WO2008092861A1

WO2008092861A1 - Bicyclic derivatives as ep4 agonists

Info

Publication number: WO2008092861A1
Application number: PCT/EP2008/051044
Authority: WO
Inventors: Joannes Theodorus Maria Linders; Guy Rosalia Eugeen Van Lommen; Louis Jozef Elisabeth Van Der Veken; Robert Jozef Maria Hendrickx; Jean Pierre Frans Van Wauwe; Jeroen Marcel Maria Roger Aerssens; Mansoor D'lavari; Sorin-Vasile Filip; Kenneth Andrew Lowerson; Petr Vladimirivich Davidenko; Mikhail Viktorovich Reynov
Original assignee: Janssen Pharmaceutica N.V.
Priority date: 2007-01-30
Filing date: 2008-01-29
Publication date: 2008-08-07

Abstract

The present invention relates to a compound of formula (I) including any stereochemically isomeric form thereof, wherein ring E represents a partiallysaturated or aromatic 5-membered heterocycle wherein the dotted lines represent an optional double bond and wherein B, C and D each independently represents CH 2, CH, N, NH, S or O and F represents N or C, provided that the 5-membered ring contains 1, 2 or 3 heteroatoms; X represents a direct bond or C 1-4alkanediyl; Y represents N or CH; R1 represents hydrogen or fluoro; R2 represents hydrogen, halo, cyano, C 1-6alkyl, C 1-6alkyloxy, C 1-6alkylcarbonyl or C 1-6alkylcarbonylamino; R3 represents hydrogen, halo, C 1-6alkyl, C 1-6alkyloxy, cyano, nitro, amino or mono-or di(C 1-6alkyl)amino; R4 represents halo; hydroxyl; carboxyl; optionallysubstituted C 1-6alkyl; polyhaloC 1-6alkyl; C 1-6alkyloxycarbonyl; polyhaloC 1-6alkyloxy; optionallysubstituted C 2-6alkenyl; cyano; nitro; NR10 R11; C 1-6alkylthio; optionally substituted C 1-6alkyloxy; or two adjacent R4 substituents may be taken together; n represents an integer of value 1, 2 or 3; m represents aninteger of value 1, 2 or 3; provided that R3 may onlybe other than hydrogen if at least one of R1 or R2 is other than hydrogen; and provided that2,6- bis(1,1-dimethylethyl)-4-[6-(2-phenylethoxy)-1H-purin-2-yl]-phenol is not included; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. The claimed compounds are useful for the treatment of a disease by activating the EP4 receptor.

Description

BICYCLIC DERIVATIVES AS EP4 AGONISTS

Field of the invention The present invention concerns bicyclic derivatives having EP4 receptor agonistic properties. The invention further relates to methods for their preparation and pharmaceutical compositions comprising them. The invention also relates to the use of said compounds for the manufacture of a medicament for the prevention or the treatment of a disease by activating the EP4 receptor.

Background prior art

WO2005/047268 relates to substituted pyrimidine compositions that are capable of modulating the activity of receptors of the NGFI-B family.

WO2006/030031 relates to thieno -pyridine and thieno -pyrimidine derivatives that are positive allosteric modulators of metabotropic receptors-subtype 2.

WO2005/116010 relates to phenyl or pyridyl derivatives having EP4 agonistic activity.

EP 1544202 relates to herbicidal compounds.

US2006/128729 describes bicyclic pyrazole derivatives for the treatment of diseases associated with cellular proliferation, diseases related to glycosidase expression or inflammatory conditions.

EP675124 relates to purine derivatives as anti- inflammatory agents.

US2006/084650 discloses (pyrazolyl)(imidazopyrimidinyl)amines as kinase inhibitors.

Description of the invention The compounds of the invention differ from the prior art compounds in structure, in their pharmacological activity and/or pharmacological potency.

One aspect of the present invention relates to a compound of formula

including any stereochemical^ isomeric form thereof, wherein ring E represents a partially saturated or aromatic 5-membered heterocycle wherein the dotted lines represent an optional double bond and wherein B, C and D each independently represent CH₂, CH, N, NH, S or O and F represents N or C, provided that the 5-membered ring contains 1, 2 or 3 heteroatoms; X represents a direct bond or Ci_₄alkanediyl; Y represents N or CH; R¹ represents hydrogen or fluoro;

R² represents hydrogen, halo, cyano, Ci_₆alkyl, Ci_₆alkyloxy, Ci_₆alkylcarbonyl or C i -βalky lcarbony lamino ; R³ represents hydrogen, halo, Ci_6alkyl, Ci_6alkyloxy, cyano, nitro, amino or mono-or di(C i _₆alkyl)amino ;

R⁴ represents halo; hydroxyl; carboxyl; Ci_6alkyl optionally substituted with one or two substituents, each substituent independently selected from NR¹⁰R¹¹, cyano, carboxyl or Ci_₆alkyloxycarbonyl; polyhaloCi-βalkyl; Ci_₆alkyloxycarbonyl; polyhaloCi-βalkyloxy; C₂-₆alkenyl optionally substituted with one or two substituents, each substituent independently selected from cyano, carboxyl or

Ci_₆alkyloxycarbonyl; cyano; nitro; NR¹⁰R¹¹; Ci_₆alkylthio; C i_₆alkyloxy optionally substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from hydroxyl, halo, cyano, carboxyl, Ci_₆alkyloxycarbonyl or NR⁵R⁶; or two adjacent R⁴ substituents may be taken together to form a radical of formula -0-CH₂-O- (a-1);

-0-CH₂-CH₂-O- (a-2); or -CH=CH-Z- (a-3); with Z representing O, S or NH;

R⁵ and R⁶ each independently represent hydrogen; Ci_₆alkyl optionally substituted with

Ci_₄alkyloxy; C₂-₆alkenyl; or C₃-₆cycloalkyl; or

RR⁵⁵ aanndd F R⁶ together with the nitrogen atom to which they are attached form a radical of formula

_{with A} representing O, NR⁷, CR⁸R⁹ or S and wherein one or more ring carbon atoms may optionally be substituted with Ci_₄alkyl or oxo; R⁷ represents hydrogen; Ci_₆alkyl optionally substituted with hydroxyl; C₂-₆alkenyl; Ci _ βalkylcarbonyl; Ci_₆alkyloxycarbonyl; arylCi-βalkyl; arylcarbonyl; or aryl; R⁸ and R⁹ each independently represent hydrogen; Ci_₆alkyloxy; Ci_₆alkylcarbonyl; arylcarbonyl; halo; amino; mono-or di(Ci_6alkyl)amino; Ci_6alkyl optionally substituted with hydroxyl; Ci_₆alkyloxycarbonylCi_₆alkyl; or C₂-₆alkenyl; or

R⁸ and R⁹ together with the carbon atom to which they are attached represent C(=O) or a 5, 6 or 7-membered saturated heterocyclic ring containing 1 or 2 oxygen atoms;

R¹⁰ and R¹¹ each independently represent hydrogen; Ci_₆alkyl optionally substituted with one or two substituents, each substituent independently selected from hydroxyl, Ci_

₄alkyloxy or Ci_₄alkyloxycarbonyl; or R¹²-C(=O)-;

R¹² represents Ci_₄alkyl; Ci_₄alkyloxy; piperidinyl optionally substituted with Ci_₄alkylcarbonyl; or aryl; n represents an integer of value 1, 2 or 3; m represents an integer of value 1, 2 or 3; p and q each independently represent an integer of value 0, 1, 2 or 3; aryl represents phenyl or phenyl substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from halo,

Ci_₆alkyl, Ci_₆alkyloxy, Ci_₆alkylcarbonyl, cyano, nitro, amino or mono-or di(C i _₆alkyl)amino ; provided that R³ may only be other than hydrogen if at least one of R¹ or R² is other than hydrogen; and provided that 2,6-bis(l , 1 -dimethylethyl)-4-[6-(2-phenylethoxy)- lH-purin-2-yl]-phenol is not included; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

The present invention also relates to the use of a compound of formula (I) for the manufacture of a medicament for preventing or treating a disease by activating the EP4 receptor, in particular for treating a disease by activating the EP4 receptor, in particular for preventing or treating, in particular for treating, a disease associated with loss of bone mass, wherein the compound is a compound of formula

-0-CH₂-CH₂-O- (a-2); or -CH=CH-Z- (a-3); with Z representing O, S or NH;

Ci_₄alkyloxy; C₂-₆alkenyl; or C₃-₆cycloalkyl; or

₄alkyloxy or Ci_₄alkyloxycarbonyl; or R¹²-C(=O)-;

R¹² represents Ci_4alkyl; Ci_4alkyloxy; piperidinyl optionally substituted with Ci_₄alkylcarbonyl; or aryl; n represents an integer of value 1, 2 or 3; m represents an integer of value 1, 2 or 3; p and q each independently represent an integer of value 0, 1, 2 or 3; aryl represents phenyl or phenyl substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from halo,

Ci_₆alkyl, Ci_₆alkyloxy, Ci_₆alkylcarbonyl, cyano, nitro, amino or mono-or di(C i _₆alkyl)amino ; provided that R³ may only be other than hydrogen if at least one of R¹ or R² is other than hydrogen; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

As used hereinbefore or hereinafter Ci_4alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl; Ci_₆alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the group defined for Ci_4alkyl and pentyl, hexyl, 2-methylbutyl and the like; Ci_4alkanediyl defines straight or branched chain saturated bivalent hydrocarbon radicals having from 1 to 4 carbon atoms such as methylene, 1 ,2-ethanediyl or 1 ,2-ethylidene, 1,3-propanediyl or 1,3-propylidene, 1 ,4-butanediyl or 1 ,4-butylidene and the like; C2-6alkenyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and having 1 double bond such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, 3-methylbutenyl and the like; C_{3 6}cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term halo is generic to fluoro, chloro, bromo and iodo. As used hereinbefore or hereinafter, polyhaloCi-βalkyl as a group or part of a group is defined as mono- or polyhalosubstituted Ci_6alkyl, for example methyl substituted with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl, 1,1-difluoro-ethyl, 1,1-difluoro- 2,2,2-trifluoro-ethyl and the like. In case more than one halogen atoms are attached to a Ci_₆alkyl group within the definition of polyhaloCi-βalkyl, they may be the same or different.

Particular examples of 5, 6 or 7-membered saturated heterocyclic rings comprising 1 or 2 oxygen atoms are tetrahydrofuranyl, dioxolanyl, dihydrooxazolyl, isoxazolidinyl, oxadiazolidinyl, dioxanyl, morpholinyl, dioxepanyl.

When any variable occurs more than one time in any constituent, each definition is independent.

For therapeutic use, salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.

The pharmaceutically acceptable salts as mentioned hereinbefore or hereinafter are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxy- acetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-l,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.

The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. The pharmaceutically acceptable salts as mentioned hereinbefore or hereinafter are meant to also comprise the therapeutically active non-toxic metal or amine addition salt forms (base addition salt forms) which the compounds of formula (I) are able to form. Appropriate base addition salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine, JV-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)- 1 ,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.

Conversely the salt form can be converted by treatment with acid into the free acid form.

The term salt also comprises the quaternary ammonium salts (quaternary amines) which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted Ci_6alkylhalide, arylhalide, Ci_6alkylcarbonylhalide, arylcarbonylhalide, or arylCi-βalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as for example Ci_6alkyl trifluoromethanesulfonates, Ci_6alkyl methanesulfonates, and Ci_6alkyl/?-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate, acetate, triflate, sulfate, sulfonate. The counterion of choice can be introduced using ion exchange resins.

The term solvate comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form, as well as the salts thereof. Examples of such forms are e.g. hydrates, alcoholates and the like.

The iV-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide.

It will be appreciated that some of the compounds of formula (I) and their JV-oxides, salts, and solvates may contain one or more centers of chirality and exist as stereochemically isomeric forms. The term "stereochemically isomeric forms" as used hereinbefore or hereinafter defines all the possible stereoisomeric forms which the compounds of formula (I), and their TV-oxides, salts, or solvates may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I) and their JV-oxides or salts, substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. Thus, when a compound of formula (I) is for instance specified as (E), this means that the compound is substantially free of the (Z) isomer.

In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans- configuration. Compounds encompassing double bonds can have an E (entgegen) or Z (zusammen) -stereochemistry at said double bond. The terms cis, trans, R, S, E and Z are well known to a person skilled in the art.

Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.

Following CAS-nomenclature conventions, when two stereogenic centers of known absolute configuration are present in a molecule, an R or S descriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the lowest-numbered chiral center, the reference center. The configuration of the second stereogenic center is indicated using relative descriptors [R*,R* ] or [i?*,i_>*], where the first R* is always specified as the reference center and [R*,R*] indicates centers with the same chirality and [i?*,i_>*] indicates centers of unlike chirality. For example, if the lowest-numbered chiral center in the molecule has an S configuration and the second center is R, the stereo descriptor would be specified as S-[R*, S*]. If "α" and "β" are used : the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest ring number, is arbitrarily always in the "α" position of the mean plane determined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is denominated "α", if it is on the same side of the mean plane determined by the ring system, or "β", if it is on the other side of the mean plane determined by the ring system. The compounds of (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula (I) are intended to be included within the scope of the present invention.

Whenever used hereinafter, the term "compounds of formula (I)" or any subgroup thereof, is meant to also include their JV-oxide forms, their salts, their stereochemically isomeric forms and their solvates. Of special interest are those compounds of formula (I) which are stereochemically pure.

Whenever used hereinbefore or hereinafter that substituents can be selected each independently out of a list of numerous definitions, all possible combinations are intended which are chemically possible.

A first interesting embodiment of the present invention are those compounds of formula (I) having the following formula

including any stereochemically isomeric form thereof, wherein ring E represents a partially saturated or aromatic 5-membered heterocycle wherein the dotted lines represent an optional double bond and wherein B, C and D each independently represent CH₂, CH, N, NH, S or O provided that the 5-membered ring contains 1 or 2 heteroatoms;

X represents a direct bond or Ci_4alkanediyl;

R¹ represents hydrogen or fluoro;

R² represents hydrogen, halo, cyano, Ci_₆alkyl, Ci_₆alkyloxy, Ci_₆alkylcarbonyl or

C i -βalky lcarbony lamino ; R³ represents hydrogen, halo, Ci_6alkyl, Ci_6alkyloxy, cyano, nitro, amino or mono-or di(C i _₆alkyl)amino ;

R⁴ represents halo; hydroxyl; carboxyl; Ci_6alkyl optionally substituted with one or two substituents, each substituent independently selected from cyano, carboxyl or

Ci_₆alkyloxycarbonyl; polyhaloCi-βalkyl; Ci_₆alkyloxycarbonyl; polyhaloCi-βalkyloxy; C₂-₆alkenyl optionally substituted with one or two substituents, each substituent independently selected from cyano, carboxyl or Ci_₆alkyloxycarbonyl; cyano; nitro; amino; mono-or di(Ci_6alkyl)amino; Ci_6alkyloxy optionally substituted with at least one substituent, each substituent independently selected from hydroxyl, halo, cyano, carboxyl, Ci_₆alkyloxycarbonyl or NR⁵R⁶; R⁵ and R⁶ each independently represent hydrogen, Ci_₆alkyl, C₂-₆alkenyl, or

C₃-₆cycloalkyl; or RR⁵⁵ aanndd F R⁶ together with the nitrogen atom to which they are attached form a radical of formula

_{with A} representing O, NR⁷, CR⁸R⁹ or S; R , 7' represents hydrogen, Ci_₆alkyl, C₂-₆alkenyl, Ci_₆alkylcarbonyl,

Ci_₆alkyloxycarbonyl, arylCi-βalkyl or aryl;

R⁸ and R⁹ each independently represent hydrogen, Ci_₆alkyloxy, halo, amino, mono-or di(Ci_₆alkyl)amino, C_halky!, Ci_₆alkyloxycarbonylCi_₆alkyl or C₂-₆alkenyl; or

R⁸ and R⁹ together with the carbon atom to which they are attached represent C(=O) or a 5, 6 or 7-membered saturated heterocyclic ring containing 1 or 2 oxygen atoms; n represents an integer of value 1, 2 or 3; m represents an integer of value 1, 2 or 3; p and q each independently represent an integer of value 0, 1, 2 or 3; aryl represents phenyl or phenyl substituted with at least one substituent, each substituent independently selected from halo, Ci_6alkyl, Ci_6alkyloxy, cyano, nitro, amino or mono-or di(Ci_6alkyl)amino; provided that R³ may only be other than hydrogen if at least one of R¹ or R² is other than hydrogen; and provided that 2,6-bis( 1 , 1 -dimethylethyl)-4- [6-(2-phenylethoxy)- 1 H-purin-2-yl] -pheno 1 is not included; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

A second interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein X represents a direct bond.

A third interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein X represents Ci_4alkanediyl, in particular CH₂.

A fourth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R¹ represents hydrogen or wherein R¹ represents fluoro.

A fifth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R² represents hydrogen, halo, cyano, Ci_6alkyl, Ci_6alkyloxy or Ci_ βalkylcarbonylamino; in particular hydrogen, halo, cyano, Ci_6alkyl or Ci_6alkyloxy.

A sixth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R represents hydrogen, halo, Ci_₆alkyl or Ci_₆alkyloxy; more in particular hydrogen.

