Carboxylic acid amides, the preparation thereof, and their use as pharmaceutical compositions

Abstract

Substituted carboxylic acid amides of general formula wherein A, B, and R 1 to R 5 are as defined herein, and the tautomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable properties, such as antithrombotic activity and factor Xa-inhibiting activity.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is an amino, C 1-5 -alkylamino, C 3-7 -cycloalkylamino, or (phenyl-C 1-3 -alkyl)-amino group each additionally optionally substituted at the amino nitrogen atom by a phenylcarbonyl or phenylsulfonyl group or by C 1-5 -alkyl or C 1-5 -alkylcarbonyl group optionally substituted in the alkyl moiety by a hydroxy, C 1-3 -alkyloxy, or carboxy group, a group that is converted in vivo into a carboxy group, an amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, or a 4- to 7-membered cycloalkyleneimino group, wherein at the abovementioned substituted C 1-5 -alkyl group, two heteroatoms are separated from one another by at least two carbon atoms, 
 a 4- to 7-membered cycloalkyleneiminocarbonyl or cycloalkyleneiminosulfonyl group, wherein:
 the cycloalkyleneimino moiety is optionally substituted in the carbon skeleton by a fluorine, chlorine, or bromine atom, one or two C 1-3 -alkyl, C 2-3 -alkenyl, C 2-3 -alkynyl, hydroxy-C 1-3 -alkyl, C 1-3 -alkyloxy-C 1-3 -alkyl, phenyl-C 1-3 -alkyl, 1,1-diphenyl-C 1-3 -alkyl, heteroaryl-C 1-3 -alkyl, amino-C 1-3 -alkyl, C 3-6 -cycloalkylamino-C 1-3 -alkyl, phenylamino-C 1-3 -alkyl, C 1-5 -alkylamino-C 1-3 -alkyl, di-(C 1-5 -alkyl)-amino-C 1-3 -alkyl, N—(C 3-6 -cycloalkyl)C 1-3 -alkylamino-C 1-3 -alkyl, a 4- to 7-membered cycloalkyleneimino-C 1-3 -alkyl, N—(C 1-3 -alkylcarbonyl)-C 1-3 -alkylamino-C 1-3 -alkyl, carboxy-C 1-3 -alkyl, C 1-3 -alkyloxycarbonyl-C 1-3 -alkyl, aminocarbonyl-C 1-3 -alkyl, C 1-3 -alkylaminocarbonyl-C 1-3 -alkyl, di(C 1-3 -alkyl)-aminocarbonyl-C 1-3 -alkyl, a 4- to 7-membered cycloalkyleneiminocarbonyl-C 1-3 -alkyl, C 1-5 -alkyloxycarbonylamino-C 1-3 -alkyl, C 1-3 -alkylcarbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonylamino-C 1-3 -alkyl, aminocarbonylamino-C 1-3 -alkyl, C 1-3 -alkylaminocarbonylamino-C 1-3 -alkyl, di-(C 1-3 -alkyl)-aminocarbonylamino-C 1-3 -alkyl, carboxy, C 1-3 -alkyloxycarbonyl, benzyloxycarbonyl, C 1-3 -alkylcarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, N—(C 3-7 -cycloalkyl)-C 1-5 -alkylaminocarbonyl, N-(phenyl-C 1-3 -alkyl)-C 1-5 -alkylaminocarbonyl, a 4- to 7-membered cycloalkyleneiminocarbonyl, aminocarbonyl-C 1-3 -alkylaminocarbonyl, hydroxy, C 1-3 -alkyloxy, allyloxy, propargyloxy, benzyloxy, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)amino, a 4- to 7-membered cycloalkyleneimino, trifluoromethylcarbonylamino, a mono-, di, or trifluoromethylamino, a phenyl or a 5- to 6-membered heteroaryl group, with the proviso that, in the substitution of a methylene group adjacent to the imino group, two heteroatoms are separated from one another by at least two carbon atoms, and/or 
 a methylene group in the 3 position of a 5-membered cycloalkyleneimino group is optionally replaced by a sulfur atom, or a sulfinyl or sulfonyl group or 
 a methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group is optionally replaced by an oxygen or sulfur atom, a carbonyl, sulfinyl, or sulfonyl group or by an —NH— group optionally substituted by a C 1-3 -alkyl, hydroxy, formyl, or C 1-3 -alkylcarbonyl group, wherein additionally a methylene group adjacent to the abovementioned optionally substituted —NH— group is optionally replaced by a carbonyl, sulfinyl, or sulfonyl group, with the proviso that in the substitution of the abovementioned 6- to 7-membered cycloalkyleneimino groups wherein a methylene group is replaced by an oxygen or sulfur atom or a sulfinyl or sulfonyl group, two heteroatoms are separated from one another by at least two carbon atoms, 
 
 a 5- to 7-membered cycloalkenyleneiminocarbonyl or cycloalkenyleneiminosulfonyl group optionally substituted by one or two C 1-3 -alkyl, amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl, di(C 1-3 -alkyl)-amino-C 1-3 -alkyl, a 4- to 7-membered cycloalkyleneimino-C 1-3 -alkyl, C 3-6 -cycloalkylamino-C 1-13 -alkyl, phenyl, phenyl-C 1-3 -alkyl, heteroaryl, heteroaryl-C 1-3 -alkyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, or 4- to 7-membered cycloalkyleneiminocarbonyl groups, wherein the double bond is not bound to a nitrogen atom and is optionally fused to a 5- or 6-membered heteroaryl group, 
 an aminocarbonyl or aminosulfonyl group optionally substituted by one or two C 1-5 -alkyl, C 2-3 -alkenyl, C 2-3 -alkynyl, C 3-6 -cycloalkyl, or 5- to 7-membered cycloalkyleneimino groups,
 wherein the substituents are identical or different, and 
 in each case one of the C 1-5 -alkyl groups is optionally substituted by one or two hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 1-3 -alkyl, benzyloxy-C 1-3 -alkyl, amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl, di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl, a 4- to 7-membered cycloalkyleneimino-C 1-3 -alkyl, C 1-5 -alkyloxycarbonylamino-C 1-3 -alkyl, C 3-6 -cycloalkylamino-C 1-3 -alkyl, aminocarbonyl, C 1-13 -alkylaminocarbonyl, N—(C 3-7 -cycloalkyl)-C 1-13 -alkylaminocarbonyl, N-(phenyl-C 1-3 -alkyl)-C 1-5 -alkylaminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, or a 4- to 7-membered cycloalkyleneiminocarbonyl group, 
 
