Boronate ester compounds and pharmaceutical compositions thereof

Abstract

The present invention provides novel compounds useful as proteasome inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.

What is claimed is: 
     
         1 . A process for generating a compound of Formula (II) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 A is 0, 1, or 2; 
 P is R c —C(O)—; R c  is R D ; R D  is substituted or unsubstituted mono- or bicyclic ring system selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, naphthyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and dihydrobenzoxazinyl; 
 R a  is hydrogen, C 1-6  aliphatic, C 1-6  fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ; 
 R a1  is hydrogen, C 1-6  aliphatic, C 1-6  fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ; 
 each R a2  independently is hydrogen, C 1-6  aliphatic, C 1-6  fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ; 
 each R B  independently is a substituted or unsubstituted mono- or bicyclic ring system; 
 each R 4  independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4  on the same nitrogen atom, taken together with the nitrogen atom, form a substituted or unsubstituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S; 
 each R 5  independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
 each R 5a  independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
 each R 5b  independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
 each R 6  independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group; 
 Y is hydrogen, —CN, or —NO 2 ; 
 m is 0, 1, or 2;
 each of R b1  and R b2  independently is hydrogen, —CO 2 H, —OH, or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
 each of R b3  and R b4  independently is hydrogen, —CO 2 H, or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
 or R b2  and R b4  are each independently hydrogen, and R b1  and R b3 , taken together with the carbon atoms to which they are attached, form an unsubstituted or substituted fused 4- to 8-membered non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S, wherein said ring may be optionally fused to an unsubstituted or substituted 4- to 8-membered non-aromatic ring, or 5- to 6-membered aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S; 
 or R b2  and R b4  are absent, and R b1  and R b3 , taken together with the carbon atoms to which they are attached, form an unsubstituted or substituted fused 5- to 6-membered aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S, wherein said ring may be optionally fused to an unsubstituted or substituted 4- to 8-membered non-aromatic ring, or 5- to 6-membered aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S; and 
 
 n is 0 or 1; 
 the process comprising:
 (1) coupling a compound of Formula (1) with a compound of Formula (ii) to form a compound of Formula (iii) 
 
 
       
         
           
           
               
               
           
         
         
           wherein X −  is a counter anion; and PG is hydrogen or a protecting group; 
           (2) deprotecting the compound of Formula (iii) to form a compound of Formula (iiia) 
         
       
       
         
           
           
               
               
           
         
         
           (3) coupling the compound of Formula (iiia) with a compound, P-LG, to form a compound of Formula (iv) 
         
       
       
         
           
           
               
               
           
         
         
           wherein LG is a leaving group;
 (4) deprotecting the compound of Formula (iv) to form the compound of Formula (v) 
 
         
       
       
         
           
           
               
               
           
         
       
       and
     (5) reacting the compound of Formula (v) with an alpha hydroxy carboxylic acid or a beta hydroxy carboxylic acid to form a compound of Formula (II).     
 
     
     
         2 . The process of  claim 1 , wherein the reaction of step (1) or step (3) or both is conducted in the presence of a peptide coupling reagent. 
     
     
         3 . The process of  claim 2 , wherein the peptide coupling reagent is selected from the group consisting of a carbodiimide reagent, phosphonium reagent, and uronium reagent. 
     
     
         4 . The process of  claim 3 , wherein the peptide coupling reagent is selected from one or more of the group consisting of dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU). 
     
     
         5 . The process of  claim 1 , further comprising converting the carboxylic acid moiety of compound (ii) to an activated ester or acid halide prior to the reaction of step (1). 
     
     
         6 . The process of  claim 5 , wherein said activated ester or acid halide is an O—(N-hydroxysuccinnimide) ester. 
     
     
         7 . The process of  claim 1 , wherein the reaction of step (3) is conducted in the presence of a solvent. 
     
     
         8 . The process of  claim 7 , wherein the solvent is tetrahydrofuran. 
     
     
         9 . The process of  claim 1 , wherein the reaction of step (4) is conducted in the presence of an aqueous mineral acid. 
     
     
         10 . The process of  claim 9 , wherein the mineral acid is hydrochloric acid. 
     
     
         11 . The process of  claim 1 , wherein the reaction of step (4) is conducted in the presence of an organic boronic acid acceptor. 
     
     
         12 . The process of  claim 11 , wherein the organic boronic acid acceptor is i-BuB(OH) 2 . 
     
     
         13 . The process of  claim 1 , wherein the reaction of step (5) is conducted in the presence of a solvent selected from the group consisting of ethyl acetate, methyl isobutyl ketone, acetone, acetonitrile, 2-methyltetrahydrofuran, anisole, isopropyl acetate, dimethoxyethane, tetrahydrofuran, dioxane, dichloromethane, toluene, heptane, methyl-cyclohexane, tert-butylmethyl ether, and any combination thereof 
     
     
         14 . The process of  claim 1 , wherein the reaction of step (5) is conducted in the presence of a catalyst, wherein the catalyst is an organic amine base. 
     
     
         15 . The process of  claim 14 , wherein the catalyst is selected from the group consisting of triethylamine, triethylenediamine, pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine, di-tertbutylpyridine, N-methylmorpholine, N-methylpiperidine, tetramethylguanidine, diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicycle[4.3.0]non-5-ene, N ,N′diisopropylethylamine, or any combination thereof. 
     
