SUBSTITUTED PYRAZOLES

Abstract: Substituted pyrazoles, methods of manufacturing them, compositions containing them, and methods of using them to treat, for example, autoimmune diseases mediated by cathepsin S are described.

Description: SUBSTITUTED PYRAZOLES 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). 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. 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. US-5976858. Certain peptidyl sulfonamides are claimed by Arris/Axys as cysteine protease (including cathepsin S) inhibitors in: Palmer, et. al. US-5776718 (assigned to Arris, now Axys) & Klaus, et. al. US-6030946 (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 US-4500525 (1985)) have described bicydic 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. US- 5264576 (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-1 H-pyrazol-1-yl)butyl]-1- piperazinylj-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]- 1 H-indazole and 5-bromo-3-(2-chlorophenyl)-1-[4-(4-phenyl-1- piperazinyl)butyl]-1 H-indazole, in particular the hydrochloride salts thereof, are known from WO-9853940 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. Summary of the Invention The present invention concerns compounds which can be represented by formula (I): (I) wherein: the dashed line adjacent C-R 6 is absent or an sp 2 bond; Y is nitrogen or R 20 C; Z is nitrogen or R 21 C; T is nitrogen or R 2 C; s is nitrogen or R 3 C; provided between 0 and 3 of S, T, Y, and Z are nitrogen; and further provided that one of S, T, Y, and Z can be =N + -0 " where the remaining three are not nitrogen; R : 20 is selected from hydrogen, halogen, C^ alkoxy, hydroxy, C^ alkyl, cyano, nitro, C L ghaloalkyl, R°R P N, R°R p NC=0, C 2 . 8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)- C 1-5 alkylene, phenyl, (phenyl)C ,. δ alkylene, R 14 OC=O, R 14 S, R 14 SO, and R 14 S0 2 ; R : 21 is selected from hydrogen, halogen, C,. 5 alkoxy, hydroxy, C^ alkyl, cyano, nitro, C^haloalkyl, R c R d N, R c R d NC=0, C 2 . 8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C ^ alkylene, phenyl, (phenyl)C ^ alkylene, R 15 OC=O, R 15 S, R 15 SO , and R 15 S0 2 ; R 2 is selected from hydrogen, halogen, C,. 5 alkoxy, hydroxy, C.,. 5 alkyl, cyano, nitro, C 1-5 haloalkyl, R e R f N, R e R f NC=0, C^acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C ^ alkylene, phenyl, (phenyl)C ,_ 5 alkylene, R 16 OC=O, R 16 S, R 16 SO , and R 16 S0 2; R 3 is selected from hydrogen, halogen, C,_g alkoxy, hydroxy, C,. 5 alkyl, cyano, nitro, haloalkyl, R 9 R h N, C 2 . 8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)- C ^ alkylene, phenyl, (phenyl)C ^ alkylene, R 17 OC=0, R m R n NC=O, R m R n NS0 2 , R 17 S, R 17 SO , and R 17 S0 2 ; R 5 and R 6 are independently selected from hydrogen and C^ alkyl; R 7 and R 8 independently are hydrogen, alkylthio, halogen, or 4-7 membered carbocyclyl or heterocyclyl; alternatively, R 7 and R 8 can be taken together to form art optionally substituted 5- to 7- membered carbocyclic or heterocyclic ring, which ring may be unsaturated or aromatic; said ring being optionally substituted with between 1 and 3 substituents independently selected from halo, hydroxy, cyano, nitro, amino, R*, R'O-, R'S-, R'0(C ^ alkylene)-, R'0(C=O)-, ^(0=0)-, R f (C=S)-, R'(C=0)0-, ^0(0=0)^=0)-, R'SO^ NHR U (C=NH)-, NHR u SO 2 -, and NHR u (C=0)-; R 1 is C .,. 6 alkyl, phenyl, benzyl, phenethyl, or C 2 . 5 heterocyclyl, (C ^ heterocyclyl)C Λ4i alkylene, NH 2 , mono- or di(C 1-β alkyl)N-, or R 49 OR 50 -, wherein R 49 is H, C ^ alkyl, C 2-5 alkenyl, phenyl, benzyl, phenethyl, C 5 heterocyclyl, or (C ^ heterocyclyl)C ^ alkylene and R 50 is C ^ alkylene, phenylene, or divalent C ^ heterocyclyl; and R u can be H in addition to the values for R*; R c is hydrogen, C^ alkyl, phenyl, C 2 . 5 heterocyclyl, C 24 acyl, aroyl, R 10 OC=O-, R'R J NC=0. R 10 SO-, R 10 SO 2 -, and R i R j NS0 2 ; R e is hydrogen, C,. 5 alkyl, phenyl, C 2 . 5 heterocyclyl, C 2 . 8 acyl, aroyl, R 40 OC=O, R 43 R NC=0, R 40 SO, R 40 SO 2 , and R 43 R 44 NS0 2 ; R is hydrogen, C^ alkyl, phenyl, C 2 . 5 heterocyclyl, C 2 _ a acyl, aroyl, R 41 OC=0, R 45 R 46 NC=0, R 41 SO, R 41 SO 2 , and R 45 R 46 NS0 2 ; R° is hydrogen, C^ alkyl, phenyl, C 2 . 5 heterocyclyl, C 2 . 8 acyl, aroyl, R 42 OC=0, R 47 R 48 NC=0, R 42 SO, R 42 S0 2 , and R 47 R 48 NS0 2 ; each of R d , R f , R n , and R p is independently selected from hydrogen, C,. 5 alkyl, phenyl, and C 2 _g heterocyclyl; in addition, R c and R d , R e and R f , R m and R n , or R° 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 9 , R 10 , R 11 , R 14 , R 15 , R 6 , R 17 , R 40 , R 41 , and R 42 is independently C^ alkyl, phenyl, or C 2 . 5 heterocyclyl; each of R 1 and R J , R k and R 1 , R 43 and R 44 , R 45 and R 46 , R 47 and R 48 are independently hydrogen, C,^ alkyl, C 3 ^ alkenyl, phenyl, or C 2 . 5 heterocyclyl; in addition, R 1 and R 1 , and R k and R 1 , R 43 and R 44 , R 45 and R 46 , and R 47 and R 48 , 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, phenyl, or C 2 . 5 heterocyclyl, C 2-8 acyl, aroyl, R 9 OC=0, R 18 R 9 NC=0, R 9 SO, R 9 SO 2 , or R 18 R 19 NS0 2 ; R h is hydrogen, Q,^ alkyl, phenyl, or C 2 . 5 heterocyclyl; alternatively, R 9 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 18 and R 19 independently are hydrogen , C,_g alkyl, phenyl, or C 2 . 5 heterocyclyl; alternatively, R 18 and R 19 can be taken together to form an optionally substituted 4- to 7- membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic; n is 0, 1 or 2; G is C 3 . 6 alkenediyl or C 3 . 6 alkanediyl, optionally substituted with hydroxy, halogen, C^ alkyl, C 1-5 alkoxy, oxo, hydroximino, C0 2 R k , NR k R, (L)-C 1-4 alkylene-, R k R'NCO 2 , [(L)-C alkoxy; L is amino, mono- or di-C,. 5 alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, or piperazinyl, wherein available ring nitrogens can be optionally substituted with 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,. 5 alkyl, C 2-5 alkenyl, cyano, azido, nitro, R^R∞N, R 22 S, R^SO, R 22 S0 2 , R 22 OC=0, R 22 R 23 NC=0, C^ haloalkyl, C,_ ghaloalkoxy, C^haloalkylthio, and C,^ alkylthio; R 22 is hydrogen, C,. 5 alkyl, C 3 ^ alkenyl, phenyl, benzyl, C M heterocyclyl, C 2 . 8 acyl, aroyl, R 1 OC=O, R 24 R 25 NC=0, R 1 S, R 11 SO, R 11 S0 2 , or R 24 R 25 NS0 2 ; R 23 is hydrogen, C^ alkyl, phenyl, benzyl, or C 2 . 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 and R 25 are independently hydrogen, C^ alkyl, phenyl, benzyl, or C .,. 5 heteroaryl; , alternatively, R 24 and R 25 can be taken together to form an optionally substituted 4- to 7- membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic; R 32 is hydrogen, C^ alkyl, cyano, C^ hydroxyalkyl, C 2 . 8 acyl, -(C=O)NR v R x , CHO, or C,. 6 alkoxycarbonyl, wherein each of R v and R x is independently selected from H , C,.g alkyl, C,. s hydroxyalkyl, C,. s heterocyclyl, heterocyclyl) C^ 5 alkylene, C^ aminoalkylene, C 3 . 8 acyloxy, CHO, C^ alkoxycarbonyl, and cyano; Q is NR 33 , S, or O; R 33 represents hydrogen, C 1-5 alkyl, phenyl, benzyl, phenethyl, C 2 ., heterocyclyl, (C 2 . 5 heterocyclyl)C s alkylene, C 2 . 8 acyl, aroyl, R 35 OC=0, R 3B R 3 NC=0, R 35 SO, R 35 S, R 35 S0 ) 22 aanndd RR 3366 RR 3377 NNSS00 22 ;; R 35 is selected from hydrogen, C,. 5 alkyl, phenyl, benzyl, phenethyl, and C 2-5 heteroaryl; R 36 and R 37 are each independently selected from hydrogen, C^ alkyl, phenyl, or C 2 . 5 heteroaryl; alternatively, R 36 and R 37 can be taken together to form an optionally substituted 4- to 7-membered ring 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 ^ alkyl, C ^ alkoxy, -COOH, C 2 _ β acyl, [di(C 1-4 alkyl)amino]C 2 . 5 alkylene, [di(C A 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. 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. Additional features and advantages of the invention will become apparent from the detailed description below, including examples, and the appended claims. 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. 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 (S0 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- memebered 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 ^ 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 n . 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 ^y 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 ^ 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 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 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) one of S, T, Y, and Z is nitrogen; (b) S and T are CR 3 and CR 2 , respectively; (c) S, T, Y, and Z are CR 3 , CR 2 , CR 20 , and CR 21 , respectively; (d) (1 ) Z is N, Y is N, S is CR 3 , and T is CR 2 ; or (2) S is N, T is N, Y is CR 20 , and Z is CR 21 ; (e) R 2 is hydrogen, halogen, alkoxy, cyano, R e R f N, or a 5-6 membered heterocyclyl; (f) R 3 is hydrogen, halogen, C 1-5 alkoxy, C,. 5 alkyl, cyano, R 17 OC=0, or R 9 R h N, where R 9 and R h are H or C ^ alkyl, or are taken together to form a 5-6 membered heterocyclyl; (g) each of R 2 and R 3 is independently selected from hydrogen, halogen, and a 5-6 membered heterocyclyl; (h) R 5 and R 6 are independently selected from hydrogen and C 1-3 alkyl; (i) one of R 5 and R 6 is H; (j) R 5 and R 6 are each H; (k) one of R 7 and R 8 is H and the other is 5-7 membered carbocyclyl or heterocyclyl; (I) R 7 and R 8 are taken together to form an optionally substituted 5- to 7- membered carbocyclic or heterocyclic ring; (m) R 7 and R 8 are taken together to form a six-membered heterocyclyl; (n) R 7 and R 8 taken together form a 5-7 membered heterocyclyl optionally N-substituted with R'(C=0)-, R^O^, or NHR u (C=O)- wherein R' is C ^ alkyl, phenyl, or C 2 . 5 heterocyclyl and R u is H, C ^ alkyl, phenyl, or C 2-5 heterocyclyl; (o) each of R c , R e , R m , and R° is independently selected from hydrogen, C 1-5 alkyl, C 2-8 acyl, (C ^ alkyl)OC=O, and the respective RRNC=0, RSO, RSO 2 , and RRNS0 2 groups; (p) each of R c , R d , R g , R h , R°, R f , and R p is independently selected from hydrogen and C^ alkyl; or , independently, R e and R f , R 9 and R h , or R° and R p taken together form an optionally substituted 4- to 7- membered carbocyclic or heterocyclic ring; (q) R e and R f taken together are morpholinyl, piperidinyl, or pyrrolidinyl; (r) each of R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R j , R j , R k and R' independently is hydrogen or C^ alkyl; (s) each of R 9 , R 11 , R 14 , R 15 , R 16 and R 17 is independently C^ alkyl; (t) R 9 is C 1-5 alkyl, C 2 . 8 acyl, R 9 OC=0, R 18 R 19 NC=0, R 9 SO, R 9 S0 2 , or R 18 R 19 NSO 2 ; and R h is H or C 1-5 alkyl; alternatively, R 9 and R h can be taken together to form an optionally substituted 5- to 6-membered heterocyclyl; (u) R 9 and R h are each C ^ alkyl; (v) R 18 and R 19 independently are hydrogen or C 1-5 alkyl; (w) n is 0 or 1 ; or n is 1 ; (x) G is C M alkanediyl, optionally substituted with hydroxy, halogen, [(L)- C .,. 5 alkylenejamino, or (LJ-C^alkyloxy; (y) G is C 3 alkanediyl, optionally substituted with hydroxy; (z) R 20 and R 21 are independently selected from hydrogen, halogen, G,^ alkoxy, G,^ alkyl, cyano, nitro, 4-7 membered heterocyclyl, and R°R P N or R c R d N, respectively; (aa) R 20 and R 21 are independently selected from hydrogen, halogen, 5- to 6-membered heterocyclyl, and R°R P N or R c R d N, respectively; (bb) Ar represents a monocyclic ring, optionally substituted with 1 to 2 substituents selected from halogen, G,^ alkyl, cyano, nitro, R 22 R 23 N, haloalkoxy; (cc) Ar is a six-membered aromatic ring monosubstituted at the 4- position with halogen, methyl, CF 3 , or OCF 3 , or disubstituted at the 3- and 4-positions with substituents independently selected from halogen, CF 3 , methyl, and OCF 3 ; (dd) each of R 22 , R 23 , and R 24 is independently hydrogen or C 1-5 alkyl; (ee) R 25 and R 26 independently are hydrogen or C 1-5 alkyl, or, alternatively, R 25 and R 26 are taken together to form an optionally substituted 4- to 7- membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic; (ff) R 25 and R 26 independently are hydrogen or C 1-5 alkyl; (gg) Q is NR 33 or S; (hh) Q is NR 33 , R 33 is H or C 2 . 5 heterocyclyl, and R 32 is H, C . 5 alkyl, hydroxyalkyl, -(C=0)NR v R x , CHO, or C ^ alkoxycarbonyl, wherein each of R v and R x is independently selected from H, C ^ hydroxyalkyl, (C 1-5 eterocyc\y\)-C ^ alkylene, and C ^ aminoalkylene; (ii) wherein Q is S and R 33 is NR 36 R 37 (C=0)- where each of R 36 and R 37 are independently selected from hydrogen and C^ alkyl; (jj) R 35 is selected from hydrogen and C.,_ 5 alkyl; R 36 and R 37 are each independently selected from hydrogen, C^ alkyl, or, alternatively, R 36 and R 37 can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring; (kk) Y is nitrogen or R 20 C; Z is nitrogen or R 21 C; T is nitrogen or R 2 C; S is nitrogen or R 3 C; provided between 0 and 2 of S, T, Y, and Z are nitrogen; for example 1 of them is N; (II) R 2 is hydrogen, halogen, hydroxy, C,^ alkoxy, C,^ alkyl, 5- to 6- membered heterocyclyl, or R e R f N; (mm) R 3 is hydrogen, halogen, C,_ 5 alkoxy, hydroxy, C^ alkyl, , 5- to 6-membered heterocyclyl, or R 9 R h N; (nn) R 7 and R 8 independently are taken together to form an optionally substituted 5- to 7- membered unsaturated heterocyclic ring; (oo) each of R a ' R e , R m , and R° is independently selected from hydrogen, C^ alkyl, C 2 . 8 acyl, (C 1 . 5 alkyl)OC=0, and the respective RRNC=O, RSO, RS0 2 , and RRNSO 2 groups; (pp) each of R b , R f , R n , and R p , is independently selected from hydrogen and C^ alkyl; each of R 9 , R 11 , R 4 , R 15 , R 16 , R 17 , R 40 , R 41 and R 42 is independently C^ alkyl; and each of R c , R d , R' , R ] , R 43 , R 44 , R 45 , R 46 , R 47 , R k and R 1 are independently are hydrogen or alkyl; (qq) R 9 is hydrogen, or C^ alkyl, C 2 . 8 acyl, R 9 OC=0, R 18 R 19 NC=0, R 9 SO, R 9 S0 2 , or R 18 R 19 NS0 2 ; R h is hydrogen or C^ alkyl; alternatively, R 9 and R h can be taken together to form an optionally substituted 4- to 7- membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic; R 18 and R 19 independently are hydrogen or C 1-5 alkyl; n is 0 or 1 ; (rr) G is C 3 alkenediyl or C^ alkanediyl, optionally substituted with hydroxy, halogen, oxo, hydroximino, C0 2 R k , R κ R'NC0 2 , or L is amino, mono- or di-C 1-5 alkylamino, pyrrolidinyl, morpholinyl, piperidinyl homopiperidinyl, or piperazinyl, available ring nitrogens being optionally with C 1-5 alkyl, benzyl, C 2 . 