ZA200302051B - Substituted pyrazoles. - Google Patents

Description

SUBSTITUTED PYRAZOLES

. Field of the Invention . 5 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 Il Peptide Loading and Germinal Center Development.

Immunity 1999, 10, 197-206.). * 30

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.; g Rudensky, A. Y. Impaired Invariant Chain Degradation and Antigen , 5 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. W0-99/24460.

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 bicyclic pyrazoles of the type shown below. R never contains a heterocyclic ring and no protease inhibitor activity is ascribed to these molecules; they are described as o1-adrenergic receptor modulators. . R,

N—N

N

Rr!

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- 9264576 (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.

R,

N—N \

X yO

N

The compound 2-[4-[4~(3-methyl-5-phenyl-1H-pyrazol-1 -yl)butyi]-1- ~ piperazinyl]-pyrimidine is known from EP-382637, which describes pyrimidines having anxiolytic properties. This compound and analogs are further described in EP-502786 as cardiovascular and central nervous system agents.

Pharmaceutical formulations with such compounds are disclosed in EP-655248 . for use in the treatment of gastric secreation and as anti-ulcer agents. WO- 9721439 describes medicaments with such compounds for treating obsessive- - 25 compulsive disorders, sleep apnea, sexual dysfunctions, emesis and motion sickness. \ :

The compounds 5-methyl-3-phenyl-1-[4-(4-phenyl-1-piperazinyl)butyl]- 1H-indazole and 5-bromo-3-(2-chlorophenyl)-1-[4-(4-phenyl-1- piperazinyl)butyl]-1H-indazole, in particular the hydrochloride salts thereof, are known from WO-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 ' 5 formula (1):

RS

R32 TO Ar

Ah

Q Lo R RE — wf y—35 10 (1) wherein: the dashed line adjacent C-R® is absent or an sp? bond;

Y is nitrogen or RC; z is nitrogen or R?'C; 15 7 is nitrogen or R%C;

S is nitrogen or RC; 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*-O" where the remaining three are not nitrogen; 20

R* is selected from hydrogen, halogen, C, alkoxy, hydroxy, C,salkyl, : cyano, nitro, C, ; haloalkyl, R°RPN, R°R’NC=0, C,; acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)- C , 5 alkylene, phenyl, ” (phenyl)C ,; alkylene, R™*OC=0, R*S, R"“S0, and R“S0,; 25 R? is selected from hydrogen, halogen, C, ; alkoxy, hydroxy, C, alkyl, cyano, nitro, C, s haloalkyl, R°RN, R°R*NC=0, C, acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyi)-C , ; alkylene, phenyl, (phenyl)C ,; alkylene, R"0C=0, R**S, R"SO and R'*SO,;

R? is selected from hydrogen, halogen, C, ; alkoxy, hydroxy, C, alkyl, ’ cyano, nitro, C, haloalkyl, R°RN, R°RNC=0, C, acyl, 4-7 membered . 5 heterocyclyl, (4-7 membered heterocyclyl)-C , 5 alkylene, phenyl, (phenyl)C , 5 alkylene, R®OC=0, RS, R"SO and R'"SO,,

R® is selected from hydrogen, halogen, C, ; alkoxy, hydroxy, C, alkyl, cyano, nitro, C,s haloalkyl, R°R"N, C, acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)- C ,; alkylene, phenyl, (phenyl)C 5 alkylene, R"OC=0, R"R"NC=0, R"R"NSO,, R"S, R"’SO and R"SO,;

R°® and R® are independently selected from hydrogen and C, ; alkyl;

R” and R® independently are hydrogen, C,; alkyl, C,; alkenyl, C, 5 alkoxy, C, alkylthio, halogen, or 4-7 membered carbocyclyl or heterocyclyl; altematively, R” and R® 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'S-, R'O(C ,, alkylene)-, R'O(C=0)-, R(C=0)-, R{C=S)-, R(C=0)0-, R'O(C=0)(C=0)-,

R'SO,, NHRY(C=NH)-, NHR"SO,-, and NHR!(C=0)-;

R! is C ,¢ alkyl, phenyl, benzyl, phenethyl, or C , heterocyclyl, (C , heterocyclyl)C , alkylene, NH,, mono- or di(C 4 alkyl)N-, or R®*OR%-, wherein R* is H, C 5 alkyl, C , alkenyl, phenyl, benzyl, phenethyl, C , heterocyclyl, or (C , 5 heterocyciyl)C , ; alkylene and R® is C , ; alkylene, phenylene, or divalent C , 5 heterocyclyl; and