A seventh interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R⁴ represents halo; hydroxyl; carboxyl; Ci_₆alkyl optionally substituted with one or two substituents, in particular one substituent, each substituent independently selected from NR¹⁰R¹¹, cyano, carboxyl or Ci_₆alkyloxycarbonyl; polyhaloCi-βalkyl; Ci_₆alkyloxycarbonyl; polyhaloCi-βalkyloxy; C₂-₆alkenyl optionally substituted with one or two substituents, in particular one substituent, each substituent independently selected from cyano, carboxyl or Ci_₆alkyloxycarbonyl; cyano; nitro; NR¹⁰R¹¹; Ci_6alkylthio; Ci_6alkyloxy optionally substituted with at least one substituent, in particular one, two or three substituents, more in particular one or two substituents, each substituent independently selected from hydroxyl, halo, cyano, carboxyl, Ci_ βalkyloxycarbonyl or NR⁵R⁶; or two adjacent R⁴ substituents may be taken together to form a radical of formula

-0-CH₂-O- (a-1); -0-CH₂-CH₂-O- (a-2); or

-CH=CH-Z- (a-3); with Z representing O, S or NH; in particular R⁴ represents halo; hydroxyl; Ci_₆alkyl optionally substituted with NR¹⁰R¹¹; polyhaloCi-βalkyl; Ci_₆alkyloxycarbonyl; C₂-₆alkenyl substituted with carboxyl or Ci_₆alkyloxyarbonyl; cyano; nitro; NR¹⁰R¹¹; Ci_6alkylthio; Ci_6alkyloxy optionally substituted with one or two substituents, each substituent independently selected from hydroxyl, halo, cyano, Ci_ βalkyloxycarbonyl or NR⁵R⁶; or two adjacent R⁴ substituents may be taken together to form a radical of formula

-0-CH₂-O- (a-1); -0-CH₂-CH₂-O- (a-2); or

-CH=CH-Z- (a-3); with Z representing O; wherein R⁵ and R⁶ each independently represent Ci_₆alkyl optionally substituted with Ci_₄alkyloxy; C₃-₆cycloalkyl; or R 5 and

R⁶ together with the nitrogen atom to which they are attached form a radical of formula

_{with A} representing O, NR⁷, CH₂ or S ; more in particular R⁴ represents halo; hydroxyl; Ci_₆alkyl; Ci_₆alkyloxycarbonyl; C₂-₆alkenyl substituted with carboxyl; cyano; Ci_6alkyloxy optionally substituted with cyano, carboxyl, Ci_

— N A (_a_i) βalkyloxycarbonyl or a radical of formula ^ — ' with A representing O, CH₂ or S; even more in particular R⁴ represents halo; hydroxyl; Ci_₆alkyl; Ci_₆alkyloxycarbonyl; cyano; C₂-₆alkenyl substituted with carboxyl;

Ci_₆alkyloxy optionally substituted with cyano, Ci_₆alkyloxycarbonyl or a radical of

— N A (_a-i) formula ^ — ' with A representing O or CH₂; still more in particular R represents halo; Ci_6alkyloxy optionally substituted with cyano, Ci_6alkyloxycarbonyl or — N A (_a-i) a radical of formula ^ — ' with A representing O or CH₂; cyano; hydroxy 1;

Ci_₆alkyl; C₂-₆alkenyl substituted with carboxyl; yet even more in particular R⁴ represents halo; Ci_6alkyloxy optionally substituted with cyano, Ci_6alkyloxycarbonyl or

— N A (_a-i) a radical of formula ^ — ' with A representing O or CH₂; cyano; hydroxy 1; or Ci_₆alkyl.

An eighth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R⁴ represents halo; hydroxyl; carboxyl; Ci_₆alkyl optionally substituted with one or two substituents, each substituent independently selected from NR¹⁰R¹¹, cyano, carboxyl or Ci_6alkyloxycarbonyl; polyhaloCi-βalkyl; Ci_ βalkyloxycarbonyl; polyhaloCi-βalkyloxy; C₂-₆alkenyl optionally substituted with one or two substituents, each substituent independently selected from cyano, carboxyl or Ci_ βalkyloxycarbonyl; cyano; nitro; NR¹⁰R¹¹; Ci_₆alkylthio; C i_₆alkyloxy optionally substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from hydroxyl, halo, cyano, carboxyl, Ci_₆alkyloxycarbonyl or NR⁵R⁶; or two adjacent R⁴ substituents may be taken together to form a radical of formula -0-CH₂-O- (a-1); -0-CH₂-CH₂-O- (a-2); or

-CH=CH-Z- (a-3); with Z representing O, S or NH; provided that if R⁴ represents hydroxyl, then said hydroxyl is placed in ortho or meta position.

A ninth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R⁴ represents halo; hydroxyl; carboxyl; Ci_₆alkyl optionally substituted with one or two substituents, each substituent independently selected from NR¹⁰R¹¹, cyano, carboxyl or Ci_₆alkyloxycarbonyl; polyhaloCi-βalkyl;

Ci_₆alkyloxycarbonyl; polyhaloCi-βalkyloxy; C₂-₆alkenyl optionally substituted with one or two substituents, each substituent independently selected from cyano, carboxyl or Ci_ ₆alkyloxycarbonyl; cyano; nitro; NR¹⁰R¹¹; Ci_₆alkylthio; C i_₆alkyloxy optionally substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from hydroxyl, halo, cyano, carboxyl,

Ci_₆alkyloxycarbonyl or NR⁵R⁶; or two adjacent R⁴ substituents may be taken together to form a radical of formula

-0-CH₂-O- (a-1); -0-CH₂-CH₂-O- (a-2); or

-CH=CH-Z- (a-3); with Z representing O, S or NH; provided that if R⁴ represents t-butyl, then said t-butyl is placed in ortho or para position.

A tenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein m represents 1 or 2, in particular 1.

An eleventh interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein n represents 1.

A twelfth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein p represents 1, 2 or 3, in particular 1 or 2, more in particular 1.

A thirteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein q represents 1 , 2 or 3, in particular 1 or 2, more in particular 1.

A fourteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R¹ is fluoro and R² is hydrogen.

A fifteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R¹ is hydrogen and R² is halo, cyano, C^aUcyl, Ci_6alkyloxy, Ci_ βalkylcarbonyl or Ci_₆alkylcarbonylamino; more in particular R¹ is hydrogen and R² represents halo, cyano, d-βalkylcarbonyl, Ci_6alkyloxy or Ci_6alkylcarbonylamino. A sixteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R¹ is fluoro and R² is halo, cyano, Ci_6alkyl, Ci_6alkyloxy, Ci_6alkylcarbonyl or Ci_6alkylcarbonylamino; more in particular R¹ is fluoro and R² represents halo, cyano, Ci_6alkylcarbonyl, Ci_6alkyloxy or Ci_6alkylcarbonylamino.

A seventeenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R¹ and R² are both hydrogen.

An eighteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein Y represents N.

A nineteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein Y represents CH.

A twentieth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein F represents C and the dotted line attached to F represents a bond.

A twenty first interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein F represents N and the dotted line attached to F does not represents a bond.

A twenty second interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein B, C and D each independently represents CH₂, CH, N, NH or O.

A twenty third interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the dotted lines at B, C and D in ring E do not represent a bond. A twenty fourth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein ring E does not represent pyrazole.

A twenty fifth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein ring E contains 1 or 2 heteroatoms.

A twenty sixth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R¹² represents Ci_₄alkyl; Ci_₄alkyloxy; or aryl. ; in particular wherein R¹² represents Ci_4alkyl or Chalky Io xy.

A twenty seventh interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R⁸ and R⁹ each independently represent hydrogen; Ci_₆alkyloxy; Ci_₆alkylcarbonyl; arylcarbonyl; halo; amino; mono-or di(Ci_6alkyl)amino; Ci_6alkyl optionally substituted with hydroxyl; Ci_₆alkyloxycarbonylCi_₆alkyl; or C₂-₆alkenyl.

A twenty eighth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is a compound having the following formula

including any stereochemical^ isomeric form thereof; a JV-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

A twenty nineth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is a compound having the following formula

including any stereochemically isomeric form thereof; a JV-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

A thirtieth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is a compound having the following formula

including any stereochemically isomeric form thereof; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

A thirty first interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is a compound having the following formula

A thirty second interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is a compound having the following formula

A thirty third interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is a compound having the following formula

including any stereochemically isomeric form thereof, a JV-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

A thirty fourth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is a compound having the following formula

A thirty fifth interesting embodiment of the present invention are those compounds of formula (I), (1-1), (I-l-a), (I-l-b), (I-l-c), (I-l-d), (1-2) or (1-3) wherein one or more, preferably all, of the following restrictions apply : a) X represents a direct bond; b) R² represents hydrogen, halo, cyano, Ci_6alkyl or Ci_6alkyloxy; c) R³ represents hydrogen, halo, Ci_₆alkyl or Ci_₆alkyloxy; more in particular hydrogen; d) R⁴ represents halo; hydroxyl; Ci_6alkyl optionally substituted with NR¹⁰R¹¹; polyhaloCi-βalkyl; Ci_₆alkyloxycarbonyl; C₂-₆alkenyl substituted with carboxyl or Ci_₆alkyloxycarbonyl; NR¹⁰R¹¹; Ci_₆alkylthio; cyano; nitro; C i_₆alkyloxy optionally substituted with one or two substituents, each substituent independently being selected from halo, hydroxyl, cyano, Ci_₆alkyloxycarbonyl, or NR⁵R⁶; or two adjacent R⁴ substituents may be taken together to form a radical of formula -0-CH₂-O- (a-1);

-0-CH₂-CH₂-O- (a-2); or -CH=CH-Z- (a-3); with Z representing O; e) n represents 1 ; f) m represents 1 or 2, in particular 1; g) R⁵ or R⁶ each independently represent Ci_₆alkyl optionally substituted with Ci_₄alkyloxy; or C₃_₆Cycloalkyl; or R⁵ and R⁶ together with the nitrogen atom to which they are attached form a radical of formula

_with A representing O, NR⁷, CR⁸R⁹ or S and wherein one or two ring carbon atoms may optionally be substituted with Ci_₄alkyl or oxo; h) R⁷ represents hydrogen; Ci_₆alkyl optionally substituted with hydroxyl; Ci_₆alkylcarbonyl; aryl; i) R⁸ and R⁹ each independently represent hydrogen; Ci_₆alkyloxycarbonylCi_₆alkyl; Ci_ ₆alkylcarbonyl; arylcarbonyl; j) R¹⁰ and R¹¹ each independently represent hydrogen; Ci_₆alkyl optionally substituted with one or two substituents, each substituent independently selected from hydroxyl, C

₄alkyloxy or Ci_₄alkyloxycarbonyl; R 12 -C(=O)-; k) R¹² represents Ci_₄alkyl; Ci_₄alkyloxy; aryl; piperidinyl optionally substituted with C i _₄alkylcarbonyl; 1) p represents 1 ; m) q represents 1 or 2; n) aryl represents phenyl substituted with halo or Ci_₆alkylcarbonyl.

A thirty sixth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is selected from the group consisting of 4-[4-(2-Fluoro-phenoxy)-thieno[3,2-d]pyrimidin-2-yl]-benzonitrile; 4-[2-(4-Fluoro- phenyl)-thieno[3,2-d]pyrimidin-4-yloxy]-benzonitrile; 4-[4-(4-Fluoro-phenoxy)- thieno[3,2-d]pyrimidin-2-yl]-benzonitrile; 3-Fluoro-4-[2-(4-fluoro-phenyl)-thieno[3,2- d]pyrimidin-4-yloxy]-benzonitrile; l-[4-(2-{4-[4-(2,4-Difluoro-phenoxy)-thieno[3,2- d]pyrimidin-2-yl]-phenoxy} -ethyl)-[ 1 ,4]iazepan- 1 -yl]-ethanone; 1 -[4-(3- {2-Bromo-4- [4-(2,4-difluoro-phenoxy)-thieno[3,2-d]pyrimidin-2-yl]-phenoxy}-2-hydroxy-propyl)- piperazin-l-yl]-ethanone; l-[4-(2-{2-Bromo-4-[4-(2,4-difluoro-phenoxy)-thieno[3,2- d]pyrimidin-2-yl]-phenoxy} -ethyl)-piperazin- 1 -yl]-ethanone; 1 -[4-(2- {4-[4-(2,4- Difluoro-phenoxy)-thieno [3 ,2-d]pyrimidin-2-yl] -phenoxy } -ethyl)-piperazin- 1 -yl] - ethanone; 3 -Fluoro-4- [2-(3 -bromo-phenyl)-thieno [3 ,2-d]pyrimidin-4-yloxy] - benzonitrile; 3-Fluoro-4-[2-(3-chloro-phenyl)-thieno[3,2-d]pyrimidin-4-yloxy]- benzonitrile; 3-{4-[4-(2,4-Difluoro-phenoxy)-thieno[3,2-d]pyrimidin-2-yl]-phenyl}- acrylic acid ethyl ester; 2-(3-Bromo-phenyl)-6-(2,4-difluoro-phenoxy)-7H-purine; 4-[2- (3-Bromo-phenyl)-7H-purin-6-yloxy]-3-fluoro-benzonitrile; 3-Fluoro-4-[2-(4-fluoro- phenyl)-pyrrolo[2,l-f][l,2,4]triazin-4-yloxy]-benzonitrile; 3-Fluoro-4-[5-(4-fluoro- phenyl)-thieno[2,3-c]pyridin-7-yloxy]-benzonitrile; a JV-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

In general, compounds of formula (I) can be prepared by reacting an intermediate of formula (II) wherein Wi represents a suitable leaving group, such as for example halo, e.g. chloro and the like, or -O-S(=O)₂-CF₃, with an intermediate of formula (III) in the presence of a suitable base, such as for example K2CO3 or sodium hydride, and a suitable solvent, such as for example acetonitrile or dimethylsulfoxide.

Depending on the ring E moiety, it may be preferred to protect the intermediate of formula (II) before reaction with an intermediate of formula (III), for instance when ring E represents an imidazolyl moiety as in the compounds of formula (I-l-c). Therefore, compounds of formula (I-l-c) can be prepared by reacting in a first step (a), an intermediate of formula (II-a) with an intermediate of formula P-W₂ wherein P represents a suitable protective group, such as for example benzyl or Ci_₄alkyloxyCi_₄alkyl and wherein W₂ represents a suitable leaving group, such as for example halo, e.g. chloro and the like, in the presence of a suitable base, such as for example K2CO3 or sodium hydride, and a suitable solvent, such as for example acetonitrile or dimethylsulfoxide. The product obtained in step (a), is then reacted in a next step (b) with an intermediate of formula (III) in the presence of a suitable base, such as for example K2CO3 or sodium hydride, and a suitable solvent, such as for example acetonitrile or dimethylsulfoxide. The product obtained in step (b) is then deprotected in a next step (c) by reaction with a suitable acid, such as for example hydrochloric acid, in the presence of a suitable solvent, such as for example an alcohol, e.g. methanol, or acetonitrile.

(II-a) (III)

(I-l-c)

The compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.

The compounds of formula (I) may be converted to the corresponding JV-oxide forms following art-known procedures for converting a trivalent nitrogen into its iV-oxide form. Said JV-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert.butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.

Compounds of formula (I) wherein R⁴ represents methoxy, can be converted into a compound of formula (I) wherein R⁴ represents hydroxyl, by reaction with BBr₃ in the presence of a suitable solvent, such as for example dichloromethane.

Compounds of formula (I) wherein R⁴ represents hydroxyl, can be converted into a compound of formula (I) wherein R⁴ represents Chalky Io xy optionally substituted with cyano, halo, carboxyl, Ci_₆alkyloxycarbonyl or NR 5r R> 6 , by reaction with W₃-Ci_₆alkyl-R⁴ wherein W₃ represents a suitable leaving group, such as for example halo, e.g. chloro, and R⁴ represents hydrogen, cyano, halo, carboxyl, Ci_6alkyloxycarbonyl or NR⁵R⁶, in the presence of a suitable base, such as for example K2CO3 or CS2CO3, and a suitable solvent, such as for example acetonitrile, N, N- dimethylformamide or an alcohol, e.g. butanol.

Compounds of formula (I) wherein R⁴ represents Ci_6alkyloxy substituted with halo, can be converted into a compound of formula (I) wherein R⁴ represents Ci_6alkyloxy substituted with NR⁵R⁶, by reaction with HNR⁵R⁶ in the presence of a suitable base, such as for example K2CO3, optionally in the presence of a catalytic amount of KI, and in the presence of a suitable solvent, such as for example acetone or 4-methyl-2- pentanone (MIK).

Compounds of formula (I) wherein R⁴ represents Ci_6alkyloxy substituted with NR⁵R⁶ wherein NR⁵R⁶ represents a radical of formula (a) wherein A represents NH, can be converted into a compound of formula (I) wherein R⁴ represents Ci_6alkyloxy substituted with NR⁵R⁶ wherein NR⁵R⁶ represents a radical of formula (a) wherein A represents N-Q=O)-C₁ -βalkyl, by reaction with a suitable corresponding ester, such as for example acetyl acetate, in the presence of a suitable solvent, such as for example dichloromethane .

This kind of reaction can also be used to convert a compound of formula (I) wherein R⁴ represents NHR¹¹ wherein R¹¹ represents R¹²-C(=O)- with R¹² representing unsubstituted piperidinyl into a compound of formula (I) wherein R⁴ represents NHR¹¹ wherein R¹¹ represents R¹²-C(=O)- with R¹² representing piperidinyl substituted with C ₁ _₄alky lcarbony 1.

Compounds of formula (I) wherein R⁴ represents Ci_6alkyloxy substituted with NR⁵R⁶ wherein NR > 5r R> 6 represents a radical of formula (a) wherein A represents N-C(=O)-O-C βalkyl, can be converted into a compound of formula (I) wherein R represents

Ci_6alkyloxy substituted with NR⁵R⁶ wherein NR⁵R⁶ represents a radical of formula (a) wherein A represents NH, by reaction with a suitable acid, such as for example trifluoroacetic acid, in the presence of a suitable solvent, such as for example dichloromethane .