 a C 1-17 -alkylcarbonyl or C 3-7 -cycloalkylcarbonyl group, wherein:
 the methylene group in the 2, 3, or 4 position in a C 3-7 -cycloalkylcarbonyl group is optionally replaced by an oxygen or sulfur atom, or a carbonyl, sulfinyl, sulfonyl, or —NH— group, wherein the hydrogen atom of the —NH— group is optionally replaced by a C 1-3 -alkyl or C 1-3 -alkylcarbonyl group, 
 
 a phenylcarbonyl or heteroarylcarbonyl group which is optionally substituted in the phenyl or heteroaryl moiety by a fluorine, chlorine, or bromine atom, or a trifluoromethyl, C 1-3 -alkyl, amino-C 1-3 -alkyl, C 1-13 -alkylamino-C 1-3 -alkyl, di-(C 1-13 -alkyl)-amino-C 1-3 -alkyl, 4- to 7-membered cycloalkyleneimino-C 1-3 -alkyl, or C 1-3 -alkoxy group, 
 a C 1-3 -alkyl group optionally monosubstituted by an amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)amino, hydroxy, phenyl, heteroaryl, or 4- to 7-membered cycloalkyleneimino group, wherein:
 the phenyl moiety is optionally substituted by a fluorine, chlorine, or bromine atom, or a trifluoromethyl, C 1-3 -alkyl, amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl, di-(C 1-3 -alkyl)amino-C 1-3 -alkyl, 4- to 7-membered cycloalkyleneimino-C 1-3 -alkyl, or C 1-3 -alkoxy group, and/or 
 a —CH 2 —CH 2 — group in a 5- to 7-membered cycloalkyleneimino group is optionally replaced by a —NH—CO—, —CO—NH—, —CO—N(CH 3 )—, or —N(CH 3 )—CO— group, or 
 a methylene group, which is adjacent to the nitrogen atom, in a 5- to 7-membered cycloalkyleneimino group is optionally replaced by a carbonyl group, 
 
 or a group of formula: 
 
       
         
           
           
               
               
           
         
         
           wherein in the heterocyclic moiety in each case a hydrogen atom is optionally replaced by a C 1-3 -alkyl, C 1-3 -alkyloxy, C 1-3 -alkyloxycarbonyl, C 1-5 -alkyloxycarbonylamino-C 1-3 -alkyl, methylsulfonylmethyl, amino-C 1-3 -alkyl, C 1-13 -alkylamino-C 1-3 -alkyl, di-(C 1-13 -alkyl)-amino-C 1-3 -alkyl, 4- to 7-membered cycloalkyleneimino-C 1-3 -alkyl, morpholin-4-yl-C 1-3 -alkyl, piperazinyl-C 1-3 -alkyl, N—(C 1-3 -alkyl)piperazin-4-yl-C 1-3 -alkyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, or di-(C 1-3 -alkyl)-aminocarbonyl group, and 
           m is 1 or 2; 
         
         R 2  is a hydrogen, fluorine, chlorine, or bromine atom, or a C 1-3 -alkyl group wherein the hydrogen atoms are optionally wholly or partly replaced by fluorine atoms, or a C 2-3 -alkenyl, C 2-3 -alkynyl, C 1-3 -alkoxy, or mono-, di-, or trifluoromethoxy groups; 
         R 3  is a hydrogen atom or a C 1-3 -alkyl group; 
         R 4  is a hydrogen atom, or a C 2-3 -alkenyl or C 2-3 -alkynyl group, or a straight-chain or branched C 1-5 -alkyl group which is optionally substituted by a fluorine atom, or a mono-, di-, or trifluoromethyl, a nitrile, hydroxy, a C 1-5 -alkyloxy group wherein the hydrogen atoms are optionally wholly or partly replaced by fluorine atoms, an allyloxy, propargyloxy, benzyloxy, C 1-5 -alkylcarbonyloxy, C 1-5 -alkyloxycarbonyloxy, carboxy-C 1-3 -alkyloxy, C 1-5 -alkyloxycarbonyl-C 1-3 -alkyloxy, C 1-8 -alkyloxycarbonylamino, chloro-C 2-3 -alkylaminocarbonylamino, mercapto, C 1-3 -alkylsulfanyl, C 1-3 -alkylsulfinyl, C 1-3 -alkylsulfonyl, C 1-3 -alkylcarbonylamino-C 1-3 -alkylsulfanyl, C 1-3 -alkylcarbonylamino-C 1-3 -alkylsulfinyl, C 1-3 -alkylcarbonylamino-C 1-13 -alkylsulfonyl, carboxy, C 1-13 -alkyloxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, benzyloxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, aminosulfonyl, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, C 1-5 -alkylcarbonylamino, C 1-3 -alkylsulfonylamino, N—(C 1-3 -alkylsulfonyl)-C 1-3 -alkylamino, C 3-6 -cycloalkylcarbonylamino, aminocarbonylamino, C 1-13 -alkylaminocarbonylamino, di-(C 1-13 -alkyl)-aminocarbonylamino, a 4- to 7-membered cycloalkyleneiminocarbonylamino, benzyloxycarbonylamino, phenylcarbonylamino, heteroaryl, or guanidino group, 
         a group of formula 
       
