Multicyclic compounds and methods of their use

Abstract

This invention relates to multicyclic compounds, pharmaceutical compositions comprising them, and methods of their use in, for example, the treatment of cognitive disorders.

1 . A specific proline transporter inhibitor of formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 A is an optionally substituted non-aromatic heterocycle;  
 each of D 1  and D 2  is independently N or CR 1 ;  
 each of E 1 , E 2  and E 3  is independently N or CR 2 ;  
 X is optionally substituted heteroaryl;  
 Y is O, C(O), CH(OH), or CH 2 ;  
 each R 1  is independently hydrogen, halogen, cyano, R A , OR A , C(O)R A , C(O)OR A , C(O)N(R A R B ), N(R A R B ), or SO 2 R A ;  
 each R 2  is independently hydrogen, halogen, cyano, R A , OR A , C(O)R A , C(O)OR A , C(O)N(R A R B ), N(R A R B ), or SO 2 R A ;  
 each R A  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle; and  
 each R B  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle.  
 
   
   
       2 . The specific proline transporter inhibitor of  claim 1 , which has a PTIC 50  of less than about 150 nM.  
   
   
       3 . The specific proline transporter inhibitor of  claim 2 , which has a PTIC 50  of less than about 100 nM.  
   
   
       4 . The specific proline transporter inhibitor of  claim 3 , which has a PTIC 50  of less than about 50 nM.  
   
   
       5 . The specific proline transporter inhibitor of  claim 1 , which has a DTIC 50  of greater than about 1 μM.  
   
   
       6 . The specific proline transporter inhibitor of  claim 5 , which has a GTIC 50  of greater than about 1 μM.  
   
   
       7 - 23 . (canceled)  
   
   
       24 . The specific proline transporter inhibitor of  claim 1 , wherein X is an optionally substituted 5-, 6-, 9- or 10-membered heteroaryl.  
   
   
       25 . The specific proline transporter inhibitor of  claim 24 , wherein X is optionally substituted 5- or 6-membered heteroaryl.  
   
   
       26 - 41 . (canceled)  
   
   
       42 . The specific proline transport inhibitor of  claim 25 , which is of formula IA:  
     
       
         
         
             
             
         
       
     
   
   
       43 . The specific proline transport inhibitor of  claim 25 , which is of formula IB:  
     
       
         
         
             
             
         
       
     
     wherein: 
 each R 5  is independently halogen, cyano, R 5A , OR 5A , C(O)R 5A , C(O)OR 5A , C(O)N(R 5A R 5B ), N(R 5A R 5B ), or SO 2 R 5A ;  
 each R 5A  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle;  
 each R 5B  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle; and  
 n is 0-5.  
 
   
   
       44 . The specific proline transport inhibitor of  claim 25 , which is of formula IC:  
     
       
         
         
             
             
         
       
     
     wherein: 
 Y is O,l C(O) or CH 2 ;  
 each R 5  is independently halogen, cyano, R 5A , OR 5A , C(O)R 5A , C(O)OR 5A , C(O)N(R 5A R 5B ), N(R 5A R 5B ), or SO 2 R 5A ;  
 each R 5A  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle;  
 each R 5B  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle; and  
 m is 0-4.  
 
   
   
       45 . The specific proline transport inhibitor of  claim 25 , which is of formula ID:  
     
       
         
         
             
             
         
       
     
     wherein: 
 each R 5  is independently halogen, cyano, R 5A , OR 5A , C(O)R 5A , C(O)OR 5A , C(O)N(R 5A R 5B ), N(R 5A R 5B ), or SO 2 R 5A ;  
 each R 5A  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle;  
 each R 5B  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle; and  
 p is 0-7.  
 
   
   
       46 . The specific proline transport inhibitor of  claim 25 , which is of formula IE:  
     
       
         
         
             
             
         
       
     
     wherein: 
 Y is O, C(O) or CH 2 ;  
 each R 5  is independently halogen, cyano, R 5A , OR 5A , C(O)R 5A , C(O)OR 5A , C(O)N(R 5A R 5B ), N(R 5A R 5B ), or SO 2 R 5A ;  
 each R 5A  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle;  
 each R 5B  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle; and  
 q is 0-6.  
 
