WO2008131859A2

WO2008131859A2 - Use of cyclically substituted furopyrimidine derivatives for treating pulmonary arterial hypertonia

Info

Publication number: WO2008131859A2
Application number: PCT/EP2008/003008
Authority: WO
Inventors: Thomas Lampe; Eva-Maria Becker; Raimund Kast; Hartmut Beck; Mario Jeske; Joachim Schuhmacher; Friederike Stoll; Martina Klein; Metin Akbaba; Andreas Knorr; Johannes-Peter Stasch; Lars BÄRFACKER; Alexander Hillisch; Gunter Karig; Mark Meininghaus; Karl-Heinz Schlemmer; Rudolf Schohe-Loop
Original assignee: Bayer Schering Pharma Aktiengesellschaft
Priority date: 2007-04-26
Filing date: 2008-04-16
Publication date: 2008-11-06
Also published as: CA2685134A1; DE102007019690A1; WO2008131859A3

Abstract

The invention relates to the use of cyclically substituted furopyrimidine derivatives of formula (I) for the treatment and/or prophylaxis of pulmonary arterial hypertonia and other forms of pulmonary hypertonia and to the use of said derivatives for producing medicaments for the treatment and/or prophylaxis of pulmonary arterial hypertonia and other forms of pulmonary hypertonia.

Description

Use of cyclic substituted furopyrimidine derivatives for the treatment of pulmonary arterial hypertension

The present application relates to the use of cyclically substituted furopyrimidine derivatives of the formula (I) for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension and their use for the preparation of medicaments for the treatment and / or prophylaxis of the pulmonary arterial hypertension and other forms of pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive lung disease that, if untreated, leads to an average death within 2.8 years of diagnosis. An increasing constriction of the pulmonary circulation leads to an increase in the burden on the right heart, which can lead to right heart failure. By definition, chronic pulmonary hypertension has a pulmonary arterial mean pressure (mPAP) of> 25 mmHg at rest or> 30 mmHg under exercise (normal value <20 mmHg). The pathophysiology of pulmonary arterial hypertension is characterized by vasoconstriction and remodeling of the pulmonary vessels. In chronic PAH, neomuscularization of primarily non-muscularized pulmonary vessels occurs, and the vascular musculature of the already muscularized vessels increases in size. As a result of this increasing obstruction of the pulmonary circulation, there is a progressive load on the right heart, which leads to a reduced output of the right heart and ultimately ends in right heart failure [M. Humbert et al., J. Am. Coli. Cardiol. 2004, 43, 13S-24S]. With a prevalence of 1-2 per million, PAH is an extremely rare disease. The median age of the patients was estimated at 36 years, only 10% of the patents were over 60 years old. Significantly more women than men are affected [G.E. D'Alonzo et al., Ann. Intern. Med. 1991, 115, 343-349].

Despite all advances in the treatment of pulmonary arterial hypertension, there is no prospect of curing this serious disease. Standard therapies on the market (e.g., prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase inhibitors) are able to improve the quality of life, exercise tolerance, and prognosis of patients. However, the applicability of these drugs is limited by the z.T. restricted serious side effects and / or complex application forms. The period of time during which a patient's clinical situation can be improved or stabilized under specific monotherapy is limited. Finally, there is a therapy escalation and thus a combination therapy in which several drugs have to be given at the same time.

There is therefore a great need for new drugs and new pharmacological therapeutic principles for the treatment of pulmonary arterial hypertension, which new therapies should be combined with the already known [Ghofrani et al., Herz 2005, 30, 296-302; EB Rosenzweig, Expert Opinion. Emerging Drugs 2006, 11, 609-619; T. Ito et al., Curr. Med. Chem. 2007, 14, 719-733]. In order to minimize the risk of interfering drug-drug interactions in such a combination therapy, these new drugs should not or only to a limited extent inhibit metabolising P450 CYP enzymes.

The term "pulmonary arterial hypertension" includes certain forms of pulmonary hypertension, such as e.g. by the World Health Organization (WHO) [Clinical Classification of Pulmonary Hypertension, Venice 2003; G. Simonneau et al., J. Am. Coli. Cardiol. 2004, 43, 5S-12S].

According to this classification, pulmonary arterial hypertension includes idiopathic pulmonary arterial hypertension (IPAH, also referred to as primary pulmonary hypertension), familial pulmonary arterial hypertension (FPAH), and associated pulmonary arterial hypertension (APAH), which is associated with collagenosis congenital systemic pulmonary shunt veins, portal hypertension, HIV infection, use of certain drugs and medicines, with other diseases (thyroid disorders, glycogen storage disorders, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy), with significant venous disease capillary involvement such as pulmonary veno-occlusive disease and pulmonary-capillary haemahgiomatosis, as well as persistent pulmonary hypertension of newborns.

Other forms of pulmonary hypertension include, for example, pulmonary hypertension associated with left ventricular disease, e.g. in ventricular or valvular diseases, pulmonary hypertension associated with respiratory and / or pulmonary diseases, e.g. in chronic obstructive pulmonary disease, interstitial lung disease or pulmonary fibrosis, the pulmonary causes of chronic thrombotic and / or embolic diseases

Hypertension, e.g. in the case of thromboembolic obstruction of pulmonary arteries, as well as pulmonary inflammation caused by generalized inflammatory processes or by special causes

Hypertension (e.g., schistosomiasis, sarcoidosis, tumors).

Prostacyclin (PGI ₂ ) belongs to the family of bioactive prostaglandins, which are derivatives of arachidonic acid. PGI ₂ is the major product of arachidonic acid metabolism in endothelial cells and has potent vasodilating and anti-aggregating properties. PGI ₂ is the physiological antagonist of thromboxane A ₂ (TxA ₂ ), a potent vasoconstrictor and platelet aggregation stimulator, thus contributing to the maintenance of vascular homeostasis. A reduction in PGI ₂ levels is probably responsible for the development of various cardiovascular diseases [Dusting, GJ. et al., Pharmac. Ther. 1990, 48: 323-344; Vane, J. et al., Eur. J. Vase. Endovasc. Surg. 2003, 26: 571-578]. After release of the arachidonic acid from phospholipids via phospholipases A ₂ PGI ₂ is synthesized by cyclooxygenases and then by the PGl ₂ synthase. PGI ₂ is not stored, but released immediately after synthesis, causing its effects locally. PGI ₂ is an unstable molecule that is rapidly (half-life about 3 minutes) non-enzymatically rearranged to an inactive metabolite, 6-keto-prostaglandin Fl alpha [Dusting, GJ. et al., Pharmac. Ther. 1990, 48: 323-344].

The biological effects of PGI ₂ are due to the binding to a membrane-bound receptor, the so-called prostacyclin or IP receptor [Narumiya, S. et al., Physiol. Rev. 1999, 79: 1193-1226]. The IP receptor belongs to the G protein-coupled receptors that are characterized by seven transmembrane domains. In addition to the human IP receptor, rat and mouse prostacyclin receptors have also been cloned [Vane, J. et al., Eur. J. Vase. Endovasc. Surg. 2003, 26: 571-578]. In smooth muscle cells, activation of the IP receptor leads to the stimulation of adenylate cyclase, which catalyzes the formation of cAMP from ATP. The increase in intracellular cAMP concentration is responsible for prostacyclin-induced vasodilation and inhibition of platelet aggregation. In addition to the vasoactive properties, PGI ₂ still has anti-proliferative [Schroer, K. et al., Agents Actions Suppl. 1997, 48: 63-91; Kothapalli, D. et al., Mol. Pharmacol. 2003, 64: 249-258; Planchon, P. et al., Life Sei. 1995, 57: 1233-1240] and anti-arteriosclerotic effects [Rudic, RD et al., Circ. Res. 2005, 96: 1240-1247; Egan KM et al., Science 2004, 114: 784-794]. In addition, metastasis formation is inhibited by PGI ₂ [Schneider, MR et al., Cancer Metastasis Rev. 1994, 13: 349-64]. Whether these effects are due to stimulation of cAMP production or by IP receptor-mediated activation of other signal transduction pathways in the respective target cell [Wise, H. et al. TIPS 1996, 17: 17-21], such as the phosphoinositide cascade and potassium channels, is unclear.

Although the overall effects of PGI _{2 are} therapeutically useful, clinical use of PGI ₂ is severely limited by its chemical and metabolic instability. More stable PGI ₂ analogs such as iloprost [Badesch, DB et al., J. Am. Coli. Cardiol. 2004, 43: 56S-61S] and treprostinil [Chattaraj, SC, Curr. Opion. Invest. Drugs 2002, 3: 582-586] could be made available, but the duration of these compounds is still very short. Also, the substances can be administered to the patient only via complicated routes of administration, such as by continuous infusion, subcutaneously or via repeated inhalations. These routes of administration can also lead to additional side effects, such as infections or pain at the injection site. The use of the only PGI ₂ derivative orally available to the patient, beraprost [Barst, RJ. et al., J. Am. Coli. Cardiol. 2003, 41: 2119-2125], again limited by its short duration of action. Compared to PGI ₂ , the compounds described in the present application are chemically and metabolically stable, non-prostanoid activators of the IP receptor, which mimic the biological activity of PGI ₂ and also have a sufficiently high bioavailability after oral administration and / or a good Have solubility for parenteral administration. Thus, they represent promising starting points for new drugs for the treatment of pulmonary arterial hypertension as a single therapy or in combination with other drugs.

DE 1 817 146, EP 1 018 514, EP 1 132 093, WO 02/092603, WO 03/022852, WO 2005/092896, WO 2005/121149 and WO 2006/004658 disclose various 4-oxy, 4-thio and / or 4-amino-furo [2,3-d] pyrimidine derivatives and their use for the treatment of diseases. In WO 03/018589 4-aminofuropyrimidines are disclosed as adenosine kinase inhibitors for the treatment of cardiovascular diseases. The preparation of certain 4-aminofuropyrimidine derivatives is described in Chemica Scripta 1986, 26 (2): 337-342, Yakugaku Zasshi 1969, 89 (10): 1434-1439 and Yakugaku Zasshi 1977, 97 (9): 1022-1033 published. In WO 00/75145 compounds with a bicyclic heteroaryl core structure are claimed as inhibitors of cell adhesion.

Compared with the compounds of the prior art, the compounds described in the present application are characterized by a 5,6-diphenylfuro [2,3-d] pyrimidine core structure, which differs via the 4-position in a specific case spatial distance is associated with a carboxylic acid or carboxylic acid-like functionality.

The present invention relates to the use of compounds of the general formula (I)

in which

A is O, S or NR ⁴ , in which

R ⁴ is hydrogen, (C _r _C6) alkyl, (C ₃ -C ₇₎ -cycloalkyl or (G "-C ₇₎ cycloalkenyl,

L ^{1 is} a bond or (C _r C ₄ ) alkanediyl, the ring Q is (C ₃ -C ₇ ) -cycloalkyl, (C ₄ -C ₇ ) -cycloalkenyl, a 5- to 7-membered heterocycle,

Phenyl or 5- or 6-membered heteroaryl, which are each up to twice, identically or differently, with fluorine, chlorine, (Ci-Gi) -alkyl, trifluoromethyl, hydroxy, (Ci-C ₄ ) -

Alkoxy, trifluoromethoxy, amino, mono- (C 1 -C ₄ ) -alkylamino and / or di- (C 1 -C ₄ ) -alkyl-amino may be substituted,

wherein (Ci-C ₄₎ alkyl may in turn be substituted with hydroxy, (Ci-C ₄₎ alkoxy, amino, mono- or di- (C _r C ₄₎ alkylamino,

L ^{2 is} (C 1 -C ₄ ) -alkanediyl which is mono- or disubstituted by fluorine and in which a methylene group is substituted by O or NR ⁵ , in which

R ⁵ is hydrogen, (C _r _C6) alkyl or (C ₃ -C ₇₎ -cycloalkyl,

can be exchanged,

or is (C ₂ -C ₄ ) -alkendiyl,

Z is a group of the formula

stands in which

# the point of attachment to the group L ²

and

R ^{6 is} hydrogen or (C 1 -C ₄ ) -alkyl,

R ¹ and R ² independently of one another are selected from the group halogen, cyano, nitro, (C 1 -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₄ ) -alkynyl, (C ₃ -C ₇ ) -cycloalkyl, (C ₄ -

C ₇ ) -cycloalkenyl, (C ₁ -C ₆ ) -alkoxy, trifluoromethyl, trifluoromethoxy, (C 1 -C ₆ ) -alkylthio,

(Ci-Co) -Acyl, amino, mono- (Ci-C ₆ ) -alkylamino, di- (Ci-CβValkylamino and (Ci-Ce) -

Acylamino stand,

wherein (Ci-Ce) -AUCyI and (Ci-Cβ) alkoxy in turn each with cyano, hydroxy, (Ci-C ₄ ) - alkoxy, (Ci-C ₄ ) alkylthio, amino, mono- or di- (C _r C ₄ ) -alkylamino may be substituted, or

two radicals R ¹ and / or R ² bound to adjacent carbon atoms of the respective phenyl ring together form a group of the formula -O-CH ₂ -O-, -O-CHF-O-, -O-CF ₂ -O-, -O- CH ₂ -CH ₂ -O- or -O-CF ₂ -CF ₂ -O- form,

n and o are independently of one another the number O, 1, 2 or 3,

wherein, in the event that R ¹ or R ² occur several times, their meanings may be the same or different,

and

R ³ is hydrogen, (C _r _C4) alkyl or cyclopropyl,

and their salts, solvates and solvates of the salts for the manufacture of a medicament for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension.

Compounds which can be used according to the invention, hereinafter also referred to as compounds according to the invention, are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds of the formula (I) of the formulas below and their salts, solvates and solvates the salts and the compounds of formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of Salts acts.

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention. Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, Malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, trisethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

In the context of the invention, solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

In addition, the present invention also encompasses the use of prodrugs of the compounds according to the invention. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).

In particular, the present invention in the case of the compounds of the formula (I) in which

Z is a group of the formula

stands,

also hydrolysable ester derivatives of these compounds. These are understood to mean esters which, in physiological media, under the conditions of the biological tests described below and in particular in vivo, enzymatically or chemically to the free carbon acids, as the main biologically active compounds, can be hydrolyzed. As such esters, (C 1 -C ₄ ) -alkyl esters in which the alkyl group may be straight-chain or branched are preferred. Particularly preferred are methyl or ethyl esters (see also corresponding definitions of the radical R ⁶ ).

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:

(C ₁ -C _n VAIkVl. (C ₁ -C ₅ VAIkVl. (C ₁ -C ₄ VAIkVl and (C ₁ -CV) -alkyl are in the context of the invention a straight-chain or branched alkyl radical having from 1 to 6, 1 to A straight-chain or branched alkyl radical having 1 to 4, more preferably having 1 to 3, carbon atoms is preferred, and may be mentioned by way of example and preferably: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, 1-ethyl-propyl, n-pentyl and n-hexyl.

In the context of the invention, (C 7 -Q-alkenyl and (C 7 -C ₅₎ -alkenyl are a straight-chain or branched alkenyl radical having 2 to 6 or 2 to 5 carbon atoms and one or two double bonds By way of example and preferably, mention may be made of vinyl, AHyI, isopropenyl and n-but-2-en-1-yl.

The invention relates to a straight-chain or branched alkynyl radical having 2 to 4 carbon atoms and a triple bond. Preference is given to a straight-chain alkynyl radical having 2 to 4 carbon atoms. By way of example and preferably mention may be made of: ethynyl, n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-one in-l-yl.

(CRQ and alkanediyl (C _j -CQ-alkanediyl in the context of the invention a straight-chain or branched divalent alkyl radical having 1 to 4 or 1 to 3 carbon atoms. Preferred is in each case a straight-chain alkanediyl radical having 1 to 4 or 1 to 3 Examples which may be mentioned are: methylene, 1,2-ethylene, ethane-1,1-diyl, 1,3-propylene, propane-1,1-diyl, propane-1,2-diyl, propane-2, 2-diyl, 1,4-butylene, butane-1,2-diyl, butane-l, 3-diyl and butane-2,3-diyl.

In the context of the invention, fC ₂ -glyVAlkendiyl and ( ^" C 1 -C 4) -alkendiyl are a straight-chain or branched divalent alkenyl radical having 2 to 4 or 2 to 3 carbon atoms and up to 2 double bonds to 4 or 2 to 3 carbon atoms and one double bond, by way of example and preferably: ethene-1,1-diyl, ethene-1,2-diyl, propene-1,1-diyl, propylene-1,2-diyl, Propene-1,3-diyl, but-1-en-1, 4-diyl, but-1-en-1, 3-diyl, but-2-en-1, 4-diyl and buta- 1,3 - dien-1,4-diyl. (C ₁ -C _j ) -alkoxy and (C ₁ -Q) -alkoxy are in the context of the invention a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

(C ₁ -Cg) -AlkVlUiJo and (C ₁ -Ca) -AlkVUhJo in the context of the invention represent a straight-chain or branched alkylthio radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched alkylthio radical having 1 to 4 carbon atoms. Examples which may be mentioned are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthio and n-hexylthio.

(C ₁ -C _j ) -AcVl [(C _r C ₆ ) alkanoyl], (C ₁ -CS) -ACVI [(C, C ₅ ) alkanoyl] and (C _r Ca) acyl [(C _r C ₄ ) - alkanoyl] are in the context of the invention for a straight-chain or branched alkyl radical having 1 to 6, 1 to 5 or 1 to 4 carbon atoms, which carries a double-bonded oxygen atom in the 1-position and the 1-position is linked. Preference is given to a straight-chain or branched acyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: formyl, acetyl, propionyl, n-butyryl, isobutyryl and pivaloyl.

The invention relates to an amino group having a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

Di (C ₁ -C 6) -alkylamino and di (C ₁ -C 4) -alkylamino in the context of the invention are an amino group having two identical or different straight-chain or branched alkyl substituents, each of which has 1 to 6 or 1 to Have 4 carbon atoms. Straight-chain or branched dialkylamino radicals having in each case 1 to 4 carbon atoms are preferred. Examples which may be mentioned are: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N -methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

(C ₁ -C _j ) acylamino and (C ₁ -C 4 -cyclo-amino in the context of the invention represent an amino group having a straight-chain or branched acyl substituent which has 1 to 6 or 1 to 4 carbon atoms and is linked via the carbonyl group Preference is given to an acylamino radical having 1 to 4 carbon atoms, by way of example and by preference: formamido, acetamido, propionamido, n-butyramido and pivaloylamido. In the context of the invention, (C ₂ -C 4 -ClOalkyl) and (C 1 -C 6 -cycloalkyl represent a monocyclic, saturated cycloalkyl group having 3 to 7 or 3 to 6 carbon atoms, preferably a cycloalkyl radical having 3 to 6 carbon atoms may be mentioned: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the context of the invention, (C 1 -C 4 -cycloalkenyl) (C 1 -C 6 -cycloalkenyl and C 2 -C 8 -cycloalkenyl represent a monocyclic cycloalkyl group having 4 to 7, 4 to 6 or 5 or 6 carbon atoms and one double bond a cycloalkenyl radical having 4 to 6, particularly preferably 5 or 6, carbon atoms, by way of example and preferably: cyclobutyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.

A 5- to 7-membered heterocycle in the context of the invention is a saturated or partially unsaturated heterocycle having 5 to 7 ring atoms which contains one or two ring heteroatoms from the series N and / or O and via ring carbon atoms and / or optionally ring nitrogen atoms is linked. Preference is given to a 5- or 6-membered saturated heterocycle having one or two ring heteroatoms from the series N and / or O. Examples which may be mentioned are: pyrrolidinyl, pyrrolinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, hexahydroazepinyl and hexahydro-1,4-diazepinyl. Preference is given to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and tetrahydropyranyl.

5- or 6-membered heteroaryl in the context of the invention represents an aromatic heterocycle (heteroaromatic) having 5 or 6 ring atoms which contains one or two ring heteroatoms from the series N, O and / or S and via ring carbon atoms and / or optionally a ring nitrogen atom is linked. Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl. Preference is given to 6-membered heteroaryl radicals such as, for example, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.

If radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.

Preferred within the scope of the present invention is the use of compounds of the formula (I) in which A is O, S or NR ⁴ , in which

R ^{4 is} hydrogen, (C 1 -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or (C ₄ -C ₇ ) -cycloalkenyl,

L ^{1 is} a bond or (C 1 -C ₄ ) -alkanediyl,

the ring Q is (C ₃ -C ₇ ) -cycloalkyl, (C ₄ -C ₇ ) -cycloalkenyl, a 5- to 7-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each of which is up to twice, the same or differently, with fluorine, chlorine, (C 1 -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C 1 -C ₄ ) -alkoxy, trifluoromethoxy, amino, mono- (C 1 -C ₄ ) -alkylamino and / or di- ( C 1 -C ₄ ) -alkylamino may be substituted,

where (C 1 -C ₄ ) -alkyl in turn with hydroxy, (C 1 -C ₄ ) -alkoxy, amino, mono- or di- (C _r

C ₄ ) -alkylamino may be substituted,

R ^{5 is} hydrogen, (C 1 -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,

can be exchanged,

or is (C ₂ -C ₄ ) -alkendiyl,

Z is a group of the formula

o _the

stands in which

# the point of attachment to the group L ²

and

R ^{6 is} hydrogen or (C 1 -C ₄ ) -alkyl,

R ¹ and R ² independently represent a substituent selected from the group halogen,

Cyano, nitro, (C ₁ -C ₆ ) -ABLY, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₄ ) -alkynyl, (C ₃ -C ₇ ) -cycloalkyl, (C ₄ -C ₇ ) cycloalkenyl, (C, -C ₆₎ alkoxy, trifluoromethyl, trifluoromethoxy, (C _r _C6) alkylthio, (C ₁ -C ₆ ) acyl, amino, mono- (C ₁ -C ₆ ) -alkylamino, di (C 1 -C ₆ ) -alkylamino and (C ₁ -C ₆ ) -acylamino,

where (C ₁ -C ₆ ) -alkyl and (C ₁ -C ₆ ) -alkoxy in turn may each be substituted by hydroxyl, (C 1 -C ₄ ) -alkoxy, amino, mono- or di (C 1 -C ₄ ) -alkylamino,

or

two radicals R ¹ and / or R ² attached to adjacent carbon atoms of the respective phenyl ring together form a group of the formula -O-CH ₂ -O-, -O-CHF-O-, -O-CF ₂ -O-, -O- CH ₂ -CH ₂ -O- or -O-CF ₂ -CF ₂ -O- form,

n and o are independently of one another the number O, 1, 2 or 3,

and

R ^{3 is} hydrogen, (C 1 -C ₄ ) -alkyl or cyclopropyl,

and their salts, solvates and solvates of the salts.

Particularly preferred in the context of the present invention is the use of compounds of the formula (I) in which

A is O or NR ⁴ , in which

R ^{4 is} hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl,

L ^{1 is} a bond or (C ₁ -C ₃ ) -alkanediyl,

the ring Q is (C ₃ -C ₆ ) -cycloalkyl, (C ₄ -C ₆ ) -cycloalkenyl, a 5- or 6-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each of which may be up to twice, identical or different, with fluorine, chlorine, (Ci-C ₃ ) alkyl, trifluoromethyl, hydroxy, methoxy, ethoxy, trifluoromethoxy, amino, methylamino, ethylamino, dimethylamino and / or diethylamino may be substituted,

where (C ₁ -C ₃ ) -alkyl in turn contains hydroxyl, methoxy, ethoxy, amino, methylamino,

Ethylamino, dimethylamino or diethylamino may be substituted, L ^{2 is} (C ₁ -C ₃ ) -alkanediyl which may be mono- or disubstituted by fluorine, (C ₂ -C ₃ ) -alkendiyl or a group of the formula * -M-CR ⁷ R ⁸ -, * -M-CH ₂ -CR ⁷ R ⁸ - or * -CH ₂ -M-CR ⁷ R ⁸ - in which

* the point of attachment to the ring Q,

MO or NR ⁵ , in which

R ^{5 represents} hydrogen, (C _r C ₃ ) -alkyl or cyclopropyl,

and

R ⁷ and R ^{8 are} independently hydrogen or fluorine

mean,

Z is a group of the formula

stands in which

# the point of attachment to the group L ²

and

R ^{6 is} hydrogen, methyl or ethyl,

R ¹ and R ² independently represents a substituent chosen from the series fluorine, chlorine, cyano, (C _r C ₅₎ alkyl, (C ₂ -C ₅₎ -alkenyl, (C ₃ -C ₆₎ cycloalkyl, ( C ₄ -C ₆₎ -cycloalkenyl, (C ₁ - C ₄₎ alkoxy, trifluoromethyl, trifluoromethoxy, (Ci-C ₄₎ alkylthio, _(Ci-C5) acyl, amino, mono- (Ci-C ₄ ) alkylamino, di- (C _r C ₄₎ alkylamino and (C _r _C4) acylamino stand,

or

two radicals R ¹ and / or R ² bound to adjacent carbon atoms of the respective phenyl ring together form a group of the formula -O-CH ₂ -O-, -O-CHF-O- or -O-CF ₂ -O-,

n and o are independently of one another the number O, 1, 2 or 3, wherein, in the event that R ¹ or R ² occur several times, their meanings may be the same or different,

and

R ^{3 is} hydrogen or (C ₁ -C ₃ ) -alkyl,

and their salts, solvates and solvates of the salts.

Very particularly preferred in the context of the present invention is the use of compounds of the formula (I) in which

A is O or NR ⁴ , in which

R ⁴ is hydrogen or (C _r C ₄₎ alkyl,

L ^{1 is} a bond or (C ₁ -C ₃ ) -alkanediyl,

the ring Q is (GrCβJ-cycloalkyl, (C ₅ -C ₆ ) -cycloalkenyl, a 5- or 6-membered heterocycle or phenyl, each of which is up to twice, identically or differently, with fluorine,

Chlorine, (C ₁ -C ₃ ) -alkyl, trifluoromethyl, hydroxy, methoxy, ethoxy, trifluoromethoxy,

Amino, methylamino, ethylamino, dimethylamino and / or diethylamino may be substituted,

L ^{2 is} (C ₁ -C ₃ ) -alkanediyl which may be mono- or disubstituted by fluorine, (C ₂ -C ₃ ) -alkendiyl or a group of the formula * -M-CR ⁷ R ⁸ -, * -M-CH ₂ -CR ⁷ R ⁸ - or * -CH ₂ -M-CR ⁷ R ⁸ - in which

* the point of attachment to the ring Q,

MO or NR ⁵ , in which

R ^{5 is} hydrogen or (C ₁ -C ₃ ) -alkyl,

and

R ⁷ and R ^{8 are} independently hydrogen or fluorine

mean,

Z is a group of the formula

stands in which

# the point of attachment to the group L ²

and

R ^{6 is} hydrogen, methyl or ethyl,

R ¹ and R ² independently of one another are selected from the group consisting of fluorine, chlorine, cyano, (C 1 -C ₅ ) -alkyl, (C ₂ -C ₅ ) -alkenyl, (C ₃ -C ₆ ) -cycloalkyl, (C ₄ -C ₆ ) -cycloalkenyl, (C 1 -C ₄ ) -alkoxy, trifluoromethyl, trifluoromethoxy, (C 1 -C ₄ ) -alkylthio, (C 1 -C ₅ ) -acyl, amino, mono- (C 1 -C ₄ -alkyl) ₄ ) -alkylamino, di (C 1 -C ₄ ) -alkylamino and (C 1 -C ₄ ) -acylamino,

or

n and o are independently of one another the number O, 1 or 2,

wherein, in the event that R ¹ or R ² occur twice, their meanings may be the same or different,

and

R ^{3 is} hydrogen or (C ₁ -C ₃ ) -alkyl,

and their salts, solvates and solvates of the salts.

Of particular importance in the context of the present invention is the use of compounds of the formula (I) in which

A is O or NH,

L 'is a bond, methylene, ethane-1, 1 -diy 1 or ethane-1, 2-diyl,

the ring Q is cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl or phenyl, each of which being bis may be substituted by fluorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino and / or dimethylamino in duplicate, identically or differently,

L ^{2 is} (C ₁ -C ₃ ) -alkanediyl, (C ₂ -C ₃ ) -alkendiyl or a group of the formula * -M-CH ₂ - or "-M-CH ₂ -CH ₂ -" wherein

* the point of attachment to the ring Q

and

MO or NR ⁵ , in which

R ^{5 is} hydrogen or (C, -C ₃ ) -alky 1,

means

Z is a group of the formula

stands in which

# the point of attachment to the group L ²

and

R ^{6 is} hydrogen, methyl or ethyl,

R ¹ and R ² independently represents a substituent chosen from the series fluorine, chlorine, cyano, (C _r C ₅₎ alkyl, (C ₂ -C ₅₎ -alkenyl, (C ₃ -C ₆₎ cycloalkyl, ( C ₄ -C ₆₎ -cycloalkenyl, (C, - C ₄₎ alkoxy, trifluoromethyl, trifluoromethoxy, (C _r _C4) alkylthio, (C, -C ₅₎ acyl, amino, mono- (Ci-C ₄₎ -alkylamino, di- (C _r C ₄₎ alkylamino and (C _r _C4) acylamino stand,

or

n and o independently of one another represent the number 0, 1 or 2, wherein, in the event that R ¹ or R ² occur twice, their meanings may be the same or different,

and

R ^{3 is} hydrogen,

and their salts, solvates and solvates of the salts.

A is O or NH,

L 'is a bond, methylene or ethane-1, 1 -diyl,

the ring Q is cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl or phenyl, which may each be up to twice, identically or differently, substituted by fluorine, methyl, hydroxy and / or methoxy,

L ^{2 is} (C ₁ -C ₃ ) -alkanediyl, (C ₂ -C ₃ ) -alkendiyl or a group of formula * -M-CH ₂ - or * -M-CH ₂ -CH ₂ -, wherein

* the point of attachment to the ring Q

and

M is O or NH,

Z is a group of the formula

stands in which

# the point of attachment to the group L ²

and

R ^{6 is} hydrogen, methyl or ethyl, R ^{1 represents} a substituent selected from the group fluorine, chlorine, methyl, ethyl, vinyl, trifluoromethyl and methoxy,

R ^{2 is} a substituent selected from the group fluorine, chlorine, cyano, methyl, ethyl, n-propyl, vinyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methylthio, ethylthio, amino, methylamino and ethylamino,

n and o independently of one another represent the number 0, 1 or 2,

and

R ^{3 is} hydrogen,

and their salts, solvates and solvates of the salts.

The residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

The compounds of the formula (I) which can be used according to the invention, in which Z represents -COOH or -C (= O) -COOH, can be prepared by reacting either

[A] compounds of the formula (II)

in which R ¹ , R ² , R ³ , n and o each have the meanings given above

and

X ^{1 represents} a leaving group such as, for example, halogen, in particular chlorine, in the presence of a base, optionally in an inert solvent, with a compound of the formula (III)

in which A, L, L and Q each have the meanings given above

and

Z is cyano or a group of the formula - [C (O)] _y -COOR 6A. stands in which

the number 0 or 1

and

R ^{6A is} (C 1 -C ₄ ) -alkyl,

to compounds of the formula (IV)

in which A, L ¹ , L ² , Q, Z ¹ , R ¹ , R ² , R ³ , n and o are each as defined above,

implements

or

[B] Compounds of the formula (V-I)

in which R, R, X and n each have the meanings given above,

in the presence of a base, if appropriate in an inert solvent, with a compound of the formula (III) to give compounds of the formula (VI-I)

in which A, L ¹ , L ² , Q, Z ¹ , R ¹ , R ³ and n are each as defined above,

reacted, then in an inert solvent, for example with N-bromosuccinimide to give compounds of the formula (VII-I)

brominated and then in an inert solvent in the presence of a base and a suitable palladium catalyst with a phenylboronic acid of the formula (VIII-I)

in which R ² and o have the meanings given above,

Coupling to compounds of formula (IV)

or [C] Compounds of the formula (V-2)

in which R, R, X and o each have the meanings given above,

in the presence of a base, if appropriate in an inert solvent, with a compound of the formula (III) to give compounds of the formula (VI-2)

in which A, L ¹ , L ² , Q, Z ¹ , R ² , R ³ and o are each as defined above,

reacted, then in an inert solvent, for example with N-bromosuccinimide to give compounds of the formula (VII-2)

in which A, L 1, τ L2, Q, Z, R, R and o each have the meanings given above,

brominated and then in an inert solvent in the presence of a base and a suitable palladium catalyst with a phenylboronic acid of the formula (VIII-2)

in which R ¹ and n have the meanings given above,

coupling to compounds of formula (IV),

and the respectively resulting compounds of formula (IV) then by hydrolysis of the ester or cyano group Z ¹ in the carboxylic acids of the formula (IA)

in which A, L ¹ , L ² , Q, R ¹ , R ² , R ³ , n, o and y each have the meanings given above,

and optionally with the corresponding (i) solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts.

Inert solvents for process steps (II) + (III) → (IV), (VI) + (III) → (VI-I) and (V-2) + (III) - »(VI-2) are, for example, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, tetrachloro - ethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝMP) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or mixtures of these.

Optionally, however, the process steps (II) + (III) → (TV), (VI) + (III) → (VI-I) and (V-2) + (III) - »(VI-2) can also be carried out without a solvent be performed.

Suitable bases for the process steps (II) + (III) → (IV), (VI) + (III) → (VI-I) and (V-2) + (III) → (VI-2) are customary inorganic or organic bases. These include preferably alkali hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal. carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal alcoholates such as sodium or potassium tert.-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, organometallic compounds such as butyllithium or phenyllithium, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN-diisopropylethylamine or pyridine.

In the case of reaction with alcohol derivatives [A in (III) = O] also phosphazene bases (so-called "Schwesinger bases") such as P2-t-Bu or P4-t-Bu are useful [see. e.g. R. Schwesinger, H. Schlemper, Angew. Chem. Int. Ed. Engl. 26, 1167 (1987); T. Pietzonka, D. Seebach, Chem. Ber. 124, 1837 (1991)].

In the reaction with amine derivatives [A in (III) = Ν] preferably tertiary amines, in particular NN-diisopropylethylamine, are used as the base. If appropriate, however, these reactions can also be carried out without the use of an auxiliary base, if an excess of the amine component (III) is used. In the reaction with alcohol derivatives [A in (III) = O], potassium or cesium carbonate or the phosphazene bases P2-t-Bu and P4-t-Bu are preferred.

The process steps (II) + (III) → (IV), (VI) + (III) → (VI-I) and (V-2) + (III) → (VI-T) may optionally be advantageous with the addition of a crown ether be performed.

In a process variant, the reactions (II) + (III) → (IV), (VI) + (III) → (VI-I) and (V-2) + (III) - »(VI-2) can also be used in a two-phase mixture consisting of an aqueous alkali metal hydroxide solution as the base and one of the abovementioned hydrocarbons or halogenated hydrocarbons as further solvent, using a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate or tetrabutylammonium bromide.

The process steps (IT) + (III) -> (IV), (VI) + (III) → (VI-I) and (V-2) + (III) → (VI-2) are carried out in the reaction with amine derivatives [A in (III) = Ν] generally in a temperature range of +50 ⁰ C to +150 ⁰ C. When reacted with alcohol derivatives [A in (III) = O], the reactions are generally in a temperature range of -20 ⁰ C to +120 ⁰ C, preferably carried out at 0 ⁰ C to +60 ⁰ C.

The bromination in process steps (VII) -> (VII-I) or (VI-2) -> (VII-2) is preferably in a halogenated hydrocarbon as solvent, in particular in tetrachloromethane, in a temperature range of +50 ⁰ C to + 100 ⁰ C performed. Suitable brominating agents are elemental bromine and in particular N-bromosuccinimide (ΝBS), optionally with the addition of α, α'-azobis (isobutyronitrile) (AIBΝ) as initiator. Inert solvents for the process steps (VII-I) + (VHl-1) → (TV) and (VII-2) + (VΗI-2) → (IV) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylsulfoxide, N, N-dimethylpropyleneurea (DMPU ), N-methylpyrrolidone (ΝMP), pyridine, acetonitrile or even water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to a mixture of dimethyl sulfoxide and water.

Suitable bases for process steps (VII-I) + (VIII-I) → (IV) and (VII-2) + (VIII-2) → (IV) are customary inorganic bases. These include in particular alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, or alkali hydrogen phosphates such as disodium or dipotassium hydrogen phosphate. Preferably, sodium or potassium carbonate is used.

As a palladium catalyst for the process steps (VII-I) + (VIII-I) → (TV) and (VII-2) + (VIII-2) - »(IV) [" Suzuki coupling "], for example, palladium on Activated carbon, palladium (IΙ) acetate, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride and [l, l'-bis (diphenylphosphino) ferrocene] dichloro-palladium (II) -dichloromethane complex suitable [see. e.g. J. Hassan et al., Chem. Rev. 102, 1359-1469 (2002)].

The reactions (VII-I) + (VIII-I) → (TV) and (VII-2) + (Vffl-2) → (TV) are generally in a temperature range of +20 ⁰ C to + 15O ⁰ C, preferably carried out at +50 ⁰ C to +100 ⁰ C.

The hydrolysis of the ester or nitrile group Z ¹ in process step (IV) -> (I-A) is carried out by customary methods by treating the esters or nitriles in inert solvents with acids or bases, wherein the latter resulting salts are treated by treatment with acid in the free carboxylic acids. In the case of tert-butyl esters, the ester cleavage is preferably carried out with acids.

Suitable inert solvents for these reactions are water or the organic solvents customary for ester cleavage. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned. In the case of basic ester hydrolysis, preference is given to mixtures of water with dioxane, tetrahydrofuran, methanol and / or ethanol, water and / or n-propanol are preferably used in the nitrile hydrolysis. In the case of the reaction with trifluoroacetic acid, preference is given to using dichloromethane and, in the case of the reaction with hydrogen chloride, preferably tetrahydrofuran, diethyl ether, dioxane or water.

Suitable bases are the customary inorganic bases. These include preferably alkali or alkaline earth hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Particularly preferred are sodium or lithium hydroxide.

Suitable acids for the ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water. Hydrogen chloride or trifluoroacetic acid are preferred in the case of tert-butyl esters and hydrochloric acid in the case of methyl esters.

The ester cleavage is generally carried out in a temperature range from 0 ⁰ C to + 100 ⁰ C, preferably at +0 ⁰ C to +50 ⁰ C. The nitrile hydrolysis is generally in a temperature range from +50 ⁰ C to +150 ⁰ C, preferably at +80 ⁰ C to +120 ⁰ C performed.

The reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, one works at normal pressure.

The compounds of the formula (I) which can be used according to the invention, in which Z represents a group of the formula

stands,

can be prepared by reacting compounds of formula (FV) in which Z ^{1 is} cyano, in an inert solvent with an alkali azide in the presence of ammonium chloride or with trimethylsilyl azide, optionally in the presence of a catalyst.

Inert solvents for this reaction are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents, such as dimethyl sulfoxide, dimethylformamide, N, N'-dimethylpropyleneurea (DMPU). or N-methylpyrrolidone (ΝMP). It is likewise possible to use mixtures of the solvents mentioned. Preferably, toluene is used. In particular, sodium azide in the presence of ammonium chloride or trimethylsilyl azide is suitable as an azide reagent. The latter reaction can advantageously be carried out in the presence of a catalyst. Compounds such as di-n-butyltin oxide, trimethylaluminum or zinc bromide are particularly suitable for this purpose. Preferably, trimethylsilyl azide is used in combination with di-n-butyltin oxide.

The reaction is generally carried out in a temperature range of +50 ⁰ C to + 15O ⁰ C, preferably at +60 ⁰ C to +110 ⁰ C. The reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.

stands,

can be prepared by reacting compounds of the formula (IV) in which Z ^{1 is} methoxy- or ethoxycarbonyl first in an inert solvent with hydrazine in compounds of the formula (IX)

in which A, L ¹ , L ² , Q, R ¹ , R ² , R ³ , n and o are each as defined above,

and then reacted in an inert solvent with phosgene or a phosgene equivalent, such as NN'-carbonyldiimidazole.

Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether are suitable as inert solvents for the first step of this reaction sequence. It is also possible to use mixtures of these solvents. Preferably, a mixture of methanol and tetrahydrofuran is used. The second reaction step will be preferred example in an ether, in particular carried out in tetrahydrofuran. The reactions are generally carried out in a temperature range of 0 ⁰ C to +70 ⁰ C under atmospheric pressure.

