Title of Invention

BICYCLIC HETEROAROMATIC COMPOUNDS

Abstract

The present invention relates to a bicyclic heteroaromatic compound according to general formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is (3- 8C)cycloalkyl, (2- 7C)heterocycloalkyl, (6-14C)aryl or (4-13C)heteroaryl; all optionally substituted with one or more substituents; R2 is (1-4C)alkyl, (2-4C)alkenyl, (2- 4C)alkynyl, (6-14C)aryl or (4-13C)heteroaryl; R3 is (1-8C)alkyl, (3-8C)cycloalkyl, (2- 1C)heterocycloalkyl, (6-14C)aryl or (4-13C)heteroaryl; Y is CH or N;Z is NH2 or OR; A is S,n(H), N@,O or a bond and B is N(H), 0 or a bond; XI-X2 is C=C, C(O)-NH,NH- C(O),O,O-C(O), C=N, N=C or S or O. The compound of the invention can be used in fertility regulation therapies.

Full Text

BICYCLIC HETEROAROKATIC COMPOUNDS The invention relates to compounds having glycoprotein hormone agonistic or antagonistic activity, in particular to compounds having Luteinizing Hormone (LH) agonistic activity. The invention furthennore relates to bicyclic heteroaromatic derivatives, to pharmaceutical compositions containing the same as well as to the use of these compounds in medical therapy, particularly for use as a control of fertility. Gonadotropins serve important functions in a variety of bodily functions including metaboHsm, temperature regulation and the reproductive process. The hypophyseal gonadotropin FSH for example plays a pivotal role in the stimulation of folhcle development and maturation whereas LH induces ovulation (Sharp, R.M. Clin Endocrinol, 33:787-807, 1990; Dorrington and Armstrong, Recent Prog. Honn. Res. 35:301-342,1979). Currently, LH is applied clinically, in combination with FSH, for ovarian stimulation i.e. ovarian hyperstimulation for in vitro fertilisation (IVF) and induction of ovulation in infertile anovulatory women (Insler, V., Int. J. Fertility 33:S5-97, 1988, Navot and Rosenwaks, J. Vitro Fert. Embryo Transfer 5:3-13, 1988), as well as for male hypogonadism and male iniertility. Gonadotropins act on specific gonadal cell types to initiate ovarian and testicular differentiation and steroidogenesis. The actions of these pituitary and placental hormones are mediated by specific plasma membrane receptors that are members of the large family of G-protein coupled receptors. They consist of a single polypeptide with seven transmembrane domains and are able to interact with the Gs protein, leading to the activation of adenyl cyclase. Gonadotropins destined for therapeutic purposes can be isolated from human urine sources and are of low purify (Morse et al, Amer, J. Reproduct. Immunol, and Microbiology 17:143, 1988). Altemativeiy, they can be prepared as recombinant gonadotropins. As with other therapeutic proteins, it is necessary to administer gonadotropins either subcutaneous or mtra-muscular. It woxild be advantageous, however, to activate the receptor with a small molecule that could be administered through e.g. the oral or transdennal ixjute. The present invention describes the preparation of such low moleciilar weight hormone analogs that selectively activate one of the gonadotropin receptors. This should be considered as one of the major advantages of the present invention. Thus, the invention resides in bicyclic heteroaromatic derivatives according to general formula I, or a pharmaceutically acceptable salt thereof wherein R" is (3-8C)cycloallcyl, (2-7C)heterocycloalkyl, (6-14C)aryl or (4-13C)heteroaryl; preferably R" is (6-14C)ary] or (4-13C)heteroaryl; R^ is (l-4C)alkyl, (2-4C)a]kenyl, (2-4C)aIkynyl, or (6-14C)aryl or (4-13C)heteroaryl; R^ is (l-8C)alkyl, (3-8C)cycloalkyl, (2-7C)heterocycloaikyl, C6-14C)aryl or (4- I3C)heteroaiyl; YisCHorK; Z is NH2 or OH; A is S, N(H), NCR"), O or a bond and R can be selected from the same groups as described for R and BisN{H), Oorabond. The ring system in R" may optionally be substituted with one or more substituents selected from R^ NHR^ N(R"*)R^ OR^ and/or SR^ in which R^ is (6-14C)ary!, (4- 13C)heteroaiyl, (6-14C)arylcarbonyl, (2-7C)heterocycloaB:yl, (3-8C)cycloalkyl, (6- 14C)arylsulfonyl, (6-14C)arylaminocarbonyl, (6-14C)aryloxycarbonyl, (6- 14C)arylaminosizIfonyI, (6-]4C)aryIoxysit]fonyl, (2-SC)alkenyI, (2-SC)aIkynyl, (2- TQhetearocycloalkylcarhonyl, (2-8C)al]cenylsulfonyl, (2-8C)alkenoxycarbonyi or (l-8C)alkyl, (l-8C)alkylcaibonyl, (l-8C)alky]sxilfonyl, (l-8C)(di)alkylaminocarbonyl, (l-8C)alkoxycarbonyl, (l-8C)(di)alkylanu]iosulfonyl, or (l-8C)alkoxysulfonyl, the altyl group of which may be optionally substituted with one or more substituents selected from hydroxyl, (l-8C)alkoxy, (2-7C)heterocycIoaIkyi(l-8C)alkoxy, (3-8C)cycloaIkyl(l-8C)alkoxy, (6-14C)aryl(l-8Qalkoxy, (4-13C)heteroaiyl(l-8C)alkoxy, (2-7C)heterocycloaIkyl, (3-SC)cyc]oalky], (6-140aiyl, (4-13C)heteroaiyl, (I-8C)alkoxycarbonyl, {6-14C)aryloxycarbonyl, (l-SC)alkylcarbonyloxy, (6-14C)arylcarbonyloxy, (l-8C)alkylcarbonyl, (6-14C)arylcarbonyl, amine, (1-8C)a]kylaminocarbonyl, (6-14C)arylaminocarbotiyl, (l-8C)alkylcarbonylamiiio, (6-UQarylcarbonylamino, (6-14C)(di)arylamino, (di)[(l-3C)alkoxy(l-3C)allcyl]amino and/or(l-8C)(di)aIkyIamino. Preferably the substituents in R" are chosen fi"om NHR^ or OR^. R^ in any of the substituents at R^ preferably is (2-7C)lieterocycloalkylcaibonyl, (6-14C)arylcarbonyI or (l-8C)aIkyl, (l-8C)aIkyIcarbonyI, or (1-8C)(di)alkylaniinocarbonyl, the alkyl group of which may be optionally substituted with (2-7C)heterocycIoaikyl, (4-13C}heteroaryl, (l-SC)alkoxycarbonyl, (1-8C)aIkylaminocarbonyl, (l-SC)alkylcarbonylanmio, (6-14C)arylcarbonylainino, amine and/or(l-8C)(di)alkylamino. The most preferred substituents at the alkylgroup are (2-7C)heterocycloalkyl, (l-8C)(di)alkylamino, amine and (l-8C)(di)alkyiaminocarbonyI. Most preferred at Rl is phenyl optionally substituted with one of the above identified substituents, the substitution being preferably at the meta position. In the compounds according to the invention X1-X2 is C=C, C(0)-NH, KB-C{0), C(0)-0, O-C(O), C=N or N=C. If R^ is (l-8C)aIkylsulfonyl, (6-14C)arylsulfonyl, (1-8C)(di)alkylaminocarbonyl, (6-14C)arylaininocarbonyl, (l-8C)alkoxycarbonyl, (6-14C)aryloxycarbonyl, (l-8C)(di)alkylaminosulfonyl, (6-14C)arylaminosulfonyl, (1-8C)aOcoxysulfonyl, (2-7C)heterocycloalkylcarbonyl, (2-8C)alkenylsulfonyl, (2-8C)aIkenoxycarbonyl or (6~14C)aryloxysulfonyl then XI-X2 may additionally be S or 0. Preferred compoimds according to the invention are compoxmds according to general formula I wherein B is N(H) or a bond and/or Z is NH2. Amongst these preferred compounds those wherein B is N(H) or a bond and Z is NH2 are especially preferred. More preferred are the compounds which preferably in addition to the above mentioned definitions of B and Z are defined by R^ being (6-14C)aryl or (4-13C)beteroaryl, optionally substituted with one or more substituents selected from N(R^)R^, NHR^, R^, OR^ and/or SR^ preferably with NHR^ or OR^ Preferred for Y in all the above identified confounds is N, preferred for B is N(H) or a bond. If B is a bond, R^ preferably is (2-7C)heterocycloalkyI. Furthermore, in all the above identified compounds X1-X2 preferably is C=C, C=N or N=C most preferably C=C. If R^ is (l-8C)alkylsulfonyl, (6-14C)arylsuIfonyl, (1-8C)(di)alkylaniinocarbonyl, (6-14C)arylaniinocarbonyl, (l-8C)alkoxycarbonyl, (6-14C)aryloxycarbonyl, (l-8C)(di)alkylaminosulfonyl, (6-14C)arylaminosulfonyl, (1-8C)alkoxysulfonyl, (2-7C)heterocycIoaIkylcarbonyl, (2-8C)aIkenylsulfonyl, (2-SQalkenoxycarbonyl or (6-14C)aryloxysulfonyl then preferred for X1-X2 is, in addition to the above identified groups, also S. Most preferred are compounds selected from the group rert-butyl 5-aniino-2- methylthio-4-{3-((N,N-diethylarnino)-carbonyloxy)-phenyl)-thieno[2,3-£f]pyriimdine- 6-carboxamide, teri-hntyl 5-amino-2-methylthio-4-(3-(methoxycarbonylamino)- phenyi)-tIiieno[2,3-£^pyrimidine-6-caitoxaniide, tert-bntyl 5-aniino-2-methylthio-4-(3- (al]yloxycarbonylamino)-phenyl)-thieno[2,3-£f|pyrimidine-6-carboxamide, iert-hutyl 5- amino-2-methylthio-4-(3-(ethoxycarbonylamino)-phenyl)-thieno[2,3-£(lpyrimidiDe-6- carboxamide, tert-hutyl 5-amiQO-2-methylthio-4-(3-((morphohn-4-yl)-carbonylainino)- phenyl)-thieno[2,3-tflpyrimidine-6-carboxamide, tert-hutyl 5-aiiiino-2-methylthio-4-(3- (l,2,3,6-tetrahydropyridinocarbonylamino)-plienyl)-thieno[2,3-cripyruiiidine-6- carboxamide, tert-hutyl 5-amino~2-phenyl-4-(3-((N,N-diinethylainino)- carbonylamuio)-phenyl)-thieno[2,3-(f|pyiimidine-6-carboxamide. Excluded from the invention are the compounds ethyl 5-hydroxy-2-inetbyl-4-(piperidin-l-yl)-pyrido[2,3-(f]pyriniidiQe-6-carboxylate, ethyl 5-hydroxy-2-tnethyi-4-(moipbolin-4-yl)-pyrido[2,3-ii]pyTimidine-6-carboxylate and ethyl 5-hydroxy-2-methyl-4-(pyiT0lidin-1-yl)-pyTido [2,3-rfJpyrimidine-6-carboxylate. The disclaimer relates to the disclosures in Chem. Phaim. BuU. 18(7), 1385-1393 (1970). The tenn (l-SC)alkyl as used in the definition of formula I means a branched or unbranched alkyl group having 1-S carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyi, hexyl and octyl. (l-6QAlkyl groups are preferred, (l-3C)aIkyl groups being the most preferred. The term (2-8C)aIk:enyl means a branched or unbranched alkenyl group having 2-8 carbon atoms, such as ethenyl, 2-butenyl etc. (l-6C)AIk:enyl groups are preferred, (1-3C)alkenyl groups being the most preferred. The term (2-8C)alkynyl means a branched or unbranched alkynyl group having 2-8 carbon atoms, such as ethynyl and propynyl. Most preferred are (2-4C)alkynyl groups. The term (6-14C)aiyl means an aromatic hydrocarbon group having 6-14 carbon atoms, such as phenyl, naphthyl, tetrahydron^hthyl, indenyl, anthracyl, which may optionally be substituted with one or more substituents such as -but not Umited to-hydroxy, halogen, nitro, trifluoromethyl, cyano, (l-8C)alkylcarbonylamino, (1-8C)aIkylaminocariJonyl or (l-SC)(di)alkylamino, the alkyl moieties having the same meaning as previously defined. More preferred are (6-10C)aryl groups. The most preferred aromatic hydrocarbon group is phenyl. The term (3-8C)cycloalkyl means a cycloalky] group having 3-8 carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclo-octyl. The term (2-7C)heterocycIoaIkyI means a heterocycloalkyi group having 2-7 carbon atoms, preferably 2-5 carbon atoms, and at least including one heteroatom selected from N, O or S. Preferred heteroatoms are N or O. Kitrogen-containing heterocycloalkyi groups may either be connected via a carbon or a nitrogen atom. Most preferred heterocycloalkyi groups are piperidine, morpholine and pyrrolidine. The term (2-7C)heterocycioalkylcarbonyl means a heterocycloalkyi group having 2-7 carbon atoms as previously defined, connected to a carbonyl group. The term (l-8C)alkoxy means an alkoxy group having 1-S carbon atoms, the alkyl moiety having the same meaning as previously defined. (l-6C)Alkoxy groups are preferred, (l-3C)aIkoxy groups being the most preferred. The term (l-8C)alkoxycarbonyl means an alkoxycarbonyl group, the alkyl group of which contains 1-8 cariion atoms and has the same meaning as previously defined. (1-6C)Alkoxycarbonyl groups are preferred, (l-3C)alkoxycarbonyl groups being the most preferred. The term (2-SC)alkenoxycarboiiyl means an alkenoxycarbonyl group, the alkenyl group of which contains 2-8 carbon atoms and has the same meaning as previously defined. (2-6C)A!kenoxycarbonyl groups are preferred, (2-3C)aikenoxycarbonyl groups being the most preferred. The term (l-8C)aIkoxysuIfonyl means an alkoxysulfonyl group, the alkyl group of which contains 1-8 carbon atoms and has the same meaning as previously defined. (1-6C)Alkoxysulfonyl groups are preferred, (l-3C)alkoxysulfonyl groups being the most preferred. The term (l-8C)(di)alkylamino means an (di)alkylamino group having 1-8 carbon atoms, tbe alkyl moiety having the same meaning as previoxisly defined. More preferred are (l-6C)(di)alkylaniino ^oups. The term di[(l-3C)alkoxy(l-3C)alkyl]amino means a (di)[alkoxyalkyl]anuno group, both the alkyl and alkoxy moieties of which having 1-3 carbon atoms and having the same meaning as previously defined. The term C6-14C)(di)arylamino means an (di)arylamiao group having 6-14 carbon atoms, the aryl moiety having the same meaning as previously defined. More preferred are (6-10C)(di)arylanmio groups. The most preferred (di)arylainino group is (di)-phenylamino. The