Processes for the Synthesis of Substituted Urea Compounds

Abstract

The present invention concerns a process for preparing a compound having the Formula A: or a pharmaceutically acceptable salt or derivative thereof, or for preparing a substituted urea compound of Formula IIa, or a pharmaceutically acceptable salt or ester thereof, the process comprising the reaction of an imidazolyl intermediate of Formula IIa′, with a carbamoyl halide of the formula: R1R2NC(═O)Hal, wherein Hal represents Cl, F, I or Br, wherein the intermediate of Formula IIa′ is prepared by oxidation of the derivative of R5 and R6, R6-C(═O)CH 2 R5 to form a glyoxal intermediate R6-C(═O)(C═O)R5, which is subjected to treatment with ammonium hydroxide and an aldehyde R8CHO to provide the intermediate of Formula IIa′, and wherein the compound substituents are as defined herein.

1 . A process for preparing a compound having the Formula A: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or derivative thereof, or for preparing a substituted urea compound of Formula IIa, or a pharmaceutically acceptable salt or ester thereof, 
       
       
         
           
           
               
               
           
         
         the process comprising the reaction of an imidazolyl intermediate of Formula IIa′, 
       
       
         
           
           
               
               
           
         
         with a carbamoyl halide of the formula: R1R2NC(═O)Hal, wherein Hal represents Cl, F, I or Br, 
         wherein the intermediate of Formula IIa′ is prepared by oxidation of the derivative of R5 and R6, R6-C(═O)CH 2 R5 to form a glyoxal intermediate R6-C(═O)(C═O)R5, which is subjected to treatment with ammonium hydroxide and an aldehyde R8CHO to provide the intermediate of Formula IIa′, 
         wherein, in the case of preparation of the compound of Formula A, R6 is NH 2 CONH-phenyl, or a nitrophenyl, aminophenyl or amino-protected aminophenyl precursor of this moiety which can be subjected to conversion to the NH 2 CONH-phenyl group after urea formation, and R5 is H, R1 is methyl and R2 is cyclopentyl; 
         and wherein, in the case of preparation of a compound of Formula IIa, R1 and R2 can each be independently selected from H, C 1-20  alkyl, C 1-6  alkoxy, aryl, heteroaryl, partially or fully saturated heterocyclyl, C 3-10  cycloalkyl, aryl C 1-6  alkyl, heteroaryl C 1-6  alkyl, heterocyclyl C 1-6  alkyl, C 3-10  cycloalkyl C 1-6  alkyl, R1a, halogen, OH, OR1a, OCOR1a, SH, SR1a, SCOR1a, NH 2 , NHR1a, NHSO 2 NH 2 , NHSO 2 R1a, NR1aCOR1b, NHCOR1a, NR1aR1b, COR1a, CSR1a, CN, COOH, COOR1a, CONH 2 , CONHOH, CONHR1a, CONHOR1a, SO 2 R1a, SO 3 H, SO 2 NH 2 , CONR1aR1b, SO 2 NR1aR1b, wherein R1a and R1b are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl, or R1a and R1b, together with the heteroatom to which they are joined, can form heterocyclyl, 
         wherein, when R1 or R2 is C 1-20  alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, C 3-10  cycloalkyl, aryl C 1-6  alkyl, heteroaryl C 1-6  alkyl, heterocyclyl C 1-6  alkyl, C 3-10  cycloalkyl C 1-6  alkyl, or is a group containing one or more of these moieties, each of these moieties may optionally be substituted with one or more groups selected from R1c, halogen, aryl, heteroaryl, heterocyclyl, C 1-6  alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aryl C 1-6  alkyl, heteroaryl C 1-6  alkyl, heterocyclyl C 1-6  alkyl, aryl C 1-6  alkoxy, heteroaryl C 1-6  alkoxy, heterocyclyl C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  dialkylamino, C 1-10  alkyl, OH, OR1c, OCOR1c, SH, SR1c, SCOR1c, NH 2 , NO 2 , NHR1c, NHSO 2 NH 2 , NHSO 2 R1c, NR1cCOR1d, NHC(NH)NH 2 , NHCOR1c, NR1cR1d, COR1c, CSR1c, CN, COOH, COOR1c, CONH 2 , CONHOH, CONHR1c, CONHOR1c, C(NOH)NH 2 , CONR1cR1d, SO 2 R1c, SO 3 H, SO 2 NH 2 , SO 2 NR1cR1d, wherein R1c and R1d are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl, or R1c and R1d, together with the heteroatom to which they are joined, can form heterocyclyl, 
