The present invention relates to cyclic indolizinecarboxamides and azaindolizinecarboxamides of the formulae Ia and Ib 

wherein R  Ra  R10  R20  R30  R40  Y  n  p and q have the meanings indicated below  which are valuable pharmaceutical active compounds. Specifically  they inhibit the enzyme renin and modulate the activity of the renin-angiotensin system  and are useful for the treatment of diseases such as hypertension  for example. The invention furthermore relates to processes for the preparation of the compounds of the formulae Ia and Ib  their use and pharmaceutical compositions comprising them.

The renin-angiotensin system (RAS; also designated as renin-angiotensin aldosterone system  RAAS) is a key regulator of cardiovascular functions as well as for the balance of electrolytes and for maintaining body fluid volume  and a determinant of blood pressure (cf.  for example  E. Lonn  Can. J. Cardiol. 20 (Suppl. B) (2004)  83B; I. A. Reid  Am. J. Physiol.: Advances in Physiology Education 20 (1998)  S236). It acts via the effects of angiotensin II  an octapeptide hormone  which binds to angiotensin receptors. The formation of angiotensin II involves two main steps. In the first step  renin (EC 3.4.23.15; formerly EC 3.4.99.19 and EC 3.4.4.15)  a 340 amino acid aspartyl proteinase  cleaves angiotensinogen to form the biologically inactive decapeptide angiotensin I. In the second step  angiotensin I is converted into angiotensin II by the zinc-dependent protease angiotensin-converting enzyme (ACE). Renin is produced in the juxtaglomerular cells of the kidney primarily in the form of the biologically inactive prorenin. Its release from the kidney and activation and subsequent RAS activation in normotensive humans is stimulated by sodium or volume depletion  or by a reduction in blood pressure.

RAS activity is the principal determinant of several pathological states since angiotensin II  the major effector molecule of this system  increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating the sodium-retaining hormone aldosterone from the adrenal glands  accompanied by an increase in extracellular fluid volume  as well as having growth-promoting effects on vascular  cardiac and renal tissues which contribute to end-organ damage.

Pharmacological blockade of the RAS is an established way of treating various diseases  for example hypertension (cf.  for example  Handbook of Hypertension  W. H. Birkenhäger et al. (ed.)  Elsevier Science Publishers  Amsterdam (1986)  vol. 8  489). However  the therapeutic response achieved with the currently used types of RAS blockers  ACE inhibitors and angiotensin receptor blockers  although efficacious  is limited. This may be due to the rise in renin which is induced by these agents and results in an increase in angiotensin I which can be converted into angiotensin II via other pathways than by means of ACE. An inhibition of renin  which controls the initial and rate-limiting step in the RAS by catalyzing the cleavage of the Leu10-Val11 peptide bond of angiotensinogen resulting in the formation of the angiotensin peptides  would inhibit the complete RAS and thus be more efficient. Furthermore  whereas inhibition of ACE also affects the level of other peptides which are cleaved by ACE such as bradykinin  for example  which is associated with side effects of ACE inhibitors like cough or angioedema  renin is specific in that angiotensinogen is its only natural substrate. Inhibition of renin thus offers a specific and powerful way of lowering blood pressure (cf. M. Moser et al.  J. Clin. Hypertension  9 (2007)  701) as well as providing organ protection of organs such as the heart  kidney and brain and  besides for treating hypertension  thus is useful for treating disorders of the cardiovascular system  such as heart failure  cardiac insufficiency  cardiac failure  cardiac infarction  cardiac hypertrophy  vascular hypertrophy  left ventricular dysfunction  in particular left ventricular dysfunction after myocardial infarction  restenosis and angina pectoris; renal diseases  such as renal fibrosis  renal failure and kidney insufficiency; diabetes complications  such as nephropathy and retinopathy; glaucoma; and cerebral afflictions  such as cerebral hemorrhage  for example (with respect to the effect of the RAS on renal diseases and cardiac damage  cf.  for example  U. C. Brewster  Am. J. Med. 116 (2004)  263; J. Gaedeke et al.  Expert Opin. Pharmacother. 7 (2006)  377; B. Pilz et al.  Hypertension 46 (2005)  569).

A large number of peptidic and peptidomimetic inhibitors of human renin with various stable transition-state analogues of the scissile peptide bond have been developed since about 1980 and contributed to the validation of renin as a therapeutic target (cf.  for example  B. B. Scott et al.  Curr. Protein Pept. Sci. 7 (2006)  241; J. Maibaum et al.  Expert Opin. Ther. Patents 13 (2003)  589). However  these compounds generally suffer from deficiencies such as insufficient bioavailability (cf. H. D. Kleinert  Cardiovasc. Drugs Therapy 9 (1985)  645) or duration of action  or high cost of production. Recently  an orally active renin inhibitor  aliskiren (cf. Drugs Fut. 26 (2001)  1139; J. Wood et al.  J. Hypertens. 23 (2005)  417; M. Azizi et al.  J. Hypertens. 24 (2006)  243) has been marketed. But the property profile of aliskiren is not yet ideal  for example with respect to oral bioavailability  and a particular drawback of aliskiren is its complex molecular structure with four chiral centers and its multistep synthesis. Thus  there is still a great need for new  non-peptidic small molecule renin inhibitors which exhibit favorable properties  for example with respect to oral bioavailability or low molecular complexity and simple synthetic access. The present invention satisfies this need by providing the renin-inhibiting cyclic (aza)indolizinecarboxamides of the formulae Ia and Ib.

Various indolizine and azaindolizine derivatives have already been described. For example  certain indolizine derivatives  i.e. compounds containing the bicyclic ring system that is present in the compounds of the formulae Ia and Ib in case Y is a carbon atom  are described in WO 2004/054507  which relates to inhibitors of PDE4 useful for the treatment of diseases such as cancer or inflammatory disorders  or in WO 2006/136859  which relates to ligands of the CRTH2 receptor useful for the treatment of respiratory diseases. Certain 5-azaindolizine  or pyrrolo[1 2-b]pyridazine  derivatives  i.e. compounds containing the bicyclic ring system that is present in the compounds of the formulae Ia and Ib in case Y is nitrogen atom  are described in EP 1085021  which relates to inhibitors of sPLA2 useful for the treatment of diseases such as septic shock or adult respiratory distress syndrome  or in WO 2005/030144  which relates to inhibitors of protein kinases useful for the treatment of proliferative disorders  such as cancer  and inflammatory disorders. The indolizinecarboxamides and azaindolizinecarboxamides of the present invention  wherein the amide nitrogen atom is a ring member of a 1 4- or 1 5-diazacycloalkane ring system  one of the carbon atoms in the 5-membered ring of the (aza)indolizine ring system  which is adjacent to a fusion position  carries a cyclic group  and the carbon atom in the 5-membered ring of the (aza)indolizine ring system which is not adjacent to the fusion positions  is linked via a carbon atom to a (hetero)aromatic group  have not yet been disclosed.

Thus  a subject of the present invention are the compounds of the formulae Ia and Ib  in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  and the physiologically acceptable salts thereof  and the physiologically acceptable solvates of any of them 

wherein
Ra is chosen from hydrogen  fluorine and (C1-C4)-alkyl  wherein the two groups Ra are independent of each other and can be identical or different  or the two groups Ra together are a divalent (C2-C5)-alkyl group;

R is chosen from hydrogen  (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents R1  and (C3-C7)-cycloalkyl  wherein all groups R are independent of each other and can be identical or different  or two groups R bonded to the same carbon atom together are a divalent (C2-C5)-alkyl group;

R1 is chosen from (C3-C7)-cycloalkyl  phenyl  heteroaryl  Het1  hydroxy  (C1-C4)-alkyl O-  (C1-C4)-alkyl-S(O)m-  R2-N(R3)-C(O)-  R4-O-C(O)- and cyano;

R2 is chosen from hydrogen  (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents R5  and (C3-C7)-cycloalkyl  wherein all groups R2 are independent of each other and can be identical or different;

R3  R4  R6  R7 and R8 are chosen from hydrogen and (C1-C4)-alkyl  wherein all groups R3  R4  R6  R7 and R8 are independent of each other and can be identical or different;

R5 is chosen from hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R6 N(R7)-C(O)-  R8-O-C(O)-  cyano  (C3-C7)-cycloalkyl  phenyl  heteroaryl and Het1;

R10 is chosen from hydrogen  (C1-C6)-alkyl-O-C(O)- and (C3-C7)-cycloalkyl-CvH2v-O-C(O)-;

R20 is chosen from phenyl and heteroaryl which are optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m- and cyano;

R30 is chosen from (C5-C7)-cycloalkyl  (C5-C7)-cycloalkenyl  tetrahydropyranyl  phenyl and heteroaryl  wherein cycloalkyl and cycloalkenyl are optionally substituted by one or more identical or different substituents chosen from fluorine  (C1-C4)-alkyl and hydroxy  and phenyl and heteroaryl are optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O- and cyano;

R40 is chosen from halogen  (C1-C4)-alkyl  (C3-C7)-cycloalkyl-CvH2v-  hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R41-N(R42)-  Het2  R41-N(R42)-C(O)-  Het2-C(O)-  cyano  R41-N(R42)-S(O)2- and Het2-S(O)2-  wherein all substituents R40 are independent of each other and can be identical or different;

R41 is chosen from hydrogen  (C1-C4)-alkyl and (C3-C7)-cycloalkyl-CvH2v-  wherein all groups R41 are independent of each other and can be identical or different;

R42 is chosen from hydrogen and (C1-C4)-alkyl  wherein all groups R42 are independent of each other and can be identical or different;

Y is chosen from N  CH and C((C1-C4)-alkyl);

heteroaryl is an aromatic monocyclic  5-membered or 6-membered  heterocyclic group which comprises 1  2 or 3 identical or different ring heteroatoms chosen from N  O and S  wherein one of the ring nitrogen atoms can carry a hydrogen atom or a (C1-C4)-alkyl substituent  and wherein the heteroaryl group is bonded via a ring carbon atom;

Het1 is a saturated  monocyclic  4-membered to 7-membered heterocyclic group which comprises 1 or 2 identical or different ring heteroatoms chosen from N  O and S  wherein the group Het1 is bonded via a ring carbon atom or a ring nitrogen atom  wherein ring nitrogen atoms can carry a hydrogen atom or a substituent chosen from (C1-C4)-alkyl  (C1-C6)-alkyl-O-C(O)- and (C3-C7)-cycloalkyl-CvH2v-O-C(O)-  wherein ring sulfur atoms can carry one or two oxo groups  and wherein Het1 is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from fluorine  (C1-C4)-alkyl and oxo;

Het2 is a saturated  monocyclic  4-membered to 7-membered heterocyclic group which comprises a ring nitrogen atom via which the group Het2 is bonded and optionally an additional ring heteroatom chosen from N  O and S  wherein the additional ring nitrogen atom carries a hydrogen atom or a substituent chosen from (C1-C4)-alkyl  (C1-C6)-alkyl-O-C(O)- and (C3-C7)-cycloalkyl-CvH2v-O-C(O)-  wherein the ring sulfur atom can carry one or two oxo groups  and wherein Het2 is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from fluorine  (C1-C4)-alkyl and oxo;

m is chosen from 0  1 and 2  wherein all numbers m are independent of each other and can be identical or different;

n is chosen from 0  1  2 and 3;

p and q  which are independent of each other and can be identical or different  are chosen from 2 and 3;

v is chosen from 0  1 and 2  wherein all numbers v are independent of each other and can be identical or different;

wherein all alkyl groups  independently of each other  are optionally substituted by one or more fluorine atoms;

wherein all cycloalkyl groups  independently of each other  are optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl  unless specified otherwise;

wherein all phenyl and heteroaryl groups present in R1 and R5  independently of each other  are optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)2- and cyano.

If structural elements such as groups  substituents or numbers can occur several times in the compounds of the formulae Ia and Ib  they are all independent of one another and can in each case have any of the indicated meanings  and can in each case be identical to or different from any other such element.

Alkyl groups  i.e. saturated hydrocarbon residues  can be straight-chain (linear) or branched. This also applies if these groups are substituted or are part of another group  for example an alkyl O- group (alkyloxy group  alkoxy group) or an alkyl S(O)m- group. Depending on the respective definition  the number of carbon atoms in an alkyl group can be 1  2  3  4  5 or 6. Examples of alkyl are methyl  ethyl  propyl including n-propyl and isopropyl  butyl including n-butyl  sec-butyl  isobutyl and tert-butyl  pentyl including n pentyl  1-methylbutyl  isopentyl  neopentyl and tert-pentyl  and hexyl including n-hexyl  3 3-dimethylbutyl and isohexyl. Examples of alkyl O are methoxy  ethoxy  n-propoxy  isopropoxy  n-butoxy  isobutoxy  tert-butoxy and n-pentoxy. Examples of alkyl S(O)m are methylsulfanyl- (CH3 S )  methanesulfinyl- (CH3 S(O) )  methanesulfonyl- (CH3 S(O)2 )  ethylsulfanyl- (CH3 CH2 S )  ethanesulfinyl- (CH3 CH2 S(O) )  ethanesulfonyl- (CH3 CH2 S(O)2 )  1-methylethylsulfanyl- ((CH3)2CH S )  1-methylethanesulfinyl- ((CH3)2CH S(O) ) and 1-methylethanesulfonyl- ((CH3)2CH S(O)2 ). In one embodiment of the invention the number m is chosen from 0 and 2  in another embodiment it is 0  in another embodiment it is 2  wherein all numbers m are independent of each other and can be identical or different.

A substituted alkyl group can be substituted in any positions  provided that the resulting compound is sufficiently stable and is suitable as a pharmaceutical active compound. The prerequisite that a specific group and a compound of the formula Ia or Ib are sufficiently stable and suitable as a pharmaceutical active compound  applies in general with respect to all groups in the compounds of the formulae Ia and Ib. If an alkyl group is optionally substituted by one or more fluorine atoms  it can be unsubstituted  i.e. not carry fluorine atoms  or substituted  for example by 1  2  3  4  5  6  7  8  9  10 or 11 fluorine atoms  or by 1  2  3  4 or 5 fluorine atoms  or by 1  2 or 3 fluorine atoms  which can be present in any positions. For example  in a fluoro-substituted alkyl group one or more methyl groups can carry three fluorine atoms each and be present as trifluoromethyl groups  and/or one or more methylene groups (CH2) can carry two fluorine atoms each and be present as difluoromethylene groups. The explanations with respect to the substitution of a group by fluorine also apply if the group additionally carries other substituents and/or is part of another group  for example of an alkyl O group. Examples of fluoro-substituted alkyl groups are trifluoromethyl  2-fluoroethyl  1 1-difluoroethyl  2 2 2-trifluoroethyl  pentafluoroethyl  3 3 3-trifluoropropyl  2 2 3 3 3-pentafluoropropyl  4 4 4-trifluorobutyl and heptafluoroisopropyl. Examples of fluoro-substituted alkyl O groups are trifluoromethoxy  2 2 2-trifluoroethoxy  pentafluoroethoxy and 3 3 3-trifluoropropoxy. Examples of fluoro-substituted alkyl S(O)m groups are trifluoromethylsulfanyl- (CF3 S )  trifluoromethanesulfinyl- (CF3 S(O) ) and trifluoromethanesulfonyl- (CF3 S(O)2 ).

If applicable  the above explanations with respect to alkyl groups apply correspondingly to divalent alkyl groups (alkanediyl groups) including the divalent alkyl group CvH2v which can also be regarded as the alkyl part of a substituted alkyl group. Thus  divalent alkyl groups including the divalent alkyl group CvH2v can also be straight-chain or branched  the bonds to the adjacent groups can be present in any positions and can start from the same carbon atom or from different carbon atoms  and they can be substituted by fluorine. Examples of divalent alkyl groups are CH2   CH2 CH2   CH2 CH2 CH2   CH2 CH2 CH2 CH2  
CH2 CH2 CH2 CH2 CH2   CH(CH3)   C(CH3)2   CH(CH3) CH2   CH2 CH(CH3)  
C(CH3)2 CH2 and CH2 C(CH3)2 . Examples of fluoro-substituted divalent alkyl groups which can contain 1  2  3  4  5 or 6 fluorine atoms  for example  are CHF  
CF2   CF2 CH2   CH2 CF2   CF2 CF2   CF(CH3)   C(CF3)2   C(CH3)2-CF2
and CF2 C(CH3)2 . If the number v in a divalent alkyl group CvH2v is 0 (zero)  the two adjacent groups which are bonded to this group are directly bonded to one another through a single bond. For example  if the group R40 is the group (C3-C7)-cycloalkyl-CvH2v   which group is bonded to the remainder of the molecule via the CvH2v moiety as is symbolized by the terminal line (hyphen) next to the CvH2v moiety representing the free bond  and the number v therein is 0  the (C3-C7)-cycloalkyl group is bonded directly through a single bond to the carbon atom which carries the group R40. In one embodiment of the invention the number v is chosen from 0 and 1  in another embodiment it is 0  in another embodiment it is 1  wherein all numbers v are independent of each other and can be identical or different.

The number of ring carbon atoms in a cycloalkyl group can be 3  4  5  6 or 7. The number of ring carbon atoms in a cycloalkenyl group can be 5  6 or 7. Examples of cycloalkyl are cyclopropyl  cyclobutyl  cyclopentyl  cyclohexyl and cycloheptyl  examples of cycloalkenyl are cyclopentenyl  cyclohexenyl and cycloheptenyl. The double bond in a cycloalkenyl group can be present in any position with respect to the carbon atom in position 1 via which the group is bonded to the (aza)indolizine ring  and cycloalkenyl can thus be cyclopent-1-enyl  cyclopent-2-enyl  cyclopent-3-enyl  cyclohex-1-enyl  cyclohex-2-enyl  cyclohex-3-enyl  cyclohept-1-enyl  cyclohept-2-enyl  cyclohept-3-enyl  cyclohept-4-enyl  for example. In one embodiment of the present invention  a cycloalkyl group  such as (C3-C7)-cycloalkyl  in the definition of any group is chosen from any one or more of the said specific cycloalkyl groups  for example from cyclopropyl and cyclobutyl  or from cyclopropyl  cyclobutyl and cyclopentyl  or from cyclopropyl  cyclopentyl and cyclohexyl  or from cyclopentyl and cyclohexyl  or from cyclopentyl  cyclohexyl and cycloheptyl  wherein all cycloalkyl groups are independent of each other and can be identical or different. Similarly  in one embodiments a cycloalkenyl group is chosen from any one or more of the said specific cycloalkenyl groups  for example from cyclopentenyl and cyclohexenyl  or from cyclohexenyl and cycloheptenyl  or from cyclopent-1-enyl  cyclopent-2-enyl  cyclohex-1-enyl  cyclohex-2-enyl  cyclohept-1-enyl and cyclohept-2-enyl  or from cyclopent-2-enyl  cyclopent-3-enyl  cyclohex-2-enyl  cyclohex-3-enyl  cyclohept-2-enyl  cyclohept-3-enyl and cyclohept-4-enyl  or from cyclopent-2-enyl and cyclohex-2-enyl  or from cyclopent-2-enyl  cyclohex-2-enyl and cyclohept-2-enyl. In one embodiment of the invention  the carbon atom via which the cycloalkenyl group representing R30 is bonded to the (aza)indolizine ring  is not part of the double bond  i.e.  the cycloalkenyl group is not a cycloalk-1-enyl group. Cycloalkyl groups and cycloalkenyl groups generally are optionally substituted by one or more (C1-C4)-alkyl substituents. I.e.  they are unsubstituted and do not carry alkyl substituents  or are substituted  for example by 1  2  3 or 4 identical or different (C1-C4)-alkyl substituents  for example by methyl groups and/or ethyl groups and/or isopropyl groups and/or tert-butyl groups  in particular by methyl groups  which substituents can be present in any positions. Examples of alkyl-substituted cycloalkyl groups are 1-methyl-cyclopropyl  2 2-dimethyl-cyclopropyl  1-methyl-cyclopentyl  2 3-dimethyl-cyclopentyl  1-methyl-cyclohexyl  4-methyl-cyclohexyl  4-isopropyl-cyclohexyl  4-tert-butyl-cyclohexyl and 3 3 5 5-tetramethyl-cyclohexyl. Examples of alkyl-substituted cycloalkenyl groups are 1-methyl-cyclopent-2-enyl  2-methyl-cyclopent-2-enyl  3-methyl-cyclopent-2-enyl  3 4-dimethyl-cyclopent-3-enyl  1-methyl-cyclohex-2-enyl  2-methyl-cyclohex-2-enyl  3-methyl-cyclohex-2-enyl  4-methyl-cyclohex-2-enyl  2-methyl-cyclohex-3-enyl  3-methyl-cyclohex-3-enyl  4-methyl-cyclohex-3-enyl  2 3-dimethyl-cyclohex-2-enyl  4 4-dimethyl-cyclohex-2-enyl  3 4-dimethyl-cyclohex-3-enyl. Cycloalkyl groups and cycloalkenyl groups generally also are optionally substituted by one or more fluorine atoms. I.e.  they are unsubstituted and do not carry fluorine atoms  or are substituted  for example by 1  2  3  4  5  6  7  8  9  10 or 11 fluorine atoms  or by 1  2  3  4  5 or 6 fluorine atoms. Cycloalkyl groups and cycloalkenyl groups can also be substituted simultaneously by fluorine and alkyl. The fluorine atoms can be present in any positions and can also be present in an alkyl substituent. Examples of fluoro-substituted cycloalkyl groups are 1-fluoro-cyclopropyl  2 2-difluoro-cyclopropyl  3 3-difluoro-cyclobutyl  1-fluoro-cyclohexyl  4 4-difluoro-cyclohexyl and 3 3 4 4 5 5-hexafluoro-cyclohexyl. Examples of fluoro-substituted cycloalkenyl groups are 1-fluoro-cyclopent-2-enyl  1-fluoro-cyclohex-2-enyl  4-fluoro-cyclohex-2-enyl  4 4-difluoro-cyclohex-2-enyl. In one embodiment of the invention  cycloalkyl groups are not optionally substituted by substituents chosen from fluorine and (C1-C4)-alkyl. If a cycloalkyl group or cycloalkenyl group can be substituted by further substituents like hydroxy  as in the case of a cycloalkyl group or cycloalkenyl group representing R30  it can be substituted merely by one or more such further substituents like hydroxy and not by substituents chosen from fluorine and (C1-C4)-alkyl  or by one or more such further substituents and simultaneously by one or more substituents chosen from fluorine and (C1-C4)-alkyl. In one embodiment  the number of such further substituents like hydroxy which can be present on a cycloalkyl or cycloalkenyl group  is 1  2 or 3  in another embodiment 1 or 2  in another embodiment 1. In one embodiment  the total number of all substituents in a cycloalkyl group or cycloalkenyl group is 1  2  3  4  5  6  7 or 8  in another embodiment 1  2  3  4 or 5  in another embodiment 1  2 or 3. Such further substituents like hydroxy can be present in any positions  provided that the resulting compound is sufficiently stable and is suitable as a subgroup in a pharmaceutical active compound. In one embodiment  a hydroxy substituent is not present in position 1 of a cycloalkenyl group or cycloalkyl group representing R30. In one embodiment  in a cycloalkenyl group a hydroxy substituent is not present on a carbon atom which is part of the double bond. Examples of hydroxy-substituted cycloalkyl groups are 3-hydroxy-cyclobutyl  2-hydroxy-cyclopentyl  3-hydroxy-cyclopentyl  3 4-dihydroxy-cyclopentyl  2-hydroxy-cyclohexyl  3-hydroxy-cyclohexyl  4-hydroxy-cyclohexyl  2 3-dihydroxy-cyclohexyl  2 4-dihydroxy-cyclohexyl  3 4-dihydroxy-cyclohexyl  3 5-dihydroxy-cyclohexyl  3 4 5-trihydroxy-cyclohexyl  2-hydroxy-cycloheptyl  3-hydroxy-cycloheptyl  4-hydroxy-cycloheptyl. Examples of hydroxy-substituted cycloalkenyl groups are 5-hydroxy-cyclopent-2-enyl  4-hydroxy-cyclohex-2-enyl  5-hydroxy-cyclohex-2-enyl  6-hydroxy-cyclohex-2-enyl  6-hydroxy-cyclohex-3-enyl. Examples of the group cycloalkylalkyl-  which can be present in the group (C3-C7)-cycloalkyl-CvH2v-  are cyclopropylmethyl-  cyclobutylmethyl-  cyclopentylmethyl-  cyclohexylmethyl-  cycloheptylmethyl-  cyclopropyldifluoromethyl-  cyclobutyldifluoromethyl-  cyclopentyldifluoromethyl-  cyclohexyldifluoromethyl-  cycloheptyldifluoromethyl-  1-cyclopropylethyl-  2-cyclopropylethyl-  1-cyclobutylethyl-  2-cyclobutylethyl-  1-cyclopentylethyl-  2-cyclopentylethyl-  1-cyclohexylethyl-  2-cyclohexylethyl-  1-cycloheptylethyl-  2-cycloheptylethyl-.

A tetrahydropyranyl group representing R30  which group can also be designated as oxanyl group or tetrahydro-2H-pyranyl group  can be bonded via any carbon atom and can be tetrahydropyran-2-yl  tetrahydropyran-3-yl or tetrahydropyran-4-yl. In one embodiment of the invention  tetrahydropyranyl is tetrahydropyran-3-yl or tetrahydropyran-4-yl  in another embodiment tetrahydropyranyl is tetrahydropyran-4-yl.

In substituted phenyl groups  the substituents can be present in any positions. In monosubstituted phenyl groups  the substituent can be present in the 2-position  the 3-position or the 4-position. In disubstituted phenyl groups  the substituents can be present in 2 3-position  2 4-position  2 5-position  2 6-position  3 4-position or 3 5-position. In trisubstituted phenyl groups  the substituents can be present in 2 3 4-position  2 3 5-position  2 3 6-position  2 4 5-position  2 4 6-position or 3 4 5-position. If a phenyl group carries four substituents  of which one  two  three or four substituents can be fluorine atoms  for example  the unsubstituted ring carbon atom can be present in the 2-position  the 3-position or the 4-position. If a polysubstituted phenyl group or heteroaryl group carries different substituents  each substituent can be present in any suitable position  and the present invention comprises all positional isomers. The number of substituents in a substituted phenyl group can be 1  2  3  4 or 5. In one embodiment  a substituted phenyl group  and likewise a substituted heteroaryl group  carries 1  2 or 3  in another embodiment 1 or 2  identical or different substituents  in another embodiment 1 substituent  wherein all phenyl and heteroaryl groups are independent of each other. In one embodiment of the invention  the substituents in substituted phenyl and heteroaryl groups are independently of each other chosen from any one or more of the substituents listed in the respective definition  for example by substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O- and (C1-C4)-alkyl-S(O)m-  or from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O- and (C1-C4)-alkyl-S(O)2-  or from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O- and cyano  or from halogen  (C1-C4)-alkyl and (C1-C4)-alkyl-O-  or from halogen and (C1-C4)-alkyl  provided that the substituents are comprised by the definition of the respective phenyl or heteroaryl group  wherein all alkyl groups can be unsubstituted or substituted by one or more fluorine atoms and  as an example of substituents containing fluorine-substituted alkyl  the substituents comprising the group CF3 (trifluoromethyl) such as CF3 itself  CF3-O- or CF3-S- may be included in each list of substituents in addition to substituents comprising unsubstituted alkyl.

