6-5 RING COMPOUNDS FUSED AS C5a INHIBITORS

Abstract

Claim 1: A compound characterized in that it is of formula (1), or a pharmaceutically acceptable salt thereof, wherein: the vertex of ring A⁰ is NH or C(O); each of the vertices of rings A¹ and A³ is independently selected from the group consisting of N, NH, CH, C(O) and C(R⁴); each of the vertices of rings A², A⁵ and A⁶ is independently selected from the group consisting of N, CH, and C(R⁴); the vertex of ring A⁴ is selected from the group consisting of N, N(C₁₋₄ alkyl), CH, and C(R⁴); and no more than two of A³, A⁴, A⁵ and A⁶ are N; each of the bonds in dashed lines is independently a single or double bond; R¹ is selected from the group consisting of heteroaryl, C₆₋₁₀ aryl, C₁₋₈-alkylene, C₁₋₈-heteroaryl, C₆₋₁₀-alkylene, C₃₋₈-cycloalkyl, four- to eight-membered heterocycloalkyl, C₁₋₈ alkyl, C₁₋₈ haloalkyl, -C(O)NR¹ᵃR¹ᵇ, and -CO₂R¹ᵃ;wherein the heterocycloalkyl group is a 4- to 8-membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S; and the heteroaryl group is a 5- to 10-membered aromatic ring having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S; wherein R¹ᵃ and R¹ᵇ are each independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, C₆₋₁₀ aryl, and C₁₋₆-alkylene-C₆₋₁₀ aryl; wherein R¹ is optionally substituted with 1 to 5 R⁵ substituents; R²ᵃ and R²ᵉ are each independently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, -O-C₁₋₆ haloalkyl, -S-C₁₋₆ alkyl, -O-C₁₋₆ alkyl, -S-C₁₋₆ alkyl, CN, and halogen;R²ᵇ, R²ᶜ, and R²ᵈ are each independently selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, -O-C₁₋₆ haloalkyl, -S-C₁₋₆ alkyl, -O-C₁₋₆ alkyl, -S-C₁₋₆ alkyl, cyano, and halogen; Each R³ is independently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl and hydroxyl, and optionally two R³ groups on the same carbon atom combine to form oxo(=O); each R⁴ is independently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, -O-C₁₋₆ haloalkyl, halogen, cyano, hydroxyl, -S-C₁₋₆ alkyl, -C₁₋₆-O-C₁₋₆ alkyl, -C₁₋₆-S-C₁₋₆ alkyl, -NR⁴ᵃR⁴ᵇ, -CONR⁴ᵃR⁴ᵇ, -CO₂R⁴ᵃ, -COR⁴ᵃ, -OC(O)NR⁴ᵃR⁴ᵇ, -NR⁴ᵃC(O)R⁴ᵇ, -NR⁴ᵃC(O)₂R⁴ᵇ, and -NR⁴ᵃ-C(O)NR⁴ᵃR⁴ᵇ; each R⁴ᵃ and R⁴ᵇ is independently selected from the group consisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl;each R⁵ is independently selected from the group consisting of C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, C₁₋₈ hydroxyalkyl, -C₁₋₈ alkyl-heterocycloalkyl, -C₁₋₈ alkyl-C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl, heterocycloalkyl, halogen, OH, C₂₋₈ alkenyl, C₂₋₈ alkynyl, CN, C(O)R⁵ᵃ, -NR⁵ᵇC(O)R⁵ᵃ, -CONR⁵ᵃR⁵ᵇ, -NR⁵ᵃR⁵ᵇ, -C₁₋₈-NR⁵ᵃR⁵ᵇ, -C₁₋₆-S-alkyl, -C₁₋₆-O-alkyl, -C₁₋₆-S-alkyl, -OC(O)NR⁵ᵃR⁵ᵇ, -NR⁵ᵃC(O)₂R⁵ᵇ, -NR⁵ᵃ-C(O)NR⁵ᵃR⁵ᵇ and CO₂R⁵ᵃ; wherein the heterocycloalkyl group is a 4- to 8-membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S;wherein each R⁵ᵃ and R⁵ᵇ is independently selected from the group consisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl or, when attached to the same carbon atom, R⁵ᵃ and R⁵ᵇ combine with the nitrogen atom to form a five- or six-membered ring having between 0 and 1 additional heteroatoms as ring vertices selected from N, O, or S; and the subscript n is 0, 1, 2, or 3.

Description

[0001] This application claims benefit under United States Code 35 U.S.C. § 119(e) of US Provisional Patent Application No. 62 / 513,010 filed May 31, 2017, which is fully incorporated herein by reference. STATEMENT REGARDING THE RIGHTS TO INVENTIONS MADE UNDER RESEARCH AND DEVELOPMENT FUNDED BY THE GOVERNMENT

[0002] NOT APPLICABLE. REFERENCE TO “SEQUENCE LIST”, TABLE, OR LIST OF ANNEXED COMPUTER PROGRAM PRESENTED ON COMPACT DISC

[0003] DOES NOT APPLY. BACKGROUND OF THE INVENTION

[0004] The complement system plays a central role in clearing 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 deleterious and even life-threatening consequences due to severe inflammation and consequent tissue destruction. These consequences are clinically manifested in various disorders, including septic shock; myocardial injury as well as intestinal ischemia / reperfusion; graft rejection; organic failure; nephritis; pathological inflammation; and autoimmune diseases.

[0005] The complement system is composed of a group of proteins that are normally present in the serum in an inactive state. Activation of the complement system mainly involves three distinct 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 is normally activated by the formation of antigen-antibody complexes. It can also be activated independently of antibodies by C-reactive protein binding, complexing 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 (eg, yeast and bacterial cell wall polysaccharides, and certain biopolymeric materials). 3) The lectin pathway involves the initial binding of mannose-binding lectin and the subsequent activation of C2 and C4, which are common to the classical pathway (Matsushita, M. et al., J. Exp. Med. 176: 1497-1502 (1992; Suankratay, C. et al., J. Immunol. 160:3006-3013 (1998)).

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

[0007] C5a complement is one of the most potent pro-inflammatory mediators of the complement system. (C5a anaphylactic peptide 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, a 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)).

[0008] C5 is cleaved into C5a and C5b fragments 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 of (C3b) 2, Bb and P for the alternative pathway (Goldlust, Μ. B. et al.,J Immunol 113:998-1007 (1974), Schreiber, R.D. et al, Proc. Nati. Acad. Sci. 75:3948-3952 (1978)). C5 is activated by cleavage at position 74-75 (Arg-Leu) on the a chain. After 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)).

[0009] In addition to its anaphylotoxic properties, C5a induces 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 138:387-390 1971)). Both C5a and C5b-9 activate endothelial cells to express adhesion molecules essential for 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); Rollins, S.A. et al., Transplantation 69:1959-1967 (2000)). C5a also mediates inflammatory reactions by causing smooth muscle contraction, increasing vascular permeability, inducing degranulation of basophils and mast cells, and inducing the release of lysosomal proteases and oxidative free radicals (Gerard, C. et al., Ann. Rev. Immunol 12:775-808 (1994)). In addition, C5a modulates hepatic acute phase gene expression and 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).

[0010] The anaphylactic and chemotactic effects of C5a are believed to be mediated through its interaction with the C5a receptor. The human C5a receptor (C5aR) is a 52 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); Haviland, D.L. et al., J. Immunol. 154:1861-1869 (1995); Wetsel, R.A., Immunol. Leff 44:183-187 (1995);Buchner, R.R. et al., J. Immunol.155:308-315 (1995);Chenoweth, D.E. et al., Proc.Nati.Acad.Sci.75:3943-3947 (1978; Zwimer, J. et al., Mol. Immunol. 36:877-884 (1999)). The C5aR ligand binding site is complex and comprises at least two physically separable binding domains. One joins the C5a amino terminus (amino acids 1-20) and the disulfide-linked nucleus ( (amino acids 21-61), while the second is attached to the carboxy-terminus C5a (amino acids 62-74) ( Wetsel, R. A., Curr. Opin. Immunol. 7:48-53 (1995 )).

[0011] C5a plays an important role in inflammation and tissue injury. In cardiopulmonary bypass and hemodialysis, C5a is formed as a result of alternative complement pathway activation 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); Kirklin, J. K. et al., J. Cardiovasc. Surg. 86:845-857 (1983); Craddock, P. R. et al., N Engl. J. Med. 296:769-774 (1977)). C5a causes increased permeability and capillary edema, bronchoconstriction, pulmonary vasoconstriction, activation of leukocytes and platelets, and infiltration into tissues, particularly the lung (Czermak, 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)). .

[0012] 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 1980 1:947949 Heideman M et al J Trauma 1984 4:1038-1043 Marc MM et al Am J Respir Cell and Mol. Biol., 2004:31:216-219). C5a increases monocyte production of two important proinflammatory cytokines, TNF-a and IL-1. C5a has also been shown to play an important role in the development of tissue damage, and particularly lung damage, 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 animals prior to treatment with endotoxin or E. coli resulted in decreased tissue injury, as well as decreased 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, blockade or C5a with anti-C5a polyclonal antibodies has been shown to significantly improve survival rates in a rat cecal puncture / ligation model of sepsis (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 model of sepsis, anti-C5a antibodies have been shown to inhibit thymocyte apoptosis (Guo, R.F. et al., J. Clin. Invest. 106:1271-1280 (2000)) and prevent IOM (Huber- Lang, M. et al., J. Immunol. 166:1193-1199 (2001)). Anti-C5a antibodies were also protective in a cobra venom factor model of rat lung injury, and in immune complex-induced lung injury (Mulligan, M.S. et al. J. Clin. Invest. 98:503 -512 (1996)). The importance of C5a in immune complex-mediated lung injury was subsequently confirmed in mice (Bozic, C.R. et al., Science 26:1103-1109 (1996)).

[0013] C5a has been found to be an important mediator of myocardial ischemia-reperfusion injury. Depletion of complement reduced myocardial infarct size in mice (Weisman, H.F. et al., Science 249:146-151 (1990)), and anti-C5a antibody treatment reduced injury in a rat model of ischemia. -reperfusion of the hindlimbs (Bless, N.M. et al., Am. J. Physiol. 276:L57-L63 (1999)). Reperfusion injury during myocardial infarction was also markedly reduced in pigs recreated 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)).

[0014] C5a-driven neutrophils also contribute to many bubous diseases (eg, bubous pemphigoid, pemphigus vulgaris, and pemphigus foliaceus). These are chronic and recurrent inflammatory disorders clinically characterized by sterile bullae 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, bullae are also characterized by accumulation of neutrophils in the upper dermal layers and within the cavities of the epidermis. the blisters. In experimental models, the reduction of neutrophils or the absence of complement (total or C5-selective) can inhibit subepidermal bleb formation, even in the presence of high autoantibody titers.

[0015] Complement levels are elevated in patients with rheumatoid arthritis (José, P. J. et al., Ann. rheum. Dis. 49:747-752 (1990); Grant, E.P., et al., J. of Exp. Med., 196(11):14611471, (2002)), lupus nephritis (Bao, L., et al., Eur. J. of Immunol., 35(8), 2496-2506, (2005)), and lupus systemic erythematosus (SLE) ( Porcel, J.M. et al., Clin. Immunol. Immunopathol. 74:283288 (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 antibodies. (Banda, N.K., et al., J. of Immunol., 2003, 171:2109-2115). Therefore, inhibition of the C5a and / or C5a receptor (C5aR) could be useful in the treatment of these chronic diseases.

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

[0017] C5aR expression is upregulated in reactive astrocytes, microglia and endothelial cells in an inflamed human central nervous system (Gasque, P. et al., Am. j. Pathol. 150:31-41 (1997)) . C5a could be involved in neurodegenerative diseases, such as Alzheimer's disease (Mukherjee, P. et al., J. Neuroimmunol. 105:124130 (2000); O'Barr, S. et al., J. Neuroimmunol. (2000) 105:87-94, Farkas, L, et al J. Immunol (2003) 170:5764-5771), Parkinson's disease, Pick's disease and transmissible spongiform encephalopathies. Activation of neuronal C5aR can induce apoptosis (Farkas I et al. J. Physiol. 1998; 507:679-687). Therefore, inhibition of C5a and / or C5aR could also be useful in the treatment of neurodegenerative diseases.

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

[0019] 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 may also be involved in the pathogenesis of the disease (Terui, T. et al., Exp. Dermatol. 9:1-10; 2000); Werfel, T. et al, Arch. Dermatol. Res. 289:83-86 (1997)). Neutrophil accumulation under the stratum corneum is seen in the highly inflamed areas of psoriatic plaques, and extracts of psoriatic lesions (flakes) contain highly elevated levels of C5a and exhibit potent chemotactic activity towards neutrophils, an effect that can be inhibited. by adding a C5a antibody. T cells and neutrophils are chemoattracted by 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)). In addition, C5aR expression has been demonstrated in plasmacytoid dendritic cells (pDCs) isolated from cutaneous lupus erythematosus lesions and these cells exhibited chemotactic behavior towards C5a, suggesting that C5aR blockade 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.

[0020] Immunoglobulin G-containing immune complexes, or immune complexes (ICs), contribute to the pathophysiology of several autoimmune diseases, including 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); Bolten, W.K., Kidney Int. 50:1754-1760 (1996), Ando, ​​M. et al., Curr. Opin. Pulm. Med. 3:391-399 (1997)). These diseases are highly heterogeneous and generally affect one or more of the following organs: skin, blood vessels, joints, kidneys, heart, lungs, nervous system, and liver (including cirrhosis and liver fibrosis). The classic animal model for the inflammatory response in these HF diseases is the Arthus reaction, featuring polymorphonuclear cell infiltration, hemorrhage, and plasmatic exudation (Arthus, M., C.R. Soc. Biol. 55:817-824 (1903)). ). Recent studies show that C5aR-deficient mice are protected from IC-induced tissue damage (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 peptide anti-C5aR antagonist inhibits the inflammatory response caused by IC deposition (Strachan, A.J. et al., J. Immunol. 164:6560-6565 (2000)). 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. Description of related art:

[0021] 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 IBD 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, (eg, W02004 / 043925, W02004 / 018460, W02005 / 007087, WO03 / 082826, W003 / 08828, WO02 / 49993 , WO03 / 084524); Dompe S.P.A. (W002 / 029187); The University of Queenland (W02004 / 100975); and ChemoCentryx (W02010 / 075257).

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

[0023] In one aspect, the present invention provides the compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: the vertex of ring A° is NH or C(O); ring vertices A1 and A3 are each independently selected from the group consisting of N, NH, CH, C(O) and C(R4); ring vertices A2, A5, and A6 are each independently selected from the group consisting of N, CH, and C(R4); ring vertex A4 is selected from the group consisting of N, N(C1-4 alkyl), CH, and C(R4); and no more than two of A3, A4, A5 and A6 are N; each of the dashed bonds is independently a single or double bond; R1 is selected from the group consisting of heteroaryl, Có-io aryl, -C1-8 alkyleneheteroaryl, -C1-8 alkyleneCe-io aryl, C3-8 cycloalkyl, four to eight membered heterocycloalkyl, C1-8 alkyl, haloC1-8alkyl, -C(O)NRlaRlb, and -CO2Rla; wherein the heterocycloalkyl group is a 4 to 8-membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S; the heteroaryl group is a 5 to 10-membered aromatic ring having 1 to 3 heteroatoms as ring vertices selected from N, O, and S; wherein Rla and Rlb are each independently selected from the group consisting of hydrogen, C1-8 alkyl, Có-io aryl, and -C1-6 alkyleneCó-io aryl; wherein R1 is optionally substituted with 1 to 5 R5 substituents; R2a and R2e are each independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, -O-haloC1-6 alkyl, -S-C1-6 alkyl, -C1 alkyl -6 -OC1-6alkyl, -C1-6alkyl-S-C1-6alkyl, CN, and halogen; R2b, R2c, and R2d are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, -O-C1-6 haloalkyl, -S-C1-6 alkyl- 6, Ci-6 alkyl-O-Ci-6 alkyl, -Ci-6 alkyl-S-Ci-6 alkyl, cyano, and halogen; each R3 is independently selected from the group consisting of C1.4 alkyl, C1-4 haloalkyl, and hydroxy, and optionally two R3 groups on the same carbon atom combine to form oxo (=0); each R4 is independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, hydroxyC1-6 alkyl, haloC1-6 alkyl, haloC1-6 alkoxy, -O-haloCi-6 alkyl, halogen, cyano, hydroxy, -S-C1-6 alkyl, -Ci-6 alkyl-O-C1-6 alkyl, -Ci-6 alkyl-S-C1-6 alkyl, NR4aR4b, -CONR4aR4b, -CO2R4a , -COR4a, -OC(O) NR4aR4b, -NR4aC(O)R4b, -NR4aC(O)2R4b, and 9 NR4a-C(O)NR4aR4b; each R4a and R4b is independently selected from the group consisting of hydrogen, C1-4alkyl, and C1-4haloalkyl; each R5 is independently selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkyl, C1-8 haloalkoxy, C1-8 hydroxyalkyl, -C1-8 alkylheterocycloalkyl, -Ci-8 alkyl -C3-8cycloalkyl, C3-6cycloalkyl, heterocycloalkyl, halogen, OH, C2-8alkenyl, C2-8alkynyl, CN, C(O)R5a, -NR5bC(O)R5a, -CONR5aR5b, -NR5aR5b, -alkylene C].8-NR5aR5b, S-C1-6 alkyl, -C1-6 alkyl -O-C1-6 alkyl, -Ci-6 alkyl-S-C1-6 alkyl, -OC(O)NR5aR5b, NR5aC(O )2R5b, -NR5a-C(O)NR5bR5b and CO2R5a; wherein the heterocycloalkyl group is a 4 to 8-membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S; wherein each R5a and R5b is independently selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 haloalkyl, when attached to the same carbon atom, R5a and R5b combine with the nitrogen atom to form a five or six membered ring having between 0 and 1 additional heteroatoms as ring vertices selected from N, O, or S; and the subscript n is 0, 1, 2, or 3.

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

[0025] In yet another aspect, the present invention provides methods of diagnosing disease 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 location of cells expressing a C5aR receptor. In a related aspect, a disease diagnostic method is carried out by contacting a tissue or blood sample with a labeled compound as provided herein and determining the presence, absence, amount or location of C5aR in the sample. show. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] NOT APPLICABLE. DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

[0027] The term alkyl, alone or as part of another substituent, means, unless otherwise indicated, a straight or branched chain 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, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term alkenyl refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term alkynyl refers to an unsaturated alkyl group having one or more triple bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), isobutenyl, 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3 -butynyl, and the higher homologues and isomers. The term "cycloalkyl" refers to hydrocarbon rings that have the indicated number of ring atoms (eg, C3-6 cycloalkyl) and that are fully saturated or have no more than one double bond between 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 quaternized. The 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, thiomorpholine-S,S- oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine and the like. A heterocycloalkyl group can be attached to the rest of the molecule through a carbon ring or heteroatom.

[0028] The term "alkylene", by itself or as part of another substituent, means a divalent radical derived from an alkane, as for example in -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 the unsaturated forms of alkylene that have double or triple bonds, respectively.

[0029] The term heteroalkyl, alone or in combination with another term, means, unless otherwise indicated, a stable straight or branched chain or cyclic hydrocarbon radical, or combinations thereof, comprising the indicated number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quatemized. The heteroatom(s) O, N and S can be placed at any interior position of the heteroalkyl group. The heteroatom Si 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, -CH2CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O) -CH3, -CH2-CH2S(O)2-CH3, -CH=CH-O-CH3, -Yes(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)- CH3. Up to two heteroatoms can be consecutive, such as -CH2-NH-OCH3 and -CH2-OSi(CH3)3. Similarly, the terms heteroalkenyl and heteroalkynyl, alone or in combination with another term, mean, unless otherwise indicated, an alkenyl group or alkynyl group, respectively, containing the indicated number of carbons and having one to three heteroatoms selected from the group consisting of O, N, Si, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom optionally quaternized. The heteroatom(s) O, N and S can be placed at any interior position of the heteroalkyl group.

[0030] The term "heteroalkylene" by itself 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-, -CH212 CH=C(H)CH2-O-CH2- and -S-CEE-C^C-. For heteroalkylene groups, heteroatoms may also occupy one or both ends of the chain (eg, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).

[0031] 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 understood to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, and the like.

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

[0033] The terms halo or halogen, by themselves or as part of another substituent, mean, unless otherwise 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.

[0034] The term "aryl" means, unless otherwise indicated, a polyunsaturated hydrocarbon group, typically aromatic, which can be a single ring or multiple rings (up to three rings) that are fused together or covalently bonded. The term "heteroaryl" refers to aryl groups (or rings) containing from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. A heteroaryl group 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, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, nalazinium, benzotriazinyl, purinyl, benzimidazolyl, benzopirazolilo, benzooxazolilo, benzotriazolilo, bencisoxazolilo, isobenzofurilo, isoindolilo, indolizinilo, benzotriazinilo, tienopiridinilo, tienopirimidinilo, pirazolopirimidinilo, pirrolopiridilo, imidazopiridinas, benzotiaxolilo, benzofuranilo, benzotienilo, indolilo, quinolilo, isoquinolilo, isotiazolilo, pirazolilo, indazolilo, pteridinilo, imidazolilo, triazolilo, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. The substituents for each of the aryl and heteroaryl ring systems noted above are selected from the group of acceptable substituents described below.

[0035] The term "pharmaceutically acceptable salts" is intended to include salts of the active compounds that are prepared with relatively non-toxic acids or bases, depending on the particular substituents found on 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, neat 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, and the like. Salts derived from pharmaceutically acceptable organic bases include primary, secondary, and tertiary amine salts, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, Diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, Netylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, neat 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, hydroiodic or phosphorous monohydrogen 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, 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 Salis", 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 acid or base addition salts.

[0036] 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 purposes of the present invention.

[0037] In addition to salt forms, the present invention provides compounds in prodrug or prodrug form. Prodrugs or 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 to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

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

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

[0040] Accordingly, a wavy line, . / wv, that intersects a single, double, or triple bond in any chemical structure depicted herein, represents the point of attachment of the single, double, or triple bond to the rest of the molecule. Description of Embodiments Compounds

[0041] In one aspect, the present invention provides the compounds of Formula (I): R1 γΎ3 / a2-a' O eO nn < '.a3 R2a zR2eA R2b\y^R2d r2c (I) or a pharmaceutically acceptable salt thereof, wherein: the vertex of ring A° is NH or C(O); ring vertices A1 and A3 are each independently selected from the group consisting of N, NH, CH, C(O) and C(R4); ring vertices A2, A5, and A6 are each independently selected from the group consisting of N, CH, and C(R4); ring vertex A4 is selected from the group consisting of N, N(Cm alkyl), CH, and C(R4); and no more than two of A3, A4, A5 and A6 are N; each of the dashed bonds is independently a single or double bond; R' is selected from the group consisting of heteroaryl, Có-io aryl, -Ci-8 alkyleneheteroaryl, -Ci-8 alkyleneCó-io aryl, C3-8 cycloalkyl, four to eight membered heterocycloalkyl, C1-8 alkyl , haloC1-8alkyl, -C(O)NRlaRlb, and -CO2Rla; wherein the heterocycloalkyl group is a 4 to 8-membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S; the heteroaryl group is a 5 to 10-membered aromatic ring having 1 to 3 heteroatoms as ring vertices selected from N, O, and S; wherein Rla and R,b are each independently selected from the group consisting of hydrogen, Ci-8 alkyl, Có-io aryl, and -Ci-6-aryl Có-io alkylene; wherein R1 is optionally substituted with 1 to 5 R5 substituents; R2a and r2c are each independently selected from the group consisting of Ci-or alkyl, Ci-or alkoxy, Ci-or haloalkyl, -O-Ci-or haloalkyl, -S-Ci-or alkyl, -Ci alkyl -ó-Oalkyl Ci-ó, -alkyl Ci-ó -S-alkyl Ci-ó, CN, and halogen; R2b, R2c, and R2d are each independently selected from the group consisting of hydrogen, Ci-or alkyl, Ci-or alkoxy, Ci-or haloalkyl, -O-Ci-or haloalkyl, -S-Ci-alkyl ó, alkyl Ci-ó-O-alkyl Ci-ó, -alkyl Ci-ó-S-alkyl Ci-ó, cyano, and halogen; each R3 is independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, and hydroxyl, and optionally two R3 groups on the same carbon atom combine to form oxo (=0); each R4 is independently selected from the group consisting of Ci-or alkyl, Ci-or alkoxy, Ci-or hydroxyalkyl, Ci-or haloalkyl, Ci-or haloalkoxy, -O-Ci-or haloalkyl, halogen, cyano, hydroxy, -S-alkyl Ci-ó, -alkyl Ci-6-O-alkyl Ci-ó, -alkyl Ci-ó -S-alkyl Ci-ó, NR4aR4b, -CONR4aR4b, -CO2R4a , -COR4a, -OC(O) NR4aR4b, -NR4aC(O)R4b, -NR4aC(O)2R4b, and NR4a-C(O)NR4aR4b; each R4a and R4b is independently selected from the group consisting of hydrogen, C1-4alkyl, and haloC1-4alkyl; 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, -Ci-8 alkylheterocycloalkyl, -Ci-8 alkyl- C3-8cycloalkyl, C3-6cycloalkyl, heterocycloalkyl, halogen, OH, C2-8alkenyl, C2.8alkynyl, CN, C(O)R5a, -NR5bC(O)R5a, -CONR5aR5b, -NR5aR5b, -Ci_8alkylene -NR5aR5b, S-Ci-6 alkyl, -C1-6 alkyl-O-C1-6 alkyl, -Ci-6 alkyl-S-C1-6 alkyl, -OC(O)NR5aR5b, NR5aC(O)2R5b, - NR5a-C(O)NR5bR5b and -CChR53; wherein the heterocycloalkyl group is a 4 to 8-membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S; wherein each R5a and R5b is independently selected from the group consisting of hydrogen, C1-4 alkyl, and haloC1-4 alkyl or, when attached to the same carbon atom, R5a and R5b combine with the nitrogen atom to form a five or six membered ring having between 0 and 1 additional heteroatoms as ring vertices selected from N, O, or S; and the subscript n is 0, 1, 2, or 3.

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

[0043] In some embodiments, the portion of the ring having A°, A1, A2, A3, A4, A5, and A6 as ring vertices is a bicyclic heteroaryl selected from: where m is 0, 1, 2, or 3.

[0044] In some embodiments, each R4 is independently selected from the group consisting of C1-4 alkyl, Cm alkoxy, C1-6 hydroxyalkyl, Cm haloalkyl, halogen, cyano, hydroxyl, -ΝΗ2, -CONR4aR4b, and- CO2R4a; wherein R4a and R4b have the definition given above, and wherein the R4 substituents can be attached to any suitable carbon ring vertex of the bicyclic heteroaryl.

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

[0046] In some embodiments, the portion of the ring having A°, A1, A2, A3, A4, A5, and A6 as ring vertices is a bicyclic heteroaryl selected from:

[0047] Returning to R1 and the additional substituent(s), in some embodiments, R1 is heteroaryl, Ce-io aryl, -Ci-6 alkylene-heteroaryl, -Ci-6-arylCó-io alkylene, four-carbon heterocycloalkyl. eight-membered, C3-8cycloalkyl, C1-8alkyl, -C(O)NRlaRlb, and CC>2Rla, where Rla and Rlb and heterocycloalkyl have the definition given above; the heteroaryl group is a 5- or 6-membered aromatic ring having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S, and wherein R1 is optionally substituted with 1 to 3 R5 substituents.

[0048] In some embodiments, the heterocycloalkyl groups of R1 or R5 are 4 to 6 membered rings having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S. In some embodiments, the heteroaryl groups of R1 or R5 are 5 to 6-membered aromatic rings having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S. In some embodiments, the Ce-io aryl group of R1 is phenyl .

[0049] In some embodiments, R1 is pyridyl, pyrimidyl, pyrazinyl, thiadiazolyl, phenyl, benzyl, cyclopentyl, tetrahydropyranyl, -C(O)NRlaRlb, -CCER13, or Ci-8alkyl, where Ría and Rib t¡ They have the definition given above for Formula I, and wherein R1 is optionally substituted with 1 to 3 R5 substituents.

[0050] In some embodiments, R1 is each of which is optionally substituted with 1 to 3 R5 substituents.

[0051] In some embodiments, R1 is each of which is optionally substituted with 1 or 2 R5 substituents.

[0052] In some embodiments, R1 is

[0053] In each of the described embodiments of R1, R5 may have the definition given above, or may be further defined as follows.

[0054] In some embodiments, each R5 is independently Ci-8 alkyl, alkoxy Ci-8, HaloCi-8alkyl, HaloCi-8alkoxy, HydroxyC¡-8alkyl, -Ci-8alkylheterocycloalkyl, C3-6cycloalkyl, halogen,—CONR5aR5b, —NR5aR5b, or —Ci-8alkylene-NR5aR5b, each R5a and R5b is independently selected from the group consisting of hydrogen and C1-4alkyl or, when attached to the same carbon atom, may combine with the nitrogen atom to form a 5- or 6-membered ring; and the heterocycloalkyl group is a 4 to 6-membered ring having 1 to 3 heteroatoms as ring vertices selected from N, O, and S.

[0055] In some embodiments, R5 is halogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, -C(O)NR5aR5b, and -CC>2R5a, where R5a and R5b have the given definition above (with reference to Formula I).

[0056] In some embodiments, R5 is cyclopropyl, isopropyl, isopropyloxy, OMe, Cl, F, -CONH2, -CF3, -0-CF3, either.

[0058] In some embodiments, R1 is

[0059] Returning to Formula I and the substituents R2a, R2b, R2c, R2d, and R2e, in some embodiments, R2a and R2e are each independently Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl. 6, -O-haloCi-6alkyl, or halogen. In some embodiments, R2b, R2c, and R2d are independently H, Cm alkyl, Cm haloalkyl, or halogen.

[0060] In some embodiments, R2b, R2c, and R2d are each H.

[0061] In some embodiments, R2a and R2e are each independently Me, Et, F, Cl, OMe, OCF3, and

[0062] In some embodiments, R2a and R2e are each independently C1-6alkyl or C1-6haloalkyl.

[0063] In some embodiments, R2a and R2e are each independently methyl or ethyl. In some embodiments, R2a and R2e are both methyl, or are both ethyl.

[0064] In some embodiments, the portion of Formula I represented by: MeO

[0065] Each R3 of Formula I, in some embodiments, is independently C1-4 alkyl, or when two R3 groups are on the same carbon atom, combine to form oxo (=0).

[0066] In some embodiments, n, the subscript of R3, is 0. In some embodiments n is 2 and the two R3 groups are on the same carbon atom and combine to form oxo (=0).

[0067] In some embodiments, the portion of Formula (I) represented by is

[0068] In some embodiments, the compound of Formula I is represented by the Formula (la) or (Ib):

[0069] In embodiments in which the compound of Formula (I) is represented by Formula (la), R1, R3, n, R2a, R2e, the portion of the ring having A1, A2, A3, A4 , A5, and A6 as vertices of the ring have the definition given above for Formula (I).

[0070] In embodiments where the compound of Formula (I) is represented by Formula (Ib), R', R2a, R2e, the portion of the ring having A1, A2, A3, A4, A5, and A6 as vertices of the ring has the definition given above for Formula (I).

[0071] In some embodiments, the compound of Formula (I) is represented by the Formula (le), (Id), or (le) (you).

[0072] In embodiments in which the compound of Formula (I) is represented by Formula (Ic), (Id) or (le), R1, R4, m, R2a, and R2e have the definition given with above for Formula (I).

[0073] In some embodiments, the compound of Formula (I) is represented by the Formula (lí), (Ig), (Ih), or (Ii):

[0074] In embodiments in which the compound of Formula (I) is represented by Formula (If), (Ig), (Ih), or (Ii), the portion of the ring having A1, A2, A3, A4, A5, and A6 as vertices of the ring, R2a, R2e, and R5 have the definition given above for Formula (I), and p is 0, 1, or 2.

[0075] In some embodiments, the compound of Formula (I) is represented by Formula (Ik), (II), or (Im):

[0076] In embodiments in which the compound of Formula (1) is represented by Formula (Ik), (II) or (Im), R4, m, and R5 have the definition given above for Formula (1), and p is 0, 1, or 2.

[0077] In some embodiments of Formulas (Ik), (II), and (Im), p is 1 or 2; m is 1 or 2; each R5 is independently C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkyl, C1-8 haloalkoxy, Cm hydroxyalkyl, -Ci-8 alkylheterocycloalkyl, C3-6 cycloalkyl, halogen, -CONR5aR5b, NR5aR5b, and -alkylene Ci-8-NR5aR5b, where each R5a and R5b is independently selected from the group consisting of hydrogen and Cm alkyl or, when attached to the same carbon atom, may combine with the nitrogen atom to form a 5-ring or 6-membered, wherein the heterocycloalkyl group is a 4 to 6-membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S; and each R4 is independently Cm alkyl, Cm alkoxy, Cm hydroxyalkyl, Cm haloalkyl, halogen, cyano, hydroxyl, -NH2, -CONR4aR4b, and -CO2R4a, wherein R4a and R4b have the definition given above.

[0078] In some embodiments, the compound of Formula (I) is a compound described in the Examples section. Preparation of Compounds

[0079] Certain compounds of the invention can be prepared following the methodology as described in the Examples section of this document. In addition, syntheses of certain intermediate compounds that are useful in the preparation of the compounds of the invention are also described. Pharmaceutical Compositions

[0080] In addition to the compounds provided above, compositions for modulating C5a activity in humans and animals will typically contain a pharmaceutical carrier or diluent.

[0081] The term composition, as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from the combination of the specified ingredients in the specified amounts. specified. By pharmaceutically acceptable is meant that the vehicle, diluent or excipient must be compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

[0082] Pharmaceutical compositions for administration of the compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy and drug delivery. All of the methods include the step of bringing the active ingredient into association with the vehicle constituting one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately associating the active ingredient with either 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.

[0083] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use; for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsions as described in US Patent Application 2002-0012680, hard or soft capsules, syrups, elixirs, solutions, mouth 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, flavoring, coloring, antioxidant and preservative agents to provide pharmaceutically elegant and appetizing preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, eg, corn starch or alginic acid; binding agents, for example PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated, enterically or otherwise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated using the techniques described in US Pat. 4,256,108; 4,166,452; and 4,265,874 to form controlled release osmotic therapeutic tablets.

[0084] Formulations for oral use 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 where the active ingredient is mixed with water or an oil medium, eg 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 mono-diglycerides, PEG esters, and the like.

[0085] The aqueous suspensions contain the active materials in admixture 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 acacia; dispersing or wetting agents may be a natural phosphatide, for example lecithin, or condensation products of alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, e.g. for example heptadecatonylenoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of hexitol, for example monooleate of polyethylene sorbitan. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0086] Oily 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. The oily suspensions may contain a thickening agent, eg 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 the addition of an antioxidant such as ascorbic acid.

[0087] Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient mixed with a dispersing or wetting agent, 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, flavors and colors. ]0088] The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be natural gums, for example gum acacia or gum tragacanth, natural phosphatides, for example soybean, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and products of condensation of said partial esters with ethylene oxide; for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

[0089] 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.

[0090] 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 to parental administration, for example a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be used including synthetic mono- or diglycerides. Furthermore, fatty acids such as oleic acid find use in the preparation of injectables.

[0091] The compounds of the present invention may 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 temperatures 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 via solutions or ointments. Furthermore, transdermal administration of the compounds of the invention can be carried out by means of iontophoretic patches and the like. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are used. Topical application herein is also intended to include the use of mouthwashes and gargling rinses.

