Hiv replication inhibiting pyrimidines

Abstract

This invention concerns HIV replication inhibitors of formula the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, wherein the ring containing -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - represents phenyl, pyridyl, pyrimidinyl, pirazinyl, pyridazinyl; n is 0 to 5; m is 1 to 4; R 1 is hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; C 1-6 alkyl; C 1-6 alkyloxycarbonyl; substituted C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyloxy; substituted C 1-6 alkyloxyC 1-6 alkylcarbonyl; R 2 is hydroxy, halo, optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 , —C(═NH)R 6 or a 5-membered heterocycle; X 1 is —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, C 1-4 alkanediyl, —CHOH—, —S—, —S(═O) p —, —X 2 —C 1-4 alkanediyl- or —C 1-4 alkanediyl-X 2 —; R 3 is NHR 13 ; NR 13 R 14 ; —C(═O)—NHR 13 ; —C(═O)—NR 13 R 14 ; —C(═O)—R 15 ; —CH═N—NH—C(═O)—R 16 ; substituted C 1-6 alkyl; optionally substituted C 1-6 alkyloxyC 1-6 alkyl; substituted C 2-6 alkenyl; substituted C 2-6 alkynyl; C 1-6 alkyl substituted with hydroxy and a second substituent; —C(═N—O—R 8 )—C 1-4 alkyl; R 7 ; or —X 3 —R 7 ; R 4 is halo, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyl, formyl, amino, mono- or di(C 1-4 alkyl)amino; their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them.

1 . A compound of formula 
       
         
           
           
               
               
           
         
         an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein 
         -a 1 =a 2 -a 3 =a 4 - represents a bivalent radical of formula
   —CH═CH—CH═CH—   (a-1);
 
 
         -b 1 =b 2 -b 3 =b 4 - represents a bivalent radical of formula
   —CH═CH—CH═CH—   (b-1);
 
 
         n is 0, 1, 2, 3, 4, or 5; 
         m is 1, 2, 3, or 4; 
         R 1  is selected from the group consisting of: hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C1-6alkyl; C1-6alkyl substituted with a member selected from the group consisting of: formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, and C1-6alkylcarbonyloxy; and C1-6alkyloxyC1-6alkylcarbonyl substituted with C1-6alkyloxycarbonyl; 
         each R 2  is independently selected from: hydroxy; halo; C1-6alkyl optionally substituted with cyano or —C(═O)R 6 ; C 3-7 cycloalkyl; C 2-6 alkenyl optionally substituted with one or more halogen atoms or cyano; C 2-6 alkynyl optionally substituted with one or more halogen atoms or cyano; C1-6alkyloxycarbonyl; carboxyl; cyano; nitro; amino; mono- or di(C 1-6 alkyl)amino; polyhalomethyl; polyhalomethylthio; —S(═O) p R 6 ; 
         —NH—S(═O) p R 6 ; —C(═O)R 6 ; —NHC(═O)H; —C(═O)NHNH 2 ; —NHC(═O)R 6 ;—C(═NH)R 6  and a radical of formula 
       
       
         
           
           
               
               
           
         
         wherein each A 1  is independently selected from the group consisting of: N, CH and CR 6 ; and 
         A 2  is selected from the group consisting of: NH, O, S and NR 6 ; 
         X 1  is selected from the group consisting of: —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, C 1-4 alkanediyl, —CHOH—, —S—, —S(═O) p —, —X 2 —C 1-4 alkanediyl- and —C 1-4 alkanediyl-X 2 —; X 2  is —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O) p —; 
         R 3  is C1-6alkyl substituted with R 7 ; X 3  is —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O) p —, —X 2 —C 1-4 alkanediyl-, —C 1-4 alkanediyl-X 2a —, —C 1-4 alkanediyl-X 2b —C 1-4 alkanediyl, —C(═N—OR 8 )—C 1-4 alkanediyl-; 
         with X 2a  being —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O) p —; and 
         with X 2b  being —NH—NH—, —N═N—, —C(═O)—, —S—, —S(═O) p —; 
         R 4  is selected from the group consisting of: halo, hydroxy, C1-6alkyl, C 3-7 cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl, formyl, amino, mono- or di(C 1-4 alkyl)amino and R 7 ; 
         R 5  is hydrogen; 
         R 6  is selected from the group consisting of: C 1-4 alkyl; amino; mono- or di(C 1-4 alkyl)amino; and polyhaloC 1-4 alkyl; 
         R 7  is selected from the group consisting of: a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle; or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle; wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl, C 3-7 cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, —CH(═N—O—R 8 ), R 7a , —X 3 —R 7a  and R 7a —C 1-4 alkyl; 
         R 7a  is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle; or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle; wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl, C 3-7 cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, and —CH(═N—O—R 8 ); 
         R 8  is selected from the group consisting of: hydrogen, C 1-4 alkyl, aryl and arylC 1-4 alkyl; 
         p is 1 or 2; 
         aryl is phenyl; or phenyl substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylcarbonyl, C 3-7 cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, R 7  and —X 3 —R 7 . 
       
