Beta-carbolines useful for treating inflammatory disease

Abstract

This invention provides beta-carboline compounds of formula wherein Ring A is a substituted pyridinyl, pyrimidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyranyl, tetrahydrofuranyl, cyclohexyl, cyclopentyl or thiomorpholinyl ring and R 1 , R 2 and R 3 are as described in the specification. The compounds are IKK-2 inhibitors that are useful for treating IKK-2-mediated diseases such as inflammatory diseases and cancer.

1 . A compound of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 Ring A is selected from the group consisting of:
 (a) a pyridinyl or pyrimidinyl ring that is substituted by (i) —CH 2 C(O)-G and 0-1 R 6a  or (ii) 1-2 R 6a , and 
 (b) a morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyranyl, tetrahydrofuranyl, cyclohexyl, cyclopentyl or thiomorpholinyl ring that is substituted by (i) —C(R 9 ) 3 , —W-G, or -G, (ii) 0-4 R 6b  and (iii) 0-1 oxo groups on a ring carbon or 0-2 oxo groups on a ring sulfur; 
 
 each R 6a  is independently selected from C 1-6  aliphatic, halo, alkoxy, or amino; 
 each R 6b  is independently selected from C 1-3  aliphatic or —N(R 7 ) 2 , and two R 6b  on the same or an adjacent carbon optionally are taken together with the intervening carbon(s) to form a 5-6 membered ring having 1-2 ring heteroatoms selected from N, O or S; 
 W is -Q-, -Q-C(O)—, —C(R 9 ) 2 —C(R 9 )(R 12 )—, or —C(R 9 ) 2 -[C(R 9 )(R 12 )] 2 —; 
 Q is —C(R 9 ) 2 — or —C(R 9 ) 2 C(R 9 ) 2 —; 
 G is —OH, —NR 4 R 5 , —N(R 9 )CONR 4 R 5 , —N(R 9 )SO 2  (C 1-3  aliphatic), —N(R 9 )COCF 3 —N(R 9 )CO(C 1-6  aliphatic), —N(R 9 )CO(heterocyclyl), —N(R 9 )CO(heteroaryl)) —N(R 9 )CO(aryl), a 3-7 membered heterocyclyl ring, or a 5-6 membered heteroaryl, wherein each of the heteroaryl, aryl and heterocyclyl moieties of G is optionally substituted by 1-3 R 10 ; 
 R 1  is hydrogen, halo, C 1-3  aliphatic, amino, cyano, (C 1-3  alkyl) 1-2  amino, C 1-3  alkoxy, —CONH 2 , —NHCOCF 3 , or —CH 2 NH 2 ; 
 R 2  is hydrogen, halo, C 1-3  aliphatic, —CF 3 ; 
 R 3  is hydrogen, halo, C 1-6  aliphatic, C 1-6  haloalkyl, C 1-6  alkoxy, hydroxy, amino, cyano, or (C 1-6  alkyl) 1-2  amino; 
 R 4  is hydrogen, 3-7 membered heterocyclyl, or C 1-6  aliphatic; 
 R 5  is hydrogen, C 1-6  aliphatic group or a 3-7 membered heterocyclic ring having 1-2 ring heteroatoms selected from N, O, or S, wherein R 5  is optionally substituted by halo, —OR′, —CN, —SR O , —S(O) 2 R 8 , —S(O) 2 N(R 7 ) 2 , —C(O)R 7 , —CO 2 R 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )CO 2 R 13 , or —N(R 7 )C(O)N(R 7 ) 2 ; 
 each R 7  is independently selected from hydrogen or C 1-4  aliphatic, or two R 7  on the same nitrogen atom are taken together with the nitrogen to form a 5-6 membered heteroaryl or heterocyclyl ring; 
 each R 8  is independently selected from C 1-4  aliphatic; 
 each R 9  is independently selected from hydrogen or C 1-3  aliphatic; 
 each R 10  is independently selected from oxo, —R 11 , -T-R 11 , or -V-T-R 11 ; 
 each R 11  is independently selected from C 1-6  aliphatic, halo, —S(O) 2 N(R 7 ) 2 , —OR 7 , —CN, —SR 8 , —S(O) 2 R 8 , —C(O)R 7 , —CO 2 R 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )CO 2 R 7 , or —N(R 7 )C(O)N(R 7 ) 2 ; 
 T is a straight or branched C 1-4  alkylene chain; 
 V is —O—, —N(R 7 )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, or —CO 2 —, and 
 R 12  is hydrogen or an amino acid side chain. 
 
