Pyrimidine derivatives as posh and posh-ap inhibitors

Abstract

Pyrimidine deriviatives are ubiquination inhibitors that inhibit the ubiquitin ligase activity, particularly of POSH polypeptides, are useful for the treatment of viral infections and neurological disorders.

1 - 71 . (canceled) 
     
     
         72 . A method for treating a neurological disease, disorder or condition in a subject, comprising administering to said subject a compound that inhibits the ubiquitin ligase activity of a human polypeptide, wherein said compound is of the formula I: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is alkyl, aryl, heteroaryl, —COR 6 , —COOR 6 , —NR 7 R 8 , —CONR 7 R 8  or —NR 9 COR 10 ; 
         R 2  is aryl or heteroaryl; 
         R 3  represents H or one to three radicals selected from lower alkyl, lower alkoxy, halogen, —NR 7 R 8 , —COOR 6  or —CONR 7 R 8 ; 
         R 4  is H, alkyl, aryl, carbocyclyl, acyl, —OH or heterocyclyl; 
         R 5  is H, halogen, alkyl, aryl, heteroaryl, —OR 6 , —SR 6 , —COR 6 , —COOR 6 , —NR 7 R 8 , —CONR 7 R 8  or —NR 9 COR 10 ; or R 4  and R 5  together with the carbon and nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring optionally containing a further double bond; 
         R 6  is H, hydrocarbyl or heterocyclyl; 
         R 7  and R 8  each independently is H, hydrocarbyl or heterocyclyl, or R 7  and R 8  together with the nitrogen atom to which they are attached form a 5-6 saturated heterocyclic ring, optionally containing 1 or 2 further heteroatoms selected from the group consisting of N, S and O, and wherein said further N atom is optionally substituted by alkyl, aralkyl, haloalkyl or hydroxyalkyl; 
         R 9  is H, alkyl or phenyl; 
         R 10  is aryl or heteroaryl; 
         wherein said hydrocarbyl, heterocyclyl, aryl and heteroaryl is optionally substituted by one or more radicals selected from the group consisting of lower alkyl, halogen, aryl, heterocyclyl, heteroaryl, nitro, epoxy, epithio, —OR 6 , —SR 6 , —COR 6 , —COOR 6 , —NR 7 R 8 , —CONR 7 R 8 , —NR 7 —COR 6 , —SO 3 R 6 , —SO 2 R 6 , —SO 2 NR 7 R 8  and —NR 7 SO 2 R 6 , wherein R 6 , R 7  and R 8  are as defined above; 
         or an enantiomer or a pharmaceutically acceptable salt thereof; 
         wherein said compound is administered in an amount effective for inhibiting the ubiquitin ligase activity of said human polypeptide. 
       
     
     
         73 . The method according to  claim 72 , wherein:
 (i) said hydrocarbyl is a straight or branched, acyclic or cyclic, saturated, unsaturated or aromatic, hydrocarbyl radical, of 1-20 carbon atoms, selected from the group consisting of an alkyl, alkenyl, alkynyl, carbocyclyl, aryl and an aralkyl radicals;   (ii) said alkyl is a straight or branched alkyl of 1 to 10 carbon atoms (C 1 -C 10  alkyl), or a lower alkyl (C 1 -C 4  alkyl) selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, sec-butyl and tert-butyl, optionally interrupted by one or more heteroatoms selected from the group consisting of O, S and N, and/or substituted by one or more radicals selected from the group consisting of halogen, aryl, heteroaryl, heterocyclyl, nitro, epoxy, epithio, —OR, —SR, —COR, —COOR, —NRR′, —CONRR′, —NRCOR′, —SO 3 R, —SO 2 R, —SO 2 NRR′ and —NRSO 2 R, wherein R and R′ are each independently H, hydrocarbyl or heterocyclyl, or R and R′ together with the nitrogen atom to which they are attached form a saturated 5-6 membered heterocyclic ring, optionally containing 1 or 2 further heteroatoms selected from the group consisting of N, S and O, said further N atom is optionally substituted by alkyl, aralkyl, haloalkyl or hydroxyalkyl;   (iii) said carbocyclyl is a saturated C 5 -C 6  cycloalkyl or partially unsaturated C 5 -C 6  cycloalkenyl radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl, optionally substituted by one or more radicals selected from the group consisting of halogen, hydrocarbyl, heterocyclyl, nitro, epoxy, epithio, OR, —SR, —COR, —COOR, —NRR′, —CONRR′, —NRCOR′, —SO 3 R, —SO 2 R, —SO 2 NRR′ and —NRSO 2 R, wherein R and R′, independently, each is H, hydrocarbyl or heterocyclyl, or R and R′ together with the nitrogen atom to which they are attached form a saturated 5-6 membered heterocyclic ring, optionally containing 1 or 2 further heteroatoms selected from the group consisting of N, S and O, and wherein said further N atom is optionally substituted by alkyl, aralkyl, haloalkyl or hydroxyalkyl;   (iv) said aryl is a substituted or unsubstituted monocyclic, bicyclic or tricyclic aromatic carbocyclic radical of 6 to 14 carbon atoms, selected from the group consisting of phenyl, biphenyl, naphthyl, and anthracenyl;   (v) said heterocyclyl is a saturated or partially unsaturated, optionally substituted, monocyclic, bicyclic or tricyclic heterocycle, of 3 to 12 ring members, of which one to three atoms is a heteroatom selected from the group consisting of O, S and N; or   (vi) said heteroaryl is a substituted or unsubstituted mono- or poly-cyclic heteroaromatic ring containing one to three heteroatoms selected from the group consisting of O, S and N.   
     