5 acyl, or C,_g alkyloxycarbonyl; (ss) R 20 and R 21 are independently selected from hydrogen, halogen, C,. s alkyl, cyano, nitro, and R°R p N; 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; and Ar represents a monocyclic or bicyclic aryl or heteroaryl ring, optionally substituted with hydrogen, halogen, alkyl, cyano, nitro, R 22 R 23 N, R 24 S0 2 , R 24 OC=0, R 25 R 26 NC=0, CF 3 , OCF 3 , SCF 3 , or C^ alkylthio; R 22 is hydrogen, C^ alkyl, phenyl, benzyl, phenethyl, C 2 . 5 heteroaryl, C 2 . 8 acyl, aroyl, R 24 OC=0, R 25 R 26 NC=0, R 24 SO, R 2 S0 2 , or R 25 R 26 NSO 2 ; R 23 is hydrogen or C^alkyl; alternatively, R 22 and R 23 can be taken together to form an optionally substituted 4- to 7- membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic; R 24 is hydrogen or C^ alkyl; R 25 and R 26 are independently hydrogen or C^ alkyl; or, alternatively, R 25 and R 26 can be taken together to form an optionally substituted 4- to 7- membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic; (tt) R 32 is hydrogen, C^ alkyl, C^ hydroxyalkyl, CHO, C 2 . 6 acyl, C ^ alkoxycarbonyl, or -(C=0)NR v R x , wherein each of R V R X is independently selected from H, C ^ alkyl, C,_ 5 hydroxyalkyl, C 3 acyloxy, (amino)C ^ alkylene, (C ^ heterocyclyl)C 1-5 alkylene, or C 1-6 alkoxycarbonyl; and Q is NR 33 or S; R 33 represents hydrogen, alkyl, phenyl, benzyl, (C 2 . 5 heterocyclyl)C 1-s alkylene, C 2 . s acyl, aroyl, R 35 OC=0, R 36 R 37 NC=0, R 35 SO 2 and R 36 R 37 NS0 2 ; R 35 is selected from hydrogen and C 1-5 alkyl; R 36 and R 37 are each independently selected from hydrogen and C 1-5 alkyl; (uu) 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^ alkyl, cyano, nitro, R 22 R 23 N, CF 3 and OCF 3 ; (vv) both R 5 and R 6 are each H, and (ww) Ar is a six membered ring substituted with halogen, CF 3 , methyl, halomethyl, or OCF 3 , at the 3- or 4- position, or disubstituted at the 3- and 4- positions; (xx) R 7 and R 8 taken together form pyridinyl, pyrimidinyl, or piperazinyl, optionally N-substituted with -(C=0)R t , S0 2 -R', or - (C=0)NHR u ; (yy) R e and R f taken together are independently morpholinyl, piperidyl, or pyrrolidinyl, optionally substituted; (zz) the dashed line adjacent C-R 6 is absent; (aaa) or combinations of the above. Specific preferred compounds include those in the Examples below, such as: 1 -[1 -{2-Hydroxy-3-[4-(1 H-indol-3-yl)-piperidin-1 -yl]-propyl}-3-(4-trifluoromethyl- phenyl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone ; 1-[4-(5- Fluoro-1 H-indol-3-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 ; 1 -[3-(4- Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1- yl]-3-[4-(5-chloro-1 H-indol-3-yl)-piperidin-1-yl]-propan-2-ol ; 1-[3-(4-Bromo- phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4- (5-chloro-2-methyl-1 H-indol-3-yl)-piperidin-1-yl]-propan-2-ol ; 1-[5- Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-1 -yl]-3-[4-(5-methyl-1 H-indol-3-yl)-piperidin-1 -yl]-propan-2-ol ; 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 H-indole-5-carbonitrile ; 1-[5- Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-1-yl]-3-[4-(5-methoxy-1 H-indol-3-yl)-piperidin-1-yl]-propan-2-ol ; 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 H-indole-5- carboxylic acid ethyl ester ; 1-[4-(6-Chloro-1 H-indol-3-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 ; 1-[1-(3-{4-[6-Chloro-1-(2 r morpholin-4-yl-ethyl)-1 H- indol-3-yl]-piperidin-1-yl}-2-hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1 ,4,6,7- tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone ; 1 -[5-Methanesulfonyl-3-(4- trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1H- pyrrolo[3,2-b]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol ; 1-[5-Methanesulfonyl-3- (4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4- (1 H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol ; 1-[5- Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-1 -yl]-3-[4-(5-oxy-1 H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1 -yl]-propan-2- ol ; 1-[4-(5-Dimethylamino-1 H-pyrrolo[3,2-b]pyridin-3-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 ; 1-[4-(5-Dimethylamino-1 H-pyrrolo[2,3-c]pyridin-3- 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 ; 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 H-pyrrolo[2,3-b]pyridine-6-carbonitrile ; 1 - [5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-1 -yl]-3-{4-[1 -(2-morpholin-4-yl-ethyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl]- piperidin-1 -yl}-propan-2-ol ; 1 -[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)- 4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(7-morpholin-4-yl-1 H- pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1 -ylJ-propan-2-ol ; 1 -[4-(6-Fluoro-2- hydroxymethyl-benzo[b]thiophen-3-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-Fluoro-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)-benzo[b]thiophene-2-carbaldehyde ; 6-Fluoro-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)-benzo[b]thiophene-2-carboxylic acid methyl ester ; 6-Fluoro-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)benzo[b]thiophene-2-carboxylic acid amide ; and 6-Fluoro-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)benzo[b]thiophene-2-carboxylic. Furthermore, preferred compounds include those wherein Ar is selected from 4-trifluoromethylphenyl, 4-bromophenyl, 4-chlorophenyl, 4-chloro-3- methylphenyl and 3,4-dichlorophenyl. More preferred compounds include those in Examples 4, 9, 13, and 26. 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 8 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 & 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 methyoxy methyl, methylthiomethyl, f-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, f-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, f-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4- dinitrophenyl, and benzyl. Substituted Benzyl Ethers Examples of substituted benzyl ethers include p-methoxy benzyl, 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-(/midazol-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, f-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and f-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)fiuorenylmethyl, 9-(2,7-dibromo)fiuorenylmethyl, 2,7- di-f-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- -butylphenyl)-1-methylethyl, 2-(2'- and 4'-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, f-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, tτ?-chloro-p- acyloxy benzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and 2- (trifluoromethyl)-6-chromonylmethyl. Photolytic Cleavage Examples of photolytic cleavage include /n-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 f-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl methyl, 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, isobomyl, 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-f-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-chlorobutyry|, 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. I mine 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, 0,0'-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 0-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, 0-1 -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- -butyl-4-methylphenoxide)(MAD)complex. PROTECTION FOR THE CARBOXYL GROUP Esters Substituted Methyl Esters Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylth.iomethyl, 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, f-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)anthry I methyl, 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, f-butyldimethylsilyl, /-propyldimethylsilyl, phenyldimethylsilyl and dπf- butyl methylsilyl. 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(lli) 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 12 below, and Examples 1 to 13. Those of ordinary skill in the art will be able to modify and adapt the guidance provided herein to make the disclosed compounds. Scheme 1 P = H, tert-butoxycarbonyl (BOC), EtOCO, Ac, etc. Scheme 2 Scheme 3 X = S, O Scheme 4 Scheme 5 Scheme 6 Scheme 7 Scheme 8 Scheme 9 oxidant Scheme 10 Scheme 11 base Scheme 12 ( T ^OTBS base 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. 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 componds, 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 forms 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. 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 1 -[4-(5-Chloro-1 H-indol-3-yl)-piperidin-1 -yl]-3-[5-methanesulfonyl-3-(4- trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c3pyridin-1-yl]-propan-2- ol. 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 (gas evolution was observed). The reaction mixture was allowed to shake for 72 h and was partitioned between CH 2 CI 2 (500 mL) and saturated aqueous NaHC0 3 (500 mL). The aqueous layer was extracted with CH 2 CI 2 (3 X 200 mL). The organic layer was washed with 1 % KHS0 4 (250 mL), dried (Na 2 S0 4 ), and concentrated to afford 90.5 g (87%) of a white solid. MS (electrospray): exact mass calculated for 177.1 ; m/z found, 178.1 [M+H] + . HPLC (reverse phase conditions): t R = 2.19 min. 1 H NMR (400 MHz, CDCI 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-phenvπ-4.5.6.7-tetrahvdro-1H- pyrazolo[4.3-clpyridine. 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 CI 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 CI 2 (82 mL). The reaction mixture was allowed to warm to room temperature and stirred for 20 h. The reaction mixture was washed with 1 N aqueous HCl (250 mL) and the CH 2 CI 2 layer was separated, dried (Na 2 S0 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 room temperature 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-1 H-pyrazolo[4,3-c]pyridine as a white solid. MS (electrospray): exact mass calculated for C 14 H 14 F 3 N 3 0 2 S, 345.0; m/z found, 346.0 [M+H] + . HPLC (reverse phase conditions): t R = 6.33 min. Η NMR (400 MHz, CDCI 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. .5-Methanesulfonyl-1 -oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4.5.6.7- tetrahvdro-1H-pyrazolor4.3-c1pyridine. 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 C0 3 (10.4 g, 31.9 mmol). After stirring at room temperature for 4 days the mixture was evaporated, brought up in EtOAc and washed with water. The organics were dried (MgS0 4 ) and evaporated to give a light yellow solid. Column chromatography (silica, 5% acetone/CH 2 CI 2 ) gave 4.1g (35%) of a white solid. TLC (silica, 5% acetone/CH 2 CI 2 ): R f = 0.28. MS (electrospray): exact mass calculated for C 17 H 18 F 3 N 3 0 3 S, 401.10; m/z found, 402.1 [M+H] + . 1 H NMR (400 MHz, CDCI 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, 1 H), 3.90-3.70 (m, 2H), 3.47 (m, 1 H), 3.10-2.9 (m, 6H), 2.65-2.60 (m, 1 H). P. 4-(5-Chloro-1 H-indol-3-vπ-3.6-dihvdro-2H-pyridine-1 -carboxylic acid tert- butyl ester. 5-Chloro-1H-indole (3.2 g, 20 mmol), 4-oxo-piperidine-1 -carboxylic acid tert- butyl ester (7.97 g, 40 mmol) and potassium hydroxide (4.5 g, 80 mmol) were added in MeOH (40 mL) and heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (200 mL). The mixture were extracted with 10% MeOH/CH 2 CI 2 (5 x 100 mL). The organic extracts was dried over Na 2 S0 4 and concentrated to form a solid. The solid was washed with MeOH (100 mL), filtered and dried to give a light yellow solid 6.3 g (94%). TLC (silica, 5% MeOH/CH 2 CI 2 ): R f = 0.8. MS (electrospray): exact mass calculated for C 18 H 21 CIN 2 0 2 , 332.12; m/z found, 355.0 [M + +Na]. 1 H NMR (CDCIg, 400 MHz): 8.26 (br s, 1 H), 7.83 (d, J = 1.76 Hz, 1 H), 7.28 (d, J = 8.80 Hz, 1 H), 7.19-7.14 (m, 2H), 6.09 (br s, 1 H), 4.15-4.10 (m, 2H), 3.66 (t, J = 5.67 Hz, 2H), 2.56-2.49 (m, 2H), 1.50 (s, 9H). E. 4-(5-Chloro-1 H-indol-3-v0-piperidine-1 -carboxylic acid tert-butyl ester. 4-(5-Chloro-1 H-indol-3-yl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid tert-butyl ester (6.3 g, 18.9 mmol) in EtOH (125 mL) containing Pt0 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 white solid 6.0 g (94%). TLC (silica, 5% MeOH/CH 2 CI 2 ): R f = 0.8. MS (electrospray): exact mass calculated for C 18 H 23 CIN 2 0 2 , 334.14; m/z found, 335.1 [M + +H]. 1 H NMR (CDCI 3 , 400 MHz) 8.46 (br s, 1 H), 7.51 (d, J = 8.41 Hz, 1 H), 7.32 (d, J = 1.57 Hz, 1 H), 7.06 (dd, J = 6.46 Hz, 2.15 Hz, 1 H), 6.92 (d, J = 2.35 Hz, 1 H), 4.24 (d, J = 13.11 Hz, 2H), 2.98-2.84 (m, 3H), 2.00 (d, J = 12.72 Hz, 2H), 1.69-1.55 (m, 2H), 1.50 (s, 9H). F. 5-Chloro-3-piperidin-4-yl-1 H-indole. 4-(5-Chloro-1 H-indol-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester (3.4 g, 10.2 mmol) was set stirring in 1 :1 TFA/CH 2 CI 2 . After 45 min the mixture was evaporated and the golden oil brought up in Et 2 0. A solid formed and was filtered, washed with Et 2 0 and air dried to give 3.5 g (97%) of a white solid as a TFA salt. MS (electrospray): exact mass calculated for C 12 H 15 CIN 2 , 234.09; m/z found, 235.1 [M + +H]. G. 1 - r 4-(5-Chloro-1 H-indol-3-yl)-piperidin-1 -yl1-3- r 5-methanesulfonyl-3-(4- trifluoromethyl-phenvπ-4.5.6.7-tetrahvdro-pyrazolor4.3-clpyridin-1-yl1-propan-2- 5-Chloro-3-piperidin-4-yl-1H-indole (350 mg, 1.00 mmol) and 5-methane- sulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1 H- pyrazolo[4,3-c]pyridine (401 mg, 1.00 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 CI 2 and washed with water. The organics were dried over Na 2 S0 4 and concentrated. Column chromatography (silica, 0-10% MeOH/CH 2 CI 2 ) provided 551 mg (88%) of a white solid. TLC (silica, 10% MeOH/CH 2 CI 2 ): R f = 0.8. MS (electrospray): exact mass calculated for C 30 H 33 CIF 3 N 5 O 3 S, 635.19; m/z found, 636.2 [M + +H]. 1 H NMR (CDCI 3 , 400 MHz): 8.82 (br s, 1 H), 7.68 (d, J = 8.41 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.54 (br s, 1 H), 7.16 (d, J = 8.41 Hz, 1 H), 7.03 (dd, J = 7.0 Hz, 1.6 Hz, 1H), 6.85 (br s, 1H), 4.43 (dd, J = 25.2 Hz, 14.6 Hz, 2H), 4.30-4.05 (m, 3H), 4.00-3.88 (m, 1 H), 3.62-3.50 (m, 1H), 3.47-3.35 (m, 1 H), 3.02-2.89 (m, 2H), 2.88-2.81 (m, 2H), 2.79 (s, 3H), 2.72-2.60 (m, 1 H), 2.47-2.28 (m, 3H), 2.12-2.00 (m, 1 H), 1.96-1.85 (m, 2H), 1.74-1.50 (m, 2H). EXAMPLE 2 1 -[4-(7-Chloro-1 H-indol-3-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-(7-Chloro-1 H-indol-3-yl)-3.6-dihvdro-2H-pyridine-1 -carboxylic acid tert- butyl ester. 