The compounds of the formula (I) according to the invention in which L ^{2 is} a group of the formula * -M-CR ⁷ R ⁸ - or * -M-CH ₂ -CR ⁷ R ⁸ -, where M, R ⁷ and R ⁸ alternatively have the meanings given above, can alternatively be prepared by reacting compounds of the formula (X)

in which A, L, M, Q, R, R, R, n and o are each as defined above,

in the presence of a base, optionally in an inert solvent, with a compound of the formula (XI)

X- (CH ₂ ) -CR ⁷ R ⁸ -Z ¹ (XI),

in which R ⁷ , R ⁸ and Z ¹ each have the meanings given above,

m for the number 0 or 1

and

X ^{2 is} a leaving group such as halogen, mesylate or tosylate,

or in the case where L ^{2 is} * -M-CH ₂ CH ₂ -, with a compound of the formula (XII)

H ₂ C ^^ Z ¹ (XII),

in which Z ^{1 has} the meaning given above,

in compounds of the formula (IV-A)

in which A, L ¹ , M, Q, Z ¹ , R ¹ , R ² , R ³ , R ⁷ , R ⁸ , m, n and o are each as defined above,

überfuhrt and then further implemented according to the method described above.

The compounds of the formula (X) can be prepared from a compound of the formula (II), (V-I) or (V-2) by base-catalysed reaction with a compound of the formula (XIII)

in which A, L ¹ , M and Q each have the meanings given above

and

is hydrogen or a temporary O or N-protecting group,

and correspondingly further reaction analogous to the previously described process variants [B] or [C] are obtained, wherein in the case of the reaction sequence (VI) or (V-2) -> (IV-A), the order of the individual process steps, if expedient, can also be varied (see also the following reaction schemes 2-9).

For the process steps (X) + (XI) or (XII) → (IV-A) and (II) + (XIII) → (X), the above for the reactions (II) + (III) → (IV) , (VI) + (III) → (VI-I) or (V-2) + (III) → (VI-2) described reaction parameters such as solvents, bases and reaction temperatures in an analogous manner.

The compounds of the formulas (II), (III), (VI), (VIII-I), (V-2), (VIII-2), (XI), (XII) and (XIII) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature (cf., for example, WO 03/018589, see also Reaction Scheme 1).

The preparation of the compounds of the invention can be illustrated by the following synthesis schemes: Scheme 1

POCl

Scheme 2

Scheme 3

Scheme 4

TFA

Scheme 5

NaOH

Scheme 7

[Y = O, NH or CH ₂ ]. Scheme 8

Scheme 9

TFA

[A = O or NH; x = 1-3].

The compounds of the invention are chemically and metabolically stable, non-prostanoid activators of the IP receptor with good physicochemical and pharmacokinetic properties. In particular, they have a sufficiently high bioavailability after oral administration and / or good solubility for parenteral administration.

The compounds according to the invention are therefore particularly suitable for the treatment and / or prophylaxis of pulmonary arterial hypertension including their subforms, such as idiopathic, familial and, for example, with portal hypertension, fibrotic disorders, HIV infection or improper medication or toxins associated pulmonary arterial hypertension. The compounds of the invention may also be used for the treatment and / or prophylaxis of other forms of pulmonary hypertension. Thus, they can be used, for example, for the treatment and / or prophylaxis of pulmonary hypertension in left atrial or left ventricular diseases and in left-sided heart valve diseases. In addition, the compounds according to the invention are suitable for the treatment and / or prophylaxis of pulmonary hypertension in chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sleep apnea syndrome, diseases with alveolar hypoventilation, altitude sickness and pulmonary developmental disorders.

Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of pulmonary hypertension due to chronic thrombotic and / or embolic diseases, such as thromboembolism of the proximal pulmonary arteries, obstruction of the distal pulmonary arteries and pulmonary embolism. Furthermore, the compounds according to the invention can be used for the treatment and / or prophylaxis of pulmonary hypertension in connection with sarcoidosis, histiocytosis X or lymphangioleiomyomatosis as well as pulmonary hypertension caused by external vascular compression (lymph node, tumor, fibrosing mediastinitis).

Because of their pharmacological profile of action, the compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of pulmonary arterial hypertension and pulmonary hypertension associated with chronic obstructive and / or fibrotic lung diseases and pulmonary hypertension due to chronic thrombotic and / or embolic diseases.

In addition, the compounds according to the invention can also be used for the treatment and / or prophylaxis of peripheral and cardial vascular diseases, of peripheral occlusive diseases (PAOD, PVD) as well as of peripheral circulatory disorders.

The compounds according to the invention can be used alone or in combination with other active substances. Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients for the treatment and / or prophylaxis of the aforementioned diseases. As suitable combination active ingredients may be mentioned by way of example and preferably:

• organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-I, and inhaled NO;

Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of Phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil;

NO-independent, but heme-dependent guanylate cyclase stimulators, such as, in particular, the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

Guanylate cyclase NO- and heme-independent activators, in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;

Compounds which inhibit human neutrophil elastase (HNE), such as, for example, Sivelestat, DX-890 (Reltran), Elafin or in particular those described in WO 03/053930, WO 2004 /

020410, WO 2004/020412, WO 2004/024700, WO 2004/024701, WO 2005/080372, WO 2005/082863 and WO 2005/082864 described compounds;

The signal transduction cascade inhibiting compounds, for example and preferably from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or serine / threonine kinase inhibitors;

Compounds which inhibit the soluble epoxide hydrolase (sEH), such as NN'-dicyclohexylurea, 12- (3-adamantan-1-yl-ureido) -dodecanoic acid or 1-adamantan-1-yl-3- {5- [2- (2-ethoxyethoxy) ethoxy] pentyl} urea;

Compounds affecting the energy metabolism of the heart, such as by way of example and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine;

Agonists of VPAC receptors, such as by way of example and preferably the vasoactive intestinal polypeptide (VIP);

Antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;

Antihypertensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor B-relaxer, mineralocorticoid receptor Antagonists, Rho kinase inhibitors and diuretics; and or

Lipid metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a kinase inhibitor such as, for example and preferably, canertinib, imatinib, gefitinib, erlotinib, lapatinib, lestaurtinib, lonafarnib, pegaptinib, pelitinib, semaxanib, tandutinib, tipifarnib, Vatalanib, sorafenib, sunitinib, bortezomib, lonidamine, leflunomide, fasudil or Y-27632.

Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaraban, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982 , EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin. Among the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor - Antagonists, Rho-kinase inhibitors and diuretics understood.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol administered.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist, such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone. In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a rho-kinase inhibitor, such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI- 23095, SB-772077, GSK-269962A or BA-1049.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably furosemide.

Among the lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as, by way of example and by way of preference, torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-gamma agonist, such as by way of example and preferably pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polymeric bile acid adsorber, such as by way of example and with preference cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.

In a preferred embodiment of the invention, the compounds of the invention are used in combination with a bile acid reabsorption inhibitor, such as by way of example and preferably ASBT (= IBAT) inhibitors such as e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.

Another object of the present invention is the use of the compounds of the invention alone or in combination with one or more of the aforementioned active ingredients for the manufacture of a medicament for the treatment and / or prophylaxis of idiopathic, familial or associated with drugs, toxins or other diseases pulmonary arterial hypertension , for the treatment and / or prophylaxis of pulmonary hypertension in left atrial or left ventricular diseases, left-sided heart valve diseases, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sleep apnea syndrome, diseases with alveolar hypoventilation, altitude sickness, pulmonary developmental disorders, chronic thrombotic and / or embolic diseases such as thromboembolism of the proximal pulmonary arteries, obstruction of the distal pulmonary arteries and pulmonary embolism, or in association with sarcoidosis, histiocytosis X or lymph angioleiomyomatosis, as well as for the treatment and / or prophylaxis of external vascular compression due to pulmonary hypertension.

Another object of the present invention is a method for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension in humans and animals by administering an effective amount of at least one of the compounds of the invention or a drug containing at least one of the compounds of the invention.

The medicaments to be produced according to the invention or to be used according to the invention comprise at least one of the compounds according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients.

Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention in combination with one or more inert, non-toxic, pharmaceutically suitable excipients, for the treatment and / or prophylaxis of the aforementioned diseases.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For the oral administration are according to the prior art working, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (e.g. Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be done bypassing a resorption step (eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or using absorption (for example by inhalation, intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). For parenteral administration are suitable as forms of application, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable, for example Inhalation medicaments (including powder inhalants, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg plasters), milk, pastes, foams, powdered powders, implants or stents.

Preference is given to oral or parenteral administration, in particular oral, intravenous and inhalative administration.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, in order to achieve effective results. When administered orally, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day. The following exemplary embodiments illustrate the invention. The invention is not limited to the examples.

The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume, unless stated otherwise.

A. Examples

Abbreviations:

Section. absolutely

Ac acetyl

Ac ₂ O acetic anhydride

Boc tert. butoxycarbonyl

Bu Butyl

C concentration

DCI direct chemical ionization (in MS)

DIEA diisopropylethylamine ("Hünig-Base")

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide d. Th. Of theory (at yield)

EI electron impact ionization (in MS) eq equivalent (s)

ESI electrospray ionization (in MS)

Et ethyl

Mp melting point

GC-MS gas chromatography-coupled mass spectrometry sat. saturated h hour (s)

HPLC high pressure liquid chromatography conc. concentrated

LC-MS liquid chromatography-coupled mass spectrometry

Me Methyl min minute (s)

Ms methanesulfonyl (mesyl)

MS mass spectrometry

NBS N-bromosuccinimide

NMR nuclear magnetic resonance spectrometry

Pd / C palladium on charcoal rac. racemic

RP reverse phase (reversed phase, for HPLC)

RT room temperature

R. Retention time (by HPLC)

TFA trifluoroacetic acid THF tetrahydrofuran

LC-MS. GC-MS and HPLC methods:

Method 1 (HPLCV

Instrument: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ (70%) / 1 water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 9 min 90% B → 9.2 min 2% B → 10 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ^° C .; UV detection: 210 nm.

Method 2 (HPLO:

Instrument: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ (70%) / 1 water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 6.5 min 90% B -> 6.7 min 2% B → 7.5 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ^° C .; UV detection: 210 nm.

Method 3 (LC-MSV

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - »2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 210 nm.

Method 4 (LC-MSV

Instrument: Micromass platform LCZ with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3μ 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 5.5 min 10% A; Oven: 50 ^° C .; Flow: 0.8 ml / min; UV detection: 210 nm.

Method 5 (LC-MS):

Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 210 nm.

Method 6 (LC-MS):

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 208-400 nm.

Method 7 (LC-MS):

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 100 x 4.6 mm; Eluent A: water + 500 μl 50% formic acid / 1, eluent B: acetonitrile + 500 μl 50% formic acid / 1; Gradient: 0.0 min 10% B → 7.0 min 95% B → 9.0 min 95% B; Oven: 35 ^° C; Flow: 0.0 min 1.0 ml / min → 7.0 min 2.0 ml / min → 9.0 min 2.0 ml / min; UV detection: 210 nm.

Method 8 (LC-MS):

Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3μ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min -> 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 210 nm.

Method 9 (GC-MS):

Instrument: Micromass GCT, GC6890; Column: Restek RTX-35, 15 m × 200 μm × 0.33 μm; constant flow with helium: 0.88 ml / min; Oven: 70 ^° C; Inlet: 250 ^° C; Gradient: 7O ⁰ C, 30 ° C / min → 310 ⁰ C (hold for 3 min).

Method 10 (GC-MS):

Instrument: Micromass GCT, GC6890; Column: Restek RTX-35MS, 30 m × 250 μm × 0.25 μm; constant flow with helium: 0.88 ml / min; Oven: 60 ^° C; Inlet: 250 ^° C; Gradient: 60 ⁰ C (0.30 min hold), 50 ° C / min → 120 ⁰ C, 16 ° C / min → 25O ⁰ C, 30 ° C / min → 300 ⁰ C (1.7 min hold). Method 11 (GC-MSV

Instrument: Micromass GCT, GC6890; Column: Restek RTX-35, 15 m × 200 μm × 0.33 μm; constant flow with helium: 0.88 ml / min; Oven: 70 ^° C; Inlet: 250 ^° C; Gradient: 70 ⁰ C, 30 ° C / min → 310 ⁰ C (12 min hold).

Method 12 (LC-MSV

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Gemini 3μ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 208-400 nm.

Method 13 (LC-MS):

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Onyx Monolithic C18, 100 mm x 3 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2 min 65% A → 4.5 min 5% A -> 6 min 5% A; Flow: 2 ml / min; Oven: 40 ^° C; UV detection: 208-400 nm.

Starting compounds and intermediates:

Example IA

3-nitrophenoxy-methyl acetate

50 g (359.4 mmol) of 3-nitrophenol and 175.67 g (539 mmol) of cesium carbonate are initially charged in 1.0 liter of acetone and admixed with 71.5 g (467.3 mmol) of methyl bromoacetate. The mixture is stirred for 1 h at 50 ⁰ C and poured after cooling to 7.5 liters of water. The suspension is stirred for 30 minutes, then filtered with suction and the filter residue washed with water. The solid is dried in a drying oven at 50 ^° C. and 100 mbar. This gives 64.3 g (84.7% of theory) of the target compound.

HPLC (Method 1): R, = 4.07 min

MS (DCI): m / z = 229 (M + NH,) ^*

¹ H-NMR (300 MHz, CDCl _3): δ = 7.90 (dd, IH), 7:43 (t, IH), 7:48 (t, IH), 7.28 (dd, IH), 4.75 (s, 2H), 3.86 (s, 3H).

Example 2A

3-aminophenoxy-methyl acetate

To 13 g (61.6 mmol) of methyl 3-nitrophenoxyacetate in 150 ml of methanol, 1.3 g of palladium on activated carbon (10%) are added under argon. The mixture is stirred for 18 h at RT under a hydrogen atmosphere (atmospheric pressure). The catalyst is filtered through kieselguhr and the filtrate is concentrated in vacuo. After drying in a high vacuum, 10.7 g (95.9% of theory) of the target compound are obtained.

HPLC (method 2): R ₁ = 2.81 min MS (DCI): m / z = 199 (NH-NHO ⁺ , 182 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 7:10 to 7:02 (m, IH), 6:35 to 6:23 (m, 2H), 4:58 (s, 2H), 3.79 (s, 3H), 3.65 (br. s, 2H).

Example 3A

2-amino-4,5-diphenyl-3-furonitrile

100 g (470 mmol) of benzoin, 62.25 g (940 mmol) of malononitrile and 47.68 g (470 mmol) of triethylamine are stirred overnight at RT in 1345 ml of DMF. Another 41 g (620 mmol) of malononitrile are added and the mixture is stirred again for 24 h at RT. Thereafter, ethyl acetate and water are added, and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated in vacuo. After column chromatography on silica gel (eluent: dichloromethane → dichloromethane / methanol 98: 2), 120 g (97.9% of theory) of the target product are obtained as a yellowish solid.

HPLC (method 2): R _t = 4.68 min

MS (DCI): m / z = 278 (MJ-NHt) ⁺ , 261 (M + H) ⁺ .

Example 4A

5,6-Diphenylfuro [2,3-d] pyrimidin-4 (3H) -one

To 57 ml of acetic anhydride 28.5 ml of formic acid are added dropwise at 0 ⁰ C. The mixture is stirred for 30 min at 0 ⁰ C and then added 10.0 g (40 mmol) of 2-amino-4,5-diphenyl-3-furonitrile. The cooling is removed and the mixture is refluxed overnight. After cooling, a little diethyl ether is added and the precipitated solid is filtered off with suction. The residue is washed with diethyl ether and dried under high vacuum. This gives 6 g (52.2% of theory) of the target product.

HPLC (method 2): R ₁ = 4.40 min

MS (DCI): m / z = 306 (M + NR, ^, 289 (M + H) ⁺ .

Example 5A

4-chloro-5,6-diphenylfüro [2,3-d] pyrimidine

570 ml of phosphorus oxychloride are added to 57 g (200 mmol) of 5,6-diphenylfuro [2,3-d] pyrimidin-4 (3H) -one. The mixture is stirred at reflux for 3 h, then cooled and concentrated in vacuo. The residue is stirred for 30 min with ice water and then treated with dichloromethane. The resulting organic phase is washed three times with water, dried over sodium sulfate and concentrated in vacuo. 58 g (93.2% of theory) of the target product are obtained.

ΗPLC (Method 1): R _t = 5.26 min

MS (DCI): m / z = 324 (M + N + ₄ ) ⁺ , 307 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 8.78 (s, IH), 7.62-7.58 (m, 2H), 7:55 to 7:42 (m, 5H), 7:38 to 7:30 (m, 3H).

Example 6A

(4-methoxyphenyl) [(trimethylsilyl) oxy] acetonitrile

Analogously to the literature [J. Chem. Soc. Perkin Trans. I, 1992, 2409-2417] is added to a mixture of 290.0 g (2130 mmol) of 4-methoxybenzaldehyde and 1156 g (3.622 mmol) of zinc iodide in 37.5 liters of benzene at RT while cooling within about 5 min a solution of Add 221.88 g (2236 mmol) of trimethylsilyl cyanide in 25 liters of benzene. The mixture is stirred for 90 min at RT and then concentrated in vacuo. The residue is purified by column filtration on silica gel (mobile phase: cyclohexane / ethyl acetate 4: 1). 442.4 g (88.3% of theory) of the target compound are obtained.

HPLC (Method 2): R, = 3.76 min

MS (DCI): m / z = 253 (M + NH ^

¹ H-NMR (400 MHz, CDCl _3): δ = 7:49 (d, 2H), 6.92 (d, 2H), 5:42 (s, IH) 3.81 (s, 3H).

Example 7A

2-hydroxy-1- (4-methoxyphenyl) -2-phenylethanone

According to the literature [J. Chem. Soc. Perkin Trans. I, 1992, 2409-2417], 292 ml (2.08 mol) of diisopropylamine are dissolved in 3.6 liters of 1,2-dimethoxyethane and cooled to -78 ° C. 826 ml of n-butyllithium solution (2.5 M in n-hexane, 2.066 mol) are added below -60 ° C. The mixture is stirred for 15 min at <-60 ° C and then added dropwise a solution of 442 g (1.877 mol) of (4-methoxyphenyl) [(trimethylsilyl) oxy] acetonitrile in 1.41 liters of 1,2-dimethoxyethane at <-60 ⁰ C. , After further stirring for 30 min at -60 ⁰ C, a solution of 199.3 g (1.878 mol) of benzaldehyde in 1.4 liters of 1,2-dimethoxyethane within 20 min at -60 ⁰ C is added. The reaction mixture is then warmed slowly to RT over 4 h. Add 7 liters of saturated ammonium chloride solution and extract with ethyl acetate. The organic phase is washed with saturated ammonium chloride solution, dried and concentrated in vacuo. The residue is taken up in 7 liters of dioxane and 5 liters of methanol and treated with 6 liters of 1 N hydrochloric acid. The mixture is stirred for 3 h at RT, then 3 liters of saturated sodium chloride solution are added and the mixture is extracted with 6.5 liters of ethyl acetate. The organic phase is washed with 1.0 liter of 1 N sodium hydroxide solution and with saturated sodium chloride solution, dried and concentrated in vacuo. The residue is taken up in 2 liters of diisopropyl ether, decanted from the insoluble material and seeded with crystals. The resulting suspension is stirred for 2 h at RT and the crystals are then filtered off with suction. It is washed with 300 ml of diisopropyl ether and petroleum ether and dried in vacuo. 236.8 g (47.8% of theory) of the target compound are obtained.

HPLC (Method 2): R, = 4.23 min

MS (DCI): m / z = 260 (M + NH,) ^* , 243 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 7.92 (d, 2H), 7:38 to 7:28 (m, 5H), 6.88 (d, 2H), 5.90 (d, IH), 4.64 (d, IH) , 3.82 (s, 3H).

Example 8A

2-Amino-4- (4-methoxyphenyl) -5-phenyl-3-furonitrile

236 g (974 mmol) of 2-hydroxy-1- (4-methoxyphenyl) -2-phenylethanone and 83.66 g (1266 mmol) of malononitrile are dissolved in 470 ml of DMF and admixed with ice bath cooling with 86.6 ml (836.7 mmol) of diethylamine. After 1 h, the mixture is warmed to RT and stirring is continued for 4 h at RT, before 2.5 liters of water and some seed crystals are added. After 30 minutes, supernatant water is decanted off and replaced by 1.25 liters of fresh water. The suspension is mixed and supernatant water is decanted again. The sticky crystalline residue is taken up in ethyl acetate and then almost completely concentrated in vacuo. The residue is stirred with 730 ml of diisopropyl ether and the suspension is left at RT overnight. The solid is then filtered off with suction and dried in vacuo. 211.5 g (57.6% of theory) of the title compound are obtained.

HPLC (Method 2): R, = 4.60 min

MS (DCI): m / z = 308 (M + NH 2, 291 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.39-7.33 (m, 5H), 7.28-7.18 (m, 3H), 6.93 (d, 2H), 5.02 (s, 2H), 3.85 (s, 3H). Example 9A

5- (4-methoxyphenyl) -6-phenylfLiro [2,3-d] pyrimidin-4 -one (3H)

800 ml (21.21 mol) of formic acid are added dropwise at ⁰ ° C. to 1600 ml (16.96 mol) of acetic anhydride. The mixture is stirred at 0 ^° C. for 30 minutes and then 211 g (727 mmol) of 2-amino-4- (4-methoxyphenyl) -5-phenyl-3-furonitrile are added. The cooling is removed and the mixture is heated; At about 80 ⁰ C begins gas evolution, which ceases after about 3 h. The mixture is stirred for a total of 24 h under reflux (bath temperature about 13O ⁰ C). After cooling to RT, the mixture is stirred for 2 h at 10 ⁰ C and the resulting solid was filtered off. The residue is washed with diethyl ether and dried under high vacuum. There are obtained 135.6 g (58.6% of theory) of the title compound.

HPLC (Method 2): R, = 4.38 min

MS (DCI): m / z = 336 (M + NH,) ⁺ , 319 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 10.3 (br.s, IH), 7.95 (s, IH), 7.58-7.53 (m, 2H), 7.47 (d, 2H), 7.33-7.27 ( m, 3H), 6.95 (d, 2H), 3.86 (s, 3H).

Example IQA

4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine

135 g (424 mmol) of 5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4 (3H) -one are added at RT in

Suspended 675 ml (7241 mmol) of phosphorus oxychloride and then the mixture is heated to boiling (ΗCl evolution). After 1 h, the dark solution is cooled to RT and vigorously stirred mixture of 2.25 liters of water and 4.05 liters of conc. Ammonia solution (25 wt .-%) added dropwise (heating to 55-75 ° C, pH> 9). After the end of the addition, the mixture is cooled to RT and the mixture extracted three times with 1.0 liter of dichloromethane. The combined organic phases are dried and concentrated in vacuo. The residue is stirred with diethyl ether, filtered off with suction and dried under high vacuum. There are obtained 134.4 g (94.1% of theory) of the title compound.

HPLC (Method 2): R, = 4.96 min

MS (DCI): m / z = 354 (M + NPL,) ^* , 337 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 8.76 (s, IH), 7.62 (d, 2H), 7:40 to 7:30 (m, 5H), 7:03 (d, 2H), 3.90 (s, 3H) ,

Example IIA

2-amino-5-phenyl-3-furonitrile

68.6 ml (663 mmol) of diethylamine are added dropwise at RT to a mixture of 60.0 g (301 mmol) of bromoacetophenone and 25.89 g (391.86 mmol) of malononitrile in 130 ml of DMF (cooling is necessary to maintain the temperature). Towards the end of the addition, the cooling is removed, the

Stirred mixture for 1 h at RT and then added to 385 ml of water. It comes with another 125 ml

Water diluted and stirred for 20 min at RT. The precipitated solid is filtered off with suction, washed twice with 125 ml of water each time, filtered off with suction and washed with petroleum ether. The residue is dried under high vacuum. There are 33.3 g (50.1% of theory) of the target compound as a yellow-brown

Received crystals.

HPLC (Method 2): R, = 4.27 min

MS (DCI): m / z = 202 (M + NH,) ⁺ , 185 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 7:51 to 7:45 (m, 2H), 7:39 to 7:32 (m, 3H), 6:54 (s, IH), 4.89 (br s, IH.).

Example 12A

6-phenylfuro [2,3-d] pyrimidin-4 (3H) -one

To 884.9 ml (9.378 mol) of acetic anhydride at 0 ⁰ C 424.5 ml (11.25 mol) was added dropwise formic acid. The mixture is stirred for 30 min at 0 ⁰ C and then added 69.1 g (0.375 mol) of 2-amino-5-phenyl-3-furonitrile. The cooling is removed and the mixture is heated; At about 80 ⁰ C begins gas evolution, which ceases after about 3 h. The mixture is stirred for a total of 24 h under reflux (bath temperature about 130 ⁰ C). After the suspension has cooled to RT, 750 ml of diisopropyl ether are added, the mixture is cooled to 0 ^° C. and filtered off. The residue is washed with diisopropyl ether and dried under high vacuum. Obtained are 50.83 g (58.7% of theory) of the target compound as a brown solid.

HPLC (Method 2): R, = 3.92 min

MS: m / z = 213 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 12.68 (br.s, IH), 8.17 (s, IH), 7.88 (d, 2H), 7.52-7.48 (m, 3H), 7.42 -7.38 (m, IH).

Example 13A

4-chloro-6-phenylfuro [2,3-d] pyrimidine

50 g (235.6 mmol) of 6-phenylfuro [2,3-d] pyrimidin-4 (3H) -one are suspended at RT in 375 ml (4023 mmol) of phosphorus oxychloride and the mixture is heated to boiling (ΗCl evolution). After 1 h, the dark solution is cooled to RT and added to a vigorously stirred mixture of 1.25 liters of water and 2.25 liters of conc. Ammonia solution (25 wt .-%) added dropwise (heating to 55- 75 ° C, pH> 9). After the end of the addition, the mixture is cooled to RT and the mixture extracted three times with 1.6 liters of dichloromethane. The combined organic phases are dried and concentrated in vacuo. The residue is stirred with diethyl ether, filtered off with suction and dried under high vacuum. 47.3 g (87% of theory) of the target compound are obtained.

HPLC (Method 2): R _t = 4.67 min MS: m / z = 231 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO- (I ₆ ): δ = 8.84 (s, IH), 8.05 (m, 2H), 7.77 (s, IH), 7.61-7.50 (m, 3H).

Example 14A

2-amino-4-phenyl-3-furonitrile

3.78 ml (36.7 mmol) of diethylamine are added dropwise to a mixture of 10 g (73.4 mmol) of hydroxyacetophenone and 4.852 g (73.4 mmol) of malononitrile in 24 ml of DMF while cooling at RT. The dark mixture is stirred at RT for 2 h and then added slowly to water (200 mL) with stirring and cooling. The precipitate is stirred for 30 min at about 10 ⁰ C, filtered with suction, reslurried twice with water and again filtered with suction. The residue is dried under high vacuum to constant weight. 10.99 g (81.2% of theory) of the target compound are obtained as a yellow-brown solid.

LC-MS (Method 3): R, = 1.81 min .; m / z = 185 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-de): δ = 7.54 (d, 2H), 7.50 (s, 2H), 7.45-7.32 (m, 4H).

Example 15A

5-phenylfuro [2,3-d] pyrimidin-4 (3H) -one

108.5 ml (1154 mmol) of acetic anhydride are cooled to 0 ° C and under argon with 52.2 ml (1384 mmol) of formic acid. The mixture is stirred for about 45 min at 0 ⁰ C and then added 8.5 g (46.2 mmol) of 2-amino-4-phenyl-3-furonitrile in portions. The result is a dark mixture, which assumes a violet color after 15 min at 0 ⁰ C. The cooling is removed and the now blue suspension is heated to RT. After 15 min, the mixture is heated to reflux (bath temperature 125-130 ⁰ C), whereupon gas evolution begins. The mixture is stirred at reflux overnight. After cooling, the mixture is concentrated in vacuo and the residue dried in a high vacuum. From the crude product, about 3 g of a dark red to black solid are obtained by column filtration on silica gel (mobile phase gradient: dichloromethane → dichloromethane / methanol 50: 1). This is dissolved in about 8 ml of dichloromethane, precipitated with diisopropyl ether, filtered off with suction and dried under high vacuum. Obtained are 1.81 g (purity about 84%, yield about 15% of theory) of the target compound as a dark red solid.

LC-MS (Method 4): R _t = 3.2 min .; m / z = 211 (MH) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.7 (s, IH), 8.26 (s, IH), 8.19 (s, IH), 7.98 (d, 2H), 7.50-7.30 (m, 3H) ,

Example 16A

4-chloro-5-phenylfuro [2,3-d] pyrimidine

1.8 g (about 6.8 mmol) of 5-phenylfuro [2,3-d] pyrimidin-4 (3H) -one are admixed at RT with 9.5 ml (101.8 mmol) of phosphorus oxychloride and the mixture is refluxed for 1 h. The resulting black mixture is cooled to RT and carefully added dropwise at <10 ° C to a well-stirred, cooled to 0 ⁰ C solution of 70 ml of conc. Ammonia solution and 50 ml of water added dropwise (pH> 9). After the end of the addition, the black suspension is warmed to RT and stirred for a further 15 min. The black solid is filtered off, re-slurried three times with water, filtered off with suction again and dried under high vacuum. The solid is dissolved in dichloromethane and column-filtered on silica gel (eluent: dichloromethane). This gives 1371 mg (80.6% of theory) of the target compound as a yellow solid.

LC-MS (Method 5): R _t = 2.47 min .; m / z = 231 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.90 (s, IH), 8.49 (s, IH), 7.64-7.58 (m, 2H), 7.52-7.45 (m, 3H). Example 17A

3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} phenol

500 mg (1.49 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine, 654 mg (5.94 mmol) of resorcinol and 726 mg (2.23 mmol) of cesium carbonate in 10 ml of DMF 2 h heated to 120 ⁰ C. After cooling, the mixture is filtered off and the filtrate is purified directly by preparative HPLC. The resulting product is stirred with dichloromethane, filtered off, washed with dichloromethane and dried in vacuo. 171.4 mg (27% of theory) of the target product are obtained as a beige solid.

LC-MS (Method 5): R, = 2.78 min .; m / z = 411 (M + H) ⁺ .

Example 18A

3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} aniline

1000 mg (2.97 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine, 1296 mg (11.9 mmol) of 3-aminophenol and 615.6 mg (4.45 mmol) of potassium carbonate in 10 ml DMF are stirred for 8 h at 80 ⁰ C. After cooling, the mixture is concentrated under reduced pressure and the residue is taken up in water. It is filtered from the precipitated solid, washed the filter residue several times with water and the solid is dried at 50 ⁰ C in a high vacuum. 1195 mg (98.3% of theory) of the target product are obtained as a brownish solid.

LC-MS (Method 3): R, = 2.53 min .; m / z = 410 (M + H) ⁺ ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.53 (s, IH), 7.60-7.40 (m, 7H), 7.06-6.99 (m, 3H), 6.45 (dd, IH), 6.34- 6.27 (m, 2H), 6.25 (brs s, 2H), 3.80 (s, 3H).

Example 19A

2- (3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxy) acetamide

800 mg (1.66 mmol) of methyl 3 - {[5- (4-methoxyphenyl) -phenylmro [2,3-d] pyrimidin-4-yl] amino} phenoxyacetate (Example 9) are treated with ammonia at RT in methanol (14.2 ml of a ca. 7 M solution) and stirred overnight. The mixture is concentrated in vacuo, stirred with a little methanol and filtered with suction. The filter residue is washed downstream with diisopropyl ether and dried overnight at 50 ⁰ C in a high vacuum. 663 mg (86.5% of theory) of the target product are obtained as an almost white solid.

LC-MS (Method 3): R _t = 2.40 min .; m / z = 467 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO- (I ₆ ): δ = 8.54 (s, IH), 7.63-7.50 (m, 5H), 7.45-7.20 (m, 9H), 6.90 (s, IH), 6.81 (dd, IH), 6.64 (dd, IH), 4.41 (s, 2H), 3.90 (s, 3H).

Example 2OA

(3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxy) acetonitrile

800 mg (1.72 mmol) of 2- (3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxy) -acetic acid amide are dissolved in 5 ml of DMF cooled, cooled to 0 ⁰ C and treated with 316 mg (1.72 mmol) of cyanuric chloride. The mixture is stirred at 0 ^° C. for 2 h. Then water and ethyl acetate added. After phase separation, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed three times with buffer solution (pH 7), dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by chromatography on silica gel (eluent: dichloromethane / ethyl acetate 20: 1). 179 mg (22.3% of theory) of the target product are obtained as a white solid.

LC-MS (Method 3): R, = 2.84 min .; m / z = 449 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO-ds): δ = 8.57 (s, IH), 7.63-7.51 (m, 4H), 7.45-7.20 (m, 7H), 6.99 (s, IH), 6.89 (dd , IH), 6.28 (dd, IH), 5.65 (s, 2H), 3.90 (s, 3H).

Example 21A

3- (3-aminophenyl) -propanoic acid methyl ester hydrochloride

2000 mg (12.1 mmol) of 3- (3-aminophenyl) -propanoic acid are initially introduced into 30 ml of methanol, cooled to 0 ⁰ C and treated dropwise with 0.93 ml (12.7 mmol) of thionyl chloride. The mixture is slowly warmed to RT and stirred overnight. After concentration in vacuo, the residue is taken up in a little methanol. After addition of diisopropyl ether, the precipitated solid is filtered off with suction. 2450 mg (93.8% of theory) of the target product are obtained as a white solid.

LC-MS (Method 4): R, = 2.30 min .; m / z = 180 (M-Cl + H) ⁺

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 10.15 (br.s, ca. 3H), 7.42-7.38 (m, IH), 7.28-7.17 (m, 3H), 3.60 (s, 3H), 2.38 (t, 2H), 2.68 (t, 2H).

The free aniline is obtained by washing a solution (or suspension) of the hydrochloride in dichloromethane with saturated sodium bicarbonate solution and concentration in vacuo.

Example 22A

4- (4-aminophenyl) butanoic acid methylester hydrochloride

x HCl

700 mg (3.91 mmol) of 4- (4-aminophenyl) butanoic acid are initially charged in 7 ml of methanol, cooled to 0 ⁰ C and treated dropwise with 0.3 ml (4.1 mmol) of thionyl chloride. The mixture is slowly warmed to RT and stirred overnight. After concentration in vacuo, the residue is stirred in a little methanol and the resulting solid is filtered off with suction. 800.6 mg (89.2% of theory) of the target product are obtained as a white solid.

LC-MS (Method 5): R _t = 1.10 min .; m / z = 194 (M-CB-H) ⁺ .

Example 23A

4- (2-nitrophenyl) butanoic acid methylester

705 mg (3:37 mmol) of 4- (2-nitrophenyl) butanoic acid are initially charged in 7 ml of methanol, cooled to 0 ⁰ C and treated dropwise with 0:26 ml (3:54 mmol) of thionyl chloride. The mixture is slowly warmed to RT and stirred overnight. To complete the reaction, about 20% excess of thionyl chloride are added and the mixture is stirred at RT for a further 5 h. After concentration in vacuo, the residue is stirred in a little methanol and the resulting solid is filtered off with suction. 700 mg (95.5% of theory) of the target product are obtained as a white solid.

LC-MS (method 5): R _t = 2.34 min .; m / z = 224 (M + H) ⁺ .

Example 24A

4- (2-aminophenyl) butanoic acid methylester

715 mg (3.2 mmol) of methyl 4- (2-nitrophenyl) butanoate are initially charged in 1.5 ml of ethanol, combined with 34 mg of palladium on charcoal (10%) under argon and stirred at RT under a hydrogen atmosphere (normal pressure) overnight. To complete the reaction, palladium on charcoal is added again and the mixture is stirred for a further 24 h at RT under a hydrogen atmosphere. It is filtered from the catalyst and the solution is concentrated in vacuo. This gives 229 mg (37.1% of theory) of the target product.

LC-MS (Method 5): R, = 1.67 min .; m / z = 194 (M + H) ⁺ .

Example 25A

2- (3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenyl) acetic acid hydrazide

To 100 mg (0.215 mmol) of methyl 3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenylacetate (Example 28), dissolved in 1.5 ml THF and 2 ml of methanol are added at RT 215 mg (4.3 mmol) of hydrazine hydrate. The mixture is stirred for 1 h at 65 ° C and overnight at RT and then concentrated in vacuo. After stirring with diisopropyl ether, the solid is filtered off with suction and dried in vacuo. 89.3 mg (89.3% of theory) of the target product are obtained.

LC-MS (Method 3): R, = 2.16 min .; m / z = 466 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 9.20 (s, IH), 8.51 (s, IH), 7.62-7.51 (m, 4H), 7.43-7.36 (m, 3H), 7.30- 7.20 (m, 5H), 6.95 (d, IH), 6.89 (s, IH), 4.24 (br, s, 2H), 3.89 (s, 3H). General Procedure A: Reaction of amines with 4-chlororforor2,3-dlpyrimidine derivatives

A mix of 1.0 eq. 4-Chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine, 1.0 to 1.4 eq. Amine component and 1.5 to 3.0 eq. DIEA is stirred in DMF (concentration 0.5 to 1.5 mol / l) at 80-140 ⁰ C for 1-24 h. After cooling, the DMF is removed in vacuo and the residue treated with water. It is extracted with dichloromethane, the organic phase is washed with saturated sodium bicarbonate and sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. From the crude product the target compound can be obtained by crystallization from alcoholic solvents (eg methanol), by chromatography on silica gel (preferred eluant systems are dichloromethane / methanol and cyclohexane / ethyl acetate), by preparative RP-HPLC (eluent: water / acetonitrile) or by a combination of these Methods are isolated and purified.

General Procedure B: Reaction of alcohols with 4-chlorofuroF2.3-d1pyrimidine derivatives

To a mix of 1.0 eq. 4-Chloro-5- (4-methoxyphenyl) -6-phenyl-pent [2,3-d] pyrimidine and 1.0 to 1.5 eq. Alcohol component in THF or DMF (or mixtures thereof, concentration 0.2 to 1.0 mol / 1) at 0 ⁰ C to RT, a solution of 1.0 to 1.5 eq. Phosphazene base P2-t-Bu in THF (about 2 mol / l) [Fa. Fluka, Art. 79416] or phosphazene base P4-t-Bu in cyclohexane (about 1 mol / l) [Fa. Fluka, Art. 79421] dropped. The mixture is stirred for 30 min to 6 h at RT. It is then diluted with dichloromethane or ethyl acetate and worked up with water. The organic phase is washed with 1 N hydrochloric acid, saturated sodium bicarbonate solution and / or sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. From the crude product the target compound can be obtained by crystallization from alcoholic solvents (eg methanol), by chromatography on silica gel (preferred eluant systems are dichloromethane / methanol and cyclohexane / ethyl acetate), by preparative RP-HPLC (eluent: water / acetonitrile) or by a combination of these Methods are isolated and purified.

The following compounds are prepared according to the general procedure A or B starting from 4-chloro-5- (4-methoxyphenyl) -6-phenyl-pent [2,3-d] pyrimidine and the corresponding amines or alcohols:

(S,

Example 32A

(+/-) - c / ₁ y / frαn5-3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexanol

Dissolve 1,552 g (13.36 mmol) of 1,3-cyclohexanediol (c / 5 // rα 5 mixture) in 12 ml of absolute THF, cool to 0 ⁰ C and add 13.36 ml of phosphazene base P2-t-Bu in THF (about 2 M solution). After the addition is about 10 min at RT, then cooled again to 0 ⁰ C and 3.0 g (8.91 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine in

Portions added. The reaction mixture is stirred for 1 h at RT, added to water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.

The residue is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1 → 1: 1). Obtained 3.02 g (81% of theory) of the target compound.

LC-MS (Method 3):

Isomer 1 R, = 2.52 min .; m / z = 417 (M + H) ⁺ , isomer 2 R ₁ = 2.55 min .; m / z = 417 (M + H) ⁺ .

The separation of the thus obtained c / s / fraMs isomer mixture is carried out by means of HPLC [eluent: water / acetonitrile 1: 1; Kromasil column 100 C 18, 250 mm x 20 mm; Flow: 25 ml / min; UV detection: 210 nm; Temperature: 30 ^° C]. 2.0 g isomer mixture, dissolved in 35 ml of THF and about 15 ml of water, in several injections (injection volume about 1 ml) are added. Obtained are 750 mg of (+/-) - c / 5-3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexanol (Example 33A) and 640 mg of (+/-) - / raws-3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} -cyclohexanol (Example 34A).

Example 33A

(+/-) - ci5-3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexanol

LC-MS (Method 5): R, = 2.86 min .; m / z = 417 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.57 (s, IH), 7.53 (m, 2H), 7.42-7.37 (m, 5H), 7.0 (d, 2H), 5.11 (m, IH), 4.69 (d, IH), 3.83 (s, 3H), 2.27 (d, IH), 2.01 (d, IH), 1.79 (d, IH), 1.62-1.68 (m, IH), 1.30-1.05 (m, 4H).

