Patent Publication Number: US-2007117785-A1

Title: Substituted pyrazoles and methods of treatment with substituted pyrazoles

Description:
This application is a continuation-in-part application of U.S. patent application Ser. No. 09/947,117, filed on Sep. 5, 2001. The present application is also a continuation-in-part application of U.S. patent application Ser. No. 11/174,077, filed on Jun. 30, 2005. Application Ser. No. 11/174,077 is a continuation of U.S. patent application Ser. No. 09/927,324, filed on Aug. 10, 2001, now U.S. Pat. No. 6,953,793, which claims priority to U.S. provisional application Ser. No. 60/225,178, filed on Aug. 14, 2000. Application Ser. No. 09/947,117 claims priority to U.S. provisional application Ser. No. 60/230,407, filed on Sep. 6, 2000, and is a continuation-in-part application of U.S. patent application Ser. No. 09/927,324. All the applications of which the present patent application is a continuation-in-part application and their predecessors in the priority chain (U.S. Ser. No. 09/927,324; U.S. Ser. No. 60/225,178; and U.S. Ser. No. 60/230,407) are incorporated herein by reference. 
    
    
     FIELD OF THE INVENTION  
      This invention relates to a series of substituted pyrazoles, pharmaceutical compositions containing these compounds, and intermediates used in their manufacture, and methods of using them.  
     BACKGROUND OF THE INVENTION  
      Cathepsin S (EC 3.4.22.27) is a cysteine protease of the papain family found primarily in lysosomes (Bromme, D.; McGrath, M. E. High Level Expression and Crystallization of Recombinant Human Cathepsin S.  Protein Science  1996, 5, 789-791).  
      Cathepsin S (‘CatS’) is a cysteine protease expressed in lymphatic tissues. CatS mediates invariant chain proteolysis, which is a prerequisite for peptide loading of MHC class II molecules (Riese et al. (1996) Immunity 4:357). CatS has 50-60% homology with cathepsins L and K, but differs from them in that it has a broad pH optimum that extends to alkaline pH. CatS modulates antigen presentation in animal models, and inhibitors are effective in an asthma model (Riese et al. (1998) J. Clin. Invest. 101:2351). Mice deficient in cathepsin S have an impaired ability to present exogenous proteins by professional antigen presenting cells (Nakagawa et al. (1999) Immunity 10:207; Shi et al. (1999) Immunity 10:197).  
      The role of cathepsin S in the immune response is anticipated by its tissue distribution: cathepsin S is found primarily in lymphatic tissues, lymph nodes, the spleen, B lymphocytes, and macrophages (Kirschke, H. Chapter 211. Cathepsin S. In Handbook of Proteolytic Enzymes. Barrett, A. J.; Rawlings, N. D.; Woessner, J. F., Eds. San Diego: Academic Press, 1998. pp. 621-624.). Cathepsin S inhibitors have been shown in animal models to modulate antigen presentation and are effective in an animal model of asthma (Riese, R. J.; Mitchell, R. N.; Villadangos, J. A.; Shi, G.-P.; Palmer, J. T.; Karp, E. R.; De Sanctis, G. T.; Ploegh, H. L.; Chapman, H. A. Cathepsin S Activity Regulates Antigen Presentation and Immunity.  J. Clin. Invest.  1998, 101, 2351-2363 and Shi, G.-P.; Villadangos, J. A.; Dranoff, G.; Small, C.; Gu, L.; Haley, K. J.; Riese, R.; Ploegh, H. L.; Chapman, H. A. Cathepsin S Required for Normal MHC Class II Peptide Loading and Germinal Center Development.  Immunity  1999, 10, 197-206.).  
      Mice in which the gene encoding cathepsin S has been knocked out are less susceptible to collagen-induced arthritis and their immune systems have an impaired ability to respond to antigens (Nakagawa, T. Y.; Brissette, W. H.; Lira, P. D.; Griffiths, R. J.; Petrushova, N.; Stock, J.; McNeish, J. D.; Eastman, S. E.; Howard, E. D.; Clarke, S. R. M.; Rosloniec, E. F.; Elliott, E. A.; Rudensky, A. Y. Impaired Invariant Chain Degradation and Antigen Presentation and Diminished Collagen-induced Arthritis in Cathepsin S Null Mice.  Immunity  1999, 10, 207-217).  
      These data demonstrate that compounds that inhibit the proteolytic activity of human cathepsin S should find utility in the treatment of chronic autoimmune diseases including, but not limited to, lupus, rheumatoid arthritis, and asthma; and have potential utility in modulating the immune response to tissue transplantation.  
      Methods of modulating autoimmunity with an agent that modulates cathepsin S activity, e.g., proteolysis of the Ii chain, as well as methods of treating a subject having an autoimmune disorder, methods of evaluating a treatment for its ability to modulate an immune response are described in WO 99/58153.  
      There are a number of cathepsin S inhibitors reported in the literature. The most important patents are listed below.  
      Certain dipeptidyl nitriles are claimed by Novartis as cathepsin S inhibitors in: Altmann, et. al. WO-99/24460.  
      Dipeptidyl vinyl sulfones are claimed by Arris (now Axys) as cysteine protease (including cathepsin S) inhibitors in: Palmer, et. al. U.S. Pat. No. 5,976,858.  
      Certain peptidyl sulfonamides are claimed by Arris/Axys as cysteine protease (including cathepsin S) inhibitors in: Palmer, et. al. U.S. Pat. No. 5,776,718 (assigned to Arris, now Axys) &amp; Klaus, et. al. U.S. Pat. No. 6,030,946 (assigned to Axys).  
      Compounds somewhat similar to those of the present invention are described in the following references.  
      Winters, et. al. (Winters, G.; Sala, A.; Barone, D.; Baldoli, E.  J. Med. Chem.  1985, 28, 934-940; Singh, P.; Sharma, R. C.  Quant. Struct .- Act. Relat.  1990, 9, 29-32; Winters, G.; Sala, A.; Barone, D. in U.S. Pat. No. 4,500,525 (1985)) have described bicyclic pyrazoles of the type shown below. R never contains a heterocyclic ring and no protease inhibitor activity is ascribed to these molecules; they are described as α1-adrenergic receptor modulators.  
                 
 
      Shutske, et. al. claim the bicylic pyrazoles below. The pyridine ring is aromatic in their system (Shutske, G. M.; Kapples, K. J.; Tomer, J. D. U.S. Pat. No. 5,264,576 (1993)). Although reference is made to R being a linker to a heterocycle, the claims specify only R=hydrogen. The compounds are referred to as serotonin reuptake inhibitors.  
                 
 
      The compound 2-[4-[4-(3-methyl-5-phenyl-1H-pyrazol-1-yl)butyl]-1-piperazinyl]-pyrimidine is known from EP-382637, which describes pyrimidines having anxiolytic properties. This compound and analogs are further described in EP-502786 as cardiovascular and central nervous system agents. Pharmaceutical formulations with such compounds are disclosed in EP-655248 for use in the treatment of gastric secreation and as anti-ulcer agents. WO-9721439 describes medicaments with such compounds for treating obsessive-compulsive disorders, sleep apnea, sexual dysfunctions, emesis and motion sickness.  
      The compounds 5-methyl-3-phenyl-1-[4-(4-phenyl-1-piperazinyl)butyl]-1H-indazole and 5-bromo-3-(2-chlorophenyl)-1-[4-(4-phenyl-1-piperazinyl)butyl]-1H-indazole, in particular the hydrochloride salts thereof, are known from WO-9852940 and CA 122:314528, where these and similar compounds are described as kinase inhibitors in the former reference and possessing affinity for benzodiazepine receptors in the latter reference.  
      Atopic allergies afflict at least 20% of populations in developed countries and comprise a wide range of IgE-mediated diseases such as hay fever, asthma, atopic dermatitis, and food allergies. Exposure of an allergic subject to relevant allergens cross-links allergen specific IgE bound to mast cells, triggering degranulation and release of proinflammatory mediators, such as histamine and eicosanoids, which cause the weal-and-flare response on a skin test. Characteristically, this early response is followed by a prolonged late reaction in which inflammatory cells, particularly eosinophils and activated TH-2 CD4 T cells, are recruited to the site of allergen exposure. Inflammatory cytokines such as IL-4 and IL-5, both produced by TH-2 cells, are important for IgE production by B cells and for eosinophilia, respectively. Immunotherapies targeting CD4 T cells have been shown to be effective in reducing the production of IgE, the activation of proinflammatory cells, and the release of inflammatory mediators.  
      Current allergy therapies targeting CD4 T cells have met with mixed success. Desensitization with allergen extracts or vaccines is effective for many allergens, such as the  Hymenoptera  insect sting which can induce life-threatening allergic reactions. The mechanism may be either induction of T cell tolerance or the conversion of TH-2 to TH-1. However, such treatment requires a long-term treatment regime, frequent doctor visits and prior stabilization by other medications, and is associated with a certain morbidity rate and rare deaths. Alternatively, immunosuppressive drugs such as steroids which effectively stabilize ongoing allergy responses, are often associated with severe side effects. 
      The activation of CD4 T cells is a major factor in the initiation and maintenance of the allergic response. Allergens are taken up by specialized antigen presenting cells (APCs) such as dendritic cells and B cells. Protein allergens pass through the endosomal or lysosomal system where they are degraded by different proteases. These peptide fragments are bound by the MHC class II molecules which, at the cell surface, are heterotrimeric complexes consisting of two transmembrane glycoprotein chains (α and β) that form a binding scaffold for the third component, a peptide of 11-20 amino acids. The antigen-MHC class II molecule complex is recognized by CD4 T cells and leads to the activation of the T cell. Activated T cells in turn activate several other components of the immune system, such as B cells and macrophages, that are crucial for the body&#39;s response to pathogens, but also lead to the symptoms of allergies.    

      Class II molecules, like other transmembrane proteins, are translocated into the endoplasmic reticulum (ER) after synthesis, where they associate with a third protein, the invariant chain (Ii). The invariant chain molecule is a type II transmembrane protein that serves as a class II-specific chaperone, promoting the exit of class II-Ii complexes from the ER and preventing class II molecules from binding to peptides and unfolded proteins in the ER and in the secretory pathway. A targeting motif in the cytoplasmic tail of Ii directs the class II-Ii complexes from the secretory pathway into the endosomal system.  
      Before the MHC class II molecules can present antigen the Ii must be removed by a series of proteases that break down Ii. The resultant Ii peptide fragments, called class II-associated invariant chain peptides (CLIP), occupy the peptide binding groove of the class II molecule, and in most cases are not spontaneously released. The CLIP protects the class II binding pocket from collapsing both during intracellular transport and after Ii degradation in the endosomal system. Binding of antigenic peptides generated from endocytosed proteins requires an empty, and yet open binding site. The CLIP therefore must be released while the open binding site is stabilized to allow the binding of other peptides. Human Leukocyte Antigen-DM (‘HLA-DM’) mediates both of these functions, thus promoting the binding of antigenic peptides. After acquiring peptides, the class II molecules are transported to the cell surface via routes that are largely unknown.  
      In view of the above, inhibition of invariant chain proteolysis will prevent removal of Ii from the class II binding pocket, which in turn will specifically block antigen binding to the MHC class II molecule.  
     SUMMARY OF THE INVENTION  
      The present invention concerns compounds which can be represented by formula (I):  
                 
 
 wherein: 
      Ar 2  is a monocyclic or bicyclic ring system, unsaturated, saturated or aromatic, optionally fused, optionally including between 1 and 5 heteroatom ring moieties independently selected from O, S, N, SO 2 , and C═O; said Ar 2  ring system being optionally substituted with between 1 and 4 substituents;     R 5  and R 6  are independently selected from hydrogen and C 1-5  alkyl;     R 7  and R 8  are independently hydrogen, C 1-5  alkyl, C 2-5  alkenyl, C 1-5  alkoxy, C 1-5  alkylthio, halogen, or a 4-7 membered carbocyclyl or heterocyclyl;     alternatively, R 7  and R 8  can be taken together to form an optionally substituted 5- to 7- membered carbocyclic or heterocyclic ring, which ring may be unsaturated or aromatic, and may be optionally substituted with between one and three substituents independently selected from halo, cyano, amino, hydroxy, nitro, R 4 , R 4 O—, R 4 S—, R 4 O(C 1-5  alkylene)-, R 4 O(C═O)—, R 4 (C═O)—, R 4 (C═S)—, R 4 (C═O)O—, R 4 O(C═O)(C═O)—, R 4 SO 2 , NHR 44 SO 2 —, and NHR 44 (C═O)—;     R 4  is H, C 1-5  alkyl, C 2-5  alkenyl, C 1-5  heterocyclyl, (C 1-5  heterocyclyl)C 1-6  alkylene, phenyl, benzyl, phenethyl, NH 2 , mono- or di(C 1-6  alkyl)N—, or R 42 OR 43 —, wherein R 42  is H, C 1-5  alkyl, C 2-5  alkenyl, phenyl, benzyl, phenethyl, C 1-5  heterocyclyl, or (C 1-5  heterocyclyl)C 1-6  alkylene and R 43  is C 1-5  alkylene, phenylene, or divalent C 1-5  heterocyclyl;     R 44  is any one of the values for R 4 ;     n is 0, 1, or 2;     G is C 3-6  alkenediyl or C 3-6  alkanediyl, optionally substituted with hydroxy, halogen, C 1-5  alkoxy, C 1-5  alkyl, oxo, hydroximino, CO 2 R k , R k R l N, R k R l NCO 2 , (L)-C 1-4  alkylene-, (L)-C 1-5  alkoxy, N 3  or [(L)-C 1-5  alkylene]amino;     each of R k  and R l  is independently hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, or C 1-5  heterocyclyl; alternatively R k  and R l , can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;     L is amino, mono- or di-C 1-5  alkylamino, pyrrolidinyl, morpholinyl, piperidinyl homopiperidinyl, or piperazinyl, wherein available ring nitrogens may be optionally substituted with C 1-5  alkyl, benzyl, C 2-5  acyl, C 1-5  alkylsulfonyl, or C 1-5  alkoxycarbonyl;     Ar represents a monocyclic or bicyclic aryl or heteroaryl ring, optionally substituted with between 1 and 3 substituents independently selected from halogen, C 1-5  alkoxy, C 1-5  alkyl, C 2-5  alkenyl, cyano, nitro, R 22 R 23 N, R 24 SO 2 , R 24 S, R 24 SO, R 24 OC═O, R 22 R 23 NC═O, C 1-5  haloalkyl, C 1-5  haloalkoxy, C 1-5  haloalkylthio, and C 1-5  alkylthio;     R 22  is hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, phenethyl, benzyl, or C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R 38 OC═O, R 25 R 26 NC═O, R 38 SO, R 38 SO 2 , R 38 S, or R 25 R 26 NSO 2 ;     R 38  is H, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, or C 1-5  heterocyclyl;     R 23  is hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl or C 1-5  heterocyclyl; 
        alternatively, R 22  and R 23  can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;    
        R 24  is C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, or C 1-5  heterocyclyl;     R 25  and R 26  independently are hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, or C 1-5  heterocyclyl; 
        or, alternatively, R 25  and R 26  can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;    
        W represents O, S, NR 27 , C═O, (C═O)NH, NH(C═O), CHR 28 , or a covalent bond;     R z  is H or OH and the dashed line is absent; or R z  is absent where the dashed line is an sp 2  bond; 
        R 27  is hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, naphthyl, benzyl, phenethyl, C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R 29 OC═O, R 30 R 31 NC═O, R 29 SO, R 29 S, R 29 SO 2 , or R 30 R 31 NSO 2 ;     or, alternatively, R 27  and part of Ar 2  can be taken together to form an optionally substituted 5- or 6-membered heterocyclic ring with optionally 1 to 3 additional heteroatom moieties in the ring selected from O, NR 9 , NR 10 , N, SO 2 , C═O, and S; which ring may be saturated, unsaturated or aromatic;     R 9  and R 10  are independently selected from H, C 1-3  alkyl, and —CH 2 CO 2 (C 1-4  alkyl);    
        R 28  is hydrogen, C 1-5  alkyl, C 3-5  alkenyl, hydroxy, phenyl, benzyl, C 1-5  heterocyclyl, R 29 O, R 30 R 31 NC═O, R 29 S, R 29 SO, R 29 SO 2 , or R 30 R 31 NSO 2 ;     R 29  is C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, or C 1-5  heterocyclyl;     R 30  and R 31  are independently selected from hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, naphthyl, and C 1-5  heteroaryl; alternatively, R 30  and R 31  can be taken together to form an optionally substituted 4- to 7-membered ring carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic; 
        wherein each of the above hydrocarbyl or heterocarbyl groups, unless otherwise indicated, and in addition to any specified substituents, is optionally and independently substituted with between 1 and 3 substituents selected from methyl, halomethyl, hydroxymethyl, halo, hydroxy, amino, nitro, cyano, C 1-5  alkyl, C 1-5  alkoxy, —COOH, C 2-6  acyl, [di(C 1-4  alkyl)amino]C 2-5  alkylene, [di(C 1-4  alkyl)amino]C 2-5  alkyl-NH—CO—, and C 1-5  haloalkoxy;    
        or a pharmaceutically acceptable salt, amide, or ester thereof; or a stereoisomeric form thereof.    

      One embodiment of the invention is a compound of formula(I), wherein Ar 2  is selected from 5-7 membered monocyclic rings, and [5,6], [6,6], [6,5], and [5,5] fused bicyclic ring systems, said ring or ring system being carbocyclic or heterocyclic, saturated, unsaturated, or aromatic, optionally substituted with halo, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  hydroxyalkyl, nitro, hydroxy, amino, mono- or di-(C 1-6  alkyl)amino, C 1-4  alkoxy, C 2-4  alkoxycarbonyl, C 2-6  acyl, C 2-6  acyloxy, C 1-5  alkylsulfonyl, C 1-5  alkoxycarbonylC 1-4  alkoxy, cyano, and mono- or di-(C 1-6  alkyl)carbamoyl.  
      Another embodiment of the invention is a compound of formula (I), wherein Ar 2  is selected from 2,5-di(C 1-6  alkyl)aminopyrrolyl and the following 6 formulae:  
                 
 
 wherein 
          each dashed line may be an sp 2  bond or absent;     X c  is O, S, or N; and X d  is O or S;         R 1  is hydrogen, halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, C 2-5  alkenyl, cyano, nitro, R a R b N, C 2-8  acyl, C 1-5  heterocyclyl, (C 1-5  heterocyclyl)C 1-5  alkylene, R 11 S, R 11 SO, R 11 SO 2 , R c OC═O, R c R d NC═O, or R c R d NSO 2 ; or R 1  can be taken together with R 27  as provided below;     R 2  is hydrogen, halogen, C 1-5  alkoxy, hydroxy, C 1-5 alkyl, C 2-5  alkenyl, cyano, nitro, R e R f N, C 1-5  heterocyclyl, or C 2-8  acyl;     R 3  is hydrogen, halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, C 2-5  alkenyl, cyano, nitro, R g R h N, C 2-8  acyl, C 1-5  heterocyclyl, R h OC═O, R g R h NC═O, or R g R h NSO 2 ;     R a  is selected from hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R j OC═O, R i R j NC═O, R 12 SO, R 12 SO 2 , R 12 S, and R i R j NSO 2 ;     R e  is selected from hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R 32 OC═O, R 32 R 33 NC═O, R 13 SO, R 13 SO 2 , R 13 S, and R 32 R 33 NSO 2 ;     R m  is selected from hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R 34 OC═O, R 34 R 35 NC═O, R 15 SO, R 15 SO 2 , R 15 S, and R 34 R 35 NSO 2 ;     R o  is selected from hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R 36 OC═O, R 36 R 37 NC═O, R 19 SO, R 19 SO 2 , R 19 S, and R 36 R 37 NSO 2 ;     each of R b , R f , R n , R p , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 39 , and R 40  is independently selected from hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, and C 1-5  heteroaryl; 
        alternatively, R a  and R b , R e  and R f , R m  and R n , and R o  and R p , independently, can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;    
        each of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 19 , R 38 , and R 41  is independently C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, or C 1-5  heterocyclyl;     each of R c  and R d , and R i  and R j  are independently are hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, or C 1-5  heteroaryl; alternatively, R c  and R d , and R i  and R j , independently, can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;     R 9  is hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R 17 OC═O, R 17 R 18 NC═O, R 16 S, R 16 SO, R 16 SO 2 , or R 17 R 18 NSO 2 ;     R h  is hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl or C 1-5  heterocyclyl; alternatively, R g  and R h  can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;     R 17  and R 18  independently are hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, or C 1-5  heterocyclyl;     alternatively, R 17  and R 18  can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;     Y e  is nitrogen or R 20 C;     Z e  is nitrogen or R 21 C; 
        R 20  is hydrogen, halogen, C 1-5  alkoxy, C 1-5  alkyl, C 2-5  alkenyl, cyano, nitro, R m R n N, C 2-8  acyl, R m OC═O, R 14 S, R 14 SO, or R 14 SO 2 ;    
        R 21  is hydrogen, halogen, C 1-5  alkoxy, C 1-5  alkyl, C 2-5  alkenyl, cyano, nitro, R o R p N, C 2-8  acyl, R 16 OC═O, R 11 S, R 11 SO, or R 11 SO 2 ; 
        alternatively, R 3  and R 20  or R 3  and R 21  can be taken together to form an optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic; wherein said ring may be optionally substituted with halo, di(C 1-5  alkyl)amino, C 2-5  acyl, and C 1-5  alkoxy;    
        R 27  is hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, naphthyl, benzyl, phenethyl, C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R 29 OC═O, R 30 R 31 NC═O, R 29 SO, R 29 S, R 29 SO 2 , or R 30 R 31 NSO 2 ; 
        or, alternatively, R 27  and R 1  can be taken together to form an optionally substituted 5- or 6-membered heterocyclic ring with optionally 1 to 3 additional heteroatom moieties in the ring selected from O, NR 9 , NR 10 , N, SO 2 , C═O, and S; which ring may be saturated, unsaturated or aromatic;     R 9  and R 10  are independently selected from H, C 1-3  alkyl, and —CH 2 CO 2 (C 1-4  alkyl);    
        X f  is CHR 1f , ═N—, NH, C═O, SO 2 , CHSR 1f  wherein, in formula (f), R 1f  is hydrogen, halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, C 3-5  alkenyl, cyano, nitro, R 39 R 40 N, C 2-8  acyl, C 1-5  heterocyclyl, (C 1-5  heterocyclyl)C 1-5  alkylene, R 41 S, R 41 SO, R 41 SO 2 , R 39 OC═O, R 39 R 40 NC═O, R 39 R 40 NSO 2 , R 41 SO 3 — or R 39 (C═O)O—;     Y f  is CH 2 , CHR 2f , ═CR 2f , O, or NR 2f , wherein R 2f  is H, C 1-5  alkyl, C 3-5  alkenyl, C 2-8  acyl, C 1-5  heterocyclyl, (C 1-5  heterocyclyl)-C 1-5  alkylene, C 1-5  haloalkyl, C 1-5  cyanoalkyl, (C 1-5  alkoxycarbonyl)C 1-5  alkylene, and (phenylcarbonyl)NH—;     m is 0 or 1;     p is 0 or 1;    

      wherein each of the above hydrocarbyl or heterocarbyl groups, unless otherwise indicated, and in addition to any specified substituents, is optionally and independently substituted with between 1 and 3 substituents selected from methyl, halomethyl, hydroxymethyl, halo, hydroxy, amino, nitro, cyano, C 1-5  alkyl, C 1-5  alkoxy, —COOH, C 2-6  acyl, [di(C 1-4  alkyl)amino]C 2-5  alkylene, [di(C 1-4  alkyl)amino]C 2-5  alkyl-NH—CO—, and C 1-5  haloalkoxy.  
      The disclosed compounds are high-affinity inhibitors of the proteolytic activity of human cathepsin S. For use in medicine, the preparation of pharmaceutically acceptable salts of compounds of formula (I) may be desirable.  
      Certain compounds of the present invention may have one stereogenic atom and may exist as two enantiomers. Certain compounds of the present invention may have two or more stereogenic atoms and may further exist as diastereomers. It is to be understood by those skilled in the art that all such stereoisomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.  
      Another aspect of the invention provides pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier. A further embodiment of the invention is a process for making a pharmaceutical composition comprising mixing a disclosed compound as described above, with a suitable pharmaceutically acceptable carrier.  
      The invention also contemplates pharmaceutical compositions comprising more than one compound of formula (I) and compositions comprising a compound of formula (I) and another pharmaceutically active agent.  
      The invention features a method of treating disorders or conditions mediated by the cathepsin S enzyme, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. If more than one active agent is administered, the therapeutically effective amount may be a jointly effective amount. The compounds described herein inhibit the protease activity of human cathepsin S, an enzyme involved in the immune response. In preferred embodiments, cathepsin S inhibition is selective. As such, the disclosed compounds and compositions are useful in the prevention, inhibition, or treatment of autoimmune diseases such as lupus, rheumatoid arthritis, and asthma, and for the prevention, inhibition, or treatment of tissue transplant rejection.  
      The present invention features the use of cathepsin S inhibitors to treat allergic conditions, including but not limited to atopic allergies. Examples of an allergic condition include hay fever, asthma, atopic dermatitis and food allergies. Allergens include dust, pollen, mold, and pet dander or pet hair.  
      In one aspect, the invention provides a method for treating a subject suffering from an allergic condition, in particular an atopic allergic condition, said method comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising a cathepsin S inhibitor.  
      In another aspect, the invention provides a method for treating a subject suffering from an IgE-mediated allergic condition, in particular an atopic allergic condition, said method comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising a cathepsin S inhibitor.  
      A third aspect of the invention provides the use, or the use for the manufacture of a medicament, of a cathepsin S inhibitor for treating an allergic condition, more in particular for treating IgE-mediated allergic conditions, still more in particular treating hay fever, asthma, atopic dermatitis or food allergies. The invention also features anti-allergic pharmaceutical compositions comprising as active ingredient an effective amount of a cathepsin S inhibitor, and a pharmaceutically acceptable carrier. The active ingredient can be formulated in any manner suitable for the particular allergic condition, including aerosol, oral and topical formulations and time-release formulations.  
      The present invention concerns the treatment of an allergic condition using one or more compounds which can be represented by formula (I) as defined above.  
      One embodiment of the invention is the treatment of an allergic condition using a compound of formula(I), wherein Ar 2  is selected from 5-7 membered monocyclic rings, and [5,6], [6,6], [6,5], and [5,5] fused bicyclic ring systems, said ring or ring system being carbocyclic or heterocyclic, saturated, unsaturated, or aromatic, optionally substituted with halo, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  hydroxyalkyl, nitro, hydroxy, amino, mono- or di-(C 1-6  alkyl)amino, C 1-4  alkoxy, C 2-4  alkoxycarbonyl, C 2-6  acyl, C 2-6  acyloxy, C 1-5  alkylsulfonyl, C 1-5  alkoxycarbonylC 1-4  alkoxy, cyano, and mono- or di-(C 1-6  alkyl)carbamoyl.  
      Another embodiment of the invention is the use of a compound of formula (I), wherein Ar 2  is selected from 2,5-di(C 1-6  alkyl)aminopyrrolyl and the following 6 formulae:  
                 
 
 wherein 
          each dashed line may be an sp 2  bond or absent;     X c  is O, S, or N; and X d  is O or S;         R 1  is hydrogen, halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, C 2-5  alkenyl, cyano, nitro, R a R b N, C 2-8  acyl, C 1-5  heterocyclyl, (C 1-5  heterocyclyl)C 1-5  alkylene, R 11 S, R 11 SO, R 11 SO 2 , R c OC═O, R c R d NC═O, or R c R d NSO 2 ; or R 1  can be taken together with R 27  as provided below;     R 2  is hydrogen, halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, C 2-5  alkenyl, cyano, nitro, R e R f N, C 1-5  heterocyclyl, or C 2-8  acyl;     R 3  is hydrogen, halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, C 2-5  alkenyl, cyano, nitro, R g R h N, C 2-8  acyl, C 1-5  heterocyclyl, R h OC═O, R g R h NC═O, or R g R h NSO 2 ;     R a  is selected from hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R j OC═O, R i R j NC═O, R 12 SO, R 12 SO 2 , R 12 S, and R i R j NSO 2 ;     R e  is selected from hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R 32 OC═O, R 32 R 33 NC═O, R 13 SO, R 13 SO 2 , R 13 S, and R 32 R 33 NSO 2 ;     R m  is selected from hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R 34 OC═O, R 34 R 35 NC═O, R 15 SO, R 15 SO 2 , R 15 S, and R 34 R 35 NSO 2 ;     R o  is selected from hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R 36 OC═O, R 36 R 37 NC═O, R 19 SO, R 19 SO 2 , R 19 S, and R 36 R 37 NSO 2 ;     each of R b , R f , R n , R p , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 39 , and R 40  is independently selected from hydrogen, C 1-5 alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, and C 1-5  heteroaryl; 
        alternatively, R a  and R b , R e  and R f , R m  and R n , and R o  and R p , independently, can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;    
        each of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 19 , R 38 , and R 41  is independently C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, or C 1-5  heterocyclyl;     each of R c  and R d , and R i  and R j  are independently are hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, or C 1-5  heteroaryl; alternatively, R c  and R d , and R i  and R j , independently, can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;     R 9  is hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl, C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R 17 OC═O, R 17 R 18 NC═O, R 16 S, R 16 SO, R 16 SO 2 , or R 17 R 18 NSO 2 ;     R h  is hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, phenethyl or C 1-5  heterocyclyl; alternatively, R g  and R h  can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;     R 17  and R 18  independently are hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, benzyl, or C 1-5  heterocyclyl;     alternatively, R 17  and R 18  can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;     Y e  is nitrogen or R 20 C;     Z e  is nitrogen or R 21 C; 
        R 20  is hydrogen, halogen, C 1-5  alkoxy, C 1-5  alkyl, C 2-5  alkenyl, cyano, nitro, R m R n N, C 2-8  acyl, R m OC═O, R 14 S, R 14 SO, or R 14 SO 2 ;    
        R 21  is hydrogen, halogen, C 1-5  alkoxy, C 1-5  alkyl, C 2-5  alkenyl, cyano, nitro, R o R p N, C 2-8  acyl, R 16 OC═O, R 11 S, R 11 SO, or R 11 SO 2 ; 
        alternatively, R 3  and R 20  or R 3  and R 21  can be taken together to form an optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic; wherein said ring may be optionally substituted with halo, di(C 1-5  alkyl)amino, C 2-5  acyl, and C 1-5  alkoxy;    
        R 27  is hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, naphthyl, benzyl, phenethyl, C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R 29 OC═O, R 30 R 31 NC═O, R 29 SO, R 29 S, R 29 SO 2 , or R 30 R 31 NSO 2 ; 
        or, alternatively, R 27  and R 1  can be taken together to form an optionally substituted 5- or 6-membered heterocyclic ring with optionally 1 to 3 additional heteroatom moieties in the ring selected from O, NR 9 , NR 10 , N, SO 2 , C═O, and S; which ring may be saturated, unsaturated or aromatic;     R 9  and R 10  are independently selected from H, C 1-3  alkyl, and —CH 2 CO 2 (C 1-4  alkyl);    
        X f  is CHR 1f , ═N—, NH, C═O, SO 2 , CHSR 1f  wherein, in formula (f), R 1f  is hydrogen, halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, C 3-5  alkenyl, cyano, nitro, R 39 R 40 N, C 2-8  acyl, C 1-5  heterocyclyl, (C 1-5  heterocyclyl)C 1-5  alkylene, R 41 S, R 41 SO, R 41 SO 2 , R 39 OC═O, R 39 R 40 NC═O, R 39 R 40 NSO 2 , R 41 SO 3 — or R 39 (C═O)O—;     Y f  is CH 2 , CHR 2f , ═CR 2f , O, or NR 2f , wherein R 2f  is H, C 1-7  alkyl, C 3-5  alkenyl, C 2-8  acyl, C 1-5  heterocyclyl, (C 1-5  heterocyclyl)-C 1-5  alkylene, phenyl, (phenyl)-C 1-5  alkylene, (C 3-7  cycloalkyl)-C 1-5  alkylene, (H 2 NCO)—C 1-5  alkylene, C 1-5  haloalkyl, C 1-5  cyanoalkyl, (C 1-5  alkoxycarbonyl)C 1-5  alkylene, and (phenylcarbonyl)NH—;     m is 0 or 1;     p is 0 or 1;    

