Novel Selective Inhibitors of Ubiquitin Specific Protease 7, the Pharmaceutical Compositions Thereof and Their Therapeutic Applications

Abstract

The present invention concerns the discovery of new selective inhibitors of ubiquitin specific proteases, their process of preparation and their therapeutic use.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 i is an integer chosen from 0, 1, 2 or 3 when n is 1, or from 0, 1, 2, 3 or 4 when n is 2, or from 0, 1, 2, 3, 4 or 5 when n is 3; 
 j is an integer chosen from 0, 1, 2 or 3; 
 k is an integer chosen from 0 or 1; 
 n and n′ identical or different are integers chosen from 0, 1, 2 or 4, provided that 2≦n+n′≦4; 
 Z is CH 2 <, —HC<, —N<, NH< or O<; 
 each Ri located on any available position of the A ring is identical or different and chosen from halogen, alkyl, aryl, -alkylaryl, OR, NRR′, CN, CF 3 , COR, COOR, CONRR′; 
 each Rj located on any available position of the C ring is identical or different and chosen from halogen, alkyl, aryl, -alkylaryl, OR, NRR′, CN, COR, COOR, CONRR′; 
 each Rk, identical or different, is independently chosen from halogen, alkyl, alkoxy, cyano; 
 X is chosen from H, alkyl, aryl, -alkylaryl, wherein said alkyl and/or aryl is optionally substituted by halogen, alkyl, CN, CF 3 , OR, NRR′, COR, COOR, CONRR′; 
 Y is chosen from:
 (CHT) p NRaRb where
 Ra and Rb, identical or different, are independently chosen from H, alkyl, aryl or arylalkyl, wherein said aryl is optionally substituted by halogen, alkyl, CN, CF 3 , ═O, OR, NRR′, COR, COOR, CONRR′; 
 or Ra and Rb together form with the N atom to which they are attached a N comprising 5 to 7-membered heterocycle which may comprise one or two more heteroatoms chosen from N, O or S, said heterocycle being optionally substituted by one or more of halogen; ═O; alkyl; -alkylaryl or aryl wherein said aryl is optionally substituted by halogen; CN; CF 3 ; OR; NRR′; COR; COOR; CONRR′; 
 p is an integer chosen from 0 to 6; 
 each T, identical or different is independently chosen from H or alkyl. 
 
 
 
       
         
           
           
               
               
           
         
         
           
              wherein: 
           
         
       
       
         
           
           
               
               
           
         
         
           
              is saturated or partially unsaturated heterocycle or heteroaryl, mono or bicyclic, comprising 1, 2 or 3 heteroatom(s) chosen from N, O or S, optionally substituted by one or more of alkyl; -alkylaryl; OR; C(═O)OR; ═O; CN; CF 3 ; COR; NRR′; CONRR′; aryl or -alkylaryl wherein said aryl is optionally substituted by alkyl, halogen, OR or COR; 
             q is an integer chosen from 0 to 6; 
             each T, identical or different is independently chosen from H or alkyl. 
           
           —(CHT) r -aryl wherein:
 said mono or bicyclic aryl is optionally substituted by one or more of alkyl; OR; CF 3 , SO 2 NRR′; —C(═O)—R; Halogen; CN; —NRR′; CONRR; C(═O)—Oalkyl wherein said alkyl is optionally substituted by NRR′; and/or said mono or bicyclic aryl is optionally fused with a monocyclic 5 to 7-membered heterocycle; 
 r is an integer chosen from 0 to 6; 
 each T, identical or different is independently chosen from H or alkyl; 
 
           (CHT) s -(C3-C7)cycloalkyl where
 s is an integer chosen from 0 to 6; 
 each T, identical or different is independently chosen from H or alkyl; 
 said cycloalkyl is monocyclic, or fused with an aryl; 
 
           alkyl optionally substituted by CN, Oalkyl; 
           U-S(O) t -alkyl where
 t is an integer chosen from 0, 1 or 2; 
 -U- is an alkylene optionally substituted by one or more of OR; ═O; CF 3 , SO 2 NRR′; —C(═O)—R; Halogen; CN; —NRR′; CONRR; C(═O)OR; 
 
         
         or X and Y together form with the N atom to which they are attached an heterocycle comprising said N atom and optionally one or two more heteroatoms, said heterocyle being optionally insaturated and/or
 being optionally substituted by one or more of: ═O; Hal, CN, NRR′, C(═O)alkyl, alkyl; cycloalkyl; heterocycle; C(═O)—Oalkyl; aryl or -alkylaryl where said aryl is optionally fused with an heterocycle and/or said aryl being optionally substituted by alkyl or COalkyl; 
 being optionally fused with an aryl; 
 
       
       where R and R′, identical or different are independently chosen from H, alkyl, aryl, -alkylaryl, 
       or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound according to  claim 1 , wherein k=1 and Rk is a halogen. 
     
