Multicyclic compounds which inhibit leukocyte adhesion mediated by VLA-4

Abstract

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

1 . A compound of formula I:  
     
       
         
         
             
             
         
       
       wherein ring A is a multicyclic bridged cycloalkyl, multicyclic bridged cycloalkenyl or multicyclic bridged heterocyclic group provided the multicyclic bridged heterocyclic group does not contain a lactam and further wherein said multicyclic bridged cycloalkyl, multicyclic bridged cyloalkenyl or multicyclic bridged heterocyclic group is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where each R is independently hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, —N[S(O) 2 —R′] 2  and —N[S(O) 2 —NR′] 2  where each R′ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -cycloalkyl, —SO 2 -substituted cycloalkyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, —SO 2 -substituted heterocyclic and —SO 2 NRR where R is hydrogen or alkyl;  
       R 1  is selected from the group consisting of:  
       (a) —(CH 2 ) x —Ar—R 5  where R 5  is selected from the group consisting of —O-Z-NR 6 R 6′  and —O-Z-R 7  wherein R 6  and R 6′  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and where R 6  and R 6′  are joined to form a heterocycle or a substituted heterocycle, R 7  is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of —C(O)— and —SO 2 —,  
       Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl,  
       x is an integer of from 1 to 4; and  
       (b) Ar 1 —Ar 2 —C 1-10 alkyl-, Ar 1 —Ar 2 —C 2-10 alkenyl- and Ar 1 —Ar 2 —C 2-10 alkynyl-, wherein Ar 1  and Ar 2  are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from R b ; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from R a ;  
       R 2  is selected from the group consisting of hydrogen, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, aryl C 1-10 alkyl, heteroaryl, and heteroaryl C 1-10  alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from R a , and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R b ;  
       R 3  is selected from the group consisting of hydrogen, C 1-10  alkyl optionally substituted with one to four substituents independently selected from R a  and Cy optionally substituted with one to four substituents independently selected from R b ;  
       R a  is selected from the group consisting of Cy, —OR d , —NO 2 , halogen, —S(O) m R d , —SR d , —S(O) 2 OR d , —S(O) m NR d R e , —NR d R e , —O(CR f R g )NR d R e , —C(O)R d , —CO 2 R d , —CO 2 (CR f R g ) n CONR d R e , OC(O)R d , —CN, —C(O)NR d R e , —N[[r d ]]C(O)R e , —OC(O)NR d R e , —NR C(O)OR e , —NR C(O)NR d R e , —CR d (N—OR e ), CF 3 , and —OCF 3 ; wherein Cy is optionally substituted with one to four substituents independently selected from R c ;  
       R b  is selected from the group consisting of R a , C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl C 1-10  alkyl, heteroaryl, C 1-10  alkyl, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from R c ;  
       R c  is selected from the group consisting of halogen, amino, carboxy, C 1-4  alkyl, C 1-4  alkoxy, aryl, aryl C 1-4- alkyl, hydroxy, CF 3 , and aryloxy;  
       R d  and R e  are independently selected from hydrogen, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, Cy and Cy-C 1-10 alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from R c ; or R d  and R e  together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;  
       R f  and R g  are independently selected from hydrogen, C 1-10  alkyl, Cy and Cy-C 1-10  alkyl; or R f  and R g  together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;  
       R h  is selected from the group consisting of hydrogen, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, cyano, aryl, aryl C 1-10  alkyl, heteroaryl, heteroaryl C 1-10  alkyl, or —SO 2 R i ; wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substitutents independently selected from R a ; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R b ;  
       R i  is selected from the group consisting of C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, and aryl;  
       wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R c ;  
       Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;  
       X 1  is selected from the group consisting of —C(O)OR d , —P(O)(OR d )(OR e ), —P(O)(R d )(OR e ), S(O) m OR d  —C(O)NR d R h , and -5-tetrazolyl;  
       m is an integer from 1 to 2;  
       n is an integer from 1 to 10;  
       and pharmaceutically acceptable salts thereof.  
     
   
   
       2 - 5 . (canceled)  
   
   
       6 . A compound of the formula:  
     
       
         
         
             
             
         
       
       where R is a multicyclic cycloalkenyl group or a multicyclic cycloalkenyl group substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxy-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where each R is independently hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, —N[S(O) 2 —R′] 2  and —N[S(O) 2 —NR′] 2  where each R′ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups selected from the group consisting of Boc, Cbz, and formyl, or alkyl/substituted alkyl groups substituted with —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -cycloalkyl, —SO 2 -substituted cycloalkyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, —SO 2 -substituted heterocyclic and —SO 2 NRR where R is hydrogen or alkyl;  
       R 1  is selected from the group consisting of:  
       (a) —(CH 2 ) x —Ar—R 5  where R 5  is selected from the group consisting of —O-Z-NR 6 R 6′  and —O-Z-R 7  wherein R 6  and R 6′  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and where R 6  and R 6′  are joined to form a heterocycle or a substituted heterocycle, R 7  is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of —C(O)— and —S(O) 2 —, 
 Ar is aryl, heteroaryl, substituted aryl and substituted heteroaryl,  
 x is an integer from 1 to 4;  
 
