Nitrogen-containing heterocyclic compounds and methods of use thereof

Abstract

The present invention provides compounds of Formula (I): and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof, wherein: Q is selected from the group consisting of: and L is selected from the group consisting of: pharmaceutically compositions comprising one or more compounds of formula (I), and methods of using the compounds of formula (I).

1 - 53 . (canceled) 
     
     
         54 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein:
 Q is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         L is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         R 1  is selected from the group consisting of H, alkyl, arylalkyl, -alkylene-S-alkyl, alkenyl, alkynyl, haloalkyl, wherein an alkyl group can be optionally substituted with one or more of the following groups, which can be the same or different: —OH, cycloalkyl, —C(O)-alkyl, -alkylene-C(O)—O-alkyl, —O—R 10 , -alkylene-O-alkyl, aryl, -alkylene-aryl, heteroaryl, -alkylene-heteroaryl, halogen, —(CH 2 ) n —N(R 7 ) 2 , -alkylene-cycloalkyl, or -alkylene-cycloalkenyl,
 wherein the cycloalkyl or the cycloalkyl portion of said -alkylene-cycloalkyl of R 1  is unsubstituted or substituted with one or more X groups, said aryl or the aryl portion of said -alkylene-aryl of R 1  is unsubstituted or substituted with one or more Y groups, and said heteroaryl or the heteroaryl portion of said -alkylene-heteroaryl of R 1  is unsubstituted or substituted with one or more Y groups; 
 
         R 2  is selected from the group consisting of H, halogen, alkyl, haloalkyl, alkyl substituted with one or more —OH, —C(O)-alkyl, —C(O)—O-alkyl, —C(O)—OH, —O—R 10 , -alkylene-O-alkyl, unsubstituted aryl, aryl substituted with one or more Y groups, unsubstituted heteroaryl, heteroaryl substituted with one or more Y groups, and halogen; or 
         R 1  and R 2  together with the ring carbon atoms to which they are shown attached, form a 5- or 6-membered cycloalkenyl ring or a 5- or 6-membered heterocyclic ring having 1 or 2 heteroatoms; 
         R 3  is selected from the group consisting of H, alkyl, alkyl substituted with one or more hydroxyl groups, -alkylene-O-alkyl, cycloalkyl, -alkylene-cycloalkyl, -alkylene-C(O)—O-alkyl, -alkylene-O—C(O)-alkyl, alkenyl, aryl, and heteroaryl,
 wherein the cycloalkyl or the cycloalkyl portion of said -alkylene-cycloalkyl of R 3  is unsubstituted or substituted with one or more X groups, said aryl of R 3  is unsubstituted or substituted with one or more Y groups, and said heteroaryl of R 3  is unsubstituted or substituted with one or more Y groups; 
 
         R 4  is selected from the group consisting of H, halogen, alkyl, haloalkyl, —O-cycloalkyl, —O-alkynyl, —O—R 10 , —C(O)—O-alkyl, —S(O) m —R 9 , —N(R 7 ) 2 , —N(R 7 )—NH—C(O)-alkyl, —N(R 7 )—NH—C(O)—O-alkyl, —O—N═C(R 12 ) 2 , —N(R 7 )—N═C(R 12 ) 2 , —C(O)-alkyl, unsubstituted heterocyclyl, heterocyclyl substituted with one or more X groups, —O—N(R 7 )—C(O)—O-alkyl, —C(O)—N(R 7 ) 2 , —CN, —N 3 , and —O—C(O)-alkyl; 
         R 5  is selected from the group consisting of H, alkyl, —OH, haloalkyl, arylalkyl, —O-alkyl, —O-aryl, cycloalkyl, heterocyclyl, —O-cycloalkyl, —O-heterocyclyl, —O-arylalkyl or -alkylene-β-alkyl -alkylene-C(O)—R 8 , -alkylene-C(O)—N(R 11 ) 2 , -alkylene-C(═N—O-alkyl)-aryl, cycloalkyl, -alkylene-cycloalkyl, -alkylene-C(O)—O-alkyl, -alkylene-O—C(O)-alkyl, -alkylene-C(O)-heterocyclyl, and alkenyl,
 wherein the cycloalkyl or the cycloalkyl portion of said -alkylene-cycloalkyl of R 5  is unsubstituted or substituted with one or more X groups, and the aryl portion of said -alkylene-C(═N—O-alkyl)-aryl of R 5  is unsubstituted or substituted with one or more Y groups; 
 
