Fatty acid fumarate derivatives and their uses

Abstract

The invention relates to Fatty Acid Fumarate Derivatives; compositions comprising an effective amount of a Fatty Acid Fumarate Derivative; and methods for treating or preventing cancer, a metabolic disorder or neurodegenerative disorder comprising the administration of an effective amount of a Fatty Acid Fumarate Derivative.

1 . A molecular conjugate comprising a fumarate and a fatty acid selected from lipoic acid, omega-3 fatty acids or fatty acids metabolized in vivo into omega-3 fatty acids. 
     
     
         2 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer, or stereoisomer thereof;
 wherein 
 each W 1  and W 2  is independently null, O, S, NH, or NR, or W 1  and W 2  can be taken together to form an optionally substituted imidazolidine or piperazine group; 
 each a, b, c, and d, is independently —H, -D, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —C(O)OR, —O—Z, or benzyl, or two of a, b, c, and d can be taken together, along with the single carbon to which they are bound, to form a cycloalkyl or heterocycle; 
 each n, o, p, and q is independently 0, 1, or 2; 
 each L is independently null, —O—, —C(O)—, —S—, —S(O)—, —S(O) 2 —, —S—S—, —(C 1 -C 6 alkyl)-, —(C 3 -C 6 cycloalkyl)-, a heterocycle, a heteroaryl, 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the representation of L is not limited directionally left to right as is depicted, rather either the left side or the right side of L can be bound to the W 1  side of the compound of Formula I; 
         each R 6  is independently —H, -D, —C 1 -C 4  alkyl, -halogen, cyano, oxo, thiooxo, —OH, —C(O)C 1 -C 4  alkyl, —O-aryl, —O-benzyl, —OC(O)C 1 -C 4  alkyl, —C 1 -C 3  alkene, —C 1 -C 3  alkyne, —C(O)C 1 -C 4  alkyl, —NH 2 , —NH(C 1 -C 3  alkyl), —N(C 1 -C 3  alkyl) 2 , —NH(C(O)C 1 -C 3  alkyl), —N(C(O)C 1 -C 3  alkyl) 2 , —SH, —S(C 1 -C 3  alkyl), —S(O)C 1 -C 3  alkyl, —S(O) 2 C 1 -C 3  alkyl; 
         each g is independently 2, 3, or 4; 
         each h is independently 1, 2, 3, or 4; 
         each m is independently 0, 1, 2, or 3; if m is more than 1, then L can be the same or different; 
         each m1 is independently 0, 1, 2, or 3; 
         k is 0, 1, 2, or 3; 
         z is 1, 2, or 3; 
         each R 4  is independently H or optionally substituted C 1 -C 6  alkyl, wherein a methylene unit of the C 1 -C 6  alkyl can be optionally substituted for either O or NR, and in NR 4 R 4 , both R 4  when taken together with the nitrogen to which they are attached can form a heterocyclic ring such as a pyrrolidine, piperidine, morpholine, piperazine or pyrrole; 
         each Z is independently H, 
       
       
         
           
           
               
               
           
         
         provided that 
         there is at least one 
       
       
         
           
           
               
               
           
         
         in the compound; 
         each t is independently 0 or 1; 
         each r is independently 2, 3, or 7; 
         each s is independently 3, 5, or 6; 
         each v is independently 1, 2, or 6; 
         each R 1  and R 2  is independently —H, -D, —C 1 -C 4  alkyl, -halogen, —OH, —C(O)C 1 -C 4  alkyl, —O-aryl, —O-benzyl, —OC(O)C 1 -C 4  alkyl, —C 1 -C 3  alkene, —C 1 -C 3  alkyne, —C(O)C 1 -C 4  alkyl, —NH 2 , —NH(C 1 -C 3  alkyl), —N(C 1 -C 3  alkyl) 2 , —NH(C(O)C 1 -C 3  alkyl), —N(C(O)C 1 -C 3  alkyl) 2 , —SH, —S(C 1 -C 3  alkyl), —S(O)C 1 -C 3  alkyl, —S(O) 2 C 1 -C 3  alkyl; 
         each R 3  is independently H, —C 1 -C 6  alkyl or —C(CH 2 OH) 2 ; 
         each R 5  is independently e, H or straight or branched C 1 -C 10  alkyl which can be optionally substituted with OH, NH 2 , CO 2 R, CONH 2 , phenyl, C 6 H 4 OH, imidazole or arginine; 
         each e is independently H or any one of the side chains of the naturally occurring amino acids; 
         each R is independently —H, —C 1 -C 3  alkyl, or straight or branched C 1 -C 4  alkyl optionally substituted with OH, or halogen; 
         provided that 
         when each of m, n, o, p, and q is 0, W 1  and W 2  are each null, and Z is 
       
