Fused Bicyclic Nitrogen-Containing Heterocycles

Abstract

Compounds, pharmaceutical compositions and methods that are useful in the treatment or prevention of metabolic and cell proliferative diseases or conditions are provided herein. In particular, the invention provides compounds which modulate the activity of proteins involved in lipid metabolism and cell proliferation.

1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein 
 X is selected from the group consisting of C(R 1 ) and N;  
 Y is selected from the group consisting of C(R 1 ), C(R 2 )(R 2 ), N and N(R 2 );  
 Z is selected from the group consisting of O and S;  
 W 1  is a substituted or unsubstituted member selected from the group consisting of cyclo(C 3 -C 8 )alkyl, heterocyclo(C 3 -C 8 )alkyl, aryl and heteroaryl;  
 W 2  is a substituted or unsubstituted member selected from the group consisting of cyclo(C 3 -C 8 )alkyl, heterocyclo(C 3 -C 8 )alkyl, aryl and heteroaryl;  
 L 1  is selected from the group consisting of a bond, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, O and N(R a )C(O);  
 L 2  is selected from the group consisting of a bond, O, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, (C 1 -C 4 )heteroalkylene and N(R a )C(O);  
 the subscript m is 0 or 1;  
 optionally, when m is 1 and L 2  is a bond, a substituent on W 2  may be combined with a substituent on W 1  to form a 5-, 6- or 7-membered ring fused to W 1  and spiro or fused to W 2 , wherein said ring is saturated or unsaturated and has 0, 1 or 2 heteroatoms selected from the group consisting of N, O and S as ring members;  
 each R 1  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, C(O)R a , CO 2 R a  and C(O)NR a R b ;  
 each R 2  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, C(O)R a , CO 2 R a , C(O)NR a R b , aryl and aryl(C 1 -C 4 )alkyl;  
 R 3  and R 4  are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a , CO 2 R a , C(O)NR a R b  and (C 1 -C 4 )alkylene-OR a ;  
 optionally, R 3  and R 4  may be combined to form a 3-, 4-, 5- or 6-membered spiro ring;  
 optionally, R 2 , R 3  or R 4  may be combined with W 1  to form a 5-, 6- or 7-membered fused ring having from 0 to 3 heteroatoms selected from the group consisting of N, O and S;  
 R 5  and R 6  are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a  and CO 2 R a ;  
 optionally, R 5  and R 6  may be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring;  
 optionally, when X is C(R 1 ) or when Y includes an R 1  or R 2  group, R 5  or R 6  may be combined with R 1  or R 2  to form a 5-, 6- or 7-membered fused ring containing the nitrogen atom to which R 5  or R 6  is attached;  
 R 7  is selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 4 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a , OR a  and NR a R b ;  
 optionally, when X is C(R 1 ), R 7  may be combined with R 1  to form a 5-, 6- or 7-membered fused ring;  
 each R a  and R b  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, aryl and aryl(C 1 -C 4 )alkyl; and  
 the dotted line indicates an optional bond;  
 with the proviso that said compound is other than  
                     
 wherein R 8  is selected from the group consisting of H, NO 2 , Cl, methoxy, methyl and phenyl.  
 
     
     
         2 . A compound of  claim 1 , wherein X is N.  
     
     
         3 . A compound of  claim 2 , wherein Z is O.  
     
     
         4 . A compound of  claim 3 , wherein L 1  is a bond and W 1  is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, thiophene, oxazole, thiazole, benzoxazole, benzthiazole, benzofuran, benzothiophene, (C 4 -C 7 )cycloalkane, (C 5 -C 7 )cycloalkene, 1,2,3,4-tetrahydronaphthalene and indane.  
     
     
         5 . A compound of  claim 4 , wherein W 1  is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, thiophene, 1,2,3,4-tetrahydronaphthalene and indane.  
     
     
         6 . A compound of  claim 5 , wherein the subscript m is 1.  
     
     
         7 . A compound of  claim 5 , wherein the subscript m is 1 and L 2  is a bond.  
     
     
         8 . A compound of  claim 7 , wherein W 2  is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, (C 4 -C 7 )cycloalkane, (C 5 -C 7 )cycloalkene, pyrrolidine, piperidine, piperazine and morpholine.  
     
     
         9 . A compound of  claim 4 , wherein R 5  and R 6  are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, C(O)R a  and CO 2 R a .  
     
