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′; 
         Rk 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:
 (CT 2 ′) 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′; said heterocycle being optionally fused with an aryl;
 p is an integer chosen from 0 to 6; 
 each T′, identical or different is independently chosen from H or a linear or branched alkyl wherein the alkyl is optionally substituted by one or more OR, aryl; 
 
 
       
       
         
           
           
               
               
           
         
         
           
              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 or -alkylaryl wherein said aryl is optionally substituted by a linear or branched alkyl, halogen, OR, COR or NR′R; 
             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′ or NR″R′″; 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; 
 
         
       
       where R″ and R′″ 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; alkyl; CN; CF 3 ; OR; NRR′; COR; COOR; CONRR′;
 (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; -alkylheterocycle; aryl or -alkylaryl where said aryl is optionally fused with an heterocycle and/or said aryl being optionally substituted by alkyl or COalkyl; said heterocycle being optionally substituted by an alkyl; 
 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:
 (CT 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 to 4; 
 
 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′; said heterocycle being optionally fused with an aryl and; 
 p is chosen from 2 or 3; 
 
 each T′, identical or different, is independently chosen from H or a linear or branched alkyl, wherein the alkyl is optionally substituted by one or more OR, aryl; 
   
       
         
           
           
               
               
           
         
         
            wherein: 
         
       
       
         
           
           
               
               
           
         
         
            is a bicyclic saturated or partially unsaturated 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, COR or NR′R;
 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′ or NR″R′″; 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; -alkylheterocyle; C(═O)—Oalkyl; aryl or -alkylaryl where said aryl is optionally substituted by alkyl; said heterocycle being optionally substituted by an alkyl; 
 being optionally fused with an aryl; 
 
 
       where, preferably, 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:
 (CT 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 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′; said heterocycle being optionally fused with an aryl;
 p is an integer chosen from 2 to 3; 
 each T′, identical or different is independently chosen from H or a linear or branched alkyl; wherein the alkyl is optionally substituted by one or more OR, aryl; in one embodiment at least one of T′ is different from H; or 
 
   
       
         
           
           
               
               
           
         
         
           
              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; wherein said aryl is optionally substituted by alkyl, halogen, OR, COR or NR′R; 
             q is 1, 2 or 3; 
             each T, identical or different is independently chosen from H or alkyl; 
           
           (CHT) r -aryl wherein:
 said aryl is a monocyclic aryl and is optionally substituted by one or more of alkyl, SO 2 NRR′; —C(═O)—R; CN; C(═O)—Oalkyl; wherein said alkyl is substituted by NRR′ or NR″R′″; 
 r is an integer chosen from 0 to 6; 
 each T, identical or different is independently chosen from H or alkyl; 
 
         
       
       where R″ and R′″ 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; alkyl; CN; CF 3 ; OR; NRR′; COR; COOR; CONRR′;
 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; -alkylheterocycle; C(═O)—Oalkyl; -alkylaryl where said aryl is optionally fused with an heterocycle and/or said aryl being optionally substituted by alkyl or COalkyl; said heterocycle comprising one or two nitrogen atom and being optionally substituted by an alkyl; 
 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:
 (CT 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 halogen, alkyl, CN, CF 3 , OR, NRR′, COR, COOR, CONRR′; 
 
 p is 1, 2 or 3; or
 Ra and Rb together form with the N atom to which they are attached a N comprising 5 to 7-membered heterocycle wherein the carbon atom adjacent to the heteroatom is optionally substituted by an alkyl; said heterocycle being optionally fused with an aryl; 
 
 p is 3 or 4; 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 a linear or branched alkyl, wherein the alkyl is optionally substituted by one or more OR, aryl, and at least one of T′ is different from H. 
 (CHT) r -aryl wherein:
 said aryl is a monocyclic aryl and is optionally substituted by one or more of alkyl, SO 2 NRR′; —C(═O)—R; CN; C(═O)—Oalkyl; wherein said alkyl is substituted by NRR′ or NR″R′″; 
 r is an integer chosen from 0 to 6; 
 each T, identical or different is independently chosen from H or alkyl; 
 
   
       
         
           
           
               
               
           
         
         
           
              wherein: 
           
         
       
       
         
           
           
               
               
           
         
         
           
              is a saturated monocyclic five membered heterocycle comprising a nitrogen atom and substituted by an alkyl, provided that the alkyl is not an ethyl, -alkylaryl, OR; C(═O)OR; ═O; CN; CF 3 ; COR; NRR′; CONRR′; aryl; wherein said aryl is optionally substituted by alkyl, halogen, OR, COR or NR′R; or a monocyclic 6 membered heterocycle comprising an nitrogen atom and optionally substituted by one or more of -alkylaryl, OR; C(═O)OR; ═O; CN; CF 3 ; COR; NRR′; CONRR′; aryl; wherein said aryl is optionally substituted by halogen, COR, OR or NR′R; 
             q is an integer chosen from 0 to 6; 
             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; -alkylheterocycle; C(═O)—Oalkyl; -alkylaryl where said aryl is optionally fused with an heterocycle and/or said aryl being optionally substituted by alkyl or COalkyl; said heterocycle comprising one or two nitrogen atom and being optionally substituted by an alkyl; 
 being optionally fused with an aryl; 
 