7-Chloro-1H-indole (3.2g, 20 mmol), 4-oxo-piperidine-1 -carboxylic acid tert- butyl ester (7.97 g, 40 mmol) and potassium hydroxide (4.5 g, 80 mmol) were added in MeOH (40 mL) and heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (200 mL). The mixture was extracted with 10% MeOH/CH 2 CI 2 (5 x 100 mL). The organic extracts was dried over Na 2 S0 4 and concentrated to form a solid. The solid was washed with MeOH (100 mL), filtered and dried to give a light yellow solid 6.3 g (94%). TLC (silica, 5% MeOH/CH 2 CI 2 ): R f = 0.8. MS (electrospray): exact mass calculated for C 18 H 21 CIN 2 0 2 , 332.12; m/z found, 355.0 [M + +Na]. 1 H NMR (CDCI 3 , 400 MHz): 8.26 (br s, 1 H), 7.83 (d, J = 1.76 Hz, 1 H), 7.28 (d, J = 8.80 Hz, 1 H), 7.19-7.14 (m, 2H), 6.09 (br s, 1 H), 4.15-4.10 (m, 2H), 3.66 (t, J = 5.67 Hz, 2H), 2.56-2.49 (m, 2H), 1.50 (s, 9H). B. 4-(7-Chloro-1 H-indol-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester. 4-(7-Chloro-1 H-indol-3-yl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid tert-butyl ester (6.3 g, 18.9 mmol) in EtOH (125 mL) containing Pt0 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 white solid 6.0 g (94%). TLC (silica, 5% MeOH/CH 2 CI 2 ): R f = 0.8. MS (electrospray): exact mass calculated for C 18 H 23 CIN 2 0 2 , 334.14; m/z found, 335.1 [M + +H]. Η NMR (CDCI 3 , 400 MHz): 8.46 (br s, 1 H), 7.51 (d, J = 8.41 Hz, 1 H), 7.32 (d, J = 1.57 Hz, 1 H), 7.06 (dd, J = 6.46 Hz, 2.15 Hz, 1 H), 6.92 (d, J = 2.35 Hz, 1 H), 4.24 (d, J = 13.11 Hz, 2H), 2.98-2.84 (m, 3H), 2.00 (d, J = 12.72 Hz, 2H), 1.69-1.55 (m, 2H), 1.50 (s, 9H). C. 7-Chloro-3-piperidin-4-yl-1 H-indole. 4-(7-Chloro-1 H-indol-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester (3.4 g, 10.2 mmol) was set stirring in 1 :1 TFA/CH 2 CI 2 . After 45 min the mixture was evaporated and the golden oil brought up in Et 2 0. A solid formed and was filtered, washed with Et 2 0 and air dried to give 3.5 g (97%) of a white solid. MS (electrospray): exact mass calculated for C 12 H 15 CIN 2 , 234.09; m/z found, 235.1 [M + +H]. P. 1 -r4-(7-Chloro-1 H-indol-3-vn-piperidin-1 -yl]-3-[5-methanesulfonyl-3-(4- trifluoromethyl-phenyl)-4.5.6.7-tetrahvdro-pyrazolo[4.3-c]pyridin-1-yl]-propan-2- 7-Chloro-3-piperidin-4-yl-1H-indole (341 mg, 0.97 mmol) and 5-methane- sulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1 H- pyrazolo[4,3-c]pyridine (130 mg, 0.32 mmol) were set stirring in EtOH (15 mL) containing Et 3 N (135 μL, 0.97 mmol) at 80 °C. After 16 h the mixture was cooled, evaporated, brought up in CH 2 CI 2 and washed with water. The organics were dried over Na 2 S0 4 and concentrated. Column chromatography (silica, 0-10% MeOH/CH 2 CI 2 ) gave 120 mg (65%) of a white solid. TLC (silica, 10% MeOH/CH 2 CI 2 ): R f = 0.7. MS (electrospray): exact mass calculated for C 30 H 33 CIF 3 N 5 O 3 S, 635.19; m/z found, 636.2 [M + +H]. Η NMR (CDCI 3 , 400 MHz): 8.55 (br s, 1 H), 7.70 (d, J = 8.22 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 9.4 Hz, 1 H), 7.14 (d, J = 7.8 Hz, 1 H), 7.00 (t, J = 8.02 Hz, 1 H), 6.94 (br s, 1 H), 4.51 (dd, J = 12.5 Hz, 14.5 Hz, 2H), 4.25-4.11 (m, 3H), 4.07-3.95 (m, 1 H), 3.73-3.61 (m, 1 H), 3.61-3.50 (m, 1 H), 3.11-2.98 (m, 2H), 2.88-2.85 (m, 2H), 2.83 (s, 3H), 2.82-2.72 (m, 1 H), 2.55-2.38 (m, 3H), 2.24-2.10 (m, 1 H), 2.05-1.90 (m, 2H), 1.82-1.61 (m, 2H). EXAMPLE 3 1 -[4-(5-Chloro-2-methyl-1 H-indol-3-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-(5-Chloro-2-methyl-1 H-indol-3-ylV3.6-dihvdro-2H-pyridine-1 -carboxylic acid tert-butyl ester. 5-Chloro-2-methyl-1 H-indole (3.3 g, 20 mmol), 4-oxo-piperidine-1 -carboxylic acid tert-butyl ester (7.97 g, 40 mmol) and potassium hydroxide (4.5 g, 80 mmol) were added in MeOH (40 mL) and heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (200 mL). The mixture was extracted with 10% MeOH/CH 2 CI 2 (5 x 100 mL). The organic extracts was dried over Na 2 S0 4 and concentrated to form a solid. The solid was washed with MeOH (100 mL), filtered and dried to give a light yellow solid 6.2 g (90%). TLC (silica, 5% MeOH/CH 2 CI 2 ): R, = 0.8. MS (electrospray): exact mass calculated for C 19 H 23 CIN 2 0 2 , 346.14; m/z found, 347.1 [M + +H]. B. 4-(5-Chloro-2-methyl-1 H-indol-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester. 4-(5-Chloro-2-methyl-1 H-indol-3-yl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid tert-butyl ester (6.2 g, 17.9 mmol) in EtOH (125 mL) containing Pt0 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 white solid 6.2 g (99%). TLC (silica, 5% MeOH/CH 2 CI 2 ): R f = 0.8. MS (electrospray): exact mass calculated for C 19 H 25 CIN 2 0 2 , 348.16; m/z found, 349.1 [M + +H]. C. 5-Chloro-2-methyl-3-piperidin-4-yl-1 H-indole. 4-(5-Chloro-2-methyl-1 H-indol-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester (6.2 g, 107.8 mmol) was set stirring in 1 :1 TFA/CH 2 CI 2 . After 45 min the mixture was evaporated and the golden oil brought up in Et 2 0. A solid formed and was filtered, washed with Et 2 0 and air dried to give 6.2 g (95%) of a white solid as a TFA salt. MS (electrospray): exact mass calculated for C 14 H 17 CIN 2 , 248.11 ; m/z found, 249.1 [M + +H]. P. 1 -[4-(5-Chloro-2-methyl-1 H-indol-3-vπ-piperidin-1 -vn-3-r5-methanesulfonyl- 3-(4-trifluoromethyl-phenyl)-4.5.6.7-tetrahydro-pyrazolof4.3-c " |pyridin-1-yl]- propan-2-ol. 5-Chloro-2-methyl-3-piperidin-4-yl-1 H-indole (480 mg, 1.32 mmol) and 5- methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7- tetrahydro-1 H-pyrazolo[4,3-c]pyridine (177 mg, 0.44 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 CI 2 and washed with water. The organics were dried over Na 2 S0 4 and concentrated. Column chromatography (silica, 0-10% MeOH/CH 2 CI 2 ) gave 169 mg (62%) of a white solid. TLC (silica, 10% MeOH/CH 2 CI 2 ): R f = 0.6. MS (electrospray): exact mass calculated for C 31 H 35 CIF 3 Ng0 3 S, 649.21 ; m/z found, 650.2 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz): 8.00 (s, 1 H), 7.70 (d, J = 8.11 Hz, 2H), 7.64 (d, J = 8.41 Hz, 2H), 7.57 (d, J = 1.96 Hz, 1 H), 7.12 (d, J = 8.61 Hz, 1 H), 6.99 (dd, J = 6.85 Hz, 1.96 Hz, 1 H), 4.53 (dd, J = 14.28 Hz, 12.91 Hz, 2H), 4.26-4.14 (m, 2H), 4.09-3.99 (m, 1H), 3.75-3.65 (m, 1 H), 3.64-3.54 (m, 1 H), 3.14-3.02(m, 2H), 3.00-2.89 (m, 2H), 2.86 (s, 3H), 2.76-2.63 (m, 1 H), 2.54-2.45 (m, 2H), 2.45-2.36 (m, 1 H), 2.34 (s, 3H), 2.25-2.00 (m, 3H), 1.77-1.63 (m, 2H). EXAMPLE 4 1 -{4-[6-Chloro-1 -(2-morpholin-4-yl-ethyl)-1 H-indol-3-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. 6-Chloro-3-piperidin-4-yl-1 H-indole. 6-Chloro-1 H-indole (3.2g, 20 mmol), piperidin-4-one monohydrate (6.1 g, 40 mmol) and potassium hydroxide (4.5 g, 80 mmol) were added in MeOH (40 mL) and heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (200 mL). The mixture was extracted with 10% MeOH/CH 2 CI 2 (5 x 100 mL). The organic extracts were dried over Na 2 S0 4 and concentrated. Column chromatography (silica, 20- 100% MeOH/CH 2 CI 2 with 2% NH 4 OH) to obtain 5.8 9 (100%) of a yellow solid. The solid (5.8 g, 20 mmol) in EtOH (150 mL) containing Pt0 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 an off white solid 4.6 g (97%). MS (electrospray): exact mass calculated for C 13 H 15 CIN 2 , 234.09; m/z found, 235.0 [M + +H]. B. 4-(6-Chloro-1 H-indol-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester. To a solution of 6-chloro-3-piperidin-4-yl-1 H-indole (4.6 g, 19.5 mmol) in DMF (20 mL) was added di-tert-butyl dicarbonate (4.6 g, 21.4 mmol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was dissolved in EtOAc (400 mL), washed with water (3 x 50 mL), brine (1 x 50 mL). The organic layer was dried over Na 2 S0 4 and concentrated. Column chromatography (silica, 20-50% EtOAc/hexanes) gave 4.2 g (64%) of the desired product. TLC (silica, 20% EtOAc/hexanes): R f = 0.24. MS (electrospray): exact mass calculated for C 18 H 23 CIN 2 0 2 , 334.14; m/z found, 335.1 [M + +H]. 1 H NMR (CDCI 3 , 400 MHz) 8.46 (br s, 1 H), 7.42 (d, J = 8.61 Hz, 1 H), 7.14 (d, J = 1.57 Hz, 1 H), 6.96 (dd, J = 6.65 Hz, 1.76 Hz, 1 H), 6.74 (s, 1 H), 4.14 (br s, 2H), 2.89-2.70 (m, 3H), 1.90 (d, J = 12.13, 2H), 1.65-1.50 (m, 2H), 1.41 (s, 9H). C. 4-r6-Chloro-1 -(2-morpholin-4-yl-ethvD-1 H-indol-3-yl1-piperidine-1 -carboxylic acid tert-butyl ester. 4-(6-Chloro-1 H-indol-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester (2.0 g, 5.95 mmol) was dissolved in THF (30 mL). At 0 °C, potassium bis(trimethylsilyl)amide (2.37 g, 11.9 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. 4-(2-Chloro-ethyl)-morpholine hydrochloride (1.8 g, 11.9 mmol) was added and stirred at room temperature for an additional 1 h. The mixture was dissolved in EtOAC (250 mL) and washed with water (2 x 30 mL) and brine (30 mL). The organics were dried over Na 2 S0 4 and concentrated. Column chromatography (silica, 0-5% MeOH/CH 2 CI 2 ) provided 2.6 g (97%) of a white solid. TLC (silica, 5% MeOH/CH 2 CI 2 ): R f = 0.67. MS (electrospray): exact mass calculated for C 24 H 34 CIN 3 0 3 , 447.23; m/z found, 448.2 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz): 7.45 (d, J = 8.61 Hz, 1 H), 7.27 (d, J = 1.57 Hz, 1 H), 6.99 (dd, J = 6.65 Hz, 1.76 Hz, 1 H), 6.84 (s, 1 H), 4.18 (br s, 2H), 4.06 (t, J = 6.85 Hz, 2H), 3.69-3.60 (m, 4H), 2.92-2.80 (m, 2H), 2.69-2.60 (m, 3H), 2.44 (t, J = 4.89 Hz, 2H), 2.40 (t, J = 4.30 Hz, 2H), 1.94 (d, J = 12.13, 2H), 1.65-1.50 (m, 2H), 1.45 (s, 9H). P. 6-Chloro-1 -(2-morpholin-4-yl-ethvπ-3-piperidin-4-yl-1 H-indole. 4-[6-Chloro-1-(2-morpholin-4-yl-ethyl)-1 H-indol-3-yl]-piperidine-1 -carboxylic acid tert-butyl ester (2.6 g, 5.81 mmol) was set stirring in 1 :1 TFA/CH 2 CI 2 . After 45 min the mixture was evaporated and the golden oil brought up in Et 2 0. A solid formed and was filtered, washed with Et 2 0 and air dried to give 2.5 g (95%) of a white solid. MS (electrospray): exact mass calculated for C 19 H 26 CIN 3 0, 347.18; m/z found, 348.2 [M + +H]. E. 1 -(4-r6-Chloro-1 -(2-morpholin-4-yl-ethvn-1 H-indol-3-yll-piperidin-1 -yl}-3-[5- methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4.5,6.7-tetrahvdro-pyrazolo[4.3- c]pyridin-1 -yll-propan-2-ol. 6-Chloro-1-(2-morpholin-4-yl-ethyl)-3-piperidin-4-yl-1 H-indole (209 mg, 0.6 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)- 4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridine (120 mg, 0.3 mmol) were set stirring in EtOH (20 mL) containing Et 3 N (84 μL, 0.6 mmol) at 80 °C. After 16 h the mixture was cooled, evaporated, brought up in CH 2 CI 2 and washed with water. The organics were dried over Na 2 S0 4 and concentrated. Column chromatography (silica, 0-10% MeOH/CH 2 CI 2 ) provided 180 mg (85%) of a white solid. TLC (silica, 10% MeOH/CH 2 CI 2 ): R f = 0.54. MS (electrospray): exact mass calculated for C 36 H 44 CIF 3 N 6 0 4 S, 748.28; m/z found, 749.3 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz): 7.70 (d, J = 8.61 Hz, 2H), 7.64 (d, J = 8.261 Hz, 2H), 7.47 (d, J = 8.80 Hz, 1 H), 7.29 (d, J = 1.96, 1 H), 7.02 (dd, J = 6.46 Hz, 1.76 Hz, 1 H), 6.81 (br s, 1 H), 4.54 (dd, J = 4.09 Hz, 7.43 Hz, 2H), 4.24-4.14 (m, 2H), 4.14-4.08 (m, 2H), 4.06-3.98 (m, 1 H), 3.73-3.57 (m, 5H), 3.12-3.02 (m, 2H), 2.97-2.87 (m, 2H), 2.86 (s, 3H), 2.83-2.74 (m, 1H), 2.70-2.64 (t, J = 7.24 Hz, 2H), 2.54-2.42 (m, 8H), 2.23-2.14 (m, 1 H), 2.05-1.96 (m, 2H), 1.82-1.60 (m, 2H). EXAMPLE 5 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(1 H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1 -yl]- propan-2-ol. A. 4-f 1 H-Pyrrolo[3.2-clpyridin-3-v0-3.6-dihvdro-2H-pyridine-1 -carboxylic acid tert-butyl ester. A solution of 1.9 g (8.47 mmol) of 1 H-pyrrolo[3,2-c]pyridine (synthesized following the procedure described in Synthesis, 1996, 882), 4-oxo-piperidine-1- carboxylic acid tert-butyl ester (3.4 g, 16.9 mmol) and potassium hydroxide (1.9 g, 33.9 mmol) in MeOH (20 mL) was heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (100 mL). The mixture was extracted with 10% MeOH/CH 2 CI 2 (5 x 50 mL). The organic extracts was dried over Na 2 S0 4 and concentrated to form a solid. The solid was washed with MeOH (50 mL), filtered and dried to give a light yellow solid 2.0 g (79%). TLC (silica, 10% MeOH/CH 2 CI 2 ): R f = 0.5. MS (electrospray): exact mass calculated for C 17 H 21 N 3 0 2 , 299.16; m/z found, 300.1 [M + +H]. 1 H NMR (COCIg, 400 MHz): 12.26 (br s, 1 H), 9.20 (s, 1 H), 8.28 (d, J = 5.67 Hz, 1 H), 7.35 (dd, J = 5.09 Hz, 0.78 Hz, 1 H), 7.32 (s, 1 H), 6.19 (br s, 1 H), 4.14 (br s, 2H), 3.68 (t, J = 5.67 Hz, 2H), 2.61-2.55 (m, 2H), 1.48 (s, 9H). B. 4-f 1 H-Pyrrolor3.2-clpyridin-3-vπ-piperidine-1 -carboxylic acid tert-butyl ester. 4-(1 H-Pyrrolo[3,2-c]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid tert- butyl ester (2 g, 6.6 mmol) in EtOH (50 mL) containing Pt0 2 (500 mg) 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 white solid (2.0 g, 100%). TLC (silica, 10% MeOH/CH 2 CI 2 ): R f = 0.49. MS (electrospray): exact mass calculated for C 17 H 23 N 3 0 22 , 301.18; m/z found, 302.2 [M + +H]. 1 H NMR (COCI 3 , 400 MHz): 13.66 (br s, 1 H), 8.88 (s, 1 H), 8.79 (d, J = 6.46 Hz, 1 H), 7.69 (d, J - 6.46 Hz, 1 H), 7.30 (s, 1 H), 4.14 (br s, 2H), 2.99-2.87 (m, 1 H), 2.86-2.71 (m, 2H), 1.91 (d, J = 11.54 Hz, 2H), 1.64-1.50 (m, 2H), 1.38 (s, 9H). C. 3-Pi perid i n-4-yl- 1 H-pyrrolof3,2-c|pyridine. 4-(1 H-Pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester (2.0 g, 6.6 mmol) was set stirring in 1 :1 TFA/CH 2 CI 2 . After 45 min the mixture was evaporated and the golden oil brought up in Et 2 0. A solid formed and was filtered, washed with Et 2 0 and air dried to give 2.1 g (100%) of a white solid as a TFA salt. MS (electrospray): exact mass calculated for C 12 H 15 N 3 , 201.13; m/z found, 202.1 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz): 9.4 (br s, 1 H), 8.96 (s, 1 H), 8.26 (d, J - 5.87 Hz, 1 H), 7.24 (s, 1 H), 6.99 (s, 1 H), 3.22-3.16 (m, 2H), 3.05- 2.95 (m, 1H), 2.86-2.77 (m, 2H), 2.05 (d, J = 12.72 Hz, 2H), 1.89 (br s, 1 H), 1.75-1.63 (m, 2H). P. 1-| ' 5-Methanesulfonyl-3-f4-trifluoromethyl-phenyl)-4.5.6.7-tetrahvdro- pyrazolor4.3-clpyridin-1-yl1-3-f4-(1 H-pyrrolor3.2-clpyridin-3-yl)-piperidin-1-yl1- propan-2-ol. 3-Piperidin-4-yl-1 H-pyrrolo[3,2-c]pyridine (159 mg, 0.5 mmol) and 5- methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7- tetrahydro-1 H-pyrazolo[4,3-c]pyridine (200 mg, 0.5 mmol) were set stirring in EtOH (10 mL) containing Et 3 N (112 μL, 0.77 mmol) at 80 °C. After 16 h the mixture was cooled, evaporated, brought up in CH 2 CI 2 and washed with water. The organics were dried over Na 2 S0 4 and concentrated. Column chromatography (silica, 0-10% (2 N NH 3 in MeOH)/CH 2 CI 2 ) provided 82 mg (27%) of a white solid. TLC (silica, 10% MeOH/CH 2 CI 2 ): R, = 0.8. MS (electrospray): exact mass calculated for C 29 H 33 F 3 N 6 0 3 S, 602.23; m/z found, 603.2 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz): 9.62 (s, 1H), 8.90 (s, 1H), 8.21 (d, J = 5.87 Hz, 1 H), 7.69 (d, J = 7.83 Hz, 2H), 7.62 (d, J = 8.41 Hz, 2H), 7.23 (d, J = 5.87, 1 H), 6.97 (s, 1 H), 4.51 (dd, J = 14.48 Hz, 8.80 Hz, 2H), 4.23-4.13 (m, 2H), 4.05-3.95 (m, 1 H), 3.72-3.54 (m, 3H), 3.11-2.98 (m, 2H), 2.95-2.86 (m, 2H), 2.84 (s, 3H), 2.51-2.39 (m, 3H), 2.20-2.11 (m, 1 H), 2.07-1.97 (m, 2H), 1.85-1.63 (m, 2H). EXAMPLE 6 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1 -yl]- propan-2-ol. A. 4-f 1 H-Pyrrolof2.3-blpyridin-3-ylY-3.6-dihvdro-2H-pyridine-1 -carboxylic acid tert-butyl ester. 