     
         10 . A compound of  claim 9 , wherein R 5  and R 6  are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.  
     
     
         11 . A compound of  claim 10 , wherein R 3  and R 4  are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.  
     
     
         12 . A compound of  claim 11 , wherein R 7  is selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 4 )alkyl, OH and NR a R b  wherein R a  and R b  are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.  
     
     
         13 . A compound of  claim 11 , wherein R 7  is H, (C 1 -C 8 )alkyl or halo(C 1 -C 4 )alkyl.  
     
     
         14 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein 
 X is selected from the group consisting of C(R 1 ) and N;  
 Y is selected from the group consisting of C(R 1 ), C(R 2 )(R 2 ), N and N(R 2 );  
 Z is selected from the group consisting of O and S;  
 W 1  is a substituted or unsubstituted member selected from the group consisting of cyclo(C 3 -C 8 )alkyl, heterocyclo(C 3 -C 8 )alkyl, aryl and heteroaryl;  
 W 2  is a substituted or unsubstituted member selected from the group consisting of cyclo(C 3 -C 8 )alkyl, heterocyclo(C 3 -C 8 )alkyl, aryl and heteroaryl;  
 L 1  is selected from the group consisting of a bond, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, O and N(R a )C(O);  
 L 2  is selected from the group consisting of a bond, O, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, (C 1 -C 4 )heteroalkylene and N(R a )C(O);  
 the subscript m is 0 or 1;  
 optionally, when m is 1 and L 2  is a bond, a substituent on W 2  may be combined with a substituent on W 1  to form a 5-, 6- or 7-membered ring fused to W 1  and spiro or fused to W 2 , wherein said ring is saturated or unsaturated and has 0, 1 or 2 heteroatoms selected from the group consisting of N, O and S as ring members;  
 each R 1  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, C(O)R a , CO 2 R a  and C(O)NR a R b ;  
 each R 2  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, C(O)R a , CO 2 R a , C(O)NR a R b , aryl and aryl(C 1 -C 4 )alkyl;  
 R 3  and R 4  are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a , CO 2 R a , C(O)NR a R b  and (C 1 -C 4 )alkylene-OR a ;  
 optionally, R 3  and R 4  may be combined to form a 3-, 4-, 5- or 6-membered spiro ring;  
 optionally, R 2 , R 3  or R 4  may be combined with W 1  to form a 5-, 6- or 7-membered fused ring having from 0 to 3 heteroatoms selected from the group consisting of N, O and S;  
 R 5  and R 6  are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a  and CO 2 R a ;  
 optionally, R 5  and R 6  may be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring;  
 optionally, when X is C(R 1 ) or when Y includes an R 1  or R 2  group, R 5  or R 6  may be combined with R 1  or R 2  to form a 5-, 6- or 7-membered fused ring containing the nitrogen atom to which R 5  or R 6  is attached;  
 R 7  is selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 4 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a , OR a  and NR a R b ;  
 optionally, when X is C(R 1 ), R 7  may be combined with R 1  to form a 5-, 6- or 7-membered fused ring;  
 each R a  and R b  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, aryl and aryl(C 1 -C 4 )alkyl; and  
 the dotted line indicates an optional bond;  
 with the proviso that said compound is other than  
                     
 wherein R 8  is selected from the group consisting of H, NO 2 , Cl, methoxy, methyl and phenyl.  
 
     
     
         15 . A pharmaceutical composition of  claim 14 , wherein X is N.  
     
     
         16 . A pharmaceutical composition of  claim 15 , wherein Z is O.  
     
     
         17 . A pharmaceutical composition of  claim 16 , wherein L 1  is a bond and W 1  is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, thiophene, oxazole, thiazole, benzoxazole, benzthiazole, benzofuran, benzothiophene, (C 4 -C 7 )cycloalkane, (C 5 -C 7 )cycloalkene, 1,2,3,4-tetrahydronaphthalene and indane.  
     
     
         18 . A pharmaceutical composition of  claim 17 , wherein W 1  is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, thiophene, 1,2,3,4-tetrahydronaphthalene and indane.  
     
     
         19 . A pharmaceutical composition of  claim 18 , wherein the subscript m is 1.  
     
     
         20 . A pharmaceutical composition of  claim 18 , wherein the subscript m is 1 and L 2  is a bond.  
     
     
         21 . A pharmaceutical composition of  claim 20 , wherein W 2  is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, (C 4 -C 7 )cycloalkane, (C 5 -C 7 )cycloalkene, pyrrolidine, piperidine, piperazine and morpholine.  
     
