6,7,8,9-substituted 1-phenyl-1,5-dihydro-pyrido[3,2-b]indol-2-ones useful as anti-infective pharmaceutical agents

Abstract

This invention concerns the compounds the N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, wherein X is NR 2 , O, S, SO, SO 2 ; R 1 is hydrogen, cyano, halo, substituted carbonyl, methanimidamidyl, N-hydroxy-methanimidamidyl, mono- or di(C 1-4 alkyl)methanimidamidyl, Het 1 or Het 2 ; n is 1, 2 or 3; R 2 is hydrogen, aryl substituted with a radical —COOR 4 ; or R 2 is substituted C 1-10 alkyl, C 2-10 alkenyl or C 3-7 cycloalkyl; or R 2 is a radical of formula: —C p H 2p —CH(OR 14 )—C q H 2q —R 15 (b-3); —CH 2 —CH 2 —(O—CH 2 —CH 2 ) m —OR 14 (b-4); —CH 2 —CH 2 —(O—CH 2 —CH 2 ) m —NR 5a R 5b (b-5) -a 1 =a 2 -a 3 =a 4 - is —CH═CH—CH═CH—; —N═CH—CH═CH—; —CH═N—CH═CH—; —CH═CH—N═CH—; —CH═CH—CH═N— (c-5); wherein one of the hydrogen atoms in (c-1)-(c-5) is replaced by particular radicals; R 3 is nitro, cyano, amino, halo, hydroxy, C 1-4 alkyloxy, hydroxycarbonyl, substituted carbonyl, methanimidamidyl, mono- or di(C 1-4 alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het 1 .

1 - 16 . (canceled) 
   
   
       17 . A process for preparing a compound of formula (I): 
     
       
         
         
             
             
         
       
       the N-oxides, salts, quaternary ammonium salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, 
       wherein 
       n is 1, 2 or 3; 
       R 1  is hydrogen, cyano, halo, aminocarbonyl hydroxycarbonyl C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyl mono- or di(C 1-4 alkyl)aminocarbonyl arylaminocarbonyl N-(aryl)-N—(C 1-4 alkyl)aminocarbonyl, methanimidamidyl, N-hydroxy-methanimidamidyl, mono- or di(C 1-4 alkyl)methanimidamidyl, Het 1  or Het 2 ; 
       X is a bivalent radical NR 2 , O, S SO, SO 2 ; 
       R 2  is: 
       i) hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl, wherein said C 1-10 alkyl, C 2-10 alkenyl, and C 3-7 cycloalkyl, each individually and independently, may be optionally substituted with a substituent selected from the group consisting of cyano, N(R 16a R 16b ) pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C 1-4 alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, aryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, hydroxy-carbonyl, C 1-4 alkylcarbonyl, N(R 16a R 16b )carbonyl, C 1-4 alkyloxycarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C 1-4 alkyl)-piperazin-1-ylcarbonyl, morpholin-1-yl-carbonyl, thiomorpholin-1-ylcarbonyl, 1-oxothiomorpholin-1-ylcarbonyl and 1,1-dioxo-thiomorpholin-1-ylcarbonyl; or R 2  is 
       ii) aryl substituted with a radical —COOR 4 ; or R 2  is 
       iii) C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl, each of said C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl each individually and independently, being substituted with aryl wherein said aryl is substituted with a radical —COOR 4 ; or R 2  is 
       iv) C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl, each individually and independently, substituted with a radical selected from —NR 5a —C(═NR 5b )—NR 5c R 5d , —NR 5a —C(═NR 5e )—R 5f , —O—NR 5a —C(═NR 5b )—NR 5c R 5d , —O—NR 5a —C(═NR 5e )—R 5f , -sulfonyl-R 6 , —NR 7 R 8 , —NR 9 R 10 , a radical 
     
     
       
         
         
             
             
