Heterocyclic compounds

Abstract

Pharmaceutically useful heterocyclic compounds, compositions containing them, and methods of using them, for example, as histamine H 3 receptor mediators.

What is claimed:  
     
         1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 Q 1  is selected from the group consisting of C 1-7  alkyl, C 1-7  haloalkyl and C 2-7  alkenyl; 
 wherein Q 1  may be substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, OR 11 , C 1-5  alkyl, C 1-5  haloalkyl, C 2-5  alkenyl, nitro, amino, R 11 HN—, R 11 R 12 N—, amido, R 11 HNC(O), R 11 R 12 NC(O) and R 11 OC(O), and 
 wherein R 11  and R 12  are independently C 1-5  alkyl, C 1-5  haloalkyl or C 2-5 alkenyl;  
 
 
 M is a moiety of the formula —CH 2 R M , —CHOHR M , —C(═O)R M  or —C(═N—OH)R M , 
 wherein, R M  is selected from the group consisting of C 1-7  alkyl, R M1 HN—, R M1 R M2 N—, C 5-7 cycloalkyl, aryl, biaryl and 4-7 membered heterocyclyl containing between 1 and 2 heteroatoms,  
 wherein R M  may be substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, OR M1 , C 1-5  alkyl, C 1-5  haloalkyl, C 2-5  alkenyl, nitro, amino R M1 HN—, R M1 R M2 N—, amido, R M1 HNC(O) and R M1 R M2 NC(O), and 
 wherein R M1  and R M2  are independently C 1-5  alkyl, C 1-5  haloalkyl or C 2-5  alkenyl;  
 
 or M is hydrogen;  
 
 A 3  is NH, NR 3 , sulfur, sulfoxide, sulfone or oxygen, wherein R 3  is C 1-5  alkyl;  
 L 3  is C 1-7  alkyl or C 2-7  alkenyl; 
 wherein L 3  may be substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy and amino;  
 or L 3  is absent; and  
 
 Q 3  is selected from the group consisting of C 1-7  alkyl, C 1-7  haloalkyl, C 2-7  alkenyl, C 3-7  cycloalkyl, C 5-7 cycloalkenyl, aryl, 4-7 membered heterocyclyl, C 3-7  cycloalkyl-4-7 membered heterocyclyl, 4-7 membered heterocyclyl-C 3-7  cycloalkyl, bi-(4-7 membered heterocyclyl), R 31 HN—, R 31 R 32 N—, azinoyl, C 3-7 cycloalkylamino, 4-7 membered heterocyclylamino, aryl C 1-6  alkylamino, C 3-7 cycloalkylsulfanyl, 4-7 membered heterocyclylsulfanyl and 4-7 membered heterocyclyloxy; 
 wherein Q 3  may be substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, OR 31 , C 1-5  alkyl, C 1-5  haloalkyl, C 2-5  alkenyl, nitro, amino, R 31 HN—, R 31 R 32 N—, amido, R 31 HNC(O), R 31 R 32 NC(O), R 31 OC(O), C 3-7  cycloalkyl, monocyclic 4-7 membered heterocyclyl and monocyclic 4-7 membered heterocyclylalkyl, and 
 wherein R 31  and R 32  are independently C 1-5  alkyl, C 1-5  haloalkyl or C 2-5  alkenyl;  
 
 or A 3  and L 3  are absent and Q 3  is sulfanyl;  
 
 or a pharmaceutically acceptable ester, ether, N-oxide, amide, salt, hydrate or isotopically labeled form thereof.  
 
     
     
         2 . A compound of  claim 1  of the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 Q 1  is C 1-3 alkyl 
 wherein Q 1  may be substituted with one substituent selected from the group consisting of amino, R 11 HN—, R 11 R 12 N—, amido, R 11 HNC(O), R 11 R 12 NC(O) and R 11 OC(O), and 
 wherein R 11  and R 12  are independently C 1-5  alkyl, C 1-5  haloalkyl or C 2-5  alkenyl;  
 
 
 M is a moiety of the formula —CH 2 R M , —CHOHR M , or —C(═O)R M , 
 wherein, R M  is selected from the group consisting of C 1-3  alkyl, R M1 HN—, C 1-3  R M1 R M2 N—, C 5-7 cycloalkyl, aryl, biaryl and 4-7 membered heterocyclyl containing between 1 and 2 heteroatoms,  
 wherein R M  may be substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, OR M1 , C 1-5  alkyl, nitro, and amino; and  
 
