achieve a serum concentration of 20 ng-1 pg / ml serum, more preferably, sufficient compound to achieve a serum concentration of 50 ng / ml-200 ng / ml serum. For direct injection into the synovial membrane (for the treatment of IF-2019-40565613-APN-ANP#INPI Page 42 of 183 arthritis) sufficient compounds should be administered to achieve a local concentration of approximately 1 micromole. The dosage frequency may also vary depending on the compound used and the particular disease treated. However, for the treatment of most disorders, a dosing regimen of 4 times a day, three times a day or less is preferred, with a dosing regimen of once a day or 2 times a day being particularly preferred. It will be understood, however, that the specific dosage 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, the route of administration, and the rate of excretion, the combination of drugs (i.e., other medications administered to the patient), the severity of the particular disease being treated, and other factors, including the judgment of the patient. GP. Combined therapy The compounds described herein may be used in combination with one or more additional therapeutic agents that are used in the treatment, prevention, suppression or amelioration of diseases or conditions for which the compounds and compositions of the present invention are tools. Said one or more additional therapeutic agents can 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 at the same time with one or more other drugs, a pharmaceutical composition containing said other drugs in addition to the compound or composition of the present invention is preferred. Accordingly, 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. Examples of such one or more therapeutic agents are: corticosteroids, steroids, immunosuppressants, Immunoglobulin G agonists, dipeptidyl peptidase IV inhibitors, lymphocyte function antigen 3 receptor antagonists, ligand inhibitors. IF-2019-40565613-APN-ANP#INPI Page 43 of 183 interleukin-1 beta, IL-2 receptor alpha subunit inhibitors, HGF gene stimulators, IL-6 antagonists, IL-5 antagonists, IL-5 antagonists, stimulators alpha 1 antitrypsin, cannabinoid receptor antagonists, histone deacetylase inhibitors, AKT protein kinase inhibitors, CD20 inhibitors, Abl tyrosine kinase inhibitors, JAK tyrosine kinase inhibitors, TNF alpha ligand inhibitors, modulators hemoglobin, TNF antagonists, proteasome inhibitors, CD3 modulators, Hsp 70 family inhibitors, immunoglobulin agonists, CD30 antagonists, tubulin antagonists, sphingosine-1-phosphate receptor 1 agonists, ligand inhibitors connective tissue growth factor, caspase inhibitors, adrenocorticotropic hormone ligands, Btk tyrosine kinase inhibitors, complement subcomponent Cls inhibitors, erythropoietin receptor agonists, B-cell stimulating ligand inhibitors, cyclin-dependent kinase-2, P-selectin glycoprotein ligand-1 stimulators, mTOR inhibitors, elongation factor 2 inhibitors, cell adhesion molecule inhibitors, factor XIII agonists, calcineurin inhibitors, agonists immunoglobulin Gl, inosine monophosphate dehydrogenase inhibitors, complement subcomponent Cls inhibitors, thymidine kinase modulators, cytotoxic T lymphocyte protein 4 modulators, angiotensin II receptor antagonists, angiotensin receptor modulators II, TNF superfamily 12A receptor antagonists, CD52 antagonists, adenosine deaminase inhibitors, T cell differentiation antigen CD6 inhibitors, FGF-7 ligands, dihydroorotate dehydrogenase inhibitors, tyrosine kinase inhibitors Syk, type I interferon receptor antagonists, interferon alpha ligand inhibitors, macrophage migration inhibitory factor inhibitors, alpha-V / beta-6 integrin antagonists, cysteine ​​protease stimulators, p38 MAP kinase, TP53 gene inhibitors, Shiga toxin I inhibitors, fucosyltransferase 6 stimulators, interleukin 22 ligands, IRS1 gene inhibitors, protein kinase C stimulators, protein kinase C alpha inhibitors, antagonists CD74, immunoglobulin gamma Fe receptor IIB antagonists, T cell antigen CD7 inhibitors, CD95 antagonists, N acetylmannosamine kinase stimulators, cardiotrophin1 ligands, leukocyte elastase inhibitors, CD40 ligand receptor antagonists, modulators of CD40 ligand, IL-17 antagonists, TLR-2 antagonists, 44 inhibitors IF-2019-40565613-APN-ANP#INPI Page 44 of 183 mannan-binding lectin serine protease-2 (MASP-2), factor B inhibitors, factor D inhibitors, C3aR modulators, C5aR2 modulators, T cell receptor antagonists, PD-1 inhibitors , PD-L1 inhibitors, TIGIT inhibitors, TIM-3 inhibitors, LAG-3 inhibitors, VISTA inhibitors, STING agonists, IDO inhibitors, adenosine receptor modulators, CD39 inhibitors, CD73 inhibitors, chemokine receptor antagonists, especially CXCR1, CXCR2, CXCR3, CXCR4, CXCR7, CCR1, CCR2, CCR3, CCR4, CCR5, CCR7, CCR7, CCR9, CX3CR1 and CXCR6, and combinations thereof. In some embodiments, the additional therapeutic agent used in the therapeutic methods herein is selected from the group consisting of obinutuzumab, rituximab, ocrelizumab, cyclophosphamide, prednisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desomda, fluocinomda, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone 17 -valerate, HALOMETASONA, Dipropionato de Alconlometasone, Beclomethasone, Betamethasone Valerate, Betamethasone Dipropionate, Prednicarbate, Clobtassa -17-Aceponato , hydrocortisone-17-buteprate, ciclesonide and prednicarbate, GB0998, immuglo, begelomab, alefacept, aldesleukin, gevokizumab, daclizumab, basiliximab, inolimomab, beperminogen perplasmid, sirukumab, tocilizumab, clazakizumab, mepolizumab, fingolimod, panobinostat, triciribine, ni lotinib, imatinib, tofacitinib, momelotinib, peficitinib, itacitinib, infliximab, PEG-bHb-CO, etanercept, ixazomib, bortezomib, muromonab, otelixizumab, gusperimus, brentuximab vedotin, Ponesimod, KRP-203, FG-3019, emricasan, corticotropin, ibrutinib, cinryze, conestat , methoxy polyethylene glycol-epoietin beta, belimumab, blisibimod, atacicept, seliciclib, neihulizumab, everolimus, sirolimus, denileukin diftitox, LMB-2, natalizumab, catridecacog, cyclosporine, tacrolimus, voclosporin, voclosporin, canakinumab, mycophenolate, mizoribine, CE-1145, TK-DLI, abatacept, belatacept, olmesartan medoxomil, sparsentan, TXA-127, BIIB-023, alemtuzumab, pentostatin, itolizumab, palifermin, leflunomide, PRO-140, cenicriviroc, fostamatinib, anifrolumab, sifalimumab, BAX IF-2019-40565613-APN-ANP#INPI Page 45 of 183 069, BG-00011, losmapimod, QPI-1002, ShigamAbs, TZ-101, F-652, reparixin, ladarixin, PTX-9908, aganirsen, APH-703, sotrastaurin, sotrastaurin, milatuzumab, SM-101, T-Guard, APG-101, DEX-M74, cardiotropin-1, tiprelestat, ASKP-1240, BMS-986004, HPH-116, KD-025, OPN-305, TOL-101, defibrotide, pomalidomide, Thymoglobulin, laquinimod, remestemcel-L, equine antithymocyte immunoglobulin, Stempeucel, LIV-Gamma, Octagam 10%, t2c-001, 99mTc-sestamibi, Clairyg, Prosorba, pomalidomide, laquinimod, teplizumab, FCRx, solnatide, foralumab, ATIR-101, BPX-501, ACP-01, ALLO-ASC-DFU, irbesartan + propagerman io, ApoCell, cannabidiol, RGI-2001, saratin, diphtheria toxin-bivalent anti-CD3 antibody conjugate, NOX-100, LT-1951, OMS721, ALN-CC5, ACH-4471, AMY -101, Gel Acthar, and T cells CD4+CD25+, Media CX587, CCX624, CCX282, CCX025, CCX507, CCX430, CCX765, CCX758, CCX771, CCX662, CCX650, and combinations thereof. The disease or disorder being treated will determine which additional therapeutic agent or agents are most suitable to be administered in combination with the compounds of the present invention. Such determination may be made by the person skilled in the art. The weight ratio between the compound of the present invention and the second active ingredient can 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 about 1000:1 to about 1:1000, preferably about 200: 1 at approximately 1:200. Typically, 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 In another aspect of the invention, the compounds of the invention can be used in a variety of non-pharmaceutical applications in vitro and in vivo. For example, the compounds of the invention can be labeled and used as probes for the detection and localization of the C5a receptor 46 IF-2019-40565613-APN-ANP#INPI Page 46 of 183 (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 to determine 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 (SCT) imaging. SPECT (Single Photon Emission Computerized Tomography). 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., radiolabeled with a radionuclide such as tritium), and can be incubated with a sample for a suitable incubation time (e.g., determined firstly the time of the union). 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 may be used). to detect luminescent groups and fluorescent groups). As a control, a tailored sample containing the labeled compound and a larger (e.g., 10-fold) amount of 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, NY. 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 interior surface of a tissue culture dish or other support, for use as affinity ligands to immobilize, and thereby isolate, C5a receptors (e.g., isolate cells that express the recipient) in vitro. In a preferred application, a modulator linked to a fluorescent label, such as fluorescein, is contacted with the IF-2019-40565613-APN-ANP#INPI Page 47 of 183 cells, which are then analyzed (or isolated) by fluorescence activated cell sorting (FACS). EXAMPLES The following examples are illustrative and do not limit the claimed invention. The reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Ή Nuclear Magnetic Resonance (Ή-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 ratio of mass to charge, followed by the relative abundance of each ion (in parentheses). In the examples, a single m / e value is reported for the M + H (or, as indicated, M-H) ion containing the most common atomic isotopes. The isotope patterns correspond to the expected formula in all cases. Electrospray ionization (ESI) and mass spectrometry analysis was carried out on a Hewlett-Packard MSD electrospray mass spectrometer using HP 1100 HPLC for sample elution. Typically, the analyte was dissolved in methanol at 0.1 mg / mL and 1 microliter was infused with the elution solvent into the mass spectrometer, which scanned from 100 to 1500 daltons. All compounds could be analyzed in the positive ESI mode, using acetonitrile / water with 1% formic acid as elution solvent. The compounds provided below could also be analyzed in negative ESI mode, using 2 mM NH4OAc in acetonitrile / water as the elution system. 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. . 48 IF-2019-40565613-APN-ANP#INPI Page 48 of 183 MeOH: Methanol 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. One skilled in the art will also recognize that alternative methods may be employed to synthesize the subject compounds of the invention, and that the approaches described in the body of this document are not exhaustive, but rather provide practical and widely applicable avenues for the compounds of interest. Certain molecules claimed in this patent may exist in different enantiomeric and diastereomeric forms, and all variants of these compounds are claimed. 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 identifies them, as well as by the structural representations associated with them. Those skilled in the art will also recognize that, during standard procedures in organic chemistry, acids and bases are frequently used. 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. IF-2019-40565613-APN-ANP#INPI Page 49 of 183 Synthesis of intermediate 1: 3-(6-chloro-7-methoxy-lH-indol-4-yl)-2-(2,6-diethylpheml)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4 ,5,6,7-tetrahydro-2Zf-pyrazolo[4,3-c]pyridine 1) HCI, NaNO22)SnCI2«2H2O 3) NaOH 4) HCI / EI2O EtOH, reflux 2) Isoamyl nitrite CuBr. MeCN Step b Step to Caution: Diazonium formation could be potentially hazardous; Please treat with care and wear appropriate personal protective equipment. Step a: To a 250 mL flask loaded with 90 mL of concentrated hydrochloric acid under magnetic stirring, 2,6-diethylaniline (10.0 g, 67.0 mmol) was added. The resulting mixture was stirred for 30 min and cooled with a salt / ice bath until the internal temperature reached −5 °C. A solution of sodium nitrite (5.5 g, 80.0 mmol) in water (60 mL) was slowly added to the above mixture while maintaining the internal temperature below 5 C. Separately, tin(II) chloride dihydrate (31.6 g, 140.0 mmol) was added to a 500 mL 3-neck round-bottom flask loaded with concentrated hydrochloric acid (60 mL) under mechanical stirring. The resulting solution was then cooled with an ice bath. The diazonium suspension was then filtered into the 500 mL flask containing the cooled stannous chloride solution with vigorous stirring. After 90 minutes, the reaction mixture 50 IF-2019-40565613-APN-ANP#INPI Page 50 of 183 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 entire liquid layer was decanted to obtain a wet solid. The material recovered in this way was dried in vacuo for one day and then transferred to a 500 mL 3-neck round-bottom flask equipped with an overhead mechanical stirrer and stirred with ether (180 mL). The resulting mixture was cooled in an ice bath, and NaOH solution (10 N, 30 mL) was added slowly to the above mixture while maintaining the internal temperature below 12 C. After addition, the mixture was left rest for 2 hours on ice. The ether layer was decanted into a 500 mL flask, and a stream of hydrogen chloride gas was bubbled into the ether solution while stirring. 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. Step b: 7V,7V-diisopropylethylamine (8 mL, 46.0 mmol) was added to a mixture of (2,6-diethylphenyl)hydrazine hydrochloride (8 g, 39.9 mmol), tert-butyl 3-cyano- 4-oxopiperidine-l-carboxylate (5 g, 22.3 mmol) and EtOH (60 mL) in a 250 mL round bottom flask under magnetic stirring. The resulting mixture was stirred under reflux for 3 h. Glacial acetic acid (12 mL, 208 mmol) was added and the mixture was stirred under reflux for another 2 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and washed with NaOH solution (2 N), brine, and dried in the presence of MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 55% EtOAc in hexanes) to obtain phor-butyl 3-amino-2-(2,6-diethylphenyl)-6, 7-dihydro-27 / -pyrazolo[4,3-c]pyridine-5(4 / 7)carboxylate. MS: (ES) m / z calculated for C21H31N4O2 [M + H]+371.2, found 371.2. Caution: Diazonium formation could be potentially hazardous; Please treat with care and wear appropriate personal protective equipment. Isopentenyl nitrite (4 mL, 28.6 mmol) was added slowly at room temperature to a mixture of tert-butyl 3-amino-2-(2,6-diethylphenyl)-6,7-dihydro-277-pyrazolo[4, 3-c]pyridine-5(4 / 7)-carboxylate (3 g, 8.1 mmol), CuBr (4 g, 27.9 mmol), and MeCN (50 mL) in a low 250 mL round bottom flask magnetic stirring. The resulting mixture was stirred at room temperature for 1 h, diluted with EtOAc, filtered through Celite, washed with saturated NH4CI solution, and IF-2019-40565613-APN-ANP#INPI Page 51 of 183 was dried in the presence of MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (2 to 25% EtOAc in hexanes) to obtain tor-butyl 3-bromo-2-(2,6-diethylphenyl)-6, 7-dihydro-2Z7-pyrazolo[4,3-c]pyridine-5(4^carboxylate. MS: (ES) m / z calculated for C2iH29BrN3O2[M + H]+434.1, found 434.2. Step c: Iodomethane (1.5 mL, 24 mmol) was added to a suspension of 4-bromo-2-chloro-6nitrophenol (3.2 g, 12.7 mmol) and K2CO3 (3 g, 21.7 mmol) in DMF (40 mL) in a 250 mL round bottom flask under magnetic stirring. The resulting mixture was stirred at 45 °C for 4 h, diluted with EtOAc, washed with brine, and dried in the presence of MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (2 to 25% EtOAc in hexanes) to obtain 5-bromo-l-chloro-2-methoxy-3-mtrobenzene. MS: (ES) m / z calculated for C7H6BrClNO3[M + H]+265.9, found 265.9. A solution of vinylmagnesium bromide in THF (1 M, 40 mL, 40 mmol) was quickly added to a solution of 5-bromo-l-chloro-2-methoxy-3-nitrobenzene (3.2 g, 12 mmol) in Anhydrous THF (40 mL) under N2 and vigorous stirring at -60 °C. The reaction mixture was allowed to warm to −30 °C in 1.5 h. The reaction was stopped with saturated NH4C1 solution and the mixture was allowed to warm to room temperature in 1 h. The reaction mixture was diluted with EtOAc, washed with brine and dried in the presence of MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (2 to 20% EtOAc in hexanes) to obtain 4-bromo-6-chloro-7-methoxy-177-indole. MS: (ES) m / z calculated for CgHgBrCINO [M + H]+259.9, found 259.9. To a suspension of 4-bromo-6-chloro-7-methoxy-l / Aindol (1.2 g, 4.6 mmol), 4,4,4',4',5,5,5',5' octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.4 g, 9.5 mmol), and KOAc (2.3 g, 23.4 mmol) in DMSO (10 mL) was added Pd(dppf)Cl2 complex with dichloromethane (600 mg, 0.73 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 120 °C for 2 h. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine and dried in the presence of MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 20% EtOAc in hexanes) to obtain 6chloro-7-methoxy-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-17 / -indole. MS: (ES) m / z calculated for Ci5H20BC1NO3[M + H]+308.1, found 308.1. . 52 IF-2019-40565613-APN-ANP#INPI Page 52 of 183 To a suspension of tert-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-27 / -pyrazolo[4,3-c]pyridine5(4H)-carboxylate (600 mg, 1, 4 mmol), 6-chloro-7-methoxy-4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)-lH-indole (550 mg, 1.8 mmol), K2CO3 (500 mg, 3.6 mmol) in p-dioxane (6 mL) and water (1 mL) Pd(dppf)C12 complex with dichloromethane (300 mg, 0.37 mmol) was added. The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 100 °C for 2 h. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine and dried in the presence of MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 20% EtOAc in hexanes) to obtain tert-butyl 3-(6-chloro-7-methoxy-l / 7-indole -4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2Z7pyrazolo[4,3-c]pyridine-5(4 / 7)-carboxylate. MS: (ES) m / z calculated for C30H36CIN4O3 [M + H]+535.2, found 535.2. tert-Butyl 3-(6-chloro-7-methoxy-l / 7-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2 / / -pyrazolo[4, The above 3c]pyridine-5(4H)-carboxylate was dissolved in dichloromethane (5 mL) and loaded with 4N HC1 in dioxane (5 mL, 20 mmol). The resulting mixture was stirred at room temperature for 2 h. Once the reaction was complete, the solvent was evaporated in vacuo to obtain 3-(6-chloro-7methoxy-lH-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7- tetrahydro-2H-pyrazolo[4,3-c]pyridine hydrochloride. MS: (ES) m / z calculated for C25H29CIN4O [M + H]+435.2, found 435.2. Step d: N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspension of 3-(6-chloro-7-methoxy-l / 7-indol-4-yl)-2 hydrochloride. -(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2 / 7pyrazolo[4,3-c]pyridine (100 mg, 0.21 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine (45 mg, 0.25 mmol), and LI2CO3 (20 mg, 0.27 mmol) in MeCN (10 mL) under magnetic stirring. The resulting mixture was stirred at 75 °C for 30 min. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine and dried in the presence of MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (40% EtOAc in hexanes) followed by trituration in MeOH to obtain 3-(6-chloro-7-methoxyl / 7-indol-4-yl)- 2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2Z7pyrazolo[4,3-c]pyridine. Ή NMR (400 MHz, CDCI3) δ 8.48 (s, 2H), 8.46 (s, 1H), 7.06-7.27 (m, 4H), 6.62 (d, J = 1, 0 Hz, 1H), 6.42-6.49 (m, 1H), 4.83 (s, 2H), 4.36 (t, J= 5.7 Hz, 2H), 4.00 (s, 3H), 3.03 (t, J = 5.7 Hz, 2H), 2.10-2.40 (m, 4H), 0.80-1.08 (m, 6H). MS: (ES) m / z calculated for C30H29CIF3N6O [M + H]+581.2, found 581.2. IF-2019-40565613-APN-ANP#INPI Page 53 of 183 Synthesis of intermediate 2: [4-[2-(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7dihydro-4 / 7-pyrazolo[4,3-c] pyridin-3-yl]-5-fluoro-177-indol-7-yl]methanol Step a: A solution of vinylmagnesium bromide in THF (1 M, 341 mL, 341 mmol) was added to a solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (15.0 g, 56.8 mmol) in anhydrous THF (200 mL) under N2 at -50 °C. The reaction mixture was stirred at the same temperature and allowed to warm to −40 °C in 1.5 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and allowed to warm to room temperature in 1 h. The reaction mixture was acidified with 1 N aqueous HC1, diluted with EtOAc, washed with brine and dried in the presence of Na2SO4. The solvent was removed under reduced pressure to obtain a crude residue. The above crude residue was stirred in a mixture of H2SO4 (25 mL) in MeOH (250 mL) at reflux for 5 h. It was then cooled to room temperature and concentrated under reduced pressure. The residue obtained was diluted with EtOAc and brine. The organic layer was separated, dried with Na2SO4, concentrated under reduced pressure and purified by flash gel chromatography. IF-2019-40565613-APN-ANP#INPI Page 54 of 183 silica (O to 50% EtOAc in hexanes) to obtain methyl 4-bromo-5-fluoro-l / / -indole-7carboxylate. MS: (ES) m / z calculated for C10H8BrFNO2[M + H]+271.9, found 271.9. To a suspension of methyl 4-bromo-5-fluoro-lH-indole-7-carboxylate (0.900 g, 3.3 mmol), 4,4,4,,4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.51 g, 5.94 mmol), and KOAc (1.62 g, 16.5 mmol) in DMSO (19 mL) was added Pd(dppf)Cl2 complex with dichloromethane (400 mg, 0.49 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 115 C for 1.5 h. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine and dried in the presence of Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 100% CH2Cl2 / hexanes) to obtain methyl 5-fluoro-4-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)-l / / -indole-7carboxylate. MS: (ES) m / z calculated forCi6H2oBFN04 [M + H]+320.l, found 320.1. To a suspension of tert-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2 / / -pyrazolo[4,3-c]pyridine5(4H)-carboxylate (1.00 g , 2.31 mmol), methyl 5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)-l / Aindol-7-carboxylate (740 mg, 2.31 mmol) and K2CO2 (1.28 g, 9.24 mmol) in p-dioxane (14 mL) and water (2.5 mL) Pd(dppf)Cl2 complex with dichloromethane (400 mg, 0.49 mmol) was added. The reaction mixture was degassed (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 NaHCOs and dried in the presence of Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 70% EtOAc in hexanes) to obtain tert-butyl 2-(2,6-diethylphenyl)-3-(5-fluoro -7-methoxycarbonyl-l / / -indol-4-yl)-6,7-dihydro-4 / / pyrazolo[4,3-c]pyridine-5-carboxylate. MS: (ES) m / z calculated for C31H36 FN4O4[M + H]+547.2, found 547.2. Step b: tert-Butyl 2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxycarbonyl-17f-indol-4-yl)-6,7-dihydro477-pyrazolo[4,3-c ]pyridine-5-carboxylate above (1.00 g, 1.83 mmol) was dissolved in THF (35 mL) and loaded with a solution of L1AIH4 in ether (1 M, 2.7 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 40 min. It was then quenched with water, diluted with IPA / CHCh (1 3), washed with brine and dried in the presence of Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 90% EtOAc in hexanes) to obtain tert-butyl 2-(2,6-diethylphenyl)-3-[5-fluoro -7-(hydroxymethyl)-lH IF-2019-40565613-APN-ANP#INPI Page 55 of 183 indol-4-yl]-6,7-dihydro-4 / 7-pyrazolo[4,3-c]pyridine-5-carboxylate. MS: (ES) m / z calculated for C30H36 FN4O3 [Μ + Η]+519.2, found 519.2. / er-butyl 2-(2,6-diethylphenyl)-3-(5-fluoro-7-(hydroxymethyl)-l / / -indol-4-yl]-6,7-dihydro-4 / A pyrazolo[ The above 4,3-c]pyridine-5-carboxylate (650 mg, 1.25 mmol) was dissolved in dichloromethane (13 mL) and charged with 4 N HC1 in dioxane (35 mL, 140 mmol). stirred at room temperature for 1.5 h. Once the reaction was complete, the solvent was evaporated in vacuo to obtain [4-[2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[ hydrochloride. 4,3-c]pyridin3-yl]-5-fluoro-l / / -indol-7-yl]methanol MS: (ES) m / z calculated for C25H28FN4O [M + H]+419.2, found 419. ,2. Step c: Triethylamine (1.50 mL, 10.7 mmol) was added to a suspension of (4-[2-(2,6-diethylphenyl)4,5,6,7-tetrahydropyrazolo[4,3-c] pyridin-3-yl]-5-fluoro-177-indol-7-yl]methanol hydrochloride (600 mg, 1.32 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (350 mg, 1.9 mmol) in MeCN (70 mL). The resulting mixture was stirred at 80 °C for 30 min. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCCh and dried in the presence of Na2SO4. Solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 90% EtOAc in hexanes) to obtain [4-[2-(2,6diethylphenyl)-5-[5-(trifluoromethyl) pyrimidin-2-yl]-6,7-dihydro-4íApyrazolo[4,3-c]pyridin-3-yl]-5fluoro-lH-indol-7-yl]methanol Ή NMR (400 MHz, CDCI3) δ 9. .05 (br s, 1H), 8.47 (br s, 2 H), 7.27 (m, 1H), 7.16 (m, 2H), 6.86 (d, J= 7.26 Hz , 1H), 6.56 (d, J= 10.0 Hz, 1H), 6.37 (t, J= 2.6 Hz, 1H), 4.88 (m, 3H), 4.68 (d , J= 16.4 Hz, 1H), 4.43 (m, 1H), 4.29 (m, 1H), 3.04 (t, J= 6.0 Hz, 2H), 2.38-2 .58 (m, 3H), 2.17 (sextet, J= 7.3 Hz, 1H), 1.94 (sextet, J= 7.3 Hz, 1H), 1.21 (t, J = 7, 4 Hz, 3H), 0.75 (t, J= 7.4 Hz, 3H). MS: (ES) m / z calculated for C30H29F4N6O [M + H]+565.2, found 565.2. Synthesis of intermediate 3: l-(4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6-tetrahydropyrrolo[3 ,4-c]pyrazol-3-yl)-2,5-difluorophenyl)urea IF-2019-40565613-APN-ANP#INPI Page 56 of 183 NC EIOH, reflux 2) tert-butyl nitrite· CH2I21MeCN Step to Pd(dppf)CI2· CH2CI2K2CO3, dioxanofH2O Step b Step a: Pyridine (4.0 mL, 49.5 mmol) was added to a mixture of (2,6-diethylphenyl)hydrazine hydrochloride (5.0 g, 24.9 mmol), tert-butyl 4-cyano-2 ,2-dimethyl-3-oxopyrrolidine-l-carboxylate (5.0 g, 21.0 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 removed under reduced pressure, and the residue was diluted with EtOAc and washed with aqueous citric acid solution, saturated aqueous NaHCO1 solution, brine, and dried in the presence of MgSO4. The solvent was removed under reduced pressure and the residue was crystallized from cyclohexane to obtain ter IF-2019-40565613-APN-ANP#INPI Page 57 of 183 butyl 3-amino-2-(2,6-diethylphenyl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4 / / )-carboxylate. MS: (ES) m / z calculated for C22H33N4O2 [M + H]+385.2, found 385.2. Caution: Diazonium formation could be potentially hazardous; Please treat with care and wear appropriate personal protective equipment. For-butyl nitrite (0.5 mL, 3.8 mmol) was added slowly at room temperature to a mixture of for-butyl 3-amino-2-(2,6-diethylphenyl)-6,6-dimethyl-2, 6-dihydropyrrolo[3,4-c]pyrazole-5(4 / 7)carboxylate (1 g, 2.6 mmol), diiodomethane (1.5 mL, 18.6 mmol), and MeCN (15 mL) in a bottom flask 100 mL round under magnetic stirring. The resulting mixture was stirred at 45 °C for 3 h before being diluted with toluene, washed with saturated NH4CI / NH4OH solution (3:1), brine, and dried in the presence of MgSCU. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (2 to 25% EtOAc in hexanes) to obtain tert-butyl 2-(2,6-diethylphenyl)-3-iodo-6, 6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole5(4F / )-carboxylate. MS: (ES) m / z calculated for C22H31IN3O2 [M + H]+496.1, found 496.2. Step b: A mixture of 4-bromo-2,5-difluoroaniline (1.5 g, 7.2 mmol), 4,4,4',4',5,5,5',5'octamethyl-2,2'-bi (l,3,2-dioxaborolane) (2.2 g, 8.7 mmol), KOAc (l.8 g, 18.3 mmol) and Pd(dppf)Cl2 complex with dichloromethane (580 mg, 0.7 mmol ) in dioxane (12 mL) was stirred at 95 °C for 2 h under nitrogen. The mixture was then cooled to room temperature and filtered in the presence of Celite. The filtrate was collected, concentrated under reduced pressure, and purified by flash chromatography on silica gel (0 to 50% EtOAc in hexanes) to obtain 2,5difluoro-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)aniline. MS: (ES) m / z calculated for C12H17BF2NO2 [M + H]+256.1, found 256.2. To a suspension of tor-butyl 2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,6-dihydropyrrolo[3,4c]pyrazole-5(4#)-carboxylate (0.7 g, 1.4 mmol), 2,5-difluoro-4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)aniline (0.7 g, 2.7 mmol), K2CO3 (1.3 g, 7.2 mmol) in dioxane (10 mL) and water (2 mL) was added Pd(dppf)Cl2 complex with dichloromethane (300.0 mg, 0.37 mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 100 °C for 2 h. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine, dried in the presence of MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (2 to 10% EtOAc in hexanes) to obtain 58 IF-2019-40565613-APN-ANP#INPI Page 58 of 183 phor-butyl 3-(4-amino-2,5-difluorophenyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4c]pyrazole-5 (4 / / )-carboxylate. MS: (ES) m / z calculated for C28H35F2N4O2 [M + H]+497.3, found 497.5. Step c: A mixture of tor-butyl 3-(4-amino-2,5-difluorophenyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,6dihydropyrrolo[3,4-c]pyrazole -5(477)-carboxylate (0.5 g, 1.0 mmol) and benzoyl isocyanate (0.5 g, 3.4 mmol) in THF (10 mL) were stirred for 3 h at room temperature. The mixture was concentrated under reduced pressure to obtain tert-butyl 3-(4-(3-benzoylureido)-2,5-difluorophenyl)-2-(2,6diethylphenyl)-6,6-dimethyl-2,6-dihydropyrrolo[ 3,4-c]pyrazole-5(4 / / )-carboxylate. A mixture of tert-butyl 3-(4-(3-benzoylureido)-2,5-difluorophenyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,6-dihydropyrrolo[3,4-c] pyrazole-5(4 / / )-carboxylate (-1.0 mmol, above) and K2CO3 (1.3 g, 7.2 mmol) in MeOH (15 mL) were stirred for 2 h at room temperature followed by 20 mm at 50°C. The mixture was extracted with EtOAc. The organic layer was separated, dried in the presence of MgSO4, concentrated under reduced pressure and purified by flash chromatography on silica gel (10 to 50% EtOAc in hexanes) to obtain tert-butyl 2-(2,6-diethylphenyl )-3-(2,5-difluoro-4ureidophenyl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4 / 7)-carboxylate. MS: (ES) m / z calculated for C29H36F2N5O3 [M + H]+540.3, found 540.3. Step d: The tert-butyl 2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4 / 7)carboxylate above is dissolved in dichloromethane (10 mL) and loaded with 4 N HC1 in dioxane (5 mL, 20 mmol). The resulting mixture was stirred at room temperature for 12 h. Upon completion, the solvent was evaporated in vacuo to obtain l-(4-(2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3 -yl)-2,5-difluorophenyl)urea hydrochloride. MS: (ES) m / z calculated for C24H28 F2N5O [M + H]+440.2, found 440.3. Step e: A.A-diisopropylethylamine (0.2 mL, 1.2 mmol) was added to a suspension of 1-(4-(2(2,6-diethylphenyl)-6,6-dimethyl-2,4,5, 6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoropheml)urea hydrochloride (0.1 g, 0.2 mmol), and 2,4-ari(trifluoromethyl)benzaldehyde (0. 2 g, 0.8 mmol) in 1,2dichloroethane (10 mL) under magnetic stirring. After stirring at room temperature for 10 min, NaBH(OAc)3 (0.3 g, 1.4 mmol) was added portionwise. 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 NaHCOs solution, brine, and dried in the presence of 59 IF-2019-40565613-APN-ANP#INPI Page 59 of 183 MgSCU. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (50% EtOAc in hexanes) followed by HPLC (MeCN / fhO, with 0.1% TFA) to obtain 1(4-(5-(2 ,4-6w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4c]pyrazol-3-yl)-2,5 -difluorophenyl)urea. Ή NMR (400 MHz, CDCb)b 8.18 (d, J - 8.3 Hz, 1H), 7.88-7.98 (m, 2H), 7.75-7.83 (m, 1H) , 7.31 (t, J= 7.7 Hz, 1H), 7.14 (d, 7.7 Hz, 2H), 6.796.85 (br, 1H), 6.40 (dd, J= 6, 5, 12.1 Hz, 1H), 4.79 (s, 2H), 4.13 (s, 2H), 3.74 (s, 2H), 2.20-2.34 (m, 4H), 1.51 (s, 6H), 1.06 (t, J= 7.6 Hz, 6H). MS: (ES) m / z calculated for C33H32F8N5O [M + H]+666.2, found 666.2. Synthesis of intermediate 4: 4-(5-(2,4-Z>w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6-tetrahydropyrrolo[3, 4-c]pyrazol-3-yl)-7-fluoro-l / 7-indole 1) HCI. CH2CI2 2} 2,4 -bis (triflu or rometi I )benzald e hy id or Nal3H(OAc)3’ cich2ch2ci Step to Pd(dppf)CI2· CH2CI2K2CO3, dioxanoi / hbO Step b Step a: The tert-butyl 2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4F0carboxylate above was dissolved in dichloromethane ( 10 mL) and loaded with 4 N HCl in dioxane (5 mL 20 mmol). The resulting mixture was stirred at room temperature for 12 h Al '60. IF-2019-40565613-APN-ANP#INPI Page 60 of 183 completion, the solvent was evaporated in vacuo to obtain 2-(2,6-diethylphenyl)-3-iodo-6,6-dimetii2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride . MS: (ES) m / z calculated for C17H23IN3 [M + H]+396.1, found 396.2. VW-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 2,4-5w(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 portionwise. 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 removed under reduced pressure and the residue was purified by flash chromatography on silica gel (2 to 25% EtOAc in hexanes) to obtain 5-(2,4-¿>w(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 622.1. Step b: To a suspension of 4-bromo-7-fluoro-l / 7-indole (1.00 g, 4.67 mmol), bis(pinacolato)diboron (1.31 g, 5.14 mmol) and KOAc (1.15 g, 11.7 mmol) in dioxane (15 mL) Pd(dppf)Ch complex with dichloromethane (416 mg, 0.51 mmol) was added. The reaction mixture 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 removed 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-l, 3,2dioxaborolan-2-yl)-l / 7-indole. MS: (ES) m / z calculated for C14H18BFNO2 [M + H]+262.1, found 262.1. A mixture of 5-(2,4-6w(trifluoromethyl)benzyl)-3-iodo-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4-c ]pyrazole (200 mg, 0.32 mmol), 7-fluoro-4-(4,4,5,5-tetramethi 1-1,3,2dioxaborolan-2-yl)-lH-indole (150 mg, 0.32 mmol) 57 mmol), K2CO3 (276 mg, 2.0 mmol) and Pd(dppf)Cl2 complex with dichloromethane (60 mg, 0.07 mmol) in dioxane (6 mL) and water (1 mL) were stirred at 100 °C for 5 h under N2. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through a plug of Celite. The filtered product was collected, concentrated in vacuo and the IF-2019-40565613-APN-ANP#INPI Page 61 of 183 residue was purified by flash chromatography on silica gel (0 to 50% EtOAc in hexanes) to form 4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6- diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-17 / -indole. Ή NMR (400 MHz, CDCh) δ 8.44 (s, 1H), 8.19 (d, J= 8.0 Hz, 1H), 7.86 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.22 (m, 2H), 7.07 (d, J = 7.6 Hz, 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= 7.6 Hz, 6H). MS: (ES) m / z calculated for C34H32F7N4 [M + H]+629.2, found 629.2. Example 1: Synthesis of (phosphonooxy)methyl 4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[ 3,4-c]pyrazol-3-yl)-7-fluoro-lH-indole-lcarboxylate Step a: To a stirred solution of 4-(5-(2,4-6w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6-tetrahydropyrrolo[3 ,4-c]pyrazol-3-yl)-7-fluoro-l / 7-indole (240 mg, 0.35 mmol) in DMF NaH (60%, 60 mg, 1.5 mmol) was added at 0 ° c. The mixture was stirred at 0 °C for 10 min. IF-2019-40565613-APN-ANP#INPI Page 62 of 183 followed by the addition of dibenzyloxyphosphoryloxymethyl carbonhydrochloride (263 mg, 0.71 mmol) at 0 °C. The resulting mixture was stirred and allowed to warm to room temperature in 30 min. After completion of the reaction, the reaction was quenched with water, extracted with EtOAc, dried in the presence of Mg2SO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography (10 to 50% EtOAc in hexanes) to obtain ((¿> / Xbenzyloxy)phosphoryl)oxy)methyl 4-(5-(2,4-Z>zXtrifluoromethyl)benzyl )-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4c]pyrazol-3-yl)-7-fluoro-177-indole-l-carboxylate . MS: (ES) m / z calculated for C50H47F7N4O6P [M + H]+963.3, found 963.3. Step b: To a solution of ((¿¿s(benzyloxy)fbsfbril)oxy)methyl 4-(5-(2,4-6w(trifluoromethyl)benzyl)2-(2,6-diethylphenyl)-6,6- dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-lff-indole-lcarboxylate (79 mg, 0.08 mmol) in ethyl acetate (40 mL) 10% Pd / C (100 mg) was added, and hydrogenated under 45 psi for 20 min. The reaction mixture was filtered through Cehte, rinsed with 1:1 EtOAc / MeOH (15 mL), and concentrated to dryness. The residue was purified by HPLC (MeCN / H2O, with 0.1% TFA) to form (phosphonooxy)methyl 4-(5-(2,4ÓÍ5(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)- 6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-7-fluoro-17 / -indole-l-carboxylate. Ή NMR (400 MHz, cfc-DMSO) δ 8.13 (d, J- 8.2 Hz, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.95 (s, 1H ), 7.80 (d, J= 4.8 Hz, 1H), 7.30 (t, J= 7.8 Hz, 1H), 7.12 (d, J= 7.8 Hz, 2H), 6.95 (dd, J = 8.6, 12.1 Hz, 1H), 6.56-6.66 (m, 2H), 5.70 (d, J= 14.4 Hz, 2H), 4 .15 (s, 2H), 3.60 (s, 2H), 3.35 (br, 2H), 2.14-2.22 (m, 4H), 1.47 (s, 6H), 0, 90 (t, J = 7.6 Hz, 6H). MS: (ES) m / z calculated for C36H35F7N4O6P [M + H]+783.2, found 783.2. Example 2: Synthesis of (5)-(4-(5-(2,4-Z>w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6 -tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-lZlr-indol-l-yl)-L-cysteine IF-2019-40565613-APN-ANP#INPI Page 63 of 183 Step a: To a stirred solution of di-tert-butyl 3,3'-disulfanediyl(27?,2 R)-bis(2-((tert-butoxycarbonyl)amino)propanoate) (830 mg, 1.5 mmol) in dichloroethane (6 mL) at 0 C, thionyl chloride (0.14 mL, 1.9 mmol) was added. The mixture was stirred at 0 °C for 15 min to form tert-butyl A-(tert-butoxycarbonyl)-S-chloro-L-cysteinate which was used directly in the next step. To a stirred solution of 4-(5-(2,4-ó / s(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3, 4-c]pyrazol-3-yl)-7-fluoro-l / / -indole (240 mg, 0.35 mmol) in THF (10 mL) under N2 at -45 °C 1 M LiHMDS solution was added in THF (0.8 mL, 0.8 mmol). After stirring for 15 min at −45 °C, previously formed tert-butyl A-(tert-butoxycarbonyl)-S-chloro-Lcysteinate (~1.5 mmol) was added. The resulting mixture was stirred and allowed to warm to room temperature in 30 min. Once complete, the reaction was stopped with water, extracted with EtOAc, dried in the presence of MgSO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography (10 to 50% EtOAc in hexanes) to obtain tert-butyl (5)-(4-(5-(2,4-(trifluoromethyl)benzyl)-2-(2, 6-diethylphenyl)-6,6-dimethyl-2,4,5,6 IF-2019-40565613-APN-ANP#INPI Page 64 of 183 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-l / / -indol-l-yl)-A^-(tert-butoxycarbonyl)-Z-cysteinate. MS: (ES) m / z calculated for C46H53F7N5O4S [Μ + Η]+904.4, found 904.5. Step b: To a solution of tert-butyl (S)-(4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)6,6-dimethyl-2,4 ,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-177-indol-l-yl)- / V-(terbutoxycarbonyl)-L-cysteinate (220 mg, 0.24 mmol) in dichloromethane (6 mL) was added 4 N HC1 in dioxane (5 mL, 20 mmol). The resulting mixture was stirred at room temperature overnight. Once complete, the mixture was concentrated in vacuo. The residue was purified by HPLC (MeCN / FhO, with 0.1% TFA) to form (S)-(4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6diethylphenyl) -6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-l / / -indol-l-yl)-Lcysteine. Ή NMR (400 MHz, CD3OD) δ 8.24 (d, J= 7.6 Hz, 1H), 7.98-8.10 (m, 2H), 7.63-7.66 (m, 2H) , 7.22-7.37 (m, 2H), 6.97-7.03 (m, 1H), 6.63-6.68 (m, 1H), 6.43-6.47 (m, 1H), 4,714.86 (m, 5H), 4.07-4.27 (m, 3H), 3.14-3.33 (m, 2H), 2.37-2.49 (m, 2H) , 2.02-2.26 (m, 2H), 1.85-1.94 (m, 6H), 1.25-1.42 (m, 3H), 0.77-0.84 (m, 3H). MS: (ES) m / z calculated for C37H37F7N5O2S [M + H]+748.3, found 748.2. Example 3: Synthesis of acid (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4,5,6,7-tetrahydro-2 / / -pyrazolo[ 4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-l / / -indol-l-yl)phosphonic IF-2019-40565613-APN-ANP#INPI Page 65 of 183 Step a: To a stirred solution of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-l / / -indol-4-yl)-5-(5(trifluoromethyl)pyrimidin-2 -yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine (230 mg, 0.4 mmol) in THF (10 mL) under N2 at -70 °C was added 1 M LiHMDS solution in THF (0.6 mL, 0.6 mmol). After stirring 15 min at -70 °C, diethyl phosphorohydrochloride (0.1 mL, 0.8 mmol) was added. The resulting mixture was allowed to warm to room temperature in 1 h. Once complete, the mixture was quenched with water, extracted with EtOAc, washed with saturated aqueous NaHCOj solution, dried in the presence of MgSO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography (5 to 25% EtOAc in hexanes) to obtain diethyl (4-(2-(2,6diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl) -4,5,6,7-tetrahydro-27 / -pyrazolo[4,3-c]pyridin-3-yl)6-fluoro-7-methoxy-17 / -indol-l-yl)phosphonate. MS: (ES) m / z calculated for C34H38F4N6O4P [M + H]+701.3, found 701.3. Step b: To a solution of diethyl (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4,5,6,7-tetrahydro-2 / / - pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-177-indol-l-yl)phosphonate (75 mg 0.11 mmol) in dichloromethane (6 mL) at 0 °C TMSBr (0.2 mL, 1.5 mmol) was added. The °' 66 IF-2019-40565613-APN-ANP#INPI Page 66 of 183 resulting mixture was allowed to warm to room temperature in 1 h, and then stirred at 40 °C overnight. Once complete, the reaction mixture was concentrated in vacuo. The residue was purified by HPLC (MeCN / HiO, with 0.1% TFA) to form acid (4-(2-(2,6-diethylpheml)-5-(5(trifluoromethyl)pyrimidin-2-yl)- 4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-l / 7-indol-l-yl)phosphonic. Ή NMR (400 MHz, CD3OD) δ 8.58 (s, 2H), 7.68 (dd, J = 2.5, 3.5 Hz, 1H), 7.32 (t, J= 7.7 Hz , 1H), 7.16 (br, 2H), 6.49-6.57 (m, 2H), 4.82-4.90 (m, 4H), 4.39 (s, 2H), 3, 99 (s, 3H), 2.98 (t, J= 5.9 Hz, 2H), 2.05-2.42 (m, 4H), 0.78-1.25 (m, 6H). MS: (ES) m / z calculated for C30H30F4N6O4P [M + H]+645.2, found 645.4. Example 4: Synthesis of (phosphonooxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo [4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-l / / -indole-lcarboxylate IF-2019-40565613-APN-ANP#INPI Page 67 of 183 Step a: To a stirred solution of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-l / / -indol-4-yl)-5-(5(trifluoromethyl)pyrimidin-2 -yl)-4,5,6,7-tetrahydro-27 / -pyrazolo[4,3-c]pyridine (570 mg, 1.0 mmol) in DMF NaH (60%, 60 mg, 1.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min, followed by the addition of dibenzyloxyphosphoryloxymethyl carbonhydrochloride (526 mg, 1.42 mmol). The resulting mixture was stirred and allowed to warm to room temperature in 30 min. Once complete, the mixture was stopped with water, extracted with EtOAc, dried in the presence of MgSÜ4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (10 to 100% EtOAc in hexanes) to obtain ((0zs(benzyloxy)phosphryl)oxy)methyl 4-(2-(2,6diethylphenyl)-5-(5- (trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)6-fluoro-7-methoxy-lH-indole- l-carboxylate. MS: (ES) m / z calculated for C46H44F4N6O7P [M + H]+899.3, found 899.3. Step b: To a solution of ((bzs(benzyloxy)phosphoryl)oxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6 ,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-l / 7-indole-l-carboxylate (120 mg, 0.13 mmol) in ethyl acetate (45 mL), 10% Pd / C (200 mg) was added, and hydrogenated under 50 psi for 20 min. The reaction mixture was filtered through Celite, rinsed with 1:1 EtOAc / MeOH (15 mL), concentrated to dryness. The residue was purified by HPLC (MeCN / H2O, with 0.1% TFA) to form (phosphonooxy)methyl 4(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl )-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3c]pyridin-3-yl)-6-fluoro-7-methoxy-l / / -indole-l-carboxylate. Ή NMR (400 MHz, CD3OD) δ 8.58 (s, 2H), 7.87 (d, J= 3.9 Hz, 1H), 7.33 (t, J= 7.6 Hz, 1H), 7.16 (br s, 2H), 6.59-6.64 (m, 2H), 5.87 (d, J= 14.4 Hz, 2H), 4.74-4.86 (m, 4H ), 4.39 (s, 2H), 3.97 (s, 3H), 2.98 (t, J= 5.7 Hz, 2H), 2.05-2.42 (m, 4H), 0 .76-1.28 (m, 6H). MS: (ES) m / z calculated for C32H32F4N6O7P [M + H]+719.2, found 719.2. Example 5: Synthesis of (£)-4-(((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2yl)-4,5,6,7-tetrahydro acid -2ZT-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-lZf-indol-lcarbonyl)oxy)methoxy)-4-oxobut-2-enoic IF-2019-40565613-APN-ANP#INPI Page 68 of 183 Step a: To a stirred solution of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-lH-indol-4-yl)-5-(5(trifluoromethyl)pyrimidin-2-iI )-4,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridine (280 mg, 0.5 mmol) in THF (10 mL) at -78 °C 1 M LiHMDS solution was added in THF (0.8 mL, 0.8 mmol). The mixture was stirred at −78 °C for 15 min, followed by the addition of chloromethyl carbonhydrochloride (80 A, 0.9 μμολ). The resulting mixture was stirred and allowed to warm to room temperature in 30 min. Once complete, the mixture was quenched with saturated aqueous NH4C1 solution, extracted with EtOAc, dried in the presence of Mg2SO4, and concentrated in vacuo to obtain chloromethyl 4-(2-(2,6-diethylphenyl)-5-(5 -(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-U / -indole -l-carboxylate, which was used directly in the next step. MS: (ES) m / z calculated for C32H3oC1F4N603 [M + H]+657.2, found 657.2. Step a: Nal (350 mg, 2.33 mmol) was added to a stirred solution of chloromethyl 4-(2-(2,6diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5 ,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridin-3-yl)6-fluoro-7-methoxy-l / 7-indole-l-carboxylate (300 mg, 0.46 mmol) in acetone (10 mL) at 69 IF-2019-40565613-APN-ANP#INPI Page 69 of 183 room temperature. The resulting mixture was stirred at 45 °C overnight. Once complete, the mixture was quenched with brine, extracted with EtOAc, dried in the presence of MgSO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography (5 to 25% EtOAc in hexanes) to obtain iodomethyl 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2yl)- 4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-l / f-indole-l-carboxylate. MS: (ES) m / z calculated for C32H30F4IN6O3 [M + H]+749.1, found 749.2. Step c: To a solution of iodomethyl 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4,5,6,7-tetrahydro-2Zf-pyrazolo[4 ,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-lH-indole-l-carboxylate (50 mg, 0.07 mmol) in THF (5 mL) at 0 °C salt was added Fumaric acid tetrabutylammonium (25 mg, 0.07 mmol) in DMF (1 mL). The resulting mixture was allowed to warm to room temperature in 1 h. Once complete, the mixture was concentrated in vacuo. The residue was purified by HPLC (MeCN / FhO, with 0.1% TFA) to obtain (E)-4-(((4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl) )pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / f-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-l / f-indol-l -carbonyl)oxy)methoxy)-4-oxobut-2-enoic acid. Ή NMR (400 MHz, CD3OD) δ 8.58 (s, 2H), 7.87 (d, J= 3.9 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.16 (br s, 2H), 6.59-6.64 (m, 2H), 5.87 (d, J= 14.4 Hz, 2H), 4.74-4.86 (m, 4H ), 4.39 (s, 2H), 3.97 (s, 3H), 2.98 (t, J= 5.7 Hz, 2H), 2.05-2.42 (m, 4H), 0 .76-1.28 (m, 6H). MS: (ES) m / z calculated for C36H33F4N6O7 [M + H]+737.2, found 737.2. Example 6: Synthesis of ((dimethylglycyl)oxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2Zf -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-lZf-indole-l-carboxylate Page 70 of 183 To a solution of iodomethyl 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2 / / -pyrazolo[4,3 -c]pyridin-3-yl)-6-fluoro-7-methoxy-177-indole-l-carboxylate (40 mg, 0.06 mmol) in MeCN (5 mL) at 0 °C tetrabutylammo dimethylglycinate was added ( 20 mg, 0.06 mmol) in DMF (1 mL). The resulting mixture was allowed to warm to room temperature in 1 h. Once complete, the mixture was quenched with 1 N HC1 (0.1 mL, 0.1 mmol) and purified by HPLC (MeCN / FhO, with 0.1% TFA) to obtain ((dimethylglycyl)oxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin -3-yl)-6-fluoro-7methoxy-l / Z-indole-l-carboxylate as TFA salt. Ή NMR (400 MHz, CD3OD) δ 8.59 (s, 2H), 7.92 (d, J= 3.9 Hz, 1H), 7.34 (t, J= 7.6 Hz, 1H), 7.17 (br s, 2H), 6.63-6.74 (m, 2H), 5.83 (s, 2H), 4.81-4.88 (br s, 1H), 4.46 ( s, 2H), 4.39 (s, 2H), 3.97 (s, 3H), 3.45 (s, 5H), 2.95-3.03 (m, 5H), 2.05-2 .42 (m, 4H), 0.76-1.28 (m, 6H). MS: (ES) m / z calculated for C36H38F4N7O5 [M + H]+724.2, found 724.2. Example 7: Synthesis of ((4-(5-(2,4-Z>zs(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6-tetrahydropyrrole acid [3,4-c]pyrazol-3-yl)-2,5difluorophenyl)carbamoyl)phosphoramidic IF-2019-40565613-APN-ANP#INPI Page 71 of 183 Step a: To a solution of 4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylpheml)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3, 4-c]pyrazol-3-yl)-2,5-difluoroaniline (100 mg, 0.16 mmol) in THF (6 mL) at -50 °C phosphorisocyanatide dichloride (0.04 mL, 0.41 mmol) was added ). The mixture was allowed to warm to room temperature over 1 h, and then concentrated in vacuo. The residue was triturated with hexanes to obtain dichloride ((4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)phosphoramidic which was used directly in the next step. Step b: To a solution of the dichloride ((4-(5-(2,4-¿>w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6 -tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)phosphoramidic above (-0.16 mmol) in THF (6 mL) at room temperature water (3 mL) was added. The mixture was stirred at room temperature for 2 h, followed by the addition of 1 N NaOH (0.5 mL, 0.5 mmol). The mixture was stirred for another 2 h. Once complete, the mixture was purified by HPLC (MeCN / H2O, with 0.1% TFA) to form acid ((4-(5-(2,4Z>ri(trifluoromethyl)benzyl)-2-(2, 6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3 IF-2019-40565613-APN-ANP#INPI Page 72 of 183 il)-2,5-difluorophenyl)carbamoyl)phosphoramidic. Ή NMR (400 MHz, DMSO-cfc) δβρσ8.16 (δ, J 8.2 Hz, 2H), 7.92-8.08 (m, 2H), 7.38 (d, J= 7.9 Hz , 1H), 7.21 (d, J= 7.7 Hz, 2H), 6.45 (dd, J = 6.7, 11.9 Hz, 1H), 4.13 (s, 2H), 3 .64 (s, 2H), 3.24-3.48 (br, 2H), 2.16 (q, J= 7.6 Hz, 4H), 1.42 (s, 6H), 0.95 ( t, J= 7.6 Hz, 6H). MS: (ES) m / z calculated for C33H33F8N5O4P [M + H]+746.2, found 746.2. Example 8: Synthesis of ((3,3-dimethyl-5-(phosphonooxy)pentanoyl)oxy)methyl 4-(2-(2,6-diethylphenyl)-5(5-(trifluoromethyl)pyrimidin-2-yl)- 4,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro7-methoxy-lZT-indole-l-carboxylate Step a: To a flask containing 4,4-dimethyldihydro-2 / / -pyran-2,6(3Z / )-dione (5 g, 35 mmol) in THF (140 mL) a 1 M solution was added dropwise. of LiAlH4 in THF (35 mL, 35 mmol). The mixture was heated at 75 °C for 2 h. Once complete, the reaction was stopped with H2O and the mixture was filtered. The filtrate was concentrated to form 3,3-dimethylpentane-1,5-dioL To a solution of 3,3-dimethylpentane-1,5-diol (1 g, 7.6 mmol) in THF (15.6 mL), a 1 M solution of iBuOK (8.3 mL, 8.6 mL) was added dropwise. 