Tetracyclic lactame derivatives

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 atomscan 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 ethy lene 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, halo-C 1 -C 7 -alkyl, hydroxy-C 1 -C 7 alkyl, unsubstituted or substituted aryl-C 1 -C 7 -alkyl or acyl,

X is N; 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;

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,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 imi-dazolidinyl -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 alkoxy-carbonyl, 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 -alkanesutfonyl, benzoyl, naphthoyl, C l -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;

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, halo, 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, C3-C 8 -cycloalkyl that is unsubstituted or substituted by hydroxyl, C 1 -C 7 alkanoyl or C 1 -C 7 .alkoxycarbonyl,

X is N; 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;

and/or a pharrnaceutically acceptable salt thereof.

4. A compound of the formula I according to claim 1 , selected from the group of compounds consisting of:

2-(1-amino-cyclobutylmethyl)-8-(4-methoxy-phenyl)-4,5-dihydro-1 H-1,7,9-triazacyclopenta[a]naph-thalene-3-carboxylic acid lactame,

2-(1-amino-cyclobutylmethyl)-8-[4-(3-amino-3-methyl-but-1-ynyl)-phenyl]-4,5-dihydro-1H-1,7,9-triaza- cyclopenta[a]naphthalene-3-carboxylic acid lactame,

2-(1-amino-cyclobutylmethyl)-8-[4-(3-amino-3-methyl-butyl)-phenyl]-4,5-dihydro-1H-1,7,9-triaza -cyclopenta[a]naphthalene-3-carboxylic acid lactame,

2-(1-aminomethyl-cyclopropyl)-8-(4-methoxy-phenyl)-4,5-dihydro-1H-1,7,9-triaza -cyclopenta[a]naph thalene-3-carboxylic acid lactame,

2-(3-amino-azetidin-3-ylmethyl)-8-(4-methoxy-phenyl)-4,5-dihydro-1H-1,7,9-triaza -cyclopenta[a]naphthalene-3-carbcoxylic acid lactame,

2-(1-amino-cyclobutylmethyl)-8-(3-fluoro-phenyl)-4,5-dihydro-1H-1,7,9-triaza -cyclopenta[a]naphthalene-3-carboxylic acid lactame,

2-(3-amino-oxetan-3-ylmethyl)-8-(4-methoxy-phenyl)-4,5-dihydro-1H-1,7,9-triaza -cyclopenta[a]naphthalene-3-carboxylic acid lactame,

2-(3-amino-oxetan-3-ylmethyl)-8-(3-fluoro-phenyl)-4,5-dihydro-1H-1,7,9-triaza -cyclopenta[a]naphthalene-3-carboxylic acid lactame,

and/or a pharmaceutically acceptable salt thereof.

5. A compound selected from the group of compounds consisting of

2-(3-Aminomethyl-azetidin-3-yl)-8-(4-methoxy-phenyl)-4,5-dihydro-1H-1,7,9-triaza -cyclopenta[a]naphthalene-3-carboxylic acid lactam hydrochloride,

2-(3-Aminomethyl-1-methyl-azetidin-3-yl)-8-(4-methoxy-phenyl)-4,5-dihydro-1H-1,7,9-triaza -cyclopenta[a]naphthalene-3-carboxylic acid lactam,

2-(3-Aminomethyl-azetidin-3-yl)-8-(3-fluoro-4-morpholin-4-ylmethyl-phenyl)-4,5-dihydro-1H -1,7,9-triaza-cyclopenta[a]naphthalene-3-carboxylic acid lactam,

and/or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound of formula (IA) or (IB), and/or a pharmaceutically acceptable salt thereof, according to claim 1 , and at least one pharmaceutically acceptable carrier.

7. A process for the manufacture of a compound of the formula IA or IB according to claim 1 , comprising

a) for the manufacture of a compound of the formula IB wherein A is —CH 2 — or —CH 2 —CH 2 — and X is N, reacting a compound of the formula IV,

wherein R is as defined for a compound of the formula IB in any one of claims 1 to 5 , Hal is halo and A* is —CH 2 — or is —CH 2 —CH 2 —, with a compound of the formula V,

wherein PG is a protecting group, e.g. tert-butoxycarbonyl, and R2, R3 and D are as defined for a compound of the formula IB, in the presence of an amine of the formula VI,

R7-NH 2   (VI)

wherein R7 is as defined for a compound of the formula IB in any one of claims 1 to 5 , or a salt thereof, and removing the protecting group PG, or

b) 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), b) 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 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 enantionmers of a compound of the formula (IA) or (IB) into the enantiomers thereof.

8. 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.

9. 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, imidazolidinyl-C 1 -C 7 -alkyl, pyrazoldin-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 froth 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, C 1 -C 7 -alkyl, hydroxy- C 1 -C 2 -alkyl, acyl, C 1 -C 7 -alkoxy-C 1 -C 7 -alkoxy, halo, amino, mono- or di- C 1 -C 7 -alkyl -amino, and hydroxyl;

and/or a pharmaceutically acceptable salt thereof.

10. The compound of the formula IA or IB according to claim 1 , wherein A is —CH 2 —CH 2 —, and/or a pharmaceutically acceptable salt thereof.

11. 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

and/or a pharmaceutically acceptable salt thereof.

12. 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 7 —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 N; 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;

and/or a pharmaceutically acceptable salt thereof.