   
   
       47 . The specific proline transport inhibitor of  claim 25 , which is of formula IF:  
     
       
         
         
             
             
         
       
     
     wherein: 
 each R 5  is independently halogen, cyano, R 5A , OR 5A , C(O)R 5A , C(O)OR 5A , C(O)N(R 5A R 5B ), N(R 5A R 5B ), or SO 2 R 5A ;  
 each R 5A  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle;  
 each R 5B  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle; and  
 m is 0-4.  
 
   
   
       48 . A compound of formula II:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 A is an optionally substituted non-aromatic heterocycle containing no more than two nitrogen atoms;  
 each of D 1  and D 2  is independently N or CR 1 ;  
 each of E 1 , E 2  and E 3  is independently N or CR 2 ;  
 each of G 1  and G 2  are independently N or CR 3 ;  
 each of J 1 , J 2  and J 3  are independently N or CR 4 ;  
 Y is O, C(O), CH(OH), or CH 2 ;  
 each R 1  is independently hydrogen, halogen, or (C 1-10 )alkyl;  
 each R 2  is independently halogen, cyano, R 2A , OR 2A , or SO 2 R 2A ;  
 each R 2A  is independently hydrogen or (C 1-10 )alkyl optionally substituted with one or more halogens;  
 each R 3  is independently hydrogen, cyano, or (C 1-10 )alkyl optionally substituted with one or more halogens; and  
 each R 4  is independently hydrogen, cyano, or (C 1-10 )alkyl optionally substituted with one or more halogens;  
 with the provisos that: 1) at least one of G 1 , G 2 , J 1 , J 2  or J 3  is N; 2) at least one of J 1 , J 2  and J 3  is CR 4 ; 3) if Y is C(O), A is piperazine, all of G 1 , G 2 , J 1 , J 3 , D 1 , D 2 , E 1 , and E 3  are CH, and all of R 1  are hydrogen, then none of R 2  are lower alkyl; 4) if Y is C(O), A is piperazine, D 2  and E 1  are both N, and all of R 1  and R 2  are hydrogen, then R 4  is not cyano; 5) if Y is O, A is pyrrolidine, all of G 1 , G 2 , J 1 , J 3 , D 1 , D 2 , E l , E 2 , and E 3  are CH, and all of R 1  are hydrogen, then at least one R 2  is not hydrogen; 6) if Y is CH 2 , A is piperazine, all of G 2 , J 1 , J 2 , J 3 , D 1 , and D 2  are CH, all of E 1 , E 2  and E 3  are CR 2 , and all of R 1  are hydrogen, at least one R 2  is not hydrogen; and 7) if Y is C(O) or CH 2 , A is piperazine, at least one of G 1  and G 2  is N, all of J 1 , J 2 , J 3 , D 1 , D 2 , E 1 , E 2  and E 3  are CH, and all of R 1  are hydrogen, then at least one R 2  is not hydrogen.  
 
   
   
       49 - 51 . (canceled)  
   
   
       52 . The compound of  claim 48 , wherein A is monocyclic.  
   
   
       53 . The compound of  claim 48 , wherein A is bicyclic.  
   
   
       54 . The compound of  claim 48 , wherein A is unsubstituted.  
   
   
       55 . The compound of  claim 48 , wherein A is optionally substituted pyrrolidine, piperidine, piperazine, hexahydropyrimidine, 1,2,3,6-tetrahydropyridine, octahydrocyclopenta[c]pyrrole, or octahydropyrrolo[3,4-c]pyrrole.  
   
   
       56 . The compound of  claim 48 , wherein one of D 1  and D 2  is N.  
   
   
       57 . The compound of  claim 48 , wherein both D 1  and D 2  are N.  
   
   
       58 . The compound of  claim 48 , wherein both D 1  and D 2  are CR 1 .  
   
   
       59 . The compound of  claim 48 , wherein one of E 1 , E 2  and E 3  is N.  
   
   
       60 . The compound of  claim 48 , wherein two of E 1 , E 2  and E 3  are N.  
   
   
       61 . The compound of  claim 48 , wherein all of E 1 , E 2  and E 3  are N.  
   
