C5A RECEPTOR ANTAGONIST REPLACED PIPERIDINE COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF COMPOU

专利摘要:
c5a receptor antagonist substituted piperidine compound, pharmaceutical composition, and use of the compound compounds are provided that are c5a receptor modulators. the compounds are substituted piperidines and are useful in pharmaceutical compositions, methods of treating diseases and disorders that involve pathological activation of c5a receptors.
公开号:BR112012033075B1
申请号:R112012033075-6
申请日:2011-06-24
公开日:2021-06-01
发明作者:Kevin Lloyd Greenman；Manmohan Reddy Leleti；Pingchen Fan；Yandong Li；Jay Powers；Hiroko Tanaka；Ju Yang；Yibin Zeng
申请人:Chemocentryx, Inc；
IPC主号:

专利说明:

CROSS REFERENCES WITH RELATED ORDERS
[001] This application claims the priority benefit of US Serial Application No. 12/823,039, filed June 24, 2010, and US Serial Application No. 13/072,616, filed March 25, 2011, the contents of which are hereby incorporated by reference in their entirety for all purposes. DECLARATION OF RIGHTS TO INVENTIONS MADE UNDER RESEARCH AND DEVELOPMENT SPONSORED BY THE FEDERAL GOVERNMENT NOT APPLICABLE REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR AN ATTACHMENT OF COMPUTER PROGRAM LISTING PRESENTED AND A COMPACT DISK. NOT APPLICABLE FUNDAMENTALS OF THE INVENTION
[002] The complement system plays a central role in the clearance of immune complexes and in immune responses to infectious agents, foreign antigens, virus-infected cells and tumor cells. Inappropriate or excessive activation of the complement system can lead to harmful, and even potentially life-threatening consequences due to severe inflammation and resulting tissue destruction. These consequences are clinically manifested in a variety of disorders including septic shock; myocardial ischemia/reperfusion as well as intestinal injuries; graft rejection; organ failure; nephritis; pathological inflammation; and autoimmune diseases.
[003] The complement system is composed of a group of proteins that are normally present in serum in an inactive state. Complement system activation mainly encompasses three distinct pathways, namely, the classical pathway, the alternative pathway, and the lectin pathway (VM Holers, In Clinical Immunology: Principles and Practice, ed. RR Rich, Mosby Press; 1996, 363- 391): 1) The classic pathway is a calcium/magnesium-dependent cascade, which is normally activated by the formation of antigen-antibody complexes. It can also be activated in an antibody-independent manner by the binding of C-reactive protein, complexed with ligand, and by many pathogens including gram negative bacteria. 2) The alternative pathway is a magnesium-dependent cascade that is activated by the deposition and activation of C3 on certain susceptible surfaces (eg, yeast and bacterial cell wall polysaccharides, and certain biopolymer materials). 3) the lectin pathway involves the initial binding of lectin that binds mannose 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)).
[004] Activation of the complement pathway generates biologically active fragments of complement proteins, for example, anaphylatoxins C3a, C4a and C5a and membrane attacking complexes (MAC) C5b-9, all of which mediate inflammatory responses by affecting chemotaxis of leukocyte; activate macrophages, neutrophils, platelets, mastoids and endothelial cells; and increase vascular permeability, cytolysis and tissue damage.
[005] Complement C5a is one of the most potent pro-inflammatory mediators of the complement system. (The anaphylactic peptide C5a is 100 times more potent, on a molar basis, at evoking inflammatory responses than C3a.) C5a is the activated form of C5 (190 kD, molecular weight). C5a is present in human serum at approximately 80 µg/ml (Kohler, P.F. et al., J. Immunol. 99: 1211-1216 (1967)). It is composed of two polypeptide chains, α and β, with approximate molecular weights of 115 kD and 75 kD, respectively (Tack, B.F. et al., Biochemistry 18: 1490-1497 (1979)). Biosynthesized as a single-chain promolecule, 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)).
[006] C5 is cleaved into C5a and C5b fragments during activation of complement pathways. The convertase enzymes responsible for C5 activation are multi-subunit complexes of C4b, C2a, and C3b for the classical pathway and (C3b)2, Bb, and P for the alternative pathway (Goldlust, MB et al., J Immunol. 113: 998-1007 (1974); Schreiber, RD et al, Proc. Natl. Acad. Sci. 75: 3948-3952 (1978)). C5 is activated by cleavage at position 74-75 (Arg-Leu) in the α chain. After activation, the 11.2 kD C5a peptide, 74 amino acids from the amino terminal portion of the α chain, is released. Both C5a and C3a are potent stimulators of neutrophils and monocytes ( Schindler, R. et al., Blood 76: 1631-1638 (1990); Haeffner-Cavaillon, N. et al., J. Immunol. 138: 794-700 ( 1987); Cavaillon, JM et al., Eur. J. Immunol. 20: 253-257 (1990)).
In addition to its anaphylatoxic properties, C5a induces chemotactic migration of neutrophils (Ward, PA et al., J. Immunol. 102:93-99 (1969)), eosinophils (Kay, AB et al., Immunol. 24). :969-976 (1973)), basophils (Lett-Brown, MA et al., J. Immunol. 117:246-252 1976)), and monocytes (Snyderman, R. et al., Proc. Soc. Exp. Biol. Med. 138: 387-390 1971)). Both C5a and C5b-9 activate endothelial cells to express the adhesion molecules essential for the sequestration of activated leukocytes, which mediate inflammation and tissue damage (Foreman, KE et al., J. Clin. Invest. 94: 1147- 1155 (1994); Foreman, KE et al., Inflammation 20: 1-9 (1996); Rollins, SA et al., Transplantation 69: 1959-1967 (2000)). C5a also mediates inflammatory reactions by causing smooth muscle contraction, increasing vascular permeability, inducing basophil and mastoid degranulation, 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 global immune response by increasing the production of TNF-α, IL-1-β, IL-6, IL-8, prostaglandins and leukotrienes (Lambris, JD et al ., In: The Human Complement System in Health and Disease, Volanakis, JE ed., Marcel Dekker, New York, pp. 83-118).
[008] It is believed that the anaphylactic and chemotactic effects of C5a should be mediated through its interaction with the C5a receptor. The human C5a receptor (C5aR) is a 52 kD membrane-bound G protein-linked receptor, and is expressed on neutrophils, monocytes, basophils, eosinophils, hepatocytes, pulmonary smooth muscle and endothelial cells, and renal glomerular tissues (Van-Epps , DE et al., J. Immunol. 132: 2862-2867 (1984); Haviland, DL et al., J. Immunol. 154: 1861-1869 (1995); Wetsel, RA, Immunol. Leff. 44: 183 -187 (1995); Buchner, RR et al., J. Immunol. 155: 308-315 (1995); Chenoweth, DE et al., Proc. Natl. Acad. Sci. 75: 3943-3947 (1978); Zwirner, J. et al., Mol. Immunol. 36:877-884 (1999)). The C5aR ligand binding site is complex and consists of at least two physically separable binding domains. One binds to the amino terminus of C5a (amino acids 1 to 20) and disulfide-linked nucleus (amino acids 21 to 61), while the second binds to the end of the C5a carboxy terminus (amino acids 62 to 74) (Wetsel, RA, Curr. Opin. Immunol. 7: 48-53 (1995)).
[009] C5a plays important roles in inflammation and tissue damage. In cardiopulmonary bypass and hemodialysis, C5a is formed as a result of activation of the alternative complement pathway when human blood contacts the artificial surface of the heart-lung machine or renal dialysis machine (Howard, RJ et al., Arch Surg. 123: 1496-1501 (1988); Kirklin, JK et al., J. Cardiovasc. Surg. 86: 845-857 (1983); Craddock, PR et al., N. Engl. J. Med. :769-774 (1977)). C5a causes increased capillary permeability and edema, bronchoconstriction, pulmonary vasoconstriction, leukocyte and platelet activation, and tissue infiltration, particularly the lung (Czermak, BJ et al., J. Leukoc. Biol. 64: 40-48 (1998) ). Administration of an anti-C5a monoclonal antibody has been shown to reduce cardiopulmonary bypass and cardioplegia-induced coronary endothelial dysfunction (Tofukuji, M. et al., J. Thorac. Cardiovasc. Surg. 116: 1060-1068 (1998)).
[0010] C5a is also involved in acute respiratory distress syndrome (ARDS), Chronic Obstructive Pulmonary Disorder (COPD) and multiple organ failure (MOF) (Hack, CE et al., Am. J. Med. 1989: 86: 20-26; Hammerschmidt DE et al. Lancet 1980; 1: 947-949; 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 pro-inflammatory cytokines, TNF-α and IL-1. C5a has also been shown to play an important role in the development of tissue injury, and particularly lung injury, in animal models of septic shock (Smedegard G et al. Am. J. Pathol. 1989; 135: 489-497; Markus, S ., et al., FASEB Journal (2001), 15: 568-570). In septicemia models using rats, pigs and non-human primates, anti-C5a antibodies administered to the animals prior to treatment with endotoxin or E. coli resulted in decreased tissue damage as well as decreased IL-6 production (Smedegard, G. et al., Am. J. Pathol. 135: 489-497 (1989); Hopken, U. et al., Eur. J. Immunol. 26: 1103-1109 (1996); Stevens, JH et al., J Clin. Invest. 77: 1812-1816 (1986)). More importantly, blocking or C5a with anti-C5a polyclonal antibodies has been shown to significantly improve survival rates in a rat cecal ligation/puncture model of septicemia (Czermak, BJ 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, RF et al., J. Clin. Invest. 106: 1271-1280 (2000)) and prevent MOF (Huber-Lang, M. et al., J. Immunol. 166: 1193-1199 (2001)). Anti-C5a antibodies were also protective in a snake venom factor model of lung injury in rats, and in immune complex-induced lung injury (Mulligan, MS et al. J. Clin. Invest. 98: 503512 (1996) ). The importance of C5a in immune complex-mediated lung injury was later confirmed in mice (Bozic, C.R. et al., Science 26: 1103-1109 (1996)).
[0011] C5a is found to be a major mediator in myocardial ischemia-reperfusion injury. Complement depletion reduced myocardial infarction size in mice (Weisman, HF et al., Science 249: 146-151 (1990)), and treatment with anti-C5a antibodies reduced the lesion in a mouse model of ischemia- hind limb reperfusion ( Bless, NM et al., Am. J. Physiol. 276: L57-L63 (1999)). Reperfusion injury during myocardial infarction was also markedly reduced in pigs that were retracted with a monoclonal anti-C5a IgG (Amsterdam, E.A. et al., Am. J. Physiol. 268: H448-H457 (1995)). A recombinant human C5aR antagonist reduces infarct size in a porcine model of surgical revascularization (Riley, R.D. et al., J. Thorac. Cardiovasc. Surg. 120: 350-358 (2000)).
C5a-targeted neutrophils also contribute to many bullous diseases (eg, bullous pemphigoid, pemphigus vulgaris, and pemphigus foliaceus). These are chronic, recurrent inflammatory disorders clinically characterized by sterile blisters that appear in the subepidermal space of the skin and mucosa. Although autoantibodies to keratinocytes located in the cutaneous basement membranes are believed to underlie the detachment of basal epidermal keratinocytes from the underlying basement membrane, blebs are also characterized by the accumulation of neutrophils both in the upper dermal layers and within the blister cavities. In experimental models, a reduction in neutrophils or the absence of complement (total or selective in C5) can inhibit the formation of subepidermal bullae, even in the presence of high autoantibody titers.
Complement levels are elevated in patients with rheumatoid arthritis (Jose, PJ et al., Ann. Rheum. Dis. 49: 747-752 (1990); Grant, EP, et al., J. of Exp. Med., 196(11): 1461-1471, (2002)), lupus nephritis (Bao, L., et al., Eur. J. of Immunol., 35(8), 2496-2506, (2005)) and systemic lupus erythematosus (SLE) (Porcel, JM et al., Clin. Immunol. Immunopathol. 74: 283-288 (1995)). C5a levels correlate with 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 from arthritis induced by injection of monoclonal anti-collagen antibodies (Banda, N.K., et al., J. of Immunol., 2003, 171: 2109-2115). Therefore, inhibition of C5a and/or C5a receptor (C5aR) would be useful in the treatment of these chronic diseases.
The complement system is believed to be activated in patients with inflammatory bowel disease (IBD) and is considered to play a role in the pathogenesis of the disease. Complement-activated products have been found in the luminal face of surface epithelial cells, as well as in the muscular mucosa and submucosal blood vessels in IBD patients (Woodruff, T.M., et al., J of Immunol., 2003, 171: 55145520).
C5aR expression is up-regulated 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 would be involved in neurodegenerative diseases, such as Alzheimer's disease (Mukherjee, P. et al., J. Neuroimmunol. 105: 124-130 (2000); O'Barr, S. et al., J. Neuroimmunol. ( 2000) 105: 87-94; Farkas, I., et al. J. Immunol. (2003) 170: 5764-5771), Parkinson's disease, Pick's disease and transmissible spongiform encephalopathies. Activation of neuronal C5aR can induce apoptosis ( Farkas I et al. J. Physiol. 1998; 507: 679-687). Therefore, inhibition of C5a and/or C5aR would also be useful in the treatment of neurodegenerative diseases.
There is some evidence that C5a production worsens inflammation associated with atopic dermatitis (Neuber, K., et al., Immunology 73:83-87, (1991)), and chronic urticaria (Kaplan, AP, J. Allergy Clin Immunol 114;465-474 (2004).
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 mastoids 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 from psoriatic lesions (scale) contain highly elevated levels of C5a and exhibit potent chemotactic activity against neutrophils, an effect that can be inhibited by the addition of a C5a antibody. T cells and neutrophils are chemoattracted by C5a ( Nataf, S. et al., J. Immunol. 162: 4018-4023 (1999 ); Tsuji, RF et al., J. Immunol. 165: 1588-1598 ( 2000); Cavaillon, JM et al., Eur. J. Immunol. 20: 253-257 (1990)). Additionally, C5aR expression was demonstrated in plasmacytoid dendritic cells (pDC) isolated from cutaneous lupus erythematosus lesions and these cells were shown to demonstrate chemotactic behavior against C5a, suggesting that blocking C5aR in pDC would be effective in reducing pDC infiltration into the skin inflamed in both SLE and psoriasis. Therefore C5a would be an important therapeutic target for the treatment of psoriasis.
[0018] Immune complexes (IC) containing immunoglobulin G contribute to the pathophysiology in various autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, Sjogren's disease, Goodpasture's syndrome, and hypersensitivity pneumonitis (Madaio, MP, Semin Nephrol 19: 48-56 (1999); Korganow, AS et al., Immunity 10: 451-459 (1999); Bolten, WK, Kidney Int. 50: 1754-1760 (1996); 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 responses in these HF diseases is the Arthus reaction, which characterizes polymorphonuclear cell infiltration, hemorrhage, and plasma exudation (Arthus, M., CR Soc. Biol. 55: 817-824 ( 1903)). Recent studies show that C5aR-deficient mice are protected from IC-induced tissue 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)). Along with its receptor, C5a plays an important role in the pathogenesis of HF diseases. Inhibitors of C5a and C5aR would be useful to treat these diseases. Description of Related Art:
Only recently have non-peptide-based C5a receptor antagonists been described in the literature (eg, Sumichika, H., et al., J. Biol. Chem. (2002), 277, 49403-49407). The non-peptide-based C5a receptor antagonist has been reported to be effective for treating endotoxic shock in rats (Stracham, A.J., et al., J. of Immunol. (2000), 164(12): 6560-6565); and to treat IBD in a mouse model ( Woodruff, T.M., et al., J of Immunol., 2003, 171: 5514-5520 ). Non-peptide-based C5a receptor modulators have also been described in the patent literature by the Neurogen Corporation, (for example, WO2004/043925, WO2004/018460, WO2005/007087, WO03/082826, WO03/08828, WO02/49993, WO03 /084524); Dompe S.P.A. (WO02/029187); and The University of Queenland (WO2004/100975).
[0020] There is considerable experimental evidence in the literature that implicates increased levels of C5a with various diseases and disorders, in particular in autoimmune and inflammatory diseases and disorders. Thus, there remains a need in the art for new small organic molecule modulators, eg, agonists, preferably antagonists, partial agonists, of the C5a (C5aR) receptor that are useful for inhibiting pathogenic events, eg, chemotaxis, associated with increased levels of anaphylatoxin activity. The present invention satisfies these and other needs. BRIEF SUMMARY OF THE INVENTION
[0021] In one aspect, the present invention provides compounds having the formula:
and pharmaceutically acceptable salts, hydrates and rotamers thereof; wherein C1 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has 1 to 3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R1 substituents; C2 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has 1 to 3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R2 substituents; C3 is selected from the group consisting of C1-8 alkyl or heteroalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, heterocycloalkyl or heterocycloalkyl -C 1-4 alkyl, wherein the heterocycloalkyl group or moiety has 1 to 3 heteroatoms selected from N, O and S, and wherein the heteroaryl group has 1 to 3 heteroatoms as ring members selected from N, O and S, and each C3 is optionally substituted with 1 to 3 R3 substituents; each R1 is independently selected from the group that ca ab a ab consists of halogen, -CN, -R , -CO2R , -CONR R , -C(O)R , -OC(O)NR R , babca ab a ab ab - NR C(O)R , -NR C(O)2R , -NR -C(O)NR R , -NR C(O)NR R , -NR R , -ORa, and -S(O)2NRaRb; wherein each Ra and Rb is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five- or six-membered ring having a 0 to 2 additional heteroatoms as ring members selected from N, O or S, and is optionally substituted with one or two oxo; each Rc is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of Ra, Rb and Rc are optionally substituted still with one to three halogen groups, hydroxy methyl, amino, alkylamino and dialkylamino; and optionally when two R 1 substituents are on adjacent atoms, they are combined to form a fused five- or six-membered carbocyclic or heterocyclic ring; each R2 is independently selected from the group consisting of halogen, -CN, -NO2, -Rf, -CO2Rd, -CONRdRe, -C(O)Rd, - of edefd of OC(O)NR R , -NR C(O )R , -NR C(O)2R , -NR C(O)NR R , - d of d of NR C(O)NR R , -NR R , -OR , and -S(O)2NR R ; wherein each R and R is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom may be combined with the nitrogen atom to form a five- or six-membered ring having a 0 to 2 additional heteroatoms as ring members selected from N, O or S, and is optionally substituted with one or two oxo; each Rf is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl and wherein the aliphatic and cyclic portions of Rd, Re and Rf are optionally further substituted with one to three halogen, hydroxy methyl, amino, alkylamino and dialkylamino groups, and optionally when two R2 groups are on adjacent atoms, they are combined to form a five- or six-membered ring; each R3 is independently selected from the group consisting of halogen, -CN, -Ri, -CO2Rg, -CONRgRh, -C(O)Rg, -C(O)Ri, - OC(O)NRgRh, -NRhC(O) Rg, -NRhCO2Ri, -NRgC(O)NRgRh, -NRgRh, -ORg, -j gh 4 j 4 j 4 j 4 gh 4 j 4 OR, -S(O)2NR R , -X -R, -NH- X -R, -OX -R, -X -NR R , -X -NHR, -X -gh 4 hg 4 g 4 g 4 g 4 CONR R , -X -NR C(O)R , -X -CO2R , -OX -CO2R, -NH-X -CO2R, -X -NRhCO2Ri, -O-X4-NRhCO2Ri, -NHRj and -NHCH2Rj, wherein X4 is a C1-4 alkylene; each Rg and Rh is independently selected from hydrogen, C18 alkyl or heteroalkyl, C3-6 cycloalkyl and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a four, five, or ring. six members having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo; each R1 is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each Rj is selected from the group consisting of C3-6 cycloalkyl, imidazolyl, pyrimidinyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and S,S-dioxo-tetrahydrothiopyranyl and wherein the aliphatic and cyclic moieties of Rg, Rh, Ri and Rj are optionally further substituted with one to three halogen groups, methyl, CF3, hydroxy C1-4 alkoxy, C1-4 alkoxy C1-4 alkyl, -C(O)O-C1-8 alkyl, amino, alkylamino and dialkylamino, and optionally when two R3 groups are on adjacent atoms, they are combined to form a five- or six-membered ring; and X is hydrogen or CH3.