 A 3  is sulfur or oxygen  
 L 3  is C 1-7  alkyl or C 2-7  alkenyl; 
 wherein L 3  may be substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy and amino (H 2 N—);  
 or L 3  is absent; and  
 
 Q 3  is selected from the group consisting of C 1-7  alkyl, C 1-7  haloalkyl, C 2-7  alkenyl, C 3-7  cycloalkyl, C 5-7  cycloalkenyl, aryl, 4-7 membered heterocyclyl, C 3-7  cycloalkyl-4-7 membered heterocyclyl, 4-7 membered heterocyclyl-C 3-7  cycloalkyl, bi-(4-7 membered heterocyclyl), R 31 HN—, R 31 R 32 N—, azinoyl, C 3-7 cycloalkylamino, 4-7 membered heterocyclylamino, aryl C 1-6  alkylamino, C 3-7  cycloalkylsulfanyl, 4-7 membered heterocyclylsulfanyl and 4-7 membered heterocyclyloxy; 
 wherein Q 3  may be substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, OR 31 , C 1-5  alkyl, C 1-5  haloalkyl, C 2-5  alkenyl, nitro, amino, R 31 HN—, R 31 R 32 N—, amido, R 31 HNC(O), R 31 R 32 NC(O), R 31 OC(O), C 3-7 cycloalkyl, monocyclic 4-7 membered heterocyclyl and monocyclic 4-7 membered heterocyclylalkyl, and 
 wherein R 31  and R 32  are independently C 1-5  alkyl, C 1-5  haloalkyl or C 2-5  alkenyl;  
 
 or A 3  and L 3  are absent and Q 3  is sulfanyl;  
 
 or a pharmaceutically acceptable ester, ether, N-oxide, amide, salt, hydrate or isotopically labeled form thereof.  
 
     
     
         3 . The compound of  claim 1  wherein Q 1  is unsubstituted C 1-3  alkyl.  
     
     
         4 . The compound of  claim 1  wherein Q 1  is methyl.  
     
     
         5 . The compound of  claim 1  wherein M is a moiety of the formula —CH 2 R M , —CHOHR M , —C(═O)R M  or —C(═N—OH)R M .  
     
     
         6 . The compound of  claim 1  wherein M is —CHOHR M .  
     
     
         7 . The compound of  claim 1  wherein M is —C(═O)R M .  
     
     
         8 . The compound of  claim 1  wherein R M  is unsubstituted or substituted C 3-7  cycloalkyl, aryl or 4-7 membered heterocyclyl.  
     
     
         9 . The compound of  claim 1  wherein R M  is aryl unsubstituted or substituted with halo, cyano, hydroxy, methoxy, C 1-3  alkyl, perhalomethyl, nitro, or amino.  
     
     
         10 . The compound of  claim 1  wherein R M  is phenyl unsubstituted or substituted with F, Cl, Br, cyano, methoxy, C 1-3  alkyl, CF 3 , hydroxy, or nitro.  
     
     
         11 . The compound of  claim 1  wherein A 3  is oxygen, sulfur or NH.  
     
     
         12 . The compound of  claim 1  wherein A 3  is oxygen.  
     
     
         13 . The compound of  claim 1  wherein A 3  is sulfur.  
     
     
         14 . The compound of  claim 1  wherein L 3  is unsubstituted or substituted C 1-5  alkyl or C 2-5  alkenyl.  
     
     
         15 . The compound of  claim 1  wherein L 3  is selected from (a) C 1-3  alkyl, which may be unsubstituted or substituted, and independently may be unbranched or branched, and (b) C 4-5  alkyl, which is branched or substituted, or both.  
     
     
         16 . The compound of  claim 1  wherein L 3  is absent.  
     
     
         17 . The compound of  claim 1  wherein Q 3  is R 31 HN— or R 31 R 32 N—, or an unsubstituted or substituted nitrogen-containing 4-7 membered heterocyclyl, C 3-7  cycloalkyl-4-7 membered heterocyclyl, 4-7 membered heterocyclyl-C 3-7 cycloalkyl or bi-(4-7 membered heterocyclyl).  
     
     
         18 . The compound of  claim 1  wherein Q 3  is an unsubstituted or substituted, nitrogen-containing, 5-6 membered heterocyclyl.  
     