term (l-8C)alkylthio means an alkylthio group having 1-8 carbon atoms, the alkyl moiety having the same meaning as previously defined. Most preferred are (1-4C)alkylthio groups. The term (6-14C)aryloxycarbonyl means an aryloxycarbonyl group, the aryl group of which contains 6-14 carbon atoms, more preferably 6-10 carbon atoms and has the same meaning as previously defined. Most preferred are phenoxycarbonyl groups. The term (6-14C)aryloxysulfonyl means an aryloxysutfonyl group, the aryl group of which contains 6-14 carbon atoms, more preferably 6-10 carbon atoms and has the same meaning as previously defined. Most preferred are phenoxysulfonyl groups. The term (6~14C)aryl(l-8C)alkyl means an aiylalkyl group having 7-22 carbon atoms, wherein the alkyl group is a (l-8C)alkyl group and the aryl group is a (6-14C)aryl group as previously defined. More preferred are (6-10C)aiyl(l-4C)allcyI groups. Phenyl(l-4C)alkyl groups, such as benzyl, are the most preferred arylalkyi ^oups. The term (4-13C)heteroaryi means a substituted or imsubstituted aromatic group having 4-13 carbon atoms, preferably 4-9, at least including one heteroatom selected from N, O and/or S, like imidazolyl, thienyl, benzthienyl, quinolyl, tetrahydroquinolyi, isoquinolyl, tetrahydroisoquinolyl, indolyl, acridinolyl, furyl or pyridyl. The substituents on the heteroaryl group may be selected from the group of substituents listed for the aiyl group. Preferred heteroaryl groups are thienyl, furyl, pyridyl and pyrimidyl. Nitrogen-containing heteroaryl groups may either be connected via a carbon or a nitrogen atom. The term halogen means fluorine, chlorine, bromine or iodine. The term (2-7C)heterocycloalkyl(l-SC)alkoxy means a heterocycloalkyi group containing 2-7 carbon atoms as defined previously, attached to a (l-8C)alkoxy group, the alkoxy moiety having the meaning as previously defined. More preferred are 2-5C)heterocyGloalkyl(l-4C)alkoxy groups. The term (3-8C)cycloalkyl(l-8C)alkoxy means a cycloalkyl group containing 3-S caibon atoms as defined previously, attached to a (l-8C)alkoxy group, the alkoxy moiety having the meaning as previously defined. More preferred are 3-6C)cycloaIkyl(l-4C)alkoxy groups. The term (6-14C)aryl(l-8C)allcoxy means an aryl group containing 6-14 carbon atoms as defined previously, attached to a (l-8C)a]koxy group, the alkoxy moiety having the meaning as previously defined. More preferred are (6-10C)aryI(I-4C)alkoxy groups, phenyl(l-4C)alkoxy groups being the most preferred. (4-13C)Heteroaryl(l-SC)alkoxy groups are analogs of the (6-14C)aiyi(l-8C)alkoxy groups, at least including one heteroatom selected fi-om N, O and S in the heteroaryl ring. More preferred are (4-9C}heteroaryl(l-4C)alkoxy groups. The term (l-8C)alkylcarbonyl means an alkylcarbonyl group, the alkyl group of which contains 1-8 caibon atoms aad has the same meaning as previously defined. More preferred are (l-6C)alkylcarbonyl groups, (l-4C)alkylcarbonyl groups being the most preferred. The term (6-14C)arylcaibonyl means an arylcarbonyl group, the aiyl group of which contains 6-14 carbon atoms and has the same meaning as previously defined. More preferred are (6-10C)arylcarbonyI groups, phenylcarbonyl groups being the most preferred. The term (l-8C)aIkyIsulfonyi means an alkylsulfonyl group, the allcyl group of which contains 1-8 carbon atoms and has the same meaning as previously defined. More preferred are (l-6C)alkylsulfonyl groups, (l-4C)aIkylsulfonyl groups being the most preferred. The term (2-8C)alkenylsulfonyl means an alkenylsulfonyl group, the alkenyl group of which contains 2-8 carbon atoms and has the same meaning as previously defined. More preferred are (2-6C)aIkenylsulfonyl groups, (2-4C)alkenylsulfonyl groups being the most preferred. The term (6-14C)arylsulfonyl means an aiylsulfonyl group, the aryl group of which contains 6-14 carbon atoms and has the same meaning as previously defined. More preferred are (6-10C)arylsulfonyl groups, phenylsulfonyl groups bemg the most preferred. The term {l-3C}aikylcarbonyioxy means an alkylcarbonyloxy group, the a!lr/l group of which contains 1-3 carbon atoms and has the same meaning as pre"."iou::.;/ ":e:^-ied. More prei"arred are (l-6C)aIkylcarbcnylo:c/ gr:;uT:s. Most prefe-"cd zz^. (1-" "--.""^■icarbcnvloxv groirjs. The tenn (6-14C)arylcarbonyloxy means an arylcaibonyloxy group, the aryl group of which contains 6-14 carbon atoms and has the same meaning as previously defined. More preferred are (6-10C)arylcarbonylQxy groups, phenylcarbonyloxy groups being the most preferred. The tenn (l-8C)(di)aIkylaminocarbonyl means a (di)alkylaminocarbonyl group, the alkyl group of which contains 1-8 carbon atoms and has the same meaning as previously defined. More prefened are (1-6C)(di)a]kylaminocarbonyl groups, (1-4C)(di)alkylaminocarbonyl groups being the most preferred. The term (6-14C)(di)arylaniinocarbonyl means a (di)arylaminocarbonyl group, the aryl group of which contains 6-14 carbon atoms and has the same meaning as previously defined. More prefened are (6-10C)(di)arylaminocarbonyl groups, (di)-phenylaminocarhonyl groups being the most preferred. The term (l-8C)(di)aikylaminosulfQnyl means a (di)aIkylaminosulfonyl group, the alkyl group of which contains 1-8 carbon atoms and has the same meaning as previously defined. More preferred are (l-6C)(di)alkyIaminosulfonyl groups, (1-4C)(di)alkylaminosulfonyl groups being the most prefrared. The term (6-14C)(di)arylaininosulfonyl means a (di)arylaininosulfonyl group, the aryl group of which contains 6-14 carbon atoms and has the same meaning as previously defined. More preferred are (6-10C)(di)arylaniinosulfonyl groups, (di)-phenylaminosulfonyl groups being the most preferred. The term (l-8C)alkylcaibonylamino means an alkylcarbonylamino group, the alkyl group of which contains 1-8 carbon atoms and has the same meaning as previously defined. More preferred are (l-6C)alkyIcarbonylamino groups, (1-4C)aIkylcarbonylaniino groups being the most preferred. The term (6-14C)arylcarbonylamino means an arylcarbonylamino group, the aryl group of which contains 6-14 carbon atoms and has the same meaning as previously defined. More preferred are (6-10C)arylcarbonylamuio groups, phenylcarbonylamino groups being the most preferred. The term (2-7C)heterocycloaikyloxy means a heterocycIoaUcyl group containing 2-7 carbon atoms as defined previously, attached to an oxygen atom. Most prefened are (2-5C)heterocycloalkyloxy groups. The term (3-8C)cycloalkyloxy means a cycloalkyl group containing 3-8 carbon atoms as defined previously, attached to an oxygen atom. The tenn (6-14C)aryloxy means an aryl group containing 6-14 carbon atoms as defined previously, attached to an oxygen atom. More preferred are (6-10C)aiyfoxy groups, phenoxy groups being most preferred. (4-13C)Heteroaiyloxy groups are analogs of the (6-14C)aryloxy groups, at least including one heteroatom selected from N, 0 and S in heteroaryl ring. More preferred are (4-9C)heteroaTyloxy groups. It has been shown that compounds of the above mentioned formula I are capable of binding to the LH receptor and show agonistic LH activity. The invention fiirther resides in a pharmaceutical composition comprising a bicyclic heteroaromatic derivative or salts thereof having the general formula I. Thus, the compounds accordiug to the invention can be used in therapy. A fiirther aspect of the invention resides in the use of a bicyclic heteroaromatic compound having the general formula I for the manufacture of a medicament for the control of fertility. Preferably the present compounds are used to activate the LH receptor. The bicyclic heteroaromatic derivatives of this invention may possess one or more chiral carbon atoms. The compounds may therefore be obtained as chiraUy pure compounds or as a mixture of diastereomers and/or enantiomers. Methods for obtaining the chiraUy pure compounds are well known in the art, e.g. crystallization or chromatography. For therapeutic use, salts of the compounds of formula I are those wherein the counterion is pharmaceutically acceptable. However, acid addition salts of bases according to formula I, 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. Examples of acid addition salts include those derived from mineral acids such as hydrochloric acid, phosphoric acid, sulphuric acid, preferably hydrochloric acid, and organic acids like citric acid, tartaric acid, acetic acid, lactic acid, maleic acid, malonic acid, fiunaric acid, glycoUc acid, succinic acid, and the like. Suitable administration routes for the compounds of foromla I or pharmaceutically acceptable salts thereof, also referred to herein as the active ingredient are intramuscular injections, subcutaneous injections, intravenous injections or intr^eritoneal injections, oral and intranasal administratioa Preferably, the compounds may be administered orally. The exact dose and regimen of administration of the active ingredient, or a pharmaceutical composition thereof will necessarily be dependent upon the therapeutic effect to be achieved (treatment of infertility; contraception), and may vary with flie particular compound, the route of administration, and the age and condition of the individual subject to whom the medicament is to be administered. In general parenteral administration requires lower dosages than other methods of administration which are more dependent upon adsorption. Tlowever, a dosage for humans preferably contains 0.0001-25 mg per kg body weighi. The desired dose may be presented as one dose or as multiple subdoses administered at qjpropriate intervals throughout the day, or, in case of female recipients, as doses to be administered at appropriate daily intervals throughout the menstrual cycle. The dosage as well as the regimen of administration may differ between a female and a male recipient. In case of in vitro or ex vivo applications, like in IVF applications, the compounds of the inventions are to be used in the incubation media in a concentration of approximately 0.01-5 |ig/ ml. The present invention thus also relates to pharmaceutical compositions comprising a bicyclic heteroaromatic compound according to formula in admixture with pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents. The auxiliaries must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and irvtradennal) administration. The compositions may be prepared by any method well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington"s Pharmaceutical Sciences (18th ed., Mack Publishing company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture). Such methods include the step of bringing in association the active ingredient with any auxiliary agent. The auxiliary agent(s), also named accessory ingredients, include those conventional in the art (Gennaro, supra)., such as, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents and wetting agents. Pharmaceutical compositions suitable for oral administration may be presented as . discrete dosage units such as pills, tablets or capsules, or as a powder or granules, or as a solution or suspension. The active ingredient may also be presented as a bolus or paste. The compositions can further be processed into a suppository or enema for rectal administration For parenteral administration, suitable compositions include aqueous and non-aqueous sterile injection. The compositions may be presented in unit-dose or multi-dose containers, for example sealed vials and ampoules, and may be stored in a freeze-dried (lyophihsed) condition requiring only the addition of sterile Uquid carrier, for example, water prior to use. Compositions, or formulations, suitable for administration by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurized aerosols, nebulisers or insufflators. The bicyclic heteroaromatic derivatives of the invention can also be administered in the form of implantable phamiaceutical devices, consisting of a core of active material, encased by a release rate-regulating membrane. Such implants are to be applied subcutaneously or locally, and will release the active ingredient at an approximately constant rate over relatively large periods of time, for instance from weeks to years. Methods for the preparation of implantable pharmaceutical devices as such are known in the art, for example as described