IP Library › Granted Patent US 11,174,246

Granted Patent B2

US 11,174,246 · App. 15/677,809 · Granted Nov 16, 2021

Direct AMPK activators

Inventors: Simon Shaw (Oakland, CA); Xiang Xu (Foster City, CA); Sarkiz Issakani (Redwood City, CA); Rajinder Singh (Belmont, CA); Yasumichi Hitoshi (Brisbane, CA); Matthew Duncton (San Bruno, CA); Nan Lin (Foster City, CA)

Assignee: Rigel Pharmaceuticals, Inc.

C07D403/04 C07D235/26 C07D403/12 C07D403/14

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Quick Facts

Patent No.: US 11,174,246
App. No.: 15/677,809
Granted: Nov 16, 2021
Kind: B2

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Abstract

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.

Claims (121)

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,

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):

or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

ring A is a 5- or 6-membered Het; and

n is 1, 2, 3 or 4.

10. The compound of claim 9 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

ring A is a 5-membered Het.

11. The compound of claim 9 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

ring A is a 6-membered Het.

12. The compound of claim 9 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

ring A is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl or thiazolyl.

13. The compound of claim 10 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

ring A is pyrrolyl.

14. The compound of claim 10 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

ring A is N-methylpyrrolyl.

15. The compound of claim 9 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

16. The compound of claim 9 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

X is —O—.

17. The compound of claim 9 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

each R is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

18. The compound of claim 1 , having the structure of formula (III):

or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

each R A1 is independently hydrogen, 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, cyano, C 1-6 haloalkyl, -C 1 -C 6 alkoxy, —OR, —SR, —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(0) 2 R, —OP(O)(OR) 2 or —CH 2 —OP(O)(OR);

each R A2 is independently hydrogen, 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, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -C 1 -C 6 alkoxy, —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 A3 is hydrogen, 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, C 1-6 alkyl, C 1-6 haloalkyl, -C 1 -C 6 alkoxy, —SR, —NR 2 , —C(O)R, —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 in each R A1 , R A2 and R A3 is optionally substituted by one or two -R Ax groups,

R 3 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 4 is 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

provided that

(a) at least one of R A1 , R A2 or R A3 is not hydrogen;

(b) when R A1 or R A5 is hydroxyl, R 3 is not fluoro; and

19. The compound of claim 18 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

each R A1 is independently hydrogen, cyano, C 1-6 haloalkyl, -C 1 -C 6 alkoxy, —OR, —SR, —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);

each R A2 is independently hydrogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -C 1 -C 6 alkoxy, —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 A3 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 1 -C 6 alkoxy, —SR, —NR 2 , —C(O)R, —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 in each R A1 , R A2 and R A3 is optionally substituted by one or two -R Ax groups.

20. The compound of claim 18 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

X is —O—.

21. The compound of claim 18 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

each R is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

22. The compound of claim 1 , having the structure of formula (IIIa):

or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof,

wherein

R A1 is 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, cyano, C 1-6 haloalkyl, -C 1 -C 6 alkoxy, —OH, —SR, —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);

each R A2 group is independently hydrogen, 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, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -C 1 -C 6 alkoxy, —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 in each R A1 , R A2 and R A3 is optionally substituted by one or two -R Ax groups,

R 3 is hydrogen, chloro, bromo, 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

23. The compound of claim 22 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

R A1 is cyano, C 1-6 haloalkyl, -C 1 -C 6 alkoxy, —OH, —SR, —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);

each R A2 group is independently hydrogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -C 1 -C 6 alkoxy, —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 in each R A1 , R A2 and R A3 is optionally substituted by one or two -R Ax groups.

24. The compound of claim 22 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

X is —O—.

25. The compound of claim 22 , or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein

each R is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

26. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, and a pharmaceutically acceptable excipient, diluent, or carrier.

27. 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 , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof.

28. A method for increasing fatty acid oxidation in a cell, the method comprising contacting the cell with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof.

29. A method for decreasing glycogen concentration in a cell, the method comprising contacting the cell with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof.

30. A method for increasing glucose uptake in a cell, the method comprising contacting the cell with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof.

31. A method for reducing triglyceride levels in a subject, the method comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof.

32. A method for treating type II diabetes in a subject with type II diabetes, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof to ameliorate type II diabetes or at least one symptom thereof in the subject.

33. A method for treating atherosclerosis or cardiovascular disease in a subject with atherosclerosis or cardiovascular disease, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, to ameliorate atherosclerosis, cardiovascular disease, or at least one symptom thereof in the subject.

Assignments (4)

SECURITY INTEREST Recorded Aug 25, 2022

From: RIGEL PHARMACEUTICALS, INC.

To: MIDCAP FINANCIAL TRUST

Reel/Frame 061327/0712 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 9, 2019

From: SINGH, RAJINDER; SHAW, SIMON; ISSAKANI, SARKIZ; LIN, NAN

To: RIGEL PHARMACEUTICALS, INC.

Reel/Frame 049703/0417 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 9, 2019

From: HITOSHI, YASUMICHI; XU, XIANG

To: RIGEL PHARMACEUTICALS, INC.