       
         
           
           
               
               
           
         
       
       then t must be 0;
 when each of m, n, o, p, and q is 0, and W 1  and W 2  are each null, then Z must not be 
 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound of  claim 2 , wherein the compound is of Formula IA: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer, or stereoisomer thereof;
 wherein 
 each W 1  and W 2  is independently null, O, S, NH, or NR, or W 1  and W 2 , can be taken together to form an optionally substituted imidazolidine or piperazine group; 
 each a, b, c, and d is independently —H, -D, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —C(O)OR, or benzyl, or two of a, b, c, and d can be taken together, along with the single carbon to which they are bound, to form a cycloalkyl or heterocycle; 
 each n, o, p, and q is independently 0, 1 or 2; 
 each L is independently null, —O—, —C(O)—, —S—, —S(O)—, —S(O) 2 —, —S—S—, —(C 1 -C 6 alkyl)-, —(C 3 -C 6 cycloalkyl)-, a heterocycle, a heteroaryl, 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the representation of L is not limited directionally left to right as is depicted, rather either the left side or the right side of L can be bound to the W 1  side of the compound of Formula IA; 
         each R 6  is independently —H, -D, —C 1 -C 4  alkyl, -halogen, cyano, oxo, thiooxo, —OH, —C(O)C 1 -C 4  alkyl, —O-aryl, —O-benzyl, —OC(O)C 1 -C 4  alkyl, —C 1 -C 3  alkene, —C 1 -C 3  alkyne, —C(O)C 1 -C 4  alkyl, —NH 2 , —NH(C 1 -C 3  alkyl), —N(C 1 -C 3  alkyl) 2 , —NH(C(O)C 1 -C 3  alkyl), —N(C(O)C 1 -C 3  alkyl) 2 , —SH, —S(C 1 -C 3  alkyl), —S(O)C 1 -C 3  alkyl, —S(O) 2 C 1 -C 3  alkyl; 
         each g is independently 2, 3 or 4; 
         each h is independently 1, 2, 3 or 4; 
         each m is independently 0, 1, 2, or 3; if m is more than 1, then L can be the same or different; 
         each m1 is independently 0, 1, 2 or 3; 
         k is 0, 1, 2, or 3; 
         z is 1, 2, or 3; 
         each R 4  is independently H or optionally substituted C 1 -C 6  alkyl, wherein a methylene unit of the C 1 -C 6  alkyl can be optionally substituted for either O or NR, and in NR 4 R 4 , both R 4  when taken together with the nitrogen to which they are attached can form a heterocyclic ring such as a pyrrolidine, piperidine, morpholine, piperazine or pyrrole; 
         each R 3  is independently H, —C 1 -C 6  alkyl or —C(CH 2 OH) 2 ; 
         each R 5  is independently e, H or straight or branched C 1 -C 10  alkyl which can be optionally substituted with OH, NH 2 , CO 2 R, CONH 2 , phenyl, C 6 H 4 OH, imidazole or arginine; 
         each e is independently H or any one of the side chains of the naturally occurring amino acids; 
         each R is independently —H, or straight or branched C 1 -C 4  alkyl optionally substituted with OH, or halogen. 
       
     
     
         4 . The compound of  claim 2 , wherein W 1  and W 2  are each NH. 
     
     
         5 . The compound of  claim 2 , wherein each of n, o, p, and q is 1. 
     
     
         6 . The compound of  claim 2 , wherein two of n, o, p, and q are each 1. 
     
     
         7 . The compound of  claim 2 , wherein two of n, o, p, and q each 1 and the other two are each 0. 
     
     
         8 . The compound of  claim 2 , wherein m is 1. 
     
