Inhibitors of cathepsin s

Abstract

The present invention provides compounds, compositions and methods for the selective inhibition of cathepsin S. In a preferred aspect, cathepsin S is selectively inhibited in the presence of at least one other cathepsin isozyme. The present invention also provides methods for treating a disease state in a subject by selectively inhibiting cathepsin S. More particularly, the present invention provides compounds having Formula 1: wherein Q is an optionally substituted azetidinyl, pyrrolidinyl, piperidyl, and indolinyl; or Q is NR 25 R 26 ; and A, R 5 , R 6 , R 7 , R 8 , R 9 , R 25 , R 26 and Ar are substituents.

1 . A compound having the Formula I: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
       Q is a heterocycle selected from the group consisting of azetidinyl, pyrrolidinyl, piperidyl, and indolinyl substituted with 0-2R Q , wherein Q is connected to —C(═O)— via a ring nitrogen atom; or NR 25 R 26 ; 
       each R Q  is independently a member selected from the group consisting of OH, F, Cl, —S(═O) 2 CH 3 —, acetyl, ═O, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , OCF 3  and NR 10 R 11 ; 
       A is a member selected from the group consisting of —O—CR 1 R 2 , NH—CR 1 R 2 —, —CR 3 R 4 —O—, and —CR 3 R 4 —CR 1 R 2 —; 
       each of R 1  and R 3  is independently a member selected from the group consisting of H, a C 1 -C 6  alkoxy, a C 1 -C 6  alkyl substituted with 0-2 R 1a , wherein said C 1 -C 6  alkyl may optionally contain a heteroatom selected from the group consisting of —O—, —S—, —S(═O)— and —S(═O) 2 —; a C 2 -C 6  alkenyl, a C 3 -C 6  alkynyl, a C 3 -C 7  cycloalkyl substituted with 0-2R Q , and a C 7 -C 11  bicycloalkyl substituted with 0-2R Q ; phenyl substituted with 0-3 R 13 , a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 13 ; 
       each R 1a  is independently a member selected from the group consisting of a C 6 -C 10  aryl substituted with 0-3 R 13 , a 5- to 6-membered monocyclic or 8- to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 13 , a C 3 -C 8  cycloalkyl substituted with 0-2R Q , a C 7 -C 11  bicycloalkyl substituted with 0-2R Q , and a C 1 -C 3  perfluoroalkyl; 
       each of R 2  and R 4  is independently a member selected from the group consisting of H, F, OH, C 1 -C 6  alkyl and C 1 -C 6  alkoxy; 
       R 5  is a member selected from the group consisting of H, C(═O)OR 14 , C(═O)NR 15 R 16 , phenyl substituted with 0-2 R 13 , and a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-2 R 13 , C 3 -C 7  cycloalkyl, C 1 -C 6  alkyl substituted with 0-2 R 21 , wherein said C 1 -C 6  alkyl may optionally contain a heteroatom selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O) 2 — and —NR 22 —; 
       each of R 6 , R 7 , R 8  and R 9  is independently a member selected from the group consisting of H and C 1 -C 6  alkyl; 
       alternatively, R 5  and R 7  are taken together to form a C 5 -C 7  cycloalkyl, wherein a methylene of said C 5 -C 7  cycloalkyl may optionally be replaced with a heteroatom selected from the group of —O—, —S—, —S(═O)—, and —S(═O) 2 —; 
       each R 10  is independently a member selected from the group consisting of H, C 1 -C 4  alkyl, (C 1 -C 4  alkyl)-C(═O)— and (C 1 -C 4  alkyl)-S(═O) 2 —; 
       each R 11  is independently a member selected from the group consisting of H and C 1 -C 4  alkyl; 
       each R 12  is independently a member selected from the group consisting of H, C 3 -C 8  cycloalkyl, a phenyl substituted with 0-3 R 13 , a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said 5- to 6-membered heteroaryl is substituted with 0-3 R 13 , and a C 1 -C 6  alkyl substituted with 0-1 R 19 ; 