      wherein each of the above hydrocarbyl or heterocarbyl groups, unless otherwise indicated, and in addition to any specified substituents, is optionally and independently substituted with between 1 and 3 substituents selected from methyl, halomethyl, hydroxymethyl, halo, hydroxy, amino, nitro, cyano, C 1-5  alkyl, C 1-5  alkoxy, —COOH, C 2-6  acyl, [di(C 1-4  alkyl)amino]C 2-5  alkylene, [di(C 1-4  alkyl)amino]C 2-5  alkyl-NH—CO—, and C 1-5  haloalkoxy.  
      Another aspect of the invention provides pharmaceutical anti-allergic compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier. A further embodiment of the invention is a process for making a pharmaceutical anti-allergic composition comprising mixing a disclosed compound as described above, with a suitable pharmaceutically acceptable carrier.  
      The invention features a method of treating allergic disorders or conditions mediated by the cathepsin S enzyme, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. If more than one active agent is administered, the therapeutically effective amount may be a jointly effective amount. The compounds described herein inhibit the protease activity of human cathepsin S, an enzyme involved in the immune response. In preferred embodiments, cathepsin S inhibition is selective.  
      Additional features and advantages of the invention will become apparent from the detailed description below, including examples, and the appended claims. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       FIG. 1  shows the inhibition of human T cell proliferative responses to two species of dust mites,  Der p  and  Der f . Top panel,  FIG. 1A : Dilution curve for purified PBMC from an allergy donor were cultured with titrated doses of allergen extracts prepared from  Der p  and  Der f  for seven days. Proliferation of T cells was scored by measuring  3 H-thymidine incorporation for 18 h at the end of culture. Bottom panel,  FIG. 1B : Effect of titrated doses of LHVS on proliferative responses of T cells to dust mite extracts.  
       FIG. 2  shows the inhibition of human T cell proliferative responses to ragweeds but not ConA by LHVS. Top panel,  FIG. 2A : Dilution curve for purified PBMC from an allergy donor were cultured with titrated doses of allergen extracts prepared from Ragweed short and Ragweed giant for seven days. Proliferation of T cells was scored by measuring  3 H-thymidine incorporation for 18 h at the end of culture. Bottom panel,  FIG. 2B : Effect of titrated doses of LHVS on proliferative responses of T cells to ragweed extracts.  
       FIG. 3  shows the inhibition of human T cell proliferative responses to  Der f  but not ConA by two cathepsin S inhibitors. Purified PBMC from an allergy donor were cultured with allergen extracts prepared from  Der f  in the presence of titrated doses of indicated example compounds for seven days. Proliferation of T cells was scored by measuring  3 H-thymidine incorporation for 18 h at the end of culture. Top panel,  FIG. 3A  shows the effect of titrated doses of Example 8. Bottom panel,  FIG. 3B  shows the effect of titrated doses of Example 52.  
       FIG. 4  shows the inhibition of human T cell proliferative responses to ragweeds but not ConA by two cathepsin S inhibitors. Top panel,  FIG. 4A : Effect of titrated doses of Example 8 on proliferative responses of T cells to ragweed extracts. Bottom panel,  FIG. 4B : Effect of titrated doses of Example 53 on proliferative responses of T cells to ragweed extracts.  
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
      The invention features pyrazole compounds of formula (I), methods of making them, compositions containing them, and methods of using them to treat diseases and conditions, including those mediated by Cathepsin S.  
      A target of the present invention was to determine whether the presentation of particular antigens in a human system is affected by the inhibition of cathepsin S. According to the invention, it now has been found that inhibitors of cathepsin S block the presentation of several crude allergen extracts in a human ex vivo assay, thereby supporting the use of cathepsin S inhibitors for the treatment of such allergic conditions.  
      Blocking Ii degradation should decrease antigen presentation to CD4 T cells and disrupt-the normal immune response. A cathepsin S inhibitor should specifically affect the activation of CD4 T cells, thus limiting the extent of concomitant immunosuppression, an undesirable side effect of corticosteroid therapy.  
      By using cathepsin S inhibitors according to the methods of the present invention, the immunological component of the allergic reaction can be blocked to varying degrees, with the advantage over current therapies of being more selective, having fewer or reduced side effects, or both. The present invention is based, in part, on the finding that cathepsin S inhibitors can block the presentation of crude allergen extracts in a human ex vivo assay. This ex vivo system closely mimics the process that occurs in the whole body wherein antigens enter the blood stream, and are presented by antigen presenting cells, which in turn activate CD4 T cells. In the case of treating a subject, the inhibitor or a metabolite thereof would also be present in the blood as in the ex vivo assay.  
      The invention features the treatment of an allergic condition using one or more pyrazole compounds of formula (I).  
      A. Terms  
      The following terms are defined below and by their usage throughout this disclosure.  
      “Alkyl” includes optionally substituted straight chain and branched hydrocarbons with at least one hydrogen removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, and so on. Alkyl includes cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.  
      “Alkenyl” includes optionally substituted straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon double bond (sp 2 ). Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkenyl includes cycloalkenyl. Cis and trans or (E) and (Z) forms are included within the invention.  
      “Alkynyl” includes optionally substituted straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon triple bond (sp). Alkynyls include ethynyl, propynyls, butynyls, and pentynyls. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkynyl does not include cycloalkynyl.  
      “Alkoxy” includes an optionally substituted straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on. “Aminoalkyl”, “thioalkyl”, and “sulfonylalkyl” are analogous to alkoxy, replacing the terminal oxygen atom of alkoxy with, respectively, NH (or NR), S, and SO 2 . Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl, and so on.  
      “Aryl” includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl, and so on, any of which may be optionally substituted. Aryl also includes arylalkyl groups such as benzyl, phenethyl, and phenylpropyl. Aryl includes a ring system containing an optionally substituted 6-membered carbocyclic aromatic ring, said system may be bicyclic, bridge, and/or fused. The system may include rings that are aromatic, or partially or completely saturated. Examples of ring systems include indenyl, pentalenyl, 1-4-dihydronaphthyl, indanyl, benzimidazolyl, benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl, and so on.  
      “Heterocyclyl” includes optionally substituted aromatic and nonaromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatom moiety (SO 2 , CO, CONH, COO) in the ring. Unless otherwise indicated, a heterocyclic radical may have a valence connecting it to the rest of the molecule through a carbon atom, such as 3-furyl or 2-imidazolyl, or through a heteroatom, such as N-piperidyl or 1-pyrazolyl. Preferably a monocyclic heterocyclyl has between 4 and 7 ring atoms, or between 5 and 6 ring atoms; there may be between 1 and 5 heteroatoms or heteroatom moieties in the ring, and preferably between 1 and 3. A heterocyclyl may be saturated, unsaturated, aromatic (e.g., heteroaryl), nonaromatic, or fused.  
      Heterocyclyl also includes fused, e.g., bicyclic, rings, such as those optionally condensed with an optionally substituted carbocyclic or heterocyclic five- or six-membered aromatic ring. For example, “heteroaryl” includes an optionally substituted six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms condensed with an optionally substituted five- or six-membered carbocyclic or heterocyclic aromatic ring. Said heterocyclic five- or six-membered aromatic ring condensed with the said five- or six-membered aromatic ring may contain 1, 2 or 3 nitrogen atoms where it is a six-membered ring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur where it is a five-membered ring.  
      Examples of heterocyclyls include thiazoylyl, furyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl. For example, preferred heterocyclyls or heterocyclic radicals include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino, cycloheptylimino, and more preferably, piperidyl.  
      Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl.  
      “Acyl” refers to a carbonyl moiety attached to either a hydrogen atom (i.e., a formyl group) or to an optionally substituted alkyl or alkenyl chain, or heterocyclyl.  
      “Halo” or “halogen” includes fluoro, chloro, bromo, and iodo, and preferably chloro or bromo as a substituent.  
      “Alkanediyl” or “alkylene” represents straight or branched chain optionally substituted bivalent alkane radicals such as, for example, methylene, ethylene, propylene, butylene, pentylene or hexylene.  
      “Alkenediyl” represents, analogous to the above, straight or branched chain optionally substituted bivalent alkene radicals such as, for example, propenylene, butenylene, pentenylene or hexenylene. In such radicals, the carbon atom linking a nitrogen preferably should not be unsaturated.  
      “Aroyl” refers to a carbonyl moiety attached to an optionally substituted aryl or heteroaryl group, wherein aryl and heteroaryl have the definitions provided above. In particular, benzoyl is phenylcarbonyl.  
      As defined herein, two radicals, together with the atom(s) to which they are attached may form an optionally substituted 4- to 7-, 5- to 7-, or a 5- to 6-membered ring carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic. Said rings may be as defined above in the Summary of the Invention section. Particular examples of such rings are as follows in the next section.  
      “Pharmaceutically acceptable salts, esters, and amides” include carboxylate salts (e.g., C 1-8  alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic) amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate. These may include alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine. See example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference. Representative′pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C 1-6  alkyl amines and secondary di (C 1-6  alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C 1-3  alkyl primary amines, and di (C 1-2  alkyl)amines. Representative pharmaceutically acceptable esters of the invention include C 1-7  alkyl, C 5-7  cycloalkyl, phenyl, and phenyl(C 1-6  )alkyl esters. Preferred esters include methyl esters.  
      “Patient” or “subject” includes mammals such as humans and animals (dogs, cats, horses, rats, rabbits, mice, non-human primates) in need of observation, experiment, treatment or prevention in connection with the relevant disease or condition. Preferably, the patient or subject is a human.  
      “Composition” includes a product comprising the specified ingredients in the specified amounts as well as any product which results directly or indirectly from combinations of the specified ingredients in the specified amounts.  
      “Therapeutically effective amount” or “effective amount” means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.  
      Concerning the various radicals in this disclosure and in the claims, three general remarks are made. The first remark concerns valency. As with all hydrocarbon radicals, whether saturated, unsaturated or aromatic, and whether or not cyclic, straight chain, or branched, and also similarly with all heterocyclic radicals, each radical includes substituted radicals of that type and monovalent, bivalent, and multivalent radicals as indicated by the context of the claims. The context will indicate that the substituent is an alkylene or hydrocarbon radical with at least two hydrogen atoms removed (bivalent) or more hydrogen atoms removed (multivalent). An example of a bivalent radical linking two parts of the molecule is G in formula (I) which links two rings.  
      Second, radicals or structure fragments as defined herein are understood to include substituted radicals or structure fragments. Hydrocarbyls include monovalent radicals containing carbon and hydrogen such as alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl (whether aromatic or unsaturated), as well as corresponding divalent radicals such as alkylene, alkenylene, phenylene, and so on. Heterocarbyls, include monovalent and divalent radicals containing carbon, hydrogen, and at least one heteroatom. Examples of monovalent heterocarbyls include acyl, acyloxy, alkoxyacyl, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl, and so on.  
      Using “alkyl” as an example, “alkyl” should be understood to include substituted alkyl having one or more substitutions, such as between 1 and 5, 1 and 3, or 2 and 4 substituents. The substituents may be the same (dihydroxy, dimethyl), similar (chlorofluoro), or different (chlorobenzyl- or aminomethyl-substituted). Examples of substituted alkyl include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, perfluoromethyl, and 3-iodocyclopentyl), hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, aminoalkyl (such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and 2-aminopropyl), nitroalkyl, alkylalkyl, and so on. A di(C 1-6  alkyl)amino group includes independently selected alkyl groups, to form, for example, methylpropylamino and isopropylmethylamino, in addition dialkylamino groups having two of the same alkyl group such as dimethyl amino or diethylamino.  
      Third, only stable compounds are intended. For example, where there is an NR′R″ group, and R can be an alkenyl group, the double bond is at least one carbon removed from the nitrogen to avoid enamine formation. Similarly, where a dashed line is an optional sp 2  bond, if it is absent, the appropriate hydrogen atom(s) is(are) included.  
      Preferred substitutions for Ar or Ar 1  include methyl, methoxy, fluoromethyl, difluoromethyl, perfluoromethyl (trifluoromethyl), 1-fluoroethyl, 2-fluoroethyl, ethoxy, fluoro, chloro, and bromo, and particularly methyl, bromo, chloro, perfluoromethyl, perfluoromethoxy, methoxy, and fluoro. Preferred substitution patterns for Ar or Ar 1  are 4-substituted or 3,4-disubstituted phenyl.  
      Compounds of the invention are further described in the next section.  
      B. Compounds  
      The invention features compounds of formula (I) as described in the Summary section.  
      Preferred compounds include those wherein: 
      (a) Ar 2  is selected from formulae (e);     (b) Ar 2  is selected from formulae (f);     (c) Ar 2  is selected from formula (a)-(d);     (d) R 1  is halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, cyano, nitro, R a R b N or is taken together with R 27 ;     (e) R 1  is taken together with R 27 ;     (f) R 1  and R 27  taken together are selected from: 
        (1) —CH 2 NR 9 —(C═O)—    (2) OCH 2 (C═O)—    (3) —CH 2 CH 2 (C═O)—    (4) —CH 2 —O(C═O)—    (5) —CH 2 S(C═O)—    (6) —O(C═O)—    (7) —CH 2 (C═O)—    (8) —NR 9 (C═O)—    (9) —NR 9 (SO 2 )—    (10) —CH 2 NR 9 SO 2 —    (11) —NR 9 CH 2 (C═O)— and —SCH 2 (C═O)—   
        (g) R 1  and R 27  taken together are selected from: 
        a) —CH 2 —(C═O)—    b) —O(C═O)—    c) —CH 2 CH 2 —    d) —S(C═O)—    e) —N═N—    f) —NR 9 SO 2 —    g) —N═CR 9 —    h) —NR 9 (C═O)— and     i) —CH═CH—;    
        (h) R 2  is hydrogen, halogen, C 1-5  alkoxy, C 1-5  alkyl, cyano, or R e R f N, where R e  and R f  are H or C 1-5  alkyl, or are taken together to form a 5-7 membered heterocyclic ring;     (i) R 3  is hydrogen, halogen, C 1-5  alkoxy, C 1-5  alkyl, cyano, nitro, or R g R h N, where R e  and R f  are H or C 1-5  alkyl, or are taken together to form a 5-7 membered heterocyclic ring;     (j) R 5  and R 6  are independently selected from hydrogen and C 1-3  alkyl;     (k) one of R 5  and R 6  is H;     (l) R 5  and R 6  are each H;     (m) one of R 7  and R 8  is H and the other is 5-7 membered carbocyclyl or heterocyclyl;     (n) R 7  and R 8  are taken together to form an optionally substituted 5- to 7-membered carbocyclic or heterocyclic ring;     (o) R 7  and R 8  taken together form a six-membered heterocyclyl;     (p) R 7  and R 8  taken together form pyridinyl, pyrimidinyl, or piperazinyl, optionally N-substituted with —(C═O)R 4 , SO 2 —R 4 , or —(C═O)NHR 4 ;     (q) each of R a , R e , R m , and R o  is independently selected from hydrogen, C 1-5  alkyl, C 2-8  acyl, and the respective ROC═O, RRNC═O, RSO, RSO 2 , and RRNSO 2  groups;     (r) each of R a , R e , R m , R o , R b , R f , R n , and R p  is independently selected from hydrogen and C 1-5  alkyl; or, independently, R a  and R b , R e  and R f , R m  and R n , and R o  and R p , taken together, form an optionally substituted 4- to 7-membered carbocyclic or heterocyclic ring;     (s) (1)R a  and R b  taken together are independently morpholinyl, piperidinyl, or pyrrolidinyl; (2) R e  and R f  taken together are morpholinyl, piperidinyl, or pyrrolidinyl; or (3) both (1) and (2) apply;     (t) each of R c  and R d , R i  and R j , R k  and R l  is independently hydrogen or C 1-5  alkyl, alternatively, R c  and R d , R i  and R j , and R k  and R l , independently, can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;     (u) R c  and R d , R i  and R j , and R k  and R l , independently, are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;     (v) each of R b , R f , R n , R p , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 39  and R 40  is independently H or C 1-5  alkyl;     (w) each of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 19 , R 38 , and R 41  is independently H or C 1-5  alkyl;     (x) R g  is C 1-5  alkyl, C 2-8  acyl, R 17 OC═O, R 17 R 18 NC═O, R 16 S, R 16 SO, R 16 SO 2 , or R 17 R 18 NSO 2 ; and R h  hydrogen or C 1-5  alkyl; alternatively, R g  and R h  can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring;     (y) R 17  and R 18  independently are hydrogen or C 1-5  alkyl;     (z) n is 1;     (aa) n is 0;     (bb) G is C 3-4  alkanediyl, optionally substituted with hydroxy, halogen, (L)-C 1-5  alkyloxy, or [(L)-C 1-5  alkylene]amino;     (cc) G is C 3  alkanediyl, optionally substituted with hydroxy, (L)-C 1-5  alkyloxy, or [(L)-C 1-5  alkylene]amino;     (dd) each of R 20  and R 21  is independently selected from hydrogen, halogen, C 1-5  alkoxy, C 1-5  alkyl, cyano, nitro, and R m R n N or R o R p N, respectively;     (ee) each of R 20  and R 21  is independently selected from hydrogen, halogen, C 1-3  alkyl, and R m R n N or R o R p N, respectively;     (ff) Ar represents a monocyclic ring, optionally substituted with 1 to 2 substituents selected from halogen, C 1-5  alkyl, cyano, nitro, R 22 R 23 N, halomethyl, and halomethoxy;     (gg) Ar is a six membered ring substituted with between 1 and 2 substituents independently selected from methyl, halogen, CF 3 , and OCF 3 , said substituent or substituents being at the 4-position, or at the 3- and 4-positions, respectively;     (hh) each of R 22 , R 23 , and R 24  is hydrogen or C 1-5  alkyl;     (ii) R 25  and R 26  independently are hydrogen or C 1-5  alkyl; or, alternatively, R 25  and R 26  can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring;     (jj) each of R 25  and R 26  is independently hydrogen or C 1-5  alkyl;     (kk) W is NR 27 ;     (ll) W is CHR 28 , and R 28  is hydrogen or C 1-5  alkyl;     (mm) R 29  is C 1-5  alkyl; or R 30  and R 31  are independently selected from hydrogen and C 1-5  alkyl, or R 30  and R 31  are taken together to form a 5-6 membered heterocyclyl;     (nn) Ar 2  is formula (e) and R 1  is halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, cyano, nitro, and R a R b N, or R 1  can be taken together with R 27  as provided below; R 2  is hydrogen, halogen, C 1-5  alkoxy, C 1-5  alkyl, or R e R f N; R 3  is hydrogen, halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, cyano, R g R h N; R 5  and R 6  are independently selected from hydrogen and C 1-3  alkyl;     (oo) R 7  and R 8  independently are taken together to form an optionally substituted 5- to 7-membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic;     (pp) each of R a , R e , R m , and R o  is independently selected from hydrogen, C 1-5  alkyl, C 2-8  acyl, and the respective ROC═O, RRNC═O, RS, RSO, RSO 2 , and RRNSO 2  groups;     (qq) each of R b , R f , R n , and R p , is independently selected from hydrogen and C 1-5  alkyl; each of R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 19 , and R 38  is independently C 1-5  alkyl; each of R c  and R d , R i  and R j , R k  and R l , R 32  and R 33 , R 34  and R 35 , R 36  and R 37  are independently are hydrogen or C 1-5 -alkyl, or are taken together to form an optionally substituted 4- to 7-membered heterocyclic ring;     (rr) R g  is hydrogen, C 1-5  alkyl, C 2-8  acyl, R 17 OC═O, R 17 R 18 NC═O, R 16 S, R 16 SO, R 16 SO 2 , or R 17 R 18 NSO 2 ; R h  is hydrogen or C 1-5  alkyl; 
        alternatively, R g  and R h  can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring; R 17  and R 18  independently are hydrogen or C 1-5  alkyl; n is 0 or 1;    
        (ss) G is C 3-4  alkenediyl or C 3-4  alkanediyl, optionally substituted with hydroxy, halogen, C 1-5  alkyloxy, (L)-C 1-5  alkoxy, or [(L)-C 1-5  alkylene]amino; L is amino, mono- or di-C 1-5  alkylamino, pyrrolidinyl, morpholinyl, piperidinyl homopiperidinyl, or piperazinyl, wherein available ring nitrogens may be optionally substituted with C 1-5  alkyl, benzyl, C 1-5  alkylcarbonyl, or C 1-5  alkyloxycarbonyl;     (tt) Y e  is nitrogen or R 20 C; Z e  is nitrogen or R 21 C;     (uu) R 20  and R 21  are independently selected from hydrogen, halogen, C 1-5  alkoxy, C 1-5  alkyl, cyano, nitro, and R m R n N or R o R p N, respectively; alternatively, R 3  and R 20  or R 3  and R 21  can be taken together to form an optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring;     (vv) Ar represents a monocyclic or bicyclic aryl or heteroaryl ring, optionally substituted with between 1 and 3 substituents independently selected from halogen, C 1-5  alkoxy, C 1-5  alkyl, cyano, nitro, R 22 R 23 N, R 24 SO 2 , R 24 OC═O, R 25 R 26 NC═O, CF 3 , OCF 3 , CF 3 S, and C 1-5  alkylthio; R 22  is hydrogen, C 1-5  alkyl, phenyl, benzyl, phenethyl, C 1-5  heterocyclyl, C 2-8  acyl, aroyl, R 24 OC═O, R 25 R 26 NC═O, R 24 SO, R 24 SO 2 , or R 25 R 26 NSO 2 ; R 23  is hydrogen or C 1-5 alkyl;     (ww) alternatively, R 22  and R 23  can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring; R 24  is hydrogen or C 1-5  alkyl; R 25  and R 26  are independently hydrogen or C 1-5  alkyl; or, alternatively, R 25  and R 26  can be taken together to form an-optionally substituted 4- to 7-membered heterocyclic; W is NR 27  or CHR 28 ; R 27  is hydrogen, C 1-5  alkyl, R 29 OC═O, R 30 R 31 NC═O, R 29 SO, R 29 SO 2 , or R 30 R 31 NSO 2 ; or, alternatively, R 27  and R 1  can be taken together to form an optionally substituted 5- or 6-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic; R 28  is hydrogen, hydroxy, C 1-5  heterocyclyl, phenyl, or C 1-5  alkyl; R 29  is C 1-5  alkyl; R 30  and R 31  are independently selected from hydrogen, C 1-5  alkyl; alternatively, R 30  and R 31  can be taken together to form an optionally substituted 4- to 7-membered heterocyclic;     (xx) one of R 5  and R 6  is H; R 7  and R 8  are taken together to form an optionally substituted 6-membered carbocyclic or heterocyclic ring; and Ar represents a monocyclic ring, optionally substituted with 1 to 2 substituents selected from halogen, C 1-5  alkyl, cyano, nitro, R 22 R 23 N, CF 3  and OCF 3 ;     (yy) both R 5  and R 6  are each H, and Ar is a six membered ring substituted with between 1 and 2 substituents independently selected from halogen, methyl, CF 3 , and OCF 3 , said substituent or substituents being at the 4-position, or at the 3- and 4-positions;     (zz) a R 7  and R 8  taken together form tetrahydropyridinyl, optionally N-substituted with —(C═O)R 4 , SO 2 —R 4 , or —(C═O)NHR 4 ;     (aaa) X f  is C═O, SO 2 , or CHR 1F , and Y f  is O or NR 2f , where R 2f  is H, C 1-5  alkyl, C 2-5  heterocyclyl, C 1-5  cyanoalkyl, or (C 1-5  alkoxycarbonyl)C 1-5  alkylene;     (bbb) R 2f  is H, C 1-3  alkyl, or a C 2-5  heterocyclyl;     (ccc) X f  is C═O, and Y f  is O, CHR 2f  or NR 2f , where R 2f  is H, C 1-5  alkyl, C 2-5  heterocyclyl, C 1-5  cyanoalkyl, or (C 1-5  alkoxycarbonyl)C 1-5  alkylene;     (ddd) X f  is C═O and Y f  is O;     (eee) m is 0 and p is 0; m is 0 and p is 1; or m is 1 and p is 0;     (fff) p is 0;     (ggg) R z  is H;     (hhh) R z  is OH;     (iii) R z  is absent;     (jjj) R 20  and R 3  taken together are a six-membered carbocyclic or heterocyclic ring optionally substituted with between 1 and 3 substituents independently selected from halo, C 1-3  alkoxy, di(C 1-3  alkyl)amino, and C 2-5  acyl;     (kkk) each of R 20  and R 3  is H; and     (lll) combinations of the above.    

      Specific preferred compounds include:  
      1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one; 1-(1-{3-[3-(3,4-Dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one; 3-(3,4-Dichloro-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide; 6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one; 3-(3,4-Dichloro-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide; [3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetonitrile; [3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetic acid ethyl ester; 5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-one; 1-{3-[4-(6-Chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide; 3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dimethyl-1,3-dihydro-benzoimidazol-2-one; 3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one; 3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-imidazo[4,5-b]pyridin-2-one; 3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(5-methoxy-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide; 3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one; 5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one; 6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one; 1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one; 4-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one; 4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one; 1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one; 1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-benzoimidazol-2-one; and 6-Chloro-1-(1-{3-[3-(4-chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one.  
      Furthermore, preferred compounds include those wherein Ar or Ar 1  is selected from 4-trifluoromethylphenyl, 4-bromophenyl, 4-chlorophenyl, 4-chloro-3-methylphenyl and 3,4-dichlorophenyl.  
      Related Compounds  
      The invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, acids, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms. Related compounds also include compounds of the invention that have been modified to be detectable, e.g., isotopically labelled with  18 F for use as a probe in positron emission tomography (PET) or single-photon emission computed tomography (SPECT).  
      The invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. See, e.g., Greene and Wuts,  Protective Groups in Organic Synthesis,  3 rd  ed., (1999) John Wiley &amp; Sons, NY. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention.  
      Hydroxyl Protecting Groups  
      Protection for the hydroxyl group includes methyl ethers, substituted methyl ethers, substituted ethyl ethers, substitute benzyl ethers, and silyl ethers.  
      Substituted Methyl Ethers  
      Examples of substituted methyl ethers include methyoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.  
      Substituted Ethyl Ethers  
      Examples of substituted ethyl ethers include 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.  
      Substituted Benzyl Ethers  
      Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.  
      Silyl Ethers  
      Examples of silyl ethers include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenylsilyl.  
      Esters  
      In addition to ethers, a hydroxyl group may be protected as an ester. Examples of esters include formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate(mesitoate)  
      Carbonates  
      Examples of carbonate protecting groups include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate.  
      Assisted Cleavage  
      Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate, 4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.  
      Miscellaneous Esters  
      Examples of miscellaneous esters include 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate), o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkyl N,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate.  
      Sulfonates  
      Examples of sulfonates include sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.  
      Amino Protecting Groups  
      Protection for the amino group includes carbamates, amides, and special—NH protective groups.  
      Examples of carbamates include methyl and ethyl carbamates, substituted ethyl carbamates, assisted cleavage carbamates, photolytic cleavage carbamates, urea-type derivatives, and miscellaneous carbamates.  
      Carbamates  
      Examples of methyl and ethyl carbamates include methyl and ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl, and 4-methoxyphenacyl.  
      Substituted Ethyl  
      Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and 4′-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.  
      Assisted Cleavage  
      Examples of assisted cleavage include 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and 2-(trifluoromethyl)-6-chromonylmethyl.  
      Photolytic Cleavage  
      Examples of photolytic cleavage include m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o-nitrophenyl)methyl.  
      Urea-Type Derivatives  
      Examples of urea-type derivatives include phenothiazinyl-(10)-carbonyl derivative, N′-p-toluenesulfonylaminocarbonyl, and N′-phenylaminothiocarbonyl.  
      Miscellaneous Carbamates  
      Examples of miscellaneous carbamates include t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and 2,4,6-trimethylbenzyl.  
      Examples of Amides Include:  
      Amides  
      N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl, N-p-phenylbenzoyl.  
      Assisted Cleavage  
      N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (N′-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine derivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-one.  
      Cyclic Imide Derivatives  
      N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl.  
      Special —NH Protective Groups  
      Examples of special NH protective groups include N-Alkyl and N-Aryl Amines  
      N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and N-2-picolylamine N′-oxide.  
      Imine Derivatives  
      N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, and N-(N′,N′-dimethylaminomethylene).  
      Protection for the Carbonyl Group  
      Acyclic Acetals and Ketals  
      Examples of acyclic acetals and ketals include dimethyl, bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.  
      Cyclic Acetals and Ketals  
      Examples of cyclic acetals and ketals include 1,3-dioxanes, 5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane, 5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane, 4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane, O,O′-phenylenedioxy and 1,5-dihydro-3H-2,4-benzodioxepin.  
      Acyclic Dithio Acetals and Ketals  
      Examples of acyclic dithio acetals and ketals include S,S′-dimethyl, S,S′-diethyl, S,S′-dipropyl, S,S′-dibutyl, S,S′-dipentyl, S,S′-diphenyl, S,S′-dibenzyl and S,S′-diacetyl.  
      Cyclic Dithio Acetals and Ketals  
      Examples of cyclic dithio acetals and ketals include 1,3-dithiane, 1,3-dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.  
      Acyclic Monothio Acetals and Ketals  
      Examples of acyclic monothio acetals and ketals include O-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or —S-phenyl and O-methyl-S-2-(methylthio)ethyl.  
      Cyclic Monothio Acetals and Ketals  
      Examples of cyclic monothio acetals and ketals include 1,3-oxathiolanes.  
      Miscellaneous Derivatives  
      O-Substituted Cyanohydrins Examples of O-substituted cyanohydrins include O-acetyl, O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.  
      Substituted Hydrazones  
      Examples of substituted hydrazones include N,N-dimethyl and 2,4-dinitrophenyl.  
      Oxime Derivatives  
      Examples of oxime derivatives include O-methyl, O-benzyl and O-phenylthiomethyl.  
      Imines  
      Substituted Methylene Derivatives, Cyclic Derivatives  
      Examples of substituted methylene and cyclic derivatives include oxazolidines, 1-methyl-2-(1′-hydroxyalkyl)imidazoles, N,N′-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles, diethylamine adducts, and methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide)(MAD)complex.  
      Protection for the Carbonyl Group  
      Esters  
      Substituted Methyl Esters  
      Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl, p-bromophenacyl, α-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N-phthalimidomethyl.  
      2-Substituted Ethyl Esters  
      Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl, 2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2′-pyridyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, α-methylcinnamyl, phenyl, p-(methylmercapto)phenyl and benzyl.  
      Substituted Benzyl Esters  
      Examples of substituted benzyl esters include triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, 4-picolyl and p-P-benzyl.  
      Silyl Esters  
      Examples of silyl esters include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl and di-t-butylmethylsilyl.  
      Activated Esters  
      Examples of activated esters include thiols.  
      Miscellaneous Derivatives  
      Examples of miscellaneous derivatives include oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group and pentaaminocobalt(III) complex.  
      Stannyl Esters  
      Examples of stannyl esters include triethylstannyl and tri-n-butylstannyl.  
      Amides and Hydrazides  
      Amides  
      Examples of amides include N,N-dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-Nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides.  
      Hydrazides  
      Examples of hydrazides include N-phenyl and N,N′-diisopropyl hydrazides.  
      C. Synthesis  
      The compounds of the present invention may be prepared by conventional synthetic organic chemistry and by matrix or combinatorial methods according to Schemes 1 to 10 below, and Examples 1 to 31. Those of ordinary skill in the art will be able to modify and adapt the guidance provided herein to make the disclosed compounds.  
                 
 
                 
 
                 
 
                 
 
                 
 
                 
 
                 
 
                 
 
                 
 
                 