[0092] The compounds of the present invention may also be coupled with a carrier that is a suitable polymer such as addressable pharmaceutical carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds of the invention may be coupled with a carrier that is a class of biodegradable polymers useful for achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, polyepsilon caprolactone, polyhydroxybutyric acid. , polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels. The semipermeable polymers and polymer matrices can be formed into molded articles, such as valves, stents, tubes, prostheses, and the like. In one embodiment of the invention, the compound of the invention is coupled with a semi-permeable polymer or polymeric matrix that is in the form of a stent or graft stent device.

[0093] The pharmaceutical compositions of the present invention may be formulated with one or more additional therapeutic agents. Said one or more additional therapeutic agents may include corticosteroids, steroids, immunosuppressants, or CD 20 inhibitors. 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, halomethasone, alclometasone dipropionate, beclomethasone, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidenide-17-hydrocortisone-acetate, hydrocortisone-17-propionate - 17-aceponate, hydrocortisone-17-buteprate, ciclesonide, and prednicarbate. Other discussions of combination therapy are included in the Methods of Use section of this application. Methods of Use

[0094] 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 C5a receptor ligand (eg, 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 herein, in the presence of the C5a receptor ligand in aqueous solution and under conditions suitable for binding. of the ligand to the C5a receptor. The C5a receptor may be present in suspension (eg, in an isolated membrane or cell preparation), in a cultured or isolated cell, or in a tissue or organ.

[0095] Preferably, the amount of C5a receptor modulator in contact with the receptor should be sufficient to inhibit C5a binding to the C5a receptor in vitro as established, eg, using a radioligand binding assay, mobilization assay of calcium or chemotaxis assay according to the present.

[0096] 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 signal transduction activity can be assessed by detecting an effect on calcium mobilization or by detecting an effect on C5a receptor-mediated cellular chemotaxis. In general, an effective amount of one or more C5a modulators is an amount sufficient to modulate C5a receptor signal transducing activity in vitro within a calcium mobilization assay or C5a receptor-mediated cellular chemotaxis within a migration assay. .

[0097] When the compounds of the invention are used to inhibit C5a receptor-mediated cellular chemotaxis, preferably leukocyte (eg neutrophil) chemotaxis, in an in vitro chemotaxis assay, such methods comprise contacting white blood cells 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, than the levels observed in a control assay. assay in which a compound of the invention has been added.

[0098] In another embodiment, the compounds of the present invention may additionally be used to treat patients suffering from conditions that are responsive to modulation of the C5a receptor. As used herein, the term "treat" or "treatment" encompasses both disease-modifying treatment and symptomatic treatment, either of which can be prophylactic (i.e., before the onset of symptoms to prevent, delay, or reduce the severity of symptoms) or therapeutic (i.e. after the onset of symptoms, in order to reduce the severity and / or duration of symptoms). Accordingly, a condition is considered responsive to C5a receptor modulation if modulation of C5a receptor activity results in the reduction of inappropriate activity of a C5a receptor. As used herein, 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 modulating C5a:

[0099] Autoimmune disorders: eg, rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barre syndrome, pancreatitis, lupus nephritis, lupus, glomerulonephritis, psoriasis, Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, asthma bronchial, dense deposit disease, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture syndrome (and associated glomerulonephritis and pulmonary hemorrhage), C3 glomerulopathy, C3 glomerulonephritis, membranoproliferative glomerulonephritis, Kawasaki disease, IGA nephropathy , immunovasculitis, tissue graft rejection, graft-versus-host disease, hyperacute rejection of transplanted organs; and the like.

[0100] Inflammatory disorders and related conditions: eg, neutropenia, sepsis, septic shock, Alzheimer's disease, multiple sclerosis, neutrophilia, stroke, inflammatory bowel disease (IBD), inflammation associated with severe burns, lung injury, and ischemia injury- reperfusion, osteoarthritis, as well as acute respiratory distress syndrome (adult) (ARDS), chronic obstructive pulmonary disease (COPD), systemic inflammatory response syndrome (SIRS), atopic dermatitis, psoriasis, chronic urticaria, and multi-organ dysfunction syndrome (MODS) , hemolytic uremic syndrome, atypical hemolytic uremic syndrome (aHUS). Also included are pathologic sequelae associated with insulin-dependent diabetes mellitus (including diabetic retinopathy), lupus nephropathy, Heyman's nephritis, membranous nephritis, and other forms of glomerulonephritis, touch sensitivity responses, and inflammation resulting from contact of blood with artificial surfaces that may cause complement activation, as occurs, for example, during extracorporeal circulation of blood (for example, during hemodialysis or through a heart-lung machine, for example, in association with vascular surgery such as coronary artery bypass grafting or valve replacement heart), or in association with contact with other artificial vessel or container surfaces (for example, ventricular assist devices, artificial heart machines, transfusion tubes, blood storage bags, plasmapheresis, plateletpheresis, and the like). Diseases related to ischemia / reperfusion injury, such as those resulting from transplantation, including solid organ transplantation, and syndromes such as ischemic reperfusion injury, ischemic colitis, and cardiac ischemia are also included. The compounds of the present invention may also be useful in the treatment of age-related macular degeneration. (Hageman et al, P.AU.S. 102:7227-7232, 2005).

[0101] Cardiovascular and cerebrovascular disorders: eg, myocardial infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, atherosclerosis, traumatic central nervous system injury, and ischemic heart disease. In one embodiment, an effective amount of a compound of the invention may be administered to a patient at risk for myocardial infarction or thrombosis (i.e., a patient who has one or more recognized risk factors for myocardial infarction or thrombosis). such as, but not limited to, obesity, smoking, hypertension, hypercholesterolemia, prior history or genetic history of myocardial infarction or thrombosis) to reduce the risk of myocardial infarction or thrombosis.

[0102] Oncological Diseases or Disorders: eg, melanoma, lung cancer, lymphoma, sarcoma, carcinoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, mesothelioma, meningioma, leukemia, lymphoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, pleomorphic adenoma, cell papilloma hepatic, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma and fibroma.

[0103] 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 believed to play an important role in initiating leukocyte migration, as well as in the resulting damage manifested at the site of inflammation. (Vasculitis, Second Edition, Edited by Ball and Bridges, Oxford University Press, pp. 47-53, 2008). The compounds provided in the present invention can be used to treat leukocytic vasculitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune vasculitis, Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, Henoch-Schonlein purpura, polyatheritis nodosa, rapidly progressive glomerulonephritis (RPGN), cryoglobulinemia, giant cell arteritis (GCA), Behcet's disease, and Takayasu's arteritis (TAK).

[0104] HIV Infection and AIDS: The C5a receptor modulators provided herein can be used to inhibit HIV infection, delay the progression of AIDS, or lessen the severity of HIV infection and AIDS symptoms or infection.

[0105] Neurodegenerative Disorders and Related Diseases: In other aspects, the C5a antagonists provided herein can be used to treat Alzheimer's disease, multiple sclerosis, and decreased cognitive function associated with cardiopulmonary bypass surgery, and procedures. related.

[0106] In one embodiment of the invention, the compounds of the invention may 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.

[0107] The methods of treatment described herein generally include administration to a patient of an effective amount of one or more compounds herein. Suitable patients include those patients who have or are likely to have (ie, prophylactic treatment) a disorder or disease identified herein. Typical patients for treatment in accordance with 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.

[0108] In general, the methods of treatment 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 (eg, a human) orally or topically. The effective amount may be an amount sufficient to modulate C5a receptor activity and / or an amount sufficient to reduce or alleviate symptoms experienced by the patient. Preferably, the amount administered is sufficient to produce a plasma concentration of the compound (or its active metabolite, if the compound is a prodrug) high enough to detectably inhibit white blood cell (eg, neutrophil) chemotaxis in vitro . Treatment regimens may vary depending on the compound used and the particular condition being treated. For the treatment of most disorders, a frequency of administration of 4 times per 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 dose level and treatment regimen for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination (i.e., other drugs being administered to the patient), and severity of the particular disease being treated, as well as the discretion of the GP. In general, the use of the lowest dose sufficient to provide effective treatment is preferred. In general, patients can generally be monitored for therapeutic effectiveness using appropriate medical or veterinary criteria for the condition being treated or prevented.

[0109] 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 C5a pathogenic activity (about 0.5 mg to approximately 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 pg (micrograms) / ml serum, more preferably, it is a compound should be administered to achieve a serum concentration of 20 ng-1 pg / ml serum, more preferably, compound sufficient to achieve a serum concentration of 50 ng / ml-200 ng / ml serum. For direct injection into the synovium (for the treatment of arthritis) sufficient compounds should be administered to achieve a local concentration of approximately 1 micromole.

[0110] Dosing frequency may also vary depending on the compound used and the particular disease being treated. However, for the treatment of most disorders, a dosing regimen of 4 times a day, 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 dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, the route of administration, and the rate of excretion, the combination of drugs (i.e., other drugs being administered to the patient), the severity of the particular disease being treated, and other factors, including the criteria of the GP. Combination Treatment

[0111] The compounds described herein may be used in combination with one or more additional therapeutic agents that are employed in the treatment, prevention, suppression, or amelioration of the diseases or conditions for which the compounds and compositions of the present invention are useful. Said one or more additional therapeutic agents can be administered, by one route and in an amount commonly used for that purpose, simultaneously or sequentially! with a compound or composition of the present invention. When a compound or composition of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound or composition of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound or composition of the present invention.

[0112] Examples of one or more additional therapeutic agents that may be combined with a compound or composition of the present invention, administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists, (b) steroids and corticosteroids, such as beclomethasone, betamethasone (including betamethasone sodium phosphate, betamethasone valerate, betamethasone dipropionate) prednisone, prenisolone, methylprednisolone, mometasone, dexamethasone (including dexamethasone sodium phosphate), fluticasone, cortisone (including cortisone acetate) hydrocortisone ( including hydrocortisone acetate, hydrocortisone-17-valerate, hydrocortisone-17-butyrate, hydrocortisone-17aceponate, hydrocortisone-17-buterate), budesonide, desonide, fluocinonide (including fluocinolone acetonide), triamcinolone (including triamcinolone acetonide and triamcinolone alcohol ), tixocortol (including tixocortol pivalate) fluocortolone (including fluocortolone capr oate and fluocortolone pivalate), amcinonide, halcinonide, halomethasone, fluprednidene acetate, salmeterol, salmeterol, salbutamol, ciclesonide, formeterol, alclomethasone (including alclomethasone dipropionate), prednicarbate, clobetasone (including clobetasone-17butene), clobetasol (including clobetasol-17 -propionate); (c) immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506-type immunosuppressants, and nicophenolate, for example, mycophenolate mofetil (CellCept8); (d) antihistamines (HIhhistamine antagonists) such as brompheniramine, chlorpheniramine, dexchloipheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyralamine, tripelenamine, hydroxyzine, metdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine , fexofenadine, descarbo ethoxyloratadine and the like; (e) nonsteroidal antiasthmatics (for example, terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (for example, zafmlukast, montelukast, pranlukast, iralukast , pobilukast and SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); (f) Non Steroidal Anti-Inflammatory Agents (NSAIDs) such as propionic acid derivatives (for example, alminoprofen, benoxaprofen, bucoxy acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, riroprofen, naproxen, oxaprozin, pirprofen), pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (for example, indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinaco, sulindac, thiopinac, tolmetin, zidomethacin and zomepirac), fenamic acid derivatives (for example, flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (for example, diflunisal and flufenisal ), oxicam (for example, isoxicam, piroxicam, sudoxicam, and tenoxican), salicylates (for example, acetylsalicylic acid and sulfasalazine) and pyrazolones (eg apazone, bezpiperilon, feprazone, mofebutazone, oxyphenbutazone and phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (h) phosphodiesterase type IV (PDE IV) inhibitors; (i) gold compounds such as auranofin and aurothioglucose, (j) etanercept (EnbrelO), (k) cyclophosphamide, (1) antibody therapies such as orthoclone (0KT3), daclizumab (Zenapax®), basiliximab (Simulect®) and infliximab (Remicade®), (m) CD20-directed antibody therapies such as obinutuzumab, rituximab, or ocrelizumab; (n) Chemotherapeutic agents such anthracyclines (for example, daunorubicin (daunomycin, rubidomycin), doxorubicin, epirubicin, idarubicin, and valrubicin), mitoxantrone, and pixantrone; platinum-based agents (eg, cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, and lipoplatin); tamoxifen and metabolites thereof such as 4-hydroxytamoxifen (afimoxifen) and N-desmethyl-4-hydroxytamoxifen (endoxifen); taxanes such as paclitaxel (taxol) and docetaxel; alkylating agents (for example, nitrogen mustards such as mechlorethamine (HN2), cyclophosphamide, ifosfamide, melphalan (L-sarcolysine) and chlorambucil); ethyleneimines and methylmelamines (for example, hexamethylmelamine, thiotepa, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine (BCNLJ), lomustine (CCNLJ), semustine (methyl-CCN-U), and streptozoein (streptozotocin), and triazenes such as decarbazine (DTIC; dimethyltriazenoimidazolecarboxamide )); antimetabolites (for example, folic acid analogues such as methotrexate (ametopterin), pyrimidine analogues such as fluorouracil (5-fluorouracil, 5-FU), floxuridine (fluorodeoxyuridine; FUdR), and cytarabine (cytosine arabinoside), and purine and related inhibitors such as mercaptopurine (6-mercaptopurine; 6-MP), thioguanine (6-thioguanine; 6-TG), and pentostatin (2'deoxycophonincin)); (o) other chemokine receptor antagonists, especially CXCR2, CXCR3, CCR2, CCR3, CCR4, CCR7, CX3CR1 and CXCR6.

[0113] The disease or disorder being treated will determine which additional therapeutic agent(s) are most suitable in combination with the compounds of the present invention. Such a determination can be made by one skilled in the art.

[0114] The weight ratio between the compound of the present invention and the second active ingredient may be altered, and will depend on the effective dose of each ingredient. In general, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID, the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200: 1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also fall within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. Non-Pharmaceutical Applications

[0115] In another aspect of the invention, the compounds of the invention may 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 (cell preparations or tissue section samples). The compounds of the invention may 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 PET or SPECT imaging. , for its acronym in English 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 well-known techniques (for example, radiolabeled with a radionuclide such as tritium), and incubated with a sample for a suitable incubation time (for example, determined firstly the time of the union). After incubation, unbound compound is removed (eg by washing) and bound compound is detected using any method suitable for the marker employed (eg autoradiography or scintillation counting for radiolabeled compounds; spectroscopic methods can be used to detect luminescent groups and fluorescent groups). As a control, an adapted sample containing the labeled compound and a larger amount (eg, 10-fold larger) of unlabelled compound can be processed in the same way. 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, New York.

[0116] The compounds provided herein can also be used within a variety of well-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 (eg, isolate cells expressing the receptor). recipient) in vitro. In a preferred application, a modulator linked to a fluorescent marker, such as fluorescein, is contacted with cells, which are then analyzed (or isolated) by Fluorescence Activated Cell Sorting (FACS). Cell Sorting). Examples

[0117] The following examples are illustrative and do not limit the claimed invention.

[0118] The reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). 1H Nuclear Magnetic Resonance ('H-NMR) spectra were recorded on a Vary 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 Μ + H (or, as indicated, M-H) ion containing the most common atomic isotopes. The isotope patterns correspond to the predicted formula in all cases. Electrospray ionization (ESI) and mass spectrometry analysis was performed on a Hewlett-Packard MSD electrospray mass spectrometer using HP1100 HPLC for sample elution. Typically, the analyte was dissolved in methanol at 0.1 mg / mL and 1 microliter infused with the eluting 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 the eluting solvent. The compounds provided below could also be analyzed in the negative ESI mode, using 2 mM NH4OAc in acetonitrile / water as the elution system.

[0119] The following abbreviations are used in the Examples and throughout the description of the invention: EtOH: Ethanol EthONa: Sodium ethoxide THF: Tetrahydrofuran TLC (Thin Layer Chromatography): Thin layer chromatography MeOH: Methanol

[0120] 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 can be employed to synthesize the subject compounds, and that the approaches described in the body of this document are not exhaustive, but rather provide practical and widely applicable pathways to the compounds of interest.

[0121] Certain molecules claimed in this disclosure can exist in different enantiomeric and diastereomeric forms, and all variants of these compounds are claimed.

[0122] 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.

[0123] Those skilled in the art will also recognize that acids and bases are frequently used during standard procedures in organic chemistry. Salts of the parent compounds are sometimes produced, if they possess the necessary intrinsic acidity or basicity, during the experimental procedures described in this invention. Synthesis of tert-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2 / 7-pyrazoIo[4,3-c|pyridine5(4Z7)-carboxylate 1) HCI, NaNO2 2) SnCl2-2H2O 3) NaOH 4) HCl.'Et2O step by step NC EtOH, reflux pas or b 2) Isoamyl nitrites CuBr, MeCN Caution: Diazonium formation could be potentially dangerous; please treat with care and wear appropriate personal protective equipment.

[0124] Step a: To a 250 mL flask charged with 90 mL of concentrated hydrochloric acid under magnetic stirring was added 2,6-diethylaniline (10 g, 67 mmol). 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 mmol) in water (60 mL) was slowly added to the above mixture while keeping the internal temperature below 5 °C.

[0125] Separately, tin(II) chloride dihydrate (31.6 g, 140 mmol) was added to a 500 mL 3-neck round bottom flask charged with concentrated hydrochloric acid (60 mL) under mechanical stirring. The resulting solution was then cooled with an ice bath.

[0126] 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 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 thus recovered 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 shaken with ether (180 mL). The resulting mixture was cooled in an ice bath, and NaOH solution (10 N, 30 mL) was slowly added to the above mixture while keeping the internal temperature below 12 °C. After the addition, the mixture was allowed to stand for 2h 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.

[0127] Step b: Λζ-V-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 3h. Glacial acetic acid (12 mL, 208 mmol) was added and the mixture was stirred under reflux for a further 2 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and washed with NaOH solution (2N), 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 for-butyl 3-amino-2-(2,6-diethylphenyl)-6, 7-dihydro-2 / / pyrazolo[4,3-c]pyridine-5(427)-carboxylate. MS: (ES) m / z calculated for C21H31 N4O2 [M + H]+ 371.2, found 371.2. Caution: Diazonium formation could be potentially dangerous; please treat with care and wear appropriate personal protective equipment.

[0128] Isopentenyl nitrite (4 mL, 28.6 mmol) was added slowly at room temperature to a mixture of / er-butyl 3-amino-2-(2,6-diethylphenyl)-6,7-dihydro-2 / 7-Pyrazolo[4,3-c]pyridine-5(4Z7)carboxylate (3 g, 8.1 mmol), CuBr (4 g, 27.9 mmol), and MeCN (50 mL) in a 100 ml round bottom flask. 250 mL under magnetic stirring. The resulting mixture was stirred at room temperature for 1 h, diluted with EtOAc, filtered through Celite, washed with saturated NH4Cl soln, and dried over 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 for-butyl 3-bromo-2-(2,6-diethylphenyl)-6, 7-dihydro-277-pyrazolo[4,3c]pyridine-5(477)-carboxylate. MS: (ES) m / z calculated for C2iH29BrN3O2 [M+H]+ 434.1, found 434.2. Synthesis of 7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-LEf-indole step to B is(pina co llatojdiboroi Pd(dppf)Cl2-CH2CI!2 Step b

[0129] Step a: A solution of vinylmagnesium bromide in THF (1 M, 60 mL, 60 mmol) was rapidly added to a solution of 4-bromo-l-chloro-2-nitrobenzene (4.7 g, 19.9 mmol) in anhydrous THF (50 mL) under N2 and stirring vigorously at -60 °C. The reaction mixture was stirred at the same temperature and allowed to warm to -30 °C in 1.5 h. The reaction was quenched with saturated NH4CI 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 over 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-7-chloro-17 / -indole. MS: (ES) m / z calculated for CgHóBrCIN [M + H]+229.9, found 229.9.

[0130] Step b: To a suspension of 4-bromo-7-chloro-17 / -indole (1.7 g, 7.4 mmol), 4,4,4',4',5,5,5' ,5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.4 g, 13.4 mmol), and KOAc (3 g, 30.6 mmol) in p-dioxane (12 mL) Pd(dppf)Cl2 complex was added with dichloromethane (800 mg, 0.97 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 100 °C for 3 h. The reaction mixture was 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 (5 to 20% EtOAc in hexanes) to obtain 7-chloro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2yl)-17 / -indole. MS: (ES) m / z calculated for Ci5H2oBFN02 [M+H]+276.1, found 276.1. Synthesis of 2,3-difluoro-5-(l-methylethyl)pyridine 1) Pd(dppf)CI2’CH2CI2 2) H2, Pd / C

[0131] To a suspension of 5-bromo-2,3-difluoropyridine (9.0 g, 46 mmol), 4,4,5,5-tetramethyl- 2-(l-methylethenyl)-1,3,2-dioxaborolane (11 g, 65 mmol), and sodium carbonate (15 g, 140 mmol) in a mixture of dioxane (150 mL) and water (40 mL) were added Pd(dppf)Ch complex with dichloromethane (2.0 g, 2.4 mmol). The reaction mixture was degassed (N2) for 2 min and refluxed for 1 h. The dioxane was removed in vacuo and the residue was taken up in dichloromethane and water. The organic phase was separated, filtered through Celite, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (5% EtOAc in hexanes) to obtain 2,3-difluoro-5-(1-methylethenyl)pyridine. Ή NMR (400 MHz, CDCI3) δ 8.04 (t, J= 1.9 Hz, 1H), 7.58-7.65 (m, 1H), 5.39 (s, 1H), 5.22 (s, 1H), 2.14 (s, 3H).

[0132] To the above 2,3-difluoro-5-(l-methylethenyl)pyridine (5.9 g, 38 mmol) dissolved in EtOAc (100 mL) was added 10% Pd / C (Degussa type E101 NE / W , 420mg). The mixture was stirred under an atmosphere of hydrogen for 17h. When the reaction was complete, the mixture was filtered through Celite and the solvent was removed in vacuo to obtain 2,3-difluoro-5-(l-methylethyl)pyridine. 'H NMR (400 MHz, CDCI3) δ 7.82 (t, J = 1.7 Hz, 1H), 7.38-7.45 (m, 1H), 2.91-3.10 (m, 1H ), 1.27 (d, .7=7.2Hz, 6H). Synthesis of / er-butyl 4-bromo-6-fluoro-7-(hydroxymethyl)-lE?-benzo[íZ]imidazole-l-carboxylate F br F CO2M& The step by step HNO3, h2so4 NH3 / dioxane NH3 / MeOH 'C step b Faith, NH4CI HCO2H, IPA ao'c step c 1) LÍAIH.-., THF 2HBoc)2O, DMAP DCM step d

[0133] Step a: A mixture of methyl 4-bromo-2,6-difluorobenzoate (5.5 g, 21.9 mmol), conc. (25 mL) and HNO3 (25 mL) was stirred at room temperature for 0.5 hr. It was then poured onto ice and extracted with EtOAc. The organic layer was separated, dried in the presence of Na2SO4, concentrated on a rotary evaporator under reduced pressure, and the residue was purified by flash chromatograph on silica gel (0-40% EtOAc / hexanes) to obtain methyl 4-bromo. -2,6-difluoro-3-nitrobenzoate. MS: (ES) m / z calculated for CgH4BrF2NO4 [M + H]+ 295.1, found 295.1.

[0134] Step b: A mixture of methyl 4-bromo-2,6-difluoro-3-nitrobenzoate (6.0 g, 20.2 mmol) and NHs / dioxane (0.5M, 200 mL, 100 mmol) was stirred at 60 °C for 1 hr. To the mixture was then added NHs / MeOH (1.0M, 100 mL, 100 mmol) and heating continued for another 15 min at the same temperature. It was then cooled to room temperature, poured into water, and extracted with EtOAc. The organic layer was separated, dried in the presence of Na2SO4, concentrated on a rotary evaporator under reduced pressure, and the residue was purified by flash chromatograph on silica gel (0 to 100% EtOAc / hexanes) to obtain methyl 2- amino-4-bromo-6fluoro-3-nitrobenzoate. MS: (ES) m / z calculated for CsHóBrFNsCh [M + H]+292.0, found 292.0.

[0135] Step c: A mixture of methyl 2-amino-4-bromo-6-fluoro-3-nitrobenzoate (3.6 g, 12.2 mmol), Fe (25 g, 447 mmol), NH4C1 (30 g , 560 mmol), trimethyl orthoformate (50 mL), formic acid (70 mL), and IPA (120 mL) conc. (25 mL) and HNO3 (25 mL) were stirred at 80 °C for 5 hours. It was then cooled to room temperature, diluted with 20% MeOH / DCM, and filtered through Celite. The filtrate was collected, concentrated on a rotary evaporator under reduced pressure and the residue was purified by flash chromatograph on silica gel (0 to 100% EtOAc / hexanes) to obtain methyl 4-bromo-6-fluoro-17 / -benzo[í / ]imidazol7-carboxylate. MS: (ES) m / z calculated for C9H6BrFN2O2 [M+H]+272.2, found 272.2.

[0136] Step d: A mixture of methyl 4-bromo-6-fluoro-177-benzo[íZ]imidazol-7-carboxylate (0.64 g, 2.35 mmol) and LiAlH4 (3.3 mL, IM / ether, 3.3 mmol) in THF (7 mL) was stirred at 0 °C for 1 hr. It was then poured into aq. NH4OH. and extracted with IPA / CHCI3. The organic layer was separated, dried in the presence of Na2SO4, concentrated on a rotary evaporator under reduced pressure. The residue was purified by flash chromatograph on silica gel (0 to 30% MeOH / EtOAc) to obtain (4-bromo-6-fluoro-1 / 7-benzo[Z]imidazo!-7-yl)methanol . MS: (ES) m / z calculated for CgHóBrF^O[M+H]+243.9, found 243.9.

[0137] A mixture of (4-bromo-6-fluoro-177-benzo[<7]iniidazol-7-yl)methanol (0.48 g, 1.96 mmol), (BOCjzO (2.0 g, 9 0.2 mmol) and DMAP (0.36 g, 3 mmol) in DCM (25 mL) was stirred at room temperature for 1 hr, then poured into aq. dried in the presence of Na2SO4, concentrated on a rotary evaporator under reduced pressure, the residue was purified by flash chromatograph on silica gel (0 to 60% EtOAc / hexanes) to give phor-butyl 4-bromo-6- fluoro-7-(hydroxymethyl)127-benzo[<7]imidazole-l-carboxylate MS: (ES) m / z calculated for CnHuBrF^Ch [M + H]+ 344.0, found 344.0. Synthesis of thor-butyl 4-bromo-7-chloro-lZf-pyrrolo[3,2-c]pyridine-l-carboxylate HgO3, TEA step by hno3, h2so4 step b P8r3, DCM step c Boc2O. DMAP, MeCN step e MgBr step di

[0138] Step a: A solution of 2-bromo-5-chloropyridine (25 g, 0.13 mol) in 70 mL TFA was added dropwise to 35% w / w aqueous H2O2 solution. The solution was heated at 70 °C for 16 hrs, then quenched with saturated sodium sulfite solution. The mixture was extracted with ethyl acetate and the organic layers combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (70% EtOAc in hexanes) to obtain 2-bromo-5-chloropyridine 1-oxide. MS: (ES) m / z calculated for CsFEBrCYNO[M+H]+207.9, found 207.9.

[0139] Step b: To a solution of 2-bromo-5-chloropyridine 1-oxide in 100 mL H2SO4 at 0 °C, 46 mL HNO3 was added dropwise. The solution was heated at 65 °C for 16 hrs, then quenched with 250 mL of FEO. The mixture was stirred at room temperature overnight and the precipitate was filtered and collected. The solid was further purified on silica gel column chromatography to obtain 2-bromo-5-chloro-4-nitropyridine 1-oxide 2-bromo-5-chloropyridine 1-oxide. MS: (ES) m / z calculated for CsEEBrCnxhCh [M + H]+252.9, found 252.9.

[0140] Step c: To a solution of PBn (1.32 mL, 14.3 mmol) in 3 mL DCM was added portionwise 2-bromo-5-chloro-4-nitropyridine 1-oxide 2-bromo-5-chloropyridine (1.5 g, 6.0 mmol). The mixture was stirred at room temperature for 30 min, then cooled to 0 °C and slowly quenched with ice water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (10% ethyl acetate in hexanes) to obtain 2-bromo-5-chloro-4-nitropyridine.

[0141] Step d: To a solution of 2-bromo-5-chloro-4-nitropyridine (1.6 g, 6.6 mmol) in 26 mL THF at -78 °C was added dropwise a solution of bromide of 1.0 M vinylmagnesium in THF (23.2 mL, 23.2 mmol). The solution was stirred at -78 °C for 30 min, then quenched slowly with 1N HC1 solution. The aqueous and organic layers were separated, and the aqueous layer was washed with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (40% ethyl acetate in hexanes) to obtain 4-bromo-7-chloro-177-pyrrolo[3,2-c]pyridine. MS: (ES) m / z calculated for C?H4BrClN2 [M+H]+230.9, found 230.9.

[0142] Step e: A solution of 4-bromo-7-chloro-1β7-pyrrolo[3,2-c]pyridine (0.3 g, 1.3 mmol) in 2.6 mL of acetonitrile is added di-tert-butyl dicarbonate (0.6 mL, 2.6 mmol) followed by DMAP (0.16 g, 1.3 mmol). The solution was stirred at room temperature for 15 min. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (10% ethyl acetate in hexanes) to provide Zer-butyl 4-bromo-7-chloro-1 / / -pyrrolo[3,2c] pyridine-l-carboxylate. MS: (ES) m / z calculated for Ci2Hi2BrClN2O2 [M+H]+ 331.0, found 331.0. Example 1 Synthesis of 3-(6-chloro-7-methoxy-1H-indoI-4-yl)-2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5, 6,7-tetrahydro-2ZLpyrazolo[4,3-c]pyri'idine step to B yes pina c o lato )dibo ro- Pd(dppf)CI2'CH2CI2 step b

[0143] Step a: Iodomethane (1.5 mL, 24 mmol) was added to a suspension of 4-bromo-2chloro-6-nitrophenol (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 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 5-bromo-1-chloro-2-methoxy-3-nitrobenzene. MS: (ES) m / z calculated for CvHóBrCINOs [M + H]+265.9, found 265.9.

[0144] 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 stirring vigorously at -60 °C. The reaction mixture was allowed to warm to -30 °C in 1.5 h. The reaction was quenched with saturated NH4CI 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 over 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 C9H8BrClNO [M+H]+259.9, found 259.9.

[0145] Step b: To a suspension of 4-bromo-6-chloro-7-methoxy-1 / 7-indole (1.2 g, 4.6 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.4 g, 9.5 mmol), and KOAc (2.3 g, 23.4 mmol) in DMSO (10 mL) was added Pd(dppf)C12 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 over 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 6-chloro-7-methoxy-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1 / / -indole. MS: (ES) m / z calculated for C15H20BCINO3 [M+H]+308.1, found 308.1.

[0146] Step c: To a suspension of / er-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2 / / pyrazolo[4,3-c]pyridine-5(4H )-carboxylate (600 mg, 1.4 mmol), 6-chloro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 / / -indole (550 mg, 1.8 mmol), K2CO3 (500 mg, 3.6 mmol) in p-dioxane (6 mL), and water (1 mL) Pd(dppf)Ch complex with dichloromethane (300 mg, 0. 37mmol). 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 over 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 / er-butyl 3-(6-chloro-7-methoxy-177-indole- 4-yl)-2-(2,6-diethylphenyl)-6,7dihydro-2H-pyrazolo[4,3-c]pyridine-5(4 / / )-carboxylate. MS: (ES) m / z calculated for C3oH36C1N403 [M+H]+535.2.1, found 535.2.

[0147] / er-Butyl 3-(6-chloro-7-methoxy-l / / -indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2Zfpyrazolo[4, 3-c]pyridine-5(4Z / )-carboxylate above was dissolved in dichloromethane (5 mL) and charged with HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. Once the reaction was complete, the solvent was evaporated in vacuo to obtain 3-(6chloro-7-methoxy-177-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7- tetrahydro-27 / -pyrazolo[4,3-c]pyridine hydrochloride. MS: (ES) m / z calculated for C2sH29C1N4O [M+H]+435.2, found 435.2.

[0148] Step d: ΛζΑ-Diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspension of 3-(6-chloro-7-methoxy-l / / -indol-4-yl)-hydrochloride. 2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-277pyrazolo[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 over 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-methoxy127-indol-4-yl)-2- (2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / 7pyrazolo[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. Example 2 Synthesis of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl-1ZT-indol-4-yl)-5-(5(trifluoromethyl)pyrinidin-2-yl)-4,5, 6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridine Pd(dppf)CI2-CH2CI2 pas or b Bis(p ¡na co I a to) díbo roí

[0149] Step a: A solution of vinylmagnesium bromide in THF (1 M, 70 mL, 70 mmol) was rapidly added to a solution of 5-bromo-l-fluoro-2-methyl-3-nitrobenzene (5.0 g, 21.3 mmol) in anhydrous THF (40 mL) under N2 and stirred vigorously at -60 °C. The reaction mixture was allowed to warm to -30 °C in 1.5 h. The reaction was quenched with saturated NH4CI 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-fluoro-7-methyl-177-indole. MS: (ES) m / z calculated for C^sBrFN[M+H]+227.9, found 227.9.

[0150] Step b: To a suspension of 4-bromo-6-fluoro-7-methyl-1 / 7-indo 1 (1.0 g, 4.4 mmol), 4,4,4',4', 5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.0 g, 7.9 mmol), and KOAc (2 g, 20.4 mmol) In / ?-dioxane (12 mL) was added Pd(dppf)Ch complex with dichloromethane (600 mg, 0.73 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 100 °C for 3 h. The reaction mixture was diluted with EtOAc, filtered through Celite. 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 6-fluoro-7-methyl-4-(4,4,5,5 -tetramethyl-1,3,2dioxaborolan-2-yl)-1 / 7-indole. MS: (ES) m / z calculated for C15H20BFNO2 [M + H]+ 276.1, found 276.1.

[0151] Step c: To a suspension of tert-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2 / / pyrazolo[4,3-c]pyridine-5(4Z / )-carboxylate (500 mg, 1.2 mmol), 6-fluoro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroIan-2-yl)-1 / / -indole (260 mg, 0.94 mmol), K2CO3 (500 mg, 3.6 mmol) in / / -dioxane (6 mL), and water (1 mL), Pd(dppf)C12 complex with dichloromethane (100 mg, 0 0.12mmol). 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 over 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 2-(2,6-diethylphenyl)-3-(6-fluoro -7-methyl-l / / -indol-4-yl)- 6,7-dihydro-22 / -pyrazolo[4,3-c]pyridine-5(4 / / )-carboxylate. MS: (ES) m / z calculated for C30H36FN4O2 [M+H]+503.2, found 503.2.

[0152] / er-Butyl 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl-1 / / -indol-4-yl)-6,7-dihydro-2 / fpyrazolo[ 4,3-c]pyridine-5(42f)-carboxylate above was dissolved in dichloromethane (5 mL) and charged with HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. Once the reaction was complete, the solvent was evaporated in vacuo to obtain 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl-l / / -indol-4-yl)-4,5,6 ,7-tetrahydro-2Ff-pyrazolo[4,3-c]pyridine hydrochloride. MS: (ES) m / z calculated for C25H28FN4 [M+H]+403.2, found 403.2.

