Inhibitors of histone lysine specific demethylase (lsd1) and histone deacetylases (hdacs)

Abstract

A series of phenelzine analogs comprising a phenelzine scaffold linked to an aromatic moiety and their use as inhibitors of lysine-specific demethylase 1 (LSD1) and/or one or more histone deacetylases (HDACs) is provided. The presently disclosed phenelzine analogs exhibit potency and selectivity for LSD1 versus MAO and LSD2 enzymes and exhibit bulk, as well as, gene specific histone methylation changes, anti-proliferative activity in several cancer cell lines, and neuroprotection in response to oxidative stress. Accordingly, the presently disclosed phenelzine analogs can be used to treat diseases, conditions, or disorders related to LSD1 and/or HDACs, including, but not limited to, cancers and neurodegenerative diseases.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 t is an integer selected from the group consisting of 0, 1, 2, 3, and 4; 
 L is a linking group selected from the group consisting of —X 1 —, —[X 1 —C(═O)—NR 1 ] d —, —[X 1 —NR 1 —C(═O)] d —, —[C(═O)—NR 1 —X 1 ] d —, —[NR 1 —C(═O)—X 1 ] d —, —[NR 1 —C(═O)—NR 1 —X 1 ] d —, —[X 1 —NR 1 —C(═O)—NR 1 ] d —, —[X 1 —O—C(═O)—NR 1 ] d —, —[O—C(═O)—NR 1 —X 1 ] d —, —[X 1 —NR 1 —C(═O)—O] d —, —[NR 1 —C(═O)—O—X 1 ] d —, —X 1 —O—, —X 1 —NR 1 , —X—S—, —X 1 —SO—, —X 1 —SO 2 —, —X 1 —O—X 1 —, —X 1 — NR 1 —X 1 —, —X 1 — S—X 1 —, —X 1 —SO—X 1 —, and —X 1 — SO 2 —X 1 —, wherein d is an integer selected from the group consisting of 1, 2, 3, and 4; 
 wherein X 1  is selected from the group consisting of —(CH 2 ) n —, —[(CH 2 ) n —CH═CH—(CH 2 ) m ] e —, —[(CH 2 ) n C≡C—(CH 2 ) m ] e —, and —(CH 2 ) m —O—, wherein n and m are each independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, e is an integer selected from the group consisting of 1, 2, 3 and 4, wherein the —(CH 2 ) n —, —(CH 2 ) m —, and —CH═CH— groups can optionally be substituted with a substituent selected from the group consisting of substituted or unsubstituted linear or branched alkyl, hydroxyl, alkoxyl, amino, cyano, halogen, and oxo, and wherein one or more carbon atoms of —(CH 2 ) n — and —(CH 2 ) m — can optionally be replaced with one or more heteroatoms selected from the group consisting of O, S, and NR′ 1 , wherein each —(CH 2 ) n — or —(CH 2 ) m — group can contain a cycloalkyl or cycloheteroalkyl unit; 
 R 1  and R′ 1  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted linear or branched alkyl, alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl, and R 1  can form a ring system with ring B via a substituted or unsubstituted alkylene or heteroalkylene chain; 
 R 2  is —(CH 2 ) p —NR 3 —NR 4 R 5  or —(CH 2 ) p —X 2 ; wherein p is an integer selected from the group consisting of 0, 1, 2, 3, and 4, and wherein the —(CH 2 ) p — group can be saturated or unsaturated or contain a cycloalkyl unit and optionally be substituted with a substituent selected from the group consisting of substituted or unsubstituted linear or branched alkyl, hydroxyl, alkoxyl, amino, cyano, halogen, and oxo, and one or more carbon atoms of —(CH 2 ) p — can optionally be replaced with one or more heteroatoms selected from the group consisting of O, S, and NR′ 1 ; 
 each R′ 2  is independently selected at each occurrence from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, allyl, hydroxyl, alkoxyl, amino, cyano, carboxyl, halogen, nitro, oxo, —CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; 
 R 3  R 4 , and R 5  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted linear or branched alkyl, alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl, and —C(═O)—O—R 21 , or R 4  and R 5  together can form a substituted or unsubstituted 4- to 6-membered cycloalkyl, and wherein R 24  is substituted or unsubstituted linear or branched alkyl; 
 X 2  is selected from the group consisting of hydroxyl, halogen, and —O—Si(R 21 R 22 ) 2 —R 23 , wherein R 21 , R 22 , and R 23  are each independently substituted or unsubstituted linear or branched alkyl; 
 A is selected from the group consisting of mono- or multicyclic substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl; 
 B is selected from the group consisting of aryl or heteroaryl; 
 wherein one or more carbon atoms of ring B can be replaced with one or more heteroatoms selected from the group consisting of N, O, and S; 
 wherein one or both of ring structures A and B can be optionally substituted with one or more reactive groups capable of forming a prodrug; 
 and pharmaceutically acceptable salts, hydrates, and solvates thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein the compound of Formula (I) has the following structure: 
       
         
           
           
               
               
           
         
         wherein n′ is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. 
       
