US2015157605A1PendingUtilityA1

Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes

Assignee: JENRIN DISCOVERYPriority: Nov 2, 2007Filed: Oct 6, 2014Published: Jun 11, 2015
Est. expiryNov 2, 2027(~1.3 yrs left)· nominal 20-yr term from priority
A61P 35/00A61P 9/12A61P 3/10A61P 43/00A61P 9/00A61P 3/06A61P 25/28A61P 25/20A61P 3/04A61P 3/00A61P 11/00A61P 1/16A61K 31/415A61P 19/02C07D 231/06A61P 15/02A61P 17/02A61P 1/00
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Claims

Abstract

The present invention provides novel pyrazoles that are useful as cannabinoid receptor antagonists and pharmaceutical compositions thereof and methods of using the same for treating obesity, diabetes, hepatic disorders, and/or cardiometabolic disorders.

Claims

exact text as granted — not AI-modified
1 . A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the disease is Type 2 diabetes: 
       
         
           
           
               
               
           
         
         wherein: 
         X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C 1-6  alkyl, halogen, CF 3 , O—C 1 - 6  alkyl, NO 2 , NR 2 , O(CH 2 ) n CO 2 R, O(CH 2 ) n CN, OCH 2 CH═CHCO 2 R, CH 2 O(CH 2 ) n CO 2 R, CH 2 OCH 2 CH═CHCO 2 R, O(CH 2 ) n PO(OR) 2 , CH 2 O(CH 2 ) n PO(OR) 2 , NR a (CH 2 ) n CO 2 R, NR a (CH 2 ) n PO(OR) 2 , NR a CH 2 CH═CHCO 2 R, NR a SO 2 R, NR a CO(CH 2 ) n CO 2 R, NR a CO(CH 2 ) n CONR a   2 , O(CH 2 ) n C 6 H 4 CO 2 R, O(CH 2 ) n C 6 H 4 (CH 2 ) n CO 2 R, CH 2 O(CH 2 ) n C 6 H 4 CO 2 R, O(CH 2 ) n C 6 H 4 CONR a   2 , O(CH 2 ) n C 6 H 4 (CH 2 ) n CONR a   2 , O(CH 2 ) n C 6 H 4 -tetrazole, CH 2 O(CH 2 ) n C 6 H 4 CONR a   2 , CH 2 O(CH 2 ) n C 6 H 4 -tetrazole, O(CH 2 ) n C 6 H 4 (CH 2 ) n -tetrazole, NR a (CH 2 ) n C 6 H 4 CO 2 R, CH 2 NR a (CH 2 ) n C 6 H 4 CO 2 R, NR a (CH 2 ) n C 6 H 4 (CH 2 ) n CO 2 R, NR a (CH 2 ) n C 6 H 4 CONR a   2 , CH 2 NR a (CH 2 ) n C 6 H 4 CONR a   2 , NR a (CH 2 ) n C 6 H 4 (CH 2 ) n CONR a   2 , NR a (CH 2 ) n C 6 H 4 -tetrazole, CH 2 NR a (CH 2 ) n C 6 H 4 -tetrazole, NR a (CH 2 ) n C 6 H 4 (CH 2 ) n -tetrazole, CONHOH, C(NH)NR a   2 , (CH 2 ) n C(NH)NR a   2 , O(CH 2 ) n CONR a   2 , O(CH 2 ) n C(NH)NR a   2 , O(CH 2 ) n C(NOH)NR a   2 , CH 2 O(CH 2 ) n CONR a   2 , NR a (CH 2 ) n CONR a   2 , OCH 2 CH═CHCONR a   2 , CH 2 OCH 2 CH═CHCONR a   2 , NR a CH 2 CH═CHCONR a   2 , (CH 2 ) m -tetrazole, O(CH 2 ) n -tetrazole, O(CH 2 CH 2 O) p R, NR a (CH 2 CH 2 O) p R, and SO 2 NHCH 3 ; 
         Z is selected from: H, C 1-6  alkyl, OH, O—C 1-6  alkyl, O(CH 2 CH 2 O) p R, OC(O)-C 1-6  alkyl, O(CH 2 ) n CO 2 R, OCH 2 CH═CHCO 2 R, O(CH 2 ) n PO(OR) 2 , O(CH 2 ) n CONR a   2 , O(CH 2 ) n C(NH)NH 2 , O(CH 2 ) n C(NOH)NR a   2 , OCH 2 CH═CHCONR a   2 , O(CH 2 ) n -phenyl-(CH 2 ) m CO 2 R, and O(CH 2 ) n -phenyl-(CH 2 ) m -tetrazole; 
         Z′ is selected from H, CO 2 R, and CONR a   2 ; 
         Q is selected from: (CH 2 ) n CHA(CH 2 ) m C(O)NR 2 , (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 , (CH 2 ) n CHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m SO 2 NR 2 , (CH 2 ) m CHA(CH 2 ) m SO 3 R, (CH 2 ) m CHA(CH 2 ) m C(NH)NH 2 , (CH 2 ) m CHA(CH 2 ) m C(NOH)NH 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , C 3 -C 6 -cyclic amino-(CH 2 ) m CO 2 R, C 3 -C 6 -cyclic amino-(CH 2 ) m CONR a   2 , C 3 -C 6 -cycloalkylene-(CH 2 ) m CO 2 R, and C 3 -C 6 -cycloalkylene-(CH 2 ) m CONR a   2 ; 
         provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2  or (CH 2 ) m CAA″(CH 2 ) m CO 2 R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b); 
         A is selected from H, C 1-6  alkyl, (CH 2 ) m C 3-6 -cycloalkyl, OH, CH 2 OH, CH(CH 3 )OH, C(CH 3 ) 2 OH, (CH 2 ) n CO 2 R b , (CH 2 ) n C(O)NR b   2 , and (CH 2 ) m -phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C 1-4  alkyl, halogen, CF 3 , O—C 1-4  alkyl, and NO 2 ; 
         alternatively, Q is CHA(CH 2 ) m C(O)NR 2  or CHA(CH 2 ) m CO 2 R, and (a) A is selected from OH, (CH 2 ) n CO 2 R b , and (CH 2 ) n C(O)NR b   2 ; (b) R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ; or (c) both (a) and (b); 
         A″ is C 1-6  alkyl; 
         M is C═O or SO 2 ; 
         R is independently selected from H, (CH 2 ) m (CHR b ) n (CH 2 ) m OH, CH(CH 2 OH) 2 , C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
         R a  is independently selected from H, (CH 2 ) m (CHR) n (CH 2 ) m OH, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
         R b  is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
         p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12; 
         m is selected from 0, 1, 2, 3, and 4; and, 
         n is selected from 1, 2, 3, and 4. 
       