       
         
           
           
               
               
           
         
       
       wherein:
 o is 2, 3, 4, or 5, 
 R 11  is a hydrogen atom or a C 1-3 -alkyl group, and 
 A is a heteroaryl group or a C 5-7 -cycloalkyl group wherein:
 the methyne group is optionally replaced in the 1 position by a nitrogen atom, and/or 
 a methylene group is optionally replaced by an oxygen or sulfur atom, or an —NH—, —N(OH)—, —N(C 1-3 -alkyl)-, —N(C 1-3 -alkylcarbonyl)-, or —N(heteroaryl)- group, and/or 
 a methylene group adjacent to an —NH—, —N(OH)—, —N(C 1-3 -alkyl)-, —N(C 1-3 -alkylcarbonyl)-, or —N(heteroaryl)- group are additionally optionally replaced by a carbonyl, sulfinyl, or sulfonyl group, 
 
 a 4- to 7-membered cycloalkyleneiminocarbonyl-C 1-3 -alkyl group, wherein:
 a methylene group of the cycloalkyleneimino moiety is optionally substituted by a C 1-3 -alkyl group optionally substituted by a hydroxy, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, 4- to 7-membered cycloalkyleneimino, or C 1-5 -alkyloxycarbonylamino group, an aminocarbonyl, C 1-3 -alkylaminocarbonyl, or di-(C 1-3 -alkyl)-aminocarbonyl group, and a methylene group of the cycloalkyleneimino moiety not adjacent to the imino group is optionally substituted by a hydroxy, amino, C 1-3 -alkylamino, or di-(C 1-3 -alkyl)-amino- group, and/or 
 a methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group is optionally replaced by an oxygen or sulfur atom, or a carbonyl, sulfinyl, sulfonyl, or —NH— group optionally substituted by a C 1-3 -alkyl group and additionally a methylene group adjacent to an abovementioned —NH— or —N(C 1-3 -alkyl) group is optionally replaced by a carbonyl group, or 
 a methylene group in the 2 position of a 5-membered cycloalkyleneimino group is optionally replaced by a carbonyl, sulfinyl, or sulfonyl group, 
 
 a C 1-3 -alkyl group which is terminally substituted by a group of formula 
 
       
         
           
           
               
               
           
         
       
       wherein:
 p in each case is 1 or 2, and 
 R 8  is a hydrogen atom, or a C 1-3 -alkyl or C 1-3 -alkylcarbonyl group, 
 a phenyl or heteroaryl, phenylcarbonyl-C 1-3 -alkyl, phenyl-C 1-3 -alkyl, or heteroaryl-C 1-3 -alkyl group which is optionally mono- or polysubstituted by fluorine, chlorine, or bromine atoms, or C 1-3 -alkyl, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, hydroxy, C 1-4 -alkyloxy, mono-, di-, or trifluoromethoxy, benzyloxy, carboxy-C 1-3 -alkyloxy, C 1-3 -alkyloxycarbonyl-C 1-3 -alkyloxy, aminocarbonyl-C 1-3 -alkyloxy, C 1-3 -alkylaminocarbonyl-C 1-3 -alkyloxy, di-(C 1-3 -alkyl)aminocarbonyl-C 1-3 -alkyloxy, a 4- to 7-membered cycloalkyleneiminocarbonyl-C 1-13 -alkoxy, carboxy, or C 1-3 -alkyloxycarbonyl group, 
 a C 3-6 -cycloalkyl or a 4- to 7-membered cycloalkyleneimino group optionally substituted by a C 1-3 -alkylcarbonyl or C 1-4 -alkyloxycarbonyl group which is bound via a carbon atom, or 
 a 3- to 7-membered cycloalkyl-C 1-3 -alkyl or cycloalkyleneimino-C 1-3 -alkyl group wherein in the cyclic moiety a methylene group is optionally replaced by an —NH— group optionally substituted by a C 1-3 -alkyl or C 1-3 -alkylcarbonyl group and wherein additionally a methylene group adjacent to an —NH—, —N(C 1-3 -alkylcarbonyl)-, or —N(C 1-3 -alkyl)- group is optionally replaced in each case by a carbonyl or sulfonyl group, with the proviso that a cycloalkyleneimino group as hereinbefore defined wherein two nitrogen atoms are separated from one another by precisely one —CH 2 — group is excluded, 
 R 5  is a hydrogen atom or a C 1-3 -alkyl group, or 
 R 4  and R 5  together with the carbon atom to which they are bound, is a C 3-7 -cycloalkyl group, wherein one of the methylene groups of the C 3-7 -cycloalkyl group is optionally replaced by an imino, C 1-3 -alkylimino, acylimino, or sulfonylimino group, 
 A is a carbonylamino or aminocarbonyl group, wherein the hydrogen atom of the amino function is optionally substituted by a C 1-3 -alkyl group, and 
 B is 
 
       
         
           
           
               
               