     
     
         3 . The compound of  claim 2 , wherein the compound of Formula (Ia) has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein q is an integer selected from the group consisting of 0, 1, 2, 3, 4, and 5; s is an integer selected from the group consisting of 0, 1, 2, 3, and 4; 
         R 6 , R 7 , and R 8  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkoxyl, hydroxyl, halogen, nitro, cyano, oxo, amino, —CF 3 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl, —C(═O)—R 10 , and —O—SO 2 —R 11 ; 
         wherein R 10  and R 11  are each independently selected from the group consisting of substituted or unsubstituted linear or branched alkyl, alkoxyl, —CF 3 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl; and 
         R 9  is selected from the group consisting of hydrogen, substituted or unsubstituted linear or branched alkyl, alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl. 
       
     
     
         5 . The compound of  claim 3 , wherein the compound of Formula (Ia′) has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 t is an integer selected from the group consisting of 0, 1, 2, 3, and 4; 
 f is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; 
 A is selected from the group consisting of mono- or multicyclic substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl; 
 B is selected from the group consisting of aryl or heteroaryl; 
 L is a linking group selected from the group consisting of —X 1 —, —[X 1 —C(═O)—NR 1 ] d —, —[X 1 —NR 1 —C(═O)] d —, —[C(═O)—NR 1 —X 1 ] d —, —[NR 1 —C(═O)—X 1 ] d —, —[NR 1 —C(═O)—NR 1 —X 1 ] d —, —[X 1 —NR 1 —C(═O)—NR 1 ] d —, —[X 1 —O—C(═O)—NR 1 ] d —, —[O—C(═O)—NR 1 —X 1 ] d —, —[X 1 —NR 1 —C(═O)—O] d —, —[NR 1 —C(═O)—O—X 1 ] d —, —X 1 —O—, —X 1 —NR 1 , —X—S—, —X 1 —SO—, —X 1 —SO 2 —, —X 1 —O—X 1 —, —X 1 — NR 1 —X 1 —, —X 1 — S—X 1 —, —X 1 —SO—X 1 —, and —X 1 — SO 2 —X 1 —, wherein d is an integer selected from the group consisting of 1, 2, 3, and 4; 
 wherein X 1  is selected from the group consisting of —(CH 2 ) n —, —[(CH 2 ) n —CH═CH—(CH 2 ) m ] e —, —[(CH 2 ) n C≡C—(CH 2 ) m ] e —, and —(CH 2 ) m —O—, wherein n and m are each independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, e is an integer selected from the group consisting of 1, 2, 3 and 4, wherein the —(CH 2 ) n —, —(CH 2 ) m —, and —CH═CH— groups can optionally be substituted with a substituent selected from the group consisting of substituted or unsubstituted linear or branched alkyl, hydroxyl, alkoxyl, amino, cyano, halogen, and oxo, and wherein one or more carbon atoms of —(CH 2 ) n — and —(CH 2 ) m — can optionally be replaced with one or more heteroatoms selected from the group consisting of O, S, and NR′ 1 , wherein each —(CH 2 ) n — or —(CH 2 ) m — group can contain a cycloalkyl or cycloheteroalkyl unit; 
 L 2  is selected from the group consisting of aryl, heteroaryl, —(CH 2 ) n —, —(CH 2 ) n —CH═CH—(CH 2 ) m —, —(CH 2 ) n —C≡C—(CH 2 ) m —, —(CH 2 ) m —O—, wherein n and m are each independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6, wherein the —(CH 2 ) n —, (CH 2 ) m —, and —CH═CH— groups can optionally be substituted with a substituent selected from the group consisting of substituted or unsubstituted linear or branched alkyl, hydroxyl, alkoxyl, amino, cyano, halogen, and oxo, and wherein one or more carbon atoms of —(CH 2 ) n — and —(CH 2 ) m — can optionally be replaced with one or more heteroatoms selected from the group consisting of O, S, and NR′ 1 ; 
 R 1  and R′ 1  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted linear or branched alkyl, alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl, and R 1  can form a ring system with ring B via a substituted or unsubstituted alkylene or heteroalkylene chain; 
 R 2  is —(CH 2 ) p —NR 3 —NR 4 R 5  or —(CH 2 ) p —X 2 ; wherein p is an integer selected from the group consisting of 0, 1, 2, 3, and 4, and wherein the —(CH 2 ) p — group can be saturated or unsaturated or contain a cycloalkyl unit and optionally be substituted with a substituent selected from the group consisting of substituted or unsubstituted linear or branched alkyl, hydroxyl, alkoxyl, amino, cyano, halogen, and oxo, and one or more carbon atoms of —(CH 2 ) p — can optionally be replaced with one or more heteroatoms selected from the group consisting of O, S, and NR′ 1 ; 
 each R′ 2  is independently selected at each occurrence from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, allyl, hydroxyl, alkoxyl, amino, cyano, carboxyl, halogen, nitro, oxo, —CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; 
 R 3  R4, and R 5  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted linear or branched alkyl, alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl, and —C(═O)—O—R 21 , or R 4  and R 5  together can form a substituted or unsubstituted 4- to 6-membered cycloalkyl, and wherein R 24  is substituted or unsubstituted linear or branched alkyl; 
 X 2  is selected from the group consisting of hydroxyl, halogen, and —O—Si(R 21 R 22 ) 2 —R 23 , wherein R 21 , R 22 , and R 23  are each independently substituted or unsubstituted linear or branched alkyl; 
 Y is selected from the group consisting of null, —N(R 10 )C(═O)—, —C(═O)N(R 10 )—, —N(R 10 )C(═S)—, —C(═S)N(R 10 )—, —SO 2 —, —N(R 10 )SO 2 —, —N(R 10 )SO 2 N(R 10 )—, —SO 2 N(R 10 )—, and —CH═CH—; 
 Z is selected from the group consisting of: 
 —C(═O)N(R 10 )OH, —C(═O)OR 16 , N(R 10 )OH, —N(R 10 )C(═O)C(R 11 ) n S(R 12 ), —B(OR 13 ) m , —SR 14 , 
 