Compounds of formula (I) wherein R⁴ represents halo, can be converted into a compound of formula (I) wherein R⁴ represents C₂-₆alkenyl optionally substituted with cyano or Ci_₆alkyloxycarbonyl, by reaction with the appropriate C₂-₆alkenyl derivative in the presence of a suitable catalyst, such as for example palladium acetate, a suitable ligand, such as for example l,3-bis(diphenylphosphino)propane, a suitable base, such as for example triethylamine, and a suitable solvent, such as for example tetrahydrofuran. Compounds of formula (I) wherein R⁴ represents

C₂-₆alkenyl substituted with Ci_₆alkyloxycarbonyl can be converted into a compound of formula (I) wherein R⁴ represents C₂-₆alkenyl substituted with carboxyl, by reaction with a suitable base, such as for example sodium hydroxide, and a suitable solvent, such as dioxane.

Compounds of formula (I) wherein R⁴ represents halo, can also be converted into a compound of formula (I) wherein R⁴ represents Ci_₆alkyloxycarbonyl, e.g. CH₃-O-C(=O)-, by reaction with CO and Ci_6alkylOH, e.g. methanol, in the presence of a suitable base, such as for example potassium acetate, a suitable catalyst, such as for example palladium acetate, a suitable ligand, such as for example l,3-bis(diphenylphosphino)propane, and a suitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R⁴ represents nitro, can be converted into a compound of formula (I) wherein R⁴ represents amino, by hydrogenation in the presence of a suitable catalyst, such as for example palladium on charcoal, a suitable catalyst poison, such as for example a thiophene solution, and a suitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R⁴ represents amino, can be converted into a compound of formula (I) wherein R⁴ represents NHR¹¹ wherein R¹¹ represents Ci_₆alkyl substituted with Ci_₄alkyloxycarbonyl, by reaction with W₃-Ci_₆alkyl-C(=O)- O-Ci_4alkyl wherein W₃ represents a suitable leaving group, such as for example halo, e.g. chloro, in the presence of a suitable base, such as for example sodium hydride, and a suitable solvent, such as for example JV,iV-dimethylforamide.

Compounds of formula (I) wherein R⁴ represents amino, can be converted into a compound of formula (I) wherein R⁴ represents NHR^{1 λ} wherein R^{1 λ} represents R¹²-C(=O)- with R¹² representing aryl, by reaction with aryl-C(=O)-W₃ wherein W₃ represents a suitable leaving group, such as for example halo, e.g. chloro, in the presence of a suitable base, such as for example pyridine, and a suitable solvent, such as for example dichloromethane. Compounds of formula (I) wherein R⁴ represents amino, can be converted into a compound of formula (I) wherein R⁴ represents NHR^{1 λ} wherein R^{1 λ} represents R¹²-C(=O)- with R¹² representing unsubstituted piperidinyl, by reaction with for instance 1 ,4-piperidinedicarboxylic acid, l-(l,l-dimethylethyl) ester followed by deprotecting the piperidine moiety in the presence of a suitable acid, such as for example trifluoroacetic acid, and a suitable solvent, such as for example dichloromethane .

Compounds of formula (I) wherein R⁴ represents cyano, can be converted into a compound of formula (I) wherein R⁴ represents -CH₂-NH₂, by hydrogenation in the presence of a suitable catalyst, such as for example Raney Nickel, a suitable catalyst poison, such as for example a thiophene solution, and a suitable solvent, such as for example methanol/NH₃.

Compounds of formula (I) wherein R⁴ represents -CH₂-NH₂, can be converted into a compound of formula (I) wherein R⁴ represents -CH₂-NH-R^{1 λ} wherein R^{1 λ} represents R¹²-C(=O)-, by reaction with R¹²-C(=O)-W3 wherein W3 represents a suitable leaving group, such as for example halo, e.g. chloro, or CH₃-C(=O)-O-, optionally in the presence of a suitable base, such as for example pyridine, or a suitable solvent, such as for example acetonitrile.

The compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, chiral liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography or SCF (Super Critical Fluid) chromatography, in particular using a chiral stationary phase.

Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared according to art-known procedures.

Intermediates of formula (II) wherein Wi represents chloro, said intermediates being represented by formula (II -b), can be prepared by reacting an intermediate of formula (IV) with SOCl₂ or phosphoric trichloride optionally in the presence of a suitable solvent, such as for example chloroform, N,Λ/-dimethylformamide or N,Λ/-dimethylbenzeneamine.

(II-b)

(IV)

Intermediates of formula (II) wherein Wi represents -O-S(=O)₂-CF₃, said intermediates being represented by formula (II-c), can be prepared by reacting an intermediate of formula (IV) with O(S(=O)2-CF3)2 in the presence of a suitable base, such as for example iV,jV-diisopropylethanamine, and a suitable solvent, such as for example dichloromethane .

(IV) (π-c)

Intermediates of formula (IV) wherein Y represents N, said intermediates being represented by formula (IV-a), can be prepared by cyclizing an intermediate of formula (V) in the presence of an aqueous ammoniak solution or NH₄OH or NH₃ in acetonitrile or an alcohol, e.g. methanol.

(IV-a)

Intermediates of formula (IV-a) can also be prepared by reacting an intermediate of formula (VI) in the presence of a suitable base, such as for example K2CO3, NaOCH₃ or l,8-diazabicyclo[5.4.0]undecene-7 (DBU), and a suitable solvent, such as for example water, alcohol, e.g. ethanol or isopropanol, chlororform.

(IV-a)

Intermediates of formula (IV-a) can also be prepared by reacting an intermediate of formula (XIV) with an intermediate of formula (XIII) in the presence of a suitable base such as for example potassium t-butoxide, and a suitable solvent, such as for example tetrahydrofuran.

(IV-a)

Intermediates of formula (IV-b) can be prepared by reacting an intermediate of formula (VII) with an intermediate of formula (VIII) in the presence of a suitable base, such as for example K2CO3, and a suitable solvent, such as for example water.

Intermediates of formula (IV-c) can be prepared by reacting an intermediate of formula (XII) with an intermediate of formula (XIII) in the presence of lithium diisopropylamide (LDA) and a suitable solvent, such as for example tetrahydrofuran.

(IV-c)

Intermediates of formula (III) and (V) are known in the art or can be prepared according to art-known reactions.

For example intermediates of formula (V) can be prepared by reacting an intermediate of formula (IX) with an intermediate of formula (X) wherein W₄ represents a suitable leaving group, such as for example halo, e.g. chloro and the like, in the presence of a suitable solvent, such as for example acetone or pyridine, and optionally a suitable base, such as for example pyridine or 4-dimethylaminopyridine.

Intermediates of formula (VI) can be prepared by reacting an intermediate of formula (XI) with an intermediate of formula (X) in the presence of a suitable base, such as for example JV,jV-dimethyl-4-pyridme amine, and a suitable solvent, such as for example pyridine.

Intermediates of formula (VI) can also be prepared from the corresponding carboxylic acid derivative of formula (VF) by reaction with ethyl chloro formate and NH3 in the presence of a suitable base, such as for example triethylamine, a suitable solvent, such as for example acetonitrile.

(VI') (VI)

Intermediates of formula (VF) can be prepared by hydrolysis of an intermediate of formula (V) in the presence of a suitable base, such as for example KOH, and a suitable solvent, such as for example an alcohol, e.g. ethanol.

Pharmacological part

The compounds of formula (I) and any subgroup thereof show EP4 agonist properties, in particular selective EP4 agonist properties. EP4 is one of the four subtype receptors (EPl, EP2, EP3 EP4) of prostaglandine E2.

Prostaglandins are arachidonic acid metabolites that are synthetized by the cyclo- oxygenase pathway. A major cyclo-oxygenase product is prostaglandin E₂ (PGE₂), which participates in a broad range of biological activities, such as smooth muscle relaxation, vasodilation, fever, inflammatory pain, enteric mucus secretion, renal regulation and bone formation. Mechanistically, PGE₂ can exert agonistic activities on four G-protein-coupled receptor subtypes, which are termed EPl, EP2, EP3 and EP4. Each of these receptor subtypes has a distinct pharmacological signature based on their ligand preference and coupling to intracellular signalling pathways. The EPl and EP3 receptors are coupled to calcium metabolism and inhibition of cyclic adenosine 5 -monophosphate (cAMP) via GqZG₁ G-proteins. In contrast, EP2 and EP4 are linked to the stimulation of adenylyl cyclase and increased cAMP synthesis via G_s G-proteins.

A considerable number of PGE₂ effects are linked to its activation of the EP4 receptor, as evidenced by experiments using EP4-deficient mice and specific EP4 agonists or antagonists. Thus, EP4-defϊcient mice produce a reduced vasodepressor response following PGE₂ infusion, exhibit decreased contact hypersensitivity and show reduced incidence and intensity of disease in the collagen antibody- induced arthritis model, while they have increased colitis induced by dextran sulphate treatment. Furthermore, the absence of EP4 decreases bone mass and impaired fracture healing in aged male mice, whilst PGE₂ administration fails to induce bone formation in EP4-deficient mice. In rats, administration of EP4 selective agonists suppresses dextran sulphate colitis, restores bone mass and strength in both normal and aged, ovariectomized animals, reduces indomethacin-induced small intestinal ulceration, attenuates endotoxin/galactosamine-induced liver injury, reduces mercury chloride-evoked acute kidney failure and attenuated pain responses in Freund's complete adjuvant-induced joint inflammation. In glaucomatous Cynomolgus monkeys, topical application of an EP4 agonist reduces the increased intraocular pressure. In line with these findings, EP4 antagonists block the bone anabolic effects OfPGE₂ in rats. Unfortunately, the use of PGE₂ in human therapy is compromised by its inability to discern EP receptor subtypes, which leads to a number of untoward effects, including nausea, emesis, diarrhea and hypotension. Rather, based on the abovementioned observations, the use of selective EP4 agonists is believed to be of therapeutic interest, particularly for the treatment of diseases associated with loss of bone mass (primary and secondary osteoporosis, bone fracture, metastatic bone disease, rheumatoid arthritis, osteoarthritis, periodontitis, osteogenesis imperfecta, hypercalcemia), diseases associated with liver injury and acute hepatitis, renal failure and nephritis, ulcerative colitis, Crohn's disease, stomatitis, gastritis, ocular hypertension, glaucoma, neuropathic pain, bone pain, Reflex Sympathetic Dystrophy syndrome (RSD) also known as Complex Regional Pain Syndrome (CRPS)).

Due to their EP4 agonistic activity, the compounds of formula (I), their JV-oxides, pharmaceutically acceptable salts, or solvates are useful for the treatment or prevention, in particular for the treatment, of a disease by activating the EP4 receptor.

In view of the above-described pharmacological properties, the compounds of formula (I), their JV-oxides, pharmaceutically acceptable salts or solvates, may be used as a medicine. In particular, the present compounds can be used for the manufacture of a medicament for treating or preventing a disease by activating the EP4 receptor, in particular for treating a disease by activating the EP4 receptor. More in particular, the compounds of the invention can be used for the manufacture of a medicament for treating or preventing, preferably treating, a disease associated with loss of bone mass (primary and secondary osteoporosis, bone fracture, metastatic bone disease, rheumatoid arthritis, osteoarthritis, periodontitis, osteogenesis imperfecta, hypercalcemia), diseases associated with liver injury and acute hepatitis, renal failure and nephritis, ulcerative colitis, Crohn's disease, stomatitis, gastritis, ocular hypertension, glaucoma, neuropathic pain, bone pain, Reflex Sympathetic Dystrophy syndrome (RSD) also known as Complex Regional Pain Syndrome (CRPS)). In view of the utility of the compounds of formula (I), there is provided a method of treating a warm-blooded mammal, including a human, suffering from or a method of preventing a warm-blooded mammal, including a human, to suffer from a disease by activating the EP4 receptor, in particular a method of treating a warm-blooded mammal, including a human, suffering from a disease by activating the EP4 receptor. Said methods comprise the administration of an effective amount of a compound of formula (I), a JV-oxide form thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, to a warm-blooded mammal, including a human.

The present invention also provides compositions for preventing or treating a disease by activating the EP4 receptor, in particular for treating a disease by activating the EP4 receptor. Said compositions comprise a therapeutically effective amount of a compound of formula (I), a JV-oxide form thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier or diluent.

The compounds of the present invention may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneous Iy, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. The compounds of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds.

The compounds of the present invention may also be topically administered in the form of drops, in particular eye drops. Said eye drops may be in the form of a solution or a suspension. Any system developed for the delivery of solutions or suspensions as eye drops are suitable for the administration of the present compounds.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.

The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

The following examples are intended to illustrate the present invention.

Experimental Part

Hereinafter "DMF" means N,Λ/-dimethylformamide, "DIPE" means diisopropyl ether, "DCM" means dichloromethane, "THF" means tetrahydrofuran, "DMSO" means dimethylsulfoxide and "TFA" means CF₃COOH.

Where solutions were "dried," they were generally dried over a drying agent such as Na₂SO₄ or MgSO₄. Where mixtures, solutions, and extracts were "concentrated", they were typically concentrated on a rotary evaporator under reduced pressure.

A. Preparation of the intermediate compounds

Example Al a-1) Preparation of intermediate 1

3-Methyl-benzoyl chloride (0.018 mol) in acetone (20 ml) was added dropwise to a stirring mixture of 3-amino-2-thiophenecarboxylic acid, methyl ester (0.016 mol) in acetone (130 ml) and pyridine (10 ml). The reaction mixture was stirred overnight. Then the solvent was evaporated and the residue was dissolved in DCM. This solution was washed with H₂O, dried, filtered and the filtrate's solvent was evaporated. The residue was triturated under DIPE. The precipitate was filtered off, yielding 2.3 g of intermediate 1. a-2) Preparation of intermediate 13

Intermediate 13 was prepared according to Al.a-1, but after evaporation of the reaction mixture, the residue was not redissolved in DCM, but was directly triturated under DIPE.

a-3) Preparation of intermediate 18

Intermediate 18 was prepared according to Al.a-1, but was triturated under DIPE/CH₃OH.

a-4) Preparation of intermediate 27

Intermediate 27 was prepared according to Al.a-1, but was triturated under DIPE/2- propanol.

a-5) Preparation of intermediate 56

Intermediate 56 was prepared according to Al. a- 1.

b-1) Preparation of intermediate 2

A mixture of intermediate 1 (0.008 mol) and NH3 in acetonitrile (200 ml) was stirred for 48 hours at 100 ⁰C in a closed vessel. The reaction mixture was cooled and the solvent was evaporated. The residue was triturated under DIPE/CH3OH. The precipitate was filtered off, yielding 1.4 g of intermediate 2 (70 %).

b-2) Preparation of intermediate 14

Intermediate 14 was prepared according to Al. b-1, but starting from intermediate 13.

b-3) Preparation of intermediate 19

Intermediate 19 was prepared according to Al. b-1, but starting from intermediate 18.

b-4) Preparation of intermediate 28

A mixture of intermediate 27 (1 g, 0.0027 mol) and CH3OH/NH3 (200 ml) was reacted for 48 hours at 90 ⁰C. Then the solvent was evaporated. The residue was stirred in DIPE/2-propanol. The precipitate was filtered off and dried. Yield: 0.6 g of intermediate

28. b-5) Preparation of intermediate 47

Intermediate 47 was prepared according to Al.b-4, but starting from 3-[(4-nitrobenzoyl)amino]-2-thiophenecarboxylic acid, methyl ester. The residue was triturated under DIPE/MeOH. Yield: 16.2 g of intermediate 47.

C-I) Preparation of intermediate 3

Phosphoric trichloride (0.005 mol) was added dropwise to a stirring mixture of intermediate 2 (0.0057 mol) in DMF (150 ml) and was stirred for 3 hours. The solvent was evaporated. The residue was dissolved in DCM, washed, dried, filtered and the filtrate's solvent was evaporated. The residue was triturated under DIPE. The precipitate was filtered off, yielding 1 g of intermediate 3.

c-2) Preparation of intermediate 15

Intermediate 15 was prepared according to Al.c-1, but starting from intermediate 14 and with a different work-up. After the reaction, the mixture was poured in H₂O. The resulting mixture was stirred for 10 minutes and was then extracted with ethyl acetate. The separated organic layer was dried (MgSO₄), filtered and the solvent was evaporated, yielding 2.2 g of intermediate 15.

c-3) Preparation of intermediate 20

Intermediate 20 was prepared according to Al.c-1, but starting from intermediate 19 and with a different work-up. After the reaction, the mixture was poured in H₂O and was stirred for 30 minutes. The precipitate was filtered off, yielding 2.7 g of intermediate 20.

c-4) Preparation of intermediate 29

A mixture of intermediate 28 (5.8 g, 0.0172 mol) and phosphoric trichloride (3.6 g, 0.025 mol) in DMF (100 ml) was stirred overnight. The solution was poured in ice water. The precipitate was filtered off and dried (vacuum, 50 ⁰C, 12 hours). Yield: 4.1 of intermediate 29 (67 %).

c-5) Preparation of intermediate 48

Intermediate 48 was prepared according to Al.c-3 (starting from intermediate 47). Yield: 17.0 g of intermediate 48.