       each R 13  is independently a member selected from the group consisting of H, OH, F, Cl, Br, CN, NO 2 , COOR 17 , C(═O)NR 17 R 18 , S(═O) 2 NR 17 R 18 , acetyl, —SCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , NR 10 R 11 , C 1 -C 6  alkoxy, C 1 -C 3  perfluoroalkyl, C 1 -C 3  perfluoroalkoxy and a C 1 -C 6  alkyl; 
       each R 14  is independently a member selected from the group consisting of H, C 3 -C 7  cycloalkyl, C 1 -C 4  alkyl substituted with 0-1 R 19 , and a phenyl substituted with 0-3 R 13 ; 
       each R 15  is independently a member selected from the group consisting of H, C 3 -C 8  cycloalkyl, a phenyl substituted with 0-3 R 13 , and a C 1 -C 6  alkyl substituted with 0-1 R 19 ; 
       each R 16  is independently a member selected from the group consisting of H and C 1 -C 4  alkyl; 
       alternatively, R 15  and R 16  on the same N atom are taken together to form a C 5 -C 7  heterocycle containing 1-2 heteroatoms each independently a member selected from the group consisting of N, O and S; 
       each of R 17  and R 18  is independently a member selected from the group consisting of H, C 1 -C 4  alkyl and C 3 -C 6  cycloalkyl; 
       each R 19  is independently a member selected from the group consisting of H, C 3 -C 7  cycloalkyl, a phenyl substituted with 0-3 R 13  and a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said 5- to 6-membered heteroaryl is substituted with 0-3 R 13 ; 
       Ar is a member selected from the group consisting of phenyl substituted with 0-3 R 20 , 
       and a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S; 
       wherein said heteroaryl is substituted with 0-3 R 20 ; 
       each R 20  is independently a member selected from the group consisting of H, F, Cl, Br, CN, OR 12 , SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , S(═O) 2 NR 17 R 18 , NR 10 R 11 , acetyl, —S(═O) 2 NH(C═O)CH 3 , C(═O)NR 17 R 18 , CO 2 R 17 , C(═NH)NH 2 , C 1 -C 6  alkyl, CF 3 , OCF 3  and OCF 2 H; 
       alternatively, R 20  and R 9  are taken together to form a 5- to 7-membered heterocyclic ring containing 1-2 heteroatoms each independently a member selected from the group consisting of N, O and S; wherein said 5 to 7 membered heterocyclic ring is ortho-fused to Ar; wherein said 5- to 7-membered heterocyclic ring may be optionally substituted with 0-2 R 24 ; 
       each R 21  is independently a member selected from the group consisting of H, OH, F, Cl, CN, NO 2 , C(═O)OR 14 , C(═O)NR 15 R 16 , NR 22 R 23 , C 1 -C 3  perfluoroalkoxy, C 1 -C 4  alkoxy, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, phenyl substituted with 0-3 R 13 , a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 13 , C 3 -C 8  heterocycle containing 1 to 2 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heterocycle is substituted with 0-2 R 13  and is saturated or partially unsaturated, and C 3 -C 8  cycloalkyl; 
       R 22  is independently a member selected from the group consisting of H,  t BOC, Cbz, C 3 -C 8  cycloalkyl, (C 1 -C 6  alkyl)-C(═O)—, (C 1 -C 6  alkyl)-S(═O) 2 —, a C 1 -C 6  alkyl substituted with 0-1 R 19 , a phenyl substituted with 0-3 R 13  and a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said 5- to 6-membered heteroaryl is substituted with 0-3 R 13 ; 
       each R 23  is independently a member selected from the group consisting of H and 
       C 1 -C 4  alkyl; 
       each R 24  is independently a member selected from the group consisting of C 1 -C 4  alkyl, F, C 1  and C 1 -C 4  alkoxy, CF 3  and OCF 3 ; 
       alternatively, two R 24  may be combined to form C 3 -C 6  cycloalkyl; and 
       each of R 25  and R 26  is independently a member selected from the group consisting of C 1 -C 6  alkyl, wherein said C 1 -C 6  alkyl may optionally contain a heteroatom selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O) 2 — and —NR 22 —. 
     