Example 34A

(+/-) - / rα «5-3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexanol

LC-MS (Method 5): R _t = 2.88 min .; m / z = 417 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d "): δ = 8.58 (s, IH), 7.54 (d, 2H), 7.42-7.39 (m, 5H), 7.04 (d, 2H), 5.59 (m, IH), 4.42 (d, IH), 3.82 (s, 3H), 3.48 (m, IH), 1.90-1.82 (m, IH), 1.62-1.45 (m, 5H), 1.25- 1.15 (m, 2H) ,

Example 35A

(+/-) - all-cis-5- {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexane-1,3-diol

Dehydration of α // - cw-l, 3,5-cyclohexanetriol dihydrate: α // - ml, 3,5-cyclohexanetriol dihydrate is dissolved in DMF at 70 ⁰ C. In vacuo, the volatile components are removed and the residue dried under high vacuum.

0.81 g (6.12 mmol) of α // c / sl, 3,5-cyclohexanetriol are dissolved in 15 ml of DMF, cooled to 0 ^° C. and dissolved in portions with 245 mg of sodium hydride (about 60% dispersion in oil, approx 6.12 mmol). The suspension is stirred for 1 h at room temperature and about 2.5 h at 40-50 ⁰ C. After cooling to RT, 1.376 g (4.09 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine are added and the mixture is stirred at RT overnight. Carefully add the reaction mixture to water. After saturation with sodium chloride, it is extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (mobile phase: dichloromethane / methanol 30: 1 → 4: 1). Obtained are 1.38 g (77.8% of theory) of the target compound.

LC-MS (Method 3): R _t = 2.04 min .; m / z = 433 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.59 (s, IH), 7.55 (m, 2H), 7.46-7.40 (m, 5H), 7.02 (d, 2H), 5.61 (m , IH), 4.74 (d, 2H), 3.84 (s, 3H), 3.58-3.49 (m, 2H), 2.27-2.20 (m, 2H), 2.05 (d, IH), 1.06 (q, 3H).

General Procedure C: Cleavage of Boc protecting groups

To a solution of Boc-protected amine in dichloromethane (concentration 0.1 to 1.5 mol / 1, possibly with a few drops of water) are added dropwise at 0 ⁰ C to RT 0.5-1.0 parts by volume of TFA (resulting in a dichloromethane / TF A ratio of about 2: 1 to 1: 1). The mixture is for one

Stirred from 30 min to 18 h at RT. After dilution with dichloromethane, it is washed with saturated sodium carbonate or sodium bicarbonate solution. The organic phase is dried over magnesium or sodium sulfate and concentrated in vacuo. Optionally, further purification of the amine by preparative HPLC or chromatography on

Silica gel (eluent: dichloromethane / methanol) take place. The following compounds are prepared according to General Procedure C starting from compounds 26A-31A:

Example 42A

(+/-) - c / s - {[3-hydroxycyclohexyl] oxy} acetic acid tert-butyl ester terΛ

Dissolve 5.0 g (43 mmol) of cw / fr <3 "5-l, 3-cyclohexanediol (about 1.2: 1 cis / trans mixture) in 20 ml of absolute THF and add dropwise at RT with 24.8 ml (about 49.5 mmol ) Phosphazene base P2-t-Bu in THF (about 2 M solution). The solution is stirred for 30 min at RT and then added dropwise to a mixture of 9.5 ml (64.6 mmol) of bromoacetic acid tert-butyl ester and 10 ml of THF. The mixture is stirred overnight at RT, then diluted with dichloromethane, the organic phase is washed successively with 1 N hydrochloric acid, buffer solution (pH 7) and sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product is separated by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1 -> 1: 1). The pure fraction is 2.73 g (27.6% of theory) of the c / s-conjugated target compound.

MS (DCI): m / z = 248 (M + NH,) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 4.59 (d, IH), 3.95 (s, 2H), 3.38-3.21 (m, 2H), 2.20-2.12 (m, IH), 1.89 (d, IH), 1.74 (d, IH), 1.66-1.60 (m, IH), 1.41 (s, 9H), 1.14-0.95 (m, 4H).

Example 43A

(+/-) - trans - {[3-aminocyclohexyl] oxy} -acetic acid-tert. butyl

Stage a):

500 mg (2.17 mmol) (+/-) - c / s - {[3-hydroxycyclohexyl] oxy} -acetic acid tert. butyl ester and 0.907 ml (6.51 mmol) of triethylamine are dissolved in 2 ml of dichloromethane and cooled to 0 ⁰ C. Dropwise, 0.20 ml (2.61 mmol) of methanesulfonyl chloride are added. The mixture is stirred for 1 h at 0 ⁰ C and then added to water. The organic phase is separated and the aqueous extracted with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. There are obtained 690 mg of mesylate, which is further reacted directly. Stage b):

690 mg of the mesylate obtained above are dissolved at RT in 2 ml of DMF and admixed with 873 mg (13.4 mmol) of sodium azide. The suspension is stirred vigorously overnight at 60 ^° C. and then added to water after cooling. It is extracted three times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried on magnesium sulfate and concentrated in vacuo. There are 416 mg of the azide obtained as a yellowish oil, which is reacted directly.

Stage c):

418 mg of the azide obtained above are dissolved in 1.8 ml of ethanol and 0.2 ml of water, treated with palladium on charcoal and stirred for 2 h at RT under a hydrogen atmosphere (atmospheric pressure). The catalyst is removed by filtration through kieselguhr, the filtrate is concentrated under reduced pressure and the residue is dried under high vacuum. There are obtained 456 mg of the title compound, which is used without further purification.

Example 44A

(+/-) - c / Vfrα "5-3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexanol

1.0 g (2.97 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine and 513 mg (about 4.5 mmol) (+/-) are dissolved in 2.7 ml of DMF. 3-cis / trans mixture prepared according to J. Chem. Soc., Perkin Trans., 1994, 537). After adding 1.03 ml (5.94 mmol) DIEA the mixture for 2 h heated to 120 ⁰ C. After cooling, it is poured onto ice-water. The precipitated solid is filtered off, washed with water and dried in vacuo. The crude product is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 2: 1 → 1: 2). 1.05 g (85.1% of theory) of the target product are obtained as cw / fraHS mixture.

LC-MS (Method 6): R _t = 2.53 min .; m / z = 416 (M + H) ⁺ . Example 45A

(+/-) - c / 5-3 - [(6-phenylfuro [2,3-d] pyrimidin-4-yl) amino] cyclohexanol

A mixture of 4.0 g (17.34 mmol) of 4-chloro-6-phenylfuro [2,3-d] pyrimidine, 4.5 ml (26 mmol) of DIEA and 2.8 g (+/-) - c / s / oil. 3-Aminocyclohexanol (about 85%, about 20.8 mmol, about 3: 1 cis / trans mixture, prepared according to J. Chem. Soc., Perkin Trans. I, 1994, 537) in 15 ml of DMF is about Heated to 120 ⁰ C overnight. After cooling, the reaction mixture is added to water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. By repeated stirring of the crude product with a mixture of methyl tert-butyl ether and dichloromethane, the product is enriched in the mother liquor. After concentrating the mother liquor, the product is filtered off with suction after crystallization from dichloromethane / methanol (10: 1) and dried in vacuo. This gives 1.11 g (20.7% of theory) of the target product.

LC-MS (Method 6): R, = 1.95 min .; m / z = 310 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.25 (s, IH), 7.88-7.72 (m, 3H), 7.55-7.47 (m, 2H), 7.46-7.38 (m, 2H), 4.71 (d, IH), 4.11-4.01 (m, IH), 3.59-3.47 (m, IH), 2.19 (d, IH), 1.96-1.19 (m, 3H), 1.36-1.05 (m, 4H).

Example 46A

(+/-) - cw - ({3 - [(6-phenylfuro [2,3-d] pyrimidin-4-yl) -amino] -cyclohexyl} oxy) -acetic acid tert -butyl ester

To a mixture of 517 mg of 50% sodium hydroxide solution (6.5 mmol) and 0.5 ml of toluene at 40 ⁰ C about 0.06 mmol of tetrabutylammonium hydrogen sulfate and a solution of 200 mg (0.646 mmol) (+/-) - c / j-3 - Added [(6-phenylfuro [2,3-d] pyrimidin-4-yl) amino] cyclohexanol in 0.5 ml of toluene and 0.1 ml of THF. The resulting mixture is introduced under vigorous stirring 0.19 ml (1.29 mmol) of bromoacetic acid-TEA '/.- offset butyl ester and heated to 70 ⁰ C. After 2 hours, the mixture is cooled and added to water. It is extracted three times with dichloromethane, the combined organic phases are washed with saturated sodium chloride solution and concentrated in vacuo. 152 mg (55.5% of theory) of the target product are isolated from the crude product by preparative RP-HPLC (eluent: acetonitrile / water).

LC-MS (Method 6): R, = 2.87 min .; m / z = 424 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.26 (s, IH), 7.89-7.78 (m, 3H), 7.51 (t, 2H), 7.45-7.39 (m, 2H), 4.17 -4.05 (m, IH), 4.01 (s, 2H), 3.49-3.40 (m, IH), 2.33 (br d, IH), 2.01 (br d, IH), 1.91 (br d, IH) , 1.81-1.75 (m, IH), 1.42 (s, 9H), 1.34-1.10 (m, 4H).

Example 47A

(+/-) - c / 5 - ({3 - [(5-Bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) -amino] -cyclohexyl} oxy) -acetic acid tert -butyl ester

132 mg (0.312 mmol) of (+/-) - m - ({3 - [(6-phenyl-furo [2,3-d] pyrimidin-4-yl) -amino] -cyclohexyl-oxy) -acetic acid tert. butyl ester are suspended in 0.3 ml of tetrachloromethane, admixed with 61 mg (0.343 mmol) of NBS and heated to reflux. After complete conversion (about 1 h), the reaction mixture is cooled and the product is isolated directly by preparative RP-HPLC. 104 mg (66.4% of theory) of the target compound are obtained.

LC-MS (Method 5): R, = 3.36 min .; m / z = 502, 504 (M + H) ⁺

¹ H NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.34 (s, IH), 8.01 (d, 2H), 7.60-7.49 (m, 3H), 7.08 (br d, IH), 4.42- 4.25 (m, IH), 4.09 (s, 2H), 3.65-3.58 (m, IH), 2.11 (br d, IH), 1.81-1.68 (m, 4H), 1.65-1.47 (m, 2H), 1.43 (s, 9H), 1.41-1.30 (m, IH). Example 48A

(+/-) - c / 5 - ({3 - [(5-Phenylnαro [2,3-d] pyrimidin-4-yl) oxy] cyclohexyl} oxy) acetic acid ter-butyl ester /.-

500 mg (2.17 mmol) of (+/-) - m - {[3-hydroxycyclohexyl] oxy} acetic acid-fert.-butyl ester are dissolved in 2.0 ml of dry THF, cooled to 0 ⁰ C and treated with 1.24 ml (ca. 2.5 mmol) of a 2 N solution of phosphazene base P2-t-Bu in THF. After removal of the cooling, the mixture is stirred for 30 min at RT before 500.7 mg (2.17 mmol) of 4-chloro-5-phenylfuro [2,3-d] pyrimidine are added at RT. The mixture is stirred overnight at RT and then concentrated in vacuo. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1 → 8: 1). The target product is obtained after further purification by means of RP-HPLC (eluent: acetonitrile / water). 380 mg (41.2% of theory) are isolated.

LC-MS (Method 3): R, = 2.89 min .; m / z = 425 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.61 (s, IH), 8.35 (s, IH), 7.27 (d, 2H), 7.49-7.39 (m, 3H), 5.25 (m, IH), 3.99 (s, 2H), 3.47 (m, IH), 2.12 (br s, IH), 1.99 (br d, IH), 1.32-1.26 (m, IH), 1.41 (s, 9H) , 1.40-1.12 (m, 5H).

Example 49A

(+/-) - cϊ5 - ({3 - [(6-bromo-5-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] cyclohexyl} oxy) acetic acid / erΛ-butyl ester

100 mg (0.236 mmol) (+/-) - cύ - ({3 - [(5-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] cyclohexyl} oxy) - acetic acid tert. butyl ester are suspended in 0.2 ml of tetrachloromethane and treated with 46.1 mg (0.259 mmol) NBS. The reaction mixture is stirred for a total of 2 hours at 60 ^° C., after which additional 23 mg of NBS are added after 1 hour. After cooling, the carbon tetrachloride is removed in vacuo and the residue is purified by preparative RP-HPLC (eluent: acetonitrile / water). 43.6 mg (36.8% of theory) of the target product are obtained.

LC-MS (Method 5): R ₁ = 3.31 min .; m / z = 503, 505 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.59 (s, IH), 7.62 (d, 2H), 7.53-7.43 (m, 3H), 5.15 (m, IH), 3.98 (s , 2H), 3.41 (m, IH), 2.45 (br d, IH), 2.04 (br d, IH), 1.95 (br d, IH), 1.41 (s, 9H), 1.30 - 1.06 (m , 5H).

Example 5OA

(4-ethylphenyl) [(trimethylsilyl) oxy] acetonitrile

600 g (4.47 mol) of 4-ethylbenzaldehyde are mixed in 5.3 liters of toluene with 2.4 g (7.5 mmol) of zinc iodide. At room temperature, 587.4 ml (4.7 mol) of trimethylsilyl cyanide, dissolved in 3.6 liters of toluene, are added over about 5 minutes under gentle cooling. The mixture is stirred for 90 min at RT, before volatile components are removed in vacuo and the residue is chromatographed rapidly on silica gel (eluent: petroleum ether / ethyl acetate 9: 1). 990 g (94.9% of theory) of the title compound are obtained as a colorless oil.

¹ H-NMR (400 MHz, CDCl _3): δ = 7.38 (d, 2H), 7.23 (d, 2H), 4.97 (s, IH), 2.68 (q, 2H), 1.25 (t, 3H), 0:23 (s, 9H).

Example 51A

l- (4-ethylphenyl) -2-hydroxy-2-phenylethanone

290 ml (2.069 mol) of diisopropylamine are dissolved in 3.6 liters of DME and pre-cooled to -78 ° C.

820 ml (2:05 moles) of n-butyllithium (2.5 M solution in hexane) within 20 min of about conces- dropwise (temperature <-60 ⁰ C). After 15 min at -60 ⁰ C a solution of 435 g (1.864 mol) of 4- ( Ethylphenyl) [(trimethylsilyl) oxy] acetonitrile in 1.4 liters of DME added dropwise (temperature <-60 ⁰ C). The mixture is stirred for 30 min at -60 ⁰ C before a solution of 189.5 ml (1.864 mol) of benzaldehyde in 1.4 liters of DME is added (duration about 20 min, temperature -60 ⁰ C). The mixture is warmed to RT over 4 h, before 7 liters sat. Ammonium chloride solution can be added. The reaction mixture is extracted with ethyl acetate. After phase separation, the organic phase is washed with sat. Washed with ammonium chloride solution, dried and concentrated in vacuo. The residue is dissolved in 7 liters of dioxane and 5 liters of methanol and 6 liters

I hydrochloric acid added. The mixture is stirred overnight at rt before addition of

I 1 liter sat. Sodium chloride solution is extracted with 6.5 liters of ethyl acetate. The organic phase is washed with water and with sat. Sodium chloride solution, dried and concentrated in vacuo. The residue is dissolved in 2 liters of diisopropyl ether, treated with seed crystals and stirred for 2 h. The precipitated solid is filtered off, washed with 300 ml of diisopropyl ether and petroleum ether and dried in vacuo. The mother liquor is concentrated, and after storage for 2 days at 4 ° C is again filtered with suction from the precipitated solid, washed with about 100 ml of diisopropyl ether and petroleum ether and dried in vacuo. Both solids are combined to give 154.9 g (34% of theory) of the target product.

HPLC (Method 1): R, = 4.55 min.

MS (DCI): m / z = 258 (M + NH,) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 7.85 (d, 2H), 7:48 to 7:35 (m, 5H), 7.21 (d, 2H), 5.92 (d, IH), 4:59 (d, IH) , 2.65 (q, 2H), 1.20 (t, 3H).

Example 52A

2-Amino-4- (4-ethylphenyl) -5-phenyl-3-furonitrile

A mixture of 145 g (603 mmol) l- (4-ethylphenyl) -2-hydroxy-2-phenyl-ethanone and 51.8 g (784.4 mmol) of malononitrile in 23.2 liters of DMF is cooled to 0 ⁰ C and under cooling with

53.7 ml (518 mmol) of diethylamine were added. After 1 h, the reaction mixture is warmed to RT and stirred for a further 4 h before 1.5 liters of water are added. After 30 min, a large part decanted from the water and replaced with 750 ml of fresh water. The mixture is stirred vigorously before being decanted off from the sticky organic residue. The residue is dissolved in ethyl acetate, dried and concentrated in vacuo until the product begins to crystallize out. 450 ml of diisopropyl ether are added, stirred and then allowed to stand overnight. The crystalline precipitate is filtered off with suction, washed twice with 50 ml of diisopropyl ether and dried in vacuo. 98.5 g (56.6% of theory) of the target product are obtained.

HPLC (Method 1): R, = 5.10 min.

MS (DCI): m / z = 306 (MH-NKO ⁺

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.90-7.82 (m, 4H), 7.28-7.18 (m, 5H), 4.98 (s, 2H), 2.69 (q, 2H), 1.28 (t, 3H).

Example 53A

5- (4-ethylphenyl) -6-phenylturo [2,3-d] pyrimidin-4 (3H) -one

770 ml (8.16 mol) of acetic anhydride are cooled to 0 ⁰ C and treated with cooling 372 ml (10.4 mol) of formic acid. The mixture is stirred for 30 min at 0 ⁰ C, before 98 g (340 mmol) of 2-amino-4- (4-ethylphenyl) -5-phenyl-3-turonitrile be registered. The mixture is heated to reflux (thereby increasing the evolution of gas) and stirred at reflux for 24 h.

After cooling, the mixture is stirred for about 2 h at 10 ⁰ C and then the precipitated solid is filtered off, with

Washed diisopropyl ether and dried under high vacuum. Obtained are 69.3 g (64.5% of theory) of the target product.

HPLC (method 1): R, = 4.77 min.

MS (DCI): m / z = 334 (M + NHJ ", 317 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.63 (br.s, IH), 8.19 (s, IH), 7.43 (d, 2H), 7.40-7.30 (m, 5H), 7.25 (m, 2H), 3.35 (s, 2H), 2.68 (d, 2H), 1.25 (t, 3H). Example 54A

4-chloro-5- (4-ethylphenyl) -6-phenylfuro [2,3-d] pyrimidine

72 g (227.6 mmol) of 5- (4-ethylphenyl) -6-phenyl-2- [2,3-d] pyrimidin-4 (3H) -one are introduced into 360 ml (4.6 mol) of phosphorus oxychloride and heated to reflux. The mixture is stirred for about 1 h at 120 ⁰ C, before the reaction mixture after cooling to RT metered-controlled with vigorous stirring to a mixture of 2.2 liters of 25% ammonia solution and 1.2 liters of water is added dropwise (pH> 9, temperature 55 -75 ° C). The aqueous mixture is extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate and concentrated in vacuo. The residue is washed with a little diisopropyl ether and, after filtering off and drying in a high vacuum, 66.1 g (85.2% of theory) of the target product are obtained.

HPLC (Method 1): R, = 5.68 min.

MS (DCI): m / z = 335 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 8.76 (s, IH), 7.61 (d, 2H), 7:48 to 7:30 (m, 7H), 2.78 (q, 2H), 1:36 (t, 3H) ,

Example 55A

6-phenylfuro [2,3-d] pyrimidin-4-amine

110 g (597 mmol) of 2-amino-5-phenyl-3-furonitrile are suspended in 355 ml (9 mol) of formamide and heated for 1.5 h (bath temperature about 210 ⁰ C). The mixture is then cooled to RT and stirred into water. The precipitated solid is filtered off with suction and washed with water. The still moist product is stirred in dichloromethane, filtered off with suction again and dried in vacuo. This gives 106 g (80% of theory) of the target compound.

LC-MS (Method 4): R, = 3.1 min .; m / z = 212 (M + H) ⁺

HPLC (Method 1): R, = 3.63 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.20 (s, IH), 7.8 (d, 2H), 7.55-7.32 (m, 6H).

Example 56A

5-bromo-6-phenylfuro [2,3-d] pyrimidin-4-amine

80 g (378.7 mmol) of 6-phenylfuro [2,3-d] pyrimidin-4-amine are heated in 770 ml of carbon tetrachloride at 60 ⁰ C. 84.3 g (473.4 mmol) of N-bromosuccinimide are added and the mixture is stirred at reflux overnight. After cooling, the mixture is filtered off, the filter cake is stirred successively with dichloromethane and acetonitrile and filtered off again. The filter cake is then dried in vacuo. 86 g of the target product are obtained (78.2% of theory).

MS (DCI): m / z = 290/292 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.28 (s, IH), 8.03 (d, 2H), 7.60-7.50 (m, 5H).

Example 57A

5-bromo-4-chloro-6-phenylfuro [2,3-d] pyrimidine

54 g (186 mmol) of 5-bromo-6-phenylfuro [2,3-d] pyridin-4-amine are initially charged in 135 ml of chloroform, 70 ml of 4N hydrogen chloride in dioxane (280 mmol) and heated to reflux heated.

50 ml (372 mmol) of isoamylnitrite are added dropwise with evolution of gas. To

End of the addition is stirred for 3 h at reflux before the cooled reaction mixture in water. added and extracted with dichloromethane. The organic phase is washed with sat. Washed sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by chromatography on silica gel (eluent: dichloromethane). The product is stirred in methanol for further purification, filtered off with suction and dried under high vacuum. 32 g of the target product are obtained (55.5% of theory).

LC-MS (Method 3): R, = 2.54 min .; m / z = 309/310 (M + H) ⁺

HPLC (Method 1): R, = 5.08 min.

¹ H-NMR (400 MHz, CDCl _3): δ = 8.79 (s, IH), 8:23 to 8:20 (m, 2H), 7:58 to 7:51 (m, 3H).

Example 58A and Example 59A

(+/-) - trans- and (+/-) - cw-3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} -cyclohexanol

300 mg (0.72 mmol) of (+/-) - 3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} -cyclohexanol (cis / trans mixture ) are separated by preparative HPLC in the pure cis and trans isomers [column: Phenomenex Gemini, C-18, 5 microns, 250 mm x 21.2 mm; Flow: 20 ml / min; Temperature: 25 ° C; Eluent: water / THF 60:40]. Obtained are 43 mg (14.3% of theory) of (+/-) - / rαn5-3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino } cyclohexanol {Example 58A) and 150 mg (50.0% of theory) (+/-) - c / s-3 - {[5- (4-memoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine 4-yl] amino} cyclohexanol (Example 59A).

Example 58A:

LC-MS (Method 6): R, = 2.49 min .; m / z = 416 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.32 (s, IH), 7.50 (d, 4H), 7.40-7.30 (m, 3H), 7.19 (d, 2H), 4.75 (i.e. , IH), 4.49 (s, IH), 4.40-4.30 (m, IH), 3.86 (s, 3H), 3.48 (s, IH), 1.67-1.01 (m, 8H). Example 59A:

LC-MS (Method 6): R, = 2.51 min .; m / z = 416 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.32 (s, IH), 7.49-7.41 (m, 4H), 7.40-7.30 (m, 3H), 7.13 (d, 2H), 5.15 ( s, IH), 4.52 (s, IH), 4.10-4.00 (m, IH), 3.88 (s, 3H), 3.53-3.48 (m, IH), 1.80-0.89 (m, 8H).

Example 6OA

(+/-) - 4- (3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} piperidin-1-yl) butanitrile

To a mixture of 200 mg (0.498 mmol) of (+/-) - 5- (4-methoxyphenyl) -6-phenyl-4- (piperidin-3-yloxy) furo [2,3-d] pyrimidine, 0.25 ml ( 1.5 mmol) of diisopropylethylamine and 8.3 mg of potassium iodide in 2 ml of THF are added at RT 147.5 mg (0.996 mmol) of 4-bromobutyronitrile. The mixture is stirred for 10 h under reflux. After addition of a further 0.25 ml (1.5 mmol) of diisopropylethylamine and 147.5 mg (0.996 mmol) of 4-bromobutyronitrile, stirring is continued overnight under reflux. After cooling to RT, it is diluted with dichloromethane, washed with sat. Washed sodium bicarbonate solution, the organic phase separated, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by preparative RP-HPLC (eluent: acetonitrile / water gradient) gives 189 mg of the target product (81.1% of theory).

LC-MS (Method 6): R, = 1.80 min .; m / z = 469 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Ci ₆ ): δ = 8.59 (s, IH), 7.55 (d, 2H), 7.45-7.35 (m, 5H), 7.00 (d, 2H), 5.31-5.23 ( m, IH), 3.81 (s, 3H), 2.82-2.76 (m, IH), 2.40 (t, 3H), 2.31 (t, 2H), 2.29-2.12 (m, 2H), 1.93-1.85 (m, IH), 1.67 (t, 3H), 1.50-1.30 (m, 2H).

Example 61A

(+/-) - c / 5-3 - {[3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl] oxy} -propanenitrile

To a solution of 150 mg (0.36 mmol) (+/-) - c / s-3 - {[5- (4-methoxyphenyl) -6-phenylfro [2,3-d] pyrimidin-4-yl] oxy } cyclohexanol in 1 ml of acrylonitrile is added dropwise a solution of 10 mg of potassium ^' m-tert-butoxide in 0.5 ml of THF. The reaction mixture is stirred for about 2 h at RT under exclusion of light. After dilution with dichloromethane, successively with 1 N hydrochloric acid, sat. Sodium bicarbonate solution and sat. Washed sodium chloride solution and the organic phase concentrated in vacuo. Purification of the residue by preparative RP-HPLC (eluent: acetonitrile / water gradient) gives 136.9 mg of the target product (81% of theory).

LC-MS (Method 3): R _t = 2.88 min .; m / z = 470 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-de): δ = 8.60 (s, IH), 7.55 (d, 2H), 7.43-7.34 (m, 5H), 7.00 (d, 2H), 5.20-5.10 (m , IH), 3.81 (s, 3H), 3.63-3.55 (m, 2H), 3.50-3.40 (m, IH), 2.70 (t, 2H), 2.48-1.40 (m, IH), 2.19-1.90 (m , 2H), 1.80-1.70 (m, IH), 1.38-1.02 (m, 4H).

Example 62A

(+/-) -? ra »5-3 - {[3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexyl] -oxy} propanenitrile

To a solution of 34.4 mg (0.059 mmol) (+/-) - fr- <ms-3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexanol in 0.23 ml of acrylonitrile is added dropwise a solution of about 2 mg of potassium tert-butoxide in 0.2 ml of THF. The reaction mixture is stirred for about 2 h at RT under exclusion of light. After dilution with dichloromethane, successively with 1 N hydrochloric acid, sat. Sodium bicarbonate solution and sat. Washed sodium chloride solution and the organic phase concentrated in vacuo. After purification of the residue by preparative RP- HPLC (eluent: acetonitrile / water gradient) will give 33.6 mg of the target product (86.6% of theory).

LC-MS (Method 6): R, = 2.86 min .; m / z = 469 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.32 (s, IH), 7.52-7.49 (m, 3H), 7.19 (d, 2H), 4.73 (d, IH), 4.85-4.25 (m, IH), 3.88 (s, 3H), 3.60-3.50 (m, 2H), 2.78-2.70 (m, 2H), 1.80-1.62 (m, 2H), 1.60- 1.49 (m, 4H), 1.27-1.12 ( m, 3H).

Example 63A

(+/-) - 4- [2 - ({[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} methyl) pyrrolidin-1-yl-butanenitrile

To a solution of 300 mg (0.747 mmol) of (+/-) - 5- (4-methoxyphenyl) -6-phenyl-4- (pyrrolidin-2-ylmethoxy) furo [2,3-d] pyrimidine, 0.37 ml ( 2.24 mmol) of diisopropylethylamine and 12.4 mg of potassium iodide in 3 ml of THF are added at RT 221.2 mg (0.996 mmol) of 4-bromobutyronitrile. The mixture is stirred under reflux for 6 h. After cooling to RT, it is diluted with dichloromethane, washed with sat. Washed sodium bicarbonate solution, the organic phase separated, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by preparative RP-HPLC (eluent: acetonitrile / water gradient) gives 178.1 mg of the target product (50.9% of theory).

LC-MS (Method 3): R, = 1.59 min .; m / z = 469 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.49 (s, IH), 7.57-7.50 (m, 2H), 7.43-7.36 (m, 5H), 7.01 (d, 2H), 4.36 ( dd, IH), 4.24 (dd, IH), 3.81 (s, 3H), 2.99-2.90 (m, IH), 2.69-2.60 (m, 2H), 2.41-2.01 (m, 4H), 1.79-1.70 ( m, IH), 1.61-1.40 (m, 5H). Example 64A

(+/-) - 3- (3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} piperidin-1-yl) propane nitrile

A mixture of 900 mg (2.24 mmol) (+/-) - 5- (4-methoxyphenyl) -6-phenyl-4- (piperidin-3-yloxy) furo [2,3-d] pyrimidine and 1.5 ml (22.4 mmol) of acrylonitrile is stirred under reflux for 3 h. After cooling to RT, the mixture is concentrated under reduced pressure and the residue is dried under high vacuum. 1000 mg (98.1% of theory) of the target compound are obtained.

LC-MS (Method 3): R, = 1.97 min .; m / z = 455 (M + H) ⁺ .

1.0 g (2.2 mmol) of (+/-) 3- (3 - {[5- (4-methoxyphenyl) -6-phenylruro [2,3-d] pyrimidin-4-yl] oxy} piperidine obtained in this way l-yl) propanenitrile are separated into the enantiomers by chromatography on a chiral phase (see Examples 65A and 66A) [column: Daicel Chiralpak AS-H, 5 μm, 250 mm x 20 mm; Flow: 15 ml / min; Temperature: 30 ° C; Eluent: iso-hexane / THF 50:50].

Example 65A

(-) - 3- (3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} piperidin-1-yl) propane nitrile (Enantiomer 1)

Yield: 459 mg (45.1% of theory)

[α] _D ²⁰ = -60.5 °, c = 0.545, CHCl ₃

LC-MS (Method 6): R _t = 2.05 min .; m / z = 455 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.60 (s, IH), 7.54 (d, 2H), 7.48-7.37 (m, 5H), 7.01 (d, 2H), 5.31-5.23 ( m, IH), 3.81 (s, 3H), 2.91-2.82 (m, IH), 2.68-2.58 (m, 3H), 2.55 (s, 2H), 2.38-2.22 (m, 2H), 1.93-1.82 ( m, IH), 1.69-1.58 (m, IH), 1.50-1.29 (m, 2H). Example 66A

(+) - 3- (3 - {[5- (4-Methoxyphenyl) -6-phenylfliro [2,3-d] pyrimidin-4-yl] oxy} piperidin-1-yl) propane nitrile (Enantiomer 2)

Yield: 479 mg (47.0% of theory)

[α] _D ²⁰ = + 59.1 °, c = 0.545, CHCl ₃

LC-MS (Method 6): R _t = 2.05 min .; m / z = 455 (M + Hf

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.60 (s, IH), 7.54 (d, 2H), 7.48-7.37 (m, 5H), 7.01 (d, 2H), 5.31-5.23 (m, IH), 3.81 (s, 3H), 2.91-2.82 (m, IH), 2.68-2.58 (m, 3H), 2.55 (s, 2H), 2.38-2.22 (m, 2H), 1.93-1.82 (m, IH), 1.69-1.58 (m, IH), 1.50-1.29 (m, 2H).

Example 67A

(2 _J E) -3 - {(2S, 4R) -4-hydroxy-1 - [(1R) -l-phenylethyl] -piperidin-2-yl} -acrylate

2.0 g (8.647 mmol) of (15,5R) -2 - [(lΛ) -1-phenylethyl] -6-oxa-2-azabicyclo [3.2.1] octan-7-one [prepared from N - [(IR) -l-phenylethyl] but-3-en-1-amine according to Bioorg. Med. Chem. Leu. 6 (8), 964 (1996)] are added in 8 ml abs. THF dissolved, cooled to -78 ° C and treated with 9.5 ml (9.5 mmol) of a 1 M solution of L-Selectrid in THF. After the addition is stirred for 1 h at -78 ⁰ C, then warmed to -20 ⁰ C and treated with 2.1 ml (13 mmol) Phosphonoessigsäuretrimethylester. The reaction mixture is then warmed to 0 ⁰ C and stirred for 1 h. Thereafter, water is added and adjusted to a pH of about 7-8 with 1 N hydrochloric acid. The mixture is extracted three times with dichloromethane, the organic phases are combined, dried over magnesium sulfate and concentrated in vacuo. There are obtained 4.32 g of crude product, which is used without further purification in the next stage.

LC-MS (Method 4): R, = 2.48 min .; m / z = 290 (M + H) ⁺ . Example 68A

terΛ-butyl (2R, 4R) -4-Hydroxy-2- (3-methoxy-3-oxopropyl) piperidine-l-carboxylate

3.8 g (2 lbs) -3 - {(2S, 4R) -4-hydroxy-l - [(lR) -l-phenylethyl] piperidin-2-yl} acrylic acid methyl ester (as crude product) are dissolved in 50 ml of isopropanol and washed with 4.3 g of di-tert-butyl dicarbonate and a catalytic amount of 10% Pd / C added. The mixture is stirred overnight at RT and atmospheric pressure under a hydrogen atmosphere. It is filtered through kieselguhr and the filtrate is concentrated in vacuo. From the residue, after purification by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 5: 1 → 1: 1), 0.98 g of the target product are obtained.

LC-MS (Method 8): R, = 1.87 min .; m / z = 288 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-dg): δ = 4.64 (d, IH), 4.08-3.99 (m, IH), 3.91 (d, IH), 3.69 (d, IH), 3.58 (s, 3H ), 3.05 (dt, IH), 2.36-2.12 (m, 3H), 1.82-1.71 (m, IH), 1.60 (s, 2H), 1.55-1.41 (m, 2H), 1.38 (s, 9H).

Example 69A

(+/-) - ({3 - [(6-phenylfuro [2,3-d] pyrimidin-4-yl) amino] cyclohexyl} oxy) acetic acid / erΛ-butyl ester

1.61 g (6.98 mmol) of 4-chloro-6-phenylfuro [2,3-d] pyridine and 1.60 g (6.98 mmol) of (+/-) - trans - {[3-aminocyclohexyl] oxy} acetic acid ter. butyl ester are introduced into 6.0 ml of DMF and treated with 1.8 ml (10.5 mmol) of NN-diisopropylethylamine. The reaction mixture for 3 h at 120 ⁰ C ER- hitzt, then cooled to RT and poured into water. It is extracted three times with ethyl acetate, the organic phases combined, washed with sat. Sodium chloride solution and concentrated in vacuo one. After purification by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 20: 1 → 2: 1), 1.67 g of the target product are isolated from the residue (56.5% of theory).

LC-MS (Method 3): R, = 2.62 min .; m / z = 424 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.27 (s, IH), 7.88-7.68 (m, 3H), 7.50 (t, 2H), 7.47-7.39 (m, IH), 4.40 ( s, IH), 4.03 (s, 2H), 3.80 (s, IH), 2.15-1.50 (m, 8H), 1.50-1.30 (m, 9H).

Example 7OA

(+/-) - ({3 - [(5-Bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) -amino] -cyclohexyl} oxy) -acetic acid / tert-butyl ester

1.65 g (3.9 mmol) of (+/-) - ({3 - [(6-phenylfuro [2,3-d] pyrimidin-4-yl) amino] cyclohexyl} oxy) acetic acid tert. butyl ester are suspended in 4 ml of carbon tetrachloride and treated with 762 mg (4.3 mmol) of N-bromosuccinimide. The reaction mixture is heated under reflux for 1 h. After cooling to RT, an additional 350 mg of N-bromosuccinimide are added. The reaction mixture is stirred for 1 h under reflux, then cooled and concentrated in vacuo. From the residue, after purification by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1), 0.99 g of the target product are isolated (50.6% of theory).

LC-MS (Method 3): R, = 3.09 min .; m / z = 502 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.38 (s, IH), 8.00 (d, 2H), 7.61-7.49 (m, 3H), 6.39 (d, IH), 4.53-4.42 ( m, IH), 4.03 (s, 2H), 3.78 (s, IH), 2.09-1.42 (m, 8H), 1.40 (s, 9H).

Example 71A and Example 72A

(+) - cis- {[3-hydroxycyclohexyl] oxy} -acetic acid-tert. butyl ester (enantiomer 1) and

(-) - cw - {[3-hydroxycyclohexyl] oxy} -acetic acid / er /. butyl ester {enantiomer 2)

500 mg (2.17 mmol) of (+/-) - c "- {[3-hydroxycyclohexyl] oxy} -acetic acid tert-butyl ester are separated into the enantiomers by chromatography on a chiral phase [column: Daicel Chiralpak AS-H, 5 μm , 250 mm x 20 mm; Flow: 15 ml / min; Temperature: 30 ^° C .; Eluent: iso-hexane / ethanol 75:25].

Enantiomer 1:

Yield: 124 mg (24.8% of theory)

[α] _D ²⁰ = + 2.4 °, c = 0.50, CHCl ₃

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 4.60 (d, IH), 3.97 (s, 2H), 3.39-3.29 (m, IH), 3.28-3.19 (m, IH), 2.20- 2.12 (m, IH), 1.90 (d, IH), 1.74 (d, IH), 1.69-1.59 (m, IH), 1.41 (s, 9H), 1.17-0.90 (m, 4H).

Enantiomer 2:

Yield: 121 mg (24.2% of theory)

[α] _D ²⁰ = -3.4 °, c = 0.50, CHCl ₃

Example 73A

(+/-) - 3- (benzyloxy) -piperidine- / erΛ-butylcarbamate

15 g (74.5 mmol) of (+/-) 3-hydroxypiperidine-tert-butylcarbamate are dissolved in 86.5 ml of toluene in the heat and washed successively with 11.9 ml of 50% strength sodium hydroxide solution (447 mmol), 2.53 g (7.5 mmol). Tetra-n-butylammonium hydrogen sulfate and 11.5 ml (96.9 mmol) of benzyl bromide added. The two-phase reaction mixture is stirred vigorously at 70 ° C. for 4 h. After cooling, water is added and treated with conc. Hydrochloric acid neutralized. The organic phase is separated, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 30: 1 -> 10: 1). 16.21 g of the target product are obtained (74.6% of theory).

LC-MS (Method 3): R ₁ = 2.64 min .; m / z = 293 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.38-7.24 (m, 5H), 4.53 (dd, 2H), 3.43-3.35 (m, 2H), 3.30- 3.18 (m, 2H), 1.84 ( br, s, IH), 1.71-1.48 (m, 4H), 1.36 (s, 9H).

Example 74A and Example 75A

(-) - (3R) -3- (Benzyloxy) -piperidine-tert-butylcarbamate {enantiomer 1) and

(+) - (3S) -3- (Benzyloxy) piperidine-tert-butylcarbamate {enantiomer T)

16.0 g (54.9 mmol) of (+/-) - 3- (benzyloxy) piperidine / erΛ-butylcarbamate are separated into the enantiomers by chromatography on a chiral phase [column: Daicel Chiralpak AS-H, 5 μm, 250 mm × 20 mm ; Flow: 15 ml / min; Temperature: 28 ° C; Eluent: iso-hexane / 2-propanol 95: 5].

Enantiomer 1:

Yield: 7.40 g (49.3% of theory)

[α] _D ²⁰ = -5.8 °, c = 0.635, CHCl ₃

LC-MS (Method 3): R _t = 2.65 min .; m / z = 292 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 7.49-7.23 (m, 5H), 4.60-4.45 (m, 2H), 3.42-3.38 (m, 2H), 1.82 (br. IH), 1.70-1.48 (m, 2H), 1.34 (s, 9H), 1.40-1.26 (m, 4H).

Enantiomer 2:

Yield: 6.50 g (43.3% of theory) [α] _D ²⁰ = + 6.0 °, c = 1.045, CHCl ₃

LC-MS (Method 3): R ₁ = 2.65 min .; m / z = 292 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-U ₆ ): δ = 7.49-7.23 (m, 5H), 4.60-4.45 (m, 2H), 3.42-3.38 (m, 2H), 1.82 (br.s, IH ), 1.70-1.48 (m, 2H), 1.34 (s, 9H), 1.40-1.26 (m, 4H).

Example 76A

(+) - 4 - [(3R) -3- (Benzyloxy) piperidine-1-yl] butanoic acid methyl ester

To a solution of 3.025 g (10.38 mmol) of (+) - (3 <S) -3- (benzyloxy) piperidine-tert-butylcarbamate in 14.4 ml of dichloromethane at RT is added a drop of water and 7.7 ml of trifluoroacetic acid. The mixture is stirred for 1 h and then diluted with water and dichloromethane. After phase separation, the organic phase is washed with sat. Sodium chloride solution and sat. Washed sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. This gives 2.12 g of crude product, which is dissolved without further purification in 37 ml of THF and successively with 5.7 ml (32.9 mmol) of NN-diisopropylethylamine, 182 mg (1.1 mmol) of potassium iodide and 3.98 g (22 mmol) of 4-Brombuttersäuremethylester is added. The mixture is then stirred under reflux for 3 h. After cooling, it is diluted with dichloromethane, washed successively with water, sat. Ammonium chloride solution and sat. Washed sodium chloride solution, the organic phase dried over sodium sulfate and concentrated in vacuo. After purification by preparative RP-HPLC (eluent: acetonitrile / water), 2.0 g of the target product are isolated from the residue (62.6% of theory over both stages).