           
         
       
       wherein:
 n is 1 or 2, 
 R 6  is a hydrogen atom or a C 1-3 -alkyl, hydroxy, C 1-5 -alkyloxycarbonyl, carboxy-C 1-3 -alkyl, C 1-3 -alkyloxycarbonyl-C 1-3 -alkyl, amino, or C 1-3 -alkylamino group and 
 R 7  is a hydrogen, fluorine, chlorine, or bromine atom, a C 1-3 -alkyl group wherein the hydrogen atoms is optionally wholly or partly replaced by fluorine atoms, a C 2-3 -alkenyl or C 2-3 -alkynyl, a hydroxy, C 1-3 -alkoxy, trifluoromethoxy, amino, nitro, or cyano group, 
 
       wherein, unless otherwise stated:
 (i) “heteroaryl group” means a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a fluorine, chlorine, bromine, or iodine atom, or a C 1-3 -alkyl, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, C 1-3 -alkyloxy, carboxy, C 1-3 -alkoxycarbonyl, or C 1-13 -alkoxycarbonylamino group, wherein: 
 the 6-membered heteroaryl group contains one, two, or three nitrogen atoms and
 the 5-membered heteroaryl group contains an imino group optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group, or an oxygen or sulfur atom, or 
 an imino group optionally substituted by a C 1-3 -alkyl, amino-C 2-3 -alkyl, C 1-3 -alkylamino-C 2-3 -alkyl, di-(C 1-3 -alkyl)-amino-C 2-3 -alkyl, a 4- to 7-membered cycloalkyleneimino-C 1-3 -alkyl, or phenyl-C 1-3 -alkyl group, or an oxygen or sulfur atom and additionally a nitrogen atom or 
 an imino group optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group and two or three nitrogen atoms, 
 and also a phenyl ring optionally substituted by a fluorine, chlorine, or bromine atom, or a C 1-3 -alkyl, hydroxy or C 1-3 -alkyloxy group is optionally fused to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, and 
 the bond is effected via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, 
 
 (ii) the alkyl and alkoxy groups contained in the above definitions which have more than two carbon atoms is straight-chain or branched and the alkyl groups in the above-mentioned dialkylated groups are identical or different, and 
 (iii) the hydrogen atoms of the methyl or ethyl groups contained in the above-mentioned definitions are optionally wholly or partly replaced by fluorine atoms, 
 
       wherein R 2  is a hydrogen when B is 
       
         
           
           
               
               
           
         
       
       the tautomers and the salts thereof. 
     
     
         2 . The compound of formula I according to  claim 1 , wherein each group which is converted in vivo into a carboxy group is selected from a carboxy group esterified with an alcohol reagent, with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C 3-8 -cycloalkyl-C 1-3 -alkanol, or an alcohol of formula:
   R 9 —CO—O—(R 10 CR 11 )—OH,   
       wherein:
 R 9  is a C 1-8 -alkyl, C 5-7 -cycloalkyl, phenyl, or phenyl-C 1-3 -alkyl group; 
 R 10  is a hydrogen atom, a C 1-3 -alkyl, C 5-7 -cycloalkyl, or phenyl group; and 
 R 11 ″ is a hydrogen atom or a C 1-3 -alkyl group, 
 
       and the tautomers and the salts thereof. 
     
     
         3 . The compound of formula I according to  claim 1 , wherein the alcohol reagent is a C 1-16 -alkanol, a phenyl-C 1-3 -alkanol, a C 3-9 -cycloalkanol, a C 5-7 -cycloalkenol, a C 3-5 -alkenol, a phenyl-C 3-5 -alkenol, a C 3-5 -alkynol, or a phenyl-C 3-5 -alkynol, and the tautomers and the salts thereof. 
     
     
         4 . The compound of formula I according to  claim 1 , wherein R 3  is a hydrogen atom, and the tautomers and the salts thereof. 
     
     
         5 . A compound of formula Ia 
       
         
           
           
               
               
           
         
       
       wherein: R 1 , R 2 , R 4 , R 5 , and B are as defined in  claim 1 , wherein R 4  is not a hydrogen atom, and
 R 6  is a hydrogen atom, 
 
       and the tautomers and the salts thereof. 
     
     
         6 . The compound of formula I according to  claim 1 , wherein R 2  is not a hydrogen atom, and
 B is   
       
         
           
           
               
               
           
         
       
       and the tautomers and the salts thereof. 
     
     
         7 . The compound of formula I according to  claim 5 , wherein R 2  is a hydrogen atom, and the tautomers and the salts thereof. 
     
     
         8 . A compound of formula Ib 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 4 , and R 5  are as defined in  claim 1 , wherein R 2  is hydrogen, wherein R 4  is not a hydrogen atom, and
 R 7  is a fluorine, chlorine, or bromine atom, a C 1-3 -alkyl group wherein the hydrogen atoms are optionally wholly or partly replaced by fluorine atoms, or a C 2-3 -alkenyl or C 2-3 -alkynyl, a C 1-3 -alkyloxy, trifluoromethoxy, or cyano group, 
 
       and the tautomers and the salts thereof. 
     