In a heteroaryl group  which is a residue of an aromatic monocyclic  5-membered or 6-membered heterocyclic ring system  the ring heteroatoms indicated in the definition of the group can be present in any combination and can be present in any suitable position  provided that the group is in line with its definition and the resulting compound of the formula Ia or Ib is stable and suitable as a pharmaceutical active compound. The one of the ring nitrogen atoms specifically referred to in the definition of the group heteroaryl which can carry a hydrogen atom or a substituent such as alkyl  is the ring nitrogen atom in a 5-membered ring system such as pyrrole  pyrazole  imidazole or triazole to which an exocyclic atom or group is bonded. Examples of ring systems from which a heteroaryl group can be derived are pyrrole  furan  thiophene  imidazole  pyrazole  triazoles such as [1 2 3]triazole and [1 2 4]triazole  oxazole ([1 3]oxazole)  isoxazole ([1 2]oxazole)  thiazole ([1 3]thiazole)  isothiazole ([1 2]thiazole)  oxadiazoles such as [1 2 4]oxadiazole  [1 3 4]oxadiazole and [1 2 5]oxadiazole  thiadiazoles such as [1 3 4]thiadiazole  pyridine  pyridazine  pyrimidine  pyrazine  triazines such as [1 2 3]triazine  [1 2 4]triazine and [1 3 5]triazine. In one embodiment of the invention  a heteroaryl group comprises one or two identical or different ring heteroatoms  in another embodiment of the invention heteroaryl comprises one ring heteroatom  which are defined as indicated. In another embodiment heteroaryl is chosen from thiophenyl  thiazolyl and pyridinyl  in another embodiment from thiophenyl and pyridinyl  in another embodiment heteroaryl is thiophenyl  in another embodiment heteroaryl is pyridinyl. Heteroaryl groups can be bonded via any ring carbon atom. For example  a thiophenyl group (thienyl group) can be thiophen-2-yl (2-thienyl) or thiophen-3-yl (3-thienyl)  furanyl can be furan-2-yl or furan-3-yl  pyridinyl (pyridyl) can be pyridin-2-yl  pyridin-3-yl or pyridin-4-yl  pyrazolyl can be 1H-pyrazol-3-yl  1H-pyrazol-4-yl or 2H-pyrazol-3-yl  imidazolyl can be 1H-imidazol-2-yl  1H-imidazol-4-yl or 3H-imidazolyl-4-yl  thiazolyl can be thiazol-2-yl  thiazol-4-yl or thiazol-5-yl  [1 2 4]triazolyl can be 1H-[1 2 4]triazol-3-yl  2H-[1 2 4]triazol-3-yl or 4H-[1 2 4]triazol-3-yl.

In substituted heteroaryl groups  the substituents can be present in any positions  for example in a thiophen-2-yl group or a furan-2-yl group in the 3-position and/or in the 4-position and/or in the 5-position  in a thiophen-3-yl group or a furan-3-yl group in the 2-position and/or in the 4-position and/or in the 5-position  in a pyridin-2-yl group in the 3-position and/or in the 4-position and/or in the 5-position and/or in the 6-position  in a pyridin-3-yl group in the 2-position and/or in the 4-position and/or in the 5-position and/or in the 6-position  in a pyridin-4-yl group in the 2-position and/or in the 3-position and/or in the 5-position and/or in the 6-position. In one embodiment  a substituted heteroaryl group is substituted by one  two or three  in another embodiment by one or two  identical or different substituents  in another embodiment by one substituent. If a ring nitrogen atom is present which can carry a hydrogen atom or a substituent  the substituent on this nitrogen atom can be a methyl group  an ethyl group  a propyl group or a tert-butyl group  for example  which groups are optionally substituted by one or more fluorine atoms. Generally  suitable ring nitrogen atoms in the compounds of the formulae Ia and Ib  for example the nitrogen atom in a pyridinyl group or a nitrogen atom in a [1 2 5]oxadiazolyl group  can also carry an oxido substituent O? and the compound thus be present in the form of an N oxide.

In one embodiment of the invention  the ring heteroatoms in Het1 are chosen from N and O  in another embodiment from O and S  in another embodiment they are O atoms  in another embodiment they are N atoms. In one embodiment  the number of ring heteroatoms in Het1 is 1. In one embodiment  two ring oxygen atoms in Het1 are not present in adjacent ring positions  in another embodiment two ring heteroatoms chosen from O and S are not present in adjacent ring positions  in another embodiment two ring heteroatoms are not present in adjacent ring positions. Ring nitrogen atoms in Het1  except for a ring nitrogen atom via which Het1 is bonded  carry a hydrogen atom or a substituent as specified. In one embodiment  optional substituents on ring nitrogen atoms in Het1 are chosen from (C1-C4)-alkyl and (C1-C6)-alkyl-O-C(O)-  in another embodiment from (C1-C6)-alkyl-O-C(O)- and (C3-C7)-cycloalkyl-CvH2v-O-C(O)-  in another embodiment from (C1-C4)-alkyl  in another embodiment from (C1-C6)-alkyl-O-C(O)-. In one embodiment  optional substituents on ring carbon atoms in Het1 are chosen from fluorine and (C1-C4)-alkyl  in another embodiment from (C1-C4)-alkyl and oxo  in another embodiment from (C1-C4)-alkyl. In case Het1 contains any oxo groups as substituents  in one embodiment not more than two such oxo substituents are present  and in another embodiment not more than one such oxo substituent is present. In one embodiment  the number of optional substituents on Het1 is 1  2  3  4 or 5  in another embodiment 1  2  3 or 4  in another embodiment 1  2 or 3  in another embodiment 1 or 2  in another embodiment 1  in another embodiment Het1 is unsubstituted. Het1 can be bonded via any suitable ring carbon atom or ring nitrogen atom. In one embodiment  Het1 is bonded via a ring carbon atom. In another embodiment Het1 is bonded via a ring nitrogen atom. Het1 can be 4-membered  5-membered  6-membered or 7-membered. In one embodiment  Het1 is 4-membered or 5-membered  in another embodiment 5-membered to 7-membered  in another embodiment 5-membered or 6-membered  in another embodiment 5-membered  in another embodiment 6-membered. Examples of Het1  from any one or more of which Het1 is chosen in one embodiment  are oxetanyl including oxetan-2-yl and oxetan-3-yl  tetrahydrofuranyl including tetrahydrofuran-2-yl and tetrahydrofuran-3-yl  tetrahydropyranyl including tetrahydropyran-2-yl  tetrahydropyran-3-yl and tetrahydropyran-4-yl  oxepanyl including oxepan-2-yl  oxepan-3-yl and oxepan-4-yl  [1 3]dioxolanyl including [1 3]dioxolan-2-yl and [1 3]dioxolan-4-yl  [1 4]dioxanyl including [1 4]dioxan-2-yl  thietanyl including thietan-2-yl and thietan-3-yl  tetrahydrothiophenyl including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl  tetrahydrothiopyranyl including tetrahydrothiopyran-2-yl  tetrahydrothiopyran-3-yl and tetrahydrothiopyran-4-yl  [1 4]dithianyl including [1 4]dithian-2-yl  azetidinyl including azetidin-1-yl  azetidin-2-yl and azetidin-3-yl  pyrrolidinyl including pyrrolidin-1-yl  pyrrolidinyl-2-yl and pyrrolidinyl-3-yl  piperidinyl including piperidin-1-yl  piperidinyl-2-yl  piperidinyl-3-yl and piperidinyl-4-yl  azepanyl including azepan-1-yl  azepan-2-yl  azepan-3-yl and azepan-4-yl  imidazolidinyl including imidazolidin-1-yl  imidazolidin-2-yl and imidazolidin-4-yl  oxazolidinyl including oxazolidin-2-yl  oxazolidin-3-yl  oxazolidin-4-yl and oxazolidin-5-yl  thiazolidinyl including thiazolidin-2-yl  thiazolidin-3-yl  thiazolidin-4-yl and thiazolidin-5-yl  piperazinyl including piperazin-1-yl and piperazin-2-yl  morpholinyl including morpholin-2-yl  morpholin-3-yl and morpholin-4-yl  thiomorpholinyl including thiomorpholin-2-yl  thiomorpholin-3-yl and thiomorpholin-4-yl  which all are optionally substituted as specified with respect to Het1.

In one embodiment of the invention  the additional ring heteroatom which is optionally present in Het2 besides the ring nitrogen atom via which Het2 is bonded  is chosen from N and O  in another embodiment from O and S  in another embodiment it is an O atom  in another embodiment it is an N atom. In one embodiment  no additional ring heteroatom is present in Het2 besides the ring nitrogen atom via which Het2 is bonded. In one embodiment  two ring heteroatoms are not present in adjacent ring positions of Het2. An additional ring nitrogen atom  which is present in Het2 besides the ring nitrogen atom via which Het2 is bonded  carries a hydrogen atom or a substituent as specified. In one embodiment  the optional substituent on such an additional ring nitrogen atom in Het2 is chosen from (C1-C4)-alkyl and (C1-C6)-alkyl-O-C(O)-  in another embodiment from (C1-C6)-alkyl-O-C(O)- and (C3-C7)-cycloalkyl-CvH2v-O-C(O)-  in another embodiment from (C1-C4)-alkyl  in another embodiment from (C1-C6)-alkyl-O-C(O)-. In one embodiment  optional substituents on ring carbon atoms in Het2 are chosen from fluorine and (C1-C4)-alkyl  in another embodiment from (C1-C4)-alkyl and oxo  in another embodiment from (C1-C4)-alkyl. In case Het2 contains any oxo groups as substituents  in one embodiment not more than two such oxo substituents are present  and in another embodiment not more than one such oxo substituent is present. In one embodiment  the number of optional substituents on Het2 is 1  2  3  4 or 5  in another embodiment 1  2  3 or 4  in another embodiment 1  2 or 3  in another embodiment 1 or 2  in another embodiment 1  in another embodiment Het2 is unsubstituted. Het2 can be 4-membered  5-membered  6-membered or 7-membered. In one embodiment  Het2 is 4-membered or 5-membered  in another embodiment 5-membered to 7-membered  in another embodiment 5-membered or 6-membered  in another embodiment 5-membered  in another embodiment 6-membered. Examples of Het2  from any one or more of which Het2 is chosen in one embodiment  are azetidin-1-yl  pyrrolidin-1-yl  piperidin-1-yl  azepan-1-yl  imidazolidin-1-yl  oxazolidin-3-yl  thiazolidin-3-yl  piperazin-1-yl  morpholin-4-yl  thiomorpholin-4-yl  which all are optionally substituted as specified with respect to Het2.

Halogen is fluorine  chlorine  bromine or iodine. In one embodiment of the invention  halogen is fluorine  chlorine or bromine  in another embodiment fluorine or chlorine  where all occurrences of halogen in the compounds of the formulae Ia and Ib are independent of each other.

The present invention comprises all stereoisomeric forms of the compounds of the formulae Ia and Ib  for example all possible enantiomers and diastereomers including cis/trans isomers. The invention likewise comprises mixtures of two or more stereoisomeric forms  for example mixtures of enantiomers and/or diastereomers including cis/trans isomers  in all ratios. Asymmetric centers contained in the compounds of the formulae Ia and Ib  for example in unsubstituted or substituted alkyl groups or in the diazacycloalkane ring depicted in formulae Ia and Ib  can all independently of one another have S configuration or R configuration. The invention relates to enantiomers  both the levorotatory and the dextrorotatory antipode  in enantiomerically pure form and substantially enantiomerically pure form and in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. The invention likewise relates to diastereomers in the form of pure and substantially pure diastereomers and in the form of mixtures of two or more diastereomers in all ratios. The invention also comprises all cis/trans isomers of the compounds of the formulae Ia and Ib in pure form and substantially pure form and in the form of mixtures of the cis isomer and the trans isomer in all ratios. Cis/trans isomerism can occur in substituted cycloalkane rings and in the diazacycloalkane ring depicted in formulae Ia and Ib  for example. The preparation of individual stereoisomers  if desired  can be carried out by resolution of a mixture according to customary methods  for example by chromatography or crystallization  or by use of stereochemically uniform starting compounds in the synthesis or by stereoselective reactions. Optionally  before a separation of stereoisomers a derivatization can be carried out. The separation of a mixture of stereoisomers can be carried out at the stage of the compound of the formula Ia or Ib or at the stage of an intermediate in the course of the synthesis. The invention also comprises all tautomeric forms of the compounds of the formulae Ia and Ib.

In case the compounds of the formulae Ia and Ib contain one or more acidic and/or basic groups  i.e. salt-forming groups  the invention also includes their corresponding physiologically or toxicologically acceptable salts  i.e. non-toxic salts  in particular their pharmaceutically acceptable salts. The salts can contain inorganic or organic salt components. Salts can be formed  for example  from compounds of the formulae Ia and Ib which contain an acidic group  for example a carboxylic acid group (HO CO-)  and non-toxic inorganic or organic bases. Suitable bases are  for example  alkaline metal compounds or alkaline earth metal compounds  such as sodium hydroxide  potassium hydroxide  sodium carbonate or sodium hydrogencarbonate  or ammonia  organic amino compounds and quaternary ammonium hydroxides. Reactions of compounds of the formulae Ia and Ib with bases for the preparation of the salts are in general carried out according to customary procedures in a solvent or diluent. On account of the physiological and chemical stability  advantageous salts of acidic groups are in many cases sodium  potassium  magnesium or calcium salts or ammonium salts which can also carry one or more organic groups on the nitrogen atom. Compounds of the formulae Ia and Ib which contain a basic  i.e. protonatable  group  for example an amino group  the diazacycloalkane moiety depicted in formulae Ia and Ib in case R10 is hydrogen  or another basic heterocycle such as the 6-membered ring in the (aza)indolizine moiety in case Y is a nitrogen atom  can be present in the form of their acid addition salts with physiologically acceptable acids  for example as salt with hydrogen chloride  hydrogen bromide  phosphoric acid  sulfuric acid  acetic acid  benzoic acid  methanesulfonic acid  p-toluenesulfonic acid  which in general can be prepared from the compounds of the formulae Ia and Ib by reaction with an acid in a solvent or diluent according to customary procedures. As usual  in particular in the case of acid addition salts of a compound containing two or more basic groups  in an obtained salt the ratio of the salt components can deviate upward or downward from the stoichiometric ratio  such as the molar ratio 1:1 or 1:2 in the case of the acid addition salt of a compound of the formula Ia or Ib containing one or two basic groups with a monovalent acid  and vary depending on the applied conditions. The present invention comprises also salts containing the components in a non-stoichiometric ratio  and an indication that an acid addition salt of a compound of the formula Ia or Ib contains an acid in a twofold molar amount  for example  also allows for a lower or higher amount of acid in the obtained salt  for example about 1.8 or about 2.1 mol of acid per mol of compound of the formula Ia or Ib. If a compound of the formula Ia or Ib simultaneously contains an acidic and a basic group in the molecule  the invention also includes internal salts (betaines  zwitterions) in addition to the salt forms mentioned. The present invention also comprises all salts of the compounds of the formulae Ia and Ib which  because of low physiological tolerability  are not directly suitable for use as a pharmaceutical  but are suitable as intermediates for chemical reactions or for the preparation of physiologically acceptable salts  for example by means of anion exchange or cation exchange. A subject of the present invention also are solvates of the compounds of the formulae Ia and Ib and their salts  such as hydrates and adducts with alcohols like (C1-C4)-alkanols  in particular physiologically acceptable solvates  as well as active metabolites of compounds of the formulae Ia and Ib and prodrugs of the compounds of the formulae Ia and Ib  i.e. compounds which in vitro may not necessarily exhibit pharmacological activity but which in vivo are converted into pharmacologically active compounds of the formula Ia or Ib  for example compounds which are converted by metabolic hydrolysis into compounds of the formula Ia or Ib. Examples of such prodrugs are compounds in which an acylatable nitrogen atom  for example the nitrogen atom carrying the group R10 in the diazacycloalkane moiety depicted in formulae Ia and Ib in case R10 is hydrogen  carries an alkyl-O-CO- group or an acyl group such as an alkyl-CO- group  for example  and thus has been converted into a carbamate group or an amide group  or compounds in which a carboxylic acid group has been esterified.

If the two groups Ra together are a divalent (C2-C5)-alkyl group  in one embodiment of the invention the said divalent alkyl group is bonded to the carbon atom carrying the groups Ra via two distinct carbon atoms and forms  together with the carbon atom carrying the groups Ra  a cycloalkane ring to which the (aza)indolizine ring depicted in formulae Ia and Ib and the group R20 are bonded in the same ring position. The said cycloalkane ring  like a cycloalkane ring in the compounds of the formulae Ia and Ib in general  can carry one or more (C1-C4)-alkyl groups  for example one  two  three or four methyl groups  and/or one or more  for example one  two  three or four fluorine atoms. The said cycloalkane ring can be a cyclopropane  cyclobutane  cyclopentane or cyclohexane ring which can all be unsubstituted or substituted by alkyl and/or fluorine as indicated. In one embodiment of the invention the said cycloalkane ring is a cyclopropane ring which can be unsubstituted or substituted by alkyl and/or fluorine as indicated  i.e.  in this embodiment the divalent (C2-C5)-alkyl group is an ethane-1 2-diyl group (1 2-ethylene group) which is unsubstituted or substituted by alkyl and/or fluorine as indicated. In one embodiment  the divalent (C2-C5)-alkyl group is a (C2-C4)-alkyl group  in another embodiment a (C2-C3)-alkyl group  in another embodiment a C2-alkyl group. In one embodiment of the invention  the groups Ra are chosen from hydrogen and fluorine  in another embodiment from hydrogen and (C1-C4)-alkyl  wherein the two groups Ra are independent of each other and can be identical or different  or in all these embodiments the two groups Ra together are a divalent (C2-C5)-alkyl group. In one embodiment of the invention the groups Ra are identical or different groups chosen from hydrogen and fluorine  in another embodiment they are identical and different groups chosen from hydrogen and (C1-C4)-alkyl. In another embodiment of the invention the groups Ra are identical and chosen from hydrogen  fluorine and (C1-C4)-alkyl  or the two groups Ra together are a divalent (C2-C5)-alkyl group. In another embodiment of the invention the groups Ra both are hydrogen or the two groups Ra together are a divalent (C2-C5)-alkyl group. In another embodiment of the invention  the groups Ra both are hydrogen  i.e. the group C(Ra)2 is the group CH2. In one embodiment  a (C1-C4)-alkyl group representing Ra is a (C1-C2)-alkyl group  in another embodiment it is a methyl group.

In one embodiment of the invention  one  two  three or four of the groups R  in another embodiment one  two or three of the groups R  in another embodiment one or two of the groups R  in another embodiment one of the groups R  which are present in the diazacycloalkane moiety depicted in formulae Ia and Ib  are defined as above or below and are chosen from all denotations comprised by the respective definition of R including hydrogen  and all other groups R are hydrogen  where all groups R which are not hydrogen  are independent of each other and can be identical or different. In one embodiment of the invention  all groups R are hydrogen and the diazacycloalkane moiety depicted in formulae Ia and Ib is a piperazine ring  homopiperazine ring or 1 5-diazocane ring which carries the group R10 but is not substituted by any substituents on ring carbon atoms. In another embodiment  all groups R are hydrogen and the diazacycloalkane moiety depicted in formulae Ia and Ib is a piperazine ring which carries the group R10 but is not substituted by any substituents on ring carbon atoms. Groups R which are different from hydrogen can be present in any positions of the diazacycloalkane moiety. For example  in case one group R is present which is different from hydrogen  in one embodiment this group R is present on a ring carbon atom which is adjacent to the ring nitrogen atom which carries the group R10  in another embodiment this group R is present on a ring a carbon atom which is adjacent to the ring nitrogen atom which does not carry the group R10  and in another embodiment  which applies to the case that at least one of the numbers p and q is 3  this group R is present on a carbon atom which is not adjacent to any ring nitrogen. In case two groups R are present which are different from hydrogen  in one embodiment these two groups R are present on one and the same ring carbon atom which is adjacent to the ring nitrogen atom which carries the group R10  in another embodiment one of these two groups R is present on each of the two ring carbon atoms which are adjacent to the ring nitrogen atom which carries the group R10  in another embodiment these two groups R are present on one and the same ring carbon which is adjacent to the ring nitrogen atom which does not carry the group R10  in another embodiment one of these two groups R is present on each of the two ring carbon atoms which are adjacent to the ring nitrogen atom which does not carry the group R10  in another embodiment one of these two groups R is present on a ring carbon atom which is adjacent to the ring nitrogen atom which carries the group R10 and the other group R is present on a ring carbon atom adjacent to the ring nitrogen atom which does not carry the group R10  wherein in this latter embodiment the two ring carbon atoms carrying the said groups R can be present on the same side of the diazacycloalkane moiety  either in the chain (C(R)2)p or in the chain (C(R)2)q  or on different sides of the diazacycloalkane moiety  one being present in the chain (C(R)2)p and the other in the chain (C(R)2)q.

In one embodiment of the invention the groups R are chosen from hydrogen  (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents R1  and (C3-C7)-cycloalkyl  wherein all groups R are independent of each other and can be identical or different. In another embodiment  the groups R are chosen from hydrogen and (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents R1  wherein all groups R are independent of each other and can be identical or different  or two groups R bonded to the same carbon atom together are a divalent (C2-C5)-alkyl group. In another embodiment  the groups R are chosen from hydrogen and (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents R1  wherein all groups R are independent of each other and can be identical or different. In one embodiment of the invention  an optionally substituted (C1-C6)-alkyl group representing R is an optionally substituted (C1-C4)-alkyl group  in another embodiment an optionally substituted (C1-C2)-alkyl group  in another embodiment an optionally substituted methyl group. If two groups R together are a divalent (C2-C5)-alkyl group  in one embodiment of the invention the said divalent alkyl group is bonded to the carbon atom carrying the groups R via two distinct carbon atoms and forms  together with the carbon atom carrying the groups R  a spiro-fused cycloalkane ring. The said cycloalkane ring  like a cycloalkane ring in the compounds of the formulae Ia and Ib in general  can carry one or more (C1-C4)-alkyl groups  for example one  two  three or four methyl groups  and/or one or more  for example one  two  three or four fluorine atoms. The said cycloalkane ring can be a cyclopropane  cyclobutane  cyclopentane or cyclohexane ring which can all be unsubstituted or substituted by alkyl and/or fluorine as indicated. In one embodiment of the invention the said cycloalkane ring is a cyclopropane ring which can be unsubstituted or substituted by alkyl and/or fluorine as indicated  i.e.  in this embodiment the divalent (C2-C5)-alkyl group is an ethane-1 2-diyl group (1 2-ethylene group) which is unsubstituted or substituted by alkyl and/or fluorine as indicated. In one embodiment  the divalent (C2-C5)-alkyl group is a (C2-C4)-alkyl group  in another embodiment a (C2-C3)-alkyl group  in another embodiment a C2-alkyl group.

In one embodiment of the invention  an alkyl group representing R is optionally substituted by one  two  three or four identical or different substituents R1  in another embodiment by one  two or three identical or different substituents R1  in another embodiment by one or two identical or different substituents R1  in another embodiment by one substituent R1  and in another embodiment an alkyl group representing R is unsubstituted  wherein all alkyl groups representing R are independent of each other with respect to their substitution pattern. In one embodiment  R1 is chosen from (C3-C7)-cycloalkyl  phenyl  heteroaryl  hydroxy  R2 N(R3)-C(O)-  R4-O-C(O)- and cyano  in another embodiment from phenyl  heteroaryl  hydroxy  R2-N(R3)-C(O)-  R4-O-C(O)- and cyano  in another embodiment from phenyl  hydroxy  R2-N(R3)-C(O)- and R4-O-C(O)-  in another embodiment from phenyl  hydroxy and R2-N(R3)-C(O)-  in another embodiment from hydroxy  R2-N(R3)-C(O)- and R4-O-C(O)-  in another embodiment from hydroxy and R2 N(R3)-C(O)-  in another embodiment from R2-N(R3)-C(O)- and R4-O-C(O)-  and in another embodiment R1 is R2-N(R3)-C(O)-.

In one embodiment of the invention the groups R2 are chosen from hydrogen and (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents R5  in another embodiment the groups R2 are chosen from (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents R5  and (C3-C7)-cycloalkyl  and in another embodiment the groups R2 are (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents R5  wherein all groups R2 are independent of each other and can be identical or different. In one embodiment  an optionally substituted (C1-C6)-alkyl group representing R2 is an optionally substituted (C2-C6)-alkyl group  in another embodiment an optionally substituted (C1-C4)-alkyl group  in another embodiment an optionally substituted (C2-C4)-alkyl group. In one embodiment  an alkyl group representing R2 is optionally substituted by one  two  three or four identical or different substituents R5  in another embodiment by one  two or three identical or different substituents R5  in another embodiment by one or two identical or different substituents R5  in another embodiment by one substituent R5  and in another embodiment an alkyl group representing R2 is unsubstituted  wherein all alkyl groups representing R2 are independent of each other with respect to their substitution pattern.

In one embodiment of the invention  R3 is chosen from hydrogen and (C1-C2)-alkyl  in another embodiment from hydrogen and methyl  in another embodiment R3 is (C1-C4)-alkyl  in another embodiment R3 is hydrogen.

In one embodiment of the invention  R4 is chosen from hydrogen and (C1-C3)-alkyl  in another embodiment R4 is (C1-C4)-alkyl  in another embodiment R4 is (C1-C3)-alkyl  in another embodiment R4 is hydrogen.

in one embodiment of the invention  R5 is chosen from hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R6 N(R7)-C(O)-  R8-O-C(O)-  (C3-C7)-cycloalkyl  heteroaryl and Het1  in another embodiment from hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R6 N(R7)-C(O)-  (C3-C7)-cycloalkyl  heteroaryl and Het1  in another embodiment from hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R6 N(R7)-C(O)-  (C3-C7)-cycloalkyl and Het1  in another embodiment from hydroxy  (C1-C4)-alkyl-O-  R6 N(R7)-C(O)-  (C3-C7)-cycloalkyl and Het1  in another embodiment from hydroxy  (C1-C4)-alkyl-O-  (C3-C7)-cycloalkyl and Het1  in another embodiment from hydroxy and (C1-C4)-alkyl-O-  in another embodiment from (C1-C4)-alkyl-O-  (C3-C7)-cycloalkyl and Het1  in another embodiment from hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R6 N(R7)-C(O)-  R8-O-C(O)-  heteroaryl and Het1  in another embodiment from hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R6 N(R7)-C(O)-  heteroaryl and Het1  in another embodiment from hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R6 N(R7)-C(O)- and Het1  in another embodiment from hydroxy  (C1-C4)-alkyl-O-  R6 N(R7)-C(O)- and Het1  in another embodiment from hydroxy  (C1-C4)-alkyl-O- and Het1  in another embodiment from hydroxy  (C1-C4)-alkyl-O- and (C1-C4)-alkyl-S(O)m-  and in another embodiment from (C1-C4)-alkyl-O- and Het1  in another embodiment R5 is (C1-C4)-alkyl-O-  in another embodiment R5 is Het1  in another embodiment R5 is hydroxy  in another embodiment R5 is R6 N(R7)-C(O)-. In one embodiment  a group heteroaryl representing R5 is a pyridinyl group. In one embodiment  a group Het1 representing R5 comprises one or two ring heteroatoms one of which is an oxygen atom and the other of which  which is optionally present  is chosen from oxygen and nitrogen  in another embodiment it comprises one ring heteroatom which is an oxygen atom and optionally one further ring heteroatom which is a nitrogen atom  in another embodiment it comprises one ring heteroatom which is an oxygen atom  and in another embodiment a group Het1 representing R5 is a tetrahydropyranyl group.

In one embodiment of the invention  R6 is chosen from hydrogen and (C1-C2)-alkyl  in another embodiment from hydrogen and methyl  in another embodiment R6 is (C1-C4)-alkyl  in another embodiment R6 is hydrogen.

In one embodiment of the invention  R7 is chosen from hydrogen and (C1-C2)-alkyl  in another embodiment from hydrogen and methyl  in another embodiment R7 is (C1-C4)-alkyl  in another embodiment R7 is hydrogen.

In one embodiment of the invention  R8 is chosen from hydrogen and (C1-C3)-alkyl  in another embodiment R8 is (C1-C4)-alkyl  in another embodiment R8 is (C1-C3)-alkyl  in another embodiment R8 is hydrogen.

In one embodiment of the invention  R10 is chosen from hydrogen and (C1-C6)-alkyl-O-CO-  in another embodiment from hydrogen and (C1-C4)-alkyl-O-CO-  in another embodiment R10 is hydrogen.