3 mmol) followed by tetrabenzyl diphosphate (4.2 g, 7.8673 IF-2019-40565613-APN-ANP#INPI Page 73 of 183 mmol). After heating at 70 °C for 16 h, the mixture was concentrated and purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to form dibenzyl (5-hydroxy-3,3-dimethylpentyl). phosphate. MS: (ES) m / z calculated for C21H29O5P [M + H]+393.2, found 393.1. To a solution of dibenzyl (5-hydroxy-3,3-dimethylpentyl) phosphate (400 mg, 1 mmol), in DMF (10 mL) was added pyridinium dichromate (2.3 g, 6 mmol). The mixture was stirred at room temperature for 2 h then concentrated and purified by silica gel column chromatography (0 to 100% EtOAc in hexanes). The purified residue was dissolved in 10 mL of a 1:1 solution of / BuOH and H2O. NaH2PÜ4 (0.61 g, 5 mmol) was added to the solution, followed by sodium chlorite (0.46 g, 5 mmol) and a 2 M solution of 2-methyl-2-butene (5 mL, 10 mmol). . The mixture was stirred at room temperature for 16 h. Upon completion, the mixture was concentrated in vacuo and the crude residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to obtain 5-((¿>w(benzyloxy)phosphoryl)oxy)- acid. 3,3-dimethylpentanoic acid. MS: (ES) m / z calculated for C21H27O6P [M + H]+407.2, found 407.1. To a solution of iodomethyl 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2 / / -pyrazolo[4,3 -c]pyridin-3-yl)-6-fluoro-7-methoxy-l / Aindol-l-carboxylate (70 mg, 0.09 mmol) in 0.2 mL of DMF 5-((6w( benzyloxy)phosphoryl)oxy)-3,3-dimethylpentanoic acid (54 mg, 0.13 mmol) followed by Et3N (0.02 mL, 0.14 mmol). The mixture was stirred at room temperature for 2 hours; then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to yield (((5((ori(benzyloxy)phosphoryl)oxy)-3,3-dimethylpentanoyl)oxy)methyl 4 -(2-(2,6-diethylpheml)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin- 3-yl)-6-fluoro-7methoxy-l / 7-indole-l-carboxylate. Step b: To a solution of (((5-((ów(benzyloxy)phosphoryl)oxy)-3,3-dimethylpentanoyl)oxy)methyl 4-(2(2,6-diethylphenyl)-5-(5-( trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin3-íl)-6-fluoro-7-methoxy-l / / -indole -l-carboxylate (50 mg, 0.05 mmol) in MeOH (ImL) was added with 10% Pd / C (6 mg, 0.005 mmol). The mixture was stirred under a balloon of H2 for 1 h, then filtered. through Celite, concentrated and purified by HPLC (MeCN / FhO, with 0.1% TFA) to form ((3,3-dimethyl-5-(phosphonooxy)pentanoyl)oxy)methyl 4-(2-( 2,6-diethylphenyl)-5-(5 . IF-2019-40565613-APN-ANP#INPI Page 74 of 183 (trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / f-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-l / f-indole-l-carboxylate. Ή NMR (400 MHz, CDCh) δ 8.54 (s, 2H), 7.63 (d, J - 3.9 Hz, 1H), 7.28 (t, .7= 7.7 Hz, 1H) , 7.08 (d, .7=7.6 Hz, 2H), 6.59 (d,J = 12.1 Hz, 1H), 6.47 (d,J=3.8 Hz, 1H), 6.02 (s, 2H), 5.60 (br s, 2H), 4.76 (bs, 2H), 4.38 (t, J= 5.9 Hz, 2H), 4.03 (dd, J= 14.1, 7.1 Hz, 2H), 3.99 (s, 3H), 3.10 (t, J= 3.1 Hz, 2H), 2.35 (s, 2H), 2, 20 (br s, 4H), 1.74 (t, J = 7.0 Hz, 2H), 1.05 (br s, 12H). MS: (ES) m / z calculated for C39H43FN6O9P [M + H]+847.3, found 847.2. Example 9: Synthesis of (3-fluoro-4-phosphonooxyphenyl)methyl / V-((4-(5-((2,4¿ís(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)- 6,6-dimethyl-4 / f-pyrrolo[3,4-c]pyrazol-3-yl)2,5-difluorophenyl)carbamoyl]carbamate IF-2019-40565613-APN-ANP#INPI Page 75 of 183 Step a: To a solution of 3-fluoro-4-hydroxybenzaldehyde (5 g, 35.7 mmol) in dichloromethane (36 mL) was added Et3N (7.5 mL, 53.8 mmol) followed by diethylchlorophosphate (5.7 mL, 39.4 mmol). The mixture was stirred at room temperature for 3 hours; then stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried with sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to form diethyl(2fluoro-4-formylphenyl) phosphate. MS: (ES) m / z calculated for C11H14FO5P [M + H]+277.1, found 277.0. To a solution of diethyl (2-fluoro-4-formylphenyl) phosphate (8.99 g, 32.5 mmol) in THF (32.5 mL) at -78 °C was added NaBH4 (3.6 g, 97. 3 mmol). After stirring at −78 °C for 1 h, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (85 to 100% EtOAc in hexanes) to yield diethyl (2-fluoro-4(hydroxymethyl)phenyl) phosphate. MS: (ES) m / z calculated for CiiHi6FO5P [M + H]+279.1, found 279.0. To a solution of diethyl (2-fluoro-4-(hydroxymethyl)phenyl) phosphate (1 g, 3.6 mmol) in THF (8.7 mL) at 0 °C was added diisopropylethylamine (0.76 mL, 4. 4 mmol) and triphosgene (0.53 g, 1.8 mmol). After stirring at 0 °C for 1 h, NH4OH (1.6 mL, 41 mmol) was added. The mixture was stirred at room temperature for 16 h then concentrated in vacuo and the residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to form 4((diethoxyphosphoryl)oxy)-3-fluorobenzyl. carbamate. MS: (ES) m / z calculated for C12H17FNO6P [M + H]+322.1, found 322.0. To a solution of 4-((diethoxyphosphoryl)oxy)-3-fluorobenzyl carbamate (155 mg, 0.48 mmol) in dichloromethane (4.8 mL) at 0 °C was added oxalyl chloride (0.06 mL, 0. 71 mmol). The mixture was heated at 40 °C for 16 hours; then concentrated in vacuo. The residue was dissolved in THF (2 mL) and added to a solution of 4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2, 4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoroaniline (100 mg, 0.16 mmol) in THF (2 mL). The mixture was stirred at room temperature for 5 hours; then he concentrated on IF-2019-40565613-APN-ANP#INPI Page 76 of 183 empty. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to obtain (4-diethoxyphosphoryloxy-3-fluorophenyl)methylV-((4-(5-((2,4¿>w (trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4í / -pyrrolo[3,4-c]pyrazol-3-yl)-2,5difluorophenyl)carbamoyl)carbamate. MS: (ES) m / z calculated for C45H45F9N5O7P [M + H]+970.3, found 970.0. Step b: To a solution of (4-diethoxyphosphoryloxy-3-fluorophenyl)methyl 7V-((4-(5-((2,4ów(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6 ,6-dimethyl-4 / f-pyrrolo[3,4-c]pyrazol-3-yl)-2,5difluorophenyl)carbamoyl)carbamate (77 mg, 0.08 mmol) in dichloromethane (1 mL) was added dropwise TMSBr (0.13 mL, 0.10 mmol). The mixture was stirred at room temperature for 16 hours; then concentrated in vacuo. The residue was purified on HPLC (MeCN / HiO, with TFA at Qjo / θ) to form (3-fluoro-4-phosphonooxyphenyl)methyl7V-((4-(5-((2,4¿>w(trifluoromethyl)phenyl)) methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4 / / -pyrrolo[3,4-c]pyrazol-3-yl)-2,5difluorophenyl)carbamoyl)carbamate. Ή NMR (400 MHz, CD3OD) δ8.22 (δ, J - 8.2 Hz, 1H), 8.15 (s, 1H), 8.08-8.15 (m, 2H), 7.46 ( dd, J = 7.6, 7.9 Hz, 1H), 7.38 (dd, J= 8.2, 8.2 Hz, 1H), 7.28 (d, J= 7.6 Hz, 2H ), 7.17 (d, J= 11.0 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.42 (dd, J= 6.5, 11.5 Hz , 1H), 5.14 (s, 2H), 4.77 (s, 2H), 4.57 (s, 2H), 3.34 (s, 2H), 2.24 (q, J = 7, 7 Hz, 4H), 1.89 (s, 6H), 1.05 (t, J= 7.2 Hz, 6H). MS: (ES) m / z calculated for C41H37F9N5O7P [M + H]+914.2, found 914.1. Example 10: Synthesis of 3-nitro-4-(phosphonooxy)benzyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidín-2-yl)-4,5,6, 7-tetrahydro-2Zf-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-l / í-indole-l-carboxylate IF-2019-40565613-APN-ANP#INPI Page 77 of 183 Step a: To a solution of 4-hydroxy-3-nitrobenzaldehyde (1 g, 6.0 mmol) in dichloromethane (6 mL) was added Et3N (1.25 mL, 9.0 mmol) and diethylchlorophosphate (0.95 mL , 6.6 mmol). The mixture was stirred at room temperature for 16 hours; then stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (85 to 100% EtOAc in hexanes) to form diethyl (4-formyl-2-nitrophenyl) phosphate. MS: (ES) m / z calculated for C11H14NO7P [M + H]+304.1, found 304.0. To a solution of diethyl (4-formyl-2-nitrophenyl) phosphate (1.36 g, 4.5 mmol) in THF (4.5 mL) at 78 °C was added NaBH4 (500 mg, 13.5 mmol) . After stirring at −78 °C for 1 h, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography 78 IF-2019-40565613-APN-ANP#INPI Page 78 of 183 silica gel (85 to 100% EtOAc in hexanes) to provide diethyl (4-hydroxymethyl-2nitrophenyl) phosphate. MS: (ES) m / z calculated for C11H16NO7P [M + H]+306.l, found 306.0. To a solution of diethyl (4-(hydroxymethyl)-2-nitrophenyl)phosphate (100 mg, 0.33 mmol) in THF (1.6 mL) at 0 °C was added diisopropylethylamine (0.07 mL, 0.40 mmol) and triphosgene (50 mg, 0.17 mmol). After stirring at 0 °C for 1 h, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to form the crude chloroformate intermediate. To a solution of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-17 / -indol-4-yl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4 ,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridine (93 mg, 0.16 mmol) in THF (1 mL) at 0 °C NaH (13 mg, 0.32 mmol) was added ). After stirring at 0 °C for 30 min, a solution of the crude chloroformate (prepared as stated above) in THF (0.5 mL) was added to the mixture. The solution was stirred at room temperature for 16 hours. The reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to yield 4-((diethoxyphosphoryl)oxy)-3-nitrobenzyl 4(2-(2,6-diethylphenyl)-5- (5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / f-pyrazolo[4,3c]pyridin-3-yl)-6-fluoro-7-methoxy-l / 7-indole-l-carboxylate. Step b: To a solution of 4-((diethoxyphosphoryl)oxy)-3-nitrobenzyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5, 6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-177-indole-l-carboxylate (128 mg, 0.14 mmol) in dichloromethane ( 1.4 mL) was added dropwise TMSBr (0.11 mL, 0.86 mmol). After stirring at room temperature for 5 h, an additional amount of TMSBr (0.11 mL, 0.86 mmol) was added to the mixture. The mixture was stirred at room temperature for 16 h, concentrated in vacuo, and purified by HPLC (MeCN / H2O, with 0.1% TFA) to form 3-nitro-4-(phosphonooxy)benzyl 4-(2- (2,6-diethylpheml)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl) -6-fluoro-7methoxy-l / 7-indole-l-carboxylate. Ή NMR (400 MHz, DMSO-¿6) δ 8.68 (σ, 2H), 8.12 (δδ, J = 0.9, 2.3 Hz, 1H), 7.85 (d, J = 3 .8 Hz, 1H), 7.85 (dd, J= 2.2, 8.6 Hz, 1H), 7.60 (dd, J= 1.1, 8.5 IF-2019-40565613-APN-ANP#INPI Page 79 of 183 Hz, 1H), 7.29 (t, J= 7.6 Hz, 1H), 7.12 (br s, 2H), 6.62 (d, J-3.8 Hz, 1H), 6.55 (d, J 12.4 Hz, 1H), 5.48 (s, 2H), 4.76 (s, 2H), 4.30 (br s, 2H), 3.83 (d, J= 1, 2 Hz, 3H), 2.91 (t, J= 6.0 Hz, 2H), 2.16 (br s, 4H), 2.04 (s, 2H), 0.91 (br s, 6H) . MS: (ES) m / z calculated for C38H34FN7O9P [M + H]+840.2, found 840.0. Example 11: Synthesis of 3-fluoro-4-(phosphonooxy)benzyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7- tetrahydro-2ZLpyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-lH-indole-l-carboxylate Step a: To a solution of 3-fluoro-4-hydroxybenzaldehyde (1 g, 7.1 mmol) in THF (32 mL) was added a 1 M solution of tBuOK in THF (7.6 mL, 7.6 mmol) . The mixture was heated to 70°C and tetrabenzylphosphate (4.0 g, 7.4 mmol) was added. After 1 h at 70 °C, hexanes were added to the mixture and the contents were filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (0 to 100% EtOAc in IF-2019-40565613-APN-ANP#INPI Page 80 of 183 hexanes) to produce dibenzyl (2-fluoro-4-formylphenyl)phosphate. MS: (ES) m / z calculated for C21H18FO5P [M + H]+401.1, found 401.1. To a solution of dibenzyl (2-fluoro-4-formylphenyl) phosphate (2.68 g, 6.7 mmol) in THF (6.7 mL) at -78 °C was added NaBH4 (0.76 g, 20, 5 mmol). After stirring at −78 °C for 1 h, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified on a silica gel column (0 to 100% EtOAc in hexanes) to provide dibenzyl (2-fluoro-4-(hydroxymethyl)phenyl) phosphate. MS: (ES) m / z calculated for C21H20FO5P [M + H]+403.1, found 403.0. To a solution of dibenzyl (2-fluoro-4-(hydroxymethyl)phenyl)phosphate (200 mg, 0.50 mmol) in THF (2.4 mL) at 0 °C was added diisopropylethylamine (0.1 mL, 0. 57 mmol) and triphosgene (72 mg, 0.24 mmol). After stirring at 0 °C for 1 h, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to form the crude chloroformate intermediate. To a solution of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-l / 7-indol-4-yl)-5-(5(trifluoromethyl)pyrimidin-2-yl)- 4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridine (70 mg, 0.12 mmol) in THF (1.2 mL) at 0 °C NaH (10 mg) was added , 0.24 mmol). After stirring at 0 °C for 30 min, a solution of the crude chloroformate (prepared as described above) in THF (1.2 mL) was added to the mixture. The solution was stirred at 0 °C for 1 hour; then stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to give 4-((¿>w(benzyloxy)phosphoryl)oxy)-3-fluorobenzyl 4-(2(2,6 -diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / Apyrazolo[4,3-c]pyridin3-yl)-6-fluoro-7- methoxy-lH-indole-l-carboxylate. Step b: To a solution of 4-((6ri(benzyloxy)phosphoryl)oxy)-3-fluorobenzyl 4-(2-(2,6-diethylphenyl)-5(5-(trifluoromethyl)pyrimidin-2-yl)- 4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-l / Wndol-l-carboxylate (100 mg, 0.10 mmol ) in MeOH (1 mL) 10% Pd / C was added IF-2019-40565613-APN-ANP#INPI Page 81 of 183 (10 mg, 0.01 mmol). The mixture was stirred under a balloon of H2 for 1 h, then filtered through Celite, concentrated, and purified by HPLC (MeCN / H2O, with 0.1% TFA) to form 3fluoro-4-(phosphonooxy). benzyl 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2 / / -pyrazolo[4,3-c]pyridin -3-yl)-6-fluoro-7-methoxy-l / / -indole-l-carboxylate. Ή NMR (400 MHz, DMSO-tifc) δ 8.68 (s, 2H), 7.84 (s, 1H), 7.52-7.38 (m, 2H), 7.37-7.25 ( m, 2H), 7.11 (br s, 2H), 6.62 (s, 1H), 6.54 (d, J= 12.3 Hz, 1H), 5.40 (s, 2H), 4 .76 (s, 2H), 4.30 (s, 2H), 3.83 (s, 3H), 2.90 (bs, 2H), 2.16 (br s, 4H), 2.04 (br s, 2H), 0.90 (br s, 6H). MS: (ES) m / z calculated for C38H34F5N6O7P [M + H]+813.2, found 813.2. Example 12: Synthesis of (2-(4-(phosphonooxy)phenyl)acetoxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5, 6,7-tetrahydro-2Z / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-l / f-indole-l-carboxylate Step a: To a flask containing ethyl 2-(4-hydroxyphenyl)acetate (1 g, 5.6 mmol) in THF (11 mL), a 1 M solution of tBuOK in THF (5.9 mL, 5.9 mmol) and tetrabenzyldiphosphate 82 IF-2019-40565613-APN-ANP#INPI Page 82 of 183 (3 g, 5.6 mmol). The mixture was heated at 70 °C for 2 h. An additional amount of zBuOK. 1.0 M (1.2 mL, 1.2 mmol) and tetrabenzyldiphosphate (0.6 g, 1.1 mmol) was added. The mixture was heated for an additional 3 h. Upon completion, hexanes were added, and the contents were filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to obtain ethyl 2-(4((ów(benzyloxy)phosphoryl)oxy)phenyl)acetate. MS: (ES) m / z calculated for C24H25O6P [M + H]+441.1, found 441.1. To a solution of ethyl 2-(4-((0zri(benzyloxy)phosphoryl)oxy)phenyl)acetate (1.54 g, 3.5 mmol) in THF (9 mL) was added dropwise to LiOH solution (0.32 g, 7.6 mmol) in H2O (9 mL). The mixture was stirred at room temperature for 1 hour. The reaction was stopped with 1 N HC1. The aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to form 2-(4-((¿>w(benzyloxy)phosphoryl)oxy)phenyl)acetic acid. MS: (ES) m / z calculated for C22H21O6P [M + H]+413.1, found 413.1. To a solution of iodomethyl 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-27 / -pyrazolo[4,3- c]pyridin-3-yl)-6-fluoro-7-methoxy-l / f-indole-l-carboxylate (100 mg, 13 mmol) in DMF (0.5 mL) 2-(4-() acid was added (ów(benzyloxy)phosphoryl)oxy)phenyl)acetic acid (82 mg, 20 mmol) and triethylamine (0.03 mL, 0.20 mmol). The mixture was stirred at room temperature for 16 hours; then he concentrated. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to obtain (2-(4((ózs(benzyloxy)phosphoryl)oxy)phenyl)acetoxy)methyl 4-(2-( 2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)- 6-fluoro-7methoxy-1 / f-indole-1 -carboxylate. Step b: To a solution of (2-(4-((¿>w(benzyloxy)phosphoryl)oxy)phenyl)acetoxy)methyl 4-(2-(2,6diethylphenyl)-5-(5-(trifluoromethyl )pyrimidin-2-yl)-4,5,6,7-tetrahydro-27 / -pyrazolo[4,3-c]pyridin-3-yl)6-fluoro-7-methoxy-17 / -indole-l- carboxylate (66 mg, 0.06 mmol) in MeOH (1 mL) 10% Pd / C (7 mg, 0.006 mmol) was added. The mixture was stirred under a balloon of H2 for 1 h, then filtered through Celite, concentrated, and purified by HPLC (MeCN / FhO, with 0.1% TFA) to form (2-(4-( phosphonooxy)phenyl)acetoxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidine IF-2019-40565613-APN-ANP#INPI Page 83 of 183 2-11)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-17 / -indole-lcarboxylate. Ή NMR (400 MHz, CDCh) δ 8.47 (s, 2H), 7.38 (d, J= 3.8 Hz, 1H), 7.22-7.26 (m, 2H), 7.10 (d, J= 7.7 Hz, 2H), 7.01-7.06 (m, 4H), 6.57 (d, J= 12.1 Hz, 1H), 6.45 (d, J= 3.8 Hz, 1H), 5.97 (s, 2H), 5.02 (br s, 2H), 4.77 (s, 2H), 4.36 (br s, 2H), 3.95 ( s, 3H), 3.60 (s, 2H), 3.07 (br s, 2H), 2.05-2.35 (m, 4H), 0.99 (br s, 6H). MS: (ES) m / z calculated for C40H37F4N6O9P [M + H]+853.2, found 853.0. Example 13: Synthesis of (4-phosphonooxy-3-(trifluoromethyl)phenyl)methyl 7V-((4-(5-((2,4ÚA(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)- 6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)2,5-difluorophenyl)carbamoyl)carbamate Or HgN-^ Step a: To a solution of 4-hydroxy-3-(trifluoromethyl)benzaldehyde (1 g, 0.53 mmol) in dichloromethane (10 mL) was added triethylamine (1.1 mL, 0.79 mmol) followed by diethylchlorophosphate ( 0.84 mL, 0.58 mmol). The mixture was stirred at room temperature for 1 hour; then concentrated in vacuo. The residue was purified by silica gel column chromatography. IF-2019-40565613-APN-ANP#INPI Page 84 of 183 (85 to 100% EtOAc in hexanes) to form diethyl (4-formyl-2-(trifluoromethyl)phenyl) phosphate. MS: (ES) m / z calculated for C12H14F3O5P [M + H]+327.1, found 327.0. To a solution of diethyl (4-formyl-2-(trifluoromethyl)phenyl)phosphate (1.43 g, 4.4 mmol) in THF (4.5 mL) at -78 °C was added NaBH4 (0.49 g , 13.2 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. Once complete, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (85 to 100% EtOAc in hexanes) to yield diethyl (4-(hydroxymethyl)-2-(trifluoromethyl)phenyl) phosphate. MS. (ES) m / z calculated for C12H16F3O5P [M + H]+329.l, found 329.1. To a solution of diethyl (4-(hydroxymethyl)-2-(trifluoromethyl)phenyl)phosphate (0.6 g, 1.8 mmol) in THF (4.4 mL) at 0 °C was added diisopropylethylamine (0.39 mL, 2.2 mmol) and triphosgene (0.27 mL, 0.9 mmol). After stirring at 0 °C for 1 h, NH4OH (0.8 mL, 21 mmol) was added. The mixture was stirred at room temperature for 1 h then concentrated in vacuo and the residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to obtain 4-((diethoxyphosphoryl)oxy)-3 -(trifluoromethyl)benzyl carbamate. MS: (ES) m / z calculated for C13H17F3NO6P [M + H]+372.1, found 372.0. To a solution of 4-((diethoxyphosphoryl)oxy)-3-(trifluoromethyl)benzyl carbamate (240 mg, 0.65 mmol) in dichloromethane (2 mL) at 0 °C was added oxalyl chloride (0.09 mL, 1 .0 mmol). The mixture was heated at 40 °C for 16 hours; then concentrated in vacuo. The residue was dissolved in 2 mL of THF and a solution of 4-(5-(2,4-Z>w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2 was added. 4,5,6-Tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoroaniline (200 mg, 0.32 mmol) in THF (4 mL). The mixture was stirred at room temperature for 5 hours; then concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to obtain (4-diethoxyphosphoryloxy-3-(trifluoromethyl)phenyl)methyl A-((4-(5-((2, 4¿zs(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4 / f-pyrrolo[3,4-c]pyrazol-3-yl)-2,5difluorophenyl) carbamoyl)carbamate. Step b: To a solution of (4-diethoxyphosphoryloxy-3-(trifluoromethyl)phenyl)methylV-((4-(5-((2,4¿>w(trifluoromethyl)phenyl)methyl)-2-(2,6 -diethylphenyl)-6,6-dimethyl-4 / Z-pyrrolo[3,4-c]pyrazol-3-yl)-2.585 IF-2019-40565613-APN-ANP#INPI Page 85 of 183 difluorophenyl)carbamoyl)carbamate (176 mg, 0.17 mmol) in dichloromethane (1.7 mL) was added dropwise TMSBr (0.29 mL, 2 mmol). The mixture was stirred at room temperature for 16 hours; then concentrated in vacuo. The residue was purified on HPLC (MeCN / H2O, with 0.1% TFA) to form (4-phosphonooxy-3-(trifluoromethyl)phenyl)methyl V-((4-(5-((2,4¿w( trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4 / 7-pyrrolo[3,4-c]pyrazol-3-yl)-2,5difluorophenyl)carbamoyl)carbamate. Ή NMR (400 MHz, DMSO-í / ó) δ: 10.80 (s, 1H), 10.11 (s, 1H), 8.15 (s, 1H), 7.90-8.15 (m , 3H), 7.73 (bs, 1H), 7.63-7.69 (m, 1H), 7.54-7.61 (m, 1H), 7.35-7.42 (m, 1H ), 7.18-7.24 (m, 2H), 6.49-6.58 (m, 1H), 5.19 (s, 2H), 4.13 (s, 2H), 3.65 ( s, 2H), 2.07-2.23 (m, 4H), 1.30-1.40 (m, 6H), 0.88-1.03 (m, 6H). MS: (ES) m / z calculated for C42H37Fi 1N5O7P [M + H]+964.2, found 964.0. Example 14: Synthesis of (3-nitro-4-phosphonooxyphenyl)methyl / V-((4-(5-((2,4 / ns(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)- 6,6-dimethyl-4 / / -pyrrolo[3,4-c]pyrazol-3-yl)2,5-difluorophenyl)carbamoyl)carbamate IF-2019-40565613-APN-ANP#INPI Page 86 of 183 Step a: To a solution of 4-hydroxy-3-nitrobenzaldehyde (1 g, 6.0 mmol) in dichloromethane (6 mL) was added Et3N (1.25 mL, 9.0 mmol) and diethylchlorophosphate (0.95 mL , 6.6 mmol). The mixture was stirred at room temperature for 16 hours; then stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (85 to 100% EtOAc in hexanes) to form diethyl (4-formyl-2-nitrophenyl)phosphate. MS: (ES) m / z calculated for C11H14NO7P [M + H]+304.1, found 304.0. To a solution of diethyl (4-formyl-2-nitrophenyl)phosphate (1.36 g, 4.5 mmol) in THF (4.5 mL) at - 78 °C was added NaBH4 (500 mg, 13.5 mmol ). After stirring at −78 °C for 1 h, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (85 to 100% EtOAc in hexanes) to provide diethyl (4-hydroxymethyl-2-nitrophenyl) phosphate. MS: (ES) m / z calculated for C11H16NO7P [M + H]+306.1, found 306.1. To a solution of diethyl (4-(hydroxymethyl)-2-nitrophenyl)phosphate (200 mg, 0.66 mmol) in THF (1.6 mL) at 0 °C was added diisopropylethylamine (0.14 mL, 0.80 mmol) and triphosgene (100 mg, 0.34 mmol). After stirring at 0 °C for 1 h, NH4OH (0.32 mL, 8.2 mmol) was added. The mixture was stirred at room temperature for 1 h then concentrated in vacuo and the residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to obtain 4((diethoxyphosphoryl)oxy)-3- nitrobenzyl carbamate. MS: (ES) m / z calculated for C12H17N2O8P [M + H]+349.1, found 349.0. To a solution of 4-((diethoxyphosphoryl)oxy)-3-(trifluoromethyl)benzyl carbamate (0.4 g, 1.2 mmol) in dichloromethane (11.5 mL) at 0 °C was added oxalyl chloride (0. 15 mL, 1.8 mmol). The mixture was heated at 40 °C for 16 hours; then concentrated in vacuo. The residue was dissolved in THF (1 mL) and added to a solution of 4-(5-(2,4-¿> / s(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl -2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoroaniline (200 mg, 0.32 mmol) in THF (5 mL). The mixture was stirred at room temperature for 3 hours; then concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc IF-2019-40565613-APN-ANP#INPI Page 87 of 183 in hexanes) to obtain (4-diethoxyphosphoryloxy-3-nitrophenyl)methyl7V-((4-(5-((2.46w(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)- 6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5difluorophenyl)carbamoyl)carbamate. Step b: To a solution of (4-diethoxyphosphoryloxy-3-nitrophenyl)methyl 7V-((4-(5-((2,4¿w(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl) -6,6-dimethyl-4 / / -pyrrolo[3,4-c]pyrazol-3-yl)-2,5difluorophenyl)carbamoyl)carbamate (100 mg, 0.10 mmol) in dichloromethane (1 mL) was added drops TMSBr (0.09 mL, 0.6 mmol). After stirring at room temperature for 3 h, an additional amount of TMSBr (0.09 mL, 0.6 mmol) was added to the mixture. The mixture was stirred at room temperature for 16 h, concentrated in vacuo, and purified by HPLC (MeCN / PhO, with 0.1% TFA) to form (3-nitro-4-phosphonooxyphenyl)methylA-((4- (5-((2,4¿>is(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-47 / -pyrrolo[3,4-c]pyrazole-3- il)-2,5difluorophenyl)carbamoyl)carbamate. Ή NMR (400 MHz, CD3OD) δ: 8.25 (d, J - 8.0 Hz, 1H), 8.16 (s, 2H), 8.01-8.12 (m, 1H), 7. 