         wherein, when the substituent of R1 or R2 is C 1-10  alkyl, aryl, heteroaryl, heterocyclyl, C 1-6  alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aryl C 1-6  alkyl, heteroaryl C 1-6  alkyl, heterocyclyl C 1-6  alkyl, aryl C 1-6  alkoxy, heteroaryl C 1-6  alkoxy, heterocyclyl C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  dialkylamino, C 1-6  alkyl, C 3-8  cycloalkyl or is a group containing one or more of these moieties, each of these moieties may optionally be substituted with one or more groups selected from R1e, halogen, C 1-10  alkyl, OH, OR1e, OCOR1e, SH, SR1e, SCOR1e, NH 2 , NO 2 , NHR1e, NHSO 2 NH 2 , NHSO 2 R1e, NR1eCOR1f, NHC(NH)NH 2 , NHCOR1e, NR1eR1f, COR1e, CSR1e, CN, COOH, COOR1e, CONH 2 , CONHOH, CONHR1e, CONHOR1e, C(NOH)NH 2 , CONR1eR1f, SO 2 R1e, SO 3 H, SO 2 NH 2 , SO 2 NR1eR1f, wherein R1e and R1f are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl, or R1e and R1f, together with the heteroatom to which they are joined, can form heterocyclyl, 
         with the exception that R1 and R2 are not both H; 
         or 
         R1 and R2, together with the N to which they are attached, can form a heteroaryl or heterocyclyl group, each of which may optionally be substituted with one or more oxygen atoms or one or more groups selected from aryl, heteroaryl, partially or fully saturated heterocyclyl, C 3-8  cycloalkyl, C 1-6  alkyl, aryl C 1-6  alkyl, heteroaryl C 1-6  alkyl, heterocyclyl C 1-6  alkyl, C 3-8  cycloalkyl C 1-6  alkyl, C 1-6  alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, R2a, halogen, OH, OR2a, OCOR2a, SH, SR2a, SCOR2a, NH 2 , NO 2 , NHR2a, NHSO 2 NH 2 , NHSO 2 R2a, NR2aCOR2b, NHC(NH)NH 2 , NHCOR2a, NR2aR2b, COR2a, CSR2a, CN, COOH, COOR2a, CONH 2 , CONHOH, CONHR2a, CONHOR2a, C(NOH)NH 2 , CONR2aR2b, SO 2 R2a, SO 3 H, SO 2 NH 2 , SO 2 NR2aR2b, wherein R2a and R2b are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl, or R2a and R2b, together with the heteroatom to which they are joined, can form heterocyclyl, 
         wherein, when the substituent of the heteroaryl or heterocyclyl formed by R1 and R2 together is aryl, heteroaryl, heterocyclyl, C 3-8  cycloalkyl, C 1-6  alkyl, aryl C 1-6  alkyl, heteroaryl C 1-6  alkyl, heterocyclyl C 1-6  alkyl, C 3-8  cycloalkyl C 1-6  alkyl, C 1-6  alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, or a group containing one or more of these moieties, each of these moieties may optionally be substituted with one or more groups selected from halogen, hydroxyl, C 1-6  alkyl, aryl, heteroaryl, heterocyclyl, C 3-8  cycloalkyl, C 1-4  alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, C 3-8  cycloalkyloxy, aryl C 1-4  alkoxy, heteroaryl C 1-6  alkoxy, heterocyclyl C 1-4  alkoxy, C 3-8  cycloalkyl C 1-4  alkoxy, R2c, OR2c, OCOR2c, SH, SR2c, SCOR2c, NH 2 , NO 2 , NHR2c, NHSO 2 NH 2 , NHSO 2 R2c, NR2cCOR2d, NHC(NH)NH 2 , NHCOR2c, NR2cR2d, COR2c, CSR2c, CN, COOH, COOR2c, CONH 2 , CONHOH, CONHR2c, CONHOR2c, C(NOH)NH 2 , CONR2cR2d, SO 2 R2c, SO 3 H, SO 2 NH 2 , SO 2 NR2cR2d, wherein R2c and R2d are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl, or R2c and R2d, together with the heteroatom to which they are joined, can form heterocyclyl, 