In one embodiment of the invention  R20 is chosen from phenyl and heteroaryl wherein heteroaryl is chosen from thiophenyl  thiazolyl and pyridinyl  in another embodiment from phenyl and heteroaryl wherein heteroaryl is chosen from thiophenyl and pyridinyl  in another embodiment from phenyl and heteroaryl wherein heteroaryl is thiophenyl  in another embodiment from phenyl and heteroaryl wherein heteroaryl is pyridinyl  which are all optionally substituted as indicated. In another embodiment of the invention  R20 is phenyl which is optionally substituted as indicated. In one embodiment  the number of optional substituents in the group R20 is one  two  three or four  in another embodiment one  two or three  in another embodiment one or two  in another embodiment one. The substituents in a substituted group R20 can be present on carbon atoms in any positions as indicated above with respect to substituted phenyl and heteroaryl groups in general. Thus  for example  in the case of a monosubstituted phenyl group representing R20  the substituent can be present in the 2-position  the 3-position or the 4-position  and in the case of a disubstituted phenyl group the substituents can be present in positions 2 and 3  or positions 2 and 4  or positions 2 and 5  or positions 2 and 6  or positions 3 and 4  or positions 3 and 5. Likewise  a trisubstituted phenyl group representing R20 can carry the substituents in any positions and can be a group such as 3-chloro-2 6-dimethyl-phenyl  3-fluoro-2 6-dimethyl-phenyl  6-chloro-3-fluoro-2-methyl-phenyl or 2-chloro-3-fluoro-6-methyl-phenyl  for example  in case of a phenyl group trisubstituted by fluorine and/or chlorine and methyl. In one embodiment  the substituents which can be present in the group R20  are chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O- and (C1-C4)-alkyl-S(O)m-  in another embodiment from halogen  (C1-C4)-alkyl and (C1-C4)-alkyl-O-  in another embodiment from halogen and (C1-C4)-alkyl  for example from chlorine  fluorine and methyl  wherein in one embodiment of the invention the alkyl groups in substituents in the group R20 can be unsubstituted or substituted by one or more fluorine atoms and  as an example of substituents containing fluorine-substituted alkyl  the substituents comprising the group trifluoromethyl such as CF3 itself  CF3-O- or CF3-S- may be included in each list of substituents in addition to substituents comprising unsubstituted alkyl  and in another embodiment of the invention the alkyl groups in substituents in the group R20 are not substituted by fluorine and in this latter embodiment the said alkyl thus means unsubstituted alkyl. Specific groups in addition to the afore-mentioned specific groups  which can represent the group R20 and from any one or more of which R20 is chosen in one embodiment of the invention  include phenyl  i.e. unsubstituted phenyl  2-fluoro-phenyl  3-fluoro-phenyl  4-fluoro-phenyl  2-chloro-phenyl  3-chloro-phenyl  4-chloro-phenyl  2-methyl-phenyl (o-tolyl)  3-methyl-phenyl (m-tolyl)  4-methyl-phenyl (p-tolyl)  2-ethyl-phenyl  3-ethyl-phenyl  4-ethyl-phenyl  2-methoxy-phenyl  3-methoxy-phenyl  4-methoxy-phenyl  2 3-difluoro-phenyl  2 4-difluoro-phenyl  2 5-difluoro-phenyl  2 6-difluoro-phenyl  3 4-difluoro-phenyl  3 5-difluoro-phenyl  2 3-dichloro-phenyl  2 4-dichloro-phenyl  2 5-dichloro-phenyl  2 6-dichloro-phenyl  3 4-dichloro-phenyl  3 5-dichloro-phenyl  2-chloro-3-fluoro-phenyl  2-chloro-4-fluoro-phenyl  2-chloro-5-fluoro-phenyl  2-chloro-6-fluoro-phenyl  3-chloro-2-fluoro-phenyl  3-chloro-4-fluoro-phenyl  3-chloro-5-fluoro-phenyl  4-chloro-2-fluoro-phenyl  4-chloro-3-fluoro-phenyl  5-chloro-2-fluoro-phenyl  2 3-dimethyl-phenyl  2 4-dimethyl-phenyl  2 5-dimethyl-phenyl  2 6-dimethyl-phenyl  3 4-dimethyl-phenyl  3 5-dimethyl-phenyl  2-fluoro-3-methyl-phenyl  2-fluoro-4-methyl-phenyl  2-fluoro-5-methyl-phenyl  2-fluoro-6-methyl-phenyl  3-fluoro-2-methyl-phenyl  3-fluoro-4-methyl-phenyl  3-fluoro-5-methyl-phenyl  4-fluoro-2-methyl-phenyl  4-fluoro-3-methyl-phenyl  5-fluoro-2-methyl-phenyl  2-chloro-3-methyl-phenyl  2-chloro-4-methyl-phenyl  2-chloro-5-methyl-phenyl  2-chloro-6-methyl-phenyl  3-chloro-2-methyl-phenyl  3-chloro-4-methyl-phenyl  3-chloro-5-methyl-phenyl  4-chloro-2-methyl-phenyl  4-chloro-3-methyl-phenyl  5-chloro-2-methyl-phenyl  2-methoxy-3-methyl-phenyl  2-methoxy-4-methyl-phenyl  2-methoxy-5-methyl-phenyl  2-methoxy-6-methyl-phenyl  3-methoxy-2-methyl-phenyl  3-methoxy-4-methyl-phenyl  3-methoxy-5-methyl-phenyl  4-methoxy-2-methyl-phenyl  4-methoxy-3-methyl-phenyl  5-methoxy-2-methyl-phenyl  for example.

In one embodiment of the invention  R30 is chosen from (C5-C7)-cycloalkyl  (C5-C7)-cycloalkenyl  tetrahydropyranyl and phenyl  in another embodiment from (C5-C7)-cycloalkyl  tetrahydropyranyl and phenyl  in another embodiment from (C5-C7)-cycloalkyl  (C5-C7)-cycloalkenyl and phenyl  in another embodiment from (C5-C7)-cycloalkyl  (C5-C7)-cycloalkenyl and tetrahydropyranyl  in another embodiment from (C5-C7)-cycloalkyl  (C5-C7)-cycloalkenyl  phenyl and heteroaryl  in another embodiment from (C5-C7)-cycloalkyl  tetrahydropyranyl  phenyl and heteroaryl  in another embodiment from (C5-C7)-cycloalkyl  phenyl and heteroaryl  in another embodiment from (C5-C7)-cycloalkyl and (C5-C7)-cycloalkenyl  in another embodiment from (C5-C7)-cycloalkyl and phenyl  in another embodiment from phenyl and heteroaryl  in another embodiment R30 is phenyl  wherein the cycloalkyl  cycloalkenyl  phenyl and heteroaryl groups are all optionally substituted as indicated. In one embodiment  a cycloalkyl group representing R30 is (C5-C6)-cycloalkyl  in another embodiment cyclohexyl. In one embodiment  a cycloalkenyl group representing R30 is (C5-C6)-cycloalkenyl  in another embodiment cyclohexenyl. In one embodiment  a heteroaryl group representing R30 is chosen from thiophenyl and pyridinyl  in another embodiment it is thiophenyl  in another embodiment it is pyridinyl  which are all optionally substituted as indicated. In one embodiment  the number of optional substituents in the group R30 is one  two  three or four  in another embodiment one  two or three  in another embodiment one or two  in another embodiment one  and in another embodiment the group R30 is unsubstituted. The substituents in a substituted group R30 can be present on carbon atoms in any positions as indicated above with respect to substituted cycloalkyl  cycloalkenyl  phenyl and heteroaryl groups in general. For example  in the case of a monosubstituted phenyl group representing R30  the substituent can be present in the 2-position  the 3-position or the 4-position  and in the case of a disubstituted phenyl group the substituents can be present in positions 2 and 3  or positions 2 and 4  or positions 2 and 5  or positions 2 and 6  or positions 3 and 4  or positions 3 and 5. In one embodiment  the substituents which can be present in a cycloalkyl or cycloalkenyl group representing R30 are chosen from fluorine  methyl and hydroxy  in another embodiment from fluorine and methyl. In one embodiment of the invention  the substituents in a cycloalkyl or cycloalkenyl group representing R30 are hydroxy. In another embodiment  a cycloalkyl or cycloalkenyl group representing R30 is unsubstituted. In one embodiment  the substituents which are optionally present in a phenyl or heteroaryl group representing R30  are chosen from halogen  (C1-C4)-alkyl and (C1-C4)-alkyl-O-  in another embodiment from halogen  (C1-C4)-alkyl and cyano  in another embodiment from halogen and (C1-C4)-alkyl  wherein in one embodiment of the invention the alkyl groups in substituents in phenyl and heteroaryl groups representing R30 can be unsubstituted or substituted by one or more fluorine atoms and  as an example of substituents containing fluorine-substituted alkyl  the substituents comprising the group trifluoromethyl such as CF3 itself or CF3-O- may be included in each list of substituents in addition to substituents comprising unsubstituted alkyl  and in another embodiment of the invention the alkyl groups in substituents in the group R30 are not substituted by fluorine and in this latter embodiment the said alkyl thus means unsubstituted alkyl. In one embodiment of the invention  the substituents which are optionally present in a phenyl or heteroaryl group representing R30  are chosen from halogen  in another embodiment from fluorine  chlorine and bromine  in another embodiment from fluorine and chlorine. Specific groups which can occur as the group R30 and from any one or more of which R30 is chosen in one embodiment of the invention  include cyclopentyl  cyclohexyl  cycloheptyl  cyclopent-2-enyl  cyclohex-2-enyl  cyclohept-2-enyl  4-fluoro-cyclohexyl  4-methyl-cyclohexyl  2-hydroxy-cyclopentyl  3-hydroxy-cyclopentyl  2-hydroxy-cyclohexyl  3-hydroxy-cyclohexyl  4-hydroxy-cyclohexyl  2-hydroxy-cycloheptyl  3-hydroxy-cycloheptyl  4-hydroxy-cycloheptyl  4 4-difluoro-cyclohexyl  3 3-dimethyl-cyclohexyl  4 4-dimethyl-cyclohexyl  tetrahydropyran-3-yl  tetrahydropyran-4-yl  phenyl  i.e. unsubstituted phenyl  2-fluoro-phenyl  3-fluoro-phenyl  4-fluoro-phenyl  2-chloro-phenyl  3-chloro-phenyl  4-chloro-phenyl  3-bromo-phenyl  4-bromo-phenyl  2-methyl-phenyl  3-methyl-phenyl  4-methyl-phenyl  2-methoxy-phenyl  3-methoxy-phenyl  4-methoxy-phenyl  thiophen-2-yl  thiophen-3-yl  pyridin-2-yl  pyridin-3-yl  pyridin-4-yl  2-methoxy-pyridin-3-yl  4-methoxy-pyridin-3-yl  5-methoxy-pyridin-3-yl  6-methoxy-pyridin-3-yl  2-methoxy-pyridin-4-yl  3-methoxy-pyridin-4-yl  for example.

The substituents R40 can be present on ring carbon atoms in any of the positions in the 6-membered ring of the (aza)indolizine moiety depicted in formulae Ia and Ib  which is not occupied by the group Y and is not a fusion position. In case the number n of the substituents R40 is less than 3  all carbon atoms in the said positions of the 6-membered ring of the (aza)indolizine moiety depicted in formulae Ia and Ib  which are not occupied by the group Y or are a fusion position  which do not carry a substituent R40  carry a hydrogen atom  i.e.  in the respective positions CH groups are present. In case the number n is 0  all three of such ring carbon atoms carry hydrogen atoms. In the case of a compound of the formula Ia or Ib which carries one substituent R40  in one embodiment of the invention the substituent R40 is present on the ring carbon atom in the 6-membered ring in the (aza)indolizine moiety depicted in formulae Ia and Ib which is adjacent to the group Y  in another embodiment the substituent R40 is present on the ring carbon atom which is separated from the group Y by one ring carbon atom  and in another embodiment the substituent R40 is present on the ring carbon atom which is separated from the group Y by two ring carbon atoms. In the case of a compound of the formula Ia or Ib which carries two substituents R40  in one embodiment the substituents R40 are present on the ring carbon atom which is adjacent to the group Y and on the ring carbon atom which is separated from the group Y by one ring carbon atom  in another embodiment the substituents R40 are present on the ring carbon atom which is adjacent to the group Y and on the ring carbon atom which is separated from the group Y by two ring carbon atoms  and in another embodiment the substituents R40 are present on the ring carbon atom which is separated from the group Y by one ring carbon atom and on the ring carbon atom which is separated from the group Y by two ring carbon atoms. In one embodiment of the invention  the number n of the substituents R40 is 0  1 or 2  in another embodiment it is 0 or 1. In one embodiment of the invention the number n is 1 or 2  in another embodiment it is 1. In another embodiment the number n is 0  i.e. no substituent R40 is present in the compound of the formula Ia or Ib. In one embodiment of the invention  R40 is chosen from halogen  (C1-C4)-alkyl  hydroxy  (C1-C4)-alkyl-O-  R41-N(R42)-  Het2  R41-N(R42)-C(O)-  Het2-C(O)-  cyano  R41-N(R42)-S(O)2- and Het2-S(O)2-  in another embodiment from halogen  (C1-C4)-alkyl  hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R41-N(R42)-  Het2  R41-N(R42)-C(O)-  Het2-C(O)-  R41-N(R42)-S(O)2- and Het2-S(O)2-  in another embodiment from halogen  (C1-C4)-alkyl  hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  Het2  R41-N(R42)-C(O)-  Het2-C(O)-  R41-N(R42)-S(O)2- and Het2-S(O)2-  in another embodiment from halogen  (C1-C4)-alkyl  hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R41-N(R42)-C(O)-  Het2-C(O)-  R41-N(R42)-S(O)2- and Het2-S(O)2-  in another embodiment from halogen  (C1-C4)-alkyl  hydroxy  (C1-C4)-alkyl-O-  R41-N(R42)-  Het2  R41-N(R42)-C(O)- and Het2-C(O)-  in another embodiment from halogen  (C1-C4)-alkyl  hydroxy  (C1-C4)-alkyl-O-  R41-N(R42)-C(O)- and Het2-C(O)-  in another embodiment from halogen  hydroxy  (C1-C4)-alkyl-O-  Het2  R41-N(R42)-C(O)- and Het2-C(O)-  in another embodiment from halogen  hydroxy  (C1-C4)-alkyl-O-  R41-N(R42)-C(O)- and Het2-C(O)-  in another embodiment from halogen  (C1-C4)-alkyl-O-  R41-N(R42)-C(O)- and Het2-C(O)-  in another embodiment from halogen  (C1-C4)-alkyl  R41-N(R42)-  Het2  R41-N(R42)-C(O)- and Het2-C(O)-  in another embodiment from halogen  (C1-C4)-alkyl  R41-N(R42)-C(O)- and Het2-C(O)-  in another embodiment from halogen  Het2  R41-N(R42)-C(O)- and Het2-C(O)-  in another embodiment from halogen  R41-N(R42)-C(O)- and Het2-C(O)-  in another embodiment from R41-N(R42)-C(O)- and Het2-C(O)-  in another embodiment from halogen and R41-N(R42)-C(O)-  in another embodiment from halogen and Het2-C(O)-  in another embodiment from halogen  hydroxy and (C1-C4)-alkyl-O-  in another embodiment from halogen and (C1-C4)-alkyl-O-  in another embodiment R40 is (C1-C4)-alkyl-O-  in another embodiment R40 is R41-N(R42)-C(O)-  in another embodiment R40 is Het2-C(O)  wherein all substituents R40 are independent of each other and can be identical or different.

In one embodiment of the invention  R41 is chosen from hydrogen and (C1-C4)-alkyl  in another embodiment from hydrogen and (C3-C7)-cycloalkyl-CvH2v-  in another embodiment from (C1-C4)-alkyl and (C3-C7)-cycloalkyl-CvH2v-  in another embodiment R41 is (C1-C4)-alkyl  in another embodiment R41 is hydrogen  wherein all groups R41 are independent of each other and can be identical or different.

In one embodiment of the invention  R42 is chosen from hydrogen and methyl  in another embodiment R42 is (C1-C4)-alkyl  in another embodiment R42 is hydrogen  wherein all groups R42 are independent of each other and can be identical or different.

In one embodiment of the invention  Y is chosen from CH and C((C1-C4)-alkyl)  in another embodiment from N  CH and C(CH3)  in another embodiment from N and CH  in another embodiment Y is CH  and in another embodiment Y is N. In one embodiment of the invention  the compound of the formula Ia or Ib is a compound of the formula Ia  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them  in another embodiment it is a compound of the formula Ia in which the group Y is chosen from CH and C((C1-C4)-alkyl)  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them  i.e. it is an indolizine-3-carboxamide derivative which may be represented by the formula Ic  and in another embodiment it is a compound of the formula Ia in which the group Y is N  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them  i.e. it is a 5-azaindolizine-3-carboxamide derivative  or a pyrrolo[1 2 b]pyridazine-7-carboxamide derivative  which may be represented by the formula Id.

In another embodiment of the invention  the compound of the formula Ia or Ib is a compound of the formula Ib  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them  in another embodiment it is a compound of the formula Ib in which the group Y is chosen from CH and C((C1-C4)-alkyl)  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them  i.e. it is an indolizine-1-carboxamide derivative which may be represented by the formula Ie  and in another embodiment it is a compound of the formula Ib in which the group Y is N  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them  i.e. it is a 5-azaindolizine-1-carboxamide derivative  or a pyrrolo[1 2-b]pyridazine-5-carboxamide derivative  which may be represented by the formula If.

All statements and explanations above and below with respect to the compounds of the formulae Ia and Ib and the present invention in general apply correspondingly to the compounds of the formulae Ic  Id  Ie and If. In particular are R  Ra  R10  R20  R30  R40  n  p and q in the compounds of the formulae Ic  Id  Ie and If defined as in the general definition of the compounds of the formulae Ia and Ib or in any embodiment specified above or below. The group R45 in the compounds of the formulae Ic and Ie is chosen from hydrogen and (C1-C4)-alkyl. In one embodiment  R45 is chosen from hydrogen and methyl  and in another embodiment R45 is hydrogen. In one embodiment of the invention the compound of the formula Ia or Ib is a compound of the formula Ia in which the group Y is chosen from N  CH and C((C1-C4)-alkyl)  or a compound of the formula Ib in which the group Y is chosen from CH and C((C1-C4)-alkyl)  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them  i.e.  in this embodiment the compounds of the formulae Ia and Ib may be represented by the formulae Ic  Id and Ie.

In one embodiment of the invention the number p is 2 and the number q is chosen from 2 and 3. In another embodiment of the invention both p and q are 2  i.e.  the diazacycloalkane ring depicted in formulae Ia and Ib is a piperazine ring and the compound of the formula Ia or Ib is a compound of the formula Ig or Ih  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them. All statements and explanations with respect to the compounds of the formulae Ia and Ib and the present invention in general apply correspondingly to the compounds of the formulae Ig and Ih. In particular are R  Ra  R10  R20  R30  R40  Y and n in the compounds of the formulae Ig and Ih defined as in the general definition of the compounds of the formulae Ia and Ib or in any embodiment specified above or below.

A subject of the invention are all compounds of the formulae Ia and Ib wherein any one or more structural elements such as groups  substituents and numbers are defined as in any of the specified embodiments or definitions of the elements or have any one or more of the specific meanings which are mentioned herein as examples of elements  wherein all combinations of one or more specified embodiments and/or definitions and/or specific meanings of the elements are a subject of the present invention  and wherein structural elements in the compounds of the formula Ia are defined independent from the structural elements in the compounds of the formula Ib and can be identical or different in the compounds of the two formulae. Also with respect to all such compounds of the formulae Ia and Ib  all their stereoisomeric forms and mixtures of stereoisomeric forms in any ratio  and their physiologically acceptable salts  and the physiologically acceptable solvates of any of them  are a subject of the present invention. Likewise  also with respect to all specific compounds disclosed herein  such as the example compounds which represent embodiments of the invention wherein the structural elements in the general definition of the compounds of the formulae Ia and Ib have the specific meanings present in the respective specific compound  it applies that they are a subject of the present invention in any of their stereoisomeric forms and or a mixture of stereoisomeric forms in any ratio  and in the form of their physiologically acceptable salts  and in the form of the physiologically acceptable solvates of any of them. Irrespective thereof whether a specific compound is disclosed herein as a free compound and/or as a specific salt  it is a subject of the invention both in the form of the free compound and in the form of all its physiologically acceptable salts  and if a specific salt is disclosed  additionally in the form of this specific salt  and in the form of the physiologically acceptable solvates of any of them.

As an example of compounds of the invention in which any one or more structural elements are defined as in any of the specified embodiments or definitions  compounds of the formulae Ia and Ib may be mentioned wherein p and q both are 2  R10 is chosen from hydrogen and (C1-C6)-alkyl-O-C(O)-  and the groups Ra both are hydrogen  i.e. the compounds of the formulae Ig and Ih wherein R10 is chosen from hydrogen and (C1-C6)-alkyl-O-C(O)- and Ra is hydrogen. Another example are compounds of the formulae Ia and Ib wherein p and q both are 2  one  two or three of the groups R are independently of each other chosen from hydrogen  (C1-C6)-alkyl which is optionally substituted by one  two or three identical or different substituents R1  and (C3-C7)-cycloalkyl  or two of these groups R bonded to the same carbon atom together are a divalent (C2-C5)-alkyl group  and all other groups R are hydrogen  R10 is chosen from hydrogen and (C1-C6)-alkyl-O-C(O)-  and the groups Ra both are hydrogen. Another example are compounds of the formulae Ia and Ib wherein p and q both are 2  one  two or three of the groups R are independently of each other chosen from hydrogen and (C1-C6)-alkyl which is optionally substituted by one  two or three identical or different substituents R1  and all other groups R are hydrogen  R10 is hydrogen  and the groups Ra both are hydrogen. All these compounds  in which all other groups and numbers are defined as in the general definition of the compounds of the formulae Ia and Ib or in any of the specified embodiments or definitions  are a subject of the invention in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  and the physiologically acceptable salts thereof  and the physiologically acceptable solvates of any of them.

Another such example are compounds of the formulae Ia and Ib  in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  and the physiologically acceptable salts thereof  and the physiologically acceptable solvates of any of them  wherein

Ra is chosen from hydrogen and fluorine;

R is chosen from hydrogen and (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents R1  wherein all groups R are independent of each other and can be identical or different  or two groups R bonded to the same carbon atom together are a divalent (C2-C5)-alkyl group;

R1 is chosen from phenyl  hydroxy  (C1-C4)-alkyl O-  R2-N(R3)-C(O)-  R4-O-C(O)- and cyano;

R2 is chosen from hydrogen and (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents R5  wherein all groups R2 are independent of each other and can be identical or different;

R3  R4  R6  R7 and R8 are chosen from hydrogen and (C1-C4)-alkyl  wherein all groups R3  R4  R6  R7 and R8 are independent of each other and can be identical or different;

R5 is chosen from hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R6 N(R7)-C(O)-  R8-O-C(O)-  cyano  (C3-C7)-cycloalkyl  phenyl  heteroaryl and Het1;

R10 is chosen from hydrogen and (C1-C6)-alkyl-O-C(O)-;

R20 is chosen from phenyl and heteroaryl which are optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m- and cyano;

R30 is chosen from (C5-C7)-cycloalkyl  tetrahydropyranyl  phenyl and heteroaryl  wherein cycloalkyl is optionally substituted by one or more identical or different substituents chosen from fluorine  (C1-C4)-alkyl and hydroxy  and phenyl and heteroaryl are optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O- and cyano;

R40 is chosen from halogen  (C1-C4)-alkyl  (C3-C7)-cycloalkyl-CvH2v-  hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R41-N(R42)-  Het2  R41-N(R42)-C(O)-  Het2-C(O)-  cyano  R41-N(R42)-S(O)2- and Het2-S(O)2-  wherein all substituents R40 are independent of each other and can be identical or different;

R41 is chosen from hydrogen and (C1-C4)-alkyl  wherein all groups R41 are independent of each other and can be identical or different;

R42 is chosen from hydrogen and (C1-C4)-alkyl  wherein all groups R42 are independent of each other and can be identical or different;

Y is chosen from N  CH and C((C1-C4)-alkyl);

heteroaryl is an aromatic monocyclic  5-membered or 6-membered  heterocyclic group which comprises 1 or 2 identical or different ring heteroatoms chosen from N  O and S  wherein one of the ring nitrogen atoms can carry a hydrogen atom or a (C1-C4)-alkyl substituent  and wherein the heteroaryl group is bonded via a ring carbon atom;

Het1 is a saturated  monocyclic  4-membered to 7-membered heterocyclic group which comprises 1 or 2 identical or different ring heteroatoms chosen from N  O and S  wherein the group Het1 is bonded via a ring carbon atom or a ring nitrogen atom  wherein ring nitrogen atoms can carry a hydrogen atom or a substituent chosen from (C1-C4)-alkyl and (C1-C6)-alkyl-O-C(O)-  wherein ring sulfur atoms can carry one or two oxo groups  and wherein Het1 is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from fluorine  (C1-C4)-alkyl and oxo;

Het2 is a saturated  monocyclic  4-membered to 7-membered heterocyclic group which comprises a ring nitrogen atom via which the group Het2 is bonded and optionally an additional ring heteroatom chosen from N  O and S  wherein the additional ring nitrogen atom carries a hydrogen atom or a substituent chosen from (C1-C4)-alkyl and (C1-C6)-alkyl-O-C(O)-  wherein the ring sulfur atom can carry one or two oxo groups  and wherein Het2 is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from fluorine  (C1-C4)-alkyl and oxo;

m is chosen from 0  1 and 2  wherein all numbers m are independent of each other and can be identical or different;

n is chosen from 0  1 and 2;

p and q are 2;

v is chosen from 0  1 and 2  wherein all numbers v are independent of each other and can be identical or different;

wherein all alkyl groups  independently of each other  are optionally substituted by one or more fluorine atoms;

wherein all cycloalkyl groups  independently of each other  are optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl  unless specified otherwise;

wherein all phenyl and heteroaryl groups present in R1 and R5  independently of each other  are optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)2- and cyano.

Another such example are compounds of the formulae Ia and Ib  in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  and the physiologically acceptable salts thereof  and the physiologically acceptable solvates of any of them  wherein

Ra is hydrogen;

one or two of the groups R are independently of each other chosen from hydrogen and (C1-C6)-alkyl which is optionally substituted by one or two identical or different substituents R1  and the other groups R are hydrogen;

R1 is chosen from hydroxy  R2-N(R3)-C(O)- and R4-O-C(O)-;

R2 is chosen from hydrogen and (C1-C6)-alkyl which is optionally substituted by one or two identical or different substituents R5  wherein all groups R2 are independent of each other and can be identical or different;

R3  R4  R6  R7 and R8 are chosen from hydrogen and (C1-C4)-alkyl  wherein all groups R3  R4  R6  R7 and R8 are independent of each other and can be identical or different;

R5 is chosen from hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R6 N(R7)-C(O)-  R8-O-C(O)-  heteroaryl and Het1 

R10 is chosen from hydrogen and (C1-C6)-alkyl-O-C(O)-;

R20 is phenyl which is optionally substituted by one  two or three identical or different substituents chosen from halogen and (C1-C4)-alkyl;

R30 is phenyl which is optionally substituted by one or two identical or different substituents chosen from halogen and (C1-C4)-alkyl;

R40 is chosen from halogen  (C1-C4)-alkyl  hydroxy  (C1-C4)-alkyl-O-  R41-N(R42)-  Het2  R41-N(R42)-C(O)- and Het2-C(O)-  wherein all substituents R40 are independent of each other and can be identical or different;

R41 is chosen from hydrogen and (C1-C4)-alkyl  wherein all groups R41 are independent of each other and can be identical or different;

R42 is chosen from hydrogen and (C1-C4)-alkyl  wherein all groups R42 are independent of each other and can be identical or different;

Y is chosen from N  CH and C((C1-C4)-alkyl);

heteroaryl is an aromatic monocyclic  5-membered or 6-membered  heterocyclic group which comprises 1 or 2 identical or different ring heteroatoms chosen from N  O and S  wherein one of the ring nitrogen atoms can carry a hydrogen atom or a (C1-C4)-alkyl substituent  and wherein the heteroaryl group is bonded via a ring carbon atom;

Het1 is a saturated  monocyclic  4-membered to 7-membered heterocyclic group which comprises 1 or 2 identical or different ring heteroatoms chosen from N  O and S  wherein the group Het1 is bonded via a ring carbon atom or a ring nitrogen atom  wherein ring nitrogen atoms can carry a hydrogen atom or a substituent chosen from (C1-C4)-alkyl and (C1-C6)-alkyl-O-C(O)-  wherein ring sulfur atoms can carry one or two oxo groups  and wherein Het1 is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl;

Het2 is a saturated  monocyclic  4-membered to 7-membered heterocyclic group which comprises a ring nitrogen atom via which the group Het2 is bonded and optionally an additional ring heteroatom chosen from N  O and S  wherein the additional ring nitrogen atom carries a hydrogen atom or a substituent chosen from (C1-C4)-alkyl and (C1-C6)-alkyl-O-C(O)-  wherein the ring sulfur atom can carry one or two oxo groups  and wherein Het2 is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl;

m is chosen from 0  1 and 2  wherein all numbers m are independent of each other and can be identical or different;

n is chosen from 0  1 and 2;

p and q are 2;

wherein all alkyl groups  independently of each other  are optionally substituted by one or more fluorine atoms;

wherein all heteroaryl groups present in R5  independently of each other  are optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)2- and cyano.