     
     
         2 . A compound according to  claim 1  wherein R 3  is C1-6alkyl substituted with R 7 ; where R 7  is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylcarbonyl, C 3-7 cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, R 7a , —X 3 —R 7a  or R 7a —C 1-4 alkyl; R 7a  is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylcarbonyl, C 3-7 cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl; R 9  and R 10  each independently are hydrogen; hydroxy; C 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; amino; mono- or di(C 1-6 alkyl)amino; mono- or di(C 1-6 alkyl)aminocarbonyl or R 7 , wherein each of the aforementioned C 1-6 alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C 1-6 alkyloxy, hydroxyC 1-6 alkyloxy, carboxyl, C 1-6 alkyloxycarbonyl, cyano, amino, imino, mono- or di(C1-4alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 , —C(═NH)R 6 , R 7 . 
     
     
         3 . A compound according to  claim 1  having the formula 
       
         
           
           
               
               
           
         
         wherein 
         -a 1 =a 2 -a 3 =a 4 -, -b 1 =b 2 -b 3 =b 4 -, R 1 , R 2 , R 3 , R 4 , m and X 1  are as defined in  claim 1 ; 
         n′ is 0, 1, 2, 3, or 4; 
         R 2′  is selected from the group consisting of: halo, C 1-6 alkyl, trihalomethyl, trihalomethyloxy, cyano, aminocarbonyl, and C 1-6 alkyl substituted with cyano or aminocarbonyl; 
         provided that R 2′  is placed at the para position in respect of the NR 1  moiety. 
       
     
     
         4 . A compound according to  claim 3  wherein R 2′  is selected from the group consisting of: cyano; aminocarbonyl; and C 1-6 alkyl substituted with cyano or aminocarbonyl. 
     
     
         5 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound as claimed in  claim 1 . 
     
     
         6 . A process for preparing a compound as claimed in  claim 1 , characterized by
 a) reacting an intermediate of formula (II) with an intermediate of formula (III)   
       
         
           
           
               
               
           
         
         with W 1  being a suitable leaving group, and R 1 , R 2 , R 3 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 ; 
         b) reacting an intermediate of formula (IV) with an intermediate of formula (V) in the presence of a suitable catalyst, a suitable salt and a suitable solvent 
       
       
         
           
           
               
               
           
         
         with W 2  being a suitable leaving group, and R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1  and R 7′  representing a monocyclic, bicyclic or tricyclic aromatic ring system and R a  representing a boronate or a tri(C 1-4 alkyl)stannane; 
         c) reacting an intermediate of formula (IV) with an intermediate of formula (VI) 
       
       
         
           
           
               
               
           
         
         with W 2  being a suitable leaving group, and R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1  and R 7″  representing a monocyclic, bicyclic or tricyclic saturated ring system; 
         d) reacting an intermediate of formula (VII) with a suitable cyanide salt in the presence of a suitable solvent 
       
       
         
           
           
               
               
           
         
         with W 3  being a suitable leaving group, and R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 ; 
         e) reacting an intermediate of formula (VII) with an intermediate of formula (VIII) optionally in the presence of a suitable salt and a suitable solvent 
       
       
         
           
           
               
               
           
         
         with W 3  being a suitable leaving group, and R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1  and Q representing R 7 ; NR 9 R 10  or C 1-6 alkyloxy optionally substituted with CN, R 7  or NR 9 R 10 ; 
         f) reacting an intermediate of formula (IX) with an intermediate of formula (X) in the presence of a suitable solvent 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , R 8 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 ; 
         g) reacting an intermediate of formula (XI) with a Wittig or Horner-Emmons reagens of formula (XII) representing a suitable precursor of a phosphorus ylide in the presence of a suitable salt and a suitable solvent 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 , R c  representing hydrogen or C 1-4 alkyl, R c′  representing hydrogen, C 1-4 alkyl or R 7 , provided that CR c′ ═CR c  is limited to C 2-6 alkenyl, and R b  representing (Phenyl) 3 P + —Cl −  or (CH 3 CH 2 —O) 2 P(═O)—; 
         h) reacting an intermediate of formula (XI) with an intermediate of formula (XIII) in the presence of a suitable solvent 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , R 7 , X 1 , m, n, and -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 , R c  representing hydrogen or C 1-4 alkyl, R c″  representing NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; 
         i) reacting an intermediate of formula (XI-b) with 2-butenedinitrile in the presence of tributylphosphine and a suitable solvent 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 ; 
         j) reacting an intermediate of formula (XI-b) with propanedintrile in the presence of a suitable base and a suitable solvent 
       
       
         
           
           
               
               