         wherein, when the substituent of the substituent of the heteroaryl or heterocyclyl formed by R1 and R2 together is C 1-6  alkyl, aryl, heteroaryl, heterocyclyl, C 3-8  cycloalkyl, C 1-6  alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, C 3-8  cycloalkyloxy, aryl C 1-4  alkoxy, heteroaryl C 1-4  alkoxy, heterocyclyl C 1-4  alkoxy, C 3-8  cycloalkyl C 1-4  alkoxy, or is a group containing one or more of these moieties, each of these moieties may optionally be substituted with one or more groups selected from C 1-4  alkoxy, R2e, halogen, OH, OR2e, OCOR2e, SH, SR2e, SCOR2e, NH 2 , NO 2 , NHR2e, NHSO 2 NH 2 , NHSO 2 R2e, NR2eCOR2f, NHC(NH)NH 2 , NR2eR2f, NHCOR2e, COR2e, CSR2e, CN, COOH, COOR2e, CONH 2 , CONHOH, CONHR2e, CONHOR2e, C(NOH)NH 2 , CONR2eR2f, SO 2 R2e, SO 3 H, SO 2 NH 2 , SO 2 NR2eR2f, wherein R2e and R2f are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl, or R2e and R2f, together with the heteroatom to which they are joined, can form heterocyclyl; 
         R5 together with the C to which it is attached, can form a carbonyl group with the double bonds in Formula IIa rearranged accordingly, or R5 is selected from H, C 1-6  alkyl, aryl, heteroaryl, heterocyclyl, C 3-8  cycloalkyl, C 1-6  alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, R5a, halogen, OH, OR5a, SH, SR5a, OCOR5a, SCOR5a, NH 2 , NO 2 , NHR5a, NHSO 2 NH 2 , NHSO 2 R5a, NR5aCOR5b, NHCOR5a, NHC(NH)NH 2 , NR5aR5b, COR5a, CSR5a, CN, COOH, COOR5a, CONH 2 , CONHOH, CONHR5a, CONHOR5a, C(NOH)NH 2 , CONR5aR5b, SO 2 R5a, SO 3 H, SO 2 NH 2 , SO 2 NR5aR5b, wherein R5a and R5b are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl, or R5a and R5b, together with the heteroatom to which they are joined, can form heterocyclyl, 
         wherein, when R5 is C 1-6  alkyl, aryl, heteroaryl, heterocyclyl, C 1-6  alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, C 1-6  alkyl, C 3-8  cycloalkyl, or is a group containing one or more of these moieties, each of these moieties may optionally be substituted with one or more groups selected from halogen, aryl, heteroaryl, heterocyclyl, C 1-6  alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, R5c, C 1-6  alkyl, OH, OR5c, OCOR5c, SH, SR5c, SCOR5c, NH 2 , NO 2 , NHR5c, NHSO 2 NH 2 , NHSO 2 R5c, NR5cCOR5d, NHCOR5c, NHC(NH)NH 2 , NR5cR5d, COR5c, CSR5c, CN, COOH, COOR5c, CONH 2 , CONHOH, CONHR5c, CONHOR5c, C(NOH)NH 2 , CONR5cR5d, SO 2 R5c, SO 3 H, SO 2 NH 2 , SO 2 NR5cR5d, wherein R5c and R5d are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl, or R5c and R5d, together with the heteroatom to which they are joined, can form heterocyclyl, 
         wherein, when the substituent of R5 is C 1-6  alkyl, aryl, heteroaryl, heterocyclyl, C 1-6  alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, C 3-8  cycloalkyl, or is a group containing one or more of these moieties, each of these moieties may optionally be substituted with one or more groups selected from halogen, R5e, C 1-6  alkyl, OH, OR5e, OCOR5e, SH, SR5e, SCOR5e, NH 2 , NO 2 , NHR5e, NHSO 2 NH 2 , NHSO 2 R5e, NR5eCOR5f, NHCOR5e, NHC(NH)NH 2 , NR5eR5f, COR5e, CSR5e, CN, COOH, COOR5e, CONH 2 , CONHOH, CONHR5e, CONHOR5e, C(NOH)NH 2 , CONR5eR5f, SO 2 R5e, SO 3 H, SO 2 NH 2 , SO 2 NR5eR5f, wherein R5e and R5f are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl, or R5e and R5f, together with the heteroatom to which they are joined, can form heterocyclyl; 
         R6 is selected from C 1-6  alkyl, aryl, heteroaryl, heterocyclyl, C 1-6  alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, R6a, halogen, OH, OR6a, SH, SR6a, OCOR6a, SCOR6a, NH 2 , NO 2 , NHR6a, NHSO 2 NH 2 , NHSO 2 R6a, NR6aCOR6b, NHCOR6a, NHC(NH)NH 2 , NR6aR6b, COR6a, CSR6a, CN, COOH, COOR6a, CONH 2 , CONHOH, CONHR6a, CONHOR6a, C(NOH)NH 2 , CONR6aR6b, SO 2 R6a, SO 3 H, SO 2 NH 2 , SO 2 NR6aR6b, wherein R6a and R6b are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl, or R6a and R6b, together with the heteroatom to which they are joined, can form heterocyclyl, 