 
      D. Formulation and Administration  
      The present compounds inhibit the proteolytic activity of human cathepsin S and therefore are useful as a medicine especially in methods for treating patients suffering from disorders or conditions which are modulated or regulated by the inhibition of cathepsin S activity.  
      The invention features a method for treating a subject with a condition mediated by cathepsin S, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention. The invention also provides a method for inhibiting cathepsin S activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention. A third method is a method for treating an autoimmune disease, or inhibiting the progression of an autoimmune disease, in a subject, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a disclosed compound. The autoimmune disease can be, for example, lupus, rheumatoid arthritis, or preferably, asthma. The invention also provides a method for treating or inhibiting the progression of tissue transplant rejection in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention. The administration step can occur before, during, and/or after a tissue transplant procedure.  
      The invention features a method for treating a subject with an allergic condition mediated by cathepsin S, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention. The invention also provides a method for inhibiting cathepsin S activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.  
      Atherosclerosis is a life-threatening disease that is now recognized as an inflammatory disease characterized by significant remodeling of the extracellular matrix architecture of the arterial wall. J. Liu, et al., Arterioscler. Thromb. Vasc. Biol. 24, 1359 (2004). Cathepsin S has been implicated in atherogenesis in mice, and observations in diseased human arterial tissue reportedly suggest a similar function for this protease in human atherosclerotic lesions. G. K. Sukhova, et al., J. Clinicla Investigation 111(6), 897, 905 (2003); S. Taleb, et al., The FASEB Journal 19, 1540 (2005). Atherosclerotic lesions in Apo E-deficient mice reportedly showed an increase in expression of lysosomal cathepsins, including cathepsin S, and this cathepsin reportedly localized mainly in intimal smooth muscle cells and macrophages and medial smooth muscle cells in human atherosclerotic lesions, whereas nonatherosclerotic arteries showed no cathepsin S expression. J. Liu, et al., Arterioscler. Thromb. Vasc. Biol. 24, 1359, 1361 (2004), and refs. therein. This expression pattern is considered to affirm an association of proteases, such as cathepsin S, with atherogenesis in human beings, and the inflammatory process at the core of atherogenesis is reportedly linked with proteolisis due to cathepsins. J. Liu, et al., Arterioscler. Thromb. Vasc. Biol. 24, 1359, (2004). Furthermore, cathepsin S was reported as a plausible molecular link between enlarged fat mass and atherosclerosis (S. Taleb, et al., The FASEB Journal 19, 1540, 1542 (2005)), and serum cathepsin S levels were reportedly increased in patients with atherosclerotic stenosis. J. Liu, et al., in press, reported as ref 23 in S. Taleb, et al., J. Clin. Endocrinol. Metab. 91(3), 1042, 1045 (2006). A significant increase of serum cathepsin S levels in both atherosclerosis and diabetes was also reported. J. Liu, et al., Atherosclerosis 186, 411, 418 (2006). Despite reported associations of and correlations between cathepsin S and the atherosclerotic process, such as those provided by the foregoing references, it was recently acknowledged that “direct participation of cathepsin S or other cysteine proteases in human atherosclerosis remains uncertain.” J. Liu, et al., Atherosclerosis 186, 411, 412 (2006). Furthermore, it has also been recently acknowledged that “[i]n humans, limited information is available [concerning the importance of cysteine proteases in atherosclerosis]”, that “more human studies are needed to confirm . . . that cathepsin S may have a significant influence on human atherogenesis” (J. Liu, et al., Atherosclerosis 186, 411, 417 (2006)), and that “the pathophysiology of cathepsin S and cystatin C in human atherosclerosis and diabetes requires further investigation”. J. Liu, et al., Atherosclerosis 186, 411, 418 (2006). However, recently obtained direct evidence of the role played by cathepsin S in atherosclerosis strengthens an earlier claim of the need to consider cathepsin S as a therapeutic target in arterial diseases. G. K. Sukhova, et al., J. Clinical Investigation 111(6), 897, 905 (2003). Recent first direct demonstrations of the role played by cathepsin S in atherosclerosis include the “demonstrat[ion] for the first time that weight loss, which is known to be associated with a clear improvement in vascular function in human obesity leads to a marked decrease in serum [cathepsin S] and its enzymatic activity.” S. Taleb, et al., J. Clinical Endocrinology &amp; Metabolism 91(3), 1042, 1045 (2006). Further concluding that “this is the first study in humans showing that weight loss is associated with a decrease in [cathepsin S] circulating levels as well as adipose [cathepsin S] content along with soluble adhesion markers.” S. Taleb, et al., J. Clinical Endocrinology &amp; Metabolism 91(3), 1042, 1046 (2006). Another recent study “tested the hypothesis that cathepsin S is involved in plaque destabilization” in mice. K. J. Rodgers, et al., Arterioscler. Thromb. Vasc. Biol. 26, 851, 852 (2006). This recent study being “the first to show directly that cathepsin S is involved in atherosclerotic plaque destabilization and rupture.” K. J. Rodgers, et al., Arterioscler. Thromb. Vasc. Biol. 26, 851, 854, 855 (2006). In light of the currently ascertained role that is played by cathepsin S in atherosclerosis, there is the need for cathepsin S inhibitors to address therapeutic needs in the fight against atherosclerosis. Embodiments of this invention provide cathepsin S inhibitors and further embodiments of this invention provide methods for treating atherosclerosis by administering, in suitable pharmaceutical form, at least one cathepsin S inhibitor of this invention.  
      Microvasculature development, known as angiogenesis, occurs under many pathological and physiological conditions, and it generally accompanies cancer-related processes, such as tumor cell invasion, tumor growth and metastasis. Lysosomal cysteine protease cathepsins have been shown to be highly expressed in human and murine tumors, where angiogenesis plays important roles. B. Wang, et al., J. Bio. Chem. 281(9), 6020 (2006), and refs. therein. In light of the cathepsin variety, it was important to ascertain whether individual cathepsins, such as cathepsin S, affect angiogenesis, tumor growth, cell proliferation, and metastasis. With no prior in vivo evidence for or any mechanistic explanation of cathepsin S involvement in angiogenesis and presumably in tumor growth, it was recently ascertained that inhibition of cathepsin S activity or the absence of cathepsin S expression reduced microvessel formation. B. Wang, et al., J. Bio. Chem. 281(9), 6020, 6026 (2006). The study “demonstrated an important role for [cathepsin] S and its endogenous inhibitor Cyst C in regulating angiogenesis and tumor growth in a genetically engineered mouse model of pancreatic islet cancer” and “clearly demonstrated that [cathepsin] S contributes to angiogenesis and tumor progression” in mice. B. Wang, et al., J. Bio. Chem. 281(9), 6020, 6026 (2006). The same study “support[ed] the hypothesis that [cathepsin S] is required for angiogenesis and is associated with the pathobiology of tumor growth, at least in the RIP1-Tag2 model system”, and concluded that “it might be possible to manage tumor growth critically dependent on angiogenesis by targeting [cathepsin S] activity.” B. Wang, et al., J. Bio. Chem. 281(9), 6020, 6028 (2006). In light of the currently ascertained role that is played by cathepsin S in cancer-related processes, such as angiogenesis, tumor growth, cell proliferation, and metastasis, there is the need for cathepsin S inhibitors to address therapeutic needs in the fight against cancer. Embodiments of this invention provide cathepsin S inhibitors and further embodiments of this invention provide methods for treating cancer, and cancer-related processes such as angiogenesis, tumor growth, cell proliferation, and metastasis, by administering, in suitable pharmaceutical form, at least one cathepsin S inhibitor of this invention.  
      Cathepsin S inhibitors have been shown to block antigen presentation and attenuate the ability of class II major histocompatibility complex to load and present antigenic peptide, thus modulating autoimmunity and providing a means for treating diseases such as multiple sclerosis. S. N. Desai, et al., Eur J. Pharmacology 538, 168, 169 (2006); H. Beck, et al., Eur. J. Immunol. 31, 3726 (2001); H. L. Ploegh, et al., WO 97/40066. In light of the currently ascertained role that is played by cathepsin S in multiple sclerosis, there is the need for cathepsin S inhibitors to address therapeutic needs in the fight against such disease. Embodiments of this invention provide cathepsin S inhibitors and further embodiments of this invention provide methods for treating multiple sclerosis by administering, in suitable pharmaceutical form, at least one cathepsin S inhibitor of this invention.  
      Articular cartilage is progressively destroyed in an osteoarthritits condition, which affects approximately 80% of people over the age of 65. Despite this incidence, “there is essentially no pharmaceutical intervention for [osteoarthritis] available”. Y. Yasuda, et al., Advanced Drug Delivery Reviews 57, 973, 975 (2005). Furthermore, treatments rely on drugs that “are unable to significantly halt joint destruction, [and] novel ideas for the development of drugs for . . . [osteoarthritis] are urgently needed.” Y. Yasuda, et al., Advanced Drug Delivery Reviews 57, 973, 976 (2005), and ref. therein. Cathepsin S is a cysteine protease that has been implicated as a direct contributor to bone and cartilage degradation and also as mediator of inflammation in such degradative processes. Y. Yasuda, et al., Advanced Drug Delivery Reviews 57, 973, 979 (2005). Cathepsin S is selectively expressed in dendritic cells, which reportedly defines this cysteine protease as an attractive drug target. In addition, cathepsin S “has potent proteoglycan-degrading activity and is extremely efficient in hydrolyzing aggrecan at neutral and acidic pH.” Y. Yasuda, et al., Advanced Drug Delivery Reviews 57, 973, 981 (2005). In light of the currently ascertained role that is played by cathepsin S in osteoarthritis, there is the need for cathepsin S inhibitors to address therapeutic needs in the fight against such disease. Embodiments of this invention provide cathepsin S inhibitors and further embodiments of this invention provide methods for treating osteoarthritis by administering, in suitable pharmaceutical form, at least one cathepsin S inhibitor of this invention.  
      Chronic pain, such as pain due to conditions such as cancer, neuropathic pain, rheumatoid arthritis, osteoarthritis and inflammatory conditions, is difficult to treat, and current analgesics are proven of only limited effect while they present sometimes unacceptable side effects. It has been discovered that gene expression for cathepsin S is upregulated in animal models of chronic pain, and administration of cathepsin S inhibitors causes a reversal of mechanical hyperalgesia in such animals. Cathepsin S should therefore be a drug target for chronic pain. H. Wang, et al., Neuroscience 114(3), 529 (2002); F. P. Buxton, et al., WO 03/020287. In light of the currently ascertained role that is played by cathepsin S in chronic pain, there is the need for cathepsin S inhibitors to address therapeutic needs in the fight against such condition. Embodiments of this invention provide cathepsin S inhibitors and further embodiments of this invention provide methods for treating chronic pain by administering, in suitable pharmaceutical form, at least one cathepsin S inhibitor of this invention.  
      To mount a specific immune response, the skin immune system has to generate antigenic peptides and present them so that lymphocyte stimulation is allowed. This function is usually performed by professional antigen-presenting cells that are characterized by their major histocompatibility complex (MHC) class II positive phenotype. Keratinocytes are part of the skin immune system and they function as nonprofessional antigen-presenting cells in pathophysiologic conditions when they express MHC class II molecules, such as in psoriasis. Cathepsin S degrades the invariant chain to class II associated invariant chain peptide, and cathepsin S activity has been found in human keratinocytes. This is an important step for the correct loading of MHC class II molecules with antigenic peptides and subsequent surface expression of this complex. G. Schwarz, et al., J. Investigative Dermatology 119(1), 44, 47 (2002); J. O. Link, et al., Current Opinion in Drug discovery &amp; Dev. 9(4), 471-482 (2006). Because of this functional characteristic, cathepsin S is believed to be of particular relevance in the context of antigen processing. Inhibiting cathepsin S, and thus blocking antigen presentation, leads to the blocking or reduction of the associated inflammatory response. In light of the currently ascertained role that is played by cathepsin S in skin immune system disorders, such as psoriasis, there is the need for cathepsin S inhibitors to address therapeutic needs in the fight against such disorders. Embodiments of this invention provide cathepsin S inhibitors and further embodiments of this invention provide methods for treating skin immune system disorders, such as psoriasis, by administering, in suitable pharmaceutical form, at least one cathepsin S inhibitor of this invention.  
      Inflammation of the nasal mucous membrane is called rhinitis. The reaction is often also manifest in the eyes and throat in addition to the nose. In an allergic attack, the body is exposed to irritants (allergens), and antibodies, mainly immunoglobin E (IgE), attach to mast cells. Chemicals are released upon this attachment, and one of such chemicals is histamine, a substance that causes the blood vessels to open, the skin turn red, and membranes swell. When these effects affect the nose, then sneezing and congestion result. Inflammation and fluid production and release under these conditions typically affect the sinuses and eyelids in addition to the linings of the nasal passages. This type of rhinitis is known as allergic rhinitis. Non-allergic rhinitis does not depend on the presence of IgE, and the symptoms can be triggered by physical agents, such as smoke, cold, and pollutants, anomalous anatomical conditions, such as a deviated septum and nasal polyps, and infections. Although this type of rhinitis is not in principle due to an allergic reaction, its manifestation eventually leads to inflammation, a condition that is common with allergic rhinitis, and consequently treatments for allergic rhinitis are envisioned as being also applicable to the treatment of non-allergic rhinitis because of their effects on inflammation. Cathepsin S is an enzyme that is essential for antigen processing and presentation to immune system cells, and cathepsin S inhibitors block antigen presentation in vitro and in vivo. In vivo treatment with cathepsin S inhibitors reportedly reduce inflammation. This is attributed to the effects of cathepsin S inhibition on the attenuation of antigenic peptide load and presentation. S. N. Desai, et al., European J. Pharmacology 538, 168 (2006). Cathepsin S inhibition is therefore envisaged as a therapeutic mechanism for inflammation reduction and treatment of rhinitis. In light of the currently ascertained role that is played by cathepsin S in inflammation and rhinitis, there is the need for cathepsin S inhibitors to address therapeutic needs in the fight against such disorders. The term “rhinitis” as used herein refers to allergic rhinitis and to the inflammation caused by non-allergic rhinitis. Embodiments of this invention provide cathepsin S inhibitors and further embodiments of this invention provide methods for treating rhinitis, such as allergic rhinitis and the inflammation due to non-allergic rhinitis, by administering, in suitable pharmaceutical form, at least one cathepsin S inhibitor of this invention.  
      In view of their inhibitory effect on the proteolytic activity of human cathepsin S the compounds of the present invention may be formulated into various pharmaceutical forms for administration purposes. To prepare these pharmaceutical compositions, an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is intimately mixed with a pharmaceutically acceptable carrier.  
      A carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for oral administration or parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. These include water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. In view of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are generally employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Such additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acid addition salts of the compounds of formula I, due to their increased water solubility over the corresponding base form, are more suitable in the preparation of aqueous compositions.  
      It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.  
      Pharmaceutically acceptable acid addition salts include the therapeutically active non-toxic acid addition salt forms which the disclosed compounds are able to form. The latter can conveniently be obtained by treating the base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, palmoic and the like acids. The term addition salt also comprises the solvates which the disclosed compounds, as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like. Conversely the salt form can be converted by treatment with alkali into the free base form.  
      Stereoisomeric form defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the (R)- or (S)-configuration; substituents on bivalent cyclic saturated radicals may have either the cis- or trans-configuration. The invention encompasses stereochemically isomeric forms including diastereoisomers, as well as mixtures thereof in any proportion of the disclosed compounds. The disclosed compounds may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above and following formulae are intended to be included within the scope of the present invention.  
      Those of skill in the treatment of disorders or conditions mediated by the cathepsin S enzyme could easily determine the effective daily amount from the test results presented hereinafter and other information. In general it is contemplated that a therapeutically effective dose would be from 0.001 mg/kg to 5 mg/kg body weight, more preferably from 0.01 mg/kg to 0.5 mg/kg body weight. It may be appropriate to administer the therapeutically effective dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.05 mg. to 250 mg, and in particular 0.5 to 50 mg of active ingredient per unit dosage form. Examples include 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg, and 35 mg dosage forms. Compounds of the invention may also be prepared in time-release or subcutaneous or transdermal patch formulations. Disclosed compound may also be formulated as a spray or other topical or inhalable formulations.  
      Those of skill in the treatment of allergic disorders or conditions mediated by the cathepsin S enzyme could easily determine the effective daily amount from the test results presented hereinafter and other information. In general it is contemplated that a therapeutically effective dose would be from 0.001 mg/kg to 5 mg/kg body weight, more preferably from 0.01 mg/kg to 0.5 mg/kg body weight. It may be appropriate to administer the therapeutically effective dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.05 mg to 250 mg, and in particular 0.5 to 50 mg of active ingredient per unit dosage form. Examples include 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg, and 35 mg dosage forms. Compounds of the invention may also be prepared in time-release or subcutaneous or transdermal patch formulations. Disclosed compound may also be formulated as a spray or other topical or inhalable formulations.  
      The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the patient may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated patient and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned herein are therefore only guidelines.  
      The next section includes detailed information relating to the preparation, characterization, and use of the disclosed compounds.  
     E. EXAMPLES  
     Example 1 
     
       
         
         
             
             
         
       
     
     2-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-ylamino)-benzonitrile  
      A. 1-[3-(4-Chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      To a stirred solution of 50 g (0.35 mol) of N-acetyl-4-piperidone and 31 g (0.35 mol) of morpholine in benzene (350 mL) was added a catalytic amount (˜0.25 g) of p-toluenesulfonic acid. The mixture was heated to reflux for 10 h with a Dean-Stark trap. The solvent was removed under reduced pressure to give a brown oil. The crude product was diluted with CH 2 Cl 2  (175 mL) and 50.0 mL (0.35 mol) of Et 3 N was added. The mixture was cooled to 0° C. and a solution of 45.0 mL (0.35 mol) of 4-chlorobenzoyl chloride in CH 2 Cl 2  (50 mL) was added slowly by dropping funnel over 1 h. The mixture was allowed to warm to room temperature (rt) and stirred overnight. The reaction was then diluted with 1 N HCl (150 mL) and stirred vigorously for 3 h. The aqueous layer was extracted with CH 2 Cl 2  (3×250 mL) and the combined extracts were dried over Na 2 SO 4  and the solvent was removed under reduced pressure. The crude oil was diluted with EtOH (350 mL) and cooled to 0° C. To this stirred solution was slowly added 33.0 mL (1.06 mol) of hydrazine and the mixture was allowed to warm to rt and stir overnight during which time a white precipitate formed. The volume of the reaction was reduced to ˜150 mL and EtOAc (750 mL) was added to the mixture. The suspension was stirred vigorously for 2 h and was filtered then washed with EtOAc (2×200 mL) and dried under vacuum to afford 41.4 g (42% over 3 steps) of a pale yellow solid. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.3. MS [ESI (electrospray)]: m/z calcd for C 14 H 14 ClN 3 O [M+H] +  276.08, observed 276.0.  1 H NMR (400 MHz, CDCl 3 , a mixture of amide rotamers): 7.65 (d, J=8.4 Hz, 2H), 7.64 (d, J=9.3 Hz, 2H), 7.58 (d, J=10.5 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 4.94 (s, 2H), 4.78 (s, 2H), 4.08 (t, J=5.9 Hz, 2H), 3.90 (t, J=5.8 Hz, 2H), 3.02 (t, J=5.8 Hz, 2H), 2.96 (t, J=5.9 Hz, 2H), 2.36 (s, 3H), 2.31 (s, 3H).  
      B. 1-[3-(4-Chloro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      To a stirred solution of 1.00 g (3.63 mmol) of 1-[3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone and 2.85 mL (36.3 mmol) of epichlorohydrin was added 1.30 g (3.99 mmol) of solid Cs 2 CO 3 . The reaction was stirred for 48 h and the solvent was removed under reduced pressure. The residue was then diluted with H 2 O (50 mL) and EtOAc (50 mL). The layers were separated, and the organic layer was washed with H 2 O (25 mL) and brine (25 mL), dried over Na 2 SO 4  and the solvent was removed under reduced pressure. Purification by flash chromatography (silica, 0-15% acetone/CH 2 Cl 2 ) afforded 0.72 g (60%) of a white solid. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.5. MS (ESI): m/z calcd for C 17 H 18 ClN 3 O 2  [M+H] + , 332.11, observed 332.0.  1 H NMR (400 MHz, CDCl 3 , a mixture of amide rotamers): 7.60 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 4.80 and 4.73 (A and B of AB quartet, J ab =15.8 Hz, 2H), 4.60 (s, 2H), 4.47 (dd, J=15.3, 2.5 Hz, 1H), 4.42 (dd, J=15.0, 2.7 Hz, 1H), 4.11 (dd, J=5.3, 2.5 Hz, 1H), 4.08 (dd, J=5.1, 3.3 Hz, 1H), 3.99-3.85 (m, 2H), 3.73 (dt, J=5.9, 1.8 Hz, 2H), 3.37 (m, 2H), 2.87-2.80 (m, 3H), 2.80-2.69 (m, 3H), 2.53 (dd, J=4.7, 2.5 Hz, 1H), 2.48 (dd, J=4.6, 2.6, 1H), 2.19 (s, 3H), 2.15 (s, 3H).  
      C. 1-{3-(4-Chloro-phenyl)-1-[3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-hydroxy-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone.  
      To a stirred solution of 3.20 g (9.64 mmol) of 1-[3-(4-chloro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone and 2.07 g (14.5 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane in CH 2 Cl 2  (65 mL) was added 1.79 g (2.89 mmol) of Yb(OTf) 3 .H 2 O. The reaction was stirred overnight and was then directly purified by flash chromatography (silica, 0-5% MeOH/CH 2 Cl 2 ) to afford 3.70 g (81%) of the title compound. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.35. MS (ESI), m/z calcd for C 24 H 31 ClN 4 O 4  [M + +H], 475.20, observed 475.1.  
      D. 1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-one.  
      A suspension of 0.50 g (0.96 mmol) of 1-{3-(4-chloro-phenyl)-1-[3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-hydroxy-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone in 1 N HCl (2.0 mL) was heated to 65° C. for 48 h in a sealed vessel. The reaction was allowed to cool to rt and was diluted with CHCl 3  (20 mL) and saturated NaHCO 3  (20 mL). The aqueous phase was extracted with CHCl 3  (2×10 mL) and the combined organic extracts were dried over Na 2 SO 4  and the solvent was removed under reduced pressure. The crude material was then diluted with Ac 2 O (3.0 mL) and was stirred for 48 h. The solvent was removed under reduced pressure and the crude material was pumped down overnight. The resulting solid was dissolved in MeOH (5.0 mL) and a catalytic amount (0.05 g) of K 2 CO 3  was added to the mixture and stirring was continued overnight. The reaction was then diluted with H 2 O (20 mL) and CH 2 Cl 2  (20 mL) and the layers were separated. The aqueous phase was extracted with CH 2 Cl 2  (2×10 mL) and the combined organic extracts were dried over Na 2 SO 4  and the solvent was removed under reduced pressure. Purification by flash chromatography (silica, 0-10% MeOH/CH 2 Cl 2 ) afforded 0.29 g (65% over 3 steps) of a white solid. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.35. MS (ESI); m/z calcd for C 22 H 27 ClN 4 O 3 , [M+H] + , 431.18, observed 431.1.  1 H NMR (400 MHz, CDCl 3 , a mixture of amide rotamers): 7.59 (d, J=8.3 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 4.85 and 4.73 (A and B of AB quartet, J ab =15.8 Hz, 1H), 4.62 (s, 1H), 4.26-4.12 (m, 2H), 4.09-3.68 (m, 4H), 3.49 (s, 1.5H), 3.28 (s, 1.5H).  
      E. 2-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl-2-hydroxy-propyl}-piperidin-4-ylamino)-benzonitrile.  
      To a stirred solution of 50.0 mg (116.0 μmol) of 5-1-{3-[5-acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-one and 9.6 mg (82.5 μmol) of 2-aminobenzonitrile in AcOH (0.5 mL) was added 130.0 mg (917.0 μmol) Na 2 SO 4  and the reaction was allowed to stir for 1 h. To this mixture was added 58.0 mg (275.0 μmol) NaBH(OAc) 3  and the reaction was stirred for 48 h. The mixture was diluted with CH 2 Cl 2  (20 mL) and saturated NaHCO 3  (20 mL). The aqueous phase was extracted with CH 2 Cl 2  (2×10 mL) and the combined organic extracts were dried over Na 2 SO 4  and the solvent was removed under reduced pressure. Purification by flash chromatography (silica, 0-5% MeOH/CH 2 Cl 2 ) afforded 9.0 mg (20%) of a white solid. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.2. MS (ESI): m/z calcd for C 29 H 33 ClN 6 O 2 , [M+H] + , 533.24, observed 533.3.  1 H NMR (400 MHz, CDCl 3 , a mixture of amide rotamers): 7.58 (d, J=8.6 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.43-7.34 (m, 4H), 6.69 (dt, J=7.6, 4.0 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 4.83 and 4.73 (A and B of AB quartet, J ab =15.7 Hz, 1H), 4.61 (s, 1H), 4.44 (d, J=7.3 Hz, 1H), 4.33-4.14 (m, 2H), 4.11-3.84 (m, 2H), 3.83-3.67 (m, 1H), 3.55-3.43 (m, 1H), 3.17-2.94 (m, 1H), 2.93-2.75 (m, 2H), 2.74-2.54 (m, 2H), 2.21 (s, 1.5H), 2.16 (s, 1.5H), 2.23-1.53 (m, 9H).  
     Example 2 
     
       
         
         
             
             
         
       
     
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
      A. 1-[3-(4-Trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      A solution of N-acetyl-4-piperidone (2.82 g, 20 mmol), morpholine (1.93 mL, 22 mmol) and p-toluenesulfonic acid (5 mg) in benzene (8.5 mL) was refluxed for 8 h in a Dean-Stark apparatus. The solvent was removed and the residue dissolved in CH 2 Cl 2  (20 mL). Triethylamine (3.1 mL) was added and p-trifluoromethylbenzoyl chloride (3.27 mL, 22 mmol) in CH 2 Cl 2  (4 mL) was added dropwise into the solution at 0° C. The reaction mixture was stirred at 25° C. for 24 h and diluted with aqueous HCl (5%, 25 mL). After stirring for another 30 min, the organic layer was separated, washed with H 2 O (20 mL), dried (Na 2 SO 4 ), and concentrated. The residue was dissolved in EtOH (95%, 18 mL) and treated at 0° C. with hydrazine (2.9 mL, 60 mmol). The mixture was stirred at 25° C. for 3 h and H 2 O (4 mL) was added. Most of the volatiles were removed and the residue extracted with CH 2 Cl 2  (50 mL). The organic layer was separated, washed with H 2 O (20 mL), dried over Na 2 SO 4 , and concentrated. Column chromatography (silica, 5% MeOH/CH 2 Cl 2 ) provided 5.1 g (83%) of a white powder. TLC (silica, 10% MeOH/CH 2 Cl 2 ): R f =0.30. MS (ESI): m/z 332.0 ([M+Na] + , C 15 H 14 F 3 N 3 O requires 309.1).  1 H NMR (CDCl 3 , 400 MHz, a mixture of two rotamers): 7.73-7.67 (m, 4H), 4.85 (s, 1.2H), 4.68 (s, 0.8H), 3.96 (t, J=4.5 Hz, 0.8H), 3.78 (t, J=4.5 Hz, 1.2H), 2.89 (t, J=4.5 Hz, 1.2H), 2.83 (t, J=4.5 Hz, 0.8H), 2.23 (s, 1.8H), 2.18 (s, 1.2H).  
      B. 1-[1-Oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      A solution of 1-[3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (2.4 g, 7.77 mmol) in DMF (15 mL) was treated with cesium carbonate (5.05 g, 15.5 mmol) and epichlorohydrin (6.1 mL, 77.7 mmol) at 25° C. and stirred for 24 h before it was diluted with EtOAc (100 mL) and H 2 O (50 mL). The organic layer was separated, washed with H 2 O (2×50 mL), brine (50 mL), dried over Na 2 SO 4 , and concentrated. Column chromatography (silica, 10% acetone/CH 2 Cl 2 ) provided 2.30 g (81%) of a white powder. TLC (silica, 10% MeOH/CH 2 Cl 2 ): R f =0.35. MS (ESI): m/z 388.0 ([M+Na] + , C 18 H 18 F 3 N 3 O 2  requires 365.1).  1 H NMR (CDCl 3 , 400 MHz, a mixture of two rotamers): 7.77 and 7.63 (AB pattern, J ab =8.2 Hz, 2H), 7.71 and 7.67 (AB pattern, J ab =8.4 Hz, 2H), 4.82 and 4.76 (AB pattern, J ab =15.5 Hz, 1.2H), 4.58 (s, 0.8H), 4.45-4.35 (m, 1H), 4.08-4.02 (m, 1H), 3.92-3.80 (m, 1H), 3.70-3.63 (m, 1H), 3.30 (m, 1H), 2.80-2.67 (m, 3H), 2.48-2.42 (m, 1H), 2.13 (s, 1.3H), 2.08 (s, 1.7H).  
      C. 1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one.  
      A solution of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (1.17 g, 3.2 mmol) in DMF (10 mL) was treated with ytterbium(III) triflate (0.4 g, 0.64 mmol) and 4-(2-keto-1-benzimidazolinyl)piperidine (1.04 g, 4.8 mmol) at 25° C. and stirred for 48 h before it was diluted with CH 2 Cl 2  (100 mL) and H 2 O (50 mL). The organic layer was separated, washed with H 2 O (2×50 mL), dried over Na 2 SO 4 , and concentrated. Flash column chromatography (silica, 5% MeOH/CH 2 Cl 2 ) afforded 1.71 g (92%) of a white powder. TLC (silica, 10% MeOH/CH 2 Cl 2 ): R f =0.25. MS (ESI): m/z 583.5 ([M+H] + , C 30 H 33 F 3 N 6 O 3  requires 582.3).  1 H NMR (CDCl 3 , 400 MHz, a mixture of two rotamers): 9.30 (br s, 0.5H), 9.25 (br s, 0.5H), 7.82 and 7.68 (AB pattern, J ab =8.2 Hz, 2H), 7.76 and 7.72 (AB pattern, J ab =8.4 Hz, 2H), 7.25-7.05 (m, 4H), 4.92 and 4.80 (AB pattern, J ab =15.6 Hz, 1.1H), 4.70 (s, 0.9H), 4.40-3.70 (m, 7H), 3.20-2.82 (m, 4H), 2.60-2.45 (m, 4H), 2.35-2.25 (m, 1H), 2.25 (s, 1.5H), 2.20 (s, 1.5H), 1.90-1.87 (m, 2H).  
     Example 3 
     
       
         
         
             
             
         
       
     
     3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3H-benzooxazol-2-one  
      A. 1-[3-(4-Bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      A flask equipped with a Dean-Stark trap, was charged with N-acetyl-4-piperidone (100.1 g, 709 mmol), piperidine (68 mL, 779 mmol), pTsOH (3.7 g) and benzene (500 mL). The mixture was heated to 125° C. After 17 h the mixture was allowed to cool and divided into two portions. A solution of p-bromobenzoyl chloride (70.0 g, 319 mmol) in CH 2 Cl 2 . (400 mL) was added dropwise to a 0° C. solution of the enamine (ca. 355 mmol) in CH 2 Cl 2  (320 mL) over 15 h. The mixture was then allowed to warm to 23° C. and stirred for an additional 5 h. The solution was treated with 1 N HCl (500 mL) and stirred vigorously for 1.5 h. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2  (2×300 mL). The combined extracts were washed with sat. aqueous NaHCO 3  (300 mL), H 2 O (300 mL), brine (300 mL), dried over Na 2 SO 4  and concentrated. The residue was dissolved in MeOH (300 mL) and treated with NH 2 NH 2  (50.0 mL, 1.59 mol). The mixture was stirred for 17 h before the precipitate formed was collected by filtration and air dried to give 52 g (50%) of the title compound which was suitable for use without further purification. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.3. MS (ESI): m/z calcd for C 14 H 15   79 BrN 3 O [M+H] + , 320.04, found 320.  1 H NMR (CD 3 OD/CDCl 3 , 400 MHz, a mixture of amide rotamers): 7.53 and 7.35 (A and B of AA′BB′, J=8.5 Hz, 2H), 7.51 and 7.39 (A and B of AA′BB′, J=8.6 Hz, 2H), 4.72 (s, 2H), 4.58 (s, 2H), 3.85 (t, J=5.9 Hz, 2H), 3.71 (t, J=5.8 Hz, 2H), 2.81, (t, J=5.8 Hz, 2H), 2.74, (t, J=5.8 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H).  
      B. 1-[3-(4-Bromo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      Cs 2 CO 3  (11.58 g, 35.5 mmol) was added to a solution of 1-[3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (7.59 g, 23.7 mmol) and epichlorohydrin (20 mL, 234 mmol) in DMF (100 mL). The mixture was stirred for 18 h then diluted with EtOAc (800 mL) and washed with saturated aqueous NaHCO 3  (2×100 mL), H 2 O (2×100 mL), and brine (100 mL). The NaHCO 3  layer was extracted with EtOAc (2×150 mL). The combined washes were extracted with EtOAc (2×100 mL). The combined extracts were dried over Na 2 SO 4  and concentrated. Column chromatography (silica, 10-20% acetone/CH 2 Cl 2 ) afforded 4.98 g (56%) of the title compound. HPLC (reverse phase conditions), t R =4.90 min. MS (ESI): m/z calcd for C 17 H 19   79 BrN 3 O 2 , [M+H] + , 376.07, found 376.0.  1 H NMR (CDCl 3 , 400 MHz, a mixture of amide rotamers): 7.47 (d with fine splittings, J=8.5, Hz, 2H), 7.44 (m, 4H), 7.38 (d with fine splittings, J=8.5, Hz, 2H), 4.71 and 4.64 (A and B of AB quartet, J ab =15.7 Hz, 2H), 4.51 (s, 2H), 4.39 (dd, J=15.1, 2.5 Hz, 1H), 4.34 (dd, J=15.0, 2.9 Hz, 1H), 4.02 (dd, J=5.2, 3.9 Hz, 1H), 3.98 (dd, J=5.3, 3.7 Hz, 1H), 3.83 (m, 2H), 3.64 (m, 2H), 3.25 (br m, 2H), 2.80-2.60 (m, 6H), 2.46 (dd, J=4.6, 2.6 Hz, 1H), 2.38 (dd, J=4.6, 2.6 Hz, 1H), 2.10 (s, 3H), 2.06 (s, 3H).  
      C. 4-(2-Oxo-benzooxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester.  
      To a stirred solution of 1.00 g (5.01 mmol) of tert-butyl 4-oxo-1-piperidine-carboxylate and 0.55 g (5.01 mmol) of 2-aminophenol in CH 2 Cl 2  (15 mL) under nitrogen at rt was added 1.62 g (7.52 mmol) of NaBH(OAc) 3  in one portion and the mixture was stirred for 14 h. The mixture was diluted with CH 2 Cl 2  (50 mL) and saturated NaHCO 3  (75 mL) and the layers were separated. The aqueous layer was extracted with CH 2 Cl 2  (2×25 mL) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure. The crude solid was diluted with CH 2 Cl 2  (15 mL) and 0.89 g (5.51 mmol) of carbonyldiimidazole was added in one portion and mixture was stirred for 16 h. The mixture was diluted with CH 2 Cl 2  (50 mL) and 1 N HCl (50 mL) and the layers were separated. The aqueous layer was extracted with CH 2 Cl 2  (2×25 mL) and the combined organic layers were washed with brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure. Flash chromatography (silica, 0-5% acetone/CH 2 Cl 2 ) afforded 1.59 g (99%) of a white solid. TLC (silica, 5% acetone/CH 2 Cl 2 ): R f =0.6. MS (ESI): m/z calcd for C 17 H 22 N 2 O 4 , [M+Na] + , 341.1, observed 341.1.  
      D. 3-Piperidin-4-yl-3H-benzooxazol-2-one.  
      To a stirred solution of 1.00 g (2.87 mmol) of 4-(2-oxo-benzooxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester in CH 2 Cl 2  (6.0 mL) was added TFA (6.0 mL) and the mixture was stirred for 12 h. The solvents were removed under reduced pressure and the crude solid was diluted in MeOH (10 mL) and saturated NaHCO 3  (15 mL) was added to the mixture and stirring was continued for 10 min. The solution was diluted with CH 2 Cl 2  (30 mL) and the layers were separated. The aqueous phase was extracted with CH 2 Cl 2  (2×20 mL) and the organic layers were combined, dried over Na 2 SO 4  and the solvent was removed under reduced pressure to afford 1.02 g (88%) of a pale yellow solid. TLC (silica, 10% MeOH/CH 2 Cl 2 ): R f =0.1. MS (ESI): m/z calcd for C 12 H 14 N 2 O 2 , [M+H] + , 219.11, observed 219.1.  
      E. 3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3H-benzooxazol-2-one.  
      To a stirred mixture of 0.025 g (0.066 mmol) of 3-piperidin-4-yl-3H-benzooxazol-2-one and 0.015 g (0.066 mmol) of 1-[3-(4-bromo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone in EtOH (0.5 mL) was added 0.01 mL (0.066 mmol) of Et 3 N. The mixture was heated to 80° C. in a sealed vessel for 16 h. The reaction was cooled and the solvent was removed under reduced pressure. Flash chromatography (silica, 0-5% MeOH/CH 2 Cl 2 ) afforded 0.030 g (79%) of a white foam. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.4. MS (ESI): m/z calcd for C 29 H 32 BrN 5 O 4 , [M+H] + , 594.16, observed 594.2.  1 H NMR (400 MHz, CDCl 3 , a mixture of amide rotamers): 7.60-7.43 (m, 4H), 7.23-7.06 (m, 4H), 4.83 and 4.73 (A and B of AB quartet, J ab =15.4 Hz, 1H), 4.61 (s, 1H), 4.38-3.66 (m, 7H), 3.37-3.02 (m, 2H), 2.99-2.28 (m, 6H), 2.21 (s, 1.5H), 2.16 (s, 1.5H), 1.99-1.83 (m, 3H).  
     Example 4 
     
       
         
         
             
             
         
       
     
     1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
      A. 1-[3-(4-Chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      To a stirred solution of 1-acetyl-4-piperidone (3 g, 0.021 mol) and morpholine (1.86 g, 0.21 mol) in benzene (21 mL) was added a catalytic amount (˜0.015 g) of p-toluenesulfonic acid. The mixture was heated to reflux for 10 h under a Dean-Stark trap. The solvent was removed under reduced pressure to give a brown oil. The crude product was diluted with CH 2 Cl 2  (10.5 mL), and Et 3 N (3.0 mL, 0.021 mol) was added. The mixture was cooled to 0° C., and a solution of 3-methyl-4-chlorobenzoyl chloride (2.7 mL, 0.021 mol) in CH 2 Cl 2  (3.0 mL) was added slowly by dropping funnel over 1 h. The mixture was allowed to warm to rt and stir overnight. The reaction mixture was then diluted with 1 N HCl (9.0 mL) and stirred vigorously for 3 h. The aqueous layer was extracted with CH 2 Cl 2  (3×15 mL). The combined extracts were dried over Na 2 SO 4 , and the solvent was removed under reduced pressure. The crude oil was diluted with EtOH (21 mL) and cooled to 0° C. To this stirred solution was slowly added hydrazine (2.0 mL, 0.064 mol), and the mixture was allowed to warm to rt and stir overnight, during which time a white precipitate formed. The volume of the reaction mixture was reduced to ˜9 mL, and EtOAc (45 mL) was added. The suspension was stirred vigorously for 2 h and was filtered then washed with EtOAc (2×12 mL) and dried under vacuum to afford 4.93 g (81% over 3 steps) of a pale yellow solid. TLC (silica, 10% acetone/CH 2 Cl 2 ): R f =0.2. MS (ESI): exact mass calcd for C 15 H 16 ClN 3 O, 289.10; m/z found, 290.1 [M + +H].  
      B. 1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      Cs 2 CO 3  (11 g, 33.8 mmol) was added to a solution of 1-[3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (4.9 g, 16.9 mmol) in DMF (49 mL), which was then stirred for 15 min. Epichlorohydrin (13.2 mL, 169 mmol) was added, and the mixture was stirred under N 2  at rt for 16 h. EtOAc (250 mL) was added to the reaction mixture, which was then stirred for 5 min. The resulting solution was washed with water (2×50 mL) and brine (1×50 mL). The organic extracts were dried over Na 2 SO 4  and concentrated. The residue was purified by column chromatography (silica, 10-20% acetone/CH 2 Cl 2 ) to obtain 3.8 g (65%) of a white solid. TLC (silica, 10% acetone/CH 2 Cl 2 ): R f =0.3. MS (ESI): exact mass calcd for C 18 H 20 ClN 3 O 2 , 345.12; m/z found, 346.1 [M + +H], 368.0 [M + +Na],  
      C. 4-(3,4-Dichlorophenoxy)-piperidinium trifluoroacetate.  
      A suspension of 0.69 g (20.0 mmol) of triphenylphosphine (polymer supported, 3 mmol P/g) in CH 2 Cl 2  (4.0 mL) was stirred for 15 min to swell the resin. To this suspension was added 0.20 g (1.00 mmol) of 1-tert-butoxycarbonyl-4-piperidinol, 0.16 g (1.00 mmol) of 3,4-dichlorophenol, and 0.35 g (1.50 mmol) of di-tert-butyl azodicarboxylate. The reaction was stirred for 4 h and was filtered and the resin was washed with 5% MeOH/CH 2 Cl 2  (2×20 mL) and Et 2 O (20 mL). The organic layers were combined and the solvent was removed. The crude oil was diluted with CH 2 Cl 2  (2.0 mL) and TFA (2.0 mL) and the mixture was stirred overnight. The solvent was removed under reduced pressure to afford the crude TFA salt which was used without further purification. TLC (silica, 10% MeOH/CH 2 Cl 2 ): R f =0.1. MS (ESI): m/z calcd for C 11 H 13 Cl 2 NO, [M+H] + , 246.04, observed 246.1.  
      D. 1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone.  
      To a stirred solution of 25.0 mg (0.066 mmol) of 1-[3-(4-chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone and 25.0 mg (0.10 mmol) of 4-(3,4-dichlorophenoxy)-piperidinium trifluoroacetate in EtOH (0.5 mL) was added 0.019 mL (0.014 mmol) of Et 3 N. The mixture was heated to 80° C. in a sealed vessel for 16 h. The reaction was cooled and the solvent was removed under reduced pressure. Flash chromatography (0-5% MeOH/CH 2 Cl 2 ) afforded 28 mg (74%) of a pale yellow foam. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.5. MS (ESI): m/z calcd for C 29 H 33 Cl 3 N 4 O 3 , [M+H] + , 591.16, observed 591.2.  1 H NMR (400 MHz, CDCl 3 , a mixture of amide rotamers): 7.51 (d, J=6.9 Hz, 1H), 7.41-7.29 (m, 3H), 6.99 (d, J=2.9 Hz, 1H), 6.74 (dd, J=9.0, 3.1 Hz, 1H), 4.82 and 4.73 (A and B of AB quartet, J ab =15.7 Hz, 1H), 4.60 (s, 1H), 4.46-3.93 (m, 4H), 3.92-3.83 (m, 1H), 3.82-3.68 (m, 1H), 3.08-2.51 (m, 6H), 2.43 (s, 1.5H), 2.41 (s, 1.5H), 2.21 (s, 1.5H), 2.15 (s, 1.5H) 2.00-1.83 (m, 3H), 1.75-1.39 (m, 4H).  
     Example 5 
     
       
         
