Substituted bicyclic aza-heterocycles and analogues as sirtuin modulators

Abstract

Provided herein are novel substituted bicyclic aza-heterocycle sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.

We claim: 
     
         1 . A method of increasing sirtuin-1 activity in a cell comprising the step of contacting the cell with a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein:
 one of D and E is N and the other is C; and 
 when D is N, one of A and B is N and the other is CR; and 
 when E is N, B is N and A is N or CR; or 
 
       a salt thereof, wherein:
 each R is independently selected from hydrogen, halo, OH, C≡N, C 1 -C 4  alkyl, halo-substituted C 2 -C 4  alkyl, C 1 -C 4  alkoxy-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 8  alkyl, OR 3 , O—(C 1 -C 4  alkyl)-OR 3 , S—(C 1 -C 2  alkyl), S-(halo-substituted C 1 -C 4  alkyl), N(hydroxy-substituted C 1 -C 4  alkyl) 2 , N(methoxy-substituted C 1 -C 4  alkyl) 2 , N(C 1 -C 4  alkyl)(hydroxy-substituted C 1 -C 4  alkyl), N(C 1 -C 4  alkyl)(methoxy-substituted C 1 -C 4  alkyl), N(hydroxy-substituted C 1 -C 4  alkyl)(methoxy-substituted C 1 -C 4  alkyl), C 5 -C 7  cycloalkyl, and 4- to 8-membered non-aromatic heterocycle, and when one or both of E and A is N, then R can additionally be selected from halo-substituted methyl and C 3 -C 4  cycloalkyl; 
 R 1  is an aromatic heterocycle or a fused carbocycle, wherein R 1  is optionally substituted with one or more substituents independently selected from halo, C≡N, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, C 1 -C 4  alkoxy-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 8  alkyl, O—R 3 , O—(C 1 -C 4  alkyl)-OR 3 , ═O, C 3 -C 7  cycloalkyl, SO 2 R 3 , S—R 3 , (C 1 -C 4  alkyl)-N(R 3 )(R 3 ), N(R 3 )(R 3 ), O—(C 1 -C 4  alkyl)-N(R 3 )(R 3 ), O—(C 0 -C 4  alkyl)-CR 3 R 3 (C 0 -C 4  alkyl), (C 1 -C 4  alkyl)-O—(C 1 -C 4  alkyl)-N(R 3 )(R 3 ), C(═O)—N(R 3 )(R 3 ), (C 1 -C 4  alkyl)-C(═O)—N(R 3 )(R 3 ), O—(C 0 -C 4  alkyl)-CR x R x —(C 0 -C 4  alkyl), CR x R x , phenyl, O-phenyl, second heterocycle, O-(second heterocycle), 3,4-methylenedioxy, halo-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, and halo substituted 3,4-ethylenedioxy, wherein any phenyl, saturated heterocycle, or second heterocycle substituent of R 1  is optionally substituted with one or more substituents independently selected from halo, C≡N, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  lkyl, O-(halo-substituted C 1 -C 4  alkyl), O—(C 1 -C 4  alkyl), S—(C 1 -C 4  alkyl), and S-(halo-substituted C 1 -C 4  alkyl); 
 R 2  is a carbocycle or a heterocycle, wherein R 2  is optionally substituted with one or more substituents independently selected from halo, C≡N, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, C 1 -C 4  alkoxy-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 8  alkyl, O—R 3 , —O—(C 1 -C 4  alkyl)-OR 3 , ═O, C 3 -C 7  cycloalkyl, SO 2 R 3 , S—R 3 , (C 1 -C 4  alkyl)-N(R 3 )(R 3 ), N(R 3 )(R 3 ), O—(C 1 -C 4  alkyl)-N(R 3 )(R 3 ), O—(C 0 -C 4  alkyl)-CR 3 R 3 (C 0 -C 4  alkyl), (C 1 -C 4  alkyl)-O—(C 1 -C 4  alkyl)-N(R 3 )(R 3 ), C(═O)—N(R 3 )(R 3 ), (C 1 -C 4  alkyl)-C(═O)—N(R 3 )(R 3 ), O-phenyl, O-(second heterocycle), 3,4-methylenedioxy, halo-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, and halo-substituted 3,4-ethylenedioxy, and when E is N, substituents on R 2  can additionally be selected from a second heterocycle, and when both D and A are N, substituents on R 2  can additionally be selected from phenyl and a second heterocycle, wherein any phenyl, saturated heterocycle or second heterocycle substituent of R 2  is optionally substituted with one or more substituents independently selected from halo, C≡N, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, O-(halo-substituted C 1 -C 4  alkyl), O—(C 1 -C 4  alkyl), S—(C 1 -C 4  alkyl), and S-(halo-substituted C 1 -C 4  alkyl); 
