Pyrazole Derivatives

Abstract

This invention relates to pyrazole derivatives of formula (I) or pharmaceutically acceptable salts, solvates or derivatives thereof, and to processes for the preparation thereof, intermediates used in their preparation of, compositions containing them and the uses of such derivatives. The compounds of the present invention bind to the enzyme reverse transcriptase and are modulators, especially inhibitors thereof. As such, the compounds of the present invention are useful in the treatment of a variety of disorders including those in which the inhibition of reverse transcriptase is implicated. Disorders of interest include those caused by Human Immunodificiency Virus (HIV) and genetically related retroviruses, such as Acquired Immune Deficiency Syndrome (AIDS).

1 . A process for preparing a compound of formula (I) or a salt, solvate or pharmaceutically acceptable derivative thereof according to any one of  claims 1  to  31 , comprising:
 (A) except where either R 1  or R 3  is halo, —OR 8  or —CN, condensing a compound of formula (II), (VI) or (VII): 
 
       
         
           
           
               
               
           
         
       
       with a compound of formula (V):
   H 2 NNHR 2   (V)
 
 or a salt or hydrate thereof; 
 (B) for preparing a compound of formula (I) in which R 1  or R 3  is —OR 8 , reacting a compound of formula (XIII) or (XIV); 
 
       
         
           
           
               
               
           
         
         wherein L 1 , L 2  and L 3  are each suitable leaving groups; 
         with an alcohol of formula (XXI);
   R 8 OH  (XXI)
 
 
         in the presence of a suitable palladium catalyst and carbon monoxide; 
         (C) for preparing a compound of formula (I) in which R 1  or R 3  is —OR 8 , reacting a compound of formula (XV) or (XVI); 
       
       
         
           
           
               
               
           
         
         with a compound of formula (XXI);
   R 8 OH  (XXI)
 
 
         under dehydrating conditions; or 
         (D) for preparing a compound of formula (I) in which R 1  or R 3  is halo, reacting a compound of formula (XV) or (XVI); 
       
       
         
           
           
               
               
           
         
       
       with a halogenating agent; or
 (E) interconverting a compound of formula (I) into another compound of formula (I); or 
 (F) deprotecting a protected derivative of a compound of formula (I); and optionally converting a compound of formula (I) prepared by any one of processes (A) to (F) into a pharmaceutically acceptable salt, solvate or derivative thereof. 
 
     
     
         2 . A compound of formula (II), (VI), (VII), (XIII) or (XIV): 
       
         
           
           
               
               
           
         
       
       wherein:
 either:
 R 1  is H, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, phenyl, benzyl, halo, —CN, —OR 7 , —CO 2 R 18 , —CONR 5 R 10 , R 8  or R 9 , said C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, phenyl and benzyl being unsubstituted or substituted by halo, —CN, —OR 10 , S(O) x R 10 , —CO 2 R 10 , —CONR 5 R 10 , —OCONR 5 R 10 , —NR 5 CO 2 R 10 , —NR 10 R 11 , —NR 5 COR 10 , SO 2 NR 5 R 10 , —NR 5 CONR 5 R 10 , —NR 5 SO 2 R 10  or R 10 ; and 
 R 2  is H, C 1 -C 6  alkyl, C 3 -C 6  alkenyl, C 3 -C 6  alkynyl, C 3 -C 7  cycloalkyl, C 3 -C 7  cycloalkenyl, phenyl, benzyl, R 8  or R 9 , said C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, phenyl and benzyl being unsubstituted or substituted by halo, —OR 5 , —OR 12 , —CN, —CO 2 R 7 , —OCONR 5 R 5 , —CONR 5 R 5 , —C(═NR 5 )NR 5 OR 5 , —CONR 5 NR 5 R 5 , —NR 6 R 6 , —NR 5 R 12 , —NR 5 COR 5 , —NR 5 COR 8 , —NR 5 COR 12 , —NR 5 CO 2 R 5 , —NR 5 CONR 5 R 5 , —SO 2 NR 5 R 5 , —NR 5 SO 2 R 5 , —NR 5 SO 2 NR 5 R 5 , R 8  or R 9 ; or 
 R 1  and R 2 , when taken together, represent unbranched C 3 -C 4  alkylene, unsubstituted or substituted by oxo, wherein one methylene group of said C 3 -C 4  alkylene may be replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being unsubstituted or substituted by R 10 ; 
 
