Therapeutic ureas

Abstract

This invention relates to urea compounds that are muscarinic receptor antagonists and agonists, pharmaceutical compositions comprising such compounds, and methods of preparing these compounds.

What is claimed is:  
     
         1 . A compound of Formula (I):  
       L 1 -X-L 2    (I)  
       wherein: 
 L 1  is a group of formula (a):  
                     
 wherein:  
 A is an aryl or a heteroaryl ring;  
 B″ is —NR a — wherein R a  is hydrogen, alkyl, aryl, heteroaryl, or substituted alkyl;  
 R 1  is hydrogen or alkyl;  
 R 2  is Het, or is selected from a group consisting of formula (i), (ii), and (iii):  
                     
 wherein:  
    is an optional double bond;  
 n 1  is an integer of from 1 to 4;  
 n 2  is an integer of from 1 to 3;  
 V is —CH—, —O—, —S(O)n 3  - (where n 3  is an integer of from 0 to 2), or —NR 4 — (wherein R 4  is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);  
 “Het” is a heteroaryl ring which optionally attaches (a) to a linker;  
 R 3  is hydrogen, alkyl, halo, amino, substituted amino, —OR a  (where R a  is hydrogen, alkyl, or acyl), or a covalent bond attaching (a) to a linker;  
 R 5  is hydrogen, alkyl, halo, amino, substituted amino, —OR b  (where R b  is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a linker;  
 R 6 , R 7 , and R 8  are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching (a) to a linker;  
 K is a bond or an alkylene group;  
 K″ is a bond, —C(O)—, —S(O) n4 — (where n 4  is an integer of from 0 to 2), or an alkylene group optionally substituted with a hydroxyl group; and  
 B is heterocycloamino or heteroarylamino, which optionally attaches (a) to a linker;  
 provided that at least one of the R 5 , R 6 , R 7 , R 8 , “Het”, heterocycloamino or heteroarylamino groups attaches (a) to a linker;  
 X is a linker; and  
 L 2  is an organic group comprising at least one primary, secondary, or tertiary amine;  
 or a pharmaceutically acceptable salt; or prodrug thereof.  
 
     
     
         2 . The compound of  claim 1  wherein L 2  is a group selected from a group consisting of: 
 (i) a group of formula (b):  
                     
 wherein:  
 D″ is alkylene;  
 D is —NR 31 R 32 , —N + (R 33 R 34 R 35 ) or —OR 32  where R 31 , R 33 , and R 34  are, independently of each other, hydrogen, alkyl, or aralkyl; and R 32  and R 35  represent a covalent bond attaching (b) to a linker;  
 R 27  is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;  
 R 28  is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;  
 R 29  and R 30  are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino; or  
 one of R 27 , R 28 , R 29 , or R 30  together with the adjacent group forms a methylenedioxy or ethylenedioxy group; 
 (ii) a group of formula (c):  
                     
 wherein:  
 
 n 11  is an integer of from 1 to 7;  
 n 12  is 0 to 7;  
 F is —NR 40 —, —O—, —S—, or —CHR 41 — (wherein R 40  and R 41  are, independently of each other, hydrogen, alkyl, or substituted alkyl);  
 F″ is a covalent bond, —OR 43 , —NR 42 R 43 , or —N + R 43 R 44 R 45  wherein R 42  is hydrogen or alkyl, R 44  and R 45  are alkyl, and R 43  is hydrogen, alkyl, or a covalent bond attaching (c) to a linker;  
 R 36  is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;  
 R 37  is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio; heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; and  
 R 37  is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bond attaching the ligand to a linker provided that at least one of R 38  and R 43  attaches (c) to a linker;  
 R 39  is hydrogen, alkyl, halo, hydroxy, alkoxy, or substituted alkyl; and 
 (iii) a group of formula (d) or (e):  
                     
 wherein:  
 
 R 46  is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle;  
 R 47  is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —COOR 50  where R 50  is alkyl; or  
 R 46  and R 47  together with the nitrogen atom to which they are attached form heterocycle, which heterocycle, in addition to optionally bearing the optional substituents defined hereinbelow for a heterocycle, can also optionally be substituted with one or more alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.  
 R 48  is a covalent bond that attaches the (d) to a linker; and  
 R 49  is alkyl.  
 
     
     
         3 . The compound of  claim 1  or  2  wherein A is phenyl or pyridyl.  
     
     
         4 . The compound of  claim 1  or  2  wherein B″ is —NH—.  
     
     
         5 . The compound of  claim 1  or  2  wherein R 1  is hydrogen, methyl, or ethyl.  
     
     
         6 . The compound of  claim 1  or  2  wherein R 2  is pyrrolyl, pyridinyl, or imidazolyl.  
     