         
       
       wherein 
       each Q 1  independently is a direct bond, —CH 2 —, or —CH 2 —CH 2 —; 
       each Q 2  independently is O, S, SO or SO 2 ; 
       each R 4  independently is hydrogen, C 1-4 alkyl, arylC 1-4 alkyl; 
       each R 5a , R 5b , R 5c , R 5d  independently is hydrogen, C 1-4 alkyl or arylC 1-4 alkyl; 
       each R 5e , R 5f  independently is hydrogen, C 1-4 alkyl or arylC 1-4 alkyl, or R 5e  and R 5f  taken together may form a bivalent alkanediyl radical of formula —CH 2 —CH 2 — or —CH 2 —CH 2 —CH 2 —; 
       R 6  is C 1-4 alkyl, —N(R 5a R 5b ), C 1-4 alkyloxy, pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, piperazin-1-yl, 4-(C 1-4 alkyl)-piperazin-1-yl, morpholin-4-yl-, thiomorpholin-4-yl-, 1-oxothiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4-yl; 
       R 7  is hydrogen C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl or C 1-4 alkylcarbonyloxyC 1-4 alkyl; 
       R 8  is hydrogen C 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkoxycarbonyloxyC 1-4 alkyl or arylC 4 alkyl; 
       R 9  is hydrogen or C 1-4 alkyl; 
       R 10  is Het 1 , Het 2  or a radical 
     
     
       
         
         
             
             
         
       
       R 11  is aryl, arylC 1-4 alkyl, formyl, C 1-4 alkylcarbonyl, arylcarbonyl, arylC 1-4 alkyl-carbonyl, C 1-4 alkyloxycarbonyl, arylC 1-4 alkyloxycarbonyl, R 5a R 5b N-carbonyl, hydroxyC 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl, arylC 1-4 alkyloxyC 1-4 alkyl, aryloxyC 1-4 alkyl, Het 2 ; 
       each R 12  independently is hydroxy, C 1-4 alkyl, arylC 1-4 alkyl, C 1-4 alkyloxy, arylC 1-4 alkyloxy oxo, spiro(C 2-4 alkanedioxy), spiro(diC 1-4 alkyloxy), —NR 5a R 5b ; 
       R 13  is hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, or arylC 1-4 alkyloxy; or 
       R 13a  is C 1-4 alkyl, arylC 1-4 alkyl, C 1-4 alkyloxycarbonyl or arylC 1-4 alkyloxycarbonyl; 
       each R 13b  is hydrogen or C 1-4 alkyl; or R 2  is 
       iv) a radical of formula:
                     C p H 2p —CH(OR 14 )—C q H 2q —R 15   (b-3); 
   —CH 2 —CH 2 —(O—CH 2 —CH 2 ) m —OR 14   (b-4); 
   —CH 2 —CH 2 —(O—CH 2 —CH 2 ) m —NR 17a R 17b   (b-5); 
 
