Fluorinated epoxyketone-based compounds and uses thereof as proteasome inhibitors

Abstract

The present application relates to novel fluorinated epoxyketone-based compounds, compositions comprising these compounds and their use, in particular for the treatment of diseases, disorders or conditions mediated by proteasome inhibition. In particular, the present application includes compounds of Formula I, and compositions and uses thereof:

1 . A compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 haloalkyl, C 1-10 cyanoalkyl, C 1-10 alkoxy, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 3-10 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-O—C 1-6 haloalkyl, C 2-6 alkenylene-O—C 1-6 haloalkyl, C 2-6 alkynylene-O—C 1-6 haloalkyl, C 1-6 alkylene-C 3-8 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-aryl, C 1-6 alkylene-heteroaryl, C(O)R 7 , OC(O)R 7 , C(O)OR 7 , C 1-6 alkylene-O—R 7 , C 1-6 alkylene-C(O)R 7 , C 1-6 alkylene-O—C(O)R 7 , C 1-6 alkylene-C(O)OR 7 , C 1-6 alkylene-O—C(O)OR 7 , C 1-6 alkylene-NR 7 R 8 , C 1-6 alkylene-C(O)NR 7 R 8 , C 1-6 alkylene-NR 7 C(O)R 8 , C 1-6 alkylene-NR 7 C(O)NR 7 R 8 , C 1-6 alkylene-S—R 7 , C 1-6 alkylene-S(O)R 7 , C 1-6 alkylene-SO 2 R 7 , C 1-6 alkylene-SO 2 NR 7 R 8 , C 1-6 alkylene-NR 7 SO 2 R 8 , C 1-6 alkylene-NR 7 SO 2 NR 7 R 8 , C(O)NR 7 R 8  and C 1-6 alkylene-NR 7 C(O)OR 8 , wherein any cyclic moiety is optionally substituted with C 1-4 alkyl and/or is optionally fused to a further cyclic moiety; 
 X is absent or is selected from the group consisting of O, NH, NC 1-6 alkyl, S, S(O), SO 2 , C(O), C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 haloalkylene, C 3-8 cycloalkylene, heterocycloalkylene, arylene and heteroarylene, or X is a combination of two or three of O, NH, NC 1-6 alkyl, S, S(O), SO 2 , C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 haloalkylene, C 3-8 cycloalkylene, heterocycloalkylene, arylene or heteroarylene, bonded together in a linear fashion, provided that two or three of O, NH, NC 1-6 alkyl, S, S(O) and SO 2  and not bonded directly to each other; 
 R 2 , R 3  and R 4  are each independently selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 haloalkyl, C 1-10 cyanoalkyl, C 1-10 alkoxy, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 3-10 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-O—C 1-6 haloalkyl, C 2-6 alkenylene-O—C 1-6 haloalkyl, C 2-6 alkynylene-O—C 1-6 haloalkyl, C 1-6 alkylene-C 3-8 cycloalkyl, C 1-6 alkylene-heterocycloalkyl, C 1-6 alkylene-aryl, C 1-6 alkylene-heteroaryl, C(O)R 7 , OC(O)R 7 , C(O)OR 7 , C 1-6 alkylene-O—R 7 , C 1-6 alkylene-C(O)R 7 , C 1-6 alkylene-O—C(O)R 7 , C 1-6 alkylene-C(O)OR 7 , C 1-6 alkylene-O—C(O)OR 7 , C 1-6 alkylene-NR 7 R 8 , C 1-6 alkylene-C(O)NR 7 R 8 , C 1-6 alkylene-NR 7 C(O)R 8 , C 1-6 alkylene-NR 7 C(O)NR 7 R 8 , C 1-6 alkylene-S—R 7 , C 1-6 alkylene-S(O)R 7 , C 1-6 alkylene-SO 2 R 7 , C 1-6 alkylene-SO 2 NR 7 R 8 , C 1-6 alkylene-NR 7 SO 2 R 8 , C 1-6 alkylene-NR 7 SO 2 NR 7 R 8 , C(O)NR 7 R 8  and C 1-6 alkylene-NR 7 C(O)OR 8 , wherein any cyclic moiety is optionally fused to a further 5- to 7-membered cyclic moiety, wherein at least one of R 2 , R 3  and R 4  is C 1-6 -alkylene-O—C 1-6 haloalkyl, and wherein R 2 , R 3  and R 4  are optionally substituted with one or more independently-selected R 6  groups; 
 R 5  is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkylene-C 3-8 cycloalkyl, aryl, heteroaryl, and heterocycloalkyl; 
 R 6  is selected from the group consisting of C 1-6 alkyl, OH, halo, O—(C 2-3 alkylene)-O, C 1-6 alkoxy, aryloxy, —NH—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , C 1-6 alkylene-N(C 1-6 alkyl) 2 , C 1-6 alkylene-NH—C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and 
 R 7  and R 8  are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-6 alkylene-C 3-10 cycloalkyl, heterocycloalkyl, aryl, C 1-6 alkylene-aryl, C 1-6 alkylene-heterocycloalkyl, heteroaryl, and C 1-6 alkylene-heteroaryl, wherein any cyclic moiety is optionally fused to a further cyclic moiety. 
 
