Autotaxin inhibitors

Abstract

The present invention relates to novel compounds that are autotaxin inhibitors, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in diseases and disorders mediated by autotaxin.

1 - 15 . (canceled) 
     
     
         16 . A method of treating a disease or condition mediated by Autotaxin in a subject comprising: administering to said subject a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         A is selected from 
       
       
         
           
           
               
               
           
         
         Y 1  is —(CR 2b R 2c ) m — or —CH═CH—; 
         X is selected from —C(═O)—, —N(R 3 )—C(═O)— and —C(═O)—N(R 3 )—; 
         Y 2  is —(CR 4a R 4b ) n —; 
         m is selected from 0, 1, 2, 3, 4 and 5; 
         n is selected from 0, 1, 2, 3, 4 and 5; 
         wherein when Y 1  is —(CR 2b R 2c ) m —; the sum of m and n is not less than 2 and no more than 5; 
         or 
         A-Y 1 —X— is 
       
       
         
           
           
               
               
           
         
         L is selected from 
       
       
         
           
           
               
               
           
         
         W is CH or N; 
         Z is selected from CH 2 , O and NR 5c ; 
         Y 3  is selected from —O—(CR 6a R 6b )—, —(CR 6c R 6d )—O—, —CH═CH—, —CR 6e R 6f —CR 6g R 6h —, and —O—(CR 6i R 6j —CR 6k R 6l )—; 
         R 1a , R 1b , R 1c , R 1d  and R 1e  are defined according to any one of 
         (a) R 1b  is halogen; R 1d  is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy; and R 1a , R 1c  and R 1e  are H; 
         (b) R 1b  is halogen; R 1d  is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy; R 1c  is halogen; and R 1a  and R 1e  are H; 
         (c) R 1b  is C 1-4 alkyl; R 1d  is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy or CN; R 1a , R 1c  and R 1e  are H; 
         (d) R 1b  is CN; R 1d  is C 1-4 haloalkyl or C 1-4 haloalkoxy; and R 1a , R 1c  and R 1e  are H; 
         (e) R 1b  is C 1-4 haloalkyl or C 1-4 haloalkoxy; and R 1a , R 1c  and R 1e  are H; and R 1d  is H or CN; 
         (f) R 1a  is halogen; R 1c  is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy; and Rib, R 1d  and R 1e  are H; 
         (g) R 1c  is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy; and R 1a , R 1b  and R 1e  are H;
 and R 1d  is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, or H; 
 R 2a , R 2b , R 2c , R 3 , R 4a , R 4b , R 4c , R 4d , R 5a , R 5b , R 5c , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R 6i , R 6j , R 6k  and R 6l  are independently selected from H and C 1-4 alkyl. 
 
       
     
     
         17 . The method according to  claim 16  or a pharmaceutically acceptable salt thereof, wherein R 1a , R 1b , R 1c , R 1d  and R 1e  are defined according to any one of
 (a) R 1b  is fluoro, chloro or bromo; R 1d  is fluoro, chloro, bromo, CN, methyl, trifluoromethyl or trifluoromethoxy; and R 1a , R 1c  and R 1e  are H; 
 (c) R 1b  is methyl; R 1d  is methyl, trifluoromethyl, trifluoromethoxy or CN; R 1a , R 1c  and R 1e  are H; 
 (f) R 1a  is fluoro, chloro or bromo; R 1c  is fluoro, chloro, bromo, CN, methyl, trifluoromethyl or trifluoromethoxy; and R 1b , R 1d  and R 1e  are H; and 
 (g) R 1c  is fluoro, chloro, bromo, CN, methyl, trifluoromethyl or trifluoromethoxy; and R 1a R 1b  and R 1e  are H; and R 1d  is fluoro, chloro, bromo, CN, methyl, trifluoromethyl, trifluoromethoxy, or H. 
 
     
     
         18 . The method according to  claim 16  or a pharmaceutically acceptable salt thereof, wherein Y 3  is —O—(CR 6a R 6b )— or —(CR 6c R 6d )—O—. 
     
