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.

What is claimed is:  
     
         1 . A method for inhibiting the proteolitic activity of cathepsin S, comprising exposing cathepsin S to an effective amount of a compound of formula (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 that one of S, T, Y, and Z is nitrogen; and further provided that one of S, T, Y, and Z can be ═N + —O −  with the remaining three not being nitrogen;  
 
 R 20  is selected from hydrogen, halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, cyano, nitro, C 1-5  haloalkyl, R 0 R p N, R 0 R p NC═O, C 2-8  acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C 1-5  alkylene, phenyl, (phenyl)C 1-5  alkylene, R 14 OC═O, R 14 S, R 14 SO, and R 14 SO 2 ;  
 R 21  is selected from hydrogen, halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, cyano, nitro, C 1-5  haloalkyl, R c R d N, R c R d NC═O, C 2-8  acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C 1-5  alkylene, phenyl, (phenyl)C 1-5  alkylene, R 15 OC═O, R 15 S, R 15 SO, and R 15 SO 2 ;  
 R 2  is selected from hydrogen, halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, cyano, nitro, C 1-5  haloalkyl, R e R f N, R e R f NC═O, C 2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C 1-5  alkylene, phenyl, (phenyl)C 1-5  alkylene, R 16 OC═O, R 16 S, R 16 SO, and R 16 SO 2 ;  
 R 3  is selected from hydrogen, halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, cyano, nitro, C 1-5  haloalkyl, R g R h N, C 2-8  acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl)-C 1-5  alkylene, phenyl, (phenyl)C 1-5  alkylene, R 17 OC═O, R m R n NC═O, R m R n NSO 2 , R 17 S, R 17 S, and R 17 SO 2 ;  
 R 5  and R 6  are independently selected from hydrogen and C 1-5  alkyl;  
 R 7  and R 8  independently are hydrogen, C 1-5  alkyl, C 1-5  alkenyl, C 1-5  alkoxy, C 1-5  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 t , R t O—, R t S—, R t O(C 1-5  alkylene)-, R t O(C═O)—, R t (C═O)—, R t (C═S)—, R t (C═O)O—, R t O(C═O)(C═O)—, R t SO 2 , NHR u (C═NH)—, NHR u SO 2 —, and NHR u (C═O)—;  
 R t  is C 1-6  alkyl, phenyl, benzyl, phenethyl, or C 2-5  heterocyclyl, (C 1-5  heterocyclyl)C 1-6  alkylene, NH 2 , mono- or di(C 1-6  alkyl)N—, or R 49 OR 50 —, wherein R 49  is H, C 1-5  alkyl, C 2-5  alkenyl, phenyl, benzyl, phenethyl, C 1-5  heterocyclyl, or (C 1-5  heterocyclyl)C 1-6  alkylene and R 50  is C 1-5  alkylene, phenylene, or divalent C 1-5  heterocyclyl; and  
 R u  can be H in addition to the values for R t ;  
 R c  is hydrogen, C 1-5  alkyl, phenyl, C 2-5  heterocyclyl, C 2-8  acyl, aroyl, R 10 OC═O—, R i R j NC═O, R 10 SO—, R 10 SO 2 —, and R i R j NSO 2 ;  
 R e  is hydrogen, C 1-5  alkyl, phenyl, C 2-5  heterocyclyl, C 2-8  acyl, aroyl, R 40 OC═O, R 43 R 44 NC═O, R 40 SO, R 40 SO 2 , and R 43 R 44 NSO 2 ;  
 R m  is hydrogen, C 1-5  alkyl, phenyl, C 2-5  heterocyclyl, C 2-8  acyl, aroyl, R 41 OC═O, R 45 R 46 NC═O, R 41 SO, R 41 SO 2 , and R 45 R 46 NSO 2 ;  
 R o  is hydrogen, C 1-5  alkyl, phenyl, C 2-5  heterocyclyl, C 2-8  acyl, aroyl, R 42 OC═O, R 47 R 48 NC═O, R 42 SO, R 42 SO 2 , and R 47 R 48 NSO 2 ;  
 each of R d , R f , R n , and R p  is independently selected from hydrogen, C 1-5 alkyl, phenyl, and C 2-5  heterocyclyl; in addition, R c  and R d , R e  and R f , R m  and R n , or R o  and R p , independently, can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;  
 each of R 9 , R 10 , R 11 , R 14 , R 15 , R 16 , R 17 , R 40 , R 41 , and R 42  is independently C 5  alkyl, phenyl, or C 2-5  heterocyclyl;  
 each of R i  and R j , R k  and R l , R 43  and R 44 , R 45  and R 46 , R 47  and R 48  are independently hydrogen, C 1-5  alkyl, C 3-5  alkenyl, phenyl, or C 2-5  heterocyclyl; in addition, R i  and R j , and R k  and R l , 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 g  is hydrogen, C 1-5 alkyl, phenyl, or C 2-5  heterocyclyl, C 2-8  acyl, aroyl, R 9 OC═O, R 18 R 19 NC═O, R 9 SO, R 9 SO 2 , or R 18 R 19 NSO 2 ;  
 R h  is hydrogen, C 1-5 alkyl, phenyl, or C 2-5  heterocyclyl; 
 alternatively, R g  and R h  can be taken together to form an optionally substituted 4- to 7-membered heterocyclic ring, which ring may be saturated, unsaturated or aromatic;  
 