 each R 3  is independently selected from hydrogen and C 1 -C 4  alkyl optionally substituted with one or more of OH, O—(C 1 -C 4  alkyl), halo, NH 2 , NH(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , NH(methoxy-substituted C 1 -C 4  alkyl), NH(hydroxy-substituted C 1 -C 4  alkyl), N(hydroxy-substituted C 1 -C 4  alkyl) 2  and N(methoxy-substituted C 1 -C 4  alkyl) 2 ; or 
 two R 3  are taken together with the nitrogen or carbon atom to which they are bound to form a 4- to 8-membered saturated heterocycle optionally comprising one additional heteroatom independently selected from N, S, S(═O), S(═O) 2 , and O, wherein the heterocycle formed by two R 3  is optionally substituted at any carbon atom with one or more of OH, halo, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, NH 2 , NH(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , —O(C 1 -C 4  alkyl), NH(hydroxy-substituted C 1 -C 4  alkyl), N(hydroxy-substituted C 1 -C 4  alkyl) 2 NH(methoxy-substituted C 1 -C 4  alkyl), or N(methoxy-substituted C 1 -C 4  alkyl) 2 , and optionally substituted at any substitutable nitrogen atom with C 1 -C 4  alkyl or halo-substituted C 1 -C 4  alkyl; 
 two R x  taken together with the carbon atom to which they are bound form a 4- to 8-membered carbocycle or heterocycle optionally comprising one or two heteroatoms independently selected from N, S, S(═O), S(═O) 2 , and O, wherein the carbocycle or heterocycle is optionally substituted at any carbon atom with one or more of OH, halo, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, NH 2 , and N(R 3 )(R 3 ) and optionally substituted at any substitutable nitrogen atom with C 1 -C 4  alkyl or halo-substituted C 1 -C 4  alkyl; and 
 when D is N, A is CR and B is N, then X is selected from C(═O)—NH-†, NH—C(═O)-†, S(═O)—NH-†, S(═O) 2 —NH-†, and NH—C(═O)—O—CR 4 R 5 -†; and 
 when E is N, B is N and A is N or CR then X is selected from C(═O)—NH-†, NH—C(═O)-†, S(═O)—NH-†, S(═O) 2 —NH-†, NH—C(═S)-†, C(═S)—NH-†, NH—S(═O)-†, NH—S(═O) 2 -†, NH—S(═O) 2 —NR 4 -†, NR 4 —S(═O) 2 —NH-†, NH—C(═O)—O-†, O—C(═O)—NH-†, NH—C(═O)—NH-†, NH—C(═O)—NR 4 -†, NR 4 —C(═O)—NH-†, CH 2 —NH—C(═O)-†, NH—C(═S)—CR 4 R 5 -†, CR 4 R 5 —C(═S)—NH-†, NH—S(═O)—CR 4 R 5 -†, CR 4 R 5 —S(═O)—NH-†, NH—S(═O) 2 —CR 4 R 5 -†, CR 4 R 5 —S(═O) 2 —NH-†, CR 4 R 5 —O—C(═O)—NH-†, NH—C(═O)—CR 4 R 5 -†, NH—C(═O)—CR 4 R 5 —NH-†, CR 4 R 5 —NH—C(═O)—O—† and NH—C(═O)—O—CR 4 R 5 —; and 
 when D is N, A is N and B is CR then X is selected from C(═O)—NH-†, NH—C(═O)†, NH—CR 4 R 5 -†, C(═O)—NH—CR 4 R 5 -†, S(═O)—NH-†, S(═O) 2 —NH-†, CR 4 R 5 —NH-†, —NH—C(═O)O—CR 4 R 5 -†, NH-†, NH—C(═S)-†, C(═S)—NH-†, NH—S(═O)-†, NH—S(═O) 2 -†, NH—S(═O) 2 —NR 4 -†, NR 4 —S(O) 2 —NH-†, NH—C(═O)—O-†, O—C(═O)—NH-†, NH—C(═O)—NH-†, NH—C(═O)—NR 4 -†, NR 4 —C(═O)—NH-†, CR 4 R 5 —NH—C(O)-†, NH—C(═S)—CR 4 R 5 -†, CR 4 R 5 —C(═S)—NH-†, NH—S(═O)—CR 4 R 5 -†, CR 4 R 5 —S(═O)—NH-†, NH—S(═O) 2 —CR 4 R 5 -†, CR 4 R 5 —S(═O) 2 —NH-†, CR 4 R 5 —O—C(═O)—NH-†, NH—C(═O)—CR 4 R 5 -†, NH—C(═O)—CR 4 R 5 —NH† and CR 4 R 5 —NH—C(═O)—O-†; 
 wherein: 
 † represents where X is bound to R 1 ; and 
 each R 4  and R 5  is independently selected from hydrogen, C 1 -C 4  alkyl, CF 3  and (C 1 -C 3  alkyl)-CF 3 . 
 