Another subject of the present invention are processes for the preparation of the compounds of the formulae Ia and Ib  including their salts and solvates  which are outlined below and by which the compounds are obtainable. For example  in one approach for the preparation of a compound of the formula Ia or Ib a compound of the formula IIa or IIb  or a compound in which instead of the carboxylic acid group depicted in formulae IIa and IIb a reactive carboxylic acid derivative group is present  for example a carboxylic acid chloride group  is reacted with a compound of the formula III to give a compound of the formula IVa or IVb  respectively 

wherein R  Ra  R20  R30  R40  Y  n  p and q in the compounds of the formulae IIa  IIb  III  IVa and IVb are defined as in the compounds of the formulae Ia and Ib and additionally functional groups can be present in protected form or in the form of a precursor group  which is later converted into the final group  and R50 is defined as R10 in the compounds of the formulae Ia and Ib with the exception of hydrogen  or R50 is a protective group  and removing the protective group R50 in the compound of the formula IVa or IVb in the case of the preparation of a compound of the formula Ia or Ib in which R10 is hydrogen  and optionally converting any other protected groups or precursor groups into the final groups. I.e.  the group R50 in the compounds of the formulae III  IVa and IVb can be (C1-C6)-alkyl-O-CO- or (C3-C7)-cycloalkyl-CvH2v-O-CO-  which groups protect the nitrogen atom carrying R50 against a reaction with the compound of the formula IIa or IIb  or R50 can be another protective group which prevents a reaction at the said nitrogen atom and can later be removed to give a final compound of the formula Ia or Ib in which R10 is hydrogen. Examples of groups which prevent a reaction at the said nitrogen atom  besides groups such as the tert-butyloxycarbonyl group which can later be removed by treatment with an acid such as trifluoroacetic acid or hydrogen chloride  are the benzyloxycarbonyl group and the benzyl group which can later be removed by hydrogenation in the presence of a catalyst such as a palladium catalyst  or the fluoren-9-yloxycarbonyl group which can later be removed by treatment with piperidine.

The reaction of the carboxylic acids of the formulae IIa and IIb or reactive derivatives thereof with the diazacycloalkane of the formula III to give the compounds of the formulae IVa and IVb comprises the formation of an amide bond  and can be performed under standard conditions for such amide couplings. If a carboxylic acid of the formula IIa or IIb is employed in the reaction  it is usually converted into a reactive derivative  which can be isolated or prepared in situ  or activated in situ by a customary amide coupling reagent. For example  the compound of the formula IIa or IIb can be converted into a carboxylic acid chloride by treatment with thionyl chloride  oxalyl chloride or (1-chloro-2-methyl-propenyl)-dimethylamine  into a reactive ester  or into a mixed anhydride by treatment with an alkyl chloroformate like ethyl chloroformate or isobutyl chloroformate  or it can be activated with a reagent such as propanephosphonic anhydride  an N N""-carbonyldiazole like N N""-carbonyldiimidazole (CDI)  a carbodiimide like N N""-diisopropylcarbodiimide (DIC)  N N""-dicyclohexylcarbodiimide (DCC) or N-ethyl-N""-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)  a carbodiimide together with an additive like 1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT)  a uronium-based coupling reagent like O-(benzotriazol-1-yl)-N N N"" N""-tetramethyluronium tetrafluoroborate (TBTU)  O-(7-azabenzotriazol-1-yl)-N N N"" N""-tetramethyluronium hexafluorophosphate (HATU)  O-(benzotriazol-1-yl)-N N N"" N""-tetramethyluronium hexafluorophosphate (HBTU) or O-(cyano(ethoxycarbonyl)methyleneamino)-N N N"" N""-tetramethyluronium tetrafluoroborate (TOTU)  or a phosphonium-based coupling reagent like (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP)  (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP). The activation of the compound of the formula IIa or IIb and the reaction of the activated compound of the formula IIa or IIb or a reactive carboxylic acid derivative with the compound of the formula III is generally carried out in an inert solvent  such as an ether like tetrahydrofuran (THF)  dioxane or 1 2-dimethoxyethane (DME)  or a hydrocarbon like toluene or a chlorinated hydrocarbon like dichloromethane or chloroform  or an amide like dimethylformamide (DMF) or N-methylpyrrolidin-2-one (NMP)  for example  or a mixture of solvents  at temperatures from about 0 °C to about 60 °C in the presence of a suitable base such as a tertiary amine like triethylamine  ethyl-diisopropylamine  N-methylmorpholine or pyridine  or a basic alkaline metal compound such as an alkaline metal carbonate like sodium carbonate  potassium carbonate or cesium carbonate  for example.

The carboxylic acids of the formula IIa  or compounds which instead of the carboxylic acid group depicted in formula IIa contain a carboxylic acid derivative group  for example a carboxylic acid chloride group  can be obtained from the (aza)indolizines of the formula V by directly introducing a carboxylic acid group or carboxylic acid derivative group  or by first introducing an aldehyde group into the compound of the formula V to give a compound of the formula VI  and subsequently oxidizing the aldehyde group to the carboxylic group.

Ra  R20  R30  R40  Y and n in the compounds of the formulae V and VI are defined as in the compounds of the formula Ia and additionally functional groups can be present in protected form or in the form of a precursor group  which is later converted into the final group.

The direct introduction of a carboxylic acid group or carboxylic acid derivative group into the compounds of the formula V can conveniently be accomplished by reaction with phosgene or a phosgene derivative such as triphosgene  which reaction results in the formation of the acid chlorides of the compounds of the formula IIa which can then be used in the subsequent reaction with the compound of the formula III without a further activation step and without isolation. The reaction with phosgene or a phosgene derivative such as triphosgene is generally carried out in an inert solvent  such as a hydrocarbon like toluene or benzene or a chlorinated hydrocarbon like dichloromethane  or a mixture of solvents at temperatures from about 0 °C to about 30 °C  favorably in the presence of a base such as pyridine (cf. G. A. M. Giardina et al.  Farmaco 54 (1999)  364). The formylation of the (aza)indolizines of the formula V to the compounds of the formula VI can conveniently be carried out under the conditions of the Vilsmeier reaction (cf. G. Jones  Organic Reactions 49 (1997)  1). The Vilsmeier reagent can be prepared in situ from dimethylformamide (DMF) and a suitable inorganic or organic chloride such as phosgene  oxalyl chloride or phosphorus oxychloride in an inert aprotic solvent  such as a hydrocarbon or a chlorinated hydrocarbon like benzene  dichloromethane or chloroform  or an ether like DME or an excess of DMF  or a mixture thereof  at temperatures from about 0 °C to about 10 °C. Favorably  phosphorus oxychloride in an excess of DMF as solvent is employed. The reaction of the Vilsmeier reagent with the compound of the formula V is usually carried out at temperatures from about 0 °C to about 60 °C. Hydrolytic workup of the reaction mixture  which like the workup of all reactions in the preparation of the compounds of the formulae Ia and Ib can generally be performed under standard conditions  then yields the aldehyde of the formula VI. Reagents for the oxidation of the aldehyde to the carboxylic acid of the formula IIa are permanganates such as potassium permanganate  which can be used in a mixture of water and an inert organic solvent  such as a ketone like acetone  or an ether like THF  at temperatures from about 10 °C to about 30 °C at about neutral pH values  or halogen oxidants such as chlorites like sodium chlorite  which can be used in the presence of 2-methylbut-2-ene in a mixture of water and an inert organic solvent  such as an alcohol like tert-butanol or an ether like THF  or a mixture thereof  at temperatures from about 0 °C to about 30 °C at weakly acidic pH values  for example in the presence of a dihydrogenphosphate.

Synthetic procedures which can be used in the preparation of the compounds of the formula V and further (aza)indolizine derivatives  are described in T. Uchida et al.  Synthesis (1976)  209  for example. Compounds of the formula V in which the group Y is an optionally substituted carbon atom  i.e. compounds of the formula Va  can be synthesized from pyridine derivatives carrying an R30-CH2- substituent in the 2-position  i.e. compounds of the formula VII  and 3-substituted 1-halo-propanones of the formula VIII by the well-known Tschitschibabin method (cf. A. E. Tschitschibabin  Ber. Dtsch. Chem. Ges. 60 (1927)  1607; W. Chai et al.  Synlett (2003)  2086)  for example.

Ra  R20  R30  R40 and n in the compounds of the formulae Va  VII  VIII and IX are defined as in the compounds of the formula Ia and additionally functional groups can be present in protected form or in the form of a precursor group  which is later converted into the final group. The group R45 in the compounds of the formulae Va  VII and IX is defined as in the compounds of the formula Ic  i.e. R45 is chosen from hydrogen and (C1-C4)-alkyl and corresponds to the hydrogen atom or the alkyl group present in the group Y in case Y in the compounds of the formula Ia is an optionally substituted carbon atom. The group X1 in the compounds of the formula VIII favorably is chlorine or bromine  and accordingly the anion X1? in the compounds of the formula IX then is the chloride ion or the bromide ion  but can also be another anion  for example in case an anion exchange is performed and the compound of the formula IX is isolated.

According to the Tschitschibabin method for the preparation of indolizine derivatives  the 2-(R30-CH2)-substituted pyridine derivative of the formula VII is quaternized with the halo-propanone of the formula VIII to give the quaternary salt of the formula IX  which is then cyclized in the presence of a base to give the compound of the formula Va. The procedure can be carried out with or without isolation of the compound of the formula IX. The reaction of the compounds of the formulae VII and VIII and the cyclization are generally carried out in a solvent  such as a hydrocarbon like toluene  or an ether like THF or dioxane  or a ketone like acetone or 2-butanone  or an alcohol like methanol  ethanol or isopropanol  or water  for example  or a mixture of solvents  with heating  for example at temperatures from about 50 °C to about 110 °C. As a base in the cyclization step  an inorganic base  such as a basic alkaline metal salt  for example a carbonate or hydrogencarbonate like sodium carbonate  potassium carbonate or sodium hydrogencarbonate  or an organic base  for example an amine like triethylamine  or 1 8-diazabicyclo[5.4.0]undec-7-ene (DBU)  can be employed. The reaction can also be performed with an excess of the pyridine derivative of the formula VII which then acts as the base in the cyclization step.

Compounds of the formula VII are commercially available or can be obtained by various procedures under standard conditions  for example from the respective compound containing a chlorine atom instead of the group R30 CH2- in the 2-position by reaction with the respective 9-(R30-CH2)-substituted 9-borabicyclo[3.3.1]nonane (cf. A. Flaherty et al.  Org. Lett. 7 (2005)  4975  for example)  or from the respective compound containing a methyl group instead of the R30-CH2- group in the 2-position by metalation  for example with a lithium amide or an organolithium compound like n butyllithium  and direct reaction of the compound metalated on the methyl group with an electrophilic reagent introducing the group R30  for example a suitable reactive halo-substituted or sulfonyloxy-substituted cycloalkane  cycloalkene  tetrahydropyran  benzene or heteroarene derivative  or by first reacting the compound metalated on the methyl group with diisopropylketone and then reacting the obtained 1 1-diisopropyl-2-(pyridin-2-yl)-ethanol derivative with such an electrophilic reagent according to the procedure in T. Niwa et al.  Angew. Chem. Int. Ed. 46 (2007)  2643  where such reactions are performed in the presence of a palladium compound like tetrakis(triphenylphosphine)palladium(0)  tris(dibenzylideneacetone)dipalladium(0)  palladium(II) acetate or palladium(II) trifluoroacetate and a phosphine like triphenylphosphine  tricyclohexylphosphine or 2-dicyclohexylphosphino-2"" 6""-dimethoxy-biphenyl  if necessary. Compounds of the formula VIII likewise are commercially available or can be prepared by various procedures under standard conditions  for example by reaction of the respective compound of the formula VIII containing a hydrogen atom instead of the group X1 with bromine according to the bromination-debromination procedure described in H. Y. Choi et al.  Org. Lett. 5 (2003)  411  to give the compound of the formula VIII in which X1 is bromine  or by reaction of the respective 2-R20-substituted acetyl chloride with trimethylsilyl diazomethane and treatment of the intermediary 3-R20-substituted 1-diazo-propan-2-one with hydrobromic acid to give the compound of the formula VIII in which X1 is bromine (cf. N. Desideri  Lett. Org. Chem. 3 (2006)  546)  or by reaction of the respective compound of the formula R20-M1  in which R20 is defined as in the compounds of the formula Ia and additionally functional groups can be present in protected form or in the form of a precursor group  and M1 is a magnesium monohalide group and the compound of the formula R20-M1 is a Grignard compound  or M1 is a metal like lithium  with a chloromethyl-oxirane  in particular epichlorohydrine  favorably in the presence of a copper compound like copper(I) iodide  followed by oxidation of the obtained 3-R20-substituted 1-chloro-propan-2-ol to the ketone by means of one of the many common agents for the oxidation of secondary alcohols  for example by means of the Dess-Martin periodinane reagent  i.e. 1 1 1-triacetoxy-1 1-dihydro-1 2-benziodoxol-3(1H)-one  to give the compound of the formula VIII in which X1 is chlorine (cf. H.-D. Becker et al.  J. Org. Chem. 54 (1989)  3182; K. Okano et al.  J. Am. Chem. Soc. 128 (2006)  7136). If desired  a compound of the formula VIII in which X1 is chlorine  can conveniently be converted by treatment with lithium bromide in a solvent such as acetone  for example  into the respective compound of the formula VIII in which X1 is bromine.

Compounds of the formula V in which Y is a nitrogen atom  i.e. compounds of the formula Vb  can be synthesized via pyrrole derivatives of the formula XIV  which can be obtained according to the Barton-Zard pyrrole synthesis (cf. D. H. R. Barton et al.  Tetrahedron 46 (1990)  7587) from isocyanoacetates of the formula XIII and nitroolefines of the formula XII  which in turn can be obtained from nitro compounds of the formula X and aldehydes of the formula XI  N-amination on the pyrrole ring to give the compound of the formula XV  reaction with a malonaldehydic acid ester acetal of the formula XVI and introduction and/or modification of functional groups in the 6-membered ring of the azaindolizine ring system in the compound of the formula XVII.

Ra  R20  R30  R40 and n in the compounds of the formulae Vb  X  XI  XII  XIII  XIV  XV  XVI and XVII are defined as in the compounds of the formula Ia and additionally functional groups can be present in protected form or in the form of a precursor group  which is later converted into the final group. The groups R51  R52 and R53  which can be identical or different  conveniently are (C1-C4)-alkyl groups like methyl  ethyl or tert-butyl  for example. The starting compounds for this synthesis of compounds of the formula Vb are commercially available or can be obtained according to standard procedures which are described in the literature and known to the person skilled in the art  and are also outlined in the following.

The condensation reaction of the nitro compound of the formula X with the aldehyde of the formula XI to give the nitroolefin of the formula XII is generally carried out by heating the components in an inert solvent  such as a hydrocarbon like toluene or xylene  for example under removal of water by azeotropic distillation at reflux temperature of the solvent  and/or with addition of an acid like acetic acid or an amine like n-butylamine or an ammonium salt like ammonium acetate or n-butylammonium acetate  for example. By a similar condensation reaction of an aldehyde of the formula R20-CHO  in which R20 is defined as in the compounds of the formula Ia and additionally functional groups can be present in protected form or in the form of a precursor group  and nitromethane according to the Knoevenagel reaction  for example in acetic acid at reflux temperature in the presence of ammonium acetate  and reduction of the obtained nitrostyrene of the formula R20 CH=CH-NO2  in which R20 is defined as in the compounds of the formula Ia and additionally functional groups can be present in protected form or in the form of a precursor group  for example by means of sodium borohydride in the presence of silica gel as described in A. K. Sinhababu et al.  Tetrahedron Lett. 24 (1983)  227  compounds of the formula X can be obtained in which the groups Ra are hydrogen. A procedure for the preparation of compounds of the formula X in which Ra is different from hydrogen  in which the respective compound of the formula R20-C(Ra)2-NO2  in which Ra and R20 are defined as in the compounds of the formula Ia and additionally functional groups can be present in protected form or in the form of a precursor group  is reacted with nitromethane in the presence of sodium hydride in dimethyl sulfoxide  is described in N. Kornblum et al.  J. Org. Chem. 46 (1981)  1037. The reaction of the compound of the formula XII with the isocyanoacetic acid ester of the formula XIII to give the pyrrole derivate of the formula XIV is favorably carried out in an inert solvent  such as an ether like THF or dioxane or an alcohol such as isopropanol  or a mixture of solvents  in the presence of a base  for example tetramethylguanidine or DBU (cf. D. H. R. Barton et al.  Tetrahedron 46 (1990)  7587; J. A. Pfefferkorn et al.  Bioorg. Med. Chem. Lett. 17 (2007)  4538).

As reagents for the N-amination of the compound of the formula XIV to give the compound of the formula XV  hydroxylamine-O-sulfonic acid/potassium hydroxide  ammonia/ammonium chloride/sodium hypochlorite/sodium hydroxide  or O-(4-nitrobenzoyl)-hydroxylamine/potassium tert-butoxide may be mentioned. Favorably  the N-amination is performed by treating the compound of the formula XIV in an inert solvent such as an amide like DMF with a base such as sodium hydride and with O (2 4-dinitrophenyl)-hydroxylamine as aminating reagent at temperatures from about 0 °C to about 30 °C. (cf. C. Legault et al.  J. Org. Chem. 68 (2003)  7119; P. H. Boyle et al.  ARKIVOC (2003) (vii)  67; K. S. Kim et al.  Bioorg. Med. Chem. Lett. 16 (2006)  3937). The condensation of the 1-amino-group of the pyrrole derivative of the formula XV with the masked aldehyde group of the malonaldehydic acid ester acetal of the formula XVI and the subsequent cyclization of give the 4-hydroxy-pyrrolo[1 2 b]pyridazine derivative of the formula XVII  which can also be present in a tautomeric form and designated as a 4-oxo-1 4-dihydro-pyrrolo[1 2-b]pyridazine or 1H-pyrrolo[1 2-b]pyridazin-4-one derivative  can be carried out by reacting the components in an inert solvent  for example an amide like DMF  with heating  for example to temperatures from about 40 °C to about 100 °C  first under acidic conditions  for example in the presence of a sulfonic acid like toluene-4-sulfonic acid  and subsequently under basic conditions  for example in the presence of an organic base like DBU.

Depending on the desired substituents in compound of the formula Vb or the final compound of the formula Ia  substituents can then be introduced in the 6-membered ring in the azaindolizine ring system in the compound of the formula XVII and/or the ester group and/or the hydroxy group in the compound of the XVII modified or removed. For example  the hydroxy group can be alkylated  or it can be replaced with a halogen atom  for example a chlorine atom  by treatment with a halogenating agent such as a phosphorus halide  for example phosphorus oxychloride. Such a replacement can also occur concomitantly with a Vilsmeier formylation of a compound of the formula XVII or Vb with DMF and phosphorus oxychloride  for example  to give a compound of the formula VI as outlined above. In a compound of the formula XVII  in which the hydroxy group is replaced with a chlorine atom  or in a compound which has been obtained from the compound of the formula XVII by a Vilsmeier formylation and subsequent oxidation to a carboxylic acid of the formula IIa and optionally further reactions  the chlorine atom in the 6-membered ring of the azaindolizine ring system can then be replaced with another group in a substitution reaction  or it can be replaced with a hydrogen atom  for example by hydrogenation in the presence of a transition metal catalyst such as palladium on charcoal and a base such as triethylamine. The ester group can likewise be replaced with a hydrogen atom by hydrolysis to the carboxylic acid  for example by treatment with an alkaline metal hydroxide like lithium hydroxide or sodium hydroxide  and decarboxylation of the carboxylic acid by heating it with copper in quinoline. The said carboxylic acid can also be converted into a carboxamide as outlined above with respect to the reaction of the carboxylic acids of the formula IIa with the compounds of the formula III. The ester group  or the said carboxylic acid or a suitable carboxamide obtained therefrom can either directly be reduced to the aldehyde  or they can be reduced to the hydroxymethyl compound which can be oxidized to the aldehyde  and the aldehyde group can be converted into a hydroxy group according to the Baeyer-Villiger procedure by oxidation with a peracid and hydrolysis  where the hydroxy group can then be alkylated. A primary carboxamide group obtained from the ester or the said carboxylic acid can be converted into a nitrile group  and various other modifications can be carried out  if desired. These explanations on the introduction  modification and removal of functional groups in the 6-membered ring of the (aza)indolizine ring system in the compounds of the formulae Vb and XVII apply correspondingly to the compounds of the formulae IIa  IIb  Va  XX and other compounds defined above or below  in which likewise functional groups can be introduced  modified or removed. As further examples of such reactions of these compounds the introduction of bromine substituents may be mentioned  which can conveniently be carried out via a bromination/debromination sequence by treatment with bromine and subsequently with a base such as DBU (cf. A. Kakehi et al.  Chem. Pharm. Bull. 52 (2004)  279)  or the preparation of amino-substituted compounds via the replacement of a halogen substituent such as a bromine or iodine substituent with an amine under the conditions of the Buchwald-Hartwig reaction in the presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0) and a phosphine such as tri(o-tolyl)phosphine  for example (cf. J. P. Wolfe et al.  Acc. Chem. Res. 31 (1998)  8052).

Compounds of the formula IIb  or respective compounds which instead of the carboxylic acid group depicted in formula IIb contain a carboxylic acid derivative group such as an ester group  i.e. compounds of the formula XX  can be synthesized in a procedure which starts from a pyridin-2-yl-acetic acid ester or a pyridazin-3-yl-acetic acid ester of the formula XVIII and a 3-substituted 1-halo-propanone of the formula VIII and involves the well-known Tschitschibabin method like the synthesis of the compounds of the formula Va described above. Further information on this procedure can likewise be found in T. Uchida et al.  Synthesis (1976)  209  for example.

Ra  R20  R30  R40  Y and n in the compounds of the formulae XVIII  XIX and XX are defined as in the compounds of the formula Ib and additionally functional groups can be present in protected form or in the form of a precursor group  which is later converted into the final group. The group R54 in the compounds of the formulae XVIII  XIX and XX can be a (C1-C4)-alkyl group like methyl  ethyl or tert-butyl  for example  but can also be another group such as benzyl. Compounds of the formula XX which contain a carboxylic acid group COOH instead of the group COOR54  which compounds are readily obtained from the compounds of the formula XX  are compounds of the formula IIb  and hydrogen can accordingly be regarded as a further denotation of R54 in the compounds of the formula XX.

Compounds of the formula XVIII are commercially available or can be obtained by various procedures under standard conditions  for example from the respective heteroarene containing a chlorine atom instead of the group CH2-COOR54 by reaction with a dialkyl malonate and hydrolysis and decarboxylation of one of the ester groups of the obtained dialkyl heteroarene-malonate  or from the respective heteroarene containing a methyl group instead of the group CH2-COOR54 by metalation  for example by means of a lithium compound such as n-butyllithium or lithium diisopropylamide and reaction with a dialkyl carbonate (cf. EP 1958946; A. Ohsawa et al.  Chem. Pharm. Bull. 26 (1978)  3633). The reaction of the compounds of the formulae VIII and XVIII to give the compound of the formula XIX can be performed analogously as outlined above with respect to the reaction of the compounds of the formulae VII and VIII to give the compound of the formula IX and the cyclization of the latter compound to give the compound of the formula Va  favorably without isolation of the intermediary salt corresponding to the compound of the formula IX  for example by heating the components together with a base such as an alkaline metal hydrogencarbonate like sodium hydrogencarbonate in a solvent such as a ketone like acetone or 2-butanone to temperatures from about 50 °C to about 100 °C. For the introduction of the group R30 to give the compound of the formula XX  the compound of the formula XIX is favorably reacted with a compound of the formula R30-X2 in which R30 is defined as in the compounds of the formula Ib and additionally functional groups can be present in protected form or in the form of a precursor group  and X2 is a suitable leaving group  for example halogen like bromine or iodine  in a transition metal-catalyzed coupling reaction  for example in the presence of a palladium compound such as bis(triphenylphosphine)palladium(II) chloride or tetrakis(triphenylphosphine)palladium(0) and a base such as a basic alkaline metal salt like potassium acetate in an inert solvent such as an amide like DMF or NMP at temperatures from about 60 °C to about 120 °C.

The diazacycloalkanes of the formula III  which are reacted in an amide coupling reaction with the compounds of the formulae IIa and IIb to give the compounds of the formulae IVa and IVb and  after optional conversion of the group R50 into the group R10  the final compounds of the formulae Ia and Ib  are commercially available or can be prepared according to  or analogously to  standard procedures described in the literature (cf. WO 96/31501; WO 2005/026177; WO 2005/061510; S. Fustero et al.  Org. Lett. 9 (2007)  5283  for example) which are also illustrated in an exemplary manner in the following. Chiral compounds of the formula III in which p and q both are 2  one of the groups R is different from hydrogen and all other groups R are hydrogen  for example  can be prepared in a procedure starting from chiral ?-amino acid derivatives of the formula XXI and an N-benzyl-glycine ester of the formula XXII. According to this procedure  compounds of the formula III can be obtained in which the chiral carbon atom carrying the group R which is different from hydrogen  is present adjacent to the group NH in the compound of the formula III  for example compounds of the formula IIIa  and compounds in which the chiral carbon atom carrying the group R which is different from hydrogen  is present adjacent to the group NR50 in the compound of the formula III  for example compounds of the formula IIIb. Furthermore  according to this procedure compounds of the formula III can be obtained in which the chiral carbon atom has S configuration or has R configuration or is present as a racemic mixture  for example  depending on whether an ?-amino acid derivative having S configuration or R configuration (or L configuration or D configuration) or a racemic mixture thereof is employed.

The groups R and R50 in the compounds of the formulae IIIa  IIIb  XXI  XXIII and XXIV are defined as in the compounds of the formulae Ia and Ib and additionally functional groups can be present in protected form or in the form of a precursor group  which is later converted into the final group  i.e. they are defined as in the compounds of the formula III  except that such a procedure will not be carried out in case R is hydrogen. The group R55 conveniently is a (C1-C4)-alkyl group  for example methyl or ethyl. The group Bn in the compounds of the formulae IIIa  XXII  XXIII and XXIV is the benzyl group. The group Boc in the compounds of the formulae XXI and XXIII is the tert-butyloxycarbonyl group. The starting compounds of the formulae XXI and XXII are commercially available or can be obtained according to standard procedures from the respective amino acids. For the amide coupling reaction of the compounds of the formula XXI with the compounds of the formula XXII  the compound of the formula XXI is activated or converted into a reactive derivative  and the reaction is performed  under standard conditions as outlined above with respect to the reaction of the compounds of the formulae IIa and IIb with the compounds of the formula III. Likewise  the removal of the Boc group from the compound of the formula XXIII  for example by treatment with trifluoroacetic acid  the cyclization of the obtained compound of the formula XXIII in which the Boc group is replaced with a hydrogen atom  to give the diketopiperazine derivative of the formula XXIV  for example by treatment with an organic base such as an amine like triethylamine  the reduction of the compound of the formula XXIV to give the compound of the formula IIIa  for example by treatment with a metal hydride reducing agent such as lithium aluminium hydride  and  in case a compound of the formula IIIb is to be prepared  the introduction of the group R50  for example by treatment with a chloroformate or a dicarbonate such as di-tert-butyl dicarbonate in case the group R50 in the compound of the formula IIIb is to be an ester group such as an alkyl-O-C(O)-  cycloalkyl-O-C(O)- or cycloalkylalkyl-O-C(O)- group like the Boc group  for example  and the removal of the Bn group  for example by hydrogenation in the presence a transition metal catalyst such as a palladium catalyst like palladium(II) hydroxide on charcoal  can be performed under standard conditions.

In the compounds of the formulae IIIa and IIIb various modifications in the group R and/or on the ring nitrogen atoms can be carried out to give further compounds of the formula III. For example  if the compound of the formula XXI which is employed in the procedure outlined afore  is an (S)-N-tert-butoxycarbonyl-aspartic acid ß alkyl ester such as the ß methyl ester or (S)-N-tert-butoxycarbonyl-aspartic acid ß-benzyl ester  i.e. the group R is the group CH2-C(O)-OCH3 or CH2-C(O)-O-benzyl  for example  in the reduction of the compound of the formula XXIV  for example with lithium aluminium hydride in THF at a temperature of about 60 °C  simultaneously the ß ester group can be reduced to a hydroxymethyl group  and thus the compound of the formula IIIc  i.e. the compound (S)-2-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester  can be obtained in case the introduced group R50 is the Boc group. In the compound of the formula IIIc  in which the hydroxy group can be protected as a silyl ether by treatment with tert-butyl-dimethyl-silyl chloride and later deprotected by treatment with a fluoride such as potassium fluoride  cesium fluoride of tetrabutylammonium fluoride  for example  can the NH group in the ring be protected by introduction of the benzyloxycarbonyl group by treatment with benzyl chloroformate in the presence of a base such as sodium hydrogencarbonate  for example.