in European Patent 0,303,306 (AK20N.V.). Thus, the compounds according to the present invention can be used for the same chnical purposes as the native LH, with the advantage that they display altered stability properties and can be administered differently. The compounds of the present invention wherein B = NH, represented by formula (I-a) can generally be prepared following art-known condensation of an acid of formula (II) with an amine of formula (HI). The compounds of formula (I) wherein B is a bond, represented by formula (I-c) are accessible by reaction of an appropriate organometallic reagent with derivatives of formula (V) in an aprotic solvent such as THF. Related substitution reactions can be found in literature: S.V. Frye, M.C. Johnson, NX. Valvano, J. Org. Chem. 56: 3750, 1991. Weioreb amides of formula (V) can be synthesized from acids of formula (H) and N-methoxy-N-methyl amine using the conditions described for the preparation of amides of formula (I-a). Bicyclic lactams of fonnula (VH) are useful starting materials for the preparation of the corresponding imines (VHI). hi a typical experiment, the lactam is converted to the corresponding chioroimine using phosphoryl chlori.de at elevated temperatuie (60 °C to reflux) in an appropriate solvent such as 1,4-dioxane. Upon treatment with a reducing agent such as hydrogen in the presence of a suitable catalyst in ethanol, the desired imine of general formula (Vm) can be isolated. Related reductions have been reported in Uterature, see for example: E. Bisagni, C. Landras, S. Thirot and C. Huel, Tetrahedron 52:10427,1996. BicycUc lactams of general structure (VH) may be prepared by condensation of acids of type (DC) with diethyl aminomalonate under the agency of a coupling agent such as XBTU/DiPEA and cyclisation of the iDtermediate amides in ethanol under basic conditions. Aromatisation with concomitant deethoxycarbonylation thea yields bicycles of type (VTI). In an alternative procedure, glycine ethyl ester can be used instead of diethyl aminomalonate. See for example: M. Blanco, M.G. Lorenzo, I. Perillo, CB. Schapira, J. Heterocycl. Chem. 33: 361, 1996. Cyclisation of the intermediate amides may also be effected by tin(IV) chloride. The use of tin(IV) chloride to effect ring-closure on related systems has been reported: A.C. Veronese, R. CaUegaii, C.F. Morelli, Tetrahedron 51: 12277,1995. Alternatively, (ert-butyl ethyl malonate can be used in this procedure instead of diethyl malonate. In another approach, methyl pyri(mi)dines of general formula (XIV) are deprotonated at the methyl group using a strong base, such as lithium hexamethyldisilazane (LiHMDS) or hthium diisopropylamide (LDA) in a suitable aptotic solvent, such as THF at low temperatures (-78 °C). The anion is then reacted with ethyl 3-ethoxyacrylate. After conjugate addition, cyclisation to quinolines or quinazolines of general formula (XHO occurs, as described in: K. Kobayashi, K. Takada, H. Tanaka, T. Uneda, T. Kitamura, Chem. Lett.: 25, 1996; K. Kobayashi, T. Uneda, K. Takada, H. Tanaka, T. Kitamura, O. Morikawa, H. Konishi, J. Org. Chem. 62: 664,1997. Alternatively, imines of formula pCVUI) can be prepared from the corresponding lactams of formula (XIX) in a similar fashion (vide supra) as their regioisomeric analogs of formula (Vni), i.e. conversion to liie cWoroimine using POCI3 and subsequent dehalogenation using hydrogen and an appropriate catalyst. Furopyri(mi)dines of general formula (XXlii) are accessible by selective O-aUcylation of lactams of type (XXI) using potassium carbonate in acetone, and subsequent ring-closure under the influence of sodium ethoxide in ethanol. Thienopyri(mi)dines of general formula pOCTV) are accessible by treatment of chlorides (XV) with ethyl mercaptoacetate under the influence of a strong base. In a typical experiment, one equivalent of chloride (XV) is reacted with 1.5 equivalents of ethyl mercaptoacetate and 2 equivalents of potassium tert-butoxide in THF. Under these conditions, the acyclic sulfide undergoes spontaneous cyclisation to form the tiiienopyri(mi)dine of general formula (XXIV). If R^ is Clietero)aryl, substituted with an electron withdrawing group such as nitro, the abovementioned cyclization is accomphshed via a two-step procedure, involving isolation of the intermediate Ihioether, followed by treatment with a *crtiary base such as DIPEA in toluene/EtOH at reflux temperature, to effect thiophene rmg formation. Pyri(mi)dine carboxylates of general formula (DC) are accessible by saponification of alkoxycarbonyl pyri(mi)dines of formula (XXV) using a stroi.^, base such as lithium hydroxide or potassi^un hydroxide in a mixture of water and an organic co-solvent such as 1,4-dioxane or methanol at elevated temperature (40 °C to reflux), followed by acidic-work-up. If W = C02a31cyl, R^ preferably is benzyl, to enable selective hydiogenolysis of the benzyl ester function while substituent W remains unaffected. Compounds of foimula (XXV) could be prepared by palladium-catalysed alkoxycarbonylation of chlorides (XV) in the presence of carbon monoxide and an appropriate alcohol (R"OH, XXVI). Similar transfonnations have speared in literatore, see for example: Y. Bessard, R. Crettaz, Heterocycles 51: 2589,1999. Similarly, treatment of chlorides of general formula (XV) with trimethylalane in the I presence of a palladium catalyst in an aprotic solvent such as THF gives access to methyl pyri(mi)diiies of general fommla (XIV). Related syntheses have been published in: Q. Lu, I. Mangalagiu, T. Bsnneche and K. Undheim, Acta Chem. Sc. 51: 302,1997. In a typical experiment, components PCXVII), pOCVUI) and (XXKa-e) are suspended in an appropriate solvent, e.g. ethanol, methanol, N,N-diniethyIformamide, N-methylpyrrolidinone, tetrahydrofuran or pyridine and a base such as potassium carbonate, sodium acetate, sodium methoxide or sodium ethoxide is added. Reaction takes place at elevated temperature (70 "C to reflux). See for example: S. Kambe, K. Saito and H. Kishi, Synthesis: 287, 1979; A.M. Abd-Elfattah, S.M. Hussain and A.M. El-Reedy, Tefrahedron 39: 3197, 1983; S.M. Hussain, A.A El-Barbary and S.A. Mansour, J. Heterocycl. Chem. 22: 169, 1985. In the case of W = C(0)OEt, aromatization occurs on the addition of an oxidant, such as DDQ or oxygen. Related cyclizations may also be performed on a solid support such as Merrifield lesin using an appropriate linker, see for example A.L. Mrzinzik and E.R. Felder, J. Org. Chem. 63: 723, 1998; T. Masquelin, D. Sprenger, R. Baer, F. GcAer and Y. Mercadal, Helv. Chim. Acta 81: 646,1998. Compounds of general fonnula (XX) wherein Y = N, represented by formula (XX-a) may be prepared via a similar condensation strategy, using malonitrile. Alternatively, compounds of general formula (XX) are accessible by ammonolysis of chlorides of formula PCV), using aqueous ammonia and an jqDpropriate organic-co solvent such as 1,4-dioxane. This transformation may also be accomplished with ammonium chloride and a tertiary amine base such as DiPEA m an aprotic solvent such asDMF. Chlorides of general foimula (XV) can be synthesized by the art-known reaction of . lactams pCXI) with POCI3 in an appropriate solvent, such as 1,4-dioxane, at elevated temperatures (60 "C to reflux). Derivatives of fonnula (XV) wherein Y = N and R" is not (6-14C)aiyl or (4-13C)heteroaryl, may be prepared via monosubstitution of CI in derivatives of formula (XXX) with various nucleophiles. Related substitution reactions can be foimd in literature, e.g. S. Kohra, Y. Tonunaga and A. Hosomi, J. Heterocycl. Cbem. 25: 959, 1988; A.A. SantiUi, D.H. Kim and S.V. Wanser, J. Heterocycl. Chem. 8: 445, 1971; J. Clark, M.S. Shannet, D. Korakas and G. Varvounis, J. Heterocycl. Chem. 30: 1065, 1993; S. Tumkevicius, Liebigs Ann. Org. Bioorg. Chem. 9:1703,1995. Pyridmes of general fonnula (XXI) wherein Y = CH, A = S and W = CN, represented by formula (XXI-b) are accessible by sequential alkylation of a,p-unsaturated dinitriles of general structure (XXXI) with carbon disulfide and alkyl iodide R^-I to give compounds of general fomiula (XXXII), as described by P. Milart, Tetrahedron 54: 15643-15656, 1998. Cychzation of compounds of formula (XXXH) under acidic conditions as described by K. Peseke, Z. Chem. 29: 442-443 (1989) yields pyridines of general fonnula (XXI-b). Compounds of general formula (XXI) wherein A is a bond, Y = CH and W is as previously defined, represented by formula (XXI-c), can be prepared by reaction of , -unsaturatedketones of general formula PODQII) with amides of general fomiula (XXXIV) wherein W is as previously defined, using a strong base such as potassium tert-butoxide in the presence of oxygen in a suitable solvent, such as dimethylsulfoxide. Related cyclisations have been described in: IL Iain, F. Roschangar, MA. Ciufolini, Teh-ahedron Lett. 36: 3307, 1995. Methods to determine receptor binding as well as in vitro and in vivo assays to determine biological activity of gonadotropins are well known. In general, expressed receptor is contacted with the compound to be tested and bindiog or stimulation or inhibition of a functional response is measured. To measure a functional response isolated DNA encoding the LH receptor gene, preferably the human receptor, is expressed in sintable host ceUs. Such a cell might be the Chinese Hamster Ovary cell, but other cells are also suitable. Preferably the ceUs are of mammalian origin (Jia et al, MolEndocrin., 5:759-776,1991- Methods to construct recombinant LH expressing cell lines are weil known in the art (Sambrook et al.. Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latest edition). Expression of receptor is attained by egression of the DNA encoding the .desired protein. Techniques for site du-ected mutagenesis, Ugation of additional sequences, PCR, and construction of suitable expression systems are all, by now, well known in the art. Portions oi all of the DNA encoding the desired protein can be constructed synthetically using standard solid phase techniques, preferably to include restriction sites for ease of ligation. Suitable control elements for transcription and translation of the included coding sequence can be provided to the DNA coding sequences. As is well known, expression systems are now available which are compatible with a wide variety of hosts, including prokaryotic hosts such as bacteria and eukaryotic hosts such as yeast, plant cells, iosect cells, mammalian cells, avian cells and the like. Cells e5q>ressing the receptor are then are then contacted with the test compound to observe binding, or stimulation or inhibition of a functional response. Alternatively isolated cell membranes containing the expressed receptor may be used to measure binding of compound. For measurement of binding radioactively or fluorescently labeled compounds may be used. As reference compound human recombinant LH can be used. In the alternative also competition binding assays can be performed. Another assay involves screening for"LH receptor agonist compounds by determining stimulation of receptor mediated cAMP accumulation. Thus, such a method involves expession of the recq)tor on the cell surface of a host cell and exposing the cell to the test compound. The amount of cAMP is then measured. The level of cAMP will be reduced or increased, depending on the inhibitory or stimulating effect of the test compound upon binding to the receptor. In addition to direct measurement of e.g. cAMP levels in the exposed cell, cells lines can be used which in addition to transfection with receptor encoding DNA are also transfected with a second DNA encoding a reporter gene the expression of which responds to the level of cAMP. Such reporter genes might be cAMP inducible or might be constructed in such a way that they are connected to novel cAMP responsive elements. In general, reporter gene expression might be controlled by any response element reacting to changing levels of cAMP. Suitable reporter genes are e.g. LacZ, alkaline phosphatase, firefly luciferase and green fluorescence protein. The principles of such transactivation assays are well known in the art and are described e.g. in Sh^towa, Ch, Himmler, A and Czemilofsky, A.P. (1995) Cuir.Opin.Biotechnol.6;574. For selecting active compounds testing at 10"^ M must result in an activity of more than 20% of the maximal activity when LH is used as a reference. Another criterion might be the ECjo value which must be The skilled artisan will recognize that desirable EC50 values are dependent on the compound tested. For example, a compound with an EC50 which is less than IQ"^ M is generally considered a candidate for drug selection. Preferably this value is lower than more preferably 10"* M. However, a compound which has a higher EC50, t^ut is selective for the particular receptor, may be even a better candidate. Screening for LH receptor agonistic compounds can also be performed by using a mouse Leydig cell bioassay (Van Damme, M., Robersen, D. and Diczfalusy, E. (1974). Acta Endocrinol. 