[0153] Step d: ΛζΑ-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspension of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl-1 hydrochloride / / -indol-4-yl)-4,5,6,7-tetrahydro-277pyrazolo[4,3-c]pyridine (50 mg, 0.11 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine ( 45 mg, 0.25 mmol), and LI2CO3 (20 mg, 0.27 mmol) in DMSO (5 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 over 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 2-(2,6-diethylphenyl)-3(6-fluoro-7-methyl- 1 / 7-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / 7pyrazolo[4,3-c]pyridine. Ή NMR (400 MHz, CDCI3) δ 8.48 (s, 2H), 8.17 (s, 1H), 7.18-7.29 (m, 2H), 7.05 (d, J= 7, 8 Hz, 2H), 6.37-6.49 (m, 2H), 4.84 (s, 2H), 4.35 (t, J= 5.9 Hz, 2H), 3.04 (t, J = 5.9 Hz, 2H), 2.34 (d, J = 1.5 Hz, 3H), 2.10-2.33 (m, 4H), 0.80-1.08 (m, 6H ). MS: (ES) m / z calculated C30H29F4N6 [M+H]+549.2, found 549.2. Example 3 Synthesis of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl-1Ef-indol-4-yl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5, 6,7-tetrahydro-2Zf-pyrazolo[4,3-c]pyridine

[0154] Step a: A solution of vinylmagnesium bromide in THF (1 M, 60 mL, 60 mmol) was rapidly added to a solution of 5-bromo-l-chloro-2-methyl-3-nitrobenzene (5.0 g, 20 mmol) in anhydrous THF (100 mL) under N2 and stirred vigorously at -40 °C. The reaction mixture was stirred at the same temperature for 1.5h. The reaction was quenched with saturated NH4CI 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 over MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (4 to 6% methyl tert-butyl ether / hexane) to obtain 4-bromo-6-chloro-7-methyl-1H-indole. . MS: (ES) m / z calculated for CgHsBrQN [M + H]+243.9, found 243.9.

[0155] Step b: To a suspension of 4-bromo-6-chloro-7-methyl-177-indole (1.0 g, 4.1 mmol), 4,4,4',4',5,5 ,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.0 g, 7.9 mmol), and KOAc (2 g, 20.4 mmol) in p- dioxane (12 mL) was added Pd(dppf)C12 complex with dichloromethane (600 mg, 0.73 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 100 °C for 3 h.

[0156] The reaction mixture was diluted with EtOAc, filtered through Celite. 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 6-chloro-7-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-177-indole. MS: (ES) m / z calculated for C15H20BCINO2 [M+H]+ 292.1, found 292.1.

[0157] Step c: To a suspension of / er-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2 / 7pyrazolo[4,3-c]pyridine-5(4 / / )-carboxylate (380 mg, 0.87 mmol), 6-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 / 7- indole (250 mg, 0.86 mmol), K2CO3 (290 mg, 2.1 mmol) in p-dioxane (6 mL), and water (1 mL) Pd(dppf)C12 complex was added with dichloromethane (160 mg, 0 .19mmol). 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 over 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 / er-butyl 3-(6-chloro-7-methyl-1H-indole -4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro2Z / -pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. MS: (ES) m / z calculated for C30H36CIN4O2 [M+H]+ 519.2, found 519.2.

[0158] / er-Butyl 3-(6-chloro-7-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2 / / pyrazolo[ 4,3-c]pyridine-5(4 / 7)-carboxylate above was dissolved in dichloromethane (5 mL) and charged with HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. After the reaction was complete, the solvent was evaporated in vacuo to obtain 3-(6-chloro-7-methyl-1Z7-indol-4-yl)-2-(2,6-diethylphenyl)-4,5 hydrochloride, 6,7-tetrahydro-277pyrazolo[4,3-c]pyridine. MS: (ES) m / z calculated for C25H28FN4 [M + H]+419.2, found 419.2.

[0159] Step d: N,A-Diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspension of 3-(6-chloro-7-methyl-177-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-227-pyrazolo[4,3-c] pyridine hydrochloride (46 mg, 0.10 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine (45 mg, 0.25 mmol), and L12CO3 (20 mg, 0.27 mmol) in DMSO (5 mL) under low magnetic stirring. The resulting mixture was stirred at 75 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over 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 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methyl177 -indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CDCI3) δ 8.49 (s, 2H), 8.21 (s, 1H), 7.06-7.36 (m, 4H), 6.69 (s, 1H), 6.47 (d,J=3,lHz, 1H), 4.84 (s, 2H), 4.37 (t,J= 5.9 Hz, 2H), 3.04 (t, J= 5, 9 Hz, 2H), 2.34 (s, 3H), 2.10-2.33 (m, 4H), 0.80-1.08 (m, 6H). MS: (ES) m / z calculated C30H29CIF3N6 [M + H]+ 565.2, found 565.2. Example 4 Synthesis of 3-(6-chloro-7-methyl-LH-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl )-4,5,6,7-tetrahydro-2Zf-pyrazolo[4,3-c]pyridine

[0160] ΛζΑ-Diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspension of 3-(6-chloro-7-methyl-1 / 7-indol-4-yl)-2-(2) hydrochloride ,6-diethylphenyl)-4,5,6,7-tetrahydro-277pyrazolo[4,3-c]pyridine (46 mg, 0.10 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (20 mg , 0.11 mmol), and L12CO3 (20 mg, 0.27 mmol) in MeCN (5 mL) under magnetic stirring. The resulting mixture was stirred at 75 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over 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-methyl-1 / 7indol-4-yl)- 2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-277pyrazolo[4,3-c]pyridine. *H NMR (400 MHz, CDCI3) δ 8.16-8.21 (m, 2H), 7.03-7.40 (m, 5H), 6.67 (d, J= 0.6 Hz, 1H), 6.48 (dd, J= 2.1, 3.3 Hz, 1H), 4.63 (br s, 2H), 4.07 ( t, J= 5.8 Hz, 2H), 3.11 (t, 5.8 Hz, 2H), 2.45 (s, 3H), 2.10-2.33 (m, 4H), 0, 80-1.08 (m, 6H). MS: (ES) m / z calculated C31H29CIF4N5 [M+H]+582.2, found 582.2. Example 5 Synthesis of 2-(2,6-diethylphenyl)-3-(7-fluoro-Li7-indol-4-yl)-5-(5-isopropylpyrimidin-2-yl)-6,7dihydro-4 / / -pyrazolo[ 4,3-c]pyridine Bis(p in acoll ato)dí boroin P d(dppf)Cl2 G H2C l2 step b

[0161] Step a: To a suspension of 4-bromo-7-fluoro-17 / -indole (1.00 g, 4.67 mmol), 4,4,4',4',5,5,5' ,5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.31 g, 5.14 mmol) and KOAc (1.15 g, 11.7 mmol) in dioxane (15 mL ) Pd(dppf)C12.CH2C12 (416 mg, 0.51 mmol) was added. The reaction mixture was degassed (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-1, 3,2dioxaborolan-2-yl)-l / / -indole. MS: (ES) m / z calculated for C14H18BFNO2 [M + H]+ 262.1, found 262.1.

[0162] Step b: To a suspension of / er-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-277pyrazolo[4,3-c]pyridine-5(41 / )- carboxylate (490 mg, 1.13 mmol), 7-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-17 / -indole (350 mg, 1 0.34 mmol), and K2CO3 (830 mg, 6.78 mmol) in pdioxane (12 mL) and water (3 mL) was added Pd(dppf)C12 complex with dichloromethane (200 mg, 0.32 mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 100 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with aqueous NaHCOs, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 40% EtOAc in hexanes) to obtain Zer-butyl 3-(7-fluoro-1 / 7-indol-4-yl )-2-(2,6-diethylphenyl)-6,7dihydro-47 / -pyrazolo[4,3-c]pyridine-5-carboxylate. MS: (ES) m / z calculated for C29H35FN4O2 [M+H]+489.3, found 489.3.

[0163] Tert-butyl 3-(7-fluoro-l / / -indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4 / Z-pyrazolo[4,3c ]pyridine-5-carboxylate above (0.350 g, 0.71 mmol) was dissolved in dichloromethane (5 mL) and charged with HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. The solvent was evaporated in vacuo to obtain 3-(7-fluoro-177-indol-4yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c] hydrochloride. pyridine. MS: (ES) m / z calculated for C24H26FN4 [M+H]+389.2, found 389.2.

[0164] Step c: Triethylamine (0.13 mL, 0.93 mmol) was added to a suspension of 3-(7-fluoro-l / / -indol-4-yl)-2-(2,6 -diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine (0.040 g, 0.094 mmol), 2-chloro-5-isopropylpyrimidine (70 mg, 0.44 mmol) and LI2CO3 (0.143 g , 1.76 mmol) in DMSO (1.5 mL). The resulting mixture was stirred at 110 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCOs, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 40% EtOAc in hexanes) to obtain 2-(2,6-diethylphenyl)-3-(7-fluoro-177- indol-4-yl)-5-(5-isopropylpyrimidin-2-yl)- 6,7-dihydro-427-pyrazolo[4,3-c]pyridine. Ή NMR (400 MHz, CDCI3) δ 8.86 (br s, 1H), 8.49 (s, 2H), 7.20 (t, J = 7.6 Hz, 1H), 7.15 (t, J= 2.6 Hz, 1H), 7.02 (d, J = 6.8 Hz, 2H), 6.64 (m, 1H), 6.51 (m, 2H), 4.75 (s, 2H), 4.30 (br s, 2H), 3.03 (t, J = 5.8 Hz, 2H), 2.76 (septet, J = 7.0 Hz, 1H), 2.10-2.40 (two brs, 4H), 1.21 (d, J = 7.2 Hz, 6H), 0.98 (s brs, 6H). MS: (ES) m / z calculated for C31H34FN6 [M+H]+509.3, found 509.3. Example 6 Synthesis of 5-[3-chloro-5-(trifluoromethyl)-2-pyridyl]-2-(2,6-diethylphenyl)-3-(7-fluoro-17T-indol-4yl)-6,7-dihydro- 42f-pyrazolo[4,3-c]pyridine

[0165] To a suspension of 3-bromo-2-(2,6-diethylphenyl)-5-[3-chloro-5-(trifluoromethyl)-2-pyridyl]- 6,7-dihydro-4 / / -pyrazolo[4,3-c]pyridine (60 mg, 0.12 mmol), 7-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2dioxaborolan-2-yl)-l / 7-indole (60 mg, 0.24 mmol) and K2CO3 (180 mg, 1.30 mmol) in p-dioxane (3.2 mL) and water (0.6 mL) Pd(dppf)Ch complex was added with dichloromethane (80 mg, 0.098 mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 100 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel flash chromatography (0-100% DCM / hexanes followed by 0-40% EtOAc in hexanes) followed by preparative HPLC to obtain 5-[3-chloro-5-(trifluoromethyl)- 2-pyridyl]-2-(2,6-diethylphenyl)-3-(7-fluoro-17 / -indol-4-yl)-6,7-dihydro-4Z / -pyrazolo[4,3-c]pyridine . Ή NMR (400 MHz, CD3OD) δ 11.31 (br s, IH), 8.36 (d, J = 1.2 Hz, IH), 7.97 (d, J = 2.0 Hz, IH) , 7.39 (m, IH), 7.27 (t, J= 7.6 Hz, IH), 7.11 (br s, 2H), 6.64 (m, IH), 6.52 (m, IH), 6.45 (t, 3.2 Hz, IH), 4.47 (br s, 2H), 3.98 (t, J = 5.6Hz, 2H), 3.15 (t, J = 5.6 Hz, 2H), 2.31 (br s, 4H), 1.01 (br s, 6H). MS: (ES) m / z calculated for C30H27CIF4N5 [M+H]+ 568.2, found 568.2. Example 7 Synthesis of 5-(3,5-dichloro-2-pyridyl)-2-(2,6-diethylphenyl)-3-(7-fluoro-1Zf-indol-4-iI)-6,7-dihydro4Z¡T- pyrazolo[4,3-c]pyridine

[0166] Step a: A mixture of 3-bromo-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine hydrochloride (100 mg, 0.27 mmol), 3,5-dichloro-2-fluoro-pyridine (150 mg, 0.90 mmol), LI2CO3 (200 mg, 2.7 mmol), and NEt3 (0.20 mL, 1.42 mmol) in DMSO (3 mL) it was stirred at 100 °C for 3 h. After cooled to room temperature, diluted with EtOAc and water. The organic layer was separated, dried in the presence of Na2SO4, concentrated on a rotary evaporator under reduced pressure, and purified by flash chromatography on silica gel (0 to 30% EtOAc in hexanes) to obtain 3-bromo-5- (3,5-dichloro-2-pyridyl)-2-(2,6-diethylphenyl)- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridine.

[0167] Step b: To a suspension of 3-bromo-5-(3,5-dichloro-2-pyridyl)-2-(2,6-diethylphenyl)-6,7dihydro-477-pyrazolo[4,3- c]pyridine (60 mg, 0.12 mmol), 7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-U7-indole (63 mg, 0, 24mmol),. and K2CO3 (140 mg, 1.0 mmol) in / / -dioxane (3 mL) and water (0.6 mL) was added Pd(dppf)Cl2 complex with dichloromethane (60 mg, 0.073 mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 100 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, and dried over Na2SC>4. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel flash chromatography (0 to 100% DCM / hexanes followed by 0 to 35% EtOAc in hexanes) followed by preparative HPLC to obtain 5-(3,5-dichloro-2-pyridyl) -2-(2,6-Diethylphenyl)-3-(7-fluoro-127-indol-4-yl)-6,7-dihydro-47Zpyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CD3OD-CDCI3) δ 11.03 (br s, 1H), 8.02 (d, J= 2.4 Hz, 1H), 7.68 (d, J = 2.0 Hz , 1H), 7.30 (t, J= 2.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.06 (br s, 2H), 6.59 ( m, 1H), 6.47 (t, J= 8.0, 1H), 6.44 (m, 1H), 4.29 (br s, 2H), 3.78 (t, J= 5.6 , 2H), 3.09 (t, J = 5.6, 2H), 2.10-2.42 (2 br s, 4H), 0.399 (br s, 6H). MS: (ES) m / z calculated for C29H27CI2FN5 [M+H]+534.2, found 534.2. Example 8 Synthesis of 2-(2,6-diethylphenyl)-3-(7-fluoro-117-iiidol-4-yl)-5-[3-fliioro-5-(trifliioromethyl)-2pyridyl]-6,7-dihydro- 4 / 7-pyrazoIo[4,3-c]pyridine

[0168] Step a: Er-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-4 / / -pyrazolo[4,3c]pyridine-5-carboxylate (400 mg, 0.92 mmol) in dichloromethane (4 mL) and charged with HC1 in dioxane (4N, 6 mL). The resulting mixture was stirred at room temperature for 1.5h. The solvent was evaporated in vacuo to obtain 3-bromo-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine hydrochloride.

[0169] Step b: A mixture of 3-bromo-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine hydrochloride (100 mg, 0.27 mmol), 2,3-Difluoro-5-(trifluoromethyl)pyridine (100 mg, 0.54 mmol) and K2CO3 (150 mg, 1.08 mmol) in CH3CN (3 mL) were stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCOs, and dried over Na2SO4. 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 3-bromo-2-(2,6-diethylphenyl)-5-[3- fluoro-5-(trifluoromethyl)-2-pyridyl]-6,7-dihydro-47 / -pyrazolo[4,3-c]pyridine. MS: (ES) m / z calculated for C22H22BrF4N4 [M+H]+497.1, found 497.1.

[0170] Step c: To a suspension of 3-bromo-2-(2,6-diethylphenyl)-5-[3-fluoro-5-(trifluoromethyl)- 2-pyridyl]-6,7-dihydro-4 / / -pyrazolo[4,3-c]pyridine (60 mg, 0.12 mmol), 7-fluoro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-17 / -indole (45 mg, 0.17 mmol), and K2CO3 (120 mg, 0.86 mmol) in / (-dioxane (3 mL) and water (0 0.6 mL) Pd(dppf)C12 complex was added with dichloromethane (120 mg, 0.15 mmol).The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 100 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, and dried in the presence of Na 2 SO 4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 100 % DCM in hexanes followed by 0 to 50% EtOAc in hexanes) to give 2-(2,6-diethylphenyl)-3(7-fluoro-1 / 7-indol-4-yl)-5-[3-fluoro -5-(trifluoromethyl)-2-pyridyl]-6,7-dihydro-4 / 7-pyrazolo[4,3c]pyridine.'H NMR (400 MHz, CDCI3) δ 8.70 (br s, 1H), 8.19 (s, 1H), 7.39 (dd, J = 2, 13 Ηζ,ΙΗ), 7.20 (m, 2H), 7.03 (d, J= 7.2 Hz, 2H), 6.67 (m, 1H), 6.52 (m, 2H), 4.6 4 (br s, 2H), 4.07 (t, J= 5.6 Hz, 2H), 3.12 (t, J= 5.6 Hz, 2H), 2.1-2.4 (two br s, 4H), 0.98 (br s, 6H). MS: (ES) m / z calculated for C30H27F5N5 [M+H]+ 552.2, found 552.2. Example 9 Synthesis of 2-(2,6-diethylphenyl)-3-(7-methoxy-lZZ-indol-4-yl)-5-(5-(trifluoromethyl)pyrinidin-2-yl)- 4,5,6,7-tetrahydro-2fir-pyrazolo[4,3-c]pyridine

[0171] Step a: To a suspension of 4-bromo-7-methoxy-l / / -indole (800 mg, 3.5 mmol), 4,4,4',4',5,5,5', 5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.6 g, 6.3 mmol), and KOAc (1.6 g, 16.3 mmol) in / ?-dioxane (10 mL) Pd(dppí)Cl2 complex was added with dichloromethane (800 mg, 0.97 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 100 °C for 3 h. The reaction mixture was diluted with EtOAc, filtered through Celite. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 25% EtOAc in hexanes) to obtain 7-methoxy-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)1 / 7-indole. MS: (ES) m / z calculated for Ci5H2iBNO3 [M + H]+274.2, found 274.2.

[0172] Step b: To a suspension of / er-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2 / / pyrazolo[4,3-c]pyridine-5(4 / / )-carboxylate (300 mg, 0.72 mmol), 7-methoxy-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1 / / -indole (200 mg, 0.73 mmol), and K2CO3 (300 mg, 2.2 mmol) in pdioxane (6 mL) and water (1 mL) was added Pd(dppf)Cl2 complex with dichloromethane (100 mg, 0.12 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, and dried over 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 / er-butyl 2-(2,6-diethylphenyl)-3-(7- methoxy-1H-indol-4-yl)-6,7-dihydro-227-pyrazolo[4,3c]pyridine-5(477)-carboxylate. MS: (ES) m / z calculated for C30H37N4O3 [M + H]+ 501.2, found 501.2.

[0173] / er-Butyl 2-(2,6-diethylphenyl)-3-(7-methoxy-l / / -indol-4-yl)-6,7-dihydro-277-pyrazolo[4,3c] Pyridine-5(4 / / )-carboxylate above was dissolved in dichloromethane (5 mL) and charged with HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. After the completion of the reaction, the solvent was evaporated in vacuo to obtain 2-(2,6-diethylphenyl)-3-(7-methoxy-17 / -indol-4-yl)-4,5,6,7-tetrahydro hydrochloride. -277-pyrazolo[4,3-c]pyridine. MS: (ES) m / z calculated for C25H29N4O [M+H]+401.2, found 401.2.

[0174] Step c: A / TV-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspension of 2-(2,6-diethylphenyl)-3-(7-methoxy-l / / -indol-4-yl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3c]pyridine (50 mg, 0.11 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine (50 mg , 0.27 mmol), and LI2CO3 (20 mg, 0.27 mmol) in DMSO (10 mL) under magnetic stirring. The resulting mixture was stirred at 75 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over 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 2-(2,6-diethylphenyl)-3-(7-methoxy-177indole-4 -yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CDCI3) δ 8.45 (s, 2H), 8.18 (dt, J=1.0, 2.0 Hz, 2H), 7.37 (dd, J=2.0 , 13.2 Hz, 1H), 7.03-7.30 (m, 4H), 6.54 (dd, J = 0.8, 8.0 Hz, 1H), 6.37-6.49 ( m, 2H), 4.65 (s, 2H), 4.07 (t, J= 5.8 Hz, 2H), 3.88 (s, 3H), 3.11 (t, J= 5.8 Hz, 2H), 2.10-2.35 (br m, 4H), 0.85-1.03 (br m, 6H). MS: (ES) m / z calculated C30H30F3N6O [M+H]+ 547.2, found 547.2. Example 10 Synthesis of 2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(7-methoxy-Lffindol-4-yl)-4,5,6 ,7-tetrahydro-2 / 7-pyrazolo|4,3-c]pyridine

[0175] A / TV-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspension of 2-(2,6-diethylphenyl)-3-(7-methoxy-1 / 7-indole- 4-yl)-4,5,6,7-tetrahydro-227-pyrazolo[4,3c]pyridine (50 mg, 0.11 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (60 mg, 0.33 mmol), and LI2CO3 (20 mg, 0.27 mmol) in MeCN (5 mL) under magnetic stirring. The resulting mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over 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 2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl )pyridin-2-yl)-3-(7-methoxy-1 / / -indol-4-yl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3c]pyridine. Ή NMR (400 MHz, CDCI3) δ 8.46 (d, J= 11.4 Hz, 2H), 7.16-7.31 (m, 4H), 7.02 (d, .7 = 7.7 Hz, 1H), 6.40-6.55 (m, 3H), 4.85 (s, 2H), 4.36 (t, J= 5.9 Hz, 2H), 3.89 (s, 3H ), 3.03 (t, J = 5.9 Hz, 2H), 2.10-2.35 (br m, 4H), 0.85-1.03 (br m, 6H). MS: (ES) m / z calculated C31H30F4N5O [M+H]+564.2, found 564.2. Example 11 Synthesis of 3-(7-chloro-1Zf-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin- 2-yl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridine

[0176] Step a: / er-Butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-227-pyrazolo[4,3e]pyridine-5(4 / 7)-carboxylate was dissolved (1.5 g, 3.6 mmol), in dichloromethane (10 mL) and charged with HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. After the completion of the reaction, the solvent was evaporated in vacuo to obtain 3-bromo-2(2,6-diethylphenyl)-4,5,6,7-tetrahydro-227-pyrazolo[4,3-c]pyridine hydrochloride. . MS: (ES) m / z calculated for Ci6H2iBrN3 [M+H]+334.1, found 334.1.

[0177] jV,jV-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspension of 3-bromo-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro hydrochloride -2f / -pyrazolo[4,3-c]pyridine (750 mg, 2.02 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (800 mg, 4.37 mmol), and K2CO3 (800 mg , 5.79 mmol) in MeCN (10 mL) under magnetic stirring. The resulting mixture was stirred at 85 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (2 to 15% EtOAc in hexanes) to obtain 3-bromo-2-(2,6-diethylphenyl)-5-(3- fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine. MS: (ES) m / z calculated for C22H22BrF4N4 [M+H]+497.1, found 497.1.

[0178] Step b. To a suspension of 3-bromo-2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2 / 7- pyrazolo[4,3-c]pyridine (50 mg, 0.1 mmol), 7chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-l / / -indole (50 mg, 0.18 mmol), and K2CO3 (180 mg, 1.3 mmol) in / >-dioxane (6 mL) and water (1 mL) Pd(dppf)CI2 complex with dichloromethane (40 mg, 0.05mmol). 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 over MgSCU. 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 3-(7-chloro-177-indol-4-yl)-2-( 2,6-diethylphenyl)-5-(3fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CDCI3) δ 8.46 (s, 1H), 8.18 (s, 1H), 7.04-7.43 (m, 5H), 6.97 (d, J= 7 .9 Hz, 1H), 6,526.59 (m, 2H), 4.63 (s, 2H), 4.07 (t, J= 5.8 Hz, 2H), 3.11 (t, J = 5 0.8 Hz, 2H), 2.10-2.40 (m, 4H), 0.80-1.08 (m, 6H) . MS: (ES) m / z calculated C30H27CIF4N5 [M + H]+ 568.2, found 568.2. Example 12 Synthesis of 2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridm-2-yl)-3-(5-fluoro-7-methyl / / -indol-4-yl) -4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine step to Bis(pí na col ato) dibo roí Pd{dppf)C.I2-CH2Cls step b

[0179] Step a: A solution of vinylmagnesium bromide in THF (1 M, 66 mL, 66 mmol) was rapidly added to a solution of l-bromo-2-fluoro-4-methyl-5-nitrobenzene (5.0 g, 21.4 mmol) in anhydrous THF (50 mL) under N2 and stirring vigorously at -60 °C. The reaction mixture was stirred at the same temperature and allowed to warm to -35 °C in 1.5 h. The reaction was quenched with saturated NH4CI 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 over 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-5-fluoro-7-methyl-17 / indole. MS: (ES) m / z calculated for CgHsBrFN [M+H]+227.9, found 227.9.

[0180] Step b: To a suspension of 4-bromo-5-fluoro-7-methyl-127-indole (1.6 g, 7.0 mmol), 4,4,4',4',5,5 ,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.2 g, 12.6 mmol), and KOAc (3 g, 30.6 mmol) in 72- dioxane (10 mL) was added Pd(dppf)Ch complex with dichloromethane (800 mg, 0.97 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 95 °C for 5 h. The reaction mixture was diluted with EtOAc, filtered through Celite. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 30% EtOAc in hexanes) to obtain 5-fluoro-7-methyl-4-(4,4,5,5- tetramethyl-1,3,2dioxaborolan-2-yl)-1 / 7-indoL MS: (ES) m / z calculated for C15H20BFNO2 [M+H]+ 276.2, found 276.2.

[0181] Step c: To a suspension of 3-bromo-2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7- tetrahydro-2 / / -pyrazolo[4,3-c]pyridine (80 mg, 0.16 mmol), 5-fluoro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-l / / -indole (80 mg, 0.29 mmol), and K2CO3 (180 mg, 1.3 mmol) in / 2-dioxane (6 mL) and water (1 mL) were added. Pd(dppf)C12 complex with dichloromethane (40 mg, 0.05 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, and dried over 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) followed by HPLC (MeCN / H2O, with 1% TFA) to obtain 2-(2, 6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(5-fluoro-7-methyl-127indol-4-yl)-4,5,6,7- tetrahydro-22 / -pyrazolo[4,3-c]pyridine. ’H NMR (400 MHz, CDCI3) δ 8.13— 8.20 (m, 2H), 7.38 (dd, 7=2.0 Hz, 13.0,lH), 7.10 - 7.29 (m, 3H), 6.84-6.91 (m, 1H), 6.60 (dd, J =0.9, 10.8 Hz, 1H), 6.39 (dd, 7=2.1 3.2 Hz, 1H), 4.75 (d, J= 15.7 Hz, 1H), 4.45 (d, J = 15.7 Hz, 1H), 4.02 - 4.09 (m, 2H), 3.12 (t, 7=5.8, 2H ), 2.41 - 2.54 (m, 2H), 2.43 (s, 3H), 1.96- 2.21 (m, 2H), 1.22 (t, J= 7.5 Hz, 3H), 0.75 (t, 7= 7.5 Hz, 3H). MS: (ES) m / z calculated C31H29F5N5 [M+H]+566.2, found 566.2. Example 13 Synthesis of 3-(7-chloro-1Zf-indoI-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyridin-2-yl)4,5,6,7- tetrahydro-2E7-pyrazolo[4,3-c]pyridine

[0182] Step a: To a suspension of tert-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-277pyrazolo[4,3-c]pyridine-5(4 / / )- carboxylate (500 mg, 1.2 mmol), 7-chloro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1 / 7-indole (400 mg, 1.44 mmol), and K2CO3 (500 mg, 3.6 mmol) in pdioxane (6 mL) and water (1 mL) was added Pd(dppf)Ch complex with dichloromethane (200 mg, 0.24 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, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 35% EtOAc in hexanes) to obtain tert-butyl 3-(7-chloro-177-indol-4-yl)- 2-(2,6-diethylphenyl)-6,7-dihydro-277-pyrazolo[4,3c]pyridine-5(4 / 7)-carboxylate. MS: (ES) m / z calculated for C29H34CIN4O2 [M+H]+ 505.2, found 505.2.

[0183] Tert-butyl 3-(7-chloro-l / / -indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2 / / -pyrazolo[4,3c ]pyridine-5(4 / 7)-carboxylate above was dissolved in dichloromethane (5 mL) and charged with HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. After the reaction was complete, the solvent was evaporated in vacuo to obtain 3-(7-chloro-177indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-hydrochloride. 2 / 7-pyrazolo[4,3-c]pyridine. MS: (ES) m / z calculated for C25H28FN4 [M+H]+403.2, found 403.2.

[0184] Step b: ΛζΑ-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspension of 3-(7-chloro-l / / -indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c] pyridine hydrochloride (50 mg, 0.11 mmol), 2-fluoro-5-(trifluoromethyl)pyridine (50 mg, 0.31 mmol), and LI2CO3 (20 mg, 0.27 mmol) in MeCN (5 mL) on low magnetic stirring. The resulting mixture was stirred at 85 °C for 5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over 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-(7-chloro-1 / 7-indol-4-yl)-2- (2,6diethylphenyl)-5-(5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CDCI3) δ 8.29 - 8.37 (m, 2H), 7.70 (ddt, J= 0.6, 2.6, 9.1 Hz, 1H), 7.46 (d, J = 3.2 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.11 (br, 2H), 6.84-6.93 (m, 2H) , 6.51-6.55 (m, 2H), 4.65 (s, 2H), 4.19 (t, J= 5.8 Hz, 2H), 3.01 (t, J= 5.8 Hz, 2H), 2.10-2.33 (br,m, 4H), 0.80-1.08 (br,m, 6H). MS: (ES) m / z calculated C30H28CIF3N5 [M+H]+550.2, found 550.2. Example 14 Synthesis of 3-(7-chloro-1Zf-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-methyl-5-(trifluoromethyl)pyridin2-yl)-4,5,6 ,7-tetrahydro-22f-pyrazolo[4,3-c]pyridine

[0185] A,A-Diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspension of 3-(7-chloro-1F / -indol-4-yl)-2-(2.6 -diethylphenyl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3c]pyridine (25 mg, 0.06 mmol), 2-chloro-3-methyl-5-(trifluoromethyl)pyridine (40 mg , 0.20 mmol), and L12CO3 (20 mg, 0.27 mmol) in DMSO (5 mL) under magnetic stirring. The resulting mixture was stirred at 155 °C for 6 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN / H2O, with 0.1% TFA) to obtain 3-(7-chloro-l / / -indol-4-yl)-2-( 2,6-Diethylphenyl)-5-(3-methyl-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine. ’H NMR (400 MHz, CDC13) δ 8.48 (s, IH), 8.31 (sd, J = 0.9, 1.7 Hz, IH), 7.57 (tt, J= 0.8, 1.7 Hz, IH ), 7.19-7.29 (m, 2H), 7.04 (d, J= 7.7 Hz, 2H), 6.95 (dd, J = 0.7, 7.7 Hz, IH) , 6.51-6.57 (m, 2H), 4.32 (s, 2H), 3.66 (t, J= 5.8 Hz, 2H), 3.14 (t, J = 5.8 Hz, 2H), 2.40 (s, 3H), 2.10-2, 38 (br,m, 4H), 0.88-1.08 (br,m, 6H). MS: (ES) m / z calculated C31H30CIF3N5 [M+H]+564.2, found 564.2. Example 15 Synthesis of 3-(7-chloro-HZ-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-methyl-5-(trifluoroinethyl)pyridin- 2-yl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridine OCF3 NH Cl

[0186] jV,A-Diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspension of 3-(7-chloro-127-indol-4-yl)-2-(2.6 -diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3c]pyridine (25 mg, 0.06 mmol), 2-chloro-5-(trifluoromethoxy)pyridine (30 mg, 0.15 mmol), and LI2CO3 (20 mg, 0.27 mmol) in DMSO (5 mL) under magnetic stirring. The resulting mixture was stirred at 155 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN / HzO, with 1% TFA) to obtain 3-(7-chloro-177-indol-4-yl)-2-(2,6-diethylphenyl )-5-(5-(trifluoromethoxy)pyridin-2yl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CDCI3) δ 8.49 (s, IH), 8.09 (dd, J=1.0, 2.9 Hz, IH), 7.02-7.34 (m, 5H ), 6.98 (dd, J = 8.0 Hz, IH), 6.54-6.66 (m, 3H), 4.50 (s, 2H), 4.11 (t, J= 5, 8 Hz, 2H), 3.05 (t, J = 5.8 Hz, 2H), 2.14-2.32 (br,m, 4H), 0.88-1.08 (br,m, 6H ) . MS: (ES) m / z calculated C30H28CIF3N5O [M + H]+ 566.2, found 566.2. Example 16 Synthesis of 3-(7-chloro-1JT-indol-4-yl)-5-(3-chloro-5-fluoropyridin-2-yl)-2-(2,6-diethylphenyl)71 4,5,6,7-tetrahydro-2 / / -pyrazolo|4,3-í‘|pyridine F

[0187] A / V-Diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspension of 3-(7-chloro-177-indol-4-yl)-2-(2,6- diethylphenyl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3c]pyridine (45 mg, 0.10 mmol), 3-chloro-2,5-difluoropyridine (60 mg, 0.40 mmol), and K2CO3 (100 mg, 0.72 mmol) in DMSO (5 mL) under magnetic stirring. The resulting mixture was stirred at 120 °C for 6 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN / FLO, with 0.1% TFA) to obtain 3-(7-chloro-l / / -indol-4-yl)-5-( 3-chloro-5-fluoropyridin-2-yl)-2-(2,6-diethylphenyl)-4,5,6,7tetrahydro-27 / -pyrazolo[4,3-c]pyridine. 'HNMR (400 MHz, CDCI3) δ 8.42 (s, 1H), 8.00 (dd, J=0.5, 2.7 Hz, 1H), 7.45 (dd, J= 2.7, 7.5 Hz, 1Η), 7.19-7.30 (m, 2H), 7.03 (br, 2H), 6.95 (d,J = 7.9 Hz, 1H), 6.52-6.60 (m, 2H), 4.26 (s, 2H), 3.72 (t, J= 5.8 Hz, 2H), 3.15 ( t, J= 5.8 Hz, 2H), 2.17-2.35 (br,m, 4H), 0.88-1.08 (br,m, 6H). MS: (ES) m / z calculated C29H27CI2FN5 [M+H]+534.2, found 534.2. Example 17 Synthesis of 3-(7-chloro-LH-indol-4-yl)-5-(5-cyclopropyl-3-fluoro-2-pyridyl)-2-(2,6-diethylphenyl)- 6,7-dihydro-4Lf-pyrazolo[4,3-c]pyridine Pd(dppf)CI2*CH2Cl2 Pas or a

[0188] Step a: A mixture of 5-bromo-2,3-difluoropyridine (1.70 g, 8.76 mmol), cyclopropylboronic acid (1.10 g, 12.8 mmol), CS2CO3 (12.0 g , 36.9 mmol) and complex Pd(dppf)Ch with dichloromethane (250 mg, 0.30 mmol) in. toluene (22 mL) and water (2 mL) were stirred at 105 °C for 1.5 h under a N2 atmosphere. It was then cooled to room temperature and diluted with EtOAc, washed with aqueous NaHCOs and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 100% DCM / hexanes) to obtain 5-cyclopropyl-2,3-difluoro-pyridine. Ή NMR (400 MHz, CDCh) δ 7.63 (d, J= 2.0 Hz, 1H), 7.02 (m, 1H), 1.77 (m, 1H), 0.91 (m, 2H ), 0.54 (m, 2H).