     
     
         2 . The method of  claim 1 , wherein: M is SO 2 . 
     
     
         3 . The method of  claim 1 , wherein the compound is of formula Ia or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein the compound is of formula Ib or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein the compound is of formula Ic or a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 1 , wherein the compound is a compound of formula Ia or a stereoisomer or pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         X, Y, X′, Y′, X″, and Y″ are individually selected from the following: H, C 1-4  alkyl, halogen, CF 3 , O—C 1-4  alkyl, NO 2 , O(CH 2 CH 2 O) p R, NR a (CH 2 CH 2 O) p R, and NR 2 ; 
         Z is selected from: H, C 1-4  alkyl, OH, O—C 1-4  alkyl, acetyloxy, and propionyloxy; 
         Q is selected from: (CH 2 ) n CHA(CH 2 ) m C(O)NR 2 , (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 , (CH 2 ) n CHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m SO 2 NR 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , C 3 -C 6 -cyclic amino-(CH 2 ) m CO 2 R, C 3 -C 6 -cyclic amino-(CH 2 ) m CONR a   2 , C 3 -C 6 -cycloalkylene-(CH 2 ) m CO 2 R, and C 3 -C 6 -cycloalkylene-(CH 2 ) m CONR a   2 ; 
         provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2  or (CH 2 ) m CAA″(CH 2 ) m CO 2 R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b); 
         A is selected from H, C 1-4  alkyl, (CH 2 ) m C 3-6 -cycloalkyl, OH, CH 2 OH, CH(CH 3 )OH, C(CH 3 ) 2 OH, (CH 2 ) n CO 2 R b , (CH 2 ) n C(O)NR b   2 , and (CH 2 ) m -phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C 1-4  alkyl, halogen, CF 3 , O—C 1-4  alkyl, and NO 2 ; 
         alternatively, Q is CHA(CH 2 ) m C(O)NR 2  or CHA(CH 2 ) m CO 2 R, and A is OH or (CH 2 ) n CO 2 R b  or R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ; 
         R is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
         R b  is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
         p is selected from 2, 3, 4, 5, 6, 7, and 8; 
         m is independently selected from 0, 1, 2, and 3; and, 
         n is independently selected from 1, 2, and 3. 
       