77: 655-671 Mannaerts, B., Kloosterboer, H. and Schuurs, A. (1987). Neuroendocrinology of reproduction. R. RoUand et al. Eds., Elsevier Science Publishers B.V., 49-58). In this assay, stimulation of LH receptor mediated testosterone production can be measured in Leydig cells isolated fiiom male mice. To measure in vivo activity of LH receptor agonistic compounds ovulation induction in iimnatuie mice can be studied. In this assay immature female mice can be primed with urinary FSH and approximately 48 hours later treated with a LH agonistic compound. The animals are lolled after LH agonist treatment and the number of ova in the oviduct can be microscopically assessed. The compounds of the present invention can be applied clinically in those regimens where now LH or hCG is used. These include LH substitution among subjects with hypogonadal hypogonadism either male or female, midcycle administration to induce ovulation (ovulation induction (01) or controlled hyperstimulation (COH) or stimulation of the corpus Inteum. The following examples are illustrative for the invention and should in no way be interpreted as limiting the scope of the invention, Examples Example 1 fert-Butyl 5-amino-2-methyIthio-4-f3-fmethoxycarhonvIoxvVplienvlVthienn[2.3- tf]pyrimidine-6-carbQj{amide fa). 5-Cyano-4-i"3-methoxyphenv1>-2-methy^thio-6-hvdroyv-pvrimi(^infl A mixture of S-methylisothiourea sulfate (139 mg), 3-methoxybenzaldehyde (243 |J.1), ethyl cyanoacetate (112 |j.l) and potassium carbonate (145 mg) in abs. ethanol (2 ml) was stirred at 60°C for 5 b. The reaction mixture was cooled to 0°C in an ice bath, filtered and the residue was heated in water (H2O) until a clear solution was obtained. The solution was acidified with 2N aq. HCI to pH 2 and cooled to Q°C in an ice bath. The resulting crystals were collected by filtration and dried in vacuo. Yield: 186mg MS"ESI: [M+H]^ = 274.2 TLC: Rf = 0.50, silica gel, dichloromediane (CH2Cl2)/meflianol (CH3OH) = 9/1 (v/v) (]D) ■ 6-Chl oro-5-cvano-4-("3 -methoxvphenvl V2-methylthio-pyrimidine Phosphorus oxychloride (0.75 ml) was added to a stirred solution of 5-cyaao-4-(3- methoxyphenyl)-2-methyIthao-6-hydroxy-pyrimidine (example la, 305 mg) in dry 1,4- dioxane (1 ml). A drop of N,N-dimethylaniline was added. After 3 h at 80°C, the mixture was cooled to 0°C in an ice hath and crushed ice was slowly added. After cessation of the exothermic reaction, H^O (3 ml) was added. The solids were collected by filtration and dried in vacuo. Yield: 244 mg MS-ESI: [M+H]^ = 292.2 TLC-. Rf = 0.86, silica gel, CH2CI2 (c). F.thvl 5-amino-4-r3-methoxyphenyl)-2-methyIthio-thieno[2,3-^pyrimidine-6- carbpxylate Potassium ten-hutoxide (150 mg) was added to a stirred solution of ethyl 2- mercaptoacetate (92 p.1) and 6~cbloro-5-cyano-4-(3-methoxyphraiyl)-2-methyltbio- pyrimidine (example lb, 244 mg) in dry tetrahydrofiiran (THF) (4 ml). After 1 h, the mixture was cooled to 0°C in an ice bath, diluted with H2O (10 ml). The solids were collected by filtration and dried in vacuo. (d). 5 -Amino-4-f3 -methoxyphenv]V2-inethvlthio-fai eno[2.3-.f1pvrimidine-6-carboxv1i r acjcj Ethyl 5-aniino-4-(3-methoxyphenyl)-2-methyithio-tiiieno[2,3-i^pyrimidme-6- carboxylate (example Ic, 9.27 g) was dissolved in a mixture of 1,4-dioxane (270 ml) and H2O (30 ml). Lithium hydroxide (10 g) was added and the mixture was stirred at SO^C for 48 h. 1,4-Dioxane was removed &om the mixture by evaporation and the residue was taken up in H2O. The remaining solution was acidified to pH 2 by adding aq. 3N aq. HCl. The resulting precipitate was filtered off and washed with H2O. Traces of water in the precipitate were removed by coevaporation with 1,4"dioxane and then with diethylether and drying in vacuo at 50°C overnight. Yield: 8.45 g MS-ESI: [M+H]^ = 348.0 TLC: ■ Rf = 0.2, silica gel, CH2CI2/CH3OH = 9/1 (v/v) (e), tert-Buty\ 5-amino-2-methvlthio-4-G-metho"xvphepyl)-thieno[2,3-cr!pyrimidlne-6-carboxamide 5-Anmio-4-C3 -methoxyphenyl)-2-methylthio-thieno [2,3-if]pyrimidme-6-carboxylic acid (example Id, 7.0g) was dissolved in dry CH2CI2 (100 ml). BenzotriazoI-1-yl-N,N,N,N"-tetramethyluroniumteh^fluoroborate (TBTU) (S.O g), N,N-diisopropylethylamine (DIPEA) (6.6 ml) and rerr-butylamine (4.0 ml) were added and the mixture was stirred at room temperature for 5 h. The reaction mixture was washed with 5% aq. NaHCOs (2*100 ml) and IM aq. HCl (2*100 ml). The organic layer was dried (MgSOi) and concentrated in vacuo. The title compound was purified by chromatography on silica gel with heptane (hept)/ethyl acetate (EtOAc) = 1/0 to 3/2 (v/v) as eluent. Yield: 6.5 g MS-ESI: [M+H]^ = 403.0 HPLC: Rt = 33.56 min, column 3 pm Luna C-18(2) 100*2.0 mm, flow 0.25 ml/min, oven temperature 40°C, detection 210 mn + 254 mn, eluent H2O/acetomtrUe(CH3CN)/CH30H = 70/28.5/1.5 to 0/95/5 (v/v) in 50 min (f)- tert-Butvl 5-amiT^o-2-methvlthio-4-f3-hyd^oxyphenvi^-^:hie^n^2■3-t/]pvriT^idiT^p-fi-carboxamide rert-Butyl 5-amino-2-methylthio-4-(3-methoxyphenyl)-thieno[2,3-(f]pyrimidine-6- carboxamide (example le, l.S g) was dissolved in dry CH2CI2 (30 ml) and the resulting solution was cooled down w 0°C. A solution of boron tribromide (1.28 ml) in dry CH2CI2 (30 ml) was added dropwise and the mixture was stirred overnight at room temperature. Sat. aq. NaHCOa was added dropwise to the reaction mixture until cessation of the exothermic reaction. Thereafter, CH2CI2 was removed fi-om the mixture by evaporation and a large amount of EtOAc was added. The organic layer WEK w^hed with sat. aq. NaHCO^, dried (MgSO*) and concentrated in vacuo. Yield: 1.3 g MS-ESI: [M+H]* = 389.2 HPLC: Rt = 17-44 min, column Luna C-18 (see example le), eluent HjO/CH^CN/CHjOH- 90/9.5/0.5 to 0/95/5 (v/v) in 50 min (g). ferf-B-gtyl 5-amino-2-r[ietbylthiQ-4-(3-(methoxvcaTbonyloxy)-plienyl)-thieno[2,3-fj]pyrimiding-6-carbnxamide lert-Butyl 5-aminQ-2-methylthio-4-(3-hydroxyphenyl)-thieno[23-"/]pyrimidine-6- carboxamide (example If, 100 mg) was dissolved in dry CH2CI2 (5 ml). DIPEA (500 (J.1) and methyl chlorofonnate (199 )j.I) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with H^O. The organic layer was dried (MgS04) and concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O = 10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized firom a mixture of 1,4-dioxane and H2O. Yield: 93 mg MS-ESL [M+H]^ ^ 447.4 HPLC: Rt = 17.56 min, column Luna C-18 (see example le), eluent H2O/CH3CN = 40/60 to 0/100 (v/v) in 25 min Example 2 feri-Bnty] S-amii^n-l -■methvltbi o-4-f 3 -f alWl oxycarbonyloxvVphenvlVthien n[2.3 - tflpyrin;idine-6-carboxaTnidfi The reaction of teri-hutyl 5-amino-2-methylthio-4-(3-hydroxyphenyI)-thieno[2,3-(f]pyrimidine-6-carboxamide (example If, 100 mg) with allyl chloroformate (274 |il) was performed according to the methods described in example Ig. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O = 10/90 to 90/10 (v/v) m 30 min. The title compound was then lyophilized &om a mixture of 1,4-dioxane and H2O. Yield: 102 mg MS-ESI: pyI-Mr|* = 473.4 HPLC: Ri = 19.S2 nun, colmmi Luna C-18 (see example le), eluent H2O/CH3CN = 40/60 to 0/100 (v/v) in 25 min Example 3 fgrt-Butvl 5-amino-2-Tnethy1thio-4- The reaction of tert-huty\ 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-cOpyiimidine-6-carboxamide (example If, 100 mg) with benzyl chlorofomiate (368 |il) was performed according to the methods described in example Ig. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O = 10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxaiie and H2O. Yield: 112 mg MS-ESI: [M+H]^= 523.2 HPLC: Rt = 22.22 min, column Luna C-18 (see example le), eluent H2O/CH3CN = 40/60 to 0/100 (v/v) in 25 min Example 4 fgn-Butyl 5 -amino-2-methvlthi n-4-f 3-f n-nitro-beTizvl9vyr,arbonv1 nxv^-phen v1^- thieno[2.3-£npvrimidine-6-carboxamide The reaction of tert-butyl 5-aniino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-(/]pyriniidine-6-carboxamide (example If, 100 mg) with _p-mtrobenzyl chloroformate (554 mg) was perfoimed according to the methods described in example Ig. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O = 10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O. Yield: 47 mg MS-ESI: [M+H]"" = 568.4 HPLC: Rt = 21.45 min, column Luna C-X8 (see example 1 e), eluent H2O/CH3CN = 40/60 to 0/100 (v/v) in 25 min Example 5 fert-gutyl 5-amino-2-methylthio-4- cf]pyriniidiT|e-6-carbQxamide The reaction of ie«-butyl 5-aniino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-JJpyrimidine-e-carboxamide (example If, 100 mg) with phenyl chlorofomiate (324 jil) was performed according to the methods described in example Ig. The title componnd was purified by HPLC using a Luna C-18 column with the following grad"ant: CHsCN/HjO = 10/90 to 90/10 (v/v) in 30 min. The title compound was t;iea lyophilized from a mixture of 1,4-dioxane and H2O. Yield: 89 mg MS-ESt: [M+Hf = 509.4 HPLC: Rt = 21.12 min, column Luna C-18 (see example le), eluent H2O/CH3CN - 40/60 to 0/100 (v/v) in 25 min Example 6 tert-Bntyl 5-amino-2-methy1thio-4-(3-f7J-Tijtro-phenoxycarbonvloyy)-phenyl)- thienQ[2,3-ff]pyrimidine-6-carfaoyamide The reaction of /e«-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyI)-thieno[2,3-J]pyrimidiiie-6-carboxamide (example If, 400mg) with ^-nitro-phenyl chloroformate (207 mg) was performed according to the methods described in example Ig. Evaporation of the soWent under reduced pressure yielded the crude title compound. Yield: 569 mg MS-ESI: [M+H]"" = 554.6 TLC: Rf = 0.5, siUca gel, hep/EtOAc = 3/2 (v/v) Example 7 tert-"Buty] 5-amino-2-mefhy]thio-4-f3-((N.N-di6thylaminoVcarbonybxy)-phenyl)- thigno[2.3-]pyrimidine-6-carboxamide re?i-Butyl 5-amino-2-methyIthio-4-(3-hydroxyphenyl)-thieno[2,3-tr]pyrimidine-6- carboxamide (example If, 100 mg) was dissolved in dry CH2CI2 (5 ml) and a few drops of N,N-dimethylformamide (DMF) were added. Diethylcarbamoyl chloride (68 mg) and DIPEA (217 iJ,l) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with HiO. The organic layer was dried (MgS04) and concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-1S column with the following gradient: CH3CN/H2O = 10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O. Yield: 75 mg MS-ESI: [M^-H]^ = 483.4 TLC: Rf = 0.6, siHca gel, hept/EtOAc = 1/1 (v/v) Example 8 tert-B\ity] ■ 5-amino-2-methv1thio-4-f3-n.23.6-tetrahydropyndinocarbonvloyvV pheoyl)-thien.o[2.3-{f1pyriTnidine-6-carboxamide /ert-Butyl 5-amino-2-methyithio-4-(3-(p-mtro-phenoxycarbonyioxy)-phenyl)- thieno[2,3-t^pyninidme-6-carboxamide (example 6, 142 mg) was dissolved in CH2C];. 1^,3,6-Tetrafaydropyridine (117 ^1) and DIPEA (224 ill) were added and the mixture was stirred at room temperature overnight. The reaciion mixture was diluted with CB.2CI2 and washed with H2O. The organic layer was concentrated under reduced pressure. The title compound was purified by EPLC using a Luna C-18 column with the foUowing gradient: CH]CN/H:0 = 20/SO to 100/00 (v/v) in 45 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O. Yield: 76 mg MS-ESI; [M+H]"*" = 498.2 HPLC: Rt = 13.90 min, column 5 \im Luna C-1S(2) 150*4.60 mm, flow 1 ml/min, detection 210 nm, eluent H2O/CH3CN = 40/60 to 0/100 (v/v) in 15 min Example 9 fgrt-Buty] 5-amino-2-methvlthio-4-f3-(p-toluenesulfonamido)-phenvlVthieno[2.3- ff]pyrimidine-6-carbP.;sqmide (a). 