     
         3 . The compound according to  claim 1 , wherein n′ is 1 and n is 2. 
     
     
         4 . The compound according to  claim 1 , wherein:
 X is defined as in  claim 1  and Y is chosen from:
 (CH 2 ) p NRaRb where
 Ra and Rb, identical or different, are independently chosen from H, alkyl, aryl, -alkylaryl, wherein said aryl is optionally substituted by alkyl; 
 p is 0, 1, 2 or 3. 
 
 or where
 Ra and Rb together form with the N atom to which they are attached a 5 to 7 membered heterocycle optionally comprising one or two more heteroatoms chosen from N, O or S, said heterocycle being optionally substituted by one or more of halogen; ═O; alkyl; -alkylaryl or aryl where aryl is optionally substituted by halogen; ═O; CN; CF 3 ; OR; NRR′; COR; COOR; CONRR′ and; 
 p is chosen from 2 or 3; 
 
   
       
         
           
           
               
               
           
         
         
           
              wherein: 
           
         
       
       
         
           
           
               
               
           
         
         
           
              is a saturated or partially unsaturated bicyclic heterocycle or heteroaryl, comprising 1, 2 or 3 heteroatom(s) chosen from N, O or S, optionally substituted by one or more of alkyl; OR; C(═O)OR; aryl or -alkylaryl wherein said aryl is optionally substituted by alkyl, halogen, OR or COR; 
             q is an integer chosen from 0, 1, 2 or 3; 
             each T, identical or different is independently chosen from H or alkyl; 
           
         
         (CHT) r -aryl wherein:
 said aryl is mono or bicyclic, optionally substituted by one or more of alkyl, OR, SO 2 NRR′; —C(═O)—R; Halogen; CN; C(═O)—Oalkyl, wherein said alkyl is optionally substituted by NRR′; and said aryl is optionally fused with an heterocycle; 
 r is an integer chosen from 0, 1, 2 or 3; 
 each T, identical or different is independently chosen from H or alkyl; 
 
       
       or
 X and Y together form with the N atom to which they are attached an heterocycle comprising said N atom and optionally one or two more heteroatoms, said heterocyle being optionally insaturated and/or
 being optionally substituted by one or more of: ═O; alkyl; cycloalkyl; heterocycle; C(═O)—Oalkyl; aryl or -alkylaryl where said aryl is optionally substituted by alkyl; 
 being optionally fused with an aryl, 
 
 
       wherein q is 1, 2 or 3, r is 1, 2 or 3. 
     
     
         5 . The compound according to  claim 1 , wherein:
 n′=1, n=2 or 3;   X is defined as in  claim 1  and Y is chosen from:
 (CHT) p NRaRb where
 Ra and Rb, identical or different, are independently chosen from H, alkyl, aryl, -alkylaryl, wherein said aryl is optionally substituted by halogen, alkyl, CN, CF 3 , OR, NRR′, COR, COOR, CONRR′; 
 or Ra and Rb together form with the N atom to which they are attached a N comprising 5 to 7-membered heterocycle optionally comprising one or two more heteroatoms chosen from N, O or S, said heterocycle being optionally substituted by one or more of halogen; alkyl; -alkylaryl or aryl wherein said aryl is optionally substituted by halogen; ═O; CN; CF 3 ; OR; NRR′; COR; COOR; CONRR′; 
 p is an integer chosen from 2 or 3; 
 each T, identical or different is independently chosen from H or alkyl; or 
 
   
       
         
           
           
               
               
           
         
         
           
              wherein: 
           
         
       
       
         
           
           
               
               
           
         