         R 6  is selected from the group consisting of H, alkyl, alkenyl, alkyl substituted with one or more hydroxyl groups, -alkylene-O-alkyl, —O—R 10 , halogen, aryl, heteroaryl, and —N(R 7 ) 2 ,
 wherein the aryl of R 6  is unsubstituted or substituted with one or more Y groups, and said heteroaryl of R 6  is unsubstituted or substituted with one or more Z groups; 
 
         each R 7  is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, —C(O)-alkyl, and —C(O)-aryl,
 wherein the cycloalkyl of R 7  is unsubstituted or substituted with one or more X groups, and the aryl portion of said —C(O)-aryl or said aryl of R 7  is unsubstituted or substituted with one or more Y groups; 
 
         two R 7  groups, together with the N atom to which they are bonded form a heterocyclyl; 
         R 8  is selected from the group consisting of aryl, —OH, and heterocyclyl,
 wherein the heterocyclyl of R 8  is unsubstituted or substituted with one or more X groups, and said aryl of R 8  is unsubstituted or substituted with one or more Y groups; 
 
         R 9  is selected from the group consisting of alkyl, -alkylene-cycloalkyl, alkenyl, —N(R 11 ) 2 , and -alkylene-aryl,
 wherein the cycloalkyl portion of said -alkylene-cycloalkyl of R 9  is unsubstituted or substituted with one or more X groups, and the aryl portion of said -alkylene-aryl of R 9  is unsubstituted or substituted with one or more Y groups, and 
 with the proviso that when R 9  is —N(R 11 ) 2 , m is 1 or 2; 
 
         R 10  is selected from the group consisting of H, alkyl, cycloalkyl, arylalkyl, haloalkyl, -alkylene-O-alkyl, -alkylene-aryl, -alkenylene-aryl, -alkylene-heteroaryl, alkenyl, —C(O)-alkyl, alkynyl, and -alkylene-cycloalkyl,
 wherein an the alkynyl portion of an —O-alkynyl group can be optionally substituted with —OH or alkoxy; the cycloalkyl portion of an —O-cycloalkyl group can be optionally substituted with an -alkylene-O-alkylene-aryl group; the cycloalkyl portion of said -alkylene-cycloalkyl of R 10  is unsubstituted or substituted with one or more X groups; the aryl portion of said -alkylene-aryl or -alkenylene-aryl of R 10  is unsubstituted or substituted with one or more Y groups; and the heteroaryl portion of said -alkylene-heteroaryl of R 10  is unsubstituted or substituted with one or more Z groups; 
 
         R 11  is selected from the group consisting of H, alkyl, and aryl,
 wherein the aryl of R 11  is unsubstituted or substituted with one or more Y groups; or 
 
         two R 11  groups, together with the N atom to which they are attached, form a heterocyclyl; 
         each R 12  is independently selected from the group consisting of alkyl, aryl, and heteroaryl,
 wherein the aryl of R 12  is unsubstituted or substituted with one or more Y groups and said heteroaryl of R 12  is unsubstituted or substituted with one or more Z groups; or
 wherein both R 12  groups, together with the carbon atom to which they are attached, combine to form a heterocyclyl group; 
 
 
         R a  and R b  are each independently selected from the group consisting of H, alkyl, aryl, and heteroaryl,
 wherein the aryl of R a  and R b  is unsubstituted or substituted with one or more Y groups, and said heteroaryl of R a  and R b  is unsubstituted or substituted with one or more Z groups; 
 
         R c  is selected from the group consisting of H, alkyl, alkylene-aryl, and —C(O)-alkyl,
 wherein the aryl portion of said alkylene-aryl of R c  is unsubstituted or substituted with one or more Y groups; 
 
         R d  is selected from the group consisting of H, alkyl, and alkylene-aryl,
 wherein the aryl portion of said alkylene-aryl of R d  is unsubstituted or substituted with one or more Y groups; 
 
         each X is independently selected from the group consisting of halogen, alkyl, haloalkyl, —O-alkyl, —O-haloalkyl, and —OH; 
         each Y is independently selected from the group consisting of halogen, alkyl, haloalkyl, —O-alkyl, —O-haloalkyl, —CN, —NO 2 , —OH, —S(O 2 )-alkyl, —S(O 2 )-aryl, —S(O 2 )—NH 2 , —S(O 2 )—NH-alkyl, —S(O 2 )—NH-aryl, —S(O 2 )—N(alkyl) 2 , —S(O 2 )—N(aryl) 2 , —S(O 2 )—N(alkyl)(aryl), and aryl; 
         each Z is independently selected from the group consisting of alkyl, haloalkyl, halogen, —O-alkyl, —O-haloalkyl, —CN, —OH, aryl, and N-oxide; 
         n is 0, 1, 2, or 3; 
         m is 0, 1, or 2; and 
       
       with the proviso that when L is (f), and R 2 , R 3  and R 5  are each H, then R 1  is not —CH 3 . 
     