[α] _D ²⁰ = + 1.3 °, c = 0.51, CHCl ₃

LC-MS (Method 8): R, = 0.89 min .; m / z = 292 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 7.38-7.23 (m, 5H), 4.51 (s, 2H), 3.59 (s, 2H), 3.45-3.31 (m, IH), 3.00 -2.90 (m, IH), 2.69-2.56 (m, IH), 2.37-2.19 (m, 5H), 1.99-1.80 (m, 3H), 1.70-1.60 (m, 3H), 1.44-1.30 (m, IH), 1.22-1.10 (m, IH). Example 77A

(-) - 4 - [(3 /?) - 3-hydroxypiperidin-1-yl] butanoic acid methyl ester

To a solution of 2.0 g (6.86 mmol) of (+) - 4 - [(3R) -3- (benzyloxy) piperidin-1-yl] butanoic acid methyl ester in 15 ml of acetic acid at RT about 200 mg of 10% Given Pd / C. The suspension is stirred vigorously at RT overnight under a hydrogen atmosphere (atmospheric pressure). The reaction mixture is then filtered through Celite, the filter residue washed with dichloromethane and the filtrate concentrated in vacuo. The residue is taken up in dichloromethane, washed with sat. Washed sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. Obtained are 833.9 mg (60.4% of theory) of the target compound.

[α] _D ²⁰ = + 6.9 °, c = 0.57, CHCl ₃

GC-MS (Method 9): R, = 5.20 min .; m / z = 202 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 4.54 (br.s, IH), 3.60 (s, 3H), 3.48-3.38 (m, IH), 2.81-2.71 (m, IH), 2.65- 2.56 (m, IH), 2.32-2.15 (m, 4H), 1.81-1.70 (m, 2H), 1.70-1.52 (m, 4H), 1.42-1.30 (m, IH), 1.10-0.98 (m, IH ).

Example 78A

rαc-3 - [(5-bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] piperidin-l- he /.- butylcarbamate?

1.1 g (3.55 mmol) of 5-bromo-4-chloro-6-phenylfuro [2,3-d] pyrimidine are dissolved at 70 ⁰ C in 20 ml of toluene and 10 ml 1, 2-dimethoxyethane. 2.84 g of 50% sodium hydroxide solution (35.5 mmol), 120.6 mg (0.26 mmol) of tetra-n-butylammonium hydrogensulfate and 1.79 g (8.88 mmol) of 1-tert.-butoxycarbonyl-3-hydroxypiperidine are added and the reaction mixture is then heated at 70.degree stirred vigorously for 1 h. After cooling, the mixture is added to water and concentrated with conc. hydrochloric acid adjusted to pH about 7. The aqueous phase is extracted three times with ethyl acetate, and the combined organic phases are washed with sat. Sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. From the residue, after purification by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1), 1.06 g of the target compound are isolated (62.9% of theory).

LC-MS (Method 3): R, = 3.03 min .; m / z = 474 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.66 (s, IH), 8.07 (d, 2H), 7.63-7.51 (m, 3H), 5.33 Qx, s, IH), 4.30 ( d, IH), 4.02-3.92 (m, IH), 2.10-1.90 (m, 3H), 1.60-1.50 (m, IH), 1.34 (s, 2H), 0.92 (s, 9H).

Example 79A

rac-5-Bromo-6-phenyl-4- (piperidin-3-yloxy) furo [2,3-d] pyrimidine

A solution of 1.05 g (2.21 mmol) of rac-3 - [(5-bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] -piperidine-1-tert-butylcarbamate in 2 ml Dichloromethane is added at RT in several portions with a total of 3.4 ml of TFA and stirred for 2 h at RT. Then it is diluted with dichloromethane, the solution carefully with sat. Sodium bicarbonate solution and then washed twice with sat. Sodium bicarbonate solution washed. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The oily residue is stirred with methanol, and the precipitated solid is filtered off with suction and washed with methanol. Mother liquor and washing solution are combined, concentrated in vacuo and stirred again with a little methanol. The resulting crystals are filtered off, washed with methanol and combined with the first crystal fraction. A total of 550 mg (66.4% of theory) of the target compound are obtained.

LC-MS (Method 6): R _t = 1.61 min .; m / z = 374 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.60 (s, IH), 8.09 (d, 2H), 7.64-7.51 (m, 3H), 5.29-5.20 (m, IH), 3.15 ( dd, IH), 2.80-2.70 (m, 2H), 2.65-2.57 (m, IH), 2.21-2.08 (m, 2H), 1.82-1.68 (m, 2H), 1.56-1.43 (m, IH). Example 8OA

(+/-) - 4- {3 - [(5-bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] piperidin-l-yl} butansäuremethylester

A mixture of 550 mg (1.47 mmol) of rac-5-bromo-6-phenyl-4- (piperidin-3-yloxy) furo [2,3-d] pyrimidine, 532 mg (2.94 mmol) of 4-bromobutyrate, 24.4 mg (0.147 mmol) of potassium iodide and 0.77 ml (4.41 mmol) of N, N-diisopropylethylamine are refluxed in 1.5 ml of THF for 2 h. After cooling, it is diluted with dichloromethane and added to water. After phase separation, the aqueous phase is extracted with dichloromethane. The organic phases are combined, with sat. Washed sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. After purification by preparative RP-HPLC (eluent: acetonitrile / water), 780 mg of the target product are isolated from the residue, which are used without further purification.

LC-MS (Method 3): R ₁ = 1.62 min .; m / z = 474 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.61 (s, IH), 8.09 (d, 2H), 7.62-7.51 (m, 3H), 5.39-5.30 (m, IH), 3.52 ( s, 3H), 2.90 (d, IH), 2.60-2.52 (m, IH), 2.47-2.39 (m, IH), 2.38-2.28 (m, 4H), 2.26-2.19 (m, IH), 2.19- 2.00 (m, IH), 1.90-1.80 (m, IH), 1.70-1.51 (m, 4H).

Example 81A and Example 82A

(-) - 4 - {(3R) -3 - [(5-Bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] -piperidin-1-yl} butanoic acid methyl ester {enantiomer 1)

and

(+) - 4 - {(3S) -3 - [(5-Bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] -piperidin-1-yl} butanoate Methyl Ester {Enantiomer 2)

780 mg (1.64 mmol) of (+/-) - 3 - [(5-bromo-6-phenylniro [2,3-d] pyrimidin-4-yl) oxy] piperidin-1-yl} -butanoic acid methyl ester are obtained by chromatography chiral phase separated into the enantiomers [column: Daicel Chiralpak AS-H, 5 microns, 250 mm x 20 mm; Flow: 15 ml / min; Temperature: 28 ° C; Eluent: iso-hexane / 2-propanol (+ 0.2% diethylamine) 80:20].

Enantiomer 1:

Yield: 350 mg (44.8% of theory)

[α] _D ²⁰ = -43.1 °, c = 0.505, CHCl ₃

LC-MS (Method 3): R, = 1.59 min .; m / z = 475 (M + H) ⁺

¹ H NMR (400 MHz, DMSO- (I ₆ ): δ = 8.62 (s, IH), 8.08 (d, 2H), 7.64-7.51 (m, 3H), 5.38-5.30 (m, IH), 3.53 (s, 3H), 2.94-2.88 (m, IH), 2.47-2.40 (m, IH), 2.38-2.29 (m, 4H), 2.25-2.19 (m, IH), 2.10-2.00 (m, IH) , 1.90-1.80 (m, IH), 1.70-1.52 (m, 4H), 0.90-0.79 (m, IH).

Enantiomer 2:

Yield: 320 mg (41.0% of theory)

[α] _D ²⁰ = + 42.2 °, c = 0.53, CHCl ₃

LC-MS (Method 3): R _t = 1.59 min .; m / z = 475 (M + H) ⁺ ¹ H NMR (400 MHz, DMSO- (I ₆ ): δ = 8.62 (s, IH), 8.08 (d, 2H), 7.64-7.51 (m, 3H), 5.38-5.30 (m, IH), 3.53 (s, 3H), 2.94-2.88 (m, IH), 2.47-2.40 (m, IH), 2.38-2.29 (m, 4H), 2.25-2.19 (m, IH), 2.10-2.00 (m, IH) , 1.90-1.80 (m, IH), 1.70-1.52 (m, 4H), 0.90-0.79 (m, IH).

Example 83A

c / 5 / rrα "5-3 - [(5-bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] cyclohexanol

1.1 g (8.88 mmol) c / s / frαns-cyclohexanediol are dissolved at 70 ⁰ C in 10 ml of toluene and 5 ml of 1,2-dimethoxyethane and treated with 2.84 g of 50% sodium hydroxide solution (35.5 mmol). Water is added until a biphasic reaction mixture is formed. 120.6 mg (3.55 mmol) of tetra-n-butylammonium hydrogen sulfate and 1.10 g (3.55 mmol) of 5-bromo-4-chloro-6-phenylfuro [2,3-d] pyridine-pyrimidine are added and the mixture for 1 h at 70 ⁰ C. stirred vigorously. After cooling, the reaction mixture is added to water and acidified with conc. Hydrochloric acid neutralized. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined, washed with sat. Sodium hydrogen sulfate solution, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1 → 3: 1). 0.63 g of the target compound are obtained (45.6% of theory).

LC-MS (Method 3): R, = 2.47 min .; m / z = 389 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.61 (s, IH), 8.03 (d, 2H), 7.63-7.51 (m, 3H), 5.30-5.20 (m, IH), 4.79 ( d, IH), 3.62-3.52 (m, IH), 2.46-2.38 (m, IH), 2.20-2.10 (m, IH), 1.90-1.66 (m, 3H), 1.47-1.29 (m, 2H), 1.20-1.09 (m, IH).

Example 84A

c (5-bromo-6-phenyl-pent [[2,3-d] pyrimidin-4-yl) oxy] cyclohexyl} oxy) -acetic acid tert-butyl ester

To a mixture of 2 ml of toluene and 1.28 g of 50% sodium hydroxide solution (16.05 mmol) is a

Solution of 625 mg (1.606 mmol) c / s / fra / M-3 - [(5-bromo-6-phenylfiro [2,3-d] pyrimidin-4-yl) oxy] -cyclohexanol in 3 ml of toluene. 54.5 mg (0.16 mmol) of tetra-n-butylammonium hydrogensulfate and 626 mg (3.21 mmol) of tert-butyl bromoacetate are then added to the two-phase mixture, and the reaction mixture is stirred vigorously at 60 ^° C. for 3 hours. Then it is added to water and concentrated with conc. Hydrochloric acid neutralized. The aqueous phase is extracted three times with ethyl acetate, the organic phases combined and dried over magnesium sulfate. Of the

The residue is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1 → 8: 1). 592 mg of the target compound are obtained (73.2% of theory).

LC-MS (Method 8): R _t = 3.36 min .; m / z = 503 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-dβ): δ = 8.61 (s, IH), 8.10-8.04 (m, 2H), 7.63-7.51 (m, 3H), 5.30-5.20 (m, IH), 4.00 (s, 2H), 3.52-3.42 (m, IH), 2.20-2.10 (m, IH), 2.06-1.98 (m, IH), 1.88-1.78 (m, IH), 1.50-1.12 (m, 14H) ,

Example 85A and Example 86A

(+) - ({3 - [(5-Bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] cyclohexyl} oxy) acetic acid Fe / '/ - butyl ester (enantiomer 1 )

and

(-) - ({3 - [(5-Bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] cyclohexyl} oxy) acetic acid tert-butyl ester {enantiomer 2)

780 mg (1.64 mmol) of (+/-) - ({3 - [(5-bromo-6-phenylfiro [2,3-d] pyrimidin-4-yl) oxy] cyclohexyl} oxy) acetic acid fer /. butyl ester are separated into the enantiomers by chromatography on a chiral phase [column: Daicel Chiralpak AS-H, 5 μm, 250 mm × 20 mm; Flow: 15 ml / min; Temperature: 28 ° C; Eluent: iso-hexane / 2-propanol (+ 0.2% diethylamine) 80:20].

Enantiomer 1:

Yield: 159 mg (20.4% of theory)

[α] _D ²⁰ = + 64.5 °, c = 0.495, CHCl ₃

LC-MS (Method 8): R, = 3.37 min .; m / z = 503 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.61 (s, IH), 8.10 (d, 2H), 7.65-7.50 (m, 3H), 5.30-5.20 (m, IH), 4.01 ( s, 2H), 3.53-3.42 (m, IH), 2.20-2.10 (m, IH), 2.06-1.98 (m, IH), 1.88-1.80 (m, IH), 1.41 (s, 9H), 1.50- 1.23 (m, 5H).

Enantiomer 2:

Yield: 320 mg (41.0% of theory)

[α] _D ²⁰ = -68.9 °, c = 0.54, CHCl ₃

LC-MS (Method 8): R _t = 3.37 min .; m / z = 503 (M + H) ⁺ ¹ H-NMR (400 MHz, DMSO-O ₆ ): δ = 8.61 (s, IH), 8.10 (d, 2H), 7.65-7.50 (m, 3H), 5.30-5.20 (m, IH), 4.01 ( s, 2H), 3.53-3.42 (m, IH), 2.20-2.10 (m, IH), 2.06-1.98 (m, IH), 1.88-1.80 (m, IH), 1.41 (s, 9H), 1.50- 1.23 (m, 5H).

Example 87A

(+/-) - c / 5 // rα «5-3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclopentanol

10 g (29.7 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine are added in 150 ml of 70 ⁰ C hot toluene with 1, 2-dimethoxyethane until a homogeneous solution arises. Then 23.75 g (296.9 mmol) of 50% sodium hydroxide solution and 2.5 ml of water and, with vigorous stirring, 1.0 g (2.97 mmol) of tetra-n-butylammonium hydrogensulfate and 4.55 g (44.54 mmol) (+/-) - cw // ra «sl, added 3-cyclopentanediol and the reaction mixture for 4 h at 70 ⁰ C stirred. After cooling, the mixture is added to water and concentrated with conc. Hydrochloric acid neutralized. It is extracted three times with dichloromethane, and the combined organic phases are washed with sat. Sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. From the residue is obtained by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 4: 1 -> 2: 1) contaminated product. By stirring with methanol, this crude product is crystallized. The resulting crystals are filtered off and dried (yield: 690 mg). The mother liquor is concentrated in vacuo and further purified by preparative RP-HPLC. In this way, an additional 1230 mg of the target product are recovered. In total, 1920 mg of the target compound are obtained (16.1% of theory).

LC-MS (Method 8): R, = 2.64 min .; m / z = 403 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.59 (s, IH), 7.57 (d, 2H), 7.42-7.33 (m, 5H), 7.00 (d, 2H), 5.64-5.59 (m, IH), 4.60 (d, IH), 4.15-4.09 (m, IH), 3.82 (s, 3H), 2.15-2.03 (m, IH), 1.92-1.84 (m, IH), 1.83-1.74 (m, IH), 1.73-1.62 (m, IH), 1.61-1.51 (m, IH), 1.50-0.91 (m, IH).

Example 88A

(+/-) - c / s // ra «s - [(3-hydroxycyclopentyl) oxy] acetic acid ter /.- butyl

2.5 g (24.5 mmol) of cw // rαnj-cyclopentanediol are dissolved in 5 ml of THF and treated at 0 ⁰ C with 16.3 ml (16.3 mmol) of phosphazene base P4-t-Bu (about 1 M solution in hexane). After 10 min, the resulting solution is added dropwise to an ice-cooled solution of 4.77 g (24.5 mmol) of bromoacetic acid tert-butyl ester. After the addition is complete, warm to RT and stir the mixture overnight. Parts of the THF are removed in vacuo, diluted with ethyl acetate and washed successively with 1 N hydrochloric acid, pH 7 buffer solution and sat. Sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. From the residue, the product is isolated by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1 -> 2: 1). 631.4 mg (10.7% of theory) of the target compound are obtained as czs / frαws mixture.

GC-MS (Method 10): R, = 7.35 min (ice), 7.21 min (Iran); m / z = 217 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 4.52 (d, 0.25H, trans), 4.48 (d, 0.75H, ice), 4.20-4.13 (m, IH), 4.07-3.98 ( m, IH), 3.90 (d, 2H), 2.14-1.49 (m, 5H), 1.41 (s, 9H).

Example 89A

(+/-) - c / s / toms - [(3-Aminocyclopentyl) oxy] acetic acid teri '. butyl

Stage a):

620 mg (2.87 mmol) (+/-) - c / s // raws - [(3-hydroxycyclopentyl) oxy] -acetic acid-tert. butyl ester and 1.2 ml (8.6 mmol) of triethylamine are dissolved in 6.5 ml of dichloromethane and cooled to 0 ⁰ C. Dropwise, 0.28 ml (3.58 mmol) of methanesulfonyl chloride are added. The mixture is warmed to RT over 2 h and then diluted with dichloromethane. The organic phase is washed successively with water, 1 N hydrochloric acid, sat. Sodium bicarbonate solution and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. There are obtained 849 mg of mesylate, which is further reacted directly. Stage b):

849 mg of the mesylate obtained above are dissolved at RT in 10 ml of DMF and admixed with 1125 mg (17.3 mmol) of sodium azide. The suspension is stirred vigorously overnight at 70 ⁰ C and then added to water after cooling. It is extracted three times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried on magnesium sulfate and concentrated in vacuo. There are obtained 695 mg of the azide, which is further reacted directly.

Stage c):

695 mg of the azide obtained above are dissolved in 3 ml of ethanol and 0.3 ml of water, treated with 70 mg of palladium on activated carbon and stirred for 4 h at RT under a hydrogen atmosphere (atmospheric pressure). The catalyst is removed by filtration through kieselguhr, the filtrate is concentrated under reduced pressure and the residue is dried under high vacuum. There are obtained 560 mg of the title compound, which is used without further purification.

Example 9OA

cis - (+/-) - {[(4-Hydroxycyclopent-2-en-1-yl) oxy} acetic acid tert-butyl ester

2.0 g (20 mmol) of cis-4-cyclopentene-l, 3-diol are dissolved in 1.5 ml of DMF and 15 ml of THF and treated at 0 ⁰ C in portions with 799 mg (60% strength, about 20 mmol) of sodium hydride. After the end of the addition, the mixture is warmed to RT and stirred for 1 h at RT before 2.7 ml (18.2 mmol) of bromoacetic acid tert-butyl ester are added. The mixture is then stirred overnight at RT. It is then added to water, extracted with dichloromethane, the organic phase is washed with sat. Sodium chloride solution, concentrated in vacuo and the residue is dried under high vacuum. Chromatography on silica gel (eluent: cyclohexane / ethyl acetate 5: 1 → 2: 1) isolates the product. 1.10 g (25.6% of theory) of the target compound are obtained.

GC-MS (Method 11): R, = 7.19 min .; m / z = 233 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-de): δ = 5.90 (dt, 2H), 5.00 (d, IH), 4.44 (q, IH), 4.35 (t, IH), 3.99 (s, 2H), 2.60 (dd, IH), 1.62 (s, 9H), 1.37 (dd, IH). Example 91A

cw - (-) - {[(lR, 4S) -4-Acetoxycyclopent-2-en-l-yl] oxy} acetic acid / er /.- butyl ester

1.0 g (7.04 mmol) of (1R, 4S) -c / s-4-acetoxy-2-cyclopenten-1-ol are initially charged in 5 ml of dichloromethane and under argon with 155 mg (0.25 mmol) of rhodium (II) acetate (as dimer). 1.56 g (90% strength, approx. 9.84 mmol) of tert.-butyl diazoacetate are then added dropwise at RT to the vigorously stirred suspension. After 30 minutes, another 0.3 eq. Tert-Butyldiazoessigester added dropwise and the reaction mixture stirred for a further 30 min at RT. It is then diluted with dichloromethane and washed three times with water and with sat. Sodium chloride solution washed. It is dried over magnesium sulfate and concentrated in vacuo. From the residue, the product is isolated by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 8: 1). 1.33 g of the target compound are obtained (73.7% of theory).

[α] _D ²⁰ = -23 °, c = 0.55, CHCl ₃

GC-MS (Method 9): R _t = 5.49 min .; m / z = 257 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 6.18 (dd, IH), 5.97 (dd, IH), 5.41-5.36 (m, IH), 4.48-4.41 (m, IH), 4.01 (s, 2H), 2.72 (dt, IH), 2.10-1.98 (m, 3H), 1.55 (td, IH), 1.43 (s, 9H).

Example 92A

cis - (+) - {[(4-Hydroxycyclopent-2-en-1-yl) -yl] oxy} -acetic acid tert -butyl ester

1.30 g (5.07 mmol) of cw - (-) - {[(IR, 4S) -4-acetoxy-cyclopent-2-en-1-yl] oxy} -acetic acid / tert-butyl ester are dissolved in 3 ml of THF and 2 ml Dissolved methanol and treated dropwise at RT with 5.6 ml of 1 N sodium hydroxide solution. After 10 minutes, the mixture is diluted with water and extracted three times with dichloromethane. The organic phases are combined, with sat. Sodium bicarbonate solution and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. 780 mg of the target compound (71.8% of theory) are obtained. [α] _D ² ° = + 6.5 °, c = 0.515, CHCl ₃

GC-MS (Method 9): R, = 4.93 min .; m / z = 232 (M + NH ₄₎ ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 5.93-5.89 (m, 2H), 5.00 (d, IH), 4.45 (q, IH), 4.36 (t, IH), 3.99 (s, 2H), 2.65-2.56 (m, IH), 1.42 (s, 9H), 1.40-1.31 (m, IH).

Example 93A

cis - (+) - {[(1S, 3R) -3-hydroxycyclopentyl] oxy} -acetic acid tert -butyl ester

350 mg (1.63 mmol) of m - (+) - {[(4-hydroxycyclopent-2-en-l-yl] oxy} -acetic acid-erΛ-butyl ester are dissolved in 7 ml of ethanol and treated with 35 mg (0.163 mmol) of platinum The reaction mixture is stirred vigorously under a hydrogen atmosphere (atmospheric pressure) for 4 hours at RT, then the reaction mixture is filtered through kieselguhr, washed with ethanol, all the filtrates are combined and concentrated in vacuo to give 278.8 mg the target compound (81.5% of theory).

[α] _D ²⁰ = + 6.8 °, c = 0.51, CHCl ₃

GC-MS (Method 9): R, = 4.93 min .; m / z = 234 (M + NH ₄₎ ⁺

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 4.50 (d, IH), 4.01-3.96 (m, IH), 3.90 (s, 2H), 3.88-3.81 (m, IH), 2.14-2.05 ( m, 2H), 1.71-0.96 (m, 4H), 1.40 (s, 9H).

Example 94A

cis - {+) - {[(1S, 4i?) - 4-Acetoxycyclopent-2-en-1-ylkoxy} -acetic acid tert -butyl ester

To a solution of 1.6 g (11.26 mmol) of (1R, 3S) - (+) - m-4-cyclopentene-1,3-diol-1-acetate in 9.6 ml of dichloromethane is added 248.7 mg (0.56 mmol) of rhodium (II). acetate (as dimer). The resulting suspension is stirred vigorously and treated dropwise with 2.49 g (90% strength, about 15.8 mmol) terf.-Butyldiazoessigester. After the addition is stirred for 2 h at RT. After that will be another 0.5 eq. tert-Butyldiazoessigester post added and the mixture stirred for a further hour at RT. After concentration in vacuo, the residue is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1). 1.96 g of the target compound are obtained (68% of theory).

[α] _D ²⁰ = + 27.2 °, c = 0.59, CHCl ₃

LC-MS (Method 12): R _t = 2.06 min .; m / z = 257 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 6.20-6.15 (m, IH), 6.00-5.94 (m, IH), 5.41-5.37 (m, IH), 4.47-4.41 (m, IH), 4.00 (s, 2H), 2.79-2.70 (m, IH), 2.00 (s, 3H), 1.58-1.50 (td, IH), 1.42 (s, 9H).

Example 95A

cis - (-) - {[(1S, 4R) -4-Hydroxycyclopent-2-en-1-yl] oxy} -acetic acid tert-butyl ester

1000 mg (3.9 mmol) of tert -but-butyl cw - (+) - {[(LS, 4R) -4-acetoxycyclopent-2-en-1-yl] oxy} acetate are dissolved in 3 ml of THF and 2 ml of methanol and treated dropwise at RT with 4.7 ml of 1 N sodium hydroxide solution. After 10 minutes, the mixture is diluted with water and extracted three times with dichloromethane. The organic phases are combined, with sat. Sodium bicarbonate solution and sat. Sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. 570 mg of the target compound are obtained (68.2% of theory).

[α] _D ²⁰ = -9.3 °, c = 0.515, CHCl ₃

GC-MS (Method 9): R, = 4.93 min .; m / z = 232 (M + NH ^

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 6.39-5.92 (m, 2H), 5.00 (d, IH), 4.45 (q, IH), 4.35 (t, IH), 3.99 (s, 2H) , 2.64-2.56 (m, IH), 1.42 (s, 9H), 1.40-1.31 (m, IH).

Example 96A

cw - (-) - {[(IR, 3S) -3-hydroxycyclopentyl] oxy} acetic acid, ethyl / butyl he .-?

1170 mg (5.46 mmol) of c / 5 - (-) - {[(IS, 4R) -4-hydroxycyclopent-2-en-1-yl] oxy} acetic acid / erΛ-butyl ester are dissolved in 10 ml of ethanol and 25 mg of platinum (IV) oxide added. The suspension is vigorously stirred at RT for 4 h under a hydrogen atmosphere (atmospheric pressure). Thereafter, the reaction mixture is filtered through kieselguhr. It is washed twice with a mixture of ethanol and water, combined all filtrates and concentrated in vacuo. 940 mg of the target compound are obtained (79.9% of theory).

[α] _D ²⁰ = -7.4 °, c = 0.475, CHCl ₃

GC-MS (Method 9): R, = 3.88 min .; m / z = 234 (M + NH ₄₎ ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 4.50 (d, IH), 4.00-3.91 (m, 2H), 3.90 (s, 2H), 3.89-3.80 (m, 2H), 1.71- 1.45 (m, 6H), 1.40 (s, 9H).

Example 97A

? Ra "Λ - (-) - 4- (2-terΛ-butoxy-2-oxoethoxy) cyclopent-2-en-l-yl-4-nitrobenzoate

To a solution of 400 mg (1.87 mmol) cis - (-) - {[(? Li, 3 ₁ S) -3-hydroxycyclopentyl] oxy} acetic acid tert-butyl ester in 1.8 ml of THF under argon at RT in succession 881.4 mg (3.36 mmol) of triphenylphosphine, 561.6 mg (3.36 mmol) of 4-nitrobenzoic acid and 1.46 g (about 3.36 mmol) of a 40% solution of diethyl azodicarboxylate in toluene were added dropwise. After 3 h, another 0.5 eq. Triphenylphosphine and 0.5 eq. Diethylazodicarboxylat added in toluene and the reaction mixture stirred for a further 2 h at RT. The reaction mixture is then poured into water and extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated in vacuo. From the residue, the product is isolated by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 8: 1 → 3: 1). 555 mg (81.8% of theory) of the target compound are obtained.

[α] _D ²⁰ = -169.8 °, c = 0.48, CHCl ₃ LC-MS (Method 12): R, = 2.71 min .; m / z = 381 (M + NH ₄₎ ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.35 (d, 2H), 8.19 (d, 2H), 6.39-6.34 (m, IH), 6.20-6.17 (m, IH), 6.00- 5.95 (m, IH), 4.88-4.81 (m, IH), 4.04 (s, 2H), 2.32-2.19 (m, 2H), 1.43 (s, 9H).

Example 98A

trans - {-) - {[(4-Hydroxycyclopent-2-en-1-yl) oxy} acetic acid tert-butyl ester

300 mg (0.83 mmol) / raws - (-) - 4- (2-tert-butoxy-2-oxoethoxy) cyclopent-2-en-1-yl-4-nitrobenzoate are dissolved in 2.4 ml of THF and 0.6 ml of methanol and at RT with 0.9 ml of 1 N sodium hydroxide solution. After 30 minutes, the reaction mixture is poured into water and extracted three times with dichloromethane. The organic phases are combined and washed successively with sat. Sodium carbonate, sodium bicarbonate and sodium chloride solution. It is dried over magnesium sulfate and concentrated in vacuo. 137.3 mg (77.6% of theory) of the target compound are obtained.

[α] _D ²⁰ = -83.1 °, c = 0.525, CHCl ₃

GC-MS (Method 9): R, = 5.03 min .; m / z = 157 (MC ₄ H ₉ ) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 5.97 (s, 2H), 4.81 (d, IH), 4.79-4.71 (m, IH), 4.68-4.62 (m, IH), 3.93 ( s, 2H), 2.00-1.93 (m, IH), 1.80-1.73 (m, IH), 1.40 (s, 9H).

Example 99A

trans- [[4- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) cyclopent-2-en-1-yl] oxy} -acetic acid tert-butyl ester

250 mg (1.17 mmol) of tert-butyl (-) - {[(4-hydroxycyclopent-2-en-1-yl] oxy} acetate) are dissolved in 1.25 ml of THF and dissolved successively under argon with 309 mg (2.1 mmol) phthalimide, 550.9 mg (2.1 mmol) of triphenylphosphine and 914 mg (about 2.1 mmol) of a 40% solution of diethyl azodicarboxylate in toluene were added dropwise. After 3 h, another 0.5 eq. Triphenylphosphine and 0.5 eq. Diethylazodicarboxylat added in toluene and the reaction mixture stirred for a further 2 h at RT. The mixture is then poured into water and extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated in vacuo. From the residue, the product is isolated by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 8: 1 → 3: 1). 255 mg of the target compound are obtained (63.7% of theory).

[α] _D ²⁰ = -256.6 °, c = 0.545, CHCl ₃

LC-MS (Method 3): R, = 2.29 min .; m / z = 361 (M + NH ₄₎ ⁺

¹ H-NMR (400 MHz, DMSO-dβ): δ = 7.83 (s, 4H), 6.20-6.15 (m, IH), 5.97-5.90 (m, IH), 5.38-5.30 (m, IH), 4.92 -4.88 (m, IH), 4.03 (s, 2H), 2.40-2.30 (m, IH), 2.19-2.19 (m, IH), 1.46 (s, 9H).

Example IQOA

/ Rα «5 - {[(4-aminocyclopent-2-en-l-yl] oxy} acetic acid tert-butyl ester terΛ

120mg (0.349mmol) of "5 '- {[4- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) cyclopent-2-en-1-yl] oxy} Acetic acid tert-butyl ester in 0.3 ml of ethanol with 22 .mu.l (0.545 mmol) hydrazine monohydrate are added. The mixture is refluxed for 15 minutes. The result is a voluminous precipitate, which is removed after cooling by filtration and washed with a little ethanol. The filtrate is concentrated in vacuo and the product obtained (74 mg) used without further purification.

GC-MS (Method 9): R, = 4.93 min .; m / z = 214 (M + Η) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 5.96-5.90 (m, IH), 5.89-5.83 (m, IH), 4.68-4.60 (m, IH), 4.04-3.85 (m, 4H ), 2.07-1.98 (m, IH), 1.97-1.79 (m, IH), 1.68-1.57 (m, IH), 1.41 (s, 9H).

Example 101A

2- (2-fluorophenyl) -2-hydroxy-1- (4-methoxyphenyl) ethanone

441 ml (1.10 mol) of a 2.5 M n-butyllithium solution in n-hexane are added at -78 ° C to a solution of 156 ml (1.11 mol) of N, N-diisopropylamine in 1937 ml of 1,2-dimethoxyethane to the extent added dropwise that the temperature -60 ⁰ C does not exceed. After 15 minutes of stirring at this temperature, a solution of 236 g (1.00 mol) of (4-methoxyphenyl) [(trimethylsilyl) oxy] acetonitrile [N. Kurono, /. Org. Chem. 2005, 16, 6530-6532] was added dropwise in 753 ml of 1,2-dimethoxyethane. Subsequently, after stirring for 30 minutes at this temperature, a solution of 128 g (1.00 mol) of 2-fluorobenzaldehyde in 753 ml of 1,2-dimethoxyethane is added dropwise within 20 min. The reaction mixture is allowed to warm to room temperature over 4 h. After addition of 3800 ml sat. aqueous ammonium chloride solution is extracted with ethyl acetate. The organic phase is washed with sat. Washed ammonium chloride solution, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue is mixed with 3800 ml of dioxane, 2700 ml of methanol and 3120 ml of 1 M hydrochloric acid and stirred for 16 h at room temperature. After addition of 8000 ml sat. aqueous sodium chloride solution is extracted with 4000 ml of ethyl acetate. The aqueous phase is back-extracted with 2000 ml of ethyl acetate. The combined organic phases are washed with 2000 ml of water and 2000 ml of sat. Sodium chloride solution, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue is stirred in 600 ml of diisopropyl ether and filtered. The mother liquor is concentrated in vacuo. The residue is taken up in dichloromethane and purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 4: 1). The product fraction thus obtained is stirred in diisopropyl ether / petroleum ether (1: 1), filtered and dried in vacuo. This gives 94 g (80% purity, 29% of theory) of the title compound.

LC-MS (Method 7): R, = 4.59 min .; m / z = 261 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 7.93-7.91 (m, 2H), 7:28 to 7:18 (m, 2H), 7:10 to 7:04 (m, 2H), 6.89- 6.86 (m, 2H), 6.19 (d, IH), 4.69 (s, IH), 3.82 (s, 3H).

Example 102A

2-Amino-5- (2-fluorophenyl) -4- (4-methoxyphenyl) -3-furonitrile

84 g (0.32 mol) of 2- (2-fluoro-phenyl) -2-hydroxy-1- (4-methoxyphenyl) ethanone and 32 g (0.48 mol) of malononitrile are initially charged in 153 ml of THF. After stirring for five minutes 49 ml (36 g, 0.36 mol) of triethylamine are added with ice cooling. The reaction mixture is stirred for 1 h while cooling with ice. The reaction mixture is then allowed to warm to room temperature and stir for 4 h at this temperature. After addition of 1000 ml of ethyl acetate, the organic phase is washed five times with 300 ml of water, dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo. The residue is taken up in dichloromethane and purified by flash chromatography on silica gel (eluent: dichloromethane / methanol 70: 1, then cyclohexane / ethyl acetate 2: 1). 37 g (0.11 mol) of thereby recovered 2- (2-fluoro-phenyl) -2-hydroxy-l- (4-methoxyphenyl) ethanone are again according to the above procedure with 14 g (0.03 mol) of malononitrile and 21 ml (15 g , 0.15 mol) of triethylamine in 67 ml of THF. A total of 70 g (52% purity, 36% of theory) of the target compound are obtained.

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.23-7.11 (m, 4H), 7.03-6.95 (m, 2H), 6.82-6.79 (m, 2H), 4.86 (s, NH ₂ ), 3.74 (s, 3H).

Example 103A

6- (2-Fluoφhenyl) -5- (4-methoxyphenyl) furo [2,3-d] pyrimidin-4 (3H) -one

436 ml of acetic anhydride are added dropwise at 0 ⁰ C with 268 ml of formic acid and stirred for 30 min at this temperature. Then, a solution of 70 g (0.12 mol) of 2-amino-5- (2- fluorophenyl) -4- (4-methoxyphenyl) -3-furonitrile added in 100 ml of acetic anhydride and the mixture stirred for 24 h at 130 ⁰ C. After cooling to room temperature, the batch is in the oil pump vacuum concentrated at 50 ⁰ C. The residue is stirred in 250 ml of diisopropyl ether with ice cooling for 30 min, filtered, washed with 70 ml of diisopropyl ether and dried in vacuo. There are obtained 23.7 g (60% of theory) of the title compound.

HPLC (Method 1): R _t = 4.27 min.

MS (DCI): m / z = 354 (M + NHO ^*

¹ H-NMR (400 MHz, CDCl _3): δ = 12.68 (br s, NH.), 8.19 (d, IH), 7:53 to 7:45 (m, 2H), 7:34 to 7:25 (m, 4H), 6.91- 6.88 (m, 2H), 3.76 (s, 3H).

Example 104A

4-chloro-6- (2-fluorophenyl) -5- (4-methoxyphenyl) furo [2,3-d] pyrimidine

A mixture of 20 g (0.06 mol) of 6- (2-fluorophenyl) -5- (4-methoxyphenyl) furo [2,3-d] pyrimidin-4 (3H) -one in 78 ml sulfolane and 11 ml (18 g , 0.12 mol) of phosphoryl chloride is stirred at 120 ^° C. for 1 h. After cooling to room temperature, the reaction solution is added dropwise with vigorous stirring and ice cooling in a mixture of 1000 ml of water and 100 ml of 25% aqueous ammonia solution. The precipitated at 10 ⁰ C solid is filtered off and washed several times with water. The solid is dissolved again in 700 ml of ethyl acetate and the solution washed twice with 500 ml of water. The organic phase is dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue is stirred in 60 ml of diisopropyl ether, filtered and dried in vacuo. There are obtained 18 g (81% of theory) of the title compound.

ΗPLC (Method 1): R, = 5.03 min. ¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.90 (s, IH), 7.58-7.50 (m, 2H), 7.36-7.27 (m, 4H), 7.01-6.97 (m, 2H) , 3.79 (s, 3H).

Example 105A

l- (4-ethylphenyl) -2- (2-fluorophenyl) -2-hydroxy-ethanone

217 ml (0.54 mol) of a 2.5 M n-butyllithium solution in hexane are added dropwise at -78 ° C to a solution of 77 ml (56 g, 0.55 mol) of N, N-diisopropylamine in 960 ml of 1, 2-dimethoxyethane that the temperature does not exceed -60 ⁰ C. After stirring for 15 minutes at this temperature, a solution of 116 g (0.50 mol) of (4-ethylphenyl) [(trimethylsilyl) oxy] acetonitrile is obtained within 30 min [DS Dhanoa, J. Med. Chem. 1993, 36 (23 ), 3738-3742] in 373 ml of 1, 2-dimethoxyethane was added dropwise. Subsequently, after stirring for 30 minutes at this temperature, a solution of 64 g (0.50 mol) of 2-fluorobenzaldehyde in 373 ml of 1,2-dimethoxyethane is added dropwise within 20 min. The reaction mixture is allowed to warm to room temperature over 4 h. After addition of 1900 ml of sat. aqueous ammonium chloride solution is extracted with ethyl acetate. The organic phase is washed with sat. Ammomum chloride solution, dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo. The residue is treated with 1900 ml of dioxane, 1350 ml of methanol and 1560 ml of 1 M hydrochloric acid and stirred for 16 h at room temperature. After addition of 4000 ml of sat. aqueous sodium chloride solution is extracted with 2000 ml of ethyl acetate. The organic phase is washed with 1000 ml of water and 1000 ml sat. Washed sodium chloride solution, dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1). The product fraction thus obtained is stirred in 80 ml of diisopropyl ether and 240 ml of petroleum ether, filtered, washed with petroleum ether and dried in vacuo. There are obtained 50 g (85% purity, 33% of theory) of the title compound.

HPLC (Method 1): R, = 4.50 min.

MS (DCI): m / z = 276 (M + NK,) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 7.87-7.85 (m, 2H), 7:28 to 7:19 (m, 4H), 7:11 to 7:04 (m, 2H), 6.22 (d, IH), 4.64 ( d, IH), 2.65 (q, 2H), 1.21 (t, 3H). Example 106 A

2-Amino-4- (4-ethylphenyl) -5- (2-fluorophenyl) -3-fiironitril

50 g (0.19 mol) of 1- (4-ethylphenyl) -2- (2-fluorophenyl) -2-hydroxyethanone and 17 g (0.25 mol) of malononitrile are introduced into 93 ml of DMF. After stirring for five minutes, 17 ml (12 g, 0.12 mol) of diethylamine are added with ice-cooling. The reaction mixture is stirred for 1 h while cooling with ice. Then allowed to warm to room temperature and stir for 4 h at this temperature. After addition of 500 ml of water, the aqueous phase is decanted after stirring for 30 minutes. By adding 500 ml of water again and decanting again, an oily residue is obtained, which is dissolved in ethyl acetate, dried over sodium sulphate and filtered. The filtrate is concentrated in vacuo. The residue, according to TLC analysis (mobile phase: cyclohexane / ethyl acetate 4: 1), still contains 1- (4-ethylphenyl) -2- (2-fluorophenyl) -2-hydroxyethanone. The residue is therefore again reacted in accordance with the above instructions in 90 ml of DMF with 5.5 g (0.08 mol) of malononitrile and 10 ml (7 g, 0.10 mol) of diethylamine. The reaction mixture is poured into 500 ml of ethyl acetate and washed three times with 300 ml of water and once with 300 ml of sat. Sodium chloride solution washed. The organic phase is dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 3: 1). There are obtained 36 g (61% of theory) of the title compound, which are reacted without further characterization.