     
     
         2 . A method for treating a subject suffering from or susceptible to insulin resistance, a metabolic syndrome, diabetes, or complications thereof, or for increasing insulin sensitivity in a subject, comprising administering to the subject in need thereof of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 one of D and E is N and the other is C; and 
 when D is N, one of A and B is N and the other is CR; and 
 when E is N, B is N and A is N or CR; or 
 
       a salt thereof, wherein:
 each R is independently selected from hydrogen, halo, OH, C≡N, C 1 -C 4  alkyl, halo-substituted C 2 -C 4  alkyl, C 1 -C 4  alkoxy-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 8  alkyl, OR 3 , O—(C 1 -C 4  alkyl)-OR 3 , S—(C 1 -C 2  alkyl), S-(halo-substituted C 1 -C 4  alkyl), N(hydroxy-substituted C 1 -C 4  alkyl) 2 , N(methoxy-substituted C 1 -C 4  alkyl) 2 , N(C 1 -C 4  alkyl)(hydroxy-substituted C 1 -C 4  alkyl), N(C 1 -C 4  alkyl)(methoxy-substituted C 1 -C 4  alkyl), N(hydroxy-substituted C 1 -C 4  alkyl)(methoxy-substituted C 1 -C 4  alkyl), C 5 -C 7  cycloalkyl, and 4- to 8-membered non-aromatic heterocycle, and when one or both of E and A is N, then R can additionally be selected from halo-substituted methyl and C 3 -C 4  cycloalkyl; 
 R 1  is an aromatic heterocycle or a fused carbocycle, wherein R 1  is optionally substituted with one or more substituents independently selected from halo, C≡N, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, C 1 -C 4  alkoxy-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 8  alkyl, O—R 3 , O—(C 1 -C 4  alkyl)-OR 3 , ═O, C 3 -C 7  cycloalkyl, SO 2 R 3 , S—R 3 , (C 1 -C 4  alkyl)-N(R 3 )(R 3 ), N(R 3 )(R 3 ), O—(C 1 -C 4  alkyl)-N(R 3 )(R 3 ), O—(C 0 -C 4  alkyl)-CR 3 R 3 (C 0 -C 4  alkyl), (C 1 -C 4  alkyl)-O—(C 1 -C 4  alkyl)-N(R 3 )(R 3 ), C(═O)—N(R 3 )(R 3 ), (C 1 -C 4  alkyl)-C(═O)—N(R 3 )(R 3 ), O—(C 0 -C 4  alkyl)-CR x R x —(C 0 -C 4  alkyl), CR x R x , phenyl, O-phenyl, second heterocycle, O-(second heterocycle), 3,4-methylenedioxy, halo-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, and halo substituted 3,4-ethylenedioxy, wherein any phenyl, saturated heterocycle, or second heterocycle substituent of R 1  is optionally substituted with one or more substituents independently selected from halo, C≡N, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  lkyl, O-(halo-substituted C 1 -C 4  alkyl), O—(C 1 -C 4  alkyl), S—(C 1 -C 4  alkyl), and S-(halo-substituted C 1 -C 4  alkyl); 
 R 2  is a carbocycle or a heterocycle, wherein R 2  is optionally substituted with one or more substituents independently selected from halo, C≡N, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, C 1 -C 4  alkoxy-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 8  alkyl, O—R 3 , —O—(C 1 -C 4  alkyl)-OR 3 , ═O, C 3 -C 7  cycloalkyl, SO 2 R 3 , S—R 3 , (C 1 -C 4  alkyl)-N(R 3 )(R 3 ), N(R 3 )(R 3 ), O—(C 1 -C 4  alkyl)-N(R 3 )(R 3 ), O—(C 0 -C 4  alkyl)-CR 3 R 3 (C 0 -C 4  alkyl), (C 1 -C 4  alkyl)-O—(C 1 -C 4  alkyl)-N(R 3 )(R 3 ), C(═O)—N(R 3 )(R 3 ), (C 1 -C 4  alkyl)-C(═O)—N(R 3 )(R 3 ), O-phenyl, O-(second heterocycle), 3,4-methylenedioxy, halo-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, and halo-substituted 3,4-ethylenedioxy, and when E is N, substituents on R 2  can additionally be selected from a second heterocycle, and when both D and A are N, substituents on R 2  can additionally be selected from phenyl and a second heterocycle, wherein any phenyl, saturated heterocycle or second heterocycle substituent of R 2  is optionally substituted with one or more substituents independently selected from halo, C≡N, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, O-(halo-substituted C 1 -C 4  alkyl), O—(C 1 -C 4  alkyl), S—(C 1 -C 4  alkyl), and S-(halo-substituted C 1 -C 4  alkyl); 