     
         74 . The method according to  claim 72 , wherein in said compound of formula I:
 R 1  is NR 9 COR 10 ;   R 2  is a heteroaryl;   R 3  is H or one to three alkyl radicals;   R 4  is H, alkyl, carbocyclyl, aryl, acyl, —OH or heterocyclyl;   R 5  is H, halogen, alkyl, aryl, heteroaryl, —OR 6 , —SR 6 , —COR 6 , —COOR 6 , —NR 7 R 8 , —CONR 7 R 8  or —NR 9 COR 10 ; or R 4 , the nitrogen atom to which it is attached and R 5  form a 5-6 membered heterocyclic ring;   R 6  is H, alkyl, aryl or heterocyclyl;   R 7  and R 8  each independently is H, alkyl, aryl or heterocyclyl, or R 7  and R 8  together with the nitrogen atom to which they are attached form a saturated 5-6 membered heterocyclic ring, optionally containing 1 or 2 further heteroatoms selected from the group consisting of N, S and O, and wherein said further N atom is optionally substituted by lower alkyl, aralkyl, haloalkyl or hydroxyalkyl;   R 9  is H, alkyl or phenyl;   R 10  is aryl or heteroaryl;   wherein said alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is optionally substituted by one or more radicals selected from the group consisting of halogen, alkyl, aryl, heterocyclyl, nitro, epoxy, epithio, OR, —SR, —COR, —COOR′—NRR′, —CONRR′, —NRCOR′—SO 3 R, —SO 2 R, —SO 2 NRR′ and —NRSO 2 R, wherein R and R′, independently, each is H, hydrocarbyl or heterocyclyl, or R and R′ together with the nitrogen atom to which they are attached form a saturated heterocyclic ring, optionally containing 1 or 2 further heteroatoms selected from the group consisting of N, S and O, and wherein said further N atom is optionally substituted by hydrocarbyl.   
     
     
         75 . The method according to  claim 74 , wherein said compound is of the formula Ia or Ib: 
       
         
           
           
               
               
           
         
         wherein 
         X is O, S or NH; 
         R 3  is H or one to three (C 1 -C 4 ) alkyls; 
         R 4  is H or (C 1 -C 4 ) alkyl; 
         R 5  is H or (C 1 -C 6 ) alkyl; 
         and R 11  to R 19 , each independently is selected from H, lower alkyl, halogen, aryl, heterocyclyl, heteroaryl, nitro, epoxy, epithio, —OR 6 , —SR 6 , —COR 6 , —COOR 6 , —NR 7 R 8 , —CONR 7 R 8 , nitro, —NR 7 —COR 6 , —SO 3 R 6 , —SO 2 R 6 , —SO 2 NR 7 R 8  and —NR 7 SO 2 R 6 , wherein R 6 , R 7  and R 8  each independently is H, alkyl, aryl or heterocyclyl, or R 7  and R 8  together with the nitrogen atom to which they are attached form a saturated heterocyclic ring, optionally containing 1 or 2 further heteroatoms selected from N, S and/or O, and wherein said further N atom is optionally substituted by alkyl, optionally substituted by phenyl, halogen or hydroxy; and 
         the dotted line in formula Ib represents an optional double bond. 
       
     
     
         76 . The method according to  claim 75 , wherein in said compound of formula Ia X is S, R 3  is H or one to three methyl groups, R 4  is H, R 5  is H or methyl and R 11  to R 16  are H, and in said compound formula Ib X is S, R 3  is H or one to three methyl groups, and R 11  to R 19  are H. 
     
