DIRECT AMPK ACTIVATORS
Disclosed are benzimidazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein R 1 , R 2 , R 3 , R 4 , Y and X are as described herein. In certain embodiments, a compound disclosed herein activates AMPK, and can be used to treat disease by activating the AMPK pathway.
1 . A compound having the structure of formula (I):
wherein
R 1 and R 2 together with the atoms to which they are attached form ring A, wherein ring A is a 5- or 6-membered Het optionally substituted with one or more R A groups that are each independently C 3-8 Cak(C 0-6 alkyl), Hca(C 0-6 alkyl), Ar(C 0-6 alkyl), Het(C 0-6 alkyl), —O—C 0-6 alkyl-C 3-8 Cak, —O—C 0-6 alkyl-Hca, —O—C 0-6 alkyl-Ar, —O—C 0-6 alkyl-Het, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR)2 or —CH 2 —OP(O)(OR) wherein each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —R Ax groups,
wherein each —R Ax is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR)2 or —CH 2 —OP(O)(OR);
or one of R 1 and R 2 is Ar or Het, wherein Ar and Het are optionally substituted with one or more independently selected R A groups, and the other is hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR)2 or —CH 2 —OP(O)(OR);
R 3 and R 4 are independently hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 or —CH 2 —OP(O)(OR);
X is —O—, —S—, —NR— or —CF 2 —;
wherein R Y is hydrogen or C 1-6 alkyl; and
each R is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-Ar, —(C 0 -C 6 alkyl)-Het, —(C 0 -C 6 alkyl)-Cak, or —(C 0 -C 6 alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein
R 1 and R 2 together with the atoms to which they are attached form ring A, wherein ring A is 5- or 6-membered Het optionally substituted with one or more R A groups that are each independently C 3-8 Cak(C 0-6 alkyl), Hca(C 0-6 alkyl), Ar(C 0-6 alkyl), Het(C 0-6 alkyl), —O—C 0-6 alkyl-C 3-8 Cak, —O—C 0-6 alkyl-Hca, —O—C 0-6 alkyl-Ar, —O—C 0-6 alkyl-Het, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, -OP(O)(OR)2 or —CH 2 —OP(O)(OR), wherein each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —R Ax groups,
wherein each —R Ax is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 or —CH 2 —OP(O)(OR);
or one of R 1 and R 2 is Ar or Het, wherein Ar and Het are substituted with one or more R A groups, and the other is hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 or —CH 2 —OP(O)(OR).
3 . The compound of claim 1 , wherein
R 1 and R 2 together with the atoms to which they are attached form a 5- or 6-membered Het optionally substituted with one or more R A groups,
or one of R 1 and R 2 is Ar.
4 . The compound of claim 1 , wherein
R 1 and R 2 together with the atoms to which they are attached form a 5- or 6-membered Het optionally substituted with one or more R A groups.
5 . The compound of claim 1 , wherein
R 1 is Ar optionally substituted with one or more R A groups.
6 . The compound of claim 1 , wherein
X is —O—.
7 . The compound of claim 1 , wherein
each R A is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 or —CH 2 —OP(O)(OR), wherein each alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —R Ax groups,
wherein each —R Ax is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 or —CH 2 —OP(O)(OR).
8 . The compound of claim 1 , wherein R Y is methyl.
9 . The compound of claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt.
10 . The compound of claim 1 , wherein the compound is in the form of a solvate.
11 . A compound that is
1-(5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one;
1-(5-((6-fluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one;
1-(54(6-fluoro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one;
5-((6-fluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
1-(5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;
1-(5-((6-fluoro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof.
12 . The compound of claim 1 , having the structure of formula (II):
wherein
ring A is a 5- or 6-membered Het; and
n is 1, 2, 3 or 4.
13 . The compound of claim 12 , wherein
ring A is a 5-membered Het.
14 . The compound of claim 12 , wherein
ring A is a 6-membered Het.
15 . The compound of claim 12 , wherein
ring A is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl or thiazolyl.
16 . The compound of claim 13 , wherein
ring A is pyrrolyl.
17 . The compound of claim 13 , wherein
ring A is N-methylpyrrolyl.
18 . The compound of claim 12 , wherein
each R A is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 or —CH 2 —OP(O)(OR), wherein each alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —R Ax groups,
wherein each —R Ax is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 or —CH 2 —OP(O)(OR).
19 . The compound of claim 12 , wherein
X is —O—.
20 . A method for activating the AMPK pathway in a cell, the method comprising contacting the cell with an effective amount of the compound of claim 1 .
21 . The method of claim 20 , wherein the cell is in a subject.