         
             
             
         
       
     
     1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2,3-dihydro-indol-1-yl)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
      A. 1-Piperidin-4-yl-2,3-dihydro-1H-indole.  
      Indoline (11.0 g, 92 mmol) and N-BOC-4-piperidone (18.4 g, 92 mmol) were set stirring in 300 mL of CH 2 Cl 2  under an atmosphere of nitrogen at rt. Acetic acid (5.5 mL, 96 mmol) was then added. After 1.5 h sodium triacetoxyborohydride (27.4 g, 129 mmol) was added and the mixture was left stirring for 4 days. The mixture was quenched by the slow addition of saturated NaHCO 3 . The organics were separated, dried (MgSO 4 ) and the solvent was evaporated under reduced pressure to give 28 g (100%) of a clear dark green liquid. The crude material was brought up in 1:1 TFA/CH 2 Cl 2  (100 mL) and stirred at rt. After 45 min the solvent was evaporated under reduced pressure, the oil brought up in EtOAc, and cooled on ice to form a beige precipitate. The solid was filtered, washed with Et 2 O and air dried to give 22.5 g (57%) of a white solid as a TFA salt. MS (ESI): exact mass calcd for C 13 H 18 N 2 , 202.15; m/z found, 203.2.  1 H NMR (400 MHz, DMSO-d 6 ): 8.74 (br s, 1H), 8.46 (br s, 1H), 7.07 (m, 2H), 6.63 (m, 2H), 3.81 (br s, 1H), 3.46 (m, 2H), 3.37 (m, 2H), 3.12 (m, 2H), 2.95 (m, 2H), 1.86 (m, 4H).  
      B. 1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2,3-dihydro-indol-1-yl)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone.  
      1-Piperidin-4-yl-2,3-dihydro-1H-indole (TFA salt) (506 mg, 1.18 mmol) and 1-[3-(4-chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (261 mg, 0.75 mmol) were set stirring in 20 mL of EtOH and heated to 80° C. After 20 h the mixture was cooled, evaporated, brought up in EtOAc and washed with saturated NaHCO 3 . The organics were dried (MgSO 4 ) and evaporated to give a clear golden oil. Flash chromatography (silica, 100% acetone) gave 260 mg (63%) of a white solid. TLC (silica, 100% acetone): R f =0.10. MS (ESI): exact mass calcd for C 31 H 28 ClN 5 O 2 , 547.27; m/z found, 548.3.  1 H NMR 400  MHz, CDCl 3 ): 7.64 (m, 1H), 7.43 (m, 2H), 7.16 (m, 2H), 6.72 (s, 1H), 6.50 (m, 1H), 4.88 (m, 1H), 4.73 (s, 1H), 4.28 (m, 2H), 4.13 (m, 2H), 3.92 (m, 2H), 3.47 (m, 3H), 30.9 (m, 6H), 2.55 (m, 6H), 2.27 (m, 3H), 1.84 (m, 4H).  
     Example 6 
     
       
         
         
             
             
         
       
     
     (S)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-one  
      A. (R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-(2,3-dihydroxy-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      A solution of KHMDS (0.5 M, 8.4 mL, 4.1 mmol) was added to a solution of 1-[3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (1.01 g, 3.49 mmol) in DMF (8.5 mL). The mixture was stirred for 1 h then (2R)-1-tert-butyldimethylsilylglycidol (1.97 g, 10.5 mmol) was added. The mixture was stirred for 17 h then partitioned between EtOAc (500 mL) and saturated aqueous NaHCO 3  (100 mL). The EtOAc layer was washed with H 2 O (3×100 mL), and brine (100 mL). The combined washes were extracted with EtOAc (2×100 mL). The combined extracts were dried over Na 2 SO 4  and concentrated. The residue was dissolved in MeOH (50 mL) and treated with CSA (171 mg). The resulting mixture was stirred for 24 h then concentrated to near dryness. The residue was diluted with EtOAc (300 mL), washed with NaHCO 3  (100 mL), dried over Na 2 SO 4  and concentrated. Flash chromatography (silica, 5-10% MeOH/CH 2 Cl 2 ) provided 652 mg (50%) of the non-racemic diol. TLC (silica, 10% MeOH/CH 2 Cl 2 ): R f =0.2. MS (ESI): m/z calcd for C 18 H 23   35 ClN 3 O 3  ([M+H] + , 364.14, found 364.1.  
      B. (R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      (R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-(2,3-dihydroxy-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (452 mg, 1.24 mmol) and pyridinium p-toluenesulfonate (85 mg) were combined in MeC(OMe) 3  (50 mL) and briefly sonicated. The mixture was stirred for 17 h, concentrated, and the residue dissolved in CH 2 Cl 2  (8 mL). The solution was cooled to 0° C. and treated with AcBr (0.15 mL, 2.0 mmol). After 5 h the mixture was partitioned between EtOAc (300 mL) and saturated aqueous NaHCO 3  (75 mL). The EtOAc layer was washed with H 2 O (75 mL) and brine (75 mL), dried over Na 2 SO 4  and concentrated. The residue was combined with K 2 CO 3  (243 mg, 1.84 mmol) in MeOH (50 mL) and stirred for 3 h then worked up as described above. Purification by column chromatography (silica, 10-40% acetone/CH 2 Cl 2 ) gave 159 mg (37%) of the title compound. Chiral HPLC (Daicel OD, 0.5% Et 2 NH/MeOH) analysis indicated &gt;95% optical purity. HPLC (reverse phase conditions), t R =4.97 min. MS (ESI): exact mass calcd for C 18 H 20 ClN 3 O 2  [M + +Na], 368.11; m/z found 368.05.  1 H NMR (CDCl 3 , 400 MHz, a mixture of amide rotamers): 7.54 (br d, J=6.3 Hz, 2H), 7.41-7.35 (m, 3H), 7.29 (dd, J=8.2, 1.9 Hz, 1H), 4.81 and 4.74 (A and B of AB quartet, J ab =15.7 Hz, 2H), 4.60 (s, 2H), 4.48 (dd, J=15.2, 2.4 Hz, 1H), 4.42 (dd, J=15.4, 2.8 Hz, 1H), 4.13 (t, J=4.7 Hz, 1H), 4.09 (dd, J=4.6 Hz, 1H), 3.93 (m, 2H), 3.74 (t, J=5.8 Hz, 1H), 3.73 (t, J=5.8 Hz, 1H), 3.34 (m, 2H), 2.85-2.75 (m, 6H), 2.53 (dd, J=4.6, 2.5 Hz, 1H), 2.48 (dd, J=4.6, 2.6 Hz, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 2.20 (s, 3H), 2.15 (s, 3H).  
      C. 4-(5-Chloro-2-nitro-phenylamino)-piperidine-1-carboxylic acid ethyl ester.  
      To a solution of 2.03 g (11.6 mmol) of 4-chloro-2-fluoro-nitrobenzene in DMF (12.0 mL) at rt was added 2.00 g (11.6 mmol) of ethyl 4-amino-1-piperidinecarboxylate. A yellow precipitate formed within 30 min and the reaction was further diluted with DMF (12.0 mL) and CH 2 Cl 2  (5.0 mL) and was shaken at 300 RPM overnight. The solvent was removed under reduced pressure and the resulting solid was dried under vacuum. The crude product was purified by flash chromatography (silica, 0-5% MeOH/CH 2 Cl 2 ) to afford 2.83 g (81%) of the title compound. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.4. MS (ESI): m/z calcd for C 14 H 18 ClN 3 O 4  [M + +Na] 350.09, observed 350.0.  1 H NMR (400 MHz, CDCl 3 ): 8.13 (apparent d, J=9.1 Hz, 2H), 6.84 (d, J=2.0 Hz, 1H), 6.62 (dd, J=9.4, 2.3 Hz, 1H), 4.15 (q, J=14.9, 7.3 Hz, 2H), 4.08 (br d, J=12.4 Hz, 2H), 3.70-3.58 (m, 1H), 3.17-3.05 (m, 2H), 2.07 (br dd, J=13.1, 3.1 Hz, 2H), 1.63-1.50 (m, 2H), 1.28 (t, J=7.0 Hz, 3H).  
      D. 4-(6-Chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester.  
      To a stirred solution of 0.50 g (1.52 mmol) of 4-(5-chloro-2-nitro-phenylamino) -piperidine-1-carboxylic acid ethyl ester in EtOH (15.0 mL) was added concentrated HCl (3.0 mL) followed by 0.99 g (15.2 mmol) of zinc powder. After 1 h, additional concentrated HCl (1.5 mL) followed by 0.99 g (15.2 mmol) of zinc powder was added and the reaction was stirred for 1.5 h. The mixture was filtered through a pad of celite and was washed with 5% MeOH/CH 2 Cl 2 . The mixture was diluted with saturated NaHCO 3  and a precipitate formed. The layers were separated and the aqueous phase was extracted (3×5% MeOH/CH 2 Cl 2 ). The combined organic layers were dried over Na 2 SO 4  and the solvent was removed under reduced pressure to afford a brown oil. The crude oil was diluted with CH 2 Cl 2  (15.0 mL) and 0.64 mL (4.56 mmol) of Et 3 N was added followed by 0.45 g (1.52 mmol) of triphosgene. The reaction was allowed to stir overnight and was then diluted with 1 N NaOH (20 mL) and stirred for an additional 1 h. The layers were separated and the aqueous phase was extracted with CH 2 Cl 2  (3×20 mL). The combined organic extracts were dried over Na 2 SO 4  and the solvent was removed under reduced pressure. Purification by flash chromatography (silica, 0-5% MeOH/CH 2 Cl 2 ) afforded 0.33 g (67% over 2 steps) of the title compound. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.5. MS (ESI): m/z calcd for C 15 H 18 ClN 3 O 3  [M + +Na] 346.10, observed 346.0.  1 H NMR (400 MHz, CDCl 3 ): 9.41 (s, 1H), 7.11 (d, J=2.0 Hz, 1H), 7.04 (d, J=1.8 Hz, 1H), 7.02 (s, 1H), 4.48-4.33 (m, 3H), 4.20 (q, J=7.1 Hz, 2H), 2.92 (t, J=12.5 Hz, 2H), 2.30 (dq, J=12.9, 4.6 Hz, 2H), 2.10 (d, J=12.6 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H).  
      E. 6-Chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one.  
      A suspension of 0.20 g (0.62 mmol) of 4-(6-chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester in 10% NaOH (0.62 mL) was heated to 105° C. for 6 h and then cooled. The solution was adjusted to pH 1 (conc. HCl) and then back to pH 10 (NaOH). Then, the mixture was diluted with 5% MeOH/CH 2 Cl 2  (˜30 mL) until both layers were clear. The layers were separated and the aqueous phase was extracted with 5% MeOH/CH 2 Cl 2  (2×30 mL). The combined organic layers were dried over Na 2 SO 4  and the solvent was removed under reduced pressure to afford 0.12 g (76%) of a light brown solid. TLC (silica, 10% MeOH/CH 2 Cl 2 ): R f =0.1. MS (ESI): m/z calcd for C 12 H 14 ClN 3 O [M + +H] 252.08, observed 252.1.  1 H NMR (400 MHz, CDCl 3 ): 7.27 (d, J=1.6 Hz, 2H), 7.02 (d, J=1.6 Hz, 1H), 7.01 (s, 1H), 4.38 (m, 1H), 3.30 (br d, J=11.9 Hz, 2H), 2.82 (dt, J=12.3, 2.0 Hz, 2H), 2.35 (dq, J=12.3, 3.5 Hz, 2H), 1.85 (br dd, J=12.1, 2.1 Hz, 2H).  
      F. (S)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-one.  
      (R)-1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (31 mg, 0.10 mmol) and 6-chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (36 mg, 0.17 mmol) were combined in EtOH (0.3 mL) and heated to 70° C. After 18 h the mixture was allowed to cool, diluted with CH 2 Cl 2  and purified by preparative TLC (silica, 8% MeOH/CH 2 Cl 2 ) to give 7 mg (12%) of the title compound. HPLC (reverse phase conditions), t R =3.49 min. MS (ESI): m/z calcd for C 30 H 35   35 Cl 2 N 6 O 3  [M + +H] 597.22, found 597.20.  1 H NMR (CDCl 3 , 400 MHz, a mixture of amide rotamers): 9.16 (br d, J=10.1 Hz, 1H), 7.55 (br m, 1H), 7.40-7.28 (m, 2H), 7.18 (br s, 1H), 7.03 and 6.98 (A and B of ABX (with fine splittings), J ab =8.4 Hz, 2H), 4.85 and 4.74 (A and B of ABX (with fine splittings), J ab =15.7 Hz, 1H), 4.62 (s, 1H), 4.29-4.18 (m, 4H), 4.09-4.00 (m, 2H), 3.91-3.71 (m, 2H), 3.16-2.78 (m, 4H), 2.55-2.50 (m, 4H), 2.43 (s, 1.5H), 2.41 (s, 1.5H), 2.23 (m, 1H), 2.21 (s, 1.5H), 2.16 (s, 1.5H), 1.84 (br s, 2H).  
     Example 7 
     
       
         
         
             
             
         
       
     
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-1,3-dihydro-benzoimidazol-2-one  
      A solution of 1-(1-{3-[5-acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one (130 mg, 0.22 mmol) in DMF (1 mL) was treated with cesium carbonate (146 mg, 0.45 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (329 mg, 2.2 mmol) at 25° C. and stirred for 24 h before it was diluted with EtOAc (10 mL) and H 2 O (5 mL). The organic layer was separated, washed with H 2 O (2×5 mL), dried over Na 2 SO 4 , and concentrated. Column chromatography (silica, 5% MeOH/CH 2 Cl 2 ) afforded 124 mg (81%) of a white powder. TLC (10% MeOH/CH 2 Cl 2 ): R f =0.31. MS (ESI): m/z 696.3 ([M+H] + , C 36 H 44 F 3 N 7 O 4  requires 695.3).  1 H NMR (CDCl 3 , 400 MHz, a mixture of two rotamers): 7.82 and 7.65 (AB pattern, J ab =8.2 Hz, 2H), 7.74 and 7.68 (AB pattern, J ab =8.4 Hz, 2H), 7.23-7.05 (m, 4H), 4.92 and 4.80 (AB pattern, J ab =15.6 Hz, 1.2H), 4.69 (s, 0.8H), 4.38-4.00 (m, 5H), 4.02 (t, J=7.0 Hz, 2H), 3.92-3.70 (m, 2H), 3.70 (t, J=4.5 Hz, 4H), 3.15-2.80 (m, 4H), 2.70 (t, J=7.1 Hz, 2H), 2.60-2.20 (m, 9H), 2.24 (s, 1.6H), 2.18 (s, 1.4H), 1.85-1.75 (m, 2H).  
     Example 8 
     
       
         
         
             
             
         
       
     
     1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-one  
      A. 3-(4-Bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester.  
      To a stirred solution of 500.0 g (2.51 mol) of 1-tert-butoxycarbonyl-4-piperidone and 87.1 g (2.76 mol) of morpholine in benzene (1.25 L) was added a catalytic amount (˜0.25 g) of p-TsOH. The mixture was heated to reflux for 36 h with a Dean-Stark trap. The solvent was removed under reduced pressure to give a brown oil, which solidified on standing. The crude product was divided and 335.0 g (1.25 mol) of the enamine was diluted with CH 2 Cl 2  (1.25 L) and 175.0 mL (1.25 mol) of Et 3 N was added. The mixture was cooled to 0° C. and a solution of 275.0 g (1.25 mol) of 4-bromobenzoyl chloride in CH 2 Cl 2  (150 mL) was added slowly by dropping funnel over 1 h. The mixture was allowed to warm to rt and stir overnight. The reaction was then diluted with 1 N HCl (450 mL) and stirred vigorously for 3 h. The aqueous layer was extracted with CH 2 Cl 2  (3×500 mL) and the combined extracts were dried over Na 2 SO 4  and the solvent was removed under reduced pressure. The crude oil was diluted with EtOH (850 mL) and cooled to 0° C. To this stirred solution was slowly added 120.0 g (3.75 mol) of hydrazine and the mixture was allowed to warm to rt and stir overnight during which time a white precipitate formed. The volume of the reaction was reduced to ˜350 mL and EtOAc (1.50 L) was added to the mixture. The suspension was stirred vigorously for 2 h and was filtered then washed with EtOAc (2×500 mL) and dried under vacuum to afford 309.0 g (62% over 3 steps) of a white solid. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.3. MS (ESI): m/z calcd for C 17 H 20 BrN 3 O 2  [M + +H] 378.07, observed 378.0.  1 H NMR (400 MHz, CDCl 3 ): 7.65-7.26 (m, 4H), 4.64 (br s, 2H), 3.84-3.68 (br m, 2H), 2.87-2.74 (br m, 2H), 1.48 (br s, 9H).  
      B. 3-(4-Bromophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinium trifluoroacetate.  
      To a stirred solution of 10.0 g (26.4 mmol) of the 3-(4-bromophenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester in CH 2 Cl 2  (26.0 mL) was added 26.0 mL of TFA. The resulting mixture was allowed to stir overnight. The solvent was removed under reduced pressure and the solid was dried in vacuo. The dried solid was suspended in Et 2 O and stirred vigorously for 2 h and then filtered and dried in vacuo to give 10.1 g of a white solid, which was used without further purification. TLC (silica, 10% MeOH/CH 2 Cl 2 ): R f =0.05. MS (ESI): m/z calcd for C 12 H 12 BrN 3  [M + +H] 278.02, observed 278.0.  
      C. 3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.  
      To a stirred solution of 3.11 g (11.1 mmol) of 3-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinium trifluoroacetate and 4.71 mL (33.5 mmol) of Et 3 N in DMF (55 mL) was slowly added 1.21 mL (15.6 mmol) of methanesulfonyl chloride. After 2.5 h, the solvent was removed under reduced pressure and the residue was diluted with CH 2 Cl 2  (100 mL) and saturated NaHCO 3  (100 mL). The layers were separated and the aqueous phase was extracted with CH 2 Cl 2  (2×30 mL). The combined organic layers were dried over Na 2 SO 4  and the solvent was removed under reduced pressure. Purification by column chromatography (silica, 0-5% MeOH/CH 2 Cl 2 ) afforded 2.01 g (50%) of the title compound. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.3. MS (ESI): m/z calcd for C 13 H 14 BrN 3 O 2 S [M + +H] 356.00, observed 356.0.  
      D. 3-(4-Bromo-phenyl)-5-methanesulfonyl-1-oxiranylmethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.  
      To a stirred solution of 2.50 g (7.00 mmol) of 3-(4-bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine and 5.52 mL (70.0 mmol) of epichlorohydrin was added 2.50 g (7.72 mmol) of solid Cs 2 CO 3 . The reaction was allowed to stir for 48 h and the solvent was removed under reduced pressure. The residue was then diluted with H 2 O (150 mL) and EtOAc (150 mL). The layers were separated, and the organic layer was washed with H 2 O (50 mL) and brine (50 mL), dried over Na 2 SO 4  and the solvent was removed under reduce pressure. Purification by flash chromatography (silica, 0-20% acetone/CH 2 Cl 2 ) afforded 1.52 g (53%) of a white solid. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.5. MS (ESI): m/z calcd for C 16 H 18 BrN 3 O 3 S [M + +H] 412.03, observed 412.0.  1 H NMR (400 MHz, CDCl 3 ): 7.54 and 7.47 (A and B of AA′BB′, J=8.6 Hz, 4H), 4.56-4.45 (m, 3H), 4.10 (dd, J=15.1, 5.4 Hz, 1H), 3.73-3.58 (m, 2H), 3.38-3.32 (m, 1H), 2.96-2.87 (m, 2H), 2.86 (s, 3H), 2.83 (dd, J=4.4, 4.2 Hz, 1H), 2.48 (dd, J=4.6, 2.6 Hz, 1H).  
      E. 1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-one.  
      A stirred solution of 25.0 mg (0.061 mmol) of 3-(4-bromo-phenyl)-5-methanesulfonyl-1-oxiranylmethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine and 19.0 mg (0.073 mmol) of 6-chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one in EtOH (0.5 mL) was heated to 80° C. in a sealed vessel for 16 h. The reaction was cooled and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica, 0-5% MeOH/CH 2 Cl 2 ) to afford 0.025 g (63%) of the title compound. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.4. MS (ESI): m/z calcd for C 28 H 32 BrClN 6 O 4 S [M + +H] 663.11, observed 663.0.  1 H NMR (400 MHz, CDCl 3 ): 10.2 (s, 1H), 7.52 and 7.46 (A and B of AA′BB′, J=8.6 Hz, 4H), 7.15 (br d, J=1.5 Hz, 1H), 7.04-6.95 (m, 2H), 4.52 and 4.49 (A and B of AB quartet, J ab =14.5 Hz, 2H), 4.33-4.14 (m, 3H), 4.07-3.97 (m, 1H), 3.74-3.58 (m, 2H), 3.17-2.89 (m, 4H), 2.86 (s, 3H), 2.57-2.30 (m, 5H), 2.20 (t, J=11.1 Hz, 1H), 1.87-1.73 (m, 2H).  
     Example 9 
     
       
         
         
             
             
         
       
     
     [3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetonitrile  
      A. 3-(4-Trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester.  
      To a stirred solution of 500 g (2.51 mol) of 1-tert-butoxycarbonyl-4-piperidone and 87.1 g (2.76 mol) of morpholine in benzene (1.25 L) was added a catalytic amount (˜0.25 g) of p-TsOH. The mixture was heated to reflux for 36 h with a Dean-Stark trap. One half of the solvent was removed under reduced pressure and the resulting solution was cooled and filtered. The filtrate was then concentrated to yield 630 g (94%) of an orange red oil. The eneamine was divided and 320 g (1.19 mol) was diluted with CH 2 Cl 2  (1.0 L) and 165.0 mL (1.19 mol) of Et 3 N was added. The mixture was cooled to 0° C. and a solution of 225 g (1.08 mol) of 4-trifluoromethylbenzoyl chloride in CH 2 Cl 2  (0.5 L) was added slowly by dropping funnel over 1 h. The mixture was allowed to warm to rt and stir overnight. The reaction was then diluted with 1 N HCl (450 mL) and stirred vigorously for 3 h. The aqueous layer was extracted with CH 2 Cl 2  (3×500 mL) and the combined extracts were dried over Na 2 SO 4  and the solvent was removed under reduced pressure. The crude oil was diluted with EtOH (1 L) and cooled to 0° C. To this stirred solution was slowly added 115 g (3.57 mol) of hydrazine and the mixture was allowed to warm to rt and stir overnight during which time a white precipitate formed. The volume of the reaction was reduced to ˜500 mL and cooled. The precipitate was collected to afford 285 g (72% from eneamine) of a white solid.  1 H NMR (400 MHz, CDCl 3 ): 7.63-7.55 (m, 4H), 4.58 (br s, 2H), 3.69-3.62 (br m, 2H), 2.74-2.68 (br m, 2H), 1.47 (s, 9H).  
      B. 1-(2-Methoxycarbonyl-ethyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester.  
      3-(4-Trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.85 g, 5.04 mmol) and methyl acrylate (0.50 mL, 5.6 mmol) were combined in toluene (30 mL) and heated to 75° C. The resulting mixture was treated with t-BuONa (100 mg), and heating continued for 48 h. The mixture was allowed to cool and partitioned between EtOAc (300 mL) and NaHCO 3  (75 mL). The aqueous layer was extracted with EtOAc (3×75 mL). The combined extracts were dried over Na 2 SO 4  and concentrated. Column chromatography (silica, 30-60% EtOAc/hexanes) afforded 343 mg (15%) of the title compound. TLC (silica, 50% EtOAc/hexanes): R f =0.4. MS (ESI): m/z calcd for C 22 H 27 F 3 N 3 O 4  [M + +H] 454.20, found 454.1.  1 H NMR (CDCl 3 , 400 MHz): 7.75 (br d, J=8.1 Hz, 2H), 7.64 (br s, 2H), 4.63 (br s, 2H), 4.30 (t, J=6.6 Hz, 2H), 3.75 (br s, 2H), 3.68 (s, 3H), 2.98 (t, J=6.6 Hz, 2H), 2.79 (br t, J=5.6 Hz, 2H), 1.48 (s, 9H).  
      C. 1-(3-Hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester.  
      A solution of LiBH 4  (26 mg, 1.2 mmol) in THF (0.5 mL) was added to a 0° C. solution of 1-(2-methoxycarbonyl-ethyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (317 mg, 0.70 mmol) in THF (4.0 mL). The mixture was stirred for 5 min then additional LiBH 4  (15 mg) was added and stirring continued for 17 h. The mixture was partitioned between EtOAc (80 mL) and saturated aqueous NaHCO 3  (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined extracts were dried over Na 2 SO 4  and concentrated. Column chromatography (silica, 0-8% MeOH/CH 2 Cl 2 ) afforded 268 mg (95%) of the title compound. HPLC (reverse phase conditions), t R =6.82 min. MS (ESI): m/z calcd for C 21 H 26 F 3 N 3 O 3  [M + +Na] 448.18, found 448.10.  1 H NMR (CDCl 3 , 400 MHz): 7.73 (br d, J=8.2 Hz, 2H), 7.65 (br s, 2H), 4.64 (br s, 2H), 4.21 (t, J=6.4 Hz, 2H), 3.76 (br s, 2H), 3.66 (t, J=5.7 Hz, 2H), 2.73 (br t, J=5.4 Hz, 2H), 2.04 (q, J=6.1, 2H), 1.48 (s, 9H).  
      D. 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester.  
      1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (7.24 g, 34.1 mmol) and di-tert-butyl dicarbonate (9.12 g, 41.0 mmol) were combined in DMF (80 mL) and the mixture heated to 40° C. under N 2  for 17 h. The mixture was allowed to cool, diluted with EtOAc (800 mL) and washed with saturated aq. NaHCO 3  (150 mL), H 2 O (3×150 mL) and brine (150 mL). The combined aqueous washes were extracted with EtOAc (2×150 mL). The combined extracts were dried over Na 2 SO 4  and concentrated to afford 12.4 g of the title compound. TLC (silica, 50% EtOAc/hexanes): R f =0.3. MS (ESI): m/z calcd for C 17 H 23 N 3 O 3  [M + +Na] 340.16, found 340.1.  1 H NMR (CDCl 3 , 400 MHz): 10.59 (s, 1H), 7.15-7.11 (m, 2H), 7.08-7.02 (m, 2H), 4.49 (tt, J=8.4, 4.0 Hz, 1H), 4.32 (br s, 2H), 2.89 (br t, J=11.6, 2H), 2.34 (dq, J=12.6, 4.4 Hz, 2H), 1.83 (br d, J=10.5 Hz, 2H) 1.36 (s, 9H).  
      E. (2-Oxo-3-piperidin-4-yl-2,3-dihydro-benzoimidazol-1-yl)-acetonitrile.  
      A solution of 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.91 g, 9.16 mmol) in THF (10 mL) was added dropwise to a solution of KHMDS (2.19 g, 11.0 mmol) in THF (20 mL). The mixture was stirred for 10 min then bromoacetonitrile (3.2 mL, 46 mmol) was added. The resulting mixture was stirred for 4 h then partitioned between EtOAc (750 mL) and saturated aqueous NaHCO 3  (200 mL). The EtOAc layer was washed with H 2 O (3×200 mL) and brine (200 mL). The combined washes were extracted with EtOAc (2×150 mL). The combined extracts were dried over Na 2 SO 4  and concentrated. Column chromatography (silica, 20-60% EtOAc/hexanes) afforded 2.20 g (67%) of 4-(3-cyanomethyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester. The purified material was dissolved in CH 2 Cl 2  (40 mL) and diluted with TFA (25 mL). The resulting mixture was stirred for 1 h then diluted with CH 2 Cl 2  (250 mL) and washed with 1 N NaOH (100 mL). The aqueous layer was extracted with CH 2 Cl 2  (2×100 mL). The combined extracts were dried over Na 2 SO 4  and concentrated to 1.59 g (95%) of the title compound which was suitable for further use without purification. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.1. MS (ESI): m/z calcd for C 14 H 17 N 4 O [M + +H] 257.14, found 257.1.  1 H NMR (CDCl 3 , 400 Hz): 733-7.29 (m, 1H), 7.17-7.02 (m, 3H), 4.75 (s, 2H), 4.41 (tt, J=12.2, 4.4 Hz, 1H), 3.28 (br d, J=9.8 Hz, 2H), 3.11 (br s, 1H), 2.80 (t, J=10.0 Hz, 2H), 2.37 (dq, J=12.5, 4.2 Hz, 2H), 1.83 (br d, J=11.8 Hz, 2H).  
      F. [3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetonitrile.  
      1-(3-Hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (268 mg, 0.63 mmol) was dissolved in CH 2 Cl 2  (10 mL) and TFA (10 mL). The mixture was stirred for 1 h then concentrated to dryness. The residue was dissolved in CH 2 Cl 2  (4.0 mL), cooled to 0° C. and treated with i-Pr 2 NEt (0.36 mL, 2.1 mmol), followed by methanesulfonyl chloride (0.16 mL, 2.1 mmol). The reaction mixture was stirred for 4 h, then diluted with EtOAc (200 mL) and washed with saturated aqueous NaHCO 3  (2×25 mL). The washes were extracted with EtOAc (2×25 mL). The combined extracts were dried over Na 2 SO 4  and concentrated. A portion of the crude mesylate (197 mg, ca. 0.41 mmol) was combined with (2-oxo-3-piperidin-4-yl-2,3-dihydro-benzoimidazol-1-yl)-acetonitrile (321 mg, 1.25 mmol) in CH 2 Cl 2  (2.0 mL) and DMF (0.5 mL). The resulting mixture was treated with i-Pr 2 NEt (0.22 mL, 1.3 mmol) and stirred for 60 h. The reaction mixture was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO 3  (75 mL). The EtOAc layer was washed with H 2 O (2×75 mL), and brine (75 mL). The combined washes were extracted with EtOAc (3×50 mL). The combined extracts were dried over Na 2 SO 4  and concentrated. Purification of the residue by preparative TLC (silica, 1% MeOH/CH 2 Cl 2  then 25% acetone/CH 2 Cl 2 ) gave 37 mg (14%) of the title compound. HPLC (reverse phase conditions), t R =2.94 min. MS (ESI): m/z calcd for C 31 H 35 F 3 N 7 O 3 S [M + +H] 642.25, found 642.25.  1 H NMR (CDCl 3 , 400 MHz): 7.73 and 7.76 (A and B of AA′BB′ J ab =8.2 Hz, 4H), 7.26-7.05 (m, 4H), 4.81 (s, 2H), 4.56 (s, 2H), 4.26 (m, 1H), 4.15 (t, J=6.8 Hz, 2H), 3.70 (t, J=5.8 Hz, 2H), 3.03 (br d, J=11.1 Hz, 2H), 2.95 (t, J=5.7 Hz, 2H), 2.91 (s, 3H), 2.43 (m, 4H), 2.12 (m, 4H), 1.82 (br d, J=9.9 Hz, 2H).  
     Example 10 
     
       
         
         
             
             
         
       
     
