Amine-linked Multicyclic Compounds and Methods of Their Use

1 . 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;

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 compound of claim 1 , which is a potent proline transporter inhibitor.

3 . The compound of claim 2 , which has a PTIC 50 of less than about 150 nM.

4 . The compound of claim 3 , which has a PTIC 50 of less than about 100 nM.

5 . The compound of claim 4 , which has a PTIC 50 of less than about 50 nM.

6 . The compound of claim 1 , which has a DTIC 50 of greater than about 1 μM.

7 . The compound of claim 1 , which has a GTIC 50 of greater than about 1 μM.

8 . The compound of claim 1 , wherein A is monocyclic.

9 . The compound of claim 1 , wherein A is bicyclic.

10 . The compound of claim 1 , wherein A is unsubstituted.

11 . The compound of claim 1 , wherein A is optionally substituted pyrrolidine, piperidine, hexahydropyrimidine, 1,2,3,6-tetrahydropyridine, octahydrocyclopenta[c]pyrrole, or octahydropyrrolo[3,4-c]pyrrole.

12 . The compound of claim 1 , wherein one of D 1 and D 2 is N.

13 . The compound of claim 1 , wherein both D 1 and D 2 are N.

14 . The compound of claim 1 , wherein both D 1 and D 2 are CR 1 .

15 . The compound of claim 1 , wherein one of E 1 , E 2 and E 3 is N.

16 . The compound of claim 1 , wherein two of E 1 , E 2 and E 3 are N.

17 . The compound of claim 1 , wherein all of E 1 , E 2 and E 3 are N.

18 . The compound of claim 1 , wherein all of E 1 , E 2 and E 3 are independently CR 2 .

19 . The compound of claim 1 , wherein R 1 is hydrogen, halogen, or optionally substituted alkyl.

20 . The compound of claim 1 , wherein R 1 is OR A .

21 . The compound of claim 20 , wherein R A is hydrogen or optionally substituted alkyl.

22 . The compound of claim 1 , wherein R 2 is hydrogen, halogen, or optionally substituted alkyl.

23 . The compound of claim 1 , wherein R 2 is OR A .

24 . The compound of claim 23 , wherein R A is hydrogen or optionally substituted alkyl.

25 . The compound of claim 1 , wherein X is an optionally substituted 5-, 6-, 9- or 10-membered heteroaryl.

26 . The compound of claim 25 , wherein X is optionally substituted 5- or 6-membered heteroaryl.

27 . The compound of claim 26 , wherein X is of the formula:

wherein:

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 ;

each R 3 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 ; and

each R 4 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 ;

provided that at least one of J 1 , J 2 and J 3 is CR 4 .

28 . The compound of claim 27 , wherein one of G 1 and G 2 is N.

29 . The compound of claim 27 , wherein both G 1 and G 2 are N.

30 . The compound of claim 27 , wherein both G 1 and G 2 are CR 3 .

31 . The compound of claim 27 , wherein one of J 1 , J 2 and J 3 is N.

32 . The compound of claim 27 , wherein two of J 1 , J 2 and J 3 are N.

33 . The compound of claim 27 , wherein all of J 1 , J 2 and J 3 are independently CR 4 .

34 . The compound of claim 27 , wherein R 3 is hydrogen, halogen, or optionally substituted alkyl.

35 . The compound of claim 27 , wherein R 3 is OR A .

36 . The compound of claim 35 , wherein R A is hydrogen or optionally substituted alkyl.

37 . The compound of claim 27 , wherein R 4 is hydrogen, halogen, or optionally substituted alkyl.

38 . The compound of claim 27 , wherein R 4 is OR A .

39 . The compound of claim 38 , wherein R A is hydrogen or optionally substituted alkyl.

40 . The compound of claim 27 , which is of formula I(A):

41 . The compound of claim 40 , which is of formula I(B):

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.

42 . The compound of claim 40 , which is of formula I(C):

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.

43 . The compound of claim 40 , which is of formula I(D):

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.

44 . A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

N-(3′-chloro-3-methylbiphenyl-4-yl)-1-(pyrimidin-2-yl)piperidin-4-amine;

N-(4′-chloro-2′-fluorobiphenyl-4-yl)-8-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-amine;

N-(2′,4′-difluorobiphenyl-4-yl)-1-(pyrimidin-2-yl)piperidin-4-amine;

(3′-chloro-3-nitro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

3′-chloro-N 4 -(1-(pyrimidin-2-yl)piperidin-4-yl)biphenyl-3,4-diamine;

N 4 -(1-(pyrimidin-2-yl)piperidin-4-yl)biphenyl-3,4-diamine;

(3′-chloro-3-cyano-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(3′-chloro-2-methoxy-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(3′-chloro-3-chloro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(3′-chloro-2-chloro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(2,3′-dichloro-3-methyl-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(3′-chloro-3-trifluoromethyl-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(3′-chloro-2-trifluoromethyl-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(3′-chloro-3-methyl-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(3′-chloro-2-methyl-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(3′-chloro-3-fluoro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(3′-chloro-2-fluoro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(3-cyano-2′,4′-difluoro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(2′,4′-difluoro-2-methoxy-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(3-chloro-2′4′-difluoro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(2-chloro-2′,4′-difluoro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(2-chloro-2′,4′-difluoro-3-methyl-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(2′,4′-difluoro-3-trifluoromethyl-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(2′,4′-difluoro-2-trifluoromethyl-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(2′,4′-difluoro-3-methyl-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(2′,4′-difluoro-2-methyl-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(1-pyrimidin-2-yl-piperidin-4-yl)-(3,2′,4′-trifluoro-biphenyl-4-yl)-amine;

(1-pyrimidin-2-yl-piperidin-4-yl)-(2,2′,4′-trifluoro-biphenyl-4-yl)-amine;

(5-chloro-2′-fluoro-3-methyl-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(5′-chloro-3,2′-difluoro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(5′-chloro-2,2′-difluoro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(4′-chloro-3-methyl-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(4′-chloro-2-methyl-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine;

(4′-chloro-3-fluoro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine; or

(4′-chloro-2-fluoro-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-amine.

45 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

46 . A single unit dosage form comprising the pharmaceutical composition of claim 45 .

47 . A method of inhibiting a proline transporter, which comprises contacting a proline transporter with sufficient amount of a compound of claim 1 .

48 . The method of claim 47 , wherein the proline transporter is encoded by the human gene SLC6A7.

49 . A method of improving the cognitive performance of a human patient, which comprises administering to the patient an amount of a compound of claim 1 sufficient to improve the cognitive performance.

50 . The method of claim 49 , wherein the cognitive performance is rapidity of learning, comprehension, reasoning, or memory.

51 . A method of treating, managing or preventing a cognitive disorder, memory loss, or a learning disorder in a human patient, which comprises administering to the patient a therapeutically or prophylactically effective amount of a compound of claim 1 .

52 . A method of treating, managing or preventing a disease or disorder in a patient, which comprises administering to the patient a therapeutically or prophylactically effective amount of a compound of claim 1 , wherein the disease or disorder is age-associated memory impairment, Alzheimer's disease, Attention-Deficit/Hyperactivity Disorder, autism, Down syndrome, Fragile X syndrome, Huntington's disease, Parkinson's disease, or schizophrenia.

53 . A method of treating, managing or preventing dementia in a patient, which comprises administering to the patient a therapeutically or prophylactically effective amount of a compound of claim 1 .

54 . The method of claim 53 , wherein the dementia is associated with a metabolic-toxic, structural or infectious cause.