R* can be H in addition to the values for R,

R® is hydrogen, C, ; alkyl, phenyl, C ,; heterocyclyl, C ,, acyl, aroyl,

R°0C=0-, RRNC=0, R"SO-, R""S0O,-, and RRNSO,; ” R® is hydrogen, C, alkyl, phenyl, C, heterocyclyl, C ,, acyl, aroyl,

R*0C=0, R®R*NC=0, R*“S0, R*S0,, and R®R*NSO,;

Co R™ is hydrogen, C, alkyl, phenyl, C ,; heterocyclyl, C ,, acyl, aroyi,

R*0OC=0, R*R*NC=0, R*'S0, R*S0,, and R*R*NSO, ;

R° is hydrogen, C, s alkyl, phenyl, C , heterocyclyl, C , acyl, aroyl,

R*0C=0, RYR*®NC=0, R*S0, R**S0,, and R"R*NSO,; each of RY, R', R", and RP is independently selected from hydrogen, C, ; alkyl, ] phenyl, and C ,4 heterocyclyl; in addition, R° and RY, R® and R/, R™ and i 5 R", or R® and RP, 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%, RR", R*, R®, R*, RY, R®, R*, and R* is independently C, alkyl, phenyl, or C ,; heterocyclyl; each of R'and R/, R*and R!, R® and R*, R* and R*, R* and R* are independently hydrogen, C,salkyl, C5; alkenyl, phenyl, or C , heterocyclyl; in addition, R and R}, and R* and R', R*®* and R*, R* and

R*, and R* and R*, 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® is hydrogen, C,_s alkyl, phenyl, or C ,5 heterocyclyl, C , acyl, aroyl,

R°0C=0, R"®¥R"NC=0, R*SO, RS0,, or R"®R"*NSO,;

R" is hydrogen, C,_ alkyl, phenyl, or C , 5 heterocyclyl; alternatively, R® and R" can be taken together to form an optionally substituted 4- to 7- membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;

R* and R" independently are hydrogen , C, ; alkyl, phenyl, or C , heterocyclyl; alternatively, R'" and R" 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, 1or2;

G is C,¢ alkenediyl or C,, alkanediyl, optionally substituted with hydroxy, halogen, C, salkyl, C, alkoxy, oxo, hydroximino, CO,R¥, NR'R!, (L)-C ,, ‘ alkylene-, R'RINCO,, [(L)-C , 5 alkylenelamino, N;, or (L)-C, ; alkoxy;

L is amino, mono- or di-C, ; alkylamino, pyrrolidinyl, morpholinyl, i piperidinyl, homopiperidinyl, or piperazinyl, wherein available ring nitrogens can be optionally substituted with C, 5 alkyl, benzyl, C,sacyl, 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, alkenyl, cyano, azido, nitro,

RZR%N, R*S, R¥S0, R%S0,, R20C=0, RZR®NC=0, C4 haloalkyl, C,. s haloalkoxy, C,_; haloalkyithio, and C,; alkylthio;

R# is hydrogen, C,salkyl, C,salkenyl, phenyl, benzyl, C ,5 heterocyclyl, C ,, acyl, aroyl, R""OC=0, R*R*NC=0, R"'S, R''SO, R"'S0O,, or

R*R*®NSO,;

R%® is hydrogen, C,salkyl, phenyl, benzyl, or C , 5 heterocyclyl; alternatively, R?? and R? can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;

R* and R* are independently hydrogen, C, salkyl, phenyl, benzyl, or C , 4 heteroaryl; alternatively, R** and R* 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* is hydrogen, C,salkyl, cyano, C, hydroxyalkyl, C,, acyl, -(C=0)NR'R*,

CHO, or C, ; alkoxycarbonyl, wherein each of R' and R* is independently selected from H , C; alkyl, C, 5 hydroxyalkyl, C,; heterocyclyl, (C, 5 heterocyclyl) C,; alkylene, C, ; aminoalkylene, C, 4 acyloxy, CHO, C, alkoxycarbonyl, and cyano; -Q is NR®, S, or O;

R* represents hydrogen, C, alkyl, phenyl, benzyl, phenethyl, C, heterocyclyl, (C..; heterocyclyl)C ,; alkylene, C,; acyl, aroyl, R®*0OC=0,

R¥R¥NC=0, R¥S0, R*S, R*S0, and R®*R¥NSO,;

R* is selected from hydrogen, C, alkyl, phenyl, benzyl, phenethyl, and C , heteroaryl; : R% and R¥ are each independently selected from hydrogen, C, salkyl, phenyl, or C ,5 heteroaryl; ) alternatively, R* and R¥ 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 co optionally and independently substituted with between 1 and 3 i 5 substituents selected from methyl, halomethyl, hydroxymethyl, halo, hydroxy, amino, nitro, cyano, C , alkyl, C ,; alkoxy, -COOH, C ,; acyl, [di(C 4 alkyl)amino]C , 5 alkylene, [di(C , alkyl)amino] C , alkyl-NH-

CO-, and C , 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 (1) 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 (1), methods of ’ 5 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?). 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 frans 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 cycloalkyny!.