   
   
       2 . The compound of  claim 1 , wherein said compound has the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  is independently a member selected from the group consisting of H, C 1 -C 6  alkyl substituted with 0-1 R 1a , wherein said C 1 -C 6  alkyl may optionally contain a heteroatom selected from the group consisting of —O—, —S—, and —S(═O) 2 , a C 2 -C 6  alkenyl, a C 3 -C 7  cycloalkyl substituted with 0-2 R Q , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R Q ; phenyl substituted with 0-3 R 13 , a 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms each independently a member selected from the group consisting of N, O and S, wherein said heteroaryl is substituted with 0-3 R 13 ; and 
       R 4  is a member selected from the group consisting of H, F, OH and C 1 -C 6  alkyl. 
     
   
   
       3 . The compound of  claim 1 , wherein said compound has the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  is selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 4  alkyl substituted with 1 R 1a , wherein said C 1 -C 4  alkyl may optionally contain a heteroatom selected from the group consisting of —O—, —S— and —S(═O) 2 —; and 
       R 1a  is a member selected from the group consisting of a phenyl substituted with 0-3 R 13 , a C 3 -C 7  cycloalkyl substituted with 0-2R Q , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R Q . 
     
   
   
       4 . The compound of  claim 1 , wherein said compound has the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 3  is selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 4  alkyl substituted with 1 R 1a , wherein said C 1 -C 4  alkyl may optionally contain a heteroatom selected from the group consisting of —O—, —S— and —S(═O) 2 —; a C 3 -C 7  cycloalkyl substituted with 0-2R Q , and a C 7 -C 11  bicycloalkyl substituted with 0-2R Q ; phenyl substituted with 0-3 R 13 ; and 
       R 1a  is a member selected from the group consisting of a phenyl substituted with 0-3 R 13 , a C 3 -C 7  cycloalkyl substituted with 0-2R Q , and a C 7 -C 11  bicycloalkyl substituted with 0-2 R Q . 
     
   
   
       5 . The compound of  claim 1 , wherein said compound has the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  is selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 4  alkyl substituted with 1 R 1a , wherein said C 1 -C 4  alkyl may optionally contain a heteroatom selected from the group consisting of —O—, —S—, and —S(═O) 2 ; 
       R 1a  is a member selected from the group consisting of a phenyl substituted with 0-3 R 13 , C 3 -C 7  cycloalkyl substituted with 0-2R Q , and a C 7 -C 11  bicycloalkyl substituted with 0-2R Q ; 
       R 5  is a member selected from the group consisting of H, phenyl substituted with 0-2 R 13 , C 3 -C 7  cycloalkyl, C 1 -C 6  alkyl substituted with 0-1 R 21 , wherein said C 1 -C 6  alkyl may optionally contain a heteroatom selected from the group consisting of —O—, —S—, —S(═O) 2 —; 
       each R 21  is independently a member selected from the group consisting of H, OH, F, C(═O)OR 14 , C(═O)NR 15 R 16 , NR 22 R 23 , phenyl substituted with 0-3 R 13 , and C 3 -C 7  cycloalkyl; 
       Ar is a member selected from the group consisting of phenyl substituted with 0-3 R 20 ; 
       each R 20  is independently a member selected from the group consisting of H, F, Cl, Br, CN, OR 12 , SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , S(═O) 2 NR 17 R 18 , NR 10 R 11 , acetyl, C(═O)NR 17 R 18 , CO 2 R 17 , C(═NH)NH 2 , C 1 -C 6  alkyl, CF 3 , OCF 3 ; 
       alternatively, R 20  and R 9  are taken together to form a 5-membered heterocyclic ring containing 1 nitrogen, wherein said 5-membered heterocyclic ring is ortho-fused to Ar; wherein said 5-membered heterocyclic ring may be optionally substituted with 0-2 R 24 . 
     