     
     wherein in radical (b-3) one of the hydrogen atoms in —C p H 2p — and one of the hydrogen atoms in —CH(OR 14 )—C q H 2q —, that is not part of R 14 , may be replaced by a direct bond or a C 1-4 alkanediyl group;
 p is 1, 2 or 3; 
 q is 0, 1, 2 or 3; 
 each m independently is 1 to 10; 
 each R 14  independently is hydrogen, C 1-4 alkyl aryl C 1-4 alkyl, aryl C 1-4 alkylcarbonyl, —SO 3 H, —PO 3 H 2 . 
 R 15  is a substituent selected from the group consisting of cyano, NR 16a R 16b , pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C 1-4 alkyl)-piperazinyl 4-(C 1-4 alkylcarbonyl)-piperazinyl, 4-(C 1-4 alkyloxycarbonyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, aryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, hydroxy-carbonyl, C 1-4 alkylcarbonyl N(R 16a R 16b )carbonyl C 1-4 alkyloxycarbonyl pyrrolidin-1-yl-carbonyl, piperidin-1-ylcarbonyl, homopiperidin-1-ylcarbonyl, piperazin-1-yl-carbonyl 4-(C 1-4 alkyl)-piperazin-1-ylcarbonyl morpholin-1-yl-carbonyl thiomorpholin-1-yl-carbonyl, 1-oxothiomorpholin-1-ylcarbonyl and 1,1-dioxo-thiomorpholin-1-ylcarbonyl; or R 15  may additionally be aryl substituted with a radical —COOR 4 ; or a radical selected from —NR 5a —C(═NR 5b )—NR 5c R 5d , —NR 5a —C(═NR 5e )—R 5f , —O—NR 5a —C(═NR 5b )—NR 5c R 5d , —O—NR 5a —C(═NR 5e )—R 5f , -sulfonyl-R 6 , —NR 7 R 8 , —NR 9 R 10 , a radical (a-1), (a-2), (a-3), (a-4) or (a-5); wherein R 4 R 5a , R 5b , R 5c , R 5d , R 6 , R 7 , R 8 , R 9 , R 10 , and the radicals (a-1), (a-2) (a-3), (a-4), (a-5) independently are as defined above: 
 R 16a  and R 16b  independently from one another are hydrogen, C 1-6 alkyl or C 1-6 alkyl substituted with a substituent selected from the group consisting of amino, mono- or di(C 1-4 alkyl)amino, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C 1-4 alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl and aryl; 
 R 17a  and R 17b  independently from one another are hydrogen, C 1-4 alkyl or arylC 1-4 alkyl; 
 or R 17a  and R 17b  together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, 1-oxothio-mompholinyl 1,1-dioxo-thiomompholinyl piperazinyl 4-C 1-4 alkyl-piperazinyl, 4-(C 1-4 alkylcarbonyl)-piperazinyl, 4-(C 1-4 alkyloxycarbonyl)-piperazinyl ring; each R 18  independently is hydrogen, C 1-4 alkyl, arylC 1-4 alkyl, C 1-4 alkylcarbonyl or C 1-4 alkyloxycarbonyl; 
 R 19  is hydrogen, hydroxy, C 1-4 alkyl or a radical —COOR 4 ; 
 -a 1 =a 2 -a 3 =a 4 - represents a bivalent radical of formula
   —CH═CH—CH═CH—  (c-1); 
   —N═CH—CH═CH—  (c-2): 
   —CH═N—CH═CH—  (c-3); 
   —CH═CH—N═CH—  (c-4): 
   —CH═CH—CH═N—  (c-5); 
 
 wherein one, two, three or four of the hydrogen atoms in (c-1) is replaced by a radical, C 1-6 alkyl C 1-4 alkoxy, halo, hydroxy, (R 5g )(R 5h ) N—(C 1-4 alkanediyl)-O—, (R 7 )(R 8 )N—(C 1-4 alkanediyl)-O— (R 8 )(R 9 )N—(C 1-4 alkanediyl)-O-, trifluoromethyl cyano, a radical —COOR 4 , (R 5a )(R 5 )N-carbonyl, (R 5a )(R 5b )N-sulfonyl, pyrrolidinylsulfonyl, piperidinylsulfonyl, homopiperidinylsulfonyl, formyl, C 1-6 alkylcarbonyl, nitro, hydroxyC 1-6 alkyl, C 1-4 alkoxyC 1-6 alkyl, (R 4 OOC)—C 1-6 alkyl a radical —N(R 5a )(R 5b )—N(R 7 )(R 8 ), —N(R 9 )(R 10 ), a radical 
 
     
       
         
         
             
             
         
       
     
     mompholinyl, thiomompholinyl, 1-oxothiomorpholinyl 1,1-dioxo-thiomorpholinyl, (R 5g )(R 5h ) N—(C 1-4 alkanediyl)-N(R 5c )—, (R 7 )(R 8 )N—(C 1-4 alkanediyl)-N(R 5c )—, (R 9 )(R 10 )N—(C 1-4 alkanediyl)-N(R 5c )—, C 1-6 alkylcarbonylamino, C 1-6 alkyloxycarbonylamino, trifluoroacetylamino, C 1-6 alkylsulfonylamino, (R 5a )(R 5b )N—C 1-4 alkyl; aryl; Het 1  or Het 2 ;
 R 20  is hydrogen, hydroxy, C 1-4 , alkyl, arylC 1-4 alkyl, C 1-4 alkyloxy, arylC 1-4 alkyloxy, oxo, spiro(C 2-4 alkylenedioxy), spiro(diC 1-4 alkyloxy), —NR 5g R 5h ; 
 each R 5g  or R 5h  independently is hydrogen, C 1-4 alkyl or arylC 1-4 alkyl, or R 5g  and R 5h  together with the nitrogen to which they attached form a pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl or 4-C 1-4 alkylpiperazinyl radical; wherein each of said pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl or 4-C 1-4 alkylpiperazinyl radical may optionally be substituted with hydroxy or oxo; or
 wherein one or more of the hydrogen atoms in (c-2) (c-3) (c-4) or (c-5) may be replaced with a radical selected from halo and C 1-6 alkyl 
 