         wherein, when R6 is heteroaryl or heterocyclyl, each of these moieties may optionally be substituted with one or more oxygen atoms, and when R6 is C 1-6  alkyl, aryl, heteroaryl, heterocyclyl, C 1-6  alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, C 3-8  cycloalkyl, or is a group containing one or more of these moieties, each of these moieties may optionally be substituted with one or more groups selected from halogen, R6c, C 1-6  alkyl, C 1-6  alkynyl, aryl, heteroaryl, heterocyclyl, C 1-6  alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aryl C 1-6  alkyl, heteroaryl C 1-6  alkyl, heterocyclyl C 1-6  alkyl, aryl C 1-6  alkoxy, heteroaryl C 1-6  alkoxy, heterocyclyl C 1-6  alkoxy, OH, OR6c, OCOR6c, SH, SR6c, SCOR6c, NH 2 , NO 2 , NHR6c, NHSO 2 NH 2 , NHC(NH)NH 2 , NHSO 2 R6c, NR6cCOR6d, NHCOR6c, NR6cR6d, COR6c, CSR6c, CN, COOH, COOR6c, CONH 2 , CONHR6c, CONHOR6c, CONHOH, C(NOH)NH 2 , CONR6cR6d, SO 2 R6c, SO 3 H, SO 2 NH 2 , SO 2 NR6cR6d, wherein R6c and R6d are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl, or R6c and R6d, together with the heteroatom to which they are joined, can form heterocyclyl, 
         wherein, when the substituent of R6 is heteroaryl or heterocyclyl, each of these moieties may optionally be substituted with one or more oxygen atoms, or when the substituent of R6 is C 1-6  alkyl, C 1-6  alkynyl, aryl, heteroaryl, heterocyclyl, C 1-6  alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aryl C 1-6  alkyl, heteroaryl C 1-6  alkyl, heterocyclyl C 1-6  alkyl, aryl C 1-6  alkoxy, heteroaryl C 1-6  alkoxy, heterocyclyl C 1-6  alkoxy, C 3-8  cycloalkyl, or is a group containing one or more of these moieties, each of these moieties may optionally be substituted with one or more groups selected from halogen, R6e, C 1-6  alkyl, C 1-4  alkoxy, OH, OR6e, OCOR6e, SH, SR6e, SCOR6e, NH 2 , NO 2 , NHR6e, NHSO 2 NH 2 , NHC(NH)NH 2 , NHSO 2 R6e, NR6eCOR6f, NHCOR6e, NR6eR6f, COR6e, CSR6e, CN, COOH, COOR6e, CONH 2 , CONHOH, CONHR6e, CONHOR6e, C(NOH)NH 2 , CONR6eR6f, SO 2 R6e, SO 3 H, SO 2 NH 2 , SO 2 NR6eR6f, wherein R6e and R6f are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl, or R6e and R6f, together with the heteroatom to which they are joined, can form heterocyclyl; and 
         R8 is hydrogen or a group selected from C 1-6  alkyl, aryl, heteroaryl, heterocyclyl, C 3-8  cycloalkyl, and acyl, wherein each of these moieties may be optionally substituted with one or more groups selected from halogen, hydroxy, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, aryl, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, heterocyclyloxy, and acyl, 
         wherein when the substituent of R8 is C 1-6  alkyl, C 1-6  alkoxy, or acyl, each of these moieties may optionally be substituted with one or more groups selected from halogen, hydroxy, C 1-6  alkoxy, heterocyclyl optionally substituted with 1 to 3 groups selected from halogen, C 1-6  alkyl, C 1-6  haloalkyl, and heteroaryl, C 1-6  alkylamino, and C 1-6  dialkylamino, and 
         wherein when the substituent of R8 is aryl, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, or heterocyclyloxy, each of these moieties may optionally be substituted with one or more groups selected from halogen, hydroxy, C 1-6  alkoxy, C 1-6  alkylamino, C 1-6  dialkylamino, aryl optionally substituted with 1 to 3 groups selected from halogen and C 1-6  haloalkyl, and acyl. 
       