Claims (70)

1. A compound of formula (1): . 5 RS G R32 N~ ONT "\ Ar =~ NE In =~ Q R RS R6 TW If N\ y—S t) wherein: the dashed line adjacent C-R® is absent or an sp? bond; Y is nitrogen or R*C; Z is nitrogen or R?'C; T is nitrogen or R*C; S is nitrogen or RC; 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'-O" where the remaining three are not nitrogen; R* is selected from hydrogen, halogen, C,s alkoxy, hydroxy, C, alkyl, cyano, nitro, C, haloalkyl, R°RPN, R°R"NC=0, C, acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)- C ,; alkylene, phenyl, (phenyl)C , 5 alkylene, R™*OC=0, R"S, R™S0, and R"“S0,; 'R? is selected from hydrogen, halogen, C, s alkoxy, hydroxy, C, alkyl, cyano, nitro, C, ; haloalkyl, R°RN, R°RINC=0, C,z acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C ,; alkylene, phenyl, (phenyl)C , 5 alkylene, R"™0C=0, R"S, R"SO and R"*SO,;

R? is selected from hydrogen, halogen, C, alkoxy, hydroxy, C, alkyl, cyano, nitro, C, haloalkyl, R°RN, R°RINC=0, C,; acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C , 5 alkylene, phenyl, (phenyl)C , 5 alkylene, R"°OC=0, RS, R"®SO and R'"S0O,, . 5 R is selected from hydrogen, halogen, C, alkoxy, hydroxy, C, alkyl, cyano, nitro, C, ; haloalkyl, R%R"N, C,, acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)- C , 5 alkylene, phenyl, (phenyl)C , alkylene, R70OC=0, R"R"NC=0, R"R"NSO,, R"’S, R""SO and R""SO,; R® and R® are independently selected from hydrogen and C, alkyl;

R” and R®independently are hydrogen, C,; alkyl, C, alkenyl, C, alkoxy, C, alkylthio, halogen, or 4-7 membered carbocyclyl or heterocyclyl; alternatively, R” and R® 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'S-, R'O(C , alkylene)-, R'O(C=0)-, R{(C=0)-, R(C=S)-, R{(C=0)0-, R'O(C=0)(C=0)-, R'SO,, NHRY(C=NH)-, NHR"SO,-, and NHR*(C=0)-;

R is C 4 alkyl, phenyl, benzyl, phenethyl, or C , heterocyclyl, (C heterocyclyl)C ,; alkylene, NH,, mono- or di(C , alkyl)N-, or R®OR%-, wherein R* is H, C , alkyl, C ,; alkenyl, phenyl, benzyl, phenethyl, C , heterocyclyl, or (C , heterocyclyl)C , alkylene and R® is C , 5 alkylene, phenylene, or divalent C , ; heterocyclyl; and

R’ can be H in addition to the values for RY;

R° is hydrogen, C, alkyl, phenyl, C , heterocyclyl, C ,; acyl, aroyl, R*0OC=0-, RRNC=0, R"SO-, R"SO,-, and RRINSO,;

R® is hydrogen, C,;alkyl, phenyl, C, heterocyclyl, C ,; acyl, aroyl, R*0C=0, R®R*NC=0, R*S0, R*SQ,, and R®R*“NSO; R™ is hydrogen, C,salkyl, phenyl, C , heterocyclyl, C ,, acyl, aroyl,

R*0OC=0, R*R*NC=0, R*'SO, R*'SO,, and R®R*NSO, ;