In addition to the compounds provided herein, the present invention further provides pharmaceutical compositions containing one or more of these compounds, as well as methods for using these compounds in therapeutic methods, primarily to treat diseases associated with C5a signaling activity.
[0023] 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 diagnostic imaging to determine the presence or absence of C5aR. In a related aspect, a method of diagnosing disease is carried out by contacting a tissue or blood sample with a compound labeled as provided herein and determining the presence or absence, or amount of C5aR in the sample. BRIEF DESCRIPTION OF THE FIGURES
[0024] Figure 1 provides structures and activity for representative compounds of the present invention. Compounds prepared using methods as described generally below, as well as methods provided in the Examples. DETAILED DESCRIPTION OF THE INVENTION I. Abbreviation and Definitions
[0025] The term "alkyl", alone or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical having the designated number of carbon atoms (ie. is, C1-8 means one to eight carbons). Examples of the 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 "alkyl" in its broadest sense is also intended to include those unsaturated groups such as alkenyl and alkynyl groups. 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), 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 having the indicated number of ring atoms (eg, C3-6 cycloalkyl) and being fully saturated or having no more than one double bond between ring vertices. "Cycloalkyl" is also intended to refer 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 atom(s) of nitrogen(s) are optionally quaternized. The heterocycloalkyl can be a monocyclic, a bicyclic or a 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, thiomorpholino-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 ring carbon or heteroatom.
The term "alkylene" alone or as part of another substituent means a bivalent radical derived from an alkane, as exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group generally having four or fewer carbon atoms. Similarly, "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having double or triple bonds, respectively.
[0027] The term "heteroalkyl," alone or in combination with another term, means, unless otherwise stated, a stable straight or branched or cyclic hydrocarbon radical, or combinations thereof, consisting of the set 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 can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The O, N and S heteroatom(s) can be placed in any interior position of the heteroalkyl group. The heteroatom Si can be placed at any position on the heteroalkyl group, including the position to which the alkyl group is attached to the rest of the molecule. Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S( O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N (CH3)-CH3. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the terms "heteroalkenyl" and "heteroalkynyl" alone or in combination with another term, mean, unless otherwise stated, an alkenyl group or alkynyl group, respectively, which contains the stated number of carbons and having from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The O, N and S heteroatom(s) can be placed in any interior position of the heteroalkyl group.
The term "heteroalkylene" alone or as part of another substituent means a bivalent radical, saturated or unsaturated or polyunsaturated, derived from heteroalkyl, as exemplified by -CH2-CH2-S-CH2CH2- and - CH2-S-CH2-CH2-NH-CH2-, -O-CH2-CH=CH-, -CH2-CH=C(H)CH2-O-CH2- and -S-CH2-C=C-. For hetero-alkylene groups, heteroatoms can also occupy either or both of the chain ends (for example, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
[0029] 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 be combined to form a 3- to 7-membered ring with the nitrogen atom to which each is attached. Accordingly, a group represented as -NRaRb is intended to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.
The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, an atom of fluorine, chlorine, bromine or iodine. Additionally, such terms as "haloalkyl," are intended to include monoalloalkyl and polyaloalkyl. For example, the term "C1-4 haloalkyl" is intended to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.
[0031] The term "aryl" means, unless otherwise stated, a polyunsaturated, typically aromatic hydrocarbon group which may be a single ring or multiple rings (up to three rings) which are fused together or covalently bonded. The term "heteroaryl" refers to aryl groups (or rings) that contain one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the atom(s) s) of nitrogen(s) are optionally quaternized. A heteroaryl group can be attached to the rest of the molecule through a heteroatom. Non-limiting examples of the aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of the heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinolinyl, phthalaziniyl, benzotriazinyl benzoyl pyrazole, purin , benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, pyridinyl, thiazolylazolyl, isoxidinyl, isoquinolyl, isdolyl, thiazolylazolyl, isoxidinyl, isoquinolyl, pyrazolyl, thiazolyl, isoquinolyl, , thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. Substituents for each of the aryl and heteroaryl ring systems mentioned above are selected from the group of acceptable substituents described below.
[0032] For brevity, the term "aryl" when used in combination with other terms (eg, aryloxy, arylthiooxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is intended to include those radicals where an aryl group is attached to an alkyl group (for example, benzyl, phenethyl, pyridylmethyl and the like).
The above terms (for example, "alkyl", "aryl" and "heteroaryl"), in some embodiments, will include both the substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below. For brevity, the terms aryl and heteroaryl will refer to the substituted or unsubstituted versions as provided below, while the term "alkyl" and related aliphatic radicals are intended to refer to the unsubstituted version, unless otherwise indicated. be replaced.
Substituents for alkyl radicals (including those groups often referred to as alkylene, alkenyl, alkynyl and cycloalkyl) can be a variety of groups selected from: -halogen, -OR', -NR'R", -SR ', -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", - OC(O)NR'R", -NR" C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH , -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -CN and - NO2 in a number ranging from zero to (2 m' + 1), where m' is the total number of carbon atoms in such a radical. R', R" and R"' each independently refer to the groups hydrogen, unsubstituted C1-8 alkyl, unsubstituted heteroalkyl, unsubstituted aryl, substituted aryl with 1 to 3 halogens, unsubstituted C1-8 alkyl, alkoxy C1-8 or C1-8 thioalkoxy, or unsubstituted aryl-C1-4 alkyl groups. When R' and R" are bonded to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR’R" is intended to include 1-pyrrolidinyl and 4-morpholinyl. The term "acyl" as used alone or as part of another group refers to an alkyl radical in which two substituents on the carbon which is closest to the point of attachment for the radical are replaced with the substituent =O( for example, -C(O)CH3, -C(O)CH2CH2OR' and the like).
[0035] Similarly, substituents for aryl and heteroaryl groups are varied and are generally selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O )2R', -NR' -C(O)NR"R"', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', - S(O)R', -S(O)2R', -S(O)2NR'R", - NR'S(O)2R", -N3, perfluoro-alkoxy (C1-C4), and perfluoro-alkyl( C1-C4), in a number ranging from zero to the total number of open valences in the aromatic ring system; and where R', R" and R"' are independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-alkyl C1-4 and unsubstituted aryloxy-C1-4 alkyl. Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene string of 1 to 4 carbon atoms.
Two of the substituents on adjacent aryl or heteroaryl ring atoms may optionally be substituted with a substituent of the formula -TC(O)-(CH2)qU-, wherein T and U are independently -NH-, -O- , -CH2- or a single bond, eq is an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring optionally may be substituted with a substituent of the formula -A-(CH2)rB- , where A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a bond single, and r is an integer from 1 to 3. One of the single bonds of the new ring thus formed can optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent aryl or heteroaryl ring atoms may optionally be substituted with a substituent of the formula -(CH2)sX-(CH2)t-, where set are independently integers from 0 to 3, and X is - O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The R' substituent in -NR'- and -S(O)2NR'- is selected from unsubstituted hydrogen or C1-6 alkyl.
[0037] As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
[0038] The term “ionic liquid” refers to any liquid that contains primarily ions. Preferably, in the present invention, "ionic liquid" refers to salts whose melting point is relatively low (e.g. below 250°C). Examples of ionic liquids include but not limited to 1-butyl-3-methylimidazolium tetrafluoroborate, 1-hexyl-3-methylimidazolium tetrafluoroborate, 1-octyl-3-methylimidazolium tetrafluoroborate, 1-nonyl-3-methylimidazolium tetrafluoroborate, 1-decyl-3-methylimidazolium tetrafluoroborate, 1-hexyl-3-methylimidazolium hexafluorophosphate and 1-hexyl-3-methylimidazolium bromide, and the like.
The term "pharmaceutically acceptable salts" is intended to include salts of the active compounds which are prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. When the compounds of the present invention contain relatively acidic functionality, base addition salts can be obtained by contacting the natural form of such 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, manganese, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, which include substituted amines, cyclic amines, naturally occurring amines and the like such as arginine, betaine, caffeine, choline, N,N'- dibenzylethyleneamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glycamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglycamine, morpholine, piperazine, piperidine, 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 natural 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, monohydrocarbon, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids and the like, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic or galactunic acids and the like (see, for example, Berge, SM, et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science , 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities which allow the compounds to be converted to base or acid addition salts.
The natural forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the precursor compound in a conventional manner. The precursor form of the compound differs from various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the precursor form of the compound for the purpose of the present invention.
[0041] In addition to the salt forms, the present invention provides compounds that are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to compounds of the present invention by chemical or biomedical methods in an ex vivo environment. 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.
Certain compounds of the present invention may exist in non-soluble forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be encompassed 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 use contemplated by the present invention and are intended to be within the scope of the present invention.
[0043] 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) are all intended to be encompassed within the scope of the present invention. The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium (H), iodine-125 (I) or carbon-14 (C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. For example, the compounds can be prepared such that any number of hydrogen atoms are replaced with an isotope of deuterium (2H). II. Compounds
[0044] In one aspect, the present invention provides compounds having the formula I:
and pharmaceutically acceptable salts, hydrates and rotamers thereof; wherein C1 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has 1 to 3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with 1 to 3 R1 substituents; C2 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has 1 to 3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with 1 to 3 R2 substituents; C3 is selected from the group consisting of C1-8 alkyl or heteroalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, heterocycloalkyl or heterocycloalkyl -C 1-4 alkyl, wherein the heterocycloalkyl group or moiety has 1 to 3 heteroatoms selected from N, O and S, and wherein the heteroaryl group has 1 to 3 heteroatoms as ring members selected from N, O and S, and each C3 is optionally substituted with 1 to 3 R3 substituents; each R1 is independently selected from the group that ca ab a ab consists of halogen, -CN, -R , -CO2R , -CONR R , -C(O)R , -OC(O)NR R , babca ab a ab ab - NR C(O)R , -NR C(O)2R , -NR -C(O)NR R , -NR C(O)NR R , -NR R , -ORa, and -S(O)2NRaRb; wherein each Ra and Rb is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five- or six-membered ring having a 0 to 2 additional heteroatoms as ring members selected from N, O or S, and is optionally substituted with one or two oxo; each Rc is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl and wherein the aliphatic and cyclic portions of Ra, Rb and Rc are optionally further substituted with one to three halogen groups, hydroxy methyl, amino, alkylamino and dialkylamino; and optionally when two R 1 substituents are on adjacent atoms, they are combined to form a fused five- or six-membered carbocyclic or heterocyclic ring; each R2 is independently selected from the group consisting of halogen, -CN, -NO2, -Rf, -CO2Rd, -CONRdRe, -C(O)Rd, - of edefd of OC(O)NR R , -NR C(O )R , -NR C(O)2R , -NR C(O)NR R , - d of d of NR C(O)NR R , -NR R , -OR , and -S(O)2NR R ; wherein each R and R is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five- or six-membered ring having a 0 to 2 additional heteroatoms as ring members selected from N, O or S, and is optionally substituted with one or two oxo; each Rf is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl and wherein the aliphatic and cyclic portions of Rd, Re and Rf are optionally further substituted with one to three halogen, hydroxy methyl, amino, alkylamino and dialkylamino groups, and optionally when two R2 groups are on adjacent atoms, they are combined to form a five- or six-membered ring; each R3 is independently selected from the group consisting of halogen, -CN, -Ri, -CO2Rg, -CONRgRh, -C(O)Rg, -C(O)Ri, - OC(O)NRgRh, -NRhC(O) Rg, -NRhCO2Ri, -NRgC(O)NRgRh, -NRgRh, -ORg, -j gh 4 j 4 j 4 j 4 gh 4 j 4 OR, -S(O)2NR R , -X -R, -NH- X -R, -OX -R, -X -NR R , -X -NHR, -X -gh 4 hg 4 g 4 g 4 g 4 CONR R , -X -NR C(O)R , -X -CO2R , -OX -CO2R, -NH-X -CO2R, -X -NRhCO2Ri, -O-X4-NRhCO2Ri, -NHRj and -NHCH2Rj, wherein X4 is a C1-4 alkylene; each Rg and Rh is independently selected from hydrogen, C18 alkyl or heteroalkyl, C3-6 cycloalkyl and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a four, five, or ring. six members having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo; each R1 is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each Rj is selected from the group consisting of C3-6 cycloalkyl, imidazolyl, pyrimidinyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and S,S-dioxo-tetrahydrothiopyranyl and wherein the aliphatic and cyclic moieties of Rg, Rh, Ri and Rj are optionally further substituted with from one to three halogen groups, methyl, CF3, hydroxy C1-4 alkoxy, C1-4 alkoxy C1-4 alkyl, -C(O)O-C1-8 alkyl, amino, alkylamino and dialkylamino , and optionally when two R3 groups are on adjacent atoms, they are combined to form a five- or six-membered ring; and X is hydrogen or CH3.
[0045] In formula I, the C1 substituent is, in one embodiment, selected from the group consisting of phenyl, pyridyl, indolyl and thiazolyl, each of which is optionally substituted with 1 to 3 R1 substituents. Preferably, each R1 is independently selected from the group consisting of halogen, -CN, -Rc, -NRaRb and -ORa, and wherein each Ra and Rb is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom it can be combined with the nitrogen atom to form a pyrrolidine ring; each Rc is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl and C3-6 cycloalkyl and wherein the aliphatic and cyclic portions of Ra, Rb and Rc are optionally further substituted with one to three hydroxy methyl groups, amino, alkylamino and dialkylamino; and optionally when two R 1 substituents are on adjacent atoms, they are combined to form a fused five- or six-membered carbocyclic ring. In selected embodiments of the invention, C1 is selected from:

[0046] Returning to formula I, the C2 substituents, in one embodiment, are selected from the group consisting of phenyl, naphthyl, pyridyl and indolyl, each of which is optionally substituted with 1 to 3 R2 substituents. Preferably, each R2 is independently selected from the group consisting of halogen, -Rf and -ORd; wherein each Rd is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl; each Rf is independently selected from the group consisting of C18 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl and heteroaryl and wherein the aliphatic and cyclic portions of Rd and Rf are optionally further substituted with one to three halogen groups, hydroxy methyl, amino, alkylamino and dialkylamino. In selected embodiments of the invention, C2 is selected from the group consisting of:

[0047] The C3 substituent is, in some embodiments, selected from the group consisting of C3-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-2 alkyl, phenyl, pyridinyl, pyrazolyl, piperidinyl, pyrrolidinyl, piperidinylmethyl and pyrrolidinylmethyl, each of which is optionally substituted with 1 to 3 R3 substituents. Preferably, each R3 is independently selected from the group consisting of halogen, -Ri, -g gh hghi gh g 4j 4 CO2R , -CONR R , -NR C(O)R , -NR C(O)2R, -NR R , -OR, -X -R, -X -NRgRh, -X4-CONRgRh, -X4-NRhC(O)Rg, -NHRj and -NHCH2Rj, wherein X4 is a C1-3 alkylene; each Rg and Rh is independently selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five- or six-membered ring having from 0 to 1 additional heteroatom as ring members selected from N, O or S and is optionally substituted with one or two oxo; each R1 is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each Rj is selected from the group consisting of C3-6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl and tetrahydropyranyl and wherein the aliphatic and cyclic portions of Rg, Rh, Ri and Rj are optionally further substituted with one to three halogen groups , methyl, CF3, hydroxyamino, alkylamino and dialkylamino. In selected embodiments of the invention, C3 is selected from the group consisting of:

[0048] In the other embodiments, C3 is selected from the group consisting of:

[0049] Returning to formula I, X is preferably H. Subformulas of Formula I:
[0050] In one embodiment of the invention, the compounds of formula I have the subformula Ia:

[0051] In a second embodiment of the invention, the compounds of formula I have the subformula Ib:

[0052] In a third embodiment of the invention, the compounds of formula I have the subformula Ic:
wherein X1 is selected from the group consisting of N, CH and CR1; the subscript n is an integer from 0 to 2; X2 is selected from the group consisting of N, CH and CR2; and the subscript m is an integer from 0 to 2.
[0053] In a fourth embodiment of the invention, the compounds of formula I have the subformula Id:

[0054]wherein X1 is selected from the group consisting of N, CH and CR1; the subscript n is an integer from 0 to 2; X2 is selected from the group consisting of N, CH and CR2; and the subscript m is an integer from 0 to 2.
[0055] In a fifth embodiment of the invention, the compounds of formula I have the subformula Ie:
where the subscript p is an integer from 0 to 3; X1 is selected from the group consisting of N, CH and CR1; the subscript n is an integer from 0 to 2; X2 is selected from the group consisting of N, CH and CR2; and the subscript m is an integer from 0 to 2.
[0056] In other selected embodiments, the compounds of the invention are represented by:
wherein the substituents R 1 , R 2 and R 3 , and the subscript p all have the meanings given with reference to formula I.
[0057] In still other selected embodiments, the compounds of the invention are represented by:
wherein the substituents R1 and R3 and the subscript p all have the meanings given with reference to formula I.
[0058] In a particularly preferred group of embodiments, compounds of the invention are represented by formula (Ie5) wherein R3 is a member selected from the group consisting of -NRgRh, -NHRj and -NHCH2Rj, and each Rg, Rh and Rj have the meanings given with reference to formula I.
[0059] In another particularly preferred group of embodiments, compounds of the invention are represented by formula (Ie5) wherein R3 is a member selected from the group consisting of -X4-NRgRh, -X4-Rj and -X4- NRhCORg, and each of X4, Rg, Rh and Rj have the meanings given with reference to formula I.
Compounds of the invention having formula I may exist in different diastereomeric forms, for example the C1 and C2 substituents in subformula Ia and Ic may be cis to each other or trans to each other. As used herein, the terms cis or trans are used in their conventional sense in the chemical techniques, i.e., referring to the position of the substituents relative to one another relative to a plane of reference, e.g., a double bond, or a ring system, such as a dekaline-type ring system or a hydroquinolone ring system: in the cis isomer the substituents are on the same side of the reference plane, in the trans isomer the substituents are on opposite sides. Additionally, different conformers are considered by the present invention, as well as different rotamers. Conformers are conformational isomers that can differ by rotations around one or more o-bonds. Rotamers are conformers that differ in rotation around just a single o-bond. Compound Preparation
[0061] Those skilled in the art will recognize that there are a variety of methods available to synthesize molecules depicted in the claims. In general, the methods useful for synthesizing compounds depicted in the claims consist of four parts, which can be done in any order: Piperidine ring formation, installation of two amide bonds, and installation and/or modification of functional groups at C1, C2, and C3.
[0062] Various methods for preparing the claimed compounds are illustrated below (eq. 1 to 6).

[0063] Equations 1 to 4 demonstrate some methods of forming the piperidine ring. Bonding at the 2-position of the pyridine ring can be accomplished via transition metal mediated bonds as shown in eq. 1 and 2, or metal catalyzed addition of an organometallic species such as the zincate or magnesium salt (eq. 3). Subsequent to attachment at the 2-position, transition metal-mediated hydrogenation of the pyridine ring produces the piperidine ring system (eq. 1 and 3). Another method results in the elaboration of an α-amino acid to a piperidine ring as described in eq. 4. Those skilled in the art will recognize that many synthetic methodologies can produce substituted piperidines, including the CC or CN cyclization of acyclic precursors via alkylation or ring closing metathesis. Relative stereochemistry can be adjusted by a variety of methods, including facial selectivity during the hydrogenation step. Absolute stereochemistry can also be adjusted through a variety of methods, through the use of chiral ligands or a chiral auxiliary, separation of chiral diastereomers, use of chiral starting materials, or classical resolution. Compounds with 2,3-trans stereochemistry can have the relative stereochemistry adjusted during piperidine formation, or can be derived via epimerization of a 2,3-cis piperidine as illustrated in eq. 5.

[0064] The acylation of the piperidine ring is described in equation 6. In the case of eq. 6, X can be chosen from an appropriate group such as OH, Cl and F, or from any group capable of activating a carbonyl group for the addition of an amine (eg OSu, imidazole, etc.). Such linkages can be assisted by the use of inorganic or organic bases, activating agents such as HBTU, and also by catalysts, in particular by those catalysts known in the art which aid in the formation of amide bonds, such as DMAP, HOBT, etc. suitable binding partners include a carboxylic acid and a piperidine, an acyl fluoride and an amine, and so on. Those skilled in the art will recognize that there are other possible combinations that will also result in the desired product.

