Substituted mono- and polyazanaphthalene derivatives and their use

Abstract

Disclosed are compounds of formula (I) wherein A is CH or N, B is CR or N; and D is CR; R represents hydrogen, OH or NH 2 ; R1 and R2, independently of each other, represent hydrogen, N(R3) 2 , halogen, cyano, nitro, R4-C1-C4alkyl, R4-C1-C4halogenoalkyl, OH, R4-C1-C4alkoxy, R4-C1-C4halogenoalkoxy, SH, R4-C1-C4alkythio, R4-C1-C4halogenoalkylthio; R3 represents, independently at each occurrence, hydrogen, R4-C1-C4alkyl or R4-C1-C4halogenoalkyl; R3a represents, independently at each occurrence, hydrogen or C1-C4 alkyl; R4 represents, independently at each occurrence, hydrogen, halogen, cyano, OH, SH, NH 2 , NH(CH 3 ) or N(CH 3 ) 2 ; X represents a group of formula -E- or -E-F—, wherein E and F are different from each other and represent a group selected from —C(R3a)2-, —(C═O)—, —NR3a- and —O— and F is linked to Y, with the proviso that if X represents -E-F— one of E or F represents —C(R3a) 2 — or —(C═O)—; Y represents a group selected from C1-C6alkyl, mono- or bicyclic C3-C11cycloalkyl, which may be partially unsaturated, mono- or bicyclic 3 to 11-membered heterocycloalkyl, which may be partially unsaturated, a mono- or bicyclic group comprising at least one aryl or heteroaryl cycle, wherein said heterocycloalkyl group and said group comprising at least one heteroaryl cycle comprise one or more heteroatoms selected from nitrogen, oxygen and sulfur and said group Y is either unsubstituted or substituted by one or more substituents and comprises including its substituents one or more than one nitrogen atom having a lone electron pair; and Z represents a mono- or bicyclic group comprising at least one aryl or heteroaryl cycle, said heteroaryl cycle comprising one or more heteroatoms selected from nitrogen, oxygen and sulfur, which aryl or heteroaryl group is unsubstituted or substituted by one or more substituents; including tautomers of said compounds, mixtures of two tautomeric forms of said compounds, and pharmaceutically acceptable salts of said compounds, tautomers thereof or mixtures of two tautomeric forms thereof, preferably with the proviso that Y comprises one or more primary amino group —NH 2 , when X represents —(C═O)— or (C═O)—NR3a-, wherein R3a represents hydrogen or C1-C4alkyl; which are useful for the treatment of proliferation disorders or diseases, such as cancer.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein 
         A is CH or N, 
         B is CR or N; and 
         D is CR; 
         R represents hydrogen, OH or NH 2 ; 
         R1 and R2, independently of each other, represent hydrogen, N(R3) 2 , halogen, cyano, nitro, R4-C1-C4alkyl, R4-C1-C4halogenoalkyl, OH, R4-C1-C4alkoxy, R4-C1-C4halogenoalkoxy, SH, R4-C1-C4alkythio, R4-C1-C4halogenoalkylthio; 
         R3 represents, independently at each occurrence, hydrogen, R4-C1-C4alkyl or R4-C1-C4halogenoalkyl; 
         R3a represents, independently at each occurrence, hydrogen or C1-C4 alkyl; 
         R4 represents, independently at each occurrence, hydrogen, halogen, cyano, OH, SH, NH 2 , NH(CH 3 ) or N(CH 3 ) 2 ; 
         X represents a group of formula -E- or -E-F—, wherein E and F are different from each other and represent a group selected from —C(R3a) 2 -, —(C═O)—, —NR3a- and —O— and F is linked to Y, with the proviso that if X represents -E-F— one of E or F represents —C(R3a) 2 - or —(C═O)—; 
         Y represents a group selected from C1-C6alkyl, mono- or bicyclic C3-C11cycloalkyl, which may be partially unsaturated, mono- or bicyclic 3 to 11-membered heterocycloalkyl, which may be partially unsaturated, a mono- or bicyclic group comprising at least one aryl or heteroaryl cycle, wherein said heterocycloalkyl group and said group comprising at least one heteroaryl cycle comprise one or more heteroatoms selected from nitrogen, oxygen and sulfur and said group Y is either unsubstituted or substituted by one or more substituents and comprises including its substituents one or more than one nitrogen atom having a lone electron pair; and 
         Z represents a mono- or bicyclic group comprising at least one aryl or heteroaryl cycle, said heteroaryl cycle comprising one or more heteroatoms selected from nitrogen, oxygen and sulfur, which aryl or heteroaryl group is unsubstituted or substituted by one or more substituents; including tautomers of said compound, mixtures of two tautomeric forms of said compound, a pharmaceutically acceptable salt of said compound, tautomers thereof or mixtures of two tautomeric forms thereof; 
         preferably with the proviso that Y comprises one or more primary amino group —NH 2  when X represents —(C═O)— or —(C═O)—NR3a-, wherein R3a represents hydrogen or C1-C4alkyl. 
       
     
     
         2 . The compound according to  claim 1 , wherein Y comprises one or more primary amino group —NH 2  when X represents —(C═O) 13   or —(C═O)—NR3a-, wherein R3a represents hydrogen or C1-C4alkyl. 
     
     
         3 . The compound according to  claim 1 , wherein Y comprises one or more primary amino group —NH 2 . 
     
     
         4 . The compound according to  claim 1 , wherein Y comprises one or more structural element of formula: 
       
         
           
           
               
               
           
         
       
       wherein R3 represents hydrogen or C1-C4alkyl and «-» indicates a lone electron pair at the nitrogen atom and «*» indicates a chemical bond to a further atom when X represents —(C═O)—or —(C═O)—NR3a- and R3a represents hydrogen or C1-C4alkyl, 
     
     
         5 . The compound according to  claim 1 , wherein X represents a group of formula -E- or -E-F—, wherein E and F are different from each other and represent a group selected from —C(R3a)2—, —NR3a- and —O— and F is linked to Y, with the proviso that if X represents -E-F— one of E or F represents —C(R3a) 2 -. 
     
     
         6 . The compound according to  claim 1 , wherein A and B are CH and D is CR. 
     
     
         7 . The compound according to  claim 1 , wherein A and D are CH and B is CR. 
     
     
         8 . The compound according to  claim 1 , wherein A is N, B is CR and D is CH. 
     
     
         9 . The compound according to  claim 1 , wherein:
 X represents a spacer group of formula -E-, wherein   E represents —C(R3a) 2 -, —NR3a- or —O—, and   R3a represents hydrogen or methyl.   
     
     
         10 . The compound according to  claim 9 , wherein:
 X represents —CH 2 —, —NH— or —O—.   
     
     
         11 . The compound according to  claim 1 , wherein:
 X represents —CH 2 —, —NH— or —O—; and   Y comprises one or more primary amino group —NH 2 , and preferably wherein there are at least three concatenated atoms between at least one of said primary amino groups and the X—Y bond.   
     
     
         12 . The compound according to  claim 1 , wherein Y comprises one or more structural element of formula: 
       
         
           
           
               
               
           
         
         wherein R3 has the meaning as defined in  claim 1  and «-» indicates a lone electron pair at the nitrogen atom and «*» indicates a chemical bond to a further atom. 
       
     
     
         13 . The compound according to  claim 1 , wherein:
 Y is unsubstituted or substituted by one, two or more substituents, preferably one substituent, selected from halogen, cyano, nitro, —(C═O)—R3, —(C═O)—OR3, —N(R3) 2 , —(C═O)—N(R3) 2 , —NR3-(C═O)—R3, —NR3-(C═O)—OR3, R4-C1-C4alkyl, R4-C1-C4halogenoalkyl, OH, SH, R4-C1-C4alkoxy, R4-C1-C4halogenoalkoxy, R4-C1-C4alkylthio and R4-C1-C4halogenoalkylthio, as well as oxo in case that the substituent is not located at an aryl or heteroaryl cycle.   
     
     
         14 . The compound according to  claim 1 , wherein:
 Z is unsubstituted or substituted by one, two or more substituents, preferably one substituent, selected from halogen, cyano, nitro, R4-C1-C4alkyl, R4-C1-C4halogenoalkyl, OH, SH, R4-C1-C4alkoxy, R4-C1-C4halogenoalkoxy, R4-C1-C4alkylthio, R4-C1-C4halogenoalkylthio, —(C═O)—R3, —(C═O)—OR3, —N(R3) 2 , —(C═O)—N(R3) 2 , —N(R3)-(C═O)—R3, —N(R3)-(C═O)—N(R3) 2  and —N(R3)-(C═O)—NR3-Z1; wherein   Z1 represents C3-C6cycloalkyl, phenyl or 5- to 6-membered heteroaryl comprising one or more heteroatoms selected from nitrogen, oxygen and sulfur, preferably 1 or 2, and is unsubstituted or substituted by one, two or more substituents selected from halogen, cyano, R4-C1-C4alkyl, R4-C1-C4halogenoalkyl, OH, R4-C1-C4alkoxy and R4-C1-C4halogenoalkoxy.   
     
     
         15 . The compound according to  claim 1 , wherein;
 Y is selected from:   (A) C1-C4alkyl, which is unsubstituted or substituted as defined in  claim 13  and saturated or partially unsaturated;   (B) a group, which is unsubstituted or substituted as defined in  claim 13  saturated or partially unsaturated and selected from the groups of formula:   
       
         
           
           
               
               
           
         
         wherein p is 0, 1, 2 or 3; 
       
       
         
           
           
               
               
           
         
         wherein p and q are independently selected from 0, 1, 2 and 3 so that (p+q) is 0 to 4 and the linking bond may be located at both cycles of the group; 
       
       
         
           
           
               
               
           
         
         wherein p is 0, 1, 2 or 3 and wherein 1, 2 or 3 ring carbon atoms are replaced by nitrogen atoms and one ring carbon ring atom may furthermore be replaced by a sulfur or an oxygen atom and the number of remaining ring carbon atoms is at least 2; 
       
       
         
           
           
               
               
           
         
         wherein p and q are independently selected from 0, 1, 2 and 3 so that (p+q) is 0 to 4, the linking bond may be located at both cycles of the group and wherein 1 to 4 ring carbon atom of the group are replaced by nitrogen atoms and one ring carbon ring atom per cycle of the group may furthermore be replaced by a sulfur or an oxygen atom so that the number of remaining ring carbon atoms per cycle of the group is at least 2; 
         (C) an aryl group, which is unsubstituted or substituted as defined in  claim 13  and selected from 
         (Ca): phenyl and 
         (a): naphthyl; and 
         (D) a heteroaryl group, which is unsubstituted or substituted and selected from the groups of formula: 
       
       
         
           
           
               
               
           
         
         wherein is selected from NR3, preferably NH, O and S and one or two of K1, K2, K3 and K4 may be nitrogen and all others are selected from CH and C substituted as defined in  claim 13 ; 
       
       
         
           
           
               
               
           
         
         wherein one or two of K5, K6, K7, K8 and K9 may be nitrogen and all others are selected from CH and C substituted as defined in  claim 13 ; 
       
       
         
           
           
               
               
           
         
         wherein G is selected from NR3, preferably NH, O and S and one of K3 and K4 may be nitrogen, CH or C substituted as defined in  claim 13  and the other is CH or C substituted as defined in  claim 13  and one or two of K5, K6, K7, and K10 may be nitrogen and all others are selected from CH and C substituted as defined in  claim 13  and the linking bond may be located at both cycles of the group; and 
       
       
         
           
           
               
               
           
         
       
       wherein one of K5, K6, K7, K8, K9, K10, K11 and K12 is nitrogen and one of the others in the same cycle and two of the others in the other cycle may also be nitrogen and all others in both cycles are selected from CH and C substituted as defined in  claim 13  and the linking bond may he located at both cycles of the group. 
     
     
         16 . The compound according to  claim 1 , wherein:
 Y is selected from substituted C1-C4alkyl or substituted monocyclic saturated 5-, 6- or 7-membered cycloalkyl, which comprise at least one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 ; unsubstituted or substituted, monocyclic saturated 5-, 6- or 7-membered heterocycloalkyl, which comprises 1 or 2 nitrogen heteroatoms and optionally at least one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 ; a substituted mono- or bicyclic aryl group which comprises at least one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 , and an unsubstituted or substituted mono- or bicyclic heteroaryl group, which comprises 1 or 2 nitrogen heteroatoms per cycle present in said heteroaryl group and optionally at least one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 .   
     
     
         17 . The compound according to  claim 1 , wherein:
 Z is selected from a monocyclic aryl group or a bicyclic group comprising at least one aryl cycle, more preferably two aryl cycles, and having 6 to 10 ring atoms; as well as a monocyclic heteroaryl group and a bicyclic group comprising at least one heteroaryl group, preferably fused with a further aryl or heteroaryl group, and having 5 to 10 ring atoms, wherein a heteroaryl cycle comprises 1 to 3 heteroatoms, preferably I or 2 heteroatoms, and said groups Z are unsubstituted or substituted by one or more substituents as defined in  claim 14 .   
     
     
         18 . The compound according to  claim 1 , wherein:
 Z is selected from:   (E) an unsubstituted aryl group or an aryl group substituted as defined in  claim 14 , said aryl group being selected from   (Ea): phenyl and   (Eb): naphthyl; and   (F) an unsubstituted heteroaryl group or a heteroaryl group substituted as defined in  claim 14 , said heteroaryl group being selected from the groups of formula:   
       
         
           
           
               
               
           
         
       
       wherein L is selected from NR3, preferably NH, O and S and one or two of M1, M2, M3 and M4 may be nitrogen and all others are selected from CH and C substituted as defined in  claim 14 ; 
       
         
           
           
               
               
           
         
       
       wherein one or two of M5, M6, M7, M8 and M9 may be nitrogen and all others are selected from CH and C substituted as defined in  claim 14 ; 
       
         
           
           
               
               
           
         
       
       wherein L is selected from NR3, preferably NH, O and S, one of M3 and M4 may be nitrogen, CH or C substituted as defined in  claim 14 , the other is CH or C substituted as defined in  claim 14  and one or two of M5, M6, M7, and M10 may be nitrogen and all others are selected from CH and C substituted as defined in  claim 14  and the linking bond may be located at both cycles of the group; and 
       
         
           
           
               
               
           
         
       
       wherein one of M5, M6, M7, M8, M9, M10, M11 and M12 may be nitrogen and one of the others in the same cycle and two of the others in the other cycle may also be nitrogen and all others in both cycles are selected from CH and C substituted as defined in  claim 14  and the linking bond may be located at both cycles of the group. 
     
     
         19 . The compound according to  claim 1 , wherein:
 Y is selected from straight-chain C1-C4alkyl, preferably C2-C4alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl, in particular pyrrolidin-1-yl or pyrrolidin-3-yl, piperidinyl, in particular piperidin-1-yl, piperidin-3-yl or piperidin 4-yl, piperazinyl, in particular piperazin-1-yl, morpholinyl, in particular morpholin-4-yl, phenyl, pyrazolyl, in particular pyrazol-5-yl, pyridinyl, in particular pyridinium-1-yl, pyridin-3-yl or pyridin-4-yl, pyrimidinyl, in particular pyrimidin-4-yl, pyridazinyl, in particular pyridazinium-1-yl, 1-H-pyrrolo[3,2-c]pyridine, 3H-pyrrolo[2,3-c]-pyridin-1-yl, which are substituted or substituted by one or two groups selected from fluoro, chloro, cyano, nitro, C1-C2alkyl, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2fluoroalkoxy, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , H 2 N—C1-C2alkyl, H 2 N—C1-C2fluoro-alkyl, —OH and oxo, wherein when Y is not substituted by oxo when aromatic or heteroaromatic.   
     
     
         20 . The compound according to  claim 1 , wherein:
 Y is selected from 3-aminocyclopentyl, 3- or 4-aminocyclohexyl and 4-aminopiperidin-1-yl, in particular 4-aminocyclohexyl and 4-aminopiperidin-1-yl.   
     
     
         21 . A The compound according to  claim 1 , wherein:
 Z is selected from phenyl, naphthyl and a group of one of the formulae:   
       
         
           
           
               
               
           
         
       
       wherein T represents a group selected from NH and N(CH3), or an O- or S-atom; T1 represents a N-atom; the free valence can be located at any of the ring carbon atoms of the entire group Z; and wherein one to three of the ring carbon atoms can furthermore be replaced by a N-atom, and wherein group Z is unsubstituted or substituted by one to three groups selected from halogen, C1-C4alkyl and C1-C4alkoxy; in particular group Z is selected from furan-2-yl, furan-3-yl, thiophen-2yl, thiophen-3-yl, phenzofuran-2-yl, benzooxazol-2-yl, benzothiazol-2-yl, furo[3,2-c]pyridin-2yl, furo[2,3-c]pyridin-2yl, benzo[b]thiophen-2yl, 1H-indol-2-yl, 1H-indol 5-yl, pyridinyl, in particular pyridine-4-yl and pyridine-3-yl, quinolinyl, in particular quinolin-3-yl; isoquinolinyl, in particular isoquinolin-6-yl and isoquinolin-7-yl. 
     
     
         22 . The compound according to  claim 1 , wherein:
 Z is selected from phenyl, which is unsubstitued or substituted by Cl or F, benzofuran-2-yl.   
     
     
         23 . The compound according to  claim 1 , wherein:
 X—Y is selected from.   
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound according to  claim 1 , wherein:.
 A is CH;   B is CH or C—NH2; and   D is CH.   
     
     
         25 . The compound according to  claim 1 , wherein:
 A and B are CH and D is CR; or   A and D are CH and B is CR; or   B is N and A and D are CH; or   A is N, B is CR and D is CH;   R represents hydrogen, OH or NH 2 ;   R1 and R2, independently of each other, represent hydrogen, N(R3) 2 , halogen, cyano, nitro, R4-C1-C4alkyl, R4-C1-C4halogenokyl, OH, R4-C1-C4alkoxy, R4-C1-C4halogenoalkoxy;   R3 represents, independently at each occurrence, hydrogen, R4-C1-C4alkyl or   R4-C1-C4halogenoalkyl;   R3a represents, independently at each occurance, hydrogen or methyl;   R4 represents, independently at each occurrence, hydrogen, halogen, cyano, OH, NH 2 , NH(CH 3 ) or N(CH 3 ) 2 ;   X represents C(R3a) 2 —, —NR3a- or —O—;   Y is selected from substituted C1-C4alkyl or substituted monocyclic saturated 5-, 6- or 7-membered cycloalkyl, which comprise at least one substituent selected from NH 2 , NH(CH3) and N(CH 3 ) 2 , unsubstituted or substituted, monocyclic saturated 5-, 6- or 7-membered heterocycloalkyl, which comprises 1 or 2 nitrogen heteroatoms and optionally at least one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 , and a substituted mono- or bicyclic aryl group which comprise at least one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 , and an unsubstituted or substituted mono- or bicyclic heteroaryl group, Which comprises 1 or 2 nitrogen heteroatoms per cycle present in said heteroaryl group and optionally at least one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 ;   Z is selected from:   (E) an unsubstituted aryl group or an aryl group substituted as defined below, said aryl group being selected from   (Ea): phenyl and   (Eb): naphthyl; and   (F) a unsubstituted heteroaryl group or a heteroaryl group substituted as defined below, said heteroaryl group being selected from the groups of formula:   
       
         
           
           
               
               
           
         
       
       wherein L is selected from NR3, preferably NH, O and S and one or two of M1, M2, M3 and M4 may be nitrogen and all others are selected from CH and C substituted as defined below; 
       
         
           
           
               
               
           
         
       
       wherein one or two of M5, M6, M7, M8 and M9 may be nitrogen and all others are selected from CH and C substituted as defined below; 
       
         
           
           
               
               
           
         
       
       wherein L is selected from NR3, preferably NH, O and S, one of M3 and M4 may be nitrogen, CH or C substituted as defined below, the other is CH or C substituted as defined below and one or two of MS, M6, M7, and M10 may be nitrogen and all others are selected from CH and C substituted as defined below and the linking bond may be located at both cycles of the group; and 
       
         
           
           
               
               
           
         
       
       wherein one of M5, M6, M7, M8, M9, M10, M11 and M12 may be nitrogen and one of the others in the same cycle and two of the others in the other cycle may also be nitrogen and all others in both cycles are selected from CH and C substituted as defined below and the linking bond may be located at both cycles of the group;
 when substituted group Z is substituted by one, two or more, preferably one, substituents selected from halogen, cyano, nitro, R4-C1-C4alkyl, R4-C1-C4halogenoalkyl, OH, R4-C1-C4alkoxy, R4-C1-C4halogenoalkoxy, R4-C1-C4alkylthio, R4-C1-C4halogenoalkylthio, —(C═O)—R3; —(C═O)—OR3, —N(R3) 2 , —(C═O)—N(R3) 2 , —N(R3)-(C═O)—R3, —N(R3)-(C═O)—N(R3) 2  or a group —N(R3)-(C═O)—NR3-Z1; wherein 
 Z1 represents C3-C6cycloalkyl, phenyl or 5- to 6-membered heteroaryl comprising one or more heteroatoms selected from nitrogen, oxygen and sulfur, preferably 1 or 2 and is unsubstituted car substituted by one, two or more substituents selected from halogen, cyano, nitro, R4-C1-C4alkyl, R4-C1-C4halogenoalkyl, OH, R4-C1-C4alkoxy and R4-C1-C4halogenoalkoxy. 
 
     
     
         26 . The compound according to  claim 1 , having the formula I-1, I-2 or I-3: 
       
         
           
           
               
               
           
         
       
       wherein
 represents hydrogen, OH or NH 2 ; 
 R1 and R2, independently of each other, represent hydrogen, halogen, NH 2 , C1-C4halogenalkyl, C1-C4alkoxy, or C1-C4halogenalkoxy; 
 R3 represents, independently at each occurrence, hydrogen or methyl; 
 R3a represents, independently at each occurrence, hydrogen or methyl; 
 R4 represents independently at each occurrence hydrogen, halogen, cyano, OH, NH 2 , NH(CH 3 ) or N(CH 3 ) 2 ; 
 X represents C(R3a) 2 -, —NR3a- or —O—; 
 Y is selected from substituted C1-C4alkyl or substituted monocyclic saturated 5-, 6- or 7-membered cycloalkyl, which comprise at least one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 , substituted or substituted, monocyclic saturated 5-, 6- or 7-membered heterocycloalkyl, which comprises 1 or 2 nitrogen heteroatoms and optionally at least one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 , and a substituted mono- or bicyclic aryl group which comprise at least one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 , and an substituted or substituted mono- or bicyclic heteroaryl group, which comprises 1 or 2 nitrogen heteroatoms per cycle present in said heteroaryl group and optionally at least one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 ; 
 and wherein group Y may be additionally substituted by one group selected from C1-C4alkyl, hydroxy, nitro, C1-C4alkoxy, C1-C4fluoroalkyl, cyano, halogen, and C1-C4alkoxycarbonyl; 
 Z is selected from: 
 (F) an unsubstituted aryl group or an aryl group substituted as defined below, said aryl group being selected from 
 (Ea): phenyl and 
 (F) an unsubstituted heteroaryl group or a heteroaryl group substituted as defined below, said heteroaryl group being selected from the groups of formula: 
 
       
         
           
           
               
               
           
         
       
       wherein L is selected from NH, O and S and one or two of M1, M2, M3 and M4 may be nitrogen and all others are selected from CH and C substituted as defined below; 
       
         
           
           
               
               
           
         
       
       wherein L is selected from NH, O and S one of M3 and M4 may be nitrogen, CH or C substituted as defined below, the other is CH or C substituted as defined below and one or two of M5, M6, M7, and M10 may be nitrogen and all others are selected from CH and C substituted as defined below and the linking bond may be located at both cycles of the group; and
 when substituted group Z is substituted by one, two or more, preferably one, substituents selected from halogen, cyano, nitro, R4-C1-C4alkyl, R4-C1-C4halogenoalkyl, OH, N(R3) 2 , and R4-C1-C4alkoxy. 
 
     
     
         27 . The compound according to  claim 1 , having the formula I-1 or I-3: 
       
         
           
           
               
               
           
         
         wherein 
         R represents hydrogen or NH 2 ; 
         R1 and R2, independently of each other, represent hydrogen, N(R3) 2 , halogen, cyano, nitro, C1-C4alkyl, C1-C4halogenoalkyl, OH, C1-C4alkoxy or C1-C4halogenoalkoxy; 
         R3 represents, independently at each occurrence, hydrogen or C1-C4alkyl; 
         X represents —CH 2 —, —NH— or —O—; 
         Y is selected from substituted C1-C4alkyl or substituted monocyclic saturated 5-, 6- or 7-membered cycloalkyl, which comprise one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 , unsubstituted or substituted, monocyclic saturated 5-, 6- or 7-membered heterocycloalkyl, which comprises 1 or 2 nitrogen heteroatoms and, when substituted, one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 , and a substituted phenyl group which comprise one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 , and an unsubstituted or substituted 5 or 6-membered monocyclic heteroaryl group, which comprises 1 or 2 nitrogen heteroatoms and, when substituted, one substituent selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 ; 
         Z is selected from phenyl and a group of one of the formulae: 
       
       
         
           
           
               
               
           
         
       
       wherein T represents a group selected from NH and N(CH 3 ), or an O- or S-atom; the free valence can be located at any of the ring atoms of the entire group Z including the group T if T is not an O- or S-atom; and wherein one to three of the ring carbon atoms can furthermore be replaced by a N-atom, and wherein group Z is=substituted or substituted by one to three groups selected from halogen, C1-C4alkyl and C1-C4alkoxy. 
     
     
         28 . The compound according to  claim 1 , having the formula I-1: 
       
         
           
           
               
               
           
         
       
       wherein
 R represents hydrogen or —NH 2 ; 
 R1 and R2, independently of one another, represent hydrogen, fluoro, chloro, hydroxy, methoxy, ethoxy, propoxy, —NH 2  or nitro; 
 X—Y is selected from 
 
       
         
           
           
               
               
           
         
       
       Z is selected from phenyl, which is unsubstituted of substituted by one or two substituents selected from fluoro and chloro; and a group of one of the formulae 
       
         
           
           
               
               
           
         
         T is selected from an O- or S-atom; and, more preferably, 
         Z is an unsubstituted group selected from phenyl, furan-2-yl, thiophen-2yl, and benzofuran-2-yl. 
       
     
     
         29 - 30 . (canceled) 
     
     
         31 . A pharmaceutical composition, comprising a compound according to  claim 1 , tautomers of said compound, mixtures of two tautomeric forms of said compound, a pharmaceutically acceptable salt of said compound, tautomers thereof or mixtures of two tautomeric forms thereof, and a pharmaceutically acceptable carrier. 
     
     
         32 . The pharmaceutical composition according to  claim 31 , wherein A in formula (I) represents CR. 
     
     
         33 - 34 . (canceled) 
     
     
         35 . A method for treating proliferation diseases, in a subject in need of such treatment, comprising the administration of an antiproliferatively effective amount of a compound according to  claim 1 , or tautomers of said, compound, mixture of two tautomeric forms of said compound, a pharmaceutically acceptable salt of said compound, or tautomers thereof or mixtures of two tautomeric forms thereof. 
     
     
         36 . The method according to  claim 35 , wherein A in formula (I) represents CH. 
     
     
         37 . The method according to  claim 35 , wherein said subject is a mammal. 
     
     
         38 . The method according to  claim 35 , wherein said subject is a human.