     
     
         2 . The process according to  claim 1 , wherein the oxidation of the derivative of R5 and R6 employs an inorganic acid. 
     
     
         3 . The process according to  claim 2 , wherein the inorganic acid is HX, where X is a halogen atom. 
     
     
         4 . The process according to  claim 3 , wherein the inorganic acid is HCl or HBr. 
     
     
         5 . The process according to any preceding claim, wherein DMSO is used as a solvent and oxidising agent in the oxidation of the derivative of R5 and R6. 
     
     
         6 . The process according to any preceding claim, wherein R1 is selected from H and C 1-4  alkyl. 
     
     
         7 . The process according to  claim 6 , wherein R1 is selected from H, methyl and ethyl. 
     
     
         8 . The process according to any preceding claim, wherein R2 is selected from aryl, heteroaryl, heterocyclyl, C 3-10  cycloalkyl, aryl C 1-6  alkyl, heteroaryl C 1-6  alkyl, heterocyclyl C 1-6  alkyl and C 3-10  cycloalkyl C 1-6  alkyl, each of which may be substituted or unsubstituted. 
     
     
         9 . The process according to  claim 8 , wherein R2 is selected from aryl, heteroaryl, heterocyclyl, and C 3-10  cycloalkyl each of which may be substituted or unsubstituted. 
     
     
         10 . The process according to  claim 8  or  claim 9 , wherein R2 is selected from fully saturated heterocyclyl, and C 5-8  cycloalkyl each of which are monocyclic and may be substituted or unsubstituted. 
     