In the obtained compound of the formula XXV can the hydroxy group be alkylated to give an alkyl-O- group  or it can be activated  for example by conversion into the methanesulfonate  and reacted with an alkanethiol or a metal cyanide to give a thioether or a nitrile  or it can be oxidized to give the aldehyde of the formula XXVI  for example by treatment with the Dess-Martin periodinane reagent (cf. above). The methanesulfonate of the compound of the formula XXV and the compound of the formula XXVI can also be reacted with other nucleophilic compounds  for example amino compounds  and heterocycles prepared  and the compound of the formula XXVI can be oxidized to the carboxylic acid of the formula XXVII  for example by treatment with sodium chlorite as outlined above with respect to the oxidation of the aldehydes of the formula VI. The compound of the formula XXV can also be oxidized directly to the compound of the formula XXVII  for example by treatment with pyridinium dichromate. The carboxylic acid of the formula XXVII can be activated as outlined above with respect to the compounds of the formulae IIa and IIb and converted into carboxamides and heterocycles  or esterified  for example by treatment with a haloalkane in the presence of a base such as potassium carbonate in a solvent such as a ketone like acetone or butanone to give a compound of the formula XXVIII. The group R56 in the compounds of the formula XXVIII  as well as in the compounds of the formula IIId  is a (C1-C4)-alkyl group such as methyl or ethyl  for example. In the compounds of the XXVIII can the benzyloxycarbonyl group Bn-O-C(O)- be removed by catalytic hydrogenation in the presence of a transition metal catalyst such as palladium on charcoal to give the compounds of the formula IIId  which can then be reacted with the compounds of the formulae IIa and IIb to give compounds of the formulae IVa and IVb. Like in the compounds of the formula XXVIII can in all other compounds  which can be obtained from the compounds of the formula IIIc as outlined afore  the benzyloxycarbonyl group be removed and the respective compounds containing a free NH group reacted with the compounds of the formulae IIa and IIb to give compounds of the formulae IVa and IVb. Further compounds of the formulae IVa and IVb can be obtained by removing the Boc group instead of the benzyloxycarbonyl group  for example by treatment with trifluoroacetic acid  and reacting the obtained compounds with the compounds of the formulae IIa and IIb  and finally removing the benzyloxycarbonyl group.

Besides in the compounds of the formula III  or in the course of the preparation of compounds of the formula III  as outlined afore  can respective modifications of functional groups also be made  or functional groups also be introduced  subsequent to the reaction of the compounds of the formula III with the compounds of the formulae IIa and IIb  i.e. in the compounds of the formulae IVa and IVb. All explanations made afore apply correspondingly to such a synthetic approach. For example  a compound of the formula IIa or IIb can be reacted with the compound of the formula IIIc  wherein in such a reaction the hydroxy group in the compound of the formula IIIc generally is protected  for example as the tert-butyl-dimethyl-silyl ether which has been obtained by treatment with tert-butyl-dimethyl-silyl chloride in the presence of imidazole and later is cleaved by treatment with a fluoride  to give a compound of the formula IVc or IVd. Analogously to the procedures outlined afore  the CH2OH group depicted in the formulae IVc and IVd can be oxidized to the aldehyde group C(O)H by treatment with the Dess-Martin periodinane reagent  and the aldehyde group can in turn be oxidized with sodium chlorite to give the carboxylic acids of the formulae IVe and IVf.

Ra  R20  R30  R40  Y and n in the compounds of the formulae IVc  IVd  IVe and IVf are defined as in the compounds of the formulae IVa and IVb  and Boc is the tert-butyloxycarbonyl group. The compounds of the formulae IVe and IVf are as well obtained by reaction of the compounds of the formula IIId with the compounds of the formulae IIa and IIb and hydrolysis of the ester group C(O)-OR56  for example by treatment with lithium hydroxide in case R56 is methyl or ethyl. The C(O)-OH group depicted in the formulae IVe and IVf can be activated or converted into a reactive derivative as outlined above with respect to the compounds of the formulae IIa and IIb and reacted with an amine of the formula R2-N(R3)-H  in which the groups R2 and R3 are defined as in the compounds of the formulae Ia and Ib and additionally functional groups can be present in protected form or in the form of a precursor group  which is later converted into the final group  to give the respective compounds of the formulae IVe and IVf in which the group C(O)-OH is replaced with the group C(O)-N(R3)-R2  and which can be converted into compounds of the formulae Ia and Ib in which R10 is hydrogen by treatment with trifluoroacetic acid or hydrogen chloride for removal of the Boc group. As another example of modifications of functional groups which can be made in the compounds of the formulae IVc and IVd  the conversion of the hydroxy group depicted in formulae IVc and IVd into an alkoxy group may be mentioned  which can be performed by alkylating a compound of the formula IVc or IVd with a reactive haloalkane  for example a bromoalkane or a iodoalkane  or reacting an alkanol with a compound containing a leaving group instead of the hydroxy group  such as a methanesulfonyloxy group obtained by reaction of the compound of the formula IVc or IVd with methanesulfonyl chloride  for example  in the presence of a base such as potassium carbonate or cesium carbonate in an inert solvent such as a ketone like acetone or butanone or an amide such as DMF or NMP. All explanations relating to the preparation of compounds in which p and q both are 2  one of the groups R is different from hydrogen and all other groups R are hydrogen  apply correspondingly to other compounds.

In order to obtain further compounds of the formulae Ia and Ib  various other transformations of functional groups can be carried out in compounds of the formulae Ia and Ib as well as in the compounds occurring as intermediates in the synthesis of the compounds of the formulae Ia and Ib. With respect to all parts of the molecules it applies that  for example  a hydroxy group can be etherified under standard conditions by alkylation with the respective halogen compound  in particular a bromide or iodide  in the presence of a base such an alkaline metal carbonate in an inert solvent  or with the respective alcohol under the conditions of the Mitsunobu reaction in the presence of an azodicarboxylate like diethyl azodicarboxylate or diisopropyl azodicarboxylate and a phosphine like triphenylphosphine or tributylphosphine in an inert aprotic solvent such as an ether like THF or dioxane (cf. O. Mitsunobu  Synthesis (1981)  1). An amino group can be modified under standard conditions for alkylation  for example by reaction with a halogen compound or by reductive amination of a carbonyl compound  or for acylation  for example by reaction with an activated carboxylic acid or a carboxylic acid derivative like an acid chloride or anhydride. A carboxylic acid group can be activated or converted into a reactive derivative as outlined above and reacted with an alcohol or amine to give an ester or amide. An alkyl S- group can be oxidized with a peroxide like hydrogen peroxide or a peracid to give an alkyl S(O) or alkyl S(O)2 group  and a protected mercapto group can be deprotected and oxidized to give a sulfonic acid which can then be activated and reacted with an amine under standard conditions to give a sulfonamide. Hydroxy groups which have been activated  for example by conversion into the methanesulfonyl or the trifluoromethanesulfonyl derivative  and reactive halogen atoms can be replaced with groups bonded via an oxygen  sulfur  nitrogen or carbon atom in nucleophilic substitution reactions and metal-catalyzed reactions.

As already indicated above  in case the group R50 in the compound of the formulae IVa and IVb has any of the meanings of the group R10 in the compounds of the formulae Ia and Ib and all other groups have the desired meanings comprised by the definition of the compounds of the formulae Ia and Ib  the compounds of the formulae IVa and IVb are already the final compounds of the formulae Ia and Ib. In case R50 is a protective group and a compound of the formula Ia or Ib is to be prepared in which R10 is hydrogen  and/or any other groups are present in protected form or in the form of a precursor group  the compound of the formula IVa or IVb can finally be converted into the desired compound of the formula Ia or Ib by removal of protection groups and/or conversion of any other groups. As already indicated above  in order to avoid an undesired course of a reaction or side reactions  in any one or more steps in the synthesis of the compounds of the formulae Ia and Ib functional groups can generally be present in protected form or in the form of a precursor group. Besides in the final step of the synthesis of a compound of the formula Ia or Ib  protective groups can be removed  and precursor groups can be converted  also at other stages of the synthesis. Respective synthetic strategies and details about suitable protective groups and their introduction and removal are known to a person skilled in the art and are found in P. G. M. Wuts and T. W. Greene  Greene""s Protective Groups in Organic Synthesis  4. ed. (2007)  John Wiley & Sons  for example. Examples of protective groups which may be mentioned in general  are benzyl protective groups such as in benzyl ethers of hydroxy groups and benzyl esters of carboxylic acid groups from which the benzyl group can be removed by catalytic hydrogenation in the presence of a palladium catalyst  tert-butyl protective groups such as in tert-butyl esters of carboxylic acid groups from which the tert-butyl group can be removed by treatment with trifluoroacetic acid  acyl protective groups which can protect hydroxy groups and amino groups in the form of esters and amides and which can be cleaved by acidic or basic hydrolysis  alkyloxycarbonyl protective groups such as in tert-butoxycarbonyl derivatives of amino groups  including the cyclic amino group being part of the diazacycloalkane moiety depicted in formulae Ia and Ib in case R10 is hydrogen  which can be cleaved by treatment with trifluoroacetic acid  and silyl protective groups like tert-butyl-dimethyl-silyl and trimethylsilyl which can protect hydroxy groups in the form of the silyl ethers and which be can cleaved by treatment with a fluoride. Examples of precursor groups which may be mentioned are nitro groups which can be converted to amino groups by catalytic hydrogenation or by reduction with sodium dithionite  for example  and cyano groups which can be converted to carboxamide groups and carboxylic acid groups by hydrolysis.

The reactions carried out in the preparation of the compounds of the formulae Ia and Ib are known per se and can be carried out in a manner familiar to a person skilled in the art by  or analogously to  procedures which are described in the standard literature  for example in Houben-Weyl  Methods of Organic Chemistry  Thieme; Organic Reactions  John Wiley & Sons; or R. C. Larock  Comprehensive Organic Transformations: A Guide to Functional Group Preparations  2. ed. (1999)  John Wiley & Sons  and the references quoted therein.

A subject of the present invention also are the novel starting compounds and intermediates occurring in the synthesis of the compounds of the formulae Ia and Ib  including the compounds of the formulae IIa  IIb  III  IIIa  IIIb  IIId  IVa  IVb  IVc  IVd  IVe  IVf  V  Va  Vb  VI  VII  VIII  IX  X  XI  XII  XIV  XV  XVII  XVIII  XIX  XX  XXI  XXIII  XXIV  XXVI  XXVII  XXVIII  wherein R  Ra  R20  R30  R40  R45  R50  R51  R53  R54  R55  R56  Bn  Boc  X1  Y  n  p and q are defined as above  in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  and their salts  and solvates of any of them  and their use as intermediates. The general explanations  preferred definitions of groups and numbers and embodiments of the invention given above with respect to the compounds of the formulae Ia and Ib apply correspondingly to the said intermediates and starting compounds. A subject of the invention are in particular the novel specific starting compounds and intermediates disclosed herein. Independently thereof whether they are disclosed as a free compound and/or as a specific salt  they are a subject of the invention both in the form of the free compounds and in the form of their salts  and if a specific salt is disclosed  additionally in the form of this specific salt  and in the form of solvates of any of them.

The compounds of the formulae Ia and Ib inhibit the enzyme renin as can be demonstrated in the pharmacological tests described below and in other pharmacological tests which are known to a person skilled in the art  for example in in vitro tests in which the inhibition of human renin is determined  or in animal models in which the antihypertensive activity and other effects are determined in vivo. The compounds of the formulae Ia and Ib are suitable for the treatment of hypertension including pulmonary hypertension  for example  and other disorders of the cardiovascular system and heart diseases  such as heart failure  cardiac infarction  angina pectoris  cardiac insufficiency  cardiac failure  cardiac hypertrophy  cardiac fibrosis  vascular hypertrophy  left ventricular dysfunction  in particular left ventricular dysfunction after myocardial infarction  endothelial dysfunction  ischemic and obstructive peripheral circulation disorders and restenosis including restenosis post-angioplasty  for example  for the treatment of renal diseases such as renal fibrosis  renal ischemia  renal failure and kidney insufficiency  for example  and for the treatment of other diseases  for example diabetes complications  such as nephropathy and retinopathy  cerebral afflictions  such as cerebral hemorrhage  glaucoma  and end-organ damage. The treatment of diseases is to be understood as meaning both the therapy of existing pathological changes or malfunctions of the organism or of existing symptoms with the aim of relief  alleviation or cure  and the prophylaxis or prevention of pathological changes or malfunctions of the organism or of symptoms in humans or animals who are susceptible thereto and are in need of such a prophylaxis or prevention  with the aim of prevention or suppression of their occurrence or of an attenuation in the case of their occurrence. For example  in patients who on account of their disease history are susceptible to ventricular dysfunction after myocardial infarction  by means of the prophylactic or preventive medicinal treatment the occurrence of ventricular dysfunction can be prevented or its extent and sequelae decreased. The treatment of diseases can occur both in acute cases and in chronic cases.

The compounds of the formulae Ia and Ib and their physiologically acceptable salts and physiologically acceptable solvates thereof can therefore be used in animals  in particular in mammals and specifically in humans  as a pharmaceutical or medicament on their own  in mixtures with one another or in the form of pharmaceutical compositions. A subject of the present invention also are the compounds of the formulae Ia and Ib and their physiologically acceptable salts and physiologically acceptable solvates thereof for use as a pharmaceutical  as well as pharmaceutical compositions and medicaments which comprise an efficacious dose of at least one compound of the formula Ia or Ib and/or a physiologically acceptable salt thereof and/or a physiologically acceptable solvate of any of them as an active ingredient and a pharmaceutically acceptable carrier  i.e. one or more pharmaceutically innocuous vehicles and/or excipients. A subject of the present invention furthermore are the compounds of the formulae Ia and Ib and their physiologically acceptable salts and physiologically acceptable solvates thereof for use in the treatment of the diseases mentioned above or below  for example of hypertension  or for the inhibition of renin  as well as the use of the compounds of the formulae Ia and Ib and their physiologically acceptable salts and physiologically acceptable solvates thereof for the manufacture of a medicament for the treatment of the diseases mentioned above or below  for example of hypertension  or for the manufacture of a medicament for the inhibition of renin  wherein the treatment of diseases comprises their therapy and prophylaxis. A subject of the invention also are methods for the treatment of the diseases mentioned above or below  which comprise administering an efficacious amount of at least one compound of the formula Ia or Ib or a physiologically acceptable salt thereof or a physiologically acceptable solvate of any of them to a human or an animal who is in need thereof. The compounds of the formulae Ia and Ib and pharmaceutical compositions and medicaments comprising them can be administered enterally  for example by oral  buccal  sublingual or rectal administration  parenterally  for example by intravenous  intramuscular or subcutaneous injection or infusion  or by another type of administration such as topical  percutaneous  transdermal  intratracheal  intranasal or intraocular administration.

The pharmaceutical compositions and medicaments according to the invention normally contain about 0.5 to about 90 percent by weight of compounds of the formulae Ia and Ib and/or their physiologically acceptable salts and/or physiologically acceptable solvates thereof. The amount of active ingredient of the compound of the formula Ia or Ib and/or its physiologically acceptable salt and/or a physiologically acceptable solvate of any of them in the pharmaceutical compositions and medicaments is in general about 0.2 mg to about 1000 mg  preferably about 0.2 mg to about 500 mg  particularly preferably about 1 mg to about 300 mg  per unit dose. The production of the pharmaceutical compositions and medicaments can be carried out in a manner known per se. For this  the compounds of the formulae Ia and Ib and/or their physiologically acceptable salts and/or physiologically acceptable solvates thereof are mixed together with one or more solid or liquid vehicles and/or excipients  if desired also in combination with one or more other active ingredients such as  for example  an angiotensin converting enzyme inhibitor  an angiotensin receptor antagonist  a diuretic  an endothelin receptor antagonist  an endothelin converting enzyme inhibitor  a neutral endopeptidase inhibitor  a calcium channel blocker  a nitrate like isosorbiddinitrate  a ?-receptor blocker  an ?1-adrenoreceptor antagonist  a cannabinoid receptor antagonist  a potassium channel modulator  a thromboxane synthetase inhibitor  an anti-serotoninergic agent  or another agent useful for treating hypertension  heart failure  vascular diseases related to diabetes or renal diseases such as acute or chronic renal failure  for example  and are brought into a suitable form for dosage and administration which can then be used in human medicine or veterinary medicine. A subject of the present invention also is in particular a pharmaceutical composition which comprises an efficacious dose of at least one compound of the formula Ia or Ib and/or a physiologically acceptable salt thereof and/or a physiologically acceptable solvate of any of them and one or more other active ingredients and a pharmaceutically acceptable carrier  wherein the other active ingredients are useful for the treatment of hypertension  cardiac infarction  heart failure  vascular diseases related to diabetes  end-organ damage such as cardiac insufficiency or kidney insufficiency  renal diseases such as acute or chronic renal failure  restenosis or glaucoma  and wherein as examples of such other active ingredients angiotensin converting enzyme inhibitors  angiotensin receptor antagonists  diuretics  endothelin receptor antagonists  endothelin converting enzyme inhibitors  neutral endopeptidase inhibitors  calcium channel blockers  nitrates like isosorbiddinitrate  ?-receptor blockers  ?1-adrenoreceptor antagonists  cannabinoid receptor antagonists  potassium channel modulators  thromboxane synthetase inhibitors and anti-serotoninergic agents may be mentioned.

As vehicles and excipients  suitable organic and inorganic substances can be used which do not react in an undesired manner with the compounds of the formulae Ia and Ib. Examples which may be mentioned are water  vegetable oils  waxes  alcohols such as ethanol  isopropanol  1 2-propanediol  benzyl alcohols or glycerol  polyols  polyethylene glycols  polypropylene glycols  glycerol triacetate  gelatin  carbohydrates such as lactose or starch  stearic acid and its salts such as magnesium stearate  talc  lanolin  petroleum jelly  or mixtures thereof  for example mixtures of water with one or more organic solvents such as mixtures of water with alcohols. For oral and rectal use  in particular pharmaceutical forms such as  for example  tablets  film-coated tablets  sugar-coated tablets  granules  hard and soft gelatin capsules  suppositories  solutions  preferably oily  alcoholic or aqueous solutions  syrups  juices or drops  furthermore suspensions or emulsions  can be used. For parenteral use  for example by injection or infusion  in particular pharmaceutical forms such as solutions  preferably aqueous solutions  can be used. For topical use  in particular pharmaceutical forms such as ointments  creams  pastes  lotions  gels  sprays  foams  aerosols  solutions or powders can be used. Further suitable pharmaceutical forms are  for example  implants and patches and forms adapted to inhalation. The compounds of the formulae Ia and Ib and their physiologically acceptable salts and physiologically acceptable solvates of any of them can also be lyophilized and the obtained lyophilizates used  for example  for the production of injectable compositions. In particular for topical application  liposomal compositions are also suitable. As examples of types of excipients or additives which can be contained in the pharmaceutical compositions and medicaments  lubricants  preservatives  thickeners  stabilizers  disintegrants  wetting agents  agents for achieving a depot effect  emulsifiers  salts  for example for influencing the osmotic pressure  buffer substances  colorants and flavoring substances may be mentioned. The pharmaceutical compositions and medicaments can also contain one or more other active ingredients and/or  for example  one or more vitamins.

As usual  the dosage of the compounds of the formulae Ia and Ib depends on the circumstances of the specific case and is adjusted by the physician according to the customary rules and procedures. It depends  for example  on the compound of the formula Ia or Ib administered and its potency and duration of action  on the nature and severity of the individual syndrome  on the sex  age  weight and the individual responsiveness of the human or animal to be treated  on whether the treatment is acute or chronic or prophylactic  or on whether further pharmaceutical active compounds are administered in addition to the compound of the formula Ia or Ib. Normally  in the case of administration to an adult weighing about 75 kg  a dose of from about 0.1 mg to about 100 mg per kg per day  preferably from about 1 mg to about 10 mg per kg per day (in each case in mg per kg of body weight)  is sufficient. The daily dose can be administered in the form of a single dose or divided into a number of individual doses  for example two  three or four individual doses. The administration can also be carried out continuously  for example by continuous injection or infusion. Depending on the circumstances of the specific case  it may be necessary to deviate upward or downward from the indicated dosages.

Besides as a pharmaceutical active compound in human medicine and veterinary medicine  the compounds of the formulae Ia and Ib can also be employed as an aid in biochemical investigations or as a scientific tool or for diagnostic purposes  for example in in vitro diagnoses of biological samples  if an inhibition of renin is intended. The compounds of the formulae Ia and Ib and their salts can also be used as intermediates  for example for the preparation of further pharmaceutical active substances.

The following examples illustrate the invention.

When compounds prepared in the examples which contain a basic group  were purified by preparative high pressure liquid chromatography (HPLC) on reversed phase (RP) column material and  as customary  the eluent was a gradient mixture of water and acetonitrile (ACN) containing trifluoroacetic acid (TFA)  they were in general obtained in the form of an acid addition salt with trifluoroacetic acid  depending on the details of the workup such as the lyophilization conditions. Such contained trifluoroacetic acid  whose amount can vary and can be up to about two equivalents of acid in the case of a compound containing two basic groups  for example  is not specified in the names in the headings of the examples and not depicted in the structural formulae  but indicated in the description of the examples. This applies accordingly to compounds which were obtained in the form of another acid addition salt such as an acid addition salt with hydrochloric acid  whose amount can likewise vary and can be up to about two equivalents of acid in the case of a compound containing two basic groups  for example  and which is not specified in the names in the headings of the examples and not depicted in the structural formulae  but indicated in the description of the examples.

Characterization of the compounds
The prepared compounds were in general characterized by spectroscopic data and chromatographic data  in particular mass spectra (MS) and HPLC retention times (Rt; in min) which were obtained by combined analytical HPLC/MS characterization (LC/MS)  and nuclear magnetic resonance (NMR) spectra  by melting points or decomposition points (Mp  in °C) and/or by optical rotations (?  i.e. [?]D20  in ° (degree) at the specified concentration c (in g/100 ml)). Unless specified otherwise  1H-NMR spectra were recorded at 400 MHz and in DMSO-D6 as solvent. In the NMR characterization  the chemical shift d (in ppm)  the number of hydrogen atoms and the multiplicity (s: singlet  d: doublet  dd: double doublet  t: triplet  dt: double triplet  q: quartet  m: multiplet; br: broad) of the peaks are given. In the MS characterization  in general the mass number (m/z) of the peak of the molecular ion (M  for example M+) or of a related ion such as the ion M+1 (protonated molecular ion MH+  i.e. M+1+)  which was formed depending on the ionization method used  is given. Generally  the ionization method was electrospray ionization (ESI). The particulars of the LC/MS methods used were as follows.

LC/MS Method LC1
Column: Waters Acquity BEH C18  50 x 2.1 mm  1.7 µm; flow: 1.0 ml/min; eluent A: water + 0.05 % TFA; eluent B: ACN + 0.035 % TFA; gradient: from 98 % A + 2 % B to 0 % A + 100 % B within 1.6 min  then 0 % A + 100 % B for 1.5 min  then to 98 % A + 2 % B within 3.0 min; MS ionization method: ESI+

LC/MS Method LC2
Column: Waters XBridge C18  30 x 4.6 mm  3 µm; flow: 1.0 ml/min; eluent A: water + 0.1 % formic acid; eluent B: ACN + 0.01 % formic acid; gradient: from 95 % A + 5 % B to 0 % A + 100 % B within 5.5 min  then 0 % A + 100 % B for 2 min  then to 95 % A + 5 % B within 8 min; MS ionization method: ESI+

LC/MS Method LC3
Column: YMC J""sphere ODS H80  20 x 2.1 mm  4 µm; flow: 1 ml/min; eluent A: water + 0.05 % TFA; eluent B: ACN; gradient: from 96 % A + 4 % B to 5 % A + 95 % B within 2 min  then 5 % A + 95 % B for 0.4 min  then to 96 % A + 4 % B within 0.05 min; MS ionization method: ESI+

LC/MS Method LC4
Column: Luna C18  10 x 2 mm  3 µm; flow: 1.1 ml/min; eluent A: water + 0.05 % TFA; eluent B: ACN + 0.05 % TFA; gradient: from 93 % A + 7 % B to 5 % A + 95 % B within 1.2 min  then 5 % A + 95 % B for 0.2 min  then to 93 % A + 7 % B within 0.05 min; MS ionization method: ESI+

Abbreviations
ACN acetonitrile
DBU 1 8-diazabicyclo[5.4.0]undec-7-ene
DCM dichloromethane
DMF dimethylformamide
DMSO dimethyl sulfoxide
EA ethyl acetate
EDIA ethyl-diisopropylamine
HEP n-heptane
MOH methanol
NMP N-methylpyrrolidin-2-one
TBTU O-(benzotriazol-1-yl)-N N N"" N""-tetramethyluronium tetrafluoroborate
TFA trifluoroacetic acid
THF tetrahydrofuran

Example 1
[2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizin-3-yl]-piperazin-1-yl-methanone

Step 1: 1-Chloro-3-(3-fluoro-2-methyl-phenyl)-propan-2-one
0.867 g (35.67 mmol) of magnesium turnings were dried and suspended in 17 ml of anhydrous THF under argon. A solution of 1 2-dibromoethane (0.14 ml  1.62 mmol) and 2-bromo-6-fluoro-toluene (6.74 g  35.67 mmol) in 17 ml of anhydrous THF was then added dropwise so as to maintain a gentle reflux. Once the magnesium had been consumed  copper(I) iodide (0.432 g  2.27 mmol) was then added  followed by a solution of epichlorohydrine (3.00 g  32.42 mmol) in DMF (8 ml). The mixture was stirred for 3.5 h at room temperature and then quenched with a saturated solution of ammonium chloride (120 ml). The organic layer was separated  and the aqueous phase was extracted twice with EA. The combined organic phases were washed twice with a saturated solution of ammonium chloride  dried over sodium sulfate  filtered and evaporated to dryness. The product was purified by chromatography on silica gel (cyclohexane/EA  from 100:0 to 90:10) to give 6.89 g of 1-chloro-3-(3-fluoro-2-methyl-phenyl)-propan-2-ol. 3.92 g (16.23 mmol) of this alcohol were dissolved in DCM under argon  and 1 1 1-triacetoxy-1 1-dihydro-1 2-benziodoxol-3(1H)-one (Dess-Martin periodinane reagent; 7.57 g  16.23 mmol) was added. The mixture was stirred at room temperature overnight and then diethyl ether (150 ml) was added. The mixture was washed three times with 1 N hydrochloric acid (70 ml) and twice with a saturated solution of sodium chloride  and extracted with ether. The extracts were dried over sodium sulfate  filtered and evaporated to dryness. 2.69 g of the title compound were obtained as a white powder.

Step 2: 1-Bromo-3-(3-fluoro-2-methyl-phenyl)-propan-2-one
The compound of step 1 (3.20 g  15.95 mmol) was dissolved in acetone (70 ml)  and lithium bromide (11.08 g  127.59 mmol) was added. The mixture was stirred overnight. The solvent was evaporated  the resulting solid was dissolved in EA and the solution washed twice with water followed by a saturated solution of sodium chloride  dried over sodium sulfate  filtered and evaporated to dryness. 3.66 g of the title compound were obtained as a white powder.

Step 3: 2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizine
The compound of step 2 (1.50 g  6.12 mmol) and 2-benzyl-pyridine (2.071 g  12.24 mmol) were dissolved in acetone (30 ml) and the mixture was stirred under reflux overnight. The mixture was concentrated to dryness and the residue was purified by chromatography on silica gel (cyclohexane) to give 0.653 g of the title compound.