Example 107A

5- (4-ethylphenyl) -6- (2-fluoφhenyl) furo [2,3-d] pyrimidin-4 (3H) -one

280 ml (2.97 mol) of acetic anhydride are treated dropwise at 0 ⁰ C with 140 ml (3.71 mol) of formic acid and stirred for 30 min at this temperature. Then 36.0 g (0:12 mol) of 2-amino-4- (4-ethylphenyl) -5- (2-fluoφhenyl) -3-ruronitril are added and the mixture stirred for 24 h at 130 ⁰ C. After cooling to room temperature, the mixture is concentrated in an oil pump vacuum at 50 ⁰ C. The residue is stirred in 150 ml of diisopropyl ether at -10 ⁰ C for 30 minutes, filtered, washed with 50 ml of ice-cold diisopropyl ether and dried in vacuo. There are obtained 20.6 g (86% purity, 45% of theory) of the title compound.

HPLC (Method 1): R, = 4.65 min.

MS (ESIpos): m / z = 335 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.68 (br.s, NH), 8.20 (s, IH), 7.53-7.45 (m, 2H), 7.36-7.25 (m, 4H), 7.21- 7.16 (m, 2H), 2.61 (q, 2H), 1.19 (t, 3H).

Example 108A

4-chloro-5- (4-ethylphenyl) -6- (2-fluorophenyl) furo [2,3-d] pyrimidine

A suspension of 20.0 g (0.06 mol) of 5- (4-ethylphenyl) -6- (2-fluorophenyl) furo [2,3-d] pyrimidine-4 (3H) -one in 100 ml (165 g, 1.07 mol) Phosphoryl chloride is stirred at 120 ⁰ C for 1 h. After cooling to room temperature, the reaction solution with vigorous stirring in a mixture of Added dropwise 330 ml of water and 610 ml of 25% aqueous ammonia solution, with a temperature increase to 55-65 ° C is observed. The reaction mixture is allowed to cool to room temperature. After two extractions with 500 ml dichloromethane, the organic phase is washed with sat. washed aqueous sodium chloride solution, dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo. The residue is stirred in 150 ml of petroleum ether, filtered off, washed with ice-cooled petroleum ether and dried in vacuo. There are obtained 18.7 g (90% purity, 80% of theory) of the title compound.

LC-MS (Method 6): R _t = 3.14 min .; m / z = 353 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.91 (s, IH), 7.58-7.49 (m, 2H), 7.36-7.24 (m, 6H), 2.66 (q, 2H), 1.21 (t, 3H).

Example 109A

l - [(Z) -2-chloro-2-nitro-vinyl] -4-ethylbenzene

Analogous literature specification [D. Dauzonne, Synthesis, 1990, 66-70], a mixture of 10.0 g (74.5 mmol) of 4-ethylbenzaldehyde, 6.8 ml (13.7 g, 97.6 mmol) of bromonitromethane, 54.7 g (670.7 mmol) of dimethyl ammonium chloride and 0.6 g (11.2 mmol) of potassium fluoride in 150 ml of xylene on

Water at 160 ⁰ C for 15 hours and then stirred at 175 ° C for seven hours. After addition of 25 ml of water and 100 ml of dichloromethane, the organic phase is separated and the aqueous phase extracted three times with 100 ml of dichloromethane. The combined organic extracts are dried over sodium sulfate, filtered and concentrated in vacuo.

The residue is chromatographed on silica gel (mobile phase: cyclohexane / dichloromethane 1: 1).

11.9 g (85% purity, 64% of theory) of the target compound are obtained.

LC-MS (Method 8): R, = 2.84 min.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.60 (s, IH), 7.94 (d, 2H), 7.42 (d, 2H), 2.68 (q, 2H), 1.21 (t, 3H).

Example HOA

5- (4-ethylphenyl) furo [2,3-d] pyrimidin-4 -one (3H)

Analogous literature specification [D. Dauzonne, Tetrahedron, 1992, 3069-3080], a suspension of 11.9 g (85% purity, 47.6 mmol) of l - [(Z) -2-chloro-2-nitrovinyl] -4-ethylbenzene and 5.9 g (52.3 mmol) 4,6-Dihydroxypyrimidine in 200 ml of ethanol for 30 minutes at 60-70 ° C stirred. Subsequently, 14.4 ml (14.6 g, 96.1 mmol) of l, 8-diazabicyclo [5.4.0] undec-7-ene are slowly added. The resulting reaction solution is refluxed for six hours and then for 15 hours

6O ⁰ C stirred. After concentration in vacuo, the residue is taken up in dichloromethane and chromatographed on silica gel (mobile phase: cyclohexane / ethyl acetate 1: 1 -> 1: 5). The resulting solid is stirred in diethyl ether and filtered. There are obtained 5.0 g (44% of theory) of the target compound.

LC-MS (Method 8): R _t = 2.14 min .; m / z = 241 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.68 (br, s, NH), 8.18 (d, 2H), 7.87 (d, 2H), 7.26 (d, 2H), 2.63 (q, 2H), 1.20 (t, 3H).

Example 11 IA

5- (4-ethylphenyl) -6-iodfuro [2,3-d] pyrimidin-4 (3H) -one

A solution of 5.0 g (20.9 mmol) of 5- (4-ethylphenyl) furo [2,3-d] pyrimidin-4 (3H) -one in 250 ml

Acetonitrile / tetrachloromethane (1: 1) is treated with 7.0 g (31.3 mmol) of N-iodosuccinimide. The resulting suspension is stirred under reflux for two hours. After cooling to room temperature, the reaction mixture is concentrated in vacuo. The residue is dissolved in acetic acid stirred ethyl ester and filtered. The filtrate is mixed with water. After separation of the organic phase, the aqueous phase is extracted several times with ethyl acetate. The combined organic phases are concentrated in vacuo. The residue is taken up in ethyl acetate and chromatographed on silica gel (mobile phase: cyclohexane / ethyl acetate 1: 1 → 1: 2). The resulting solid is stirred in diethyl ether / n-pentane and filtered. 1.4 g (85% purity, 16% of theory) of the target compound are obtained.

LC-MS (Method 8): R, = 2.34 min .; m / z = 367 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 12.68 (br.s, NH), 8.10 (s, IH), 7.48 (d, 2H), 7.29 (d, 2H), 2.66 (q , 2H), 1.23 (t, 3H).

Example 1 12.Λ

4-chloro-5- (4-ethylphenyl) -6-iodfuro [2,3-d] pyrimidine

A suspension of 1.4 g (85% purity, 3.3 mmol) of 5- (4-ethylphenyl) -6-iodo-furo [2,3-d] pyrimidin-4 (3H) -one in 20 ml (32.9 g, 214.6 mmol ) Phosphoryl chloride is stirred for one hour under reflux. After concentration in vacuo, the residue is treated with ice-cold water and dichloromethane. The organic phase is dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo and dried. 1.0 g (70% purity, 57% of theory) of the target compound is obtained.

LC-MS (Method 6): R, = 2.97 min .; m / z = 385 (M + Η) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.80 (s, IH), 7.43-7.36 (m, 4H), 2.70 (q, 2H), 1.26 (t, 3H).

Example 113A

4 - {[(5Λ) -l-benzyl-3-yl] oxy} -5- (4-ethylphenyl) -6-iodfuro [2,3-d] pyrimidine

A solution of 483 mg (2.53 mmol) of (5R) -l-benzylpiperidin-3-ol [H. Tomori, Bull. Chem. Soc. Jpn. 69, 1, 207-216 (1996)] in 5 ml of THF, 106 mg (2.65 mmol) of sodium hydride (60% dispersion in mineral oil) are added. After stirring for ten minutes, a solution of 1020 mg (70% purity, 1.86 mmol) of 4-chloro-5- (4-ethylphenyl) -6-iodofiiro [2,3-d] pyrimidine in 5 ml of THF and 47 mg (0.13 mmol) of tetra-n-butylammonium iodide. The reaction mixture is stirred for five hours at room temperature. After addition of water and ethyl acetate, the separated organic phase with 1 N hydrochloric acid and sat. Sodium chloride solution and then concentrated in vacuo. The residue is taken up in acetonitrile and purified by preparative RP-HPLC (gradient: water / acetonitrile). There are obtained 266 mg (20% of theory) of the desired product.

LC-MS (Method 8): R, = 1.93 min .; m / z = 540 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.46 (s, IH), 7.58-7.56 (m, 2H), 7.32-7.29 (m, 2H), 7.24-7.17 (m, 5H), 5.34- 5.29 (m, IH), 3.45 (d, 2H), 2.71-2.63 (m, 3H), 2.39-2.33 (m, 2H), 2.30-2.24 (m, IH), 1.89-1.84 (m, IH), 1.66-1.60 (m, IH), 1.47-1.39 (m, 2H), 1.21 (t, 3H).

Example 114A

4 - {[(5A) -l-benzyl-3-yl] oxy} -5- (4-ethylphenyl) -6- (2-fluoφhenyl) furo [2,3-d] pyrimidine

A mixture of 365 mg (0.68 mmol) of 4 - {[(3R) -l-benzylpiperidin-3-yl] oxy} -5- (4-ethylphenyl) -6-iodo-furo [2,3-d] pyrimidine and 24 mg (0.03 mmol) bis (triphenylphosphine) palladium (II) chloride in 15 ml of DMSO is mixed with 0.68 ml of a 2 M aqueous sodium carbonate solution. Subsequently, 118 mg (0.85 mmol) (2-fluorophenyl) boronic acid was added and the mixture stirred for 15 hours at 80 ⁰ C. The reaction mixture is then filtered and purified directly by preparative RP-HPLC (gradient: water / acetonitrile). 291 mg (84% of theory) of the target compound are obtained.

LC-MS (Method 12): R _t = 2.18 min .; m / z = 508 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.57 (s, IH), 7.57-7.53 (m, 2H), 7.39-7.29 (m, 4H), 7.24-7.18 (m, 7H) , 5.40-5.34 (m, IH), 3.49-3.46 (m, 2H), 2.74-2.69 (m, IH), 2.62 (q, 2H), 2.43-2.35 (m, 2H), 2.32-2.25 (m, IH), 1.94-1.87 (m, IH), 1.71-1.64 (m, IH), 1.50-1.44 (m, 2H), 1.17 (t, 3H).

Example 115A

(JΛ) -3 - {[5- (4-ethylphenyl) -6- (2-fluoφhenyl) furo [2,3-d] pyrimidin-4-yl] oxy} piperidiniumformiat

An argon-overlaid solution of 275 mg (0.54 mmol) of 4 - {[(3R) -l-benzylpiperidin-3-yl] oxy} -5- (4-ethylphenyl) -6- (2-fluorophenyl) furo [2, 3-d] pyrimidine in 5 ml of methanol / ethanol (1: 2) is mixed with 30 mg of 10% palladium on activated charcoal and stirred for three hours under a hydrogen atmosphere (atmospheric pressure) at room temperature. After addition of another 70 mg of 10% palladium on activated carbon, the reaction mixture is again stirred for 19 hours under a hydrogen atmosphere (atmospheric pressure) at room temperature. Another 175 mg of 10% palladium on charcoal and 0.2 ml of formic acid are added and the reaction mixture stirred again for 15 hours under a hydrogen atmosphere (atmospheric pressure) at room temperature. After filtering off the catalyst, the catalyst residue is washed with methanol / water. The filtrate is concentrated in vacuo, the residue taken up in acetonitrile / DMSO and purified by preparative RP-HPLC (gradient: water / acetonitrile / formic acid). There are obtained 137 mg (54% of theory) of the desired product.

LC-MS (Method 8): R ₁ = 1.74 min .; m / z = 418 (M-HCO ₂ H + H) ⁺ ¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.57 (s, IH), 7.57-7.53 (m, 2H), 7.39-7.29 (m, 4H), 7.24-7.18 (m, 7H), 5.40-5.34 (m, IH), 3.49-3.46 (m, 2H), 2.74-2.69 (m, IH), 2.62 (q, 2H), 2.43-2.35 (m, 2H), 2.32-2.25 (m, IH ), 1.94-1.87 (m, IH), 1.71-1.64 (m, IH), 1.50-1.44 (m, 2H), 1.17 (t, 3H).

Example 116A

3 - {[5- (4-ethylphenyl) -6- (2-fluoφhenyl) furo [2,3-d] pyrimidin-4-yl] oxy} cyclohexanol

A mixture of 1.65 g (14.17 mmol) of cyclohexane-l, 3-diol in 45 ml of toluene, 15 ml of 1, 2-dimethoxy- ethane and 15 ml of water is added at 70 ⁰ C with 4.5 ml of 12.5 N sodium hydroxide solution. After addition of 0.19 g (0.57 mmol) of tetra-n-butylammonium hydrogensulfate and 2.0 g (5.67 mmol) of 4-chloro-5- (4-ethylphenyl) -6- (2-fluoro-phenyl) furo [2,3-d] pyrimidine the reaction mixture was stirred at 70 ⁰ C for 17 hours. After cooling to room temperature with conc. Hydrochloric acid adjusted to pH 7. It is extracted with dichloromethane. The organic phase is washed with sat. Sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed on silica gel (mobile phase: cyclohexane / ethyl acetate 2: 1). 0.60 g (24% of theory) of the desired product are obtained as racemic diastereomer mixture.

LC-MS (Method 8): R, = 2.96 min .; m / z = 433 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): [minor stereoisomer in parentheses] δ = 8.62 (s, IH), [8.61, s, IH], 7.57-7.52 (m, 2H), 7.34-7.28 (m, 4H), 7.20-7.18 (m, 2H), [5.68-5.64, m, IH], 5.21-5.14 (m, IH), 4.75 (d, OH), [4.45, d, OH], 3.57 -3.48 (m, IH), 2.63 (q, 2H), 2.37-2.31 (m, IH), 2.08-2.03 (m, IH), 1.82-1.77 (m, IH), 1.74-1.69 (m, IH) , 1.34-1.02 (m, 4H), 1.20 (t, 3H).

Example 117A

4 - {[(3R) -l-benzyl-3-yl] oxy} -6- (2-fluorophenyl) -5- (4-methoxyphenyl) furo [2,3-d] pyrimidine

1037 mg (5.37 mmol) of (3R) -l-benzylpiperidin-3-ol [H. Tomori, Bull. Chem. Soc. Jpn. 69, 1, 207-216 (1996)] are dissolved in 10 ml of THF and treated with 268 mg (6.71 mmol) of sodium hydride (60% in mineral oil). After 10 minutes, a solution of 2000 mg (5.64 mmol) of 4-chloro-6- (2-fluorophenyl) -5- (4-methoxyphenyl) furo [2,3-d] pyrimidine in 10 ml of THF and 99 mg (0.27 mmol) of tetra-n-butylammonium iodide. The reaction mixture is refluxed for 16 hours. Subsequently, 100 ml of water and 100 ml of ethyl acetate are added. The organic phase is separated and washed with 50 ml of 1 N hydrochloric acid and 100 ml of sat. Sodium chloride solution washed. The aqueous phase is back-extracted with 50 ml of ethyl acetate, the combined organic extracts are dried over sodium sulfate, filtered and concentrated in vacuo. There are obtained 2645 mg (89% of theory, 92% purity) of the desired product.

LC-MS (Method 8): R _t = 1.92 min .; m / z = 510 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.63 (s, IH), 7.58-7.51 (m, 2H), 7.51-7.43 (m, 5H), 7.34-7.25 (m, 4H) , 6.93-6.88 (m, 2H), 5.62-5.58 (m, IH), 3.77 (s, 3H), 3.68-3.66 (m, IH), 2.89-2.83 (m, IH), 2.36-2.27 (m, 2H), 1.91-1.81 (m, 3H), 1.51-1.45 (m, IH).

Example 118A

6- (2-fluorophenyl) -5- (4-methoxyphenyl) -4 - [(3R) -piperidin-3-yloxy] ruro [2,3-d] pyrimidin-formate

An argon-overlaid solution of 510 mg (1.00 mmol) of 4 - {[(3R) -l-benzyl-piperidin-3-yl] -oxy} -6- (2-fluoro-phenyl) -5- (4-methoxyphenyl) -tetiro [2 , 3-d] pyrimidine in 5 ml of a 4.4% solution of formic acid in methanol is treated with 400 mg of palladium black and stirred for two days at room temperature. After filtering off the catalyst, the catalyst residue is washed with methanol / water. The filtrate is concentrated in vacuo and the residue is purified by preparative RP-HPLC (eluent: water / acetonitrile gradient with 0.1% formic acid). There are obtained 70 mg (12% of theory, 80% purity) of the desired product.

LC-MS (Method 8): R _t = 1.66 min .; m / z = 420 (M-HCO ₂ H + H) ⁺ .

Example 119A

6- (2-fluorophenyl) -5- (4-methoxyphenyl) -4 - [(3R) -piperidin-3-yloxy] furo [2,3-d] pyrimidine

An argon-overlaid solution of 2600 mg (4.69 mmol) of 4 - {[(3R) -l-benzylpiperidin-3-yl] oxy} -6- (2-fluorophenyl) -5- (4-methoxyphenyl) ruro [2, 3-d] pyrimidine in 25 ml of a 4.4% solution of formic acid in methanol is mixed with 300 mg of palladium black and stirred for five hours at room temperature. Thereafter, 300 mg of palladium black and 0.9 ml of formic acid are added again and stirred for a further 16 hours at room temperature. After filtering off the catalyst, the catalyst residue is washed with methanol / water. The filtrate is concentrated in vacuo, the residue is stirred in acetonitrile, filtered off and dried in vacuo. There are obtained 1376 mg (68% of theory) of the desired product.

LC-MS (Method 8): R, = 1.62 min .; m / z = 420 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.66 (s, IH), 7.58-7.52 (m, 2H), 7.42 (d, 2H), 7.35-7.30 (m, 2H), 6.93 ( d, 2H), 5.45-5.40 (m, IH), 3.77 (s, 3H), 3.47-3.30 (m, 2H), 3.10-3.04 (m, 2H), 2.07-2.02 (m, IH), 1.78- 1.71 (m, 3H). Example 120A

3 - [(2R, 4R) -1- (tert -butoxycarbonyl) -4- {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} piperidine 2-yl] propansäuremethylester

631.7 mg (1.87 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine and 490 mg (1.71 mmol) of tert-butyl (2R, 4R) -4-hydroxy 2- (3-methoxy-3-oxopropyl) piperidine-l-carboxylate are dissolved in 1 ml DMF, cooled to -10 ⁰ C and 1:02 ml (2:05 mmol) of phosphazene base P2-t-Bu (about 2 M Solution in THF). The reaction mixture is stirred for 1 h at 0 ⁰ C and then added to water. Extract three times with dichloromethane, combine the organic phases, wash with sat. Sodium chloride solution and dried over magnesium sulfate. After concentration in vacuo, the product is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 20: 1 → 3: 1). 420 mg (38.1% of theory) of the target compound are obtained.

LC-MS (Method 8): R, = 3.26 min .; m / z = 588 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.60 (s, IH), 7.55 (d, 2H), 7.43-7.32 (m, 5H), 7.02 (d, 2H), 5.58 (s , IH), 4.02-3.93 (m, IH), 3.82 (s, 3H), 3.70-3.60 (m, IH), 3.51 (s, 3H), 1.91-1.60 (m, 6H), 1.47-1.39 (m , IH), 1.36 (s, 9H), 1.16-1.05 (m, 2H).

Example 121A

3 - [(2R, 4R) -l- (/ erΛ-butoxycarbonyl) -4 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} piperidine 2-yl] propanoic acid

35 mg (0.06 mmol) of 3 - [(2R, 4R) -l- (tert-butoxycarbonyl) -4 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine-4- yl] oxy} piperidin-2-yl] propanoic acid methyl ester are dissolved in 0.1 ml of methanol, cooled to 0 ⁰ C and treated with about 240 mg of 10% sodium hydroxide solution. The mixture is stirred at about 40 ⁰ C for several hours, then at RT overnight. The reaction mixture is then made slightly acidic with 1 N hydrochloric acid (pH about 3) and extracted several times with dichloromethane. The combined organic phases are washed with sat. Sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The target compound is obtained in quantitative yield (34 mg) and not further purified.

Example 122A

[L - ({[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} methyl) cyclobutyl] methanol

A solution of 1.72 g (14.85 mmol) cyclobutane-1,1-diyl-dimethanol [FX Tavares, J. Med. Chem. 2004, 47 (21), 5057-5068] in 20 ml toluene, 8 ml 1,2- Dimethoxyethane and 8 ml of water are added at 70 ^° C. with 2.6 ml of an 11.25 N sodium hydroxide solution. After addition of 0.10 g (0.30 mmol) tetra-rt-butylammoniumhydrogensulfat and 1.00 g (2.97 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine, the reaction mixture is 17 h at 70 ⁰ C stirred. After cooling to room temperature, it is adjusted to pH 7 with concentrated hydrochloric acid. It is extracted three times with 50 ml dichloromethane. The combined organic extracts are washed with sat. Sodium chloride solution, dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo. The residue is stirred in acetonitrile, filtered and the filtrate is purified by prepara ratified RP-HPLC (gradient: water / acetonitrile). There are obtained 0.30 g (24% of theory) of the desired product.

LC-MS (Method 3): R, = 2.67 min .; m / z = 417 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.58 (s, IH), 7.56-7.54 (m, 2H), 7.42-7.37 (m, 5H), 7.04-6.99 (m, 2H) , 4.56 (t, IH), 4.30 (s, 2H), 3.81 (s, 3H), 3.21 (d, 2H), 1.77-1.58 (m, 6H).

EXAMPLES

example 1

3 - {[6- (4-bromophenyl) -5-phenylfiiro [2,3-d] pyrimidin-4-yl] amino} phenoxy-methyl acetate

400 mg (1.04 mmol) of 6- (4-bromophenyl) -4-chloro-5-phenylfuro [2,3-d] pyrimidine (preparation according to WO 03/018589) and 225.5 mg (1.25 mmol) of methyl 3-aminophenoxyacetate heated in an oil bath for 1.5 h at 150 ⁰ C. After cooling, the residue is taken up in DMSO and filtered through silica gel (mobile phase: cyclohexane / ethyl acetate 2: 1). 140 mg (25.5% of theory) of the target compound are obtained as a yellowish solid.

LC-MS (method 5): R, = 3.30 min .; m / z = 530, 532 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.57 (s, IH), 7.19 (s, 5H), 7.61 (d, 2H), 7.44 (d, 2H), 7.22- 7.18 (m, 2H), 6.82 (s, IH), 6.86 (dd, IH), 6.61 (dd, IH), 4.77 (s, 2H), 3.71 (s, 3H).

Example 2

3 - [(5,6-Diphenylfüro [2,3-d] pyrimidin-4-yl) amino] phenoxy-methyl acetate

200 mg (0.377 mmol) of methyl 3 - {[6- (4-bromophenyl) -5-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxyacetate are dissolved in 5 ml of dichloromethane and 2 ml of THF and under argon with 40 mg of 10% palladium on activated carbon. The mixture is stirred under a hydrogen atmosphere of 3 bar overpressure for 3 h at RT, before the catalyst is filtered off. Wash the catalyst residue with dichloromethane and methanol, concentrate the combined Filtrate in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / ethyl acetate 10: 1). 79.1 mg (45.5% of theory) of the target compound are obtained as a colorless solid.

LC-MS (Method 3): R, = 2.87 min .; m / z = 452 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO-Cl ₆ ): δ = 8.58 (s, IH), 7.70 (s, 5H), 7.56-7.51 (m, 2H), 7.44-7.38 (m, 3H), 7.25- 7.18 (m, 2H), 6.80 (s, IH), 6.78 (dd, IH), 6.61 (dd, IH), 4.78 (s, 2H), 3.72 (s, 3H).

Example 3

3 - [(5,6-Diphenylfuro [2,3-d] pyrimidin-4-yl) amino] phenoxy-acetic acid

50 mg (0.111 mmol) of methyl 3 - [(5,6-diphenylfuro [2,3-d] pyrimidin-4-yl) amino] phenoxyacetate are dissolved in 2 ml of THF, at RT with 0.33 ml of 1 N sodium hydroxide solution added and stirred at 50 ⁰ C for 1 h. It is cooled to RT and the THF removed in vacuo. The residue is treated with water and then with ice cooling with 1 N hydrochloric acid. The precipitated solid is filtered off, washed several times with water and dried in vacuo. 39.4 mg (81.3% of theory) of the target compound are obtained as a white solid.

LC-MS (Method 3): R, = 2.52 min .; m / z = 438 (M + H) ⁺

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 13.04 (br.s, IH), 8.58 (s, IH), 7.19 (s, 5H), 7.55-7.50 (m, 2H), 7.44-7.36 ( m, 3H), 7.24-7.14 (m, 2H), 6.82-6.77 (m, 2H), 6.60 (dd, IH), 4.62 (s, 2H).

Example 4

3 - {[6- (4-Bromophenyl) -5- (4-fluoro-phenyl) -furo [2,3-d] pyrimidin-4-yl] -amino} -phenoxy-acetic acid methyl ester

400 mg (0.991 mmol) of 6- (4-bromophenyl) -4-chloro-5- (4-fluorophenyl) mro [2,3-d] pyrimidine (preparation see WO 03/018589) and 215.5 mg (1.19 mmol) of 3 -Aminophenoxy-acetic acid methyl ester are heated in an oil bath for 1.5 h at 150 ⁰ C. After cooling, the residue is taken up in DMSO and filtered through silica gel (mobile solvent: dichloromethane / ethyl acetate 10: 1). 242 mg of a mixture are isolated, which is further purified by preparative HPLC. 120 mg (15% of theory) of the target compound are obtained as a colorless solid.

LC-MS (Method 6): R _t = 3.2 min .; m / z = 548, 550 (M + H) ⁺ .

Example 5

3 - {[5- (4-fluorophenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxy-methyl acetate

115 mg (0.21 mmol) of methyl 3 - {[6- (4-bromophenyl) -5- (4-fluorophenyl) furo [2,3-d] pyrimidin-4-yl] amino} phenoxyacetate are dissolved in 5 ml of dichloromethane Dissolved 5 ml of ethyl acetate and added under argon with 22 mg of 10% palladium on activated carbon. The mixture is stirred under a hydrogen atmosphere of 3 bar overpressure at RT until the starting material is completely reacted. The catalyst is filtered off, the resulting filtrate is concentrated in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / ethyl acetate 10: 1). 27.9 mg (28.3% of theory) of the target compound are obtained as a colorless solid.

LC-MS (Method 6): R _t = 3.02 min .; m / z = 470 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO- (I ₆ ): δ = 8.55 (s, IH), 7.74-7.68 (m, 2H), 7.55-7.39 (m, 6H), 7.26-7.20 (m, 2H) , 7.02 (s, IH), 6.86 (d, IH), 6.63 (dd, IH), 4.78 (s, 2H), 3.71 (s, 3H). Example 6

3 - {[5- (4-Fluoφhenyl) -6-phenylfiiro [2,3-d] pyrimidin-4-yl] amino} phenoxy-acetic acid

21.1 mg (0.045 mmol) of methyl 3 - {[5- (4-fluorophenyl) -phenyl-2,3-d] pyrimidin-4-yl] -amino} -phenoxyacetate are dissolved in 1 ml of THF at RT with 0.135 ml of 1 N sodium hydroxide solution and stirred at 50 ⁰ C for 1 h. It is cooled to RT and the THF removed in vacuo. The residue is treated with water and then with ice cooling with 1 N hydrochloric acid. The precipitated solid is filtered off, washed several times with water and dried at 40 ⁰ C in a vacuum. Obtained are 11.5 mg (56.2% of theory) of the target compound as a white solid.

LC-MS (Method 3): R, = 2.51 min .; m / z = 456 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO-Ct ₆ ): δ = 13.03 (br.s, IH), 8.55 (s, IH), 7.75-7.69 (m, 2H), 7.55-7.38 (m, 7H), 7.8-7.19 (m, 2H), 6.98 (s, IH), 6.83 (dd, IH), 6.61 (dd, IH), 4.65 (s, 3H).

Example 7

3 - {[5,6-bis (4-methoxyphenyl) -furo [2,3-d] pyrimidin-4-yl] amino} phenoxy-methyl acetate

400 mg (1.091 mmol) of 4-chloro-5,6-bis (4-methoxyphenyl) furo [2,3-d] pyrimidine (preparation see WO 03/018589) and 237.1 mg (1.309 mmol) of methyl 3-aminophenoxyacetate heated in an oil bath for 1.5 h at 150 ⁰ C. After cooling, the residue is treated with dichloromethane and purified over silica gel (mobile phase: dichloromethane / ethyl acetate 10: 1). Contained are 139.3 mg (25% of theory) of the target compound as a pale yellow solid. LC-MS (Method 6): R, = 3.02 min .; m / z = 512 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.51 (s, IH), 7.58 (d, 2H), 7.48 (d, 2H), 7.28-7.18 (m, 4H), 6.99 (d, 2H), 6.87 (s, IH), 6.80 (d, IH), 6.61 (dd, IH), 4.78 (s, 2H), 3.89 (s, 3H), 3.28 (s, 3H), 3.21 (s, 3H ).

Example 8

3 - {[5,6-bis (4-methoxyphenyl) -furo [2,3-d] pyrimidin-4-yl] amino} phenoxy-acetic acid

107 mg (0.209 mmol) of methyl 3 - {[5,6-bis (4-methoxyphenyl) furo [2,3-d] pyrimidin-4-yl] amino} phenoxyacetate are dissolved in 2 ml of THF at RT with 0.628 g ml of 1 N sodium hydroxide solution and stirred at 50 ⁰ C for 1 h. It is cooled to RT and the THF removed in vacuo. The residue is treated with water and then with ice cooling with 1 N hydrochloric acid. The precipitated solid is filtered off, washed several times with water and dried at 40 ⁰ C in a vacuum. Obtained are 92.5 mg (88.9% of theory) of the target compound as a white solid.

LC-MS (Method 5): R ₁ = 2.74 min .; m / z = 498 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO- (I ₆ ): δ = 13.04 (br.s, IH), 8.51 (s, IH), 7.61 (d, 2H), 7.46 (d, 2H), 7.28-7.18 (m, 4H), 6.98 (d, 2H), 6.85 (s, IH), 6.77 (d, IH), 6.59 (dd, IH), 4.65 (s, 2H), 3.90 (s, 3H), 3.78 ( s, 3H).

Example 9

3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxy-acetic acid methyl ester

4.7 g (14 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine and 3.03 g (16.7 mmol) of methyl 3-aminophenoxyacetate are heated to 150 in an oil bath for 1.5 h ⁰ C heated. After cooling, the residue is treated with dichloromethane and purified over silica gel (mobile phase: cyclohexane / ethyl acetate 2: 1). 2.29 g (34.1% of theory) of the target compound are obtained as a pale yellowish solid.

LC-MS (Method 5): R _t = 3.08 min .; m / z = 482 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO- (I ₆ ): δ = 8.56 (s, IH), 7.60 (d, 2H), 7.56-7.50 (m, 2H), 7.44-7.35 (m, 3H), 7.28 -7.20 (m, 4H), 6.91 (s, IH), 6.81 (dd, IH), 6.64 (dd, IH), 4.78 (s, 2H), 3.90 (s, 3H), 3.71 (s, 3H).

Example 10

3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxy-acetic acid

1000 mg (2.08 mmol) of 3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxy oxyacetate are dissolved in 10 ml of THF, at RT mixed with 4.2 ml of 1 N sodium hydroxide solution and stirred at 50 ⁰ C for 1 h. It is cooled to RT and the THF removed in vacuo. The residue is treated with water and then with ice cooling with 1 N hydrochloric acid. The precipitated solid is filtered off, washed several times with water and dried at 40 ⁰ C in a vacuum. 913.7 mg (92.5% of theory) of the target compound are obtained as a white solid.

LC-MS (Method 5): R ₁ = 2.75 min .; m / z = 468 (M + H) ⁺ ¹ H-NMR (300 MHz, DMSO- (I ₆ ): δ = 12.90 (br.s, IH), 8.54 (s, IH), 7.59 (d, 2H), 7.57-7.51 (m, 2H), 7.44 -7.35 (m, 3H), 7.26-7.18 (m, 4H), 6.89 (s, IH), 6.78 (d, IH), 6.59 (dd, IH), 4.60 (s, 2H), 3.91 (s, 3H ).

Example 11

3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxy-acetic acid trisethanolamine salt

50 mg (0.107 mmol) of 3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxyacetic acid are dissolved in 2 ml of a 1: 1 Submitted mixture of methanol and dichloromethane, treated with 13 mg (0.107 mmol) of 2-amino-2-hydroxymethyl-l, 3-propanediol (trisethanolamine) and stirred at RT overnight. Thereafter, the mixture is concentrated in vacuo. 60.3 mg of the target compound are obtained as a colorless glass.

LC-MS (Method 5): R, = 2.53 min .; m / z = 468 (C ₂₇ H ₂₁ N ₃ Os) ⁺

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.45 (s, IH), 7.60-7.51 (m, 4H), 7.36-7.11 (m, 7H), 6.81 (dd, IH), 6.63 (dd , IH), 4.38 (s, 2H), 3.94 (s, 3H), 3.65 (s, 6H).

Example 12

3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxyacetic acid sodium salt

N / A

2.52 g (5.39 mmol) of 3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxyacetic acid are dissolved in a mixture of 10 ml of THF, 10 ml Methanol and 1 ml of water at RT. 5.39 ml of 1 N sodium hydroxide solution are added dropwise and the resulting solution is stirred for 10 minutes at RT, before being filtered off with suction through a fine frit (removal of suspended particles). The solution is concentrated in vacuo and the residue treated with ethanol. The insoluble solid is filtered off, washed with a little ethanol and dried in vacuo, then under high vacuum. The filtrate is concentrated, the residue is stirred again with a little ethanol and thus obtained after suction, a second batch of product. After combining the two fractions, a total of 2.32 g (87.9% of theory) of the target compound are obtained as a colorless solid.

LC-MS (Method 5): R, = 2.83 min .; m / z = 467 (M-Na + 2H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.54 (s, IH), 7.62-7.51 (m, 4H), 7.43-7.36 (m, 3H), 7.27 (d, 2H), 7.11 (t, IH), 7.01 (s, IH), 6.82-6.79 (m, 2H), 6.50 (d, IH), 4.03 (s, 2H), 3.91 (s, 3H).

Example 13

3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} phenoxy) acetic acid ethyl ester

300 mg (0.731 mmol) of 3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} phenol, 159 mg (0.95 mmol) of ethyl bromoacetate and 357 mg (1.1 mmol) of cesium carbonate are stirred under reflux for 1.5 h. After cooling, the mixture is concentrated, the residue is taken up in ethyl acetate and the mixture is washed several times with water. The organic phase is dried over magnesium sulfate and concentrated in vacuo. 331.4 mg (91.3% of theory) of the target compound are obtained as a yellowish solid.

LC-MS (Method 3): R, = 2.92 min .; m / z = 497 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO- (I ₆ ): δ = 8.51 (s, IH), 7.60-7.51 (m, 4H), 7.46-7.41 (m, 3H), 7.33 (t, IH), 7.02 (d, 2H), 6.88-6.81 (m, 3H), 4.78 (s, 2H), 4.17 (q, 2H), 3.80 (s, 3H), 1.19 (t, 3H). Example 14

3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} phenoxy) acetate

500 mg (01.22 mmol) of 3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} phenol, 242 mg (1.58 mmol) of methyl bromoacetate and 595 mg (1.83 mmol) cesium carbonate are stirred for 45 min under reflux. After cooling, the mixture is concentrated and the crude product reacted without further purification in the subsequent reaction.

Example 15

3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} phenoxy) acetic acid

587 mg (about 1.217 mmol) of methyl 3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} phenoxy) acetic acid (crude product from example 14) , 2.43 ml of 1 N sodium hydroxide solution and 4 ml of dioxane are stirred overnight at 50 ⁰ C. After cooling, it is acidified with 1 N hydrochloric acid and the precipitated solid is filtered off with suction, washed with water and dried at 40 ⁰ C in a vacuum. The solid is taken up in dichloromethane and THF and the solution re-evaporated to dryness. 477.1 mg (81.2% of theory) of the target compound are obtained as a yellowish solid.

LC-MS (Method 3): R, = 2.49 min .; m / z = 469 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 13.00 (br.s, IH), 8.54 (s, IH), 7.61-7.51 (m, 4H), 7.47-7.40 (m, 3H), 7.32 (t, IH), 7.03 (d, 2H), 6.88-6.78 (m, 3H), 4.68 (s, 2H), 3.80 (s, 3H). Example 16

N- (3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} phenyl) -glycinniethylester

450 mg (1.1 mmol) of 3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} aliline, 202 mg (1.32 mmol) of methyl bromoacetate and 465.5 mg (1.43 mmol) cesium carbonate in 10 ml

Acetone are stirred overnight under reflux. The acetone is removed in vacuo and the

The residue was taken up in water and extracted repeatedly with dichloromethane / ethyl acetate (1: 1).

The combined organic phases are dried over magnesium sulfate and concentrated. Of the

The residue is chromatographed twice on silica gel (eluent: dichloromethane / ethyl acetate 1: 1). 75.4 mg (13.8% of theory) of the target compound are obtained as white foam.

LC-MS (Method 6): R, = 2.92 min .; m / z = 482 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.53 (s, IH), 7.59-7.40 (m, 7H), 7.09 (t, IH), 7.02 (d, 2H), 6.45-6.39 (m, 3H), 6.20 (t, IH), 3.91 (d, 2H), 3.70 (s, 3H), 3.65 (s, 3H).

Example 17

N- (3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} phenyl) glycine

65 mg (0.135 mmol) of N- (3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} -phenyl) -glycine methyl ester, 0.27 ml of 1N sodium hydroxide solution and 2 ml of dioxane are stirred at RT overnight. The mixture is made acidic with 1 N hydrochloric acid and extracted several times with ethyl acetate / dichloromethane (1: 1). The combined organic phases are over magnesium sulfate dried and concentrated. The residue is chromatographed on silica gel (mobile phase: dichloromethane / methanol 100: 1 → 50: 1). 16.8 mg (13.8% of theory) of the target compound are obtained as a yellowish hard oil.

LC-MS (Method 6): R, = 2.63 min .; m / z = 468 (M + H) ⁺

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 12.30 (br.s, IH), 8.52 (s, IH), 7.59-7.40 (m, 8H), 7.09 (t, IH), 7.04-7.00 ( m, 2H), 6.93 (d, IH), 6.40-6.35 (m, 2H), 3.80 (s, 3H), 3.78 (s, 2H).

Example 18

5- (4-Methoxyphenyl) -6-phenyl-N- [3- (1H-tetrazol-5-ylmethoxy) phenyl] ruro [2,3-d] pyrimidin-4-amine

A mixture of 100 mg (0.223 mmol) of (3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxy) acetonitrile, 383 mg (3.345 mmol) trimethylsilyl azide and 83.32 mg (0.334 mmol) of di-n-butyltin in 5 ml toluene is stirred overnight at 80 ⁰ C. After cooling, the precipitated solid is filtered off, washed with toluene and dried overnight at 50 ⁰ C under high vacuum. Obtained are 80.1 mg (73.1% of theory) of the target compound as an off-white solid.

LC-MS (Method 6): R, = 2.70 min .; m / z = 492 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO-de): δ = 8.55 (s, IH), 7.62-7.50 (m, 4H), 7.45-7.35 (m, 4H), 7.29-7.21 (m, 3H), 6.93 (s, IH), 6.81-6.73 (m, 2H).

Example 19

(3 - {[5- (4-hydroxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxy) acetic acid

To a mixture of 170 mg (0.364 mmol) of 3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenoxyacetic acid and 4.5 ml of dichloromethane At RT, add 109 mg (0.435 mmol) of boron tribromide. The mixture is stirred overnight at RT and then hydrolyzed with 1 N hydrochloric acid. After addition of dichloromethane, the insoluble solid is filtered off and dried overnight under high vacuum. This gives 128.6 mg of the target compound, which can be further purified by recrystallization from isopropanol.

LC-MS (Method 6): R ₁ = 2.41 min .; m / z = 454 (M + H) ⁺ .

Example 20

(2 £) -3- (3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenyl) -acrylic acid ethyl ester

500 mg (1.85 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine and 369 mg (1.93 mmol) of ethyl 3-amino- / rα-cinnamate are stirred for 1.5 h heated to 150 ⁰ C. After cooling, dichloromethane is added and the crude product is purified by chromatography on silica gel (eluent: dichloromethane / ethyl acetate 20: 1). 539.5 mg (73.9% of theory) of the target product are obtained as a yellowish solid.

