Multicyclic compounds and methods of their use

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)