R° is hydrogen, C, alkyl, phenyl, C ,5 heterocyclyl, C ,; acyl, aroyl, R*?0C=0, RYR*NC=0, R*S0, R*S0O,, and RYR*®NSO,;

each of R, R', R", and RP is independently selected from hydrogen, C, alkyl, phenyl, and C 5 heterocyclyl; in addition, R® and R?, R® and R', R™ and R", or R° and RP, independently, can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring } 5 may be saturated, unsaturated or aromatic; each of R®, R", R"", R™, R"®, R™®, R”, R*, R”, and R* is independently C, alkyl, phenyl, or C ,; heterocyclyl; each of R'and R/, R*and R, R® and R*, R* and R%, R* and R* are independently hydrogen, C, alkyl, C, alkenyl, phenyl, or C 5 heterocyclyl; in addition, R' and RJ, and Rand R', R* and R*, R* and R*, and R* and R*, independently, can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic; RY is hydrogen, C, ; alkyl, phenyl, or C , heterocyclyl, C ,, acyl, aroyl, R°0C=0, R"™R'"NC=0, R°SO, R°S0,, or R"®*R'*NSO,; R" is hydrogen, C,; alkyl, phenyl, or C , 5 heterocyclyl: alternatively, R? and R" can be taken together to form an optionally ~ substituted 4- to 7- membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;

R¥and R" independently are hydrogen , C, alkyl, phenyl, or C , heterocyclyl: alternatively, R™ and R™ can be taken together to form an optionally substituted 4- to 7- membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;

n is0, 1o0r2;

GC is C4 alkenediyl or C4 alkanediyl, optionally substituted with hydroxy, halogen, C, alkyl, C, ;alkoxy, oxo, hydroximino, CO,R¥, NR'R, (L)-C ,., alkylene-, R'RNCO,, [(L)-C ,; alkylene]amino, N,, or (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 C, 5 alkyl, benzyl, C, acyl, C

1s 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, s alkoxy, C, alkyl, C, alkenyl, cyano, azido, nitro, RZR®N, R¥S, R¥ZS0, R*S0,, RZ0C=0, R?R®NC=0, C,; haloalkyl, C,. s haloalkoxy, C, ; haloalkylthio, and C, 5 alkylthio; R#? is hydrogen, C, alkyl, C, alkenyl, phenyl, benzyl, C , heterocyclyl, C ,, acyl, aroyl, R"OC=0, R*R*NC=0, R"'S, R"'SO, R"'SO,, or R*R®NSO,; R#® is hydrogen, C, salkyl, phenyl, benzyl, or C , heterocyclyl; alternatively, R? and R® can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic; R* and R* are independently hydrogen, C, s alkyl, phenyl, benzyl, or C heteroaryl; alternatively, R** and R* 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* is hydrogen, C, alkyl, cyano, C, hydroxyalkyl, C,, acyl, (C=O)NR'R¥, CHO, or C,; alkoxycarbonyl, wherein each of R* and R* is independently selected from H , C,; alkyl, C, 5 hydroxyalkyl, C, 5 heterocyclyl, (C, heterocyclyl) C, 5 alkylene, C, ; aminoalkylene, C,, acyloxy, CHO, C. alkoxycarbonyl, and cyano; Q is NR®, S, or O; R*® represents hydrogen, C, alkyl, phenyl, benzyl, phenethyl, C, heterocyclyl, (C,s heterocyclyl)C , ; alkylene, C,, acyl, aroyl, R*0C=0, R*¥RYNC=0, R¥*S0, R*S, R*S0, and R*R¥NSO,; R® is selected from hydrogen, C, alkyl, phenyl, benzyl, phenethyl, and C , heteroaryl; R* and R¥ are each independently selected from hydrogen, C, alkyl, phenyl, or C , heteroaryl; i alternatively, R* and R¥ 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 5 alkyl, C , alkoxy, -COOH, C ,, acyl, [di(C ,, alkyl)amino]C , alkylene, [di(C ,_, alkyl)amino] C , 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® and CR?, respectively.

4. A compound of claim 1, wherein S, T, Y, and Z are CR®, CR? CR?, and CR?, respectively.

5. A compound of claim 1, wherein: (@)ZisN,YisN, Sis CR? and T is CR% or (b)SisN, TisN,Yis CR®, and Z is CR*..

6. A compound of claim 1, wherein R?is hydrogen, halogen, C, alkoxy, cyano, R°R'N, or a 5-6 membered heterocyclyl.

7. A compound of claim 1, wherein R® is hydrogen, halogen, C, 4 alkoxy, Cs alkyl, cyano, R"OC=0, or R®R"N, where R? and Rare Hor C ,., alkyl, or are taken together to form a 5-6 membered heterocyclyl.

8. Acompound of claim 1, wherein each of R? and R® is independently selected from hydrogen, halogen, and a 5-6 membered heterocyclyl.