LC-MS (Method 6): R, = 3.34 min .; m / z = 492 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO-Cl ₆ ): δ = 8.53 (s, IH), 7.71 (s, IH), 7.62-7.51 (m, 5H), 7.46-7.35 (m, 6H), 7.23 ( d, 2H), 7.05 (s, IH), 6.54 (d, IH), 4.21 (q, 2H), 3.90 (s, 3H), 1.27 (t, 3H). Example 21

(2 £) -3- (3 - {[5- (4-methoxyphenyl) -6-phenylfliro [2,3-d] pyrimidin-4-yl] amino} phenyl) acrylic acid

To a mixture of 120 mg (0.244 mmol) (2 lb) -3- (3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenyl) Ethyl acrylate in 2 ml of THF are added dropwise 0.73 ml of 1 N sodium hydroxide solution. The mixture is stirred overnight at 50 ⁰ C, then cooled and acidified with 1 N hydrochloric acid. The precipitated solid is filtered off, washed several times with water and dried overnight at 50 ⁰ C under high vacuum. 106 mg (93.7% of theory) of the target compound are obtained as a colorless solid.

LC-MS (Method 7): R ₁ = 5.09 min .; m / z = 464 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.47 (br.s, IH), 8.55 (s, IH), 7.71 (s, IH), 7.62-7.50 (m, 5H), 7.45-7.31 ( m, 6H), 7.23 (d, 2H), 7.04 (s, IH), 6.44 (d, IH), 3.39 (s, 3H).

Example 22

(2 £) -3- (3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenyl) -acrylic acid, sodium salt

76 mg (0.164 mmol) (2 lb) -3- (3 - {[5- (4-methoxyphenyl) -6-phenylmolo [2,3-d] pyrimidin-4-yl] amino} phenyl) -acrylic acid are dissolved in Submitted 1.5 ml of a 1: 1 mixture of methanol and THF and treated at RT with 0.164 ml of 1 N sodium hydroxide solution. The mixture is stirred for 2 h at RT, then concentrated in vacuo and the residue dried overnight under high vacuum. 79.6 mg (99.9% of theory) of the target compound are obtained as a yellowish solid.

LC-MS (Method 5): R ₁ = 3.01 min .; m / z = 464 (M-Na + 2H) ⁺

¹ H-NMR (400 MHz, DMSO-de): δ = 8.54 (s, IH), 7.65-7.48 (m, 5H), 7.43-7.34 (m, 3H), 7.31-7.21 (m, 4H), 7.15 (br s, IH), 6.97 (d, IH), 6.92 (s, IH), 6.71 (d, IH), 3.91 (s, 3H).

Example 23

Methyl 3- (4 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} phenyl) propanoate

300 mg (0.891 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine, 642 mg (3.65 mmol) of methyl 3- (4-hydroxyphenyl) propanoate and 435.4 mg (1.34 mmol) cesium carbonate are heated to 120 ⁰ C for 2 h. After cooling, water is added and the precipitated crude product is filtered off. The solid is dissolved in ethyl acetate and the solution washed twice with buffer solution (pH 7), dried over magnesium sulfate and reconcentrated. After treating the residue with methanol, a solid precipitates, which is filtered off, washed with a little methanol and dried in vacuo. 160 mg (36.3% of theory) of the target compound are obtained as a colorless solid.

LC-MS (Method 3): R _t = 2.93 min .; m / z = 481 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO-de): δ = 8.52 (s, IH), 7.60-7.50 (m, 4H), 7.45-7.38 (m, 3H), 7.28 (d, 2H), 7.12 (i.e. , 2H), 7.02 (d, 2H), 3.80 (s, 3H), 3.60 (s, 3H), 2.87 (t, 2H), 2.67 (t, 2H).

Example 24

3- (4 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} phenyl) propanoic acid

137 mg (0.285 mmol) of methyl 3- (4 - {[5- (4-methoxyphenyl) -6-phenyl-pentano [2,3-d] pyrimidin-4-yl] oxy} -phenyl) propanoate are initially introduced in 4.5 ml of THF and at RT with 0.855 ml of 1 N sodium hydroxide solution. The mixture is stirred for 1 h at 50.degree. After cooling, it is acidified with 1 N hydrochloric acid and the precipitated solid is filtered off with suction, washed with water and dried under high vacuum. 125.9 mg (94.7% of theory) of the target compound are obtained.

LC-MS (Method 6): R, = 2.76 min .; m / z = 467 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.16 (s, IH), 8.52 (s, IH), 7.61-7.51 (m, 4H), 7.48-7.40 (m, 3H), 7.29 (d, 2H), 7.12 (d, 2H), 7.02 (d, 2H), 3.79 (s, 3H), 2.85 (t, 2H), 2.56 (t, 2H).

Example 25

3- (3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenyl) -propanoic acid methyl ester

2100 mg (6.34 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine and 1453 mg (8.11 mmol) of methyl 3- (3-aminophenyl) propanoate are obtained for 1.5 h Heated to 150 ⁰ C. After cooling, dichloromethane is added and the crude product is purified by chromatography on silica gel (eluent: dichloromethane / ethyl acetate 20: 1). The product thus obtained is stirred with diisopropyl ether and the resulting solid is filtered off with suction and washed with a little diisopropyl ether. 1367 mg (45.7% of theory) of the target product are obtained as a colorless solid.

LC-MS (Method 5): R, = 3.19 min .; m / z = 480 (M + H) ⁺ . Example 26

3- (3 - {[5- (4-methoxyphenyl) -6-phenylfliro [2,3-d] pyrimidin-4-yl] amino} phenyl) propanoic acid

1000 mg (2.085 mmol) of 3- (3 - {[5- (4-methoxyphenyl) -6-phenylmolo [2,3-d] pyrimidin-4-yl] amino} phenyl) -propanoic acid methyl ester are initially charged in 30 ml of THF and at RT with 6.3 ml of 1 N sodium hydroxide solution. The mixture is stirred for 1 h at 50 ⁰ C and then slightly acidified after cooling with 1 N hydrochloric acid. The precipitated solid is filtered off, washed several times with water and dried overnight at 40 ⁰ C under high vacuum. 934.5 mg (96.3% of theory) of the target product are obtained as a colorless solid.

LC-MS (Method 3): R _t = 2.62 min .; m / z = 465 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO-Cl ₆ ): δ = 12.15 (br.s, IH), 8.52 (s, IH), 7.62-7.51 (m, 4H), 7.45-7.36 (m, 3H), 7.27-7.20 (m, 5H), 6.95-6.90 (m, IH), 6.88 (s, IH), 3.89 (s, 3H), 2.78 (t, 2H), 2.51 (t, 2H).

Example 27

3 - (3 - {[5- (4-Methoxyphenyl) -6-phenyl-furo [2,3-d] pyrimidin-4-yl] amino} phenyl) -propanoic acid sodium salt

150 mg (0.322 mmol) of 3- (3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} -phenyl) -propanoic acid are dissolved in 5 ml of THF and mixed with 0.322 ml of 1 N sodium hydroxide solution. The mixture is stirred for 1 h at RT, then concentrated in vacuo and the residue overnight in Dried under high vacuum. 155.7 mg (99.1% of theory) of the target product are obtained as a colorless solid.

LC-MS (Method 5): R, = 2.95 min .; m / z = 466 (M-Na + 2H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.52 (s, 2H), 7.63-7.51 (m, 4H), 7.45-7.33 (m, 3H), 7.39-7.12 (m, 5H) , 6.89 (d, IH), 6.80 (s, IH), 3.90 (s, 3H), 2.68 (br, s, 2H), 2.08 (br, s, 2H).

Example 28

3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenyl methyl acetate

300 mg (0.89 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine and 191.3 mg (1.16 mmol) 3-Aminophenylessigsäuremethylester be for 1.5 h heated to 150 ⁰ C. After cooling, dichloromethane is added and the resulting solid is filtered off with suction, washed with dichloromethane and dried overnight at 50 ^° C. in a high vacuum. The crude product is purified by chromatography on silica gel (eluent: dichloromethane / ethyl acetate 10: 1). 273.2 mg (65.9% of theory) of the target product are obtained as a yellowish solid.

LC-MS (Method 3): R ₁ = 2.88 min .; m / z = 466 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.52 (s, IH), 7.59 (d, 2H), 7.53 (d, 2H), 7.44-7.37 (m, 3H), 7.32-7.21 (m, 5H), 6.95 (d, IH), 6.90 (s, IH), 3.90 (s, 3H), 3.65 (s, 2H), 3.61 (s, 3H).

Example 29

3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenyl-acetic acid

50 mg (0.107 mmol) of methyl 3 - {[5- (4-methoxyphenyl) -6-phenyl-pentachloro [2,3-d] pyrimidin-4-yl] amino} phenylacetate are dissolved in 2 ml of THF at RT with 0.322 ml of 1 N sodium hydroxide added and stirred at 50 ⁰ C for 4 h. It is cooled to RT and the THF removed in vacuo. The residue is mixed with water and then with 1 N hydrochloric acid. The precipitated solid is filtered off, washed with water and dried at 50 ⁰ C in a vacuum. 41.7 mg (86% of theory) of the target compound are obtained as a white solid.

LC-MS (Method 5): R, = 2.85 min .; m / z = 452 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.51 (s, IH), 7.60 (d, 2H), 7.53 (d, 2H), 7.44-7.37 (m, 3H), 7.32-7.20 (m, 5H), 6.96 (d, IH), 6.91 (s, IH), 3.91 (s, 3H), 3.53 (s, 2H).

Example 30

Methyl 4- (4 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenyl) butanoate

200.8 mg (0.596 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine and 149.8 mg (0.775 mmol) of methyl 4- (4-aminophenyl) butanoate are obtained for 1.5 h Heated to 150 ⁰ C. After cooling, concentrate in vacuo, add dichloromethane to the residue and purify the crude product by chromatography on silica gel (eluent: dichloromethane / ethyl acetate 20: 1). The product thus obtained is stirred with diisopropyl ether and the resulting solids are filtered off with suction and washed with a little diisopropyl ether. 236.7 mg (80.4% of theory) of the target product are obtained as a slightly pink solid. LC-MS (Method 3): R, = 3.08 min .; m / z = 494 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-dβ): δ = 8.49 (s, IH), 7.60 (d, 2H), 7.53 (d, 2H), 7.43-7.37 (m, 3H), 7.32 (d, 2H ), 7.23 (d, 2H), 7.13 (d, 2H), 6.84 (s, IH), 3.88 (s, 3H), 3.59 (s, 3H), 2.58-2.50 (m, 2H), 2.29 (t, 2H), 1.84-1.77 (m, 2H).

Example 31

4- (4 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenyl) butanoic acid

175.6 mg (0.356 mmol) of 4- (4 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} -phenyl) -butanoic acid methyl ester are dissolved in 3.5 ml of THF , mixed at RT with 1.07 ml of 1 N sodium hydroxide solution and stirred at 50 ⁰ C for 1 h. It is cooled to RT and the THF removed in vacuo. The residue is treated with water and then with 1 N hydrochloric acid. The precipitated solid is filtered off, washed several times with water and dried overnight at 40 ° C in a vacuum. This gives 130 mg (76.2% of theory) of the target compound as a white solid.

LC-MS (Method 5): R, = 3.03 min .; m / z = 480 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 8:54 (s, IH), 7:59 (d, 2H), 7:49 (d, 2H), 7:38 to 7:25 (m, 5H), 7.18- 7.10 (m, 4H), 6.60 (s, IH), 2.68-2.61 (m, 2H), 2.40-2.33 (m, 2H), 1.98-1.90 (m, 2H).

Example 32

Methyl 4- (2 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenyl) butanoate

259.8 mg (0.771 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfiiro [2,3-d] pyrimidine and 228 mg of methyl 4- (2-aminophenyl) butanoate (85% strength, approx. 1.0 mmol) are heated to 150 ⁰ C overnight. After cooling, it is concentrated in vacuo, dichloromethane is added to the residue and the crude product is purified by chromatography on silica gel (mobile phase: dichloromethane / ethyl acetate 50: 1 → 10: 1). The product thus obtained is further purified by preparative RP-HPLC. Obtained are 33.1 mg (8.7% of theory) of the target product.

LC-MS (Method 3): R _t = 3.08 min .; m / z = 494 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.48 (s, IH), 7.61 (d, 2H), 7.53 (d, 2H), 7.42-7.12 (m, 9H), 6.83 (s , IH), 6.39 (s, 3H), 3.58 (s, 3H), 2.59-2.50 (m, 2H), 2.33-2.28 (m, 2H), 1.83-1.75 (m, 2H).

Example 33

4- (2 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenyl) butanoic acid

28.9 mg (0.059 mmol) of methyl 4- (2 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenyl) butanoate are dissolved in 1 ml of THF , mixed at RT with 0.176 ml of 1 N sodium hydroxide solution and stirred at 50 ⁰ C for 1 h. It is cooled to RT and the THF removed in vacuo. The residue is treated with water and then with 1 N hydrochloric acid. The precipitated solid is filtered off, washed several times with water and dried overnight at 40 ⁰ C in vacuo. 16.9 mg (60.2% of theory) of the target compound are obtained as a white solid.

LC-MS (Method 6): R _t = 2.89 min .; m / z = 480 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 12.02 (br.s, IH), 8.50 (s, IH), 7.60 (d, 2H), 7.52 (d, 2H), 7.43-7.12 (m, 9H), 6.84 (s, IH), 3.89 (s, 3H), 2.58-2.49 (m, 2H), 2.20 (t, 2H), 1.27 (t, 2H).

Example 34

5- (3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} benzyl) -1,3,4-oxadiazol-2 (3H) -one

0.85 mg (0.183 mmol) of 2- (3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} phenyl) -acetic acid hydrazide and 35.5 mg (0.219 mmol ) N, N'-Carbonyldiimidazole are refluxed in 3 ml of THF for 2 h. After cooling to RT, it is added to water and extracted several times with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated in vacuo. This gives 79.9 mg (89% of theory) of the target product as a beige solid.

LC-MS (Method 3): R _t = 2.55 min .; m / z = 492 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.51 (s, IH), 7.68 (s, IH), 7.58 (d, 2H), 7.54 (d, 2H), 7.44- 7.38 (m, 3H), 7.30-7.27 (m, 2H), 7.21 (d, 2H), 7.06-6.97 (m, 3H), 3.90 (s, 2H), 3.88 (s, 3H).

Example 35 and Example 36

(+/-) - c / 5-N- (3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexyl) glycine methyl ester

and

(+/-) - / rα 5-N- (3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexyl) glycine methyl ester

132 mg (0.318 mmol) (+/-) - c / Vαrα / J5-N- [5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] -cyclohexane 1,3-Diamine (Example 36A) is dissolved in 1.5 ml of dichloromethane and treated at RT with 18.7 .mu.l of acetic acid. 28 mg (0.318 mmol) of methyl oxoacetate are added and after 5 min, 101 mg (0.478 mmol) sodium triacetoxyborohydride. The mixture is stirred for 2 h at RT and then diluted with water and dichloromethane. The organic phase is washed with saturated sodium carbonate solution, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative RP-HPLC (eluent: acetonitrile / water gradient), thereby separating the c «/ fra / w isomers:

(+/-) - c / 5-N- (3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexyl) glycine methyl ester (Example 35 )

Yield: 26.5 mg (17.1% of theory)

LC-MS (Method 3): R _t = 1.70 min .; m / z = 487 (M + H) ⁺ ;

(+/-) - / rα / 75-N- (3 - {[5- (4-Methoxyphenyl) -6-phenyl-2- [2,3-d] pyrimidin-4-yl] -amino} cyclohexyl) -glycine methyl ester (Ex 36)

Yield: 22.1 mg (14.3% of theory)

LC-MS (Method 3): R, = 1.61 min .; m / z = 487 (M + H) ⁺ .

Example 37

(+/-) - cw - [(3 - {[5- (4-methoxyphenyl) -6-phenylruro [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl) oxy] -acetic acid tert. butyl ester

350 mg (0.84 mmol) (+/-) - cw-3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} -cyclohexanol are dissolved in 1 ml Dissolved absolute THF, cooled to 0 ⁰ C and treated with 0.48 ml (about 0.97 mmol) of phosphazene base P2-t-Bu (2 M solution in THF). The cooling is removed and the solution is stirred for 10 min at RT and then added dropwise at RT to a solution of 295 mg (1.51 mmol) of bromoacetic acid tert-butyl ester in 2 ml of THF. After 2 h at RT, the reaction mixture is concentrated in vacuo and purified directly by chromatography on silica gel (Biotage, mobile phase: cyclohexane / ethyl acetate 10: 1 → 1: 1). In addition to 180 mg starting material, 207 mg (46.4% of theory) of the target product are obtained. LC-MS (Method 6): R ₁ = 3.38 min .; m / z = 531 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.58 (s, IH), 7.54 (dd, 2H), 7.43-7.39 (m, 5H), 7.0 (d, 2H), 5.13 (m , IH), 3.98 (s, 2H), 3.82 (s, 3H), 3.42 (m, IH), 2.41 (brd, IH), 2.05-1.93 (m, 2H), 1.78- 1.70 (m, IH ), 1.40 (s, 9H), 1.30-1.05 (m, 4H).

Separation of the enantiomers:

0.2 g (+/-) - cis - [(3- {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl) oxy] -acetic acid tert-butyl ester are dissolved in 4 ml of ethanol and 16 ml of iso-hexane. The racemate is separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 38 and 39) [column: Daicel Chiralcel OJ-H, 5 μm, 250 mm × 20 mm; Flow: 15 ml / min; Detection: 220 nm; Injection volume 0.5 ml; Temperature: 45 ° C; Eluent: t = 0 min 90% iso-hexane / 10% ethanol - »t = 7 min 90% iso-hexane / 10% ethanol].

Example 38

c / 5 - [(3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl) oxy] -acetic acid tert-butyl ester ( Enantiomer 1)

LC-MS (Method 3): R _t = 3.22 min .; m / z = 531 (M + H) ⁺

[α] _D ²⁰ = -59 °, c = 0.525, CHCl ₃ .

Example 39

cw - [(3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl) oxy] -acetic acid tert-butyl ester (enantiomer 2)

LC-MS (method 3): R _t = 3.22 min .; m / z = 531 (M + H) ⁺

[α] _D ²⁰ = + 55.5 °, c = 0.51, CHCl ₃ .

Example 40

(+/-) - / rα "5 - [(3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl) oxy] acetic acid ter /. butyl

920 mg (11:53 mmol) of 50% sodium hydroxide solution and 5 ml of toluene are heated to 40 ⁰ C and treated with 65.2 mg (0.192 mmol) of tetrabutylammonium hydrogen sulfate and 800 mg (1.91 mmol) of (+/-) - trans-3- { [5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexanol was added. The suspension is diluted with a little THF, whereby the solid dissolves. After adding 749 mg (3.84 mmol) of tert-butyl bromoacetate, the suspension is heated to 60 ° C. with very vigorous stirring. After a total of 3 h at 60 ⁰ C, wherein in the meantime a further 920 mg of 50% sodium hydroxide solution and about 1500 mg bromoacetic acid te / Y.-butyl ester are added, the reaction mixture is cooled and added to water. It is extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated in vacuo. The crude product is separated by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1 → 1: 1). In addition to 473 mg of starting material, 286 mg (28.1% of theory) of the target compound are isolated.

LC-MS (Method 6): R, = 3.36 min .; m / z = 531 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.58 (s, IH), 7.54 (d, 2H), 7.43-7.39 (m, 5H), 7.05 (d, 2H), 5.58 (m , IH), 3.88 (d, 2H), 3.82 (s, 3H), 3.21 (m, IH), 1.99-1.92 (m, IH), 1.78-1.70 (m, IH), 1.61- 1.53 (m, 3H ), 1.49-1.40 (m, IH), 1.38 (s, 9H), 1.27-1.17 (m, 2H).

Separation of the enantiomers:

0.3 g (+/-) - trans - [(3- {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl) oxy] -acetic acid tert-butyl ester are dissolved in 2 ml of ethanol and 8 ml of iso-hexane. The racemate is separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 41 and 42) [column: Daicel Chiralcel OJ-H, 5 μm, 250 mm × 20 mm; Flow: 15 ml / min; Detection: 220 nm; Injection volume 0.5 ml; Temperature: 40 ^° C .; Eluent: t = 0 min 90% iso-hexane / 10% ethanol -> t = 10 min 90% iso-hexane / 10% ethanol].

Example 41

(+) - "rα" 5 - [(3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl) oxy] -acetic acid tert. butyl ester (enantiomer 1) [α] _D ²⁰ = + 60.6 °, c = 0.50, CHCl ₃

¹ H-NMR (400 MHz, DMSO-CI ₆ ): δ = 8.58 (s, IH), 7.54 (d, 2H), 7.43-7.39 (m, 5H), 7.05 (d, 2H), 5.58 (br. s, IH), 3.88 (d, 2H), 3.82 (s, 3H), 3.21 (m, IH), 1.99-1.92 (m, IH), 1.78-1.70 (m, IH), 1.61-1.53 (m, 3H), 1.49-1.40 (m, IH), 1.38 (s, 9H), 1.27-1.17 (m, 2H).

Example 42

(-) - / ra «5 - [(3 - {[5- (4-methoxyphenyl) -6-phenyl-2- [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl) oxy] - acetic acid ter / .-butyl ester (β-enantiomer 2)

[α] _D ²⁰ = -70.4 °, c = 0.525, CHCl ₃

Example 43

(+/-) - α // - c / 5 - [(3-hydroxy-5 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl) oxy] -acetic acid tert-butyl ester

A to ⁰ ° C cooled solution of 600 mg (1:39 mmol) of (+/-) - α // - c / s-5 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexane-l, 3-diol in 1.2 ml of DMF is treated with 0.69 ml (about 1.39 mmol) of phosphazene base P2-t-Bu (about 2 M solution in THF). The resulting solution is stirred for 5 min at ⁰ ° C. and then mixed with 0.25 ml (1.67 mmol) tert-butyl bromoacetate. The cooling is removed and the mixture is stirred for 15 min at RT. It is then added to water and extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated in vacuo. After purification by preparative RP-HPLC (eluent: acetonitrile / water gradient), 207 mg (27.3% of theory) of the target product are obtained. LC-MS (Method 6): R, = 2.90 min .; m / z = 547 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-U ₆ ): δ = 8.60 (s, IH), 7.56 (dd, 2H), 7.43-7.38 (m, 5H), 7.02 (d, 2H), 5.13 (m, IH), 4.85 (d, IH), 3.98 (s, 2H), 3.83 (s, 3H), 3.59-3.49 (m, 2H), 2.96-2.90 (m, 2H), 2.30-2.18 (m, 2H) , 1.42 (s, 9H), 1.13-1.02 (m, 3H).

> Example 44

(+/-) - 3- (3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} piperidin-1-yl) -propanoic acid methyl ester

200 mg (0.5 mmol) of (+/-) - 5- (4-methoxyphenyl) -6-phenyl-4- (piperidin-3-yloxy) -fuhr [2,3-d] pyrimidine (Example 37A) are dissolved in 1 Dissolved in THF and treated with 69 .mu.l (0.5 mmol) of triethylamine. After addition of 54 .mu.l (0.5 mmol) of 3-bromopropionate, the mixture is stirred for about 8 hours at 20-40 ⁰ C. In the meantime, triethylamine (a total of about 1.2 mmol) and methyl 3-bromopropionate (a total of about 1.2 mmol) are added twice more. To

Dilution with dichloromethane, the mixture is washed with saturated sodium bicarbonate solution and concentrated in vacuo. The crude product is purified by preparative RP-

HPLC (eluent: acetonitrile / water gradient). 118 mg (45.7% of theory) of the

Target product.

LC-MS (Method 5): R, = 1.91 min .; m / z = 488 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.59 (s, IH), 7.58-7.52 (m, 2H), 7.43-7.39 (m, 5H), 7.01 (d, 2H), 5.26 ( m, IH), 3.82 (s, 3H), 3.50 (s, 3H), 2.80-2.75 (m, IH), 2.60-2.50 (m, 2H), 2.46-2.22 (m, 5H), 1.89-1.81 ( m, IH), 1.68-1.59 (m, IH), 1.45-1.32 (m, 2H).

Example 45

(+/-) - 4- (3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} piperidin-1-yl) -butanoic acid methyl ester

500 mg (1.25 mmol) of (+/-) - 5- (4-methoxyphenyl) -6-phenyl-4- (piperidin-3-yloxy) -firo [2,3-d] pyrimidine (Example 37A) in 1 ml of THF are successively treated with 0.65 ml (3.74 mmol) of DIEA, 20.6 mg (0.125 mmol) of potassium iodide and 450 mg (2.5 mmol) of 4-bromobutyrate. The mixture is refluxed for 4 h, then cooled, diluted with dichloromethane, washed with saturated sodium bicarbonate solution and concentrated in vacuo. The crude product is purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 4: 1 → 1: 1). 662 mg (100% of theory) of the target compound are obtained.

LC-MS (Method 5): R, = 1.89 min .; m / z = 502 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.58 (s, IH), 7.54 (d, 2H), 7.43-7.39 (m, 5H), 7.00 (d, 2H), 5.24 (m, IH) , 3.81 (s, 3H), 3.52 (s, 3H), 2.79-2.74 (m, IH), 2.48-2.41 (m, IH), 2.28-2.21 (m, 5H), 2.14 (m, IH), 1.92 -1.85 (m, IH), 1.68-1.58 (m, 3H), 1.47-1.30 (m, 2H).

Separation of the enantiomers:

Racemic (+/-) - 4- (3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} piperidin-1-yl) -butanoic acid methyl ester is described in US Pat a 1: 4 mixture of ethanol and iso-hexane and separated by preparative HPLC on chiral phase into the enantiomers (see Example 46 and 47) [column: Daicel Chiralpak AS-H, 5 microns, 250 mm x 20 mm; Flow: 15 ml / min; Detection: 220 nm; Injection volume 0.5 ml; Temperature: 28 ° C; Eluent: t = 0 min 90% iso-hexane / 10% ethanol - »t = 8 min 90% iso-hexane / 10% ethanol].

Example 46

Methyl 4- (3 - {[5- (4-methoxyphenyl) -6-phenylruro [2,3-d] pyrimidin-4-yl] oxy} piperidin-1-yl) butanoate (enantiomer 1)

LC-MS (Method 6): R ₁ = 1.84 min .; m / z = 502 (M + H) ⁺

R _t = 7.26 min [column: Daicel Chiralpak AS-H, 5 μm, 250 mm × 4.6 mm; Flow: 1.0 ml / min; Detection: 230 nm; Temperature: 25 ° C; Eluent: 90% iso-hexane / 10% ethanol with 0.2% diethylamine]; ¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.58 (s, IH), 7.54 (d, 2H), 7.43-7.39 (m, 5H), 7.00 (d, 2H), 5.24 (m, IH) , 3.81 (s, 3H), 3.52 (s, 3H), 2.79-2.74 (m, IH), 2.48-2.41 (m, IH), 2.28-2.21 (m, 5H), 2.18-2.12 (m, IH) , 1.92-1.85 (m, IH), 1.68-1.58 (m, 3H), 1.47-1.30 (m, 2H).

Example 47

4- (3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} piperidin-1-yl) -butanoic acid methyl ester (enantiomer 2)

LC-MS (Method 3): R, = 1.67 min .; m / z = 502 (M + H) ⁺

R, = 7.63 min [column: Daicel Chiralpak AS-H, 5 μm, 250 mm × 4.6 mm; Flow: 1.0 ml / min; Detection: 230 nm; Temperature: 25 ° C; Eluent: 90% iso-hexane / 10% ethanol with 0.2% diethylamine];

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.58 (s, IH), 7.54 (d, 2H), 7.43-7.39 (m, 5H), 7.00 (d, 2H), 5.24 (m, IH) , 3.81 (s, 3H), 3.52 (s, 3H), 2.79-2.74 (m, IH), 2.48-2.41 (m, IH), 2.28-2.21 (m, 5H), 2.19-2.12 (m, IH) , 1.92-1.85 (m, IH), 1.68-1.58 (m, 3H), 1.47-1.30 (m, 2H).

Example 48

(+/-) - 3- [2 - ({[5- (4-Methoxyphenyl) -6-phenylfiiro [2,3-d] pyrimidin-4-yl] oxy} methyl) pyrrolidin-1-yl] -propanoic acid methyl ester

160 mg (0.4 mmol) of (+/-) - 5- (4-methoxyphenyl) -6-phenyl-4- (pyrrolidin-2-ylmethoxy) furo [2,3-d] pyrimidine (Example 38A) are dissolved in 0.8 Dissolved in THF and treated with 110 ul (0.8 mmol) of triethylamine and 87 .mu.l (0.8 mmol) of 3-Brompropionsäuremethylester. The mixture is stirred overnight at 20-40 ⁰ C, then diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The solution is concentrated in vacuo and the resulting oil is purified by preparative RP-HPLC (eluent: acetonitrile / water gradient). 90 mg (44% of theory) of the target product are obtained.

LC-MS (Method 6): R, = 1.79 min .; m / z = 488 (M + H) ⁺ ¹ H-NMR (400 MHz, DMSO-de): δ = 8.58 (s, IH), 7.53 (d, 2H), 7.42-7.36 (m, 5H), 7.01 (d, 2H), 4.39 (dd, IH ), 4.18 (dd, IH), 3.81 (s, 3H), 3.51 (s, 3H), 2.96-2.89 (m, 2H), 2.64 (m, IH), 2.41-2.30 (m, 3H), 2.12 ( q, IH), 1.75-1.35 (m, 4H).

The following enantiomerically pure compounds are prepared in an analogous manner (4 h reaction time at about 4O ⁰ C, a total of greater excesses of DIEA and 3-bromopropionate), starting from the enantiomerically pure pyrrolidine derivatives Example 4OA, 41 A:

Example 51

(+/-) - (3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} piperidin-1-yl) -propanoic acid methyl ester

A solution of 150 mg (0.375 mmol) of (+/-) - 5- (4-methoxyphenyl) -6-phenyl-N-piperidin-3-ylfuro [2,3-d] pyrimidin-4-amine (Example 39A ) in 0.75 ml of THF (82 ul 0.749 mmol) of 3-bromo propansäuremethylester and 104 .mu.l (0.749 mmol) of triethylamine and stirred overnight at 20-40 ⁰ C. The mixture is diluted with dichloromethane and washed with saturated sodium bicarbonate solution. After concentration in vacuo, the residue is stirred with methanol, the precipitated product is filtered off with suction and dried under high vacuum. After concentration by preparative RP-HPLC (eluent: acetonitrile / water gradient), a second product batch is isolated from the filtrate. In total, 124 mg (67.1% of theory) of the target product are obtained.

LC-MS (Method 5): R _t = 1.83 min .; m / z = 487 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.31 (s, IH), 7.49-7.44 (m, 4H), 7.39-7.30 (m, 3H), 7.14 (d, 2H), 5.59 (d, IH), 4.24 (m, IH), 3.83 (s, 3H), 3.59 (s, 3H), 2.42-2.35 (m, 2H), 2.28-2.18 (m, 2H), 2.05-1.97 (m , IH), 1.62-1.55 (m, IH), 1.40 (br, s, 2H).

Example 52

(+/-) - 4- [2- ({[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} methyl) pyrrolidin-1-yl] -butanoic acid methyl ester

100 mg (0.25 mmol) of (+/-) - 5- (4-methoxyphenyl) -6-phenyl-4- (pyrrolidin-2-ynethoxy) ruro [2,3-d] pyrimidine (Example 38A) are dissolved in 2 Dissolved THF and added successively with 65 ul (0.374 mmol) of DIEA, 4.1 mg (0.025 mmol) of potassium iodide and 45 mg (0.25 mmol) of 4-bromobutyrate. The mixture is heated at reflux for 1 h and then added to water after cooling. It is extracted three times with ethyl acetate and the combined organic phases are washed twice. with buffer solution (pH 7) and with saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by preparative RP-HPLC (eluent: acetonitrile / water gradient). 47 mg (37.6% of theory) of the target product are obtained.

LC-MS (Method 3): R, = 1.73 min .; m / z = 502 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.60 (s, IH), 7.55-7.52 (m, 2H), 7.42-7.37 (m, 5H), 7.01 (d, 2H), 4.32 (dd, IH), 4.19 (dd, IH), 3.80 (s, 3H), 3.49 (s, 3H), 2.93 (t, IH), 2.62-2.50 (m, 2H), 2.20- 2.02 (m, 4H ), 1.74-1.67 (m, IH), 1.60-1.37 (m, 5H).

The following enantiomerically pure compounds are prepared analogously starting from the enantiomerically pure pyrrolidine derivatives Example 4OA or 41A:

Example 55

(+/-) - 4- (3 - {[5- (4-Methoxyphenyl) -6-phenylfliro [2,3-d] pyrimidin-4-yl] amino} -piperidin-1-yl) -butanoic acid methyl ester

A mixture of 100 mg (0.25 mmol) of (+/-) - 5- (4-methoxyphenyl) -6-phenyl-N-piperidin-3-yl-furo [2,3-d] pyrimidin-4-amine (Ex 39A), 65 μl (0.375 mmol) DIEA, 4.1 mg (0.025 mmol) potassium iodide and 45 mg (0.25 mmol) 4-bromobutyrate in 2 ml THF are refluxed for 1 h. After cooling, the reaction mixture is added to water and extracted three times with ethyl acetate. The combined organic phases are washed twice with buffer solution (pH 7) and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by preparative RP-HPLC (eluent: acetonitrile / water gradient), followed by chromatography on silica gel (eluent: dichloromethane -> dichloromethane / methanol 50: 1). After stirring the resulting product with methanol, the precipitate is filtered off, washed with a little methanol and dried under high vacuum. 58 mg (46.4% of theory) of the target product are isolated.

LC-MS (Method 6): R, = 1.85 min .; m / z = 501 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.31 (s, IH), 7.48-7.42 (m, 4H), 7.39-7.30 (m, 3H), 7.13 (d, 2H), 5.58 ( br d, IH), 4.28 (br s, IH), 3.83 (s, 3H), 3.59 (s, 3H), 2.50-2.42 (m, IH), 2.38-2.31 (m, IH), 2.22- 2.15 (m, 3H), 2.12 (t, IH), 2.02 (br s, IH), 1.58-1.40 (m, 6H).

Example 56

(+/-) - "rα" 5 ^r - [(3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexyl) oxy] - acetic acid ter /. butyl

A mixture of 549 mg (1.63 mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine, 0.43 ml (2.45 mmol) DIEA and 456 mg (+/-) - / ra / «- {[3-aminocyclohexyl] oxy} -acetic acid-tert. Butyl ester (Example 43A / crude product, about 1.63 mmol) in 1.5 ml of DMF is stirred for 2 h at 120 ⁰ C After cooling, the mixture is added to water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and concentrated in vacuo. The crude product is purified by preparative RP-HPLC (eluent: acetonitrile / water gradient). 434 mg (50.3% of theory) of the target product are obtained. LC-MS (Method 5): R, = 3.29 min .; m / z = 530 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d "): δ = 8.35 (s, IH), 7.50-7.45 (m, 4H), 7.40-7.31 (m, 3H), 7.18 (d, 2H), 4.71 ( d, IH), 4.31 (m, IH), 3.92 (s, 2H), 3.87 (s, 3H), 3.38-3.30 (m, IH), 1.77-1.67 (m, 2H), 1.55-1.42 (m, 4H), 1.38 (s, 9H), 1.18-1.10 (m, 2H).

Separation of the enantiomers:

0.39 g (+/-) - / rαM5 - [(3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexyl) oxy] - Acetic acid tert-butyl ester are dissolved in 4 ml of 2-propanol and 13 ml of iso-hexane. The racemate is separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 57 and 58) [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; Flow: 15 ml / min; Detection: 215 nm; Injection volume 1.0 ml; Temperature: 30 ^° C .; Eluent: t = 0 min 80% iso-hexane / 20% 2-propanol → t = 9.5 min 80% iso-hexane / 20% 2-propanol].

Example 57

(+) - / rα 5 - [(3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexyl) oxy] -acetic acid tert. butyl ester (β-enantiomer 1)

[α] _D ²⁰ = + 43.3 °, c = 0.51, CHCl ₃

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.34 (s, IH), 7.50-7.45 (m, 4H), 7.40-7.31 (m, 3H), 7.18 (d, 2H), 4.72 (d, IH), 4.36-4.28 (m, IH), 3.93 (s, 2H), 3.87 (s, 3H), 3.38-3.30 (m, IH), 1.77-1.67 (m, 2H), 1.55-1.42 (m, 4H), 1.40 (s, 9H), 1.18-1.10 (m, 2H).

Example 58

(-) - ^ rα "5 - [(3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexyl) oxy] acetic acid ter / .-butyl ester (β-enantiomer 2)

[α] _D ²⁰ = -49.1 °, c = 0.49, CHCl ₃

¹ H-NMR (400 MHz, DMSO- (I ₅ ): δ = 8.35 (s, IH), 7.50-7.45 (m, 4H), 7.40-7.31 (m, 3H), 7.18 (d, 2H), 4.72 (d, IH), 4.36-4.28 (m, IH), 3.93 (s, 2H), 3.87 (s, 3H), 3.38-3.30 (m, IH), 1.77-1.67 (m, 2H), 1.55-1.42 (m, 4H), 1.40 (s, 9H), 1.19-1.10 (m, 2H).

Example 59

(+/-) - c / 5 - [(- 3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexyl) oxy] acetic acid terΛ-butyl ester

To a mixture of 2.02 g of 50% sodium hydroxide solution (25.3 mmol), 2.5 ml of toluene and 85.8 mg (0.25 mmol) of tetrabutylammonium hydrogen sulfate are added at 4O ⁰ C 1.05 g (2.53 mmol) (+/-) - cis / trans-3 {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexanol (Example 44A) as a solution in 2.5 ml of toluene and 0.75 ml (5.05 mmol) of bromoacetic acid-te / Given 7-butyl ester. The heterogeneous mixture is stirred vigorously at 70 ^° C. for 2 hours. After cooling, the mixture is added to water and extracted three times with dichloromethane. The combined organic phases are washed with saturated ammonium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Chromatography on silica gel (Biotage, mobile phase: dichloromethane / methanol 500: 1 → 100: 1) yields 671 mg (50.2% of theory) of the target compound from the crude product.

LC-MS (Method 5): R ₁ = 3.33 min .; m / z = 530 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.34 (s, IH), 7.48-7.41 (m, 4H), 7.39-7.30 (m, 3H), 7.14 (d, 2H), 5.13 ( d, IH), 4.14-4.08 (m, IH), 3.85 (s, 3H), 3.82 (d, 2H), 3.43-3.35 (m, IH), 2.09 (br d, IH), 1.81- 1.60 (m, 3H), 1.41 (s, 9H), 1.30-1.04 (m, 4H).

Separation of the enantiomers:

(+/-) - C / J - [(3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexyl (l) oxy] acetic acid tert-butyl ester is dissolved in equal amounts of ethanol and iso-hexane. The racemate is separated into the enantiomers by preparative HPLC on a chiral phase (see Examples 60 and 61) [column: Daicel Chiralcel OJ-H, 5 μm, 250 mm × 20 mm; Flow: 15 ml / min; Detection: 220 nm; Injection volume 0.5 ml; Temperature: 29 ° C; Eluent: t = 0 min 80% iso-hexane / 20% ethanol -> t = 12 min 80% iso-hexane / 20% ethanol].

Example 60

(+) - c / 5 - [(- 3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexyl) oxy] - acetic acid ter / -butyl ester (enantiomer 1)

[α] _D ²⁰ = + 77.4 °, c = 0.53, CHCl ₃ LC-MS (Method 3): R ₁ = 3.10 min .; m / z = 530 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.34 (s, IH), 7.48-7.41 (m, 4H), 7.39-7.30 (m, 3H), 7.14 (d, 2H), 5.13 (br d, IH), 4.14-4.08 (m, IH), 3.85 (s, 3H), 3.82 (d, 2H), 3.43-3.35 (m, IH), 2.09 (br d, IH), 1.81 -1.71 (m, 2H), 1.68-1.60 (m, IH), 1.41 (s, 9H), 1.30-1.04 (m, 4H).

Example 61

(-) -? rαn5 - [(- 3 - {- 5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclohexyl) oxy] -acetic acid ter-butyl ester (Enantiomer 2)

[α] _D ²⁰ = -71.4 °, c = 0.54, CHCl ₃

LC-MS (Method 3): R, = 3.09 min .; m / z = 530 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.34 (s, IH), 7.48-7.41 (m, 4H), 7.39-7.30 (m, 3H), 7.14 (d, 2H), 5.13 (br. d, IH), 4.14-4.08 (m, IH), 3.85 (s, 3H), 3.82 (d, 2H), 3.43-3.35 (m, IH), 2.09 (br d, IH), 1.81-1.71 ( m, 2H), 1.68-1.60 (m, IH), 1.41 (s, 9H), 1.30-1.04 (m, 4H).