     5-Chloro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-one  
      A. 1-Methanesulfonyl-piperidin-4-one.  
      Potassium carbonate (324 g, 2340 mmol) was added to a solution of 4-piperidone monohydrate hydrochloride (90 g, 586 mmol) in chloroform (300 mL) and water (300 mL). The slurry was cooled to 0° C. and treated with methylsulfonyl chloride (136 mL, 1760 mmol) by dropwise addition over a 1 h period. The reaction mixture was allowed to shake for 72 h and was partitioned between CH 2 Cl 2  (500 mL) and saturated aqueous NaHCO 3  (500 mL). The aqueous layer was extracted with CH 2 Cl 2  (3×200 mL). The organic layer was washed with 1% KHSO 4  (250 mL), dried (Na 2 SO 4 ), and concentrated to afford 90.5 g (87%) of a white solid. HPLC (reverse phase conditions), t R =2.19 min. MS (ESI): exact mass calcd for C 6 H 11 NO 3 S, 177.1; m/z found, 178.1 [M+H] + .  1 H NMR (400 MHz, CDCl 3 ): 3.60 (t, J=6.5 Hz, 4H), 2.89 (s, 3H), 2.59 (t, J=6.3 Hz, 4H).  
      B. 5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.  
      p-Toluenesulfonic acid (1.34 g, 7.0 mmol) and morpholine (25.83 mL, 296 mmol) were added to a solution of 1-methanesulfonyl-piperidin-4-one (50.0 g. 282 mmol) in benzene (282 mL). The reaction mixture was heated in a flask equipped with a condenser and a Dean-Stark trap at reflux for 15 h. The reaction mixture was cooled and concentrated in vacuo to give the enamine which was used without further purification. The enamine was dissolved in CH 2 Cl 2  (200 mL) and cooled to 0° C. To this was added triethylamine (47.2 mL, 339 mmol) followed by dropwise addition of 4-trifluoromethylbenzoyl chloride (42.3 mL, 285 mmol) dissolved in CH 2 Cl 2  (82 mL). The reaction mixture was allowed to warm to rt and stirred for 20 h. The reaction mixture was washed with 1 N HCl (250 mL) and the CH 2 Cl 2  layer was separated, dried (Na 2 SO 4 ), and concentrated. The resulting oil was taken up in ethanol (300 mL) and treated with hydrazine (44.3 mL, 1.41 mol) at 0° C. The reaction mixture was allowed to warm to rt and stirred for 24 h. The mixture was concentrated and the resulting solid was filtered with ethanol wash and dried in vacuo to afford 70 g (72%) of 5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine as a white solid. HPLC (reverse phase conditions), t R =6.33 min. MS (ESI): exact mass calcd for C 14 H 14 F 3 N 3 O 2 S, 345.0; m/z found, 346.0 [M+H] + .  1 H NMR (400 MHz, CDCl 3 ): 7.72 (s, 4H), 4.58 (s, 2H), 3.69 (t, J=5.7 Hz, 2H), 2.99 (t, J=5.7 Hz, 2H), 2.92 (s, 3H).  
      C. 3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]-pyridin-1-yl]-ropan-1-ol.  
      Cs 2 CO 3  (33.74 g, 103.5 mmol) was added to a solution of 5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (29.8 g, 86.3 mmol) in anhydrous DMF (70 mL) and stirred for 25 min. 3-Bromo-1-propanol (8.6 mL, 13.2 g, 94.9 mmol) was added and stirred under N 2  at rt for 18 h. Water (500 mL) was added to the reaction and stirred for 5 min. The precipitated material was filtered out and washed with water (4×100 mL) and dried in a Freeze Drying System. The crude material (31.0 g) was taken up in anhydrous DMF (65 mL) and Cs 2 CO 3  (33.74 g, 103.5 mmol) was added, and stirred for 10 min. 3-Bromo-1-propanol (8.6 mL, 13.2 g, 94.9 mmol) and MeOH (6.0 mL, 4.75 g, 148 mmol) were added and stirring continued under N 2  at rt for 15 h. Water (500 mL) was added to the reaction and stirred for 10 min. The precipitated material was filtered and washed with water (3×100 mL). The filter cake was dissolved in CH 2 Cl 2  (200 mL) and washed with brine (50 mL), dried (Na 2 SO 4 ), and concentrated. The solid was triturated with Et 2 O (200 mL), filtered, then washed with Et 2 O, and dried to furnish 16.0 g of the desired compound. The mother liquor was chromatographed (silica, 0-10% acetone/EtOAc) to obtain an additional 3.0 g of the title compound. The combined yield was 54.6%. MS (ESI): exact mass calcd for C 17 H 20 F 3 N 3 O 3 S, 403.12; m/z found, 404.0 [M+H] + , 426.0 [M+Na] + .  1 H NMR (400 MHz, CDCl 3 ): 7.71 (d, J=8.2 Hz, 2H), 7.66.(d, J=8.5 Hz, 2H), 4.55 (s, 2H), 4.23 (t, J=6.5 Hz, 2H), 3.70-3.63 (m, 4H), 2.90 (s, 3H), 2.90 (t, J=5.1 Hz, 2H), 2.62 (t, J=5.9 Hz, 1H), 2.06 (q, J=6.1 Hz, 2H).  
      D. 5-Chloro-1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one.  
      To a stirred suspension of 0.97 g (2.99 mmol) of 4-(6-chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester in THF (30 mL) was added 0.5 M KHMDS in toluene. This mixture was stirred for 1 h and 0.25 mL (3.89 mmol) of MeI was added in one portion. After 1.5 h the reaction was diluted with 1 N HCl (75 mL) and EtOAc (75 mL). The layers were separated, and the organic layer was washed with H 2 O (50 mL) and brine (50 mL), dried over Na 2 SO 4  and the solvent was removed under reduced pressure. Purification by flash chromatography (silica, 0-5% MeOH/CH 2 Cl 2 ) afforded 0.92 g (91%) of a white solid. A suspension of 0.92 g (2.72 mmol) of the ethyl carbamate in 1:1 EtOH (7.0 mL) and 10% NaOH (7.0 mL) was heated to 110° C. for 36 h and then cooled. The mixture was diluted with EtOAc (30 mL) and H 2 O. The layers were separated and the aqueous phase was extracted with EtOAc (2×30 mL). The combined organic layers were dried over Na 2 SO 4  and the solvent was removed under reduced pressure to afford 0.56 g (78%) of a pale yellow solid. TLC (silica, 10% MeOH/CH 2 Cl 2 ): R f =0.1. MS (ESI): m/z calcd for C 13 H 16 ClN 3 O [M + +H] 266.10, observed 266.0.  1 H NMR (400 MHz, CDCl 3 ): 7.28 (d, J=1.8 Hz, 2H), 7.05 (dd, J=8.3, 2.0 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 4.41 (tt, J=12.5, 4.3 Hz, 1H), 3.39 (s, 3H), 3.30 (br d, J=11.9 Hz, 2H), 2.82 (dt, J=12.4, 2.0 Hz, 2H), 2.30 (dq, J=12.3, 4.3 Hz, 2H), 1.81 (br dd, J=12.1, 2.3 Hz, 2H).  
      E. 5-Chloro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5.6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-one. To a stirred solution of 0.33 mL (3.72 mmol) of oxalyl chloride in CH 2 Cl 2  (10 mL) under N 2  at −78° C. was added 0.36 mL (4.96 mmol) of DMSO and the reaction was stirred for 15 min. To this solution was added a solution of 1.0 g (2.48 mmol) of 3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-1-ol in 10 mL over 10 min and stirring was continued for 25 min. To this solution was added 1.40 mL (9.92 mmol) of Et 3 N and the reaction was stirred for 10 min at −78° C. and was then allowed to warm to rt and stir for 1 h. The mixture was diluted with EtOAc (75 mL) and saturated NaHCO 3  (75 mL) and the layers were separated. The combined organic layers were dried over Na 2 SO 4  and the solvent was removed under reduced pressure. The resulting solid was dried in vacuo and was suspended in Et 2 O (20 mL) and stirred vigorously for 1 h. The solid was filtered and washed with Et 2 O (2×10 mL) to afford the crude aldehyde which was carried on without further purification. The crude aldehyde, 5-chloro-1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.60 g, 2.3 mmol), and 0.20 mL (3.72 mmol) of AcOH was dissolved in CH 2 Cl 2  (15 mL) followed by 0.69 g (3.25 mmol) of NaBH(OAc) 3 , and the reaction was allowed to stir overnight. The mixture was diluted with CH 2 Cl 2  (75 mL) and saturated NaHCO 3  (75 mL) and the layers were separated. The combined organic layers were dried over Na 2 SO 4  and the solvent was removed under reduced pressure. Purification by flash chromatography (silica, 0-4% MeOH/CH 2 Cl 2 ) afforded 1.28 g (79% over 2 steps) of a white solid. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.5. MS (ESI): m/z calcd for C 30 H 34 ClF 3 N 6 O 3 S [M + +H] 651.21, observed 651.2.  1 H NMR (400 MHz, CDCl 3 ): 7.71 and 7.63 (A and B of AA′BB″, J AB =8.17 Hz, 4H), 7.16 (d, J=1.8 Hz, 1H), 7.04 (d, J=8.3, 1.8 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 4.55 (s, 2H), 4.23 (tt, J=12.4, 4.3 Hz, 1H), 4.13 (t, J=6.7 Hz, 2H), 3.69 (t, J=5.7 Hz, 2H), 3.36 (s, 3H), 3.0 (d, J=11.6 Hz, 2H), 2.95 (t, J=5.7 Hz, 2H), 2.90 (s, 3H), 2.45-2.32 (m, 4H), 2.16-2.04 (m, 4H), 1.76 (dd, J=11.9, 2.0 Hz, 2H).  13 C NMR (100 MHz, CDCl 3 ): 171.0, 153.7, 144.7, 137.1, 136.8, 129.3, 129.0, 128.7, 126.4, 125.5 (q, J=3.8 Hz), 122.7, 120.7, 109.8, 109.2, 108.0, 60.3, 54.7, 53.0, 51.3, 46.8, 43.1, 42.4, 36.8, 29.0, 27.2, 27.0, 22.3, 21.0, 14.1.  
     Example 11 
     
       
         
         
             
             
         
       
     
     1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one  
      A. Methyl 2-nitrophenylacetate.  
      2-Nitrophenylacetic acid (60 g, 0.3 mol) was set stirring in 250 mL of methanol. Sulfuric acid (0.5 mL) was added and the mixture heated to reflux. After 20 h the mixture was cooled and evaporated under reduced pressure to give a clear yellow oil. The oil was brought up in EtOAc and washed with saturated NaHCO 3 . The organics were dried (MgSO 4 ) and evaporated to give 63 g (98%) of the ester as a clear orange liquid. TLC (silica, 25% EtOAc/hexanes): R f =0.36.  1 H NMR (400 MHz, CDCl 3 ): 8.24 (m, 1H), 7.16 (m, 1H), 7.60 (m, 1H), 7.47 (m, 1H), 4.15 (s, 2H), 3.83 (s, 3H).  
      B. Methyl 2-aminophenylacetate.  
      Methyl 2-nitrophenylacetate (10.1 g, 51.2 mmol) in 125 mL of methanol containing 221 mg of 10% Pd/C was placed on the Parr hydrogenator at 40 psi. After 5 h the mixture was filtered through celite and evaporated under reduced pressure to give a clear red oil. The solvent was evaporated under reduced pressure to give 8.5 g (100%) of methyl 2-aminophenylacetate as a clear red oil. TLC (silica, EtOAc/hexanes): R f =0.24.  1 H NMR (400 MHz, CDCl 3 ): 7.21 (m, 2H), 6.86 (m, 2H), 3.81 (s, 3H), 3.70 (s, 2H).  
      C. 4-(2-Oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester.  
      Methyl 2-aminophenylacetate (3.0 g, 18.2 mmol) and 1-tert-butoxycarbonyl-4-piperidone (4.5 g, 22.6 mmol) were set stirring in 50 mL of CH 2 Cl 2  under an atmosphere of nitrogen. Sodium triacetoxyborohydride (5.4 g, 25.5 mmol) was added followed by 1 mL of acetic acid. After 20 h at rt the mixture was quenched by the slow addition of saturated NaHCO 3 . After stirring for 30 min, the organics were separated, dried (MgSO 4 ), and evaporated to afford 7.5 g of a purple oil. Purification by column chromatography (silica, 10-50% EtOAc/hexanes) gave 3.9 g (62%) of the title compound. TLC (silica, 25% EtOAc/hexanes): R f =0.15.  1 H NMR (400 MHz, CDCl 3 ): 7.25 (m, 2H), 7.01 (m, 2H), 4.40 (m, 1H), 3.53 (s, 2H), 2.83 (m, 2H), 2.32 (m, 2H), 1.70 (m, 2H), 1.51 (s, 9H).  
      D. 1-Piperidin-4-yl-1,3-dihydro-indol-2-one.  
      4-(2-Oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.9 g, 12.3 mmol) was set stirring in 30 mL of 1:1 TFA/CH 2 Cl 2 . After 45 min the solvent was evaporated under reduced pressure to give a clear purple oil. The oil was brought up in diethyl ether and cooled on ice to give a precipitate. The solid was filtered, washed with ether and air dried to give 4.0 g (100%) of the title compound as a TFA salt.  1 H NMR (400 MHz, DMSO-d 6 ): 8.6 (br s, 1H), 7.27 (m, 3H), 7.03 (m, 1H), 4.45 (m, 1H), 3.56 (s, 2H), 3.42 (m, 2H), 3.09 (m, 2H), 2.53 (m, 2H), 1.78 (m, 2H).  
      E. 1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one.  
      3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-1-ol (304 mg, 0.754 mmol) was set stirring in 5 mL of CH 2 Cl 2  at rt under nitrogen. Dess-Martin reagent (394 mg, 0.929 mmol) was added in one portion and the reaction mixture was left stirring. After 1.5 h the mixture was added to a stirring solution of thiosulphate (10 equiv) in 20 mL of water and 5 mL of saturated NaHCO 3 . After 2 h the organic layer was separated, dried (MgSO 4 ) and evaporated to give the aldehyde as a light yellow solid. The above aldehyde (303 mg, 0.754 mmol) and 1-piperidin-4-yl-1,3-dihydro-indol-2-one were set stirring in 15 mL of CH 2 Cl 2  containing Et 3 N (0.15 mL, 1.1 mmol). A solution of Na(AcO) 3 BH in 5 mL of CH 2 Cl 2  was added dropwise via pipette over 10 min and the mixture was left to stir overnight. The mixture was quenched with saturated NaHCO 3  and the organic layer separated. The organics were dried (MgSO 4 ) and evaporated to a clear purple oil. Purification with column chromatography (silica, 50-100% acetone/CH 2 Cl 2 ) gave 240 mg (53%) of a light pink solid. TLC (silica, 50% acetone/CH 2 Cl 2 ): R f =0.17.  1 H NMR (400 MHz, DMSO-d 6 ): 7.82 (m, 4H), 7.24 (m, 2H), 7.11 (m, 1H), 6.98 (m, 1H), 4.49 (s, 2H), 4.12 (m, 3H), 3.54 (s, 2H), 3.32 (s, 4H), 2.95 (m, 7H), 2.32 (m, 4H), 1.99 (m, 4H), 1.55 (m, 2H).  
     Example 12 
     
       
         
         
             
             
         
       
     
     1-[3-(4-Chloro-3-methyl-phenyl)-1-(3-{4-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-2-hydroxy-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
      1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.069 g. 0.20 mmol) was dissolved in CH 2 Cl 2  (1 mL), and 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]piperidine (0.105 g, 0.4 mmol) was added, followed by Yb(OTf) 3  (0.031 g, 0.22 mmol). The mixture was stirred at rt for 16 h. Preparative TLC (silica, 7.5% MeOH/CH 2 Cl 2 ) afforded 84 mg (69%) of the title compound. MS (ESI): exact mass calcd for C 31 H 34 Cl 2 N 6 O 3 , 608.21; m/z found, 609.2 [M + +H].  1 H NMR (400 MHz, CDCl 3 , 1:1 mixture of rotamers): 8.00 (d, J=8.4 Hz, 2H), 7.56-7.53 (m, 1H), 7.48-7.42 (d, J=8.6 Hz, 2H), 7.41-7.30 (m, 2H), 4.84 and 4.73 (A and B of AB quartet J=15.6 Hz, 1H), 4.62 (br s, 1H), 4.25-4.13 (m, 2H), 4.10-3.98 (m, 2H), 3.90-3.70 (m, 2H), 3.04-2.71 (m, 5H), 2.51-2.40 (m, 6H), 2.30-2.15 (m, 6H), 2.10-1.90 (m, 2H).  
     Example 13 
     
       
         
         
             
             
         
       
     
     1-[1-{2-Hydroxy-3-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
      A. 2-Piperidin-4-yl-5-trifluoromethyl-benzothiazole.  
      To a stirred solution of 5 g (29.2 mmol) of 1-acetyl-piperidine-4-carboylic acid in toluene (100 mL) and a catalytic amount of DMF (1 mL) was added dropwise 2.4 mL of oxalyl chloride (33.3 mmol). The reaction mixture was allowed to stir at rt overnight. A 20 mL aliquot (6 mmol) of the acid chloride solution was then placed in a separate flask and treated with a solution of 1.4 g (6.10 mmol) of 2-amino-4-(trifluoromethyl)thiophene hydrochloride in triethyl amine (4 mL). The reaction was then heated to 80° C. for 30 min and then partitioned between ethyl acetate (50 mL) and water (20 mL) and separated. The aqueous layer was further extracted with EtOAc (2×30 mL). The combined organic layers were then washed with water (25 mL), brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure. This was then heated to 60° C. in a 1 N HCl/MeOH solution overnight with stirring. The reaction mixture was cooled and concentrated to dryness. The solid was then taken back up in 35 mL MeOH and stirred over sodium bicarbonate (1 g) for 1 h then filtered and stripped to give 1.05 g (60%) of the desired product which was used without further purification. MS (ESI): exact mass calcd for C 13 H 13 F 3 N 2 S, 286.08; m/z found, 287.1 [M+H] + .  1 H NMR (CDCl 3 , 400 MHz): 8.25 (s, 1H), 7.98 (d, J=8.41 Hz, 1H), 7.65 (d, J=8.41 Hz, 1H), 3.38 (tt, J=11.35, 4.11 Hz, 1H), 3.28 (ddd, J=13.69, 11.74, 2.74 Hz, 1H), 3.16 (ddd, J=13.89, 11.15, 2.74 Hz, 1H), 2.85 (m, 1H), 2.25 (br m, 2H), 1.97 (br m, 2H).  
      B. 1-[1-{2-Hydroxy-3-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      A solution of 63 mg (0.22 mmol) 2-piperidin-4-yl-5-trifluoromethyl-benzothiazole was dissolved in 4 mL EtOH and treated with 40 mg (0.11 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 57 mg (80%) of a white solid. MS (ESI): exact mass calcd for C 31 H 31 F 6 N 5 O 2 S, 651.21; m/z found, 652.2 [M+H] + .  1 H NMR (CDCl 3 , 400 MHz, a mixture of amide rotamers): 8.24 (s, 1H), 7.97 (d, J=8.41 Hz, 1H), 7.78 (d, J=8.41 Hz, 1H), 7.70 (m, 2H), 7.65 (d, J=8.41 Hz, 1H), 7.60 (dd, J=8.41, 1.37 Hz, 1H), 4.88 and 4.76 (A and B of AB quartet, J=15.85 Hz, 1H), 4.66 (br s, 1H), 4.25-4.15 (m, 2H), 4.08-3.99 (m, 1.5H), 3.91-3.83 (m, 0.5H), 3.82-3.68 (m, 1H), 3.16 (tt, J=11.35, 3.52 Hz, 1H), 3.12-3.06 (m, 1H), 3.02-2.97 (m, 1H), 2.9-2.87 (m, 1.4H), 2.87-2.75 (m, 0.6H), 2.55-2.43 (m, 3H), 2.27-2.17 (m, 3H), 2.21 (s, 1.5H), 2.17 (s, 1.5H), 2.04-1.87 (m, 2H).  
     Example 14 
     
       
         
         
             
             
         
       
     
     1-[1-{3-[4-(Benzo[d]isoxazol-3-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
      A. 4-(Benzo[d]isoxazol-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester.  
      To a stirred solution of 263 mg of t-butyl-4-hydroxy-1-piperidinecarboxylate (1.3 mmol) in 5 mL of dry DMF was added 52 mg of 60% NaH in mineral oil (1.3 mmol). After stirring at rt for 10 min, 100 mg (0.65 mmol) of 3-chloro-1,2-benzisoxazole in DMF (1 mL) was added. The mixture was stirred at 40° C. overnight and then partitioned between EtOAc (50 mL) and water (20 mL) and separated. The aqueous layer was further extracted with EtOAc (2×30 mL). The combined organic layers were then washed with water (25 mL), brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure to give crude product. Purification by chromatography (silica, gradient elution of 40% hexanes/CH 2 Cl 2  to 100% CH 2 Cl 2 ) gave 176 mg (85%) product as a light yellow solid. MS (ESI): exact mass calcd for C 17 H 22 N 2 O 4 , 318.16; m/z found, 341.1 [M+Na] + .  1 H NMR (CDCl 3 , 400 MHz): 7.64 (dt, J=8.02, 1.17 Hz, 1H), 7.53 (ddd, J=8.41, 7.04, 1.17 Hz, 1H), 7.43 (dt, J=8.41, 0.78 Hz, 1H), 7.27 (ddd, J=8.02, 7.04, 0.78 Hz, 1H), 5.07 (m, 1H), 3.87-3.77 (br m, 2H), 3.30 (m, 2H), 2.17-2.10 (br m, 2H), 1.93-1.84 (br m, 2H), 1.48 (s, 9H).  
      B. 1-[1-{3-[4-(Benzo[d]isoxazol-3-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      A solution of 176 mg (0.55 mmol) of 4-(benzo[d]isoxazol-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in CH 2 Cl 2 (2 mL) was treated with trifluoroacetic acid (0.5 mL) at rt overnight. The solvent was then removed and the crude product dissolved in methanol and stirred over 100 mg of sodium bicarbonate for 1 h, the solid was then filtered off and the filtrate concentrated. The crude piperidine was then dissolved in 4 mL EtOH and treated with 202 mg (0.55 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 220 mg (68%) of a white solid. MS (ESI): exact mass calcd for C 30 H 32 F 3 N 5 O 4 , 583.24; m/z found, 584.2 [M+H] + .  1 H NMR (CDCl 3 , 400 MHz, a mixture of amide rotamers): 7.77 (d, J=8.22 Hz, 1H), 7.69 (m, 2H), 7.66-7.61 (m, 2H), 7.54-7.49 (m, 1H), 7.41 (d, J=8.41 Hz, 1H), 7.28-7.23 (m, 1H), 4.93 (br m, 1H), 4.88 and 4.75 (A and B of AB quartet, J=15.65 Hz, 1H), 4.65 (br s, 1H), 4.24-4.18 (m, 0.75H), 4.18-4.09 (m, 1.25H), 4.07-3.98 (m, 1.5H), 3.91-3.79 (m, 0.5H), 3.79-3.67 (m, 1H), 3.02-2.85 (m, 2.4H), 2.85-2.70 (m, 1.6H), 2.61-2.52 (m, 1H), 2.51-2.40 (m, 2H), 2.39-2.30 (m, 1H), 2.24-2.12 (br m, 2H), 2.20 (s, 1.5H), 2.16 (s, 1.5H), 2.02-1.86 (m, 2H).  
     Example 15 
     
       
         
         
             
             
         
       
     
     1-[1-{3-[4-(5-Chloro-benzooxazol-2-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
      A. 5-Chloro-2-piperidin-4-yl-benzooxazole.  
      A flask was charged with 1.35 mL (10 mmol) of methyl isonipicotate, 1.43 g (10 mmol) of 2-amino-4-chlorophenol, and 5 g of polyphosphoric acid. The flask was then heated to 180° C. for 5 h. The reaction mixture was then poured into water while still warm and treated with 50% KOH solution until pH 12. This was then extracted with CH 2 Cl 2  (3×50 mL), then washed with water (25 mL), brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure to give 1.53 g (57%) of crude product which was used without further purification. MS (ESI): exact mass calcd for C 12 H 13 ClN 2 O, 236.07; m/z found, 237.1 [M+H] + .  
      B. 1-[1-{3-[4-(5-Chloro-benzooxazol-2-yl)-piperidin-1-yl]-2-hydroxy-propyl]-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      A solution of 130 mg (0.55 mmol) of 5-chloro-2-piperidin-4-yl-benzooxazole was dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 156 mg (95%) of a white solid. MS (ESI): exact mass calcd for C 30 H 31 ClF 3 N 5 O 3 , 601.21; m/z found, 602.2 [M+H] + .  1 H NMR (CDCl 3 , 400 MHz, a mixture of amide rotamers):7.76 (d, J=8.41 Hz, 1H), 7.71 and 7.67 (A and B of AB quartet, J=8.41 Hz, 2H), 7.65-7.61 (m, 2H), 7.38 (d, J=8.61 Hz, 1H), 7.26 (dd, J=8.61, 1.96, 1H), 4.86 and 4.74 (A and B of AB quartet, J=15.65 Hz, 1H), 4.64 (br s, 1H), 4.24-4.10 (m, 2.3H), 4.07-3.97 (m, 1.7H), 3.89-3.67 (m, 2H), 3.06-3.00 (m, 1H), 3.00-2.90 (m, 2H), 2.90-2.74 (m, 2H), 2.51-2.38 (m, 3H), 2.25-2.10 (m, 2.3H), 2.20 (s, 1.5H), 2.15 (s, 1.5H), 2.06-1.83 (m, 2.7H).  
     Example 16 
     
       
         
         
             
             
         
       
     
     1-[1-{3-[4-(Benzothiazol-2-ylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
      A. 4-(Benzothiazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester.  
      To a stirred solution of 300 mg (1.77 mmol) of 2-chlorobenzothiazole in dry DMF (3.5 mL) was added 2.9 g of cesium carbonate (8.8 mmol) and 535 mg of tert-butyl-4-hydroxy-1-piperidinecarboxylate (2.66 mmol). The mixture was stirred at rt for 4 h before it was partitioned between EtOAc (70 mL) and water (30 mL) and separated. The aqueous layer was further extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (25 mL), brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure. Purification by flash chromatography (silica, 0-15% EtOAc/hexanes) afforded 220 mg (37%) of the desired product as a white solid. MS (ESI): exact mass calcd for C 17 H 23 N 3 O 2 S, 333.15; m/z found, 334.2 [M+H] + .  1 H NMR (CDCl 3 , 400 MHz): 7.65 (t, J=7.63 2H), 7.36 (ddd, J=8.41, 7.43, 1.37 Hz, 1H), 7.22 (dt, J=7.63, 1.17 Hz, 1H), 5.36 (m, 1H), 3.79-3.70 (br m, 2H), 3.36 (m, 2H), 2.12-2.04 (br m, 2H), 1.92-1.82 (br m, 2H), 1.48 (s, 9H).  
      B. 1-[1-{3-[4-(Benzothiazol-2-ylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      A solution of 220 mg (0.66 mmol) of 4-(benzothiazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (2 mL) was treated with trifluoroacetic acid (0.5 mL) at rt overnight. The solvent was then removed and the crude product dissolved in MeOH and stirred over 100 mg of sodium bicarbonate for 1 h. The solid was filtered off and the filtrate concentrated. The crude piperidine was then dissolved in 4 mL EtOH and treated with 220 mg (0.60 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 240 mg (66%) of a white solid. MS (ESI): exact mass calcd for C 30 H 33 F 3 N 6 O 2 S: 598.23; m/z found, 599.3 [M+H] + .  1 H NMR (CDCl 3 , 400 MHz, a mixture of amide rotamers): 7.78 (d, J=8.22 Hz, 1H), 7.72 and 7.68 (A and B of AB quartet, J=8.41 Hz, 2H), 7.64 (d, J=8.22 Hz, 1H), 7.56 (bd, J=8.02 Hz, 1H), 7.51 (bd, J=8.02 Hz, 1H), 7.29 (bd, J=7.63 Hz, 1H), 7.08 (bt, J=7.63 Hz, 1H), 5.29 (br s, 1H), 4.88 and 4.75 (A and B of AB quartet, J=15.65 Hz, 1H), 4.65 (br s, 1H), 4.23-4.16 (m, 1H), 4.16-4.08 (m, 1H), 4.06-3.98 (m, 2H), 3.92-3.65 (m, 3H), 3.03-2.70 (m, 4H), 2.52-2.41 (m, 3H), 2.26-2.18 (m, 1H), 2.21 (s, 1.5H), 2.16 (s, 1.5H), 2.16-2.08 (m, 2H), 1.66-1.44 (m, 2H).  
     Example 17 
     
       
         
         
             
             
         
       
     
     1-[1-{3-[4-(3,5-Dichloro-pyridin-4-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
      A. 4-(3,5-Dichloro-pyridin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester.  
      To a stirred solution of 828 mg (4.12 mmol) of tert-butyl-4-hydroxy-1-piperidinecarboxylate in 10 mL of dry DMF was added 165 mg of 60% NaH in mineral oil (4.12 mmol). After stirring at rt for 10 min, 500 mg (2.74 mmol) of 3,4,5-trichloropyridine was added. The mixture was stirred at 80° C. overnight and then partitioned between EtOAc (50 mL) and water (20 mL) and separated. The aqueous layer was further extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (25 mL), brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure. Column chromatography (silica, 60-100% CH 2 Cl 2 /hexanes) gave 265 mg (28%) of desired product. MS (ESI): exact mass calcd for C 15 H 20 Cl 2 N 2 O 3 , 346.09; m/z found, 369.1 [M+Na] + .  1 H NMR (CDCl 3 , 400 MHz): 8.45 (s, 2H), 4.66 (m, 1H), 3.90-3.80 (br m, 2H), 3.26 (m, 2H), 1.96-1.83 (br m, 4H), 1.47 (s, 9H).  
      B. 1-[1-{3-[4-(3,5-Dichloro-pyridin-4-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethml-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      A solution of 103 mg (0.30 mmol) of 4-(3,5-dichloro-pyridin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in CH 2 Cl 2  (2 mL) was treated with trifluoroacetic acid (0.5 mL) at rt overnight. The solvent was then removed and the crude product dissolved in MeOH and stirred over 100 mg of sodium bicarbonate for 1 h. The solid was filtered off and the filtrate concentrated. The crude piperidine was then dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 90 mg (54%) of a white solid. MS (ESI): exact mass calcd for C 28 H 30 Cl 2 F 3 N 5 O 3 , 611.17; m/z found, 612.2 [M+H] + .  1 H NMR (CDCl 3 , 400 MHz, a mixture of amide rotamers): 8.44 (s, 2H), 7.77 (d, J=8.41 Hz, 1H), 7.72 and 7.68 (A and B of AB quartet, J=8.41 Hz, 2H), 7.65 (d, J=8.41 Hz, 1H), 4.88 and 4.76 (A and B of AB quartet, J=15.65 Hz, 1H), 4.66 (br s, 1H), 4.55 (br s, 1H), 4.26-4.08 (m, 2H), 4.08-3.98 (m, 2H), 3.91-3.69 (m, 2H), 3.03-2.92 (m, 1.6H), 2.91-2.85 (m, 0.8H), 2.85-2.75 (m, 1.6H), 2.52-2.40 (m, 3H), 2.35-2.24 (br m, 1H), 2.22 (s, 1.5H), 2.17 (s, 1.5H), 2.03-1.90 (m, 4H).  
     Example 18 
     
       
         
         
             
             
         
       
     
     1-[1-{3-[4-(1H-Benzoimidazol-2-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
      A. 2-Piperidin-4-yl-1H-benzoimidazole.  
      A flask was charged with 1.35 mL (10 mmol) of methyl isonipicotate, 1.0 g (10 mmol) of 1,2-phenylenediamine and 5 g of polyphosphoric acid. The flask was then heated to 180° C. for 5 h. The reaction mixture was then poured into water while still warm and treated with 50% KOH solution until pH 12. This was then extracted with CH 2 Cl 2  (3×50 mL), washed with water (25 mL), brine, dried over Na 2 SO 4 , and the solvent was removed under reduced pressure to give 530 mg (27%) of crude product which was used without further purification. MS (ESI): exact mass calcd for C 12 H 15 N 3 , 201.13; m/z found, 202.1 [M+H] + .  1 H NMR (400 MHz, DMSO-d 6 ): 12.1 (br s, 1H), 7.49 (br m, 1H), 7.38 (br m, 1H), 7.09 (br m, 2H), 3.00 (dt, J=12.13, 3.33 Hz, 2H), 2.88 (tt, J=11.54, 3.74 Hz, 1H), 2.57 (dt, J=12.13, 2.35 Hz, 2H), 1.90 (m, 2H), 1.66 (m, 2H).  
      B. 1-[1-{3-[4-(1H-Benzoimidazol-2-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone.  
      A solution of 83 mg (0.41 mmol) of 2-piperidin-4-yl-1H-benzoimidazole was dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 55 mg (36%) of a white solid. MS (ESI): exact mass calcd for C 30 H 33 F 3 N 6 O 2 , 566.26; m/z found, 567.3 [M+H] + .  1 H NMR (CDCl 3 , 400 MHz, a mixture of amide rotamers): 10.66 (br s, 0.5H), 10.57 (br s, 0.5H), 7.73 (bd, J=8.41 Hz, 1H), 7.72-7.63 (m, 3H), 7.60 (bd, J=8.41 Hz, 1H), 7.39-7.32 (m, 1H), 7.23-7.13 (m, 2H), 7.02 (br s, 1), 4.86 and 4.75 (A and B of AB quartet, J=15.85 Hz, 1.25H), 4.64 (br s, 1H), 4.21-4.06 (m, 2H), 4.06-3.81 (m, 2H), 3.80-3.63 (m, 1H), 3.80-3.69 (m, 1H), 3.00-2.68 (m, 5H), 2.44-2.36 (m, 2H), 2.39-2.23 (m, 2H), 2.19 (s, 1.6H), 2.15 (s, 1.4H), 2.13-2.00 (m, 4H), 2.00-1.80 (m, 2H).  
     Example 19 
     
       
         
         
             
             
         
       
     
     6-Chloro-4-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one  
      A. 5-Methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.  
      5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (10.0 g, 29.0 mmol) and epichlorohydrin (24 mL, 307 mmol) were set stirring in DMF (150 mL) containing Cs 2 CO 3  (10.4 g, 31.9 mmol). After stirring at rt for 4 days the mixture was evaporated, brought up in EtOAc and washed with water. The organics were dried (MgSO 4 ) and evaporated to give a light yellow solid. Column chromatography (silica, 5% acetone/CH 2 Cl 2 ) gave 4.1 g (35%) of a white solid. TLC (silica, 5% acetone/CH 2 Cl 2 ): R f =0.28. MS (ESI): exact mass calcd for C 17 H 18 F 3 N 3 O 3 S, 401.10; m/z found, 402.1 [M+H] + .  1 H NMR (400 MHz, CDCl 3 ); 7.84 (d, J=8.3 Hz, 2H), 7.79 (d, J=8.3 Hz, 2H), 4.70-4.62 (m, 3H), 4.25 (d, J=5.4 Hz, 1H), 3.90-3.70 (m, 2H), 3.47 (m, 1H), 3.10-2.9 (m, 6H), 2.65-2.60 (m, 1H).  
      B. 4-(5-Chloro-2-hydroxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester.  
      2-Amino-4-chloro-phenol (30.0 g, 209 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (46.0 g, 231 mmol) were set stirring in dichloromethane (600 mL). Sodium triacetoxyborohydride (58.0 g, 274 mmol) was added in portions over 10 min. Acetic acid (12 mL, 210 mmol) was then added and the mixture left to stir for 18 h. Saturated NaHCO 3  was added and the organics separated. The organics were dried (MgSO 4 ) and evaporated to give 56 g (82%) of a light beige solid. TLC (silica, 50% EtOAc/hexanes): R f =0.66. MS (ESI): exact mass calcd for C 16 H 23 ClN 2 O 3 , 326.14; m/z found, 349.1 [M+Na] + .  1 H NMR (400 MHz, DMSO-d 6 ): 6.70 (d, J=8.3 Hz, 1H), 6.63 (s, 1H), 6.47 (d, J=8.2 Hz, 1H), 3.97 (d, J=12.2 Hz, 2H), 3.55-3.50 (m, 1H), 2.93 (br s, 2H), 1.93 (d, J=11.1 Hz, 2H), 1.48 (s, 9H), 1.35 (d, J=11.2 Hz, 2H).  
      C. 4-[(5-Chloro-2-hydroxy-phenyl)-ethoxycarbonylmethyl-amino]-piperidine-1-carboxylic acid tert-butyl ester. 4-(5-Chloro-2-hydroxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (15.6 g, 47.7 mmol) was set stirring in THF (200 mL) and cooled to 5° C. Sodium hydride (1.37 g, 54.2 mmol) was added in portions over 10 min and the mixture left to stir for 1 h. Ethyl bromoacetate (5.8 mL, 52.3 mmol) was added and the ice bath removed. After stirring for 20 h the mixture was evaporated, brought up in EtOAc and washed with water. The organics were dried (MgSO 4 ) and evaporated to give 22.5 g of a deep red oil. The oil was purified (silica, 5% acetone/CH 2 Cl 2 ) to give 12.9 g (65%) of a clear orange liquid. TLC (silica, 5% acetone/CH 2 Cl 2 ): R f =0.43. MS (ESI): exact mass calcd for C 20 H 29 ClN 2 O 5 , 412.18; m/z found, 413.2 [M+H] + .  1 H NMR (400 MHz, CDCl 3 ): 6.75-6.62 (m, 3H), 4.71 (s, 1H), 4.37 (q, J=7.2 Hz, 2H), 4.14 (br s, 2H), 3.55-3.50 (m, 1H), 3.08 (br t, 2H), 2.14 (m, 2H), 1.65-1.45 (m, 12H), 1.41 (t, J=7.2 Hz, 3H).  
      D. 4-(6-Chloro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester.  
      4-[(5-Chloro-2-hydroxy-phenyl)-ethoxycarbonylmethyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (12.9 g, 31.2 mmol) was set stirring in MeOH (100 mL). A solution of NaOH (2.5 g, 62.5 mmol) in water (100 mL) was added and the mixture stirred at rt for 3 h. The mixture was acidified to pH 2 and MeOH evaporated. The aqueous layer was extracted twice with EtOAc. The organics were combined, dried (MgSO 4 ) and evaporated to give 11 g of a clear orange oil. The oil was set stirring in CH 2 Cl 2  (150 mL) and EDC (8.2 g, 42.8 mmol) was added. After 1 h the organics were washed with 1 N HCl (100 mL), water (100 mL) and dried (MgSO 4 ). The solvent was evaporated to give 7.2 g (63%) of a clear orange solid. TLC (silica, 5% acetone/CH 2 Cl 2 ): R f =0.53. MS (ESI): exact mass calcd for C 18 H 23 ClN 2 O 4 , 366.13; m/z found, 389.1 [M+Na] + .  1 H NMR (400 MHz, CDCl 3 ): 7.19 (s, 1H), 7.11-7.00 (m, 2H), 4.60 (s, 2H), 4.50-4.30 (m, 3H), 3.00-2.80 (m, 2H), 2.70-2.60 (m, 2H), 1.86 (d, J=11.4 Hz, 2H), 1.60 (s, 9H).  
      E. 6-Chloro-4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one.  
      4-(6-Chloro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (7.2 g, 19.6 mmol) was set stirring and a 1:1 TFA/CH 2 Cl 2  solvent mixture was added. After 1 h the mixture was evaporated under reduced pressure and the resulting red oil brought up in Et 2 O. A solid formed and was filtered and air dried to give 7.2 g (96%) of a light beige solid. MS (ESI): exact mass calcd for C 13 H 15 ClN 2 O 2 , 266.08; m/z found, 267.1 [M+H] + .  1 H NMR (400 MHz, CD 3 OD): 7.52 (s, 1H), 7.20-7.00 (m, 2H), 4.60 (s, 2H), 4.50-4.40 (m, 1H), 3.65-3.55 (m, 2H), 3.28 (t, J=13.1 Hz, 2H), 3.10-3.00 (m, 2H), 2.15 (d, J=13.9 Hz, 2H).  
      F. 6-Chloro-4-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one.  
      6-Chloro-4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one (252 mg, 0.66 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (209 mg, 0.52 mmol) were set stirring in EtOH (10 mL) containing Et 3 N (115 μL, 0.83 mmol) at 70° C. After 2 days the mixture was cooled, evaporated, brought up in EtOAc and washed with saturated NaHCO 3 . The organics were dried (MgSO 4 ) and evaporated to give a clear golden oil. The oil was purified (silica, 50% acetone/CH 2 Cl 2 ) to give 191 mg (55%) of a white solid. TLC (silica, 50% acetone/CH 2 Cl 2 ): R f =0.38. MS (ESI): exact mass calcd for C 30 H 33 ClF 3 N 5 O 5 S, 667.18; m/z found, 668.2 [M+H] + .  1 H NMR (400 MHz, CDCl 3 ): 7.83 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 2H), 7.21 (s, 1H), 7.10-7.00 (m, 2H), 4.68 (d, J=5.1 Hz, 2H), 4.58 (s, 2H), 4.40-4.10 (m, 4H), 3.90-3.70 (s, 2H), 3.30-3.0 (m, 4H), 3.00 (s, 3H), 2.90-2.70 (m, 2H), 2.65-2.50 (m, 3H), 2.35-2.20 (m, 2H), 1.88 (d, J=11.3 Hz, 2H).  
     Example 20 
     