5-Cyaiio-4-G-nitrophenv|")-2-methylthio-6-hydroxy-pyrimijJios A mixture of S-methyUsothiourea sulfate (69.0 g), 3-nitrobenzaldehyde (75.0 g), ethyl cyanoacet^te (56.0 ml) and potassium carbonate (72.5 g) in abs. EtOH (1500 ml) was stirred at 60°C for 16 h. The reaction mixture was cooled to 0""C in an ice bath. The resulting precipitate was filtered off, washed with abs. EtOH and dissolved in hot water (100°C). The solution was cooled to room temperature, acidified with 2N HCl to pH 2 and cooled to 0°C in an ic:^ bath. The resulting precipitate was filtered off and washed with ice water. Resid^.:^: ".v::ter in the precipitate was removed by coevaporation with 1,4-dioxane. Yield: 54.0 r.:^. MS^ESi: [}/-:;]" = ::?.o TLC: Rr= C.?, si.:^a gel. I-C^LO.ltO::: - :;": iv v). rb). 6-ChloTO-5-cvanQ-4-f3-mtrophenylV2-methyH3iio-pvriTm"diTie POCI3 (100 ml) was added to -a stirred solution of 5-cyano-4-(3-mtrophenyl)-2- methylthio-6-hydroxy-pyriniidine (example 9(a), 25.0 g) in dry 1,4-dioxane (300 ml). After 3 h at 90°C, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (100 ml) and the resulting solution was cooled to 0°C. Ice water was cautiously added. The resulting precipitate was filtered off and washed with water. Residual water m the precipitate was removed by coevaporation with 1,4-dioxane. Yield: 26.0 g. MS-ESI: [M+Hf =307.0 TLC: Rf = 0.5, silica gel, heptane/EtOAc = 3/2 (v/v). (c). Ethyl 5-cyano-4-r3-nitrophenyl)-2-methvlthio-6-(ethoxycarboTiylmsthylthioV pyrimidine DIPEA (15.7 ml) was added to a stirred solution of ethyl 2-mercaptoacetate (9.3 ml) and 6-chloro-5-cyano-4-(3-mtrophenyl)-2-methylthio-pyrimidine (example 9(b), 26.0 g) in a mixture of EtOH (250 ml) aad DCM (250 ml). After 1 h at room temperature, O.IN aq. HCl (500 ml) was added to the mixture which was then extracted with DCM (3*500 ml), dried (MgSOa) and concentrated under reduced pressure. Yield: 28.0 g MS-ESI". [M+H]^ - 390.4 TLC: Rf = 0.5, siHca gel, heptane/EtOAc = 3/2 (v/v). (d). Ethyl 5-amino-4-(3-nitrophenyl)-2-methylthio-thieno[2,3-tfjpyrimidine-6- carboxylate A mixture of ethyl 5-cyano-4-(3-nitropheEyl)-2-methyltliio-6- (ethoxycarbonylmethylthio)-pyrimidine (example 9(c), 28.0 g) and DIPEA (30 ml) in a mixture of toluene (150 ml) and EtOH (150 ml) was stirred at reflux temperature (lOO^C) for 16 h. The mixture was then cooled to room temperature and concentrated under reduced pressure. Residual DIPEA was removed by coevaporation with toluene. Yield: 28.0 g MS-ESI: [M+H]""= 391.2 TLC: Rf = 0.6, siUca gel, heptane/EtOAc = 3/2 (v/v). (e). ferf-Butvl 5-ainino-2-methvlthio-4-f3-aminophenvn-thienor2.3-J1-pvriTnidine-6-carboxamide Ethyl 5-amino-2-methylthio-4-(3-nitrophenyl)-thieno[2,3-£/]-pyTiimdine-6-carboxylate (example 9d, 780 mg) was dissolved in 1,4-dioxane (10 ml). Ethanol (10 ml) and tin(II)chloride (1.1 g) were added and the reaction mixture was stirred overnight at 90°C. After concentration of the reaction mixture in vacuo, the residue was redissolved in EtOAc (50 ml) and washed with 4M aq. NaOH (10 ml), dried (MgSO^) and concentrated under reduced pressure. The ethyl ester group in the resulting derivative ethyl 5-amino-2-methyithio-4-(3-aminophenyl)-thieno[2,3-tfl-pyrimidine-6-carboxylate (558 mg) was saponified to the corresponding acid (430 mg) using the method described in example Id and subsequently reacted with /err-butylamine (200 yd) to form the corresponding fer/-butylamide (according to example le). The title compound was purified by chromatography on silicagel with hept/EtOAc = 3/1 (v/v) as eluent. Yield; 391 mg MS-ESI: [M+Hf = 388.0 TLC: Rf = 0.43, siUca gel, hept/EtOAc - 3/2 (v/v) (f). ten-Butyl 5-amino-2-methylthiQ-4-(3-(/7-t(?1uenesulfnnamidoVphenylVthienQ[2.3-]pyriTnidine-6-c3rbQxamidQ ten-Butyl 5-amino-2-methylthio-4-(3-aimnophenyl)-thieno[2,3-£f]pyrimidine-6- carboxamide (example 9e, 100 mg) was dissolved in dry pyridine (5 ml), p-Toluenesulfonyl chloride (70 mg) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with CH2CI2 and washed with O.IM aq. HCl. The organic layer was dried (MgS04) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with hept/EtOAc = 3/2 (v/v) as eluent. Yield: 63 mg MS-ESI: [M+H]^= 542.4 HPLC: R, = 23.46 min, column Luna C-18 (see example le), eluent phosphate buffer 50 mM pH 2.I/H2O/CH3CN/CH3OH = lO/72/17/l to 10/18/68/4 (v/v) in 50 min Example 10 fert-Butyl 5-amino-2-methylthio-4-(3-(vinyIsuifonamidoVpheny])-thieno["2.3- cf[pyrimidine-6-carboxaTnide rert-Butyl 5-amino-2-methylthio-4-(3-amiiiophenyl)-thieno[2,3-ifipyriniidine-6- caitoxamide (example 9e, 2.5 g) was dissolved in a mixture of CH2CI2 (25 ml) and pyridine (25 ml). 2"Bromo-ethanesulfonyl chloride was prepared as described in Bull. Chem. Soc. Jpn. 39, 1937-1941 (1966). A solution of 2-bromo-ethanesulfonyI chloride (2 g) in CH2CI2 (5 ml) was added dropwise and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with CHaCli and washed with sat. aq. NaHCOs- The organic layer was dried (MgS04) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel withhept/EtOAc = 3/2 (v/v) as eluent. Yield: 1.4 g MS-ESI: [M+H]^ = 478.6 TLC: Rf = O.SO, silica gel, hept/EtOAc = 3/2 (v/v) Example 11 rerf-Butvl "S-amino-2-methv!thio-4-(3-f2-piperidinoethanesulfonamido)-phenvi")- thieno[2.3-tflpyrimidine-6-carboxamide tert-Butyl 5-amiao-2-methylthio-4-(3-(vinylsulfonamido)-phenyl)-thieno[2,3- £f|pyriinidine-6-carboxamide (example 10, 87 mg) was dissolved in dry THF (5 ml). Piperidine (181 \iV) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted wili CH2CI2 and washed with sat. aq. NaHCOs. The organic layer was dried (MgS04) and concentrated under reduced pressure. The title compound was first purified by chromatography on silica gel with hept/EtOAc = 3/2 (v/v) as eluent and then by HPLC using a Luna C-18 column with the following gradient: CHaCN/O.lVo aq. trifluoroacetic acid (TFA) = 10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophihzed from a mixture of 1,4-dioxane and 0.1% aq TFA. Yield: 89 mg (TFA salt) MS-ESI: |>1+H]*= 563.4 HPLC; Rt = 18.4 min, column Luna C-18 (see example le), eluent H2O/CH3CN = 60/40 to 0/100 (v/v) in 25 min Example 12 tert-Buty] 5-amino-2-methvlthio-4-(3-(2-(thiomoTpholin-4-vlVefhanesulfonaTnidoV phenvl)-thieno[23~fi]pyrimidine-6-carhoxamide Reaction of thiomorpholine (1S4 fil) with rert-butyl 5-aiiiino-2-methylthio-4-(3-(vinylsulfonan2ido)-phenyl)-thieno[2,3-(f]pyrimidine-6-carboxamide (example 10, 87 mg) was performed according to the method described in example 11. The title compound was first purified by chromatography on silica gel with hept/EtOAc = 3/2 (v/v) as eluent and then by HPLC using a Luna C-18 column with the following gradient: CHsCN/O.P/o aq. TFA = 10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophihzed fiom a mixture of lAtHoxane and 0.1% aq TFA. Yield: 120 mg (TFA salt) MS-ESL [M+H]^ = 581.2 HPLC: Ri = 17.2 min, column Luna C-18 (see example le), eluent H2O/CH3CN = 60/40 to 0/100 (v/v) in 25 min Example 13 tert-Bnty] 5-amino-2-methylthio-4- ethanesulfonamidoVphenyl)-thi?po[2,3-f/]pyrimidine-6-carboxainide Reaction of bis-(2-methQxyethyl) amine (244 mg) with fe;t-butyl 5-aniino-2-methylthio-4-(3-(vinylsulfonaniido)-phenyI)-thieno[2,3-rf]pyrimidine-6-carboxaniide (example 10, 87 mg) was perfbnned according to the method described in example 11. The title compound was first purified by chromatography on silica gel with hepfEtOAc = 3/2 (v/v) as eluent and then by HPLC using a Luna C-IS column with the following gradient: CH3CN/0.1% aq. TFA = 10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophihzed fi^om a mixture of 1,4-dioxane and 0.1% aq TFA. Yield: 60 mg (TFA salt) MS-ESL [M+H]* = 611.4 HPLC: Rt = 17.9 min, column Luna C-18 (see example le), eluent H2O/CH3CN = 60/40 to 0/100 (v/v) in 25 min Example 14 tert-Butyl 5-amino-2-methyIthio-4-f3-f2-n^-methvIpiperazino)-ethaneRuTfonamido)-phenyl)~thien(>[2,3 -rf]pyrimi dine-6-carbi3?c amide Reaction of N-methyl piperazine (184 fil) with terl-hntyl 5-amino-2-methylfliio-4~(3-(vinylsulfonainido)-phenyl)-thieno[2,3-tf]pyrimidine-6-carboxamide (example 10, 87 mg) was performed according to the method described in example 11. The title compound was fiist purified by chromatography on silica gel with hept/EtOAc = 3/2 (v/v) as eluent and then by HPLC using a Luna C-18 column with the following gradient: CHaCN/O.r/o aq. TFA = 10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and 0.1 % aq TFA. Yield: 85 mg (TFA salt) MS-ESI: [M+H]"" = 578.4 HPLC: Rt = 16.1 min, column Luna C-18 (see example le), eluent H2O/CH3CN = 60/40 to 0/100 (v/v) in 25 min Exa"mple 35 tert-Butyl 5-amino-2-methy]thio-4-G-rmethQXvcarhonylaminoVphenvl1-thieno[2.3-ii]pyriTnidine-fi-carbo>; amide tert-Bntyl 5-amino-2-methylthio-4-(3-aminophenyl)-thieno[2,3-tf]pyrimidLne-6- carboxamide (example 9e, 100 mg) was dissolved in dry CH2CI2 (5 ml). Methyl chloroformate (199 y.1) and DEPEA (500 ^1) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with HjO. The organic layer was dried (MgSOa) and concentrated under reduced pressure. The title compound was purified by HPLC using a Lima C-18 column with the following gradient: CH3CN/10% aq. CH3CN = 10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophihzed fiom a mixture of 1,4-dioxane and H2O. Yield: 80 mg MS-ESI: [M+H]"" = 446.2 HPLC: Ri = 20.44 min, column Luna C-18 (see example le), eluent phosphate buffer 50 mM pH 2.I/H2O/CH3CN = 10/72/18 to 10/18/72 (v/v) m 20 rnin Example 16 ferf-Butvl 5-aTnino-2-methylthio-4-(3- The reaction of tert-hutyl 5-amino-2-methyIthio-4-(3-amiaophenyl)-tfaieno[2,3-£f]pyrimidine-6-carboxamide (example 9e, 100 mg) witii allyl chloroformate (274 ]il) was performed using the methods described in example 15. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/10% aq. CH3CN = 10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophiHzed from a mixture of 1,4-dioxane and H2O. Yield: 66 mg + MS-ESI: [M+H]" = 472.2 HPLC: • Ri = 22.37 min, column Luna C-18 (see example le), eluent phosphate buffer 50 mM pH 2.I/H2O/CH3CN = 10/72/18 to 10/18/72 (v/v) m 20 min Example 17 tert-Butvl 5-ami no-2-m ethyl thio-4-("3-rbenzyloxycarbony] amino VphenylVthi eno[2.3-iflpyrimidine-6-carboxamide The reaction of tert-buty\ 5 -amino-2 -methylthio-4-(3-aminophenyl)-fliieno [2,3-£f]pyTiinidine-6-carboxamide (example 9e, 100 mg) with benzyl chloroformate (368 |il) was performed using the methods described in example 15. The title compound was purified by HPLC using a Luna C-IS column with the following gradient: CH3CN/10% aq. CH3CN = 10/90 to 90/10 (v/v) in 30 miiL The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O. Yield: 112 mg MS-ESL [M+H]"" = 522.4 HPLC: Ri = 24.10 min, column Luna C-18 (see example le), eluent phosphate buffer 50 mM pH 2.I/H2O/CH3CN = 10/72/18 to 10/18/72 (v/v) m 20 min Example 18 fert-Butyl 5-amino-2-methvlthio-4-l"3-(;ethQxycarbonv]aminoVphenvn-thienn[2.:^- t/]pyrimidine-()-carbo?{ amide The reaction of /ert-buty] 5-amino-2-methy]thio-4-(3-aminophenyl)-thieiio[2,3-rflpyriniidine-6-carboxamide (example 9e, 100 mg) with ethyl chlorofomiate (247 |il) was performed using the methods described in example 15. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/10% aq. CH3CN = 10/90 to 90/10 (v/v) in 30 min. The title compound was then iyophihzed fi-om a mixture of 1,4-dioxane and H2O. Yield: 74 mg MS-ESI: [M+H]"" = 460.4 HPLC: Rt = 21.77 min, colimm Luna C-18 (see example le), eluent phosphate buffer 50 mM pH 2.I/H2O/CH3CN = 10/72/18 to 10/18/72 (v/v) in 20 min Example 19 fert-Butyl 5-amino-2-methylthio-4-(3-fphenoxycarbonyIaminoVphenyl)-thiei^o[2,3-tflpyrimidine-6-carfaoxamide The reaction of fert-butyl 5-amino-2-methylthio-4-(3-aminophenyl)-thieno[2,3-(f|pyrimidine-6-carboxamide (example 9e, 100 mg) with phenyl chlorofomiate (324 yd) was performed using the methods described in example 15. The title compound was purified by HPLC using a Luna C-18 column with the following gradient-. CH3CN/10% aq. CH3CN = 10/90 to 90/10 (v/v) m 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O. Yield: 47 mg MS-ESI: [M-^H]^ = 508.4 HPLC: Ri = 23.25 min, column Luna C-18 (see example le), eluent phosphate buffer 50 mM pH 2.I/H2O/CH3CN = 10/72/18 to 10/18/72 (v/v) in 20 Example 20 ■ter^Butvl 5-aTninn-2-methvlthio-4-(3-(p-nitro-phenoxvcarbonylaTTiino1-phenvlVthienn-[2.3-rf]pyTimidine-6-carbox amide ren-Butyl 5-amino-2-methylthio^-(3-aininophenyl)-ttiieno[2,3-tCpyrimiduie-6- carboxamide (example 9e, 1 g) was dissolved in dry CHiCli (10 ml). Subsequently, a solution of p-nitro-phenyl chloroformate (520 mg) in dry CH2a2 (10 ml) was added dropwise and the reaction mixture was stirred at room temperature. After 1 h, the reaction mixture was washed with H2O. The organic layer was dried (MgS04) aud concentrated under reduced pressure. Yield: 1.42 g MS-ESI: [M+H]^= 553.6 TLC; Rf = 0.7, silica gel, hep/EtOAc = 3/2 (v/v) Example 21 ferf-lPutyl 5-amino-2-methy1thio-4-l"3-ffmoTpho1in-4-y]")-caTbonvlami-noVphenyl)- thieno ["2.3 -ifjpyrimidine-6-carhox amide tert"Biityl 5-amino-2-methylthio-4-(3-(p-nitro-phenoxycarbcnylamino)-phenyl)- tiiieno[2,3-tf]pyrimidine-6-carboxaniide (example 20, 142 mg) was dissolved in dry CH2CI2 (5 ml). MoTpholine (112 pi) and DIPEA (225 ^1) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2CI2 and washed with H2O. The organic layer was concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: H2O/CH3CN = 80/20 to 0/100 (v/v) in 45 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O. Yield: 22 rog MS-EST. tM+-H]""=501.2 HPLC: R^ = 8.62 min, colunm Luna C-18 (see example 8), eluent H2O/CH3CN = 40/60 to 0/100 (v/v) m 15 min Example 22 ten-Bntv\ 5-amino-2-methvlthio-4-f3-l"o-anisidinncarhnTivlaminoVphenyn-thieno[2.3-ffjpyriniidine-6-carfaoxamide The urea coupling of tert-Butyl 5-ainino-2-methyltliio-4-(3-(p-mtro-phenoxycarbonylaimno)-phenyl)-thieno[2,3-(f]pyriinidine-6-carboxamide (example 20, 142 mg) witii ortho-anisidiae (159 mg) was performed according to the methods described in example 21. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: H2O/CH3CN = 80/20 to 0/100 (v/v) in 45 min. The title compoxmd was then lyophihzed from a mixture of 1,4-dioxane and H2O. Yield: 18mg MS-ESL [M+Hf =537.2 HPLC: Ri = 12.94 min, column Luna C-18 (see example 8), eluent H2O/CH3CN = 40/60 to 0/100 (v/v) in 15 min Example 23 fert-gutyl 5-aminOr2-methylthio-4-n-fl.2.3.6-tetrahydfopyridinocarbonylaminQ)- phenylVtbieno [2.3 -rfjpyrimi dine-6-carhnx ami H e The urea coupling of lert-Butyl 5-ainino-2-methyithiD-4-(3-(p-mtro-phenoxycarbonylamino)-phenyl)-thieno[2,3-tf]pyrimidine-6-carboxamide (example 20, 142 mg) with 1,2,3,6-tetrahydropyridine (IIS p,]) was perforaied according to the methods described in example 21. The title compoxmd was purified by HPLC using a Luna C-18 column with the following gradient: H2O/CH3CN = 80/20 to 0/100 (v/v) in 45 min. The title compound was flien lyophilized from a mixture of 1,4-dioxane and H2O. Yield: 18 mg MS-ESI: IM^nT = 497.2 HPLC: Rt= 11.19 min, column Luna C-18 (see example S), eluent H2O/CH3CN = 40/60 to 0/100 (v/v) in 15 min Example 24 eert-B^tvlS-hvd^nxv-2-methy^th^o^4-f3-methnx^^phenyU-Quina^oline-6-carbo■xamide (a). Ethvl 2-methvlthio-4-(3-methoxyphenylV6-methvl-1.4-dihvdropyrimidine-S- carboxylate A mixture of S-methyUsothiourea sulfate (13.9 g), 3-methoxybenzaldehyde (7.5 g), ethyl acetoacetate (6.5 g) and sodium hydrogenocarbonate (21 g) in DMF (200 ml) was stirred at 70°C for 18 h. The reaction mixture was cooled to room temperature, diluted with diethylether and washed with H2O and sat. aq. NaCl. The title compound was purified by chromatography on silica gel with hept/EtOAc = 3/2 (v/v) as eluent. Yield: 7.3 g MS-ESI: [M+H]"*"= 321.0 TLC: Rf = 0.2, silica gel, hept/EtOAc = 3/1 (v/v) (b). Ethyl 2-methylthio-4- Ethyl-2-methylthio-4-(3-methoxyphenyl)-6-melhyl-l,4-dihydro-pyriinidine-5- carboxylate (example 24a, 7.65g) was dissolved in a mixture of toluene (200 ml) and CH2CI2 (100 ml). 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone (5.45 g) was added and the reaction mixture was stirred at room temperature for 15 min. 0.2M aq. NaOH (250 ml) was added. The organic layer was separated, washed with H2O (2*250 ml) and sat. aq. NaCl (2*250 ml), dried (MgS04) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel witli hept/EtOAc = 4/1 (v/v) as eluent. Yield: 4.0 g MS-ESI: [M+H]^ = 319.2 TLC: Rf = 0.4, siHca gel, hepVEtOAc = 3/1 (v/v) (c). Ethvl 5-hydroxy-2-methy]thio-4-(3-TnethoxypheTiyl)-quiTiazQline-6-carboxy1ate A solution of ethyl 2-methylthio-4-(3-methoxyphenyl)-6-methylpyrimidine-5-carboxylate (example 24bj 318 mg) in dry THF (2 ml) was added to a freshly prepared solution of LDA in dry THF (Iml) cooled to -78""C. Tlie mixture was stirred at -78°C for 30 min and 3-ethoxy acrylate (217 jil) was added. The mixture was then stirred for 3 h at -1S°C up to room temperature. O.IM aq. HCl (20 ml) was added to the reaction mixture which was subsequently-extracted with EtOAc (25 ml). The organic layer was washed with water (25 ml) and sat. aq. NaCl (25 ml), dried (MgSO^) and concentrated mider reduced pressure. The title compound was purified by chromatography on siMca gel with hept/EtOAc = 3/1 (v/v) as eluent and recrystaUized fiom CH3OH. Yield: 38 mg MS-ESI: [M+H]"*" = 371.2 TLC: Rf = 0.6, sihca gel, hept/EtOAc = 2/3 (v/v) (d). tert-Butvl 5 -}iydTOxy-2-methylthio-4-f 3 -methoxyphenylVquinazoline-6- cariiox amide Ethyl-5-hydroxy-2-methylthio-4-(3-methoxyphenyl)-quina2oline-6-carboxylate (example 24c, 38 mg) was dissolved in a mixture of 1,4-dioxane (4 ml) and IM aq. KOH (0.5 ml). The mixture was refluxed for 48 h, then cooled down to room temperature and acidified by adding O.IM aq. HCl (15 ml). The mixture was extracted with CH2C12 (15 ml). The organic layer was dried (MgS04) and evaporated under reduced pressure to give 5-hydroxy-4-(3-methoxyphenyi)-2-methylthio-quinazoline-6- carboxylic acid. The latter was dissolved in DMF (2 ml). /ert-Butylamine (53 |i.l) and TBTU (96 mg) were added and the mixture was stirred at room temperature for 3 h. BtOAc (15 ml) was added and the organic layer was washed with sat. aq. NaHCOs (15 ml) and sat. aq. NaCl (15 ml), dried (MgS04) and ev^orated xmder reduced pressure. The title compound was first purified by chromatography on siHca gel with hept/EtOAc = 7/3 (v/v) as eluent. It was Then purified by HPLC with the following gradient: 10% aq. CH3CN/CH3CN/0.1% aq. TEA = 57/40/3 to 7/90/3 (v/v) in 30 min. The title compound was lyophilized from a mixture of water and 1,4-dioxane. Yield: 25 mg MS-ESI: [M+H]"" = 398.2 HPLC: Rt = 9.75 min, column Luna C-18 (see example le), eluent phosphate buffer 50 mM pH 2.I/H2O/CH3CN/CH3OH = 5/35/57/3 to 5/10/81/4 (v/v) m 15 min Example 25 fer^■B^ty^ $-aminQ-2-metliylthio-4-(3-methoxyphenylVquinazoline-6-carboxamic^e (a). 5 -Cyano-4-r3-methoxyphenyl)-2-methylthi o-6-vinyl-pyrimidine 6-Chloro-5-cyano-4-(3-methoxyphenyl)-2-methylthio-pyriniidine (example lb, 1.46g) was suspended in 1,4-dioxane (10 ml). Tetralds(triphenylphosphine)palladium(0) (350 mg) was added and the mixture was flushed with a nitrogen atmosphere. Tetravinyltin (1.26 ml) was added and the mixture was refluxed for 5 h. The reaction mixture was then poured in a mixture of EtOAc (100 ml) and H20 (100 ml). The organic layer was washed with sat. aq. NaCl, dried (MgS04) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with hepf CH2CI2 = 1/0 to 1/3 (v/v). Yield: 1.05 g MS-ESI: [M+H]^ = 284.2 TLC: Rf = 0.4, silica gel, hept/CHjCl: = 1/2 (v/v) (b). 5-Cyano-4-(3-methoxyphenv1V2-methylthio-6-fl.l-bis-feth9?iycarbonynprnp-3- yl)pyrimidine 5-Cyano-4-(3-methoxyphenyl)-2-methylthio-6-vinyl-pyTimidine (example 25a) was dissolved in a mixture of ethanol (2 ml) and toluene (2 ml). Potassium carbonate (690 mg) and diethylmalonate (272 ^1) were added and the mixture was stirred at room temperature for 4 h. The reaction mixture was then poured in a mixture of 0.5M aq. HCl (25 ml) and EtOAc (50 ml). The orgamc layer was washed with H2O (50 ml) and sat. aq. NaCl (50 ml), dried (MgS04) and concentrated imder reduced pressure. The title compound was purified by chromatography on silica gel with toluene/EtOAC = 100/0 to 95/5 (v/v) as eluent. Yield: 344 mg MS-ESI: [M+H]"" = 444.2 TLC: Rf = 0.3, silica gel, toluene/EtOAc = 95/5 (v/v) (c). Ethyl 5-amino-2-methy]thio-4-D-methoxypheny]V7.8-dihydroquina2oli7iR-6 carboxvlate 5-Cyano-4-(3-methoxyphenyl)-2-methylthio-6-(l,l-bis(ethoxycartionyl)prop-3- yl)pyrimidine (example 25b, 81 mg) was dissolved in dry CH2CI2 (1 ml). A IM solution of tin(rv) chloride in CH2CI2 (1 ml) was added dropwise and the mixture was stirred at room temperature for 1 h. HjO (10 ml) and EtOAc (10 ml) were then added to the reaction mixture. The organic layer was washed with H2O (10 ml) and sat. aq. NaCl (10 ml), dried (MgS04) and concentrated under reduced pressure. The title compound was purified by chromatography on siUca gel with hept^tOAc = 1/0 to 3/2 (v/v) as eluent- Yield: 24 mg MS-ESr. [M+H]^= 372.2 TLC: Rf = 0.5, silica gel, hept/EtOAc = 3/1 (v/v) (d). Ethyl 5-amino-2-methylthio-4-f3-methoxyphenyI)-quinazoline-6-carboxvlat6 Ethyl 5-aniino-2-methylthio-4-(3-methoxyphenyl)-7,S-dihydroquinazoline-6- carboxylate (example 25c, 22 mg) was dissolved in CH2CI2 (1 ml). A 0.06M solution of 2,3-dichloro-5,6-dicyano-l,4-beazoquinone in CH2C12 (1.2 ml) was added and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with toluene/EtOAc = 95/5 (v/v) as eluent. Yield: 20 mg MS-ESI: \M+Hf = 370.0 TLC: Rf = 0.3, sihca gel, hept/EtOAc = 1/3 (v/v) (e). 5-Amino-2-methylthio-4-n-methoxypheny1)"quinazoline-6-carboxylic acid Ethyl 5-amino-2-methylthio-4-(3-methoxyphenyl)-quinazoline-6-carboxylate (example 25d, 490 mg) was dissolved in 15 ml 1,4-dioxane and a 2 M aqueous KOH solution (3 ml) was added. The mixture was heated at reflux for 5 h and at 70 °C for 76 h. The mixture was cooled to room temperature and a 0.5 M HCI-solution in water was added. The mixture was extracted with CH2CI2 (2 x 50 ml), the combined organic layers were dried (MgS04) and concentrated under reduced pressure to yield the crude title compound. Yield: 406 mg (crude) MS-ESI: [M+H]* = 342.2 TLC: Rf = 0.0, silica gel, hept/EtOAc = 2/3 (v/v) rf).lerf-Butvl5-amino-2-Tnethvlthio-4-n-methoxvphenvn-qiiinazo]ine-6-carboyamide To a l.S M solution of 5-aniino-2-methylthio-4-(3-methoxyphenyl)-quinazDluie-6- carboxylic acid in DMF (l.S ml) were added TBTU (173 mg) and /ert-butyiamine (95 1). The reaction mixture was stirred for 2 h and then poured into a mixture ofEtOAc (25 ml) and saturated aqueous NaHCOj (50 ml). The organic phase was separated and washed with 0.5 M aqueous HCl (50 mi) and brine (50 ml), followed by drying (MgS04) and concentration under reduced pressure. The title compound was purified by chromatography on silica gel using hept/EtOAc = 1/0 to 2/3 (v/v) as the eluent. The title compound was lyophilized &om a mixture of dioxane and water containing 1.5 equiv. of HCl. Yield; 44 mg MS-ESI: tM+H]^ = 397.2 HPLC:Rt = 21.52 min, column Luna C-18 (see example le), eluent phosphate buffer 50 mM pH 2.I/H2O/CH3CN = 10/70/20 to 10/10/80 (v/v) in 20 min Example 26 tert-"BvLty] 5-amino-2-Tnethylthio-4-(3-f2- oyrrolidin-1-ylVethoxvVphenyIV quina7n1ine-6-carboxamide (a). tert-Buty] 5-amipo-2-roethylthio-4-f3-hydroxypheiiyl)-quinazo1ine-6-carbo>;amide A solution of tert-hutyl 5-aminD-2-methylthio-4-(3-methoxyphenyl)-quinazoline-6- carboxamide (example 25f, 1.5 g) in dry CH2CI2 was cooled to 0 "C. A solution of BBrj (1.1 ml) in CH2CI2 (25 ml) was added dropwise and after the addition was complete, the mixture was stirred for 3h at room temperature. The mixture was diluted with CH2CI2 and a saturated aqueous NaHC03 solution (200 ml) was carefully added. The mixture was vigorously stirred for 1.5 h until all soHds dissolved. The aqueous layer was extracted twice v/ith CH2CI2. The &st organic layer was washed with sat. aq. NaHCOs and brine. The combined organic layers were dried (MgS04) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with hept/EtOAc = 1/0 to 1/1 (v/v) as eluent. Yield: 930 mg MS-ESI: [M+H]^ = 383.4 TLC: Rf = 0.3, silica gel, hept/EtOAc - 2/3 (v/v) (b). fert-Butyl 5-amTno-2-methylthio-4-(3-(2-(pyrro1idin-1-y1)-ethoxyVphenvl")-quinazo1ine-6-carboy:amide A mixture of K2CO3 (1.0 g), l-(2-ohioroethyl)pyiTolidine hydrochloride (66 mg) and tert-hutyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-quinazoiine-6-carboxamide (example 26a, 121 mg) in acetone was heated overnight at reflux. The mixture was cooled to room temperature, the solids were removed by filtration and the filtrate concentrated mider reduced pressure. The residue was taken up in EtOAc and washed with water and brine. The organic phase was dried (MgS04) and concentrated in vacuo. The title compound was purified by HPLC using a Luna C-18 column with the following gradient; 10% aq. CHsCN/CHaCN/G.P/o aq. TFA = 72/25/3 to 27/70/3 (v/v/v) in 30 min. The title compound was lyophilized from a mixture of water, TFA and CH3CN. Yield: 42 mg (TFA salt) MS-ESI: [M+Hf = 480.4 HPLCiRt = 12.93 min, colunm Luna C-IS (see example le), eluent phosphate buffer 50 mM pH 2.1/H20/CH3CN - 10/70/20 to 10/10/80 (v/v) in 20 min Example 27 fej-f-Bnty] 5-amino-2-methy!thio-4-(3-aminophenylVqxiina?;oline-6-carboxamide (a). 