1 H-Pyrrolo[2,3-b]pyridine (3 g, 25 mmol), 4-oxo-piperidine-1 -carboxylic acid tert-butyl ester (4.2 g, 21 mmol) and potassium hydroxide (3.56 g, 63 mmol) were added in MeOH (60 mL) and heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (300 mL). The mixture was extracted with 10% MeOH/CH 2 CI 2 (5 x 150 mL). The organic extracts was dried over Na 2 S0 4 and concentrated to form a solid. The solid was washed with MeOH (150 mL), filtered and dried to give a light yellow solid 5.7 g (91 %). TLC (silica, 50% EtOAc/hexanes): R f = 0.3. MS (electrospray): exact mass calculated for C 17 H 21 N 3 0 2 , 299.16; m/z found, 300.2 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz) 10.97 (br s, 1 H), 8.33 (dd, J = 3.33 Hz, 1.37 Hz, 1 H), 8.20 (dd, J = 6.65 Hz, 1.37 Hz, 1 H), 7.34 (br s, 1 H), 7.25 (s, 1 H), 7.13 (dd, J = 4.89 Hz, 3.13 Hz, 1 H), 4.14 (br s, 2H), 3.68 (t, J = 5.28 Hz, 2H), 2.56 (br s, 2H), 1.49 (s, 9H). B. 4-f 1 H-Pyrrolo[ " 2.3-b " |pyridin-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester. 4-(1 H-Pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid tert- butyl ester (1 g, 3.3 mmol) in EtOH (25 mL) containing Pt0 2 (250 mg) was placed on a Parr hydrogenator at 60 psi H 2 . After 18 h the mixture was filtered through celite and evaporated to give 0.96 g (97%) of a white solid. TLC (silica, 50%o EtOAc/hexanes): R f = 0.5. MS (electrospray): exact mass calculated for C 17 H 23 N 3 0 22 , 301.18; m/z found, 302.2 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz) 10.95 (br s, 1 H), 8.26 (dd, J = 3.33 Hz, 1.37 Hz, 1 H), 7.96 (dd, J = 6.26 Hz, 1.57 Hz, 1 H), 7.11 (s, 1 H), 7.05 (dd, J = 4.89 Hz, 3.13 Hz, 1 H), 4.22 (br s, 2H), 3.00-2.79 (m, 3H), 1.99 (d, J = 13.89 Hz, 2H), 1.74-1.60 (m, 2H), 1.47 (s, 9H). C. 3-Piperidin-4-yl-1 H-pyrrolo[2.3-b]pyridine. 4-(1 H-Pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester (963 mg, 3.2 mmol) was set stirring in 1 :1 TFA CH 2 CI 2 . After 45 min the mixture was evaporated and the golden oil brought up in Et 2 0. A solid formed and was filtered, washed with Et 2 0 and air dried to give 974 mg (96%) of a white solid as a TFA salt. MS (electrospray): exact mass calculated for C 12 H 15 N 3 , 201.13; m/z found, 202.1 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz): 8.09 (dd, J = 3.33 Hz, 1.57 Hz, 1 H), 7.89 (dd, J = 6.26 Hz, 1.57 Hz, 1 H), 7.01 (s, 1 H), 6.99 (dd, J = 4.89 Hz, 3.13 Hz, 1 H), 5.04 (br s, 2H), 3.11-3.04 (m, 2H), 2.88-2.79 (m, 1 H), 2.73-2.64 (m, 2H), 1.94 (d, J = 12.52 Hz, 2H), 1.65-1.63 (m, 2H). P. 1-f5-Methanesulfonyl-3-f4-trifluoromethyl-phenylV4.5.6.7-tetrahvdro- pyrazolor4.3-clpyridin-1 -vπ-3-l4-( 1 H-pyrrolo^.S-blpyridin-S-vO-piperidin-l -yl " |- propan-2-ol. 3-Piperidin-4-yl-1 H-pyrrolo[2,3-b]pyridine (443 mg, 1.4 mmol) and 5- methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4, 5,6,7- tetrahydro-1 H-pyrazolo[4,3-c]pyridine (289 mg, 0.7 mmol) were set stirring in EtOH (10 mL) containing Et 3 N (146 μL, mmol) at 80 °C. After 16 h the mixture was cooled, evaporated, brought up in CH 2 CI 2 and washed with water. The organics were dried over Na 2 S0 4 and concentrated. Column chromatography (silica, 0-10% (2 N NH 3 in MeOH)/CH 2 CI 2 ) provided 107 mg (25%) of a white solid. TLC (silica, 10% MeOH/CH 2 CI 2 ): R f = 0.45. MS (electrospray): exact mass calculated for C 29 H 33 F 3 N 6 0 3 S, 602.23; m/z found, 603.3 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz): 10.6 (br s, 1 H), 8.24 (m, 1 H), 7.91 (m, 1 H), 7.70 (m, 2H), 7.63 (m, 2H), 7.05 (br s, 1 H), 7.02 (m, 1 H), 4.52 (dd, J = 4.28 Hz, 9.78 Hz, 2H), 4.24-4.16 (m, 2H), 4.06-3.98 (m, 1 H), 3.72-3.64 (m, 1 H), 3.64-3.55 (m, 1 H), 3.11-3.00 (m, 2H), 2.96-2.87 (m, 2H), 2.85 (s, 3H), 2.82-2.74 (m, 1H), 2.53- 2.40 (m, 3H), 2.22-2.12 (m, 1 H), 2.05-1.95 (m, 2H), 1.85-1.64 (m, 2H). EXAMPLE 7 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-morpholin-4-yl-1 H-pyrrolo[2,3-c]pyridin-3-yl)- piperidin-1-yl]-propan-2-ol. A. [2-(2-Chloro-5-nitro-pyridin-4-yl)-vinyn-dimethyl-amine. A solution of 2-chloro-4-methyl-5-nitro-pyridine (2 g, 11.59 mmol) in PMF (11.6 mL) was treated with 3.08 mL (23.2 mmol, 2 eq) of PMF-dimethylacetal and the reaction mixture was stirred at 100 °C for 4 h. All volatiles were removed under reduced pressure. Column chromatography (silica, 20% EtOAc/hexanes) provided 2.37 g (90%) of [2-(2-chloro-5-nitro-pyridin-4-yl)-vinyl]-dimethyl-amine. TLC (silica, 20% EtOAc/hexanes): R f = 0.30. MS (electrospray): exact mass calculated for C 9 H 10 CIN 3 O 2 , 227.05; m/z found, 228.1 [M+H] + . H NMR (400 MHz, CDCI 3 ): 8.79 (s, 1 H), 8.02 (s, 1 H), 7.35 (d, J = 13 Hz, 1 H), 5.94 (d, J = 13 Hz, 1 H), 2.96 (s, 3H), 2.87 (s, 3H). A solution of 450 mg (2 mmol) of [2-(2-chloro-5-nitro-pyridin-4-yl)-vinyl]- dimethyl-amine in a 20 mL of mixed solvent of MeOH-CH 2 CI 2 (1 :1 ) was treated with 3 mL of morpholine. The reaction mixture was stirred at 65 °C for 8 h. Volatiles were then removed. CH 2 CI 2 (100 mL) and H 2 0 (30 mL) were added. The organic layer was separated and washed with H 2 0 (30 mL), brine (30 mL), dried over Na 2 S0 4 , and concentrated. The red powder was treated with 4.0 g (63 mmol, 32 eq) of ammonium formate and 10% Pd-C (120 mg). The reaction mixture was stirred at 65 °C for 30 min. The reaction mixture was then filtered through a pad of celite and concentrated to obtain a yellow solid. Column chromatography (silica, 5% MeOH/CH 2 CI 2 ) provided 210 mg (52% for 2 steps) of 5-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridine as a yellow solid. TLC (silica, 5% MeOH/CH 2 CI 2 ): R f = 0.40. MS (electrospray): exact mass calculated for C^H^N 203.11 ; m/z found, 204.2 [M+H] + . C. 4-(5-Morpholin-4-yl-1 H-pyrrolo|2,3-c]pyridin-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester. A solution of 200 mg (1.0 mmol) of 5-morpholin-4-yl-1 H-pyrrolo[2,3-c]pyridine and 398 mg (2.0 mmol, 2 eq) of 4-oxo-piperidine-1 -carboxylic acid tert-butyl ester in 5 mL of MeOH was treated with 224 mg (4.0 mmol, 4 eq) of potassium hydroxide. The reaction mixture was stirred at 65 °C for 12 h and volatiles were removed. The crude product was partitioned between CH 2 CI 2 (100 mL) and 20 mL of H 2 0. The organic layer was washed with H 2 0 (2 x 20 mL), dried over Na 2 S0 4 and concentrated. The yellow powder was treated with 630 mg (10 mmol, 10 eq) of ammonium formate and 10% Pd-C (50 mg). The reaction mixture was stirred at 65 °C for 1 h. The reaction mixture was then filtered through a pad of celite and concentrated to obtain a yellow solid. Column chromatography (silica, 5% MeOH/CH 2 CI 2 ) provided 180 mg (47% for 2 steps) of a yellow solid. TLC (silica, 5% MeOH/CH 2 CI 2 ): R f = 0.40. MS (electrospray): exact mass calculated for C 21 H 30 N 4 O 3 , 386.23; m/z found, 387.2 [M+Hf. P. 1 -| " 5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl ' )-4.5.6.7- tetrahvdropyrazolo[4.3-c1pyridin-1-yl1-3-r4-(5-morpholin-4-yl-1 H-pyrrolo[2.3- c]pyridin-3-ylVpiperidin-1-yl1-propan-2-ol. 4-(5-Morpholin-4-yl-1 H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester (180 mg, 0.47 mmol) was dissolved in 3.0 mL of CH 2 CI 2 and treated with 2.5 mL of trifluoroacetic acid. The reaction mixture was stirred at 25 °C for 1 h before all volatiles were removed. The solid was dissolved in MeOH (20 mL) and neutralized with POWEX 550A OH anion exchange resin to pH 8. The resin was then filtered off and MeOH was removed under reduced pressure. The residue was dissolved in 2.5 mL of 'PrOH and treated with 187 mg (0.47 mmol, 1 eq) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4- trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridine. The reaction was stirred at 85 °C for 3 h before solvent was removed. Column chromatography (silica, 5-10% MeOH/CH 2 CI 2 then 5-10% (2 N NH 3 in MeOH)/CH 2 CI 2 ) provided 97 mg (30%) of the title compound. TLC (silica, 5% MeOH/CH 2 CI 2 ): R f = 0.25. MS (electrospray): exact mass calculated for C 33 H 40 F 3 N 7 O 4 S, 687.28; m/z found, 688.3 [M+H] + . 1 H NMR (400 MHz, CPCI 3 ): 8.47 (br s, 1H), 8.44 (d, J = 1.0 Hz, 1H), 7.70 and 7.65 (AB pattern, J = 8.4 Hz, 4H), 7.03 (d, J = 2.1 Hz, 1 H), 6.76 (s, 1 H), 4.58- 4.50 (m, 2H), 4.21-4.00 (m, 3H), 3.90 (t, J = 4.5 Hz, 4H), 3.72-3.58 (m, 2H), 3.40 (t, J = 4.5 Hz, 4H), 3.10- 2.85 (m, 4H), 2.88 (s, 3H), 2.80-2.70 (m, 1H), 2.52-2.41 (m, 3H), 2.20-2.00 (m, 3H), 1.80-1.60 (m, 2H). EXAMPLE 8 1 -[4-(6-Pimethylamino-1 H-pyrrolo[3,2-c]pyridin-3-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. Pimethyl-(5-methyl-4-nitro-1-oxy-pyridin-2-yl)-amine. A solution of 2-bromo-5-methyl-4-nitro-pyridine 1 -oxide (674 mg, 2.78 mmol) in 2 M dimethylamine in methanol (20 mL) was heated at 65 °C for 16 h. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica, 30-80% EtOAc/hexanes) to obtain 290 mg (53%) of the desired product. TLC (silica, 50% EtOAc/hexanes): R f = 0.10. MS (electrospray): exact mass calculated for 197.08; m/z found, 198.1 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz): 8.04 (s, 1 H), 7.50 (s, 1 H), 3.00 (s, 6H), 2.44 (s, 3H). B. Pimethyl-f 1 H-pyrrolo[3.2-c1pyridin-6-yl)-amine. A solution of dimethyl-(5-methyl-4-nitro-1-oxy-pyridin-2-yl)-amine (290 mg, 1.47 mmol) in PMF (3 mL) was treated with PMF-dimethylacetal (390 μL, 2.94 mmol) and the reaction mixture was stirred at 100 °C for 4 h. All volatiles were removed under reduced pressure. The red powder was treated with ammonium formate (927 mg, 14.7 mmol) and 10% Pd-C (156 mg). The reaction mixture was stirred at 65 °C for 30 min. The reaction mixture was then filtered through a pad of celite and concentrated to obtain a yellow solid. Column chromatography (silica, 5% MeOH/CH 2 CI 2 ) provided 100 mg (42% for two steps) of product as a yellow solid. TLC (silica, 10% MeOH/CH 2 CI 2 ): R f = 0.2. MS (electrospray): exact mass calculated for 161.10; m/z found, 162.1 [M + +H]. Η NMR (CPCI 3 , 400 MHz): 8.55 (s, 1H), 8.28 (br s, 1H), 6.96 (dd, J = 1.96 Hz, 1.37 Hz, 1 H), 6.45-6.43 (m, 1 H), 6.39 (s, 1 H), 3.08 (s, 6H). C. 4-(6-Pimethylamino-1 H-Pyrrolor3.2-c1pyridin-3-yl)-3.6-dihvdro-2H-Pyridine- 1 -carboxylic acid tert-butyl ester. Pimethyl-(1H-pyrroio[3,2-c]pyridin-6-yl)-amine (100 mg, 0.62 mmol), 4-oxo- piperidine-1 -carboxylic acid tert-butyl ester (248 mg, 1.24 mmol) and potassium hydroxide (139 mg, 2.48 mmol) were added in MeOH (5 mL) and heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (20 mL). The mixture was extracted with 10% MeOH/CH 2 CI 2 (5 x 10 mL). The organic extracts was dried over Na 2 S0 4 and concentrated. The residue was purified by column chromatography (silica, 0- 5% MeOH/CH 2 CI 2 ) to obtain 180 mg (85%) of the title compound. TLC (silica, 10% MeOH/CH 2 CI 2 ): R f = 0.58. MS (electrospray): exact mass calculated for C 19 H 26 N 4 0 2 , 342.21 ; m/z found, 343.2 (M + +H). 1 H NMR (CPCI 3 , 400 MHz): 9.09 (br s, 1 H), 8.76 (s, 1 H), 6.90 (d, J = 2.15 Hz, 1 H), 6.32 (s, 1 H), 6.10 (br s, 1 H), 4.10-4.05 (m, 2H), 3.62 (t, J = 5.87 Hz, 2H), 3.03 (s, 6H), 2.52-2.44 (m, 2H), 1.46 (s, 9H). P. 4-(6-Pimethylamino-1 H-Pyrrolof3.2-c1pyridin-3-ylVpiperidine-1 -carboxylic acid tert-butyl ester. A solution of 4-(6-dimethylamino-1 H-pyrrolo[3,2-c]pyridin-3-yl)-3,6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester (180 mg, 0.53 mmol) in MeOH (10 mL) was treated with ammonium formate (332 mg, 5.3 mmol) and 10% Pd-C (56 mg). The reaction mixture was stirred at 65 °C for 1 h. The reaction mixture was then filtered through a pad of celite and concentrated to obtain an off white solid. Column chromatography (silica, 0-5% MeOH/CH 2 CI 2 ) provided 135 mg (75%) of product as a white solid. TLC (silica, 10% MeOH/CH 2 CI 2 ): R f = 0.50. MS (electrospray): exact mass calculated for C 19 H 28 N 4 0 2 , 344.22; m/z found, 345.2 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz): 8.53 (s, 1 H), 8.30 (br s, 1 H), 6.67 (dd, J = 1.17 Hz, 0.78 Hz, 1 H), 6.34 (d, J = 0.78 Hz, 1 H), 4.33-4.16 (m, 2H), 3.05 (s, 6H), 2.97-2.80 (m, 3H), 1.99 (d, J = 12.72 Hz, 2H), 1.69-1.53 (m, 2H), 1.46 (s, 9H). E. Pimethyl-f3-piperidin-4-yl-1 H-pyrrolor3.2-c]pyridin-6-yl)-amine. The 4-(6-dimethylamino-1 H-pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester (135 mg, 0.39 mmol) was set stirring in 1 :1 TFA/CH 2 CI 2 . After 45 min the mixture was evaporated. The residue was dissolved in MeOH (10 mL) and neutralized with POWEX 550A OH anion exchange resin to pH 8. The resin was then filtered off and MeOH was removed under reduced pressure to give 96 mg (100%) of a yellow solid. MS (electrospray): exact mass calculated for C 14 H 20 N 4 , 244.17; m/z found, 245.2 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz): 9.23 (br s, 1 H), 8.54 (s, 1 H), 6.67 (s, 1 H), 6.31 (d, J = 0.98 Hz, 1 H), 3.15 (d, J = 2.13 Hz, 2H), 3.02 (s, 6H), 2.91-2.81 (m, 1 H), 2.81-2.72 (m, 2H), 2.01 (d, J = 12.52 Hz, 2H), 1.69-1.52 (m, 2H). F. 1 -[4-(6-Pimethylamino-1 H-pyrrolo[3.2-c1pyridin-3-yl)-piperidin-1 -yl]-3-[5- methanesulfonyl-3-(4-trifluoromethyl-phenvπ-4.5.6.7-tetrahvdro-pyrazolo[4.3- clpyridin-1 -yl]-propan-2-ol. Pimethyl-(3-piperidin-4-yl-1 H-pyrrolo[3,2-c]pyridin-6-yl)-amine (96 mg, 0.53 mmol) and 5-methanesulfonyl-1 -oxiranylmethyl-3-(4-trifluoromethyl-phenyl)- 4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridine (319 mg, 0.80 mmol) were set stirring in 'PrOH (10 mL) at 80 °C. After 16 h the mixture was cooled and concentrated. The residue was purified by column chromatography (silica, 0- 10% (2 N NH 3 in MeOH)/CH 2 CI 2 to obtain 61 mg (18%) of a white solid. TLC (silica, 10% MeOH/CH 2 CI 2 ): R f = 0.12. MS (electrospray): exact mass calculated for C 31 H 38 F 7 N 7 0 3 S, 645.27; m/z found, 646.3 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz): 8.53 (s, 1 H), 7.93 (br s, 1 H), 7.71 (d, J = 8.22 Hz, 2H), 7.64 (d, J = 8.22, 2H), . 