     
     
         2 . The compound of  claim 1  wherein R 1  is selected from:
 (i) C 1-6 alkyl; 
 (ii) a substituted or unsubstituted 5- or 6-membered heteroaryl; and 
 (iii) C 3-8 heterocycloalkyl, 
 
       wherein the substituents for the 5- or 6-membered heteroaryl are independently selected from C 1-4 alkyl. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is selected from:
 (i) substituted or unsubstituted thiazolyl;   (ii) substituted or unsubstituted isothiazolyl;   (iii) substituted or unsubstituted oxazolyl;   (iv) substituted or unsubstituted isooxazolyl;   (v) substituted or unsubstituted thiophenyl;   (vi) substituted or unsubstituted furanyl;   (vii) substituted or unsubstituted 1,2,4-triazolyl;   (viii) substituted or unsubstituted pyridyl;   (ix) substituted or unsubstituted pyrazinyl;   (x) substituted or unsubstituted pyrimidinyl; and   (xi) substituted or unsubstituted 1,2,4-triazinyl,   
       wherein the substituents for thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, thiophenyl, furanyl, 1,2,4-triazolyl, pyridyl, pyrazinyl, pyrimidinyl and 1,2,4-triazinyl are independently selected from C 1-4 alkyl. 
     
     
         4 . The compound of  claim 3 , wherein R 1  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 2 , wherein R 1  is C 3-8 heterocycloalkyl and X is C 1-6 alkylene. 
     
     
         6 . The compound of  claim 5 , wherein R 1  is selected from morpholinyl, 1,4-oxazepanyl, thiomorpholinyl, 1,4-thiazepanyl, 1,4-thiazepanyl-1-oxide, 1,4-thiazepanyl-1,1-dioxide, 1,4-thiazinanyl-1-oxide, 1,4-thiazinanyl-1,1-dioxide, aziridinyl, azetidinyl, pyrrolidinyl, piperazinyl and 1,4-diazepanyl. 
     
     
         7 . The compound of  claim 6 , wherein X is —CH 2 —. 
     
     
         8 . The compound of  claim 1 , wherein R 2  and R 3  are each independently selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-O—C 1-6 haloalkyl, C 2-6 alkenylene-O—C 1-6 haloalkyl and C 2-6 alkynylene-O—C 1-6 haloalkyl, wherein at least one of R 2  and R 3  is C 1-6 -alkylene-O—C 1-6 haloalkyl. 
     
     
         9 . The compound of  claim 8 , wherein R 2  and R 3  are each independently selected from the group consisting of isobutyl, —CH 2 —O—CH 3  and —CH 2 —O—CHF 2 , wherein at least one of R 2  and R 3  is —CH 2 —O—CHF 2 . 
     
     
         10 . The compound of  claim 8 , wherein R 4  is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-6 alkyleneC 3-8 cycloalkyl and C 1-6 alkyleneC 6-14 aryl. 
     
     
         11 . The compound of  claim 1 , wherein R 5  is selected from the group consisting of H and C 1-6 alkyl. 
     
