Novel tetracyclic inhibitors of cysteine proteases, the pharmaceutical compositions thereof and their therapeutic applications

Abstract

The present invention concerns new compounds of formula (I), their process of preparation and their therapeutic use: Formula (I) wherein R3, R4, R5, R6, Y, Het1, T, U, V, W, X, Ru, Rv and Rw are as defined in claim 1

1 . A compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein
    is either a single or double bond, as appropriate; 
 ------ is either none or a single bond, as appropriate; 
 
     
       
         
         
             
             
         
       
     
     is a 5 to 7-membered heterocycle, preferably heteroaryl comprising 1 to 5 heteroatoms optionally substituted by one or more substituents chosen from the group consisting in H, CN, ═O, Hal, Alk, OAlk, OH, NRCN, C(CN)═C(OH)(OAlk), SR, NRR′, C(O)NRR′, Heterocycle, Aryl, Heteroaryl, where Alk, Aryl, Heteroaryl, heterocycle are optionally substituted by Hal, NRR′, CN, OH, CF 3 , Aryl, Heteroaryl, OAlk;
 where 
 
     
       
         
         
             
             
         
       
     
     are fused together by T and X;
 T, U, V, W, X are the same or different and may be chosen from C, N, O, S. 
 Y is N—OR1, NR′1, CR2R′2; 
 R1 is H, Alkyl, Alkenyl, Alkoxyalkyl, Aryloxyalkyl, Arylalkyl, Alkoxycarbonylalkyl, Carboxyalkyl; 
 R′1 is H, Alkyl, Aryl or Aralkyl; 
 R2, R′2 are each the same or different and are independently selected from H, Alkyl, Aryl or Aralkyl; 
 Ru, Rv, Rw are the same or different and may be chosen from the group consisting in H, CN, ═O, Hal, Alk, OAlk, OH, NRCN, C(CN)═C(OH)(OAlk), SR, NRR′, C(O)NRR′, Heterocycle, Aryl, Heteroaryl, Cycloalkyl, where Alk, Aryl, Heteroaryl, Heterocycle, Cycloalkyl are optionally substituted by Hal, NRR′, CN, OH, CF 3 , Aryl, Heteroaryl, OAlk. 
 R3, R4, R5, R6 are each identical or different and are independently chosen from the group consisting in H, OAlk, Alk, Hal, NRR′, CN, OH, OCF 3 , CF 3 , Aryl, Heteroaryl; 
 R and R′ are each identical or different and are independently chosen from the group consisting in H, Alk, wherein Alk is optionally substituted by Hal, NRR′, CN, OH, CF 3 , Aryl, Heteroaryl; 
 or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers, or their regioisomers, geometrical isomers (E and Z) or mixtures thereof. 
 
   
   
       2 . A compound of formula (I) according to  claim 1 , wherein T, U, V, W, X are independently C or N. 
   
   
       3 . A compound of formula (I) according  claim 1 , wherein 
     
       
         
         
             
             
         
       
       contains 2 or 3 heteroatoms. 
     
   
   
       4 . A compound of formula (I) according to  claim 1 , wherein at least one of Ru, Rv, Rw is chosen from H, Aryl, Alk, NRR′, Hal, -AlkAryl, -AlkOH, -AlkOAlk, Cycloalkyl. 
   
   
       5 . A compound according to  claim 1 , wherein R3, R4, R5, R6 are each identical or different and are independently chosen from the group consisting in H, Hal, Alk, OAlk, OCF 3 . 
   
   
       6 . A compound according to  claim 1 , wherein Rv, Rw are independently either H or absent. 
   
   
       7 . A compound of formula (I) according to  claim 1 , wherein they are of formula (Ia): 
     
       
         
         
             
             
         
       
       wherein R3, R4, R5, R6, Y, T, U, V, W, X, Ru are as defined in  claim 1 . 
     
   
   