   
   
       2 . The compound of  claim 1  where Ring A is a 3-pyridinyl or 5-pyrimidinyl ring substituted by 1-2 R 6a  groups. 
   
   
       3 . The compound of  claim 2  having formula II-C: 
     
       
         
         
             
             
         
       
     
     wherein:
 Y is N or CH; 
 R 1  is hydrogen, halo, C 1-3  aliphatic, amino, cyano, (C 1-3  alkyl) 1-2  amino, C 1-3  alkoxy, —CONH 2 , —NHCOCF 3 , or —CH 2 NH 2 ; 
 R 2  is hydrogen, halo, C 1-3  aliphatic, —CF 3 ; 
 R 3  is hydrogen, halo, C 1-6  aliphatic, C 1-6  haloalkyl, C 1-6  alkoxy, hydroxy, amino, cyano, or (C 1-6  alkyl) 1-2  amino; and 
 R 6a  is selected from C 1-6  aliphatic or halo. 
 
   
   
       4 . The compound of  claim 3  where R 6a  is methyl. 
   
   
       5 . The compound of  claim 4  where R 1  is hydrogen, methyl, amino or fluoro; R 2  is hydrogen or halo; and R 3  is hydrogen, halo or C 1-4 alkoxy. 
   
   
       6 . The compound of  claim 5  where Y is CH. 
   
   
       7 . The compound of  claim 5  where Y is N. 
   
   
       8 . The compound of  claim 1  where Ring A is selected from morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyranyl, tetrahydrofuranyl, cyclohexyl, cyclopentyl or thiomorpholinyl and where Ring A is substituted by (i) —C(R 9 ) 3  or —W-G, (ii) 0-4 R 6b  and (iii) 0-1 oxo groups on a ring carbon or 0-2 oxo groups on a ring sulfur. 
   
   
       9 . The compound of  claim 8  where the —W-G or —C(R 9 ) 3  substituent on Ring A is ortho to the position where the beta-carboline portion is attached. 
   
   
       10 . A compound of formula III-A: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 Ring A is substituted by 0-4 R 6b ; 
 each R 6b  is independently selected from C 1-3  aliphatic or —N(R 7 ) 2 , and two R 6b  on the same or an adjacent carbon optionally are taken together with the intervening carbon(s) to form a 5-6 membered ring having 1-2 ring heteroatoms selected from N, O or S; 
 W is -Q-, -Q-C(O)—, —C(R 9 ) 2 —C(R 9 )(R 12 )—, or —C(R 9 ) 2 —[C(R 9 )(R 12 )] 2 —; 
 Q is —C(R 9 ) 2 — or —C(R 9 ) 2 C(R 9 ) 2 —; 
 G is —OH, —NR 4 R 5 , —N(R 9 )CONR 4 R 5 , —N(R 9 )SO 2  (C 1-3  aliphatic), —N(R 9 )COCF 3 , —N(R 9 )CO(C 1-6  aliphatic), —N(R 9 )CO(heterocyclyl)-N(R 9 )CO(heteroaryl) —N(R 9 )CO(aryl), a 3-7 membered heterocyclyl ring, or a 5-6 membered heteroaryl, wherein each of the heteroaryl, aryl and heterocyclyl moieties of G is optionally substituted by 1-3 R 10 ; 
 R 1  is hydrogen, halo, C 1-3  aliphatic, amino, cyano, (C 1-3  alkyl) 1-2  amino, C 1-3  alkoxy, —CONH 2 , —NHCOCF 3 , or —CH 2 NH 2 ; 
 R 2  is hydrogen, halo, C 1-3  aliphatic, —CF 3 ; 
 R 3  is hydrogen, halo, C 1-6  aliphatic, C 1-6  haloalkyl, C 1-6  alkoxy, hydroxy, amino, cyano, or (C 1-6  alkyl) 1-2  amino; 
 R 4  is hydrogen, 5-6 membered heterocyclyl, or C 1-6  aliphatic; 
 R 5  is hydrogen, C 1-6  aliphatic group or a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms selected from N, O, or S, wherein R 5  is optionally substituted by halo, —OR 7 , —CN, —SR 8 , —S(O) 2 R 8 , —S(O) 2 N(R 7 ) 2  (O)R 7 , —CO 2 R 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )CO 2 R 8 , or —N(R 7 )C(O)N(R 7 ) 2 ; 
 each R 7  is independently selected from hydrogen or C 1-4  aliphatic, or two R 7  on the same nitrogen atom are taken together with the nitrogen to form a 5-6 membered heteroaryl or heterocyclyl ring; 
 each R 8  is independently selected from C 1-4  aliphatic; 
 each R 9  is independently selected from hydrogen or C 1-3  aliphatic; 
 each R 10  is independently selected from oxo, —R 11 , -T-R 11 , or -V-T-R 11 ; 
 each R 11  is independently selected from C 1-6  aliphatic, halo, —S(O) 2 N(R 7 ) 2 , —CN, —SR 8 , —S(O) 2 R 8 , —C(O)R 7 , —CO 2 R 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )CO 2 R 7 , or —N(R 7 )C(O)N(R 7 ) 2 ; 
 T is a straight or branched C 1-4  alkylene chain; 
 V is —O—, —N(R 7 )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, or —CO 2 —; and 
 
