AMPK-activating piperidinyloxy-substituted 2,3-dihydro-1H-indene-1-amine compounds and pharmaceutical compositions including the same
View Patent ↗Disclosed are carboxamide, sulfonamide and amine compounds including certain AMPK-activating piperidinylxoy-substituted 2,3-dihydro-1H-indene-1-amine compounds, as well as pharmaceutical compositions including them. One embodiment is a compound having the structure in which R 1 , R 3 ,R 4 ,R 5 ,R 14 ,R 15 ,R 17 , G, Q, k, v, x and y are as described herein. In certain embodiments, a compound disclosed herein activates the AMPK pathway, and can be used to treat metabolism-related disorders and conditions.
1. A compound having the structural formula
or a pharmaceutically acceptable salt, or N-oxide thereof, wherein
R 1 is H;
each R 15 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)—NR 8 R 9 , —(C 0 -C 3 alkyl)—OR 10 , —(C 0 -C 3 alkyl)—(C 0 -C 3 alkyl)—C(O)R 10 , —(C 0 - C 3 alkyl)—S(O) 0-2 R 10 , -halogen, —NO 2 and —CN and two R 15 on the same carbon optionally combine to form oxo;
v is 0, 1 or 2;
G is —CH 2 —, —C(O)—, —S(O) 2 — or —CH(CH 3 )—; and
R 17 is phenyl, pyridyl, pyrimidinyl or imidazolyl, unsubstituted or substituted with 1, 2 or 3 substituents independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)—NR 8 R 9 , —(C 0 -C 3 alkyl)—OR 10 , —(C 0 -C 3 alkyl)—C(O)R 10 , (C 0 -C 3 alkyl)—S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;
each R 3 is substituted on a benzo and is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)—NR 8 R 9 , —(C 0 -C 3 alkyl)—OR 10 , —(C 0 -C 3 alkyl)—C(O)R 10 , —(C 0 -C 3 alkyl)—S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;
w is 0, 1 or 2;
each R 14 is substituted on a non-benzo carbon of the 2,3-dihydro-1H-indene and is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)—NR 8 R 9 , —(C 0 -C 3 alkyl)—OR 10 , —(C 0 -C 3 alkyl)—S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;
k is 0, 1 or 2;
each R 4 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)—NR 8 R 9 , —(C 0 -C 3 alkyl)—OR 10 , —(C 0 -C 3 alkyl)—C(O)R 10 , —(C 0 -C 3 alkyl)—S(O) 0-2 R 10 , -halogen, —NO 2 and —CN, and two R 4 on the same carbon optionally combine to form oxo;
x is 0, 1 or 2;
Q is —CH 2 —, a single bond, —C(O)—, —S(O) 2 — or —CH(CH 3 )—;
each R 5 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)—NR 8 R 9 , —(C 0 -C 3 alkyl)—OR 10 , —(C 0 -C 3 alkyl)—C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and -CN; and
y is 0,1,2 or 3;
in which
each L is independently selected from —NR 9 C(O)O—, —OC(O)NR 9 —, —NR 9 C(O)—NR 9 —, —NR 9 C(O)S—, —SC(O)NR 9 —, —NR 9 C(O)—, —C(O)—NR 9 —, —NR 9 C(S)O—, —OC(S)NR 9 —, —NR 9 C(S)—NR 9 —, —NR 9 C(S)S—, —SC(S)NR 9 —, —NR 9 C(S)—, —C(S)NR 9 —, —SC(O)NR 9 —, —NR 9 C(S)—, —S(O) 0-2 —, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR 9 C(NR 2 )NR 9 —, —NR 9 SO 2 —, —SO 2 NR 9 —and —NR 9 SO 2 NR 9 —,
each R 7 , R 8 and R 10 is independently selected from H, —(C 1 -C 2 alkyl) and —(C 1 -C 2 fluoroalkyl), each R 9 is independently selected from —H, —(C 1 -C 4 alkyl) and —C(O)O—(C 1 -C 4 alkyl).
2. A compound according to claim 1 , having the structural formula
3. A compound according to claim 1 , having the structural formula
4. A compound according to claim 1 , wherein v is 0.
5. A compound according to claim 1 , wherein G is —CH 2 — or —C(O)—.
6. A compound according to claim 1 , wherein R 17 is phenyl, pyridyl, pyrimidinyl or imidazolyl, each optionally substituted with 1, 2 or 3 substituents independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)—NR 8 R 9 , —(C 0 -C 3 alkyl)—OR 10 , —(C 0 -C 3 alkyl)—C(O)R 10 , —(C 0 -C 3 alkyl)—S(O) 0-2 R 10 , -halogen, —NO 2 and —CN.
7. A compound according to claim 1 , wherein R 17 is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from —(C i -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)—NR 8 R 9 , —(C 0 -C 3 alkyl)—OR 10 , —(C 0 -C 3 alkyl)—C(O)R 10 , —(C 0 -C 3 alkyl)—S(O) 0-2 R 10 , -halogen, —NO 2 and —CN.