     
         22 . A pharmaceutical composition of  claim 17 , wherein R 5  and R 6  are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, C(O)R a  and CO 2 R a .  
     
     
         23 . A pharmaceutical composition of  claim 22 , wherein R 5  and R 6  are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.  
     
     
         24 . A pharmaceutical composition of  claim 23 , wherein R 3  and R 4  are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.  
     
     
         25 . A pharmaceutical composition of  claim 24 , wherein R 7  is selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 4 )alkyl, OH and NR a R b  wherein R a  and R b  are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.  
     
     
         26 . A pharmaceutical composition of  claim 24 , wherein R 7  is H, (C 1 -C 8 )alkyl or halo(C 1 -C 4 )alkyl.  
     
     
         27 . A method of treating a disease or condition selected from the group consisting of obesity, diabetes, anorexia nervosa, bulimia, cachexia, syndrome X, insulin resistance, hyperglycemia, hyperuricemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis, vascular stenosis, solid tumors, skin cancer, melanoma, lymphoma, breast cancer, lung cancer, colorectal cancer, stomach cancer, esophageal cancer, pancreatic cancer, prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer and ovarian cancer, comprising administering to a subject in need thereof an effective amount of a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein 
 X is selected from the group consisting of C(R 1 ) and N;  
 Y is selected from the group consisting of C(R 1 ), C(R 2 )(R 2 ), N and N(R 2 );  
 Z is selected from the group consisting of O and S;  
 W 1  is a substituted or unsubstituted member selected from the group consisting of cyclo(C 3 -C 8 )alkyl, heterocyclo(C 3 -C 8 )alkyl, aryl and heteroaryl;  
 W 2  is a substituted or unsubstituted member selected from the group consisting of cyclo(C 3 -C 8 )alkyl, heterocyclo(C 3 -C 8 )alkyl, aryl and heteroaryl;  
 L 1  is selected from the group consisting of a bond, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, O and N(R a )C(O);  
 L 2  is selected from the group consisting of a bond, O, (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, (C 1 -C 4 )heteroalkylene and N(R a )C(O);  
 the subscript m is 0 or 1;  
 optionally, when m is 1 and L 2  is a bond, a substituent on W 2  may be combined with a substituent on W 1  to form a 5-, 6- or 7-membered ring fused to W 1  and spiro or fused to W 2 , wherein said ring is saturated or unsaturated and has 0, 1 or 2 heteroatoms selected from the group consisting of N, O and S as ring members;  
 each R 1  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, C(O)R a , CO 2 R a  and C(O)NR a R b ;  
 each R 2  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, C(O)R a , CO 2 R a , C(O)NR a R b , aryl and aryl(C 1 -C 4 )alkyl;  
 R 3  and R 4  are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a , CO 2 R b , C(O)NR a R b  and (C 1 -C 4 )alkylene-OR a ;  
 optionally, R 3  and R 4  may be combined to form a 3-, 4-, 5- or 6-membered spiro ring;  
 optionally, R 2 , R 3  or R 4  may be combined with W 1  to form a 5-, 6- or 7-membered fused ring having from 0 to 3 heteroatoms selected from the group consisting of N, O and S;  
 R 5  and R 6  are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a  and CO 2 R a ;  
 optionally, R 5  and R 6  may be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring;  
 optionally, when X is C(R 1 ) or when Y includes an R 1  or R 2  group, R 5  or R 6  may be combined with R 1  or R 2  to form a 5-, 6- or 7-membered fused ring containing the nitrogen atom to which R 5  or R 6  is attached;  
 R 7  is selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 4 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, C(O)R a , OR a  and NR a R b ;  
 optionally, when X is C(R 1 ), R 7  may be combined with R 1  to form a 5-, 6- or 7-membered fused ring;  
 each R a  and R b  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, fluoro(C 1 -C 8 )alkyl, aryl and aryl(C 1 -C 4 )alkyl; and  
 the dotted line indicates an optional bond;  
 with the proviso that said compound is other than  
                     
 wherein R 8  is selected from the group consisting of H, NO 2 , Cl, methoxy, methyl and phenyl.  
 
     
     
         28 . A method in accordance with  claim 27 , wherein said compound is administered orally.  
     
     
         29 . A method in accordance with  claim 27 , wherein said compound is administered in combination with an additional active agent.  
     