     
         16 . The process of  claim 1 , wherein step (5) further comprises cooling the solution. 
     
     
         17 . The process of  claim 16 , wherein the cooling comprises cooling the solution uncontrolled until the internal temperature is about 25° C. 
     
     
         18 . The process of  claim 1 , wherein the reaction of step (5) is conducted in the presence of a co-solvent. 
     
     
         19 . The process of  claim 18 , wherein the co-solvent is selected from the group consisting of heptane, methylcyclohexane, toluene, tert-butylmethyl ether, ethyl acetate, or any combination thereof. 
     
     
         20 . The process of  claim 1 , further comprising
 (6) isolating the compound of Formula (II) as a crystalline solid.   
     
     
         21 . The process of  claim 1 , wherein PG is a protecting group selected from the group consisting of an acyl protecting group and a urethane protecting group. 
     
     
         22 . The process of  claim 21 , wherein PG is a protecting group selected from the group consisting of formyl, acetyl, succinyl, methoxysuccinyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and fluorenylmethoxycarbonyl (Fmoc). 
     
     
         23 . The process of  claim 1 , wherein LG is —Cl. 
     
     
         24 . The process of  claim 1 , wherein X −  is CF 3 CO 2   − . 
     
     
         25 . The process of  claim 1 , wherein R D  is 2,5-dichlorophenyl. 
     
     
         26 . The process of  claim 1 , wherein
 A is 0;   R a  is C 1-6  aliphatic;   R a1  is hydrogen, C 1-6  aliphatic, —(CH 2 ) m —CH 2 —R B , or —(CH 2 ) m —CH(R 5a )—OR 5b ;   each of R b1  and R b2  independently is hydrogen, —CO 2 H, —OH, or a substituted or unsubstituted aliphatic;   each of R b3  and R b4  independently is hydrogen, C 1-6  aliphatic, or —(CH 2 ) p CO 2 H; and   p is 0 or 1.   
     
     
         27 . The process of  claim 1 , wherein
 A is 0;   R D  is 2,5-dichlorophenyl;   R a  is isobutyl;   R a1  is hydrogen;   each R b1  and R b2  independently is hydrogen;   each R b3  and R b4  independently is —(CH 2 ) p —CO 2 H; p is 0 or 1; and n is 0 or 1.   
     
     
         28 . The process of  claim 1 , wherein the alpha hydroxy carboxylic acid or a beta hydroxy carboxylic acid is citric acid. 
     
     
         29 . The process of  claim 1 , wherein the compound of Formula (II) is 4-(R,S)-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid. 
     
     
         30 . The process of  claim 1 , wherein the compound of Formula (II) is 2,2′-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid. 
     
     
         31 . A process for generating a compound of Formula (II) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         A is 0, 1, or 2; 
         P is R c —C(O)—; R c  is R D ; R D  is substituted or unsubstituted mono- or bicyclic ring system selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, naphthyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and dihydrobenzoxazinyl; 
         R a  is hydrogen, C 1-6  aliphatic, C 1-6  fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ; 
         R a1  is hydrogen, C 1-6  aliphatic, C 1-6  fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ; 
         each R a2  independently is hydrogen, C 1-6  aliphatic, C 1-6  fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ; 
         each R B  independently is a substituted or unsubstituted mono- or bicyclic ring system; 
         each R 4  independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4  on the same nitrogen atom, taken together with the nitrogen atom, form a substituted or unsubstituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S; 
         each R 5  independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
         each R 5a  independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
         each R 5b  independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
         each R 6  independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group; 
         Y is hydrogen, —CN, or —NO 2 ; 
         m is 0, 1, or 2;
 each of R b1  and R b2  independently is hydrogen, —CO 2 H, —OH, or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
 each of R b3  and R b4  independently is hydrogen, —CO 2 H, or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
 or R b2  and R b4  are each independently hydrogen, and R b1  and R b3 , taken together with the carbon atoms to which they are attached, form an unsubstituted or substituted fused 4- to 8-membered non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S, wherein said ring may be optionally fused to an unsubstituted or substituted 4- to 8-membered non-aromatic ring, or 5- to 6-membered aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S; 
 or R b2  and R b4  are absent, and R b1  and R b3 , taken together with the carbon atoms to which they are attached, form an unsubstituted or substituted fused 5- to 6-membered aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S, wherein said ring may be optionally fused to an unsubstituted or substituted 4- to 8-membered non-aromatic ring, or 5- to 6-membered aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S; and 
 
       
       n is 0 or 1; 
       the process comprising:
 (1a) coupling a compound of Formula (vi) with a compound, P-LG, to form a compound of Formula (vii) 
 
       
         
           
           
               
               
           
         
         
           wherein PG is hydrogen or a protecting group; and LG is a leaving group; 
           (2a) deprotecting the compound of Formula (vii) to form a compound of Formula (viia) 
         
       
       
         
           
           
               
               
           
         
         
           (3a) coupling the compound of Formula (viia) with a compound of Formula (i) to form a compound of Formula (iv) 
         
       
       
         
           
           
               
               
           
         
         
           wherein X −  is a counter anion; 
           (4) deprotecting the compound of Formula (iv) to form a compound of Formula (v) 
         
       
       
         
           
           
               
               
           
         
       
       and
   (5) reacting the compound of Formula (v) with an alpha hydroxy carboxylic acid or a beta hydroxy carboxylic acid to form a compound of Formula (II).