   
   
       6 . The compound of  claim 1 , wherein said compound has the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       R 2  is H; 
       R 3  are each independently selected from the group consisting of H, C 1 -C 6  alkyl, C 1 -C 4  alkyl substituted with 1 R 1a , R 1a  is a member selected from the group consisting of a C 3 -C 7  cycloalkyl substituted with 0-2R Q , and a C 7 -C 11  bicycloalkyl substituted with 0-2R Q ; 
       R 5  is a member selected from the group consisting of H, phenyl substituted with 0-2 R 13 , C 3 -C 7  cycloalkyl, C 1 -C 6  alkyl substituted with 0-1 R 21 , wherein said C 1 -C 6  alkyl may optionally contain a heteroatom selected from the group consisting of —O—, —S—, —S(═O) 2 —; 
       each R 21  is independently a member selected from the group consisting of H, OH, C(═O)OR 14 , C(═O)NR 15 R 16 , NR 22 R 23 , phenyl substituted with 0-3 R 13 , and C 3 -C 8  cycloalkyl; 
       Ar is a member selected from the group consisting of phenyl substituted with 0-3 R 20 , 
       each R 20  is independently a member selected from the group consisting of H, F, Cl, Br, CN, OR 12 , SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , S(═O) 2 NR 17 R 18 , NR 10 R 11 , acetyl, —S(═O) 2 NH(C═O)CH 3 , C(═O)NR 17 R 18 , CO 2 R 17 , C(═NH)NH 2 , C 1 -C 6  alkyl, CF 3 , OCF 3  and OCF 2 H; 
       alternatively, R 20  and R 9  are taken together to form a 5-membered heterocyclic ring containing 1 nitrogen; wherein said 5-membered heterocyclic ring is ortho-fused to Ar; wherein said 5-membered heterocyclic ring may be optionally substituted with 0-2 R 24 . 
     
   
   
       7 . The compound of  claim 2 , wherein:
 R 5  is a member selected from the group consisting of H, phenyl substituted with 0-2 R 13 , C 3 -C 7  cycloalkyl, C 1 -C 6  alkyl substituted with 0-1 R 21 , wherein said C 1 -C 6  alkyl may optionally contain a heteroatom selected from the group consisting of —O—, —S—, —S(═O) 2 —; and   each R 21  is independently a member selected from the group consisting of H, OH, C(═O)OR 14 , C(═O)NR 15 R 16 , NR 22 R 23 , phenyl substituted with 0-3 R 13 , and C 3 -C 7  cycloalkyl.   
   
   
       8 . The compound of  claim 7 , wherein:
 R 1  is independently a member selected from the group consisting of C 1 -C 4  alkyl substituted with 1 R 1a , wherein said C 1 -C 4  alkyl may optionally contain a heteroatom selected from the group consisting of —O—, —S—, and —S(═O) 2 ; C 1 -C 6  alkyl, a C 2 -C 6  alkenyl, a C 3 -C 7  cycloalkyl substituted with 0-2R Q , and a C 7 -C 11  bicycloalkyl substituted with 0-2R Q ; phenyl substituted with 0-3 R 13 ;   each R 1a  is independently a member selected from the group consisting of a phenyl substituted with 0-3 R 13 , a C 3 -C 8  cycloalkyl substituted with 0-2R Q , a C 7 -C 11  bicycloalkyl substituted with 0-2R Q ;   R 4  is H, F, OH, methyl, ethyl, propyl or butyl; and   Ar is a phenyl substituted with 0-3 R 20 ; a 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms each independently a member selected from the group consisting of N, O and S; wherein said heteroaryl is substituted with 0-2 R 20 .   
   