   
       62 . The compound of  claim 48 , wherein all of E 1 , E 2  and E 3  are CR 2 .  
   
   
       63 . The compound of  claim 48 , wherein R 1  is hydrogen.  
   
   
       64 . The compound of  claim 48 , wherein R 2  is halogen.  
   
   
       65 . The compound of  claim 48 , wherein R 2  is OR A .  
   
   
       66 . The compound of  claim 65 , wherein R A  is hydrogen or optionally substituted alkyl.  
   
   
       67 . The compound of  claim 48 , wherein one of G 1  and G 2  is N.  
   
   
       68 . The compound of  claim 48 , wherein both G 1  and G 2  are N.  
   
   
       69 . The compound of  claim 48 , wherein both G 1  and G 2  are CR 3 .  
   
   
       70 . The compound of  claim 48 , wherein one of J 1 , J 2  and J 3  is N.  
   
   
       71 . The compound of  claim 48 , wherein two of J 1 , J 2  and J 3  are N.  
   
   
       72 . The compound of  claim 48 , wherein all of J 1 , J 2  and J 3  are CR 4 .  
   
   
       73 . The compound of  claim 48 , wherein R 3  is hydrogen, halogen, or optionally substituted alkyl.  
   
   
       74 . The compound of  claim 48 , wherein R 4  is hydrogen, halogen, or optionally substituted alkyl  
   
   
       75 . The compound of  claim 48 , wherein Y is C(O).  
   
   
       76 . The compound of  claim 48 , wherein Y is CH(OH).  
   
   
       77 . The compound of  claim 48 , wherein Y is CH 2 .  
   
   
       78 . The compound of  claim 48 , which is of formula IIA:  
     
       
         
         
             
             
         
       
     
     wherein: 
 Z is CR 5  or N;  
 each R 5  is independently halogen, cyano, R 5A , OR 5A , C(O)R 5A , C(O)OR 5A , C(O)N(R 5A R 5B ), N(R 5A R 5B ), or SO 2 R 5A ;  
 each R 5A  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle;  
 each R 5B  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle; and  
 n is 0-5 if Z is CR 5 , or 0-4if Z is N.  
 
   
   
       79 . The compound of  claim 78 , wherein Z is CH, G 1  is N, and at least one R 2  is not hydrogen.  
   
   
       80 . The compound of  claim 48 , which is of formula IIB:  
     
       
         
         
             
             
         
       
     
   
   
       81 . The compound of  claim 48 , which is of formula IIC:  
     
       
         
         
             
             
         
       
     
     wherein: 
 Z is CR 5  or N;  
 each R 5  is independently halogen, cyano, R 5A , OR 5A , C(O)R 5A , C(O)OR 5A , C(O)N(R 5A R 5B ), N(R 5A R 5B ), or SO 2 R 5A ;  
 each R 5A  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle;  
 each R 5B  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle; and  
 n is 0-5if Z is CR 5 , or 0-4if Z is N.  
 
   
   
       82 . The compound of  claim 82 , wherein Z is CH, G 1  is N, and at least one R 2  is not hydrogen.  
   