       (b) Ar 1 —Ar 2 —C 1-10  alkyl-, Ar 1 —Ar 2 —C 2-10  alkenyl- and Ar 1 —Ar 2 —C 2-10  alkynyl-, wherein Ar 1  and Ar 2  are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from R b ; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from R a ; 
 R 2  is selected from the group consisting of hydrogen, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, aryl C 1-10 alkyl, heteroaryl, heteroaryl C 1-10  alkyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R a , and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R b ;  
 R 3  is selected from the group consisting of hydrogen, C 1-10 alkyl optionally substituted with one to four substituents independently selected from R a  and Cy optionally substituted with one to four substituents independently selected from R b ;  
 R a  is selected from the group consisting of Cy, —OR d , —NO 2 , halogen, —S(O) m R d , —SR d , —S(O) 2 OR d, —S(O) m NR d R e , —NR d R e , O(CR f R g ) n NR d R e , —C(O)R d , —CO 2 R d , —CO 2 (CR f R g )NR d R e , —OC(O)R d , CN, —C(O)NR f R e , —NRC(O)R e , —OC(O)NR d R e , —NR d C(O)OR e , —NRC(O)NR d R e , —CR d (N—OR e ), CF 3  and OCF 3 ; wherein Cy is optionally substituted with one to four substituents independently selected from R e ;  
 R b  is selected from the group consisting of R a , C 1-10  alkyl, C 2-10  alkenyl and C 2-10  alkynyl, aryl, aryl C 1-10 alkyl, heteroaryl C 1-10 alkyl, wherein alkyl, alkenyl, aryl and alkynyl are optionally substituted with a group independently selected from R e ,  
 R c  is selected from the group consisting of halogen, amino, carboxy, C 1-4  alkyl, C 1-4  alkoxy, aryl, aryl C 1-4  alkyl, hydroxyl, CF 3  and aryloxy;  
 R d  and R e  are independently selected from hydrogen, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, Cy and Cy-C 1-10  alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from R c ; or R d  and R e  together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;  
 R f  and R g  are independently selected from hydrogen, C 1-10  alkyl, Cy and Cy-C 1-10  alkyl; or R f  and R g  together with the carbon atom to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;  
 R h  is selected from the group consisting of hydrogen, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, cyano, aryl, aryl C 1-10  alkyl, heteroaryl, heteroaryl C 1-10  alkyl, and —SO 2 R i , wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R a ; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R b ;  
 R i  is selected from the group consisting of C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, and aryl, wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R e ;  
 Cy is cycloalkyl, heterocyclyl, aryl or heteroaryl;  
 X 1  is selected from the group consisting of —C(O)OR d , —P(O)(OR d )(OR e ), —P(O)(R d )(OR e ), —S(O) m R d , —C(O)NR d R h , and 5-tetrazolyl;  
 m is an integer from 1 to 2;  
 n is an integer from 1 to 10;  
 or pharmaceutically acceptable salts thereof.  
 
     
   
   
       7 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more compounds of  claim 6 .  
   
   
       8 . A method for the treatment of an inflammatory disease in a patient which method comprises administering to the patient the pharmaceutical compositions of  claim 6  wherein said disease is selected from the group consisting of multiple sclerosis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, and asthma.  
   
   
       9 . The compound of  claim 6 , wherein R 1  is —(CH 2 ) x —Ar—R 5  where R 5  is selected from the group consisting of —O-Z-NR 6 R 6  and —O-Z-R 7  wherein R 6  and R 6′  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and where R 6  and R 6′  are joined to form a heterocycle or a substituted heterocycle, R 7  is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of —C(O)— and —S(O) 2 —, 
 Ar is aryl, heteroaryl, substituted aryl and substituted heteroaryl, and    x is an integer from 1 to 4.    
   