   
       9 . The compound of  claim 8 , wherein
 Q is a heterocycle selected from the group consisting of azetidinyl, pyrrolidinyl, piperidyl, wherein Q is connected to —C(═O)— via a ring nitrogen atom;   R 1  is independently a member selected from the group consisting of cyclohexylmethyl, 4,4-dimethyl-cyclohexylmethyl, spiro[2.5]oct-6-ylmethyl, spiro[3.5]non-7-ylmethyl, cyclohexylethyl, cyclopentylmethyl, cyclopentylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopropylmethyl, cyclopropylethyl, allyl, butenyl, cyclopentyl, cyclohexyl, t-butylmethyl, t-butylethyl, 4-ethyl-4-hydroxyl-cyclohexylmethyl, phenethyl, phenylpropyl, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl and 4-methylsulfonylphenyl;   R 4  is H or methyl;   R 5  is a member selected from the group consisting of H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, cyclopropyl, cyclopropylmethyl, methylsulfonylmethyl, methylsulfonylethyl, hydroxylmethyl, hydroxyethyl, phenethyl, benzyl, phenyl and benzyloxymethyl;   Ar is phenyl substituted with 0-3 R 20 , isoxazolyl substituted with 0-2 R 20 , pyridyl substituted with 0-2 R 20 ;   each R 20  is independently a member selected from the group consisting of H, F, Cl, OCH 3 , CH 3 , SCH 3 , S(═O) 2 CH 3 , S(═O) 2 NH 2 , acetyl, C(═O)NH 2 , CO 2 H, OCF 3  and OCHF 2 ;   alternatively, R 20  and R 9  are taken together to form a 5-membered heterocyclic ring containing 1 nitrogen atom; wherein said 5-membered heterocyclic ring is ortho-fused to Ar; wherein said 5-membered heterocyclic ring may be optionally substituted with 0-2 R 24 ;   each R 24  is independently a member selected from the group consisting of methyl, and F;   alternatively, two R 24  may be combined to form cyclopropyl and cyclobutyl.   
   
   
       10 . The compound of  claim 3 , wherein
 R 5  is a member selected from the group consisting of H, phenyl substituted with 0-2 R 13 , C 3 -C 7  cycloalkyl, C 1 -C 6  alkyl substituted with 0-1 R 21 , wherein said C 1 -C 6  alkyl may optionally contain a heteroatom selected from the group consisting of —O—, —S—, —S(═O) 2 —; and   each R 21  is independently a member selected from the group consisting of H, OH, C(═O)OR 14 , C(═O)NR 15 R 16 , NR 22 R 23 , C 1 -C 4  alkoxy, phenyl substituted with 0-3 R 13 , and C 3 -C 8  cycloalkyl.   
   
   
       11 . The compound of  claim 10 , wherein
 Q is a heterocycle selected from the group consisting of azetidinyl, pyrrolidinyl, piperidyl, wherein Q is connected to —C(═O)— via a ring nitrogen atom;   R 1  is independently a member selected from the group consisting of cyclohexylmethyl, 4,4-dimethyl-cyclohexylmethyl, spiro[2.5]oct-6-ylmethyl, spiro[3.5]non-7-ylmethyl, cyclohexylethyl, cyclopentylmethyl, cyclopentylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopropylmethyl, cyclopropylethyl, t-butylmethyl, t-butylethyl, phenylmethylsulfonylmethyl and benzylsulfanylmethyl;   R 5  is a member selected from the group consisting of H, methyl, ethyl, propyl, propyl, butyl, i-butyl, cyclopropyl, cyclopropylmethyl, methylsulfonylmethyl, methylsulfonylethyl, hydroxylmethyl, hydroxyethyl, benzyloxymethyl, phenethyl, benzyl and phenyl;   Ar is phenyl substituted with 0-3 R 20 , pyridinyl substituted with 0-2 R 20 , and isoxazolyl substituted with 0-2 R 20 ;   each R 20  is independently a member selected from the group consisting of H, F, Cl, CH 3 , OCH 3 , SCH 3 , S(═O) 2 CH 3 , S(═O) 2 NH 2 , acetyl, C(═O)NH 2 , CO 2 H, OCF 3  and OCHF 2 ;   alternatively, R 20  and R 9  are taken together to form a 5-membered heterocyclic ring containing 1 nitrogen atom; wherein said 5-membered heterocyclic ring is ortho-fused to Ar; wherein said 5-membered heterocyclic ring may be optionally substituted with 0-2 R 24 ;   each R 24  is independently a member selected from the group consisting of methyl, ethyl and F;   alternatively, two R 24  may be combined to form cyclopropyl and cyclobutyl.   
   