82 (s, 1H), 7.54 (s, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.28 (d, J = 7.8 Hz, 2H), 6, 38 (dd, J= 7.6, 11.2 Hz, 1H), 5.20 (s, 2H), 4.81 (s, 2H), 4.66 (s, 2H), 2.25 (q , J= 7.7 Hz, 4H), 1.92 (s, 6H), 1.05 (t, J= 7.7 Hz, 6H). MS: (ES) m / z calculated for C41H37F8N6O9P [M + H]+941.2, found 941.1. IF-2019-40565613-APN-ANP#INPI Page 88 of 183 Example 15: Synthesis of 2-(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2.H-pyrazolo[ 4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-l / 7-indol-l-carboníl)-5fluorobenzyl dihydrogen phosphate Step to: One vial containing 5-fluoroisobenzofuran-l(3 / 7)-one (50 mg, 0.33 mmol), boric acid (2 mg, 0.03 mmol), and triethylbenzylammonium chloride (6 mg, 0.03 mmol) was heated to 110 °C. Thionyl chloride (0.05 mL, 0.69 mmol) was added to the mixture. After stirring at 110 °C for 16 h, the contents were concentrated to obtain 2-(chloromethyl)-4-fluorobenzoyl chloride. IF-2019-40565613-APN-ANP#INPI Page 89 of 183 A. a solution of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-l / / -indol-4-yl)-5-(5(trifluoromethyl)pyrimidin-2-yl) -4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine (46 mg, 0.08 mmol) in THF (0.5 mL) at -78 °C a 1 M solution of LHMDS in THF (0.12 mL, 0.12 mmol). The mixture was stirred at −78 °C for 30 min, warmed to 0 °C and stirred for 15 min, then cooled again to −78 °C. A solution of 2-(chloromethyl)-4-fluorobenzoyl chloride (0.33 mmol) in THF (0.5 mL) was added dropwise to the mixture. After stirring at room temperature for 16 h, the reaction was stopped with H2O. The aqueous and organic layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to form (2-(chloromethyl)-4fluorophenyl)(4-(2-(2,6-diethylphenyl)-5-( 5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / fpyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-U7-indole -l-yl)methanone. MS: (ES) m / z calculated for C38H32CIF5N6O2 [M + H]+735.2, found 735.1. Step b: To a solution of (2-(chloromethyl)-4-fluorophenyl)(4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5, 6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-l / 7-indol-l-yl)methanone (48 mg, 0.065 mmol) in Acetone (1 mL) sodium iodide (32 mg, 0.21 mmol) was added. The mixture was heated at 70 °C for 1 hour; then concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to yield (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2- il)-4,5,6,7tetrahydro-27 / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-l / 7-indol-l-yl)(4- fluoro-2(iodomethyl)phenyl)methanone. MS: (ES) m / z calculated for C38H32F5IN6O2 [M + H]+827.2, found 827.0. Step c: To a solution of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-27 / -pyrazolo[4 ,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-177-indol-l-yl)(4-fluoro-2(iodomethyl)phenyl)methanone (26 mg, 0.031 mmol) in toluene ( 1 mL) silver dibenzyl phosphate (24 mg, 0.062 mmol) was added. The mixture was heated at 110 °C for 16 hours; then concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100 EtOAc in hexanes) to obtain dibenzyl (2-(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidine)). 2-yl)4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-l / 7-indole-l-carbonyl )-5fluorobenzyl) phosphate. IF-2019-40565613-APN-ANP#INPI Page 90 of 183 Step d: To a solution of dibenzyl (2-(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-l / / -indol-l-carbonyl)-5fluorobenzyl) phosphate (17 mg, 0.017 mmol) in MeOH ( 1 mL) 10% Pd / C (2 mg) was added. The mixture was stirred under a balloon of H2 for 1 h, then filtered through Celite, concentrated, and purified by HPLC (MeCN / H2O, with 0.1% TFA) to form 2-(4-(2- (2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl) -6-fluoro-7methoxy-l / Aindol-l-carbonyl)-5-fluorobenzyl dihydrogen phosphate. Ή NMR (400 MHz, CD3OD) δ 8.58 (s, 2H), 7.60 (d, J= 10.0 Hz, 1H), 7.49 (br s, 2H), 7.33 (t, J= 7.6 Hz, 1H), 7.11-7.24 (m, 3H), 6.65 (s, 1H), 6.59 (d, J= 13.0 Hz, 1H), 5, 35 (d, J= 7.3 Hz, 2H), 4.87 (s, 2H), 4.38 (s, 2H), 3.75 (s, 3H), 2.98 (s, 2H), 2.25 (br s, 4H), 1.02 (br s, 6H). MS: (ES) m / z calculated for C38H34F5N6O6P [M + H]+797.2, found 797.1. Example 16: Synthesis of 2-(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2Hr-pyrazolo[4, 3-c]pyridin-3-yl)-6-fluoro-7-methoxy-l^f-indol-l-carbonyl)benzyl dimethylglycinate IF-2019-40565613-APN-ANP#INPI Page 91 of 183 Step a: To a solution of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-l / / -indol-4-yl)-5-(5(trifluoromethyl)pyrimidin-2- il)-4,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridine (500 mg, 0.9 mmol) in THF (8.8 mL) at -78 °C a solution was added 1 M LHMDS in THF (0.98 mL, 0.98 mmol). After stirring at −78 °C for 30 min, 2-(chloromethyl)benzoyl chloride (0.25 mL, 1.78 mmol) was added to the mixture. After stirring at room temperature for 16 h, the reaction was stopped with H2O. The aqueous and organic layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel 92 column chromatography. IF-2019-40565613-APN-ANP#INPI Page 92 of 183 (O to 100% EtOAc in hexanes) to form (2-(chloromethyl)phenyl)(4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl) -4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-1 / 7-indol-l-yl)methanone. MS: (ES) m / z calculated for C38H33CIF4N6O2 [M + H]+717.2, found 717.0. Step b: To a solution of (2-(chloromethyl)phenyl)(4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7 -tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-l / 7-indol-l-yl)methanone (156 mg, 0.22 mmol) in acetone (2.2 mL) sodium iodide (129 mg, 0.9 mmol) was added. After heating at 70 °C for 1 h, the reaction was stopped with H2O. The aqueous and organic layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to give (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl )-4,5,6,7tetrahydro-27 / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-17 / -indol-l-yl)(2(iodomethyl) phenyl)methanone. Step c: To a solution of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2 / 7-pyrazolo[ 4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-l / 7-indol-l-yl)(2(iodomethyl)phenyl)methanone (76 mg, 0.094 mmol) in DMF (1 mL) at 0 °C, CS2CO3 (31 mg, 0.1 mmol) and dimethylglycine (10 mg, 0.1 mmol) were added. After stirring at room temperature for 16 h, the reaction was stopped with H2O. The aqueous and organic layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by HPLC (MeCN / H2O, with 0.1% TFA) to obtain 2-(4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl) -4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-177-indol-l-carbonyl)benzyl dimethylglycinate. Ή NMR (400 MHz, CDCh) δ 8.54 (s, 2H), 7.65-7.81 (m, 4H), 7.31 (t, .7=7.7 Hz, 1H), 7, 22 (d,J=3.7 Hz, 1H), 7.11 (br s, 2H), 6.64 (d, J= 12.7 Hz, 1H), 6.52 (d, J= 3, 7 Hz, 1H), 5.08 (s, 2H), 4.76 (s, 2H), 4.37 (s, 2H), 4.14 (s, 2H), 3.85 (s, 3H) , 3.32 (s, 6H), 3.09 (t, J= 5.9 Hz, 2H), 2.08 (br s, 4H), 1.04 (br s, 6H). MS: (ES) m / z calculated for C42H41F4N7O4 [M + H]+784.3, found 784.2. IF-2019-40565613-APN-ANP#INPI Page 93 of 183 Example 17: Synthesis of 3-chloro-4-(phosphonooxy)benzyl 4-(5-(2,4-ázs(trifluoromethyl)benzyl)-2(2,6-diethylphenyl)-6,6-dimethyl-2,4 ,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-177-indole-lcarboxylate. Step a: To a flask containing 3-chloro-4-hydroxybenzoic acid (5 g, 29 mmol) in MeOH (100 mL) thionyl chloride (7.4 mL, 102 mmol) was added dropwise. The mixture was heated at 60 C for 1 hour; then concentrated in vacuo. The crude residue was dissolved in THF (100 mL). L1AIH4 (4.4 g, 110 mmol) was added to the solution. After heating at 65 C for 1 h, the reaction was quenched with 1 N HC1. The aqueous and organic layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (85 to 100% EtOAc in hexanes) to form 2-chloro-4-(hydroxymethyl)phenol. To a solution of 2-chloro-4-(hydroxymethyl)phenol (2 g, 12.7 mmol) in dioxane (25 mL) was added DDQ (2.87 g, 12.7 mmol). The mixture was stirred at room temperature for 4 hours; then 94 IF-2019-40565613-APN-ANP#INPI Page 94 of 183 leaked. The filtrate was washed with H2O, then dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (85 to 100% EtOAc in hexanes) to form 3-chloro-4-hydroxybenzaldehyde. MS: (ES) m / z calculated for C7H5CIO2 [M + H]+157.0, found 157.0. To a flask containing 3-chloro-4-hydroxybenzaldehyde (1.4 g, 9.0 mmol) in THF (14.6 mL) was added dropwise a 1.0 M solution of / BuOK in THF (9.5 mL, 9.5 mmol) and tetrabenzyldiphosphate (4.8 g, 8.9 mmol). The mixture was heated at 70 °C for 2 h. Upon completion, hexanes were added, and the contents were filtered. The filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to obtain dibenzyl (2-chloro-4-formylphenyl)phosphate. MS: (ES) m / z calculated for C21H18CIO5P [M + H]+417.l, found 417.0. To a solution of dibenzyl (2-chloro-4-formylphenyl)phosphate (2.75 g, 6.6 mmol) in THF (6.6 mL) at -78 °C was added NaBH4 (0.73 g, 19.7 mmol ). After stirring at −78 °C for 1 h, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to yield dibenzyl (2-chloro-4(hydroxymethyl)phenyl) phosphate. MS: (ES) m / z calculated for C21H20CIO5P [M + H]+419.1, found 419.0. To a solution of dibenzyl (2-chloro-4-(hydroxymethyl)phenyl)phosphate (250 mg, 0.6 mmol) in THF (3 mL) at 0 °C was added diisopropylethylamine (0.12 mL, 0.69 mmol ) and triphosgene (92 mg, 0.3 mmol). After stirring at 0 °C for 1 h, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to form the crude chloroformate. To a solution of 4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4-c ]pyrazol-3-yl)-7-fluoro-l / 7-indole (187 mg, 0.30 mmol) in THF (1.5 mL) at 0 °C NaH (24 mg, 0.60 mmol) was added . After stirring at 0 °C for 30 min, a solution of the crude chloroformate (prepared as above) in THF (1.5 mL) was added at 95 IF-2019-40565613-APN-ANP#INPI Page 95 of 183 mix. After stirring at O ​​°C for 1 h, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to give 4-((6w(benzyloxy)phosphoryl)oxy)-3-chlorobenzyl 4-(5-(2,4- bis(trifluoromethyl)benzyl)-2-(2,6diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-177- indole-lcarboxylate. Step b: To a solution of 4-((0zs(benzyloxy)phosphoryl)oxy)-3-chlorobenzyl 4-(5-(2,4ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6, 6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-7-fluoro-l / 7-indole-l-carboxylate (298 mg, 0.28 mmol) in MeOH ( 4 mL) 10% Pd / C (30 mg, 0.03 mmol) was added. The mixture was stirred under a balloon of H2 for 1 h, then filtered through Celite, concentrated, and purified by HPLC (MeCN / H2O, with 0.1% TFA) to form 3-chloro-4-(phosphonooxy )benzyl 4-(5-(2,4-6w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole -3-yl)-7-fluoro-l / 7-indole-l-carboxylate. Ή NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 8.04-8.12 (m, 2H), 7.83 (s, 1H), 7.55 (s, 1H), 7 .51 (d, J = 8.4 Hz, 1H), 7.33-7.37 (m, 2H), 7.17 (d, J= 7.9 Hz, 2H), 6.82 (dd, J= 10.2, 10.2 Hz, 1H), 6.67 (br s, 2H), 5.36 (s, 2H), 4.77 (s, 2H), 4.50 (s, 2H) , 2.16-2.29 (m, 4H), 1.93 (br s, 6H), 0.99 (br s, 6H). MS: (ES) m / z calculated for C^FbvClFvN^óP [M + H]+893.2, found 893.1. Example 18: Synthesis of 3-fluoro-4-(phosphonooxy)benzyl 4-(5-(2,4-ó¿s(trifluoromethyl)benzyl)-2(2,6-diethylphenyl)-6,6-dimethyl-2 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1Z7-indole-lcarboxylate IF-2019-40565613-APN-ANP#INPI Page 96 of 183 Step a: To a flask containing 3-fluoro-4-hydroxybenzaldehyde (1 g, 7.1 mmol) in THF (32 mL), a 1.0 M solution of tBuOK in THF (7.6 mL, 7.6 mmol) and tetrabenzyl diphosphate (4.0 g, 7.4 mmol). The mixture was heated at 70 °C for 1 h. Upon completion, hexanes were added, and the contents were filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to obtain dibenzyl (2-fluoro-4-formylphenyl) phosphate. MS: (ES) m / z calculated for C21H18FO5P [M + H]+401.1, found 401.1. To a solution of dibenzyl (2-fluoro-4-formylphenyl) phosphate (2.68 g, 6.7 mmol) in THF (6.7 mL) at -78 °C was added NaBH4 (0.76 g, 20, 5 mmol). After stirring at −78 °C for 1 h, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to yield dibenzyl (2-fluoro-4 IF-2019-40565613-APN-ANP#INPI Page 97 of 183 (hydroxymethyl)phenyl) phosphate. MS: (ES) m / z calculated for C21H20FO5P [Μ + H]+403.1, found 403.0. To a solution of dibenzyl (2-fluoro-4-(hydroxymethyl)phenyl)phosphate (250 mg, 0.62 mmol) in THF (3 mL) at 0 °C was added diisopropylethylamine (0.12 mL, 0.69 mmol ) and triphosgene (92 mg, 0.3 mmol). After stirring at room temperature for 30 min, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to form the crude chloroformate. To a solution of 4-(5-(2,4-6w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4-c ]pyrazol-3-yl)-7-fluoro-l / 7-indole (195 mg, 0.31 mmol) in THF (1.5 mL) at 0 °C NaH (24 mg, 0.60 mmol) was added . After stirring at room temperature for 30 min, a solution of the crude chloroformate (prepared as above) in THF (1.5 mL) was added to the mixture. After stirring at room temperature for 16 h, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to yield 4-((bis(benzyloxy)phosphoryl)oxy)-3fluorobenzyl 4-(5-(2,4-¿> w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-l / 7-indole-l-carboxylate. Step b: To a solution of 4-((Z>zXbenzyloxy)phosphoryl)oxy)-3-fluorobenzyl 4-(5-(2,4bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6, 6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-7-fluoro-l / / -indole-l-carboxylate (307 mg, 0.29 mmol) in EtOAc ( 1.5 mL) 10% Pd / C (30 mg, 0.03 mmol) was added. The mixture was stirred under a balloon of H2 for 3 h, then filtered through Celite, concentrated, and purified by HPLC (MeCN / H2O, with 0.1% TFA) to form 3-fluoro-4-( phosphonooxy)benzyl 4-(5-(2,4-¿>w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3-yl)-7-fluoro-l / 7-indole-l-carboxylate. Ή NMR (400 MHz, CD3OD) δ: 8.13 (s, 1H), 8.05-8.11 (m, 2H), 7.83 (m, 1H), 7.44 (dd, J = 8 .4, 8.4 Hz, 1H), 7.30-7.37 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 7.17 (d, J= 7, 8 Hz, 2H), 6.83 (dd, J = 10.4, 10.4 Hz, 1H), 6.67 (br s, 2H), 5.38 (s, 2H), 4.80 (s , 2H), 4.54 (s, 2H), 2.15-2.29 (m, 4H), 1.96 (br IF-2019-40565613-APN-ANP#INPI Page 98 of 183 s, 6H), 0.99 (br s, 6H). MS: (ES) m / z calculated for C42H37F8N4O6P [M + H]+877.2, found 877.1. Example 19: Synthesis of 2-((phosphonooxy)methyl)phenyl 4-(5-(2,4-A / s(trifluoromethyl)benzyl)-2-(2,6diethylphenyl)-6,6-dimethyl-2,4 ,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-l / f-indole-lcarboxylate triphosgene DIPEA, THF NaH.THF Step to Step b Pd / C, H2, EtOAc Step a: To a flask containing 2-hydroxybenzaldehyde (10 g, 82 mmol) in DMF (82 mL), imidazole (6.1 g, 90 mmol) and TBDMSC1 (13.6 g, 90 mmol) were added dropwise. After stirring at room temperature for 3 h, the reaction was stopped with H2O. The mixture was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (85 to -100% EtOAc in hexanes) to form 2-((tert-butyldimethylsilyl)oxy)benzaldehyde. MS: (ES) m / z calculated for C13H20O2S1 [M + H]+237.1, found 237.1. IF-2019-40565613-APN-ANP#INPI Page 99 of 183 To a solution of 2-(( / er-butyldimethylsilyl)oxy)benzaldehyde (16.4 g, 69 mmol) in MeOH (126 mL) was added NaBH4 (2.55 g, 67.4 mmol). After stirring at room temperature for 2 h, the reaction was stopped with H2O. The mixture was concentrated in vacuo, then extracted with hexanes. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (85 to 10% EtOAc in hexanes) to yield 2-(( / er-butyldimethylsilyl)oxy)phenyl)methanol. To a flask containing (2-((tert-butyldimethylsilyl)oxy)phenyl)methanol (1 g, 4.2 mmol) in THF (42 mL) was added dropwise a 1.0 M solution of tBuOK in THF (4 .6 mL, 4.6 mmol) and tetrabenzyl diphosphate (2.5 g, 4.6 mmol). The mixture was heated at 60 °C for 1 h. Upon completion, hexanes were added, and the contents were filtered. The filtrate was concentrated, and the residue was used without further purification. To a solution of the crude residue dissolved in MeCN (42 mL), HF-pyridine (4.2 mL) was added dropwise. After stirring at room temperature for 1 hour; The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (85 to 100% EtOAc in hexanes) to obtain dibenzyl (2-hydroxybenzyl)phosphate. MS: (ES) m / z calculated for C21H21O5P [M + H]+385.1, found 385.0. ' To a solution of dibenzyl (2-hydroxybenzyl)phosphate (366 mg, 0.95 mmol) in THF (4.8 mL) was added diisopropylethylamine (0.18 mL, 1.0 mmol) and triphosgene (139 mg, 0. 47 mmol). After stirring at room temperature for 30 min, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. To a solution of 4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4-c ]pyrazol-3-yl)-7-fluoro-l / 7-indole (300 mg, 0.48 mmol) in THF (4.8 mL) NaH (37 mg, 0.97 mmol) was added. After stirring at room temperature for 20 mm, a solution of the crude chloroformate (prepared as above) in 1 mL of THF was added to the mixture. After stirring at room temperature for 16 h, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100 IF-2019-40565613-APN-ANP#INPI Page 100 of 183 100% EtOAc in hexanes) to produce 2-(((¿>w(benzyloxy)phosphoryl)oxy)methyl)phenyl 4-(5-(2,4¿«(trifluoromethyl)benzyl)-2-(2,6- diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3i l)-7-fluoro-1 TZ-indole-1 -carboxy lato. Step b: To a solution of 2-(((Z>w(benzyloxy)phosphoryl)oxy)methyl)phenyl 4-(5-(2.46w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)- 6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-7-fluoro-l / / -indole-l-carboxylate (500 mg, 0.48 mmol) in EtOAc (2.4 mL) was added with 10% Pd / C (51 mg). The mixture was stirred under balloon H2 for 2 h, then filtered through Celite, concentrated and purified by HPLC (MeCN / H2O, with 0.1% TFA) to form 2((phosphonooxy)methyl)phenyl 4 -(5-(2,4-ozs(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3- il)-7-fluoro-17 / -indole-l-carboxylate. Ή NMR (400 MHz, DMSO-í / ó) δ 8.12 (d, J = 8.1 Hz, IH), 7.94-8.06 (m, 2H), 7.85 (s, IH) , 7.51 (d, J= 7.6 Hz, IH), 7.35-7.39 (m, IH), 7.28-7.33 (m, 2H), 7.07-7.20 (m, 3H), 6.90-6.95 (m, IH), 6.60 (s, IH), 6.56 (dd, J= 8.4, 3.7 Hz, IH), 5, 42 (s, 2H), 4.15 (br s, 2H), 3.59 (br s, 2H), 2.16 (q, J= 7.8 Hz, 4H), 1.48 (br s, 6H), 0.90 (t, J = 7.5 Hz, 6H). MS: (ES) m / z calculated for C42H38F7N4O6P [M + H]+859.2, found 859.2. Example 20: Synthesis of 2-(4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3 ,4-c]pyrazol-3-yl)-7-fluoro-ll / -indole-l-carbonyl)benzyl dihydrogen phosphate 101 IF-2019-40565613-APN-ANP#INPI Page 101 of 183 Step a: To a solution of 4-(5-(2,4-¿>w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[ 3,4-c]pyrazol-3-yl)-7-fluoro-177-indole (500 mg, 0.80 mmol) in THF (8 mL) at -78 °C was added to 0.5 M KHMDS solution in THF (2.6 mL, l.3mmol). After stirring at −78 °C for 30 min, 2-(chloromethyl)benzoyl chloride (0.28 mL, 1.9 mmol) was added to the mixture. After stirring at room temperature for 16 h, the reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution. The aqueous and organic layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography in 102 IF-2019-40565613-APN-ANP#INPI Page 102 of 183 silica gel column (0 to 100% EtOAc in hexanes) to form (4-(5-(2,4¿>¿y(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl) -6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-7-fluoro-l / / -indol-l-yl)(2-(chloromethyl)phenyl) methanone. MS: (ES) m / z calculated for C42H36CIF7N4O [M + H]+781.3, found 781.0. Step b: To a solution of (4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3 ,4-c]pyrazol-3-yl)-7-fluoro-l / / -indol-l-yl)(2-(chloromethyl)phenyl)methanone (194 mg, 0.25 mmol) in acetone (3.1 mL) sodium iodide (149 mg, 0.99 mmol) was added. After heating at 70 °C for 2 h, the reaction was diluted with EtOAc and washed with H2O. The aqueous and organic layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give (4-(5-(2,4-dw(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6, 6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-17f-indol-l-yl)(2-(iodomethyl)phenyl)methanone, which was used in the next step without further purification. Step c: To a solution of (4-(5-(2,4-¿»w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrole Crude [3,4-c]pyrazol-3-yl)-7-fluoro-177-indol-l-yl)(2-(iodomethyl)phenyl)methanone (0.25 mmol) in toluene (1 mL) was added silver dibenzyl phosphate (190 mg, 0.49 mmol). After heating the mixture at 110 °C for 3 h, the mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to obtain dibenzyl (2-(4-(5-(2,4¿>w(trifluoromethyl) benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3i l)-7-fluoro-1 / / -indole -1-carbonyl)benzyl)phosphate. Step d: To a solution of dibenzyl (2-(4-(5-(2,4-¿>w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5 ,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-l / / -indol-l-carbonyl)benzyl)phosphate (96 mg) in EtOAc (1 mL) 10% of Pd / C (10 mg, 0.009 mmol). The mixture was stirred under balloon H2 for 4 h, then filtered through Celite, concentrated and purified by HPLC (MeCN / H2O, with 0.1% TFA) to form 2-(4-(5-( 2,4-6w(trifluoromethyl)benzyl)-2-(2,6diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7- fluoro-l / Aindol-lcarbonyl)benzyl dihydrogen phosphate. Ή NMR (400 MHz,CD3OD) δ: 8.12 (s, 1H), 8.09 (br s, 2H), 7.74 (d, 7.7 Hz, 1H), 7.67 (ddd, J = 1.4, 7.3, 7.3 Hz, 1H), 7.57 (dd, J= 1.4, 7.7 Hz, 1H), 103 IF-2019-40565613-APN-ANP#INPI Page 103 of 183 7.49 (ddd, J= 1.4, 7.2, 7.2 Hz, 1H), 7.40 (d, J= 3.7 Hz, 1H), 7.36 (d, J-Ί, Ί Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.84 (dd, J= 8.3, 11.3 Hz, 1H), 6.72 (dd, J= 3.8, 8.4 Hz, 1H), 6.67 (dd, J= 1.8, 3.8 Hz, 1H), 5.19 (d, J= 7.4 Hz, 2H), 4, 75 (s, 2H), 4.55 (s, 2H), 2.26 (q, J= 7.5 Hz, 4H), 1.93 (s, 6H), 1.03 (t, J= 7 .5Hz, 6H). MS: (ES) m / z calculated for C42H38F7N4O5P [M + H]+843.3, found 843.2. Example 21: Synthesis of ((4-(piperazin-l-ylmethyl)benzoyl)oxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4, 5,6,7-tetrahydro-21 / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-l / 7-indole-l-carboxylate Step a: A mixture of iodomethyl 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4,5,6,7-tetrahydro-2 / / -pyrazolo[ 4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-l / / -indole-l-carboxylate (840 mg, 1.12 mmol), 4-formylbenzoic acid (252 mg, 1, 68 mmol) and diisopropylethylamine (0.74 mL, 104 IF-2019-40565613-APN-ANP#INPI Page 104 of 183 4.48 mmol) in dichloromethane (20 mL) was heated at 50 °C for 3 h. The mixture was cooled to room temperature, poured into saturated aqueous NaHCCh solution and extracted with dichloromethane. The organic layer was separated, dried in the presence of Na2SO4, concentrated under reduced pressure and purified by flash chromatography on silica gel (0 to 60% EtOAc in hexanes) to obtain ((4-formylbenzoyl)oxy)methyl 4 -(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin- 3-yl)-6-fluoro-7methoxy-l / f-indole-l-carboxylate. MS: (ES) m / z calculated for C40H35F4N6O6 [M + H]+771.2, found 771.2. Step b: To a 200 mL flask containing piperazine (1.0 g, 11.6 mmol) in dichloromethane (25 mL) at 0 °C, acetic acid (40 mL), NaBH(OAc)s were added sequentially. (1.5 g, 7.0 mmol) and ((4-formylbenzoyl)oxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4, 5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-l / / -indole-l-carboxylate (0.5 g, 0.65 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0 °C and charged with 2 M HC1 solution in ether (20 mL, 40 mmol). The mixture was purified by flash chromatography on silica gel (0 to 100% EtOAc in hexanes followed by 0 to 60% MeOH in CH2Cl2). The pure fractions were combined, cooled to 0 °C, loaded with 2 M HCl solution in ether (10 mL, 20 mmol), and concentrated under reduced pressure to form the HCl salt of ((4-(piperazin-l -ylmethyl)benzoyl)oxy)methyl 4-(2-(2,6diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-27 / -pyrazolo[4 ,3-c]pyridin-3-yl)6-fluoro-7-methoxy-l / / -indole-l-carboxylate.1H NMR (400 MHz, CDsODjb 8.58 (s, 2H), 8.21 (d, J = 8.4 Hz, 2H), 7.80 (d, J= 3.6 Hz, 1H), 7.75 (d, J= 8.0 Hz, 2H), 7.33 (t, J= 7 .8 Hz, 1H), 7.16 (br s, 2H), 6.59-6.66 (m, 2H), 6.30 (s, 2H), 4.32-4.50 (m, 4H ), 3.96 (d, J = 1.2 Hz, 3H), 3.403.60 (m, 9H), 3.28-3.34 (m, 3H), 2.98 (dd, J= 5, 8, 5.8 Hz, 2H), 2.25 (br s, 4H), 1.00 (br s, 6H); MS (free form): (ES) m / z calculated for C44H45F4N8O5 [M + H] +841.3, found 841.7. Example 22: Synthesis of ((4-((phosphonooxy)methyl)benzoyl)oxy)methyl 4-(5-(2,4áA(trifluoromethyl)-benzyl)-2-(2,6-diethylphenyl)-6,6- dimethyl-2,4,5,6-tetrahydropyrrolo[3,4c]pyrazol-3-yl)-7-fluoro-lZT-indole-l-carboxylate 105 IF-2019-40565613-APN-ANP#INPI Page 105 of 183 Step a: To a solution of 4-(5-(2,4-6w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3, 4-c]pyrazol-3-yl)-7-fluoro-l / / -indole (3.0 g, 4.76 mmol) in THF (30 mL) at -78 °C 1 M LiHMDS solution was added in toluene (7.61 mL, 7.61 mmol) dropwise. The mixture was stirred at the same temperature for an additional 15 min. Chloromethyl carbonhydrochloride (0.83 mL, 9.52 mmol) was added to the mixture. The resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. The mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, dried in the presence of Na2SO4, concentrated under reduced pressure and 106 IF-2019-40565613-APN-ANP#INPI Page 106 of 183 was purified by flash chromatography on silica gel (0 to 40% EtOAc in hexanes) to obtain chloromethyl 4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl )-6,6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-l / / -indole-l-carboxylate. MS: (ES) m / z calculated for C36H33CIF7N4O2 [M + H]+721.1, found 721.0. Step b: A mixture of chloromethyl 4-(5-(2,4-¿>w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-l / 7-indole-l-carboxylate. (2.5 g, 3.46 mmol) and Nal (6.0 g, 40.0 mmol) in acetone (50 mL) was heated at 45 °C for 7 h. The mixture was cooled to room temperature, poured into saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was separated, dried in the presence of Na2SO4, concentrated under reduced pressure and purified by flash chromatography on