         
           
              is a saturated or partially unsaturated heterocycle or heteroaryl, mono or bicyclic, comprising 1, 2 or 3 heteroatom(s) chosen from N, O or S, optionally substituted by one or more of alkyl; -alkylaryl; OR; C(═O)OR; ═O; CN; CF 3 ; COR; NRR′; CONRR′; aryl; wherein said aryl is optionally substituted by alkyl, halogen, OR, COR; 
             q is 1, 2 or 3; 
             each T, identical or different is independently chosen from H or alkyl; 
           
         
         or X and Y together form with the N atom to which they are attached an heterocycle comprising said N atom and optionally one or two more heteroatoms, said heterocyle being optionally insaturated and/or
 being optionally substituted by one or more of: ═O; alkyl; cycloalkyl; C(═O)—Oalkyl; -alkylaryl where said aryl is optionally fused with an heterocycle and/or said aryl being optionally substituted by alkyl or COalkyl; 
 being optionally fused with an aryl; 
 
       
       where R and R′, identical or different are independently chosen from H, alkyl, aryl, -alkylaryl. 
     
     
         6 . The compound according to  claim 1 , wherein
 n′=1, n=2 or 3;   X is chosen from H, alkyl, aryl, -alkylaryl, wherein said alkyl and/or aryl is optionally substituted by halogen, alkyl, CN, CF 3 , OR, NRR′, COR, COOR, CONRR′;   and Y is chosen from:
 (CHT) p NRaRb where
 Ra and Rb, identical or different, are independently chosen from H, alkyl, aryl, -alkylaryl, wherein said aryl is optionally substituted by halogen, alkyl, CN, CF 3 , OR, NRR′, COR, COOR, CONRR′; 
 p is 1, 2 or 3. 
 
   
     
     
         7 . The compound according to  claim 1 , wherein:
 9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid [1-(3-methyl-benzyl)-piperidin-4-ylmethyl]-amide   9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid (1-ethyl-pyrrolidin-2-ylmethyl)-amide   9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid (2-dipropylamino-ethyl)-amide   9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid [2-(butyl-ethyl-amino)-ethyl]-amide   9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid [3-(benzyl-ethyl-amino)-propyl]-amide   9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid (3-dipropylamino-propyl)-amide   9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid (2-diethylamino-ethyl)-amide   9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide   9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid [3-(2,6-dimethyl-piperidin-1-yl)-propyl]-amide   9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid (3-diethylamino-propyl)-amide   9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid (2-dimethylamino-ethyl)-amide   Azepan-1-yl-(9-chloro-5,6,7,8-tetrahydro-acridin-3-yl)-methanone   9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid [3-(4-propyl-piperazin-1-yl)-propyl]-amide   9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid [3-(benzyl-methyl-amino)-propyl]-amide   9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid [3-(4-methyl-piperazin-1-yl)-propyl]-amide   [1,4′]Bipiperidinyl-1′-yl-(9-chloro-5,6,7,8-tetrahydro-acridin-3-yl)-methanone   
       or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         8 . A compound of formula (VI): 
       
         
           
           
               
               
           
         
       
       where i, j, n, Z, Ri, Rj are defined as in  claim 1 . 
     
     
         9 . A pharmaceutical composition comprising a compound of formula (I) as defined in  claim 1  or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof, with a pharmaceutical acceptable excipient. 
     
     
         10 . A method for inhibiting a USP comprising administering a compound of formula (I) as defined in  claim 1  or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method according to  claim 10  for inhibiting USP7. 
     
     
         12 . A method for treating and/or preventing cancer and metastasis, neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, immunological disorders, bone and joint diseases, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, viral infections and diseases, and/or viral infectivity and/or latency, bacterial infections and diseases, comprising administering a compound according to  claim 1  or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method according to  claim 12 , wherein said viral infections and diseases are chosen from herpes simplex-1 or -2 viral infections, hepatitis A, hepatitis C, SARS coronavirus infection and disease, Epstein-Barr virus, rhinoviral infections and diseases, adenoviral infections and diseases, poliomyelitis. 
     
     
         14 . A combination comprising a compound of formula (I) as defined in  claim 1  or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof, with one or more active agents chosen from anti-cancer agents, neurological agents, thrombolytic agents, antioxidant agents. anti-infective, anti-hypertensive agents, diuretic agents, thrombolytic agents, immunosuppressive agents, cardiovascular agents, immunomodulatory agents, anti-inflammatory agents, antiviral agents, anti-bacterial agents.