     
     
         7 . The method of  claim 6 , wherein:
 Q is selected from: (CH 2 ) n CHA(CH 2 ) m C(O)NR 2 , (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 , (CH 2 ) m CHA(CH 2 ) m SO 2 NR 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , C 3 -C 6 -cyclic amino-(CH 2 ) m CO 2 R, C 3 -C 6 -cyclic amino-(CH 2 ) m CONR a   2 , and C 3 -C 6 -cycloalkylene-(CH 2 ) m CONR a   2 ;   provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2  then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);   alternatively, Q is CHA(CH 2 ) m C(O)NR 2  and A is OH or (CH 2 ) n CO 2 R b  or R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ;   M is SO 2 ;   R is independently selected from H and C 1-4  alkyl;   R b  is independently selected from H and C 1-4  alkyl;   m is independently selected from 0, 1, and 2; and,   n is independently selected from 1 and 2.   
     
     
         8 . The method of  claim 1 , wherein the compound is a compound of formula Ib or a stereoisomer or pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         X, Y, X′, Y′, X″, and Y″ are individually selected from the following: H, C 1-4  alkyl, halogen, CF 3 , O—C 1-4  alkyl, NO 2 , O(CH 2 CH 2 O) p R, NR a (CH 2 CH 2 O) p R, and NR 2 ; 
         Z is selected from: H, C 1-4  alkyl, OH, O—C 1-4  alkyl, acetyloxy, and propionyloxy; 
         Q is selected from: (CH 2 ) n CHA(CH 2 ) m C(O)NR 2 , (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 , (CH 2 )CHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m SO 2 NR 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , C 3 -C 6 -cyclic amino-(CH 2 ) m CO 2 R, C 3 -C 6 -cyclic amino-(CH 2 ) m CONR a   2 , C 3 -C 6 -cycloalkylene-(CH 2 ) m CO 2 R, and C 3 -C 6 -cycloalkylene-(CH 2 ) m CONR a   2 ; 
         provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2  or (CH 2 ) m CAA″(CH 2 ) m CO 2 R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b); 
         A is selected from H, C 1-4  alkyl, (CH 2 ) m C 3-6 -cycloalkyl, OH, CH 2 OH, CH(CH 3 )OH, C(CH 3 ) 2 OH, (CH 2 ) n CO 2 R b , (CH 2 ) n C(O)NR b   2 , and (CH 2 ) m -phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C 1-4  alkyl, halogen, CF 3 , O—C 1-4  alkyl, and NO 2 ; 
         alternatively, Q is CHA(CH 2 ) m C(O)NR 2  or CHA(CH 2 ) m CO 2 R, and A is OH or (CH 2 ) n CO 2 R b  or R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ; 
         R is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
         R b  is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl; 
         p is selected from 2, 3, 4, 5, 6, 7, and 8; 
         m is independently selected from 0, 1, 2, and 3; and, 
         n is independently selected from 1, 2, and 3. 
       