silica gel (0 to 40% EtOAc in hexanes) to obtain iodomethyl 4-(5-(2,4- áw(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-12 / -indole-l-carboxylate. MS: (ES) m / z calculated for C36H33F7IN4O2 [M + H]+813.2, found 813.2. Step c: A mixture of iodomethyl 4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6-tetrahydropyrrolo[3, 4-c]pyrazol-3-yl)-7-fluoro-l / / -indole-l-carboxylate (156 mg, 0.19 mmol) and ((4-(((6w(benzyloxy)phosphoryl)oxy) Methyl)benzoyl)oxy)silver (100 mg, 0.19 mmol) in toluene (10 mL) was heated at 110 °C for 1 h. It was cooled to room temperature, poured into saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was separated, dried in the presence of Na2SO4, concentrated under reduced pressure and purified by flash chromatography on silica gel (0 to 60% EtOAc in hexanes followed by 0 to 30% EtOAc in CH2CI2) to obtain (( 4-(((Mbenzyloxy)phosphoryl)oxy)methyl)-benzoyl)oxy)methyl 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-17f-indole-lcarboxylate. MS: (ES) m / z calculated for C58H53F7N4OsP[M + H]+1097.3, only parental MS fragment observed. Step d: A mixture of ((4-(((óA(benzyloxy)phosphoryl)oxy)methyl)benzoyl)oxy)methyl 4-(5-(2,4bis(trifluoromethyl)benzyl)-2-(2,6- diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3i|)-7-fluoro-l / 7-indole-l-carboxylate (0.10 g, 0.09 mmol) TFA (1 mL), dichloromethane (1 mL), and water (1 mL) was heated at 45 °C for 6 h. It was cooled to room temperature, concentrated under reduced pressure and purified by HPLC (MeCN / fLO, with 0.1% TFA) to obtain ((4 107. IF-2019-40565613-APN-ANP#INPI Page 107 of 183 ((phosphonooxy)methyl)benzoyl)oxy)methyl 4-(5-(2,4-¿>w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2, 4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-l / / -indole-l-carboxylate as TFA salt. Ή NMR (400 MHz, CD3OD)5 8.01-8.13 (m, 6H), 7.85 (d, J= 3.6 Hz, 1H), 7.54 (d, J = 8.4 Hz , 2H), 7.35 (dd, J= 7.8, 7.8 Hz, 1H), 7.16 (d, J= 8.0 Hz, 2H), 6.81-6.88 (m, 1H), 6,666.71 (m, 2H), 6.26 (s, 2H), 5.07 (d, J = 7.2 Hz, 2H), 4.70 (br s, 2H), 4.40 (br s, 2H), 3.30 (br s, 2H), 2.16-2.30 (m, 4H), 1.88 (s, 6H), 1.00 (t, J = 7.6 Hz, 6H); MS: (ES) m / z calculated for C44H41F7N4O8P [M + H]+917.3, found 917.1. Example 23: Synthesis of ((4-(piperazin-l-ylmethyl)benzoyl)oxy)methyl 4-(5-(2,4¿w(trifluoromethyl)-benzyl)-2-(2,6-diethylphenyl)-6 ,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4c]pyrazol-3-yl)-7-fluoro-lHr-indole-l-carboxylate Step a: A mixture of 4-formylbenzoic acid (0.5 g, 3.3 mmol) and LiOH monohydrate (0.15 g, 3.7 mmol) in THF (7.5 mL), MeOH (1 mL) and water (0.5 mL) was stirred at room temperature 108 IF-2019-40565613-APN-ANP#INPI Page 108 of 183 for 15 minutes. AgNCh (0.65 g, 3.8 mmol) was added to the mixture. The mixture was stirred for an additional 15 minutes and evaporated to dryness under reduced pressure to obtain ((4-formylbenzoyl)oxy)silver. A mixture of iodomethyl 4-(5-(2,4-¿>zXtrifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3,4-c ]pyrazol-3-yl)-7-fluoro-177-indole-l-carboxylate (0.30 g, 0.37 mmol) and the above ((4-formylbenzoyl)oxy)silver (0.14 g, 0.37 mmol) 55 mmol) in toluene (5 mL) was heated at 100 °C for 1 h. It was cooled to room temperature, poured into saturated aqueous NaHCCh solution and extracted with EtOAc. The organic layer was separated, dried in the presence of Na2SO4, concentrated under reduced pressure and purified by flash chromatography on silica gel (0 to 60 Λ EtOAc in hexanes) to obtain ((4-formylbenzoyl)oxy)methyl 4- (5-(2,4-6w(trifluoromethyl)benzyl)2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3- il)-7-fluoro-127-indole-lcarboxylate. MS: (ES) m / z calculated for C44H38F7N4O5 [M + H]+835.3, found 835.3. Step c: To a vial containing piperazine (0.150 g, 1.74 mmol) in dichloromethane (4 mL) at 0 °C was added acetic acid (3 mL), NaBH(OAc)3 (0.400 g, 1.88 mmol ) and ((4-formylbenzoyl)oxy)methyl 4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5, 6-tetrahydropyrrolo[3,4c]pyrazol-3-yl)-7-fluoro-17 / -indole-l-carboxylate (0.060 g, 0.071 mmol) in sequence. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0 C and quenched with 2 M HC1 solution in ether (2 mL, 4 mmol). The mixture was purified by flash chromatography on silica gel (0 to 100% MeOH in CH2C12). The pure fractions were combined, cooled to 0 °C, loaded with 2 M HC1 solution in ether (2 mL, 4 mmol), and concentrated under reduced pressure to form HC1 salt of ((4-(piperazin-lylmethyl) benzoyl)oxy)methyl 4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3-yl)-7-fluoro-177-indole-l-carboxylate.lH NMR (400 MHz, CD3ÜD)6 8.04-8.26 (m, 6H), 7.74-7.90 (m, 3H), 7.35 (dd, J= 7.2, 7.2 Hz, 1H), 7.16 (d, J= 7.2 Hz, 2H), 6.80-6.90 ( m, 2H), 6.66-6.74 (m, 1H), 6.27 (s, 2H), 4.80-5.00 (m, 2H), 4.58 (s, 2H), 4 .36 (br s, 1H), 3.63 (br s, 10H), 2.23 (br s, 4H), 2.03 (br s, 6H), 0.99 (t, J= 6.4 Hz, 6H); MS: (ES) m / z calculated for C48H48F7N6O4 [M + H]+905.3, found 905.3. 109 IF-2019-40565613-APN-ANP#INPI Page 109 of 183 Example 24: Synthesis of ((4-((phosphonooxy)methyl)benzoyl)oxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5 ,6,7-tetrahydro-2jff-pyrazolo[4,3-c]pyridin-3-yl)-6-fIuoro-7methoxy-lH-indole-l-carboxylate Step a: A mixture of iodomethyl 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4,5,6,7-tetrahydro-27 / -pyrazolo[4 ,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-177-indole-l-carboxylate (0.15 g, 0.20 mmol) and ((4-(((ów(benzyloxy) Phosphoryl)oxy)methyl)benzoyl)oxy)silver (0.11 g, 0.21 mmol) in toluene (4 mL) was heated at 110 °C for 1 h. The mixture was cooled to room temperature, poured into saturated aqueous NaHCCh solution and extracted with EtOAc. The organic layer was separated, dried in the presence of Na2SO4, concentrated under reduced pressure and purified by flash chromatography on silica gel (0 to 40% EtOAc in CH2CI2) to obtain ((4(((Z>z.s(benzyloxy )phosphoryl)oxy)methyl)benzoyl)oxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-277 -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-177-indole-l-carboxylate. MS: (ES) m / z calculated for C54H5oF4Nó09P[M + H] 1033.3, only parental MS fragment observed. 110 IF-2019-40565613-APN-ANP#INPI Page 110 of 183 Step b: A mixture of ((4-(((Z>w(benzyloxy)phosphoryl)oxy)methyl)benzoyl)oxy)methyl 4-(2-(2,6diethylphenyl)-5-(5-(trifluoromethyl)pyrimidine -2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)6-fluoro-7-methoxy-l / / -indol-l- carboxylate (0.08 g, 0.08 mmol), TFA (1 mL), dichloromethane (1 mL), and water (1 mL) was heated at 45 °C for 7 h. It was cooled to room temperature, concentrated under reduced pressure and purified by HPLC (MeCN / ftO, with 0.1% TFA) to obtain ((4-((phosphonooxy)methyl)benzoyl)oxy)methyl 4-(2 -(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl )-6-fluoro-7methoxy-UT-indole-l-carboxylate. Ή NMR (400 MHz, CDjOD)5 8.55 (s, 2H), 8.10 (d, J- 7.6 Hz, 2H), 7.78 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.32 (dd, J = 7.2 Hz, 1H), 7.15 (br s, 2H), 6.57-6.64 (m, 2H), 6, 28 (s, 2H), 5.08 (d, J= 7.6 Hz, 2H), 4.81 (br s, 2H), 4.36 (br s, 2H), 3.95 (s, 3H ), 3.25-3.34 (m, 2H), 2.92-3.00 (m, 2H), 2.20 (br s, 4H), 1.00 (br s, 6H); MS: (ES) m / z calculated for C40H38F4N6O9P [M + H]+853.2, found 853.0. 111 IF-2019-40565613-APN-ANP#INPI Page 111 of 183 Example 25: Synthesis of (glycyloxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin2-yl)-4,5,6,7-tetrahydro-2j7-pyrazolo[4 ,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-l / / -indole-lcarboxylate Step a: A mixture of iodomethyl 4-(2-(2,6-diethylphenii)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4,5,6,7-tetrahydro-2H-pyrazolo[4, 3-c]pyridin-3-yl)-6-fluoro-7-methoxy-17 / -indole-l-carboxylate (0.080 g, 0.10 mmol), (tert-butoxycarbonyl)glycine (0.056 g, 0.32 mmol) and diisopropylethylamine (0.088 mL, 0.53 mmol) in dichloromethane (3 mL) was heated at 45 °C for 1.5 h. Cooled to room temperature, concentrated under reduced pressure to obtain {{{tertbutoxycarbonyl)glycyl)oxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl) -4,5,6,7tetrahydro-277-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-l / f-indole-l-carboxylate. MS: (ES) m / z calculated for C39H42F4N7O7 [M + H]+796.3, found 796.3. Step b: A mixture of (((tert-butoxycarbonyl)glycyl)oxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6 ,7-tetrahydro-277-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-177-indole-l-carboxylate 0.10 mmol) and 4 M HC1 solution in dioxane (1, 5 mL, 6 mmol) 112 IF-2019-40565613-APN-ANP#INPI Page 112 of 183 in dichloromethane (3 mL) was stirred at room temperature for 1.5 h. The mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (0 to 100% EtOAc in hexanes followed by 0 to 80% MeOH in EtOAc). The pure fractions were combined, cooled to 0 °C, loaded with 2 M HC1 solution in ether (1 mL, 2 mmol), and concentrated under reduced pressure to form (glycyloxy)methyl 4-(2-(2, 6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-227-pyrazolo[4,3-c]pyridin-3-i!)-6-fluoro -7methoxy-177-indole-l-carboxylate as HC1 salt. Ή NMR (400 MHz, CDsODjó 8.59 (s, 2H), 7.78-7.83 (m, 1H), 7.34 (dd, J= 7.2, 7.2 Hz, 1H), 7.18 (br s, 2H), 6.60-6.68 (m, 2H), 6.17 (s, 2H), 4.83 (br s, 2H), 4.39 (br s, 2H), 4 .01 (br s, 2H), 3.97 (s, 3H), 2.96-3.03 (m, 2H), 2.26 (br s, 4H), 1.96-2.03 (m , 2H), 1.20-1.26 (m, 1H), 1.00 (br s, 6H); MS: (ES) m / z calculated for C34H34F4N7O5 [M + H]+696.2, found 696 ,2. Example 26: Synthesis of ((L-valyl)oxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro -2 / / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-lZf-indole-l-carboxylate 113 IF-2019-40565613-APN-ANP#INPI Page 113 of 183 Step a: A mixture of iodomethyl 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4,5,6,7-tetrahydro-2 / 7-pyrazolo[ 4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-l / f-indole-l-carboxylate (0.080 g, 0.10 mmol), (tert-butoxycarbonyl)-L-valine ( 0.07 g, 0.32 mmol) and diisopropylethylamine (0.09 mL, 0.53 mmol) in dichloromethane (3 mL). Stirred at room temperature for 2 h. Concentrated on a rotary evaporator under reduced pressure and purified. by flash chromatography on silica gel (0 to 60% EtOAc in hexanes) to obtain (((Zer-butoxycarbonyl)-Lvalyl)oxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5- (trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / 7pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-lH-indole-l -carboxylate; MS: (ES) m / z calculated for C42H48F4N7O7 [M + H]+838.4, found 838.8. Step b: A mixture of (((rer-butoxycarbonyl)-L-valyl)oxy)methyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4, 5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-l / T-indole-l-carboxylate (31 mg, 0.037 mmol) and Solution of 4 M HC1 in dioxane (0.5 mL, 2 mmol) in dichloromethane (0.5 mL) was stirred at room temperature for 1 h. It was concentrated under reduced pressure and purified by flash chromatography on silica gel (0 to 30% MeOH in CH2Cl2). The pure fractions were combined, cooled to 0 °C, loaded with 2 M HC1 solution in ether (0.5 mL, 2 mmol), and concentrated under reduced pressure to form ((Lvalyl)oxy)methyl 4-( 2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / 7pyrazolo[4,3-c]pyridin-3-yl )-6-fluoro-7-methoxy-l / 7-indole-l-carboxylate as HC1 salt. Ή NMR (400 MHz, CD3OD)5 8.60 (s, 2H), 7.81 (s, 1H), 7.36 (dd, J= 7.2, 7.2 Hz, 1H), 7.19 (br s, 2H), 6.62-6.72 (m, 2H), 6.24 (d, J= 5.6 Hz, 1H), 6.13 (d, 5.2 Hz, 1H), 5.49 (s, 1H), 4.82 (br s, 2H), 4.41 (br s, 2H), 4.10 (s, 1H), 3.98 (s, 3H), 3.01 (s, 2H), 1.80-2.60 (m, 5H), 0.60-1.40 (m, 14H); MS: (ES) m / z calculated for C37H40F4N7O5 [M + H]+738.3, found 738.2. Example 27: Synthesis of (glycyloxy)methyl 4-(5-(2,4-óís(trifluoromethyl)benzyl)-2-(2,6diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[ 3,4-c]pyrazol-3-yl)-7-fluoro-lZT-indole-lcarboxylate 114 IF-2019-40565613-APN-ANP#INPI Page 114 of 183 Step a: A mixture of iodomethyl 4-(5-(2,4-6w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6-tetrahydropyrrolo[3, 4-c]pyrazol-3-yl)-7-fluoro-l / / -indole-l-carboxylate (0.06 g, 0.07 mmol), (tert-butoxycarbonyl)glycine (0.04 g, 0.18 mmol) and diisopropylethylamine (0.08 mL, 0.48 mmol) in dichloromethane (1 mL) was stirred at 45 °C for 1.5 h. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain ((( / erbutoxycarbonyl)glycyl)oxy)methyl 4-(5-(2,4-6w(trifluoromethyl)benzyl)-2-(2,6- diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-177-indole-l-carboxylate. MS: (ES) m / z calculated for C43H45F7N5O6 [M + H]+860.3, found 860.3. Step b: A mixture of (((tert-butoxycarbonyl)glycyl)oxy)methyl 4-(5-(2,4-ów(trifluoromethyl)benzyl)2-(2,6-diethylphenyl)-6,6-dimethyl- 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-17 / -indole-lcarboxylate (~0.07 mmol) and 4 M HC1 solution in dioxane (1 mL, 4 mmol) in dioxane (2 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and purified by HPLC (MeCN / H2O, with 0.1% TFA) to form (glycyloxy)methyl 4-(5-(2,4ów(trifluoromethyl)benzyl)-2-(2 ,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-7-fluoro-l / f-indole-l-carboxylate as TFA salt. Ή NMR (400 MHz, CDCh)6 8.37 (d, J 115 IF-2019-40565613-APN-ANP#INPI Page 115 of 183 7.6 Hz, 1H), 7.88-7.94 (m, 2H), 7.59 (d, J= 4.0 Hz, 1H), 7.20-7.30 (m, 2H), 7.07 (d, J= 7.6 Hz, 2H), 6.58-6.70 (m, 3H), 5.96 (s, 2H), 4.50^1.70 (m, 2H) , 4.30 (br s, 2H), 3.79 (s, 2H), 2.19 (br s, 4H), 1.83-2.03 (m, 8H), 0.98 (t, J = 7.2 Hz, 6H); MS: (ES) m / z calculated for C38H37F7N5O4 [M + H]+760.3, found 760.1. Example 28: Synthesis of ((L-valyl)oxy)methyl 4-(5-(2,4-Z>zs(trifluoromethyl)benzyl)-2-(2,6diethylphenyl)-6,6-dimethyl-2,4 ,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-17 / -indole-lcarboxylate Step a: A mixture of iodomethyl 4-(5-(2,4-6w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6-tetrahydropyrrolo[3, 4-c]pyrazol-3-yl)-7-fluoro-l / / -indole-l-carboxylate (0.10 g, 0.12 mmol), (tert-butoxycarbonyl)-L-valine (0.08 g , 0.37 mmol) and diisopropylethylamine (0.10 mL, 0.61 mmol) in dichloromethane (3 mL) was stirred at 45 °C. After 2 h, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by flash chromatography on silica gel (0 to 50% EtOAc in hexanes) to obtain (((for-butoxycarbonyl)-Lvalyl) oxy)methyl 4-(5-(2,4-zs(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6 116 IF-2019-40565613-APN-ANP#INPI Page 116 of 183 tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-l / / -indole-l-carboxylate. MS: (ES) m / z calculated for C46H51F7N5O6 [Μ + Η]+902.3, found 902.3. Step b: To a solution of (((tert-butoxycarbonyl)-L-valyl)oxy)methyl 4-(5-(2,4¿w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6 ,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-7-fluoro-l / 7-indole-l-carboxylate (25 mg, 0.028 mmol) in dichloromethane (0 .3 mL) 4 M HC1 in dioxane (0.1 mL, 0.4 mmol) was added. The mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure to form ((L-valyl)oxy)methyl 4-(5-(2,4Z>w(trifluoromethyl)benzyl)-2-(2,6 -diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-7-fluoro-l / / -indole-l-carboxylate as HC1 salt. Ή NMR (400 MHz, CDCh)5 9.33 (s, 1H), 8.99 (s, 2H), 7.99-8.06 (m, 1H), 7.93 (s, 1H), 7 .72 (s, 1H), 7.10-7.30 (m, 3H), 6.97 (br s, 1H), 6.68-6.78 (m, 1H), 6.59-6, 66 (m, 1H), 6.16-6.22 (m, 1H), 5.90-5.98 (m, 1H), 4.69 (br s, 2H), 4.47 (br s, 1H), 4.03 (s, 1H), 3.60-3.90 (m, 3H), 1.70-2.60 (m, 10H), 0.75-1.34 (m, 12H) ; MS: (ES) m / z calculated for C41H43F7N5O4 [M + H]+802.3, found 802.2. Example 29: Synthesis of ((4-((dimethylamino)methyl)benzoyl)oxy)methyl 4-(5-(2,4ów(trifluoromethyl)-benzyl)-2-(2,6-diethylphenyl)-6,6- dimethyl-2,4,5,6-tetrahydropyrrolo[3,4c]pyrazol-3-yl)-7-fluoro-l / 7-indole-l-carboxylate A mixture of dimethylamine (0.40 mL, saturated in dichloromethane), HOAc (0.80 mL), ((4formylbenzoyl)oxy)methyl 4-(5-(2,4-áw(trifluoromethyl)benzyl)-2-( 2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-17 / -indole-l-carboxylate (0.080 g, 0.096 mmol) and NaBH(OAc)3 (0.200 g, 0.94 mmol) in dichloromethane was stirred at room temperature 117 IF-2019-40565613-APN-ANP#INPI Page 117 of 183 for 1 hour. The mixture was poured into saturated aqueous NaHCCL solution and extracted with EtOAc. The organic layer was separated, dried in the presence of Na2SC>4, concentrated under reduced pressure and purified by flash chromatography on silica gel (0 to 100% EtOAc in hexanes followed by 0 to 30% MeOH in EtOAc). to obtain ((4((dimethylamino)methyl)benzoyl)oxy)methyl 4-(5-(2,4-6íí(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)6,6-dimethyl-2, 4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-177-indole-l-carboxylate. Ή NMR (400 MHz, CDCh) 8.15 (d, J= 8.0 Hz, 1H), 8.03 (d, 7.2 Hz, 2H), 7.86 (s, 1H), 7.75 ( d, J= 8.0 Hz, 1H), 7.66 (m, 1H), 7.40 (d, J= 7.6 Hz, 2H), 7.25 (m, 1H), 7.07 ( d, J=l,6 Hz, 2H), 6.77 (m, 1H), 6.62 (m, 1H), 6.56 (m, 1H), 6.23 (s, 2H), 4, 12 (s, 2H), 3.63 (s, 2H), 3.47 (s, 2H), 2.23 (s, 6H), 2.10-2.40 (m, 4H), 1.55 (s, 6H), 1.01 (t, J = 7.4 Hz, 6H); MS: (ES) m / z calculated for C46H45F7N5O4 [M + H]+864.3, found 864.2. Example 30: Synthesis of ((dimethylglycyl)oxy)methyl 4-(5-(2,4-Z»»(trifluoromethyl)-benzyl)-2-(2,6diethylphenyl)-6,6-dimethyl-2,4, 5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-lZf-indole-lcarboxylate A mixture of iodomethyl 4-(5-(2,4-¿> / j(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3, 4-c]pyrazol-3-yl)-7-fluoro-l / f-indole-l-carboxylate (0.03 g, 0.04 mmol) and tetrabutylammonium dimethylglycinate (20 mg, 0.06 mmol) in THF (0.6 mL) was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and purified by HPLC (MeCN / H2O, with 1% HOAc) to form ((dimethylglycyl)oxy)methyl 4-(5-(2,4bis(trifluoromethyl)benzyl)-2-( 2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-7-fluoro-l / / -indole-l-carboxylate. Ή NMR (400 MHz, CDjODjó 8.21 (d, J = 8.4 Hz, 1H), 118 IF-2019-40565613-APN-ANP#INPI Page 118 of 183 7.91-7.96 (m, 2H), 7.80 (d, J= 4.0 Hz, 1H), 7.34 (dd, J= 7.6, 7.6 Hz, 1H), 7 .17 (d, J- 7.6 Hz, 2H), 6.81-6.87 (m, 1H), 6.65-6.72 (m, 2H), 6.12 (s, 2H), 4.23 (s, 2H), 4.17 (s, 2H), 3.69 (s, 2H), 2.90 (s, 6H), 2.17-2.36 (m, 4H), 1 .57 (s, 6H), 1.02 (t, J= 7.4 Hz, 6H); MS: (ES) m / z calculated for C40H41F7N5O4 [M + H]+788.3, ​​found 788.2. Example 31: Synthesis of ((dimethoxyphosphoryl)oxy)methyl 4-(5-(2,4- / >z\(trifluoromethyl)benzyl)-2(2,6-diethylphenyl)-6,6-dimethyl-2,4 ,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-iI)-7-fluoro-l / / -indole-lcarboxylate A mixture of iodomethyl 4-(5-(2,4-¿>w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3,4 -c]pyrazol-3-yl)-7-fluoro-l / / -indole-l-carboxylate (40 mg, 0.037 mmol) and tetrabutylammonium dimethylphosphate (30 mg, 0.08 mmol) in THF (6 mL) It was stirred at room temperature for 1.5 h. Once complete, the mixture was diluted with EtOAc, washed with brine, and dried in the presence of MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 20% EtOAc in hexanes) to form ((dimethoxyphosphoryl)oxy)methyl 4-(5-(2,4-¿>w (trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-l / / -indole-l-carboxylate. Ή NMR (400 MHz, CD3OD)5 8.13 (d, J= 8.2 Hz, 1H), 7.75-7.88 (m, 2H), 7.66-7.68 (m, 1H) , 7,237.27 (m, 1H), 7.07-7.09 (m, 2H), 6.77 (dd, J= 8.4, 11.8 Hz, 1H), 6.59-6.66 (m, 2H), 5.81 (d, J = 14.1 Hz, 2H), 4.12 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3 .70 (s, 2H), 2.14-2.38 (m, 4H), 1.56 (s, 6H), 1.02 (t, J= 7.6 Hz, 6H). MS: (ES) m / z calculated for C3sH39F7N4O6P [M + H]+811.2, found 811.2. 119 IF-2019-40565613-APN-ANP#INPI Page 119 of 183 Example 32: [4-[2-(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-4,5-dihydro-2Zfpyrazolo[4,3-c]pyridin-3- il]-6-fluoro-l / f-indol-l-yl]methanol A mixture of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-l / 7-indol-4-yl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4 ,5,6,7-tetrahydro-27 / -pyrazolo[4,3-c]pyridine (200 mg, 0.35 mmol), di-tert-butyl (chloromethyl) phosphate (183 mg, 0.35 mmol) and NaH (100 mg, 60% in mineral oil, 2.5 mmol) in DMF (5 mL) was stirred at room temperature for 2 h. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, dried in the presence of Na2SO4, concentrated under reduced pressure and purified by flash chromatography on silica gel (0 to 80% EtOAc in hexanes) to obtain (4-(2-(2.6 -diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-227-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy -l / / -indol-l-yl)methanol.'H NMR (400 MHz, CDCh)5 8.48 (s, 2H), 7.24 (dd, J = 7.2, 7.2 Hz, 1H ), 7.15 (d, J= 3.2 Hz, 1H), 7.00-7.10 (m, 2H), 6.44 (d, J= 12.8 Hz, 1H), 6.33 (d, J= 3.2 Hz, 1H), 5.59 (d, J= 8.0 Hz, 2H), 4.80 (s, 2H), 4.35 (s, 2H), 4.11 (d, J= 2.4 Hz, 3H), 3.71 (t, J= 8.2 Hz, 1H), 3.02 (t, J = 5.8 Hz, 2H), 2.30 (br s, 4H), 1.02 (br s, 6H). MS: (ES) m / z calculated for C31H31F4N6O2 [M + H]+595.2, found 595.5. Example 33: Synthesis of (4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro2 / Z-pyrazolo[4,3-c] pyridin-3-yl)-5-fluoro-l / 7-indol-7-yl)methyl glycinate hydrochloride 120 IF-2019-40565613-APN-ANP#INPI Page 120 of 183 A vial with DMF (3.0 mL) was loaded with (4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7tetrahydro-2ZApyrazolo[4, 3-c]pyridin-3-yl)-5-fluoro-17 / -indol-7-yl)methanol (100 mg, 0.18 mmol), (tert-butoxycarbonyl)glycine (61 mg, 0.35 mmol) , HATU (134 mg, 0.35 mmol) and diisopropylethylamine (68 mg, 0.52 mmol). The mixture was stirred at room temperature for 24 h. Once complete, the reaction was stopped with FhO and the crude product was purified by silica gel chromatography (10 to 50% EtOAc in hexanes) and concentrated in vacuo. The residue was then dissolved in dichloromethane (3.0 mL) and treated with 4 N HC1 in dioxane (2.0 mL) at room temperature for 2 h. After completion of the reaction, the solvent was removed and the residue was triturated with dichloromethane to obtain (4-(2-(2,6-diethylphenyl)-5-(4(trifluoromethyl)phenyl)-4,5,6, 7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-l / / -indol-7yl)methyl glycinate hydrochloride. Ή NMR (400 MHz, CD3OD) δ 11.07 (bs, 1H), 8.56 (bs, 2H), 7.47-7.50 (m, 1H), 7.19-7.26 (m, 2H), 6.91 (dd, J= 1.9, 3.1 Hz, 1H), 6.85 (d, J= 10.9 Hz 1H), 6.40-6.43 (m, 1H) , 5.53 (s, 2H), 4.90 (d, J= 16.1 Hz, 1H), 4.62 (d, J= 16.0 Hz, 1H), 4.42-4.50 ( m, 1H), 4.25-4.35 (m, 1H), 3.90 (s, 2H), 3.76 (s, 2H), 3.00 (t, J= 5.9 Hz, 2H ), 2.43-2.50 (m, 2H), 2.12-2.20 (m, 1H), 1.90 -1.98 (m, 1H), 1.22 (t, J= 7 .8 Hz, 3H), 0.73 (t, J= 7.4 Hz, 3H) MS: (ES) m / z calculated for C32H31F4N7O2 [M + H]+622.3, found 622.2. Example 34: Synthesis of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2H-pyrazolo[4,3- c]pyridin-3-yl)-5-fluoro-lH-indol-7-yl)methyl-L-valinate hydrochloride 121 IF-2019-40565613-APN-ANP#INPI Page 121 of 183 Step a: A vial with DMF (3.0 mL) was loaded with (4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-l / 7-indol-7-yl)methanol (100 mg, 0.18 mmol), (Zer-butoxycarbonyl)valine (77 mg, 0.35 mmol), HATU (134 mg, 0.35 mmol) and diisopropylethylamine (68 mg, 0.53 mmol). The reaction mixture was stirred at 50 °C for 24 h. Once complete, the mixture was quenched with FhO and the crude product was purified by silica gel chromatography (10 to 50% EtOAc in hexanes) and concentrated in vacuo to obtain (4-(2-(2,6-diethylphenyl )-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-277pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-177-indol- 7-yl)methyl(tert-butoxycarbonyl)-¿-valinate. MS: (ES) m / z calculated for C40H45F4N7O4 [M + H]+764.4, found 764.3. Step b: To a stirred solution of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4,5,6,7-tetrahydro-277-pyrazolo[ 4,3-c]pyridin-3-yl)-5-fluoro-l / Wndol-7-yl)methyl (tert-butoxycarbonyl)-L-valinate (60 mg, 0.08 mmol) in dichloromethane (5 mL) was added 4 N HC1 in dioxane (0.2 mL, 0.8 mmol). The resulting mixture was stirred at room temperature for 2 h. Once complete, the reaction mixture was diluted with water and saturated aqueous NaHCOj, 122 IF-2019-40565613-APN-ANP#INPI Page 122 of 183 extracted with dichloromethane, washed with brine, and dried in the presence of MgSCL. The solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN / HzO, with 0.1% TFA) to obtain the desired product. The material was converted to HC1 salt to obtain (4-(2(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2Z / - pyrazolo[4,3-c]pyridin3-yl)-5-fluoro-1 / 7-indol-7-yl)methyl-¿-valinate hydrochloride. Ή NMR (400 MHz, DMSO-ufe) δ 11.65 (bs, 1H), 8.61-8.72 (m, 2H), 8.42 (bs, 2H), 7.56 (bs, 1H) , 7.15-7.25 (m, 2H), 6.88-6.98 (m, 2H), 6.33 (s, 1H), 5.42-5.55 (m, 2H), 4 .74 (dd, J= 6.2, 15.2 Hz, 1H), 4.57 (d, J= 15.7 Hz, 1H), 4.35—4.45 (m, 1H), 4, 15^1.20 (m, 1H), 3.92^1.05 (m, 1H), 2.85-2.95 (m, 2H), 2.28-2.40 (m, 2H), 2.00-2.20 (m, 2H), 1.85-1.92 (m, 1H), 1.12 (t, J = 7.4 Hz, 3H), 0.83-0.90 ( m, 6H), 0.61-0.63 (m, 3H). MS: (ES) m / z calculated for C35H37F4N7O2 [M + H]+664.3, found 664.2. Example 35: Synthesis of 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2 / / -pyrazolo[4,3 -c]pyridin-3-yl)-5-fluoro-l / f-indol-7-yl)methyl (5)-2,5diaminopentanoate hydrochloride IF-2019-40565613-APN-ANP#INPI Page 123 of 183 Step a: A vial with DMF (3.0 mL) was loaded with (4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)4,5,6,7-tetrahydro- 2 / 7-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-l / / -indol-7-yl)methanol (110 mg, 0.19 mmol), 2,5-6z acid .y(tor-butoxycarbonylamino)pentanoic acid (96 mg, 0.29 mmol), HATU (149 mg, 0.39 mmol) and diisopropylethylamine (75 mg, 1.17 mmol). The reaction was stirred at room temperature for 24 h. Once complete, the mixture was quenched with H2O and the crude product was purified by silica gel chromatography (10 to 100% EtOAc in hexanes), concentrated, dried under vacuum to obtain 4-(2-(2,6- diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-177 -indol-7-yl)methyl (S)-2,5-bis((terbutoxycarbonyl)amino)pentanoate. MS: (ES) m / z calculated for C45H54F4N8O6 [M + H]+879.41, found 879.5. Step b: To a stirred solution of 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4,5,6,7-tetrahydro-2 / 7-pyrazolo [4,3-c]pyridin-3-yl)-5-fluoro-l / 7-indol-7-yl)methyl-(S)-2,5-Z>zX(tert-butoxycarbonyl)-amino)pentanoate (75 mg, 3.6 mmol) in dichloromethane (5 mL) was added 4 N HC1 in dioxane (0.18 mL, 0.68 mmol). The resulting mixture was stirred at room temperature for 2 h. Once complete, the reaction mixture was diluted with H2O and saturated aqueous NaHCCh, extracted with dichloromethane, washed with brine, and dried in the presence of MgSO4. The solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN / H2O, with 0.1% TFA) to obtain the desired product. The material was converted to HC1 salt to obtain (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H- pyrazolo[4,3c]pyridin-3-yl)-5-fluoro-l / / -indol-7-yl)methyl (5)-2,5-diaminopentanoate hydrochloride. Ή NMR (400 MHz, DMSO-íZó) δ 11.77 (bs, IH), 8.50-8.65 (m, 4H), 7.90-8.25 (m, 2H), 7.55 ( bs, IH), 7.15— 7.25 (m, 2H), 6.97 (dd, J= 1.9, 10.9 Hz, IH), 6.91 (d, J= 7.4 Hz IH), 6.34 (bs, IH), 5.35-5.54 (m, 2H), 4.73 (d, J= 15.7 Hz, IH), 4.56 (d, J= 16 .0 Hz, IH), 4.38-4.45 (m, 2H), 4.05-4.25 (m, 2H), 2.85-3.00 (m, 2H), 2.75- 2.80 (m, 2H), 2.31-2.40 (m, 2H), 1.95-2.10 (m, IH), 1.65-1.78 (m, 4H), 1, 12 (t, J = 7.4 Hz, 3H), 0.65 (t, J = 7.4 Hz, 3H), MS: (ES) m / z calculated for C35H38F4N8O2 [M + H]+679.3 , found 679.2. Example 36: Synthesis of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-22Z-pyrazolo[4,3- c]pyridin-3-yl)-5-fluoro-lZf-indol-7-yl)methyl L-lysinate hydrochloride 124 IF-2019-40565613-APN-ANP#INPI Page 124 of 183 Example 36 was prepared similarly to the procedure described in Example 35 using M / Ve-óAsfter-butoxycarbonylj-L-lysine and (4-(2-(2,6-diethylphenyl)-5-(4-( trifluoromethyl)phenyl)4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-l / Aindol-7-yl)methanol. Ή NMR (400 MHz, DMSO-¿6) δ 11.71 (bs, 1H), 8.50-8.75 (m, 4H), 7.89 (bs, 2H), 7.56 (t, J = 2.8 Hz 1H), 7.15-7.25 (m, 2H), 6.94 (d, J= 11.0 Hz, 1H), 6.91 (d, J= 7.1 Hz 1H ), 6.30-6.35 (m, 1H), 5.38 5.54 (m, 2H), 4.73 (d, J= 15.6 Hz, 1H), 4.57 (d, J = 15.7 Hz, 1H), 4.35-4.45 (m, 1H), 4.15-4.30 (m, 1H), 4.05-4.15 (m, 2H), 2, 85-3.00 (m, 2H), 2.65-2.75 (m, 2H), 2.30-2.42 (m, 2H), 2.002.15 (m, 1H), 1.75- 1.90 (m, 3H), 1.25-1.60 (m, 3H), 1.12 (t, <7= 7.4 Hz, 3H), 0.65 (t, J=7.4 Hz, 3H),MS: (ES) m / z calculated for C36H40F4N8O2 [M+H]+693.3, found 693.3. Example 37: Synthesis of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-27 / -pyrazolo[4,3 -c]pyridin-3-yl)-5-fluoro-l / 7-indol-7-yl)methyl 4-aminobutanoate hydrochloride 125 IF-2019-40565613-APN-ANP#INPI Page 125 of 183 Example 37 was prepared similarly to the procedure described in Example 35 using 4-((tert-butoxycarbonyl)amino)butanoic acid and (4-(2-(2,6-diethylphenyl)-5-(4( trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2Z / -pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-117-indol-7yl)methanol Ή NMR (400 MHz, DMSO-¿ / 6) δ 11.98 (s, 1H), 8.52-8.72 (m, 2H), 7.79 (bs, 2H), 7.52 (t, J= 3.1 Hz 1H), 7.14-7.30 (m, 2H), 6.91 (dd, J= 1.6, 7.4 Hz, 1H), 6.84 (d, J= 10.9 Hz, 1H ), 6.31 (dd, J= 1.9, 3.1 Hz, 1H), 5.27 (d, .7=3.1 Hz, 2H), 4.74 (d, J= 15.6 Hz, 1H), 4.57 (d, J = 15.6 Hz, 1H), 4.35-4.50 (m, 2H), 4.15-4.25 (m, 2H), 2.85 -3.00 (m, 2H), 2.76-2.84 (m, 2H), 2.31-2.40 (m, 2H), 2.0-2.15 (m, 1H), 1 .76-1.90 (m, 3H), 1.12 (t, J = 7.4 Hz, 3H), 0.65 (t, J= 7.5 Hz, 3H), MS: (ES) m / z calculated for C34H35F4N7O2 [M+H]+650.3, found 650.3. Example 38: Synthesis of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-27 / -pyrazolo[4,3 -c]pyridin-3-yl)-5-fluoro-lH-indol-7-yl)methyl-L-histidinate hydrochloride 126 IF-2019-40565613-APN-ANP#INPI Page 126 of 183 Example 38 was prepared similarly to the procedure described in Example 35 using (rer-butoxycarbonyl)-L-histidine and (4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl) phenyl)4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-l / Aindol-7-yl)methanol. Ή NMR (400 MHz, DMSO-í / ó) δ 11.76 (br s, 1H), 9.01 (d, J= 3.9 Hz 1H), 8.55-8.75 (m, 4H) , 7.55 (d, J= 2.8 Hz 1H), 7.48 (s, 1H), 7.15-7.25 (m, 2H), 6.90-6.98 (m, 2H) , 6.34 (bs, 1H), 5.37-5.54 (m, 2H), 4.75 (dd, J= 2.7, 15.6 Hz, 1H), 4.56 (d, J = 15.6 Hz, 1H), 4.35-4.45 (m, 2H), 4.15-4.25 (m, 1H), 3.25-3.35 (m, 2H), 2, 85-2.95 (m, 3H), 2.30-2.42 (m, 2H), 2.00-2.10 (m, 1H), 1.82-1.90 (m, 1H), 1.13 (t, J = 7.8 Hz, 3H), 0.65 (t, J = 7.8 Hz, 3H). MS: (ES) m / z calculated for C36H35F4N9O2 [M+H]+702.3, found 701.9. Example 39: Synthesis of (S)-3-amino-4-((4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5) acid hydrochloride ,6,7-tetrahydro-2Zf-pyrazolo[4,3-c]pyridin-3-yl)-5-fluorolJ7-indol-7-yl)methoxy)-4-oxobutanoic acid 127 IF-2019-40565613-APN-ANP#INPI Page 127 of 183 Example 39 was prepared similarly to the procedure described in Example 35 using (Sj-4-(yer-butoxy)-2-((Zer-butoxycarbonyl)amino)-4-oxobutanoic acid and (4-(2 -(2,6diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-5-fluorol / / -indol-7-yl)methanol. Ή NMR (400 MHz, DMSO-í / ó) δ 11.65 (bs, 1H), 8.60-8.75 (m, 2H), 8.46 ( bs, 3H), 7.52 (t, J= 2.9 Hz 1H), 7.15-7.25 (m, 2H), 6.90 (d, J= 7.8 Hz, 1H), 6 .87 (bs, 1H), 6.31 (bs, 1H), 5.25-5.40 (m, 2H), 4.57 (d, J= 15.7 Hz, 1H), 4.35- 4.45 (m, 1H), 4.15-4.30 (m, 2H), 3.53 (s, 2H), 2.99 (d, J= 5.5 Hz, 1H), 2.85 -2.92 (m, 2H), 2.30-2.38 (m, 2H), 2.00-2.15 (m, 1H), 1.82-1.90 (m, 1H), 1 .11 (t, J = 7.8 Hz, 3H), 0.65 (t, J = 7.8 Hz, 3H). MS: (ES) m / z calculated for C34H33F4N7O2 [M+H]+680, 3, found 680.1. 128 IF-2019-40565613-APN-ANP#INPI Page 128 of 183 Example 40: Synthesis of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7L-valylglycinate tetrahydro-2fl'- pyrazolo[43-c]pyridin-3-yl)-5-fluoro-ljH-indol-7-yl)methyl Step a: A vial with DMF (3.0 mL) was loaded with (4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)4,5,6,7-tetrahydro- 227-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-l / / -indol-7-yl)methanol (150 mg, 0.27 mmol), (tert-butoxycarbonyl)-L- valylglycine (145 mg, 0.53 mmol), EDCI (101 mg, 0.53 mmol), HOBT (61 mg, 0.39 mmol), and DIPEA (102 mg, 0.77 mmol). The mixture was stirred at 50 °C for 24 h. Once the reaction was complete, it was subjected to final workup, and the crude product was purified by silica gel chromatography (10 to 60% EtOAc in hexanes) to form (4-(2-(2,6-diethylphenyl)- 5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3c]pyridin-3-yl)-5-fluoro-177-indole-7- yl)methyl (tert-butoxycarbonyl)-L-valylglycinate. Step b: To a stirred solution of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4,5,6,7-tetrahydro-2 / / - pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-l / / -indol-7-yl)methyl-(tert-butoxycarbonyl)-L-valylglycinate (180 mg, 0.02 mmol) in dichloromethane ( 5 mL) was added 129 IF-2019-40565613-APN-ANP#INPI Page 129 of 183 solution of 4 N HC1 in dioxane (0.25 mL, 0.1 mmol). The resulting mixture was stirred at room temperature for 5 h. Once complete, the solvent was diluted with water and saturated aqueous NaHCCh, extracted with dichloromethane, washed with brine and dried in the presence of NazSO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (20-100% EtOAc / hexane) to obtain the desired product, which was converted to HC1 salt to obtain (4-(2-(2.6 -diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-l / / -indol-7-yl)methyl-L-valylglycinate hydrochloride. Ή NMR (400 MHz, DMSO-¿6) δ 11.58 (br s, 1H), 8.85 (br s, 1H), 8.60-8.75 (m, 2H), 8.09 (br s, 2H), 7.53 (t, J= 3.1 Hz 1H), 7.12-7.25 (m, 2H), 6.90 (d, J= 6 .3 Hz, 1H),6.86 (d, J= 10.9 Hz, 1H), 6.31 (t, J=2.8 Hz, 1H), 5.25-5.35 (m, 2H ), 4.72 (d, J= 15.9 Hz, 1H),4.57 (d, J= 16.3 Hz, 1H), 4.40-4.45 (m, 1H), 4.10 -4.25(m, 2H), 3.91 (dd, J= 5.1, 17.2 Hz, 1H),3.59 (t, J = 0.8 Hz, 1H), 2.85- 2.92 (m, 2H), 2.31-2.40 (m, 2H), 1.90-2.08 (m, 2H), 1.80-1.90 (m, 1H), 1, 12 (t, J = 7.8 Hz, 3H), 0.80-0.85 (m, 6H), 0.65 (t, J = 7.8 Hz, 3H), MS: (ES) m / z calculated for C37H40F4N8O3 [M+H]+721.3, found 721.3. Example 41: Synthesis of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2 / / -pyrazolo[4, 3-c]pyridin-3-yl)-5-fluoro-l / 7-indol-7-yl)methyl L-isoleucinate hydrochloride 130 IF-2019-40565613-APN-ANP#INPI Page 130 of 183 Example 41 was prepared similarly to the procedure described in Example 35 using (tert-butoxycarbonyl)-L-isoleucine and (4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl) phenyl)4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-l#-indol-7-yl)methanol. Ή NMR (400 MHz, DMSO-í / ó) δ 11.63 (br s, 1H), 8.60-8.75 (m, 2H), 8.42 (br s, 2H), 7.43- 7.60 (m, 1H), 7.14-7.25 (m, 2H), 6.85-6.95 (m, 2H), 6.30-6.35 (m, 1H), 5, 38-5.45 (m, 2H), 4.76 (dd, J= 5.8, 16.0 Hz, 1H), 4.56 (d, J= 15.7 Hz, 1H), 4.35 ^.45 (m, 1H), 4.15-4.20 (m, 1H), 3.98^.05 (m, 1H), 2.82-2.97 (m, 2H), 2.30 -2.42 (m, 3H), 2.00-2.10 (m, 1H), 1.80-1.90 (m, 2H), 1.25-1.35 (m, 1H), 1 .12 (t, J = 7.4 Hz, 3H), 0.72-0.85 (m, 6H), 0.65 (t, J = 7.4 Hz, 3H). MS: (ES) m / z calculated for C36H39F4N7O2 [M+H]+678.3, found 678.3. Example 42: Synthesis of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2Z / -pyrazolo[4,3 -c]pyridin-3-yl)-5-fluoro-1Z / -indol-7-yl)methyl L-alaninate hydrochloride 131 IF-2019-40565613-APN-ANP#INPI Page 131 of 183 Example 42 was prepared similarly to the procedure described in Example 35 using (for-butoxycarbonyl)-L-alanine and (4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl) phenyl)-4,5,6,7tetrahydro-277-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-17 / -indol-7-yl)methanol. Ή NMR (400 MHz, DMSO-í / ó) δ 11.62 (br s, 1H), 8.60-8.75 (m, 2H), 8.35 (br s, 2H), 7.56 ( t, J= 2.7 Hz, 1H), 7.127.25 (m, 2H), 6.85-6.95 (m, 2H), 6.30-6.35 (m, 1H), 5.35 -5.50 (m, 2H), 4.73 (d, J= 17.0 Hz, 1H), 4.56 (d, J = 15.76 Hz, 1H), 4.35-4.45 ( m, 1H), 4.15-4.22 (m, 2H), 2.85-2.95 (m, 2H), 2.25-2.40 (m, 2H), 2.00-2, 10 (m, 1H), 1.82 -1.90 (m, 1H), 1.38 (dd, J= 2.4, 7.5 Hz, 3H), 1.12 (t, J= 7, 8 Hz, 3H), 0.65 (dd, J = 7.2, 15.6 Hz, 3H). MS: (ES) m / z calculated for C33H33F4N7O2 [M+H]+636.3, found 636.2. Example 43: Synthesis of 4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2H-pyrazolo[4,3-c ]pyridin-3-yl)-5-fluoro-ltf-indol-7-yl)methyl-L-phenylalaninate hydrochloride 132 IF-2019-40565613-APN-ANP#INPI Page 132 of 183 Example 43 was prepared similarly to the procedure described in Example 35 using (Zer-butoxycarbonyl)-L-phenylalanine and (4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl) phenyl)4,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-l / / -indol-7-yl)methanol. Ή NMR (400 MHz, DMSO-íZó) δ 11.55 (br s, 1H), 8.60-8.75 (m, 2H), 8.45-8.52 (m, 2H), 7.52 -7.58 (m, 1H), 7.10-7.25 (m, 7H), 6.88-6.95 (m, 1H), 6.71 (dd, J= 11.4, 24, 3Hz, 1H), 6.30-6.38 (m, 1H), 5.35-5.45 (m, 2H), 4.73 (d, J = 15.9 Hz, 1H), 4.57 (d, J = 16.0 Hz, 1H), 4.35-4 .45 (m, 2H), 4.15-4.22 (m, 1H), 3.05-3.15 (m, 2H), 2.85-2.95 (m, 2H), 2.30-2.45 (m, 2H) ), 2.00-2.15 (m, 1H), 1.82-1.90 (m, 1H), 1.13 (t, J = 7.4 Hz, 3H), 0.64 (t, J = 7.8 Hz, 3H). MS: (ES) m / z calculated for C39H37F4N7O2 [M+H]+712.3, found 712.2. Example 44: Synthesis of (5)-2-amino-5-((4-(2-(2,6-diethylpheniI)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5) acid hydrochloride ,6,7-tetrahydro-2Zr-pyrazolo[4,3-c]pyridin-3-yl)-5-fluorolH-indol-7-yl)methoxy)-5-oxopentanoic 133 IF-2019-40565613-APN-ANP#INPI Page 133 of 183 Example 44 was prepared similarly to the procedure described in Example 35 using (Sj-5-( / er-butoxy)-4-((7er-butoxycarbonyl)amino)-5-oxopentanoic acid and (4-( 2-(2,6diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-5- fluoro17 / -indol-7-yl)methanol Ή NMR (400 MHz, DMSO-íZó) δ 11.61 (br s, 1H), 8.62-8.75 (m, 2H), 8.35-8 .45 (m, 3H), 7.52 (t, J= 2.7 Hz 1H), 7.12-7.25 (m, 2H), 6.90 (dd, J= 7.8, 11, 6 Hz, 1H), 6.84 (d, 11.0 Hz, 1H), 6.31 (q, J= 2.0 Hz, 1H), 5.23-5.31 (m, 2H), 4 .74 (d, J= 16.0 Hz, 1H), 4.57 (d, J= 16.0 Hz, 1H), 4.35^1.45 (m, 1H), 3.85-4.00 (m, 2H), 2.85-2.95 ( m, 2H), 2.45-2.65 (m, 2H), 2.25-2.40 (m, 2H), 1.85-2.10 (m, 3H), 1.80-1, 95 (m, 1H), 1.12 (t, J= 7.8 Hz, 3H), 0.64 (t, J= 7.8 Hz, 3H). MS: (ES) m / z calculated for C35H35F4N7O4 [M+H]+694.3, found 694.2. Example 45: Synthesis of acid (5)-2-acetamido-5-((4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6 ,7-tetrahydro-2ZT-pyrazolo[4,3-c]pyridin-3-yl)-5-fluorolJ / -indol-7-yl)methoxy)-5-oxopentanoic acid 134 IF-2019-40565613-APN-ANP#INPI Page 134 of 183 To a stirred solution of acid (5)-2-amino-5-((4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6 ,7-tetrahydro-227-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-l / 7indol-7-yl)methoxy)-5-oxopentanoic acid (70 mg, 0.113 mmol) in dichloromethane ( 3.0 mL) at room temperature, pyridine (27 mg, 0.4 mmol) and acetic anhydride (30 mg, 0.34 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. Once complete, the solvent was removed and the crude material was purified by HPLC (MeCN / PhO, with 0.1% TFA) to obtain the acid (S)-2-acetamido-5-((4-(2- (2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)- 5-fluoro-l / 7-indol-7-yl)methoxy)-5oxopentanoic acid. Ή NMR (400 MHz, DMSO-cfe) δ 11.53 (br s, 1H), 8.55—8.80 (m, 2H), 8.12 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 2.7 Hz, 1H), 7.15-7.25 (m, 2H), 6.91 (d, J= 7.5 Hz, 1H), 6.85 (d , J = 10.2 Hz, 1H), 6.31 (t,7 = 10.2 Hz, 1H), 5.25 (d,7=2.7 Hz, 2H), 4.75 (d, 7 =16.0 Hz, 1H), 4.58 (d, 7= 16.0 Hz, 1H), 4.37-4.45 (m, 1H), 4.18-4.25 (m, 2H) , 3.45-3.85 (m, 1H), 2.85-2.98 (m, 2H), 2.30-2.45 (m, 4H), 1.95-2.10 (m, 2H), 1.85-1.92 (m, 1H), 1.81 (s, 3H), 1.70-1.78 (m, 1H), 1.12 (t, 7= 7.8 Hz , 3H), 0.65 (t, 7 = 7.8 Hz, 3H), MS: (ES) m / z calculated for C37H37F4N7O5 [M+H]+736.3, found 736.2. Example 46: Synthesis of (S)-4-amino-5-((4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5) acid hydrochloride ,6,7-tetrahydro-2 / T-pyrazolo[4,3-c]pyridin-3-yl)-5-fluorolH-indol-7-yl)methoxy)-5-oxopentanoic 135 IF-2019-40565613-APN-ANP#INPI Page 135 of 183 Example 46 was prepared similarly to the procedure described in Example 35 using (S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid and (4-( 2-(2,6diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-5- fluorol / 7-indol-7-yl)methanol. Ή NMR (400 MHz, DMSO-¿6) δ 11.56 (br s, 1H), 8.60-8.75 (m, 2H), 8.30-8.45 (m, 2H), 7, 56 (t, J= 2.7 Hz 1H), 7.15-7.25 (m, 2H), 6.90-6.98 (m, 2H), 6.30-6.38 (m, 1H ), 5.36-5.52 (m, 2H), 4.74 (dd, J= 5.6, 16.0 Hz, 1H), 4.57 (d, 15.7 Hz, 1H), 4 .35-4.45 (m, 1H), 4.05-4.25 (m, 2H), 3.35^1.00 (m, 1H), 2.85-2.95 (m, 2H), 2.30-2.45 ( m, 4H), 1.95-2.10 (m, 3H), 1.83-1.95 (m, 1H), 1.12 (t, J= 7.8 Hz, 3H), 0.65 (dd, J = 7.5, 14.9 Hz, 3H), MS: (ES) m / z calculated for C35H35F4N7O4 [M+H]+694.3, found 694.2. Example 47: Synthesis of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-27 / -pyrazolo[4,3 -c]pyridin-3-yl)-5-fluoro-17 / -indol-7-yl)methyl glycyl-L-valinate hydrochloride 136 IF-2019-40565613-APN-ANP#INPI Page 136 of 183 Example 47 was prepared similarly to the procedure described in Example 40 using (yer-butoxycarbonyl)glycyl-L-valine and (4-(2-(2j6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl )4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-177-indol-7-yl)methanol. Ή NMR (400 MHz, DMSO-í / ó) δ 11.60 (br s, 1H), 8.60- 8.75 (m, 2H), 8.05 (br s, 2H), 7.55 ( br s, 1H), 7,147.25 (m, 2H), 6.90-6.95 (m, 1H), 6.86 (dd, J= 2.0, 11.0 Hz, 1H), 6, 32 (t, J= 2.3 Hz, 1H), 5.305.45 (m, 2H), 4.78 (d, 3.5 Hz, 1H), 4.74 (d, J = 3.1 Hz, 1H), 4.58 (d, J= 16.0 Hz, 2H), 4.354.45 (m, 2H), 4.15-4.25 (m, 1H), 3.55-3.70 (m , 2H), 2.85-2.96 (m, 2H), 2.30-2.45 (m, 2H), 2.00-2.10 (m, 2H), 1.83-1.90 (m, 1H), 1.12 (t, J= 7.5 Hz, 3H), 0.75-0.85 (m, 6H), 0.63 (t, J = 7.4 Hz, 3H) . MS: (ES) m / z calculated for C37H40F4N8O3 [M+H]+721.3, found 721.2. 137 IF-2019-40565613-APN-ANP#INPI Page 137 of 183 Example 48: Synthesis of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-27Z-pyrazolo[4,3- c]pyridin-3-yl)-5-fluoro-lH-indol-7-yl)methyl L-alanyl-L-alaninate hydrochloride Example 48 was prepared similarly to the procedure described in Example 40 using (zer-butoxycarbonyl)-L-alanyl-L-alanine and (4-(2-(2,6-diethylphenyl)-5-(4 (trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-l / Wndol-7yl)methanol. Ή NMR (400 MHz, DMSO-íZ6) δ 11.58 (br s, 1H), 8.50-8.95 (m, 3H), 8.10 (br s, 2H), 7.53 (br s , 1H), 7.12-7.25 (m, 2H), 6.90 (d, J= 7.5 Hz, 1H), 6.84 (dd, J= 6.0, 10.6 Hz, 1H), 6.31 (br s, 1H), 5.25-5.38 (m, 2H), 4.73 (d, J= 16.5 Hz, 1H), 4.57 (d, J= 16.0 Hz, 1H), 4.354;45 (m, 2H), 4.15-4.25 (m, 1H), 3.70-3.92 (m, 1H), 2.85-2.95 (m, 2H), 2.30-2.38 (m, 2H), 2.00-2.10 (m, 1H), 1.80-1.87 (m, 1H), 1.30 (t , J= 5.6 Hz, 3H), 1.10-1.18 (m, 6H), 0.60-0.66 (m, 3H). MS: (ES) m / z calculated for C36H38F4N8O3 [M+H]+707.3, found 707.2. 138 IF-2019-40565613-APN-ANP#INPI Page 138 of 183 Example 49: Synthesis of 4-(((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2tf-pyrazolo[ 4,3-c]pyridin-3-yl)-5-fluoro-ltf-indol-7-yl)methoxy)methyl)-5-methyl-l,3dioxol-2-one To a stirred solution of (4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2J7pyrazolo[4,3-c]pyridin- 3-yl)-5-fluoro-l / / -indol-7-yl)methanol (100 mg, 0.18 mmol) in dichloromethane (4.0 mL) at room temperature diisopropylethylamine (151 mg, 1.2 mmol) and 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one (150 mg, 0.78 mmol). The reaction was stirred at room temperature for 24 h. Once complete, the mixture was quenched with H2O and the crude product was purified by HPLC (MeCN / H2O, with 0.1% TFA) to obtain 4-(((4-(2(2,6-diethylphenyl) -5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin3-yl)-5-fluoro-17Wndol-7 -yl)methoxy)methyl)-5-methyl-l,3-dioxol-2-one. Ή NMR (400 MHz, CDCI3) δ 9.17 (br s, 1H), 8.47 (br s, 2H), 7.32-7.40 (m,lH), 7.10-7.35 ( m, 2H), 6.85 (d, J = 7.4 Hz, 1H), 6.63 (d, J = 10.5 Hz, 1H), 6.35-6.45 (m, 1H), 5.49 (d, J = 15.1 Hz, 1H), 5.29 (d, J = 15.5 Hz, 1H), 4.87 (dd, J= 4.3, 16.1 Hz, 1H ), 4.66 (dd, J= 6.0, 16.5 Hz, 1H), 4.38-4.45 (m, 1H), 4.25-4.35 (m, 1H), 3, 04 (t, J= 5.8 Hz, 1H), 2.38-2.55 (m, 2H), 2.35 (s, 3H), 2.11-2.25 (m, 2H), 1 .85-2.05 (m, 2H), 0.91-1.12 (m, 3H), 0.70-0.89 (m, 3H). MS: (ES) m / z calculated for C35H32F4N6O4 [M + H]+677.2, found 677.3. 139 IF-2019-40565613-APN-ANP#INPI Page 139 of 183 Example 50: Synthesis of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2H-pyrazolo[4,3- c]pyridin-3-yl)-5-fluoro-17f-indol-7-yl)methyl dihydrogen phosphate Step a: To a stirred solution of (4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7tetrahydro-27 / -pyrazolo[4,3- c]pyridin-3-yl)-5-fluoro-17 / -indol-7-yl)methanol (100 mg, 0.16 mmol) in dichloromethane (30 mL) at -20 °C PBr3 (95 mg, 0.32 mmol). The reaction mixture was allowed to warm to 0 °C and stirred for 2 h. After completion of the reaction, the solvent was removed in vacuo to obtain 3-(7-(bromomethyl)-5-fluoro-l / / -indol-4-yl)-2-(2,6-diethylphenyl)-5- (5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine which was used directly in the next step without further purification. Step b: To a stirred solution of 3-(7-(bromomethyl)-5-fluoro-177-indol-4-yl)-2-(2,6-diethylphenyl)5-(5-(trifluoromethyl)pyrimidin-2 -yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine (85 mg, 1.24 mmol) in THF (4 mL) tetrabutylammonium di-Zer-butyl phosphate was added (91 mg, 0.2 mmol). The 140 IF-2019-40565613-APN-ANP#INPI Page 140 of 183 reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (10 to 100% EtOAc in hexanes) to obtain di-tert-butyl-((4-(2-(2,6-diethylphenyl) -5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-l / / indol-7-yl)methyl)phosphate. MS: (ES) m / z calculated for C38H45F4N6O4P [M+H]+757.32, found 757.3. Step c: To a stirred solution of di-Zer-butyl-((4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7 -tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1 / 7indol-7-yl)methyl)phosphate (70 mg, 0.92 mmol) in anhydrous dichloromethane (15 mL) at 0 °C, TFA (52 mg, 0.46 mmol) was added dropwise over 5 min. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the solvent was removed in vacuo and the residue was purified by HPLC (MeCN / H2O, with 0.1% TFA) to obtain (4-(2-(2,6diethylphenyl)-5-(5 -(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin-3-yl)5-fluoro-l / f-indol-7 -yl)methyl dihydrogen phosphate. Ή NMR (400 MHz, CD3OD) δ 8.56 (br s, 2H), 7.43 (d,J= 3.2 Hz, 1H), 7.15-7.25 (m, 2H), 6, 90 (d, J= 5.9 Hz, 1H), 6.81 (d, J= 11.3 Hz, 1H), 6.37 (d, 7=3.1 Hz, 1H), 5.20- 5.30 (m, 2H), 4.91 (d, J= 16.1 Hz, 1H), 4.64 (d, J= 15.6 Hz, 1H), 4.42-4.50 (m , 1H), 4.30^1.37 (m, 1H), 2.98 (t, J= 5.1 Hz, 2H), 2.44 (q, J= 7.8 Hz, 2H), 2 .12-2.19 (m, 1H), 1.90-1.98 (m, 2H), 1.22 (t, 7= 7.4 Hz, 3H), 0.72 (t, J= 7 .4 Hz, 3H), MS: (ES) m / z calculated for C30H29F4N6O4P [M + H]+645.2, found 645.6. Example 51: Synthesis of ((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-27f-pyrazolo[4,3 -c]pyridin-3-yl)-5-fluoro-l / f-indol-7-yl)methoxy)methyl dihydrogen phosphate 141 IF-2019-40565613-APN-ANP#INPI Page 141 of 183 Step a: To a stirred solution of (4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7tetrahydro-2J7-pyrazolo[4,3-c ]pyridin-3-yl)-5-fluoro-l / / -indol-7-yl)methanol (140 mg, 0.25 mmol) in dichloromethane (4 mL) at room temperature diisopropylethylamine (77 mg, 0. 74 mmol) and ((chloromethoxy)methyl)benzene (77 mg, 0.49 mmol). The reaction mixture was warmed to 50 °C and stirred for 4 h. Once complete, the reaction mixture was cooled to room temperature. The mixture was diluted with water and saturated aqueous NaHCCh, extracted with dichloromethane, washed with brine and dried in the presence of Na2SÜ4· The solvent was extracted under reduced pressure and the residue was purified by silica gel chromatography (10 to 100 % EtOAc in hexanes) to obtain 3-(7-(((benzyloxy)methoxy)methyl)-5-fluoro-127-indol-4-yl)-2-(2,6diethylphenyl)-5-(5-( trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine. Ή NMR (400 MHz, CDCh) δ 8.82 (br s, 1H), 8.47 (br s, 2H), 7.32-7.40 (m, 4H), 7.12-7.25 ( m, 3H), 6.85 (d, J= 7.4 Hz, 1H), 6.63 (d, J= 10.5 Hz, 1H), 6.35 (t, J= 3.1 Hz, 1H), 4.85-4.98 (m, 142 IF-2019-40565613-APN-ANP#INPI Page 142 of 183 7H), 4.69 (d, J= 16.8 Hz, 1H), 4.65 (s, 2H), 4.40-4.50 (m, 1H), 4.25-4.35 (m , 1H), 3.0-3.12 (m, 1H), 2.45-2.60 (m, 2H), 2.15-2.25 (m, 1H), 1.85-2.05 (m, 1H), 1.12 (t, J = 7.4 Hz, 3H), 0.73 (t, J= 7.4 Hz, 3H). MS: (ES) m / z calculated for C38H36F4N6O2 [M+H]+685.74, found 685.5. Step b: To a stirred solution of 3-(7-(((benzyloxy)methoxy)methyl)-5-fluoro-l / / -indol-4-yl)-2(2,6-diethylphenyl)-5-( 5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridine (140 mg, 0.20 mmol) in dichloromethane (3 mL) trimethylsilyl iodide (0.5 mL, 0.51 mmol) was added. The reaction mixture was stirred for 2 h at room temperature. After completion of the reaction, the solvent was removed in vacuo to obtain 2-(2,6-diethylphenyl)-3-(5fluoro-7-((iodomethoxy)methyl)-l / / -indol-4-yl)-5 -(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2 / 7-pyrazolo[4,3-c]pyridine, which was used directly in the next step without further purification. Step c: To a stirred suspension of diisopropyl ethylamine salt of phosphonic acid (482 mg, 1.0 mmol) in MeCN (5 mL) and H2O (5 drops) was added 2-(2,6-diethylphenyl)-3 -(5-fluoro-7((iodomethoxy)methyl)-l / 7-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro- 2 / / pyrazolo[4,3-c]pyridine (140 mg, 0.19 mmol). The reaction mixture was stirred for 2 h at room temperature. After completion of the reaction, the solvent was removed in vacuo and the mixture was diluted with water and extracted with EtOAc. The solvent was extracted under reduced pressure and the residue was purified by HPLC (MeCN / H2O, with 0.1% NH4CO3) and lyophilized to obtain the ammonium salt of ((4-(2-(2,6-diethylphenyl )-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro27 / -pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-l / Aindol -7-yl)methoxy)methyl dihydrogen phosphate. The material was converted to sodium salt by dilution with MeCN (0.6 mL) / H2O (0.4 mL) and addition of 0.1 M NaOH (213 pL, 2 equiv.) and lyophilization to dryness to obtain the salt. ((4(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3c]pyridin) disodium -3-yl)-5-fluoro-l / / -indol-7-yl)methoxy)methyl dihydrogen phosphate. Ή NMR (400 MHz, D2O) δ 8.07 (br s, 2H), 7.37 (br s, 1H), 7.07-7.15 (m, 2H), 6.79 (d, J= 6.6 Hz, 1H), 6.21 (br s, 2H), 4.87—4.95 (m, 2H), 4.76 (d, J= 11.3 Hz, 1H), 4.15 -4.25 (m, 2H), 3.60-3.85 (m, 2H), 2.79 (br s, 2H), 2.00-2.25 (m, 4H), 1.65- 1.85 (m, 2H), 0.93 (t, J= 7.4 Hz, 3H), 0.35-0.50 (m, 3H), MS: (ES) m / z calculated for C31H31F4N6O5P [ M + H]+675.2, found 675.7. 