[0189] Step b: A mixture of 3-(7-chloro-17 / -indol-4-yl)-2-(2,6-diethylphenyl)-hydrochloride 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine (40 mg, 0.090 mmol), NEt3 (0.15 mL, 1.07 mmol), 5-cyclopropyl-2,3-difluoro-pyridine (120 mg , 0.77 mmol) and LI2CO3 (120 mg, 1.62 mmol) in DMSO (2 mL) was stirred at 120 °C overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCOs, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 40% EtOAc in hexanes) to obtain 3-(7-chloro-1 / 7-indol-4-yl)-5 -(5-cyclopropyl-3-fluoro-2-pyridyl)-2-(2,6-diethylphenyl)-6,7-dihydro-477-pyrazolo[4,3-c]pyridine. Ή NMR (400 MHz, CDCI3) δ 8.44 (br s, 1H), 7.66 (s, 1H), 7.07 (m, 2H), 6.89 (m, 2H), 6.78 ( m, 2H), 6.42 (m, 2H), 4.26 (br s, 2H), 3.69 (t, J= 5.8 Hz, 2H), 2.96 (t, J = 5, 8 Hz, 2H), 2.00-2.30 (m, 4H), 1.66 (m, 1H), 0.86 (br s, 6H), 0.78 (m, 2H), 0.45 (m, 2H). MS: (ES) m / z calculated for C32H32CIFN5 [M+H]+540.2, found 540.2. Example 18 Synthesis of 2-[2-[3-(7-chloro-1Z / -indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-417-pyrazolo[4,3c]pyridine -5-yl]pyrimidm-5-yl]propan-2-ol

[0190] Step a: A mixture of 3-(7-chloro-1 / 7-indol-4-yl)-2-(2,6-diethylphenyl)-hydrochloride 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine (75 mg, 0.17 mmol), methyl 2-chloropyrimidine-5-carboxylate (60 mg, 0.34 mmol), and NEt3 (0.12 mL, 0.85 mmol) in CH3CN (2 mL) was stirred at 80 °C for 15 min. It was then cooled to room temperature, 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 60% EtOAc in hexanes) to obtain methyl 2-[3-(7-chloro-1Z7-indol-4-yl) -2-(2,6-diethylphenyl)-6,7-dihydro-477pyrazolo[4,3-c]pyridin-5-yl]pyrimidine-5-carboxylate. MS: (ES) m / z calculated for C30H30CIN6O2 [M+H]+541.2, found 541.2.

[0191] Step b: To a solution of methyl 2-[3-(7-chloro-17 / -indol-4-yl)-2-(2,6-diethylphenyl)-6,7dihydro-417-pyrazolo[4 ,3-c]pyridin-5-yl]pyrimidine-5-carboxylate (35 mg, 0.064 mmol) in THF (2 mL) was added CH3LI (0.25 mL, 0.40 mmol, 1.6 M in ether) at 0°C. The obtained mixture was stirred at the same temperature for 20 min, quenched with saturated NH4Cl, and extracted with EtOAc. The organic layer was separated, washed with aqueous NaHCO3, dried in the presence of Na2SO4, concentrated under reduced pressure, and purified by flash chromatography on silica gel (0 to 100% EtOAc in hexanes) to obtain 2-[2 -[3-(7-chloro-177-indol-4-yl)-2-(2,6-diethylphenyl)-6,7dihydro-4 / 7-pyrazolo[4,3-c]pyridin-5-yl] pyrimidin-5-yl]propan-2-ol. ’H NMR (400 MHz, CDCI3) δ 8.41 (br s, 1H), 8.30 (m, 2H), 7.13 (m, 2H), 7.06 (t, J= 7.6 Hz, 1H), 6.88 (m, 2H), 6.80 (d, J = 8.4 Hz, 1H), 6.40 (m, 2H), 4.63 (br s, 2H), 4.16 (br s, 2H), 2.88 (t, 5.8, 2H), 2.1 (m, 4H), 1.41 (m, 6H), 0.85 (br s, 6H). MS: (ES) m / z calculated for C31H34CIN6O [M+H]+ 541.2, found 541.2. Example 19 Synthesis of 2-|3-(7-chloro-l / / -indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4 / / -pyrazolo[4,3c]pyridine -5-yl]pyrimidine-5-carboxamide

[0192] Step a: A mixture of methyl 2-[3-(7-chloro-l / / -indol-4-yl)-2-(2,6-diethylphenyl)-6,7dihydro-4 / / -pyrazolo [4,3-c]pyridin-5-yl]pyrimidine-5-carboxylate (40 mg, 0.074 mmol) (intermediate from Example 9) and L1OH.H2O (100 mg, 2.5 mmol) in a mixed solvent of MeOH (1.2 mL), THF (1.2 mL) and water (0.6 mL) were stirred at 45 °C for 1 h. It was then cooled to room temperature, acidified with 1M aq. HC1 and extracted with EtOAc. The organic layer was separated, dried in the presence of Na2SO4, and concentrated under reduced pressure to obtain 2-[3-(7-chloro-1 / / -indol-4-yl)-2-(2,6-diethylphenyl) acid. )-6,7-dihydro-477-pyrazolo[4,3c]pyridin-5-yl]pyrimidine-5-carboxylic acid.

[0193] Step b: To a mixture of 2-[3-(7-chloro-l / / -indol-4-yl)-2-(2,6-diethylphenyl)-6,7dihydro-4 / / - acid pyrazolo[4,3-c]pyridin-5-yl]pyrimidine-5-carboxylic acid (35 mg, 0.66 mmol) and HATU (100 mg, 0.26 mmol) in DMF (5 mL) added ammonia in dioxane (0.5 µ, 1 mL, 0.5 mmol). After stirring for 15 min, the reaction mixture was quenched with 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 100% EtOAc in hexanes) to obtain 2-[3-(7-chloro- 1 / / -indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4J7pyrazolo[4,3-c]pyridin-5-yl]pyrimidine-5-carboxamide. Ή NMR (400 MHz, CD3OD-CDCI3) δ 8.74 (br s, 1H), 7.93 (s, 1H), 7.47 (m, 1H), 7.34 (d, J= 3.2 Hz, 1H), 7.21 (d, J = 7.6Hz, 1H), 7.02 (d, J= 6.0 Hz, 2H), 6.90 (d, J= 7.6 Hz, 1H), 6.48 (d, J= 7.6 Hz, 1H), 6, 45 (d, J= 3.6 Hz, 1H), 4.81 (br s, 2H), 4.49 (br s, 4H), 4.35 (br s, 2H), 2.10-2.40 (m, 4H), 0.91 ( brs, 6H). MS: (ES) m / z calculated for C29H29CIN7O [M + H]+ 526.2, found 526.2. Example 20 Synthesis of 2-[3-(7-chloro-1Z7-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-427-pyrazolo[4,3c]pyridine-5- acid iI] -5-methyl-pyrimidine-4-carboxylic

[0194] A mixture of 3-(7-chloro-17 / -indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine hydrochloride (25 mg, 0.056 mmol), 2-chloro-5-methyl-pyrimidine-4-carboxylic acid (60 mg, 0.34 mmol), LI2CO3 (120 mg, 1.6 mmol), and NEt3 (0.12 mL, 0.86 mmol) in DMSO (1.5 mL) was stirred at 120 °C for 3 h. It was then cooled to room temperature, diluted with EtOAc, and extracted with 10% aqueous HCl. The organic layer was separated, dried in the presence of Na2SO4, concentrated on a rotary evaporator under reduced pressure, and purified by preparative HPLC to obtain 2-[3-(7-chloro-l / / -indol-4-yl acid )-2-(2,6-diethylphenyl)-6,7-dihydro477-pyrazolo[4,3-c]pyridin-5-yl]-5-methyl-pyrimidine-4-carboxylic. Ή NMR (400 MHz, CD3OD) δ 11.27 (br s, 1H), 8.43 (br s, 1H), 7.52 (s, 1H), 7.35 (t, J= 7.6 Hz , 1H), 7.18 (d, 3.6Hz, 2H), 6.98 (d, J= 7.6 Hz, 1H), 6.66 (d, J= 3.2 Hz, 1H), 6.60 (d, J= 7.6 Hz, 1H), 4, 90 (m, 2H), 4.39 (t, J= 5.6 Hz, 2H), 3.06 (t, J= 5.6 Hz, 6H), 2.38 (m, 7H), 1, 06 (br s, 6H). MS: (ES) m / z calculated for C30H30CIN6O2 [M+H]+541.2, found 541.2. Example 21 Synthesis of |2-|3-(7-chloro-l / / -indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4 / / -pyrazolo|4,3c] pyridin-5-yl]-5-methyl-pyrimidin-4-yl]methanol

[0195] Step a: A mixture of 2-[3-(7-chloro-177-indol-4-yl)-2-(2,6-diethylphenyl)-6,7dihydro-4Z / -pyrazolo[4, 3-c]pyridin-5-yl]-5-methyl-pyrimidine-4-carboxylic acid (12 mg, 0.022 mmol) and conc. (0.40 mL) in MeOH (5 mL) was refluxed for 1 h. It was then cooled to room temperature, made basic with saturated NaHCOs, and extracted with EtOAc. The organic layer was separated, dried in the presence of Na2SO4, concentrated on a rotary evaporator under reduced pressure to obtain methyl 2-[3-(7-chloro-177-indol-4-yl)-2-(2,6 -diethylphenyl)-6,7-dihydro-4 / / -pyrazolo[4,3c]pyridin-5-yl]-5-methyl-pyrimidine-4-carboxylate.

[0196] Step b: Methyl 2-[3-(7-chloro-1Z / -indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4J7pyrazolo[4,3- c]pyridin-5-yl]-5-methyl-pyrimidine-4-carboxylate above (10 mg, 0.020 mmol) was dissolved in THF (2 mL) and loaded with L1AIH4 in THF (1 M, 0.07 mL, 0.14 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 20 min. It was then quenched with MeOH, diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 80% EtOAc in hexanes) to obtain [2-[3-(7-chloro-177-indol-4-yl) -2-(2,6-diethylphenyl)-6,7-dihydro4 / / -pyrazolo[4,3-c]pyridin-5-yl]-5-methyl-pyrimidin-4-yl]methanol. ’H NMR (400 MHz, CDCI3) δ 8.38 (br s, 1H), 7.91 (s, 1H), 7.33 (br s, 1H), 7.07 (t, J= 7.6 Hz, 1H), 6.90 (br s, 1H), s, 2H), 6.81 (d, J = 7.6 Hz, 1H), 6.44 (br s, 1H), 6.40 (d, J= 7.6 Hz, 1H), 4.68 (br s, 2H), 4.42 (d, J = 4.2Hz, 2H), 4.20 (t, J = 4.4 Hz, 1H), 4.15 (s, 2H), 2.89 (t, J= 5.6 Hz, 2H), 2.00-2.30 (2 br s, 4H), 1.87 (s, 3H), 0.85 (6H). MS: (ES) m / z calculated for C30H32CIN6O [M+H]+527.2, found 527.2. Example 22 Synthesis of 3-(7-chloro-1Z7-indol-4-yl)-2-(2,6-diethylphenyl)-N-phenyl-6,7-dihydro-227-pyrazoIo[4,3c]pyridine-5( 4 / 7)-carboxamide

[0197] ΛζΑ-Diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspension of 3-(7-chloro-l / / -indol-4-yl)-2-(2,6- diethylphenyl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3c]pyridine (45 mg, 0.10 mmol), and phenyl isocyanate (0.1 mL, 0.92 mmol) in THF (5 mL) under magnetic stirring. The resulting mixture was stirred at 50 °C for 1 h and quenched with MeOH. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCOs soln, brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (40% EtOAc in hexanes) followed by HPLC (MeCN / H2O, with 1% TFA) to obtain 3-(7-chloro-17A indole-4 -yl)-2-(2,6-diethylphenyl)-N-phenyl-6,7-dihydro-227-pyrazolo[4,3-c]pyridine-5(4 / 7)-carboxamide. 'H NMR (400 MHz, CDCI3) δ 8.52 (s, 1H), 7.21-7.40 (m, 5H), 6.98-7.10 (m, 4H), 6.50-6 .61 (m, 2H), 6.35 (s, 1H), 4.50 (s, 2H), 3.98 (t, J= 5.9 Hz, 2H), 3.05 (t, J= 5.9 Hz, 2H), 2.17-2.35 (br,m, 4H), 0.88-1.08 (br,m, 6H). MS: (ES) m / z calculated C31H31CIN5O [M+H]+ 524.2, found 524.2. Example 23 Synthesis of (4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7tetrahydro-2Zf-pyrazoIo[4,3 -c]pyridin-3-yl)-lZir-indol-7-yl)methanol Step b

[0198] Step a: To a suspension of methyl 4-bromo-l / / -indole-7-carboxylate (300 mg, 1.18 mmol), 4,4,4',4',5,5,5' ,5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (330 mg, 1.30 mmol), and KOAc (290 mg, 2.96 mmol) in / >-dioxane (8 mL ) Pd(dppf)C12 complex was added with dichloromethane (100 mg, 0.12 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 100 °C for 1 h. The reaction mixture was diluted with EtOAc, filtered through Celite. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 30% EtOAc in hexanes) to obtain methyl 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan -2-yl)-1 / 7-indole-7-carboxylate. MS: (ES) m / z calculated for C16H21BNO4 [M + H]+ 302.2, found 302.2.

[0199] Step b: To a suspension of 3-bromo-2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7- tetrahydro-277-pyrazolo[4,3-c]pyridine (100 mg, 0.20 mmol), methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 177-indole-7-carboxylate (100 mg, 0.33 mmol), and K2CO3 (180 mg, 1.3 mmol) in / 2-dioxane (6 mL) and water (1 mL) Pd(dppf) complex was added Ch with dichloromethane (50 mg, 0.06 mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 100 °C for 3 h. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 35% EtOAc in hexanes) to obtain methyl 4-(2-(2,6-diethylphenyl)-5-(3fluoro- 5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-117-indole7-carboxylate. MS: (ES) m / z calculated C32H3oF4Ns02 [M+H]+592.2, found 592.2.

[0200] Step c: To a solution of methyl 4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7- tetrahydro-2Z / -pyrazolo[4,3-c]pyridin-3-yl)-17 / -indole-7-carboxylate (25 mg, 0.04 mmol) in anhydrous THF (6 mL) under an ice bath added a solution of L1AIH4 in THF (2M, 0.3 mL, 0.6 mmol). The reaction mixture was stirred at 0 °C for 30 min and then quenched with MeOH. The reaction mixture was diluted with EtOAc, washed with aq. NaHCO3 solution, brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by HPLC (MeCHTLO, with 0.1% TFA) to obtain (4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5- (trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridin-3-yl)-ÍZ / -indol-7-yl)methanol. 'H NMR (400 MHz, CD3OD) δ 8.20 (dt, J= 1.0, 1.9 Hz, 1H), 7.63 (dd, J= 2.1, 13.5 Hz, 1H), 7.38 (d, J= 3.2 Hz, 1H), 7.24 (t, J= 7.7 Hz, 1H), 7.08 (s, 2H), 6.89 (d, J = 7 0.4 Hz, 1H), 6.57 (d, J= 7.4 Hz, 1H), 6.45 (dd, J = 0.6, 3.2 Hz, 1H), 4.83-4.89 (m, 4H), 4.63 (s, 2H), 4.11 (t, J= 5.7 Hz, 2H), 3.06 (t, J= 5.7 Hz, 2H), 2.11 -2.46 (m, 4H), 0.85-1.08 (m, 6H). MS: (ES) m / z calculated C31H30F4N5O [M+H]+564.2, found 564.2. Example 24 Synthesis of 4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7tetrahydro-2 / / -pyrazolo|4, 3-c]pyridin-3-yl)-l / / -indole-7-carboxamide

[0201] Step a: To a solution of methyl 4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7- tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-17 / -indole-7-carboxylate (25 mg, 0.04 mmol) in MeOH (5 mL) and water (1 mL) was added LiOH monohydrate (100 mg, 2.38 mmol). The reaction mixture was stirred at 60 °C for 2 h and quenched with 1 N HCl. The reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure to obtain 4(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro acid. -2 / / -pyrazolo[4,3c]pyridin-3-yl)-177-indole-7-carboxylic acid. MS: (ES) m / z calculated C31H28F4N5O2 [M+H]+ 578.2, found 578.2.

[0202] Step b: A solution of 4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro acid Above -2 / f-pyrazolo[4,3-c]pyridin-3-yl)-l / 7-indole-7carboxylic acid in DMF (5 mL) was loaded with HATU (50 mg, 0.13 mmol), DIEA ( 0.2mL, 1.15 mmol) and followed by ammonia in dioxane (0.5 µ, 1 mL, 0.5 mmol). The reaction mixture was stirred at room temperature for 2h. The reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN / FbO, with 1% TFA) to obtain 4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl) pyridin-2-yl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3c]pyridin-3-yl)-l / / -indole-7-carboxamide. 'H NMR (400 MHz, CD3OD) δ 8.21 (d, J = 2.1 Hz, 1H), 7.64 (dd, J = 2.0, 13.5 Hz, 1H), 7.49 ( d, J = 3.2 Hz, 1H), 7.40 (d, J= 7.8 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.11 (br, 2H), 6.62 (d, J = 7.8 Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H), 4.67 (s, 2H), 4.13 (t, J= 5.8 Hz, 2H), 3.25 - 3.34 (br s, 3H) 3.07 (t, J= 5.8 Hz, 2H), 2.11-2.44 (m, 4H ), 0.87-1.08 (m, 6H). MS: (ES) m / z calculated C31H29F4N6O [M+H]+577.2, found 577.2. Example 25 Synthesis of 4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7tetrahydro-2 / 7-pyrazolo|4, 3-c]pyridin-3-yl)-l / / -indole-7-carboxamide

[0203] Step a: To a solution of methyl 4-(2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-iI)-4,5,6,7- Tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-17 / -indole-7-carboxylate (25 mg, 0.04 mmol) in THF (5 mL) under an ice bath added a solution of methyl lithium in THF (3 M, 0.2 mL, 0.6 mmol). The reaction mixture was stirred at 0 °C for 15 min and quenched with MeOH. The reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (45% EtOAc in hexanes) followed by HPLC (MeCN / ftO, with 1% TFA) to obtain 4-(2-(2,6-diethylphenyl) -5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)- 4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-l / / -indole-7-carboxamide. 'H NMR (400 MHz, CDCI3) δ 9.54 (s, 1H), 8.18 (dt, J=1.0, 2.1 Hz, 1H), 7.38 (dd, J=2.0 , 13.2Hz, 1H), 7.03- 7.39 (m, 5H), 6.75 (d, J= 7.6 Hz, 1H), 6.46-6.55 (m, 2H), 4.65 (br s, 2H), 4, 07 (t, J= 5.8 Hz, 2H), 3.11 (t, J= 5.8 Hz, 2H), 2.14-2.32 (br m, 4H), 1.67 (s, 6H), 1.57 (br s, 1H), 0.88-1.28 (br m, 6H). MS: (ES) m / z calculated C33H34F4N5O [M+H]+592.2, found 592.2. Example 26 Synthesis of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indoI-4-yl)-5-[5(trifluoromethyl)pyrimidin-2-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridine <=^MgBr Bis(pinacolate)d I boron; Pd(dppf)CI2-CH2CI2 step b Pas or a

[0204] Step a: A mixture of vinylmagnesium bromide in THF (1 M, 70 mL, 70 mmol) was added to a solution of 4-bromo-2-fluoro-6-nitroanisole (5.0 g, 20 mmol) in anhydrous THF (70 mL) under N2 at -50 °C. The reaction mixture was stirred at the same temperature and allowed to warm to -30 °C 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 diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (0 to 100% EtOAc in hexanes) to obtain 4-bromo-6-fluoro-7-methoxy-1 / 7-indole. MS: (ES) m / z calculated for C9H8BrFNO [M+H]+243.9, found 243.9.

[0205] Step b: To a suspension of 4-bromo-6-fluoro-7-methoxy-177-indole (900 mg, 3.68 mmol), 4,4,4',4',5,5,5 ',5'-Octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.21 g, 4.8 mmol) and KOAc (1.08 g, 11 mmol) in dioxane (16 mL) Pd(dppf)Ch complex was added with dichloromethane (400 mg, 0.49 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 100 °C for 2 h. The reaction mixture was diluted with EtOAc and filtered through Celite. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 100% EtOAc in hexanes) to obtain 6-fluoro-7-methoxy-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-177-indole. MS: (ES) m / z calculated for C15H20BFNO3 [M+H]+292.1, found 292.1.

[0206] Step c: To a suspension of for-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2 / / pyrazolo[4,3-c]pyridine-5(4H) -carboxylate (380 mg, 0.87 mmol), 6-fluoro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (230 mg , 0.79 mmol) and K2CO3 (445 mg, 3.22 mmol) in / / -dioxane (8 mL) and water (1.2 mL) Pd(dppf)Ch complex with dichloromethane (150 mg, 0. 18mmol). 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 NaHCO3 and dried over 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 3-(6-fluoro-7-methoxy-1 / / -indole -4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2Z7pyrazolo[4,3-c]pyridine-5(477)-carboxylate. MS: (ES) m / z calculated for C30H36FN4O3 [M + H]+ 519.2, found 519.2.

[0207] For-butyl 3-(6-fluoro-7-methoxy-l / / -indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2Hpyrazolo[4,3 -c]pyridine-5(4 / 7)-carboxylate above (290 mg, 0.56 mmol) was dissolved in dichloromethane (2 mL) and charged with HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. After the completion of the reaction, the solvent was evaporated in vacuo to obtain 3-(6-fluoro-7-methoxy-177-indol-4-yl)-2-(2,6-diethylphenyl)-4,5 hydrochloride, 6,7tetrahydro-27 / -pyrazolo[4,3-c]pyridine. MS: (ES) m / z calculated for C25H28FN4O [M+H]+419.2, found 419.2.

[0208] Step d: Triethylamine (0.42 mL, 3 mmol) was added to a suspension of 3-(6-fluoro-7-methoxy-127-indol-4-yl)-2-(2,6 -diethylphenyl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3c]pyridine (350 mg, 0.77 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (183 mg, 1 0.0 mmol) in MeCN (8 mL). The resulting mixture was stirred at 80 °C for 45 min. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCOs, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 60% EtOAc in hexanes) to obtain 3-(6-fluoro-7-methoxy-177-indol-4-yl) -2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2yl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CDCI3) δ 8.47 (two br s, 3H), 7.20-7.27 (m, 2H), 7.05 (d, J= 7.6 Hz, 2H), 6.61 (s, IH), 6.40-6.50 (m, 2H), 4.83 (br s, 2H), 4.36 (t, J= 5.8 Hz, 2H), 4, 06 (d, J = 2.4 Hz, 2H), 3.03 (t, J = 5.8 Hz, 2H), 2.26 (m, 4H), 1.00 (m, 6H). MS: (ES) m / z calculated for C30H29F4N6O [M+H]+565.2, found 565.2. Synthesis of [4-[2-(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4Z / pyrazoIo[4,3-c]pyridin-3 -il]-5-fliioro-117-indol-7-yl]methanol Example 27 1) ............................-Br 2) MeOH; H^SO, step to Bis{pinacolate)diboron Pd(dppf)CI2 C H2 Cl2 step b

[0209] 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 1N aqueous HCl, diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure to obtain a crude residue.

[0210] 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 obtained residue was diluted with EtOAc and brine. The organic layer was separated, dried over Na2SO4, concentrated under reduced pressure, and purified by flash chromatography on silica gel (0 to 50% EtOAc in hexanes) to obtain methyl 4-bromo-5-fluoro-177-indole7 -carboxylate. MS: (ES) m / z calculated for CioH8BrFN02 [M+H]+271.9, found 271.9.

[0211] Step b: To a suspension of methyl 4-bromo-5-fluoro-l / / -indole-7-carboxylate (0.900 g, 3.3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.51 g, 5 0.94 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 over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (0 to 100% CHCh / hexanes) to obtain methyl 5-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-127-indole-7carboxylate. MS: (ES) m / z calculated for C16H20BFNO4 [M + H]+320.1, found 320.1.

[0212] Step c: To a suspension of er-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-277pyrazolo[4,3-c]pyridine-5(4 / / )- carboxylate (1.00 g, 2.31 mmol), methyl 5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-177-indole-7-carboxylate ( 740 mg, 2.31 mmol) and K2CO3 (1.28 g, 9.24 mmol) in p-dioxane (14 mL) and water (2.5 mL) was added Pd(dppf)Ch complex with dichloromethane (400 mg , 0.49mmol). 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 aq. NaHCOs, and dried over 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-4Z7-pyrazolo[4,3-c]pyridine-5-carboxylate. MS: (ES) m / z calculated for C31H36FN4O4 [M+H]+ 547.2, found 547.2.

[0213] Step d: Zer-butyl 2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxycarbonyl-1 / 7-indol-4-yl)-6,7dihydro-427-pyrazolo[ 4,3-c]pyridine-5-carboxylate above (1.00 g, 1.83 mmol) was dissolved in THF (35 mL) and charged with ethereal solution of L1AIH4 (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 / CHCI3 (1:3), washed with brine, and dried in the presence of Na2SÜ4. 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 / er-butyl 2-(2,6-diethylphenyl)-3-(5- fluoro-7-(hydroxymethyl)-1 / 7indol-4-yl]-6,7-dihydro-4 / 7-pyrazolo[4,3-c]pyridine-5-carboxylate MS: (ES) m / z calculated for C30H36FN4O3 [M+H]+519.2, found 519.2.

[0214] / er-Butyl 2-(2,6-diethylphenyl)-3-(5-fluoro-7-(hydroxymethyl)-1 / 7-indol-4-yl]-6,7-dihydro4 / / - Pyrazolo[4,3-c]pyridine-5-carboxylate above (650 mg, 1.25 mmol) was dissolved in dichloromethane (13 mL) and charged with HC1 in dioxane (4N, 35 mL).The resulting mixture was stirred. at room temperature for 1.5 h.After the reaction was complete, the solvent was evaporated in vacuo to obtain [4-(2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3 -c]pyridin-3-yl]-5-fluoro-l / / -indol-7-yl]methanol MS: (ES) m / z calculated for C25H28FN4O [M+H]+419.2, found 419, 2.

[0215] Step e: Triethylamine (1.50 mL, 10.7 mmol) was added to a suspension of [4-(2-(2,6diethylphenyl)-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 NaHCO3, 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 [4-(2-(2,6-diethylphenyl)-5-[5 -(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4 / 7-pyrazolo[4,3c]pyridin-3-yl]-5-fluoro-177-indol-7-yl]methanol Ή NMR (400 MHz, CDCI3) δ 9.05 (br s, 1H), 8.47 (br s, 2H), 7.27 (m, 1H), 7.16 (m, 2H), 6.86 (d, J= 7.26 Hz, 1H), 6.56 (d , J = 10.0Hz, 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 C3oH29F4N60 [M+H]+565.2, found 565.2. Example 28 Synthesis of [4-[5-(5-cyclopropypyrimidin-2-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4Ef-pyrazolo[4,3c]pyridin-3-yl]-5 -fluoro-lEf-indol-7-yl]methanol

[0216] A mixture of [4-[2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazoIo[4,3c]pyridin-3-yl]-5-fluoro-177-indole hydrochloride -7-yl]methanol (35 mg, 0.077 mmol) (intermediate from Example 2), NEts (0.12 mL, 0.86 mmol), 2-chloro-5-cyclopropyl-pyrimidine (40 mg, 0.025 mmol) and LI2CO3 (120 mg, 1.62 mmol) in DMSO (1.5 mL) was stirred at 120 °C for 6 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCOs, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 85% EtOAc in hexanes) to obtain [4-[5-(5-cyclopropylpyrimidin-2-yl)-2-( 2,6-diethylphenyl)-6,7-dihydro-427-pyrazolo[4,3c]pyridin-3-yl]-5-fluoro-177-indol-7-yl]methanol. 'H NMR (400 MHz, CDCI3) δ 8.96 (br s, 1H), 8.10 (s, 2H), 7.22 (t, J = 2.8 Hz, 1H), 7.14 (m, 2H), 6.86 (dd, J= 1.2, 7.2 Hz, 1H), 6.49 (d, J = 10.0 Hz, 1H), 6.37 (t, 2.6, 1H), 4.68-4.76 (m, 2H), 4.58 -4.70 (m, 2H), 4.44 (m, 1H), 4.12 (quint, J= 6.4 Hz, 1H), 3.10 (br s, 1H), 3.02 (d , J= 5.8 Hz, 2H), 2.51 (sextet, J= 7.5 Hz, 1H), 2.44 (sextet, J= 7.6 Hz, 1H), 2.08 (m, 1H ), 1.95 (sextet, 7.5 Hz, 1H), 1.68 (m, 1H), 1.21 (t, J= 7.6 Hz, 3H), 0.87 (m, 2H), 0.76 (t, J= 7.5 Hz, 3H), 0.55 (m, 2H). MS: (ES) m / z calculated for C32H34FN6O [M+H]+537.2, found 537.2. Example 29 Synthesis of [4-[2-(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4j7pyrazolo[4,3-c]pyridin-3-yl ]-6-fluoro-lZZ-indol-7-yl]methanol NOT, br ΝΗ catch me KMnO'j ———»· Br pin dyna1 step to NO2 1) ^MgBr -CO2H --------------------------* Br 2) MeOH, HgSO* step b

[0217] Step a: A mixture of 4-bromo-2-fluoro-6-nitrotoluene (5.50 g, 23.5 mmol), KMnO4 (40 g, 253 mmol) in pyridine (100 mL) and water (75 mL) was stirred at 100 °C for 5 h. It was then cooled to room temperature, diluted with MeOH, and filtered through Celite. The filtrate was acidified with 1M aqueous HCl. The mixture was 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 100% EtOAc in DCM) to give acid 4-bromo-2-fluoro-6-nitro-benzoic. Ή NMR (400 MHz, CDCh) δ 8.89 (br s, 1H), 8.14 (t, J = 1.6Hz, 1H), 7.70 (dd, J=1.6, 8.0Hz, 1H).

[0218] Step b: A solution of vinylmagnesium bromide in THF (1 M, 32.4 mL, 32.4 mmol) to a solution of 4-bromo-2-fluoro-6-nitro-benzoic acid (1.43 g, 5.4 mmol) in anhydrous THF (30 mL) under N2 at —40 °C. The reaction mixture was stirred at the same temperature and allowed to warm to -30 °C in 1 h. The reaction mixture was quenched with saturated aqueous NH4C1 solution and allowed to warm to room temperature in 1 h. The reaction mixture was acidified with 1N aqueous HCl, diluted with EtOAc, washed with brine, and dried in the presence of Na2SO4. The solvent was removed under reduced pressure to obtain a crude acid residue.

[0219] The above acid was stirred in a mixture of conc. (5 mL) in MeOH (100 mL) at reflux for 6 h. The mixture was then cooled to room temperature and concentrated under reduced pressure. The obtained residue was diluted with EtOAc and made basic with saturated aqueous NaHC03. The organic layer was separated, washed with brine, dried over Na2SO4, concentrated under reduced pressure, and purified by flash chromatography on silica gel (0 to 100% DCM / hexanes) to obtain methyl 4-bromo-6-fluoro -l / f-indole-7-carboxylate. MS: (ES) m / z calculated for CioH8BrFN02 [M+H]+271.9, found 271.9.

[0220] Step c: To a suspension of methyl 4-bromo-6-fluoro-l / / -indole-7-carboxylate (380 mg, 1.4 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (461 mg, 1.8 mmol) and KOAc (412 mg, 4.2 mmol) in dioxane (9 mL) was added Pd(dppf)C12 complex with dichloromethane (160 mg, 0.20 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 and filtered through Celite. The filtrate was concentrated under reduced pressure and the obtained residue was purified by flash chromatography on silica gel (0 to 100% CHCh / hexanes, followed by 0 to 20% EtOAc in DCM) to obtain methyl 6-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 / / -indole-7-carboxylate. MS: (ES) m / z calculated for C16H20BFNO4 [M + H]+320.l, found 320.1.

[0221] Step d: To a suspension of thor-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2 / 7pyrazolo[4,3-c]pyridine-5(4Z / ) -carboxylate (295 mg, 0.68 mmol), methyl 6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-117-indole-7-carboxylate (220 mg, 0.68 mmol), K2CO3 (400 mg, 2.9 mmol) in / 2-dioxane (7 mL) and water (1.4 mL), Pd(dppf)Ch complexed with dichloromethane (160 mg, 0 0.20mmol). 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 NalCOs 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 50% EtOAc in hexanes) to obtain tert-butyl 2-(2,6-diethylphenyl)-3-(6-fluoro -7-methoxycarbonii-1Hindol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate. MS: (ES) m / z calculated for C31H36FN4O4 [M+H]+547.2, found 547.2.

[0222] Step e: / er-butyl 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxycarbonyl-127-indol-4-yl)-6,7dihydro-477-pyrazolo[4 ,3-c]pyridine-5-carboxylate above (300 mg, 0.54 mmol) was dissolved in THF (4 mL) and charged with LÍAIH4 in ether (2 M, 0.548 mL, 1.1 mmol) at 0° c. The resulting mixture was stirred at 0 °C for 10 min. It was then quenched with methanol and diluted with EtOAc and brine. 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 100% EtOAc in hexanes) to obtain / er-butyl 2-(2.6 -diethylphenyl)-3-[6-fluoro-7-(hydroxymethyl)-l / / -indoI-4-yl]- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate. MS: (ES) m / z calculated for C30H36FN4O3 [M+H]+ 519.2, found 519.2. thor-Butyl 2-(2,6-diethylphenyl)-3-[6-fluoro-7-(hydroxymethyl)177-indol-4-yl]-6,7-dihydro-477-pyrazolo[4,3-c ]pyridine-5-carboxylate above (195 mg, 0.37 mmol) was dissolved in dichloromethane (1.3 mL) and charged with HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 1.5h. The solvent was evaporated in vacuo to obtain [4-[2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-6fluoro-1 hydrochloride. / / -indol-7-yl]methanol. MS: (ES) m / z calculated for C25H28FN4O [M + H]+ 419.2, found 419.2.

[0223] Step f: Triethylamine (0.12 mL, 0.85 mmol) was added to a suspension of [4-[2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[ 4,3-c]pyridin-3-yl]-6-fluoro-177-indol-7yl]methanol (25 mg, 0.055 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (60 mg, 0.32 mmol ) in MeCN (1.5 mL). The resulting mixture was stirred at 85 °C for 30 min. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCOs, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 85% EtOAc in hexanes) to obtain [4-[2-(2,6-diethylphenyl)-6-[5- (trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-477-pyrazolo[4,3c]pyridin-3-yl]-5-fluoro-177-indol-7-yl]methanol. ’H NMR (400 MHz, CDCI3) δ 9.17 (br s, 1H), 8.48 (br s, 2H), 7.27 (m, 1H), 7.22 (t, J= 7.6 Hz, 1H), 7.04 (d, J= 7.6 Hz, 2H ), 6.44 (t, J= 2.6 Hz, 1H), 6.37 (d, J = 11.6 Hz, 1H), 5.05 (d, J= 5.6 Hz, 2H), 4.84 (br s, 2H), 4.36 (br s, 2H), 3.03 (t, J= 5.8 Hz, 2H), 2.10-2.40 (m, 4H), 2 .15 (t, J= 5.4 Hz, 1H), 1.01 (m, 6H). MS: (ES) m / z calculated for C30H29F4N6O [M+H]+565.2, found 565.2. Example 30 Synthesis of 2-[2-[2-(2,6-diethylphenyl)-3-[6-fluoro-7-(hydroxymethyl)-1Z?-indol-4-iI]-6,7-dihydro4ZTpyrazolo[4,3 -c]pyridin-5-yl]pyrimidin-5-yl]propan-2-ol

[0224] Step to: A mixture of [4-[2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-6-fluoro-177-indole-7- yl]methanol (38 mg, 0.083 mmol) (intermediate from Example 10), methyl 2-chloropyrimidine-5-carboxylate (70 mg, 0.40 mmol) and NEt3 (0.12 mL, 0.85 mmol) in CH3CN ( 2 mL) was stirred at 80 °C for 20 min. It was then cooled to room temperature, diluted with EtOAc, washed with aqueous NaHCOs, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 80% EtOAc in hexanes) to obtain methyl. 2-[2-(2,6-Diethylphenyl)-3-[6-fluoro-7-(hydroxymethyl)-1Z / -indol-4-yl]-6,7-dihydro-4H-pyrazolo[4,3c] pyridin-5-yl]pyrimidine-5-carboxylate. MS: (ES) m / z calculated for C31H32FN6O3 [M + H]+ 555.2, found 555.2.