Step 4: [2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizin-3-yl]-piperazin-1-yl-methanone
The compound of step 3 (0.635 g  2.01 mmol) was dissolved in DCM (5 ml) under argon and cooled at 0°C. Pyridine (0.16 ml  2.01 mmol) and triphosgene (0.598 g  2.01 mmol) were added  and the mixture was stirred at room temperature for 80 min. The mixture was then added dropwise to a solution of 1-tert-butoxycarbonyl-piperazine (1.50 g  8.05 mmol) and triethylamine (1.12 ml  8.05 mmol) in DCM (15 ml) cooled to 0°C. After stirring at room temperature overnight  the mixture was diluted with 1 N hydrochloric acid and extracted with DCM. The extracts were washed with a saturated solution of sodium hydrogencarbonate and twice washed with saturated solution of sodium chloride. The organic phase was dried over sodium sulfate  filtered and evaporated to dryness. The residue was purified by silica gel chromatography with DCM/MOH (from 100:0 to 98:2) and subsequent silica gel chromatography with cyclohexane/EA (from 100:0 to 70:30) to give 0.815 g of 4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizin-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester as a light pink powder. For removal of the tert-butoxycarbonyl group and conversion into the hydrochloride  0.689 g of the obtained product were dissolved in DCM (10 ml)  the solution cooled to 0 °C and saturated with gaseous hydrogen chloride. After stirring for 1 h at 0 °C  the mixture was evaporated to dryness. The residue was triturated with diethyl ether  filtered  washed with diethyl ether and dried under reduced pressure to give 0.53 g of the title compound in the form of [2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizin-3-yl]-piperazin-1-yl-methanone hydrochloride as an off-white powder with the following characteristics:
Mp: 263 °C
LC/MS (Method LC 1): m/z = 428 [MH+]; Rt = 1.10 min
1H-NMR: ? (ppm) = 2.00 (s  3H)  2.85 (m  2H)  3.11 (m  2H)  3.48 (m  2H)  3.76 (m  2H)  4.12 (s  2H)  6.68 (d  1H)  6.88 (t  1H)  6.95 (m  2H)  7.02 (m  1H)  7.35 (m  3H)  7.49 (m  3H)  8.32 (d  1H)  9.40 (br s  1H)

Example 2
[1-Cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-indolizin-3-yl]-piperazin-1-yl-methanone

Step 1: 2-Cyclohexylmethyl-pyridine
Following a modified version of the procedure given in J. M. Ontoria et al.  Bioorg. Med. Chem. Lett. 16 (2006)  4026  a solution of 2-methyl-pyridine (0.50 g  5.37 mmol) in 10 ml of anhydrous THF was cooled to -78 °C under an atmosphere of argon. n-Butyllithium (2.36 ml of a 2.5 M solution in hexane  5.91 mmol) was added dropwise and the solution was stirred at -78 °C for 1 h. 3-bromo-cyclohexene (0.68 ml  5.91 mmol) was added then dropwise and the temperature was allowed to rise to ambient temperature over 3 h. After stirring overnight  the mixture was quenched by addition of 20 ml of water and extracted twice with EA. The combined organic phases were washed with a saturated solution of sodium chloride  dried over sodium sulfate  filtered and evaporated to dryness to give 0.436 g of 2-(cyclohex-2-en-1-ylmethyl)-pyridine as an orange oil. This product was dissolved in 8.4 ml of ethanol  5 % palladium on charcoal (50 % in water; 0.087 g) was added  and the mixture was hydrogenated under a hydrogen pressure of 3.2 bar for 4 h at room temperature. The catalyst was then filtered off and the filtrate was evaporated to dryness under reduced pressure to give 0.415 g of the title compound as an oil.

Step 2: 1-Cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-indolizine
The compound of step 1 (0.415 g  2.37 mmol) and the compound of step 2 of example 1 (0.58 g  2.37 mmol) were dissolved in 15 ml of acetone and the solution was stirred under reflux for 36 h. The solution was evaporated to dryness and the solid (0.92 g) dissolved in 10 ml of isopropanol. Sodium carbonate (0.70 g  6.57 mmol) was added  the mixture was stirred under reflux for 2 h and then evaporated to dryness under reduced pressure. The residue was taken up in DCM and water  and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over sodium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (HEP/EA  100:0  then 70:30) to give 0.489 g of the title compound as a thick yellow oil.

Step 3: [1-Cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-indolizin-3-yl]-piperazin-1-yl-methanone
The compound of step 2 (0.488 g  1.52 mmol) was dissolved in DCM (15.2 ml) under argon and cooled at 0 °C. Pyridine (0.12 ml  1.52 mmol) and triphosgene (0.45 g  1.52 mmol) were added and the mixture stirred at room temperature for 2 h. The mixture was then cooled to 0 °C and triethylamine (0.85 ml  6.07 mmol) and 1-tert-butoxycarbonyl-piperazine (1.13 g  6.07 mmol) were added. The mixture was stirred at room temperature overnight  then diluted with 1 N hydrochloric acid and extracted with DCM. The organic phases were washed with a saturated solution of sodium hydrogencarbonate and twice with a saturated solution of sodium chloride  dried over sodium sulfate  filtered and evaporated to dryness. The residue was purified by silica gel chromatography (cyclohexane/EA  100:0  then 50:50) to give 0.686 g of 4-[1-cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-indolizine-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester as a beige foam. The obtained product was dissolved in 10 ml of DCM  the solution cooled to 0 °C under a nitrogen atmosphere and a solution of TFA (1.91 ml  25.7 mmol) in 1.91 ml of DCM added. After stirring at room temperature overnight  the mixture was evaporated to dryness under reduced pressure and the residue two times admixed with toluene and evaporated to dryness again. The residue was purified by chromatography on silica gel (DCM/MOH  9:1  containing 1 % of ammonia) to give 0.600 g of [1-cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-indolizin-3-yl]-piperazin-1-yl-methanone. For conversion into the hydrochloride  the obtained product was dissolved in 15 ml of DCM and a 4 N solution of hydrogen chloride in dioxane (0.69 ml  2.77 mmol) was added. The solution was stirred for 1 h at room temperature and concentrated to dryness under reduced pressure. The solid was triturated three times with diethyl ether  filtered and dried in vacuo at 65 °C to give 0.422 g of the title compound in the form of [1-cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-indolizin-3-yl]-piperazin-1-yl-methanone hydrochloride as an off-white powder with the following characteristics:
Mp: 317-318 °C
LC/MS (Method LC2): m/z = 434.2 [MH+]; Rt = 4.10 min
1H-NMR: ? (ppm) = 1.0-1.25 (m  3H)  1.45 (m  2H)  1.61 (m  5H)  2.13 (s  3H)  2.47 (m  1H)  2.78 (m  2H)  3.01 (m  2H)  3.35 (m  2H)  3.56 (m  2H)  3.94 (s  2H)  6.52 (m  2H)  7.02 (m  1H)  6.90 (m  1H)  6.98 (m  1H)  7.55 (d  1H)  8.09 (d  1H)  9.08 (br s  2H)

Example 3
[2-(2-Chloro-6-fluoro-benzyl)-1-phenyl-indolizin-3-yl]-piperazin-1-yl-methanone

Step 1: 1-Bromo-3-(2-chloro-6-fluoro-phenyl)-2-propanone
To a 2 M solution of trimethylsilyl-diazomethane in hexane (6.54 ml  13.07 mmol) cooled to 0 °C under argon was added dropwise a solution of 2-chloro-6-fluoro-phenylacetyl chloride (1.23 g  5.94 mmol) in 24 ml of a mixture of THF and ACN (1:1). The mixture was stirred at 0 °C for 5 h. Then 48 % aqueous hydrobromic acid (5.91 ml  52.28 mmol) was added dropwise and the solution was stirred at room temperature overnight. Then 40 ml of water were added. The aqueous phase was extracted twice with EA  and the combined organic phases were washed with water  a saturated solution of sodium hydrogencarbonate and brine  dried over sodium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA  100:0  then 95:5) to give 1.20 g of the title compound as a white powder having a melting point of 47 °C.

Step 2: 2-(2-Chloro-6-fluoro-benzyl)-1-phenyl-indolizine
The compound of step 1 (1.17 g  4.41 mmol) and 2-benzyl-pyridine (1.49 g  8.82 mmol) were dissolved in acetone (15 ml) and the mixture was stirred under reflux overnight. The mixture was concentrated to dryness and the residue was purified by chromatography on silica gel (DCM/MOH  100:0  then 95:5) to give 1.13 g of the title compound.

Step 3: 4-[2-(2-Chloro-6-fluoro-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester
The compound of step 2 (0.576 g  1.72 mmol) was dissolved in DCM (8 ml) under argon and cooled at 0 °C. Pyridine (0.14 ml  1.72 mmol) and triphosgene (0.509 g  1.72 mmol) were added and the mixture was stirred at room temperature for 2 h. The mixture was then added dropwise to a solution of 1-tert-butoxycarbonyl-piperazine (1.28 g  6.85 mmol) and triethylamine (0.86 ml  6.85 mmol) in DCM (8 ml) cooled to 0 °C. The mixture stirred at room temperature overnight  then diluted with 1 N hydrochloric acid and extracted with DCM. The combined organic phases were washed with a saturated sodium hydrogencarbonate solution and twice with a saturated sodium chloride solution  were dried over sodium sulfate  filtered and evaporated to dryness. The residue was purified by silica gel chromatography (cyclohexane/EA  100:0  then 75:25) to give 0.895 g of the title compound as an off-white powder.

Step 4: [2-(2-Chloro-6-fluoro-benzyl)-1-phenyl-indolizin-3-yl]-piperazin-1-yl-methanone
The compound of step 3 (0.886 g  1.62 mmol) was dissolved in DCM (6.5 ml). The solution was cooled at 0°C and a 4 N solution of hydrogen chloride in dioxane (2.02 ml  8.08 mmol) was added. After stirring overnight at room temperature  the mixture was concentrated to dryness. The residue was triturated several times with diethyl ether  filtered  rinsed with diethyl ether and dried in a vacuo at 65 °C to give 0.70 g of the title compound in the form of [2-(2-chloro-6-fluoro-benzyl)-1-phenyl-indolizin-3-yl]-piperazin-1-yl-methanone hydrochloride as an off-white powder with the following characteristics:
Mp: 304 °C
LC/MS (method LC1): m/z = 448 [MH+]; Rt = 1.05 min
1H-NMR: ? (ppm) = 3.01 (m  2H)  3.11 (m  2H)  3.35 (m  6H)  3.73 (m  2H)  4.21 (s  2H)  6.73 (t  1H)  6.88 (dd  1H)  6.98 (t  1H)  7.10 (d  1H)  7.18 (q  1H)  7.38 (m  3H)  8.23 (d  1H)  9.35 (br s  2H)

Example 4
2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-3-(piperazine-1-carbonyl)-indolizine-7-carboxylic acid methylamide

Step 1: Methyl 2-benzyl-pyridine-4-carboxylate
To 35 ml of anhydrous DMF under argon in a sealed tube were added tripotassium phosphate (9.28 g  43.71 mmol)  2-dicyclohexylphosphino-2"" 6""-dimethoxy-biphenyl (SPhos  0.239 g  0.58 mmol)  palladium(II) acetate (0.065 g  0.29 mmol) and then methyl 2-chloro-pyridine-4-carboxylate (2.50 g  14.57 mmol) and B-benzyl-9-borabicyclo[3.3.1]nonane (6.80 g  32.05 mmol). The mixture was heated overnight at 60 °C. After cooling to room temperature  the mixture was diluted into 200 ml of EA  the solution washed three times with 100 ml of a 1 N sodium hydroxide solution and twice with 100 ml of brine. The organic phase was dried over sodium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was then purified by chromatography on silica gel (cyclohexane/EA  100:0  then 80:20) to give 2.784 g of the title compound as an orange oil.

Step 2: Methyl-2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-7-carboxylate
The compound of step 1 (1.555 g  6.84 mmol) and the compound of example 1  step 2 (1.677 g  6.84 mmol) were dissolved in 28.5 ml of acetone and the solution was heated to reflux overnight. The mixture was then evaporated to dryness under reduced pressure and the residue dissolved in 28.5 ml of isopropanol. Sodium carbonate (2.176 g  20.53 mmol) was added and the mixture was heated at 105 °C with stirring for 2 h. The solids were filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA  100:0  then 95:5) to give 0.497 g of the title compound as a yellow solid melting at 55 °C.

Step 3: Methyl-2-(3-fluoro-2-methyl-benzyl)-3-formyl-1-phenyl-indolizine-7-carboxylate
To phosphorus oxychloride (0.35 ml  3.82 mmol) cooled at 0 °C under argon  was added dropwise anhydrous DMF (0.34 ml  4.46 mmol) and the mixture was stirred for 5 min forming a precipitate. 1.5 ml of DMF were added and stirring was continued at 0 °C for 15 min. To this mixture was added dropwise a solution of the compound of step 2 (0.476 g  1.27 mmol) in 5 ml of DMF  and the mixture was heated at 60 °C for 1.5 h and then stirred at room temperature overnight. A solution of sodium acetate (0.837 g) in 6.5 ml water was added  the mixture was heated at 50 °C for 1 h  and evaporated to dryness under reduced pressure. The residue was dissolved in EA  the solution was washed with a saturated solution of sodium hydrogencarbonate  water and brine  dried over sodium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA  100:0  then 90:10) to give 0.297 g of the title compound.

Step 4: 2-(3-fluoro-2-methyl-benzyl)-7-methoxycarbonyl-1-phenyl-indolizine-3-carboxylic acid
The compound of step 3 (0.293 g  0.73 mmol) was suspended in 4 ml of tert-butanol and cooled to 0 °C. To this suspension were added a solution of sodium dihydrogenphosphate (0.263 g  2.19 mmol) in 1 ml of water  a 2 M solution of 2-methyl-2-butene in THF (2.19 ml  4.38 mmol) and sodium chlorite (0.124 g  1.09 mmol) in small portions. After stirring at room temperature for 18 h  once more a solution of sodium dihydrogenphosphate (0.263 g  2.19 mmol) in 2 ml water  a 2 M solution of 2-methyl-2-butene in THF (2.19 ml  4.38 mmol) and sodium chlorite (0.124 g  1.09 mmol) were added again and stirring was continued for an additional 48 h. Then 30 ml of a 1:1 mixture of brine and EA were added  the organic phase was separated  and the aqueous phase was extracted with EA. The combined organic phases were washed with brine  dried over sodium sulfate  filtered and evaporated to dryness under reduced pressure to give 0.420 g of the crude title compound as a yellow powder which was directly used in the next step.

Step 5: 3-(4-tert-Butoxycarbonyl-piperazine-1-carbonyl)-2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-7-carboxylic acid methyl ester
To a solution of the crude compound obtained in step 4 (0.420 g  0.69 mmol)  1-tert-butoxycarbonyl-piperazine (0.142 g  0.76 mmol) and triethylamine (0.48 ml  2.78 mmol) in 3.5 ml of DMF cooled at 0 °C  was added TBTU (0.490 g  1.53 mmol) in small portions  and the mixture was stirred at room temperature overnight. 10 ml of EA and 20 ml of brine were then added  the aqueous phase was separated and extracted twice with EA. The combined organic phases were washed with water  1 N hydrochloric acid  water  an saturated solution of sodium hydrogencarbonate and brine  dried over sodium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA  100:0  then 70:30) to give 0.162 g of the title compound as a beige solid.

Step 6: 3-(4-tert-Butoxycarbonyl-piperazine-1-carbonyl)-2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-7-carboxylic acid
The compound of step 5 (0.159 g  0.27 mmol) was dissolved in 2 ml of dioxane  and a solution of lithium hydroxide hydrate (0.034 g  0.82 mmol) in 0.8 ml water was added. The solution was stirred at 50 °C overnight. The solvents were then evaporated under reduced pressure  the residue was dissolved in 6 ml of water and acidified to pH 1 with 1 N hydrochloric acid. The product was filtered off  dissolved in EA and the solution washed with brine. The organic phase was dried over sodium sulfate  filtered and evaporated to give 0.139 g of the title compound as a light-brown powder.

Step 7: 4-[2-(3-fluoro-2-methyl-benzyl)-7-methylcarbamoyl-1-phenyl-indolizine-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester
The compound of step 6 (0.139 g  0.24 mmol)  methylamine hydrochloride (0.022 g  0.32 mmol) and triethylamine (0.17 ml  0.97 mmol) were dissolved in 2 ml of DMF and cooled to 0 °C. TBTU (0.195 g  0.61 mmol) was added and the solution was stirred at room temperature overnight. Water (8 ml) was then added and the mixture was extracted three times with EA. The combined organic phases were washed with 1 N hydrochloric acid  water  a saturated solution of sodium hydrogencarbonate and brine  dried over sodium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (DCM/MOH  100:0  then 96:4) to give 0.065 g of the title compound as a beige solid.

Step 8: 2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-3-(piperazine-1-carbonyl)-indolizine-7-carboxylic acid methylamide
The compound of step 7 (0.065 g  0.11 mmol) was dissolved in 1.1 ml of DCM and cooled to 0 °C and a 4 N solution of hydrogen chloride in dioxane (0.54 ml  2.20 mmol) was added. The mixture was stirred at room temperature overnight and then evaporated to dryness under reduced pressure. The obtained solid was triturated several times with diethyl ether and dried in vacuo at 40 °C. 0.053 g of the title compound were obtained in the form of 2-(3-fluoro-2-methyl-benzyl)-1-phenyl-3-(piperazine-1-carbonyl)-indolizine-7-carboxylic acid methylamide hydrochloride as a light yellow solid with the following characteristics:
Mp: 205 °C
LC/MS (method LC1): m/z = 485 [MH+]; Rt = 0.94 min
1H-NMR: ? (ppm) = 1.85 (s  3H)  2.68 (d  3H)  2.73 (m  2H)  3.03 (m  2H)  3.39 (m  2H)  3.59 (m  2H)  4.0 (s  2H)  5.57 (d  1H)  6.81 (t  1H)  6.92 (q  1H)  7.09 (dd  1H)  7.30 (m  3H)  7.39 (m  2H)  7.89 (d  1H)  8.08 (dd  1H)  8.46 (dd  1H)  9.04 (br s  2H)

Example 5
[2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizin-3-yl]-[(S)-3-(2-hydroxy-ethyl)-piperazin-1]-yl-methanone

Step 1: (S)-4-Benzyl-2-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester
Di-tert-butyl dicarbonate (8.737 g  40.3 mmol) was added to a solution of (S)-4-benzyl-piperazine-2-ethanol (prepared from methyl N-benzyl-glycinate and N-tert-butoxycarbonyl-L-aspartic acid ?-methyl ester according to WO 2005/026177; 5.88 g  26.69 mmol) in 130 ml of DCM. The solution was stirred at room temperature overnight and then evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA  100:0  then 70:30) to give 6.711 g of the title compound as a colorless oil.

Step 2: (S)-2-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester
To a solution of the compound of step 1 (6.675 g  20.83 mmol) in 100 ml of ethanol was added 0.293 g of 20 % palladium hydroxide on charcoal and the solution was hydrogenated under a hydrogen pressure of 4 bar at room temperature overnight. The catalyst was filtered off and the filtrate was evaporated to dryness to give 4.636 g of the title compound as a grey oil.

Step 3: (S)-2-[2-(tert-butyl-dimethyl-silyloxy)-ethyl)-piperazine-1-carboxylic acid tert-butyl ester
Tert-butyl-dimethyl-silyl chloride (3.62 g  24.02 mmol) and imidazole (3.27 g  48.03 mmol) were added to a solution of the compound of step 2 (4.609 g  20.01 mmol) in 75 ml of DCM and the resulting solution was stirred at room temperature for 3 h. The mixture was washed with 50 ml of water and then 50 ml of brine. The aqueous phase was extracted once with DCM. The combined organic phases were dried over sodium sulfate  filtered and evaporated under reduced pressure to give 6.90 g of the title compound as a pale yellow oil.

Step 4: (S)-2-[2-(tert-Butyl-dimethyl-silyloxy)-ethyl]-4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester
The compound of example 1  step 3 (1.00 g  3.17 mmol) was dissolved in 15 ml of DCM and cooled to 0 °C. To this solution was added pyridine (0.26 ml  3.17 mmol) and a 20 % solution of phosgene in toluene (1.67 ml  3.17 mmol) and the mixture was stirred for 2.5 h at room temperature. This solution was then added dropwise to a solution of the compound of step 3 (1.202 g  3.49 mmol) in 25 ml of DCM containing triethylamine (0.44 ml  3.49 mmol) and the mixture stirred overnight at room temperature. DCM (25 ml) was added and the solution was washed with 25 ml of 0.5 N hydrochloric acid  25 ml of a saturated solution of sodium hydrogencarbonate and 25 ml of brine. The organic phase was dried over sodium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA  85:15  then 80:20) to give 1.33 g of the title compound as an off-white powder melting at 70 °C.

Step 5: (S)-4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-2-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester
A 1 M solution of tetrabutylammonium fluoride in THF (2.82 ml  2.82 mmol) was added to a solution of the compound of step 4 (1.29 g  1.88 mmol) in 7.5 ml of THF cooled to 0 °C under argon. The mixture was stirred at room temperature for 2 h and then 100 ml of a saturated solution of ammonium chloride were added. The solution was extracted twice with 50 ml each of EA  and the combined organic phases were washed with brine  dried over sodium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (DCM/MOH  100:0  then 98:2) to give 1.069 g of the title compound as an off-white powder melting at 85 °C.

Step 6: [2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizin-3-yl]-[(S)-3-(2-hydroxy-ethyl)-piperazin-1]-yl-methanone
To a solution of the compound of step 5 (0.10 g  0.17 mmol) in 1.75 ml of DCM cooled to 0°C was added a 4 N solution of hydrogen chloride in dioxane (0.87 ml  3.50 mmol). The mixture stirred at room temperature for 3.5 h and then evaporated to dryness. The obtained solid was triturated several times with diethyl ether and dried in vacuo at 60 °C to give 0.070 g of the title compound in the form of [2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizin-3-yl]-[(S)-3-(2-hydroxy-ethyl)-piperazin-1]-yl-methanone hydrochloride as an off-white powder with the following characteristics:
Mp: 202 °C
LC/MS (method LC1): m/z = 472 [MH+]; Rt = 1.07 min
1H-NMR: ? (ppm) = 1.68 (m  2H)  2.0 (d  3H)  2.95 (m  1H)  3.21 (m  3H)  3.50 (m  3H)  3.85 (m  1H)  4.10 (m  3H)  4.86 (br s  1H)  6.64 (m  1H)  6.80 (dd  1H)  6.97 (m  3H)  7.48 (m  6H)  8.30 (m  1H)  9.21 (br s  2H)
? = -0.291 ° (c = 4.7 g/100 ml  MOH)

Example 6
2-{(S)-4-[2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazin-2-yl}-N-(tetrahydropyran-4-ylmethyl)-acetamide

Step 1: (S)-4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-2-(2-oxo-ethyl)-piperazine-1-carboxylic acid tert-butyl ester
To a solution of the compound of example 5  step 5 (0.955 g  1.67 mmol) in 10 ml of DCM under argon was added 1 1 1-triacetoxy-1 1-dihydro-1 2-benziodoxol-3(1H)-one (7.78 g  1.84 mmol). The mixture was stirred at room temperature for 3.5 h and then diluted with 40 ml of diethyl ether. The solution was washed three times with a 1 N solution of sodium hydroxide (15 ml) and twice with brine (15 ml). The organic phase was dried over sodium sulfate  filtered and evaporated to dryness under reduced pressure to give 0.965 g of the title compound as a green powder which was directly used in the next step.

Step 2: {(S)-1-tert-Butoxycarbonyl-4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazin-2-yl}-acetic acid
The compound obtained in step 1 (0.960 g  1.69 mmol) was suspended in 9.6 ml of tert-butanol and cooled to 0 °C. A solution of sodium dihydrogenphosphate (0.607 g  5.06 mmol) in 2.4 ml or water  a 2 M solution of 2-methyl-but-2-ene in THF (5.06 ml  10.11 mmol) and sodium chlorite (0.286 g  2.53 mmol) were then added and the mixture was stirred for 3.75 h. Brine (30 ml) was added and the mixture was extracted three times with EA. The combined organic phases were washed twice with 1 N hydrochloric acid and once with brine  dried over sodium sulfate  filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (DCM/MOH  100:0  then 96:4) to give 0.398 g of the title compound.

Step 3: (S)-4-[2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-2-{[(tetrahydropyran-4-ylmethyl)-carbamoyl]-methyl}-piperazine-1-carboxylic acid tert-butyl ester
To a stirred  ice-cold solution of 4-aminomethyl-tetrahydropyran (0.047 g  0.40 mmol)  EDIA (0.19 ml  1.08 mmol) and the compound of step 2 (0.190 g  0.27 mmol) was added TBTU (0.259 g  0.81 mmol) in small portions. The solution was stirred at room temperature for 18 h. Then water (8 ml) was added and the mixture was extracted 3 times with EA. The combined organic phases were washed with 1 N hydrochloric acid  water  a saturated solution of sodium hydrogencarbonate and brine  dried over sodium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA  100:0  then 50:50) to give 0.117 g of the title compound as an orange gum.

Step 4: 2-{(S)-4-[2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazin-2-yl}-N-(tetrahydropyran-4-ylmethyl)-acetamide
To a solution of the compound of step 3 (0.113 g  0.17 mmol) in 1.65 ml of DCM cooled to 0 °C was added a 4 N solution of hydrogen chloride in dioxane (0.41 ml  1.65 mmol). The mixture was stirred for 3 h at room temperature and then evaporated to dryness. The solid was triturated several times with diethyl ether and dried in vacuo at 40 °C to give 0.071 g of the title compound in the form of 2-{(S)-4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazin-2-yl}-N-(tetrahydropyran-4-ylmethyl)-acetamide hydrochloride with the following characteristics:
Mp: 147 °C
LC/MS (method LC1): m/z = 583 [MH+]; Rt = 1.10 min
1H-NMR: ? (ppm) = 1.15 (m  3H)  1.54 (m  3H)  1.60 (m  1H)  1.97 and 2.03 (two s  1H)  2.51 (m  2H)  2.98 (m  5H)  3.2 (m  4H)  3.81 (m  4H)  4.15 (m  2H)  6.60 (t  1H)  6.78 (dd  1H)  6.92 (m  4H)  7.40 (m  6H)  8.18 (m  2H)  8.35 (m  1H)  9.13 (br s  2H)
?: -2.69 ° (c = 0.346 g/100 ml  MOH)

Example 7
3-(2-{(S)-4-[2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazin-2-yl}-acetylamino)-2 2-dimethyl-propionamide

Step 1: [(S)-4-Benzyloxycarbonyl-1-tert-butoxycarbonyl-piperazin-2-yl]-acetic acid
(S)-2-(2-Hydroxy-ethyl)-piperazine-1 4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (cf. WO 96/31501; S. Fustero et al.  Org. Lett. 9 (2007)  5283; 2.862 g  7.85 mmol) was dissolved in 78.5 ml of DCM and pyridinium dichromate (14.772 g  39.27 mmol) was added. The mixture was stirred at room temperature overnight  then diluted into brine (330 ml) and extracted three times with EA (70 ml). The combined organic phases were washed with water (300 ml)  filtered over diatomaceous earth  dried over sodium sulfate  filtered and evaporated to dryness under reduced pressure. The product was dissolved in EA and extracted thee times with a 1 N solution of sodium hydroxide. The combined aqueous phases were acidified to pH 1 with 6 N hydrochloric acid  extracted with EA and the combined extracts were washed with water and brine  dried over sodium sulfate  filtered and evaporated to dryness. 2.226 g of the title compound were obtained as a thick colorless oil.

Step 2: (S)-2-Methoxycarbonylmethyl-piperazine-1 4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester
To a solution of the compound of step 1 (2.52 g  6.66 mmol) in 45 ml of acetone were added potassium carbonate (5.522 g  39.96 mmol) and iodomethane (1.24 ml  19.98 mmol) and the solution was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated to dryness. The residue was dissolved in EA  washed twice with brine  dried over sodium sulfate  filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA  100:0  then 85:15) to give 2.334 g of the title compound as a colorless oil.

Step 3: (S)-2-Methoxycarbonylmethyl-piperazine-1-carboxylic acid tert-butyl ester
To the compound of step 2 (2.317 g  5.90 mmol) in 40 ml of MOH was added 0.063 g of 10 % palladium on charcoal and the mixture was hydrogenated under a hydrogen pressure of 4 bar for 45 min at room temperature. The catalyst was filtered off and the filtrate evaporated to dryness under reduced pressure. 1.488 g of the title compound were obtained as a pale grey oil.

Step 4: (S)-4-[2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-2-methoxycarbonylmethyl-piperazine-1-carboxylic acid tert-butyl ester
To a solution of the compound of example 1  step 3 (1.32 g  4.19 mmol) in 20 ml of DCM at 0 °C were added pyridine (0.34 ml  4.19 mmol) and then a 20 % solution of phosgene in toluene (2.20 ml  4.19 mmol). The mixture was stirred at room temperature for 1.5 h and then added dropwise to an ice-cooled (0 °C) solution of the compound of step 3 (1.189 g  4.60 mmol) and triethylamine (0.58 ml  4.60 mmol) in 32 ml of DCM. The mixture was stirred at room temperature overnight  then diluted with 30 ml of DCM and washed twice with 1 N hydrochloric acid  twice with a saturated sodium hydrogencarbonate solution and twice with brine. The organic phase was dried over sodium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA  80:20  then 70:30) to give 1.44 g of the title compound as a pale yellow-green powder.