5-Cvano-2-methylthio-4"(3-nitro-phenyl)-6-[flTiphenv]phosphanylidepe)-methyl]-pvrimidJTie To a suspension of anhydrous methyltiiphenylphosphonium bromide (29.5 g) in dimethoxyethane (400 ml) at-78 °C was added a 1.6 M solution of n-butylUthium in hexanes. The mixture was stirred at -78 "C for 1 h and a solution of 6-chloro-5-cyano-4-(3-nitrophenyl)-2-methylthio-pyrimidine (example 9b, 10.1 g,) in dimethoxyethane (100 ml) was added and the cooling bath removed. After 1 h the reaction was complete and water (15 ml) was added. Removal of the sohds by filtration was followed by concentration of the reaction mixture gave a dark residue which was stirred with ethylacetate to give a suspension. Filtration, washing of the residue with water and brine and drying of the organic layer with MgS04 was followed by concentration in vacuo. The title compound was purified by chromatography oa sihca gel with hept/EtOAc = 4/1 to 1/1 (v/v) as eluent. Yield: 7.04 g MS-ESI: [M+Hr = 299.2 TLC: Rf = 0.4, silica gel, hept/EtOAc = 3/2 (v/v) (h\ 5-Cyano-2-met}iylthio-4-n-nitro-pheny1V6-vinvl-pyrimidine A solution of 5-cyano-2-methylthio-4-(3-nitro-phenyI)-6-[(triphenylphosphanylidene)-methyl]-pyrimidine (example 27a, 7.04 g,)) in THF (64 ml) was treated with aqueous formaldehyde (37 wt. %, 3.55 ml) at 60 "C for 1 h. After the mixture was cooled to room temperature, it was diluted with EtOAc (100 ml) and washed with water (2 x 50 ml), dried (MgSO^) and concentrated under reduced pressure. The title compound was purified by chromatography on sihca gel using hept/EtOAc = 9/1 to 3/2 (y/v) as the eluent. Yield: 1.42 g MS-ESI: [M+H]^ = 547.2 TLC: Rf - 0.6, silica gel, hept/EtOAc = 3/2 (v/v) (c). tert-huty\ ethyl f2-("5-cyano-2-methylthio-4-f3-nitro-phenyl)-pyrimidin-6-ylV ethyl)-maIonate Potassium carbonate (1.88 g) and ieri-butyl ethylmalonate were suspended m EtOH (82 ml) and a solution of 5-cyano-2-methylthio-4-(3-nitro-phenyl)-6-vuiylpyrimidine (example 27b, 2.71 g) in toIuene/CH2Cl2 (33 ml) was slowly added (ca 1.5 h). After the addition was complete, the mixture was stirred for an additional 40 min. The mixture was diluted with EtOAc and washed with water (2x) and brine. Th^ organic layer was dried (MgSOa) and concentrated under reduced pressure. The title compound was purified by chromatography on sihca gel with hept/CH2Cl2 = 1/1 (v/v) as eluent. Yield: 1.42 g MS-ESI: [M+Hf = 487.2 TLC: Rf = 0.5, siHca gel, hept/EtOAc = 3/2 (v/v) (d). Ethvl 5-amino-2-methy1thio-4-r3-mtro-phenylV7.8-dihydro-quinazo]jpe-6-carboxylate " A solution of rert-butyl ethyl {2-[5-cyano-2-methylthio-4-(3-mtro-phKiyl)-pyrimidin- 6-yl>ethyl}-malonate (example 27c, 1.40 g) m CH2CI2 (15 ud) was cooled to 0 "C. A solution of SnCL} (1 M in CH2CI2,11.5 ml) was added dropwise, the ice-bath removed and the solution was stirred for an additional 30 rnin at room temperature. Water (64 ml) and EtOAc (64 ml) were added and the mixture was vigorously stirred until al solids dissolved. The organic phase was washed with water and brine, dried (MgS04) and concentrated under reduced pressure, giving the title compound as a crude product. Yield: 1.19 g (crude) MS-ESI: [M+H]""-387.2 TLC: Rf = 0.5, silica gel, hept/EtOAc = 3/2 (v/v) (e). Ethyl 5-amino-2-methylthio-4-{3-nitro-pheny1)-quinazoline-6-carboxylate A solution of crude ethyl 5-amino-2-methylthio-4-(3-nitro-phenyI)-7,8-dihydro- quinazoIine-6-carboxylate (example 27d, 1.19 g) in CH2CI2 (31 ml) was cooled to 0 "C. A solution of DDQ (1.14 g) in toluene (31 ml) was added dropwise, the ice-bath removed and the solution was stirred for an additional 30 min at room temperature. The mixture was diluted with CHzCU (ca 100 ml) and washed with a saturated aqueous solution of NaHCOs (3 x 100 ml) and brine (2 x 50 ml). The combined aqueous layers were back-extracted with CH2CI2. The combined organic layers were dried (MgS04) and concentrated under reduced pressure. The title oompound was purified by chromatography on. siUca gel using hept/EtOAc = 9/1 to 3/2 (v/v) as eluent. Yield: 735 mg MS-ESI: [M+H]"" = 385.2 TLC; Rf = 0.5, silica gel, hept/EtOAc = 3/2 (v/v) (fi. Ethyl 5-amino-2-Ti>ethylthio-4-n-aminophenvl^-quinazoline-6-carboxylate To a mixture of ethyl 5-ainino-2-methylfhio-4-(3-iiitro-phenyl)-quinazoline-6- carboxylate (example 27e, 1.54 g) and SnCl2-2H20 (4.52 g) in 1,4-dioxane (35 ml) were added EtOH (35 red) and concentrated aqueous HCI (690 1). The reaction mixture was stirred at 90 "C for 5 h. After cooling to room temperature and concentration under reduced pressure the residue was suspended in EtOAc (35 ml). The mixture was brought to pH 10 by the addition of 2 M NaOH and THE and brine were added. The resulting mixture was stirred for 40 min, after which time the organic layer was seperated, dried (MgS04) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel using hept/EtOAc = 9/1 to 3/2 (v/v) as eluent. Yield: 818 mg MS-ESI: [M+H]^ = 355.2 TLC: Rf = 0.3, silica gel, hept/EtOAc = 3/2 (v/v) fg\ 5-amino-2-methylthio-4-(3-aTniTiophenyn-quina2oline-6-carfaoxylic acid A solution of 5-amino-2-methylthio-4-(3-aminophenyl)-quinazoliae-6-carboxylate (example lit, 658 mg) in 1,4-dioxane was treated with an aqiteous solution of KOH (2 M, 4.2 ml) at 70 "C for 18 h. After the reaction mixture was cooled to room temperature, it was acidified to pH 1 with 4 N HCl. The mixture was extracted with CH2CI2 (3 x). The combined organic layers were dried (MgSOa) and concentrated under reduced pressure to give the crude title compound. Yield: 215 mg MS-ESI: [M+H]^ = 327.2 TLC: Rf = 0, sihca gel, hept^tOAc = 3/2 (v/v) fhl fert-Butvl 5-amino-2-methvlthio-4-(3-aminophenyl)-quinazo]ine-6-carboxamide The conversion of 5-amino-2-methylthio-4-(3-aminophenyl)-quiQazoline-6-carboxylic acid (example 27g, 192 mg) to the conespondiag ^ert-butyl amide was performed according to the procedure described in example le. The title compound was purified by chromatography on silica gel using hept/EtOAc = 9/1 to 3/2 (v/v) as eluent. Yield: 243 mg MS-ESI: [M+H]^ = 382.2 HPLC;Rt = 6.57 min, column Luna C-IS (see example le), eluent H2O/CH3CN = 45/55 to 0/100 (v/v) in 20 min Example 28 ferf-Butyl 5-amino-2-"methyltbio-4-(3-(2-(morpholin-4-vlVacetamido)-pl>enyl)- quinazoline-6-carboxamide (a). fe?-f-Butyl 5-amino-2-TnethYltliio-4-f3-("2-bromoacetamidoVphenyIVquinazoliTie-6-carboxamide To a suspension of /eri-butyl 5-amino-2-methyltIiio-4-(3-aminophenyl)-quina2oline-6-carboxamide (example 27h, 791 mg) in CH2CI2 (60 ml) was added DIPEA (1.08 ml), followed by the slow addition of bromoacetyl chloride (242 1) in CIiCl2 (20 ml). After 40 min at room temperature the reaction mixture was washed with sat. aqueous NHCO3 (3x), followed by drying (MgS04) and concentration under reduced pressure. The crude title compound was used wdthout further purification in the next step. ^ield: 1.20 g (crude) MS-ESI: [M+H]"" = 504.2 TLC: Rf = 0.4, silica gel, hept/EtOAc = 3/2 (v/v) (b). tert-Butyl 5-amino-2-methvlthio-4-r3- To a solution of tert-huty\ 5-amino-2-methylthio-4-(3-(2-bromoacetamido)-phenyl)-q"uinazoline-6-carboxamide (example 28a, 88 mg) in acetonitrile was added morpholine (148 1) and the mixture was stirred for ISh. After this time CHzCh (15 ml) was added and the mixture was washed with sat. aqueous NaHCOs. The organic layer was dried (MgS04) and concentrated in vacuo. The title compound was purified by chromatography on silica gei using CH2Cl2/M:eOH = 1/0 to 9/1 (v/v) as eluent. The title compound was lyophilized from a mixture of acetonitrile and water containing 1.5 eqmv. ofHCl. Yield: 82 rag (HCl salt) MS-ESI: [M+Hf = 509,2 HPLC:Rt = 13.00 min, column Luna C-18 (see example le), eluent H2O/CH3CN = 75/25 to 0/100 (v/v) in 20 min Example 29 tert-Butyl ";-FimiTio-2-methvlthio-4-(3-((N-(f erf-butyl)-glycinylVaminoVphenylV qmna2o1irte-6-carbox amide Reaction of rerr-butylamine (275 [il) with ferr-butyl 5-araino-2-methy!thio-4-(3-(2- bromoacetamido)-phenyl)-quinazoline-6-carboxamide (example 28a, 130 mg) was performed according to the method described in example 28b. The title compound was first purified by chromatography on siUca gel with hept/EtOAc = 3/2 (v/v) as eluent and then by HPLC using a Luna C-18 column with the following gradient: CH3CN/0.1% aq. TFA = 10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and aq HCl. Yield: 28 mg (HCl salt) MS-ESI: [M+H]^ = 495.4 HPLC."Rt = 12.93 TTiin^ column Luna C-18 (see example le), eluent phosphate buffer 50 mM pH 2.I/H2O/CH3CN = 10/70/20 to 10/10/80 (v/v) m 20 min. Example 30 Ethyl 5-amino-2-methylthio-4-f3-nitrophenvlV7-hvdrQxy-pyrido[2.3-c/]pvrimidine-6-carbojtylate raV6-Amino-5-cvano-2-methvlthio-4-f3-nitrophenvi;^pvrimidine A solution of 6-chloro-5-cyano-4-(3-nitrophenyl)-2-methylthio-pyrimidine (example 9b, 10.0 g) was treated with ammonium hydroxide (28% NH3 in water, 15 ml) and the mixture was stirred overnight. The formed crystals were collected by filtration and washed with water. The product was dried at 50 "C under vacuum yielding the title compound. Yield: 8.9 g MS-ESI: [M+H]^ = 288.2 TLC: Rf = 0.3, silica gel, hept/EtOAc = 3/2 (v/v) (b). Diethyl 2-fATnino-[6-amino-2-methylthio-4-r3-nitrophenyl1-pvrimidin-5-yl]-methylene)malonate To a suspension of 6-amino-5-cyano-2-methylthio-4-(3-nitrophenyl)pyrimidine (example 30a, 5.74 g) in 1,2-dichloropropane (200 ml) was added diethylmalonate (9.1 ml). The mixture was cooled to 0 "C and a solution of SnCU (14 ml) in ia 1,2- dichloropropane (50 ml) was added dropwise. After the addition was complete, the suspension was heated at reflux for 18 h. The mixture was allowed to cool to room temperature and after sohds were settled the 1,2-dichloropropane was carefully decanted. The resulting solids were stirred with EtOAc (300 ml) and water (300 ml) until dissolution was complete. The organic layer was washed with water (500 ml) and brine (500 ml), dried (MgSOa) and concentrated in vacuo. The title compound was purified by chromatography on sihca gel using hept/EtOAc = 1/0 to 3/2 (v/v) as eluent. Yield: 3.78 g MS-ESI: [M-4-H]^ = 448.4 TLC: Rf = 0.2, silica gel, hept/EtOAc = 3/2 (v/v) (cVEthvl 5-amino-2-piftthvlthio-4-("3-nitrnphenylV7-hydroxy-pyrido[2.3-cr]pyrimidtne-6-carboxylate A suspension of diethyl 2-(amino-[6-amino-2-methyIthio-4-(3-iiitrophenyl)-pyriniidin- 5-yl]-methylene)-maIan^e (example 30b, 1.34 g) in diphenyl ether (30 ml) was-heated under a stream of nitrogen to 240 "C for 2 h. After the mixture was cooled to room temperature, heptane was added (200 ml) and the solids were collected by filtration. The title compound was purified by chromatography on silica gel using CH2Cl2/acetone = 1/0 to 4/1 (v/v) as eluent. Yield: 590 mg MS-ESI: [M+H]"" = 402.4 TLC: Rf = 0.3, sihca gel, CH2Cl2/acetone = 9/1 (v/v) Example 31 /e??-Butyl 5-amino-2-phenvl-4-- thieno[2.3- faV 5-Cvano-4-f3-iiitrophenyl)-2-pheny]-6-hydroxy-pyrimidine A mixture of benzamidine hydrochloride (16.4 g), 3-Ditroben2aldehyde (15.1 g), ethyl cyanoacetate (11.2 ml) and potassium carbonate (16.6 g) in abs. EtOH (250 ml) was stirred at 60°C for 8 h. The reaction mixture was cooled to 0""C in an ice bath. The resulting precipitate was filtered off, washed with abs. EtOH and heated in water (100°C) until a clear solution was obtained. The solution was cooled to 50°C, acidified to pH 2 by adding 2N aq. HCl and cooled to 0°C in an ice bath. The resulting precipitate was filtered off and washed with ice water. Residual water was removed by coevaporation with 1,4-dioxane. Yield: 15.0 g. MS-ESI: [M+H]* = 319.2 TLC: Rf = 0.3, sihca gel, DCM/MeOH = 9/1 (v/v). (b). 