       
         
         
             
             
         
       
     
     6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3 ,4-dihydro-1H-quinolin-2-one  
      A. 3-(2-Amino-5-chloro-phenyl)-acrylic acid ethyl ester.  
      2-Amino-5-chlorobenzaldehyde (7.58 g, 48.7 mmol) and 36 g (103 mmol) of (carbethoxymethylene)triphenylphosphorane were added in benzene (300 mL) and heated to reflux for 20 h. The reaction mixture was cooled and concentrated to give an orange oil. The oil was brought up in Et 2 O and precipitated appeared. This was filtered and washed with Et 2 O. The organics were evaporated to give a clear orange oil. The oil was purified by column chromatography (silica, 10-40% EtOAc/hexanes) to obtain 10.4 g (95%) of a yellow solid. MS (ESI): exact mass calcd for C 11 H 12 ClNO 2 , 225.06; m/z found, 226.1 [M + +H].  1 H NMR (400 MHz, CDCl 3 ): 7.69 (d, J=15.85 Hz, 1H), 7.30 (d, J=2.54 Hz, 1H), 7.07 (dd, J=6.26 Hz, 2.35 Hz, 1H), 6.60 (d, J=8.61 Hz, 1H), 6.30 (d, J=15.85 Hz, 1H), 4.22 (dd, J=7.24 Hz, 7.24 Hz, 2H), 3.98 (br s, 2H), 1.30 (t, J=7.04 Hz, 3H).  
      B. 4-[4-Chloro-2-(2-ethoxycarbonyl-vinyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester.  
      3-(2-Amino-5-chloro-phenyl)-acrylic acid ethyl ester (10.4 g, 46 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (13.8 g, 69 mmol) were set stirring in CH 2 Cl 2  (230 mL). Sodium triacetoxyborohydride (14.6 g, 69 mmol) was added in portions over 10 min. Acetic acid (1.3 mL, 25 mmol) was then added and the mixture left to stir. After 18 h saturated NaHCO 3  was added and the organics separated. The organics were dried over Na 2 SO 4  and concentrated. The residue was purified by column chromatography (silica, 20-50% EtOAc/hexanes) to obtain 12.4 g (66%) of a light beige solid. TLC (silica, 25% EtOAc/hexanes): R f =0.5. MS (ESI): exact mass calcd for C 21 H 29 ClN2O 4 , 408.18; m/z found, 409.1 [M + +H].  1 H NMR (400 MHz, CDCl 3 ): 7.64 (d, J=15.65 Hz, 1H), 7.29 (d, J=2.35 Hz, 1H), 7.14 (dd, J=6.26 Hz, 2.54 Hz, 1H), 6.59 (d, J=9.00 Hz, 1H), 6.28 (d, J=15.65 Hz, 1H), 4.23 (dd, J=7.04 Hz, 7.04 Hz, 2H), 4.11-3.98 (m, 2H), 3.81 (br s, 1H), 3.46-3.36 (m, 1H), 2.89 (t, J=11.74 Hz, 2H), 2.04-1.95 (m, 2H), 1.44 (s, 9H), 1.42-1.33 (m, 2H), 1.30 (t, J=7.24 Hz, 3H).  
      C. 4-[4-Chloro-2-(2-ethoxycarbonyl-ethyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester.  
      4-[4-Chloro-2-(2-ethoxycarbonyl-vinyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (12.4 g, 30.4 mmol) in EtOAc (150 mL) containing PtO 2  (1 g) was placed on a Parr hydrogenator at 60 psi H 2 . After 18 h the mixture was filtered through celite and evaporated to give a clear brown liquid. The liquid was purified by column chromatography (silica, 20-50% EtOAc/hexanes) to obtain 5.7 g (46%) of the title compound. TLC (silica, 25% EtOAc/hexanes): R f =0.5. MS (ESI): exact mass calcd for C 21 H 31 ClN 2 O 4 , 410.2; m/z found, 411.2 [M + +H].  1 H NMR (400 MHz, CDCl 3 ): 7.05 (dd, J=6.06 Hz, 2.54 Hz, 1H), 6.99 (d, J=2.35 Hz, 1H), 6.55 (d, J=8.61 Hz, 1H), 4.13 (dd, J=7.04 Hz, 3.13 Hz, 2H), 4.11-3.98 (m, 2H), 3.81 (br s, 1H), 3.72 (t, J=6.26 Hz, 2H), 3.46-3.36 (m, 1H), 2.75 (t, J=7.43 Hz, 2H), 2.60 (t, J=7.04, 2H), 2.04-1.95 (m, 2H), 1.46 (s, 9H), 1.42-1.33 (m, 2H), 1.26 (t, J=7.24 Hz, 3H).  
      D. 4-[2-(2-Carboxy-ethyl)-4-chloro-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester.  
      4-[4-Chloro-2-(2-ethoxycarbonyl-ethyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (5.7 g, 13.9 mmol) was set stirring in MeOH (40 mL). A solution of NaOH (1.4 g, 34.7 mmol) in water (10 mL) was added and the mixture stirred at rt. After 3 h the mixture was acidified to pH 7 and MeOH was evaporated. The aqueous layer was extracted with CH 2 Cl 2  (3×100 mL). The organics were combined, dried over Na 2 SO 4  and concentrated to afford 3.9 g (73%) of the desired product. TLC (silica, 50% EtOAc/hexanes): R f =0.4. MS (ESI): exact mass calcd for C 19 H 27 ClN 2 O 4 , 382.17; m/z found, 381.1 [M − −H].  
      E. 4-(6-Chloro-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester.  
      4-[2-(2-Carboxy-ethyl)-4-chloro-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (3.9 g, 10.1 mmol) and EDC (2.9 g, 15.3 mmol) were set stirring in CH 2 Cl 2  (50 mL) for 2 h. The reaction mixture was dissolved in CH 2 Cl 2  (150 mL), washed with water (2×50 mL) and brine (1×50 mL). The organic layer was dried over Na 2 SO 4  and concentrated. The residue was purified by column chromatography (silica, 30-50% EtOAc/hexanes) to obtain 1.9 g (52%) of the desired product. TLC (silica, 50% EtOAc/hexanes): R f =0.67. MS (ESI): exact mass calcd for C 19 H 25 ClN 2 O 3 , 364.16; m/z found, 365.1 [M + +H].  1 H NMR (400 MHz, CDCl 3 ): 7.14-7.08 (m, 2H), 6.98. (d, J=8.61 Hz, 1H), 4.33-3.98 (m, 3H), 2.75 (t, J=7.83 Hz, 4H), 2.55-2.36 (m, 4H), 1.70-1.65 (m, 2H), 1.44 (s, 9H).  
      F. 6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-quinolin-2-one.  
      4-(6-Chloro-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 3.28 mmol) was set stirring in 1:1 TFA/CH 2 Cl 2 . After 45 min the mixture was evaporated and the golden oil brought up in Et 2 O. A solid formed and was filtered, washed with Et 2 O and air dried to give 1.3 g (93%) of a white solid. MS (ESI): exact mass calcd for C 13 H 17 ClN 2 O, 264.10; m/z found, 265.1 [M + +H].  
      G. 6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one.  
      6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-quinolin-2-one (270 mg, 0.62 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (165 mg, 0.41 mmol) were set stirring in EtOH (10 mL) containing Et 3 N (97 μL, 0.70 mmol) at 80° C. After 16 h the mixture was cooled, evaporated, brought up in dichloromethane and washed with water. The organics were dried over Na 2 SO 4  and concentrated. The residue was purified by column chromatography (silica, 5-10% MeOH/CH 2 Cl 2 ) to obtain 205 mg (75%) of a white solid. TLC (silica, 10% MeOH/CH 2 Cl 2 ): R f =0.75. MS (ESI): exact mass calcd for C 31 H 35 ClF 3 N 5 O 4 S, 665.21; m/z found, 666.2 [M + +H].  1 H NMR (CDCl 3 , 400 MHz): 7.69 (d, J=8.41 Hz, 2H), 7.62 (d, J=8.41 Hz, 2H), 7.16-7.08 (m, 2H), 7.00 (d, J=9.00 Hz, 1H), 4.52 (dd, J=14.28 Hz, 5.48 Hz, 2H), 4.18 (dd, J=10.56 Hz, 3.13 Hz, 1H), 4.14-4.04 (m, 2H), 4.03-3.96 (m, 1H), 3.72-3.56 (m, 2H), 3.10-2.96 (m, 2H), 2.95-2.86 (m, 2H), 2.85 (s, 3H), 2.75 (t, J=6.26 Hz, 2H), 2.69-2.54 (m, 2H), 2.53-2.47 (m, 2H), 2.44-2.31 (m, 3H), 2.15-2.05 (m, 1H), 1.71-1.62 (m, 2H).  
     Example 21 
     
       
         
         
             
             
         
       
     
     6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one  
      A. Spiro[piperidine-4,2′(1′H)-6′-chloro-3′,4′-dihydro-4′-oxo-quinazoline]-1-carboxylic acid tert-butyl ester.  
      To a stirred solution of 2-amino-5-chlorobenzamide (5.67 g, 33.2 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (6.62 g, 33.2 mmol) in benzene (70 mL) was added a catalytic amount (˜0.3 g) of p-toluenesulfonic acid. The mixture was heated to reflux for 20 h under a Dean-Stark trap. The resulting suspension was concentrated. Saturated NaHCO 3  (68 mL) was added. The mixture was extracted with EtOAc and the precipitated crystals in the aqueous layer was collected by filtration. The solid was washed with water and dried to afford 11.22 g (96%) of the desired product. MS (ESI): exact mass calcd for C 17 H 22 ClN 3 O 3 , 351.13; m/z found, 352.1 [M + +H].  1 H NMR (CD 3 OD, 400 MHz): 7.50 (d, J=2.54 Hz, 1H), 7.13 (dd, J=6.06 Hz, 2.54 Hz, 1H), 6.65 (d, J=8.61 Hz, 1H), 3.56-3.47 (m, 2H), 3.36-3.25 (m, 2H), 1.79-1.66 (m, 4H), 1.32 (s, 9H).  
      B. 4-(2-Aminomethyl-4-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester.  
      Spiro[piperidine-4,2′(1′H)-6′-chloro-3′,4′-dihydro-4′-oxo-quinazoline]-1-carboxylic acid tert-butyl ester (1 g, 2.8 mmol) and borane-tetrahydrofurane complex (1.0 M, 9.9 mL, 9.9 mmol) were added in THF (10 mL) and heated to reflux for 6 h. The reaction mixture was cooled and poured into ice water. The resulting suspension was extracted with CH 2 Cl 2  (2×100 mL). The organics were dried and concentrated. The residue was purified by column chromatography (silica, 5-10% MeOH/CH 2 Cl 2 ) to obtain 795 mg (79%) of the product. MS (ESI): exact mass calcd for C 17 H 26 ClN 3 O 2 , 339.17; m/z found, 362.1 [M + +Na].  1 H NMR (CDCl 3 , 400 MHz): 7.07 (dd, J=6.06 Hz, 2.54 Hz, 1H), 6.97 (d, J=2.54 Hz, 1H), 6.54 (d, J=8.61 Hz, 1H), 3.94-3.70 (m, 4H), 3.48-3.38 (m, 1H), 3.05 (t, J=11.15 Hz, 2H), 2.68-2.55 (m, 1H), 2.02-1.90 (m, 4H), 1.46 (s, 9H).  
      C. 4-(6-Chloro-2-oxo-3,4-dihydro-2H-quinazolin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester.  
      1,1′-Carbonyldiimidazole (0.51 g, 3.15 mmol) was added to a solution of 4-(2-aminomethyl-4-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.79 g, 2.25 mmol) in CH 3 CN (10 mL) over 3 h with stirring at 50° C. The reaction mixture was then cooled to rt and stirred for additional 2 h. The reaction mixture was dissolved in CH 2 Cl 2  (100 mL), washed with water (2×10 mL), brine (1×10 mL). The organic layer was dried over Na 2 SO 4  and concentrated. The residue was purified by column chromatography (silica, 30-50% EtOAc/hexanes) to obtain 0.46 g (63%) of the desired product. TLC (silica, 50% EtOAc/hexanes): R f =0.5. MS (ESI): exact mass calcd for C 18 H 24 ClN 3 O 3 , 365.15; m/z found, 388.1 [M + +Na].  1 H NMR (CDCl 3 , 400 MHz): 7.18 (dd, J=6.26 Hz, 2.54 Hz, 1H), 7.05 (d, J=2.15 Hz, 1H), 6.94 (d, J=9.00 Hz, 1H), 6.29 (s, 1H), 4.32-4.18 (m, 4H), 4.13-4.02 (m, 1H), 2.88-2.71 (m, 2H), 2.64-2.50 (m, 2H), 1.82-1.73 (m, 2H), 1.49 (s, 9H).  
      D. 6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one.  
      4-(6-Chloro-2-oxo-3,4-dihydro-2H-quinazolin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.52 g, 1.42 mmol) was set stirring in 1:1 TFA/CH 2 Cl 2 . After 45 min the mixture was evaporated and the golden oil brought up in Et 2 O. A solid formed and was filtered, washed with Et 2 O and air dried to give 0.52 g (97%) of an off-white solid. MS (ESI): exact mass calcd for C 13 H 16 ClN 3 O, 265.10; m/z found, 266.1 [M + +H].  
      E. 6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one.  
      6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (183 mg, 0.42 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (112 mg, 0.28 mmol) were set stirring in EtOH (10 mL) containing Et 3 N (66 μL, 0.47 mmol) at 80° C. After 16 h the mixture was cooled, evaporated, brought up in CH 2 Cl 2  and washed with water. The organics were dried over Na 2 SO 4  and concentrated. The residue was purified by column chromatography (silica, 5-10% MeOH/CH 2 Cl 2 ) to obtain 141 mg (76%) of a white solid. TLC (silica, 10% MeOH/CH 2 Cl 2 ): R f =0.6. MS (ESI): exact mass calcd for C 30 H 34 ClF 3 N 6 O 4 S, 666.20; m/z found, 667.2 [M + +H].  1 H NMR (CDCl 3 , 400 MHz): 7.70 (d, J=7.83 Hz, 2H), 7.63 (d, J=8.02 Hz, 2H), 7.12 (dd, J=6.65 Hz, 2.35 Hz, 1H), 7.01 (br s, 1H), 6.92 (d, J=9.00 HZ, 1H), 5.44 (br s, 1H), 4.54 (dd, J=14.67 Hz, 6.46 Hz, 2H), 4.23-4.08 (m, 4H), 4.05-3.97 (m, 1H), 3.92-3.80 (m, 1H), 3.74-3.57 (m, 2H), 3.14-2.99 (m 2H), 2.97-2.87 (m, 2H), 2.86 (s, 3H), 2.78-2.57 (m, 2H), 2.48-2.32 (m, 3H), 2.10 (t, J=11.50 Hz 1H), 1.80-1.70 (m, 2H).  
     Example 22 
     
       
         
         
             
             
         
       
     
     1-[4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2λ 6 -benzo[1,2,6]thiadiazin-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol  
      A. 4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2λ 6 -benzo[1,2,6]thiadiazin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester. A solution of 4-(2-aminomethyl-4-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (678 mg, 2 mmol) and sulfamide (596 mg, 6.2 mmol) in pyridine (12 mL) was heated to reflux for 6 h. The reaction mixture was then cooled to rt and poured into ice water (50 mL). The solution was extracted with CH 2 Cl 2  (4×100 mL). The organic extracts was dried over Na 2 SO 4  and concentrated. The residue was purified by column chromatography (silica, 30-50% EtOAc/hexanes) to obtain 767 mg (96%) of the desired product. TLC (silica, 50% EtOAc/hexanes): R f =0.75. MS (ESI): exact mass calcd for C 17 H 24 ClN 3 O 4 S, 401.12; m/z found, 400.1 [M − −H].  1 H NMR (CDCl 3 , 400 MHz): 7.13 (dd, J=6.46 Hz, 2.15 Hz, 1H), 7.00 (d, J=1.96 Hz, 1H), 6.92 (d, J=8.60 Hz, 1H), 5.54 (br s, 1H), 4.35 (s, 2H), 4.11-3.81 (m, 3H), 2.62 (br s, 2H), 1.90-1.66 (m, 4H), 1.34 (s, 9H).  
      B. 6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-benzo[1,2,6]thiadiazine 2,2-dioxide.  
      4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2l6-benzo[1,2,6]thiadiazin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (767 mg, 1.91 mmol) was set stirring in 1:1 TFA/CH 2 Cl 2 . After 45 min the mixture was evaporated and the golden oil brought up in Et 2 O. A solid formed and was filtered, washed with Et 2 O and air dried to give 730 mg (91%) of an off-white solid. MS (ESI): exact mass calcd for C 12 H 16 ClN 3 O 2 S, 301.07; m/z found, 302.0 [M + +H].  
      C. 1-[4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2λ 6 -benzo[1,2,6]thiadiazin-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.  
      6-Chloro-1-piperidin-4-yl-3,4-dihydro-1H-benzo[1,2,6]thiadiazine 2,2-dioxide (440 mg, 1.03 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (415 mg, 1.03 mmol) were set stirring in EtOH (20 mL) containing Et 3 N (215 μL, 1.54 mmol) at 80° C. After 16 h the mixture was cooled, evaporated, brought up in CH 2 Cl 2  and washed with water. The organics were dried over Na 2 SO 4  and concentrated. The residue was purified by column chromatography (silica, 0-5% MeOH/CH 2 Cl 2 ) to obtain 229 mg (32%) of a white solid. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.8. MS (ESI): exact mass calcd for C 29 H 34 ClF 3 N 6 O 5 S 2 , 702.17; m/z found, 703.2 [M + +H].  1 H NMR (CDCl 3 , 400 MHz, a mixture of two rotamers): 7.66 (d, J=8.61 Hz, 2H), 7.60 (d, J=8.61 Hz, 2H), 7.16 (dd, J=6.85 Hz, 1.96 Hz, 1H), 6.98 (s, 1H), 6.95 (d, J=9.00 HZ, 1H), 4.47 (s, 2H), 4.33 (s, 2H), 4.16-3.99 (m, 2H), 3.98-3.90 (m, 1H), 3.89-3.78 (m, 1H), 3.62-3.52 (m, 2H), 3.05-2.95 (m, 1H), 2.93-2.84 (m, 2H), 2.82 (s, 3H), 2.81-2.76 (m, 1H), 2.33 (d, J=6.46 Hz, 2H), 2.25 (t, J=11.24 Hz, 1H), 2.09-1.90 (m, 3H), 1.90-1.78 (m, 2H).  
     Example 23 
     
       
         
         
             
             
         
       
     
     4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one  
     A. 4-(3-Hydroxy-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester.  
      To a stirring solution of 4.7 g (0.042 mol) of 2-amino-3-hydroxypyridine and 12.75 g (0.064 mol) of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester in CH 2 Cl 2 /AcOH (150 mL/60 mL) was added 10 g (0.070 mol) of Na 2 SO 4 . After 3.5 h, 9.9 g (0.047) of sodium triacetoxyborohydride was added in three portions, and the mixture was stirred at rt for 15 h. The reaction was then quenched with NaHCO 3  (150 mL), extracted with CH 2 Cl 2  (500 mL), washed with NaHCO 3  (2×100 mL), and the combined aqueous layers were extracted with EtOAc (150 mL). The combined organic layers were dried over Na 2 SO 4 , concentrated, and purified using flash chromatography (silica, 3-10% MeOH/CH 2 Cl 2 ) to afford 5.9 g (48%) of a beige powder. MS (ESI): exact mass calcd for C 15 H 23 N 3 O 3 , 293.17; m/z found, 294.2 [M+H] + .  1 H NMR (400 MHz, CDCl 3 ): 7.52 (dd, J=5.3 Hz, 1.3 Hz, 1H), 6.79 (dd, J=7.6 Hz, 1.3 Hz, 1H), 6.40 (dd, J=7.6 Hz, 5.3 Hz, 1H), 4.06-3.94 (m, 3H), 3.02-2.86 (m, 2H), 2.72 (br s, 1H), 2.06-1.97 (m, 2H), 1.42 (s, 9H), 1.46-1.28 (m, 2H).  
      B. 4-(3-Ethoxycarbonylmethoxy-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester.  
      A stirring solution of 1.4 g (0.0048 mol) of 4-(3-hydroxy-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester was dissolved in THF (24 mL) was cooled to 0° C., and 0.13 g (0.0052 mol) of NaH was added. After 30 min, 0.8 g (0.0052 mol) of ethyl bromoacetate was added, and reaction was allowed to warm to rt and stirred overnight. Saturated NaHCO 3  (20 mL) was added and the reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO 3  (75 mL). The organic layer was washed with water (50 mL) and NaCl (50 mL), dried over Na 2 SO 4 , and concentrated to afford 0.9 g (49%) of a white powder. MS (ESI): exact mass calcd for C 19 H 29 N 3 O 5 , 379.21; m/z found, 380.2 [M+H] + .  1 H NMR (400 MHz, CDCl 3 ): 7.74 (d, J=5.3 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.46 (dd, J=7.8 Hz, 5.3 Hz, 1H), 5.05 (d, J=7.33 Hz, 1H), 4.59 (s, 2H), 4.26 (q, J=7.3 Hz, 2H), 4.18-3.92 (m, 3H), 2.97 (t, J=11.6 Hz, 2H), 2.06 (d, J=12.1 Hz, 2H), 1.46 (s, 9H), 1.46-1.34 (m, 2H) 1.29 (t, J=7.3 Hz, 3H).  
      C. 4-(3-Oxo-2,3-dihydro-pyrido[3,2-b][1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester.  
      To a stirring solution of 0.9 g (0.0023 mol) of 4-(3-ethoxycarbonylmethoxy-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester in H 2 O/MeOH (1 mL/11 mL) was added 0.05 g (0.0023 mol) of LiOH. After 6 h, the solvent was removed under reduced pressure. The residue was dissolved in DMF (12 mL) and to the stirring solution was added 1.82 g (0.0048 mol) of HATU. After 3 h, the reaction was partitioned between EtOAc (250 mL) and saturated NaHCO 3  (100 mL), and washed with water (3×100 mL). The combined aqueous layers were extracted with EtOAc (100 mL). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , and concentrated to afford 0.37 g (46%) of a white solid. MS (ESI): exact mass calcd for C 17 H 23 N 3 O 4 , 333.17; m/z found, 356.1 [M+Na] + .  1 H NMR (400 MHz, CDCl 3 ): 7.97 (dd, J=4.8 Hz, 1.5 Hz, 1H), 7.25 (dd, J=8.1 Hz, 1.5 Hz, 1H), 6.96 (dd, J=8.1 Hz, 4.8 Hz, 1H), 5.03 (tt, J=11.9 Hz, 4.0 Hz, 1H), 4.55 (s, 2H), 4.13 (d, J=10.9 Hz, 2H), 2.82-2.69 (m, 2H), 2.68 (qd, J=12.4 Hz, 4.0 Hz, 2H), 1.65 (d, J=12.1 Hz, 2H), 1.46 (s, 9H).  
      D. 4-Piperidin-4-yl-4H-pyrido[3.2-b][1,4]oxazin-3-one.  
      To a stirring solution of 0.37 g (0.0011 mol) of 4-(3-oxo-2,3-dihydro-pyrido[3,2-b][1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester in CH 2 Cl 2  (2.5 mL) was added 2.5 mL of TFA. After 2.5 h, the solvent was removed. The residue was partitioned between EtOAc (200 mL) and 1 N NaOH (150 mL). The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were dried over Na 2 SO 4 , and concentrated to afford 0.24 g (94%) of a white/pink solid.  1 H NMR (400 MHz, CDCl 3 ): 7.87 (dd, J=4.8 Hz, 1.5 Hz, 1H), 7.25 (dd, J=7.8 Hz, 1.8 Hz, 1H), 6.84 (dd, J=7.8 Hz, 4.8 Hz, 1H), 4.98-4.83 (m, 1H), 4.45 (s, 2H), 3.90 (s, 1H), 3.06 (d, J=8.3 Hz, 2H), 2.65-2.53 (m, 4H), 1.65-1.53 (m, 2H).  
      E. 4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one.  
      To a stirring solution of 0.24 g (0.001 mol) of 4-piperidin-4-yl-4H-pyrido[3,2-b][1,4]oxazin-3-one in EtOH/Dichloroethane (2 mL/2 mL) was added 0.27 g (0.0007 mol) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoro-methyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture was heated to 80° C. and stirred for 16 h. The solvent was then removed under reduced pressure, and the crude product was purified using flash chromatography (30% acetone/CH 2 Cl 2 ), affording 0.42 g (96%) of a white solid. MS (ESI): exact mass calcd for C 29 H 33 F 3 N 6 O 5 S, 634.22; m/z found, 635.3 [M+H] + .  1 H-NMR (400 MHz, CDCl 3 ): 8.00 (dd, J=4.8 Hz, 1.5 Hz, 1H), 7.71 and 7.67 (A and B of AA′BB′ quartet, J ab =8.4 Hz, 4H), 7.22 (dd, J=7.9 Hz, 1.5 Hz, 1H), 6.94 (dd, J=7.9 Hz, 4.8 Hz, 1H), 4.94 (tt, J=12.1 Hz, 4.0 Hz, 1H) 4.57 and 4.55 (A and B of AB quartet, J ab =14.5 Hz, 2H), 4.57 (s, 2H), 4.25-4.02 (m, 3H), 3.78-3.61 (m, 2H), 3.16-2.90 (m, 4H), 2.90 (s, 3H), 2.89-2.76 (m, 1H), 2.56-2.43 (m, 3H) 2.23 (t, J=11.2 Hz, 1H), 1.67 (d, J=11.3 Hz, 2H).  
     Example 24 
     
       
         
         
             
             
         
       
     
     5-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one  
      A. 2-(5-Chloro-2-nitro-phenyl)-malonic acid diethyl ester.  
      Sodium hydride (2.94 g, 123 mmol) was set stirring in DMSO (100 mL) and heated to 100° C. Diethyl malonate (17.5 mL, 115 mmol) in DMSO (30 mL) was added and after 10 min a clear red solution was obtained. 2,4-Dichloronitrobenzene in DMSO (50 mL) was added. After 1.5 h the mixture was cooled and added to water (1000 mL). The product was extracted with ether. The organics were dried (MgSO 4 ) and evaporated to a clear yellow oil (10 g, 59%). TLC (silica, 20% EtOAc/hexanes): R f =0.36. MS (ESI): exact mass calcd for C 13 H 14 ClNO 6 , 315.05; m/z found, 338.0 [M+Na] + .  1 H NMR (400 MHz, CDCl 3 ): 8.05 (d, J=8.7 Hz, 1H), 7.55-7.40 (m, 2H), 5.30 (s, 1H), 4.30 (q, J=7.1 Hz, 4H), 1.31 (t, J=7.1 Hz, 6H).  
      B. (5-Chloro-2-nitro-phenyl)-acetic acid ethyl ester.  
      2-(5-Chloro-2-nitro-phenyl)-malonic acid diethyl ester (10.3 g, 32.6 mmol) in DMSO (200 mL) containing LiCl (2.9 g, 68.4 mmol) and water (0.6 mL, 33.3 mmol) was set stirring and heated to 100° C. After 5 h the mixture was cooled to rt and added to water (750 mL). The product was extracted with two portions of EtOAc. The organics were combined, washed with water, dried (MgSO 4 ) and evaporated to give 5.9 g (75%) of a clear yellow oil. TLC (silica, 25% EtOAc/hexanes): R f =0.50.  1 H NMR (400 MHz, CDCl 3 ): 8.21 (d, J=8.8 Hz, 1H), 7.56 (dd, J=8.8, 2.3 Hz, 2H), 7.47 (d, J=2.3 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 4.12 (s, 2H), 1.38 (t, J=7.1 Hz, 3H).  
      C. (2-Amino-5-chloro-phenyl)-acetic acid ethyl ester.  
      (5-Chloro-2-nitro-phenyl)-acetic acid ethyl ester (5.9 g, 24.2 mmol) in benzene (125 mL) containing PtO 2  (500 mg) was placed on a Parr hydrogenator at 40 psi H 2 . After 18 h the mixture was filtered through celite and evaporated to give a clear brown liquid. The liquid was purified (silica, 25% EtOAc/hexanes) to give 3.3 g (64%) of a clear golden liquid. TLC (silica, 25% EtOAc/hexanes): R f =0.30. MS (ESI): exact mass calcd for C 10 H 12 ClNO 2 , 213.06; m/z found, 214.1 [M+H] + .  1 H NMR (400 MHz, CDCl 3 ): 7.20-7.10 (m, 2H), 6.78 (d, J=8.3 Hz, 1H), 4.26 (q, J=7.2, 2H), 1.18 (t, J=7.1 Hz, 3H).  
      D. 4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester.  
      (2-Amino-5-chloro-phenyl)-acetic acid ethyl ester (3.3 g, 15.4 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.6 g, 23 mmol) were set stirring in CH 2 Cl 2  (50 mL) and sodium triacetoxyborohydride (4.9 g, 23.1 mmol) was added followed by acetic acid (3 mL). After 5 days saturated NaHCO 3  was added and the organics separated. The organics were dried (MgSO 4 ) and evaporated to give 7.5 g of a clear golden oil. The oil was purified (silica, 50% EtOAc/hexanes) to give 3.4 g (63%) of a white solid. TLC (silica, 25% EtOAc/hexanes): R f =0.18. MS (ESI): exact mass calcd for C 18 H 23 ClN 2 O 3 , 350.14; m/z found, 373.1 [M+Na] + .  1 H NMR (400 MHz, CDCl 3 ): 7.40-7.30 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 4.55-4.45 (m, 1H), 4.40 (m, 2H), 3.63 (s, 2H), 2.94 (m, 2H), 2.45-2.30 (m, 2H), 1.82 (m, 2H), 1.62 (s, 9H).  
      E. 5-Chloro-1-piperidin-4-yl-1,3-dihydro-indol-2-one.  
      4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.4 g, 9.7 mmol) was set stirring in 1:1 TFA/CH 2 Cl 2 . After 45 min the mixture was evaporated and the golden oil brought up in Et 2 O. A solid formed and was filtered, washed with Et 2 O and air dried to give 3.4 g (97%) of a white solid. MS (ESI): exact mass calcd for C 13 H 15 ClN 2 O, 250.09; m/z found, 251.1 [M+H] + .  1 H NMR (400 MHz, DMSO-d 6 ); 7.45 (s, 2H), 7.31 (d, J=8.1 Hz, 1H), 4.55-4.45 (m, 1H), 3.68 (s, 2H), 3.50 (d, J=12.3, 2H), 3.14 (m, 2H), 2.70-2.55 (m, 2H), 1.87 (d, J=13.1 Hz, 2H).  
      F. 5-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one.  
      5-Chloro-1-piperidin-4-yl-1,3-dihydro-indol-2-one (256 mg, 0.70 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (255 mg, 0.64 mmol) were set stirring in EtOH (15 mL) containing Et 3 N (107 □L, 0.77 mmol) at 80° C. After 20 h the mixture was cooled, evaporated, brought up in CH 2 Cl 2  and washed with water. The organics were dried (MgSO 4 ) and evaporated to give a clear golden oil. The oil was purified (silica, 50% acetone/CH 2 Cl 2 ) to give 225 mg (54%) of a white solid. TLC (silica, 50% acetone/CH 2 Cl 2 ): R f =0.32. MS (ESI): exact mass calcd for C 30 H 33 ClF 3 N 5 O 4 S, 651.19; m/z found, 652.2 [M+H] + .  1 H NMR (400 MHz, CDCl 3 ): 7.82 (d, J=8.1 Hz, 2H), 7.76 (d, J=8.1 Hz, 2H), 7.40-7.25 (m, 2H), 7.04 (d, J=8.1 Hz, 2H), 4.66 (d, J=4.0 Hz, 2H), 4.40-4.10 (m, 4H), 4.05-3.70 (m, 3H), 3.59 (s, 2H), 3.30-3.0 (m, 4H), 2.99 (s, 3H), 2.70-2;40 (m, 5H), 2.28 (m, 2H).  
     Example 25 
     
       
         
         
             
             
         
       
     
     1-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol  
      A. 5-Chloro-2-(2,2-dimethoxy-ethyl)-phenylamine.  
      To a stirred solution of 10.3 g (60 mmol) of 4-chloro-2-nitrotoluene in dry DMF (120 mL) was added 16.45 g of N,N-dimethylformamide dimethylacetal (138 mmol). The mixture was heated to 140° C. for 18 h after which the solvent was removed under reduced pressure and the residue diluted with 150 mL of MeOH and 15.2 mL of chlorotrimethylsilane (120 mmol). The reaction mixture was then heated to 60° C. overnight. Methanol was then removed under reduced pressure and the residue was taken up in EtOH and transferred to a Parr bottle. 100 mg of 10% Platinum on carbon was added and the reaction mixture was put under 2 atmospheres of hydrogen on a Parr shaker for 8 h. When the reaction was completed the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The crude aniline was used without further purification. TLC (silica, 35% EtOAc/hexanes): R f =0.4. MS (ESI): exact mass calcd for C 10 H 14 ClNO 2 , 215.07; m/z found, 216.1 [M+H] + .  
      B. 4-[5-Chloro-2-(2,2-dimethoxy-ethyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester.  
      To a stirred solution of 2 g of 5-chloro-2-(2,2-dimethoxy-ethyl)-phenylamine, (9.27 mmol) in 50 mL of acetic acid was added 3.7 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (18.5 mmol). The reaction mixture was allowed to stir for 1 h at rt before the portion wise addition of 5.9 g of sodium triacetoxyborohydride (27.9 mmol). The reaction mixture was allowed to stir an additional 5 h before removing the solvent under reduced pressure. The crude product was partitioned between CH 2 Cl 2  (250 mL) and water. The aqueous layer was further extracted with CH 2 Cl 2  (2×75 mL). The combined organic layers were then washed with 1 N NaOH (2×50 mL), brine, dried over Na 2 SO 4 , and concentrated. Purification by chromatography (silica, 10-25% EtOAc/hexanes) afforded 1.5 g (71%) of desired product. TLC (silica, 35% EtOAc/hexanes): R f =0.49. MS (ESI): exact mass calcd for C 20 H 31 ClN 2 O 4 , 398.20; m/z found, 399.2 [M+H] + .  1 H NMR (CDCl 3 , 400 MHz): 6.94 (d, J=7.83 Hz, 1H), 6.61 (dd, J=7.83, 2.02 Hz, 1H), 6.57 (d, J=2.02 Hz, 1H), 4.87 (br s, 1H), 4.40 (t, J=5.31 Hz, 1H), 3.97 (br m, 2H), 3.36 (s, 6H), 3.02 (m, 2H), 2.78 (d, J=5.05 Hz, 2H), 2.00 (m, 2H), 1.47 (s, 9H), 1.37 (m, 2H).  
      C. 6-Chloro-1-piperidin-4-yl-1H-indole.  
      To a stirred solution of 1.03 g (2.59 mmol) of 4-[5-chloro-2-(2,2-dimethoxy-ethyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester in 15 mL toluene was added 1.0 g (5.2 mmol) of p-toluenesulfonic acid. The reaction mixture was heated to 60° C. for 20 min, allowed to cool to rt and quenched with 100 mL of sat. aqueous NaHCO 3  then extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , and concentrated to afford 590 mg (98%) of the desired product as a pink oil. MS (ESI): exact mass calcd for C 13 H 15 ClN 2 , 234.09; m/z found, 235.1 [M+H] + .  1 H NMR (CDCl 3 , 400 MHz, a mixture of amide rotamers): 7.52 (d, J=8.34 Hz, 1H), 7.38 (br s, 1H), 7.21 (d, J=3.28 Hz, 1H), 7.06 (dd, J=8.34, 1.77 Hz, 1H), 6.49 (d, J=3.28 Hz, 1H), 4.24 (m, 1H), 3.30 (m, 2H), 2.85 (dt, J=12.38, 2.53 Hz, 2H), 2.08 (m, 2H), 1.94 (m, 2H).  
      D. 1-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol.  
      To a stirred solution of 86 mg (0.21 mmol) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine in 4 mL of EtOH was added 50 mg (0.39 mmol) of 6-chloro-1-piperidin-4-yl-1H-indole. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, gradient elution from 0-5% 2 N NH 3 /MeOH in CH 2 Cl 2 ) to afford 64 mg (48%) of a white solid. MS (ESI), exact mass calcd for C 30 H 33 ClF 3 N 5 O 3 S: 635.19; m/z found, 636.2 [M+H] + . HPLC (reverse phase conditions 10-90%), t R =4.88 min.  1 H NMR (CDCl 3 , 400 MHz): 7.72 and 7.67 (A and B of AB quartet, J=8.80 Hz, 4H), 7.52 (d, J=8.41, 1H), 7.34 (s, 1H), 7.18 (d, J=3.33 Hz, 1H), 7.07 (dd, J=8.41, 1.76 Hz, 1H), 6.50 (d, J=3.33 Hz, 1H), 4.59 and 4.54 (A and B of AB quartet, J=14.48 Hz, 2H), 4.24 (dd, J=13.69, 2.39 Hz, 1H), 4.21-4.14 (m, 2H), 4.05 (dd, J=13.69, 6.46 Hz, 1H), 3.69 (m, 2H), 3.15 (br d, J=11.54 Hz, 1H), 3.11-2.91 (m, 3H), 2.60-2.48 (m, 3H), 2.28 (dt, J=11.74, 2.15 Hz, 1H), 2.13-1.93 (m, 4H).  
     Example 26 
     