 R 3  is H, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, phenyl, benzyl, halo, —CN, —OR 7 , —CO 2 R 5 , —CONR 5 R 5 , R 8  or R 9 , said C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, phenyl and benzyl being unsubstituted or substituted by halo, —CN, —OR 5 , —CO 2 R 5 , —CONR 5 R 5 , —OCONR 5 R 5 , —NR 5 CO 2 R 5 , —NR 5 R 5 , —NR 5 COR 5 , —SO 2 NR 5 R 5 , —NR 5 CONR 5 R 5 , —NR 5 SO 2 R 5 , R 8  or R 9 ; 
 R 4  is phenyl, naphthyl or pyridyl, each being unsubstituted or substituted by R 8 , halo, —CN, C 9 -C 6  alkyl, C 1 -C 6  haloalkyl, C 3 -C 7  cycloalkyl, C 1 -C 6  alkoxy, —CONR 5 R 5 , OR 13 , SO x R 6 , O—(C 1 -C 6  alkylene)-CONR 5 R 5 , O—(C 1 -C 6  alkylene)-NR 5 R 5 , or O—(C 1 -C 6  alkylene)-OR 6 ; 
 each R 5  is independently either H, C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl or, when two R 5  groups are attached to the same nitrogen atom, those two groups taken together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl and morpholinyl being optionally substituted by C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl; 
 each R 6  is independently either H, C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl; 
 R 7  is C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl; 
 R 8  is a five or six-membered, aromatic heterocyclic group containing (i) from 1 to 4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1 oxygen or 1 sulphur heteroatom or (iii) 1 or 2 oxygen or sulphur heteroatom(s), said heterocyclic group being unsubstituted or substituted by halo, oxo, —CN, —COR 5 , —CONR 5 R 5 , —SO 2 NR 5 R 5 , NR 5 SO 2 R 5 , —NR 5 R 5 , —(C 1 -C 6  alkylene)-NR 5 R 5 , C 1 -C 6  alkyl, fluoro(C 1 -C 6 )alkyl or C 3 -C 7  cycloalkyl; 
 R 9  is a four to seven-membered, saturated or partially unsaturated heterocyclic group containing (i) 1 or 2 nitrogen heteroatom(s) or (ii) 1 nitrogen heteroatom and 1 oxygen or 1 sulphur heteroatom or (iii) 1 oxygen or sulphur heteroatom, said heterocyclic group being unsubstituted or substituted by oxo, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, —SO 2 R 5 , —CONR 5 R 5 , —COOR 5 , —CO—(C 1 -C 6  alkylene)-OR 5  or —COR 5  and unsubstituted or substituted on a carbon atom which is not adjacent to a heteroatom by halo, —OR 5 , —NR 5 R 5 , —NR 5 COR 5 , —NR 5 COOR 5 , —NR 5 CONR 5 R 5 , —NR 5 SO 2 R 5  or —CN; 
 R 10  is H, R 8 , R 9 , R 13 , C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl or —(C 1 -C 6  alkyl)-(C 3 -C 7  cycloalkyl), said C 1 -C 6  alkyl and C 3 -C 7  cycloalkyl being unsubstituted or substituted by —OR 5 , —OR 13 , R 8 , R 9 , R 13  or —COR 13 ; 
 R 11  is H, C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, said C 1 -C 6  alkyl and C 3 -C 7  cycloalkyl being unsubstituted or substituted by —OR 5 , —NR 5 R 5 , —NR 5 COR 5 , —CONR 5 R 5 , R 8  or R 9 ; 
 R 12  is C 1 -C 6  alkyl substituted by R 8 , R 9 , —OR 5 , —CONR 5 R 5 , —NR 5 COR 5  or —NR 5 R 5 ; 
 R 13  is phenyl unsubstituted or substituted by halo, —CN, —COR 5 , —CONR 5 R 5 , SO 2 NR 5 R 5 , —NR 5 SO 2 R 5 , —OR 5 , —NR 5 R 5 , —(C 1 -C 6  alkylene)-NR 5 R 5 , C 1 -C 6  alkyl, halo(C 1 -C 6 )alkyl or C 3 -C 7  cycloalkyl; and 
 x is 0, 1 or 2; 
 
       with the proviso that:
 (a) when R 1  and R 3  are both phenyl, R 2  is not methyl; and 
 (b) when R 1  is ethoxy and R 3  is ethoxycarbonyl, R 2  is not phenyl; and L 1 , L 2  and L 3  are each suitable leaving groups.