 each R 3  is independently selected from hydrogen and C 1 -C 4  alkyl optionally substituted with one or more of OH, O—(C 1 -C 4  alkyl), halo, NH 2 , NH(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , NH(methoxy-substituted C 1 -C 4  alkyl), NH(hydroxy-substituted C 1 -C 4  alkyl), N(hydroxy-substituted C 1 -C 4  alkyl) 2  and N(methoxy-substituted C 1 -C 4  alkyl) 2 ; or 
 two R 3  are taken together with the nitrogen or carbon atom to which they are bound to form a 4- to 8-membered saturated heterocycle optionally comprising one additional heteroatom independently selected from N, S, S(═O), S(═O) 2 , and O, wherein the heterocycle formed by two R 3  is optionally substituted at any carbon atom with one or more of OH, halo, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, NH 2 , NH(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , —O(C 1 -C 4  alkyl), NH(hydroxy-substituted C 1 -C 4  alkyl), N(hydroxy-substituted C 1 -C 4  alkyl) 2 NH(methoxy-substituted C 1 -C 4  alkyl), or N(methoxy-substituted C 1 -C 4  alkyl) 2 , and optionally substituted at any substitutable nitrogen atom with C 1 -C 4  alkyl or halo-substituted C 1 -C 4  alkyl; 
 two R x  taken together with the carbon atom to which they are bound form a 4- to 8-membered carbocycle or heterocycle optionally comprising one or two heteroatoms independently selected from N, S, S(═O), S(═O) 2 , and O, wherein the carbocycle or heterocycle is optionally substituted at any carbon atom with one or more of OH, halo, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, NH 2 , and N(R 3 )(R 3 ) and optionally substituted at any substitutable nitrogen atom with C 1 -C 4  alkyl or halo-substituted C 1 -C 4  alkyl; and 
 when D is N, A is CR and B is N, then X is selected from C(═O)—NH-†, NH—C(═O)-†, S(═O)—NH-†, S(═O) 2 —NH-†, and NH—C(═O)—O—CR 4 R 5 -†; and 
 when E is N, B is N and A is N or CR then X is selected from C(═O)—NH-†, NH—C(═O)-†, S(═O)—NH-†, S(═O) 2 —NH-†, NH—C(═S)-†, C(═S)—NH-†, NH—S(═O)-†, NH—S(═O) 2 -†, NH—S(═O) 2 —NR 4 -†, NR 4 —S(═O) 2 —NH-†, NH—C(═O)—O-†, O—C(═O)—NH-†, NH—C(═O)—NH-†, NH—C(═O)—NR 4 -†, NR 4 —C(═O)—NH-†, CH 2 —NH—C(═O)-†, NH—C(═S)—CR 4 R 5 -†, CR 4 R 5 —C(═S)—NH-†, NH—S(═O)—CR 4 R 5 -†, CR 4 R 5 —S(═O)—NH-†, NH—S(═O) 2 —CR 4 R 5 -†, CR 4 R 5 —S(═O) 2 —NH-†, CR 4 R 5 —O—C(═O)—NH-†, NH—C(═O)—CR 4 R 5 -†, NH—C(═O)—CR 4 R 5 —NH-†, CR 4 R 5 —NH—C(═O)—O—† and NH—C(═O)—O—CR 4 R 5 —; and 
 when D is N, A is N and B is CR then X is selected from C(═O)—NH-†, NH—C(═O)†, NH—CR 4 R 5 -†, C(═O)—NH—CR 4 R 5 -†, S(═O)—NH-†, S(═O) 2 —NH-†, CR 4 R 5 —NH-†, —NH—C(═O)O—CR 4 R 5 -†, NH-†, NH—C(═S)-†, C(═S)—NH-†, NH—S(═O)-†, NH—S(═O) 2 -†, NH—S(═O) 2 —NR 4 -†, NR 4 —S(O) 2 —NH-†, NH—C(═O)—O-†, O—C(═O)—NH-†, NH—C(═O)—NH-†, NH—C(═O)—NR 4 -†, NR 4 —C(═O)—NH-†, CR 4 R 5 —NH—C(O)-†, NH—C(═S)—CR 4 R 5 -†, CR 4 R 5 —C(═S)—NH-†, NH—S(═O)—CR 4 R 5 -†, CR 4 R 5 —S(═O)—NH-†, NH—S(═O) 2 —CR 4 R 5 -†, CR 4 R 5 —S(═O) 2 —NH—, CR 4 R 5 —O—C(═O)—NH-†, NH—C(═O)—CR 4 R 5 -†, NH—C(═O)—CR 4 R 5 —NH† and CR 4 R 5 —NH—C(═O)—O-†; 
 wherein: 
 † represents where X is bound to R 1 ; and 
 each R 4  and R 5  is independently selected from hydrogen, C 1 -C 4  alkyl, CF 3  and (C 1 -C 3  alkyl)-CF 3 . 
 