 R 18  and R 19  independently are hydrogen, C 1-5  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 1-5 alkyl, C 1-5  alkoxy, oxo, hydroximino, CO 2 R k , NR k R l , (L)—C 1-4  alkylene-, R k R l NCO 2 , [(L)—C 1-5  alkylene]amino, N 3 , or (L)—C 1-5  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 C 1-5  alkyl, benzyl, C 2-5 acyl, C 1-5  alkylsulfonyl, or C 1-5  alkoxycarbonyl;  
 Ar represents a monocyclic or bicyclic aryl or heteroaryl ring, optionally substituted with between 1 and 3 substituents independently selected from halogen, C 1-5 alkoxy, C 1-5 alkyl, C 2-5 alkenyl, cyano, azido, nitro, R 22 R 23 N, R 22 S, R 22 SO, R 22 SO 2 , R 22 OC═O, R 22 R 23 NC═O, C 1-5  haloalkyl, C 1-5  haloalkoxy, C 1-5  haloalkylthio, and C 1-5  alkylthio;  
 R 22  is hydrogen, C 1-5 alkyl, C 3-5 alkenyl, phenyl, benzyl, C 2-5  heterocyclyl, C 2-8  acyl, aroyl, R 11 OC═O, R 24 R 25 NC═O, R 11 S, R 11 SO, R 11 SO 2 , or R 24 R 25 NSO 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, C 1-5  alkyl, 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, C 1-5  hydroxyalkyl, C 2-8  acyl, —(C═O)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, C 1-5  hydroxyalkyl, C 1-5  heterocyclyl, (C 1-5  heterocyclyl) C 1-5  alkylene, C 15  aminoalkylene, C 3-8  acyloxy, CHO, C 1-6  alkoxycarbonyl, and cyano;  
 Q is NR, S, or O;  
 R 33  represents hydrogen, C 1-5  alkyl, phenyl, benzyl, phenethyl, C 2-5  heterocyclyl, (C 2-5  heterocyclyl)C 1-5  alkylene, C 2-8  acyl, aroyl, R 35 OC═O, R 36 R 37 NC═O, R 35 SO, R 35 S, R 35 SO 2  and R 36 R 37 NSO 2 ;  
 R 35  is selected from hydrogen, C 1-5  alkyl, phenyl, benzyl, phenethyl, and C 2-5  heteroaryl;  
 R 36  and R 37  are each independently selected from hydrogen, C 1-5  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 1-5  alkyl, C 1-5  alkoxy, —COOH, C 2-6  acyl, [di(C 1-4  alkyl)amino]C 2-5  alkylene, [di(C 1-4  alkyl)amino] C 2-5  alkyl-NHCO—, and C 1-5  haloalkoxy;  
 or a pharmaceutically acceptable salt, amide, or ester thereof; or a stereoisomeric form thereof.  
 