9. A compound of claim 1, wherein R® and R® are independently selected from hydrogen and C,; alkyl.

10. A compound of claim 9, wherein one of R® and R® is H. v 5

11. A compound of claim 10, wherein R® and R® are each H.

12. A compound of claim 1, wherein one of R” and R® is H and the other is 5-7 membered carbocyclyl or heterocyclyl.

13. A compound of claim 1, wherein R” and R® are taken together to form an optionally substituted 5- to 7- membered carbocyclic or heterocyclic ring.

14. A compound of claim 13, wherein R” and R® are taken together to form a six-membered heterocyclyl.

15. A compound of claim 13 wherein R” and R® taken together form a 5-7 membered heterocyclyl optionally N-substituted with R(C=0)-, R'SO,-, : or NHR*(C=0)- wherein R'is C ,; alkyl, phenyl, or C , heterocyclyl and R"is H, C , alkyl, phenyl, or C , heterocyclyl.

16. A compound of claim 1, wherein each of R%, R®, R™, and R° is independently selected from hydrogen, C, alkyl, C,sacyl, (C 5 alkyl)OC=0, and the respective RRNC=0, RSO, RSO,, and RRNSO, groups.

17. A compound of claim 1, wherein each of R°, RY, R%, R", R°, Rf, and RP is independently selected from hydrogen and C, alkyl; or, independently, : R® and R', R? and R", or R° and RP taken together form an optionally substituted 4- to 7- membered carbocyclic or heterocyclic ring.

18. A compound of claim 17 wherein R® and R’ taken together are morpholinyl, piperidinyl, or pyrrolidinyl.

19. A compound of claim 1, wherein each of R®, R¥, R®, R*, RY, R*¥,R', Rl , Rand R' independently is hydrogen or C,_; alkyl.

20. A compound of claim 1, wherein each of R®, R", R", RS, R"®and R" is independently C, ; alkyl.

21. A compound of claim 1, wherein R? is C, salkyl, C ,, acyl, R°OC=0, R*®R"NC=0, R’SO, R°*S0,, or R"®*R"NSO,; and R" is H or C, alkyl; alternatively, R? and R" can be taken together to form an optionally substituted 5- to 6-membered heterocyclyl.

22. A compound of claim 21, wherein R? and R" are each C ,, alkyl.

23. A compound of claim 1, wherein R' and R' 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,, alkanediyl, optionally substituted with hydroxy, halogen, [(L)-C ,_; alkylene]amino, or (L)-C, alkyloxy.

26. A compound of claim 25, wherein G is C; alkanediyl, optionally substituted with hydroxy. -

27. A compound of claim 1, wherein R® and R?' are independently selected from hydrogen, halogen, C, alkoxy, C,salkyl, cyano, nitro, 4-7 membered heterocyclyl, and R°RPN or R°R°N, respectively.

28. A compound of claim 27, wherein R® and R* are independently selected from hydrogen, halogen, 5- to 6-membered heterocyclyl, and R°RPN or R°RN, respectively.

29. A compound of claim 1, wherein Ar represents a monocyclic ring, optionally substituted with 1 to 2 substituents selected from halogen, C,salkyl, cyano, nitro, R?R®N, C,_; haloalkyl, and C,_;haloalkoxy. : 5

30. A compound of claim 29, wherein Ar is a six-membered aromatic ring monosubstituted at the 4-position with halogen, methyl, CF,, or OCF,, or disubstituted at the 3- and 4-positions with substituents independently selected from halogen, CF;, methyl, and OCF,.

31. A compound of claim 29, wherein each of RZ, R%, and R* is independently hydrogen or C, ; alkyl.

32. A compound of claim 1, wherein R* and R* independently are hydrogen or C, 5 alkyl, or, alternatively, R* and R* 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® and R% independently are hydrogen or C, ; alkyl.

34. A compound of claim 1, wherein Q is NR** or S.

35. A compound of claim 34, wherein Q is NR*®, R® is H or C, heterocyclyl, and R*®is H, C ,; alkyl, C, hydroxyalkyl, (C=O)NR'R*, CHO, or C ,, alkoxycarbonyl, wherein each of R* and R* is independently selected from H, C ,s hydroxyalkyl, (C , 5 heterocyclyl)-C , ; alkylene, and C aminoalkylene.

36. A compound of claim 34, wherein Q is S and R* is NR¥*R¥(C=0)- where each of R*® and R¥ are independently selected from hydrogen and C, alkyl.