[0065] A variety of methods described above were used to prepare the compounds of the invention, some of which are described in the examples.
A family of specific compounds of particular interest having formula I consists of pharmaceutically acceptable compounds, salts, hydrates and rotamers thereof, as shown in Figure 1. For the compounds of Figure 1, any bond which is not shown at the atom or linked group is intended to be a methyl group. For example,
is intended to illustrate
III. Pharmaceutical Compositions
[0067] In addition to the compounds provided above, compositions for modulating C5a activity in humans and animals will typically contain a pharmaceutical carrier or diluent.
[0068] 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 which results, directly or indirectly, from combining the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is intended that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not harmful to its recipient.
Pharmaceutical compositions for administering the compounds of this 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 methods include the step of bringing the active ingredient in association with the carrier that constitutes one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect on the disease process or condition.
[0070] The compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, pills, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifications as described in the patent application US 2002-0012680, hard or soft capsules, syrups, elixirs, solutions, mouth patches, oral gel, chewing gum, chewable tablets, effervescent powders and effervescent tablets. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, antioxidants and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which 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, for example 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 can be uncoated or they can be coated, enteric or otherwise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a prolonged 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 by the techniques described in Pats. US 4,256,108, 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlled release.
[0071] 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, polyethylene glycol (PEG) of various medium sizes (eg PEG400, PEG4000) and certain surfactants such as cremophor or solutol, or such soft gelatine capsules in which the active ingredient is mixed with water or an oily medium, eg peanut oil, liquid paraffin, or olive oil. Additionally, emulsions can be prepared with a water-immiscible ingredient such as oils and stabilized with surfactants such as mono- or di-glycerides, PEG esters and the like.
[0072] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such 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 naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with aliphatic alcohols of long chain, for example heptadecaethyleneoxycetanol, 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 hexitol anhydrides, for example polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
[0073] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those presented above, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.
[0074] Dispersible powders or granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
[0075] The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally occurring gums, for example acacia gum or gum tragacanth, naturally occurring phosphatides, for example soybean, lecithin, and esters or partial esters derived from fatty acids and anhydrides of hexitol, for example mono- sorbitan oleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Emulsions can also contain sweetening and flavoring agents.
[0076] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG and surfactants.
[0077] 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 those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose any bland fixed oil can be used including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the present invention can also be administered in the form of suppositories for the rectal administration of the drug. These compositions can be prepared by mixing the drug with a sterile non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. Additionally, the compounds can be administered via ocular delivery via solutions or ointments. Furthermore, transdermal delivery of the subject compounds can be accomplished 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. As used herein, topical application is also intended to include the use of mouth rinses and gargles.
[0079] The compounds of this invention can also be linked to a carrier which is a polymer suitable as targetable drug carriers. such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethylene-oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the invention can be attached to a carrier which is a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, polyepsilon caprolactone, poly acid -butyric hydroxy, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic hydrogel block copolymers. Semipermeable polymers and polymeric matrices can be formed into formed articles such as valves, stents, tubes, prostheses and the like. In one embodiment of the invention, the compound of the invention is bonded to a semipermeable polymer or polymeric matrix that is formed as a stent or stent-graft device. IV. Methods of Treating Diseases and Disorders Modulated by C5a
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 (e.g., C5a) to the C5a receptor in vitro or in vivo. In general, such methods comprise the step of contacting a C5a receptor with a sufficient amount of one or more C5a receptor modulators as provided herein, in the presence of the C5a receptor ligand in aqueous solution and under conditions otherwise suitable for the binding of the ligand to the C5a receptor. The C5a receptor can be present in suspension (eg, in an isolated membrane or cell preparation), in a cultured or isolated cell, or in a tissue or organ.
[0081] Preferably, the amount of C5a receptor modulator contacted with the receptor should be sufficient to inhibit the binding of C5a to the C5a receptor in vitro as measured, for example, using a radioligand binding assay, radioligand mobilization assay calcium, or chemotaxis assay as described herein.
[0082] In one embodiment of the invention, the C5a modulators of the invention are used to modulate, preferably inhibit, the signal transduction activity of a C5a receptor, for example, by contacting one or more compounds of the invention with a C5a receptor (in vitro or in vivo) under conditions suitable for binding the modulator(s) to the receptor. The receptor can 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 evaluated by detecting an effect on calcium ion mobilization or by detecting an effect on C5a receptor-mediated cell chemotaxis. In general, an effective amount of C5a modulator(s) is an amount sufficient to modulate the signal transduction activity of the C5a receptor in vitro within a C5a receptor-mediated cell chemotaxis or calcium mobilization assay within a migration test.
When the compounds of the invention are used to inhibit C5a receptor-mediated cellular chemotaxis, preferably leukocyte (e.g. neutrophil) chemotaxis, in an in vitro chemotaxis assay, such methods comprise contacting white blood cells (particularly primate white blood cells, especially human white blood cells) with one or more compounds of the invention. Preferably the concentration is sufficient to inhibit white blood cell chemotaxis in an in vitro chemotaxis assay, such that the levels of chemotaxis observed in a control assay are significantly higher, as described above, than the levels observed in a test to which a compound of the invention has been added.
[0084] In another embodiment, the compounds of the present invention are useful to facilitate organ transplants. In this embodiment, the compounds can be placed in a solution, with the organ prior to transplantation.
[0085] In another embodiment, the compounds of the present invention can be used to further treat patients suffering from conditions that are responsive to C5a receptor modulation. As used herein, the term "treat" or "treatment" encompasses both disease-modifying treatment and symptomatic treatment, each of which may be prophylactic (ie, prior to the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms) or therapeutic (ie, after the onset of symptoms, in order to reduce the severity and/or duration of symptoms). As used herein, 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 pets (such as dogs, cats, horses, and the like) and farm animals (such as cattle, pigs, sheep, and the like ), with dosages as described herein. Conditions that can be handled by C5a modulation:
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 bronchial, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), immunovasculitis, tissue graft rejection, hyperacute rejection of transplanted organs; and the like.
[0087] Inflammatory disorders and related conditions -- eg, Neutropenia, septicemia, septic shock, Alzheimer's disease, multiple sclerosis, stroke, inflammatory bowel disease (IBD), age-related macular degeneration (AMD, the forms both dry and wet), inflammation associated with severe burns, lung injury, and ischemia-reperfusion injury, osteoarthritis, as well as (adult) acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disorder (COPD), inflammatory response syndrome systemic (SIRS), atopic dermatitis, psoriasis, chronic urticaria and multiple organ dysfunction syndrome (MODS). Also included are pathological sequelae associated with insulin-dependent diabetes mellitus (including diabetic retinopathy), lupus nephropathy, Heyman's nephritis, membranous nephritis and other forms of glomerulonephritis, contact sensitivity responses, and inflammation resulting from blood contact with artificial surfaces that can cause complement activation, as occurs, for example, during extracorporeal circulation of blood (for example, during hemodialysis or via a heart-lung machine, for example, in association with vascular surgery such as graft coronary artery bypass or heart valve replacement), or in association with contact with other artificial vessel or container surfaces (eg, ventricular assist device, artificial heart machines, transfusion tube, blood storage bags, plasmapheresis, plateletpheresis, and the like). Also included are diseases related to ischemia/reperfusion injury, such as those that result from transplants, including solid organ transplantation, and syndromes such as ischemic reperfusion injury, ischemic colitis, and cardiac ischemia. The compounds of the present invention may also be useful in the treatment of age-related macular degeneration (Hageman et al, P.N.A.S, 102:7227-7232, 2005).
[0088] Cardiovascular and Cerebrovascular Disorders - eg, myocardial infarction, coronary thrombosis, vascular occlusion, postsurgical vascular reocclusion, atherosclerosis, traumatic central nervous system injury, and ischemic heart disease. In one embodiment, an effective amount of a compound of the invention can 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, high blood pressure, hypercholesterolemia, prior or genetic history of myocardial infarction or thrombosis) in order to reduce the risk of myocardial infarction or thrombosis.
[0089] Vasculitis Diseases - Vasculitis diseases are characterized by inflammation of the vessels. Leukocyte infiltration leads to destruction of vessel walls, and the complement pathway is believed to play a major role in the initiation of leukocyte migration as well as the resulting damage manifested at the site of inflammation (Vasculitis, Second Edition, Edited by Ball and Bridges, Oxford University Press, pp 47-53, 2008). The compounds provided in the present invention can be used to treat leukoclastic 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).
[0090] 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 and AIDS symptoms or infection.
[0091] Neurodegenerative Disorders and Related Diseases Within other aspects, the C5a antagonists provided herein can be used to treat Alzheimer's disease, multiple sclerosis, and decline in cognitive function associated with cardiopulmonary bypass surgery and related procedures.
[0092] Cancers - The C5a antagonists provided herein are also useful for the treatment of cancers and precancerous conditions in an individual. Specific cancers that can be treated include, but are not limited to, sarcomas, carcinomas, and mixed tumors. Exemplary conditions that may be treated in accordance with the present invention include fibrosarcomas, liposarcomas, chondrosarcomas, osteogenic sarcomas, angiosarcomas, lymphangiosarcomas, synoviomas, mesotheliomas, meningiomas, leukemias, lymphomas, leiomyosarcomas with squamous cells, squamous cell carcinomas, squamous cell carcinomas , adenocarcinomas, papillary carcinomas, cystadenocarcinomas, bronchogenic carcinomas, melanomas, renal cell carcinomas, hepatocellular carcinomas, transitional cell carcinomas, choriocarcinomas, seminomas, embryonic carcinomas, wilm tumors, pleomorphic adenomas, tubular adenomas, renal cell papillomas, , papillomas, adenomas, leiomyomas, rhabdomyomas, hemangiomas, lymphangiomas, osteomas, chondromas, lipomas and fibromas.
[0093] In another embodiment, the compounds of the present invention are useful in the treatment of cisplatin-induced nephrotoxicity. In this embodiment, compound treatment can alleviate cisplatin chemotherapy-induced nephrotoxicity of malignancies (Hao Pan et al, Am J Physiol Renal Physiol, 296, F496-504, 2009).
[0094] In one embodiment of the invention, the compounds of the invention can be used for the treatment of diseases selected from the group consisting of septicemia (and associated disorders), COPD, rheumatoid arthritis, lupus nephritis and multiple sclerosis.
The methods of treatment provided herein generally include administering to a patient an effective amount of one or more compounds provided herein. Suitable patients include those patients who are suffering from or susceptible to (i.e., prophylactic treatment) a disorder or disease identified herein. Typical patients for treatment as described herein include mammals, particularly primates, especially humans. Other suitable patients include domesticated pets such as a dog, cat, horse, and the like, or a farm animal such as cattle, pig, sheep and the like.
In general, methods of treatment provided herein comprise administering to a patient an effective amount of a compound of one or more compounds provided herein. In a preferred embodiment, the compound(s) of the invention are preferably administered to a patient (e.g. a human) orally or topically. The effective amount can be an amount sufficient to modulate C5a receptor activity and/or an amount sufficient to reduce or alleviate the symptoms exhibited 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, an administration frequency of 4 times a day or less is preferred. In general, a twice-daily dosing regimen is more preferred, with once-daily dosing 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 used, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination (ie, other drugs that are administered to the patient), and the severity of the particular disease undergoing therapy, as well as the judgment of the prescribing physician. In general, the use of the minimum dose sufficient to provide effective therapy is preferred. Patients in general can be monitored for therapeutic efficacy using medical or veterinary criteria appropriate to the condition being treated or prevented.
[0097] Dosage levels on the order of about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in treating or preventing conditions involving pathogenic C5a activity (from about 0.5 mg to about 7 g per human patient per day). The amount of active ingredient that can be combined with carrier materials 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 from about 1 mg to about 500 mg of an active ingredient. For compounds administered orally, transdermally, intravenously, or subcutaneously, it is preferred that sufficient amount of the compound is administered to obtain a serum concentration of 5 ng (nanograms)/ml to 10 μg (micrograms)/ml of serum, more preferably compound sufficient to obtain a serum concentration of 20 ng to 1 µg/ml of serum should be administered, most preferably sufficient compound to obtain a serum concentration of 50 ng/ml to 200 ng/ml of serum should be administered. For direct injection into the synovium (for the treatment of arthritis) sufficient compounds should be administered to achieve a local concentration of approximately 1 micromolar.
Dosing frequency may also vary depending on the compound used and the particular disease treated. However, for the treatment of most disorders, a dosing regimen of 4 times a day, three times a day, or less is preferred, with a once-daily or twice-daily dosing regimen 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 used, age, body weight, general health, sex, diet, time of administration, route of administration, and excretion rate, drug combination (ie, other drugs that are administered to the patient), the severity of the particular disease undergoing therapy, and other factors, including the judgment of the prescribing physician.
[0099] In another aspect of the invention, the compounds of the invention can be used in a variety of non-pharmaceutical applications in vitro and in vivo. For example, compounds of the invention can be labeled and used as probes for the detection and localization of C5a receptor (cell preparations or tissue section samples). The compounds of the invention can also be used as possible 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 the imaging of the positron emission tomography (PET) or for single photon emission computed tomography (SPECT). Such methods can be used to characterize C5a receptors in living individuals. For example, a C5a receptor modulator can be labeled using any of a variety of well-known techniques (eg, radiolabeled with a radionuclide such as tritium), and incubated with a sample for a suitable incubation time (eg, determined by first rehearsing a link time course). Following incubation, unbound compound is removed (eg, by washing), and bound compound detected using any method suitable for the label used (eg, autoradiography or scintillation counting for radiolabeled compounds; spectroscopic methods can be used to detect luminescent groups and fluorescent groups). As a control, a paired sample containing labeled compound and a larger amount (eg 10 times greater) of unlabeled compound can be processed in the same way. A greater amount of detectable label remaining in the test sample than in the control indicates the presence of C5a receptor in the sample. Detection assays, including receptor autoradiography (receptor mapping) of the C5a receptor on cultured cells or tissue samples can be performed as described by Kuhar in sections 8.1.1 through 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York.
[00100] The compounds provided herein can also be used within a variety of well-known cell separation methods. For example, modulators can be attached to the inner surface of a tissue culture dish or other support, for use as affinity ligands to immobilize, and thereby isolate, C5a receptors (e.g., isolate receptor-expressing cells) in vitro . In a preferred application, a modulator linked to a fluorescent marker, such as fluorescein, is contacted with the cells, which are then analyzed (or isolated) by fluorescence activated cell sorting (FACS).
[00101] In Figure 1, structures and activities are provided for the representative compounds described herein. Activity is provided as follows for binding assays as described herein: +, 500 nM < IC50 < 2000 nM; ++, 50 nM < IC 50 < 500 nM; +++, 5 nM < IC 50 < 50 nM; and ++++, IC50 < 5 nM. V. Examples
[00102] The following examples are offered to illustrate but not limit the claimed invention.
[00103] The reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). 1H-NMR spectra were recorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaks are given relative to TMS and are tabulated in order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and number of protons. Mass spectrometry results are reported as the ratio of mass to charge, followed by the relative abundance of each ion (in parentheses). In the examples, a single m/e value is reported for the M+H (or, as mentioned, M-H) ion containing the most common atomic isotopes. The isotope patterns match the expected formula in all cases. Electrospray ionization mass spectroscopy (ESI) analysis was conducted on a Hewlett-Packard MSD electrospray mass spectrometer using the HP1100 HPLC for sample release. Typically the analyte was dissolved in methanol at 0.1 mg/ml and 1 microliter was infused with the releasing 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 release solvent. The compounds provided below would also be analyzed in the negative ESI mode, using 2 mM NH4OAc in acetonitrile/water as the delivery system.
[00104] The following abbreviations are used in the Examples and throughout the description of the invention: EtOH: Ethanol EtONa: Sodium Ethoxide THF: Tetrahydrofuran TLC: Thin Layer Chromatography MeOH: Methanol Compounds within the scope of this invention can be synthesized as described below, using a variety of reactions known to the skilled technician. A person skilled in the art will also recognize that alternative methods can be used to synthesize the target compounds of this invention, and that the methods described within the body of this document are not exhaustive, but provide broadly applicable and practical pathways to the compounds of interest.
Certain molecules claimed in this patent may exist in different enantiomeric and diastereomeric forms and all such variants of these compounds are claimed.
[00106] The detailed description of the experimental procedures used to synthesize key compounds in this text lead to molecules that are described by the physical data that identify them as well as the structural representations associated with them.
[00107] Those skilled in the art will also recognize that during standard working procedures in organic chemistry, acids and bases are frequently used. Salts of precursor compounds are sometimes produced, if they possess the necessary intrinsic acidity or basicity, during the experimental procedures described within this patent. Example 1
[00108] Synthesis of cis-1-(2-fluoro-6-methyl-benzoyl)-2-phenylpiperidine-3-carboxylic acid (3-trifluoromethylphenyl)amide

[00109] a) Pd(PPh3)4 (3.0 g, 2.6 mmol) was added to a solution of 2-chloro-3-carboxyethylpyridine (25 g, 134.7 mmol), phenylboronic acid (21.04 g, 172.6 mmol) and K2CO3 (55.1 g, 399 mmol) in 1,4-dioxane (200 ml) and water (200 ml). The reaction mixture was heated at 100°C for 2 hours. The solution was then cooled to room temperature and dioxane was removed under reduced pressure. The resulting aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried (Na2SO4), filtered through celite, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 , 10 to 100% EtOAc/hexanes) to obtain the 2-phenylpyridine derivative in 91% yield (27.98 g). LC-MS Rt (retention time): 2.45 minutes, MS: (ES) m/z 228 (M + H+).
[00110] b) PtO2 (800 mg, 3.52 mmol) was added to a solution of 2-phenyl-nicotinic acid ethyl ester (20 g, 88 mmol, prepared in step a above) in EtOH (60 ml) and Concentrated HCl (15 ml). The reaction mixture was hydrogenated using a Parr shaker at 40 to 45 psi (276 to 310 kPa) for 1 hour. The reaction mixture was then filtered through celite, washed with EtOH, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with saturated NaHCO3. Purification by flash chromatography (SiO 2 , 0 to 20% MeOH/CH 2 Cl 2 ) gave the desired product in 85% yield (17.4 g). LC-MS Rt (retention time): 1.73 minutes, MS: (ES) m/z 234 (M + H+).
[00111] [0001] c) Oxalyl chloride (3.2 ml, 30.75 mmol) was added to the solution of 2-fluoro-6-methylbenzoic acid (3.79 g, 24.6 mmol) in CH2Cl2 ( 20 ml) in a reaction flask at room temperature, followed by the addition of a catalytic amount of DMF. The reaction was kept under stirring for 2 hours at room temperature. The solvent and excess oxalyl chloride were removed in vacuo and the residue was dried under high vacuum for 20 minutes. The resulting acid chloride was dissolved in dry 2Cl2 (20 ml) and cooled to 0°C followed by the addition of the piperidine manufactured in step b (5.56 g, 20.5 mmol) and Et3N (8.6 ml, 61.5 mmol). The mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with CH2Cl2 and water was added. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (MgSO4 ) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 , 10 to 35% EtOAc/hexanes) to give 7.47 g of the desired compound 99% yield). LC-MS Rt (retention time): 2.50 minutes and 2.58 minutes (two rotamers), MS: (ES) m/z 370 (M + H+).
[00112] d) Lithium aluminum hydride solution (2.0 M in THF, 8.2 ml, 16.4 mmol) was added to a solution of the ester from step c (2.98 g, 8.06 mmol) in THF (100 ml) at 0°C. The resulting solution was kept under stirring at 0°C for 2 hours at which time the reaction was completed. 15% aqueous NaOH (625 µl) was added dropwise to quench the reaction followed by H2O (625 µl). To the cloudy colloidal mixture, more water (1.85 ml) was added, and the mixture was kept under stirring for 1 hour at room temperature. The mixture was then filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO 2 , 33 to 67% EtOAc/hexanes) gave 2.46 g of desired product (93% yield). LC-MS: Rt (retention time): 1.90 minutes and 2.09 minutes (two rotamers), MS: (ES) m/z 328 (M + H+).
[00113] e) A solution of the alcohol from step d (1.42 g, 4.33 mmol) in acetic acid (65 ml) was added to a slurry of CrO3 (2.61 g, 26.1 mmol) in H2O (16 ml) at room temperature. The resulting mixture was kept under stirring at room temperature until the reaction was complete (90 min). The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO 2 , 3 to 10% CH 2 Cl 2 : MeOH followed by 50 to 67% EtOAc/hexanes) gave 1.03 g of desired product (70% yield). LC-MS: Rt (retention time): 1.88 minutes and 2.12 minutes (two rotamers), MS: (ES) m/z 342 (M + H+).
[00114] f) 3-trifluoromethylaniline (16.2 mg, 0.1 mmol, 1.0 eq) was added to a solution of the acid prepared above (34.2 mg, 0.1 mmol) and triethylamine (6 eq) in CH2Cl2 (1 ml). T3P (95.5 mg, 0.15 mmol) was then slowly added and the solution was allowed to stir at room temperature for 1.5 hours. The reaction mixture was diluted with CH2Cl2 (1 ml), washed with 1N aqueous HCl followed by saturated aqueous NaHCO3. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under reduced pressure. Purification by flash chromatography (SiO 2 , 5 to 40% EtOAc/hexanes) gave 35 mg (73% yield) of the product as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.22 - 2.45 (m, 8H), 2.93 - 3.32 (m, 3H), 6.77 - 7.82 (m, 12H) , 9.10 (s, 0.38H), 9.30 (s, 0.62H). LC-MS: Rt (retention time) = 2.88 minutes, MS: (ES) m/z 485 (M + H+). Example 2
[00115] Synthesis of N-(3-tert-butylphenyl)-1-(5-chloro-3-methylpicolinoyl)-2-phenylpiperidine-3-carboxamide

