US2008269256A1PendingUtilityA1

Pyridine-2-carboxyamide derivatives

57
Assignee: JAESCHKE GEORGPriority: Mar 4, 2005Filed: Jul 1, 2008Published: Oct 30, 2008
Est. expiryMar 4, 2025(expired)· nominal 20-yr term from priority
Inventors:Georg JaeschkeSabine KolczewskiRichard Hugh Philip PorterEric Vieira
A61P 43/00A61P 25/34A61P 27/02A61P 25/24A61P 25/00A61P 25/22A61P 25/14A61P 3/00A61P 25/04A61P 25/16A61P 25/32A61P 25/28A61P 3/04A61P 25/08A61P 21/00A61P 1/04A61K 9/4858C07D 409/12C07D 417/12A61P 13/02A61K 9/2018C07D 401/12C07D 213/81C07D 417/14C07D 401/14
57
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Claims

Abstract

The invention relates to compounds of formula I: wherein R 1 to R 3 are as defined in the specification, to processes for their preparation, to pharmaceutical compositions containing them, and to methods for treating CNS disorders.

Claims

exact text as granted — not AI-modified
1 . A compound formula (Ia): 
       
         
           
           
               
               
           
         
       
       wherein
 R 2  is H, C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R a ; 
 R 3  is aryl or a 5- or 6-membered heteroaryl each of which is optionally substituted by: 
 CN, Cl, F, Br, CF 3 , CHF 2 , —O—C 1 -C 7 -alkyl, —(CO)—R b , —(CH 2 ) m —R c , —NH—(CO)—C 1 -C 7 -alkyl, —O—CH 2 F, —O—CHF 2 , —O—CF 3 , —S(O) 2 —R d , C 3 -C 6 -cycloalkyl, or heteroaryl which is optionally substituted by C 1 -C 7 -alkyl; 
 R 4  is H, —OH, Cl, F, Br, CN, —CHF 2 , CF 3 , C 1 -C 7 -alkyl, —O—(CO)—C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R e ; 
 R a  is —O—C 1 -C 7 -alkyl or —OH; 
 R b  is C 1 -C 7 -alkyl, NH 2 , or —O—C 1 -C 7 -alkyl; 
 R c  is —OH, NH 2 , or NH—(CO)—O—C 1 -C 7 -alkyl; 
 R d  is C 1 -C 7 -alkyl, —NH 2 , —NH—C 1 -C 7 -alkyl, or —N-di(C 1 -C 7 -alkyl); 
 R e  is —OH, —CH 2 F, —CHF 2 , —CF 3 , or —O—(CO)—C 1 -C 7 -alkyl; and 
 m is 1 to 4 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , wherein:
 R 2  is H or C 1 -C 7 -alkyl;   R 3  is phenyl or a 5- or 6-membered heteroaryl each of which is optionally substituted by:   CN, Cl, F, Br, CF 3 , CHF 2 , —O—C 1 -C 7 -alkyl, —(CO)—R b , —(CH 2 ) m —R c , —NH—(CO)—C 1 -C 7 -alkyl, —O—CH 2 F, —O—CHF 2 , —O—CF 3 , —S(O) 2 —R d , or heteroaryl which is optionally substituted by C 1 -C 7 -alkyl; and   R 4  is H, —OH, Cl, F, Br, CN, —CHF 2 , CF 3 , C 1 -C 7 -alkyl, —O—(CO)—C 1 -C 7 -alkyl, or —(CH 2 ) m —R e      
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound of  claim 2 , selected from the group consisting of: 
       6-Methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid (5-methyl-thiazol-2-yl)-amide, and 
       6-Methyl-3-(pyridin-3-ylamino)-pyridine-2-carboxylic acid (5-methyl-thiazol-2-yl)-amide. 
     