Step 5: {(S)-1-tert-Butoxycarbonyl-4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazin-2-yl}-acetic acid
To a solution of the compound of step 4 (1.40 g  2.33 mmol) in 15.5 ml of dioxane was added 3.5 ml of a 1 M aqueous solution of lithium hydroxide and the mixture was heated at 50 °C for 1 h. The solvents were evaporated under reduced pressure and the residue was dissolved in 45 ml of water. The solution was cooled to 0 °C and acidified to pH 2 with 5 N hydrochloric acid. The obtained suspension was extracted with EA and the combined organic phases were washed with brine  dried over sodium sulfate  filtered and evaporated to dryness. 1.37 g of the title compound were obtained as a green solid melting at 103-105 °C.

Step 6: (S)-2-[(2-Carbamoyl-2-methyl-propylcarbamoyl)-methyl]-4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester
The compound of step 5 (0.176 g  0.30 mmol) was dissolved in 2.5 ml of anhydrous DCM at 0 °C. 3-Amino-2 2-dimethyl-propionamide (0.044 g  0.38 mmol)  EDIA (0.13 ml  0.75 mmol) and TBTU (0.120 g  0.38 mmol) were added and the solution was stirred at room temperature for 60 h. EA (15 ml) was then added and the solution was washed with water  1 N hydrochloric acid  a saturated solution of sodium hydrogencarbonate and brine. The organic phase was dried over magnesium sulfate  filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (EA/MOH  100:0  then 97:5  then 95:5) to give 0.188 g of the title compound as a greenish-brown wax.

Step 7: 3-(2-{(S)-4-[2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazin-2-yl}-acetylamino)-2 2-dimethyl-propionamide
A 4 N solution of hydrogen chloride in dioxane (0.68 ml  2.71 mmol) was added to a solution of the compound of step 6 (0.185 g  0.27 mmol) in 2.7 ml of anhydrous DCM and the mixture stirred at room temperature for 2.5 h. After evaporation of the solvents  the obtained solid was triturated with anhydrous diethyl ether/DCM (9:1) and dried in vacuo at 45 °C to give 0.131 g of the title compound in the form of 3-(2-{(S)-4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazin-2-yl}-acetylamino)-2 2-dimethyl-propionamide hydrochloride as a light green powder with the following characteristics:
Mp: 174-176 °C
LC/MS (method LC1) m/z = 584 [MH+]; Rt = 1.04 min
1H-NMR: ? (ppm) = 1.02 (s  6H)  1.96 and 2.03 (two s  3H)  2.60 (d  2H)  3.20 (m  5H)  3.52 (m  3H)  3.95 (m  2H)  4.11 (m  2H)  6.61 (m  1H)  6.9 (m  4H)  7.32 (m  3H)  7.40 (m  3H)  7.96 (dd  1H)  8.21 and 8.36 (two d  1H)  9.30 (br s  1H)  9.55 (br s  1H)
?: -7.53 ° (c = 0.425 g/100 ml  MOH)

Example 8
6-(3-Fluoro-2-methyl-benzyl)-5-phenyl-7-(piperazine-1-carbonyl)-pyrrolo[1 2 b]pyridazin-3-carboxylic acid methylamide

Step 1: 1-Fluoro-2-methyl-3-((E)-2-nitro-ethenyl)-benzene
A Knoevenagel condensation was carried out by stirring 3-fluoro-2-methyl-benzaldehyde (20.721 g  150 mmol)  nitromethane (48.75 ml  900 mmol) and ammonium acetate (34.687 g  450 mmol) in 300 ml of acetic acid at 115 °C for 3.5 h. The mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 250 ml of EA. The solution was washed with water (250 ml)  three times with a 1 N sodium hydroxide solution (125 ml) and with brine (125 ml)  dried over magnesium sulfate  filtered and evaporated to dryness. 24.18 g of the title compound were obtained as a yellow solid.

Step 2: 1-Fluoro-2-methyl-3-(2-nitro-ethyl)-benzene
Analogously to the procedure described in A. K. Sinhababu et al.  Tetrahedron Lett. 24 (1983)  227  to a solution of the compound of step 1 (16.85 g  93.01 mmol) in isopropanol (275 ml) and chloroform (825 ml) were added dry silica gel (110 g) and then in small portions sodium borohydride (7.038 g  186.02 mmol). The mixture was stirred at room temperature for 0.5 h  then cooled to 0 °C and quenched by slow addition of 10 ml of 5 N hydrochloric acid. After stirring for 10 min  the silica gel was filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 150 ml of DCM and the solution washed with water (75 ml) and brine (75 ml)  dried over magnesium sulfate  filtered and evaporated to dryness to give 15.02 g of the title compound as a thick orange oil.

Step 3: 1-Fluoro-2-methyl-3-(2-nitro-3-phenyl-prop-2-en-1-yl)-benzene
The compound of step 2 (17.951 g  98 mmol)  benzaldehyde (10.43 ml  102.90 mmol)  n-butylamine (0.49 ml  4.90 mmol) and acetic acid (0.28 ml  4.90 mmol) in 49 ml of toluene were heated at 180 °C in a Dean-Stark apparatus for 6 h. After cooling to room temperature  the mixture was evaporated to dryness under reduced pressure. The residue was taken up in 49 ml of toluene  benzaldehyde (10.43 ml  102.90 mmol)  n-butylamine (0.49 ml  4.90 mmol) and acetic acid (0.28 ml  4.90 mmol) were added  and the mixture was heated at 180 °C in a Dean-Stark apparatus for 3 h. After cooling to room temperature  the mixture was evaporated to dryness under reduced pressure. The residue was triturated with 25 ml of diethyl ether/pentane (1:1). The solid was filtered off  rinsed with cyclohexane  and dissolved in 75 ml of DCM. The solution was dried with magnesium sulfate and evaporated to dryness to give 21.57 g of the title compound as a yellow solid melting at 111-112 °C.

Step 4: 4-(3-Fluoro-2-methyl-benzyl)-3-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester
The compound of step 3 (21.45 g  79.07 mmol) and ethyl isocyanoacetate (10.37 ml  94.88 mmol) were dissolved in 225 ml of anhydrous THF under a nitrogen atmosphere at 5°C and DBU (14.16 ml  94.88 mmol) was added dropwise. The solution was stirred at room temperature for 18 h. Then 200 ml of water and 200 ml of EA were added. The organic phase was washed with 1 N hydrochloric acid (200 ml) and brine (150 ml)  dried over magnesium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA  90:10  then 85:15) to give 16.68 g of the title compound as a yellow solid melting at 120-122 °C.

Step 5: 1-Amino-4-(3-fluoro-2-methyl-benzyl)-3-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester
To a solution of the compound of step 4 (6.748 g  20.00 mmol) in 60 ml of anhydrous DMF under a nitrogen atmosphere at 0°C was added sodium hydride (60 % in mineral oil  0.960 g  24 mmol) in small portions. After stirring for 10 min at 0 °C  the mixture was allowed to warm to room temperature over 15 min. After cooling to 0 °C again  O-(2 4-dinitro-phenyl)-hydroxylamine (cf. C. Legault et al.  J. Org. Chem. 68 (2003)  7119; P. H. Boyle et al.  ARKIVOC (2003) (vii)  67; 4.779 g  24.00 mmol) was added in small portions and the mixture was stirred at room temperature for 1 h. Water (250 ml) and EA (250 ml) were added and the organic phase was washed twice with 125 ml each of a 1 N sodium hydroxide solution and 125 ml of brine  dried over magnesium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel  first eluting with cyclohexane/DCM (40:60  then 20:80  then 0:100)  then with DCM/EA (97.5:2.5  then 95:5) to give 6.33 g of the title compound as a beige solid melting at 87-88 °C.

Step 6: 6-(3-Fluoro-2-methyl-benzyl)-4-oxo-5-phenyl-1 4-dihydro-pyrrolo[1 2 b]pyridazine-3-carboxylic acid ethyl ester
To a solution of the compound of step 5 (6.290 g  17.85 mmol) in 180 ml of anhydrous DMF under nitrogen were added ethyl 3 3-diethoxy-propanoate (10.42 ml  53.55 mmol) and p-toluenesulfonic acid hydrate (0.509 g  2.68 mmol)  and the solution was heated at 90 °C for 1.5 h. After cooling to 60 °C  DBU (13.32 ml  89.24 mmol) was added dropwise and the mixture was stirred for 45 min at 60 °C. The solution was then cooled to room temperature  water (600 ml) was added and the solution was extracted four times with EA (200 ml). The combined organic phases were washed with 0.5 N hydrochloric acid (300 ml) and brine (300 ml)  dried over magnesium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was triturated several times with cyclohexane and dried in vacuo at 50 °C. 5.43 g of the title compound were obtained as a brown solid melting at 176-177 °C.

Step 7: 4-Chloro-6-(3-fluoro-2-methyl-benzyl)-7-formyl-5-phenyl-pyrrolo[1 2 b]pyridazine-3-carboxylic acid ethyl ester
Phosphorus oxychloride (24.5 ml  268.00 mmol) was slowly added to the compound of step 6 (5.42 g  13.40 mmol) followed by anhydrous DMF (5.18 ml  67 mmol). The mixture was heated at 60 °C for 1 h and then concentrated to dryness. The residue was dissolved in DCM (200 ml) and the solution was added dropwise at room temperature to a saturated solution of sodium hydrogencarbonate. The mixture was stirred at room temperature for 1 h  then water (50 ml) and DCM (200 ml) were added  the phases were separated and the aqueous phase was extracted with DCM (100 ml). The combined organic phases were washed with a saturated solution of sodium hydrogencarbonate and brine  dried over sodium sulfate  filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (cyclohexane/EA  85:15  then 80:20) to give 5.19 g of the title compound as a yellow solid melting at 110-111 °C.

Step 8: 4-Chloro-3-ethoxycarbonyl-6-(3-fluoro-2-methyl-benzyl)-5-phenyl-pyrrolo[1 2 b]pyridazine-7-carboxylic acid
The compound of step 7 (5.15 g  11.42 mmol) was suspended in tert-butanol (90 ml)  and a 2 M solution of isobutene in THF (34.27 ml  68.53 mmol)  a solution of sodium dihydrogenphosphate (4.111 g  34.27 mmol) in 25 ml of water and sodium chlorite (1.937 g  17.13 mmol) were added. The mixture was stirred at room temperature for 2 h. Then brine (200 ml)  water (50 ml)  EA (400 ml) and DCM (100 ml) were added and the organic phase was separated  dried over magnesium sulfate  filtered and evaporated to dryness. The obtained solid was triturated several times with cyclohexane and dried in vacuo at 50 °C. 5.23 g of the title compound were obtained as a yellow solid melting at 193-194 °C.

Step 9: 7-(4-tert-Butoxycarbonyl-piperazine-1-carbonyl)-4-chloro-6-(3-fluoro-2-methyl-benzyl)-5-phenyl-pyrrolo[1 2-b]pyridazine-3-carboxylic acid ethyl ester
The compound of step 8 (2.335 g  5.00 mmol)  1-tert-butoxycarbonyl-piperazine (1.024 g  5.50 mmol)  EDIA (2.18 ml  12.50 mmol) and TBTU (1.766 g  5.50 mmol) in 50 ml of anhydrous DCM were stirred at room temperature for 1 h. The solution was then washed with 0.5 N hydrochloric acid (75 ml) and the aqueous phase was extracted with DCM (25 ml). The combined organic phases were washed with a saturated solution of sodium hydrogencarbonate (50 ml) and brine (50 ml)  dried over magnesium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA  80:20  then 75:25) to give 3.01 g of the title compound as a yellow solid melting at 88-90 °C.

Step 10: 7-(4-tert-Butoxycarbonyl-piperazine-1-carbonyl)-6-(3-fluoro-2-methyl-benzyl)-5-phenyl-pyrrolo[1 2-b]pyridazine-3-carboxylic acid ethyl ester
The compound of step 9 (1.880 g  2.96 mmol) in 29.6 ml of ethanol/THF (1:1) was hydrogenated under a hydrogen pressure of 2 bar for 3.5 h at room temperature in the presence of 0.315 g of 10 % palladium on charcoal and triethylamine (0.62 ml  4.44 mmol). The catalyst was filtered off and the filtrate was washed with brine (50 ml)  dried with magnesium sulfate  filtered and concentrated to dryness under reduced pressure. 1.67 g of the title compound were obtained as a yellow solid.

Step 11: 7-(4-tert-Butoxycarbonyl-piperazine-1-carbonyl)-6-(3-fluoro-2-methyl-benzyl)-5-phenyl-pyrrolo[1 2-b]pyridazine-3-carboxylic acid
The compound of step 10 (1.680 g  2.80 mmol) was dissolved in 20 ml of dioxane and a 1 M aqueous solution of lithium hydroxide (4.30 ml  4.30 mmol) was added. After stirring for 45 min at room temperature  the dioxane was evaporated under reduced pressure and 50 ml of water were added. The mixture was acidified to pH 2 with 5 N hydrochloric acid. The solid was filtered off  rinsed with water and dissolved in EA (100 ml). The solution was washed with water (50 ml) and brine (50 ml)  dried over magnesium sulfate  filtered and evaporated to dryness under reduced pressure to give 1.64 g of the title compound which was directly used in the subsequent step.

Step 12: 4-[6-(3-Fluoro-2-methyl-benzyl)-3-methylcarbamoyl-5-phenyl-pyrrolo[1 2 b]pyridazine-7-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester
To a solution of the compound obtained in step 11 (0.286 g  0.50 mmol) in 5 ml of DCM were added EDIA (0.26 ml  1.50 mmol)  methylamine hydrochloride (0.051 g  0.75 mmol)  a 2 M solution of methylamine in THF (2.5 ml  0.50 mmol) and TBTU (0.107 g  0.57 mmol). The solution was stirred at room temperature for 18 h  then diluted with DCM (15 ml)  washed with 0.5 M hydrochloric acid  a saturated solution of sodium hydrogencarbonate and brine  dried over magnesium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA  30:70  then 20:80  then 10:90) to give 0.153 g of the title compound as a yellow solid melting at 153-154 °C.

Step 13: 6-(3-Fluoro-2-methyl-benzyl)-5-phenyl-7-(piperazine-1-carbonyl)-pyrrolo[1 2 b]pyridazine-3-carboxylic acid methylamide
To a solution of the compound of step 12 (0.150 g  0.260 mmol) in 2.6 ml of DCM was added a 4 N solution of hydrogen chloride in dioxane (0.64 ml  2.56 mmol). The mixture was stirred at room temperature for 5 h and then evaporated to dryness. The obtained solid was triturated several times with diethyl ether and dried in vacuo at 50 °C to give 0.118 g of the title compound in the form of 6-(3-fluoro-2-methyl-benzyl)-5-phenyl-7-(piperazine-1-carbonyl)-pyrrolo[1 2-b]pyridazine-3-carboxylic acid methylamide hydrochloride as a pale orange solid with the following characteristics:
Mp: 208-210 °C
LC/MS (method LC1): m/z = 486 [MH+]; Rt = 0.93 min
1H-NMR: ? (ppm) = 1.85 (s  3H)  2.71 (d  3H)  2.92 (m  4H)  3.49 (s  2H)  3.65 (m  2H)  4.02 (m  2H)  6.69 (d  1H)  6.88 (dd  1H)  6.98 (dd  1H)  7.37 (m  3H)  7.45 (m  2H)  8.22 (s  1H)  8.60 (m  2H)  9.06 (br s  2H)

Example 9
[6-(3-Fluoro-2-methyl-benzyl)-5-phenyl-pyrrolo[1 2-b]pyridazin-7-yl]-piperazin-1-yl-methanone

A mixture of the compound of example 8  step 11 (0.057 g  0.10 mmol)  copper powder (0.007 g  0.10 mmol) and quinoline (0.40 ml) was plunged into an oil bath pre-heated at 170 °C for 1.25 h. After cooling to room temperature and evaporation of the volatiles under reduced pressure  the residue was dissolved in EA (10 ml) and the solution washed with water and brine  dried over magnesium sulfate  filtered and concentrated to dryness. The obtained orange oil was purified by chromatography on silica gel (DCM/MOH  100:0  then 90:10). The product was dissolved in 2 ml of DCM and a 4 N solution of hydrogen chloride in dioxane (0.25 ml  0.98 mmol) was added. After stirring at room temperature overnight  the solution was evaporated to dryness. The obtained solid was triturated several times with diethyl ether and dried in vacuo at 50 °C to give 0.016 g of the title compound in the form of [6-(3-fluoro-2-methyl-benzyl)-5-phenyl-pyrrolo[1 2-b]pyridazin-7-yl]-piperazin-1-yl-methanone hydrochloride as an orange solid with the following characteristics:
Mp: 140-142 °C
LC/MS (method LC1): m/z = 429 [MH+]; Rt = 1.25 min
1H-NMR: ? (ppm) = 1.89 (s  3H)  2.98 (m  3H)  3.23 (s  2H)  3.62 (m  4H)  4.04 (m  4H)  6.70 (d  1H)  6.78 (m  1H)  6.90 (t  1H)  6.99 (dd  1H)  7.32 (m  3H)  7.41 (m  2H)  7.89 (dd  1H)  8.27 (d  1H)  8.93 (br s  2H)

Example 10
[6-(3-Fluoro-2-methyl-benzyl)-3-hydroxy-5-phenyl-pyrrolo[1 2-b]pyridazin-7-yl]-piperazin-1-yl-methanone

Step 1: 4-[6-(3-Fluoro-2-methyl-benzyl)-3-(N-methoxy-N-methyl-carbamoyl)-5-phenyl-pyrrolo[1 2-b]pyridazin-7-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester
A solution of the compound of example 8  step 11 (1.002 g  1.75 mmol)  N O-dimethylhydroxylamine hydrochloride (0.213 g  2.19 mmol)  EDIA (0.76 ml  4.38 mmol) and TBTU (0.702 g  2.19 mmol) in 15 ml of anhydrous DCM was stirred at room temperature for 4 h. DCM (15 ml) was then added and the solution was washed with 0.5 N hydrochloric acid (30 ml)  a saturated solution of sodium hydrogencarbonate (15 ml) and brine (15 ml)  dried over magnesium sulfate  filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA  50:50  then 40:60  then 35:65) to give 0.99 g of the title compound as a yellow oil.

Step 2: 4-[6-(3-Fluoro-2-methyl-benzyl)-3-formyl-5-phenyl-pyrrolo[1 2-b]pyridazin-7-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester
To a solution of the compound of step 1 (0.990 g  1.61 mmol) in 11 ml of anhydrous THF  cooled to 0°C under an atmosphere of nitrogen  was added a 1 M solution of lithium tri-tert-butoxy-aluminium hydride in THF. The mixture was stirred at 0-5 °C for 3.5 h. Then a 0.5 M aqueous solution of potassium hydrogensulfate (20 ml) was added  the mixture was vigorously stirred for 1 min and then extracted twice with EA (30 ml). The combined organic phases were washed with a saturated solution of sodium hydrogencarbonate (20 ml) and brine (40 ml)  dried over magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (cyclohexane/EA  70:30  then 65:35) to give 0.363 g of the title compound as a yellow solid melting at 208-209 °C.

Step 3: 4-[6-(3-Fluoro-2-methyl-benzyl)-3-hydroxy-5-phenyl-pyrrolo[1 2-b]pyridazin-7-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester
To a solution of the compound of step 2 (0.395 g  0.71 mmol) in 7.1 ml of DCM was added 77 % 3-chloro-perbenzoic acid (0.239 g  1.06 mmol) in small portions and the solution was stirred at room temperature for 2.75 h. Then DCM (15 ml) and a saturated solution of sodium hydrogencarbonate (15 ml) were added and the aqueous phase was separated and extracted with DCM (15 ml). The combined organic phases were washed with brine (30 ml)  dried over magnesium sulfate  filtered and evaporated to dryness under reduced pressure. The obtained oil was dissolved in 14 ml of MOH and stirred in the presence of potassium carbonate (0.147 g  1.06 mmol) at room temperature for 15 min. Then water was added (15 ml) and the mixture was acidified to pH 5 by dropwise addition of a 1 M aqueous solution of potassium hydrogensulfate. The solution was then extracted twice with 15 ml each of EA and the combined organic phases were washed with brine (15 ml)  dried over magnesium sulfate  filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (DCM/EA  80:20  then 60:40  then 40:60) to give 0.180 g of the title compound as a yellow solid melting at 165 °C.

Step 4: [6-(3-Fluoro-2-methyl-benzyl)-3-hydroxy-5-phenyl-pyrrolo[1 2-b]pyridazin-7-yl]-piperazin-1-yl-methanone
The compound of step 3 (0.109 g  0.20 mmol) was dissolved in 3 ml of anhydrous DCM and a 4 M solution of hydrogen chloride in dioxane (1.0 ml  4.0 mmol) was added. After stirring at room temperature overnight  the mixture was evaporated to dryness under reduced pressure. The obtained solid was triturated several times with diethyl ether and dried in vacuo at 55 °C to give 0.073 g of the title compound in the form of [6-(3-fluoro-2-methyl-benzyl)-3-hydroxy-5-phenyl-pyrrolo[1 2-b]pyridazin-7-yl]-piperazin-1-yl-methanone hydrochloride as a greenish-yellow solid with the following characteristics:
Mp: 206-208 °C
LC/MS (method LC1): m/z = 445 [MH+]; Rt = 0.96 min
1H-NMR: ? (ppm) = 2.00 (s  3H)  2.91 (m  4H)  3.46 (m  4H)  4.08 (s  2H)  6.77 (d  1H)  6.96 (m  1H)  7.05 (dd  1H)  7.10 (s  1H)  7.34 (m  2H)  7.46 (m  2H)  8.15 (s  1H)  9.11 (br s  2H)  10.42 (br s  1H)

Example 11
[2-(3-Fluoro-2-methyl-benzyl)-3-phenyl-indolizin-1-yl]-piperazin-1-yl-methanone

Step 1: 1-Bromo-3-(3-fluoro-2-methyl-phenyl)-propan-2-one
Analogously to the procedure described in H. Y. Choi et al.  Org. Lett. 5 (2003)  411  a solution of bromine (8.46 g  52.95 mmol) in acetic acid (12 ml) was added at 0 °C to a solution of 1-(3-fluoro-2-methyl-phenyl)-propan-2-one (4.00 g  24.07 mmol) in acetic acid (4 ml) and a 33 % solution of hydrogen bromide in acetic acid (4 ml). The mixture was warmed to room temperature and stirred for 12 h. Then acetone was added and the mixture was stirred for 24 h. After evaporation under reduced pressure  the residue was extracted several times with DCM. The combined extracts were dried over sodium sulfate and evaporated to dryness. The residue was purified by preparative HPLC to give 4.10 g of the title compound as an oil.
LC/MS (method LC3): m/z = 245 [M+]

Step 2: 2-(3-Fluoro-2-methyl-benzyl)-indolizine-1-carboxylic acid methyl ester
The compound of step 1 (3.89 g  15.88 mmol)  pyridin-2-ylacetic acid methyl ester (1.65 g  10.92 mmol) and sodium hydrogencarbonate (4.59 g  54.60 mmol) in butan-2-one (43 ml) were heated under reflux for 24 h. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel chromatography (HEP/EA) to give 1.99 g of the title compound.
LC/MS (method LC4): m/z = 298 [MH+]

Step 3: 2-(3-Fluoro-2-methyl-benzyl)-3-phenyl-indolizine-1-carboxylic acid methyl ester
The compound of step 2 (1.79 g  6.02 mmol)  iodo-benzene (1.47 g  7.22 mmol)  potassium acetate (1.18 g  12.03 mmol) and bis(triphenylphosphine)palladium(II) chloride (844 mg  1.20 mmol) in NMP were heated at 100 °C for 10 min under argon. Then water (844 mg  36.10 mmol) was added and heating continued for 12 h. The mixture was cooled to room temperature  diluted with DCM and washed with water. The organic phase was dried over sodium sulfate  and evaporated. The residue was purified by silica gel chromatography (HEP/EA) to give 729 mg of the title compound.
LC/MS (method LC4): m/z = 374 [MH+]

Step 4: 2-(3-Fluoro-2-methyl-benzyl)-3-phenyl-indolizine-1-carboxylic acid
The compound of step 3 (250 mg  0.67 mmol) was dissolved in dioxane (10 ml) and treated with 10 ml of an aqueous 10 N solution of sodium hydroxide. The mixture was heated to 90 °C for 12 h  cooled to room temperature and neutralized with dilute hydrochloric acid. The aqueous phase was extracted with DCM and the combined organic phases dried over sodium sulfate and filtered. The solution was evaporated to give 258 mg of the crude title compound which was used in the next step without purification.
LC/MS (method LC4): m/z = 360 [MH+]

Step 5: 4-[2-(3-Fluoro-2-methyl-benzyl)-3-phenyl-indolizine-1-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester
To a solution of the crude compound obtained in step 4 (125 mg  0.35 mmol)  1-tert-butoxycarbonyl-piperazine (67.9 mg  0.37 mmol)  N-ethyl-N""-(3-dimethylaminopropyl)carbodiimide hydrochloride (73.4 mg  0.38 mmol) and 1-hydroxybenzotriazole (61.3 mg  0.40 mmol) in DMF (2 ml) was added N-methyl-morpholine (0.115 ml  1.04 mmol). The mixture was stirred at room temperature overnight  then quenched with water and extracted with EA. The organic layer was separated  dried over sodium sulfate  filtered and evaporated. The residue was purified by silica gel chromatography (HEP/EA) to give 158 mg of the title compound.
LC/MS (method LC4): m/z = 528 [MH+]

Step 6: [2-(3-Fluoro-2-methyl-benzyl)-3-phenyl-indolizin-1-yl]-piperazin-1-yl-methanone
A solution of the compound of step 5 (158 mg  299 mmol) in DCM (8 ml) and TFA (4 ml) was stirred at room temperature for 2 h. The solvents were evaporated and the residue was purified by preparative HPLC. The fractions containing the title compound were combined and lyophilized overnight. The obtained solid was dissolved in a small quantity of MOH  mixed with 0.1 N hydrochloric acid and the mixture lyophilized overnight to give 108 mg of the title compound in the form of [2-(3-fluoro-2-methyl-benzyl)-3-phenyl-indolizin-1-yl]-piperazin-1-yl-methanone hydrochloride with the following characteristics:
LC/MS (method LC4): m/z = 428.20 [MH+]; Rt = 0.82 min
1H-NMR (500 MHz  DMSO-D6): ? (ppm) = 1.93 (s  3H)  2.56 (m  6H)  3.10 (m  2H)  3.47 (m  2H)  3.59 (m  2H)  4.01 (m  2H)  6.71 (m  2H)  6.92 (m  1H)  7.01 (m  2H)  7.47 (m  4H)  7.58 (m  2H)  8.06 (m  1H)  9.05 (m  1H)  9.28 (m  1H)

Example 12
[7-Bromo-2-(3-fluoro-2-methyl-benzyl)-3-phenyl-indolizin-1-yl]-piperazin-1-yl-methanone

Step 1: 7-Bromo-2-(3-fluoro-2-methyl-benzyl)-3-phenyl-indolizine-1-carboxylic acid methyl ester
The compound of example 11  step 3  (550 mg  1.47 mmol) was dissolved in a mixture of benzene (15 ml) and chloroform (15 ml) and treated at room temperature with bromine (235 mg  1.47 mmol) under stirring. After 2 h  DBU (224 mg  1.47 mmol) was added and the mixture stirred for 18 h at room temperature. The solvent was removed in vacuo and the remaining residue was purified by silica gel chromatography (HEP/EA). 460 mg of the title compound were obtained.
LC/MS (method LC4): m/z = 452 [M+]

Step 2: 7-Bromo-2-(3-fluoro-2-methyl-benzyl)-3-phenyl-indolizine-1-carboxylic acid
The compound of step 1 (450 mg  0.99 mmol) was dissolved in 1 4-dioxane (10 ml) and treated with 10 ml of an aqueous 10 N solution of sodium hydroxide. The mixture was heated to 90 °C for 12 h  cooled to room temperature and neutralized with dilute hydrochloric acid. The aqueous phase was extracted with DCM  and the combined organic phase were dried over sodium sulfate. The crude title product obtained after evaporation was used without purification in the next step.
LC/MS (method LC4): m/z = 439 [MH+]

Step 3: 4-[7-Bromo-2-(3-fluoro-2-methyl-benzyl)-3-phenyl-indolizine-1-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester
To a solution of the crude compound obtained in step 2 (219 mg  0.50 mmol)  1-tert-butoxycarbonyl-piperazine (98 mg  0.55 mmol)  N-ethyl-N""-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg  0.55 mmol) and 1-hydroxybenzotriazole (88 mg  0.58 mmol) in DMF (5 ml) was added N-methyl-morpholine (330 µl  3.00 mmol)  and the mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with EA. The organic layer was separated  dried over sodium sulfate  filtered and evaporated. The residue was purified by silica gel chromatography (HEP/EA). 300 mg of the title compound were obtained.
LC/MS (method LC4): m/z = 607 [MH+]

Step 4: [7-Bromo-2-(3-fluoro-2-methyl-benzyl)-3-phenyl-indolizin-1-yl]-piperazin-1-yl-methanone
A solution of the compound of step 3 (70 mg  115 µmol) in DCM (4 ml) and TFA (2 ml) was stirred at room temperature for 2 h. The solvents were evaporated and the resulting solid was purified by preparative HPLC. The fractions containing the title compound were combined and lyophilized overnight. The obtained solid was dissolved in a small quantity of MOH  mixed with 0.1 N hydrochloric acid and the mixture lyophilized overnight to give 15 mg of the title compound in the form of [7-bromo-2-(3-fluoro-2-methyl-benzyl)-3-phenyl-indolizin-1-yl]-piperazin-1-yl-methanone hydrochloride with the following characteristics:
LC/MS (method LC4): m/z = 508.2 [MH+]; Rt = 0.85 min
1H-NMR (500 MHz  DMSO-D6): ? (ppm) = 1.92 (s  3H)  3.13 (m  2H)  3.58 (m  2H)  4.01 (m  2H)  6.71 (m  1H)  6.79 (m  1H)  6.93 (m  1H)  7.01 (m  1H)  7.46 (m  3H)  7.58 (m  2H)  7.74 (m  1H)  7.97 (m  1H)  9.01 (m  2H)

Analogously to the example compounds described above  the compounds of examples 13 to 46 were prepared.