[00116] a) chloronicotinoyl chloride (1.05 eq) dissolved in anhydrous dichloromethane (0.5 M) was added to a solution of 3-tert-butylaniline (1 eq) and 2 M aqueous K2CO3 (2.2 eq) in anhydrous dichloromethane (0.5M) at 0°C over a period of 30 minutes, and the reaction mixture was allowed to stir at room temperature for a further 1.5 hour. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried (MgSO 4 ), filtered and concentrated to give the desired amide as a foamy solid which was used as such in the next step without further purification. MS: (ES) m/z 289.1 (M + H+).
[00117] b) Pd(PPh3)4 (2 to 5% in mol) was added to a solution of the above pyridine amide (1 eq), phenylboronic acid (1.4 eq) and 2 M aqueous K2CO3 (2.4 eq ) in toluene (0.7M) and the reaction mixture was heated at 100°C overnight (~12 hours). After cooling to room temperature, the reaction mixture was filtered through celite and the celite plug was washed with EtOAc. The filtrate was diluted with water and extracted with EtOAc, dried (MgSO4), filtered and concentrated and concentrated under reduced pressure. The residue was purified by automated flash chromatography (SiO2, gradient 10% to 100% EtOAc-hexanes) and dried in vacuo to give 2-phenyl-3-carboxyamidopyridine in 60 to 75% yield, MS: (ES) m/z 331.2 (M + H+).
[00118] c) PtO2 (10 mol%) was added to a solution of the 2-phenylpyridine derivative prepared above (1 eq) in EtOH and concentrated HCl (excess, 4:1 ratio) and the reaction mixture was hydrogenated using a Parr shaker at 40 to 45 psi (276 to 310 kPa) for 1.5 hour. It was filtered through celite, washed with EtOH, and the filtrate was concentrated. The residue was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The residue was then purified by automated flash chromatography (SiO 2 , 1% to 30% gradient of CH 2 Cl 2 -MeOH) and dried in vacuo to give the title compound in ~85% yield as a foamy solid. MS: (ES) m/z 337.2 (M + H+).
[00119] d) 5-chloro-3-methylpicolinic acid (30 mg, 0.16 mmol) and N-(3-tert-butylphenyl)-2-phenylpiperidine-3-carboxamide (50 mg, 0.15 mmol, prepared in step c above) were dissolved in anhydrous DMF (1 ml). N,N-Diisopropylethylamine (0.15ml) was added at room temperature followed by HCTU (67mg, 0.16mmol). After stirring 2 hours at room temperature, LC-MS and TLC indicated the completion of the reaction. The reaction mixture was diluted with EtOAc (50 ml) and washed with 1N HCl (20 ml), saturated NaHCO3 (30 ml), and brine (30 ml) and the resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (20% de 95% MeCN-H2O with 0.1% TFA) and pure fractions were lyophilized to yield the title compound (50 mg, 67% yield). HPLC retention time = 2.88 minutes. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, 1H, J = 0.8Hz), 7.97 (br, 1H), 7.59 (d, 1H, J = 0.8 Hz), 7.56 (d, 1H, J = 7.6Hz), 7.34 (m, 3H), 7.20 (m, 3H), 7.10 (d, 1H, J = 7.6 Hz), 6.61 (two sets of br, 1H), 3.12 (two sets of m, 2H), 2.94 (three sets of m, 1H), 2.36 ( s, 3H), 2.20 (two sets of br, 2H), 1.74 (complex of br, 2H), 1.29 (s, 9H). MS: (ES) m/z 490.2 (M + H+). Example 3
[00120] Synthesis of cis-1-(2-methylbenzoyl)-2-(3-fluorophenyl)piperidine-3-carboxylic acid (3-tert-butylphenyl)amide

[00121] [0002] a) To a mixture of N-(3-tert-butylphenyl)-2-chloronicotinamide (570.2 mg, 2 mmol), 3-fluorophenylboronic acid (401.2 mg, 2.8 mmol) , 3 ml of toluene, and 1 ml of 2N potassium carbonate in water was added tetrakis(triphenylphosphine)palladium (0) (234.5 mg, 0.2 mmol). The mixture was then heated at 90°C for 3 hours under nitrogen, before it was cooled to room temperature. The reaction mixture was then diluted with 30 ml of water and 150 ml of EtOAc. The organic layer was separated, washed with brine, and dried (Na2SO4). The organic solvent was removed under reduced pressure and the residue was purified by silica gel column (40% EtOAc in hexanes) to give N-(3-tert-butylphenyl)-2-(3-fluorophenyl)nicotinamide (691, 4mg, 99%). MS: (ES) m/z 394.5 (M + H+).
[00122] b) A mixture of N-(3-tert-butylphenyl)-2-(3-fluorophenyl)-nicotinamide (501.2 mg, 1.4 mmol), platinum oxide (51.9 mg, 0, 21 mmol), and concentrated HCl (400 µl, 5.2 mmol) in 5 ml ethanol was stirred vigorously under hydrogen balloon overnight. The mixture was filtered, and the solids washed with 25 ml of methanol three times. The combined solution was dried under reduced pressure. To the residue were added 30 ml of saturated sodium bicarbonate and 150 ml of EtOAc. The organic layer was separated, and dried over sodium sulfate. Evaporation of solvent gave crude 2-(3-fluorophenyl)-piperidine-3-carboxylic acid (3-tert-butylphenyl)amide as a brown solid, which was used directly for the next step. MS: (ES) m/z 355.7 (M + H+).
[00123] c) To a solution of 2-(3-fluorophenyl)piperidine-3-carboxylic acid (3-tert-butylphenyl)amide (prepared above, 177.3 mg, 0.5 mmol) in 2 ml of dichloromethane Et3N (100 µl, excess), and 2-methylbenzoyl chloride (92.3 mg, 0.6 mmol) was added at room temperature. The resulting solution was then stirred at this temperature until completion of the reaction (10 minutes). The reaction mixture was then directly loaded onto a silica gel column, and purified by using ISCO (30% EtOAc in hexanes) to give the final product of 2-(3-tert-butylphenyl)amide. 3-fluorophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid (151.2 mg, 64% yield). 1H NMR (400 MHZ, CDCl 3 , mixture of rotamers): δ 7.91 (s, 0.6H), 7.85 (s, 0.4H), 7.18 - 7.46 (m, 9H ), 7.11 (m, 1 H), 6.95 (m, 1 H), 6.67 (d, J = 1.2 Hz, 1 H), 3.36 (d, J = 1.6 Hz, 0.4H), 3.26 (d, J = 1.6Hz, 1H), 3.05 (m, 1H), 2.89 (t, J = 1.2Hz, 1H ), 2.45 (s, 1H), 2.02 - 2.40 (m, 4H), 1.70 - 1.84 (m, 3H), 1.44 - 1.64 (s, 1H), 1.32 (s, 6H), 1.25 (s, 1H). MS: (ES) m/z 473.2 (M + H+). Example 4
[00124] Synthesis of cis-1-(2-methylbenzoyl)-2-(2,2-dimethylpropyl)piperidine-3-carboxylic acid (3-tert-butylphenyl)amide

[00125] a) To a stirred solution of 2-bromonicotinic acid (1.01 g, 5 mmol) dissolved in anhydrous dichloromethane (8 ml) were added EDCI (1.34 g, 7 mmol) and 3-tert-butylaniline ( 0.74 g, 5 mmol) at room temperature and the reaction mixture was stirred for 12 hours. The mixture was then diluted with dichloromethane, followed by washing with saturated sodium bicarbonate and water. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to obtain 2-bromo-N-(3-tert-butylphenyl)nicotinamide in 59% yield (950 mg). Rt: 2.44 minutes (method 20-100-5). MS: (ES) m/z 333, 335 (M + H+).
[00126] b) 2,2-dimethylpropylmagnesium chloride (1M-diethylether, 4.8ml, 4.8mmol) was added to a suspension of copper cyanide (215mg, 2.40mmol) in THF ( 6 ml) at -78°C. After stirring at the same temperature for 1 hour, 2-bromo-N-(3-tert-butylphenyl)nicotinamide (200 mg, 0.601 mmol) was added all at once as a solid. The reaction mixture was gradually warmed to room temperature and the reaction was allowed to stir overnight. A saturated solution of ammonium chloride and ethyl acetate was added, and the reaction mixture was filtered through celite and rinsed with ethyl acetate. The layers were separated and the product was extracted once more with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After removal of solvent under reduced pressure, the crude material was purified using column chromatography on silica gel using a gradient of 20% to 50% ethyl acetate in hexanes to yield N-(3-tert-butylphenyl)-2 -(2,2-dimethylpropyl)-nicotinamide (168 mg, 0.517 mmol, 86%). Rf = 0.45 (toluene : ethyl acetate = 2 : 1).
[00127] c) N-(3-tert-Butylphenyl)-2-(2,2-dimethylpropyl)nicotinamide (168 mg, 0.517 mmol) was dissolved in ethanol (5 ml). Platinum oxide (11.6 mg, 0.0511 mmol) was added followed by concentrated hydrochloric acid (250 µl). The reaction mixture was hydrogenated using a Parr apparatus for 1.5 hours at 45 psi (310 kPa). Analysis of the reaction mixture showed incomplete conversion, and the sequence was repeated once more. Platinum oxide was filtered off and solvents were removed under reduced pressure. The crude material was neutralized using saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was then washed with brine and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave crude 2,3-cis-2-(2,2-dimethylpropyl)piperidine-3-carboxylic acid (3-tert-butylphenyl)amide (153 mg) which was used in the next step without further purification.
[00128] d) To a solution of 2,3-cis-2-(2,2-dimethylpropyl)piperidine-3-carboxylic acid 3-tert-butylphenyl)amide ( (84.8 mg, 0.257 mmol) in pyridine (415 µl, 5.13 mmol) at room temperature was added 2-methylbenzoyl chloride (81.6 mg, 0.528 mmol) in chloroform (415 µl) A catalytic (unweighed) amount of dimethylaminopyridine was added to enhance the reaction and the mixture was stirred for three days. Ethyl acetate and water were then added to the reaction mixture and the product was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the crude material was purified by silica gel chromatography using 10% to 20% ethyl acetate in hexanes to give 2,3-cis-2 acid (3-tert-butylphenyl)amide -(2,2-dimethylpropyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid (47.0 mg, 0.105 mmol, 41%) Rf = 0.6 (hexanes: ethyl acetate = 2 : 1). Rt = 3.16 minutes, 3.26 minutes. (Compound exists as mixtures of various conformers. Method 20-100-5). 1H NMR (CDCl 3 ) δ 9.68 (s, 1H), 9.43 (s, 1H), 8.33 (s, 1H), 8.28 (s, 1H)), 6.97 - 7.79 (m, 8 H), 5.48 (br, 1 H), 5.39 (dd, J = 4, 10 Hz, 1 H), 5.33 (dd, J = 6.6 Hz , 1 H), 3.38 (ddd, J = 4, 14, 14 Hz, 2 H), 3.25 (dd, J = 13. 13 Hz, 2 H), 2.66 (dd, J = 4 , 8.4Hz, 1H), 2.63 (ddd, J = 2.8, 2.8, 8Hz, 1H), 2.50 (s, 9H), 2.40 (s, 9 H), 2.25 (s, 9H), 2.13 (s, 9H), 1.79 - 1.99 (m, 2H), 1.23 - 1.56 (m, 2H) , 1.32 (s, 9H), 1.07 (s, 9H), 1.06 (s, 9H), 0.97 (s, 9H), 0.95 (s, 9H) . MS: (ES) m/z 449 (M + H+). Example 5
[00129] Synthesis of cis-2-cyclopentyl-1-(2-methylbenzoyl)piperidine-3-carboxylic acid (3-tert-butylphenyl)amide

[00130] a) Cyclopentylzinc bromide (0.5 M, 6.5 ml, 3.26 mmol) was added to a stirred at room temperature solution of 2-chloronicotinic acid methyl ester (400 mg, 2.33 mmol) , CuI (19mg, 0.1mmol) and Pd(dppf)Cl 2 (42mg, 0.06mmol) in anhydrous dimethylacetamide (1.7ml) under nitrogen. The reaction mixture was heated to 70°C for 3.5 hours, cooled to room temperature, filtered through celite, and the cake rinsed with ethyl acetate. The filtrate was washed with water, brine, dried (MgSO4), filtered and concentrated under reduced. The residue was purified by flash chromatography (SiO 2 from 10 to 100% EtOAc/hexanes) to obtain the desired compound in 83% yield (400 mg). LC-MS Rt (retention time): 1.87 min; MS: (ES) m/z 206 (M + H+).
[00131] b) n-BuLi (1.47 ml, 3.68 mmol) was added to 3-tert-butylaniline (580 mg, 3.89 mmol) at -78°C in dry THF (2 ml) under nitrogen and the solution was allowed to stir at 0°C for 10 minutes. The reaction mixture was re-cooled to -78°C and 2-cyclopentyl-nicotinic acid methyl ester (400 mg, 1.94 mmol) dissolved in dry THF (2 ml) was added thereto. The reaction mixture was allowed to reach 0°C over a period of 2 hours, quenched with saturated aqueous NH4Cl, and extracted with ethyl acetate. The combined organic layers were dried (MgSO4 ), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 from 10 to 100% EtOAc/hexanes) to give the pure compound in 91% yield (572 mg). LC-MS Rt (retention time): 2.61 min; MS: (ES) m/z 323 (M + H+).
[00132] c) To a solution of N-(3-tert-butylphenyl)-2-cyclopentyl-nicotinamide (570 mg, 1.77 mmol) in ethanol (10 ml) containing concentrated HCl (1 ml) was added sodium oxide platinum (40 mg, 0.17 mmol) and the solution was hydrogenated using a Parr shaker at 40 psi (276 kPa) for 1.5 hour. The reaction mixture was filtered through celite, and the cake was rinsed with ethanol. The filtrate was concentrated, and the residue was dried under high vacuum for 2 hours to obtain quantitative yield of the desired piperidine as an HCl salt. LC-MS Rt (retention time): 1.97 min; MS: (ES) m/z 329 (M + H+).
[00133] d) To a solution of cis-2-cyclopentylpiperidine-3-carboxylic acid (3-tert-butyl-phenyl)amide prepared above (123 mg, 0.34 mmol) in dry CH 2 Cl 2 (1 ml) containing Et 3 N (142 µl, 1.02 mmol) was added 2-methylbenzoyl chloride (53 mg, 0.34 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with ethyl acetate (20 ml), washed with 1N aqueous HCl, water, and brine. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (20 to 95% CH 3 CN-H 2 O gradient) and dried (Lyophilizer) to give the title compound in 65% yield (109 mg). 1H NMR (400 MHz, CDCl3): δ 1.22 - 1.48 (m, 11H), 1.56 - 1.80 (m, 5H), 1.84 - 2.06 (m, 4H) ), 2.10 - 2.23 (m, 1H), 2.30 (s, 1.6H), 2.39 (s, 1.4H), 2.41 - 2.50 (m, 1H), 2.71 - 2.76 (m, 1H), 3.02 - 3.09 (m, 1H), 3.25 - 3.39 (m, 1H), 5.11 ( bs, 1H), 7.05 - 7.30 (m, 6H), 7.47 - 7.55 (m, 2H), 8.32 (bs, 1H). LC-MS Rt (retention time): 3.16 min; MS: (ES) m/z 447 (M + H)+. LC-MS Method: Agilent Zorbax SB-C18, 2.1x 50mm, 5μ, 35°C, flow rate 1ml/min, a 2.5 minute gradient from 20% to 100% B with a wash of 1.0 minutes at 100% B; A = 0.1% formic acid / 5% acetonitrile / 94.9 water, B = 0.1% formic acid / 5% water / 94.9 acetonitrile. Example 6
Synthesis of (2R, 3S)-2-(4-Acid (3-chloro-4-methylphenyl)amide)