[0225] Step b: To a solution of methyl 2-[2-(2,6-diethylphenyl)-3-[6-fluoro-7-(hydroxymethyl)-177indol-4-yl]-6,7-dihydro- 477-pyrazolo[4,3-c]pyridin-5-yl]pyrimidine-5-carboxylate (38 mg, 0.068 mmol) in THF (2 mL) was added CH3LI (0.35 mL, 0.56 mmol, 1. 6 M in ether) at 0 °C. The obtained mixture was stirred at the same temperature for 20 min, quenched with saturated NH4C1 and extracted with EtOAc. The organic layer was separated, washed with aqueous NaHCOa, dried in the presence of Na2SO4, concentrated under reduced pressure, and purified by flash chromatography on silica gel (0 to 100% EtOAc in hexanes) to obtain 2-[2 -[2-(2,6-diethylphenyl)-3-[6fluoro-7-(hydroxymethyl)-177-indol-4-yl]-6,7-dihydro-4 / / -pyrazolo[4,3-c] pyridin-5-yl]pyrimidin-5yl]propan-2-ol. Ή NMR (400 MHz, CDCI3) δ 8.91 (br s, 1H), 8.20 (br s, 2H), 6.95-7.10 (m, 2H), 6.80 (br s, 2H), 6.23 (br s, 1H), 6.14 (d, J= 11.2 Hz, 1H), 4.67 (s, 2H), 4.54 (s , 2H), 4.09 (br s, 1Η), 3.91 (m, 1H), 2.80 (br s, 2H), 2.71 (br s, 1H), 1.90-2.20 (br m, 4H), 1.83 ( br s, 6H), 1.61 (br s, 6H). MS: (ES) m / z calculated for C32H36FN6O2 [M+H]+ 555.3, found 555.3. Example 31 Synthesis of 3-(7-chloro-6-fluoro-1ZT-indol-4-yl)-2-(2,6-diethylphenyl)-5-[5(trifluoromethyl)pyrimidin-2-yl]-6,7- dihydro-4.H-pyrazolo[4,3-c]pyridine

[0226] Step a: / er-Butyl nitrite (5.03 mL, 42.4 mmol) was added dropwise to a solution of 4-bromo-2-fluoro-6-nitroaniline (5.00 g, 21.2 mmol) and CuCh (8.55 g, 63.6 mmol) in CH3CN (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 1h and quenched with water. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. 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 5-bromo-2-chloro-1-fluoro-3-nitro-benzene.

[0227] Step b: A solution of vinylmagnesium bromide in THF (1 M, 56 mL, 56 mmol) was added to a solution of 5-bromo-2-chloro-l-fluoro-3-nitro-benzene (4, 10 g, 16 mmol) in anhydrous THF (100 mL) under N2 at -40 °C. The reaction mixture was allowed to warm to -30 °C in 1 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 diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 100% DCM / hexanes) to obtain 4-bromo-7-chloro-6-fluoro-1H-indole. Ή NMR (400 MHz, CDCI3) δ 7.29 (t, J = 2.8 Hz, 1H), 7.20 (d, J= 8.8 Hz, 1H), 6.60 (t, J= 2 .6Hz, 1H).

[0228] Step c: To a suspension of 4-bromo-7-chloro-6-fluoro-127-indole (800 mg, 3.2 mmol), 4,4,4',4',5,5,5 ',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (981 mg, 3.86 mmol), and KOAc (942 mg, 9.6 mmol) in dioxane (15 mL) was added Pd(dppf)Ch complex with dichloromethane (300 mg, 0.37 mmol). The reaction mixture was degassed (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 100% DCM / hexanes) to obtain 7-chloro-6-fluoro-4(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-17 / -indole. MS: (ES) m / z calculated for C14H17BCIFNO2 [M+H]+296.1, found 296.1.

[0229] Step d: To a suspension of / er-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2 / 7pyrazolo[4,3-e]pyridine-5(427) -carboxylate (293 mg, 0.67 mmol), 7-chloro-6-fluoro-4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)-l / / -indole ( 200 mg, 0.67 mmol) and K2CO3 (370 mg, 2.67 mmol) in 72-dioxane (6 mL) and water (0.7 mL) Pd(dppf)Ch complex with dichloromethane (150 mg, 0 0.18mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 100 °C for 1.5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with aqueous NaHCO3, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 50% EtOAc in hexanes) to obtain / er-butyl 3-(7-chloro-6-fluoro-177-indole- 4-il)- 2-(2,6-diethylphenyl)-6,7-dihydro-427-pyrazolo[4,3-e]pyridine-5-carboxylate. MS: (ES) m / z calculated for C29H33CIFN4O2 [M+H]+523.2, found 523.2.

[0230] / er-Butyl 3-(7-chloro-6-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-4f / 94-pyrazolo[4 ,3-c]pyridine-5-carboxylate above (226 mg, 0.56 mmol) was dissolved in dichloromethane (2 mL) and charged with HC1 in dioxane (4Ν, 7 mL). The resulting mixture was stirred at room temperature for 1h. The solvent was evaporated in vacuo to obtain 3-(7-chloro-6fluoro-12 / -indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4] hydrochloride ,3-c]pyridine. MS: (ES) m / z calculated for C24H25CIFN4 [M+H]+423.2, found 423.2.

[0231] Step e: Triethylamine (0.49 mL, 3.48 mmol) was added to a suspension of 3-(7-chloro-6-fluoro-177-indol-4-yl)-2-(2) hydrochloride ,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine (400 mg, 0.87 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (192 mg, 1.05 mmol) in MeCN (9 mL). The resulting mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCOs, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 45% EtOAc in hexanes) to obtain 3-(7chloro-6-fluoro-l / / -indol-4-yl) -2-(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro4Z / -pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CDCh) δ 8.54 (br s, 1H), 8.49 (br s, 2H), 7.30 (d, J= 2.8 Hz, 1H), 7.26 ( d, J = 7.0 Hz, 1H), 7.06 (d, J= 7.2 Hz, 2H), 6.50 (m, 2H), 4.84 (br s, 2H), 4.36 (t, J= 5.6 Hz, 2H), 3.04 (t, J=.5.6 Hz, 2H), 2.25 (m, 4H), 1.01 (br s, 6H). MS: (ES) m / z calculated for C29H26CIF4N6 [M+H]+ 569.2, found 569.2. Example 32 Synthesis of 2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-1H-indol-4-yl)-5-[3-fluoro-5(trifluoromethyl)-2-pyridyl]-6 ,7-dihydro-4H-pyrazolo[4,3-c]pyridine Bis(pin acol ato)d I boro Pd{dppf)Cl2’CH2Cl2 step c 1) Pd(dppf)Cl2*CH2Cl2 2) HCI step d

[0232] Step a: A mixture of 4-bromo-5-fluoro-2-nitrophenol (4.70 g, 19.9 mmol), CH3I (3.72 mL, 59.7 mmol), and K2CO3 (8.25 g, 59.7 mmol) in DMF (60 mL) was stirred at 45 °C for 45 min. It was then cooled to room temperature, diluted with ether, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (0 to 100% CFLCh / hexanes) to obtain 1-bromo2-fluoro-4-methoxy-5-nitro-benzene. 'H NMR (400 MHz, CDCI3) δ 8.16 (d, J= Ί.6 Hz, 1H), 6.88 (d, J= 9.6 Hz, 1H), 3.96 (s, 3H) .

[0233] Step b: A solution of vinylmagnesium bromide in THF (1 M, 60 mL, 60 mmol) was added to a solution of 1-bromo-2-fluoro-4-methoxy-5-nitro-benzene (4, 55 g, 18.2 mmol) in anhydrous THF (180 mL) under N2 at -50 °C. The reaction mixture was stirred at the same temperature and allowed to warm to -30 °C in 3 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 diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 100% DCM in hexanes) to obtain 4-bromo-5-fluoro-7-methoxy-l / / -indole. MS: (ES) m / z calculated for CsHsBrFNO [M + H]+243.9, found 243.9.

[0234] Step c: To a suspension of 4-bromo-5-fluoro-7-methoxy-l / / -indole (0.200 g, 0.82 mmol), 4,4,4',4',5,5 ,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.271 g, 1.06 mmol) and KOAc (0.241 g, 2.46 mmol) in dioxane (5 mL) Pd(dppf)CI2 complex was added with dichloromethane (0.130 g, 0.16 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 100 °C for 10 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 100% DCM in hexanes) to obtain 5-fluoro7-methoxy-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-177-indole. MS: (ES) m / z calculated for C15H20BFNO3 [M+H]+292.1, found 292.1.

[0235] Step d: To a suspension of / er-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2 / 7pyrazolo[4,3-c]pyridine-5(4 / / )-carboxylate (0.060 g, 0.137 mmol), 5-fluoro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.040 g , 0.137 mmol), K2CO3 (0.076 g, 0.50 mmol) in / >-dioxane (2 mL) and water (0.3 mL), Pd(dppf)Ch complex with dichloromethane (0.070 g, 0.086 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 cooled to room temperature, diluted with EtOAc, washed with aqueous NaHCO3, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 100% EtOAc in hexanes) to obtain / er-butyl 2-(2,6-diethylphenyl)-3-(5- fluoro-7-methoxy-1Hindol-4-iI)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate. MS: (ES) m / z calculated for C3oH3óFN403 [M+H]+ 519.2, found 519.2. / er-Butyl 2-(2,6-diethylphenyl)-3-(5-fluoro-7methoxy-1Z / -indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-e] Pyridine-5-carboxylate above (0.019 g, 0.036 mmol) was dissolved in dichloromethane (1 mL) and charged with HCI in dioxane (4N, 2 mL). The resulting mixture was stirred at room temperature for 1h. The solvent was evaporated in vacuo to obtain 2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-17 / -indol-4-yl)-4,5,6,7-tetrahydropyrazolo[4,3 -c]pyridine hydrochloride. MS: (ES) m / z calculated for C25H2sFN4O[M + H]+ 419.2, found 419.2.

[0236] Step e: Triethylamine (0.12 mL, 0.86 mmol) was added to a suspension of 2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-1 / / -indole-4 -yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine hydrochloride (0.019 g, 0.034 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (0.030 g, 0.16 mmol) in MeCN (1.5 mL). The resulting mixture was stirred at 80 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aq. NaHCCh, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 50% EtOAc in hexanes) to obtain 2-(2,6-diethylphenyl)-3-(5-fluoro-7- methoxy-127-indol-4-yl)-5-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]-6,7-dihydro-4Z / -pyrazolo[4,3-c]pyridine. Ή NMR (400 MHz, CDC13) δ 8.46 (two br s, 3H), 7.12-7.22 (m, 3H), 6.89 (d, J= 6.0 Hz, 1H), 6 .33 (t, J= 2.8 Hz, 1H), 6.28 (d, J = 11.6 Hz, 1H), 4.90 (d, J= 16 Hz, 1H), 4.70 (d , J= 16 Hz, 1H), 4.43 (quint, J= 6.2 Hz, 1H), 4.29 (quint, J = 6.3 Hz, 1H), 3.87 (s, 3H), 3.04 (t, J= 6.0 Hz, 2H), 2.51 (sextet, J= 7.4 Hz, 1H), 2.43 (sextet, J= 7.6 Hz, 1H), 2, 17 (sextet, J= 7.5 Hz, 1H), 1.97 (sextet, 7.5 Hz, 1H), 1.21 (t, J= 7.6 Hz, 3H), 0.75 (t, J = 7.6Hz, 3H). MS: (ES) m / z calculated for C30H29CIF4N6O [M+H]+ 565.2, found 565.2. Example 33 Synthesis of 2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-1 / / -indol-4-yl)-5-[3-fluoro-5(trifluoromethyl)-2-pyridyl] -6,7-dihydro-4Zf-pyrazolo[4,3-c]pyridine

[0237] Triethylamine (0.12 mL, 0.86 mmol) was added to a suspension of 2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-177-indol-4-yl) hydrochloride -4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine (13 mg, 0.023 mmol) and 2,3-difluoro-5-(trifluoromethyl)pyridine (50 mg, 0.29 mmol) in MeCN ( 1.5mL). The resulting mixture was stirred at 80 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCOs, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 45% EtOAc in hexanes) to obtain 2(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy -1Z / -indol-4-yl)-5-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]-6,7dihydro-4H-pyrazolo[4,3-c]pyridine. Ή NMR (400 MHz, CDCI3) δ 8.44 (br s, 1H), 8.17 (d, J = 0.8 Hz, 1H), 7.38 (dd, J= 13.2 Hz, 1, 6, 1H), 7.12-7.22 (m, 3H), 6.88 (d, J = 7.6 Hz, 1H), 6.34 (t, 2.6 Hz, 1H), 6.27 (d, J= 11.6 Hz, 1H), 4.73 (d, J= 16 Hz, 1H), 4.46 (d, J= 16 Hz, 1H ), 4.06 (m, 2H), 3.87 (s, 3H), 3.11 (t, J= 5.6 Hz, 2H), 2.52 (sextet, J= 7.6 Hz, 1H ), 2.43 (sextet, J = 7.5 Hz, 1H), 2.17 (sextet, J= 7.6 Hz, 1H), 1.96 (sextet, J = 7.5 Hz, 1H), 1.24 (t, J= 7, 6Hz, 3H), 0.75 (t, J = 7.6Hz, 3H). MS: (ES) m / z calculated for C31H29F5N5O [M+H]+ 582.2, found 582.2. Example 34 Synthesis of 3-(7-chloro-lfl-indazol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)4,5,6,7- tetrahydro-22 / -pyrazolo[4,3-c]pyridine

[0238] Step a: To a suspension of tert-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-227pyrazolo[4,3-c]pyridine-5(477)-carboxylate ( 500 mg, 1.2 mmol), 7-chloro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-177-indazole (350 mg, 1.26 mmol ), and K2CO3 (300 mg, 2.2 mmol) in pdioxane (6 mL) and water (1 mL) was added Pd(dppf)Cl2 complex with dichloromethane (200 mg, 0.24 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, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 30% EtOAc in hexanes) to obtain tert-butyl 3-(7-chloro-17 / -indazol-4-yl) -2-(2,6-diethylphenyl)-6,7-dihydro-277-pyrazolo[4,3-c]pyridine-5(4 / / )-carboxylate. MS: (ES) m / z calculated for C28H33CIN5O2 [M + H]+ 506.2, found 506.2. Zer-butyl 3-(7-chloro-U7-indazol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro2 / / -pyrazolo[4,3-c]pyridine-5( 477)-carboxylate above was dissolved in dichloromethane (5 mL) and charged with HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. After the reaction was complete, the solvent was evaporated in vacuo to obtain 3-(7-chloro-1 / 7-indazol-4-yl)-2-(2,6-diethylphenyl)-4,5,6 hydrochloride, 7-tetrahydro-2F / -pyrazolo[4,3c]pyridine. MS: (ES) m / z calculated for C23H25CIN5 [M+H]+406.2, found 406.2.

[0239] Step b: Λζ / V-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspension of 3-(7-chloro-177-indazol-4-yl)-2-(2) hydrochloride ,6-diethylphenyl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3c]pyridine (50 mg, 0.11 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine (20 mg, 0 0.11 mmol), and LI2CO3 (20 mg, 0.27 mmol) in DMSO (10 mL) under magnetic stirring. The resulting mixture was stirred at 65 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (45% EtOAc in hexanes) followed by trituration in MeOH to obtain 3-(7-chloro-17f-indazol-4-yl)-2-(2 ,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2J7-pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CDCI3) δ 10.43 (s, IH), 8.58 (s, 2H), 8.15 (s, IH), 7.24-7.28 (m, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.69 (d, <7 = 7.7 Hz, IH), 4.95 (s, 2H), 4.44 (t, J = 6.0 Hz, 2H), 3.12 (t, J=6.0 Hz, 2H), 2.21-2.39 (m, 4H), 1.02-1.09 (m, 6H). MS: (ES) m / z calculated C28H26CIF3N7 [M+H]+552.2, found 552.2. Example 35 Synthesis of 3-(7-chloro-12Z-indazol-4-yl)-5-(5-cyclopropylpyrimidin-2-yl)-2-(2,6-diethylphenyl)- 4,5,6,7-tetrahydro-2jEr-pyrazolo[4,3-c]pyridine 100

[0240] jV,jV-Diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspension of 3-(7-chloro-l / / -indazol-4-yl)-2-(2, 6-diethylphenyl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3c]pyridine (50 mg, 0.11 mmol), 2-chloro-5-cyclopropylpyrimidine (40 mg, 0.26 mmol) , and LI2CO3 (20 mg, 0.27 mmol) in DMSO (5 mL) under magnetic stirring. The resulting mixture was stirred at 120 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (45% EtOAc in hexanes) to obtain 3-(7-chloro-177-indazol-4-yl)-5-(5-cyclopropylpyrimidin-2- yl)-2-(2,6diethylphenyl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CDCI3) δ 10.41 (s, 1H), 8.10-8.17 (m, 2H), 8.13 (s, 1H), 7.12-7.21 (m , 2H), 7.04 (d, J=7.7Hz, 2H), 6.61 (d, J=7.7Hz, 1H), 4.79 (s, 2H), 4.28 (t, J= 5.9 Hz, 2H), 3.02 (t, J= 5.9 Hz, 2H), 2.10-2.36 (m, 4H), 1.71 (m, 1H), 1, 00 (t, J=4.0Hz, 6H), 0.88 (m, 2H), 0.59 (m, 2H). MS: (ES) m / z calculated C30H31CIN7 [M+H]+524.2, found 524.2. Example 36 Synthesis of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1Eir-indazol-4-yl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5, 6,7-tetrahydro-2Z7-pyrazolo[4,3-c]pyridine 101 F 1) ALD. DMF 2) NH2NH2.H2O step to Bi$(pinacolalu)dibom Pd(dppf)C(2’CH2Cfe step b

[0241] Step a: A solution of lithium diisopropylamine in THF (1 M, 25 mL, 25 mmol) was added slowly to a solution of 5-bromo-1,3-difluoro-2-methoxybenzene (4.5 g, 20 0.2 mmol) in anhydrous THF (50 mL) under N2 and stirred vigorously at -78 °C. The reaction mixture was stirred at -60 °C for 1 h, followed by rapid addition of DMF (5 mL). The reaction mixture was stirred at the same temperature and allowed to warm to -50 °C in 1 h. The reaction was poured into a mixture of ice (200 g), concentrated hydrochloric acid (20 mL) and MTBE (100 mL) and the mixture was stirred and allowed to warm to room temperature in 2 h. The organic layer was separated, washed with brine, and dried in the presence of MgSCU. The solvent was removed under reduced pressure to obtain 6-bromo-2,4-difluoro-3-methoxybenzaldehyde. MS: (ES) m / z calculated for CgH6BrF2O2 [M+H]+250.9, found 250.9.

[0242] To the solution of the above 6-bromo-2,4-difluoro-3-methoxybenzaldehyde (1.5 g, 6.0 mmol) in DME (7 mL) was added hydrazine monohydrate (7 mL). The resulting mixture was stirred at 90 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 40% EtOAc in hexanes) to obtain 4-bromo-6-fluoro-7-methoxy-1 / / -indazole. MS: (ES) m / z calculated for CsHvBrF^O[M+H]+ 244.9, found 244.9. 102

[0243] Step b: To a suspension of 4-bromo-6-fluoro-7-methoxy-1 / / -indazole (500 mg, 2.04 mmol), 4,4,4',4',5, 5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.0 g, 3.9 mmol), and KOAc (1 g, 10.2 mmol) in DMSO (12 mL) was added Pd(dppf)Ch complex with dichloromethane (500 mg, 0.61 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 120 °C for 1.5 hrs. The reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 25% EtOAc in hexanes) to obtain 6-fluoro-7-methoxy-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-177-indazole. MS: (ES) m / z calculated for C14H19BFN2O3 [M+H]+293.1, found 293.2.

[0244] Step c: To a suspension of / er-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-277pyrazolo[4,3-c]pyridine-5(4 / / ) -carboxylate (500 mg, 1.2 mmol), 6-fluoro-7-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-177-indazole (400 mg , 1.37 mmol), K2CO3 (600 mg, 4.4 mmol) in p-dioxane (6 mL) and water (1 mL) was added Pd(dppf)C12 complex with dichloromethane (200 mg, 0.24 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, and dried over 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 / er-butyl 2-(2,6-diethylphenyl)-3-(6- fluoro-7-methoxy-1 / / -indazol-4yl)-6,7-dihydro-2E / -pyrazolo[4,3-c]pyridine-5(477)-carboxylate. MS: (ES) m / z calculated for C29H35FN5O3 [M+H]+ 520.3, found 520.3. / er-Butyl 2-(2,6-diethylphenyl)-3-(6-fluoro-7methoxy-177-indazol-4-yl)-6,7-dihydro-277-pyrazolo[4,3-c]pyridine -5(4 / 7)-carboxylate above was dissolved in dichloromethane (5 mL) and charged with HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. After the completion of the reaction, the solvent was evaporated in vacuo to obtain 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1 / 7-indazol-4-yl)-4,5 hydrochloride, 6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine. MS: (ES) m / z calculated for C24H27FN5O [M+H]+420.2, found 420.2.

[0245] Step d: 7V,. / V-Diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspension of 2-(2,6-diethylphenyl)-3-(6-fluoro-7 -methoxy-l / / -indazol-4-yl)-4,5,6,7-tetrahydro-227pyrazolo[4,3-c]pyridine (50 mg, 0.11 mmol), 2-chloro-5-( trifluoromethyl)pyrimidine (20 mg, 0.11 mmol), and LI2CO3 (20 mg, 0.27 mmol) in DMSO (10 mL) under magnetic stirring. Mix The resulting 103 was stirred at 65 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (50% EtOAc in hexanes) followed by trituration in MeOH to obtain 2-(2,6-diethylphenyl)-3-(6fluoro-7-methyl-1 / 7-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2Hpyrazolo[4,3-c]pyridine. Ή NMR (400 MHz, CDC13) δ 10.27 (s, 1H), 8.51 (s, 2H), 7.96 (d, J = 0.6 Hz, 1H), 7.26 (m, 1H ), 7.07 (d, 7.7 Hz, 1H), 6.43-6.51 (m, 1H), 4.88 (s, 2H), 4.37 (t, J = 5.9 Hz , 2H), 4.13 (dd, J= 0.6, 3.0 Hz, 3H), 3.04 (t, J = 5.9 Hz, 2H), 2.14-2.33 (m, 4H), 1.02 (t, J=7.5Hz, 6H). MS: (ES) m / z calculated C29H28F4N7O [M+H]+ 566.2, found 566.2. Example 37 Synthesis of 2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(6-fluoro-7methoxy-l / Lindazol-4-yl)-4 ,5,6,7-tetrahydro-2jHr-pyrazolo[4,3-c]pyridine

[0246] ΛζΑ-Diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspension of 2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1 / 7- indazol-4-yl)-4,5,6,7-tetrahydro-227pyrazolo[4,3-c]pyridine (30 mg, 0.07 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (15 mg, 0.08 mmol), and LI2CO3 (20 mg, 0.27 mmol) in DMSO (10 mL) under magnetic stirring. The resulting mixture was stirred at 65 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over 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 2-(2,6-diethylphenyl)-5-(3fluoro-5-(trifluoromethyl) pyridin-2-yl)-3-(6-fluoro-7-methoxy-l / / -indazol-4-yl)-4,5,6,7-tetrahydro2 / 7-pyrazolo[4,3-c]pyridine . Ή NMR (400 MHz, CDCI3) δ 10.30 (s, 1H), 8.22 (dd, J = 1.2, 2.3 104 Hz, 1H), 8.00 (s, 1H), 7.41 (dd, J= 2.0, 13.2 Hz, 1H), 7.18 - 7.30 (m, 1H), 7.07 (d, J= 7.7 Hz, 2H), 6.46 (d, J= 13.1 Hz, 1H), 4.67 (s, 2H), 4.13 (s, 3H), 4.08 (t, J= 5.9 Hz, 2H), 3.10 (t, J = 5.9 Hz, 2H), 2.13-2.36 (m, 4H), 1.02 (t, J=8.0 Hz, 6H). MS: (ES) m / z calculated C30H28F5N6O [M+H]+583.2, found 583.2. Example 38 Synthesis of 3-(7-methoxy-1ZT-indazol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2yl)-4,5,6,7-tetrahydro -2 / / -pyrazolo|4,3-c)pyridine step b

[0247] Step a: To a suspension of 4-bromo-7-methoxy-17 / -indazole (500 mg, 2.2 mmol), 4,4,4',4',5,5,5',5 '-Octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.2 g, 2.7 mmol), and KOAc (690 mg, 7.0 mmol) in DMSO (8 mL) were added. Pd(dppf)Ch complex with dichloromethane (400 mg, 0.49 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 and filtered through Celite. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 40% EtOAc in hexanes) to obtain 7-methoxy-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)177-indazole. MS: (ES) m / z calculated for C14H20BN2O3 [M + H]+ 275.2, found 275.2. 105

[0248] Step b: To a suspension of / er-butyl 3-bromo-2-(2,5-diethylphenyl)-6,7-dihydro-277pyrazolo[4,3-c]pyridine-5(477)- carboxylate (250 mg, 0.56 mmol), 7-methoxy-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1 / / -indazole (310 mg, 1.1 mmol), K2CO3 (260 mg, 1.9 mmol) in pdioxane (6 mL) and water (1.5 mL) was added Pd(dppf)Ch complex with dichloromethane (200 mg, 0.25 mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 100 °C for 3 h. The reaction mixture was 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 (10 to 80% MTBE in hexane) to obtain / er-butyl 3-(7-methoxy-1 / 7-indazol-4-yl )-2(2,6-diethylphenyl)-6,7-dihydro-2Z / -pyrazolo[4,3-c]pyridine-5-(477)-carboxylate. MS: (ES) m / z calculated for C29H36N5O3 [M+H]+ 502.3, found 502.3.

[0249] / er-Butyl 3-(7-methoxy-l / / -indazol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2 / / pyrazolo[4,3 -c]pyridine-5-(4 / / )-carboxylate above was dissolved in dichloromethane (15 mL) and treated with HC1 in dioxane (4N, 3 mL). The resulting mixture was stirred at room temperature for 1h. Once the reaction was complete, the solvent was evaporated in vacuo to obtain 3-(7-methoxy-1 / 7-indazol-4-yl)-2(2,6-diethylphenyl)-4,5,6,7 hydrochloride -tetrahydro-2Z7-pyrazolo[4,3c]pyridine. MS: (ES) m / z calculated for C24H28N5O [M + H]+ 402.2, found 402.2.

[0250] Step c: A / jV-diisopropylethylamine (0.040 mL, 0.23 mmol) was added to a suspension of 3-(7-methoxy-l / / -indazol-4-yl)-2(2, 6-diethylphenyl)-4,5,6,7-tetrahydro-277pyrazolo[4,3-c]pyridine (52 mg, 0.11 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine (25 mg, 0, 14 mmol) and LI2CO3 (20 mg, 0.27 mmol) in DMSO (1 mL) under magnetic stirring. The resulting mixture was stirred at room temperature for 9h. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (4 to 40% EtOAc in hexanes) to obtain 3-(7-methoxy-127-indazol-4-yl)-2-(2 ,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine. Ή NMR (400 MHz, Jd-DMSO) δ 8.70 (br s, 2H), 7.95 (s, 1H), 7.25 (t, J= 8.0 Hz, 1H), 7.09 ( d, J= 8.0 Hz, 2H), 6.69 (d, J= 8.0 Hz, 1H), 6.49 (d, J= 8.0 Hz, 1H), 4.79 (s, 2H), 4.31 (t, J = 5.6 Hz, 2H), 3.88 (s, 3H), 2.89 (t, J = 5.6 Hz, 2H), 2.0-2, 3 (m, 4H), 0.8-1.0 (m, 6H). MS: (ES) m / z calculated for C29H29F3N7O [M+H]+ 548.2, found 548.2. Example 39 Synthesis of 2-(2,6-diethylphenyl)-3-(6,7-difluoro-1Ef-indol-4-yl)-5-[5-(trifluoromethyl)pyrimidin-2106-yl]-6,7-dihydro- 4Zf-pyrazolo[4,3-c]pyridine

[0251] Step a: A solution of vinylmagnesium bromide in THF (1 M, 65.8 mL, 65.8 mmol) to a solution of 5-bromo-1,2-difluoro-3-nitro-benzene (4.90 g, 20.58 mmol) in anhydrous THF (70 mL) under N2 at -55 °C. The reaction mixture was stirred at the same temperature and allowed to warm to -45 °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 diluted with EtOAc, washed with brine, and dried over Na2SO4. 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 4-bromo-6,7-difluoro-1 / / -indole. MS: (ES) m / z calculated for CsHsBrFsN [M+H]+231.9, found 231.9.

[0252] Step b: To a suspension of 4-bromo-6,7-difluoro-177-indole (0.500 g, 2.15 mmol), 4,4,4',4',5,5,5', 5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.657 g, 2.6 mmol) and KOAc (0.633 g, 6.45 mmol) in dioxane (12 mL) was added Pd(dppf)Ch complex with dichloromethane (0.200 g, 0.24 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 100 °C for 1.5 hrs. The reaction mixture was 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 80% DCM / hexanes) to obtain 6,7-difluoro-4-(4,4,5,5-tetramethyl- 1,3,2dioxaborolan-2-yl)-1 / 7-indole. MS: (ES) m / z calculated for C14H17BF2NO2 [M + H]+ 280.1, 107 found 280.1.

[0253] Step c: To a suspension of tert-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2 / 7pyrazolo[4,3-c]pyridine-5(477)- carboxylate (0.356 g, 0.82 mmol), 6,7-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-177-indole (0.230 g, 0, 82 mmol), K2CO3 (0.350 g, 2.53 mmol) in p-dioxane (10 mL) and water (1.2 mL) was added Pd(dppf)Ch complex with dichloromethane (0.150 g, 0.18 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, washed with aqueous NaHCO3 and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 60% EtOAc in hexanes) to obtain tert-butyl 2-(2,6-diethylphenyl)-3-(6.7 -difluoro-1 / / -indol-4-yl)-6,7-dihydro-4 / 7-pyrazolo[4,3c]pyridine-5-carboxylate. MS: (ES) m / z calculated for C29H33F2N4O2 [M + H]+507.2, found 507.2.

[0254] Tert-butyl 2-(2,6-diethylphenyl)-3-(6,7-difluoro-1 / 7-indol-4-ii)-6,7-dihydro-4Hpyrazolo[4,3-c ]pyridine-5-carboxylate above (0.255 g, 0.60 mmol) was dissolved in dichloromethane (1.5 mL) and charged with HC1 in dioxane (4N, 4 mL). The resulting mixture was stirred at room temperature for 1h. The solvent was evaporated in vacuo to obtain 2-(2,6-diethylphenyl)-3-(6,7-difluoro-1 / 7-indol-4-yl)-4,5,6,7-tetrahydropyrazolo[4, 3-c]pyridine. MS: (ES) m / z calculated for C25H27FN4O [M+H]+407.2, found 407.2.

[0255] Step d: Triethylamine (0.12 mL, 0.86 mmol) was added to a suspension of 2-(2,6-diethylphenyl)-3-(6,7-difluoro-1Z / -indole- 4-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine (0.025 g, 0.056 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (60 mg, 0.33 mmol) in MeCN (1.5 mL). The resulting mixture was stirred at 80 °C for 45 min. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCO3, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 45% EtOAc in hexanes) to obtain 2(2,6-diethylphenyl)-3-(6,7-difluoro-1H -indol-4-yl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro4H-pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CDCI3) δ 8.60 (br s, 1H), 8.50 (br s, 2H), 7,207.25 (m, 2H), 7.06 (d, J= 7.2 Hz, 2H), 6.47 (m, 2H), 4.83 (br s, 2H), 4.36 (t, J = 5.4 Hz, 2H), 3.04 (t, J = 5, 4 Hz, 2H), 2.02-2.40 (br s, 4H), 1.00 (br s, 6H). MS: (ES) m / z calculated for C29H26F5N6 [M+H]+553.2, found 553.2. 108 Example 40 Synthesis of 3-(7-chloro-5-fluoro-1Zf-indol-4-yl)-2-(2,6-diethylphenyl)-5-[5(trifluoromethyl)pyrimidin-2-yl]-6,7- dihydro-4 / / -pyrazolo[4,3-í|pyridine ^MgBr step to bis(pinacolate)diboron Pd(dppf)CII2’CH2CI2 pas or b

[0256] Step a: A solution of vinylmagnesium bromide in THF (1 M, 37.7 mL, 37.7 mmol) was added to a solution of 1-bromo-4-chloro-2-fluoro-5-nitro- benzene (3.00 g, 11.8 mmol) in anhydrous THF (40 mL) under N2 at -60 °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 NH4C1 solution and allowed to warm to room temperature in 1 h. The reaction mixture was diluted with ether, washed with brine, and dried in the presence of NazSCh. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 40% EtOAc in hexanes) to obtain 4-bromo-7-chloro-5-fluoro-1 / / -indoL MS: (ES) m / z calculated for C8H5BrClFN [M+H]+247.9, found 247.9.

[0257] Step b: To a suspension of 4-bromo-7-chloro-5-fluoro-l / 7-indole (300 mg, 1.2 mmol), 4,4,4',4',5,5 ,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.44 g, 0.368 mmol), and KOAc (356 mg, 3.6 mmol) in dioxane (8 mL) was added Pd(dppf)Ch complex with dichloromethane (120 mg, 0.15 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 100 °C overnight. 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 109 Flash chromatography on silica gel (0 to 100% DCM in hexanes) to obtain 7-chloro-5-fluoro4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- l / / -indole. MS: (ES) m / z calculated for C14H17BCIFNO2 [M+H]+296.1, found 296.1.

[0258] Step c: To a suspension of tert-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2 / 7pyrazolo[4,3-c]pyridine-5(477)- carboxylate (169 mg, 0.39 mmol), 7-chloro-5-fluoro-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1 / 7-indole (115 mg, 0.39 mmol), K2CO3 (230 mg, 1.66 mmol) in 72-dioxane (6 mL) and water (0.7 mL), Pd(dppf)C12 complex with dichloromethane (120 mg, 0. 15mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 100 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with aqueous NaHCO3, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 50% EtOAc in hexanes) to obtain tert-butyl 3-(7-chloro-5-fluoro-127-indole-4 -yl)-2-(2,6diethylphenyl)-6,7-dihydro-4 / 7-pyrazolo[4,3-c]pyridine-5-carboxylate. MS: (ES) m / z calculated for C29H33CIFN4O2 [M+H]+523.2, found 523.2.

[0259] Tert-butyl 3-(7-chloro-5-fluoro-177-indol-4-iI)-2-(2,6-diethylphenyl)-6,7-dihydro-477pyrazolo[4,3-c ]pyridine-5-carboxylate above (90 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL) and charged with HC1 in dioxane (4N, 4 mL). The resulting mixture was stirred at room temperature for 1h. The solvent was evaporated in vacuo to obtain 3-(7-chloro-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4, 3-c]pyridine. MS: (ES) m / z calculated for C24H25CIFN4 [M+H]+423.2, found 423.2.