6.67 (br s, 1 H), 6.33 (d, J = 0.98 Hz, 1H), 4.54 (dd, J = 14.28 Hz, 9.59 Hz, 2H), 4.22-4.10 (m, 2H), 4.04-3.97 (m, 1 H), 3.74-3.57 (m, 2H), 3.13-3.06 (m, 1H), 3.05 (s, 6H), 3.03-2.87 (m, 3H), 2.85 (s, 3H), 2.82-2.71 (m, 1H), 2.50-2.37 (m, 3H), 2.20-2.11 (m, 1H), 2.06-1.97 (m, 2H), 1.82-1.61 (m, 2H). EXAMPLE 9 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(6-morpholin-4-yl-1 H-pyrrolo[3,2-c]pyridin-3-yl)- piperidin-1 -yl]-propan-2-ol. A. 4-f 5-Methyl-4-nitro-1 -oxy-pyridin-2-vπ-morpholine. A solution of 2-bromo-5-methyl-4-nitro-pyridine 1-oxide (500 mg, 2.14 mmol) in morpholine (15 mL) was heated at 70 °C for 16 h. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica, 30-80% EtOAc/hexanes) to obtain 480 mg (94%) of the desired product. TLC (silica, 50% EtOAc/hexanes): R f = 0.10. MS (electrospray): exact mass calculated for C 10 H 13 N 3 O 4 , 239.09; m/z found, 240.1 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz): 8.09 (s, 1 H), 7.55 (s, 1 H), 3.90 (t, J = 4.50 Hz, 4H), 3.36 (t, J = 4.70 Hz, 4H), 2.50 (s, 3H). B. 6-Morpholin-4-yl-1 H-pyrrolor3.2-c1pyridine. A solution of 4-(5-methyl-4-nitro-1-oxy-pyridin-2-yl)-morpholine (480 mg, 2 mmol) in PMF (5 mL) was treated with PMF-dimethylacetal (533 μL, 4 mmol) and the reaction mixture was stirred at 100 °C for 4 h. All volatiles were removed under reduced pressure. The red powder was treated with ammonium formate (1.26 g, 20 mmol) and 10% Pd-C (212 mg). The reaction mixture was stirred at 65 °C for 30 min. The reaction mixture was then filtered through a pad of celite and concentrated to obtain a yellow solid. Column chromatography (silica, 5% MeOH/CH 2 CI 2 ) provided 197 mg (49% for two steps) of a yellow solid. TLC (silica, 10% MeOH/CH 2 CI 2 ): R f = 0.55. MS (electrospray): exact mass calculated for C^H^NaO, 203.11 ; m/z found, 204.1 [M+H] + . 1 H NMR (CPCI 3 , 400 MHz) 8.68 (br s, 1 H), 8.59 (s, 1 H), 7.04 (dd, J = 2.15 Hz, 1.17 Hz, 1 H), 6.51 (s, 1 H), 6.49-6.47 (m, 1H), 3.86 (t, J = 4.70 Hz, 4H), 3.40 (t, J = 4.70 Hz, 4H). C. 4-f6-Morpholin-4-yl-1 H-Pyrrolor3.2- yridin-3-vπ-3.6-dihvdro-2H-pyridine-1 - carboxylic acid tert-butyl ester. 6-Morpholin-4-yl-1 H-pyrrolo[3,2-c]pyridine (197 mg, 0.97 mmol), 4-oxo- piperidine-1 -carboxylic acid tert-butyl ester (387 mg, 1.94 mmol) and potassium hydroxide (218 mg, 3.88 mmol) were added in MeOH (10 mL) and heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (50 mL). The mixture was extracted with 10% MeOH/CH 2 CI 2 (5 x 20 mL). The organic extracts was dried over Na 2 S0 4 and concentrated. The residue was purified by column chromatography (silica, 0- 5% MeOH/CH 2 CI 2 ) to obtain 337 mg (91 %) of the desired product. TLC (silica, 5% MeOH/CH 2 CI 2 ): R f = 0.50. MS (electrospray): exact mass calculated for C 21 H 28 N 4 0 3 , 384.22; m/z found, 749.3 [M + +H]. Η NMR (CPCI 3 , 400 MHz): 9.24 (br s, 1 H), 8.77 (s, 1 H), 6.95 (d, J = 2.15 Hz, 1 H), 6.45 (s, 1 H), 6.09 (br s, 1 H), 4.09-4.04 (m, 2H), 3.66 (t, J = 6.06 Hz, 4H), 3.60 (t, J = 5.28 Hz, 2H), 3.25 (t, J = 5.09 Hz, 4H), 2.38 (d, J = 6.26 Hz, 2H), 1.44 (s, 9H). P. 4-(6-Morpholin-4-yl-1 H-Pyrrolof3.2-c,pyridin-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester. 4-(6-Morpholin-4-yl-1 H-pyrrolo[3,2-c]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester (337 mg, 0.9 mmol) in MeOH (20 mL) was treated with ammonium formate (568 mg, 9.0 mmol) and 10% Pd-C (95 mg). The reaction mixture was stirred at 65 °C for 1 h. The reaction mixture was then filtered through a pad of celite and concentrated to obtain an off-white solid. Column chromatography (silica, 0-5% MeOH/CH 2 CI 2 ) provided 340 mg (98%) of a white solid. TLC (silica, 5% MeOH/CH 2 CI 2 ): R f = 0.40. MS (electrospray): exact mass calculated for C 21 H 30 N 4 O 3 , 386.23; m/z found, 387.3 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz) 9.14 (br s, 1 H), 8.55 (s, 1 H), 6.74 (d, J = 1.96 Hz, 1 H), 6.45 (s, 1H), 4.27-4.08 (m, 2H), 3.80 (t, J = 4.50 Hz, 4H), 3.34 (t, J = 4.89 Hz, 4H), 2.96-2.77 (m, 3H), 1.97 (d, J = 12.91 Hz, 2H), 1.67-1.52 (m, 2H), 1.44 (s, 9H). E. 6-Morpholin-4-yl-3-piperidin-4-yl-1 H-pyrrolor3.2-clPyridine. 4-(6-Morpholin-4-yl-1 H-pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1 -carboxylic acid tert-butyl ester (380 mg, 0.98 mmol) was set stirring in 1 :1 TFA/CH 2 CI 2 . After 45 min the mixture was evaporated. The residue was dissolved in MeOH (20 mL) and neutralized with POWEX 550A OH anion exchange resin to pH 8. The resin was then filtered off and MeOH was removed under reduced pressure to give 281 mg (100%) of a yellow solid. MS (electrospray): exact mass calculated for C 16 H 22 N 4 0, 286.18; m/z found, 287.1 [M + +H]. F. 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4.5.6.7-tetrahvdro- pyrazolo[4.3-clpyhdin-1-yl1-3-r4-(6-morpholin-4-yl-1 H-pyrrolo[3.2-c]pyridin-3-yl)- piperidin-1 -yl]-propan-2-ol. 6-Morpholin-4-yl-3-piperidin-4-yl-1 H-pyrroIo[3,2-c]pyridine (281 mg, 0.98 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7- tetrahydro-1 H-pyrazolo[4,3-c]pyridine (591 mg, 1.47 mmol) were set stirring in 'PrOH (10 mL) at 80 °C. After 16 h the mixture was cooled and concentrated. The residue was purified by column chromatography (silica, 0-10% (2 N NH 3 in MeOH)/CH 2 CI 2 ) to obtain 468 mg (69%) of a white solid. TLC (silica, 10% (2 N NH 3 in MeOH)/CH 2 CI 2 ): R f = 0.62. MS (electrospray): exact mass calculated for C 33 H 40 F 3 N 7 O 4 S, 687.28; m/z found, 688.3 [M + +H]. 1 H NMR (CPCI 3 , 400 MHz): 8.56 (s, 1 H), 8.40 (br s, 1 H), 7.69 (d, J = 8.41 Hz, 2H), 7.63 (d, J = 8.41 , 2H), 6.73 (br s, 1 H), 6.46 (s, 1 H), 4.51 (dd, J = 14.28 Hz, 8.80 Hz, 2H), 4.21-4.10 (m, 2H), 4.03-3.95 (m, 1 H), 3.82 (t, J = 4.11 Hz, 4H), 3.71-3.54 (m, 2H), 3.36 (t, J = 4.89 Hz, 4H), 3.10-2.97 (m, 2H), 2.93-2.86 (m, 2H), 2.84 (s, 3H), 2.82-2.72 (m, 1 H), 2.50-2.37 (m, 3H), 2.20-2.10 (m, 1 H), 2.04-1.95 (m, 2H), 1.80-1.60 (m, 2H). EXAMPLE 10 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(6-morpholin-4-yl-5-oxy-1 H-pyrrolo[3,2- cJpyridin-3-yl)-piperidin-1-yl]-propan-2-ol. A. 6-Morpholin-4-yl-1H-pyrrolo[ " 3.2-clpyridine 5-oxide. A solution of 4-(5-methyl-4-nitro-1-oxy-pyridin-2-yl)-morpholine (480 mg, 2 mmol) in PMF (5 mL) was treated with PMF-dimethylacetal (533 μL, 4 mmol) and the reaction mixture was stirred at 100 °C for 4 h. All volatiles were removed under reduced pressure. The red powder was treated with ammonium formate (1.26 g, 20 mmol) and 10% Pd-C (212 mg). The reaction mixture was stirred at 65 °C for 30 min. The reaction mixture was then filtered through a pad of celite and concentrated to obtain a yellow solid. Column chromatography (silica, 5% MeOH/CH 2 CI 2 ) provided 130 mg (30% for two steps) of a yellow solid. TLC (silica, 10% MeOH/CH 2 CI 2 ): R f = 0.28. MS (electrospray): exact mass calculated for C^H^N^, 219.10; m/z found, 220.1 [M+H] + . 1 H NMR (CPCI 3 , 400 MHz): 8.42 (br s, 1 H), 7.25 (s, 1 H), 7.14 (s, 1 H), 6.82 (s, 1 H), 6.35 (s, 1 H), 3.79 (t, J = 4.70 Hz, 4H), 3.18 (t, J = 4.70 Hz, 4H). B. 4-f6-Morpholin-4-yl-5-oxy-1H-pyrrolo r 3.2-clPyridin-3-vn-3.6-dihvdro-2H- pyridine-1 -carboxylic acid tert-butyl ester. 6-Morpholin-4-yl-1 H-pyrrolo[3,2-c]pyridine 5-oxide (130 mg, 0.59 mmol), 4-oxo- piperidine-1 -carboxylic acid tert-butyl ester (237 mg, 1.19 mmol) and potassium hydroxide (133 mg, 2.37 mmol) were added in MeOH (8 mL) and heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (30 mL). The mixture was extracted with 10% MeOH/CH 2 CI 2 (5 x 10 mL). The organic extracts was dried over Na 2 S0 4 and concentrated. The residue was purified by column chromatography (silica, 0- 5% MeOH/CH 2 CI 2 ) to obtain 140 mg (59%) of the desired product. TLC (silica, 10% MeOH/CH 2 CI 2 ): R f = 0.55. MS (electrospray): exact mass calculated for C 21 H 28 N 4 0 4 , 400.21 ; m/z found, 401.2 (M + +H). C. 4-(6-Morpholin-4-yl-5-oxy-1 H-pyrrolo[3.2-c]pyridin-3-yl)-piperidine-1 - carboxylic acid tert-butyl ester. 4-(6-Morpholin-4-yl-5-oxy-1 H-pyrrolo[3,2-c]pyridin-3-yl)-3,6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester (140 mg, 0.35 mmol) in EtOH (20 mL) containing Pt0 2 (50 mg) was placed on a Parr hydrogenator at 60 psi H 2 . After 18 h mixture was filtered through celite and evaporated to give a white solid. Column chromatography (silica, 0-5% (2 N NH 3 in MeOH)/CH 2 CI 2 ) provided 56 mg (40%) of a white solid. TLC (silica, 5% MeOH/CH 2 CI 2 ): R, = 0.13. MS (electrospray): exact mass calculated for C 21 H 30 N 4 O 4 , 402.23; m/z found, 403.2 (M + +H). 1 H NMR (CPCI 3 , 400 MHz): 11.63 (br s, 1 H), 8.58 (s, 1 H), 6.97 (br s, 1 H), 6.69 (s, 1 H), 4.26-4.08 (m, 2H), 3.73 (t, J = 4.30 Hz, 4H), 3.17 (t, J = 4.50 Hz, 4H), 2.92-2.74 (m, 3H), 1.91 (d, J = 11.93 Hz, 2H), 1.62-1.50 (m, 2H), 1.43 (s, 9H). P. 6-Morpholin-4-yl-3-piperidin-4-yl-1 H-pyrrolof3.2-c1pyridine 5-oxide. 4-(6-Morpholin-4-yl-5-oxy-1 H-pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (56 mg, 0.14 mmol) was set stirring in 1:1 TFA/CH 2 CI 2 . After 45 min the mixture was evaporated. The residue was dissolved in MeOH (10 mL) and neutralized with POWEX 550A OH anion exchange resin to pH 8. The resin was then filtered off and MeOH was removed under reduced pressure to give 42 mg (100%) of a yellow solid. MS (electrospray): exact mass calculated for C 16 H 22 N 4 0 2 , 302.17; m/z found, 303.1 [M + +H]. E. 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4.5.6.7-tetrahydro- pyrazolo[4.3-c1pyridin-1-yl]-3-[4-(6-morpholin-4-yl-5-oxy-1 H-pyrrolo[3.2- clpyridin-3-yD-piperidin-1-yl]-propan-2-ol. 6-Morpholin-4-yl-3-piperidin-4-yl-1 H-pyrrolo[3,2-c]pyridine 5-oxide (42 mg, 0.14 mmol) and 5-methanesulfonyl-1 -oxiranylmethyl-3-(4-trifluoromethyl-phenyl)- 4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridine (84 mg, 0.21 mmol) were set stirring in 'PrOH (5 mL) at 80 °C. After 6 h the mixture was cooled and concentrated. The residue was purified by column chromatography (silica, 0- 10% (2 N NH 3 in MeOH)/CH 2 CI 2 ) to obtain 5.1 mg (5%) of a white solid. TLC (silica, 10% (2 N NH 3 in MeOH)/CH 2 CI 2 ): R f = 0.54. MS (electrospray): exact mass calculated for C 33 H 40 F 3 N 7 OgS, 703.28; m/z found, 704.3 [M + +H]. 1 H NMR (CDCI 3 , 400 MHz): 8.60 (s, 1 H), 7.71 (d, J = 8.41 Hz, 2H), 7.66 (d, J = 8.41 , 2H), 7.27 (s, 1 H), 6.95 (s, 1 H), 6.70 (s, 1 H), 4.55 (dd, J = 14.48 Hz, 3.13 Hz, 2H), 4.23-4.11 (m, 2H), 4.05-3.97 (m, 1 H), 3.84 (t, J = 4.30 Hz, 4H), 3.72-3.60 (m, 2H), 3.23 (t, J = 4.30 Hz, 4H), 3.12-2.98 (m, 2H), 2.97-2.89 (m, 2H), 2.88 (s, 3H), 2.73-2.63 (m, 1 H), 2.51-2.36 (m, 3H), 2.17-2.08 (m, 1 H), 1.99-1.90 (m, 2H), 1.78-1.58 (m, 2H). EXAMPLE 11 6-Fluoro-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)benzo[b]thiophene- 2-carboxylic acid (2-hydroxy-ethyl)-amide. A. 1 -|4-(2,4-Pifluoro-benzov0-piperidin-1 -yll-ethanone. A stirred solution of 10 g (58.5 mmol) of 1-acetylpiperidine-4-carboxylic acid in anhydrous dichloroethane (35 mL) was treated with 5.1 mL (70.2 mmol) of thionyl chloride in 7 mL of dichloroethane and then heated to 60 °C for 30 min. Another flask containing a suspension of 8.02 mL (81.8 mmol) of 1 ,3- difluorobenzene and 17.9 g (134 mmol) of aluminum chloride in 55 mL of dichloroethane was prepared, to this was added the previously prepared acid chloride suspension in portions. The resulting suspension was refluxed for 4 h, cooled and then poured over ice and HCl. The acidic solution was extracted with CH 2 CI 2 (3 x 300 mL) and the combined organic extracts were washed with brine, dried over Na 2 S0 4 , and concentrated. The crude product was recrystallized from hexanes to afford 9.5 g (61 %) of the desired product as a white solid. MS (electrospray): exact mass calculated for C 14 H 15 F 2 N0 2 , 267.11 ; m/z found, 268.1 [M+H] + , 1 H NMR (CPCI 3 , 400 MHz): 7.87 (dt, J = 8.41 , 6.65 Hz 1 H), 6.98 (m, 1 H), 6.88 (ddd, J = 10.96, 8.61 , 2.35 Hz, 1 H), 4.55 (m, 1 H), 3.87 (m, 1 H), 3.32 (dtt, J = 10.76, 3.91 , 1.37 Hz, 1 H), 3.19 (ddd, J = 13.89, 11.93, 2.93 Hz, 1 H), 2.79 (ddd, J = 13.89, 12.24, 2.93 Hz, 1 H), 2.10 (s, 3H), 1.95 (br d, J = 12.91 Hz, 2H), 1.72 (br m, 1 H), 1.56 (br m, 1 H). B. 3-(1 -Acetyl-piperidin-4-yl)-6-fluoro-benzo[b]thiophene-2-carboxylic acid methyl ester. To a stirred solution of 33.6 g (0.126 mol) of 1-[4-(2,4-difluoro-benzoyl)- piperidin-1-yl]-ethanone and 13 mL (145 mol) of methyl thioglycolate in 320 mL dry THF was added 5.8 g (145 mol) of 60% sodium hydride in mineral oil in portions. The reaction mixture was heated to reflux overnight, allowed to cool to room temperature and the solvent removed under reduced pressure. The residue was then partitioned between 300 mL of CH 2 CI 2 and 200 mL of water. The aqueous layer was further extracted with CH 2 CI 2 (2 x 500 mL). The combined organic layers were washed with brine, dried over Na 2 S0 4 , and concentrated to give a residue which was then triturated with hexanes/EtOAc to give 27.5 g (65%) of the desired product as a white solid. MS (electrospray): exact mass calculated for C 17 H 18 FN0 3 S, 335.1 ; m/z found, 336.1 [M+H] + . 1 H NMR (PMSO-d 6 , 400 MHz, a mixture of amide rotamers): 7.12 (m, 2H), 6.92 (dt, J = 8.41 , 1.77 Hz, 1 H), 4.43 (d, J = 3.79 Hz, 1 H), 4.43-4.36 (m, 1 H), 3.82 (bt, J = 14.65 Hz, 1 H), 3.57 (s, 3H), 2.92-2.79 (m, 1 H), 2.38-2.34 (m, 1 H), 1.94 (s, 1.5H), 1.93 (s, 1.5H), 1.86-1.72 (m, 1 H), 1.47-1.38 (m, 1 H), 1.38-1.27 (m, 0.5H), 1.27-1.16 (m, 1 H), 1.15-1.03 (m, 0.5H). C. 6-Fluoro-3-piperidin-4-yl-benzo[b1thiophene-2-carboxylic acid methyl ester hydrochloride salt. A solution of 24.4 g (66.8 mmol) of 3-(1-acetyl-piperidin-4-yl)-6-fluoro- benzo[b]thiophene-2-carboxylic acid methyl ester in 400 mL of MeOH and 50 mL of concentrated HCl was heated a reflux for 2 days. When the solution was allowed to cool to room temperature the white precipitate was filtered, washed with methanol and dried to give 17.9 g (74%) of product as a white powder. MS (electrospray): exact mass calculated for C 15 H 16 FN0 2 S, 293.09; m/z found, 294.1 [M+H] + . 