       
         
         
             
             
         
       
     
     1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzotriazole  
      To a stirred solution of 3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde (0.084 g, 0.21 mmol) in CH 2 Cl 2  (0.5 mL) were added 1-piperidin-4-yl-1H-benzotriazole hydrochloride (Maybridge Chemicals, 0.050 g, 0.21 mmol), Et 3 N (0.1 mL) and glacial AcOH (12 uL, 0.21 mmol) in that order and stirred for 20 min. NaBH(OAc) 3  (0.058 g, 0.27 mmol) was added and stirred under nitrogen overnight. Saturated NaHCO 3  (1 mL) was added and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2  (3 mL). The combined organic extracts were washed with brine (3 mL), dried over Na 2 SO 4 , and removed under reduced pressure. MPLC of the crude afforded the desired compound as a white solid (0.098 g, 80%). TLC (silica, 12% MeOH/CH 2 Cl 2 ): R f =0.44. MS (ESI): exact mass calcd for C 28 H 32 F 3 N 7 O 2 S, 587.23; m/z found 588.2 [M+H] + .  1 H NMR (400 MHz, CDCl 3 ): 8.00 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.41 (dt, J=0.9, 7.6 Hz, 1H), 7.30 (dt, J=0.9, 7.6 Hz, 1H), 4.59 (br t, J=11.2 Hz, 1H), 4.50 (s, 2H), 4.10 (t, J=6.7 Hz, 2H), 3.63 (t, J=5.8 Hz, 2H), 3.00 (br d, J=12.0 Hz, 2H), 2.89 (t, J=5.8 Hz, 2H), 2.86 (s, 3H), 2.38-2.27 (m, 4H), 2.17-1.99 (m, 6H).  
     Example 27 
     
       
         
         
             
             
         
       
     
     1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonic acid amide.  
      A. 1-(3-Oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester.  
      Dess-Martin periodinane (1.43 g, 3.36 mmol) was added portion wise to a stirred solution of 1-(3-hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydropyrazolo-[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.30 g, 3.05 mmol) in CH 2 Cl 2  (15 mL) at 0° C. under N 2 . Then the reaction was stirred at 0° C. for 15 min and allowed to warm to rt. After stirring at rt for 1.5 h the reaction was diluted with Et 2 O (50 mL) and saturated NaHCO 3  (15 mL) was added slowly (caution! gas evolution). Then Na 2 S 2 O 3 .5H 2 O (5.31 g, 21.4 mmol) was added and stirred for 30 min. The layers were separated and the aqueous layer was extracted with Et 2 O (2×30 mL). The combined extracts were washed with brine, dried (Na 2 SO 4 ) and concentrated. MPLC (1-10% MeOH/CH 2 Cl 2 ) afforded the aldehyde in 79% yield (1.02 g). TLC (silica, 10% MeOH/CH 2 Cl 2 ): R f =0.67. MS (ESI) calcd for C 21 H 24 F 3 N 3 O 3 , 424.2 ([M+H] + ), m/z found, 424.2.  1 H NMR (400 MHz, CDCl 3 ): 9.82 (s, 1H), 7.65 (br d, J=8.0 Hz, 2H), 7.54 (br s, 2H), 4.53 (s, 2H), 4.21 (t, J=6.2 Hz, 2H), 3.68 (br s, 2H), 3.04 (t, J=6.2 Hz, 2H), 2.70 (t, J=5.6 Hz, 2H), 1.39 (s, 9H).  
      B. 1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester.  
      To a stirred solution of 1-(3-oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.99 g, 23.6 mmol) in CH 2 Cl 2  (20 mL) were added 1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.60 g, 25.9 mmol) and glacial AcOH (0.13 mL, 23.6 mmol) in that order and stirred for 20 min. NaBH(OAc) 3  (0.65 g, 30.6 mmol) was added and stirred under nitrogen for 2 h. Saturated NaHCO 3  (20 mL) was added and stirred for 30 min, and the layers were separated. The organic extract was washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure. MPLC of the crude afforded the desired compound as a white solid (1.27 g, 85%). TLC (silica, 7% MeOH/CH 2 Cl 2 ): R f =0.35. MS (ESI): exact mass calcd for C 34 H 41 F 3 N 6 O 3 , 638.32; m/z found, 639.3 [M+H] + , 661.2 [M+Na] + .  1 H NMR (400 MHz, CDCl 3 ): 7.81 (br d, J=8.0 Hz, 2H), 7.68 (br s, 2H), 7.25 (dd, J=1.6, 7.5 Hz, 1H), 7.15-7.07 (m, 2H), 7.02(dd, J=1.6, 7.9 Hz, 1H), 4.70 (br s, 2H), 4.38 (tt, J=4.2, 12.4 Hz, 1H), 4.18 (t, J=6.8 Hz, 2H), 3.82 (s, 2H), 3.45 (s, 3H), 3.07 (d, J=11.6 Hz, 2H), 2.84 (t, J=5.5 Hz, 2H), 2.53-2.42 (m, 2H), 2.44 (t, J=6.7 Hz, 2H), 2.21-2.03 (m, 4H), 1.84 (d, J=12.0 Hz, 2H), 1.52 (s, 9H).  
      C. 1-Methyl-3-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one.  
      1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.19 g, 1.86 mmol) was dissolved in trifluoroacetic acid (5 mL) and CH 2 Cl 2  (5 mL) and allowed to stir at rt for 2 h. The reaction mixture was concentrated, diluted with CH 2 Cl 2 , and washed with saturated NaHCO 3 . The organic layer was dried over Na 2 SO 4  and concentrated to afford 1-methyl-3-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one (0.955 g, 96%) as a white foam. TLC (silica, 10% MeOH/CH 2 Cl 2 ): R f =0.19. MS (ESI) calcd for C 29 H 33 F 3 N 6 O, 539.3 ([M+H] + ), m/z found, 539.3.  
      D. 1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonic acid (N-t-butoxycarbonyl)amide. To a solution of chlorosulfonyl isocyanate (0.018 mL, 0.209 mmol) in CH 2 Cl 2  (0.150 mL) was added 2-methyl-2-propanol (0.020 mL, 0.209 mmol) and the solution was stirred at rt for 15 min. This solution was then added dropwise to a solution of 1-methyl-3-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one (75 mg, 0.139 mmol) and triethylamine (0.039 mL, 0.279 mmol) in CH 2 Cl 2  (0.4 mL). An additional 0.15 mL of CH 2 Cl 2  was used to transfer all of the material to the reaction mixture. The reaction mixture was allowed to stir overnight. Column chromatography (silica, 2-10% MeOH/CH 2 Cl 2 ) gave 93 mg (93%) of the title compound. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.24. MS (ESI): calcd for C 34 H 42 F 3 N 7 O 5 S, 718.3 ([M+H] + ); m/z found, 718.3.  
      E. 1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonic acid amide.  
      1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonic acid (N-t-butoxycarbonyl)amide (75 mg, 0.105 mmol) was dissolved in trifluoroacetic acid (0.75 mL) and CH 2 Cl 2  (0.75 mL). The reaction mixture was allowed to stir for 2 h, concentrated, diluted with CH 2 Cl 2  (25 mL) and washed with saturated NaHCO 3 . The organic layer was dried over Na 2 SO 4 , concentrated, and purified by silica gel chromatography (5-10% MeOH/CH 2 Cl 2 ) to afford 1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonic acid amide (15 mg, 23%). MS (ESI) calcd for C 29 H 34 F 3 N 7 O 3 S, 618.2 ([M+H] + ), m/z found, 618.2.  1 H NMR (400 MHz, CDCl 3 ): 7.72 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.22 (br s, 1H), 7.04-7.11 (m, 2H), 6.95-7.00 (m, 1H), 5.02 (br s, 1H), 4.53 (s, 1H), 4.08-4.36 (m, 3H), 3.68 (br t, J=5.9 Hz, 2H), 3.38 (s, 3H), 2.95-3.01 (m, 2H), 2.41-2.70 (m, 4H), 2.11-2.34 (m, 4H), 1.52-1.94 (m, 6H).  
     Example 28 
     
       
         
         
             
             
         
       
     
     5-Chloro-3-(1-{2-hydroxy-3-[4-pyridin-4-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-one  
      A. 4-[1-Oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine.  
      To a solution of 4-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (0.5 g, 1.73 mmol) and epichlorohydrin (1.35 mL, 17.3 mmol) in DMF (2 mL) was added cesium carbonate (0.676 g, 2.07 mmol). The reaction mixture was allowed to stir for 24 h, diluted with EtOAc and washed successively with saturated NaHCO 3 , water, and brine. The organic layer was dried over Na 2 SO 4 , concentrated and partially purified by running through a plug of silica gel (5% acetone/CH 2 Cl 2 ) to afford 4-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (0.198 g, 33%) as an unstable oil. TLC (silica, 20% acetone/CH 2 Cl 2 ): R f =0.39. MS (ESI): exact mass calcd for C 18 H 14 F 3 N 3 O, 346.1 [M+H] + , m/z found, 346.1.  
      B. 5-Chloro-3-(1-{2-hydroxy-3-[4-pyridin-4-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-one.  
      To a solution of 4-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (68 mg, 0.197 mmol) and 5-chloro-1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.055 g, 0.207 mmol) in EtOH (1 mL) was added triethylamine (0.027 mL, 0.197 mmol). The reaction mixture was heated at 80° C. overnight, concentrated, and purified by column chromatography (silica, 2-10% MeOH/CH 2 Cl 2 ) to afford the title compound (0.026 g, 22%). MS (ESI): exact mass calcd for C 31 H 30 ClF 3 N 6 O 2 , 611.2 [M+H] + , m/z found, 611.2.  1 H NMR (400 MHz, CDCl 3 ): 8.59 (br s, 2H), 8.20 (s, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.61 (d, J=5.9 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.35 (br s, 1H), 7.09 (dd, J=8.2, 1.8 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 4.55-4.60 (m, 2H), 4.39 (d, J=14.2, 4.1 Hz, 1H), 4.31 (d, J=14.2, 6.1 Hz, 1H), 3.80-3.90 (m, 2H), 3.37 (s, 3H), 3.18-3.33 (m, 2H), 3.02-3.17 (m, 2H), 2.77-2.95 (m, 2H), 1.99 (t, J=12.4 Hz, 2H).  
     Example 29 
     
       
         
         
             
             
         
       
     
     4-(1-{2-Hydroxy-3-[4-pyrazin-2-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one  
      A. 4-(2-Hydroxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester.  
      2-Aminophenol (15.0 g, 137 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (27.4 g, 138 mmol) were set stirring in CH 2 Cl 2  (200 mL) at rt. Sodium triacetoxyborohydride (40.8 g, 193 mmol) was added in portions over 10 min followed by acetic acid (7.8 mL, 136 mmol). After 18 h saturated NaHCO 3  was added, the organics separated, dried (MgSO 4 ) and evaporated to give 36.4 g (91%) of a beige solid. TLC (silica, 50% EtOAc/hexanes): R f =0.56. MS (ESI): exact mass calcd for C 16 H 24 N 2 O 3 , 292.18; m/z found, 315.1 [M+Na] + .  1 H NMR (400 MHz, CDCl 3 ): 9.20 (s, 1H), 6.80-6.50 (m, 3H), 6.40 (t, J=6.1 Hz, 1H), 4.30 (d, J=8.7 Hz, 1H), 3.88 (d, J=12.6 Hz, 2H), 3.45-3.35 (m, 1H), 3.00-2.75 (br s, 2H), 1.88 (d, J=10.5 Hz, 2H), 1.40 (s, 9H), 1.30-1.20 (m, 2H).  
      B. 4-(2-Ethoxycarbonylmethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester.  
      A mixture of NaH (1.56 g, 65 mmol) in THF (100 mL) was set stirring and cooled to 5° C. 4-(2-Hydroxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (17.5 g, 60 mmol) in THF (100 mL) was added dropwise over 30 min. After 2 h ethyl bromoacetate (7.3 mL, 66 mmol) was added. After stirring at rt for 24 h saturated NH 4 Cl (100 mL) was added and the organics evaporated. The aqueous layer was extracted with EtOAc (2×150 mL). The organics were combined, dried (MgSO 4 ) and evaporated to give 24 g of a deep red liquid. The liquid was purified (silica, 5% acetone/CH 2 Cl 2 ) to give 21.4 g (94%) of a clear orange liquid. TLC (silica, 5% acetone/CH 2 Cl 2 ): R f =0.48. MS (ESI): exact mass calcd for C 20 H 30 N 2 O 5 , 378.22; m/z found, 379.2 [M+H] + .  1 H NMR (400 MHz, DMSO): 7.02 (m, 1H), 6.90-6.70 (m, 3H), 4.74 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 4.13 (br s, 2H), 3.60-3.50 (m, 1H), 3.08 (m, 2H), 2.16 (m, 2H), 1.60-1.50 (m, 2H), 1.58 (s, 9H), 1.41 (t, J=7.1 Hz, 3H).  
      C. 4-(2-Carboxymethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester.  
      4-(2-Ethoxycarbonylmethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (21.4 g, 56.5 mmol) was set stirring in MeOH (150 mL). A solution of NaOH (4.5 g, 112.5 mmol) in water (150 mL) was added. After 3 h the mixture was acidified to pH 4 with 6 N HCl. MeOH was removed under reduced pressure and the aqueous layer extracted with EtOAc (2×150 mL). The organics were combined, dried (MgSO 4 ) and evaporated to give 20 g (100%) of a brown solid. MS (ESI): exact mass calcd for C 18 H 26 N 2 O 5 , 350.18; m/z found, 351.2 [M+H] + .  
      D. 4-(3-Oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester.  
      4-(2-Carboxymethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (22 g, 63 mmol) was set stirring in CH 2 Cl 2  (200 mL). EDC (13 g, 68 mmol) was added in one portion. After 30 min 1 N HCl was added. The organics were separated, dried (MgSO 4 ) and evaporated to give 17 g (81%) of a clear brown oil. TLC (silica, 5% acetone/CH 2 Cl 2 ): R f =0.45. MS (ESI): exact mass calcd for C 18 H 24 N 2 O 4 , 332.17; m/z found, 259.1 [M−BOC+H] + .  1 H NMR (400 MHz, CDCl 3 ): 7.30-7.20 (m, 1H), 7.15-7.10 (m, 3H), 4.61 (s, 2H), 4.60-4.45 (m, 1H), 4.45-4.30 (br s, 2H), 2.88 (t, J=12.5 Hz, 2H), 2.65 (dd, J=12.6, 4.5 Hz, 2H), 1.87 (d, J=12.4 Hz, 2H), 1.60 (s, 9H).  
      E. 4-Piperidin-4-yl-4H-benzo[1,4]oxazin-3-one. 4-(3-Oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (17 g, 51 mmol) and 1:1 TFA/CH 2 Cl 2  (40 mL) were combined and set stirring. After 45 min the mixture was evaporated to give a clear brown oil. The oil was set stirring and Et 2 O was added (300 mL). A solid formed and was filtered, washed with Et 2 O and air dried to give 16 g (90%) of a light beige solid. MS (ESI): exact mass calcd for C 13 H 16 N 2 O 2 , 232.12; m/z found, 233.1 [M+H] + .  1 H NMR (400 MHz, CD 3 OD): 7.44 (dd, J=6.5, 1.4 Hz, 1H), 7.20-7.7.10 (m, 3H), 4.58 (s, 2H), 4.55-4.45 (m, 1H), 4.65-4.55 (m, 2H), 3.27 (dt, J=13.0, 2.3 Hz, 2H), 3.05 (dd, J=12.3, 4.1 Hz, 2H), 2.15 (d, J=13.8 Hz, 2H).  
      F. 2-[1-Oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine.  
      To a solution of 2-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (200 mg, 0.69 mmol) and epichlorohydrin (0.540 mL, 6.9 mmol) in DMF (2 mL) was added cesium carbonate (450 mg, 1.38 mmol). The reaction mixture was allowed to stir for 24 h, diluted with EtOAc, and washed with saturated NaHCO 3 , water, and brine. The organic layer was dried over Na 2 SO 4 , concentrated and purified by column chromatography (silica, 5% acetone/CH 2 Cl 2 ) to afford 2-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (141 mg, 59%). TLC (silica, 20% acetone/CH 2 Cl 2 ): R f =0.38. MS (ESI) m/z 347.1 (347.1, calcd for C 17 H 13 F 3 N 4 O, M + +H).  1 H NMR (400 MHz, CDCl 3 ): 8.51 (dd, J=2.8, 1.8 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H), 8.38 (d, J=12.8 Hz, 1H), 8.01 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 4.57 (dd, J=14.7, 3.1 Hz, 1H), 4.21 (dd, J=14.7, 6.1 Hz, 1H), 3.44 (m, 1H), 2.91 (t, J=4.5 Hz, 1H), 2.62 (dd, J=4.0, 2.5 Hz, 1H).  
      G. 4-(1-{2-Hydroxy-3-[4-pyrazin-2-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one.  
      To a solution of 2-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (76 mg, 0.220 mmol) and 4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one (61 mg, 0.231 mmol) in EtOH (1.1 mL) was added triethylamine (0.031 mL, 0.220 mmol). The reaction mixture was heated to 80° C. overnight, concentrated, and purified by column chromatography (silica, 5-10% MeOH/CH 2 Cl 2 ) to afford 4-(1-{2-hydroxy-3-[4-pyrazin-2-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one (27 mg, 21%). TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.09. MS (ESI): m/z 579.2 (579.2, calcd for C 30 H 29 F 3 N 6 O 3 , M + +H).  1 H NMR (400 MHz, CDCl 3 ): 8.53 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.16 (d, J=5.4 Hz, 1H), 7.00-7.03 (m, 3H), 4.49 (s, 2H), 4.39 (d, J=10.8 Hz, 1H), 3.13 (d, J=11.9 Hz, 1H), 2.96 (d, J=11.9 Hz, 1H), 2.59-2.80 (m, 2H), 2.40-2.55 (m, 3H), 2.17 (t, J=11.9 Hz, 1H), 1.77 (d, J=11.9 Hz, 2H).  
     Example 30 
     
       
         
         
             
             
         
       
     
     (S)-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
      A. 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester.  
      1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (7.24 g, 34.1 mmol) and di-tert-butyl dicarbonate (9.12 g, 41.0 mmol) were combined in DMF (80 mL) and the mixture heated to 40° C. under N 2  for 17 h. The mixture was allowed to cool, diluted with EtOAc (800 mL) and washed with saturated NaHCO 3  (150 mL), H 2 O (3×150 mL) and brine (150 mL). The combined aqueous washes were extracted with EtOAc (2×150 mL). The combined extracts were dried over Na 2 SO 4  and concentrated, to give 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (12.36 g, 94%). TLC (silica, 50% EtOAc/hexanes): R f =0.3. MS (ESI): exact mass calcd for C 17 H 23 N 3 O 3 , 340.16; m/z found, 340.1 [M +Na] + .  1 H NMR (CDCl 3 , 400 MHz): 10.59 (s, 1H), 7.15-7.11 (m, 2H), 7.08-7.02 (m, 2H), 4.49 (tt, J=8.4, 4.0 Hz, 1H), 4.32 (br s, 2H), 2.89 (br t, J=11.6, 2H), 2.34 (dq, J=12.6, 4.4 Hz, 2H), 1.83 (br d, J=10.5 Hz, 2H) 1.36 (s, 9H).  
      B. 1-Methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one.  
      A solution of KHMDS (5.07 g, 25.4 mmol) in THF (40 mL plus a 10 mL rinse) was added via cannula to a solution of 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (6.64 g, 20.2 mmol) in THF (20 mL). The mixture was stirred for 25 min then iodomethane (5.2 mL, 84 mmol) was added. The resulting mixture was stirred for 45 min then diluted with EtOAc (700 mL). The EtOAc was washed with H 2 O (3×200 mL), saturated NaHCO 3  (150 mL) and brine (150 mL). The combined washes were extracted with EtOAc (2×150 mL). The combined extracts were dried over Na 2 SO 4  and concentrated. The crude reaction mixture was purified by column chromatography (silica, 15-60% EtOAc/hexanes) to give the methylated adduct (5.21 g, 78%). The purified material was dissolved in a mixture of CH 2 Cl 2  (40 mL) and TFA (35 mL). The mixture was stirred for 4 h then concentrated in vacuo. The residue was dissolved in CH 2 Cl 2  (300 mL) and washed with saturated NaHCO 3  (100 mL). The aqueous layer was extracted with 5% MeOH/CH 2 Cl 2  (4×150 mL). The combined extracted were dried over Na 2 SO 4  and concentrated to yield the title compound (3.85 g, containing inorganic salts) which was suitable for further use. TLC (silica, 5% MeOH/CH 2 Cl 2 ): R f =0.1. MS (ESI): exact mass calcd for C 13 H 18 N 3 O, 232.14; m/z found 232.1 [M+H] + .  1 H NMR (CDCl 3 , 400 Hz): 7.27-7.29 (m, 1H), 7.05-7.12 (m, 2H), 6.99 (dd, J=6.1, 2.1 Hz, 1H), 4.45 (tt, J=12.5, 4.2 Hz, 1H), 3.42 (s, 3H), 3.27 (dd, J=10.2, 2.1 Hz, 2H), 2.81 (dt, J=2.4, 12.4 Hz, 2H), 2.35 (dq, J=12.5, 4.2 Hz, 2H), 2.26 (br s, 1H), 1.83 (dd, J=12.1, 2.1 Hz, 2H).  
      C. (R)-tert-Butyl-dimethyl-oxiranylmethoxy-silane.  
      tert-Butyl-chloro-dimethylsilane (12.9 g, 85.5 mmol) followed by Et 3 N (19 mL, 136 mmol) was added to a 0° C. solution of (S)-(+)-glycidol (5.0 g, 67 mmol) in CH 2 Cl 2  (200 mL). The solution was allowed to warm to 23° C. with stirring over 17 h. The resulting pink solution was diluted with Et 2 O (800 mL) and stirred an additional 30 min. The Et 2 O layer was washed with saturated aqueous NaHCO 3  (200 mL), H 2 O (2×100 mL), brine (100 mL), dried over Na 2 SO 4  and concentrated. Purification by column chromatography (silica, 5-10% Et 2 O/hexanes) gave (R)-tert-Butyl-dimethyl-oxiranylmethoxy-silane (10.01 g, 79%). TLC (silica, 10% Et 2 O/hexanes): R f =0.5.  1 H NMR (CDCl 3 , 400 MHz): 3.85 (dd, J=11.9, 3.2 Hz, 1H), 3.66 (dd, J=11.9, 4.8 Hz, 1H), 3.09 (m, 1H), 2.77 (dd, J=5.0, 4.2 Hz, 1H), 2.64 (dd, J=5.2, 2.7 Hz, 1H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).  
      D. (R)-3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propane-1,2-diol.  
      Cs 2 CO 3  (1.88 g, 5.77 mmol) was added to a solution of (R)-tert-Butyl-dimethyl-oxiranylmethoxy-silane (2.72 g, 14.4 mmol) and 5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (1.70 g, 4.81 mmol) in DMF (13 mL). The mixture was stirred at rt for 5 days, then partitioned between EtOAc (400 mL) and saturated NaHCO 3  (100 mL). The EtOAc layer was washed with H 2 O (3×75 mL) and brine (100 mL), dried over Na 2 SO 4  and concentrated. The residue was dissolved in MeOH (125 mL) and treated with CSA (800 mg). The mixture was stirred for 20 h then concentrated. The residue was re-dissolved in EtOAc (200 mL), washed with saturated NaHCO 3  (100 mL), dried over Na 2 SO 4  and concentrated. Purification by column chromatography (silica, 20-60% acetone/CH 2 Cl 2 ) gave the corresponding diol (0.78 g, 40%). TLC (25% acetone/CH 2 Cl 2 ): R f =0.2. MS (ESI): exact mass calcd for C 17 H 21 F 3 N 3 O 4 S, 420.11; m/z found, 420.1 [M+H] + .  1 H NMR (CD 3 OD/CDCl 3 , 400 MHz): 7.74 and 7.67 (A and B of AA′BB′, J ab =8.3 Hz, 4H), 4.52 (s, 2H), 4.23 (dd, J=13.0, 3.0 Hz, 1H), 4.04-4.11 (m, 2H), 3.64 (t, J=5.9 Hz, 2H), 3.52 and 3.57 (A and B of ABX, J ab =11.4, J ax =4.8, J bx =4.9 Hz, 2H), 2.98 (m, 2H), 2.91 (s, 3H).  
      E. (R)-5-Methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.  
      PpTs (271 mg, 1.1 mmol) and (R)-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propane-1,2-diol (317 mg, 0.756 mmol) were combined in trimethylorthoacetate (30 mL). The mixture was stirred for 18 h then diluted with EtOAc (125 mL), washed with saturated NaHCO 3  (2×50 mL), brine (50 mL), dried over Na 2 SO 4  and concentrated. Purification by chromatography (silica, 100% EtOAc) gave the corresponding orthoacetate (313 mg, 0.678 mmol). The purified orthoacetate was dissolved in CH 2 Cl 2  (2.25 mL), cooled to 0° C., and treated with MeOH (25 μL) and AcBr (110 μL, 1.48 mmol). The mixture was allowed to warm over 3 h, then partitioned between EtOAc (50 mL) and saturated NaHCO 3  (20 mL). The EtOAc layer was washed with saturated NaHCO 3  (2×20 mL). The combined washes were extracted with EtOAc (3×20 mL). The combined extracts were dried over Na 2 SO 4  and concentrated. The residue was dissolved in EtOH (40 mL) and treated with KOEt (1.0 mL, 40 wt % solution in EtOH). After 1 h the mixture was concentrated to ca. 20 mL and worked up as above. Purification by column chromatography (silica, 100% EtOAc) gave the epoxide (189 mg, 62%). TLC (100% EtOAc): R f =0.35. MS (ESI): exact mass calcd for C 17 H 19 F 3 N 3 O 3 S, 402.10; m/z found, 402.1 M+H] + .  1 H NMR (CDCl 3 , 400 MHz): 7.72 and 7.67 (A and B of AA′BB′, J ab =8.3 Hz, 4H), 4.57 and 4.53 (A and B of AB, J ab =12.9 Hz, 2H), 4.52 (dd, J=15.2, 2.7 Hz, 1H), 4.12 (dd, J=15.2, 5.4 Hz, 1H), 3.67 (m, 2H), 3.36 (m, 1H), 2.92 (m, 2H), 2.88 (s, 3H), 2.85 (dd, J=4.4, 4.3 Hz, 1H), 2.49 (dd, J=4.6, 2.6 Hz, 1H).  
      F. (S)-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one.  
      A solution of (R)-5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (134 mg, 0.334 mmol) and 1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (110 mg, 0.476 mmol) in EtOH (0.8 mL) and dichloroethane (0.8 mL) was heated to 80° C. for 18 h. The mixture was then concentrated and the residue purified by column chromatography (silica, 0-50% acetone/CH 2 Cl 2 ) to give the title compound (134 mg, 86%). TLC (20% acetone/CH 2 Cl 2 ) R f =0.3. MS (ESI): calcd for C 30 H 36 F 3 N 6 O 4 S, [M+H] +  633.24; m/z found, 633.3.  1 H NMR (CDCl 3,  400 MHz): 7.72 and 7.66 (A and B of AA′BB′, J ab =8.3 Hz, 4H), 7.15 (dd, J=7.0, 1.7 Hz, 1H), 7.08 (m, 2H), 6.98 (dd, J=6.6, 1.8 Hz, 1H), 4.60 and 4.55(A and B of AB, J ab =14.5 Hz, 2H), 4.34 (m, 1H), 4.23 (dd, J=13.8, 2.8 Hz, 1H), 4.15 (m, 1H), 4.23 (dd, J=13.8, 6.6 Hz, 1H), 3.71 (m, 2H), 3.40 (s, 3H), 3.08 (m, 2H), 2.96 (m, 2H), 2.89 (s, 3H), 2.56-2.36 (m, 4H), 2.23 (d, J=11.6 Hz, 1H), 1.81 (m, 2H).  
     Example 31 
     
       
         
         
             
             
         
       
     
     (S)-5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
      A. 4-(6-Chloro-3-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester.  
      A stirring solution of 20 g (0.10 mol) of 2,6-dichloro-3-nitro-pyridine in DMF (245 mL) was cooled to 0° C. After 5 min, 9.87 g (0.05 mol) of 4-amino-piperidine-1-carboxylic acid tert-butyl ester and 6.8 g (0.05 mol) of K 2 CO 3  were added, resulting in a suspension. The mixture was allowed to stir for 5 h at 0° C. The mixture was then partitioned between water (300 mL) and EtOAc (400 mL). The aqueous layer was then extracted with EtOAc (5×400 mL). The organic layer was dried over anhydrous Na 2 SO 4 , and concentrated to give a brown oil. The product was purified using silica gel chromatography (silica, 100% CH 2 Cl 2 , then 10% EtOAc/hexanes) to afford 8.99 g (51%) of the desired product as a bright yellow solid. MS (ESI): exact mass calcd for C 15 H 21 ClN 4 O 4 , 356.13; m/z found, 379.1 [M+Na] + .  1 H NMR (400 MHz, CDCl 3 ): 8.36 (d, J=8.4 Hz, 1H), 8.27 (d, J=7.3 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 4.38-4.26 (m, 1H), 4.14-3.96 (m, 2H), 3.01 (t, J=11.6 Hz, 2H), 2.05 (dd, J=12.4 Hz, 3.03 Hz, 2H), 1.58-1.44 (m, 2H), 1.47 (s, 9H).  
      B. 4-(6-Dimethylamino-3-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester.  
      To a stirring solution of 6 g (0.016 mol) of 4-(6-chloro-3-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester in MeOH/CH 2 Cl 2  (84 mL/15 mL) was added 2.2 g (0.05 mol) of dimethylamine in THF (25 mL). The reaction mixture was stirred at rt for 16 h, and was then concentrated. The crude product was then dissolved in CH 2 Cl 2  (400 mL) and washed with saturated NaHCO 3  (2×200 mL). The washes were combined and extracted with EtOAc (100 mL). The combined organic layers were dried over Na 2 SO 4  and concentrated to afford 6.1 g (99%) of the desired product as a bright yellow solid. MS (ESI): exact mass calcd for C 17 H 27 N 5 O 4 , 365.21; m/z found, 388.19 [M+Na] + .  1 H NMR (400 MHz, CDCl 3 ): 8.74 (d, J=7.07 Hz, 1H), 8.18 (d, J=9.4 Hz, 1H), 5.97 (d, J=7.3 Hz, 1H), 4.28-4.16 (m, 1H), 4.07-3.93 (m, 2H), 3.17 (s, 6H), 3.01 (t, J=11.9 Hz, 2H), 2.05 (dd, J=12.4 Hz and 3.03 Hz, 2H), 1.60-1.50 (m, 2H), 1.47 (s, 9H).  
      C. 4-(5-Dimethylamino-1-methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester. A stirring solution of 5.3 g (0.014 mol) of 4-(6-dimethylamino-3-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester in methanol/EtOAc (73 mL/15 mL) was degassed. 10% Pd/C (1.17 g, 0.5 mmol) was added as a suspension in EtOH (5 mL), followed by ammonium formate (4.5 g, 0.073 mol). The mixture was stirred at rt for 3 h. The reaction mixture was then filtered through celite and the filtrate was concentrated, giving a purple oil. The residue was then dissolved in THF (73 mL), and 11.7 g (0.073 mol) of CDI was added, and the reaction was heated to 98° C. and stirred for 16 h. The mixture was then cooled and concentrated. The crude product was then partitioned between EtOAc (800 mL) and NaHCO 3  (100 mL), and the organic layer was washed with water (5×100 mL) and NaCl (100 mL). The combined aqueous layers were back-extracted with EtOAc (150 mL). The resulting organic layers were combined and dried over Na 2 SO 4  and concentrated. The residue (2.4 g) was dissolved in THF (73 mL). To this stirring solution was added KHMDS (3.46 g, 0.017 mol) and iodomethane (10.3 g, 0.072 mol), and the mixture was allowed to stir for 20 min. The solvent was then concentrated, and the crude product was partitioned between EtOAc (600 mL) and NaHCO 3  (200 mL). The organic layer was washed with NaHCO 3  (150 mL), dried over Na 2 SO 4 , and concentrated. Purification using flash chromatography (silica, 80% EtOAc/hexanes) afforded 2.4 g (67% yield, 3 steps, based upon using 2/3 material at methylation stage) of desired product as a white solid. MS (ESI): exact mass calcd for C 19 H 29 N 5 O 3 , 375.23; m/z found, 276.17 [M+H−100] + .  1 H NMR: (400 MHz, CDCl 3 ): 7.02 (d, J=8.6 Hz, 1H), 6.15 (d, J=8.6 Hz, 1H), 4.46 (tt, J=12.0 Hz and 4.0 Hz, 1H), 4.38-4.11(m, 2H), 3.33 (s, 3H), 3.01 (s, 6H), 2.95-2.73 (m, 2H), 2.73-2.55 (m, 2H), 1.77-1.61 (m, 2H), 1.47 (s, 9H).  
      D. 5-Dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one.  
      To a stirring solution of 1.07 g (0.0028 mol) of 4-(5-dimethylamino-1-methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester in CH 2 Cl 2  (7 mL) was added 7 mL of TFA. After 35 min, the solvent was removed. The residue was partitioned between EtOAc (200 mL) and 1 N NaOH (150 mL). The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were dried over Na 2 SO 4  and concentrated to afford 0.74 g (96%) of 5-dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one as a white/pink solid.  1 H NMR (400 MHz, CDCl 3 ): 6.95 (d, J=8.3 Hz, 1H), 6.08 (d, J=8.3 Hz, 1H), 4.35 (tt, J=12.1 Hz, 4.0 Hz, 1H), 3.25 (s, 3H), 3.14 (d, J=12.4 Hz, 2H) 2.97 (s, 6H), 2.66 (td, J=12.9 Hz, 1.3 Hz, 2H), 2.53 (qd, J=12.4 Hz, 4.0 Hz, 2H), 1.69 (d, J=11.9 Hz, 2H).  
      E. (S)-5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one.  
      To a stirring solution of 0.24 g (0.0009 mol) of 5-dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one in EtOH/Dichloroethane (1.5 mL/1.5 mL) was added 0.23 g (0.0005 mol) of (R)-5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture was heated to 80° C. and stirred for 16 h and concentrated. The crude product was then dissolved in CH 2 Cl 2  (40 mL) and purified using flash chromatography (0-6% MeOH/CH 2 Cl 2 ) affording 0.38 g (97%) of the desired product as a white solid. MS (ESI): exact mass calcd for C 31 H 39 F 3 N 8 O 4 S, 676.28; m/z found, 677.28 [M+H] + .  1 H NMR (400 MHz, CDCl 3 ): 7.71 and 7.67 (A and B of AA′BB′ quartet, J ab =8.3 Hz, 4H), 7.03 (d, J=8.6 Hz, 1H), 6.16 (d, J=8.6 Hz, 1H), 4.58 and 4.56 (A and B of AB quartet, J ab =14.5 Hz, 2H), 4.36 (tt, J=12.1 Hz, 4.04 Hz, 1H), 4.25-4.01 (m, 4H), 3.77-3.60 (m, 2H), 3.33 (s, 3H), 3.16-3.04 (m, 2H), 3.03 (s, 6H), 2.99-2.90 (m, 2H), 2.88 (s, 3H), 2.77 (qd, J=12.1 Hz, 3.54 Hz, 2H), 2.56-2.42 (m, 3H), 2.21 (t, J=11.6 Hz, 1H), 1.75 (d, J=11.6 Hz, 2H).  
     Example 32 
     