     
     
         2 . A method according to  claim 1 , wherein Y is N, S is CR 3 , and T is CR 2 .  
     
     
         3 . A method according to  claim 1 , wherein S and T are CR 3  and CR 2 , respectively.  
     
     
         4 . A method according to  claim 1 , wherein T is N, Y is CR, and Z is CR 21 .  
     
     
         5 . A method according to  claim 1 , wherein: 
 (a) Z is N, S is CR 3 , and T is CR 2 ; or    (b) S is N, Y is CR 20 , and Z is CR 21 .    
     
     
         6 . A method according to  claim 1 , wherein R 2  is hydrogen, halogen, C 1-5  alkoxy, cyano, R e R f N, or a 5-6 membered heterocyclyl.  
     
     
         7 . A method according to  claim 1 , wherein R 3  is hydrogen, halogen, C 1-5  alkoxy, C 1-5  alkyl, cyano, R 17 OC═O, or R g R h N, where R g  and R h  are H or C 1-5  alkyl, or are taken together to form a 5-6 membered heterocyclyl.  
     
     
         8 . A method according to  claim 1 , wherein each of R 2  and R 3  is independently selected from hydrogen, halogen, and a 5-6 membered heterocyclyl.  
     
     
         9 . A method according to  claim 1 , wherein R 5  and R 6  are independently selected from hydrogen and C 1-3  alkyl.  
     
     
         10 . A method according to  claim 9 , wherein one of R 5  and R 6  is H.  
     
     
         11 . A method according to  claim 10 , wherein R 5  and R 6  are each H.  
     
     
         12 . A method according to  claim 1 , wherein one of R 7  and R 8  is H and the other is 5-7 membered carbocyclyl or heterocyclyl.  
     
     
         13 . A method according to  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 method according to  claim 13 , wherein R 7  and R 8  are taken together to form a six-membered heterocyclyl.  
     
     
         15 . A method according to  claim 13  wherein R 7  and R 8  taken together form a 5-7 membered heterocyclyl optionally N-substituted with R t (C═O)—, R t SO 2 —, or NHR u (C═O)— wherein R t  is C 1-6  alkyl, phenyl, or C 2-5  heterocyclyl and R u  is H, C 1-6  alkyl, phenyl, or C 2-5  heterocyclyl.  
     
     
         16 . A method according to  claim 1 , wherein each of R c , R e , R m , and R o  is independently selected from hydrogen, C 1-5  alkyl, C 2-8  acyl, (C 1-5  alkyl)OC═O, and the respective RRNC═O, RSO, RSO 2 , and RRNSO 2  groups.  
     
     
         17 . A method according to  claim 1 , wherein each of R c , R d , R g , R h , R o , R f , and R p  is independently selected from hydrogen and C 1-5  alkyl; or, independently, R e  and R f , R g  and R h , or R o  and R p  taken together form an optionally substituted 4- to 7-membered carbocyclic or heterocyclic ring.  
     
     
         18 . A method according to  claim 17  wherein R e  and R f  taken together are morpholinyl, piperidinyl, or pyrrolidinyl.  
     
     
         19 . A method according to  claim 1 , wherein each of R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R i , R j , R k  and R l  independently is hydrogen or C 1-5 alkyl.  
     
     
         20 . A method according to  claim 1 , wherein each of R 9 , R 11 , R 14 , R 15  R 16  and R 17  is independently C 1-5 alkyl.  
     
     
         21 . A method according to  claim 1 , wherein R 9  is C 1-5  alkyl, C 2-8  acyl, R 9 OC═O, R 18 R 19 NC═O, R 9 SO, R 9 SO 2 , or R 18 R 19 NSO 2 ; and R h  is H or C 1-5 alkyl; alternatively, R g  and R h  can be taken together to form an optionally substituted 5- to 6-membered heterocyclyl.  
     
     
         22 . A method according to  claim 21 , wherein R g  and R h  are each C 1-3  alkyl.  
     
     
         23 . A method according to  claim 1 , wherein R 18  and R 19  independently are hydrogen or C 1-5  alkyl.  
     