     
         9 . The compound of  claim 2 , wherein L is selected from —O—, —N(R 4 )—, 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound of  claim 2 , wherein the compound is of Formula IB: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer, or stereoisomer thereof;
 wherein 
 each W 1  and W 2  is independently null, O, S, NH, or NR, or W 1  and W 2 , can be taken together to form an optionally substituted imidazolidine or piperazine group; 
 each a, b, c, and d is independently —H, -D, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —C(O)OR, or benzyl, or two of a, b, c, and d can be taken together, along with the single carbon to which they are bound, to form a cycloalkyl or heterocycle; 
 each n, o, p, and q is independently 0, 1, or 2; 
 each L is independently null, —O—, —C(O)—, —S—, —S(O)—, —S(O) 2 —, —S—S—, —(C 1 -C 6 alkyl)-, —(C 3 -C 6 cycloalkyl)-, a heterocycle, a heteroaryl, 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the representation of L is not limited directionally left to right as is depicted, rather either the left side or the right side of L can be bound to the W 1  side of the compound of Formula IB; 
         each R 6  is independently —H, -D, —C 1 -C 4  alkyl, -halogen, cyano, oxo, thiooxo, —OH, —C(O)C 1 -C 4  alkyl, —O-aryl, —O-benzyl, —OC(O)C 1 -C 4  alkyl, —C 1 -C 3  alkene, —C 1 -C 3  alkyne, —C(O)C 1 -C 4  alkyl, —NH 2 , —NH(C 1 -C 3  alkyl), —N(C 1 -C 3  alkyl) 2 , —NH(C(O)C 1 -C 3  alkyl), —N(C(O)C 1 -C 3  alkyl) 2 , —SH, —S(C 1 -C 3  alkyl), —S(O)C 1 -C 3  alkyl, —S(O) 2 C 1 -C 3  alkyl; 
         each g is independently 2, 3 or 4; 
         each h is independently 1, 2, 3 or 4; 
         each m is independently 0, 1, 2, or 3; if m is more than 1, then L can be the same or different; 
         each m1 is independently 0, 1, 2 or 3; 
         k is 0, 1, 2, or 3; 
         z is 1, 2, or 3; 
         each R 4  is independently H or optionally substituted C 1 -C 6  alkyl, wherein a methylene unit of the C 1 -C 6  alkyl can be optionally substituted for either O or NR, and in NR 4 R 4 , both R 4  when taken together with the nitrogen to which they are attached can form a heterocyclic ring such as a pyrrolidine, piperidine, morpholine, piperazine or pyrrole; 
         each R 3  is independently H, —C 1 -C 6  alkyl or —C(CH 2 OH) 2 ; 
         each R 5  is independently e, H or straight or branched C 1 -C 10  alkyl which can be optionally substituted with OH, NH 2 , CO 2 R, CONH 2 , phenyl, C 6 H 4 OH, imidazole or arginine; 
         each e is independently H or any one of the side chains of the naturally occurring amino acids; 
         each R is independently —H, or straight or branched C 1 -C 4  alkyl optionally substituted with OH, or halogen. 
       
     
     
         11 . A compound of  claim 2 , wherein the compound is of Formula IC: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer, or stereoisomer thereof;
 wherein 
 each W 1  and W 2  is independently null, O, S, NH, or NR, or W 1  and W 2 , can be taken together to form an optionally substituted imidazolidine or piperazine group; 
 each a, b, c, and d is independently —H, -D, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —C(O)OR, or benzyl, or two of a, b, c, and d can be taken together, along with the single carbon to which they are bound, to form a cycloalkyl or heterocycle; 
 each n, o, p, and q is independently 0, 1, or 2; 
 each L is independently null, —O—, —C(O)—, —S—, —S(O)—, —S(O) 2 —, —S—S—, —(C 1 -C 6 alkyl)-, —(C 3 -C 6 cycloalkyl)-, a heterocycle, a heteroaryl, 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the representation of L is not limited directionally left to right as is depicted, rather either the left side or the right side of L can be bound to the W 1  side of the compound of Formula IC; 
         each R 6  is independently —H, -D, —C 1 -C 4  alkyl, -halogen, cyano, oxo, thiooxo, —OH, —C(O)C 1 -C 4  alkyl, —O-aryl, —O-benzyl, —OC(O)C 1 -C 4  alkyl, —C 1 -C 3  alkene, —C 1 -C 3  alkyne, —C(O)C 1 -C 4  alkyl, —NH 2 , —NH(C 1 -C 3  alkyl), —N(C 1 -C 3  alkyl) 2 , —NH(C(O)C 1 -C 3  alkyl), —N(C(O)C 1 -C 3  alkyl) 2 , —SH, —S(C 1 -C 3  alkyl), —S(O)C 1 -C 3  alkyl, —S(O) 2 C 1 -C 3  alkyl; 
         each g is independently 2, 3 or 4; 
         each h is independently 1, 2, 3 or 4; 
         each m is independently 0, 1, 2, or 3; if m is more than 1, then L can be the same or different; 
         each m1 is independently 0, 1, 2 or 3; 
         k is 0, 1, 2, or 3; 
         z is 1, 2, or 3; 
         each R 4  is independently H or optionally substituted C 1 -C 6  alkyl, wherein a methylene unit of the C 1 -C 6  alkyl can be optionally substituted for either O or NR, and in NR 4 R 4 , both R 4  when taken together with the nitrogen to which they are attached can form a heterocyclic ring such as a pyrrolidine, piperidine, morpholine, piperazine or pyrrole; 
         each R 3  is independently H, —C 1 -C 6  alkyl or —C(CH 2 OH) 2 ; 
         each R 5  is independently e, H or straight or branched C 1 -C 10  alkyl which can be optionally substituted with OH, NH 2 , CO 2 R, CONH 2 , phenyl, C 6 H 4 OH, imidazole or arginine; 
         each e is independently H or any one of the side chains of the naturally occurring amino acids; 
         each R is independently —H, or straight or branched C 1 -C 4  alkyl optionally substituted with OH, or halogen. 
       