 R 3  is nitro, cyano, amino, halo, hydroxy C 1-4 alkyloxy, hydroxycarbonyl, amino-carbonyl, C 1-4 alkyloxycarbonyl, mono- or di(C alkyl)aminocarbonyl, C 1-4 alkyl-carbonyl, methanimidamidyl, mono- or di(C 1-4 alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het 1 ; 
 aryl is phenyl optionally substituted with one or more substituents each individually selected from the group consisting of C 1-6 alkyl, C 1-4 alkoxy, halo, hydroxy, amino, trifluoromethyl, cyano, nitro, hydroxyC 1-6 alkyl, cyanoC 1-6 alkyl, mono- or di(C 1-4 alkyl)amino, aminoC 1-4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl; 
 Het 1  is a 5-membered ring system wherein one, two, three or four ring members are heteroatoms each individually and independently selected from the group consisting of nitrogen oxygen and sulfur, and wherein the remaining ring members are carbon atoms; and, where possible any nitrogen ring member may optionally be substituted with C 1-4 alkyl; any ring carbon atom may, each individually and independently optionally be substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, hydroxy, C 1-4 alkoxy, halo, amino, cyano, trifluoromethyl, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, mono- or di(C 4 alkyl)amino, aminoC 1-4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl, arylC 1-4 alkyl, amino C 2-6 alkenyl, mono- or di(C 1-4 alkyl)aminoC 2-6 alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C 1-4 alkyloxycarbonyl mono- or di(C 1-4 alkyl)aminocarbonyl C 1-4 alkylcarbonyl oxo, thio; and wherein any of the foregoing furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, and triazolyl moieties may optionally be substituted with C 1-4 alkyl; and 
 Het 2  is pyridyl pyrimidinyl pyrazinyl pyridazinyl or triazinyl wherein any ring carbon atom of each of said 6-membered nitrogen containing aromatic rings may optionally be substituted with a substituent selected from the group consisting of C 1-4 alkyl 
 said process comprising:
 (a) cyclizing an intermediate (II-5) to obtain a compound of formula (I-b): 
 
 
     
       
         
         
             
             
         
       
       
         and optionally N-alkylating the compound of formula (I-b) to obtain a compound of formula (I-e): 
       
     
     
       
         
         
             
             
         
       
       
         (b) cyclizing an intermediate (VII-d) thus obtaining compounds of formula (I-f): 
       
     
     
       
         
         
             
             
         
       
       
         c) halogenating an intermediate (VIII-a) to obtain a compound of formula (I-g) and if desired reacting the compound (I-g) with an amine HNR c R d  to obtain a compound (I-h): 
       
     
     
       
         
         
             
             
         
       
       
         d) alkoxycarbonylating a compound (I-g) with CO in the presence of C 1-4 alkyl-OH to obtain a compound (I-i): 
       
     
     
       
         
         
             
             
         
       
       
         e) and if desired, preparing salts of the compounds of formula (I) by treating the free forms with an acid or with a base; or conversely treating the salt form with an acid or base to prepare the free form. 
       