     
     
         3 . A method for treating a subject suffering from or susceptible to diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, chemotherapeutic-induced neuropathy, neuropathy associated with an ischemic event, ocular diseases and/or disorders, cardiovascular disease, blood clotting disorders, inflammation, and/or flushing, comprising administering to the subject in need thereof of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 one of D and E is N and the other is C; and 
 when D is N, one of A and B is N and the other is CR; and 
 when E is N, B is N and A is N or CR; or 
 
       a salt thereof, wherein:
 each R is independently selected from hydrogen, halo, OH, C≡N, C 1 -C 4  alkyl, halo-substituted C 2 -C 4  alkyl, C 1 -C 4  alkoxy-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 8  alkyl, OR 3 , O—(C 1 -C 4  alkyl)-OR 3 , S—(C 1 -C 2  alkyl), S-(halo-substituted C 1 -C 4  alkyl), N(hydroxy-substituted C 1 -C 4  alkyl) 2 , N(methoxy-substituted C 1 -C 4  alkyl) 2 , N(C 1 -C 4  alkyl)(hydroxy-substituted C 1 -C 4  alkyl), N(C 1 -C 4  alkyl)(methoxy-substituted C 1 -C 4  alkyl), N(hydroxy-substituted C 1 -C 4  alkyl)(methoxy-substituted C 1 -C 4  alkyl), C 5 -C 7  cycloalkyl, and 4- to 8-membered non-aromatic heterocycle, and when one or both of E and A is N, then R can additionally be selected from halo-substituted methyl and C 3 -C 4  cycloalkyl; 
 R 1  is an aromatic heterocycle or a fused carbocycle, wherein R 1  is optionally substituted with one or more substituents independently selected from halo, C≡N, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, C 1 -C 4  alkoxy-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 8  alkyl, O—R 3 , O—(C 1 -C 4  alkyl)-OR 3 , ═O, C 3 -C 7  cycloalkyl, SO 2 R 3 , S—R 3 , (C 1 -C 4  alkyl)-N(R 3 )(R 3 ), N(R 3 )(R 3 ), O—(C 1 -C 4  alkyl)-N(R 3 )(R 3 ), O—(C 0 -C 4  alkyl)-CR 3 R 3 (C 0 -C 4  alkyl), (C 1 -C 4  alkyl)-O—(C 1 -C 4  alkyl)-N(R 3 )(R 3 ), C(═O)—N(R 3 )(R 3 ), (C 1 -C 4  alkyl)-C(═O)—N(R 3 )(R 3 ), O—(C 0 -C 4  alkyl)-CR x R x —(C 0 -C 4  alkyl), CR x R x , phenyl, O-phenyl, second heterocycle, O-(second heterocycle), 3,4-methylenedioxy, halo-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, and halo substituted 3,4-ethylenedioxy, wherein any phenyl, saturated heterocycle, or second heterocycle substituent of R 1  is optionally substituted with one or more substituents independently selected from halo, C≡N, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  lkyl, O-(halo-substituted C 1 -C 4  alkyl), O—(C 1 -C 4  alkyl), S—(C 1 -C 4  alkyl), and S-(halo-substituted C 1 -C 4  alkyl); 