     
     
         12 . A compound of Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer, or stereoisomer thereof;
 wherein 
 each W 1 , W 2 , W 1 ′ and W 2 ′ is independently null, O, S, NH, or NR, or W 1  and W 2 , or W 1 ′ and W 2 ′ can be taken together to form an optionally substituted imidazolidine or piperazine group; 
 each a, b, c, d, a′, b′, c′, and d′ is independently —H, -D, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —C(O)OR, —O—Z, or benzyl, or two of a, b, c, and d or any two of a′, b′, c′, and d′ can be taken together, along with the single carbon to which they are bound, to form a cycloalkyl or heterocycle; 
 each n, o, p, q, n′, o′, p′, and q′ is independently 0, 1, or 2; 
 each L and L′ is independently null, —O—, —C(O)—, —S—, —S(O)—, —S(O) 2 —, —S—S—, —(C 1 -C 6 alkyl)-, —(C 3 -C 6 cycloalkyl)-, a heterocycle, a heteroaryl, 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the representation of L and L′ is not limited directionally left to right as is depicted, rather either the left side or the right side of L and L′ can be bound to the W 1  or W 1 ′ side of the compound of Formula II, respectively; 
         each R 6  is independently —H, -D, —C 1 -C 4  alkyl, -halogen, cyano, oxo, thiooxo, —OH, —C(O)C 1 -C 4  alkyl, —O-aryl, —O-benzyl, —OC(O)C 1 -C 4  alkyl, —C 1 -C 3  alkene, —C 1 -C 3  alkyne, —C(O)C 1 -C 4  alkyl, —NH 2 , —NH(C 1 -C 3  alkyl), —N(C 1 -C 3  alkyl) 2 , —NH(C(O)C 1 -C 3  alkyl), —N(C(O)C 1 -C 3  alkyl) 2 , —SH, —S(C 1 -C 3  alkyl), —S(O)C 1 -C 3  alkyl, —S(O) 2 C 1 -C 3  alkyl; 
         each g is independently 2, 3 or 4; 
         each h is independently 1, 2, 3 or 4; 
         each m and m′ is independently 0, 1, 2, or 3; if m is more than 1, then L or L′ can be the same or different; 
         each m1 is independently 0, 1, 2 or 3; 
         k is 0, 1, 2, or 3; 
         z is 1, 2, or 3; 
         each R 4  is independently H or optionally substituted C 1 -C 6  alkyl, wherein a methylene unit of the C 1 -C 6  alkyl can be optionally substituted for either O or NR, and in NR 4 R 4 , both R 4  when taken together with the nitrogen to which they are attached can form a heterocyclic ring such as a pyrrolidine, piperidine, morpholine, piperazine or pyrrole; 
         each Z and Z′ is independently H, 
       
       
         
           
           
               
               
           
         
         provided that 
         there is at least one 
       
       
         
           
           
               
               