     
         9 . The compound of formula I according to  claim 1 , wherein:
 R 1  is an amino, C 1-5 -alkylamino, C 3-7 -cycloalkylamino, or (phenyl-C 1-3 -alkyl)-amino group which is optionally additionally substituted in each case at the amino nitrogen atom by a C 1-5 -alkyl or C 1-5 -alkylcarbonyl group optionally substituted in the alkyl moiety by a carboxy group, a group which is converted in vivo into a carboxy group, an amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino or a 4- to 7-membered cycloalkyleneimino group, wherein in the abovementioned substituted C 1-5 -alkyl group, two heteroatoms are separated from one another by at least two carbon atoms,   a 4- to 7-membered cycloalkyleneiminocarbonyl or cycloalkyleneiminosulfonyl group, wherein:
 the cycloalkyleneimino moiety in the carbon skeleton is optionally substituted by one or two C 1-13 -alkyl, hydroxy-C 1-3 -alkyl, C 1-13 -alkyloxy-C 1-3 -alkyl, phenyl-C 1-3 -alkyl, heteroaryl-C 1-3 -alkyl, amino-C 1-3 -alkyl, C 3-6 -cycloalkylamino-C 1-3 -alkyl, C 1-5 -alkylamino-C 1-3 -alkyl, di(C 1-5 -alkyl)-amino-C 1-3 -alkyl, N—(C 3-6 -cycloalkyl)-C 1-13 -alkylamino-C 1-3 -alkyl, a 4- to 7-membered cycloalkyleneimino-C 1-3 -alkyl, carboxy-C 1-3 -alkyl, C 1-13 -alkyloxycarbonyl-C 1-3 -alkyl, aminocarbonyl-C 1-3 -alkyl, C 1-3 -alkylaminocarbonyl-C 1-3 -alkyl, di-(C 1-3 -alkyl)aminocarbonyl-C 1-3 -alkyl, a 4- to 7-membered cycloalkyleneiminocarbonyl-C 1-13 -alkyl, C 1-5 -alkyloxycarbonylamino-C 1-3 -alkyl, C 1-3 -alkylcarbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulfonylamino-C 1-3 -alkyl, aminocarbonylamino-C 1-3 -alkyl, C 1-3 -alkylaminocarbonylamino-C 1-3 -alkyl, di-(C 1-3 -alkyl)-aminocarbonylamino-C 1-3 -alkyl, C 1-13 -alkyloxycarbonyl, aminocarbonyl, C 1-13 -alkylaminocarbonyl, di-(C 1-3 -alkyl)aminocarbonyl, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, a phenyl, or a 5- to 6-membered heteroaryl group, with the proviso that in the substitution of a methylene group adjacent to the imino group, two heteroatoms are separated from one another by at least two carbon atoms, and/or 
 a methylene group in the 3 position of a 5-membered cycloalkyleneimino group is optionally replaced by a sulfur atom, or a sulfinyl or sulfonyl group or 
 a methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group is optionally replaced by an oxygen or sulfur atom, or a carbonyl or by an —NH— group optionally substituted by a methyl or hydroxy group, wherein additionally a methylene group adjacent to the abovementioned —NH— group is optionally replaced by a carbonyl group, 
   a 5- to 7-membered cycloalkenyleneiminocarbonyl group optionally substituted by one or two C 1-3 -alkyl, amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl, di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl, a 4- to 7-membered cycloalkyleneimino-C 1-3 -alkyl, or C 3-6 -cycloalkylamino-C 1-3 -alkyl groups, wherein the double bond is not bound to a nitrogen atom and is optionally fused to a 5- or 6-membered heteroaryl group,   an aminocarbonyl group optionally substituted by one or two C 1-5 -alkyl, allyl, propargyl, C 3-6 -cycloalkyl, or 5- to 7-membered cycloalkyleneimino groups,
 wherein the substituents are identical or different, and 
 in each case one of the C 1-5 -alkyl groups is optionally substituted by one or two hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy-C 1-3 -alkyl, amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl, di(C 1-3 -alkyl)-amino-C 1-3 -alkyl, a 4- to 7-membered cycloalkyleneimino-C 1-3 -alkyl, or C 3-6 -cycloalkylamino-C 1-3 -alkyl group, 
   a C 1-3 -alkyl group optionally monosubstituted by a di-(C 1-3 -alkyl)-amino, heteroaryl, or a 4- to 7-membered cycloalkyleneimino group, wherein:
 a —CH 2 —CH 2 — group in a 5- to 7-membered cycloalkyleneimino group is optionally replaced by a —NH—CO—, —CO—NH—, —CO—N(CH 3 )—, or a —N(CH 3 )—CO— group or 
 a methylene group, which is adjacent to the nitrogen atom, in a 5- to 7-membered cycloalkyleneimino group is optionally replaced by a carbonyl group, 
   or a group of formula   
       
         
           
           
               
               
           
         
         
           wherein in the heterocyclic moiety a hydrogen atom is optionally replaced in each case by a C 1-3 -alkyloxycarbonyl, C 1-5 -alkyloxycarbonylamino-C 1-3 -alkyl, amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl, di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl, or aminocarbonyl group, and 
           m is 1 or 2; 
         
         R 2  is a fluorine, chlorine, or bromine atom, or a C 1-3 -alkyl group wherein the hydrogen atoms is optionally wholly or partly replaced by fluorine atoms, a C 2-3 -alkenyl, C 2-3 -alkynyl, or C 1-3 -alkyloxy group wherein the hydrogen atoms is optionally wholly or partly replaced by fluorine atoms; 
         R 3  is a hydrogen atom; 
         R 4  is a hydrogen atom, a C 2-3 -alkenyl or C 2-3 -alkynyl group or a straight-chain or branched C 1-5 -alkyl group which is optionally substituted by a hydroxy, a C 1-3 -alkyloxy group wherein the hydrogen atoms is optionally wholly or partly replaced by fluorine atoms, an allyloxy, propargyloxy, benzyloxy, carboxy-C 1-3 -alkyloxy, C 1-5 -alkyloxycarbonyl-C 1-3 -alkyloxy, C 1-15 -alkyloxycarbonylamino, chloro-C 1-13 -alkylaminocarbonylamino, mercapto, C 1-3 -alkylsulfanyl, C 1-3 -alkylsulfinyl, C 1-3 -alkylsulfonyl, carboxy, C 1-3 -alkyloxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, a 4- to 7-membered cycloalkyleneimino, C 1-5 -alkylcarbonylamino, C 3-6 -cycloalkylcarbonylamino, C 1-3 -alkylsulfonylamino, benzyloxycarbonylamino or phenylcarbonylamino group, 
         a 4- to 7-membered cycloalkyleneiminocarbonyl-C 1-3 -alkyl group, wherein:
 a methylene group of the cycloalkyleneimino moiety is optionally substituted by a C 1-3 -alkyl group optionally substituted by a hydroxy, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, a 4- to 7-membered cycloalkyleneimino or C 1-5 -alkyloxycarbonylamino group and a methylene group of the cycloalkyleneimino moiety not adjacent to the imino group is optionally substituted by a hydroxy, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, aminocarbonyl, C 1-13 -alkylaminocarbonyl, or di-(C 1-13 -alkyl)-aminocarbonyl group, and/or 
 a methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group is optionally replaced by an oxygen or sulfur atom, or a carbonyl, sulfinyl, sulfonyl, or —NH— group optionally substituted by a C 1-3 -alkyl group, and additionally a methylene group adjacent to an abovementioned —NH— or —N(C 1-3 -alkyl) group is optionally replaced by a carbonyl group, 
 
         a C 1-3 -alkyl group which is terminally substituted by a group of formula 
       
       
         