[0260] Step d: Triethylamine (0.12 mL, 0.86 mmol) was added to a suspension of 3-(7-chloro-5-fluoro-127-indol-4-yl)-2-(2) hydrochloride ,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine (23 mg, 0.05 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (50 mg, 0.27 mmol) in MeCN (1.3 mL). The resulting mixture was stirred at 85 °C for 45 min. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCO3, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 50% EtOAc in hexanes) to obtain 3-(7chloro-5-fluoro-1H-indol-4-yl)-2 -(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro4H-pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CDCI3) δ 8.53 (br s, 1H), 8.49 (br s, 2H), 7.30 (d, J= 3.0 Hz, 1H), 7.20 ( t, J= 7.6 Hz, 1H), 7.14 (d, J= 6.4 Hz, 1H), 6.90 (d, J = 7.2 Hz, 1H), 110 6.86 (d, J = 9.6 Hz, 1H), 6.43 (t, J = 2.8 Hz, 1H), 4.91 (d, J= 16 Hz, 1H), 4.68 ( d, J= 16 Hz, 1H), 4.40 (m, 1H), 4.34 (m, 1H), 3.05 (t, J= 5.8, 2H), 2.50 (m, 1H), 2.40 (m , 1H), 2.15 (sextet, J = 7.5 Hz, 1H), 1.93 (sextet, J = 7.5 Hz, 1H), 1.21 (t, J= 7.6 Hz, 3H), 0.76 (t, J = 7.4hz, 3H). MS: (ES) m / z calculated for C29H26CIF4N6 [M+H]+ 569.2, found 569.2. Example 41 Synthesis of 3-(7-chloro-5-fluoro-127-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(l-ineethylethyl)pyridin-2-yl)- 4,5,6,7-tetrahydro-2Z7-pyrazolo[4,3-c]pyridine 2) H2, Pd / C step to

[0261] Step a: To a suspension of 5-bromo-2-fluoropyridine (10 g, 57 mmol), 4,4,5,5-tetramethyl-2-(l-methylethenyl)-1,3,2-dioxaborolane (16 g, 93 mmol), and sodium carbonate (18 g, 17 mmol) in a mixture of dioxane (150 mL) and water (45 mL) Pd(dppf)Ch complex with dichloromethane (2.0 g, 2, 4mmol). The reaction mixture was degassed (N2) for 2 min and refluxed for 1.5 h. The dioxane was removed in vacuo and the residue was taken up in ether and water. The organic phase was separated and washed with brine. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (hexane) to obtain 2-fluoro-5-(1-methylethenyl)pyridine. ’H NMR (400 MHz, CDCI3) δ 8.28 (d, J= 2.3 Hz, 1H), 7.82- 7.88 (m, 1H), 6.89 (dd, J= 3.0, 8.8 Hz, 1H), 5.36 (s, 1H), 5.16 (s, 1H), 2.15 (s, 3H).

[0262] To the above 2-fluoro-5-(l-methylethenyl)pyridine (7.3 g, 53 mmol) dissolved in EtOAc (100 mL) was added 10% Pd / C (Degussa type E101 NE / W, 700 mg ), and the mixture was stirred under an atmosphere of hydrogen for 4 h. Upon completion, the mixture was filtered through Celite and the solvent was removed in vacuo to obtain 2-fluoro-5-(1-methylethyl)pyridine. ’H NMR (400 MHz, 111 CDCh) δ 8.05 (s, 1H), 7.59-7.66 (dd, J= 3.0, 8.4 Hz, 1H), 2.88-3.00 (m, 1H), 1 .26 (d, J= 6.8 Hz, 6H).

[0263] Step b: 7V,7V-Diisopropylethylamine (0.050 mL, 0.23 mmol) was added to a suspension of 3-(7-chloro-5-fluoro-1H-indol-4-yl)-2( 2,6-diethylphenyl)-4,5,6,7-tetrahydro-2 / fpyrazolo[4,3-c]pyridine (58 mg, 0.13 mmol), 2-fluoro-5-(l-methylethyl)pyridine (240 mg, 1.7 mmol) and LI2CO3 (28 mg, 0.38 mmol) in DMSO (0.5 mL) under magnetic stirring. The resulting mixture was stirred at a temperature of 140 °C for 4 d. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (10 to 100% MTBE in hexanes) followed by HPLC (MeCN / 1LO with 0.1% TFA) to obtain 3-(7- chloro-5-fluoro17 / -indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(l-methylethyl)pyridin-2-yl)-4,5,6,7-tetrahydro -2Z / pyrazolo[4,3-c]pyridine. Ή NMR (400 MHz, CD3OD) δ 7.92 (d, J= 2.5 Hz, 1H), 7.45-7.52 (m, 2H), 7.18-7.28 (m, 2H) , 6.94 (d, J= 7.2 Hz, 1H), 6.86 (d, J= 10 Hz, 1H), 6.82 (d, J= 9.2 Hz, 1H), 6.42 (d, J= 3.1 Hz, 1H), 4.58 (d, J= 16 Hz, 1H), 4.27 (d, J-16 Hz, 1H), 4.03 (t, J= 6 0.0 Hz, 2H), 3.01 (t, J= 6.0 Hz, 2H), 2.76-2.87 (m, 1H), 1.86-2.5 (m, 4H), 1 0.18-1.26 (m, 9H), 0.72 (t, J = 7.6 Hz, 3H)). MS: (ES) m / z calculated for C32H34CIFN5[M+H]+ 542.2, found 542.2. Example 42 Synthesis of 3-(7-chloro-5-fluoro-lFT-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(lmethylethyl)pyridin-2-yl) -4,5,6,7-tetrahydro-2FT-pyrazolo[4,3-c]pyridine

[0264] ΛζΑ-Diisopropylethylamine (0.050 mL, 0.29 mmol) was added to a suspension of 3-(7-chloro-5-fluoro-177-indol-4-yl)-2(2,6-diethylphenyl) hydrochloride )-4,5,6,7-tetrahydro-2 / 7pyrazolo[4,3-c]pyridine (77 mg, 0.17 mmol), 2,3-difluoro-5-(l-methylethyl)pyridine (200 mg , 1.3 mmol) and LI2CO3 (42 mg, 0.30 mmol) in DMSO (0.5 mL) under magnetic stirring. Mix The resulting 112 was stirred at a temperature of 140 °C for 6 h. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (4 to 60% MTBE in hexanes) to obtain 3-(7-chloro-5-fluoro-177-indol-4-yl)- 2-(2,6-diethylphenyl)-5-(3-fluoro-5-(lmethylethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridine . ’H NMR (400 MHz, CD3OD) δ 7.89 (s, 1H), 7.54 (d, 3.2 Hz, 1H), 7.43 (d, J = 14 Hz, 1H), 7.27-7.37 (m, 2H), 7.03 (d, J = 6.8 Hz, 1H), 6.93 (d, J= 10 Hz, 1H), 6.56 (d, J= 3.0 Hz, 1H), 4.63 ( d, J= 16 Hz, 1H), 4.23 (d, J= 16 Hz, 1H), 3.83-4.05 (m, 2H), 3.12 (t, .7 = 6.0 Hz , 2H), 1.96-2.5 (m, 4H), 1.25-1.37 (m, 9H), 0.81 (t, J = 7.2 Hz, 3H). MS: (ES) m / z calculated for C32H33CIF2N5 [Μ ΤΗ]4 560.2, found 560.2. Example 43 Synthesis of 3-(7-chloro-5-fluoro-LH-indol-4-yl)-5-(5-cyclopropylpyrimidin-2-iI)-2-(2,6diethylphenyl)-4,5,6,7- tetrahydro-2Zf-pyrazolo[4,3-c]pyridine

[0265] 7V,7V-Diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspension of 3-(7-chloro-5-fluoro-1 / 7-indol-4-yl)-2 hydrochloride -(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2 / 7pyrazolo[4,3-c]pyridine (30 mg, 0.07 mmol), 2-chloro-5-cyclopropylpyrimidine (20 mg , 0.13 mmol), and L12CO3 (20 mg, 0.27 mmol) in DMSO (5 mL) under magnetic stirring. The resulting mixture was stirred at 100 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (45% EtOAc in hexanes) followed by trituration in MeOH to obtain 3-(7-chloro-5-fluoro-177indol-4-yl)-5- (5-cyclopropylpyrimidin-2-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3c]pyridine. Ή NMR (400 MHz, CDCI3) δ 8.44 (d, J= 2.7 Hz, 1H), 8.12 (s, 2H), 7.12-7.32 (m, 113 5Η), 6.87 (dd, .7=8.5, 15.4 Hz, 1H), 6.47 (t, J= 2.5 Hz, 1H), 4.76 (d, J= 15, 9 Hz, 1H), 4.61 (d, J = 15.9 Hz, 1H), 4.38 (m, 1H), 4.18 (m, 1H), 3.03 (t, J= 5, 9Hz, 2H), 1.91-2.54 (br,m, 4H), 1.66 (m, 1H), 1.23 (t, J= 7.5 Hz, 3H), 0.89 (m, 2H), 0.76 (t, J= 7.5 Hz, 3H), 0.58 (m, 2H). MS: (ES) m / z calculated C31H31CIFN6 [M+H]+541.2, found 541.2. Example 44 Synthesis of (2-(3-(7-chloro-5-fluoro-l£f-indol-4-iI)-2-(2,6-diethylphenyl)-6,7-dihydro-2£ / pyrazolo[4 ,3-c]pyridin-5(4.H)-yl)pyriniidin-5-yl)(pyrrolidin-l-yl)iiiethaiione

[0266] Step a: Oxalyl chloride (1 mL, 11.8 mmol) was added to a mixture of 2-chloropyrimidine-5-carboxylic acid (500 mg, 3.2 mmol) in dichloromethane (10 mL) followed by DMF (0 ,1 mL). The resulting mixture was stirred at room temperature for 1h. After removing the solvent under reduced pressure, the residue was dissolved in dichloromethane (5 mL). The above acid chloride solution was slowly added to a solution of pyrrolidine (1 mL) and DIEA (1 mL, 5.8 mmol) in dichloromethane (20 mL) at -40 °C. The resulting mixture was stirred at -40 °C for 1 h and quenched with aqueous citric acid solution. The reaction mixture was diluted with dichloromethane, washed with brine and dried in the presence of MgSC>4. The solvent was removed under reduced pressure to obtain (2-chloropyrimidin-5-yl)(pyrrolidin-lyl)methanone. MS: (ES) m / z calculated for C9H11CIN3O [M+H]+ 212.1, found 212.1.

[0267] ΛζΑ-Diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspension of 3-(7-chloro-5-fluoro-177-indol-4-yl)-2-(2, 6-diethylphenyl)-4,5,6,7-tetrahydro-2 / 7pyrazolo[4,3-c]pyridine (45 mg, 0.11 mmol), (2-chloropyrimidin-5-yl)(pyrrolidin-l- yl)methanone (80 114 mg, 0.38 mmol), and LI2CO3 (30 mg, 0.41 mmol) in DMSO (5 mL) under magnetic stirring. The resulting mixture was stirred at 85 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (75% EtOAc in hexanes) followed by trituration in MeOH to obtain (2-(3-(7-chloro-5fluoro-177-indol-4-yl )-2-(2,6-diethylphenyl)-6,7-dihydro-277-pyrazolo[4,3-c]pyridin-5(4H)yl)pyrimidin-5-yl)(pyrrolidin-l-yl)methanone . ’H NMR (400 MHz, CDCI3) δ 8.56 (2, 2H), , 2H), 8.54 (s, IH), 7.13 - 7.32 (m, 3H), 6.84-6.90 (m, 2H), 6.44 (dd, J= 2.2, 3.2 Hz, IH), 4.87 (d, J = 16.0Hz, IH), 4.68 (d, 7= 16.0 Hz, IH), 4.24 - 4.47 (m, 2H), 3 .48 - 3.63 (m, 6H), 3.05 (t, J = 6.0, 2H), 2.40 - 2.51 (m, 2H), 1.92-2.17 (m, 4H), 1.23 (t, J=8.0Hz, 3H), 0.76 (t, J=8.0Hz, 3H). MS: (ES) m / z calculated C33H34CIFN7O [M+H]+598.2, found 598.2. Example 45 Synthesis of 3-(7-chloro-5-fluoro-1Zf-indoI-4-yl)-2-(2,6-diethylphenyl)-5-[5-(pyrrolidin-lylmethyl)pyrimidin-2-yl]-6 ,7-dihydro-4Zf-pyrazolo[4,3-c]pyridine O,

[0268] To a mixture of [2-[3-(7-chloro-5-fluoro-1 / 7-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro4 / / -pyrazolo[4,3-c]pyridin-5-yl]pyrimidin-5-yl]-pyrrolidin-l-yl-methanone (0.025 g, 0.042 mmol) in THF (2 mL) was added a solution of LIAIH4 in ether (2 M, 0.15 mL, 0.30 mmol). The resulting mixture was stirred for 30 min at room temperature. It was then quenched with water and diluted 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 30% MeOH in DCM) to obtain 3-(7-chloro-5-fluoro -l / / -indol-4-yl)-2-(2,6-diethylphenyl)-5-[5-(pyrrolidin-115-ylmethyl)pyrimidin-2-yl]-6,7-dihydro-477-pyrazolo[ 4,3-c]pyridine. ’H NMR (400 MHz, CDCh) δ 8.51 (brs, 1H), 8.28 (s, 2H), 7.30 (t, 5.6 Hz, 1H), 7.19 (t, J= 7.6 Hz, 1H), 7, 15 (m, 1H), 6.87 (d, J= 7.6 Hz, 1H), 6.84 (d, J= 10 Hz, 1H), 6.46 (dd, J= 2.8, 2 .8 Hz, 1H), 4.80 (d, J= 16 Hz, 1H),), 4.62 (d, J= 15.6 Hz, 1H), 4.39 (m, 1H), 4, 22 (m, 1H), 3.50 (br s, 2H), ), 3.03 (t, J = 5.8 Hz, 2H), 2.36-2.60 (m, 6H), 2, 15 (sextet, J = 7.6 Hz, 1H), 1.92 (sextet, J = 7.6 Hz, 1H), 1.81 (br s, 4H), 1.22 (t, J = 7, 6Hz, 3H), 0.74 (t, J = 7.6Hz, 3H). MS: (ES) m / z calculated for C33H36CIFN7 [M+H]+584.2, found 584.2. Example 46 Synthesis of 3-(7-methyl-H / -indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(l-methylethyl)pyridin-2-yl)-4,5, 6,7tetrahydro-2 / / -pyrazolo|4,3-<?]pyridine

[0269] 7V,jV-Diisopropylethylamine (0.06 mL, 0.35 mmol) was added to a suspension of 3-(7- methyl-1Z / -indol-4-yl)-2(2,6-diethylphenyl)-4,5,6,7-tetrahydro-27 / -pyrazolo[4,3c]pyridine (51 mg, 0.12 mmol) , 2-fluoro-5-(l-methylethyl)pyridine (100 mg, 0.73 mmol) and LI2CO3 (24 mg, 0.32 mmol) in DMSO (0.25 mL) under magnetic stirring. The resulting mixture was stirred at 140 °C for 23 h. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (0 to 70% MTBE in hexanes) to obtain 3-(7-methyl-1 / / -indol-4-yl)-2- (2,6-diethylphenyl)-5-(5-(l-methylethyl)pyridin-2-yl)-4,5,6,7tetrahydro-27 / -pyrazolo[4,3-c]pyridine. ’H NMR (400 MHz, CD3OD) δ 7.91 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 2.9 Hz, 1H), 7.08 (br s, 2H), 6.74 (d, 9.2 Hz, 1H), 6, 68 (d, J = 7.6 Hz, 1H), 6.48 (d, J= 7.2 Hz, 1H), 6.40 (d, J= 3.1 Hz, 1H), 4.43 (s, 2H), 4.03 ( t, J= 5.6 Hz, 2H), 2.99 (t, J = 5.6 Hz, 2H), 2.75-2.85 (m, 1H), 2.45 (s, 3H), 2.06-2.40 (br s, 4H ), 1.17-1.24 (m, 116 6Η), 0.79-1.13 (br s, 6H). MS: (ES) m / z calculated for C33H38N5 [M + H]+ 504.3, found 504.3. Example 47 Synthesis of 3-(7-methyl-lEf-indol-4-iI)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(l-methylethyl)pyridin-2-yl)4, 5,6,7-Tetrahydro-2ZT-pyrazolo[4,3-c]pyridine

[0270] 7V,7V-Diisopropylethylamine (0.050 mL, 0.29 mmol) was added to a suspension of 3-(7-methyl -177-indol-4-yl)-2(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3c]pyridine (49 mg, 0.12 mmol), 2,3-difluoro-5-(l-methylethyl)pyridine (100 mg, 0.64 mmol) and LI2CO3 (34 mg, 0.46 mmol) in DMSO (0.50 mL) under magnetic stirring. The resulting mixture was stirred at 130 °C for 23 h. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (0 to 70% MTBE in hexanes) to obtain 3-(7-methyl-1 / / -indol-4-yl)-2- (2,6-diethylphenyl)-5-(3-fluoro-5-(l-methylethyl)pyridin-2-yl)- 4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine. ’HNMR (400 MElz, CD3OD) δ 7.91 (s, 1H), 7.30- 7.35 (m, 2H), 7.24 (t, J=7.6 Hz, 1H), 7.09 (br s, 2H), 6.67 (d, J= 7.6 Hz, 1H) , 6.48 (d, J= 7.6 Hz, 1H), 6.43 (d, J= 3.1 Hz, 1H), 4.38 (br s, 2H), 3.84 (t, J = 5.6 Hz, 2H), 3.03 (t, J= 5.6 Hz, 2H), 2.83-2.92 (m, 1H), 2.44 (s, 3H), 2.33 (br s, 4H), 1.22 (d, J = 7.2 Hz, 6H), 0.99 (br s, 6H). MS: (ES) m / z calculated for C33H37N5 [M+H]+ 522.3, found 522.3. Example 48 Synthesis of 3-(7-chloro-3-methyl-1 / f-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl )-4,5,6,7-tetrahydro-2.fir-pyrazolo[4,3-c]pyridine 117

[0271] Step a: A solution of 1-propenylmagnesium bromide in THF (0.5 M, 50 mL, 25 mmol) was added rapidly to a solution of 5-bromo-2-chloronitrobenzene (2.0 g, 8, 5 mmol) in anhydrous THF (100 mL) under N2 and stirred vigorously at -60 °C. The reaction mixture was stirred at -40 to -50 °C for 35 minutes, then quenched with saturated NH4Cl solution and 100 mL of water and allowed to warm to room temperature. The organic phase was separated, and the aqueous phase was extracted with ether. The combined organic phases were washed with brine and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (2 to 4% MTBE in hexanes) to obtain 4-bromo-7-chloro-3-methyl-1 / / -indole. 'H NMR (400 MHz, CDCI3) δ 8.16 (br s, 1H), 7.17 (d, J= 8.4 Hz, 1H), 7.04 (s, 1H), 6.99 (d , J= 8.4Hz, 1H), 2.54 (s, 3H).

[0272] Step b: To a suspension of 4-bromo-7-chloro-3-methyl-l / / -indole (420 mg, 1.7 mmol), 4,4,4',4',5,5 ,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (650 mg, 2.6 mmol), and KOAc (500 mg, 5.1 mmol) in dioxane (4 mL ) Pd(dppf)Ch complex was added with dichloromethane (250 mg, 0.31 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 100 °C for 3 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 4% MTBE in hexanes) to obtain 7-chloro-3-methyl-4-(4,4,5,5-tetramethyl - 1,3,2-dioxaborolan-2-yl)-1Z / -indole. MS: (ES) m / z calculated for C15H20BCINO2 [M+H]+ 292.1, found 292.1. 118

[0273] Step c: To a suspension of 3-bromo-2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7 -tetrahydro-2 / / -pyrazolo[4,3-c]pyridine (51 mg, 0.10 mmol), 7-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-17 / -indole (52 mg, 0.18 mmol), K2CO3 (43 mg, 0.31 mmol) in p-dioxane (3 mL), and water (1 mL) Pd complex was added (dppf)Ch with dichloromethane (31 mg, 0.038 mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 100 °C for 1 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (12% EtOAc in hexanes) followed by trituration with methanol to obtain 3-(7-chloro-3-methyl-1 / / -indole -4-yl)-2-(2,6diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-27 / -pyrazolo[4, 3c]pyridine. ’H NMR (400 MHz, d6-DMSO) δ 11.45 (s, 1H), 8.27 (s, 1H), 7.95 (d, J= 14 Hz, 1H), 7.31 (s, 1H), 7.20-7.28 (m, 2H), 6.97 (d, J= 8.0 Hz, 1H), 6.93 (d, J= 6.0 Hz , 1H), 6.38 (d, J = 8.0 Hz, 1H), 4.49 (d, J = 16 Hz, 1H), 4.18 (d, J = 16 Hz, 1H), 3, 85^.04 (m, 2H), 2.90-3.16 (m, 2H), 2.11-2.45 (m, 3H), 2.01 (s, 3H), 1.89-2 .00 (m, 1H), 1.20 (t, J= 7.6 Hz, 3H), 0.71 (t, J= 7.6 Hz, 3H). MS: (ES) m / z calculated for C31H29CIF4N5 [M+H]+ 582.2, found 582.2. Example 49 Synthesis of 3-(7-fluoro-3-cIoro-127-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)- 4,5,6,7-tetrahydro-2 / ¿-pyrazolo[4,3-c]pyridine step b Pas or a 119

[0274] Step a: To a solution of 4-bromo-7-fluoro-lZ / -indole (1.0 g, 4.7 mmol) in DMF (5 mL) was added 7V-chlorosuccinimide (690 mg, 5 0.2 mmol), and the mixture was stirred for 2 h. When the reaction was complete, the mixture was diluted in EtOAc and water, the organic phase was separated and EtOAc was extracted under reduced pressure. The residue was purified by flash chromatography on silica gel (4 to 20% MTBE in hexanes) to obtain 4-bromo-3-chloro-7-fluoro-1 / / -indole. Ή NMR (400 MHz, CDCh) δ 8.34 (br s, 1H), 7.27 (d, J= 2.9 Hz, 1H), 7.22 (dd, J= 4.4, 8.4 Hz, 1H), 6.81 (dd, J= 8.4 Hz, 10, 1H).

[0275] Step b: To a suspension of 4-bromo-3-chloro-7-fluoro-17 / -indole (810 mg, 3.3 mmol), 4,4,4',4',5,5, Added 5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (920 mg, 3.6 mmol), and KOAc (980 mg, 10 mmol) in dioxane (15 mL). Pd(dppf)C12 complex with dichloromethane (820 mg, 1.0 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 100 °C for 1 h. 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 3-chloro-7-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-177-indole. ]H NMR (400 MHz, 6-DMSO) δ 12.00 (s, 1H), 7.63 (d, J= 2.7 Hz, 1H), 7.24 (dd, J = 5.2, 8.0 Hz, 1H), 7.01 (dd, J= 8.0, 12 Hz , 1H), 1.33 (s, 12H).

[0276] Step c: To a suspension of 3-bromo-2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7- Tetrahydro-2 / / -pyrazolo[4,3-c]pyridine (52 mg, 0.10 mmol), 3chloro-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-127-indole (50 mg, 0.16 mmol), K2CO3 (51 mg, 0.37 mmol) in / >-dioxane (3 mL), and water (1 mL), Pd( dppf)Ch with dichloromethane (39 mg, 0.048 mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 100 °C for 1 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (4 to 60% EtOAc in hexanes) followed by trituration with methanol to obtain 3-(3-chloro-7-fluoro-1FLindol-4 -yl)-2-(2,6diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-27 / -pyrazolo[4,3c] pyridine. 'H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 7.62 (dd, J=2.0, 13 Hz, 1H), 7.44 (s, 1H), 7.22- 7.29 (m, 2H), 6.96 (dd, J= 2.6, 6.8 Hz, 1H), 6.75 (dd, J= 8.8, 11 Hz, 1H), 6.56 (dd, J = 4.8, 8.8 Hz, 1H), 4.75 (d, J= 15 Hz, 1H), 4.37 (d, J= 15 Hz, 1H), 3.97^1 .15 (m, 2H), 3.01- 3.10 (m, 2H), 2.29-2.54 (m, 3H), 2.01-2.15 (m, 1H), 1.30 (t, J= 7.2, 3H), 0.77 (t, J= 7.2Hz, 3H). MS: (ES) m / z calculated for C30H26CIF5N5 [M+H]+ 586.2, found 586.2. 120 Synthesis of 3-(3-chloro-7-methyl-1Zf-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)- 4,5,6,7-tetrahydro-2Z7-pyrazolo[4,3-c]pyridine Example 50

[0277] Step a: To a solution of 4-bromo-7-methyl-177-indole (750 mg, 3.6 mmol) in DMF (5 mL) was added JV-chlorosuccinimide (500 mg, 3.7 mmol) , and the mixture was stirred for 3 h. When the reaction was complete, the mixture was diluted in EtOAc and water, the organic phase was separated and EtOAc was extracted under reduced pressure. The residue was purified by silica gel flash chromatography (4 to 20% MTBE in hexanes) to obtain 4-bromo-3-chloro-7-methyl-177-indole. Ή NMR (400 MHz, 6-DMSO) δ 11.68 (s, 1H), 7.62 (d, J= 2.8 Hz, 1H), 7.16 (d, J= 8.0 Hz, 1H), 6.86 (d, J= 8.0 Hz, 1H), 2.41 (s, 3H).

[0278] Step b: To a suspension of 4-bromo-3-chloro-7-methyl-l / / -indole (700 mg, 2.9 mmol), 4,4,4',4',5,5 ,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (870 mg, 3.4 mmol), and KOAc (1.1 g, 11 mmol) in dioxane (7 mL ) Pd(dppf)Ch complex was added with dichloromethane (350 mg, 0.42 mmol). The reaction mixture was degassed (N2) for 2 min and stirred at 100 °C for 14 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (4 to 30% MTBE in hexanes) to obtain 3-chloro-7-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-177-indole. Ή NMR (400 MHz, tZ6-DMSO) δ 11.38 (s, 1H), 121 7.51 (d, J= 2.6 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.95 (d, J= 7.2 Hz, 1H), 2 .46 (s, 3H), 1.33 (s, H).

[0279] Step c: To a suspension of 3-bromo-2-(2,6-diethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7- Tetrahydro-2 / / -pyrazolo[4,3-c]pyridine (56 mg, 0.11 mmol), 3-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-l / 7-indole (60 mg, 0.21 mmol), K2CO3 (51 mg, 0.37 mmol) in p-dioxane (3 mL), and water (1 mL) Pd complex was added (dppi)Ch with dichloromethane (53 mg, 0.064 mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 100 °C for 3.5 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (4 to 14% EtOAc in hexanes) followed by HPLC (MeCN / H2O with 0.1% TFA) to obtain 3-(3 -chloro-7-methyl-127-indol-4yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7 -tetrahydro-2 / / pyrazolo[4,3-c]pyridine. ’H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 7.61 (d, J= 14 Hz, 1H), 7.35 (s, 1H), 7.22-7.26 (m, 2H), 6.94 (dd, J= 3.4, 6.4 Hz, 1H), 6.77 (d, J = 7.2 Hz, 1H), 6.51 (d, J = 7.2 Hz, 1H), 4.76 (d, J = 16 Hz, 1H), 4.34 (d, J= 16 Hz, 1H ), 3.94-4.14 (m, 2H), 2.98-3.10 (m, 2H), 2.33-2.55 (m, 3H), 2.43 (s, 3H), 2.03-2.16 (m, 1H), 1.30 (t, J=8.0 Hz, 3H), 0.77 (t, J=8.0 Hz, 3H). MS: (ES) m / z calculated for C31H29CIF4N5 [M+H]+ 582.2, found 582.2. Example 51 Synthesis of 3-(7-chloro-1ZT-indol-4-yl)-2-(2,6-dimethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5, 6,7-tetrahydro-2Ef-pyrazolo[4,3-c]pyridine 122

[0280] Step a: Added A / V-diisopropylethylarnine (6 mL, 34.5 mmol) to a mixture of (2,6-dimethylphenyl)hydrazine hydrochloride (5 g, 28.9 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 3h. Glacial acetic acid (6 mL, 104 mmol) was added and the mixture was stirred under reflux for a further 2 h. After removing the solvent under reduced pressure, the residue was dissolved in EtOAc and washed with aqueous NaOH (2N), brine, and dried over 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 / er-butyl 3-amino-2-(2,6-dimethylphenyl)-6 ,7-dihydro-2Z / pyrazolo[4,3-c]pyridine-5(4 / / )-carboxylate. MS: (ES) m / z calculated for C19H27N4O2 [M + H]+ 343.2, found 343.2. Caution: Diazonium formation could be potentially dangerous; please treat with care and wear appropriate personal protective equipment.

[0281] Step b: Isopentenyl nitrite (96%, 4 mL, 28.6 mmol) was slowly added at room temperature to a mixture of / er-butyl 3-amino-2-(2,6-dimethylphenyl)-6, 7-dihydro-2 / 7pyrazolo[4,3-c]pyridine-5(4Z / )-carboxylate (3 g, 8.8 mmol), CuBr (4 g, 27.9 mmol), and MeCN (50 mL) in a 250 mL round bottom flask under magnetic stirring. The resulting mixture was stirred at room temperature for 1 h, diluted with EtOAc, filtered through Celite, washed with saturated NH4Cl soln, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (2 to 123 25% EtOAc in hexanes) to give phor-butyl 3-bromo-2-(2,6-dimethylphenyl)-6,7-dihydro-277pyrazolo[4,3-c]pyridine-5(4 / / )-carboxylate . MS: (ES) m / z calculated for Ci9H25BrN3O2 [M + H]+ 406.1, found 406.1.

[0282] Step c: / er-Butyl 3-bromo-2-(2,6-dimethylphenyl)-6,7-dihydro-277-pyrazolo[4,3c]pyridine-5(4 / / )-carboxylate was dissolved (1.5 g, 3.7 mmol) in dichloromethane (10 mL) and charged with HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. After the completion of the reaction, the solvent was evaporated in vacuo to obtain 3-bromo-2(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c ]pyridine. MS: (ES) m / z calculated for Ci4Hi7BrN3 [M+H]+ 306.1, found 306.1.

[0283] A / jV-Diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspension of 3-bromo-2-(2,6-dimethylphenyl)-4,5,6,7-tetrahydro hydrochloride -2 / / -pyrazolo[4,3-c]pyridine (1 g, 2.9 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (1.1 g, 6 mmol), and K2CO3 (1.38 g, 10 mmol) in MeCN (10 mL) under magnetic stirring. The resulting mixture was stirred at 85 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (2 to 15% EtOAc in hexanes) to obtain 3-bromo-2-(2,6-dimethylphenyl)-5-(3- fluoro-5-(trifluoromethyl)pyridin-2-yl)- 4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridine. MS: (ES) m / z calculated for C2oHi7BrF4N4 [M+H]+469.1, found 469.1.

[0284] Step d: To a suspension of 3-bromo-2-(2,6-dimethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7- tetrahydro-2 / / -pyrazolo[4,3-c]pyridine (50 mg, 0.11 mmol), 7-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-177-indole (50 mg, 0.18 mmol), and K2CO3 (180 mg, 1.3 mmol) in / / -dioxane (6 mL) and water (1 mL) Pd(dppf)Ch complex was added with dichloromethane (40 mg, 0.05 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, and dried over 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 3-(7-chloro-177-indol-4-yl)-2-( 2,6-dimethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2Z / -pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CD3OD) δ 8.22 (d, 7= 1.3 Hz, IH), 7.64 (dd, 7= 2.0, 13.5 Hz, IH), 7.44 ( d, 7= 3.2 Hz, IH), 124 1,\5(t,J= 7.6 Hz, 2H), 7.04 (br s, 2H), 6.94 (d, J= 7.9 Hz, 1H), 6.52-6.57 (m, 2H), 4.65 (s, 2H), 4.11 (t, J= 5.8 Hz, 2H), 3.29 (s, 1H), 3.06 (t, J= 5.8 Hz, 2H), 1.96 (br m , 6H). MS: (ES) m / z calculated C28H23CIF4N5 [M+H]+540.2, found 540.2. Example 52 Synthesis of 3-(3-chloro-7-fluoro-1H-indol-4-iI)-2-(2,6-dimethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)- 4,5,6,7-tetrahydro-227-pyrazolo[4,3-c]pyridine

[0285] Step a: To a suspension of 3-bromo-2-(2,6-dimethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7- tetrahydro-227-pyrazolo[4,3-c]pyridine (100 mg, 0.22 mmol), 7-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-177-indole (100 mg, 0.38 mmol), K2CO3 (200 mg, 1.45 mmol) in / / -dioxane (6 mL), and water (1 mL) Pd(dppf)C12 complex was added with dichloromethane (50mg, 0.06mmol). 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 over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (40% EtOAc in hexanes) followed by HPLC (MeCN / H2O, with 0.1% TFA) to obtain 2-(2,6-dimethylphenyl) -3(7-fluoro-l / / -indol-4-yl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2 / / pyrazolo[4,3-c]pyridine. Ή NMR (400 MHz, CDCI3) δ 8.52 (s, 1H), 8.19 (dt, J= 1.1, 1.9 Hz, 1H), 7.39 (dd, J= 2.0, 13.2 Hz, 1H), 7.26 (d, 4.8 Hz, 1H), 7.08 (t, 7.5 Hz, 1H), 6.96 (br, 2H), 6.70 (dd , J= 8.1,10.7 Hz, 1H), 6.50-6.59 (m, 2H), 4.64 (s, 2H), 4.07 (t, 5.8 Hz, 2H), 3.12 (t, J=5.8 Hz, 2H), 1.96 (brm, 6H). MS: (ES) m / z calculated C28H23F5N5 [M + H]+ 524.2, found 524.2.

[0286] Step b: N-chlorosuccinimide (33 mg, 0.25 mmol) was added to a solution of 2-(2,6-dimethylphenyl)-3-(7-fluoro-1 / 7-indol-4-yl) -5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7tetrahydro-21 / -pyrazolo[4,3-c]pyridine (30 mg, 0.06 mmol) in DMF (5 mL). The resulting mixture was stirred at 60 °C for 6 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (40% EtOAc in hexanes) followed by HPLC (MeCN / FLO, with 0.1% TFA) to obtain 3-(3-chloro-7fluoro- ?-indoI-4-yl)-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7tetrahydro-277-pyrazolo [4,3-c]pyridine. 'H NMR (400 MHz, CDCI3) δ 8.56 (s, 1H), 8.16 (dt, J = 1.0, 2.0 Hz, 1H), 7.18-7.41 (m, 2H ), 7.03-7.13 (m, 2H), 6.70-6.86 (m, 2H), 6.58 (ddd, J = 0.7, 4.6, 8.2 Hz, 1H), ), 4.71 (d, J= 15.5 Hz, 1H), 4.48 (d, J= 15.5 Hz, 1H), 3.84^ 1.21 (m, 2H), 3.06-3.21 (m, 2H), 2.22 (d, J= 0.7 Hz, 3H), 1.87 (d, J= 0.7 Hz , 3H). MS: (ES) m / z calculated C28H22CIF5N5 [M+H]+ 558.1, found 558.2. Example 53 Synthesis of 2-(2,6-dimethylphenyl)-3-(6-fluoro-7-methyl-127-indol-4-yl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5, 6,7-tetrahydro-217-pyrazolo[4,3-c]pyridine

[0287] Step a: To a suspension of Zer-butyl 3-bromo-2-(2,6-dimethylphenyl)-6,7-dihydro-277pyrazolo[4,3-c]pyridine-5(4 / 7)- carboxylate (440 mg, 1.08 mmol), 6-fluoro-7-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-17 / -indole (260 mg , 0.94 mmol), K2CO3 (500 mg, 3.6 mmol) in / i-dioxane (6 mL) and water (1 mL), Pd(dppf)Ch complex with dichloromethane (200 mg, 0.24 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, 126 washed with brine and dried in the presence of MgSÜ4. 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 2-(2,6-dimethylphenyl)-3-(6-fluoro -7-methyl-177-indol-4-yl)-6,7dihydro-27 / -pyrazolo[4,3-c]pyridine-5(4 / 7)-carboxylate. MS: (ES) m / z calculated for C28H32FN4O2 [M+H]+475.2, found 475.2.