           
         
         in the compound; 
         each t is independently 0 or 1; 
         each r is independently 2, 3, or 7; 
         each s is independently 3, 5, or 6; 
         each v is independently 1, 2, or 6; 
         each R 1  and R 2  is independently —H, -D, —C 1 -C 4  alkyl, -halogen, —OH, —C(O)C 1 -C 4  alkyl, —O-aryl, —O-benzyl, —OC(O)C 1 -C 4  alkyl, —C 1 -C 3  alkene, —C 1 -C 3  alkyne, —C(O)C 1 -C 4  alkyl, —NH 2 , —NH(C 1 -C 3  alkyl), —N(C 1 -C 3  alkyl) 2 , —NH(C(O)C 1 -C 3  alkyl), —N(C(O)C 1 -C 3  alkyl) 2 , —SH, —S(C 1 -C 3  alkyl), —S(O)C 1 -C 3  alkyl, —S(O) 2 C 1 -C 3  alkyl; 
         each R 3  is independently H, —C 1 -C 6  alkyl or —C(CH 2 OH) 2 ; 
         each R 5  is independently e, H or straight or branched C 1 -C 10  alkyl which can be optionally substituted with OH, NH 2 , CO 2 R, CONH 2 , phenyl, C 6 H 4 OH, imidazole or arginine; 
         each e is independently H or any one of the side chains of the naturally occurring amino acids; 
         each R is independently —H, or straight or branched C 1 -C 4  alkyl optionally substituted with OH, or halogen; 
         provided that 
         when each of m, n, o, p, and q is 0, W 1  and W 2  are each null, and Z is 
       
       
         
           
           
               
               
           
         
       
       then t must be 0;
 when each of m′, n′, o′, p′, and q′ is 0, W 1 ′ and W 2 ′ are each null, and Z′ is 
 
       
         
           
           
               
               
           
         
       
       then t must be 0; and
 when each of m, n, o, p, and q is 0, and W 1  and W 2  are each null, or when each of m′, n′, o′, p′, and q′, is 0, W 1 ′ and W 2 ′ are each null, then Z or Z′ must not be 
 
       
         
           
           
               
               
           
         
       
     