       8 . A compound according to  claim 1  chosen from the group consisting in:
 3-Methyl-1,2,3a,4,10-pentaaza-cyclopenta[b]fluoren-9-one O-methyl-oxime   3-Methyl-1,2,3a,4,10-pentaaza-cyclopenta[b]fluoren-9-one O-allyl-oxime   1-Methyl-2,3,4,10,10a-pentaaza-cyclopenta[b]fluoren-9-one O-allyl-oxime   3-Butyl-1,2,3a,4,10-pentaaza-cyclopenta[b]fluoren-9-one O-allyl-oxime   1-Butyl-2,3,4,10,10a-pentaaza-cyclopenta[b]fluoren-9-one O-allyl-oxime   1,2,3,3a,4,10-hexaaza-cyclopenta[b]fluoren-9-one O-allyl-oxime   1,2,3,3a,4,10-hexaaza-cyclopenta[b]fluoren-9-one oxime   1,2,3,3a,4,10-Hexaaza-cyclopenta[b]fluoren-9-one O-decyl-oxime   1,2,3,3a,4,10-Hexaaza-cyclopenta[b]fluoren-9-one O-(2-methoxy-ethyl)-oxime   1,2,3,3a,4,10-Hexaaza-cyclopenta[b]fluoren-9-one O-(3-phenoxy-propyl)-oxime   1-Ethyl-2,3,4,10,10a-pentaaza-cyclopenta[b]fluoren-9-one O-methyl-oxime   3-Ethyl-1,2,3a,4,10-pentaaza-cyclopenta[b]fluoren-9-one O-methyl-oxime   1-Ethyl-2,3,4,10,10a-pentaaza-cyclopenta[b]fluoren-9-one O-ethyl-oxime   3-Ethyl-1,2,3a,4,10-pentaaza-cyclopenta[b]fluoren-9-one O-ethyl-oxime   1-Ethyl-2,3,4,10,10a-pentaaza-cyclopenta[b]fluoren-9-one O-allyl-oxime   3-Ethyl-1,2,3a,4,10-pentaaza-cyclopenta[b]fluoren-9-one O-allyl-oxime   1-Ethyl-2,3,4,10,10a-pentaaza-cyclopenta[b]fluoren-9-one O-benzyl-oxime   3-Ethyl-1,2,3a,4,10-pentaaza-cyclopenta[b]fluoren-9-one O-benzyl-oxime   [1-Ethyl-2,3,4,10,10a-pentaaza-cyclopenta[b]fluoren-9-ylidene]-phenyl-amine   (1,2,3,3a,4,10-Hexaaza-cyclopenta[b]fluoren-9-ylideneaminooxy)-acetic acid ethyl ester   (1,2,3,3a,4,10-Hexaaza-cyclopenta[b]fluoren-9-ylideneaminooxy)-acetate lithium salt,
 or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers, or their regioisomers, geometrical isomers (E and Z) or mixtures thereof. 
   
   
   
       9 . Process of preparation of a compound of formula (I) according to  claim 1  comprising the step of reacting a corresponding compound of formula (I′): 
     
       
         
         
             
             
         
       
       wherein R3, R4, R5, R6, Het1, T, U, V, W, X, Ru, Rv, Rw are defined as in  claim 1 , and wherein each of Ru′, Rv′, Rw′ is similar to Ru, Rv, Rw or is a precursor group of corresponding Ru, Rv, Rw, by one or more step allowing a precursor group to be transformed into the desired Ru, Rv or Rw group, and optionally isolating the compound of formula (I). 
     
   
   
       10 . Process of preparation of a compound according to  claim 1  comprising the step of reacting corresponding compounds of formula (II) and (III): 
     
       
         
         
             
             
         
       
       wherein R3, R4, R5, R6, T, U, V, W, X, Ru, Rv, Rw are defined as in  claim 1 . 
     
   
   
       11 . (canceled) 
   
   
       12 . A pharmaceutical composition comprising a compound of formula (I) 
     
       
         
         
             
             
         
       
       wherein R3, R4, R5, R6, T, U, V, W, X, Het1, Ru, Rv and Rw are as defined in  claim 1 . 
     
   
   
       13 . A method for inhibiting one or more cysteine proteases comprising administering a compound of formula (I) as defined in  claim 12 . 
   
   
       14 . Use according to  claim 13 , wherein said cysteine proteases belong to one or more groups of de-ubiquitination enzymes, caspases, cathepsins, calpains as well as viral, bacterial, fungal or parasitic cysteine proteases. 
   
   
       15 . Use of a compound of formula (I) as defined in  claim 12  for the preparation of a medicament for treating and/or preventing cancer and metastasis, neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, inflammatory disorders, cardiovascular diseases and/or viral infectivity and/or latency in particular for Herpes simplex virus-1, Epstein-Barr virus or SARS coronavirus inflammatory disorders, neurodegenerative disorders, preferably nervous cell damage caused by stroke, liver damage and liver failure resulting from acute or chronic infectious, ischemic or chemical liver injury, renal damage and renal failure resulting from acute or chronic infectious, ischemic or chemical kidney injury, heart damage and heart failure resulting from acute or chronic infectious, ischemic or chemical cardiac injury, diabetes resulting from acute or chronic autoimmune, chemical, oxidative or metabolic injury to the insulin beta-cells of the pancreatic islets, cancer and metastasis, cardiovascular diseases, immunological disorders, bone and joint diseases, osteoporosis and arthritis, ageing disorders, late onset diabetes and cataract, viral infections and diseases are chosen from hepatitis A, hepatitis C, SARS coronavirus infection and disease, rhinoviral infections and diseases, adenoviral infections and diseases, poliomyelitis, bacterial infections or diseases including streptococcal infections and diseases, infections and diseases caused by bacteria of the  Clostridium  sp. Genus, staphylococcal infections and diseases, gingivitis and periodontal diseases, fungal infections and diseases, protozoal parasitic infections and diseases, lat worm parasitic infections and diseases, round worm parasitic infections and diseases, comprising administering a compound according to  claim 12 . 
   
   
       16 - 37 . (canceled) 
   
   
       38 . A combination comprising a compound according to  claim 12  with one or more therapies chosen from anti-cancer therapies, neurological therapies, thrombolytic therapies, antioxidant therapies, anti-infective, anti-hypertensive therapies, diuretic therapies, thrombolytic therapies, immunosuppressive therapies, cardiovascular therapies, immunomodulatory therapies, anti-inflammatory therapies, antiviral therapies, anti-bacterial therapies, anti-fungal therapies, anti-protozoal therapies, antiparasitic therapies.