1 H NMR (PMSO- / 6 , 400 MHz): 9.38 (br s, 1 H), 9.02 (br s, 1 H), 8.60 (dd, J = 9.19, 5.09 Hz, 1H), 7.98 (dd, J = 9.00, 2.54 Hz, 1 H), 7.36 (dt, J = 9.00, 2.54 Hz, 1 H), 4.37 (br t, J = 12.72 Hz, 1 H), 3.87 (s, 3H), 3.40 (br d, J = 11.93 Hz, 2H), 3.02 (q, J = 11.35 Hz, 2H), 2.61 (dq, J = 13.30, 3.72 Hz, 2H), 1.77 (br d, J = 12.91 Hz, 2H). P. 3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4.5.6.7-tetrahydro- pyrazolo[4.3-c1pyridin-1 -yl]-propan-1 -ol. Cs 2 C0 3 (33.74 g, 103.5 mmol) was added to a solution of 5-methanesulfonyl-3- (4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridine (29.8 g, 86.3 mmol) in anhydrous PMF (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 room temperature 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 X 100 mL) and dried. The crude material (31.0 g) was taken up in anhydrous PMF (65 mL) and Cs 2 C0 3 (33.74 g, 103.5 mmol) was added, and stirred for 10 min. Then 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 X 100 mL). The filter cake was dissolved in CH 2 CI 2 (200 mL) and washed with brine (50 mL), dried (Na 2 S0 4 ), and concentrated. The solid was triturated with Et 2 0 (200 mL), filtered, then washed with Et 2 0, 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 (electrospray): exact mass calculated for C 17 H 20 F 3 N 3 O 3 S, 403.12; m/z found, 404.0 [M+H] + . Η NMR (400 MHz, CPCI 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, 1 H), 2.06 (q, J = 6.1 Hz, 2H). E. 3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenvπ-4.5.6.7-tetrahvdro- pyrazolo[4.3-clpyridin-1-yl]-propionaldehvde. Pess-Martin periodinane (3.45 g, 8.2 mmol) was added to a solution of 3-[5- methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-1-yl]-propan-1-ol (3.0 g, 7.4 mmol) in CH 2 CI 2 (20 mL) at 0 °C under N 2 . After 15 min, the reaction was allowed to warm to room temperature and stirred for another 1.5 h. The reaction was diluted with Et 2 0 (60 mL) and 20 % aq. NaHC0 3 (35 mL) was added slowly (caution! rapid gas evolution). Then Na 2 S 2 0 3 was added and stirred at room temperature for 30 min. The layers were separated and the aqueous portion was extracted with Et 2 0 (2x30 mL). The combined organic extracts were washed with brine, dried (Na 2 S0 4 ) and concentrated. MPLC (silica, 1-10% MeOH/CH 2 CI 2 ) afforded 2.53 g of the desired aldehyde in 85% yield. MS (electrospray): exact mass calculated for C 17 H 18 F 3 N 3 0 3 S, 401.11 ; m/z found, 402.1 [M+H]. 1 H NMR (400 MHz, COCI 3 ): 9.82 (s, 1 H), 7.63 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 4.68 (s, 2H), 4.25 (t, J = 6.1 Hz, 2H), 3.63 (t, J = 5.8 Hz, 4H), 3.14 (t, J = 6.1 Hz, 2H), 2.92 (t, J = 5.8 Hz, 2H), 2.81 (s, 3H). F. 6-Fluoro-3-(1-(3-r5-methanesulfonyl-3-f4-trifluoromethyl-phenvn-4.5.6.7- tetrahvdro-pyrazolo[4.3-clpyridin-1-yl1-propyl}-piperidin-4-vπbenzo b1thiophene- 2-carboxylic acid methyl ester. To a stirred solution of 410 mg (1.25 mmol) of 6-fluoro-3-piperidin-4-yl- benzo[b]thiophene-2-carboxylic acid methyl ester hydrochloride salt in 10 mL of dichloromethane and 0.18 mL (1.25 mmol) of triethylamine was added 500 mg of 3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde (1.25 mmol) and 2 g of NaHC0 3 . The mixture was stirred for 4 h before the portion wise addition of 792 mg (3.73 mmol) sodium triacetoxyborohydride. The reaction was stirred at room temperature for 3 h before quenching with 20 mL of water. The aqueous phase was extracted with CH 2 CI 2 (3 x 50 mL). The combined organic layers were then washed with brine, dried over Na 2 S0 4 , and concentrated. The crude product was purified by column chromatography (silica, 0-5% MeOH/CH 2 CI 2 ) to afford 650 mg (77%) of a white solid. MS (electrospray): exact mass calculated for C 32 H 34 F 4 N 4 0 4 S 2 : 678.20; m/z found, 679.2 [M+H] + . 1 H NMR (CDCI 3 , 400 MHz): 7.74 and 7.66 (A and B of AB quartet, J = 8.22 Hz, 4H), 7.50 (dd, J = 8.41 , 2.54 Hz 1 H), 7.14 (t, J = 8.22 Hz, 1 H), 4.56 (s, 2H), 4.17 (m, 3H), 3.91 (s, 3H), 3.70 (t, J = 5.67 Hz, 2H), 3.03 (br m, 2H), 3.00 (t, J = 5.67 Hz, 2H), 2.90 (s, 3H), 2.40 (br m, 4H), 2.13 (br m, 4H), 1.76 (br d, J = 11.15 Hz, 4H). G. 6-Fluoro-3-(1-(3-f5-methanesulfonyl-3-f4-trifluoromethyl-phenvπ-4.5.6.7- tetrahvdro-pyrazolof4.3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)benzo[b1thiophene- 2-carboxylic acid. To a stirred solution of 635 mg (0.94 mmol) of 6-fluoro-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)-benzo[b]thiophene-2-carboxylic acid methyl ester in 10 mL of THF was treated a solution of 53 mg (0.94 mmol) of KOH in 0.5 mL of water. This was stirred overnight, after the hydrolysis was deemed complete 1 mL of 1 N HCl solution was added. This was then extracted with EtOAc (3 x 30 mL). The combined organic layers were then washed with brine, dried over Na 2 S0 4 , and concentrated to yield 622 mg (100%) of a white solid. MS (electrospray): exact mass calculated for C 31 H 32 F 4 N 4 0 4 S 2 : 664.18; m/z found, 665.2 [M+H] + . Η NMR (PMSO-c 6) 400 MHz): 8.12 (dd, J = 8.81 , 5.28 Hz, 1 H), 7.83 and 7.76 (A and B of AB quartet, J = 8.41 Hz, 4H), 7.17 (br t, J = 8.61 Hz, 1 H), 4.47 (s, 2H), 4.29 (br s, 1 H), 4.16 (t, J = 7.04 Hz, 2H), 3.53 (t, J = 5.67 Hz, 2H), 3.28 (br m, 4H), 3.00 (s, 3H), 2.96 (m, 2H), 2.73 (br s, 2H), 2.52 (br m, 2H), 2 .13 (br m, 2H), 1.76 (br m, 2H). H. 6-Fluoro-3-(1-(3-r5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4.5.6.7- tetrahydro-pyrazolor4.3-c1pyridin-1-yl1-propyl}-piperidin-4-yl)benzorblthiophene- 2-carboxylic acid (2-hvdroxy-ethyl)-amide. A stirred solution of 20 mg (0.03 mmol) of 6-fluoro-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)-benzo[b]thiophene-2-carboxylic acid in 0.3 mL of dry PMF was treated with 14 mg (0.036 mmol) of HBTU and 8 μL (0.045 mmol) of PIEA. The solution was stirred for 5 min before the addition of 0.01 mL (0.15 mmol) of ethanol amine. The reaction was stirred at room temperature for 30 min then partitioned between EtOAc (30 mL) and saturated NaHC0 3 (20 mL). The aqueous layer was further extracted with EtOAc (2 x 20 mL). The combined organic layers were then washed with brine, dried over Na 2 S0 4 , and concentrated. Purification by column chromatography (silica, 5-10% of 2 N NH 3 in MeOH/CH 2 CI 2 ) yielded 16 mg (76%) of a white solid. MS (electrospray): exact mass calculated for C 33 H 37 F 4 N 5 0 4 S 2 : 707.22; m/z found, 708.2 [M+H] + . 1 H NMR (CDCI 3 , 400 MHz): 7.97 (br s, 1H), 7.73 and 7.66 (A and B of AB quartet, J = 8.41 Hz, 4H), 7.49 (dd, J = 8.41 , 2.35 Hz, 1 H), 7.15 (dt, J = 8.61 , 2.54 Hz, 1 H), 6.41 (t, J = 5.67 Hz, 1 H), 4.56 (s, 2H), 4.16 (t, J = 7.04 Hz, 2H), 3.84 (dd, J = 5.28, 4.70 Hz, 2H), 3.70 (t, J = 5.67 Hz, 2H), 3.62 (m, 2H), 3.58 (br s, 1 H), 3.05 (br m, 2H), 2.97 (t, J = 5.67 Hz, 2H), 2.91 (s, 3H), 2.40 (br m, 4H), 2.13 (br m, 4H), 1.84 (br d, J = 12.32 Hz, 2H). EXAMPLE 12 6-Fluoro-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)benzo[b]thiophene- 2-carboxylic acid (2-amino-ethyl)-amide. A stirred solution of 300 mg (0.43 mmol) 6-fluoro-3-(1-{3-[5-methanesuIfonyl-3- (4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}- piperidin-4-yl)-benzo[b]thiophene-2-carboxylic acid in 5 mL of dry PMF was treated with 812 mg (2.14 mmol) of HBTU and 0.75 mL (4.28 mmol) of PIEA. The solution was stirred for 5 min before the addition of 0.28 mL (4.28 mmol) of ethylenediamine. The reaction was stirred at room temperature for 30 min then partitioned between EtOAc (30 mL) and saturated sodium bicarbonate (20 mL). The aqueous layer was further extracted with EtOAc (2 x 20 mL). The combined organic layers were then washed with brine, dried over Na 2 S0 4 , and concentrated. Purification by column chromatography (silica, 5-10% of (2 N NH 3 in MeOH)/CH 2 CI 2 ) afforded 200 mg (66%) of a clear oil. MS (electrospray): exact mass calculated for C 33 H 38 F 4 N 6 0 3 S 2 : 706.24; m/z found, 707.2 [M+H] + . 1 H NMR (C0 3 OP, 400 MHz): 8.14 (m, 1 H), 7.84 and 7.72 (A and B of AB quartet, J = 8.41 Hz, 4H), 7.68 (m, 1 H), 7.21 (dt, J = 8.81 , 2.74 Hz, 1 H), 4.54 (s, 2H), 4.27 (t, J = 6.26 Hz, 2H), 4.00-3.90 (m, 2H), 3.76-3.61 (m, 8H), 3.28- 3.23 (br m, 1 H), 3.19-3.09 (br m, 3H), 2.98 (s, 3H), 2.97-2.93 (m, 2H), 2.67 (br m, 2H), 2.52-2.37 (m, 3H), 2.02 (br d, J = 13.89 Hz, 2H). EXAMPLE 13 6-Fluoro-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)benzo[b]thiophene- 2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide. A stirred solution of 20 mg (0.03 mmol) of 6-fluoro-3-(1-{3-[5-methanesulfonyl- 3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]- propyl}-piperidin-4^/l)-benzo[b]thiophene-2-carboxylic acid in 0.3 mL of dry PMF was treated with 14 mg (0.036 mmol) of HBTU and 8 μL (0.045 mmol) of PIEA. The solution was stirred for 5 min before the addition of 20 μL (0.15 mmol) of 4-(2-aminoethyl)morpholine. The reaction was stirred at room temperature for 30 min then partitioned between EtOAc (30 mL) and saturated NaHC0 3 (20 mL). The aqueous layer was further extracted with EtOAc (2 x 20 mL). The combined organic layers were then washed with brine, dried over Na 2 S0 4 , and concentrated. Purification by column chromatography (silica, 5- 10% of (2 N NH 3 in MeOH)/CH 2 CI 2 ) afforded 15 mg (65%) of a white solid. MS (electrospray), exact mass calculated for C^H^F^eO^;,: 776.28; m/z found, 777.3 [M+H] + . 1 H NMR (CPCI 3 , 400 MHz): 8.07 (br s, 1 H), 7.73 and 7.66 (A and B of AB quartet, J = 8.41 Hz, 4H), 7.50 (dd, J = 8.41 , 2.35 Hz, 1 H), 7.14 (dt, J = 8.61 , 2.54 Hz, 1 H), 6.64 (t, J = 4.70 Hz, 1 H), 4.56 (s, 2H), 4.16 (t, J = 6.85 Hz, 2H), 3.80-3.67 (m, 7H), 3.53 (q, J = 5.48 Hz, 2H), 3.03 (br m, 2H), 2.98 (t, J = 5.67 Hz, 2H), 2.90 (s, 3H), 2.60 (t, J = 5.87 Hz, 2H), 2.38 (br m, 4H), 2.12 (br m, 4H), 1.86-1.73 (br m, 3H). EXAMPLE 14 1-[1-{2-Hydroxy-3-[4-(1 H-indol-3-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl- phenyl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. EXAMPLE 15 1 -[4-(5-Fluoro-1 H-indol-3-yI)-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 16 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-1 -yl]-3-[4-(5-chloro-1 H-indol-3-yl)-piperidin-1 -yl]-propan-2-ol. EXAMPLE 17 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-1 -yl]-3-[4-(5-chloro-2-methyl-1 H-indol-3-yl)-piperidin-1 -yl]-propan-2-ol. EXAMPLE 18 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(5-methyl-1 H-indol-3-yl)-piperidin-1 -yl]-propan- 2-ol. EXAMPLE 19 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 H-indole-5- carbonitrile. EXAMPLE 20 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(5-methoxy-1 H-indol-3-yl)-piperidin-1 -yl]- propan-2-ol. EXAMPLE 21 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 H-indole-5- carboxylic acid ethyl ester. EXAMPLE 22 1 -[4-(6-Chloro-1 H-indol-3-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 23 1 -[1 -(3-{4-[6-Chloro-1 -(2-morpholin-4-yl-ethyl)-1 H-indol-3-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 24 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(1 H-pyrrolo[3,2-b]pyridin-3-yl)-piperidin-1 -yl]- propan-2-ol. EXAMPLE 25 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(1 H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1 -yl]- propan-2-ol. EXAMPLE 26 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-oxy-1 H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin- 1-yl]-propan-2-ol. EXAMPLE 27 1-[4-(5-Pimethylamino-1 H-pyrrolo[3,2-b]pyridin-3-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 28 1 -[4-(5-Pimethylamino-1 H-pyrrolo[2,3-c]pyridin-3-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 29 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 H-pyrrolo[2,3- b]pyridine-6-carbonitrile. EXAMPLE 30 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-{4-[1 -(2-morpholin-4-yl-ethyl)-1 H-pyrrolo[2,3- b]pyridin-3-yl]-piperidin-1-yl}-propan-2-ol. EXAMPLE 31 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(7-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)- piperidin-1 -yl]-propan-2-ol. EXAMPLE 32 1-[4-(6-Fluoro-2-hydroxymethyl-benzo[b]thiophen-3-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 33 6-Fluoro-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-yI)- benzo[b]thiophene-2-carbaldehyde. EXAMPLE 34 6-Fluoro-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)- benzo[b]thiophene-2-carboxylic acid methyl ester. EXAMPLE 35 6-Fluoro-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)benzo[b]thiophene- 2-carboxylic acid amide. EXAMPLE 36 6-Fluoro-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)benzo[b]thiophene- 2-carboxylic acid ethylamide. EXAMPLE 37 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 PTT and 100 mM NaCl. The substrate for the assay is (Aedens)EKARVLAEAA(Pabcyl)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 % SPS 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 , 2 and 3 below). Table 1 Table 2 EXAMPLE 101 1 -(3-(4-Chloro-3-methyl-phenyl)-1 -{2-hydroxy-3-[4-(1 H-indol-3-yl)-piperidin-1 - yl]-propyl}-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone EXAMPLE 102 1-[1-{3-[4-(5-Chloro-1 H-indol-3-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 103 1-{3-[4-(5-Chloro-1 H-indol-3-yl)-piperidin-1-yl]-propyl}-5-methanesulfonyl-3-(4- trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridine EXAMPLE 104 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 H-indole-5- carbonitrile EXAMPLE 105 1 -[4-(6-Chloro-1 -methyl-1 H-indol-3-yl)-piperidin-1 -yl]-3-[5-methanesuIfonyl-3-(4- trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan- 2-ol EXAMPLE 106 1 -[4-(6-Chloro-1 -methanesulfonyl-1 H-indol-3-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 107 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-1 -yl]-3-[4-(7-chloro-1 H-indol-3-yl)-piperidin-1 -yl]-propan-2-ol EXAMPLE 108 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 H-indole-5-carbonitrile EXAMPLE 109 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-1 -yl]-3-{4-[6-chloro-1 -(2-morpholin-4-yl-ethyl)-1 H-indol-3-yl]-piperidin- 1-yl}-propan-2-ol EXAMPLE 110 1 -[3-(4-Bromo-phenyl)-1 -(3-{4-[6-chloro-1 -(2-morpholin-4-yl-ethyl)-1 H-indol-3- yl]-piperidin-1-yl}-2-hydroxy-propyl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5- yl]-ethanone EXAMPLE 111 1 -[1 -{2-Hydroxy-3-[4-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1 -yl]-propyl}-3-(4- trifluoromethyl-phenyl)-1 ,4,6,7-tetrahydro-pyrazoIo[4,3-c]pyridin-5-yl]-ethanone EXAMPLE 112 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-1 -yl]-3-[4-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1 -yl]-propan-2-ol EXAMPLE 113 1 -(3-(4-Bromo-phenyl)-1 -{2-hydroxy-3-[4-(1 H-pyrrolo[2,3-b]pyridin-3-yl)- piperidin-1 -yl]-propyl}-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone EXAMPLE 114 1 -[1 -(2-Hydroxy-3-{4-[1 -(2-morpholin-4-yl-ethyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl]- piperidin-1-yl}-propyl)-3-(4-trifluoromethyl-phenyl)-1 ,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]-ethanone EXAMPLE 115 5-Methanesulfonyl-1-{3-[4-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H- pyridin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine EXAMPLE 116 5-Methanesulfonyl-1-{3-[4-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]-propyl}- 3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridine EXAMPLE 117 