       
         
           
           
               
               
           
         
         wherein R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted linear or branched alkyl, alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl; 
         R 16 , R 17 , R 18 , and R 19  are each independently substituted or unsubstituted linear or branched alkyl; 
         and n and m are integers each independently selected from the group consisting of 0, 1, and 2; and pharmaceutically acceptable salts, hydrates, and solvates thereof. 
       
     
     
         8 . The compound of  claim 7 , wherein the compound of Formula (II) has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 7 , wherein the compound of Formula (II) has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 9 , wherein the compound of Formula (IIb) has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 8 , wherein the compound of Formula (IIa) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 10 , wherein: 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         13 . A pharmaceutical composition comprising a compound of Formula (I) or Formula (II). 
     
     
         14 . The pharmaceutical composition of  claim 13 , further comprising one or more additional therapeutic agents. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the one or more additional therapeutic agents is selected from the group consisting of a histone deacetylase (HDAC) inhibitor, a DNA methyltransferase (DNMT) inhibitor, and combinations thereof. 
     
     
         16 . A method for inhibiting lysine-specific demethylase 1 (LSD1) and/or one or more histone deacetylases (HDACs), the method comprising administering to a subject a compound of Formula (Ia) or a compound of Formula (II), or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit LSD1 or one or more HDACs. 
     
     
         17 . A method for treating a disease, disorder, or condition associated with lysine-specific demethylase 1 (LSD1) and/or one or more histone deacetylases (HDACs), the method comprising administering to a subject in need of treatment thereof subject a compound of Formula (Ia) or Formula (II), or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit LSD1 and/or one or more histone deacetylases (HDACs). 
     
     
         18 . The method of  claim 17 , wherein the disease, disorder, or condition associated with LSD1 and/or one or more histone deacetylases (HDACs) is a cancer. 
     
     
         19 . The method of  claim 17 , wherein the treating of the disease, disorder, or condition associated with LSD1 and/or one or more histone deacetylases (HDACs) includes activating one or more tumor suppressors silenced in cancer by an epigenetic mechanism. 
     
     
         20 . The method of  claim 17 , wherein the treating of the cancer includes modulating bulk histone methylation in one or more cancer cells. 
     
     
         21 . The method of  claim 17 , wherein the treating of the cancer results in a reduction in proliferation rate of one or more cancer cells. 
     
     
         22 . The method of  claim 17 , wherein the disease, disorder, or condition associated with LSD1 and/or one or more histone deacetylases (HDACs) is a neurodegenerative disease. 
     
     
         23 . The method of  claim 22 , wherein the treating of the neurodegenerative disease includes protection of neurons against oxidative stress-mediated cell death. 
     
     
         24 . The method of  claim 17 , wherein the compound of Formula (Ia) or Formula (II) is administered in combination with one or more additional therapeutic agents. 
     
     
         25 . The method of  claim 24 , wherein the administration of the combination of a compound of Formula (Ia) or Formula (II) with one or more additional therapeutic agents has an additive or synergistic effect on cancer cell growth. 
     
     
         26 . The method of  claim 25 , wherein the one or more additional therapeutic agents is selected from the group consisting of a histone deacetylase (HDAC), a DNA methyltransferase (DNMT) inhibitor, and combinations thereof. 
     
     
         27 . The method of  claim 26 , wherein the one or more additional therapeutic agents is selected from the group consisting of azacytidine, SAHA, TSA, MGCD0103, MS-275, and LBH-589. 
     
     
         28 . The method of  claim 17 , wherein the compound of Formula (Ia) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         29 . The method of  claim 17 , wherein the compound of Formula (II) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         30 . The method of  claim 17 , wherein for the compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of: