Tetracyclic Lactame Derivatives

Abstract

The present invention describes tetracyclic compounds of formula (IA) or (IB), wherein the symbols R, X, A, Y, R2, R3 and D are as defined in the specification, their use in the treatment of certain diseases, e.g. depending on MK-2 or TNF activity, and ways of manufacturing them.

1 . A compound of formula (IA) or (IB), 
       
         
           
           
               
               
           
         
       
       wherein
 R is hydrogen, halogen, —Y—C 3 -C 7 cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl-C 2 -C 7 -alkenyl, mono- or di(unsubstituted or substituted C 1 -C 7 -alkyl)-amino or unsubstituted or substituted-arylamino; 
 A is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 — or —CH═CH—; 
 D is a bond between the carbon and the nitrogen atom to which it is bound or is C(R4R5); 
 R2 and R3 are hydrogen or together form an ethylene or trimethylene bridge in each of which one of the carbon atoms can be replaced with O, S or NR6; 
 R3 and R4 are hydrogen or C 1 -C 4 -alkyl or together form an ethylene or trimethylene bridge in each of which one of the carbon atoms can be replaced with O, S or NR6; 
 or one of R2 and R3 is hydrogen and one of R4 and R5 is hydrogen, while the other of R2 and R3 together with the other of R4 and R5 forms an ethylene wherein one of the carbon atoms can be replaced with O, S or NR6, or a methylene bridge, 
 with the proviso that at least one of the mentioned bridges must be present in a compound of formula (IA) or (IB) and is formed by R2 and R3, by R4 and R5, or by R2 or R3 and R4 or R5, so that not more than two of R2, R3, R4 and R5 are hydrogen or C 1 -C 4 -alkyl; 
 R6 is hydrogen, alkyl, C 1 -C 7 -alkyl, hydroxy-C 1 -C 7 -alkyl, unsubstituted or substituted aryl-C 1 -C 7 -alkyl or acyl, 
 X is CH; and 
 Y is O, S or NR7 wherein R7 is hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl-C 1 -C 7 -alkyl, unsubstituted or substituted saturated heterocyclyl or unsubstituted or substituted heterocyclyl-C 1 -C 7 -alkyl; 
 
       a pharmaceutically acceptable cleavable ester or amide thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A compound of the formula IA or IB according to  claim 1 , wherein, where mentioned,
 unsubstituted or substituted aryl is aryl with 6 to 28, and may be mono-, bi-, tri- or tetracyclic, and is unsubstituted or substituted by one or more substituents independently selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted phenyloxy, unsubstituted or substituted saturated heterocyclyl, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl, hydroxyl-C 1 -C 7 -alkyl, amino-C 1 -C 7 -alkyl, mono- or di-C 1 -C 7 -alkyl-amino-C 1 -C 7 -alkyl, saturated heterocyclyl-C 1 -C 7 -alkyl, pyrrolidinyl-C 1 -C 7 -alkyl, imidazolidino-C 1 -C 7 -alkyl, imidazolidino-C 1 -C 7 -alkyl, pyrazolidinyl-C 1 -C 7 -alkyl, piperidinyl-C 1 -C 7 -alkyl, (unsubstituted or C 1 -C 7 -alkyl-substituted piperazino)-C 1 -C 7 -alkyl, morpholinyl-C 1 -C 7 -alkyl, thiomorpholinyl-C 1 -C 7 -alkyl, S oxo-thiomorpholinyl-C 1 -C 7 -alkyl, or S,S-dioxo-thiomorpholinyl-C 1 -C 7 -alkyl, C 2 -C 7 -alkenyl, C 6 -C 10 -aryl-C 2 -C 7 -alkenyl, C 2 -C 7 -alkynyl, amino-C 3 -C 7 -alkynyl, hydroxyl-C 3 -C 7 -alkynyl, halo, hydroxyl, C 1 -C 7 -alkoxy, C 1 -C 7 -alkoxy-C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkoxy, saturated heterocyclyl-C 1 -C 7 -alkoxy imidazolidinyl-C 1 -C 7 -alkoxy, imidazolidino-C 1 -C 7 -alkoxy, pyrazolidinyl-C 1 -C 7 -alkoxy, piperidinyl-C 1 -C 7 -alkoxy, (unsubstituted or C 1 -C 7 -alkyl-substituted piperazino)-C 1 -C 7 -alkoxy, morpholinyl-C 1 -C 7 -alkoxy, thiomorpholinyl-C 1 -C 7 -alkoxy, S-oxo-thiomorpholinyl-C 1 -C 7 -alkoxy, or S,S-dioxo-thiomorpholinyl-C 1 -C 7 -alkoxy, mono- or di-(C 1 -C 7 -alkyl)-amino-C 1 -C 7 -alkoxy, C 1 -C 7 -alkylenedioxy, amino, mono- or di-(C 1 -C 7 -alkyl and/or phenyl-C 1 -C 7 -alkyl)-amino, formyl, carboxy, C 1 -C 7 -alkoxycarbonyl, aryl-C 1 -C 7 -alkoxycarbonyl, carbamoyl, mono- or di-(C 1 -C 7 -alkyl, unsaturated heterocyclyl-C 1 -C 7 -alkyl and/or aryl-C 1 -C 7 -alkyl, sulfonyl (—S(O) 2 —OH), sulfamoyl, mono- or di-(C 1 -C 7 -alkyl and/or phenyl-C 1 -C 7 -alkyl)-sulfamoyl, nitro, acyl and cyano;   unsubstituted or substituted heterocyclyl is a mono-, di- or tricyclic ring with 3 to 24 ring atoms, of which one or more, independently of each other, are heteroatoms selected from N, O and S, and is saturated, or partially unsaturated or unsaturated (=carrying the highest possible number of conjugated double bonds in the ring), where heterocyclyl is unsubstituted or substituted by one or more substituents independently selected from those mentioned as substituents for substituted aryl,   mono- or di-(unsubstituted or substituted C 1 -C 7 -alkyl)-amino is amino substituted by one or two moieties selected from C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl, amino- or mono- or di-(C 1 -C 7 -alkyl and/or C 6 -C 10 -aryl-C 1 -C 7 -alkyl), or C 1 -C 7 -alkyl substituted by one or more of the further substituents mentioned as substitutents for substituted aryl;   in unsubstituted or substituted-arylamino, unsubstituted or substituted aryl is as defined above;   A is —CH 2 —, —CH 2 —CH 2 —CH 2 — or —CH═CH—,   if D is a bond between the two carbon atoms to which it is bound, then the ring including D has five ring atoms;   If R2 and R3 together form an ethylene or trimethylene bridge in each of which one of the carbon atoms can be replaced with O, S or NR6, then R2 and R3 together with the binding carbon atoms form a 3- to 4-membered ring;   if R3 and R4 together form an ethylene or trimethylene bridge in each of which one of the carbon atoms can be replaced with O, S or NR6, then R3 and R4 together with the binding carbons atoms form a 3- to 4-membered ring;   if one of R2 and R3 is hydrogen and one of R4 and R5 is hydrogen, while the other of R2 and R3 together with the other of R4 and R5 forms an ethylene wherein one of the carbon atoms can be replaced with O, S or NR6, or a methylene bridge, R2 or R3 and R4 or R5 together with the two carbon atoms to which they are bound form a three- to four-membered ring;   the proviso that at least one ring is formed by R2 and R3, by R4 and R5, or by R2 or R3 and R4 or R5, so that not more than two of R2, R3, R5 and R5 are hydrogen or C 1 -C 4 -alkyl, means that at least one annealed or spiro ring must be formed by these substituents and the carbon atoms to which they are bound;   alkyl may be branched, unbranched or cyclic, and is C 1 -C 20 -alkyl in substituted alkyl, it may be substituted by one or more substituents as mentioned as substituents mentioned for aryl;   unsubstituted or substituted aryl-C 1 -C 7 -alkyl is C 1 -C 7 -alkyl that is substituted by unsubstituted or substituted aryl as defined above;   cycloalkyl represents a cyclic hydrocarbon containing from 3 to 12 ring atoms where cycloalkyl may optionally be substituted by one or more substituents independently selected from those mentioned as substituents for substituted aryl, in the (R,S)- or in the (R)- or (S)-form; in the case of R7, cycloalkyl is cyclohexyl or cyclopentyl, each unsubstituted or substituted with hydroxyl;   acyl is the radical of an organic acid, or is C 1 -C 7  alkanoyl, C 1 -C 7 -alkanesulfonyl, benzoyl, naphthoyl, C 1 -C 7 -alkoxycarbonyl, or C 6 -C 10 -aryl-C 1 -C 7 -alkoxycarbonyl;   unsubstituted or substituted saturated heterocyclyl is unsubstituted or substituted saturated heterocyclyl as defined above and is unsubstituted or substituted by one or more of the substituents independently selected from the substituents mentioned for substituted aryl above;   in unsubstituted or substituted heterocyclyl-C 1 -C 7 -alkyl, unsubstituted or substituted heterocyclyl is as defined above and is unsubstituted or substituted by one or more of the substituents independently selected from the substituents mentioned for substituted aryl above;   
       a pharmaceutically acceptable cleavable ester or amide thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         3 . A compound of the formula IA or of the formula IB according to  claim 1 , wherein
 R is phenyl, pyridyl, each of which is unsubstituted or substituted by up to three moieties independently selected from the group consisting of halo-C 1 -C 7 -alkyl, hydroxyl-C 1 -C 7 -alkyl, amino-C 1 -C 7 -alkyl, pyrrolidinyl-C 1 -C 7 -alkyl, pyrrolidino-methyl, imidazolidinyl-C 1 -C 7 -alkyl, imidazolidino-C 1 -C 7 -alkyl, piperidinyl-C 1 -C 7 -alkyl, (unsubstituted or C 1 -C 7 -alkyl-substituted piperazino)-C 1 -C 7 -alkyl, C 6 -C 10 -aryl-C 2 -C 7 -alkenyl, amino-C 3 -C 7 -alkynyl, hydroxyl-C 3 -C 7 -alkynyl, C 1 -C 7 -alkoxy, C 1 -C 7 -alkoxy-C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkoxy, pyrrolidinyl-C 1 -C 7 -alkoxy, imidazolidinyl-C 1 -C 7 -alkoxy, imidazolidino-C 1 -C 7 -alkoxy, piperidinyl-C 1 -C 7 -alkoxy, (unsubstituted or C 1 -C 7 -alkyl-substituted piperazino)-C 1 -C 7 -alkoxy, C 1 -C 7 -alkylenedioxy, amino, carbamoyl, nitro and cyano;   A is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 — or —CH═CH—,   D is a bond between the two carbon atoms to which it is bound or is C(R4R5);   R2 and R3 are hydrogen or together form an ethylene or trimethylene bridge in each of which one of the carbon atoms can be replaced with O, S or NR6;   R3 and R4 are hydrogen or C 1 -C 4 -alkyl or together form an ethylene or trimethylene bridge in each of which one of the carbon atoms can be replaced with O, S or NR6;   or one of R2 and R3 is hydrogen and one of R4 and R5 is hydrogen, while the other of R2 and R3 together with the other of R4 and R5 forms a forms an ethylene bridge wherein one of the carbon atoms can be replaced with O, S or NR6, or a methylene bridge,   with the proviso that at least one of the mentioned bridges is formed by R2 and R3, by R4 and R5, or by R2 or R3 and R4 or R5, so that not more than two of R2, R3, R5 and R5 are hydrogen or C 1 -C 4 -alkyl;   R6 is hydrogen, C 1 -C 7 -alkyl, phenyl-C 1 -C 7 -alkyl, C 3 -C 8 -cycloalkyl that is unsubstituted or substituted by hydroxyl, C 1 -C 7 -alkanoyl or C 1 -C 7 -alkoxycarbonyl,   X is CH; and   Y is O, N or NR7 wherein R7 is hydrogen, C 1 -C 7 -alkyl, hydroxyl-C 1 -C 7 -alkyl or C 3 -C 8 -cycloalkyl that is unsubstituted or substituted by hydroxyl;   
       a pharmaceutically acceptable cleavable ester or amide thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         4 . A compound of the formula I according to  claim 1 , selected from the group of compounds consisting of:
 2-(1-aminomethyl-cyclopropyl)-8-[5-(2-methoxy-ethoxy)-pyridin-3-yl]-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactame,   2-(1-aminomethyl-cyclopropyl)-8-((E)-styryl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactame,   2-(1-amino-cyclobutylmethyl)-8-[5-(2-methoxy-ethoxy)-pyridin-3-yl]-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactame,   2-(1-amino-cyclopropylmethyl)-8-[4-(3-amino-3-methyl-but-1-ynyl)-phenyl]-4,5-dihydro-2H-1,2,7-triaza-cyclopenta[a]naphthalene-3-carboxylic acid lactame,   2-(1-amino-cyclopropylmethyl)-8-[4-(3-amino-3-methyl-butyl)-phenyl]-4,5-dihydro-2H-1,2,7-triaza-cyclopenta[a]naphthalene-3-carboxylic acid lactame,   2-(1-amino-cyclobutylmethyl)-8-((E)-styryl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactame,   2-(1-amino-cyclopropylmethyl)-8-[4-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-4,5-dihydro-2H-1,2,7-triaza-cyclopenta[a]naphthalene-3-carboxylic acid lactame,   2-(1-amino-cyclopropylmethyl)-8-[4-(3-hydroxy-3-methyl-butyl)-phenyl]-4,5-dihydro-2H-1,2,7-triaza-cyclopenta[a]naphthalene-3-carboxylic acid lactame,   2-(1-amino-cyclopropylmethyl)-8-[5-(2-methoxy-ethoxy)-pyridin-3-yl]-4,5-dihydro-2H-1,2,7-triaza-cyclopenta[a]naphthalene-3-carboxylic acid lactame,   2-(1-amino-cyclopropylmethyl)-8-((E)-styryl)-4,5-dihydro-2H-1,2,7-triaza-cyclopenta[a]naphthalene-3-carboxylic acid lactame,   2-(3-amino-azetidin-3-ylmethyl)-8-(4-methoxy-phenyl)-4,5-dihydro-2H-1,2,7-triaza-cyclopenta[a]naphthalene-3-carboxylic acid lactame,   2-(1-acetyl-3-amino-azetidin-3-ylmethyl)-8-(4-methoxy-phenyl)-4,5-dihydro-2H-1,2,7-triaza-cyclopenta[a]naphthalene-3-carboxylic acid lactame,   2-(3-amino-azetidin-3-ylmethyl)-8-[5-(2-methoxy-ethoxy)-pyridin-3-yl]-4,5-dihydro-2H-1,2,7-triaza-cyclopenta[a]naphthalene-3-carboxylic acid lactame,   2-(3-amino-oxetan-3-ylmethyl)-8-(4-methoxy-phenyl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactame,   and 2-(3-amino-azetidin-3-ylmethyl)-8-(4-methoxy-phenyl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactame,   
       a pharmaceutically acceptable ester or amide thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A compound selected from the group of compounds consisting of
 2-(1-Amino-cyclopropylmethyl)-8-(6-fluoro-pyridin-3-yl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactam,   2-(1-Amino-cyclopropylmethyl)-8-(6-methyl-pyridin-3-yl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactam,   2-(1-Amino-cyclobutylmethyl)-8-(6-methyl-pyridin-3-yl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactam,   2-(3-Aminomethyl-1-methyl-azetidin-3-yl)-8-(2-fluoro-phenyl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactam,   2-(3-Aminomethyl-1-methyl-azetidin-3-yl)-8-(6-isopropoxy-pyridin-3-yl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactam hydrochloride,   2-(3-Aminomethyl-azetidin-3-yl)-8-(6-isopropoxy-pyridin-3-yl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactam hydrochloride,   2-[3-Aminomethyl-azetidin-3-yl]-8-(3-chloro-phenyl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactam hydrochloride,   2-[3-Aminomethyl-1-methyl-azetidin-3-yl]-8-(3-chloro-phenyl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactam,   2-[3-(1-Amino-cyclopropyl)-1-methyl-azetidin-3-yl]-8-(3-fluoro-phenyl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactam,   2-[3-(1-Amino-cyclopropyl)-1-methyl-azetidin-3-yl]-8-(6-trifluoromethyl-pyridin-3-yl)-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid lactam,   
       a pharmaceutically acceptable ester or amide thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         6 . A method of treating a cytokine mediated disease comprising administering to a subject in need thereof an effective amount of a compound according to  claim 1 . 
     
     
         7 . The method of  claim 6 , wherein said cytokine is MK-2 and/or TNF. 
     
     
         8 . A method of treating an autoimmune disease comprising administering to a subject in need thereof an effective amount of a compound according to  claim 1 . 
     
     
         9 . A method of treating or preventing a disease comprising administering to a subject in need thereof an effective amount of a compound according to  claim 1 , wherein said disease is arthritis (e.g. rheumatoid arthritis, psoriatic arthritis, juvenile chronic arthritis, reactive arthritis, arthritis deformans, gouty arthritis, osteoarthritis, Lyme disease), acute synovitis, enterogenic spondyloarthropathies, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, gastritis, pancreatitis, Crohn's disease, multiple sclerosis, lumbar spondylarthrosis, systemic lupus erythematosus, lupus nephritis, glomerulonephritis, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, polymyositis, tendonitis and bursitis, graft-versus-host disease, sepsis, septic shock, Behcet's disease, uveitis (anterior and posterior), psoriasis, cutaneous lupus erythematosus, dermatitis, atopic dermatitis, contact dermatitis, eczema, xerosis, Sjogrens syndrome, atherosclerosis, myocarditis, inflammatory pain, cachexia or wasting syndrome associated with morbid TNF release (e.g. consequent to infection, cancer or organ dysfunction, especially AIDS-related cachexia), asthma and bronchitis, or chronic obstructive pulmonary disease (COPD). 
     
     
         10 . A pharmaceutical composition comprising a compound of formula (IA) or (IB), a pharmaceutically acceptable cleavable ester or amide thereof, and/or a pharmaceutically acceptable salt thereof, according to  claim 1 , and at least one pharmaceutically acceptable carrier. 
     
     
         11 . A process for the manufacture of a compound of the formula IA or IB according to  claim 1 , comprising
 a) reacting, for the manufacture of a compound of the formula IA wherein X is CH and the other moieties are as defined for a compound of the formula IA, a compound of the formula IIA,   
       
         
           
           
               
               
           
         
          wherein LG is a leaving group and A, Y, R2, R3 and D are as defined for a compound of the formula IA in any one of  claims 1  to  5 , with a compound of the formula III,
   R—B(R a ) 2   (III)
 
 
          wherein R is as defined for a compound of the formula IA in any one of  claims 1  to  5  and R a  is hydroxyl or C 1 -C 7 -alkoxy or both moieties R a  together form a C 2 -C 4 -alkylene bridge that is unsubstituted or substituted by up to 4 C 1 -C 4 -alkyl moieties, under coupling conditions in the presence of a catalyst; or 
         c) for the manufacture of a compound of the formula IB, deprotecting a compound of the formula VII, 
       
       
         
           
           
               
               
           
         
          wherein R, A, Y, R2, R3 and D are as defined for a compound of the formula IB in any one of  claims 1  to  5 , and PG* is an amino protecting group; 
          wherein in any of the starting materials mentioned in process variants a) or c) protecting groups may be present that can be removed at appropriate stages; 
       
       and, if desired, converting an obtainable free compound of the formula (IA) or (IB) into a pharmaceutically acceptable cleavable ester or amide thereof, and/or a pharmaceutically acceptable salt thereof, respectively, an obtainable salt into the free compound or into a different salt, and/or into a different compound of the formula IA or IB, if desired separating the isomers of a compound of the formula (IA) or (IB) into the isomers thereof. 
     
     
         12 . A composition comprising a compound according to  claim 1  in combination with one or more active agents selected from the group consisting of: Anti IL-1 agents, anti cytokine and anti-cytokine receptor agents, B-cell and T-cell modulating drugs, disease-modifying anti-rheumatic agents (DMARDs), gold salts, penicillamine, hydroxychloroquine and chloroquine, azathioprine, glucocorticoids, non-steroidal anti-inflammatories (NSAIDs), selective COX-2 inhibitors, agents which modulate migration of immune cells, chemokine receptor antagonists, modulators of adhesion molecules, for simultaneous, separate or sequential administration. 
     
     
         13 . The compound of the formula IA or IB according to  claim 1 , wherein, where mentioned,
 unsubstituted or substituted aryl is phenyl, indenyl, naphthyl or fluorenyl, and is unsubstituted or substituted by-up to three, substituents independently selected from the group consisting of 4-fluorophenyl, 2,4-difluorophenoxy, 1-morpholinyl, 4-alkyl-piperazin-1-yl or 1-piperidinyl, methyl, trifluoromethyl or bromomethyl, 3-hydroxy-3-methyl-butyl, 3-amino-3-methyl-butyl, pyrrolidinyl-C 1 -C 7 -alkyl, pyrrolidino-methyl, pyrazolidin-1-yl-C 1 -C 7 -alkyl, piperidino-methyl, 2-piperidino-ethyl, 4-methylpiperazin-1-yl-methyl, -ethyl, morpholino-methyl, 2-morpholino-ethyl, thiomorpholino-methyl, 2-thiomorpholino-ethyl, S-oxo-thiomorpholino-methyl, 2-S-oxo-thiomorpholino-ethyl, S,S-di-thiomorpholino-methyl, 2-S,S-di-thiomorpholino-ethyl, (E,Z)-, (E)-, (Z)-styryl, 3-amino-3-methyl-but-1-ynyl, 3-hydroxy-3-methylbut-1-ynyl, fluoro, chloro, bromo, methoxy, isopropoxy, 2-methoxy-ethoxy, trifluoromethoxy, pyrrolidinyl-C 1 -C 7 -alkoxy, pyrrolidino-methoxy, pyrazilidin-1-yl-C 1 -C 7 -alkoxy, piperidino-methoxy, 2-piperidino-ethoxy, 4-methylpiperazin-1-yl-methoxy, 2-(4-methylpiperazin-1-yl)-ethoxy, morpholino-methoxy, 2-morpholino-ethoxy, thiomorpholino-methoxy, 2-thiomorpholino-ethoxy, S-oxo-thiomorpholino-methoxy, 2-S-oxo-thiomorpholino-ethoxy, S,S-di-thiomorpholino-methoxy, 2-S,S-di-thiomorpholino-ethoxy, dimethylamino-ethoxy, ethlyendioxy, phenyl-C 1 -C 7 -alkoxycarbonyl, and phenyl-C 1 -C 7 -alkyl)-carbamoyl;   unsubstituted or substituted heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, S-oxo-thiomorpholinyl and S,S-dioxothiomorpholinyl; pyrrolyl, imidazolyl, pyrazolyl, indazolyl, purinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyll, isoindolyl, quinolyl, isoquinolyl, quinolizinyl, phthalazinyl, napthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, indolizinyl, carbazolyl, beta-carbolinyl, acridinyl, phenanthridinyl, phenazinyl, phenanthrolinyl, perimidinyl, furyl, thiophenyl (=thienyl), 2H- or 4H-pyranyl or -thiopyranyl, oxazolyl, thiazolyl, isochromanyl, chromanyl, benzofuranyl, 2H-benzo[1,4]oxazinyl, isobenzofuranyl, 2H-chromenyl, 2H-thiochromenyl, thianthrenyl, xanthenyl, phenoxathiinyl, phenoxazinyl and phenothiazinyl; where heterocyclyl is unsubstituted or substituted by one to three, substituents independently selected from C 1 -C 7 -alkoxy, hydroxy-acyl, C 1 -C 7 -alkoxy-C 1 -C 7 -alkoxy, halo, amino, mono- or di-C 1 -C 7 -alkyl-amino, and hydroxyl;   