37. A compound of claim 1, wherein R* is selected from hydrogen and C,s alkyl; R* and R¥ are each independently selected from hydrogen,

C,.s alkyl, or, alternatively, R* and R* 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*C; Z is nitrogen or R*'C; T is nitrogen or RC; S is nitrogen or R°C; provided between O and 2 of S, T, Y, and Z are nitrogen; R? is hydrogen, halogen, hydroxy, C, ; alkoxy, C, ; alkyl, 5- to 6- membered heterocyclyl, or R°R'N; R® is hydrogen, halogen, C, alkoxy, hydroxy, C,salkyl, , 5- to 6- membered heterocyclyl, or R°R"N; R® and R® are each H; R” and R® independently are taken together to form an optionally substituted 5- to 7- membered unsaturated heterocyclic ring; each of R*R®, R™, and R° is independently selected from hydrogen, C, ; alkyl, C 5 acyl, (C,5alkyl)OC=0, and the respective RRNC=0, RSO, RSO,, and RRNSO, groups; each of R® R’, R", and RP, is independently selected from hydrogen and C, alkyl; each of R%, R", RR", R", R", R®, R* and R* is independently C, ; alkyl; each of R°, RY, R', RI, R®, R* R*, R®, R¥ Rand R' are independently are hydrogen or C, ; alkyl; RY is hydrogen, or C, alkyl, C ,, acyl, R®OC=0, R"®¥R'NC=0, R°SO, R°SO0,, or R®¥R"*NSO,; R" is hydrogen or C, alkyl; alternatively, R? and R" 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™ and R" independently are hydrogen or C, ; alkyl; nis0or1; G is Cy, alkenediyl or C,, alkanediyl, optionally substituted with hydroxy, halogen, C, ;alkyloxy, oxo, hydroximino, CO,R¥, R‘RINCO,, N,, or (L)-C,. s alkoxy; L is amino, mono- or di-C, ; alkylamino, pyrrolidinyl, morpholinyl, piperidinyl homopiperidinyl, or piperazinyl, available ring nitrogens being optionally with C5 alkyl, benzyl, C,sacyl, or C, 5 alkyloxycarbonyl; R* and R* are independently selected from hydrogen, halogen, C,s alkoxy, C,salkyl, cyano, nitro, and R°R°N; alternatively, R® and R* or R® and R* 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, salkyl, cyano, nitro, R”R®N, R*S0,, R*0C=0, R®*R*NC=0, CF,, OCF,, SCF,, or C, alkylthio; R* is hydrogen, C, salkyl, phenyl, benzyl, phenethyl, C, heteroaryl, C,, acyl, aroyl, R*0C=0, R*R*NC=0, R*S0, R*S0,, or R*R®NSO0,; R?® is hydrogen or C, alkyl; ) alternatively, R* and R* 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* is hydrogen or C, alkyl; R® and R* are independently hydrogen or C, z alkyl; or, alternatively, R* and R® 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* is hydrogen, C, alkyl, C,; hydroxyalkyl, CHO, C , acyl, C 4 alkoxycarbonyl, or -(C=0)NR'R*, wherein each of R'R* is independently } selected from H, C ; alkyl, C, 5 hydroxyalkyl, C , acyloxy, (amino)C , alkylene, (C , heterocyclyl)C , 5 alkylene, or C , alkoxycarbonyl; Qis NR®¥ or S;

R*® represents hydrogen, C,; alkyl, phenyl, benzyl, (C ,; heterocyclyl)C , 5 alkylene, C , acyl, aroyl, R*0C=0, R*R*NC=0, R¥S0, and R¥R¥NSO,; R¥ is selected from hydrogen and C, alkyl;

a. 5 R%* and R¥ are each independently selected from hydrogen and C, ; alkyl.

39. A compound of claim 1, wherein one of R® and R% is H, R” and R® 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?R*N, CF, and OCF,

40. A compound of claim 39, wherein both R® and R® are each H, and Ar is a six membered ring substituted with halogen, CF,, methyl, halomethyl, or OCF, at the 3- or 4- position, or disubstituted at the 3- and 4- positions.

41. A compound of claim 40, wherein R” and R® taken together form pyridinyl, pyrimidinyl, or piperazinyl, optionally N-substituted with — (C=0O)R!, SO,-R!, or -(C=0)NHR®".

42. A compound of claim 39, wherein RZ and R® taken together are independently morpholinyl, piperidyl, or pyrrolidinyl, optionally substituted.