   
       83 . A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: 
 (1-(pyrimidin-2-yl)piperidin-4-yl)(4′-(trifluoromethyl)biphenyl-4-yl )methanol;    (4′-chlorobiphenyl-4-yl)(2,6-dimethyl-4-(pyridin-2-yl)piperazin-1-yl)methanone;    (3′-chloro-3-methoxybiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone;    (4-(pyrimidin-2-yl)piperazin-1-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    (3-fluoro-4′-methylbiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (4′-chlorobiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (2′-methylbiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (4-(benzo[d]oxazol-2-yl)piperazin-1-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    biphenyl-4-yl(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone;    (S)-(2-benzyl-4-(pyrimidin-2-yl)piperazin-1-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    (5-(pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-p-tolylpyridin-3-yl)methanone;    (5-(pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)methanone;    (6-(4-chlorophenyl)pyridin-3-yl)(5-(pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone;    (5-(pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methanone;    (5-(4-chlorophenyl)isoxazol-3-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (3′-chlorobiphenyl-4-yl)(1-(pyridin-2-yl)piperidin-4-yl)methanone;    biphenyl-4-yl(4-(pyrimidin-2-yl)-1,4-diazepan-1-yl)methanone;    (8-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    biphenyl-4-yl(1-(pyrimidin-2-yl)azetidin-3-yl)methanone;    (6-(4-chloro-3-(trifluoromethyl)phenyl)pyridin-3-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (6-(4-chloro-3-methylphenyl)pyridin-3-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (4′-chlorobiphenyl-4-yl)(1-(pyridin-2-yl)piperidin-4-yl)methanone;    (2-methylbiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (3,4′-dimethylbiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (5-(3-chlorophenyl)pyridin-2-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (4-(pyrimidin-2-yl)piperazin-1-yl)(5-p-tolylpyridin-2-yl)methanone;    (4-(pyridin-2-yl)piperazin-1-yl)(3′-(trifluoromethyl)biphenyl-4-yl)methanone;    (1-(pyrimidin-2-yl)piperidin-4-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    (3-fluoro-3′-(trifluoromethyl)biphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (4-(pyrimidin-2-yl)piperazin-1-yl)(3′-(trifluoromethoxy)biphenyl-4-yl)methanone;    (5-(pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3′-(trifluoromethyl)biphenyl-4-yl)methanone;    biphenyl-4-yl(5-(pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone;    (1-phenyl-5-(pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    biphenyl-4-yl (4-(thiazol-2-yl)piperazin-1-yl)methanone;    (4-(4-chlorophenyl)cyclohexyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    4′-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)biphenyl-3-carbonitrile;    (4′-(methylsulfonyl)biphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    2-(4-((3′-chlorobiphenyl-4-yl)(hydroxy)methyl)piperidin-1-yl)pyrimidin-5-ol;    (4-(pyridin-3-yl)phenyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (3′-chloro-3-hydroxybiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone;    1-(4′-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)biphenyl-3-yl)ethanone;    (2′,4′-difluoro-3-methylbiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (5-phenyl-1H-pyrrol-2-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (6-(4-chlorophenyl)pyridin-3-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (5′-chloro-2′-fluorobiphenyl-4-yl)(8-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methanone;    2-(4-(biphenylcarbonyl)piperazin-1-yl)nicotinonitrile;    2-(4-(biphenyl-4-yloxy)piperidin-1-yl)pyrimidine;    (2′-fluoro-5′-(trifluoromethyl)biphenyl-4-yl)(1-(pyrimidin-2-yl)pyrrolidin-3-yl)methanone;    (4-(4-methylthiophen-2-yl)phenyl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone;    (4′-fluorobiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (2-fluoro-4′-methylbiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    biphenyl-4-yl(3-methyl-4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (2′-fluoro-5′-(trifluoromethyl)biphenyl-4-yl)(4-methyl-1-(pyrimidin-2-yl)piperidin-4-yl)methanone;    biphenyl-4-yl(4-(5-methylpyridin-2-yl)piperazin-1-yl)methanone;    biphenyl-4-yl(2-methyl-4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (1-(pyridin-2-yl)piperidin-4-yl)(3′-(trifluoromethyl)biphenyl-4-yl)methanone;    (6-(3-chlorophenyl)pyridin-3-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (4-(pyrimidin-2-yl)piperazin-1-yl)(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)methanone;    (4-(pyrimidin-2-yl)piperazin-1-yl)(6-p-tolylpyridin-3-yl)methanone;    (4′-chloro-3′-(trifluoromethyl)biphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone;    (4-(2-chloropyridin-4-yl)phenyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (2′,4′-difluorobiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (6-(2,4-difluorophenyl)pyridin-3-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (3′,5′-dichlorobiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    2-(4-(biphenyl-4-ylmethyl)piperazin-1-yl)pyrimidine;    (4′-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone;    (6-(3-chlorophenyl)pyridin-3-yl)(5-(pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone;    (1-(pyridin-2-yl)piperidin-4-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    (2′-fluoro-5′-(trifluoromethyl)biphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (4′-methylbiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    biphenyl-4-yl(4-(5-methylpyridin-2-yl)piperazin-1-yl)methanone;    1-(biphenylcarbonyl)-4-(pyrimidin-2-yl)piperazin-2-one;    biphenyl-4-yl(1-(pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)methanone;    (3′-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone;    biphenyl-4-yl(1-(pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)methanol;    (3′-chlorobiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (4-(pyrimidin-2-yl)piperazin-1-yl)(3′-(trifluoromethyl)biphenyl-4-yl)methanone;    (3′-chlorobiphenyl-4-yl)(1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl)methanone;    (4′-ethylbiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    biphenyl-4-yl(4-(4-methylpyrimidin-2-yl)piperazin-1-yl)methanone;    (6-(2,4-difluorophenyl)pyridin-3-yl)(5-(pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone;    (4′-chlorobiphenyl-4-yl)(4-(pyridin-2-yl)piperazin-1-yl)methanone;    (5-methyl-1-(pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    biphenyl-4-yl(4-(5-ethylpyrimidin-2-yl)piperazin-1-yl)methanone;    (4-(pyridin-2-yl)piperazin-1-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    (4-(pyridin-2-yl)phenyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    biphenyl-4-yl(4-(pyrazin-2-yl)piperazin-1-yl)methanone;    (4′-methoxybiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    biphenyl-4-yl(4-(6-methylpyridazin-3-yl)piperazin-1-yl)methanone;    4′-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)biphenyl-4-carbonitrile;    (2,6-dimethyl-4-(pyridin-2-yl)piperazin-1-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    (5-phenylthiophen-2-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (6-(5-methylthiophen-2-yl)pyridin-3-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    biphenyl-4-yl(4-(pyridin-4-yl)piperazin-1-yl)methanone;    (R)-(2-methyl-4-(pyrimidin-2-yl)piperazin-1-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    biphenyl-4-yl((2S ,5S)-2,5-dimethyl-4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (3′-chlorobiphenyl-4-yl)(4-(pyridin-2-yl)piperazin-1-yl)methanone;    (4-(pyrimidin-2-yl)piperazin-1-yl)(2′-(trifluoromethyl)biphenyl-4-yl)methanone;    (S)-(4′-chlorobiphenyl-4-yl)(2-methyl-4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (5′-chloro-2′-fluorobiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (4-(5-methylthiophen-2-yl)phenyl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone;    biphenyl-4-yl(4-(4,6-dimethylpyrimidin-2-yl)piperazin-1-yl)methanone;    (S)-(2-methyl-4-(pyrimidin-2-yl)piperazin-1-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    (S)-(2-benzyl-4-(pyrimidin-2-yl)piperazin-1-yl)(4′-chlorobiphenyl-4-yl)methanone;    biphenyl-4-yl(4-(pyridazin-3-yl)piperazin-1-yl)methanone;    (6-(4-methylthiophen-2-yl)pyridin-3-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    1-(2′,4′-difluorobiphenylcarbonyl)-4-(pyrimidin-2-yl)piperazine-2-carbonitrile;    (4′-chlorobiphenyl-4-yl)((2S ,5S)-2,5-dimethyl-4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    biphenyl-4-yl(2-tert-butyl-4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (S)-biphenyl-4-yl(2-isopropyl-4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    biphenyl-4-yl(2,6-dimethyl-4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (3′-chloro-2′-fluorobiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (4-(pyrimidin-2-yl)piperazin-1-yl)(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methanone;    (4′-chloro-3′-methylbiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone;    (3′-chloro-2-fluorobiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (2,6-dimethyl-4-(pyridin-2-yl)piperazin-1-yl)(4′-methylbiphenyl-4-yl)methanone;    3′-chloro-4-(1-(pyrimidin-2-yl)piperidine-4-carbonyl)biphenyl-3-yl acetate;    biphenyl-4-yl(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)methanone;    1-(biphenyl-4-ylmethyl)-4-(pyrimidin-2-yl)piperazin-2-one;    (3′,4′-dichlorobiphenyl-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (3′-chlorobiphenyl-4-yl)(8-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methanol;    (S)-biphenyl-4-yl(2-isobutyl-4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (3′-chlorobiphenyl-4-yl)(8-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methanone;    (S)-(4′-chlorobiphenyl-4-yl)(2-isopropyl-4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (4′-methylbiphenyl-4-yl)(4-(pyridin-2-yl)piperazin-1-yl)methanone;    (S)-(2-isopropyl-4-(pyrimidin-2-yl)piperazin-1-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    (3′-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanol;    (S)-(2-isobutyl-4-(pyrimidin-2-yl)piperazin-1-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    (S)-(4′-chlorobiphenyl-4-yl)(2-isobutyl-4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (3′-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)pyrrolidin-3-yl)methanone;    (2′,4′-difluorobiphenyl-4-yl)(8-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methanone;    4′-(4-(pyridin-2-yl)piperazine-1-carbonyl)biphenyl-4-carbonitrile;    (4-(pyrimidin-2-yl)-1,4-diazepan-1-yl)(3′-(trifluoromethyl)biphenyl-4-yl)methanone;    methyl 1-(5′-chloro-2′-fluorobiphenylcarbonyl)-4-(pyrimidin-2-yl)piperazine-2-carboxylate;    (4-(benzo[d]oxazol-2-yl)piperazin-1-yl)(4′-chlorobiphenyl-4-yl)methanone;    (3′-chlorobiphenyl-4-yl)(4-(thiazol-2-yl)piperazin-1-yl)methanone;    (4-(5-chlorothiophen-2-yl)phenyl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanone;    1-(5′-chloro-2′-fluorobiphenylcarbonyl)-4-(pyrimidin-2-yl)piperazine-2-carbonitrile;    (4-phenylthiophen-2-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    biphenyl-4-yl(4-(pyrimidin-2-yl)-3,4-dihydroquinoxalin-1 (2H)-yl)methanone;    (5′-chloro-2′-fluorobiphenyl-4-yl)(8-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methanol;    (5-phenylfuran-2-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone;    (4′-chlorobiphenyl-4-yl)(5-(pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone;    4-(4′-chlorobiphenyl-4-yl)-1-(pyrimidin-2-yl)piperidin-4-ol;    (5-(pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanone;    biphenyl-4-yl(5-(pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone;    (3′-chlorobiphenyl-4-yl)(5-(pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone;    biphenyl-4-yl((2S,5S)-2,5-dimethyl-4-(pyrirnidin-2-yl)piperazin-1-yl)methanone;    1-((3′-chlorobiphenyl-4-yl)methyl)-N,N-dimethyl-4-(pyrimidin-2-yl)piperazine-2-carboxamide;    (2′,4′-difluorobiphenyl-4-yl)(3-methyl-1-(pyrimidin-2-yl)piperidin-4-yl)methanone;    (4-(benzo[d]thiazol-2-yl)piperazin-1-yl)(biphenyl-4-yl)methanone;    biphenyl-4-yl(4-(quinolin-2-yl)piperazin-1-yl)methanone;    4-(biphenyl-4-yl)-1-(pyrimidin-2-yl)piperidin-4-ol;    4′-chloro-N-methyl-N-(2-(methyl(pyrimidin-2-yl)amino)ethyl)biphenyl-4-carboxamide; or    2-(biphenyl-4-yl)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethanone.    
   
   
       84 - 85 . (canceled)  
   
   
       86 . A method of inhibiting a proline transporter, which comprises contacting a proline transporter with sufficient amount of a compound of formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 A is an optionally substituted non-aromatic heterocycle;  
 each of D 1  and D 2 is independently N or CR 1 ;  
 each of E 1 , E 2  and E 3  is independently N or CR 2 ;  
 X is optionally substituted heteroaryl;  
 Y is O, C(O), CH(OH), or CH 2 ;  
 each R 1  is independently hydrogen, halogen, cyano, R A , OR A , C(O)R A , C(O)OR A , C(O)N(R A R B ), N(R A R B ), or SO 2 R A ;  
 each R 2  is independently hydrogen, halogen, cyano, R A , OR A , C(O)R A , C(O)OR A , C(O)N(R A R B ), N(R A R B ), or SO 2 R A ;  
 each R A  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle; and  
 each R B  is independently hydrogen or optionally substituted alkyl, aryl, arylalkyl, alkylaryl, heterocycle, heterocycle-alkyl, or alkyl-heterocycle.  
 
   
   
       87 . The method of  claim 86 , wherein the proline transporter is encoded by the human gene SLC6A7.  
   
   
       88 - 92 . (canceled)