     
         7 . The compound of  claim 1  or  2  wherein R 2  is phenyl.  
     
     
         8 . The compound of  claim 1  or  2  wherein K is a bond or a methylene group.  
     
     
         9 . The compound of  claim 1  or  2  wherein K″ is a bond.  
     
     
         10 . The compound of  claim 1  or  2  wherein B is a heterocycloamino group which attaches (a) to a linker.  
     
     
         11 . The compound of  claim 1  or  2  wherein B is pyrrolidine, piperidine, or hexahydroazepine attaching (a) to a linker.  
     
     
         12 . The compound of  claim 1  or  2  wherein B is piperidine wherein the nitrogen atom of said piperidine attaches (a) to a linker.  
     
     
         13 . The compound of  claim 1  or  2  wherein B is piperidin-4-yl, piperidin-3-yl, or 4-methylpiperidin-4-yl wherein the nitrogen at the 1 position optionally attaches (a) to a linker.  
     
     
         14 . The compound of  claim 2  wherein: R 46  is alkyl or substituted alkyl; R 47  is alkyl, substituted alkyl, or heterocycle; or R 46  and R 47  together with the nitrogen atom to which they are attached form heterocycle.  
     
     
         15 . The compound of  claim 1  or  2  wherein L 2  has any one of the formula A1-A590 shown hereinabove.  
     
     
         16 . The compound of  claim 1  or  2  wherein L 2  is A234, A363, A364, A153, A28, A324, A329, A562, A87, or A239.  
     
     
         17 . The compound of  claim 1  wherein L 1  is:  
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 18  wherein the piperidino nitrogen of L 1  is bonded to X.  
     
     
         19 . The compound of  claim 1  or  2  wherein X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups.  
     
     
         20 . The compound of  claim 1  or  2  wherein X is a group of formula:  
       —X a Z-(Y a -Z) m -Y-Z-X a — 
       wherein 
 m is an integer of from 0 to 20;  
 X a  at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—,  13  C(S)O—, —C(S)NR— or a covalent bond where R is as defined below;  
 Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;  
 Y a  and Y b  at each separate occurrence are selected from the group consisting of —O—, —C(O)—, —OC(O)—, —C(O)O—, —NR—, —S(O)n-, —C(O)NR′—, —NR′ C(O)—, —NR′ C(O)NR′—, —NR′ C(S)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —OC(O)—NR′—, —NR′—C(O)—O—, —N═C(X a )—NR′—, —NR′—C(X a )═N—, —P(O)(OR′)—O—, —O—P(O)(OR′)—, —S(O) n CR′R″—, —S(O) n —NR′—, —NR′—S(O) n —, —S—S—, and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; provided at least one of X a , Y a , Y b  or Z is not a covalent bond.  
 
     
     
         21 . The compound of  claim 1  or  2  wherein X is an alkylene group having from 3 to 20 carbon atoms; wherein one or more carbon atoms in the alkylene group is optionally replaced with —O—; and wherein the chain is optionally substituted on carbon with one or more hydroxyl.  
     
     
         22 . The compound of  claim 1  or  2  wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.  
     
     
         23 . The compound of  claim 1  or  2  wherein X has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein the phenyl ring is optionally substituted with 1, 2, or 3 fluoro groups.  
     
     
         24 . The compound of  claim 1  or  2  wherein X has one of the following the formula:  
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 2  which is a compound of Formula (Ia):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof.  
     
     
         26 . The compound of  claim 25  wherein X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups.  
     
     
         27 . The compound of  claim 25  wherein X is a group of formula:  
       —X a -Z-(Y a -Z) m -Y b -Z-X a — 
       wherein 
 m is an integer of from 0 to 20;  
 X a  at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below;  
 Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;  
 Y a  and Y b  at each separate occurrence are selected from the group consisting of —O—, —C(O)—, —OC(O)—, —C(O)O—, —NR—, —S(O)n-, —C(O)NR′—, —NR′ C(O)—, —NR′ C(O)NR′—, —NR′ C(S)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —OC(O)—NR′—, —NR′— C(O)—O—, —N═C(X a )—NR′—, —NR′—C(X a )═N—, —P(O)(OR′)—O—, —O—P(O)(OR′)—, —S(O) n CR′R″—, —S(O) n —NR′—, —NR′—S(O) n —, —S—S—, and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; provided at least one of X a , Y a , Y b  or Z is not a covalent bond.  
 
     
     
         28 . The compound of  claim 25  wherein X is an alkylene group having from 3 to carbon atoms; wherein one or more carbon atoms in the alkylene group is optionally replaced with —O—; and wherein the chain is optionally substituted on carbon with one or more hydroxyl.  
     
     
         29 . The compound of  claim 25  wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.  
     