Example 13
2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-3-(piperazine-1-carbonyl)-indolizine-6-carboxylic acid methylamide

The title compound was obtained in the form of 2-(3-fluoro-2-methyl-benzyl)-1-phenyl-3-(piperazine-1-carbonyl)-indolizine-6-carboxylic acid methylamide hydrochloride.
Mp: 273 °C
LC/MS (method LC1): m/z = 485; Rt = 0.99 min

Example 14
(2-Benzyl-3-phenyl-indolizin-1-yl)-piperazin-1-yl-methanone

The title compound was obtained in the form of (2-benzyl-3-phenyl-indolizin-1-yl)-piperazin-1-yl-methanone hydrochloride.
LC/MS (method LC3): m/z = 396.20; Rt = 1.09 min

Example 15
[2-(3-Fluoro-2-methyl-benzyl)-3-phenyl-indolizin-1-yl)-((S)-3-methyl-piperazin-1-yl)-methanone

The title compound was obtained in the form of [2-(3-fluoro-2-methyl-benzyl)-3-phenyl-indolizin-1-yl)-((S)-3-methyl-piperazin-1-yl)-methanone hydrochloride.
LC/MS (method LC4): m/z = 442.20; Rt = 0.83 min

Example 16
[7-Bromo-2-(3-fluoro-2-methyl-benzyl)-3-phenyl-indolizin-1-yl)-((S)-3-methyl-piperazin-1-yl)-methanone

The title compound was obtained in the form of [7-bromo-2-(3-fluoro-2-methyl-benzyl)-3-phenyl-indolizin-1-yl)-((S)-3-methyl-piperazin-1-yl)-methanone hydrochloride.
LC/MS (method LC4): m/z = 521; Rt = 0.88 min

Example 17
[2-(2 6-Dimethyl-benzyl)-1-phenyl-indolizin-3-yl)-((R)-3-methyl-piperazin-1-yl)-methanone

The title compound was obtained in the form of [2-(2 6-dimethyl-benzyl)-1-phenyl-indolizin-3-yl)-((R)-3-methyl-piperazin-1-yl)-methanone hydrochloride.
Mp: 302 °C
LC/MS (method LC1): m/z = 438; Rt = 4.01 min

The compounds of examples 18 to 21 listed in Table 1 are compounds of the formula Iv. They were obtained in the form of the hydrochloride. They can be named as [1-(optionally substituted phenyl)-2-(substituted benzyl)-indolizin-3-yl]-piperazin-1-yl-methanone  allowing for modifications due to the rules of nomenclature  for example as [2-(3-fluoro-2-methyl-benzyl)-1-(3-fluoro-phenyl)-indolizin-3-yl]-piperazin-1-yl-methanone in the case of example 20.

Table 1. Example compounds of the formula Iv
Exam-ple no. R20 R30 Rt
[min] MS
(m/z) LC/MS Mp
[° C]
18 5-fluoro-2-methyl-phenyl phenyl 1.08 428 LC1 271
19 2 5-difluoro-phenyl phenyl 1.05 432 LC1 295
20 3-fluoro-2-methyl-phenyl 3-fluoro-phenyl 5.50 446 LC2 355
21 2 6-dimethyl-phenyl phenyl 3.90 424 LC2 355-356

The compounds of examples 22 to 46 listed in Table 2 are compounds of the formula Iw. They were obtained in the form of the hydrochloride or  in the case of examples 32  33 and 37  in the form of the dihydrochloride. They can be named as [2-(3-fluoro-2-methyl-benzyl)-(optionally 7-R40-substituted)-1-phenyl-indolizin-3-yl]-R90-methanone in case the group Y is CH  or as [6-(3-fluoro-2-methyl-benzyl)-(optionally 3-R40-substituted)-5-phenyl-pyrrolo[1 2-b]pyridazin-7-yl]-R90-methanone in case the group Y is N  allowing for modifications due to the rules of nomenclature  for example as [2-(3-fluoro-2-methyl-benzyl)-7-methoxy-1-phenyl-indolizin-3-yl]-piperazin-1-yl-methanone in the case of example 35  or as 6-(3-fluoro-2-methyl-benzyl)-7-{(S)-3-[(2-methoxy-ethylcarbamoyl)-methyl]-piperazine-1-carbonyl}-5-phenyl-pyrrolo[1 2 b]pyridazine-3-carboxylic acid ethylamide in the case of example 42.

Table 2. Example compounds of the formula Iw
Exam-ple no. Y R40 R90 Rt
[min] MS
(m/z) LC/MS Mp
[° C] ?
(1)
22 CH hydrogen (R)-3-hydroxymethyl-piperazin-1-yl 3.62 458 LC2 180-181
23 CH hydrogen (R)-3-methyl-piperazin-1-yl 3.90 424 LC2 174
24 CH hydrogen (S)-3-(butylcarba¬moyl-methyl)-piperazin-1-yl 1.19 541 LC1 137
25 CH hydrogen (S)-3-(ethylcarba¬moyl-methyl)-piperazin-1-yl 1.09 513 LC1 135
26 CH hydrogen (S)-3-(2-methylcarba¬moyl-ethyl)-piperazin-1-yl 1.09 513 LC1 127-129
27 CH hydrogen (S)-3-[(3-methoxy-propylcarbamoyl)-methyl]-piperazin-1-yl 1.10 557 LC1 103
28 CH hydrogen (S)-3-[(2-carboxy-ethylcarbamoyl)-methyl]-piperazin-1-yl 1.04 557 LC1 173-175 +1.599 °
c =
0.319
29 CH hydrogen (S)-3-[(2-dimethylcar¬bamoyl-ethylcarba¬moyl)-methyl]-piperazin-1-yl 1.07 584 LC1 139-141 -3.604 °
c =
0.283
30 CH hydrogen (S)-3-[(2-methoxycar¬bonyl-ethylcarba¬moyl)-methyl]-piperazin-1-yl 1.10 571 LC1 112-113 +4.277 °
c =
0.325
31 CH hydrogen (S)-3-[(2-methanesul¬fonyl-ethylcarbamoyl)-methyl]-piperazin-1-yl 1.05 591 LC1 166-168 -3.538 °
c =
0.195
32 CH hydrogen (S)-3-{[(pyridin-3-ylmethyl)-carbamoyl]-methyl}-piperazin-1-yl 0.95 576 LC1 181-182 -2.414 °
c =
0.232
33 CH hydrogen (S)-3-[(2-morpholin-4-yl-ethylcarbamoyl)-methyl]-piperazin-1-yl 0.97 598 LC1 125-127 -5.021 °
c =
0.233
34 CH hydrogen (S)-3-[(2-hydroxy-ethylcarbamoyl)-methyl]-piperazin-1-yl 1.03 529 LC1 118-120 -2.015 °
c =
0.670
35 CH methoxy piperazin-1-yl 1.09 458 LC1 124-125
36 N methoxy piperazin-1-yl 1.04 459 LC1 139-141
37 CH hydrogen (S)-3-{[(pyridin-2-ylmethyl)-carbamoyl]-methyl}-piperazin-1-yl 1.00 576 LC1 131-133 -6.266 °
c =
0.316
38 N dimethyl¬carba¬moyl (S)-3-[(2-methoxy-ethylcarbamoyl)-methyl]-piperazin-1-yl 0.98 615 LC1 147-149 -1.325 °
c =
0.702
39 N piperidin-1-ylcarbo¬nyl (S)-3-[(2-hydroxy-ethylcarbamoyl)-methyl]-piperazin-1-yl 1.04 641 LC1 164-166 -2.834 °
c =
0.674
40 CH dimethyl¬carba¬moyl (S)-3-(ethylcarba¬moylmethyl)-piperazin-1-yl 1.00 584 LC1 169-170 +3.279 °
c =
1.046
41 CH dimethyl¬carba¬moyl (S)-3-[(2-methoxy-ethylcarbamoyl)-methyl]-piperazin-1-yl 0.99 614 LC1 148-149 +0.58 °
c =
0.702
42 N ethylcar¬bamoyl (S)-3-[(2-methoxy-ethylcarbamoyl)-methyl]-piperazin-1-yl 1.08 615 LC1 151-153 +11.15 °
c =
0.234
43 N piperidin-1-ylcarbo¬nyl (S)-3-[(2-methoxy-ethylcarbamoyl)-methyl]-piperazin-1-yl 1.08 655 LC1 169-171 -2.011 °
c =
0.378
44 N diethyl¬carba¬moyl (S)-3-(ethylcarba-moylmethyl)-piperazin-1-yl 1.08 613 LC1 145-147 +3.13 °
c = 1
45 N dimethyl¬carba¬moyl (S)-3-(ethylcarba¬moylmethyl)-piperazin-1-yl 0.99 585 LC1 180-182 +4.221 °
c =
0.77
46 N dimethyl¬carba¬moyl (S)-3-{[(2-methoxy-ethyl)-methyl-carbamoyl]-methyl}-piperazin-1-yl 1.01 629 LC1 130-132 +5.81 °
c =
0.494
(1) optical rotation (in °) at the concentration c (in g/100 ml) in MOH

Further compounds of the formula Iw  which can be prepared analogously to the example compounds described above  are listed in Table 3. They can be named as indicated above for the compounds listed in Table 2.

Table 3. Compounds of the formula Iw
Example no. Y R40 R90
47 CH methoxy (S)-3-[(2-hydroxy-ethylcarbamoyl)-methyl]-piperazin-1-yl
48 CH hydroxy (S)-3-(butylcarbamoylmethyl)-piperazin-1-yl
49 CH hydrogen (S)-2-benzyl-piperazin-1-yl
50 CH hydrogen 2 2-dimethyl-piperazin-1-yl
51 CH pyrrolidin-1-yl (S)-3-[(2-cyano-ethylcarbamoyl)-methyl]-piperazin-1-yl
52 N morpholin-4-yl (S)-3-[(2-cyano-ethylcarbamoyl)-methyl]-piperazin-1-yl
53 CH dimethylcarbamoyl (S)-3-[(2-cyano-ethylcarbamoyl)-methyl]-piperazin-1-yl
54 N methylcarbamoyl (S)-3-{[(2-methoxy-ethyl)-methyl-carbamoyl]-methyl}-piperazin-1-yl

Pharmacological tests

A) Inhibition of renin
The renin-inhibiting activity of compounds of the invention was demonstrated in an in vitro test in which a non-endogenous fluorogenic peptide substrate is cleaved by renin specifically at the Leu-Val bond which corresponds to the cleavage site of angiotensinogen.

Recombinant human renin (Cayman  no. 10006217) at a concentration of 5 nM was incubated with the test compounds at various concentrations and the synthetic substrate Dabcyl-?-Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-EDANS (Bachem  no. M-2050; Dabcyl means the 4-(4-dimethylamino-phenylazo)-benzoyl group and EDANS means the amide with 5-[(2-aminoethyl)amino]-naphthalene-1-sulfonic acid) at a concentration of 10 µM for 2 h at room temperature in 0.05 M Tris buffer (pH 8) containing 0.1 M NaCl  2.5 mM EDTA and 1.25 mg/ml bovine serum albumin. The increase in fluorescence  which is due to fluorescence resonance energy transfer  was recorded at an excitation wavelength of 330 nm and an emission wavelength of 485 nm in a microplate spectrofluorometer. Inhibitory concentrations IC50 were calculated from the percentage of inhibition of renin activity as a function of the concentration of the test compound. In this test  the example compounds generally inhibited renin with an IC50 value of less than about 10 micromol/l (10 µM). Representative IC50 values  which were determined with the compounds in the form of the obtained salt indicated in the examples above  are listed in Table 4.

Table 4. IC50 values for inhibition of renin (fluorogenic peptide substrate)
Compound of example no. IC50 (µM) Compound of example no. IC50 (µM)
1 0.0071 17 0.87
2 0.038 20 0.0034
6 0.0026 22 0.10
7 0.0026 26 0.23
9 0.0043 30 0.031
10 0.0082 31 0.021
11 0.023 32 0.038
12 0.36 35 0.028
13 0.064 39 0.0074
15 0.076 46 0.010

B) Inhibition of renin in human plasma
The renin-inhibiting activity of compounds of the invention was also demonstrated in an in vitro test in the presence of human plasma. The procedure followed the procedure described in pharmacological test A except that human recombinant renin at a concentration of 30 nM was incubated with the test compounds at various concentrations and the fluorogenic substrate Dabcyl-?-Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-EDANS at a concentration of 25 µM for 30 min at 37 °C and 30 min at room temperature in human plasma (Innovative Research  pooled normal human plasma collected on EDTA K3 as an anticoagulant  no. IPLA-5).

C) Antihypertensive activity
The in vivo antihypertensive activity of compounds of the invention can be demonstrated in doubly transgenic mice overexpressing both human renin and angiotensinogen genes (dTghRenhAgt mice; cf. D. C. Merrill et al.  J. Clin. Invest. 97 (1996)  1047; R. L. Davisson et al.  J. Clin. Invest. 99 (1997)  1258; J. L. Lavoie et al.  Acta Physiol. Scand. 81 (2004)  571; available by breeding strains carrying the human renin transgene and the human angiotensinogen transgene  respectively). Briefly  in this test the arterial pressure in freely moving male dTghRenhAgT mice is determined by telemetry monitoring. For this purpose  the catheter of a radio transmitter (model TA11PA-10  DSI) is implanted into the left carotid artery of dTghRenhAgT mice under anesthesia. Animals are kept on a 12 h light/dark cycle and have free access to food and water. After one week of recovery period  arterial pressure and heart rate are monitored over 24 h to establish the baseline values. Then animals receive orally by gavage either the daily dose of the test compound in vehicle (water containing 0.6 % of methylcellulose and 0.5 % of Tween® 80) or  as a control  vehicle only. Hemodynamic parameters are recorded continuously for an additional 24 h and maximal mean arterial pressure lowering effect and duration of antihypertensive activity are determined (mean arterial pressure = diastolic pressure + 1/3 · (systolic pressure - diastolic pressure)). Compounds are screened at various doses such as 3 mg/kg body weight and 10 mg/kg body weight per day.

Claims

1. A compound of the formula Ia or Ib  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them 

wherein
Ra is chosen from hydrogen  fluorine and (C1-C4)-alkyl  wherein the two groups Ra are independent of each other and can be identical or different  or the two groups Ra together are a divalent (C2-C5)-alkyl group;

R is chosen from hydrogen  (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents R1  and (C3-C7)-cycloalkyl  wherein all groups R are independent of each other and can be identical or different  or two groups R bonded to the same carbon atom together are a divalent (C2-C5)-alkyl group;

R1 is chosen from (C3-C7)-cycloalkyl  phenyl  heteroaryl  Het1  hydroxy  (C1-C4)-alkyl O-  (C1-C4)-alkyl-S(O)m-  R2-N(R3)-C(O)-  R4-O-C(O)- and cyano;

R2 is chosen from hydrogen  (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents R5  and (C3-C7)-cycloalkyl  wherein all groups R2 are independent of each other and can be identical or different;

R3  R4  R6  R7 and R8 are chosen from hydrogen and (C1-C4)-alkyl  wherein all groups R3  R4  R6  R7 and R8 are independent of each other and can be identical or different;

R5 is chosen from hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R6 N(R7)-C(O)-  R8-O-C(O)-  cyano  (C3-C7)-cycloalkyl  phenyl  heteroaryl and Het1;

R10 is chosen from hydrogen  (C1-C6)-alkyl-O-C(O)- and (C3-C7)-cycloalkyl-CvH2v-O-C(O)-;

R20 is chosen from phenyl and heteroaryl which are optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m- and cyano;

R30 is chosen from (C5-C7)-cycloalkyl  (C5-C7)-cycloalkenyl  tetrahydropyranyl  phenyl and heteroaryl  wherein cycloalkyl and cycloalkenyl are optionally substituted by one or more identical or different substituents chosen from fluorine  (C1-C4)-alkyl and hydroxy  and phenyl and heteroaryl are optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O- and cyano;

R40 is chosen from halogen  (C1-C4)-alkyl  (C3-C7)-cycloalkyl-CvH2v-  hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R41-N(R42)-  Het2  R41-N(R42)-C(O)-  Het2-C(O)-  cyano  R41-N(R42)-S(O)2- and Het2-S(O)2-  wherein all substituents R40 are independent of each other and can be identical or different;

R41 is chosen from hydrogen  (C1-C4)-alkyl and (C3-C7)-cycloalkyl-CvH2v-  wherein all groups R41 are independent of each other and can be identical or different;

R42 is chosen from hydrogen and (C1-C4)-alkyl  wherein all groups R42 are independent of each other and can be identical or different;

Y is chosen from N  CH and C((C1-C4)-alkyl);

heteroaryl is an aromatic monocyclic  5-membered or 6-membered  heterocyclic group which comprises 1  2 or 3 identical or different ring heteroatoms chosen from N  O and S  wherein one of the ring nitrogen atoms can carry a hydrogen atom or a (C1-C4)-alkyl substituent  and wherein the heteroaryl group is bonded via a ring carbon atom;

Het1 is a saturated  monocyclic  4-membered to 7-membered heterocyclic group which comprises 1 or 2 identical or different ring heteroatoms chosen from N  O and S  wherein the group Het1 is bonded via a ring carbon atom or a ring nitrogen atom  wherein ring nitrogen atoms can carry a hydrogen atom or a substituent chosen from (C1-C4)-alkyl  (C1-C6)-alkyl-O-C(O)- and (C3-C7)-cycloalkyl-CvH2v-O-C(O)-  wherein ring sulfur atoms can carry one or two oxo groups  and wherein Het1 is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from fluorine  (C1-C4)-alkyl and oxo;

Het2 is a saturated  monocyclic  4-membered to 7-membered heterocyclic group which comprises a ring nitrogen atom via which the group Het2 is bonded and optionally an additional ring heteroatom chosen from N  O and S  wherein the additional ring nitrogen atom carries a hydrogen atom or a substituent chosen from (C1-C4)-alkyl  (C1-C6)-alkyl-O-C(O)- and (C3-C7)-cycloalkyl-CvH2v-O-C(O)-  wherein the ring sulfur atom can carry one or two oxo groups  and wherein Het2 is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from fluorine  (C1-C4)-alkyl and oxo;

m is chosen from 0  1 and 2  wherein all numbers m are independent of each other and can be identical or different;

n is chosen from 0  1  2 and 3;

p and q  which are independent of each other and can be identical or different  are chosen from 2 and 3;

v is chosen from 0  1 and 2  wherein all numbers v are independent of each other and can be identical or different;

wherein all alkyl groups  independently of each other  are optionally substituted by one or more fluorine atoms;

wherein all cycloalkyl groups  independently of each other  are optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl  unless specified otherwise;

wherein all phenyl and heteroaryl groups present in R1 and R5  independently of each other  are optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)2- and cyano.

2. A compound of the formula Ia or Ib as claimed in claim 1  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them  wherein p and q are 2.

3. A compound of the formula Ia or Ib as claimed in one or more of claims 1 and 2  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them  wherein R20 is phenyl which is optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m- and cyano.

4. A compound of the formula Ia or Ib as claimed in one or more of claims 1 to 3  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them  wherein R30 is phenyl which is optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O- and cyano.

5. A compound of the formula Ia or Ib as claimed in one or more of claims 1 and 2  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them  wherein

Ra is chosen from hydrogen and fluorine;

R is chosen from hydrogen and (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents R1  wherein all groups R are independent of each other and can be identical or different  or two groups R bonded to the same carbon atom together are a divalent (C2-C5)-alkyl group;

R1 is chosen from phenyl  hydroxy  (C1-C4)-alkyl O-  R2-N(R3)-C(O)-  R4-O-C(O)- and cyano;

R2 is chosen from hydrogen and (C1-C6)-alkyl which is optionally substituted by one or more identical or different substituents R5  wherein all groups R2 are independent of each other and can be identical or different;

R3  R4  R6  R7 and R8 are chosen from hydrogen and (C1-C4)-alkyl  wherein all groups R3  R4  R6  R7 and R8 are independent of each other and can be identical or different;

R5 is chosen from hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R6 N(R7)-C(O)-  R8-O-C(O)-  cyano  (C3-C7)-cycloalkyl  phenyl  heteroaryl and Het1;

R10 is chosen from hydrogen and (C1-C6)-alkyl-O-C(O)-;

R20 is chosen from phenyl and heteroaryl which are optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m- and cyano;

R30 is chosen from (C5-C7)-cycloalkyl  tetrahydropyranyl  phenyl and heteroaryl  wherein cycloalkyl is optionally substituted by one or more identical or different substituents chosen from fluorine  (C1-C4)-alkyl and hydroxy  and phenyl and heteroaryl are optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O- and cyano;

R40 is chosen from halogen  (C1-C4)-alkyl  (C3-C7)-cycloalkyl-CvH2v-  hydroxy  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)m-  R41-N(R42)-  Het2  R41-N(R42)-C(O)-  Het2-C(O)-  cyano  R41-N(R42)-S(O)2- and Het2-S(O)2-  wherein all substituents R40 are independent of each other and can be identical or different;

R41 is chosen from hydrogen and (C1-C4)-alkyl  wherein all groups R41 are independent of each other and can be identical or different;

R42 is chosen from hydrogen and (C1-C4)-alkyl  wherein all groups R42 are independent of each other and can be identical or different;

Y is chosen from N  CH and C((C1-C4)-alkyl);

heteroaryl is an aromatic monocyclic  5-membered or 6-membered  heterocyclic group which comprises 1 or 2 identical or different ring heteroatoms chosen from N  O and S  wherein one of the ring nitrogen atoms can carry a hydrogen atom or a (C1-C4)-alkyl substituent  and wherein the heteroaryl group is bonded via a ring carbon atom;

Het1 is a saturated  monocyclic  4-membered to 7-membered heterocyclic group which comprises 1 or 2 identical or different ring heteroatoms chosen from N  O and S  wherein the group Het1 is bonded via a ring carbon atom or a ring nitrogen atom  wherein ring nitrogen atoms can carry a hydrogen atom or a substituent chosen from (C1-C4)-alkyl and (C1-C6)-alkyl-O-C(O)-  wherein ring sulfur atoms can carry one or two oxo groups  and wherein Het1 is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from fluorine  (C1-C4)-alkyl and oxo;

Het2 is a saturated  monocyclic  4-membered to 7-membered heterocyclic group which comprises a ring nitrogen atom via which the group Het2 is bonded and optionally an additional ring heteroatom chosen from N  O and S  wherein the additional ring nitrogen atom carries a hydrogen atom or a substituent chosen from (C1-C4)-alkyl and (C1-C6)-alkyl-O-C(O)-  wherein the ring sulfur atom can carry one or two oxo groups  and wherein Het2 is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from fluorine  (C1-C4)-alkyl and oxo;

m is chosen from 0  1 and 2  wherein all numbers m are independent of each other and can be identical or different;

n is chosen from 0  1 and 2;

p and q are 2;

v is chosen from 0  1 and 2  wherein all numbers v are independent of each other and can be identical or different;

wherein all alkyl groups  independently of each other  are optionally substituted by one or more fluorine atoms;

wherein all cycloalkyl groups  independently of each other  are optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl  unless specified otherwise;

wherein all phenyl and heteroaryl groups present in R1 and R5  independently of each other  are optionally substituted by one or more identical or different substituents chosen from halogen  (C1-C4)-alkyl  (C1-C4)-alkyl-O-  (C1-C4)-alkyl-S(O)2- and cyano.

6. A compound of the formula Ia or Ib as claimed in one or more of claims 1 to 5  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them  wherein one  two or three of the groups R are independently of each other chosen from hydrogen  (C1-C6)-alkyl which is optionally substituted by one  two or three identical or different substituents R1  and (C3-C7)-cycloalkyl  or two of these groups R bonded to the same carbon atom together are a divalent (C2-C5)-alkyl group  and all other groups R are hydrogen.

7. A compound of the formula Ia or Ib as claimed in one or more of claims 1 to 6  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them  which is a compound of the formula Ia.

8. A compound of the formula Ia or Ib as claimed in one or more of claims 1 to 6  in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio  or a physiologically acceptable salt thereof  or a physiologically acceptable solvate of any of them  which is a compound of the formula Ib.

9. A process for the preparation of a compound of the formula Ia or Ib or its salt or a solvate thereof as claimed in one or more of claims 1 to 8  comprising reacting a compound of the formula IIa or IIb with a compound of the formula III to give a compound of the formula IVa or IVb 

wherein R  Ra  R20  R30  R40  Y  n  p and q are defined as in claims 1 to 8 and additionally functional groups can be present in protected form or in the form of a precursor group  and R50 is defined as R10 in claims 1 to 8 with the exception of hydrogen  or R50 is a protective group  and removing the protective group R50 in case of the preparation of a compound of the formula Ia or Ib in which R10 is hydrogen.

10. A compound of the formula Ia or Ib as claimed in one or more of claims 1 to 8 or a physiologically acceptable salt thereof or a physiologically acceptable solvate of any of them for use as a pharmaceutical.

11. A pharmaceutical composition  which comprises at least one compound of the formula Ia or Ib as claimed in one or more of claims 1 to 8 or a physiologically acceptable salt thereof or a physiologically acceptable solvate of any of them and a pharmaceutically acceptable carrier.

12. The use of a compound of the formula Ia or Ib as claimed in one or more of claims 1 to 8 or a physiologically acceptable salt thereof or a physiologically acceptable solvate of any of them for the manufacture of a medicament for the treatment of hypertension  heart failure  cardiac infarction  angina pectoris  cardiac insufficiency  cardiac hypertrophy  cardiac fibrosis  vascular hypertrophy  left ventricular dysfunction  restenosis  renal fibrosis  renal ischemia  renal failure  kidney insufficiency  nephropathy  retinopathy  ischemic or obstructive peripheral circulation disorder  glaucoma or end-organ damage.

Abstract

Cyclic (aza)indolizinecarboxamides  their preparation and their use as pharmaceuticals

The present invention relates to cyclic indolizinecarboxamides and azaindolizinecarboxamides of the formulae Ia and Ib 

wherein R  Ra  R10  R20  R30  R40  Y  n  p and q have the meanings indicated in the claims  which are valuable pharmaceutical active compounds. Specifically  they inhibit the enzyme renin and modulate the activity of the renin-angiotensin system  and are useful for the treatment of diseases such as hypertension  for example. The invention furthermore relates to processes for the preparation of the compounds of the formulae Ia and Ib  their use and pharmaceutical compositions comprising them.