     
         12 . The compound of  claim 1 , wherein having the following relative stereochemistry: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 1 , or a salt or solvate thereof, selected from:
 2-Methyl-thiazole-5-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)-amide;   2-Methyl-thiazole-5-carboxylic acid-((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-methoxy-ethylcarbamoyl}-2-difluoromethoxyethyl)-amide;   2-Methyl-thiazole-5-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-methoxyethyl)-amide;   2-Methyl-oxazole-5-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)-amide;   3-Methyl-isoxazole-5-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)-amide;   Thiazole-5-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxoethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)amide;   Oxazole-5-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)-amide;   5-Methyl-thiophene-2-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)-amide;   5-Methyl-furan-2-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)-amide;   Thiophene-2-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)-amide;   N-[(1S)-2-[[(1S)-2-[[(1S)-1-benzyl-2-[(2R)-2-methyloxiran-2-yl]-2-oxo-ethyl]amino]-1 (difluoromethoxymethyl)-2-oxo-ethyl]amino]-1-(difluoromethoxymethyl)-2-oxo-ethyl]-1H-1,2,4-triazole-5-carboxamide;   N-[(1S)-1-(difluoromethoxymethyl)-2-[[(1S)-1-(difluoromethoxymethyl)-2-[[(1S)-3-methyl-1-[(2R)-2-methyloxirane-2-carbonyl]butyl]-amino]-2-oxo-ethyl]amino]-2-oxo-ethyl]-2-methyl-thiazole-5-carboxamide;   Pyridine-2-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)-amide;   N—((S)-1-{(S)-1-[(S)-1-Benzyl-2-((R)-2-methyl-oxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)-nicotinamide;   Pyridine-2-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)-amide;   N-[(1S)-2-[[(1S)-2-[[(1S)-1-benzyl-2-[(2R)-2-methyloxiran-2-yl]-2-oxo-ethyl]amino]-1-(difluoromethoxymethyl)-2-oxo-ethyl]amino]-1-(difluoromethoxymethyl)-2-oxo-ethyl]-pyrimidine-2-carboxamide;   [1,2,4]Triazine-3-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)-amide;   Pyrimidine-4-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-difluoromethoxyethyl)-amide;   2-Methyl-thiazole-5-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-3-methylbutylcarbamoyl}-2-difluoromethoxyethyl)-amide;   2-Methyl-thiazole-5-carboxylic acid ((S)-2-difluoromethoxy-1-{(S)-3-methyl-1-[(S)-3-methyl-1-((R)-2-methyloxiranecarbonyl)-butylcarbamoyl]-butylcarbamoyl}-ethyl)-amide,   2-Methyl-thiazole-5-carboxylic acid ((S)-1-{(S)-2-difluoromethoxy-1-[(S)-3-methyl-1-((R)-2-methyloxiranecarbonyl)-butylcarbamoyl]-ethylcarbamoyl}-3-methylbutyl)-amide;   2-Methyl-thiazole-5-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-3-methylbutyl)-amide;   2-Methyl-thiazole-5-carboxylic acid ((S)-1-{(S)-2-difluoromethoxy-1-[(S)-3-methyl-1-((R)-2-methyloxiranecarbonyl)-butylcarbamoyl]-ethylcarbamoyl}-2-phenylethyl)-amide;   2-Methyl-thiazole-5-carboxylic acid ((S)-1-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyl-oxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethylcarbamoyl}-2-phenylethyl)-amide;   2S)-2-[[(2S)-3-(difluoromethoxy)-2-[(2-morpholinoacetyl)amino]propanoyl]amino]-N-[(1S)-3-methyl-1-[(2R)-2-methyloxirane-2-carbonyl]butyl]-3-phenylpropanamide;   (S)—N—{(S)-1-[(S)-1-Benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethyl-carbamoyl]-2-difluoromethoxyethyl}-3-difluoromethoxy-2-(2-morpholin-4-yl-acetylamino)-propionamide;   (2S)—N-[(1S)-1-benzyl-2-[(2R)-2-methyloxiran-2-yl]-2-oxo-ethyl]-2-[[(2S)-3-(difluoromethoxy)-2-[(2-morpholinoacetyl)amino]propanoyl]amino]-4-methylpentanamide;   (2S)-2-[[(2S)-3-(difluoromethoxy)-2-[(2-morpholinoacetyl)amino]propanoyl]amino]-4-methyl-N-[(1S)-3-methyl-1-[(2R)-2-methyloxirane-2-carbonyl]butyl]pentanamide;   (2S)—N-[(1S)-1-benzyl-2-[(2R)-2-methyloxiran-2-yl]-2-oxo-ethyl]-2-[[(2S)-3-(difluoromethoxy)-2-[(2-morpholinoacetyl)amino]propanoyl]amino]-3-(1-methylcyclohexa-1,3,5-trien-1-yl)propanamide;   (S)-4-Methyl-2-(2-morpholin-4-yl-acetylamino)-pentanoic acid {(S)-2-difluoromethoxy-1-[(S)-3-methyl-1-((R)-2-methyloxiranecarbonyl)-butylcarbamoyl]-ethyl}-amide;   (S)-4-Methyl-2-(2-morpholin-4-yl-acetylamino)-pentanoic acid {(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxyethyl}-amide;   (2S)—N-[(1S)-2-[[(1S)-1-benzyl-2-[(2R)-2-methyloxiran-2-yl]-2-oxo-ethyl]amino]-1(difluoromethoxymethyl)-2-oxo-ethyl]-2-[(2-morpholinoacetyl)amino]-3-phenylpropanamide; and   (2S)-3-(difluoromethoxy)-N-[(1S)-1-(difluoromethoxymethyl)-2-[[(1S)-3-methyl-1-[(2R)-2-methyloxirane-2-carbonyl]butyl]amino]-2-oxo-ethyl]-2-[(2-morpholinoacetyl)amino]-propanamide.   
     
     
         14 . The compound of  claim 13 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a salt or solvate thereof. 
     
     
         15 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         16 . A method for inhibiting proteasome in a cell, comprising administering an effective amount of a compound according to  claim 1  to the cell. 
     
     
         17 . A method of inhibiting uncontrolled and/or abnormal cellular activities affected directly or indirectly by proteasome inhibition in a cell, comprising administering an effective amount of a compound according to  claim 1  to the cell. 
     
     
         18 . A method of treating a disease, disorder or condition that is mediated by proteasome inhibition, comprising administering a therapeutically effective amount of a compound according to  claim 1  to a subject in need thereof. 
     
     
         19 . A method of inhibiting the degradation of a protein by a proteasome capable of degrading the protein, comprising contacting the proteasome with an effective amount of a compound according to  claim 1 . 
     
     
         20 . A method of treating accelerated and/or enhanced proteolysis comprising administering a therapeutically effective amount of a compound according to  claim 1  to a subject in need thereof.