   
       10 . The compound according to  claim 6  wherein R 1  is selected from the group consisting of: 
 3-[(CH 3 ) 2 NC(O)O-]benzyl, 4-[(CH 3 ) 2 NC(O)O-]benzyl, 4-[(CH 3 ) 2 NS(O) 2 O-]benzyl, 4-[(piperidin-1′-yl)C(O)O-]benzyl, 4-[(piperidin-4′-yl)C(O)O-]benzyl, 4-[(1′-methylpiperidin-4′-yl)C(O)O-]benzyl, 4-[(4′-hydroxypiperidin-1′-yl)C(O)O-]benzyl, 4-[(4′-formyloxypiperidin-1′-yl)C(O)O-]benzyl, 4-[(4′-ethoxycarbonylpiperidin-1′-yl)C(O)O-]benzyl, 4-[(4′-carboxylpiperidin-1′-yl)C(O)O-]benzyl, 4-[(3′-hydroxymethylpiperidin-4′-yl)-C(O)O-]benzyl, 4-[(4′-hydroxymethylpiperidin-1′-yl)C(O)O-]benzyl, 4-[(4′-phenyl-1′-Boc-piperidin-1′-yl)C(O)O-]benzyl, 4-[(4′-piperidon-1′-yl ethylene ketal)C(O)O-]benzyl, 4-[(piperazin-4′-yl)C(O)O-]benzyl, 4-[(1′-Boc-piperazin-4′-yl)C(O)O-]benzyl, 4-[(4′-methylpiperazin-1′-yl)C(O)O-]benzyl, 4-[(4′-methylhomopiperazin-1′-yl)C(O)O-]benzyl, 4-[(4′-(2-hydroxyethyl)piperazin-1′-yl)C(O)O-]benzyl, 4-[(4′-phenylpiperazin-1′-yl)C(O)O-]benzyl, 4-[(4′-(pyridin-2-yl)piperazin-1′-yl)C(O)O-]benzyl, 4-[(4′-(4-trifluoromethylpyridin-2-yl)piperazin-1′-yl)C(O)O-]benzyl, 4-[(4′-(pyrimidin-2-yl)piperazin-1′-yl)C(O)O-]benzyl, 4-[(4′-acetylpiperazin-1′-yl)C(O)O-]benzyl, 4-[(4′-(phenyl-C(O)-)piperazin-1′-yl)C(O)O-]benzyl, 4-[(4′-(pyridin-4-yl-C(O)-)piperazin-1′-yl)C(O)O-]benzyl, 4-[(4′-(phenylNHC(O)-)piperazin-1′-yl)C(O)O-]benzyl, 4-[(4′-(phenylNHC(S)-)piperazin-1′-yl)C(O)O-]benzyl, 4-[(4′-methanesulfonylpiperazin-1′-yl)C(O)O-]benzyl, 4-[(4′-trifluoromethanesulfonylpiperazin-1′-yl)C(O)O-]benzyl, 4-[(morpholin-4′-yl)C(O)O-]benzyl, 3-nitro-4-[(morpholin-4′-yl)-C(O)O-]benzyl, 4-[(thiomorpholin-4′-yl)C(O)O-]benzyl, 4-[(thiomorpholin-4′-yl sulfone)-C(O)O-]benzyl, 4-[(pyrrolidin-1′-yl)C(O)O-]benzyl, 4-[(2′-methylpyrrolidin-1′-yl)-C(O)O-]benzyl, 4-[(2′-(methoxycarbonyl)pyrrolidin-1′-yl)C(O)O-]benzyl, 4-[(2′-(hydroxymethyl)pyrrolidin-1′-yl)C(O)O-]benzyl, 4-[(2′-(N,N-dimethylamino)-ethyl)(CH 3 )NC(O)O-]benzyl, 4-[(2′-(N-methyl-N-toluene-4-sulfonylamino)ethyl(CH 3 )NC(O)O-]benzyl, 4-[(2′-(morpholin-4′-yl)(CH 3 )pyrrolidin-1′-yl)C(O)O-]benzyl, 4-[(2′-(hydroxyethyl)(CH 3 )NC(O)O-]benzyl, 4-[bis(2′-hydroxyethyl)NC(O)O-]benzyl, 4-[(2′-(formyloxy)ethyl)(CH 3 )NC(O)O-]benzyl, 4-[(CH 3 )C(O)CH 2 )HNC(O)O-]benzyl, 4-[(2′-(phenylNHC(O)O—)HNC(O)O-]benzyl, 3-chloro-4-[(CH 3 ) 2 NC(O)O-]benzyl, 3-chloro-4-[4′-methylpiperazin-1′-yl)C(O)O-]benzyl, 3-chloro-4-[4′-pyridin-2-yl)piperazin-1′-yl)C(O)O-]benzyl, 3-chloro-4-[thiomorpholin-4′-yl)C(O)O-]benzyl, and 3-fluoro-4-[(CH 3 ) 2 NC(O)O-]benzyl.    
   
   
       11 . The compound according to  claim 6 , wherein R 1  is Ar 2 —Ar 1 —C 1-10  alkyl-.  
   
   
       12 . The compound according to  claim 6 , wherein R 2  is hydrogen.  
   
   
       13 . The compound according to  claim 6 , wherein R 3  is hydrogen.