Example 62

(+/-) - c / 5 - ({- [(5,6-Diphenylruro [2,3-d] pyrimidin-4-yl) -amino] -cyclohexyl} oxy) -acetic acid / tert-butyl ester

50 mg (0.10 mmol) of (+/-) - m - ({[(5-bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) -amino] -cyclohexyl} -oxy) -acetic acid ter / , butyl ester (Example 47A) are dissolved in 0.33 ml of DMSO and treated with 3.5 mg of bis (triphenylphosphine) palladium (II) chloride. 0.1 ml of 2 N sodium carbonate solution and 15.2 mg (0.124 mmol) of phenylboronic acid are added successively at RT under argon. The heterogeneous mixture is vigorously stirred at 80 ^° C. for 4 hours. After cooling, the product is isolated directly by preparative RP-HPLC (eluent: acetonitrile / water gradient). 43.9 mg (88.3% of theory) of the target compound are obtained.

LC-MS (Method 5): R _t = 3.38 min .; m / z = 500 (M + H) ⁺ ¹ H-NMR (400 MHz, DMSO-dβ): δ = 8.35 (s, IH), 7.64-7.53 (m, 5H), 7.46-7.40 (m, 2H), 7.38-7.31 (m, 3H), 5.03 (d, IH), 4.07 (br d, IH), 3.71 (s, 2H), 3.41-3.35 (m, IH), 2.08 (d, IH), 1.70-1.60 (m, 2H), 1.65-1.55 (m, IH), 1.41 (s, 9H), 1.30-1.12 (m, 2H), 1.08-0.95 (m, 2H).

Example 63

(+/-) - c / 5 - ({3 - [(5,6-Diphenylfiiro [2,3-d] pyrimidin-4-yl) oxy] cyclohexyl} oxy) acetic acid tert-butyl ester

36 mg (0.072 mmol) (+/-) - czs - ({[(6-bromo-5-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] cyclohexyl} oxy) acetic acid ter / .-Butyl ester (Example 49A) are dissolved in 0.15 ml of DMSO and treated with 2.5 mg of bis (triphenylphosphine) palladium (II) chloride. Under argon, 0.07 ml of 2 N sodium carbonate solution and 10.9 mg (0.089 mmol) of phenylboronic acid are added successively at RT. The heterogeneous mixture is vigorously stirred at 8O ⁰ C for 4 h. After cooling, the product is isolated directly by preparative RP-HPLC (eluent: acetonitrile / water gradient). 19.8 mg (55.3% of theory) of the target compound are obtained.

LC-MS (Method 6): R _t = 3.41 min. ; m / z = 501 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.59 (s, IH), 7.56-7.39 (m, 10H), 5.11 (m, IH), 3.98 (s, 2H), 3.40 (m , IH), 2.39 (br d, IH), 2.03-1.92 (m, 2H), 1.75-1.67 (m, IH), 1.40 (s, 9H), 1.28-1.02 (m, 4H).

General Procedure D: Hydrolysis of methyl or ethyl esters to the corresponding carboxylic acid derivatives

To a solution of the methyl or ethyl ester in THF or THF / methanol (1: 1) (concentration about 0.05 to 0.5 mol / 1) at RT 1.5 to 10 eq. Sodium hydroxide as a 1 N aqueous solution. The mixture is stirred for a period of 0.5-18 h at RT and then neutralized with 1 N hydrochloric acid or slightly acidified. If a solid precipitates, the product can be isolated by filtration, washing with water and drying in a high vacuum. Alternatively, the target compound is isolated directly from the crude product, optionally after extractive work-up with dichloromethane, by preparative RP-HPLC (eluent: water / acetonitrile gradient). General Procedure E: Cleavage of tert-butyl esters to give the corresponding carboxylic acid derivatives

To a solution of the tert-butyl ester in dichloromethane (concentration 0.05 to 1.0 mol / 1, in addition a drop of water) is added dropwise at 0 ° C to RT TFA until a ratio of dichloromethane / TFA of about 2: 1 to 1: 1 is reached. The mixture is stirred for 1-18 h at RT and then concentrated in vacuo. The residue is purified by preparative RP-HPLC (eluent: acetonitrile / water gradient).

The following examples are prepared according to General Procedure D or E from the compounds described above:

Example 93

(+/-) - (? 5-c / 5,3- rα «5) - [(3-fluoro-5 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine 4-yl] oxy} - cyclohexyl) oxy] acetic acid

150 mg (0.27 mmol) (+/-) - α // - c / 5 - [(3-hydroxy-5 - {[5- (4-methoxyphenyl) -6-phenylfliro [2,3-d] pyrimidine -4-yl] oxy} cyclohexyl) oxy] acetic acid tert-butyl ester are initially introduced in 2.5 ml dichloromethane and cooled to 0 ⁰ C. Add 53 mg (0.33 mmol) of diethylaminosulfur trifluoride (DAST) and then allow to come to RT. It is then diluted with water and dichloromethane and the phases are separated. The aqueous phase is extracted twice with dichloromethane, the combined organic phases are washed once with sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. Dissolve the residue in 5 ml of dichloromethane, add 1 ml of trifluoroacetic acid and stir for 30 min at RT. You then give ges. Sodium bicarbonate solution, the aqueous phase is separated and the aqueous phase is washed once with diethyl ether. It is then acidified with 1 N hydrochloric acid and the aqueous phase extracted twice with ethyl acetate. The combined organic phases are washed once with sat. Sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica gel thick-layer plate (eluent: dichloromethane / methanol 9: 1). The product zone is extracted with dichloromethane / methanol 9: 1. It is then purified again by preparative RP-HPLC (eluent: acetonitrile / water gradient) to give 46 mg (34.0% of theory) of the target compound.

LC-MS (Method 8): R, = 2.76 min .; m / z = 493 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-dβ): δ = 12.55 (s, IH), 8.61 (s, IH), 7.55 (d, 2H), 7.44-7.35 (m, 5H), 7.01 (d, 2H ), 5.45-5.35 (m, IH), 5.15-4.96 (d, IH), 4.05 (s, 2H), 3.81 (s, 3H), 3.78-3.69 (m, IH), 2.52-2.42 (m, IH ), 2.42-2.21 (m, 2H), 1.65-1.33 (m, 3H).

General Procedure F: Reaction of nitriles with trimethylsilyl azide to give the corresponding tetrazole derivatives

To a solution of the nitrile in toluene (concentration about 100 mg / ml) at RT about 15 eq. Trimethylsilyl azide and about 1.5 eq. Given di-n-butyltin oxide. The mixture is stirred in a temperature range from 70 ^° C. to reflux for several hours, preferably overnight. After the reaction has ended, a larger excess of ethylene glycol is added and the mixture is stirred for about 1 h at reflux. After cooling, it is diluted with ethyl acetate, washed with sat. Sodium bicarbonate solution, 1 N hydrochloric acid and sat. Sodium chloride solution and concentrated in vacuo. The product is obtained after purification by preparative RP-HPLC (eluent: water / acetonitrile gradient) or by chromatography on silica gel.

The following examples are obtained in accordance with General Procedure F:

(M,

Example 101

(+) - 3 - [(35) -3 - {[5- (4-Methoxyphenyl) -6-phenylfiro [2,3-d] pyrimidin-4-yl] oxy} piperidin-1-yl] propanoic acid

50 mg (0.10 mmol) of (+) - 3- (3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} -piperidin-1-yl) propanenitrile are concentrated in 0.5 ml conc. Hydrochloric acid suspended and heated under reflux for 30 min. After cooling, the mixture is concentrated in a high vacuum and the residue is adjusted to pH 7 with 1 N sodium hydroxide solution. The mixture is purified by preparative RP-HPLC (eluent: acetonitrile / water gradient). Obtained are 29.8 mg (57.2% of theory) of the target compound.

[α] _D ²⁰ = + 76.1 °, c = 0.49, CHCl ₃

LC-MS (Method 8): R, = 1.94 min .; m / z = 474 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.59 (s, IH), 7.55 (d, 2H), 7.45-7.34 (m, 5H), 7.00 (d, 2H), 5.28-5.19 (m, IH), 3.80 (s, 3H), 3.60-3.00 (br, 4H), 2.84 (d, IH), 2.28-2.09 (m, 4H), 1.92-1.81 (m, IH), 1.64-1.51 (m, IH), 1.49-1.37 (m, IH), 1.36-1.21 (m, IH).

Example 102

(-) - 3 - [(3R) -3 - {[5- (4-Methoxyphenyl) -6-phenylruro [2,3-d] pyrimidin-4-yl] oxy} piperidin-1-yl] propanoic acid

55 mg (0.121 mmol) of (-) - 3- (3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} -piperidin-1-yl) Propanenitrile is concentrated in 0.55 ml. Suspended hydrochloric acid and 30 min. river heated. After cooling, the mixture is concentrated in a high vacuum and the residue is adjusted to pH 7 with 1 N sodium hydroxide solution. The mixture is purified by preparative RP-HPLC (eluent: acetonitrile / water gradient). 38.4 mg (67.0% of theory) of the target compound are obtained.

[α] _D ²⁰ = -87.9 °, c = 0.565, CHCl ₃

LC-MS (Method 3): R ₁ = 1.68 min .; m / z = 474 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 12.60 (br, IH), 8.60 (s, IH), 7.55 (d, 2H), 7.46-7.35 (m, 5H), 7.00 (i.e. , 2H), 5.29-5.20 (m, IH), 3.80 (s, 3H), 2.82 (d, IH), 2.61-2.54 (m, IH), 2.40-2.21 (m, 4H), 2.19 (s, 2H ), 1.91-1.81 (m, IH), 1.65-1.52 (m, IH), 1.49-1.29 (m, 2H).

Example 103

3 - [(2Λ, 4R) -4 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} piperidin-2-yl] propanoic acid

34 mg of 3 - [(2i, 4R) -l- (tert-butoxycarbonyl) -4 - {[5- (4-methoxyphenyl) -6-phenylruro [2,3-d] pyrimidin-4 -yl] oxy} piperidin-2-yl] propanoic acid are stirred in about 0.1 ml of a 3: 2 mixture of trifluoroacetic acid and dichloromethane at RT for 30 min. The volatile components are then removed in vacuo and the residue dried under high vacuum. The residue is taken up in acetonitrile / water and neutralized with 1 N sodium hydroxide solution (pH about 7). The precipitated colorless solid is filtered off, washed twice with water and twice with acetonitrile and dried under high vacuum. Obtained are 20 mg (71.3% of theory) of the target compound.

LC-MS (Method 4): R, = 3.12 min .; m / z = 474 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.59 (s, IH), 7.55 (d, 2H), 7.45-7.38 (m, 5H), 7.00 (d, 2H), 5.30-5.20 ( m, IH), 3.81 (s, 3H), 3.05-2.99 (m, IH), 2.31-2.23 (m, IH), 2.10 (s, 7H), 2.02-1.95 (m, IH). Example 104

3 - [(2 / ?, 4 /?) - 4 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} -1-methylpiperidine 2- yl] propanoic acid

8 mg (17 μmol) of 3 - [(2R, 4R) -4 - {[5- (4-methoxyphenyl) -6-phenylfliro [2,3-d] pyrimidin-4-yl] oxy} -piperidine-2 yl] propanoic acid are dissolved in 50 .mu.l of acetic acid and washed successively with 13 .mu.l of conc. (about 37%) formalin solution and 53.7 micrograms (253 .mu.mol) Natriumtriacetoxyborhydrid added. The mixture is stirred for 4 h at RT. Thereafter, again 13 .mu.l conc. Formalin solution and 53.7 micrograms (253 .mu.mol) sodium triacetoxyborohydride was added and the mixture was further stirred overnight. The mixture is then purified directly by preparative RP-HPLC (eluent: acetonitrile / water gradient). 5 mg of the target product are obtained (60.7% of theory).

LC-MS (Method 8): R _t = 1.69 min .; m / z = 488 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.59 (s, IH), 7.55 (d, 2H), 7.43-7.36 (m, 5H), 7.01 (d, 2H), 5.19-5.10 ( m, IH), 3.81 (s, 3H), 2.84-2.79 (m, IH), 2.66-2.57 (m, 6H), 2.13-1.93 (m, 2H), 1.72- 1.58 (m, 2H), 1.48- 1.38 (m, IH), 1.21 (s, 3H).

General Procedure G: Palladium-catalyzed arylation of 5-bromo-6-phenylfuror2,3-d1pyrimidine derivatives

To a solution of 1.0 eq. 5-bromo-6-phenylruro [2,3-d] pyrimidine derivative in DMSO (about 0.1 to 0.5 mol / 1) at RT 1.2 to 1.5 eq successively. the corresponding arylboronic acid and as a base either about 2.0 eq. Sodium carbonate (as a 2 M aqueous solution) or about 1.5 to 2.5 eq. solid potassium carbonate and methanol (about 10% by volume). Thereafter, about 5 mol% of bis (triphenylphosphine) palladium (H) chloride are added under argon. The mixture is stirred for a period of 3-18 h at temperatures of 70-100 ⁰ C. After cooling, the target product is isolated directly from the reaction solution by RP-HPLC (eluent: acetonitrile / water gradient). If necessary, further purification may be by chromatography on silica gel (eluent: dichloromethane / methanol or cyclohexane / ethyl acetate mixtures).

The following examples are obtained in accordance with General Regulation G:

Example 120

(-) - {[(3 - {[5- (4-Ethylphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl] oxy} -acetic acid tert -butyl ester

To a mixture of tert-butyl (40 mg, 0.174 mmol) (^ -czs-IP-hydroxycyclohexyl) oxyacetate and 58.15 mg (0.174 mmol) 4-chloro-5- (4-ethylphenyl) -6-phenylfuro [2, 0.104 ml (0.208 mmol) of phosphazene base P2-t-Bu (2 M solution in THF) are added under cooling to 3-d] pyrimidine in 0.3 ml of DMF and the mixture is stirred for one hour at RT The organic phase is washed with pH 7 buffer solution and with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo, 45.6 mg (49.7% of theory) of the target compound are obtained from the residue by preparative RP -HPLC (eluent: acetonitrile / water) isolated.

[α] _D ²⁰ = -56.7 °, c = 0.485, CHCl ₃

LC-MS (Method 3): R, = 3.41 min .; m / z = 529 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.60 (s, IH), 7.58-7.50 (m, 2H), 7.43-7.35 (m, 5H), 7.29 (d, 2H), 5.18-5.07 ( m, IH), 3.90 (s, 2H), 3.46-3.36 (m, IH), 2.70 (q, 2H), 2.44-2.36 (m, IH), 2.05-1.90 (m, 2H), 1.78-1.69 ( m, IH), 1.41 (s, 9H), 1.25 (t, 3H), 1.20-1.01 (m, 4H).

Example 121

( ⁺ ) - {[(3 - {[5- (4-Ethylphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl] oxy} -acetic acid tert -butyl ester

The title compound is prepared analogously to Example 120 by reacting (+) - cis- {[3-hydroxycyclohexyl] oxy} -acetic acid tert-butyl ester with 4-chloro-5- (4-ethylphenyl) -6- phenylruro [2,3-d] pyrimidine.

[α] _D ²⁰ = + 54.7 °, c = 0.505, CHCl ₃

LC-MS (Method 3): R _t = 3.41 min .; m / z = 529 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.60 (s, IH), 7.58-7.50 (m, 2H), 7.43-7.35 (m, 5H), 7.29 (d, 2H), 5.18- 5.07 (m, IH), 3.90 (s, 2H), 3.46-3.36 (m, IH), 2.70 (q, 2H), 2.44-2.36 (m, IH), 2.05-1.90 (m, 2H), 1.78- 1.69 (m, IH), 1.41 (s, 9H), 1.25 (t, 3H), 1.20-1.01 (m, 4H).

Example 122

(-) - 4 - [(3R) -3 - {[5- (4-Ethylphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} -piperidin-1-yl] -butanoic acid methyl ester

To a mixture of 798 mg (2.39 mmol) of 4-chloro-5- (4-ethylphenyl) -6-phenylfuro [2,3-d] pyrimidine and 600 mg (2,981 mmol) of (-) - 4 - [( 3Λ) -3-Hydroxypiperidin-l-yl] butanoate in 2 ml of DMF under ice-cooling, 1.55 ml (3.10 mmol) of phosphazene base P4-t-Bu (1 M solution in hexane). After 2 h at RT, an additional 220 mg of (-) - 4 - [(3R) -3-hydroxypiperidin-1-yl] -butanoic acid methyl ester and also 0.57 ml of phosphazene base P4-t-Bu (1 M solution in hexane) are added and the mixture is stirred for a further 2 h at RT. For workup, the mixture is diluted with dichloromethane, washed with water, dried over sodium sulfate and in vacuo concentrated. Purification of the residue by preparative RP-HPLC (eluent: acetonitrile / water gradient) gives 548.4 mg of the target product (46.0% of theory).

[α] _D ²⁰ = -40.6 °, c = 0.505, CHCl ₃

LC-MS (Method 8): R ₁ = 1.95 min .; m / z = 500 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.59 (s, IH), 7.59-7.52 (m, 2H), 7.46-7.38 (m, 5H), 7.30-7.21 (m, 2H) , 5.25-5.19 (m, IH), 3.52 (s, 3H), 2.73-2.65 (m, 3H), 2.44-2.38 (m, IH), 2.30-2.20 (m, 5H), 2.19-2.05 (m, IH), 1.90-1.80 (m, IH), 1.64-1.50 (m, 3H), 1.44-1.39 (m, 2H), 1.23 (t, 3H).

Example 123

4 - [(3S) -3- {[5- (4-ethylphenyl) -6-phenyl-touro [2,3-d] pyrimidin-4-yl] oxy} -piperidine-1-yl] -butanoic acid methyl ester

To a solution of 70 mg (0.148 mmol) of (+) - 4 - {(3S) -3 - [(5-bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] piperidine-1 methyl (-yl) butanoate in 0.4 ml of DMSO, 5.2 mg (0.007 mmol) of bis (triphenylphosphine) palladium (II) chloride, 30.6 mg (0.221 mmol) of potassium carbonate, 0.04 ml of methanol and 31 mg (0.207 mmol) are added successively under argon. Ethylbenzene boronic acid. The mixture is stirred at 80 ^° C. for a total of 3.5 hours. After cooling, the reaction mixture is purified directly by preparative RP-HPLC (eluent: acetonitrile / water gradient). 37.3 mg (50.6% of theory) of the target compound are isolated.

LC-MS (Method 8): R, = 1.86 min .; m / z = 500 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-dβ): δ = 8.59 (s, IH), 7.59-7.52 (m, 2H), 7.46-7.38 (m, 5H), 7.30-7.21 (m, 2H), 5.25 -5.19 (m, IH), 3.52 (s, 3H), 2.73-2.65 (m, 3H), 2.44-2.38 (m, IH), 2.30-2.20 (m, 5H), 2.19-2.05 (m, IH) , 1.90-1.80 (m, IH), 1.64-1.50 (m, 3H), 1.44-1.39 (m, 2H), 1.23 (t, 3H). Example 124

roc-fc / s / frα "5) - {[3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclopentyl] oxy} acetic acid tert-butyl

4.97 g (62.1 mmol) of 50% sodium hydroxide solution and 10 ml of toluene are rac- successively at 40 ⁰ C with a solution of 2.5 g (6.2 mmol) (c / s / fra "s) -3 - {[5- ( 4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclopentanol in 10 ml of toluene and 10 ml of 1,2-dimethoxyethane, 210.9 mg (0.62 mmol) of tetra-n-butylammonium hydrogensulfate and 1.8 ml (12.4 mmol) of bromoacetic acid tert-butyl ester. The biphasic reaction mixture is stirred vigorously at 60 ^° C. for a total of 3 hours. After cooling, the reaction mixture is added to water and acidified with conc. Hydrochloric acid neutralized. Extract three times with ethyl acetate, combine the organic phases, dry over magnesium sulfate and concentrate in vacuo. From the residue, 300 mg (9.4% of theory) of the target compound are isolated by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1 → 1: 1).

LC-MS (Method 3): R _t = 3.17 min .; m / z = 517 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.60 (s, IH), 7.59-7.52 (m, 2H), 7.45-7.36 (m, 5H), 7.08-6.99 (m, 2H) , 5.62-5.40 (m, IH), 3.89 (d, IH), 3.81 (s, 3H), 2.10-1.60 (m, 6H), 1.40 (d, 9H), 1.10-1.00 (m, IH), 0.90 -0.79 (m, IH).

Separation of cisItransΛsomeτe and enantiomers:

300 mg (0.581 mmol) of rac- (cis / trans) - {[3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclopentyl] oxy} Acetic acid tert-butyl esters are separated by chromatography on a chiral phase into the isomers / enantiomers (see Examples 125-128) [column: Daicel Chiralpak AD-H 5 μm, 250 mm x 20 mm; Flow: 15 ml / min; Detection: 220 nm; Temperature: 25 ° C; Eluent: iso-hexane / 2-propanol 90:10]. Example 125

(-) - c "- {[3 - {[5- (4-Methoxyphenyl) -6-phenylnolo [2,3-d] pyrimidin-4-yl] oxy} cyclopentyl] oxy} acetic acid ter. butyl

Yield: 75 mg (25.0% of theory)

[α] D = -24.7 °, c = 0.455, CHCl ₃

LC-MS (Method 3): R, = 3.17 min .; m / z = 517 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.59 (s, IH), 7.56 (d, 2H), 7.47-7.35 (m, 5H), 7.00 (d, 2H), 5.47-5.40 (m, IH), 4.00-3.92 (m, IH), 3.88 (d, 2H), 3.80 (s, 3H), 2.37-2.26 (m, IH), 1.96-1.61 (m, 5H), 1.40 (s , 9H).

Example 126

(+) - c / 5 - {[3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclopentyl] oxy} - acetic acid ter /. butyl

Yield: 57 mg (19.0% of theory)

[α] _D ^2υ = + 24.2 °, c = 0.48, CHCl ₃ . Example 127

(+) - "rα" 5 - {[3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclopentyl] oxy} acetic acid teλY. butyl

Yield: 23 mg (7.7% of theory)

[α] _D ²⁰ = + 32.6 °, c = 0.48, CHCl ₃

LC-MS (Method 6): R _t = 3.31 min .; m / z = 517 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.59 (s, IH), 7.56 (d, 2H), 7.45-7.36 (m, 5H), 7.01 (d, 2H), 5.63-5.58 (m, IH), 3.97-3.90 (m, IH), 3.89 (s, 2H), 3.82 (s, 3H), 2.10-1.84 (m, 3H), 1.76-1.57 (m, 3H), 1.42 (s , 9H).

Example 128

(-) - / ra «5 - {[3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclopentyl] oxy} -acetic acid ter / .-butyl ester

Yield: 39 mg (13.0% of theory)

[α] iT 20 _ = -30.1 °, c = 0.54, CHCl ₃ . Example 129

(+) - c / 5 - {[(lR, 3S) -3 - {[5- (4-methoxyphenyl) -6-phenylfiiro [2,3-d] pyrimidin-4-yl] oxy} cyclopentyl] oxy } acetic acid tert-butyl ester

233.6 mg (0.694 mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine and 150 mg (0.694 mmol) of c / s - (-) - {[(li? 3S) -3-hydroxycyclopentyl] oxy} acetic acid / e /'-butyl ester are dissolved in 0.35 ml of DMF, cooled to 0 ⁰ C and with 0.69 ml (0.69 mmol) of phosphazene base P4-t-Bu (1 M Solution in hexane). After 1 h of stirring at RT, the reaction mixture is added to water, adjusted to pH 7 with 1 N hydrochloric acid and extracted three times with dichloromethane. The organic phases are united, with ges. Sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Purification by preparative RP-HPLC (eluent: acetonitrile / water gradient) gives 27.2 mg (7.6% of theory) of the target compound.

[α] _D ²⁰ = + 28.4 °, c = 0.48, CHCl ₃

LC-MS (Method 3): R, = 3.18 min .; m / z = 517 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.59 (s, IH), 7.56 (d, 2H), 7.47-7.35 (m, 5H), 7.00 (d, 2H), 5.47-5.40 (m, IH), 4.00-3.92 (m, IH), 3.88 (d, 2H), 3.80 (s, 3H), 2.37-2.26 (m, IH), 1.96-1.61 (m, 5H), 1.40 (s, 9H) ,

Example 130 and Example 131

rαc- / rα «5 - {[3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclopentyl] oxy} acetic acid ter. butyl ester

and

rac-cis- {[3- {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] -amino} cyclopentyl] oxy} -acetic acid, t -V.V.-butyl ester

To a mixture of 560.4 mg (+/-) - cw / fra "5 - [(3-aminocyclopentyl) oxy] -acetic acid terr-butyl ester (crude product, ca. 2.60 mmol) and 964.3 mg (2.86 mmol) 4 Chloro-5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidine in 2.0 ml of DMF is added 0.86 ml (5.2 mmol) of diisopropylethylamine. The reaction mixture is heated at 100 ^° C. for 6 h. After cooling, water is added and the mixture is extracted with dichloromethane. The organic phase is washed with sat. Sodium hydrogen carbonate solution and sat. Sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After drying in a high vacuum, the product mixture is purified by preparative RP-HPLC (eluent: acetonitrile / water gradient) and separated into the c / s / isomers.

rac-trans-isomer (Example 130):

Yield: 153.7 mg (11.5% of theory)

LC-MS (Method 3): R, = 3.02 min .; m / z = 516 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.32 (s, IH), 7.47-7.39 (m, 4H), 7.38-7.29 (m, 3H), 7.10 (d, 2H), 5.31 (d, IH), 4.61-4.52 (m, IH), 3.92 (br s, IH), 3.84 (s, 3H), 3.65 (s, 2H), 2.00-1.90 (m, 2H), 1.70-1.60 (m, 2H), 1.52-1.43 (m, 2H), 1.40 (s, 9H).

rac c / s isomer (Example 131):

Yield: 404.1 mg (30.1% of theory)

LC-MS (Method 3): R ₁ = 3.05 min .; m / z = 516 (M + H) ⁺ ¹ H-NMR (400 MHz, DMSO-de): δ = 8.35 (s, IH), 7.51-7.45 (m, 4H), 7.40-7.30 (m, 3H), 7.15 (d, 2H), 4.81 (i.e. , IH), 4.51-4.40 (m, IH), 3.90 (br s, 3H), 3.86 (s, 3H), 2.10-1.99 (m, 2H), 1.81-1.53 (m, 2H), 1.49-1.35 (m, 2H), 1.42 (s, 9H).

Separation of the racemic mixtures into the enantiomers:

350 mg (0.679 mmol) of rac-cw - {[3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] -amino} cyclopentyl] oxy} acetic acid / e / -Λ-butyl ester or 119 mg (0.231 mmol) rac-trans - {[3 - {[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclopentyl] oxy} acetic acid tert-butyl ester are separated into the enantiomers by chromatography on a chiral phase (see Examples 132-135) [column: Sepapak-2 5 μm, 250 mm × 20 mm; Flow: 15 ml / min; Detection: 220 nm; Temperature: 4O ⁰ C; Eluent: iso-hexane / 2-propanol 50:50].

Example 132

c / 5 - (-) - {[3 - {[5- (4-Methoxyphenyl) -6-phenylruro [2,3-d] pyrimidin-4-yl] amino} cyclopentyl] oxy} - acetic acid ter /. butyl

Yield: 165 mg (47.1% of theory)

[α] _D ²⁰ = -12.2 °, c = 0.455, CHCl ₃

LC-MS (Method 6): R _t = 3.20 min .; m / z = 516 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.35 (s, IH), 7.48-7.40 (m, 4H), 7.39-7.29 (m, 3H), 7.11 (d, 2H), 5.32 ( d, IH), 4.62-4.52 (m, IH), 3.97-3.90 (m, IH), 3.82 (s, 3H), 3.68 (s, 2H), 2.00-1.90 (m, 2H), 1.70-1.60 ( m, 2H), 1.53-1.44 (m, 2H), 1.40 (s, 9H).

Example 133

Cis - (+) - {[3 - {[5- (4-Methoxyphenyl) -6-phenyl-furo [2,3-d] pyrimidin-4-yl] amino} cyclopentyl] oxy} -acetic acid tert-butyl ester

Yield: 163 mg (46.6% of theory)

[α] _D = + 8.4 °, c = 0.51, CHCl ₃

LC-MS (Method 6): R ₁ = 3.20 min .; m / z = 516 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.34 (s, IH), 7.47-7.39 (m, 4H), 7.38-7.29 (m, 3H), 7.10 (d, 2H), 5.32 ( d, IH), 4.61-4.51 (m, IH), 3.97-3.90 (m, IH), 3.83 (s, 3H), 3.66 (s, 2H), 2.00-1.89 (m, 2H), 1.70-1.60 ( m, 2H), 1.53-1.47 (m, IH), 1.40 (s, 9H), 0.90-0.79 (m, IH).

Example 134

5 - (+) - {[3 - {[5- (4-Methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] amino} cyclopentyl] oxy} acetic acid terf. butyl

Yield: 54 mg (45.4% of theory)

[αV ^υ = + 29.5 °, c = 0.46, CHCl ₃

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.35 (s, IH), 7.50-7.45 (m, 4H), 7.40-7.30 (m, 3H), 7.16 (d, 2H), 4.80 (d, IH), 4.50-4.40 (m, IH), 3.95-3.39 (m, 3H), 3.86 (s, 3H), 2.08-1.98 (m, 2H), 1.81-1.71 (m, IH), 1.63 -1.54 (m, IH), 1.42 (s, 9H), 1.40-1.32 (m, IH), 1.21-1.10 (m, IH). Example 135

/ rαπ5 - (-) - {[3 - {[5- (4-methoxyphenyl) -6-phenylnolo [2,3-d] pyrimidin-4-yl] amino} cyclopentyl] oxy} -acetic acid ter. butyl ester

Yield: 50 mg (42.0% of theory)

[α] _D ²⁰ = -30.3 °, c = 0.52, CHCl ₃

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.36 (s, IH), 7.51-7.44 (m, 4H), 7.40-7.30 (m, 3H), 7.17 (d, 2H), 4.81 (d, IH), 4.51-4.40 (m, IH), 3.95-3.89 (m, 3H), 3.85 (s, 3H), 2.10-1.99 (m, 2H), 1.81-1.71 (m, IH), 1.65-1.54 ( m, IH), 1.42 (s, 9H), 1.40-1.35 (m, IH), 1.21-1.11 (m, IH).

Example 136

cύ - (+/-) - {[4 - {[5- (4-ethylphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclopent-2-en-l-yl] oxy} acetic acid tert-butyl ester

390.7 mg (1.17 mmol) of 4-chloro-5- (4-ethylphenyl) -6-phenylfuro [2,3-d] pyrimidine and 250 mg (1.17 mmol) of ci5 - (+/-) - {[(4-hydroxycyclopent -2-en-l-yl] oxy} acetic acid / er / .- butyl ester are dissolved in 0.95 ml of DMF, cooled to ^{0 0} C and with 0.58 ml (1.17 mmol) of phosphazene base P2-t-Bu (2 M After the addition has ended, the mixture is warmed to RT and stirred for a further hour, the reaction mixture is then added to water, adjusted to pH 7 with 1 N hydrochloric acid and extracted three times with dichloromethane. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo Crude product is isolated by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 20: 1 → 5: 1). 510 mg (85.3% of theory) of the target compound are obtained.

LC-MS (Method 8): R, = 3.47 min .; m / z = 513 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d "): δ = 8.61 (s, IH), 7.49-7.51 (m, 2H), 7.44-7.35 (m, 5H), 7.28 (d, 2H), 6.13 dd, 2H), 5.84-5.79 (m, IH), 4.53-4.48 (m, IH), 3.93 (s, 2H), 2.88-2.79 (m, IH), 2.68 (q, 2H), 1.52 (td, IH), 1.40 (s, 9H), 1.23 (t, 3H).

Example 137

c / 5 - (-) - {[4 - {[5- (4-ethylphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclopent-2-en-l-yl] oxy} - acetic acid tert-butyl ester

125 mg (0.373 mmol) of 4-chloro-5- (4-ethylphenyl) -6-phenylfuro [2,3-d] pyrimidine and 80 mg (0.373 mmol) of c / 5- (+) - {[(4-hydroxycyclopent -2-en-l-yl] oxy} acetic acid tert-butyl ester are dissolved in 0.19 ml of DMF, cooled to 0 ⁰ C and with 0.19 ml (0.373 mmol) of phosphazene base P2-t-Bu (2 M solution After completion of the addition, the mixture is warmed to RT and stirred for a further 1 h, the reaction mixture is then added to water, adjusted to pH 7 with 1 N hydrochloric acid and extracted three times with dichloromethane. Wash with saturated sodium chloride solution, dry over magnesium sulfate and concentrate in vacuo, purify the crude product by preparative RP-HPLC (eluent: acetonitrile / water gradient) to give 140.5 mg (73.4% of theory) of the title compound.

[α] _D ²⁰ = -92.2 °, c = 0.515, CHCl ₃

LC-MS (Method 12): R, = 3.37 min .; m / z = 513 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.61 (s, IH), 7.58-7.52 (m, 2H), 7.42-7.37 (m, 5H), 7.28 (d, 2H), 6.12 ( dd, 2H), 5.85-5.79 (m, IH), 4.53-4.49 (m, IH), 3.92 (s, 2H), 2.88-2.79 (m, IH), 2.69 (q, 2H), 1.53 (td, IH), 1.40 (s, 9H), 1.23 (t, 3H). Example 138

c / s - (-) - {[4- {[5- (4-ethylphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclopent-2-en-1-yl ] oxy} - tert-butyl acetate

218 mg (0.652 mmol) of 4-chloro-5- (4-ethylphenyl) -6-phenyl-furo [2,3-d] pyrimidine and 141 mg (0.652 mmol) of c / 5- (+) - {[(IS, 3R ) -3-hydroxycyclopentyl] oxy} acetic acid tert-butyl ester are dissolved in 0.19 ml of DMF, cooled to ⁰ ° C. and treated with 0.65 ml (0.65 mmol) of phosphazene base P4-t-Bu (1 M solution in hexane). added. After the end of the addition, the mixture is warmed to RT and stirred for 1 h. The reaction mixture is then added to water, adjusted to pH 7 with 1 N hydrochloric acid and extracted three times with dichloromethane. The organic phases are combined, washed with sat. Sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by preparative RP-HPLC (eluent: acetonitrile / water gradient). Obtained are 92.1 mg (27.5% of theory) of the target compound.

[α] _D ²⁰ = -36.2 °, c = 0.490, CHCl ₃

LC-MS (Method 12): R ₁ = 3.40 min .; m / z = 515 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.60 (s, IH), 7.54 (d, 2H), 7.45-7.37 (m, 5H), 7.29 (d, 2H), 5.45-5.39 (m, IH), 4.00-3.94 (m, IH), 3.81 (d, 2H), 2.69 (q, 2H), 2.34-2.22 (m, IH), 1.94-1.83 (m, IH), 1.81-1.71 (m, IH), 1.70-1.56 (m, 3H), 1.40 (s, 9H), 1.22 (t, 3H).

Example 139

/ Raλ75 - (-) - {[4 - {[5- (4-ethylphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclopent-2-en-l-yl] - oxy} acetic acid ter. -buty lester

393.9 mg (1.18 mmol) of 4-chloro-5- (4-ethylphenyl) -6-phenylfuro [2,3-d] pyrimidine and 274 mg (80% purity, ca. 1.02 mmol) of raws - (-) - { [(4-hydroxycyclopent-2-en-l-yl] oxy} acetic acid / erΛ-butyl ester are dissolved in 00:59 ml THF, cooled to 0 ⁰ C and slowly (at 1:02 ml 1:02 mmol) phosphazene base P4 T-Bu (in solution in hexane) is added and the reaction mixture is stirred for 1 h at 0 ^° C. It is adjusted to pH 7 with 1 N hydrochloric acid and extracted three times with dichloromethane, the organic phases are combined and washed Sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo The crude product is purified by preparative RP-HPLC (eluent: acetonitrile / water gradient) to give 258.3 mg (42.8% of theory) of the target compound.

[α] _D ²⁰ = -102.7 °, c = 0.58, CHCl ₃

LC-MS (Method 8): R, = 3.49 min .; m / z = 513 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.61 (s, IH), 7.59-7.51 (m, 2H), 7.47-7.31 (m, 5H), 7.30-7.21 (m, 2H) , 6.28-6.22 (m, IH), 6.19-6.09 (m, 2H), 4.67-4.60 (m, IH), 4.00 (s, 2H), 2.69 (q, 2H), 2.65- 2.57 (m, IH) , 2.20-2.10 (m, IH), 2.05-1.95 (m, IH), 1.46 (s, 9H), 1.29-1.20 (m, 2H).

Example 140

^ R <3AJ5 - (-) - {[4 - {[5- (4-ethylphenyl) -6-phenylfιιro [2,3-d] pyrimidin-4-yl] amino} cyclopent-2-en-l-yl ] - oxy} acetic acid terΛ-butyl ester

To a mixture of 128.6 mg (0.384 mmol) of 4-chloro-5- (4-ethylphenyl) -6-phenylfuro [2,3-d] pyrimidine and 74.5 mg / ra.s - {[(4-aminocyclopent-2 -en-l-yl] oxy} -acetic acid tert-butyl ester (crude product) in 0.5 ml of DMF is added 87 μl (0.524 mmol) of diisopropylethylamine. The reaction mixture is heated to 100 ^° C. for 4.5 h. After cooling, water is added and the mixture is extracted with dichloromethane. The organic phase is washed with sat. Sodium bicarbonate solution and sat. Sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative RP-HPLC (eluent: acetonitrile / water gradient). 70.5 mg (39.5% of theory) of the target compound are obtained.

[α] _D ²⁰ = -195.3 °, c = 0.50, CHCl ₃

LC-MS (Method 3): R, = 3.20 min .; m / z = 512 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.39 (s, IH), 7.52-7.48 (m, 2H), 7.47-7.30 (m, 7H), 6.07-6.01 (m, IH), 5.90 (d, IH), 5.24-5.16 (m, IH), 4.65 (d, IH), 4.59-4.51 (m, IH), 3.98 (s, 2H), 2.72 (q, 2H), 2.20-2.10 ( m, IH), 1.67-1.58 (m, IH), 1.42 (s, 9H), 1.27 (t, 3H).

Example 141

cis - (+) - {[4- {[5- (4-ethylphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} cyclopent-2-en-1-yl] oxy} - tert-butyl acetate

233.6 mg (0.698 mmol) of 4-chloro-5- (4-ethylphenyl) -6-phenylfuro [2,3-d] pyrimidine and 150.9 mg (0.698 mmol) of c / s - (-) - {[(IR, 3 <S) -3-Hydroxycyclopentyl] oxy} acetic acid tert-butyl ester are dissolved in 0.35 ml of DMF, cooled to 0 ° C and with 0.7 ml (0.7 mmol) of phosphazene base P4-t-Bu (1 M solution in hexane ). After 2 h stirring at 0 ° C, the reaction mixture is added to water. It is adjusted to pH 7 with 1 N hydrochloric acid and extracted three times with dichloromethane. The organic phases are combined, washed with sat. Sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by preparative RP-HPLC (eluent: acetonitrile / water gradient). 60.9 mg (17.0% of theory) of the target compound are obtained.

[α] _D ²⁰ = + 26.7 °, c = 0.475, CHCl ₃

LC-MS (Method 12): R, = 3.39 min .; m / z = 515 (M + H) ⁺ ¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.60 (s, IH), 7.56 (d, 2H), 7.44-7.38 (m, 5H), 7.29 (d, 2H), 5.45-5.40 (m, IH), 4.00-3.92 (m, IH), 3.82 (d, 2H), 2.69 (q, 2H), 2.32-2.25 (m, IH), 1.92-1.85 (m, IH), 1.81-1.74 (m, IH), 1.70-1.58 (m, 3H), 1.40 (s, 9H), 1.22 (t, 3H).

The following examples are prepared according to the general procedure D or E (see above) from the compounds described above:

(d. (br.

(Dd,

(T,

s, s, 3H),

(d, (d,

(D,

Example 177

[(3 - {[5- (4-Ethylphenyl) -6- (2-fluorophenyl) furo [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl) oxy] -acetic acid tert-butyl ester ( rac. mixture of diastereomers)

A solution of 700 mg (1.62 mmol) of 3 - {[5- (4-emylphenyl) -6- (2-fluoro-phenyl) -furo [2,3-d] pyrimidin-din-4-yl] oxy} cyclohexanol in 15 ml Toluene is added at 70 ⁰ C with 1.4 ml of a 11.25 N sodium hydroxide solution. After addition of 55 mg (0:16 mmol) of tetra-n-butylammonium hydrogen sulfate and 631 mg (3.24 mmol) of bromoacetic acid-tert-butyl ester terΛ the reaction mixture is stirred for 30 hours at 70 ⁰ C. The reaction mixture is then treated with a further 330 mg (1.69 mmol) bromoacetic acid tert-butyl ester and stirred again at 70 ⁰ C for 14 hours. After cooling to room temperature with conc. Hydrochloric acid adjusted to pH 7. It is extracted with dichloromethane. The organic phase is washed with sat. Sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative RP-HPLC (eluent: water / acetonitrile gradient). 632 mg (69% of theory) of the desired product are obtained as racemic mixture of diastereomers.