Example A2 a-1) Preparation of intermediate 4

3-[(4-methylbenzoyl)amino]-2-thiophenecarboxylic acid, methyl ester (369 g, 1.34 mol) was suspended in a saturated aqueous NH3 solution (11070 ml; 30 ml per g of starting material) and the suspension was heated at 120 ⁰C in a pressure reactor (autoclave). The resulting solution was cooled and the insoluble residue was filtered off, washed with H₂O and dried. The remaining solution was neutralized with concentrated HCl. The resulting precipitate was filtered off, washed with H₂O and dried. Any uncyclized material was refluxed in a NaOH solution for 1 hour. The mixture was cooled and neutralized with HCl (2 N). The precipitate was filtered off, washed with H₂O and dried. The different dried precipitates resulted in intermediate 4 (crude; used as such in the next reaction). a-2) Preparation of intermediate 8

Intermediate 8 was also prepared according to A2.a-1. a-3) Preparation of intermediate 16

Intermediate 16 was also prepared according to A2.a-1.

a-4) Preparation of intermediate 25

Intermediate 25 was also prepared according to A2.a-1.

b-1) Preparation of intermediate 5

A mixture of intermediate 4 (2.9 g, 0.012 mol) and CHCI3 (60 ml, dry) in a flask was heated to reflux temperature. SOCl₂ (4.7 ml) and DMF (5 ml, dry) were added while keeping reflux temperature. The mixture became a solution and was refluxed for 3 hours. The solvent was evaporated in vacuo and then anhydrous toluene was added to the residue and evaporated in vacuo. This was repeated 3 times to remove the last traces Of SOCl₂. The residue was taken up in DCM and this mixture was washed with aqueous sodium bicarbonate (saturated) and then with brine. The separated organic layer was evaporated in vacuo. The residue was purified by column chromatography over silica gel (eluent: hexane/ethyl acetate 10/1). The product fractions (top spot) were collected and the solvent was evaporated. Yield: 0.7 g of intermediate 5.

b-2) Preparation of intermediate 9

A suspension of intermediate 8 (10 g; 0.0406 mol) in CHCI3 (160 ml) was refluxed. A solution of SOCl₂ (5 equiv) in DMF (5 equiv) was added to the suspension while refluxing and the reaction mixture was continued refluxing for 2 hours. Then the solvent was evaporated and the residue was suspended in anhydrous toluene. The solvent was evaporated and the residue was dissolved in DCM. The solution was washed with an aqueous NaHCOs solution (saturated) and brine. The separated organic layer was dried (MgSO₄), filtered and the solvent was evaporated. The residue was slurried with hexane, filtered and dried. Yield: Intermediate 9 (49 %). b-3) Preparation of intermediate 40

Intermediate 40 was prepared according to A2.b-2 starting from 2-(2-chlorophenyl)- thieno[3,2-d]pyrimidin-4(7H)-one.

Example A3 a) Preparation of intermediate 6

A mixture of 3-[(3-fluorobenzoyl)amino]-2-thiophenecarboxylic acid, methyl ester (3.6 g, 0.013 mol) and CH₃OH/NH₃ (200 ml) was stirred at 100 ⁰C in an autoclave for 48 hours. Then the mixture was cooled and the solvent was evaporated. The residue was triturated in DIPE/MeOH. Yield: 2.7 g of intermediate 6 (85 %).

b-1) Preparation of intermediate 7

A mixture of intermediate 6 (2.7 g, 0.01 mol) in DMF (150 ml) was stirred. POCl₃ (3 g, 0.02 mol) was added drop wise and the reaction mixture was stirred for 3 hours. The mixture was poured in H₂O and the resulting mixture was stirred for 30 minutes. The precipitate was filtered off and was then dissolved in DCM. The organic layer was dried, filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried. Yield: 2.2 g of intermediate 7 (85 %).

b-2) Preparation of intermediate 17

Intermediate 17 was prepared according to A3.b-1, but starting from intermediate 16 and the reaction mixture was stirred overnight at room temperature.

Example A4 a-1) Preparation of intermediate 10

2,4-Difluorobenzoyl chloride (0.016 mol) was added dropwise to a stirring mixture of 3-amino-2-thiophenecarboxylic acid, methyl ester (0.016 mol) in acetone (200 ml) and pyridine (20 ml). The reaction mixture was stirred overnight and then the solvent was evaporated. The residue was dissolved in DCM. This mixture was washed with H₂O, dried, filtered and the filtrate's solvent was evaporated. The residue was triturated under DIPE. The precipitate was filtered off, yielding 3.6 g of intermediate 10.

a-2) Preparation of intermediate 41

Intermediate 41 was prepared according to A4.a-1, but the organic DCM layer was washed with H₂O, HCl (1 N), NaOH (1 N) and brine. Then the separated organic layer was dried, filtered and the solvent was evaporated, yielding compound 41.

b-1) Preparation of intermediate 11

A mixture of intermediate 10 (0.011 mol) and CH3OH/NH3 (100 ml) was stirred for 44 hours at 90⁰C. The solvent was evaporated. The residue was crystallized in butanol and the precipitate was filtered off. The precipitate was purified by column chromatography (Biotage) over silica gel (eluent: DCM/CH3OH 99/1). The product fractions were collected and the solvent was evaporated. Yield : 1.1 g of intermediate 11. b-2) Preparation of intermediate 42

Intermediate 41 (1.4 g; 0.038 mol) in CH3OH/NH3 (300 ml) was heated for 48 hours at 100 ⁰C. The solvent was partially evaporated and the concentrate was filtered. The filtered-off solid was stirred in DIPE/CH3OH 9/1. The precipitate was filtered off and dried, yielding intermediate 42. C-I) Preparation of intermediate 12

Phosphoric trichloride (0.006 mol) was added dropwise to a stirring mixture of intermediate 11 (0.0041 mol) in DMF (20 ml) and was stirred for 3 hours. The reaction mixture was poured out in H₂O (or ice-water) and stirred for 15 minutes. The precipitate was filtered off and dried. Yield : 1 g of intermediate 12.

c-2) Preparation of intermediate 43

Intermediate 43 was prepared according to A4.C-1, but starting from intermediate 42.

Example A5 a-1) Preparation of intermediate 21

3-[(3-bromobenzoyl)amino]-2-thiophenecarboxylic acid, methyl ester (10 g) was suspended in NH₄OH (300 ml) and the suspension was heated at 140 ⁰C for 6 hours in a pressure reactor (autoclave). The resulting solution was cooled and the insoluble residue was filtered off, washed with H₂O and dried. The remaining solution was neutralized with concentrated HCl. The resulting precipitate was filtered off, washed with H₂O and dried. Any uncyclized material was refluxed in a NaOH solution for 1 hour. The mixture was cooled and neutralized with HCl (2 N). The precipitate was filtered off, washed with H₂O and dried. The different dried precipitates yielded 8.0 g of intermediate 21. a-2) Preparation of intermediate 44

3-[(4-bromobenzoyl)amino]-2-thiophenecarboxylic acid, methyl ester (10 g) was suspended in NH₄OH (300 ml) and the suspension was heated at 140 ⁰C for 5 hours in a pressure reactor (autoclave). Then the solvent was evaporated. The residue was taken up in DCM/H2O (200 ml/100 ml). The separated organic layer was washed (aqueous solution of NaCl), dried (MgSO₄), filtered and the solvent was evaporated. Yield: 9.0 g of intermediate 44 (mixture of the desired product and the carboxylic acid; used as such in the next reaction).

b-1) Preparation of intermediate 22

Intermediate 21 (0.0146 mol) was dissolved in DMF (100 ml) and then phosphoric trichloride (0.0175 mol) was added. The reaction mixture was stirred for 4 hours at room temperature. Then the mixture was poured on ice. The precipitate was filtered, washed with H₂O and dried. Yield: 5.3 g of intermediate 22.

b-2) Preparation of intermediate 26

Intermediate 26 was prepared according to A5.b-1 starting from intermediate 25. b-3) Preparation of intermediate 45

A mixture of intermediate 44 (0.014 mol) in DMF (50 ml) was stirred. Then phosphoric trichloride (0.015 mol) was added and the reaction mixture was stirred for 3 hours. The mixture was poured out into H₂O. The precipitate was filtered off, washed and dried. Yield: 4 g of intermediate 45 (88 %).

Example A6 a) Preparation of intermediate 23

3-[(3-methoxybenzoyl)amino]-2-thiophenecarboxylic acid, methyl ester (6.5 g; 0.025 mol) was reacted in NH₄OH (100 ml) for 4 hours at 150 ⁰C in a closed vessel. The reaction mixture was concentrated by partial evaporation of the solvent. The concentrate was acidified to pH = ± 1. The resulting precipitate was filtered off and was then triturated under DIPE/CH3OH 9/1. The precipitate was filtered off and dried. Yield: 3.8 g of intermediate 23 (50 %).

b) Preparation of intermediate 24

Intermediate 23 (0.015 mol) was dissolved in DMF (50 ml). Phosphoric trichloride (5 ml) was added dropwise to the solution. The reaction mixture was stirred for 2 hours at room temperature. The mixture was poured out into ice-water and the resulting precipitate was filtered off and dried. Yield: 3.8 g of intermediate 24 (95 %). Example A7 a) Preparation of intermediate 30

5-Amino-imidazole-4-carboxamide, monohydrochloride (0.0133 mol) was dissolved in pyridine (15 ml), and Λ/,Λ/-dimethyl-4-pyridinamine (0.030 g) was added. Afterwards, 4-fluorobenzoyl chloride (0.0110 mol) was added dropwise while stirring. The reaction mixture was stirred for 5 hours at 70 ⁰C. The reaction mixture was poured into water. The precipitate was filtered off, washed with water and dried. Yield: 2.560 g of intermediate 30 (77 %).

b) Preparation of intermediate 31

K₂CO₃ (0.0121 mol) was dissolved in a mixture OfH₂O (80 ml) and EtOH (23 ml). Then intermediate 30 (0.0103 mol) was added. The resulting mixture was stirred and refluxed for 16 hours. The hot reaction mixture was filtered, and its pH was neutralized with an aqueous HCl solution (1 N). The formed precipitate was filtered off, suspended in ethanol (50 ml) and was then refluxed for 30 minutes. Then the mixture was cooled to room temperature. The formed precipitate was filtered off, washed with 2-propanol and dried. Yield: 1.00 g of intermediate 31 (42 %).

c) Preparation of intermediate 32

A mixture of intermediate 31 (0.00430 mol) in phosphoric trichloride (20 ml) and N, N- dimethyl-benzenamine (2 ml) was stirred at room temperature. The resulting reaction mixture was stirred and refluxed for 2 hours. Then, the excess of phosphoric trichloride was evaporated off (in vacuum). The residue was treated with water. The formed precipitate was filtered off, washed with water and dried. Yield: 0.60 g of intermediate 32 (93 %). d-1) Preparation of intermediate 33

Intermediate 32 (0.000414 mol), (bromomethyl)benzene (0.000451 mol) and K₂CO₃ (0.0009 mol) were mixed and acetonitrile (10 ml, dry) was added. The resulting mixture was stirred and refluxed for 2 hours. The resulting mixture was poured into water. The formed precipitate was filtered off, washed with water and dried. Yield: 0.11 g of intermediate 33 (79 %).

d-2) Preparation of intermediate 35

Intermediate 35 was prepared according to A7.d-1, but the reaction mixture was refluxed for 3 hours. Yield: Intermediate 35 (94 %).

e-1) Preparation of intermediate 34

Intermediate 33 (prepared according to A7.d-1) (0.00031 mol), phenol (0.00093 mol) and K₂CO₃ (0.00094 mol) were mixed and acetonitrile (10 ml) was added. The resulting reaction mixture was stirred and refluxed for 2 hours. The solvent was evaporated in vacuum. The residue was treated with water. The formed precipitate was filtered off, washed with water and dried. Yield: 0.115 g of intermediate 34 (94 %). e-2) Preparation of intermediate 36

Intermediate 36 was prepared according to A7.e-1 starting from intermediate 35, but the reaction mixture was refluxed for 3 hours. Yield: Intermediate 36 (80 %).

e-3) Preparation of intermediate 46

Intermediate 46 was prepared according to A7.e-2.

Example A8 a-1) Preparation of intermediate 49

1 ,4-Piperidinedicarboxylic acid, l-(l,l-dimethylethyl) ester (0.2 g, 0.00056 mol) was stirred in DCM (5 ml). lH-Benzotriazole (0.4 ml; 1.5 M solution in DCM) was added and the mixture was stirred for 30 minutes. This mixture was added to a second mixture consisting of compound 162 (0.2 g, 0.00056 mol), CH₃CN (15 ml) and pyridine (1.5 ml). The final reaction mixture was stirred over the weekend. Subsequently the mixture was washed with H₂O and extracted with DCM. The separated organic layer was dried, filtered and the filtrate was concentrated. The residue was purified over silica gel (eluent: DCM/MeOH/ 99/1). The product fractions were collected and the solvent was evaporated. Yield: 0.23 g of intermediate 49. a-2) Preparation of intermediate 50

A mixture of compound 187 (0.200 g, 0.00044mol), hexahydro-lH-l,4-diazepine-l- carboxylic acid, 1,1-dimethylethyl ester (0.132 g, 0.00066 mol), K₂CO₃ (0.091 g, 0.00066 mol) and acetone (10 ml) was stirred and refluxed overnight. Subsequently the mixture was evaporated and extracted in DCM. The organic layer was washed with H₂O, filtered over Extrelut NT3 and the filtrate was evaporated. The residue was purified on short column chromatography (SUPELCO; eluent: DCM). The pure fractions were evaporated. The residue was dried (vacuum, 12 hours, 60 ⁰C). Yield: 0.0295 g of intermediate 50.

Example A9 a) Preparation of intermediate 51

A mixture of 3-amino-2-thiophenecarboxylic acid, methyl ester (5 g, 0.030 mol), 1,4- benzenedicarbonitrile (12 g, 0.093 mol) and THF (300 ml) was stirred on ice. Subsequently, potassium tert-butoxide (5.3 g, 0.047 mol) was added and the reaction mixture was stirred overnight. Then the solvent was evaporated and the residue was triturated in a saturated NH₄Cl solution. The crude product was filtered off, dried and triturated in DCM. The product was filtered off and dried. Yield: 6.5 g of intermediate 51. b) Preparation of intermediate 52

A mixture of intermediate 51 (5.4 g, 0.0213 mol) in DMF (300 ml) was stirred. POCl₃ (20 ml) was added and the reaction mixture was stirred during the weekend. The solvent was evaporated and the residue was triturated in H₂O. The product was filtered off and dried. Yield: 5 g of intermediate 52.

Example AlO a) Preparation of intermediate 53

A mixture of compound 202 (0.4 g, 0.000919 mol), (±)-epichlorohydrin (0.8 g, 0.009 mol), K₂CO₃ (0.250 g, 0.0018 mol) and acetone (10 ml) was stirred and refluxed overnight. The solvent was evaporated and the residue was taken up in DCM and was then washed with H₂O. The organic layer was dried (MgSO₄), filtered and the solvent was evaporated. The residue was purified by short column chromatography (SUPELCO; eluent: DCM). The pure fractions were collected and the solvent was evaporated. Yield: 0.075 g of intermediate 53.

Example Al l a) Preparation of intermediate 54

A mixture of 3-[(l,3-benzodioxol-5-ylcarbonyl)amino]-2-thiophenecarboxylic acid, methyl ester (3.2 g, 0.0105 mol) and MeOH/NH₃ (300 ml) was stirred in a sealed tube at 90 ⁰C for 48 hours. The solvent was evaporated and the residue was stirred in the microwave with NaOCH₃ (30 %) (6 g) and 2-propanol (20 ml) for 2 hours at 120 ⁰C. The solvent was evaporated and the residue was triturated in H₂O and neutralized with CH₃COOH. The precipitate was filtered off and dried (vacuum, 60 ⁰C, 24 hours). Yield: 2.33 g of intermediate 54. b) Preparation of intermediate 55

POCl₃ (1.9 g, 0.0128 mol) was added to a mixture of intermediate 54 (2.33 g, 0.0086 mol) and DMF (25 ml) and the resulting mixture was stirred overnight at room temperature. Subsequently the mixture was quenched on ice and the precipitate was filtered off and dried (vacuum, 60 ⁰C, 24 hours). Yield: 2.1 g of intermediate 55.

Example Al 2 a) Preparation of intermediate 57

4-(Methylthio)benzoyl chloride (2 g, 0.0107 mol) was added to a mixture of 3-amino-2- thiophenecarboxylic acid methyl ester (1.68 g, 0.0107 mol), pyridine (0.85 g, 0.0107 mol) and acetone (100 ml). The reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was taken up in DCM. This solution was then washed with 0.1 N HCl and H₂O. The organic layer was dried (MgSO₄), filtered and the solvent was evaporated. The residue was triturated in petroleum ether and the precipitate was filtered off and dried (vacuum, 50 ⁰C, 4 hours). Yield: 3.16 g of intermediate 57.

b) Preparation of intermediate 58

Intermediate 57 (2.5 g, 0.0081 mol) and CH₃OH/NH₃ (300 ml) was stirred in a sealed tube for 48 hours at 90 ⁰C. The reaction mixture was cooled and the solvent was evaporated. The residue was extracted with DCM, washed with H₂O, dried (MgSO₄), filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried (vacuum, 60 ⁰C, 24 hours). Yield: 1.39 g of intermediate 58. Intermediate 58 was used as an intermediate in the synthesis of compounds 127 and 128.