143 IF-2019-40565613-APN-ANP#INPI Page 143 of 183 Example 52: Synthesis of 4-((4-(5-(2,4-6w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[ 3,4-c]pyrazol-3-yl)-7-fluoro-lZf-indol-l-yl)methyl)-5-methyl-l,3-dioxol2-one LiHMDS THF Step a: To a stirred solution of 4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6-tetrahydropyrrolo[3 ,4-c]pyrazol-3-yl)-7-fluoro-l / / -indole (400 mg, 0.64 mmol) in THF (10 mL) 1 M LiHMDS solution in THF (1 mL, 1 mmol) at -78 °C. After stirring for 30 min, a solution of 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one (113 mg, 0.76 mmol) in THF (3 mL) was added at −78° c. The mixture was warmed to room temperature and stirred for 3 h. Once complete, saturated NH4Cl solution was added, and the mixture was extracted with EtOAc. The organic layers were combined, dried in the presence of Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (10 to 30% EtOAc in hexanes) to obtain 4-((4-(5-(2,4-&w(trifluoromethyl)benzyl)-2-(2, 6diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-l / / -indol-l-yl)methyl)5- methyl-l,3-dioxol-2-one. Ή NMR (400 MHz, DMSO-¿6) δ 8.16 (d, J= 8.2 Hz, 1H), 8.01 (d,J = 8.2 Hz, 1H), 7.97 (br s , 1H), 7.82 (d, J= 3.5 Hz, 1H), 7.28 (t, J= 7.8 Hz, 1H), 7.13 (d, J= 8.1 Hz, 1H ), 7.08 (d, J= 7.0 Hz, 1H), 6.84 (dd, J= 8.06, 13.7 Hz, 1H), 6.54 (dd, J= 2.8, 3.6 Hz, 1H), 6.45 (dd, J= 4.3, 8.2 Hz, 1H), 4.99 (d, J= 4.7 Hz, 1H), 4.45 (d, J= 4.7 Hz, 1H), 4.15 (br s, 2H), 3.61 (q, J= 3.5 Hz, 1H), 2.33 (s, 3H), 2.20-2 .25 (m, 2H), 2.05-2.15 (m, 2H), 1.85-2.05 (m, 1H), 1.47 (s, 6H), 0.90 (t, J = 7.4 Hz, 3H), 0.85 (t, J= 7.4 Hz, 3H), MS: (ES) m / z calculated for C39H35F7N4O3 [M+H]+741.3, found 741.2 . 144 IF-2019-40565613-APN-ANP#INPI Page 144 of 183 Example 53: Synthesis of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 4-(5-(2,4bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)- 2,4,5,6-tetrahydro-6,6-dimethylpyrrolo[3,4c|pyrazol-3-yl)-7-fluoro-l / / -indole-l-carboxylate To a 50 mL round bottom flask charged with 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one (0.5 g, 3.84 mmol) in anhydrous dichloromethane (6 mL) a - At 40 °C, triethylamine (0.77 g, 7.62 mmol) was added followed by triphosgene (0.88 g, 4.58 mmol) dropwise over 5 min. The reaction mixture was stirred at −40 °C for 1 h then warmed to room temperature for 1 h. Once complete, the reaction mixture was diluted with H2O and extracted with dichloromethane. The combined organic layers were dried in the presence of Na2SO4, filtered, and concentrated in vacuo to obtain (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl carbonhydrochloride which was used directly in the next step. without additional purification. Example 53 was prepared similarly to the procedure described in Example 52 using (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl-carbon hydrochloride and 4-(5-(2,4 zs(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-7-fluoro- l / / -indol. Ή NMR (400 MHz, CD3OD) δ 8.22 (d, J= 6.6 Hz, 1H), 7.90-7.97 (m, 2H), 7.81 (br s, 1H), 7, 34 (t, J= 7.4 Hz, 1H), 7.16 (d, J= 7.4 Hz, 2H), 6.83 (t, J= 8.6 Hz, 1H), 6.60- 6.75 (m, 2H), 5.24 (s, 2H), 4.23 (br s, 2H), 3.71 (s, 2H), 2.25-2.38 (m, 4H), 2.24 (s, 3H), 1.57 (s, 6H), 1.03 (t, J= 7.4 Hz, 6H). MS: (ES) m / z calculated for C40H35F7N4O5 [M+H]+785.2, found 785.1. 145 IF-2019-40565613-APN-ANP#INPI Page 145 of 183 Example 54: Synthesis of 4-((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2 / / -pyrazolo [4,3-c|pyridin-3-yl)-6-fluoro-7-methoxy-177-indol-l-yl)methyl)-5-methyll,3-dioxol-2-one Example 54 was prepared similarly to the procedure described in Example 52 using 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one and 2-(2,6-diethylphenyl)-3- (6-fluoro-7-methoxy-l / A indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[ 4,3-c]pyridine Ή NMR (400 MHz, CD3OD) δ 8.70 (br s, 2H), 7.86 (s, 1H), 7.28 (t, J= 6.9 Hz, 1H) , 6.59 (br s, 1H), 6.40 (d, J= 13.3 Hz, 1H), 5.02 (br s, 2H), 4.78 (br s, 2H), 4.25 ^1.60 (m, 2H), 3.79 (s, 3H), 3.30 (br s, 2H), 2.89 (br s, 2H), 2.47 (s, 3H), 2, 36 (br s, 4H), 0.67-1.12 (m, 6H). MS: (ES) m / z calculated for C35H32F4N6O4 [M+H]+677.24, found 677.2. · Example 55: Synthesis of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl )-4,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-l / T-indole-l-carboxylate Page 146 of 183 Example 55 was prepared similarly to the procedure described in Example 52 using (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl chloroformate and 2-(2,6-diethylphenyl)- 3-(6-fluoro-7methoxy-l / 7-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo [4,3c]pyridine. *H NMR (400 MHz, CD3OD) δ 8.58 (br s, 2H), 7.78 (d, 7—1.2 Hz, 1H), 7.32 (t, 7 — 1.2 Hz, 1H ), 7.15-7.22 (m, 2H), 6.50-6.65 (m, 2H), 5.28 (s, 2H), 4>38 (br s, 2H), 3.95 (s, 3H), 2.97 (br s, 2H), 2.30-2.40 (m, 6H), 2.26 (s, 3H), 0.98-1.25 (m, 6H) . MS: (ES) m / z calculated for C36H32F4N6O6 [M+H]+721.23, found 721.2. Example 56: Synthesis of 4-((4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-2,4,5,6tetrahydro-6,6-dimethylpyrrolo[ 3,4-c]pyrazol-3-yl)-7-fluoro-17 / -indole-lcarboxyloxy)methyl)phenyl dihydrogen phosphate Step a: To a 50 mL round bottom flask loaded with anhydrous 4-(hydroxymethyl)phenol (0.27 g, 1.73 mmol), triethylamine (0.27 g, 1.73 mmol), and dichloromethane (6 mL) at 0 °C, diethylphosphoryl chloride (0.54 g, 4.32 mmol) was added dropwise over 5 min. The reaction mixture was stirred at 147 IF-2019-40565613-APN-ANP#INPI Page 147 of 183 room temperature for 16 hours. Once complete, the mixture was extracted with EtOAc. The organic layers were combined, dried in the presence of Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (85 to 80% EtOAc in hexanes) to form diethyl 4-(hydroxymethyl)-phenyl phosphate. To a stirred solution of diethyl 4-(hydroxymethyl)phenyl phosphate (0.27 g, 1.73 mmol) and triethylamine in anhydrous dichloromethane (10 mL) at 0 °C was added triphosgene (0.54 g, 4.32 mmol ) slowly in 5 min. The reaction mixture was stirred at room temperature for 1 h. Once complete, the reaction mixture was diluted with H2O and extracted with dichloromethane. The combined organic layers were dried in the presence of Na2SO4, filtered, and concentrated in vacuo to obtain 4-((diethoxyphosphoryl)oxy)benzyl carbonhydrochloride which was used directly in the next step without further purification. To a solution of 4-(5-(2,4-6w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-2,4,5,6-tetrahydro-6,6dimethylpyrrolo[3,4-c ]pyrazol-3-yl)-7-fluoro-l / / -indole (150 mg, 0.23 mmol) in THF (4 mL) 1 M LiHMDS solution in THF (0.38 mL, 0.38 mmol) was added. at —78°C. After stirring for 30 min, a solution of 4-((diethoxyphosphoryl)oxy)benzyl carbonhydrochloride (153 mg, 0.47 mmol) in THF (2 mL) was added at −78 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. Once complete, saturated aqueous NH4CI solution was added and extracted with EtOAc. The organic layers were combined, dried in the presence of Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (10 to 60% EtOAc in hexanes) to obtain 4-((diethoxyphosphoryl)oxy)benzyl-4-(5(2,4-6w(trifluoromethyl)benzyl)- 2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4c]pyrazol-3-yl)-7-fluoro-l / f-indole-l-carboxylate . MS: (ES) m / z calculated for C46H46F7N4O6P [M+H]+915.3, found 915.3. Step b: To a stirred solution of 4-((diethoxyphosphoryl)oxy)benzyl-4-(5-(2,4¿>Xtrifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl- 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-7-fluoro-17 / -indole-l-carboxylate (100 mg, 0.11 mmol) in dichloromethane (2.5 mL) Bromotrimethylsilane (83 mg, 0.55 mmol) was added at room temperature for 8 h. Once complete, the mixture was concentrated to dryness and purified by HPLC (MeCN / H2O, with 0.1% TFA) to obtain 4-(phosphonooxy)benzyl-4-(5-(2,4-¿>w (trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6 148 IF-2019-40565613-APN-ANP#INPI Page 148 of 183 dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-lJ / -indole-l-carboxylate. Ή NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 8.06 (s, 2H), 7.82 (d, J= 3.5 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.35 (t, J= 7.8 Hz, 1H), 7.22(d, J= 7.9 Hz, 2H), 7.16 (d, J= 7 .8 Hz, 2H), 6.83 (dd, J= 8.2, 12.1 Hz, 1H), 6.65-6.75 (m, 2H), 5.40 (s, 2H), 4 .72 (br s, 2H), 4.50 (br s, 2H), 2.15-2.30 (m, 4H), 1.93 (s, 6H), 0.99 (t, J= 7 .4 Hz, 6H) MS: (ES) m / z calculated for C42H38F7N4O6P [M+H]+859.24, found 859.2. Example 57: Synthesis of 4-(phosphonooxy)benzyl-4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro- 2 / 7-pyrazolo|4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-lHindole-l-carboxylate Step a: To a solution of 4-hydroxybenzaldehyde (3.0 g, 24.5 mmol) in 100 mL of THF was added a 1.0 M solution of rBuOK in THF (27.04 mL, 27.04 mmol). The mixture was heated to 149 IF-2019-40565613-APN-ANP#INPI Page 149 of 183 °C and tetrabenzyl phosphate (14.5 g, 26.95 mmol) was added. After 1 h at 70 C, hexanes were added to the mixture and the contents were filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to produce dibenzyl (4-formylphenyl)phosphate. MS: (ES) m / z calculated for C21H19O5P [M + H]+383.1, found 383.2. To a solution of dibenzyl (4-formylphenyl)phosphate (3.5 g, 9.16 mmol) in 50 mL of THF at -78 C was added NaBH4 (0.65 g, 18.3 mmol). After stirring at room temperature for 2 h, the mixture was quenched with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on a silica gel column (0 to 100% EtOAc in hexanes) to provide dibenzyl-4-(hydroxymethyl)phenyl)phosphate. MS: (ES) m / z calculated for C21H21O5P [M + H]+385, found 385.1. To a solution of dibenzyl-4-(hydroxymethyl)phenyl)phosphate (3.56 g, 9.24 mmol) in 30 mL of THF at 0 °C was added diisopropylethylamine (2.98, 23.1 mmol) and triphosgene ( 3.0 g, 10.1 mmol). After stirring at 0 °C for 1 h, the reaction was stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to form the crude chloroformate. To a solution of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-l / / -indol-4-yl)-5-(5(trifluoromethyl)pyrimidin-2-yl)- 4,5,6,7-tetrahydro-2 / f-pyrazolo[4,3-c]pyridine (250 mg, 0.442 mmol) in 1.2 mL of THF at 0 °C, NaH (26 mg, 1, 05 mmol). After stirring at 0 °C for 30 min, a solution of the crude chloroformate formed above (247 mg, 0.553 mmol) in THF (2 mL) was added to the mixture. The solution was stirred at 0 °C for 1 hour; then stopped with H2O. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 50% EtOAc in hexanes) to obtain 4-((¿>zs(benzyloxy)phosphoryl)oxy)benzyl 4-(2-(2,6diethylphenyl)- 5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin-3-yl)6-fluoro-7-methoxy -177-indole-l-carboxylate. 150 IF-2019-40565613-APN-ANP#INPI Page 150 of 183 Step b: To a solution of 4-((ori(benzyloxy)phosphoryl)oxy)benzyl 4-(2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4 ,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-l / 7-indol-l-carboxylate (150 mg, 0, 15 mmol) in 7 mL of THF, 10% Pd / C (50 mg) was added. The mixture was stirred under a balloon of H2 for 1 h, then filtered through Celite, concentrated and purified by HPLC (MeCN / H2O, with 0.1% TFA) to obtain 4(phosphonooxy)benzyl 4-( 2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro2 / 7-pyrazolo[4,3-c]pyridin-3-yl )-6-fluoro-7-methoxy-l / / -indole-l-carboxylate. Ή NMR (400 MHz, DMSO-í / ó) δ 7.90 (br s, 1H), 6.99 (d, J = 3.5 Hz, 1H), 6.20-6.60 (m, 10H ), 5.80 (d, J = 3.5 Hz, 1H), 5.69 (d, J= 12.5 Hz, 1H), 4.53 (s, 2H), 3.94 (br s, 2H), 3.48 (br s, 2H), 3.0 (s, 3H), 2.08 (br s, 2H), 1.68-1.95 (m, 2H), 0.98-1 .45 (m, 6H), MS: (ES) m / z calculated for C38H35F4N6O7P [M + H]+795.22, found 795.2. Example 58: Synthesis of 2-(4-(4-(5-(2,4- / ns(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-2,4,5,6tetrahydro-6,6 -dimethylpyrrolo-[3,4-c]pyrazol-3-yl)-7-fluoro-lZf-indol-l-yl)-2-methyl-4oxobutan-2-yl)-3,5-dimethylphenyl dihydrogen phosphate To a solution of 3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoic acid (1.0 g, 2.07 mmol) in anhydrous dichloromethane (10 mL) added diisopropylethylamine followed by isobutyl chloroformate (298 mg, 2.49 mmol) in dichloromethane (10 mL) at 0 °C dropwise over 5 min. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with H2O and extracted with dichloromethane. The combined organic layers were dried in the presence of Na2SO4, filtered, and concentrated in 151 IF-2019-40565613-APN-ANP#INPI Page 151 of 183 vacuum to obtain 3-(2-((ózXbenzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3methylbutanoic anhydride (isobutyl carbonic acid), which was used directly in the next step without further purification. To a solution of 4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4 -c]pyrazol-3-yl)-7-fluoro-17 / -indole (400 mg, 0.63 mmol) in THF (10 mL) 1M LiHMDS solution in THF (1.01 mL, 1.01 mmol) at -78 C. After stirring for 30 min, a solution of 3-(2-((ozXbenzyloxy)phosphoryl)oxy)-4,6dimethylphenyl)-3-methylbutanoic (isobutyl carbonic) anhydride (0.46 g, 0.8 mmol) in THF (5 mL) at −78 °C and stirred for 1 h. The mixture was warmed to room temperature and stirred for 2 h. Once complete, saturated aqueous NH4Cl solution was added, and the mixture was extracted with EtOAc. The organic layers were combined, dried in the presence of Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (10 to 60% EtOAc in hexanes) to obtain dibenzyl (2-(4-(4-(5-(2,4-6w(trifluoromethyl)benzyl))-2 -(2,6diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-l / / -indol-l-yl) -2methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl)phosphate. To a solution of the resulting phosphate (270 mg, 0.25 mmol) in ethanol (10 mL) was added 10% Pd / C (200 mg) at room temperature. The resulting mixture was stirred under a hydrogen atmosphere (balloon) for 1 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain 2-(4-(4-(5-(2,46zXtrifluoromethyl)benzyl)-2-(2,6-diethylphenyl)- 6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-7-fluoro-l / / -indol-l-yl)-2-methyl-4-oxobutan- 2-yl)-3,5-dimethylphenyl dihydrogen phosphate. Ή NMR (400 MHz, DMSO-¿¿) δ 12.22 (br s, IH), 8.47 (d, J= 8.2 Hz, IH), 8.35 (d, J = 7.4 Hz , IH), 8.30 (s, IH), 8.23 ​​(s, IH), 7.62 (t, J= 8.2 Hz, IH), 7.44 (d, J= 7.0 Hz , 2H), 7.32 (br s, IH), 7.15 (t, J= 10.9 Hz, IH), 6.82-6.95 (m, 3H), 4.49 (br s, 2H), 3.85-4.05 (m, 4H), 3.66 (br s, IH), 2.72 (s, 3H), 2.42-2.60 (m, 4H), 2, 38 (s, 3H), 1.90 (s, 4H), 1.80 (s, 6H), 1.23 (t, J = 7.4 Hz, 6H). MS: (ES) m / z calculated for C47H48F7N4O5P [M+H]+913.3, found 913.3. Example 59: Synthesis of 2-(4-(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4,5,6,7-tetrahydro-2ZT- pyrazolo-[4,3-c]pyridin-3-yl)-7-fluoro-lfyr-indol-l-yl)-2-methyl-4oxobutan-2-yl)-3,5-dimethylphenyl dihydrogen phosphate 152 IF-2019-40565613-APN-ANP#INPI Page 152 of 183 To a solution of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-l / 7-indol-4-yl)-5-(5(trifluoromethyl)pyrimidin-2-yl)- 4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine (150 mg, 0.27 mmol) in THF (5 mL) was added 1M LiHMDS in THF (0.43 mL, 0.43 mmol) at -78 °C. After stirring for 30 min, a solution of 3-(2-((Zn5(benzyloxy)phosphoryl)oxy)-4,6dimethylphenyl)-3-methylbutanoic (isobutylcarbonic) anhydride (193 mg, 0.33 mmol) in THF (2.5 mL) was added at −78 °C and stirred for 1 h. The mixture was warmed to room temperature and stirred for 2 h. Once complete, saturated NH4CI solution was added, and the mixture was extracted with EtOAc. The organic layers were combined, dried in the presence of Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (10 to 40% EtOAc in hexanes) to obtain dibenzyl (2-(4-(4-(2-(2,6-diethylphenyl))-5-(5( trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-177-indol-l- yl)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl)phosphate. To a solution of the resulting phosphate (120 mg, 0.12 mmol) in ethanol (5 mL) was added 10% Pd / C (100 mg) at room temperature. The resulting mixture was stirred under a hydrogen atmosphere (balloon) for 1 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain 2-(4-(4-(2-(2,6-diethylphenyl)5-(5-(trifluoromethyl)pyrimidin-2 -yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7methoxy-lZ / -indol-l-yl)-2 -methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl dihydrogen phosphate. Ή NMR (400 MHz, DMSO-í / ó) δ 8.74 (br s, 2H), 7.89 (d, 7 = 1.2 Hz, 1H), 7.30-7.38 (m, 1H ), 7.21 (br s, 2H), 7.07 (d, 7= 6.2 Hz, 2H), 6.96 (s, 1H), 6.64 (s, 1H), 6.54 ( s, 1H), 6.46-6.50 (m, 2H), 4.76 (bs, 2H), 4.25-4.45 (m, 2H), 3.72 (s, 6H), 2 .91 (br s, 2H), 2.46 (br s, 5H), 2.14 (s, 3H), 1.65-2.05 153 IF-2019-40565613-APN-ANP#INPI Page 153 of 183 (m, 4H), 0.80-1.20 (m, 6H). MS: (ES) m / z calculated for C43H45F4N6O6P [M+H]+849.31, found 849.2. Example 60: Synthesis of (4-phosphonoxyphenyl)methyl 7V-((4-(5-((2,4-ów(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl -4Z7-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate Step a: To a solution of dibenzyl-4-(hydroxymethyl)phenyl)phosphate (3.56 g, 9.24 mmol) in 2.4 mL of THF at 0 °C was added diisopropylethylamine (2.98, 23.1 mmol) and triphosgene (3.0 g, 10.1 mmol). After stirring at 0 °C for 1 h, NH4OH (5.0 mL, 41 mmol) was added. The mixture was stirred at room temperature for 16 h then concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (20 to 80% EtOAc in hexanes) to obtain 4-((ózXbenzyloxy)phosphoryl)oxy )benzyl carbamate. MS: (ES) m / z calculated for C22H22NO6P [M + H]+428.1, found 428.1. 154 IF-2019-40565613-APN-ANP#INPI Page 154 of 183 To a solution of 4-((á¿s(benzyloxy)phosphoryl)oxy)benzyl carbamate (700 mg, 1.63 mmol) in dichloromethane (12 mL) at 0 °C was added oxalyl chloride (0.3 g, 2 .45 mmol). After stirring at 0 °C for 1 h, the mixture was heated to 50 °C for 16 h; then concentrated in vacuo. The residue was dissolved in THF (2 mL) and added to a solution of 4-(5-(2,4¿>w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl -2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)-2,5-difluoroaniline (150 mg, 0.16 mmol) in THF (2 mL). The mixture was stirred at room temperature for 5 hours; then concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to obtain (4-dibenzyloxyphosphoryloxy-3-phenyl)methyl W((4-(5-((2,4-ori(trifluoromethyl) phenyl)methyl)-2-(2,6diethylphenyl)-6,6-dimethyl-4Z / -pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate. Step b: To a solution of 4-dibenzyloxyphosphoryloxy-3-phenyl)methylV-((4-(5-((2,4¿>w(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)- 6,6-dimethyl-4 / / -pyrrolo[3,4-c]pyrazol-3-yl)-2,5difluorophenyl)carbamoyl)carbamate (150 mg, 0.14 mmol) in dichloromethane (2 mL) was added to drops a 1:1 mixture of TFA:CH2C12(2 mL) and H2O (0.4 mL). The mixture was heated at 50 °C for 48 h, then concentrated in vacuo. The residue was purified on HPLC (MeCN / H2O, with 0.1% TFA) to form (4-phosphonoxyphenyl)methyl jV-((4-(5-((2,4-6w(trifluoromethyl)phenyl)methyl) 2-(2,6-diethylphenyl)-6,6-dimethyl-4Z / -pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate. Ή NMR (400 MHz, DMSO-cfe) δ 10.78 (s, 1H), 10.15 (s, 1H), 8.14 (d, J= 8.4 Hz, 1H), 7.95-8 .08 (m, 3H), 7.35-7.45 (m, 3H), 7.08-7.25 (m, 4H), 6.53 (dd, J= 6.7, 11.7 Hz , 1H), 5.11 (s, 2H), 4.12 (br s, 2H), 3.65 (br s, 2H), 2.05-2.25 (m, 4H), 1.43 ( s, 6H), 0.96 (t, J = 7.4 Hz, 6H). MS: (ES) m / z calculated for C41H38F8N5O7P [M + H]+896.2, found 896.2. Example 61: 4-(benzyloxy(hydroxy)phosphoryl)oxyphenyl)methyl jV-((4-(5-((2.46w(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6 -dimethyl-42f-pyrrolo[3,4-c]pyrazol-3-yl)2,5-difluoro-phenyl)carbamoyl)carbamate 155 IF-2019-40565613-APN-ANP#INPI Page 155 of 183 Step b of Example 60 also gave Example 61. Ή NMR (400 MHz, DMSO-ufe) δ 10.79 (s, 1H), 10.14 (brs, 1H), 8.14 (d, J= 7 .0 Hz, 1H), 7.85-8.10 (m, 3H), 7.25-7.40 (m, 7H),), 7.20 (d, 7=22.2 Hz, 2H) , 7.14 (d, 7 = 9.0 Hz, 2H), 6.53 (dd, J= 6,Ί, 11.4 Hz, 1H), 5.13 (s, 2H), 4.99 ( d, J= 7.9 Hz, 2H), 4.12 (br s, 2H), 3.65 (br s, 2H), 2.10-2.25 (m, 4H), 1.43 (s , 6H), 0.96 (t, J = 7.4 Hz, 6H). MS: (ES) m / z calculated for C48H44F8N5O7P [M + H]+986.3, found 986.3. Example 62: Synthesis of 7V-((4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6dimethyl-2,4,5,6-tetrahydropyrrolo[ 3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)-2(dimethylamino)acetamide. To a stirred solution of 4-(5-(2,4-¿>w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3, 4-c]pyrazol-3-yl)-2,5-difluoroaniline (400 mg, 0.64 mmol) in THF (5 mL) was added to 2-chloroacetyl isocyanate at room temperature. After stirring for 16 h, the mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to obtain N-((4-(5-(2.4156 IF-2019-40565613-APN-ANP#INPI Page 156 of 183 ¿>«(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3yl)- 2,5-difluorophenyl)carbamoyl)-2-chloroacetamide. To a solution of A-((4-(5-(2,4-ZnXtrifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4 -c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)-2-chloroacetamide according to the above (125 mg, 0.17 mmol) in THF (5 mL) dimethylamine was added (0.35 mL, 0.34 mmol) at room temperature. The reaction mixture was stirred for 16 hours; then concentrated in vacuo. The residue was purified by HPLC (H2O / ACN, 0.1% TFA) to obtain jV-((4-(5-(2,4-ótf(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl) -6,6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)-2-(dimethylamino)acetamide. H NMR (400 MHz, DMSO-ufc) δ 11.3 (br s, 1H), 10.3 (br s, 1H), 9.85 (br s, 1H), 7.90-8.25 (m , 4H), 7.40-7.45 (m, 1H), 7.20-7.28 (m, 2H), 6.55-6.65 (m, 1H), 4.10-4.35 (m, 3H), 3.70 (br s, 2H), 2.83 (s, 6H), 2.17 (q, J= 8.2 Hz, 4H), 1.45 (s, 6H), 0.95 (t, J = 7.4 Hz, 6H). MS: (ES) m / z calculated for C37H38F8N6O2P [M + H]+751.3, found 751.2. Example 63: Synthesis of l-(4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3 ,4-c]pyrazol-3-yl)-2,5-difluorophenyl)-3-(pyrrolidin-l-ylmethyl)urea 1) TMS-Br, CH2CI2 2) pyrrolidine / THF Step b 157 IF-2019-40565613-APN-ANP#INPI Page 157 of 183 Step a: To a stirred solution of 2-hydroxy acetic acid (5.0 g, 65.7 mmol) in dichloromethane (100 mL) at 0 °C, imidazole (11.7 g, 164.3 mmol) and TBSC1 (19.7 g, 131.4 mmol). The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was quenched with dropwise addition of saturated aqueous NaHCO3 and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous Na2SÜ4, filtered and concentrated. The crude material was used directly in the next step without further purification. To a solution of 2-tert-butyldimethylsilyloxy acetic acid (10.0 g, 32.6 mmol) in 50 mL of dichloromethane at 0 °C was added oxalylchloride (8.23 g, 65.3 mmol). The reaction mixture was stirred for 3 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure and dried under vacuum. The raw material was used directly in the next step. To a stirred solution of 2- / er-butyldimethylsilyloxy acetyl chloride (5.0 g, 15.4 mmol) in a 1:1 mixture of acetone:H2O (30 mL) was added NaN3 (2.5 g, 38.5 mmol) at room temperature and stirred for 2 h. Once complete, the solvent was removed under reduced pressure and the mixture was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to form 2-rer-butyldimethylsilyloxy acetyl azide. The azide (3.2 g 1.63 mmol) was dissolved in 20 mL of chloroform at room temperature and the mixture was heated to 80 °C for 2 h. The solvent was removed in vacuo and used directly in the next step. To a solution of tert-butyl(isocyanatomethoxy)dimethylsilane (0.56 g) was dissolved in THF (5 mL) and added to a solution of 4-(5-(2,4-6í5'(trifluoromethyl)benzyl)- 2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoroaniline (1.25 g, 2, 0 mmol) in THF (10 mL). The mixture was stirred at room temperature for 5 hours; then concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes, with 1% Et3N) to obtain l-(4-(5-(2,4-Z>w(trifluoromethyl)benzyl )-2-(2,6-diethylphenyl)6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)-3-( ((tert-butyldimethylsilyl)oxy)methyl)urea. MS: (ES) m / z calculated for C4oH47FsN502Si [M + H]+810.3, found 810.1. 