[00135] b) cis-2-(4-tert-butoxycarbonylamino-phenyl)-piperidine-3-carboxylic acid ethyl ester was synthesized similarly as illustrated in example 1.
[00136] [0003] c:1): cis-2-(4-tert-butoxycarbonylamino-phenyl)-piperidine-3-carboxylic acid ethyl ester (61 g, 174.8 mmol) and di-p-toluoyl-acid L-tartaric (62 g, 174.8 mmol) were dissolved in EtOH (500 ml). The clear solution was concentrated and pumped dry. The white salt obtained was then dissolved in 250 ml of ethyl acetate to form a clear solution. To this solution 500 ml of TBME was added slowly. The solution obtained was left at room temperature undisturbed for 3 days. At that time a batch of white crystals were formed. They were then filtered and washed with 100 ml of TBME to obtain a white solid (60 g).
[00137] The above salt was redissolved in ethanol, concentrated and pumped until dry. The salt obtained was dissolved in 500 ml of THF, followed by the addition of TBME (500 ml). The clear solution obtained was left at room temperature undisturbed for another 2.5 days. The white crystals obtained were filtered to obtain 20.5 g (64 : 1 enrichment) of the salt.
[00138] c:2) To a stirred at 0°C suspension of the salt (16.7 g) in CH 2 Cl 2 (150 ml) was added saturated aqueous NaHCO 3 solution (100 ml) and the reaction mixture was allowed to stir at temperature environment in a period of 30 minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2 (50 ml). The combined organic layer was washed with saturated aqueous NaHCO3 (2 X100 ml), dried and concentrated to give (2R, 3S)-2-(4-tert-Butoxycarbonylaminophenyl)-piperidine-3-carboxylic acid ethyl ester in 90% of yield e ~ 97% ee.
To a 0°C solution of (2R,3S)-2-(4-tert-butoxycarbonylaminophenyl)-piperidine-3-carboxylic acid ethyl ester prepared above (600 mg, 1.72 mmol) in Dry CH2Q2 (5 ml) containing EtβN (480 µl, 3.44 mmol) was added 2-methylbenzoyl chloride (266 mg, 1.72 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with CH2Cl2 (20 mL), washed with 1N aqueous HCl, water, and brine. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to give (2R, 3S)-2-(4-tert-butoxycarbonylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester in quantitative yield and the crude product was used as such in the next step.
[00140] e) 4N HCl in 1,4-dioxane (5 ml, 20 mmol) was slowly added to a 0°C solution of the above crude product (2R, 3S)-2-(4- tert-butoxycarbonylaminophenyl)-1-(2-methylbenzoyl)-piperidine-3-carboxylic acid (840 mg, 1.72 mmol) in dry CH 2 Cl 2 (4 ml). After addition of HCl, the reaction mixture was allowed to reach room temperature and stirred for 1 hour. It was diluted with CH 2 Cl 2 (30 ml), cooled to 0°C and neutralized with saturated aqueous NaHCO 3 to obtain the acid ethyl ester (2R, 3S)-2-(4-aminophenyl)-1-(2-methylbenzoyl) -Piperidine-3-carboxylic acid (612 mg) in 97% yield over two steps.
[00141] f) Na(OAC)3BH (495 mg, 2.33 mmol) was added to a solution of (2R, 3S)-2-(4-aminophenyl)-1-(2-methyl-) acid ethyl ester. benzoyl)piperidine-3-carboxylic acid (612 mg, 1.67 mmol), cyclopentanone (140 mg, 1.67 mmol) and acetic acid (100 mg, 1.67 mmol) in dry dichloroethane at room temperature and the reaction mixture it was heated to 50°C for 4 hours, cooled to room temperature and stirred for 48 hours. It was then diluted with CH 2 Cl 2 (30 ml), washed with a saturated aqueous solution of NaHCO 3 , dried and concentrated in vacuo. The residue was purified by the ISCO scintillating column using ethyl acetate and hexanes as the mobile phase (40 g column, 0 to 40% gradient) to yield (2R, 3S)-2-(4-cyclopentylaminophenyl)-1 acid ethyl ester -(2-Methylbenzoyl)-piperidine-3-carboxylic acid (450 mg).
[00142] g) MesAl (290 µl, 0.57 mmol, 2 M in toluene) was added to a solution of 3-Chloro-4-methylphenylamine (65 mg, 0.46 mmol) in dry dichloroethane (1 ml) in the room temperature. Stirred for 20 minutes, then (2R,3S)-2-(4-cyclopentylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester (100mg, 0.23mmol) dissolved in dry dichloroethane (1 ml) was added thereto. The reaction mixture was then heated to 85°C for 3 hours, cooled to room temperature, diluted with CH 2 Cl 2 (20 ml), washed with saturated aqueous NaHCO 3 solution. The aqueous layer was extracted with CH 2 Cl 2 (20 ml) and the combined organic layer was dried (MgSO 4 ) and concentrated. The residue was purified by preparative reverse phase HPLC (20 to 95% CH3CN-H2O gradient with 0.1% TFA as an additive), the product-containing fractions were pooled together and concentrated. The residue was diluted with CH2Cl2 (30 ml), washed with saturated aqueous NaHCO3 solution. The CH2Cl2 layer was dried (MgSO4) and concentrated to obtain (2R,3S)-2-(4-cyclopentylaminophenyl)-1-(2-methyl-benzoyl) acid (3-chloro-4-methyl-phenyl)amide pure )piperidine-3-carboxylic acid in 50% yield.
1H NMR (400 MHz, CDCl3) δ 8.4 (bs, 1H), 7.55 (s, 1H), 7.37 - 7.05 (m, 9H), 6.55 - 6.52 (m, 2H), 3.77 - 3.70 (m, 1H), 3.30 - 3.16 (m, 1H), 3.04 - 2.91 (m, 2H) ), 2.43 - 1.94 (m, 8H), 1.71 - 1.46 (m, 11H). Example 7
Synthesis of ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylate.

[00145] Step a) To a solution of (2R,3S)-2-(4-tert-butoxycarbonylaminophenyl)-piperidine-3-carboxylic acid ethyl ester (13.74 g, 39.36 mmol, prepared as in WO 2010/075257), 2-fluoro-6-methylbenzoic acid (6.37 g, 41.33 mmol) and Et3N (14.4 ml, 102.3 mmol) in dry DMF (110 ml) at 0°C was added HATU (15.71 g, 41.33 mmol) and the mixture was then stirred at room temperature for 3 hours. The reaction mixture was then diluted with water, extracted with ethyl acetate, and washed with brine. The combined organic layers were dried (MgSO4 ), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 from 10 to 55% ethyl acetate in hexanes) to give 19 g (100%) of the product (2R,3S)-2-[4-(tert-butoxycarbonylamino)phenyl] Ethyl -1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylate. MS: (ES) m/z 485 (M + H+)
[00146] Step b) 4N HCl in 1,4-dioxane (110 ml, 440 mmol) was slowly added to a solution of the above (2R, 3S)-2-[4-(tert-butoxycarbonylamino)phenyl]-1 Ethyl -(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylate (19 g, 39.36 mmol) in dry CH 2 Cl 2 (110 ml) at 0°C. After addition of HCl, the reaction mixture was allowed to reach room temperature and stirred for 3 hours. The solution was then diluted with ethyl acetate (200 ml), cooled to 0°C, and neutralized with saturated aqueous NaHCOβ to obtain (2R, 3S)-2-(4-aminophenyl)-1-(2-fluoro-6). - ethyl methylbenzoyl)piperidine-3-carboxylate (15 g, 100%). MS: (ES) m/z 385 (M + H+).
Step c) NaBH(OAc)3 (14.12 g, 66.60 mmol) was added to a solution of (2R, 3S)-2-(4-aminophenyl)-1-(2-fluoro-6) ethyl -methylbenzoyl)-piperidine-3-carboxylate (16 g, 41.65 mmol), and cyclopentanone (10.51 g, 125 mmol) in dry dichloroethane (200 ml) at room temperature. The reaction mixture was heated to 45°C for 3 hours, cooled to room temperature, quenched with saturated aqueous NaHCO3 solution, extracted with dichloromethane, dried and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, ethyl acetate/hexanes 15 to 40%) to yield (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl ethyl )piperidine-3-carboxylate as a white solid (17 g, 90%). MS: (ES) m/z 453 (M + H+).
[00148] Synthesis of (2R, 3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-(hydroxymethyl)-3-(trifluoromethyl) phenyl] piperidine-3-carboxamide

[00149] Step a) Ethyl (2R, 3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylate (2 g, 4.4 mmol) in 1,4-dioxane (9 ml) was added to aqueous 3N HCl (6 ml) at room temperature and the reaction mixture was heated at 80°C for 15 hours. The solution was then cooled to 0°C and neutralized with saturated aqueous NaHCO3 and extracted with ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO 2 , 20% EtOAc in CH 2 Cl 2 ) to obtain the desired acid (1.4 g, 74%). MS: (ES) m/z 425 (M + H+).
[00150] Step b) Methanesulfonyl chloride (378 mg, 3.3 mmol) was added to a solution of (2R, 3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6) acid -methyl-benzoyl)piperidine-3-carboxylic acid prepared above (1.4 g, 3.3 mmol) and Hunig's base (586 µl, 3.3 mmol) in dry CH 2 Cl 2 (25 ml) at 0°C under one atmosphere of nitrogen. The solution was stirred for a further 15 minutes, then [4-amino-2-(trifluoromethyl)phenyl]methanol (631 mg, 3.3 mmol) and Hunig's base (586 µl, 3.3 mmol) were added sequentially. The reaction mixture was allowed to reach room temperature over a period of 30 minutes. When TLC and LCMS indicated the completion of the reaction, excess solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO 2 , 0 to 20% ethyl acetate in dichloromethane) to obtain the desired compound (1.2 g) in 61% yield. 1H NMR (400 MHz, CDCl3) δ 9.50 (bs, 0.6H), 9.38 (bs, 0.4H), 7.75 - 7.70 (m, 1H), 7.50 - 7.33 (m, 3H), 7.24 - 7.19 (m, 2H), 7.06 - 6.90 (m, 2H), 6.67 - 6.55 (m, 3 H), 4.77 - 4.76 (m, 2H), 3.78 - 3.66 (m, 1H), 3.32 - 3.00 (m, 3H), 2.44 - 1 .45 (m, 17H). MS: (ES) m/z 598 (M + H+). Example 8
Synthesis of 4-[[(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carbonyl]amino]-2- (trifluoromethyl) benzoic.

[00152] The title compound was synthesized in a similar manner as the above example: 1H NMR (400 MHz, CD3OD) δ 10.4 (br, 1H), 8.05 - 7.65 (m, 4H) , 7.36 - 6.95 (m, 5H), 6.50 - 6.47 (m, 1H), 3.92 - 3.94 (m, 1H), 3.50 - 3.21 (m, 3H), 2.50 - 1.59 (m, 18H). MS: (ES) m/z 612 (M + H+). Example 9
[00153] Synthesis of cis-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-formyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide.

To a solution of cis-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-(hydroxymethyl)-3-(trifluoromethyl)phenyl] - piperidine-3-carboxamide (130 mg, 0.22 mmol) in 1,2-dichloroethane (2 ml) was added MnO2 (380 mg, 4.4 mmol) at room temperature. The reaction mixture was stirred for 3 hours and was then diluted with dichloromethane, filtered through a plug of SiO 2 , and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to obtain the desired compound (as a mixture of cis enantiomers) in 31% yield (40 mg). 1H NMR (400 MHz, CDCl3) δ 10.2 (bs, 1H), 8.12 - 6.88 (m, 10H), 3.82 - 3.04 (m, 4H), 2.88 - 1.40 (m, 18H). MS: (ES) m/z 596 (M + H+). Example 10
[00155] (2R, 3S)-2-(4-aminophenyl)-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide .

[00156] The title compound was synthesized in a similar manner as the above examples: 1HRMN (400 MHz,CDCl3) δ 9.21 (br, 0.6H), 8.91 (br,0.4H), 7.67 (d, J = 2.2 Hz, 0.4 H), 7.60 (d, J = 2.2 Hz, 0.6 H), 7.51 - 7.47 (m, 1 H ), 7.41 (d, J = 8.4 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 7.24 - 7.03 (m, 2 H), 6.95 - 6.84 (m, 2H), 6.68 (d, J = 5.5Hz, 1H), 6.62 - 6.60 (m, 1H), 3.65 (br , 2H), 3.28 - 2.96 (m, 3H), 2.44 (s, 1H), 2.41 - 2.38 (m, 3H), 2.11 (s, 3 H), 1.80 - 1.74 (m, 1H), 1.70 (s, 3H). MS: (ES) m/z 514 (M + H+) Example 11
[00157] The following are representative compounds prepared and evaluated using methods similar to the examples here. Characterization data are provided for the compounds below. Biological evolution is shown in Figure 1 for these compounds and others prepared as described herein.
[00158] (2R, 3S)-2-(4-cyclopentyl-aminophenyl)-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylic acid (4-methyl-3-trifluoromethylphenyl)amide

[00159] 1H NMR (400 MHz, TFA-d) δ 7.91 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 8.6Hz, 1H), 7. 58 - 6.82 (m, 8H), 6.75 (t, J = 8.6Hz, 1H), 4.10 - 4.00 (m, 1H), 3.60 - 3.47 (m, 1H), 3.45 - 3.41 (m, 1H), 3.33 - 3.25 (m, 1H), 2.44 - 2.22 (m, 7H), 2 .04 - 1.92 (m, 4H), 1.82 -.169 (m, 7H)
[00160] (2R,3S)-1-(2-chloro-benzoyl)-2-(4-cyclopentylaminophenyl)piperidine-3-carboxylic acid (4-methyl-3-trifluoromethylphenyl)amide

[00161] 1H NMR (400 MHz, CDCl3) δ 9.41 (bs, 0.5H), 9.03 (bs, 0.5H), 7.55 (s, 1H), 7.49 - 7.39 (m, 3H), 7.31 - 7.27 (m, 2H), 7.18 - 7.04 (m, 2H), 6.83 - 6.74 (m, 3H) ), 3.76 - 3.64 (m, 1H), 3.22 - 2.90 (m, 5H), 2.39 (s, 3H), 2.32 - 2.20 (m, 1H), 2.16 - 2.04 (m, 1H), 2.0 - 1.86 (m, 2H) 1.80 - 1.72 (m, 3H), 1.56 (bs , 5 h).
(2R, 3S)-2-(4-Cyclopentylaminophenyl)-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylic acid (3-chloro-4-methylphenyl)amide

[00163] 1H NMR (DMSO-d6) δ 10.22 (s, 1H), 7.67 (dd, J = 1.8 Hz, J = 11.0 Hz, 1H), 7.04 - 7 .33 (m, 9H), 6.30 (dd, J=5.8Hz, J=9.4Hz, 1H), 5.52 (br, 1H), 3.56 - 3.64 (m, 1H), 3.00 - 3.17 (m, 2H), 2.90 - 2.98 (m, 1H), 2.23 (2.24) (s, 3H), 1.97(2.33) (s, 3H), 1.32 - 2.22 (m, 12H)
[00164] (2R,3S)-1-(4-chloro-benzoyl)-2-(4-Cyclopentylaminophenyl)piperidine-3-carboxylic acid (4-methyl-3-trifluoromethylphenyl)amide

1H NMR (400 MHz, CDCl 3 ) δ 8.79 (bs, 1H), 7.62 (s, 1H), 7.52 - 7.48 (m, 1H), 7.37 - 7.30 (m, 5H), 7.13 (d, J = 8.4Hz, 1H), 6.52 - 6.50 (m, 3H), 3.75 - 3.69 (m , 1H), 3.44 (bs, 1H), 3.09 - 2.97 (m, 2H), 2.39 (s, 3H), 2.37 - 2.30 (m, 1 H), 2.13 - 2.08 (m, 1H), 2.10 - 1.93 (m, 2H), 1.80 - 1.59 (m, 7H), 1.48 - 1 .42 (m, 2H)
[00166] (2R,3S)-2-(4-Cyclohexylaminophenyl)-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylic acid (3-t-butylphenyl)amide

[00167] 1H NMR (400 MHz, CDCl3) : δ 8.24 (m, 1H), 7.40 - 6.85 (m, 8H), 6.65 - 6.40 (m, 3H) , 3.57 (s, 1H), 3.30 - 2.90 (m, 4H), 2.50 - 1.85 (m, 9H), 1.80 - 1.50 (m, 5 H), 1.40 - 1.00 (m, 13 H)
[00168] (2R,3S)-2-(4-cyclopentyl-aminophenyl)-1-(2-fluoro-6-methylbenzoyl)piperidine-acid (4-methyl-3-pyrrolidin-1-yl-phenyl)amide 3-carboxylic

[00169] 1H NMR (400 MHz, CDCl3): δ 7.98 (m, 1H), 7.40 - 7.18 (m, 3H), 7.10 - 6.80 (m, 4H) , 6.64 - 6.40 (m, 3H), 3.80 - 3.50 (m, 2H), 3.30 - 2.90 (m, 6H), 2.50 - 2.10 (m, 7H), 2.10 - 1.80 (m, 8H), 1.80 - 1.20 (m, 9H)
[00170] (2R,3S)-2-[4-(cyclopentyloxy)phenyl]-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylic acid (3-chloro-4-methylphenyl)amide

[00171] 1H NMR (400 MHz, CDCl3) δ 8.68 (bs, 0.6H), 8.58 (bs, 0.4H), 7.59 - 7.40 (m, 3H), 7 .29 - 6.90 (m, 4H), 6.80 (m, 2H), 6.65 (m, 1H), 4.72 (m, 1H), 3.30 - 2.92 (m, 3H), 2.44 (s, 1H), 2.42 - 2.30 (m, 1H), 2.30 (s, 1H), 2.29 (s, 2H) , 2.20 (s, 2H), 2.19 - 2.12 (m, 1H), 2.08 - 1.92 (m, 2H), 1.90 - 1.72 (m, 7 H) 1.60 (m, 2H).
(±)-(2R, 3S)-2-(4-cyclopentylamino-phenyl)-1-(2-fluoro-6-methylbenzoyl)piperidine-3-acid (4-chloro-3-methylphenyl)amide carboxylic

1H NMR (400 MHz, CDCl 3 ) 3)8.25 (bs, 0.4H), 8.16 (bs, 0.6H), 7.44 - 7.20 (m, 6H), 7.06 - 6.84 (m, 2H), 6.59 - 6.50 (m, 2H), 3.75 (m, 1H), 3.66 (bs, 1H), 3.26-2.92 (m, 3H), 2.43 (s, 1H), 2.42 - 2.30 (m, 1H), 2.30 (s, 1H), 2.29 (s, 2H), 2.20 (s, 2H) ), 2.19-2.12 (m, 1H), 2.08 - 1.92 (m, 2H), 1.80 - 1.58 (m, 7H) 1.45 (m, 2H).
[00174] (2R,3S)-2-(4-Cyclobutylaminophenyl)-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylic acid (3-t-butylphenyl)amide

[00175] 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 0.6H), 8.39 (s, 0.4H), 7.44 - 6.88 (m, 10H), 6.25 (dd, J = 12 Hz, J = 6 Hz, 1 H), 6.45 (t, J = 8.4 Hz, 1 H), 3.87 (m, 1 H), 3.2 1.95 (m, 3H), 2.46 - 2.05 (m, 8H), 1.86 - 1.61 (m, 5H), 1.34 - 1.11 (m, 9H)
(2R,3S)-1-(2-fluoro-6-methylbenzoyl)-2-[4-(tetrahydropyran-4-ylamino)phenyl]piperidine- (3-morpholin-4-yl-phenyl)amide 3-carboxylic

[00177] 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.34 - 6.92 (m, 10H), 6.78 - 6.65 (m, 1H), 6.62 - 6.53 (m, 1H), 3.98 - 3.85 (m, 4H), 3.83 - 3.70 (m, 1H), 3.55 - 3.30 ( m, 3H), 3.2.98 (M, 4H), 2.42 - 1.92 (m, 8H), 1.81 - 1.45 (m, 7H)
(2R,3S)-1-(2-fluoro-6-methylbenzoyl)-2-[4-((R)-2-trifluoromethylpyrrolidin-1-ylmethyl)phenyl acid (3-t-butylphenyl)amide ] piperidine-3-carboxylic acid