 R 2  is a carbocycle or a heterocycle, wherein R 2  is optionally substituted with one or more substituents independently selected from halo, C≡N, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, C 1 -C 4  alkoxy-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 8  alkyl, O—R 3 , —O—(C 1 -C 4  alkyl)-OR 3 , ═O, C 3 -C 7  cycloalkyl, SO 2 R 3 , S—R 3 , (C 1 -C 4  alkyl)-N(R 3 )(R 3 ), N(R 3 )(R 3 ), O—(C 1 -C 4  alkyl)-N(R 3 )(R 3 ), O—(C 0 -C 4  alkyl)-CR 3 R 3 (C 0 -C 4  alkyl), (C 1 -C 4  alkyl)-O—(C 1 -C 4  alkyl)-N(R 3 )(R 3 ), C(═O)—N(R 3 )(R 3 ), (C 1 -C 4  alkyl)-C(═O)—N(R 3 )(R 3 ), O-phenyl, O-(second heterocycle), 3,4-methylenedioxy, halo-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, and halo-substituted 3,4-ethylenedioxy, and when E is N, substituents on R 2  can additionally be selected from a second heterocycle, and when both D and A are N, substituents on R 2  can additionally be selected from phenyl and a second heterocycle, wherein any phenyl, saturated heterocycle or second heterocycle substituent of R 2  is optionally substituted with one or more substituents independently selected from halo, C≡N, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, O-(halo-substituted C 1 -C 4  alkyl), O—(C 1 -C 4  alkyl), S—(C 1 -C 4  alkyl), and S-(halo-substituted C 1 -C 4  alkyl); 
 each R 3  is independently selected from hydrogen and C 1 -C 4  alkyl optionally substituted with one or more of OH, O—(C 1 -C 4  alkyl), halo, NH 2 , NH(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , NH(methoxy-substituted C 1 -C 4  alkyl), NH(hydroxy-substituted C 1 -C 4  alkyl), N(hydroxy-substituted C 1 -C 4  alkyl) 2  and N(methoxy-substituted C 1 -C 4  alkyl) 2 ; or 
 two R 3  are taken together with the nitrogen or carbon atom to which they are bound to form a 4- to 8-membered saturated heterocycle optionally comprising one additional heteroatom independently selected from N, S, S(═O), S(═O) 2 , and O, wherein the heterocycle formed by two R 3  is optionally substituted at any carbon atom with one or more of OH, halo, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, NH 2 , NH(C 1 -C 4  alkyl), N(C 1 -C 4  alkyl) 2 , —O(C 1 -C 4  alkyl), NH(hydroxy-substituted C 1 -C 4  alkyl), N(hydroxy-substituted C 1 -C 4  alkyl) 2 NH(methoxy-substituted C 1 -C 4  alkyl), or N(methoxy-substituted C 1 -C 4  alkyl) 2 , and optionally substituted at any substitutable nitrogen atom with C 1 -C 4  alkyl or halo-substituted C 1 -C 4  alkyl; 