     
   
   
       18 . A method of treating a subject infected with human immunodeficiency virus (HIV), said method comprising the systemic administration to said HIV-infected subject of an amount of a compound of formula (I) effective in the treatment of the conditions associated with HIV infection, wherein the compound of formula (I) comprises: 
     
       
         
         
             
             
         
       
       the N-oxides, salts, quaternary ammonium salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, 
       wherein 
       n is 1, 2 or 3; 
       R 1  is hydrogen, cyano, halo, aminocarbonyl, hydroxycarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, arylaminocarbonyl, N-(aryl)-N—(C 1-4 alkyl)aminocarbonyl, methanimidamidyl, N-hydroxy-methanimidamidyl, mono- or di(C 1-4 alkyl)methanimidamidyl, Het 1  or Het 2 ; 
       X is a bivalent radical NR 2 , O, S, SO, SO 2 ; 
       R 2  is: 
       i) hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl, wherein said C 1-10 alkyl, C 2-10 alkenyl and C 3-7 cycloalkyl, each individually and independently, may be optionally substituted with a substituent selected from the group consisting of cyano, N(R 16a R 16b ), pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C 1-4 alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, aryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, hydroxy-carbonyl, C 1-4 alkylcarbonyl, N(R 16a R 16b )carbonyl, C 1-4 alkyloxycarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C 1-4 alkyl)-piperazin-1-ylcarbonyl, morpholin-1-yl-carbonyl, thiomorpholin-1-ylcarbonyl, 1-oxothiomorpholin-1-ylcarbonyl and 1,1-dioxo-thiomorpholin-1-ylcarbonyl; or R 2  is 
       ii) aryl substituted with a radical —COOR 4 ; or R 2  is 
       iii) C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl, each of said C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl, each individually and independently, being substituted with aryl wherein said aryl is substituted with a radical —COOR 4 ; or R 2  is 
       iv) C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl, each individually and independently, substituted with a radical selected from —NR 5a —C(═NR 5b )—NR 5c R 5d , —NR 5a —C(═NR 5e )—R 5f , —O—NR 5a —C(═NR 5b )—NR 5c R 5d , —O—NR 5a —C(═NR 5e )—R 5f , -sulfonyl-R 6 , —NR 7 R 8 , —NR 9 R 10 , a radical 
     
     
       
         
         
             
             
         
       
       wherein 
       each Q 1  independently is a direct bond, —CH 2 —, or —CH 2 —CH 2 —; 
       each Q 2  independently is O, S, SO or SO 2 ; 
       each R 4  independently is hydrogen, C 1-4 alkyl, arylC 1-4 alkyl; 
       each R 5 , R 5b , R 5c , R 5d  independently is hydrogen, C 1-4 alkyl or arylC 1-4 alkyl; 
       each R 5e , R 5f  independently is hydrogen, C 1-4 alkyl or arylC 1-4 alkyl, or R 5e  and R 5f , taken together may form a bivalent alkanediyl radical of formula —CH 2 —CH 2 — or —CH 2 —CH 2 —CH 2 —; 
       R 6  is C 1-4 alkyl, —N(R 5a R 5b ), C 1-4 alkyloxy, pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, piperazin-1-yl, 4-(C 1-4 alkyl)-piperazin-1-yl, morpholin-4-yl-, thiomorpholin-4-yl-, 1-oxothiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4-yl; 
       R 7  is hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl or C 1-4 alkylcarbonyloxyC 1-4 alkyl; 
       R 8  is hydroxyC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylcarbonyloxyC 1-4 alkyl, aryl or arylC 1-4 alkyl; 
       R 9  is hydrogen or C 1-4 alkyl; 
       R 10  is Het 1 , Het 2  or a radical 
     
     
       
         
         
             
             
         
       
       R 11  is aryl, arylC 1-4 alkyl, formyl, C 1-4 alkylcarbonyl, arylcarbonyl, arylC 1-4 alkyl-carbonyl, C 1-4 alkyloxycarbonyl, arylC 1-4 alkyloxycarbonyl, R 5a R 5b N-carbonyl, hydroxyC 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl, arylC 1-4 alkyloxyC 1-4 alkyl, aryloxyC 1-4 alkyl, Het 2 ; 
       each R 12  independently is hydroxy, C 1-4 alkyl, arylC 1-4 alkyl, C 1-4 alkyloxy, arylC 1-4 alkyloxy, oxo, spiro(C 2-4 alkanedioxy), spiro(diC 1-4 alkyloxy), —NR 5a R 5b ; 
       R 13  is hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, or arylC 1-4 alkyloxy; or 
       R 13a  is C 1-4 alkyl, arylC 1-4 alkyl, C 1-4 alkyloxycarbonyl or arylC 1-4 alkyloxycarbonyl; 
       each R 13b  is hydrogen or C 1-4 alkyl; or R 2  is 
       iv) a radical of formula:
                     —C p CH 2p —CH(OR 14 )—C q H 2q —R 15   (b-3) 
   —CH 2 —CH 2 —(O—CH 2 —CH 2 ) m —OR 14   (b-4); 
   —CH 2 —CH 2 —(O—CH 2 —CH 2 ) m —NR 17a R 17b   (b-5); 
 