       
         
         
             
             
         
       
     
     1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 33 
     
       
         
         
             
             
         
       
     
     1-(1-{3-[3-(3,4-Dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 34 
     
       
         
         
             
             
         
       
     
     3-(3,4-Dichloro-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 35 
     
       
         
         
             
             
         
       
     
     6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 36 
     
       
         
         
             
             
         
       
     
     3-(3,4-Dichloro-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 37 
     
       
         
         
             
             
         
       
     
     [3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetonitrile  
     Example 38 
     
       
         
         
             
             
         
       
     
     [3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetic acid ethyl ester  
     Example 39 
     
       
         
         
             
             
         
       
     
     5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 40 
     
       
         
         
             
             
         
       
     
     1-{3-[4-(6-Chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 41 
     
       
         
         
             
             
         
       
     
     3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dimethyl-1,3-dihydro-benzoimidazol-2-one  
     Example 42 
     
       
         
         
             
             
         
       
     
     3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 43 
     
       
         
         
             
             
         
       
     
     3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 44 
     
       
         
         
             
             
         
       
     
     3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(5-methoxy-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 45 
     
       
         
         
             
             
         
       
     
     3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 46 
     
       
         
         
             
             
         
       
     
     5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 47 
     
       
         
         
             
             
         
       
     
     6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one  
     Example 48 
     
       
         
         
             
             
         
       
     
     1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one  
     Example 49 
     
       
         
         
             
             
         
       
     
     4-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one  
     Example 50 
     
       
         
         
             
             
         
       
     
     4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one  
     Example 51 
     
       
         
         
             
             
         
       
     
     1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one  
     Example 52 
     
       
         
         
             
             
         
       
     
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-benzoimidazol-2-one  
     Example 53 
     
       
         
         
             
             
         
       
     
     6-Chloro-1-(1-{3-[3-(4-chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 54  
     Cathepsin S Inhibition Assay  
      Recombinant human cathepsin S (CatS) was expressed in the baculovirus system and purified in one step with a thiopropyl-sepharose column. 10-L yielded ˜700 mg of CatS and N-terminal sequencing confirmed identity. The assay is run in 100 mM sodium acetate pH 5.0 containing 1 mM DTT and 100 mM NaCl. The substrate for the assay is (Aedens)EKARVLAEAA(Dabcyl)K-amide. The K m  for the substrate is around 5 μM but the presence of substrate inhibition makes kinetic analysis difficult. With 20 μM substrate the assay rate is linear over the range of 1-8 ng CatS in 100 μl reaction. Using 2 ng/well of CatS, the production of product is linear and yields ˜7-fold signal after 20 min with only 20% loss of substrate. Primary assays are run by quenching the reaction after 20 min with 0.1% SDS and then measuring the fluorescence. For other assays, measurements are taken every min for 20 min. The rate is calculated from the slope of the increase and the percent inhibition is calculated from this (See Tables 1 and 2 below).  
                           TABLE 1                                   EXAMPLE   IC 50  (μM)                                                    1   0.73           2   0.07           3   0.28           4   0.19           5   1.16           6   0.19           7   0.26           8   0.04           9   0.10           10   0.09           11   0.03           12   0.62           13   0.37           14   0.29           15   0.23           16   0.30           17   1.30           18   0.25           19   0.02           20   0.01           21   0.02           22   0.03           23   0.08           24   0.03           25   0.23           26   0.18           27   0.09           28   0.89           29   0.78           30   0.04           31   0.07                      
 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 2 
               
               
                   
                   
               
               
                   
                   
               
               
                   
                 EXAMPLE 
                 IC 50  (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 32 
                 0.06 
               
               
                   
                 33 
                 0.01 
               
               
                   
                 34 
                 0.02 
               
               
                   
                 35 
                 0.03 
               
               
                   
                 36 
                 0.04 
               
               
                   
                 37 
                 0.05 
               
               
                   
                 38 
                 0.02 
               
               
                   
                 39 
                 0.04 
               
               
                   
                 40 
                 0.04 
               
               
                   
                 41 
                 0.03 
               
               
                   
                 42 
                 0.08 
               
               
                   
                 43 
                 0.02 
               
               
                   
                 44 
                 0.03 
               
               
                   
                 45 
                 0.02 
               
               
                   
                 46 
                 0.03 
               
               
                   
                 47 
                 0.04 
               
               
                   
                 48 
                 0.02 
               
               
                   
                 49 
                 0.02 
               
               
                   
                 50 
                 0.02 
               
               
                   
                 51 
                 0.02 
               
               
                   
                 52 
                 0.13 
               
               
                   
                 53 
                 0.05 
               
               
                   
                   
               
            
           
         
       
     
     Example 55  
     Ex Vivo Inhibition by Cathepsin S Inhibitors of the Allergenic Response  
      The following assay demonstrates that cathepsin S inhibitors block the response of human T cells to crude allergen extracts.  
      Materials and Methods.  
     
         
          Reagents. Glycerinated crude allergen extracts of house dust mites ( Dermataphagoides pteronyssinus, Dermataphagoides farinae ) and ragweed [ Ambrosia trifida  (giant),  Ambrosia artemisiifolia  (short)] were purchased from Hollister-Stier Laboratories (Minneapolis, Minn.). Concanavalin A (ConA) was purchased from Calbiochem (La Jolla, Calif.).  
          Donors. All allergic donors were prescreened for their specific allergies using RAST tests. The HLA class II haplotypes of these donors were determined using PCR.  
          Cell culture. Human peripheral blood mononuclear cells (PBMC) were purified from blood of allergic donors using Ficoll-Hypaque gradient followed by washes with phosphate buffered saline (PBS). PBMC were cultured in triplicate or duplicate at 0.5-1.0×10 6  cells/well with titrated doses of allergen extracts, in the presence or absence of a known cathepsin S inhibitor, LHVS (morpholinurea-leucine-homo-phenylalanine-vinylsulfonephenyl) (Palmer et al. (1995), J. Med. Chem. 38:3193 and Riese et al. (1996), Immunity 4:357). Serial diluted stock solutions of LHVS were first made in 100% DMSO and then diluted 1:15 in 40% Hydroxypropynyl cyclodextrin (HPCD). Three microliters of LHVS in HPCD was added into PBMC cultures (200 μL/well). After 6 days of culture, 1 μLCi/well of  3 H-thymidine (TdR) was added. Eighteen hours later, cells were harvested using a Filtermate Harvester (Packard) and counted for  3 H-TdR incorporation on Topcount (Packard). 
 
 Inhibition of T Cell Proliferative Responses to House Dust Mites 
 
       
    
      About 10% of most populations are allergic to house dust mites (HDM) of the genus  Dermatophagoides  with  Dermatophagoides pteronyssinus  ( Der p ) and  D. farinae  ( Der f ) being the two major species present in varying proportions in most countries. The major clinical manifestations are asthma and perennial rhinitis.  
      Effect of cathepsin S inhibition on activation of HDM allergen-specific CD4 T cells was tested in an ex vivo human T cell-proliferation assay. Culturing PBMC with crude extracts from either  Der p  or  Der f , resulted in strong proliferation ( FIG. 1A ). This proliferation consisted primarily of allergen-specific CD4 T cells. When cathepsin S activity was blocked by a specific cathepsin S inhibitor, LHVS (cf. Riese et al. (1996) Immunity 4:357) the proliferation was strongly inhibited ( FIG. 1B ). Inhibition by LHVS was specific for responses induced by HDM extracts since T cell proliferative responses induced by ConA, a pan-T cell mitogen, were not affected. Furthermore, this inhibition was observed for all four HDM-allergic donors tested regardless of the different HLA class II haplotypes (DR4; DR7, 15; DR11, 15; and DR4, 11).  
      This system is very similar to an in vivo situation. The allergic subject would be exposed to a crude mixture of allergens that would lead to the proliferation of T cells and an allergic response. The observation of inhibition of CD4 T cell activation by a cathepsin S inhibitor shows that such inhibitors can be effective in treating a generalized population of patients allergic to house dust mites.  
      Inhibition of T Cell Proliferative Responses to Ragweed  
      About 10% of population in US are allergic to ragweed pollen, making it one of the most important allergens in terms of clinical diseases. Allergens from pollens are a common precipitant of rhinitis and asthma in this population.  
      The effect of cathepsin S inhibition on activation of ragweed allergen-specific CD4 T cells was tested in an ex vivo human T cell-proliferation assay. Culturing PBMC with crude extracts from both short and giant ragweed resulted in strong proliferation ( FIG. 2A ). This proliferation consisted mainly of allergen-specific CD4 T cells. When cathepsin S activity was blocked by a specific cathepsin S inhibitor, LHVS (cf. Riese et al. (1996) Immunity 4:357) the proliferation was strongly inhibited ( FIG. 2B ). Inhibition by LHVS was specific for responses induced by ragweed since T cell proliferative responses induced by ConA, a pan-T cell mitogen, were not affected. Furthermore, this inhibition was observed for the two ragweed-allergic donors tested regardless of the different HLA class II haplotypes (DR7, 15 and DR4, 11).  
      Similar experiments were run using three additional CatS inhibitors, compounds from Examples 8, 52, and 53 above, with the results shown in  FIGS. 3A, 3B ,  4 A, and  4 B.  
      This system is very similar to an in vivo situation. The allergic subject would be exposed to a crude mixture of allergens that would lead to the proliferation of T cells and an allergic response. The observation of inhibition of CD4 T cell activation by a cathepsin S inhibitor shows that such inhibitors can be effective in treating a generalized population of patients allergic to ragweed.  
     Example 56  
     Monitoring Cathepsin S Inhibition in Human Blood  
      The effect of in vivo administration of cathepsin S inhibitors, in a clinical trial setting, can be monitored by measuring accumulation of an intermediate degradation product of invariant chain (Ii), i.e. the p10Ii fragment, in blood of dosed subjects. After administration of a cathepsin inhibitor for a certain period of time, for example, between 0.01 and 50 mg/kg/day, to result in a blood concentration of between 1 nM-10 μM, for 16-30 h, blood is drawn and white blood cells are purified, e.g. either by lysis of red blood cells or by a Ficoll-Hypaque gradient centrifugation. Whole cell lysates of WBC are then made and analyzed by either a Western blot assay or an ELISA assay. For the Western blot assay, cell lysates are first resolved on SDS-PAGE gels. After transferring to nitrocellulose membranes, Ii and its intermediate degradation products, including the p10Ii, can be detected using a mouse mAb against Ii, e.g. Pin1.1, or rabbit polyclonal antibodies specific for the C-terminus of the p10Ii fragment or against the entire p10Ii fragment. For ELISA assay, a pair of antibodies against Ii, including Pin1.1, and a rabbit polyclonal antibody or a mouse monoclonal antibody specific for p10Ii, can be used. The same assay can also be applied to monitor the effect of cathepsin S inhibitors in vivo in animal studies, for example in monkeys, dogs, pigs, rabbits, guinea pigs, and rodents.  
      In the present example PBMC from human blood were incubated with the cathepsin S inhibitor, LHVS (morpholinurea-leucine-homo-phenylalanine-vinylsulfonephenyl, also referred to as 4-morpholinecarboxamide, N-[(1S)-3-methyl-1-[[[(1S,2E)-1-(2-phenylethyl)-3-(phenylsulfonyl)-2-propenyl]amino]carbonyl]butyl]-. This compound has been described in U.S. Pat. No. 5,976,858 and in Palmer et al. (1995) J. Med. Chem. 38:3193 and Riese et al. (1996) Immunity 4:357. After incubation for 24 h the samples were run using standard SDS-PAGE protocols, transferred to nitrocellulose membranes and probed with an antibody that recognizes the invariant chain including the p10Ii fragment. In the presence of LHVS the p10Ii fragment was seen, representing a block in the degradation of Ii due to inhibition of cathepsin S.  
     Example 57  
     Monitoring In Vivo Inhibition of Allergenic Response by Cathepsin S Inhibitors  
      To demonstrate the efficacy of cathepsin S inhibitors for suppressing allergic responses in vivo, allergic volunteers are dosed with cathepsin S inhibitors to levels where invariant chain degradation is inhibited. Allergens are deposited subcutaneously, and the size of the cutaneous reactions are determined at 15 min, 6 h and 24 h. Skin biopsies are performed at 24 h. The immediate weal and flare response is not mediated by a T cell response and is not expected to be influenced by cathepsin S inhibitors, while the late phase induration (noticeable at 6 hours, more pronounced at 24 hours) is characterized by activation and infiltration of CD4 T cells (as well as of eosinophils) and should be inhibited by administration of inhibitors of cathepsin S. The skin biopsies are used to determine the cellular composition in the induration, and cathepsin S treated subjects are expected to have fewer activated CD4 T cells present than placebo-treated subjects.  
      References for these procedures are provided in Eberlein-Konig et al. (1999) Clin. Exp. Allergy 29:1641-1647 and in Gaga et al. (1991) J. Immunol. 147:816-822.  
      As controls for the experiment, prednisone and cyclosporine A will be used. Prednisone will inhibit both the immediate and the late phase responses, while cyclosporin A will inhibit only the late phase response.  
     Example 58  
     Skin Immune Disorder Treatments  
      In the treatment of these disorders, such as psoriasis, a pharmaceutical composition containing at least one compound of this invention is administered. In some embodiments, a pharmaceutical composition containing at least the compound of Example 31 is administered as an oral capsule once a day at doses of 50 mg, 100 mg, 200 mg, and 300 mg of the compound in Example 31. In an embodiment of this methodology, psoriasis patients have at least 3% of their body surface areas covered by psoriasis. In an embodiment of this methodology, patients take the medication for twelve weeks.  
      The following compounds in Examples 101-405 were prepared according to the methods described above.  
     Example 101  
     1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-octahydro-benzoimidazol-2-one  
     Example 102  
     1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-octahydro-benzoimidazol-2-one  
     Example 103  
     Acetic acid 1-(1-{3-[5-acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-yl ester  
     Example 104  
     Methanesulfonic acid 1-(1-{3-[3-(4-bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-yl ester  
     Example 105  
     1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-indol-2-one  
     Example 106  
     1-{3-[4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 107  
     1-{3-[4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methylamide  
     Example 108  
     Acetic acid 1-(1-{3-[5-acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-yl ester  
     Example 109  
     Methanesulfonic acid 1-(1-{3-[3-(3,4-dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-benzoimidazol-2-yl ester  
     Example 110  
     1-[1-{3-[4-(3,5-Dichloro-pyridin-4-ylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 111  
     1-[1-{3-[4-(Benzooxazol-2-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 112  
     1-[1-{3-[4-(Benzooxazol-2-ylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 113  
     1-(4-Benzooxazol-2-yl-piperidin-1-yl)-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol  
     Example 114  
     1-(4-Benzothiazol-2-yl-piperidin-1-yl)-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol  
     Example 115  
     1-{3-[4-(5-Methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 116  
     N-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-N-(3-chloro-phenyl)-benzamide  
     Example 117  
     4-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-one  
     Example 118  
     4-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-one  
     Example 119  
     3-(4-Bromo-phenyl)-1-{3-[4-(5-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 120  
     4-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-one  
     Example 121  
     4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-one  
     Example 122  
     3-(4-Bromo-phenyl)-1-{3-[4-(6-ethanesulfonyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 123  
     4-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-6-ethanesulfonyl-4H-benzo[1,4]oxazin-3-one  
     Example 124  
     4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-6-ethanesulfonyl-4H-benzo[1,4]oxazin-3-one  
     Example 125  
     1-[1-[3-(4-Benzothiazol-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 126  
     1-[1-[3-(4-Benzothiazol-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 127  
     1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1H-quinolin-2-one  
     Example 128  
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1H-quinolin-2-one  
     Example 129  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1H-quinolin-2-one  
     Example 130  
     1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1H-quinazolin-2-one  
     Example 131  
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-3,4-dihydro-1H-quinazolin-2-one  
     Example 132  
     1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(6-chloro-2,2-dioxo-3,4-dihydro-2H-2λ 6 -2,1,3-benzothiadiazin-1-yl)-piperidin-1-yl]-propan-2-ol  
     Example 133  
     1-[4-(6-Chloro-2,2-dioxo-2,3-dihydro-2λ 6 -2,1,3-benzothiadiazol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol  
     Example 134  
     1-[1-{3-[4-(6-Chloro-2,2-dioxo-2,3-dihydro-2λ 6 -2,1,3-benzothiadiazol-1-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 135  
     4-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4-1,4-benzoxazi n-3-one  
     Example 136  
     1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one  
     Example 137  
     1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one  
     Example 138  
     4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one  
     Example 139  
     4-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one  
     Example 140  
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one  
     Example 141  
     1-{2-Hydroxy-3-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester  
     Example 142  
     1-{2-Hydroxy-3-[4-(3-oxo-2,3-dihydro-1,4-benzoxazin-4-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester  
     Example 143  
     4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-4H-1,4-benzoxazin-3-one  
     Example 144  
     4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one  
     Example 145  
     1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one  
     Example 146  
     1-{3-[4-(2-Oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester  
     Example 147  
     1-{3-[4-(3-Oxo-2,3-dihydro-1,4-benzoxazin-4-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester  
     Example 148  
     6-Chloro-4-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one  
     Example 149  
     4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-6-chloro-4H-1,4-benzoxazin-3-one  
     Example 150  
     4-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one  
     Example 151  
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one  
     Example 152  
     4-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one  
     Example 153  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one  
     Example 154  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one  
     Example 155  
     1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one  
     Example 156  
     1-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one  
     Example 157  
     1-(1-{3-[3-(4-Chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one  
     Example 158  
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one  
     Example 159  
     1-(1-{3-[5-Acetyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one  
     Example 160  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one  
     Example 161  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-indol-2-one  
     Example 162  
     6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one  
     Example 163  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-indol-2-one  
     Example 164  
     5-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one  
     Example 165  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-indol-2-one  
     Example 166  
     1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1,3-dihydro-indol-2-one  
     Example 167  
     4-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-pyrido[3,2-b]-1,4-oxazin-3-one  
     Example 168  
     1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dihydro-4,1-benzoxazepin-2-one  
     Example 169  
     1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,4-dihydro-3,1-benzoxazin-2-one  
     Example 170  
     1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,4-dihydro-3,1-benzoxazin-2-one  
     Example 171  
     1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dihydro-4,1-benzoxazepin-2-one  
     Example 172  
     1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,4-dihydro-3,1-benzoxazin-2-one  
     Example 173  
     1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,4-dihydro-3,1-benzoxazin-2-one  
     Example 174  
     1-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(5-nitro-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 175  
     1-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(6-nitro-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 176  
     1-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-methyl-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 177  
     1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H&gt;-quinazolin-2-one  
     Example 178  
     1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one  
     Example 179  
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one  
     Example 180  
     1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one  
     Example 181  
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one  
     Example 182  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1-(3-chloro-phenyl)-3-methyl-urea  
     Example 183  
     1-[3-(4-Benzotriazol-1-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester  
     Example 184  
     1-{3-[4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-propyl}-3-(3,4-dichloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester  
     Example 185  
     5-Chloro-1-(1-{3-[3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one  
     Example 186  
     1-{3-[4-(5-Methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester  
     Example 187  
     3-(4-Bromo-phenyl)-1-{3-[4-(5-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester  
     Example 188  
     3-(4-Bromo-phenyl)-1-{3-[4-(6-ethanesulfonyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester  
     Example 189  
     1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperidin-1-yl]-propan-2-ol  
     Example 190  
     5-Methyl-4-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one  
     Example 191  
     4-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methyl-4H-benzo[1,4]oxazin-3-one  
     Example 192  
     4-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-6-ethanesulfonyl-4H-benzo[1,4]oxazin-3-one  
     Example 193  
     1-{3-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine  
     Example 194  
     3-(4-Bromo-phenyl)-1-{3-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester  
     Example 195  
     3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester  
     Example 196  
     3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(3-oxo-2,3-dihydro-1,4-benzoxazin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester  
     Example 197  
     1-(1-{3-[3-(4-Trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one  
     Example 198  
     3-(4-Bromo-phenyl)-1-{3-[4-(3-oxo-2,3-dihydro-1,4-benzoxazin-4-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester  
     Example 199  
     1-(1-{2-Hydroxy-3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one  
     Example 200  
     4-(1-{3-[3-(4-Trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one  
     Example 201  
     1-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one  
     Example 202  
     4-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-C]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one  
     Example 203  
     1-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinolin-2-one  
     Example 204  
     4-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one  
     Example 205  
     4-(1-{2-Hydroxy-3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-4H-1,4-benzoxazin-3-one  
     Example 206  
     1-(3-(3,4-Difluoro-phenyl)-1-{3-[4-(2,3-dihydro-indol-1-yl)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 207  
     1-[1-{3-[4-(5-Bromo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 208  
     1-(1-{3-[5-Acetyl-3-(3,4-difluoro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one  
     Example 209  
     1-[1-{3-[4-(5-Bromo-2,3-dihydro-indol-1-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(3,4-difluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 210  
     1-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one  
     Example 211  
     1-(1-{3-[3-(4-Trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one  
     Example 212  
     1-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3,4-dihydro-1H-quinazolin-2-one  
     Example 213  
     1-(3-(4-Chloro-phenyl)-1-{3-[4-(3-chloro-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 214  
     N-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-N-(3-chloro-phenyl)-acetamide  
     Example 215  
     1-(4-Benzoimidazol-1-yl-piperidin-1-yl)-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol  
     Example 216  
     1-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenylamino)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 217  
     1-(3-(4-Chloro-phenyl)-1-{3-[4-(2-fluoro-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 218  
     1-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-phenylamino-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone  
     Example 219  
     1-(3-(4-Chloro-phenyl)-1-{3-[4-(4-chloro-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 220  
     1-[1-{3-[4-(4-Bromo-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 221  
     4-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-ylamino)-benzonitrile  
     Example 222  
     1-{3-(4-Chloro-phenyl)-1-[2-hydroxy-3-(4-p-tolylamino-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone  
     Example 223  
     1-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 224  
     1-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(3-methoxy-phenylamino)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 225  
     1-(3-(4-Chloro-phenyl)-1-{3-[4-(3,5-dimethoxy-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 226  
     1-[1-{3-[4-(5-Chloro-2-methyl-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 227  
     1-(3-(4-Chloro-phenyl)-1-{3-[4-(3-chloro-phenylamino)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 228  
     [2-(1-{3-[3-(4-Bromo-phenyl)-5-carbamoyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-acetic acid methyl ester  
     Example 229  
     [2-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-acetic acid methyl ester  
     Example 230  
     [2-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-acetic acid methyl ester  
     Example 231  
     3-(4-Bromo-phenyl)-1-{3-[4-(5-ethanesulfonyl-2-methoxycarbonylmethoxy-phenylamino)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester  
     Example 232  
     [2-(1-{3-[3-(4-Bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-ylamino)-4-ethanesulfonyl-phenoxy]-acetic acid methyl ester  
     Example 233  
     1-{3-(4-Bromo-phenyl)-1-[2-hydroxy-3-(4-o-tolyloxy-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone  
     Example 234  
     1-{3-(4-Bromo-phenyl)-1-[2-hydroxy-3-(4-phenoxy-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone  
     Example 235  
     1-{3-(4-Bromo-phenyl)-1-[2-hydroxy-3-(4-p-tolyloxy-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone  
     Example 236  
     1-(3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 237  
     1-(3-(4-Bromo-phenyl)-1-{3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 238  
     1-(3-(4-Bromo-phenyl)-1-{3-[4-(3-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 239  
     1-(3-(4-Bromo-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 240  
     1-{3-(4-Chloro-3-methyl-phenyl)-1-[2-hydroxy-3-(4-phenoxy-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone  
     Example 241  
     1-{3-(4-Chloro-3-methyl-phenyl)-1-[2-hydroxy-3-(4-p-tolyloxy-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone  
     Example 242  
     1-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 243  
     1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 244  
     1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 245  
     1-{3-(4-Chloro-3-methyl-phenyl)-1-[2-hydroxy-3-(4-o-tolyloxy-piperidin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone  
     Example 245A  
     1-(3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 246  
     2-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yloxy)-benzonitrile  
     Example 247  
     2-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yloxy)-benzonitrile  
     Example 248  
     1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-propan-2-ol  
     Example 249  
     1-[1-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 250  
     1-(1-{3-[5-Acetyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 251  
     1-{1-[3-(5-Acetyl-3-phenyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl)-2-hydroxy-propyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one  
     Example 252  
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethoxy-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 253  
     1-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 254  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 255  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 256  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 257  
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethylsulfanyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 258  
     1-(1-{3-[5-Acetyl-3-(4-methanesulfonyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 259  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-one  
     Example 260  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 261  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-ethyl-1,3-dihydro-benzoimidazol-2-one  
     Example 262  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-isopropyl-1,3-dihydro-benzoimidazol-2-one  
     Example 263  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-butyl-1,3-dihydro-benzoimidazol-2-one  
     Example 264  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-benzyl-1,3-dihydro-benzoimidazol-2-one  
     Example 265  
     1-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-fluoro-1,3-dihydro-benzoimidazol-2-one  
     Example 266  
     3-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carbonitrile  
     Example 267  
     1-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-fluoro-1,3-dihydro-benzoimidazol-2-one  
     Example 268  
     3-(1-{3-[5-Acetyl-3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbonitrile  
     Example 269  
     1-{2-Hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 270  
     1-(1-{3-[3-(4-Chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 271  
     3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methylamide  
     Example 272  
     3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid ethylamide  
     Example 273  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 274  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 275  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5,6-dichloro-1,3-dihydro-benzoimidazol-2-one  
     Example 276  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 277  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 278  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5,6-dichloro-1,3-dihydro-benzoimidazol-2-one  
     Example 279  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-one  
     Example 280  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 281  
     1-(1-{3-[3-(4-Chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-morpholin-4-yl-ethyl)-1,3-dihydro-benzoimidazol-2-one  
     Example 282  
     1-(1-{3-[5-Acetyl-3-(3-fluoro-4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 283  
     1-(1-{3-[5-Acetyl-3-(4-bromo-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 284  
     (R)-1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 285  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-benzoimidazol-2-one  
     Example 286  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-7-chloro-1,3-dihydro-benzoimidazol-2-one  
     Example 287  
     3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 288  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-7-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 289  
     (R)-1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-one  
     Example 290  
     1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 291  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 292  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-one  
     Example 293  
     (S)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-one  
     Example 294  
     (R)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 295  
     (R)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-one  
     Example 296  
     2-{2-[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-ethyl}-isoindole-1,3-dione  
     Example 297  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-amino-ethyl)-1,3-dihydro-benzoimidazol-2-one  
     Example 298  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 299  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-ethyl-1,3-dihydro-benzoimidazol-2-one  
     Example 300  
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 301  
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-ethyl-1,3-dihydro-benzoimidazol-2-one  
     Example 302  
     6-Chloro-1-(1-{3-[3-(4-chloro-3-methyl-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 303  
     1-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 304  
     3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-1-(2-morpholin-4-yl-ethyl)-1,3-dihydrobenzoimidazol-2-one  
     Example 305  
     [3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetic acid ethyl ester  
     Example 306  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2,2,2-trifluoro-ethyl)-1,3-dihydrobenzoimidazol-2-one  
     Example 307  
     [3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]acetonitrile  
     Example 308  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-hydroxy-ethyl)-1,3-dihydro-benzoimidazol-2-one  
     Example 309  
     1-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-chloro-1,3-dihydro-benzoimidazol-2-one  
     Example 310  
     1-(1-{3-[5-Acetyl-3-(3-chloro-4-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 311  
     1-Ethyl-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 312  
     1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 313  
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-hydroxy-ethyl)-1,3-dihydro-benzoimidazol-2-one  
     Example 314  
     3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 315  
     [3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2, 3-dihydro-benzoimidazol-1-yl]-acetonitrile  
     Example 316  
     2-[3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetamide  
     Example 317  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-oxo-tetrahydro-furan-3-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 318  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-methoxy-ethyl)-1,3-dihydro-benzoimidazol-2-one  
     Example 319  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-oxo-butyl)-1,3-dihydro-benzoimidazol-2-one  
     Example 320  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-diethylamino-ethyl)-1,3-dihydro-benzoimidazol-2-one  
     Example 321  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-cyclopropylmethyl-1,3-dihydro-benzoimidazol-2-one  
     Example 322  
     1-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-(2-methyl-allyl)-1,3-dihydro-benzoimidazol-2-one  
     Example 323  
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 324  
     5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 325  
     6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 326  
     N-[4-(5-Acetyl-1-{2-hydroxy-3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-acetamide  
     Example 327  
     [3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetic acid  
     Example 328  
     1-(1-{3-[5-Acetyl-3-(3-bromo-4-chloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 329  
     3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 330  
     3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 331  
     1-(1-{3-[5-(1H-Imidazole-4-carbonyl)-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 332  
     1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 333  
     1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid ethylamide  
     Example 334  
     1-(1-{3-[5-(Isoxazole-5-carbonyl)-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 335  
     1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonic acid (N-t-butoxycarbonyl)amide  
     Example 336  
     1-Methyl-3-(1-{3-[5-(5-methyl-isoxazole-3-carbonyl)-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 337  
     3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 338  
     3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 339  
     5-Dimethylamino-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 340  
     3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-ethyl-5-methoxy-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 341  
     1-(1-{3-[5-Acetyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 342  
     1-(1-{3-[5-Acetyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 343  
     3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-ethyl-5-methoxy-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 344  
     3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 345  
     1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid benzyl ester  
     Example 346  
     5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 347  
     1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbothioic acid methylamide  
     Example 348  
     3-(4-Bromo-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid phenylamide  
     Example 349  
     1-(1-{3-[5-Benzoyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 350  
     1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 351  
     1-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 352  
     3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 353  
     1-{3-[4-(6-Chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 354  
     1-(1-{3-[3-(4-Bromo-phenyl)-5-phenylmethanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 355  
     1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 356  
     3-(4-Bromo-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 357  
     3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 358  
     3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-chloro-1-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 359  
     3-(4-Bromo-phenyl)-1-{3-[4-(6-chloro-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 360  
     3-(1-{3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,5-dimethyl-1,3-dihydro-benzoimidazol-2-one  
     Example 361  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 362  
     3-(4-Bromo-phenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonic acid t-butoxycarbonyl-amide  
     Example 363  
     1-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 364  
     1-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one  
     Example 365  
     3-(4-Bromo-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-sulfonic acid t-butoxycarbonyl-amide  
     Example 366  
     3-(4-Bromo-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 367  
     (R)-5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 368  
     1-(1-{3-[5-Acetyl-3-(3,4-dichloro-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 369  
     1-(1-{3-[3-(3,4-Dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 370  
     1-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methoxy-1,3-dihydro-benzoimidazol-2-one  
     Example 371  
     3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 372  
     3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 373  
     1-{2-Hydroxy-3-[4-(2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 374  
     3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid amide  
     Example 375  
     [3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl]-acetonitrile  
     Example 376  
     3-(3,4-Dichloro-phenyl)-1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methylamide  
     Example 377  
     3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 378  
     3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-5-methoxy-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 379  
     [3-(1-{3-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetic acid ethyl ester  
     Example 380  
     [3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetic acid ethyl ester  
     Example 381  
     [3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-acetic acid ethyl ester  
     Example 382  
     5-Chloro-3-(1-{3-[3-(3,4-dichloro-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 383  
     (R)-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one  
     Example 384  
     1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3-pyridin-4-ylmethyl-1,3-dihydro-benzoimidazol-2-one  
     Example 385  
     (R)-5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one  
     Example 386  
     3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-3H-benzooxazol-2-one  
     Example 387  
     3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4-methyl-3H-benzooxazol-2-one  
     Example 388  
     3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzooxazole-6-carboxylic acid ethyl ester  
     Example 389  
     3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-ethanesulfonyl-3H-benzooxazol-2-one  
     Example 390  
     3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-4-methyl-3H-benzooxazol-2-one  
     Example 391  
     3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-2-oxo-2,3-dihydro-benzooxazole-6-carboxylic acid ethyl ester  
     Example 392  
     3-(1-{3-[5-Acetyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methoxy-3H-benzooxazol-2-one  
     Example 393  
     3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-ethanesulfonyl-3H-benzooxazol-2-one  
     Example 394  
     3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-methoxy-3H-benzooxazol-2-one  
     Example 395  
     3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-3H-benzooxazol-2-one  
     Example 396  
     3-(1-{3-[5-Acetyl-3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-5-chloro-3H-benzooxazol-2-one  
     Example 397  
     3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-3H-oxazolo[4,5-b]pyridin-2-one  
     Example 398  
     1-[1-[3-(4-Benzooxazol-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 399  
     1-[1-{2-Hydroxy-3-[4-(6-methyl-benzooxazol-2-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 400  
     1-[1-{3-[4-(Benzothiazol-2-yloxy)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 401  
     1-[1-{2-Hydroxy-3-[4-(5-methyl-benzooxazol-2-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 402  
     1-(3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone  
     Example 403  
     3-(4-Chloro-phenyl)-1-{2-hydroxy-3-[4-(2-methoxy-phenyl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbaldehyde  
     Example 404  
     1-[1-[3-(4-Benzo[b]thiophen-2-yl-piperidin-1-yl)-2-hydroxy-propyl]-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone  
     Example 405  
     1-[4-(6-Chloro-indol-1-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-2-ol  
      F. Other Embodiments  
      The features and advantages of the invention are apparent to one of ordinary skill in the art. Based on this disclosure, including the summary, detailed description, background, examples, and claims, one of ordinary skill in the art will be able to make modifications and adaptations to various conditions and usages. These other embodiments are also within the scope of the invention.