 two R x  taken together with the carbon atom to which they are bound form a 4- to 8-membered carbocycle or heterocycle optionally comprising one or two heteroatoms independently selected from N, S, S(═O), S(═O) 2 , and O, wherein the carbocycle or heterocycle is optionally substituted at any carbon atom with one or more of OH, halo, C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkyl, NH 2 , and N(R 3 )(R 3 ) and optionally substituted at any substitutable nitrogen atom with C 1 -C 4  alkyl or halo-substituted C 1 -C 4  alkyl; and 
 when D is N, A is CR and B is N, then X is selected from C(═O)—NH-†, NH—C(═O)-†, S(═O)—NH-†, S(═O) 2 —NH-†, and NH—C(═O)—O—CR 4 R 5 -†; and 
 when E is N, B is N and A is N or CR then X is selected from C(═O)—NH-†, NH—C(═O)-†, S(═O)—NH-†, S(═O) 2 —NH-†, NH—C(═S)-†, C(═S)—NH-†, NH—S(═O)-†, NH—S(═O) 2 -†, NH—S(═O) 2 —NR 4 -†, NR 4 —S(═O) 2 —NH-†, NH—C(═O)—O-†, O—C(═O)—NH-†, NH—C(═O)—NH-†, NH—C(═O)—NR 4 -†, NR 4 —C(═O)—NH-†, CH 2 —NH—C(═O)-†, NH—C(═S)—CR 4 R 5 -†, CR 4 R 5 —C(═S)—NH-†, NH—S(═O)—CR 4 R 5 -†, CR 4 R 5 —S(═O)—NH-†, NH—S(═O) 2 —CR 4 R 5 -†, CR 4 R 5 —S(═O) 2 —NH-†, CR 4 R 5 —O—C(═O)—NH-†, NH—C(═O)—CR 4 R 5 -†, NH—C(═O)—CR 4 R 5 —NH-†, CR 4 R 5 —NH—C(═O)—O—† and NH—C(═O)—O—CR 4 R 5 —; and 
 when D is N, A is N and B is CR then X is selected from C(═O)—NH-†, NH—C(═O)†, NH—CR 4 R 5 -†, C(═O)—NH—CR 4 R 5 -†, S(═O)—NH-†, S(═O) 2 —NH-†, CR 4 R 5 —NH-†, —NH—C(═O)O—CR 4 R 5 -†, NH-†, NH—C(═S)-†, C(═S)—NH-†, NH—S(═O)-†, NH—S(═O) 2 -†, NH—S(═O) 2 —NR 4 -†, NR 4 —S(O) 2 —NH-†, NH—C(═O)—O-†, O—C(═O)—NH-†, NH—C(═O)—NH-†, NH—C(═O)—NR 4 -†, NR 4 —C(═O)—NH-†, CR 4 R 5 —NH—C(O)-†, NH—C(═S)—CR 4 R 5 -†, CR 4 R 5 —C(═S)—NH-†, NH—S(═O)—CR 4 R 5 -†, CR 4 R 5 —S(═O)—NH-†, NH—S(═O) 2 —CR 4 R 5 -†, CR 4 R 5 —S(═O) 2 —NH—, CR 4 R 5 —O—C(═O)—NH-†, NH—C(═O)—CR 4 R 5 -†, NH—C(═O)—CR 4 R 5 —NH† and CR 4 R 5 —NH—C(═O)—O-†; 
 wherein: 
 † represents where X is bound to R 1 ; and 
 each R 4  and R 5  is independently selected from hydrogen, C 1 -C 4  alkyl, CF 3  and (C 1 -C 3  alkyl)-CF 3 . 
 