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-1-yl]-3-{4-[1-(2-morpholin-4-yl-ethyl)-1 H-pyrrolo[2,3-b]pyridin-3-yl]- piperidin-1 -yl}-propan-2-ol EXAMPLE 118 1-[3-(4-Bromo-phenyl)-1-(2-hydroxy-3-{4-[1-(2-morpholin-4-yl-ethyl)-1 H- pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-propyl)-1 ,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]-ethanone EXAMPLE 119 6-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)-pyrrolo[2,3- b]pyridine-1 -carboxylic acid methyl ester EXAMPLE 120 1-[4-(6-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-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 121 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(7-oxy-1 H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin- 1 -yl]-propan-2-ol EXAMPLE 122 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(6-morpholin-4-yl-1 H-pyrrolo[2,3-b]pyridin-3-yl)- piperidin-1 -yl]-propan-2-ol EXAMPLE 123 1 -[1 -{2-Hydroxy-3-[4-(1 H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1 -yl]-propyl}-3-(4- trifluoromethyl-phenyl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone EXAMPLE 124 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-1 -yl]-3-[4-(1 H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1 -yl]-propan-2-ol EXAMPLE 125 1 -(3-(4-Bromo-phenyl)-1 -{2-hydroxy-3-[4-(1 H-pyrrolo[3,2-c]pyridin-3-yl)- piperidin-1-yl]-propyl}-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone EXAMPLE 126 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-oxy-pyrrolo[3,2- c]pyridine-1 -carboxylic acid methyl ester EXAMPLE 128 3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-fluoro- benzofuran-2-carboxylic acid methyl ester EXAMPLE 129 3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-fluoro- benzo[b]thiophene-2-carboxylic acid methyl ester EXAMPLE 130 1-[4-(6-Fluoro-benzo[b]thiophen-3-yl)-piperidin-1-yl]-3-[5-methanesulfonyl-3- (4trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan- 2-ol EXAMPLE 131 1-[1-{3-[4-(6-Fluoro-benzofuran-3-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3- (4trifluoromethyl-phenyl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]- ethanone EXAMPLE 132 6-Fluoro-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)- benzo[b]thiophene-2-carboxylic acid EXAMPLE 133 6-Fluoro-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)- benzo[b]thiophene-2-carboxylic acid dimethylamide EXAMPLE 134 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)-6-fluoro-benzo[b]thiophene-2- carbonitrile EXAMPLE 135 6-Fluoro-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)- benzo[b]thiophene-2-carbonitrile Table 3 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. What is claimed is:

Claims: CLAIMS A compound of formula (I): (I) wherein: the dashed line adjacent C-R 6 is absent or an sp 2 bond; Y is nitrogen or R 20 C; Z is nitrogen or R 21 C; T is nitrogen or R 2 C; s is nitrogen or R 3 C; provided between 0 and 3 of S, T, Y, and Z are nitrogen; and further provided that one of S, T, Y, and Z can be =N + -0 ~ where the remaining three are not nitrogen; R : 20 is selected from hydrogen, halogen, C^ alkoxy, hydroxy, C^ alkyl, cyano, nitro, C 2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)- C ^ alkylene, phenyl, (phenyl)C ,_ 5 alkylene, R 14 OC=0, R 1 S, R 14 SO, and R 14 S0 2 ; R 21 is selected from hydrogen, halogen, C,^ alkoxy, hydroxy, C^ alkyl, cyano, nitro, C^haloalkyl, R c R d N, R c R d NC=0, C 2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C ^ alkylene, phenyl, (phenyl)C ^ alkylene, R 15 OC=0, R 15 S, R 15 SO and R 15 S0 2 ; R 2 is selected from hydrogen, halogen, G,^ alkoxy, hydroxy, C h alky!, cyano, nitro, C,.g haloalkyl, R e R f N, R e R f NC=0, C 2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C ^ alkylene, phenyl, (phenyl)C ^g alkylene, R 16 OC=0, R 16 S, R 16 SO and R 16 S0 2; R 3 is selected from hydrogen, halogen, hydroxy, C,. 5 alkyl, cyano, nitro, haloalkyl, R 9 R h N, C 2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)- C ^ alkylene, phenyl, (phenyl)C ^ alkylene, R 17 OC=0, R m R n NC=0, R m R π NS0 2 , R 7 S, R 17 SO , and R 7 S0 2 ; R 5 and R 6 are independently selected from hydrogen and C^ alkyl; R 7 and R 8 independently are hydrogen, alkylthio, halogen, or 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; said ring being optionally substituted with between 1 and 3 substituents independently selected from halo, hydroxy, cyano, nitro, amino, R R'O-, R^-, R'0(C ^ alkylene)-, RO(C=0)-, R l (C=0)-, R'(C=S}-, R'(C=0)0-, R t O(C=0)(C=0)-, R^Os, NHR U (C=NH)-, NHR u S0 2 -, and NHR u (C=0)-; R l is C lJβ alkyl, phenyl, benzyl, phenethyl, or C 2 . 5 heterocyclyl, (C ^ heterocyclyl)C ^ alkylene, NH 2 , mono- or di(C ^ alkyl)N-, or R 49 OR 50 -, wherein R 49 is H, C ^ alkyl, C 2 . 5 alkenyl, phenyl, benzyl, phenethyl, C ^ heterocyclyl, or (C ^ heterocyclyl)C ^ alkylene and R 50 is C ^ alkylene, phenylene, or divalent C 1-5 heterocyclyl; and R u can be H in addition to the values for R f ; R c is hydrogen, C^ alkyl, phenyl, C 2 _g heterocyclyl, C 2 . 8 acyl, aroyl, R 10 OC=O-, R'R'NC s O, R 10 SO-, R 10 SO 2 -, and RWNSOy, R e is hydrogen, C,. 5 alkyl, phenyl, C 2-5 heterocyclyl, C 2-8 acyl, aroyl, R 40 OC=O, R 43 R 44 NC=0, R 40 SO, R 40 SO 2 , and R 43 R 4 NS0 2 ; R m is hydrogen, C^ alkyl, phenyl, C 2-5 heterocyclyl, C 2-8 acyl, aroyl, R 41 OC=0, R 45 R 46 NC=0, R 41 SO, R 41 S0 2 , and R 45 R 46 NS0 2 ; R° is hydrogen, C 1-5 alkyl, phenyl, C 2-5 heterocyclyl, C 2-8 acyl, aroyl, R 42 OC=0, R 7 R 48 NC=0, R 42 SO, R 42 S0 2 , and R 47 R 48 NS0 2 ; each of R d , R f , R n , and R p is independently selected from hydrogen, G,^ alkyl, phenyl, and C 2-s heterocyclyl; in addition, R c and R d , R e and R f , R and R n , or R° 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 9 , R 10 , R 11 , R 14 , R 15 , R 16 , R 17 , R 40 , R 41 , and R 42 is independently C 1-5 alkyl, phenyl, or C 2 . 5 heterocyclyl; each of R 1' and R j , R k and R 1 , R 43 and R 44 , R 45 and R 46 , R 47 and R 48 are independently hydrogen, alkyl, C 3 . 5 alkenyl, phenyl, or C 2 . 5 heterocyclyl; in addition, R 1 and R j , and R k and R 1 , R 43 and R 44 , R 45 and R 46 , and R 47 and R 48 , 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.^ alkyl, phenyl, or C 2 . 5 heterocyclyl, C 2 . 8 acyl, aroyl, R 9 OC=0, R 18 R 19 NC=0, R 9 SO, R 9 S0 2 , or R 18 R 19 NS0 2 ; R h is hydrogen, C,. 5 alkyl, phenyl, or C 2 . 5 heterocyclyl; alternatively, R 9 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 18 and R 19 independently are hydrogen , alkyl, phenyl, or C 2 . 5 heterocyclyl; alternatively, R 18 and R 19 can be taken together to form an optionally substituted 4- to 7- membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic; n is O, 1 or 2; G is C 3 . 6 alkenediyl or C 3 . 6 alkanediyl, optionally substituted with hydroxy, halogen, C 1-5 alk rvyyli,, alkylene-, alkoxy; L is amino, mono- or di-C 1-5 alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, or piperazinyl, wherein available ring nitrogens can be optionally substituted with alkyl, benzyl, C 2 . 5 acyl, C ^ alkylsulfonyl, or C,^ alkoxycarbonyl; Ar represents a monocyclic or bicyclic aryl or heteroaryl ring, optionally substituted with between 1 and 3 substituents independently selected from halogen, C^ alkoxy, C^ alkyl, C 2 . 5 alkenyl, cyano, azido, nitro, R 22 R 23 N, R^S, R^SO, R 22 S0 2 , R 22 OC=0, R 22 R 23 NC=0, C,_ 5 haloalkyl, C^ ghaloalkoxy, C^haloalkylthio, and C^ alkylthio; R 22 is hydrogen, C 1-5 alkyl, C 3 . 5 alkenyl, phenyl, benzyl, C 2 . 5 heterocyclyl, C 2-8 acyl, aroyl, R 11 OC=0, R 24 R 25 NC=0, R 11 S, R 11 SO, R 11 S0 2 , or R 2 R 25 NS0 2 ; R 23 is hydrogen, C 1-5 alkyl, phenyl, benzyl, or C 2 . 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 and R 25 are independently hydrogen, phenyl, benzyl, or C 1-5 heteroaryl; alternatively, R 24 and R 25 can be taken together to form an optionally substituted 4- to 7- membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic; R 32 is hydrogen, C 1-5 alkyl, cyano, G,^ hydroxyalkyl, C 2 . 8 acyl, -(C=0)NR v R x , CHO, or C 1-6 alkoxycarbonyl, wherein each of R v and R x is independently selected from H , C 1-5 alkyl, hydroxyalkyl, C.,. 5 heterocyclyl, heterocyclyl) C 1-5 alkylene, aminoalkylene, C 3 . 8 acyloxy, CHO, C.,. 6 alkoxycarbonyl, and cyano; Q is NR 33 , S, or O; R 3 represents hydrogen, G,^ alkyl, phenyl, benzyl, phenethyl, C : 2-5 heterocyclyl, (C 2 . 5 heterocyclyl)C ^ alkylene, C 2-8 acyl, aroyl, R 35 OC=0, R 36 R 37 NC=0, R 35 SO, R 35 S, R 35 S0 2 and R 36 R 37 NS0 2 ; R 35 is selected from hydrogen, C,^ alkyl, phenyl, benzyl, phenethyl, and C 2-5 heteroaryl; R 36 and R 37 are each independently selected from hydrogen, phenyl, or C 2 _g heteroaryl; alternatively, R 36 and R 37 can be taken together to form an optionally substituted 4- to 7-membered ring 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 ^ alkoxy, -COOH, C 2 . 6 acyl, [di(C 1-4 alkyl)amino]C 2 _g alkylene, [difC w alkyl)amino] C 2 . 5 alkyl-NH- CO-, and C ^ haloalkoxy; or a pharmaceutically acceptable salt, amide, or ester thereof; or a stereoisomeric form thereof. 2. A compound of claim 1 , wherein one of S, T, Y, and Z is nitrogen. 3. A compound of claim 1 , wherein S and T are CR 3 and CR 2 , respectively. 4. A compound of claim 1 , wherein S, T, Y, and Z are CR 3 , CR 2 , CR 20 , and CR 21 , respectively.. 5. A compound of claim 1 , wherein: (a) Z is N, Y is N, S is CR 3 , and T is CR 2 ; or (b) S is N, T is N, Y is CR 20 , and Z is CR 21 . 6. A compound of claim 1 , wherein R is hydrogen, halogen, C.,_ 5 alkoxy, cyano, R e R f N, or a 5-6 membered heterocyclyl. 7. A compound of claim 1 , wherein R 3 is hydrogen, halogen, alkoxy, alkyl, or are taken together to form a 5-6 membered heterocyclyl. 8. A compound of claim 1 , wherein each of R 2 and R 3 is independently selected from hydrogen, halogen, and a 5-6 membered heterocyclyl. 9. A compound of claim 1 , wherein R 5 and R 6 are independently selected from hydrogen and C,_ 3 alkyl. 10. A compound of claim 9, wherein one of R 5 and R 6 is H. 11. A compound of claim 10, wherein R 5 and R 6 are each H. 12. A compound of claim 1 , wherein one of R 7 and R 8 is H and the other is 5-7 membered carbocyclyl or heterocyclyl. 13. A compound of claim 1 , wherein R 7 and R 8 are taken together to form an optionally substituted 5- to 7- membered carbocyclic or heterocyclic ring. 14. A compound of claim 13, wherein R 7 and R 8 are taken together to form a six-membered heterocyclyl. 15. A compound of claim 13 wherein R 7 and R 8 taken together form a 5-7 membered heterocyclyl optionally N-substituted with R t (C=0)-, R f S0 2 -, or NHR u (C=0)- wherein R* is C 1-6 alkyl, phenyl, or C 2 . 5 heterocyclyl and R u is H, C ^e alkyl, phenyl, or C 2-5 heterocyclyl. 16. A compound of claim 1 , wherein each of R c , R e , R , and R° is independently selected from hydrogen, alkyl)OC=0, and the respective RRNC=0, RSO, RS0 2 , and RRNS0 2 groups. 17. A compound of claim 1 , wherein each of R c , R d , R 9 , R h , R°, R f , and R p is independently selected from hydrogen and C h alky!; or , independently, R e and R f , R 9 and R h , or R° and R p taken together form an optionally substituted 4- to 7- membered carbocyclic or heterocyclic ring. 18. A compound of claim 17 wherein R e and R f taken together are morpholinyl, piperidinyl, or pyrrolidinyl. 19. A compound of claim 1 , wherein each of R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R j , R j , R k and R 1 independently is hydrogen or C^ alkyl. 20. A compound of claim 1 , wherein each of R 9 , R 11 , R 14 , R 15 , R 16 and R 17 is independently C^ alkyl. 21. A compound of claim 1 , wherein R 9 is C^ alkyl, C 2 . 8 acyl, R 9 OC=0, R 18 R 19 NC=0, R 9 SO, R 9 S0 2 , or R 18 R 19 NS0 2 ; and R h is H or C^ alkyl; alternatively, R 9 and R h can be taken together to form an optionally substituted 5- to 6-membered heterocyclyl. 22. A compound of claim 21 , wherein R 9 and R h are each C 1-3 alkyl. 23. A compound of claim 1 , wherein R 18 and R 19 independently are hydrogen or C^ alkyl. 24. A compound of claim 1 , wherein n is 1. 25. A compound of claim 1 , wherein G is C 3 alkanediyl, optionally substituted with hydroxy, halogen, [(L)-C ^ alkylenejamino, or (L)-C^ alkyloxy. 26. A compound of claim 25, wherein G is C 3 alkanediyl, optionally substituted with hydroxy. 27. A compound of claim 1 , wherein R 20 and R 21 are independently selected from hydrogen, halogen, C^ alkoxy, C^ alkyl, cyano, nitro, 4-7 membered heterocyclyl, and R°R P N or R c R d N, respectively. 28. A compound of claim 27, wherein R 20 and R 21 are independently selected from hydrogen, halogen, 5- to 6-membered heterocyclyl, and R°R P N or R c R d N, respectively. 29. A compound of claim 1 , wherein Ar represents a monocyclic ring, optionally substituted with 1 to 2 substituents selected from halogen, G,_ 5 alkyl, cyano, nitro, R 22 R 23 N, C^haloalkyl, and C^ haloalkoxy. 30. A compound of claim 29, wherein Ar is a six-membered aromatic ring monosubstituted at the 4-position with halogen, methyl, CF 3 , or OCF 3 , or disubstituted at the 3- and 4-positions with substituents independently selected from halogen, CF 3 , methyl, and OCF 3 . 31. A compound of claim 29, wherein each of R 22 , R 23 , and R 24 is independently hydrogen or C^ alkyl. 32. A compound of claim 1 , wherein R 25 and R 26 independently are hydrogen or or, alternatively, R 25 and R 26 are taken together to form an optionally substituted 4- to 7- membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic. 33. A compound of claim 32, wherein R 25 and R 26 independently are hydrogen or C^ alkyl. 34. A compound of claim 1 , wherein Q is NR 33 or S. 35. A compound of claim 34, wherein Q is NR 33 , R 33 is H or C 2 . 5 heterocyclyl, and R 32 is H, C 1-5 alkyl, hydroxyalkyl, -(C=0)NR v R x , CHO, or C ,. 6 alkoxycarbonyl, wherein each of R v and R x is independently selected from H, C 1-5 hydroxyalkyl, (C 1-5 heterocyclyl)-C ^ alkylene, and C .,_ 5 aminoalkylene. 36. A compound of claim 34, wherein Q is S and R 33 is NR 36 R 37 (C=0)- where each of R 36 and R 37 are independently selected from hydrogen and C 1-5 alkyl. 37. A compound of claim 1 , wherein R 35 is selected from hydrogen and alkyl; R 36 and R 37 are each independently selected from hydrogen, C.,. 