           
           
               
               
           
         
       
       wherein:
 p is 1 or 2, and 
 R 8  is a hydrogen atom, or a C 1-3 -alkyl or C 1-3 -alkylcarbonyl group, 
 a phenyl, thiophenyl or pyridinyl, phenyl-C 1-3 -alkyl, tetrazolyl-C 1-3 -alkyl, imidazolyl-C 1-3 -alkyl, thiazolyl-C 1-3 -alkyl, or thiophenyl-C 1-3 -alkyl group which is optionally substituted by a chlorine atom, or a hydroxy, C 1-4 -alkyloxy, trifluoromethoxy, carboxy, or C 1-3 -alkyloxycarbonyl group, 
 R 5  is a hydrogen atom, 
 A is a carbonylamino or aminocarbonyl group, and 
 B is 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 7  is a fluorine, chlorine, or bromine atom, 
 
       and the tautomers and the salts thereof. 
     
     
         10 - 12 . (canceled) 
     
     
         13 . A compound of formula I according to  claim 1 , wherein:
 R 1  is a 2,5-dihydro-1H-pyrrol-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, N-acetyl-N-cyclobutylamino, 2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl, 2-(aminomethyl)pyrrolidin-1-ylcarbonyl, 3-oxopiperazin-1-ylcarbonyl, 4-methyl-3-oxopiperazin-1-ylcarbonyl, 2,3-dihydroimidazo[2,1-b]-thiazol-5-yl, thiazolidin-3-ylcarbonyl, 1,2,3,6-tetrahydropyridin-1-ylcarbonyl, 2-methylthiomorpholin-4-ylcarbonyl, thiomorpholin-4-ylcarbonyl, N-isopropyl-N-methylaminocarbonyl, 2-methoxymethylpyrrolidin-1-ylcarbonyl, 3-(pyrrolidin-1-ylmethyl)piperidin-1-ylcarbonyl, azetidin-1-ylcarbonyl, 2-methylpyrrolidin-1-ylcarbonyl, N-isobutyl-N-methylaminocarbonyl, [1,4]oxazepan-1-ylcarbonyl, 2,5-dimethylpyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, 4-hydroxypiperidin-1-ylcarbonyl, 4-acetylpiperazin-1-ylcarbonyl, N,N-diethylaminocarbonyl, 3-methylpiperidin-1-ylcarbonyl, 4-methylpiperidin-1-ylcarbonyl, 2-aminomethylpiperidin-1-ylcarbonyl, 3-aminomethylpiperidin-1-ylcarbonyl, 3-(2-aminoethyl)piperidin-1-ylcarbonyl, 3-aminopiperidin-1-ylcarbonyl, N-(2-dimethylamino)ethyl-N-ethylaminocarbonyl, 2-(N-tert-butoxycarbonylaminoethyl]pyrrolidin-1-ylcarbonyl, 2-(aminoethyl)pyrrolidin-1-ylcarbonyl, 2-(aminocarbonyl)pyrrolidin-1-ylcarbonyl, 1-oxothiazolidin-3-ylcarbonyl, 1,1-dioxothiazolidin-3-ylcarbonyl, 2-ethoxycarbonylmethyl-3-oxopiperazin-1-ylcarbonyl, 2-dimethylaminocarbonylmethyl-3-oxopiperazin-1-ylcarbonyl, 2-aminomethyl-3-oxopiperazin-1-ylcarbonyl, (2-acetylaminoethyl)pyrrolidin-1-ylcarbonyl, dimethylaminocarbonyl, 2-hydroxymethylpyrrolidin-1-ylcarbonyl, 2-(methylsulfonylaminomethyl)pyrrolidin-1-ylcarbonyl, 2-(acetylaminomethyl)pyrrolidin-1-ylcarbonyl, pyrrolidin-1-ylsulfonyl, 2-(2-ethoxycarbonylethyl)pyrrolidin-1-ylcarbonyl, 2-[(3-ethyl-ureido)methyl]pyrrolidin-1-ylcarbonyl, 4,5,6,7-tetrahydrobenzimidazol-1-yl, 3-(ethoxycarbonyl)-5,6-dihydro-4H-cyclopentapyrazol-1-yl, 3-(tert-butoxycarbonylamino)methyl-5,6-dihydro-4H-cyclopentapyrazol-1-yl, 3-(aminocarbonyl)-5,6-dihydro-4H-cyclopentapyrazol-1-yl, 3-aminomethyl-5,6-dihydro-4H-cyclopentapyrazol-1-yl, 4-formylpiperazin-1-ylcarbonyl, N-ethyl-N-(piperidin-4-yl)aminocarbonyl, 2-(2-dimethylaminoethyl)piperidin-1-ylcarbonyl, 2-(piperidin-1-ylmethyl)piperidin-1-ylcarbonyl, 2-(3-diethylaminopropyl)piperidin-1-ylcarbonyl, 2-(N-butyl-N-ethylaminomethyl)piperidin-1-ylcarbonyl, 2-(N-cyclohexyl-N-methylaminomethyl)piperidin-1-ylcarbonyl, 1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-ylcarbonyl, 6,7-dihydro-4H-thieno[3,2-c]pyridin-5-ylcarbonyl, 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-ylcarbonyl, 2-(ethoxycarbonyl)pyrrolidin-1-ylcarbonyl, 4-hydroxypiperazin-1-ylcarbonyl, 2-(methyloxycarbonyl)pyrrolidin-1-ylcarbonyl, 