     
         19 . The compound of  claim 1  wherein Q 3  is R 31 R 32 N—.  
     
     
         20 . The compound of  claim 1  wherein: Q 1  is methyl; M is a moiety of the formula —CH 2 R M , —CHOHR M , —C(═O)R M  or —C(═N—OH)R M ; R M  is phenyl unsubstituted or substituted with F, Cl, Br, cyano, methoxy, C 1-3  alkyl, CF 3 , hydroxy, or nitro; A 3  is oxygen or sulfur; L 3  is selected from (a) C 1-3  alkyl, which may be unsubstituted or substituted, and independently may be unbranched or branched, and (b) C 4-5  alkyl, which is branched or substituted, or both; and Q 3  is R 31 R 32 N—.  
     
     
         21 . The compound of  claim 1  wherein: Q 1  is methyl; M is a moiety of the formula —CH 2 R M , —CHOHR M  or —C(═O)R M ; R M  is phenyl unsubstituted or substituted with F, Cl, Br, cyano, methoxy, C 1-3  alkyl, CF 3 , hydroxy, or nitro; A 3  is oxygen or sulfur; L 3  is unsubstituted or substituted C 1-5  alkyl or C 2-5  alkenyl, or 
 L 3  is absent; and Q 3  is an unsubstituted or substituted, nitrogen-containing, 5-6 membered heterocyclyl.  
 
     
     
         22 . A compound of  claim 1  selected from the group consisting of: 
 (2-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 (4-Bromophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;  
 (4-Chlorophenyl)-{3-methyl-2-[2-(1-methylpyrrolidin-2-yl)-ethylsulfanyl]-3H-imidazol-4-yl}-methanone;  
 (4-Fluorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 (3-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 (4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;  
 (4-Chlorophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanone;  
 (4-Chlorophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone oxime;  
 (4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 [2-(3-Dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-phenyl-methanone;  
 (3,5-Dichlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 [2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-trifluoromethyl-phenyl)-methanone;  
 [2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-nitro-phenyl)-methanone;  
 (4-Bromophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 (4-Bromophenyl)-[2-(1-ethyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 (4-Chlorophenyl)-[3-methyl-2-(1-methyl-piperidin-4-ylsulfanyl)-3H-imidazol-4-yl]-methanone;  
 (4-Bromophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylsulfanyl)-3H-imidazol-4-yl methanone;  
 4-{Hydroxy-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methyl}-benzonitrile; and  
 (4-Bromophenyl)-[2-(1-sec-butyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 or a pharmaceutically acceptable ester, ether, N-oxide, amide, salt, hydrate or isotopically labeled form thereof.  
 
     
     
         23 . A compound of  claim 1  selected from the group consisting of: 
 (2-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 (4-Bromophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;  
 (4-Chlorophenyl)-{3-methyl-2-[2-(1-methylpyrrolidin-2-yl)-ethylsulfanyl]-3H-imidazol-4-yl}-methanone;  
 (4-Fluorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 (3-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 (4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;  
 (4-Chlorophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanone;  
 (4-Chlorophenyl)-[2-(3-dimethylamino-propylsulfanyl) -3-methyl-3H-imidazol-4-yl]-methanone oxime;  
 (4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-yl methoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 [2-(3-Dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-phenyl-methanone;  
 (3,5-Dichlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 [2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-trifluoromethyl-phenyl)-methanone;  
 [2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-nitrophenyl)-methanone; and  
 (4-Bromophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 or a pharmaceutically acceptable ester, ether, N-oxide, amide, salt, hydrate or isotopically labeled form thereof.  
 
     
     
         24 . A compound of  claim 1  selected from the group consisting of: 
 (4-Fluorophenyl)-[2-(1-isopropyl-piperidin-4-yl methoxy)-3-methyl-3H-imidazol-4-yl]-methanone;  
 (4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone; and  
 [2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-nitrophenyl)-methanone;  
 or a pharmaceutically acceptable ester, ether, N-oxide, amide, salt, hydrate or isotopically labeled form thereof.  
 
     
     
         25 . The compound of  claim 1  having the formula (4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone or a pharmaceutically acceptable ester, ether, N-oxide, amide, salt, hydrate or isotopically labeled form thereof.  
     
     
         26 . The compound of  claim 1  having the formula (4-Fluorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone or a pharmaceutically acceptable ester, ether, N-oxide, amide, salt, hydrate or isotopically labeled form thereof.  
     