     
         19 . The method according to  claim 16  or a pharmaceutically acceptable salt thereof, wherein X is selected from —N(R 3 )—C(═O)— and —C(═O)—N(R 3 )—. 
     
     
         20 . The method according to  claim 16  or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (II) 
       
         
           
           
               
               
           
         
       
     
     
         21 . The method according to  claim 16  or a pharmaceutically acceptable salt thereof, wherein —Y 1 —X—Y 2 — is selected from 
       
         
           
           
               
               
           
         
       
     
     
         22 . The method according to  claim 16  which is selected from the group consisting of:
 3,5-dichlorobenzyl 4-(2-(3-hydroxy-N-methylisoxazole-5-carboxamido)ethyl) piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(2-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)(methyl)amino)ethyl)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(2-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)ethyl)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(2-((2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)amino)ethyl)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-((3-(3-hydroxyisoxazol-5-yl)propanamido)methyl)-2-methylpiperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(2-(N-methyl-2-(1H-1,2,3-triazol-4-yl)acetamido)ethyl)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(2-(2-(1H-1,2,3-triazol-4-yl)acetamido)ethyl)piperidine-1-carboxylate; 
 (E)-3,5-dichlorobenzyl 4-(3-(1H-imidazol-4-yl)acrylamido)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 2-(2-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)ethyl)morpholine-4-carboxylate; 
 3,5-dichlorobenzyl 2-(2-(2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)morpholine-4-carboxylate; 
 3,5-dichlorobenzyl 2-(2-(N-methyl-2-oxo-2,3-dihydrooxazole-5-carboxamido) ethyl)morpholine-4-carboxylate; 
 3,5-dichlorobenzyl 2-(2-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)(methyl)amino)ethyl)morpholine-4-carboxylate; 
 3,5-dichlorobenzyl 4-(2-(N-methyl-2-oxo-2,3-dihydrothiazole-5-carboxamido)ethyl)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(N-methyl-4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(3-(1H-1,2,3-triazol-4-yl)propanamido)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(5-(1H-1,2,3-triazol-4-yl)pentanamido)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(2-(2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(2-(3-(3-hydroxyisoxazol-5-yl)propanamido)ethyl)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(3-(3-hydroxyisoxazol-5-yl)propanamido)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(2-(N-methyl-2-oxo-2,3-dihydrooxazole-4-carboxamido)ethyl)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(3-(N-methyl-2-oxo-2,3-dihydrooxazole-5-carboxamido)propyl)piperazine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(2-(2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)piperazine-1-carboxylate; 
 (E)-N-(2-(1-(3-(3,5-dichlorophenyl)acryloyl)piperidin-4-yl)ethyl)-N-methyl-2-oxo-2,3-dihydrooxazole-5-carboxamide; 
 (E)-N-(2-(1-(3-(3,5-dichlorophenyl)acryloyl)piperidin-4-yl)ethyl)-2-oxo-2,3-dihydrooxazole-5-carboxamide; 
 3,5-dichlorobenzyl 4-(2-(N-methyl-2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-((3-(3-hydroxyisoxazol-5-yl)propanamido)methyl)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(3-(1H-1,2,3-triazole-4-carboxamido)propyl)piperazine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl)piperidine-1-carboxylate; 
 3-Chloro-5-cyanobenzyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl) piperidine-1-carboxylate; 