2-(benzyloxycarbonyl)pyrrolidin-1-ylcarbonyl, 3,4,5,6-tetrahydro-2H-[2,3]-bipyridinyl-1-ylcarbonyl, N-(2-aminoethyl)-N-ethylaminocarbonyl, N-(3-aminopropyl)-N-ethylaminocarbonyl, N-cyclopropyl-N-methylaminocarbonyl, 1,4,6,7-tetrahydropyrazol-[4,3-c]pyridin-5-ylcarbonyl, 2-(pyridin-2-yl)pyrrolidin-1-ylcarbonyl, 2-(pyridin-4-yl)pyrrolidin-1-ylcarbonyl, 2,5-dimethyl-2,5-dihydropyrrol-1-ylcarbonyl, 2,5-dimethyl-2,5-dihydropyrrol-1-ylcarbonyl, 2-phenylaminomethylpyrrolidin-1-ylcarbonyl, 2-benzylpyrrolidin-1-ylcarbonyl, 2-phenethylpyrrolidin-1-ylcarbonyl, 2-isopropylpyrrolidin-1-ylcarbonyl, 2-methylpiperidin-1-ylcarbonyl, 4-oxopiperidin-1-ylcarbonyl, [1,4]-diazepan-1-ylcarbonyl, 2-(dimethylaminocarbonyl)pyrrolidin-1-ylcarbonyl, 2-(methylaminocarbonyl)pyrrolidin-1-ylcarbonyl, 2-(aminocarbonylmethylaminocarbonyl)pyrrolidin-1-ylcarbonyl, 2-benzhydrylpyrrolidin-1-ylcarbonyl, 3-(2,2,2-trifluoroacetylamino)pyrrolidin-1-ylcarbonyl, 3-dimethylaminopyrrolidin-1-ylcarbonyl, imidazol-1-ylmethyl, 2-oxopyrrolidin-1-ylmethyl, 3-oxopiperazin-1-ylmethyl, 2-(ethoxycarbonylmethyl)pyrrolidin-1-ylcarbonyl, 2-dimethylaminomethylpyrrolidin-1-ylcarbonyl, 2-(carboxymethyl)pyrrolidin-1-ylcarbonyl, 2-(carboxyethyl)pyrrolidin-1-ylcarbonyl, pyrrol-1-ylcarbonyl, 2-methylpyrrolidin-1-ylcarbonyl, 2-(tert-butoxycarbonylaminomethyl)thiazolidin-3-ylcarbonyl, 2-aminomethylthiazolidin-3-ylcarbonyl, N-ethyl-N-(6-methoxy-hexanoyl)amino, 3-fluoropyrrolidin-1-ylcarbonyl, 2-methylaminocarbonylethylpyrrolidin-1-yl, N-acetyl-N-cyclopentylamino, 2-methylaminocarbonylmethylpyrrolidin-1-yl, 2-(imidazol-1-ylmethyl)pyrrolidin-1-ylcarbonyl, 2-[(N-acetyl-N-methylamino)methyl]pyrrolidin-1-ylcarbonyl, benzoyl, 3-methyl-5,6-dihydro-4H-cyclopentapyrazol-1-yl, 4-oxo-4,5,6,7-tetrahydroindol-1-yl, 4,5,6,7-tetrahydroindol-1-yl, 4,5,6,7-tetrahydroindazol-1-yl, 4-oxo-2-propyl-4,5-dihydroimidazo[4,5-c]pyridin-1-yl, 2-methyl-5,6-dihydro-4H-cyclopentaimidazol-1-yl, 2-methyl-4,5,6,7-tetrahydrobenzimidazol-1-yl, 2-hydroxycarbonylmethyl-3-oxopiperazin-1-ylcarbonyl, 4-methoxyimidazo[4,5-c]pyridin-1-yl, 2-carboxypyrrolidin-1-ylcarbonyl, 2-dimethylaminomethylbenzimidazol-1-yl, 4-oxo-4,5-dihydroimidazo[4,5-c]pyridin-1-yl, 2-dimethylaminomethyl-indol-1-yl, 4-oxo-4,5-dihydropyrrol-[3,2-c]pyridin-1-yl, 3-oxo-[1,4]diazepan-1-ylcarbonyl, 2-(pyrrolidin-1-yl)methyl-5,6-dihydro-4H-cyclopentaimidazol-1-yl, 2-(2-(pyrrolidin-1-yl)ethyl)-5,6-dihydro-4H-cyclopentaimidazol-1-yl, 2-(pyrrolidin-1-yl)methyl-4,5,6,7-tetrahydrobenzimidazol-1-yl, 2-(2-pyrrolidin-1-ylethyl)-4,5,6,7-tetrahydrobenzimidazol-1-yl, 2-(morpholin-4-yl)methyl-5,6-dihydro-4H-cyclopentaimidazol-1-yl, 2-(2-(morpholin-4-yl)ethyl)-5,6-dihydro-4H-cyclopentaimidazol-1-yl, 2-(morpholin-4-yl)methyl-4,5,6,7-tetrahydrobenzimidazol-1-yl, 2-(2-(morpholin-4-yl)ethyl)-4,5,6,7-tetrahydrobenzimidazol-1-yl, 2-oxohexahydrocyclopentaimidazol-1-yl, 4-oxo-4,5,6,7-tetrahydropyrrol[3,2-c]pyridin-1-yl, 4-oxooctahydropyrrol[3,2-c]pyridin-1-yl, octahydrocyclopentapyrazin-1-yl, 2,3-dioxooctahydrocyclopentapyrazin-1-yl, 2-oxo-2,5,6,7-tetrahydrocyclopentapyrazin-1-yl, 5,6,7,7a-tetrahydro-1H-pyrrol-[1,2-c]-imidazol-3-yl, or 3,4,4a,5,6,7-hexahydropyrrol-[1,2-c]pyrimidin-1-yl group;   R 2  is a fluorine, chlorine, or bromine atom, or a C 1-3 -alkyl group wherein the hydrogen atoms are optionally wholly or partly replaced by fluorine atoms, or a C 1-3 -alkyloxy or a C 2-3 -alkynyl group;   R 3  is a hydrogen atom;   R 4  is a hydrogen atom or a methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, hydroxymethyl, 1-hydroxyethyl, methoxymethyl, 2-methoxyethyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, benzyl, 