Substituted heterocyclic compounds

Abstract

The present invention relates to novel heterocyclic compounds and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula (I): wherein Q1, Q2, R2, R3, R4, R5, and R6 are as described herein. The invention also relates to methods for the preparation of the compounds, and to pharmaceutical compositions containing such compounds.

1 . A compound of Formula (I), 
     
       
         
         
             
             
         
       
       wherein:
 Q1 is carbon or nitrogen, 
 Q2 is oxygen or R1-N<, where R1 is hydrogen or optionally substituted lower alkyl; 
 the double dotted line indicated by the arrow is a single bond or a double bond; 
 R2 is hydrogen, optionally substituted lower alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or —NR21R22, where R21 and R22 are independently hydrogen, lower alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl; 
 R3 is hydrogen, lower alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, cyano, —C(O)—R31, or —C(O)—O—R31, where R31 is hydrogen, lower alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 or R2 and R3 taken together with Q1 and the carbon to which R2 is attached form a 5 or 6 membered heterocyclyl, heteroaryl, cycloalkyl, or a saturated or unsaturated carbocyclic moiety, all of which are optionally substituted, by halo, optionally substituted lower alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl; 
 R4 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, provided that any substituent of R4 may itself be optionally substituted, by halo, optionally substituted lower alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl; 
 R5 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —O—R51, or —NR52R53, where R51 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, where R52 and R53 are each independently hydrogen, lower alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or R52 and R53 taken together with the nitrogen to which they are both directly attached form 5 or 6 membered heterocyclyl or heteroaryl moiety, which is optionally substituted by halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 R6 is hydrogen, lower alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, —NR61R62, where R61 and R62 are independently hydrogen, lower alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl; 
 or R5 and R6 taken together with the carbons to which R5 and R6 are directly attached and the carbon directly attached to both of the carbons to which R5 and R6 are directly attached form a 5 or 6 membered heterocyclyl, heteroaryl, cycloalkyl, or a saturated or unsaturated carbocyclic moiety, all of which are optionally substituted by halo, optionally substituted lower alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. 
 
     
   
   
       2 . The compound of  claim 1 , wherein R2 and R3 taken together with Q1 and the carbon to which R2 is directly attached form a tetrazole ring. 
   
   
       3 . The compound of  claim 1 , wherein R2 and R3 taken together with Q1 and the carbon to which R2 is directly attached form a pyrazole ring. 
   
   
       4 . The compound of  claim 1 , wherein R2 and R3 taken together with Q1 and the carbon to which R2 is directly attached form an imidazole ring. 
   
   
       5 . The compound of  claim 1 , wherein R2 and R3 taken together with Q1 and the carbon to which R2 is directly attached form a five or six membered carbocyclic ring. 
   
   
       6 . The compound of  claim 1 , wherein R4 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. 
   
   
       7 . The compound of  claim 6 , wherein R4 is aryl substituted with one or more groups selected from aryl, lower alkyl, alkyl, heteroaryl, halo, heterocyclyl, amino, and carboxyl, wherein said one or more groups are optionally substituted with alkyl, aryl, heteroaryl, heterocyclyl, halo, or carboxyl. 
   
   
       8 . The compound of  claim 1 , wherein R5 is —O—R51, wherein R51 is optionally substituted lower alkyl, optionally substituted alkyl, optionally substituted benzyl, optionally substituted biphenyl, optionally substituted diphenylmethyl, methyl, ethyl, 1-propyl, 2-propyl. 
   
   
       9 . The compound of  claim 1 , wherein R5 is —NR52R53, where R52 and R53 are each independently selected from hydrogen, lower alkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted benzyl; or where R52 and R53 taken together with the nitrogen to which they are both directly attached form a 5 or 6 membered heterocyclyl or heteroaryl moiety, said 5 or 6 membered heterocyclyl or heteroaryl moiety optionally substituted by a group selected from halo, alkyl, alkenyl, alkynyl, alkoxy, aryl, and cycloalkyl and combinations thereof, wherein said alkyl, alkenyl, alkynyl, alkoxy, aryl, or cycloalkyl are optionally substituted. 
   
   
       10 . The compound of  claim 1 , wherein R5 and R6 taken together with the carbons to which R5 and R6 are directly attached and the carbon directly attached to both of the carbons to which R5 and R6 are directly attached form a 5 or 6 membered heterocyclyl, heteroaryl, cycloalkyl, or a saturated or unsaturated carbocyclic moiety, each which are optionally substituted. 
   
   
       11 . A compound named in at least one Table selected from Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, Table 10 Table 11, Table 12, Table 13, or Table 14. 
   
   
       12 . The compound of  claim 11 , wherein the compound is named in Table 1 or Table 2. 
   
   
       13 . The compound of  claim 11 , wherein the compound is named in Table 3, Table 4, or Table 5. 
   
   
       14 . The compound of  claim 11 , wherein the compound is named in Table 6 or Table 7. 
   
   
       15 . The compound of  claim 11 , wherein the compound is named in Table 9. 
   
   
       16 . The compound of  claim 11 , wherein the compound is named in Table 10 or Table 11. 
   
   
       17 . The compound of  claim 11 , wherein the compound is named in Table 12, Table 13, or Table 14. 
   
   
       18 . A pharmaceutical formulation comprising a compound according to  claim 1  or a pharmaceutically acceptable salt, ester, hydrate, polymorph, prodrug or tautomeric form thereof, and at least one pharmaceutically acceptable excipient. 
   
   
       19 . A method of treating a disease state in a mammal that is alleviable by treatment with an agent capable of reducing late sodium current, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound according to  claim 1 . 
   
   
       20 . The method of  claim 18 , wherein the disease state is a cardiovascular disease selected from one or more of atrial and ventricular arrhythmias, heart failure (including congestive heart failure, diastolic heart failure, systolic heart failure, acute heart failure), Prinzmetal's (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, ischemia, recurrent ischemia, reperfusion injury, myocardial infarction, acute coronary syndrome, peripheral arterial disease, and intermittent claudication. 
   
   
       21 . The method of  claim 18 , wherein the disease state is diabetes or diabetic peripheral neuropathy. 
   
   
       22 . The method of  claim 18 , wherein the disease state results in one or more of neuropathic pain, seizures, or paralysis.