     
         24 . A method according to  claim 1 , wherein n is 1.  
     
     
         25 . A method according to  claim 1 , wherein G is C 3-4  alkanediyl, optionally substituted with hydroxy, halogen, [(L)—C 1-5  alkylene]amino, or (L)—C 1-5  alkyloxy.  
     
     
         26 . A method according to  claim 25 , wherein G is C 3  alkanediyl, optionally substituted with hydroxy.  
     
     
         27 . A method according to  claim 1 , wherein R 20  and R 21  are independently selected from hydrogen, halogen, C 1-5 alkoxy, C 1-5 alkyl, cyano, nitro, 4-7 membered heterocyclyl, and R o R p N or R c R d N, respectively.  
     
     
         28 . A method according to  claim 27 , wherein R 20  and R 21  are independently selected from hydrogen, halogen, 5- to 6-membered heterocyclyl, and R o R p N or R c R d N, respectively.  
     
     
         29 . A method according to  claim 1 , wherein Ar represents a monocyclic ring, optionally substituted with 1 to 2 substituents selected from halogen, C 1-5 alkyl, cyano, nitro, R 22 R 23 N, C 1-3 haloalkyl, and C 1-3 haloalkoxy.  
     
     
         30 . A method according to  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 method according to  claim 29 , wherein each of R 22 , R 23 , and R 24  is independently hydrogen or C 1-5 alkyl.  
     
     
         32 . A method according to  claim 1 , wherein 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.    
     
     
         33 . A method according to  claim 32 , wherein R 25  and R 26  independently are hydrogen or C 1-5  alkyl.  
     
     
         34 . A method according to  claim 1 , wherein Q is NR 33  or S.  
     
     
         35 . A method according to  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, C 1-5  hydroxyalkyl, —(C═O)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  hydroxyalkyl, (C 1-5  heterocyclyl)-C 1-5  alkylene, and C 1-5  aminoalkylene.  
     
     
         36 . A method according to  claim 34 , wherein Q is S and R 33  is NR 36 R 37 (C═O)— where each of R 36  and R 37  are independently selected from hydrogen and C 1-5 alkyl.  
     
     
         37 . A method according to  claim 1 , wherein R 35  is selected from hydrogen and C 1-5  alkyl; R 36  and R 37  are each independently selected from hydrogen, C 1-5  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 method according to  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 that one of S, T, Y, and Z is nitrogen;    R 2  is hydrogen, halogen, hydroxy, C 1-5  alkoxy, C 1-5  alkyl, 5- to 6-membered heterocyclyl, or R e R f N;    R 3  is hydrogen, halogen, C 1-5  alkoxy, hydroxy, C 1-5  alkyl, 5- to 6-membered heterocyclyl, or R g 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 o  is independently selected from hydrogen, C 1-5  alkyl, C 2-8  acyl, (C 1-5  alkyl)OC═O, and the respective RRNC═O, RSO, RSO 2 , and RRNSO 2  groups;    each of R b , R f , R n , and R p , is independently selected from hydrogen and C 1-5  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 1-5 alkyl;    each of R c , R d , R i , R j , R 43 , R 44 , R 45 , R 46 , R 47 , R k  and R l  are independently are hydrogen or C 1-5  alkyl;    R g  is hydrogen, or C 1-5  alkyl, C 2-8  acyl, R 9 OC═O, R 18 R 19 NC═O, R 9 SO, R 9 SO 2 , or R 18 R 19 NSO 2 ;    R h  is hydrogen or C 1-5  alkyl; 
 alternatively, R g  and R h  can be taken together to form an optionally substituted 4- to 7-membered 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;    G is C 3-4  alkenediyl or C 3-4  alkanediyl, optionally substituted with hydroxy, halogen, C 1-5 alkyloxy, oxo, hydroximino, CO 2 R k , R k R l NCO 2 , N 3 , or (L)—C 1-5  alkoxy;    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 1-5 alkyloxycarbonyl;    R 20  and R 21  are independently selected from hydrogen, halogen, C 1-5  alkoxy, C 1-5 alkyl, cyano, nitro, and R o 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 1-5  alkoxy, C 1-5  alkyl, cyano, nitro, R 22 R 23 N, R 24 O 2 , R 24 OC═O, R 25 R 26 NC═O, CF 3 , OCF 3 , SCF 3 , or C 1-5  alkylthio;    R 22  is hydrogen, C 1-5  alkyl, phenyl, benzyl, phenethyl, C 2-5  heteroaryl, C 2-8  acyl, aroyl, R 24 OC═O, R 25 R 26 NC═O, R 24 SO, R 24 SO 2 , or R 25 R 26 NSO 2 ;    R 23  is hydrogen or C 1-5 alkyl;    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 1-5  alkyl;    R 25  and R 26  are independently hydrogen or C 1-5  alkyl;    or, alternatively, R 25  and R 26  can be taken together to form an optionally substituted 4- to 7-membered carbocyclic or heterocyclic ring, which ring may be saturated, unsaturated or aromatic;    R 32  is hydrogen, C 1-5 alkyl, C 1-5  hydroxyalkyl, CHO, C 2-6  acyl, C 1-6  alkoxycarbonyl, or —(C═O)NR v R x , wherein each of R v R x  is independently selected from H, C 1-5  alkyl, C 1-5  hydroxyalkyl, C 3-8  acyloxy, (amino)C 1-6  alkylene, (C 1-5  heterocyclyl)C 1-5  alkylene, or C 1-6  alkoxycarbonyl;    Q is NR 33  or S;    R 33  represents hydrogen, C 1-5  alkyl, phenyl, benzyl, (C 2-5  heterocyclyl)C 1-5  alkylene, C 2-8  acyl, aroyl, R 35 OC═O, R 36 R 37 NC═O, R 35 SO 2  and R 36 R 37 NSO 2 ;    R 35  is selected from hydrogen and C 1-5 alkyl; and    R 36  and R 37  are each independently selected from hydrogen and C 1-5 alkyl.    
     