Example Al 3 a) Preparation of intermediate 59

4-Amino-5-thiazolecarboxylic acid ethyl ester (0.00665 mol) was dissolved in pyridine (15 ml). N,Λ/-Dimethyl-4-pyridinamine (0.00016 mol) was added to the solution and subsequently 4-fluorobenzoyl chloride (0.00732 mol) was added dropwise. The reaction mixture was stirred for 24 hours at room temperature and was then poured out in H₂O (25 ml). The precipitate was filtered off, washed with H₂O and dried (on air). Yield: 1.85 g of intermediate 59 (95 %).

b) Preparation of intermediate 60

Intermediate 59 (0.008 mol) was dissolved in EtOH (50 ml). Then a solution of KOH (0.0092 mol) in H₂O (5 ml) was added and the reaction mixture was stirred for 5 hours at room temperature. About 30 ml of EtOH was removed by distillation in vacuum. The formed precipitate was filtered off and washed with 2-propanol. A mixture of the crude product in H₂O (50 ml) was acidified with HCl to pH 5-6 and stirred for 2 hours at room temperature. The precipitate was filtered off, washed with water and dried. Yield: 1.22 g of intermediate 60 (57 %). c) Preparation of intermediate 61

Intermediate 60 (0.00459 mol) and Et₃N (0.0072 mol) were dissolved in CH₃CN (30 ml). Ethyl chloro formate (0.53 ml, 0.0055 mol) was added to this solution and after stirring for 5 minutes, NH₃ (aqueous solution, 30 %; 2.0 ml) was added dropwise. The reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated and the residue was diluted with H₂O (10 ml). The precipitate was filtered off, washed with H₂O and dried (on air). Yield: 0.923 g of intermediate 61 (76 %).

d) Preparation of intermediate 62

A mixture of intermediate 61 (0.003483 mol) and l,8-diazabicyclo[5.4.0]undecene-7 (DBU) (0.003483 mol) in CHCl₃ (20 ml) was refluxed and stirred for 5 hours. Then the CHCl₃ was evaporated and the residue was diluted with H₂O (50 ml) and acidified with acetic acid to pH 7. The precipitate was filtered off, washed with H₂O and dried (on air). The crude compound was dissolved in a mixture of CHCl₃/MeOH (7/3; 150 ml) and then 2-propanol (50 ml) was added to the solution. Subsequently about 100 ml of the solvent was evaporated. The obtained suspension was allowed to cool to room temperature. The precipitate was filtered off and washed with 2-propanol. Yield: 0.6 g of intermediate 62 (70 %).

e) Preparation of intermediate 63

SOCl₂ (0.710 ml) was added dropwise to a mixture of intermediate 62 (0.00243 mol), DMF (1.3 ml) and CHCl₃ (30 ml). The mixture was refluxed and stirred for 2 hours. The excess of SOCl₂ and the CHCl₃ were removed in vacuum. The residue was diluted with water (5 ml). The precipitate was filtered off, washed with H₂O and dried (on air). Yield: 0.620 g of intermediate 63 (70 %). Example Al 4 a-1) Preparation of intermediate 66

l-Amino-iH-pyrrole-2-carboxamide (2.50 g, 0.0199 mol) was added to a solution of 3- bromobenzoyl chloride (21 g, 0.100 mol), DCM (10 ml) and CH₃CN (10 ml) under N₂ atmosphere while cooling on ice (temperature < 5 ⁰C). The reaction mixture was continued stirring for 2 hours at room temperature. Then the precipitate was filtered off and crystallized from 2-propanol. The precipitate was filtered off and dried (vacuum, 60 ⁰C, 12 hours). Yield: 3.8 g of intermediate 66.

a-2) Preparation of intermediate 69

Intermediate 69 was prepared by analogy to A14.a-1 (using 4-fluorobenzoyl chloride), but Et₃N was additionally added and CHCl₃ was used instead of DCM. When the reaction was finished, the solvent was evaporated and the residue was dissolved in CH₂Cl₂. The organic solution was washed with H₂O, dried, filtered and the solvent was evaporated. The residue was further purified over silicagel (eluent: DCM/MeOH 99/1). The desired fractions were collected and the solvent was evaporated, yielding 0.85 g of intermediate 69.

b-1) Preparation of intermediate 67

A mixture of intermediate 66 (3.2 g, 0.0104 mol), NaOCH₃ 30 % (3 g) and 2-propanol (30 ml) was reacted in a microwave for 1 hour at 150 ⁰C. Then the solvent was evaporated. H₂O was added to the residue and this mixture was neutralized with CH3COOH. The precipitate was filtered off and triturated in MeOH. The precipitate was filtered off and dried (vacuum, 60 ⁰C, 12 hours). Yield: 2.8 g of intermediate 67.

b-2) Preparation of intermediate 70

Intermediate 70 was prepared by analogy to A14.b-1, but starting from intermediate 69. After removal of the solvent, the crude product was dissolved in DCM. The organic solution was washed with H₂O, dried (MgSO₄), filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 0.39 g of intermediate 70 (85 %).

C-I) Preparation of intermediate 68

A mixture of intermediate 67 (2.8 g, 0.0097 mol), DIPEA (3.9 g, 0.030 mol) and DCM (100 ml) was stirred at room temperature. Triflic anhydride (8.2 g, 0.0289 mol) was added and the reaction mixture was stirred overnight. Subsequently the mixture was quenched in H₂O, extracted with DCM, washed with H₂O, dried (MgSO₄), filtered and the solvent was evaporated. The residue was triturated in DIPE and the precipitate (intermediate 67) was filtered off. The filtrate was evaporated and triturated in petroleum ether. The precipitate was filtered off and dried (vacuum, 50 ⁰C, 4 hours). Yield: 1.5 g of intermediate 68. c-2) Preparation of intermediate 71

Intermediate 71 was prepared by analogy to A14.C-1, but starting from intermediate 70. After removal of the solvent, the crude intermediate 71 (48 % yield) was used as such in the next reaction step.

Example Al 5 a) Preparation of intermediate 64

Λ/-(l-methylethyl)-2-propanamine, lithium salt (1 :1) (0.035 mol) was cooled to -78 ⁰C. A solution of 3-methyl-2-thiophenecarboxylic acid (2.5 g, 0.0175 mol) in THF (100 ml) was added drop wise and the mixture was stirred for 1 hour at 0 ⁰C. Then the mixture was cooled to -78 ⁰C and a solution of 4-fluorobenzonitrile (2.1 g, 0.0175 mol) in THF (100 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature and then H₂O was added dropwise. The mixture was extracted with DCM. The separated organic layer was washed with H₂O, dried, filtered and the solvent was evaporated. The residue was stirred in DIPE. The precipitate was filtered off and dried. Yield: 1.9 g of intermediate 64.

b) Preparation of intermediate 65

A mixture of intermediate 64 (1.9 g, 0.0077 mol) and POCI3 (25 ml) was stirred and refluxed for 4 hours. Then the mixture was cooled and was poured on ice. The mixture was extracted with DCM. The separated organic layer was washed with H₂O, dried, fϊltered and the solvent was evaporated. The residue was filtered over silica (eluent: DCM). The desired fractions were collected and the solvent was evaporated. Yield: 1.1 g of intermediate 65.

B. Preparation of the compounds Example Bl a-1) Preparation of compound 2

A mixture of intermediate 3 (0.00038 mol), 4-fluoro-phenol (0.0005 mol) and K₂CO₃ (0.0006 mol) in acetonitrile (10 ml) was stirred overnight at 90⁰C. The reaction mixture was cooled and then washed with a NaOH 2 N aqueous solution. This mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography (Supelco) over silica gel (eluent: DCM/hexane 50/50). The product fractions were collected and the solvent was evaporated. Yield: 0.044 g of compound 2 (35 %).

a-2) Preparation of compound 34

Compound 34 was prepared according to Bl. a-1, but starting from intermediate 15 and with a different work-up. After extraction with DCM, the separated organic layer was washed, dried, filtered and the solvent was evaporated. The residue was triturated under CH₃OH and the precipitate was filtered off and dried, yielding 0.116 g of compound 34 (85 %). a-3) Preparation of compound 54

Compound 54 was prepared according to Bl.a-2 (72 %), but starting from intermediate 20.

a-4) Preparation of compound 101

A mixture of intermediate 29 (0.1 g, 0.0003 mol), 3-fluoro-4-hydroxybenzonitrile (0.057 g, 0.0004 mol) and K₂CO₃ (0.058 g, 0.0004 mol) in acetonitrile (10 ml) was stirred overnight at 90 ⁰C. The solvent was evaporated and the residue was dissolved in DCM. The organic layer was washed with 1% NaOH, dried, filtered and the solvent was evaporated . The residue was purified by short column chromatography (SUPELCO) (eluent : DCM/n-Hexane 80/20). The desired fractions were collected and the solvent was evaporated. The residue was dried (vacuum, 60 ⁰C, 12 hours). Yield: 0.073 g of compound 101 ( 57 % ).

a-5) Preparation of compound 29

A mixture of intermediate 9 (0.00037 mol), 3-fluoro-4-hydroxy-benzonitrile (0.0005 mol) and K₂CO₃ (0.150 g) in acetonitrile (10 ml) was stirred overnight at 90 ⁰C. The reaction mixture was cooled and was then washed with a 10 % aqueous NaOH solution. This mixture was extracted with DCM. The separated organic layer was washed, dried, filtered and the solvent evaporated. Yield: 0.134 g of compound 29. a-6) Preparation of compound 52

Compound 52 was prepared according to Bl.a-5, but starting from intermediate 17.

a-7) Preparation of compound 16

3-Fluoro-4-hydroxy-benzonitrile (0.0005 mol) was added to a stirring mixture of intermediate 7 (0.00037 mol) and K₂CO₃ (0.005 mol) in acetonitrile (10 ml), and the reaction mixture was stirred overnight at 90 ⁰C. Then the mixture was cooled and washed with an aqueous NaOH solution (2 N). This mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was triturated under CH₃OH and the precipitate was filtered off. Yield : 0.112 g of compound 16 (83 %).

a-8) Preparation of compound 32

Compound 32 was prepared according to Bl.a-1, but starting from intermediate 12. a-9) Preparation of compound 65

A mixture of intermediate 22 (0.00023 mol, 0.100 g), 3-fluoro-4-hydroxybenzonitrile (0.00035 mol, 0.050 g) and K₂CO₃ (0.00035 mol, 0.048 g) in acetonitrile (10 ml) was stirred overnight at 100 ⁰C. The mixture was evaporated and the residue was solved in DCM. The mixture was washed with NaOH (10 %). The separated organic layer was dried, filtered and the solvents were evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM). The desired fractions were collected and the solvent was evaporated. Yield: 0.180 g of compound 65.

a- 10) Preparation of compound 14

Compound 14 was prepared according to Bl.a-7 but starting from intermediate 7.

a-11) Preparation of compound 26

Compound 26 was prepared according to Bl.a-5 starting from intermediate 9, but the residue after evaporation was further purified over silica gel (Supelco; eluent: DCM/hexane 98/2). The product fractions were collected and the solvent was evaporated, yielding compound 26. a- 12) Preparation of compound 24

Compound 24 was prepared according to Bl.a-5 starting from intermediate 9, but the residue after evaporation was further purified by column chromatography over silica gel (eluent: DCM). The product fractions were collected and the solvent was evaporated, yielding compound 24.

a- 13) Preparation of compound 25

Compound 25 was prepared according to Bl.a-5 starting from intermediate 9, but the residue after evaporation was further purified by trituration under DIPE. The precipitate yielded compound 25.

a- 14) Preparation of compound 23

A mixture of intermediate 9 (0.000944 mol), 2,4-difluorophenol (0.15 g) and K₂CO₃ (0.2 g) in acetonitrile (5 ml) was stirred and refluxed for 2 hours. The reaction mixture was cooled to room temperature, then diluted with DCM (50 ml). The mixture was washed with 1 N NaOH (25 ml), dried, filtered and the solvent evaporated. The residue was crystallized from 2-propanol. The precipitate was filtered off and dried. Yield: 0.12 g of compound 23 (40%). a- 15) Preparation of compound 36

Compound 36 was prepared according to Bl.a-1, but starting from intermediate 15, and before the column purification the residue was first triturated under CH₃OH.

a- 16) Preparation of compound 64

A mixture of intermediate 22 (0.000307 mol), 4-hydroxybenzonitrile (0.00046 mol) and K₂CO₃ (0.00046 mol) in acetonitrile (10 ml) was stirred overnight at 80 ⁰C. The mixture was cooled and the solvent was evaporated. The residue was dissolved in DCM and was washed with 10 % NaOH. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was triturated under CH3OH. The precipitate was filtered off and dried. Yield: 0.117 g of compound 64. a- 17) Preparation of compound 59

Compound 59 was prepared according to Bl. a- 16 starting from intermediate 22, but the final residue was triturated in DIPE/2-propanol. a- 18) Preparation of compound 58

Compound 58 was prepared according to Bl. a- 14, but starting from intermediate 22,.

a- 19) Preparation of compound 69

Compound 69 was prepared according to Bl. a- 14, but starting from intermediate 43.

Example B2 a-1) Preparation of compound 28

A mixture of intermediate 9 (0.2 g, 1 eq, 0.000755 mol) and 4-hydroxybenzonitrile (0.27 g, 3 eq, 0.00227 mol) in acetonitrile (5 ml) was added to a microwave tube. K2CO3 (0.31 g, 3 eq, 0.00227 mol) was added to the suspension and the mixture was microwaved for 35 minutes at 160 ⁰C. Then the mixture was cooled and added to a NaOH solution (10 %). This mixture was stirred and the precipitate was filtered off, washed with H₂O and dried, yielding compound 28.

a-2) Preparation of compound 12

Compound 12 was prepared according to B2.a-1, but starting from intermediate 5.

a-3) Preparation of compound 95

Compound 95 was prepared according to B2.a-1, but starting from intermediate 26.

a-4) Preparation of compound 10

Compound 10 was prepared according to B2.a-1, but starting from intermediate 5 and with an additional purification. The dried precipitate was further purified by column chromatography (eluent: ethyl acetate/hexane in different amounts). The desired fractions were collected and the solvent was evaporated, yielding compound 10.

a-5) Preparation of compound 40

Compound 40 was prepared according to B2.a-1 but starting from intermediate 40 and with a different work-up procedure. After addition of the reaction mixture to the NaOH solution, the mixture was extracted with DCM. The separated organic layer was concentrated and purified by column chromatography (Isolute SPE column Flash Si). The desired fractions were collected and the solvent was evaporated, yielding compound 40.

Example B3 a-1) Preparation of compound 84

Intermediate 24 (0.0065 mol) was dissolved in acetonitrile (50 ml). 2,4-Difluorophenol (0.01 mol) and K2CO3 (2 g) were added. The reaction mixture was stirred and refluxed for 1 hour. The solvent was evaporated. The residue was dissolved in DCM and was then washed with 1 N NaOH and then with brine. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was first crystallized from DIPE and then from 2-propanol. The precipitate was filtered off and dried. Yield: 1.3 g of compound 84 (60 %).

a-2) Preparation of compound 85

Compound 85 was prepared according to B3.a-1 starting from intermediate 24, except that the reaction mixture was refluxed for 4 hours. After the extraction and washing procedure, the residue was first crystallized from 2-propanol and then from DIPE, yielding compound 85 (60 %).

a-3) Preparation of compound 91

Compound 91 was prepared according to B3.a-1, but starting from intermediate 26 and except that the reaction mixture was stirred overnight at 80 ⁰C. After the extraction in DCM, the organic layer was only washed with a NaOH solution (10 %). After removal of the solvent, the residue was triturated under 2-propanol/DIPE. The precipitate was filtered off and dried, yielding compound 91. a-4) Preparation of compound 94

Compound 94 was prepared according to B3.a-3 starting from intermediate 26, except for the purification. The residue was purified by column chromatography over silica gel (eluent: DCM). The desired fractions were collected and the solvent was evaporated, yielding compound 94.

a-5) Preparation of compound 90

Compound 90 was prepared according to B3.a-3 starting from intermediate 26, except for the purification. The residue was triturated in 2-propanol. The solid was filtered off and dried, yielding compound 90.

b-1) Preparation of compound 80

A mixture of compound 84 (0.0027 mol) in DCM (50 ml) was stirred on ice. A solution OfBBr₃ in DCM (15 ml; 1 M) was added dropwise to the reaction mixture and was stirred over the weekend at 25 ⁰C. The reaction mixture was poured on ice/NH4OH and was stirred overnight. The reaction mixture was extracted with DCM. The separated organic layer was washed, dried, filtered and the filtrate's solvent was evaporated (yield: 0.7 g). The residue was stirred in CH₃OH and the precipitate was filtered off. Yield : 0.16O g of compound 80. b-2) Preparation of compound 117

A solution OfBBr₃ in DCM (40 ml) was added dropwise to a mixture of compound 85 (0.0032 mol) in DCM (160 ml). The mixture was stirred for 30 minutes and was then poured out into a mixture of ice and ammonia and was stirred for 30 minutes. The layers were separated. The organic layer was washed with brine, dried, filtered and the solvent evaporated. Yield: 1.00 g of compound 117.

b-3) Preparation of compound 82

Compound 82 was prepared according to B3.b-1, but starting from compound 91 and the residue was triturated in DIPE. The precipitate was filtered off and dried, yielding compound 82.

b-4) Preparation of compound 83

A mixture of compound 94 (0.00185 mol), a solution OfBBr₃ in DCM (0.0111 mol; 1 M) and DCM (50 ml) was stirred overnight at room temperature. Then an extra amount of the solution Of BBr₃ in DCM (25 ml; 1 M) was added and the reaction mixture was stirred overnight at room temperature. Then the solvent was evaporated and the residue was dissolved in DCM. The organic solution was washed with NH4OH/H2O. The separated organic layer was dried, filtered and the solvent was evaporated, yielding compound 83. b-5) Preparation of compound 81

A mixture Of BBr₃ in DCM (0.035 mol; 1 M) in DCM (50 ml) was stirred. Then a solution of compound 90 (0.0053 mol) in 50 ml of DCM was added dropwise. The mixture was stirred overnight at room temperature. The mixture was poured out on ice/NH4OH. The mixture was extracted with DCM. The separated organic layer was washed with H₂O, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/CH₃OH 99/1). The desired fractions were collected and the solvent was evaporated. Yield: 0.220 g of compound 81.