[0288] Tert-butyl 2-(2,6-dimethylphenyl)-3-(6-fluoro-7-methyl-1 / 7-indol-4-yl)-6,7-dihydro-277pyrazolo[4,3 -c]pyridine-5(4 / / )-carboxylate above was dissolved in dichloromethane (5 mL) and charged with HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. After the reaction was complete, the solvent was evaporated in vacuo to obtain 2-(2,6-dimethylphenyl)-3-(6-fluoro-7-methyl-1 / / -indol-4-yl)-4 hydrochloride, 5,6,7-tetrahydro-217pyrazolo[4,3-c]pyridine. MS: (ES) m / z calculated for C23H24FN4 [M + H]+ 375.2, found 375.2.

[0289] Step b: ΛζΑ-Diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspension of 2-(2,6-dimethylphenyl)-3-(6-fluoro-7-methyl-1 hydrochloride / 7-indol-4-yl)-4,5,6,7-tetrahydro-217pyrazolo[4,3-c]pyridine (50 mg, 0.12 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine ( 45 mg, 0.25 mmol), and LI2CO3 (30 mg, 0.41 mmol) in DMSO (5 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 over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (40% EtOAc in hexanes) followed by HPLC (MeCN / FLO, with 0.1% TFA) to obtain 2(2,6-dimethylphenyl)- 3-(6-fluoro-7-methyl-177-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2H-pyrazolo[4,3 -c]pyridine. Ή NMR (400 MHz, CDCI3) δ 8.54 (s, 2H), 8.25 (s, 1H), 7.04-7.18 (m, 3H), 6.46-6.53 (m, 1H), 4.91 (s, 2H), 4.42 (br, 2H), 3.11 (t, J = 5.8 Hz, 2H), 2.42 (d, J= 1.7 Hz, 3H), 1.92-2.13 (br m, 6H). MS: (ES) m / z calculated C28H25F4N6 [M + H]+ 521.2, found 521.2. Example 54 Synthesis of 3-(5-fluoro-7-methyl-ll / -indol-4-yl)-2-(2,6-diinethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5 ,6,7-tetrahydro-2 / 7-pyrazolo[43-c]pyridine 127

[0290] Step a: To a suspension of / er-butyl 3-bromo-2-(2,5-dimethylphenyl)-6,7-dihydro-2 / / pyrazolo[4,3-c]pyridine-5(477 )-carboxylate (430 mg, 1.0 mmol), 5-fluoro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 / / -indazole (220 mg, 0.80 mmol), and K2CO3 (420 mg, 3.0 mmol) in jo-dioxane (8 mL) and water (2 mL) was added Pd(dppf)Ch complex with dichloromethane (250 mg, 0 0.30mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 100 °C for 15 h. The reaction mixture was diluted with dichloromethane, dried over Na2SO4 and filtered through Celite. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (10 to 60% MTBE in hexanes) to obtain / er-butyl 3-(5-fluoro-7-methyl-1 / / - indazol-4-yl)-2-(2,6-dimethylphenyl)-6,7-dihydro-2 / 7pyrazolo[4,3-c]pyridine-5-(4 / / )-carboxylate. MS: (ES) m / z calculated for C28H32FN4O2 [M + H]+ 475.3, found 475.3.

[0291] / er-Butyl 3-(5-fluoro-7-methyl-127-indazol-4-yl)-2-(2,6-dimethylphenyl)-6,7-dihydro-2 / fpyrazolo[4, 3-c]pyridine-5-(477)-carboxylate was dissolved in dichloromethane (50 mL) and treated with HC1 in dioxane (4N, 4 mL). The resulting mixture was stirred at room temperature for 1 d. After the completion of the reaction, the solvent was evaporated in vacuo to obtain 3-(5fluoro-7-methyl-1 / / -indazol-4-yl)-2(2,6-dimethylphenyl)-4,5,6 hydrochloride ,7-tetrahydro-2Z / -pyrazolo[4,3-e]pyridine. MS: (ES) m / z calculated for C23H24FN4 [M + H]+ 375.2, found 375.2.

[0292] Step b: ΛζΑ-Diisopropylethylamine (0.040 mL, 0.23 mmol) was added to a suspension of 3-(5-fluoro-7-methyl-1 / 7-indazol-4-yl)-2( 2,6-dimethylphenyl)-4,5,6,7-tetrahydro-277pyrazolo[4,3-c]pyridine (48 mg, 0.12 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine (25 mg, 0.14 mmol) and LI2CO3 (20 mg, 0.27 mmol) in acetonitrile (1 mL) under magnetic stirring. The resulting mixture was stirred at 80 °C for 4 h. The solvent was removed in vacuo and the residue was purified. 128 by flash chromatography on silica gel (4 to 100% MTBE in hexanes) followed by trituration with MTBE in hexanes to obtain 3-(5-fluoro-7-methyl-1 / / -indazol-4-yl)-2 -(2,6dimethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CD3OD) δ 8.57 (br s, 2H), 7.38 (d, J= 3.0 Hz, 1H), 7.10 (d, J= 4.8 Hz, 2H ), 6.84 (t, J= 4.8 Hz, 1H), 6.58 (d, J= 11 Hz, 1H), 6.33 (d, J = 3.0 Hz, 1H), 4, 3^.5 (m, 2H), 3.00 (t, J= 5.4 Hz, 2H), 2.48 (s, 3H), 2.18 (s, 3H), 1.70 (s, 3H). MS: (ES) m / z calculated for C28H25F4N6 [M+H]+ 521.2, found 521.2. Example 55 Synthesis of 3-(5-fluoro-7-methyl-LH-indazol-4-yl)-2-(2,6-dimethylphenyl)-5-(3-fluoro-5(trifluoromethyl)pyridin-2-yl)- 4,5,6,7-tetrahydro-22Z-pyrazolo[4,3-c]pyridine

[0293] 7V,jV-Diisopropylethylamine (0.040 mL, 0.23 mmol) was added to a suspension of 3-(5-fluoro-7-methyl-l / / -indazol-4-yl)-2(2) hydrochloride ,6-dimethylphenyl)-4,5,6,7-tetrahydro-2 / / pyrazolo[4,3-c]pyridine (48 mg, 0.12 mmol) and 2,3-difluoro-5-(trifluoromethyl)pyridine (94 mg, 0.51 mmol) in acetonitrile (1 mL) under magnetic stirring. The resulting mixture was stirred at 80 °C for 4 h. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (0 to 60% MTBE in hexanes) followed by trituration with MTBE in hexanes to obtain 3-(5-fluoro-7-methyl-1 / / -indazol-4-yl)-2-(2,6-dimethylphenyl)-5-(2-fluoro-5(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2 / 7 -pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 7.63 (dd, J= 1.9, 13 Hz, 1H), 7.10 (d, J= 4.8 Hz, 2H), 6.84 (t, J= 4.8 Hz, 1H), 6.57 (d, J= 12 Hz, 1H), 6.32 (d, J= 2.9 Hz, 1H), 4 .78 (d, J= 16 Hz, 1H), 4.40 (d, J = 16 Hz, 1H), 4.10 (t, 5.6 Hz, 2H), 3.07 (t, J= 5 .6 Hz, 2H), 2.47 (s, 3H), 2.18 (s, 3H), 1.70 (s, 3H). MS: (ES) m / z calculated for C29H25F5N5 [M+H]+ 538.2, found 538.2. 129 Synthesis of 3-(7-chloro-5-fluoro-l / / -indol-4-yl)-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(lmethylethyl)pyridin-2- yl)-4,5,6,7-tetrahydro-2Zf-pyrazolo[4,3-c]pyridine Example 56

[0294] Step a: To a suspension of tert-butyl 3-bromo-2-(2,5-dimethylphenyl)-6,7-dihydro-2 / 7pyrazolo[4,3-c]pyridine-5(477)- carboxylate (500 mg, 1.2 mmol), 7-chloro-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-17 / -indole (470 mg , 1.6 mmol), and K2CO3 (500 mg, 3.6 mmol) in 72-dioxane (10 mL) and water (2 mL) was added Pd(dppf)Ch complex with dichloromethane (300 mg, 0.37 mmol ). 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 and filtered through Celite. The organic phase was separated, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (10 to 60% EtOAc in hexanes) to obtain tert-butyl 3-(7-chloro-5-fluoro-l / / -indol-4-yl)-2-(2,6-dimethylphenyl)-6,7-dihydro-2Z / -pyrazolo[4,3c]pyridine-5-(4 / / )-carboxylate. MS: (ES) m / z calculated for C27H29CIFN4O2 [M+H]+ 495.2, found 495.2.

[0295] Tert-butyl 3-(7-chloro-5-fluoro-l / / -indol-4-yl)-2-(2,6-dimethylphenyl)-6,7-dihydro-2 / 7pyrazolo[4 ,3-c]pyridine-5-(477)-carboxylate above was dissolved in dichloromethane (50 mL) and treated with HCI in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 16h. After the completion of the reaction, the solvent was evaporated in vacuo to obtain 3-(7-chloro-5-fluoro-1 / 7-indol-4-yl)-2(2,6-dimethylphenyl)-4,5 hydrochloride ,6,7-tetrahydro-227pyrazolo[4,3-c]pyridine. MS: (ES) m / z calculated for C22H21CIFN4 [M + H]+ 395.1, found 395.1. 130

[0296] Step b: Λζ-V-diisopropylethylamine (0.04 mL, 0.23 mmol) was added to a suspension of 3-(7-chloro-5-fluoro-177-indol-4-yl) hydrochloride -2(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-27 / pyrazolo[4,3-c]pyridine (48 mg, 0.12 mmol), 2,3-difluoro-5-( 1-methylethyl)pyridine (50 mg, 0.32 mmol) and LI2CO3 (20 mg, 0.27 mmol) in DMSO (1 mL) under magnetic stirring. The resulting mixture was stirred at 140 °C for 14 h. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (4 to 100% MTBE in hexanes) followed by HPLC (MeCN / l-EO with 0.1% TFA) to obtain 3-( 7-chloro-5-fluoro177-indol-4-yl)-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(l-methylethyl)pyridin-2-yl)-4,5, 6,7-tetrahydro-2Z7pyrazolo[4,3-c]pyridine. ’H NMR (400 MHz, CD3OD) δ 7.19 (s, 1H), 7.54 (d, 7=3.0 Hz, 1H), 7.42 (dd, J= 1.8, 14 Hz, 1H), 7.21 (d, J= 4.8 Hz, 2H), 6.9-7.0 (m, 2H), 6.57 (d, J= 3.3Hz, 1H), 4.64 (d, J= 16 Hz, 1H), 4.23 (d, J= 16 Hz, 1H), 3.8^1.1 (m, 2H), 3.13 (t, J = 6 .0 Hz, 2H), 2.93.0 (m, 1H), 2.28 (s, 3H), 1.78 (s, 3H), 1.31 (d, J= 7.2 Hz, 6H ). MS: (ES) m / z calculated for C30H29CIF2N5 [M+H]+ 532.2, found 532.2. Example 57 Synthesis of 5-(3,5-dichloro-2-pyridyl)-2-(2,6-dimethylphenyl)-3-(1H-indol-4-yl)-6,7-dihydro-4Hpyrazolo[4,3- c]pyridine

[0297] Step a: / er-Butyl 3-bromo-2-(2,6-dimethylphenyl)-6,7-dihydro-2 / 7-pyrazolo[4,3c]pyridine-5(4 / / ) was dissolved -carboxylate (1.5 g, 3.7 mmol) in dichloromethane (10 mL) and charged with HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. After the completion of the reaction, the solvent was evaporated in vacuo to obtain 3-bromo-2(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-227-pyrazolo[4,3-c]pyridine hydrochloride. . MS: (ES) m / z calculated for 131 Ci4Hi7BrN3 [Μ + H]+306.1, found 306.1.

[0298] A / TV-Diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspension of 3-bromo-2-(2,6-dimethylphenyl)-4,5,6,7-tetrahydro hydrochloride -2 / / -pyrazolo[4,3-c]pyridine (1 g, 2.9 mmol), 3,5-dichloro-2-fluoropyridine (1.1 g, 6.6 mmol), and K2CO3 (1.38 g, 10 mmol) in MeCN (10 mL) under magnetic stirring. The resulting mixture was stirred at 90 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine, and dried over 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 3-bromo-5-(3,5-dichloropyridin-2-yl)-2 -(2,6-dimethylphenyl)-4,5,6,7-tetrahydro22f-pyrazolo[4,3-c]pyridine. MS: (ES) m / z calculated for CigHisBrCh^[M+H]+ 451.0, found 451.1.

[0299] Step b: To a degassed solution of 3-bromo-5-(3,5-dichloropyridin-2-yl)-2-(2,6dimethylphenyl)-4,5,6,7-tetrahydro-277-pyrazolo [4,3-c]pyridine (80 mg, 0.18 mmol), indole-4-boronic acid (26 mg, 0.18 mmol), and sodium carbonate (47 mg, 0.44 mmol) in dioxane (5 mL ) and water (2 mL) was added Pd(dppf)C12 complex with dichloromethane (13 mg, 0.018 mmol). The mixture was purged with nitrogen and heated to 80 °C. After 18 h, the mixture was cooled to room temperature and diluted with EtOAc (20 mL). The organic layer was washed with water (20 mL), dried in the presence of Na2SO4, filtered, and concentrated in vacuo. The crude material was passed through a plug of silica gel and rinsed with EtOAc. The filtrate was concentrated and purified by reverse phase HPLC (MeCN / H2O, with 0.1% TFA) to obtain the title compound. 'H NMR (400 MHz, CD3OD) δ 8.13 (ddd, J= 15.9, 2.3, 0.6 Hz, 1H), 7.86 (dd, J= 2.3, 0.6 Hz , 1H), 7.46 (d, J= 8.2 Hz, 1H), 7.27 (t, J = 7.7 Hz, 2H), 7.13 (br s, 1H), 7.01- 6.94 (m, 2H), 6.69 (d, J= 7.3 Hz, 2H), 4.53 (s, 2H), 3.88 (t, J= 5.7 Hz, 2H), 3.21 (t, J=5.7Hz, 2H). 2.06 (br s, 6H), MS: (ES) m / z calculated for C27H23CI2N5 [M+H]+ 488.14, found 488.5. Example 58 Synthesis of [4-[2-(2,6-dimethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4Z7pyrazolo[4,3-c]pyridin-3-yl ]-5-fluoro-lZf-indol-7-yl]methanol 132

[0300] Step a: To a suspension of / er-butyl 3-bromo-2-(2,6-dimethylphenyl)-6,7-dihydro-4 / / pyrazolo[4,3-c]pyridine-5-carboxylate (90 mg, 0.22 mmol), methyl 5-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1 / / -indole-7-carboxylate (70 mg, 0.22 mmol) (intermediate from Example 2), and K2CO3 (150 mg, 1.1 mmol) in p-dioxane (3 mL) and water (0.5 mL) was added Pd(dppf) complex C12 with dichloromethane (70 mg, 0.085 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, washed with aq. NaHCO3 and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 80% EtOAc in hexanes) to obtain Zer-butyl 2-(2,6-dimethylphenyl)-3-(5-fluoro -7methoxycarbonyl-1 / 7-indol-4-yl)-6,7-dihydro-4 / / -pyrazolo[4,3-c]pyridine-5-carboxylate. MS: (ES) m / z calculated for C29H32FN4O4 [M+H]+519.2, found 519.2.

[0301] Step b: For-butyl 2-(2,6-dimethylphenyl)-3-(5-fluoro-7-methoxycarbonyl-177-indol-4-yl)- 6,7-Dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate above (38 mg, 0.073 mmol) was dissolved in THF (3 mL) and charged with a solution of LIAH4 in ether (2 M , 0.15 mL, 0.30 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 20 min. It was then quenched with methanol and diluted 133 with EtOAc and brine. 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 100% EtOAc in hexanes) to obtain / er-butyl 2-(2,6-dimethylphenyl)-3-[5-fluoro-7(hydroxymethyl)-l / / -indol-4-yl]-6,7- dihydro-4 / / -pyrazolo[4,3-c]pyridine-5-carboxylate. MS: (ES) m / z calculated for C28H32FN4O3 [M+H]+491.2, found 491.2.

[0302] Step c: / er-butyl 2-(2,6-dimethylphenyl)-3-[5-fluoro-7-(hydroxymethyl)-177-indol-4-yl]- 6,7-Dihydro-42 / -pyrazolo[4,3-c]pyridine-5-carboxylate above (21 mg, 0.042 mmol) was dissolved in dichloromethane (1 mL) and charged with HC1 in dioxane (4N, 3 mL ). The resulting mixture was stirred at room temperature for 1h. The solvent was evaporated in vacuo to obtain [4-[2-(2,6-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-5-fluoro hydrochloride. -1H-indole-7yljmethanol. MS: (ES) m / z calculated for C23H24FN4O [M+H]+391.2, found 391.2.

[0303] Step d: Triethylamine (0.12 mL, 0.85 mmol) was added to a suspension of [4-[2-(2,6-dimethylphenyl)-4,5,6,7-tetrahydropyrazolo[ 4,3-c]pyridin-3-yl]-5-fluoro-l / / -indol-7yl]methanol (20 mg, 0.044 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (60 mg, 0. 32 mmol) in MeCN (2 mL). The resulting mixture was stirred at 85 °C for 30 min. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCOs, and dried over 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 [4-[2-(2,6-dimethylphenyl)-6-[5- (trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-427-pyrazolo[4,3c]pyridin-3-yl]-5-fluoro-1Zf-indol-7-yl]methanol. Ή NMR (400 MHz, CDCI3) δ 8.46 (br s, 2H), 7.50 (s, 1H), 7.31 (d, J= 2.8 Hz, 1H), 7.03 (m, 2H), 6.76 (m, 1H), 6.72 (d, J= 11 Hz, 1H), 6.32 (d, J= 3.2 Hz, 1H), 4.84 (m, 2H) , 4.64 (d, 16 Hz, 1H), 4.43 (m, 1H), 4.25 (m, 1H), 3.55-3.76 (m, 2H), 3.00 (t, J = 5.6 Hz, 2H), 2.16 (s, 3H), 1.69 (s, 3H). MS: (ES) m / z calculated for C28H25F4N6O [M+H]+537.2, found 537.2. Example 59 Synthesis of / er-butyl 3-(6,7-dihydro-3-(1 / 7-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-2 / Zpyraz.olo[4,3 -c]pyridine-5(4 / / )-carboxylate 134 K2CO3 step to H2 PS / C Pass or b 1) HCI, NaNO2 2) SnCI2-2H2O step c 2) isoamyl: niphrite: CuBr2 mouth

[0304] Step a: A mixture of 3-methyl-2-nitro-phenol (50 g, 326 mmol), l-iodo-2-methyl-propane (184 g, 1 mol) and CS2CO3 (326 g, 1 mol ) in acetone (500 mL) was stirred overnight under reflux. It was then cooled to room temperature and filtered through Celite. The filtrate was collected and concentrated under reduced pressure. The obtained solid was redissolved in EtOAc, washed with brine, dried in the presence of Na2SO4 and concentrated on a rotary evaporator under reduced pressure to obtain 1-isobutoxy-3-methyl-2-nitro-benzene. 'H NMR (400 MHz, CDCI3) δ 7.26 (t, J= 8.0 Hz, 1H), 6.82 (m, 2H), 3.78 (d, J= 6.8 Hz, 2H) , 2.94 (s, 3H), 2.07 (m, 1H), 0.98 (d,J=6.4Hz, 6H).

[0305] Step b: A pressure vessel containing l-isobutoxy-3-methyl-2-nitro-benzene (130.4 g, 623 mmol), 10% Pd / C (25 g, 50% wet), and EtOH (750 mL) was stirred under an atmosphere of hydrogen at 45 psi for 3 h. It was then filtered through Celite. The filtrate was collected and concentrated under reduced pressure to obtain 2-isobutoxy-6-methyl-aniline. 135 ChHi8NO [Μ + Η]+ 180.2, found 180.2. Caution: Diazonium formation could be potentially dangerous; please treat with care and wear appropriate personal protective equipment.

[0306] Step c: To 100 mL of HC1 conc. at -10 °C isobutoxy-6-methyl aniline (26.4 g, 147 mmol) was added portionwise to obtain a stirrable suspension. After stirring for 30 min at the same temperature, a solution of NaNCh (12.2 g, 176 mmol) in water (25 mL) was added dropwise within 20 min to obtain the diazonium salt.

[0307] To the above diazonium salt was added SnC12.2H2O (83 g, 368 mmol) in conc. (120 mL) in portions. The obtained mixture was then stirred for 10 min at -10 °C followed by 1 h at room temperature. The mixture was then diluted in DCM (400 mL) and water. The organic layer was separated, dried in the presence of Na2SO4, and concentrated on a rotary evaporator under reduced pressure to obtain (2-isobutoxy-6-methyl-phenyl)hydrazine hydrochloride. C11H19N2O [M+H]+195.1, found 195.1.

[0308] Step d: To a stirred suspension of (2-isobutoxy-6-methylphenyl)hydrazine hydrochloride (8 g, 39.9 mmol) in EtOH (60 mL) and glacial acetic acid (12 mL, 208 mmol) were added. added tert-butyl 3-cyano-4-oxopiperidine-l-carboxylate (5 g, 22.3 mmol) at room temperature. The resulting mixture was stirred under reflux for 16h. After removing the solvent under reduced pressure, the residue was dissolved in EtOAc and washed with aqueous NaOH (2N), 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 tert-butyl 3-amino-2-(2-isobutoxy-6-methylphenyl)-6, 7-dihydro-227-pyrazolo[4,3-c]pyridine-5(4Z / )carboxylate. MS: (ES) m / z calculated for C22H33N4O3 [M+H]+401.2, found 401.2. Caution: Diazonium formation could be potentially dangerous; please treat with care and wear appropriate personal protective equipment.

[0309] Isoamyl nitrite (96%, 4 mL, 28.6 mmol) was added slowly at room temperature to a mixture of tert-butyl-3-amino-2-(2-isobutoxy-6-methylphenyl)-6,7 -dihydro-2 / 7-pyrazolo[4,3c]pyridine-5(477)-carboxylate (3 g, 8.1 mmol), CuBr (4 g, 27.9 mmol), and MeCN (50 mL) in a flask round bottom container of 250 mL under magnetic stirring. The resulting mixture was stirred at 136 room temperature for 1 h, diluted with EtOAc, filtered through Celite, washed with saturated NH4CI solution, and dried over 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 tert-butyl 3-bromo-2-(2-isobutoxy-6-methylphenyl)- 6,7-dihydro2 / / -pyrazolo[4,3-c]pyridine-5(4 / / )-carboxylate. MS: (ES) m / z calculated for C22H3iBrN3O3 [M+H]+464.1, found 464.2.

[0310] Step e: To a suspension of tert-butyl 3-bromo-2-(2-isobutoxy-6-methylphenyl)-6,7dihydro-277-pyrazolo[4,3-c]pyridine-5(4 / / )-carboxylate (125 mg, 0.32 mmol), 177-indol-5-yl-acid 5-boronic (74 mg, 0.48 mmol), and NajCOs (85 mg, 0.81 mmol) in 72-dioxane (4 mL) and water (1 mL) Pd(dppí)Ck complex was added with dichloromethane (26 mg, 0.032 mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 95 °C for 6 h. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 20% to 40% EtOAc in hexanes) to obtain tert-butyl 3-(6,7-dihydro-3-(l / / -indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-227-pyrazolo[4,3c]pyridine-5(4 / 7)-carboxylate.'H NMR (400 MHz, CD3OD) δ 7.40 (s, 1H), 7.20-7.26 (m, 3H), 6.92 (d, J= 9.7 Hz, 1H), 6.85 (d, J= 8.2 Hz, 1H), 6.78 (d, J= 7.8 Hz, 1H), 6, 34 (d, J= 3.1 Hz, 1H), 4.54-1.65 (m, 2H), 3.80-3.95 (m, 2H), 3.67-3.70 (m, 2H), 2.85 (t, J= 5.6 Hz, 2H), 1.96 (s, 3H), 1.80-1.90 (m, 1H), 1.47 (s, 9H), 0.86 (dd, 3.5, 6.6Hz, 6H). MS: (ES) m / z calculated for C30H37N4O3 [M+H]+501.28, found 501.2. Example 60 Synthesis of tert-butyl-3-(lZ?-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-2Zfpyrazolo[4,3-ijpyridine-5(4A / ) -carboxamide 137

[0311] Step a: Tert-butyl-6,7-dihydro-3-(1H-indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl)-2Hpyrazolo[4,3-c] Pyridine-5(4H)-carboxylate above was dissolved in dichloromethane (5 mL) and TFA (4N, 5 mL) was added. The resulting mixture was stirred at room temperature for 2h. After completion of the reaction, the solvent was diluted with water and aqueous NaHCCl and extracted with dichloromethane (2x50 mL), washed with brine, and dried in the presence of MgSO4. The solvent was removed under reduced pressure and dried under vacuum to obtain 4,5,6,7-tetrahydro-3(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-2H-pyrazolo [4,3-c]pyridine. MS: (ES) m / z calculated for C25H29C1N4O [M+H]+401.2, found 401.3.

[0312] Step b: To a stirred solution of 4,5,6,7-tetrahydro-3-(1H-indol-5-yl)-2-(2-isobutoxy- 6-methylphenyl)-2H-pyrazolo[4,3-c]pyridine (30 mg, 0.074 mmol) in anhydrous THF (1.5 mL) were added jV,7V-diisopropylethylamine (24 mg, 0.185 mmol) and tert-butyl isocyanate (10 mg, 0.089 mmol). The reaction mixture was stirred at room temperature for 16h. Upon completion, the reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by prep HPLC. (20-100% H2O / ACN) and lyophilized to obtain 7V-tert-butyl-6,7-dihydro-3(1H-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-2H -pyrazolo[4,3-c]pyridine-5(4H)-carboxamide. Ή 138 NMR (400 MHz, CD3OD) δ 7.44 (d, 7= 1.5 Hz, IH), 7.21-7.26 (m, 3H), 6.94 (dd, 7= 1.5, 8 .6 Hz, 2H), 6.85 (d, 7= 8.2 Hz, HI), 6.78 (d, 7= 7.6 Hz, HI), 6.35 (dd, 7= 3.2, 10 .8Hz, HI), 4.54 (dd, 7= 15.2, 29.2 Hz, 2H), 3.70-3.76 (m, 2H), 3.64-3.70 (m, 2H), 2.85 ( t, 7= 5.6 Hz, 2H), 1.96 (s, 3H), 1.80-1.90 (m, IH), 1.32 (s, 9H), 0.86 (dd, 7-3.5, 6.6 Hz , 6H). MS: (ES) m / z calculated C30H38N5O2 [M+H]+ 500.29, found 500.2. Example 61 Synthesis of tert-butyl 3-(6,7-dihydro-3-(12Z-indol-5-yl)-2-(2-methoxy-6-methylphenyl)-2jErpyrazolo[4,3-¿]pyridine-5( 4 / / )-carboxylate 2) Isoamij n ythrite step to

[0313] Step a: To a stirred suspension of l-(2-methoxy-6-methylphenyl)hydrazine hydrochloride (3.77 g, 20.0 mmol) in EtOH (50 mL) and glacial acetic acid (10 mL, 208 mmol) tert-butyl 3-cyano-4-oxopiperidine-l-carboxylate (4.5 g, 22.0 mmol) was added at room temperature. The resulting mixture was stirred under reflux for 16h. After removing the solvent under reduced pressure, the residue was dissolved in EtOAc and washed with aqueous NaOH (2N), 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 tert-butyl 3-amino-2-(2-methoxy-6-methylphenyl)-6, 7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(47 / )carboxylate. MS: (ES) m / z calculated for C19H27N4O3 [M+H]+359.2, found 359.2. 139 Caution: Diazonium formation could be potentially dangerous; please treat with care and wear appropriate personal protective equipment.

[0314] Isoamyl nitrite (3.2 g, 27.8 mmol) was added slowly at room temperature to a mixture of tert-butyl-3-amino-2-(2-methoxy-6-methylphenyl)-6,7- dihydro-227-pyrazolo[4,3-c]pyridine5(4H)-carboxylate (5.0 g, 13.9 mmol), CH2I2 (14.9 g, 55.7 mmol), and MeCN (60 mL) in a 250 mL round bottom flask under magnetic stirring. The resulting mixture was stirred at room temperature for 1 h, diluted with EtOAc, filtered through Celite, washed with saturated NH4Cl soln, and dried over 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 / er-butyl 3-iodo-2-(2-methoxy-6-methylphenyl) -6,7-dihydro-277pyrazolo[4,3-c]pyridine-5(4 / / )-carboxylate. MS: (ES) m / z calculated for C19H25IN3O3 [M+H]+ 469.1, found 469.3.

[0315] Step b: To a suspension of / er-butyl 3-iodo-2-(2-methoxy-6-methylphenyl)-6,7-dihydro27 / -pyrazolo[4,3-c]pyridine-5(4 / 7)-carboxylate (250 mg, 0.53 mmol), 177-indol-5-yl-5-boronic acid (128 mg, 1.8 mmol), Na2C03 (139 mg, 3.6 mmol) in / j-dioxane (4 mL) and water (1 mL) was added Pd(dppf)C12 complex with dichloromethane (300 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, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 40% EtOAc in hexanes) to obtain / er-butyl 3-(6,7-dihydro-3-(l / 7 -indol-5-yl)-2-(2-methoxy-6-methylphenyl)-2Z / -pyrazolo[4,3-c]pyridine-5(4J7)carboxylate Ή NMR (400 MHz, CD3OD) δ 7, 35-7.40 (m, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.24 (bs, 1H), 7.21-7.30 (m, 1H), 6 .90 (d, J= 8.4 Hz, 1H), 6.87 (d, J= 8.4 Hz, 1H), 6.71 (d, J= 8.4 Hz, 1H), 6.35 (dd, J = 0.8, 2.8 Hz, 1H), 4.54 (dd, J = 15.2, 21.6 Hz, 2H), 3.80-3.90 (m, 1H), 3.70-3.78 (m, 1H), 3.69 (s, 3H), 2.82 (t, J= 6.0 Hz, 2H), 1.91 (s, 3H), 1.40 -1.50 (m, 9H) MS: (ES) m / z calculated for C27H31N4O3 [M+H]+459.23, found 459.2. Example 62 Synthesis of 5-(5- / er-butyl-2-methylphenyl)-4,5,6,7-tetrahydro-3-(l / / -indol-5-yl)-2-(2-methoxy-6-methylphenyl) -27 / -pyrazolo[4,3-c]pyridine 140 TFA, CH5Cr2_ NaHCO3 aq. pass b Pd(OAc)2, NaOtBu X-Fos, efioxane W5°C step c

[0316] Step a: To a stirred solution of tert-butyl 3-(6,7-dihydro-3-(17 / -indol-5-yl)-2-(2methoxy-6-methylphenyl)-2H-pyrazolo[ 4,3-c]pyridine-5(4H)-carboxylate (250 mg, 0.544 mmol) in anhydrous THF (4 mL) were added K2CO3 (150 mg, 1.08 mmol) and trimethylacetyl chloride (163 mg, 1, 36 mmol) at 0 °C. The resulting mixture was stirred for 16 h at room temperature. After the reaction was complete, the residue was dissolved in EtOAc / H2O and 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 (0 to 20% EtOAc in hexanes) to obtain tert-butyl 6,7-dihydro-2-(2-methoxy-6-methylphenyl)-3-(l -(pivaloyl)-l / / -indol-5-yl)-2 / / -pyrazolo[4,3c]pyridine-5(4H)-carboxylate (220 mg) MS: (ES) m / z calculated for C32H39N4O4 [M+H]+ 542.2, found 542.2.

[0317] Step b: To a solution of tert-butyl 6,7-dihydro-2-(2-methoxy-6-methylphenyl)-3-(l(pivaloyl)-1H-indol-5-yl)-27 / -pyrazolo[4,3-c]pyridine-5(477)-carboxylate (220 mg, 0.405 mmol) in dichloromethane (5 mL) was added TFA (115 mg, 1.01 mmol). The resulting mixture was stirred at room temperature for 2h. Once the reaction was complete, the solvent was diluted with water and aqueous NaHCOs and extracted with dichloromethane (2x50 mL), washed with brine, and dried in the presence of MgSO4. The solvent was removed under reduced pressure and dried under vacuum to 141 obtain 1-(5-(4,5,6,7-tetrahydro-2-(2-methoxy-6-methylphenyl)-2 / / -pyrazolo[4,3-c]pyridin-3-yl)-lHindol -2-dimethylpropan-l-one (125 mg) MS: (ES) m / z calculated for C27H31N4O2 [Μ ΤΗ]* 443.24, found 443.2.

[0318] Step c: To a mixture of 1-(5-(4,5,6,7-tetrahydro-2-(2-methoxy-6-methylphenyl)-277pyrazolo[4,3-c]pyridin-3- yl)-1H-indol-l-yl)-2,2-dimethylpropan-l-one (120 mg, 0.270 mmol), 4-tert-butyl-2-bromo-1-methylbenzene (93 mg, 0.406 mmol), NaOtBu ( 52 mg, 2.2 mmol) and X-Fos (27 mg, 2.2 mmol) in p-dioxane (6 mL) was added Pd(OAc)2 (6 mg, 0.027 mmol). The reaction mixture was degassed (N2) for 5 min and stirred under N2 at 105 °C for 6 h. Upon completion, the mixture was cooled to room temperature, diluted with EtOAc (10 mL), filtered through Celite, washed with brine, and dried over MgSCU. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 30% EtOAc in hexanes) followed by prep HPLC to obtain 5-(5-tert-butyl-2-methylphenyl)- 4,5,6,7-tetrahydro-3-(1H-indol-5-yl)-2-(2-methoxy-6-methylphenyl)-2 / 7-pyrazolo[4,3-c]pyridine (12 mg ). Ή NMR (400 MHz, CD3OD) δ 7.42-7.48 (m, 2H), 7.20-7.35 (m, 5H), 6.92-6.97 (m, 2H), 6.81 (d, J = 8.0 Hz, 1H), 6.35 (d, J= 3.2 Hz, 1H), 4.60 (d, J= 13.6 Hz, 1H), 4, 44 (d, J= 13.6 Hz, 1H), 3.75-3.85 (m, 2H), 3.72 (s, 3H), 3.10-3.18 (m, 2H), 2 .41 (s, 3H), 1.96 (s, 3H), 1.26 (s, 9H). MS: (ES) m / z calculated for C33H37N4O [M+H]+505.2, found 505.2. Example 63 Synthesis of 5-(3,5-dichloropyridin-2-yl)-4,5,6,7-tetrahydro-3-(1 / Z-indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)- 22Z-pyrazolo[4,3-c]pyridine mouth step b 142 Pd(dppf)Cl2 CH2CI2 step c

[0319] Step a: To a solution of thor-butyl 3-bromo-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro2Z / -pyrazolo[4,3-c]pyridine-5(4 / / )-carboxylate (1.2 g, 3.6 mmol) in dichloromethane (10 mL) was added TFA (1.47 g, 12.93 mmol). The resulting mixture was stirred at room temperature for 2 h. On completion of the mixture was diluted with water and aq. NaHCCh and extracted with dichloromethane, washed with brine, and dried in the presence of MgSO 4. The solvent was removed under reduced pressure and dried under vacuum to obtain 3-bromo-2-(2- isobutoxy-6-methylphenyl)- 4,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridine. (1.0 g) MS: (ES) m / z calculated for CigF^BrNa[M+H]+364.28, found 364.2.

[0320] Step b: To a mixture of 3-bromo-2-(2-isobutoxy-6-methylphenyl)-4,5,6,7-tetrahydro-27 / pyrazolo[4,3-c]pyridine (1, 0 g, 2.58 mmol) in DMSO (5 mL) was added 3,5-dichloro-5-fluoropyridine (680 mg, 4.37 mmol), and LI2CO3 (610 mg, 12.3 mmol) at room temperature . The resulting mixture was stirred at 100 °C for 4 h. After the reaction was complete, it was cooled to room temperature, the reaction mixture was diluted with EtOAc (20 mL), washed with brine, and dried in the presence of MgSO4. 1 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 3-bromo-5-(3,5-dichloropyridin-2-yl)-4 ,5,6,7-tetrahydro-2-(2-isobutoxy-6-methylphenyl)-2Z7pyrazolo[4,3-c]pyridine (0.8 g). MS: (ES) m / z calculated for C22H24BrC12N4O [M+H]+ 509.04, found 509.2.