4-hydroxybenzyl, 4-methoxycarbonylmethoxyphenylmethyl, pyridin-4-ylmethyl, pyridin-2-ylmethyl, piperidin-1-ylmethyl, piperidin-3-ylmethyl, 1H-imidazol-4-ylmethyl, aminocarbonylmethyl, 4-benzyloxycarbonylaminobutyl, 2-methylsulfanylethyl, 2-methylsulfinylethyl, 2-methylsulfonylethyl, ethylsulfanylmethyl, ethylsulfinylmethyl, ethylsulfonylmethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-phenylethyl, acetylaminomethyl, methylsulfonylaminomethyl, phenylcarbonylaminomethyl, 3-acetylaminopropyl, 4-acetylaminobutyl, 2,2,2-trifluoroethyl, hydroxymethyl, tert-butoxycarbonylaminomethyl, 3-(tert-butoxycarbonylamino)propyl, 4-hydroxybenzyl, 2-carboxyethyl, 2-(benzyloxycarbonyl)ethyl, 2-(ethylaminocarbonyl)ethyl, 2-(pyrrolidin-1-ylcarbonyl)ethyl, 2-(diethylaminocarbonyl)ethyl, tetrazol-2-ylmethyl, carboxymethyloxymethyl, tert-butoxycarbonylmethyloxymethyl, 2-(benzyloxycarbonylamino)ethyl, 2-(aminosulfonyl)ethyl, 2-(2-oxoimidazolidin-1-yl)ethyl, 2-(2-chloroethyl)ureido]ethyl, 1-methoxy-1-methylethyl, 1-(3-tert-butoxycarbonyl)piperidin-3-yl, 1-acetylpiperidin-3-yl, 2-(pyridin-4-yl)ethyl, 2-[3-(dimethylamino)pyrrolidin-1-ylcarbonyl]ethyl, 2-(3-hydroxypyrrolidin-1-yl)carbonylethyl, 2-[2-(hydroxymethyl)pyrrolidin-1-ylcarbonyl]ethyl, 2-(2-methyl-2,6-diazaspiro[3.4]oct-6-ylcarbonyl)ethyl, 2-[2-(aminocarbonyl)pyrrolidin-1-ylcarbonyl)ethyl, 2-[2-(tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]ethyl, 2-[3-(hydroxymethylpyrrolidin-1-yl)carbonyl]ethyl, 2-(1,1-dioxo-1-thiomorpholin-4-ylcarbonyl)ethyl, 2-(4-methyl-3-oxopiperazin-1-ylcarbonyl)ethyl, 2-(2-aminomethylpyrrolidin-1-ylcarbonyl)ethyl, isopropoxycarbonyloxymethyl, 2-(2-isopropylaminothiazol-4-yl)ethyl, 2-(5-chloro-1H-benzimidazol-2-yl)ethyl, 5-chloro-1H-benzimidazol-2-yl, thiophen-3-yl, 2-methylsulfonylaminoethyl, benzyloxymethyl, methylsulfanylmethyl, 2-(1,1-dioxoisothiazolidin-2-yl)ethyl, ethoxymethyl, 1-methoxyethyl, allyloxymethyl, 1-tert-butyloxyethyl, 1-hydroxyethyl, prop-2-ynyloxymethyl, 2-(1H-tetrazol-5-yl)ethyl, 1-prop-2-ynyl, 4-[(5-oxopyrrolidin-3-yl)carbonylamino]butyl, 4-[(pyridin-3-yl-)carbonylamino]butyl, 4-[(5-oxopyrrolidin-2-yl)carbonylamino]butyl, 4-[(pyridin-4-yl)carbonylamino]butyl, 4-(1-methylpyrrolidin-2-ylcarbonylamino)butyl, prop-2-enyl, acetylaminomethylsulfanylmethyl, 2-aminocarbonylethyl, 1H-indol-3-yl)methyl, 4-hydroxy-3,5-dimethylphenylmethyl, methoxycarbonylmethyl, 4-hydroxy-2,6-dimethylphenylmethyl, 4-difluoromethoxyphenylmethyl, 3-bromophenylmethyl, 4-trifluoromethylphenylmethyl, 4-ureidobutyl, 3-ureidopropyl, 4-amino-3,5-dibromophenylcarbonylmethyl, allyloxycarbonylmethyl, 3,4-dimethoxyphenylmethyl, thiazol-4-ylmethyl, 3,5-difluorophenylmethyl, 4-fluorophenylmethyl, mercaptomethyl, 1-methyl-1H-imidazol-5-ylmethyl, 1H-benzimidazol-5-ylmethyl, cyclopropylmethyl, 2,2,2-trifluoroethyloxymethyl, trifluoromethoxymethyl, difluoromethoxymethyl, or monofluoromethoxymethyl group;   R 5  is a hydrogen atom;   A is an aminocarbonyl or carbonylamino group; and   B is   
       
         
           
           
               
               
           
         
       
       wherein R 7  is a fluorine, chlorine, or bromine atom or a methyl group, and 
       the tautomers and the salts thereof. 
     
     
         14 - 15 . (canceled) 
     
     
         16 . The physiologically acceptable salts of a compound according to  claim 1 . 
     
     
         17 . A pharmaceutical composition comprising a compound according to  claim 1  or a physiologically acceptable salt thereof and one or more inert carriers and/or diluents.