8. A compound according to claim 7 , wherein v is 0 and G is —CH 2 — or —C(O)—.
9. A compound according to claim 1 , wherein R 2 is
10. A compound according to claim 9 , wherein v is 0 and G is —CH 2 — or —C(O)—.
11. A compound according to claim 1 , wherein w is 0.
12. A compound according to claim 1 , wherein k is 0.
13. A compound according to claim 1 , wherein x is 0.
14. A compound according to claim 1 , wherein Q is a single bond.
15. A compound according to claim 1 , wherein Q is —CH 2 —.
16. A compound according to claim 1 , having the structural formula
wherein
G is —CH 2 — or —C(O)— and
R 17 is phenyl, pyridyl, pyrimidinyl or imidazolyl, each optionally substituted with 1, 2 or 3 substituents independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)—NR 8 R 9 , —(C 0 -C 3 alkyl)—OR 10 , —(C 0 -C 3 alkyl)—C(O)R 10 , —(C 0 -C 3 alkyl)—S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;
Q is a single bond or —CH 2 —;
y is 0, 1, 2 or 3; and
each R 5 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)—NR 8 R 9 , —(C 0 -C 3 alkyl)—OR 10 , —(C 0 -C 3 alkyl)—C(O)R 10 , —(C 0 -C 3 alkyl)—S(O) 0-2 R 10 , -halogen, —NO 2 and —CN.
17. A compound according to claim 1 , having the structural formula
wherein in which Q is —CH 2 — or a single bond; G is a —CH 2 — or —C(O)—: and R 11 , R 12 and R 13 are independently selected from H, halo, cyano, —(C 1 -C 3 fluoroalkyl), —O—(C 1 -C 2 fluoroalkyl), —(C 1 -C 3 alkyl), —O—(C 1 -C 2 alkyl), —C(O)—(C 0 -C 2 alkyl), —C(O)O—(C 0 -C 2 alkyl), —C(O)N(C 0 -C 4 alkyl)(C 0 -C 2 alkyl) and NO 2 .
18. A compound according to claim 1 , wherein the compound is
1-(pyridin-4-ylmethyl)-N-(5-(1-(4(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-yl)piperidin-4-amine;
1-(4-fluorobenzyl)-N-(5-(1-(4(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-yl)piperidin-4-amine; or
4-((4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-ylamino)piperidin-1-yl)methyl)benzonitrile.
19. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent or excipient; and a compound according to claim 1 .
20. A compound according to claim 1 , wherein R 1 is H;
each R 15 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), -L-R 7 , —NR 8 R 9 , —OR 10 , —C(O)R 10 , —S(O) 0-2 R 10 , -halogen, —NO 2 and —CN and two R 15 on the same carbon optionally combine to form oxo;
v is 0, 1 or 2;
G is —CH 2 —, —C(O)—, —S(O) 2 — or —CH(CH 3 )—; and
R 7 is phenyl, pyridyl, pyrimidinyl or imidazolyl, unsubstituted or substituted with 1, 2 or 3 substituents independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), -L-R 7 , —NR 8 R 9 , —OR 10 , —C(O)R 10 , —S(O) 0-2 R 10 , —halogen, —NO 2 and —CN and two R 15 on the same carbon optionally combine to form oxo;
each R 3 is substituted on a benzo and is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), -L-R 7 , —NR 8 R 9 , —OR 10 , —C(O)R 10 , —S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;
w is 0, 1 or 2;
each R 14 is substituted on a non-benzo carbon of the 2,3-dihydro-1H-indene and is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), -L-R 7 , —NR 8 R 9 , —OR 10 , —C(O)R 10 , —S(O) 0-2 R 10 , -halogen, —NO 2 and —CN and two R 15 on the same carbon optionally combine to form oxo;
k is 0, 1 or 2;
each R 4 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), -L-R 7 , —NR 8 R 9 , —OR 10 , —C(O)R 10 , —S(O) 0-2 R 10 , -halogen, —NO 2 and —CN and two R 15 on the same carbon optionally combine to form oxo;
x is 0, 1 or 2;
Q is —CH2—, a single bond, —C(O)—, —S(O) 2 — or —CH(CH 3 )—;
each R 5 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 fluoroalkyl), -L-R 7 , —NR 8 R 9 , —OR 10 , —C(O)R 10 , —S(O) 0-2 R 10 , -halogen, —NO 2 and —CN; and
y is 0, 1, 2 or 3;
in which
each L is independently selected from —NR 9 C(O)—, —C(O)—NR 9 —, —NR 9 C(S)—, —C(S)NR 9 —, —C(O)O—, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —NR 9 SO 2 — and —SO 2 NR 9 —,
each R 7 , R 8 and R 10 is independently selected from H, —(C 1 -C 2 alkyl) and —(C 1 -C 2 fluoroalkyl),
each R 9 is independently selected from —H, —(C 1 -C 4 alkyl) and —C(O)—O—(C 1 -C 4 alkyl).
21. A compound according to claim 20 , wherein
v is 0;
w is 0;
k is 0; and
x is O.
22. A compound according to claim 21 , wherein each L is independently selected from —NR 9 C(O)—, —C(O)—NR 9 —, —NR 9 C(S)—, —C(S)NR 9 —, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —NR 9 SO 2 — and —SO 2 NR 9 —.
23. A compound according to claim 1 , wherein
each L is independently selected from —NR 9 C(O)—, —C(O)—NR 9 —, —NR 9 C(S)—, —C(S)NR 9 —, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —NR 9 SO 2 — and —SO 2 NR 9 —.