           
         
         k) reacting an intermediate of formula (XI-b) with CH 3 —CN in the presence of a suitable proton abstracting agent, a suitable substrate for the proton abstracting agent and in the presence of a suitable solvent 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 ; 
         l) reacting an intermediate of formula (XI) with a Wittig or Horner-Emmons reagens of formula (XII′) representing a suitable precursor of a phosphorus ylide in the presence of nBuLi and a suitable solvent 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 , R c  representing hydrogen or C 1-4 alkyl, R c′  representing hydrogen, C 1-4 alkyl or R 7 , provided that CR c′ ═CR c  is limited to C 2-6 alkenyl, and R b  representing (Phenyl) 3 P + —Cl −  or (CH 3 CH 2 —O) 2 P(═O)—; 
         m) reacting an intermediate of formula (XI-a) with an intermediate of formula (XIII′) in the presence of a suitable Horner-Emmons reagent, nBuLi, 1,1,1-trimethyl-N-(trimethylsilyl)-silanamine, and a suitable solvent 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 , R c  representing hydrogen or C 1-4 alkyl, R c′″  representing CN, NR 9 R 10 , —C(═O)—NR 9 R 10 , —C(═O)—C 1-6 alkyl or R 7 ; 
         n) reacting an intermediate of formula (XVIII) with CBr 4  in the presence of a suitable catalyst salt, a suitable base and a suitable solvent 
       
       
         
           
           
               
               
           
         
         o) reacting an intermediate of formula (XIV) with Cl 2 C═S in the presence of a suitable solvent 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 ; 
         p) reacting an intermediate of formula (XV) with an intermediate of formula (XVI) in the presence of a suitable solvent 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 ; 
         q) reacting an intermediate of formula (XXIX) with an intermediate of formula (XXX) in the presence of hydroxybenzotriazole and ethyldimethylaminopropyl carbodiimide, a suitable solvent and optionally in the presence of a suitable base 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , R 9 , R 10 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1  and C 2-6 alkenyl′ representing C 2-6 alkenyl optionally substituted with cyano; 
         r) reacting an intermediate of formula (XXXI) with an intermediate of formula (XXXII-1) or (XXXII-2) in the presence of hydroxybenzotriazole, ethyldimethylaminopropyl carbodiimide and a suitable solvent, and optionally in the presence of a suitable base 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , R 13 , R 14 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 ; 
         s) reacting an intermediate of formula (XI-b) with an intermediate of formula (XXXIII) in the presence of a suitable solvent 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , R 16 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 ; 
         t) reductive methylation of an intermediate of formula (XXXIV) with formaldehyde in the presence of a suitable catalyst, a suitable reductive agent and a suitable solvent 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 ; 
         u) reacting an intermediate of formula (XXXIV) with 2,5-dimethoxytetrahydrofuran in the presence of a suitable acid 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 ; 
         v) reacting an intermediate of formula (XXXV) with an intermediate of formula (XXXVI) in the presence of nBuLi and a suitable solvent 
       
       
         
           
           
               
               
           
         
         with R 1 , R 2 , R 4 , R 7 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - as defined in  claim 1 ; 
         and, if desired, converting compounds of formula (I) into each other following art-known transformations; and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or conversely, converting the acid addition salt form into the free base by treatment with alkali; and, if desired, preparing stereochemically isomeric forms, N-oxide forms or quaternary amines thereof. 
       
     
     
         7 . A product containing (a) a compound according to  claim 1 , and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of HIV infection. 
     
     
         8 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound according to  claim 1 , and (b) another antiretroviral compound. 
     
     
         9 . A compound of formula 
       
         
           
           
               
               
           
         
         a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein 
         R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - are as defined in  claim 1  and W 3  represents a suitable leaving group. 
       
     
     
         10 . A compound of formula 
       
         
           
           
               
               
           
         
         a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein 
         R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - are as defined in  claim 1 . 
       
     
     
         11 . A compound of formula 
       
         
           
           
               
               
           
         
         a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein 
         R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - are as defined in  claim 1  and C 2-6 alkenyl′ represents C 2-6 alkenyl optionally substituted with cyano. 
       
     
     
         12 . A compound of formula 
       
         
           
           
               
               
           
         
         a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein 
         R 1 , R 2 , R 4 , X 1 , m, n, -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - are as defined in  claim 1  and C 2-6 alkenyl′ represents C 2-6 alkenyl optionally substituted with cyano. 
       
     
     
         13 . A compound of formula 
       
         
           
           
               
               
           
         
         a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein R 4  and X 1  are as defined in  claim 1 . 
       
     
     
         14 . A method of treating subjects suffering from HIV (Human Immunodeficiency Virus) infection comprising administering to the subject an effective amount of a compound according to  claim 1 . 
     
     
         15 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and
 pharmaceutically acceptable addition salts thereof.