     
         11 . The process according to  claim 10 , wherein R2 is an unsubstituted cyclopentyl or unsubstituted cyclohexyl. 
     
     
         12 . The process according to  claim 10 , wherein R2 is a fully saturated heterocyclyl, and wherein the heterocyclyl ring contains a single heteroatom, such as nitrogen or oxygen. 
     
     
         13 . The process according to  claim 12 , wherein the heterocyclyl is six membered and the heteroatom in the said heterocyclyl group is at the 4-position relative to the position of attachment of the heterocyclyl group R2 to the urea nitrogen. 
     
     
         14 . The process according to  claim 13 , wherein the heteroatom is a nitrogen heteroatom which is substituted with a group selected from CN, CONH 2 , C(NOH)NH 2 , SO 2 —C 1-4  alkyl, SO 2 -aryl, CO-heteroaryl, CO—C 1-4  alkyl, COO—C 1-4  alkyl, C 1-4  alkyl, aryl C 1-3  alkyl, heteroaryl C 1-3  alkyl, heterocyclyl C 1-3  alkyl, aryl, heteroaryl, and heterocyclyl, wherein the C 1-4  alkyl may optionally be substituted with OH, CN, COOH, the SO 2 -aryl may optionally be substituted with a C 1-4  alkyl or C 1-4  haloalkyl, the CO-heteroaryl may optionally be substituted with a heteroaryl or halogen, the heteroaryl C 1-3  alkyl may optionally be substituted with COO—C 1-3  alkyl, and the heteroaryl may optionally be substituted with one or more halogens. 
     
     
         15 . The process according to  claim 14 , wherein the nitrogen heteroatom is substituted with phenyl C 1-3  alkyl. 
     
     
         16 . The process according to any preceding claim, wherein R6 is selected from monocyclic aryl, monocyclic heteroaryl, and heterocyclyl, each of which may be substituted or unsubstituted. 
     
     
         17 . The process according to  claim 16 , wherein R6 is a substituted aryl, and wherein said aryl is substituted with one or more groups selected from halogen, R6a, OH, OR6a, NH 2 , NO 2 , NHC(NH)NH 2 , NHR6a, NR6aR6b, C(NOH)NH 2 , COR6a, COOH, COOR6a, CONH 2 , CONHOH, SO 2 R6a, SO 2 NR6aR6b, wherein R6a and R6b are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl, wherein R6a and R6b are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl,
 wherein, when the substituent of R6 is C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl, heterocyclyl or is a group containing one or more of these moieties, each of these moieties may optionally be substituted with one or more groups selected from OR6c, OH, and CONH 2 , wherein R6c and R6d are independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl, and wherein, when the substituent of R6 is heteroaryl or heterocyclyl, each of these moieties may optionally be substituted with one or more oxygen atoms.   
     
     
         18 . The process according to  claim 17 , wherein R6 is a substituted aryl which is substituted with one or more groups selected from halogen, OH, C 1-4  alkoxy, CONH 2 , C(NOH)NH 2 , CONHOH, SO 2 —C 1-4  alkyl, heterocyclyl, and aryl, wherein the heterocyclyl may optionally be substituted with an oxygen atom and the aryl may optionally be substituted with CONH 2 . 
     
     
         19 . The process according to  claim 16 , wherein R6 is a heterocyclyl which is substituted with an oxygen atom. 
     
     
         20 . The process according to  claim 16 , wherein R6 is a monocyclic heteroaryl which is substituted with an oxygen atom. 
     
     
         21 . The process according to any preceding claim, wherein R5 is hydrogen. 
     