     
         4 . A pharmaceutical composition comprising a therapeutically effective amount of a compound formula (Ia): 
       
         
           
           
               
               
           
         
       
       wherein
 R 2  is H, C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R a ; 
 R 3  is aryl or heteroaryl each of which is optionally substituted by:
 CN, Cl, F, Br, CF 3 , CHF 2 , —O—C 1 -C 7 -alkyl, —(CO)—R b , —(CH 2 ) m —R c , —NH—(CO)—C 1 -C 7 -alkyl, —O—CH 2 F, —O—CHF 2 , —O—CF 3 , —S(O) 2 —R d , C 3 -C 6 -cycloalkyl, or heteroaryl which is optionally substituted by C 1 -C 7 -alkyl; 
 
 R 4  is H, —OH, Cl, F, Br, CN, —CHF 2 , CF 3 , C 1 -C 7 -alkyl, —O—(CO)—C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R e ; 
 R a  is —O—C 1 -C 7 -alkyl or —OH; 
 R b  is C 1 -C 7 -alkyl, NH 2 , or —O—C 1 -C 7 -alkyl; 
 R c  is —OH, NH 2 , or NH—(CO)—O—C 1 -C 7 -alkyl; 
 R d  is C 1 -C 7 -alkyl, —NH 2 , —NH—C 1 -C 7 -alkyl, or —N-di(C 1 -C 7 -alkyl); 
 R e  is —OH, —CH 2 F, —CHF 2 , —CF 3 , or —O—(CO)—C 1 -C 7 -alkyl; and 
 m is 1 to 4 
 
       or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         5 . A compound of formula (II): 
       
         
           
           
               
               
           
         
         R 2  is H, C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R a ; 
         R 3  is aryl or heteroaryl each of which is optionally substituted by: 
         CN, Cl, F, Br, CF 3 , CHF 2 , —O—C 1 -C 7 -alkyl, —(CO)—R b , —(CH 2 ) m —R c , —NH—(CO)—C 1 -C 7 -alkyl, —O—CH 2 F, —O—CHF 2 , —O—CF 3 , —S(O) 2 —R d , C 3 -C 6 -cycloalkyl, or heteroaryl which is optionally substituted by C 1 -C 7 -alkyl; 
         R 4  is H, —OH, Cl, F, Br, CN, —CHF 2 , CF 3 , C 1 -C 7 -alkyl, —O—(CO)—C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R e ; 
         R a  is —O—C 1 -C 7 -alkyl or —O H; 
         R b  is C 1 -C 7 -alkyl, NH 2 , or —O—C 1 -C 7 -alkyl; 
         R c  is —OH, NH 2 , or NH—(CO)—O—C 1 -C 7 -alkyl; 
         R d  is C 1 -C 7 -alkyl, —NH 2 , —NH—C 1 -C 7 -alkyl, or —N-di(C 1 -C 7 -alkyl); 
         R e  is —OH, —CH 2 F, —CHF 2 , —CF 3 , or —O—(CO)—C 1 -C 7 -alkyl; and 
         m is 1 to 4 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound of  claim 5 , wherein:
 R 2  is H or C 1 -C 7 -alkyl;   R 3  is phenyl or a 5- or 6-membered heteroaryl each of which is optionally substituted by:   CN, Cl, F, Br, CF 3 , CHF 2 , —O—C 1 -C 7 -alkyl, —(CO)—R b , —(CH 2 ) m —R c , —NH—(CO)—C 1 -C 7 -alkyl, —O—CH 2 F, —O—CHF 2 , —O—CF 3 , —S(O) 2 —R d , or heteroaryl which is optionally substituted by C 1 -C 7 -alkyl; and   R 4  is H, —OH, Cl, F, Br, CN, —CHF 2 , CF 3 , C 1 -C 7 -alkyl, —O—(CO)—C 1 -C 7 -alkyl, or —(CH 2 ) m —R e  or   
       a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound of  claim 6  selected from the group consisting of: 
       6-Methyl-3-(pyridin-3-ylamino)-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide; 
       6-Methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide; 
       3-(5-Fluoro-pyridin-3-ylamino)-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide; 
       6-Methyl-3-(pyridin-3-ylamino)-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide; 
       6-Methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide; 
       3-(5-Fluoro-pyridin-3-ylamino)-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide; 
       6-Methyl-3-(4-methyl-pyridin-3-ylamino)-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide; 
       6-Methyl-3-(2-methyl-pyridin-3-ylamino)-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide; 
       3-(3-Fluoro-phenylamino)-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide; and 
       3-(3-Cyano-phenylamino)-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide. 
     
