Triamide-substituted heterobicyclic compounds

1. A compound of formula 1b

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is substituted at the 5 or 6 position of formula 1b and has the structure:

m is an integer from 0 to 5;

n is an integer from 0 to 3;

p is an integer from 0 to 3;

L is —C(O)N(R 9 )—;

X 1 is N(R 4 );

X 2 is C(R c );

R 2 , R 8 , R 11 , R 12 , R 13 and R 16 are each independently selected from halo, cyano, nitro, azido, amino, hydroxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkoxy, methoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, mono-, di- or tri-halo(C 2 -C 6 )alkyl, perfluoro(C 2 -C 4 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 5 )alkyl, mono-, di- or tri-halo(C 2 -C 6 )alkoxy, trifluoromethyl(C 1 -C 5 )alkoxy, (C 1 -C 6 )alkylthio, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl(CR a R b ) q —, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylamino-, (C 1 -C 6 )dialkylamino, amino(C 1 -C 6 )alkyl-, —(CR a R b ) q NR a R 14 , —C(O)NR a R 14 , —NR 14 C(O)R 15 , —NR 14 OR 15 , —CH═NOR 15 , —NR 14 C(O)OR 15 , —NR 14 S(O) j R 15 , —C(O)R 15 , —C(S)R 15 , —C(O)OR 15 , —OC(O)R 15 , —SO 2 NR a R 14 , —S(O) j R 15 , or —(CR a R b ) q S(O) j R 15 ;

each R a and R b is independently H or (C 1 -C 6 )alkyl;

R c is H or R 11 ;

each q is independently an integer from 0 to 6;

each j is independently 0, 1 or 2;

R 3 is H, halo, (C 1 -C 6 )alkyl, or mono-, di- or tri-halo(C 1 -C 6 )alkyl;

R 4 is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —C(O)R 15 , —C(S)R 15 , —(CR a R b ) t O(C 1 -C 6 alkyl), —(CR a R b ) t S(C 1 -C 6 alkyl), —(CR a R b ) r C(O)R 15 , —(CR a R b ) r R 15 , —SO 2 R 15 or —(CR a R b ) q -phenyl, wherein the phenyl moiety is optionally substituted with from one to five independently selected R 16 ;

each r is independently an integer from 2 to 5;

each t is independently an integer from 1 to 6;

R 5 and R 9 are each independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —C(O)R 15 , —C(S)R 15 , —(CR a R b ) t O(C 1 -C 6 alkyl), —(CR a R b ) t S(C 1 -C 6 alkyl), —(CR a R b ) r C(O)R 15 , —(CR a R b ) r R 15 or —SO 2 R 15 ;

R 6 is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —C(O)R 15 , —C(S)R 15 , —(CR a R b ) q O(C 1 -C 6 alkyl), —(CR a R b ) q S(C 1 -C 6 alkyl), —(CR a R b ) r C(O)R 15 , —(CR a R b ) r R 15 or —SO 2 R 15 ;

R 7 is pyridyl or pyridyl-Z 1 - optionally substituted with one to five independently selected R 12 ;

Z 1 is —SO 2 — or —(CR a R b ) v —;

v is independently an integer from 1 to 6;

R 10 is phenyl, pyridyl, phenyl-Z 2 - or pyridyl-Z 2 -, wherein the phenyl or pyridyl moiety is optionally substituted with one to five independently selected R 13 ;

Z 2 is —S(O) j —, —O—, —(CR a R b ) w —, or —(O) k (CR a R b ) w (O) k (CR a R b ) q —;

w is independently an integer from 1 to 6;

each k is independently 0 or 1;

or R 10 is OR 17 , wherein R 17 is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, mono-, di- or tri-halo(C 2 -C 6 )alkyl, perfluoro(C 2 -C 4 )alkyl, trifluoromethyl(C 1 -C 5 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl(CR a R b ) q —, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl;

each R 14 is independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —C(O)R 15 , —C(S)R 15 , —(CR a R b ) t O(C 1 -C 6 alkyl), —(CR a R b ) t S(C 1 -C 6 alkyl), —(CR a R b ) r C(O)R 15 , —(CR a R b ) t R 15 or —SO 2 R 15 ;

each R 15 is independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, trifluoromethyl, trifluoromethyl(C 1 -C 5 )alkyl, wherein the alkyl, moieties of the foregoing R 15 groups are independently optionally substituted with 1 to 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, hydroxy, halo, cyano, nitro, trifluoromethyl and trifluoromethoxy;

and wherein any of the above “alkyl”, “alkenyl” or “alkynyl” moieties comprising a CH 3 (methyl), CH 2 (methylene), or CH (methine) group which is not substituted with halogen, SO or SO 2 , or attached to a N, O or S atom, optionally bears on said methyl, methylene or methine group a substituent selected from the group consisting of halo, —OR a , —SR a and —NR a R b .

2. The compound of claim 1 , wherein L is attached to the 2 position of R 1 and to the 5 position of formula 1b.

3. The compound of claim 2 , wherein R 10 is phenyl attached at the 3 position of R 1 , wherein the phenyl moiety of R 10 is optionally substituted with one to five independently selected R 13 .