     
     
         4 . The method of  claim 1 , wherein both E and B are N, and A is N or CR. 
     
     
         5 . The method of  claim 4 , wherein A is N. 
     
     
         6 . The method of  claim 4 , wherein A is CR. 
     
     
         7 . The method of  claim 1 , wherein both D and B are N and A is CR. 
     
     
         8 . The method of  claim 1 , wherein both A and D are N and B is CR. 
     
     
         9 . The method of  claim 1 , wherein R is selected from hydrogen, halo, C 1 -C 4  alkyl, 0-R 3  and 4- to 8-membered non-aromatic heterocycle. 
     
     
         10 . The method of  claim 1 , wherein R 1  is selected from optionally substituted 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 10 , wherein R 1  is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 11 , wherein R 1  is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 1 , wherein R 2  is selected from optionally substituted 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 13 , wherein R 2  is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 12 , wherein R 2  is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 1 , wherein R 2  is selected from optionally substituted carbocycle and optionally substituted non-aromatic heterocycle. 
     
     
         17 . The method of  claim 1 , wherein R 2  is selected from optionally substituted aromatic carbocycle and optionally substituted non-aromatic heterocycle. 
     
     
         18 . The method of  claim 1 , wherein R 2  is selected from optionally substituted non-aromatic carbocycle and optionally substituted non-aromatic heterocycle. 
     
     
         19 . The method of  claim 16  wherein R 2  is an optionally substituted non-aromatic heterocycle. 
     
     
         20 . The method of  claim 19 , wherein R 2  is attached to the remainder of the compound by a nitrogen atom of R 2 . 
     
     
         21 . The method of  claim 1 , wherein X is C(═O)—NH—†. 
     
     
         22 . The method of  claim 1 , wherein X is NH—C(═O)†. 
     
     
         23 . The method of  claim 1 , wherein the compound is any one of Compound Numbers 14, 94, 97, 98, 99, 100, 105, 119, 143, 159, 164, 165, 224, 225, 226, 230, 233, 301, 308, 318, 342, 344, 355, 370, 379, 424, 474, 479, 537, 577, 581, 586, 601, 638, 661, 665, 668, 684, 703, 761, 801, 806, 811, 812, 870, 880, 890, 918, 924, 925 928, 945, 953, 957, 958, 959, 966, 968, 969, 970, 974, 978, 979, 986, 990, 994, 998, 999, 1000, 1001, 1005, 1007, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1020, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1046, 1047, 1048, 1049, 1050, 1060, 1062, 1063, 1064, 1066, 1069, 1071, 1072, 1073, 1074, 1077, 1080, 1081, 1082, 1083, 1085, 1086, 1087, 1092, 1096 and 1098.