       a pharmaceutically acceptable cleavable ester or amide thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The compound of the formula IA or IB according to  claim 1 , wherein A is —CH 2 —CH 2 —, a pharmaceutically acceptable cleavable ester or amide thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The compound of the formula IA or IB according to  claim 1 , wherein where mentioned,
 alkyl is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl or 2,2-dimethylpropyl; each of which may be substituted with hydroxyl;   unsubstituted or substituted aryl-C 1 -C 7 -alkyl is benzyl;   cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, where cycloalkyl may optionally with hydroxyl, the (R,S)- or in the (R)- or (S)-form;   acyl is a carboxylic acid or a sulfonic acid, or acetyl, or tert-butoxycarbonyl, or benzyloxycarbonyl; or   
       a pharmaceutically acceptable cleavable ester or amide thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A compound of the formula IA or of the formula IB according to  claim 3 , wherein R is phenyl, pyridine-2-yl or 2-phenylvinyl, each of which is unsubstituted or substituted by up to three moieties independently selected from the group consisting of trifluoromethyl or bromomethyl, 3-hydroxy-3-methyl-butyl, 3-amino-3-methyl-butyl, piperidino-methyl or 2-piperidino-ethyl, 4-methylpiperazin-1-yl-methyl or -ethyl, (E,Z)-, (E)-, (Z)-styryl, 3-amino-3-methyl-but-1-ynyl, 3-hydroxy-3-methylbut-1-ynyl, fluoro, chloro or bromo, methoxy, isopropoxy, 2-methoxy-ethoxy, trifluoromethoxy, pyrrolidino-methoxy, piperidino-methoxy or 2-piperidino-ethoxy, 4-methylpiperazin-1-yl-methoxy and 2-(4-methylpiperazin-1-yl)-ethoxy;
 A is CH 2 — or —CH 2 —CH 2 —;   D is a bond between the two carbon atoms to which it is bound or is C(R4R5);   R2 and R3 are hydrogen or together form an ethylene or trimethylene bridge in each of which one of the carbon atoms can be replaced with O, S or NR6;   R3 and R4 are hydrogen or C 1 -C 4 -alkyl or together form an ethylene or trimethylene bridge in each of which one of the carbon atoms can be replaced with O, S or NR6;   or one of R2 and R3 is hydrogen and one of R4 and R5 is hydrogen, while the other of R2 and R3 together with the other of R4 and R5 forms a forms an ethylene bridge wherein one of the carbon atoms can be replaced with O, S or NR6, or a methylene bridge,   with the proviso that at least one of the mentioned bridges is formed by R2 and R3, by R4 and R5, or by R2 or R3 and R4 or R5, so that not more than two of R2, R3, R5 and R5 are hydrogen or C 1 -C 4 -alkyl;   R6 is hydrogen, C 1 -C 7 -alkyl, phenyl-C 1 -C 7 -alkyl, C 3 -C 8 -cycloalkyl that is unsubstituted or substituted by hydroxyl, C 1 -C 7 -alkanoyl or C 1 -C 7 -alkoxycarbonyl,   X is CH; and   Y is NR7 wherein R7 is hydrogen, C 1 -C 7 -alkyl, hydroxyl-C 1 -C 7 -alkyl or C 3 -C 8 -cycloalkyl that is unsubstituted or substituted by hydroxyl;   
       a pharmaceutically acceptable cleavable ester or amide thereof, and/or a pharmaceutically acceptable salt thereof.