(S)-PHENYL(HETEROCYCLE)METHANOL-BASED COMPOUNDS, COMPOSITIONS COMPRISING THEM AND METHODS OF THEIR USE
Multicyclic compounds, pharmaceutical compositions comprising them, and methods of their use are described. Compounds described include those of formula I:
1 . A stereomerically pure 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(E):
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 stereomerically pure compound or a pharmaceutically acceptable salt thereof, wherein the compound is:
(S)-2-(4-((3′-chlorobiphenyl-4-yl)(hydroxy)methyl)piperidin-1-yl)pyrimidin-5-ol;
(S)-(3′-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanol;
(S)-(1-(pyrimidin-2-yl)piperidin-4-yl)(4′-(trifluoromethyl)biphenyl-4-yl)methanol;
(S)-(5′-chloro-2′-fluorobiphenyl-4-yl)(8-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methanol;
(S)-biphenyl-4-yl-(1-pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol;
(S)-(1-(pyrimidin-2-yl)piperidin-4-yl)(2′,3,4′-trifluorobiphenyl-4-yl)methanol;
(S)-(3′-chloro-3-methylamino-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanol;
(S)-(3-amino-3′-chlorobiphenyl-4-yl)(1-(pyrimidin-2-yl)piperidin-4-yl)methanol;
(S)—N-(3′-chloro-4-(hydroxy(1-(pyrimidin-2-yl)piperidin-4-yl)methyl)biphenyl-3-yl)acetamide;
(S)—N-{3′-chloro-4-[hydroxyl-(1-pyrimidin-2-yl-piperidin-4-yl)-methyl]-biphenyl-3-yl}-acetamide;
(S)-3′-chloro-4-[hydroxy-(1-pyrimidin-2-yl-piperidin-4-yl)-methyl]-biphenyl-3-ol;
or
(S)-(3′-chloro-3-methoxy-biphenyl-4-yl)-(1-pyrimidin-2-yl-piperidin-4-yl)-methanol.
45 . A stereomerically enriched composition 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;
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.
46 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
47 . A single unit dosage form comprising the pharmaceutical composition of claim 46 .
48 . A pharmaceutical composition comprising a composition of claim 45 and a pharmaceutically acceptable excipient.
49 . A single unit dosage form comprising the pharmaceutical composition of claim 48 .
50 . A method of inhibiting a proline transporter, which comprises contacting a proline transporter with sufficient amount of a compound of claim 1 .
51 . A method of inhibiting a proline transporter, which comprises contacting a proline transporter with sufficient amount of a composition of claim 45 .
52 . The method of claim 50 or 51 , wherein the proline transporter is encoded by the human gene SLC6A7.
53 . 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.
54 . A method of improving the cognitive performance of a human patient, which comprises administering to the patient an amount of a composition of claim 45 sufficient to improve the cognitive performance.
55 . The method of claim 53 or 54 , wherein the cognitive performance is rapidity of learning, comprehension, reasoning, or memory.
56 . 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 .
57 . 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 composition of claim 45 .
58 . 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.
59 . 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 composition of claim 45 , 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.
60 . 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 .
61 . 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 composition of claim 45 .
62 . The method of claim 60 or 61 , wherein the dementia is associated with a metabolic-toxic, structural or infectious cause.