     R 12  is hydrogen or an amino acid side chain. 
   
   
       11 . The compound of  claim 10  having the formula (S)-III-A: 
     
       
         
         
             
             
         
       
     
     where n is 0-4 and R 1 , R 2 , R 3 , W, G and R 6b  are as defined in  claim 10 . 
   
   
       12 . The compound of  claim 11  where:
 R 1  is hydrogen, halo, methyl or amino;   R 2  is hydrogen, methyl or halo;   R 3  is hydrogen, halo, alkoxy, or (C 1-6  aliphatic) 2  amino;   n is 0-2;   R 6b  is C 1-3  aliphatic;   W is -Q-, -Q-C(O)—, —C(R 9 ) 2 —C(R 9 )(R 12 )—, or —C(R 9 ) 2 —[C(R 9 )(R 12 )] 2 —;   Q is —C(R 9 ) 2 — or —C(R 9 ) 2 C(R 9 ) 2 —;   G is —NR 4 R 5 , —N(R 9 )C(O)NR 4 R 5 , —N(R 9 )SO 2 (C 1-3  aliphatic), —N(R 9 )C(O)CF 3 , —N(R 9 )CO(C 1-6  aliphatic), and —N(R 9 )CO(heterocyclyl)-N(R 9 )CO(heteroaryl) —N(R 9 )CO(aryl), a 5-6 membered heterocyclyl ring, or a 5-6 membered heteroaryl, wherein each of the heteroaryl, aryl and heterocyclyl moieties of G is optionally substituted by 1-3 R 10 ;   R 4  is hydrogen or C 1-6  aliphatic;   R 5  is hydrogen or a C 1-6  aliphatic group that is optionally substituted by halo, —OR 7 , —CN, —SR 8 , —S(O) 2 R 8 , —S(O) 2 N(R 7 ) 2 , —C(O)R 7 , —CO 2 R 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )CO 2 R 8 , or —N(R 7 )C(O)N(R 7 ) 2 ;   each R 7  is independently selected from hydrogen or C 1-4  aliphatic, or two R 7  on the same nitrogen atom are taken together with the nitrogen to form a 5-6 membered heteroaryl or heterocyclyl ring;   each R 8  is independently selected from C 1-4  aliphatic;   R 9  is hydrogen;   each R 10  is independently selected from oxo, R 11 , T-R 11 , or V-T-R 11 ;   each R 11  is independently selected from C 1-6  aliphatic, halo, —S(O) 2 N(R 7 ) 2 , —OR 7 , —CN, —SR 8 , —S(O) 2 R 8 , —C(O)R 7 , —CO 2 R 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )CO 2 R 7 , or —N(R 7 )C(O)N(R 7 ) 2 ;   T is a straight or branched C 1-4  alkylene chain;   V is —O—, —N(R 7 )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, or —CO 2 —; and   R 12  is hydrogen, C 1-6  aliphatic, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl.   
   
   
       13 . The compound of  claim 12  where:
 R 1  is hydrogen, methyl, fluoro or amino;   R 2  is chloro;   R 3  is hydrogen or alkoxy;   n is zero or 2;   R 6b  is methyl;   W is -Q-, -Q-C(O)— or —C(R 9 ) 2 —C(R 9 )(R 12 )—;   Q is —C(R 9 ) 2 — or —C(R 9 ) 2 C(R 9 ) 2 —;   G is —NR 4 R 5 , —N(R 9 )C(O)NR 4 R 5 , —N(R 9 )C(O)CF 3 , —N(R 9 )CO(C 1-6  aliphatic), and —N(R 9 )CO(heterocyclyl) —N(R 9 )CO(heteroaryl), a 5-6 membered heterocyclyl ring, or a 5-6 membered heteroaryl, wherein each of the heteroaryl and heterocyclyl moieties of G is optionally substituted by 1-3 R 10 ;   R 4  is hydrogen or C 1-6  aliphatic;   R 5  is hydrogen or C 1-6  aliphatic;   each R 7  is independently selected from hydrogen or C 1-4  aliphatic, or two R 7  on the same nitrogen atom are taken together with the nitrogen to form a 5-6 membered heteroaryl or heterocyclyl ring;   each R 8  is independently selected from C 1-4  aliphatic;   R 9  is hydrogen;   each R 10  is independently selected from oxo, R 11 , T-R 11 , or V-T-R 11 ;   each R 11  is independently selected from C 1-6  aliphatic, halo, —S(O) 2 N(R 7 ) 2 , —OR 7 , —CN, —SR 8 , —S(O) 2 R 8 , —C(O)R 7 , —CO 2 R 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )CO 2 R 7 , or —N(R 7 )C(O)N(R 7 ) 2 ;   T is a straight or branched C 1-4  alkylene chain;   V is —O—, —N(R 7 )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, or —CO 2 —; and   R 12  is hydrogen, C 1-6  aliphatic, phenyl, or benzyl.   
   
   
       14 . A compound of formula (S)-III-A′: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen, methyl, fluoro or amino; 
 R 2  is chloro; 
 R 3  is hydrogen or alkoxy; 
 W is -Q-, -Q-C(O)— or —C(R 8 ) 2 —C(R 8 )(R 12 ); 
 Q is —C(R 9 ) 2 — or —C(R 8 ) 2 C(R 9 ) 2 —; 
 G is —NR 4 R 5 , —N(R 9 )C(O)NR 4 R 5 , —N(R 9 )C(O)CF 3 , —N(R 9 )CO(C 1-6  aliphatic), and —N(R 8 )CO(heterocyclyl) —N(R 9 )CO(heteroaryl), a 5-6 membered heterocyclyl ring, or a 5-6 membered heteroaryl, wherein each of the heteroaryl and heterocyclyl moieties of G is optionally substituted by 1-3 R 10 ; 
 R 4  is hydrogen or C 1-6  aliphatic; 
 R 5  is hydrogen or C 1-6  aliphatic; 
 each R 7  is independently selected from hydrogen or C 1-4  aliphatic, or two R 7  on the same nitrogen atom are taken together with the nitrogen to form a 5-6 membered heteroaryl or heterocyclyl ring; 
 each R 8  is independently selected from C 1-4  aliphatic; 
 R 9  is hydrogen; 
 each R 18  is independently selected from oxo, R 11 , T-R 11 , or V-T-R 11 ; 
 each R 11  is independently selected from C 1-6  aliphatic, halo, —S(O) 2 N(R 7 ) 2 , —CN, —SR a , —S(O) 2 R 8 , —C(O)R 7 , —CO 2 R 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )CO 2 R 7 , or —N(R 7 )C(O)N(R 7 ) 2 ; 
 T is a straight or branched C 1-4  alkylene chain; 
 V is —O—, —N(R 7 )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, or —CO 2 —; and 
 R 12  is hydrogen, C 1-6 , aliphatic, phenyl, or benzyl. 
 
   
   
       15 . The compound of  claim 14  having the formula (S)-III-A-a: 
     
       
         
         
             
             
         
       
       where R 1  is hydrogen, halo, methyl or amino; 
       R 2  is hydrogen, methyl or halo; 
       R 3  is hydrogen, halo, alkoxy, or (C 1-6  aliphatic) 2  amino; 
       Ring A is substituted by 0-2 R 6b ; 
       R 6b  is C 1-3  aliphatic; 
       Q is —C(R 9 ) 2 — or —C(R 9 ) 2 C(R 9 ) 2 —; 
       G is —NR 4 R 5  or a substituted or unsubstituted 5-6 membered heterocyclyl ring; 
       R 4  is hydrogen or C 1-6  aliphatic; 
       R 5  is hydrogen or a C 1-6  aliphatic group that is optionally substituted by halo, —OR 7 , —CN, —SR 8 , —S(O) 2 R 8 , —S(O) 2 N(R 7 ) 2 , —C(O)R 7 , —CO 2 R 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )CO 2 R 8 , or —N(R 7 )C(O)N(R 7 ) 2 ; 
       each R 7  is independently selected from hydrogen or C 1-4  aliphatic, or two R 7  on the same nitrogen atom are taken together with the nitrogen to form a 5-6 membered heteroaryl or heterocyclyl ring; 
       each R 8  is independently selected from C 1-4  aliphatic; and 
       each R 9  is independently hydrogen or C 1-3  aliphatic. 
     
   
   
       16 . A compound selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       17 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       18 . A pharmaceutical composition comprising a compound of  claim 16  and a pharmaceutically acceptable carrier. 
   