     
         77 . The method according to  claim 76 , wherein said compound of formula Ia is selected from the group consisting of:
 Compound 1 of the formula:   
       
         
           
           
               
               
           
         
         Compound 2 of the formula: 
       
       
         
           
           
               
               
           
         
         Compound 3 of the formula: 
       
       
         
           
           
               
               
           
         
       
       and
 Compound 4 of the formula: 
 
       
         
           
           
               
               
           
         
       
       and said compound of formula Ib is selected from the group consisting of:
 Compound 5 of the formula: 
 
       
         
           
           
               
               
           
         
         Compound 6 of the formula: 
       
       
         
           
           
               
               
           
         
       
       and
 Compound 7 of the formula: 
 
       
         
           
           
               
               
           
         
       
     
     
         78 . The method according to  claim 72 , wherein said human polypeptide contains a RING domain. 
     
     
         79 . The method according to  claim 78 , wherein said human polypeptide contains at least one SH3 domain. 
     
     
         80 . The method according to  claim 78 , wherein said human polypeptide is a human POSH polypeptide. 
     
     
         81 . The method according to  claim 72 , wherein said compound inhibits the ubiquitination of a POSH-associated protein (POSH-AP). 
     
     
         82 . The method according to  claim 81 , wherein said POSH-associated protein (POSH-AP) is HERPUD1. 
     
     
         83 . The method according to  claim 72 , wherein said neurological disorder or disease is selected from diseases or disorders associated with increased levels of plasma homocysteine, increased levels of amyloid beta production, or aberrant presenilin activity. 
     
     
         84 . The method according to  claim 83 , wherein said neurological disorder or disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, Niemann-Pick's disease, prion-associated diseases such as Mad Cow disease, stroke, cerebral vascular disease, depression, schizophrenia and other neurological disorders associated with unwanted apoptosis. 
     
     
         85 . The method according to  claim 84 , wherein said neurological disorder or disease is Alzheimer's disease. 
     
     
         86 . The method according to  claim 84 , wherein the compound administered is Compound 1, Compound 2 or Compound 5. 
     
     
         87 . A method of treating a chronic or acute neurological disease, disorder or condition in a subject, comprising administering to said subject a compound of formula I: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is alkyl, aryl, heteroaryl, —COR 6 , —COOR 6 , —NR 7 R 8 , —CONR 7 R 8  or —NR 9 COR 10 ; 
         R 2  is aryl or heteroaryl; 
         R 3  represents H or one to three radicals selected from lower alkyl, lower alkoxy, halogen, —NR 7 R 8 , —COOR 6  or —CONR 7 R 8 ; 
         R 4  is H, alkyl, aryl, carbocyclyl, acyl, —OH or heterocyclyl; 
         R 5  is H, halogen, alkyl, aryl, heteroaryl, —OR 6 , —SR 6 , —COR 6 , —COOR 6 , —NR 7 R 8 , —CONR 7 R 8  or —NR 9 COR 10 ; or R 4  and R 5  together with the carbon and nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring optionally containing a further double bond; 
         R 6  is H, hydrocarbyl or heterocyclyl; 
         R 7  and R 8  each independently is H, hydrocarbyl or heterocyclyl, or R 7  and R 8  together with the nitrogen atom to which they are attached form a 5-6 saturated heterocyclic ring, optionally containing 1 or 2 further heteroatoms selected from the group consisting of N, S and O, and wherein said further N atom is optionally substituted by alkyl, aralkyl, haloalkyl or hydroxyalkyl; 
         R 9  is H, alkyl or phenyl; 
         R 10  is aryl or heteroaryl; 
         wherein said hydrocarbyl, heterocyclyl, aryl and heteroaryl is optionally substituted by one or more radicals selected from the group consisting of lower alkyl, halogen, aryl, heterocyclyl, heteroaryl, nitro, epoxy, epithio, —OR 6 , —SR 6 , —COR 6 , —COOR 6 , —NR 7 R 8 , —CONR 7 R 8 , —NR 7 —COR 6 , —SO 3 R 6 , —SO 2 R 6 , —SO 2 NR 7 R 8  and —NR 7 SO 2 R 6 , wherein R 6 , R 7  and R 8  are as defined above; 
         or an enantiomer or a pharmaceutically acceptable salt thereof; 
         wherein said compound is administered in an amount effective for inhibiting the ubiquitin ligase activity of said human polypeptide. 
       
     
     
         88 . The method according to  claim 87 , wherein the neurological disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, Niemann-Pick's disease, prion-associated diseases such as Mad Cow disease, stroke, cerebral vascular disease, depression, schizophrenia and other neurological disorders associated with unwanted apoptosis. 
     
     
         89 . The method according to  claim 88 , wherein the compound administered is Compound 1, Compound 2 or Compound 5. 
     
     
         90 . The method according to  claim 83 , wherein the compound of formula I inhibits the transport of amyloid precursor protein (APP) in a cell.