5 alkyl, or, alternatively, R 36 and R 37 can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring. 38. A compound of claim 1 , wherein Y is nitrogen or R 20 C; Z is nitrogen or R 21 C; T is nitrogen or R 2 C; S is nitrogen or R 3 C; provided between 0 and 2 of S, T, Y, and Z are nitrogen; R 2 is hydrogen, halogen, hydroxy, C,_ 5 alkoxy, C^ alkyl, 5- to 6- membered heterocyclyl, or R e R f N; R 3 is hydrogen, halogen, C,^ alkoxy, hydroxy, C 1-5 alkyl, , 5- to 6- membered heterocyclyl, or R 9 R h N; R 5 and R 6 are each H; R 7 and R 8 independently are taken together to form an optionally substituted 5- to 7- membered unsaturated heterocyclic ring; each of R a ' R e , R m , and R° is independently selected from hydrogen, C^ alkyl, C 2 . 8 acyl, (C^alkyOOC^, and the respective RRNC=0, RSO, RS0 2 , and RRNS0 2 groups; each of R b , R f , R n , and R P , is independently selected from hydrogen and alkyl; each of R 9 , R 11 , R 14 , R 15 , R 16 , R 17 , R 40 , R 41 and R 42 is independently C^ alkyl; each of R c , R d , R' , R j , R 43 , R 44 , R 45 , R 46 , R 47 , R k and R 1 are independently are hydrogen or C,. 5 alkyl; R 9 is hydrogen, or C^ alkyl, C 2 . 8 acyl, R 9 OC=0, R 18 R 9 NC=0, R 9 SO, R 9 S0 2 , or R 18 R 19 NS0 2 ; R h is hydrogen or C,. 5 alkyl; alternatively, R 9 and R h can be taken together to form an optionally substituted 4- to 7- membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic; R 18 and R 19 independently are hydrogen or C^ alkyl; n is 0 or 1 ; G is C ZA alkenediyl or C^ alkanediyl, optionally substituted with hydroxy, halogen, alkyloxy, oxo, hydroximino, C0 2 R k , R k R'NC0 2 , N 3 , or (L)-C 1 . g alkoxy; L is amino, mono- or pyrrolidinyl, morpholinyl, piperidinyl homopiperidinyl, or piperazinyl, available ring nitrogens being optionally with R 20 and R 21 are independently selected from hydrogen, halogen, alkoxy, C^alkyl, cyano, nitro, and R°R P N; 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; Ar represents a monocyclic or bicyclic aryl or heteroaryl ring, optionally substituted with hydrogen, halogen, C^ alkoxy, C^ alkyl, cyano, nitro, R 22 R 23 N, R 24 S0 2 , R 24 OC=0, R 25 R 26 NC=0, CF 3 , OCF 3 , SCF 3 , or C^ alkylthio; R 22 is hydrogen, C 1-5 alkyl, phenyl, benzyl, phenethyl, C 2 . 5 heteroaryl, C 2-8 acyl, aroyl, R 2 OC=0, R 25 R 26 NC=0, R 2 SO, R 24 S0 2 , or R 25 R 26 NS0 2 ; R 23 is hydrogen or C^alkyl; alternatively, R 22 and R 23 can be taken together to form an optionally substituted 4- to 7- membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic; R 24 is hydrogen or C,. 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 carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic; R 32 is hydrogen, C 1-5 alkyl, alkoxycarbonyl, or -(C=0)NR v R x , wherein each of R v R x is independently selected from H, C 1-5 alkyl, alkylene, (C ^ heterocyclyl)C ^ alkylene, or C 1-6 alkoxycarbonyl; Q is NR 33 or S; R 33 represents hydrogen, C^ alkyl, phenyl, benzyl, (C M heterocyclyl)C ^ alkylene, C 2 . 8 acyl, aroyl, R 35 OC=0, R 36 R 37 NC=0, R 35 S0 2 and R 36 R 37 NS0 2 ; R 35 is selected from hydrogen and C^ alkyl; R 36 and R 37 are each independently selected from hydrogen and C^ alkyl. 39. A compound of claim 1 , wherein 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^ alkyl, cyano, nitro, R 2 R 23 N, CF 3 and OCF 3 . 40. A compound of claim 39, wherein both R 5 and R 6 are each H, and Ar is a six membered ring substituted with halogen, CF 3 , methyl, halomethyl, or OCF 3 , at the 3- or 4- position, or disubstituted at the 3- and 4- positions. 41. A compound of claim 40, wherein R 7 and R 8 taken together form pyridinyl, pyrimidinyl, or piperazinyl, optionally N-substituted with - (C=0)R l , S0 2 -R\ or-(C=0)NHR u . 42. A compound of claim 39, wherein R 22 and R 23 taken together are independently morpholinyl, piperidyl, or pyrrolidinyl, optionally substituted. 43. A compound of claim 1 , wherein the dashed line adjacent C-R 6 is absent. 44. A compound of claim 1 , selected from: 1 -[4-(5-Chloro-1 H-indol-3-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; 1 -[4-(7-Chloro-1 H-indol-3-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; 1-[4-(5-Chloro-2-methyl-1H-indol-3-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; 1-{4-[6-Chloro-1-(2-morpholin-4-yl-ethyl)-1 H-indol-3-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; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(1 H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1 -yl]- propan-2-ol; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl]- propan-2-ol; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-morpholin-4-yl-1 H-pyrrolo[2,3-c]pyridin-3-yl)- piperidin-1 -yl]-propan-2-ol; 1 -[4-(6-Pimethylamino-1 H-pyrrolo[3,2-c]pyridin-3-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; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(6-morpholin-4-yl-1H-pyrrolo[3,2-c]pyridin-3-yl)- piperidin-1 -yl]-propan-2-ol; 1-[5-Methanesulfonyl-3-(4-trifIuoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(6-morpholin-4-yl-5-oxy-1 H-pyrrolo[3,2- c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol; 6-Fluoro-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)benzo[b]thiophene- 2-carboxylic acid (2-hydroxy-ethyl)-amide; 6-Fluoro-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)benzo[b]thiophene- 2-carboxylic acid (2-amino-ethyl)-amide; and 6-Fluoro-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)benzo[b]thiophene- 2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide. 45. A compound of claim 1 , selected from: 1 -[1 -{2-Hydroxy-3-[4-(1 H-indol-3-yl)-piperidin-1 -yl]-propyl}-3-(4- trifluoromethyl-phenyl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1 -[4-(5-Fluoro-1 H-indol-3-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 ; 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(5-chloro-1 H-indol-3-yl)-piperidin-1 -yl]-propan- 2-ol ; 1 -[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(5-chloro-2-methyl-1 H-indol-3-yl)-piperidin-1 - yl]-propan-2-ol ; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-methyl-1 H-indol-3-yl)-piperidin-1-yl]-propan- 2-ol ; 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 H-indole- 5-carbonitrile ; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(5-methoxy-1 H-indol-3-yl)-piperidin-1 -yl]- propan-2-ol ; 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 H-indole- 5-carboxylic acid ethyl ester ; 1 -[4-(6-Chloro-1 H-indol-3-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 ; 1 -[1 -(3-{4-[6-Chloro-1 -(2-morpholin-4-yl-ethyl)-1 H-indol-3-yl]-piperidin-1 - yl}-2-hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1 ,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]-ethanone ; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(1 H-pyrrolo[3,2-b]pyridin-3-yl)-piperidin-1 -yi]- propan-2-ol ; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1 H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]- propan-2-ol ; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-oxy-1 H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin- 1 -yl]-propan-2-ol ; 1 -[4-(5-Pimethylamino-1 H-pyrrolo[3,2-b]pyridin-3-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 ; 1 -[4-(5-Pimethylamino-1 H-pyrrolo[2,3-c]pyridin-3-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 ; 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)-1H- pyrrolo[2,3-b]pyridine-6-carbonitrile ; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-{4-[1 -(2-morpholin-4-yl-ethyl)-1 H-pyrrolo[2,3- b]pyridin-3-yl]-piperidin-1-yl}-propan-2-ol ; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(7-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)- piperidin-1-yl]-propan-2-ol ; 1-[4-(6-Fluoro-2-hydroxymethyl-benzo[b]thiophen-3-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-Fluoro-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)- benzo[b]thiophene-2-carbaldehyde ; 6-Fluoro-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)- benzo[b]thiophene-2-carboxylic acid methyl ester ; 6-Fluoro-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)benzo[b]thiophene-2-carboxylic acid amide ; and 6-Fluoro-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)benzo[b]thiophene-2-carboxylic acid ethylamide. 46. A compound of claim 1 , selected from: 1 -{4-[6-Chloro-1 -(2-morpholin-4-yl-ethyl)-1 H-indol-3-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-Fluoro-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)benzo[b]thiophene- 2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(5-oxy-1 H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin- 1-yl]-propan-2-ol; and 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(6-morpholin-4-yl-1H-pyrrolo[3,2-c]pyridin-3-yl)- piperidin-1 -yl]-propan-2-ol. 47. A compound of claim 1 , selected from: 1 -(3-(4-Chloro-3-methyl-phenyl)-1 -{2-hydroxy-3-[4-(1 H-indoi-3-yl)- piperidin-l-yll-propylJ-l ^. β ^-tetrahydro-pyrazolo^.S-cjpyridin-δ-y -ethanone; 1-[1-{3-[4-(5-Chloro-1H-indol-3-yl)-piperidin-1-yl]-2-hydroxy-propyl}-3-(4- trifluoromethyl-phenyl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1 -{3-[4-(5-Chloro-1 H-indol-3-yl)-piperidin-1 -yl]-propyl}-5- methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1 H- pyrazolo[4,3-c]pyridine; 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 H-indole- 5-carbonitrile; 1 -[4-(6-Chloro-1 -methyl-1 H-indol-3-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; 1 -[4-(6-Chloro-1 -methanesulfonyl-1 H-indol-3-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; 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(7-chloro-1 H-indol-3-yl)-piperidin-1 -yl]-propan- 2-ol; 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 H-indole-5- carbonitrile; 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-{4-[6-chloro-1-(2-morpholin-4-yl-ethyl)-1 H-indol-3- yl]-piperidin-1-yl}-propan-2-ol; 1 -[3-(4-Bromo-phenyl)-1 -(3-{4-[6-chloro-1 -(2-morpholin-4-yl-ethyl)-1 H- indol-3-yl]-piperidin-1 -yl}-2-hydroxy-propyl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]-ethanone; 1 -[1 -{2-Hydroxy-3-[4-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1 -yl]- propyl}-3-(4-trifluoromethyl-phenyl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5- yl]-ethanone; 1 -[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1 -yl]- propan-2-ol; 1 -(3-(4-Bromo-phenyl)-1 -{2-hydroxy-3-[4-(1 H-pyrrolo[2,3-b]pyridin-3-yl)- piperidin-1-yl]-propyl}-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone; 1 -[1 -(2-Hydroxy-3-{4-[1 -(2-morpholin-4-yl-ethyl)-1 H-pyrrolo[2,3-b]pyridin- 3-yl]-piperidin-1-yl}-propyl)-3-(4-trifluoromethyl-phenyl)-1 ,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 5-Methanesulfonyl-1-{3-[4-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H- pyridin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine; and 5-Methanesulfonyl-1 -{3-[4-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1 -yl]- propyl}-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3- c]pyridine. 48. A compound of claim 1 , selected from: 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-{4-[1-(2-morpholin-4-yl-ethyl)-1 H-pyrrolo[2,3- b]pyridin-3-yl]-piperidin-1-yl}-propan-2-ol; 1 -[3-(4-Bromo-phenyl)-1 -(2-hydroxy-3-{4-[1 -(2-morpholin-4-yl-ethyl)-1 H- pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-propyl)-1 ,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 6-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)- pyrrolo[2,3-b]pyridine-1 -carboxylic acid methyl ester; 1 -[4-(6-Chloro-1 H-pyrrolo[2,3-b]pyridin-3-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; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(7-oxy-1 H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin- 1-yl]-propan-2-ol; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(6-morpholin-4-yl-1 H-pyrrolo[2,3-b]pyridin-3-yl)- piperidin-1 -yl]-propan-2-ol; 1-[1-{2-Hydroxy-3-[4-(1 H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]- propyl}-3-(4-trifluoromethyl-phenyl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5- yl]-ethanone; 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1 -yl]-3-[4-(1 H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1 -yl]- propan-2-ol; 1 -(3-(4-Bromo-phenyl)-1 -{2-hydroxy-3-[4-(1 H-pyrrolo[3,2-c]pyridin-3-yl)- piperidin-1-yl]-propyl}-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone; 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-oxy- pyrrolo[3,2-c]pyridine-1 -carboxylic acid methyl ester; 3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-fluoro- benzofuran-2-carboxylic acid methyl ester; 3-(1-{3-[5-Acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3c]pyridin-1-yl]-2-hydroxy-propyl}-piperidin-4-yl)-6-fluoro- benzo[b]thiophene-2-carboxylic acid methyl ester; 1 -[4-(6-Fluoro-benzo[b]thiophen-3-yl)-piperidin-1 -yl]-3-[5- methanesulfonyl-3-(4trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-1-yl]-propan-2-ol; 1 -[1 -{3-[4-(6-Fluoro-benzofuran-3-yl)-piperidin-1 -yl]-2-hydroxy-propyl}-3- (4trifluoromethyl-phenyl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]- ethanone; 6-Fluoro-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)- benzo[b]thiophene-2-carboxylic acid; 6-Fluoro-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)- benzo[b]thiophene-2-carboxylic acid dimethylamide; 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)-6-fluoro- benzo[b]thiophene-2-carbonitrile; and 6-Fluoro-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)- benzo[b]thiophene-2-carbonitrile. 49. A pharmaceutical composition, comprising a compound of claim 1 , 38, 44, 45, or 46 and a pharmaceutically acceptable carrier. 50. 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 claim 1 , 38, 44, 45, or 46. 51. A method for inhibiting cathepsin S activity in a subject, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 1 , 27, 44, or 46. 52. 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 compound of claim 1 , 27, 44 or 46. 53. A method of claim 52, wherein the autoimmune disease is selected from lupus, rheumatoid arthritis, and asthma. 54. A method of claim 52, wherein the autoimmune disease is asthma. 55. A method for treating or inhibiting the progression of tissue transplant rejection in a subject, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 1, 27, 44 or 46. 56. A method of claim 55, wherein said administration occurs after said subject has undergone a tissue transplant procedure. 57. A method of claim 55, wherein said administration to said subject occurs before or during a tissue transplant procedure.

Inventors: CAI HUI, EDWARDS JAMES P, MEDUNA STEVEN P, PIO BARBARA A, WEI JIANMEI, CAI, HUI, EDWARDS, JAMES, P., MEDUNA, STEVEN, P., PIO, BARBARA, A., WEI, JIANMEI
Applicants: ORTHO MCNEIL PHARM INC, ORTHO MCNEIL PHARMACEUTICAL, INC.
Application year: 2001
Main classification: C07D471
IPC codes: A61K31, A61P11, A61P19, A61P29, A61P37, C07D413, C07D471, C07D519