       
     
     
         7 . The compound according to  claim 1 , wherein the compound is of the following formula: 
       
         
           
           
               
               
           
         
         wherein:
 i is an integer chosen from 0, 1, 2, 3 or 4; 
 j is an integer chosen from 0, 1, 2 or 3; 
 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′; 
 
       
       where R and R′, identical or different are independently chosen from H, alkyl, aryl, -alkylaryl;
 X is H 
 Y is chosen from:
 (CHT) r -aryl wherein:
 said aryl is a monocyclic aryl and is optionally substituted by one or more of alkyl, SO 2 NRR′; —C(═O)—R; CN; —NRR′, CONRR, C(═O)—Oalkyl; wherein said alkyl is substituted by NRR′ or NR″R′″; 
 r is an integer chosen from 0 to 6; 
 each T is H; 
 
 
 
       where R″ and R′″ 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; alkyl; CN; CF 3 ; OR; NRR′; COR; COOR; CONRR′; 
       where R and R′, identical or different are independently chosen from H, alkyl, aryl, -alkylaryl;
 (CT 2 ′) p NRaRb where 
 when each T′ is H,
 Ra and Rb together form with the N atom to which they are attached
 a N comprising 6-membered mono substituted heterocycle wherein the carbon atom adjacent to the heteroatom is substituted by an alkyl; and p is 1, 3 or 4; or 
 a N-comprising 6-membered heterocycle and p is 1 to 4; or 
 a N-comprising 5-membered heterocycle wherein the carbon atom adjacent to the heteroatom is substituted by an alkyl; and p is 1 to 4; or 
 a N-comprising 7-membered heterocycle optionally substituted by an alkyl and p is 1, 2 or 4; or 
 a N-comprising 5-membered heterocycle and p is 1, 2 or 4; 
 a N-comprising 5- to 7-membered heterocycle substituted by one or more of halogen, -alkylaryl, or aryl, wherein said aryl is optionally substituted by one or more of halogen, —CN, CF 3 ; OR; NRR′; COR; COOR; CONRR′; 
 
 
 
       where R and R′, identical or different are independently chosen from H, alkyl, aryl, -alkylaryl;
 when each T′, identical or different, is independently chosen from H or a linear or branched alkyl, wherein the alkyl is optionally substituted by one or more OR, aryl, and at least one of the T′ is different from H,
 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′; and p is an integer chosen from 0 to 6; 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′; and p is an integer chosen from 0 to 6; 
 
 
       where R and R′, identical or different are independently chosen from H, alkyl, aryl, -alkylaryl, 
       
         
           
           
               
               
           
         
       
       wherein: 
       
         
           
           
               
               
           
         
       
       is
 a saturated monocyclic 5-membered heterocycle comprising a nitrogen atom and substituted by an alkyl, provided that the alkyl is not an ethyl; -alkylaryl; OR; C(═O)OR; ═O; CN; CF 3 ; COR; NRR′; CONRR′; aryl; wherein said aryl is optionally substituted by alkyl, halogen, OR, COR or NR′R; or 
 a monocyclic 6 membered heterocycle comprising an nitrogen atom and optionally substituted by one or more of -alkylaryl, OR; C(═O)OR; ═O; CN; CF 3 ; COR; NRR′; CONRR′; aryl; wherein said aryl is optionally substituted by halogen, COR, OR or NR′R;   q is an integer chosen from 0 to 6; 
 each T, identical or different is independently chosen from H or alkyl; 
 
       where R and R′, identical or different are independently chosen from H, alkyl, aryl, -alkylaryl;
 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 is optionally insaturated and/or is optionally substituted by one or more heterocycle or -alkylheterocycle said heterocycle, comprising one or two heteroatom, and being optionally substituted by an alkyl; 
 