[0321] Step c: To a suspension of 3-bromo-5-(3,5-dichloropyridin-2-yl)-4,5,6,7-tetrahydro-2(2-isobutoxy-6-methylphenyl)-2Z / -pyrazolo[4,3-c]pyridine (600 mg, 1.4 mmol), 177-indol-5-yl-5-boronic acid (550 mg, 1.8 mmol), Na2CÜ3 (500 mg, 3.6 mmol ) in p-dioxane (6 mL) and water (1 mL) was added Pd(dppf)Ch complex with dichloromethane (300 mg, 0.37 mmol). The mixture of The reaction 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 over MgSOzt. 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 5(3,5-dichloropyridin-2-yl)-4,5,6, 7-tetrahydro-3-(1 / / -indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-2 / / pyrazolo[4,3-c]pyridine. Ή NMR (400 MHz, CD3OD) δ 8.08 (d, J= 2.4 Hz, 1H), 7.80 (d, J= 2.4 Hz, 1H), 7.35 (d, J= 8 .0 Hz, IH), 7.29 (bs, 1H), 7.20 (t, J= 8.4 Hz, 1H), 6.92 (t, J= 7.2 Hz, 1H), 6, 79-6.88 (m, 2H), 6.68-6.85 (m, IH), 6.39 (d, 7= 3.1 Hz, IH), 4.40-4.55 (m, 1H), 4.20- 4.40 (m, IH), 3.82 (t, 7= 6.0 Hz, 2H), 3.60-3.75 (m, 2H), 3.09-3.13 (m, 2H) , 1.99 (m, 4H), 0.80-0.90 (m, 6H). MS: (ES) m / z calculated for C30H30CI2N5O [M + H]+ 546.17, found 546.5 Example 64 Synthesis of 5-(3,5-dichloropyridin-2-yl)-4,5,6,7-tetrahydro-3-(17 / -indol-6-yl)-2-(2-isobutoxy-6methylphenyl)-2ZZ -pyrazolo[4,3-c]pyridine

[0322] To a suspension of 3-bromo-5-(3,5-dichloropyridin-2-yl)-4,5,6,7-tetrahydro-2-(2isobutoxy-6-methylphenyl)-2 / / -pyrazolo [4,3-c]pyridine (600 mg, 1.4 mmol), l / / -indol-6-yl-6-boronic acid (550 mg, 1.8 mmol), and Na2CO3 (500 mg, 3, 6 mmol) inp-dioxane (6 mL) and water (1 mL) was added Pd(dppf)Cl2 complex with dichloromethane (300 mg, 0.37 mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 95 °C for 2 h. The reaction mixture was diluted with EtOAc, filtered through Celite, washed with brine, and dried over 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 5-(3.5 144 dichloropyridin-2-yl)-4,5,6,7-tetrahydro-3-(12 / -indol-6-yl)-2-(2-isobutoxy-6-methylphenyl)-2 / 7pyrazolo[4,3 -c]pyridine. Ή NMR (400 MHz, CD3OD) δ 8.14 (d, J= 2.2 Hz, 1H), 7.81 (d, J= 2.3 Hz, 1H), 7.45 (d, J= 1 .6 Hz, 1H), 7.22-7.28 (m, 4H), 6.96 (dd, J= 1.6, 8.6 Hz, 1H), 6.87 (d, J = 8, 0 Hz, 1H), 6.81 (d, J= 7.6 Hz, 1H), 4.50 (dd, J= 10.9, 18.6 Hz, 2H), 3.78 (t, J= 4.2 Hz, 2H), 3.66 (d, J= 6.4 Hz, 2H), 3.06 (t, J= 6.0 Hz, 2H), 1.99 (s, 3H), 1 .83-1.90 (m, 1H), 0.85 (dd, J = 3.5, 6.7 Hz, 6H). MS: (ES) m / z calculated for C30H30CI2N5O [M+H]+ 546.17, found 546.1. Example 65 Synthesis of 3-chloro-5-[3-(l / 7-indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl)-6,7-dihydro-4 / / pyrazolo[4, 3-c]pyridin-5-yl]-1,2,4-thiadiazole

[0323] Step a: To a solution of 3-bromo-2-(2-isobutoxy-6-methyl-phenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine (363 mg, 1.0 mmol) and Et8N (153 pL, 1.1 mmol) in THF (4 mL) was added 3,5-dichloro-1,2,4-thiadiazole (171 mg, 1.1 mmol) in THF (2 mL) to room temperature. After 30 min, the reaction mixture was diluted with CH2CI2 (20 mL) and washed with water (20 mL), dried over Na2SC>4, and concentrated in vacuo. The residue obtained is 145 was purified by silica gel flash chromatography (50% EtOAc in hexanes) to obtain 5-[3-bromo-2-(2-isobutoxy-6-methyl-phenyl)-6,7-dihydro-477-pyrazolo[4,3-c]pyridin-5-yl]-3-chloro1,2, 4-thiadiazole. MS: (ES) m / z calculated for CjglfeBrClNsOS [M + H]+ 482.8, found 482.8.

[0324] Step b: To a solution of 5-[3-bromo-2-(2-isobutoxy-6-methyl-phenyl)-6,7-dihydro-4 / 7pyrazolo[4,3-c]pyridin-5 -yl]-3-chloro-1,2,4-thiadiazole (471 mg, 0.977 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added 17 / -indol-5-ylboronic acid ( 157 mg, 0.977 mmol), Na2CO3 (155 mg, 1.465 mmol) and the resulting reaction mixture was degassed for 1 minute with nitrogen gas. Pd(dppf)Ch complex with dichloromethane (80 mg, 0.0977 mmol) was then added, the reaction mixture was degassed for another minute with nitrogen gas and stirred at 50 °C overnight. The reaction mixture was filtered through a small pad of Celite, washed with CH2CI2 (15 mL), dried over Na2SO4, and concentrated in vacuo. The obtained residue was purified by silica gel flash chromatography (75% EtOAc in hexanes) to obtain 3-chloro-5-[3-(1Z / -indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl)-6,7-dihydro-4Z7-pyrazolo[4,3-c] pyridin5-yl]-1,2,4-thiadiazole. Ή NMR (400 MHz, Methane!-^) δ 7.45 (d, J = 1.6 Hz, 1H), 7.32-7.20 (m, 3H), 6.97 (dd, J= 8 .4, 1.7 Hz, 1H), 6.83 (dd, 8.0, 24.5 Hz, 2H), 6.41 - 6.35 (m, 1H), 4.77 (d, J = 14.8 Hz, 1H), 4.68 (s, 1H), 4.03-3.97 (m, 2H), 3.71-3.59 (m, 2H), 3.02 (t, J = 6.0Hz, 2H), 1.97 (s, 3H), 1.88 (dt, J= 6.5, 13.2 Hz, 1H), 1.28 (s, 1H), 0.85 (dd, J= 3.0, 6.7 Hz, 6H).MS: (ES) m / z calculated for C27H28CIN6OS[M+H]+ 519.2, found 519.1. Example 66 Synthesis of 5-[3-(1 / Z-indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl)-6,7-dihydro-4Z7-pyrazolo[4,3c]pyridin-5 -yl]-3-isopropyl-1,2,4-thiadiazole Pd(dppf)2-CH2CI2 N a2COg, Dioxane -H20 step to 146 pas or b PS / C. Hz (401psi) TheOAc

[0325] Step a: To a solution of 3-chloro-5-[3-(l / / -indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl)- 6,7-dihydro-4 / 7-pyrazolo[4,3-c]pyridin-5-yl]-1,2,4-thiadiazole (100 mg, 0.193 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was added 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54 pL, 0.977 mmol), and Na2C03 (155 mg, 1.465 mmol). The resulting reaction mixture was degassed for 1 minute with nitrogen gas. Pd(dppf)Cl2 complex with dichloromethane (80 mg, 0.0977 mmol) was then added and the mixture degassed for another minute with nitrogen gas and stirred at 50 °C overnight. The reaction mixture was filtered through a pad of Celite, washed with CH2C12 (15 mL), dried over Na2SO4, and concentrated in vacuo. The obtained residue was purified by silica gel flash chromatography (75% EtOAc in hexanes) to obtain 5-[3-(177-indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl) -6,7-dihydro-477-pyrazolo[4,3c]pyridin-5-yl]-3-isopropenyl-1,2,4-thiadiazole. MS: (ES) m / z calculated for C30H33N6OS [M + H]+ 525.2, found 525.2.

[0326] Step b: To a solution of 5-[3-(177-indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl)-6,7dihydro-47 / -pyrazolo[4, 3-c]pyridin-5-yl]-3-isopropenyl-1,2,4-thiadiazole (50 mg, 0.095 mmol) in EtOAc (5 mL) was added 10% Pd / C (20 mg). The resulting suspension was shaken under H2 gas (40 psi) on a Parr shaker at room temperature for 3 h. The reaction mixture was filtered through a pad of Celite, washed with EtOAc (15 mL), and concentrated in vacuo. The obtained residue was purified by HPLC (CHbCN / H2O with 0.1% TFA) to obtain 5-[3(1Z7-indol-5-yl)-2-(2-isobutoxy-6-methyl-phenyl)-6 ,7-dihydro-4 / / -pyrazolo[4,3-c]pyridin-5-yl]-3-isopropyl-1,2,4-thiadiazole. 'H NMR (400 MHz, Methane!-^) δ 7.46 (dd, .1 = 1.6, 0.7 Hz, 1H), 7.32-7.19 (m, 3H), 6.97 (dd, J= 8.5, 1.7 Hz, 1H), 6.89-6.76 (m, 2H), 6.38 (dd, J= 0.9, 3.2 Hz, 1H), 4.76 (d, J= 15.2 Hz, 1H), 4.67 (d, J= 15.0 Hz, 1H), 4.00 (t, J= 5.9 Hz, 2H), 3, 71-3.59 (m, 147 2Η), 3.00 (td, J= 2.8, 6.4, 6.9 Hz, 3H), 1.97 (s, 3H), 1.88 (dt, J= 6.5, 13, 2 Hz, IH), 1.27 (d, J = 6.9 Hz, 6H), 0.84 (dd, 7=1.7, 6.5 Hz, 6H).MS: (ES) m / z calculated for C30H35N6OS [M + H]+ 527.3, found 527.2. Example 67 Synthesis of tert-Butyl 2-(2,6-dimethylphenyl)-3-(17 / -indol-5-yl)-6,7-dihydro-47f-pyrazolo[4,3c]pyridine-5-carboxylate

[0327] Step a: To a mixture of tor-butyl 3-amino-2-(2,6-dimethylphenyl)-6,7-dihydro-4Z / pyrazolo[4,3-c]pyridine-5-carboxylate (485 mg, 1.41 mmol) and CuBr2 (1.50 g, 6.7 mmol) in CH3CN (30 mL) was added isopentenyl nitrite (0.60 mL, 4.46 mmol) dropwise. After stirring for 1h, the mixture was quenched with 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 35% EtOAc in hexanes) to obtain tert-butyl 3-bromo-2-(2, 6-dimethylphenyl)-6,7-dihydro-4Z / -pyrazolo[4,3-c]pyridine-5-carboxylate. MS: (ES) m / z calculated for Ci9H25BrFN3O2 [M+H]+406.1, found 406.1.

[0328] Step b: To a suspension of / er-butyl 3-bromo-2-(2,6-dimethylphenyl)-6,7-dihydro-477pyrazolo[4,3-c]pyridine-5-carboxylate (35 mg , 0.086 mmol), indole-5-boronic acid (42 mg, 0.26 mmol) and K2CO3 (36 mg, 0.26 mmol) in toluene (1.5 mL) and water (0.2 mL) Pd was added (PPh3)4 (30mg, 0.026mmol). The reaction mixture was degassed (N2) for 2 min and stirred under N2 at 110 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 45% EtOAc in hexanes) to obtain thor-butyl 2-(2,6-dimethylphenyl)-3-(l / 7 -indol-5-yl)-6,7-dihydro477-pyrazolo[4,3-c]pyridine-5-carboxylate. ’H NMR (400 MHz, CDCI3) δ 8.27 (br s, IH), 7.39 (s, 148 1Η), 7.18 (m, 2H), 7.12 (dd, J= 7.6, 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 2H), 6, 85 (dd, J= 1.6, 8.0 Hz, 1H), 6.44 (br s, 1H), 4.66 (br s, 2H), 3.82 (br s, 2H), 2.89 (t, J= 5.8 Hz, 2H) , 1.99 (s, 6H), 1.50 (s, 9H). MS: (ES) m / z calculated for C27H31 Ν4θ2 [M + H]+443.2, found 443.2. Example 68 Synthesis of 2-(2,6-dimethylphenyl)-3-(lJff-indol-5-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine hydrochloride

[0329] Step to: / er-butyl 2-(2,6-dimethylphenyl)-3-(1 / 7-indol-5-yl)-6,7-dihydro-4 / 7-pyrazolo[4,3e] Pyridine-5-carboxylate (81 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL) and charged with HC1 in dioxane (4N, 2 mL). The resulting mixture was stirred at room temperature for 1h. The solvent was evaporated in vacuo to obtain 2-(2,6-dimethylphenyl)-3-(1 / f-indol-5-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine hydrochloride.

[0330] Step b: A mixture of 2-(2,6-dimethylphenyl)-3-(1 / / -indol-5-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine hydrochloride (25 mg, 0.066 mmol), 2,2-dimethylpropanal (100 mg, 1.16 mmol), NaBH(OAc)3 (100 mg, 0.47 mmol), NEts (0.015 mL, 0.11 mmol), and acid acetic acid (0.06 mL, 1 mmol) in DCM (1 mL) was stirred at 35 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCOs, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by reverse phase preparative HPLC to obtain 2-(2,6-dimethylphenyl)-5-(2,2dimethylpropyl)-3-(177-indol-5-yl)- 6,7-dihydro-477-pyrazolo[4,3-c]pyridine. 'H NMR (400 MHz, CDCI3) δ 8.35 (br s, 1H), 7.35 (s, 1H), 7.19 (d, J= 8.4, 1H), 7.14 (m, 1H), 7.10 (d, J= 7.6 Hz, 1H), 6.99 (d, J= 7.6 Hz, 2H), 6.83 (dd, J = 1.6, 8.8 Hz, 1H), 6.46 (m, 1H), 3.76 (br s, 2H), 2.93 (m, 4H), 2.33 (br s, 2H), 1.98 (br s, 6H), 0.92 (br s, 9H). MS: (ES) m / z calculated for C27H33N4 [M+H]+413.2, found 413.2. 149 Example 69 Synthesis of 2-(2,6-diethylphenyl)-3-(l_ff-indol-5-yl)-5-(2-(trifluoromethyl)benzyl)-4,5,6,7tetra hidro-2 / / -pyrazolo [4,3-c] pi rid i na

[0331] Step a: To a suspension of tert-butyl 3-bromo-2-(2-isobutoxy-6-methylphenyl)-6,7dihydro-2 / / -pyrazolo[4,3-c]pyridine-5(477 )-carboxylate (500 mg, 1.08 mmol), 1 / / -indole-5-ylboronic acid (900 mg, 5.59 mmol), K2CO3 (2.0 g, 14.5 mmol) in / >-dioxane (10 mL) and water (2 mL) was added Pd(dppf)C12 complex with dichloromethane (200 mg, 0.24 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, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 30% EtOAc in hexanes) to obtain tert-butyl 3-(177-indol-5-yl)-2-(2-isobutoxy -6-methylphenyl)-6,7-dihydro-22 / -pyrazolo[4,3-c]pyridine5(4 / / )-carboxylate. MS: (ES) m / z calculated for C30H37N4O3 [M+H]+501.2, found 501.2.

[0332] The above / er-butyl 3-(1 / / -indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-2 / / pyrazolo[4,3- c]pyridine-5(427)-carboxylate was dissolved in dichloromethane (5 mL) and charged with 150 HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. Once the reaction was complete, the solvent was evaporated in vacuo to obtain 3-(l / / -indol-5-yl)-2(2-isobutoxy-6-methylphenyl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine hydrochloride. MS: (ES) m / z calculated for C25H29N4O [M+H]+401.2, found 401.2.

[0333] Step b: NaBH(OAc)s (75 mg, 0.36 mmol) was added to a mixture of 3(1Z / -indol-5-yl)-2-(2-isobutoxy-6-methylphenyl) hydrochloride )-4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridine (30 mg, 0.07 mmol), 2-(trifluoromethyl)benzaldehyde (75 mg, 0.42 mmol) , and A(7V-diisopropylethylamine (0.2 mL, 1.15 mmol) in dichloromethane (10 mL) under magnetic stirring. The resulting mixture was stirred at 35 °C for 1 h. After cooling to room temperature, the mixture The reaction was quenched with MeOH.The solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN / H2O, with 0.1% TFA) to obtain 3-(7-chloro-1 / / -indazol-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, CDCI3) δ 8.17 (s, 1H), 7.94 (d, J= 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.08-7.35 (m, 4H), 6.95 (sd , J= 1.3, 8.4 Hz, 1H), 6.44-6.77 (m, 3H), 3.92 (s, 2H), 3.81 (d, J= 13.5 Hz, 1H), 3.71 (d, J= 13.5 Hz, 1H), 3.57 (m, 2H), 2.82-2.91 (m, 4H), 2.04 (s, 3H) , 1.92 (m, 1H), 0.83-0.88 (m, 6H). MS: (ES) m / z calculated C33H34F3N4O [M+H]+559.3, found 559.3. Example 70 Synthesis of 3-(l / / -indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-5-(2-phenylpropan-2-yl)-4,5,6,7tetrahydro-2ZZ- pyrazolo[4,3-c]pyridine Acetone Step by step 151 PhMgiBr step b

[0334] Step a: To a suspension of 3-(7-chloro-1 / / -indazol-4-yl)-2-(2,6diethylphenyl)-4,5,6,7-tetrahydro-2Z / hydrochloride -pyrazolo[4,3-c]pyridine (50 mg, 0.11 mmol) in acetone (5 mL) under magnetic stirring A / V-diisopropylethylamine (0.1 mL, 0.58 mmol) was added, followed by acetone cyanohydrin (1 mL, 10.95 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (10 to 75% EtOAc in hexanes) to obtain 2-(3-(1Hindol-5-yl)-2-(2- isobutoxy-6-methylphenyl)-6,7-dihydro-2 / / -pyrazolo[4,3-c]pyridin-5(4 / / )-yl)-2-methylpropanenitrile. MS: (ES) m / z calculated for C29H34N5O [M+H]+468.3, found 468.2.

[0335] Step b: 2-(3-(l / / -indol-5-yl)-2-(2-isobutoxy-6-methylphenyl)-6,7-dihydro-227pyrazolo[4,3-c] Pyridin-5(477)-yl)-2-methylpropanenitrile above (25 mg, 0.05 mmol) was dissolved in THF (5 mL) and charged with a solution of phenylmagnesium bromide in THF (1 µ, 1 mL, 1mmol). The resulting mixture was stirred at room temperature overnight and quenched with aqueous NH4Cl solution. The reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (45% EtOAc in hexanes) followed by HPLC (MeCN / H2O, with 0.1% TFA) to obtain 3-(17 / -indole-5- yl)-2-(2-isobutoxy-6-methylphenyl)-5-(2-phenylpropan-2yl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridine. Ή NMR (400 MHz, CDCI3) δ 8.13 (s, 1H), 7.61-7.68 (m, 2H), 7.47 (d, J= 0.9 Hz, 1H), 7.07 -7.37 (m, 5H), 7.00 (dd, J = 1.7, 8.5 Hz, 1H), 6.63-6.76 (m, 2H), 6.48 (t, J = 2.7 Hz, 1H), 3.91 (d, J= 13.0 Hz, 1H), 3.82 (d, J= 13.0 Hz, 1H), 3.52-3.64 (m , 2H), 2.62-2.80 (m, 4H), 2.04 (s, 3H), 1.93 (dq, J= 6.8 Hz, 13.6, 1H), 1.45 ( d, J = 3.5 Hz, 6H), 0.86 (dd, J = 3.5, 6.8 Hz, 6H). MS: (ES) m / z calculated C34H39N4O [M + H]+ 519.3, found 519.3. 152 Example 71 Synthesis of 3-(lZZ-indole-5-iI)-2-(2-isobutoxy-6-inethylphenyl)-5-(l-(2-(trifluoroinethyl)phenyl)ethyl)- 4,5,6,7-tetrahydro-2jfir-pyrazoio[4,3-c]pyridine mouth

[0336] Step a: To a suspension of / er-butyl 3-bromo-2-(2-isobutoxy-6-methylphenyl)-6,7dihydro-277-pyrazolo[4,3-c]pyridine-5(47 / )-carboxylate (1 g, 2.16 mmol) in dichloromethane (5 mL) was added a solution of HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (2 to 10% MeOH in dichloromethane with 1% NH4OH) to obtain 3-bromo-2-(2-isobutoxy-6-methylphenyl) -4,5,6,7-tetrahydro-2Z / pyrazolo[4,3-c]pyridine. MS: (ES) m / z calculated for Ci?H23BrN3O [M + H]+ 364.1, found 364.3.

[0337] The above 3-bromo-2-(2-isobutoxy-6-methylphenyl)-4,5,6,7-tetrahydro-2?7-pyrazolo[4,3-c]pyridine (100 mg, 0. 27 mmol) was dissolved in DMF (5 mL) and charged with K2CO3 (300 mg, 2.17 mmol) and 1-(1-bromoethyl)-2-(trifluoromethyl)benzene (100 mg, 0.40 mmol). The reaction mixture was stirred under N2 at 50 °C for 14 h. The reaction mixture was diluted with EtOAc, washed with 153 brine and dried in the presence of MgSC>4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (10 to 35% EtOAc in hexanes) to obtain 3-bromo-2-(2-isobutoxy-6-methylphenyl)-5-( 1-(2-(trifluoromethyl)phenyl)ethyl)4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridine. MS: (ES) m / z calculated for C2óH3oBrF3N30 [M + H]+ 536.1, found 536.4.

[0338] To a suspension of 3-bromo-2-(2-isobutoxy-6-methylphenyl)-5-(l-(2(trifluoromethyl)phenyl)ethyl)-4,5,6,7-tetrahydro-277- pyrazolo[4,3-c]pyridine (50 mg, 0.09 mmol), 1 / Z-indol-5-ylboronic acid (150 mg, 0.93 mmol), and K2CO3 (300 mg, 2.17 mmol) In pdioxane (6 mL) and water (1 mL) was added Pd(dppf)Cl2 complex with dichloromethane (35 mg, 0.04 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, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (50% EtOAc in hexanes) followed by HPLC (MeCN / H2O, with 1% TFA) to obtain 3-(l / 7-indol-5-yl )-2-(2-isobutoxy-6-methylphenyl)-5-(l-(2(trifluoromethyl)phenyl)ethyl)-4,5,6,7-tetrahydro-2Z / -pyrazolo[4,3-c] pyridine as a mixture of rotamers. Ή NMR (400 MHz, CDCI3) δ 8.84 (m, 1H), 8.20-8.45 (m, 1H) 7.40-7.75 (m, 3H) 7.14-7.35 ( m, 5H), 6.44-6.77 (m, 3H), 4.45-5.04 (m, 4H), 3.25-3.92 (m, 5H), 2.17 (s, 3H), 1.85 (m, 1H), 1.28 (s, 3H), 0.83-0.88 (m, 6H). MS: (ES) m / z calculated C34H36F3N4O [M + H]+ 573.3, found 573.3. Example 72 Synthesis of 2-(2,6-diethylphenyl)-3-(l / / -indol-5-yl)-5-(2-(trifluoromethyl)benzyl)-4,5,6,7tetrahydro-2 / 7-pyrazolo [4,3-c]pyridine 1) Pd(dppf)CI2-CH2Cl2 2) HC1 Pas or a 154 CHO NaBH(OAc)3 step b

[0339] Step a: To a suspension of / er-butyl 3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2 / 7pyrazolo[4,3-c]pyridine-5(4 / 7)-carboxylate (500 mg, 1.2 mmol), 1 / Z-indol-5-ylboronic acid (650 mg, 4.04 mmol), K2CO3 (1.2 g, 8.8 mmol) in p-dioxane (8 mL) and water (1 mL) was added Pd(dppf)C12 complex with dichloromethane (200 mg, 0.24 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, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (5 to 30% EtOAc in hexanes) to obtain tert-butyl 2(2,6-diethylphenyl)-3-(1 / 7- indol-5-yl)-6,7-dihydro-277-pyrazolo[4,3-c]pyridine-5(4 / 7)-carboxylate. MS: (ES) m / z calculated for C29H35N4O2 [M+H]+471.2, found 471.2.

[0340] / er-Butyl 2-(2,6-diethylphenyl)-3-(177-indol-5-yl)-6,7-dihydro-277-pyrazolo[4,3-c]pyridine5(4 / / )-carboxylate above was dissolved in dichloromethane (5 mL) and charged with a solution of HC1 in dioxane (4N, 5 mL). The resulting mixture was stirred at room temperature for 2h. Once the reaction was complete, the solvent was evaporated in vacuo to obtain 2-(2,6-diethylphenyl)-3(U7-indol-5-yl)-4,5,6,7-tetrahydro-2 / 7-pyrazolo [4,3-c]pyridine hydrochloride. MS: (ES) m / z calculated for C24H27N4 [M+H]+371.2, found 371.2.

[0341] Step b: NaBH(OAc)3 (150 mg, 0.71 mmol) was added to a mixture of 2-(2,6-diethylphenyl)-3-(177-indol-5-yl)-hydrochloride. 4,5,6,7-tetrahydro-277-pyrazolo[4,3-c]pyridine (50 mg, 0.12 mmol), 2-(trifluoromethyl)benzaldehyde (100 mg, 0.57 mmol), and ΛζΑ- diisopropylethylamine (0.2 mL, 1.15 mmol) in dichloromethane (10 mL) under magnetic stirring. The resulting mixture was stirred at 35 °C for 1 h. After cooling to room temperature, the reaction mixture was quenched with MeOH. The solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN / H2O, with 0.1% TFA) to obtain 3-(7-chloro-1H-indazol-4-yl)-2-(2, 6155 diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-227-pyrazolo[4,3-c]pyridine. Ή NMR (400 MHz, CDCI3) δ 8.20 (s, 1H), 7.91-7.98 (m, 1H), 7.62 (dd, J=1.2, 7.6 Hz, 1H), 7.52 (t, .7=7.6 Hz, 1H), 7.14-7.38 (m, 5H), 7.08 (d, J= 7.6 Hz, 2H), 6.83 ( dd, J= 1.7, 8.5Hz, 1H), 6.44 (m, 1H), 3.94 (s, 2H), 3.79 (s, 2H), 2.84-2.95 (m, 4H), 2.21-2.39 (m, 4H), 1.04 (sd, J = 0.7, 7.6Hz, 6H). MS: (ES) m / z calculated C32H32F3N4 [M+H]+529.3, found 529.3. Example 73 Synthesis of 2-(2,6-diethylphenyl)-3-(H7-indol-5-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2 / / -pyrazolo|4,3-c|pyridine

[0342] Step a: A mixture of 3-bromo-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3c]pyridine hydrochloride (700 mg, 1.89 mmol), 2 -chloro-5-(trifluoromethyl)pyrimidine (420 mg, 2.30 mmol) and TEA (1 mL, 7.11 mmol) in CH3CN (10 mL) was stirred at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCOs, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0 to 40% EtOAc in hexanes) to obtain 3-bromo-2-(2,6-diethylphenyl)-5-(5- (trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro277-pyrazoIo[4,3-c]pyridine. MS: (ES) m / z calculated for C2iH22BrF3N5 [M+H]+ 480.1, found 480.1.

[0343] Step b: To a suspension of 3-bromo-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin2-yl)-4,5,6,7-tetrahydro-2 / / -pyrazolo[4,3-c]pyridine (70 mg, 0.15 mmol), 177-indol-5-ylboronic acid (70 mg, 0.43 mmol), and K2CO3 (240 mg, 1.72 mmol) in / « -dioxane (6 mL) and water (1 mL) was added Pd(dppf)Ch complex with dichloromethane (50 mg, 0.06 mmol). The mixture of The reaction was degassed (N2) for 2 min and stirred under N2 at 100 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (30% EtOAc in hexanes) followed by trituration in MeOH to obtain 2-(2,6-diethylphenyl)-3-(1 / f-indole-5 -yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydro-2 / 7-pyrazolo[4,3-c]pyridine. ’H NMR (400 MHz, CDCI3) δ 8.50 (s, 2H), 8.20 (s, 1H), 7.43 (s, 1H), 7.08-7.27 (m, 4H), 6.90 (dd, J= 1.6, 8.8 Hz, 2H), 6.44-6.50 ( m, 1H), 5.08 (s, 2H), 4.35 (t, J= 6.0 Hz, 2H), 3.00 (t, J= 6.0 Hz, 2H), 2.16- 2.40 (m, 4H), 1.04 (t, J=7.2Hz, 6H). MS: (ES) m / z calculated for C29H28F3N6 [M+H]+517.2, found 517.3. Example 74 Synthesis of (4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2Hpyrazolo[4,3-c]pyridine -3-yl)-6-fluoro-1ZF-benzo[í / ]imidazol-7-yl)methanol CF, )=N

[0344] Step a: A mixture of 3-bromo-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)- 4,5,6,7-tetrahydro-2 / 7-pyrazolo[4,3-c]pyridine (1.00 g, 2.08 mmol), 4,4,4',4',5,5,5 ',5'-octamethyl- 157 2,2'-bi(1,3,2-dioxaborolane) (1.32 g, 5.2 mmol), K2CO3 (1.15 g, 8.3 mmol) and Pd(dppf)C12 complexed with dichloromethane (0 0.25 g, 0.3 mmol) in dioxane (12 mL) and water (0.7 mL) was stirred at 100 °C for 7 hours under nitrogen. It was then cooled to room temperature, diluted with 20% MeOH / DCM, and filtered through Celite. The filtrate was collected, dried in the presence of Na2SC>4, concentrated on a rotary evaporator under reduced pressure. The residue was purified by flash chromatograph on silica gel (0 to 100% EtOAc / hexanes) to obtain 2-(2,6-diethylphenyl)-3-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-5-(5(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine. MS: (ES) m / z calculated for C27H33BF3N5O2 [M+H]+527.6, found 527.6.

[0345] Step b: A mixture of 2-(2,6-diethylphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-5-(5-(trifluoromethyl )pyrimidin-2-yl)-4,5,6,7-tetrahydro-2Z / -pyrazolo[4,3-c]pyridine (0.400 g, 0.76 mmol), tert-butyl 4-bromo-6-fluoro -7-(hydroxymethyl)-177-benzo[Z]imidazol-l-carboxylate (0.345 g, 1 mmol), K2CO3 (0.368 g, 2.66 mmol) and Pd(dppf)Ch complex with dichloromethane (0.15 g, 0.18 mmol) in dioxane (5 mL) and water (0.7 mL) was stirred at 100 °C for 3.5 hours under nitrogen. It was then cooled to room temperature, diluted with 20% MeOH / DCM, and filtered through a plug of Na2SO4 / Celite. The filtrate was collected, dried over Na2SO4, concentrated on a rotary evaporator under reduced pressure. The obtained crude product was stirred with a mixture of TFA (1 mL) and DCM (5 mL) for 1.5 hours. The mixture was basified with aq. NH4OH, extracted with IPA / CHCl3, and purified by flash chromatograph on silica gel (0 to 100% EtOAc / hexanes), followed by reverse phase HPLC to obtain (4(2- (2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-277-pyrazolo[4,3c]pyridin-3-yl)-6- fluoro-17 / -benzo[íZ]imidazol-7-yl)methanol. 'H NMR (400 MHz, CDCI3) δ 7.53 (br s, 2H), 7.06 (s, IH), 6.30 (m, 2H), 6.10 (m, 2H), 5.46 (d, J= 11.6, IH), 4.00 (m, 4H), 3.41 (m, 2H), 2.05 (m, 2H), 1.26 (m, 4H), 0, 01 (br s, 6H). MS: (ES) m / z calculated for C29H27F4N7O [M+H]+565.2, found 565.2. Example 75 Synthesis of 3-(7-chloro-1Ef-pyrrolo[3,2-c]pyridin-4-iI)-2-(2,6-diethylphenyl)-5-(5(trifluoromethyl)pyrimidin-2-yl)- 4,5,6,7-tetrahydro-2£?-pyrazolo[4,3-c]pyridine 158 Pd(dppf)Ct2*CH2CI2 step b

[0346] Step a: To a solution of tert-butyl 3-bromo-2-(2,6-diethylphenyl)-2,4,6,7-tetrahydro-5 / 7pyrazolo[4,3-c]pyridine-5 -carboxylate (6.2 g, 14.3 mmol) in 56 mL THF at -78 °C was added dropwise a 1.85 M solution of rcBuLi in hexanes (9.9 mL, 18.3 mmol). After stirring at -78 °C for 1 hr, trimethyl borate (5 mL, 44.3 mmol) was added and the solution was warmed to room temperature and allowed to stir for 16 hrs. The reaction was quenched with 1N HC1 and the aqueous and organic layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (80% ethyl acetate in hexanes) to obtain (5-(tert-Butoxycarbonyl)-2-(2,6-diethylphenyl)-4,5,6,7 -tetrahydro-277-pyrazolo[4,3c]pyridin-3-yl)boronic. MS: (ES) m / z calculated for C21H30BN3O4 [M + H]+ 400.2, found 400.5.

[0347] Step b: To a solution of acid (5-(tert-butoxycarbonyl)-2-(2,6-diethylphenyl)-4,5,6,7tetrahydro-277-pyrazolo[4,3-c]pyridin- 3-yl)boronic acid (0.42 g, 1.1 mmol) and tert-butyl 4-bromo-7chloro-177-pyrrolo[3,2-c]pyridine-l-carboxylate (0.35 g, 1.1 mmol) in 3.5 mL of dioxane was added a solution of potassium carbonate (0.58 g, 4.2 mmol) in 0.5 mL of H2O followed by complex 159 Pd(dppf)Cl2 with dichloromethane (0.17 g, 0.2 mmol). The mixture was degassed with N2 for five minutes and then heated at 100 °C for 16 hrs. The contents were filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (40% ethyl acetate in hexanes) to obtain ferr-butyl 3-(7-chloro-1 / 7-pyrrolo[3,2c]pyridin-4-yl)- 2...

Claims

1. A compound of Formula (I): (FORMULA I) or a pharmaceutically acceptable salt thereof, wherein: the portion of the ring having A0, A1, A2, A3, A4, A5, and A6 as ring vertices is a bicyclic heteroaryl selected from the group consisting of: (FORMULAS) wherein m is 0, 1, 2, or 3; and wherein the R4 substituents, when present, are attached to any vertex of the carbon ring of the bicyclic heteroaryl; R1 is selected from the group consisting of (FORMULA) each of which is optionally substituted with 1 or 2 R5 substituents; wherein (FORMULA) is selected from the group consisting of (FORMULAS); each R4 is independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, C1-6 hydroxyalkyl, C1-4 haloalkyl, halogen, cyano, hydroxyl, -NH2, -CONR4aR4b, and -CO2R4a; each R4a and R4b is independently selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 haloalkyl;Each R5 is independently selected from the group consisting of cyclopropyl, isopropyl, isopropyloxy, OMe, Me, Cl, F, -CONH2, -CF3, -O-CF3, (FORMULAS); and the subscript n is 0, characterized in that the compound is selected from the group consisting of: (FORMULA 1.001 / 1.240). Four claims follow;