       wherein in radical (b-3) one of the hydrogen atoms in —C p H 2p  and one of the hydrogen atoms in —CH(OR 14 )—C q H 2q —, that is not part of R 14 , may be replaced by a direct bond or a C 1-4 alkanediyl group; 
       p is 1, 2 or 3; 
       q is 0, 1, 2 or 3; 
       each m independently is 1 to 10; 
       each R 14  independently is hydrogen, C 1-4 alkyl, aryl C 1-4 alkyl, aryl, C 1-4 alkylcarbonyl, —SO 3 H, —PO 3 H 2 ; 
       R 15  is a substituent selected from the group consisting of cyano, NR 16a R 16b , pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C 1-4 alkyl)-piperazinyl, 4-(C 1-4 alkylcarbonyl)-piperazinyl, 4-(C 1-4 alkyloxycarbonyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, aryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, hydroxy-carbonyl, C 1-4 alkylcarbonyl, N(R 16a R 16b )carbonyl, C 1-4 alkyloxycarbonyl, pyrrolidin-1-yl-carbonyl, piperidin-1-ylcarbonyl, homopiperidin-1-ylcarbonyl, piperazin-1-yl-carbonyl, 4-(C 1-4 alkyl)-piperazin-1-ylcarbonyl, morpholin-1-yl-carbonyl, thiomorpholin-1-yl-carbonyl, 1-oxothiomorpholin-1-ylcarbonyl and 1,1-dioxo-thiomorpholin-1-ylcarbonyl; or R 15  may additionally be aryl substituted with a radical —COOR 4 ; or a radical selected from —NR 5a —C(═NR 5b )—NR 5c R 5d , —NR 5a —C(═NR 5e )—R 5f , —O—NR 5a —C(═NR 5b )—NR 5c R 5d , —O—NR 5a —C(═NR 5e )—R 5f , -sulfonyl-R 6 , —NR 7 R 8 , —NR 9 R 10 , a radical (a-1), (a-2), (a-3), (a-4) or (a-5); 
       wherein R 4 R 5a , R 5b , R 5c , R 5d , R 6 , R 7 , R 8 , R 9 , R 10 , and the radicals (a-1), (a-2), (a-3), (a-4), (a-5) independently are as defined above; 
       R 16a  and R 16b  independently from one another are hydrogen, C 1-6 alkyl or C 1-6 alkyl substituted with a substituent selected from the group consisting of amino, mono- or di(C 1-4 alkyl)amino, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C 1-4 alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl and aryl; 
       R 17a  and R 17b  independently from one another are hydrogen, C 1-4 alkyl or arylC 1-4 alkyl; or R 17a  and R 17b  together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, 1-oxothio-morpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, 4-C 1-4 alkyl-piperazinyl, 4-(C 1-4 alkylcarbonyl)-piperazinyl, 4-(C 1-4 alkyloxycarbonyl)-piperazinyl ring; 
       each R 18  independently is hydrogen, C 1-4 alkyl, arylC 1-4 alkyl, C 1-4 alkylcarbonyl or C 1-4 alkyloxycarbonyl; 
       R 19  is hydrogen, hydroxy, C 1-4 alkyl or a radical —COOR 4 ; 
       -a 1 =a 2 -a 3 =a 4 - represents a bivalent radical of formula
   —CH═CH—CH═CH—  (c-1); 
   —N═CH—CH═CH—  (c-2); 
   —CH═N—CH═CH—  (c-3); 
   —CH═CH—N═CH—  (c-4); 
   —CH═CH—CH═N—  (c-5); 
 