6-Chloro-5-cyaTio-4- POCI3 (50 ml) was added to a stirred solution of 5-cyano-4-(3-nitrophenyl)-2-phenyl-6-hydroxy-pyrimidine (example 31(a), 15.0 g) and dimethyianiline (0.5 ml) in dry 1,4-dioxane p.a. (200 ml). After 3 h at 90°C, the warm mixture was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in 1,4- dioxane and ice water was added. The resulting precipitate was filtered off and washed with water. Residual water was removed "by coevaporation with 1,4-dioxane. Yield: 15.8 g MS-ESI: [M+H]*= 337.4 TLC: Rf = 0.8, sihca gel, heptane/EtOAc = 3/2 (v/v). (c). Ethyl 5-cya-no-4-(3-nitrophenyl")-2-phenyl-6-(ethoxycarbonylmethylthio)- pyrimidine DEPEA (8.71 ml) was added to a stirred solution of ethyl 2-mercaptoacetate (5.15 ml) and 6-chloro-5-cyano-4-(3-nitrophenyl)-2-phenyl-pyiimidine (example 31(b), 15.8 g) in a mixture of EtOH (125 ml) and DCM (125 ml) under a nitrogen atmosphere. After 2 h at room temperature, the mixture was diluted with DCM until complete dissolution, washed with 0.5N aq. HCl, dried (MgS04) and concentrated imder reduced pressure. Yield; 19.7 g MS-ESI: [M+H]"^ = 421.2. TLC: Rf = 0.7, sihca gei, heptane/EtOAc = 3/2 (v/v). (d\ Ethyl 5-amino-4-(3-nitrophenyl"i-2-phenyl-thieno[2.3- DIPEA (20.0 ml) was added to a stirred solution of ethyl 5-cyano-4-(3-nitrophenyl)-2-phenyl-6-(ethoxycarboifyhnethylthio)-pyrimidine (example 31(c), 19.7 g) in a mixture of abs. EtOH (100 ml) and toluene p.a. (100 ml). After 48 h at lOO^C, the mixture was cooled to 0°C. The resulting precipitate was filtered off^ washed with cold EtOH and dried in vacuo at 40""C. Yield: 17.0 g MS-ESI: [M+H]^ = 421.2 TLC: Rf = 0.5, silica gel, heptaue/EtOAc = 3/2 (v/v). (e). Ethyl 5-amino-4-(3-aminophenyl)-2-phenyl-thieno[2,3-ff)pyrimidine-6-carbQxylate A solution of tin (TT) chloride (23.0 g) in abs. EtOH (250 ml) was added to a solution of ethyl 5-amino-4-(3-nitrophenyl)-2-phenyI-thieno[2,3-isr|pyrimidine-6-carboxylate (example 31(d), 16.6 g) in 1,4-dioxane p.a. (250 ml). 37% aq. HCl (6.9 ml) was added and the mixture was heated under reflux (90°C) for 16 h. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was suspended in EtOAc (500 ml). 4N aq. NaOH was added to obtain a pH of 10-11. The mixture was diluted by adding sat. aq. NaCl. The organic layer was separated, dried (MgS04) and concentrated under reduced pressure. Yield: 17.0 g MS-ESI: [M+H]^ = 421.2 TLC: Rf = 0.5, silica gel, heptane/EtOAc = 3/2 (v/v). (f). 5-Amino-4-n-aminQphepylV2-phenvl-thieno[2.3-tf]pvrimidine-6-carhoxvlic acifi Potassium hydroxide (20.0 g) was added to a solution of ethyl 5-ainino-4-(3- aininophenyl)-2-phenyl-thieno[2,3-ifjpyiiniidine-6-carboxylate (example 3i(e), 17.0 g) in a mixture of 1,4-dioxane (210 ml) and water (80 ml). After 16 h at 90°C, the mixture was cooled to 0°C. The resulting precipitate was filtered off, suspended in water (300 ml) and cooled to 0°C. The mixture was acidified to pH 3 by adding 2N aq. citric acid and stirred at 0°C up to room temperature for 2 h. The resulting precipitate was filtered off, washed with water and dried in vacuo at 40""C. Yield: 13.3 g MS-ESI: JM+H}^ = 363.0 TLC: Rf = 0.2, siHca gel, DCM/MeOH = 95/5 (v/v). (g). ferf-Butyl 5-aTnino-4-("3-ami nophenylV2-phenyl-thieno [2.3-t/]pyrin}i din e-6- carboxamide DIPEA (15.3 ml), /erf-butylamine (9.3 ml) and TBTU (14.1 g) were added to amixUire of 5-aniino-4-(3-aniinophenyl)-2-phenyl-thieno[2,3-tf]pyrimidine-6-carboxylic acid (example 31(f), 13.3 g) in a mixture of DCM (250 ml) and DMF (50 ml) under a nitrogen atmosphere. After 3 h at room temperature, the mixture was diluted with DCM and washed with sat. aq. NaHCOs, O.IN aq. HCl and sat. aq. NaCl. The organic layer was dried (MgSO-i) and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, using heptane/EtOAc = 3/7 to I/l (v/v) as eluent. Yield: 14.7 g MS-ESI: [M+H]""= 418.4 TLC: Rf = 0.4, silica gel, heptane/EtOAc = 3/2 (v/v). (h). ferf-Butyl 5-amino-2-plienyM-(3-(p-nitro-phenoxycaTbonylamino)-phenvl)-thieno [g.3 -tJ]pyrunidine-6-carhoxamide tert-Butyl 5-amnio-2-phenyl-4-(3-aminophenyI)-thieno[2,3-(f]pyriimdine-6- carboxamide (example 31(g), 2.0 g) was dissolved in dry CH2CI2 (20 ml). Subsequently, a solution of_p-nitro-phenyl chlorofomiate (520 mg) in dry CHaCh (10 ml) was added dropwise and the reacCton mixture was stirred at room temperature. After 3 h, the reaction mixture was washed with H2O. The organic layer was dried (MgS04) and concentrated imder reduced pressure. Yield: 2.9 g MS-ESI-. [M+Hf = 583.2 TLC: Rf = 0.6, silica gel, heptane/EtOAc = 1/1 (v/v). (\\ feri^-Buty] 5-amino-2-phenyi-4-r3-ffthiomorpho]in-4-yiVcarbonylaminoVphenylV thi 6110(2.3-tflpyrimidin$-6-carbQxamide Thiomoipholine (300 |il) was added to a solution of tert-hv."^l 5-amino-2-phenyl-4-(3-(p-nitro-phenoxycarbonylamino)-phenyl)-tbieno[2,3-cr|pyrL. iine-6-carboxamide (example 31(h), 150 mg) in dichloromethane (5 ml) anc the reaction mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with CH2CI2 and washed with H2O. The organic layer was concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: H2O/CH3CN = 80/20 to 0/100 (v/v) in 45 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O. Yield: 89 mg MS-ESI: [M+H]^ = 547.2 HPLC:Rt = 11.71 min, column Luna C-18(2), 3 pm, 100 x 2.0 mm, detection UV = 210 mn, oven temperature ^ 40""C, flow = 0.25 ml/min, eluent phosphate buffer 50 toM pH 2.1/water/ACN = 10/30/60 to 10/5/85 (v/v/v), run time = 20 min. Example 32 fgrf-Butyl 5-aroino-2-Dhenyl-4-f3-rfN.N-dimethvlaminQVcarbonvlamino)-phenyn- thieno[2.3-gnpyrimidine-6-carhnYamiHe Dimethyl amine hydrochloride (150 mg) was added to a solution of N^-diisopropylethylamine (DIPEA, 0.50 ml) and ?e«-butyl 5-amino-2-phenyl-4-(3-(p-nitro-phenoxycarbonylamiiio)-phenyl)-thieno[2,3-"^pyrumdine-6-carboxamide (example 31(h), 250 mg) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with CH2CI2 and washed with H2O. The organic layer was concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: H2O/CH3CN = 80/20 to 0/100 (v/v) m 45 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O. Yield: 75 mg MS-ESI: [M-f-H]""= 489.2 HPLC:R[ = 19.58 min, column Luna C-18(2), 3 ym, 100 x 2.0 mm, detection UV = 210 mn, oven temperature = 40°C, flow = 0.25 ml/min, eluent phosphate buffer 50 mM pH 2.1/water/ACN = 10/60/30 to 10/5/85 (v/v/v), run time = 20 min. Example 33 fen-Butyl 5-aminQ-2-phenvl-4-(3-C/morpholin-4-yl)-carbonylamino)-phenvlV thieno[2.3-^pyrim}dine-6-caTfeoy amide MorphoHne (250 mg) was added to a solution of tert-hutyl 5-amino-2-phenyl-4-(3-(p-mtro-phenoxycarbonylanuno)-phenyl)-thieno[2,3-J]pyiimidine-6-carboxamide (example 31(h), 150 mg) ia dichloromethane (5 ml) and the reaction mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with CH2CI2 and washed with H2O. The organic layer was concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the foUowing gradient: H2O/CH3CN = SO/20 to 0/100 (v/v) in 45 min. The tiUe compound was then lyophilized from a mixture of 1,4-dioxane and H2O. Yield; 63 mg MS-ESI: [M+H]"" = 489.2 HPLC:Rt = 19.39 min, colmrm Luna C-18(2), 3 [im, 100 x 2.0 mm, detection UV = 210 mn, oven temperature = 40°C, flow = 0.25 ml/min, eluent phosphate buffer 50 mM pH 2.1/water/ACN = 10/60/30 to 10/5/85 (v/v/v), run time = 20 min. Example 34 CHO-LH and CHO-FSH in vitro bioactivity LH agonistic activity of compounds was tested in Chinese Hamster Ovaiy (CHO) cells stably transfected with the human LH receptor and cotransfected with a cAMP responsive element (CRE) / promotor directing the expression of a firefly luciferase reporter gene. Binding of ligand to the Gs-coupled LH receptor will result in an increase of cAMP, which in tum will induce an increased transactivation of the luciferase reporter construct. The luciferase signal was quantified using a luminescence counter. For test compoxmds, EC50 values (concentration of test compound causing half-maximal (50 %) stimulation) were calculated. For that puipose the software program GraphPad PRISM, version 3.0 (GraphPad software Inc., San Diego) was used. Results indicated that ECso value for the compounds of examples 9, 11, 12, li3; 14, 25 and 27 was between 10"^ and 10"^ M. The compo\mds of examples 1,2,3A5,17,22, 26, 28, 29, 31, and 33 showed an EC50 value between 10""" and 10"^ M, whereas the EC50 value of the compounds of examples 7,15, 16, IS, 21, 23 and 32 were lower than 10"^ M. WE CLAIM: 1. A bicyclic heteroaromatic compound according to general formula I, or a pharmnaceutically acceptable salt hereof, R^ is (3-8C)cycloalkyl, (2-7C)lieterocycloa]l;yl, (6-14C)aryl or (4- 13C)heteroaiyU all optionally substituted with one or more substituents selected from N(R"^R^ ^3HR^ R^ OR^ and/or SR"; R^ is (l-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl. (6-14C)aiyl or (4- 13C)heteroaryl; R" is (l-8C)alkyl, (3-8C)cycloallcyl, (2-7C)beterocycloa]kyl, C6-14C)aryl or (4- 13Qheteroaxyl; R* can be selected from the same groiqjs as described for R^, R^ is (6-14C)aiyl, C4-13C)heteroaryI, (6-14C)ajylcarboayl, (2- 7C)beterocycloalkyl. C2-7C)lieterocycloalkylcaibony], (2-8C)alkenylsulfonyI, (2- 8C)alken.oxycarbonyl, (3-8C)cycloalbyl, (6-l4G)axylsulfbnyl, (6- 14C)aiylamiiiocarbonyl, (6-14C)aryloxycarbonyl, (6-14C)arylamiiiosulfonyl, (6- 14C)aryloxysulfonyl, (2.8C)alfcenyl, (2-8C)alkynyl, or (l-SQalkyl, {l-8C)alkylcarbonyl, (l-SQaDcylsulfonyl, (1- 8C)Cdi)alkylaniinocarboayl, (l-8C)alkoxycarbonyl, (1- 8C)(di)alkyIaminosulfonyl, or (l-8C)alkoxysulfonyl, the alkyl group of ■which nmy be optionally substituted with one or more substituents selected from hydroxyl, (l-8C)aIkoxy, (2-7C)heterocycloalkyl(l- 8C)alkoxy. (3-8C)cycIoalkyl(l-8C)alfcoxy, (6-14C)aryl(l"8C)alkoxy, (4- l3C)heteroaryl(l-8C)aIkoxy, (2-7C)heterocycloa]kyl, (3-8C)cycloalkyl, (6- 14C)aiyl, (4-13C)heteroaryl. (l-SQaUcoxycatbonyl, (6-14C)aryloxyoarbonyl, (1- 8C)alkylcarboGyIoxy, (6-14C)aiylcarbonyloxy, (l-8C)aUq"lcarbonyl, (6- 14C)arylcatbonyl, amine, (l-8C)alkyIaminocarbonyl, (6-14C)arylaniinocarbonyl, (l-8C)alkyIcarbonylamino, (6-14C)arylcari)onylanmio, (6-14C)(di)aiylanmio, (di)[(l-3QaUcoxy(l-3C)al] YisCHorN; ZisNHaorOH; A is S, N(H), N{R*). O or a bond; B is NCH), O or a bond and X1-X2 is C= additionally S or O if R^ is (l-8C)alkylsulfonyl, (6-14C)arylsuifonyl, (1- 8C)(di)alkylaminocaibonyl, (6-l4C)arylanunocaibonyl, (l-8C)aIkoxycarbonyl, (6-14C)aryloxycarbonyl, (l-8C)(di)jdfcylaminosulfonyl, (6- 14C)arylaminosulfonyl, (l-8C)aIkoxysulfonyl, (6-14C)aryloxysulfcoyl, (2- 7C)heterocycloalkylcarbonyl, (2-8C)alkenylsulfonyl or (2-8C)aIkenoxycaibonyl with the proviso that the compoimd is not ethyl 5-hydroxy-2-meGtiyl-4-(piparidin- l-yl)-pyrido[2,3-(/ipyrimidine-6-caiboxylate, ethyl 5-hydroxy-2-inefliyl-4- (morphoIin-4-yl)-pyrido[2,3-d]pyrinaidine-6-carboxylate or ethyl 5-hydroxy-2- methyl-4-(pyrrolidin-l-yl>pyrido[2,3-£3]pyrimidiQe-6-carboxyiate. 2. The compound as claimed in claim 1 whaem B is N(EI) or a bond. 3- The compound as claimed in claim 1 or 2 wherein Z is NH2. 4. The compound as claimed in claim 1-3 whwein B} is (6-14C)aryl or (4-ISQheteroaryl, optionally substituted with one or more substituents selected jErom NCR"^R^ NHR^ R^ OR^ or SR^ 5. The compound as claimed in claim 4 wherein R is (6-14C)aTylcarboi3yl, (2- 7C)lieteax)cycloalkylcarbonyl, or (l-8C)allcyl, (l-8C)alkylcaibonyl, (1-8C)(di)alkylaminocarbonyl, the aDsyl group of which may be optionally substi&ited with (2-7C)heterocyctoa]]cyl, (4-13C)heteroaryl, (l-8C)alkoxycarbonyl, (1-8C)aIiylaminocarbonyl, (I-SQalkylcarbonylamino, (6-14C)aryIcarbonylamino, amine and/or(l-8C)(di)alkylamino. 6. The compound as claimed in claim 4 OT 5 wherem R" is phenyl, optionally substituted with one or more substitiKnts. 7. The compound as claimed in claim 6 wherein R1 is substituted at the meta position. S. The compound as claimed in claims 1-7 wherein Y is N. 9. The compound as claimed in claims 1-8 whereinB is N(H), or Bis a bond and R3 is (2-7C)heterocycloalkyl. 10. The compound as claimed in claims 1-9 wherdji X1-X2 is C==C, C=N, S or N=C. 11. The compound as claimed in claim 10 wherein X1-X2 is C=Cor S. 12 The compound as claimed in claim 11, selected from the groupof tert-butyl 5-amino-2-methylthio-4(3 ((N,N-diethylaraino)-caibonyloxy)-phenyl)-thieno[2,3-ii]pyrinudine-6-carboxamide, (ert-butyl 5-aniino-2-methylttuo-4-(3-(niethoxycarbonylamino)-phenyl)-thieno[2,3-£0pyrinudine-6-carboxamide, ferf-butyl 5-aniino-2-methyl^o-4-(3-(allyloxycarbonylamino)-phenyl)-thieno[2,3-d]pyriimdiiie-6-carboxamide, teri-hvctyl 5-aniino-2-methylthio-4-(3-(ethoxycarbonylamino)-phettyl)-thieno[2,3-£fjpyriinidine-6-carboxamide, tert-hxityl 5-amino-2- melhylthio-4-(3-{Cmoridiolin-4-yl)-carbonylamino)-phenyl)--thieno[23- 13- A pharmaceutical composition comprising a bicycUc heteroaromatic compound as claimed in daims 1-32 or a pharmaceutically accq>table salt or solvate ihs-eof, in admixture with a pharmaceutically acceptable auxihary.

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