     
         8 . The compound of  claim 6 , selected from the group consisting of: 
       3-(3,5-Difluoro-phenylamino)-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide; 
       6-Methyl-3-(4-methyl-pyridin-3-ylamino)-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide; 
       6-Methyl-3-(2-methyl-pyridin-3-ylamino)-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide; 
       3-(3-Fluoro-phenylamino)-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide; 
       3-(3,5-Difluoro-phenylamino)-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide; 
       3-(3-Cyano-phenylamino)-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide; 
       6-Methyl-3-(2-methyl-2H-pyrazol-3-ylamino)-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide; 
       6-Methyl-3-(1-methyl-1H-pyrazol-4-ylamino)-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide; 
       6-Methyl-3-(1-methyl-1H-pyrazol-4-ylamino)-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide; 
       3-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-ylamino)-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide; and 
       3-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-ylamino)-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide. 
     
     
         9 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (II): 
       
         
           
           
               
               
           
         
         R 2  is H, C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R a ; 
         R 3  is aryl or heteroaryl each of which is optionally substituted by: 
         CN, Cl, F, Br, CF 3 , CHF 2 , —O—C 1 -C 7 -alkyl, —(CO)—R b , —(CH 2 ) m —R c , —NH—(CO)—C 1 -C 7 -alkyl, —O—CH 2 F, —O—CHF 2 , —O—CF 3 , —S(O) 2 —R d , C 3 -C 6 -cycloalkyl, or heteroaryl which is optionally substituted by C 1 -C 7 -alkyl; 
         R 4  is H, —OH, Cl, F, Br, CN, —CHF 2 , CF 3 , C 1 -C 7 -alkyl, —O—(CO)—C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R e ; 
         R a  is —O—C 1 -C 7 -alkyl or —OH; 
         R b  is C 1 -C 7 -alkyl, NH 2 , or —O—C 1 -C 7 -alkyl; 
         R c  is —OH, NH 2 , or NH—(CO)—O—C 1 -C 7 -alkyl; 
         R d  is C 1 -C 7 -alkyl, —NH 2 , —NH—C 1 -C 7 -alkyl, or —N-di(C 1 -C 7 -alkyl); 
         R e  is —OH, —CH 2 F, —CHF 2 , —CF 3 , or —O—(CO)—C 1 -C 7 -alkyl; and 
         m is 1 to 4 
       
       or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         10 . A compound of formula (Ij): 
       
         
           
           
               
               
           