C-I) Preparation of compound 109

A mixture of compound 83, 4-(2-chloroethyl)-morpholine, hydrochloride (0.00041 mol) and K₂CO₃ (0.00045 mol) in acetonitrile (10 ml) was stirred overnight at 80 ⁰C. The solvent was evaporated and the residue was dissolved in DCM and was then washed with a NaOH solution (10 %). The separated organic layer was dried, filtered and the solvent was evaporated. The residue was stirred in CH₃OH. The precipitate was filtered off and dried, yielding 0.037 g of compound 109.

c-2) Preparation of compound 106

A mixture of compound 117 (0.001 mol), bromoacetic acid ethyl ester (0.4 g) and K₂CO₃ (1.0 g) in DMF (10 ml) was stirred for 3 hours at 70 ⁰C. The reaction mixture was cooled and was then diluted with ethyl acetate. This mixture was washed with a HCl solution (1 N) and with brine, and was then dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: ethyl acetate/hexane 1/1). The product fractions were collected and the solvent was evaporated. Yield: 0.030 g of compound 106 (± 10 %).

c-3) Preparation of compound 102

A mixture of compound 81 (0.000275 mol, 0.100 g), 2-chloroacetonitrile (0.0004 mol, 0.028 g) and K₂CO₃ (0.0004 mol, 0.051 g) in DMF (5 ml) was stirred overnight at 60 ⁰C. The mixture was evaporated and the residue was dissolved in DCM. The mixture was washed with H₂O. The separated organic layer was dried, filtered and the solvents were evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM). The desired fractions were collected and the solvent was evaporated. Yield: 0.094 g of compound 102.

c-4) Preparation of compound 105

Compound 105 was prepared according to B3.C-3 starting from compound 81 except that acetone was used as the solvent. c-5) Preparation of compound 108

A mixture of compound 81 (0.00056 mol, 0.200 g), 4-(2-chloroethyl)morpholine (0.00062 mol, 0.115 g) and K₂CO₃ (0.0012 mol, 0.165 g) in DMF was stirred overnight at 100 ⁰C. The mixture was cooled and H₂O was added. This mixture was extracted with DCM and washed with H₂O. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/CH3OH). The pure fractions were collected and the solvent was evaporated. Yield: 0.130 g of compound 108.

Example B4 a-1) Preparation of compound 66

A mixture of intermediate 45 (0.008 mol), 2,4-difluorophenol (0.012 mol) and K₂CO₃ (0.015 mol) in acetonitrile (150 ml) was stirred and refluxed for 3 hours. The reaction mixture was cooled and then washed with an aqueous NaOH solution (10 %). This mixture was extracted with DCM. The separated organic layer was washed, dried, filtered and the solvent was evaporated. The residue was triturated under DIPE. The precipitate was filtered off and dried. Yield: 2.7 g of compound 66. a-2) Preparation of compound 68

A mixture of intermediate 45 (0.0003 mol), 2,4,6-trifluorophenol (0.0012 mol) and K2CO3 (0.165 g) in acetonitrile (10 ml) was stirred overnight at 90 ⁰C. The reaction mixture was cooled and then washed with an aqueous NaOH solution (10 %). This mixture was extracted with DCM. The separated organic layer was dried (MgSO₄), filtered and the solvent was evaporated. Yield: 0.141 g of compound 68. b-1) Preparation of compound 118

A mixture of compound 66 (0.0011 mol), 2-propenoic acid, ethyl ester (2 g), palladium acetate (0.044 g), l,3-bis(diphenylphosphino)propane (0.164 g) and Et₃N (3 ml) in THF (100 ml) was stirred overnight at room temperature. The reaction mixture was filtered and the filtrate's solvent was evaporated. The residue was dissolved in DCM. The organic solution was washed, then dried, filtered and the solvent was evaporated. The residue was purified by Supelco column chromatography over silica gel (eluent: DCM). The product fractions were collected and the solvent was evaporated. Yield: 0.118 g of compound 118 (E).

b-2) Preparation of compound 104

A mixture of compound 66 (0.0012 mol), palladium acetate (0.010 g), 1,3- bis(diphenylphosphino)propane (0.040 g) and potassium acetate (0.5 g) in THF/CH3OH 4/1 (50 ml) was stirred for 16 hours at 125 ⁰C under 50 atmosphere of CO pressure. The reaction mixture was cooled, filtered and the filtrate's solvent was evaporated. The residue was dissolved in DCM. The organic solution was washed, dried, filtered and the solvent was evaporated. The residue was triturated under DIPE, filtered off and dried. Yield: 0.25 g of compound 104.

c) Preparation of compound 103

A mixture of compound 118 (0.00022 mol), a NaOH solution (1 N) and dioxane (4 ml) was stirred overnight at room temperature. The mixture was acidified with HCl (6 N) and extracted with DCM. The separated organic layer was washed, dried, filtered and the solvent was evaporated. Yield: 0.076 g of compound 103 (77 %; E).

Example B5 a) Preparation of compound 113

A mixture of NaH (0.00120 mol) in DMSO (1.5 ml) was stirred. 4-Chlorophenol (0.00160 mol) was added to the mixture. The resulting mixture was stirred at room temperature until full resolution of NaH. Then, intermediate 32 (0.00040 mol) was added. The resulting reaction mixture was stirred for 6 hours at 80 ⁰C. Then, 30 ml of CHCI3 was added, and the resulting mixture was poured into water. The organic layer was separated and washed with water. The solvent was evaporated in vacuum. The residue was purified by column chromatography over silica gel (Si 60/100; eluent: CHCI3/CH3OH - 15/1). The product fractions were collected and the solvent was evaporated. Yield: 0.047 g of compound 113 (34%). Example B6 a) Preparation of compound 110

Intermediate 34 (0.000379 mol) was dissolved in CH₃OH (20 ml). Pd/C 10 % (0.050 g) and ammonium formate (0.100 g) were added to the solution. The resulting reaction mixture was stirred and refluxed for 8 hours. The catalyst was filtered off. The solvent was evaporated in vacuum. The residue was separated by column chromatography over silica gel (Si 60/100; eluent: CHCI3/CH3OH - 15/1). The product fractions were collected and the solvent was evaporated. Yield: 0.032 g of compound 110 (14%).

Example B7 a-1) Preparation of compound 114

Intermediate 36 (0.00022 mol) and CH₃OH (2 ml) were mixed. Then, a mixture of 35 % HCl (0.5 ml) and H₂O (2.5 ml) was added. The resulting reaction mixture was stirred and refluxed for 2 hours. The solvent was evaporated in vacuum. The residue was treated with a 5 % aqueous potassium acetate solution. The formed precipitate was filtered off, washed with H₂O and dried. The residue was purified by column chromatography over silica gel (Si 60/100; eluent: CHCI₃/CH₃OH 15:1). The product fractions were collected and the solvent was evaporated. Yield: 0.024 g of compound 114 (30 %). a-2) Preparation of compound 112

Compound 112 was prepared according to B7.a-1, but starting from intermediate 46, and except that acetonitrile was used as the solvent and the mixture was refluxed for 1 hour. Yield: Compound 112 (24 %).

Example B8 a) Preparation of compound 163

A mixture of intermediate 48 (5 g, 0.017 mol), 2,4-difluorophenol (2.5 g) and K₂CO₃ (3.5 g) in CH₃ CN (350 ml) was stirred and refluxed during 4 hours. The reaction mixture was cooled, washed with NaOH (2 M solution), and extracted with DCM. The organic layer was separated, dried, filtered and concentrated in vacuo. Yield: 5.7 g of compound 163

b) Preparation of compound 162

A mixture of compound 163 (5.7 g, 0.014 mol) in THF (150 ml) was hydrogenated overnight with Pd/C 10 % (1 g) as a catalyst in the presence of a thiophene solution (1 ml; 4 % in DIPE). After uptake of H₂ (3 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated under MeOH, filtered off and dried. Yield: 3 g of compound 162. c) Preparation of compound 199

A mixture of intermediate 49 (0.21 g, 0.0003 mol) and a 10 % CF3COOH/DCM solution (5 ml) was stirred overnight. The reaction mixture was washed with an aqueous Na₂CO₃ solution. The separated organic layer was dried and the solvent was evaporated. Yield: 0.126 g of compound 199.

d) Preparation of compound 119

Compound 199 (0.1 g, 0.0002 mol) was stirred in DCM (10 ml).

Acetyl acetate (0.04 g, 0.0004 mol) was added and the reaction mixture was stirred over the weekend. The reaction mixture was washed with an aqueous Na₂CO₃ solution. The organic layer was dried, filtered and the solvent was evaporated. Yield: 0.031 g of compound 119.

Example B9 a) Preparation of compound 187

A mixture of compound 82 (3.1 g, 0.0087 mol), 1 ,2-dibromoethane (15 g, 0.080 mol), K₂CO₃ (1.3 g, 0.010 mol) and nBuOH (200 ml) was stirred and refluxed overnight. Then the reaction mixture was evaporated, extracted in DCM and washed with H₂O. The organic layer was dried (MgSO₄), filtered and the solvent was evaporated. The residue was triturated in DIPE and the precipitate was filtered off and dried (vacuum, 60 ⁰C, 4 hours). Yield: 2.0 g of compound 187.

Compound 204 was prepared according to B9a), but the compound was purified by column chromatography with DCM as eluent instead of by trituration.

b) Preparation of compound 200

A mixture of intermediate 50 (0.150 g, 0.000257 mol), 10 % TFA/DCM (10 ml) and DCM (10 ml) was stirred for 4 hours at 40 ⁰C. The mixture was washed with NaHCOs and with H2O. The organic layer was dried (MgSO₄), filtered and the solvent was evaporated. Yield: 0.120 g of compound 200.

c) Preparation of compound 120

A mixture of compound 200 (0.120 g, 0.000248 mol) and acetyl acetate (5 ml) in DCM (10 ml) was stirred at room temperature overnight. Then the reaction mixture was washed with a 10 % Na₂CO₃ solution and filtered (through Extrelut NT3). The filtrate's solvent was evaporated and the residue was purified by short colum chromatography (eluent: DCM). The pure fractions were collected and the solvent was evaporated. The residue was dried (vacuum, 60 ⁰C, 12 hours). Yield: 0.018 g of compound 120. Example BlO a) Preparation of compound 201

A mixture of intermediate 52 (3 g, 0.011 mol), 2,4-difluorophenol (1.7 g, 0.013 mol), K₂CO₃ (1.8 g) and CH₃CN (100 ml) was stirred and refluxed for 4 hours. Then the mixture was cooled, washed with H₂O and extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was triturated with MeOH. The precipitate was filtered off and dried. Yield: 3.6 g of compound 201.

b) Preparation of compound 160

A mixture of compound 201 (3 g, 0.0082 mol), Raney Nickel (1/10 scoop), a thiophene solution (2 ml; 4 % in DIPE), MeOH/NH₃ (250 ml) and H₂ gas (410 ml) was stirred overnight. The mixture was filtered and the solvent was evaporated. The residue was triturated (2 x) in DIPE, finally yielding 1.8 g of compound 160.

C-I) Preparation of compound 156

A mixture of compound 160 (0.1 g, 0.00027 mol), carbonochloridic acid, ethyl ester (0.3 g), CH3CN (5 ml) and pyridine (1 ml) were stirred overnight. Then the reaction mixture was washed with H₂O and extracted with DCM. The separated organic layer was dried and the solvent was evaporated. The residue was purified over silica gel (eluent: DCM/MeOH 99/1). The desired fractions were collected and the solvent was evaporated. Yield: 0.063 g of compound 156.

c-2) Preparation of compound 159

Compound 159 was prepared according to a similar procedure as compound 156 (B 10. c-1), but in this case acetic anhydride was used as the starting material and no pyridine was added. Yield: Compound 159 (88 %).

c-3) Preparation of compound 138

A mixture of compound 160 (0.1 g, 0.00027 mol), 2-[(l-methylethoxy)methyl]-oxirane, toluene (2 ml) and MeOH (2 ml) was refluxed overnight. The mixture was evaporated and the residue was purified over silica (eluent: DCM/MeOH 99/1). The desired fractions were collected and the solvent was evaporated. Yield: 0.066 g of compound 138.

Example BI l a) Preparation of compound 185

A mixture of compound 187 (0.1 g, 0.00021 mol), l-(l-piperazinyl)ethanone (0.032 g, 0.00025 mol) and K₂CO₃ (0.0345 g, 0.00025 mol) in 2-propanone (5 ml) was stirred and refluxed overnight. The solvent was evaporated and the residue was dissolved in DCM. This solution was washed with a small amount of H₂O and was then filtered through Extrelut NT3. The filtrate's solvent was evaporated. The residue was purified by short column chromatography (SUPELCO; eluent: DCM/MeOH 98/2). The desired fractions were collected and the solvent was evaporated. Yield: 0.126 g of compound 185. Example B 12 a) Preparation of compound 202

A mixture of compound 99 (2.8 g, 0.0062 mol), a 1 M BBr₃ solution in DCM (100 ml) and DCM (100 ml) was stirred overnight. Then the reaction mixture was quenched in a mixture OfNH₄OHZMeOH and ice, stirred for 4 hours and extracted 3x with DCM. The combined organic layers were washed with H₂O, dried (MgSO₄), filtered and the solvent was evaporated. The residue was triturated in DIPE and the precipitate was filtered off and dried (vacuum, 60 ⁰C, 12 hours). Yield: 1.7 g of compound 202.

b) Preparation of compound 203

A mixture of compound 202 (1.7 g, 0.0039 mol), 1,2-dibromoethane (7.5 g, 0.040 mol), K₂CO₃ (0.7 g, 0.005 mol) and nBuOH (150 ml) was stirred and refluxed overnight.

Subsequently, the reaction mixture was evaporated, extracted in DCM and washed with

H₂O. The organic layer was dried (MgSO₄), filtered and the solvent was evaporated.

The residue was triturated in DIPE. The desired compound was filtered off and was dried (vacuum, 60 ⁰C, 4 hours). Yield: 1 g of compound 203.

c) Preparation of compound 153

A mixture of compound 203 (0.1 g, 0.00018 mol), l-(l-piperazinyl)ethanone (0.036 g, 0.00027 mol), K₂CO₃ (0.037 g, 0.00027 mol) and acetone (10 ml) was stirred and refluxed overnight. The solvent was evaporated and the residue was dissolved in DCM. The organic solution was washed with a small amount of H₂O and was then filtered through Extrelut NT3. The solvent was evaporated. The residue was purified by short column chromatography (SUPELCO; eluent: DCM/MeOH 98/2). The desired fractions were collected and the solvent was evaporated. Yield: 0.0796 g of compound 153.

Example B13 a) Preparation of compound 137

A mixture of intermediate 53 (0.075 g, 0.000153 mol), l-(l-piperazinyl)ethanone (0.0195 g, 0.000153 mol), toluene (5 ml) and MeOH (5 ml) was stirred and refluxed overnight. The solvent was evaporated and the residue was purified on short column chromatography (SUPELCO; eluent: DCM/MeOH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was dried (vacuum, 60 ⁰C, 12 hours). Yield: 0.047 g of compound 137. Example B 14 a) Preparation of compound 122

A mixture of intermediate 55 (0.1 g, 0.000345 mol), 4-hydroxybenzonitrile (0.060 g, 0.0005 mol), K₂CO₃ (0.066 g, 0.0005 mol) and CH₃CN (10 ml) was stirred and refluxed overnight. The solvent was evaporated and the residue was taken up in DCM, washed with H₂O (2 ml) and filtered over Extrelut NT3. The solvent was evaporated and the residue was purified over short column chromatography (SUPELCO; eluent: DCM). The pure fractions were collected and the solvent was evaporated. The residue was dried (vacuum, 60 ⁰C, 12 hours). Yield: 0.118 g of compound 122.

Example B15 a-1) Preparation of compound 126

A mixture of compound 162 (0.2 g, 0.00056 mol) in DMF (10 ml) was stirred at 80 ⁰C. NaH (0.028 g) was added and the reaction mixture was stirred for 1 hour. Ethyl bromacetate (0.09 g, 0.00056 mol) was added twice (0.18 g in total), and the reaction mixture was stirred for 4 hours at 80 ⁰C. Then the mixture was poured out on ice and the mixture was extracted with ethyl acetate. The organic layer was separated, dried and the filtrate was concentrated. The residue was purified over silica gel (eluent: heptane/EtOAc 90/10). The product fractions were collected and the solvent was evaporated. Yield: 0.069 g of compound 126. a-2) Preparation of compound 174

A mixture of compound 162 (0.1 g, 0.00028 mol), 3-bromobenzoyl chloride (0.065 g, 0.0003 mol), DCM (5 ml) and pyridine (0.2 ml) was stirred during the weekend. Then the mixture was washed with H₂O and the organic layer was dried (MgSO₄), filtered and the filtrate was concentrated. The product was purified over silica (eluent: DCM). The desired fractions were collected and the solvent was evaporated. Yield: 0.049 g of compound 174.

Example B16 a) Preparation of compound 186

A mixture of compound 80 (3 g, 0.0084 mol), 1 ,2-dibromoethane (40 g, 0.2 mol) and CS2CO3 (8 g, 0.025 mol) in butanol (200 ml) was stirred and refluxed for 2 hours. More CS2CO3 (0.025 mol) was added and the mixture was stirred and refluxed for 2 hours. Then CS2CO3 (0.025 mol) was added a third time and the mixture was stirred and refluxed again for 2 hours. Subsequently the mixture was cooled, washed with H₂O and extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was triturated under DIPE and the precipitate was filtered off. The product was purified by column chromatography (eluent: DCM/hexane 90/10). The product fractions were collected and the solvent was evaporated. Yield: 1.8 g of compound 186 (47 %). b) Preparation of compound 157

A mixture of compound 186 (0.1 g, 0.0003 mol), 2,6-dimethylmorpholine (0.046 g, 0.0004 mol), K₂CO₃ (0.1 g) and KI (catalytic quantity) in 4-methyl-2-pentanone (MIK) (10 ml) was stirred and refluxed overnight. The mixture was cooled and then washed with H₂O. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: DCM/MeOH 95/5). The product fractions were collected and the solvent was evaporated. Yield: 0.031 g of compound 157.