     
         30 . A method in accordance with  claim 29 , wherein said additional active agent is selected from the group consisting of an antihyperlipidemic agent, a plasma HDL-raising agent, an antihypercholesterolemic agent, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a pancreatic lipase inhibitor, SNRI, appetite suppressive agent, a PPAR modulator, a MTP inhibitor, a CETP inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, an acyl-coenzyme A cholesterol acyltransferase inhibitor, vitamin B 3 , a cholesterol absorption inhibitor, a bile acid sequestrant anion exchange resin, a low density lipoprotein receptor inducer, a fibrate, probucol, vitamin B 6 , vitamin B 12 , an anti-oxidant vitamin, a β-blocker, an angiotensin II antagonist, an angiotensin converting enzyme inhibitor, a platelet aggregation inhibitor, a fibrinogen receptor antagonist, aspirin, phentiramines, β 3  adrenergic receptor agonists, sulfonylureas, biguanides, α-glucosidase inhibitors, insulin secretogogues, insulin and a hepatoprotective agent.  
     
     
         31 . A method in accordance with  claim 27 , wherein said disease or condition is selected from the group consisting of diabetes, obesity and syndrome X.  
     
     
         32 . A method in accordance with  claim 27 , wherein said disease or condition is obesity.  
     
     
         33 . A method in accordance with  claim 27 , wherein said disease is associated with DGAT.  
     
     
         34 . A method in accordance with  claim 27 , wherein said disease is mediated by DGAT.  
     
     
         35 . A method in accordance with  claim 27 , wherein said compound interferes with the interaction between DGAT and a ligand.  
     
     
         36 . A method in accordance with  claim 27 , wherein said subject is selected from the group consisting of human, rat, dog, cow, horse and mouse.  
     
     
         37 . A method in accordance with  claim 27 , wherein said subject is human.  
     
     
         38 . A method in accordance with  claim 27 , wherein X is N.  
     
     
         39 . A method in accordance with  claim 38 , wherein Z is O.  
     
     
         40 . A method in accordance with  claim 39 , wherein L 1  is a bond and W 1  is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, thiophene, oxazole, thiazole, benzoxazole, benzthiazole, benzofuran, benzothiophene, (C 4 -C 7 )cycloalkane, (C 5 -C 7 )cycloalkene, 1,2,3,4-tetrahydronaphthalene and indane.  
     
     
         41 . A method in accordance with  claim 40 , wherein W 1  is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, thiophene, 1,2,3,4-tetrahydronaphthalene and indane.  
     
     
         42 . A method in accordance with  claim 41 , wherein the subscript m is 1.  
     
     
         43 . A method in accordance with  claim 41 , wherein the subscript m is 1 and L 2  is a bond.  
     
     
         44 . A method in accordance with  claim 43 , wherein W 2  is a substituted or unsubstituted member selected from the group consisting of benzene, pyridine, (C 4 -C 7 )cycloalkane, (C 5 -C 7 )cycloalkene, pyrrolidine, piperidine, piperazine and morpholine.  
     
     
         45 . A method in accordance with  claim 40 , wherein R 5  and R 6  are independently selected from the group consisting of H, (C 1 -C 8 )alkyl, C(O)R a  and CO 2 R a .  
     
     
         46 . A method in accordance with  claim 45 , wherein R 5  and R 6  are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.  
     
     
         47 . A method in accordance with  claim 46 , wherein R 3  and R 4  are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.  
     
     
         48 . A method in accordance with  claim 47 , wherein R 7  is selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 4 )alkyl, OH and NR a R b  wherein R a  and R b  are independently selected from the group consisting of H and (C 1 -C 8 )alkyl.  
     
     
         49 . A method in accordance with  claim 47 , wherein R 7  is H, (C 1 -C 8 )alkyl or halo(C 1 -C 4 )alkyl.  
     
     
         50 . A compound of  claim 1 , selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         51 . A compound of  claim 1 , selected from the group consisting of  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         52 . A compound having a formula selected from the group consisting of Ia, Ib, Ic, Id, Ie, If and Ig.  
     
     
         53 . A compound having a formula selected from the group consisting of Ih, Ii, Ij and Ik.  
     
     
         54 . A compound having a formula selected from the group consisting of Il, Im, In, Io, Ip and Iq.  
     
     
         55 . A compound having a formula selected from the group consisting of Ir, Is, It, Iu, Iv, Iw, Ix and Iy.