LC-MS (Method 8): R, = 3.47 min .; m / z = 547 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): [minor stereoisomer in parentheses] δ = 8.62 (s, IH), 7.57-7.50 (m, 2H), 7.34-7.28 (m, 4H), 7.21-7.19 ( m, 2H), [5.69-5.64, m, IH], 5.23-5.16 (m, IH), 3.99 (d, 2H), [3.89, d, 2H], 3.47-3.40 (m, IH), 2.64 ( q, 2H), 2.46-2.42 (m, IH), 2.09-2.05 (m, IH), 1.99-1.93 (m, IH), 1.78-1.73 (m, IH), 1.41 (s, 9H), 1.30- 1.12 (m, 4H), 1.20 (t, 3H).

Example 178

[(3 - {[5- (4-Ethylphenyl) -6- (2-fluorophenyl) furo [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl) oxy] acetic acid tert-butyl ester (cis Enantiomer 1)

Starting from 600 mg (1.10 mmol) of [(3 - {[5- (4-ethylphenyl) -6- (2-fluorophenyl) furo [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl) oxy ] acetic acid / tert-butyl ester (rac. Diastereomerengemisch) are obtained after chromatographic separation of enantiomers on chiral phase 236 mg (39% of theory) of the pure c / s enantiomer 1 [column: Daicel Chiralpak AD-H, 5 microns , 250 mm x 20 mm; Flow: 15 ml / min; Detection: 220 μm; Temperature: 30 ° C; Eluent: 93% iso-hexane / 7% ethanol].

HPLC [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 4.6 mm; Flow: 1 ml / min; Detection: 215 nm; Temperature: 35 ° C; Eluent: 93% iso-hexane / 7% ethanol]: R, = 6.64 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.62 (s, IH), 7.56-7.52 (m, 2H), 7.34-7.28 (m, 4H), 7.21-7.19 (m, 2H), 5.23-5.16 (m, IH), 3.98 (d, 2H), 3.47-3.40 (m, IH), 2.64 (q, 2H), 2.48-2.44 (m, IH), 2.09-2.05 (m, IH), 1.98-1.94 (m, IH), 1.78-1.73 (m, IH), 1.41 (s, 9H), 1.30-1.10 (m, 4H), 1.20 (t, 3H).

Example 179

[(3 - {[5- (4-Ethylphenyl) -6- (2-fluorophenyl) furo [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl) oxy] acetic acid tert-butyl ester { cis enantiomer 2)

Starting from 600 mg (1.10 mmol) of [(3 - {[5- (4-ethylphenyl) -6- (2-fluorophenyl) furo [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl) oxy ] acetate-tert.-butyl ester (rac. mixture of diastereomers), after chromatographic separation of enantiomers on a chiral phase, 263 mg (43% of theory) of the pure c / s enantiomer 2 obtained [column: Daicel Chiralpak AD-H, 5 microns, 250 mm x 20 mm; Flow: 15 ml / min; Detection: 220 nm; Temperature: 30 ^° C .; Eluent: 93% iso-hexane / 7% ethanol].

HPLC [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 4.6 mm; Flow: 1 ml / min; Detection: 215 nm; Temperature: 35 ° C; Eluent: 93% iso-hexane / 7% ethanol]: R _t = 8.06 min.

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.62 (s, IH), 7.56-7.52 (m, 2H), 7.34-7.28 (m, 4H), 7.21-7.19 (m, 2H) , 5.23-5.16 (m, IH), 3.98 (d, 2H), 3.47-3.40 (m, IH), 2.64 (q, 2H), 2.48-2.44 (m, IH), 2.09-2.05 (m, IH) , 1.98-1.94 (m, IH), 1.78-1.73 (m, IH), 1.41 (s, 9H), 1.30-1.10 (m, 4H), 1.20 (t, 3H).

Example 180

Methyl 4 - [(3R) -3 - {[5- (4-ethylphenyl) -6- (2-fluoro-phenyl) -furo [2,3-d] pyrimidin-4-yl] oxy} -piperidin-1-yl] -butyrate

A solution of 2250 mg (4.9 mmol) of 5- (4-ethylphenyl) -6- (2-fluoro-phenyl) -4 - [(3R) -piperidin-3-yl-oxy] -furo [2,3-d] pyrimidine in 100 ml of THF and 10 ml of acetonitrile are mixed with 1677 mg (12.1 mmol) of potassium carbonate. Subsequently, 0.74 ml (1054 mg, 5.8 mmol) of methyl 4-bromobutyrate and 72 mg (0.19 mmol) of tetra-n-butylammonium iodide are added. The reaction mixture is stirred at 80 ^° C. for 13 hours. After cooling to room temperature, the residue is filtered off, washed with THF, the filtrate concentrated in vacuo and the residue purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 1: 2). 2005 mg (75% of theory) of the target compound are obtained.

LC-MS (Method 12): R _t = 1.82 min .; m / z = 518 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO-Cl ₆ ): δ = 8.63 (s, IH), 7.56-7.53 (m, 2H), 7.35-7.28 (m, 4H), 7.18 (d, 2H), 5.33- 5.31 (m, IH), 3.52 (s, 3H), 2.78-2.75 (m, IH), 2.64 (q, 2H), 2.44-2.40 (m, IH), 2.36-2.23 (m, 6H), 1.93- 1.89 (m, IH), 1.67-1.59 (m, 3H), 1.44-1.42 (m, 2H), 1.19 (t, 3H). Example 181

4 - [(3R) -3 - {[5- (4-Ethylphenyl) -6- (2-fluoro-phenyl) -propyl] -2,3-d] pyrimidin-4-yl] oxy} -piperidin-1-yl] -butyric acid

500 mg (0.97 mmol) of 4 - [(3R) -3 - {[5- (4-ethylphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} piperidin-1-yl ] Buttersäuremethylester are dissolved in 10 ml of dioxane and treated with 2.9 ml of a 1 N sodium hydroxide solution. It is stirred for 16 hours at room temperature. Thereafter, 2.9 ml of 1 N hydrochloric acid are added, and the mixture is extracted with 20 ml of ethyl acetate. The organic phase is separated, dried over sodium sulfate, filtered and concentrated. The residue is purified by preparative RP-HPLC (eluent: water / acetonitrile gradient with 0.1% formic acid). The product obtained is taken up in 10 ml of ethyl acetate and washed twice with 10 ml of a 1 M aqueous sodium bicarbonate solution. The organic phase is separated, dried over sodium sulfate, filtered and concentrated. 309 mg (62% of theory) of the target compound are obtained.

LC-MS (Method 3): R, = 1.74 min .; m / z = 504 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.12 (s, IH), 8.62 (s, IH), 7.56-7.51 (m, 2H), 7.36-7.27 (m, 4H), 7.18 (d, 2H), 5.32 (t, IH), 2.83-2.80 (m, IH), 2.63 (q, 2H), 2.49-2.47 (m, IH), 2.33-2.25 (m, 4H), 2.19 (t, 2H) , 1.94-1.91 (m, IH), 1.65-1.57 (m, 3H), 1.43-1.39 (m, 2H), 1.19 (t, 3H).

Example 182

4 - [(3R) -3 - {[5- (4-ethylphenyl) -6- (2-fluoro-phenyl) -furo [2,3-d] pyrimidin-4-yl] oxy} -piperidin-1-yl] -butyric acid formate

500 mg (0.97 mmol) of 4 - [(3A) -3 - {[5- (4-ethylphenyl) -6-phenylftiro [2,3-d] pyrimidin-4-yl] oxy} piperidin-1-yl ] Buttersäuremethylester are dissolved in 10 ml of dioxane and treated with 2.9 ml of a 1 N sodium hydroxide solution. It is stirred for 16 hours at room temperature. Thereafter, 2.9 ml of 1N hydrochloric acid are added, and the mixture is extracted with 20 ml of ethyl acetate. The organic phase is separated, dried over sodium sulfate, filtered and concentrated. The residue is purified by preparative RP-HPLC (eluent: water / acetonitrile gradient with 0.1% formic acid). 411 mg (77% of theory) of the target compound are obtained.

LC-MS (Method 8): R _t = 1.88 min .; m / z = 504 (M-HCO ₂ H + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.62 (s, IH), 8.14 (s, IH), 7.56-7.51 (m, 2H), 7.36-7.29 (m, 4H), 7.19 (d, 2H), 5.33 (t, IH), 2.83-2.80 (m, IH), 2.63 (q, 2H), 2.49-2.47 (m, IH), 2.33-2.25 (m, 4H), 2.19 (t, 2H) , 1.94-1.91 (m, IH), 1.66-1.58 (m, 3H), 1.48-1.34 (m, 2H), 1.19 (t, 3H).

Example 183

4 - [(3R) -3 - {[6- (2-Fluorophenyl) -5- (4-methoxyphenyl) ruro [2,3-d] pyrimidin-4-yl] oxy} piperidin-1-yl] -butyric acid, methyl ester

A suspension of 500 mg (1.2 mmol) of 6- (2-fluoro-phenyl) -5- (4-methoxyphenyl) -4 - [(3Λ) -piperidin-3-yloxy] furo [2,3-d] pyrimidine in 10 ml of THF are mixed with 411 mg (3.0 mmol) of potassium carbonate. Subsequently, 0.18 ml (259 mg, 1.4 mmol) of 4-bromobutyrate and 17 mg (0.05 mmol) tetra-n-butylammonium iodide added. The reaction mixture is stirred at 80 ^° C. for 13 hours. Thereafter, 10 ml of DMF are added and the mixture stirred again for 13 hours at 70 ⁰ C. After addition of 10 ml of water, 1 N hydrochloric acid and ethyl acetate, the organic phase is separated, concentrated in vacuo and the residue purified by preparative RP-HPLC (eluent: water / acetonitrile gradient). 146 mg (22% of theory) of the target compound are obtained.

LC-MS (method 13): R, = 2.77 min .; m / z = 520 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.61 (s, IH), 7.56-7.52 (m, 2H), 7.35 (d, 2H), 7.32-7.28 (m, 2H), 6.90 (d, 2H), 5.34-5.31 (m, IH), 3.76 (s, IH), 3.53 (s, 3H), 2.81-2.79 (m, IH), 2.48-2.42 (m, IH), 2.32-2.18 (m, 6H), 2.00-1.92 (m, IH), 1.67-1.60 (m, 3H), 1.45-1.41 (m, 2H).

Example 184

4 - [(3R) -3 - {[6- (2-Fluoro-phenyl) -5- (4-methoxyphenyl) -furo [2,3-d] pyrimidin-4-yl] oxy} -piperidin-1-yl] -butyric acid, methyl ester formate

A solution of 70 mg (0.15 mmol) of 6- (2-fluorophenyl) -5- (4-methoxyphenyl) -4 - [(3R) -piperidin-3-yloxy] furo [2,3-d] pyrimidine formate in 1 ml of THF is mixed with 52 mg (0.38 mmol) of potassium carbonate. Subsequently, 0.02 ml (33 mg, 0.18 mmol) of 4-bromobutyrate and 2 mg (0.01 mmol) of tetra-n-butylammonium iodide are added. The reaction mixture is stirred at 80 ^° C. for 13 hours. After cooling to room temperature, the mixture is concentrated under reduced pressure and the residue is purified by preparative RP-HPLC (eluent: water / acetonitrile gradient with 0.1% formic acid). 40 mg (42% of theory) of the target compound are obtained.

LC-MS (Method 3): R, = 1.75 min .; m / z = 520 (M + H) ⁺

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 8.62 (s, IH), 8.15 (s, IH), 7.53-7.51 (m, 2H), 7.35 (d, 2H), 7.32-7.28 (m, 2H), 6.90 (d, 2H), 5.5-5.30 (m, IH), 3.76 (s, 3H), 3.52 (s, 3H), 2.82-2.79 (m, IH), 2.36-2.24 (m, 5H) , 1.94-1.88 (m, IH), 1.67-1.60 (m, 2H), 1.45-1.41 (m, 2H). Example 185

4 - [(3Λ) -3 - {[6- (2-Fluoro-phenyl) -5- (4-methoxyphenyl) -furo [2,3-d] pyrimidin-4-yl] oxy} -piperidin-1-yl] -butyric acid

113 mg (0.20 mmol) of 4 - [(3R) -3 - {[6- (2-fluoro-phenyl) -5- (4-methoxyphenyl) -furo [2,3-d] pyrimidin-4-yl] oxy} -piperidine 1-yl] butyrate are dissolved in 3 ml of dioxane and treated with 0.8 ml of a 1 N sodium hydroxide solution. It is stirred for 16 hours at room temperature, then 0.8 ml of 1 N hydrochloric acid added and treated with 10 ml of ethyl acetate. The organic phase is separated, dried over sodium sulfate, filtered and concentrated. 95 mg (90% of theory) of the target compound are obtained.

LC-MS (Method 8): R _t = 1.70 min .; m / z = 504 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 12.20 (br.s, IH), 8.63 (s, IH), 7.56-7.51 (m, 2H), 7.37-7.29 (m, 4H) , 6.91 (d, 2H), 5.35 (t, IH), 3.76 (s, IH), 2.99-2.94 (m, IH), 2.64-2.62 (m, IH), 2.40-2.32 (m, 4H), 2.20 (t, 2H), 2.02-1.98 (m, IH), 1.67-1.63 (m, 3H), 1.43-1.39 (m, 2H).

Example 186

{[(IS, 3R) -3 - {[5- (4-ethylphenyl) -6- (2-fluoro-phenyl) -furo [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl] oxy} acetic acid

237 mg (0.43 mmol) of {[(IS, 3R) -3 - {[5- (4-ethyl-phenyl) -6- (2-fluoro-phenyl) -furo [2,3-d] pyrimidin-4-yl] -oxy} cyclohexyl] oxy} acetic acid teλ - / .- butylester are mixed with 10 ml of 4 N hydrogen chloride in dioxane and stirred for 16 hours at room temperature. After removal of the solvent in vacuo, the residue is purified by preparative RP-HPLC (eluent: water / acetomtril gradient). 132 mg (62% of theory) of the target compound are obtained.

LC-MS (Method 8): R _t = 3.10 min .; m / z = 491 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-dβ): δ = 12.54 (s, IH), 8.63 (s, IH), 7.56-7.52 (m, 2H), 7.34-7.28 (m, 4H), 7.20 (i.e. , 2H), 5.22-5.16 (m, IH), 4.03 (s, 2H), 3.48-3.43 (m, IH), 2.63 (q, 2H), 2.12-2.06 (m, IH), 2.00-1.96 (m , IH), 1.77-1.73 (m, IH), 1.29-1.08 (m, 4H), 1.19 (t, 3H).

[α] _D ²⁰ = + 62 °, c = 0.525, CHCl ₃ .

Example 187

{[(lΛ, 3S) -3 - {[5- (4-ethylphenyl) -6- (2-fluorophenyl) furo [2,3-d] pyrimidin-4-yl] oxy} cyclohexyl] oxy} acetic acid

215 mg (0.39 mmol) of {[(1 /?, 3S) -3 - {[5- (4-ethylphenyl) -6- (2-fluorophenyl) furo [2,3-d] pyrimidin-4-yl] - oxy} cyclohexyl] oxy} acetic acid / erf. butyl ester are mixed with 10 ml of 4 N hydrogen chloride in dioxane and stirred for 16 hours at room temperature. After removal of the solvent in vacuo, the residue is purified by preparative RP-HPLC (eluent: water / acetonitrile gradient). 128 mg (66% of theory) of the target compound are obtained.

LC-MS (Method 8): R _t = 3.11 min .; m / z = 491 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 12.54 (s, IH), 8.63 (s, IH), 7.56-7.52 (m, 2H), 7.34-7.28 (m, 4H), 7.20 ( d, 2H), 5.22-5.16 (m, IH), 4.03 (s, 2H), 3.48-3.43 (m, IH), 2.63 (q, 2H), 2.12-2.06 (m, IH), 2.00-1.96 ( m, IH), 1.77-1.74 (m, IH), 1.29-1.08 (m, 4H), 1.18 (t, 3H).

[α] _D ²⁰ = -57 °, c = 0.660, CHCl ₃ . Example 188

{[! ■ ({[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} methyl) cyclobutyl] methoxy} acetic acid tert. butyl

A solution of 285 mg (0.68 mmol) of [1- ({[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} methyl) cyclobutyl] methanol in 5 ml of toluene is added with 0.6 ml of a 1 1.25 N sodium hydroxide solution. After addition of 23 mg (0.07 mmol) of tetra-w-butylammonium hydrogen sulfate and 267 mg (1.37 mmol) of bromoacetic acid tert. butyl ester, the reaction mixture is stirred at 70 ⁰ C for 20 h. After cooling to room temperature with conc. Hydrochloric acid adjusted to pH 7. It is extracted three times with 20 ml of dichloromethane each time. The combined organic extracts are washed with sat. washed aqueous sodium chloride solution, dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo. The crude product is purified by preparative RP-HPLC (gradient: water / acetonitrile). 260 mg (72% of theory) of the desired product are obtained.

LC-MS (Method 8): R, = 3.38 min .; m / z = 531 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.58 (s, IH), 7.56-7.54 (m, 2H), 7.42-7.37 (m, 5H), 7.04-7.00 (m, 2H) , 4.34 (s, 2H), 3.85 (s, 2H), 3.81 (s, 3H), 3.22 (s, 2H), 1.78-1.65 (m, 6H), 1.38 (s, 9H).

Example 189

{[l - ({[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} methyl) cyclobutyl] methoxy} acetic acid

237 mg (0.45 mmol) of {[1- ({[5- (4-methoxyphenyl) -6-phenylfuro [2,3-d] pyrimidin-4-yl] oxy} -methyl) cyclobutyl] methoxy} acetic acid ter / .-Butyl ester are dissolved in 1 ml of dioxane, mixed with 2 ml of 4 N hydrogen chloride in dioxane and stirred for 16 h at RT. After concentration of the reaction solution in vacuo, the residue is purified by preparative RP-HPLC (gradient: water / acetonitrile). 180 mg (85% of theory) of the desired product are obtained.

LC-MS (Method 8): R. = 2.84 min .; m / z = 475 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-de): δ = 12.49 (br.s, IH), 8.57 (s, IH), 7.56-7.54 (m, 2H), 7.42-7.36 (m, 5H), 7.04 -7.00 (m, 2H), 4.34 (s, 2H), 3.87 (s, 2H), 3.81 (s, 3H), 3.23 (s, 2H), 1.80-1.67 (m, 6H).

B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds according to the invention can be demonstrated in the following assays:

BI. Binding studies with prostacyclin receptors (IP receptors) of human thrombocyte membranes

To obtain platelet membranes, 50 ml of human blood (buffy coats with CDP stabilizer, Maco Pharma, Langen) are centrifuged for 20 min at 160 × g. The supernatant (platelet-rich plasma, PRP) is removed and then centrifuged again at 2000 xg for 10 min at room temperature. The sediment is dissolved in 50 mM tris (hydroxymethyl) amino methane, which is adjusted to a pH of 7.4 with 1N hydrochloric acid, resuspended, and stored at -20 ⁰ C overnight. The following day, the suspension is centrifuged at 80,000 xg and 4 ° C for 30 minutes. The supernatant is discarded. The sediment is re-suspended in 50 mM tris- (hydroxymethyl) -aminomethane / hydrochloric acid, 0.25 mM ethylenediaminetetraacetic acid (EDTA), pH 7.4 and then centrifuged again at 80,000 × g and 4 ° C. for 30 minutes. The membrane bransediment is added to binding buffer ((50 mM Tris-hydroxymethyl) aminomethane / hydrochloric acid, 5 mM magnesium chloride, pH 7.4) and stored at -70 ⁰ C until the binding assay.

For the binding experiment, 3 mM ³ H-iloprost (592 GBq / mmol, Amersham Bioscience) are incubated for 60 min with 300-1000 μg / ml human platelet membranes per batch (maximum 0.2 ml) in the presence of the test substances at room temperature. After stopping, the membranes are mixed with cold binding buffer and washed with 0.1% bovine serum albumin. After addition of Ultima Gold scintillator, the radioactivity bound to the membranes is quantified by means of a scintillation counter. Non-specific binding is defined as radioactivity in the presence of 1 μM iloprost (Cayman Chemical, Ann Arbor) and is typically <25% of the total bound radioactivity. The binding data (IC ₅₀ values) are determined by means of the program GraphPad Prism Version 3.02.

Representative results for the compounds according to the invention are listed in Table 1: Table 1

B-2. IP receptor stimulation on whole cells

The IP agonist activity of test substances is determined using the human erythroleukemia cell line (HEL), which endogenously expresses the IP receptor [Murray, R., FEBS Letters 1989, 1: 172-174]. For this purpose, the suspension cells (4 x 10 ⁷ cells / ml) in buffer [10 mM HEPES (4- (2-hydroxyethyl) -1-piperazinethansulfonsäure) / PBS (phosphate-buffered saline, Fa. Oxoid, UK)], 1 mM Calcium chloride, 1 mM magnesium chloride, 1 mM IBMX (3-isobutyl-l-methylxanthine), pH 7.4, with the respective test substance for 5 minutes at 30 ⁰ C incubated. Subsequently, the reaction is stopped by the addition of 4 ° C cold ethanol and the mixtures stored for a further 30 minutes at 4 ° C. Thereafter, the samples are centrifuged at 10,000 xg and 4 ° C. The resulting supernatant is discarded and the sediment used to determine the concentration of cyclic adenosine monophosphate (cAMP) in a commercially available cAMP radioimmunoassay (IBL, Hamburg). IP agonists lead to an increase in the cAMP concentration in this test, IP antagonists are ineffective. The effective concentration (EC _5O values) is determined using the program GraphPad Prism Version 3.02.

B-3. Platelet aggregation inhibition in vitro

To determine the antiplatelet activity, blood from healthy volunteers of both sexes is used. One part of 3.8% sodium citrate solution as coagulant is mixed with 9 parts of blood. The blood is centrifuged at 900 rpm for 20 min. The pH of the recovered platelet-rich plasma is adjusted to pH 6.5 with ACD solution (sodium citrate / citric acid / glucose). The platelets are then centrifuged off, taken up in buffer and centrifuged again. The platelet precipitate is taken up in buffer and additionally re-suspended with 2 mmol / l calcium chloride.

For the aggregation measurements, aliquots of the platelet suspension are incubated with the test substance at 37 ° C. for 10 min. Subsequently, the aggregation is induced by the addition of ADP and determined by the turbidimetric method according to Born in the aggregometer at 37 ° C [Born G.V.R., J. Physiol. (London) 168, 178-179 (1963)].

B-4. Blood pressure measurement on anesthetized rats

Male Wistar rats weighing 300-350 g are anesthetized with thiopental (100 mg / kg ip). After tracheostomy, the femoral artery is catheterized for blood pressure measurement. The substances to be tested are administered as a solution orally by gavage or via the femoral vein intravenously in a suitable vehicle. B-fifth PAH model in anesthetized dog

In this animal model of pulmonary arterial hypertension (PAH), Mongrel dogs with a body weight of about 25 kg are used. The anesthesia is induced by slow intravenous administration of 25 mg / kg of sodium thiopental (Trapanal ^®) and (ferin Aho ^®) 00:15 mg / kg alcuronium chloride and maintained throughout the experiment by means of a continuous infusion of 0.04 mg / kg / hr fentanyl ^® , 0.25 mg / kg / h droperidol (dehydrobenzperidol ^® ) and 15 μg / kg / h alcuronium chloride (Alloferin ^® ). Reflective effects on the heart rate by lowering blood pressure are minimized by autonomic blockade [continuous infusion of atropine (approximately 10 μg / kg / h) and propranolol (approximately 20 μg / kg / h)]. After intubation, the animals are ventilated via a respirator with a constant breathing volume, so that an end-tidal CO ₂ concentration of about 5% is achieved. Ventilation takes place with room air, enriched with approx. 30% oxygen (normoxie). To measure the hemodynamic parameters, a catheter filled with fluid is implanted in the femoral artery to measure blood pressure. A dual lumen Swan-Ganz catheter ^® is jugularis on the V. in the pulmonary artery is flooded (distal lumen for measuring the pulmonary arterial pressure, proximal lumen for measuring the central venous pressure). Left ventricular pressure is measured after the introduction of a Mikro-Tip catheter (Millar Instruments ^®) through the carotid artery into the left ventricle and derived from the dP / dt value as a measure of contractility. Substances are administered iv via the femoral vein. The hemodynamic signals are recorded and evaluated by means of pressure transducers / amplifiers and PONEMAH ^® as data acquisition software.

To induce acute pulmonary hypertension, either hypoxia or a continuous infusion of thromboxane A ₂ or a thromboxane A ₂ analogue is used as the stimulus. Acute hypoxia is induced by gradual reduction of oxygen in the ventilation air to about 14%, so that the mPAP increases to values of> 25 mm Hg. In the case of a thromboxane A ₂ analogue stimulus, 0.21-0.32 μg / kg / min U-46619 [9, 11-dideoxy-9α, 11α-epoxy-methano-prostaglandin F _2α (Sigma)] is infused to obtain to increase the mPAP to> 25 mm Hg.

B-sixth PAH model in anesthetized Göttinger Minipig

In this animal model of pulmonary arterial hypertension (PAH), Göttingen mini-pigs with a body weight of approx. 25 kg are used. The anesthesia is induced by 30 mg / kg Ketamine (Ketavet ^®) in, followed by an intravenous administration of 10 mg / kg of sodium thiopental (Trapanal ^®); it is maintained during the experiment by inhalation anesthesia from enflurane (2-2.5%) in a mixture of room air enriched with approximately 30-35% oxygen / N ₂ O (1: 1.5). To measure the hemodynamic parameters, a catheter filled with fluid is implanted in the carotid artery to measure blood pressure. A double-lumen Swan-Ganz catheter is ^® vein via the jugular in the pulmonary artery is flooded (distal lumen for measuring the pulmonary arterial pressure, proximal lumen for measurement of central venous pressure). Left ventricular pressure is measured after the introduction of a Mikro-Tip catheter (Millar Instruments ^®) through the carotid artery into the left ventricle and derived from the dP / dt value as a measure of contractility. Substances are administered iv via the femoral vein. The hemodynamic signals are recorded by means of DruckaufhehmeπWerstärkern and Ponemah data acquisition software as ^® and evaluated.

To induce acute pulmonary hypertension, a continuous infusion of a thromboxane A ₂ analogue is used as the stimulus. Here, 0.12-0.14 μg / kg / min of U-46619 [9, 11-dideoxy-9α, 11α-epoxymethano-prostaglandin F _2α (Sigma)] are infused to increase the mPAP to> 25 mm Hg.

C. Embodiments of Pharmaceutical Compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

production:

The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h. Orally administrable solution:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention correspond to 20 g of oral solution.

production:

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the erfϊndungsgemäßen connection.

iv solution:

The compound of the invention is dissolved in a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Claims

claims

1. Use of a compound of the formula (I)

in which

A is O, S or NR ⁴ , in which

L ^{1 is} a bond or (C 1 -C ₄ ) -alkanediyl,

the ring Q is (C ₃ -C ₇ ) -cycloalkyl, (C ₄ -C ₇ ) -cycloalkenyl, a 5- to 7-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each of which is up to twice, identically or differently, with fluorine, chlorine, (C 1 -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C 1 -C ₄ ) -alkoxy, trifluoromethoxy, amino, mono- (C 1 -C ₄ ) -alkylamino and / or Di- (C iC ₄ ) -alkylamino may be substituted,

wherein (Ci-C ₄₎ -alkyl for its part with hydroxy, (Ci-C ₄₎ alkoxy, amino, mono- or di- (Ci -C ₄₎ alkylamino may be substituted,

R ^{5 is} hydrogen, (C 1 -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,

can be exchanged,

or is (C ₂ -C ₄ ) -alkendiyl,

for a group of the formula

stands in which

# the point of attachment to the group L ²

and

R ⁶ is hydrogen or (C _r C ₄₎ alkyl,

R ¹ and R ² independently represent a substituent selected from the series

Halogen, cyano, nitro, (C 1 -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₄ ) -alkynyl, (C ₃ -C ₇ ) -

Cycloalkyl, (C ₄ -C ₇ ) -cycloalkenyl, (C ₁ -C ₆ ) -alkoxy, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₆ ) -alkylthio, (C ₁ -C 8) -acyl, amino, mono (C ₁ -C ₆ ) -acyl, -C ₆₎ alkylamino, di (Ci- C ₆₎ alkylamino and (Ci-C ₆₎ acylamino stand,

in which (C ₁ -C ₆ ) -alkyl and (C ₁ -C ₆ ) -alkoxy in turn in each case with cyano, hydroxy, (C] -C ₄ ) -alkoxy, (Cj-C ₄ ) -alkylthio, amino, mono- or di- (C 1 -C ₄ ) -alkylamino may be substituted,

or

two bound to adjacent carbon atoms of the respective phenyl ring

Radicals R ¹ and / or R ² together form a group of the formula -O-CH ₂ -O-, -O-CHF-O-, -O-CF ₂ -O-, -O-CH ₂ -CH ₂ -O- or form -O-CF ₂ -CF ₂ -O-,

n and o are independently of one another the number O, 1, 2 or 3,

and

R ^{3 is} hydrogen, (C 1 -C ₄ ) -alkyl or cyclopropyl,

or one of its salts, solvates or solvates of the salts for the manufacture of a medicament for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension.

2. Use according to claim 1 of a compound of formula (I) according to claim 1, in which

A is O, S or NR ⁴ , in which

R ⁴ is hydrogen, (C _r _C6) alkyl, (C ₃ -C ₇₎ -cycloalkyl or (C ₄ -C ₇₎ cycloalkenyl,

L ^{1 is} a bond or (C 1 -C ₄ ) -alkanediyl,

the ring Q is (C ₃ -C ₇ ) -cycloalkyl, (C ₄ -C ₇ ) -cycloalkenyl, a 5- to 7-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each of which is up to doubly, identically or differently, with fluorine, chlorine, (C 1 -C ₄ ) -alkyl, trifluoromethyl,

Hydroxy, (C 1 -C ₄ ) -alkoxy, trifluoromethoxy, amino, mono- (C 1 -C ₄ ) -alkylamino and / or di- (C 1 -C ₄ ) -alkylamino,

where (C 1 -C ₄ ) -alkyl in turn may be substituted by hydroxy, (C 1 -C ₄ ) -alkoxy, amino, mono- or di (C 1 -C ₄ ) -alkylamino,

R ^{5 is} hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,

can be exchanged,

or is (C ₂ -C ₄ ) -alkendiyl,

Z is a group of the formula

stands in which # the point of attachment to the group L ²

and

R ^{6 is} hydrogen or (C 1 -C ₄ ) -alkyl,

R ¹ and R ² independently of one another are selected from the group halogen, cyano, nitro, (C 1 -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₄ ) -alkynyl, (C ₃ -C ₇ ) -

Cycloalkyl, (C ₄ -C ₇₎ cycloalkenyl oxy, (C _r _C6) alkoxy, trifluoromethyl, Trifluormeth-, (C, -C ₆₎ alkylthio, (C ₁ -Ce) -acyl, amino, mono- (C _r _C6) alkylamino, di (Ci-

C ₆ ) -alkylamino and (C ₁ -C ₆ ) -acylamino,

where (C ₁ -C ₆ ) -alkyl and (C ₁ -C ₆ ) -alkoxy may in each case in each case be substituted by hydroxyl, (C 1 -C ₄ ) -alkoxy, amino, mono- or di (C 1 -C ₄ ) -alkylamino .

or

n and o are independently of one another the number O, 1, 2 or 3,

and

R ^{3 is} hydrogen, (C 1 -C ₄ ) -alkyl or cyclopropyl,

or one of its salts, solvates or solvates of the salts.

3. Use according to claim 1 of a compound of formula (I) according to claim 1 or 2, in which

A is O or NR ⁴ , in which

R ^{4 is} hydrogen, (C 1 -C ₄ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl,

L ^{1 is} a bond or (C ₁ -C ₃ ) -alkanediyl,

the ring Q is (C ₃ -C ₆ ) -cycloalkyl, (C ₄ -C ₆ ) -cycloalkenyl, a 5- or 6-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each being bis may be monosubstituted, identically or differently, substituted by fluorine, chlorine, (C ₁ -C ₃ ) -alkyl, trifluoromethyl, hydroxy, methoxy, ethoxy, trifluoromethoxy, amino, methylamino, ethylamino, dimethylamino and / or diethylamino,

where (C ₁ -C ₃ ) -alkyl may in turn be substituted by hydroxyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino or diethylamino,

L ^{2 is} (C _r C ₃ ) -alkanediyl which may be mono- or di-substituted by fluorine, (C ₂ -C ₃ ) -alkendiyl or a group of the formula * -M-CR ⁷ R ⁸ -, * -M-CH ₂ - CR ⁷ R ⁸ - or ^ CH ₂ -M-CR ⁷ R ⁸ - in which

* the point of attachment to the ring Q,

MO or NR ⁵ , in which

R ^{5 represents} hydrogen, (C _r C ₃ ) -alkyl or cyclopropyl,

and

R ⁷ and R ^{8 are} independently hydrogen or fluorine

mean,

Z is a group of the formula

stands in which

# the point of attachment to the group L ²

and

R ^{6 is} hydrogen, methyl or ethyl,

R ¹ and R ² independently represent a substituent selected from the series

Fluorine, chlorine, cyano, (C _r C ₅₎ alkyl, (C ₂ -C ₅₎ -alkenyl, (C ₃ -C ₆₎ cycloalkyl, (C ₄ -C ₆₎ -

Cycloalkenyl, (C _r _C4) alkoxy, Trifiuormethyl, trifluoromethoxy, (Ci-C ₄₎ -alkylthio, _(Ci-C5) acyl, amino, mono- (Ci-C ₄₎ -aücylamino, di- (C 1 -C ₄ ) -alkylamino and (C 1 -C ₄ ) -acylamino, or

n and o are independently of one another the number O, 1, 2 or 3,

and

R ^{3 is} hydrogen or (C _r C ₃ ) -alkyl,

or one of its salts, solvates or solvates of the salts.

4. Use according to claim 1 of a compound of formula (I) according to claim 1, 2 or 3, in which

A is O or NR ⁴ , in which

R ^{4 is} hydrogen or (C 1 -C ₄ ) -alkyl,

L ^{1 is} a bond or (C ₁ -C ₃ ) -alkanediyl,

the ring Q is (C ₄ -C ₆ ) -cycloalkyl, (C ₅ -C ₆ ) -cycloalkenyl, a 5- or 6-membered heterocycle or phenyl, each of which may be up to twice, identically or differently, with fluorine, chlorine (C ₁ -C ₃ ) -alkyl, trifluoromethyl, hydroxy, methoxy, ethoxy, trifluoromethoxy, amino, methylamines, ethylamino, dimethylamino and / or diethylamino may be substituted,

L ² is (Ci-C ₃₎ -alkanediyl which may be mono- or di-substituted by fluorine, (C ₂ -C ₃₎ alkenediyl or a group of the formula * -M-CR ⁷ R ⁸ -, * -M-CH ₂ - CR ⁷ R ⁸ - or * -CH ₂ -M-CR ⁷ R ⁸ - in which

* the point of attachment to the ring Q,

MO or NR ⁵ , in which

R ^{5 represents} hydrogen or (C ₁ -C ₃ ) -alkyl,

and R ⁷ and R ^{8 are} independently hydrogen or fluorine

mean,

Z is a group of the formula

stands in which

# the point of attachment to the group L ²

and

R ^{6 is} hydrogen, methyl or ethyl,

R ¹ and R ² independently of one another are selected from the group consisting of fluorine, chlorine, cyano, (C 1 -C ₅ ) -alkyl, (C ₂ -C ₅ ) -alkenyl, (C ₃ -C ₆ ) -cycloalkyl, (C ₄ -C ₆ ) -

Cycloalkenyl, (Ci-C ₄₎ alkoxy, trifluoromethyl, trifluoromethoxy, (C _r _C4) -alkylthio, _(Ci-C5) acyl, amino, mono- (Ci-C ₄₎ alkylamino, di- (C iC ₄ ) -alkylamino and

(Ci-C ₄ ) -acylamino,

or

two bound to adjacent carbon atoms of the respective phenyl ring

Radicals R ¹ and / or R ² together form a group of the formula -O-CH ₂ -O-, -O-CHF-O- or -O-CF ₂ -O-,

n and o independently of one another represent the number 0, 1 or 2,

and

R ^{3 is} hydrogen or (C ₁ -C ₃ ) -alkyl,

or one of its salts, solvates or solvates of the salts.

5. Use according to claim 1 of a compound of formula (I) according to any one of claims 1 to 4, in which A is O or NH,

L ^{1 is} a bond, methylene, ethane-1, 1-diyl or ethane-1, 2-diy 1,

the ring Q represents cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl,

Piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, polypholinyl or phenyl, each containing up to twice, identically or differently, with fluorine, methyl, ethyl,

Trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino and / or dimethylamino may be substituted,

L ^{2 is} (C _r C ₃ ) -alkanediyl, (C ₂ -C ₃ ) -alkendiyl or a group of formula * -M-CH ₂ - or * -M-CH ₂ -CH ₂ -, wherein

* the point of attachment to the ring Q

and

MO or NR ⁵ , in which

R ^{5 is} hydrogen or (C _r C ₃ ) -alkyl,

means

Z is a group of the formula

stands in which

# the point of attachment to the group L ²

and

R ^{6 is} hydrogen, methyl or ethyl,

R ¹ and R ² independently represent a substituent selected from the series

Fluorine, chlorine, cyano, (C 1 -C ₅ ) -alkyl, (C ₂ -C ₅ ) -alkenyl, (C ₃ -C ₆ ) -cycloalkyl, (C ₄ -C ₆ ) -

Cycloalkenyl, (C _r C ₄₎ alkoxy, trifluoromethyl, trifluoromethoxy, (Ci-C ₄₎ -alkylthio, _(Ci-C5) acyl, amino, mono- (Ci-C ₄₎ alkylamino, di- (C 1 -C ₄ ) -alkylamino and (C 1 -C ₄ ) -acylamino, or

n and o are independently of one another the number O, 1 or 2,

and

R ^{3 is} hydrogen,

or one of its salts, solvates or solvates of the salts.

6. Use according to claim 1 of a compound of formula (I) according to any one of claims

1 to 5, in which

A is O or NH,

L ^{1 is} a bond, methylene or ethane-1, l-diyl,

Piperidinyl or phenyl, each of which may be substituted up to twice, identically or differently, by fluorine, methyl, hydroxy and / or methoxy,

L ^{2 is} (C] -C ₃ ) alkanediyl, (C ₂ -C ₃ ) -alkendiyl or a group of formula * -M-CH ₂ - or * -M-CH ₂ -CH ₂ -, wherein

* the point of attachment to the ring Q

and

M is O or NH,

Z is a group of the formula

stands in which

# the point of attachment to the group L ²

and

R ^{6 is} hydrogen, methyl or ethyl,

R ^{1 represents} a substituent selected from the group fluorine, chlorine, methyl, ethyl,

Vinyl, trifluoromethyl and methoxy,

n and o independently of one another represent the number 0, 1 or 2,

and

R ^{3 is} hydrogen,

or one of its salts, solvates or solvates of the salts.

7. A combination comprising at least one compound of the formula (I) as defined in any one of claims 1 to 6, and one or more further active compounds selected from the group consisting of kinase inhibitors, stimulators and activators of the soluble guanylate cyclase, elastase inhibitors, Endothelin receptor antagonists and phosphodiesterase inhibitors.

8. Use of the combination according to claim 7 for the manufacture of a medicament for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension.

9. Use of a compound of formula (I) as defined in any one of claims 1 to 6 or a combination as defined in claim 7 for the manufacture of a medicament for the treatment and / or prophylaxis of idiopathic, familial or with For the treatment and / or prophylaxis of pulmonary hypertension in patients with left atrial or left ventricular disease, left-sided cardiac valve diseases, pulmonary arterial hypertension associated with drugs, toxins or other diseases. conditions, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sleep apnea syndrome, diseases with alveolar hypoventilation, altitude sickness, pulmonary developmental disorders, chronic thrombotic and / or embolic diseases or in connection with sarcoidosis, histiocytosis X or lymphangioleiomyomatosis, and for treatment and / or Prophylaxis of external pulmonary hypertension due to vascular compression.

10. A medicament containing a combination as defined in claim 7, optionally in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.

11. A pharmaceutical composition according to claim 10 for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension.

12. A method for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension in humans and animals by administering an effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 6, a combination, as defined in claim 7, or a pharmaceutical composition containing at least one compound of formula (I) as defined in any one of claims 1 to 6.