         
         R 2  is H, C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R a ; 
         R 3  is aryl or heteroaryl each of which is optionally substituted by: 
         CN, Cl, F, Br, CF 3 , CHF 2 , —O—C 1 -C 7 -alkyl, —(CO)—R b , —(CH 2 ) m —R c , —NH—(CO)—C 1 -C 7 -alkyl, —O—CH 2 F, —O—CHF 2 , —O—CF 3 , —S(O) 2 —R d , C 3 -C 6 -cycloalkyl, or heteroaryl which is optionally substituted by C 1 -C 7 -alkyl; 
         R 4  is H, —OH, Cl, F, Br, CN, —CHF 2 , CF 3 , C 1 -C 7 -alkyl, —O—(CO)—C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R e ; 
         R a  is —O—C 1 -C 7 -alkyl or —OH; 
         R b  is C 1 -C 7 -alkyl, NH 2 , or —O—C 1 -C 7 -alkyl; 
         R c  is —OH, NH 2 , or NH—(CO)—O—C 1 -C 7 -alkyl; 
         R d  is C 1 -C 7 -alkyl, —NH 2 , —NH—C 1 -C 7 -alkyl, or —N-di(C 1 -C 7 -alkyl); 
         R e  is —OH, —CH 2 F, —CHF 2 , —CF 3 , or —O—(CO)—C 1 -C 7 -alkyl; and 
         m is 1 to 4 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The compound of  claim 10 , wherein:
 R 2  is H or C 1 -C 7 -alkyl;   R 3  is phenyl or a 5- or 6-membered heteroaryl each of which is optionally substituted by:   CN, Cl, F, Br, CF 3 , CHF 2 , —O—C 1 -C 7 -alkyl, —(CO)—R b , —(CH 2 ) m —R c , —NH—(CO)—C 1 -C 7 -alkyl, —O—CH 2 F, —O—CHF 2 , —O—CF 3 , —S(O) 2 —R d , or heteroaryl which is optionally substituted by C 1 -C 7 -alkyl; and   R 4  is H, —OH, Cl, F, Br, CN, —CHF 2 , CF 3 , C 1 -C 7 -alkyl, —O—(CO)—C 1 -C 7 -alkyl, or —(CH 2 ) m —R e , or a pharmaceutically acceptable salt thereof.   
     
     
         12 . The compound of  claim 11 , selected from the group consisting of: 
       6-Methyl-3-(pyridin-3-ylamino)-pyridine-2-carboxylic acid (3-chloro-phenyl)-amide; 
       6-Methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid (3-chloro-phenyl)-amide; and 
       3-(5-Chloro-pyridin-3-ylamino)-6-methyl-pyridine-2-carboxylic acid (3-chloro-phenyl)amide. 
     
     
         13 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (Ij): 
       
         
           
           
               
               
           
         
         R 2  is H, C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R a ; 
         R 3  is aryl or heteroaryl each of which is optionally substituted by: 
         CN, Cl, F, Br, CF 3 , CHF 2 , —O—C 1 -C 7 -alkyl, —(CO)—R b , —(CH 2 ) m —R c , —NH—(CO)—C 1 -C 7 -alkyl, —O—CH 2 F, —O—CHF 2 , —O—CF 3 , —S(O) 2 —R d , C 3 -C 6 -cycloalkyl, or heteroaryl which is optionally substituted by C 1 -C 7 -alkyl; 
         R 4  is H, —OH, Cl, F, Br, CN, —CHF 2 , CF 3 , C 1 -C 7 -alkyl, —O—(CO)—C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R e ; 
         R a  is —O—C 1 -C 7 -alkyl or —OH; 
         R b  is C 1 -C 7 -alkyl, NH 2 , or —O—C 1 -C 7 -alkyl; 
         R c  is —OH, NH 2 , or NH—(CO)—O—C 1 -C 7 -alkyl; 
         R d  is C 1 -C 7 -alkyl, —NH 2 , —NH—C 1 -C 7 -alkyl, or —N-di(C 1 -C 7 -alkyl); 
         R e  is —OH, —CH 2 F, —CHF 2 , —CF 3 , or —O—(CO)—C 1 -C 7 -alkyl; and 
         m is 1 to 4 
       
       or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         14 . A compound of formula (Ik): 
       
         
           
           
               
               
           
         
         R 2  is H, C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R a ; 
         R 3  is aryl or heteroaryl each of which is optionally substituted by:
 CN, Cl, F, Br, CF 3 , CHF 2 , —O—C 1 -C 7 -alkyl, —(CO)—R b , —(CH 2 ) m —R c , —NH—(CO)—C 1 -C 7 -alkyl, —O—CH 2 F, —O—CHF 2 , —O—CF 3 , —S(O) 2 —R d , C 3 -C 6 -cycloalkyl, or heteroaryl which is optionally substituted by C 1 -C 7 -alkyl; 
 