     
         30 . The compound of  claim 25  wherein X has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein the phenyl ring is optionally substituted with 1, 2, or 3 fluoro groups.  
     
     
         31 . The compound of  claim 25  wherein X has one of the following the formula:  
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 1  which is a compound of formula (IVa):  
       
         
           
           
               
               
           
         
       
       wherein X, an L 2  are defined as in  claim 1;  or a pharmaceutically acceptable salt or prodrug thereof.  
     
     
         33 . The compound of  claim 32  wherein X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups.  
     
     
         34 . The compound of  claim 32  wherein X is a group of formula:  
       —X a -Z-(Y a -Z) m -Y b -Z-X a — 
       wherein 
 m is an integer of from 0 to 20;  
 X a  at each separate occurrence is selected from the group consisting of —O—, —S—, —NR—, —C(O)—, —C(O)O—, —C(O)NR—, —C(S)—, —C(S)O—, —C(S)NR— or a covalent bond where R is as defined below;  
 Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;  
 Y a  and Y b  at each separate occurrence are selected from the group consisting of —O—, —C(O)—, —OC(O)—, —C(O)O—, —NR—, —S(O) n —, —C(O)NR′—, —NR′ C(O)—, —NR′ C(O)NR′—, —NR′ C(S)NR′—, —C(═NR′)—NR′—, —NR′—C(═NR′)—, —OC(O—NR′—, —NR′— C(O)—O—, —N═C(X a )—NR′—, —NR′—C(X a )═N—, —P(O)(OR′)—O—, —O—P(O)(OR′)—, —S(O) n CR′R″—, —S(O) n —NR′—, —NR′—S(O) n —, —S—S—, and a covalent bond; where n is 0, 1 or 2; and R, R′ and R″ at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; provided at least one of X a , Y a , Y b  or Z is not a covalent bond.  
 
     
     
         35 . The compound of  claim 32  wherein X is an alkylene group having from 3 to 20 carbon atoms; wherein one or more carbon atoms in the alkylene group is optionally replaced with -O-; and wherein the chain is optionally substituted on carbon with one or more hydroxyl.  
     
     
         36 . The compound of  claim 32  wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.  
     
     
         37 . The compound of  claim 32  wherein X has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein the phenyl ring is optionally substituted with 1, 2, or 3 fluoro groups.  
     
     
         38 . The compound of  claim 32  wherein X has one of the following the formula:  
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound of  claim 1  wherein L 2  is a group of formula (d) wherein R 46  and R 47  together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 5 substituents independently selected from the group consisting of substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.  
     
     
         40 . The compound of  claim 1  wherein L 2  is a group of formula (d) wherein R 46  is a heterocycle, optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and R 47  is alkyl, substituted alkyl, acyl, or —COOR 50 .  
     
     
         41 . The compound of  claim 1  wherein L 2  is a group of formula (d) wherein R 46  is alkyl that is optionally substituted with from 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, NR a R b , wherein R a  and R b  may be the same or different and and are chosen from hydrogen, alkyl, substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and heterocyclic.  
     
     
         42 . The compound of  claim 1  wherein L 2  is a group of formula (d) wherein R 46  is a heterocycle which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl —SO 2 -heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.  
     
     
         43 . The compound of  claim 1  wherein L 2  is a group of formula (d) wherein R 46  is 3-piperidinyl, 4-piperidinyl, or 3-pyrrolidinyl, which R 46  is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.  
     
     
         44 . The compound of  claim 1  wherein R 46  and R 47  together with the nitrogen atom to which they are attached form a piperidine or pyrrolidine ring which ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.  
     
     
         45 . The compound of  claim 1  wherein R 46  and R 47  together with the nitrogen atom to which they are attached form a heterocycle that is an aza-crown ether (e.g. 1-aza-12-crown-4, 1-aza-15-crown-5, or 1-aza-18-crown-6).  
     
     
         46 . Compound number 1-643 as described in Table A, Table B, Table C, Table D, Table E, or Table F; or a pharmaceutically acceptable salt or prodrug thereof.  
     
     
         47 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 1  or  2 .  
     
     
         48 . A method of treating a disease mediated by a muscarinic receptor in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of  claim 1  or  2 .  
     
     
         49 . The method of  claim 48  wherein the disease is urinary incontinence, chronic pulmonary obstructive disease, asthma, hyper-salivation, a cognitive disorder, blurred vision, or irritable bowel syndrome.  
     
     
         50 . A compound of formula L 1 -H wherein L 1,  has the values defined in  claim 1;   
       or a salt thereof  
     
     
         51 . The compound of  claim 50  which is  
       
         
           
           
               
               
           
         
       
       or a salt thereof.