       wherein one, two, three or four of the hydrogen atoms in (c-1) is replaced by a radical, C 1-6 alkyl, C 1-4 alkoxy, halo, hydroxy, (R 5g )(R 5h )N—(C 1-4 alkanediyl)-O—, (R 7 )(R 8 )N—(C 1-4 alkanediyl)-O—, (R 8 )(R 9 )N—(C 1-4 alkanediyl)-O—, trifluoromethyl, cyano, a radical —COOR 4 , (R 5a )(R 5b )N-carbonyl, (R 5a )(R 5b )N-sulfonyl, pyrrolidinylsulfonyl, piperidinylsulfonyl, homopiperidinylsulfonyl, formyl, C 1-6 alkylcarbonyl, nitro, hydroxyC 1-6 alkyl, C 1-4 alkoxyC 1-6 alkyl, (R 4 OOC)—C 1-6 alkyl, a radical —N(R 5a )(R 5b ), —N(R 7 )(R 8 ), —N(R 9 )(R 10 ), a radical 
     
     
       
         
         
             
             
         
       
     
     morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, (R 5g )(R 5h )N—(C 1-4 alkanediyl)-N(R 5c )—, (R 7 )(R 8 )N—(C 1-4 alkanediyl)-N(R 5c ), (R 9 )(R 10 )N—(C 1-4 alkanediyl)-N(R 5c )—, C 1-6 alkylcarbonylamino, C 1-6 alkyloxycarbonylamino, trifluoroacetylamino, C 1-6 alkylsulfonylamino, (R 5a )(R 5b )N—C 1-4 alkyl; aryl; Het 1  or Het 2 ;
 R 20  is hydrogen, hydroxy, C 1-4 alkyl, arylC 1-4 alkyl, C 1-4 alkyloxy, arylC 1-4 alkyloxy, oxo, spiro(C 2-4 alkylenedioxy), spiro(diC 1-4 alkyloxy), —NR 5g R 5h ; 
 each R 5g  or R 5h  independently is hydrogen, C 1-4 alkyl or arylC 1-4 alkyl, or R 5g  and R 5h  together with the nitrogen to which they attached form a pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl or 4-C 1-4 alkylpiperazinyl radical; wherein each of said pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl or 4-C 1-4 alkylpiperazinyl radical may optionally be substituted with hydroxy or oxo; or
 wherein one or more of the hydrogen atoms in (c-2), (c-3), (c-4) or (c-5) may be replaced with a radical selected from halo and C 1-6 alkyl; 
 
 R 3  is nitro, cyano, amino, halo, hydroxy, C 1-4 alkyloxy, hydroxycarbonyl, amino-carbonyl, C 1-4 alkyloxycarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkyl-carbonyl, methanimidamidyl, mono- or di(C 1-4 alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het 1 ; 
 aryl is phenyl optionally substituted with one or more substituents each individually selected from the group consisting of C 1-6 alkyl, C 1-4 alkoxy, halo, hydroxy, amino, trifluoromethyl, cyano, nitro, hydroxyC 1-6 alkyl, cyanoC 1-6 alkyl, mono- or di(C 1-4 alkyl)amino, aminoC 1-4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl; 
 Het 1  is a 5-membered ring system wherein one, two, three or four ring members are heteroatoms each individually and independently selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the remaining ring members are carbon atoms; and, where possible, any nitrogen ring member may optionally be substituted with C 1-4 alkyl; any ring carbon atom may, each individually and independently, optionally be substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, hydroxy, C 1-4 alkoxy, halo, amino, cyano, trifluoromethyl, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, mono- or di(C 1-4 alkyl)amino, aminoC 1-4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl, arylC 1-4 alkyl, aminoC 2-6 alkenyl, mono- or di(C 1-4 alkyl)aminoC 2-6 alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C 1-4 alkyloxycarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkylcarbonyl, oxo, thio; and wherein any of the foregoing furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl moieties may optionally be substituted with C 1-4 alkyl; and 
 Het 2  is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, wherein any ring carbon atom of each of said 6-membered nitrogen containing aromatic rings may optionally be substituted with a substituent selected from the group consisting of C 1-4 alkyl