         R 4  is H, —OH, Cl, F, Br, CN, —CHF 2 , CF 3 , C 1 -C 7 -alkyl, —O—(CO)—C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R e ; 
         R a  is —O—C 1 -C 7 -alkyl or —OH; 
         R b  is C 1 -C 7 -alkyl, NH 2 , or —O—C 1 -C 7 -alkyl; 
         R c  is —OH, NH 2 , or NH—(CO)—O—C 1 -C 7 -alkyl; 
         R d  is C 1 -C 7 -alkyl, —NH 2 , —NH—C 1 -C 7 -alkyl, or —N-di(C 1 -C 7 -alkyl); 
         R e  is —OH, —CH 2 F, —CHF 2 , —CF 3 , or —O—(CO)—C 1 -C 7 -alkyl; and 
         m is 1 to 4 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The compound of  claim 14 , wherein:
 R 2  is H or C 1 -C 7 -alkyl;   R 3  is phenyl a or 5- or 6-membered heteroaryl each of which is optionally substituted by:   CN, Cl, F, Br, CF 3 , CHF 2 , —O—C 1 -C 7 -alkyl, —(CO)—R b , —(CH 2 ) m —R c , —NH—(CO)—C 1 -C 7 -alkyl, —O—CH 2 F, —O—CHF 2 , —O—CF 3 , —S(O) 2 —R d , or heteroaryl which is optionally substituted by C 1 -C 7 -alkyl; and   R 4  is H, —OH, Cl, F, Br, CN, —CHF 2 , CF 3 , C 1 -C 7 -alkyl, —O—(CO)—C 1 -C 7 -alkyl, or —(CH 2 ) m —R e      
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The compound of  claim 15 , selected from the group consisting of: 
       6-Methyl-3-(pyridin-3-ylamino)-pyridine-2-carboxylic acid (2-chloro-pyridin-4-yl)-amide; 
       6-Methyl-3-(pyridin-3-ylamino)-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide; 
       6-Methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide; 
       3-(5-Fluoro-pyridin-3-ylamino)-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide; 
       6-Methyl-3-(4-methyl-pyridin-3-ylamino)-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide; 
       6-Methyl-3-(2-methyl-pyridin-3-ylamino)-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide; 
       3-(5-Cyano-pyridin-3-ylamino)-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide; 
       3-(3-Fluoro-phenylamino)-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide; 
       3-(3-Cyano-phenylamino)-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide; and 
       3-(3,5-Difluoro-phenylamino)-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide. 
     
     
         17 . A pharmaceutical composition comprising a therapeutically effectively amount of a compound of formula (Ik): 
       
         
           
           
               
               
           
         
         R 2  is H, C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R a ; 
         R 3  is aryl or heteroaryl each of which is optionally substituted by: 
         CN, Cl, F, Br, CF 3 , CHF 2 , —O—C 1 -C 7 -alkyl, —(CO)—R b , —(CH 2 ) m —R c , —NH—(CO)—C 1 -C 7 -alkyl, —O—CH 2 F, —O—CHF 2 , —O—CF 3 , —S(O) 2 —R d , C 3 -C 6 -cycloalkyl, or heteroaryl which is optionally substituted by C 1 -C 7 -alkyl; 
         R 4  is H, —OH, Cl, F, Br, CN, —CHF 2 , CF 3 , C 1 -C 7 -alkyl, —O—(CO)—C 1 -C 7 -alkyl, C 3 -C 6 -cycloalkyl, or —(CH 2 ) m —R e ; 
         R a  is —O—C 1 -C 7 -alkyl or —OH; 
         R b  is C 1 -C 7 -alkyl, NH 2 , or —O—C 1 -C 7 -alkyl; 
         R c  is —OH, NH 2 , or NH—(CO)—O—C 1 -C 7 -alkyl; 
         R d  is C 1 -C 7 -alkyl, —NH 2 , —NH—C 1 -C 7 -alkyl, or —N-di(C 1 -C 7 -alkyl); 
         R e  is —OH, —CH 2 F, —CHF 2 , —CF 3 , or —O—(CO)—C 1 -C 7 -alkyl; and 
         m is 1 to 4 
       
       or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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