     
         13 . A compound of  claim 2 , wherein the compound is selected from the group consisting of:
 (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate (I-1);   (E)-methyl 4-(2-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidoethylamino)-4-oxobut-2-enoate (I-2);   (E)-methyl 4-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethoxy)ethylamino)-4-oxobut-2-enoate (I-3);   (S)-6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-((E)-4-methoxy-4-oxobut-2-enamido)hexanoic acid (I-7);   (S)-6-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-2-((E)-4-methoxy-4-oxobut-2-enamido)hexanoic acid (I-71);   (S)-1,3-dihydroxypropan-2-yl 6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-((E)-4-methoxy-4-oxobut-2-enamido)hexanoate (I-8);   (S)-1,3-dihydroxypropan-2-yl 6-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-2-((E)-4-methoxy-4-oxobut-2-enamido)hexanoate (I-96);   (S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-6-((E)-4-methoxy-4-oxobut-2-enamido)hexanoic acid (I-10);   (S)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-6-((E)-4-methoxy-4-oxobut-2-enamido)hexanoic acid (I-72);   (S)-1,3-dihydroxypropan-2-yl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-6-((E)-4-methoxy-4-oxobut-2-enamido)hexanoate (I-11);   (S)-1,3-dihydroxypropan-2-yl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-6-((E)-4-methoxy-4-oxobut-2-enamido)hexanoate (I-97);   (E)-methyl 4-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)ethylamino)-4-oxobut-2-enoate (I-24);   (E)-methyl 4-(2-(2-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidoethylamino)ethylamino)-4-oxobut-2-enoate (I-73);   (E)-methyl 4-(2-((2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)(methyl)amino)ethylamino)-4-oxobut-2-enoate (I-4);   (E)-methyl 4-(2-((2-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidoethyl)(methyl)amino)ethylamino)-4-oxobut-2-enoate (I-74);   (S)-5-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-((E)-4-methoxy-4-oxobut-2-enamido)pentanoic acid (I-80);   (S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-5-((E)-4-methoxy-4-oxobut-2-enamido)pentanoic acid (I-81);   (S)-1,3-dihydroxypropan-2-yl 5-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-((E)-4-methoxy-4-oxobut-2-enamido)pentanoate (I-82);   (S)-1,3-dihydroxypropan-2-yl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-5-((E)-4-methoxy-4-oxobut-2-enamido)pentanoate (I-83);   (S)-5-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-2-((E)-4-methoxy-4-oxobut-2-enamido)pentanoic acid (I-84);   (S)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-5-((E)-4-methoxy-4-oxobut-2-enamido)pentanoic acid (I-85);   (S)-1,3-dihydroxypropan-2-yl 5-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-2-((E)-4-methoxy-4-oxobut-2-enamido)pentanoate (I-86);   (S)-1,3-dihydroxypropan-2-yl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-5-((E)-4-methoxy-4-oxobut-2-enamido)pentanoate (I-87);   (E)-ethyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate (I-66);   (E)-ethyl 4-(2-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidoethylamino)-4-oxobut-2-enoate (I-75);   (S)-6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-((E)-4-ethoxy-4-oxobut-2-enamido)hexanoic acid (I-69);   (S)-2-((E)-4-ethoxy-4-oxobut-2-enamido)-6-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)hexanoic acid (I-76);   (S)-1,3-dihydroxypropan-2-yl 6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-((E)-4-ethoxy-4-oxobut-2-enamido)hexanoate (I-98);   (S)-1,3-dihydroxypropan-2-yl 2-((E)-4-ethoxy-4-oxobut-2-enamido)-6-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)hexanoate (I-99);   (S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-6-((E)-4-ethoxy-4-oxobut-2-enamido)hexanoic acid (I-70);   (S)-6-((E)-4-ethoxy-4-oxobut-2-enamido)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)hexanoic acid (I-77);   (S)-1,3-dihydroxypropan-2-yl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-6-((E)-4-ethoxy-4-oxobut-2-enamido)hexanoate (I-100);   (S)-1,3-dihydroxypropan-2-yl 6-((E)-4-ethoxy-4-oxobut-2-enamido)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)hexanoate (I-101);   (E)-ethyl 4-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)ethylamino)-4-oxobut-2-enoate (I-68);   (E)-ethyl 4-(2-(2-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidoethylamino)ethylamino)-4-oxobut-2-enoate (I-79);   (E)-ethyl 4-(2-((2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)(methyl)amino)ethylamino)-4-oxobut-2-enoate (I-67);   (E)-ethyl 4-(2-((2-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidoethyl)(methyl)amino)ethylamino)-4-oxobut-2-enoate (I-78);   (S)-5-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-((E)-4-ethoxy-4-oxobut-2-enamido)pentanoic acid (I-88);   (S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-5-((E)-4-ethoxy-4-oxobut-2-enamido)pentanoic acid (I-89);   (S)-1,3-dihydroxypropan-2-yl 5-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-((E)-4-ethoxy-4-oxobut-2-enamido)pentanoate (I-90);   (S)-1,3-dihydroxypropan-2-yl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-5-((E)-4-ethoxy-4-oxobut-2-enamido)pentanoate (I-91);   (S)-2-((E)-4-ethoxy-4-oxobut-2-enamido)-5-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)pentanoic acid (I-92);   (S)-5-((E)-4-ethoxy-4-oxobut-2-enamido)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)pentanoic acid (I-93);   (S)-1,3-dihydroxypropan-2-yl 2-((E)-4-ethoxy-4-oxobut-2-enamido)-5-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)pentanoate (I-94); and   (S)-1,3-dihydroxypropan-2-yl 5-((E)-4-ethoxy-4-oxobut-2-enamido)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)pentanoate (I-95).   
     
     
         14 . A pharmaceutical composition comprising a compound of Formula I, IA, IB, IC, or II and a pharmaceutically acceptable carrier. 
     
     
         15 . A method of treating inflammation or an inflammatory disease, comprising administering to a patient in need thereof, an effective amount of a compound of Formula I, IA, IB, IC, or II. 
     
     
         16 . The method of  claim 15 , wherein the inflammatory disease is associated with a metabolic disorder. 
     
     
         17 . The method of  claim 16 , wherein the metabolic disorder is Type II diabetes, insulin resistance cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hypertriglyceridemia, dyslipidemia, retinopathy, neuropathy, macular edema, diabetic nephropathy, IgA nephropathy, chronic kidney disease (CKD), inflammatory diseases of the kidney including uremic complications, glomerulonephritis and nephrosis. 
     
     
         18 . The method of  claim 15 , wherein the inflammatory disease is cystic fibrosis, asthma, sclerodermatitis, psoriasis or eczema. 
     
     
         19 . A method of treating neurodegenerative disease, comprising administering to a patient in need thereof, an effective amount of a compound of Formula I, IA, IB, IC, or II. 
     
     
         20 . The method of  claim 19 , wherein the neurodegenerative disease is multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease or muscular dystrophy.