     
     
         9 . The method of  claim 8 , wherein:
 Q is selected from: (CH 2 ) n CHA(CH 2 ) m C(O)NR 2 , (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 , (CH 2 ) m CHA(CH 2 ) m SO 2 NR 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a   2 , C 3 -C 6 -cyclic amino-(CH 2 ) m CO 2 R, C 3 -C 6 -cyclic amino-(CH 2 ) m CONR a   2 , and C 3 -C 6 -cycloalkylene-(CH 2 ) m CONR a   2 ;   provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2  then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);   alternatively, Q is CHA(CH 2 ) m C(O)NR 2  and A is OH or (CH 2 ) n CO 2 R b  or R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ;   M is SO 2 ;   R is independently selected from H and C 1-4  alkyl;   R b  is independently selected from H and C 1-4  alkyl;   m is independently selected from 0, 1, and 2; and,   n is independently selected from 1 and 2.   
     
     
         10 . The method of  claim 1 , wherein the compound is selected from Table B or a stereoisomer or a pharmaceutically acceptable salt thereof: 
       
         
           
                 
               
                   TABLE B 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                 
                 
                 
                 
                 
               
                   Number 
                   Q 
                   Y″ 
                   X″ 
                   X 
                 
                     
                 
                    1 
                   CH 2 CH 2 CH(OH)CO 2 Me 
                   4-Cl 
                   H 
                   Cl 
                 
                    2 
                   CH(CH 2 CO 2 tBu)CO 2 Me 
                   4-Cl 
                   H 
                   Cl 
                 
                    3 
                   C(CH 3 ) 2 CO 2 H 
                   4-Cl 
                   H 
                   Cl 
                 
                    4 
                   C(CH 3 ) 2 CONH—CH(CH 3 )CO 2 Me 
                   4-Cl 
                   H 
                   Cl 
                 
                    5 
                   CH(CH(CH 3 ) 2 )—CONHCH 2 CH 2 OH 
                   4-OMe 
                   H 
                   Cl 
                 
                    6 
                   CH 2 CH(OH)CH 2 CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                    7 
                   CHCH(CH 3 ) 2 CONH—CH(CH 2 OH) 2   
                   4-Cl 
                   H 
                   Cl 
                 
                    8 
                   CH 2 CH 2 CH(OH)CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                    9 
                   CHCH(CH 3 ) 2 CONH—CH(CH 2 OH) 2   
                   4-OMe 
                   H 
                   Cl 
                 
                   10 
                   CH(CH 2 CONH 2 )CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   11 
                   CH 2 CONHCH 2 CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   12 
                   CH 2 CONHCH 2 CONH 2   
                   4-OMe 
                   H 
                   Cl 
                 
                   13 
                   CH 2 CONH—CH(CHCH 3 OH)CONH 2   
                   4-OMe 
                   H 
                   Cl 
                 
                   14 
                   CHCH 3 CONHCH 2 CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   15 
                   CHCH 3 CONH—CH 2 CONH 2   
                   4-OMe 
                   H 
                   Cl 
                 
                   16 
                   CHCH(CH 3 ) 2 CONH—CH 2 CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   17 
                   CHCH(CH 3 ) 2 CONH—CHCH 3 CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   18 
                   CHCH 3 CONH—CHCH 2 OHCONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   19 
                   CHCH 3 CONH—CHCH 3 CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                     
                 
                   20 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   4-Cl 
                   H 
                   Cl 
                 
                     
                 
                   21 
                   CH 2 CH 2 SO 2 NH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                     
                 
             
                
               
               
                
                
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         11 . A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound selected from the compounds of Table A and C or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the disease is Type 2 diabetes: 
       
         
           
                 
               
                   TABLE A 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                 
                 
                 
                 
                 
               
                   Num- 
                     
                     
                     
                     
                 
                   ber 
                   Q 
                   Y″ 
                   X″ 
                   X 
                 
                     
                 