43. A compound of claim 1, wherein the dashed line adjacent C-R® is absent.

44. A compound of claim 1, selected from: 1-[4-(5-Chloro-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-(7-Chloro-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-(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-yi]-propan-2-ol; 1-{4-[6-Chloro-1-(2-morpholin-4-yi-ethyl)-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-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl}-3-[4-(1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-ylj- propan-2-ol; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yI]-3-[4-(1H-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-1H-pyrrolo[2,3-c]pyridin-3-yl)- piperidin-1-yl]-propan-2-ol; 1-[4-(6-Dimethylamino-1H-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- clpyridin-1-yiJ-propan-2-ol; 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyi)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yi]-3-[4-(6-morpholin-4-yl-1H-pyrrolo[3,2-c]pyridin-3-yi)- 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-5-oxy-1H-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-pyrazolof4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)benzobjthiophene- 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[bjthiophene- 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[bjthiophene- 2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide.

45. A compound of claim 1, selected from: 1-[1-{2-Hydroxy-3-[4~(1H-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-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-[3-(4-Bromo-phenyl)-5-methanesulfonyi-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-chloro-1H-indol-3-yl)-piperidin-1-yl)-propan- 2-0l ; 1-[3~(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yl}-3-[4-(5-chioro-2-methyl-1H-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-1H-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-y1)-1H-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-1H-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)-1H-indole- 5-carboxylic acid ethyl ester ; 1-[4-(6-Chloro-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-y{]-propan-2- ol; 1-[1-(3-{4-[6-Chloro-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-piperidin-1- yl}-2-hydroxy-propyl)-3-(4-trifluoromethyi-phenyl)-1,4,6,7-tetrahydro- pyrazolof4,3-c]pyridin-5-yl]-ethanone ;

1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolof4,3-c]pyridin-1-yl]-3-[4-(1 H-pyrrolo[3,2-b]pyridin-3-yl)-piperidin-1 -yl}- propan-2-ol ;

1-[5-Methanesulfonyi-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-ylI]-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-(5-0oxy-1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin- 1-yl}-propan-2-ol ;

1-[4-(5-Dimethylamino-1H-pyrrolo[3,2-b]pyridin-3-yl)-piperidin-1-yI]-3-[5-

methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-1-yi}-propan-2-ol ;

1-[4-(5-Dimethylamino-1H-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-of ;

3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)- 4,5,6,7-tetrahyd ro-pyrazolo[4,3-c]pyridin-1 -yi}-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-yi]-3-{4-[1-(2-morpholin-4-yl-ethyl)-1H-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- pyrazolof4,3-c]pyridin-1-yl]-3-[4-(7-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yi)- piperidin-1-yl]-propan-2-ol ;

1 [4~(6-Fluoro-2-hydroxymethyl-benzob]thiophen-3-yl)-piperidin-1 -yi]-3- [5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3- clpyridin-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)- benzol[bjthiophene-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)-1H-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; 6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-pheny!)-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-1H-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-yi]-propan-2-ol.

47. A compound of claim 1, selected from: 1-(3-(4-Chloro-3-methyl-phenyl)-1-{2-hydroxy-3-[4~(1H-indol-3-yi)- piperidin-1-yl]-propyi}-1,4,6,7-tetrahyd ro-pyrazolo[4,3-c]pyridin-5-yi)-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-1H-indol-3-yl)-piperidin-1-yl}-propyl}-5- methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine;

3-(1 {2-Hyd roxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)- 4,5,6,7-tetrahydro-pyrazolof4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1H-indole- 5-carbonitrile;

' 1-[4-(6-Chloro-1-methyl-1H-indol-3-yl)-piperidin-1-yl}-3-[5-

methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-

clpyridin-1-yl]-propan-2-ol; 1-[4-(6-Chloro-1-methanesulfonyl-1H-indol-3-yl)-piperidin-1-y{]-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-1H-indol-3-yl)-piperidin-1-yl]-propan- 2-ol;

3-(1-{3-[3-(4-Bromo-phenyi)-5-methanesulfonyl-4,5,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-1-yi}-2-hydroxy-propyl}-piperidin-4-yl)-1H-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-yi-ethyl)-1H-indol-3- yi]-piperidin-1-yl}-propan-2-of;

1-{3-(4-Bromo-phenyl)-1-(3-{4-[6-chloro-1-(2-morpholin-4-yl-ethy!)-1H-

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-(1H-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-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidin-1-yl}- propan-2-ol;

1-(3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(1H-pyrrolo[2,3-b]pyridin-3-yi)- 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)-1H-pyrrolo[2,3-bjpyridin- 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-(1H-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-(1H-pyrrolo[2,3-b]pyridin-3-yi)-piperidin-1-yi}- propyl}-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- clpyridine.