     
         27 . The compound of  claim 1  having the formula [2-(1-Isopropylpiperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-nitro-phenyl)-methanone or a pharmaceutically acceptable ester, ether, N-oxide, amide, salt, hydrate or isotopically labeled form thereof.  
     
     
         28 . A compound of  claim 1  of the formula (II):  
       
         
           
           
               
               
           
         
       
       wherein: 
 Q 1  is selected from the group consisting of C 1-7  alkyl, C 1-7  haloalkyl and C 2-7  alkenyl; 
 wherein Q 1  may be substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, OR 11 , C 1-5  alkyl, C 1-5  haloalkyl, C 2-5  alkenyl, nitro, amino (H 2 N—), R 11 HN—, R 11 R 2 N—, amido (H 2 NC(O)), R 11 HNC(O), R 11 R 2 NC(O) and R 11 OC(O), and 
 wherein R 11  and R 12  are independently C 1-5  alkyl, C 1-5  haloalkyl or C 2-5  alkenyl;  
 
 
 R M  is selected from the group consisting of C 1-7  alkyl, R M1 HN—, R M1 R M2 N—, C 3-7  cycloalkyl, aryl, biaryl and 4-7 membered heterocyclyl, 
 wherein R M  may be substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, OR M1 , C 1-5  alkyl, C 1-5  haloalkyl, C 2-5  alkenyl, nitro, amino (H 2 N—), R M1 HN—, R M1 R M2 N—, amido (H 2 NC(O)), R M1 HNC(O) and R M1 R M2 NC(O), and 
 wherein R M1  and R M2  are independently C 1-5  alkyl, C 1-5  haloalkyl or C 2-5  alkenyl;  
 
 
 L 3  is C 1-7  alkyl or C 2-7  alkenyl; 
 wherein L 3  may be substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy and amino (H 2 N—);  
 or L 3  is absent; and  
 
 Q 4  is hydrogen;  
 or a derivative thereof that bears one or more protecting groups.  
 
     
     
         29 . A compound of  claim 28 , wherein Q 1  is unsubstituted C 1-3  alkyl.  
     
     
         30 . A compound of  claim 28 , wherein Q 1  is methyl.  
     
     
         31 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of  claim 1 ,  20 ,  21 , or  24 .  
     
     
         32 . A Method of inhibiting histamine H 3  receptor activity in a subject, comprising administering an effective amount of a compound of  claim 1 ,  21 , or  24  to a subject in need of such inhibition of histamine H 3  receptor activity.  
     
     
         33 . A method of treating a subject having a disease or condition modulated by histamine H 3  receptor activity, comprising administering to the subject a therapeutically effective amount of a compound of  claim 1 ,  21 , or  24 .  
     
     
         34 . A method of  claim 33 , wherein said disease or condition is selected from the group consisting of sleep/wake disorders, arousal/vigilance disorders, migraine, asthma, dementia, mild cognitive impairment (pre-dementia), Alzheimer's disease, epilepsy, narcolepsy, eating disorders, motion sickness, vertigo, attention deficit hyperactivity disorders, learning disorders, memory retention disorders, schizophrenia, and upper airway allergic response.  
     
     
         35 . A method for treating a disease or condition modulated by at least one receptor selected from the histamine H 1  receptor and the histamine H 3  receptor, said method comprising (a) administering to a subject a histamine H 1  receptor antagonist compound, and (b) administering to the subject a compound of  claim 1 , said method providing a therapeutically effective amount of said compounds.  
     
     
         36 . The method of  claim 35  wherein the histamine H 1  receptor antagonist and the compound of  claim 1  are present in the same dosage form.  
     
     
         37 . A method for treating diseases or conditions modulated by at least one receptor selected from the histamine H 2  receptor and the histamine H 3  receptor in a subject, comprising (a) administering to the subject a histamine H 2  receptor antagonist compound, and (b) administering to the subject a compound of  claim 1 , said method providing a therapeutically effective amount of said compounds.  
     
     
         38 . The method of  claim 37  wherein the histamine H 2  receptor antagonist and the compound of  claim 1  are present in the same dosage form.  
     
     
         39 . A method for studying disorders mediated by the histamine H 3  receptor, comprising using an  18 F-labeled compound of  claim 1  or  23  as a positron emission tomography molecular probe.  
     