4. The compound of claim 2 , wherein the carbon designated “a” in formula 1b is in the (S) absolute configuration.

5. The compound of claim 4 , wherein R 13 is trifluoromethyl.

6. The compound of claim 5 , wherein R 3 is H, halo, or (C 1 -C 6 )alkyl.

7. A compound of the formula 1:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is substituted at the 5 or 6 position of formula 1 and has the structure:

m is an integer from 0 to 5;

n is an integer from 0 to 3;

p is an integer from 0 to 3;

L is —C(O)N(R 9 )—;

X is C(R c )—;

R 2 , R 8 , R 11 , R 12 , R 13 and R 16 are each independently selected from halo, cyano, nitro, azido, amino, hydroxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkoxy, methoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, mono-, di- or tri-halo(C 2 -C 6 )alkyl, perfluoro(C 2 -C 4 )alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 5 )alkyl, mono-, di- or tri- halo(C 2 -C 6 )alkoxy, trifluoromethyl(C 1 -C 5 )alkoxy, (C 1 -C 6 )alkylthio, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl(CR a R b ) q —, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylamino-, (C 1 -C 6 )dialkylamino, amino(C 1 -C 6 )alkyl-, —(CR a R b ) q NR a R 14 , —C(O)NR a R 14 , —NR 14 C(O)R 15 , —NR 14 OR 15 , —CH═NOR 15 , —NR 14 C(O)OR 15 , —NR 14 S(O) j R 15 , —C(O)R 15 , —C(S)R 15 , —C(O)OR 15 , —OC(O)R 15 , —SO 2 NR a R 14 , —S(O) j R 15 , or —(CR a R b ) q S(O) j R 15 ;

each R a and R b is independently H or (C 1 -C 6 )alkyl;

R c is H or R 11 ;

each q is independently an integer from 0 to 6;

each j is independently 0, 1 or 2;

R 3 is H, halo, (C 1 -C 6 )alkyl, or mono-, di- or tri-halo(C 1 -C 6 )alkyl;

R 4 is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —C(O)R 15 , —C(S)R 15 , —(CR a R b ) t O(C 1 -C 6 alkyl), —(CR a R b ) t S(C 1 -C 6 alkyl), (CR a R b ) r C(O)R 15 , —(CR a R b ) r R 15 , —SO 2 R 15 or —(CR a R b ) q — phenyl, wherein the phenyl moiety is optionally substituted with from one to five independently selected R 16 ;

each r is independently an integer from 2 to 5;

each t is independently an integer from 1 to 6;

R 5 , R 6 and R 9 are each independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —C(O)R 15 , —C(S)R 15 , —(CR a R b ) t O(C 1 -C 6 alkyl), —(CR a R b ) t S(C 1 -C 6 alkyl), —(CR a R b ) r C(O)R 15 , —(CR a R b ) r R 15 , —(CR a R b ) r R 15 or —SO 2 R 15 ;

R 7 is pyridyl or pyridyl-Z 1 -, wherein the pyridyl moiety is optionally substituted with one to five independently selected R 12 ;

Z 1 is —SO 2 — or —(CR a R b ) v —;

v is independently an integer from 1 to 6;

R 10 is pyridyl or pyridyl-Z 2 -, wherein the pyridyl moiety is optionally substituted with one to five independently selected R 13 ;

Z 2 is —S(O) j —, —O—, —(CR a R b ) w —, or —(O) k (CR a R b ) w (O) k (CR a R b ) q —;

w is independently an integer from 1 to 6;

each k is independently 0 or 1;

each R 14 is independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —C(O)R 15 , —C(S)R 15 , —(CR a R b ) t O(C 1 -C 6 alkyl), —(CR a R b ) t S(C 1 -C 6 alkyl), —(CR a R b ) r C(O)R 15 , —(CR a R b ) t R 15 or —SO 2 R 15 ;

each R 15 is independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, trifluoromethyl, trifluoromethyl(C 1 -C 5 )alkyl, wherein the alkyl, moieties of the foregoing R 15 groups are independently optionally substituted with 1 to 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, hydroxy, halo, cyano, nitro, trifluoromethyl and trifluoromethoxy;

and wherein any of the above “alkyl”, “alkenyl” or “alkynyl” moieties comprising a CH 3 (methyl), CH 2 (methylene), or CH (methine) group which is not substituted with halogen, SO or SO 2 , or attached to a N, O or S atom, optionally bears on said methyl, methylene or methine group a substituent selected from the group consisting of halo, —OR a , —SR a and —NR a R b .

8. The compound of claim 7 , wherein L is attached to the 2 position of R 1 and to the 5 position of formula 1.

9. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1 or 7 , or a stereoisomer, pharmaceutically acceptable salt or hydrate thereof in combination with a pharmaceutically-acceptable carrier or diluent.

10. A method of treating obesity in an animal in need of treatment thereof, which comprises administering to the animal a therapeutically effective amount of the compound of any claim 1 or 7 .

11. A method of treating atherosclerosis; pancreatitis secondary to hypertriglyceridemia; hyperglycemia (1) by causing a reduced absorption of dietary fat through MTP inhibition, (2) by lowering triglycerides through MTP inhibition or (3) by decreasing the absorption of free fatty acids through MTP inhibition; in an animal in need of treatment thereof, which comprises administering to the animal a therapeutically effective amount of the compound of claim 1 or 7 .

12. A method of treating diabetes in an animal in need of treatment thereof, which comprises administering to the animal a therapeutically effective amount of the compound of claim 1 or 7 .