     
         39 . A method according to  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 1-5  alkyl, cyano, nitro, R 22 R 23 N, CF 3  and OCF 3 .    
     
     
         40 . A method according to  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 method according to  claim 40 , wherein R 7  and R 8  taken together form pyridinyl, pyrimidinyl, or piperazinyl, optionally N-substituted with —(C═O)R t , SO 2 —R t , or —(C═O)NHR u .  
     
     
         42 . A method according to  claim 39 , wherein R 22  and R 23  taken together are independently morpholinyl, piperidyl, or pyrrolidinyl, optionally substituted.  
     
     
         43 . A method according to  claim 1 , wherein the dashed line adjacent C—R 6  is absent.  
     
     
         44 . A method according to  claim 1 , wherein said compound is selected from: 
 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4, 5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1H-pyrrolo[3,2-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol;    1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4, 5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-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-tetrahydropyrazolo[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-c]pyridin-1-yl]-propan-2-ol;    1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4, 5,6,7-tetrahydropyrazolo[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; and    1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydropyrazolo[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.    
     
     
         45 . A method according to  claim 1 , wherein said compound is selected from: 
 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydropyrazolo[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-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-[4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol    1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5, 6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-oxy-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-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-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-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-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-{4-[1-(2-morpholin-4-yl-ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-propan-2-ol; and    1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydropyrazolo[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.    
     
     
         46 . A method according to  claim 1 , wherein said compound is selected from: 
 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydropyrazolo[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-tetrahydropyrazolo[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 method according to  claim 1 , wherein said compound is selected from: 
 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-tetrahydropyrazolo[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-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)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-propyl)-3-(4-trifluoromethyl-phenyl )-1,4,6,7-tetrahydropyrazolo[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-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.    
     
     
         48 . A method according to  claim 1 , wherein said compound is selected from: 
 1-[3-(4-Bromo-phenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-{4-[1-(2-morpholin-4-yl-ethyl)-1H-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)-1H-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-trifluoromethylphenyl)-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-tetrahydropyrazolo[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-tetrahydropyrazolo-[4,3-c]pyridin-1-yl]-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-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-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-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-yl)-piperidin-1-yl]-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethanone; and    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.