Example B17 a) Preparation of compound 175

A mixture of intermediate 63 (0.000282 mol), 4-fluorophenol (0.000564 mol) and K₂CO₃ (0.00072 mol) in CH₃CN (5 ml) was refluxed and stirred for 4 hours. Then the mixture was cooled to room temperature and diluted with H₂O (5 ml). The precipitate was filtered off, washed with H₂O, with H₂O/EtOH 1/1 and dried on air. Yield: 0.066 § of compound 175 (69 %).

Example Bl 8 a-1) Preparation of compound 196

A mixture of intermediate 68 (1.5 g, 0.0036 mol), 3-fluoro-4-hydroxybenzonitrile (0.730 g, 0.0053 mol) and K₂CO₃ (0.735 g, 0.0053 mol) in CH₃CN (50 ml) was stirred overnight at 50 ⁰C. The solvent was evaporated and the residue was dissolved in DCM. The organic solution was washed with H₂O, dried (MgSO₄), filtered and the solvent was evaporated. The residue was purified over silicagel (eluent: DCM). The pure fractions were collected and the solvent was evaporated. The residue was dried (vacuum, 60 ⁰C, 6 hours). Yield: 0.290 g of compound 196.

a-2) Preparation of compound 197

Compound 197 was prepared by analogy to Bl 8. a- 1, but starting from intermediate 71.

Example B19 a) Preparation of compound 193

A mixture of intermediate 65 (0.1 g, 0.00038 mol), 3-fluoro-4-hydroxybenzonitrile (0.156 g, 0.00114 mol) and K₂CO₃ (0.1575 g, 0.00114 mol) in CH₃CN (10 ml) was stirred in the microwave for 5 hours at 190 ⁰C. The solvent was evaporated and the residue was dissolved in DCM. The solution was washed with a 2 N NaOH solution and the separated organic layer was dried (MgSO₄), filtered and the solvent was evaporated. The residue was purified by short column chromatography (Supelco) over silica gel (eluent: DCM/n-hexane 50/50). The desired fractions were collected and the solvent was evaporated. Yield: 0.043 g of compound 193 (31 %).

The following compounds of formula (I), as depicted in Tables Ia, Ib, Ic, 2a, 2b and 3, were prepared by analogy to the above examples (Ex. No.). Table Ia

Table Ib

Table Ic

Table 2a

Table 2b

Table 3

C. Analytical Part

LCMS conditions

General procedure A

The HPLC measurement was performed using an Alliance HT 2790 (Waters) system comprising a quaternary pump with degasser, an autosampler, a column oven (set at 40 °C, unless otherwise indicated), a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 1 second using a dwell time of 0.1 second. The capillary needle voltage was 3 kV and the source temperature was maintained at 140 ⁰C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.

General procedure B The LC measurement was performed using an Acquity UPLC (Waters) system comprising a binary pump, a sample organizer, a column heater (set at 55 ⁰C), a diode- array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.18 seconds using a dwell time of 0.02 seconds. The capillary needle voltage was 3.5 kV and the source temperature was maintained at 140 ⁰C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx- Openlynx data system. General procedure C

The LCMS analyses for the compounds were done at the Surveyor MSQ™ (Thermo Finnigan, USA) comprising a photo diode array detector (PDA; 190-800 nm) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with APCI (atmospheric pressure chemical ionization, + or - ions). Mass spectra were acquired by scanning from 45 to 1000 (of atomic mass unit) in 0.3 seconds. Typical APCI conditions use a corona discharge current of 10 μA and a cone voltage of 30 V. The APCI probe temperature was 640 ⁰C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with an Xcalibur™ data system.

Method 1

In addition to general procedure A: Reversed phase HPLC was carried out on an Xterra

MS Cl 8 column (3.5 μm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 1 % A, 49 % B and 50 % C in 6.5 minutes, to 1 % A and 99 % B in 1 minute and hold these conditions for 1 minute and reequilibrate with 100 % A for 1.5 minutes. An injection volume of 10 μl was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.

Method 2

In addition to general procedure A: Reversed phase HPLC was carried out on a

Chromolith (4.6 x 25 mm) with a flow rate of 3 ml/min. Three mobile phases (mobile phase A: 95 % 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 96 % A, 2 % B and 2 % C, to 49 % B and 49 % C in 0.9 minutes, to 100 % B in 0.3 minutes and hold for 0.2 minutes. An injection volume of 2 μl was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode. Method 3

In addition to general procedure B: Reversed phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a bridged ethylsiloxane/silica hybrid (BEH) Cl 8 column (1.7 μm, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: 0.1 % formic acid in IHtO/methanol 95/5; mobile phase B: methanol) were used to run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 minutes and hold for 0.2 minutes. An injection volume of 0.5 μl was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.

Method 4

In addition to general procedure C: Reversed phase HPLC was carried out on a Waters XTerra MS Cl 8 column (3.5 μm, 2.1 x 30 mm) with a flow rate of 1.0 ml/min. Two mobile phases (mobile phase A: 0.1 % aqueous solution of formic acid; mobile phase B: acetonitrile) were used. First, 100 % A was hold for 0.1 minutes. Then a gradient was applied to 5 % A and 95 % B in 3 minutes and hold for 0.8 minutes. The injection volume was 1 μl. The column was at room temperature.

Method 5 In addition to general procedure A: Reversed phase HPLC was carried out on an Atlantis Cl 8 column (3.5 μm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Two mobile phases (mobile phase A: 70 % methanol + 30 % H₂O; mobile phase B: 0.1 % formic acid in H2θ/methanol 95/5) were employed to run a gradient condition from 100 % B to 5 % B + 95 % A in 12 minutes. An injection volume of 10 μl was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.

Method 6

Method 6 was identical to method 5, except that the reversed phase HPLC was carried out on an Xbridge Cl 8 column (3.5 μm, 4.6 x 100 mm). Method 7

In addition to general procedure A: In addition to the general procedure: Reversed phase HPLC was carried out on a Chromolith (4.6 x 25 mm) with a flow rate of 3 ml/min. Three mobile phases (mobile phase A: 95 % 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 96 % A, 2 % B and 2 % C, to 49 % B and 49 % C in 0.9 minutes, to 100 % B in 0.3 minutes and hold for 0.2 minutes. An injection volume of 2 μl was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.

Method 8

In addition to general procedure A: Column heater was set at 60 ⁰C. Reversed phase HPLC was carried out on an Xterra MS C18 column (3.5 μm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 50 % B and 50 % C in 6.5 minutes, to 100 % B in 0.5 minute and hold these conditions for 1 minute and reequilibrate with 100 % A for 1.5 minutes. An injection volume of 10 μl was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.

Method 9

In addition to general procedure A: Column heater was set at 45 ⁰C. Reversed phase HPLC was carried out on an Xterra MS C18 column (3.5 μm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 0.1 % formic acid in H2θ/methanol 95/5; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 1 % A, 49 % B and 50 % C in 7 minutes and hold these conditions for 1 minute. An injection volume of 10 μl was used. Cone voltage was 10 V for positive ionization mode.

Table 4 : Analytical data (R(t) means retention time in minutes; MH(+) means the protonated mass of the compound).

n.d. means not determined.

Melting Points For a number of compounds, melting points (m.p.) were determined with a Sanyo Gallenkamp melting point apparatus.

For compound 185, the melting point (m.p.) was determined with a DSC823e (Mettler- Toledo). The melting point was measured with a temperature gradient of 30 C/minute. Maximum temperature was 400 ⁰C. The reported value is a peak value. m.p. compound 185: 111.9 ⁰C

D. Pharmacological example

Stimulation of cAMP-production in response to activation of the human EP4 receptor

Functional activity of the test compounds was assessed by measuring their potency to stimulate cAMP production upon activation of the human EP4 (hEP4) receptor through homogenous time resolved fluorescence (HTRF) assays. HEK293 cells stably transfected with hEP4 (Euroscreen, Belgium) were grown up to 80-90% confluence in T175 Falcon flasks in Dulbecco's modified Eagle's medium (DMEM) (Invitrogen) supplemented with 100 IU/ml penicillin G, 100 μg/ml streptomycin sulphate, 1 mM sodium pyruvate, 300 μg/ml L-glutamine and 10% heat inactivated foetal calf serum (Biochrom AG) in a humidified atmosphere of 5%CO₂ at 37°C. Cells were washed with 5 ml PBS containing EDTA 0.04% and detached from culture flasks with 3 ml PBS containing EDTA 0.04%, resuspended in prewarmed culture medium and centrifuged at 500 g for 5 minutes. The pellet was resuspended in freezing medium (culture medium with 20% heat inactivated foetal calf serum and centrifuged at 1,500 RPM for 5 minutes. The pellet was washed by adding 15 ml HBSS (per vial) and centrifuged at 1,500 RPM for another 5 minutes. The final pellet wlθ% DMSO) to a concentration of 10⁷ cells/ml and frozen at -80⁰C. The experiments were performed with the cAMP Dynamic HTRF kit (CIS bio international, France), used according to the supplier's instructions. Specifically, cells were thawed rapidly by warming up the vials in a warm water bath at 37°C. The thawed cell suspension (2 ml; 10⁷ cells/ml) was transferred to a 50 ml Falcon tube and for each vial, 10 ml prewarmed culture medium was added. The falcon tube was as resuspended in stimulation buffer (HBSS Ix, IBMX ImM, Hepes 5mM, MgCl₂ 1OmM, BSA 0.1%, pH 7.4). The suspension was counted in a nucleocounter and further diluted in stimulation buffer at a concentration of 500,000 cells/ml. The cells were seeded out in a MW384 COSTAR 3710 with the compounds using a Multidrop 384 at a density of 10,000 cells/well in 20 μl.

To test for agonistic activity, the cells were incubated for 30 minutes at room temperature in the dark in the presence of different concentrations of the compounds diluted in stimulation buffer in a final volume of 30 μl/well. The final concentration of DMSO (whenever needed to dissolve the compounds) did not exceed 1% (v/v) and was also included in the corresponding control samples. Reaction was stopped by adding 10 μl cAMP-d2 conjugate and subsequently 10 μl of anti-cAMP with the Multidrop. After equilibration of the reaction mixtures for 1 to 24 hours in dark at room temperature, fluorescence was measured at 665 nm and 620 nm using a Discovery microplate fluorescence counter (Perkin Elmer) and the signal ratio of 665 nm / 620 nm was calculated. The signal ratios of the test compounds were expressed relative to the signal ratios of the DMSO control (maximal signal ratio, no stimulation of cAMP) and prostaglandin E2 (PGE2) (minimal signal ratio, maximal stimulation of cAMP). From the dose response curves generated for each test compound, the dose at which 50% of the maximal stimulation of cAMP level is observed (EC50) and the level of stimulation reached of the test compound compared to PGE2 was calculated. Table 5 below discloses pECso values (= -log(ECso) values).

Table 5

n.d. means not determined

Selectivity of the compounds for EP4 compared to EP2 can be demonstrated with the above test by also measuring stimulation of cAMP production upon activation of the human EP2 (hEP2) receptor by the present compounds.

Selectivity of the compounds for EP4 can also be demonstrated by determining whether the compounds have activity on the EPl receptor, for instance by [Ca²⁺J₁ measurements in response to activation or inhibition of the monkey EPl receptor as follows : The antagonistic and agonistic effect of the test compounds on intracellular Ca²⁺ concentrations ([Ca²⁺J₁) was measured in a fluorescent based assay, using the calcium assay kit (Molecular Devices, Crawley, England). HEK293 cells stably transfected with monkey EPl receptor were cultured in T 175 Falcon flasks in Dulbecco's modified Eagle's medium (DMEM) (Invitrogen) supplemented with 100 IU/ml penicillin G, 100 μg/ml streptomycin sulphate, 1 mM sodium pyruvate, 300 μg/ml L-glutamine and 10% heat inactivated foetal calf serum (Biochrom AG) in a humidified atmosphere of 5%CO₂ at 37°C. Before the experiments, the cells were grown on 384-well (black wall/transparent bottom) plates from Greiner for 1 day until they reached confluency. The cells were loaded with loading buffer supplied by the kit supplemented with 10 mM probenecid and 0.1% fatty acid free bovine serum albumine, adjusted to pH 7.4 with 1 M Hepes-acid, for 90 minutes at 37°C in a CO₂ incubator.

Ca²⁺ signals were measured in a Fluorometric Imaging Plate Reader (FLIPR, from Molecular Devices). To test antagonistic activity the loaded cells were preincubated with the compounds for 30 minutes at room temperature before starting the experiment in the FLIPR, where 100 nM of the reference agonist prostaglandin E2 (PGE2) was added. To test agonistic activity the compounds were added to the loaded cells during the measurement in the FLIPR where 1000 nM PGE2 was used as the reference agonist. In the FLIPR changes in relative fluorescence units were recorded in function of time. The final concentration of DMSO (whenever needed to dissolve the compounds) did not exceed 1% (v/v) and was also included in the corresponding control samples. ZD6416 was used as the reference antagonist. The peak fluorescence (maximum signal between 1 and 50 sec) was considered as the relevant signal. Concentration response curves were constructed based on peak fluorescence for each concentration of test drug. For antagonistic activity the peak fluorescence of the test compounds were expressed relative to the peak fluorescence of the DMSO control (minimal signal, maximal inhibition of calcium release) and 100 nM PGE2 (maximal signal, minimal inhibition of calcium release). From the inhibition curves generated for each test compound, the dose at which 50% of the maximal inhibition of calcium release is observed (IC₅₀ or pICso = -log(ICso) values) and the level of inhibition reached of the test compound was calculated.

For agonistic activity the peak fluorescence of the test compounds were expressed relative to the peak fluorescence of the DMSO control (minimal signal, minimal calcium release) and 1000 nM PGE2 (maximal signal, maximal calcium release). From the curves generated for each test compound, the dose at which 50% of the maximal stimulation of calcium release is observed (EC50 or pECso = -log(ECso) values) and the level of stimulation reached of the test compound was calculated. PEC50 (agonism) and pICso (antagonism) values for the tested compounds were <5.

Claims

1. A compound of formula

including any stereochemical^ isomeric form thereof, wherein ring E represents a partially saturated or aromatic 5-membered heterocycle wherein the dotted lines represent an optional double bond and wherein B, C and D each independently represent CH₂, CH, N, NH, S or O and F represents N or C, provided that the 5-membered ring contains 1, 2 or 3 heteroatoms; X represents a direct bond or Ci_₄alkanediyl;

Y represents N or CH; R¹ represents hydrogen or fluoro;

R² represents hydrogen, halo, cyano, C^alkyl, Ci_6alkyloxy, Ci_6alkylcarbonyl or C i -βalky lcarbony lamino ; R³ represents hydrogen, halo, C^alkyl, Ci_6alkyloxy, cyano, nitro, amino or mono- or di(Ci_6alkyl)amino;

R⁴ represents halo; hydroxyl; carboxyl; Ci_6alkyl optionally substituted with one or two substituents, each substituent independently selected from NR¹⁰R¹¹, cyano, carboxyl or Ci_₆alkyloxycarbonyl; polyhaloCi-βalkyl; Ci_₆alkyloxycarbonyl; polyhaloCi-βalkyloxy; C₂-6alkenyl optionally substituted with one or two substituents, each substituent independently selected from cyano, carboxyl or Ci-βalkyloxycarbonyl; cyano; nitro; NR¹⁰R¹¹; Ci_6alkylthio; C i_6alkyloxy optionally substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from hydroxyl, halo, cyano, carboxyl, Ci_₆alkyloxycarbonyl or NR⁵R⁶; or two adjacent R⁴ substituents may be taken together to form a radical of formula -0-CH₂-O- (a-1);

-0-CH₂-CH₂-O- (a-2); or -CH=CH-Z- (a-3); with Z representing O, S or NH; R⁵ and R⁶ each independently represent hydrogen; Ci_₆alkyl optionally substituted with Ci_₄alkyloxy; C₂-₆alkenyl; or C₃_₆Cycloalkyl; or

R⁵ and R⁶ together with the nitrogen atom to which they are attached form a radical of formula

_{with A re}p_resenti_ng O, NR⁷, CR⁸R⁹ or S and wherein one or more ring carbon atoms may optionally be substituted with Ci_₄alkyl or oxo;

R⁷ represents hydrogen; Ci_6alkyl optionally substituted with hydroxyl;

C₂-₆alkenyl; Ci_₆alkylcarbonyl; Ci_₆alkyloxycarbonyl; arylCi-βalkyl; arylcarbonyl; or aryl; R⁸ and R⁹ each independently represent hydrogen; Ci_₆alkyloxy;

Ci_₆alkylcarbonyl; arylcarbonyl; halo; amino; mono-or di(Ci_₆alkyl)amino;

Ci_₆alkyl optionally substituted with hydroxyl; Ci_₆alkyloxycarbonylCi_₆alkyl; or C₂- βalkenyl; or

R¹⁰ and R¹¹ each independently represent hydrogen; Ci_₆alkyl optionally substituted with one or two substituents, each substituent independently selected from hydroxyl,

Ci_₄alkyloxy or Ci_₄alkyloxycarbonyl; or R¹²-C(=O)-;

Ci_₆alkyl, Ci_₆alkyloxy, Ci_₆alkylcarbonyl, cyano, nitro, amino or mono-or di(C i _₆alkyl)amino ; provided that R³ may only be other than hydrogen if at least one of R¹ or R² is other than hydrogen; and provided that 2,6-bis(l,l-dimethylethyl)-4-[6-(2-phenylethoxy)-lH-purin-2-yl]- phenol is not included; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

2. The compound according to claim 1 wherein the compound has the following structure

3. The compound according to claim 1 wherein the compound has the following structure

including any stereochemical^ isomeric form thereof; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

4. The compound according to claim 1 wherein the compound has the following structure

5. The compound according to claim 4 wherein ring E represents a partially saturated or aromatic 5-membered heterocycle wherein the dotted lines represent an optional double bond and wherein B, C and D each independently represent CH₂, CH, N, NH, S or O provided that the 5-membered ring contains 1 or 2 heteroatoms;

X represents a direct bond or Ci_₄alkanediyl;

R¹ represents hydrogen or fluoro;

C i -βalky lcarbony lamino ; R represents hydrogen, halo, Ci_6alkyl, Ci_6alkyloxy, cyano, nitro, amino or mono- or di(Ci_6alkyl)amino;

Ci_₆alkyloxycarbonyl; polyhaloCi-βalkyl; Ci_₆alkyloxycarbonyl; polyhaloCi-βalkyloxy; C₂-6alkenyl optionally substituted with one or two substituents, each substituent independently selected from cyano, carboxyl or

Ci_6alkyloxycarbonyl; cyano; nitro; amino; mono-or di(Ci_6alkyl)amino;

Ci_₆alkyloxy optionally substituted with at least one substituent, each substituent independently selected from hydroxyl, halo, cyano, carboxyl, Ci_₆alkyloxycarbonyl or NR⁵R⁶;

R⁵ and R⁶ each independently represent hydrogen, C_halky!, C₂-₆alkenyl, or

C₃_₆Cycloalkyl; or

with A representing O, NR⁷, CR⁸R⁹ or S;

R⁷ represents hydrogen, C^aUcyl, C₂-₆alkenyl, Ci_₆alkylcarbonyl, Ci_₆alkyloxycarbonyl, arylCi-βalkyl or aryl;

R⁸ and R⁹ each independently represent hydrogen, Ci_₆alkyloxy, halo, amino, mono- or di(Ci_₆alkyl)amino, Ci_₆alkyl, Ci-ealkyloxycarbonylCi-βalkyl or C₂-₆alkenyl; or

R⁸ and R⁹ together with the carbon atom to which they are attached represent C(=O) or a 5, 6 or 7-membered saturated heterocyclic ring containing 1 or 2 oxygen atoms; n represents an integer of value 1, 2 or 3; m represents an integer of value 1, 2 or 3; p and q each independently represent an integer of value 0, 1, 2 or 3; aryl represents phenyl or phenyl substituted with at least one substituent, each substituent independently selected from halo, Ci_6alkyl, Ci_6alkyloxy, cyano, nitro, amino or mono-or di(Ci_6alkyl)amino.