   
       12 . The compound of  claim 4 , wherein
 R 5  is a member selected from the group consisting of H, phenyl substituted with 0-2 R 13 , C 3 -C 7  cycloalkyl, C 1 -C 6  alkyl substituted with 0-1 R 21 , wherein said C 1 -C 6  alkyl may optionally contain a heteroatom selected from the group consisting of —O—, —S—, —S(═O) 2 —;   each R 21  is independently a member selected from the group consisting of H, OH, C(═O)OR 14 , C(═O)NR 15 R 16 , NR 22 R 23 , C 1 -C 4  alkoxy, phenyl substituted with 0-3 R 13 , and C 3 -C 8  cycloalkyl; and   R 7  is H.   
   
   
       13 . The compound of  claim 12 , wherein
 Q is a azetidinyl, pyrrolidinyl, piperidyl, wherein Q is connected to —C(═O)— via a ring nitrogen atom; or NR 25 R 26 ;   R 3  is independently a member selected from the group consisting of cyclohexylmethyl, 4,4-dimethyl-cyclohexylmethyl, spiro[2.5]oct-6-ylmethyl, spiro[3.5]non-7-ylmethyl, cyclohexylethyl, cyclopentylmethyl, cyclopentylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopropylmethyl, cyclopropylethyl, t-butylmethyl, t-butylethyl, phenyl, cyclohexyl, cyclopentyl, 4,4-dimethylcyclohexyl, phenylmethylsulfonylmethyl and benzylsulfanylmethyl;   R 5  is a member selected from the group consisting of H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, cyclopropyl, cyclopropylmethyl, methylsulfonylmethyl, methylsulfonylethyl, hydroxylmethyl, hydroxyethyl, phenethyl, benzyl, phenyl and benzyloxymethyl;   Ar is phenyl substituted with 0-3 R 20 , and isoxazolyl substituted with 0-2 R 20 ;   each R 20  is independently a member selected from the group consisting of H, F, Cl, OCH 3 , CH 3 , SCH 3 , S(═O) 2 CH 3 , S(═O) 2 NH 2 , —S(═O) 2 NH(C═O)CH 3 , acetyl, C(═O)NH 2 , CO 2 H, OCF 3  and OCHF 2 ;   alternatively, R 20  and R 9  are taken together to form a 5-membered heterocyclic ring containing 1 nitrogen atom; wherein said 5-membered heterocyclic ring is ortho-fused to Ar; wherein said 5-membered heterocyclic ring may be optionally substituted with 0-2 R 24 ;   each R 24  is independently a member selected from the group consisting of methyl, and F;   alternatively, two R 24  may be combined to form cyclopropyl and cyclobutyl;   each of R 25  and R 26  is independently a member selected from the group consisting of C 1 -C 4  alkyl; wherein said C 1 -C 6  alkyl may optionally contain a heteroatom selected from the group consisting of —O—.   
   
   
       14 . The compound of  claim 1 , wherein said compound is selected from the group consisting of:
 [2-(5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethyl]-carbamic acid 1-(S)-cyclohexylmethyl-2-oxo-2-piperidin-1-yl-ethyl ester;   [2-(5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethyl]-carbamic acid 1-(S)-cyclohexylmethyl-2-oxo-2-pyrrolidin-1-yl-ethyl ester;   [2-(5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethyl]-carbamic acid   2-cyclohexyl-1-(S)-dimethylcarbamoyl-ethyl ester;   [2-(5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethyl]-carbamic acid 2-cyclohexyl-1-(S)-[(2-methoxy-ethyl)-methyl-carbamoyl]-ethyl ester; and   [2-(5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-1-(S)-methyl-ethyl]-carbamic acid 2-azetidin-1-yl-1-(S)-cyclohexylmethyl-2-oxo-ethyl ester.   
   
   
       15 . A pharmaceutical composition, said composition comprising a compound of  claim 1  and an excipient. 
   
   
       16 . A pharmaceutical composition, said composition comprising a compound of  claim 14  and an excipient.