 3-Chloro-5-fluorobenzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate; 
 (E)-N-(1-(3-(3,5-Dichlorophenyl)acryloyl)piperidin-4-yl)-4-(1H-1,2,3-triazol-4-yl)butanamide; 
 (E)-N-(1-(3-(2,4-Dichlorophenyl)acryloyl)piperidin-4-yl)-4-(1H-1,2,3-triazol-4-yl)butanamide; 
 3,5-Dichlorobenzyl 4-((4-(1H-1,2,3-triazol-5-yl)butanamido)methyl)piperidine-1-carboxylate; 
 N-(1-(3-(3,5-Dichlorophenyl)propanoyl)piperidin-4-yl)-4-(1H-1,2,3-triazol-4-yl)butanamide; 
 N-(1-(3-(2,4-Dichlorophenyl)propanoyl)piperidin-4-yl)-4-(1H-1,2,3-triazol-4-yl)butanamide; 
 3-Chloro-5-cyanobenzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate; 
 3,5-Dichlorobenzyl 3-(4-(1H-1,2,3-triazol-4-yl)butanamido)-8-azabicyclo[3.2.1]octane-8-carboxylate; 
 3,5-Dichlorobenzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)azepane-1-carboxylate; 
 3,5-Dichlorobenzyl (8-(4-(1H-1,2,3-triazol-4-yl)butanoyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate; 
 3,5-Dichlorobenzyl (1-(4-(1H-1,2,3-triazol-4-yl)butanoyl)azepan-4-yl)carbamate; 
 3,5-Dichlorobenzyl 3-(4-(1H-1,2,3-triazol-4-yl)butanamido)pyrrolidine-1-carboxylate; 
 (S)- or (R)-3,5-Dichlorobenzyl 3-(4-(1H-1,2,3-triazol-4-yl)butanamido)pyrrolidine-1-carboxylate; 
 (S)- or (R)-3,5-Dichlorobenzyl 3-(4-(1H-1,2,3-triazol-4-yl)butanamido)pyrrolidine-1-carboxylate; 
 3,5-Dichlorobenzyl 3-(4-(1H-1,2,3-triazol-4-yl)butanamido)azetidine-1-carboxylate; 
 3,5-Dimethylbenzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate; 
 3,5-Dichlorobenzyl (1-(5-(1H-1,2,3-triazol-4-yl)pentanoyl)piperidin-4-yl)carbamate; 
 4-(Trifluoromethyl)benzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate; 
 4-(1H-1,2,3-Triazol-4-yl)-N-(1-(3-(4-(trifluoromethyl)phenyl)propanoyl)piperidin-4-yl)butanamide; 
 N-(1-(2-(3,5-Dichlorophenoxy)acetyl)piperidin-4-yl)-4-(1H-1,2,3-triazol-4-yl)butanamide; 
 3-Chloro-5-methylbenzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate; 
 3,5-Dichlorobenzyl 4-((3-(1H-1,2,3-triazol-5-yl)propanamido)methyl)piperidine-1-carboxylate; 
 2,4-Dichlorobenzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate; 
 3,5-Dichlorophenethyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(3-(((1H-1,2,3-triazol-4-yl)methyl)amino)-3-oxopropyl)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(2-((2-(1H-1,2,3-triazol-4-yl)ethyl)amino)-2-oxoethyl)piperidine-1-carboxylate; 
 3-methyl-5-(trifluoromethyl)benzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate; 
 3-bromo-5-(trifluoromethyl)benzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate; 
 3-chloro-5-cyanobenzyl 4-(5-(1H-1,2,3-triazol-4-yl)pentanamido)piperidine-1-carboxylate; 
 3-chloro-5-cyanobenzyl 4-(3-(1H-1,2,3-triazol-4-yl)propanamido)piperidine-1-carboxylate; 
 3-cyano-5-(trifluoromethyl)benzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate; 
 3,5-dichlorobenzyl 4-(6-(1H-1,2,3-triazol-4-yl)hexanamido)piperidine-1-carboxylate; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         23 . The method according to  claim 16 , wherein the compound is 3,5-dichlorobenzyl 4-(3-(1H-1,2,3-triazole-4-carboxamido)propyl)piperazine-1-carboxylate. 
     
     
         24 . The method according to  claim 16 , wherein the compound is 3-Cyano-5-(trifluoromethyl)benzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate. 
     
     
         25 . The method according to  claim 16  wherein the disease or condition is selected from fibrosis, pruritus, cirrhosis, cancer, diabetes, kidney diseases and neuropathic pain. 
     
     
         26 . The method according to  claim 16 , wherein the disease or condition is idiopathic pulmonary fibrosis.