       or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         8 . 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   9-chloro-N-(3-(2-methylpiperidin-1-yl)propyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(3-(pyrrolidin-1-ylmethyl)benzyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(3-(pyrrolidin-1-ylmethyl)phenyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(4-(pyrrolidin-1-ylmethyl)benzyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-((1-(4-methoxybenzyl)piperidin-4-yl)methyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-((1-4-N,N-dimethylbenzyl)piperidin-4-yl)methyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-((piperidin-4-yl)methyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(3-hydroxy-3-phenyl-2-pyrrolidin-1-ylmethylpropyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   N-(2-(azepan-1-yl)ethyl)-9-chloro-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(2-(piperidin-1-yl)ethyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   (9-chloro-5,6,7,8-tetrahydroacridine-3-yl)(44(1-methylpiperidin-4-yl)methyl)piperazin-1-yl)methanone   (9-chloro-5,6,7,8-tetrahydroacridine-3-yl)(4-(1-methylpiperidin-4-yl)piperazin-1-yl)methanone   (9-chloro-5,6,7,8-tetrahydroacridine-3-yl)(piperidin-1-yl)methanone   N-((1-benzylpiperidin-4-yl)methyl)-9-chloro-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-((1-(3-phenylpropyl)piperidin-4-yl)methyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-((1-phenethylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(5-(diethylamino)pentan-2-yl)-5,6,7,8-tetrahydroacridine-3-carboxamide   (R)-9-chloro-N-((1-ethylpyrrolidin-2-yl)methyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   (S)-9-chloro-N-((1-ethylpyrrolidin-2-yl)methyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(3-(dimethylamino)-2,2-dimethylpropyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)propyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   Chlorhydrate of 9-chloro-5,6,7,8-tetrahydroacridine-3-carboxylic acid (2-diethylamino-ethyl)amide or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof.   
     
     
         9 . The compound according to  claim 1 , chosen among:
 9-chloro-N-(3-(2-methylpiperidin-1-yl)propyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(3-(pyrrolidin-1-ylmethyl)benzyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(3-(pyrrolidin-1-ylmethyl)phenyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(4-(pyrrolidin-1-ylmethyl)benzyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-((1-(4-methoxybenzyl)piperidin-4-yl)methyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-((1-4-N,N-dimethylbenzyl)piperidin-4-yl)methyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-((piperidin-4-yl)methyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(3-hydroxy-3-phenyl-2-pyrrolidin-1-ylmethylpropyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-Chloro-5,6,7,8-tetrahydro-acridine-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide   Azepan-1-yl-(9-chloro-5,6,7,8-tetrahydro-acridin-3-yl)-methanone   [1,4′]Bipiperidinyl-1′-yl-(9-chloro-5,6,7,8-tetrahydro-acridin-3-yl)-methanone   N-(2-(azepan-1-yl)ethyl)-9-chloro-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(2-(piperidin-1-yl)ethyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   (9-chloro-5,6,7,8-tetrahydroacridin-3-yl)(44(1-methylpiperidin-4-yl)methyl)piperazin-1-yl)methanone   (9-chloro-5,6,7,8-tetrahydroacridin-3-yl)(4-(1-methylpiperidin-4-yl)piperazin-1-yl)methanone   (9-chloro-5,6,7,8-tetrahydroacridin-3-yl)(piperidin-1-yl)methanone   N-((1-benzylpiperidin-4-yl)methyl)-9-chloro-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-((1-(3-phenylpropyl)piperidin-4-yl)methyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-((1-phenethylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(5-(diethylamino)pentan-2-yl)-5,6,7,8-tetrahydroacridine-3-carboxamide   (R)-9-chloro-N-((1-ethylpyrrolidin-2-yl)methyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   (S)-9-chloro-N-((1-ethylpyrrolidin-2-yl)methyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   9-chloro-N-(3-(dimethylamino)-2,2-dimethylpropyl)-5,6,7,8-tetrahydroacridine-3-carboxamide   Chlorhydrate of 9-chloro-5,6,7,8-tetrahydroacridine-3-carboxylic acid (2-diethylamino-ethyl)amide or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof.   
     
     
         10 . Process for preparing a compound according to  claim 1 , comprising the reaction of a corresponding compound of formula (VII): 
       
         
           
           
               
               
           
         
         by peptidic coupling 
         with a corresponding compound of formula (VIII): 
       
       
         
           
           
               
               
           
         
         where i, j, k, n, Z, Ri, Rj and Rk are defined as in formula (I), R is OH or a halogen and X′ and Y′ are identical to X and Y respectively, or a precursor thereof, or an amino protecting group, optionally followed by alkylation(s) or deprotection. 
       
     
     
         11 . A compound of formula (VI): 
       
         
           
           
               
               
           
         
         where i, j, n, Z, Ri, Rj are defined as in  claim 1 , with the exception of 
       
       
         
           
           
               
               
           
         
       
     
     
         12 . 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. 
     
     
         13 . A compound of formula (I) as defined in  claim 1  or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof for use for inhibiting a USP. 
     
     
         14 . The compound for use according to  claim 13  for inhibiting USP7. 
     
     
         15 . A compound according to  claim 1  or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof for use 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. 
     
     
         16 . The compound for use according to  claim 15 , 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. 
     
     
         17 . 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.