     
         22 . The process according to any preceding claim, wherein R8 is hydrogen or a group selected from:
 C 1-6  alkyl optionally substituted with one or more groups selected from halogen, hydroxy, and C 1-6  alkoxy optionally substituted with 1 to 3 groups selected from hydroxy, C 1-6  alkyl, C 1-6  alkylamino, and C 1-6  dialkylamino;   aryl optionally substituted with one or more groups selected from halogen, hydroxy, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, acyl, and aryl optionally substituted with 1 to 3 groups selected from halogen, C 1-6  haloalkyl, and acyl;   heteroaryl optionally substituted with one or more groups selected from halogen, hydroxy, C 1-6  alkoxy, acyl, and C 1-6  alkyl optionally substituted with 1 to 3 groups selected from heterocyclyl and heteroaryl each of which is optionally further substituted with 1 to 3 groups selected from C 1-6  alkyl, and heteroaryl C 1-6  haloalkyl;   heterocyclyl optionally substituted with one or more groups selected from halogen, hydroxy, C 1-6  alkoxy, and acyl;   C 3-8  cycloalkyl optionally substituted with one or more groups selected from halogen, hydroxy, C 1-6  alkoxy, and acyl; and   acyl.   
     
     
         23 . The process according to any preceding claim, wherein R8 is hydrogen. 
     
     
         24 . A process for preparing an imidazolyl intermediate of Formula IIa′: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, the process comprising the oxidation of the derivative of R5 and R6, R6-C(═O)CH 2 R5, to form a glyoxal intermediate R6-C(═O)(C═O)R5, which is subjected to treatment with ammonium hydroxide and an aldehyde R8CHO to provide the intermediate of Formula IIa′, 
         wherein R5, R6, and R8 are as defined in  claim 1 , 
         and wherein, when the intermediate of Formula IIa′ is 4-(3-pyridyl)imidazole, the intermediate of Formula IIa′ is not extracted from the reaction mixture using dichloromethane. 
       
     
     
         25 . The process according to  claim 24 , wherein the intermediate of Formula IIa′ is extracted from the reaction mixture using a solvent comprising butanol. 
     
     
         26 . A compound having the formula R6(C═O)(C═O)R5, wherein R5 and R6 are as defined in  claim 1 , provided that when R6 is pyridyl, R5 is not H. 
     
     
         27 . The compound according to  claim 26 , wherein R5 is hydrogen. 
     
     
         28 . The compound according to  claim 26  or  claim 27 , wherein R6 selected from monocyclic aryl, monocyclic heteroaryl, and heterocyclyl, each of which may be substituted with one or more of the substituents defined for R6 in  claim 1  or with NH 2 CONH—. 
     
     
         29 . A process for preparing the compound of Formula A as defined in  claim 1 , or a pharmaceutically acceptable salt or derivative thereof, the process comprising the reaction of an intermediate of Formula IIa′ as defined in  claim 1 , with a carbamoyl halide of the formula: R1R2NC(═O)Hal, in a solvent consisting essentially of pyridine, wherein R6 is NH 2 CONH-phenyl, or a nitrophenyl, aminophenyl or an amino-protected aminophenyl precursor of this moiety which can be subjected to conversion to the NH 2 CONH-phenyl group after urea formation, and R5 is H, R1 is methyl and R2 is cyclopentyl, and wherein Hal represents Cl, F, I or Br. 
     
     
         30 . The process according to  claim 29 , further comprising treating the product mixture after urea formation with water. 
     
     
         31 . The process according to  claim 29  or  claim 30 , further comprising treating the product mixture after urea formation with a C 5-10  alkane or mixtures thereof. 
     
     
         32 . The process according to  claim 31 , wherein the C 5-10  alkane comprises heptane. 
     
     
         33 . The process according to any one of  claims 29  to  32 , wherein the carbamoyl halide is a carbamoyl chloride. 
     
     
         34 . A process for the synthesis of N-methylcyclopentylamine hydrochloride, the process comprising the reaction of cyclopentylamine with a chloroformate, carried out in 2-methyltetrahydrofuran as the solvent, so as to form a cyclopentylcarbamate, followed by reduction of the cyclopentylcarbamate and acidification with HCl to N-methylcyclopentylamine hydrochloride.