[00179] 1H NMR (400 MHz, CDCl3) δ 8.01 (bs, 0.5H), 7.96 (bs, 0.5H), 7.55 - 7.37 (m, 3H), 7.30 - 7.19 (m, 6H), 7.13 - 7.06 (m, 1H), 7.01 - 6.90 (m, 1H), 6.85 - 6.64 ( m, 1H), 4.15 - 4.11 (m, 1H), 3.58 - 3.54 (m, 1H), 3.30 - 3.20 (m, 2H), 3, 17 - 2.80 (m, 2 H), 2.45 - 2.17 (m, 4 H), 2.00 - 1.94 (m, 2 H), 1.86 - 1.60 (m, 8H), 1.31 - 1.26 (m, 7H) Example 12 Materials and Methods A. Cells 1. Cells expressing the C5a receptor a) U937 cells
[00180] U937 cells are a monocytic cell line that express C5aR, and are available from the American Tissue Cell Collection (Virginia). These cells were cultured as a suspension in RPMI-1640 medium supplemented with 2 mM L-glutamine, 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10 mM HEPES, 1 mM pyruvate sodium, and 10% FBS. Cells were grown under 5% CO2/95% air, 100% humidity at 37°C and subcultured twice a week at 1:6 (cells were grown in a density range of 1 x 105 to 2 x 106 cells/ml) and harvested at 1 x 106 cells/ml. Prior to assay, cells are treated overnight with 0.5 mM cyclic AMP (Sigma, OH) and washed once prior to use. U937 cells treated with cAMP can be used in C5aR ligand binding and functional assays. b) Isolated human neutrophils
[00181] Optionally, human or murine neutrophils can be used to test for compound activity. Neutrophils can be isolated from fresh human blood using density separation and centrifugation. Briefly, whole blood is incubated with equal parts of 3% dextran and allowed to separate for 45 minutes. After separation, the top layer is deposited on top of 15 ml of Ficoll (15 ml of Ficoll for every 30 ml of blood suspension) and centrifuged for 30 minutes at 400 x g without any brakes. The pellet at the bottom of the tube is then isolated and resuspended in Lyse Pharmlyse RBC Buffer (BD Biosciences, San Jose, CA) after the sample is again centrifuged for 10 minutes at 400 x g with brake. The remaining cell pellet is resuspended as appropriate and consists of isolated neutrophils. B. Assays 1. Inhibition of 125I-C5a binding to C5aR
U937 cells treated with cAMP expressing C5aR were centrifuged and resuspended in assay buffer (20 mM HEPES pH 7.1, 140 mM NaCl, 1 mM CaCl2, 5 mM MgCl2, and with 0 .1% bovine serum albumin) at a concentration of 3 x 106 cells/ml. Binding assays were established as follows. 0.1 ml of cells was added to assay plates containing 5 µl of compound, giving a final concentration of ~2 to 10 µM of each compound for screening (or part of a dose response for compound IC50 determinations) . Then 0.1 ml 125I-labeled C5a (obtained from Perkin Elmer Life Sciences, Boston, MA) diluted in assay buffer to a final concentration of ~50 pM, yielding ~30,000 cpm per well, was added, the plates sealed and incubated for approximately 3 hours at 4°C on a shaking platform. Reactions were aspirated onto GF/B glass filters pre-soaked in 0.3% polyethyleneimine (PEI) solution in a vacuum cell harvester (Packard Instruments; Meriden, CT). Scintillation fluid (40 µl; Microscint 20, Packard Instruments) was added to each well, the plates were sealed and radioactivity measured in a Topcount scintillation counter (Packard Instruments). Control wells containing only diluent (for total counts) or excess C5a (1 µg/ml, for non-specific binding) were used to calculate the percentage of total inhibition for the compound. The Prism computer program from GraphPad, Inc. (San Diego, Ca) was used to calculate IC50 values. IC50 values are those concentrations required to reduce the binding of radiolabeled C5a to the receptor by 50%. (For additional descriptions of ligand binding and similar functional assays, see Dairaghi, et al., J. Biol. Chem. 274:21569-21574 (1999), Penfold, et al., Proc. Natl. Acad. Sci. USA 96: 9839-9844 (1999), and Dairaghi, et al, J. Biol. Chem. 272: 28206-28209 (1997 )). 2. Mobilization of Calcium
Optionally, the compounds can be further tested for their ability to inhibit calcium flux in cells. To detect release from intracellular calcium stores, cells (eg, U937 stimulated with cAMP or neutrophils) are incubated with 3 μM of the dye INDO-1AM (Molecular Probes; Eugene, OR) in the cell medium for 45 minutes in the at room temperature and washed with phosphate buffered saline (PBS). After loading INDO-1AM, cells are resuspended in flow buffer (Hank's balanced salt solution (HBSS) and 1% FBS). Calcium mobilization is measured using a Photon Technology International spectrophotometer (Photon Technology International; New Jersey) with excitation at 350 nm and simultaneous double recording of fluorescence emission at 400 nm and 490 nm. relative intracellular calcium levels are expressed as the 400 nm/490 nm emission ratio. Experiments are performed at 37°C with constant mixing in cuvettes each containing 106 cells in 2 ml of flow buffer. Chemokine ligands can be used in a range of 1 to 100 nM. The emission rate is plotted over time (typically 2-3 minutes). Candidate ligand blocking compounds (up to 10 µM) are added within 10 seconds, followed by chemokines within 60 seconds (ie, C5a; R&D Systems; Minneapolis, MN) and control chemokine (ie, SDF-1α; R&D Systems; Minneapolis, MN) at 150 seconds. 3. Chemotaxis tests
Optionally, compounds can be further tested for their ability to inhibit chemotaxis in cells. Chemotaxis assays are performed using 5 μm pore polycarbonate filters coated with polyvinylpyrrolidone in 96-well chemotaxis chambers (Neuroprobe; Gaithersburg, MD) using chemotaxis buffer (Hank's balanced salt solution (HBSS) and 1% FBS). C5aR ligands (ie, C5a, R&D Systems; Minneapolis, MN) are used to assess compound-mediated inhibition of C5aR-mediated migration. Other chemokines (ie, SDF-1α; R&D Systems; Minneapolis, MN) are used as specificity controls. The lower chamber is loaded with 29 µl of chemokine (ie, 0.03 nM C5a) and varying amounts of compound; the top chamber contains 100,000 U937 or neutrophil cells in 20 µl. The chambers are incubated 1.5 hours at 37o C, and the number of cells in the lower chamber quantified by direct cell counts in five high-power fields per reservoir or by the CyQuant assay (Molecular Probes), a fluorescent dye method that measures the nucleic acid content and microscopic observation. C. Identification of C5aR inhibitors 1. Assay
To evaluate small organic molecules that prevent the C5a receptor from binding ligand, an assay was used that detected the binding of 125I-C5a to cells expressing C5aR on the cell surface (eg U937 cells stimulated with cAMP or neutrophils isolated humans). For compounds that inhibited binding, whether competitive or not, fewer radioactive counts are observed when compared to uninhibited controls. Equal numbers of cells were added to each well on the plate. Cells were then incubated with radiolabeled C5a. Unbound ligand was removed by washing the cells, and bound ligand was determined by quantifying radioactive counts. Cells that were incubated without any organic compounds gave total counts; non-specific binding was determined by incubating cells with unlabeled ligand and labeled ligand. Percent inhibition was determined by the equation:
2. Dose Response Curves
[00186] To ascertain an affinity of the candidate compound for C5aR as well as confirm its ability to inhibit ligand binding, the inhibitory activity was titrated over a range of 1 x 10-10 to 1 x 10-4 M compound concentrations . In the trial, the amount of compound was varied; while cell number and ligand concentration were kept constant. D. In Vivo Effectiveness Models
Compounds of interest can be evaluated for potential efficacy in treating a C5a-mediated condition by determining the efficacy of the compound in an animal model. In addition to the models described below, other animal models suitable for studying the compound of interest can be found in Mizuno, M. et al., Expert Opin. Investigation Drugs (2005), 14(7), 807-821, which is incorporated herein by reference in its entirety. 1. C5a-Induced Leukopenia Models a) C5a-Induced Leukopenia in a Mouse Model Silenced in Human C5aR
[00188] To study the efficacy of compounds of the present invention in an animal model, a recombinant mouse can be created using standard techniques, in which the genetic sequence encoding the mouse C5aR is replaced with the sequence encoding the human C5aR, to create an hC5aR-KI mouse. In this mouse, administration of hC5a leads to upregulation of adhesion molecules on blood vessel walls that bind blood leukocytes, sequestering them from the bloodstream. Animals are administered 20 µg/kg of hC5a and 1 minute later leukocytes are quantified in peripheral blood by standard techniques. Pretreatment of mice with varying doses of the present compounds can almost completely block hC5a-induced leukopenia. b) C5a-Induced Leukopenia in a Cynomolgus Monkey Model
[00189] To study the efficacy of compounds of the present invention in a non-human primate model, C5a-induced leukopenia is studied in a cynomolgus model. In this model, administration of hC5a leads to upregulation of adhesion molecules on blood vessel walls that bind blood leukocytes, thereby sequestering them from the bloodstream. Animals are administered 10 µg/kg of hC5a and 1 minute later leukocytes are quantified in peripheral blood. c) Mouse model of ANCA-induced Vasculitis
On day 0, hC5aR-KI mice are intravenously injected with 50 mg/kg of purified antibody to myeloperoxidase ( Xiao et al, J. Clin. Invest. 110: 955-963 (2002)). Mice are further dosed with daily oral doses of compounds of the invention or vehicle for seven days, then the mice are sacrificed and kidneys collected for histological examination. Analysis of renal sections may show significantly reduced number and severity of crescentic and necrotic lesions in the glomeruli when compared to vehicle-treated animals. d) Mouse Model of Choroidal Neovascularization
[00191] To study the efficacy of compounds of the present invention in treating age-related macular degeneration (AMD) Bruch's membranes in the eyes of hC5aR-KI mice are disrupted by laser photocoagulation (Nozika et al, PNAS 103: 2328 -2333 (2006). Mice are treated with vehicle or a daily oral dose or appropriate intravitreal dose of a compound of the invention for one to two weeks. Laser-induced damage repair and neovascularization are assessed by histology and angiography. Rheumatoid Arthritis Models a) Rabbit Model of Destructive Joint Inflammation
[00192] To study the effects of candidate compounds on inhibiting the inflammatory response of rabbits to an intra-articular injection of the lipopolysaccharide (LPS) component of the bacterial membrane, a rabbit model of destructive joint inflammation is used. This study design mimics the destructive joint inflammation seen in arthritis. Intraarticular injection of LPS causes an acute inflammatory response characterized by the release of cytokines and chemokines, many of which have been identified in rheumatoid arthritic joints. Marked increases in leukocytes occur in the synovial fluid and synovium in response to the elevation of these chemotactic mediators. Selective chemokine receptor antagonists have shown efficacy in this model (see Podolin, et al., J. Immunol. 169(11):6435-6444 (2002)).
[00193] A rabbit LPS study is conducted essentially as described in Podolin, et al. ibid., female New Zealand rabbits (approximately 2 kg) are treated intra-articularly in one knee with LPS (10 ng) along with vehicle alone (phosphate buffered saline with 1% DMSO) or with the addition of the candidate compound ( dose 1 = 50 μM or dose 2 =100 μM) in a total volume of 1.0 ml. Sixteen hours after the LPS injection, the knees are washed and cell counts are performed. The beneficial effects of treatment were determined by histopathological evaluation of synovial inflammation. Inflammation scores are used for histopathological evaluation: 1 - minimal, 2 - mild, 3 - moderate, 4 - moderate-marked. b) Evaluation of a compound in a collagen-induced arthritis rat model
[00194] A 17-day developmental type II collagen arthritis study is conducted to evaluate the effects of a candidate compound on arthritis-induced clinical ankle swelling. Rat collagen arthritis is an experimental model of polyarthritis that has been widely used for preclinical testing of numerous antiarthritic agents (see Trentham, et al., J. Exp. Med. 146(3): 857-868 (1977) , Bendele, et al., Toxicologic Pathol. 27: 134-142 (1999), Bendele, et al., Arthritis Rheum. 42: 498-506 (1999)). The hallmarks of this model are reliable onset and progression of robust, easily measurable polyarticular inflammation, marked cartilage destruction in association with tissue formation and mild to moderate bone resorption, and periosteal bone proliferation.
[00195] Female Lewis rats (approximately 0.2 kg) are anesthetized with isoflurane and injected with Incomplete Freund's Adjuvant containing 2 mg/ml bovine type II collagen at the base of the tail and two sites on the back on days 0 and 6 of this 17-day study. A candidate compound is dosed daily in a subcutaneous manner from day 0 through day 17 at an effective dose. Ankle diameter gauge measurements were taken, and reduced joint swelling is taken as a measure of effectiveness. 3. Rat Model of Septicemia
To study the effect of compounds of interest on inhibiting the generalized inflammatory response that is associated with a disease such as sepsis, the Cecal Puncture (CLP) rat model of sepsis is used. A mouse CLP study is conducted essentially as described in Fujimura N, et al. (American Journal Respiratory Critical Care Medicine 2000;161:440-446). In summary described here, Albino Wistar Rats of both sexes weighing between 200 and 250 g are fasted for twelve hours before the experiments. Animals are maintained on normal 12-hour dark light cycles and fed standard rat chow until 12 hours before the experiment. Then the animals are divided into four groups; (i) two simulated operation groups and (ii) two PLC groups. Each of these two groups (i.e., (i) and (ii)) is divided into vehicle control group and test compound group. Septicemia is induced by the CLP method. Under light anesthesia a midline laparotomy is performed using minimal dissection and the cecum is ligated just below the ileocecal valve with 3-0 silk so that bowel continuity is maintained. The antimesenteric surface of the cecum is pierced with an 18 gauge needle at two locations 1 cm apart and the cecum is gently squeezed until fecal matter is extruded. The bowel is then returned to the abdomen and the incision closed. At the end of the operation, all rats are resuscitated with saline solution, 3 ml/100 g of body weight, given subcutaneously. Postoperatively, rats are deprived of food but have free access to water for the next 16 hours until they are sacrificed. Simulated operated groups are given a laparotomy and the cecum is manipulated but not ligated or perforated. The beneficial effects of treatment are measured by histopathological tissue and organ counts as well as measurement of several key indicators of liver function, renal function, and lipid peroxidation. To test how much liver function aspartate transaminase (AST) and alanine transaminase (ALT) are measured. Blood urea and creatinine nitrogen concentrations are studied to assess renal function. Pro-inflammatory cytokines such as TNF-alpha and IL-1beta are also tested by ELISA for ceric levels. 4. Mouse SLE model of experimental lupus nephritis.
[00197] To study the effect of the compounds of interest on a systemic Lupus erythematosus (SLE), the MRL/lpr murine SLE model is used. The MRL/Mp-Tmfrsf6lpr/lpr (MRL/lpr) strain is a commonly used mouse model of human SLE. To test the efficacy of compounds in this model, male MRL/lpr mice are equally divided between control and C5aR antagonist groups at 13 weeks of age. Then for the next 6 weeks compound or vehicle is administered to the animals via osmotic pumps to maintain coverage and minimize stress effects on the animals. Serum and urine samples are collected bi-weekly during the six weeks of disease onset and progression. In a minority of these mice, glomerulosclerosis develops leading to the animal's death from renal failure. Tracking mortality as an indicator of renal failure is one of the measured criteria and successful treatment will usually result in a delay in the onset of sudden death between test groups. In addition, the presence and magnitude of kidney disease can also be continuously monitored with measurements of blood urea nitrogen (BUN) and albuminuria. Tissues and organs were also harvested at 19 weeks and subjected to histopathology and immunohistochemistry and counting based on tissue damage and cellular infiltration. 5. COPD Mouse Model
[00198] Smoke-induced airway inflammation in rodent models can be used to assess the efficacy of compounds in Chronic Obstructive Pulmonary Disease (COPD). Selective chemokine antagonists have shown efficacy in this model (see, Stevenson, et al., Am. J. Physiol Lung Cell Mol Physiol. 288 L514-L522, (2005)). An acute rat model of COPD is conducted as described by Stevenson et al. A compound of interest is administered systemically via oral or IV dosing; or locally with nebulized compost. Male Sprague-Dawley rats (350-400 g) are placed in Perspex chambers and exposed to cigarette smoke drawn in by a pump (50 ml every 30 seconds with fresh air in between). Rats are exposed for a total period of 32 minutes. Rats are sacrificed up to 7 days after the initial exposure. Any of the beneficial effects of the treatment are evaluated by a decreased inflammatory cell infiltrate, decreases in chemokine and cytokine levels.
[00199] In a chronic model, mice or rats are exposed to tobacco smoke exposures daily for up to 12 months. The compound is administered systemically via once-daily oral dosing, or potentially locally via nebulized compound. In addition to the inflammation seen with the acute model (Stevensen et al.), animals may also exhibit other pathologies similar to that seen in human COPD such as emphysema (as indicated by the increased mean linear intercept) as well as altered lung chemistry (see Martorana et al. , Am. J. Respiratory Crit Care Med. 172(7): 848-53 6. EAE Mouse Model of Multiple Sclerosis
[00200] Experimental autoimmune encephalomyelitis (EAE) is a model of human multiple sclerosis. Variations of the model have been published, and are well known in the field. In a typical protocol, C57BL/6 mice (Charles River Laboratories) are used for the EAE model. Mice are immunized with 200 μg myelin oligodendrocyte glycoprotein (MOG) 35-55 (Peptide International) emulsified in Complete Freund's Adjuvant (CFA) containing 4 mg/ml Mycobacterium tuberculosis (Sigma-Aldrich) sc on day 0. In addition, on day 0 and day 2 animals are given 200 ng pertussis toxin (Calbiochem) iv Clinical count is based on a scale of 0 to 5: 0, no sign of disease; 1, flabby tail; 2, hind limb weakness; 3, hind limb paralysis; 4, forelimb weakness or paralysis; 5, dying. The dosage of the compounds of interest to be evaluated can be started on day 0 (prophylactic) or day 7 (therapeutic, when histological evidence of disease is present but few animals are showing clinical signs) and dosed once or more daily at the appropriate concentrations its activity and pharmacokinetic properties, eg 100 mg/kg sc The efficacy of compounds can be assessed by comparing severity (maximum mean clinical count in the presence of compound compared to vehicle), or by measuring a decrease in the number of macrophages (F4/80 positive) isolated from the spinal cords. Spinal cord mononuclear cells can be isolated using a discontinuous Percoll gradient. Cells can be stained using rat anti-mouse F4/80-PE or rat IgG2b-PE (Caltag Laboratories) and quantified by FACS analysis using 10 µl of Polibeads per sample (Polisciences). 7. Kidney Transplant Mouse Model
[00201] Transplant models can be performed in mice, for example an allogeneic kidney transplant model from C57BL/6 to BALB/c mice is described in Faikah Gueler et al, JASN Express, August 27, 2008. In summary, the mice are anesthetized and the left donor kidney connected to an aortic sheath and the renal vein with a small caval sheath, and the ureters removed en bloc. After the recipient's left nephrectomy, the vascular sheaths are anastomosed to the recipient abdominal aorta and vena cava, respectively, below the level of the native renal vessels. The ureter is directly anastomosed to the bladder. The cold ischemia time is 60 min, and the hot ischemia time is 30 min. The right native kidney can be removed at the time of allograft transplantation or on day 4 after transplantation for long-term survival studies. The overall physical condition of the mice is monitored for evidence of rejection. Compound treatment of animals can be started before surgery or immediately after transplantation, for example by subcutaneous injection once daily. Mice are studied for kidney function and survival. Serum creatinine levels are measured by an automated method (Beckman Analyzer, Krefeld, Germany). 8. Ischemia/Reperfusion Mouse Model
[00202] A mouse model of ischemia/reperfusion injury can be performed as described by Xiufen Zheng et al, Am. J. Pathol, Vol 173: October 4, 2008. In summary, CD1 mice aged 6 to 8 weeks they are anesthetized and placed on a heating pad to keep warm during surgery. Following the abdominal incisions, the renal pedicles are abruptly dissected and a microvascular clamp placed on the left renal pedicle for 25 to 30 minutes. Following ischemia the clamps are removed along with the right kidney, the incisions sutured, and the animals allowed to recover. Blood is drawn for serum creatinine and BUN analysis as an indicator of kidney health. Alternatively, the animal's survival is monitored over time. The compound can be administered to animals before and/or after surgery and the effects on serum creatinine, BUN or animal survival used as indicators of compound efficacy. 9. Mouse Tumor Growth Model
6 to 16 weeks old C57BL/6 mice are injected subcutaneously with 1 x 105 TC-1 cells (ATCC, VA) in the right or left rear flank. Starting about 2 weeks after cell injection, tumors are measured with gauges every 2 to 4 days until tumor size requires the mice to be killed. At the time of sacrifice, the animals undergo a complete necropsy and the spleens and tumors are removed. Excised tumors are measured and weighed. The compounds can be administered before and/or after tumor injections, and a delay or inhibition of tumor growth used to assess the efficacy of the compound.

权利要求:
Claims (12)
[0001]
1. Compound, characterized by having the formula
[0002]
2. Compound according to claim 1, characterized in that it has the formula
[0003]
3. Compound according to claim 1, characterized in that it has the formula
[0004]
4. Pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and a compound as defined in any one of claims 1 to 3.
[0005]
5. Use of a compound as defined in any one of claims 1 to 4, characterized in that it is for the manufacture of a medicament for the treatment of a mammal suffering from or susceptible to a disease or disorder involving pathological activation of receptors C5a, wherein said disease or disorder is an inflammatory disease or disorder, a cardiovascular or cerebrovascular disorder, an autoimmune disorder, or a pathological sequelae associated with insulin-dependent diabetes mellitus, lupus nephropathy, Heyman's nephritis, membranous nephritis, glomerulonephritis , contact sensitivity responses and inflammation that result from blood contact with artificial surfaces.
[0006]
6. Use according to claim 5, characterized in that the disease or disorder is an inflammatory disease or disorder.
[0007]
7. Use according to claim 6, characterized in that the disease or disorder is selected from the group consisting of neutropenia, septicemia, septic shock, Alzheimer's disease, multiple sclerosis, stroke, inflammatory bowel disease, degeneration age-related macular disorders, chronic obstructive pulmonary disorder, inflammation associated with burns, lung injury, osteoarthritis, atopic dermatitis, chronic urticaria, ischemia-reperfusion injury, acute respiratory distress syndrome, systemic inflammatory response syndrome, organ dysfunction syndrome multiple, tissue graft rejection, cancer and hyperacute organ transplant rejection.
[0008]
8. Use according to claim 5, characterized in that the disease or disorder is a cardiovascular or cerebrovascular disorder.
[0009]
9. Use according to claim 8, characterized in that the disease or disorder is selected from the group consisting of myocardial infarction, coronary thrombosis, vascular occlusion, postsurgical vascular reocclusion, atherosclerosis, traumatic central nervous system injury and ischemic heart disease.
[0010]
10. Use according to claim 5, characterized in that the disease or disorder is an autoimmune disorder.
[0011]
11. Use according to claim 10, characterized in that the disease or disorder is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barre syndrome, pancreatitis, lupus nephritis, lupus glomerulonephritis, psoriasis, disease Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune and thrombocytopenic hemolytic states, Goodpasture's syndrome, immunovasculitis, tissue graft rejection, and hyperacute organ transplant rejection .
[0012]
12. Use according to claim 5, characterized in that the disease or disorder is a pathological sequelae associated with the group consisting of insulin-dependent diabetes mellitus, lupus nephropathy, Heyman's nephritis, membranous nephritis, glomerulonephritis, responses to contact sensitivity and inflammation resulting from blood contact with artificial surfaces.

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-07-02| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-09-03| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-03-30| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-06-01| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 24/06/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US12/823,039|2010-06-24|

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US12/823,039|US20100311753A1|2008-12-22|2010-06-24|C5aR ANTAGONISTS|

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US13/072,616|2011-03-25|

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US13/072,616|US20110275639A1|2008-12-22|2011-03-25|C5aR ANTAGONISTS|

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PCT/US2011/041910|WO2011163640A1|2010-06-24|2011-06-24|C5ar antagonists|

---