6. The compound according to any one of claims 1, 4 or 5 wherein the compound has the following formula

7. The compound according to any one of claims 1, 4 or 5 wherein the compound has the following formula

8. The compound according to any one of claims 1, 4 or 5 wherein the compound has the following formula

9. The compound according to any one of claims 1, 4 or 5 wherein the compound has the following formula

10. The compound according to any one of the preceding claims wherein X represents a direct bond.

11. The compound according to any one of claims 1 to 10 wherein X represents Ci_4alkanediyl.

12. The compound according to any one of the preceding claims wherein R¹ represents hydrogen.

13. The compound according to any one of claims 1 to 11 wherein R¹ represents fluoro.

14. The compound according to any one of the preceding claims wherein R² represents hydrogen, halo, cyano, Ci_₆alkyl, Ci_₆alkyloxy or C i _6alkylcarbonylamino .

15. The compound according to any one of the preceding claims wherein R³ represents hydrogen, halo, Ci_₆alkyl or Ci_₆alkyloxy.

16. The compound according to any one of the preceding claims wherein

R⁴ represents halo; hydroxyl; Ci_6alkyl optionally substituted with NR¹⁰R¹¹; polyhaloCi-βalkyl; Ci_₆alkyloxycarbonyl; C₂-₆alkenyl substituted with carboxyl or Ci_6alkyloxyarbonyl; cyano; nitro; NR¹⁰R¹¹; Ci_6alkylthio; Ci_6alkyloxy optionally substituted with one or two substituents, each substituent independently selected from hydroxyl, halo, cyano, Ci_₆alkyloxycarbonyl or NR⁵R⁶; or two adjacent R⁴ substituents may be taken together to form a radical of formula -0-CH₂-O- (a-1);

-0-CH₂-CH₂-O- (a-2); or -CH=CH-Z- (a-3); with Z representing O; wherein R⁵ and R⁶ each independently represent Ci_₆alkyl optionally substituted with Ci_₄alkyloxy; C₃-₆cycloalkyl; or R and R > 6 together with the nitrogen atom to which they are attached form a radical of formula

_{with A} representing O, NR⁷, CH₂ or S.

17. The compound according to any one of claims 1 to 15 wherein R⁴ represents halo; hydroxyl; Ci_₆alkyl; Ci_₆alkyloxycarbonyl; C₂-₆alkenyl substituted with carboxyl; cyano; Ci_6alkyloxy optionally substituted with cyano, carboxyl, Ci_ βalkyloxycarbonyl or a radical of formula

— N A (_a_i)

^ — ' with A representing O, CH₂ or S.

18. The compound according to any one of the preceding claims provided that if R⁴ represents hydroxyl, then said hydroxyl is placed in ortho or meta position.

19. The compound according to any one of the preceding claims provided that if R⁴ represents t-butyl, then said t-butyl is placed in ortho or para position.

20. The compound according to any one of the preceding claims wherein n represents 1.

21. The compound according to any one of the preceding claims wherein m represents 1 or 2.

22. The compound according to any one of the preceding claims wherein p represents 1.

23. The compound according to any one of claims 1 to 16, 18 to 22 wherein q represents l or 2.

24. The compound according to any one of claims 1 to 11, 13 to 23 wherein R¹ is fluoro and R² is hydrogen.

25. The compound according to any one of claims 1 to 12, 14 to 23 wherein R¹ is hydrogen and R² represents halo, cyano, d-βalkyl, Ci_6alkyloxy, Ci_6alkylcarbonyl or Ci_6alkylcarbonylamino.

26. The compound according to any one of clams 1 to 11, 13 to 23 wherein R¹ is fluoro and R² represents halo, cyano, d-βalkyl, Ci_6alkyloxy, Ci_6alkylcarbonyl or

C i _6alkylcarbonylamino .

27. The compound according to any one of claims 1 to 12, 14 to 23 wherein R¹ and R² are both hydrogen.

28. The compound according to any one of claims 1 to 5, 10 to 27 wherein ring E contains 1 or 2 heteroatoms.

29. The compound according to any one of claims 1 to 16, 18 to 28 wherein R¹² represents Ci_4alkyl or Ci_4alkyloxy.

30. The compound according to any one of claims 1 to 15, 18 to 29 wherein R⁸ and R⁹ each independently represent hydrogen; Ci_₆alkyloxy; d-βalkylcarbonyl; arylcarbonyl; halo; amino; mono-or di(Ci_₆alkyl)amino; Ci_₆alkyl optionally substituted with hydroxyl; d-βalkyloxycarbonyld-βalkyl; or C_2-6alkenyl.

31. The compound according to any one of claims 1 to 4, 6 to 9 wherein X represents a direct bond; R² represents hydrogen, halo, cyano, Ci_6alkyl or Ci_6alkyloxy; R³ represents hydrogen, halo, Ci_6alkyl or Ci_6alkyloxy; R 4 represents halo; hydroxyl;

Ci_₆alkyl optionally substituted with NR 10τ R> l l ;. polyhaloC_1-6alkyl; Ci_₆alkyloxycarbonyl; C₂-₆alkenyl substituted with carboxyl or

Ci_₆alkyloxycarbonyl; NR , 1Or R, 11 ; Ci_₆alkylthio; cyano; nitro; C i_₆alkyloxy optionally substituted with one or two substituents, each substituent independently being selected from halo, hydroxyl, cyano, Ci_6alkyloxycarbonyl, or NR⁵R⁶; or two adjacent R⁴ substituents may be taken together to form a radical of formula -0-CH₂-O- (a-1);

-0-CH₂-CH₂-O- (a-2); or

-CH=CH-Z- (a-3); with Z representing O; n represents 1; m represents 1 or 2; R⁵ or R⁶ each independently represent Ci_₆alkyl optionally substituted with Ci_₄alkyloxy; or C₃-₆cycloalkyl; or R⁵ and R⁶ together with the nitrogen atom to which they are attached form a radical of formula

two ring carbon atoms may optionally be substituted with Ci_₄alkyl or oxo; R⁷ represents hydrogen; Ci_₆alkyl optionally substituted with hydroxyl; Ci_₆alkylcarbonyl; aryl; R⁸ and R⁹ each independently represent hydrogen;

Ci_₆alkyloxycarbonylCi_₆alkyl; Ci_₆alkylcarbonyl; arylcarbonyl; R¹⁰ and R¹¹ each independently represent hydrogen; Ci_₆alkyl optionally substituted with one or two substituents, each substituent independently selected from hydroxyl, Ci_₄alkyloxy or Ci_₄alkyloxycarbonyl; R¹²-C(=O)-; R¹² represents Ci_₄alkyl; Ci_₄alkyloxy; aryl; piperidinyl optionally substituted with Ci_₄alkylcarbonyl; p represents 1; q represents 1 or 2; aryl represents phenyl substituted with halo or C i -βalky lcarbony 1.

32. The compound according to claim 1 wherein the compound is selected from the group consisting of

4-[4-(2-fluoro-phenoxy)-thieno[3,2-d]pyrimidin-2-yl]-benzonitrile; 4-[2-(4-fluoro-phenyl)-thieno[3,2-d]pyrimidin-4-yloxy]-benzonitrile; 4-[4-(4-fluoro-phenoxy)-thieno[3,2-d]pyrimidin-2-yl]-benzonitrile; 3-fluoro-4-[2-(4-fluoro-phenyl)-thieno[3,2-d]pyrimidin-4-yloxy]-benzonitrile; l-[4-(2-{4-[4-(2,4-difluoro-phenoxy)-thieno[3,2-d]pyrimidin-2-yl]-phenoxy}- ethyl)-[ 1 ,4]iazepan- 1 -yl]-ethanone; l-[4-(3-{2-bromo-4-[4-(2,4-difluoro-phenoxy)-thieno[3,2-d]pyrimidin-2-yl]- phenoxy} -2-hydroxy-propyl)-piperazin- 1 -yl]-ethanone; l-[4-(2-{2-bromo-4-[4-(2,4-difluoro-phenoxy)-thieno[3,2-d]pyrimidin-2-yl]- phenoxy} -ethyl)-piperazin- 1 -yl]-ethanone; l-[4-(2-{4-[4-(2,4-difluoro-phenoxy)-thieno[3,2-d]pyrimidin-2-yl]-phenoxy}- ethyl)-piperazin- 1 -yl]-ethanone;

3-fluoro-4-[2-(3-bromo-phenyl)-thieno[3,2-d]pyrimidin-4-yloxy]-benzonitrile; 3-fluoro-4-[2-(3-chloro-phenyl)-thieno[3,2-d]pyrimidin-4-yloxy]-benzonitrile;

3-{4-[4-(2,4-difluoro-phenoxy)-thieno[3,2-d]pyrimidin-2-yl]-phenyl}-acrylic acid ethyl ester;

2-(3-bromo-phenyl)-6-(2,4-difluoro-phenoxy)-7H-purine;

4-[2-(3-bromo-phenyl)-7H-purin-6-yloxy]-3-fluoro-benzonitrile; 3-fluoro-4-[2-(4-fluoro-phenyl)-pyrrolo[2,l-f][l,2,4]triazin-4-yloxy]-benzonitrile;

3-fluoro-4-[5-(4-fluoro-phenyl)-thieno[2,3-c]pyridin-7-yloxy]-benzonitrile; a JV-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

33. The compound according to any one of the preceding claims for use as a medicine.

34. The compound according to any one of claims 1 to 32 for use as a medicine for the treatment of a disease by activating the EP4 receptor.

35. The compound according to any one of claims 1 to 32 for the treatment of primary osteoporosis, secondary osteoporosis, bone fracture, metastatic bone disease, rheumatoid arthritis, osteoarthritis, periodontitis, osteogenesis imperfecta, hypercalcemia, a disease associated with liver injury and acute hepatitis, renal failure and nephritis, ulcerative colitis, Crohn's disease, stomatitis, gastritis, ocular hypertension, glaucoma, neuropathic pain, bone pain, Reflex Sympathetic Dystrophy syndrome (RSD) also known as Complex Regional Pain Syndrome

(CRPS).

36. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as claimed in any one of claims 1 to 32.

37. A process of preparing a composition as claimed in claim 36 characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as claimed in any one of claims 1 to 32.

38. Use of a compound for the manufacture of a medicament for treating a disease by activating the EP4 receptor , wherein the compound is a compound of formula

including any stereochemically isomeric form thereof, wherein ring E represents a partially saturated or aromatic 5-membered heterocycle wherein the dotted lines represent an optional double bond and wherein B, C and D each independently represent CH₂, CH, N, NH, S or O and F represents N or C, provided that the 5-membered ring contains 1, 2 or 3 heteroatoms;

X represents a direct bond or Ci_₄alkanediyl;

Y represents N or CH; R¹ represents hydrogen or fluoro;

C i -βalky lcarbony lamino ;

R represents hydrogen, halo, Ci_6alkyl, Ci_6alkyloxy, cyano, nitro, amino or mono- or di(Ci_6alkyl)amino; R⁴ represents halo; hydroxyl; carboxyl; Ci_6alkyl optionally substituted with one or two substituents, each substituent independently selected from NR¹⁰R¹¹, cyano, carboxyl or Ci_₆alkyloxycarbonyl; polyhaloCi-βalkyl; Ci_₆alkyloxycarbonyl; polyhaloCi-βalkyloxy; C₂-6alkenyl optionally substituted with one or two substituents, each substituent independently selected from cyano, carboxyl or Ci_6alkyloxycarbonyl; cyano; nitro; NR¹⁰R¹¹; Ci_6alkylthio; Ci_6alkyloxy optionally substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from hydroxyl, halo, cyano, carboxyl,

Ci_₆alkyloxycarbonyl or NR⁵R⁶; or two adjacent R⁴ substituents may be taken together to form a radical of formula -0-CH₂-O- (a-1); -0-CH₂-CH₂-O- (a-2); or

-CH=CH-Z- (a-3); with Z representing O, S or NH;

R⁵ and R⁶ each independently represent hydrogen; Ci_₆alkyl optionally substituted with Ci_₄alkyloxy; C₂-₆alkenyl; or C₃-₆cycloalkyl; or

_with A representing O, NR⁷, CR⁸R⁹ or S and wherein one or more ring carbon atoms may optionally be substituted with Ci_₄alkyl or oxo; R⁷ represents hydrogen; Ci_₆alkyl optionally substituted with hydroxyl;

C₂_₆alkenyl; Ci_₆alkylcarbonyl; Ci_₆alkyloxycarbonyl; arylCi-βalkyl; arylcarbonyl; or aryl;

R⁸ and R⁹ each independently represent hydrogen; Ci_₆alkyloxy;

Ci_₆alkylcarbonyl; arylcarbonyl; halo; amino; mono-or di(Ci_₆alkyl)amino; Ci_₆alkyl optionally substituted with hydroxyl; Ci_₆alkyloxycarbonylCi_₆alkyl; or

C₂_₆alkenyl; or

Ci_₄alkyloxy or Ci_₄alkyloxycarbonyl; or R¹²-C(=O)-;

R¹² represents Ci_₄alkyl; Ci_₄alkyloxy; piperidinyl optionally substituted with

Ci_₄alkylcarbonyl; or aryl; n represents an integer of value 1, 2 or 3; m represents an integer of value 1, 2 or 3; p and q each independently represent an integer of value 0, 1, 2 or 3; aryl represents phenyl or phenyl substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from halo, Ci_₆alkyl, Ci_₆alkyloxy, Ci_₆alkylcarbonyl, cyano, nitro, amino or mono-or di(C i _6alkyl)amino ; provided that R³ may only be other than hydrogen if at least one of R¹ or R² is other than hydrogen; a JV-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

39. Use of a compound as claimed in claim 38 wherein the compound is a compound as claimed in any one of claims 1 to 32.

40. Use of a compound for the manufacture of a medicament for treating primary osteoporosis, secondary osteoporosis, bone fracture, metastatic bone disease, rheumatoid arthritis, osteoarthritis, periodontitis, osteogenesis imperfecta, hypercalcemia, a disease associated with liver injury and acute hepatitis, renal failure and nephritis, ulcerative colitis, Crohn's disease, stomatitis, gastritis, ocular hypertension, glaucoma, neuropathic pain, bone pain, Reflex Sympathetic Dystrophy syndrome (RSD) also known as Complex Regional Pain Syndrome (CRPS), wherein the compound is a compound as claimed in any one of claims 1 to 32.

41. A process of preparing a compound as defined in claim 1 characterized by a) reacting an intermediate of formula (II) wherein Wi represents a suitable leaving group with an intermediate of formula (III) in the presence of a suitable base and a suitable solvent,

with the variables as defined in claim 1 ; b) reacting in a first step (a), an intermediate of formula (II-a) with an intermediate of formula P-W₂ wherein P represents a suitable protective group and wherein W₂ represents a suitable leaving group, in the presence of a suitable base and a suitable solvent, followed by reaction (step b) with an intermediate of formula (III) in the presence of a suitable base and a suitable solvent, further followed by deprotection (step c) by reaction with a suitable acid in the presence of a suitable solvent,

(Il-a) (III)

(I-l-c) with the variables as defined in claim 1 ;

or, if desired, converting compounds of formula (I) into each other following art-known transformations, and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; or, if desired, preparing stereochemically isomeric forms, quaternary amines, solvates or JV-oxide forms thereof.