158 IF-2019-40565613-APN-ANP#INPI Page 158 of 183 Step b: To a solution of l-(4-(5-(2,4-ów(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrole [3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)urea (150 mg, 0.19 mmol) in dichloromethane (3 mL) was added drops TMSBr (84 mg, 0.55 mmol) at 0 °C. The mixture was stirred at room temperature for 1 hour, and concentrated in vacuo. This material was dissolved in dichloromethane (4.0 mL) and pyrrolidine (65 mg, 0.92 mmol) was added. The mixture was stirred at room temperature for 4 hours; then concentrated in vacuo. The residue was purified by HPLC (MeCN / ELO, with 0.1 / o TFA) to obtain 1-(4-(5-(2,4-6w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl )-6,6-dimethyl-2,4,5,6tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)-3-(pyrrolidin-l-ylmethyl)urea. Ή NMR (400 MHz, CD3OD) δ 8.19 (d, J= 5.9, Hz, 1H), 8.00-8.10 (m, 3H), 7.42-7.48 (m, 1H ), 7.20-7.35 (m, 2H), 6.45 (dd, J = 6.6, 11.7 Hz, 1H), 4.61 (s, 2H), 4.35-4, 55 (m, 2H), 3.85^1.20 (m, 2H), 3.453.55 (m, 2H), 3.10-3.35 (m, 3H), 2.25 (q, J = 7.4 Hz, 4H), 1.90-2.18 (m, 5H), 1.65 (s, 6H), 1.06 (t, J = 7.8 Hz, 6H). MS: (ES) m / z calculated for C38H40F8N6O [M + H]+749.3, found 749.2. Example 64: Synthesis of l-(4-(5-(2,4-ótf(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrolo[3 ,4-c]pyrazol-3-yl)-2,5-difluorophenyl)-3-(hydroxymethyl)urea Step a: To a solution of 1 -(4-(5-(2,4-6w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl2,4,5,6-tetrahydropyrrole [3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)-3-(((torbutyldimethylsilyl)oxy)methyl)urea (200 mg, 0.24 mmol) in dichloromethane (1.4 mL) TMSBr (0.11 mL, 0.86 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h, then concentrated in vacuo and purified by HPLC (MeCN / H2O, with 0.1% TFA) to 159 IF-2019-40565613-APN-ANP#INPI Page 159 of 183 obtain 1-(4-(5-(2,4-¿>w(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6tetrahydropyrrole [3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)-3-(hydroxymethyl)urea. Ή NMR (400 MHz, CD3OD) δ 8.00-8.25 (m, 4H), 7.42-7.50 (m, 1H), 7.25-7.30 (m, 2H), 6, 36-6.45 (m, 1H), 4.75 (br s, 1H), 4.40-4.70 (m, 5H), 2.25 (q, J= 7.4 Hz, 4H), 1.80-1.95 (m, 6H), 1.04 (t, J= 3.5 Hz, 6H). MS: (ES) m / z calculated for C34H33F8N5O2 [M + H]+696.3, found 696.3. Example 65 This example illustrates the evaluation of the biological activity associated with the specific compounds of the invention. MATERIALS AND METHODS Cells Cells that express the C5a receptor U937 cells 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-1640 medium 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 al FBS. 10%. Cells were cultured with 5% CO2 / 95% air, 100% humidity at 37 °C and subcultured twice a week at 1:6 (cells were grown in a density range of 1 x 105a 2 x 106cells / mL) and harvested at 1 x 106cells / mL. Before the assay, cells are treated overnight with 0.5 mM cyclic AMP (Sigma, OH) and washed once before use. U937 cells treated with cAMP can be used in C5aR ligand binding assays and functional assays. Isolated human neutrophils Optionally, human or murine neutrophils can be used to test 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 3% dextran and allowed to separate for 45 minutes. After separation, the top layer is overlaid 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 brake. The sediment at the bottom of the tube is isolated and 160 IF-2019-40565613-APN-ANP#INPI Page 160 of 183 resuspended in PharmLyse RBC lysis buffer (BD Biosciences, San Jose, CA) after which the sample was centrifuged again for 10 minutes at 400 x g with brake. The remaining cell pellet is resuspended accordingly and is composed of isolated neutrophils. essays Inhibition of C5aR ligand binding cAMP-treated U937 cells expressing C5aR were centrifuged and resuspended in buffer or assay buffer (20 mM HEPES, pH 7.1, 140 mM NaCl, 21 mM CaCl, 5 mM MgCh and with 0.1% bovine serum albumin). up 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 pL of compound, giving a final concentration of ~2-10 μΜ of each compound for screening (or part of a dose response for IC50del determinations). compound). Then 0.1 ml of 1251-labeled C5a (obtained from Perkin Elmer Life Sciences, Boston, MA) diluted in assay buffer was added to a final concentration of ~50 pM, yielding ~30,000 cpm per well. The plates were sealed and incubated for approximately 3 hours at 4 °C on a shaking platform. Reactions were aspirated onto GF / B glass filters pre-soaked in a 0.3% polyethyleneimine (PEI) solution, into a vacuum cell harvester (Packard Instruments, Meriden, CT). Scintillation fluid (40 μΐ; Microscint 20, Packard Instruments) was added to each well, the plates were sealed, and radioactivity was measured in a Topcount scintillation counter (Packard Instruments). Control wells containing only diluent (for total counts) or excess C5a (1 pg / ml, for nonspecific binding) were used to calculate the percentage of total inhibition for the compound. Prism software from GraphPad, Inc. (San Diego, CA) was used to calculate ICso values. IC50 values ​​are those concentrations required to reduce binding of radiolabeled C5a to the receptor by 50%. (For further 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). Calcium mobilization 161 IF-2019-40565613-APN-ANP#INPI Page 161 of 183 Optionally, the compounds can be further analyzed for their ability to inhibit calcium flux into cells. To detect the release of intracellular calcium stores, cells (e.g., U937 stimulated by cAMP or neutrophils) are incubated with 3 μΜ of IND0-1AM dye (Molecular Probes; Eugene, OR) in cell medium for 45 minutes at room temperature and They are washed with Phosphate Buffered Saline (PBS). After INDO-1 AM loading, cells are resuspended in flow buffer (Hank's Balanced Salt Solution (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 dual simultaneous recording of fluorescence emission at 400 nm and 490 nm. Relative intracellular calcium levels are expressed as the 400 nm / 490 nm emission ratio. The 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 a range of 1 to 100 nM. The emission ratio is plotted over time (typically 2-3 minutes). Candidate ligand blocking compounds (up to 10 μΜ) are added at 10 seconds, followed by chemokines at 60 seconds (i.e., C5a, R&D Systems, Minneapolis, MN) and the control chemokine (i.e., SDF- Ια; R&D Systems; Minneapolis, MN) at 150 seconds. Chemotaxis assays Optionally, the compounds can be further analyzed for their ability to inhibit chemotaxis in cells. Chemotaxis assays are performed using filters coated with 5 μm pore polycarbonate 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-Ια, R&D Systems, Minneapolis, MN) are used as specificity controls. The lower chamber is loaded with 29 μΐ of chemokine (i.e., 0.03 nM C5a) and varying amounts of compound; the upper chamber contains 100,000 U937 cells or neutrophils at 20 μΐ. 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 assay (Molecular 162 IF-2019-40565613-APN-ANP#INPI Page 162 of 183 Probes), a fluorescent dye method that measures nucleic acid content and microscopic observation. Identification of C5aR inhibitors Rehearsal To evaluate small organic molecules that prevent the C5a receptor from binding to ligand, we employed an assay that detected radioactive ligand (i.e., C5a) that binds to cells expressing C5aR on the cell surface (e.g., U937 cells stimulated with cAMP or isolated human neutrophils). For compounds that inhibit binding, whether competitive or not, lower radioactive counts are observed compared to uninhibited controls. Equal numbers of cells were added to each well on 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 that were incubated without any organic compounds yielded the total counts; Nonspecific binding was determined by incubating the cells with unlabeled ligand and labeled ligand. The percentage of inhibition was determined by the equation: % inhibition = (1 - [(sample cpm) - (non-specific cpm)1 / l(total cpm) - (non-specific cpm)]) x 100. Dose-response curves To determine the affinity of the candidate compound for C5aR and confirm its ability to inhibit ligand binding, the inhibitory activity was titrated over a range of compound concentrations from 1 x IO'10 to 1 x ΙΟ'4M. In the assay, the amount of compound was varied, while the number of cells and the concentration of the ligand were kept constant. In vivo efficacy models Compounds of interest can be evaluated for potential efficacy in treating C5a-mediated conditions by determining the efficacy of the compound in an animal model. 163 IF-2019-40565613-APN-ANP#INPI Page 163 of 183 In addition to the models described below, other animal models suitable for studying the compound of interest can be found in Mizuno, M. et al., Expert Opinion. Research Drugs (2005), 14(7), 807-821, which is fully incorporated herein by reference. Models of C5a-induced leukopenia C5a-induced leukopenia in a human C5aR knock-in mouse model To study the efficacy of the compounds of the present invention in an animal model, 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 blood leukocytes, sequestering them from the bloodstream. The animals are administered 20 pg / 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 present compounds can almost completely block hC5a-induced leukopenia. C5a-induced leukopenia in a Cynomolgus monkey model 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 monkey model. In this model, hC5a administration leads to upregulation of adhesion molecules on blood vessel walls that bind to blood leukocytes, thereby sequestering them from the blood flow. The animals receive 10 pg / kg of hC5a and 1 minute later the leukocytes are quantified in the peripheral blood. ANCA-induced vasculitis mouse model On day 0, hC5aR-KI mice receive intravenously 50 mg / kg of purified antibody against myeloperoxidase (Xiao et al, J Clin. Invest. 110: 955-963 (2002)). Mice further receive daily oral doses of the compounds of the invention or vehicle for seven days, then are sacrificed and the kidneys removed for histological examination. Analysis of kidney sections may show a significantly lower number and severity of 164 IF-2019-40565613-APN-ANP#INPI Page 164 of 183 crescentic and necrotic lesions in the glomeruli compared to animals treated with vehicle. Mouse model of choroidal neovascularization 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-Kl mice was rupture by laser photocoagulation (Nozika et al, PNAS 103: 2328-2333 (2006). Mice are treated with vehicle or an appropriate daily oral or intravitreal dose of a compound of the invention for one to two weeks. Repair of the Laser-induced damage and neovascularization are evaluated by histology and angiography. Rheumatoid arthritis models Rabbit model of destructive joint inflammation To study the effects of candidate compounds on the inhibition of the inflammatory response of rabbits to an 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 arthritic joints. Marked increases in leukocytes occur in the synovial fluid and synovial membrane in response to 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)). A rabbit LPS study was performed essentially as described in Podolin, et al. ibid., Female New Zealand rabbits (approximately 2 kilograms) are treated intra-articularly in one knee with LPS (10 ng) along with vehicle only (phosphate-buffered saline with 1% DMSO) or with the addition of the candidate compound (dose 1 = 50 μΜ or dose 2 = 100 μΜ) in a total volume of 1.0 mL. Sixteen hours after 165 IF-2019-40565613-APN-ANP#INPI Page 165 of 183 LPS injection, the knees are washed and cell counts are performed. The beneficial effects of treatment were determined by histopathological evaluation of synovial inflammation. Inflammation values ​​are used for histopathological evaluation: 1 minimal, 2 - mild, 3 - moderate, 4 - moderate to marked. Evaluation of a compound in a rat collagen-induced arthritis model A 17-day type II collagen arthritis study was conducted to evaluate the effects of a candidate compound on clinical arthritis-induced ankle inflammation. Collagen-induced arthritis in the rat is an experimental model of polyarthritis that has been widely used for 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 hallmarks of this model are reliable onset and progression of robust and easily measurable polyarticular inflammation, marked cartilage destruction in association with pannus formation, and mild to moderate bone resorption and periosteal bone proliferation. Female Lewis rats (approximately 0.2 kilogram) are anesthetized with isoflurane and injected with incomplete Freund's adjuvant containing 2 mg / ml 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 daily subcutaneously from day 0 to day 17 at an effective dose. Ankle joint diameter gauge measurements were taken, and reduction in joint swelling was taken as a measure of effectiveness. Rat sepsis model To study the effect of the compounds of interest on the inhibition of the generalized inflammatory response that is associated with a sepsis-like disease, the Cecal Ligation and Puncture (CLP) rat model of sepsis is used. Puncture). A CLP study in rats is performed essentially as described in Fujimura N, et al. (American Journal Respiratory Critical Care Medicine 2000; 161: 440-446). Briefly, albino Wistar rats of both sexes weighing between 200-250 g are fasted for twelve hours before the experiments. The animals are kept on normal 12-hour light-dark cycles and fed regular rat chow for up to 12 hours before 166 IF-2019-40565613-APN-ANP#INPI Page 166 of 183 experiment. Later the animals are divided into four groups; (i) two simulation groups and (ii) two CLP groups. Each of these two groups (i.e., (i) and (ii)) is divided into a vehicle control 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 thread, thereby maintaining intestinal continuity. The antimesineric surface of the cecum is pierced with an 18-gauge needle in two places 1 cm apart, and the cecum is gently squeezed until fecal matter is extruded. The intestine is returned to the abdomen and the incision is closed. At the end of the operation, all rats are resuscitated with saline, 3 ml / 100 g body weight, applied subcutaneously. After the operation, the rats are not fed, but have free access to water for the next 16 hours until they are euthanized. The sham groups receive a laparotomy and the cecum is manipulated but not ligated or perforated. The beneficial effects of treatment are measured by histopathological classification of tissues and organs, as well as through the measurement of several key indicators of liver function, kidney function and lipid peroxidation. To evaluate liver function, aspartate transaminase (AST) and alanine transaminase (ALT) are measured. Blood urea nitrogen and creatinine concentrations are studied to evaluate kidney function. Proinflammatory cytokines such as TNF-alpha and IL-lbeta are also analyzed by ELISA to determine serum levels. SLE mouse model of experimental lupus nephritis. To study the effect of compounds of interest on systemic lupus erythematosus (SLE), the MRL / Zpr murine SLE model is used. The MRL / Mp-Tw / ra / ó^'' (MRL / (pr) strain is a commonly used mouse model of human SLE. To test the efficacy of the compounds in this model, male MRL / lpr mice are divided equally between control groups and C5aR antagonist groups at 13 weeks of age. Then, for the next 6 weeks, the compound or vehicle is administered to the animals via osmotic pumps to maintain coverage and minimize the effects of the compound. stress in the animals. Serum and urine samples are drawn every two weeks during the six weeks of onset and progression of the disease. In a minority of these mice, glomerulosclerosis develops leading to the death of the animal from failure ' 167. IF-2019-40565613-APN-ANP#INPI Page 167 of 183 kidney. Tracking mortality as an indicator of kidney failure is one of the measurement criteria and successful treatment will generally result in a delay in sudden death between the test groups. Additionally, the presence and extent of kidney disease can also be monitored continuously with measurements of blood urea nitrogen (BUN) and albuminuria. Tissues and organs were also obtained at 19 weeks and subjected to histopathology and immunohistochemistry and classified based on tissue damage and cellular infiltration. Rat COPD model Smoke-induced airway inflammation in rodent models can be used to evaluate the efficacy of compounds in chronic obstructive pulmonary disease, COPD, or 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)). A rat model of acute COPD is implemented as described by Stevenson et al. A compound of interest is administered systemically orally or IV; or locally with nebulized compound. Male Sprague-Dawley rats (350-400 g) are placed in Perspex chambers and exposed to pump-inhaled cigarette smoke (50 ml every 30 seconds with fresh air in between). The rats are exposed for a total period of 32 minutes. Rats are sacrificed up to 7 days after initial exposure. Any beneficial effect of treatment is evaluated by a decrease in the infiltrate of inflammatory cells, decreases in chemokine and cytokine levels. In a chronic model, mice or rats are exposed to daily exposures of 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 seen with the acute model (Stevensen et al.), animals may also exhibit other pathologies similar to those seen in human COPD, such as emphysema (as indicated by increased mean linear intercept) as well as lung chemistry. altered (see Martorana et al, Am. J. Respir. Crit Care Med. 172(7). 848-53. 168 IF-2019-40565613-APN-ANP#INPI Page 168 of 183 EAE model of multiple sclerosis in mouse Experimental autoimmune encephalomyelitis (EAE) is a model of human multiple sclerosis. Variations of the model have been published and are well known in the art. In a typical protocol, C57BL / 6 mice (Charles River Laboratories) are used for the EAE model. Mice are immunized with 200 pg of Myelin Oligodendrocyte Glycoprotein (MOG) 35-55 (Peptide International) emulsified in Complete Freund's Adjuvant (CFA). with a content of 4 mg / ml of Mycobacterium tuberculosis (SigmaAldrich) s.c. on day 0. Additionally, on day 0 and day 2, animals received 200 ng of pertussis toxin (Calbiochem) i.v. The clinical score is based on a scale of 0-5: 0, no signs of disease; 1, flaccid tail; 2, weakness of the hind limbs; 3, paralysis of the hind limbs; 4, weakness or paralysis of the forelimbs; 5, dying. The administration of the compounds of interest to be evaluated can begin on day 0 (prophylactic) or day 7 (therapeutic, when there is histological evidence of the disease but few animals present clinical signs) and are administered one or more times a day at the concentrations appropriate for its activity and pharmacokinetic properties, for example 100 mg / kg s.c. The efficacy of compounds can be assessed by comparisons of severity (maximum average clinical score in the presence of compound compared to vehicle), or by measuring a decrease in the number of macrophages (F4 / 80 positive) isolated from spinal cords. Spinal mononuclear cells can be isolated by discontinuous Percoll gradient. Cells can be labeled using rat anti-mouse F4 / 80-PE or rat IgG2bPE (Caltag Laboratories) and quantified by FACS analysis using 10 μΐ Polybeads per sample (Polysciences). Mouse kidney transplant model Transplantation models can be performed on mice; For example, an allogeneic kidney transplant 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 attached to a cuff of the aorta and the renal vein with a small cuff of cava, and the ureters are removed en bloc. After the recipient's left nephrectomy, the 169 IF-2019-40565613-APN-ANP#INPI Page 169 of 183 vascular cuffs are anastomosed to the recipient's aorta and abdominal vena cava, respectively, below the level of the native renal vessels. The ureter anastomoses directly into the bladder. The cold ischemia time is 60 minutes and the warm ischemia time is 30 minutes. The right native kidney can be harvested at the time of allograft transplantation or on day 4 posttransplant for long-term survival studies. The general physical condition of the mice is monitored for evidence of rejection. Compound treatment of animals can be initiated before surgery or immediately after transplantation; for example, by subcutaneous injection once a day. The kidney function and survival of the mice is evaluated. Serum creatinine levels are measured via an automated method (Beckman Analyzer, Krefeld, Germany). Mouse ischemia / reperfusion model A mouse model of ischemia / reperfusion injury can be run 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 keep warm during surgery. After the 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 forceps are removed along with the right kidney, the incisions are sutured, and the animals are allowed to recover. Blood samples are taken for analysis of serum creatinine and BUN as an indicator of kidney health. Alternatively, the survival of the animals 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 efficacy of the compound. Mouse tumor growth model 1x105 TC-1 cells (ATCC, VA) are injected subcutaneously into 6-16 week old C57BL / 6 mice in the right or left hind flank. Beginning approximately 2 weeks after cell injection, tumors are measured with calipers every 2-4 days until tumor size requires euthanizing the mice. At the time of slaughter, the animals undergo a complete necropsy and the spleens and tumors are removed. The removed tumors are measured and weighed. The compounds can be administered before and / or after injections 170 IF-2019-40565613-APN-ANP#INPI Page 170 of 183 tumors, and the delay or inhibition of tumor growth can be used to evaluate the effectiveness of the compound. Intermediates 1 to 4 are potent C5aR antagonists with IC50 < 5 nM in the chemotaxis assay using U937 cells as d...

Claims

1. A compound of any one of Formulas (IA), (IB), (IC), (IIA), (IIB) or (IIC): (FORMULA) or a pharmaceutically acceptable salt thereof, characterized in that: the vertex of ring a is N or C(R 2c ), the vertex of ring b is N or C(R 2d ), and the vertex of ring e is N or C(R 2e ), wherein no more than one of a, b, and e is N; X 1 is selected from the group consisting of a linkage, C1-8 alkylene, C(O), C(O)-C1-4 alkylene, and S(O)2; R 1 is selected from the group consisting of: a) a 5- to 10-membered heteroaryl having from 1 to 4 heteroatoms as ring vertices selected from N, O and S; b) a C6-10 aryl; c) a C3-8 cycloalkyl; d) 4- to 8-membered heterocycloalkyl having from 1 to 2 heteroatoms as ring vertices selected from N, O and S; and e) C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkyl, -C(O)NR 1a R 1b , and -CO2R 1a ;wherein R1a and R1b are each independently selected from the group consisting of hydrogen, C1-8 alkyl, C6-10 aryl, and C1-6 -alkylene -C6-10 -aryl; wherein the -X1 -R1 group is either unsubstituted or substituted with 1 to 5 Rx substituents; R2a and R2e are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 -O-haloalkyl, C1-6 -S-alkyl, C1-6 -alkyl-C1-6 O-alkyl, C1-6 -alkyl-C1-6 S-alkyl, CN, and halogen, and at least one of R2a and R2e is other than hydrogen; R 2b , R 2c , and R 2d are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C 1-6 alkoxy, C1-6 haloalkyl, -O-C1-6 haloalkyl, -S-C1-6 alkyl, -C1-6 alkyl-C1-6 O-alkyl, -C1-6 alkyl-C1-6 S-alkyl, cyano, and halogen;Each R3 is independently selected from the group consisting of hydroxyl, C1-4 alkyl, C1-4 haloalkyl and C1-4 hydroxyalkyl, and optionally two R3 groups on the same carbon atom combine to form oxo(=O), and optionally two R3 groups and the carbon atoms to which they are attached to form a 3-6 membered ring with 0-2 heteroatoms as ring members selected from O, N, and S; R4 is a member selected from the group consisting of: -NHP1, -NHC(O)NHP1, -CH2NHP1 and -CH2NHC(O)NHP1; each R 5 is independently selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkyl, C1-8 haloalkoxy, C1-8 hydroxyalkyl, halogen, OH, CN, C(O)R 5a and CO2R 5a; R 5' is a member selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl, C1-8 hydroxyalkyl, C(O)R 5a and CO2R 5a;wherein each R 5a is independently selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 haloalkyl; R 6 is a member 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-C1-6 O-alkyl, -C1-6 alkyl-C1-6 S-alkyl, cyano, and halogen; R 7 is P 1 ; and R 8 is -CH2OP 1 ; each P 1 is: (i) selected from the group consisting of: (FORMULA), wherein each R y is independently selected from the group consisting of: -OP(O)(OR y1 )2, -OC(O)CH2N(R y2 )2, -N(R y2 )2 and piperazine; each R y1 is independently selected from the group consisting of H, C1-3 alkyl and benzyl; each R y2 is independently H or C1-3 alkyl;and each phenyl ring bearing an R-CH2R substituent and further substituted with 0 to 3 members independently selected from the group consisting of nitro, halogen, CN, CF3, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy and C1-4 hydroxyalkyl; or (ii) is selected from the group consisting of: (FORMULA), wherein each R9 is independently selected from the group consisting of H and C1-3 alkyl; and each R10 is independently selected from the group consisting of H, C1-3 alkyl, phenyl and benzyl; or (iii) is selected from the group consisting of -CH2OH, -P(O)(OR 10 )2, and -CH2-OP(O)(OR 10 )2, wherein each R 10 is independently selected from the group consisting of H, C1-3 alkyl, phenyl, and benzyl; or (iv) is selected from the group consisting of an amino acid, a dipeptide, and a tripeptide; or (v) is selected from the group consisting of: (FORMULA);each R x is independently selected from the group consisting of halogen, CN, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 hydroxyalkyl, C2-4 alkenyl, C3-6 cycloalkyl, C1-4 CO2-alkyl, and CONH2; the subscript m is 0, 1, 2, 3 or 4; and the subscript n is 0, 1, 2 or 3. 43 Claims follow;