Direct AMPK activators

Patent metadata

Field	Value
Publication number	US-11174246-B2
Application number	US-201715677809-A
Country	US
Kind code	B2
Filing date	Aug 15, 2017
Priority date	Aug 19, 2016
Publication date	Nov 16, 2021
Grant date	Nov 16, 2021

Abstract

Disclosed are benzimidazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structureand pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein R1, R2, R3, R4, 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.

First claim

What is claimed:

1. A compound having the structure of formula (I):

or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof,
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—Co_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 —;
Y is selected from NR 2 , —CN, —C(O)NHOH,

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 or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, 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 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, 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 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, 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 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
R 1 is Ar optionally substituted with one or more R A groups.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
X is —O—.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, 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 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 the compound A compound that is
5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-N-hydroxy-2-methylbenzamide;
5-((6-chloro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-N-hydroxy-2-methylbenzamide;
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-(5-((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;
5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylaniline;
4′-(6-fluoro-2-(4-methyl-3-(1H-tetrazol-1-yl)phenoxy)-1H-benzo [d]imidazol-5-yl)-[1,1′-biphenyl]-2-01;
5-((6-fluoro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzonitrile;
4′-(6-fluoro-2-(4-methyl-3-(2H-tetrazol-5-yl)phenoxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-2-ol;
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.

9. The compound of claim 1 , having the structure of formula (II):

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Shaw Simon
• Xu Xiang
• Issakani Sarkiz
• Singh Rajinder
• Hitoshi Yasumichi
• Duncton Matthew
• Lin Nan

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title