                    1 
                   CH(CH 3 )CH 2 CO 2 Et 
                   4-Cl 
                   H 
                   Cl 
                 
                    2 
                   CH(CH 3 )CH 2 CO 2 H 
                   4-Cl 
                   H 
                   Cl 
                 
                    3 
                   CH 2 CO 2 Me 
                   4-Cl 
                   H 
                   Cl 
                 
                    4 
                   CH 2 CO 2 H 
                   4-Cl 
                   H 
                   Cl 
                 
                    5 
                   CH(CH 3 )CO 2 Me 
                   4-Cl 
                   H 
                   Cl 
                 
                    6 
                   CH(CHOHCH 3 )CO 2 Me 
                   4-Cl 
                   H 
                   Cl 
                 
                    7 
                   CH(C(CH 3 ) 3 )CO 2 Me 
                   4-Cl 
                   H 
                   Cl 
                 
                    8 
                   CH 2 CO 2 Me 
                   4-OMe 
                   3- 
                   Cl 
                 
                     
                     
                     
                   OMe 
                     
                 
                   10 
                   CH 2 CO 2 Me 
                   4-OMe 
                   3-Cl 
                   Cl 
                 
                   11 
                   CH(CH 2 OH)CO 2 Me 
                   4-Cl 
                   H 
                   Cl 
                 
                   12 
                   CH 2 CONHCH 2 CO 2 Me 
                   4-Cl 
                   H 
                   Cl 
                 
                   13 
                   CH(CH 3 )CONH—CH 2 CO 2 Me 
                   4-Cl 
                   H 
                   Cl 
                 
                   14 
                   CH(CH(CH 3 ) 2 )CONH—CH 2 CO 2 Me 
                   4-Cl 
                   H 
                   Cl 
                 
                   15 
                   CH 2 CONHCH 2 CO 2 Me 
                   4-OMe 
                   H 
                   Cl 
                 
                   16 
                   CH 2 CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   16 
                   CH(CH 3 )CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   17 
                   CH 2 CH 2 CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   18 
                   CH(CH 3 )CH 2 CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   19 
                   CH(C(CH 3 ) 3 )CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   20 
                   CH(CH(CH 3 ) 2 )CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   21 
                   CHCH(CH 3 ) 2 )—CONHCH 3   
                   4-Cl 
                   H 
                   Cl 
                 
                   22 
                   CH(CHOHCH 3 )CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   23 
                   CH 2 CONH 2   
                   4-OMe 
                   H 
                   Cl 
                 
                   24 
                   CH(CH 3 )CONH 2   
                   4-OMe 
                   H 
                   Cl 
                 
                   25 
                   CH(CH 3 )CONH 2   
                   4-OCH 2 —CN 
                   H 
                   Cl 
                 
                   26 
                   C(CH 3 ) 2 CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   27 
                   CH 2 CH(CH 3 )CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                   28 
                   CH(CH 3 )CONH 2   
                   4-OMe 
                   4- 
                   Cl 
                 
                     
                     
                     
                   OMe 
                     
                 
                   29 
                   CH(CH 3 )CONH 2   
                   4-OMe 
                   3-Cl 
                   Cl 
                 
                   30 
                   CH 2 CONH 2   
                   4-Cl 
                   H 
                   OMe 
                 
                   31 
                   CH(CH(CH 3 ) 2 )CONH 2   
                   3-OMe 
                   H 
                   Cl 
                 
                   32 
                   CH 2 CH 2 CONH 2   
                   4-Cl 
                   H 
                   Cl 
                 
                     
                 
             
                
               
               
                
                
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         
           
                 
               
                   TABLE C 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                 
                 
                 
                 
                 
               
                   Number 
                   Q 
                   Y″ 
                   X″ 
                   X 
                 
                     
                 
                   1 
                   Me 
                   4-OCH 2 CO 2 Et 
                   H 
                   Cl 
                 
                   2 
                   Me 
                   4-CONHOH 
                   Cl 
                   Cl 
                 
                     
                 
             
                
                
               
               
                
                
               
            
             
                
                
                
                
                
               
            
           
         
       
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         23 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         24 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         25 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         27 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         28 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         29 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         30 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         31 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         32 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         33 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         34 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         35 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         36 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         37 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         38 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a stereoisomer or a pharmaceutically acceptable salt thereof.

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