   
       19 . A method of treating an IKK-mediated disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of  claim 1 . 
   
   
       20 . The method of  claim 19  wherein the disease is an inflammatory disease or an immune-related disease. 
   
   
       21 . The method of  claim 19  wherein the disease is selected from the group consisting of rheumatoid arthritis, asthma, psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease, inflammatory bowel disease or multiple sclerosis. 
   
   
       22 . The method of  claim 19  wherein the disease is cancer. 
   
   
       23 . The method of  claim 22  wherein the cancer is selected from lymphoma, multiple myeloma, osteolytic bone mestasis, head or neck cancer, lung cancer, prostate cancer or pancreatic cancer. 
   
   
       24 . The method of  claim 23  wherein the cancer is a lymphoma. 
   
   
       25 . A method of inhibiting IRK in a patient in need thereof comprising administering to the patient a compound of  claim 1 . 
   
   
       26 . A compound of formula 3a: 
     
       
         
         
             
             
         
       
     
     where R 13  is halo, OH, OR 15 , or a carboxylic acid protecting group;
 R 15  is an aliphatic, aryl, heteroaryl, aralkyl, or heteroaralkyl; 
 R 14  is an amino protecting group, hydrogen or —W-G; 
 W is -Q-, -Q-C(O)—, —C(R 9 ) 2 —C(R 9 )(R 12 )—, or —C(R 9 ) 2 —[C(R 9 )(R 12 )] 2 —; 
 Q is —C(R 9 ) 2 — or —C(R 9 ) 2 C(R 9 ) 2 —; 
 G is —OH, —NR 4 R 5 , —N(R 9 )CONR 4 R 5 , —N(R 9 )SO 2  (C 1-3  aliphatic), —N(R 9 )COCF 3 , —N(R 9 )CO(C 1-6  aliphatic), —N(R 9 )CO(heterocyclyl), —N(R 9 )CO(heteroaryl) —N(R 9 )CO(aryl), a 3-7 membered heterocyclyl ring, or a 5-6 membered heteroaryl, wherein each of the heteroaryl, aryl and heterocyclyl moieties of G is optionally substituted by 1-3 R 10 ; 
 R 4  is hydrogen, 3-7 membered heterocyclyl, or C 1-6  aliphatic; 
 R 5  is hydrogen, C 1-E , aliphatic group or a 3-7 membered heterocyclic ring having 1-2 ring heteroatoms selected from N, O, or S, wherein R 5  is optionally substituted by halo, —CN, —SR 8 , —S(O) 2 O, —S(O) 2 N(R 7 ) 2 , —C(O)R 7 , —CO 2 R 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )CO 2 R 8 , or —N(R 7 )C(O)N(R 7 ) 2 ; 
 each R 7  is independently selected from hydrogen or C 1-4  aliphatic, or two R 7  on the same nitrogen atom are taken together with the nitrogen to form a 5-6 membered heteroaryl or heterocyclyl ring; 
 each R 8  is independently selected from C 1-4  aliphatic; 
 each R 9  is independently selected from hydrogen or C 1-3  aliphatic; 
 each R 10  is independently selected from oxo, —R 11 , -T-R 11 , or -V-T-R 11 ; 
 each R 11  is independently selected from C 1-6  aliphatic, halo, —S(O) 2 N(R 7 ) 2 , —OR 7 , —CN, —SR 8 , —S(O) 2 R 8 , —C(O)R 7 , —CO 2 R 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )CO 2 R 7 , or —N(R 7 )C(O)N(R 7 ) 2 ; 
 T is a straight or branched C 1-4  alkylene chain; 
 V is —O—, —N(R 7 )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, or —CO 2 —; and 
 R 12  is hydrogen or an amino acid side chain. 
 
   
   
       27 . The compound of  claim 26  that is (S)-3a. 
   
   
       28 . A compound of formula IV: 
     
       
         
         
             
             
         
       
       where R 14  is an amino protecting group or hydrogen; 
       R 1  is hydrogen, halo, C 1-3  aliphatic, amino, cyano, (C 1-3  alkyl) 1-2  amino, C 1-3  alkoxy, —CONH 2 , —NHCOCF 3 , or —CH 2 NH 2 ; 
       R 2  is hydrogen, halo, C 1-3  aliphatic, —CF 3 ; and 
       R 3  is hydrogen, halo, C 1-6  aliphatic, C 1-6  haloalkyl, C 1-6  alkoxy, hydroxy, amino, cyano, or (C 1-6  alkyl) 1-2  amino. 
     
   
   
       29 . The compound of  claim 28  that is (S)-IV.