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)-1H-pyrrolo[2,3- b]pyridin-3-yi}-piperidin-1-yi}-propan-2-ol; 1-[3-(4-Bromo-phenyl)-1-~(2-hydroxy-3-{4-[1-(2-morpholin-4-yl-ethyl)-1H- pyrrolof2,3-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-1H-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-1H-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-yi]-3-[4-(6-morpholin-4-yl- 1H-pyrrolo[2,3-b]pyridin-3-yl)- piperidin-1-yl}-propan-2-ol;

1-[1-{2-Hydroxy-3-[4-(1H-pyrrolo[3,2-c]pyridin-3-yi)-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- pyrazolof4,3-c]pyridin-1-yli}-3-[4-(1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]- propan-2-ol; 1-(3-(4-Bromo-phenyl)-1-{2-hydroxy-3-[4-(1H-pyrrolo[3,2-c]pyridin-3-y)- piperidin-1-yl}-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yi)-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-yi}-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]blthiophene-2-carboxylic acid methyl ester;

1-[4-(6-Fluoro-benzo[bjthiophen-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-yI]- 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[blthiophene-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- pyrazolof4,3-c]pyridin-1-yl]-2-hydroxy-propy!}-piperidin-4-yl)-6-fluoro- benzo[b]thiophene-2-carbonitrile; and

PCT/US01/25180 6-Fluoro-3-(1-{2-hydroxy-3-[56-methanesulfonyl-3-(4-trifluoromethyl- phenyl)-4,5,6,7-tetrahydro-pyrazolo{4,3-clpyridin-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. Use of a compound of claim 1, 38, 44, 45, or 46 in the manufacture of a medicament for treating a subject with a condition that is modulated by the inhibition of cathepsin S.

51. Use of a compound of claim 1, 27, 44, or 46 in the manufacture of a medicament for inhibiting cathepsin S activity in a subject.

52. Use of a compound of claim 1, 27, 44 or 46 in the manufacture of a medicament for treating an autoimmune disease, or inhibiting the progression of an autoimmune disease, in a subject.

53. Use of claim 52, wherein the autoimmune disease is selected from lupus, rheumatoid arthritis, and asthma.

54. Use of claim 52, wherein the autoimmune disease is asthma.

55. Use of a compound of claim 1, 27, 44 or 46 in the manufacture of a medicament for treating or inhibiting the progression of tissue transplant rejection in a subject, by administering to the subject a therapeutically effective amount of said medicament.

56. Use of claim 55, wherein said administration occurs after said subject has undergone a tissue transplant procedure. 117 AMENDED SHEET

' PCT/US01/25180

57. Use of claim 55, wherein said administration to said subject occurs before or during a tissue transplant procedure.

58. A substance or composition for use in a method for treating a subject with a condition mediated by cathepsin S, said substance or composition comprising a compound of claim 1, 38, 44, 45, or 46, and said method comprising administering to the subject a therapeutically effective amount of said substance or composition.

59. A substance or composition for use in a method for inhibiting cathepsin S activity in a subject, said substance or composition comprising a compound of claim 1, 27, 44, or 46, and said method comprising administering to the subject a therapeutically effective amount of said substance or composition.

60. A substance or composition for use in a method for treating an autoimmune disease, or inhibiting the progression of an autoimmune disease, in a subject, said substance or composition comprising a compound of claim 1, 27, 44 or 46, and said method comprising administering to the subject a therapeutically effective amount of said substance or composition.

61. A substance or composition for use in a method of treatment of claim 60, wherein the autoimmune disease is selected from lupus, rheumatoid arthritis, and asthma.

62. A substance or composition for use in a method of treatment of claim 60, wherein the autoimmune disease is asthma.

63. A substance or composition for use in a method for treating or inhibiting the progression of tissue transplant rejection in a subject, 118 AMENDED SHEET

PCT/US01/25180 said substance or composition comprising a compound of claim 1, 27,

. 44 or 46, and said method comprising administering to the subject a therapeutically effective amount of said substance or composition.

64. A substance or composition for use in a method of treatment of claim 63, wherein said administration occurs after said subject has undergone a tissue transplant procedure.

65. A substance or composition for use in a method of treatment of claim 63, wherein said administration to said subject occurs before or during a tissue transplant procedure.

66. A compound according to any one of claims 1 to 48, substantially as herein described and illustrated.

67. A composition according to claim 49, substantially as herein described and illustrated.

68. Use according to any one of claims 50 to 57, substantially as herein described and illustrated.

69. A substance or composition for use in a method of treatment according to any one claims 58 to 65, substantially as herein described and illustrated.

70. A new compound, a new composition, a new use of a compound as claimed in any one of claims 1 to 48, or a substance or composition for a new use in a method of treatment, substantially as herein described. 119 AMENDED SHEET