     
         55 . The compound of  claim 54 , having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein:
 Q is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         R 1  is —H, alkyl, haloalkyl, arylalkyl, -alkylene-S-alkyl or -alkylene-cycloalkyl; 
         R 2  is —H, —CN, or —NHC(O)-alkyl; 
         R 4  is —O-cycloalkyl, —O-alkynyl, —O-alkynylene-cycloalkyl, haloalkyl or —O—N═C(R 12 ) 2 , wherein both R 12  groups, together with the carbon atom to which they are attached, combine to form a heterocyclyl group, and wherein the alkynyl portion of an —O-alkynyl group can be optionally substituted with —OH or alkoxy; and wherein the cycloalkyl portion of an —O-cycloalkyl group can be optionally substituted with an -alkylene-O-alkylene-aryl group; 
         R 5  is —H, —OH, alkyl, haloalkyl, arylalkyl, —O-alkyl, —O-aryl, cycloalkyl, heterocyclyl, —O-cycloalkyl, —O-heterocyclyl, —O-arylalkyl or -alkylene-O-alkyl; and 
         R 6  is alkoxy, —O-alkylene-O-alkyl, —O-arylalkyl or —O-haloalkyl. 
       
     
     
         56 . The compound of  claim 54 , wherein
 Q is:   
       
         
           
           
               
               
           
         
       
       R 1  is alkyl or -alkylene-cycloalkyl and R 2  is —H. 
     
     
         57 . The compound of  claim 56 , wherein R 4  is haloalkyl or —O—N═C(R 12 ) 2 , wherein both R 12  groups, together with the carbon atom to which they are attached, combine to form a heterocyclyl group. 
     
     
         58 . The compound of  claim 57 , wherein R 4  is —CH 2 F or —CH(F) 2 . 
     
     
         59 . The compound of  claim 54  wherein L is 
       
         
           
           
               
               
           
         
       
     
     
         60 . The compound of  claim 59  wherein L is. 
       
         
           
           
               
               
           
         
       
     
     
         61 . The compound of  claim 59  wherein L is. 
       
         
           
           
               
               
           
         
       
     
     
         62 . A composition comprising at least one compound of  claim 54  and a pharmaceutically acceptable carrier. 
     
     
         63 . The composition of  claim 62 , further comprising at least one additional therapeutic agent selected from the group consisting of hydroxy-substituted azetidinone compounds, substituted β-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants, aspirin, NSAID agents, Vytorin®, ezetimibe, inorganic cholesterol sequestrants, AcylCoA:Cholesterol O-acyltransferaseinhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CB 1  antagonists/inverse agonists, ghrelin antagonists, H 3  antagonists/inverse agonists, MCH1R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 agonists, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti-hypertensive agents, anti-dyslipidemic agents, DP receptor antagonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti-related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, α-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP). 
     
     
         64 . The composition of  claim 63 , wherein the at least one additional therapeutic agent is an HMG CoA synthetase inhibitor selected from the group consisting of lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, and pitavastatin. 
     
     
         65 . The composition of  claim 64 , wherein the at least one additional therapeutic agent is simvastatin. 
     
     
         66 . The composition of  claim 63 , wherein the at least one additional therapeutic agent is a cholesteryl ester transfer protein inhibitor. 
     
     
         67 . The composition of  claim 66 , wherein the cholesteryl ester transfer protein inhibitor is torcetrapib. 
     
     
         68 . The composition of  claim 63 , wherein the at least one additional therapeutic agent is Vytorin®, ezetimibe, aspirin, ibuprofen or acetaminophen or a combination thereof. 
     
     
         69 . A method of treating metabolic syndrome, dyslipidemia, a cardiovascular disease, a disorder of the peripheral and central nervous system, a hematological disease, cancer, inflammation, a respiratory disease, a gastroenterological disease, diabetes or non-alcoholic fatty liver disease in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of at least one compound of  claim 54 , or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof. 
     
     
         70 . The method of  claim 69 , wherein the treating is for dyslipidemia. 
     
     
         71 . The method of  claim 69 , further comprising administering at least one additional therapeutic agent selected from the group consisting of hydroxy-substituted azetidinone compounds, substituted β-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants, inorganic cholesterol sequestrants, aspirin, NSAID agent, ezetimibe, Vytorin®, AcylCoA:Cholesterol O-acyltransferase inhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols, Omacor®, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport protein inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CB 1  antagonists/inverse agonists, ghrelin antagonists, H 3  antagonists/inverse agonists, MCH1R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 agonists, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti-hypertensive agents, anti-dyslipidemic agents, DP receptor antagonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti-related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, α-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP). 
     
     
         72 . The method of  claim 71 , wherein the at least one additional active ingredient is an HMG CoA synthetase inhibitor selected from: lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, and pitavastatin. 
     
     
         73 . The method of  claim 72 , wherein the additional active ingredient is simvastatin.