     
         40 . A process for the production of a compound of the formula (11):  
       
         
           
           
               
               
           
         
       
       wherein: 
 Q 1  is selected from the group consisting of C 1-7  alkyl, C 1-7  haloalkyl and C 2-7  alkenyl; 
 wherein Q 1  may be substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, OR 11 , C 1-5  alkyl, C 1-5  haloalkyl, C 2-5  alkenyl, nitro, amino (H 2 N—), R 11 HN—, R 11 R 12 N—, amido (H 2 NC(O)), R 11 HNC(O), R 11 R 12 NC(O) and ROC(O), and 
 wherein R 11  and R 12  are independently C 1-5  alkyl, C 1-5  haloalkyl or C 2-5  alkenyl;  
 
 
 R M  is selected from the group consisting of C 1-7  alkyl, R M1 HN—R M1 R M2 N—, C 3-7  cycloalkyl, aryl, biaryl and 4-7 membered heterocyclyl, 
 wherein R M  may be substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, OR M1 , C 1-5  alkyl, C 1-5  haloalkyl, C 2-5  alkenyl, nitro, amino (H 2 N—), R M1 HN—, R M1 R M2 N—, amido (H 2 NC(O)), R M1 HNC(O) and R M1 R M2 NC(O), and 
 wherein R M1  and R M2  are independently C 1-5  alkyl, C 1-5  haloalkyl or C 2-5  alkenyl;  
 
 
 A 3  is NH, NR 3 , sulfur or oxygen, wherein R 3  is C 1-5  alkyl;  
 L 3  is C 1-7  alkyl or C 2-7  alkenyl; 
 wherein L 3  may be substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy and amino (H 2 N—);  
 or L 3  is absent; and  
 
 Q 3  is selected from the group consisting of C 1-7  alkyl, C 1-7  haloalkyl, C 2-7  alkenyl, C 3-7  cycloalkyl, C 5-7  cycloalkenyl, aryl, 4-7 membered heterocyclyl, C 3-7  cycloalkyl-4-7 membered heterocyclyl, 4-7 membered heterocyclyl-C 3-7  cycloalkyl, bi-(4-7 membered heterocyclyl), R 31 HN—, R 31 R 32 N—, azinoyl (R 31 HN + (O − ) or R 31 R 32 N + (O − )), C 3-7 cycloalkylamino, 4-7 membered heterocyclylamino, aryl C 1-6 alkylamino, C 3-7 cycloalkylsulfanyl, 4-7 mebered heterocyclylsulfanyl and 4-7 membered heterocyclyloxy; 
 wherein Q 3  may be substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, OR 31 , C 1-5  alkyl, C 1-5  haloalkyl, C 2-5  alkenyl, nitro, amino (H 2 N—), R 31 HN—, R 31 R 32 N—, amido (H 2 NC(O)), R 31 HNC(O), R 31 R 32 NC(O), R 31 OC(O), C 3-7  cycloalkyl, monocyclic 4-7 membered heterocyclyl and monocyclic 4-7 membered heterocyclyl-C 1-6  alkyl, and 
 wherein R 31  and R 32  are independently C 1-5  alkyl, C 1-5  haloalkyl or C 2-5  alkenyl;  
 
 
 that comprises treating a compound of the formula (5b)  
                     
 wherein Q 4  is hydrogen, with an oxidizing agent resulting in an intermediate compound of the formula (10)  
                     
 and treating said intermediate compound (10) with a reagent H—A 3 —L 3 —Q 3 , wherein L 3  of the reagent H—A 3 —L 3 —Q 3  is independent of L 3  of formula (5b) and formula (10), in the presence of a base in a suitable solvent yielding said compound of formula II.  
 
     
     
         41 . A process according to  claim 40 , wherein said oxidizing agent is either hydrogen peroxide in acetic acid, or 3-chloroperoxybenzoic acid in dichloromethane or diethyl ether.  
     
     
         42 . A process according to  claim 40 , wherein said base is an alkali metal hydride.  
     
     
         43 . A process according to  claim 42 , wherein said alkali metal hydride is sodium hydride.  
     
     
         44 . A process according to  claim 40 , wherein said suitable solvent is a member selected from the group consisting of dimethylformamide, benzene, 1,2-dimethoxyethane and tetrahydrofuran.  
     
     
         45 . A process according to  claim 44 , wherein said suitable solvent is tetrahydrofuran.